Emerging Fluorinated Motifs Synthesis, Properties, and Applications Volume 1&2

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Emerging Fluorinated Motifs

Emerging Fluorinated Motifs Synthesis, Properties, and Applications

Volume 1 Edited by

Dominique Cahard Jun‐An Ma

Editors Dr. Dominique Cahard

CNRS ‐ UMR 6014 COBRA University of Rouen Normandy 76821 Mont‐Saint‐Aignan France Prof. Jun‐An Ma

Tianjin University Department of Chemistry 300072 Tianjin China Cover Images: Fluorine symbol © antonel adrian tudor/Alamy Stock Photo 3d Silver Sphere © Rashevskyi Viacheslav/ Shutterstock Abstract background © FotoMak/Getty Images

All books published by Wiley‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing‐in‐Publication Data

A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978‐3‐527‐34681‐3 ePDF ISBN: 978‐3‐527‐82432‐8 ePub ISBN: 978‐3‐527‐82433‐5 oBook ISBN: 978‐3‐527‐82434‐2 Typesetting  SPi Global, Chennai, India Printing and Binding

Printed on acid‐free paper 10 9 8 7 6 5 4 3 2 1

Emerging Fluorinated Motifs Synthesis, Properties, and Applications

Volume 2 Edited by

Jun‐An Ma Dominique Cahard

Editors Prof. Jun‐An Ma

Tianjin University Department of Chemistry 300072 Tianjin China Dr. Dominique Cahard

CNRS ‐ UMR 6014 COBRA University of Rouen Normandy 76821 Mont‐Saint‐Aignan France Cover Images: Fluorine symbol © antonel adrian tudor/ Alamy Stock Photo 3d Silver Sphere © Rashevskyi Viacheslav/ Shutterstock Abstract background © FotoMak/Getty Images

All books published by Wiley‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing‐in‐Publication Data

A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978‐3‐527‐34681‐3 ePDF ISBN: 978‐3‐527‐82432‐8 ePub ISBN: 978‐3‐527‐82433‐5 oBook ISBN: 978‐3‐527‐82434‐2 Typesetting  SPi Global, Chennai, India Printing and Binding

Printed on acid‐free paper 10 9 8 7 6 5 4 3 2 1

v

Contents Preface  xiii Volume 1 Part I  1

Carbon‐Linked Fluorine‐Containing Motifs  1

Difluoromethylation and Difluoroalkylation of (Hetero)Arenes: Access to Ar(Het)–CF2H and Ar(Het)–CF2R  3 Yu‐Lan Xiao and Xingang Zhang

1.1 Introduction  3 1.2 Difluoromethylation of (Hetero)aromatics  3 1.2.1 Transition‐Metal‐Mediated/Catalyzed Nucleophilic Difluoromethylation of (Hetero)aromatics  3 1.2.2 Catalytic Metal‐Difluorocarbene‐Involved Coupling (MeDIC) Reaction  10 1.2.3 Transition‐Metal‐Catalyzed Radical Difluoromethylation of (Hetero)aryl Metals/Halides and Beyond  11 1.2.4 Radical C─H Bond Difluoromethylation of (Hetero)aromatics  19 1.3 Difluoroalkylation of Aromatics  22 1.3.1 Transition‐Metal‐Catalyzed Phosphonyldifluoromethylation of (Hetero)aromatics  23 1.3.2 Transition‐Metal‐Catalyzed Difluoroacetylation of (Hetero)aromatics and Beyond  26 1.3.3 Other Catalytic Difluoroalkylations of (Hetero)aromatics  37 1.4 Outlook  39 References  42 2

Difluoromethylation and Difluoroalkylation of Aliphatic Unsaturated C=C, C≡C, and −N=C Bonds  47 Sebastian Barata‐Vallejo and Al Postigo

2.1 Introduction  47 2.2 Difluoromethylation of C═C Double Bonds  49 2.2.1 Intermolecular Difunctionalization of C═C Double Bonds  56

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Contents

2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.2

By Means of BrCF2P(O)(OR)2  56 By Means of Ph3P+CF2CO2−  59 By Means of HCF2R (R = CO2H, SO2NHNHBoc)  62 By Means of Selectfluor  65 By Means of BrCF2CO2Et  66 Difluoromethylation of C═C Double Bonds and Subsequent Cyclization  69 2.2.3 Difluoromethylation of C═C Double Bonds with Rearrangements  73 2.3 Difluoromethylation of Isocyanides  76 2.4 Difluoromethylation of Alkynes  79 2.5 Conclusion and Perspectives  82 References  85 3

3.1 3.1.1 3.1.2 3.1.3

Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds  89 Qiqiang Xie and Jinbo Hu

Nucleophilic Difluoromethylation and Difluoroalkylation  89 By Means of XCF2PO(OEt)2  89 By Means of BrCF2CO2Et and BrCF2CH═CH2  89 By Means of Difluoromethylcadmium, Difluoromethylcopper, and Difluoromethylzinc Reagents  90 3.1.4 By Means of Difluoroalkylated Sulfone Reagents (XCF2SO2Ar) and Difluoromethylated Sulfoxides  90 3.1.5 By Means of Difluoroalkylated Silanes and Trifluoromethylsilane Reagents  94 3.1.6 By Means of Difluoromethyl Sulfoximine Reagent  96 3.1.7 Miscellaneous Reagents  96 3.2 Electrophilic Difluoromethylation and Difluoroalkylation  97 3.2.1 By Means of Difluorocarbene Reagents  97 3.2.2 By Means of CF3X (X ═ H, I, TMS) Reagents  99 3.2.3 By Means of I(III)–CF2SO2Ph Reagent  100 3.2.4 By Means of S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts  100 3.3 Free Radical Difluoromethylation and Difluoroalkylation  101 3.3.1 By Means of Iododifluoroacetates  101 3.3.2 By Means of CF2Br2, CF2BrCl, or TMSCF2Br  102 3.3.3 By Means of Phosphorus‐containing Reagents  103 3.3.4 By Means of BrCF2CO2Et  104 3.3.5 By Means of Halodifluoroketone or ‐Amide  107 3.3.6 By Means of HCF2I and PhCH2CF2I  107 3.3.7 By Means of HCF2SO2Cl and HCF2SO2Na or Zn(SO2CF2H)2  108 3.3.8 By Means of Difluoromethylated Sulfones, Sulfoximines, Thioethers, and Sulfonium Salts  109 3.3.9 By Means of TMSCF2CO2Et and ArCF2CO2H  112 References  112

Contents

4

Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes  119 Qiqiang Xie and Jinbo Hu

4.1 4.1.1 4.1.2 4.1.3 4.1.4 4.1.5

Nucleophilic Monofluoromethylation  119 By Means of Fluoromalonates  119 By Means of Fluoromethyl Phenyl Sulfone  119 By Means of Fluorobis(phenylsulfonyl)methane  121 By Means of 2‐Fluoro‐2‐Sulfonylketone  122 By Means of 2‐Fluoro‐1,3‐benzodithiole‐1,1,3,3‐tetraoxide (FBDT)  123 4.1.6 By Means of TMSCF(SO2Ph)2 (TFBSM)  123 4.1.7 By Means of PhSO(NTBS)CH2F  123 4.1.8 By Means of CH2FI  124 4.1.9 By Means of Monofluoromethyl Phosphonium Salts  124 4.2 Electrophilic Monofluoromethylation  125 4.2.1 By Means of CH2FX (X = Cl, Br, I, OTf, OTs, OMs)  125 4.2.2 By Means of S‐(monofluoromethyl)diarylsulfonium Tetrafluoroborate  125 4.2.3 By Means of Monofluoromethylsulfoxinium Salts  126 4.2.4 By Means of Monofluoromethylsulfonium Ylides  127 4.2.5 By Means of Monofluoromethyl Phosphonium Salts  127 4.3 Free Radical Monofluoromethylation  128 4.3.1 By Means of (PhSO2)2CFI  128 4.3.2 By Means of (H2FCSO2)2Zn (MFMS)  128 4.3.3 By Means of CH2FSO2Cl  128 4.3.4 By Means of PhSO(NTs)CH2F  129 4.3.5 By Means of Monofluoromethyl Sulfone  130 4.4 Transition‐Metal‐Catalyzed/Mediated Monofluoromethylation  130 4.4.1 By Means of CH2FI  130 4.4.2 By Means of PhSO2CHFI  131 4.4.3 By Means of CH2FBr  131 4.4.4 By Means of PTSO2CH2F  132 References  132 5

Synthesis of gem‐Difluorocyclopropanes  135 Dmitriy M. Volochnyuk and Oleksandr O. Grygorenko

5.1 Introduction  135 5.2 Intramolecular Wurtz (Freund) Reaction  140 5.3 Nucleophilic Fluorination of Pre‐existing Ring System  140 5.4 Cyclopropanation of 1,1‐Difluoroalkenes  142 5.5 Difluorocyclopropanation of Alkenes and Alkynes  143 5.5.1 Fragmentation of Trihalomethyl Anions CF2X− (X = Cl, Br)  145 5.5.2 Reduction of CF2Br2 with Zn or Other Reductants  146 5.5.3 Decarboxylative Difluorocarbene Generation  149 5.5.4 Difluorocarbene Generation by Nucleophilic Cleavage of a Carbene Precursor  153

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Contents

5.5.5

Decomposition of CF3‐substituted Organometallic Derivatives  164 5.5.6 Lewis Base‐promoted Cleavage of the Ruppert–Prakash‐type Reagents XCF2SiMe3 (X = F, Cl, Br)  169 5.5.7 Photodissociation of Difluorodiazirine  182 5.5.8 Thermal Decomposition of Hexafluoropropene Oxide  183 5.6 Michael‐induced Ring Closure (MIRC)  183 5.7 Reactions at the Double Bond of gem‐Difluorocyclopropenes  185 5.8 Conclusions  187 References  187 Part II 

6

Oxygen‐Linked Fluorine‐Containing Motifs  195

Indirect Construction of the OCF3 Motif  197 Pingping Tang and Xiaohuan Jiang

6.1 Introduction  197 6.2 Fluorination of Trichloromethyl Ethers  197 6.3 Deoxyfluorination of Fluoroformates  198 6.4 Oxidative Fluorodesulfurization  198 6.5 Decarboxylative Fluorination  199 6.6 Direct Trifluoromethylation  200 6.7 Intramolecular OCF3 Migration  202 References  204 7

Reagents for Direct Trifluoromethoxylation  207 Pingping Tang and Xiaohuan Jiang

7.1 Introduction  207 7.2 Trifluoromethyl Hypofluorite (FTM)  207 7.3 Chloroxytrifluoromethane  209 7.4 Bistrifluoromethyl Peroxide (BTMP)  210 7.5 Bis(trifluoromethyl) Trioxide  210 7.6 N‐Trifluoromethoxy Benzimidazole  211 7.7 N‐Trifluoromethoxypyridinium  213 7.8 N‐Trifluoromethoxy Triazolium Salts  214 7.9 Trifluoromethyl Trifluoromethanesulfonate (TFMT)  215 7.10 Organometallic Trifluoromethoxides  217 7.11 Perfluoroalkylsulfurane  219 7.12 Perfluoroalkylsulfurane Oxide  219 7.13 2,4‐Dinitro(trifluoromethoxy)benzene (DNTFB)  221 7.14 Trifluoromethyl Sulfonates (TFMS)  221 7.15 Trifluoromethyl Benzoate (TFBz)  222 References  223

Contents

8

Direct Trifluoromethoxylation of Aromatics and Heteroaromatics  225 Johnny W. Lee, Katarzyna N. Lee, and Ming‐Yu Ngai

8.1 Introduction  225 8.2 Direct Anionic Trifluoromethoxylation  226 8.3 Direct Radical Trifluoromethoxylation  239 8.4 Conclusion and Future Perspective  249 References  249 9

Direct Trifluoromethoxylation of Aliphatic Compounds  251 Chaohuang Chen and Guosheng Liu

9.1 9.1.1 9.1.2

Direct Trifluoromethoxylation of Alkenes  251 Radical Trifluoromethoxylation of Alkenes  251 Pd(II)‐Catalyzed Oxidative Trifluoromethoxylation of Alkenes  252 9.1.3 Silver(I)‐catalyzed Trifluoromethoxylation of Alkenes  255 9.1.4 Direct Trifluoromethoxylation at sp3‐Carbon Atoms  258 9.1.4.1 Trifluoromethoxylation of Alkyl Halides and Alkyl Triflates  258 9.1.4.2 Trifluoromethoxylation of Alkyl Alcohols and Alkyl Silanes  259 9.1.4.3 Trifluoromethoxylation of C–H Bonds  260 9.1.4.4 Nucleophilic Trifluoromethoxylation of Epoxides  262 9.2 Trifluoromethoxylation of α‐Diazo Esters  263 9.3 Summary and Outlook  264 References  265

10

Extension to the Construction of ORf Motifs (OCF2H, OCFH2, OCH2CF3, OCFHCH3)  267 Jin‐Hong Lin and Ji‐Chang Xiao

10.1 Introduction  267 10.2 Construction of the OCF2H Group  269 10.2.1 Insertion of Difluorocarbene into O─H Bond  269 10.2.2 Decarboxylative Fluorination  272 10.2.3 Direct Electrophilic Difluoromethylation  272 10.2.4 Difluoromethoxylation  273 10.2.5 Nucleophilic Fluorination  274 10.3 Construction of the OCFH2 Group  275 10.3.1 Monofluoromethylation  275 10.3.2 Fluorination  278 10.4 Construction of the OCH2CF3 Group  280 10.4.1 Trifluoroethoxylation  281 10.4.2 Trifluoroethylation  283 10.5 Construction of the OCFHCH3 Group  285 10.6 Conclusions and Perspectives  285 References  285

ix

x

Contents

Volume 2 Preface  xvii Part III 

Sulfur‐Linked Fluorine‐Containing Motifs  289

11

Indirect Trifluoromethylthiolation Methods  291 Xiu‐Hua Xu and Feng‐Ling Qing

12

Reagents for Direct Trifluoromethylthiolation  309 He Liu, Hangming Ge, and Qilong Shen

13

Trifluoromethylthiolation of Aromatic and Heteroaromatic Compounds  343 Wenbin Yi, Zhidong Song, Jie Liu, Yasir Mumtaz, and Wei Zhang

14

Synthesis of Trifluoromethylthiolated Alkenes and Alkynes  373 Matthew N. Hopkinson

15

Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds  403 Yumeng Liang, Dominique Cahard, and Norio Shibata

16

Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)  449 Tatiana Besset and Thomas Poisson

17

Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)  477 Vinayak Krishnamurti, Colby Barrett, and G.K. Surya Prakash

18

Pentafluorosulfanylation of Aromatics and Heteroaromatics  551 Petr Beier

19

Pentafluorosulfanylation of Aliphatic Substrates  571 Günter Haufe

20

Extension to SF4CF3 and SF4FG Groups  611 Peer Kirsch

21

Properties and Applications of Sulfur(VI) Fluorides  621 Nicholas D. Ball

22

Construction of S–RF Sulfilimines and S–RF Sulfoximines  675 Emmanuel Magnier

Contents

Part IV  23

When Fluorine Meets Selenium  693 Thierry Billard and Fabien Toulgoat Part V 

24

Nitrogen‐Linked Fluorine‐Containing Motifs  723

Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs  725 Thierry Milcent and Benoit Crousse Part VI 

25

Selenium‐Linked Fluorine‐Containing Motifs  691

Phosphorus‐Linked Fluorine‐Containing Motifs  763

Synthesis and Applications of P–Rf‐Containing Molecules  765 Fa‐Guang Zhang and Jun‐An Ma

Index  809

xi

v

Contents Preface  xiii Volume 1 Part I 

Carbon‐Linked Fluorine‐Containing Motifs  1

1

Difluoromethylation and Difluoroalkylation of (Hetero)Arenes: Access to Ar(Het)–CF2H and Ar(Het)–CF2R  3 Yu‐Lan Xiao and Xingang Zhang

2

Difluoromethylation and Difluoroalkylation of Aliphatic Unsaturated C=C, C≡C, and −N=C Bonds  47 Sebastian Barata‐Vallejo and Al Postigo

3

Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds  89 Qiqiang Xie and Jinbo Hu

4

Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes  119 Qiqiang Xie and Jinbo Hu

5

Synthesis of gem‐Difluorocyclopropanes  135 Dmitriy M. Volochnyuk and Oleksandr O. Grygorenko Part II 

Oxygen‐Linked Fluorine‐Containing Motifs  195

6

Indirect Construction of the OCF3 Motif  197 Pingping Tang and Xiaohuan Jiang

7

Reagents for Direct Trifluoromethoxylation  207 Pingping Tang and Xiaohuan Jiang

vi

Contents

8

Direct Trifluoromethoxylation of Aromatics and Heteroaromatics  225 Johnny W. Lee, Katarzyna N. Lee, and Ming‐Yu Ngai

9

Direct Trifluoromethoxylation of Aliphatic Compounds  251 Chaohuang Chen and Guosheng Liu

10

Extension to the Construction of ORf Motifs (OCF2H, OCFH2, OCH2CF3, OCFHCH3)  267 Jin‐Hong Lin and Ji‐Chang Xiao

Volume 2 Preface  xvii Part III  11

Sulfur‐Linked Fluorine‐Containing Motifs  289

Indirect Trifluoromethylthiolation Methods  291 Xiu‐Hua Xu and Feng‐Ling Qing

11.1 Introduction  291 11.2 Fluorination of Polyhalogenalkyl Thioethers  292 11.3 Electrophilic Trifluoromethylation of Thiolates or Thiols  293 11.4 Nucleophilic Trifluoromethylation  294 11.5 Radical Trifluoromethylation  298 11.6 Trifluoromethylation of Thiones and Thioureas  302 11.7 Reduction of Trifluoromethyl Sulfoxides  303 References  305 12

Reagents for Direct Trifluoromethylthiolation  309 He Liu, Hangming Ge, and Qilong Shen

12.1 Introduction  309 12.2 Nucleophilic Trifluoromethylthiolation Reagents  309 12.2.1 Bis(trifluoromethylthio) Mercury: Hg(SCF3)2  309 12.2.1.1 Representative Synthesis Procedure of Hg(SCF3)2  310 12.2.2 Silver Trifluoromethylthiolate: AgSCF3  311 12.2.2.1 Representative Synthesis Procedure of AgSCF3  311 12.2.3 Copper Trifluoromethylthiolate: CuSCF3  312 12.2.3.1 Representative Synthesis Procedure of CuSCF3  313 12.2.4 2,2′‐Bipyridine Copper Trifluoromethylthiolate: (bpy)CuSCF3  313 12.2.4.1 Synthesis Procedure of (bpy)CuSCF3  314 12.2.5 Tetramethylammonium and Cesium Trifluoromethylthiolates: Me4NSCF3, CsSCF3  315 12.2.5.1 Synthesis Procedure of Me4NSCF3  316 12.3 Electrophilic Trifluoromethylthiolation Reagents  317

Contents

12.3.1

Bistrifluoromethyl Disulfide CF3SSCF3 and Trifluoromethanesulfenyl Chloride CF3SCl  317 12.3.1.1 Representative Synthesis Procedure of CF3SSCF3  317 12.3.1.2 Representative Synthesis Procedure of CF3SCl  317 12.3.2 Haas Reagents  318 12.3.3 Lu–Shen Reagents  319 12.3.3.1 Synthetic Procedure of the Preparation of Lu–Shen Reagent  320 12.3.3.2 Representative Synthesis Procedure of the Reagent  321 12.3.4 N‐Trifluoromethylthiosuccinimide (Haas reagent)  322 12.3.4.1 Representative Synthesis Procedure of the Reagent  322 12.3.5 N‐(Trifluoromethylthio)phthalimide (Munavalli reagent)  323 12.3.5.1 Representative Synthesis Procedure of the Reagent  324 12.3.6 Billard Reagents  325 12.3.6.1 Synthetic Procedure for the Preparation of Billard's reagent I  325 12.3.6.2 Synthetic Procedure for the Preparation of Billard's reagent II  325 12.3.7 N‐(Trifluoromethylthio)saccharin (Shen Reagent)  328 12.3.7.1 Representative Synthesis Procedure of the Reagent  328 12.3.8 N‐(Trifluoromethylthio)‐bis(phenylsulfonyl)imide  329 12.3.8.1 Representative Synthesis Procedure of the Reagent  330 12.3.9 Chiral Enantiopure N‐SCF3 Reagents (Shen Reagents)  331 12.3.10 Shibata Reagents  331 12.3.10.1 Synthetic Procedure for the Preparation of Shibata’s Reagent I  333 12.3.10.2 Synthetic Procedure for the Preparation of Shibata’s Reagent II  333 12.3.11 CF3SO2Na, CF3SO2Cl, and CF3SOCl as Electrophilic SCF3 Donors  334 12.4 Conclusion and Perspectives  337 References  338 13

Trifluoromethylthiolation of Aromatic and Heteroaromatic Compounds  343 Wenbin Yi, Zhidong Song, Jie Liu, Yasir Mumtaz, and Wei Zhang

13.1 Introduction  343 13.2 Reactions of Aromatic Compounds  343 13.2.1 Direct Functionalization of Aromatic C–H Bonds  343 13.2.2 Reactions of Aryl Diazonium Salts  347 13.2.3 Reactions of Aryl Triflates  349 13.2.4 Reactions of Aryl Metallic Species  350 13.2.5 Reactions of Aryl Boronic Acids  352 13.2.6 Reactions of Aryl Halides  354 13.2.7 Reactions of Di(hetero)aryl‐λ3‐iodanes  357 13.3 Trifluoromethylthiolation of Heteroaromatic Compounds  358 13.3.1 Reactions of Indoles and Pyrroles  358 13.3.2 Reaction of Pyridines, Quinolines, and Isoquinolines  362 13.3.3 Reactions of Thiophenes and Furans  364 13.3.4 Reaction of Other Heteroaromatics  366

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13.4 Summary and Outlook  368 References  369 14

Synthesis of Trifluoromethylthiolated Alkenes and Alkynes  373 Matthew N. Hopkinson

14.1 Introduction  373 14.2 Synthesis of SCF3‐Substituted Alkenes and Alkynes via Manipulation of SCF3‐Containing Building Blocks  374 14.3 Synthesis of SCF3‐Substituted Alkenes via S‐Trifluoromethylation  376 14.4 Synthesis of SCF3‐Substituted Alkenes and Alkynes via Direct Trifluoromethylthiolation  377 14.4.1 Nucleophilic Trifluoromethylthiolation  377 14.4.2 Electrophilic Trifluoromethylthiolation  381 14.4.3 Radical Trifluoromethylthiolation  391 References  398 15

Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds  403 Yumeng Liang, Dominique Cahard, and Norio Shibata

15.1 Introduction  403 15.2 Approaches in Radical Trifluoromethylthiolation  403 15.2.1 Photochemical Radical Trifluoromethylthiolation Under UV Irradiation  404 15.2.2 Radical Trifluoromethylthiolation with the Aid of Anionic SCF3 Reagents  405 15.2.3 Radical Trifluoromethylthiolation with the Aid of Electrophilic SCF3 Reagents  411 15.2.3.1 Via Preformation of R˙ Radical  411 15.2.3.2 Via the Formation of F3CS˙ Radical  415 15.3 Approaches in Electrophilic Trifluoromethylthiolation  418 15.3.1 Early Electrophilic Trifluoromethylthiolation Reagents in C(sp3)– SCF3 Bond Formation Reactions  418 15.3.2 N‐SCF3 Reagents in Direct C(sp3)−SCF3 Bond Formation Reactions  419 15.3.2.1 N‐Trifluoromethanesulfenamides  419 15.3.2.2 N‐Trifluoromethylthiophthalimide and N‐Trifluoromethylthiosuccinimide  419 15.3.2.3 N‐Trifluoromethylthiosaccharin  423 15.3.2.4 N‐Trifluoromethylthiodibenzenesulfonimide (PhSO2)2NSCF3  425 15.3.2.5 (1S)‐(−)‐N‐Trifluoromethylthio‐2,10‐camphorsultam  428 15.3.3 O‐SCF3 Reagents in Direct C(sp3)–SCF3 Bond Formation Reactions  428 15.3.4 SO2CF3 Reagents in Direct C(sp3)–SCF3 Bond Formation Reactions  431 15.3.4.1 Trifluoromethanesulfonyl Hypervalent Iodonium Ylide  431 15.3.4.2 Trifluoromethanesulfonyl Diazo Reagent  432 15.3.4.3 Trifluoromethanesulfonyl Chloride (CF3SO2Cl)  432

Contents

Other Reagents in Direct C(sp3)–SCF3 Bond Formation Reactions  432 15.3.5.1 Trifluoromethyl Diethylaminosulfur Difluoride (CF3‐DAST)  432 15.3.5.2 Silver Trifluoromethylthiolate AgSCF3  433 15.4 Approaches in Nucleophilic Trifluoromethylthiolation  434 15.4.1 Reaction with Bis(trifluoromethylthio) Mercury Hg(SCF3)2  434 15.4.2 Reactions with Cesium Trifluoromethylthiolate CsSCF3  434 15.4.3 Reactions with Silver Trifluoromethylthiolate AgSCF3  435 15.4.4 Reactions with Copper Trifluoromethylthiolate CuSCF3  437 15.4.5 Reactions with Other Nucleophilic SCF3 Reagents  439 References  443 15.3.5

16

Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)  449 Tatiana Besset and Thomas Poisson

16.1 Introduction  449 16.2 The SCF2H Motif  449 16.2.1 Construction of the SCF2H Moiety  450 16.2.2 Direct Formation of a C–SCF2H Bond  453 16.2.2.1 Difluoromethylthiolation Reaction by a Nucleophilic Pathway  453 16.2.2.2 Difluoromethylthiolation Reaction Using Electrophilic Reagents  453 16.2.2.3 PhSO2SCF2H (4) as an Efficient Reagent for the Radical Difluoromethylthiolation  457 16.3 The SCH2F Motif  462 16.4 The SCF2PO(OEt)2 Motif  465 16.5 The SCF2CO2R Motif  468 16.6 The SCF2Rf Motif  472 16.7 Conclusion and Perspectives  473 References  473 17

Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)  477 Vinayak Krishnamurti, Colby Barrett, and G.K. Surya Prakash

17.1 Introduction  477 17.2 Trifluoromethyl Sulfoxides [RS(O)CF3]  478 17.2.1 Aryl Trifluoromethyl Sulfoxides [ArS(O)CF3]: Preparation  478 17.2.2 Aryl Trifluoromethyl Sulfoxides [ArS(O)CF3]: Application  478 17.2.3 Heteroaryl Trifluoromethyl Sulfoxides [hetArS(O)CF3]: Preparation  484 17.2.4 Heteroaryl Trifluoromethyl Sulfoxides [hetArS(O)CF3]: Applications  487 17.2.5 Alkyl Trifluoromethyl Sulfoxides [(Alk)S(O)CF3]: Preparation  489 17.2.6 Alkyl Trifluoromethyl Sulfoxides [(Alk)S(O)CF3]: Applications  491 17.3 Difluoromethyl Sulfoxides [RS(O)CF2R′]  492

ix

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17.3.1

Difluoromethyl Sulfoxides [RS(O)CF2H] (R = Ar, HetAr, Alk): Preparation  493 17.3.2 Difluoromethyl Sulfoxides [RS(O)CF2H] (R = Ar, HetAr, Alk): Applications  494 17.3.3 Halodifluoromethyl Sulfoxides [RS(O)CF2X] (X = Cl, Br, I): Preparation  498 17.3.4 Halodifluoromethyl Sulfoxides [RS(O)CF2X] (X = Cl, Br, I): Applications  499 17.3.5 β‐Carbonyl Difluoromethyl Sulfoxides [RS(O)CF2Y] (Y = Enol, Ether, Ketone, Ester): Preparation  500 17.3.6 β‐Carbonyl Difluoromethyl Sulfoxides [RS(O)CF2Y] (Y = Enol, Ether, Ketone, Ester): Applications  502 17.3.7 Other Difluoromethyl Sulfoxides [RS(O)CF2Z] (Z = P, S): Preparation and Uses  502 17.4 Trifluoromethyl Sulfones [RSO2CF3]  504 17.4.1 Aryl Triflones [ArSO2CF3]: Preparation  505 17.4.2 Aryl Triflones [ArSO2CF3]: Applications  508 17.4.3 Alkynyl and Vinyl Triflones: Preparation  510 17.4.4 Alkynyl and Vinyl Triflones: Applications  510 17.4.5 Heteroaryl Triflones: Preparation  513 17.4.6 Heteroaryl Triflones: Uses  514 17.4.7 Alkyl Triflones: Preparation  514 17.4.8 Alkyl Triflones: Applications  517 17.5 Difluoromethyl Sulfones [RSO2CF2H]  520 17.5.1 Aryl and Heteroaryl Difluoromethyl Sulfones [RSO2CF2H] (R = Ar, HetAr): Preparation  520 17.5.2 Aryl and Heteroaryl Difluoromethyl Sulfones [RSO2CF2H] (R = Ar, HetAr): Applications  522 17.5.3 Aryl and Heteroaryl Halodifluoromethyl Sulfones [(Het)ArSO2CF2X] (X = Cl, Br, I): Preparation  529 17.5.4 Aryl and Heteroaryl Halodifluoromethyl Sulfones [(Het)ArSO2CF2X] (X = Cl, Br, I): Applications  530 17.5.5 Aryl(trimethylsilyl)difluoromethyl Sulfones [ArSO2CF2TMS]: Preparation  536 17.5.6 Aryl(trimethylsilyl)difluoromethyl Sulfones [ArSO2CF2TMS]: Applications  536 17.5.7 Other (Miscellaneous) Aryl Difluoromethyl Sulfones [RSO2CF2X] (X = P, S, CO2): Preparation  539 17.5.8 Other (Miscellaneous) Aryl Difluoromethyl Sulfones [RSO2CF2X] (X = P, S, CO2): Applications  540 References  542 18

Pentafluorosulfanylation of Aromatics and Heteroaromatics  551 Petr Beier

18.1 Introduction  551 18.2 Synthesis of Pentafluorosulfanyl‐Containing Aromatics Using Silver Difluoride  552

Contents

18.3

Synthesis of Pentafluorosulfanyl‐Containing Aromatics Using Xenon Difluoride  554 18.4 Synthesis of Pentafluorosulfanyl‐Containing Aromatics Using Elemental Fluorine  554 18.5 Synthesis of Pentafluorosulfanyl‐Containing (Hetero)aromatics via (Hetero)arylsulfurchlorotetrafluorides  558 18.6 Synthesis of Pentafluorosulfanyl‐Containing Heteroaromatics Using Iodine Pentafluoride  565 18.7 Other Approaches to Pentafluorosulfanyl‐Containing (Hetero) aromatics  565 References  569 19

Pentafluorosulfanylation of Aliphatic Substrates  571 Günter Haufe

19.1 19.1.1 19.1.2 19.1.2.1 19.1.2.2 19.1.2.3

Pentafluorosulfanylation Reagents  571 Pentafluorosulfanylation of Alkenes using SF6  572 Pentafluorosulfanylation of Alkenes Using SF5X  572 Thermal Pentafluorosulfanylation of Alkenes with SF5X  573 Photochemical Pentafluorosulfanylation of Alkenes with SF5X  574 Triethylborane‐mediated Radical Pentafluorosulfanylation of Alkenes Using SF5X  577 19.2 Application of β‐Haloalkyl‐perfluorosulfanyl Compounds  580 19.2.1 Halogen Substitution Reactions  580 19.2.2 Synthesis and Application of α‐Pentafluorosulfanyl Aldehydes  581 19.2.3 Synthesis and Application of Vinyl‐SF5 Compounds  583 19.2.3.1 Elimination of Hydrogen Halogenides from β‐Halogen‐ pentafluorosulfanylalkanes  583 19.2.3.2 Cycloadditions of SF5‐Vinyl Compounds  585 19.2.4 Synthesis and Applications of γ‐SF5‐α,β‐Unsaturated Aldehydes  586 19.2.5 Synthesis and Application of SF5‐substituted C2 Building Blocks  588 19.2.5.1 SF5‐Acetic Acid Derivatives  588 19.2.5.2 Difluoro‐pentafluorosulfanyl Acetic Acid (SF5CF2CO2H) Derivatives  597 19.2.5.3 2‐Pentafluorosulfanyl‐tetrafluoroethyl Derivatives (SF5CF2CF2X)  599 19.3 Synthesis and Derivatization of Alkenyl‐SF5 Compounds  602 19.3.1 Addition of SF5‐Halogenides Across Triple Bonds and Hydrogen Halogenide Elimination to Form SF5‐Acetylenes  602 19.3.2 Diels–Alder Reactions of SF5‐Acetylenes  604 19.4 Synthesis of Aliphatic SF5 Compounds by Oxidation of Aromatic SF5 Compounds  605 References  606 20

Extension to SF4CF3 and SF4FG Groups  611 Peer Kirsch

20.1 Introduction  611 20.2 Synthesis of RSF4CF3 Derivatives  612

xi

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Contents

20.3 Synthesis of Ar–SF4–Ar Derivatives  614 20.4 Synthesis of Ar–SF4–R Derivatives  615 20.5 Conclusions and Perspectives  617 References  618 21

Properties and Applications of Sulfur(VI) Fluorides  621 Nicholas D. Ball

21.1 Introduction  621 21.2 Properties and Reactivity of Sulfur(VI) Fluorides  621 21.3 Synthesis of Sulfonyl Fluorides from Sulfonyl Chlorides  624 21.4 Sulfonyl Fluoride Formation via In situ Sulfonyl Chloride Formation  625 21.5 Synthesis of Sulfonyl Fluorides Using Alternative Fluorine and Sulfur Sources  626 21.6 Synthesis of Fluorosulfates and Sulfamoyl Fluorides  630 21.7 Application of Sulfonyl Fluorides: Sulfur–Fluoride Exchange Chemistry  636 21.7.1 Sulfones  638 21.7.2 Sulfonic Esters and Polysulfonates  641 21.7.3 Sulfonamides   643 21.8 Application of Sulfonyl Fluorides: Tandem Organic Transformations  647 21.9 Application of Sulfonyl Fluorides: Cross‐Coupling Reactions with Persistent SO2F Group  649 21.10 Sulfonyl Fluorides as a Reagent in Organofluorine Chemistry  654 21.11 Application of Fluorosulfates: Dual Reactivity  656 21.11.1 Application of Fluorosulfates: C─X Bond Formation via –OSO2F as a Leaving Group  657 21.11.1.1 C─F Bond Formation  658 21.11.1.2 C─N Bond Formation  659 21.11.1.3 Dehydration/Dehydrogenation  659 21.11.2 Application of Fluorosulfates: Transition‐Metal‐Catalyzed Cross‐Coupling Reactions  660 21.11.2.1 C─C Bond Formation  660 21.11.2.2 CO or CO2 insertion  663 21.11.2.3 C─N Bond Formation  664 21.11.2.4 C─H Bond Formation  665 21.11.3 Application of Fluorosulfates: Sulfur–Fluoride Exchange (SuFEx) Chemistry  665 21.11.3.1 Sulfates and Sulfamates  666 21.12 Applications of Other S(VI) Fluorides  668 References  672 22

Construction of S–RF Sulfilimines and S–RF Sulfoximines  675 Emmanuel Magnier

22.1 Introduction  675 22.2 Construction of S–RF Sulfilimines  676

Contents

22.3 22.3.1 22.3.2

Construction of S–RF Sulfoximines  678 Synthesis of Sulfonimidoyl Fluorides  678 Synthesis of S–RF Sulfoximines by Fluorination of S–Alkyl Sulfoximines  679 22.3.3 Synthesis of S–RF Sulfoximines by Imination of Sulfoxides  680 22.3.4 Synthesis of S–RF Sulfoximines by Oxidation of Sulfilimines  682 22.3.5 Synthesis of S–RF Sulfoximines from Sulfides  683 22.3.6 Isolation of S–RF Sulfilimines and S–RF Sulfoximines as Single Enantiomers  686 22.4 Post Functionalization  688 22.5 Conclusion  688 References  689 Part IV 

23

Selenium‐Linked Fluorine‐Containing Motifs  691

When Fluorine Meets Selenium  693 Thierry Billard and Fabien Toulgoat

23.1 Introduction  693 23.2 Indirect Synthesis of CF3Se Moiety  693 23.2.1 Nucleophilic Trifluoromethylation  694 23.2.2 Radical Trifluoromethylation  695 23.3 Direct Introduction of CF3Se Moiety  697 23.3.1 Nucleophilic Trifluoromethylselenolating Reagents  697 23.3.1.1 Trifluoromethylselenocopper 697 23.3.1.2 Tetramethylammonium Trifluoromethylselenolate (Me4NSeCF3)  701 23.3.1.3 In Situ Combination of Trifluoromethylation and Elemental Selenium  705 23.3.1.4 Trifluoromethylselenotoluene Sulfonate (CF3SeTs)  707 23.3.2 Electrophilic Trifluoromethylselenolating Reagents  707 23.3.2.1 Trifluoromethylselenyl Chloride (CF3SeCl)  707 23.3.2.2 Benzyltrifluoromethylselenide (BnSeCF3) as CF3SeCl Precursor  708 23.3.2.3 Trifluoromethylselenotoluene Sulfonate (CF3SeTs)  710 23.3.2.4 CF3SeNMe4 Under Oxidative Conditions  711 23.3.3 Radical Trifluoromethylselenolation  712 23.4 Extension to Other Fluorinated Motifs  713 23.4.1 Higher Fluorinated Homologues: RFSe  713 23.4.2 Difluoromethylselenyl Motif: HCF2Se  714 23.4.3 Fluoromethylselenyl Motif: H2CFSe  715 23.4.4 FG‐CF2Se Motifs (FG = Functional Groups)  715 23.5 Conclusion  716 References  718 Part V 

Nitrogen‐Linked Fluorine‐Containing Motifs  723

xiii

xiv

Contents

24

Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs  725 Thierry Milcent and Benoit Crousse

24.1 Introduction  725 24.2 Construction of the N‐CF2H Motif  726 24.2.1 From Halodifluoromethanes  726 24.2.2 Formation of N‐CF2H by Decarboxylative Reactions  728 24.2.3 Formation of N‐CF2H Using Difluoromethyldiarylsulfoniums  733 24.2.4 Formation of N‐CF2H Using Chlorodifluoromethyl Phenyl Sulfone (PhSO2CF2Cl)  733 24.2.5 Formation of N‐CF2H Using N‐Tosyl‐S‐Difluoromethyl‐S‐ phenylsulfoximine (Ph(SO)(NTs)CF2H)  736 24.2.6 Formation of N‐CF2H Motif Using TMSCF2Cl, TMSCF2Br, and TMSCF3  737 24.2.7 Nucleophilic Difluoromethylation  737 24.3 Construction of the N‐CF3 Motif  737 24.3.1 By Nucleophilic Fluorination  739 24.3.1.1 Fluorine/Halogene Exchange  739 24.3.1.2 Oxidative Desulfurization–Fluorination of Dithiocarbamoyl Disulfides  739 24.3.1.3 Oxidative Desulfurization–Fluorination of Dithiocarbamates  741 24.3.1.4 Fluorination by Bromine Trifluoride (BrF3)  742 24.3.1.5 Via Thiocarbamoyl Fluorides  742 24.3.2 Radical Trifluoromethylation  743 24.3.2.1 By Means of Ruppert–Prakash Reagent (CF3TMS)  743 24.3.2.2 By Means of Langlois Reagent (CF3SO2Na)  743 24.3.3 Electrophilic Trifluoromethylation  743 24.3.3.1 By Means of CF2Br2  743 24.3.3.2 By Means of Umemoto’s Trifluoromethyl Oxonium  747 24.3.4 Nucleophilic Trifluoromethylation  750 24.4 Construction of the N‐CH2CF3 Motif  752 24.4.1 Trifluoroethylamine as Nucleophilic Agent  752 24.4.2 Electrophilic Trifluoroethyl Sources  753 References  756 Part VI  25

Phosphorus‐Linked Fluorine‐Containing Motifs  763

Synthesis and Applications of P–Rf‐Containing Molecules  765 Fa‐Guang Zhang and Jun‐An Ma

25.1 Introduction  765 25.1.1 Fluoro‐Organophosphine Derivatives  765 25.1.2 Achiral Fluoro‐Organophosphines  766 25.1.3 Chiral Fluoro‐Organophosphines  766 25.2 Phosphorous‐Based Fluoromethylating Reagents  770 25.2.1 Monofluoromethylphosphonate Reagents  770 25.2.2 Difluoromethylphosphonate and Difluoromethylphosphonium Reagents  772

Contents

25.2.2.1 HCF2P(O)(OR)2  773 25.2.2.2 BrCF2P(O)(OR)2  774 25.2.2.3 TMSCF2P(O)(OR)2  777 25.2.2.4 [Ph3P+CF2CO2–] and [Ph3PCF2X]+ Y– (X = H, Cl, Br, I; Y = Cl, Br, I, OTf )  779 25.2.3 Trifluoromethylphosphonate Reagents  784 25.3 Chiral Fluorinated Aminophosphonic Acid Derivatives  785 25.3.1 Trifluoromethylated Aminophosphonate Derivatives  785 25.3.2 Difluoromethylated Aminophosphonate Derivatives  787 25.3.3 Monofluoroalkylated Aminophosphonate Derivatives  788 25.4 Perfluoroalkyl Phosphonic and Phosphinic Acids  792 25.5 Fluorophosphonium and Fluoroalkylphosphonium Cations  793 25.6 Conclusion  801 References  801 Index  809

xv

xiii

Preface From the very large body of literatures generated daily, the proportion dedicated to fluorinated molecules has grown in prominence in recent decades. A plethora of synthetic fluorinated compounds are now available as the result of outstanding progresses made in methodology development in this very challenging field. Notably, a better comprehension of the specific fluorine effects has allowed the synthetic access to rare and previously unattainable fluorinated motifs. It follows from these advances a large number of applications. Indeed, fluorine chemistry is exerting a profound impact on our day‐to‐day life through the most vital industries: healthcare, food production, and energy transition. Organofluorine chemistry is a truly fantastic playground for synthetic chemists eager to explore new frontiers. Long‐established researchers in the field are nowadays joined by newcomers who are finding opportunity to extend a specific methodology, apply novel catalysts, or evaluate great physicochemical and biological potential. Fluorine chemotypes are still largely dominated by monofluoro (het)aryl and alkyl motifs as well as by trifluoromethyl (het)aryl motifs, which are the most used fluoro‐organics nowadays prepared on a routine basis. Besides, there is a large upsurge in demand of novelty and usefulness exists for emerging fluorine‐ containing motifs that are so far much less encountered. In the design of new drug candidates, which is the most prominent domain of fluorine application, there is a constant need for new chemical structures that could be potentially eligible for a patent because on‐patent drugs raise substantial benefits not only in health but also in the economy. Hence, molecules with new fluorinated motifs offer the advantage to be immediately patentable with specific therapeutic activities. This is also true in agrochemistry, materials science, energy storage, and many other fields. This book places emphasis on emerging fluorinated motifs. The book comprises six parts. The first part provides a description of carbon‐ linked fluorine‐containing groups that include monofluoromethyl and difluoromethyl groups. These motifs are attractive as bioisostere of non‐ fluorinated functional groups or as fine‐tuned substituents highly desired to provide improved properties to molecules containing them. Parts II–VI detail combinations of heteroatoms, oxygen, sulfur, selenium, nitrogen, and phosphorus with fluorine‐containing groups. For the most popular current motifs, subsections are outlined. The revival of interest for fluoroalkyl ethers and thioethers as well as the recent blossoming of the SF5 unit has generated a rich

xiv

Preface

literature. The description of these emerging fluorinated motifs (properties, synthesis, and applications) is reported in Parts II and III. Several studies have highlighted the exceptional lipophilicity that these motifs confer to molecules, a property that is very appealing for the conception of new drugs. However, the number of bioactive compounds featuring SCF3, OCF3, or SF5 group is still rather small when considering the recent huge development of synthetic routes, and it is noteworthy that only a tiny minority of them is approved for use in human medication, in fact only four CF3O‐containing molecules. Two CF3S‐containing compounds are prescribed for veterinary uses, while no F5S‐containing compound is approved. It follows that chemists must continue to innovate not only for the diversification of novel fluorinated molecules but also for the development of their applications. Parts IV–VI concentrate on selenium‐, nitrogen‐, and phosphorus‐linked fluorine‐containing groups, respectively, that are scarcely investigated to date but have the potential to be included in relevant pharmaceuticals. The parts cover the literature survey through the end of summer of 2019. Because the field of emerging fluorinated motifs is expanding rapidly, some late 2019 articles have undoubtedly appeared during the editorial process of the book and hence are not included. This book is intended for academic research institutes, university libraries, researchers, graduate students, and postdoctors. Researchers in chemical industry, experts or novices in the field, will be also interested in finding leading references and new chemical space to explore. We believe that the compilation of information about emerging fluorinated motifs is timely and this book is expected to be a reference in both academia and industry for the design of the next generation of fluorinated products. We wish to express our sincere appreciation to Dr. Lifen Yang from Wiley who suggested the idea of editing a book in our field of predilection. We also thank the Wiley team, in particular Mr. Aruna Pragasam, project editor, for the continuous support and help as well as for promoting this book worldwide. The preparation of this book would not have been possible without the willing contribution of all contributors; as editors, we gratefully acknowledge the 46 contributors for the 25 chapters of the book for their efforts to make this project a reality. 1 January 2020

Dominique Cahard and Jun‐An Ma Mont‐Saint‐Aignan, France and Tianjin, China

1

Part I Carbon‐Linked Fluorine‐Containing Motifs

3

1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes: Access to Ar(Het)–CF2H and Ar(Het)–CF2R Yu‐Lan Xiao and Xingang Zhang Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, CAS Key Laboratory of Organofluorine Chemistry, 345 Lingling Road, Shanghai 200032, China

1.1 ­Introduction The difluoromethylation of arenes has been given increasing attention due to the unique properties of the difluoromethyl group (CF2H), which is considered as a bioisostere of hydroxyl and thiol groups and also as a lipophilic hydrogen bond donor [1]. Thus, the incorporation of CF2H into an aromatic ring has become an important strategy in medicinal chemistry [2]. Conventional method for the synthesis of difluoromethylated arenes relies on the deoxyfluorination of aromatic aldehydes with diethylaminosulfur trifluoride (DAST) [3]. However, this method has a modest functional group tolerance and high cost. Transition‐metal‐catalyzed cross‐coupling difluoromethylation is one of the most efficient strategies to access this class of compounds. Over the past few years, impressive achievements have been made in this field [4]. In this chapter, we describe three modes of difluoromethylation of aromatics: nucleophilic difluoromethylation, catalytic metal difluorocarbene‐involved coupling reaction (MeDIC), and radical difluoromethylation.

1.2 ­Difluoromethylation of (Hetero)aromatics 1.2.1  Transition‐Metal‐Mediated/Catalyzed Nucleophilic Difluoromethylation of (Hetero)aromatics Copper is the first transition metal that has been used for mediating nucleophilic difluoromethylation of (hetero)aromatics. In 1990, Burton et al. synthesized the first difluoromethyl copper complex by metathesis reaction between [Cd(CF2H)2] and CuBr [5]. However, the instability of this complex restricts its further synthetic applications [6]. In 2012, Hartwig and coworker found that using TMSCF2H (5.0 equiv) as source of fluorine to generate difluoromethyl copper in situ could Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

4

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes CuI (1.0 equiv) CsF (3.0 equiv) TMSCF2H (5.0 equiv)

I R

NMP, 120°C, 24 h

CF2H R

R = EDG

30–91% Me

CF2H

MeO

CF2H

CF2H

CF2H

O Ph (a)

Me 88%

81%

I

t-BuOK (2.4 equiv) DMF, rt

R = EWG

CF2H

(b)

NC 78%

77%

CF2H R 70–93%

CF2H

CF2H O2N

80%

Br

CuCl (1.2 equiv) 1,10-phen (1.2 equiv) TMSCF2H (2.4 equiv)

R

EtO2C

48%

CF2H Cl

82%

N 74%

Scheme 1.1  Copper‐mediated difluoromethylation of aryl iodides with TMSCF2H.

lead to the difluoromethylation of aryl iodides efficiently (Scheme  1.1a) [7], ­representing the first example of copper‐mediated difluoromethylation of aromatics. In this reaction, however, only electron‐rich and ‐neutral aryl iodides were suitable substrates. A difluoromethylcuprate species [Cu(CF2H)2]− was proposed in the reaction. To overcome this limitation, Qing and coworkers reported a 1,10‐phen‐promoted copper‐mediated difluoromethylation of electron‐deficient (hetero)aryl iodides with TMSCF2H (Scheme 1.1b) [8]. The role of the ligand is to stabilize the difluoromethyl copper species. In 2012, Prakash et al. also reported a copper‐mediated difluoromethylation of aryl iodides, employing n‐Bu3SnCF2H, instead of TMSCF2H, as the difluoromethylation reagent (Scheme 1.2) [9]. This method allowed difluoromethylation of electron‐deficient (hetero)aryl iodides, but electron‐rich partners produced low yields. A transmetalation between n‐Bu3SnCF2H and CuI to generate CuCF2H species was proposed. Using similar strategy, Goossen and coworkers reported a Sandmeyer‐type copper‐mediated difluoromethylation of (hetero)arenediazonium salts with TMSCF2H (Scheme 1.3) [10]. In addition to the difluoromethylation of prefunctionalized aromatics, the copper‐mediated direct C─H bond difluoromethylation of heteroaromatics has also been reported, representing a more straightforward and atom/step‐­ economic approach. Inspired by the oxidative trifluoromethylation reaction of

1.2  Difluoromethylation of (Hetero)aromatics CuI (1.3 equiv) KF (3.0 equiv) nBu3SnCF2H (5.0 equiv)

I R

X

CF2H R

DMA, 100–120°C, 24 h

X = CH, N

X

32–82% CF2H

CF2H

CF2H

MeO2C

CHO 53%

N

CF2H

Br

82%

78%

75%

DFT calculations

H3C Sn CF2H H3C CH3

F– –3.6 F– +3.6

CH3 H3C Sn CF2H H3C F

DMF

Cu I

I

+31.8

CH3 F CH3 CF2H

H3C Sn Cu

H3C Sn F H3C CH3

–48.6

DMF +

FMD

Cu CF2H

I–

+

Scheme 1.2  Copper‐mediated difluoromethylation of (hetero)aryl iodides with n‐Bu3SnCF2H. TMSCF2H (2.5 equiv) CuSCN (1.0 equiv) DMF CsF (3.0 equiv) 40°C, 1 h NH2 R

t-BuONO HBF4

N2+BF4–

Cu–CF2H

R

CF2H R

DMF, rt, 12 h 34–86% CF2H

CF2H NC

Ph 81%

67%

CF2H

O N H

76%

CF2H N 54%

Scheme 1.3  Copper‐mediated difluoromethylation of (hetero)arenediazoniums.

heteroaromatics [11], Qing and coworkers reported a copper‐mediated direct oxidative difluoromethylation of C─H bonds on electron‐deficient heteroarenes with TMSCF2H (Scheme 1.4) [12]. The use of 9,10‐phenanthrenequinone (PQ) as an oxidant was essential for the reaction. Regioselective difluoromethylation was favorable to the more acidic C─H bond, which was readily deprotonated by t‐BuOK base, to provide the desired products. These copper‐mediated difluoromethylation reactions paved a new way to access difluoromethylated arenes. In these reactions, however, more than stoichiometric amount of copper salts were required. A more efficient and attractive alternative is the catalytic difluoromethylation. In 2010, Buchwald and coworkers reported the first example of palladium‐catalyzed trifluoromethylation of aryl chlorides with TESCF3 [13]. Direct adaptation of this strategy to difluoromethylation resulted in inefficient transmetalation between the palladium

5

6

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

X Y

R

CuCN (3.0 equiv) PQ (1.8 equiv) TMSCF2H (3 equiv)

H

Z

N

X Y

R

t-BuOK (4.5 equiv) NMP, rt, 6 h

O MeO

O

NC

CF2H

NC

NC

87%

O

77%

O PQ

46–87% N

CF2H

CF2H

Z

N N

N N Me 56%

CF2H

O

CF2H

I 48%

Scheme 1.4  Copper‐mediated oxidative difluoromethylation of heteroarenes.

­catalyst and TMSCF2H. In 2014, Shen and coworkers developed a cooperative dual palladium/silver catalytic system with both bidentate phosphine 1,1′‐ bis(diphenylphosphino)ferrocene (dppf ) and N‐heterocyclic carbene (NHC) SIPr as the ligands (Scheme 1.5a) [14]. This system enabled difluoromethylation of electron‐rich and electron‐deficient aryl bromides and iodides with TMSCF2H

Br/I R

Pd(dba)2 (5 mol%), DPPF (10 mol%) [(SIPr)AgCI] (20 mol%) TMSCF2H (2 equiv) t-BuONa (2 equiv) dioxane or toluene, 80 °C, 4–6 h

i-Pr

CF2H

i-Pr N

N

R

i-Pr i-Pr

58%~96%

SIPr CF2H

CF2H t-BuO2C

Ph (a)

BnO

BnO 84%

76%

86%

CF2H

CF2H N 58%

Proposed mechanism CF2H Ar

Pd(dppf)

(SIPr)Ag CF2H

Ar-CHF2H

TMSCF2H t-BuONa

(dppf)Pd(0)

Ar-X

i-Pr X R

Het

+

X

Pd(dppf)

N

Ar

i-Pr N

i-Pr Ag i-Pr X = Cl, Br, I (b)

(SIPr)Ag X

Pd(dba)2 (5 mol%) DPEPhos (10 mol%)

R

Het

CF2H

Toluene, 80 °C, 6 h 54%~95%

CF2H (SIPr)Ag(CF2H)

Scheme 1.5  Palladium‐catalyzed difluoromethylation of aryl halides with (SIPr)Ag(CF2H).

1.2  Difluoromethylation of (Hetero)aromatics

efficiently. An in situ generated difluoromethyl silver complex (SIPr)Ag(CF2H) was found to promote the transmetalation step and facilitate the catalytic cycle. Stoichiometric reaction showed that the reductive elimination of aryldifluoromethyl palladium complex [Ar–Pd(Ln)–CF2H] is faster than that of aryltrifluoromethyl palladium complex [Ar–Pd(Ln)–CF3], suggesting the different electronic effect between CF3 and CF2H. The method can also be extended to heteroaryl halides [15] and triflates (Scheme  1.5b) [15b], including pharmaceutical and agrochemical derivatives. Very recently, Sanford and coworkers demonstrated that the use of TMSCF2H can also lead to difluoromethylated arenes under palladium catalysis (Scheme  1.6) [16]. The use of electron‐rich monophosphine ligands [BrettPhos and P(t‐Bu)3] allowed difluoromethylation of a series of electron‐rich (hetero)aryl chlorides and bromides. Cl/Br R

CF2H

Conditions TMSCF2H

+

R Yields up to 87% OMe

Condition B: Pd(Pt-Bu3)2 (5 mol%), CsF (2 equiv), dioxane, 100–120 °C, 16–36 h

MeO i-Pr

Condition A: Pd(dba)2 (3 mol%), BrettPhos (4.5 mol%), CsF (2 equiv), dioxane, 100 °C, 16–36 h

PCy2 i-Pr

i-Pr BrettPhos S

CF2H

CF2H

87%

CF2H

O

N

Ph

CF2H

O

60%

60%

38%

N

Scheme 1.6  Palladium‐catalyzed difluoromethylation of aryl halides with TMSCF2H.

Using more reactive transmetalating zinc reagent (TMEDA)2Zn(CF2H)2 as fluorine source, Mikami and coworkers developed a palladium‐catalyzed difluoromethylation of (hetero)aryl iodides and bromides (Scheme 1.7) [17]. Similar to Shen’s work, dppf was employed as the ligand in the reaction. This method exhibited broad substrate scope, where both electron‐rich and electron‐deficient aryl iodides were suitable substrates. Besides the aryl halides, benzoic acid chlorides were also a competent coupling partner. With (DMPU)2Zn(CF2H)2 as the difluoromethylating reagent, Ritter and coworkers developed a palladium‐catalyzed decarbonylative difluoromethylation of benzoic acid chlorides (Scheme 1.8) [18]. This reaction proceeded under

7

8

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Pd(dba)2 (5 mol%), dppf (10 mol%) (TMEDA)Zn(CF2H)2 (2 equiv)

Br/I R

PPh2

CF2H

Fe

R

1,4-Dioxane, 120 °C, 6 h

PPh2

39–99%

DPPF Cl

CF2H

N

CF2H

CF2H

AcO O2N

N

Cl

MeO

80%

86%

N N

O

82%

AcO OAc

CF2H

61%

Scheme 1.7  Palladium‐catalyzed difluoromethylation of aryl bromides/chlorides with (TMEDA)Zn(CF2H)2.

mild reaction conditions with good functional group tolerance. The use of monophosphine ligand RuPhos is critical in promoting the decarbonylation and subsequent difluoromethylation. O

Pd(dba)2 (5 mol%), RuPhos (6 mol%) (DMPU)2Zn(CF2H)2 (1 equiv)

Cl

R

Dioxane, 23 °C, 1 h

CF2H

63–93% Me Me

O N

CF2H Ph

91%

72%

Me

CF2H

N Ph

CF2H R

F

CF2H

Me Me 82%

93% O

Proposed mechanism (RuPhos)Pd(0)

Ar

ArCF2H

Cl

O (RuPhos)Pd(II)

Ar

(RuPhos)Pd(II)

Ar

Cl

CF2H (DMPU)2Zn(CF2H)X X = CF2H or Cl CO

O (RuPhos)Pd(II)

Ar CF2H

(DMPU)2ZnClX

Scheme 1.8  Palladium‐catalyzed decarbonylative difluoromethylation of benzoic acid chlorides with (DMPU)2Zn(CF2H)2.

1.2  Difluoromethylation of (Hetero)aromatics

Copper can also be used as the catalyst for the difluoromethylation. In 2016, Mikami and coworkers reported a ligand‐free copper‐catalyzed difluoromethylation of (hetero)aryl iodides (Scheme 1.9), in which a cuprate [Cu(CF2H)2]− species may be involved in the reaction [19], in agreement with Hartwig’s hypothesis [7]. CuI (2–10 mol%) (DMPU)2Zn(CF2H)2 (2 equiv)

I R

CF2H R

DMPU, 60 °C, 24 h

5–94% CF2H CO2Et 92%

CF2H

N

CF2H

N

Br

CN

CF2H

60%

MeO

91%

5%

Proposed mechanism

CuI

Ar–CF2H

L2Zn(CF2H)2

+

L = DMPU L2Zn(CF2H)I

CuCF2H I

Cu Ar

L2Zn(CF2H)I

+

L2ZnI2 [O]

[Cu(CF2H)2]–

[Cu(CF2H)4]–

Detected by 19F NMR

CF2H

HF2C  CF2H +

Inactive

HFC  CFH

Ar–I

Scheme 1.9  Copper‐catalyzed difluoromethylation of aryl iodides with (DMPU)2Zn(CF2H)2.

For all these copper‐mediated or catalyzed difluoromethylation reactions, a difluoromethyl copper species was proposed as the key intermediate. However, the nature and properties of the unstable copper species have not been systematically investigated. In 2017, Sanford and coworkers reported the synthesis, reactivity, and catalytic applications of an isolable (IPr)Cu(CF2H) complex (Scheme 1.10) [20]. Unlike the previous supposition [5, 6], this complex is stable in solution at room temperature for at least 24 hours, suggesting that the bimolecular decomposition pathway is relatively slow. A variety of aryl electrophiles could react with this (IPr)Cu(CF2H) complex to furnish the corresponding difluoromethylated arenes smoothly. Based on this fundamental research, a copper‐catalyzed difluoromethylation of aryl iodides with TMSCF2H has been developed by employing IPrCuCl as the catalyst. Although palladium‐ and copper‐catalyzed nucleophilic difluoromethylation reactions have been developed, the development of fluoroalkylation catalyzed by earth‐abundant transition metals remains appealing. In 2016, Vicic and coworker reported a nickel‐catalyzed difluoromethylation of (hetero)aryl iodides,

9

10

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

R N

N R

R N

t-BuONa –NaCl

Cu

N R

R N

TMSCF2H –TMSOt-Bu

Cu

Cu CF2H

Ot-Bu

CI

From (IPr)CuCl From (SIPr)CuCl IPrCuCI (10 mol%) TMSCF2H (2 equiv) CsF (3 equiv)

I R

N R

51% 82%

i-Pr

i-Pr N

CF2H R

Dioxane/toluene 3 : 1 120 °C, 20 h

N

i-Pr i-Pr Cu CI

Yields up to 92%

IPrCuCI CF2H

CF2H

Br

CF2H

PhO

NC 64%

CF2H N

66%

71%

78%

Scheme 1.10  (NHC)CuCl‐catalyzed difluoromethylation of aryl iodides with TMSCF2H.

bromides, and triflates with (DMPU)2Zn(CF2H)2 (Scheme 1.11) [21]. This is the first example to use (DMPU)2Zn(CF2H)2 as the difluoromethylation reagent. The reaction underwent difluoromethylation smoothly with electron‐deficient substrates, but electron‐rich aryl iodides or aryl bromides were not applicable to the reaction. X (DMPU)2Zn

R

CF2H

(dppf)Ni(COD) (15 mol%)

CF2H

DMSO, 25 °C, 24 h

X = Cl, Br, I

Yields up to 91%

CF2H Ph

CF2H

CF2H NC

X = Br 78% X = I 74%

CF2H R

S X = Br 79% X = I 91%

X = Br 65% X = I 51%

CF2H N X = Br 53% X = I 60%

Scheme 1.11  Nickel‐catalyzed difluoromethylation of aryl halides with (DMPU)2Zn(CF2H)2.

1.2.2  Catalytic Metal‐Difluorocarbene‐Involved Coupling (MeDIC) Reaction Difluorocarbene is an electrophilic ground‐state singlet carbene. As an important intermediate, difluorocarbene has privileged applications in various areas [22]. However, the intrinsic electrophilic nature of difluorocarbene limits its reaction types [23]. Usually, difluorocarbene is used to react with heteroatom nucleophiles (O, S, N, P) to produce heteroatom‐substituted difluoromethylated compounds [24] or to react with alkenes/alkynes to prepare gem‐difluorocyclopropanes

1.2  Difluoromethylation of (Hetero)aromatics

/gem‐difluorocyclopropenes [25]. The use of transition metal to tune the reactivity of difluorocarbene would provide a promising strategy to develop new types of difluorocarbene transfer reaction. However, because of the inherently low reactivity of known isolated metal‐difluorocarbene complexes compared to their nonfluorinated counterparts [26], it is of great challenge to apply metal‐difluorocarbene to the catalytic cross‐coupling. The catalytic MeDIC reaction had not been reported until Zhang and coworkers reported a palladium‐catalyzed difluoromethylation of arylboronic acids with BrCF2CO2Et in 2015 (Scheme 1.12) [27]. This reaction represents the first example of a catalytic MeDIC reaction by exhibiting excellent functional group tolerance (even toward bromide and hydroxyl groups) and being compatible with both electron‐rich and electron‐deficient arylboronic acids. Compared to the catalytic nucleophilic difluoromethylation of aromatics, the advantages of this reaction are broad substrate scope and the use of inexpensive and readily available fluorine source without requiring a multistep synthetic procedure. The combination of bidentate phosphine ligand Xantphos and additive hydroquinone is essential for reaction efficiency. Kinetic studies showed that a potassium salt BrCF2CO2K was generated in situ at the initial stage, which served as a difluorocarbene precursor in the reaction. Mechanistic studies revealed that an aryl group migration to the palladium difluorocarbene carbon pathway was not involved in the reaction. Inspired by this palladium‐catalyzed MeDIC reaction, Zhang and coworkers  employed ClCF2H as the fluorine source for the difluoromethylation (Scheme 1.13) [28]. ClCF2H is an inexpensive and abundant industrial chemical used for the production of fluorinated polymers [22], representing an ideal and the most straightforward difluoromethylating reagent. The reaction allowed difluoromethylation of a wide range of (hetero)arylboronic acids and esters and was used for difluoromethylation of a series of biologically active molecules, including pharmaceuticals, agrochemicals, and natural products. Most remarkably, the late‐stage difluoromethylation of biologically active molecules through a sequential C–H/C–CN borylation [29] and difluoromethylation process proceeded smoothly, thus providing a straightforward route for applications in drug discovery and development. Deuterium‐labeling experiments demonstrated that arylboronic acids, hydroquinone, ClCF2H, and even water were the proton donors. Xiao and coworkers reported a difluoromethylation of arylboronic acids with Ph3P+CF2COO− (PDFA), but electron‐deficient arylboronic acids were not suitable substrates (Scheme  1.14) [30]. A palladium(0) difluorocarbene trimer [Pd(CF2)(PPh3)]3 was isolated. Stoichiometric reaction of this [{Pd(CF2)(PPh3)}3] complex with arylboronic acid demonstrated that this palladium difluorocarbene cluster was not an active species in the reaction. 1.2.3  Transition‐Metal‐Catalyzed Radical Difluoromethylation of (Hetero)aryl Metals/Halides and Beyond Owning to the electron‐withdrawing effect of fluorine atom, perfluoroalkyl ­halides can be readily initiated by a low‐valent transition metal to generate a radical via a single electron transfer (SET) pathway [31]. A nickel‐catalyzed ­perfluoroalkylation of aromatics with perfluoroalkyl iodides was reported in

11

B(OH)2 R

BrCF2CO2Et (2 equiv)

R = EDG, EWG

PdCI2(PPh3)2 (5 mol%) Xantphos (7.5 mol%) Hydroquinone (2.0 equiv) Fe(acac)3 (3.5 mol%) Styrene (20 mol%) K2CO3, dioxane, 80 °C

:CF2

OH

Me Me CF2H R

O 33–87%

PPh2

PPh2

Xantphos

via: LnPdCF2

OH Hydroquinone CF2H

OH CF2H

CF2H

MeO

CF2H F

EtO

TMS O

OMe

O 80%

73%

72%

N

58% F

Scheme 1.12  Palladium‐catalyzed difluoromethylation of arylboronic acids with bromodifluoroacetate via a difluorocarbene pathway.

Pd2(dba)3 (2.5 mol%) Xantphos (7.5 mol%) Hydroquinone (2.0 equiv)

B ClCF2H (10 equiv)

R

R = EDG, EWG

CF2H R

K2CO3 (4.0 equiv) Dioxane, 110 °C

via:

LnPdCF2

45–95%

:CF2

B = B(OH)2, Beg, Bneop•KOH, B(Oi-Pr)3Li O Me Me O O

OMe

O

O Me

CF2H

Me

N

80%

N

Me

45%

CF2H

O Me

NHBoc

O Me

S O N O Me

O OEt

(1) C–CN borylation

Me

NHBoc

72% Gram scale CF2H

F O

(2) C–B difluoromethylation

O Me

N

CF2H

Me Me

CN

F

H

(2) C–B difluoromethylation

O

72%

(1) C–H borylation Me

MeO

CO2Me

MeO

Me

CF2H

CF2H

O

O O

On-Bu

O

Me

Scheme 1.13  Palladium‐catalyzed difluoromethylation of aryl borons with chlorodifluoromethane via a difluorocarbene pathway.

On-Bu Me

B(OH)2 R

Ph3P+CF2CO2– PDFA (5 equiv)

Pd(PPh3)4 (20 mol%) 1,3-Cyclopentadione (1 equiv) H2O (2.5 equiv), Ca(OH)2 (4 equiv)

CF2H R

p-Xylene, 90 °C, 3 h

R = EDG

O 23–86%

via: LnPdCF2 :CF2 CF2H

CF2H

CF2H

O

MeO 83%

78%

86%

O

1,3-Cyclopentadione

CF2H

68%

Scheme 1.14  Palladium‐catalyzed difluoromethylation of arylboronic acids with PDFA via a difluorocarbene pathway.

1.2  Difluoromethylation of (Hetero)aromatics

1989 by Huang and coworker [32]. A radical initiated by nickel(0) was involved in the reaction, but no fluoroalkyl nickel species was generated. A nickel‐catalyzed radical difluoromethylation of aromatics (Scheme 1.15a) was reported in 2018 by Zhang and coworkers [33] on the basis of their previous work on the nickel‐­ catalyzed difluoroalkylation of arylboronic acids with difluoroalkyl halides [34]. The reaction exhibited high functional group tolerance and allowed difluoromethylation of a variety of arylboronic acids with simple and readily available bromodifluoromethane (BrCF2H) as the fluorine source. A combined (2 + 1) ligand system [34b,c] (a bidentate ligand and a monodentate ligand) was employed to promote the relatively low reactivity of BrCF2H and facilitate catalytic cycle. Radical inhibition, radical clock, and electron paramagnetic resonance (EPR) Ni(PPh3)2Br2 (5 mol%) bpy (10 mol%), DMAP (5 mol%) K2CO3 (4.0 equiv)

B(OH)2 BrCF2H

R

CF2H R

THF, 80 °C, 17 h

N 37–93%

MeO

CF2H

CF2H EtO

(a)

N Ph

TMS 83%

N

CF2H

CF2H

O

OMe 85%

bpy

80%

70%

Proposed mechanism ArCF2H

ArB(OH)2

NiILn

Ar HF2C

NiIIILn

Ar–NiILn

Br Single electron transfer

•CF H 2

+ Ar–Ni II(Ln)Br

B(OH)2 R

BrCF2H

Ni(OTf)2 (5 mol%) ditBuBpy (5 mol%), PPh3 (10 mol%) K2CO3 (3.0 equiv) BrCF2H R Dioxane, 80 °C, 24 h

t-Bu

N N ditBuBpy

51–92% CF2H

(b)

92%

CF2H

CF2H EtO

Ph

t-Bu

CF2H

O

O

CF2H

PhO O

86%

69%

Scheme 1.15  Nickel‐catalyzed difluoromethylation of arylboronic acids with bromodifluoromethane.

53%

15

16

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

experiments demonstrated that a difluoromethyl radical was involved in the reaction. Based on the mechanistic studies and previous reports [35], a Ni(I/III) catalytic cycle involving a radical was proposed. Similar to Zhang’s studies, Wang and coworkers reported a nickel‐catalyzed cross‐coupling of BrCF2H with arylboronic acids using PPh3 as the co‐ligand (Scheme 1.15b) [36]. Later on, Zhang and coworkers extended this (2 + 1) ligand system to the nickel‐catalyzed cross‐coupling between (hetero)aryl chlorides/bromides and ClCF2H [37], representing the first example of nickel‐catalyzed reductive cross‐ coupling between organoelectrophiles and fluoroalkyl halides (Scheme  1.16). The reaction exhibited remarkably broad substrate scope, including a range of pharmaceuticals, without preformation of aryl metals. The reaction can be scaled up to 10 g scale without loss of reaction efficiency, providing a practical application of ClCF2H in life and materials sciences. Radical clock and control experiments revealed that a difluoromethyl radical generated by direct cleavage of C─Cl bond in ClCF2H was involved in the reaction. Stoichiometric reaction of aryl nickel complex [ArNi(ditBuBpy)X] with ClCF2H and reaction of difluoromethyl nickel complex [HCF2Ni(ditBuBpy)X] with aryl chloride showed that the reaction started from the oxidative addition of aryl halides to Ni(0). This is in NiCI2 (10 mol%) Ligand (5 mol%) DMAP (20 mol%) MgCI2 (4.0 equiv) Zn (3.0 equiv) 3 Å MS, DMA, 60 °C

CI R

Het

CICF2H (6.5 equiv)

O

N

R

CF2H

72%

Me Me

O

O

N N H

CF2H 76% O

84%

N N Ligand

CO2Me N H

CF2H NBoc

NH2

Yields up to 92% O

Me

H2N

CF2H Het

N Me

OH

91%, 10.5 g CF H 2

Proposed mechanism [Ni0]

Zn [NiI]

CF2H

Zn [Ar–NiIII–CF2H] [Ar–NiII–Cl] + CF2H

[Ar–NiI]

ClCF2H

[Ar–NiIII–CF2H]

Ar–CF2H

Br Het

[NiI]

ClCF2H

a. Radical-Cage rebound process

R

Ar–Cl [Ar–NiII–Cl]

[NiII]

[Ar–NiII–Cl]

Ar–CF2H

[Ni0]

Zn

Ar–Cl

BrCF2H (1.0 equiv)

b. Radical chain mechanism

Ni(PPh3)2Br2 (10 mol%) bpy (10 mol%) KI (0.4 equiv) Zn (2.0 equiv) DMPU, 60 °C, 6 h

CF2H R

Het

Yields up to 91%

Scheme 1.16  Nickel‐catalyzed reductive difluoromethylation of aryl chlorides and bromides.

1.2  Difluoromethylation of (Hetero)aromatics

contrast to palladium‐catalyzed difluoromethylation of arylboronic acids and esters with ClCF2H, in which a difluorocarbene pathway is involved in the reaction [28]. This nickel‐catalyzed reductive process can also be applied to BrCF2H with high efficiency and good functional group tolerance (Scheme 1.16) [38]. The nickel‐catalyzed reductive difluoromethylation has also been extended to photoredox catalysis. Recently, McMillan and coworkers reported a method to access difluoromethylated (hetero)arenes through cross‐coupling of (hetero)aryl bromides with BrCF2H by combining nickel catalysis (NiBr2·4,4′‐di‐tert‐ butyl‐2,2′‐bipyridine [dtbbpy]) with iridium photocatalysis {[Ir(dF(CF3) ppy)2(dtbbpy)]PF6} (Scheme 1.17) [39]. A pathway involving silyl radical‐medi-

Br BrCF2H

R X

DME, blue LEDs, 18 h

CF3

F

Ir photocatalyst (1 mol%) NiBr2 dtbbpy (5 mol%) (TMS)3SiH (1.05 equiv) 2,6-Lutidine (2.0 equiv)

PF6–

N CF2H R

F F

Ir

X

(1–2 equiv)

tBu N N tBu

N

45–85%

F CF3 Ir photocatalyst

O OMe N MeO

N

S

NH2 CF2H

O O

CF2H O S N O Me

N

N N

Me

F3C

66%

CF2H

64%

MeO

82%

CO2Me

Proposed mechanism Formation of difluoromethyl radical: Br

(TMS)3SiH –HBr

BrCF2H

(TMS)3Si

hv visible light excitation

(TMS)3SiBr +

CF2H

Ar–Br (dtbbpy)Ni0Ln

IrIII

Br N NiII Ar N SET

CF2H

*IrIII

IrII

Br

Br

(dtbbpy)NiILn

CF2H N NiIII–Ar N

Ar–CF2H

Scheme 1.17  Metallaphotoredox difluoromethylation of aryl bromides with bromodifluoromethane.

17

18

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

ated halogen abstraction to generate difluoromethyl radical was proposed. One advantage of this method is that various N‐containing heteroaromatics were applicable to the reaction, providing an alternative access to difluoromethylated (hetero)aromatics. The nickel‐catalyzed difluoromethylation of arylmetals with difluoromethyl halides has also been applied to the cross‐coupling between arylmagnesium bromides and difluoroiodomethane (ICF2H) (Scheme 1.18) [40]. In contrast to the previous difluoromethylation via a Ni(I/III) catalytic cycle [33], a Ni(0/II) catalytic cycle was proposed by Mikami and coworkers [40] to be likely involved in the reaction. This plausible mechanism was supported by the stoichiometric reaction of a difluoromethyl nickel(II) complex with PhMgBr. Radical clock experiment showed that the free difluoromethyl radical was unlikely involved in the reaction. They also used ICF2H as the difluoromethylating reagent and ­developed a palladium‐catalyzed difluoromethylation of arylboronic acids with ICF2H (Scheme  1.19) [41]. Preliminary mechanistic studies revealed that the reaction started from the oxidative addition of ICF2H to Pd(PPh3)4; the resulting square‐planar trans‐(PPh3)2Pd(II)(CF2H)I complex underwent transmetalation to provide cis‐(PPh3)2Pd(CF2H)Ph, which subsequently underwent a ligand Ni(cod)2 (2.5 mol%) TMDEA (2.5 mol%)

MgBr +

R

ICF2H

CF2H R

THF, 0 °C to rt, 1 h

42–99%

(1.5 equiv) CF2H

CF2H

Ph

EtO2C

CF2H

CF2H

NC

MeS 89%

82%

79%

33%

Proposed mechanism Oxidative addition

N

ICF2H

Ni N

I CF2H Ar–MgBr

N Ni0 N

MgBrI N Ar–CF2H Reductive elimination

Ni N

Ar

Transmetalation

CF2H

Scheme 1.18  Nickel‐catalyzed difluoromethylation of aryl magnesium reagents with iododifluoromethane.

1.2  Difluoromethylation of (Hetero)aromatics Pd(PPh3)4 (10 mol%) DPEphos (10 mol%) K3PO4 (2 equiv)

B(OH)2 +

R

ICF2H

Toluene/H2O = 10 : 1 60 °C, 24 h

(1.5 equiv)

CF2H

CF2H PPh2 33–98%

O

NH2

TMS 89%

PPh2

DPEphos

CF2H

CF2H

Ph

O

R

90%

29%

CF2H

68% Me Me

Zn +

R

2

ICF2H

Pd2(dba)3 (5 mol%) Xantphos (11 mol%) THF, rt, 20 h

CF2H R

(1.5 equiv)

O 12–97%

PPh2

PPh2

Xantphos CF2H

MeO

CF2H

CF2H

CF2H

EtO2C 97%

67%

CN 49%

52%

Scheme 1.19  Palladium‐catalyzed difluoromethylation of arylboronic acids or aryl zinc reagents.

exchange with DPEphos, followed by reductive elimination to produce the difluoromethylated aromatics. In addition to the nickel‐catalyzed radical difluoromethylation, the use of inexpensive, nontoxic, and environmentally benign iron as the catalyst has also been given increasing attention. In 2018, Hu and coworkers reported an iron‐catalyzed difluoromethylation of arylzinc reagents with difluoromethyl 2‐pyridyl sulfone (Scheme 1.20a) [42]. Generally, moderate to high yields were obtained with electron‐rich substrates, but less reactivity was showed by electron‐deficient substrates. Preliminary mechanistic studies showed that a difluoromethyl radical, generated via SET pathway from difluoromethyl 2‐pyridyl sulfone, was involved in the reaction. In the same year, Zhang and coworkers also developed an iron‐catalyzed difluoromethylation (Scheme  1.20b) [43], in which a bulky diamine ligand with a butylene group substituted at one carbon atom of ethylene backbone in N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) was used to promote the reaction. During the reaction/catalysis process, the corresponding iron complex can be changed from five‐coordinate to more electron‐deficient four‐coordinate, thus improving its catalytic efficiency. This iron‐catalyzed difluoromethylation has later been extended to ICF2H by Mikami and coworkers (Scheme 1.20c) [44]. In contrast, no ligand was required in this reaction, mainly owing to the different reactivity between BrCF2H and ICF2H. 1.2.4  Radical C─H Bond Difluoromethylation of (Hetero)aromatics The direct C─H bond difluoromethylation of (hetero)aromatics represents a more straightforward alternative. Over the past a few years, important progress has been made in this field, providing synthetically convenient routes for

19

20

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes O Ar2Zn

N

O

Fe(acac)3 (20 mol%) TMEDA (2.0 equiv)

H

F F

CF2H

CF2H

Ar CF2H

THF, –40 °C to rt, 2 h

36–96%

Me N O

F3C

MeO

(a)

S

FeBr2 (10 mol%) L1 (10 mol%)

MgBr + BrCF2H

R

F 92%

68%

88%

CF2H

CF2H

THF/dioxane, rt, 90 min

R

Me2N L1

41–91% CF2H

CF2H

(b)

85%

TMS OMe 63%

91%

MgBr +

R

NMe2

CF2H

CF2H

MeO

F3C

Ph

CF2H

80%

ICF2H

65%

CF2H

Fe(acac)3 (2.5 mol%)

R

THF, –20 °C, 30 min

16–94% CF2H

CF2H

EtO

PhO

Ph

N

O

(c)

84%

CF2H

CF2H

85%

55%

53%

Scheme 1.20  Iron‐catalyzed difluoromethylation of aryl zinc reagents or aryl magnesium reagents.

applications in organic synthesis. In 2012, Baran and coworkers developed a new ­difluoromethylating reagent Zn(SO2CF2H)2 (DMFS) that allowed difluoromethylation of a range of N‐containing heteroarenes in the presence of t‐BuOOH via a radical pathway (Scheme  1.21) [45]. Regiochemical comparisons showed that the difluoromethylation preferred to occur at relatively more electron‐deficient carbon, suggesting a nucleophilic character of the difluoromethyl radical generated from DMFS. The use of inexpensive and readily available difluoromethylating reagents via the C─H bond difluoromethylation would be more attractive in terms of cost efficiency. In 2017, Maruoka and coworkers developed a hypervalent iodine reagent with readily available difluoroacetic acid as the ligand (Scheme 1.22) [46]. Upon irradiation of this difluoromethylating reagent with UV, a series of N‐heteroarenes can be difluoromethylated at relatively more electron‐deficient ­carbons via a difluoromethyl radical process. The regioselectivity of this reaction

1.2  Difluoromethylation of (Hetero)aromatics

Het

Zn(SO2CF2H)2 (2.0–4.0 equiv) t-BuOOH (4.0–6.0 equiv) TFA (1.0 equiv)

H

Het

CH2CI2:H2O (2.5 : 1), 23 °C

CF2H

30–90% O

O

OEt

O

4

MeO 2

CF2H

N

6

2

45% C2 : C4 : C6 1.5 : 1.5 : 2

66%

NaSO2CF3

HN N

2

H

6

N

H N

Me

N

O

79% C2 : C4 : C6 1:1:2

CF3 5

OMe CF2H

MeO

CF2H

N

O

4

5

HN

(50%) C5 : C2 4 : 1

N

2

H

CF2H N Me 90%

Zn(SO2CF2H)2 t-BuOOH

N

H N

CH2CI2/H2O (50%)

H 5

N

HN N

2

CF2H

Scheme 1.21  Radical difluoromethylation of heteroarenes with Zn(SO2CF2H)2.

Het

H

ArI(OCOCF2H)2 (2.0 equiv) hv (400 nm)

Het

CDCl3, rt, 14 h

CF2H

20–77% O Me O

N

O

Me N

O

OEt Me

CF2H N Me

N

48%

47%

CF2H

O

Me N N

CF2H

N N Me

Cl

HF2C

55%

CO2Me 22%

Scheme 1.22  Radical difluoromethylation of heteroarenes with ArI(OCOCF2H)2.

is same as that of Baran’s method [45], implying the same nucleophilic character of difluoromethyl radical generated from these two new reagents. However, only low to moderate yields were obtained. The direct use of difluoroacetic acid as the difluoromethylating reagent has also been reported almost contemporaneously. Nielsen and coworkers employed AgNO3/K2S2O8 as the oxidants to generate difluoromethyl radical from difluoroacetic acid (Scheme 1.23) [47]. This process allowed difluoromethylation at electron poor carbons adjacent to the nitrogen atom in N‐heteroarenes. Similarly, low to moderate yields were obtained. Further investigation showed that a bis‐ difluoromethylation could also be occurred by increasing the reaction temperature. In parallel to Nielsen’s work, Qing and coworkers described a direct difluoromethylation of phenanthridines and 1,10‐phenanthrolines with TMSCF2H (Scheme 1.24) [48]. The reaction used PhI(OCOCF3)2 or N‐Chlorosuccinimide (NCS) as the oxidant, and silver salt as the additive, providing the corresponding difluoromethylated heteroarenes in low to moderate yields. A pathway was pro-

21

22

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes CF2HCOOH (2 equiv) AgNO3 (0.5 equiv), K2S2O8 (5 equiv)

Het N

Het

CH3CN/H2O: 2/1, 50 °C, 5–24 h

H

CN

OPh

CF2H N

N

N CF2H 62%

CF2H

N

CF2H

61%

32%

N

Cl

N

CF2H

36%

Proposed mechanism S2O82– SO42–

Ag2+

Ag+

CF2HCOOH

CF2HCOO H+

–CO2

[H+] N

(1) –H+

CF2H N H

H

H

N H

H CF2H

(2) –H

N

CF2H

Scheme 1.23  Radical difluoromethylation of heteroarenes with HCF2COOH. TMSCF2H (3.0 equiv) t-BuOK (3.0 equiv), silver salt (1.0 equiv) Oxidant (3.0 equiv), rt

R N H

R N

Silver salt: AgOAc or AgCl Oxidant: PhI(TFA)2 or NCS

CF2H Cl

Cl

MeO N CF2H 63%

N

N 58%

CF2H

N 67%

CF2H

N

N 32%

CF2H

Scheme 1.24  Oxidative difluoromethylation of phenanthridines and 1,10‐phenanthrolines with TMSCF2H.

posed for the reaction to involve a nucleophilic addition of difluoromethyl anion to the heteroarenes, followed by aromatization process, but a difluoromethyl radical pathway cannot be ruled out.

1.3 ­Difluoroalkylation of Aromatics In addition to difluoromethylated aromatics, other difluoroalkylated aromatics also have important applications in medicinal chemistry and materials science due to the unique properties of difluoromethylene group (CF2). The incorporation of CF2 at the benzylic position not only can improve the metabolic stability

1.3  Difluoroalkylation of Aromatics

of biologically active molecules but also can enhance the acidity of its neighboring groups [49]. However, except for the conventional difluorination of ­ketoaromatics with DAST, general and efficient methods for highly selective introduction of CF2R into organic molecules to access these valuable compounds had been less explored before 2012 [4]. The transition‐metal‐catalyzed cross‐ coupling difluoroalkylation would be an attractive strategy, as it can directly construct (Het)Ar─CF2R bonds in an efficient and controllable manner. In particular, this strategy can enable late‐stage difluoroalkylation of biologically active molecules without the need of multistep synthesis. Nevertheless, the difficulty in selectively controlling the catalytic cycle to access the desired difluoroalkylated aromatics posed problems with such strategy. Difluoroalkylated metal species have a different instability compared with their non‐fluorinated counterparts due to decomposition or protonation to generate by‐products [50]; this has increased attention on the subject and impressive achievements have been made over the past a few years [4]. Here, we specifically focus on the transition‐metal‐ catalyzed difluoroalkylation of aromatics, including phosphonyldifluoromethylation and difluoroacetylation. The direct difluoroalkylation of C─H bond via a radical process will not be discussed in this session, as comprehensive reviews have been described previously [4]. 1.3.1  Transition‐Metal‐Catalyzed Phosphonyldifluoromethylation of (Hetero)aromatics Phosphonyldifluoromethyl groups (CF2PO(OR)2) have important applications in medicinal chemistry and chemical biology because CF2 is a bioisopolar and bioisostere of oxygen and replacing the oxygen atom of phosphoryl ester with CF2 results in a phosphate mimic that can protect against hydrolysis. For instance, an aromatic ring bearing this functional group can act as a protein tyrosine phosphatase (PTPase) inhibitor with significant bioactivity [51]. However, only a few methods to access aryldifluoromethylphosphonates have been developed before 2012 [52]. In 1996, Burton and coworker reported the  first example of copper‐mediated phosphonyldifluoromethylation of aryl iodides with ­ bromocadmiumdifluoromethylphosphate (BrCdCF2PO(OEt)2) (Scheme  1.25a) [52a]. The reaction was carried out under mild conditions and exhibited good functional group compatibility. However, the use of excessive toxic I R

CuI (1.16 equiv) BrCdCF2P(O)(OEt)2 (1.66 equiv) DMF, rt, 3 h

CF2P(O)(OEt)2 R 65–88%

(a) I R (b)

CuBr (2.0 equiv) BrZnCF2P(O)(OEt)2 (2.0 equiv) DMF, rt, 7–150 h

CF2P(O)(OEt)2 R 17–99%

Scheme 1.25  Copper‐mediated phosphonyldifluoromethylation of aryl iodides with difluoromethylphosphonyl cadmium or zinc reagents.

23

24

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

cadmium reagents restricts its widespread synthetic applications. In this context, Shibuya and coworkers replaced BrCdCF2PO(OEt)2 with a zinc analogue (BrZnCF2PO(OEt)2) reagent and furnished the corresponding Ar–CF2PO(OEt)2 smoothly (Scheme 1.25b) [52b]. This reaction required 2.0 equiv of copper salt due to the instability of the difluoromethylphosphonate copper–zinc complex. To overcome this limitation, in 2012 Zhang and coworkers reported the first example of copper‐catalyzed cross‐coupling of iodobenzoates with BrZnCF2PO(OEt)2 (Scheme 1.26) [53]. To stabilize the difluoromethylphosphonate copper–zinc complex, 1,10‐phenanthroline (Phen) was used as the ligand and an ester group was employed as a chelating group ortho to the iodide to ­facilitate the oxidative addition of copper to the Ar─I bond. The reaction showed high reaction efficiency and excellent functional group tolerance. A Cu(I/III) ­catalytic cycle was proposed for this reaction, which was further supported by computational studies by Jover [54], in which the Zn(II) salt can act as a linker to connect both the chelating group and the copper catalyst. When replacing the ester on aromatic ring with a removable and versatile triazene group, the aryl bromides were also suitable substrates for this reaction. The resulting triazene‐containing products could serve as a good platform for diversity‐oriented synthesis, providing a wide range of Ar–CF2PO(OEt)2 that are otherwise difficult to prepare (Scheme 1.27) [55]. CO2Me I R

+

BrCF2P(O)(OEt)2

CO2Me CF2P(O)(OEt)2

R

Zn (2.0 equiv) Dioxane, 60 °C 24-48 h

53–95%

CO2Me CF2P(O)(OEt)2

CO2Me CF2P(O)(OEt)2

CO2Me CF2P(O)(OEt)2

MeO

Me 95%

CO2Me CF2P(O)(OEt)2

CuI (0.1 equiv) Phen (0.2 equiv)

80%

OMe

NO2

54%

60%

Proposed mechanism BrCF2P(O)(OEt)2

DG CF2P(O)(OEt)2

Zn

R

Cu(I)

BrZnCF2P(O)(OEt)2

DG X2Zn .CuCF2P(O)(OEt)2

R CuCF2P(O)(OEt)2 I

DG I R

DG R I

MCF2P(O)(OEt)2

Scheme 1.26  Copper‐catalyzed cross‐coupling of bromozinc‐difluorophosphonate with 2‐iodobenzoates.

N R

N

CuCN (10 mol%)

N

+

I/Br

BrCF2P(O)(OEt)2

Ligand (20 mol%)

Zn (3.0 equiv) Dioxane, 60 °C

N R

N

Me

N

Me

Me

CF2P(O)(OEt)2

Me N

N

Ligand

40–91%

Me CF3

CF2P(O)(OEt)2

Pd(OAc)2 (5 mol%) BF3 . Et2O

N

4-CF3-C6H4B(OH)2

CF2P(O)(OEt)2

N

Pd(OAc)2 (5 mol%) BF3 . Et2O

N

3-Me-C6H4B(OH)2

CF2P(O)(OEt)2

85%

97% (1) MeI, 100 °C (2) PdCl2(PPh3)2 (10 mol%) CuI (0.1 equiv), Et3N

Pd(OAc)2 (10 mol%) Styrene, BF3 . Et2 O

BF3 . Et2O

TMS TMS

Ph

H CF2P(O)(OEt)2 82% 2 steps

CF2P(O)(OEt)2 83%

CF2P(O)(OEt)2

93%

Scheme 1.27  Copper‐catalyzed cross‐coupling of bromozinc‐difluorophosphonate with iodo/bromo‐aryl triazenes and further transformations.

26

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Chelating group free transition‐metal‐catalyzed phosphonyldifluoromethylation of (hetero)aromatics would be a more attractive strategy. In 2014, Zhang and coworkers developed a palladium‐catalyzed cross‐coupling of BrCF2PO(OEt)2 with arylboronic acids (Scheme 1.28) [56], representing the first example of catalytic difluoroalkylation of organoborons. The use of bidentate ligand Xantphos was essential in the promotion of the reaction probably due to the wide bite angle of Xantphos. This method paved a new way for the selective difluoroalkylation of aromatics. The reaction allowed the preparation of a variety of Ar–CF2PO(OEt)2, including a PTPase inhibitor. Preliminary mechanistic studies showed that a ­difluoroalkyl radical generated via an SET pathway was involved in the reaction. Recently, Poisson and coworkers also reported a palladium‐catalyzed phosphonyldifluoromethylation to prepare Ar–CF2PO(OEt)2 (Scheme  1.29) [57]. The reaction employed aryl iodides as the coupling partner, and stoichiometric amount of phosphonyldifluoromethyl copper (CuCF2PO(OEt)2) was needed. As an alternative, Qing and coworkers reported a copper‐mediated oxidative cross‐coupling between arylboronic acids and TMSCF2PO(OEt)2 (Scheme 1.30) [58]. Stoichiometric copper complex CuTc and excess of Ag2CO3 were needed. This strategy can also be extended to oxidative cross‐coupling of PhSO2CF2Cu with arylboronic acids [59]. Later on, Poisson and coworkers employed (hetero) aryl iodonium and aryl diazonium salts as the coupling partners, enabling the phosphonyldifluoromethylation (Scheme 1.31) [60]. Vinyl and alkynyl iodonium salts were also suitable substrates, thus demonstrating the generality of this method. In 2018, Amii and coworkers replaced (hetero)aryl iodonium salts with (hetero)aryl iodides and developed a copper‐mediated cross‐coupling between (hetero)aryl iodides and TMSCF2PO(OEt)2 (Scheme 1.32) [61]. They investigated the catalytic phosphonyldifluoromethylation, but only three electron‐deficient (hetero)aryl iodides with 42–69% yields were obtained by using 0.1–0.2 equiv CuI. 1.3.2  Transition‐Metal‐Catalyzed Difluoroacetylation of (Hetero) aromatics and Beyond The versatile synthetic utility of ester moiety led to the increased attention on the difluoroacetylation of aromatics. In 1986, Kobayashi and coworkers reported the first example of copper‐mediated difluoroacetylation of aryl halides with difluoroacetate iodide (Scheme 1.33a) [62]. The reaction underwent difluoroacetylation under mild conditions with good functional group compatibility. Several copper‐mediated difluoroacetylations of various aryl halides and aryl boronic acids have been reported [63]. However, excess of copper was needed. Later on, Amii and coworkers reported a copper‐catalyzed cross‐coupling of aryl iodides with TMSCF2CO2Et (Scheme 1.33b) [64]. The reaction facilitated the synthesis of difluoroacetylated arenes in 40–71% yields but was limited to electron‐deficient substrates. The resulting difluoroacetylated arenes were further used to prepare difluoromethylated arenes by sequential hydrolysis and decarboxylation. To overcome the substrate scope limitation of Amii’s method, Hartwig and coworker employed α‐silyldifluoroamides as the coupling partners and 18‐crown‐6 as the additive, enabling the efficient synthesis of aryl ­ difluoroacetamides (Scheme 1.34) [65]. Both electron‐rich and electron‐­deficient aryl iodides were

B(OH)2 + BrCF2P(O)(OEt)2

R

Pd(PPh3)4 (5 mol%) Xantphos (10 mol%)

CF2P(O)(OEt)2 R

Dioxane, 80 °C

86%

70%

CO2Me NHBoc

(EtO)2(O)PF2C

O

PPh2

Xantphos

CF2P(O)(OEt)2

EtO2C

O

PPh2

44–86%

CF2P(O)(OEt)2

CF2P(O)(OEt)2

O

K2CO3 (2.0 equiv)

80% (with 3 Å MS)

41% PTPase inhibitor

Proposed mechanism Ar –CF2R

BrCF2R

Pd0Ln

R = PO(OEt)2, CO2Et, CONR1R2

ArPdIILnCF2R

BrPdILn + CF2R

Base ArB(OH)2

BrPdIILnCF2R

Scheme 1.28  Palladium‐catalyzed phosphonyldifluoromethylation of arylboronic acids with bromodifluorophosphonate.

28

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes PdCl2(PPh3)2 (5 mol%) CuCF2P(O)(OEt)2 (1.0 equiv)

I Het

R

CF2P(O)(OEt)2 R

CH3CN, 40 °C, 16 h

Het 38–80%

CF2P(O)(OEt)2 MeO

CF2P(O)(OEt)2

MeO2C

64%

N

CF2P(O)(OEt)2

Br 58%

N N

69%

CF2P(O)(OEt)2

46%

Scheme 1.29  Palladium‐catalyzed phosphonyldifluoromethylation of aryl iodides with difluorophosphonyl copper reagents.

CuTc (1.0 equiv) Phen (1.0 equiv)

B(OH)2 R

TMSCF2P(O)(OEt)2

CF2P(O)(OEt)2 MeO2C

72%

Ag2CO3 (1.5 equiv), pyridine 4 Å MS, DMF, 45 °C

CF2P(O)(OEt)2

CF2P(O)(OEt)2 R 31–81%

CF2P(O)(OEt)2

54%

CF2P(O)(OEt)2

S 31%

MeO 40%

Scheme 1.30  Copper‐mediated oxidative phosphonyldifluoromethylation of arylboronic acids with TMSCF2PO(OEt)2.

CuSCN (1.0 equiv) CsF (3.0 equiv)

X +

R

TMSCF2P(O)(OEt)2

CF2PO(OEt)2 R

MeCN/DMF, 0 °C to rt

(2.5 equiv) X = I(Ar)OTf/BF4 N2+BF4–

Yield up to 76%

CF2P(O)(OEt)2

CF2P(O)(OEt)2 OMe 60%

71%

CF2P(O)(OEt)2

CF2P(O)(OEt)2

MeO2C

51%

Br

45%

Scheme 1.31  Copper‐mediated phosphonyldifluoromethylation of aryl hypervalent iodides or aryl diazoniums with TMSCF2PO(OEt)2.

CuI (0.2 equiv) CsF (1.2 equiv)

I +

R

TMSCF2P(O)(OEt)2

THF, 60 °C, 24 h

(1.2 equiv)

CF2P(O)(OEt)2

N

CF2P(O)(OEt)2

CF2P(O)(OEt)2 R

N

CF2P(O)(OEt)2

NC 50%

42%

69%

Scheme 1.32  Copper‐catalyzed phosphonyldifluoromethylation of (hetero)aryl iodides with TMSCF2PO(OEt)2.

1.3  Difluoroalkylation of Aromatics Cu powder (4.0 equiv)

X +

R

ICF2CO2Me (3.0 equiv)

CF2CO2Me R

DMSO, rt to 60 °C

X = Br, I

(a)

21–88% CuI (20 mol%) KF (1.2 equiv)

I +

R

TESCF2COOEt

CF2COOEt R

DMSO, 60 °C

(b)

40–71% (19F NMR) CF2COOEt Cl

CF2COOEt

CF2COOEt

Cl

EtO2C

NC

N

CF2COOEt

71%

40%

42%

67%

Preparation of difluoromethylated arenes via a decarboxylation process CF2COOEt

CF2COOH

K2CO3

R

R

MeOH/H2O rt, 1–2 h

EtO2C

NC

CF2H R

170–200 °C 2–48 h

N

CF2COOEt

CF2COOEt

CF2COOEt

KF (or CsF) DMF or NMP

CF2COOEt

Br

84%

74%

59%

89%

Scheme 1.33  Copper‐mediated/catalyzed difluoroacetylation of aryl iodides/bromides and applications in the synthesis of difluoromethylated arenes.

F F

I R

+

TMS

R1 N

CuOAc (20 mol%) KF (1.2 equiv) 18-crown-6 (1.2 equiv)

R2

Toluene, 100 °C

O

R1 N

F F R

R2

O 71–97%

O

F F N MeO

O 85%

O

F F O 92%

O

F F

F F

N

N t-BuO2C

O 73%

N

Bn N

Bn

O 75%

Scheme 1.34  Copper‐catalyzed cross‐coupling of aryl iodides with α‐silyldifluoroamides.

applicable to the reaction, providing an alternative access to difluoroacetylated arenes. The copper‐catalyzed C─H bond difluoroacetylation of furans and ­benzofurans with difluoroacetate bromide has also been reported by Poisson and coworkers (Scheme 1.35) [66]. A Cu(I/III) catalytic cycle was proposed based on no inhibition of the reaction by addition of radical inhibitor (tert‐butylhydroxytoluene) or scavenger tetramethylpiperidinooxy (TEMPO) to the reaction.

29

R1

R1 H

R

+

O

CuI (10 mol%), phen (12 mol%)

BrCF2CO2Et

R

K2CO3 ( 2 equiv), DMF, 80 °C

O 36–65%

CF2CO2Et

Ph O

CF2CO2Et

AcO

52% (60 °C)

CF2CO2Et

O

O

CF2CO2Et O 67%

50%

63% (60 °C)

CF2CO2Et

Proposed mechanism O

CF2CO2Et

O

BrCF2CO2Et

CuIX

CF2CO2Me CuIII X

Br X

CuIIICF2CO2Me

Base • HX

Base

+

O

CF2CO2Me CuIII X

O

H

Scheme 1.35  Copper‐catalyzed difluoroacetylation of furans and benzofurans with bromodifluoroacetates and the possible mechanism.

1.3  Difluoroalkylation of Aromatics

The first example of palladium‐catalyzed difluoroacetylation of aromatics was reported by Zhang and coworkers in 2014 (Scheme 1.36) [56]. The combination of Pd(PPh3)4/Xantphos with CuI provided an efficient catalytic system to prepare difluoroacetylated arenes from arylboronic acids and difluoroacetate bromide. The reaction allowed difluoroacetylation of a variety of arylboronic acids with excellent functional group tolerance. Mechanistic studies revealed that a difluoroacetyl radical via an SET pathway was involved in the reaction. This s­ trategy can also be extended to (hetero)aryl bromides. Later on, Hartwig and coworkers developed a palladium cross‐coupling of α‐trimethylsilyldifluoroacetamides with (hetero)aryl halides (Scheme  1.37a) [67]. Contrary to Zhang’s method, a palladacyclic complex containing PCy(t‐Bu)2 was used as the pre‐catalyst in this reaction. The mechanistic studies of the reductive elimination from arylpalladium difluoroacetate complexes showed that Xantphos with a wide bite angle facilitates the reductive elimination [68]. Recently, Liao, Hartwig, and coworkers also developed a palladium‐catalyzed cross‐coupling of aryl electrophiles with difluoroacetylzinc generated in situ from the reaction of BrCF2CO2Et with zinc (Scheme 1.37b) [69], providing an alternative route for applications in the synthesis of aryl difluoroacetates.

R1

B(OH)2

+ BrCF2

COR2

Pd(PPh3)4 (5 mol%) Xantphos (10 mol%)

R1

CuI (5 mol%) K2CO3 (4.0 equiv) Dioxane, 80 °C

CF2COR2

53–95%

O MeO

CF2CO2Et

OMe 77%

CF2CO2Et

H

H

OHC

CO2Me F F HN

H 74%

EtO2CF2C

71%

O

t-Bu

91%

Estrone derivative

Scheme 1.36  Palladium‐catalyzed cross‐coupling of arylboronic acids with bromodifluoroacetate and bromodifluoroacetamides.

In addition to palladium‐catalyzed difluoroacetylation of prefunctionalized (hetero)arenes, Buchwald and coworker described a palladium‐catalyzed intramolecular C─H bond difluoroalkylation from chlorodifluoroacetamides with BrettPhos as the ligand (Scheme 1.38) [70]. An intermolecular ruthenium‐catalyzed C–H difluoroacetylation of aromatics was reported by Ackermann and coworkers in 2017 (Scheme 1.39a) [71], in which a cooperative phosphine and carboxylate ligand system was used to promote the C–H difluoroacetylation. The reaction showed high meta‐selectivity with pyridine as the directing group. Mechanistic studies showed that an ortho C–H metalation was the initial step. Subsequently, the resulting ruthenium(II) complex reacted with the difluoroacetyl radical generated via an SET pathway from Ru(II) species to provide meta‐ difluoroacetylated arenes. Simultaneously to Ackermann’s work, Wang and

31

Br + TMSCF CONEt 2 2

R

NEt2 O

Toluene/dioxane (1 : 1) 100 °C, 30 h

CF2CONEt2 R 62–95%

F F

F F

F3C

[Pd] (1–3 mol%) KF (3.0 equiv)

O

82%

NEt2

NEt2

N

O

O

81%

H2N Pd Cl PCy(tBu)2 F F

F F NEt2

O

[Pd]

O

N

62%

67%

(a)

X R

+

BrCF2CO2Et

[Pd(π-cinnamyl)Cl]2 (5 mol%) Xantphos (15 mol%) Zn (1.5 equiv), TBAT (0.380–0.75 equiv) THF, 60 °C, 24 h

X = Br, OTf (b)

Scheme 1.37  Palladium‐catalyzed difluoroacetylation of aryl bromides/triflates.

CF2CO2Et R 42–96%

1.3  Difluoroalkylation of Aromatics OMe

N R2

F F

Pd2dba3 (2 mol%) BrettPhos (8 mol%)

O

R1

CF2Cl

R1

K2CO3 (1.5 equiv) CPME, 120 °C, 20 h

O

MeO i-Pr

PCy2 i-Pr

N R2 52–95%

i-Pr BrettPhos

MeO

OMe F

O

F O

MeO

O N Me

N

MeO Me2N 66%

F F

F F

68%

N Bn

N n-Pr F

F

O

76% Regioisomeric ratio: 5.6 : 1

t-Bu

O O

N

N

MeO 70%

Scheme 1.38  Palladium‐catalyzed intramolecular C─H bond difluoroalkylation with the aid of chlorodifluoroacetamides.

coworkers developed a ruthenium and palladium co‐catalyzed meta‐selective difluoroacetylation (Scheme 1.39b) [72]. Similarly, the ortho C–H metalation by ruthenium(II) was the initial step, but Pd(PPh3)4 was used as the radical initiator for the SET process (Scheme 1.40). Recently, a para‐selective difluoroacetylation of arenes has been reported by Zhao and coworkers with aniline derivatives as the coupling partners, in which a radical process was also involved in the reaction (Scheme 1.41) [73]. Although impressive achievements have been made in copper‐ and palladium‐ catalyzed trifluoromethylation and difluoroalkylation of aromatics, the use of earth‐abundant nickel as a catalyst has been less explored due to the thermal stability of arylnickel(II) fluoroalkyl complexes [74]. In 2014, Zhang and coworkers reported the first example of a nickel‐catalyzed difluoroacetylation of arylboronic acids with Cl/BrCF2CO2Et (Scheme  1.42) [34a]. The reaction exhibited broad substrate scope including drug derivatives and excellent functional tolerance, with inexpensive Ni(NO3)2⋅6H2O as the catalyst and readily available bipyridine (bpy) as the ligand. Notably, a wide range of difluoroalkyl bromides (BrCF2R, R  =  CO2Et, CONR1R2, COAr, COR1, HetAr) were applicable to the reaction. A Ni(I/III) catalytic cycle was proposed for the reaction, in which a nickel(III) facilitates the reductive elimination of the arylnickel(III) fluoroalkyl complex. Recently, Sanford and coworkers confirmed that arylnickel(III) trifluoromethyl complexes [(Ar)(CF3)Ni(III)LnX] are favorable for reductive elimination [75]. Compared to the palladium‐ and copper‐catalyzed difluoroalkylation, the advantage of nickel‐catalyzed process is more general in terms of the substrate scope of difluoroalkyl halides and functional group tolerance. This strategy has also been applied to the nickel‐catalyzed cross‐coupling of bromodifluoroacetamides with arylzinc reagents by using bisoxazoline as the ligand (Scheme 1.43) [76]. In addition to the nickel‐catalyzed difluoroacetylation, the cobalt‐catalyzed cross‐coupling of arylzinc reagents with bromodifluoroacetate has also been reported by Inoue and coworker(Scheme 1.44) [77].

33

DG + BrCF2CO2Et

DG

[Ru] (10 mol%) P(4-C6H4CF3)3 (20 mol%)

i-Pr Ru

Na2CO3 (2.0 equiv) 1,4-Dioxane 60 °C, 18 h

H

Me CF2COEt

MesCO2

31–89%

O O

[Ru]

Mes

CF2CO2Et N

(a)

N CF2CO2Et

CF2CO2Et

OMe

CO2Me

50%

N N

+

BrCF2CO2Et

H

N

75%

[RuCl2(p-cymene)]2 (5 mol%) Pd(PPh3)4 (10 mol%) Na2CO3 (2.0 equiv) Ba(OAc)2 (0.15 equiv) 1,4-Dioxane 90 °C, 24 h

78%

CF2CO2Et

CF2CO2Et

N

CF2COEt 53–84%

CF2CO2Et

N

N N

CF2CO2Et Br

OMe (b)

76%

55%

N n-Bu

DG

N

N

N

N

F

82%

DG

CF2CO2Et

79%

Scheme 1.39  Directing‐group promoted ruthenium‐catalyzed meta‐difluoroacetylation of arenes.

53%

1.3  Difluoroalkylation of Aromatics [RuCl2(p-cymene)]2 R2

N

H

R1 CF2CO2Et Na2CO3, Ba(OAc)2, L

R1

BaCl2

H

Na2CO3

RuCl(OAc)(p-cymene)

NaHCO3, NaOAc

NaOAc, BaCl2, NaHCO3

Me

R2

N

Ba(OAc)2

i-Pr

Me

i-Pr

Ru L

R

Ru Cl R2

N

R2

N

1

1

R CF2CO2Et

Pd(0) NaHCO3, NaBr

H L

SET

Ligand exchange

Pd(I)Br, Na2CO3

Cl–

Me

Me

i-Pr

i-Pr Ru L

Ru L R2

N R1

R2

N R1

H CF2CO2Et

H

F F O

F F

SET

OEt

OEt

Br O

Pd(0)

Pd(I)

Scheme 1.40  Possible mechanism of ruthenium/palladium co‐catalyzed meta‐ difluoroacetylation of arenes with direction groups. O + BrCF2CO2Et H

(X)

O

PPh3 (30 mol%), Ar n-Hexane or 1,4-dioxane 140 °C, 20 h

74%

CF2CO2Et

OH 63%

EtO2CF2C

(X) 36–84%

O

O

OMe

EtO2CF2C

EtO2CF2C

O

Pd(PPh3)4 (5 mol%) KOAc (4 equiv), AgF (30 mol%)

CO2Me S

Me

52%

Scheme 1.41  Palladium‐catalyzed para‐selective C─H bond difluoroacetylation of aryl ketones.

35

36

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes B(OH)2

R1

+

Ni(NO3)2 • 6H2O (2.5–5.0 mol%) bpy (2.5–5.0 mol%)

XCF2R

K2CO3 (2.0 equiv) 1,4-Dioxane, 60–80 °C

X = Br, Cl

CF2CO2Et

CF2CO2Et

CF2CO2Et

CF2CO2Et

EtO2C

MeO

X = Br, 87% X = Cl, 76%a

CF2R

R1

X = Br, 81% X = Cl, 62%a

Br

X = Br, 96% X = Cl, 40%a

X = Br, 95% O

F

F

F H N

F

H

H

N O

O

O

H

F

F

X = Br, 93%

X = Br, 88%

X = Br, 56%

a

5 mol% PPh3 was added.

Proposed mechanism

ArCF2R

ArB(OH)2

XNi(I)Ln

Ar LnNi(III) CF2R

Ar Ni(I)Ln

X BrCF2R

CF2R + Ar–Ni(II)(Ln)Br

Scheme 1.42  Nickel‐catalyzed cross‐coupling of arylboronic acids with functionalized difluoroalkyl bromides and chlorides.

ZnCl + BrCF2CONR2

R

O

F F

TMEDA (1.6 equiv) THF, 0 °C

91%

O 91%

N

N

O

Ph

20–96%

O

F

O 96%

Ph

Ligand

O

F F N

N

N MeO

O

O

NR2 R

F F

O

F F

N O

F F

NiCl2 DME ( 5 mol%) Ligand (6 mol%)

H

O O

Scheme 1.43  Nickel‐catalyzed cross‐coupling of aryl zinc reagents with bromodifluoroacetamides.

72%

1.3  Difluoroalkylation of Aromatics

ZnCl ·TMEDA + BrCF2CO2Et

R

CoCl2 (5 mol%) Ligand (5 mol%) THF, rt

NMe2

CF2CO2Et R

NMe2 48–79%

Ligand O

CF2CO2Et

CF2CO2Et F

CF2CO2Et MeO

53%

79%

70%

74%

CF2CO2Et

O

Scheme 1.44  Cobalt‐catalyzed cross‐coupling of aryl zinc reagents with bromodifluoroacetates.

Br R

F

OTMS

+ F

Ph

Pd(OAc)2 (5 mol%) t-Bu3P (10 mol%) SnBu3F (3.0 equiv) Toluene, 85 °C, 8 h

CF2COPh R 70–91%

CF2COPh

CF2COPh MeO 91%

NC 84%

CF2COPh

CF2COPh

90%

O2N

76%

Scheme 1.45  Palladium‐catalyzed cross‐coupling of aryl bromides with difluoroenol silyl.

1.3.3  Other Catalytic Difluoroalkylations of (Hetero)aromatics In 2007, Shreeve and coworker reported the first example of a palladium‐catalyzed cross‐coupling between aryl bromides and difluoroenol silyl ether with a bulky electron‐rich monophosphine P(tBu)3 as the ligand (Scheme  1.45) [78]. However, toxic tin reagent was needed to promote the reaction and the substrate scope was relatively limited. In this context, Qing and coworkers developed a palladium‐catalyzed cross‐coupling of difluoromethyl phenyl ketone with aryl bromides in the presence of a base (Scheme 1.46a) [79]. This method is synthetically convenient: no need to prepare difluoroenol silyl ether and use toxic tin reagent. Hartwig and coworkers found that the use of a cyclopalladium species as the catalyst could enable the difluoroalkylation with high efficiency and broad scope, even aryl chlorides were suitable substrates (Scheme 1.46b) [80]. Notably, the method can also be used for the preparation of difluoromethylated arenes by debenzoylation of the resulting products ArCF2COPh (Scheme 1.46). In addition to the preparation of ArCF2COAr, the catalytic gem‐difluoroallylation of aromatics has also been reported. In 2014, Zhang and coworkers ­developed a palladium‐catalyzed highly α‐selective gem‐difluoroallylation of arylboronic acids and esters with bromodifluoromethylated alkenes

37

38

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

Br

Pd(OAc)2 (10 mol%) rac-BINAP (20 mol%) Cs2CO3 (2.0 equiv)

O +

R

HF2C

Ar

CF2COAr R

Xylene, 130 °C, 8–12 h

(2.0 equiv) F F

F F O

+

(2.0 equiv)

HF2C

F3C

53%

[Pd] (0.5–2 mol%) Cs2CO3 (2.0 equiv) or K3PO4(H2O) (4 equiv)

O

X R

F F

O

MeO

88%

(a)

52–90%

Ar

Toluene, 100 °C, 24 h

F F

F F O

O 63%

CF2COAr R

HN. Pd P(tBu)Cy 2 Cl [Pd] F F

F F EtO

O

MeO

X = Br, 93% X = Cl, 88%

O 68%

65–93%

(1.0 equiv)

O O

X = Br, 84% X = Cl, 81%

OMe

F F

O

N

X = Br, 86% X = Cl, 77%

X = Br, 80% X = Cl, 80%

One-pot synthesis of difluoromethylated arenes

O

X +

R (1.0 equiv) O

CF2H

O

(b)

X = Br, 92% X = Cl, 82%

(1) [Pd] (1 mol%) K3PO4(H2O) (4 equiv) Toluene, 100 °C, 30 h

HF2C

Ph

(2) KOH/H2O, 100 °C, 2 h

63–99%

(2.0 equiv)

CF2H

CF2H

CF2H TMS X = Br, 95% X = Cl, 94%

CF2H R

EtO2C X = Br, 77%

N X = Br, 83% X = Cl, 79%

Scheme 1.46  Palladium‐catalyzed cross‐coupling of aryl bromides/chlorides with α,α‐ difluoroketones and one‐pot synthesis of difluoromethylated arenes.

(Scheme  1.47) [81]. Contrary to previous works using BrCF2PO(OEt)2 and BrCF2CO2Et as the coupling partners, this reaction was presumed to occur via  a  formal electrophilic difluoroalkylation pathway, probably because of ­stabilization of palladium intermediate by coordination with alkene, thus facilitating the oxidative addition step via a two‐electron transfer process. The high α‐regioselectivity of this reaction (α/γ > 37  :  1) may be ascribed to the strong ­electron withdrawing effect of the CF2 group, which strengthens the Pd─CF2R bond. Remarkably, even when the Pd catalyst loading was decreased to 0.02 mol%, high α‐regioselectivity and good yield of gem‐difluoroallylated arene was still obtained on the 10 g scale reaction, thus demonstrating the good practicality of this protocol. This reaction can also be extended to gem‐difluoropropargylation

1.4 Outlook

B(OH)2 R

R1 +

F F

BrF2C

80% (10 : 1) 10-gram scale

87% (28 : 1)

H2O (0.48 equiv) Dioxane, 80 °C Me F F

F F

BnO

t-Bu

R2

Pd2(dba)3 (0.01–0.4 mol%) K2CO3 (3.0 equiv)

Me

Me

78% (17 : 1)

F F R2

R

R1 60–93%

F F

F F EtO2C Ph

HO 68% (19 : 1)

53% (15 : 1)

Scheme 1.47  Palladium‐catalyzed gem‐difluoroallylation of organoborons with bromodifluoromethylated alkenes.

of arylboronic acids and esters with high efficiency and regioselectivity (Scheme 1.48) [82]. Since carbon–carbon double bond and triple bond are synthetically versatile functional groups, these resulting difluoroalkylated arenes could serve as useful building blocks for diversity‐oriented synthesis, thus offering good opportunities for applications in the organic synthesis and related chemistry. Although impressive progress has been made in the catalytic difluoroalkylation of aromatics, a π‐system adjacent to CF2 is required to activate the difluoroalkylating reagents [4a, 83]. In 2013, Baran and coworkers developed a type of sodium α,α‐difluoroalkylsulfinate (NaSO2CF2alkyl) reagents for direct difluoroalkylation of heteroarenes (Scheme 1.49) [84]. Similar to the difluoromethylating reagent DMFS, the reaction required tBuOOH to furnish the difluoroalkylated heteroarenes via a radical process. Zinc chloride was found to be critical for the reaction. The advantage of this protocol is the synthetic simplicity. However, the modest regioselectivity of this approach restricts its widespread synthetic applications. In 2016, Zhang and coworkers reported a nickel‐catalyzed difluoroalkylation of (hetero)arylboronic acids with unactivated difluoroalkyl bromides (BrCF2–alkyl) (Scheme 1.50a) [34b]. A combined (2 + 1) ligand system was used to facilitate the formal oxidative addition of nickel to the BrCF2–alkyl. The reaction showed broad substrate scope with high efficiency. A nickel‐catalyzed reductive cross‐ coupling between (hetero)aryl bromides and BrCF2–alkyl [85] and an iron‐catalyzed cross‐coupling of arylmagnesiums with BrCF2–alkyl have been reported by the same group (Scheme 1.50b,c) [43]. In 2018, Baran and coworkers also reported nickel‐catalyzed difluoroalkylation of arylzincs with difluoroalkyl sulfones, providing an alternative access to difluoroalkylated arenes (Scheme 1.51) [86].

1.4 ­Outlook We have comprehensively summarized the transition‐metal‐mediated/catalyzed difluoromethylation and difluoroalkylation of (hetero)aromatics. Several new types of difluoroalkylation reactions were developed and provided synthetically

39

F F Ar[B] +

F F

Condition A or B Ar

Br

R

R Condition A: Pd2(dba)3 (0.1–2.5 mol%), P(o-Tol)3 (0.6–15 mol%), K2CO3 or Cs2CO3 (3.0 equiv), dioxane or toluene, 80 °C, 24 h [B] = B(OH)2 F F F F F F TIPS Br

EtO2C

80%, gram scale

TIPS

[B] = Bpin F F

5

48%

O

TIPS

O

57%

60%

Condition B: NiCl2·dppe (2.5 mol%), bpy (2.5 mol%), K2CO3 (2.0 equiv), dioxane, 80 °C, 24 h

[B] = B(OH)2 F F

F F TIPS

EtO2C

92%

F F TIPS

Br

77%

F F TIPS

NC

39%

TIPS O

Scheme 1.48  Palladium‐ or nickel‐catalyzed gem‐difluoropropargylation of arylboronic reagents.

82%

1.4 Outlook

Het

H

DAAS-Na (3.0 equiv) ZnCl2 (1.5 equiv) t-BuOOH (5.0 equiv) TsOH·H2O or TFA (1.0 equiv) CH2Cl2:H2O or DMSO:H2O (2.5 : 1)

CF2(CH2)6N3

N O Et

Me2N

N3

5

F F DAAS-Na

N

CF2(CH2)6N3 N

NMe2 AcO

82%

OH O

Camptothecin

NaO

CF2(CH2)6N3

CF2(CH2)6N3

O

N

42%

Het

O S

OAc

50%

Acridine orange

Bisacodyl

MeO 8%

MeO MeO

17%

N

Me

NH

9%

9% H

H

MeO

O

H

N

N

N

H

H 16%

Nevirapine

Papaverine

Scheme 1.49  C─H bond difluoroalkylation of heteroarenes with DAAS‐Na.

B(OH)2 R

+ BrCF2Alkyl

F

F

Ph

F

3

NiCl2·DME (5–10 mol%) ditBuBpy (5–10 mol%) DMAP (20 mol%)

Ph

F

3

K2CO3 (2.0 equiv) Triglyme, 80 °C

F F

OH

t-Bu

CF2Alkyl

R

t-Bu

N N ditBuBpy

32–95% NBoc

F

F F Ph 4

F N N

92% a

SO2Me 78%

Ac 72%

F

83%a

46%

HetArB(OiPr)3Li was used.

(a) Br R

+ BrCF2Alkyl

NiBr2·diglyme (5 mol%) L2 (5 mol%) NaI (80 mol%) Zn (1.2 equiv) 3 Å MS, DMPU, 80 °C

Br

(c)

+ BrCF2Alkyl

FeI1 (10 mol%) L1 (5 mol%) THF/dioxane, rt, 90 min

MeO

OMe

N 35–88%

(b)

R

CF2Alkyl

R

N L2

CF2Alkyl

R

Me2N 24–90%

L1

NMe2

Scheme 1.50  Nickel‐ or iron‐catalyzed difluoroalkylation of aromatics with unactivated difluoroalkyl bromides.

41

42

1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes ZnCl R1

+

R2

O

S

Ph N N N N

O

F F

Ni(acac)2·xH2O (5 mol%) bpy (5.5 mol%) THF/NMP, rt

CF2R2

R1

F F F F

MsN

Me O

O 55%

NBoc

F 41%

F F

N 44%

OiPr O

Scheme 1.51  Nickel‐catalyzed difluoroalkylation of aryl zinc reagents with difluoroalkylated sulfones.

convenient and cost‐efficient methods to prepare difluoroalkylated arenes that are of great interest in life and materials sciences. In particular, a new mode of difluoromethylation reaction, i.e. catalytic MeDIC, has been developed, which expands our understanding of metal difluorocarbene chemistry, and should influence future thinking in the field. Mechanistic studies on difluoroalkylation reactions showed the differences between organofluorine chemistry and classical C–H chemistry, and thus it is imperative to develop new chemistry for fluoroalkylation reactions. In future works, the development of environmental benign, cost‐efficient, and highly regioselective difluoroalkylation reactions from inexpensive fluorine sources remains necessary. In particular, the direct C–H difluoroalkylation of heteroarenes with high regioselectivity and broad substrate scope should be considered in pharmaceutical, agrochemical, and advanced material applications. To meet the increasing demand from life science, such as design of bioactive peptides, protein engineering, probes for the investigation of enzyme kinetics, diagnosing neurodegenerative diseases and so on, the development of biocompatible fluoroalkylations, including site-selective fluoroalkylation of peptides, proteins, oligocarbohydrates and DNA, would be a promising research area.

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32 33 34

35

36 37 38 39 40 41

42 43 44 45 46 47 48 49 50

51 52

53

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1  Difluoromethylation and Difluoroalkylation of (Hetero) Arenes

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47

2 Difluoromethylation and Difluoroalkylation of Aliphatic Unsaturated C=C, C≡C, and −N=C Bonds Sebastian Barata‐Vallejo and Al Postigo Universidad de Buenos Aires, Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Junín 954, Buenos Aires, CP1113, Argentina

2.1 ­Introduction The preparation of organofluorine compounds is an area of considerable importance in pharmaceutical, agrochemical, and materials science, as the introduction of fluoro substituents into organic molecules has a profoundly positive impact on their physical properties, including metabolic stability, solubility, and lipophilicity. The fluorine atom is widely acknowledged to be a valuable heteroatomic hydrogen surrogate. Among various fluoroalkyl groups, the difluoromethyl group has been given particular attention in medicinal chemistry, because the CF2H moiety is isosteric and isopolar to the hydroxyl and thiol groups acting as a lipophilic hydrogen bond donor. This simultaneously harnesses the electronegativity of the fluorine atoms to emulate the oxygen (or sulfur) lone electron pairs while rendering the methane proton acidic and a competent hydrogen bond donor [1]. Thus, considerable research efforts have been devoted to the efficient introduction of difluoromethyl groups into organic compounds. However, compared to the well‐established trifluoromethylations, methods for the corresponding difluoromethylation reactions remain scarce and challenging. The presence of the difluoromethyl group in a compound can also induce conformational changes and dipole moment alterations, along with increasing the acidity of neighboring groups, thus modulating the pKa of proximal functional groups. At least eight FDA‐approved drugs contain the difluoromethyl group (Figure 2.1), and 74 drugs the trifluoromethyl one (https://www.drugbank.ca). Different approaches for the syntheses of compounds containing the difluoromethyl moiety have been reported, including the deoxofluorination of aldehydes with SF4, DAST (N,N‐diethylaminosulfur trifluoride), and its derivatives [2], as well as nucleophilic, electrophilic (reagents 1–5, Figure 2.2), and radical difluoromethylations [3]. Alternatively, the difluoromethylation of heteroatom nucleophiles with a difluorocarbene reagent has also been developed for the direct preparation of compounds containing the difluoromethyl group [4]. Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

48

2  Difluoromethylation and Difluoroalkylation of Aliphatic Unsaturated C=C, C C, and −N C Bonds F

F

N

H N

O

N

O O

O

F

Me

N

O

O O S N H O

NH O

N

N

O

O

F

F

O O S N H O

NH O

F

N

H N

O

Glecaprevir

O O

F

F

Voxilaprevir

F

N H N

O

F

O

F F

Cl

N

N

F

F

N

N

Isopyrazam

O

F N

F

N

Fluxapyroxad

O

F

NH N

F

N

Sedaxe

O

F

N

Cl

Bixafen

F

N H

F

N

Cl

O

F

N H

F

NH

F

F

N

Cl

Isoflucypram

Benzovindiflupyr

Figure 2.1  FDA‐approved drugs that contain the difluoromethyl group.

O +

S

N

BF4–

+

CF2H

S CF2H BF4– 1, Prakash

2, Prakash and Olah

MeO2C

–

S

CO2Me +

CF2H

O2N

OMe

HF2C + S OMe BF4–

4, Shen

O

Ts N S CF2H

3, Hu

MeO

N

5, Liu

Figure 2.2  Electrophilic difluoromethylating reagents.

Cl

2.2  Difluoromethylation of C═C Double Bonds O S

Zn(CF2HSO2)2 6

Br

O–

Na+

F F 7

Figure 2.3  Structures of zinc difluoromethylsulfinate 6 and sodium 2‐(4‐bromophenyl)‐1,1‐ difluoroethanesulfinate 7.

Other commercially available reagents, such as sodium difluoromethanesulfinate NaSO2CF2H, zinc difluoromethanesulfinate 6 [3c], and sodium 2‐(4‐bromophenyl)‐1,1‐difluoroethanesulfinate 7 (Baran’s reagents), are currently employed in difluoromethylation radical chemistry reactions (Figure 2.3). The study of synthetic pathways to introduce the CF2R moiety (R ≠ H, F) into organic substrates is also relevant, since many compounds that contain the CF2R functionality have found vast applications in medicinal chemistry and agrochemistry. All synthetic methods for the late‐stage introduction of the CF2R moiety (R ≠ H, F) are summarized in Table 2.1. Three main methodological protocols will be presented in this chapter for the late stage introduction of the CF2H or CF2R moieties into organic substrates: (i) the metal‐photoredox catalysis (PC), (ii) transition‐metal‐catalyzed thermal protocols, and (iii) transition‐metal‐free strategies. In 2017, there have been reviews describing the difluoromethylation strategies to achieve late‐stage CF2R introduction into aliphatic CC multiple bonds [33]. All these methods are summarized in Tables 2.1 and 2.2 and will not be discussed in detail in this chapter. Significant research activity in this field has been conducted since 2017 [33], which justifies a comprehensive treatment of the new difluoromethylation reactions for accomplishing CF2 introduction into aliphatic CC and CN multiple bonds. This chapter illustrates the new examples of difluoromethylation reactions realized on olefinic C(sp2), isocyanides, and alkynyl C(sp) moieties and summarizes all the previous reported methodologies together with the new strategies in comprehensive Tables 2.1 and 2.2, which are organized according to the difluoromethylating reagents used.

2.2 ­Difluoromethylation of C═C Double Bonds Difluoromethylation reactions of olefinic C═C double bonds largely proceed through the addition of the CF2R radical species, producing a radical adduct that can undergo a hydrogen atom transfer (HAT) or oxidation to a carbocation intermediate with ulterior deprotonation, or nucleophilic addition. Generation of the CF2R radical can be accomplished through diverse methods, such as photocatalysis or thermal procedures with possibly the intervention of metal catalysis. The sources of the CF2R radical are varied and could involve the use of difluoromethylphosphonate BrCF2P(O)(OR)2, phosphobetaine salt Ph3P+CF2CO2−, ­difluoroacetic acid HCF2CO2H, Selectfluor, and more commonly ethyl bromodifluoromethyl acetate BrCF2CO2Et or amide BrCF2CONR2.

49

56

2  Difluoromethylation and Difluoroalkylation of Aliphatic Unsaturated C=C, C C, and −N C Bonds

2.2.1  Intermolecular Difunctionalization of C=C Double Bonds 2.2.1.1  By Means of BrCF2P(O)(OR)2

The difluoromethylphosphonate motif, as an isosteric and electronic phosphate mimic, is a very relevant functional group, which mimics the tetrahedral transition state in peptide hydrolysis, and enables difluoromethylphosphonate‐containing molecules to be used as phosphatase inhibitors. Therefore, difluoromethylphosphonate reagents have been documented, in particular for the phosphonodifluoromethylation of alkenes through diverse processes, such as nucleophilic addition [45], transition‐metal catalysis [46], PC (by oxidative quenching cycles) [24], or radical atom transfer radical addition (ATRA) reactions [47, 48], as depicted in Scheme 2.1 (summarized in Table 2.1, entries 19–22). Anionic nucleophilic addition

R2

MCF2PO(OEt)2

X Y

R1

R2

X Y

R1 CF2PO(OEt)2

Transition-metal catalysis

O

N

+ BrCF2PO(OEt)2 + ArB(OH)2

4,4′-DiMeO-bpy (5 mol%) NiCl2-DME (2 mol%) Base, Δ

CF2PO(OEt)2 N

8 PC*/PC+

O

photoredox catalysis R2

2 mol% fac-Ir(ppy)3 Base, blue LED

O R2N R1

+

N O

BrCF2PO(OEt)2

CF2PO(OEt)2

8

Radical ATRA reaction R

+

BrCF2PO(OEt)2 8

R

+

PhXCF2PO(OEt)2

Br

Na2S2O4 Δ

R

CF2PO(OEt)2

AIBN, n-Bu3SnH, Δ or UV irradiation

R

CF2PO(OEt)2

Scheme 2.1  Strategies for constructing C(sp3)─CF2PO(OEt)2 bonds.

More recently, Huang et al. have accomplished the visible light‐induced catalytic hydrophosphonodifluoromethylation of mono‐ and disubstituted alkenes using BrCF2PO(OEt)2 8 with a Hantzsch ester (HE) as the terminal reductant [27]. The combination of thiyl radical species (HSAcOMe) with photoredox catalyst is important for achieving good chemoselectivity and high yields (Scheme 2.2). Based on control experiments, the authors postulated a mechanism (Scheme 2.3) [27]. First, a thiyl radical RS˙ generated from methyl 2‐mercaptoacetate HSAcOMe abstracts a hydrogen atom from the Hantzsch ester Et–HE,

Et–HE =

O R1 R2

+ BrCF2PO(OEt)2 8

fac-Ir(ppy)3 (0.2 mol%) Blue LEDs, Et–HE (1.5 equiv)

R1

K2CO3, HSAcOMe (10 mol%) MeCN, rt, 48 h

CF2PO(OEt)2

O

EtO

OEt

R2

N H

Selected examples

OTs CF2PO(OEt)2 4

Br

3

77%

52%

O 5

O 60%

84%

O (EtO)2OPF2C

(EtO)2OPF2C

CF2PO(OEt)2

(EtO)2OPF2C O

4 CF2PO(OEt)2

O

51%

H

O 5

O

O

60%

Scheme 2.2  Hydrophosphonodifluoromethylation of alkenes.

(EtO)2OPF2C

O 4

H 35%

O

O

EtO

R1 OEt

H

N H O

O

EtO

O OEt

N 12

EtO

SET

IrIII(ppy)3*

HAT

OEt N H

HAT RSH

9 • CF2PO(OEt)2

IrII(ppy)3

hν

14

RS•

O

•

CF2PO(OEt)2

R2

SET

10

R1 R2

IrIII(ppy)3

R1 CF2PO(OEt)2

R2

•

13 BrCF2PO(OEt)2

11

8

Scheme 2.3  Plausible reaction pathway for hydrophosphonodifluoromethylation of alkenes.

2.2  Difluoromethylation of C═C Double Bonds

g­ iving rise to a thiol and Et–HE radical 9. Radical 9 is sufficiently reductive (E1/2 red  99%)

CF2CO2Et

F

H3CO 85% (E/Z = 62 : 1)

CF2CO2Et

R

O2N 75% (E/Z >99 : 1) CF2CO2Et

CF2CO2Et 73% (>99 : 1)

Scheme 2.32  Hydrodifluoroalkylation of alkynes.

CF2CO2Et

34% (E/Z = 1.6 : 1) OH CF2CO2Et

77% (E/Z = 29 : 1)

67% (E/Z > 99 : 1)

­  References

cp2Fe (10 mol%) CF2HSO2NHNHBoc (2 equiv)

R2

Ar1

N R1

Ar2

O

HF2C Ar2 Ar1

Et4NBF4, NaHPO4 MeOH, 70 °C, 13 mA

N R1

R2

O 43–79%, 29 examples

Scheme 2.33  Electrochemical difluoromethylation of alkynes.

s­ ubstrates: metal‐mediated photocatalytic and thermal processes and transition‐ metal‐free difluoromethylation reactions. However, few of the photocatalytic strategies presented involve all‐organic photocatalysts. Further work is needed in photocatalysis, especially in transition‐metal‐free strategies involving organic dyes and other metal‐free organic compounds aimed at producing the CF2 radical species. This is of particular concern in the pharmaceutical industry to avoid the use of transition metals. Another area that deserves particular attention, in terms of difluoromethylation strategies, is the application of flow systems to achieve CF2H substitutions in high yields and minimal reaction times. This area, that is, flow systems, has received particular attention for trifluoromethylation, perfluoroalkylation, and fluorination reactions; however, few reports of a difluoromethylation flow system have been documented.

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85

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2  Difluoromethylation and Difluoroalkylation of Aliphatic Unsaturated C=C, C C, and −N C Bonds

5 6 7 8 9 10 11 12 13 14 15

16 17 18 19 20 21 22 23 24

25 26 27 28 29 30 31 32 33

34 35 36 37 38

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87

89

3 Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds Qiqiang Xie and Jinbo Hu Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, Key Laboratory of Organofluorine Chemistry, 345 Lingling Road, Shanghai 200032, China

3.1 ­Nucleophilic Difluoromethylation and Difluoroalkylation 3.1.1  By Means of XCF2PO(OEt)2 Due to the facile C─F bond cleavage in HCF2Li or HCF2MgX reagents, direct difluoroalkylation with these reagents is difficult. However, when the H atom of CF2H group is substituted by a proper electron‐withdrawing group or changing the hard Li or Mg to other soft metals, the corresponding RCF2M can be syntheti­ cally useful. Burton et al. reported that the reaction between BrCF2PO(OEt)2 and Cd would generate a stable organocadmium reagent, which can react with allyl bromide (Scheme  3.1a) [1]. Allylation of [(diethoxyphosphinyl)difluoromethyl] zinc bromide can also be accomplished under copper catalysis [2]. Obayashi et al. reported that LiCF2PO(OEt)2, generated from HCF2PO(OEt)2 and lithium diiso­ propylamide (LDA) at −78 °C, could react with alkyl bromides, allylic bromides, aldehydes, and ketones, giving the corresponding difluoroalkylated products (Scheme  3.1b) [3]. An improved method for the synthesis of 1,1‐difluoro‐2‐ hydroxyalkylphosphates was demonstrated by Obayashi and Kondo using Me3SiCF2PO(OEt)2/CsF [4]. Similar protocol was used by Prakash and coworkers to achieve difluoromethylenation of aldehydes and ketones [5]. 3.1.2  By Means of BrCF2CO2Et and BrCF2CH═CH2 In 1984, Fried and coworker reported that BrCF2CO2Et could undergo facile Reformatsky addition to aldehydes and ketones (Scheme 3.2a) [6]. This method have found many applications for the incorporation of –CF2C(O)– group or its derivatives [7]. In 1989, Burton and coworker reported that the reaction of BrCF2CH═CH2, zinc powder, and aldehydes or ketones provides a useful route to gem‐difluoro homoallylic alcohols (Scheme 3.2b) [8]. Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

90

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds O EtO P CF2Br EtO

O

Cd

O

LDA

EtO P CF2H EtO

Br

[(EtO)2POCF2CdBr] + [(EtO)2POCH2F2]2Cd

EtO P CF2Li EtO

THF, −78 °C

CF2PO(OEt)2

(a)

O (1) R

OH

R′

(2) H2O

R

CF2PO(OEt)2

(b)

R′

Scheme 3.1  Nucleophilic difluoroalkylation with XCF2PO(OEt)2. (a) for X = Br and (b) for X = H.

R

R′ O

R

OH

BrCF2CO2Et

O

Zn

R

BrCF2CHCH2 R′

Zn

CF2CO2Et

(a)

CF2CHCH2

(b)

R′ OH

R

R′

Scheme 3.2  Reformatsky‐type nucleophilic difluoroalkylation with BrCF2CO2Et and BrCF2CH═CH2.

3.1.3  By Means of Difluoromethylcadmium, Difluoromethylcopper, and Difluoromethylzinc Reagents In 1988, Burton and coworker found that difluoromethylcadmium can be pre­ pared from HCF2I or HCF2Br with acid‐washed cadmium powder in N,N‐ dimethylformamide (DMF) (Scheme 3.3a) [9]. The formed difluoromethylcadmium is a mixture of mono‐ and bis‐difluoromethylcadmium. Difluoromethylzinc can be prepared in a similar way. Difluoromethylcopper can be easily prepared from metathesis between difluoromethylcadmium and CuBr or CuCl at temperatures ranging from −50 to −60 °C (Scheme 3.3b) [10]. Both difluoromethylcadmium and difluoromethylcopper could undergo allylic difluoromethylation reaction (Scheme  3.3c) [9, 10]. Difluoromethylcopper could also react with strong alkylating reagents, such as benzyl bromide and chloromethyl ethyl ether [10]. In 2016, Mikami and coworkers reported that bis(difluoromethyl)zinc reagent (DMPU)2Zn(CF2H)2 can be prepared by the reaction of ZnEt2 and HCF2I [11]. (DMPU)2Zn(CF2H)2 was applied to the copper‐catalyzed allylic difluorometh­ ylation of allyl carbonates (Scheme 3.3d) [12] and copper‐catalyzed decarboxyla­ tion difluoromethylation (Scheme 3.3e) [13]. 3.1.4  By Means of Difluoroalkylated Sulfone Reagents (XCF2SO2Ar) and Difluoromethylated Sulfoxides Difluoromethyl phenyl sulfone (PhSO2CF2H) was first prepared by Hine and Porter [14], but its application as a difluoromethylation reagent was largely over­ looked for about three decades. In 1989, Stahly reported nucleophilic addition of PhSO2CF2H to aldehydes in a two‐phase system, and the PhSO2 group could be removed under Na/EtOH conditions (Scheme 3.4a) [15]. This seminal report

3.1  Nucleophilic Difluoromethylation and Difluoroalkylation

HCF2I

Cd, DMF, rt,1 h

HCF2CdX

91%

−50 °C to −60 °C >90%

HCF2CdX

Br

+

HCF2Br

(a)

65–75%

(X = Br, I)

CuBr, DMF

HCF2CdX

Cd, DMF, 50 °C, 5d

+ (HCF2)2Cd

HCF2Cu

(b)

DMF, 0 °C to rt, 4h

CF2H

(c)

85% (DMPU)2Zn(CF2H)2 (1.7 equiv) CuI (10 mol%)

Br R

CF2H

R′

(d)

R′

R DMPU, 40 °C, 24h

CO2H

CO2A∗

Cl4NHPI DIC, DMAP

CF2H

(DMPU)2Zn(CF2H)2 CuCl (cat.), bpy

(e)

Activation

DMSO, 60 °C

Scheme 3.3  Preparation and application of difluoromethylcadmium copper and zinc reagents.

PhSO2CF2H 50% NaOH, CH2Cl2

O R

Aliquat 336 (cat)

OH R

CF2SO2Ph

R

CF2SO2Ph

PhSO2CF2H, t-BuOK R

X

R′

THF/HMPA (10 : 1) −78 °C

O

R

t-Bu

R

CF2H

R

CF2H

(a)

R′

CF2SO2Ph

(b)

OH

Na (Hg) R

Na2HPO4, MeOH

R′

CF2H

(c)

O

N

O X S O O

O Ar

S

R

R Na (Hg) Na2HPO4, MeOH

OH

PhSO2CF2H, LiHMDS

O R

DMF, −50 °C, 1h

OH

Na, EtOH

R CF2H t-Bu S N R′ H Up to > 99 : 1 dr

(1) PhSO2CF2H, Base, −78 °C R′

(2) Na (Hg) or Mg, HOAc, NaOAc

XH

1) PhSO2CF2H, LiHMDS, THF/HMPA, −78 °C R

2) 20% aqueous H2SO4 3) Mg, HOAc, NaOAc

CF2H

(e)

X = O, NPG OH

PhSO2CF2H, chiral PTC (10 mol%) KOH (4 equiv), PhCH3

(d)

Ar

∗

CF2SO2Ph Up to 64% ee

Scheme 3.4  Nucleophilic difluoromethylation with PhSO2CF2H.

(f)

91

92

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

showcased the difluoromethylating ability of PhSO2CF2H but did not catch much attention until recently. Prakash et al. and Hu and coworkers made contri­ butions to the synthetic application of PhSO2CF2H as an efficient difluoro­ methylation reagent. In 2004, Prakash et  al. reported a facile nucleophilic difluoromethylation of primary alkyl halides through a nucleophilic substitu­ tion‐reductive desulfonation strategy (Scheme 3.4b) [16]. Later on, Hu et al. sys­ tematically studied the reaction of PhSO2CF2H with various electrophiles. Aldehydes and ketones [17], imines [18], and cyclic sulfates and sulfamidates [19] are all amenable substrates, and the desired C(sp3) phenylsulfonyldifluoro­ methylated products can be obtained in good yields (Scheme  3.4c–f ). The PhSO2 group can be successfully removed by either Na (Hg) or Mg/HOAc/ NaOAc to give the difluoromethylated products. It should be noted that, although strong bases were required to generate the anion PhSO2CF2−, both non‐enolizable and enolizable carbonyl compounds and imines are tolerated (Scheme 3.4c,d) [17a]. High diastereoselectivity was observed in the reaction of N‐tert‐butylsulfinyl imines (Scheme  3.4d) [18], while only moderate ee values were achieved in the chiral quaternary ammonium salt‐catalyzed enantioselec­ tive nucleophilic difluoromethylation of aromatic aldehydes with PhSO2CF2H (Scheme 3.4f ) [17b]. Since a strong base is required in the difluoromethylation with PhSO2CF2H, Hu and coworker developed a new difluoromethylating reagent, PhSO2CF2SiMe3, which can readily undergo difluoromethylation reaction in the presence of cata­ lytic amount of fluoride [20]. PhSO2CF2SiMe3 showed similar reactivity with PhSO2CF2H, except that it gave better results in the reaction with enolizable aldehydes [20, 21]. PhSO2CF2SiMe3 was also able to react with alkyl halides and N,N‐acetals [22]. PhSO2CF2Br can also be used as a nucleophilic difluoromethylation reagent. In 2005, Prakash et al. reported that tetrakis(dimethylamino)ethylene (TDAE) is an effective electron‐transfer agent to promote the reaction of PhSO2CF2Br with aldehydes (Scheme  3.5a) [23]. In 2017, Hu and coworkers reported that PhSO2CF2Br can be transformed to the corresponding organozinc and cadmium reagents, which are efficient difluoromethylating reagents toward aldehydes (Scheme 3.5b,c) [24].

O R

+

PhSO2CF2Br

PhSO2CF2Br

PhSO2CF2Br

Zn, TMSCl DMF Cd, TMSCl DMF

Me2N

NMe2

Me2N

NMe2

DMF, −78 °C to rt [PhSO2CF2ZnX]

[PhSO2CF2CdX]

OH R

CF2SO2Ph OH

RCHO DMF, rt

R

Scheme 3.5  Nucleophilic difluoromethylation with PhSO2CF2Br.

CF2SO2Ph

(b)

OH

RCHO LiCl, DMF, rt

(a)

R

CF2SO2Ph

(c)

3.1  Nucleophilic Difluoromethylation and Difluoroalkylation

In 2010, Hu and coworkers reported that difluoromethyl 2‐pyridyl sulfone, a previously unknown reagent, is an efficient gem‐difluoroolefination reagent [25]. In 2012, by using difluoromethyl 2‐pyridyl sulfone, Hu and coworkers real­ ized the formal nucleophilic iodo‐ and bromodifluoromethylation of carbonyl compounds (Scheme 3.6) [26]. The key to success is the halogenation of in situ generated sulfinate intermediates from the Julia−Kocienski reaction to change the reaction pathway from the traditional olefination to alkylation. O O S CF2H N

(1) t-BuONa, DMF, −78 to 5 °C

O

+

R

R′

(2) NBS or NIS

O(2-Py) R

R′

CF2Br/I

Scheme 3.6  Nucleophilic bromo‐ and iododifluoromethylation with difluoromethyl 2‐pyridyl sulfone.

In 2018, Xiao and coworkers found that phenylsulfonyl difluoroacetate salt (PhSO2CF2CO2K) could directly undergo decarboxylation upon mild heating to produce PhSO2CF2− without the need of any base or additive; therefore difluoro­ methylation of aldehydes and imines can be achieved using PhSO2CF2CO2K (Scheme 3.7) [27]. PhSO2CF2CO2K

X

+

R

H

R

XH

CH3CN, 50 °C, 7h

Scheme 3.7  Nucleophilic difluoromethylation with PhSO2CF2CO2K.

Difluoromethyl sulfoxides have also been used as difluoromethylation reagent. Hu and coworkers disclosed that difluoromethyl phenyl sulfoxide can undergo direct addition to aldehydes and ketones in the presence of t‐BuOK (Scheme 3.8a) [28]. The yields are good, while the diastereoselectivity is poor (1 : 1.04–2.03). In  2018, Leroux and coworkers reported that chiral difluoromethyl sulfoxides can be prepared and used for the synthesis of highly enantioenriched α,α‐­ difluoromethyl alcohols (Scheme 3.8b) [29]. O S

CF2H

+

CF2H

+

O R

CH3CN, 50 °C, 7h R′

O S

PhCHO

P4t-Bu in THF –30 °C

97% ee

OH

O

(a)

S R Ph R′ F F O

OH

S

Ph

F F 43%, 97 : 3 dr, 97% ee

Scheme 3.8  Nucleophilic difluoromethylation with difluoromethyl sulfoxides.

(b)

93

94

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

3.1.5  By Means of Difluoroalkylated Silanes and Trifluoromethylsilane Reagents In 1995, Fuchikami and Hagiwara demonstrated that nucleophilic difluorometh­ ylation of carbonyl compounds could be achieved using difluoromethyldi­ methylphenylsilane and difluoromethyltrimethylsilane (TMSCF2H) at elevated temperatures (Scheme 3.9a) [30]. However, this method only works well for non‐ enolizable aldehydes, and the yields are generally low for ketones and enolizable aldehydes. Because of the harsh reaction conditions and narrow substrate scope, several modified methods were reported [31]. Remarkably, in 2016, Hu and cow­ orkers disclosed an efficient protocol for the difluoromethylation of enolizable ketones using TMSCF2H (Scheme 3.9b) [31d]. The key to success is the forma­ tion of [Me3Si(CF2H)2]−, a key intermediate that acts as both the difluorometha­ nide anion source and difluoromethanide reservoir. TMSCF2H has also been used for the difluoromethylation of imines (Scheme 3.9c) [31b]. (1) KF (5 mol%), DMF, 100 °C, 6–48 h

O Si CF2H

+

R1 R1 = Ph or CH3

R′

R

+

R

R CF2H R′ 20–82% yield

(2) H3O+

(1) CsF/18-crown-6, DME, rt, overnight

O Si CF2H

OH

R′

(2) TBAF, rt, 1 h (3) HCl, rt, 1 h

OH

Si CF2H

+ t-Bu

O

t-BuOK N

R

THF, –78 °C to rt

(b)

R CF2H R′ 43–95%

O S

(a)

t-Bu

S

CF2H N H

R

(c)

Scheme 3.9  Nucleophilic difluoromethylation with TMSCF2H.

Trifluoromethyltrimethylsilane (TMSCF3) is a well‐known trifluoromethyla­ tion reagent. However, it can also be used as a formal difluoromethylation rea­ gent. In 2006, Prakash et  al. reported that the reaction of TMSCF3 with unactivated imines in the presence of half a molar of tetramethylammonium fluoride and then reduction with NaBH4 delivered the difluoromethylated amines (Scheme 3.10a) [32]. The mechanism involves the elimination of HF from trimethylsilyl (TMS)‐protected trifluoromethylated amines to produce difluoro­ methylated imines, which can be reduced to difluoromethylated amines. Portella et al. reported that the reaction between acylsilanes and TMSCF3 would produce difluoroenol silyl ethers, which can serve as electrophiles to react with amino alcohols to give difluoromethylated oxazolidines (Scheme 3.10b) [33]. Recently, Prakash and coworkers realized the difluoromethylation of aldehydes using a combination of TMSCF3/LiI/PPh3, in which difluoromethylene phosphonium ylide is the key intermediate (Scheme 3.10c) [34].

3.1  Nucleophilic Difluoromethylation and Difluoroalkylation

R

N

R′

+ TMSCF3

CF2H

TMAF (0.5 equiv) THF, rt

Ph O

+ TMSCF3 SiMe3

F–

OTMS F

(b)

CF2H OH

(1) LiI, PPh3, LiBF4, TMSCF3, DMPU/CH3CN, 85 °C

R

(a)

O

HN

PPTS (cat)

F CHO

R′

Ph

OH

H2N

N H

R

EtOH

N R′

R

CF2H

NaBH4

(c)

CF2H

R

(2) aq. KOH, rt

Scheme 3.10  Nucleophilic difluoromethylation with TMSCF3.

Phenylthiodifluoromethyltrimethylsilane (PhSCF2TMS) is also a widely stud­ ied difluoromethylation reagent. It was first prepared by Prakash et al. in 2005 for phenylthiodifluoromethylation of carbonyl compounds (Scheme  3.11a) [35]. Later on, Hu and coworker developed a new synthetic application of PhSCF2TMS as a difluoromethylene radical anion synthon for the synthesis of chiral 2,4‐dis­ ubstituted 3,3‐difluoropyrrolidines (Scheme 3.11b) [36]. Its reaction with alkyl halides was also explored [37]. Pohmakotr et al. also applied PhSCF2TMS for the synthesis of various difluoromethylene‐containing molecules [38].

R

S

R

(2) TBAF

R′

O t-Bu

OH

(1) PhSCF2TMS, TBAT (10 mol%)

O

N

R

TBAT

t-Bu

S

(a)

CF2SPh

(1) HCl, MeOH CF2SPh (2) Allylic bromide, K2CO3

O

PhSCF2TMS

R′

N H

R

F F R

(3) Bu3SnH, AIBN

(b)

N H

Scheme 3.11  Nucleophilic difluoromethylation with PhSCF2TMS.

PhSeCF2TMS [39], heteroaryl‐N‐difluoromethyltrimethylsilanes [40], TMS CF2CN [41], TMSCF2Cl, and TMSCF2TMS [42] were also used for the difluoro­ methylation of carbonyl compounds. Recently, Zhang and coworkers developed the first example of copper‐catalyzed stereospecific difluoroalkylation of sec­ ondary propargyl sulfonates with TMSCF2CONEt2 (Scheme 3.12) [43]. O O S O

O

Alkyl TIPS

TMSCF2CONEt2 CuCN (30 mol%) KF (2 equiv)

CF2CONEt2 Alkyl

DMF, 40 °C

Scheme 3.12  Nucleophilic difluoromethylation with TMSCF2CONEt2.

TIPS

95

96

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

3.1.6  By Means of Difluoromethyl Sulfoximine Reagent In 2012, Hu and coworkers developed a novel chiral difluoromethyl sulfoxi­ mine  reagent, (R)‐N‐tert‐butyldimethylsilyl‐S‐difluoromethyl‐S‐phenylsulfoxi­ mine, which can be readily used for the stereoselective difluoromethylation of aryl ketones (Scheme 3.13a) [44]. The nature of N‐substituent was found to be crucial for the success of this reaction. Subsequently, nucleophilic substitution of epoxides and alkyl halides with PhSO(NTBS)CF2H were also accomplished (Scheme 3.13b,c) [44].

O

+ R′

R O

+

O NTBS S Ph CF2H

+

O NTBS S Ph CF2H

R′

R

RX

O NTBS S Ph CF2H

(1) KHMDS, THF, –98 °C, 0.5 h (2) 12 M HCl, –98 °C to rt, 1 h

R′

OH

(3) Mg/HOAc/NaOAc

R

CF2H

OH F F

(1) BF3∙Et2O, THF, –78 °C, 3 min (2) LiHMDS, –78 °C, 0.5 h then 12 M HCl (aq) LiHMDS THF/HMPA, –78 °C, 0.5 h

(a)

Ph S O NH R′

R

O NTBS S CF2R

Ph

(b)

(c)

Scheme 3.13  Nucleophilic difluoromethylation with PhSO(NTBS)CF2H.

3.1.7  Miscellaneous Reagents Apart from the abovementioned kinds of reagents, many others have also been used for nucleophilic difluoromethylation reaction. ArCF2Br [45], PhXCF2H (X  =  S, Se, Te) [46], ArCF2H [47], difluoroolefines [48], and ArCOCF2CO2H [49]  have been applied for the difluoroalkylation of carbonyl compounds. Difluoroenol silyl ethers were used to the oxidative difluoromethylation of ter­ tiary amines [50]. Notably, trifluoromethyl α,α‐difluorinated β‐keto gem‐diols were used for the asymmetric difluoroalkylation of aldehydes using copper(II) triflate as the catalyst and chiral bisoxazoline as the ligand (Scheme 3.14a) [51]. In 2014, Dilman and coworkers reported that difluoromethylene phosphabe­ taine can be used for the difluoromethylation of Michael acceptors, aldehydes, and azomethines (Scheme 3.14b) [52]. This reaction proceeds via the addition of in situ generated difluorinated phosphonium ylide to the electrophiles, followed by hydrolysis of the C─P bond. Interestingly, Xiao and coworkers found that DFPB ([Ph3P+CF2H]Br−) can undergo difluoromethylation of carbonyl com­ pounds (Scheme  3.14c) [53]. This reaction proceeds via the direct transfer of CF2H, not via phosphonium ylide intermediate. Recently, Mikami and coworkers succeeded in the copper‐catalyzed enantioselective Michael‐type difluorometh­ ylation of arylidene Meldrum’s acids with bis(difluoromethyl)zinc reagents to give the corresponding β‐difluoromethylated carbonyl products in good yields and enantioselectivity [54].

3.2  Electrophilic Difluoromethylation and Difluoroalkylation

O R

O HO OH +

Ar F F +

Ph3P A

Cu(OTf)2 (5 mol%) chiral bisoxazoline (6 mol%)

CF3

OH O R

THF, NEt3, 10 °C

R′

(a)

F F

–

CO2

–

A

F F R

R

KOH (aq)

+

PPh3

AH CF2H

R

F F

(b)

A = C, O, N O R

Ph3P+CF2HBr – R′

Cs2CO3

O

OCO2– Ph3P CF2H

R

OH R′

R

R′

CF2H

(c)

Scheme 3.14  Nucleophilic difluoromethylation with miscellaneous reagents.

3.2 ­Electrophilic Difluoromethylation and Difluoroalkylation 3.2.1  By Means of Difluorocarbene Reagents Difluorocarbene is the most widely used electrophilic intermediate for the incor­ poration of difluoromethyl group into C(sp3) center. HCF2Cl can be used for the difluoromethylation of some carbon acids [55], while CF2Br2 has been used for the bromodifluoromethylation of lithium enolates [56]. However, these two rea­ gents only work well for a few selected carbon nucleophiles. The reactivity of difluorocarbene with various carbon nucleophiles was largely unknown before 2009. In 2009, Jonczyk and coworker found that only the carbon acids with pKa in the range 16.3–19.1 could be difluoromethylated in moderate yields using HCF2Cl in the presence of concentrated aqueous NaOH [55b]. In 2012, Shibata and coworkers developed a new method for the difluoromethylation of sp3 car­ bon nucleophiles using S‐(bromodifluoromethyl)diarylsulfonium salts. This method is efficient for dicyanoalkylidene substrates (Scheme 3.15a), while when β‐ketoesters were used, a mixture of C‐ and O‐difluoromethylated products were formed with low selectivity (Scheme 3.15b) [57]. In 2018, Shibata and cow­ orkers realized the highly selective C‐difluoromethylation of β‐ketoesters using TMSCF2Br (Scheme 3.15c) [58], a versatile difluorocarbene reagent developed by Hu and coworkers [59]. Shortly afterward, Shen and coworkers realized the  difluoromethylation of soft carbon nucleophile using difluoromethylated sulfonium ylide (Scheme  3.15d) [60]; Liu and coworkers realized the selective C‐­difluoromethylation of β‐ketoesters and malonates by developing new S‐dif­ luoromethylsulfonium salts as difluorocarbene sources (Scheme 3.15e) [61]. In early 2019, Hu and coworkers developed a general protocol for C─H difluoro­ methylation of carbon acids with TMSCF2Br; a variety of carbon nucleophiles, such as esters, amides, fluorenes, terminal alkynes, β‐ketoesters, malonates, and other activated C─H bonds, could be efficiently and selectively transformed to the C‐difluoromethylated products (Scheme 3.15f ) [62].

97

98

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds NC

CF2Br S + Ph

CN +

NC

Base P1

CN

(a)

CF2H

–

OTf

24–83% yield CF2Br S + Ph

O CO2R

+

O

DBU

–

OTf

OCF2H CO2R

CF2H CO2R +

(b)

47%-quant yield C/O 88:12 to 70:30 TMSCF2Br (3.0 equiv) LiOH (3.0 equiv)

O CO2R

O

CH3(CH2)15(CH3)3NBr (10 mol%) toluene, rt

MeO2C

O

–

S +

EWG n

CF2H

O

Li2CO3

CF2H

or LiOt-Bu

n

+

MeO

EWG

(d)

C/O 6:1 to 100:0 OMe Ph S

+

(c)

28–88% yield C/O 81:19 to >99:1

O2N

O CO2R

CO2Me

CF2H CO2R

–

BF4

CF2H

OMe

O LiOH or NaH Fluorobenzene

CF2H CO2R

(e)

Up to 95% yield C/O up to >99:1 R

H

2 R1 R

TMSCF2Br

R

Base

R1

CF2H R2

(f)

Up to quantative yield C/O up to >99:1

Scheme 3.15  Electrophilic difluoromethylation at Csp3 center with difluorocarbene reagents.

Dilman and coworkers proposed a new concept for assembling gem‐­ difluorinated molecules by using difluorocarbene as a building block for consecu­ tive bond‐forming reactions. Indeed, difluorocarbene can be considered as a bridge, connecting a nucleophile and an electrophile. Following this concept, Dilman and coworkers found that difluorocarbene can be easily inserted into ­alkylzinc reagents (RZnX) to give RCF2ZnX (Scheme 3.16a) [63]. RCF2ZnX can react with a variety of electrophiles, such as I2, Br2 (Scheme 3.16b), HOAc [63a], n‐BuONO [64], R′SSR′ [65], allylic bromide (Scheme 3.16c) [66], propargyl bro­ mide [67], alkynyl bromide [68], and nitrostyrene (Scheme  3.16d) [69], among others [70]. Difluorocarbene can also be trapped by halide anions. Although this process is reversible, using excess of halide anions should shift the equilibrium to XCF2−; therefore halodifluoromethylation of aldehydes can be realized

3.2  Electrophilic Difluoromethylation and Difluoroalkylation TMSCF2Br, AcONa, MeCN –25 °C, 18 h

R ZnX

R

ZnX

F F R

R

Br

ZnX

R1

R1

R

NO2

F F

CuCl·1.5PPh3 (5%)

R

Ar

R

TMSCF2Br (1.5 equiv), NaI (2.5 equiv) LiBr (0.3 equiv), DME, 80 °C

R

R

OTMS

TMSCF2Br, PPh3, DMPU R′

MeCN, rt

+

R

R′ F F

(e)

CF2Br

OH

then desiylation O

(d)

OH

then KHF2/TFA

O

(c)

F F

TMSCF2Br (3 equiv), Bu4NBr (1.1 equiv) LiBr (0.5 equiv), EtCN, Δ

O

(b)

I/Br

R

CuI (10%), phen (10%)

Ar

(a)

ZnX

F F

ZnX

F F

R

R

I2 or Br2

F F R

F F

or BrCF2CO2K, Bu4NBr, DMF 50 °C, 1 h

X

–

PPh3

(f)

CF2I OH

KOH (aq) R

R′

CF2H

(g)

Scheme 3.16  Representative applications of difluorocarbene in consecutive bond‐forming reactions.

(Scheme  3.16e,f ) [71]. A combination of difluorocarbene with aldehydes and potassium dithio­carbamate could lead to the formation of difluoromethylated alcohols [72]. Triphenylphosphine was also applied as a nucleophile to capture difluorocarbene. The in situ generated phosphorous ylide, which was known to undergo Wittig reaction with aldehydes to give gem‐difluoroolefins, was elegantly used for the difluoromethylation of aldehydes, ketones (Scheme  3.16g) [73], Michael acceptors [73], and acid chlorides [74]. 3.2.2  By Means of CF3X (X ═ H, I, TMS) Reagents Fluoroform CF3H can hardly undergo traditional SN2 reaction with nucleophiles because the carbon center is largely shielded by the three fluorine atoms, which will have strong repulsion toward the incoming nucleophiles. Therefore, using CF3H or its derivatives as CF2X+ equivalents in nucleophilic substitution,

99

100

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

reactions are challenging. In 2011, Mikami et  al. reported an unprecedented route to construct difluoromethyl‐substituted all‐carbon quaternary centers using lithium enolates and CF3I through activation of C─F bond rather than C─I bond (Scheme 3.17a), and the lithium cation is found to play pivotal role in the C─F bond activation [75]. Later on, by using this C─F bond activation strategy, CF3H and TMSCF3 can be directly used as electrophilic difluoromethylating rea­ gents with various nucleophiles (Scheme 3.17b–d) [76]. A mechanistic study for difluoromethylation of lithium enolates with CF3H by density functional theory (DFT) calculation supports a SN2‐type C─C bond formation [77]. O R1

R

LiHMDS (1.15 equiv)

O

Li

R

R2

CF3I, –78 °C

R1

then rt, 4 h

R2

O R

CF2I

(a)

1 R2 R

B LiHMDS (2 equiv)

Li

THF, 0 °C, 0.5 h

R

O R1

X R2 O

R1

X

Li

O

CF3H

R1

X

B = N(SiMe3)2

R2

R2

RCF3

(b)

1 R2 R

X

n-BuLi (1.1 equiv)

CN

CF2H

O

(1) LiHMDS (1 equiv), then MeLi (1 equiv) (2) TMSCF3, –78 °C

R2

R1

O

CF2TMS

R2

(c)

R1

NC

CF2R

R1

R2

(d)

R = H, TMS

Scheme 3.17  Electrophilic difluoroalkylation with CF3X (X = H, I, TMS) reagents.

3.2.3  By Means of I(III)–CF2SO2Ph Reagent In 2012, Hu and coworkers developed a new strategy for regiospecific allylic difluoromethylation. By using I(III)–CF2SO2Ph as the difluoromethyl source, Lewis acid‐catalyzed decarboxylative phenylsulfonyldifluoromethylation of β,γ‐­ unsaturated carboxylic acids was realized in high yields (Scheme 3.18) [78].

R1 R2

R4

R5

PhO2SF2C

CO2H R3

+

I

O

CuCl2·2H2O (1.6 mol%)

R1

1,4-dioxane/H2O 90 °C, 12 h

R2

R4

R5 CF2SO2Ph R3

Scheme 3.18  Electrophilic difluoromethylation with a I(III)–CF2SO2Ph reagent.

3.2.4  By Means of S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts In 2014, Shibata and coworkers designed S‐((phenylsulfonyl)difluoromethyl) thiophenium salts as novel difluoromethylation reagents. The thiophenium

3.3  Free Radical Difluoromethylation and Difluoroalkylation

salts can be efficient difluoromethylate sp3‐hybridized carbon nucleophiles such as in β‐ketoesters and dicyanoalkylidenes with exclusive C selectivity (Scheme 3.19) [79]. –

OTf

O CO2R

+

+

CF2SO2Ph S

O DBU, –78 °C CH2Cl2

CF2SO2Ph CO2R

–

OTf

CN NC

+

H

+

CF2SO2Ph S

CN

DBU, –42 °C CH3CN

NC

CF2SO2Ph

Scheme 3.19  Electrophilic difluoromethylation with S‐((phenylsulfonyl)difluoromethyl) thiophenium salts.

3.3 ­Free Radical Difluoromethylation and Difluoroalkylation Free radical difluoromethylation and difluoroalkylation are almost exclusively based on the addition of difluoroalkyl radicals into alkenes followed by various subsequent transformations, which were dependent on the alkene substrates and reaction conditions. 3.3.1  By Means of Iododifluoroacetates In 1989, Burton and coworker reported that iododifluoroacetates could undergo radical addition into alkenes under copper‐catalyzed conditions [80]. Reduction of the adducts with Bu3SnH or Zn/NiCl2·6H2O could provide α,α‐difluoroace­ tates (Scheme 3.20a) [80, 81]. Later on, they found that α,α‐difluoroacetates can be prepared directly by the reaction of iododifluoroacetates and alkenes under Zn/NiCl2·6H2O condition (Scheme  3.20b) [82]. In 2016, Shi and coworkers reported a novel palladium‐initiated radical cascade stereoselective iododifluoro­ alkylation/cycloisomerization of ene‐vinylidenecyclopropanes (Scheme  3.20c) [83]. In 2018, Xiao and coworkers carried out an enantioselective radical difluo­ romethylation of β‐ketoesters through an asymmetric photoredox and nickel catalysis cascade (Scheme 3.20d) [84]. Good enantioselectivities were observed. In the same year, Liang and coworkers reported a three‐component difluoro­ alkylation/trifluoromethylthiolation or trifluoromethylselenolation of alkenes, in which the air‐stable SCF3‐ and SeCF3− containing reagents acted as the radical initiators (Scheme 3.20e) [85]. Shortly after, the same group demonstrated a base promoted direct difunctionalization/cascade cyclization of 1,6‐enynes. By using different bases, two different difluoroalkylated cyclization products can be syn­ thesized (Scheme 3.20f,g) [86]. Very recently, Liang and coworkers presented a general organic base‐promoted difluoroalkylation of 1,4‐enynes, and a radical 1,2‐alkynyl migration process was involved [87].

101

102

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds O RO

CF2I

O RO

CF2I

R2

+ R1

+

CF2CO2R

Zn, NiCl2•6H2O

R1

THF

+

ICF2CO2Et

n = 1, 2 X = O, N O 1 CO2 Ad +

R

+

ICF2CO2Et

R2 X

(c)

O 1

R

CO2 Ad

(d)

CF2CO2Et

XCF3 1

R

CF2CO2Et

(e)

X = S, Se Ph

TsN

K2CO3

Ph CF2CO2Et

TsN ICF2CO2Et

(b)

R CF2CO2Et

NaHCO3 (2 equiv) DME(0.3 M), degas 30 h, rt, 7W blue LEDs

PhB(OH)2, ICF2CO2Et

(a)

I

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (3 mol%) NiBr2•glyme/l (20 mol%)

CsF, DME, 100 °C

CF2CO2R

1

n

bpyCuXCF3 ICF2CO2Et

R

CF2CO2R

R1

Cs2CO3 (2 equiv) dioxane, 50 °C

R2

1

or Zn, NiCl2•6H2O

Xantphos (20 mol%)

n

R

R

Bu3SnH

PdCl2(PPh3)2 (10 mol%)

• R1

1

R2

1

50–60 °C

R2 X

I

Cu (10–20 mol%)

I

TsN

N-Methylpiperidine

(f)

Ph CF2CO2Et

(g)

Scheme 3.20  Radical difluoroalkylation with iododifluoroacetates.

3.3.2  By Means of CF2Br2, CF2BrCl, or TMSCF2Br In 1991, Elsheimer and coworkers reported that CuCl‐initiated radical addition of CF2Br2 to olefins followed by reduction with NaBH4 provided a two‐step method for introducing difluoromethyl group (Scheme  3.21a) [88]. In 1997, Miethchen et al. studied the addition of CF2Br2 to glucal under sodium dithion­ ite‐initiated conditions (Scheme  3.21b) [89]. CF2BrCl was used to introduce CF2Cl group into monosaccharide derivatives by using the same mean [90]. In 2015, Qing and coworkers developed an efficient method for the selective hyd­ robromodifluoromethylation of alkenes with CF2Br2 under visible light‐induced conditions using eosin Y as the photoredox catalyst (Scheme  3.21c) [91]. In 2017, Dilman et al. reported that TMSCF2Br, a versatile difluorocarbene reagent [59], can undergo radical coupling with electron‐deficient alkenes using NHC·BH3 as the reductant, affording the products of hydrodifluoroalkylation (Scheme 3.21d) [92].

3.3  Free Radical Difluoromethylation and Difluoroalkylation Br R′

R

CF2Br2

CF2Br

R

CuCl

NaBH4

AcO O OAc

CF2Br2, Na2S2O4

AcO O OAc

NaHCO3 AcO

AcO

R1 R3

R2

(1) MeOH/Ag2CO3

Br CF2Br

TMSCF2Br, NHC•BH3 400 nm LED

O OMe (b) OAc

(2) Bu3SnH, AIBN AcO

CF2H R1

CF2Br2, eosin Y (5 mol%)

CF2Br

R2

visible light, KHCO3, THF, rt

Z

(a)

R′

R′

AcO

CF2H

R

(c)

R3

TMS

Z

F F

(d)

Z = CO2R, CONRR′ SO2Ph, CN

Scheme 3.21  Radical difluoromethylation with CF2Br2, CF2BrCl, or TMSCF2Br.

3.3.3  By Means of Phosphorus‐containing Reagents In 1992, Burton and coworker demonstrated addition of ICF2PO(OEt)2 to alkenes can be catalyzed by Pd(PPh3)4 or copper metal with good functional groups toler­ ance (Scheme  3.22a) [93]. The C─I bond of the adduct can be readily cleaved using Zn/NiCl2·6H2O. In 2006, Piettre and coworkers prepared selanylated difluo­ romethylphosphonates as phosphonodifluoromethyl radical precursors. Using azodiisobutyronitrile (AIBN) as the radical initiator, Bu3SnH as the hydrogen source, α,α‐difluorinated alkylphosphonates can be prepared by the reaction of PhSeCF2PO(OEt)2 with alkenes (Scheme 3.22b) [94]. Phosphonium salts are also good radical precursors. In 2015, Qing and coworkers found that bromodifluoro­ methylphosphonium bromide, previously used as a difluorocarbene precursor [95], can be used as a difluoromethylation reagent for the synthesis of hydrodif­ luoromethylated alkanes (Scheme 3.22c) [96]. The in situ generated difluorometh­ ylphosphonium salt and difluoromethyl radical are involved in this transformation. Interestingly, Ph3P+CF2CO2−, a difluorocarbene reagent developed by Xiao and coworkers [97], was used for cyano‐difluoromethylation of alkenes (Scheme 3.22d) [98]. Ph3P+CF2CO2− acts as both difluorocarbene source and difluoromethyl radi­ cal source. Ph3P+CF2CO2− generates difluorocarbene in situ, which was captured by NaNH2 or NH3 to form CN−. It also generates difluoromethylphosphonium salt in situ, which affords difluoromethyl radical under photoredox conditions. The direct use of difluoromethylphosphonium salts as difluoromethyl radical has also be reported in ring expansion of 1‐(1‐arylvinyl)cyclobutanols [99].

103

104

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

+

R

R1 R3 +

R2

(1) Pd(PPh3)4

ICF2PO(OEt)2

PhSe

(2) Zn, NiCl2•6H2O

R1 R2

R

+

[Ph3PCF2Br]+ Br –

+ Ph3P+CF2CO2– +

CF2PO(OEt)2

R2

Bu3SnH

(b)

R3

Visible light fac-[Ir(ppy)3] (3 mol%) PPh3, NaI, KHCO3 H2O, THF, rt, 10 h

NaNH2 or NH3

(a)

R1

AIBN

CF2PO(OEt)2

CF2PO(OEt)2

R

R1 R2

CN

Ir(ppy)3, CuI blue LED, rt, 12 h

(c)

CF2H

R

CF2H

(d)

Scheme 3.22  Radical difluoromethylation with phosphorus‐containing reagents.

3.3.4  By Means of BrCF2CO2Et BrCF2CO2Et is perhaps the most widely used radical difluoroalkylation reagent due to low cost and commercial availability. Almost all the radical reactions using BrCF2CO2Et started with the addition of ·CF2CO2Et to alkene to form a new alkyl radical. The new radical can undergo diversified transformations to construct molecules with different complexity. In 2014, Cho and coworkers reported that hydrodifluoroalkylation of aliphatic alkenes can be realized with BrCF2CO2Et using photoredox catalysis, and the choice of base was found to be crucial (Scheme 3.23a) [100]. In 2017, Zhu and coworkers reported a palladium‐catalyzed remote aryldifluoroalkylation of alk­ enyl aldehydes. The alkyl radical intermediate could abstract hydrogen from the remote CHO group, thereby enabling remote arylation (Scheme  3.23b) [101]. A similar remote hydrogen abstraction was also reported by Luo and coworkers (Scheme 3.23c) [102]. Carbodifluoroalkylation was also achieved. In 2015, Kim and coworker reported a photocatalytic difluoroalkylation/1,2‐carbon migration sequence of 1‐(1‐arylvinyl)cyclobutanol derivatives (Scheme 3.24a), in which the alkyl migra­ tion was promoted by a cation intermediate [103]. The photocatalytic difluoro­ alkylation‐induced 1,4‐heteroaryl (Scheme  3.24b) [104], 1,2‐heteroaryl [105], and 1,4‐alkynyl [106] radical migration were achieved. In 2016, Wang and cow­ orkers reported a palladium‐catalyzed difluoroalkylation/cyclization of acryla­ mides (Scheme  3.24c) [107]. A similar sequence involving difluoroalkylation/ ring opening/cyclization of α‐cyclopropylstyrene substrates was also realized [108]. Intermolecular carbodifluoroalkylations have also been developed. In 2016, Zhang and coworkers demonstrated a nickel‐catalyzed reaction for pre­ paring difluoroalkylated compounds via tandem radical difluoroalkylation– cross‐coupling arylation; both BrCF2CO2Et and the “inert” ClCF2CO2Et can

3.3  Free Radical Difluoromethylation and Difluoroalkylation

+

R

fac-Ir(ppy)3 (1 mol%) TMEDA/DBU (2.2 equiv)

BrCF2CO2Et

DCM, blue LEDs, rt

O H

+

PhB(OH)2 +

BrCF2CO2Et

OH R

+

Z

R′

BrCF2CO2Et

CF2CO2Et

R

O

Pd(PPh3)2Cl2 Cs2CO3

(b)

Ph CF2CO2Et

CH2Cl2, rt

CuI, ligand, KOAc DCE, 80 °C

(a)

O R

R′

CF2CO2Et

Z

(c)

Scheme 3.23  Radical hydrodifluoroalkylation of alkenes with BrCF2CO2Et.

OTMS Ar

+ BrCF2CO2Et

fac-Ir(ppy)3 (2 mol%) K2CO3, DMF

X

O Ar

blue LEDs, rt

X

(a)

O

OH Het

CF2CO2Et

+ BrCF2CO2Et

R

Ir(ppy)3 , blue LED

R

CF2CO2Et

imidazole, CH2Cl2, rt

(b)

Het O

O

O N

R

O N

Pd (0) + BrCF2CO2Et

+ XCF2CO2Et + ArB(OH)2 X = Br, Cl

R1 R2

R3 + BrCF2CO2Et +

O CF2CO2Et

NiCl2•DME (5 mol%) 4,4′-diMeO-bpy (5 mol%) K2CO3 (3 equiv) 1,4-dioxane or DME, 60 °C

Ts Ph

N

R

O CF2CO2Et

(d)

Ar

R2

Ir(ppy)3 , blue LED DMF, NEt3, rt

N

(c)

R1

Ph

CF2CO2Et R3

(e)

Scheme 3.24  Radical carbodifluoroalkylation of alkenes with BrCF2CO2Et.

be  used as the difluoroalkyl radical source (Scheme  3.24d) [109]. Alkynyl‐­ difluoroalkylation was realized by the reaction of BrCF2CO2Et, unactivated alkenes, and alkynyl sulfones via photoredox catalysis (Scheme 3.24e) [110]. Oxodifluoroalkylation is well developed. The difluoroalkyl radical adds to alk­ ene to generate a new alkyl radical, which can be oxidized to carbocation and then captured by an oxygen source either intramolecularly or intermolecularly.

105

106

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

By using this strategy, intramolecular cyclization for the construction of lactones (Scheme  3.25a) [111] and tetrahydrofurans (Scheme  3.25b) [112] has been reported. Intermolecular oxidation for the construction of α,α‐difluoro‐γ‐ ketoacetates (Scheme 3.25c) [113] and peroxidation (Scheme 3.25d) [114] were developed. O

O OH

+

BrCF2CO2Et

fac-Ir(ppy)3 , blue LED

R3 R4 R1 R2

+ BrCF2CO2Et

n

n = 1, 2

+ BrCF2CO2Et

Ar

R1 R3 +

R2

CF2CO2Et

R

R

HO

BrCF2CO2Et

(a)

O

HCO2Na, DCM, rt

Cu(CH3CN)4PF6 (10 mol%) R1 PMDETA (0.2 equiv) R2 O R3

Na2CO3 (2 equiv) DMSO, 85 °C

O Ar

KH2PO4, DMSO, rt

MeCN, rt

n

R4

Ir(ppy)3 , blue LED

ROOH Co(acac)2, NEt3

(b) CF2CO2Et

(c) CF2CO2Et

R2

R1 CF2CO2Et

ROO

(d)

R3

Scheme 3.25  Radical oxodifluoroalkylation of alkenes with BrCF2CO2Et.

In 2018, Song and coworkers reported a copper‐catalyzed intermolecular r­ adical difluoroalkylation–thiolation reaction of aryl alkenes, and PhSO2SR was used as the S‐source (Scheme 3.26a) [115]. A similar reaction was reported using RSH as the sulfur source by iron‐facilitated photoredox catalysis [116]. Reductive radical–radical coupling of N,N′‐cyclicazomethine imines with BrCF2CO2Et was also accomplished (Scheme 3.26b) [117]. CH3 R

+ BrCF2CO2Et + PhSO2SR′

CuTc (10 mol%) DTBBPY (10 mol%) B2Pin2 (2 equiv) CsF (2 equiv) CH3CN, 60 °C

N R

CF2CO2Et

R

(a)

O

O N

H3C SR

+

BrCF2CO2Et

Ir(ppy)3 (2 mol%), Asc-H (1.5 equiv) Cs2CO3 (1.5 equiv), DMSO blue LED, rt

HN R

(b)

N CF2CO2Et

Scheme 3.26  Radical thiodifluoroalkylation of alkenes and difluoroalkylation N,N′‐ cyclicazomethine imines of with BrCF2CO2Et.

3.3  Free Radical Difluoromethylation and Difluoroalkylation

3.3.5  By Means of Halodifluoroketone or ‐Amide In 1993, Burton and coworker found that iododifluoromethyl ketones could generate difluoroalkyl radicals using catalytic Pd(PPh3)4 [118]. The addition of iododifluoromethyl ketones to alkenes followed by reduction provides a general route to α,α‐difluoroketones (Scheme 3.27a) [118, 119]. In 2017, Zhu and cow­ orkers reported that bromodifluoromethyl ketones could undergo cascade dif­ luoroalkylation/radical cyclization of methylene‐2‐oxazolines for the synthesis of difluoroalkyl substituted spiro compounds (Scheme 3.27b) [120]. In 2016, Zhu and coworkers reported that bromodifluoromethyl amides could realize the aminodifluoroalkylation of alkenes by cascade photoredox/iodide catalysis (Scheme  3.27c), and the iodide salts were found to play an important role for controlling reaction selectivity [121]. A tandem radical addition/cyclization for the construction of oxindoles was also achieved using bromodifluoromethyl amides [122]. Very recently, Xu and coworkers reported that difluoroalkyl radi­ cals generated from bromodifluoromethyl amides could undergo addition to enols in high stereoselectivity by combining photoredox and chiral Lewis acid catalysis (Scheme 3.27d) [123]. O R

+

CF2I

R

TMEDA 33 W CFL

O

+

MTBE

N

R

N H

+ R′ CF2Br

NaI, NaOAc, DMF n

O

F

R

O

(b)

N

R

fac-Ir(ppy)3 blue LEDs

O

R

(a)

O

F CF2Br

R

R

(2) Zn, NiCl2 ·6H2O, THF

O R

F F

(1) Pd(PPh3)4

O

R

N

F F

R′

(c)

n

O R

N R′

O CF2Br

+

Ar

N N

Ir(ppy)2(dtbbpy)(PF6) Λ-RhS IIPEA, DCM 23 W CFL

O

R′ N

F F

N N

Ar

R

(d)

O

Scheme 3.27  Radical difluoroalkylation of alkenes or enols with halodifluoroketone or ‐amide.

3.3.6  By Means of HCF2I and PhCH2CF2I In 1994, Chen and coworkers reported that HCF2I could readily undergo addi­ tion to alkenes using Huang’s sulfinatodehalogenation (Scheme  3.28a) [124].

107

108

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

Recently, Dilman and coworkers reported the application of PhCH2CF2I, generated by difluorocarbene insertion into C─Zn bond followed by iodination [63a], as a difluoroalkyl radical precursor, which can undergo addition to silyl  enol ethers for preparing gem‐difluorinated ketones (Scheme  3.28b) [125]. Its  addition to electron‐deficient alkenes has also been demonstrated (Scheme 3.28c) [126].

HCF2I

+

Na2S2O4–NaHCO3 CH3CN–H2O, rt

R

OTMS Ph

CF2I

+

R′ R

Ph

CF2I

+

EWG

Ir(ppy)3, PPh3 propylene oxide CH3CN, 400 nm LED, rt

NaBH3CN, Py blue LED, MeOH, rt

CF2H

R

F F

(a)

O

Ph

R′

(b)

EWG

(c)

R F

F

Ph

Scheme 3.28  Radical difluoroalkylation of alkenes with HCF2I and PhCH2CF2I.

3.3.7  By Means of HCF2SO2Cl and HCF2SO2Na or Zn(SO2CF2H)2 In 2014, Dolbier and coworkers reported that HCF2SO2Cl is a good difluorome­ thyl radical precursor by using photoredox catalysis [127]. A tandem radical cyclization of N‐arylacrylamides to construct fluorinated 2‐oxindoles was reported first, and the R″ group was found to be essential for this cyclization reaction (Scheme  3.29a) [127]. In the absence of R″ group, an atom transfer radical addition (ATRA) process was observed instead (Scheme 3.29b) [128]. If a H‐donor was present, reductive difluoromethylation could be realized (Scheme  3.29c) [129]. The ATRA reaction between HCF2SO2Cl and unacti­ vated alkene was possible under metal‐free conditions (Scheme 3.29d) [130]. In addition, if an amino group is present in a proper position of the alkene sub­ strate, intramolecular aminodifluoromethylation can be realized (Scheme 3.29e) [131]. When N‐benzylacrylamides were used as substrates, the radical difluoro­ methylation was followed by a de‐aromatizing spirocyclization (Scheme 3.29f ) [132]. The presence of a nitrogen atom is not necessary for the cyclization reac­ tion, as demonstrated that the tetralin skeleton can also be constructed (Scheme 3.29g) [133]. In 2014, Tan and coworkers reported that difluoromethylation/cyclization of N‐arylacrylamides was realized using Zn(SO2CF2H)2 as the difluoromethyl radical precursor under silver‐catalyzed conditions (Scheme  3.30a) [134]. In 2015, Hu and coworkers developed an efficient method for the synthesis of fluorinated sulfinate salts by the NaBH4‐mediated reduction of the correspond­ ing benzo[d]thiazol‐2‐yl sulfones and the application of HCF2SO2Na in the sil­ ver‐catalyzed cascade difluoroalkylation/aryl migration/SO2 extrusion of

3.3  Free Radical Difluoromethylation and Difluoroalkylation R″

R

N

+ HCF2SO2Cl

O

R′

N

+

R1

HCF2SO2Cl

+

O

N

CF2H

(a)

O

HCF2SO2Cl

N

+

HCF2SO2Cl

fac-Ir(ppy)3 (0.5 mol%)

O

+

+

CF2H N H

70 °C, DCM Cu(dap)2Cl (1 mol%) Ag2CO3 (2 equiv)

R

HCF2SO2Cl

(d)

CF2H

R R

(e)

CF2H N Z

DCE, 70 °C, visible light

Ir(ppy)3 (2 mol%) K2HPO4 (2 equiv) H2O (2 equiv) MeCN, rt, visible light

(c)

O

Cl

R1 O

Na2HPO4 (2 equiv) fac-Ir(ppy)3 (1 mol%)

R

(b)

O

R

DLP (0.4 equiv)

HCF2SO2Cl

CF2H

N

(TMS)3SiH (2 equiv) MeCN, rt, 26 W CFL

R2 R3

Cl

DCE, 100 °C, visible light

HCF2SO2Cl

NHZ

BnO

MeCN, rt, visible light

Cu(dap)2Cl (0.5 mol%) K2HPO4 (2 equiv)

+

R

R

R″

R′

O

N H

K2HPO4 (2 equiv) fac-Ir(ppy)3 (1 mol%)

MeCN, rt, blue LED

EtO2C CO2Et

R2 N O R3

CF2H

(f)

CF2H (g) CO2Et CO2Et

Scheme 3.29  Radical difluoromethylation of alkenes with HCF2SO2Cl.

conjugated N‐­arylsulfonated amides (Scheme  3.30b) [135]. In early 2019, Xu and coworkers and Ackermann and coworkers independently reported the use of HCF2SO2Na as the difluoromethyl radical source under electrochemical con­ ditions [136]. Intramolecular oxodifluoromethylation of alkenes (Scheme 3.30c) [136a] and tandem difluoroalkylation/cyclization of N‐substituted acrylamides (Scheme 3.30d) [136b] were accomplished. 3.3.8  By Means of Difluoromethylated Sulfones, Sulfoximines, Thioethers, and Sulfonium Salts In 2004, Pohmakotr and coworkers reported the radical addition of PhSCF2Br to alkenes (Scheme 3.31a) [137]. Hu and coworkers reported that PhSO2CF2I and (2‐Py)SO2CF2I could be used for the radical difluoroalkylation of alkenes using

109

110

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

R1 X

N

+

O

Zn(SO2CF2H)2

(NH4)2S2O8 t-BuOH/H2O 40 °C O R3

O S CF2H O

N S

NaBH4

R1

R1

S

N

(a)

O N

X

O R2

O

R2

O N H

HF2C

HCF2SO2Na

R1 (b)

R3

CO2H R +

CF2H

AgNO3 (cat)

HCF2SO2Na

R'

Pt/Pt, J = 6.7 mA/cm2 CH3CN/H2O = 7/1

O O

R

CF2H

HOAc (3 equiv) undivided cell, rt

(c)

R R3

R3 R1 X

N R2

O

+ HCF2SO2Na

RVC/Pt, Et4NClO4 MeCN/H2O (2/1) 4.0 mA, 23 °C

R1

CF2H O

X

(d)

N R2

Scheme 3.30  Radical difluoromethylation of alkenes with HCF2SO2Na.

Et3B/air as the initiator (Scheme 3.31b) [138a,b]. PhSO2CF2I has also been used for the synthesis of CF2H‐containing oxindoles using palladium or iron catalysis (Scheme 3.31c) [139]. In 2016, Hu et al. reported that mono‐, di‐, and trifluori­ nated heteroaryl sulfones can be used as a new class of readily available, bench‐ stable, and reactivity‐tunable radical fluoroalkylation reagents under visible light photoredox catalysis [138c]. BTSO2CF2R (R = H, CH3, Ph, benzoyl) were used to react with isocyanides to give fluoroalkylated phenanthridines (Scheme 3.31d) [138c]. Zhu and coworkers designed an efficient docking migration strategy for the difunctionalization of alkenes with BTSO2CF2Br (Scheme 3.31e) [140]. The first example of BTSO2CF2H was used for the direct difluoromethylation of β,γ‐ unsaturated oximes for the construction of difluoromethylated isoxazolines (Scheme 3.31f ) [141]. Akita and coworkers found that PhSO(NTs)CF2H, previously used as a dif­ luorocarbene reagent by Hu and coworkers [142], could generate difluoromethyl radical using photoredox catalysis [143]. The application of PhSO(NTs)CF2H in oxodifluoromethylation of alkenes has been reported (Scheme 3.32a) [143, 144]. S‐Difluoromethyl‐S‐di(p‐xylyl)sulfonium tetrafluoroborate was developed by Akita and coworkers and its application in aminodifluoromethylation of alkenes was demonstrated using photoredox catalysis (Scheme 3.32b) [145].

3.3  Free Radical Difluoromethylation and Difluoroalkylation

Ph

S

O O S Ar CF2I

CF2SPh

R′

I

Et3B, air R

R3

+

N

(b)

CF2SO2Ph

CF2SO2Ph cat. Pd (0) or cat. FeCp2

O

R3

R1

(c) N

R2

C

R2

O O S TB CF2H

R′

R

R2

fac-Ir(ppy)3 Bu4NI, 4 Å MS

BT

5 W blue LED

R′

R

(e)

CF2I

fac-Ir(ppy)3 NaHCO3, MeCN

NOH +

R1

acetone, rt, blue LEDs

BT

(d)

N

Na2CO3, N2, 6 W blue LED, rt

R′

R

CF2R

[Ru(bpy)3]Cl2 · 6H2O, DMSO

(Ar = benzothiazol-2-yl, 2-pyridyl; R = H, CH3, Ph, COPh)

O O S CF2Br + N

O

R2

O O S Ar CF2R

+

(a)

R

R1

N

S

R

R′

+

O O S Ph CF2I

R1

n-Bu3SnH, AIBN

R

CF2Br +

N O R

CF2H R′

(f)

Scheme 3.31  Radical difluoromethylation of alkenes with PhSCF2Br or fluorinated sulfones.

O NTs S Ph CF2H –

R2 +

R3

R1

fac-Ir(ppy)3 Acetone/H2O, rt blue LEDs

R2 OH R3

S+ CF2H

R

Ar

Perylene, MeCN H2O (1 equiv), rt blue LEDs

(a)

CF2H

BF4 +

R1

Ar

NHAc R CF2H

Scheme 3.32  Radical difluoromethylation of alkenes with PhSO(NTs)CF2H and difluoromethylsulfonium salt.

(b)

111

112

3  Difluoromethylation and Difluoroalkylation in C(sp3) Centers and C═O, C═C, and C═N Bonds

3.3.9  By Means of TMSCF2CO2Et and ArCF2CO2H Nucleophilic difluoroalkylation reagents can also be used as radical difluoro­ alkylation reagents under oxidative conditions. In 2016, Hao and coworkers reported that TMSCF2CO2Et can be used to the radical addition/cyclization sequence for the synthesis of difluoroalkylated oxindoles in good yields (Scheme 3.33a), and the combination of AgNO3 and PhI(OAc)2 is crucial for the generation of CF2CO2Et radical species [146]. Qing and coworkers reported a visible light‐induced hydroaryldifluoromethylation of alkenes with ArCF2CO2H (Scheme  3.33b) [147]. This reaction proceeds via hypervalent iodine reagent promoting decarboxylation and subsequent radical addition. Later on, PhCF2CO2H was applied to acyldifluoroalkylation of unactivated alkenes by Zhu and coworkers (Scheme 3.33c) [148]. R3

R3 R1 N

O

+

TMSCF2CO2Et

Ag (I), NaOAc

CF2CO2Et

R1 N

PhI(OAc)2

R2

+ ArCF2CO2H

R

Visible light Ir[dF(CF3)ppy]2(dtbpy)BF4 BIOMe (6.3 equiv) NMP, rt

(a)

O

R2

R

CF2Ar

(b)

O R R

CHO

+

PhCF2CO2H

Z

Ir[dF(CF3)ppy]2(dtbpy)PF6 PhI(OAc)2 blue LED, DMAc

R R

CF2Ph

(c)

Z

Z = O, C, N

Scheme 3.33  Radical difluoromethylation of alkenes with TMSCF2CO2Et and ArCF2CO2H.

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4 Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes Qiqiang Xie and Jinbo Hu Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, Key Laboratory of Organofluorine Chemistry, 345 Lingling Road, Shanghai 200032, China

4.1 ­Nucleophilic Monofluoromethylation 4.1.1  By Means of Fluoromalonates For many years, direct nucleophilic monofluoromethylation with FCH2M was known as a very challenging task, owing to the instability (facile α‐fluoride elimination) of FCH2M (M  =  Li, MgX) species [1]. Therefore, functionalized fluoromethanes were developed as indirect monofluoromethylation reagents. Fluoromalonates have been known to act as nucleophilic monofluoroalkylation reagents over half a century [2]; however, these reagents were rarely used for the synthesis of CH2F‐containing molecules because decarboxylation of two carboxylate groups is very difficult. Palmer described a monofluoromethylation ­protocol for the synthesis of α‐fluoroketone by a nucleophilic monofluoroalkylation–decarboxylation sequence (Scheme  4.1) [3]. The decarboxylation step is assisted by the carbonyl group from the carboxylic acid substrate; therefore, this method may only work for the synthesis of monofluoromethylketones. Indeed, although many catalytic enantioselective nucleophilic additions of fluoromalonates to various substrates were reported, the subsequent transformation of the addition products to CH2F derivatives via decarboxylation was not demonstrated [4]. 4.1.2  By Means of Fluoromethyl Phenyl Sulfone In 2006, Hu and coworkers reported the first stereoselective nucleophilic monofluoromethylation of (R)‐(tert‐butanesulfinyl)imines with fluoromethyl phenyl sulfone in the presence of a base (Scheme 4.2) [5]. A variety of enantiomerically pure α‐monofluoromethylamines could be obtained via a nonchelation‐controlled stereoselectivity mode. By using tosylate‐bearing (R)‐(tert‐butanesulfinyl)imine as the substrate, α‐monofluoromethylated cyclic secondary amine can also be obtained. PhSO2CH2F reagent was also applicable for the (benzenesulfonyl)monofluoromethylation of epoxides [6]. Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

120

4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes O R

O

(1) 1,1′-Carbonyldiimidazole OH

(2) Magnesium fluoromalonate

O

R

O

H2/catalyst

OBn

R

CH2F

F

Scheme 4.1  Nucleophilic monofluoromethylation with fluoromalonates. CDI, 1,1′‐carbonyldiimidazole.

t-Bu

t-Bu

O S

O S

H N

NH2 ·HCl

(a) PhSO2CH2F, LiHMDS, THF (b) Na(Hg), Na2HPO4, MeOH (c) HCl(dioxane), MeOH

Ph

Ph

77% yield, 98% ee

CH2F

H

71% yield, 98% ee

OTs

N

N CH2F H • HCl

4

Scheme 4.2  Nucleophilic monofluoromethylation of N‐(tert‐butanesulfinyl)imines with PhSO2CH2F.

Later on, the Hu group extended the synthetic application of PhSO2CH2F to the synthesis of chiral α‐monofluoromethylated vicinal ethylenediamines (Scheme  4.3a) [7], the stereoselective monofluoromethylation of N‐tert‐butylsulfinyl ketimines via chelation‐controlled mode [8], and monofluoromethylation of α,β‐unsaturated compounds (Scheme 4.3b) [9].

t-Bu

O S

H

PhSO2CH2F, NaHMDS

NBn2

N Bn

CH2F Bn

(a)

PhSO2CH2F

(1) n-BuLi, THF, −78 °C (2) t-Bu

O S

t-Bu N

t-Bu

CH2F

O S

O S

65%

CH2F N H

NBn2 Bn

CHFSO2Ph N H

F

(1) Mg, HOAc, NaOAc, DMF, 0–rt

N H F

(b)

Bn

F

81% yield, 96 : 4 d.r. O S

t-Bu

90%

N H

CHFSO2Ph NBn2

Na(Hg) MeOH, rt

HCl(dioxane), MeOH, rt

NBn2

H2N

t-Bu

THF, −78 °C 99%

O S

(2) HCl(dioxane), MeOH, rt 73%

Scheme 4.3  Nucleophilic monofluoromethylation of N‐(tert‐butanesulfinyl) aldimines and ketimines with PhSO2CH2F.

4.1  Nucleophilic Monofluoromethylation

4.1.3  By Means of Fluorobis(phenylsulfonyl)methane In 2006, Shibata and coworkers [10] and Hu and coworkers [6] demonstrated fluorobis(phenylsulfonyl)methane ((PhSO2)2CHF, FBSM) as a novel nucleophilic monofluoromethylation reagent. In Hu’s work, the synthesis of FBSM was done by the reaction of bis(phenylsulfonyl)methane with Selectfluor [6]. FBSM turns out to be a good nucleophile, which can readily undergo addition to epoxides and aziridines [6], 1,4‐addition to α,β‐enones and activated alkynes [9], addition to arynes (Scheme 4.4a) [9], and allylation of simple alkynes under palladium/HOAc catalysis [11]. In Shibata’s work, FBSM was applied in the palladium‐catalyzed enantioselective allylic monofluoromethylation with allylic acetates (Scheme 4.4b) [10]. F

TMS

F

OTf

(a)

OAc R

R

(b)

SO2Ph

(c) O

(d)

FBSM (1.1 equiv) (S)-PHOS (5 mol%) [{Pd(C3H5)Cl}2] (2.5 mol%)

CsOH ·H2O (1.2 equiv) CH2Cl2, −80 °C, 1–2 d 70–98% yield, 87–99% ee

OH R2

FBSM, PPh3, DIAD benzene, rt

F R1

Mg, MeOH

∗

R

SO2Ph

R

F SO2Ph

Ar

0 °C 26–88% yield, 89–99% ee

R

MeO2C

SO2Ph SO2Ph

O

SO2Ph SO2Ph

0 °C

R

R

CH2F MeO2C

Mg, MeOH

R

CH2F

Mg, MeOH

2

CH2F

Ar

0 °C

R

CH2F ∗ R

CH2F

R

Mg, MeOH

Up to 98% ee

F

F

NH2

Mg, MeOH

SO2Ph SO2Ph

F

O

CH2F

F

R

0 °C, 2 h

R

NH2

PhCF3, 40 °C, 3–4 d

(e)

SO2Ph SO2Ph

F

Cs2CO3 (1.1 equiv) CH2Cl2 (1.0 M), 0 °C, 6 h 22–92% yield, 91–97% ee

FBSM OBoc (DHQD) AQN (10 mol%) 2 FeCl2 (10 mol%) R

MeO2C

R1

SO2Ph Na(Hg), Na2HPO4 SO2Ph MeOH, −20 °C, 3 h 82%

F

FBSM Cinchona alkaloid (5 mol%) R Cs2CO3 (3 equiv), CH2Cl2 −40 °C, 1–2 d

Ar

(f)

MeCN, reflux, 24 h 60%

FBSM (1.05 equiv) QD+Cl– (5 mol%)

NH2 R

F F

FBSM, CsF

R1

R2

F N

(g)

FBSM, DIAD, DMF 50 °C, 3 h 94% yield

N

SO2Ph SO2Ph

Na(Hg), Na2HPO4

N

CH2F

MeOH 84% yield

Scheme 4.4  Representative applications of FBSM as a monofluoromethylation reagent.

Since these two seminal reports on FBSM, the synthetic potential of FBSM has been extensively explored. Shibata and coworkers realized the first catalytic enantioselective monofluoromethylation of in situ generated imine from α‐amido sul-

121

122

4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes

fone under cinchona alkaloid catalysis with FBSM (Scheme  4.4c) [12], the first asymmetric conjugate addition of FBSM to α,β‐unsaturated ketones in high level of enantioselectivity (Scheme  4.4d) [13], the synthesis of monofluoromethylated allenes via palladium catalysis using FBSM [14], the asymmetric allylic monofluoromethylation of Morita–Baylis–Hillman carbonates by cooperative cinchona alkaloid/FeCl2 catalysis (Scheme  4.4e) [15], and the PTC‐catalyzed asymmetric monofluoromethylation of indole derivatives via in situ generated vinylogous imino intermediates [16]. Prakash et  al. reported a stereoselective monofluoromethylation of alcohols with FBSM in a Mitsunobu reaction (Scheme 4.4f) [17], a 1,4‐addition of FBSM to α,β‐unsaturated compounds [18], and the nucleophilic substitution of alkyl halides with FBSM [19]. Cordova and coworkers and Wang and coworkers independently accomplished the organocatalyzed enantioselective conjugate addition of FBSM to enals [20]. Zhao et al. reported a highly regioselective Pd‐catalyzed allylic monofluoromethylation reaction [21]. In 2011, Hu and coworkers realized the nucleophilic fluoromethylation of aldehydes with FBSM [22], which was thought to be unattainable [23]. They pointed out that both the strong Li–O coordination at low temperature and fluorine substitution play important roles. In 2013, a metal‐free dehydrogenative cross‐coupling between tertiary amines and FBSM was also achieved by Hu and coworkers, providing an efficient method for the synthesis of β‐fluorinated amines (Scheme 4.4g) [24]. 4.1.4  By Means of 2‐Fluoro‐2‐Sulfonylketone In 2008, the Hu group found that 2‐fluoro‐2‐phenylsulfonylacetophenone is a good nucleophilic fluoroalkylation reagent for the bifunctionalization of arynes and activated alkynes enabling both C—Rf bond and CC(O)Ph bond formations in a single step (Scheme 4.5) [9]. The phenylsulfonyl group can be easily cleaved under reductive conditions to give the monofluoromethylated products. O PhO2S

Ph F

+ OTf

OH Ph CH2F

O

TMS

CsF

Ph SO2Ph

MeCN, reflux, 12 h 95% OH

Na(Hg), Na2HPO4

Ph SO2Ph

MeOH, −20 °C, 3 h

F

NaBH4, MeOH, rt, 1 h 84%

F

Scheme 4.5  Nucleophilic monofluorome thylation of arynes with 2‐fluoro‐2‐phenylsulfonylacetophenone.

In 2013, Hu and coworkers developed a new method for aromatic monofluoromethylation with 2‐PySO2CHFCOR (R = 4‐methoxyphenyl) [25]. A variety of aryl iodides can be efficiently monofluoromethylated via a copper‐catalyzed debenzoylative fluoroalkylation‐reductive desulfonylation sequence (Scheme  4.6). They found that the pyridylsulfonyl group plays an important role in this Hurtley‐type cross‐coupling reaction.

4.1  Nucleophilic Monofluoromethylation O N

S

O O

I +

F

OMe

(1) CuTc (30 mol%), NaHCO3 (3 equiv), DMSO, 80 °C, 20 h

F

(2) NaHCO3 (5 equiv), DMSO, MeOH, MeO 80 °C, 1 h 75%

MeO

CH2F

N

S O O

Bu3SnH (5 equiv), AIBN (3 equiv) Toluene, 110 °C, 8 h 63%

MeO

Scheme 4.6  Copper‐catalyzed monofluoromethylation of aryl iodides with 2‐PySO2CHFCOR.

4.1.5  By Means of 2‐Fluoro‐1,3‐benzodithiole‐1,1,3,3‐tetraoxide (FBDT) In 2010, as FBSM failed to undergo nucleophilic addition to aldehydes in Shibata’s attempts, they designed a new reagent, 2‐fluoro‐1,3‐benzodithiole‐1,1,3,3‐ tetraoxide (FBDT), for nucleophilic monofluoromethylation of aldehydes [23]. Later on, by using a bifunctional cinchona alkaloid‐derived thiourea–titanium complex, the enantioselective monofluoromethylation of aldehydes can be achieved with FBDT in good yields and high ee values (Scheme 4.7) [26]. O R

O O S

+

S O O

F

Chiral thiourea catalyst (10 mol%) Ti(O-i-Pr)4 (2.3 equiv)

OH R

Toluene, rt 73–91% yield, 32–96% ee

FBDT ∗

O S O

F S O O

SmI2 (6 equiv) MeOH/THF

OH R

∗

CH2F

−70 to −40 °C

Scheme 4.7  Enantioselective monofluoromethylation of aldehydes with FBDT.

4.1.6  By Means of TMSCF(SO2Ph)2 (TFBSM) In 2012, Prakash et al. developed TFBSM as a novel monofluoromethylation reagent. Compared with FBSM, TFBSM can monofluoromethylate aldehydes under milder conditions (Scheme 4.8) [27]. F TMS

SO2Ph SO2Ph

O

+ R

CsF (20 mol%) THF, rt, 4 h

OH OTMS (1) Mg, HOAc F R CH2F R SO2Ph (2) Na/Hg, MeOH SO2Ph

Scheme 4.8  Monofluoromethylation of aldehydes with TFBSM.

4.1.7  By Means of PhSO(NTBS)CH2F In 2014, to access chiral monofluoromethylated tertiary alcohols, Hu and coworkers developed a chiral monofluoromethylation reagent, (R)‐PhSO(NTBS) CH2F. This reagent can readily undergo stereoselective nucleophilic fluorometh-

123

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4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes

ylation of arylketones (Scheme 4.9), and the high stereoselectivity was believed to be facilitated by the kinetic resolution of the chiral α‐fluorocarbanion [28]. O Ph

(1) KHMDS, THF, −78 °C, 30 min

NTBS S

(2) ArCOR, −78 °C, 3 h up to 99 : 1 d.r.

CH2F

NH Ag/Hg, THF/H2O (1 : 1) HO

HO O Ar

S R

Ph

F

R

Ar

rt, overnight up to >99% ee

CH2F

Scheme 4.9  Enantioselective monofluoromethylation of aldehydes with chiral PhSO(NTBS) CH2F.

4.1.8  By Means of CH2FI As mentioned earlier in the chapter, direct nucleophilic monofluoromethylation with FCH2M (M = Li, MgX) is challenging. However, despite the known difficulties, in 2017, Luisi and coworkers demonstrated the first direct and straightforward nucleophilic monofluoromethylation with a “fleeting” lithium fluorocarbenoid (LiCH2F) generated from commercially available CH2FI [29]. This protocol overcomes the drawbacks associated with the use of auxiliary groups, where removal of the auxiliary is required to give the monofluoromethyl group. This strategy shows broad substrate scope, where a plethora of electrophiles such as aldehydes, ketones, Weinreb amides, and imines are suitable in monofluoromethylation (Scheme 4.10). MeLi-LiBr (2 equiv)

I CH2F

Ph

F

CH2F

Ph

CH2F

93%

E CH2F

O

OH

OH Ph

Li

THF/Et2O (1 : 1) −78 °C

(1 equiv)

Electrophile (1.5 equiv)

NHBoc

CH2F Ph

90%

Ph 58%

CH2F 92%

Scheme 4.10  Nucleophilic monofluoromethylation with CH2FI via LiCH2F intermediate.

4.1.9  By Means of Monofluoromethyl Phosphonium Salts Monofluoromethyl phosphonium salts can be used for the monofluoroolefination of carbonyl compounds, after which hydrogenation of the C=C bond would give the corresponding monofluoromethylated product (Scheme 4.11) [30]. OAc O

H H

O O

CH2F

H

H

BF4 +

Ph3P CH2F

(1) n-BuLi, Et2O (2) CF3CO2H

H O

OAc H H

H

Scheme 4.11  Nucleophilic monofluoromethylation with monofluoromethyl phosphonium salt.

4.2  Electrophilic Monofluoromethylation

4.2 ­Electrophilic Monofluoromethylation 4.2.1  By Means of CH2FX (X = Cl, Br, I, OTf, OTs, OMs) Compared with nucleophilic monofluoromethylation, electrophilic monofluoromethylation is less studied. In 1953, Olah and Pavlath reported the first electrophilic monofluoromethylation of benzene with monofluoromethanol in the presence of an acid [30]. The electrophilic monofluoromethylation was neglected until 1985 when several examples of electrophilic monofluoromethylation of O‐, S‐, N‐, and C‐nucleophiles have been reported using CH2FX (X = Cl, Br, I, OTf, OTs, OMs) [31a]. In 2007, Hu and coworkers systematically explored the monofluoromethylation ability of CH2FCl as an electrophilic monofluoromethylation reagent for a number of O‐, S‐, and N‐ nucleophiles, and the yields are typically good (Scheme  4.12a) [31a]. Very recently, Jiang and coworkers reported a highly carbon‐selective electrophilic monofluoromethylation of β‐ketoesters with CH2FI under mild conditions (Scheme  4.12b) [31b]. The major feature of this reaction is that the use of lithium tert‐butoxide as base and the diglyme as solvent leads to a high C/O regioselectivity [31b].

RXH

+

Base, solvent

CH2FCl

RXCH2F

X = O, S, N OCH2F Ph

N

Ph

S

96%a

90% a

OCH2F

SCH2F

82%

CH2F N N 84%

Yield determined by 19F NMR spectroscopy.

(a) O

O

O OR

+

I

CH2F

tBuLi, digylme RT, 2 h

O

OR CH2F up to 91% yield up to >99:1 regioselectivity

(b)

Scheme 4.12  Electrophilic monofluoromethylation with CH2FX (X = Cl, I).

4.2.2  By Means of S‐(monofluoromethyl)diarylsulfonium Tetrafluoroborate In 2008, Prakash et al. developed a novel electrophilic monofluoromethylation reagent, S‐monofluoromethyl‐S‐phenyl‐2,3,4,5‐tetramethylphenylsulfonium tetrafluoroborate, which can be used for the direct FH2C+ transfer to a wide range of O‐, S‐, N‐, P‐, and C‐nucleophiles (Scheme 4.13) [32].

125

126

4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes

RXH

CH2F S

+

N

CH2F

BF4

Ph

SO3CH2F

83%

CO2CH2F

Ph

79%

88% OCH2F

F

BF4

Ph3P CH2F

RXCH2F

BF4

X = O, S, N, P, C Ph

Base, solvent

PhO2S

31%

78%

CH2F SO2Ph

72%

Scheme 4.13  Electrophilic monofluoromethylation with S‐(monofluoromethyl) diarylsulfonium tetrafluoroborate.

4.2.3  By Means of Monofluoromethylsulfoxinium Salts In 2011, Shibata and coworkers developed novel shelf‐stable N,N‐(dimethylamino)‐ S‐phenyl‐S‐monofluoromethyloxosulfonium trifluoromethanesulfonate or hexafluorophosphate salts for electrophilic monofluoromethylation reaction [33]. When β‐ketoesters were used as substrates, exclusive O‐monofluoromethylation was observed in high yields (Scheme 4.14a). This reagent can also monofluoromethylate other O‐nucleophiles, for instance, carboxylic acids, phenols, and sulfonic acids (Scheme  4.14b). A further mechanistic study revealed that monofluoromethylation of β‐ketoesters with monofluoromethylsulfoxinium salt probably involves a radical‐like species [34].

O CO2R

O

+

Ph

S

N PF6

CH2F

OCH2F CO2R

Base, MeCN rt, 1 h

64–96% yield (a) RXH

+

O Ph

S

CO2CH2F

(b)

85%

Base, solvent

N CH2F

RXCH2F

PF6 OCH2F

SO3CH2F 93%

87%

Scheme 4.14  Electrophilic monofluoromethylation with monofluoromethylsulfoxinium salts.

4.2  Electrophilic Monofluoromethylation

4.2.4  By Means of Monofluoromethylsulfonium Ylides Very recently, Shen and coworkers synthesized two electrophilic monofluoromethylation reagents, monofluoromethyl(phenyl)sulfonium bis(carbomethoxy) methylide and monofluoromethyl(4‐nitrophenyl)sulfonium bis(carbomethoxy) methylide [35]. Both reagents show much higher reactivity than those previously reported reagents. A variety of nucleophiles, such as alcohols, phenols, malonates, sulfonic acids, carboxylic acids, amides, and N‐heteroarenes, could be monofluoromethylated in high yields under mild conditions (Scheme 4.15). Mechanistic investigations support an electrophilic substitution pathway. MeO2C NuH

CO2Me S

+ R

Base

CH2F

Nu CH2F

Solvent

R = H or NO2 OCH2F Ph Ph Ph 91%

OCH2F N 76%

OCH2F

Ph CH2F EtO2C

CO2Et

O2N

94%

90% Cl

CO2CH2F

SO3CH2F

N N

Ph 99%

72%

55%

CH2F

Scheme 4.15  Electrophilic monofluoromethylation with monofluoromethylsulfonium ylides.

4.2.5  By Means of Monofluoromethyl Phosphonium Salts In 2011, Leitao and Turner reported that monofluoromethyltriphenylphosphonium tetrafluoroborate can be used as a direct electrophilic monofluoromethylation reagent for monofluoromethylation of carbothioic acid (Scheme 4.16) [36]. O HO

O

SH O

BF4 O

F O

+

Ph3P CH2F

HO

S

CH2F

O

Cs2CO3

O

MeCN, rt

F O

F

F

Scheme 4.16  Electrophilic monofluoromethylation with monofluoromethyl phosphonium salt.

127

128

4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes

4.3 ­Free Radical Monofluoromethylation 4.3.1  By Means of (PhSO2)2CFI Radical monofluoromethylation is less studied than tri‐ and difluoromethylation. In 2008, Prakash et  al. demonstrated the preparation of (PhSO2)2CFI and its application as a radical precursor, which can undergo addition to terminal alkenes. The adduct can easily undergo dehydroiodination to give E‐ alkenes (Scheme 4.17) [37]. However, although desulfonation is easy and well documented, the products were not converted into the monofluoromethylated ones. I

(PhSO2)2CFI

C5H11

Et3B, air, CH2Cl2

C5H11

DBU

CF(SO2Ph)2

CF(SO2Ph)2

C5H11

Scheme 4.17  Radical monofluoromethylation with (PhSO2)2CFI.

4.3.2  By Means of (H2FCSO2)2Zn (MFMS) Direct H2FC˙ radical reagent with synthetic utility was unprecedented until 2012. In this year, Baran and coworkers designed a new direct H2FC˙ radical transfer reagent, zinc monofluoromethanesulfinate (MFMS), which can readily be used to functionalize innate carbon–hydrogen bond of heterocycles in good yields (Scheme 4.18) [38]. O

O N O

N

N

(CH2FSO2)2Zn

N

TBHP, 2.5 : 1 solvent:water

N

N O

N

N

CH2F

80%

Scheme 4.18  Direct radical monofluoromethylation with MFMS.

4.3.3  By Means of CH2FSO2Cl Inspired by Baran’s work that (RfSO2)2Zn, which can be prepared from RfSO2Cl, is good Rf˙ radical precursor, Dolbier and coworkers presented that RfSO2Cl can act as radical precursor under photoredox catalysis. H2FC˙ radical can be generated from CH2FSO2Cl using fac‐Ir(ppy)3 as the photocatalyst, and its addition to N‐arylacrylamides delivers monofluoromethylated 3,3‐disubstituted 2‐oxindoles in moderate yields (Scheme 4.19a) [39]. Later on, they also achieved copper‐catalyzed atom transfer radical addition reaction of CH2FSO2Cl onto unsaturated carbonyl compounds to afford α‐chloro‐β‐monofluoromethylcarbonyl products in excellent yields (Scheme 4.19b) [40].

4.3  Free Radical Monofluoromethylation CH2FSO2Cl (2 equiv) K2HPO4 (2 equiv) fac-Ir(ppy)3 (1 mol%) O

N

CH2F N

DCE, 105 °C, 12 h visible light

48%

(a) 0.5 mol% Cu(dap)2Cl CH2FSO2Cl (2 equiv) 20 mol% K2HPO4

N

Ph

Cl FH2C

DCE, 100 °C, overnight visible light

O

O

N

Ph

O 94%

(b)

Scheme 4.19  Direct radical monofluoromethylation with CH2FSO2Cl.

4.3.4  By Means of PhSO(NTs)CH2F In 2014, Hu and coworkers revealed that PhSO(NTs)CH2F is a good monofluoromethylation reagent for the direct monofluoromethylation of O‐, S‐, N‐, and P‐nucleophiles (Scheme 4.20a) [41]. An accelerating effect is observed by the α‐fluorine substitution, which is in sharp contrast with previously known detrimental impact of α‐fluorine substitution on SN2 reactions. Preliminary mechanistic studies suggest a radical mechanism. In 2019, Akita and coworkers presented that monofluoromethyl radical can be generated from PhSO(NTs)CH2F by using strongly reducing 1,4‐bis(diphenylamino) naphthalene photoredox catalyst. The monofluoromethyl radical can add to alkenes, leading to facile synthesis of γ‐fluoroalcohols (Scheme 4.20b) [42].

NuH

(1) 1.25 equiv NaH, DMSO, rt, 0.5 h (2) 1.3 equiv PhSO(NTs)CH2F, DMSO, 80 °C

OCH2F

N S

Ph 95%

Nu CH2F

N SCH2F

N CH2F

CO2CH2F MeO

92%

86%

NTs

1,4-Bis(diphenylamino)naphthalene (5 mol%)

80%

(a) R1 Ar

O 2

R

+

Ph

S

CH2F

acetone/H2O (9 : 1) rt, 12 h, 425 nm LEDs

(b)

Scheme 4.20  Direct radical monofluoromethylation with PhSO(NTs)CH2F.

R1 OH CH2F

Ar 2

R 30–84% yield

129

130

4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes

4.3.5  By Means of Monofluoromethyl Sulfone In 2016, Hu and coworkers reported that fluorinated sulfones can be used as radical precursors by photoredox catalysis. By using 2‐((fluoromethyl)sulfonyl)‐6‐nitrobenzo[d]thiazole, monofluoromethyl radical can be produced smoothly and add to isocyanide for the construction of phenanthridine structure (Scheme 4.21) [43].

N

C

O2N

S

+

N

O

S O CH2F

CH2F

[Ru(bpy)3]Cl2·6H2O, DMSO, rt

N

Na2CO3, N2, 6 W blue LED 75%

Scheme 4.21  Direct radical monofluoromethylation with monofluoromethyl sulfone.

4.4 ­Transition‐Metal‐Catalyzed/Mediated Monofluoromethylation 4.4.1  By Means of CH2FI Monofluoromethylation via transition‐metal‐catalyzed/mediated cross‐coupling reactions is an emerging research area. The seminal report in this direction is the palladium(0)‐mediated cross‐coupling between pinacophenylborate and CH2FI, demonstrated by Suzuki and coworkers in 2009 (Scheme  4.22a) [44]. However, according to Suzuik’s report, stoichiometric amount of palladium and large excess of pinacophenylborate (40 equiv) are required, which restricted its application. In 2015, Hu et al. reported that a catalytic version using Pd(0) as the catalyst and P(o‐toluene)3 as the ligand, and a variety of electron‐rich and electron‐deficient arylborates could be monofluoromethylated in good yields under Bpin

CH2F

[Pd2(dba)3]/P(o-CH3C6H4)3 (1 : 6) +

CH2FI

K2CO3, DMF, 5 min, 60 °C 57%

(a)

R

Bpin + CH2FI

Pd2(dba)3 (5 mol%) or Pd(dppf)Cl2 (10 mol%)

CH2F

P(o-toluene)3 (20 mol%) H2O (5 equiv), Cs2CO3 (1.5 equiv) 55–90%

(b)

R

+ CH2FI + R = COR″. aryl, alkyl

B2R′2

R′ = mpd, pin

CuCl or CuBr (10 mol%) ligand (12 mol%) LiOt-Bu or NaOt-Bu DMSO or DMAc, rt

(c)

Scheme 4.22  Monofluoromethylation with CH2FI.

CH2F R

BR′

Up to 86% yield

4.4  Transition‐Metal‐Catalyzed/Mediated Monofluoromethylation

mild conditions (Scheme 4.22b) [45]. In 2009, Qing and coworkers realized the regioselective borylmonofluoromethylation of alkenes with CH2FI using copper catalysis (Scheme 4.22c), and the Bpin group in the products can be transformed into various functional groups [46]. 4.4.2  By Means of PhSO2CHFI In 2015, Wang and coworkers reported a nickel‐catalyzed monofluoromethylation of aryl boronic acids with PhSO2CHFI. The sulfonyl group can be readily removed under reductive conditions to give the monofluoromethylated arenes (Scheme 4.23) [47].

B(OH)2 R

(1) Ni(acac)2 (5–20 mol%) PPh3 (10–40 mol%), K2CO3 (1.5 equiv) CH2Cl2, 100 °C

F +

I

SO2Ph

(2) Na(Hg), Na2HPO4, MeOH/THF

CH2F R

Scheme 4.23  Monofluoromethylation with PhSO2CHFI.

4.4.3  By Means of CH2FBr In 2015, Zhang and coworkers reported a nickel‐catalyzed cross‐coupling ­reaction between arylboronic acids and CH2FBr for the facile access to monofluoromethylated arenes (Scheme 4.24a) [48]. Later on, in 2018, Wang and coworkers reported a nickel‐catalyzed reductive cross‐coupling of aryl halides with CH2FBr for the preparation of monofluoromethyl‐substituted arenes, and a combination of bidentate and monodentate pyridine‐type nitrogen ligand is the key to success (Scheme  4.24b) [49]. Very recently, Wang and coworkers also achieved the ­ reductive cross‐coupling between (hetero)aryl bromides and CH2FBr (Scheme 4.24c) [50]. NiCl2 ·DME (5 mol%) phen (5 mol%) DMAP (10 mol%)

B(OH)2 R

+

CH2FBr

(a) I

(b)

+

Ph

CH2FBr

Het

CH2F

NiI2 (10 mol%)/ligand Mn, DMAc, 40 °C

Ph

NiI2 (10 mol%) dtbpy (12 mol%) DMAP (24 mol%)

Br R

K2CO3 (2.0 equiv) DME/dioxane, 70 °C

CH2F R

+

CH2FBr

Mn, DMAc, 40 °C

(c)

Scheme 4.24  Monofluoromethylation with CH2FBr.

CH2F R

Het

131

132

4  Monofluoromethylation Reactions of Aliphatic Substrates and (Hetero)Arenes

4.4.4  By Means of PTSO2CH2F In 2018, Baran and coworkers reported a modular radical cross‐coupling with sulfones to access sp3‐riched (fluoro)alkylated scaffolds. Five specific sulfone reagents were developed; among them, monofluoromethyl phenyl‐tetrazole (PT) sulfone is a good monofluoromethylation reagent, which can readily undergo cross‐coupling reaction with arylzinc reagents by nickel catalysis (Scheme 4.25) [51]. H N N

ZnCl R

+

N N

O S O CH2F

Ni(acac)2·xH2O bathophenanthroline

CH2F R

THF/NMP, rt

Scheme 4.25  Monofluoromethylation with PTSO2CH2F.

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133

135

5 Synthesis of gem‐Difluorocyclopropanes Dmitriy M. Volochnyuk1,2,3 and Oleksandr O. Grygorenko1,2 1

Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094, Ukraine Taras Shevchenko National University of Kyiv, Institute of High Technologies, Department of Chemistry, Volodymyrska Street 60, Kyiv 01601, Ukraine 3 Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Department of Biologically Active Compounds, Murmanska Street 5, Kyiv, 02094, Ukraine 2

5.1 ­Introduction Cyclopropane ring is a versatile structural element of organic compounds, which is widely used in various areas of chemistry and related sciences, first of all those related to biological properties and synthetic transformations [1–5]. Being the smallest possible ring system with unique electronic structure, cyclopropane pro­ vides significant rigidity when introduced into designed molecules while modu­ lating their chemical properties so that specific reactivity appears. Fluorinated cyclopropanes attracted considerable attention in organic, bioorganic, medicinal, and agrochemistry in the last decades; their various subtypes have become sub­ jects of several reviews and book chapters [6–11]. In this section, synthesis of cyclopropane derivatives bearing two fluorine atoms at the same ring position (i.e. gem‐difluorocyclopropanes) is discussed. First of all, gem‐difluorocyclopro­ panes were considered as promising structural motifs for medicinal chemistry [11, 12]. For example, introducing the gem‐difluorocyclopropane motif into the dibenzocycloheptane moiety of P‐glycoprotein inhibitor MS‐073 led to the com­ pound with significantly improved oral bioavailability – a clinical candidate zosuquidar (LY‐335979), which reached Phase III clinical trials (Figure 5.1a) [5, 11]. Notably, the latter compound was also more stable under acidic conditions than the corresponding non‐fluorinated analogue. In another study, interleukin‐2 inducible T‐cell kinase (ITK) inhibitor GNE‐4997 was designed by implementa­ tion of the similar design principle to tetrahydroindazole derivative GNE‐9822 (Figure  5.1b) [13]. It was found that such modification resulted in significantly reduced cytotoxicity; again, GNE‐4997 was superior over its non‐fluorinated counterpart, as well as the corresponding analogue lacking the cyclopropane ring. Other successful examples of biologically active gem‐difluorocyclopropanes include metabotropic glutamate receptor (mGluR) agonist L‐F2CCG‐I [14, 15], Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

136

5  Synthesis of gem‐Difluorocyclopropanes N

N HO N

O

HO F F

N

N

N

Zosuquidar

MS-073

(a)

H N

N

O

H N

N

H N N

O

F

N

N

O

F

GNE-9822

O S O

H N N

N

GNE-4997

(b)

Figure 5.1  Design of (a) Phase III clinical candidate zosuquidar and (b) ITK inhibitor GNE‐4997.

F F

F

O

HO

O F

O– O

NH3+

F

L-F2CCG-I, EC50(mGluR2) = 90 nM

O F Cl

O

O O DDT-pyrethroid insecticide LD50(Lucilia cuprina) = 3.9 mg/kg

F F

Aliflurane

Figure 5.2  Selected biologically active gem‐difluorocyclopropanes.

inhalational anesthetic aliflurane [16], and fluorinated dichlorodiphenyltrichlo­ roethane (DDT)‐pyrethroid insecticide [17] (Figure 5.2). Methylene‐gem‐difluorocyclopropane derivatives were suggested as potential covalent modifiers of enzymes (Scheme  5.1) [18]. It was shown that these compounds could serve as Michael acceptors, which demonstrated considerable selectivity toward thiol groups as nucleophiles. F F

F F

ArSH OBn

99%

ArS

OBn

Scheme 5.1  Methylene‐gem‐difluorocyclopropanes – potential enzyme inhibitors.

Incorporation of gem‐difluorocyclopropane moiety was used to design ana­ logues of known drugs and natural products (Figure 5.3), in particular, analogues of monoamine oxidase (MAO) inhibitor tranylcypromine [19], DNA‐alkylating agents duocarmycins [20], macrolide heat shock protein 90 (Hsp90) inhibitors (e.g. radicicol) [21], nucleosides [22], proline‐containing peptides [23], and ster­ oids [24]. It should be noted, however, that in most of the above cases, biological

5.1 Introduction

F

F

F

F

F

O

NH2

N N H

O X

F

NH N

F

O

Cl

N

OH Radicicol analogue O

O

F

H N

O

F H

O

H O

O

F F Nucleoside analogues (X = H, CH3, F)

O

cis or trans

N

HO

H

O

Duocarmycin analogue

MAO inhibitor

H

O

HO

O O

O

O

F

Analogues of prolinerich peptides

H

H Steroid analogue

Figure 5.3  gem‐Difluorocyclopropane analogues of known drugs and natural products.

properties of the resulting gem‐difluorocyclopropanes were either not studied or less prominent as compared to the parent compounds. gem‐Difluorocyclopropanes have significant potential as model substrates of various biological processes, in particular, enzymatic reaction mechanisms. An interesting study involving 3,3‐difluorocyclopropene has been reported by McKenna and coworkers; in this work, the title compound was investigated as a substrate of nitrogenase, an enzyme that is used by many organisms to reduce N2 to ammonia [25]. It was found that mixtures of propene and 2‐fluoropropene are formed in this reaction, which provided a rare example of enzymatic C─F bond activation. gem‐Difluorocyclopropane derivatives have attracted certain interest in mate­ rial sciences. Indeed, isomeric spiro[2.0.2.1]heptane derivatives were found to be ferroelectric liquid crystalline compounds with unusual physical properties (Figure 5.4) [26, 27]. Direct difluorocyclopropanation of vinyl‐terminated self‐ assembled monolayers was also studied [28]. Nevertheless, one of the most important applications of gem‐difluorocyclo­ propanes is related to their chemical properties. It was shown that introducing fluorine atoms into the cyclopropane ring results in increased p‐character of the O ArO

F F

O

O

ArO

ArO

F F

F F and enantiomers, Ar = C8H17

N N

Figure 5.4  gem‐Difluorocyclopropane derivatives – ferroelectric liquid crystals.

137

138

5  Synthesis of gem‐Difluorocyclopropanes

corresponding carbon atom orbitals, which results in significant deformation of molecular geometry [8]. This also results in a nearly 1.5‐fold increase in the ring strain energy (estimated from the theoretical heat of hydrogenation: 27.1 kcal/ mol for cyclopropane vs. 42.4 kcal/mol for 1,1‐difluorocyclopropane) [29]. These data are reflected in increased chemical reactivity of gem‐difluorocyclopropanes, which provides possibilities for their numerous synthetic applications. The sub­ ject has been reviewed recently [30] so that only a short overview is given in this chapter. Despite its enhanced reactivity, the gem‐difluorocyclopropane moiety is still stable toward many typical reagents used in organic synthesis including con­ centrated aq HCl or 2 M aq NaOH at 100 °C, HNO3–H2SO4, Br2, DMF–POCl3, LiBH4, KMnO4 or MnO2, and Pd(0) catalysts (under the common C–C coupling conditions); it does not tolerate lithiation or catalytic hydrogenation conditions, as well as strong Lewis acids like AlCl3 [31]. An important synthetic transformation of gem‐difluorocyclopropanes is related to their ring opening into 2‐fluoroallyl derivatives. A prominent example of this methodology was described by Fu and coworkers who reported Pd(0)‐ catalyzed regioselective activation of gem‐difluorinated cyclopropanes followed by trapping of the organopalladium intermediates with N‐, O‐, and C‐nucleo­ philes (Scheme 5.2) [32]. F F Ar

Pd(O2CCF3)2, t-Bu-XPhos K2CO3, HNu 52–96%

Ar

Nu F

NuH = amines, alcohols, (sulfon)amides, carboxylic acids, CH-acids, pyrroles

Scheme 5.2  Pd(0)‐catalyzed ring opening of gem‐difluorocyclopropanes.

In many other literature precedents, ring opening of gem‐difluorocyclopro­ panes proceeded with retaining of the gem‐difluoro moiety. Dilman and cowork­ ers proposed a method for “difluorohomologation” of ketones, which was based on difluorocyclopropanation of silyl enolates, followed by ring opening of the resulting difluorocyclopropane intermediates (Scheme 5.3a) [33]. Other electro­ philes (e.g. halogens) might be involved into the last steps of this sequence [34]. In a related reaction sequence, gem‐difluorocyclopentenones were prepared by recyclization of vinyl‐substituted gem‐difluorocyclopropanes (Scheme  5.3b). Finally, radical rearrangements of properly functionalized gem‐difluorocyclopro­ panes were used to obtain diene precursors for the synthesis of various function­ alized gem‐difluorocycloalkenes via ring‐closing metathesis (Scheme 5.3c) [35]. As it was mentioned above, further discussion sections are focused on the known synthetic approaches to the preparation of gem‐difluorocyclopropane derivatives. Among numerous methods known for the construction of cyclopro­ panes [1–4], only selected ones are suitable for the synthesis of their gem‐dif­ luorinated derivatives; in addition, there are some approaches based on fluorination of the pre‐existing ring. The known methods can be categorized into the following subtypes (Scheme 5.4): (i) intramolecular Wurtz reaction (also called Freund reaction or Hass cyclopropane process [36]), (ii) nucleophilic fluorination of pre‐existing ring, (iii) cyclopropanation of 1,1‐difluoroalkenes,

5.1 Introduction O R3

R1

Et3N

R2

(a)

1 OTMS OTMS TMSCF2Br R R3 3 R R1 HMPA R2 F R2 F

Me3SiOTf

O

F

R1 TMSCF2Br

R2S

F F

R1 O

F

R1

78–98% (over 2 steps)

X

F

R2

X

F

F

F

or

AIBN 90%

OBn

F

R3

O

AcOH

CuCl

BnO

SnBu3

Br

OTMS R1

Bu4NBr

R2S X X = H, SR2

(b)

F

F F

HBr

BnO

F F

OBn

(c)

n

n = 1, 2 OH

Scheme 5.3  Ring opening of gem‐difluorocyclopropanes with retaining of the gem‐difluoro moiety.

R1 Br

F F

R3 Br R4

R2

Br F F R1

X X (i) F F

R3 Br R4

R2

R1 R2

R3 R4

BrF2C

F (iv)

(iii) F R1 C: + R3 R2

R1 R2

(ii)

C

F

F

R1

R3

R4

R2

R4

Br F

EWG

F F

F

–

EWG

Nu

Nu

Nu–

(v) EWG

R1

R1 Ri

R3 R4

F F

Ri

+

R2 R2 (vi) One of the possible examples

F F

Scheme 5.4  Synthetic approaches to gem‐difluorocyclopropanes.

(iv) difluorocyclopropanation of alkenes, (v) Michael‐induced ring closure (MIRC) of difluorobromometylacrylic acid derivatives, and (vi) reactions at the double bond of gem‐difluorocyclopropenes (e.g. (cyclo)additions). The following subsections of this chapter are organized according to this classification, the

139

140

5  Synthesis of gem‐Difluorocyclopropanes

largest being devoted to the most widely used approach, i.e. gem‐difluorocyclo­ propanation of alkenes (approach (iv)).

5.2 ­Intramolecular Wurtz (Freund) Reaction Intramolecular Wurtz (Freund) reaction was historically the first method for the preparation of gem‐difluorocyclopropanes. In 1955, Tarrant et  al. reported the reaction of isomeric 1,3‐dibromo‐2,2‐difluoromethylbutanes with Zn in n‐pro­ panol giving the corresponding dimethyl‐substituted gem‐difluorocyclopropanes in 27% and 39% yield (Scheme 5.5) [37]. One year later, Misani et al. reported the preparation of the parent 1,1‐difluorocyclopropane from 1,3‐dibromo‐2,2‐difluo­ ropropane using modified Freund conditions [38]. Nevertheless, the method found limited application further. In 2007, it was considered as a promising method for industrial synthesis of 1,1‐difluorocyclopropane in an autoclave using 1,3‐dichloro‐2,2‐difluoropropane as a starting material [39].

F

F Br

R1

R2 Br

R1

Zn dust, ZnCl2 n-PrOH

F

Zn dust MeCONH2, NaI Na2CO3

F F R2

Br

F R1 = Me; R2 = H, 39% R1 = H; R2 = Me, 27%

Br F F F F

Cl

Cl

Zn dust, n-PrOH, autoclave

Scheme 5.5  Synthesis of gem‐difluorocyclopropanes by the Freund reaction.

5.3 ­Nucleophilic Fluorination of Pre‐existing Ring System A general approach to gem‐difluorocycloalkanes by deoxofluorination of ketones with sulfur fluoride‐derived reagents [40–42] is not applicable to the synthesis of gem‐difluorocyclopropanes due to extreme instability of cyclopropanones [43]. Although cyclopropanone synthetic equivalents are widely used [44], to the best of our knowledge, fluorination of such substrates remains unknown. Nevertheless, nucleophilic fluorination was described for 1,1‐dichlorocyclopropanes bearing electron‐withdrawing groups. In 1990, Schlosser and coworkers described the formation of 1,1‐difluoro‐3,3‐dimethylcyclopropanecarboxylate in 60% yield upon treatment of the corresponding dichloro derivative with TBAF (Scheme 5.6) [45]. The reaction proceeded via a 1,2‐elimination/nucleophilic addition sequence and involved cyclopropane derivatives as intermediates. Later in 1996, Jonczyk and Kaczmarczyk extended the scope of the reaction to cyclopropyl sul­ fones and ketones [46].

Cl

Cl

TBAF·3H2O CO2t-Bu

F

F

Cl

Cl EWG

CO2t-Bu

MeCN

60%

R

R

R = H or Me EWG = CO2R, SO2Ph, C(O)Ph

TBAF·3H2O, DMF, 5 °C or KF, H2O, Bu4N+HSO4–, MeCN, 80 °C Cl

Cl CO2t-Bu

F

F CO2t-Bu

CO2t-Bu

F

EWG R

Scheme 5.6  Nucleophilic fluorination of 1,1‐dichlorocyclopropanes.

F

R

41–46%

5 examples

142

5  Synthesis of gem‐Difluorocyclopropanes

Another example of formal nucleophilic fluorination of 1,1‐dichlorocyclopro­ panes is the fluorination of 1,1‐dichlorocycloproparenes (Scheme  5.7). In this case, the fluorination occurs via formation of stabilized cycloproparenium ions. The most suitable conditions for such a transformation include treatment of the 1,1‐dichlorocycloproparene with excess of silver fluoride suspension in dry ace­ tonitrile [47, 48]. Cl Cl

AgF

+

X

F F

– AgCl

MeCN

85%

X = Cl, F

Scheme 5.7  Nucleophilic fluorination of 1,1‐dichlorocycloproparene.

The fluorination of gem‐dihalocyclopropenes was also reported. In particular, reaction of perchlorocyclopropene with SbF3 at 92 °C gave a mixture of 1,2‐dichloro‐3,3‐difluorocyclopropene, 1,2,3‐trichlorofluorocyclopropene, and unreacted starting material (2.5 : 1 : 1.1, 67% recovery) (Scheme 5.8) [49]. In the case of perbromocyclopropene, an analogous reaction was performed at 108– 109 °C, and the target 1,2‐dibromo‐3,3‐difluorocyclopropene could be obtained in 51% yield. It was suggested that in these examples, the driving force of the reaction was the formation of aromatic trihalocyclopropenium cations. X

X X

X X = Cl, Br

SbF3 92–109 °C

X

F

+

X X

F X

X 36–51%

Scheme 5.8  Fluorination of perhalocyclopropenes with SbF3.

5.4 ­Cyclopropanation of 1,1‐Difluoroalkenes The first example of fluorinated alkene cyclopropanation was described by Misani et al. [38]. The authors showed that reaction of 1,1,1,2,3,3‐hexafluoropro­ pene with diazomethane did not require promotion with UV irradiation and yielded 1‐trifluoromethyl‐1,2,2‐trifluorocyclopropane without isolation of inter­ mediate pyrazoline (Scheme  5.9). Similar reaction with 1,1‐difluoroethene did not lead to 1,1‐difluorocyclopropane even upon UV irradiation. While with mono‐fluorinated alkenes, various cyclopropanations have been widely used [9]; in the case of gem‐difluoroalkenes, only a few examples were described. In par­ ticular, cyclopropanation of 1,1‐difluoroalkenes bearing an electron‐withdraw­ ing group was reported by Suda in 1981 and by Haufe group in 2005. In the first case, treatment of an α,β‐unsaturated lactone with ethereal diazomethane with­ out promotion by light led to a mixture of the corresponding cyclopropane and pyrazoline; the latter could be transformed into the cyclopropane upon irradia­ tion with high pressure mercury lamp [50]. When the crude reaction product

5.5  Difluorocyclopropanation of Alkenes and Alkynes

F F

F3C

F

CH2N2

F

CH2N2, ether, 0 °C

F

Without hν

1. CH2N2, ether, 0 °C

F

Ph

30% F

O O

F

F3C

Without hν

F

F

CO2Et

2. hν (350 nm), Ph 4 days

O F

O

F 19%

F

F CO2Et 86%

OF F +

O N N 22%

CH2N2, ether, 0 °C hν

57%

Scheme 5.9  Cyclopropanation of gem‐difluoroalkenes with diazomethane.

was directly photolyzed, the cyclopropane was isolated in 57% yield. Similar pro­ cedure gave the corresponding gem‐difluorocyclopropane in 86% yield when applied to difluoroacrylate derivative, without isolation and/or characterization of an intermediate pyrazoline [19]. A single example of intramolecular Rh‐catalyzed cyclopropanation of gem‐dif­ luoroalkenes was described. The method was applied to the synthesis of the fluo­ rine‐containing activated analogue of natural sequence‐selective DNA alkylation agents, duocarmycins (Scheme  5.10) [20]. The reaction was promoted by Rh2(OAc)4 in toluene at 110 °C and gave the target product in 74% yield. F

F FF

N2 N

Rh2(OAc)4 O

O

Toluene, 110 °C

N

O 74%

O

Scheme 5.10  Intramolecular cyclopropanation of gem‐difluoroalkenes.

5.5 ­Difluorocyclopropanation of Alkenes and Alkynes Since the seminal paper by Haszeldine and coworkers [51] who described the reaction of cyclohexene with difluorocarbene generated by thermal decomposi­ tion of CF2ClCO2Na, difluorocyclopropanation of alkenes became the most important method for the gem‐difluorocyclopropane synthesis. As shown in Figure  5.5 [52], many various reagents were developed over the last 50 years. However, most of these methods presented mainly academic interest until recently. Only in 2010s the reaction has attracted attention of industrial chem­ ists, which has been reflected in more than 30 recent patent applications. The  main reason behind this might be the fact that most reagents for the

143

CHClF2 Robinson CF3SnMe3 Seyfert 1960 ClF2CO2Na Haszeldine N F and F coworkers N Mitsch

Hg(CF3)2 Knunyants CF2Br2, Pb Fritz 1980

PhHgCF3 Seyfert 1970

FSO2CF2CO2H Cd(CF3)2 Eujen Chen 1990 CF2Br2 or CF2I2, Zn Dolbier

Ph3P+CF2Br Burton

Br–

Bi(CF3)3 Yagupolskii 2000

FSO2CF2CO2SiMe3 Dolbier

Me3SiCF2Cl Huang, Hu BrCF2CO2Na Amii Me SiCF Br 3 2 Hu 2010 BrCF2PO(OEt)2 Burton Me3SiCF3 Hu, Prakash, Olah

Figure 5.5  Discovery of alkene difluorocyclopropanation reagents. Source: Nosik et al. 2017 [52]. Reproduced with permission of John Wiley & Sons.

5.5  Difluorocyclopropanation of Alkenes and Alkynes

­ ifluorocyclopropanation of alkenes known before 2010s either showed low effid ciency and limited substrate scope or were toxic and hardly available. Nevertheless, a comprehensive survey on all these difluorocyclopropanation systems is given in this subsection, taking into account both synthetic aspects (i.e. scope and limitations) and mechanistic considerations. Many of the difluorocyclopropanation methods involve formation of difluorocarbene, which has been discussed in a number of reviews [8, 10, 53], as well as in theoretical and experimental works [54–58]. These data show that difluorocarbene typically reacts in a singlet state as one of the most stable, selective (at least at room temperature), and low‐reactive electrophilic carbenes. Therefore, good preparative yields and diastereoselectivities might be anticipated in the difluorocyclopropanation reactions with sufficiently nucleophilic alkenes. The known methods for generation of difluorocarbene (or the corresponding carbenoids) in the difluorocyclopropanation reactions can be grouped into the following categories: ●● ●● ●● ●●

●● ●●

●● ●●

fragmentation of trihalomethyl anions CF2X− (X = Cl, Br) reduction of CF2Br2 with zinc or other reductants decarboxylation of CF2XCO2− (X = Cl, Br, F), FSO2CF2CO2−, and Ph3P+CF2CO2− nucleophilic cleavage of Ph3P+CF2Br, CF2ClCO2Me, FSO2CF2CO2TMS or FSO2CF2CO2Me, and BrCF2P(O)(OEt)2 decomposition of trifluoromethyl‐substituted organometallic compounds Lewis base‐promoted cleavage of the Ruppert–Prakash‐type reagents XCF2SiMe3 (X = F, Cl, Br) photodissociation of difluorodiazirine thermal decomposition of hexafluoropropene oxide (HFPO)

5.5.1  Fragmentation of Trihalomethyl Anions CF2X− (X = Cl, Br) The reaction of haloforms with a base generating dihalocarbenes, followed by their addition to alkenes is a common method for the preparation of gem‐ dichloro‐ and gem‐dibromocyclopropanes. However, in the case of gem‐ difluorocyclopropanes, this methodology faced considerable challenges. Early attempts in this area relied upon treatment of easily available CHClF2 (HCFC‐22, or R‐22) with bases (i.e. MeLi, t‐BuOK, NaOH in tetraglyme, or concentrated NaOH with a phase‐transfer catalyst) in the presence of alkene [59–62]. Under these conditions, only trace amounts of the target gem‐difluorocyclopropanes were formed. A solution to this problem was found by Buddrus and coworkers in 1976 via the reaction of chlorodifluoromethane and oxirane (or methyloxirane, chloromethyloxirane) in the presence of a tetrabutylammonium salt as a catalyst and alkene as a substrate [63]. The efficiency of the method was illustrated by 14 examples with good preparative yield of the products (52–85%). A possible mechanism of the process is shown in Scheme 5.11. The haloform is deprotonated by the halohydrin anion, which is formed upon the ring opening of the oxirane by the halide anion. The high efficiency of the method might be explained by a low concentration of base, which never exceeds the catalyst concentration. The intermediate formation of short‐living ClF2C− has been demonstrated experi-

145

146

5  Synthesis of gem‐Difluorocyclopropanes Bu4N+ Cl– +

O

O– Bu4N+ + CHClF2

Cl

:CF2 + Bu4N+Cl–

R1

R2

R3

R4

F F

:CF2 +

Ph

F F

R3 R4

R1 R2 F F

F F

Ph Ph

OH + CF2Cl– Bu4N+

Cl

CF2Cl– Bu4N+

F F

O– Bu4N+

Cl

F F

F F

F F

MeO 14 examples, 52–85%

Scheme 5.11  Synthesis of 1,1‐difluoroalkenes by the method of Buddrus and coworkers. Source: Kamel et al. (1976) [63]. Reproduced with permission from John Wiley.

mentally. Despite elegance and efficiency, the method did not find wide application due to the rather harsh conditions (heating in an autoclave at 140 °C). An alternative solution of the aforementioned problem was proposed by Balcerzak et al. in 1990s [64]. Their method relied on using CF2Br2 and involved its “halophilic” reaction of tri‐ or dibromomethyl carbanions (Scheme 5.12). The lipophilic ion pair Bu4N+CHBr2− formed upon deprotonation of CH2Br2 underwent the halophilic reaction with CF2Br2 yielding another ion pair Bu4N+CBrF2−, which generated :CF2 in the organic phase. The resulting carbene reacted with alkenes giving the target gem‐difluorocyclopropanes in good preparative yields. It was found that using CHBr3 instead CH2Br2 allowed shortening the reaction time. The difluorocarbene generated by this method was able to react only with sufficiently nucleophilic alkenes. For example, switching from Me2C═CMe2 to cyclohexene resulted in a drop of the yield from 70% to 55%. CH2Br2 (org) + Bu4N+ HSO4– (org) + KOH (aq) Bu4N+ CHBr2– (org) + CBr2F2 (org)

Bu4N+ CBrF2– (org) + CHBr3 (org) :CF2 + Bu4N+ Br–

Bu4N+ CBrF2– (org) :CF2

Bu4N+ CHBr2– (org) + KHSO4 (aq) + H2O

R1

R2

R3

R4

+

F F R1 R2

R3 R4

Scheme 5.12  Difluorocyclopropanation with CF2Br2 based on the halophilic reaction under phase‐transfer conditions.

5.5.2  Reduction of CF2Br2 with Zn or Other Reductants The latter approach shown in Scheme 5.12 can be formally considered as a two‐ electron reduction of CF2Br2 with CH2Br2 or CHBr3, followed by carbene generation. Similar strategy was also implemented in other works using metal‐based

5.5  Difluorocyclopropanation of Alkenes and Alkynes

or electrochemical reduction. The pioneering work describing electrochemical generation of difluorocarbene was published by Fritz and Kornrumpf [65]. It shown that cathodic reduction of CF2Br2 in the presence of alkenes in 0.35 M Bu4NBr–CH2C12 electrolyte with platinum electrodes at 0 °C to room tempera­ ture gave gem‐difluorocyclopropanes in up to 60% yield (Scheme 5.13). Later, the same group proposed an alternative version of the :CF2 generation using metallic lead as the reductant in the presence of TBAF in MeCN at 40–60 °C [66]. The latter method gave comparable yields to that of electrochemical reduction; how­ ever, the scope of the substrates was limited by sufficiently nucleophilic alkenes. F F 2e–

(Pt), 20 °C (i)

CF2Br2 Pb,

:CF2 Bu4N+Br–

MeCN, 40–60 °C

(ii)

R1

R4

R2

R3

Me Me F F R1 R2

Me Me Me Me

90% (ii) R4 R3

F F

F F

Me

54% (i) F F

Me Ph 57% (i) Ph 17% (ii) 55% (ii)

Scheme 5.13  Generation of :CF2 from CF2Br2 according to the methods of Fritz and Kornrumpf.

In 1990, Dolbier group reported two systems for generation of difluorocarbene from CF2Br2. First, it was found that Ti(0) species obtained from TiCl4 and LiAlH4 in THF generated the: CFCl carbene from CFCl3 via [ClTiCFCl2] as reac­ tive intermediate (Scheme 5.14). The resulting carbene reacted smoothly with a wide range of nucleophilic alkenes in high yields [67]. Applying this procedure to CF2Br2 and 2‐phenylpropene gave the target product in 45% yield; however, fur­ ther extension of the reaction scope appeared to be not feasible. An alternative method was proposed that relied on the use of Zn in THF at room temperature [68]. In the case of electron‐rich alkenes, the procedure gave the target products in good yields (71–96%); however, with less nucleophilic substrates (i.e. cyclohex­ ene or 1‐hexene), the reaction outcome was unfavorable. The Zn‐based protocol was used by Dolbier et al. for mechanistic study of dehydrofluorinative aromati­ zation reactions of 6,6‐difluorobicyclo[3.l.0]hex‐2‐enes [69]. Model 6,6‐di‐ fluorobicyclo[3.l.0]hex‐2‐ene, along with its deuterated and benzo analogues, were synthesized by difluorocyclopropanation of cyclopentadiene and indene. Further studies of the Zn/CF2Br2 system showed that low yields observed with less reactive substrates could be explained by radical side processes. In particular, reaction of cyclohexene with Zn/CF2Br2 in various solvents without any additive led to mixtures of the products 1–3 (Scheme  5.15) [70]. This result can be explained by a single electron transfer (SET) between zinc and CF2Br2, which leads to the formation of radical anion CF2Br2˙−. A second electron transfer can produce the difluorobromomethyl anion, which subsequently dissociates to give difluorocarbene. However, the radical anion might also dissociate to form the difluorobromomethyl radical. Capture of the CF2Br˙ radical by cyclohexene

147

148

5  Synthesis of gem‐Difluorocyclopropanes

F Cl TiCl4 + LiAlH4 Ti(0) + CFCl3 Ti(0) + CF2Br2

0 °C, THF 0 °C, THF 0 °C, THF

Ti(0) + AlCl3 + LiCl + 2H2 [ClTiCFCl2]

:CFCl + TiCl2

[BrTiCF2Br]

:CF2 + TiBr2

71%

CF2Br2, Zn, I2 (cat.), rt

O

78%; syn:anti = 1.29

F Cl

F F

F F Me Me

Me Me

Me Ph

66%

F Cl

Me Me Ph Ph 45% 79%; syn:anti = 1.02

F F

F F

Me Me

Me Me

Me Me

96%

F F

Me 72%

7% F F

CF2Br2, Zn(0) Zn, I2, THF, rt, 1 h

Δ quant.

F F C4H9 6% F

19–29%

Scheme 5.14  Generation of difluorocarbene from CF2Br2 according to the methods of Dolbier and coworkers.

CF2Br2, Zn

F + F

SolH 1

SolH – solvent CF2Br2 + Zn Br– + CF2Br•

2 SET

CF2Br.

3

Zn2+ + Br– + CF2Br–

:CF2 + Br – CF2Br

CF2Br + CF Br 2 2

CF2Br +SolH –

CF2Br

[Zn+ CF2Br2•–]

[Zn+ CF2Br2•–] CF2Br –

3

CF2Br + Br

Sol•

• 4

– CF2Br•

Br 2

+ Zn

SET

F F

– ZnBr

•

1

Scheme 5.15  Radical processes in the Zn/CF2Br2 system.

gives the radical intermediate 4. Bromine atom abstraction from CF2Br2 with 4 yields compound 2 with regeneration of the CF2Br˙ radical. Intermediate 4 can also abstract hydrogen from the solvent to form 3. Moreover, it was showed that the difluorocyclopropane formation also occurred via the SET zinc‐participated reductive debromination of 4.

5.5  Difluorocyclopropanation of Alkenes and Alkynes

Formation of the CF2Br˙ radical was also observed for the electrochemical dif­ luorocarbene generation. Thus, electrochemical reduction of CF2Br2 in the pres­ ence of ethyl acrylate might give three products depending on the potential chosen for electrolysis (Scheme 5.16) [71]. The data obtained confirmed initial electrochemical SET for the reduction of CF2Br2 since the intermediate CF2Br˙ radical could be trapped by the activated olefin.

CF2Br2 +

e–

SET

CF2Br2•–

Br –

(1) CH2CH2CO2Et (2) Solvent + CF2Br F2BrC + e–

CO2Et F

CO2Et

•

CH2CH2CO2Et

– Br– CF2CF2

:CF2

F

Scheme 5.16  Radical processes in the electrochemical reduction of CF2Br2.

5.5.3  Decarboxylative Difluorocarbene Generation Decarboxylative difluorocarbene generation relies on the use of reagents bearing a carboxylic function and a good living group at the gem‐difluorosubstituted car­ bon atom. At elevated temperatures, the corresponding carboxylate anions undergo cleavage of two bonds resulting in formation of difluorocarbene, CO2, and leaving group as an anion (Scheme  5.17). The first reagent based on this principle – ClCF2COONa – was introduced by Haszeldine and coworkers in as early as 1960 [51]. Further developments in this area led to development of CF2BrCOONa (Amii and coworkers in 2010) [72], fluorosulfonyldifluoroacetic acid, FSO2CF2COOH (Chen and Wu in 1989) [73], and Ph3P+CF2CO2− (Xiao and coworkers in 2013) [74]. F F

ONa

Cl F F X O

O–

F + CO F X– + C 2

O Haszeldine and coworkers [51] F F FO2S

OH

O

Chen and Wu [73]

F F Br

ONa

O

Amii and coworkers [72] F F +P

Ph3

O–

O

Xiao and coworkers [74]

Scheme 5.17  Reagents for decarboxylative difluorocarbene generation.

By far, ClCF2COONa is most popular and widely used reagent for the difluoro­ cyclopropanation. More than 40 scientific papers and over 10 patents reported successful applications of this reagent. Typically, the reactions are performed by

149

150

5  Synthesis of gem‐Difluorocyclopropanes

refluxing thoroughly dried sodium chlorodifluoroacetate with alkene in diglyme or triglyme, in some cases in the presence of 18‐crown‐6 as a catalyst. Typical reaction temperature is 180 °C. Although lithium chlorodifluoroacetate was shown to be more effective, particularly in diglyme as the solvent [75], the more accessible sodium salt became more popular. To achieve good yield of the prod­ uct, excess of the difluorocarbene precursor (sometimes over 10‐fold) is required. The method was successfully applied to the difluorocyclopropanation of enol ethers and esters, esters of allylic alcohols, 2‐phenylpropenoic acid, and steroids; representative examples of such transformations were reviewed in 1996 [76]. Since then, some principally new types of alkenes were introduced into this reaction. In 1997, Taguchi and coworkers introduced two stereoisomers of γ‐silylated O‐benzyl‐protected allylic alcohols into the difluorocyclopropanation with ClF2CCOONa, which gave both isomers of the corresponding TMS‐substituted gem‐difluorocyclopropanes in a diastereoselective manner (Scheme 5.18) [77]. These compounds were prepared to check the possibility of difluorocyclopropyl anion generation. All the previous attempts to generate such species by deproto­ nation of difluorocyclopropane derivatives with alkyllithium were unsuccessful due to facile β‐elimination of LiF. In the case of silylated difluorocyclopropanes, generation of such anions became possible upon treatment with TBAF in 1,3‐ dimethylimidazolinone, with subsequent trapping by aldehyde. Unfortunately, this step of the process lacked diastereoselectivity. BnO

ClF2CCOONa diglyme, 180 °C SiMe3 BnO

Me3Si

83%

ClF2CCOONa diglyme, 180 °C 50%

F F BnO

SiMe3 F F

BnO

TBAF (4 mol%) DMI BnO

F F –

F F

ArCHO 45–65%

SiMe3

BnO

Ar

5 examples OH

DMI = 1,3-Dimethylimidazolinone

Scheme 5.18  Generation of difluorocyclopropyl anion from TMS‐substituted difluorocyclopropanes.

In 1999, the same group reported the difluorocyclopanation of other TMS‐ substituted allylic alcohols (Scheme 5.19) [78]. In particular, difluorocyclopro­ panation of alkenes bearing the geminal CH2OR (R  =  Ac or Bz) and TMS substituents  at the double bond led to the corresponding difluoro­c yclo­pro­ panes in 76–94% yield. Their treatment with TBAF afforded the corresponding carbanion, which was followed by β‐elimination giving fluorinated methylene­ cyclopropanes. This method was used for the preparation of gem‐difluorinated analogues of a natural amino acid, methylenocyclopropylglycine (MCPG). In 2008, Fujioka and Amii reported the difluorocyclopropanation of alkenyl boronates with ClCF2COONa that gave the expected boron‐substituted gem‐dif­ luorocyclopropanes in a diastereospecific manner (Scheme  5.20) [79]. Other sources of difluorocarbene (such as trimethylsilyl fluorosulfonyldifluoroacetate (TFDA)/NaF) gave unsatisfactory results. Treatment of the resulting boronates

5.5  Difluorocyclopropanation of Alkenes and Alkynes

R2

ClF2CCOONa diglyme, 180 °C

SiMe3 OR1

F F R2

76–94%

TBAF (2 equiv.) diglyme SiMe3

F F OR1

R2

OR1

1

F F

–

R2 66–91%

R = Ac, Bz, Ms R2 = Alk, Ar, OCH2PMB F F

F F

COOH

COOH

NH2

COOH

NH2

Natural MCPG

NH2

2S,1S-F2MCPG 2S,1R-F2MCPG

Scheme 5.19  Synthesis of methylenecyclopropanes from TMS‐substituted difluorocyclopropanes. R3 R1

B O

R2

O

(i) or (ii)

F R1

46–80% 7 examples

F

R2

R3 B O

ClCH2Li

O

F

F R1

THF, –78 °C to rt

R2

(i) ClCF2CO2Na (8 equiv.) diglyme, 180 °C, 15 min (ii) ClCF2CO2Na (3–4 equiv.) diglyme, 180 °C, 5–8 h

F

BnO

F

B

O O

59%

F

F B

Ph

O

F

F

O

B Me3Si

50%

R3

F B

O

71%

O

77–95% 3 examples

F

O

O B

O O

74%

Scheme 5.20  Synthesis of gem‐difluorocyclopropyl‐substituted organoboron derivatives.

with lithium carbenoids resulted in their one‐carbon Matteson homologation giving gem‐difluorocyclopropyl‐substituted derivatives of methylboronic acid. In 2012, Komarov and coworkers extended the scope of the difluorocyclopro­ panation with ClCF2COONa to proline‐derived enecarbamates [23]. The reac­ tion proceeded in diglyme at 177 °C and used large excess of ClCF2COONa. In the case of a protected dipeptide‐like substrate, a mixture of two diastereomers was formed in 58% yield and c. 1 : 5 dr (Scheme 5.21). Both diastereomers were

N

N

F CO2t-Bu ClF2CO2Na (27 equiv.) F diglyme, 177 °C O 58% Boc

N

CO2t-Bu O

N cis, 10%

Boc

F F

N

CO2t-Bu O

+ N trans, 48%

Scheme 5.21  Difluorocyclopropanation of proline derived enecarbamate.

Boc

151

152

5  Synthesis of gem‐Difluorocyclopropanes

further used for the synthesis of conformationally restricted fluorine‐labeled polypeptides. At the moment, the scope and limitations of the difluorocyclopropanation with ClCF2COONa are well studied making the procedures widely used for the synthesis of novel compounds for medicinal chemistry, agrochemistry, and materials science. To introduce functional groups, protection of alcohols as esters, ethers, or silyl ethers are typically used. After the difluorocyclopropana­ tion step, deprotection and further functionalization at the alcohol moiety are performed. For example, Itoh group developed lipase‐catalyzed chiral desym­ metrization of prochiral gem‐difluorocyclopropane‐derived diols. These chiral building blocks were used to design liquid crystals (see also Figure 5.4) [80–84]. Also, the ClCF2COONa‐based cyclopropanation was used for the synthesis of building blocks for fluorinated nucleoside analogues (see also Figure  5.3) [22, 85–87], 1‐amino‐2,2‐difluorocyclopropane‐1‐carboxylic acid (DFACC, a fluori­ nated analogue of natural 1‐aminocyclopropane‐1‐carboxylic acid, ACC) [88], and clinical candidate Zosuquidar (Figure 5.1) [89]. Applications of this decar­ boxylative strategy in medicinal chemistry were recently reviewed [12]. The closest analogue of ClCF2COONa is BrCF2COONa, which was intro­ duced as the difluorocarbene source by Amii and coworkers [72]. The main rea­ son behind such replacement was the highly hygroscopic and deliquescent nature of ClCF2COONa, while BrCF2CO2Na lacks such deficiencies. Moreover, com­ parative studies of ClCF2COONa and BrCF2COONa clearly demonstrated enhanced reactivity of the latter reagent: similar conversion of the substrates could be achieved at either about fourfold diminished excess of the reagent or the temperatures lowered by 30–70 °C. It should be noted that CF3COONa was also used as the difluorocarbene source for difluorocyclopropane synthesis [90]. In this case, however, the carbene gen­ eration required not only thermal activation but also radical initiation with AIBN. The optimal conditions were established using 2‐phenylpropene as a model sub­ strate. They included heating of the alkene with CF3COONa (2 equiv) and AIBN (1 equiv) in DMF at 170 °C, which gave the target product in 86% yield. The exact role of AIBN in this reaction is still unknown; the mechanism is evidently more complex as compared to that for the simple thermal ClCF2COONa decomposi­ tion. Notably, difluorocyclopropanation of either nucleophilic or electrophilic alkenes (such as tetrachloroethane and acrylonitrile) with CF3COONa/AIBN ­system gave comparable yields of the target products (46–88%). The halogen atom in difluorohaloacetates can be substituted with other good leaving groups. In 1989, the fluorosulfonyl group was proposed by Chen and Wu for that purpose [73]. Fluorosulfonyldifluoroacetic acid smoothly decomposes in basic conditions giving CO2, SO2, F−, and difluorocarbene. In this pioneering paper, the principal ability of FSO2CF2CO2H to act as the difluorocyclopropana­ tion agent was demonstrated by a single example (Me2C═CMe2). Although the yield of the corresponding gem‐difluorocyclopropane was moderate (53% on 1.5 g scale), the conditions were dramatically milder as compared to ClCF2COONa (acetonitrile, Na2SO4 as a weak base, 60 °C, two hours). Further development of this reagent was not performed due to synthesis of its more efficient derivatives discussed in the subsection 5.5.4.

5.5  Difluorocyclopropanation of Alkenes and Alkynes

A new generation of difluoroacetate‐based reagents was introduced by Xiao and coworkers [91]. It was found that reaction of BrCF2CO2K with PPh3 pro­ ceeded smoothly in DMF at room temperature, giving Ph3P+CF2CO2− (PDFA) in 67% yield on up to 40 g scale (Scheme 5.22). Initially, this reagent was designed as a convenient source of difluoromethylene(triphenyl)phosphorane (Ph3P═CF2) for its further use in the Wittig reaction. Although such application of PDFA was successfully demonstrated, it was also shown that Ph3P═CF2 is not stable and could easy decompose to Ph3P and difluorocarbene. This possibility was success­ fully exploited by Xiao and coworkers. Thus, heating of PDFA with alkenes in p‐xylene at 90 °C gave the corresponding difluorocyclopropanes in good yields (50–92%) [74]. Ph3P + BrCF2CO2K Ph3P+CF2CO2–

R2

R1 R2

CF2

+

NMP 80 °C, 4 h

Ph3P CF2CO2

–

Ph3P + :CF2

R1

R3

R2

R4

F 69%

F F

p-Xylene 90 °C, 8 h

F

F 85%

Ph3P+CF2CO2– + KBr

O

F MeO

67%

CO2 + Ph3PCF2 R1

13 examples 65–96%

DMF, rt

R1 R2

R3 R4

F

F

F

F O2N

MeO 92% +

6 examples 50–93%

50%

−

Scheme 5.22  Preparation and chemical properties of Ph3P CF2CO2 (PDFA).

5.5.4  Difluorocarbene Generation by Nucleophilic Cleavage of a Carbene Precursor Methods for the difluorocarbene generation discussed in the subsection  5.5.3 can be consider as “self‐initiated” by the lone pair of the carboxylate anion. Another group of the difluorocyclopropanation reagents include compounds that decompose upon initiation by an external lone pair of a nucleophile (Figure 5.6). The first reagents of this type were introduced by Burton and cow­ orkers, methyl chlorodifluoroacetate in 1976 [92], and the phosphonium salt derived from CF2Br2 and PPh3 in 1973 [93]. Also, derivatives of fluorosulfo­ nyldifluoroacetic acid are widely used, namely, methyl and trimethylsilyl esters; these reagents were proposed by Chen and coworkers [94]. Finally, Zafrani et al. introduced bromodifluoromethyl phosphate in 2009, which can be considered as a phospha analogue of methyl chlorodifluoroacetate [95]. In 1973, Burton and Naae reported the study on the reaction of Me2C═CMe2 and Ph3P+CF2BrBr− in the presence of a nucleophile (Scheme  5.23). The dif­ luorocarbene generation was expected to be efficient due to the formation of thermodynamically stable Ph3P═O. Nevertheless, initial results with the aid of

153

154

5  Synthesis of gem‐Difluorocyclopropanes

F F

F F

OMe

Cl

FO2S

O

F F

O

FO2S

O

Burton and coworker [92]

SiMe3

O

Chen and Wu [73]

Chen and coworkers [94] F F

F F

Br– P+Ph3

Br

O

Br

Burton and Naae [93]

OEt P OEt O

Zafrani et al. [95]

Figure 5.6  Reagents for difluorocarbene generation by nucleophilic cleavage. F F Me2CCMe2 + Ph3P+CF2Br Br– + NaOMe

Ph3

P+CF

2Br

Br–

MeO–

Br–

Me Me

+ Ph3PO + MeBr + NaBr Me Me 21%

H3C

O F Ph P F Ph Ph Br

:CF2 + Ph3PO + MeBr

F F Me2CCMe2 + Ph3P+CF2Br Br– + CsF

Ph3P+CF2Br Br–

Br F Ph P F Ph Ph Br

F–

Me Me

+ Ph3PFBr + CsBr Me Me 79%

Br Ph - FF P Ph Ph F Br

:CF2 + Ph3PFBr

Scheme 5.23  Difluorocyclopropanation with Ph3P+CF2Br Br−.

MeONa as a nucleophile source gave the target gem‐difluorocyclopropane in low yield (21%) due to the side reaction of :CF2 with MeO−. Taking into account the high strength of P─F bond (c. 117 kcal/mol), the authors had switched to F− instead of MeO− (i.e. CsF was used), which led to significant increase of the prod­ uct yield (79%). It was found that (Me2N)3P+CF2Br Br− was also efficient in this transformation; however, the yield of the gem‐difluorocyclopropane was slightly lower (65%). Initial studies of the substrate scope showed that tetra‐, tri‐, and gem‐disubsti­ tuted alkenes afford difluorocyclopropanes in high yields, while 1,2‐disubsti­ tuted alkenes react unsatisfactory, with an exception of strained trans‐cyclooctene giving the target product in 92% yield [96]. In 1990, further development of the method was described by Schlosser group [97]. First of all, it was shown that Ph3P+CF2Br Br− could be easily generated as a suspension in 1,2‐dimethox­ yethane (DME) from Ph3P and CF2Br2 prior the reaction and used without isola­ tion. The best yields were achieved when the KF/18‐crown‐6 system was used as

5.5  Difluorocyclopropanation of Alkenes and Alkynes

the F− source. Moreover, comparative studies of ClCF2COONa, ClCF2COOMe, and Ph3P/CF2Br2 as the :CF2 sources showed that the latter system gave the best results [98]. The procedure gave good results with vinyl ethers (73–88% yield) and trisubstituted alkenes (89% yield). In the case of 1,2‐disubstituted alkenes the yields were moderate (37–43%). The method did not find such wide application so far as compared to the ClCF2COONa‐based one; nevertheless, it was chosen by de Meijere and coworkers as one of the best for synthesis of ferroelectric liq­ uid crystalline compounds bearing difluorocyclopropyl moiety (Scheme  5.24) [26, 27]. CBr2F2, Ph3P KF, 18-crown-6, DME, 20 °C

F F

THPO

THPO

58%

CBr2F2, Ph3P KF, 18-crown-6, DME, 20 °C THPO

F

F F

F

+ HO

HO

32%

38%

Scheme 5.24  Synthesis of building blocks for ferroelectric liquid crystals.

ClCF2COOMe was another reagent for the difluorocyclopropanation intro­ duced by Burton and coworker [92]. In 1976, they reported that treatment of ClCF2COOMe with twofold excess of LiCl/HMPA in the presence of alkenes in triglyme at 80 °C gave the corresponding gem‐difluorocyclopropanes. In the case of nucleophilic alkenes, yields were high (Me2C═CMe2, 90%; Me2C═CHMe, 45%, Me(MeO)C═CHMe, 70% (at 1 : 1 ratio of the alkene and ClCF2COOMe)); however, the yield decreased to 15% in the case of cyclohexene. In the study by Schlosser and coworkers mentioned above [98], the method demonstrated satis­ factory but lower efficiency as compared to ClCF2COONa and Ph3P/CF2Br2. Nevertheless, the reaction conditions using either LiCl/HMPA or KF/18‐crown‐6 were significantly milder (DME, 95 °C) than in the case of ClCF2COONa decomposition. Derivatives of fluorosulfonyldifluoroacetic acid proposed by Chen and cow­ orkers are currently the second most popular reagents for the difluorocyclopro­ panation of alkenes (after ClCF2COONa). Since the parent FSO2CF2CO2H is very strong acid, its application is problematic because most alkenes are prone to polymerization under strongly acidic conditions. Thus FSO2CF2CO2SiMe3 (TFDA) [94] and later FSO2CF2CO2Me (MFDA) [99] were introduced into the synthetic practice in 2000 and 2012, respectively. In the case of TFDA, NaF was used as the nucleophilic activator, whereas MFDA was activated by KI/TMSCl system (Scheme 5.25). As it follows from the scheme, activation of TFDA is cata­ lytic, whereas in the case of MFDA, equimolar amounts of the activating rea­ gents are necessary. The pioneering studies on TFDA as the difluorocarbene source showed that  using 0.012 equiv of NaF in toluene at 105 °C is very efficient for the

155

156

5  Synthesis of gem‐Difluorocyclopropanes

F F FO2S

O

O TFDA F F

FO2S MFDA

SiMe3

F–

O

I–

O

Si

O

H3C

F FO S F O O

O

F FO S F O O

FSiMe3 + CO2 + :CF2 + SO2 + F–

I–CH3 + CO2 + :CF2 + Si Cl

SO2 + FSiMe3 + F–

Scheme 5.25  Generation of difluorocarbene from TFDA and MFDA.

­ ifluorocyclopropanation of terminal alkenes having various substituents, even d highly electron‐deficient acrylic esters (Scheme 5.26). It was an unprecedented F F

+ TFDA (1.5 equiv.) R

NaF (0.012 equiv.) Toluene 105 °C, 2 h

F F 74% R

F F

F F n-C6H13

OBz 78%

F F

89%

F F OBz

O-nC4H9 O

73%

OBz 97%

Scheme 5.26  Initial results on the scope of TFDA/NaF system.

achievement, which was indexed in Organic Syntheses as an efficient preparative method for the multigram synthesis of n‐butyl gem‐difluorocyclopropanecar­ boxylates [100]. Nevertheless, attempts to extend the scope of this procedure to other types of alkenes demonstrated its insufficient generality [101]. Such unusual reactivity toward electron‐deficient alkenes, as well as the observed solvent effects, prompted mechanistic studies of the difluorocyclopro­ panation by TFDA. First of all, solubility of the fluoride source was important for the reaction outcome so that higher temperatures and excess of TFDA increased the yield of the product. Comparative reactivity/selectivity study showed that TFDA was not an exclusive carbene source reacting with acrylates. In particular, difluorocarbene generated from ClCF2CO2Na was also suitable for the butyl acrylate difluorocyclopropanation, although the reaction temperature was much higher in this case. Taking into account the temperature difference, the observed relative reactivities of 1‐octene and acrylate toward TFDA and ClCF2CO2Na were similar. Two other competitive studies showed that difluorocyclopropana­ tion with TFDA preferred electron‐rich substrates. The experiments also showed that in the case of allylic esters, the coordination of oxygen atoms was not involved. Finally, the electrophilic nature of TFDA‐derived difluorocarbene was confirmed by reactivity of various p‐substituted α‐methylstyrenes. As it was found from a series of competition experiments, the effect of the substituents on the reactivity correlated with Hammett constant values (given in brackets): p‐ CH3 (1.30) > H (1.00) > p‐F (0.84) > p‐Cl (0.85) > p‐CF3 (0.35).

5.5  Difluorocyclopropanation of Alkenes and Alkynes

In the aforementioned studies, it was found that trace amounts of FSO2CF2CO2H in TFDA could inhibit the reaction completely. Therefore, TFDA must be handled with great care: it is highly moisture sensitive, has poor shelf stability, and is most effective when prepared immediately and re‐distilled (sometimes several times) prior the use. To eliminate these issues, FSO2CF2CO2Me (MFDA), which is more stable and less moisture‐sensitive and has reasonable shelf stability, was proposed. Activation of MFDA (used at twofold excess to alkene) was performed with KI (2.25 equiv) and TMSCl (2.0 equiv) in diglyme/dioxane as the solvent at 120 °C. At these conditions, various substrates gave good preparative yields of the target gem‐difluorocyclopropanes (BzOCH2CH═CH2: 70%; CH2 = CHCO2nC4H9: 76%; cyclooctene: 65%; trans‐stilbene: 71%). Also, the possibility of scale‐up was dem­ onstrated. Moreover, TMS2O could be used as a co‐activator instead of more elec­ trophilic TMSCl. Since the first results on the difluorocyclopropanation with MFDA were pub­ lished only in 2012 (12 years after the disclosure of TFDA), relative popularity of these reagents is difficult to compare. Despite the aforementioned drawbacks of TFDA, this reagent became one of the most widely applied. In particular, TFDA was used to expand the scope of the difluorocyclopropanation to various func­ tionalized substrates. Thus, protected α,β‐unsaturated aldehyde and ketone derivatives were successfully subjected to the reaction giving the corresponding gem‐difluorocyclopropanes (Scheme  5.27) [102]. After deprotection of the resulting products, gem‐difluorocyclopropyl ketones or 1‐aryl‐2‐fluorofuran derivatives (resulting from the cyclopropane ring opening) were obtained. Later, it was found that TFDA can be used to perform difluorocyclopropanation of unprotected aryl vinyl ketones, which could be used for the preparation of aryl 3‐bromo‐2,2‐difluoropropyl ketones [103], β‐trifluoromethyl‐ and β‐halodifluo­ romethyl‐substituted ketones [104], 2‐alkylideneazetidines [105], and 2‐fluoro­ pyrroles [106]. TFDA (0.2 equiv.) cat. NaF, 120 °C O diglyme F

Ar

17 examples 42–72% R = H, Me, Ar R

O

O Ar

Ar O F

R

H2C2O4 dioxane

O Ar

O

TFDA (0.2 equiv.) cat. NaF, 110 °C O neat Ar 5 examples 47–49%

R

Ar

F F

F

F + O

R

F

Scheme 5.27  Synthesis of 2,2‐difluorocyclopropyl ketones.

Another improvement based on the use of TFDA included difluorocyclopro­ panation of allenes. Previous attempts to perform this transformation using PhHgCF3 or ClCF2CO2Na resulted in either double cyclopropanation or forma­ tion of the product mixtures. In 2003, Chen and coworkers demonstrated ­advantages of TFDA in this reaction [107]. To differentiate the reactivity of two

157

158

5  Synthesis of gem‐Difluorocyclopropanes

allenic double bonds, tosylallene derivatives were used as substrates (Scheme  5.28). The reaction gave moderate to good yields of target difluoro­

R1

TFDA (2 equiv.) cat. NaF, 120 °C xylene, 3 h

.

R2

Ts

X

Ts

F

F

R1, R2 = Alk 5 examples, 60–88%

X R1 R2 49–80% F

R1 R2

Ts NAlk2 50–80%

F

F

R1 = R2 = Me toluene, 120 °C 3 days Ts

R1 R2

Distal cleavage X2 Diels–Alder (X = Br, I) via radical reaction intermediates F MeCN F H Heck 50 °C reaction Ts R1 2 R Alk2NH Proximal cleavage via carbanionic CHCl3 intermediates 50 °C, 2 h

F 45%

F F

F 30%

Ts

ArI , Pd(PPh3)4 AgCO3 F DMF, 120°C F

Ts

Ar Ts

R1

R2

25–66%

R1 R2

[BMIm][PF6] 50 °C, 20 h

F F Ts >90%

Scheme 5.28  Synthesis and chemical properties of difluoro(methylene)cyclopropanes.

(methylene)cyclopropanes (F2MCPs) in toluene or xylene as solvent. Substituents at the double bond had critical effect on the substrate reactivity: allenes with two  geminal alkyl substituents reacted smoothly and regioselectively, whereas mono‐ (R1 = R2 = H) and 1,3‐disubstituted (R1 = H, R2 = Me) allenes did not give the target products at all. This might be related to the lower electron density at the corresponding double bonds. It should be noted that the isomeric products of formal difluorocyclopropanation at electron‐deficient double bond of the allene could be obtained in moderate yield by thermal rearrangement of F2MCP [108]. Similar to the case of 2,2‐difluorocyclopropyl ketones, the elaboration of a convenient preparative method for the preparation of F2MCPs boosted the stud­ ies of their chemical properties. Currently, at least four types of transformations were described for these compounds, including Heck reaction with aryl iodides, two different types of the cyclopropane ring opening (at the distal and proximal bonds of the ring), as well as regio‐ and stereoselective Diels–Alder cycloaddi­ tions [109, 110]. Recently, an alternative approach to F2MCPs was elaborated, which also involved the use of TFDA as the difluorocarbene source. In this case, the method relied on the Ireland–Claisen rearrangement of gem‐difluorocyclopropene deriv­ atives, in turn prepared by difluorocyclopropenation of readily available propar­ gyl glycolates (Scheme 5.29) [111]. The procedure was developed to perform both these transformations in a one‐pot manner, without isolation of unstable interme­ diate 3,3‐difluorocyclopropenylcarbinyl glycolates. The Ireland–Claisen rear­ rangement proceeded with high diastereoselectivity; the complete chirality transfer was observed to give alkylidene(gem‐difluoro)cyclopropanes incorporat­ ing a quaternary stereocenter and a protected glycolic acid moiety. The target

5.5  Difluorocyclopropanation of Alkenes and Alkynes TFDA (3 equiv.) R2 cat. NaF, 120 °C diglyme, 3 h R1

R1 O

R2

O

O

F F

OTBDPS O

Ph

OMe

PMBO

48%

2. NH4Cl, H2O OPMB 3. TMSCHN2

O

OPMB

1. TMSCl (4 equiv.), KHMDS, THF –78 °C to rt R1

F F

R2 O PMBO

F F O

BnO

BnO

OMe

PMBO

OMe

11 examples 40–76%

F F

43%

F F

40% PMBO

OTBDPS O OMe

Scheme 5.29  One‐pot difluorocyclopropenation/Ireland–Claisen rearrangement sequence for the synthesis of alkylidene(difluoro)cyclopropanes.

products are useful polyfunctional building blocks for the preparation of func­ tionalized gem‐difluorocyclopropanes. Currently, TFDA is widely used for the synthesis of various gem‐difluorocyclo­ propyl‐substituted building blocks for medicinal chemistry. An important fea­ ture of such structures is their polyfunctionality; thus, tolerance of the difluorocyclopropanating reagent is critical for rational design of the synthetic routes. Many useful data about possible side processes involving TFDA were obtained from studies on the difluorocyclopropanation of nucleoside derivatives [112]. One of such processes is insertion of difluorocarbene into the X─H bonds. It should be noted that difluoromethylation at the hydroxyl groups was reported in a pioneering paper of Chen and Wu [73]; in the case of nucleosides, other types of such transformations were discovered. In particular, reaction with an uracil derivative resulted in difluoromethylation at the carbonyl group at the C‐4 position of the pyrimidine ring. In the case of an adenosine derivative, difluoro­ carbene reacted at the low‐basic amino group yielding the N‐difluoromethyl derivative together with the hydrolysis product. Protection of the amino group with benzoyl moiety did not help since, in that case, difluoromethylation occurred at the amide oxygen. Even in the case of N‐phthaloyl derivative, an unexpected product of the carbene attack at the imidazole ring was obtained (Scheme 5.30). The rate of the latter process was comparable with that of alkene difluorocyclo­ propanation so that both reaction centers entered the reaction in the case of adenosine derivative bearing an activated double bond. Similar process was extended to (benz)imidazoles with free C‐2 position [112]. It was shown that formation of N‐difluoromethyl(benz)imidazolin‐2‐tiones had general scope, and reasonable mechanistic explanation was provided. F F O AcO

N OAc N

TFDA (4 equiv.) NaF cat.

N NPhth N

Toluene reflux, 14 h

O AcO 11%

F

S N

OAc N

N

F NPhth

N

Scheme 5.30  Studies on the difluorocyclopropanation of nucleoside derivatives.

159

160

5  Synthesis of gem‐Difluorocyclopropanes

The abovementioned study showed that the phthalimide protection is compat­ ible with TFDA‐mediated cyclopropanation and it was used for the preparation of other building blocks (Scheme 5.31). Thus, two diastereomeric conformation­ ally restricted fluorinated analogues of γ‐aminobutyric acid (GABA) were pre­ pared by difluorocyclopropanation of N‐Phth‐protected unsaturated amino acids [113]. Similar transformations were used in the syntheses of building blocks for hepatitis C virus (HCV) inhibitors [114] and anti‐HIV compounds [115] per­ formed by Gilead Science chemists. PhthN

TFDA (4 equiv.) PhthN NaF cat. Toluene reflux, 16 h

PhthN

COOMe

COOMe

F

F 63%

TFDA (4 equiv.) PhthN COOMe NaF cat. Toluene reflux, 16 h

COOMe

F

F 62% F

TFDA (4 equiv.) NaF cat. PhthN

OAc

THF, reflux

PhthN

F

OAc 34%

PhthN

OCOtBu

TFDA (4 equiv.) PhthN NaF cat. Toluene reflux, 15 h

OCOtBu

F

F

27%

Scheme 5.31  Difluorocyclopropanation of polyfunctional compounds bearing phthalimide moiety.

The tolerance of other protective groups toward TFDA is not so clear. In par­ ticular, difluorocyclopropanation of cyclic N‐Boc‐protected enecarbamates was described by Kubyshkin et al. (Scheme 5.32a) [116]. Reaction of TFDA and an N‐Boc‐protected secondary amine bearing a non‐activated double bond was described in a patent, although the yield of the product was not given in that case (Scheme 5.32b) [117]. In a recent study, however, it was shown that difluorocy­ clopropanation of less reactive alkenes bearing the N‐Boc moiety with TFDA could be accompanied by attack of difluorocarbene at the carbamate group, lead­ ing to the corresponding difluorocarbamate [118]. In particular, a tropane deriv­ ative reacted with TFDA in refluxing toluene to give a mixture of three compounds formed by addition of difluorocarbene onto the C═C bond, replace­ ment of t‐Bu by CHF2, or both reactions (Scheme 5.32c). Difluorocyclopropanation of tertiary amines was mentioned in a patent; the reaction involved sterically hindered N,N‐dialkylaniline (Scheme  5.33) [119]. However, the generality of this method is questionable since it is known that treatment of MFDA by Et3N or pyridine in dioxane leads to quantitative decom­ position of the reagent [120].

5.5  Difluorocyclopropanation of Alkenes and Alkynes

n

(a)

TFDA (2 equiv.) F F NaF cat.

N Boc

Toluene reflux, 4 h

BocN N

N N

n

TFDA, 2 equiv. CsF, cat. O

n = 1: 52% n = 3 : 64%

N Boc

F

BocN

F N

N

Toluene reflux, 14 h

N

O

(b)

Ph

Ph

F

TFDA (3 equiv.)

N Boc

+

Toluene reflux, 3 h

N O

F

F O

F

22%

(c)

Ph

Ph

F +

F N

N Boc

O

18%

F O

F

39%

Scheme 5.32  Difluorocyclopropanation of unsaturated Boc‐protected amino derivatives. F O2N (i-Bu)2N

TFDA (2 equiv.) COOEt cat. CsF Et2CO 105 °C, 5 h

F COOEt

O2N (i-Bu)2N

28%

Scheme 5.33  Difluorocyclopropanation of alkene bearing a tertiary amino function.

Carboxybenzoyl group is one more possible protective group for amines, which might be considered for the difluorocyclopropanation conditions. Recently, Cu‐catalyzed difluoromethylation of primary N‐Cbz‐protected amino alcohols with FO2SCF2CO2H was described; the NHCbz moiety remained intact under the reaction conditions [121]. However, difluorocyclopropanation of alk­ enes bearing the N‐Cbz‐protected amino function has not been reported in the literature to date. Although in some cases, difluorocyclopropanation with TFDA can be per­ formed in diethyl ketone as the solvent (especially for most reactive substrates), the method has limited compatibility with unprotected ketone function. In par­ ticular, reaction of benzylideneacetone and TFDA resulted in the product of double functionalization arising from initial attack of difluorocarbene at the ketone moiety (Scheme 5.34) [122]. As a result of this attack, an oxonium ylide was formed, which underwent hydrogen shift to give a dienol ether intermediate. The subsequent difluorocyclopropanation of this intermediate led to the final product. The indirect proof of such carbene‐induced enolization is absence of

161

162

5  Synthesis of gem‐Difluorocyclopropanes

F

F F

O TFDA (4.5 equiv.) cat. NaF

O

O

F

Benzene 80 °C _

O+

F O O 87%

F F

F

O

X

F

F

F

F

F H

F2HCO

F

F

51%

F

F

F

O

F

F

22% (NO2); 27% (H); 70% (OMe)

59%

Scheme 5.34  Difluorocyclopropanation of enolizable ketones with TFDA.

the correlation between the C–H acidity of the methyl group in a series of substi­ tuted acetophenones and the yield of the product. In 2005, this approach was used by Dolbier and coworkers in a two‐step syn­ thesis of 2‐fluoro‐1‐naphthols starting from 1‐indanones (Scheme  5.35) [123]. The primary products of 1‐indanone reaction with TFDA underwent spontane­ ous rearrangement with ring expansion and HF elimination to give difluorome­ thyl 2‐fluoro‐1‐napthyl ethers. These ethers could be then converted into the corresponding naphthols in high yield by heating with 48% aq HBr in AcOH. It is interesting to note that using 1,3‐dimesitylimidazol‐2‐ylidene (IMes) as the cata­ lyst, isolation of the O‐difluoromethyl enol ether intermediates could be achieved.

O TFDA (8 equiv.) NaF cat.

R

Benzene 80 °C

R

F2HCO

Toluene 80 °C

F

R

O TFDA (8 equiv.) IMes (1%) n

F

– HF

R

OCHF2 F

5 examples 20–53% R

:

N

OCHF2

OCHF2 DDQ (n = 2) n

N

R

63–81%

IMes

Scheme 5.35  Reaction of indanones and their homologues with TFDA.

One more difluorocyclopropanation reagent which provides difluorocarbene through nucleophilic cleavage is bromodifluoromethyl phosphate: BrCF2P(O) (OEt)2. This reagent was proposed in 2009 by Zafrani et al. as an environmentally benign difluorocarbene precursor [95]. This reagent was a logical extension of

5.5  Difluorocyclopropanation of Alkenes and Alkynes

works by Hu and coworkers dealing with non‐ozone‐depleting difluorocarbene reagents based on nucleophilic generation of the CF2Cl− anion via C─C or С─S bond cleavage [124, 125]. The reagent version of Zafrani et  al. relied on the hydrolytic C─P bond cleavage as a key step in the :CF2 generation (Scheme 5.36). Since the energy of the C─P bond in the compounds studied is c. 62 kcal/mol, its cleavage is possible only if it is activated by an electron‐withdrawing group (like CF2Br) at the carbon atom adjacent to the phosphorus. Thus, alkaline treatment of BrCF2P(O)(OEt)2 produces the CF2Br− anion and diethyl phosphate as a by‐ product. The CF2Br− instantaneously eliminates bromide to give difluorocar­ bene, which could be trapped by a substrate giving the product. The resulting eco‐friendly side product, diethyl phosphate, is easily separated from the reac­ tion mixture due to its excellent solubility in water. :CF2

X

–

X = Cl, Br

O

O F

Br F–

F FO Ph S O

F F

OEt P OEt O

Br

Zafrani et al. [95]

C–P bond cleavage HO

F

F F

Cl

Hu and Hu and coworkers [124] coworkers [125]

OEt P OEt O

HO–

Ph

Cl

F

F F Br

F F

F

OEt P OEt O

OEt P OEt O

F – OEt + Br P OEt F O – Br– OH– –OP(O)(OEt) Substrate 2 :CF2

C–P bond cleavage – Br– F

OEt P OEt O

:CF 2

Product

F F

Me2CCMe2 Me Me

Me Me 88%

Scheme 5.36  BrCF2P(O)(OEt)2 as difluorocyclopropanation reagent.

Both reagents proposed by Hu and coworkers, as well as the alkali‐based pro­ cedure of Zafrani et al., were used only for (thio)phenol difluoromethylation and not for alkene difluorocyclopropanation, possibly due to the formation of several side products resulting from the reaction of :CF2 and OH−. Nevertheless, in 2011, Flynn and Burton reported the appropriate reaction conditions for the :CF2 gen­ eration from BrCF2P(O)(OEt)2, which could be applied for the synthesis of gem‐ difluorocyclopropanes (Scheme 5.36) [126]. The driving force for the C─P bond cleavage by either F− or OH− is presumably the strength of the P─F or P─O bonds (117 and 97 kcal/mol, respectively) as compared to the C─P bond (62 kcal/ mol). In the case of fluoride, the generated difluorocarbene can react with alk­ ene, which was demonstrated by reaction with Me2C═CMe2 leading to the cor­ responding gem‐difluorocyclopropane in 88% yield.

163

164

5  Synthesis of gem‐Difluorocyclopropanes

5.5.5  Decomposition of CF3‐substituted Organometallic Derivatives Prior to the development of TFDA, trifluoromethyl‐substituted derivatives of arsenic and tin were widely used for difluorocyclopropanation. This field of organofluorine chemistry was pioneered by Ayscough and Clark groups in 1954 and 1960, respectively [127, 128]. In these works, it was shown that (CF3)3As and Me3SnCF3 decomposed at 180 °C and 150 °C, respectively, giving CF2═CF2, perfluorocyclopropane, and the corresponding As/Sn fluorides. Moreover, in the case of Me3SnCF3, perfluorocyclopropane was the major reaction product. In is interesting to note that (CF3)3As gave CF3˙ (and not :CF2) as a major pyrolysis intermediate. Later, CF3Fe(CO)4I [129], (CF3)3PF2 [130], and CF3GeI3 [131] were introduced as difluorocarbene sources; their pyrolysis in the presence of CF2═CF2 or CH2═CH2 allowed detection of the corresponding [2+1] cycloaddition products. Nevertheless, these results had not find synthetic application until 1965, when Seyferth et  al. reported that addition of NaI to Me3SnCF3 in DME allowed to generate the difluorocarbene at significantly lower temperatures, thereby making reactions with thermally unstable alkenes accessible (Scheme 5.37) [132]. This reaction was applied to the difluorocyclopropanation of various substrates including electron‐rich, some electron‐deficient, and unsaturated organo element compounds; it did not work with tri‐ and tetrachloroethylene [133, 134]. The role of NaI in the reaction was postulated to be the generation of pentacoordinated trimethyl(trifluoromethyl)tin iodide [Me3Sn(I)CF3]−, which decomposed giv­ ing Me3SnI and CF3− anion. The trifluoromethyl anion (which is known to be unstable even at −100 °C [135, 136]) then decomposed to produce the difluoro­ carbene. Fluoride and chloride anions were also effective as catalysts for the decomposition of Me3SnCF3. In particular, tris(dimethylamino)sulfonium dif­ luorotrimethylsilicate (TASF, (Me2N)3S+Me3SiF2−) could be used as the reac­ tion promoter [137]. Neither of these methods was used for the difluorocyclopropanation reaction. Despite synthetic potential of Me3SnCF3, its further development was relatively slow. A possible reason behind this might be related to low commercial accessibility of the compound, as well as Selected examples: R1

R3

R2

R4

Me3SnCF3

NaI, DME reflux, 16 h

Me Me F F

F F R1

R2

O R3

R4

F F

F F

22–89% 22%

n-C5H5 89% F F Et

56%

74%

F F SiEt3

F F

OMe

Me Me 77%

F F

F F

F F

F F

39%

53%

71% F F

n-Pr

Et

55%

F F GeEt3

SnEt3 52%

Scheme 5.37  Difluorocyclopropanation with Me3SnCF3/NaI.

F

F

O

F 61%

F F n-Pr

67%

F F

F F SiMe3

80%

Ph

SnMe3 54%

5.5  Difluorocyclopropanation of Alkenes and Alkynes

tedious method available for its synthesis in the lab starting from gaseous CF3I and toxic Me3SnSnMe3 [138]. Another important difluorocyclopropanating reagent was also introduced by Seyferth et al. In 1969, they reported that PhHgCF3 is relatively stable, surviving unchanged a 10‐day reflux period in cyclooctene, and acting as an effective donor of difluorocarbene in the presence of NaI in DME or benzene [139]. The initial evaluation of the reaction scope showed that although Me3SnCF3‐based system gave comparable or better results with most substrates, the use of PhHgCF3 could be extended to Cl2C═CHCl and CH2═CHCN (Scheme 5.38a) [140]. Further extension of the scope included sulfur‐containing compounds [141], dienes [142–144], and trimethylsilyl enol ethers [145]. The mechanism of the reaction is similar to that discussed above for Me3SnCF3. An interphase pro­ cess was suggested for the formation of [PhHg(I)CF3]− by reaction of solid NaI and dissolved in benzene PhHgCF3. [PhHg(I)CF3]− then decomposed providing PhHgI and CF3− anion, which further gave the difluorocarbene [146]. Some unexpected results were obtained in further studies on the difluorocy­ clopropanation with PhHgCF3. In particular, either cis‐ or trans‐stilbene gave only trans‐1,1‐difluoro‐2,3‐diphenylcyclopropane (Scheme 5.38b) [147]. A pos­ sible explanation might include initial formation of cis‐isomer and its subsequent rearrangement due to the weakened distal bond in the gem‐difluorocyclopro­ pane moiety. Difluorocyclopropanation of 1‐trimethylsiloxycyclopentene does not lead to difluorocyclopropane; instead, 2‐fluorocyclohexenone was isolated in 76% yield (Scheme 5.38c). Finally, 1,3‐difluorobenzene derivatives were obtained in good yields upon reaction of 1,2‐disubstituted cyclobutenes with the PhHgCF3/ NaI system (Scheme 5.38d) [148, 149]. The proposed mechanistic explanation included initial difluorocyclopropanation, HF elimination giving fluorocyclo­ pentadiene derivative, further difluorocyclopropanation, and one more HF elim­ ination. It should be noted that similar transformation was also accomplished in the case of ClCF2COONa as the difluorocarbene source, although the yields of the products were lower [149]. Apart from PhHgCF3, (СF3)2Hg was proposed as difluorocarbene source by Knunyants and coworkers in 1973 [150]. After development of optimized and scalable approach to the synthesis of this reagent published in 1986 [151], it had remained one of the most popular for the mild generation of :CF2 (together with PhHgCF3) until discovery of TFDA. The main drawback of both reagents is related to their toxicity and limited commercial availability, although they can be easy synthesized in the lab [152]. An example of using the (СF3)2Hg/NaI system was described by Nowak et al. in 2004. It included gem‐difluorocyclopropanation of cyclic enamines in reflux­ ing THF (Scheme 5.39) [153]. The corresponding bicyclo[n.1.0]alkyl‐substituted tertiary amines were obtained in these transformations. The yield as well as properties of the products varied significantly depending on the structure of the starting enamine. Thus, morpholinocyclopentene did not give the bicyclic prod­ uct, possibly because of ring expansion process analogous to that observed for 1‐trimethylsiloxycyclopentene (see Scheme 5.38c). The six‐ to eight‐membered cyclic enamines gave the target difluorocyclopropanes, although their yields dif­ fered considerably. The products were very weak bases, which did not react with

165

166

5  Synthesis of gem‐Difluorocyclopropanes Scope extension (as compared to Me3SnCF3) F F

F F 3

1

R

R

R2

R4

Cl Cl 72%

Cl

NaI, benzene reflux, 12–18 h

PhHgCF3

R1

Ph

SCF3 SCF3

SCF3

26%

92%

63%

F F

83%

Ph

F F

CO2Me 53%

Ph

56%

R3

R2

R4

NaI, benzene reflux

Ph

Ph

(b)

Ph

F F

Ph

Ph

Me3SiO

O

F

F

–Me3SiF

R

F F

R

PhHgCF3

R = Ph, n-Pr

NaI, benzene reflux

R

R F

R F

R

R

R

F

60–77% – HF

F – HF

F R

F

76%

NaI, benzene reflux

(c)

Ph

Ph

F F

NaI, benzene reflux

PhHgCF3

90%

45%

Ph

PhHgCF3

Ph

OSiMe3 F F

F F

F F

PhHgCF3

Ph

OSiMe3

F F

F F 34%

(a)

(d)

CN

F F

F F

F F

F F

R

:CF2

F

Scheme 5.38  Difluorocyclopropanation with PhHgCF3/NaI. (a) General scheme and scope; (b) Reaction with stilbenes; (c) Reaction with 1‐trimethylsiloxycyclopentene; (d) Reaction with cyclobutenes.

methyl iodide. Upon heating (at 140 °C for n = 4, 170 °C for n = 5, and 100 °C for n = 6), these bicyclo[n.1.0]alkane derivatives underwent ring expansion with HF elimination, which led to the corresponding cyclic 2‐fluoro‐α,β‐enones.

5.5  Difluorocyclopropanation of Alkenes and Alkynes Selected examples

R1

N

R2 Hg(CF3)2, NaI

R1

R2 F F N

N

F

N

F

F

F

N

F

O

n

8 examples

N

F

F 89%

18%

0%

THF reflux

n

O

O

O

O F

N

57%

F

F 93%

Scheme 5.39  Difluorocyclopropanation of cyclic enamines with (СF3)2Hg/NaI.

Later, Nowak and Robins reported the use of both PhHgCF3 and (СF3)2Hg for the preparation of gem‐difluorocyclopropyl‐substituted saccharide and nucleo­ side analogues (Figure 5.7) [154, 155]. With PhHgCF3, benzoyl protective group was required for the N‐3 atom of the uracil derivative, and 2,5‐dimethylpyrrole protection for the free amino group of the adenosine derivative. In the case of (СF3)2Hg, the N‐3 atom of another uracil derivative was protected with p‐meth­ oxybenzyl group. Difluorocyclopropanation with trifluoromethyl‐substituted organometallic reagents does not always require high temperatures or nucleophilic promotion. In 1995, Eujen and Hoge proposed bis(trifluoromethyl)cadmium as a low‐tem­ perature difluorocarbene source [156]. (СF3)2Cd could be isolated as donor‐sta­ bilized complexes with glyme, diglyme, MeCN, or pyridine. Nevertheless, when it was generated in the absence of a donor (for example, from CdMe2 and (СF3)2Hg) in low‐polar solvents such as CHCl3, CH2Cl2, or toluene, it decom­ posed quantitatively below −5 °C with formation of :CF2, which could be trapped F F

O O

O

N

N

F F

Bz

O

O

80%, cis : trans = 5 : 1 O O

N

N

O

O

TBSO F F

N

O

N

N

64%, cis : trans = 15 : 1 PMB

N

N

OPMB 83%, cis : trans ~ 1 : 1

OBz H O O

O F

F

H H

O

87%

Figure 5.7  Difluorocyclopropanation of saccharide and nucleoside derivatives with PhHgCF3/ (СF3)2Hg/NaI.

167

168

5  Synthesis of gem‐Difluorocyclopropanes

effectively with electron‐rich alkenes and alkynes. With a series of model sub­ strates, the yields of the corresponding products exceeded 95% (Scheme 5.40). It should be noted that unlike in the case of PhHgCF3, difluorocyclopropanation of cis‐stilbene with (CF3)2Cd proceeded with retention of the stereochemistry. R1

R3

R2

R4

(CF3)2Cd F F R1 R2

R2

or R1

F F

Toluene – 5 °C F F

or R3 R4

R1

F F n-C4H9

F F R2

Ph

F F

F F Ph

Ph

Me

Me

F F Ph

F F

F F

Ph

Ph

> 95%

Scheme 5.40  Difluorocyclopropanation with (CF3)2Cd.

Despite availability of methods for the preparation of (CF3)2Cd, the reagent did not find wide application due to its high toxicity [157]. As a possible solution of this problem, Mikami and coworkers reported in 2015 a stable but reactive donor‐ stabilized complex of (CF3)2Zn with N,N′‐dimethylpropyleneurea (DMPU) and TMEDA [158]. Further studies showed that (CF3)2Zn∙TMEDA could be used as a reagent for the nucleophilic CF3 addition, while (CF3)2Zn∙2DMPU appeared to be an excellent difluorocarbene source [159]. The reaction occurred efficiently with­ out any additives in toluene at 80 °C, providing the target gem‐difluorocyclopro­ panes and gem‐propenes in high yields (Scheme 5.41).

R2 (CF3)2Zn·2DMPU (2 equiv.) Toluene, 80 °C, 12 h

R1

R Ph

F F

F F

R = Me, >99% R = Br, 50%

91%

X

F

R2 R1 F F 9 examples

F

Ar F F

X = OTIPS, 60% X = 1-Morpholinyl, 52%

Ar = Ph, 54% Ar = 4-MeOC6H4, 75%

Scheme 5.41  Difluorocyclopropa(e)nation with (CF3)2Zn∙2DMPU.

Besides nucleophilic generation of difluorocarbene from trifluoromethyl‐sub­ stituted organometallic compounds, their Lewis acid‐initiated activation is also known. For Me3SnCF3, it was described in the late 1970s; however, the method

5.5  Difluorocyclopropanation of Alkenes and Alkynes

was never used for difluorocyclopropanation [138]. Later, Yagupolskii and cow­ orkers showed that Bi(CF3)3 activated by AlCl3 is an excellent low‐temperature source of difluorocarbene [160]. This method was applied for the difluorocyclo­ propanation of alkenes and dienes in good yields (40–75%) (Scheme 5.42) [161]. Since a convenient protocol for the Bi(CF3)3 synthesis in the lab is available [162], the procedure can be considered as a method of choice for low‐temperature difluorocyclopropanation. R1

R3

R2

R4

F F 40%

(CF3)3Bi AlCl3 MeCN –20 °C

F F R1 R2 F F

F F Ph 60%

Me Me 75%

R3 R4 F F

75%

Scheme 5.42  Difluorocyclopropanation with Bi(CF3)3.

Very recently, Fürstner group reported an example of difluorocyclopropana­ tion with AuCF3 complexes [163]. In this case, carbenoids were also formed by treatment of the Au complexes with Lewis acids (Scheme 5.43). It was found that π‐donation by two fluorine atoms in the resulting [(R3P)Au = CF2]+ species was insufficient for long‐term stabilization; however, the carbenoid reacted with alk­ enes without generation of the free :CF2 carbene. This was confirmed by reaction with cis‐ and trans‐stilbene, which gave the expected gem‐difluorocyclopropane (trans isomer) and the rearrangement product, 1,1‐difluoro‐3,3‐diphenylpro­ pene. Formation of the latter by‐product mandated an 1,2‐aryl shift, which in turn suggested that an intermediate with significant carbocationic nature was involved. Therefore, formation of the gem‐difluorocyclopropane in a concerted process involving free difluorocarbene was unlikely. 5.5.6  Lewis Base‐promoted Cleavage of the Ruppert–Prakash‐type Reagents XCF2SiMe3 (X = F, Cl, Br) A possibility to use organosilicon compounds as the dihalocarbene source was demonstrated by Bevan et al. in as early as 1961 [164], one year later after the first example of difluorocyclopropanation. It was found that decomposition of CCl3SiCl3 at 250 °C led to the generation of :CCl2, which could be effectively trapped with cyclohexene to give the corresponding cyclopropane in 60% yield. The unacceptably high temperature of the carbene generation from organosilicon derivatives prompted for more effective dihalocarbene precursors discussed in the Section 5.5.5 [165]. Therefore, organosilicon compounds were neglected as the dihalocarbene precursors for almost 50 years. The renaissance of this method started in 2010 when Hu and coworkers reported the study of Me3SiCF2X com­ pounds (X  =  F, Cl, and Br) as potential difluorocarbene sources [166]. It was shown that Me3SiCF2Cl could generate :CF2 in the presence of n‐Bu4N+Cl− as a

169

R3P·AuCl AgF, Me3SiCF3 CH2Cl2–MeCN R3P

Au

CF3

+

Ph Me3SiOTf Me3SiNTf2 B(C6F5)3

R3P R3P

Au Au

CF2OTf CF2NTf2

Ph

R3P

Au

F

(E) or (Z)

[R3P Au CF2]+ decomposes unless trapped in situ

R3P = PPh3, PCy3, XPhos, (p-F3CC6H4)3P, (2,4-t-BuC6H3O)3P

Scheme 5.43  Difluorocyclopropanation with AuCF3 complexes.

Ph

Ph F

PR3 Au Ph F

F

Ph

Ph F R = Ph, 26% R = Cy, N/A (for Me3SiOTf) F

F Ph

Ph +

F

Ph R = Ph, 14% (for Me3SiOTf) R = Cy, 40% R = Cy, 59% (for B(C6F5)3)

5.5  Difluorocyclopropanation of Alkenes and Alkynes

catalyst in THF at 110 °C (sealed tube); moreover, the resulting carbene was reac­ tive toward alkenes. In 2011, Hu and coworkers developed two protocols for the difluorocyclopropanation with Me3SiCF3 including promotion with tetrabutyl­ ammonium triphenyldifluorosilicate (TBAT) in THF at −50 °C or NaI in THF at 65 °C [167]. Two years later, Hu and coworkers demonstrated that Me3SiCF2Br is also an efficient source of difluorocarbene, which can be activated by n‐Bu4N+Br− as a catalyst in toluene at 110 °C [168]. The comparative analysis of these seminal studies is given in Table 5.1. Since these seminal studies, organosilanes of general formula Me3SiCF2X become valuable difluorocarbene sources, and their application was partially reviewed [10, 170–172]. The reactivity of Me3SiCF2X as the difluorocarbene source increases in the following series for X: F 15 : 1 dr Up to >99% ee

DCM, –10 °C – rt

CHO

R1

O SH

R2 N SCF3 O

Scheme 15.41  Catalytic asymmetric trifluoromethylthiolation using N‐SCF3 succinimide.

N SR3

MS 13X, DCM –20 °C, 6 d

R1 * SCF3 R SR3 2

Up to 95% ee

15.3  Approaches in Electrophilic Trifluoromethylthiolation

coworkers described the trifluoromethylthiolation of aldehydes to obtain α‐ trifluoromethylthiolated alcohols in the presence of pyrrolidine as catalyst (Scheme 15.42c) [74]. O

O Alk, Ar

SCF3 Alkyl, H

Up to 90% yield

R

SCF3 OH

O

Alk, Ar

OH Alk, H MeCN, rt, NH4OH

O R cat. pyrrolidine, DCM, rt then, NaBH4

O

O

(b) O O S N SCF3 O

(c)

O R , NaH

O R SCF3

THF, 0 °C

(a) O H R2 R3

R1

Morpholine HCl (10 mol%) CH2Cl2, 30 or 80 °C

O F3CS R2 R3

R1

Scheme 15.42  Trifluoromethylthiolation with N‐trifluoromethylthiosaccharin.

The vicinal SCF3‐amination and esterification of alkenes in a multicomponent reaction catalyzed by a diaryl selenide was reported by Zhao and cowork­ ers  (Scheme  15.43a) [75]. Similarly, the trifluoromethylthio lactonization/­ lactamization of alkenes mediated by a Lewis acid has been described by Shen and Xu (Scheme 15.43b) [76]. The trifluoromethylthiolation of silyl enol ethers using N‐trifluoromethylthi­ osaccharin as trifluoromethylthiolating reagent, activated by the presence of catalytic amounts of a Lewis base, has also been performed under flow condi­ tions by Benaglia and coworkers (Scheme 15.44) [77]. 15.3.2.4  N‐Trifluoromethylthiodibenzenesulfonimide (PhSO2)2NSCF3

In 2016, Shen and coworkers designed the electrophilic (PhSO2)2NSCF3 reagent, an analogue of the fluorinating agent NFSI [78]. Naphthol derivatives reacted with (PhSO2)2NSCF3 in a dearomative trifluoromethylthiolation reaction under catalysis with Sc(OTf )3 and a BOX ligand. In addition, the authors achieved the formoxy‐, acetoxy‐, hydroxyl‐, and amino‐trifluoromethylthiolation of styrenic olefins by a choice of appropriate solvents (Scheme 15.45). Britton and coworkers reported the trifluoromethylthiolation reaction of alkylquinazolines and purines at heterobenzylic positions that rely on transient sulfonylation of the heterocyclic nitrogen atom from (PhSO2)2NSCF3. This method provided a small series of products in good to excellent yields (Scheme 15.46) [79]. Three‐component reactions for the oxytrifluoromethylthiolation of α‐ diazoketones with alcohols, acetals, ethers, and cyclic ethers as the alkoxy sources in the presence of rhodium catalysis were reported by Szabó and cow­ orkers (Scheme 15.47) [80].

425

(b)

HO

O

MeO Ar

O

O

SCF3 Ar

Up to 95% yield

Me3SiCl MeCN, rt

10 mol%

(a)

OMe R-CN

O O S N SCF3 O

Se 1

R

R1

NHCOR SCF3 R2

R2

Up to 94% yield

H2O, TfOH R-COOH

1

R

OCOR SCF3 R2

Scheme 15.43  Acetoxy‐ and amino‐trifluoromethylthiolation of alkenes.

15.3  Approaches in Electrophilic Trifluoromethylthiolation O N SCF3 O

MeCN (0.2 M)

O

R

R3

2

SCF3

OSiR13 R3

R2

S

up to 52% yield

(10 mol%)

10 µl glass reactor

MeCN (0.2 M)

Scheme 15.44  Trifluoromethylthiolation of silyl enol ethers in flow reactions. R1

O

HO

DMF

R

F3CS R1 O

R2 R

O O Ph S N SCF3 Ph S O O

Sc(OTf)3 (10 mol%) Box-Bn (10 mol%)

R2

DCM, 40 °C

Up to 99%

O

rt

Ar Ar

OAc

HOAc 40 °C

SCF3

Ar OH

DMSO

SCF3

Ar

rt DCM 50 °C

Ar

N(SO2Ph)2 SCF3

Scheme 15.45  Trifluoromethylthiolation of naphthol derivatives and olefins. R2

R2 R1

X N X = CH, N

(PhSO2)2NSCF3 Li2CO3, MeCN

SCF3 R1

X

R2

via

R1

X

N Up to 92%

N SO2Ph

Scheme 15.46  Trifluoromethylthiolation of alkylquinazolines and purines. O

O

PhSO2 N SCF3

O N2

R1 R2

PhSO2 [Rh2(OAc)4]

DCM, 25 °C, 2 h

R3–O–R4

N(SO2Ph)2

O

1

R

SCF3

Up to 66% O

R4O or R3O

R2 = H, 25 °C, 2 h R3OH, NaOAc CDCl3, 25 °C, 0.5 h

R1 SCF3 Up to 72%

O R2 R3O

Scheme 15.47  Oxytrifluoromethylthiolation of α‐diazoketones.

R1 SCF3

H SCF3

Up to 75%

427

428

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds

Further to their initial work on acetoxy‐ and amino‐trifluoromethylthiolation of alkenes (see Scheme 15.43), Zhao and coworkers reported chiral bifunctional sulfide and selenide catalysts to effect a variety of asymmetric cascade reactions involving a trifluoromethylthiolation reaction of alkenes with the aid of (PhSO2)2NSCF3 in good to excellent enantioselectivities (Scheme  15.48). This way, SCF3‐substituted pyrrolidines and piperidines were prepared by intramo­ lecular amination of olefins catalyzed by chiral selenide Se1 (Scheme  15.48a) [81]. It is important to note that the reaction system worked well only for trans olefins. Trifluoromethylthiolated tetrahydronaphthalene skeletons were con­ structed by trifluoromethylthiolation of the C═C double bond in gem‐diaryl‐ tethered alkenes followed by a desymmetrizing aryl migration (Scheme 15.48b) [82]. Unactivated internal olefins featuring an allylic proton reacted with chiral selenide Se1 to yield chiral allylic SCF3 compounds by an allylic proton ­elimination. Notably, functional groups such as bromo, chloro, iodo, acetate, or benzoate were well tolerated. Adding a nucleophile in the reaction allowed to intercept the intermediate thiiranium ion more rapidly than the allylic proton elimination (Scheme 15.48c) [83]. A variety of 4‐aryl (E)‐but‐3‐enoic acids were converted into the corresponding lactones through a tandem trifluoromethylthi­ olation/cyclization (Scheme 15.48d) [84]. Finally, chiral trifluoromethylthiolated 2,5‐disubstituted oxazolines were prepared from N‐(2‐phenylallyl)benzamide in good yields with high enantioselectivities with catalyst Se2 (Scheme 15.48e) [85]. In these reactions, thio‐ or seleno‐catalyst reacts with the electrophilic trifluoro­ methylthiolation reagent to form an activated [S+–SCF3] or [Se+–SCF3] interme­ diate, which is then captured by an olefin in the system to obtain a sulfonium ion intermediate, which is further subjected to a nucleophilic group intra‐ or intermolecularly. 15.3.2.5 (1S)‐(−)‐N‐Trifluoromethylthio‐2,10‐camphorsultam

In 2017, Shen and coworkers reported the first chiral electrophilic trifluoro­ methylthiolation reagent based on the camphorsultam motif [86]. They found that the use of a dimethoxy‐substituted chiral sulfonamide reagent, in the pres­ ence of a catalytic amount of base K2CO3 or Cs2CO3, can well achieve electro­ philic trifluoromethylthiolation of β‐ketoesters, oxindoles, and benzofuranones with good to excellent enantioselectivities (Scheme 15.49). 15.3.3  O‐SCF3 Reagents in Direct C(sp3)–SCF3 Bond Formation Reactions Initially assigned as an electrophilic hypervalent iodine reagent, Shen and cow­ orkers reagent [87] was corrected latter by Buchwald and coworkers who reported evidences of the formation of a stable open thioperoxide based on spec­ troscopic and crystallographic studies [88]. With the aid of such thioperoxide reagents, Shen and coworkers reported the racemic α‐trifluoromethylthiolation of oxindoles and β‐ketoesters in the presence of DMAP in excellent yields (Scheme 15.50) [87].

Ar R2 Ar R2

R3

SCF3

R1

Se1 (20 mol%) TMSOTf, DCM/DCE –78 °C; 12 h (d)

O

S1 (20 mol%)

O

CO2H

R

R SCF3 Up to 93% yield Up to 90% ee

TfOH, DCM, 0 °C 12 h

H N

SCF3 R

O N

R1

Ar

R

Ar

Up to 76% yield Up to 94% ee S1

R1 R

(b)

O O Ph S N SCF3 Ph S O O

S NHBoc

R1 2

R F3CS

R1 or F CS 3

n

R

2

Ns N

Up to 99% yield >99:1 d.r.; up to 97% ee

Se1 (20 mol%)

R3

1

R

R3

R1

SCF3 Up to 95% yield Up to 95% ee

R3 = Br, Cl, I, H, OCOR′ TfNH2, DCM/toluene, –78 °C, 12 h

Ar

Ns N

R2

R2 Nu

Se1 (20 mol%)

R3 R1 SCF3 Nu = F, OH, SCN, OAc, OR″ Up to 80% yield Up to 93% ee R′–Nu

Se1

O

NHNs

R2

(e) O Se2 (20 mol%) BF3·Et2O DCM/toluene, –78 °C, 18 h

O

n

Se1 (20 mol%) BF3·Et2O or NfOH DCM/DCE, –78 °C, 12 h

(a)

(c)

2

Se2

Se NHTf

O Se

O

O

NHTf

Scheme 15.48  Asymmetric trifluoromethylthiolation reactions of olefins by chiral bifunctional sulfide and selenide catalysts.

430

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds O O

CO2R1

R n

CO2R1

R

SCF3 n Up to 96% yield, up to 98% ee

K2CO3 (10 mol%) THF, –40 °C

Ar OMe OMe N SCF

R

3

S O O

Ar

O

N

R

Cs2CO3 (10 mol%) Et2O, –30 °C

SCF3 O

N

Up to 99% yield, up to 96% ee

Ar R

O

Ar

O

SCF3

O O Up to 90% yield, up to 92% ee R

Cs2CO3 (10 mol%) Et2O, –25 °C

Scheme 15.49  Asymmetric trifluoromethylthiolation with the aid of a chiral reagent. Ar

O R

O n

SCF3 1 n CO2R

O

SCF3

CO2R1 R = I, H

DMAP, DCM

R1

N Boc

Ar SCF 3

O 1

R

N Boc

DMAP, DCM

R = I, up to 98% R = H, up to 95%

O

R = H up to 91%

Scheme 15.50  Use of thioperoxy reagents for the trifluoromethylthiolation of oxindoles and β‐ketoesters.

A copper‐catalyzed trifluoromethylthiolation of primary and secondary alkyl boronic acids led to the corresponding trifluoromethylthiolated products as reported by Shen and coworkers (Scheme 15.51) [89]. R Alk-B(OH)2

O

SCF3

+ R = I, H

Selected examples

Me O H

73% F3CS

H O

Cu(MeCN)4PF6, bpy K2CO3 Diglyme or DCE Ph

R–SCF3 Up to 81%

SCF3 80% SCF3

H

7 SCF3 71%

71%

Scheme 15.51  Cu‐catalyzed trifluoromethylthiolation of primary and secondary alkyl boronic acids.

15.3  Approaches in Electrophilic Trifluoromethylthiolation

Asymmetric reactions were conducted by Shen and coworkers who reported the enantioselective trifluoromethylthiolation of oxindoles in the presence of cin­ chona alkaloids (Scheme 15.52a) [90] and of β‐ketoesters (Scheme 15.52b) [91]. For a transition‐metal catalysis approach, Gade and coworkers used a copper– boxmi complex with Shen’s trifluoromethylsulfenate reagent (Scheme  15.52c) [92]. All trifluoromethylthiolated products were obtained in high yields and enantioselectivities. R1 R3

O N R2 Quinine (20 mol%)

R1 R3

Et2O, 35 °C, 36–60 h O

R

O

SCF3

R = I, H

n

SCF3

O N R2 Up to 99% yield Up to 99% ee

(a)

CO2Ad O

For n = 1: quinine (20 mol%), toluene, 40 °C, 36 h For n = 2,3: N-Bn quininium bromide (20 mol%) Et2O/H2O 1 : 2, 0 °C, 36 h O

SCF3 CO 2R n

(b)

Up to 97% yield Up to 94% ee O

n

CO2R

Cu(OTf)2 (10 mol%) Boxmi (12 mol%), DCM, rt

SCF3 CO 2R n

(c)

Up to 93% yield Up to 99% ee

Scheme 15.52  Enantioselective trifluoromethylthiolation of oxindoles and β‐ketoesters with the aid of Shen’s trifluoromethylsulfenate reagent.

15.3.4 SO2CF3 Reagents in Direct C(sp3)–SCF3 Bond Formation Reactions 15.3.4.1  Trifluoromethanesulfonyl Hypervalent Iodonium Ylide

In 2013, Shibata and coworkers reported the use of a novel electrophilic trifluo­ romethanesulfonyl hypervalent iodonium ylide for the trifluoromethylthiolation of β‐ketoesters in the presence of catalytic amounts of 2,4,6‐collidine and copper(I) chloride (Scheme  15.53a) [93]. Two years later, by using the same ­trifluoromethanesulfonyl hypervalent iodonium ylide, the group reported the trifluoromethylthiolation of allylsilanes and silyl enol ethers in the presence of a catalytic amount of CuF2 (Scheme 15.53b) [94].

431

432

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds X (b)

SiMe3

R

X R R′

Ph

(a)

CuCl (10 mol%) SO2CF3 2,4,6-Collidine (20 mol%)

CuF2 (20 mol%) DMAc, rt, 10 h

Up to 82%

CO2R

O

R′ SCF3

O

I

Dioxane, rt

O SCF3 CO2R Up to 54%

Scheme 15.53  Cu‐catalyzed trifluoromethylthiolation of β‐ketoesters and silyl enol ethers.

15.3.4.2  Trifluoromethanesulfonyl Diazo Reagent

In 2016, Shibata and coworkers developed a similar strategy to synthesize a diazo‐ triflone type reagent for electrophilic trifluoromethylthiolation of β‐ketoesters in the presence of a catalytic amount of copper salt (Scheme 15.54) [95]. O O O SO2CF3 N2

OMe CuCl (20 mol%),

O SCF3 CO2Me 58%

1,4-Dioxane, 50 °C

Scheme 15.54  Cu‐catalyzed trifluoromethylthiolation of β‐ketoesters.

15.3.4.3  Trifluoromethanesulfonyl Chloride (CF3SO2Cl)

In 2016, Cahard and coworkers imagined a novel use of CF3SO2Cl as electro­ philic SCF3 donor (without extrusion of SO2) in the presence of a phosphine as reducing agent [96]. Later, Zhang and coworkers expanded the use of CF3SO2Cl for the bifunctional chlorotrifluoromethylthiolation of alkenes for C(sp3)–SCF3 bond formation (Scheme 15.55) [97].

CF3SO2Cl

R

, PPh3 DMF, 90 °C

Cl R

SCF3 Up to 88% yield

Scheme 15.55  Bifunctional chlorotrifluoromethylthiolation of alkenes with CF3SO2Cl.

15.3.5  Other Reagents in Direct C(sp3)–SCF3 Bond Formation Reactions 15.3.5.1  Trifluoromethyl Diethylaminosulfur Difluoride (CF3‐DAST)

The Billard group used DAST and TMSCF3 to synthesize N‐trifluoromethylthio­ aniline [PhN(R)SCF3, R = H, Me] with CF3–DAST as a synthesis intermediate. This compound was isolated by the Shibata group according to the same method and it was found that when engaged with β‐ketoesters, a rearrangement took

15.3  Approaches in Electrophilic Trifluoromethylthiolation

place with carbon–carbon bond cleavage and attack of an intermediate enolate at the sulfur atom of the CF3–DAST reagent to furnish the final open product (Scheme 15.56a) [98]. Later, CF3–DAST was developed to be an efficient reagent for the trifluoromethylthiolation of α‐methylene‐β‐ketoesters and ‐sulfones pro­ viding α‐trifluoromethylthio‐β‐ketoesters and ‐sulfones in good to high yields (Scheme  15.56b) [99]. CF3‐DAST also induced deacylative trifluoromethylthi­ olation of cyclic 1,3‐diketones, lactams, and lactones affording cyclic α‐trifluoro­ methylthio‐ketones, ‐lactams, and ‐lactones (Scheme 15.56c) [100]. In the same vein, Anbarasan and Saravanan reported the combination of DAST and CF3TMS to prepare CF3‐DAST for the trifluoromethylthiolation of silylenol ethers and β‐naphthols (Scheme 15.56d) [101]. TMSCF3 + DAST

(b)

O O

O EWG R MeCN (0.1 M) 40–70 °C

O R

EWG SCF3

SCF3 R Up to 80% yield

R

OR

SCF3 n CO2R Up to 64% yield

O O

X n

DIPEA, DCM, –60 °C to rt

F

1,4-Dioxane, –10 °C

CF3 F S F N Et Et (CF3-DAST)

OTMS

Up to 94% yield O

n

(a) O

R

DCM, –40 °C (c) or MeCN, rt

(d)

O X

SCF3 n

Up to 84% yield

Scheme 15.56  Trifluoromethylthiolations with CF3–DAST.

15.3.5.2  Silver Trifluoromethylthiolate AgSCF3

AgSCF3 has been used as a source of electrophilic CF3S motif when placed in the presence of TCCA (trichloroisocyanuric acid). Indeed, Tan and coworkers reported the enantioselective synthesis of CF3S‐oxindoles in the presence of a bis‐cinchona alkaloid organocatalyst (Scheme 15.57) [102]. Although CF3SSCF3 has been identified as the trifluoromethylthiolating species; the authors men­ tioned the involvement of other unidentified SCF3 species in the electrophilic trifluoromethylthiolation.

Ar R AgSCF3 + TCCA

(DHQD)2Pyr THF, then TFA

N Boc

Ar SCF 3

O R

O N Boc Up to 96% yield Up to 95% ee

Scheme 15.57  Enantioselective trifluoromethylthiolation of oxindoles with AgSCF3 and TCCA.

433

434

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds

15.4 ­Approaches in Nucleophilic Trifluoromethylthiolation Traditionally, nucleophilic trifluoromethylthiolation reactions involve an elec­ trophilic substrate and the SCF3 anion. However, the low stability of the SCF3 anion represents one of the main challenges of such reactions. 15.4.1  Reaction with Bis(trifluoromethylthio) Mercury Hg(SCF3)2 Hg(SCF3)2 as the first metal‐based trifluoromethylthiolating reagent was devel­ oped by Man et  al. [103]. After that, the reaction of benzyl bromide with Hg(SCF3)2 was reported by Harris in 1966 (Scheme  15.58) [6]. Hg(SCF3)2 is a highly toxic and corrosive reagent; thus its practical use is almost entirely precluded. Br

SCF3

+ Hg(SCF3)2

Scheme 15.58  Trifluoromethylthiolation of benzyl bromide with Hg(SCF3)2.

15.4.2  Reactions with Cesium Trifluoromethylthiolate CsSCF3 Cesium trifluoromethylthiolate can react with aryl halides or alkyl halides as a nucleophilic reagent toward C(sp3)–SCF3 compounds. A method for the regiose­ lective allylic trifluoromethylthiolation of cinnamyl methyl carbonate and deriv­ atives with CsSCF3 under ruthenium catalysis was developed by You and coworkers in 2014 (Scheme 15.59) [104]. It was noted that the allylic position of the substrate required methyl carbonate as a leaving group and the product is mainly composed of linear allyl trifluoromethylsulfide. Mechanistic investiga­ tions suggested that a double allylic trifluoromethylthiolation resulted in linear selectivity. However, CsSCF3 is difficult to prepare and mostly is reported to be unstable at ambient temperature; thus it has been hardly used in nucleophilic substitution reactions. + CsSCF3

+ OCO2Me R

N

Ru-complex

PF6–

Ru

CsSCF3

O O

Ru-complex

MeCN, 50 °C

SCF3 R

SCF3

+

R

52–91% yields

Scheme 15.59  Ruthenium‐catalyzed regioselective allylic trifluoromethylthiolation.

15.4  Approaches in Nucleophilic Trifluoromethylthiolation

15.4.3  Reactions with Silver Trifluoromethylthiolate AgSCF3 The first synthesis of AgSCF3 was reported by Muetterties and coworkers by using aqueous silver nitrate reacting with bis(trifluoromethylthio)mercury [15a]. Then, its reactivity toward trifluoromethylthiolation reaction of organic halides was studied. Propargylic bromide and iodomethane reacted with AgSCF3 to afford propargyl trifluoromethyl sulfide (Scheme 15.60a) [105] and methyl trif­ luoromethyl sulfide (Scheme  15.60b) in good yields, respectively. Recently, thanks to a more convenient synthetic access to AgSCF3, Deng and coworkers employed AgSCF3 for the nucleophilic trifluoromethylthiolation of α‐­ haloketones and benzyl halides in the presence of KI. The trifluoromethyl­ thiolation reaction proceeded rapidly to afford α‐trifluoromethylthiolated carbonyl  compounds and benzyl trifluoromethyl sulfides in excellent yields (Scheme 15.60c) [106]. The addition of inorganic iodide salts seems to be crucial for the reaction as it leads to the in situ formation of active species, such as [Ag(SCF3)I]−. In recent years, Shen and coworkers expanded the scope of sub­ strates to alkyl halides to form alkyl‐SCF3 compounds in the presence of nBu4NI or nBu4NI/nBu4NBr (Scheme 15.60d) [107]. O

Br

SCF3

R

(a) 71%

Me–SCF3 82% Alk–SCF3 41–99%

Alk–X X = Br, Cl, OTs nBu4NI or nBu4NI/nBu4NBr acetone, 80 °C

O

R2

MeCN MeI

X

1

KI, acetone, rt (b)

(c)

2

R 60–99%

X = I, Br, Cl

AgSCF3

(d)

KI, acetone, rt R

SCF3

R1

SCF3

R

X 39–99%

Scheme 15.60  Trifluoromethylthiolation reactions by halide substitution with AgSCF3.

In 2015, Qing and coworkers reported an unusual reaction process for the dehydroxytrifluoromethylthiolation of alcohols in the presence of nBu4NI as activator (Scheme 15.61a) [108]. The chemoselectivity in favor of the formation of the trifluoromethylthiolated products vs. alkyl fluorides was controlled by changing the ratio of AgSCF3/nBu4NI. Mechanistically, the trifluoromethanethi­ olate anion decomposes into carbonothioic difluoride and fluoride anion. The former reacts with the alcohol to generate the carbonofluoridothioate interme­ diate, which next undergoes nucleophilic substitution by trifluoromethanethi­ olate to provide the SCF3 alkyl product. Later, Magnier and coworkers reported a new ionic liquid, [bmim][SCF3], and its application for the trifluoromethylthi­ olation of various alkyl halides and alcohols under microwave irradiation (Scheme 15.61b) [109].

435

436

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds

Alk–OH

AgSCF3, nBu4NI

Alk–SCF3

Toluene, 80 °C,10 h

(a)

30–93% [bmim][I]

N

AgSCF3,

Alk–OH or Alk–X

N

+ I–

Alk–SCF3

MW, 100 °C, 30 min

(b)

7–95%

Scheme 15.61  Trifluoromethylthiolation of alcohols and alkyl halides with AgSCF3 and iodide salts.

In 2014, Wang and coworkers reported a strategy to introduce the SCF3 group through the CuI‐promoted reaction of diazo compounds with AgSCF3 as the nucleophilic trifluoromethylthiolation reagent (Scheme 15.62a) [110]. A migra­ tory insertion of SCF3‐bearing Cu carbene intermediates is involved in this transformation. The same year, Hu and coworkers developed a copper‐­mediated trifluoromethylthiolation protocol to access diverse α‐trifluoromethylthiolated esters starting from α‐diazoesters [111]. The reaction is easily carried out at  room temperature, and water could be used to promote the reaction (Scheme 15.62b). CuI, H2O N2 R

R1

AgSCF3

MeCN, –25 °C then, rt then NH2Cl workup

SCF3

(a)

34–88% SCF3

CuCl, H2O NMP, MeCN, rt

R1

R

R

R1

(b)

13–87%

Scheme 15.62  Copper‐mediated trifluoromethylthiolation of diazo compounds with AgSCF3.

In 2018, Xu and coworkers developed an efficient method for the construc­ tion  of α‐trifluoromethylthiolated ketones using an umpolung strategy. N‐ Alkenoxypyridinium salts could be easily prepared from gold‐catalyzed addition of pyridine N‐oxide to alkynes and then reacted with AgSCF3 in the presence of nBu4NI (Scheme 15.63) [112]. N R

O–

HNTf2, [Au] / HFIP

Tf2N– R

+ N O

AgSCF3 nBu4NI MeCN

O R

SCF3 Up to 89% yield

Scheme 15.63  Trifluoromethylthiolation of N‐alkenoxy‐pyridinium with AgSCF3.

In 2019, Qing and coworkers reported the reaction of easily available Morita– Baylis–Hillman (MBH) alcohols with AgSCF3 in the presence of nBu4NI and KI

15.4  Approaches in Nucleophilic Trifluoromethylthiolation

that afforded primary allylic SCF3 products in high yields and excellent regiose­ lectivities (Scheme 15.64) [113]. The dehydroxytrifluoromethylthiolation proto­ col could also be extended to propargylic alcohols. OH O R

Ar

AgSCF3 nBu4NI, KI

O

AgSCF3 nBu4NI, KI

OH Ar

Toluene

R

Ar

Toluene

SCF3 Up to 92% Ar SCF3 Up to 54%

Scheme 15.64  Trifluoromethylthiolation of allylic and propargylic alcohols with AgSCF3.

Very recently, Anbarasan and Saravanan described a regioselective difunction­ alization of alkenes via trifluoromethylthiolation with AgSCF3 and diaryl disele­ nide in the presence of BF3·OEt2 in good to excellent yields (Scheme 15.65) [114]. The reaction proceeds via an episelenonium intermediate with subsequent, regi­ oselective ring opening by AgSCF3 to afford the target products.

R1 R2

+

(ArSe)2

AgSCF3 BF3·OEt 2 MeCN

SCF3 SeAr

R1 R2

Up to 96% yield

Scheme 15.65  Difunctionalization of alkenes with AgSCF3 and diselenides.

15.4.4  Reactions with Copper Trifluoromethylthiolate CuSCF3 The first Cu‐based nucleophilic reagent involved in trifluoromethylthiolation reactions was CuSCF3. This ligand‐free organometallic reagent can react with conventional electrophiles, including halo alkanes, allyl bromides, propargyl bromides, diazo compounds, and alcohols. In 2014, Rueping and coworkers reported a direct process for the trifluoromethylthiolation of allylic and benzylic alcohols. However, this system requires the addition of BF3·Et2O as a Lewis acid to activate the hydroxyl group; so, the functional group is less tolerant (Scheme 15.66a,b) [115]. Moreover, in 2018, Lebœuf and coworkers expanded the scope of the dehydroxytrifluoromethylthiolation to N, O‐acetals via N‐­ acyliminiums in up to 92% yield (Scheme 15.66c) [116]. In 2014, Rueping and coworkers realized the synthesis of α‐SCF3 substituted esters from a range of diazo compounds with CuSCF3. In the absence of water, N‐trifluoromethylthiophtalimide was used for the insertion of a second SCF3 motif in α‐position (Scheme 15.67) [117]. In 2017, Fujioka and coworkers developed a method for the synthesis of trif­ luoromethylthiomethyl ethers through pyridinium salt intermediates derived

437

438

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds SCF3

OH R1

(a)

R2(R1)

R1(R2)

R2

73–96% BF3 ·OEt2 CuSCF3

OH R2 Ar R1

SCF3 R2 50–98% (b) Ar R1

MeCN, rt

SCF3 R N R EWG

OH R

N EWG

R

(c)

43–92%

Scheme 15.66  Dehydrotrifluoromethylthiolation of allylic, benzylic alcohols, and N, O‐acetals. H2O (10 equiv) N2 EWG

R

rt, 3 h

CuSCF3 MeCN, 0 °C, 3 h

PhthN–SCF3 (1.2 equiv)

SCF3 R

EWG

F3CS SCF3 R

EWG

Scheme 15.67  Trifluoromethylthiolation of diazo compounds with CuSCF3.

R

O

O

N

TMSOTf, 2,2′-bipyridyl CH3CN, 0 °C, 0.5 h

R

O +N

TfO– CuSCF3 (2 equiv)

R

O

SCF3

rt, 1–5 h

Scheme 15.68  Trifluoromethylthiolation of methoxymethyl ethers via pyridinium salts with CuSCF3.

from methoxymethyl (MOM) ethers. The addition of CuSCF3 displaced the pyri­ dinium to afford the corresponding trifluoromethylthiomethyl ethers in good yields (Scheme 15.68) [118]. Well‐defined and stable copper(I) trifluoromethylthiolate complexes ligated by bipyridine ligands were prepared from the reaction of CuF2, TMSCF3, and ele­ mental sulfur in the presence of bipyridine ligand. Such complexes were employed by Weng and coworkers in the nucleophilic trifluoromethylthiolation of benzyl bromides (Scheme 15.69a) [119]. The reaction of various benzyl bromides with (bpy)CuSCF3 in mild conditions afforded the corresponding benzyl trifluorome­ thyl sulfides in excellent yields. Later the same group expanded the reaction to a wide range of alkyl halides, on which various functional groups such as ether, thioether, ester, nitrile, amide, and ketal groups are tolerated (Scheme 15.69b) [120]. More challenging secondary alkyl bromides could be employed as well; however, the cyclic secondary iodides afforded lower yields of products. α‐Bromo

15.4  Approaches in Nucleophilic Trifluoromethylthiolation

(a)

(d)

R

SCF3

Up to 96% yield

MeCN, rt

Br

R

CuI, Phen, KF MeCN, 70 °C or (PPh3)2CuSCF3 MeCN, 70 °C (e)

X

R

(bpy)CuSCF3

(b)

Alk–X (bpy)CuSCF3 MeCN, 110 °C

SCF3

R

Up to 99% yield

Alk–SCF3 Up to 99% yield

O (c)

O

X

R R

1

DCM, 50 °C

SCF3

R R1

Up to 93% yield

Scheme 15.69  Trifluoromethylthiolation of various halides with (bpy)CuSCF3 and (PPh3)2CuSCF3.

ketones and allylic bromides were also subjected to the trifluoromethylthiolation with (bpy)CuSCF3 in good to excellent yields (Scheme  15.69c,d) [121]. In the case of allylic bromides, a bis(triphenylphosphine)‐ligated CuSCF3 proved to be equally efficient (Scheme 15.69e) [122]. The catalytic trifluoromethylthiolation of primary and secondary α‐bromoke­ tones was also studied by Weng and coworkers. In that case, the SCF3 motif was constructed from elemental sulfur and TMSCF3, while copper(II) and 1,10‐ phenanthroline were used catalytically. α‐SCF3 substituted ketones were pro­ duced in good yields (Scheme 15.70a) [123]. Then, Zeng and coworkers provided a similar trifluoromethylthiolation method of primary and secondary α‐bromok­ etones under ligand‐free conditions (Scheme  15.70a) [124]. Later, Weng and coworkers developed a copper(I)‐catalyzed trifluoromethylthiolation of allylic bromides and propargylic chlorides with elemental sulfur and TMSCF3 in the presence of KF and 18‐crown‐6 (Scheme 15.70b,c) [125]. Interestingly, the addi­ tion of 18‐crown‐6 as additive greatly improved the reaction efficiency. Moreover, Zeng and coworkers provided a facile access for the copper‐mediated trifluoro­ methylthiolation of allylic chlorides with the aid of copper(I) thiocyanate (Scheme 15.70d) [126]. 15.4.5  Reactions with Other Nucleophilic SCF3 Reagents By using a difluorocarbene donor reagent (Ph3P+CF2CO2−; (Triphenylphos­ phonio)difluoroacetate (PDFA)), elemental sulfur, and CsF, Xiao and coworkers developed an efficient, fast, and transition‐metal‐free trifluoromethyl­thiolation of a broad range of alkyl trifluoromethyl sulfides (Scheme 15.71a) and α‐SCF3 substituted ketones (Scheme 15.71b) [127a]. From a mechanistic point of view, the decarboxylation of PDFA furnishes the difluorocarbene that reacts with CsF to give CsCF3 that further reacts with elemental sulfur to form the CsSCF3 species and copper(I)–SCF3 complex by transmetalation for the nucleophilic

439

O

(a) O SCF3

R

R1 Cu(OTf)2 (20 mol%), phen (20 mol%) KF, DCM, 40 °C, 16 h

1

R Up to 93% yield

or CuI (50 mol%), KF, DMF, rt

SCF3 Up to 85% yield

R

Br

CuI, Phen, KF, 18-crown-6 S8

Dioxane

R

Cl CuI, Phen, KF, 18-crown-6

TMSCF3

DMF

Scheme 15.70  Copper‐catalyzed nucleophilic trifluoromethylthiolation.

SCF3

Up to 94% yield

+

Ar

Ar (c)

(b)

X

R

Cl R CuSCN (50 mol%) KF, DMF, 45 °C

R

SCF3 Up to 88% yield

(d)

15.4  Approaches in Nucleophilic Trifluoromethylthiolation

substitution. This protocol was also applied to [18F]trifluoromethylthiolation [127b]. Similarly, the same group extended this method to the dehydrotrifluo­ romethylthiolation of alcohols (Scheme 15.71c) [128]. CsF

R–SCF3

DMF, 70 °C, 5 min

R–X

18

K F/kryptofix 222 O Ph3P CF2CO

–

R

MeNO2, 60 °C, 20 min

2

R

+

O

CsF, CuBr2

Br

1

SCF3

R1 R2

Up to 70%

O

S8

TEA 18F,CuI

R2

CsF

Up to 72 ± 2% (c)

Alk–SCF3

DMA, 70 °C, 0.5 h

(b)

[18F]SCF3

R1

MeCN, 40 °C, 2 min Alk–OH

(a)

R [18F]SCF3 Up to 83 ± 2%

DMF, 70 °C, 1 min +

Up to 99%

Up to 95%

Mechanism +

–

Ph3P CF2CO

– CO2 – PPh3

MF

CF2

MCF3

S8

MSCF3

RX

RSCF3

M = Cs, Cu

Scheme 15.71  Trifluoromethylthiolations by means of PDFA.

In 2016, Goossen and coworkers exploited tetramethylammonium tri­ fluoromethylthiolate Me4NSCF3 in a catalytic trifluoromethylthiolation of α‐ diazo esters catalyzed by CuSCN without the need of preformed CuSCF3 (Scheme 15.72) [129]. Me4NSCF3 (1.5 equiv) CuSCN (10 mol%)

N2 R1

CO2R2

MeCN, rt, 15 h

SCF3 R1

CO2R2

36–98%

Scheme 15.72  Trifluoromethylthiolation of α‐diazo esters with Me4NSCF3.

Me4NSCF3 was employed by Cahard and coworkers for the construction of trifluoromethylthiolated amines and amino acid derivatives by direct nucleo­ philic substitution of cyclic sulfamidates with the trifluoromethanethiolate anion (Scheme 15.73) [130]. Billard’s trifluoromethanesulfenamide reagents, TsNHSCF3 and TsN(Me) SCF3, have been employed to generate the CF3S− anion in situ, thanks to iodide

441

442

15  Direct Trifluoromethylthiolation Toward C(sp3)–SCF3 Compounds O O Boc N S O R

(1) Me4NSCF3, MeCN, 25 °C (2) 20% aq H2SO4, DCM

n

Boc NH SCF 3 n

R

R = H, Alk, Ar, CO2R′

58–99%

Scheme 15.73  Synthesis of trifluoromethylthiolated amines and amino acids.

activation, and then this anion was engaged in metal‐free nucleophilic substitu­ tion reactions of benzyl halides and alcohols to afford various trifluoromethylthi­ olated compounds (Scheme 15.74) [131]. X

R

Alk–OH

nBu4NI (2.2 equiv) +

Ts

+

Ts

N

SCF3

H N

Acetone, 40 °C, 20 h

SCF3

R

Up to 90%

nBu4NI (3.3 equiv) SCF3

Acetone, 60 °C, 20 h

Alk–SCF3

Up to 96%

Scheme 15.74  Trifluoromethylthiolation of halides and alcohols with Billard’s reagents.

In 2013, Li and Zard reported a new reagent, O‐octadecyl‐S‐trifluorothiolcar­ bonate, as a cheap and storable crystalline source of trifluoromethanethiol (Scheme 15.75) [132]. This reagent required activation by the lone pair of a nitro­ gen‐containing base (from gramines or by external pyrrolidine) to generate the CF3S− anion, which react with various gramines and α‐bromo ketones and ‐esters to give the corresponding trifluoromethyl sulfides in high yield.

R

SCF3 H, Me

N H Up to 91%

O

NMe2

R

R N H THF, rt

H, Me

O F3CS

Br

R1 KF, pyrrolidine OC18H37

THF, H2O, 0 °C, 1.5 h

O SCF3

R 1

R 40–93%

Scheme 15.75  Trifluoromethylthiolation of gramines, α‐bromoketones, and ‐esters with O‐octadecyl‐S‐trifluorothiolcarbonate.

Independently, the group of Cahard and Dai [133] and the group of Shi and coworkers [134] reported the trifluoromethylthiolation of MBH carbonates. While the use of in situ generated CF3S− anion gave access to the thermody­ namic primary allylic SCF3 product [133], it was found that Zard’s reagent allowed to access the kinetic secondary allylic SCF3 product [133, 134]. The regi­ oselectivity was controlled by the reaction solvent and the source of CF3S− anion (Scheme 15.76).

­  References O

Cahard,Dai S8 + TMSCF3 DABCO (10 mol%), KF

O R

OMe

DMF, rt

BocO

F3CS

O OMe

R

OC18H37

DABCO (10 mol%)

SCF3 Up to 99%

CF3S

O

R

THF, rt, 5 min

OMe R = 4-FC6H4 78%

Shi, Wei and coworkers O

R

OC18H37 F3CS O DABCO (20 mol%), KF OMe SCF3 47–96%

THF, rt, 2 h

O BocO R

F3CS

O R

OC18H37

DABCO (20 mol%) CHCl3, 0 °C, 10 h

O R

OMe SCF3

26-84% Ratio secondary / primary allylic SCF3 products 0.6:1 to >99:1

Scheme 15.76  Trifluoromethylthiolation of MBH carbonates.

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104 Ye, K.Y., Zhang, X., Dai, L.X., and You, S.L. (2014). J. Org. Chem. 79: 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127

128 129 130 131

132 133 134

12106–12110. Hanack, M. and Massa, F.W. (1981). Tetrahedron Lett. 22: 557–558. Jiang, M., Zhu, F., Xiang, H. et al. (2015). Org. Biomol. Chem. 13: 6935–6939. Xu, C., Chen, Q., and Shen, Q. (2016). Chin. J. Chem. 34: 495–504. Liu, J.B., Xu, X.H., Chen, Z.H., and Qing, F.L. (2015). Angew. Chem. Int. Ed. 54: 897–900. Anselmi, E., Simon, C., Marrot, J. et al. (2017). Eur. J. Org. Chem.: 6319–6326. Wang, X., Zhou, Y., Ji, G. et al. (2014). Eur. J. Org. Chem.: 3093–3096. Hu, M., Rong, J., Miao, W. et al. (2014). Org. Lett. 16: 2030–2033. Xia, X., Chen, B., Zeng, X., and Xu, B. (2018). Adv. Synth. Catal. 360: 4429–4434. Liu, Y.L., Xu, X.H., and Qing, F.L. (2019). Tetrahedron Lett. 60: 953–956. Saravanan, P. and Anbarasan, P. (2019). Chem. Commun. 55: 4639–4642. Nikolaienko, P., Pluta, R., and Rueping, M. (2014). Chem. Eur. J. 20: 9867–9870. Maury, J., Force, G., Darses, B., and Lebœuf, D. (2018). Adv. Synth. Catal. 360: 2752–2756. Lefebvre, Q., Fava, E., Nikolaienko, P., and Rueping, M. (2014). Chem. Commun. 50: 6617–6619. Ohta, R., Kuboki, Y., Yoshikawa, Y. et al. (2017). J. Fluorine Chem. 201: 1–6. Kong, D., Jiang, Z., Xin, S. et al. (2013). Tetrahedron 69: 6046–6050. Lin, Q., Chen, L., Huang, Y. et al. (2014). Org. Biomol. Chem. 12: 5500–5508. Tan, J., Zhang, G., Ou, Y. et al. (2013). Chin. J. Chem. 31: 921–926. Wang, Z., Tu, Q., and Weng, Z. (2014). J. Organomet. Chem. 751: 830–834. Huang, Y., He, X., Lin, X. et al. (2014). Org. Lett. 16: 3284–3287. Li, J., Xie, F.F., Wang, P. et al. (2015). Tetrahedron 71: 5520–5524. Rong, M., Li, D., Huang, R. et al. (2014). Eur. J. Org. Chem.: 5010–5016. Li, J., Wang, P., Xie, F.F. et al. (2015). Eur. J. Org. Chem.: 3568–3571. (a) Zheng, J., Cheng, R., Lin, J.H. et al. (2017). Angew. Chem. Int. Ed. 56: 3196–3200. (b) Zheng, J., Wang, L., Lin, J.H. et al. (2015). Angew. Chem. Int. Ed. 54: 13236–13240. Luo, J.J., Zhang, M., Lin, J.H., and Xiao, J.C. (2017). J. Org. Chem. 82: 11206–11211. Matheis, C., Krause, T., Bragoni, V., and Goossen, L.J. (2016). Chem. Eur. J. 22: 12270–12273. Zeng, J.L., Chachignon, H., Ma, J.A., and Cahard, D. (2017). Org. Lett. 19: 1974–1977. (a) Glenadel, Q., Bordy, M., Alazet, S. et al. (2016). Asian J. Org. Chem. 5: 428–433. (b) Glenadel, Q., Tlili, A., and Billard, T. (2016). Eur. J. Org. Chem.: 1955–1957. Li, S.G. and Zard, S.Z. (2013). Org. Lett. 15: 5898–5901. Dai, X. and Cahard, D. (2015). Synlett: 40–44. Yang, H.B., Fan, X., Wei, Y., and Shi, M. (2015). Org. Chem. Front. 2: 1088–1093.

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16 Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf) Tatiana Besset1 and Thomas Poisson1,2 1 2

Normandie University, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000, Rouen, France Institut Universitaire de France, 1 rue Descartes, 75231, Paris, France

16.1 ­Introduction Nowadays, organofluorine chemistry can be considered as a strategic research area in organic chemistry. Indeed, the importance of fluorinated molecules for the discovery of biologically active molecules cannot be denied in view of the marketed fluorine‐containing drugs [1]. Therefore, to broaden the portfolio of available fluorinated groups, researchers have devoted great efforts. Sulfur‐con­ taining fluorinated motifs are of high interest and already found applications in agrochemistry, for instance, Fipronil and Toltrazuril. As the most popular sulfur‐ containing fluorinated group, the SCF3 attracted a lot of attention and a plethora of methodologies were developed over the last decades [2]. In addition, the quest for other sulfur‐containing fluorinated groups is important, as their introduction can afford new and interesting physicochemical properties, as well as promising biological activities. In that purpose, considerable efforts were dedicated over the last 10 years. As a result, researchers community has seen the development of practical methodologies to build up molecules having SCF2H, SCH2F, and SCF2Rf motifs. In addition, recent efforts culminated in the development of new motifs bearing a functional group that can either be modulated or directly used in drug discovery program. As examples, one can mention the SCF2CO2R, SCF2PO(OEt)2, and SCF2SO2Ph [3] groups. In this chapter, the recent and most significant progress made for the access to SCF2H, SCH2F, SCF2PO(OEt)2, SCF2CO2R, and SRf will be highlighted.

16.2 ­The SCF2H Motif Over the last years, a strong interest was paid to the SCF2H group. Indeed, due to its unique properties such as its lipophilicity and its H‐bonding ability [4] and due to the presence of a more acidic proton compared with the one in the CF2H Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

group, the development of new approaches for its introduction onto various classes of compounds was reported. Two main strategies were depicted, namely, (i) the difluoromethylation of sulfur‐containing molecules and (ii) the direct C–SCF2H bond construction. In this section will be reported the most relevant advances made since 2016 [5]. 16.2.1  Construction of the SCF2H Moiety Due to the importance of the SCF2H group, various strategies were elaborated to build up a S–CF2H bond. Until 2016, the use of difluorocarbene precursors was the main approach. Alternatives based on electrophilic and nucleophilic reagents or CF2H radical precursors were promising although still in their infancy. A sum­ mary of the main reagents used in these transformations is depicted in Scheme 16.1 [5]. Reagents for the difluoromethylation of sulfur-containing molecules Difluorocarbene precursors HCF3

BrCF2PO(OEt)2

CHClF2

TMSCF2Cl

HCF2OTf

TMSCF2Br

ClCF2CO2Na

Ph3PCF2CO2

FSO2CF2CO2H

O NTs S Ph CF2H

FSO2CF2CO2TMS

Electrophilic reagents O Ph

S

Nucleophilic reagents TMSCF2H

NMe2 BF4 CF2H

In situ generated

O

O

Ar

Ar F F

CF2H radical precursor [Zn](SO2CF2H)2

Scheme 16.1  State of the art: reagents used for the difluoromethylation of sulfur‐containing molecules until 2016.

In this section, the recent advances made since 2016 will be described to con­ struct a S–CF2H bond. In 2017, the group of Fu developed a methodology for the difluoromethylation of thiophenols under visible light photocatalysis [6]. Using the readily available difluorobromoacetic acid as a difluorocarbene precursor and an iridium com­ plex as photocatalyst, a panel of thiophenols bearing halogens, ester, an nitro as functional groups was functionalized in moderate to high yields (Scheme 16.2a). Note that even the difluoromethylation of 2‐pyridinethiol was smoothly achieved (Scheme 16.2b). Another difluorocarbene precursor, namely, the diethyl bromodifluoromethyl­ phosphonate, was also used in combination with thiourea as the sulfur source [7]. With this system, Yi and coworkers successfully functionalized in a one‐pot three‐step sequence, a panel of heteroaromatic compounds (indoles, pyrroles) and electron‐rich arenes (Scheme 16.3).

16.2  The SCF2H Motif

SH

SCF2H

BrCF2CO2H (1 equiv) [fac-Ir(ppy)3] (10 mol%) Cs2CO3 (3 equiv) DMF, rt, 23 W CFL

MeO2C

MeO2C 85% and 11 examples, 51–90%

(a)

SH N

SCF2H

BrCF2CO2H (1 equiv) N

[fac-Ir(ppy)3] (10 mol%) Cs2CO3 (3 equiv) DMF, rt, 23 W CFL

(b)

93%

Scheme 16.2  Difluoromethylation of thiophenols under visible light photocatalysis. (a) Reaction with thiophenol derivatives. (b) Reaction with an heteroaryl thiol derivative. (1) I2 (1 equiv), KI (1 equiv) Thiourea (2 equiv) 1,4-Dioxane/H2O, rt N H

N H

(2) NaOH 5 M, 50 °C (3) BrCF2PO(OEt)2 (1 equiv), rt

SCF2H

95% and 27 examples, 32–95%

Selected examples Cl

SCF2H N H 63%

SCF2H

H2N

N H 80%

MeO

SCF2H OMe

NH2 47%

Scheme 16.3  Difluoromethylation of heteroaromatic compounds and electron‐rich arenes using diethyl bromodifluoromethylphosphonate and thiourea.

In 2017, the groups of Qing and Studer independently developed a method for the difluoromethylation of thiols using a difluoromethyltriphenylphosphonium salt, via a radical process. Indeed, Qing and coworkers reported an Ir‐catalyzed difluoromethylation reaction under visible light irradiation [8]. A panel of (hetero) aryl‐ and alkyl‐thiols was functionalized (Scheme  16.4a). In the case of Studer’s group, a transition‐metal‐free process was developed and not only (hetero)­ arylthiols, benzylic ones but also a benzeneselenol were difluoromethylated, lead­ ing to the corresponding products in moderate to high yields (Scheme 16.4b) [9]. An alternative was suggested by the group of Yi for the difluoromethylation of thiols (Scheme 16.5) [10]. Aiming at developing a general method for the con­ struction of S–Rf bond (Rf = CF3, CF2H, CnF2n+1), the authors reported a silver‐ catalyzed difluoromethylation of various (hetero)aromatic thiols using sodium difluoromethanesulfinate (HCF2SO2Na).

451

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16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

N

SH

S

[Ph3PCF2H]OTf (3 equiv)

N

[fac-Ir(ppy)3] (3 mol%) N,N-Dimethyl-4-toluidine (2 equiv) DMF, rt, visible light

S

73% and 20 examples, 65–94%

[Ph3PCF2H]OTf (3 equiv)

n SH

n

[fac-Ir(ppy)3] (3 mol%) DBU (2 equiv) DMSO, rt, visible light

SCF2H

[Ph3PCF2H]Br (2 equiv) NaH (2 equiv) DMF, rt, hν (365 nm)

H2N

R

H2N 49% and 18 examples,49–88%

[Ph3PCF2H]Br (2 equiv)

SH

R

NaH (2 equiv) DMF, rt, hν (365 nm)

SCF2H R = H, 55% R = Me, 69%

Selected example of an heteroaryl thiol [Ph3PCF2H]Br (2 equiv)

N N

SCF2H

n = 1, 37% n = 2, 42%

(a) SH

SCF2H

N

NaH (2 equiv) DMF, rt, hν (365 nm)

SH

SCF2H

N

81%

(b)

Scheme 16.4  Difluoromethylation of thiol derivatives with a difluoromethyltriphenylphosphonium salt. (a) Qing et al. (b) Studer et al.

MeO

SH

HCF2SO2Na (2 equiv) AgNO3 (10 mol%) K2S2O8 (2 equiv) CH3CN/H2O, 80 °C N S

SH

SCF2H

MeO

51% and 6 examples, 61–89%

same

N

as above

S

SCF2H

61%

N

N

same

N SH

as above

N

SCF2H

78%

Scheme 16.5  A silver‐catalyzed difluoromethylation of thiol derivatives.

16.2  The SCF2H Motif

16.2.2  Direct Formation of a C−SCF2H Bond Major advances were made for the direct construction of a C–SCF2H bond, as demonstrated by the contributions from several research groups. Novel methods and original reagents (nucleophilic and electrophilic ones) were developed to construct C–SCF2H bonds [5], as summarized in Scheme 16.6. Nucleophilic reagents ″CuCF2H″

Electrophilic reagents iPr

iPr N iPr

N

NSCF2H

Ag iPr SCF2H

Cu salt, TMSCF2H activator

O

(SIPr)Ag(SCF2H) 1

O 2

O

SO2CF2H I

R

Ar

3a, R = H, Ar = Ph 3b, R = NO2, Ar = Ph 3c, R = H, Ar = Mes 3d, R = NO2, Ar =Mes

Scheme 16.6  State of the art: available tools for the direct difluoromethylthiolation until 2016.

Since then, further developments have been realized for the difluoromethylthi­ olation reaction using nucleophilic reagents, newly designed electrophilic sources, and radical precursors. 16.2.2.1  Difluoromethylthiolation Reaction by a Nucleophilic Pathway

A pioneer work was reported by the group of Gooßen who developed the in situ generation of a nucleophilic CuCF2H reagent from TMSCF2H, an activator (CsF or Cs2CO3), and a suitable copper salt. This reagent was used for the functionali­ zation of organothiocyanate derivatives prepared from various classes of precur­ sors (alkyl bromides and mesylates, aryl diazonium salts, and electron‐rich arenes) [11]. As another milestone, the first nucleophilic difluoromethylthiola­ tion reagent ([(SIPr)Ag(SCF2H)], 1), developed by Shen and coworkers, was applied as a nucleophilic SCF2H source in a copper‐mediated difluoromethylthi­ olation of aryl diazonium salts and for the Pd‐catalyzed functionalization of (Het)ArX (X = I, Br, and OTf ) [12]. In 2018, the same group showed that a slightly modified catalytic system allowed the functionalization of aryl bromides and tri­ flates as well as (hetero)aryl chlorides [13]. Indeed, in the presence of the [Pd‐1] and BrettPhos, in a catalytic fashion, the difluoromethylthiolation of various aro­ matic derivatives was achieved (47 examples, up to 98% yield). With this tool in hand, the functionalization of natural, medicinal, and material molecules was possible, demonstrating the potential of such approach for the late‐stage func­ tionalization (Scheme 16.7). 16.2.2.2  Difluoromethylthiolation Reaction Using Electrophilic Reagents

From the key contributions made by the group of Shen and Shibata in the design of electrophilic SCF2H sources, 2 [14] and 3a–d (Scheme  16.6) [15], several advances were made using either these well‐known electrophilic SCF2H sources or based on original approaches.

453

454

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

X R

[Pd-1] (5–10 mol%) BrettPhos (5–10 mol%) 1 (1.2 equiv) KBr (0–2 equiv) THF, 50–80 °C

X = Br, OTf, Cl

SCF2H

NH2 Pd Brettphos OMs

R 23–99% 46 examples

[Pd-1]

(a)

N

Cl

same as above

SCF2H

N 64%

Cl

SCF2H

same as above

(b)

N

N 51%

Scheme 16.7  Pd‐catalyzed difluoromethylthiolation of (Het)ArX (X = Br, OTf, and Cl) with the nucleophilic SCF2H source 1. (a) Reaction with aryl bromide, triflate, and chlorides. (b) Reaction with heteroaryl chlorides.

In 2018, Xie, Zhu, and coworkers reported a transition‐metal‐free, umpolung difluoromethylthiolation of tertiary alkyl ethers using 2 [16]. Although restricted to only three examples, the selective difluoromethylthiolation of a C–O bond was successfully achieved using a synergistic organophotoredox catalysis and organocatalysis (Scheme 16.8). Me Me Ph

OMOM

Me Me

2 (1.5 equiv) 4CzIPN (2 mol%) Organocatalyst (2 mol%) K2CO3 (0.1 equiv), blue LEDs CH2Cl2, rt

SCF2H

Ph

51% and 2 examples, 42–51%

R O O

P

O SH

NC

CN R=

R

N

R R

Organocatalyst

4CzIPN

Scheme 16.8  Difluoromethylthiolation of tertiary alkyl ethers using 2.

Note that Shibata and coworkers recently used these two classes of reagents (2 and 3a–d) as SCF2H sources in the synthesis of racemic α‐SCF2H‐containing‐β‐ ketoallylesters. The latter were then converted into the corresponding enantioen­ riched ketones through a Pd‐catalyzed asymmetric Tsuji decarboxylative allylic alkylation with up to 94% ee [17]. More recently, the same group developed a

16.2  The SCF2H Motif

Naphth

NH

(1) 3d (2 equiv) CO2Me

CuBr (20 mol%) Toluene, rt (2) 1 M HCl

O SCF2H CO2Me 56%, 85% ee and 7 examples, 32–63% 12–93% ee

Scheme 16.9  Diastereoselective difluoromethylthiolation of indanone‐based β‐ketoesters using 3d.

diastereoselective difluoromethylthiolation of indanone‐based β‐ketoesters, thanks to the use of the ylide 3d by means of a chiral auxiliary (Scheme 16.9) [18]. One acyclic enamino ester was also functionalized albeit in a poor 12% ee [19]. Besides, the quest for new electrophilic SCF2H sources emerged over the last years and original sources were developed, especially starting from the HCF2SO2Cl, HCF2SO2Na, and HCF2SOCl reagents. In 2017, Zhao, Lu, and coworkers reported the in situ generation of the elec­ trophilic difluoromethylsulfenyl chloride (HCF2SCl) after reduction of the dif­ luoromethanesulfonyl chloride (HCF2SO2Cl) by PPh3 [20]. With this tool in hand, the difluoromethylthiolation of a panel of indoles was achieved, leading to the corresponding products in good to high yields. Note that other heteroaro­ matic derivatives (pyrrole, indolizine, pyrazole derivatives) and electron‐rich arenes were functionalized under these reaction conditions. The presence of n‐Bu4NI as an additive was mandatory, presumably for the generation of iodine in the course of the reaction, which might facilitate the transformation (Scheme 16.10). The combination of HCF2SO2Cl and PPh3 was then applied to the functionali­ zation of other classes of compounds. Zhao, Lu, and coworkers studied the ­difluoromethylthiolation of thiol derivatives using HCF2SO2Cl combined with PPh3 in the presence of NaI as the iodine source (Scheme 16.11) [21]. In the same vein, in 2018, Yi, Zhang, and coworkers investigated the difunc­ tionalization of unsaturated compounds. Indeed, using difluoromethanesulfonyl chloride (HCF2SO2Cl) in the presence of PPh3, the chloro‐difluoromethylthiola­ tion of alkenes (styrene derivatives and other classes of alkenes) and terminal alkynes was achieved leading to the corresponding products in moderate to high yields with a high atom economy [22]. Note that when styrene derivatives were used, the Markovnikov products were regioselectively obtained, while the other alkenes provided the anti‐Markovnikov adducts preferentially (Scheme 16.12). In 2016, in the course of their investigation toward the development of a gen­ eral methodology for the fluoroalkylthiolation of electron‐rich arenes and thiol derivatives using fluoroalkylsulfonyl chloride, the group of Yi depicted examples of difluoromethylthiolation of indole and pyrrole derivatives using HCF2SO2Cl and (EtO)2POH as the reducing agent (Scheme 16.13) [23]. In 2017, Shibata and coworkers depicted the astute combination of HF2CSO2 Na/Ph2PCl/TMSCl for the electrophilic difluoromethylthiolation of C(sp2) and C(sp3) centers [24]. Indeed, with this mild, metal‐ and base‐free system, a large

455

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16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

O2N N H

SCF2H

O2N

HCF2SO2Cl (1.2 equiv) PPh3 (2.4 equiv) n-Bu4NI (0.2 equiv) Toluene, 60 °C

N H

75% and 24 examples, 37–96%

(a)

SCF2H N N Ph

OH

same

OH

N N Ph

as above

57% EtO2C

same N H

as above

EtO2C

SCF2H

N H 63% and 3 examples, 46–83%

OMe

OMe same

SCF2H

as above MeO

OMe

MeO

OMe 46%

(b)

Scheme 16.10  Difluoromethylthiolation of heteroaromatic derivatives and electron‐rich arenes using PPh3 as the reducing agent and HCF2SO2Cl. (a) Reaction with indole derivatives. (b) Selected examples with other heteroarenes and electron‐rich arenes.

SH HO

SSCF2H

HCF2SO2Cl (1.8 equiv) PPh3 (3.6 equiv) NaI (0.2 equiv) CH3CN, rt

HO 55% and 6 examples, 30–55%

Scheme 16.11  Difluoromethylthiolation of thiol derivatives using PPh3 as the reducing agent and HCF2SO2Cl.

panel of nucleophiles was functionalized including a wide range of phenol and naphthol derivatives. In addition, the scope of the transformation was broad and the difluoromethylthiolation of other heterocyclic compounds (pyrroles, indoles, etc.), electron‐rich arenes, and enamines, ketones, and β‐ketoesters was effi­ ciently carried out (Scheme 16.14). The same year, the group of Yi and Zhang reported an alternative approach. Indeed, in their case, the HCF2SO2Na was reduced with (EtO)2POH in the pres­ ence of TMSCl to generate in situ an electrophilic SCF2H source [25]. With this metal‐free process, various heterocycles such as indoles (26 examples), pyrroles (10 examples), and other heteroarenes (e.g. 7‐azaindole, imidazo[1,2‐a]pyridine)

16.2  The SCF2H Motif

Cl HCF2SO2Cl (2 equiv) PPh3 (3 equiv) DMF, 90 °C (a)

HCF2SO2Cl (2 equiv)

F

PPh3 (3 equiv) DMF, 90 °C (b)

SCF2H 89% and 11 examples, 58–89% Cl F SCF2H 62% and 9 examples, 42–82%

Scheme 16.12  Chloro‐difluoromethylthiolation of alkenes and alkynes using the HCF2SO2Cl/ PPh3 system. (a) Reaction with alkene derivatives. (b) Reaction with alkyne derivatives.

HCF2SO2Cl (1.5 equiv) N H

(EtO)2POH (2 equiv) CH3CN, 90 °C

SCF2H N H 85% and 7 examples, 75–90%

Scheme 16.13  Difluoromethylthiolation of indole and pyrrole derivatives using (EtO)2POH as the reducing agent and HCF2SO2Cl.

were difluoromethylthiolated. In addition, electron‐rich arenes were also suita­ ble substrates (8 examples, Scheme 16.15). Finally, in 2018, Yi and coworkers demonstrated that trifluoromethanesulfinyl chloride and difluoromethanesulfinyl chloride reacted as CF3SCl and HCF2SCl precursors [26]. Indeed, without additional reductant, the HCF2SOCl was prone to react with several indoles and ketones such as indanone derivatives, 1‐ tetralone and 1‐acenaphthenone (Scheme 16.16). 16.2.2.3 PhSO2SCF2H (4) as an Efficient Reagent for the Radical Difluoromethylthiolation

Recently a strong interest was paid to thiosulfonate derivatives (ArSO2SRf ) as emerging reagents for the introduction of sulfur‐containing fluorinated moieties and in particular the SCF2H residue [27]. Therefore, in this section, the major breakthroughs that have been recently developed using the PhSO2SCF2H as a SCF2H source for the direct introduction of the SCF2H moiety onto molecules are summarized. In 2016, the group of Lu and Shen investigated the synthesis and the applica­ tion of the S‐(difluoromethyl)benzenesulfonothioate (4, PhSO2SCF2H) [28]. This latter was synthesized via a one‐pot two‐step sequence from benzyldifluoro­ methylsulfide (Scheme 16.17). It was then applied for the difluoromethylthiola­ tion of different classes of compounds.

457

458

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

HF2CSO2Na (4 equiv) Ph2PCl (4 equiv) CH3CN, rt, 30 min

OH

SCF2H OH

TMSCl (1.5 equiv), 90 °C 88% and 19 examples, 26–88%

(a) F3C

Cl

Cl

F3C

CN

Cl

same

N N

as above NH2

CO2Me

as above

SCF2H

(c)

56% O

O same N H

(d)

SCF2H

O

same CO2Me

N N

NH2 68% and 7 examples, 74–98%

(b) O

Cl

CN

Ph

as above

SCF2H N H

Ph

69%

Scheme 16.14  Electrophilic difluoromethylthiolation of C(sp2) and C(sp3) nucleophiles with the HF2CSO2Na/Ph2PCl/TMSCl system. (a) Reaction with naphtol and phenols derivatives. (b) Reaction with N‐heterocycles. (c) Reaction with β‐ketoester. (d) Reaction with enamide.

The silver‐catalyzed difluoromethylthiolation of both aryl and alkyl boronic acids was described (Scheme 16.17a). The reaction turned out to be functional group tolerant (halides, ester, ketone, nitro). In addition, to further demonstrate the synthetic utility of the reagent, the functionalization of aliphatic carboxylic acids was investigated under silver catalysis. Under these reaction conditions, the decarboxylative difluoromethylthiolation of cyclic and acyclic carboxylic acids (primary, secondary, and tertiary ones) was achieved (Scheme  16.17b). Finally, the 1,2‐difunctionalization of terminal aliphatic alkenes was studied leading to the corresponding phenylsulfonyl‐difluoromethylthio derivatives in the presence or absence of the silver catalyst. Note that styrenes and α,β‐unsatu­ rated esters were reluctant substrates (Scheme 16.17c). In 2019, the same group reported a Co(III)‐catalyzed hydro‐difluoromethyl­ thiolation reaction of unactivated alkenes as a complementary approach (Scheme 16.18). With this method, the functionalization of terminal alkenes and

16.2  The SCF2H Motif

MeO2C

HCF2SO2Na (2 equiv) N H

(EtO)2POH (3 equiv) TMSCl (2 equiv) Toluene, 85 °C

(a)

EtO2C

N H

80% and 25 examples, 18–93%

EtO2C

Ph HCF2SO2Na (2 equiv) N H

SCF2H

MeO2C

(EtO)2POH (3 equiv) TMSCl (2 equiv) Toluene, 85–100 °C

Ph

SCF2H N H 73% and 10 examples, 45–89% SCF2H

HCF2SO2Na (2 equiv) N H

N

(EtO)2POH (3 equiv) TMSCl (2 equiv) Toluene, 85–100 °C

N

SCF2H

HCF2SO2Na (2 equiv)

N N H (b)

N

(EtO)2POH (3 equiv) TMSCl (2 equiv) Toluene, 85–100 °C

N H 88%

OMe

OMe HCF2SO2Na (2 equiv)

MeO (c)

N H 87%

OMe

(EtO)2POH (3 equiv) TMSCl (2 equiv) Toluene, 100 °C

SCF2H MeO

OMe 82% and 7 examples,47–82%

Scheme 16.15  Electrophilic difluoromethylthiolation of C(sp2) nucleophiles with the HF2CSO2Na/(EtO)2POH/TMSCl system. (a) Reaction with indole derivatives. (b) Reaction with pyrroles and other heteroarenes. (c) Reaction with electron‐rich arenes.

1,1‐disubstituted alkenes was achieved providing the expected products with a good Markovnikov selectivity [29]. The reaction demonstrated a large functional group tolerance (halides, aldehyde, sulfonate, cyano, etc.). The difluoromethylthiolation of aromatic derivatives was also studied by sev­ eral research groups. The group of Li demonstrated that the reagent 4 was effi­ ciently used as SCF2H source under visible light irradiation for the radical difluoromethylthiolation. Various (hetero)aromatic compounds (such as indoles, pyrroles, azaindoles, pyrazoles, isoxazole, chromones, thiophene) and electron‐ rich arenes were functionalized at innate positions via a metal‐free process at room temperature (Scheme  16.19a) [30]. In the same vein, Wang, Wang, and coworkers studied the functionalization of aryldiazonium salts with 4 under photocatalytic conditions (Scheme 16.19b) [31].

459

460

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

Cl N H

SCF2H

Cl

HCF2SOCl (3 equiv) CH3CN, 90 °C

N H

75% and 5 examples, 73–85%

(a) O

O HCF2SOCl (3 equiv) Toluene, 110 °C

Cl

SCF2H Cl 80% and 7 examples, 73–90%

(b)

Scheme 16.16  Difluoromethylthiolation of indole derivatives and ketones with HCF2SOCl. (a) Reaction with indole derivatives. (b) Reaction with ketone derivatives. Preparation of 4 SCF2H

SO2SCF2H

(1) Cl2 (2) PhSO2Na 79%

B(OH)2 Br

SCF2H

4 (2 equiv), AgNO3 (30 mol%) SDS (20 mol%), K2S2O8 (1 equiv) H2O, 50 °C

(a)

4

Br

68% and 26 examples, 38–80%

4 (2 equiv), AgNO3 (30 mol%) CO2H

SDS (20 mol%), K2S2O8 (1 equiv) H2O, 50 °C

(b)

nDec

(c)

SCF2H 86% and 24 examples, 41–90%

Conditions (i) or (ii) nDec

SCF2H SO2Ph

81% (i) and 15 examples, 48–94%

Reaction conditions: (i) 4 (2 equiv), AgNO3 (30 mol%), K2S2O8 (1 equiv), NMP/H2O (1 : 1), 25 °C or (ii): 4 (1.1 equiv), Na2S2O8 (1 equiv), DMSO/H2O (8 : 1), 25 °C

Scheme 16.17  Synthesis and application of the S‐(difluoromethyl)benzenesulfonothioate 4. SDS, sodium dodecyl sulfate. (a) Reaction with aryl‐ and alkyl‐boronic acids. (b) Reaction with aliphatic carboxylic acids. (c) Reaction with alkenes.

In 2018, the synthesis of difluoromethylthioester derivatives with the aid of reagent 4 was independently studied by the groups of Wang [32] and Wang, Hu,

16.2  The SCF2H Motif O

O

4 (2 equiv) Co(OAc)2·4H2O (4 mol%) L1 (4 mol%), tBuOOH (30 mol%) PhSiH3 (1.2 equiv) EtOH, 28 °C

OHC

CH3

Ph tBu

N

SCF2H

OHC

Ph CO2K

OH

91% and 19 examples, 34–91%

tBu L1

Scheme 16.18  Co‐catalyzed hydro‐difluoromethylthiolation of unactivated terminal alkenes.

H2N

O

H2N 4 (2 equiv)

N tBu

TBAI (0–20 mol%) CH3CN, rt, CFL (40 × 2 W)

N2BF4

4 (1 equiv) Ru(bpy)3(PF6)2 (5 mol%)

(a)

(b)

N HF2CS tBu 82% and 27 examples, 40–99%

SCF2H

Sodium ascorbate (2 equiv) CH3CN, rt, visible light

PhO

O

PhO 85% and 27 examples, 17–85%

Scheme 16.19  Photocatalyzed difluoromethylthiolation of (Het)ArH and (Het)ArN2BF4 derivatives with 4. (a) Reaction with (Het)ArH (indoles, pyrroles, electron‐rich arenes, etc.). (b) Reaction with aryldiazonium salts.

Shen, and coworkers [33] via a radical process (Scheme 16.20). In the first case, the difluoromethylthiolation of (hetero)aromatic aldehydes was conducted in the presence of TBHP as the radical initiator. The transformation was not restricted to aromatic aldehydes as aliphatic ones and even α,β‐unsaturated alde­ hydes were successfully difluoromethylthiolated. The second case is a comple­ mentary approach in which the combination of NaN3 and PIFA permitted the functionalization of a panel of (hetero)aromatic and aliphatic aldehydes in ethyl acetate as a green solvent. O SCF2H

NaN3 (2 equiv) PIFA (2 equiv)

53% and 20 examples, 40–91%

4 (1.5 equiv) EtOAc, rt

O

O H

TBHP (2 equiv) 4 (1 equiv) CH3CN, reflux

SCF2H 78% and 34 examples, 43–88%

Scheme 16.20  Difluoromethylthiolation of aldehydes by means of 4.

In 2018, in the course of their study regarding the trifluoromethylthiosulfo­ nylation of alkynes via a process merging visible light photocatalysis and gold catalysis, the group of Xu also investigated the difluoromethylthiosulfonylation reaction of terminal alkynes, leading to the corresponding trisubstituted alkenes as E isomers (Scheme 16.21) [34]. Various functional groups were tolerated such as ester, halogen, and free phenol, and the reaction was not restricted to (hetero) aromatic alkynes as one example of an aliphatic alkyne was depicted. Besides, in

461

462

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

the case of 1‐methoxy‐4‐(1‐propyn‐1‐yl)‐benzene as an internal alkyne, the expected product was obtained in 77% yield as a E/Z mixture of 3  :  1 (Scheme 16.21). SCF2H 4 (2 equiv) Ph3PAuNTf2 (0.5 mol%) Ru(bpy)3Cl2 (0.1 mol%) 1.4-Dioxane, hν, rt

MeO

SO2Ph

MeO

84% and 14 examples, 32–88%

Scheme 16.21  Difluoromethylthiosulfonylation of alkynes.

A methodology allowing the synthesis of aliphatic ketones substituted by a SCF2H group at a remote position was developed by Hu, Shen, and coworkers [35]. In the presence of AgNO3, sodium dodecyl sulfate (SDS) as a surfactant, and K2S2O8, a silver‐catalyzed difluoromethylthiolation reaction of a variety of cycloalkanols as precursors of the functionalized alkyl ketones was carried out, offering an access to the corresponding difluoromethylthioethers. Various cycloalkanols were compatible such as cyclobutanols, cyclopropanols, cyclopen­ tanols, cyclohexanols, and cycloheptanols (Scheme 16.22). Ph OH

4 (2 equiv) AgNO3 (20 mol%) K2S2O8 (1 equiv) SDS (20 mol%), H2O, 40 °C

O SCF2H 82% and 30 examples, 40–95%

Scheme 16.22  Synthesis of ketones substituted by a SCF2H group at a remote position.

16.3 ­The SCH2F Motif As part of the sulfur‐containing fluorinated groups, the SCH2F one is underex­ plored compared to the SCF2H and the SCF3 residues. Indeed, prior to the twenty‐first century, only a handful of methods were available to access this class of compounds, which could suffer from a lack of stability in some cases. One should mention the different variants of the fluoro‐Pummerer rearrangement, which allowed the conversion of sulfoxides into α‐fluoromethyl thioethers [36]. Fuchigami and coworkers extensively studied the anodic oxidation of thioethers into the corresponding α‐fluoromethylthioethers, although it was restricted to a few specific substrates [37]. Finally, the use of electrophilic fluorine source to promote the oxidation of thioethers into α‐fluoromethylthioethers was also reported using N‐fluoropyridinium salt [38] or F–TEDA–BF4 [39]. From 2000, more convenient and general methods have been described and are highlighted in this section. In 2007, Hu and coworkers described the use of chlorofluor­ omethane as an electrophilic source of the fluoromethyl moiety [40]. Under basic conditions in DMF, aryl, heteroaryl, and benzyl thiols were readily converted

16.3  The SCH2F Motif

into the corresponding SCH2F‐containing derivatives in good to excellent yields (Scheme 16.23). N N N N

SH

+ CH2ClF

N N N N

NaH (1.1 equiv) DMF, 0 or 80 °C

SCH2F

86% and 7 examples, 72–82%

Scheme 16.23  Monofluoromethylation of thiols.

In 2008, Prakash et al. described the synthesis of the sulfonium salt 5, as an electrophilic source of CH2F [41]. Although a single example was described, the reaction of this salt with thiophenol yielded the corresponding and poorly stable α‐fluoromethylthioether in 88% NMR yield (Scheme 16.24).

SH

BF4 +

CH2F S

SCH2F

Cs2CO3 (1 equiv) CH3CN, rt

88% (NMR yield)

5

Scheme 16.24  Electrophilic monofluoromethylation of thiophenol using 5.

Complementary to these methods, the group of Hu reported the use of the sulfoximine 6 as a CH2F source [42]. The reaction of 6 with thiols, proceeding presumably according to an SRN1 mechanism, provided a straightforward access to the corresponding SCH2F‐containing molecules in good yields. The reaction was applied to aryl, heteroaryl, and benzyl thiol derivatives (Scheme 16.25). HN O S CH2F

1. NaH (1.25 equiv), DMSO, rt N

SH

2. 6 (1.3 equiv), DMSO, 80 °C

N

SCH2F

88% and 7 examples, 84–98%

6

Scheme 16.25  Monofluoromethylation of thiols using sulfoximine 6.

In 2017, the group of Shen described the synthesis of a new reagent to introduce the SCH2F moiety: the S‐(fluoromethyl)benzenesulfonothioate 7 (Scheme 16.26) [43]. This bench‐stable reagent 7, easily prepared from sodium benzenesulfono­ thioate, was used to convert boronic acids into the desired aryl‐SCH2F‐containing molecules in good to excellent yields with an outstanding functional group toler­ ance (Scheme 16.26a). In the same report, the authors described the radical addi­ tion of the reagent 7 onto terminal alkenes according to an ATRA reaction.

463

464

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf) Preparation of reagent 7 O

S

O SNa

O

CH2FI, DMF, rt

S

O SCH2F

or CH2FCl, DMF, 80 °C 7

B(OH)2 N

N

NaHCO3 (1.5 equiv), MeOH, rt

O

O

90% and 16 examples, 58–93%

(a) O O N

SCH2F

7, CuSO4 (5 mol%)

H

O

7 (1.2 equiv) AgNO3 (10 mol%) K2S2O8 (1 equiv) NMP/H2O (1 : 1), rt

(b)

O N

SO2Ph SCH2F

H

90% and 17 examples, 54–95%

Scheme 16.26  Preparation of 7 and monofluoromethylthiolation of aryl boronic acid and alkenes. (a) Reaction with aryl boronic acids. (b) Addition reaction on alkenes.

The reaction proceeded nicely with a complete and predictable control of the selectivity of the addition. The products were obtained in good yields and the functional group tolerance of the process was excellent (Scheme 16.26b). In 2018, Wang and coworkers [44] and Shen and coworkers [33] concomitantly reported the use of the above-mentioned reagent 7 to get access to monofluoro­ methylthioesters, starting from aldehydes. While Wang was using AMBN (2,2′‐ azobis(2‐methylbutyronitrile)) to promote the acyl radical formation followed by its recombination with SCH2F moiety onto a broad range of aldehydes, Shen used the combination of NaN3 and PIFA to carry out the same transformation. In both cases, yields were moderate to excellent and the reaction proved to be func­ tional group tolerant (Scheme 16.27). O H

SCH2F

DCE, reflux

62% and 29 examples, 42–91%

(a) O

S

O

7 (1.5 equiv), NaN3 (2 equiv) H

(b)

O

7 (0.67 equiv), AMBN (2 equiv)

PIFA (2 equiv), EtOAc, rt

SCH2F S 76% and 5 examples, 44–87%

Scheme 16.27  Synthesis of monofluoromethylthioesters using 7. (a) Wang et al. (b) Shen et al.

16.4  The SCF2PO(OEt)2 Motif

Finally, in 2018 the group of Yi described the synthesis of the Bunte salt FCH2SSO3Na 8 for the installation of the SCH2F residue (Scheme 16.28). This motif was introduced onto anilines through the in situ formation of the corre­ sponding diazonium salts (Scheme  16.28a) [45]. This transformation demon­ strated an excellent scope, various functionalities were tolerated, and heteroaromatic derivatives were compatible. The products were isolated in good to excellent yields. Note that the reaction was extended to the functionalization of thiophenol derivatives and the corresponding unsymmetrical disulfides were isolated in good to excellent yields (Scheme 16.28b). Preparation of reagent 8 CH2FI

O

N

H N O

Na2S2O3 MeOH/H2O

CH2FSSO3Na 8

NH2 S

8 (1.5 equiv), CuSO4 (10 mol%), bpy (10 mol%) tBuONO MeOH, 80 °C

O

O

N

H N O

SCH2F S

O

71% and 28 examples, 43–77%

(a) SH CO2Me

8 (1.5 equiv) MeOH, 50 °C

(b)

SSCH2F CO2Me 67% and 12 examples, 58–78%

Scheme 16.28  Preparation of Bunte salt 8 and monofluoromethylthiolation of anilines and thiols. (a) Reaction with aniline derivatives. (b) Reaction with thiols.

16.4 ­The SCF2PO(OEt)2 Motif As another interesting motif that allowed modifications of the physicochemical properties of a molecule, the SCF2PO(OEt)2 group was underexplored till 2016. Indeed, most of the previous methodologies were restricted to very few exam­ ples and/or focused on the synthesis of reagents to introduce the CF2PO(OEt)2 group [46], a phosphate bioisoster [47]. Thus, after 2016, new methods for its introduction or construction have been developed to broaden the scope of avail­ able SCF2PO(OEt)2‐containing molecules. In 2016, Besset and coworkers described the synthesis of the reagent 9, an electrophilic source of the SCF2PO(OEt)2 group, from a simple aniline derivative and TMSCF2PO(OEt)2 in two steps (Scheme 16.29) [48]. This reagent 9 allowed the introduction of this sulfur‐containing fluorinated group on various scaffolds. Indeed, 9 was reacted with indoles or electron‐rich aromatic derivatives in a SEAr‐type transformation to form the C–SCF2PO(OEt)2 bond. In addition, this reagent was efficient for the introduction of this group onto anilines and thiols.

465

466

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

Preparation of 9 H N

SCN

H N

CuSCN, CsF TMSCF2PO(OEt)2

SCF2PO(OEt)2 9

BnO

SCF2PO(OEt)2

9 (1.2 equiv), TsOH (1.2 equiv) BnO N H

CH2Cl2, 25 °C

(a) NH2

9 (1.2 equiv), TFA (1.2 equiv)

N H 87% and 9 examples, 56–91% H N

CH2Cl2, 40 °C

82% and 7 examples, 56–91%

(b) SH

9 (1 equiv), MsOH (1.2 equiv) CH2Cl2, 25 °C

S

SCF2PO(OEt)2

71% and 5 examples, 55–86%

(c) O

9 (1.8 equiv), AcCl (3 equiv) NMP, 25 °C

(d)

SCF2PO(OEt)2

O SCF2PO(OEt)2 61% and 9 examples, 28–62%

Scheme 16.29  Introduction of the SCF2PO(OEt)2 motif using the electrophilic reagent 9. (a) Reaction with electron‐rich arenes (indoles, aryles, and pyrrole). (b) Reaction with anilines. (c) Reaction with thiols. (d) Reaction with ketones and β‐ketoester.

Finally, the authors demonstrated the possibility to build up a C–SCF2PO(OEt)2 when 9 was reacted with ketones and a β‐ketoester. Later in 2019, the same group reported the use of this reagent 9 for the BiCl3‐ mediated difunctionalization of alkynes and alkenes, as well as for the synthesis of SCF2PO(OEt)2‐containing alkynes (Scheme  16.30) [49]. These transforma­ tions afforded the first access to aliphatic and vinylic SCF2PO(OEt)2‐containing molecules and SCF2PO(OEt)2‐containing alkynes. Another complementary strategy to access the SCF2PO(OEt)2 containing mol­ ecules relied on the construction of this motif. In 2016, Poisson and coworkers described the reaction of α‐diazocarbonyl derivatives with the CuCF2PO(OEt)2 reagent prepared from CuSCN and TMSCF2PO(OEt)2 (Scheme 16.31) [50]. This process allowed the formation of the corresponding α‐SCF2PO(OEt)2 arylacetates in moderate to good yields. The reaction was also extended to the α‐phenyl diazoketone and α‐alkyl diazoace­ tates, albeit in low yields in the last case.

16.4  The SCF2PO(OEt)2 Motif

nPr Ac

Cl

9 (1.2 equiv) BiCl3 (1.8 equiv)

nPr Ac

H2O (1.8 equiv) DCE, 60 °C

N H

SCF2PO(OEt)2

N H

58%, E:Z = 99 : 1 and 18 examples, 40–89%, E:Z up to 99 : 1

(a) TMS

SCF2PO(OEt)2

9 (1.2 equiv) BiCl3 (1.8 equiv) H2O (1.8 equiv) DCE, 60 °C

O

O 52% and 15 examples, 20–86%

(b)

Cl

9 (1.2 equiv) BiCl3 (1.8 equiv)

MeO

H2O (1.8 equiv) DCE, 60 °C

O

SCF2PO(OEt)2 MeO O

40% and 7 examples, 31–64%

(c)

Scheme 16.30  Addition of the SCF2PO(OEt)2 motif onto alkynes and alkenes using 9. (a) Reaction with internal alkynes. (b) Reaction with trimethylsilyl acetylene derivatives. (c) Reaction with styrene derivatives. CuSCN (1 equiv) TMSCF2PO(OEt)2 (2.5 equiv)

O

S

OEt

S

OEt SCF2PO(OEt)2

CsF (3 equiv), H2O (45 equiv) CH3CN/NMP, 0 °C to rt

N2

O

55% and 11 examples, 18–72%

Scheme 16.31  Synthesis of α‐SCF2PO(OEt)2 esters and ketone from α‐diazocarbonyl derivatives. O Br NC

CuSCN (1 equiv) TMSCF2PO(OEt)2 (2.5 equiv) CsF (3 equiv), H2O (45 equiv) CH3CN/NMP, 0 °C to rt

O SCF2PO(OEt)2 NC 71% and 16 examples, 27–73%

Scheme 16.32  Reaction of α‐bromoketones with TMSCF2PO(OEt)2 and CuSCN to access α‐SCF2PO(OEt)2 ketones.

In 2017, the same authors described the access to α‐SCF2PO(OEt)2 ketones starting from α‐bromoketones (Scheme 16.32) [51]. Although restricted to sec­ ondary α‐bromoketones, the corresponding products were obtained in good yields and the functional group tolerance was good.

467

468

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

The same year, these authors reported the construction of arenes substituted with a SCF2PO(OEt)2 moiety starting from bis‐aryldisulfides (Scheme  16.33) [52]. The reaction with the in situ generated CuCF2PO(OEt)2 reagent gave an access to the targeted molecules in moderate to good yields.

S

CuSCN (1 equiv), CsF (3 equiv) TMSCF2PO(OEt)2 (2.5 equiv)

S

1,10-Phenanthroline (1 equiv) CH3CN/DMF, 0 °C to rt

SCF2PO(OEt)2

57% and 4 examples, 48–57%

Scheme 16.33  Reaction of disulfides with the in situ generated CuCF2PO(OEt)2.

Finally, in 2019 Ou and Gooßen reported the one‐pot two‐step synthesis of aryl‐SCF2PO(OEt)2 derivatives starting from aryl diazonium salts (Scheme 16.34) [53]. The in situ generation of the aryl thiocyanate followed in a second step by the introduction of the CF2PO(OEt)2 motif on the latter, according to a Langlois‐ type substitution, yielded the corresponding aryl SCF2PO(OEt)2 derivatives in moderate to good yields.

N2 N Et

BF4

1. CuSCN (1 equiv), Cs2CO3 (2 equiv) NaSCN (1.5 equiv), CH3CN, rt 2. TMSCF2PO(OEt)2 (1.5 equiv) DMF, rt

SCF2PO(OEt)2 N Et 62% and 19 examples, 32–78%

Scheme 16.34  Synthesis of SCF2PO(OEt)2‐containing arenes from diazonium salts.

16.5 ­The SCF2CO2R Motif The adjunction of a α,α‐difluoromethylcarbonyl motif to the sulfur atom offers new fluorinated motifs of particular interest. In addition to offer specific ­physicochemical properties, it allows easy and various transformations into other functional groups (ketones, alcohols). Initially, this motif was usually built up through classical SRN1 reactions [54], electro‐ or chemical oxidation [55], and halex process [56]. From 2016, original and milder reaction conditions were developed to construct or install this motif onto molecules. Noël and coworkers reported a photocatalyzed addition of the CF2CO2Et radi­ cal on a cysteine derivative (Scheme  16.35) [57]. The developed process was applied in batch and in continuous flow conditions. The targeted compound was obtained in good yield in batch (75%) and 81% yield under continuous flow con­ ditions (residence time = five minutes). Note that the methodology was extended to the construction of SRf residues (7 examples).

16.5  The SCF2CO2R Motif O SH + BrCF2CO2Et

MeO Boc

N

H

Ru(bpy)3Cl2 (1 mol%) TMEDA (2 equiv), CH3CN, rt

O SCF2CO2Et

MeO Boc

N

H

75% (batch), 81% (flow)

Scheme 16.35  Synthesis of SCF2CO2Et cysteine analogue.

In 2017, Shen and coworkers reported the first electrophilic reagent to intro­ duce the SCF2CO2Et motif: the [[(ethoxycarbonyl)difluoromethyl]thio]phthal­ imide 10 (Scheme  16.36) [58]. This reagent, conveniently prepared from phthalimide and BrCF2CO2Et or TMSCF2CO2Et in a three‐step sequence, was reacted with various nucleophiles. Reagent 10 was reacted with indoles, pyr­ roles, thiophene, and electron‐rich arenes according to a SEAr pathway to build up SCF2CO2Et‐containing arenes and heteroarenes (Scheme  16.36a). In addi­ tion, this reagent proved to be reactive with thiol nucleophiles, giving an access to nonsymmetrical disulfides (Scheme  16.36b). Finally, the formation of the C–SCF2CO2Et bond was possible starting from β‐ketoesters, 3‐aryloxindoles, or 3‐arylbenzofuranones (Scheme 16.36c). In the same vein, Billard and coworkers reported the synthesis and the applica­ tion of the (methoxycarbonyl)difluoromethanesulfonamide 11 as a practical rea­ gent to introduce the SCF2CO2Me motif (Scheme 16.37) [59]. Similarly to the reagent 10, developed by Shen, this reagent was reacted with electron‐rich arenes and heteroarenes giving the corresponding products in high yields. Complementarily, this reagent allowed the α‐functionalization of ketones, as well as cyclization reactions to access polysubstituted benzofuran, benzothio­ phene, and isochromenone bearing the SCF2CO2Me motif, starting from the appropriate alkyne. Later, Zheng and coworkers described the construction of the SCF2CO2Et motif starting from alkyl bromides, α‐bromoketones, and aryl diazonium salts (Scheme  16.38) [60]. This reaction proceeded through the initial formation of the thiocyanate derivatives, followed by a Langlois‐type substitution using TMSCF2CO2Et and CsF as an activator, a concept already described by Gooßen [11a, 61]. Regarding the reaction with alkyl halides, the reaction proceeded well with benzyl bromides and various alkyl bromides along with a good functional group tolerance (Scheme  16.38a). α‐Bromoketones gave the α‐SCF2CO2Et ketones in low to moderate yields (Scheme 16.38b), while aryl diazonium salts gave the aryl‐SCF2CO2Et derivatives in moderate to excellent yields (Scheme 16.38c). Finally, in 2019, Jana and Koenigs described an elegant Doyle–Kirmse rear­ rangement using the reagent 12 to access quaternary center bearing the SCF2CO2Et motif (Scheme 16.39) [62]. Although the reaction was restricted to α‐aryl diazoacetates, the reaction of 12 in the presence of Rh2(OAc)4 furnished the desired compounds in good to excellent yields and a large panel of α‐aryl diazoacetates was successfully reacted. In addition, the authors demonstrated the possible formation of the product under metal free conditions, using blue

469

470

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

Preparation of reagent 10 Pathway A O N H O

O 1. S2Cl2, Et3N

N SCF2CO2Et

2. Cl2/CHCl3 or SO2Cl2 3. TMSCF2CO2Et, AgF

O 10

Pathway B O N K O

O ClSCF2CO2Et

N SCF2CO2Et

Prepared in 2 steps from BrCF2CO2Et

O 10

O2N

10 (1.2 equiv), MgBr2 (1.5 equiv) N H

DCE, 80 °C

N H 86% and 14 examples, 56–91%

10 (1.2 equiv), MgBr2 (1 equiv)

S

(a) SH

Toluene, 80 °C

MeO

SCF2CO2Et

MeO

91% and 5 examples, 74–85%

(b) O

Br

SCF2CO2Et

O 2N

10 (1.2 equiv), K2CO3 (1.5 equiv) CO2Me

O

Br

CO2Me

CH2Cl2, rt

SCF2CO2Et 89% and 5 examples, 72–95%

Ph

F

N Boc

Ph O

SCF2CO2Et

10 (1.2 equiv), K2CO3 (1.5 equiv)

N Boc

CH2Cl2, rt F

O

72% and 3 examples, 88–92% Ar O (c)

10 (1.2 equiv), K2CO3 (1.5 equiv) O

CH2Cl2, rt

Ar

SCF2CO2Et O

O

Ar = 4-Cl–C6H4, 91% Ar = 3,4-OCH2O–C6H3, 91%

Scheme 16.36  Introduction of the SCF2CO2Et group onto electron‐rich arenes, heteroarenes, thiols, β‐ketoesters, oxindoles, and benzofuranones using the electrophilic reagent 10. (a) Reaction with electron‐rich arenes and heteroarenes. (b) Reaction with thiols. (c) Reaction with β‐ketoesters, oxindoles, and benzofuranones.

16.5  The SCF2CO2R Motif

Preparation of reagent 11 O MeO

H N

1. DAST, DIPEA, CH2Cl2, –25 °C CF2SiMe3

SCF2CO2Me

2. PhNH2, 25 °C

11 Br

Br

SCF2CO2Et

11 (1 equiv), TMSCl (2 equiv) CH2Cl2, 50 °C

N H (a) O

N H 94% and 8 examples, 33–89% O

11 (1 equiv), TMSCl (2 equiv) CH3CN, 90 °C

SCF2CO2Et 52% and 4 examples, 40–46%

(b) OMe

O

11 (1 equiv), BiCl3 (2 equiv) DCE, 80 °C

Ph

SCF2CO2Et

Ph

62% and 2 examples, 54 and 46%

(c)

Scheme 16.37  Synthesis of SCF2CO2Et‐containing electron‐rich (hetero)arenes and ketones. (a) Reaction with electron‐rich arenes and heteroarenes. (b) Reaction with ketones. (c) Cyclization reactions.

Br

2. TMSCF2CO2Et (2 equiv), CsF (2 equiv), rt

F

SCF2CO2Et

1. NaSCN (2 equiv), DMA, rt F

81% and 18 examples, 49–92%

(a) O

O Br

1. NaSCN (2 equiv), DMA, rt 2. TMSCF2CO2Et (2 equiv), NaOAc (2 equiv), rt

Ph

SCF2CO2Et Ph 51% and 9 examples, 27–68%

(b) N2 N O

(c)

BF4

SCF2CO2Et

1. NaSCN (1.5 equiv), CuSCN (20 mol%), CH3CN, rt 2. TMSCF2CO2Et (1.5 equiv), CsF (2 equiv), DMA, rt

N O 70% and 15 examples, 51–91%

Scheme 16.38  Construction of the SCF2CO2Et motif on alkyl bromides, benzyl bromides, and aryl diazonium salts. (a) Reaction with benzyl bromides and alkyl bromides. (b) Reaction with α‐bromoketones. (c) Reaction with aryl diazonium salts.

471

472

16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf) O

O

O

OMe N2

+

SCF2CO2Et

Rh2(OAc)4 (1 mol%)

O

O

O

OMe SCF2CO2Et

DCM, rt

12

87% and 15 examples, 66–91%

Scheme 16.39  Doyle–Kirmse rearrangement toward the formation of quaternary carbon centers bearing the SCF2CO2Et motif.

light to promote the formation of the carbene involved in the Doyle–Kirmse rearrangement.

16.6 ­The SCF2Rf Motif Since the pioneer work from Gooßen and coworkers, who used Me4NSC2F5 as a SRf source [63], and the design by the group of Billard of an electrophilic source (ArNMeSRf ) [64], few reports dealt with the direct introduction of SRf residue. In 2016, using the combination of RfSO2Cl with (EtO)2POH, the group of Yi reported some examples of the direct introduction of SC4F9 and SC8F17 residues on indoles derivatives (four examples) as part of a more general study regarding the fluoroalkylthiolation with fluoroalkylsulfonyl chlorides (Scheme 16.40) [23]. One year later, in the course of their study to generate in situ an electrophilic SCF2H source from HCF2SO2Na with (EtO)2POH and TMSCl, Yi and coworkers extended their methodology to the introduction of other SRf groups (SRf = SC4F9 and SC8F17) on 1,3,5‐trimethoxybenzene (2 examples, Scheme 16.41) [25]. SC4F9 C4F9SO2Cl (1.5 equiv) (EtO)2POH (2 equiv) CH3CN, 90 °C

N H

N H 54% and 1 example, 63% 2 examples with SC8F17, 45–52%

Scheme 16.40  Perfluoroalkylthiolation of electron‐rich arenes with an electrophilic source in situ generated from RfSO2Na.

OMe

OMe SC4F9

C4F9SO2Na (2 equiv) MeO

OMe

(EtO)2POH (3 equiv) TMSCl (2 equiv) Toluene, 100 °C

MeO

OMe 61% and 1 example (SC8F17), 58%

Scheme 16.41  Perfluoroalkylthiolation of 1,3,5‐trimethoxybenzene with an electrophilic source in situ generated from RfSO2Na.

­  References

In 2017, the group of Yi developed a methodology to build up a S–Rf bond using the corresponding RfSO2Na as they depicted a silver‐catalyzed perfluoroalkylation of thiols [10]. With this approach, a panel of (hetero)aromatic and aliphatic thiols was functionalized. The reaction turned out to be tolerant to several functional groups such as carboxylic acids, free alcohol, and halogens (Scheme 16.42).

HO

SH

C4F9SO2Na (2 equiv) AgNO3 (10 mol%) K2S2O8 (2 equiv) CH3CN/H2O, 80 °C

HO

SC4F9

81% and 11 examples, 61–87% (Rf = C2F5, C4F9, C6F13, C8F17)

Scheme 16.42  Perfluoroalkylthiolation of thiol derivatives with RfSO2Na.

16.7 ­Conclusion and Perspectives In the last decade, tremendous advances have been published regarding the development of new sulfur‐containing fluorinated groups. Indeed, complemen­ tary to the SCF3 motif, the SCF2H and more recently the SCH2F, SCF2CO2Et, SCF2PO(OEt)2, and SRf have been implemented to the medicinal chemist tool­ box. In this chapter, we have summarized the recent progress made in that field. In addition to these pioneering works, we believe that important milestones to introduce or build up these motifs as well as newly designed sulfur‐containing fluorinated motifs will appear in the forthcoming years.

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16  Extension to the SCF2H, SCH2F, and SCF2R Motifs (R = PO(OEt)2, CO2R, Rf)

10 Ma, J.‐J., Liu, Q.‐R., Lu, G.‐P., and Yi, W.‐B. (2017). J. Fluorine Chem. 193:

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Chem. Int. Ed. 54: 5753–5756.(b) Jouvin, K., Matheis, C., and Gooßen, L.J. (2015). Chem. Eur. J. 21: 14324–14327. (a) Wu, J., Gu, Y., Leng, X., and Shen, Q. (2015). Angew. Chem. Int. Ed. 54: 7648–7652.(b) Gu, Y., Chang, D., Leng, X. et al. (2015). Organometallics 34: 3065–3071.(c) Wu, J., Liu, Y., Lu, C., and Shen, Q. (2016). Chem. Sci. 7: 3757–3762. Wu, J., Lu, C., Lu, L., and Shen, Q. (2018). Chin. J. Chem. 36: 1031–1034. For the synthesis of the electrophilic source 2, see: (a)Zhu, D., Gu, Y., Lu, L., and Shen, Q. (2015). J. Am. Chem. Soc. 137: 10547–10553. (b) Zhu, D., Hong, X., Li, D. et al. (2017). Org. Process Res. Dev. 21: 1383–1387.For selected examples regarding the application of the reagent 2 as an electrophilic SCF2H source, see: (c)Candish, L., Pitzer, L., Gómez Suárez, A., and Glorius, F. (2016). Chem. Eur. J. 22: 4753–4756. Arimori, S., Matsubara, O., Takada, M. et al. (2016). R. Soc. Open Sci. 3: 160102. Xu, W., Ma, J., Yuan, X.‐A. et al. (2018). Angew. Chem. Int. Ed. 57: 10357–10361. Kondo, H., Maeno, M., Sasaki, K. et al. (2018). Org. Lett. 20: 7044–7048. Gondo, S., Matsubara, O., Chachignon, H. et al. (2019). Molecules 24: 221–231. Hardy, M.A., Chachignon, H., and Cahard, D. (2019). Asian J. Org. Chem. 8: 591–609. Zhao, X., Wei, A., Li, T. et al. (2017). Org. Chem. Front. 4: 232–235. Zhao, X., Li, T., Yang, B. et al. (2017). Tetrahedron 73: 3112–3117. Jiang, L., Ding, T., Yi, W.‐B. et al. (2018). Org. Lett. 20: 2236–2240. Jiang, L., Yi, W., and Liu, Q. (2016). Adv. Synth. Catal. 358: 3700–3705. Huang, Z., Matsubara, O., Jia, S. et al. (2017). Org. Lett. 19: 934–937. Yan, Q., Jiang, L., Yi, W. et al. (2017). Adv. Synth. Catal. 359: 2471–2480. Jiang, L., Yan, Q., Wang, R. et al. (2018). Chem. Eur. J. 24: 18749–18756. Note that an exhaustive review was recently published by our group: Pannecoucke, X. and Besset, T. (2019). Org. Biomol. Chem. 17: 1683–1693. Zhu, D., Shao, X., Hong, X. et al. (2016). Angew. Chem. Int. Ed. 55: 15807–15811. Shao, X., Hong, X., Lu, L., and Shen, Q. (2019). Tetrahedron 75: 4156–4166. Li, J., Zhu, D., Lv, L., and Li, C.‐J. (2018). Chem. Sci. 9: 5781–5786. Wang, W., Zhang, S., Zhao, H., and Wang, S. (2018). Org. Biomol. Chem. 16: 8565–8568. Guo, S.‐H., Zhang, X.‐L., Pan, G.‐F. et al. (2018). Angew. Chem. Int. Ed. 57: 1663–1667. Xu, B., Li, D., Lu, L. et al. (2018). Org. Chem. Front. 5: 2163–2166. Li, H., Cheng, Z., Tung, C.‐H., and Xu, Z. (2018). ACS Catal. 8: 8237–8243. Xu, B., Wang, D., Hu, Y., and Shen, Q. (2018). Org. Chem. Front. 5: 1462–1465. (a) Lange, H.C. and Shreeve, J.M. (1985). J. Fluorine Chem. 28: 219–227.(b) Furuta, S., Kuroboshi, M., and Hiyama, T. (1995). Tetrahedron Lett. 36: 8243–8246. (a) Dawood, K.M. and Fuchigami, T. (1999). J. Org. Chem. 64: 138–143. (b) Dawood, K.M., Higashiya, S., Hou, Y., and Fuchigami, T. (1999). J. Org. Chem. 64: 7935–7939. (c) Shaaban, M.R., Ishii, H., and Fuchigami, T. (2000). J. Org. Chem. 65: 8685–8689. (d) Dawood, K.M., Higashiya, S., Hou, Y., and Fuchigami,

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47 48 49 50 51 52 53 54 55

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57 58 59 60 61 62 63 64

T. (1999). J. Fluorine Chem. 93: 159–164. (e) Boys, M.L., Collington, E.W., Finch, H. et al. (1988). Tetrahedron Lett. 29: 3365–3368. Umemoto, T. and Tomizawa, G. (1995). J. Org. Chem. 60: 6563–6570. Lal, G.S. (1993). J. Org. Chem. 58: 2791–2796. Zhang, W., Zhu, L., and Hu, J. (2007). Tetrahedron 63: 10569–10575. Prakash, G.K.S., Ledneczki, I., Chacko, S., and Olah, G.A. (2008). Org. Lett. 10: 557–560. Shen, X., Zhou, M., Ni, C. et al. (2014). Chem. Sci. 5: 117–122. Zhao, Q., Lu, L., and Shen, Q. (2017). Angew. Chem. Int. Ed. 56: 11575–11578. Guo, S.‐H., Wang, M.‐Y., Pan, G.‐F. et al. (2018). Adv. Synth. Catal. 360: 1861–1869. Liu, F., Jiang, L., Qiu, H., and Yi, W. (2018). Org. Lett. 20: 6270–6273. (a) Lequeux, T., Lebouc, F., Lopin, C. et al. (2001). Org. Lett. 3: 185–188.(b) Henry‐dit‐Quesnel, A., Toupet, L., Pommelet, J.‐C., and Lequeux, T. (2003). Org. Biomol. Chem. 1: 2486–2491.(c) De Schutter, C., Pfund, E., and Lequeux, T. (2013). Tetrahedron 69: 5920–5926. Ivanova, M.V., Bayle, A., Besset, T. et al. (2016). Chem. Eur. J. 22: 10284–10293. Xiong, H.‐Y., Bayle, A., Pannecoucke, X., and Besset, T. (2016). Angew. Chem. Int. Ed. 55: 13490–13494. Wang, J., Xiong, H.‐Y., Petit, E. et al. (2019). Chem. Commun. 55: 8784–8787. Ivanova, M.V., Bayle, A., Besset, T. et al. (2016). Angew. Chem. Int. Ed. 55: 14141–14145. Ivanova, M.V., Bayle, A., Besset, T. et al. (2017). Eur. J. Org. Chem.: 2475–2480. Ivanova, M.V., Bayle, A., Besset, T. et al. (2017). Chem. Eur. J. 23: 17318–17338. Ou, Y. and Gooßen, L.J. (2019). Asian J. Org. Chem. 8: 650–653. Matsnev, A.V., Kondratenko, N.V., Yagupolskii, Y.L., and Yagupolskii, L.M. (2002). Tetrahedron Lett. 43: 2949–2952. (a) Hugenberg, V. and Haufe, G. (2010). J. Fluorine Chem. 131: 942–950. (b) Fuchigami, T., Shimojo, M., and Konno, A. (1995). J. Org. Chem. 60: 3459–3464. (c) Motherwell, W.B., Greaney, M.F., and Tocher, D.A. (2002). J. Chem. Soc., Perkin Trans. 1 64B: 2809–2815. (d) Greaney, M.F. and Motherwell, W.B. (2000). Tetrahedron Lett. 41: 4463–4466. (a) Gouault, S., Guérin, C., Lemoucheux, L. et al. (2003). Tetrahedron Lett. 44: 5061–5064.(b) Jouen, C. and Pommelet, J.C. (1997). Tetrahedron 53: 12565–12574. Bottecchia, C., Wei, X.‐J., Kuijpers, K.P.L. et al. (2016). J. Org. Chem. 81: 7301–7307. Shen, F., Zhang, P., Lu, L., and Shen, Q. (2017). Org. Lett. 19: 1032–1035. Ismalaj, E., Glenadel, Q., and Billard, T. (2017). Eur. J. Org. Chem.: 1911–1914. Xu, L., Wang, H., Zheng, C., and Zhao, G. (2017). Tetrahedron 73: 6057–6066. Danoun, G., Bayarmagnai, B., Gruenberg, M.F., and Gooßen, L.J. (2014). Chem. Sci. 5: 1312–1316. Jana, S. and Koenigs, R.M. (2019). Asian J. Org. Chem. 8: 683–686. Matheis, C., Bayarmagnai, B., Jouvin, K., and Gooßen, L.J. (2016). Org. Chem. Front. 3: 949–952. Alazet, S. and Billard, T. (2014). Synlett 26: 76–78.

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17 Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) Vinayak Krishnamurti*, Colby Barrett*, and G.K. Surya Prakash# University of Southern California, Loker Hydrocarbon Research Institute, Department of Chemistry, 837 Bloom Walk, Los Angeles, CA, 90089‐1661, USA

17.1 ­Introduction The direct fluoroalkylation of organic substrates is a desired method to access fluorine‐containing molecules. Multiple fluoroalkylation reagents and method­ ologies provide convergent access to fluorinated compounds through various reaction pathways. Fluoroalkylsilanes are immensely popular reagents for the addition of fluorine‐containing groups to organic molecules. In particular, the Ruppert–Prakash reagent has been extensively utilized in direct nucleophilic [1–3] and oxidative [4–7] trifluoromethylation procedures and in difluorometh­ ylenation reactions [8–12]. Fluoroalkyl sulfinate salts offer another avenue to produce fluorine‐containing scaffolds [13–16]. Alternatively, cross‐coupling procedures with iodo‐ and bromofluoroalkanes can be performed to afford rel­ evant fluorinated molecules [17, 18]. Of all the available fluorofunctionalization reagents, fluoroalkyl sulfoxides and sulfones represent the most diverse and versatile class of compounds for the introduction of perfluoroalkyl groups. The syntheses [19] and utilization [20–22] of sulfur‐ and fluorine‐containing compounds have therefore received much attention. This chapter aims to be a comprehensive compilation of known preparations and uses of various tri‐ and difluoromethyl sulfones and sulfoxides, with coverage of most of the known uses and syntheses of these molecules. Monofluoromethylsulfones and sulfoxides, despite being prominent classes of α‐fluoro sulfur compounds [21–26], are not within the scope of this chapter. For applications and occurrences of these molecules, see the included references [21, 22]. Fluoroalkyl sulfoximines, sulfilimines, sulfinates, sulfonates, and sulfonium salts have also been extensively used [22], but their chemistry does not fall under the purview of this chapter (see Chapter 22). # Corresponding author. * These authors contributed equally.

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

478

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

17.2 ­Trifluoromethyl Sulfoxides [RS(O)CF3] 17.2.1  Aryl Trifluoromethyl Sulfoxides [ArS(O)CF3]: Preparation One of the earliest and still most popular approaches to the synthesis of aryl tri­ fluoromethyl sulfoxides involved oxidation of the corresponding trifluoromethyl thioether. This has been accomplished with a wide variety of oxidants [27–44], as illustrated in Scheme 17.1. Another synthetic path to aryl trifluoromethyl sulfoxides entails incorporation of either the aryl or trifluoromethyl unit into a sulfinyl moiety containing a leav­ ing group. Kirchmeier and coworker used a TMS‐protected pentafluorophenyl nucleophile, which upon desilylation by potassium fluoride was added to trifluo­ romethyl sulfinyl fluoride to give the pentafluorophenyl trifluoromethyl sulfox­ ide in good yield (Scheme  17.2a) [45]. The opposite approach involving nucleophilic trifluoromethylation of nucleofuge‐containing sulfinyl arenes has also been demonstrated (Scheme  17.2b,c). The trifluoromethide anion (CF3–) was used to perform nucleophilic substitution on aryl sulfinyl chlorides [46] and methyl phenylsulfinate [47], giving the corresponding sulfoxides in moderate and good yields, respectively. In both cases the Ruppert–Prakash reagent (TMSCF3) was the source of CF3− via nucleophilic desilylation by a fluoride sourced from tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) or cesium fluoride. Trifluoromethylsulfinyl (triflinyl) arenes have also been synthesized in a few other interesting ways. Wakselman et al. devised a C(sp2)–H sulfinylation of sub­ stituted arenes via superacid activation of triflinate salts (F3CSO2Na or F3CSO2K) with triflic acid (TfOH) (Scheme  17.3a) [48]. Two years later, the same group showed that these sulfoxides could be accessed through a Lewis acid‐mediated (LA) thia‐Fries rearrangement of aryl triflinates (F3CS(O)OAr), giving arene‐ dependent selectivity for the ortho‐hydroxy product (Scheme  17.3b) [49]. 2‐ Triflinyl‐N‐arylanilines have been prepared in fair to good yields via reactions of sulfinamides with in situ generated benzyne, as demonstrated by Liu and Larock (Scheme 17.3c) [50]. 17.2.2  Aryl Trifluoromethyl Sulfoxides [ArS(O)CF3]: Application Triflinyl arenes have found several applications in the realm of organic synthesis. One such application is their use as trifluoromethylation reagents. Prakash et al. showed phenyl trifluoromethyl sulfoxide to be an efficient source of nucleophilic CF3, which is released upon nucleophilic substitution of tert‐butoxide at the sul­ fur atom. This was applied to the trifluoromethylation of aldehydes and ketones, which provided the corresponding carbinols in good yields (Scheme 17.4a) [51]. In the same year, this group also reported the synthesis of trifluoromethylsilanes from chlorosilanes, using PhS(O)CF3 as a trifluoromethide source. A magnesium metal‐mediated single electron reduction of the sulfoxide results in expulsion of CF3−. This then adds to the chlorosilane to form the pentacoordinate silicate intermediate, and a subsequent chloride dissociation gives the trialkyl trifluoro­ methylsilane (Scheme 17.4b) [52]. Hu and coworkers applied Prakash’s PhS(O)

(i) XeF2 (ii) H2O (i) Cl2, SbF5 (ii) H3O+

S R

TCCA H2O

O S

CF3 (n-Bu)4N+(NO3)– [MoIV] (cat.)

F3C CF3

mCPBA

R

[CuII] (cat.)

S

H5IO6 PCC (cat.)

R

Electrochemical oxidation (a)

O O

CF3

CF3CO3H PPO

(b)

Scheme 17.1  Oxidations of aryl trifluoromethyl sulfides to sulfoxides.

O S

H2O2 R

CF3

480

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

F

O S

F C6F5–TMS

F

KF

F

CF3

O S

CF3

F F

(a)

O S

O S

TMSCF3

Cl

TASF

R

CF3

R 53–61%

(b)

O S

O S

TMSCF3

OMe

CF3

CsF 85% (c)

Scheme 17.2  Aryl trifluoromethyl sulfoxides via nucleophilic substitution.

H + R

MO

O S

O S

TfOH CF3

R

M = Na, K

(a) O R

S O

CF3

AlCl3

CF3

57–82% OH O S R

CF3

O S +

R HO

32–75%

(b)

H N R

CF3

0–38%

R S O

CF3

TMS +

CsF

NH O S

OTf

CF3

41–91% (c)

Scheme 17.3  Other aryl trifluoromethyl sulfoxide syntheses.

CF3/KOtBu system to the in situ generation of trifluoromethylcopper (CuCF3), which was then used in cross‐coupling reactions with (hetero)aryl halides, (het­ ero)aryl boronic acids, and terminal alkynes (Scheme 17.4c) [53].

17.2  Trifluoromethyl Sulfoxides [RS(O)CF3]

O Ph O S

HO CF3

H

Ph CF3

KOtBu

H 68%

HO CF3 O Ph

(a) O S

CF3

+

R3Si Cl

Ph Ph

Mg0

R3Si CF3 73–98%

(b) O S

CF3 Ar–X

KOtBu CuCl CuCF3

X = I, Br ArB(OH)2 Air Ar

(c)

Ph 83%

Air

Ar CF3

Ar CF3

Ar

CF3

Scheme 17.4  Phenyl trifluoromethyl sulfoxide as a CF3− source.

Diaryl trifluoromethyl sulfonium salts (e.g. Umemoto’s reagent), derived from aryl trifluoromethyl sulfoxides, are among the most popular electro­ philic trifluoromethylating agents. Strong Lewis acid (LA) activation of the sulfoxide followed by either an intra‐ or intermolecular electrophilic aro­ matic substitution (EAS) reaction at the sulfonium center provides the diaryl trifluoromethyl sulfonium salt (Scheme 17.5a). Umemoto and Ishihara’s pio­ neering work with these compounds employed ortho‐biaryl trifluoromethyl sulfoxides and triflic anhydride (Tf2O) to give the corresponding S‐(trifluoro­ methyl)dibenzothiophenium triflate products (Scheme  17.5b) [35]. In the same report, the authors also showed that intermolecular arylation of the aryl trifluoromethyl sulfonium intermediate gives the product trifluorome­ thyl sulfonium species with two independent aryl substituents (Scheme 17.5c) [35]. A few years later, the same group reported an alternative Lewis acid system for this process. With fuming sulfuric acid as the reaction medium, dissolved SO3 acted as the Lewis acid to provide the trifluoromethyl sulfo­ nium bisulfate. The anion was then exchanged with either triflate or tetra­ fluoroborate by mixing with the sodium salt of the desired anion, giving the

481

482

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

products in good yields (Scheme  17.5d) [41]. Prakash et  al. employed the intermolecular arylation approach (Scheme 17.5c), in which ArH was poly­ styrene, to produce a solid‐phase bound CF3‐sulfonium reagent for the pur­ pose of electrophilic trifluoromethylation [54]. A report from Magnier et al. showed that under neat (excess) Tf2O conditions, phenyl trifluoromethyl sul­ foxide can react with itself to give the CF3‐sulfonium with a SCF3 substituent on the arene (Scheme 17.5e) [55]. O S

O S

LA

CF3

LA CF3 S

CF3

OLA

H+ (a) O S R

CF3 TfO– S

Tf2O

CF3

R

R

R

(b) O S R

CF3

Tf2O ArH

R

CF3 TfO– S Ar

(c) O S

CF3

(i) 60%SO3–H2SO4

CF3 S

X–

(ii) NaX (X-exchange) X = BF4, OTf (d) O S

(e)

CF3

Tf2O (neat)

CF3 TfO– S

SCF3

Scheme 17.5  Diaryl trifluoromethyl sulfonium salts from sulfoxides.

There are a few reports in the literature regarding the production of ArSCF3 moieties from aryl trifluoromethyl sulfoxide precursors. Eberhart and Procter detailed an ortho‐propargylation of triflinyl benzene with propargyl silanes under Tf2O conditions (Scheme 17.6a) [56]. Kaiser et al. performed a hydrative arylation of alkynes with phenyl trifluoromethyl sulfoxide in the presence of triflic acid to give an aryl trifluoromethyl thioether (Scheme  17.6b) [57].

17.2  Trifluoromethyl Sulfoxides [RS(O)CF3]

An interesting ring opening rearrangement was reported by Magnier and cow­ orkers in which triflinyl benzene, activated by Tf2O, reacted with cyclopropyl carbonitrile to give a sulfilimine intermediate. Upon heating (followed by an aqueous NaCl wash), the ring opening rearrangement gave the ortho‐alkyl (trif­ luoromethylsulfanyl)benzene product (Scheme 17.6c) [58]. O S

nBu

CF3

+

CF3 S

Tf2O

n-Bu

Lutidine

TMS

83%

(a) O S

CF3 +

PMP

CF3 S O

Tf2O Lutidine

PMP 44%

(b) O S

CF3

+

CN

Tf2O

CF3 S N

(i) Δ OTf

CF3 S

Cl

(ii) aq NaCl

OTf (c)

CN

Scheme 17.6  Ortho‐substituted –SCF3 arenes from Tf2O‐activated sulfoxides.

One of the earliest applications of aryl trifluoromethyl sulfoxides is as a pre­ cursor for tunable CF3 sources, such as S‐trifluoromethyl sulfoximines [RS(O) (NR)CF3] and sulfilimines [RS(NR)CF3]. In 1984, Yagupol’skii and coworkers demonstrated the synthesis of N–H sulfoximines from triflinyl arenes and sodium azide (NaN3) in fuming sulfuric acid (Scheme 17.7a) [59]. A quarter of a century later, Magnier and coworkers reported an improved method for preparation of aryl trifluoromethyl sulfoximines via sulfilimines. The aryl trif­ luoromethyl sulfoxide is activated by triflic anhydride in the presence of an alkyl or aryl nitrile. The nitrogen of the nitrile adds to the sulfonium intermedi­ ate, and the subsequent addition of water provides the N‐acyl sulfilimine prod­ uct (Scheme 17.7b) [43]. The authors also demonstrated that the inclusion of an oxidant (KMnO4) in the water addition serves as a one‐pot path to the cor­ responding sulfoximines (Scheme  17.7c) [43]. Several expansions on this approach have been reported. The same group showed that aryl and alkyl dini­ triles give mixtures of mono‐ and bis(sulfilimines) (Scheme 17.7d) [60]. Kirsch et al. used trifluoromethanesulfonamide (TfNH2) in place of a nitrile to obtain the N‐triflyl sulfilimine in low yield (Scheme 17.7e) [37]. Magnier and cowork­ ers substituted secondary amines in place of the water addition, affording sul­ filimino iminium salts (Scheme 17.7f ) [61].

483

484

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) O S R

CF3

(i) NaN3 60%SO3–H2SO4

O NH S CF3

R

(ii) H2O

80–96%

(a)

O O S R

CF3 + R′ CN

N S

(i) Tf2O R

(ii) H2O

O S R

O NH S CF3

(i) Tf2O

CF3 + Me–CN

R

(ii) H2O, [O]

88–94%

(c)

R

CF3 + NC

CN (i) Tf2O n (ii) H2O

CF3 S N R

O

(d) F

R

O S

N n

CF3 S

N S

F CF3 + R′ CN

F

Tf2O TfNH2

+

R

O

CF3 S N R

O

CN n

Tf CF3

F

R 16%

(e)

R2 O S R

(f)

CF3

22–99%

(b)

O S

R′

CF3 + R1 CN

N S

(i) Tf2O (ii) R2R3NH

R

R3

N

OTf R1

CF3

76–98%

Scheme 17.7  SCF3 sulfoximines and sulfilimines from Tf2O‐activated sulfoxides.

17.2.3  Heteroaryl Trifluoromethyl Sulfoxides [hetArS(O)CF3]: Preparation As with aryl analogues, heteroaryl trifluoromethyl sulfoxides are often prepared from the corresponding thioether using an oxidant. One of the earliest examples was the use of sodium periodate to oxidize an –SCF3 imidazole reported by Mulvey and Jones in 1975 (Scheme 17.8a) [62]. Tang et al. displayed the efficacy of both hydrogen peroxide/trifluoroacetic acid (TFA) and trichloroisocyanuric acid (TCCA) in oxidizing a trifluoromethylsulfanylpyrazole, providing the sulfoxide, fipronil (a commercial insecticide), in 96% and 70% yield with H2O2/TFA and TCCA, respectively (Scheme  17.8b) [63]. Li and coworkers showed that this transformation also proceeds well with meta‐chloroperoxybenzoic acid (mCPBA) as the oxidant, affording 70% yield of the desired sulfoxide (Scheme 17.8b) [64].

17.2  Trifluoromethyl Sulfoxides [RS(O)CF3]

S

N N

O S

NaIO4

S

N N

CF3

O S CF3

(a)

F3C

Cl

Cl

H2O2, TFA (R = H)

Cl

TCCA (R = H)

N N

S CN

(b)

F3C

NHR

CF3

Cl

mCPBA (R = Ac)

NHR O

N N

S CN

CF3

Scheme 17.8  Heteroaryl trifluoromethyl sulfide oxidation to sulfoxides mCPBA.

Triflinyl heteroarenes can also be synthesized via an EAS‐type reaction with an electrophilic –S(O)CF3 species. Arguably the most direct approach is to use trifluoromethanesulfinyl chloride (ClS(O)CF3) as the electrophile, and Jiang et al. showed that with an indole nucleophile, 3‐triflinyl indole can be produced in 63% yield (Scheme  17.9a) [65]. Concerned with the toxicity, volatility, and poor stability of trifluoromethanesulfinyl chloride, Bertrand and coworkers employed N‐triflinyl succinimide as the electrophilic triflinyl source. Mixing this reagent with N‐methylpyrrole gave the 2‐substituted product as the major iso­ mer in 67% yield (Scheme 17.9b) [66]. O

+

N H

Cl

O S

CF3

S CF3

N H 63%

(a)

O N

+

N

O S

O S CF3 CF3

N

+

N

O (b)

10%

O S CF3

67%

Scheme 17.9  EAS‐type triflinyl heteroarene synthesis with X–S(O)CF3.

The same type of EAS approach has been applied to in situ generated triflinyl electrophiles. In these reactions a phosphine or phosphine oxide is used to per­ form a deoxygenation on the triflinyl precursor, generating the active electro­ philic species for EAS (Scheme 17.10a).

485

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17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

F3C

O S

NaO–P

Cl–P ONa

F3C

O S

NuH

F3C

O S

Nu

(a)

F3C

O S

ONa

+

POCl3

N

O S CF3

N 60%

(b)

O

F3C

O S

R ONa

+ N R′

R

POCl3

R″

R″ N R′ 63–94%

(c)

O

F3C

O S

R ONa

PCl3

R″

+

R

R″

40–88%

F3C

O S

ONa

+

N N Ph

PCl3 OH

N N Ph

O S CF3 OH

51%

(e)

O F3C S Cl O

PCy3

O F3C S O

Cl Cy P Cy Cy

R″ R O F3C S Cl + N O X R′

(g)

S CF3

N R′

N R′

(d)

(f)

S CF3

X = C, N

PCy3

O PCy3 F3C

R″

R X

O S

NuH

F3C

O S CF 3

N R′

35–91%

Scheme 17.10  EAS‐type hetArS(O)CF3 synthesis with in situ generated electrophile.

O S

Nu

17.2  Trifluoromethyl Sulfoxides [RS(O)CF3]

Langlois and coworkers used the Langlois reagent (sodium triflinate, F3CSO2Na) with phosphorus oxychloride (POCl3) to generate a triflinyl electrophile, which was then trapped with N‐methylpyrrole. This provided the 2‐substituted product in 60% yield (Scheme 17.10b) [67]. Sun et al. showed that this approach could be extended to indoles. Notably, in the case of R″ = H, indoles gave good regioselec­ tivity for substitution at the 3‐position, in contrast to the 2‐triflinyl products being favored with pyrroles (Scheme 17.10c) [68]. Zhao et al. demonstrated that phos­ phorus trichloride is also well suited for trifluoromethylsulfinylation of indoles, giving fair to excellent yields of the products. The same regioselectivity trends are seen in this system, with the only deviations occurring when the preferred 3‐posi­ tion is blocked by a substituent, in which case the 2‐triflinyl product is selectively obtained (Scheme 17.10d). The authors also applied these conditions to two pyr­ roles and an interesting pyrazole (Scheme 17.10e) [69]. Chachignon and Cahard also reported a method for this type of electrophilic trifluoromethylsulfinylation on azaarenes, but they used trifluoromethanesulfonyl chloride (TfCl) as the source of electrophilic –S(O)CF3 and tricyclohexylphosphine (PCy3) in place of the established chlorophosphines. This reaction likely proceeds via a very similar pathway to that of the sodium triflinate/chlorophosphine methods, wherein the TfCl and phosphine form a chlorophosphonium triflinate intermediate, which exhibits similar reactivity to the previously discussed systems. As shown in Scheme 17.10f, the reaction likely begins with an Appel‐type electrophilic chlo­ rination of the phosphine to give the chlorophosphonium triflinate, which then generates the active triflinyl electrophile. The authors tested this system on a series of indoles, pyrroles, pyrazoles, and a few other azaarenes. The regioselec­ tivity followed the same trends as discussed previously, and the yields were gener­ ally quite good (Scheme 17.10g) [70]. Triflinyl heteroarenes have even been prepared through heterocyclic ring clo­ sure reactions. In 1987, Kosack and Himbert reported an intriguing synthesis of a 5‐triflinyl furan via a formal [3+2] cycloaddition of a triflyl alkyne with an amino alkyne, wherein one of the oxygens of the sulfone is incorporated into the ring system to make the furan (Scheme 17.11) [71]. Ph

Ph

N

Ph

Ph Ph

+ Ph

Ph

O S O CF3

O Ph N O S CF3

N

Ph

Ph Ph O

S O CF3

N

Ph O

O S CF3

47%

Scheme 17.11  Synthesis of a trifluoromethanesulfinyl furan via formal [3+2].

17.2.4  Heteroaryl Trifluoromethyl Sulfoxides [hetArS(O)CF3]: Applications The most common transformations of trifluoromethanesulfinyl heteroarenes are reductive deoxygenations to give trifluoromethylthioethers. Rimoldi and coworkers converted fipronil, a triflinyl pyrazole, into the sulfide analogue by treating it with trifluoroacetic anhydride (TFAA) and sodium iodide (Scheme  17.12a) [72]. In an attempt to acetylate the amino group of fipronil, Liu et al. found that acetyl chloride

487

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17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

(AcCl), with an additive of dimethylammonium tosylate, not only acetylated the amino group but also performed a deoxygenation of the sulfoxide, providing the N‐ acetylated sulfide product in 35% yield (Scheme 17.12b) [64]. The EAS‐type hetArS(O) CF3 syntheses with in situ generated electrophiles (Section 17.2.3) are generally quite sensitive to the stoichiometry of the sulfinilation reagents. Any excess can perform a second deoxygenation, providing the sulfide. In this case, the sulfoxide would serve as an intermediate in these formal electrophilic trifluoromethylthiolations of heter­ oarenes. To test the hypothetical sulfoxide intermediacy in their system, Zhao et al. submitted 3‐triflinylindole to the same conditions, and indeed the expected sulfide product was obtained in excellent yield (Scheme 17.12c) [69]. Several other systems have been demonstrated to perform formal trifluoromethylthiolation of indoles via a sulfoxide intermediate including sodium triflinate/POCl3 [73], sodium triflinate/ PCl3 [74], and even trifluoromethanesulfinyl chloride itself [65]. NC

O S

N N

Cl

NC CF3

TFAA

NH2

Cl

Cl

F3C

F3C

60%

(a)

Cl

O S

N N

CF3

NH2

NaI

Cl

NC

S

N N

NC CF3

NH2 Cl

CF3 S

O Cl

Cl

N N

Me2NH2+ –OTs

F3C

Cl F3C

N H

O

35%

(b) O

S CF3

S CF3 PhPCl2

N H

(c)

H2O (X equiv)

N H X = 0 89% X = 1 98%

Scheme 17.12  Deoxygenative reduction of triflinyl heteroarenes to sulfides.

The chemistry of triflinyl heteroarenes has also been explored in other types of systems. Kosack and Himbert disclosed the oxidation of a trifluoromethylsulfi­ nyl furan to the corresponding sulfone using potassium permanganate (KMnO4) with benzyltriethylammonium chloride (BnNEt3Cl) as a phase transfer agent in a DCM/H2O solvent system (Scheme  17.13a) [71]. Casida and coworkers reported an interesting light‐induced formal ipso‐detriflinylation–trifluoro­ methylation of fipronil in an ethanol/water solution with 1% hydrogen peroxide

17.2  Trifluoromethyl Sulfoxides [RS(O)CF3]

(Scheme 17.13b). The mechanism of this transformation is not well understood, but the authors propose the homolysis of the S—CF3 bond to be the first step, accelerated by H2O2 via the hydroxyl radicals generated upon irradiation. The authors also suggest that the predominant conformation of fipronil is likely the hydrogen bonding cyclic form shown in Scheme 17.13b and that this may play an important role in this transformation [75, 76]. Ph

Ph Ph

N

O

O S CF3

Ph

Ph KMnO4

Ph

BnNEt3+ Cl–

N

O S CF 3 O

O 38%

(a) Ar N N NC

H N H O S CF3

Ar hν 1% H2O2

NH2

N N

CF3

NC 40%

(b)

Scheme 17.13  Other reactions of triflinyl heteroarenes.

17.2.5  Alkyl Trifluoromethyl Sulfoxides [(Alk)S(O)CF3]: Preparation Triflinyl alkanes have not received as much attention as the previously described aryl and heteroaryl derivatives, but their syntheses often follow a similar approach. For example, the most common synthetic pathway to make alkyl trifluoromethyl (or perfluoroalkyl) sulfoxides is via sulfide oxidation (Scheme 17.14) [77–80]. H2O2, AcOH HNO3 NaIO4 Alk

S

RF

mCPBA

Alk

O S

RF

Oxone F3CO3H

Scheme 17.14  Oxidations of alkyl perfluoroalkyl sulfides to sulfoxides.

Bis(trifluoromethyl) sulfoxide is among the simplest of these sulfoxides. It has been prepared in a couple of different ways. The first approach involves the hydrolytic cleavage of two leaving groups from a sulfur(IV) compound of the

489

490

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

general form (CF3)2SX2. The difluorosulfurane (X = F) was found by Sauer and Shreeve to be remarkably stable to hydrolysis under neutral conditions at room temperature. However, stirring in a Pyrex vessel with anhydrous HCl provided quantitative conversion to the sulfoxide. The authors propose that the reaction initiates with a halogen exchange to produce a dichlorosulfurane intermediate (X  =  Cl), along with hydrofluoric acid (HF). The HF attacks the borosilicate glass of the vessel, releasing water. This water then hydrolyzes the dichlorosul­ furane intermediate to the sulfoxide (Scheme 17.15a) [81]. In testing the effi­ cacy of their new sulfurane reagent (X  =  OCF3) for trifluoromethoxylation, Kitazume and Shreeve showed that exposure of the reagent to water produced (CF3)2S(O) in 86% yield along with two equivalents each of difluorophosgene (CF2O) and HF from the decomposition of trifluoromethanol (Scheme 17.15b) [82]. The second approach entails nucleophilic displacement of either one or two leaving groups on sulfoxides by a trifluoromethide generated from TMSCF3. Patel and Kirchmeier showed that triflinyl fluoride could undergo nucleophilic substitution, releasing a fluoride and giving the bis(trifluoromethyl) sulfoxide in good yield (Scheme  17.15c) [45]. Shreeve and coworkers used TMSCF3, activated by cesium fluoride, to perform a double addition of CF3− on  dimethyl sulfite. The desired sulfoxide was obtained in 77% yield (Scheme 17.15d) [47]. F F S CF3 F3C

Cl Cl + 2 HF S CF3 F3C

HCl (anh.)

F3C

SiO2

H2O + SiFx

O S

CF3

100%

(a) F3CO OCF3 S CF3 F3C

H2O F3C

O CF3

+ 2

F

F

+ 2 HF

86%

(b)

F3C (c)

O S

O S

TMSCF3 F

KF

F3C

O S

CF3

MeO

O S

(d)

TMSCF3 OMe

CsF

F3C

O S

CF3

77%

Scheme 17.15  Syntheses of bis(trifluoromethyl) sulfoxide.

In a 1977 report, Burton and Shreeve showcased some interesting transfor­ mations of trifluoromethanesulfinyl chloride. Its reaction with silver cyanide provides the triflinyl cyanide in modest yields (Scheme 17.16a) [83]. Triflinyl chloride was also shown to react with acetone to give the corresponding α‐ sulfinyl ketone (Scheme  17.16b) [83]. Holoch and Sundermeyer demon­ strated an intriguing [2,3]‐sigmatropic rearrangement of in situ generated allyl sulfenate to produce sulfoxides. Trifluoromethanesulfenyl chloride was

17.2  Trifluoromethyl Sulfoxides [RS(O)CF3]

reacted with allyl alcohol in the presence of pyridine, forming the allyl sulfenate ester intermediate, which quickly rearranges to the allyl trifluoro­ methyl sulfoxide product (Scheme 17.16c) [84]. Cahard and coworkers later expanded this work, further developing the substrate scope and replacing the sulfenyl chloride starting material with a safer source of electrophilic –SCF3, Shen’s reagent. The sulfoxide products were obtained in 47–92% yields (Scheme 17.16c) [85].

F3C

O S

AgCN Cl

F3C

O S

CN

F3C

O S

O Cl

F3C

O S

O

34% (a)

(b) F3C

S

Cl

R

(R = H)

R OH

O S

Shen´s reagent

CF 3

(R = H, Ar, hetAr, Alk) O O S N SCF3 O

R

O S

[2,3]-Sigmatropic CF3

Rearrangement

Shen´s reagent (c)

Scheme 17.16  Other syntheses of alkyl trifluoromethyl sulfoxides.

17.2.6  Alkyl Trifluoromethyl Sulfoxides [(Alk)S(O)CF3]: Applications Despite the availability of preparative methods, often predating those of its aryl and heteroaryl counterparts, alkyl trifluoromethyl sulfoxides have found many fewer applications. Magnier and Wakselman disclosed the oxidation of an alkyl trifluoromethyl sulfoxide and the analogous perfluoroalkyl trifluoromethyl sulfoxide to the corresponding sulfoximines using sodium azide and fuming sulfuric acid. The products were isolated in 70% and 90% yields, respectively (Scheme  17.17a) [86]. Reduction of triflinyl alkanes to sulfides has been achieved with trifluoroacetic anhydride and sodium iodide (Scheme  17.17b) [85]. Vinyl trifluoromethyl sulfoxides, accessed via dehydrohalogenation of the β‐chloroethyl precursor, have proved to be excellent Michael acceptors [79] and Heck‐type cross‐coupling partners (Scheme 17.17c) [87]. Sokolenko et al. converted an α‐triflinyl ester to an enaminone in virtually quantitative yield using dimethylformamide dimethylacetal. The enaminone products could be further functionalized to access cyclic amidines, ureas, and thioureas (Scheme 17.17d) [88].

491

492

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

F3C

F3C

O S

O S

C8H17

NaN3 H2SO4·SO3

C8F17

O NH S F3C C8H17

70%

O NH S F3C C8F17

90%

(a)

F3C

O S

TFAA NaI

Ph

Ph

S

F3C

60%

(b)

NuH

F3C

O S

NEt3 Cl

F3C

H

F3C

O S Ar

82%

Pd(OAc)2 NEt3

(c)

F3C

O S

I

MeO

O OMe

+

F3C

N

MeO

F3C

O S

Nu

O S

Ar

O S

34–96%

23–68%

O OMe N 98%

F3C

O S

O NH N H

(d)

X

or

F3C

O S

O NH N

R

X = O, S

Scheme 17.17  Synthetic applications of alkyl trifluoromethyl sulfoxides.

17.3 ­Difluoromethyl Sulfoxides [RS(O)CF2R′] Difluoromethyl sulfoxides (RS(O)CF2R′ in which R′ = H, Cl, Br, I, COR", P, or S) have attracted considerably less attention than their lauded counterparts, difluo­ romethyl sulfones; however, difluoromethyl sulfinyls have proven themselves both as functional groups with interesting physiochemical properties and as valuable synthons for fluorofunctionalization.

17.3  Difluoromethyl Sulfoxides [RS(O)CF2R′]

17.3.1  Difluoromethyl Sulfoxides [RS(O)CF2H] (R = Ar, HetAr, Alk): Preparation The most common difluoromethyl sulfoxides are those bearing a –CF2H moiety. They are often accessed via oxidation of difluoromethyl thioethers (Scheme 17.18) [89–94]. HO

O

HO S

O

H2O2 CF2H

AcOH

O S

CF2H

50%

(a) F F

F S

F

CF2H

HNO3

F

F F

F

O S

CF2H

F F 98%

(b) Ar Ar

N N H

Ar

N

Ar

N H

S CF2H

O S CF2H

S CF2H mCPBA

S CF2H

N

N

N S

O S CF2H

O S CF2H N

S

S

CF2H

N N S N N CF2H Ph

N N N N Ph

O S CF2H

O S CF2H

(c)

Scheme 17.18  Syntheses of difluoromethyl sulfoxides via oxidation of sulfides.

Difluoromethyl sulfoxides have also been prepared by methods not involving direct sulfide oxidation. As a demonstration of the utility of their iododifluoro­ methyl sulfoxide reagent, Yagupolskii and Matsnev subjected it to a zinc metala­ tion followed by quenching with water to give the –CF2H product in high yield. When using enantiopure sulfoxide starting material this reaction was shown to  be stereospecific, providing the –CF2H product with no change to the ­enantiomeric excess (Scheme  17.19a) [95]. Xiao and coworkers used difluoro­

493

494

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

methylsulfinate and triflic anhydride/triflic acid with benzene to synthesize ­phenyl difluoromethyl sulfoxide in moderate yield (Scheme 17.19b) [96]. In 2016, Shibata and coworkers reported the use of a new iodoso compound as a source of electrophilic SCF2H. Under catalytic cupric fluoride (CuF2) conditions, the reagent was reacted with allyl alcohols, forming the –OSCF2H species in situ, followed by a [2,3]‐sigmatropic rearrangement to give the difluoromethyl sulfox­ ide product in moderate yields (Scheme 17.19c) [97]. O *S Cl

O *S

Zn0

CF2I

O *S

H2O

I

F F

Cl

98% ee

Zn

Cl

CF2H

98% ee

(a)

NaO

O S

O S

Tf2O/TfOH CF2H +

CF2H

44%

(b) Ar1 + OH

O O O S 2 Ar CF2H I Ar3

CuF2 (cat.)

Ar1 O S

CF2H

̏+SCF2H˝ source

Ar1

O S

[2,3]-Sigmatropic CF2H

Rearrangement

41–50% (c)

Scheme 17.19  Other preparative methods for difluoromethyl sulfoxides.

17.3.2  Difluoromethyl Sulfoxides [RS(O)CF2H] (R = Ar, HetAr, Alk): Applications Difluoromethyl sulfoxides have found two significant modes of application in the context of fluorofunctionalization, the first of which being their use as pronu­ cleophiles via the moderately acidic –CF2H proton. The first report of this type was by Prakash et  al. in 2004, wherein phenyl difluoromethyl sulfoxide upon deprotonation by potassium tert‐butoxide was successfully added to n‐butyl iodide, giving the difluoropentyl product in moderate yield (Scheme 17.20a) [98]. Three years later, the same group applied this system to aldehyde and ketone electrophiles, which provided the corresponding carbinols in good to excellent yields (Scheme  17.20b) [93]. They also found that prolonged stirring with

17.3  Difluoromethyl Sulfoxides [RS(O)CF2R′] O S

CF2H

O S

t-BuOK

+

I

C F2

54%

(a) O S

O CF2H

+

R1

O S

t-BuOK 30 min

R2

OH R2 C 1 R F2

77–99%

(b) O S

O +

CF2H

Ph

OH OH

t-BuOK (excess) H

Ph

Overnight

(excess)

Ph

C F2 O Ph

O S

t-BuOK

O C F2 H

O

Ph Ph

(c)

O S

H

Ph

F2C Ot-Bu

O O S

O

CF2H +

Ar1

N

O S

KHMDS Ar2

N

OH Ar2 C 1 Ar F2

DBU

O S

CF2H

+

O R1

N

Ar1

74–98%

(d)

F

Ar2

45–70% O S

t-BuP4 R2

OH R2 C 1 F2 R

up to 99 : 1 d.r.

(e) O S

CF2H +

O H

O S

t-BuP4 Ph

OH C F2

Ph

97 : 3 d.r. 97% ee OH HF2C

Ph

(i) Oxidation

t-Bu NMe2 N Me2N P NMe2 Me2N P N P N NMe2 N Me2N P NMe 2 Me2N NMe2 t-BuP4

(ii) Desulfonylation

97% ee (f)

Scheme 17.20  Difluoromethyl sulfoxides as pronucleophiles.

excesses of both benzaldehyde and potassium tert‐butoxide led to formation of the 1,3‐diol in 68% yield with excellent diastereoselectivity for the anti product (d.r. = 94 : 6 anti:syn). The authors propose that after the initial carbinol/alkoxide formation, a nucleophilic substitution of tert‐butoxide on the sulfoxide releases the difluoromethyl anion. This carbanion then performs a nucleophilic addition

495

496

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

to a second equivalent of benzaldehyde, which upon aqueous workup gives the 1,3‐diol product (Scheme 17.20c) [93]. Hu and coworkers showed that this type of addition to ketones also works with 2‐pyridyl difluoromethyl sulfoxide as the pronucleophile. Deprotonation with potassium hexamethyldisilazide (KHMDS) followed by addition to diaryl ketones furnished the product alcohols in good to excellent yields. When these isolated carbinols were exposed to basic conditions 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in DMF, they underwent an interesting defluorinative olefination to give monofluoroalkenes with a pyridinone substitu­ ent  geminal to the remaining fluorine (Scheme  17.20d) [94]. The authors also detailed a one‐pot procedure for this transformation, which provided the olefin in 27% yield [94]. Inspired by the work of Prakash and coworkers on the nucleophilic addition of difluoromethyl sulfoxides to carbonyl compounds, Batisse et al. set out to find conditions to perform the reaction diastereoselectively. They found that substituting the traditional potassium tert‐butoxide base with the much stronger and bulkier Schwesinger’s superbase (t‐BuP4) provided the desired carbinol prod­ uct in 99:1 d.r. when benzaldehyde was used as the electrophile (Scheme 17.20e) [99]. The diastereoselectivity varied considerably among the aldehydes screened, but ketones consistently gave very low selectivity. The source of the diastereoselec­ tivity is not fully understood. The authors attribute it to the non‐coordinating nature of the bulky base and its effects on the energies and geometries of the transition states. They also demonstrated the use of an enantiopure aryl difluoro­ methyl sulfoxide as a fluoroalkylation reagent containing a removable chiral auxillary. (S)‐p‐Tolyl difluoromethyl sulfoxide (97% ee) was deprotonated by t‐ BuP4 and reacted with benzaldehyde to give the β‐hydroxy sulfoxide (97:3 d.r., 97% ee), which upon oxidation to the sulfone and a stereo‐retentive desulfonylation gave the difluoromethylcarbinol in 97% ee (Scheme 17.20f) [99]. The second major application of difluoromethyl sulfoxides is as a precursor to various electrophilic difluoromethylation reagents. Prakash et  al. prepared Umemoto‐type diaryl difluoromethyl sulfonium salts from difluoromethyl sulfox­ ides with triflic anhydride (Scheme 17.21a) [100]. A few months later, the same authors published a follow‐up report wherein polystyrene was used in place of the arene, producing a solid‐phase bound S‐difluoromethyl sulfonium reagent for use in electrophilic difluoromethylation (Scheme  17.21b) [54]. Hu and coworkers synthesized N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine from difluorometh­ anesulfinyl benzene by reacting it with (tosylimido)iodobenzene (PhINTs) in the presence of catalytic cupric triflate (Cu(OTf )2). This afforded the novel sulfoxi­ mine in fair yield, and it was demonstrated to be an efficient electrophilic difluo­ romethylation reagent (Scheme  17.21c) [101]. Two years later Prakash et  al. prepared the N‐H analogue of Hu’s sulfoximine and with it developed an N,N‐ dimethyl sulfoximinium derivative with even better reactivity. The sulfoximine was synthesized in 99% yield via oxidative imination by treating phenyl difluoro­ methyl sulfoxide with sodium azide in fuming sulfuric acid. The authors noted the importance of diluting the reaction system with methylene chloride, as the tradi­ tional neat fuming sulfuric acid conditions led to an explosion. Subsequent meth­ ylation of the sulfoximine gave the Johnson‐type sulfoximinium reagent (Scheme 17.21d) [102]. In a 2017 report on how different nucleophiles interact with pentafluorophenyl difluoromethyl sulfoxide, Platonov and coworkers

O S

BF4 CF2H

(i) Tf2O

+

51%

O S

N

CF2H + Ph

Ts

I

Cu(OTf)2 (cat.)

F

F

O S F

F

NaOH

BF4

S

(ii) NEt4BF4

CF2H

O S

CF2H

BF4

O NH S CF2H

NaN3 H2SO4 ·SO2

O N S CF2H

DCM

F CF2H

n (i) Tf2O

+

(b)

O NTs S CF2H 60%

(c)

F

n CF2H

(ii) NaBF4

(a)

(e)

O S

CF2H S

F F

O OH S CF2H F

F OH

99%

(d)

F F

F

Scheme 17.21  “CF2H+” sources prepared from difluoromethyl sulfoxides.

F

F

O O S CF2H

F

F

F

F + F

F

O

O S

H2O CF2H

F F

F F

498

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

described an interesting divergence from the normal SNAr reactivity seen with most nucleophiles. With sodium hydroxide as the nucleophile, the major product was pentafluorobenzene. The authors propose this reaction initiates with a nucle­ ophilic attack by HO− on the sulfoxide, and a subsequent deprotonation gives the sulfurane dianion. Heterolytic cleavage of the S—C(sp2) bond results in the pen­ tafluorophenyl anion and difluoromethyl sulfinate. The former becomes pen­ tafluorobenzene upon quenching with water. The latter product was not isolated, but considering the success of sodium difluoromethyl sulfinate in electrophilic difluoromethylation and its relatively high cost, this may represent an interesting preparative route to this reagent (Scheme 17.21e) [103]. 17.3.3  Halodifluoromethyl Sulfoxides [RS(O)CF2X] (X = Cl, Br, I): Preparation Given the success of haloalkanes in many valuable transformations (e.g. nucleo­ philic, radical, and cross coupling reactions), particularly in the case of fluoro­ alkyl halides, it is not surprising that these motifs have been expanded to difluoromethylsulfinyl systems. Bromodifluoromethyl phenyl sulfoxide was pre­ pared in moderate yield by Burton and Wiemers via mCPBA oxidation of the corresponding thioether (Scheme 17.22a) [104]. The yield and substrate scope have since been improved and expanded [105]. Holoch and Sundermeyer found that when allyl alcohol was reacted with chlororodifluoromethanesulfenyl chlo­ ride, the resultant S‐(allyloxy)sulfenyl intermediate undergoes a [2,3]‐sigmat­ ropic rearrangement to give allyl chlorodifluoromethyl sulfoxide (Scheme 17.22b)

S

O S

mCPBA

CF2Br

CF2Br

58% (a) OH

Cl

S

O S

CF2Cl

C5H5N

O S

[2,3]-Sigmatropic Rearrangement

CF2Cl

48%

(b) O S R

O C F2

OH

NaO

O S

CF2Br

O S

HgO I2

(c)

(d)

CF2Cl

PhH Tf2O/TfOH

R

CF2I

35–75% O S

CF2Br

28%

Scheme 17.22  Approaches to halodifluoromethyl sulfoxide synthesis.

17.3  Difluoromethyl Sulfoxides [RS(O)CF2R′]

[84]. Yagupolskii and Matsnev developed a mercuric oxide‐mediated decarboxy­ lative iodination of arylsulfinyldifluoroacetic acids, providing access to iododif­ luoromethanesulfinyl arenes (Scheme 17.22c) [95]. Xiao and coworkers prepared phenyl bromodifluoromethyl sulfoxide via an EAS‐type sulfinylation of benzene with triflic anhydride‐activated sodium bromodifluoromethyl sulfinate (Scheme 17.22d) [96]. 17.3.4  Halodifluoromethyl Sulfoxides [RS(O)CF2X] (X = Cl, Br, I): Applications The most common application of halodifluoromethyl sulfoxides is in the prepa­ ration of electrophilic fluoroalkylation reagents. Interestingly, only the bromodi­ fluoromethyl derivatives have been employed in this capacity. Magnier and coworkers demonstrated that the ditriflyl ketal intermediate generated via triflic anhydride activation of bromodifluoromethylsulfinylarenes in the presence of a nitrile could be quenched in three different ways to give three different products. Quenching with water gave N‐acyl sulfilimines in good yields, quenching with a secondary amine gave a sulfilimino iminium salt in good yield, and quenching with excess propylamine gave N‐H sulfilimines in moderate yields (Scheme 17.23a) [61]. The same group later showed that substituting the nitrile for a dinitrile, glutaronitrile (NC(CH2)3CN), gave a mixture of the mono and bis(sulfilimine) (Scheme 17.23b) [60]. Shibata and coworkers synthesized a series of unsymmet­ rical diaryl S‐(bromodifluoromethyl)sulfonium salts via an EAS‐type reaction between arenes and triflic anhydride‐activated aryl bromodifluoromethyl sul­ O H2O 72–83%

Ar

O S

Ar

TfO OTf R–CN CF2Br

Tf2O

Ar

N S

83%

CF2Br

57–64%

(a)

Ph

O S

CF2Br

Tf2O

Ar

(c)

CF2Br S Ph N CN 3

O 35%

(b) O S

(i) Ar1–H Tf2O CF2Br

(ii) NaBF4

Et

CF2Br

Et2NH

R

CN 3

R

TfO

n-PrNH2

NC

N S

+

Ar

N S

Ar

H

N S

CF2Br

CF2Br CF2Br S S Ph N N Ph O

3 21%

BF4 CF2Br S Ar Ar1 49–89%

Scheme 17.23  –CF2Br sulfoxides as precursors to electrophilic CF2Br reagents.

O

N

Et R

CF2Br

499

500

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

foxides. The products were isolated as the tetrafluoroborate salts in moderate to excellent yields (Scheme 17.23c) [105]. In their 2006 paper on the preparation of iododifluoromethylsulfinylarenes, Yagupolskii and Matsnev also demonstrated their reactivities in various systems. The p‐(chlorophenyl) derivative was shown to add as a nucleophile to p‐meth­ ylbenzaldehyde in the presence of tetrakis(diethylamino)ethylene (TDAE), pro­ viding the difluoromethyl carbinol as a mixture of diastereomers (Scheme 17.24a) [95]. Attempts to add the sulfinyldifluoromethyl iodide to an olefin via a light‐, AIBN‐, or benzoyl peroxide‐initiated radical pathway were unsuccessful. The authors also reported both oxidative and reductive procedures to access the cor­ responding sulfone and sulfide products, respectively (Scheme 17.24b) [95].

O S

O CF2I + H

Me2N

NMe2

Me2N

NMe2

Cl

O S Cl

CF2I

X (b)

O S

PCl5 POCl3

CF2I

O O S CF2I

mCPBA

X

45–65%

C F2 60%

(a)

S

OH

X 70–85%

Scheme 17.24  Reactions of aryl iododifluoromethyl sulfoxides.

17.3.5  β‐Carbonyl Difluoromethyl Sulfoxides [RS(O)CF2Y] (Y = Enol,  Ether, Ketone, Ester): Preparation The electronics of carbonyl‐type systems have been exploited to synthesize a variety of interesting –SCF2– sulfoxides. Blades et al. explored the reactivity of O‐protected gem‐difluoro enol ethers with an unprotected α‐hydroxyl group, which they found added to benzenesulfenyl chloride through this oxygen. A subsequent [2,3]‐sigmatropic rearrangement gives the phenyl difluoromethyl sulfoxide products (Scheme  17.25a) [106]. Similarly to 1,3‐diketones, sulfox­ ides with carbonyl moieties in the β‐position have quite acidic α‐C(sp3)–H pro­ tons. Bravo and coworkers exploited this acidity by performing two sequential α‐deprotonations, each followed by electrophilic fluorination with Selectfluor (F‐TEDA), providing the desired sulfoxide in low to moderate yield (Scheme  17.25b) [107]. A similar approach was reported by Greaney and Motherwell using a hypervalent iodine compound (difluoroiodotoluene) as the source of “F+” ethyl phenylthioacetate was converted to the corresponding α‐difluoro sulfoxide when three equivalents of the iodane were used. The authors propose that this proceeds through two sequential fluoro‐Pummerer

17.3  Difluoromethyl Sulfoxides [RS(O)CF2R′]

reactions, and the sulfoxide is likely formed upon water quenching of a dif­ luorosulfurane intermediate (generated via sulfide oxidation by the third equivalent of iodane) (Scheme 17.25c) [108]. These α,α‐difluoro β‐ester sulfox­ ide compounds have also been prepared via direct oxidation of the equivalent sulfide. Lequeux and coworkers employed mCPBA in this process, which pro­ vided the desired sulfoxides in good yields (Scheme 17.25d) [109]. Batisse et al. used periodic acid in the presence of catalytic ferric chloride (FeCl3), and although the reaction times were quite long, the sulfoxide products were obtained in excellent yields (Scheme 17.25d) [99].

OMEM F R1 R2 F OH

S

Ph

OMEM R1 R2 F O S Ph

F

Cl

Ph

Rearrangement

25–72%

Ar

CH2Cl N (BF4)2

O +

R

NaH

O Ph

F

S

+

OEt

O S

Ar

N F (F–TEDA)

(b)

O R

F F 15–41%

I F Ph

Ar

O S

3 equiv

Ph

F I S

Ar I HF

O OEt H

S F F

(d)

Ph

O OEt

Ph

S

OR2

H5IO6 FeCl3 (cat.)

OEt F

Fluoro-Pummerer reaction product

mCPBA

O R1

O S

Pummerer intermediate

(c)

OEt 38%

F

F

O

F F

F

Ar

OMEM R1

F F

(a) O S

O S

[2,3]-Sigmatropic

R1

O S

O OR2

F F 73–95%

Scheme 17.25  Syntheses of α,α‐difluoro β‐carbonyl and β‐enol ether sulfoxides.

R2

501

502

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

17.3.6  β‐Carbonyl Difluoromethyl Sulfoxides [RS(O)CF2Y] (Y = Enol,  Ether, Ketone, Ester): Applications Decarboxylation of –SCF2– esters and acetates, generating the difluoromethyl radical or anion depending upon conditions, is among the most common approaches to applying these compounds as synthons. For example, Batisse et al. showed that ethyl 2,2‐difluoro‐2‐(arylsulfinyl)acetates when heated with water and lithium chloride underwent decarboxylation to give the –CF2H product in excellent yields. The authors also found this method to be stereoretentive when using enantioenriched sulfoxide starting materials (Scheme 17.26a) [99]. Other decarboxylative methods have been discussed in previous sections and as such will not be reiterated here. Analogously, thermal conditions can lead to desulfi­ nylation of difluoromethyl sulfoxides. This was demonstrated by Kim and McCarthy when they heated neat samples of 1,1‐difluoro‐1‐(methylsulfinyl) alkanes to 160–200°C. They underwent a formal dehydrosulfination to provide gem‐difluoroolefins in moderate to excellent yields (Scheme  17.26b) [110]. Lequeux and coworkers performed a two‐step reaction sequence of a difluoro­ methylsulfinyl diester to give an interesting oxathiolanone product. The reaction likely begins with TFAA activation of the sulfoxide, allowing for trifluoroacetate deprotonation of the α‐proton and subsequent formation of the C(sp2)—S dou­ ble bond. Trifluoroacetate addition to this electrophilic sp2 carbon followed by trifluoroacetate leaving the sulfur atom provides the Pummerer rearrangement product in good yield. Exposure of this to triflic acid forms the oxonium of the trifluoroacetoxy group, which is then expelled upon formation of the C(sp2)—S double bond. The difluoromethylene‐linked ester then attacks the C(sp2)–S car­ bon via the carbonyl oxygen in a 5‐endo‐trig fashion to form the methyl oxonium, which becomes the oxathiolanone product upon nucleophilic attack of triflate on the methyl group (shown as a single step for simplicity) (Scheme 17.26c) [109]. 17.3.7  Other Difluoromethyl Sulfoxides [RS(O)CF2Z] (Z = P, S): Prepar ation and Uses In addition to the main categories of difluoromethyl sulfoxides already discussed, there is still a handful of compounds left to cover, namely, sulfoxides with difluo­ romethylene linkages to phosphorus or sulfur atoms. Published by Besset and coworkers in 2016, there is only one report on preparation of phosphorus com­ pounds of this type. The authors developed a reagent as an electrophilic source of –SCF2PO(OEt)2, which in the presence of p‐toluenesulfonic acid (TsOH) reacted with an indole to give substitution at the 3‐position. Subsequent oxida­ tion of this thioether with mCPBA gave the (phosphonatodifluoromethyl)sulfi­ nyl compound in moderate yield (Scheme 17.27) [111]. Sundermeyer and coworkers published a series of papers between 1983 and 1989 wherein they explored the chemistry of perhalogenated 1,3‐dithietanes. They were particularly interested in controlled oxidation of these compounds (Scheme  17.28a) [112–114]. The authors also found that the mixed oxidation product decomposes upon stirring with water in methanol, furnishing an inter­ esting sulfone product (Scheme  17.28b) [112–114]. Expanding on this work,

O S

O

F F

X

OEt

O S

LiCl, H2O Δ

O S

H

F F

X

R1

Δ

R2

F F

F

89–100%

R2

64–89% (b)

(a)

O S

MeOOC

O C F2

OMe

TFAA (3 equiv)

MeOOC

Pummerer rearrangement

F3C

TFAA F3COC MeOOC H

O S

OMe CF3

O

S O

O C F2

OMe

TfOH

MeOOC F3C

O

S

MeOOC

O

5-endo-trig ring closure

50%

O F3COC

O C F2

O (c)

R1

F

CF2 O

TfOMe O S

O C F2

OMe

O

Scheme 17.26  Uses of α,α‐difluoro β‐carbonyl or β‐alkyl sulfoxides.

TfOH

MeOOC F3C

S O

O

H

O C F2

OMe

MeOOC

S O

CF2

Me O TfO–

504

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

Mews and coworkers discovered that traces of water slowly but quantitatively hydrolyze the (S,S‐difluoro)sulfoxide derivative to the bis‐sulfoxide in a 4 : 1 ratio favoring the trans product (Scheme 17.28c) [115]. F F Br + Ar

H N

F F

OEt P OEt O

S

N H

TsOH

S

Br

OEt P OEt O

N H 88%

O Br

F F S

OEt P OEt O

mCPBA

N H 64%

Scheme 17.27  Preparation of (phosphadifluoromethyl)sulfinyl indoles.

In 2007 Langlois and coworkers developed a system for fluorosulfonylation of RCF2– nucleophiles. A TMS‐protected difluoromethylthioether was first desi­ lylated with cesium fluoride. The carbanion nucleophile then added to SO2, gen­ erating the cesium sulfinate intermediate, which upon addition of Selectfluor as an electrophilic fluorine source (“F+”) gives the sulfonyl fluoride. Subsequent oxidation of the sulfide with mCPBA afforded the corresponding sulfoxide (Scheme 17.29) [116].

17.4 ­Trifluoromethyl Sulfones [RSO2CF3] One of the earliest studies on triflones was conducted by Hendrickson et al. in 1974. The work serves as an initial investigation into the stabilizing and leaving group abilities of the triflyl group on organic molecules [117]. The earliest gen­ eral synthesis of trifluoromethyl sulfones was reported in 1980 by Creary [118]. The treatment of Grignard reagents with triflic anhydride yielded different prod­ ucts depending on the identity of the halide (chloride vs. bromide). While RMgCl compounds responded well to the conditions, producing the corresponding tri­ flones, RMgBr compounds were unable to furnish the desired products and instead yielded the oxidation products (corresponding halides) in moderate to good yields (Scheme 17.30). Since this seminal report, the synthesis and utiliza­ tion of trifluoromethyl sulfones as versatile synthons have been ardently pur­ sued. The following sections will serve as an account of known syntheses and reactions of trifluoromethyl sulfones, organized by general structure: aryl tri­ flones, alkynyl and vinyl triflones, heteroaryl triflones, and alkyl triflones.

17.4  Trifluoromethyl Sulfones [RSO2CF3]

F3CO3H

F X

(X = F)

F X

S S

F2

F F

F X

(X = F)

O S

F F S 63% F F S F F S

TfOOH (X = F)

39%

SiO2 (X = F), 35%

F X

F F

F3CO3H

O S

F X

(X = Cl)

S

F F

O S S O

F F

10%

F3CO3H (X = Cl)

82%

(a) TfOOH (X = F)

F X

O O S F F S

XeF2

F X

(X = F)

O O S F F S

48%

SiO2 (X = F)

F F

F X

O O S F F S

H2O/MeOH (X = Cl)

O

59% TfOOH (X = Cl)

F Cl

O O S H

H

F F

60%

23%

(b) O F F O F F

S S F F

S

F F

20%

F F

80%

O F F

H2O OH F F

(c)

S

S S O

Scheme 17.28  Interesting reactions of perhalogenated 1,3‐dithietanes.

17.4.1  Aryl Triflones [ArSO2CF3]: Preparation Following the pioneering works of Hendrickson and Creary, Umemoto and cow­ orkers in 1982 synthesized trifluoromethylazosulfonylarenes from the reaction of trifluoronitrosomethane with anilines. The thermal decomposition of the formed molecules afforded trifluoromethylarenes in low yields (Scheme 17.31a) [119]. An addition–elimination reaction by trifluoromethide at the highly elec­ trophilic sulfonyl fluoride unit was reported by Yagupolski and coworkers (Scheme 17.31b). Either (trimethylsilyl)trifluoromethane or (tributylstannyl)trif­ luoromethane, initiated by a fluoride, can be used as a trifluoromethide source for this reaction [120]. Similarly, arylsulfonic esters have been used as electro­

505

506

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) F F S

F F (i) CsF, SO2

TMS

S

S O O

(ii) Selectfluor

O

F S O O

S

34%

̏ F + ˝

TMSF F F S

mCPBA

57%

F

Cs

F F F

F F SO2

S

S O

O Cs

Scheme 17.29  Preparation of (fluorosulfonyl)difluoromethyl sulfoxides.

R–MgCl

(CF3SO2)2O

R–SO2CF3

R = aryl, allyl, alkynyl

54–81%

R–MgBr

(CF3SO2)2O

R = aryl, allyl, alkynyl

R–Br 63–81%

Scheme 17.30  Preparation of triflones from Grignard reagents.

philes in an addition elimination reaction with TMSCF3‐derived trifluorometh­ ide (Scheme 17.31c) [47]. Roques and coworker disclosed a two‐step synthesis of triflylbenzene (Scheme  17.31d) [121]. First, fluoroform is deprotonated by the base in DMF at reduced temperature. Subsequent reaction of the formed CF3 anion with diphenyl disulfide affords the corresponding trifluoromethyl thioether, which on oxidation yields the desired sulfone in good yield. The oxida­ tion of trifluoromethylthio ethers had proved challenging, often requiring harsh conditions and oxidants [122]. Su reported a mild oxidation of trifluoromethyl­

(a)

O N S Ar F3C N O

O F3CNO + H2N S Ar O O Ar S F O

TMS CF3 TASF (n-Bu3)Sn CF3

O Ar S CF3 O

(b)

(c)

O R S OMe O

PhS—SPh

(d)

TMSCF3 Cat. CsF (i) CF3H, base (ii) [O]

O R S CF3 O

PhSO2CF3

Scheme 17.31  Early preparations of aryl triflones.

Heat

O F3C S Ar O

17.4  Trifluoromethyl Sulfones [RSO2CF3]

phenyl sulfide to the corresponding sulfone in 91% yield (Scheme 17.32a). The method employs NaIO4 as the oxidant, with catalytic RuCl3·3H2O [122]. An alternative oxidation protocol, from the group of Trudell, uses catalytic chromium(VI) trioxide with stoichiometric amounts of periodic acid to generate aryl triflones from α,α,α‐trifluorothioanisoles (Scheme 17.32b) [123]. S–CF3

O S CF3

NaIO4 Cat. RuCl3 ·3H2O

S–CF3

O

H5IO6 Cat. CrO3

O S CF3 O

(b)

(a)

Scheme 17.32  Recent developments in oxidations of –SCF3 arenes to aryl triflones.

Electrophilic‐type trifluoromethylation of aryl sulfinates using isolable, shelf‐ stable reagents is an attractive option for accessing aryl triflones by virtue of the mild reaction conditions required and the ease of preparation of the staring materials. Togni’s reagent, assisted by an ammonium fluoride and catalytic load­ ings of a copper(II) catalyst, forms aryl triflones via an oxidation of the sulfur atom from its +4 to +6 oxidation state (Scheme 17.33a). Weng and coworkers demonstrated this transformation on various sodium arylsulfinates [124]. Umemoto‐type reagents have also been applied toward the formation of aryl tri­ flones from the corresponding arylsulfinates (Scheme 17.33b) [125, 126]. O Ar S ONa

F3C I

O

+

Cat. CuII

O

Bu4NF

O Ar S CF3 O

(a) TfO–

O Ar S ONa +

(b)

F

CF3 S

Conditions

O Ar S CF3 O

F

Scheme 17.33  Electrophilic‐type trifluoromethylation to obtain triflyl arenes.

In light of the above discussed electrophilic‐type trifluoromethylation, one can consider an opposite approach: electrophilic‐type arylation of trifluoromethyl­ sulfinate salts. The first instance of this reactivity paradigm can be found in the 2015 work of Aithagani et al. The researchers used O‐triflyl‐2‐(trimethylsilyl)phe­ nols to generate arynes upon fluoride activation of the silane, which then served as the electrophile for the reaction with sodium trifluoromethylsulfinate, generat­ ing the corresponding aryl triflones in good yields (Scheme 17.34a) [127]. A cross‐ coupling reaction with aryl triflates is reported [128], wherein a Pd(II) pre‐catalyst facilitates the ipso‐triflylation of the starting material (Scheme  17.34b). This approach is interesting, in that it requires the pre‐installation of a triflyl group to facilitate the addition of another, albeit on a different atom (oxygen vs. carbon).

507

508

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

Diaryl iodonium salts, a widely used class of electrophilic arylation reagents, have been used as a source of electrophilic arene moieties towards analogous transfor­ mations. Nere and coworkers reported a copper(I)‐catalyzed method employing symmetric diaryl iodonium salts (Scheme 17.34c) [15]. Similarly, aryldiazonium salts can be used in a copper‐mediated reaction with sodium triflinate, as reported by Hu and coworkers (Scheme 17.34d) [129]. TMS

R

OTf

Cat.

N2+ –

BF4

SO2CF3

PdII

X– O I NaO S CF3 + Ar Ar R

R

NaSO2CF3

(b)

SO2CF3

R

OTf

(a)

(c)

F–

+ CF3SO2Na

R

Cat. CuII

CuI CF3SO2Na

R

Ar–SO2CF3 SO2CF3

(d)

Scheme 17.34  (Electrophilic‐type) Arylation of sodium triflinate yields triflyl arenes.

17.4.2  Aryl Triflones [ArSO2CF3]: Applications The –CF3 group is a strong inductively withdrawing group. In the context of aryl triflones, this translates to a substantially enhanced electrophilicity of the SVI center. This feature of aryl triflones has been exploited to promote addition– elimination reactions at the sulfonyl S atom, wherein trifluoromethide serves as the leaving group. Grignard reagents can perform this type of chemistry, yielding aryl sulfones from aryl triflones (Scheme  17.35a) [130]. Similar chemistry is observed with bis(perfluoroalkyl)sulfones, producing mixed sulfones (Scheme 17.35b) [131]. R–MgBr

(a)

Ar–SO2CF3

O R S Ar O

O Nu– + F3C S CF3 O (b)

O F3C S Nu + CF3– O

Scheme 17.35  Synthesis of aryl sulfones from aryl triflones.

With growing interest in accessing trifluoromethyl compounds came the need for novel trifluoromethylation protocols. One solution came in the form of aryl triflones as sources of the nucleophilic trifluoromethyl group. At the

17.4  Trifluoromethyl Sulfones [RSO2CF3]

f­ orefront of this field is the work by Prakash et al., detailing the first nucleophilic trifluoromethylation of aldehydes and ketones using phenyl(trifluoromethyl) sulfone (Scheme 17.36a) [51]. Soon after, the same group devised a Mg0‐medi­ ated reductive silylation procedure to prepare (per)fluoroalkylsilanes from (per) fluoroalkyl sulfones and sulfoxides (Scheme  17.36b) [52]. Expanding on their previously reported strategy, Prakash et al. reported a base‐mediated trifluoro­ methylation and pentafluoroethylation of ketones and N‐phenyl imines, yield­ ing perfluoroalkylated amines and alcohols in good yields (Scheme  17.36c) [132]. By combining the aforementioned two concepts, Hu and coworkers cre­ ated a novel system for the nucleophilic trifluoromethylation of carbonyl com­ pounds, the mechanism of which proceeds through a Mg0‐mediated desulfonylative reduction of phenyl trifluoromethyl sulfone, releasing trifluo­ romethide (Scheme 17.36d) [133]. An extension of this methodology was imple­ mented by Petersen and coworker, furthering the substrate scope to include conjugate acceptors (Scheme 17.36e) [134]. A patent by Prakash et al. further elaborates upon their work the synthesis of diverse trifluoromethylsilanes using PhSO2CF3 as the CF3 source (Scheme  17.36b) [135]. Shibata and coworkers reported a novel ortho‐lithiation of triflyl arenes using the amide base lithium (tetramethyl)piperidine. The lithiated molecules were then reacted with elec­ trophiles, producing ortho‐substituted triflylarenes (Scheme  17.37) [136]. Ortho‐selectivity was attributed to a possible directing effect of the sulfonyl oxygen by virtue of coordination to the lithium base through the Li cation. O R

R′

+ Ph–SO2CF3

HO

KOtBu

CF3

O F3C S Ph O

R R′ 68–86% (R = H, aryl)

Mg0 R3SiCl

F3C–SiR3

(b)

(a) X R

R′

+

PhSO2Rf

(X = NPh, O)

(c) EWG

R′ Rf (Rf = CF3, C2F5) (50–99%)

PhSO2CF3

Ar EWG (EWG = electronwithdrawing group)

XH

tBuOK

HgCl2 (cat.) Mg0

R

F3C

O

PhSO2CF3

H

Mg0, HgCl2

R

(d)

EWG

Ar EWG (32–82%)

(e)

Scheme 17.36  Nucleophilic trifluoromethylation using triflyl arenes. SO2CF3

(i) LTMP (ii) Electrophile (E)

Scheme 17.37  Ortho‐lithiation of triflylarenes.

SO2CF3

E

OH R CF3 (45–88%)

509

510

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

17.4.3  Alkynyl and Vinyl Triflones: Preparation Almost a decade after Creary’s pioneering work [118], Subramanian and cow­ orkers reported [137] a synthesis of alkynyl triflones through the direct triflyla­ tion of alkynyl sodium salts prepared by direct metalation of terminal alkynes (Scheme  17.38). Electrophilic alkynylation of sodium trifluoromethylsulfinate using an alkynyl λ3‐bromane produces mixtures of triflyl alkynes and triflyl car­ bocycles (Scheme 17.39a) [138]. This method suffers from a lack of selectivity and low yield. An improvement to this electrophilic approach entails the use of alkynyl‐λ3‐iodanes as the source of the electrophilic alkyne unit. These have been reacted with sodium perfluoroalkylsulfinates to produce perfluoroalkylsul­ fonyl alkynes (Scheme 17.39b) [139]. R

H

(i) Na/Et2O (ii) (CF3SO2)2O/Et2O

R SO2CF3 17–74% yields

Scheme 17.38  Direct triflylation of alkynyl sodium salts. C8H17

Br–FBF3 NaSO2CF3

C5H11 F3CO2S

(a) TsO I

C8H17

+

SO2CF3

R

+ RfSO2Na

R

SO2Rf

(b)

Scheme 17.39  Electrophilic alkynylation of sodium triflinate produces triflyl alkynes.

Vinyl triflones have been made via the addition of organocopper reagents to triflyl alkynes, yielding triflyl alkenes as a mixture of E and Z isomers (Scheme 17.40a) [140]. This reaction likely proceeds as a formal vicinal addi­ tion of the organocopper reagent to the alkyne, followed by proto‐demetala­ tion. Finally, Shibata and coworkers reported an unprecedented –O– to –C(sp2)– migration of the triflyl group, forming (triflylvinyl) phenols when starting with 2‐(β,β‐dibromovinyl)aryl triflates, mediated by nBuLi (Scheme 17.40b) [141]. The reaction is proposed to proceed via a lithium–bro­ mine exchange reaction, which in turn induces a migration reaction of the tri­ flyl group. Reaction with a second unit of nBuLi and subsequent quenching of the reaction mixture provides the corresponding phenols in moderate to good yields (42–84%). 17.4.4  Alkynyl and Vinyl Triflones: Applications In the late 1990s, Fuchs and coworker demonstrated the potential of alkynyl triflones as building blocks in organic synthesis. The developed transforma­

17.4  Trifluoromethyl Sulfones [RSO2CF3]

R1

Cu–Rn

SO2CF3

R1 F3CO2S

R H

(a) Br R

Br O SO2CF3

SO2CF3 nBuLi

R O H

Br R

Br O SO2CF3

(b)

SO2CF3 R 1. nBuLi 2. HCO2Me

O

OH

Scheme 17.40  Synthesis of vinyl triflones.

tions take advantage of the ability of the triflyl group to form a CF3 radical (with the liberation of SO2) on treatment with AIBN. The alkynyl radical left behind can then react with the chosen substrate. With this approach, internal alkynes were synthesized by radical C(sp3)–H alkynylation of alkanes, using alkynyl triflones and catalytic AIBN (Scheme  17.41a) [142]. Organocopper reagents have been shown to react with alkynyl triflones producing vinyl tri­ flones, which on similar treatment with AIBN can perform radical C(sp3)–H alkenylation of alkanes (Scheme 17.41b) [140]. A formal C(sp2)–H alkynyla­ tion of aldehydes is reported, utilizing a similar radical alkynylation strategy (Scheme 17.41c) [143]. R

AIBN (cat.)

SO2CF3

R′–H

R

R′

(a)

R

SO2CF3

Cu(R′)n

R2

F3CO2S

AIBN (cat.) R1

H

R′–H

R2

R′

R1 H

(b) O R

R′ H

SO2CF3 AIBN (cat.)

O R′ R

(c)

Scheme 17.41  Explorations of Fuchs and coworkers into the synthetic utility of alkynyl triflones.

Inspired by the work of Fuchs and coworker, Lei et al. devised a copper‐cata­ lyzed desulfonylative gem‐trifluoromethylation–alkynylation of isocyanides, resulting in alkynyl(trifluoromethyl)imines [144]. It was hypothesized that the

511

512

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

reaction proceeds via a single electron transfer between the alkyne and Cu(OAc)2, which results in the formation of the triflyl alkynyl radical (Scheme 17.42a). A radical addition to the alkyne unit, followed by a radical desulfonylation, would yield the desired product. Yu and coworkers reported a radical 1,2‐trifluoromethylation– alkynylation of alkenes initiated by catalytic N‐methylmorpholine (NMM) and catalytic Togni’s/Umemoto’s reagent (Scheme 17.42b). In this case also, the triflyl alkyne serves as the source of both the alkynyl radical and the trifluoromethyl radical [145]. R

Cu(OAc)2 (20 mol %)

SO2CF3

RNC + Ar

N CF3

Ar

Cu(OAc)2 –

Ar

SO2CF3

Ar –SO2 – CF3

F3C–SO2 –SO2 N

RNC

CF3

R

Ar

N

SO2CF3

N +

Togni/Umemoto reagent (7.5 mol%)

R1 X

SO2CF3

Ar

R1 R X 2

NMM (10 mol%)

SO2CF3

Ph

F3C

SO2CF3

(a) + R3Si

Ar

F3C

F3C

R2

R

SiR3 CF3

(X = C, N or O)

(b) GP

N O S O

R2

R3 H

N H

R

F3CO2S AIBN (cat.)

· CF3

R2 R3

SO2 N O S O

(c)

·

R3 H R2

R4 GP

R4

· CF3 + SO2

CF3

GP

PG

· N

H

R3 R2

HAT

GP

NH

SO2CF3 ·

R3 R2

CF3

Scheme 17.42  Alkynyl triflones as radical alkynylation reagents.

Wang et al. recently reported a remote C(sp3)–H alkynylation using trifluoro­ methylsulfonyl alkynes, initiated by AIBN (Scheme 17.42c) [146]. The proposed mechanism starts with the formation of a trifluoromethyl radical, formed from the radical desulfurization of the triflyl alkyne, which reacts with the pendant ally

17.4  Trifluoromethyl Sulfones [RSO2CF3]

group on the sulfur atom forming an alkyl radical. After elimination of SO2 and allyl‐CF3, a hydrogen atom transfer (HAT), followed by reaction with another equivalent of alkyne and then a migration reaction, leads to the formation of the 1,1‐difunctionalized product. Shibata and coworkers disclosed a synthesis of pyrazole triflones by implementing a cycloaddition reaction involving triflyl alkynes [147]. A 2,3‐dipolar addition reaction between hydrazones and triflyl alkynes was performed to synthesize pyrazole triflones (Scheme 17.43).

N

SO2CF3

NHPh R1

R2 Cl iPr2NEt

R1

F3CO2S

N NBz

Ph N N

SO2CF3 DDQ

R1

R2

N N

R2 R2

F3CO2S

R1

Scheme 17.43  Triflyl alkyne cycloadditions geared toward the synthesis of triflyl heterocycles. DDQ, 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone.

17.4.5  Heteroaryl Triflones: Preparation The reported syntheses of 2‐pyridyl triflone and 2‐triflyl benzothiazole are multistep syntheses, developed by Hu and coworkers [148]. The first path involves nucleophilic trifluoromethylation of bis(2‐pyridyl) disulfide with fluoroform, followed by oxidation of the resulting trifluoromethylthio ether to the triflone using NaIO4 and catalytic RuCl3 (Scheme  17.44a). The second involves a Ru(II) catalyzed trifluoromethylation of 2‐mercaptobenzothiazole, followed by a Ru(III)‐catalyzed oxidation to the corresponding triflone (Scheme 17.44b).

S

S

N

N

1. KOtBu 2. HCF3

(a)

SCF3

SO2CF3

NaIO4, RuCl3 N

N

SO2CF3 S SH N

N Ru(bpy)3Cl2 ·6H2O

S N

SCF3

RuCl3 ·3H2O NaIO4

S N

SO2CF3

(b)

Scheme 17.44  Known preparations of synthetically useful heteroaryl triflones.

Direct triflation of heteroarenes can be used to obtain the corresponding tri­ flones. This approach has been applied to the triflylation of indoles [149], N‐het­ erocyclic carbenes[150], and iodo‐isoxazoles [151], using triflic anhydride as the electrophilic‐type triflylation reagent (Scheme  17.45). Finally, Wakselman and coworkers performed a condensation of salicylaldehyde with ethyl(trifluoro­ methylsulfonyl)acetate, accompanied by a cyclization following the loss of ethanol to yield the triflyl coumarin product (Scheme 17.46) [152].

513

514

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) SO2CF3 O N Ph

N R

Ph

I

Dipp N

O N

(CF3SO2)2 Ph

N Dipp

Ph

SO2CF3 F3CO2S

N R Dipp N N Dipp

Scheme 17.45  Direct triflation reactions on heteroarenes.

OH

CF3SO2CH2CO2Et

O

OH SO2CF3 CO2Et

– EtOH

O O SO2CF3

Scheme 17.46  Synthesis of triflyl coumarin via a tandem condensation–cyclization reaction.

17.4.6  Heteroaryl Triflones: Uses Though less exploited than simple triflyl arenes, heteroaryl triflones have seen recent use in trifluoromethylation reactions. Hu and coworkers reported a radical trifluoromethylation of isocyanides using photoredox catalysis per­ formed by a Ru(II) complex (Scheme  17.47a) [148]. The products were obtained in moderate to good yields. Zou and Wang recently disclosed a blue light‐induced iridium(III)‐catalyzed trifluoromethylation of N‐benzamides for the synthesis of trifluoromethylated isoquinolinediones in good yields (Scheme 17.47b) [153]. The direct electrophilic installation of a triflylaryl unit is an interesting way to impart structural complexity to nucleophiles. The work of Shibata and coworker toward this goal is noteworthy [154]. The group recently published a novel elec­ trophilic (triflyl)arylation of N‐, O‐, and C‐centered nucleophiles, paving the way to N‐(triflyl)aryl anilines, O‐(triflyl)aryl phenols and α‐(triflyl)aryl‐β‐diketones (Scheme 17.48). 17.4.7  Alkyl Triflones: Preparation The most common method of synthesis of alkyl triflones involves metathesis‐ type reactions between alkyl bromides and triflinate salts, with the reaction driven by the formation of alkali metal bromides. This methodology has been applied to the synthesis of α‐triflyl ketones [155], (triflylmethyl)triazoles [156], and benzylic triflones [157, 158] (Scheme 17.49) [157]. 1,2‐Triflylation functionalization of alkenes is another route to obtain alkyl tri­ flones. In 1999, Langlois and coworker delineated a 1,2‐addition of trifluoro­ methyl thiosulfonates and trifluoromethyl selenosulfonates across alkenes to generate triflyl alkanes, which could then be oxidized to their corresponding vinyl triflones with the loss of a thiol or selenol moiety (Scheme 17.50a) [159].

17.4  Trifluoromethyl Sulfones [RSO2CF3]

N R1

CF3 S O O

N

C

+ S

CF3

Ru(bpy)3Cl2 ·6H2O N

Blue LED

R2

R1

R2 (27–82%)

Ph

R1

NC R1

H CF3 C N

CF3

C N R2

R2

R1

[Ru(bpy)3]2+

R2

LED

C N R1

CF3

R2 ArSO2CF3

*[Ru(bpy)3]2+

single-electron transfer

·CF3 + ArSO2–

B–

single-electron transfer

single-electron transfer

·R

f

[Ru(bpy)3]+ – ·CO 3

ArSO2CF3

CF3 N

2–

CO3 2+

[Ru(bpy)3]

Blue LED

*[Ru(bpy)3]

2+

R1

R2

(a) O

O N R2

R1

N

+

S

CF3 O

III

Ir (cat.)

SO2CF3

R1

Blue LED

N

R2

O (50–79%)

(b)

Scheme 17.47  Heteroaryl triflones as sources of CF3 radical under photoredox catalysis. X RO

R–OH SO2CF3

X TfO I Ar

(60–98%)

Ar–NH2 SO2CF3

O R1

CO2R2

O CO2R2 SO2CF3 (30–94%)

Scheme 17.48  Direct triflylarylation of nucleophiles.

SO2CF3 (45–77%)

(X = N, CH)

R1

X ArHN

515

516

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) O

O CF3SO2K Br

SO2CF3

(a) CH2Br N (b)

N R

CH2SO2CF3 CF3SO2Na

N

CH2Br

N

N R

N

CH2SO2CF3

CF3SO2Na

(c) EWG

EWG NaSO2CF3 EWG

EWG

KI (cat.)

SO2CF3

Br (d)

Scheme 17.49  Metathesis‐type reactivity leading to the formation of benzylic triflones.

Also, a 1,3‐addition was demonstrated on quadricyclane using triflyl chloride (Scheme  17.50b) [160]. Haas and coworkers developed a direct triflation of a cyclic β‐diketone. The reaction proceeds via a NaH deprotonation, with subse­ quent triflation of the anion by triflyl chloride (Scheme 17.50c) [161]. R

H

CF3SO2YR″

R

R′

(Y = S, Se)

YR″

(a)

H SO2CF3

[O]

R

R′

R′

CF3SO2Cl SO2CF3 Cl

(b) (i) NaH O (c)

O

(ii) CF3SO2Cl

SO2CF3

O

O SO2CF3

Scheme 17.50  Addition of triflyl halides to carbon nucleophiles.

17.4  Trifluoromethyl Sulfones [RSO2CF3]

Other methods to prepare alkyl triflones include a thermal rearrangement of triflinate esters, as reported by Hendrickson and Skipper in 1976 (Scheme 17.51a) [162]. It has been demonstrated by Shreeve and coworkers that triflyl fluorides can be used as electrophiles to react with the pentafluoroethyl anion generated in situ from the reaction of tetrafluoroethylene with CsF, to produce pentafluor­ oethyl triflone (Scheme 17.51b) in 53% yield [163]. A direct C(sp3)–H fluorina­ tion of dimethyl sulfone is reported, albeit in low yield (34%), using elemental fluorine (Scheme  17.51c) [164]. Oxidation of trifluoromethyl alkyl sulfides to sulfones is yet another method to access alkyl triflones. This (overall) four‐elec­ tron oxidation, from SII to SVI, has been performed using a variety of oxidants, including Cl2 in water [165], KMnO4 [165], CrO3 [166], H2O2 [167], and H2O2/ H2WO4 [168] (Scheme 17.52). Heat

RH2C–OS(O)CF3

RH2C–SO2CF3 (25–95%)

(a) CsF

F–SO2CF3

(b)

F

F

F

F

C2F5–SO2CF3 (53%)

F2 (gas)

H3C–SO2Me

F3C–SO2CH3 (34%)

(c)

Scheme 17.51  Other reported syntheses of alkyl triflones.

R

[O]

S CF3

O R

S

O CF3

[O] = CrO3 H2O2 KMnO4 H2O2/H2WO4

Scheme 17.52  Oxidation of trifluoromethyl sulfides to sulfones.

17.4.8  Alkyl Triflones: Applications One of the first uses of an alkyl triflone as a synthon can be found in the 1993 paper by Zhu [169]. They prepared potassium bis(triflyl)methide via a simple deprotonation of bis(triflyl)methane using a potassium base. This compound was then reacted with aryldiazonium salts, in water between 0 and 25 °C, to pro­ duce aryldiazonium (ditriflyl)methides through a metathesis‐type reaction. Thermal decomposition of the aforementioned compound in acetonitrile leads to the formation of aryl(ditriflyl)methanes in good yields (Scheme 17.53a). Later, in 2000, Yamamoto and coworkers demonstrated an alternative decomposition pathway [170], wherein phenyl (((trifluoromethyl)sulfonyl)methylene) trifluo­ romethanesulfinate was obtained instead of ditriflyltoluene upon pyrolysis (Scheme 17.53b).

517

518

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

Ar–N2+Cl– +

Tf

K+

Tf

H2O

Ar–N2+

0–25 °C

Tf

Tf

Heat

Ar

Tf

Tf

(88–95%)

(68–76%)

(a) Tf

O

75–95 °C

Ph–N2+

CF3 S

Neat

Tf

O

Ph

Tf 71%

(b)

Scheme 17.53  Bis(triflyl)methanide as a powerful synthon.

The triflyl group is strongly electron withdrawing, and through resonance and induction it can stabilize α‐carbanions and also make the α‐protons more acidic. Capitalizing on these properties, Zhu et  al. synthesized a triflyl cyclopropane from 1,2‐dibromoethane and methyl triflone (Scheme 17.54a) [171]. The depro­ tonation of an acidic methyl proton generates a stable carbanion, which is the active nucleophile that performs an SN2 reaction at one of the primary alkyl hal­ ide centers, removing bromide as NaBr. A second α‐deprotonation and subse­ quent metathesis‐type transformation leads to the formation of the desired O

O S

F3C

+

O

NaH

Br

Br

O S

F3C

(a) O F3C

S

O

Ph

(1) nBuLi chiral ligand (2) PhCHO (3) TMSCl (4) HCl

OH Ph

Ph

R1

SO2CF3

N

+ Ar

Chiral ligand =

SO2CF3

OH

Bn O

N Ph

(16–74%)

(b) O

Bn O

R1 NEt3

N Ph

O N

F3CO2S

Cl

Ar

(61–91%)

(c) Ar

SO2R1

Ph

N

H

O

Cs2CHO3

Ar

N O

Ph

H

HCl Ar

O

(70–90%)

(d)

Scheme 17.54  α‐Deprotonation of alkyl triflones produces carbon‐centered nucleophiles.

17.4  Trifluoromethyl Sulfones [RSO2CF3]

cyclopropane. Nakamura et al. implemented this deprotonation strategy to add α‐triflyl carbanions to aldehydes and through the use of a chiral ligand were able to make the addition stereoselective (Scheme  17.54b) [172]. The target com­ pounds were obtained in variable yields (16–74%), in good diastereomeric ratios and enantiomeric ratios. Kawai et al. developed a novel synthesis of isoxazoles by reacting aryl imidoyl chlorides and α‐triflyl ketones. The heterocycles were obtained in yields of 61–91% (Scheme  17.54c) [151]. As was demonstrated by Cid and coworkers, benzyl triflones can be converted to aldehydes. Their approach was reacting the benzylic triflone with nitrosobenzene to form a diaryl methanimine oxide, through a base‐mediated reaction. Upon quenching the intermediate with HCl, the target aldehydes can be synthesized in good yields (Scheme 17.54d) [173]. A rise in the use of ditriflylmethane as a building block primed for the synthe­ sis of alkyl triflones was observed in 2011, with the report by Taguchi and cow­ orkers on a 2,2‐bis(trifluoromethanesulfonyl)ethylation of electron‐rich arenes using 1,1,3,3‐(tetrakistrifluoromethanesulfonyl)propane (Scheme 17.55a), which was in turn prepared by the reaction of ditriflylmethane with paraformaldehyde [174]. This tetrakistriflyl molecule is reported to undergo a retro‐Michael reac­ tion, producing (as the active electrophile) 1,1‐bistriflylethene, which is then trapped by the chosen nucleophile. In this work, the authors reported an ortho‐ selective nucleophilic addition of phenols to these electrophilic alkenes, with the reactions proceeding with good to excellent yields. The aptitude of these polytri­ flyl carbon acids toward condensation reactions was further investigated by

Tf + (CH2O)n

Tf

Tf

Tf Tf

Tf

Tf

DCM

Tf

Polar solvent or High temp

O

Tf Tf

O R′

Tf

Tf

Tf

S CF3

Tf=

Tf O

Tf

Tf

R R′

R

(72–99%)

O

(a) O

Ar

F3CO2S

SO2CF3

SO2CF3 H (78–97%)

H

(b)

Tf

SO2CF3 Ar

Tf

+

R1CHO

+

Tf Tf

R2 R2

(c)

R1

(55–99%)

Scheme 17.55  (Poly‐triflyl)alkanes as reagents to install a bis(triflyl)methane unit.

519

520

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

Taguchi and coworkers [175], with the reactivity now being extended to even α,β‐unsaturated carbonyl compounds (Scheme  17.55b). Finally, this reactivity pattern was exploited in a three‐component reaction between ditriflylmethane, an aldehyde, and a 1,3‐diene. The first step of this reaction is likely the condensa­ tion of the aldehyde with the carbon acid, forming a highly electron‐deficient alkene. This olefin can then form a ditriflyl cyclohexene derivative with the 1,3‐ diene, proceeding via a Diels–Alder reaction (Scheme 17.55c) [176]. With mono­ substituted dienes, the substituent is always para to the triflyl groups. In 1995, Fuchs and coworker [177] employed 1‐iodo‐1‐(triflyl)methane as a synthon for the 1,2‐iodination–(triflyl)methylation of alkynes, using benzoyl peroxide as a radical initiator (Scheme 17.56). SO2CF3 I

R

R′

R′ F3CO2S

Bz2O2 (0.05 equiv)

R I

(47–99%)

Scheme 17.56  Iodoalkyl triflones as building blocks to impart structural diversity.

17.5 ­Difluoromethyl Sulfones [RSO2CF2H] The “chemical chameleon” properties of arylsulfonyl groups have galvanized their use in the transfer of “masked” difluoromethyl units. One of the earliest known compounds of this class is phenyl difluoromethyl sulfone, which was pre­ pared through a two‐step procedure by Hine and Porter. First, sodium thiophe­ noxide was reacted with difluorocarbene, generated from chlorodifluoromethane and sodium methoxide, producing phenyl difluoromethyl sulfide [178]. Subsequent oxidation with H2O2 yielded the desired difluoromethyl sulfone [179]. This approach remains the most widely utilized method to synthesize this compound (Scheme 17.57). S Na

HCF2Cl

SCF2H

H2O2

SO2CF2H

NaOMe

Scheme 17.57  Most widely utilized synthesis of phenyl difluoromethyl sulfide.

17.5.1  Aryl and Heteroaryl Difluoromethyl Sulfones [RSO2CF2H] (R = Ar, HetAr): Preparation Almost five decades after the seminal work of Hine and Porter [178, 179], Hu and coworkers disclosed the first direct synthesis of phenyl difluoromethyl sulfone from phenyl sulfinic acid and the mild difluorocarbene source TMSCF2Br, in 61% yield (Scheme  17.58a) [180]. The transformation likely proceeds through a 2e− oxidation of the sulfinic acid center by :CF2, resulting

17.5  Difluoromethyl Sulfones [RSO2CF2H]

in the formation of a SVI–CF2− unit, which gets protonated by water (cosol­ vent). A more general synthesis of aryl difluoromethyl sulfones was later dis­ closed by Colby and coworkers (Scheme 17.58b) [181]. This approach invokes the good leaving group ability of trifluoromethyl ketone hydrates under basic conditions. The desired difluoromethyl aryl sulfones were furnished in mod­ erate to good yields. An interesting synthetic route was provided by Xiao and coworkers, starting from N‐arylsulfonyl hydrazones (Scheme  17.58c) [182]. Treatment of these substrates with difluorocarbene (derived from triphe­ nylphosphoniumdifluoromethyl carboxylate) results in the formation of aryl difluoromethyl sulfones in moderate to good yields (53–91%). Sodium difluo­ romethylsulfinate has been used to make diverse aryl difluoromethyl sulfones on reaction with aryldiazonium tetrafluoroborates, catalyzed by a copper(I) catalyst (Scheme 17.58d). O S

TMSCF2Br

OH

SO2CF2H

20% aq KOH DCM

(a)

Ar OH

F2C

H2O

F2C

F

R N

H

Ph

F

Ph3P S O2

O S O

D2O

CF3 OH

(26–90%)

(b)

OH

F2C

H

Ar

Et3N

O S O

O S O

CF3 OH

H N

Ar

Ar

Et3N

O S O

F2C

D

(>96% D incorporation)

O R

O

H+

SO2CF2H

CsHCO3, 100 °C

(61–91%)

PhCHN2

CsHCO3 R

Cs+ N (c)

Ph

N

S O2

CF2

H

N2 BF4

– Cs+ F2C N N S O2

Ph

R Rearrangement

H

SO2CF2H

NaSO2CF2H CuTc

R (d)

F

H

R (23–77%)

Scheme 17.58  Reported syntheses of aryl difluoromethyl sulfones.

Ph

N

N O

F

S O Cs+

521

522

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

There has been interest in the synthesis of heteroaryl difluoromethyl sul­ fones as reagents for fluorofunctionalization. Difluoromethyl 2‐pyridyl sul­ fone was synthesized for the first time by Hu and coworkers in 2010, as a reagent for deoxygenation–difluoroolefination [183a]. The deprotonation of 2‐mercapto pyridine with NaH, with subsequent reaction with chlorodifluo­ romethane, resulted in the formation of 2‐((difluoromethyl)thio)pyridine. RuCl3‐catalyzed oxidation with sodium metaperiodate furnished the desired sulfone in high yields (Scheme 17.59a). Baran and coworkers utilized a simi­ lar strategy, using bromodifluoromethyl diethylphosphonate as the source of difluoromethylene for reaction with 2‐mercapto pyridine (Scheme  17.59b) [183b]. Gueyrard and coworker published a novel oxidation of heteroaryl thioethers, using an ammonium molybdate/H2O2 system (Scheme  17.59c) [184]. The method provided very low yields of the corresponding sulfones (~25%). Hu and coworkers extended the reported RuCl3‐catalyzed oxidation of difluoromethyl sulfones to benzothiazole and pyrimidine derivatives (Scheme 17.59d). S

H

S

i. NaH ii. HCF2Cl

N

O CF2H

RuCl3 · 3H2O

N

NaIO4

H

N

S

i. NaH O ii. EtO P CF Br 2 EtO

O CF2H

N

O CF2H

N

(a) S

S

RuCl3 · 3H2O NaIO4

S

O CF2H

N

(b) S

S

S

CF2H

O CF2H

N

N

(NH4)6Mo7O24 H2O2

S

O

O CF2H

S

S

O CF2H

N

N

(c) N

S N

S

S

CF2H

N R

CF2H

RuCl3 ·3H2O NaIO4

N

O O S CF2H N

S

O

S

O CF2H

N R

(d)

Scheme 17.59  Known preparations of heteroaryl difluoromethyl sulfones.

17.5.2  Aryl and Heteroaryl Difluoromethyl Sulfones [RSO2CF2H] (R = Ar, HetAr): Applications In 1988, Stahly reported the first nucleophilic phenylsulfonyldifluoromethyla­ tion of aldehydes using phenylsulfonyldifluoromethane and sodium hydroxide to generate the PhSO2CF2− anion [185]. Using the phenylsulfonyl group as a handle for further structural elaboration, a number of novel difluoromethylene‐contain­ ing compounds were obtained (Scheme 17.60). Reduction with Na metal in etha­ nol resulted in the corresponding –CF2H compound, while oxidation using CrO3

17.5  Difluoromethyl Sulfones [RSO2CF2H]

in H2SO4 led to the formation of the phenylsulfonyldifluoromethyl ketone. Deoxygenation–fluorination and subsequent treatment with base yielded the 1,1,2‐trifluoroalkene. OH Ph–SO2CF2H

+

CHO

R

NaOH

CF2SO2Ph

DCM R

Na EtOH

(73–90%)

CrO3 H2SO4 OH

R (49%)

F

O

CF2H R

Et2NSF3

CF2 O2S Ph (95%)

F CF2

CF2SO2Ph

R

R (71%) DBU

Scheme 17.60  The first base‐mediated nucleophilic phenylsulfonyldifluoromethylation.

Almost two decades later, Prakash et al. further developed this methodol­ ogy, utilizing this compound as a difluoromethylidene source in the synthesis of gem‐difluoro olefins from iodo alkanes [186]. This transformation consti­ tutes the first SN2 reaction at a primary alkyl iodide by phenylsulfonyldifluo­ romethide, forming the corresponding alkyl difluoromethylene‐sulfone. Treatment of this product with KOtBu provides the corresponding gem‐dif­ luoroalkene in moderate to good yields (Scheme 17.61a). Alternatively, sub­ jecting the sulfonyldifluoromethyl compound to a Na(Hg)/NaHPO4 system brings about a desulfurization, serving as a facile approach to difluoromethyl alkanes (Scheme 17.61b) [98]. Aldehydes represent another important class of electrophile that has been nucleophilically sulfonyldifluoromethylated by deprotonated phenylsulfonyldifluoromethane. Subsequent desulfurization of the sulfonyldifluoromethyl carbinols yields α‐difluoromethyl alcohols (Scheme 17.61c). A variety of aliphatic and aromatic aldehydes and ketones were transformed into the corresponding difluoromethyl alcohols in moder­ ate to excellent yields [187]. The potential of PhSO2CF2H to be used as a difluoromethylene equivalent to bridge electrophiles was explored by Prakash et al. [188]. Potassium tert‐butoxide was used to perform a deprotonation of the pronucleophile, followed by a nucleophilic phenylsulfonyldifluorometh­ ylation of the chosen electrophile. Another equivalent of tert‐butoxide was used to perform a desulfurization, leading to the formation of a CF2 anion. This reactive species attacks another equivalent of electrophile, forming an internal CF2 moeity. Both aldehydes and disulfides could undergo this trans­ formation (Scheme  17.61d). Furthermore, the addition to aldehydes always yields the anti‐addition product. The developed chemistry resembles the reaction of a difluoromethylene dianion [CF2]2− with two electrophiles.

523

524

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

PhSO2CF2H

+

tBuOK –50 °C

RH2C–I

PhSO2CF2 CH2R

tBuOK –20 to 25 °C

H (55–88%)

(37–84%)

(a) PhSO2CF2H

+

tBuOK

RH2–CI

PhSO2CF2

–50 °C

CH2R

CF2

R

Na(Hg)

HF2C

MeOH, Na2HPO4

(85–91%)

(b)

PhSO2CF2H

O

+

R1

tBuOK –50 °C

R2

PhO2S HO

CF2

R1

R2

Na(Hg) MeOH, Na2HPO4

(53–92%)

(c) O PhSO2CF2H

+

2

R1

–50 °C

OH R1

PhSO2CF2H

C F2

+

SO2Ph

H CF2

R1

R2

OH OH

tBuOK (4 equiv) H

HO

(76–93%)

R1

C F2

R1

(52–82%)

KOtBu

(d)

CH2R

OH

KOtBu

PhS–SPh

R1

R1CHO

CF2

tBuOK (4 equiv) –50 °C

PhS

C F2

SPh

(99%)

Scheme 17.61  Phenylsulfonyldifluoromethylation–desulfurization yields α‐CF2– alcohols .

Further adding to this deprotonation–fluoroalkylation approach, Hu and cow­ orker published a novel method for the synthesis of chiral α‐difluoromethyl amines [189]. The reaction of deprotonated PhSO2CF2H with chiral sulfinyl imines produces addition products in excellent diastereomeric ratios and excel­ lent yields. Treatment of the thus formed compounds with Na(Hg)‐based desul­ furization conditions produces the desired products in good to excellent yields (Scheme 17.62a). Access to β‐difluoromethyl alcohols and amines, starting from ketones and amines, requires the use of electrophilic/radical difluoromethylation reagents. Hu and coworkers developed cyclic sulfates and sulfamidates as viable, electrophilic precursors to β‐difluoromethyl alcohols and amines, thus circum­ venting the necessity for electrophilic‐type reagents [190]. (Phenylsulfonyl)difluo­ romethane, upon deprotonation, performs an SN2 reaction at the primary carbon, causing the ring to open. Treating the now acyclic compound with H2O2 yields the desired product in excellent yield (Scheme 17.62b). The utility of such scaffolds was also demonstrated. The authors report transformations of their (phenylsulfo­ nyl)difluoromethylated products into difluoromethanes and 1,1‐difluoroalkenes. Asymmetric transfer of the (phenylsulfonyl)difluoromethyl unit to form chirally

17.5  Difluoromethyl Sulfones [RSO2CF2H]

pure samples has also been established. The first such work can be found in the 2007 paper by Hu and coworkers, detailing their explorations into the syntheses of difluorinated vicinal ethylenediamines from sulfinyl imines (Scheme  17.62c) [191]. The stereochemistry of the products is dictated by the predetermined ste­ reochemistry of the optically pure starting material, with the installed CF2 group trans to the sulfoxide O‐atom. The products were obtained in excellent diastere­ omeric ratios. In this case too, desulfurization of the final products enabled chem­ ical tunability after installation of the CF2‐containing groups. Later work from the O +

PhSO2CF2H

O

S

tBu

N

R1

LiHMDS

tBu

+

(i) LiHMDS, –78 °C (ii) 20% aq H2SO4 H2O2

PhSO2CF2H

X = O, N-PG

XH CF2H Ph (82–83%)

(b)

N

(i)

tBu

N

R1

H CF2H

(70–97%)

(87–99%)

Mg/HOAc/NaOAc

XH CF2 Ph (70–81%)

LiHMDS, THF

NaHMDS, –78 °C

+ PhSO2CF2H

N

CF2SO2Ph

R

O NBn2

S

tBu

XH

O S

Na(Hg)

R1

(a) O O X S O

O H

CF2SO2Ph MeOH, Na2HPO4 (ii) HCl, MeOH (85–99%) (d.r. > 99%)

–78 °C

H

S

tBu

R

S

N H

CF2SO2Ph NBn2 R

(87–99%) O

CF2SO2Ph

HCl

NBn2

H2N

tBu

R

O R1

OR2

CF2H NBn2

N H

R

+

(i) LiHMDS (ii) HCl (conc.)

PhSO2CF2H

O R1

CF2SO2Ph (72–88%)

(d)

TMS

TMS N TMS

Cat. Me4NF TMS

TMS N

O PhSO2CF2

(e)

Mg/HOAc/NaOAc

(93%)

(88%)

(c)

S

R

R

PhSO2CF2

TMS N TMS TMS

O

H

PhSO2CF2H

CF2SO2Ph

TMS

TMS + N

OTMS R

CF2SO2Ph

PhSO2CF2H

Scheme 17.62  Base‐mediated nucleophilic difluoromethylation utilizing PhSO2CF2H.

525

526

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

same group details a direct nucleophilic (phenylsulfonyl)difluoromethylation of esters. The presented addition–elimination reaction yields α,α‐difluorinated β‐ ketosulfones [192] in good yields (Scheme  17.62d). It is interesting that under these conditions, no double addition is reported, which would afford the bis(difluoromethyl) carbinol derivative instead. The deprotonation of (phenylsul­ fonyl)difluoromethane usually requires strong, often water‐ and air‐sensitive bases for facile deprotonation. To circumvent this necessity, Hu et al. developed a nucleophilic difluoromethylation of carbonyl compounds, wherein the active base (TMS)2N− is produced by the reaction of fluoride/alkoxide with (TMS)3N [193]. The products were obtained in moderate to good yields (Scheme 17.62e). A transition‐metal‐free oxidative (phenylsulfonyl)difluoromethylation of iso­ cyanides was developed by Hu and coworkers. The transformation is proposed to proceed via a 1‐electron oxidation of (phenylsulfonyl)difluoromethide, with subsequent reaction of the radical with the isocyanide moiety [194]. Following this, a cyclization–HAT reaction furnishes the desired heterocyclic products in high yields (Scheme  17.63a). Copper(I) (phenylsulfonyl)difluoromethide has been prepared in situ from the reaction of copper(I) chloride with PhSO2CF2H, mediated by NaOtBu. A transmetalation to an aryl‐palladium(II) complex, fol­ lowed by reductive elimination, results in the formation of aryl (phenylsulfonyl) difluoromethane (Scheme 17.63b) [195]. Recently, a palladium‐catalyzed desul­ fonylative cross‐coupling of aryl boronic acids with O‐Tosyl α‐(phenylsulfonyl) difluoromethyl alcohols (derived from PhSO2CF2H) was published by Hu and coworkers, producing 2,2‐diaryl‐1,1‐difluoroethenes (Scheme 17.63c) [196]. R2

R2

R1 + N

PhSO2CF2H

R1

tBuONa, Cs2CO3

C

PhI(OAc)2, I2 –50 °C

N

CF2SO2Ph

(a)

PhSO2CF2H

CuCl tBuONa

PhSO2CF2Cu

B(OH)2

R [Pd]

R

CF2SO2Ph

(b) O

CF2SO2Ph (i) PhSO2CF2H, LiHMDS

OTs

(ii) TsCl CF2

(c)

Pd2(dba)3 (cat.) P(o-tol)3 Cs3CO3 ArB(OH)2

Scheme 17.63  Fluorofunctionalization using PhSO2CF2H: oxidative or cross‐coupling.

17.5  Difluoromethyl Sulfones [RSO2CF2H]

Unlike their simple aryl counterparts, interest in heteroaryl difluoromethyl sulfones has only peaked in the last decade. 2‐Pyridyl difluoromethyl sulfone was the first heteroaryl difluoromethyl sulfone used to conduct a chemical transfor­ mation [197]. In 2010, Hu and coworkers developed the first reaction with this compound as a reagent for the deoxygenation–difluoromethylolefination of aldehydes and ketones, producing gem‐difluoroalkenes (Scheme 17.64a) [183]. Prakash et  al. then used this reagent as a deoxygenative arylsulfonyldifluoro­ methylation reagent on alcohols (Scheme 17.64b) [198]. An SN2 reaction at pri­ mary alkyl iodides was also established. The difluoromethylation of chiral sulfoximines has been performed using this reagent, forming difluoromethyl‐ containing amino sulfones [199]. Further structural elaboration leads to the for­ mation of amino sulfinic and sulfonic acids (Scheme 17.64c). Hu and coworkers found a novel desulfurization–halogenation procedure to produce α‐bromodif­ luoromethyl and α‐iododifluoromethyl O‐(2‐pyridyl) alcohols [200a]. Removal of the 2‐pyridyl unit was conducted with trifluoroacetic acid (Scheme 17.64d). Liu et al. applied 2‐pyridyl difluoromethyl sulfone to create CF2‐containing sugar lactones (Scheme  17.64e) [200b]. Treatment of the difluoromethyl ketal with aqueous base resulted in a difluoroolefin product. Reaction of the ketal with allylmagnesium chloride and Cu(OTf )2 produces the desulfurization product. Hu and coworkers disclosed an iron‐mediated difluoromethylation of aryl zinc reagents, producing difluoromethyl arenes in moderate to very good yields (Scheme 17.64f ) [200c]. Photocatalytic systems to perform radical difluoromethylation reactions are gaining popularity, owing to their mild operating conditions and low energy requirements. Hu and coworkers developed a ruthenium(II)‐catalyzed radical fluoroalkylation of 2‐isocyano biphenyls as a means to obtain 6‐difluorometh­ ylphenanthridines (Scheme 17.65a) [148]. Building upon this strategy, Fu et al. developed 2‐(difluoromethylsulfonyl)benzothiazole as a source of radical – CF2H, permitting the synthesis of difluoromethylated benzoxazines and oxa­ zolines. Using an iridium(III) catalyst irradiated with blue light, they were able to conduct an oxy‐difluoromethylation of olefinic amides (Scheme  17.65b) [201]. The reaction is proposed to proceed via a single electron transfer from Ir(III) to the –CF2H sulfone, releasing a difluoromethyl radical upon reduction. The radical then reacts with the olefinic part of the substrate, resulting in the formation of the desired products upon an intramolecular cyclization. Soon after, the same group applied an identical difluoromethylation strategy to alkynoates, aimed at the synthesis of difluoromethyl coumarins (Scheme 17.65c) [202]. The products were obtained in moderate to good yields. Zou and Wang employed this photocatalytic system in the synthesis of difluoromethylated isoquinoliones, starting from N‐methacryloyl benzamides (Scheme  17.65d) [153]. Taking advantage of the ease of reduction of the benzothiazole unit, Petrov and coworkers delineated a facile synthesis of sodium difluoromethyl­ sulfinate, as a cost‐effective and efficient radical difluoromethylation reagent [203]. Performing a NaBH4 reduction of 2‐(difluoromethylsulfonyl)benzothia­ zole yielded near‐quantitative yields of sodium difluoromethylsulfinate (Scheme 17.65e).

527

528

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

O R1

SO2CF2H

+ R2

CF2

(i) tBuOK (ii) NH4Cl

N

R2

R1

(a) O O S CF2H N

R2R1HC–OH

+

O O S CF2H N

(ii) LiHMDS, –98 °C O O S CF2 N CH2R

LiHMDS

RH2C–I

+

(b)

tBu

O S

H N

SO2CF2H

+

R +

LiHMDS –98 °C

N

R

*

H3N

C F2

N N

O R1

N R H (d.r. > 99%)

tBu

I O(2-Py)

O

NaOtBu

R2

O(2-Py)

BnO +

N

O

O

BnO

HMPA

OBn

O(2-Py)

R2

BnO

LiHMDS

R1

CF3COOH

CF2Br

R1

(d)

O(2-Py)

CF2I

R1

R2 [PhMe3N+]Br–

SO2CF2H

CF2SO2(2-Py)

(ii) EtSNa, EtSH/THF (iii) H3O+ O

+

O S

(i) HCl, MeOH

SO2–

(c)

SO2CF2H

O O S CF2 N CHR1R2

(i) Tf2O, 0 °C

R1

O

BnO

OBn

SO2 (2-Py) CF2 OH OBn

OBn (73%)

TBME

Sat. aq NaHCO3

O

BnO BnO

CF2

MgCl Cu(OTf)2

BnO

OBn

BnO

OBn (85%)

(f)

+

OBn OBn

(70% over two steps)

(e) Ar2Zn

H CF2 OH

O

SO2CF2H N

Fe(acac)3 (cat.) TMEDA

Ar–CF2H

Scheme 17.64  More recent applications of 2‐pyridyl difluoromethyl sulfones.

CF2I R2 CF2Br R2

17.5  Difluoromethyl Sulfones [RSO2CF2H] R1

S SO2CF2H

N

+

N

CF2H

[Ru(bpy)3]Cl2 ·6H2O, NaHCO3

C

N

Blue LED

R2

(a) Ph

R2

R2 NH

NH O

R1

+ ZTB–SO2CF2H

O

O

Na2CO3, blue LED

N

BTZ=

HF2C R1

O

N

Ph

(56–93%)

S

(b)

R

CF2H

fac-Ir(ppy)3 (cat.)

(85–93%)

N

R′

R +

O

ZTB–SO2CF2H

R

CF2H

fac-Ir(ppy)3 (cat.) Na2CO3, blue LED

O

R′

O

O

(52–80%)

(c) O

O N R2

R1

+

ZTB–SO2CF2H

CF2H O

fac-Ir(ppy)3 (cat.) Na2CO3, blue LED

R1

N

R2

O (52–79%)

(d) S N

SO2CF2H

NaBH4

O NaO S CF2H ( >99%)

(e)

Scheme 17.65  2‐(Difluoromethylsulfonyl) benzothiazole as a CF2H source.

17.5.3  Aryl and Heteroaryl Halodifluoromethyl Sulfones [(Het) ArSO2CF2X] (X = Cl, Br, I): Preparation Owing to the potentially lower reactivity of the C(sp3)—Cl bond, chlorodifluoro­ methyl sulfones have been scarcely explored as synthons; hence their synthesis has not received as much attention as their bromo‐ and iodo‐ counterparts. Also, the only report of an alkyl sulfonyl chlorodifluoromethane can be found in the work of Sundermeyer and coworker, with no apparent further interest in that class of molecule [84]. The earliest report (2007) for the synthesis of this class of molecules involves electrophilic chlorination of (phenylsulfonyl)difluorometh­ ane using N‐chlorosuccinimide (NCS) (Scheme  17.66a) [204]. Later work by Ochal and coworkers involved the preparing this type of compound through oxi­ dative chlorination using sodium hypochlorite (Scheme 17.66b) [205]. Bromodifluoromethyl aryl sulfones have received some attention in the syn­ thetic community, owing to the ease of preparation and higher reactivity of these compounds over their chlorinated counterparts. In 1981, Burton and Wiemers reported the first synthesis of bromodifluoromethyl phenyl sulfone [104]. The

529

530

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF) (79%)

SO2CF2H

SO2CF2Cl

LiHMDS NCS

SCH3

SCCl3

Cl2, PCl5 (cat.)

(78%)

Py ·(HF)x

NaIO4 RuCl3 (cat.)

SCClF2

(Olah’s reagent)

(87%)

(a) SO2CF2H

SO2CF2Cl

NaOCl

R

R

(b)

Scheme 17.66  Preparations of chlorodifluoromethyl phenyl sulfones via oxidative or electrophilic chlorination.

synthetic strategy involved bromodifluoromethylation of sodium thiophenoxide, producing the corresponding –CF2Br sulfide. Subsequent oxidation of the sulfide resulted in the formation of the sulfone, with a yield of 21% over two steps (Scheme 17.67a). An improvement to this method increased the overall yield to 56% [206]. Oxidative bromination of difluoromethyl phenyl sulfone has also been demonstrated to yield the bromodifluoromethyl sulfone (Scheme 17.67b) [205]. Iododifluoromethyl phenyl sulfone was first synthesized by Prakash et al. in 2004, via a deprotonation–iodination sequence utilizing potassium tert‐butox­ ide and I2 (Scheme 17.68a) [98]. An alternative preparation involves a Borodin– Hunsdiecker reaction on 2,2‐difluoro‐2‐(phenylsulfinyl)acetic acid, followed by an oxidation with mCPBA (Scheme 17.68b) [95].

S–Na+

CF2Br2

SCF2Br

O mCPBA

(25%)

(a) SO2CF2H

NaOBr

S

O CF2Br

(83%) SO2CF2Br

(b)

Scheme 17.67  Preparations of bromodifluoromethyl sulfones.

17.5.4  Aryl and Heteroaryl Halodifluoromethyl Sulfones [(Het)Ar SO2CF2X] (X = Cl, Br, I): Applications Hu and coworkers reported the only known use of chlorodifluoromethyl phenyl sulfone. On treatment with KOH, it served as a difluorocarbene source, allowing for the synthesis of difluoromethyl aryl ethers from phenols (Scheme 17.69) [204, 207].

17.5  Difluoromethyl Sulfones [RSO2CF2H] SO2CF2H

+

I2

SO2CF2I

KOtBu

(92%) (a) O S

C F2

HgO, I2

COOH

O S

C F2

I

mCPBA

O

S

O C F2

I

(b)

Scheme 17.68  Syntheses of iododifluoromethyl phenyl sulfone. SO2CF2Cl OH

OCF2H KOH

Scheme 17.69  Chlorodifluoromethyl aryl sulfone as a difluorocarbene reagent.

Owing to the higher reactivity of the C—Br bond, bromodifluoromethyl aryl sulfones have been used in difluoromethylation reactions, and in the prepara­ tion of fluorofunctionalization reagents. In 2003, Prakash et  al. developed a magnesium(0)‐mediated reductive synthesis of difluoromethylsilanes, starting from halodifluoromethylsilanes [52]. 1,2‐Bis(trimethylsilyl) tetrafluoroethane was prepared from the Mg0‐reductive silylation of bromodifluoromethyl aryl sulfones (Scheme  17.70a). Further building upon the utility of these sulfones, Prakash et al. developed a nucleophilic difluoromethylation and difluoromethyl­ enation of aldehydes using bromodifluoromethyl phenyl sulfone, mediated by tetrakis(dimethylamino) ethene [208]. The method involved nucleophilic trans­ fer of the (phenylsulfonyl)difluoromethyl anion to the aldehyde, resulting in the formation of the corresponding carbinol. Treatment of this product with Na(Hg), Na2HPO4 in methanol resulted in the formation of difluoromethyl alcohols via  proto‐desulfonylation. Alternatively, mesitylation of the product followed by  a desulfurization reaction with Na(Hg) yielded gem‐difluoroalkenes (Scheme  17.70b). In 2013, a palladium‐catalyzed Heck‐type coupling reaction between styrene derivatives and bromodifluoromethyl phenyl sulfone was devel­ oped by Reutrakul and coworkers [17], furnishing β‐difluoromethylstyrenes in moderate yields (Scheme 17.70c). As part of a series of fluorinated sugars, phe­ nylsulfonyldifluoromethyl 2‐benzyloxy‐d‐galactals, were prepared via transfer of an electrophilic PhSO2CF2– radical (Scheme 17.70d) [209]. Another example of such radical transfer can be found in the work of Kondratov et al., where a 1,2‐phenylsulfonyldifluoromethylation–ethoxylation of an unsaturated pentose derivative was performed (Scheme 17.70e) [210]. There has been much recent interest in the development of PhSO2CF2Br as a viable reagent for fluoroalkylation under photocatalysis conditions. Tong et al. demonstrated one of the first reactions of this nature, wherein vinyl isocyanides were converted to ortho‐fluoroalkyl‐containing pyridines via an Ir(III)‐catalyzed, white light‐promoted reaction with phenylsulfonyl bromodifluoromethane

531

532

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

Ph

Mg0

SO2CF2Br

TMS

TMS–Cl 0 °C to rt

C F2

F2 C

TMS

(a) Ph

OH

RCHO

SO2CF2Br

Me2N

NMe2

Me2N

NMe2

R

OH

Na(Hg) Na2HPO4

CF2SO2Ph

(i) MsCl, Et3N, DMAP (cat.) (ii) Na(Hg), Na2HPO4

R

CF2H

R

CF2

(b) Ph–SO2CF2Br

+

R

Pd(PPh3)4, K2CO3

Ph O

S

F2 C

R

O

(17–60%)

(c) OBn

OBn

OBn PhSO2CF2Br

O BnO

BEt3 (cat.) OBn

OBn O

BnO CF2SO2Ph O (38%)

(d)

Ph–SO2CF2Br

+

OEt

O

Na2S2O4, NaHCO3 EtOH

EtO

F OEt

Ph S

O

F

(58%)

(e)

Scheme 17.70  Phenyl bromodifluoromethyl sulfone. as a CF2 source

(Scheme 17.71a) [211]. The reaction was determined to proceed through the for­ mation of a PhSO2CF2– radical, likely generated by an Ir(III)–Ir(IV) one‐electron catalytic cycle. Another example of a photocatalytic system used to install the PhSO2CF2– unit into organic molecules can be found in the work of Hashmi and coworkers [212]. They designed a gold‐catalyzed fluoroalkylation protocol for the synthesis of difluoromethylene‐containing hydrazones (Scheme 17.71b). Zhu and coworkers established a vicinal difunctionalization of alkenes by combining a visible light‐mediated, Ir(III)‐catalyzed, radical phenylsulfonyldifluoromethyl­ ation with the migratory aptitude of the cyano group preinstalled on the sub­ strate (Scheme 17.71c) [213]. They also extended this methodology to encompass other migrating functional groups such as aldehydes and imines (Scheme 17.71d) [214]. This group also disclosed the only known report of a heteroaryl bromodi­ fluoromethyl sulfone as a reagent. Used in conjunction with an ammonium iodide salt, it acts a source of –CF2I in the vicinal iododifluoromethylation– arylation of alkenes (Scheme 17.71e) [215].

17.5  Difluoromethyl Sulfones [RSO2CF2H]

R

CN

+

PhSO2CF2Br

fac-Ir(ppy)3, Na2HPO4

R

N

MeO2C

CF2SO2Ph

(50–54%)

(a) O N Ph

N

O +

PhSO2CF2Br

Au(II) (cat.), imidazole

N

H

Ph

N CF2SO2Ph

(28–85%)

(b)

HO

CN

+

R

O

fac-Ir(ppy)3 (cat.)

PhSO2CF2Br

CF2SO2Ph

R CN (60–86%)

PhSO2CF2Br

visible light

Ir(III)*

–H+

Ir(III)

Ir(IV) · Ph–SO2CF2

HO · R NC

HO

CN

HO

R

HO R

CN

R

·

CF2SO2Ph

N ·

CF2SO2Ph

CF2SO2Ph

(c) O HO

+

R

PhSO2CF2Br

R2

fac-Ir(ppy)3 (cat.) Blue LEDs

R2

C F2

R

SO2Ph

(68–91%)

(d)

O R

R′

+

S N

S

O CF2Br

fac-Ir(ppy)3 (cat.) Bu4NI, acetone Blue LEDs

S R

N R′ CF2I

(e)

(90–34%)

Scheme 17.71  Photocatalytic phenylsulfonyldifluoromethylation reactions using PhSO2CF2Br.

533

534

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

Despite being the least atom economical of the halodifluoromethyl phenyl sul­ fones, PhSO2CF2I has been used as a reagent for the addition of the –CF2– unit into organic molecules. The first instance of use of this reagent for fluorofunction­ alization can be found in the work of Hu and coworkers [216]. The researchers for­mulated a novel 1,2‐phenylsulfonyldifluoromethylation–iodination of alkenes, mediated by triethyl borane (Scheme 17.72a). An extension of this work was devel­ oped using alkynes as the starting materials, forming PhSO2CF2‐containing alk­ enes (Scheme 17.72b) [217]. Wang and coworkers disclosed a visible light‐mediated C(sp2)–H difluoromethylation reaction on electron‐rich heteroarenes [218]. The transformation is mediated by a Ru(II) complex and uses iododifluoromethyl phe­ nyl sulfone as the source of difluoromethylene (Scheme 17.72c). The products thus R Ph–SO2CF2I

+

Et3B, –30 °C

R

I CF2SO2Ph (56–78%)

(a) Ph–SO2CF2I

+

I

Et3B, –30 °C

R

R PhO2SF2C (55–85%)

(b) Ph–SO2CF2I

+

Ru(bpy)3Cl2 ·6H2O

R X

R X

K2HPO4 white light

CF2SO2Ph

(58–96%)

(c) R1 Ph–SO2CF2I

Pd2(dba)3 (cat.)

+ N R2

R1

CF2SO2Ph O

Xantphos KOAc

O

N R2 (61–97%)

(d) FeCp2 (cat.) H2O2

R1 Ph–SO2CF2I

+ N R2

R1

CF2SO2Ph O

DMSO/THF

O

N R2 (62–94%)

(e)

Ph–SO2CF2I

+

N R1

N

R2

fac-Ir(ppy)3 (cat.) K2CO3 Blue LED

N R1

R2

N

CF2SO2Ph (62–91%)

(f)

Scheme 17.72  Iododifluoromethyl phenyl sulfones as reagents.

17.5  Difluoromethyl Sulfones [RSO2CF2H]

obtained were isolated in good yields. Using a Pd(II) pre‐catalyst and Xantphos as a ligand, the same group conducted a difluoromethylation–cyclization of acyclic enaminones, producing difluoromethylated oxindoles (Scheme 17.72d) [219]. An alternative approach for the same transformation was developed using an Fe(II) catalyst and H2O2 as the oxidant (Scheme 17.72e) [220]. The transformation is pre­ sumed to proceed via an Fe(II)–Fe(III) catalytic cycle, with the oxidation step performed by hydrogen peroxide. Recently, Fu and coworkers developed an Ir(III)‐catalyzed, light‐mediated system to perform difluoromethylation of benzo‐fused imidazoles (Scheme 17.72f ) [221]. Noteworthy is the work on elec­ trophilic‐type (phenylsulfonyl)difluoromethylation using λ3‐iodanes. The first synthesis and use of this class of reagent was reported in 2008, in the publication by Hu and coworkers [222]. The reagent performed a direct electrophilic‐type transfer of the PhSO2CF2– unit to thiol functionalities, producing the desired products in good yields (Scheme 17.73a). A decarboxylative allylic difluorometh­ ylation of β,γ‐­unsaturated carboxylic acids was developed using this λ3‐iodane (Scheme 17.73b) [223]. An analogous decarboxylation of α,β‐unsaturated carbox­ ylic acids yielded vinyldifluoromethyl phenyl sulfones (Scheme 17.73c) [224]. PhO2SF2C I

O

SH

S

+ R

CF2SO2Ph

R (68–87%)

(a) PhO2SF2C I

O +

R1 R2

R4 R5 COOH

CuCl2 ·2H2O (cat.)

R3

R4 R5 CF2SO2Ph

R1 R2

R3 (33–92%)

(b) PhO2SF2C I

O +

R1

COOH

CuF2 ·2H2O (cat.) TMEDA

R2

R1

CF2SO2Ph

R2

R3 (60–91%)

(c)

Scheme 17.73  IIII reagents as used in electrophilic‐type (phenylsulfonyl)difluoromethylation.

The only example of a heteroaryl iododifluoromethyl sulfone being used as a synthon can be found in the work of Hu and coworkers [225]. Catalyzed by tri­ ethylborane, the transformation produced 1,2‐iodination products in terminal alkenes in moderate to good yields (Scheme 17.74), with good regioselectivity.

N

SO2CF2I

+

R

I

Et3B, air –30 °C

R

CF2SO2 (2-Py)

Scheme 17.74  A heteroaryl sulfone as a synthon for installation of the CF2 moiety.

535

536

17  Synthesis and Applications of Fluorinated Sulfoxides (RSORF) and Sulfones (RSO2RF)

17.5.5  Aryl(trimethylsilyl)difluoromethyl Sulfones [ArSO2CF2TMS]: Preparation Fluoroalkylsilanes are one of the mildest and most widely used sources of fluoro­ alkyl anions [1–3]. It is therefore not surprising that there has been much interest in the utilization of compounds of the form RSO2CF2–TMS, which permits fluorofunctionalization under benign conditions. However, the synthesis of this class of molecules has not seen much progress, with preparations being limited to two different methods. The first method proceeds via a Mg0 reduction of bro­ modifluoromethyl phenyl sulfide followed by quenching with TMSCl. Oxidation with mCPBA yields the desired silane in good yield (Scheme 17.75a) [52]. The second method involves a lithium–halogen exchange reaction between phenyl­ sulfonyldifluoromethane and BuLi. Subsequent trapping with TMSCl yields the difluoromethylsilane in good yields (Scheme 17.75b) [226]. SCF2Br

(i) Mg0

SCF2TMS

mCPBA

SO2CF2TMS

(ii) TMSCl (a) SO2CF2H

nBuLi

SO2CF2Li

TMSCl

SO2CF2TMS

(b)

Scheme 17.75  Avenues for the preparation of phenyl (trimethylsilyl)difluoromethyl sulfone.

17.5.6  Aryl(trimethylsilyl)difluoromethyl Sulfones [ArSO2CF2TMS]: Applications Despite a disappointingly small number (two methods) for the preparation of phenyl(trimethylsilyl)difluoromethyl sulfone, the reagent has seen extensive use as a synthon, for the installation of a (phenylsulfonyl)difluoromethyl group into organic molecules under mild conditions. The first instance of its use can be found in the 2003 paper by Hu and coworker [226]. Upon initiation by tetrabutylammonium fluoride, aldehydes and ketones were converted to the corresponding α‐(phenylsul­ fonyl)difluoromethyl carbinols in good yields (Scheme 17.76a). Desulfonylation of the carbinols was performed via a reductive process utilizing Mg0 in a acetic acid– sodium acetate mixture, affording the α‐difluoromethyl carbinols in good yields. The same group later published a similar transformation on α‐amino carbonyl com­ pounds, yielding α‐difluoromethyl‐β‐amino alcohols by nucleophilic difluorometh­ ylenation [227]. Initiated by tetrabutylammonium fluoride, the process furnished the addition products in good yields (Scheme  17.76b). In an attempt to further expand on the fluoride‐initiated nucleophilic fluoroalkylation approach, Hu and coworkers tried a novel asymmetric transfer of the (phenylsulfonyl)difluoromethyl unit, with the stereochemistry of the product being set by a chiral ammonium cata­ lyst. The products were furnished in good yields, but lacked in stereoselectivity, with very low enantiomeric excess obtained (Scheme 17.76c) [228]. Nucleophilic fluorofunctionalization using perfluoroalkylsilanes is usually not tolerant to acid

17.5  Difluoromethyl Sulfones [RSO2CF2H]

conditions. In defiance of this, Kosobokov et al. designed a phenylsulfonyldifluoro­ methylation of imines and enamines using an acidic fluoride [229]. Using in situ generated HF (from the reaction of trifluoroacetic acid and potassium bifluoride) as the activator, the desired α‐difluoromethyl amines were obtained in good isolated yields. Further functionalization at the phenylsulfonyl unit was demonstrated by reduction to the difluoromethyl compound (Scheme 17.76d). Dihydroisoquinolines, upon N‐methylation with methyl triflate, reacted with the generated (phenylsulfo­ nyl)difluoromethide to form α‐CF2‐containing N‐heterocycles [230]. The products were obtained in good to excellent yields (Scheme 17.76e). O R1

R2

+

OH

[(nBu)4)N]+F–

TMS–CF2SO2Ph

R1

R2

OH

Mg0

CF2SO2Ph

AcOH/NaOAc

R1

R2

CF2H

(80–91%)

(50–92%) (a) O R

+

H

(i) [(nBu)4)N]+[Me3SiF2]–

TMS–CF2SO2Ph

+ –

OH R

CF2SO2Ph

(ii) [(nBu)4)N] F

NBn2

NBn2 (72-92%)

(b)

F– O H

Ar

+

OH

Chiral ammonium salt

TMS–CF2SO2Ph

(64–91%) (low ee: 95% yield (determined by 19F NMR) [17]. Until now, these are the only examples for pentafluorosulfanylation of alkenes using SF6. 19.1.2  Pentafluorosulfanylation of Alkenes Using SF5X For pentafluorosulfanylation of alkenes and alkynes, three primary reagents were used in literature, namely, the most reactive SF5Br, the less reactive but thermally more stable SF5Cl, and the least reactive and highly toxic S2F10. The latter property and the difficult accessibility of this SF5 dimer restricted its appli­ cation to a small number of examples  [18–21]. Currently, radical addition of SF5Cl or SF5Br across multiple bond systems is the only practical and versatile

19.1  Pentafluorosulfanylation Reagents

Ph N SF5

S Photoredox catalyst

R

SF6 5 mol% catalyst 10 mol% Cu(acac)2

365 and 525 nm LEDs MeCN, rt, 21 h

R = Ph, Me

R = Ph SF5 F BF3·OEt2 R rt, 3 h R = Ph 63%* R = Me 27%*

Ph >95%* SF5

R = Me

* 19F NMR spectroscopic

95%*

Scheme 19.2  Photoredox catalytic addition of SF6 toward α‐phenyl‐ and α‐methylstyrenes.

option for the preparation of a variety of aliphatic SF5 compounds serving as starting material for the preparation of more complex molecules [22, 23]. Two excellent reviews on synthesis, properties, and applications of organic SF5‐­ containing compounds covering the literature up to 2011 or 2014, respectively, were published by Altomonte and Zanda [24] and Savoie and Welch [25]. The mentioned reagents are hardly available commercially and their synthesis is not so easy to execute in common organic chemistry laboratories because almost all protocols require the use of sulfur tetrafluoride [25], which is difficult to handle and nowadays hardly available either. Nevertheless, these two reagents were used to synthesize a variety of SF5‐substituted aliphatic, alicyclic, and, if applicable, heterocyclic compounds, just to determine the scope and limitations for the particular variation of the given method. On the other hand, the general objective is the preparation of low molecular weight building blocks for further synthetic applications. Addition reactions of SF5X (X = Cl, Br) toward unsaturated substrates proceed predominantly through radical pathways. Heterolytic bond dissociation pro­ cesses did not lead to selective formation of SF5 compounds, because the formed SF5− decomposes to SF4 and F− and the latter together with the X+ ions facilitate the addition of the interhalogens across double bonds forming β‐haloalkyl fluo­ rides. The electrophilic SF5˙ radical, observed and characterized by different methods, can be generated thermally, photochemically, or chemically. 19.1.2.1  Thermal Pentafluorosulfanylation of Alkenes with SF5X

The thermal reactions of SF5X (X  =  Cl, Br) with alkenes were shown to be restricted to simple alkenes and haloalkenes. Due to generally harsh conditions, the reactions were usually not selective and low yielding in many cases. However, heating of ethylene and propylene with SF5Cl in an autoclave gave the vicinal addition products in 47% or 78%, respectively, and vinylchloride delivered 36% of 2,2‐dichloroethyl pentafluorosulfane. From ethylene, 4‐chloro‐1‐(pentafluoro­ sulfanyl)butane was formed as side product and from vinylchloride, 2,4,4‐ trichloro‐1‐(pentafluorosulfanyl)butane. Cyclohexene gave a 73 : 27 mixture of

573

574

19  Pentafluorosulfanylation of Aliphatic Substrates

1‐chloro‐2‐fluorocyclohexane and 1‐chloro‐2‐(pentafluorosulfanyl)cyclohexane. Also butadiene yielded a mono addition product, presumably 3‐chloro‐4‐ (­pentafluorosulfanyl)but‐1‐ene (Scheme 19.3). Isobutene and styrene oligomer­ ized under similar reaction conditions [26]. From vinyl acetate, allyl acetate, and 11‐acetoxydec‐1‐ene, the corresponding addition products were formed by heat­ ing of the reactants [27, 28]. Also different fluoroethylenes were thermally reacted with SF5Cl [29]. Cl

SF5Cl

R

47% 78% 36% 84% 57% 84%

R = H, 90 °C, 250 atm, 10 h R = Me, 100 °C, 40 atm, 3 h R = Cl, 150 °C, 6 h R = OAc, 50 °C, 1 h R = CH2OAc, 95 °C, 15 d R = (CH2)8OAc, 90 °C, 2 d Cl

SF5Cl 20 °C, 18 h SF5Cl 100 °C, 2 h

SF5

R

F

+ 73 : 27

Cl SF5

Cl SF5 37%

Scheme 19.3  Thermal addition of SF5Cl toward alkenes.

The reaction of ethylene with SF5Br at elevated temperature is less selective and delivered a 91  :  9‐mixture of 1‐bromo‐2‐fluoroethane and 1‐bromo‐2‐ (­pentafluorosulfanyl)ethane [19]. This reaction and those with different fluori­ nated alkenes became more efficient at room temperature (Scheme 19.4). The reaction of tetrafluoroethylene (not shown) was less efficient giving only 6% of the target product after 139 hours at 85–90 °C [30]. The cis/trans‐isomeric 1,2‐difluoroethylenes gave approximately 2 : 1‐­mixtures of erythro‐ and threo‐2‐bromo‐1,2‐difluoro‐pentafluorosulfanyl ethane in the dark almost independently from the stereochemistry of the starting material. Irradiation with UV light did not change the product ratio significantly but increased the yield by about 20% [31]. The bromopentafluorosulfanylation of 1,2‐dichloroethylene at ambient temperature in methylene chloride gave the 1,2‐addition product in 63% yield after UV irradiation for 64 hours [32]. The thermal reactions of SF5Br with electron‐deficient acrylates and meth­ acrylates gave the target addition products in reasonable yields after relatively long reaction times at temperatures between room temperature and 60 °C (Scheme 19.5) [28, 33, 34]. 19.1.2.2  Photochemical Pentafluorosulfanylation of Alkenes with SF5X

From the reactions of difluoroethylene with SF5Br, it became most likely that the photochemical activation of SF5X is more efficient for additions toward alkenes

19.1  Pentafluorosulfanylation Reagents

SF5Br 55–90 °C, 6 d F

X2

SF5Br

X1 X3

25 °C, 12 h

SF5

Br

F

Br

F

25–50 °C, 8 d

F

+

91 : 9

SF5Br

F

F

Br

SF5 F

91%

X2 Br X1

X1 = F, X2 = X3 = H X1 = X2 = F, X3 = H X1 = X2 = X3 = F X1 = H, X2 = X3 = Cl

SF5

X3 70% 70% 46% 63%

Scheme 19.4  Thermal addition of SF5Br toward different types of alkenes. R2 R1O O

SF5Br Neat 25–60 °C, 15–22 h

R1O

R2 Br

SF5

O

R1 = H, R2 = Et R1 = H, R2 = tBu R1 = Me, R2 = Me R1 = CH2Cl, R2 = Et R1 = n-C7H15, R2 = Et R1 = CH2CO2Me, R2 = Me

36% 68% 73% 68% 85% 75%

Scheme 19.5  Thermal addition of SF5Br toward acrylates and methacrylates.

compared to thermal reactions. Thus, irradiation of different activated alkenes or α,ω‐dienes with SF5Cl provided the target 1,2‐addition products in high yields (Scheme 19.6) [35, 36]. X

X

SF5Cl CFCl3, hν, 25 °C, 2 h

R

SF5Cl n

CFCl3, hν, 25 °C, 2 h n=1 n=2

SF5

R Cl

R = H, X = OH R = Me, X = OH R = Me, X = Cl R = CH2OH, X = H Cl

Cl n

80% 85%

SF5

+

F5S

94% 76% 91% 87%

Cl n

SF5

15% 13%

Scheme 19.6  Photochemical addition of SF5Cl toward different types of alkenes and dienes.

Moreover, the addition of SF5Cl to isobutene, which could not be realized ther­ mally (see Section  19.1.2.1) was successful photochemically. Irradiation of an

575

576

19  Pentafluorosulfanylation of Aliphatic Substrates

equimolar mixture of the reactants with a mercury pressure lamp in a sealed tube at 0 °C overnight gave the addition product in 68% yield. Methylene cyclohexane reacted analogously to provide the addition product in 77% yield. Reversed regi­ oselectivity was observed in the reaction of 1,1‐bis(trifluoro­methyl)ethane to provide the product with the SF5 group in tertiary position (Scheme 19.7) [37]. R

SF5Cl

R

Neat or CFCl3 hν, 0–20 °C, 2–16 h

R

SF5 Cl R = Me 68% R = (CH2)5 77% R

F3C

SF5Cl

F3C

F3C

Neat (gas phase) hν, 20 °C, 12 h

F3C

Cl SF5 20%

Scheme 19.7  Photochemical addition of SF5Cl toward electronically different terminal alkenes.

Additional examples were reported including those with transannular par­ ticipation of a second double bond in the intermediate carbon radicals (Scheme 19.8) [38, 39]. HO

SF5Cl Neat, hν −78 °C, 16 h

SF5 HO Cl 65% SF5

SF5Cl CFCl3, hν 98%

Cl SF5

SF5Cl Hexane, hν 25 °C, 3 h

Cl 20% SF5

X

SF5Cl

+

Hexane, hν 25 °C, 3 h 82%

Cl

SF5Cl Hexane, hν 25 °C, 3 h

Cl

SF5 44%

X = Cl 8% X = F 7% +

Cl

SF5 Cl

22%

Scheme 19.8  Photochemical addition of SF5Cl toward different types of cycloalkenes and cycloalkadienes.

19.1  Pentafluorosulfanylation Reagents

This method has also been used as the first step in a synthetic sequence to gain access to new liquid crystals (Scheme 19.9) [40]. Cl

SF5Cl R

Hexane, hν, rt, 4–6 h

R=

n

SF5

R

n = 1 65% n = 3 80%

92%

R=

Scheme 19.9  Photochemical addition of SF5Cl toward different types of liquid crystalline alkenes.

19.1.2.3  Triethylborane‐mediated Radical Pentafluorosulfanylation of Alkenes Using SF5X

A tremendous step forward was made when Dolbier and coworkers who discov­ ered that SF5˙ radical formation can be mediated by triethylborane (Et3B) [22, 23]. This became the most frequently used method for addition to unsaturated sub­ strates. In this way, a series of terminal and central alkenes were transformed to the target addition products in very high yields (Table 19.1) [22]. In a series of experiments, the outcome of chloropentafluorosulfanylation reactions of terminal alkenes was investigated under different activation condi­ tions showing that Et3B‐mediated radical transformations (method B) were supe­ rior over the photochemical radical reactions (method A) (Scheme 19.10) [41]. The Et3B‐mediated addition of SF5Cl was also very useful for dienes. While hexa‐1,5‐diene was transformed to the 1,2‐addition product, the conjugated penta‐1,3‐diene gave the 1,4‐addition product both in practically quantitative Table 19.1  Et3B‐mediated radical addition of SF5Cl toward alkenes. R2 R1

R3

SF5Cl (1.2 equiv) Et3B (10 mol%) Hexane (1 M) –30 °C to rt, 30 min

R2 Cl R1

R3 SF5

R1

R2

R3

Yield (%)

H

n‐Hex

H

95

H

n‐Bu

H

98

H

t‐Bu

H

96

Et

Et

H

89

n‐Pr

H

n‐Pr

95

H

(CH2)4

98

H

p‐tolyl

H

79

H

OAc

H

89

577

578

19  Pentafluorosulfanylation of Aliphatic Substrates

Cl

SF5Cl

R

Cl

SF5

R

A: hexane, hν, rt, 6−8 h B: CH2Cl2, Et3B, −40 °C, 2−6 h Cl SF5

SF5

SF5

SF5 Cl A: n.d. B: 92%

Cl A: 25% B: 48%

A: 56% B: 91%

A: 84% B: 95%

Scheme 19.10  Different activation for radical addition of SF5Cl toward terminal alkenes.

yields. From allene the 1,2‐addition product was isolated in 80% yield (Scheme 19.11) [23]. Cl SF5Cl (1.2 equiv) Et3B (10 mol%)

.

SF5

quant. Cl

quant. Hexane (1 M) –30 °C to rt, 30 min 80%

SF5 Cl SF5

Scheme 19.11  Et3B‐mediated radical addition of SF5Cl toward dienes.

The reaction proved to be widely insensitive to functional groups such as halides, esters, and ketones that are not conjugated with the double bond (Table 19.2) [23]. Under these conditions, the yield of the addition of SF5Cl to allylacetate was increased from 57% for the thermal reaction (see Scheme 19.8) [28] to 90% [42] and even 97% [43]. Highly welcome was a study on the compatibility of the Et3B‐mediated radical addition of SF5Cl with a series of solvents and its robustness against different additives [44], which is simulating functional group tolerance [45]. These inves­ tigations using allyl phenyl ether as a model alkene showed that low temperature (−40 °C) led to higher yields compared to the same reactions at 0 °C or room temperature. Solvents like hexanes, toluene, diethyl ether, tetrahydrofuran, ethyl acetate, and methylene chloride are most useful, and water, methanol, acetone and acetonitrile can be applied, but the reaction failed in DMF and DMSO. Robustness screen established that SF5Cl is stable in the presence of ethers, esters, carboxylic acids, aliphatic and aromatic alcohols, copper, and copper salts under the tested conditions of the radical chloropentafluorosulfanylation reac­ tion of allyl phenyl ether [44]. Interestingly, the radical addition of SF5Cl is also high‐yielding for allyl triiso­ propyl‐ and allyl triphenylsilane, while the trimethyl analogue gave a low yield (Scheme 19.12) [43].

19.1  Pentafluorosulfanylation Reagents

Table 19.2  Et3B‐mediated radical addition of SF5Cl toward functionalized alkenes. SF5Cl (1.2 equiv) Et3B (10 mol%)

R2 R1

Cl R2

Hexane (1 M) –30 °C to rt, 30 min

SF5 R1

R1

R2

Yield (%)

H

OAc

98

H

(CH2)2CO2Et

94

H

(CH2)2COCH3

93

H

(CH2)8OH

73

H

(CH2)8OAc

94

H

(CH2)8Br

89

H

CH2CO2Et

70

Me

OAc

94

R3Si

SF5Cl (4–7 equiv) Et3B (20 mol%) Hexane –50 °C to –25 °C

Cl R3Si

SF5

R = Me 14% R = i-Pr 84% R = Ph 97%

Scheme 19.12  Et3B‐mediated radical addition of SF5Cl toward allylsilanes.

As early as 1975, Berry and Fox already described the thermal additions of SF5X to vinylsilanes leading to stable products in good to excellent yields (Scheme 19.13). Reactions of SF5X with silanes such as trimethylsilane or hexa­ methyldisilane were not successful to provide analogues of the Ruppert–Prakash reagent [46] and recently the question arose “Pentafluorosulfanyltrimethylsilane: A Nonexisting Molecule?”. DFT calculations suggested that molecules of the MSF5‐type with M = Me3Si, Li, Cu, MeZn, MeCd, and MeHg are both thermo­ dynamically and kinetically unstable and attempts to synthesize such reagents are therefore likely to fail [47]. X

SF5X, neat R3Si

Conditions

R3Si

SF5

R = Me, X = Cl, 100 °C, 22 h 85% R = Me, X = Br, 25 °C, 1 h 72% R = Cl, X = Br, 0 °C, 3 h 93%

Scheme 19.13  Radical addition of SF5X toward vinylsilanes.

Generally, the addition of SF5Br across double bonds is less selective as com­ pared to SF5Cl. However, reactions profit when executed Et3B‐mediated in CFCl3

579

580

19  Pentafluorosulfanylation of Aliphatic Substrates

or hexane. Thus, ω‐functionalized terminal alkenes were transformed to the tar­ get 1,2‐addition products in excellent yields (Scheme 19.14) [48]. SF5Br (1.3 equiv) Et3B (10 mol%) R

CFCl3 (0.5–1 M) 0 °C, 10–20 h

Br SF5

R

R = C(O)OtBu R = CH2C(O)OMe R = CH2CH2C(O)OEt R = CH2CH(CH3)C(O)OEt R = CH2OC(O)CH3

94% 85% 93% 92% 99%

Scheme 19.14  Et3B‐mediated radical addition of SF5Br toward functionalized terminal alkenes.

19.2 ­Application of β‐Haloalkyl‐perfluorosulfanyl Compounds For the β‐haloalkyl‐perfluorosulfanyl compounds presented in Section 19.1.2., a variety of applications have been described, which will be discussed within this section. 19.2.1  Halogen Substitution Reactions There are only a handful of examples of direct nucleophilic halogen displace­ ment reactions in the literature and mostly silver salts have to be applied to avoid dehydrohalogenation. For example, 2‐bromo‐1‐pentafluorosulfanylethane, pre­ pared almost quantitatively from ethylene and SF5Br under dry conditions at room temperature, gave oxygen derivatives on treatment with the corresponding silver salts as shown in Scheme 19.15 [34]. SF5Br 1 atm, rt Couple of hours

F5S

Ag+Nu – Br Nu = OAc Nu = OTf Nu = OTs Nu = ONO2

F5S

Nu 67% 68% 81.5% 72%

Scheme 19.15  SF5Br addition to ethylene and halogen substitution reactions.

Moreover, the bromine of the SF5Br adducts of acrylates was reduced with tributyltinhydride to form the SF5‐substituted propionates. The tert‐butyl ester was then hydrolyzed to the carboxylic acid, while the ethyl ester was reduced to the primary alcohol. From the latter the bromide was prepared by reaction with PBr3 (Scheme 19.16) [33]. All these compounds are potential SF5‐substituted C3 building blocks. Amino groups seem not to be compatible with the conditions of halopen­ tafluorosulfanylation of olefins. In contrast, less basic N‐allyl amides gave fair to excellent yields when reacted with SF5Cl under Et3B mediation. The formed 1,2‐ addition products were subsequently cyclized to 5‐CH2SF5‐substituted oxazo­

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds O

O

Bu3SnH

RO

SF5 Br

Et2O, rt, 24 h

RO

SF5

Conc. HCl 80–90 °C, 3 h (R = t-Bu)

R = Et 76% R = t-Bu 90% (R = Me)

O HO

SF5 80%

1. BH3·SMe2 2. H2O SF5

HO 37%

PBr3 Et2O, rt, 24 h

Br

SF5 80%

Scheme 19.16  Follow‐up reactions of 2‐bromo‐1‐pentafluorosulfanyl propionates.

lines by silver‐mediated intramolecular replacement of chlorine. Ten selected examples are listed in Table 19.3 [49]. 19.2.2  Synthesis and Application of α‐Pentafluorosulfanyl Aldehydes The Et3B‐mediated addition of SF5Br has also been used to enol acetates of ali­ phatic aldehydes. The formed β‐SF5‐substituted geminal bromoacetoxyalkanes were hydrolyzed under acidic conditions to provide α‐SF5‐substituted aldehydes (Scheme 19.17) [50]. A collection of derivatization reactions of the aldehydes are depicted in Scheme 19.19. Lower homologues of these α‐SF5 aldehydes were synthesized starting from enolethers, and their borane‐mediated reactions with SF5Cl and hydrol­ Table 19.3  Chloro‐fluoropentafluorosulfanylation of N‐allyl amides and cyclization of the products to 5‐CH2SF5‐substituted oxazolines. SF5Cl (1.2 equiv) Et3B (10 mol%)

O R

N H

R

Hexane (1 M) –40 °C, 2 h

O R

SF5

AgOTf (1.1 equiv) N H

Cl 20 examples

SF5 Toluene (0.05 M) reflux, 3 h

Yield (%) chloro‐SF5 product

O R

N

20 examples

Yield (%) oxazoline

Ph

81

97

p‐Me–C6H5

96

96

p‐MeO–C6H5

92

76

p‐Br–C6H5

98

94

p‐F–C6H5

86

97

o‐F–C6H5

94

83

Thiophen‐2‐yl

78

86

Furan‐2‐yl

83

66

Cinnamyl

39

92

t‐Bu

79

56

581

582

19  Pentafluorosulfanylation of Aliphatic Substrates

H

R

OAc

SF5Br (1.3 equiv) Et3B (10 mol%)

SF5

Hexane (1 M) 0 °C, 20 min

Br

R

OAc

R = n-Pr R = n-Pent R = n-Hept R = Bn

SF5

HCl (3.5 M) HOAc reflux, 1 h

H

R O

74% 91% 45% 66%

24% 77% 80% 64%

Scheme 19.17  Addition of SF5Br toward enolacetates and hydrolysis of the products to α‐SF5 aldehydes.

ysis of the products provided the target aldehydes in good overall yields (Scheme 19.18) [51].

OEt

R

SF5Cl (1.3 equiv) Et3B (10 mol%)

SF5 Cl

R

Hexane (1 M) 25 °C, 2 h

OEt

R=H R = Me R = Et

SF5

HCl (3.5 M) HOAc reflux, 1 h

85% 77% 77%

H

R O 82% 96% 73%

Scheme 19.18  Addition of SF5Cl toward enolethers and hydrolysis of the products to α‐SF5 aldehydes.

The formed α‐SF5 aldehydes were used for a series of common carbonyl r­ eactions such as reductions to primary alcohols, Grignard‐type reactions to sec­ ondary alcohols, Horner–Wadsworth–Emmons olefination, oxidations to car­ boxylic acids, and epoxide formation using a variation of the Johnson–Corey– Chaykovsky reaction (Scheme 19.19) [50]. SF5 n-Pr

O 62%

R

R′

MeLi or R′MgBr or TMSCH2Li

OH R = n-Pr, R′ = Me 56% R = n-Pent, R′ = Me 72% R = Bn, R′ = Me 58% R = n-Pent, R′ = CH=CH 68% R = n-Hept, R′ = CH2TMS 65%

SF5 (EtO)2P(O)CHLiCO2Et

(CH3)2SCHLiCO2Et SF5

CO2Et

SF5

R

H

R O

KMnO4 or H2NSO3H/NaClO2

NaBH4

SF5 R

SF5 R

CO2Et

R = n-Pr 73% R = n-Pent 77% R = Bn 80%

H

OH R = n-Pr 79% R = n-Hept 87%

Scheme 19.19  Downstream chemistry of α‐SF5 aldehydes.

OH

O R = n-Pr 47% R = n-Hept 96%

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

19.2.3  Synthesis and Application of Vinyl‐SF5 Compounds 19.2.3.1  Elimination of Hydrogen Halogenides from β‐Halogen‐ pentafluorosulfanylalkanes

A very broad variety of vicinal halopentafluorosulfanyl compounds were treated with bases at 0 °C or elevated temperature depending of the substituent pattern to provide target SF5‐vinyl products. A selection of such products are composed in Scheme 19.20 [27, 28, 35, 36, 41, 43, 52–56]. X

AcO

SF5

7

Base

SF5

R

SF5

n

R

H H

R

H 81%

SF5

SF5

X R = H, X = OH R = Me, X = OH R = Me, X = Cl R = CH2OH, X = H

n = 1 79% n = 2 86%

91%

SF5 N O R = Ac 87% R = Ph 90%

O SF5

SF5 R R = c-Hex 91% 88% R = i-Pr R = (CH2)2Ph 87% R = CH2-c-Hex 78% R = CH2Si(Ph)3 87%

67% 76% 50% 76%

H R H R = n-Pr 74% R = n-Pent 84%

SF5

96%

SF5

H

MeO

95%

SF5

R

0 °C – 80 °C

i-Pr

SF5

H

79%

Scheme 19.20  Examples for vinylic SF5 compounds synthesized from vicinal halo‐ pentafluorosulfanyl compounds.

In cases when a conjugated system can be formed, the elimination of a hydro­ gen halide does not lead to a SF5‐vinyl, but to a SF5‐allyl product (Scheme 19.21) [23, 57].

MeO2C

O O

S

SF5Cl (1.2 equiv) Et3B (10 mol%) Hexane –30 to –20 °C, 1 h

Cl MeO2C

SF5

NaOMe (1 equiv) MeOH, rt, 1 h

MeO2C

70%

SF5Br (1.2 equiv)

O

CH2Cl2, hν, 0 °C, 6 h

O

SF5 S Br

SF5 76%

AgOTs (4.3 equiv)

O

MeCN, reflux, 5.5 d

O

SF5 S 52%

Scheme 19.21  Two‐step synthesis of allylic SF5 compounds.

The preparation of an interesting potential building block, namely, SF5‐­ acetone, is based on the thermal addition of SF5Cl toward diketene and hydroly­ sis of the formed addition product in hot water, which provided the target compound by elimination of HCl and decarboxylation (Scheme 19.22) [58].

583

584

19  Pentafluorosulfanylation of Aliphatic Substrates

Cl

SF5Cl

O O

CFCl3 50 °C, 1 d

O

H2O

O

F5SCH2

F5S

80 °C, 1 d

95%

O

80%

Scheme 19.22  Two‐step synthesis of SF5‐acetone.

The addition products of SF5Cl toward polyfluoroethylenes were treated with KOH to give the SF5‐substituted polyfluoroethylenes in reasonable yields (Scheme 19.23) [59].

X F

H F

X

SF5Cl

F5S H

Conditions

F

X

F

KOH

Cl

Conditions

88% 85% 30%

X=H X=F X = CF3

F

F5S 85% 86% 60%

F

Scheme 19.23  Two‐step synthesis of polyfluorinated SF5‐ethylenes.

Particularly, the SF5‐trifluoroethylene has been applied in a variety of com­ mon derivatization reactions, which were summarized by Savoie and Welch recently [25]. Historically, the addition of SF5X toward cyclohexene derivatives has been used as the first step in three alternative synthetic sequences to form pentafluor­ osulfanyl benzene (Scheme 19.24) [60, 61]. Br SF5

SF5Cl

SF5

SF5

Cl Br OAc

OAc

OAc SF5

SF5Br

SF5

SF5

Br OAc

OAc

OAc Cl Cl

SF5Cl

Cl

SF5

Cl

Cl

Scheme 19.24  Multistep synthesis of pentafluorosulfanylbenzene from cyclohexene derivatives.

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

19.2.3.2  Cycloadditions of SF5‐Vinyl Compounds

A couple of most common 1,3‐dienes have been reacted with 3‐SF5‐substituted acroleine and acrylic acid derivatives, which were prepared from the correspond­ ing α‐halo‐β‐pentafluorosulfanyl carbonyl compounds by hydrogen halogenide elimination (see Scheme  19.20). Thus, the thermal Diels–Alder reaction with cyclopentadiene gave mixtures of endo‐ and exo‐products with either one or the other stereoisomer as the preferred one depending on the nature of the carbonyl group (Scheme 19.25) [36, 57, 62, 63].

SF5 50–110 °C 6–10 h SF5

a b c d e

SF5

X R a b c d e

R R = CHO R = CN R = C(O)CH3 R = CO2Me R = CO2H

R 21% 18% 11% 51% 36% SF5

50–100 °C 5–12 h

R

+

R

a b c d e

SF5 52% 44% 36% 18% 12% 58% 54% 48% 65% 65%

Scheme 19.25  Diels–Alder reactions of SF5‐substituted acroleine and acrylic acid derivatives.

In contrast, the thermal reaction of pentafluorosulfanyl‐trifluoroethylene with butadiene did not provide [4+2]‐cycloadducts but led to the vinylcyclobutane derivative, the [2+2]‐cycloaddition product, in 70% yield (Scheme 19.26) [64].

F

SF5

F

F

+

190 °C, 22 h

F

F SF5 F 70% (1 : 1)

Scheme 19.26  [2+2]‐Cycloaddition of pentafluorosulfanyl‐trifluoroethylene with butadiene.

On the other hand, the SF5 group can also be placed in 2‐position of buta‐1,3‐ diene. This compound was thermally formed in situ from 3‐SF5‐3‐sulfolene by SO2 extrusion. The latter (see Scheme  19.21) was produced from 4‐SF5‐2‐sul­ folene by isomerization with silicic acid. Thermal reactions of 3‐SF5‐3‐sulfolene with different α,β‐unsaturated carbonyl compounds delivered the target Diels– Alder products (Scheme 19.27) [57]. On the other hand, 1‐SF5‐buta‐1,3‐diene did not react with in situ generated benzonitrile oxide and related dipoles, while the corresponding 1,4‐ and 1,5‐

585

586

19  Pentafluorosulfanylation of Aliphatic Substrates

SF5

O O

O H2SiO3

S

O Sealed tube CH2Cl2, 120 °C, 2 h SF5

S O O 52%

O

O Hexane 130 °C, 5 h O

SF5

O O

87% O

Δ

SF5

SF5

O Hexane 160–165 °C, 4 h

O Yield not determined MeO2C OMe O Benzene 125–135 °C, 4 h (traces of hydroquinone)

+

MeO2C

65%

SF5

SF5

Scheme 19.27  Diels–Alder reactions of 2‐SF5‐butadiene with α,β‐unsaturated carbonyl compounds.

dienes gave 4,5‐dihydroisoxazoles in a 1,3‐dipolar cycloaddition with the unsub­ stituted terminal double bond (Scheme 19.28) [54].

F5S

PhClCNOH, Et3N n

Et2O, –40 °C, 3–4 h

O N F5S

n

Ph

n = 0 No reaction n=1 85% n=2 82%

Scheme 19.28  1,3‐Dipolar cycloaddition of SF5‐substituted dienes with benzonitrile oxide.

19.2.4  Synthesis and Applications of γ‐SF5‐α,β‐Unsaturated Aldehydes The Et3B‐mediated addition of pentafluorosulfanyl chloride toward allylace­ tate gave the vicinal addition product (see Scheme 19.3), which was transformed to the SF5‐substituted allylic alcohol by treatment with aqueous potassium hydroxide. Oxidation with pyridinium chlorochromate (PPC) on silica gel delivered the target γ‐SF5 acroleine in 82% overall yield based on allylacetate (Scheme 19.29) [42]. The SF5‐allylic alcohol has been used as starting material for the construction of a series of SF5CH2‐substituted dihydrobenzofurans and 3‐(SF5‐methyl)indo­ lines. Substituted o‐bromophenols or o‐bromoanilines were alkylated with the tosylate of the allylic alcohol, and the formed products were cyclized under

OAc

SF5Cl (1.1 equiv) Et3B (10 mol%) Hexane (1 M) –35 °C, 1 h

F5S

OAc Cl 90%

KOH (4 M) rt, 12 h

F5S

OH

PCC/silica gel CH2Cl2, rt, 2 h

F5S

96% 2. 1. TsCl, Et3N, cat. DMAP Et2O, rt, 65%

O 95%

Br

R XH K2CO3 or CaCO3 Toluene, 100 °C SF5

Br

AIBN

R X

SF5

X = O 60–92% X = NH or NMe 33–94%

Conditions

R X

X = O, R = H, 5-F, 6-F, 6-CF3, 5-Ph, 5-t-Bu, 5-OMe, 7-OMe 54–95% X = NH, R = H, 5-n-Bu, 6-F 16–74% X = NMe, R = H, 5-n-Bu 31–47%

Scheme 19.29  Synthesis of γ‐SF5acroleine and radical access of SF5‐containing dihydrobenzofurans and indolines from SF5‐allylic alcohol.

588

19  Pentafluorosulfanylation of Aliphatic Substrates

radical conditions to provide the target compounds in good (dihydrobenzo­ furanes) or moderate isolated yields (indolines) (Scheme 19.29) [65]. The aldehyde (3‐SF5‐acroleine) was the crucial building block for a series of more complex molecules using typical carbonyl reactions and subsequent addi­ tional steps. Thus, the Horner–Wadsworth–Emmons (HWE) reaction with (EtO)2P(O)CH2CO2Me delivered the (E,E)‐diene selectively (46%) contaminated with traces of the (Z,E)‐isomer. Moreover, a series of secondary alcohols was available by Grignard reaction. These alcohols were oxidized with PCC on silica gel and the resulting α,β‐unsaturated ketones were transferred to the target diene esters more or less diastereoselectively depending on the nature of the substitu­ ent R. Furthermore, two of the secondary alcohols were treated with P2O5 to deliver mixtures of the 1‐pentafluorosulfanyl‐alka‐1,3‐dienes by dehydration (Scheme  19.30). Trials to increase the selectivity using alternative elimination reactions, e.g. of the bromide derived from the alcohol using CBr4/Ph3P, or via the tosylate or by Chugaev elimination were not successful [42]. Furthermore, all trials to include the SF5‐substituted allylic alcohols in [3,3]‐sigmatropic rear­ rangements failed so far. Another pathway to prepare SF5‐substituted 1,3‐dienes started from SF5‐vinyl compounds, which were synthesized as shown in Schemes  19.10 and 19.20. Thus, the allylic bromides were obtained almost quantitatively by treatment of the SF5‐vinyl compounds with bromine (or NBS) in pentane. Subsequent HBr elimination using either K2CO3 in DMF or DBU in n‐heptane gave the target compounds (Scheme 19.31) [41]. Mono‐SF5‐substituted 1,3‐, 1,4‐, and 1,5‐dienes prepared from β‐chloro‐­ pentafluorosulfanyl‐alkenes by hydrogen chloride elimination were reacted with m‐chloroperbenzoic acid (mCPBA) in methylene chloride at ambient tempera­ ture to give the terminal epoxides. In none of the cases, the SF5‐substituted dou­ ble bond was epoxidized (Scheme 19.32) [35]. The SF5‐substituted allylalcohol (see Scheme 19.20) and its 2‐methyl deriva­ tive were also applied for another derivatization line. Thus, its Jones oxidation provided the carboxylic acids in moderate yields, which were transformed to a variety of esters and amides using HOBt in combination with DCC and a base. The target products, mainly from primary and a few of secondary alcohols and amines, were obtained in 27–71% or 32–98% yield, respectively (Scheme 19.33) [36, 43]. These esters and amides have been used for several types of condensation and 1,3‐dipolar cycloaddition reactions resulting in five‐membered heterocyclic compounds [66–68], which are not covered by the scope of this chapter. 19.2.5  Synthesis and Application of SF5‐substituted C2 Building Blocks 19.2.5.1 SF5‐Acetic Acid Derivatives

The preparation of a variety of SF5‐substituted C2‐building blocks such as SF5‐ acetic acid is based on the thermal addition of SF5Cl toward ketene to form SF5‐ acetic acid chloride originally described in a patent [69] and later improved to 95% yield by changing the solvent from CCl4 to CFCl3 [58]. The acid chloride was transformed to the SF5‐acetic acid by hydrolysis. Hundsdiecker degradation of its

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

F5S

O

RBr, Mg Et2O, 40 °C, 2 h

NaH HWE reaction O F5S

OMe 46% (98 : 2)

OH F5S

CH2Cl2, rt, 2 h

R = C5H11 65% R = C14H29 62% R = c-C6H11 30% R = Ph 60% R = allyl 33% R = vinyl 53% OH F5S

O

PCC/silica gel

R

R

P 2O 5 CH2Cl2, rt, 1 h

F5S R R = C5H11 17% R = C14H29 91% R = c-C6H11 41% R = Ph 98%

F5S

NaH HWE reaction THF, rt, 2 h

R

+

R = C4H9 54% (61 : 39) R = C13H27 94% (66 : 34)

Scheme 19.30  Syntheses based on γ‐SF5acroleine.

R

O

F5S OMe R = C5H11 — R = C14H29 74% (61 : 39) R = c-C6H11 46% (100 : 0) R = Ph 41% (38 : 62)

F5S R

589

590

19  Pentafluorosulfanylation of Aliphatic Substrates SF5

Br

Br2 (1.2 equiv)

SF5

SF5

K2CO3 (5 equiv) DMF, 55 °C, 10 h

Pentane, rt, 12 h ~100% Br

Br2 (1.2 equiv) SF5

82%

Pentane, rt, 12 h

DBU (1.2 equiv) n-Heptane reflux, 4 h

SF5 >95%

SF5 24% (61%, by 19F NMR)

Scheme 19.31  Synthesis of SF5‐substituted 1,3‐dienes.

Cl F5S

K2CO3 n

Sulfolane 60 °C, 3 h

F5S n=0 n=1 n=2

mCPBA (2 equiv) n

CH2Cl2, rt, 3 d

O

F5S

n

n=0 n=1 n=2

40% 79% 86%

90% 88% 92%

Scheme 19.32  Synthesis and epoxidation of SF5‐substituted dienes.

F5S

OH R

CrO3 (4 equiv) HOAc (63 equiv) H2O, 5–10 °C, 2 h

O F5S

OH R R = H 65% R = Me 70% (3 : 1)

R1OH, HOBt DCC, DMAP CH2Cl2, 0 °C R2R3NH HOBt, DCC CH2Cl2, 0 °C

O OR1 R 6 examples 27–71% F5S

O NR2R3 R 12 examples 32–98% F5S

Scheme 19.33  Synthesis of SF5‐substituted acrylic acid derivatives.

silver salt with elemental bromine led to SF5‐bromomethane, which was reduced with Zn/HCl to SF5‐methane, a stable volatile liquid (b.p. 26 °C), which is isoelec­ tronic with SF6 [58]. The SF5‐acetic acid ethylester was prepared by reaction of the acid chloride with ethanol and the reduction of the acid with LiAlH4 gave SF5‐ethanol [70]. The SF5‐anilide was available by Schotten–Baumann reaction (Scheme 19.34); also the N‐ethyl amide and the primary amide were prepared with ethyl amine or ammonia, but no yield was reported [69]. Moreover, dehy­ dration of the SF5‐acetic acid using P2O5 gave SF5‐ketene (Scheme 19.34) [71]. The later compound and some α‐substituted derivatives are versatile starting materials for the preparation of a series of common derivatives, which were ­summarized recently [25], and therefore are not covered in this chapter. A more convenient but multistep protocol toward the SF5‐acetic acid was reported by Dolbier and coworkers starting with an Et3B‐mediated chlorofluoro­ sulfanylation of vinyl acetate and treatment with methanol. The formed dimethyl acetal was oxidized with Caro’s acid in methanol to provide the ester, which was hydrolyzed to the SF5‐acetic acid (Scheme 19.35) [72].

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds O F5S

F5S

OEt

87%

55% EtOH reflux 5h

H2CCO

SF5Cl, CFCl3 25 °C, 2 d

LiAlH4 Et2O

OH

Reflux, 1 h NH2

O F5S

Et2O, 24 °C, 18 h

Cl

O F5S

92%

95% H2O 25–35 °C, 2 h F5S

HCCO

P2O5 150 °C

O F5S

Yield not given

N H

1. AgNO3/Na2CO3, H2O

OH 2. Br2, CFCl3, 50 °C, 12 h 93%

F5S

Br

Zn, HCl HOAc

F5SCH3 27%

75%

Scheme 19.34  Synthesis of SF5‐acetic acid chloride and some common applications.

OAc

1. SF5Cl, Et3B –40 °C 2. MeOH, 50 °C

OMe F5S

OMe

Caro’s acid MeOH

O F5S

93%

aq NaOH OMe then HCl

71%

O F5S

OH 88%

Scheme 19.35  Alternative synthesis of SF5‐acetic acid.

SF5‐acetic acid chloride has been used as a building block for the preparation of long‐chain esters of monofluorinated or non‐fluorinated terminal allylic alco­ hols, which were transformed to α‐SF5‐substituted γ,δ‐unsaturated carboxylic acids by a [3,3]‐sigmatropic rearrangement via intermediate ester enolates formed with trimethylsilyltriflate (TMSOTf ) and triethylamine at reflux in methylene chloride (Table  19.4). The products were isolated as methyl esters after methylation with iodomethane [74]. Later investigations showed that the order of addition of the reagents is important and that higher yields can be obtained avoiding initial acidic conditions: i.e. triethylamine has to be added before TMSOTf [73]. Similarly, 3‐arylpent‐4‐enoic acids bearing a pentafluorosulfanyl substituent in the 2‐position were prepared by refluxing of SF5‐acetates of p‐substituted ­cinnamyl alcohols with Et3N/TMSOTf in methylene chloride (Scheme  19.36). The rearranged products were isolated as approximate 1 : 1 mixtures of syn/anti diastereomers. This is probably due to tiny differences (99 : 1

77

8‐Me

92

87 : 13

80

6‐MeO

86

85 : 15

46

7‐MeO

90

77 : 23

63

8‐MeO

95

89 : 11

78

7‐MeO2C

92

79 : 21

69

6‐MeO2C

95

78 : 22

59

6‐F

88

80 : 20

81

7‐F3C

81

80 : 20

68

F5S

OBn

+ O

n-Bu2BOTf (2.0 equiv) i-Pr2NEt (2 equiv) CH2Cl2, –78 °C to –20 °C

N3 Then aldehyde at –45 °C OTBS

N H

O

Yield (%) quinolinone

5‐Me

O

SF5 R

O F5S

O OBn

N3 OTBS 91% (d.r. 48 : 26 : 17 : 9)

F5S

NH

HO

32% (4 steps)

Scheme 19.37  Aldol reaction of benzyl SF5‐acetate with an azido aldehyde.

The stereochemical outcome of aldol reactions is highly dependent on the geometry of the intermediate enolate. The Et3N/TMSOTf‐mediated Ireland– Claisen rearrangements were shown [74] to occur preferentially via (Z)‐enolates (see Table  19.4). Suspecting similar geometry from silyl‐mediated Mukaiyama aldol reactions, octyl SF5‐acetate was refluxed in methylene chloride with the same combination of reagents and then the formed enolate (ketene silylacetal) was treated with a variety of aldehydes to provide the syn‐aldol products as major products, when benzaldehydes with electron‐withdrawing substituents in para‐ position or any substituents in meta‐position or ortho‐fluorobenzaldehyde or acetaldehyde were used. However, the reactions provided lower yields and were less diastereoselective compared to the boron‐mediated reactions (Table 19.6) of the same aldehydes (Table 19.7) [77]. In contrast, from reactions of benzaldehydes with electron‐donating para‐substituents, no aldols could be isolated. Under the quite acidic c­ onditions,

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

Table 19.6  Boron‐mediated Mukaiyama aldol reactions of octyl SF5‐acetate with aldehydes. 1. NEt3 (3.5 equiv) Cy2BCl (2.5 equiv) –78 °C, CH2Cl2, 4 h

O F5S

OR 2. R′CHO (1.0 equiv) –78 °C to rt, 17 h

R = C8H17

OR H

OR F5S

OBCy2

F5S

(E)-Enolate

OH O BCy2

O

R′

O

OR

SF5 18 examples

R′

R′

Yield (%)a) (isolated)

Anti/syna)

C6H5

96 (85)

97 : 3

4‐CH3C6H4

93 (71)

96 : 4

4‐CH3OC6H4

79 (n.d.)

94 : 6

4‐(CH3)2NC6H4

77 (n.d.)

98 : 2

4‐FC6H4

88 (84)

94 : 6

4‐SF5C6H4

94 (75)

96 : 4

4‐OH‐3‐CH3OC6H3

65 (25)

96 : 4

2‐CH3C6H4

98 (89)

96 : 4

2‐FC6H4

96 (89)

98 : 2

2,6‐(CH3)2C6H3

92 (84)

92 : 8

2,6‐Cl2C6H3

99 (82)

96 : 4

C6H4CH═CH

86 (75)

94 : 6

c‐C6H11

38 (29)

99 : 1

CH3(CH2)2

45 (27)

92 : 8

(CH3)3

88 (76)

98 : 2

a) Determined by 19F NMR.

Ph Me BnN

O

O SO2Mes

Ph SF5

1. NEt3, Cy2BCl, –78 °C, CH2Cl2 2. 4-FC6H4CHO, –78 °C to rt, 17 h 94% (79%)

Me BnN

O

OH

O SF SO2Mes 5 anti/syn: 99 : 1 d.r. for anti: 84 : 16

F

Scheme 19.38  Asymmetric approach of a boron‐mediated Mukaiyama aldol reaction using a chiral auxiliary in the SF5‐acetate.

water was eliminated from the primary formed aldols to provide the α,β‐­ unsaturated esters (Scheme 19.39), while 4‐bromo‐, 2,6‐dichloro‐, and 2,4‐dini­ trobenzaldehyde as well as cyclohexyl carbaldehyde, acroleine, and crotonaldehyde failed to give any aldol products incorporating the SF5‐acetic acid ester [77]. Analogously, the conventional TiCl4‐mediated aldol reaction of methyl SF5‐ acetate with a variety of aldehydes at −78 °C delivered preferentially or exclu­

595

596

19  Pentafluorosulfanylation of Aliphatic Substrates

Table 19.7  Silicon‐mediated Mukaiyama aldol reactions of octyl SF5‐acetate with aldehydes. TMSOTf (1.5 equiv) Et3N (1.5 equiv) CH2Cl2, reflux, 4 h

O F5S

OC8H17

OH O R

then RCHO (1.0 equiv) TiCl4 (0.3 equiv) CH2Cl2, reflux, 15 h

OH O OC8H17

+

R

SF5 syn-

OC8H17 SF5 anti-

R

Yield (%)a) (isolated)

Syn/anti a)

C6H5

44 (30)

86 : 14

4‐NO2–C6H4

53 (40)

93 : 7

4‐F–C6H4

44 (37)

86 : 14

4‐Cl–C6H4

38 (19)

81 : 19

4‐Br–C6H4

39 (19)

83 : 17

4‐SF5–C6H4

42 (22)

95 : 5

3‐NO2–C6H4

61 (44)

90 : 10

3‐CH3–C6H4

57 (41)

73 : 27

3‐CH3O–C6H4

35 (26)

88 : 12

2‐F–C6H4

58 (37)

83 : 17

58 (37)

87 : 13

CH3 19

a) Determined by F NMR.

O F5S

OC8H17

TMSOTf (1.5 equiv) Et3N (1.5 equiv) CH2Cl2, reflux, 4 h then ArCHO (1.0 equiv) TiCl4 (0.3 equiv) CH2Cl2, reflux, 15 h

Ar

O

H SF5

Ar = 4-CH3–C6H4 32% OC8H17 Ar = 4-CH3O–C6H4 36% Ar = 4-C2H5O–C6H4 36%

Scheme 19.39  Silicon‐mediated aldol condensations of octyl SF5‐acetate with electron‐rich benzaldehydes.

sively the syn‐aldol addition products in fair to good yields. Under forced conditions, at room temperature using more equivalents of both TiCl4 and Et3N, the corresponding aldol condensation products were formed with the (E)‐iso­ mer as the major product (Table 19.8) [78]. Salicylaldehyde, under the conditions of the aldol condensation, gave 3‐ SF5‐coumarin in 85% yield, probably by intramolecular dehydration of the ini­ tially formed (E)‐configured α,β‐unsaturated ester (Scheme 19.40) [78].

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

Table 19.8  TiCl4‐mediated aldol reactions of methyl SF5‐acetate with a variety of aldehydes. TiCl4 (1.2 equiv) Et3N (1.4 equiv) O F5S

OMe

1 equiv

+

CH2Cl2 –78 °C, 7–10 h

O

OH O

OH O OMe + R

R

OMe

SF5 syn-

SF5 anti-

H

R

1.2 equiv

TiCl4 (2.2 equiv) Et3N (3.0 equiv) CH2Cl2 0 °C to rt, 6 h

R

H

O

O

OMe + R

H

OMe SF5

SF5 (E)-

(Z)-

Yield (%) alkene

(E)/(Z)

90 : 10

R

Yield (%) aldol

Syn/anti

C6H5

71

98 : 2

79

—

2‐HO–C6H4

68

93 : 7

a)

3,5‐Cl2C6H3

79

Only syn

68

96 : 4

4‐CH3OC6H4

48

65 : 35

93

97 : 3

4‐NO2C6H4

80

Only syn

50

—

2‐Furyl

52

Only syn

54

94 : 6

i‐Bu

82

94 : 6

—

—

a) Product cyclized, see Scheme 19.40.

O O F5S

OMe

1 equiv

+

H OH 1.2 equiv

TiCl4 (2.2 equiv) Et3N (3.0 equiv) CH2Cl2 0 °C to rt, 2 h

SF5 O

O

85%

Scheme 19.40  TiCl4‐mediated aldol condensations of ethyl SF5‐acetate with salicylaldehyde and subsequent cyclization.

19.2.5.2  Difluoro‐pentafluorosulfanyl Acetic Acid (SF5CF2CO2H) Derivatives

Another group of SF5‐containing C2‐building blocks is based on substituted 1,1,2‐trifluoroethylenes. Thus, the radical addition of SF5X (X = Br, Cl) led to the corresponding hexasubstituted ethanes, which on reaction with sulfuric acid  under different conditions and subsequent hydrolysis delivered difluoro‐­ pentafluorosulfanyl acetic acid (SF5CF2CO2H) in fair or good yield. This acid was converted into the acid chloride in excellent yield by treatment with phosphorus pentachloride (PCl5). The latter compound has been used to prepare a variety of simple derivatives such as different alkyl or aryl esters and amides or the phenyl ketone by reaction with phenylmagnesium bromide. From the primary amide, the SF5‐acetonitrile was accessible by dehydration and SF5CF2I was prepared by Hundsdiecker reaction of the acid with AgNO3 and iodine (Scheme 19.41) [79].

597

Y

Y H2SO4 SF5Cl/(BzO)2 F F 95–115 °C, 12 h F5S X 110 °C F F F Y = OPh X = Cl 73% Y = OCH2CF3 X = Cl 57% X = Br 89% Y = Cl F

O F5S F

F 83% 45% 82%

1. AgNO3 OH

2. I2

F5SCF2I

PCl5

F5S

C

F F 75%

N

P2O5 (R = H)

O F5S

RNH2 Et3N

O F5S

ROH, NaH

Cl Et O, 25 °C, 12 h NHR CH Cl 2 2 2 F F F F 15 examples 94% R=H 73% PhMgBr THF, –95 °C R = alkyl 63–89% R = aryl 56–93% O F5S Ph F F 63%

O F5S

OR F F R = Et 73% R = C11H23 70% R = c-C6H11 71% R = Ph 96%

Scheme 19.41  Synthesis and applications of difluoro‐pentafluorosulfanyl acetic acid (SF5CF2CO2H).

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

Furthermore, the acid chloride SF5CF2C(O)Cl was used as an electrophilic C2 building block and was added toward electron‐rich enol ethers. In the presence of pyridine, however, the primary products are not stable and gave the α,β‐­ unsaturated carbonyl compounds in moderate to good yields by dehydrochlo­ rination (Scheme 19.42) [80]. R2

SF5CF2C(O)Cl pyridine

OR3

OR3

F5SCF2

CH2Cl2, rt, 4–5 h

R1

R1

O

O F5SCF2

OEt

R1 R1 = H 65% R1 = Me 47% R1 = Et 63%

R2

O

O

F5SCF2

F5SCF2

O

n = 1 55% n = 2 53%

R2

n

OMe

R2 = Me 79% R2 = C8H17 74%

Scheme 19.42  Reactions of SF5CF2C(O)Cl with enol ethers in the presence of pyridine.

Two of these products were used for further derivatization. Thus, reduction with sodium borohydride and acidic workup provided the corresponding aldols, which were transformed to α,β‐unsaturated ketones either via the mesylate (for R = Me, pathway A) or directly with P2O5 in methylene chloride (for R = C8H17, pathway B) (Scheme 19.43) [80]. O F5SCF2

R

OH R

NaBH4 OMe MeOH

OMe

Acetone

F5SCF2

F5SCF2

R

R = Me 91% R = C8H17 71%

O

A: MsCl/Et3N, CH2Cl2 or B: P2O5, CH2Cl2

F5SCF2

OH O

2 M HCl

R

R = Me 41% R = C8H17 72%

Scheme 19.43  Synthesis of γ‐SF5CF2‐α,β‐unsaturated ketones.

19.2.5.3  2‐Pentafluorosulfanyl‐tetrafluoroethyl Derivatives (SF5CF2CF2X)

Another group of perfluorinated SF5–C2 building blocks, namely, SF5CF2CF2X (X = I, Br), has been prepared from tetrafluoro ethylene. Since SF5I is unknown, the iodo derivative has been synthesized from 1,2‐diiodo‐tetrafluoroethene, tetrafluoroethylene, and the highly toxic S2F10 in 49% yield (Scheme 19.44) [21], while the bromo compound is available in low yield as a side product of polymeri­ zation of tetrafluoroethylene in the presence of SF5Br (see Section 19.1.2.1) [30]. Photochemical additions of SF5CF2CF2I (pentafluoro(1,1,2,2‐tetrafluoro‐2‐ iodoethyl)‐λ6‐sulfane) toward ethylene and fluorinated ethylenes provided the target products in low to very good yields depending on the used alkene.

599

600

19  Pentafluorosulfanylation of Aliphatic Substrates

ICF2CF2I + F2CCF2 + S2F10

150° C

SF5CF2CF2I + SF5(CF2)4I

Shaking, 4 h

49%

Minor product

Scheme 19.44  Synthesis of γ‐SF5CF2CF2I.

Acetylene gave mainly the trans‐product in good yield (Scheme 19.45) [30]. The product with tetrafluoroethylene (SF5(CF2)4I) can be used for similar reactions with ethylene and for stepwise elongation to form SF5(CF2)nI compounds (not shown) [81]. X2 X2

X1 X2

SF5CF2CF2I h𝜈, Hg, rt 7–42 d SF5CF2CF2I h𝜈, Hg, rt 15 d

X1

CF2CF2SF5 X2

X2

I

X1 = X2 = H 89% X1 = H, X2 = F 19% X1 = X2 = F 34%

X2

F5SCF2CF2

I

74% (d.r. 86 : 14)

Scheme 19.45  Addition reactions of SF5CF2CF2I toward substituted ethylenes and acetylene.

The corresponding SF5CF2CF2Br was used in Et3B‐mediated reactions with a  variety of electronically different substituted alkenes. The electrophilic SF5CF2CF2˙ radical formed volatile products. With ethyl vinyl ether, a 4 : 1 mix­ ture of the aldehyde and its diethylacetal was found. After treatment of the vola­ tile products with 2,4‐dinitrophenyl hydrazine, the formed hydrazone was isolated in 47% yield. Similarly, 2‐methoxy propene gave 2‐SF5CF2CF2‐acetone. The crude product was transformed to the hydrazone (50% yield). Under the same conditions, the primary addition products formed from 2,3‐dihydro­ furan and 3,4‐dihydro‐2H‐pyran are not stable and gave the unsaturated 3‐ SF5CF2CF2‐substituted cyclic ethers (Scheme 19.46) [82]. SF5CF2CF2Br Et3B (0.3–1.0 equiv)

R OEt

O n

Heptane, rt, 4–5 h

SF5CF2CF2Br Et3B (0.3–1.0 equiv) heptane, rt, 4–5 h

R

OEt

F5SCF2CF2

+

O 4:1 R=H 47% (hydrazone) R = Me 50% (hydrazone)

F5SCF2CF2

O n

F5SCF2CF2

n = 1, 56% (isolated as isopropyl acetal) n = 2, 61%

Scheme 19.46  Addition reactions of SF5CF2CF2Br toward enol ethers.

OEt

19.2  Application of β‐Haloalkyl‐perfluorosulfanyl Compounds

Surprisingly, SF5CF2CF2Br did not react with ordinary alkenes such as dec‐1‐ ene, cyclohexene, cycloheptene, and norbornene. Also diallylether, vinyl ace­ tate, and allyl acetate did not react. In contrast, the strained dienes norbornadiene and cycloocta‐1,5‐diene gave addition products; however after transannular ­participation of the second double bond, diastereomeric nortricyclene deriva­ tives or 2,6‐disubstituted bicycle[3.3.0]octane compounds were isolated (Scheme 19.47) [82]. SF5CF2CF2Br Et3B (1.0 equiv) Heptane, rt, 4–5 h SF5CF2CF2Br Et3B (1.0 equiv)

CF2CF2SF5 + Br Br Br

CF2CF2SF5

70% (d.r. 6 : 5) H

Heptane, rt, 4–5 h H CF CF SF 2 2 5 41% (d.r. 14 : 1)

Scheme 19.47  Addition reactions of SF5CF2CF2Br toward strained cycloalkadienes.

Surprisingly, the SF5CF2CF2˙ radical did also react with electron deficient α,β‐ unsaturated ketones in nucleophilic conjugate additions showing the ambient character of this radical. Although the yields determined by 19F NMR spectros­ copy with an internal standard were good, the isolated yields were comparatively low. In all of these reactions, SF5CF2CF2H was a side product (2–14%) (Scheme 19.48). This potential building block was formed in 63% yield (19F NMR) when SF5CF2CF2Br was reacted with 1 equiv of Et3B in heptane at room tempera­ ture [82]. SF5CF2CF2Br Et3B (1.6 equiv)

O

O + SF5CF2CF2H

CH2Cl2, rt, 4–5 h

CF2CF2SF5

1.6 equiv O

n

n = 1 71%* (22%**) n = 2 68%* (15%**) n = 3 80%* (34%**)

CF2CF2SF5 19F

NMR spectroscopy * By ** Isolated yield

O

(2–14%*)

O Me

CF2CF2SF5 42%** (d.r. 7 : 1)

CF2CF2SF5 38%*

Scheme 19.48  Conjugate addition reactions of SF5CF2CF2Br toward α,β‐unsaturated ketones.

601

602

19  Pentafluorosulfanylation of Aliphatic Substrates

19.3 ­Synthesis and Derivatization of Alkenyl‐SF5 Compounds 19.3.1  Addition of SF5‐Halogenides Across Triple Bonds and Hydrogen Halogenide Elimination to Form SF5‐Acetylenes Similar to the addition reactions across double bonds, SF5X do also add to tri­ ple bonds either thermally, photochemically, or Et3B mediated. Thus, the ther­ mal reactions of acetylene with SF5X led to the target adducts in low or good yield, respectively. The stereochemistry of products was not given. In terms of further application of these products, dehydrohalogenation reactions are of great interest. While the dehydrochlorination was very low yielding, the dehy­ drobromination gave 49% of the SF5‐acetylene (Scheme  19.49) [83, 84]. Similarly, the thermal addition of SF5Cl toward propyne gave the addition product in 23% yield. Subsequent HCl elimination produced the SF5‐propyne in 85% yield (not shown) [26]. SF5Cl 160–175 °C, 5 h

HCCH

or SF5Br, 57 °C, 4 d

XHCCHSF5 X = Cl 35% X = Br 80%

KOH (X = Br) Petroleum ether 90–120 °C, 3 h

SF5 49%

Scheme 19.49  Addition reactions of SF5X toward acetylene and dehydrobromination of the product.

The Et3B‐mediated addition of SF5Cl toward monosubstituted acetylenes gave high yields in case of alkyl derivatives and lower yields with arylacetylenes. Also internal acetylenes such as oct‐4‐yne were used successfully. Treatment of the addition products with excess lithium hydroxide in DMSO gave the SF5‐­ substituted acetylenes in moderate yields (Scheme  19.50) [22, 23, 85, 86]. The  formed acetylenes were used for different 1,3‐dipolar cycloadditions to form five‐membered heterocycles [86].

R—CCH R = n-Bu R = n-C6H13 R = (CH2)2Ph R = Ph R = p-tolyl R = p-anisyl

SF5Cl Et3B (10 mol%) Hexane (1M) –30 °C to rt

R SF5

Cl H 90% 94% — 49% 50% 68%

LiOH (5 equiv) DMSO, rt, 2 h

SF5

R 67% — 43% 93% 88% 85%

Scheme 19.50  Et3B‐mediated addition of SF5Cl toward acetylenes and dehydrochlorination of the products to SF5‐acetylenes.

19.3  Synthesis and Derivatization of Alkenyl‐SF5 Compounds

This strategy was also used to prepare liquid crystalline SF5‐substituted acety­ lenes according to the two‐step protocol depicted in Scheme 19.51 [39].

RCCH

SF5Cl Et3B (10 mol%) CH2Cl2 –30 °C to –20 °C 4–6 h

Cl R

SF5

R = n-Pr R′ = n-Pr R′ = n-Pent

R = R′

H

LiOH (5 equiv) DMSO, 50 °C, 12 h

SF5

R

92%

65%

83% 86%

70% 72%

Scheme 19.51  Et3B‐mediated addition of SF5Cl toward liquid crystalline acetylenes and dehydrochlorination of the products to SF5‐acetylenes.

Corresponding reactions of electronically different types of substituted alkynes are depicted in Scheme 19.52. While tri‐isopropylsilyl acetylene gave 80% of the addition product after 3 hours at −35 °C [87], the reaction with propyne required 12 hours at room temperature to yield 30% of the product, and trifluoromethyl acetylene and SF5‐acetylene gave 58% [88] or 75% [89], respectively, of the adducts after quite different reaction times. Ethyl propionate yielded 70% of a 95 : 5 mixture of the stereoisomeric α‐bromo‐β‐SF5‐acrylates after two days at 40–65 °C [52]. Treatment of the products with strong bases provided the corre­ sponding SF5‐substituted acetylenes by HBr elimination (Scheme 19.52).

RCCH R = Si(i-Pr)3 R = Me R = CF3 R = SF5 R = CO2Et

SF5Br Conditions CFCl3, – 35 °C, 3 h Neat, rt, 12 h Neat, 100 °C, 4 d Neat, 105 °C, 3 h CFCl3, 40–65 °C, 2 d

Br R

SF5

80% 30% 58% (~1 : 1) 75% (m.d.) 70% (95 : 5)

KOH rt

R

SF5

Yield not provided Yield not provided 64%

Scheme 19.52  Addition reactions of SF5Br toward electronically different acetylenes and HBr elimination from the products.

Diacetylene gave an 1  :  1 adduct in 50% yield when reacted with 1 equiv of SF5Br at −78 °C, while the 2 : 1 adduct was formed in 50% yield in the presence of 2 equiv of the reagent at −45 °C. Treatment of the products with KOH at 25 °C gave the SF5‐substituted acetylenes in 50% yield each (Scheme 19.53) [90]. Alkynyl ethers do also undergo radical addition of SF5Cl under UV irradiation at low temperature. The products were formed in high yields as single isomers, but the stereochemistry was not determined (Scheme 19.54) [91].

603

604

19  Pentafluorosulfanylation of Aliphatic Substrates

H

SF5Br

HCCCCH

Br SF5

1 equiv, –78 °C, 12 h or 2 equiv, –45 °C, 12 h

or

Br 50%

Br 50% KOH, 25 °C

KOH, 25 °C H

SF5

F5S

SF5

F5S

50%

SF5 50%

Scheme 19.53  Addition reactions of SF5Br toward butadiyne.

R1CCO

R2

R1 = H, R2 = Me R1 = H, R2 = Et R1 = R2 = Me R1 = R2 = Et

SF5

SF5Cl CFCl3, h𝜈, 12 h temperature –78 to 25 °C –78 to 25 °C –20 to 25 °C –20 to 25 °C

R1

OR2

Cl 94% 90% 90% 90%

Scheme 19.54  Photochemical addition of SF5X toward alkynyl ethers.

19.3.2  Diels–Alder Reactions of SF5‐Acetylenes SF5‐Acetylene itself and a couple of substituted derivatives have been used as dienophiles in Diels–Alder reactions. Thus, cyclohexa‐1,4‐dienes were formed by thermal reaction with either butadiene or 2,3‐dimethyl‐butadiene [83] and 1‐SF5‐hexyne gave the norbonadiene derivative on heating with cyclopentadiene to 120 °C for five hours (Scheme 19.55) [92]. Dehydration of SF5‐hexa‐1,4‐diene on a platinum contact gave SF5‐benzene [83]. SF5 SF5

70 – 140 °C

+ R

R

19–48 h R R R = H 78% R = Me 51%

1.2–1.6 equiv

n-Bu

120 °C

SF5 +

SF5

5h 5 equiv

50%

n-Bu

Scheme 19.55  Diels–Alder reactions of SF5‐acetylenes with 1,3‐dienes.

A collection of 1,3‐dipolar cycloadditions of substituted SF5‐acetylenes to form five‐membered heterocycles has been summarized some time ago [24, 25] and is out of the scope of this chapter.

19.4  Synthesis of Aliphatic SF5 Compounds by Oxidation of Aromatic SF5 Compounds

Recently, the yield and the selectivity of SF5Br addition toward trifluoromethyl acetylene (see Scheme  19.52) was improved giving a 1  :  2 mixture of (E)‐ and (Z)‐products in 80% yield. Treatment of the mixture with KOH at 90 °C pro­ vided  65% of the “mixed” acetylene (F3C─C≡C─SF5), which was applied for [4+2]‐cycloaddition of a series of common 1,3‐dienes. The cycloadduct with pyranone was not stable and decarboxylated to the o‐SF5‐substituted 1,1,1‐trif­ luorobenzene (Scheme 19.56) [93].

SF5 54%

CF3

SF5

97%

O

SF5

O

CF3 F3C

CF3 65%

SF5

SF5

SF5 CF3 37%

SF5 CF3

+

98% (1 : 3)

SF5

CF3 98%

CF3

Scheme 19.56  Diels–Alder reactions of F3C─C≡C─SF5 with 1,3‐dienes.

19.4 ­Synthesis of Aliphatic SF5 Compounds by Oxidation of Aromatic SF5 Compounds Earlier in this chapter, it was mentioned that aromatic SF5 compounds became readily available in the past decade. Recently, Beier and coworkers used a collec­ tion of such compounds in oxidation reactions with lead tetraacetate. Under the conditions depicted in Scheme 19.57 corresponding SF5‐substituted 1,3‐dienes were  formed in low to good yield. Corresponding oxidations of p‐SF5‐phenol and p‐SF5‐anisol with 30% hydrogen peroxide in sulfuric acid at room tempera­ ture gave the SF5‐substituted muconolactone as major product and SF5‐maleic acid as minor product (Scheme 19.57). Traces of additional products were also identified [94]. The corresponding m‐SF5‐aromatics, under similar conditions, gave the same products with remarkably lower yields [95].

605

606

19  Pentafluorosulfanylation of Aliphatic Substrates

F5S

F5S

Pb(OAc)4 Y

X X = Y = NH2 X = Y = OH X = NH2, Y = OH X = OH, Y = NH2

Toluene/MeOH rt, 1 h

Z1 = Z2 = CN Z1 = Z2 = CO2Me Z1 = CN, Z2 = CO2Me Z1 = CO2Me, Z2 = CN 30% H2O2/H2SO4 (3 : 1, v/v)

F5S

Z1 Z2

OR

F5S

25 °C, 24 h

R=H R = Me

19% 55% 70% 73%

HO2C

O 55% 42%

O

+

F5S HO2C

CO2H 9% 11%

Scheme 19.57  Oxidation of SF5‐aromatics.

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609

611

20 Extension to SF4CF3 and SF4FG Groups Peer Kirsch 1,2 1

Merck KGaA, Performance Materials – Semiconductor Solutions R&D Nanomaterials, Frankfurter Straße 250, 64293 Darmstadt, Germany 2 University of Freiburg, Institute for Inorganic and Analytical Chemistry and Freiburg Material Research Center (FMF), Albertstraße 21, Freiburg, 79104, Germany

20.1 ­Introduction Hypervalent sulfur fluorides are interesting motifs in organic chemistry for two different reasons: the first one is the strong inductive effect, surpassing that of the trifluoromethyl group, and the second one arises from their octahedral geometry. Sulfur hexafluoride with two fluorines replaced by other substituents can form two isomers: the cis‐isomer with a valence angle at the sulfur of around 90° and the trans‐isomer with the SF4 unit forming a linear (180°) connection between the two non‐fluorine substituents. In organic chemistry there are only two relatively simple elements that allow for a rigid linear connection between two cyclic units: the single bond and the acetylene bridge. Therefore, in particular for functional materials, the SF4 group is a quite useful addition to the architectural toolbox of organic compounds. The first examples of such more complex SF4‐linked compounds are typically perfluorinated ones or small molecules that were not further derivatized or put to use for functional materials. Examples of these works are found in Refs. [1–7]. Focus of this review will be on more complex organic SF4 derivatives that are of interest as synthetic intermediates, for materials science or for medicinal chemistry. Inspired by the synthesis of more complex aromatic SF5 derivatives in the late 1990s [8], the same aromatic disulfide precursors were reacted with electrophilic O–F fluorination reagents CF3OF [9, 10] and SF5OF [11], furnishing the corresponding SF4‐linked compounds as mixtures of the cis‐ and trans‐isomers. These compounds were intended for use as polar head groups of liquid crystals (Scheme 20.1). Disubstituted SF6 derivatives have also been subject of various theoretical investigations with focus on quantum chemical geometry prediction and NMR spectroscopy [12–15]. Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

612

20  Extension to SF4CF3 and SF4FG Groups S Br

Br

S

1

SF5OF F F

F F Br

S F

Br

S OSF5

F OSF5 cis-2 (16%)

F F trans-2 (84%)

Scheme 20.1  Reaction of aromatic disulfides (1) with electrophilic O–F reagents provides perfluoroether‐like functions (2) with potential applications for liquid crystals.

20.2 ­Synthesis of RSF4CF3 Derivatives λ6‐Trifluoromethyltetrafluorosulfanyl organic compounds are formally derivatives of SF5CF3 [16], with CF3SF4CF3 [17–19] as their most basic example. The SF4CF3 group can be considered a sulfur analogue of pentafluoroethyl with a strongly enhanced inductive (−I) effect (“super‐pentafluoroethyl” with σp = +0.68) [19]. At the same time it is one of the most lipophilic functions known to organic chemistry (πp = +2.13), rendering its derivatives some of the premier examples of “polar hydrophobicity” [20]. Their aromatic derivatives are readily prepared by direct fluorination of the corresponding trifluoromethylthioarenes (Scheme 20.2). The fluorination furnishes the cis–trans mixture with predominantly the thermodynamically less preferred cis‐isomer, but this one can be isomerized to the trans‐isomer using AlCl3.

NO2

SCF3

10% F2/N2 CH3CN, 0 °C 50%

3 H2N

Cat. Raney Ni H2, THF

SF4CF3

87%

trans-5 52%

(1) 47% HBr, NaNO2, 0–5 °C (2) CuBr, 85 °C C3H7

Br

SF4CF3 trans-6

F F NO2

S +

NO2

F

F CF3 F F S

48%

AlCl3(0.8 equiv) CH2Cl2 –10 °C, 30 min

CF3

F F cis/trans-4 (85 : 15) 7 B(OH)2

Cat. Pd(PPh3)4, THF Borate buffer pH 9 85 °C

F F C3H7

S 8, 14%

CF3

F F

Scheme 20.2  Synthesis of liquid crystal 8 bearing a trans‐SF4CF3 function. The liquid crystal 8 has the mesophase sequence: crystalline – 197 °C – nematic – 209.7 °C – isotropic.

The trans‐SF4CF3 group was originally explored as a potentially “enhanced” SF5 function with the axial fluorine replaced by the more electronegative CF3 group. Although SF4CF3 shows the expected strong inductive effect, its overall polarity – as expressed by the dipole moment of its arene derivatives – was found

20.2  Synthesis of RSF4CF3 Derivatives

to be lower than that of the SF5 group. Reason for this unexpected behavior is the sterical “softness” of hypervalent sulfur fluorides: the equatorial fluorine atoms can accommodate even mild steric pressure by easy deformation of the corresponding C–S–F angles [21]. Calculations for the SF5 group indicate that only c. 1 kcal/mol – much less than typical crystal packing effects – are required to deform the equatorial C–S–F angle by c. 1°. This results in quite large increase of the overall dipole moment of around 0.3 D (Figure 20.1). Aliphatic trans‐SF4CF3 derivatives are available by the triethylboron‐promoted radical addition of CF3SF4Cl to olefins or alkynes (Scheme 20.3) [22]. For its aromatic as well as aliphatic derivatives, the SF4CF3 group is highly stable toward a variety of reagents, such as bases, acids, reductants, and oxidants, and conditions like elevated temperatures up to at least 125 °C. More complex aliphatic SF4CF3 derivatives are available by standard organic conversions as demonstrated in the synthesis of carboxylic acid 26 via an Ireland–Claisen rearrangement (Scheme 20.4) [22]. The strongly electron‐withdrawing character of the SF4CF3 group compared to SF5 and CF3 is reflected in the 13C NMR chemical shifts of its derivatives (Table 20.1) [22]. The polar hydrophobic trifluoromethyl‐λ6‐tetrafluorosulfanyl (CF3SF4) group was regioselectively introduced onto methyl (S)‐N‐(tert‐butoxycarbonyl)‐2‐aminopent‐4‐enoate 27 to afford 28 and then the corresponding amino acid derivative 29 by dehydrohalogenation (Scheme 20.5) [23]. Next, 29 was incorporated at the first and fifth positions of a heptapeptide with anticipation of an effective

Car

S

Fax

α Feq 8.0

25.0

7.0 Relative energy Dipole moment

15.0

6.0 5.0 4.0

10.0

µ (D)

Erel (kcal/mol)

20.0

3.0 2.0

5.0

1.0 0.0

0.0

100 99 98 97 96 95 94 93 92 91 90 89 88 87 86 85

α (°)

Figure 20.1  Deformation of SF6 analogues by steric pressure. The calculations were done with Gaussian03 on the B3LYP/6‐31G(d) level of theory.

613

614

20  Extension to SF4CF3 and SF4FG Groups

CCl3SCl

KF, sulfolane 6h

9

KF, CH3CN, Br2, Cl2, –10 °C, 6 h trans-CF SF Cl + cis-CF SF Cl 3 4 3 4

CF3SCl + (CF3S)2 10

80%

11

trans-12

26%

12, Et3B, pentane 0 °C, 15 min

SF4CF3

44%

13

14

0 °C, 15 min

17a O

SF4CF3

Pentane/EtOAc 0 °C, 15 min

SF4CF3

O

O

12, Et3B OH

18

100%

SF4CF3 16 Cl OAc

OAc O

Cl

NaCO3, H2O 24 °C, 1 h

12, Et3B, pentane 15

cis-12

OH

+

SF4CF3

Cl 19 (12%)

OH H 20 (39%)

Scheme 20.3  Synthesis of aliphatic and olefinic SF4CF3 derivatives via radical addition of CF3SF4Cl to alkenes and alkynes. 12, Et3B, pentane 0°C, 15 min AcO 21

44% H3NSO3, NaClO3 THF/H2O 24 °C, 15 min

MeOH 24 °C, 15 h

Cl AcO

SF4CF3

OMe MeO

22

SF4CF3 23

O SF4CF3 24

HO

77% 99%

Allyl alcohol, p-TsOH; reflux, 18 h O SF4CF3

O 25

(Me3Si)2NH, Me3SiOTf CH3CN, 126 °C, 18 h 24%

O SF4CF3

HO 26

Scheme 20.4  Synthesis of carboxylic acid 26 via Ireland–Claisen rearrangement.

control of the secondary structure of this heptapeptide. The structural influence of CF3SF4‐containing amino acid on the heptapeptide was established using NMR methods.

20.3 ­Synthesis of Ar–SF4–Ar Derivatives Two arene moieties linked via an SF4 group are an attractive building block for organic materials such as liquid crystals or organic semiconductors. In particular the trans‐SF4 linker connects the arenes in a linear fashion, but in contrast to the

20.4  Synthesis of Ar–SF4–R Derivatives

Table 20.1  13C NMR chemical shifts of the α‐carbon of F3CSF4‐, SF5‐, and CF3‐substituted acetophenone (17a–c). α-C

X O Compounds

X

13

C chemical shift (ppm)

17a

trans‐SF4CF3

73.2

17b

SF5

71.6

17c

CF3

42.2

BocNH

27

CO2Me CF3SF4Cl, Et3B O2, 0 °C 91%

BocNH

CO2Me Cl

28

LiOH aq EtOH, rt 76%

SF4CF3

BocNH

29

CO2Me

SF4CF3

Scheme 20.5  Synthesis of (S,E)‐N‐(tert‐butoxycarbonyl)‐2‐amino‐6‐trifluoromethyl‐λ6‐ tetrafluorosulfanylpent‐4‐enoate 29.

single bond or the acetylene linker, it electronically separates the system, ­impeding conjugation. For medicinal chemistry it might be considered a bioisostere of the p‐phenylene unit. The first synthesis of a 2 : 1 mixture of the unsubstituted cis‐ and trans‐diphenyl‐ λ6‐tetrafluorosulfanes by Ruppert was achieved by reaction of diphenyl sulfide with diluted fluorine gas (17% F2/He) in CFCl3 at −78 °C [24]. Later on, Jantzen obtained and characterized these compounds from the same starting material more ­conveniently using XeF2 as fluorinating agent [25]. The corresponding dinitro ­derivative trans‐31 was intended as a mesogenic core structure for liquid crystals [26]. It was found to be rather sensitive to reduction, and any attempt to react it further via the diamino derivative resulted in reductive defluorination. Direct fluorination of bis(4‐nitrophenyl)sulfide (30) furnishes an 85 : 15 cis–trans mixture (31), which can be readily rearranged into the thermodynamically preferred trans product using BF3·OEt2 as a mild Lewis acid and fluoride abstractor (Scheme 20.6 and Figure 20.2). A liquid crystal (32) based on a trans‐diphenyl‐λ6‐ tetrafluorosulfane core structure was finally described several years later. It was obtained by direct fluorination of the corresponding thioether [15].

20.4 ­Synthesis of Ar–SF4–R Derivatives The key intermediate of Umemoto’s synthesis of SF5 arenes [27] and its subsequent improvements, ArSF4Cl [28–30], opened a convenient access to more

615

616

20  Extension to SF4CF3 and SF4FG Groups F F O2N O2N

S

10% F2/N2, CH3CN NaF, 5 °C

30

S

F

F cis/trans-31 (85 : 15)

80%

NO2

F F

NO2 O2 N

S

Catalytic isomerization: (1) BF3·OEt2 (0.1 equiv), CH2Cl2, rt, 1 h 87% (2) Me3SiOMe, rt, 10 min

NO2

F F O

F F S

32 O

N

F F

Scheme 20.6  Synthesis and isomerization of 31.The liquid crystal 32 has the mesophase sequence: crystalline – 175 °C – nematic – 179.8 °C – isotropic.

(a)

(b)

Figure 20.2  Crystal structures of cis‐ (a) and trans‐31 (b). The C–S–C valence angle of the cis‐isomer is 97°.

complex SF4‐linked organic compounds. For detailed syntheses of RSF4Cl species, see Chapter 18 by Petr Beier. The reactivity of ArSF4Cl derivatives is similar to that of perfluoroalkyl halides, and it can be added readily to olefins and alkynes [31, 32]. The resulting chemically rather robust products can be further reacted to a variety of new heterocyclic compounds [33–35] with high potential for application in medicinal or agricultural chemistry (Scheme 20.7).

20.5  Conclusions and Perspectives

Cl

BEt3, Et2O 0 °C, 15 min

SF4Cl 33

90%

34

LiOH, DMSO rt, 5 h

F F Cl

S Cl

F F

35

F F Cl

S

98%

F F

36

F F

Br N 37

SF4Cl

38

BEt3, cat. O2 CH2Cl2

Br 39

Br

N3

F F

43

S F F

42

F F Cl F F

Br

Toluene 110°C, 24 h

68%

S 41

N

F F Cl F F

40

Br

91%

S

S F F

N

N N

44

Scheme 20.7  Synthesis of SF4‐linked heterocyclic building blocks of interest for medicinal chemistry.

It was found that the pyridine‐SF4 motif is significantly more stable against hydrolysis to the corresponding sulfone than its unsubstituted phenyl‐SF4 counterpart. A computational analysis indicated that the electron‐withdrawing pyridine results in shortening and thus strengthening the aryl–SF4 bond [33]. A similar observation was also made for 4,4′‐X2‐phenyl‐SF4‐phenyl derivatives: whereas X  =  NO2, CN, CO2Me, and OTf are relatively robust, the electron‐ donating systems with X = OAc quickly decomposes on contact with silica during chromatography [15, 26].

20.5 ­Conclusions and Perspectives Due to recent advances in the synthesis of organic derivatives of hypervalent sulfur fluorides, SF4‐linked compounds have become readily accessible without specialized methodology or equipment and without any potentially hazardous procedures and processes. The real exploration of this chemistry has just begun, but it seems already clear that it will be picked up soon also by chemical industry. The cis‐ and trans‐SF4 bridges are completely new structural building blocks opening the way to unusual geometries for organic chemistry: there is no other way to introduce unstrained 90° valence angles into organic scaffolds except for cis‐SF4. Whereas the SF5 group is already well established as a functional group particularly in medicinal chemistry, SF4CF3 and the SF4 bridge are expected to follow soon as components of the organic chemist’s structural toolbox.

617

618

20  Extension to SF4CF3 and SF4FG Groups

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­  References

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461–471.

28 Pitts, C.R., Bornemann, D., Liebing, P. et al. (2019). Angew. Chem. Int. Ed. 58:

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29 Kanishchev, O.S. and Dolbier, W.R. Jr. (2015). Angew. Chem. Int. Ed. 54:

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10781–10785.

31 Zhong, L., Filatov, A.S., and Welch, J.T. (2014). J. Fluorine Chem. 167: 192–197. 32 Zhong, L., Savoie, P.R., Filatov, A.S., and Welch, J.T. (2014). Angew. Chem. Int.

Ed. 53: 526–529.

33 Das, P., Takada, M., Tokunaga, E. et al. (2018). Org. Chem. Front. 5: 719–724. 34 Das, P., Niina, K., Hiromura, T. et al. (2018). Chem. Sci. 9: 4931–4936. 35 Saidalimu, I., Liang, Y., Niina, K. et al. (2019). Org. Chem. Front. 6: 1157–1161.

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21 Properties and Applications of Sulfur(VI) Fluorides Nicholas D. Ball Pomona College, Department of Chemistry, 645 North College Avenue, Claremont, CA 91711, USA

21.1 ­Introduction Sulfonyl fluorides (RSO2F), fluorosulfates (ROSO2F), and sulfamoyl fluorides (R2NSO2F) are emerging as an important class of molecules with applications from chemical biology to polymers. Unlike other sulfur(VI) halides, the strong S─F bonding in sulfur(VI) fluorides result in unique properties including hydrolytic stability, resistance to reduction, and persistence of the fluorosulfuryl (–SO2F) group in transition‐metal‐catalyzed reactions. Initially used as covalent protein modifiers with applications in proteomics, protease inhibitors, and chemical probes, it was a foundational 2014 paper by Sharpless and coworkers introduced sulfur–fluoride exchange (SuFEx) chemistry where the concept of using S(VI) fluorides as synthetic precursors really took off [1]. From this initial account, the synthetic utility for S(VI) compounds has massively expanded. There are excellent existent reviews on sulfonyl fluorides and fluorosulfates [2–6]; however, the purpose of this chapter is to highlight strategies to synthesize a variety of S(VI) fluorides and provide diverse examples of their application.

21.2 ­Properties and Reactivity of Sulfur(VI) Fluorides Introduced by Sharpless and coworkers in 2014, SuFEx has emerged as a platform for new click chemistry. In contrast to other S(VI) halides, S(VI) fluorides in the presence of nucleophiles react exclusively at the sulfur atom via primarily a nucleophilic addition/elimination mechanism (Scheme 21.1a) [1, 7]. Founded from well‐known bioconjugation chemistry of sulfonyl fluorides as covalent chemical probes, Sharpless proposed that the unique chemoselectivity of S(VI) fluorides could be exploited in synthesis as synthons to sulfonylated compounds. A challenge to this approach is not only on the enhanced stability of the sulfur– fluoride (S─F) bond but also on a decrease in reactivity. For instance, the S─F bond in sulfur(VI) sulfuryl fluoride (SO2F2) is nearly 40 kcal/mol stronger than Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

622

21  Properties and Applications of Sulfur(VI) Fluorides O O S R F

O O S R F Nuc

Nuc O O S R + F

H

O

H

O O S R + F

–F

–

O O S R Nuc

LA LA

O

O R

Activation via H-bonding

(a)

S +

(b)

F

Activation via Lewis acid/base adducts

Scheme 21.1  (a) Generalized SuFEx mechanism. (b) Proposed modes of activation.

the S─Cl bond in sulfuryl chloride (SO2Cl2) [8, 9]. Nevertheless, Sharpless proposed that this challenge could be overcome by polarization of the S─F bond via hydrogen bonding or Lewis acid–base adducts (LA–X). The resulting F–H, F–LA, and sulfonyl oxygen–LA interactions serve to increase the partial positive charge at the sulfur atom (Scheme 21.1b) [10]. Furthermore, the resulting solvation or Lewis/base adduct formation with the fluoride ion stabilizes the anion as a leaving group during elimination, moving the reaction toward the SuFEx product. Additionally, S(VI) fluorides can be activated using coupling agents like  Lewis‐basic 4‐dimethylaminopyridine (DMAP) or 1,8‐diazabicyclo[5.4.0] undec‐7‐ene (DBU) [1, 11]. In all cases, increasing the electrophilicity of the sulfur atom enhances the reactivity of the sulfur(VI) fluoride and thus SuFEx transformation. A study by Mukherjee et al. provides compelling kinetic evidence that enhancing the electrophilicity of the sulfur atom of S(VI) fluorides increases SuFEx [12]. When a series of substituted 4‐substituted phenylsulfonyl fluorides were subjected to N‐acyltyrosine (N‐AcTryOH) in an aqueous buffer, the rate of SuFEx to generate a sulfonic ester is dramatically faster with electron‐withdrawing substituents. For example, the rate of substitution with 4‐nitrophenylsulfonyl fluoride is nearly 11 times faster than phenyl sulfonyl fluoride and nearly 134 times faster than more electron‐donating 4‐methoxyphenylsulfonyl fluoride. The same trend was also observed for hydrolysis where sulfonyl fluorides with electron‐ withdrawing groups were converted to sulfonic acids faster than those with electron‐donating groups. Notably, the rate of SuFEx with highly activated p‐NO2 phenyl sulfonyl fluoride and N‐acyltyrosine proceeds over 4000 times faster than hydrolysis, highlighting the relative stability of S(VI) fluorides compared to other S(VI) halides to hydrolysis (Scheme 21.2). While a systematic comparative study of the reactivity of sulfur (VI) fluorides toward SuFEx (at the sulfur atom) has yet to be conducted [7], one can surmise their comparative relative reactivity through considering resonance stabilization along the S─X bond (X = N, O, or C). Sulfamoyl fluorides are the most‐stabilized S(VI) fluoride due to the increased resonance donation of the nitrogen atom’s lone pairs along the N─S bond vs. the more electronegative oxygen in the S─O bond in fluorosulfates. In contrast, the absence of lone pairs of the carbon atom in sulfonyl fluorides results in drastically lower resonance stability along the

21.2  Properties and Reactivity of Sulfur(VI) Fluorides

R

O O N-AcTyrOH S F Phosphate buffer (100 mM) NaCl (1.0 M) R 5% MeCN pH 7.5, 35 °C Rate constant (tyrosine) M–1h–1

R

O O S OTyrNAc

Rate constant (hydrolysis) M–1h–1

NO2

1738

0.418

H NH2

164

0.044

13

0.004

Scheme 21.2  Rates of SuFEx with aryl sulfonyl fluorides.

C─S bond. As a result, sulfonyl fluorides have the most electrophilic sulfur atom and thus undergo more facile SuFEx in the presence of nucleophiles (Scheme 21.3). This hypothesis is supported in the literature where para‐ and meta‐­ carboxyphenyl fluorosulfates are resistant to hydrolysis at pH 7.5 over 24 hours, whereas the corresponding sulfonyl fluoride readily undergoes hydrolysis under the same reaction conditions [4]. Furthermore, SuFEx chemistry with dialkyl sulfamoyl fluorides require forcing conditions (see Scheme 21.71) [1].

Sulfamoyl fluoride

H N

F S O O

Least reactive

Sulfonyl fluoride

Fluorosulfate


50 examples (56–99%)

OSO2F

OSO2F

OSO2F

N

N

85%a

87%b

O O S F

SO2F2

O

N

OSO2F S

97%b

CO2Me 93%a

Scheme 21.16  Synthesis of heteroaromatic fluorosulfates from N‐ and S‐hydroxyheterocycles. Reaction conditions: aEt3N (1.5 equiv), DCM, rt, 2–24 hours; bDIPEA (1.5–3.0 equiv) in CH3CN, rt, 24 hours.

hours (4–18  hours) for completion. BEMP (2‐tert‐butyl‐imino‐2‐diethylamine‐1,3‐dimethylperhydro‐1,3,2‐diazaphosphorine) is also successful in the synthesis of enol fluorosulfates from the trimethylsilyl‐protected enol ethers [1]. Finally, cyclic ketones can be converted to enol fluorosulfates via first reduction by lithium bis(trimethylsilyl)amide (LiHMDS) followed by fluorosulfation using SO2F2 (Scheme  21.18) [1]. This approach is akin to an earlier report by Hedayatullah et al. who demonstrated the synthesis of aryl fluorosulfates from lithium phenolates and SO2F2 [28].

21.6  Synthesis of Fluorosulfates and Sulfamoyl Fluorides

SO2F2 (g) R–OSiR′3 R = aryl, alkenyl

Base (10 mol%), solvent, rt

OSO2F

OSO2F

FO2SO

99%a

86%a

BEMP OSO2F

OSO2F O

N H

NEt2 P Nt-Bu N

N

O O Ar S O F

OSO2F

O 70%a

S

O O 70%b

Scheme 21.17  Synthesis of aryl and enol‐based fluorosulfates using catalytic base. Reaction conditions: aDBU, CH3CN, rt; bBEMP, CH2Cl, rt. O

(1) LiHMDS, THF, –78 °C

OSO2F 75%

(2) SO2F2, 0 °C, 1 h

Scheme 21.18  Synthesis of enol‐based fluorosulfates from a ketone.

Sulfuryl fluoride is also effective in the synthesis of dialkyl‐substituted sulfamoyl fluorides from the corresponding amines in high yield (Scheme 21.19) [1]. In this system, DMAP is used as a coupling agent, and Et3N as a base. Only dialkyl‐substituted sulfamoyl fluorides can be prepared with this method due to elimination by‐products formed with monosubstituted analogs (Scheme 21.19). In 2019, Qin and coworkers demonstrated N‐fluorosulfurylation of amides using SO2F2 and DBU toward the synthesis of N‐acyl‐substituted sulfamoyl fluorides [32]. Although an excess of base was used (5 equiv of DBU), N‐acyl‐substituted

R1

N

N R2

SO2F2 (g)

H

DMAP (0.5–1.5 equiv) Et3N (2 equiv) CH2Cl2, rt, 6–18 h

SO2F

N3

76%

76%

N Ph Ph

N

SO2F

O O S N F R2 10 examples (65–99%) R1

SO2F

N 65%

N3 N

SO2F

Ph

SO2F O

N

N

SO2F

O

OH 94%

70%

80%

Scheme 21.19  Synthesis of dialkylsulfamoyl fluorides from amines, DMAP, and SO2F2.

633

634

21  Properties and Applications of Sulfur(VI) Fluorides

sulfamoyl fluorides were synthesized in high yield with varying aryl, alkenyl, and alkyl groups on the acyl group (Scheme 21.20). O R

NH2

DMSO, 50 °C, 12 h

(1.0 equiv) O

SO2F R R H 4-Br 4-CF3 4-t-Bu 3-NO2 3-Br 2-Br 2-CH3

O N H

Yields (%) 99 84 87 80 65 76 99 60

O O O S R N F H 36 examples (48–99%)

SO2F2 (excess), DBU (5 equiv)

SO2F

Cl

N H

79% O N H 91%

Cl O

SO2F

O SO2F O

76%

N H 85%

SO2F

68%

O SO2F

N H

O N H

48%

SO2F

H

N H

SO2F

65%

Scheme 21.20  N‐fluorosulfurylation of amides toward N‐acyl‐substituted sulfamoyl fluorides.

While sulfuryl fluoride has been demonstrated effective in the synthesis of both fluorosulfates and sulfamoyl fluorides, there are considerable challenges to its use due to issues with toxicity, commercial availability, synthetic limitations, and operations dealing with a gaseous substrate. Notably, extended exposure of >5 ppm of SO2F2 has been deemed harmful for human health, and recently the gas has been classified as a greenhouse gas [33–35]. This has led to the significant efforts toward the development of new protocols to generate SO2F2 as needed and new fluorosulfurylation reagents. In 2017, De Borggraeve and coworkers first reported a sealed, two‐chamber ex situ formation of SO2F2 [36]. In one chamber SO2F2 is generated by rapid decomposition of 1,1′‐sulfonyldiimidazole (SDI) and KF upon addition of TFA. Upon formation, the SO2F2 gas flows into the second chamber into solution of the phenol, Et3N, and DCM. The higher density of SO2F2 than that of air allows for diffusion into a solution. Fluorosulfurylation of aromatic and heteroaromatic alcohols was achieved in high yield (Scheme 21.21). This method is attractive because it does not require an excess of SO2F2 limiting health and environmental exposure. Although there are drawbacks to this method due to increased reaction time (36 hours vs. 4–12 hours), the method does obviate the need to procure SO2F2 and the need of special equipment to minimize exposure to the gas. Two other commercially available reagents have been developed to affect fluorosulfurylation of alcohols and amines. In 2018, Sharpless, Dong, and coworkers reported a fluorosulfuryl imidazolium salt as a solid surrogate for SO2F2 [37]. The benefits of this reagent is that it is shelf‐stable, and readily synthesized from methyl imidazole, SO2F2, and methyl triflate (MeOTf ). Notably, the reagent

21.6  Synthesis of Fluorosulfates and Sulfamoyl Fluorides Chamber A: SDI (1.5 equiv), KF (4.0 equiv) TFA, rt, 18 h

R–OH R = aryl, heteroaryl

Chamber B: Et3N (2.0 equiv) CH2Cl2, rt, 18 h

O O S N N

O O S RO F 27 examples (85–99%)

SDI

SO2F R

OSO2F

O

OSO2F

O OCH3 Yields (%) R 4-OMe 91 95% 95% 4-NH2 89 4-Cl 87 H3CO2C OSO2F 4-COOEt 95 4-SO2CH3 94 4-NO2 85 N 3-I 93 FO2SO 2-OMe 92 88%

OSO2F CO2CH3

S

94% OH H H

H

96%

Scheme 21.21  Two‐chamber synthesis of fluorosulfates via in situ formation of SO2F2.

can be synthesized on a nearly 200 g scale (Scheme 21.22a). A wide array of aryl fluorosulfates were generated using the salt, Et3N as a base, in CH3CN in good yield (Scheme 21.22b). Additionally, the same method was used to synthesize dialkylsulfamoyl fluorides in good to excellent yields (Scheme 21.23). While useful for the synthesis of fluorosulfates, the application of SO2F2 to synthesize NH‐sulfamoyl fluorides was not successful. Remarkably, Sharpless’ fluorosulfuryl imidazolium salt can be used to convert alkyl and aryl primary amine into corresponding mono‐­ substituted alkyl and aryl NH‐sulfamoyl fluorides in high yield (Scheme 21.23). Notably, isolation of these products required very careful control over temperature and pH. There are challenges to using the reagent: (i) the need for SO2F2 gas to make the fluorosulfuryl imidazolium salt, and (ii) the reagent being hygroscopic and requiring storage at low temperature. In 2018, a complementary reagent AISF ([4‐(acetylamino)phenyl]‐imidodisulfuryl difluoride) was developed by am Ende and coworkers at Pfizer as another bench‐stable fluorosulfurylation reagent to SO2F2 [38]. AISF was readily prepared from N‐acetylaniline and LiN(SO2F)2 in dichloroethane (DCE) up to a 400 g scale (Scheme 21.24a). In contrast to Sharpless’ fluorosulfuryl imidazolium salt, the synthesis of AISF does not require SO2F2 gas and it can be stored at room temperature. AISF was successfully applied toward the synthesis of a broad array of aryl and heteroaryl fluorosulfates and dialkylsulfamoyl fluorides in good to excellent yield (Scheme 21.24b). Due to the stability of AISF in water, AISF can be applied to selectively add the SO2F moiety to biological molecules. AISF in the presence of KF was used to selectively install a SO2F group on tyrosine residue on a peptidic macrocycle desmopressin. This fluorosulfurylation was proposed to occur in situ by generation of SO2F2 by the reaction of AISF and fluoride ion. Notably at pH 10, KF was not required due to the presence of deprotonated

635

636

21  Properties and Applications of Sulfur(VI) Fluorides (a) N

NH

+ SO2F2

Na2CO3 (2.5 equiv) CH3CN3, rt, overnight

(b) N

+

Ar–OH

O O O O MeOTf (1.0 equiv) S S N N F F N – CH2Cl2, 0 °C rt, TfO 1h 91%

N

O O S F

N

–

TfO

(1.0 equiv)

(55–99%) O

O O

H H FO2SO

Ar

rt, 1 h

(1.2 equiv)

OH

O O S O F 25 examples

Et3N (1.5 equiv), CH3CN

H

O

OSO2F

88%a

82%

81% OSO2F

OSO2F FO2SO

82%b

OSO2F

OSO2F

N OSO2F

N 85%b

FO2SO

57%

OSO2F

Scheme 21.22  Synthesis of methyl imidazolium salt‐based fluorosulfurylation reagent and synthesis of aryl fluorosulfates. Reaction conditions: a5 equiv of fluorosulfurylation reagent and 6 equiv of Et3N were used; b0.5 equiv of alcohol was used.

tyrosine at that basic pH. Unlike the fluorosulfuryl imidazolium salt, AISF was not successful in synthesizing NH‐sulfamoyl fluorides, highlighting complementarity between the reagents. The remaining sections (21.7–21.12) will highlight applications of S(VI) fluorides in organic chemistry. Notably, these sections will also highlight chemistry from each of the major S(VI) classes: sulfonyl fluorides, fluorosulfates, sulfamoyl fluorides, and iminosulfur dioxyfluorides.

21.7 ­Application of Sulfonyl Fluorides: Sulfur–Fluoride Exchange Chemistry A unique characteristic of sulfonyl fluorides (RSO2F) is their chemoselective reactivity at the sulfur center. Furthermore, their thermal and hydrolytic stability  enables the generation of bench‐stable libraries, which in the presence of nucleophiles can readily be converted to a diverse variety of S(VI) compounds including sulfones, sulfamides, and sulfonic esters. Capitalizing on this unique reactivity, methods have been developed to use sulfonyl fluorides as synthetic precursors to other S(VI) compounds via a new “click” reaction: SuFEx. The following will highlight key developments in SuFEx with sulfonyl fluorides to make

R1

H N 2 R (aliphatic amines: 0.3–1.4 M in CH3CN)

+

–

N

SO2F

85%

(1.0 to 1.1. equiv)

N N

OH

72%a

72%b

SO2F

FO2S SO2F

SO2F

FO2S

N

SO2F

53%d

SO2F N SO2F 81%d

SO2F

N 81%b

76%

HO 91%c

R2 40 examples (47–99%)

N N

O

H N

CO2Et

O O S F

N

SO2F

SO2F

92%

HN

R1

Solvent 0 °C to rt, 0.2–4 h

Ph

N

S O O

N

TfO

(anilines: 0.1 M in CH2Cl2)

H3C

O O S F

N

O

SO2F N SO2F 96%d

Scheme 21.23  Synthesis of dialkyl and NH‐sulfamoyl fluorides using methyl imidazolium salt‐based fluorosulfurylation reagent. Reaction conditions: aThe corresponding amine hydrochloride was used with Et3N to generate the free base; b2 equiv of fluorosulfurylation reagent was used and CH2Cl2 was the solvent; cEtOAc was the solvent; d2.5 equiv of fluorosulfurylation reagent and 0.5 equiv of Et3N was used, 0 °C to rt,1–12 h.

638

21  Properties and Applications of Sulfur(VI) Fluorides

1,2-Dichloroethane, reflux, 40 min

AcHN (b) Ar

SO2F N SO2F

LiN(SO2F)2, PhI(OAc)2

(a)

OH

R1

or

2

R

AISF (1.2 equiv), DBU (2.2 equiv)

NH

Ar

THF, rt, 10 min

R1, R2 = alkyl (1.0 equiv)

H3C

H2N

O

N

or

R1

O O S N F R2

5 examples (77–99%) N OSO2F

Cl

97%

95%

O

O O S O F

OSO2F

OSO2F

97%

AISF

16 examples (67–99%)

Fluorosulfates OSO2F NC

AcHN

OSO2F

92% OSO2F

O OH

O HO

OH OH

FO2SO

OSO2F HO2C

57%a

NSO2F

NSO2F N

HO Ph Ph

O 96%

85%b

94%

Sulfamoyl Fluorides

OSO2F

93%

N

H3C Cl

NSO2F

H3CO 77%

OCH3

NSO2F

76%

Scheme 21.24  Synthesis of fluorosulfurylation reagent AISF and synthesis of aryl fluorosulfates and dialkylsulfamoyl fluorides using AISF and DBU. Alternative conditions: (a) 1.2 equiv of AISF, 2.2 equiv Cs2CO3, and 0.2 M DMSO and (b) 3.2 equiv of AISF and 4.2 equiv of DBU were used.

S(VI) compounds. Notably, these reactions require the use of a non‐nucleophilic base, Lewis acid, or silylating reagent. This section will focus on SuFEx methods that results in the formation of sulfones, sulfonamides, and sulfonic esters, from sulfonyl fluorides. 21.7.1 Sulfones One of the most compelling examples to give credence to SuFEx as a click reaction was a 1982 report from Reißig and coworkers that demonstrated alkyl silyl enolates in the presence of a catalytic fluoride source could serve as effective nucleophiles with aryl sulfonyl fluorides to yield sulfones (Scheme 21.25) [39].

21.7  Application of Sulfonyl Fluorides: Sulfur–Fluoride Exchange Chemistry

The formation of a Si─F bond is key to achieve an anionic pentacoordinate silicon intermediate, which releases the free enolate for nucleophilic addition to the sulfonyl fluoride. The formation of a strong Si─F bond and the return of silicon to the preferred neutral tetracoordinate state are likely driving the reaction to product (Scheme 21.25). While several fluoride sources successfully facilitated the SuFEx transformation, BnMe3F allowed for better isolated yields of sulfone. R1

OSiMe

R2

R3

+

O O S F R4

BnMe3NF (10 mol%) rt, 16 h

(1 equiv)

R1

OSO2R4

R2

R3

17 examples (62–90%)

Scheme 21.25  Synthesis of sulfone via a SuFEx reaction of silyl enol ethers and sulfonyl fluorides.

Sulfones can also be accessed via electrophilic aromatic substitution. In 1984, Hyatt and White reported that alkyl and vinyl sulfonyl fluorides in the presence of arenes and aluminum chloride (AlCl3) resulted in asymmetric sulfones in good to excellent yield (Scheme 21.26) [40]. The reaction was conducted in either excess arene or 1,2‐dichloroethane as the solvent. As expected, monoalkyl‐­ substituted phenyl derivatives did result in a 60 : 40 ratio of para:ortho ­substituted products, suggesting challenges with regioselectivity.

O O + S F R

R

O O S

91%

AlCl3 (1.5 equiv)

O O S R

Arene as solvent or 1,2-DCE R 1–3 h 10 examples (59–91%) O O S Et

81%

O O S

70%

O O S

79%

Scheme 21.26  Formation of asymmetric sulfones via AlCl3‐mediated electrophilic aromatic substitution of arenes with sulfonyl fluorides.

In 1992, Frye and coworkers reported the synthesis of sulfones from aryl sulfonyl fluorides and organometallic reagents [41]. Grignard, organolithium, and diorganocuprate reagents were demonstrated to be effective in synthesizing a series of alkylaryl and diaryl sulfones (Scheme 21.27a). Because the reaction was conducted in an excess of organometallic reagent (3 equiv) in relation to sulfonyl fluoride, arylalkyl sulfones could undergo further deprotonation and subsequent addition of sulfonyl fluoride to give disulfones (Scheme  21.27b). Interestingly, keeping the reaction at −78 °C limited significant disulfone formation (0–18%).

639

640

21  Properties and Applications of Sulfur(VI) Fluorides O O S F

O O S R

RM (3 equiv) –78 or 0 °C , 0.5–1.5 h

34 examples (12–99%) O O S

(a)

O O S

H3C

O O S

H3C

H3C

RM = CH3Li: 94% CH3MgCl: 87% (CH3)2CuLi: 71%

nBuLi: 92% nBuMgCl: 59% nBu2CuLi: 99%

Possible disulfone formation (b)

R–M

O O S CH2R Ar

–RH

O O S Ar CHR –

PhLi: 76% PhMgBr: 95% (Ph)2CuLi: 84%

O O S F Ar

M

OO O O S S Ar C Ar R Disulfone

Scheme 21.27  Sulfone formation from aryl sulfonyl fluorides and organometallic reagents.

In 1990, drawing from the concept that Group 14 organometallic reagents can be used as source of a carbon nucleophile, Yagupolski and coworkers demonstrated that trimethyl(trifluoromethyl)silanes and stannanes in the presence of catalytic tris(dimethylamino)sulfonium difluorotrimethyl siliconate (TASF) (a  fluoride source) could be used to synthesize trifluoromethylsulfones from arylsulfonyl fluorides. Both Ruppert–Prakash reagent (Me3SiCF3) and Me3SnCF3 were successful in synthesizing trifluoromethylsulfones in good to excellent yield (Scheme 21.28) [42]. O O S F

Me3MCF3 (2 equiv) TASF (10 mol%) Petroleum ether 20 °C , 0.5–1.5 h

R

O O S CF3

O O S CF3

R O O S CF3

O2N

O O S CF3

Cl

H3C Si: 99% Sn: 96%

O O S CF3

Si: 99% Sn: 96%

Si: 96% Sn: 95%

Si: 73% Sn: 70%

Scheme 21.28  Synthesis of trifluoromethylsulfones from aryl sulfonyl fluorides and Me3MCF3 (M = Si or Sn) with TASF.

In 2015, Shibata and coworkers followed up with a catalyzed formation of trifluoromethylsulfones using fluoroform (HCF3), P4‐tBu as an organocatalyst,

21.7  Application of Sulfonyl Fluorides: Sulfur–Fluoride Exchange Chemistry

and aryl sulfonyl fluorides [43]. The addition of superbase tris(trimethylsilyl) amine – NSiMe3 – allowed for conversion of aryl sulfonyl fluorides to trifluoromethylsulfones in good yield (Scheme  21.29). An advantage of this method is that fluoroform is a side product in the formation of Teflon and is cheaper alternative to Ruppert–Prakash reagent. It should be noted that while fluoroform is cheap, it is a known greenhouse gas [44]. tBu N HCF3 (excess) O O S Ar F

P4-tBu (30 mol%) N(SiCH3)3 (1.5 equiv)

O O S CF3

DMF, 0 °C, 5–17 h

P N P N P N

O O S Ar CF3

P

10 examples (50–98%) O O S CF3

O O S CF3 CI

Ph 84% O O S CF3

P4-tBu

54% Br O O S CF3

O O S CF3 Br

57% O O S CF3

79% O O S CF3

I 79%

62%

78%

60%

Scheme 21.29  Organocatalyzed formation of trifluoromethylsulfones from aryl sulfonyl fluorides in the presence of superbase.

21.7.2  Sulfonic Esters and Polysulfonates In 2008, Gembus et al. reported an organocatalyzed SuFEx reaction to synthesize tosylates from p‐toluenesulfonyl fluorides using silyl ethers and substoichiometric amount of DBU [11]. Alkyl and benzyl trimethylsilyl (TMS)‐silyl ethers were readily converted to tosylates in high yield (Scheme  21.30). Triethylsilyl (TES) and tert-butyldimethylsilyl (TBDMS) ethers were successfully converted to tosylates. Notably in competition studies, the SuFEx reaction is selective for TMS ethers vs. TES and TBDMS ethers (Scheme 21.30a). Tandem SuFEx/substitution or SuFEx/elimination transformations were also described. A pyridylsilyl ether underwent the intramolecular SN2 reaction upon formation of the tosylate to form a pyridinium salt (Scheme 21.30b). In the presence of 1 equiv of DBU, a tandem SuFEx reaction occurred upon formation of a tosylate, followed by a base‐promoted elimination via deprotonation of acidic protons alpha to the tosylate group (Scheme 21.30b). Wu, Sharpless, and coworkers expanded on Gembus’s work, employing catalytic DBU (10 mol%) in the synthesis of aryl alkenylsulfonates using aryl TBS ethers and β‐arylethenesulfonyl fluorides. Aryl alkenylsulfonates are generated in very high yield (Scheme 21.31) [45].

641

642

21  Properties and Applications of Sulfur(VI) Fluorides O O S F

+

ROSiR′3

O O S OR

DBU (20 mol%)

(1 equiv)

MeCN, rt 0.5–48 h

TsF

12 examples (85–97%)

(a) OTs

OTs

Ph

OTs NHBoc TsO

From OTMS: 96% From OTES: 94% From OTBDMS: 0% (95% at reflux)

97%

OTs

85%

95%

OTs OTs

OH 96%

95%

90%

Tandem SuFEx/substitution TsF (1 equiv) DBU (1 equiv)

(b) N

OTMS

MeCN, rt, 48 h

N TsO

90% –

Tandem SuFEx/elimination TsF (1 equiv) DBU (1 equiv)

OTMS

90%

MeCN, rt, 48 h

Scheme 21.30  DBU‐catalyzed tosylation of aryl and alkyl silyl ethers with p‐toleunesulfonyl fluoride. DBU (10 mol%) 1

Ar

SO2F (1.0 equiv)

+

2

TBSO–Ar (1.0 equiv)

MeCN, 50 °C 10–90 min

O O S Ar2 Ar O 6 examples (88–99%) 1

H3 C O CH3

H O O S O

H

H

O O S O

H3C 95%

93%

Scheme 21.31  DBU‐catalyzed SuFEx reaction of β‐arylethenesulfonyl fluorides and aryl silyl ethers.

Polysulfonates and other sulfonylated polymers have excellent permeability and mechanical properties desired in industrial polymers. However, the paucity  of reproducible and scalable synthetic methods have hampered their application. To address this issue in 2017, Wu and coworkers developed

21.7  Application of Sulfonyl Fluorides: Sulfur–Fluoride Exchange Chemistry

­bifluoride [Ph3P═N–PPh3]+[HF2]− that could catalyze polysulfonate formation from bisethylenesulfonyl fluoride amine adducts and bisphenol bis(tert‐­ butyldimethylsilyl) ethers in quantitative yield [46]. This bifluoride‐catalyzed SuFEx reaction resulted in AA–BB polysulfonate block copolymers with good molecular weight, low catalyst loading (1.25 mol%) and high polydispersity index and on large scale (Scheme 21.32). Subsequently this strategy was expanded by Dong, Wu, Sharpless, and coworkers to synthesize block polysulfonates featuring bisalkyl and aryl sulfonyl fluorides, bis(tert‐butyldimethylsilyl) ethers, and (Me2N)3S+[FHF]− as a bifluoride catalyst [47]. Polysulfonates were generated with excellent molecular weight and polydispersity index using as low as 0.5 mol% of the bifluoride ­catalyst. Notably, using DBU and BEMP as catalyst proved challenging for alkyl sulfonyl fluorides resulting in decomposition of the starting material due to α‐H ­elimination and oligomers, highlighting the advantage of using bifluoride catalysts to afford polysulfonates (Scheme 21.33). Small molecule aryl sulfonate esters can also be generated from free alcohols and sulfonyl fluorides, obviating the need for silyl protection. Ball and coworkers reported a cesium carbonate (CsCO3)‐mediated SuFEx reaction coupling of several aryl sulfonyl fluorides with substituted phenols and trifluoroethanol in good to excellent yield (Scheme 21.34) [23]. 21.7.3 Sulfonamides Several investigations have aimed to highlight the advantage applying SuFEx chemistry vs. classical Halex chemistry (i.e. sulfonyl chlorides) toward the synthesis of sulfonamides, a very important class of molecules in medicine and agriculture. In 2014, Moroz, Mykhailiuk, and coworkers reported a systematic study comparing the synthesis of sulfonamides from alkyl sulfonyl chlorides and fluorides. The central hypothesis of the study centered around the observation that alkyl sulfonyl chlorides would often undergo elimination in the presence of base (e.g. amine), whereas the more stable sulfonyl fluoride did not react [7]. Generally, higher sulfonamide yield was observed from sulfonyl fluorides vs. chloride analogues in the presence of amine and triethylamine, highlighting the advantage of using sulfonyl fluorides. Inspired by these observations, in 2018 Ball, am Ende, and coworkers reported the first SuFEx reactions to successfully convert aryl and alkyl sulfonyl fluorides to sulfonamides via Lewis acidic calcium bistriflimide – Ca(NTf2)2 – activation [10]. This method was successful in synthesizing a broad array of electronically and sterically diverse sulfonamides in good to excellent yield (Scheme 21.35). The SuFEx reaction without calcium did not provide considerable amount of sulfonamide product, highlighting the important role of ­calcium. Highly electron‐deficient aryl sulfonyl fluorides did have considerable background reaction even in the absence calcium when paired with dialkylamines. On the other hand, the same sulfonyl fluorides in the presence of ­aniline  –  a weaker nucleophile  –  did not result in appreciable sulfonamide ­formation unless in the presence of Ca(NTf2)2. In efforts to explore bromovinylsulfonyl fluoride as a building block, Thomas and Fokin described a SuFEx reaction to synthesize triazole‐based sulfonamides from 1,2,3‐triazole sulfonyl fluorides and aryl and alkyl amines [48]. 1,2,3‐Triazole

643

FO2S

X

SO2F [Ph3PNPPh3]+[HF2]–

+

O

Neat, 130 °C, 1 h TBSO

O

O O S

(1.25 mol%)

O

O O S

X

n

OTBS

O O S O

N

O O S

O O S O

O

O O S

N

n

n

MnPS = 20 kDa, PDI = 1.3

O

O O S O

N

MnPS = 16 kDa, PDI = 1.2

O O S

O

O O S

O

N

N

OO S

n S MnPS = 14 kDa, PDI = 1.2

n MnPS = 16 kDa, PDI = 1.4

Scheme 21.32  Bifluoride‐catalyzed SuFEx reaction toward alkyl amine/bisphenol polysulfonate copolymers.

21.7  Application of Sulfonyl Fluorides: Sulfur–Fluoride Exchange Chemistry

FO2S

SO2F

(Me2N)3S+[FHF]– (0.5–5.0 mol%)

+

NMP, 130 °C, 1 h TBSO

O OO O S S O

O

n

OTBS

O O S O

O

O O S

O OF F F F S O S F F F FO O

O n

MnPS = 23 kDa, PDI = 1.3

n

MnPS = 23 kDa, PDI = 1.3 O O S O

O

S O O

MnPS = 65 kDa, PDI = 1.5

n

Scheme 21.33  Bifluoride‐catalyzed SuFEx reaction toward alkyl/bisphenol polysulfonate copolymers.

R

O O S F

Cs2CO3 (2 equiv) R

ROH (1.1 equiv), MeCN, 23 °C, 1 h

(1 equiv)

OMe

O O S O

O O S O

O O S R O

O O S O

95%

81% O O S O 84%

CF3

NH2

79% O O S O

I

84% (1.8 g scale)

Scheme 21.34  Aryl sulfonates generated from a sulfonyl fluorides and free alcohols.

sulfonyl fluorides were synthesized via [2 + 3] cycloaddition of bromovinylsulfonyl fluoride and organic azides. In the presence of a base (Et3N) and an amine, triazole sulfonyl fluorides were converted to the corresponding sulfonamides in good to excellent yield (Scheme 21.36).

645

646

21  Properties and Applications of Sulfur(VI) Fluorides Ca(NTf2)2 (1 equiv)

O O S R F

O O S N H 88%

O O S N H 85%

Ph

>25 examples (40–98%)

O O S N H

Ph

N

N

OMe

67% O O S N

N

CF3

N

N

CF3

O O S N H 85%

N

O O S N H N

N

CF3

88%

82%

85%

NBoc

Ph

O O S N

O O S N

NC

R

O O S N H 73%

N

Ph

MeO

O O S NR1R2

R1R2NH (2 equiv) t-AmylOH, 60 °C, 24 h

O O S N H N

88%

98%

Scheme 21.35  Sulfonamide synthesis from sulfonyl fluorides and amines using Ca(NTf2)2. O O S F N N N R

N

N

O O S NR1R2 N NEt3 (2 equiv), N N R MeCN (anhydrous), 75 °C, 3–40 h R1R2NH (2 equiv)

O O S N H N

76%

Ph

N

81%

OMe

N

N

O O COOtBu S N H N

81%

N

O O S N N

CF3

O

N

N

O O S N N

85%

CF3

9 examples (62–85%)

N

CF3

HO O OH

HN

N O

O

83%

O O S NH2 N N N

Scheme 21.36  Synthesis 1,2,3‐triazole‐based sulfonamides.

SuFEx chemistry has also been employed in the development of ionic liquids with bifluoride anions, highly sought after as electrolytes in solar cells, fuel cells, and capacitors. In 2018, Mirjafari and coworkers described an autocatalytic SuFEx reaction toward bifluoride‐based sulfonamide ionic liquids [49]. The sulfonyl imidazolium bifluoride product is proposed to catalyze the SuFEx akin to Sharpless’ examples of polysulfonate synthesis using bifluoride catalyst. Several ionic liquids were synthesized in quantitative yield and demonstrated to be suitable electrochemical media for Al and Li batteries (Scheme 21.37).

21.8  Application of Sulfonyl Fluorides: Tandem Organic Transformations

O O S R F

O O S R N

Toluene/THF/CHCl3 N

N

+

N2, 8 h

N

–

HF2 5 examples

R = Me, Ph, PhCH2, (CF2)3CF3, (CF2)7CF3

Scheme 21.37  Autocatalytic formation of sulfonylimidazolium bifluoride‐based ionic liquids from sulfonyl fluorides and N‐methyl imidazole.

21.8 ­Application of Sulfonyl Fluorides: Tandem Organic Transformations α,β‐Unsaturated sulfonyl fluorides present a compelling opportunity for tandem organic reactions: conjugate addition and SuFEx chemistry. Several groups have utilized this dual reactivity of unsaturated sulfonyl fluorides toward cyclic compounds or dual functionalization. The first systematic study of this transformation was conducted in 1979 by Krutak et al. highlighting over 100 cyclization, addition, and cycloaddition reactions using ethenesulfonyl fluoride (ESF) derivatives with various nucleophiles [50]. Lupton et al., in 2015, expanded this work using N‐heterocyclic carbene (NHC) catalyst in the synthesis of δ‐sultones from β‐arylethenesulfonyl fluorides and TMS‐protected 1,3‐dicarbonyl compounds [51]. δ‐Sultones were synthesized in good yield (Scheme 21.38). The key transformation in the proposed mechanism is a SuFEx reaction between β‐arylethenesulfonyl fluoride and the carbene to form an activated sulfonyl azolium salt and F− ion. Subsequent deprotection of the dicarbonyl and a series of addition reactions yield the desired sulfone (Scheme 21.38).

O

OTMs R1

O

R3

S O F

+

R2

O S O O

R3 O

R3 H3CO2C

H3C R3

CH3

CH3 Yield (%)

Ph 4-OCH3Ph 4-CH3Ph 4-ClPh

88 43 59 71

R3 Ph 4-ClPh 2-Furyl

O

4 Å MS THF, 66 °C, 6 h

O S O O

Mes

R1 R2 >18 examples (45–88%)

Ph O

Yields (%) 66 65 45

O S O O

R3

IMes C1 (2 equiv)

52%

N

N

Mes

C1

O

R3

S O O

Mes

O S O N

N Mes

Sulfonyl azolium intermediate

Scheme 21.38  NHC‐catalyzed synthesis of δ‐sultones using TMS‐protected α,β‐unsaturated ketones and β‐arylethenesulfonyl fluorides.

647

648

21  Properties and Applications of Sulfur(VI) Fluorides

In 2017, Qin and coworkers reported an annulative reaction of dienylsulfonyl fluorides and pyrazolones toward δ‐sultones via tandem addition/SuFEx chemistry [52]. Catalyzed by DBU, heterocyclic δ‐sultones were synthesized under mild conditions in moderate to excellent yield (Scheme 21.39). δ‐Sultones from 1,3‐dicarbonyl compounds in lieu of pyrazolones were also successful. O R

SO2F + Ph N N O O S O

O O S O

DBU (20–30 mol%) NaHCO3 (1 equiv)

Ph N N 82%

R O O S O

O O S O

Ph N N

13 examples (57–99%)

CH2Cl2, rt, 24–48 h Ph N N

Ph N N

OCH3 O

61%

73%

Scheme 21.39  DBU‐catalyzed synthesis of δ‐sultones from dienylsulfonyl fluorides and pyrazolones.

In 2017, Arvidsson and coworkers exploited the dual nature of β‐arylethenesulfonyl fluorides to make β‐sultams. First, the β‐arylethenesulfonyl fluoride was synthesized via an oxidative Boron–Heck reaction. This was followed by an addition of a primary amine to the alkene and sulfur center. This method was effective in the generation of a variety of aryl β‐sultams in good yield (Scheme 21.40a) [53]. Also this transformation was demonstrated in a one‐pot procedure from ESF and a primary amine using both Boron–Heck and SuFEx reactions in the O O S F

Ar

CD3CN, rt, 5–20 min

O N S O

Ar

O S O N

O S O N H3CO

77%

B(OH)2 O2N

R

1–4 equiv amine

82%

O S O N N H

85% O S O N

(1) ESF, Pd(OAc)2 Cu(OAc)2, LiOAC, THF, 3–5 h

(2) MeNH2 (excess), THF, rt, 5 min

(a)

O2N

91%

(b)

Scheme 21.40  (a) Synthesis β‐sultams from β‐arylethenesulfonyl fluorides and excess amine. (b) One‐pot synthesis of β‐sultams via a tandem oxidative Boron–Heck/SuFEx reaction.

21.9  Application of Sulfonyl Fluorides: Cross‐Coupling Reactions with Persistent SO2F Group

same reaction vessel (Scheme 21.40b). In 2018, a subsequent report by Naicker, Arvidsson, and coworkers demonstrated that β‐aminoethane sulfonamides (Scheme  21.41a) and 1,2,4‐thiadiazinane 1,1‐dioxides (Scheme  21.41b) could also be synthesized in one pot using diamines in the presence of arylethenesulfonyl fluoride in modest to good yield [54].

Ar (a)

H3C

O O S F

(b) Ar

THF, rt, overnight

CH3 NH HN S O O 80%

O2N

10 equiv amine 30 mol% DBU

O O S F

HO

O2N

R

R NH HN S O Ar O OH

NH HN S O O

CH2Cl2, reflux, 8–12 h

Ph

O2N

61%

10 equiv amine 50 mol% DBU

(7 examples) 61–83%

R Ar

N

R N S O O

NH HN Ph S O O 79%

(6 examples) 40–78%

Scheme 21.41  (a) DBU‐catalyzed synthesis β‐aminoethane sulfonamides from β‐ arylethenesulfonyl fluorides. (b) One-pot DBU‐catalyzed synthesis of 1,2,4‐thiadiazinane 1,1‐dioxides from ESF and excess amine.

In 2018, Qin and coworkers reported that β‐arylethenesulfonyl fluorides could be used to synthesize sultone‐functionalized pyridines [55]. This Ni‐catalyzed annulative coupling/SuFEx reaction of 2‐acylpyridine derivatives and β‐arylethenesulfonyl fluorides provided diverse pyridine‐based sultones in good yield (Scheme 21.42). The authors proposed that coordination of NiII to the acyl pyridine substrate promotes enolization, Michael addition to the arylethenesulfonyl fluorides, and activation of the fluorosulfuryl moiety toward SuFEx.

21.9 ­Application of Sulfonyl Fluorides: Cross‐Coupling Reactions with Persistent SO2F Group Another key characteristic of sulfonyl fluorides is their persistence under forcing conditions. This remarkable stability allows for the sulfonyl fluoride moiety to be exploited as persistent functional group, particularly in transition‐metal cross‐ coupling chemistry. Unlike fluorosulfates that can be used as electrophiles in transition‐metal‐catalyzed transformations (vide infra), sulfonyl fluorides are resistant to activation under several transition‐metal cross‐coupling conditions. The first reported example of employing sulfonyl fluorides in coupling chemistry occurred in 1930 by Steinkopf and Jaeger where iodo‐substituted aryl sulfonyl fluorides underwent Ullmann coupling to generate bis(fluorosulfuryl)biarenes (Scheme 21.43) [56].

649

650

21  Properties and Applications of Sulfur(VI) Fluorides

O SO2F +

Ar

R

N Ar

Ni(NO3)2·6H2O (20 mol%) K2CO3 (2 equiv)

O O S O R

MeCN, rt, 24 h O O S O N

N

Yields (%)

R

H 4-Ph 4-F 4-CH3 3-CH3 3-Br 2-CH3 2,4-DiCH3

90 70 75 97 89 52 92a 89

Ph

Br

N

Ph

31%b O O S

O

N

Ph

36%c

Ph

N

O O S O Ph

S

O O S

O

49%b

O O S O N

>45 examples 30–99%

N

77%

OMe

Ar

O O S O

O O S O Ar

N Ar

99%

N 61%

Ph

Scheme 21.42  Synthesis of sultone‐functionalized pyridines via Ni‐catalyzed dual enolization and SuFEx reaction. Conditions: a reaction was for 36 hours; b a second step where an additional portion of 20 mol% Ni(NO3)3·6H2O was added and reaction progressed for an additional 24 hours; and c 40 mol% Ni(acac)2 was used.

SO2F I R

SO2F

Cu powder 200–230 °C 41–54% R = H, CH2, OCH3

R

R FO2S

Scheme 21.43  Ullmann coupling of iodo‐substituted arylsulfonyl fluorides to synthesis bis‐ sulfonyl fluoride biaryl compounds.

Over 80 years later, applications of sulfonyl fluorides in Pd‐catalyzed cross‐ coupling reactions began to emerge in the literature. In 2015, a report by Jones and coworkers used Stille coupling to install an alkyne to synthesize a sulfonyl fluoride probe, SF‐p1‐yne (Scheme  21.44a) [57]. In SF‐p1‐yne, the sulfonyl fluoride part of the probe was designed to target tyrosine residues in DcpS, an mRNA‐decapping scavenger enzyme, whereas the purpose of the alkyne was for subsequent azide–alkyne bioconjugation chemistry. This work was followed up by a report from Arvidsson and coworkers that described the first Suzuki coupling to synthesize biaryl sulfonyl fluorides from aryl boronic acids and bromo‐substituted arylsulfonyl fluorides (Scheme 21.44b) [58]. This “on‐ water” reaction afforded a diverse scope of biaryl sulfonyl fluorides in good to excellent yields. The enhanced stability of sulfonyl fluorides under palladium‐catalyzed cross‐ coupling conditions also present an opportunity to utilize the fluorosulfuryl

21.9  Application of Sulfonyl Fluorides: Cross‐Coupling Reactions with Persistent SO2F Group Stille: Jones and coworkers [57] N

N

NH2 N

O

N

(1) Pd(dtbpf)Cl2 SnBu3

NHBoc +

NH2

Toluene/DMSO, 110 °C

O

NHBoc

(a)

(2) HCl, dioxane, rt SF-p1-yne

Br SO2F

SO2F

5%

Suzuki: Arvidsson and coworkers [58] B(OH)2 R

SO2F +

Pd(OAc)2 (1 mol%) Et3N (3 equiv) rt, H2O, 0.5–2 h

R

SO2F R

19 examples 67–97%

(1.5 equiv) SO2F

SO2F

SO2F

SO2F

SO2F

(b)

S

H3CO OCH3 97%

NC

91%

H3CO

92%

67%

89%

Scheme 21.44  Pd‐catalyzed cross coupling reaction with sulfonyl fluorides: (a) Stille reaction to synthesize SF‐p1‐yne chemical probe. (b) On‐water Suzuki coupling of aryl boronic acids and bromo‐substituted aryl sulfonyl fluorides.

moiety as a persistent functional group. This strategy could allow for the early installation of the SO2F in an organic compound and subsequent functional group transformations with modifying the SO2F group. A compelling example of this strategy was demonstrated by Robinson and coworkers in the design of over 12 clickable sulfonyl fluoride probes (Scheme 21.45) [59]. Starting with an aryl sulfonyl fluoride, a series of reduction, hydrolysis, oxidation, and halogenation reactions were performed, whereby the SO2F group was remarkably stable. In 2018, Grygorenko and coworkers demonstrated the versatility of heteroaryl bromides containing a SO2F group as substrates in a series of cross‐coupling reactions. A Suzuki cross‐coupling of 5‐bromopyridine‐2‐sulfonyl fluoride and a vinyl pinacolate boronic acid resulted in 79% yield of the cross coupling product (Scheme 21.46a) [60]. Nickel‐ and palladium‐catalyzed Negishi cross‐coupling of bromopyridine sulfonyl fluorides with diethylzinc and trimethyl aluminum reagents was also successful forming ethyl and methyl pyridine derivative in good yield (Scheme 21.46b,c). In the same report, bis‐heteroarenes were synthesized using Suzuki cross‐­ couplings of bromo‐substituted heteroaromatic sulfonyl fluorides and pyridine, thiophene, and furan‐based boronic acids in excellent yield (Scheme  21.47). Interestingly, cross‐coupling of bromopyridine sulfonyl fluorides and 2 equiv of 2‐thienylboronic acid resulted in additional C─SO2F bond cleavage, providing a rare example of defluorosulfurylation and C─C bond formation under metal‐ catalyzed conditions (Scheme 21.48).

651

652

21  Properties and Applications of Sulfur(VI) Fluorides CO2Me

90%

SO2F

Br

CO2Me

Sonogashira coupling

CO2H

Ester hydrolysis

SO2F

SO2F

98%

TMS

TMS

Ester reduction

Curtius rearrangment

65%

NH2

OH

Br

64%

Bromination SO2F

100%

SO2F

SO2F

TMS

TMS

TMS

Dess–Martin oxidation O

81% H

SO2F TMS

Scheme 21.45  Multistep synthesis of clickable sulfonyl fluoride monomers.

Suzuki BocN Br

B

(2 equiv) N

SO2F

O O

BocN

(a)

Pd(dppf)2Cl2 (10 mol%) Na2PO4 (3 equiv) THF, reflux

N

SO2F

79%

Negishi Br N

Br

SO2F

SO2F N

Et2Zn (1.5 equiv) Pd(dppf)2Cl2 (10 mol%) THF, reflux

Me3Al (1 equiv) Pd(dppf)2Cl2 (10 mol%) THF, reflux

(b) Et N

SO2F

2,4-Isomer, 78% 2,5-Isomer, 85% 2,6-Isomer, 94% Me

SO2F N

(c)

87%

Scheme 21.46  Suzuki (a) and Negishi (b, c) cross‐couplings of bromopyridyl sulfonyl fluorides.

Several groups have been successful in developing Heck cross‐coupling reactions using ESF as a coupling partner to make aryl/alkenyl C─C bonds. In 2016, Sharpless and coworkers first reported a Heck–Matsuda cross‐coupling reaction with aryl diazonium tetrafluoroborate salts and ESF. The method successfully

21.9  Application of Sulfonyl Fluorides: Cross‐Coupling Reactions with Persistent SO2F Group

B(OH)2 Het

SO2F +

Br

Het

Conditions reflux

SO2F

SO2F

O

98%

O

S

SO2F Cy

69%b N

94%

O

SO2F Ph

85%b

83%

69–98%, 22 examples

Cy

N

N

Het

a

(1.5 equiv) Ph

Het SO2F

Pd-catalyst, base

N S

SO2F

S

SO2F O

90%

SO2F

81%

S

SO2F

89%

Scheme 21.47  Suzuki cross‐coupling of heteroaryl bromide containing the SO2F group and boronic acids. Conditions: a Pd(PPh3)2Cl2 (10 mol%), K2CO3 (3 equiv), argon; b Pd(PPh3)2Cl2 (10 mol%), Na2PO4 (3 equiv), argon.

Br

S N

SO2F

B(OH)2 (2 equiv)

Pd(dppf)2Cl2 (10 mol%) K2CO3 (3 equiv), dioxane, reflux

S

N

S 2,4-Isomer, 46% 2,5-Isomer, 39%

Scheme 21.48  Suzuki cross‐coupling of bromopyridyl sulfonyl fluorides and thiophenyl boronic acids via C─SO2F bond cleavage.

produced a wide array of β‐arylethenesulfonyl fluorides with only Pd(OAc)2 as a catalyst (Scheme 21.49a) [45]. Concomitant with Sharpless’s efforts, Arvidsson and coworkers reported an oxidative Boron–Heck reaction coupling ESF with aryl boronic acids [53]. Using Pd(OAc)2 as a catalyst, Cu(OAc)2 as an oxidant, and LiOAc as base a comparable substrate scope of β‐arylethenesulfonyl fluoride derivatives was achieved in moderate to good yield (Scheme 21.49b). A key benefit of this approach is the extensive commercially availability and affordability of boronic acids, obviating the need to synthesize diazonium salts. In 2017, Qin and coworkers reported similar Boron–Heck coupling instead using 2,3‐dichloro‐5,6‐ dicyano‐1,4, benzoquinone (DDQ) or AgNO3 as the oxidant (Scheme  21.49c) [61]. This reaction greatly expanded the scope of β‐arylethenesulfonyl fluorides that could be synthesized in generally higher yield than that by Arvidsson although there is complementarity between Arvidsson’s basic conditions and Qin’s acidic conditions where one method may be suitable over the other depending on the other functional groups present. In efforts to move away from aryl diazonium salts, Qin and Sharpless reported a follow‐up Heck cross‐coupling reaction replacing the diazonium salts with aryl iodides. A vast scope of β‐ arylethenesulfonyl fluorides were reported in good to excellent yield (Scheme 21.49d) [62].

653

654

21  Properties and Applications of Sulfur(VI) Fluorides Heck-Matsuda: Sharpless and coworkers [45] + BF4–

N2 R

Pd(OAc)2 (10 mol%) SO2F

+

(1.1 equiv)

Acetone, rt 5–15 h

(1 equiv)

SO2F R

(a)

21 examples (43–97%)

Oxidative boron-Heck: Arvidsson and coworkers [53] Pd(OAc)2 (10 mol%)

B(OH)2 R

+

SO2F (3 equiv)

Cu(OAc)2 (2 equiv) LiOAc (1.2 equiv)

SO2F R

(b)

15 examples (40–79%)

THF, rt, 3–5 h

Oxidative boron–Heck: Qin and coworkers [61] Pd(OAc)2 (5 mol%)

B(OH)2 R

+

SO2F (6 equiv)

DDQ (1.5 equiv) or AgNO3 (2 equiv)

SO2F R

(c)

49 examples (26–99%)

AcOH, 80 °C, 12 h

Heck: Qin, Sharpless, and coworkers [62] I R

+

SO2F (2 equiv)

Pd(OAc)2 (2 mol%) AgTFA (1.2 equiv) Acetone, 60 °C, 6–24 h

SO2F R

(d) 57 examples (51–99%)

Scheme 21.49  Examples of Heck‐type cross‐coupling reactions using ethylenesulfonyl fluoride.

An alternative approach to using a Heck reaction to access β‐arylethenesulfonyl fluorides would be C–H activation of the arene coupling partner. In 2018, Qin and coworkers reported a RhIII‐catalyzed ligand‐directed ortho‐C–H activation of ethylbenzoate derivatives and ESF to synthesize β‐arylethenesulfonyl fluorides. The carboxylate group was used as an ortho‐director for C–H activation by Rh. A variety of β‐aryl and heteroaryl ESFs were formed in good yield (Scheme 21.50) [63]. Product yields generally decreased with benzoates containing electron‐withdrawing groups (e.g. 4‐CN and 4‐CHO). Interestingly, under the reaction conditions, ethyl 3‐methoxybenzoate gave a 1.2 : 1 ratio of regioisomers, highlighting a limitation of the method with meta‐substituted benzoates.

21.10 ­Sulfonyl Fluorides as a Reagent in Organofluorine Chemistry The application of sulfonyl fluorides as reagent in fluorination chemistry has been of intense interest. The primary strategy of using sulfonyl fluorides as a

21.10  Sulfonyl Fluorides as a Reagent in Organofluorine Chemistry

O SO2F

+

OEt

R

O R

OEt

4-Cl 4-COOEt 4-CN 4-t-Bu 4-NMe2 4-OCH3 4-CHO 2-CH3

71 70 24 80 70 90 27 99

OEt

+

SO2F OMe

22% 27% Regioisomers from ethyl 3-methoxybenzoate O

O

O

OEt

OEt SO2F

O

SO2F

83%

66%

SO2F 26 examples (22–99%)

OEt

SO2F

S

OEt

R

O MeO

OEt

Yields (%)

O

AcOH (5 equiv) PhCF3, 100 °C, air, 15 h

O O O

R

[Cp*RhCl2]Cl2 (2.5 mol%), AgSbF6 (10 mol%) Cu(OAc)2 (20 mol%)

O

O OMe SO2F

SO2F 40%

OiPr

61%

SO2F 89%

Scheme 21.50  Rh‐catalyzed synthesis of 2‐arylethenesulfonyl fluorides via coupling of ESF and benzoic acids through ortho‐C–H activation.

reagent in organic chemistry is not the incorporation of a fluorosulfuryl group, but to introduce fluorine – via fluoride or an organofluorine fragment – into the final product. One of the first examples of a sulfonyl fluoride used as a fluorinating agent was in 1985. Yoshioka and coworkers demonstrated that p‐toluenesulfonyl fluoride in the presence of TBAF could chemoselectively react with primary alcohols and undergo deoxyfluorination to form alkyl fluorides [64]. It  was in 1995 with the introduction of n‐perfluorobutane sulfonyl fluoride (PBSF) by Bennua‐Skalmowski and Vorbrüggen that both primary and secondary alcohols could undergo deoxyfluorination in the presence of DBU [65]. Unfortunately, the ability of the alkyl and perfluoroalkyl sulfonyl fluorides to undergo decomposition and elimination side reaction inhibited the broad ­application of the chemistry. It was not until 2015, with introduction of 2‐pyridinesulfonyl fluoride (PyFluor) by Doyle and coworkers, that a suitable sulfonyl fluoride broadly applicable for deoxyfluorination was used [66]. Employing a more stable aromatic sulfonyl fluoride, PyFluor, in combination with DBU or 7‐Methyl‐1,5,7‐triazabicyclo[4.4.0] dec‐5‐ene (MTBD) was successful in minimizing elimination products and favoring deoxyfluorination of primary and secondary alcohols. Primary and secondary alkyl fluorides were synthesized in generally good yields (Scheme 21.51). Unlike PBSF, PyFluor is remarkably stable (up to 350 °C), solid, and cheap to make. Similar to deoxyfluorination with PBSF, the key transformation is the formation of a sulfonic ester and a DBU–HF adduct where the fluoride participates in a nucleophilic aromatic substitution breaking the activated C─S bond. Sulfonyl fluorides can also be used as a difluorocarbene reagents. In 2000, Dolbier and coworkers reported the synthesis of trimethylsilyl fluorosulfonyldifluoroacetate (TFDA). TFDA was used as a difluorocarbene precursor toward gem‐difluorocyclopropanes. In the presence of catalytic NaF, TFDA undergoes

655

656

21  Properties and Applications of Sulfur(VI) Fluorides

OH R

SO2F

+

DBU or MTBD (1.25–2.0 equiv)

N

R′

Toluene (0.2–1.0 M) rt, 48 h

PyFluor

R R′ 43–91% 21 examples

OBn

F

O

CH3

CH3

F

F

BnO

via:

F

N

OBn

O O S O N R

+ DBU–HF R′

H3CO

F

CH3 H3CO

CH3

OBn 79%

91% (23 : 77 d.r.)

68%

83% OBn

O BnO

F

F

N

O2N 64%

O

F

76%

OH Ph

CH3 H3C

Ph 80%

BnO

18

F

OBn OBn

15% ± 5% RCC with [18F]PyFluor 80 °C, 20 min

Scheme 21.51  Synthesis of alkyl fluorides from alcohols using PyFluor as a deoxyfluorination reagent.

decarboxylation/sulfonylation reaction to produce SO2 (g), CO2 (g), F−, and difluorocarbene. Subsequent addition to alkenes resulted in gem‐difluorocyclopropanes in good yields (Scheme 21.52a) [67]. The poor shelf‐life and cost of TFDA has inspired efforts for a suitable alternative. In 2012, Dolbier and coworkers followed up their earlier work with development of more stable methyl 2,2‐­difluoro‐2‐(fluorosulfonyl)acetate (MDFA). MDFA in combination of KI and TMSCl as a fluoride sponge was able to generate gem‐difluorocyclopropanes in comparable yields to TFDA albeit with considerably longer reaction time (Scheme 21.52b) [68].

21.11 ­Application of Fluorosulfates: Dual Reactivity Unlike sulfonyl fluorides where in the presence of nucleophiles, reactivity is nearly exclusively at the sulfur atom and the fluoride ion (F−) serves as a leaving group, the electron‐withdrawing nature of the fluorosulfuryl moiety also promotes and enhances electrophilicity at the carbon center. As a result, fluorosulfates  –  similar to other electron‐poor S(IV) groups like triflates and tosylates – can also serve as a leaving group. The dual reactivity of fluorosulfates enable them to be used as a precursor to promote C─X bond formation (X = C, NR2, OR, etc.) in addition to SuFEx chemistry. The following sections will highlight chemistry that exploit the unique reactivity of fluorosulfates presenting examples that take advantage of the fluorosulfate moiety (–OSO2F) and fluoride (F−) as a leaving groups in addition to the SuFEx chemistry (Scheme 21.53).

21.11  Application of Fluorosulfates: Dual Reactivity TFDA (Dolbier, 2000)

O R

SO2F

TMSO

+

F F TFDA (1.5 equiv)

Neat or methyl benzoate

5 examples

F

73–97%

F F

74%

F

105 °C, 2 h

(a)

O

O Ph

O

O O

73%

R

NaF (1.2 mol%)

F F

O

Ph

89%

F F

78%

F F

MDFA (Dolbier, 2012)

R1

KI (2.25 equiv) SO2F Diglyme (10 mol%) H3CO Dioxane (1.7 equiv) + F F TMSCl (2 equiv) MDFA 2 d, 115–120 °C (2.0 equiv) O

R3 R4 R2

O

R3 1

R

R2

F

R4 F

70–89% NMR yield 67–74% isolated yield

F

67%

F F

O F F

(b) 12 examples

74%

72%

F F

F

73%a

Scheme 21.52  Synthesis of gem‐difluoropropanes using (a) TDFA/NaF and (b) MDFA/KI/ TMSCl. Conditions: a2 equiv of hexamethyldisiloxane (HMDSO) used in lieu of TMSCl.

OSO2F leaving group

Fluoride (F–) leaving group via SuFEx

O O S O F

O O S O F

Nuc:

Nuc:

Nuc

O O S O Nuc

Scheme 21.53  Modes of reactivity of aryl fluorosulfates in the presence of nucleophiles.

21.11.1  Application of Fluorosulfates: C─X Bond Formation via –OSO2F as a Leaving Group Fluorosulfates serves as versatile reagents toward several C─X bond formations including fluorinations, aminations, metal‐catalyzed cross‐coupling, and CO and CO2 insertion reactions. Key to these transformations is the loss of the fluorosulfate (–OSO2F) group, exploiting the enhanced electrophilicity of the carbon of the C─OSO2F bond. This section will highlight examples of how fluorosulfates can be used as synthetic precursors toward a diverse array of C─X bond‐forming reactions (Scheme 21.54).

657

658

21  Properties and Applications of Sulfur(VI) Fluorides O O S F

R1

OH

M (cat.)

Me3NF

Ar

B OH

HCOOH

R1 F

O

R1 H

R1

R1

Ar

R2 ZnCl or

R2

R2 SnBu3 R2 R1 N R3

R2

H N R3

R1

M (cat.)

M (cat.)

R2–OH CO2

R1

COOH

CO

COOR2

Scheme 21.54  Summary of chemical transformations toward C─X bond formation from fluorosulfates.

21.11.1.1 C─F Bond Formation

With the introduction of Pyfluor by Doyle and coworkers (Scheme  21.50), research efforts have sought to develop this fluorination strategy via putative fluorosulfate intermediates to facilitate other C─F bonds. In 2017, Sanford and coworkers expanded this concept, with a reaction that converts aryl alcohols to aryl fluoride via in situ formation of a fluorosulfate and NMe4F as a fluoride source [69]. In contrast to the work by Doyle and coworkers, the fluorosulfate intermediate was synthesized from sulfuryl fluoride (SO2F2) and the corresponding alcohol with a NMe4SO3 salt as the by‐product. Aromatic and heteroaromatic fluorides were synthesized in modest to good isolated yields from fluorosulfates (Scheme  21.55). Notably, aryl fluorosulfates with electron‐withdrawing groups gave higher yields of the corresponding aryl fluoride than aryl alcohols with electron‐donating groups. A stark example of this phenomenon is seen comparing the deoxyfluorination of 4‐methoxyphenol (electron donating) vs. 3‐methoxyphenol (electron withdrawing) where the yields of the corresponding aryl fluoride increases from 6% to 38% (NMR yields) as the aryl group goes from electron‐withdrawing to ‐donating (Scheme 21.55, bottom left). OSO2F R

F

NMe4F (2 equiv) R

DMF, rt, 24 h F

Ph

F

F

NC O

F

Ph

Ph 71%a

64%

87%

(30 examples) 21–87% isolated yield

83%a F

F H3CO

(6%)a,b

H3CO

F

F

(38%)a

Ph

N 73%a

N FO2S

21%a

Scheme 21.55  Deoxyfluorination of fluorosulfates using NMe4F as a fluorinating reagent. Reported 19F NMR yields are in parentheses. Conditions: aran at 100 °C; bused 5 equiv of NMe4F.

21.11  Application of Fluorosulfates: Dual Reactivity

Sanford and coworkers also demonstrated that phenols can undergo fluorination in the presence of NMe4F and SO2F2 to the corresponding aryl fluorides. Subsequent mechanistic studies demonstrated that the fluorination step most likely proceeds via a concerted four‐membered transition state from a penta‐ coordinate intermediate (Scheme 21.56) [70]. SO2F2 (2 equiv) NMe4F (2 equiv)

OH R

O F S

R 12 examples 19–86%

DMF, rt, 24 h

O F

O

R F

F

F

F

via:

F

N

Ph

Ph

NC O

86%

87% (13 g scale)

56% F

N

F 82%

Ph

CN

O

N 87%

O

53%

N

BzO F N

19%

Scheme 21.56  Conversion of aryl‐ and heteroaryl phenols to the corresponding aryl‐ and heteroaryl fluorides using SO2F2 and NMe4F via in situ formation of fluorosulfates.

21.11.1.2 C─N Bond Formation

Fluoroalkylation of amines offers a valuable motif in biologically active ­molecules. However their traditional synthesis via fluorinated alcohols requires forcing conditions, complicating their use with several functional groups. Sammis and coworkers reported a one‐pot method toward the 1,1-difluoroalkylation of primary and secondary amines using ex situ generated SO2F2 (see Scheme 21.21) and diethylisopropylamine (DIPEA) [71]. Key to this transformation was the in situ formation of a 2,2,2‐trifluoroethyl fluorosulfate intermediate, whereby nucleophilic substitution occurs with an amine resulting in a fluoroalkylated amine. Trifluoroalkylation of a variety of alkyl and benzyl amines were achieved in moderate to good yields. Notably, the reaction was selective for alkyl amines over aromatic amines and compatible with carbonyl groups and free alcohols (Scheme 21.57). 21.11.1.3 Dehydration/Dehydrogenation

In 2018, Qin and coworkers reported a dehydration/dehydrogenation reaction of alcohols in the presence of dimethylsulfoxide (DMSO) and base to synthesize alkynes in moderate to excellent yields (Scheme  21.58) [72]. The authors proposed a mechanism involving the formation of a fluorosulfate intermediate that undergoes substitution with DMSO followed by a series of elimination reactions

659

660

21  Properties and Applications of Sulfur(VI) Fluorides

R1 N H

RF2C OH ex situ SO2F2

R1 N

R2 (1 equiv)

DIPEA (5.8 equiv) DMF 40 °C, 2 h

R2

H N

N 61%

CF3

N

CF3

62%

RF2C

24 examples (42–80%) Ph

O HN

via:

CF2R

N

N H CF3

OH

OCH3 O

HN

CF3

N

58%

CHF2

CF3

72%a

59%

O N

O O S O F

O N

CF2CF3

42%a

52%

57%

CF2CF2CF3

N

a

Scheme 21.57  Fluoroalkylation of amines using SO2F2, fluoroalkyl alcohols, and DIPEA. Conditions: adouble addition of SO2F2 was applied.

R

(1) K2CO3 (1.5 equiv) DMSO/SO2F2 (balloon), rt, 2 h

OH

R = aryl, alkyl, alkenyl

(2) CsF (3 equiv), 100 °C, 2 h

PhO

R > 40 examples (35–95%)

Cl 92%

68%

79%

44%

35%

Cl

N 84%

49%

67%

71%

Scheme 21.58  Synthesis of alkynes via dehydration/dehydrogenation of primary alcohols.

to form alkynes. The method was also coupled with Huisgen alkyne–azide cycloaddition and Sonogashira reactions (Scheme 21.59). 21.11.2  Application of Fluorosulfates: Transition‐Metal‐Catalyzed Cross‐Coupling Reactions 21.11.2.1 C─C Bond Formation

In 1991, Roth and Fuller at Bristol Myers Squibb first reported aryl fluorosulfates as an effective electrophile and alternative to triflates in Pd cross‐coupling reactions. Both Negishi aryl–aryl bond‐forming cross‐coupling reactions with organozinc reactions and Stille coupling with vinyl tin reagents were demonstrated in good yields (Scheme 21.60) [73].

21.11  Application of Fluorosulfates: Dual Reactivity Dehydration/dehydrogenation then CuAAc reaction R

OH

R = aryl, alkynl

(1) K2CO3 (1.5 equiv)

R

DMSO/SO2F2 (balloon), rt, 2 h

N

(2) CsF (3 equiv), 100 °C, 2 h (3) PhN3 (1 equiv), CuSO4·5H2O (10 mol%) Na ascorbate (10 mol%), PPh3 (10 mol%) DMSO:H2O (1 : 1), rt, 2 h

N

N

16 examples (60–92%)

Dehydration/dehydrogenation then Sonogashira coupling

Ar

OH

Ph

(1) K2CO3 (1.5 equiv) DMSO/SO2F2 (balloon), rt, 2 h (2) CsF (3 equiv), 100 °C, 2 h (3) PhI (1.1 equiv), Pd(PPh3)2Cl2 (5 mol%) CuI (10 mol%), Et3N, argon, rt, 12 h

10 examples (51–77%)

Scheme 21.59  Synthesis of alkynes via dehydration/dehydrogenation of alcohols and further Huisgen alkyne–azide cycloaddition and Sonogashira reactions. Negishi and Stille coupling Roth and Fuller [73] Pd(PPh3)4 (5 mol%) R–ZnCl (1.5 equiv) LiCl (3 equiv) THF, 50 °C, 12 h Negishi

Ar

O O S O F

Pd(PPh3)2Cl2 (5 mol%) R–SnBu3 (1.2 equiv) LiCl (3 equiv) DMF, 25 °C, 6–18 h Stille

Ar–Ar Ar = aryl and heteroaryl 7 examples 47–95%

Ar

or

Ar

Ar

9 examples 60–92%

Scheme 21.60  Pd‐catalyzed Negishi and Stille cross‐coupling of aryl fluorosulfates and aryl zinc, aryl stannanes, and vinyl stannanes.

While a few examples followed, interest in Pd‐catalyzed cross‐coupling reactions fluorosulfates waned until a 2015 report by Hanley et al. [74]. This group of Dow chemists demonstrated Suzuki cross‐coupling toward biaryl compounds using both palladium (Scheme  21.61a) and nickel catalysts (Scheme  21.61b). A diverse array of biarenes where synthesized in good to excellent yields. The authors did report notable differences between the Pd‐ and Ni‐catalyzed s­ ystems: (i) under nickel catalysis, higher yields were achieved with electron‐­donating aryl fluorosulfates vs. electron‐withdrawing groups; (ii) cross‐coupling under nickel catalyst was more sensitive to steric congestion about the fluorosulfate; and (iii) Pd(OAc)2/PPh3 was not effective toward cross‐coupling of 4‐aminophenyl fluorosulfate and boronic acids. However, NiCl2(PCy3)2/PCy3·HBF4 condi-

661

662

21  Properties and Applications of Sulfur(VI) Fluorides Suzuki–Miyaura coupling: Hanley and coworkers [74] OSO2F R

Pd(OAc)2 (1 mol%) PPh3 (2.5 mol%)

B(OH)2

+ R

NEt3 (2 equiv), 1,4-dioxane/H2O

(1.4 equiv)

R R 16 examples 33–96%

60 °C, 12 h

(a) OSO2F R

NiCl2(PCy)3 (1 mol%) B(OH)2 PCy3·HBF4 (2 mol%)

+ R

R K3PO4 (3 equiv), 1,4-dioxane 80 °C, 15 h

(1.4 equiv)

(b)

R

10 examples 53–92%

Two-step one pot C–C bond formation from alcohols (1) SO2F2 (3 wt% in dioxane) B(OH)2 Et3N (1 equiv), rt, 24 h

OH R

+ R (1.4 equiv)

(c)

R

R (2) PhB(OH)2 Pd(OAc)2 (1 mol%) 13 examples PPh3 (2.5 mol%), 60 °C, 12 h 48–90%

Suzuki–Miyaura coupling: ligand-free Sharpless and coworkers [75] OSO2F R (d)

B(OH)2

+ R

NEt3 (3 equiv), (1.5 equiv)

R

Pd(OAc)2 (1 mol%)

H2O, rt, 2–10 h

R 21 examples 59–99%

Scheme 21.61  Synthesis of biarenes via Suzuki–Miyaura cross‐coupling of aryl fluorosulfates and boronic acids. (a) Pd‐catalyzed Suzuki–Miyaura cross‐coupling. (b) Ni‐catalyzed version. (c) One‐pot fluorosulfurylation/Pd‐catalyzed Suzuki–Miyaura cross‐coupling of aryl alcohols and aryl boronic acids toward biarenes. (d) Air and ligand‐free Pd‐catalyzed cross‐coupling.

tions gave the desired product in good yields. Lastly, Hanley et al. described an one‐pot Suzuki cross‐coupling of phenols and aryl boronic acids toward biarenes, generating the fluorosulfate in situ using sulfuryl fluoride and triethylamine in moderate to excellent yields (Scheme  21.61c). Jiang, Sharpless, and coworkers followed up this work by Hanley et  al. with a ligand‐free Pd‐catalyzed Suzuki cross‐coupling toward biarenes in good to excellent yields. Notably, this ligand‐ free method enabled catalysis in air (Scheme 21.61d) [75]. In 2016, Suzuki cross‐coupling of pyridine and thiophene‐based fluorosulfates and aryl boronic acids was reported by Zhang et al. using a NHC based Pd‐PEPPSI catalyst in EtOH and water. An array of heteroaryl‐based biarenes were synthesized in excellent yields (Scheme 21.62a) [31]. The cross‐coupling reaction was selective for C─X bond cleavage in the presence of the fluorosulfate moiety with a general selectivity preference of C–Br ≥ C–OTf >C–Cl. Pridgen and Huang, in an effort to synthesize a pair of endothelin (ET‐1) receptor antagonists, reported

21.11  Application of Fluorosulfates: Dual Reactivity

the construction of the final C─C bond formation via Pd‐catalyzed cross‐­coupling of fluorosulfonyl enol ethers and an aryl boronic acid (Scheme  21.62b) [76]. Sonogashira cross‐coupling is also possible with aryl fluorosulfates. An example by Sharpless, Jiang and coworkers demonstrated a Sonogashira coupling of 2‐ acetylphenyl sulfurofluoridate (fluorosulfate) and ethynylbenzene resulting in 2‐ (phenylethynyl)benzaldehyde (Scheme 21.63) [75]. Suzuki–Miyaura coupling of heteroaromatic fluorosulfates; Zhang et. al. [31] OSO2F N

+

Ar

Pd-PEPPSI-iPr (1 mol%)

Ar–B(OH)2

K2CO3 (3 equiv), EtOH/H2O (3 : 1) 35 °C, 1–24 h

(1.5 equiv)

(a)

N 26 examples (72–99%) OCH3

Suzuki–Miyaura coupling of fluorosulfonyl enol Pridgen and Huang [76] OSO2F O

PrO

OCH3

BnO

B(OH)2 BnO

Pd(dppf)2Cl2 (5 mol%)

+ O

OCH3

O

PrO

K2CO3 (2 equiv) Toluene/acetone/H2O (4/4/1, v/v) 70 °C

(b)

O OCH3

94%

O O

Scheme 21.62  Suzuki–Miyaura cross‐couplings with aryl boronic acids and (a) pyridyl fluorosulfates and (b) fluorosulfonyl enol ethers. Sonogashira: Jiang, Sharpless, and coworkers [75] O

H

PdCl2(PPh3)2 (2 mol%) OSO2F + (2.8 mmol)

Et3N (5 equiv), DMF 80 °C, 4 h

O

H 73%

Scheme 21.63  Pd‐catalyzed Sonogashira cross‐coupling reactions with aryl fluorosulfate and terminal alkyne.

21.11.2.2  CO or CO2 insertion

Cleavage of the C─OSO2F bond by palladium catalysts in classic cross‐coupling reactions established a platform for fluorosulfates to act as an electrophile for other Pd‐catalyzed reactions, including insertion reactions. In 1992, Roth and Thomas reported a Pd‐catalyzed alkoxycarbonylation reaction using aryl fluorosulfates. Using Pd(OAc)2/1,3‐bis(diphenylphosphino)propane (dppp) as a catalyst–ligand system, aryl fluorosulfates in the presence of triethylamine and carbon monoxide were converted to methyl benzoates in good to excellent yields (Scheme 21.64a) [77]. In 2017, Qin and coworkers followed up this work with a one‐pot synthesis of benzoate derivatives from phenols in good yields

663

664

21  Properties and Applications of Sulfur(VI) Fluorides CO Insertion: Roth and Thomas [77] Pd(OAc)2 (3 mol%) dppp (3 mol%)

OSO2F R

Et3N (1.1 equiv), CO DMSO/MeOH (3 : 2) 60 °C, 2 h

O OMe

R

(a)

6 examples (44–92%)

CO Insertion via in situ fluorosulfate formation: Qin [78]

OH R

(1) SO2F2, Et3N (2.0 equiv) DMSO, rt, 2–6 h (2) Pd(OAc)2 (3 mol%) dppp (3 mol%) NaHCO3 (1.5 equiv), CO H2O or ROH, 60 °C, 12 h CO2H

CO2H F3C

Ph 95%

97% CO2Et

H3CO

CO2iPr

O R

OR

(b)

>35 examples (36–98%) CO2H

CO2H 56% CO2Ph

98% CO2Bn

NC 81%

54%

74%

88%

Scheme 21.64  Pd‐catalyzed CO insertion reactions toward the synthesis of (a) aryl carboxylic acid esters from aryl fluorosulfates and methanol and (b) aryl carboxylic acids and esters from phenols (via in situ formation of aryl fluorosulfates) and water or alcohols.

(Scheme 21.64b). Key to this transformation was the in situ formation of a key fluorosulfate intermediate via fluorosulfurylation of the alcohol with SO2F2 gas [78]. The authors proposed that fluorosulfurylation was followed by oxidative addition of the C─OSO2F bond by Pd0 to PdII, CO insertion, and then alcoholysis of the Pd–CO insertion adduct – [LPdII–(CO)Ar]+OSO2F− – to form a PdII species and the benzoate product. Carboxylation of aryl fluorosulfates is also possible using Ni catalysis. In 2019, Mei and coworkers report a Ni(PPh3)2Cl2‐catalyzed conversion of aryl and heteroaryl fluorosulfates to carboxylic acids in good yields (Scheme 21.65, top row) [79]. Manganese was used as a reductant to form a proposed aryl NiI species followed by CO2 migratory insertion. Aryl and pyridyl methyl carboxylic esters were formed by methylation of the carboxylic acid by CH2N2 (Scheme 21.65, bottom row). Also, an one‐pot conversion of aryl alcohols to benzoic acid derivatives was reported using SO2F2/NaH to first form the fluorosulfate followed by Pd‐catalyzed CO2 insertion. 21.11.2.3 C─N Bond Formation

Several groups have reported Buchwald–Hartwig aminations of aryl fluo­ rosulfates to form diarylamines. Following up on their work involving C─C

21.11  Application of Fluorosulfates: Dual Reactivity O OSO2F

Ni(PPh3)2Cl2 (5 mol%) L1 (10 mol%)

R

Mn (3 equiv) CO2 (1 atm), rt, DMF, 20 h CO2H

CO2H

O

OH

R

24 examples (81–97%) F CO2H

N H

H3CO 94%

83%

CO2Me N 67%a

N 63%a

N L1

H3C

CO2H N

H 3C

84% CO2CH3

H3C 46%a

CH3

EtO2C

CO2Me

CO2Me N

OCH3

87%

N H3C

N

CH3

82%a

Scheme 21.65  Ni‐catalyzed CO2 insertion reactions toward the synthesis of aryl carboxylic acids and pyridyl‐based methyl esters. Conditions: aCH2N2 was added as a methylating reagent in the second step.

bond‐forming Suzuki couplings with aryl fluorosulfates, in 2016 Hanley et  al. reported Ni‐ and Pd‐catalyzed amination of aryl fluorosulfates with aryl amines in good yields (Scheme 21.66a) [80]. Using a SO2F2/CpPd (cinnamyl)/Xantphos system, a Pd‐catalyzed one‐pot conversion of amination of ethyl‐4‐hydroxybenzoate was also reported providing ethyl 4‐(phenylamino)benzoate in good yields (Scheme 21.66a). In 2017, Kim and coworkers subsequently reported a ligand‐ free Buchwald–Hartwig amination using a Pd(Ph3)4/Cs2CO3 system to synthesize diarylamines from aryl fluorosulfates and aniline (Scheme 21.66b) [81]. 21.11.2.4 C─H Bond Formation

With the tremendous interest in using biomass as a renewable alternative to petroleum for carbon feedstocks, efforts have focused on ways to convert phenols – readily available from biomass sources like lignin – to aromatic hydrocarbons. In Qin and coworkers reported a Pd‐catalyzed hydrodeoxygenation of phenols to arenes using aryl fluorosulfates as an intermediate [82]. This one‐pot reaction involved fluorosulfurylation of a phenolic derivative by SO2F2 to the fluorosulfates, followed by a net hydrogenation with formic acid. Arenes were produced under mild reaction conditions in good to excellent yields (Scheme 21.67). 21.11.3  Application of Fluorosulfates: Sulfur–Fluoride Exchange (SuFEx) Chemistry Similar to sulfonyl fluorides, fluorosulfates in the presence of nucleophiles can also react at the sulfur atom toward SuFEx chemistry. These transformations have found applications in materials, synthetic, and bioconjugation chemistry. This section highlights key examples demonstrating the diverse applications involving alkyl fluorosulfates.

665

666

21  Properties and Applications of Sulfur(VI) Fluorides Hartwig-Buchwald Coupling: Hanley and coworkers [80] CpPd (cinnamyl) (1 mol%) OSO2F R

NH2

Xanthphos (1.2 mol%)

+

K2CO3 (2 equiv) 1,4-dioxane 80 °C, 12–24 h

(1.2 equiv)

H N R 12 examples 66–99%

Ni(COD)2 (5 mol%) OSO2F R

NH2

H N

DPPF (5 mol%)

+

LiOtBu (2 equiv),

R

MeCN (2 equiv)

(1.2 equiv)

13 examples 20–85%

Toluene, 100 °C, 15 h

(a) One-pot Amination of Phenol using SO2F2 OH

NH2 +

EtO O

(1.2 equiv)

H N

(1) SO2F2, K2CO3, 1,4-dioxane, rt, 24 h (2) CpPd (cinnamyl) (1 mol%) Xanthphos (1.2 mol%) 1,4-Dioxane, 80 °C, 5 h

Ph

EtO O

82%

Hartwig-Buchwald Coupling (Kim) OSO2F R

(b)

NH2

+

Cs2CO3 (1 equiv), (1.2 equiv)

H N

Pd(PPh3)4 (5 mol%) Toluene, 4 Å MS 110 °C, 12 h

R

R 20 examples 12–80%

Scheme 21.66  Buchwald–Hartwig aminations of aryl fluorosulfates and aniline. (a) Ni‐ and Pd‐catalyzed aminations including one‐pot amination of ethyl‐4‐hydroxybenzoate with SO2F2 and aniline. (b) Ligand‐free Pd‐catalyzed amination of aryl fluorosulfates.

21.11.3.1  Sulfates and Sulfamates

One of the first examples of SuFEx chemistry using fluorosulfates was a report from 1986 from Huang and Shreeve involving the synthesis and reactivity of polyfluoroalkyl fluorosulfates. Both alcohols and amines underwent SuFEx transformations to generate alkyl sulfate esters and sulfamates, albeit in some cases with strong base (nBuLi) or at very low temperatures (Scheme  21.68a) [83]. In their 2014 report of polysulfonates formation from sulfonyl fluoride and silyl ether monomers, Sharpless also demonstrated aryl fluorosulfates can be used to generate polysulfate block copolymers [84]. Using either DBU or BEMP as catalyst, bisphenol A‐based bisfluorosulfate and bisarylsilyl ether monomers were polymerized in nearly quantitative yields to generate polysulfates with a high average molecular weight up to 143 000 Da (Scheme 21.68b). A follow‐up study by Sharpless in 2017 reported polysulfates formation in comparable yields and average molecular weights using a bifluoride salt as a catalyst [47].

21.11  Application of Fluorosulfates: Dual Reactivity (1) SO2F2, Et3N (1.2 equiv) DMSO, rt, 3–6 h

OH R

H R

(2) Pd(OAc)2 (2 mol%) dppp (2.4 mol%), Et3N (4 equiv) HCOOH (4 equiv), rt, 2–4 h

25 examples (42–93%) CN

H

H

H

H

O O

Ph 83%

54%

54%

75%

65%

O

H H H H

H H

56%

H H

93%

H

72%

Scheme 21.67  Hydrodeoxygenation of phenols to arenes via aryl fluorosulfates. Alkyl Sulfates and Sulfamates: Huang and Shreeve [83]

F3C

Rf

O O S O F

O O S O F

+

+

ROH (1 equiv)

(CH3)2NH (2 equiv)

Et3N (1 equiv) or n-BuLi (1.03 equiv)

F3C

–196 °C to rt, r.t. or 70 °C, 3–20 h

–196 °C to rt –196 °C to rt, 10 h,

2 examples (50–55%)

Rf

(a)

O O R2 S O O

O O S N(CH3)2 O

2 examples 50–55%

Aryl sulfates: Sharpless, Fokin, and coworkers [84] BPA-polysulfate FO2SO

+

OSO2F

DBU or BEMP (1–20 mol%) NMP, 150 °C, 2 h

R3SiO

OSiR3

R = TMS, TBS, TDBPS, or TIPS

(b)

O O S O O

O

10 examples

n

PS

(96–97%; Mn 17 000–143 000 Da, PDI = 1.2–2.0

Scheme 21.68  SuFEx reactions with fluorosulfates to synthesis polysulfates, alkyl sulfates, and alkyl sulfamates.

The Staudinger ligation is an important tool in chemical biology used to cross‐ link organic segments to biological molecules (e.g. fluorescent labeling, covalent

667

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21  Properties and Applications of Sulfur(VI) Fluorides

bonding of drug targets, etc.). Classically involving an azide and aryl phosphine to form an amide bond, Wang and coworkers reported a Staudinger reduction/ SuFEx reaction creating a tetrahedral sulfamate bond linkage [85]. Aryl phosphines with a fluorosulfate group first underwent a Staudinger reduction with an organoazide at the phosphorus center to form an imidophosphorane [RNPR 3 ] intermediate. The amido group (–NHR−) is then transferred to the fluorosulfate moiety via an intermolecular SuFEx transformation resulting in sulfamate bond. Several organoazides containing vancomycin, saccharide, and nucleotide derivatives underwent the ligation in excellent yields (Scheme 21.69). This was the first reported example of a Staudinger ligation forming a tetrahedral covalent bond linkage.

F

O S O

R O P

+ R N3 Ph Ph

37 °C, 1 h pH 7.4 buffer and/or DMSO/DMF –HF, –N2, 0.5–5 h

OH HO HO

O P

Ph Ph

10 examples (11–96%)

O

OH O

Van

O N HO

O S

N H

O

Ph Ph

Ph

N S O HO P

O P

86%

N HO

O S

N HO

O S

O P

Ph Ph

Van = Vancomycin 94%

Ph Ph

95%

Scheme 21.69  Staudinger ligation of amines to fluorosulfate‐based phosphine.

Other groups have used SuFEx chemistry directly as a click reaction in protein modification. In 2018, Wang and coworkers described the cross‐linking of two proteins via genetic encoding of fluorosulfate‐l‐tyrosine (FSY) into cellular proteins [86]. FSY was shown to be nontoxic to cells and selectively target histidine, lysine, and tyrosine residues. Proteins that where genetically encoded to incorporate FSY was demonstrated to efficiently undergo intra‐ and intermolecular cross‐linking with nucleophilic residues (Scheme 21.70). Overall this approach highlights the promise of using SuFEx click chemistry in live cells for a myriad of applications as therapeutics, biomaterials, and drug discovery.

21.12 ­Applications of Other S(VI) Fluorides In addition to sulfonyl fluorides and fluorosulfates, other S(VI) fluorides have also found applications in synthetic and bioconjugation chemistry. Sulfamoyl

21.12  Applications of Other S(VI) Fluorides FSY F S O O

O

O O S O Nuc

–

Nuc

SuFEx

Nuc = iysine, histidine, and tyrosine

Scheme 21.70  Covalent interprotein crosslinking via an intracellular SuFEx reaction using genetically encoded fluorosulfate‐l‐tyrosine (FSY).

fluorides (R2NSO2NR2)  –  unlike sulfonyl fluorides or fluorosulfates  –  have comparatively few applications. This is presumably due the considerably attenuated electrophilicity of the sulfur atom (see Scheme  21.3). Although, in 2014 Sharpless and coworkers reported a MgO‐mediated SuFEx reaction with dialkyl sulfamoyl fluoride with a piperazine analogue to form a sulfamide in good yields (Scheme 21.71) [1]. O O S N F

O O

HN

N CH3CN/H2O

reflux, MgO, 12 h

F

O O S N N

O

N O 82%

F

Scheme 21.71  Sulfur–fluoride exchange with dialkylsulfamoyl fluorides and amines.

Iminosulfur oxydifluorides are a class of S(VI) fluorides that contain a NSO2F2 moiety. The possibility of two fluoride leaving groups highlight the ability of iminosulfur oxydifluorides to be used for transformations to install clickable S(VI) fluoride tags as well as accessing challenging S(VI) compounds. In 2017, Sharpless and coworkers introduced thionyl tetrafluoride (SOF4) as a “hub” reagent toward other S(VI) fluorides. Commercially available and readily synthesized SOF4 selectively reacts with primary amines and anilines to rapidly produce iminosulfur oxydifluorides in good to excellent yields (Scheme 21.72a). Sharpless also demonstrated that in the presence of amines or silyl ethers, iminosulfur oxydifluorides can undergo SuFEx reaction to synthesize monofluorinated S(VI) fluorides: sulfuramidimoyl fluorides (─N═SONR2F) and sulfurofluoroimidates (– N=SOORF), respectively, in high yields (Scheme  21.72b,c) [87]. In a follow‐up report in 2019,  Sharpless and coworkers reported a bifluoride ion‐mediated SuFEx ­trifluoromethylation of iminosulfur oxydifluorides toward bis(trifluoromethyl) sulfuro­xyimines (─N═SO(CF3)2) in good to excellent yields (Scheme  21.72d) [88]. Bis(trifluoromethyl)sulfur oxyimines were used to synthesize benzothiazole

669

670

21  Properties and Applications of Sulfur(VI) Fluorides Synthesis of iminosulfur oxydifluorides H R N H (a)

SOF4

R

Et3N or DIPEA (2.2 equiv) MeCN, rt, 30 min

N F

S

O F

25 examples (54–99%)

Iminosulfur oxydifluorides and dialkylamines R

N F

S

O

R1R2NH (2 equiv)

F

CH3CN, rt, 30 min

(b)

N

O

R1 N R2 Sulfuramidimidoyl fluoride 14 examples (86–99%) R

F

S

Iminosulfur oxydifluorides and silyl ethers

R

N F

S

O F

DBU or BEMP (2–10 mol%) R1OTBS (2 equiv)

N

O

R1 O F Sulfurofluoridoimidate 7 examples (76–96%)

CH3CN, rt, 0.5–3 h

(c)

R

S

Iminosulfur oxydifluorides and TMSCF3

R

(d)

N F

S

O F

KFHF (1 mol%) TMSCF3 (2.2 equiv) DMSO, rt, 30 mins

N O S R CF3 F3C Bis(trifluoromethyl)sulfur oxyimines 18 examples (41–99%)

Scheme 21.72  Synthesis and addition of nucleophiles to iminosulfur oxydifluorides.

derivatives, demonstrated to selectively target MCF7 breast cancer and MCF10A mammary epithelial cells. Iminosulfur oxydifluorides can also be used to functionalize biological molecules toward further click chemistry. In 2019, Sharpless and coworkers reported the labeling of single‐stranded alkynes for alkyne–azide click chemistry using an alkyne‐based aryl iminosulfur oxydifluoride [89]. Alkynes were installed either via sulfurofluoridoimidate‐based click moiety or a sulfamide linkage in good yields by HPLC (Scheme 21.73). Similar bioconjugation reactions where used to modify bovine serum albumin (BSA) with biotin via installation of an alkyne‐ based aryl iminosulfur oxydifluoride on lysine residues followed by Cu‐catalyzed azide–alkyne cycloaddition with a biotin–PEG3–azide.

O OTBS

HO

OH

NH2 SIngle-stranded DNA-strand

(1) pH 8.8 Tris buffer DMT-MM, MeCN

O

(2) aq. KFHF/KF, pH = 8.0

NH

N

S

F

N

F S

O F 0.1 M in MeCN pH 8.0 buffer (0.1 M) H2O, rt, 6 h

O S NH NH 70% HPLC yield O

Sulfamide-based click moiety

Scheme 21.73  On‐DNA SuFEx chemistry with iminosulfur oxydifluorides.

F

0.1 M in MeCN pH 8.0 buffer (0.1 M) H2O, rt, 6 h

O N O S F

O O NH

82% HPLC yield d Sulfurofluoridoimidate-based click moiety

672

21  Properties and Applications of Sulfur(VI) Fluorides

­Acknowledgments Financial support from the Pomona College and Hirsch Research Initiation Grant is acknowledged.

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22 Construction of S–RF Sulfilimines and S–RF Sulfoximines Emmanuel Magnier University of Versailles, Bâtiment Lavoisier, Institut Lavoisier de Versailles (ILV ‐ UMR CNRS 8182), 45 Avenue des Etats‐Unis, 78035 Versailles cedex, France

22.1 ­Introduction The sulfilimine moiety can be assimilated to the aza‐analogue of sulfoxide as the sulfoximine one, the aza‐analogue of sulfone (Figure  22.1). The chemistry of non‐fluorinated sulfoximines is widely developed in the literature, whereas research works devoted to perfluoroalkylated sulfoximines are much rarer. For the information of the readers, it is important to precise at this stage the exact convention chosen for the definition of perfluoroalkylated sulfilimines and sulfoximines. In this chapter, only the molecules bearing a fluorine or a per­ fluoroalkyl group directly bonded to the sulfur atom are considered (i.e. SF, SCFR2, SCF2R, SCF3, SCnF2n+1). The main content of this chapter is the preparation of these two unusual poly­ heteroatomic structures and especially the many recent efforts to improve their syntheses. Such growing interest is explained by the promising properties brought by the sulfoximine moiety. Recent reviews proposed a comprehensive overview of this topic [1]. Firstly, the sulfoximines displayed highly electron‐ withdrawing properties, particularly when a trifluoromethanesulfone (triflone) is attached to the nitrogen [2]. This characteristic was used for the enhancement of reactivity in organic chemistry [3] or for materials science applications such as superacid and liquid crystals of fluorescent devices [4]. Secondly, sulfoximines can be used as reactants for late stage introduction of a fluorinated chain in organic molecules with two important advantages: the opportunity to vary the perfluoroalkyl chain (see Section 22.3) and the great versatility of their reactivity. Originally, sulfoximines were described as electrophilic reagents for the creation of carbon– and heteroatom–perfluoroalkyl bonds [5]. Then, their mono‐ and difluoromethyl versions were extensively engaged as nucleophile with a wide range of electrophiles (ketones, nitrones, epoxides) giving rise to not only stere­ oselective but also sometimes enantioselective transformations [6]. Very recently, and mainly thanks to the rebirth of the photoredox catalysis, the sulfoximines were also employed as source of perfluoroalkyl radicals [7]. Thirdly, and although Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

N S

R1

R2

O NR2 S RF R1

RF

Sulfilimine

RF = fluorine or perfluoroalkyl chain F, CFR2, CF2R, CF3, CnF2n+1

Sulfoximine

Figure 22.1  S–RF sulfilimines and S–RF sulfoximines.

the non‐fluorinated sulfoximines are intensively used as ligand for catalysis, the halogenated parent were used only one time for this goal [8]. Fourthly, the inter­ est of this so peculiar group in life science remains at its infancy [9]. To the best of our knowledge, only two examples of bioactive S‐trifluoromethyl sulfoximines are described [10].

22.2 ­Construction of S–RF Sulfilimines Very few synthetic methods are nowadays available for the preparation of S–RF sulfilimines. The first member of this family was published in 1976 by Shreeve and coworker [11]. The treatment of the bis(trifluoromethyl)sulfur difluoride (CF3)2SF2 with ammonia gave rise to the corresponding sulfilimine (Scheme 22.1). The same reaction was carried out to furnish the F‐tetramethylene sulfilimine [12]. Both compounds were readily deprotonated and the resulting lithium salt was able to react with a set of electrophiles [13]. Nevertheless, these seminal works have been restricted to fully perfluorinated substrates. F F3C

S

NH

F CF3 + NH3

or F

F F2C

S

F2C

PhCH2NH2 50–60%

CF2

S

RX

CF3

F3C n-BuLi

or

F2C

N S

NLi

NH S F2C CF2

CF2

NLi

F3C

S

R + LiX

CF2

S

CF3

or NLi S F2C CF2 F2C

CF2

R = SiMe3

66%

R = CN

13%

R = SO2CF3

22%

R = SO2Cl

45%

R = Cl

70%

R=F

20%

R = C(CO)CF3 65%

Scheme 22.1  First synthesis of S–RF sulfilimines and N‐functionalization.

Many years later, Kirsch and coworkers proposed an example of preparation of aryl S–CF3 sulfilimines albeit in a poor yield, by treatment of a trifluoro­ methyl sulfoxide with trifluoromethanesulfonic anhydride and an amine [4a] (Scheme 22.2).

22.2  Construction of S–RF Sulfilimines F H C3H7

H F

F O S CF3

H

Tf2O, TfNH2

C3H7

DCM, rt, 18 h

H F

16%

CF3 N S O S O CF3

Scheme 22.2  Synthesis of a N–Tf S–RF sulfilimine.

Inspired by previous works, Magnier and coworkers proposed the preparation of a small library of novel sulfilimines [14]. The activation of perfluoroalkylated sulfoxides by trifluoromethanesulfonic anhydride gave rise to an electrophilic species that can be attack by a nitrile through a Ritter‐like type of reaction to deliver a triflate acetal (stable below −15 °C), which hydrolysis allowed the isola­ tion of the corresponding stable sulfilimines (Scheme 22.3 right). The scope of this methodology showed the opportunity to work with many different per­ fluoroalkyl chains (only the reaction with CF2H and CFH2 sulfoxides failed), a wide range of nitriles, and various functionalized aromatic rings. Apart from an exception (the methyl perfluorooctyl sulfoxide), the method was not efficient in alkyl series. The use of dinitriles offered also the possibility to isolated bis‐sulfil­ imines [15]. Another interesting variation was proposed. The treatment of the reaction with a primary amine instead of water gave rise to the free NH sulfilim­ ines, thus providing the opportunity of further functionalization at the nitrogen atom (Scheme 22.3 left) [16]. O R1

NH S RF

17 examples 46–99%

(1) CH3CN, Tf2O –15 °C, 1 d

O S

R1

(2) propylamine (15 equiv) –15 °C to rt, 1 d RF = CFCl2, CF2Br, CF3, C4F9 R1 = Halogen, alkyl

(1) R2CN, Tf2O –15 °C, 1 d RF

R1

(2) H2O

RF = CFCl2, CF2Br, CF3, C4F9, C8F17 R1 = Halogen, alkyl R2 = Aryl, benzyl, alkyl

N S

R2 RF

31 examples 18–97%

Scheme 22.3  General synthesis of aryl S–RF sulfilimines.

One of the issues of the previous methodologies was fixed by the work of Hu and coworkers [5f]. They showed that fluoromethyl phenyl sulfide was able to react with chloramine‐T to afford the corresponding N‐tosyl sulfilimine (Scheme 22.4).

PhSCH2F

Chloramine-T.3H2O, DCM N-Benzyl-N,N-diethylethanaminium chloride reflux, 3 d

NTs S CH2F Ph 71%

Scheme 22.4  Synthesis of phenyl S–CFH2 sulfilimines.

As demonstrated in this section, the synthetic methods for the preparation of S–RF sulfilimines are still at their infancy and improved pathways are urgently needed.

677

678

22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

22.3 ­Construction of S–RF Sulfoximines Even if the synthesis of sulfoximines is more developed in the literature than the preparation of sulfilimines, the methods of construction of S–RF sulfoximines are largely less numerous than their non‐fluorinated analogues. After a long latency period, recent articles disclosed efficient and general methods. 22.3.1  Synthesis of Sulfonimidoyl Fluorides The sulfonimidoyl fluorides are obviously the most simple members of the S–RF sulfoximine family, as a single fluorine atom is bonded to the sulfur atom. Their first preparation was realized by Yagupolskii and coworkers [17]. Arenesulfinyl chlorides were able to react with the dichlorotrifluoromethanesulfonamide to afford quantitatively the corresponding sulfonimidoyl chlorides. The chloride is then displaced by a fluoride by simple treatment with silver fluoride in acetoni­ trile (Scheme 22.5). O S R

Cl

O

Cl2NSO2CF3, 20 °C 95–99%

S

NSO2CF3 Cl

R

R = H, Cl, F, Me, NO2

O

S

NSO2CF3 Cl

AgF, MeCN 25 °C, 30 min

O

98%

Cl

S

NSO2CF3 F

Cl

Scheme 22.5  First synthesis of sulfonimidoyl fluorides.

In 2011, a reappraisal of this work by Bolm and coworkers demonstrated the efficiency of this halogen exchange by the help of the less costly potassium fluo­ ride [18]. In the same article, a one‐pot, two‐step protocol was also proposed for the synthesis of the target compound (Scheme  22.6). In this approach, N‐­ benzoyl and N‐Boc sulfinamides were firstly oxidized with t‐BuOCl to provide to the desired sulfonimidoyl chlorides. Treatment of the crude mixture with a com­bination of KF and 18‐crown‐6 offered the desired sulfonimidoyl fluorides. Recently, Hu and coworkers have described the N‐tosyl‐4‐chlorobenzene

R1

O S

O N H

R2

(1) t-BuOCl

O NR2 S R1 F

(2) KF (2 equiv), 18-crown-6 (cat.) MeCN, rt., 16 h. 16 examples 35–89% Bolm and coworkers [18]

O NTs S F Cl

SulfoxFluor Hu and coworkers

Scheme 22.6  Improved synthesis of sulfonimidoyl fluorides. SulfoxFluor as new reagent.

22.3  Construction of S–RF Sulfoximines

sulfonimidoyl fluoride (SulfoxFluor, obtained via the same methodology) as a novel deoxyfluorination reagent [19]. The sulfonimidoyl fluorides are also a direct and straightforward entry to S‐­ trifluoromethyl sulfoximines as showed in a seminal work of the Ukrainian group of Yagupolskii [20]. One example of the reaction of a arenesulfonimidoyl fluoride with the Ruppert–Prakash reagent in the presence of catalytic amount of tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) gave rise to the targeted sulfoximine in 70% yield (Scheme 22.7 left). Bolm and coworkers have extended this methodology to a wider range of examples and with the help of tetrabutylammonium fluoride as catalyst (Scheme 22.7 right) [18]. O NTf S F F

O NTf S CF3

Me3SiCF3, TASF THF, –20 °C to rt, 1 h 70%

2

O NR Me3SiCF3, TBAF S 1 R F MeCN, rt, 18 h

2

O NR S CF3

R1

F

Yagupolskii and coworkers [19]

16 examples 51–79%

Bolm and coworkers [18]

Scheme 22.7  Trifluoromethyl sulfoximines from sulfonimidoyl fluorides.

22.3.2  Synthesis of S–RF Sulfoximines by Fluorination of S–Alkyl Sulfoximines As mentioned in the introduction, the preparation of non‐fluorinated sulfoxi­ mines is abundantly widespread in the literature. Fluorination of the latter could then appear as an opportunity. Hu and coworkers developed this tricky approach within three research papers. They demonstrated the efficiency of this approach in the monofluorination of S‐benzyl S‐phenyl tosylsulfoximine [6a]. The benzylic position was deprotonated with NaH in dry DMF and the resulting anion treated by N‐fluorodibenzenesulfonimide (NFSI) (Scheme  22.8 left). Five monofluori­ R O NTs S Ph

(1) NaH, DMF rt, 40 min (2) NFSI, rt overnight

O NTs R S Ph

R O NTs S Ph F R=H R = p-Br R = p-F R = o-Br R = p-Me

61% 68% 69% 83% 71%

(1) n-BuLi, THF, –78 °C, 0.5 h (2) NFSI, –78 °C to rt, 6 h

O NTs S R

Ph

F R = Me R = Et R = n-Bu

Scheme 22.8  Monofluoration of S‐benzyl and S‐alkyl sulfoximines.

69% 71% 54%

679

680

22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

nated sulfoximines were obtained in 61–83% yield. From S‐alkyl S‐phenyl tosyl­ sulfoximines, the same methodology was applied provided the use of n‐BuLi at −78 °C and NFSI as fluorinating reagent, allowing the isolation of three new compounds in 54–71% yield (Scheme 22.8 right) [6b]. Another interest of this methodology is to exploit the availability of the two enantiomers of non‐fluorinated sulfoximines. Posner and coworkers shown that the electrophilic fluorination occurred with no alteration of the chiral sulfur center [10a]. This is also one the rare example of an enantiomerically pure S–RF sulfoximines (see Section  22.3.6). Inspired by this work, Hu and coworkers employed the same monofluoromethyl sulfoximine to access the corresponding difluoromethylated product. The second fluorination was more tedious and the introduction of a benzoyl group was necessary to facilitate the deprotonation with lithium bis(trimethylsilyl)amide (LiHMDS) [6c]. After fluorination with NFSI, the removal of the benzoyl group was carried out (Scheme 22.9). O Ph

Ph

O NTBS (1) n-BuLi, THF, –78 °C S CH3 (2) NFSI, –78 °C, 42% (R)

Ph

O NTBS S CH2F (S)

N

O

KHMDS THF, –78 °C 95%

Ph

O NTBS S F O

Posner and coworkers [10a] (2) NaOH (20% aq.), rt 94% Hu and coworkers [6c]

Ph (1) LiHMDS, NFSI, THF, –78 °C

O NTBS S CF2H Ph

Scheme 22.9  Mono‐ and difluorination of S‐phenyl S‐alkyl sulfoximines.

Despite the efficiency of these reactions, they are limited to mono‐ and difluo­ romethyl sulfoximines. Other methodologies have to be considered for longer perfluoroalkylated chains. 22.3.3  Synthesis of S–RF Sulfoximines by Imination of Sulfoxides The imination of a sulfoxide consists in a very classical way to prepare a non‐ fluorinated sulfoximine. Once again, the presence of the fluorine atoms near the sulfur atom, dramatically changes the behavior and the reactivity of this chalco­ gen. Apart one exception (vide infra), all the classical methods failed to be applied to the synthesis of S–RF sulfoximines. At least, they have to be adapted, often by using harsh conditions. The first perfluoroalkylated sulfoximines were pre­ pared by Shreeve and coworkers in the early 1970s [21]. The reaction of bis(perfluoroalkyl)sulfur oxydifluorides with ammonia gave rise to a salt, which under treatment by hydrogen chloride provided the NH sulfoximines as stable solids (Scheme  22.10). In the same article, the authors showed the N‐­functionalization of the parent molecule with various groups (CF3S, CN,

22.3  Construction of S–RF Sulfoximines

Me3Si, Me, Cl). Despite its high yielding, this methodology seems limited to per­ fluoroalkylated sulfoxides. O F S RF R 2 F F 1

3 NH3 –78 °C to rt

O NH.NH3 S RF RF2

O NH S RF RF2

HCl

1

1

RF1 = RF2 = CF3 RF1 = CF3; RF2 = C2F5 RF1 = RF2 = C2F5

80% 70% 68%

Scheme 22.10  First imination of perfluoroalkylated sulfoxides.

Yagupolskii and coworkers published the first general preparation of S‐aryl sulfoximines from perfluoroalkylated sulfoxides in 1984 [22]. The treatment of aryl sulfoxides by sodium azide in hot oleum furnished in high yield the NH sul­ foximines (Scheme 22.11). A major interest of this reaction was the direct isola­ tion of free sulfoximines, prompting further N‐functionalization. To demonstrate, Shibata and coworkers employed this methodology to prepare their electrophilic trifluoromethylation reagent [5a]. An iterative methylation process followed the synthesis of the parent sulfoximine. O S R

CF3

NaN3 (1 equiv), oleum 70 °C, 1.5 h

Yagupolskii and coworkers [21]

+

O NH S CF3

O N TfO– S CF3

87% 96% 80%

Shibata reagent prepared by Yagupolskii method

R R=H R = Cl R = NO2

Scheme 22.11  First general preparation of S‐aryl sulfoximines from perfluoroalkylated sulfoxides.

The synthetic pathway developed by the Ukrainian group inspired many labs in the world. The initial conditions were nevertheless relatively harsh and espe­ cially not tolerant neither to groups sensitive to acidic conditions nor to mono‐ and difluoromethyl sulfoxides. That is why modifications were proposed in order to extend the scope of this chemistry. If the presence of the oleum (or concentrated sulfuric acid) seems crucial and cannot be replaced by another acid, the dilution by a solvent (chloroform or dichloromethane) allowed the transposition of this pathway to S‐alkyl sulfoximines (Scheme 22.12). Finch and coworkers first proposed the addition of chloroform for the efficient preparation of the fluoromethyl phenyl sulfoximine (Scheme  22.12a) [23]. Magnier and Wakselman were the first to prepare alkyl trifluoromethyl (or perfluoroalkyl) sulfoximines in high yield (Scheme  22.12b), providing dichloromethane was used [24]. Inspired by these results, Prakash et al. extended this methodology to difluoromethyl sulfoxides (Scheme  22.12c) [5c]. During their studies they pointed out the importance of the solvent. No positive result was obtained with

681

682

22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

Ph

O S

CH2F

(a)

R1

O S

R2

Ph (c)

CH3CN, rt, 98%

O NH S Ph CH2F

NaN3 (2 equiv), oleum (30–33%) CH2Cl2, rt, 16 h, 70%

(b) O S

NaN3, H2SO4 cc.

CHF2

NaN3 (2 equiv), oleum (20%) CH2Cl2, rt, 16 h, 99%

O NH S 2 R

R1

R1 = C8H17; R2 = CF3 R1 = C8F17; R2 = CH3

70% 91%

O NH S Ph CHF2

Scheme 22.12  Extensions of the seminal Yagupolskii’s methodology [5e, 14]. (a) Monofluoromethyl series; (b) Trifluoromethyl and perfluorooctyl series; (c) Difluoromethyl series.

chloroform. Despite the efficiency of this method, problems of safety should be taken into consideration. Some minor explosions have been reported [5c, d] and in our laboratory we had to deal with fortunately contained fires in the reaction flask. These reactions have to be run on small scales, under fume hood protec­ tion and with care. Hu and coworkers [5b] published the only example of copper‐catalyzed prepa­ ration of a sulfoximine. Treatment of the starting difluoromethyl phenyl sulfox­ ide by the [N‐(p‐toluenesulfonyl)imino]phenyliodinane as a source of nitrene with copper triflate as catalyst ended up to the target molecule in good yield (Scheme 22.13).

Ph

O S

CF2H

PhINTs (1.3 equiv) Cu(OTf)2 (10%) CH3CN, 50 °C, 24 h, 60%

O NTs S Ph CF2H

Scheme 22.13  Copper‐catalyzed preparation of a difluoromethyl sulfoximine.

22.3.4  Synthesis of S–RF Sulfoximines by Oxidation of Sulfilimines The S–RF sulfilimines, which preparation was detailed at the beginning of this chapter, are also important key intermediates for the synthesis of S–RF sul­ foximines. Shreeve and coworkers were the first to prepare highly perfluoro­ alkylated sulfilimines and logically also the first to oxidize such peculiar compounds by means of mCPBA (Scheme 22.14). If the transformation of the bis(trifluoromethyl) sulfilimine was quite tedious [25], that of the cyclic sulfil­ imines was successful [13c]. NH S CF3 F3C

mCPBA –120 °C to rt 3–4 d

O NH S F3C CF3

NH S F2C CF2 F2C

CF2

Scheme 22.14  Oxydation of perfluoroalkyl sulfoximines.

mCPBA 98%

O NH S F2C CF2 F2C

CF2

22.3  Construction of S–RF Sulfoximines

In the same vein, Kirsch and coworkers realized the oxidation of their sulfilim­ ines (see Scheme 22.2) with sodium periodinate and a catalytic amount of ruthe­ nium trichloride in a rather low yield [4a]. In fact, the S‐aryl S–RF sulfilimines are quite easy to oxidize as demonstrated by the work of Magnier and coworkers [14]. These sulfur derivatives reacted smoothly with potassium permanganate at room temperature. One equivalent of this nontoxic reagent was furthermore adequate for a total conversion and obtention of moderate to excellent yields (Scheme 22.15). This transformation was performed on various substrates and proved to be tolerant to different aromatic groups attached to the sulfur, to many groups bonded to the nitrogen, as well as to different perfluoroalkyl chains (Scheme 22.15a). Two additional sequences were performed allowing the in situ transformation of the halogen atom (Scheme 22.15b,c). The oxidation step was simply followed by a quench with sodium dithionite, a reducing agent, able to cleave a carbon–bromine or a carbon–chlorine bond (providing a heating pro­ moted by microwaves) revealing then the CF2H and the CFHCl moieties [5e]. The use of potassium permanganate was also successful to perform the straightforward transformation of (bis)sulfilimines into their corresponding (bis) sulfoximines (Scheme 22.16) [15]. Another major advantage of this multistep synthesis is the opportunity to eas­ ily remove the acyl function attached to the nitrogen (Scheme 22.17). A simple treatment by an aqueous solution of hydrochloric acid promoted this deprotec­ tion and produced the NH sulfoximines. This high yielding reaction was efficient for many perfluoroalkyl chains. This methodology enables the safe preparation of a wide range of NH sulfoxi­ mines but features two limitations: it is limited to S‐aryl sulfoxides and is not efficient with the monofluoromethyl sulfoxides. 22.3.5  Synthesis of S–RF Sulfoximines from Sulfides To the best of our knowledge, there is only one research article related to the direct transformation of fluoroalkyl sulfides to sulfoximines. Any of the method­ ologies developed for non‐fluorinated sulfides were not transposable, with nev­ ertheless an exception. The group of Reboul recently developed an efficient synthesis of non‐fluorinated NH‐sulfoximines from sulfides using phenyliodine diacetate (PIDA) and ammonium carbamate (AC) with methanol as the solvent [26]. During the following year, a joint work of Reboul and Magnier groups were able to use this methodology for the synthesis of S–RF sulfoximines [27]. The conditions previously proposed by Reboul were amenable to good reactivity with mono‐ and difluoromethyl sulfides (Scheme 22.18). Two monofluoromethyl sul­ foximines (with alkyl and aryl group attach to the sulfur) were isolated in excel­ lent yield after only 30 minutes. Providing an increase of the reaction time (overnight reaction), the same conditions delivered the difluoromethyl sulfoxi­ mines, once again both in aryl and alkyl series. However, when the reaction was conducted in methanol using trifluoromethyl phenyl sulfide, only traces of the desired NH‐sulfoximine were detected by 19F NMR analysis of the crude product and sulfide was recovered. As an increase of the electrophilicity of the hypervalent iodine species (precursor of the nitrene)

683

O N S

O R2

RF

MeCN, rt, 16 h

R1

O N S RF

KMnO4 (1 equiv)

R2

R1

(a) O N S (b)

CFCl2

R2 = Me R2 = Me

R1 = Br

R2 = Me

R1 = H

Ra = Bn

R1 = H

R2 = Me

R1 = H

R2 = Me

R1 = H

R2 = (CH2)2CN

R1 = H

R2 = (CH2)3CN

R1 = H

R2 = (CH2)4CN

RF = CF3

99%

RF = CF3

95%

RF = C4F9

40%

RF = CF3

44%

RF = CF2Br

70%

RF = CFCl2

60%

RF = CF3

70%

RF = CF3

91%

RF = CF3

81%

O (1) KMnO4, H2O CH3CN, rt,18 h (2) Na2S2O4 4.5 equiv

O N S CF2H

O N S

(c)

CF2Br

R1 = H R1 = Me

95% O

(1) KMnO4, H2O CH3CN, rt,18 h (2) Na2S2O4 (13 equiv), 120 °C microwaves, 30 min

O N S CFHCl 98%

Scheme 22.15  Oxidation of sulfilimines by potassium permangante. (a) General oxidation; (b) Clivage of a C─Br bond; (c) Clivage of a C─Cl bond.

22.3  Construction of S–RF Sulfoximines

CF3 O S Ph N

O

CF3 S Ph N

O O CF3 S Ph N

O CF3 O S Ph N

KMnO4, H2O CH3CN, 18 h

84%

(a) O

O

N Ph

n

S

CF3 F3C

O N S

KMnO4, H2O

O N S Ph CF3

CH3CN, 18 h

Ph

O O

N

n

F3C

S

Ph

n = 2; 72% n = 3; 54% n = 4; 55%

(b)

Scheme 22.16  Oxidation of bis(sulfilimines). (a) Aromatic scaffold; (b) Aliphatic scaffold. O O N S RF

O NH S RF

HCl 6N CH3CN, rt, 18 h

RF = C4F9 RF = CF3 RF = CF2Br RF = CFCl2 RF = CF2H RF = CFHCl

90% 99% 91% 71% 92% 95%

Scheme 22.17  Preparation of the NH sulfoximines. OAc R1

S

I R2

+

O NH S 2 R

H2NCO2NH4 (1.5 equiv)

OAc

MeOH, rt, time

R1

PIDA (2.1 equiv) Time : 30 min O NH S F 89%

Time : overnight O NH S F

Me

80%

O NH S F

O NH F S F 82%

O

F 88%

O NH F S F 68%

Scheme 22.18  Mono‐ and difluoromethyl NH‐sulfoximines.

could enhance the reactivity, the authors proposed the use of trifluoroethanol (TFE) as the best compromise (Scheme 22.19). Full conversion was achieved pro­ viding an additional addition of 1 equiv of each reagent after three hours. The use of TFE systematically delivered a constant ratio of N‐acyl and NH sulfoximines. To avoid tedious separation, the crude mixture was directly treated with HCl 6 M in acetonitrile in order to isolate the free sulfoximines. With these optimized conditions, a small library of sulfoximines was prepared. This methodology proved to be compatible with various perfluoroalkyl chains in both aryl, benzyl, and alkyl series.

685

686

22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

R

S

RF

1) PIDA (2.1 equiv), AC (1.5 equiv) TFE, rt, 3 h

O NH S R RF +

(2)PIDA (1 equiv), AC (1 equiv), 3 h

O NAc S R RF

HCl, CH3CN rt, 12 h

RF = CF3 RF = C4F9 RF = CF2Br RF = CFCl2

14 examples 3 examples 4 examples 3 examples

O NH S R RF 40–95% 46–77% 49–87% 33–88%

Scheme 22.19  General one‐pot synthesis of S–RF sulfoximines.

This method appears as the most general and efficient one‐pot synthesis of S‐ perfluoroalkylated NH‐sulfoximines from sulfides. These mild and metal‐free conditions are compatible with –CH2F, –CFCl2, –CF2H, –CF2Br, –C4F9, and – CF3 groups, in both the alkyl and aryl series. 22.3.6  Isolation of S–RF Sulfilimines and S–RF Sulfoximines as Single Enantiomers The sulfilimines and sulfoximines are chiral compounds and their non‐­ fluorinated versions are widely described in the literature. In the peculiar case of S–RF molecules, they are few examples described in research articles. The mono­ fluoromethyl version of the sulfoximine has been described in both enantiomers (see Scheme  22.20). They were both prepare by the fluorination of the corre­ sponding S‐methyl sulfoximine, starting from the readily available enantiomers. This reaction occurred with total retention of configuration. The difluoromethyl compound was isolated after a two‐step fluorination of the monofluorinated molecule. O Ph

NTBS S

CH2F (S)

Posner and coworkers [10a]

O Ph

NTBS S

CH2F (R)

O Ph

NTBS S

(R)

CF2H

Hu and coworkers [6c]

Scheme 22.20  Enantiomers of mono‐ and difluomethyl sulfoximines.

Regarding the higher fluorinated groups, no direct asymmetric synthesis of either S–RF sulfilimines nor S–RF sulfoximines is available. They have been nevertheless isolated thanks to the separation of the enantiomers by analytical methods. Two groups published such separation, in the same year. Nishimura reported in 2014 a library of molecule disruptors of the glucokinase–­glucokinase regulatory protein interaction [10b]. A piperazine ring bearing an aromatic moiety was highly important for the protein recognition (Scheme  22.21a). Among the numerous functional groups bonded to this aromatic ring, the authors have included a sulfoximine moiety and separated the two enantiomers by supercritical fluid chromatography. The same year, Vo‐Thanh and Magnier published the separation of the phenyl trifluoromethyl sulfilimine also by

O O S N

N

N

O NH S CF3

(R) and (S) separated by SFC Nishimura et al. [10b]

H2N (a) F3C NH F3C

S

°°

O S HN (R)

F3C

S

HN (S)

KMnO4 (85% yield) °° HN

S

(R)

CF3

ee > 99%

O HN

S

(S)

CF3

R O N S RF

RF = CF3 RF = CF3 RF = CF3 RF = CF2Br RF = CF2Br RF = CFCl2 RF = CFCl2

R=H R = Me R = (Me)2 R=H R = Ac R=H R = Ac

Vo-Thanh and coworkers [27]

(b)

Scheme 22.21  Separation of enantiomers of perfluoroalkyl sulfoximines. (a) Nishimura separation; (b) Vo‐Thanh and Magnier separation.

688

22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

supercritical fluid chromatography [28]. The absolute configurations were assigned by X‐ray analysis (Scheme  22.21b). Each enantiomer was indepen­ dently oxidized with total conservation of the chiral information. Once again, the absolute configurations were assigned by X‐ray analysis. No epimerization occurred for both sulfilimines and sulfoximines even after several years at room temperature. Other sulfoximines have been separated and their optical proper­ ties determined. Even if the sulfoximines can be separated on large scale thanks to preparative HPLC, many efforts are still urgently needed for a large‐scale direct preparation of enantiomerically pure sulfilimines and sulfoximines.

22.4 ­Post Functionalization The N‐functionalization of sulfoximines is highly important in order to modu­ late their properties. The description of this chemistry would be too space con­ suming and out of the scope of this chapter. It is nevertheless necessary to give a few information. Since their first preparations of sulfilimines and sulfoximines, the two pioneer groups (Shreeve [13a–c] and Yagupolskii [2a]) have demon­ strated the possibility to bond the nitrogen atom to various heteroatoms i­ ncluding electron‐withdrawing triflone group. More recently, N‐trifluoromethylthiolated sulfoximines were prepared [29]. Magnier and coworkers have also contributed to the exploration of the reactivity of the nitrogen atom in these structures. They disclosed the acylation [30] as well as its arylation [8, 31] and the introduction of unsaturated systems [32]. Photoredox catalysis was an efficient method for the N‐alkylation by the generation of fluorinated nitrogen centered sulfoximidoyl radicals [33]. Another important work relied on the functionalization of the aro­ matic ring bonded to the sulfur. NH‐sulfoximine was for the first time proposed as ortho‐directing group along a deprotonation sequence [34]. This methodol­ ogy allowed the transformation of the aromatic ring by a wide range of electro­ philes. The presence of an iodine atom was then a direct entry for the catalytic introduction of double bonds [35] or triple bonds [36]. Final cyclization between the alkyne moiety and the nitrogen gave rise to previously unknown cyclic sulfoximines.

22.5 ­Conclusion The synthesis of S–RF sulfilimines and sulfoximines was neglected for a long time and was until the recent years a curiosity of the scientific literature. After a long period of latency, the chemistry of S‐perfluoroalkylated sulfilimines and mainly sulfoximines is emerging. This could be explained by both the extended availability of the starting materials, thanks to the progress realized in their preparation, and by the increasing applications offered by these uncommon moieties. We are fully convinced that these peculiar moieties will be of importance.

­  References

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R., and Bolm, C. (2014). Chem. Soc. Rev. 43: 2426–2438. (c) Shen, X. and Hu, J. (2014). Eur. J. Org. Chem.: 4437–4451. (d) Barthelemy, A.‐L. and Magnier, E. (2018). C.R. Chim. 21: 711–722. 2 (a) Kondratenko, N.V., Popov, V.I., Radchenko, O.A. et al. (1986). Zh. Org. Khim. 22: 1716–1721. (b) Terrier, F., Magnier, E., Kizilian, E. et al. (2005). J. Am. Chem. Soc. 127: 5563–5571. 3 (a) Boiko, V.N., Kirii, N.V., and Yagupolskii, L.M. (1994). J. Fluorine Chem. 67: 119–123. (b) Garlyauskayte, R.Y., Bezdudny, A.V., Michot, C. et al. (2002). J. Chem. Soc., Perkin Trans. 1: 1887–1889. (c) Lemek, T., Groszek, G., and Cmoch, P. (2008). Eur. J. Org. Chem.: 4206–4209. 4 (a) Kirsch, P., Lenges, M., Kühne, D., and Wanczek, K.‐P. (2005). Eur. J. Org. Chem.: 797–802. (b) Garlyauskayte, R.Y., Chernega, A.N., Michot, C. et al. (2005). Org. Biomol. Chem. 3: 2239–2243. (c) Rouxel, C., Le Droumaguet, C., Macé, Y. et al. (2012). Chem. Eur. J. 18: 12487–12497. 5 (a) Noritake, S., Shibata, N., Nakamura, S. et al. (2008). Eur. J. Org. Chem.: 3465–3468. (b) Zhang, W., Wang, F., and Hu, J. (2009). Org. Lett. 11: 2109–2112. (c) Prakash, G.K.S., Zhang, Z., Wang, F. et al. (2011). J. Fluorine Chem. 132: 792–798. (d) Nomura, Y., Tokunaga, E., and Shibata, N. (2011). Angew. Chem. Int. Ed. 50: 1885–1889. (e) Pegot, B., Urban, C., Bourne, A. et al. (2015). Eur. J. Org. Chem.: 3069–3075. (f ) Shen, X., Zhou, M., Ni, C. et al. (2014). Chem. Sci. 5: 117–122. 6 (a) Zhang, W., Huang, W., and Hu, J. (2009). Angew. Chem. Int. Ed. 48: 9858–9861. (b) Zhang, W. and Hu, J. (2010). Adv. Synth. Catal. 352: 2799–2804. (c) Shen, X., Zhang, W., Ni, C. et al. (2012). J. Am. Chem. Soc. 134: 16999–17002. (d) Shen, X., Zhang, W., Luo, T. et al. (2012). Angew. Chem. Int. Ed. 51: 6966–6970. (e) Shen, X., Miao, W., Ni, C., and Hu, J. (2014). Angew. Chem. Int. Ed. 53: 775–779. (f ) Shen, X., Liu, Q., Luo, T., and Hu, J. (2014). Chem. Eur. J. 20: 6795–6800. (g) Luo, T., Zhang, R., Zhang, W. et al. (2014). Org. Lett. 16: 888–891. (h) Luo, T., Zhang, R., Shen, X. et al. (2015). Dalton Trans. 44: 19636–19641. (i) Liu, Q., Shen, X., Ni, C., and Hu, J. (2017). Angew. Chem. Int. Ed. 56: 619–623. 7 (a) Yang, Y.‐D., Lu, X., Lu, G. et al. (2012). ChemistryOpen 1: 221–226. (b) Yang, Y.‐D., Wang, X., Tsuzuki, S. et al. (2014). Bull. Korean Chem. Soc. 35: 1851–1854. (c) Arai, Y., Tomita, R., Ando, G. et al. (2016). Chem. Eur. J. 22: 1262–1265. (d) Daniel, M., Dagousset, G., Diter, P. et al. (2017). Angew. Chem. Int. Ed. 56: 3997–4001. (e) Noto, N., Koike, T., and Akita, M. (2019). ACS Catal. 9: 4382–4387. (f ) Nakayama, Y., Ando, G., Abe, M. et al. (2019). ACS Catal. 9: 6555–6563. 8 Le, T.‐N., Diter, P., Pegot, B. et al. (2015). J. Fluorine Chem. 179: 179–187. 9 Lücking, U. (2013). Angew. Chem. Int. Ed. 52: 9399–9408. 10 (a) Kahraman, M., Sinishtaj, S., Dolan, P.M. et al. (2004). J. Med. Chem. 47: 6854–6863. (b) Nishimura, N., Norman, M.H., Liu, L. et al. (2014). J. Med. Chem. 57: 3094–3116. 11 Morse, S.D. and Shreeve, J.M. (1976). J. Chem. Soc., Chem. Commun.: 560–561.

689

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22  Construction of S–RF Sulfilimines and S–RF Sulfoximines

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14

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(b) Kumar, R.C. and Shreeve, J.M. (1981). J. Am. Chem. Soc. 103: 1951–1952. (c) Abe, T. and Shreeve, J.M. (1981). J. Chem. Soc., Chem. Commun.: 242–243. (a) Mace, Y., Urban, C., Pradet, C. et al. (2009). Eur. J. Org. Chem.: 3150–3153. (b) Urban, C., Cadoret, F., Blazejewski, J.‐C., and Magnier, E. (2011). Eur. J. Org. Chem.: 4862–4867. Pégot, B., Urban, C., Diter, P., and Magnier, E. (2013). Eur. J. Org. Chem.: 7800–7808. Urban, C., Macé, Y., Cadoret, F. et al. (2010). Adv. Synth. Catal. 352: 2805–2814. Yagupolskii, L.M., Garlyauskayte, R.Y., and Kondratenko, N.V. (1992). Synthesis: 749–750. Kowalczyk, R., Edmunds, A.J.F., Hall, R.G., and Bolm, C. (2011). Org. Lett. 13: 768–771. Guo, J., Kuang, C., Rong, J. et al. (2019). Chem. Eur. J. 25: 7259–7264. Garlyauskayte, R.Y., Sereda, S.V., and Yagupolskii, L.M. (1994). Tetrahedron 50: 6891–6906. Sauer, D.T. and Shreeve, J.M. (1972). Inorg. Chem. 11: 238–242. Kondratenko, N.V., Radchenko, O.A., and Yagupolskii, L.M. (1984). Zh. Org. Khim. 20: 2250–2251. Boys, M.L., Collington, E.W., Finch, H. et al. (1988). Tetrahedron Lett. 29: 3365–3368. Magnier, E. and Wakselman, C. (2003). Synthesis: 565–569. Morse, S.D. and Shreeve, J.M. (1977). Inorg. Chem. 16: 33–35. Lohier, J.‐F., Glachet, T., Marzag, H. et al. (2017). Chem. Commun. 53: 2064–2067. Pégot, B., Magnier, E., and Reboul, V. (2018). Chem. Eur. J. 64: 17006–17010. Le, T.‐N., Kolodziej, E., Diter, P. et al. (2014). Chimia 68: 410–413. Bohnen, C. and Bolm, C. (2015). Org. Lett. 17: 3011–3013. Macé, Y., Constant‐Urban, C., Bouvet, S. et al. (2013). Synthesis: 1505–1512. Macé, Y., Pégot, B., Guillot, R. et al. (2011). Tetrahedron 67: 7575–7580. Anselmi, E., Le, T.‐N., Bouvet, S. et al. (2016). Eur. J. Org. Chem.: 4423–4428. Prieto, A., Diter, P., Toffano, M. et al. (2019). Adv. Synth. Catal. 361: 436–440. Le, T.‐N., Diter, P., Pegot, B. et al. (2016). Org. Lett. 18: 5102–5105. Barthelemy, A.‐L., Prieto, A., Diter, P. et al. (2018). Eur. J. Org. Chem.: 3764–3770. Barthelemy, A.‐L., Anselmi, E., Le, T.‐N. et al. (2019). J. Org. Chem. 84: 4086–4094.

691

Part IV Selenium‐Linked Fluorine‐Containing Motifs

693

23 When Fluorine Meets Selenium Thierry Billard 1,2 and Fabien Toulgoat 1,3 1

University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (ICBMS – UMR CNRS 5246), 43 bd du 11 Novembre 1918, Villeurbanne 69622, France 2 CERMEP – In Vivo Imaging, Groupement Hospitalier Est, 59 Bd Pinel, Lyon 69677, France 3 CPE – Lyon, 43 boulevard du 11 Novembre 1918, Villeurbanne 69616, France

23.1 ­Introduction Merging of fluorinated groups with chalcogens leads to new motifs with specific properties. This concept has been well illustrated by the CF3S [1] and CF3O moi­ eties [2]. Nevertheless, the use of the next chalcogen, namely, the selenium, has been, until recently, only scarcely described. Selenium is an important trace ele­ ment in human physiology [3] and selenolated compounds found applications in various fields from life science [4] and drug design [5] to materials science [6]. Furthermore, CF3Se group presents interesting electronic properties (Hammett constants σp = 0.45, σm = 0.44; Swain−Lupton constants F = 0.43, R = 0.02) [7] with a higher inductive effect than CF3O or CF3S but with a lower resonance parameter. Moreover, the Hansch–Leo lipophilicity parameter has been recently measured [8] and the value (πR  =  1.29) is between OCF3 and SCF3 [9]. These properties offer some modulations of molecular properties in the design of com­ pounds for various applications. This led to the recent development of original methods allowing an easy access to trifluoromethylated molecules and by exten­ sion to other fluorinated selenolated motifs.

23.2 ­Indirect Synthesis of CF3Se Moiety One of the first strategies developed to synthesize trifluoromethylselenolated molecules was an indirect approach. Thus, the trifluoromethylation of various selenolated substrates has been performed by using different available trifluoro­ methylating reagents.

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

694

23  When Fluorine Meets Selenium

23.2.1  Nucleophilic Trifluoromethylation With the development of various reagents able to generate CF3− anion, several trifluoromethylations of selenolated compounds have been developed. Because of its effectiveness and popularity, the Ruppert–Prakash reagent (CF3SiMe3) has been one of the most used. Diselenides could be trifluoromethylated with CF3SiMe3, in the presence of a stoichiometric amount of fluoride anion (Scheme 23.1a) [10]. The method has been improved by using a larger scope of easily available selenocyanates instead of diselenides (Scheme  23.1b) [11]. Furthermore, only a catalytic amount of fluoride anion was required, due to the ability of released cyanide anion to desilylate CF3SiMe3. This method has been applied to the synthesis of bioactive compounds [4a, 12]. Some years after, this method has been adapted to a one‐pot process by preforming in situ aromatic selenocyanates from the corresponding diazonium salts (Scheme 23.1c) [13]. An example of a one‐pot process starting directly from an aniline has been also described (Scheme 23.1d). These methods of trifluoromethylation of selenocy­ anates have been extended to other fluorinated groups (Section 23.4) [13, 14].

PhSeSePh

RSeCN

(1) KSeCN (1.5 equiv) CuCl/CuCl2/1,10-phen (10 mol%) Cs2CO3 (1.5 equiv) CH3CN, –25 °C, 20 min

CF3SiMe3 (2 equiv) Bu4N+F– (2 equiv) THF, 0 °C 43% CF3SiMe3 (2 equiv) Bu4N+F– (0.2 equiv) THF, 0 °C then rt 58–75%

(a)

(c)

(2) CF3SiMe3 (2 equiv), rt, 12 h

(d)

(1) HBF4 ·Et2O (1.05 equiv) iAmONO (1.1 equiv) CH3CN, 15 °C, 30 min

CF3SeR (b)

(2) KSeCN (1.5 equiv) CuCl/CuCl2/1,10-phen (10 mol%) Cs2CO3 (1.5 equiv) CH3CN, –35 °C, 40 min (3) CF3SiMe3 (2 equiv), rt, 12 h

(Het)ArN2+BF4– 40–88%

NH2 O2N 70%

Scheme 23.1  Synthesis of trifluoromethylselenoethers with CF3SiMe3.

With respect to the atom economy concept, the chemistry of fluoroform (HCF3) has been developed. Under basic conditions, HCF3 could be deproto­ nated to trifluoromethylate diselenides (Scheme  23.2a) [15]. This strategy has been used to synthesize labeled compound [18F]CF3SePh [16]. Fluoroform has also given rise to the formation of CF3Cu species by deprotonation in presence of copper salts. This complex was then reacted with diselenides (Scheme 23.2b) or selenocyanates (Scheme 23.2c) to afford the corresponding trifluoromethylsele­ noethers [17]. Of the sources of CF3− anion, fluoral hemiaminals can react with diselenides to   provide the corresponding selenoethers (Scheme  23.3a) [18]. Trifluoro­ methylselenylbenzene (CF3SePh) was obtained by trifluoromethylation of diphe­ nyl diselenides with diethyl trifluoromethylphosphonate, activated by tBuOK, but in low yield (Scheme 23.3b) [19]. Solutions of borazine‐CF3− anion prepared from HCF3, hexamethylborazine and a base can also trifluoromethylate diphe­ nyldiselenide to give CF3SePh (Scheme 23.3c) [20]. Trifluoromethyl iodide can

23.2  Indirect Synthesis of CF3Se Moiety 80–95%

DMF

RSeCN DMF

HCF3 / tBuOK / CuCl

90%

DMF RSeSeR

(c)

CF3Cu (1.5 equiv)

CF3SeR

(b)

HCF3 (excess) N(TMS)3/Me4NF (1.5 equiv) or tBuOK (1.1 equiv)

(a) R = Ph (47%)

DMF, –15 °C

Scheme 23.2  Synthesis of trifluoromethylselenoethers with HCF3.

be reduced with tetrakis(dimethylamino)ethylene (TDAE) to generate CF3− anion, which can react with diselenides (Scheme 23.3d). With an excess of CF3I, both RSe moieties of diselenide could be trifluoromethylated since the released RSe− anion (from the nucleophilic attack by CF3−) can react with CF3I through a SRN1 mechanism [21]. This last method has been extended to higher fluorinated homologues (Section 23.4). OSiMe3 N BnN

O P OEt F3C OEt (1.2 equiv)

CF3 (2 equiv)

tBuOK (2 equiv)

Bu4N+[Ph3SiF2]– (2 equiv) DME, 80 °C, 80% RSeSeR

CF3I (5 equiv) TDAE (2.2 equiv)

(a) CF3SeR (d)

(b)

PhSeSePh (c)

DMF, 0 °C to rt 180–198% (both RSe part used) N B

B N

N B

DMF, –40 °C to rt 34%

HCF3 (4.5 equiv) DMSO O (1 equiv) S CH2– K+ H 3C

DMSO, rt

N B

B N

CF3

69% – K+

N B

Scheme 23.3  Synthesis of trifluoromethylselenoethers with various nucleophilic trifluoromethylating reagents.

23.2.2  Radical Trifluoromethylation The availability of numerous methods to generate the radical CF3˙ allowed their use in the trifluoromethylation of selenolated compounds. For example, sodium trifluoromethylsulfinate (sodium triflinate, or Langlois reagent) is an efficient reagent to generate trifluoromethyl radical. It has been used, under oxidative conditions, to trifluoromethylate phenylselenol (Scheme 23.4) [22].

695

696

23  When Fluorine Meets Selenium

CF3SO2Na (2 equiv) AgNO3 (0.1 equiv) K2S2O8(2 equiv) SeH

CH3CN/H2O 80 °C, 24 h

SeCF3

CF3SO2Na (3 equiv) I2O5 (2 equiv)

74%

DMSO 110 °C, 24 h

Scheme 23.4  Radical trifluoromethylation of selenol with Langlois reagent.

Sodium triflinate has also been used to synthesize phenylselenotrifluoro­ methylsulfonates from diselenides or selenyl chlorides (Scheme 23.5) [23]. These compounds undergo a homolytic scission of the Se─SO2 bond under UV irradia­ tion to generate the CF3SO2˙ radical. This latter rapidly extrudes SO2 to release the CF3˙ radical. In presence of diselenides (1 equiv), CF3˙ is trapped to give the corresponding trifluoromethylselenolated compounds (Scheme  23.5a) [24]. In presence of 2 equiv of diphenyl diselenide, the phenyl trifluoromethylselenosul­ fonate could provide CF3SePh without any UV irradiation (Scheme 23.5b) [11b]. The supposed mechanism involves the dissociation of a charge transfer complex between CF3SO2Ph and PhSeSePh. A one‐pot process has been described to directly obtain CF3SePh (Scheme 23.5c) [11b]. CF3I (2–3 equiv) DMF/H2O RSeSeR (1 equiv) rt HOCH2SO2Na (3 equiv) PhSeCl

CF3SO2– Na+

28–90%

hν PhSeSePh (1 equiv)

CH2Cl2 PhSeSePh (0.5 equiv) Br2 CH2Cl2

CF3SO2SePh 55–95%

PhSeSePh (0.5 equiv) PhI(OCOCF3)2

CH2Cl2, 40 °C

53%

(a)

CF3SePh PhSeSePh (2 equiv) CH2Cl2, 40 °C

(b)

85% (c)

CH2Cl2 PhSeSePh (3 equiv), Br2 (1 equiv) (2 equiv of CF3SO2Na)

(d)

80%

CH2Cl2, 40 °C

Scheme 23.5  Radical trifluoromethylation of diselenide with phenylselenotrifluoromethylsulfonate.

Trifluoromethyl iodide is also a well‐known reagent to perform radical reaction. In the presence of Rongalite (sodium hydroxymethanesulfinate, HOCH2SO2Na), CF3I generates a trifluoromethyl radical, through a single electron transfer (SET) process, which could react with diselenide to provide the corresponding trifluo­ romethylselenoether (Scheme  23.5d) [25]. Note­ worthy, this approach has been also extended to higher fluorinated homo­ logues (Section 23.4).

23.3  Direct Introduction of CF3Se Moiety

23.3 ­Direct Introduction of CF3Se Moiety 23.3.1  Nucleophilic Trifluoromethylselenolating Reagents Direct nucleophilic trifluoromethylselenolation reactions require the availability of trifluoromethylselenolate salts or complexes. Considering such compounds, the association of trifluoromethylselenolate anion with several cations or metals has been reported in the literature. Among these reagents, it should be empha­ sized that two of them have emerged as trifluoromethylselenolating reagents: trifluoromethylselenocopper (Section 23.3.1.1) and ammonium trifluoromethyl­ selenolate (Section 23.3.1.2). Other salts such as mercury [26], cesium [27], thal­ lium [27], silver [27, 28], gold [28b], or platinum [29] trifluoromethylselenolate have been seldom used as trifluoromethylselenolating reagents [27, 30]. In addi­ tion, the use of pre‐reagents for the in situ generation of a trifluoromethylseleno­ late anion equivalent was also reported (Sections 23.3.1.3 and 23.3.1.4). 23.3.1.1 Trifluoromethylselenocopper

The synthesis of a trifluoromethylselenocopper was first reported by Yagupolskii and coworkers in 1985 starting from bis(trifluoromethyl)diselenide [31]. The reaction of this diselenide in the presence of copper powder in DMF furnished quantitatively CF3SeCu–DMF complex. Such complex was used as trifluoro­ methylselenolating reagent in a one‐pot two‐step reaction: after its in situ forma­ tion, the complex reacts with aryl iodides or iodopyridine to give access to the corresponding trifluoromethylselenolated compounds (Scheme 23.6). Similarly, trifluoromethylselenolation of propargylic bromide furnished the corresponding selenoether but in only 14% yield [32]. R (SeCF3)2

Cu powder DMF or NMP 95–110 °C

Y I

CuSeCF3

R

DMF or NMP 95–110 °C

Y SeCF3

Up to 95% Y = C, N; R = NO2, H, SeCF3

Scheme 23.6  One‐pot two‐step trifluoromethylselenolation involving trifluoromethylselenocopper complex.

It should be mentioned that the same strategy was applied to bis(penta­ fluorophenyl)diselenide to prepare the corresponding copper complex [31]. Of note, no DMF was associated to the complex in that case. Moreover, two examples of its use as pentafluorophenylselenolating reagent were reported (Section 23.4). Based on the procedure to prepare copper(I) trifluoromethylthiolate com­ plexes [33] and the isolation method for the complex [(phen)Cu(SeCF3)]2 (Section  23.3.1.3, Scheme  23.18) [34], four new copper(I) trifluoromethyl­ selenolate complexes have been prepared starting from Ruppert–Prakash reagent, elemental selenium, copper iodide, and a dinitrogen‐containing ligand, in the

697

698

23  When Fluorine Meets Selenium

presence of a fluoride source (Scheme 23.7) [35]. The resulting complexes were found to be air stable for months. Similarly to sulfur complexes, the nature of the ligand has a strong influence on the structure of the complex in the solid state. Dimeric selenolated complexes were isolated with bipyridine, 4,4′‐dimethylbi­ pyridine or neocuproine ligands, whereas a monomeric complex was isolated with the electron rich 4,4′‐di‐tert‐butylbipyridine. However, the structure of the complexes in the solid state appeared to have no or little influence on the reac­ tivity toward iodotoluene. Indeed, trifluoromethylselenolation was reported to occur in very good yield with the three complexes bearing a bipyridine‐type ligand (C1, C2, and C4), whereas a modest yield was achieved with the dimeric complex bearing a phenanthroline‐type ligand (C3 with neocuproine as ligand). A similar trend was observed in trifluoromethylthiolation reactions: bipyridine ligands furnished more efficient complexes than phenanthrolines ones. CF3 Se N Cu Cu N Se N CF3

N

CF3SiMe3

Se, CuI, L, KF

C1 (L = bpy), 54% C2 (L = dmbpy), 43% C3 (L = Me2Phen), 59%

CH3CN, RT

tBu N C4 (L = dtbpy) 46%

Cu SeCF3 N

tBu bpy = bipyridine, dmbpy = 4,4′-di-methylbipyridine, dtbpy = 4,4′-di-tert-butylbipyridine, Me2phen = neocuproine

Scheme 23.7  Preparation of copper(I) trifluoromethylselenolate complexes.

The group of Weng studied the reactivity of the copper trifluoromethylsele­ nolate bipyridine complex [bpyCuSeCF3]2 toward a wide variety of substrates in order to create C(sp3)─Se bond as well as C(sp2)─Se and C(sp)─Se bond. Trifluoromethylselenolation of alkyl [35], allyl [36], propargyl halides [36], and α‐haloketones [37] and α‐diazo esters [38] using [bpyCuSeCF3]2 as rea­ gent furnished the desired selenoethers in moderate to good yields (Scheme 23.8). It could be noted that an excess of electrophiles (1.6–1.8 equiv) was used in all cases. Reactions involving α‐haloketones or α‐diazo esters were reported to occur at lower temperature (40–45 °C) than reactions involv­ ing alkyl halides (110 °C) and even than those involving allyl or propargyl hal­ ides (70 °C). Except for trifluoromethylselenolation of α‐haloketones that required addition of a base to reach better yields [37], additives are not neces­ sary for other C(sp3)─Se bond formation reactions. Late‐stage trifluoro­ methylselenolation of molecules of interest such as vitamin E and coumarine were successfully performed [35].

23.3  Direct Introduction of CF3Se Moiety

Alk-SeCF3 75–94%

R 1

R2 R1

Br

Br

R

R3 (1.7

Alk-Br (1.7 equiv) CH3CN, 110 °C

Br

or

2

CF3 Se N Cu Cu N Se N CF3

SeCF3

R1 = Ar, Alk, CO2Alk R2 = H, Alk, OAlk

equiv) DMF, 70 °C

N

or

41–91%

Ar Cl

(1.7 equiv)

Ar SeCF3

DMF, 70 °C

47–83% O

O N2

R2O

THF, 40 °C

R1 (1.8 equiv) O

SeCF3

2O

R

R1 Up to 99% R1 = Het(Ar), Alk R2 = Alk, Allyl

R1

X

3 R R (1.7 equiv) X = I, Cl, Br K3PO4 (3 equiv) DCM, 45 °C O 2

R1

SeCF3

R3 34–99% R1 = Alk, Ar R2, R3 = H, Me R2

Scheme 23.8  C(sp3)─Se bond formation using [bpyCuSeCF3]2 as trifluoromethylselenolating reagent.

Aryl [35] and heteroaryl halides (pyridines, quinolones, quinoxalines, pyrimi­ dines, imidazo[1,2‐a]pyrazine, thiophenes, thiazoles, benzothiazoles, benzo­ furanes) [35, 39] were converted into the corresponding trifluoromethyl­sele­nolated derivatives in good to excellent yields (Scheme 23.9a). Of note, 2‐ bromopyridines furnished the desired trifluoromethylselenoethers in good to excellent yields (75–91%), whereas 3‐bromopyridines led to moderate yields (30–36%) and 4‐bromopyridines to low yields (14%) [39]. Trifluoromethyl­ selenolation of a series of 3‐iodopyrones was achieved in very good yields (Scheme 23.9b) [40]. The method was extended to a 4‐iodo‐ and to a 4‐bromopy­ rone (Scheme 23.9b) [40]. Similarly, substituted vinyl halides were successfully converted into the corresponding selenoethers (Scheme 23.9c) [41]. No change of the C═C double bond stereochemistry was observed during the trifluoro­ methylselenolation reaction: the E/Z ratio of the vinyl selenoethers corresponds to the one of the starting vinyl halides. In contrast, trifluoromethylselenolation of α‐bromo‐α,β‐unsaturated carbonyl compounds furnished a mixture of Z/E trifluoromethylselenoethers (Scheme 23.9d) [42]. Concerning the mechanism of the trifluoromethylselenolation of aryl halides, heteroaryl halides, vinyl hal­ ides, and α‐bromo‐α,β‐unsaturated carbonyl compounds, a radical pathway was ruled out by experiments in the presence of radical scavengers or radical clock

699

(Het)ArSeCF3 14–92%

X

I

RO

(Het)ArX (1.7 equiv) CH3CN, 110 °C or dioxane, 80 °C

Ar

SeCF3

52–69%

Fe powder (10 mol%) dioxane, rt O R′ R

89–98%

(b) R1 (c)

R2

R1

SeCF3 R2 34–94% R1 = Ar, Het(Ar), alk R2 = H, Ph; R3 = H, Ph, alk

(d) COR Ar

(e) or Br

Br (1.3 equiv) CH3CN/toluene, 80 °C

Br (1 equiv)

CsF (2 equiv) CH3CN/Xylene, 140 °C

or SeCF3

COR Ar

O

O 62–96% R R, R′ = H, Me, Ph

R3 X X = I, Br, Cl (1.7 equiv)

CH3CN, 100 °C

O

R′

O

Toluene, 100 °C

CF3 N Se N Cu Cu N Se N CF3

(f)

O or

R3

Ar Cl (1.3 equiv)

SeCF3

O O

O

or

SeCF3

(1.3 equiv) (a)

O O

RO

O

O O

X= I, Br

SeCF3

SeCF3

71–88% R = H, Ph, OAlk

Scheme 23.9  C(sp2)─Se bond formation using [bpyCuSeCF3]2 as trifluoromethylselenolating reagent.

23.3  Direct Introduction of CF3Se Moiety

[35, 36]. Weng and coworkers proposed a pathway involving an oxidative ­addition of the [bpyCuSeCF3]2 into the C(sp2)─X bond to form a Cu(III) ­intermediate, followed by a reductive elimination to furnish the desired trifluo­ romethylselenoethers [35, 36, 41, 42]. To complete the panel of trifluoromethyl­ selenolated α,β‐unsaturated carbonyl compounds, β‐bromo‐α,β‐unsaturated ketones were reacted with [bpyCuSeCF3]2 (Scheme 23.9e) [43]. In that case, the mechanism proposed is a 1,4‐addition of [bpyCuSeCF3]2 to β‐bromoenones ­followed by a copper bromide elimination. With regard to C(sp2)─Se bond formation, it should be mentioned that trifluoromethylselenoesters were ­ obtained via  an iron‐catalyzed trifluoromethylselenolation of acid chlorides (Scheme 23.9f ) [44]. Finally, C(sp)─Se bond was formed through oxidative trifluoromethylselenola­ tion of terminal alkynes (Scheme 23.10) [45]. In that case, Dess Martin periodi­ nane reagent was used as oxidant to convert [bpyCu(I)SeCF3]2 into a Cu(II) species, which can react in the presence of a base with terminal alkynes to fur­ nish the desired compounds after reductive elimination. DMP (3.3 equiv) KF (5 equiv) R H(1.7 equiv)

CF3 N Se N Cu Cu N Se N CF3

R DMF, rt

SeCF3

57–87% R = C6H13, Het(Ar)

Scheme 23.10  C(sp)─Se bond formation using [bpyCuSeCF3]2 as trifluoromethylselenolating reagent.

Moreover, the methodology proved to be scalable: several examples of trif­ luoromethylselenolation afforded up to 2 g of trifluoromethylselenoethers [36, 37, 40, 44, 45]. In addition to its nucleophilic reactivity, [bpyCuSeCF3]2 was also involved in a radical difluoroalkylation–trifluoromethylselenolation of alkynes [46]. 23.3.1.2  Tetramethylammonium Trifluoromethylselenolate (Me4NSeCF3)

Tetramethylammonium trifluoromethylselenolate (Me4NSeCF3) was initially prepared by reaction of tetramethylammonium fluoride with difluorosele­ nophosgene. Other trifluoromethylselonolate salts were prepared in a similar way and used only on one‐time experiments [27]. An alternative synthesis was reported in 2003 based on the reaction of Ruppert–Prakash reagent, elemental selenium (Se8) and tetramethylammonium fluoride at low temperature (Scheme 23.11) [47]. It should be noticed that this ammonium salt was reported Me3SiCF3 (1.05 equiv)

+

Se8 (1 equiv)

+

Me4NF (1 equiv)

DME –78 °C to rt

Me4NSeCF3 70%

Scheme 23.11  Synthesis of tetramethylammonium trifluoromethylselenolate.

701

702

23  When Fluorine Meets Selenium

to be stable at room temperature in scattered daylight for several weeks [47]. Few years later, such salt appeared to be a useful trifluoromethylselenolating reagent. Indeed, introduction of SeCF3 moiety onto a C(sp3) using Me4NSeCF3 occurs  under very mild conditions starting from alkyl bromides, chlorides, or tosylates, furnishing the desired trifluoromethylselenoethers in good yields (Scheme  23.12a) [48]. Of note, secondary alkyl bromides or iodides required longer reaction times and 2 equiv of Me4NSeCF3 to be converted in good yields. In addition to alkyl halides, α‐diazo esters or ketones were also trifluoromethyl­ selenolated by Me4NSeCF3. Initially, the group of Goossen and coworkers reported that copper thiocyanate was able to promote such reaction (Scheme 23.12b) [49]. Actually, such methodology was developed for trifluoro­ methylation of α‐diazo esters using the corresponding tetramethylammonium thiolate and extended to a few examples of trifluoromethylselenolation in the same conditions Me4NSeCF3. Regarding the mechanism, the formation of inter­ mediate Cu(I)SCF3 was proposed based on 19F NMR experiments and then reacted with the diazoester to form a copper–carbene complex [49]. The proton source required in the next step was found to come from water traces in the reac­ tion mixture and/or from the tetramethylammonium cation, but not from the solvent. However, it should be noticed that no experiment about reaction condi­ tions, optimization, or mechanism was reported for the trifluoromethylselenola­ tion reaction. A complementary approach was developed by the group of Zhang and coworkers who reported an acid‐mediated trifluoromethylselenolation of α‐diazoesters and α‐diazoketones (Scheme 23.12c) [48]. The nature of the acid (TfOH) as well as the temperature (−20 °C to rt) appeared to be two crucial parameters for this metal‐free transformation. Moreover, no product was formed in the absence of acid. Thus, initial protonation of the α‐carbon of the α‐diazo carbonyl, followed by the trifluoromethylselenolation of the resulting α‐ protonated‐α‐diazonium intermediate was proposed by the authors. R′ R

NMe4NSeCF3

X

R

CH3CN, N2, rt, 0.5–24 h 83–98%

(1.2–2 equiv)

R′

X = Br, Cl, OTs, I

SeCF3

R′ = Me, H

(a) CuSCN (10 mol%) O R NMe4NSeCF3 (1.2–1.8 equiv)

R′

CH3CN, rt, 15 h 64–95%

(b) O

N2

R TfOH (1 equiv) CH3CN, N2 –20 °C to rt, 3 h

(c)

R′ SeCF3

61–92%

Scheme 23.12  C(sp3)─Se bond formation using Me4NSeCF3 as trifluoromethylselenolating reagent.

23.3  Direct Introduction of CF3Se Moiety

The trifluoromethylselenolation of aryl iodides was reported using Me4NSeCF3 initially under metal catalysis. Based on their findings concerning the stability and the efficiency of Pd(I) dimer complexes in catalysis [50], and especially in trifluoromethylthiolation reactions [51], the group of Schoenebeck reported a Pd‐catalyzed trifluoromethylselenolation of a series of aryl iodides as well as few heteroaromatics in moderate to good yields (Scheme 23.13) [52]. The method is tolerant to a wide range of functional groups (FGs) including unpro­ tected amines. Moreover, as the initial [(PtBu3)PdI]2 complex is air stable, its handling does not require specific precautions. Similar stability was reported for  the in situ formed [(PtBu3)PdSeCF3]2 complex. Interestingly, this last one could be recovered at the end of the reaction and was found to be still active in a second reaction offering potential recycling possibilities. I tBu3P Pd R

I

+

Me4NSeCF3 (2 equiv)

Pd PtBu3 I

(5 mol%)

R

SeCF3

Toluene, 40–60 °C, 24 h

48–99%

Scheme 23.13  Pd(I)‐catalyzed trifluoromethylselenolation of aryl iodides with Me4NSeCF3.

With the aim to develop catalysis with less precious and more abundant metal, Ni‐catalyzed trifluoromethylselenolation using Me4NSeCF3 was also developed to convert aryl halides into the corresponding trifluoromethyl selenoethers (Scheme 23.14) [53]. The catalytic system Ni(COD)2 associated with bipyridine as ligand was found to be efficient to convert aryl iodides as well as aryl bromides although catalyst loading has to be increased to obtain good results for bromide derivatives [53a]. Aryl chlorides can also be transformed into the corresponding selenoethers, but it required to replace bipyridine by a bulkier and electron‐rich phosphine ligand such as 1,1′‐bis(diphenylphosphino)ferrocene (dppf ) [53a]. Trifluoromethylselenolation of heteroaromatic halides as well as one vinyl iodide was achieved with success using Ni(COD)2‐ligand system. A complementary approach was developed using a dinuclear Ni(I) complex as catalyst in order to  control the chemoselectivity of coupling reactions [53b]. Aryl iodides were Ni(COD)2 (5–30 mol%) bpy (10–30 mol%) or ddpf (20–40 mol%)

R

THF or toluene, rt–50 °C, 2–24 h X = I, Br, Cl (49–99%) X

+ Me4NSeCF3 (1.2–1.5 equiv)

I SIPr

Ni

Ni I

SIPr (10 mol%)

Benzene, 45 °C, 14–16 h X = I (68–99%)

Scheme 23.14  Ni‐catalyzed trifluoromethylselenolation of aryl halides.

R

SeCF3

703

704

23  When Fluorine Meets Selenium

converted in good to excellent yields into the corresponding trifluoromethyl selenoethers, whereas aryl bromides were found to be unreactive. Therefore, selective trifluoromethylselenolations of bromo‐, chloro‐, and fluoro‐aryl iodides were performed with exclusive functionalization of C─I bond. Me4NSeCF3 was also employed as trifluoromethylselonolating reagent in Cu‐ mediated oxidative reaction (Scheme 23.15) [54]. Actually, aryl boronic acids or esters, as well as vinyl boronic acids or esters, were converted into the corre­ sponding trifluoromethylselenoethers in moderate to very good yields in the presence of Cu(OTf )2, bipyridine, and O2 as oxidant. However, it should be men­ tioned that stoichiometric amounts of copper and ligand were required as only small amount of desired product was detected during experiments with 10 mol% of Cu. Of note, potassium trifluoroborate didn’t furnish the desired product and yields were very low using tin derivatives or N‐methyliminodiacetatic acid (MIDA) boronates. Interestingly, a one‐pot procedure involving the in situ for­ mation of Me4NSeCF3 followed by the oxidative coupling step was developed using Ruppert–Prakash reagent and elemental selenium. Thanks to this one‐pot procedure, the method was extended to perfluoroethylselenolation of one aryl boronic derivative. R

Me4NSeCF3 (1.1 equiv)

Cu(OTf)2 (1 equiv) bpy (1.1 equiv) O2

B(OR′)2

R

SeCF3

DMF, rt, 18 h 58–86% B(OR′)2

Ar R

DMF, rt, 18 h

Ar

SeCF3

R 62–75% (R = H, Me)

Scheme 23.15  Cu‐mediated oxidative trifluoromethylselenolation.

A copper‐catalyzed trifluoromethylselenolation of aromatic diazonium salts was developed by the group of Goossen and coworkers using Me4NSeCF3 (Scheme 23.16a) [55]. Independently, a metal‐ and additive‐free procedure was reported for the same reaction by the group of Zhang and coworkers (Scheme 23.16b) [48]. Reaction of 2 equiv of Me4NSeCF3 with aryldiazonium in acetonitrile under nitrogen at −40 or −20 °C to room temperature furnished the desired trifluoromethyl selenoethers in moderate to good yields, and with comparable yields to the copper‐catalyzed reaction. A few heteroaromatics were trifluoromethylselenolated employing these procedures [48, 55]. This last metal‐ and additive‐free trifluoromethylselenolation was also applied to convert diar­ yliodonium triflate into their corresponding selenoethers (Scheme 23.16c) [48]. The reaction was sensitive to electron density of the aromatic ring: electron‐ donating groups on the aromatic ring of symmetric diaryliodonium salts slow down the reaction. In contrast, shorter reaction time and higher yields were obtained with electron‐deficient diaryliodonium salts. This trend was similar

23.3  Direct Introduction of CF3Se Moiety

CuSCN (10 mol%) R Me4NSeCF3

N2+ F4B–

(1.5–2 equiv)

CH3CN, rt, 1 h 69–98%

(a)

CH3CN, N2 –20 °C to rt, 4 h

(b)

R

SeCF3

54–88% TfO– Me4NSeCF3

Ar1

I+

Ar2

CH3CN, N2 rt, 10 h 27–99%

(1.5 equiv)

Ar1–SeCF3

+

Ar2–SeCF3

(c)

Scheme 23.16  Trifluoromethylselenolation of aromatic diazonium or diaryliodonium salts.

with the one observed with unsymmetrical diaryliodonium salts as reaction occurred preferentially on the aryl bearing electron‐withdrawing groups. In  addition, it should be mentioned that (2,4‐dinitrophenyl)(trifluoromethyl) selenoether and 3‐nitro‐4‐trifluoromethylselenopyridine were obtained from  the corresponding aryl halides in good yields through a probable SNAr reaction [48]. Me4NSeCF3 reacted also with alkynes [54] and an alkynyl(phenyl)iodonium salt [56] to furnish the corresponding alkynyl trifluoromethyl selenoethers (Scheme 23.17). Similarly to boronic derivatives (Scheme 23.15) [54], terminal alkynes react with Me4NSeCF3 through an oxidative coupling in the presence of oxygen as oxidant and a stoichiometric amount of copper triflate and bipyridine.

Me4NSeCF3

+ R

H

Cu(OTf)2 (1 equiv) bpy (1.1 equiv) O2, DMF, rt, 18 h 50–95% R

Me4NSeCF3

+ R

OTs I Ph

SeCF3

CH3CN, rt, 5–10 min 14–89%

Scheme 23.17  Trifluoromethylselenolation of alkynes and an alkynyl(phenyl)iodonium.

23.3.1.3  In Situ Combination of Trifluoromethylation and Elemental Selenium

An alternative to the use of trifluoromethylselonolate salt or metal complexes is to generate in situ F3CSe− anion by reaction of trifluoromethyl anion with elemental selenium. Toward this end, copper‐catalyzed trifluoromethylsele­ nolations of alkyl bromides as well as aryl iodides were performed by using the combination of Ruppert–Prakash reagent and elemental selenium in the

705

706

23  When Fluorine Meets Selenium

presence of a fluoride source (Scheme 23.18a) [34]. Importantly, silver carbon­ ate was used as additive to improve yields. Although silver trifluoromethylse­ lenolate was found to be inactive with aryl iodides, it furnished, in the presence of copper and phenanthroline, the complex [(Phen)Cu(SeCF3)]2 that was able to convert aryl iodides into the corresponding selenoethers. It is important to mention that this method was reported before the use of [bpyCuSeCF3]2 as trifluoromethylselenolating reagent (Section  23.3.1.1). Moreover, as already described earlier in the text, trifluoromethylselenolations of boronic acids or alkynes were extended to one‐pot reactions starting [54]. A similar strategy was developed using a difluorocarbene precursor and a fluoride source instead of Ruppert–Prakash reagent in combination with ele­ mental selenium. This system was involved in trifluoromethylselenolation of benzyl halides that occurred at 70 °C in the presence of excess of copper(I) iodide, bipyridine, tetrabutylammonium chloride, and a catalytic amount of sil­ ver carbonate (Scheme 23.18b) [57]. Here again, a [CuSeCF3] species as inter­ mediate was proposed. However, in contrast to the method based on the association of Ruppert–Prakash reagent with elemental selenium, aryl halides were found to be unreactive in such conditions. Extension to trifluoromethylse­ lenolation of allyl, alkyl, or secondary benzylic halides furnished the desired product but yields remained low. Anecdotally, a solution of trifluoromethyl borazine, prepared from HCF3 (Section 23.2.1) has been mixed with grey ele­ mental selenium to form in situ the CF3Se− anion, which could react with bro­ momethyl naphthalene (Scheme 23.18c) [20].

Me3SiCF3 (3 equiv)

+

Se8 + RX (2 equiv) (1 equiv) X = I, Br

(a)

Ph3P+

O

O– + Se8 + RCH2X F F (1 equiv) (6 equiv) (2 equiv)

KF (3 equiv) CuI (20 mol%) Phen (20 mol%) Ag2CO3 (0.5 equiv) DMF, 80 °C CsF (3 equiv) CuI (3 equiv) Phen (3 equiv) Ag2CO3 (20 mol%) Bu4NCl (2 equiv) DMA, 70 °C

X = Br, Cl

R–SeCF3 53–94 % R = Alk, Ar

RCH2SeCF3 41–81% R = Ar

(b)

N B

B N

CF3 N B

– K+ (18-crown-6) Se

CF3Se– K+ (18-crown-6)

Br F3CSe 64%

THF solution

(c)

Scheme 23.18  Trifluoromethylselenolation of alkyl bromides or aryl iodides based on the combination of trifluoromethyl anion and elemental selenium.

23.3  Direct Introduction of CF3Se Moiety

23.3.1.4  Trifluoromethylselenotoluene Sulfonate (CF3SeTs)

In 2019, trifluoromethylselenotoluene sulfonate (CF3SeTs), a reagent initially designed for electrophilic trifluoromethylselenolation (Section  23.3.2.3) [58], was involved in a nucleophilic approach. Indeed, a one‐pot two‐step proce­ dure  was developed to perform trifluoromethylselenolation of alkyl halides (Scheme 23.19) [59]. Under reductive conditions by means of TDAE, which acts as two electron donors, the F3CSe− anion is generated and used directly without isolation to react with alkyl halides through nucleophilic substitutions. O O S SeCF3 (1 equiv)

(1) TDAE (1 equiv) DMSO, RT, 5 min (2) R–X (1 equiv) rt, 5 min X = Cl, Br, OMs

R–SeCF3 25–84% R = Alk, Ar, HetAr

Scheme 23.19  Trifluoromethylselenolation of alkyl halides using the TsSeCF3/TDAE system.

23.3.2  Electrophilic Trifluoromethylselenolating Reagents To complete the panel of methods to perform trifluoromethylselenolation, elec­ trophilic reagents were needed. In that context, trifluoromethylselenyl chloride (CF3SeCl) was found to be a powerful reagent (Sections 23.3.2.1 and 23.3.2.2). Recently, trifluoromethylselenotoluene sulfonate (CF3SeTs) appeared as a new versatile trifluoromethylselenolating reagent. In contrast, CF3SeBr or (CF3Se)2 have been seldom used as electrophilic reagent [30a, 60]. 23.3.2.1  Trifluoromethylselenyl Chloride (CF3SeCl)

Until recently, trifluoromethylselenyl chloride was the only reagent reported to perform electrophilic trifluoromethylselenolation reactions. This reagent was initially prepared via chlorination of bis(trifluoromethyl)diselenide in 90% yield (Scheme 23.20a) [26, 61]. However, the preparation of the diselenide was difficult as low yields ranging from 10% to 28% were obtained starting from trifluoro­ methyliodide [26] or trifluoromethylacetate salts and elemental selenium [61]. 10–28%

CF3X + Se (a)

X = I, CO2Ag, CO2Hg(O2CCF3)

BnSeSeBn + CF3I (b) BnBr (c)

CF3SeSeCF3

HOCH2SO2Na DMF, H2O, rt 90%

KSeCN THF, 60 °C

BnSeCN

Scheme 23.20  Preparation of CF3SeCl.

Cl2 90% CF3SeCl

BnSeCF3

SO2Cl2 95%

TMSCF3 (2 equiv) TBAF (0.2 equiv) THF, 0–23 °C 82%

707

708

23  When Fluorine Meets Selenium

An alternative synthesis based on the formation of benzyltrifluoromethylsele­ nide (BnSeCF3) as intermediate was reported in 2002 (Scheme  23.20b) [25b]. BnSeCF3 was prepared by reaction of dibenzyldiselenide and trifluoromethylio­ dide in the presence of a radical initiator (sodium hydroxymethanesulfinate). In a second step, CF3SeCl was obtained in 95% yield by chlorination of BnSeCF3 using sulfuryl chloride. BnSeCF3 can also be prepared in two steps starting from benzyl bromide and potassium selenocyanate to form benzylselenocyanate, which further reacted with Ruppert–Prakash reagent in the presence of a catalytic amount of fluoride to furnish the benzyltrifluoromethylselenide (Scheme  23.20c) [11, 14]. In addition, reaction of benzylic derivatives with Me4NSeCF3 constitutes a more recent route to prepare this compound [48]. Trifluoromethylselenyl chloride was used as electrophilic trifluoromethylsele­ nolating reagent in a few SEAr reactions involving dimethylaminobenzene [62], unprotected anilines [62, 63] or phenols [64], or trimethoprim (Scheme 23.21a–c) [65]. CF3SeCl was also able to perform trifluoromethylselenolation of phenyl‐ and tolylmagnesium bromide (Scheme 23.21d) [66]. Introduction of the SeCF3 moiety onto malonates or orthoacetate derivatives was also reported ­ (Scheme  23.21e,f ) [67]. Moreover, silver cyanide and silver cyanate can react with CF3SeCl to form trifluoromethylselenocyanate (CF3SeCN) and trifluoro­ methylselenoisocyanate (CF3SeNCO), respectively [61, 68]. R

R′

C(OEt)3 SeCF3

(f)

87–97% R = H, SeCF3

NR2 R

NaH/Na Et2O –30 °C to rt CO2Et

(e) EtO2C EtO2C

CO2Et

R

R

SeCF3

Na, Et2O –40 °C to rt

82–87% R = H, SeCF3

C(OEt)3

(a) ArNR2 Et2O –40 °C to rt

CF3SeCl

61–85% R = H, Me; R′ = H, o-F, o-CO2Me

SeCF3 (b) Phenol, pyridine

99% (d) ArMgBr Et2O –50 °C to rt

SeCF3

SeCF3

(c) Trimethoprim CF3SO3H, –40 °C to rt TfO– NH3+ N

R

OH

F3CSe

CHCl3, 0 °C to rt

H2N

SeCF3 OMe

N

30–75%; R = H, Me

OMe 65%

OMe

Scheme 23.21  Electrophilic trifluoromethylselenolations with CF3SeCl.

23.3.2.2  Benzyltrifluoromethylselenide (BnSeCF3) as CF3SeCl Precursor

Despite the interesting reactivity of trifluoromethylselenyl chloride as an electro­ philic trifluoromethylselenolating reagent, its use was limited to a few examples until recently (Scheme 23.21). Actually, its handling could be considered difficult due to its volatility (b.p. = 21–31 °C) [25b, 26, 61]. By analogy with its sulfur ana­ logues [69], this volatile reagent is supposed to be toxic, although data are not

23.3  Direct Introduction of CF3Se Moiety

available. The group of Billard reported the in situ generation CF3SeCl from ­benzyltrifluoromethylselenide followed by its direct use in one‐pot transforma­ tions, avoiding any contact between users and CF3SeCl. Moreover, BnSeCF3 is a stable liquid and easy to handle and can be easily prepared in multigram scale (Scheme 23.20c) [14]. Initially, CF3SeCl was prepared by chlorination of BnSeCF3 using sulfuryl chlo­ ride under neat conditions [25b]. To perform one‐pot transformations “CF3SeCl generation–trifluoromethylselenolation,” CF3SeCl was generated in solution by performing this chlorination step in THF or dichloromethane (DCM) at room temperature. Excess of sulfuryl chloride as chlorinating agent is detrimental to the process not only as it could potentially react in the second step but also because overoxidation of the desired CF3SeCl can occur to form CF3SeCl3 as by‐ product [14]. Nevertheless, very good 19F NMR yields were reported for the in situ generation of CF3SeCl using only 1 equiv of sulfuryl chloride in THF or DCM. With such conditions in hands, a series of trifluoromethylselenoethers were pre­ pared. Preparation of compounds bearing C(sp3)–SeCF3 moiety were achieved starting from alkenes [70], ketones [71] or Grignard reagents (Scheme 23.22) [8]. Actually, reaction with alkenes resulted not only in the incorporation of a tri­ fluoromethylseleno group but also into a chlorine incorporation furnishing the  corresponding α‐chloro‐β‐trifluoroalkylselenoethers (Scheme  23.22a) [70]. Formation of an episelenonium intermediate was proposed to explain the trans‐stereochemistry observed. Good yields were obtained with symmetric or activated alkenes, whereas mixtures of regioisomers were obtained with unsym­ metrical alkenes, which constitute a drawback of the method. In addition, α‐func­ tionalization of ketones was performed using in situ generation of CF3SeCl, followed by reaction with ketones without any additive (Scheme  23.22b) [71]. Considering reactions with Grignard reagents (Scheme  23.22c), it should be noticed that 2 equiv are required to achieve good yields as benzyl chloride, formed as side product during the generation of CF3SeCl, consumed part of the Grignard reagent [8]. Similarly, reactions with adequate Grignard reagents furnished prod­ ucts bearing a C(sp2)–SeCF3 group (Scheme 23.22c) [8]. However, only aromatics bearing electron‐donating groups have been reported to be trifluoromethylsele­ nolated by this route. Such electron‐rich aromatic compounds can also be con­ verted to the corresponding trifluoromethylselenides through SEAr reaction at room temperature (Scheme 23.22d) [14]. In addition, a copper‐mediated trifluo­ romethylselenolation was reported using a stoichiometric amount of copper(II) acetate, bipyridine as ligand and cesium carbonate as base (Scheme  23.22e). Another approach, which consists in a cascade transformation with a trifluoro­ methylselenolation step followed by construction of heterocycles, was reported (Scheme 23.22f ) [72]. In this metal‐free route, ortho‐alkynyl functionalized aryl compounds react with CF3SeCl to form an episelenonium species that can be trapped intramolecularly to furnish the desired heterocycles. Such strategy was applied to the synthesis of trifluoromethylselenolated benzofuranes, benzothio­ phenes, and extended to six‐membered ring such as isochromenones, isoquino­ lines, or dihydroisoquinolinones. Finally, trifluoromethylselenolated alkynes can also be prepared from lithium alkynides and CF3SeCl in moderate to good yields (Scheme 23.22c) [8]. Moreover,

709

710

23  When Fluorine Meets Selenium

alkynyl copper derivatives were found to react with CF3SeCl that allows the scope extension to compounds bearing functional groups sensitive to lithium alkynide such as cyano or ester (Scheme  23.22g) [73]. Yields are generally improved by the used of bipyridine as stoichiometric ligand and a slight excess of CF3SeCl. CF3SeBn R

SeCF3 32–75%

(g) R

R2

Cu (0.8 equiv) bpy (0.8 equiv), rt

SO2Cl2 (1 equiv) rt

R1 R2

Y

YMe (1 equiv) 0 °C to rt

R1

SeCF3 Y = O, S, CO2, CHN R1 = Alk, Ar; R2 = H, OMe 6–93%

CF3SeCl In situ generated

(e) (Het)ArB(OH)2 Cu(OAc)2 (1 equiv) bpy (1 equiv) Cs2CO3 (1 equiv) rt (Het)ArSeCF3 14–67%

0 °C to rt O (b) R2 1 R (1 equiv) rt

(c) RMgBr or RLi (2 equiv) –78 °C to rt (d) (Het)ArH (1 equiv) rt (Het)ArSeCF3 4–93%

R2

R1

R1 (1 equiv)

(f)

Cl

R2

a)

SeCF3 25–84%

O SeCF3

R1 2

R 16–84%

RSeCF3 55–56% (R = Alk) 52–61%, (R = Ar) 62–82% (R = R′-CC)

Scheme 23.22  Electrophilic trifluoromethylselenolation using BnSeCF3 as pre‐reagent.

In addition to these trifluoromethylselenolations using BnSeCF3 as pre‐rea­ gent, the extension to various fluoroalkylselenolation has been reported using the corresponding benzylfluoroalkylselenide BnSeRF (Scheme 23.20c). Replacement of Ruppert–Prakash reagent by adequate silanes furnished the desired BnSeRF. A series of fluoroalkylselenolated compounds have been synthesized by α‐chloro‐ β‐fluoroalkylselenolation of alkenes [70], fluoroalylselenolation of organometal­ lic compounds [8], SEAr of aromatic compounds [14], cascade transformation of ortho‐functionalized alkynyl–aryl compounds [72], and fluoroalkylselenolation of alkynyl copper [73] (Section 23.4.1). 23.3.2.3  Trifluoromethylselenotoluene Sulfonate (CF3SeTs)

In 2017, trifluoromethylselenotoluene sulfonate has been reported as a new elec­ trophilic trifluoromethylselenolating reagent. CF3SeTs is prepared via a one‐pot two‐step procedure: in situ generation of CF3SeCl and trapping by sodium tolue­ nesulfinate (Scheme 23.23) [58].

Ph

SeCF3

(1) SO2Cl2 (1 equiv) THF, rt (2) TsNa (1.1 equiv) DCM, –78 °C

Scheme 23.23  Preparation of CF3SeTs.

O O S SeCF3 58%

23.3  Direct Introduction of CF3Se Moiety

The reactivity of this reagent toward aryl or vinyl boronic acids has been studied (Scheme  23.24a,b) [58]. It was found that trifluoromethylselenolation occurred at room temperature using copper(II) acetate/bipyridine as catalytic system and cesium carbonate as base. A series of compounds bearing electron‐ donating or electron‐withdrawing substituents were prepared in moderate to good yields. Importantly, CF3SeTs decomposed under reaction conditions with­ out boronic derivatives and bis(trifluoromethyl)diselenide was detected. Thus, this diselenide could be considered as a potential trifluoromethylselenolating species. Similarly to products obtained during α‐chloro‐β‐fluoroalkylselenola­ tion of alkenes in the presence of CF3SeCl [70], terminal alkynes reacted with CF3SeTs in THF at room temperature without any additive to furnish a difunc­ tionalized product in modest to good yields (Scheme 23.24c) [74]. In contrast, in the presence of a catalytic amount of copper(II) and tetramethylethylenediamine (TMEDA) and 1 equiv of base, terminal alkynes reacted with CF3SeTs to give alkynyl trifluoromethyl selenoethers (Scheme  23.24d) [75]. Interestingly, addi­ tion of tosyl and SeCF3 groups leading to formation of bifunctional side product was observed with aliphatic substrates bearing a directing oxygen atom. Moreover, increasing the amount of copper allowed the formation of these prod­ ucts in good yields (Scheme  23.24e). It should be noticed that regio‐ and stererochemistry of vinyl sulfones obtained in copper‐mediated reactions differ from the ones obtained in metal‐free reactions (Scheme 23.24c,e). O O S SeCF3

Cu(OAc)2 (10mol%) bpy (10mol%) Cs2CO3 (1 equiv) THF, rt

(Het)ArB(OH)2

(Het)ArSeCF3 27–74%

B(OH)2

Ar

(a)

B(OH)2

Ar

26–47%

(b)

F3CSe THF, rt

O O S SeCF3

+

R

H

[Cu] (20mol%) TMEDA (40mol%) Cs2CO3 (1 equiv) Toluene, rt Cu(OAc)2 (40mol%) TMEDA (80mol%) Cs2CO3 (1 equiv) H2O (6 equiv), DCM, rt

R Ts 16–85% R = Alk, Ar

R

(c)

SeCF3 29–79% R = Ar, Alk

Ts R

(d)

SeCF3 50–84%

(e)

Scheme 23.24  Reactivity of CF3SeTs as electrophilic trifluoromethylselenolating reagent.

23.3.2.4 CF3SeNMe4 Under Oxidative Conditions

Although CF3SeNMe4 has been used to perform nucleophilic reactions (Section 23.3.1.2), it has been also used to trifluoromethylselenolate electron‐rich

711

712

23  When Fluorine Meets Selenium

aromatic compounds in oxidative conditions (Scheme  23.25). Even though the exact mechanism remains unclear, the authors proposed an electrophilic path­ way.  The CF3Se− anion would be oxidized to form the CF3Se˙ radical, which is further oxidized to form the CF3Se+ cation [76].

CF3Se(NMe4) + HetAr H or Ar H

mCPBA (1.3 equiv) or NIS (1.3 equiv)

HetAr SeCF3 or Ar SeCF3

CH3CN, 0 °C

(Electron-rich substrates)

31–99%

28–93%

Scheme 23.25  Electrophilic trifluoromethylselenolation with CF3SeNMe4 in oxidative conditions.

23.3.3  Radical Trifluoromethylselenolation While nucleophilic and electrophilic direct trifluoromethylselenolation of organic compounds have been developed in past years, radical reactions were investigated only recently. Tosyl trifluoromethylselenosulfonate reagent has been initially developed to perform electrophilic reactions. However, inspired by the radiative sensitivity of the CF3SO2─Se bond, previously demonstrated with CF3SO2SePh (Section  23.2.2, Scheme  23.5) [24], the homolytic scission of SO2─SeCF3 bond has been investigated. Thus, it has been demonstrated that under white LED (visible light) irradiation, CF3SeSO2Tol could generate CF3Se˙ radical that rapidly dimerized into CF3SeSeCF3. This in situ generated diselenide could then trap other radical species to provide the desired CF3SeR compounds. Trifluoromethylselenosulfonate reacted with aromatic and heteroaromatic diazonium salts in the presence of Eosin Y, under visible light irradiation, to give (hetero)aromatic trifluoromethylselenoethers (Scheme  23.26a) [77]. Radical addition of tosyl and CF3Se moieties onto alkenes or alkynes has been also observed under visible light activation, but without a photoredox catalyst (Scheme 23.26b) [78]. (Het)Ar–N2+BF4– Eosin Y (5 mol%) O O S SeCF3

(a)

White LED DMSO, rt R1

R2

White LED DMSO, rt

SeCF3 R

Het

38–83%

(b)

R1

SeRF R2 Ts 33–88%

Scheme 23.26  Radical trifluoromethylselenolation with trifluoromethylselenosulfonate.

Trifluoromethylselenyl chloride, in situ generated from CF3SeBn and SO2Cl2 (Section 23.3.2.2), reacted in the regioselective remote C–H trifluoromethyl­ selenolation of 8‐aminoquinolines (Scheme 23.27). This reaction is palladium‐­ catalyzed and an SET generating the CF3Se˙ radical was postulated [79]. These

23.4  Extension to Other Fluorinated Motifs

visible light‐induced reactions have been extended to other fluorinated groups.

SeCF3

N Ph

SeCF3

SO2Cl2 Dioxane, rt

HN CF3SeCl

Y

R

Pd(OAc)2 (10 mol%)

Y = CO, SO2

N

65 °C

HN

Y

R

22–89%

Scheme 23.27  Radical trifluoromethylselenolation of 8‐aminoquinolines derivatives.

23.4 ­Extension to Other Fluorinated Motifs In the objective to modulate properties of selenium‐containing molecules, other fluorinated groups than CF3 could be also considered. Some of the methods described above have been extrapolated to other fluorinated motifs. Furthermore, more dedicated approaches have been developed specifically for such other moieties. 23.4.1  Higher Fluorinated Homologues: RFSe Some of the methods described earlier in the text have been used to synthe­ size perfluoroalkylselenolated molecules. This is resumed in the following Table 23.1. Table 23.1  Synthesis of perfluoroalkylselenolated molecules with above described methods. RF

Reagents and methods

References

C2F5

C2F5SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

C2F5I/Rongalite/RSeSeR (23.2.2)

[25a]

C2F5I/TDAE/RSeSeR (23.2.1)

[21b]

(C2F5Se)2/Cu/ArI (23.3.1.1)

[31]

C2F5Se(NMe4)/[Cu]/ArB(OH)2 (23.3.1.2)

[54]

C2F5SeBn/SO2Cl2/(Het)ArH or RMgX or RLi or alkenes or alkynes or alkynyl copper(I) (23.3.2.2)

[8, 14, 70, 72, 73]

C2F5SeBn/SO2Cl2/[Pd]/8‐aminoquinoline derivatives (23.3.2.4)

[79]

C2F5SeTs/[Cu]/terminal alkynes (23.3.2.3)

[75]

C2F5SeTs/[Cu]/ArB(OH)2 (23.3.2.3)

[58]

C2F5SeTs/terminal alkynes (23.3.2.3)

[74]

C2F5SeTs/visible light/eosin Y/diazonium salts (23.3.2.4)

[77]

C2F5SeTs/visible light/alkenes or alkynes (23.3.2.4)

[78] (Continued)

713

714

23  When Fluorine Meets Selenium

Table 23.1  (Continued) RF

Reagents and methods

References

C3F7

C3F7SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

C3F7SeBn/SO2Cl2/(Het)ArH or RMgX or RLi (23.3.2.2)

[8, 14]

C3F7SeBn/SO2Cl2/[Pd]/8‐aminoquinoline derivatives (23.3.2.4)

[79]

C3F7SeTs/visible light/eosin Y/diazonium salts (23.3.2.4)

[77]

C3F7SeTs/visible light/alkenes or alkynes (23.3.2.4)

[78]

C4F9I/Rongalite/RSeSeR (23.2.2)

[25a]

C4F9I/TDA/RSeSeR (23.2.1)

[21b]

C4F9

C6F13 C6F13SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

C6F13I/Rongalite/RSeSeR (23.2.2)

[25a],

C6F13SeBn/SO2Cl2/(Het)ArH or RMgX or alkynyl copper(I) (23.3.2.2)

[8, 70, 73]

C6F13SeTs/[Cu]/terminal alkynes (23.3.2.3)

[75]

C6F13SeTs/[Cu]/ArB(OH)2 (23.3.2.3)

[58]

C6F13SeTs/terminal alkynes (23.3.2.3)

[74]

C8F17 C8F17I/Rongalite/RSeSeR (23.2.2)

[25a, b]

More specifically, perfluoroalkylations of phenylselenyl stannane have been described under palladium‐catalyzed conditions (Scheme 23.28) [80].

PhSeSePh (0.5 equiv)

Na, NH3 nBu3SnCl

nBu3SnSePh (1.4 equiv)

RFI (1 equiv) (PPh3)2PdCl2 (10 mol%) PPh3 (40 mol%) CsF (3 equiv)

RFSePh

DMF, 120 °C, 24 h

RF : C4F9 (28%), C6F13 (37%), C8F17 (70%), C10F21 (90%)

Scheme 23.28  Pd‐catalyzed perfluoroalkyaltion of phenylselenyl stannane.

23.4.2  Difluoromethylselenyl Motif: HCF2Se In these following cases, some of the methods described earlier in the text could be applied to obtain HCF2Se‐molecules (Table 23.2). Difluoromethylselenoethers could be obtained by reaction between arylsele­ nolates (arising from reduction of diselenides) and HCF2Cl in basic conditions, through an SRN1 mechanism (Scheme 23.29a) [81]. Phenylselenol has been dif­ luoromethylated with difluorocarbene, generated by thermic decarboxylation of difluoroacetate (Scheme 23.29b) [82]. Finally, diphenyl diselenide can react with

23.4  Extension to Other Fluorinated Motifs

Table 23.2  Synthesis of difluoromethylselenolated molecules with above described methods. RF

Reagents and methods

References

HCF2

HCF2SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

HCF2SeBn/SO2Cl2/(Het)ArH or alkenes or alkynes or ketones or alkynyl copper(I) (23.3.2.2)

[14, 70–73]

HCF2SeBn/SO2Cl2/[Pd]/8‐aminoquinoline derivatives (23.3.2.4)

[79]

α,α‐difluorodibenzoylmethane, in the presence of an excess of Cs2CO3, to afford difluoromethylselenyl benzene (Scheme 23.29c) [83]. LiAlH4 (2 equiv)

ArSeSeAr

ArSe–

1,4-Dioxane

(a)

PhSeH

ClCF2CO2– Na+ (2 equiv) K2CO3 (1.5 equiv) DMF, 95 °C

(b) O

HCF2Cl (7–8 atm) NaOH 1,4-Dioxane/H2O 55–60 °C

Ar–SeCF2H 73–84%

Ph–SeCF2H 65%

O

Ph

Ph (1.3 equiv) F F

PhSeSePh (c)

Cs2CO3 (5 equiv) DMSO, 80 °C

Ph–SeCF2H 65%

Scheme 23.29  Difluoromethylation of arylselenyl substrates.

23.4.3  Fluoromethylselenyl Motif: H2CFSe Monofluoromethylselenoethers have been obtained for the first time through a one‐pot two‐ or three‐step process. This approach is based on the fluoroalkylse­ lenolation of an in situ generated selenocyanate. The fluorinated reagent is ICFH2 in the presence of an excess of base (Scheme  23.30). This method has been applied in (hetero)aromatic and aliphatic series [84]. 23.4.4 FG‐CF2Se Motifs (FG = Functional Groups) In order to perform further post‐functionalizations, difluoromethylene bearing a FG has been considered. Such compounds have been prepared by extrapola­ tion of methods described earlier in the text (Table  23.3) or using dedicated approaches (Scheme 23.31).

715

716

23  When Fluorine Meets Selenium

(Het)Ar NH2

(1) HBF4 (2 equiv), tBuONO (2 equiv) CH3CN, 0 °C, 2 h (2) CuCl (0.1 equiv), CuCl2 (0.1 equiv) 1,10-phen (0.1 equiv), KSeCN (1.5 equiv) 0 °C, 3 h

(Het)Ar–SeCFH2

(3) ICFH2 (2 equiv), KOH (10 equiv) 0 °C, 7 h

R–Br

(1) KSeCN (1.5 equiv) CH3CN, 25 °C, 3 h (2) ICFH2 (2 equiv), KOH (10 equiv) 0 °C, 7 h

46–91%

R–SeCFH2 5–93%

Scheme 23.30  Synthesis of monofluoromethylselenoethers.

Table 23.3  Synthesis of FG–CF2Se molecules. RF

BrCF2

CF2CO2Me

CF2SO2Ph

Reagents and methods

References

BrCF2SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

BrCF2SeBn/SO2Cl2/(Het)ArH or alkenes or alkynes or ketones (23.3.2.2)

[14, 70–72]

BrCF2SeBn/SO2Cl2/[Pd]/8‐aminoquinoline derivatives (23.3.2.4)

[79]

MeO2CCF2SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

MeO2CCF2SeBn/SO2Cl2/(Het)ArH or alkenes or alkynes (23.3.2.2)

[14, 70, 72]

PhSO2CF2SiMe3/TBAF/RSeCN (23.2.1)

[13, 14]

PhSO2CF2SeBn/SO2Cl2/(Het)ArH or RMgX or alkenes or alkynes (23.3.2.2)

[8, 14, 70, 72]

Phenylselenolate (obtained by reduction of the corresponding diselenide) can react with CF2Br2 [85] or ArCF2Cl [86] to provide PhSeCF2Br or PhSeCF2Ar products, respectively, through an SRN1 process (Scheme  23.31a–b). Some RCF2− anions, generated from various reagents, can be trapped with diphenyl diselenide or phenylselenyl chloride to furnish the corresponding RCF2SePh products. Thus, (phenylselenyl)difluoromethylated amides [87], esters [88], phosphonates [89], ketones [83], and aromatics [90] have been synthesized (Scheme 23.31c–g).

23.5 ­Conclusion Despite the potential interest of trifluoromethylselenolated and fluoroalkylsele­ nolated molecules, the synthesis of these compounds has been only scarcely

23.5 Conclusion CF2Br2 (4 equiv) THF, –70 °C PhSeSePh

NaBH4

PhSe– ArCF2Cl (1 equiv) hν (visible light) DMF, 100 °C

PhSe–CF2Br 61–86%

(a)

PhSe–CF2Ar (b)

45–93%

OMe F

N F

(2 equiv)

NBn

TfOSiMe3 (2 equiv)

O PhSe

N

F F

THF, rt PhSeCl

(c)

OSiMe3 F

CO2Me

(1 equiv)

DMF, rt

MeS–CF2PO(OiPr)2 (0.7 equiv) tBuLi (0.4 equiv) THF, –78 °C O

O PhSe

F

F F

CO2Me 87%

(d)

O P OiPr OiPr F F 50%

PhSe

(e)

O Ph (1 equiv)

Ph PhSeSePh

NBn 60%

F F Cs2CO3 (3 equiv)

O PhSe

tBuOK (3 equiv) DMF, –30 °C to rt

(f)

54%

DMSO, rt

PhSO2–CF2Ar (0.7 equiv)

Ph

F F

PhSe F F

N 87%

(g)

Scheme 23.31  Various syntheses of RCF2Se molecules.

described until recently due to a crucial lack of efficient synthetic methods. These last years have known an infatuation for the CF3Se chemistry. Thus, numerous methods and reagents have been developed to provide CF3Se mole­ cules, in particular through direct trifluoromethylselenolation reactions. This should pave the way to the synthesis of new fluoroalkylselenolated products and to the study of their properties. Nowadays, CF3Se and RFSe motifs cannot be ignored in the screening of substituents in molecules design and should contrib­ ute to the increase of molecular diversity.

717

718

23  When Fluorine Meets Selenium

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79 Ghiazza, C., Ndiaye, M., Hamdi, A. et al. (2018). Tetrahedron 74: 6521–6526. 80 (a) Bonaterra, M., Martín, S.E., and Rossi, R.A. (2006). Tetrahedron Lett. 47:

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Part V Nitrogen‐Linked Fluorine‐Containing Motifs

725

24 Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs Thierry Milcent and Benoit Crousse Université Paris-Saclay, CNRS, BioCIS, 92290 Châtenay-Malabry, France

24.1 ­Introduction After nitrogen, fluorine is probably the next most favorite heteroatom for incorporation into small molecules in life science‐oriented research. Since several decades, it has been well known that the presence of fluorine atom(s) largely modified the physicochemical properties of a molecule. That is why fluor­ inated molecules are largely exploited in pharmaceutical, medical, agrochemical, and materials science [1–3]. The fluorine atom or the fluoroalkyl groups (CF3, CF2) are generally positioned in aromatic or aliphatic carbons. More recently the fluoroalkyl groups appeared directly on heteroatoms, mainly oxygen and sulfur, with, for example, the OCF3 and the SCF3 groups (see Chapters 2 and 3). The construction of N‐Rf motifs is less developed with respect to their O‐Rf and S‐Rf analogues, except for the N‐CF2H function, which has been present in the litera­ ture since the 1950s. However, more recently the N‐CF3 function appeared, thanks to new reagents that allow its incorporation into molecules of interest. In the same way, the construction of the N‐CH2CF3 motif is well documented in the literature through diverse accesses. The aim of this chapter is to give an overview of the preparation of N‐­f luoroalkyl groups that include N‐CF2H, N‐CF3, and N‐CH2CF3. Section 24.2 discusses the several conditions for the construction of the N‐CF2H motif. In  Section  24.3, the preparation of the N‐CF3 motif is detailed. Finally, Section 24.4 is devoted to the preparation of compounds featuring the motif N‐CH2CF3, which is also important in the fields of medicinal chemistry and agrochemistry.

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

726

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

24.2 ­Construction of the N‐CF2H Motif 24.2.1  From Halodifluoromethanes Under basic conditions, chlorodifluoromethane (Freon 22) decomposed into dif­ luorocarbene (:CF2), which was immediately trapped with various nucleophiles present in situ (Scheme 24.1) [2, 3]. H F

Cl F

Base – HCl

:CF2

H

Nu F

F

Nu

Scheme 24.1  Formation of difluorocarbene and reaction with nucleophiles.

For insertion of difluorocarbene onto organic molecules, in particular on heteroatoms O and S (see Chapters 2 and 3), Freon 22 is the main reagent used in comparison with bromo‐ and iododifluoromethane or fluoroform. The dif­ luoromethylation reaction to construct the N‐CF2H motif is a straightforward route that has been largely exploited for the synthesis of various molecules. In view of the large number of reactions involving Freon 22 reagent with a wide variety of nitrogen heterocycles, we selected the most relevant reaction condi­ tions that generate the difluorocarbene for reaction at a nitrogen atom. Of the bases used for the formation of the difluorocarbene in situ NaH [4], carbonate salts (K2CO3, CsCO3) [5], alkali hydroxides [6], and quaternary ammonium hydroxides under phase‐transfer catalysis conditions [7] have been employed (Scheme 24.2). Some pharmaceutical and agrochemical products feature the N‐CF2H motif, particularly encountered in herbicides. Phenyl triazolinone derivatives have entered the market as agricultural herbicides, for example, sulfentrazone is the  first commercial herbicide for weed control in soybean production (Scheme 24.3) [8]. Another example is carfentrazone‐ethyl, which is an inhibi­ tor of protoporphyrinogen oxidase playing a role in cereal crop protection. One synthesis step involved the incorporation of the difluorocarbene on tria­ zolinone (Scheme 24.3) [9]. Other Freon derivatives such as bromo‐ and iododifluoromethane have also been used in the incorporation of CF2 carbene on nitrogen heterocycles. Some examples reported their use with the aid of NaH (CHBrF2 [10], CHIF2 [11]) or carbonates (CHBrF2 [12], CHIF2 [13]) (Scheme 24.4). More recently, Dolbier and coworkers shown that fluoroform can generate difluorocarbene in a convenient process for conversion of imidazoles and ben­ zimidazoles to their difluoromethylated derivatives [14]. Reactions could be performed at room temperature, using potassium hydroxide as base in a two‐ phase (water/acetonitrile) process to provide moderate to good yields of the respective products (Scheme 24.5).

BnO

N

O

N H

Ar

O

BnO

NH N

N N N N SH

CHClF2

N H CHClF2, KOH DMF, 100 °C

Ar

N N N N S

H N

CHF2

85%

O

N

CHClF2

N

N CF2H N

NaH, DMF 50 °C, 15 h

O

O

N

O

N N NH

60–80%

Scheme 24.2  Decomposition of CHClF2 under basic conditions.

CN

Ph

K2CO3, DMF, 5 h 80 °C

CHClF2 NaOH, TEBAC THF

N

CF2H N N 52%

CN

N N Ph + HF2C N N N CF H N N 2 23% 15%

Ph

728

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

HN

K2CO3, tetraglyme X=F

X

O N N

Cl

HF2C N CHClF2 KOH, Bu4N+Br – THF X = Cl

F

O

CHClF2 X

O N N

Cl

N N

HF2C N

Cl CO2Et

Carfentrazone-ethyl

Cl

O

Cl N N

HF2C N

Cl NHMs

Sulfentrazone

Scheme 24.3  Access to carfentrazone‐ethyl and sulfentrazone.

The use of Freons is being phased out in developed countries due to their ozone depletion potential (ODP) and high global warming potential (GWP). To find alternatives to Freons, several other difluorocarbene precursors have been developed. 24.2.2  Formation of N‐CF2H by Decarboxylative Reactions The generation of difluorocarbene by thermal decarboxylation of sodium chlo­ rodifluoroacetate (SCDA) was first noted by Haszeldine and coworkers for the synthesis of difluorocyclopropanes [15]. The decomposition of SCDA has been attempted with nitrogen heterocycles to incorporate the CF2H group. The reaction conditions required high temperature and a base such as carbonate salts in a polar solvent (dimethyl formamide [DMF] [16], acetonitrile [17]) (Scheme 24.6a,b). Greaney and coworker reported that SCDA decomposes at 95 °C to afford the difluorocarbene, which next reacted with thiols. While stud­ ying the scope of the reaction, the authors observed that the insertion occurred at the sulfur atom or/and at the nitrogen atom for aza‐heteroaromatic thiols (Scheme 24.6c) [18]. Ando et al. reported the preparation of a wide range of N‐difluoromethyl‐2‐ pyridones from the corresponding N‐(pyridin‐2‐yl)‐acetamide in the pres­ ence of SCDA. The reaction is favored in the presence of a catalytic amount of 18‐crown‐6 that reduces the reaction time (Scheme  24.7a) [19]. Similar conditions have been employed for the design of inhibitors of inflammation that possess a novel pharmacophore featuring the N‐difluoromethyl motif (Scheme 24.7b) [20]. Furthermore, the decomposition of alkyl halodifluoroacetates under basic conditions have been studied. Some examples with methyl chlorodifluoroacetate [21] and ethyl bromodifluoroacetate [22] were reported (Scheme 24.8). In a recent improvement of the reaction conditions, it was found that N‐difluo­ romethylthioureas could be obtained from azoles in the presence of bromo­ difluoroacetate and elemental sulfur. The authors proposed that HOCH2SO2Na could facilitate the formation of difluorocarbene for the N‐difluoromethyla­ tion  of azoles and the sulfuration reaction through a single electron transfer (Scheme 24.9) [23].

HN

N

CHBrF2 NaH, THF, rt, 16 h 49%

NO2

O N N

HF2C

N

Br

N

O CHBrF2 CsCO3, THF, rt SO2Me

CHIF2 NBoc

NO2

H N N

H N

N N

CF2H N N SO2Me

Scheme 24.4  N‐CF2H bond formation by means of CHBrF2 or CHIF2.

NaH, DMF, 18 h, rt 52%

O Br

CF2H N

Br

N H

O

NBoc

O CHIF2 K2CO3, DMF 16 h, rt 78%

Br

O N CF2H

730

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

N N H

15 equiv KOH/H2O

R + CHF3

N

R N CF2H

MeCN, rt, 3 h

N

N

N CF2H

N CF2H

50%

N

N

SMe N CF2H

93%

72%

Scheme 24.5  Preparation of N‐CF2H azaheterocycles from fluoroform.

O

O S

HN

N

S

HN

ClCF2CO2Na

O

N

O

Cs2CO3, H2O/DMF 5.5 h, 100 °C 46% N

(a) N

NH

N

N O O Cl N S H Cl

(b) N

(c)

K2CO3, MeCN 48 h, 60 °C 62% Br

ClCF2CO2Na SH

N

ClCF2CO2Na

N

K2CO3, DMF 95 °C, 8–14 h

CF2H

N O O Cl N S

HF2C

CF2H

N

Cl

Br N

and/or

S

SCF2H

Scheme 24.6  Decomposition of sodium chlorodifluoroacetate.

R

ClCF2CO2Na N NHAc

0.2 equiv 18-crown-6 MeCN, reflux

(a) R

NHAc N

(b)

R

R N

1% aq KHSO4, reflux

N

CF2H

(1) ClCF2CO2Na MeCN, 18 h, reflux (2) KHSO4, H2O/MeCN 3 h, reflux

CF2H

O

NAc

CF2H N O

R

R = 2-SO2Me, 3-SO2Me, 4-SO2Me, 4-SO2NH2

Scheme 24.7  Preparation of substituted N‐difluoromethyl‐2‐pyridones.

24.2  Construction of the N‐CF2H Motif

EtO2C

EtO2C

NH ClCF2CO2Me

N

CF2H

N

Cs2CO3, DMF, 1 h, 50 °C 1 h, 75 °C, 1 h, 25 °C 12% (purity >52%)

I

N

I

F

F

R

Ts N

BrCF2CO2Et

H

Ts N

R

LiOH DMF, rt, 12 h

CF2H

50–98%

R = Ar, alk, amino

Scheme 24.8  Reactions of ClCF2CO2Me and BrCF2CO2Et.

X

R′ N + S8

N X = C,N

BrCF2CO2Et

X

HOCH2SO2Na DMA, 100 °C 13–88%

R′ N N

S F

F

Scheme 24.9  N‐Difluoromethylation of azoles and sulfuration.

Difluorocarbene can also be generated by decarboxylation of difluoromethyl­ ene phosphobetaine (Ph3P+CF2CO2–) at high temperature without base or other additive. This way, the N‐difluoromethylation of the activated N─H bond of vari­ ous aza‐arenes could be realized in good yields (Scheme 24.10) [24].

F

O

F

Ph3

O– P+ N

N N CF2H 88%

+ R NH R1

p-Xylene 90 °C, 2 h

N N CF2H 81%

R–N–CF2H R1

I N N CF2H 85%

N

N CF H 2 Ph 76%

Scheme 24.10  N‐Difluoromethylation by means of difluoromethylene phosphobetaine.

Other difluorocarbene precursors proceeding by decarboxylation include fluorosulfonyldifluoroacetate derivatives. In 1992, Chen et  al. introduced fluorosulfonyldifluoroacetic acid, which sodium salt decomposed to react with N‐­heterocyclic compounds such as benzotriazole, benzimidazole, and imidazole to afford the expected corresponding N‐CF2H compounds (Scheme 24.11) [25].

731

732

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

(1) NaH, THF (2) FSO2CF2CO2H

N N

MeCN, 4 h (10 °C) then 1 h (45 °C) 70%

N H

N N N CF2H

Scheme 24.11  N‐Difluoromethylation by means of fluorosulfonyldifluoroacetic acid.

The decomposition method of fluorosulfonyldifluoroacetic acid under basic conditions has been applied on 2‐halopyridinyl derivatives that allowed the syn­ thesis of N‐CF2H pyridinones [26]. The method has been further used, for exam­ ple, in the preparation of bioactive compounds for evaluation as dual 5‐LOX and COX‐1/COX‐2 isozyme inhibitors of inflammation (Scheme 24.12a) [27] or as highly potent CRTh2 receptor antagonists (Scheme 24.12b) [28]. MeO2S

MeO2S

O

Cl N N

FSO2CF2CO2H

N

NaHCO3, MeCN 12 h, reflux

N

N

N 46%

F3C

F3C

CF2H

(a) CH2CO2Et N

FSO2CF2CO2H MeCN, 18 h, 40 °C

N

CH2CO2Et N

Cl SO2Ph

HF2C

N O 36%

SO2Ph

(b)

Scheme 24.12  Preparation of N‐CF2H pyridinones.

A derivative of the fluorosulfonyldifluoroacetic acid: the trimethylsilyl fluoro­ sulfonyldifluoroacetate (TFDA) has been also studied in the N‐difluoromethyla­ tion reaction. Thus, in the attempt to incorporate the difluorocarbene on the double bond of a carbohydrate/nucleoside precursor, the authors noticed the modification of the adenine moiety with concomitant formation of a thiourea function (Scheme  24.13) [29]. The sulfur atom comes from the SO2 released during the decomposition of TFDA. In addition, a wide range of N‐alkylimidazoles and benzimidazole derivatives have been treated with TFDA in the presence of catalytic amount of sodium fluo­ ride to afford the N‐difluoromethyl thioureas (Scheme 24.14).

24.2  Construction of the N‐CF2H Motif

NPhth

NPht N

N

N N

O

TFDA, NaF

N

PhMe, reflux, 14 h

F2C

N N

O

CF2H S

N

11% O O

O O

Scheme 24.13  Modification of an adenine derivative.

R1

R N

R2

N

TFDA, NaF (cat.) DME, 105 °C

R1

S N CF2H 51–63%

R2

R = Me, Bn

N X

R

N X = H, OMe, Cl

TFDA, NaF (cat.) DME, 105 °C

R N

N X

R

S N CF2H 41–57%

Scheme 24.14  Reactivity of TFDA with (benz)imidazoles.

24.2.3  Formation of N‐CF2H Using Difluoromethyldiarylsulfoniums The S‐(difluoromethyl)diarylsulfonium tetrafluoroborate reagent was designed by Prakash et al. to introduce the electrophilic difluoromethyl group into differ­ ent nucleophiles. This reagent was efficiently used on imidazole derivatives and tertiary amines but failed with primary and secondary amines [30a]. Furthermore, the authors proposed a solid phase approach with this reagent to avoid the chro­ matographic step necessary to eliminate the phenyl 1,2,3,4‐tetramethylphenyl sulfide side product. Thus, the supported reagent was efficient with a wide range of nucleophiles and on imidazole derivatives affording pure products without purification (Scheme 24.15) [30b]. 24.2.4  Formation of N‐CF2H Using Chlorodifluoromethyl Phenyl Sulfone (PhSO2CF2Cl) Hu and coworkers developed the chlorodifluoromethyl phenyl sulfone, which can be readily prepared from non‐ozone depleting substance (ODS)‐based precursors. This reagent was found to act as a robust difluorocarbene donor for N‐difluoromethylations. The chlorodifluoromethyl phenyl sulfone decomposed under basic conditions according to the following mechanism (Scheme 24.16) [31].

733

HF2C + S R1

+ – Et3NH CF2H BF4 60%

R1

R2 N

N

+ CF2H S Ph BF4– MeCN, rt, 16 h

+ – PhNMe2 BF4 CF2H 63%

N R3

BF4

MeCN, rt, 16 h

+ – Me2N–p-tolyl BF4 60%

R2 R1

N

+ N CF2H +

R1 +

–

R2

HF2C

N

Ph

CF2H

R3

BF4

–

+ N CF2H – BF4 84%

HF2C S

R2 N

N

+ N CF2H – BF4 93%

Scheme 24.15  N‐Difluoromethylation with S‐(difluoromethyl)diarylsulfonium tetrafluoroborate.

N

+ N CF2H – BF4 77%

N

N

+ CF H 2 N –

90%

BF4

+ N CF2H – BF4 81%

N

+ CF H 2 N – BF4 86%

O 1

R

R2

NH

S

O CF2Cl

R1

KOH, MeCN/H2O

R2

CF2H N N CF2H

N 86%

CF2H N N N 69%

O

N Ph N CF2H

Ph

O N Ph N CF2H 58%

66%

HCF2Cl

O O S CF2Cl

+H+ +

KOH

CH3CN/H2O 80 °C, 4 h

Lent

R1

– CF2Cl

F2C: Cl—

Scheme 24.16  N‐Difluoromethylation by means of chlorodifluoromethyl phenyl sulfone.

N R2

H R1

N R2

CF2H

O

CF2H N N Ph 44%

736

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

24.2.5  Formation of N‐CF2H Using N‐Tosyl‐S‐Difluoromethyl‐S‐ phenylsulfoximine (Ph(SO)(NTs)CF2H) In 2009, Hu and coworkers studied the reactivity of N‐tosyl‐S‐difluoromethyl‐ S‐phenylsulfoximine as an efficient electrophilic difluoromethylating agent with azole derivatives. A wide range of N‐difluoromethyl compounds were obtained in reasonable to good yields (Scheme 24.17) [32].

O NTs S CF2H

N Na N CF2H

26–72%

Imidazoles, triazoles, tetrazoles N

N N CF2H 72%

N

N N CF2H 40%

Ph

N CF2H 60%

Scheme 24.17  Reactivity of N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine.

The N,N‐dimethyl‐S‐difluoromethyl‐S‐phenylsulfoximinium tetrafluorobo­ rate salt has been prepared and used as a robust electrophilic difluoromethylat­ ing reagent in order to prepare N‐difluoromethyl ammoniums. The mechanistic studies revealed that the salt is involved in the transfer of the difluoromethyl group via an electrophilic alkylation and not via a commonly adopted difluoro­ carbene pathway (Scheme 24.18) [33].

O Ph

S

NMe

(1) Me3O+BF4–, DCM

CF2H

(2) Amines, DCM

Et3N+–CF2H BF4– 69%

+ Ph

N

R3N+–CF2H

CF2H BF4– 71%

+ MeO

N

CF2H BF4– 53%

Scheme 24.18  Synthesis of R3N+CF2H ammoniums.

In the same year, Hu and coworkers reported the use of the N‐difluoromethyl tributyl ammonium chloride to generate the carbene in the presence of sodium hydride. Some nucleophiles such as imidazoles, triazoles, and tetrazoles could react with the salt leading to the corresponding N‐difluoromethyl derivatives in good to high yields (Scheme 24.19) [34].

24.3  Construction of the N‐CF3 Motif

+ N CF2H

+

Cl– CF2H N N 83%

CF2H N N N 63%

HNa

CH3CN 5 °C–rt, 1.5 h

F2C:

CF2H N

CF2H N

N

N

91%

73%

H

N

Ar HF2C

O N CF2H N Ph 48%

Ph

N

N

Ar

Ph

N ; N N CF2H

CF2H N N N N

98%, (1.18 : 1)

Scheme 24.19  Synthesis of N‐CF2H heterocycles by means of ammonium R3N+CF2H.

24.2.6  Formation of N‐CF2H Motif Using TMSCF2Cl, TMSCF2Br, and TMSCF3 In 2013–2014, Hu and coworkers further reported the N‐difluoromethylation of  heterocyclic amines by means of silylated reagents: TMSCF2Br [35] and TMSCF2Cl [36]. Several imidazole derivatives could be engaged in the reaction to afford N‐difluoromethyl compounds in moderate to good yields (Scheme 24.20a). The reaction involved the generation of difluorocarbene from TMSCF2X that proceeds through initial desilylation with the aid of hydroxide ions and subsequent elimination of the halide (Scheme 24.20b). More recently Prakash et  al. performed the direct N‐difluoromethylation of imidazoles and benzimidazoles using TMSCF3 (Ruppert−Prakash reagent) under neutral conditions [37]. N‐Difluoromethylated products were obtained in good to excellent yields (Scheme 24.21). Reactions are accessible through con­ ventional as well as microwave irradiation conditions. The authors proposed a mechanism in which lithium cation causes the trapping of the fluoride, thus pre­ venting a runaway reaction with the silyl group. 24.2.7  Nucleophilic Difluoromethylation Shen and coworkers prepared and characterized a thermally stable N‐heterocyclic carbene Ag(CF2H) complex. The direct nucleophilic reaction of [(SIPr)Ag(CF2H)] with a variety of activated electrophiles that include aryldiazonium salts was reported to occur smoothly at room temperature to generate the corresponding N‐difluoromethylated azo compounds in high yields (Scheme 24.22) [38].

24.3 ­Construction of the N‐CF3 Motif In contrast to O‐CF3 and S‐CF3 motifs, which are well documented in the litera­ ture, there are much fewer papers describing the synthesis of the N‐CF3 pattern. Thanks to new reagents and methods, which have been recently developed, the N‐CF3 group is becoming more and more present in the literature. In this sec­ tion, the main and recent syntheses of the N‐CF3 compounds are reported.

737

R1 TMS-CF2Br (2 equiv) NH 20% aq KOH (6 equiv) R2 CH2Cl2, 0 °C, 0.5 h

R1 2

R

N N

N CF2H

N 81%

R1R2NH

2.5 equiv TMSCF2Cl 20% KOH (4.5 equiv) Toluene, 50 °C

N

R1R2NCF2H

N CF2H 50%

(a) HO– TMSCF2X

–TMSOH

XCF2–

CF2H

N N Ph N N CF2H 70%

H2O HO–

HCF2X (trace)

Fast –X–

R2N–H

HO– – H2O

R2N–

:CF2

R2NCF2–

(b)

Scheme 24.20  Decomposition of TMSCF2X (X = Br, Cl).

H2O – HO–

R2NCF2H

N N

N Ph N

CF2H

38% N

Ph N CF2H 63%

49% N N N CF2H 68%

CF2H

24.3  Construction of the N‐CF3 Motif

N

R1

N H R3

N N H

TMS-CF3 (2.35 equiv) LiI (0.9 equiv)

R2

Triglyme 170 °C, 3 h (35–97%) or mW, 170 °C, 1.5 h (41–90%)

R4

N

R2 N CF2H

R1

R3

N

R4 N CF2H

Scheme 24.21  N‐Difluoromethylation with TMSCF3.

R

N2+BF4–

[(SIPr)Ag(CF2H)] (1 equiv)

R

R = tBu, 89% R = MeO, 75% R = EtO2C, 83%

N N CF2H

MeCN, rt, 30 min

Scheme 24.22  Nucleophilic difluoromethylation of aryldiazonium salts.

24.3.1  By Nucleophilic Fluorination 24.3.1.1  Fluorine/Halogene Exchange

The fluorine/halogen exchange is one of the first reactions that led to the con­ struction of the CF3 group on nitrogen atom. From a dichloroimine in the pres­ ence of hydrofluoric acid in ether, the N‐CF3 aniline was isolated (Scheme 24.23a) [39]. The fluorine/chlorine exchange was also performed with N‐trichloromethyl derivatives in the presence of antimony trifluoride or HF (Scheme 24.23b,c) [40].

Ar

Cl

N

Ar

H N

Cl

(a) R R (b)

HF, Et2O

N CCl3

SbF3

CF3 N

R N CF3

R R = Me, 55% R = Et, 63%

N

N

HF

CCl3

N N

N

52% CF3

(c)

Scheme 24.23  Fluorine/chlorine exchange by HF or SbF3.

24.3.1.2  Oxidative Desulfurization–Fluorination of Dithiocarbamoyl Disulfides

Another nucleophilic reaction consists in the oxidative desulfurization–fluori­ nation of dithiocarbamoyl disulfides. Sulfur tetrafluoride (SF4) was mainly used to convert hydroxyl and carbonyl groups into CF and CF2 groups, respectively. Harder and Smith reported the synthesis of N‐CF3 diethyl amine and piperidine in 58% and 70% yield from thiocarbamoyl disulfides in the presence of SF4

739

740

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

(Scheme 24.24) [41]. Interestingly, Dmowski proposed to use the N‐dialkyl for­ mamides as precursors to form the N‐CF3 derivatives. Using 2.5 equiv of SF4 and 1.5 equiv of potassium fluoride for 48 hours at 150 °C, the N‐trifluoromethyl amines were obtained in excellent yields from 89% to 94% [42]. These conditions are applicable to disubstituted amines (symmetrical or not), as well as cyclic amines. The authors demonstrated that the R2N–CF2H was an intermediate in the reaction, resulting from the fluorination of the carbonyl and not the forma­ tion of the R2N–COF (Scheme 24.24). S R = Et, 58% R = piperidine, 70%

R

S

N R

SF4 (2.5 equiv) KF (1.5 equiv) R

SF4 (3 equiv) R 120 °C, 8 h 2

N CF3 R′

150 °C, 48 h

N R′

R = Me, 89% O R = Et, 90% R = piperidine, 93% R = morpholine, 92% R = Et, R′ = Ph, 94%

Scheme 24.24  Access to N‐CF3 derivatives with SF4.

Of the other nucleophilic fluorinating reagents available, diethylaminosulfur tri­ fluoride (DAST) and bis‐(2‐methoxyethyl) aminosulfur trifluoride (Deoxofluor®) [43] have been engaged with dithiocarbamoyl disulfides. In 1973, Markovskij et al. developed mild conditions using various dialkylaminosulfur trifluoride (R1R2N– SF3) (Scheme 24.25) [44].

Et

Et N

S S

S

N Et

S

Et

Et

R1R2N–SF3 CH2Cl2, 20 °C, 20 min

1 2 N CF3 R , R = CH3, CH3CH2 1R2 = piperidine, mophiline R Et 70% R1 = Ph and R2 = CH3CH2

Scheme 24.25  Access to N‐CF3 derivatives from R1R2N–SF3 reagents.

Tyrra studied the transformation of bis‐(dialkylthiocarbamoyl) disulfides into N‐CF3 derivatives in the presence of silver fluoride [45]. By analogy, thiocarba­ moyl fluorides and silver dithiocarbamates react with AgF selectively to yield the corresponding trifluoromethylamines (Scheme 24.26).

R

R N

S S S

S

N R

R

AgF R

R N

CF3

Scheme 24.26  Access to N‐CF3 derivatives with AgF.

When using difluorophosgene, the disulfide link can be cleaved and replaced the thiono sulfur by fluorine [46]. Thus, the reaction led to both N,N‐dimethyl­ thiocarbamoyl fluoride and Ν‐trifluorotrimethyl dimethyl amine. The former was converted into the N‐CF3 derivatives by heating in the presence of difluoro­ phosgene in 55% conversion (Scheme 24.27).

24.3  Construction of the N‐CF3 Motif

COF2, heat S Me

COF2 S

N Me

Me

Heat

Me

2

Me

+

N–CF3

F

N Me

S

Scheme 24.27  Access to N‐CF3 dimethyl amine.

24.3.1.3  Oxidative Desulfurization–Fluorination of Dithiocarbamates

Reagents such as DAST, Deoxofluor® and other derivatives have been used in combination with SbCl3 as catalyst to afford N‐CF3 products (Scheme 24.28a) [47]. In 2012, Umemoto and Singh described the use of phenylsulfur chlorotetra­ fluoride and phenylsulfur trifluoride to synthesize N‐methyl‐N‐CF3‐aminopyri­ dine from the pyridine‐methyl‐dithiocarbamate (Scheme 24.28b) [48].

Ph

O

Me N

S

Me

N SF3

Me Ph

CH2Cl2, 4 h, 5% SbCl3

S

(a)

O

SF4Cl

N CF3 95%

SF3

or N

N

CS2Me

Neat, rt

N

N

CF3

91–98% ( by 19F NMR)

(b)

Scheme 24.28  Access to N‐CF3 derivatives with Deoxofluor (a) and with sulfur fluoride reagents (b).

One of the most common methods for generating trifluoromethylamines under very mild conditions was developed by Hiyama’s group, from dithiocarba­ mates, N‐halo amides, and readily available fluoride ions, such as nBu4NH2F3, HFx–pyridine, and HFx–Et3N [49]. Different conditions have been tested, by varying the nature of the fluoride ions donor and the halonium ions “X+.” NBS (N‐bromosuccinimide), NIS (N‐iodosuccinimide), or DBH (1,3‐dibromo‐5,5‐ dimethylhydantoine) gave the best results. These conditions are applicable to various types of disubstituted carbamates, including substituted phenyl, heter­ oaromatics, or alkyl groups (Scheme 24.29). S R1

N R2

–

TBA+H2F3, (HF)9 /Py or (HF)3/NEt3 SMe

NBS or NIS, CH2Cl2, rt, 1 h

R1 = Me, n-Pr, Bn, aryl R2 = aryl

R1

N R2

CF3

76–99%

Scheme 24.29  Access to N‐CF3 derivatives with the aid of fluoride sources.

741

742

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

Other reactions have been experimented from dithiocarbamates with different fluoride sources and halogenated reagents [50]. Furthermore the introduction of the CF3 group on 4‐quinolone‐3‐carboxylic acids have been realized by means of pyridinium poly(hydrogen fluoride) and NBS. This quinolone exhibited antibac­ terial activity (Scheme 24.30) [51]. O

O F N

F S

pyr·(HF)x

F

NBS, 96%

F

O CO2H

F N CF3

SMe

N CF3

N

Scheme 24.30  N‐CF3 analogue as antibacterial agent.

24.3.1.4  Fluorination by Bromine Trifluoride (BrF3)

The reaction exploiting commercially available bromine trifluoride (BrF3) pro­ ceeded under mild conditions with amides to afford N‐CF3 amides in excellent yields. In the case of aryl/alkyl amides, a mixture of N‐CF3 and RCF2N–CF3 com­ pounds were formed in 30–40% and 55–75% yields, respectively. However, the difluoro/N‐CF3 products were successfully transformed into the N‐CF3 amides by hydrolysis (Scheme 24.31a) [52]. The same group reported on the use of the pyridine BrF3 (Py·BrF3) complex in the field of aromatic fluorinations. The authors observed that the use of this complex reduced the electrophilic bromina­ tion generally observed with most other reagents. In the case of N‐diphenyl xan­ thate, the complex Py·BrF3 afforded only to the N‐phenyl N‐(trifluoromethyl) aniline, while the BrF3 led to unidentified brominated and fluorinated com­ pounds (Scheme 24.31b) [53]. O

S R

N H

SEt

R′COOH

R

DCC, DMAP CH2Cl2

N

R′

CS2Et

BrF3 0 °C, 5–10 min CHCl3

O R

N

F +

R′

R

F

N

R′

CF3

CF3 H2O

R, R′ = alkyl R = alkyl or aryl, R′ = aryl R = aryl, R′ = alkyl or aryl

(a) CS2Me N

Py·BrF3

85–90% 30–40%

– 55–75%

CF3 N 95%

(b)

Scheme 24.31  N‐CF3 from BrF3 and pyridine/BrF3 complex.

24.3.1.5  Via Thiocarbamoyl Fluorides

A simple, fast, and selective one‐pot synthesis of N‐CF3 compounds from the stable but hygroscopic Me4NSCF3 reagent and secondary amines have been

24.3  Construction of the N‐CF3 Motif

reported in 2017 by the group of Schoenebeck [54]. The thiocarbamoyl fluoride intermediates were obtained in a few minutes at room temperature and then were reacted with AgF to be transformed into N‐CF3 derivatives. Interestingly the N‐CF3 group has been incorporated in certain pharmaceutical molecules, such as Sildenafil or Terbinafine (Scheme 24.32a). In the same line, the decom­ position of difluoromethylene phosphobetaine (Ph3P+CF2CO2−, PDFA) allowed to generate in situ the difluorocarbene that reacted with secondary amines and elemental sulfur (S8) to afford the thiocarbonyl fluoride intermediate. Then, the addition AgF led to the trifluoromethylated amines (Scheme 24.32b) [24d]. 24.3.2  Radical Trifluoromethylation 24.3.2.1  By Means of Ruppert–Prakash Reagent (CF3TMS)

From the point of view of organic compound synthesis, Cheng and coworkers reported the first radical trifluoromethylation on sulfoximines with the Ruppert– Prakash reagent, CF3TMS, catalyzed by silver carbonate and 1,10‐phenanthro­ line [55]. Either symmetrical or unsymmetrical sulfoximines substituted by various aliphatics and/or aromatics were isolated in moderate to good yields (Scheme 24.33). 24.3.2.2  By Means of Langlois Reagent (CF3SO2Na)

In their latest 2017 study, Selander and coworkers reported the radical addition of the trifluoromethyl group from sodium triflinate, CF3SO2Na, on aryl nitroso derivatives [56]. The combination of copper(II) (Cu(ClO4)2) and t‐butyl hydrop­ eroxide (TBHP) generated the CF3 radical. Once the radical was added to the nitroso arenes, the hydroquinone transferred a proton and released the N‐CF3 hydroxylamines. The reaction was totally chemoselective. It was possible to con­ vert N‐trifluoromethylated hydroxylamine into N‐CF3 acetylated aniline and into N‐CF3 aniline by reduction of the N─O bond (Scheme 24.34). 24.3.3  Electrophilic Trifluoromethylation 24.3.3.1  By Means of CF2Br2

Many precursors of “CF3+” have been proposed to achieve the electrophilic trifluo­ romethylation. In 1991, Pawelke reported the N‐trifluoromethylation of second­ ary amines with the aid of dibromodifluoromethane and tetrakis (dimethylamino) ethylene (TMAE) with KF in sulfolane as solvent [42b]. The reaction proceeds through the formation of the N‐(bromodifluoromethyl) amine intermediate and further substitution with KF in the sulfolane solvent to afford the desired N‐CF3 products in moderate yields (Scheme 24.35). In 2000, the group of Yagupolskii performed the addition of 2‐methyl benzimidazole on CF2Br2 by treatment with NaH in acetonitrile [40b]. 1‐ Bromodifluoromethyl benzimidazole was next converted into 1‐trifluoromethyl benzimidazole with tetramethyl ammonium fluoride (Me4NF) at reflux in monoglyme. The reaction resulted in a mixture of the N‐CF3 (40%) and N‐CF2H (35%) derivatives, which were separated by fractional distillation (Scheme 24.36). In 2001, Kolomeitsev and coworkers described the deprotonation of imida­ zole with potassium tert‐butylate followed by the addition of CF2Br2 to afford

743

R N

F

H

(Me4N)SCF3 DCM or MeCN, rt, 10 min

R′

R N

S R′

AgF, 4 h, MeCN or ))), rt, DCM

R N

CF3

F3C

R′

N O

N

CF3

92%

CO2tBu N

CF3

F3C N

N CF3

N CO2tBu

92%

93%

S

R N

Ph3P+CF2CO2–/S8

R′

DME, 50 °C

F R N

S R′

AgF, 80 °C, 5 h

R N

CF3 R′

N

N

N

CF3

81%

(b)

Scheme 24.32  Synthesis of N‐CF3 derivatives from (Me)4NSCF3 and from Ph3P+CF2CO2− (PDFA).

95%

Bu

Sildenafil (Viagra) analogue

(a) H

HN

OEt 88%

CO2Et 93%

O

N

tBu

CF3 N

O

N

Terbinafine (Lamisil) analogue F

CF3 N 88%

N F3C

N 83%

O R

S

NH R

+ TMS-CF3

Ag2CO3 (0.2 equiv) 1,10-Phen (0.4 equiv) 1-4 dioxane, O2, 60 °C, 12 h

O R

S

CF3 N R

R = alkyl (Me, Bn or cyclohexyl) and/or aryl (Ph, o-Cl Ph or p-X Ph, X = Me, OMe, CN, F, Br, Cl, NO2)

O 51–85%

S

CF3 N

O

Me

75%

O Ph

S

CF3 N Ph

CF3 N

O Bn

O

Me

78%

OMe

85%

Scheme 24.33  Synthesis of N‐trifluoromethyl sulfoximines.

S

S

CF3 N Ph

72%

S

CF3 N Me

58%

F

O

S

Bn

S

CF3 N Bn

58%

Me

Cl 76%

O

CF3 N

NO R

CF3SO2Na (3 equiv) Cu(CIO4)2 ·6H2O (1 mol%) t-BuOOH (3 equiv) Hydroquinone (1.1 equiv) AcOEt, rt, 1 h

OH N CF3

OH N CF3

R

51–83%

82%

R = alkyl, Ar, Cl, Br, CF3, NO2, MeO, CHO, CO2Me

Me OH N CF3

81%

EtO2C 71% OAc N CF3

Ac2O, NaHCO3

OH N CF3

Pd/C (10%), H2

97%

Scheme 24.34  Synthesis of N‐CF3 hydroxylamines and chemical modifications.

OH N CF3

OH N CF3 O2N

CF3

MeO

54% OH N CF3

N Boc

51% H N

CF3

83%

OH N CF3

HN O

O

74% OH N CF3 66%

24.3  Construction of the N‐CF3 Motif

CF2Br2 + R2N H

(Me2N)2CC(NMe2)2/KF

R2N–CF3

Sulfolane, rt, 30 min

27–45%

R = Me, Et, iPr, iBu

Scheme 24.35  Preparation of N‐CF3 amines by means of dibromodifluoromethane. N N H

(1) NaH, MeCN Me

(2) CF2Br2, 16 h, rt

N

Me

N CF2Br 76%

N

Me4NF Monoglyme reflux, 5 h

40%

N

Me +

N CF3

Me N CF2H 35%

Scheme 24.36  Synthesis of N‐CF3 benzimidazoles.

the N‐bromodifluoromethyl imidazole. The latter was converted into the N‐ CF3 imidazole with antimony trifluoride in 30% yield (Scheme 24.37a) [57a]. Sokolenko et al. presented in 2009 a method for synthesizing N‐CF3 imidazole and N‐CF3 pyrazole (Scheme  24.37a,b) [57b]. Imidazole and pyrazole were deprotonated by NaH followed by the addition of CF2Br2 and tetrabutyl ammonium bromide (nBu4NBr) as catalyst to afford the 1‐bromodifluorome­ thyl imidazole and 1‐bromodifluoromethyl pyrazole, respectively. Substitution of bromide by Me4NF was next performed in sulfolane at 170–180 °C. 1‐Trifluoromethyl imidazole and 1‐trifluoromethyl pyrazole were obtained by distillation in 36% and 39% yields, respectively. SbF3

(1) tBuOK, DMF (2) CF2Br2 48 h, 85%

N N H

(1) NaH, nBu4NBr cat. DMF

N H (b)

N CF2Br

N

(1) NaH, nBu4NBr cat. DMF (2) CF2Br2, DMF 4 h, 78%

Me4NF

N N CF3

Sulfolane, 170–180 °C 36%

(2) CF2Br2, DMF 4 h, 78%

(a)

60 °C, 24 h 30%

N

N

Me4NF

N Sulfolane, 170–180 °C 39% CF2Br

N + N CF3

N N CF2H

Scheme 24.37  Synthesis of N‐CF3 imidazole and pyrazole.

24.3.3.2  By Means of Umemoto’s Trifluoromethyl Oxonium

New reagents have been designed to generate trifluoromethyl carbocations in 2007 by Umemoto et al. who prepared O‐(trifluoromethyl) dibenzofuranylium derivatives (Scheme 24.38). The CF3+ could be generated at very low tempera­ ture and under photochemical irradiation from CF3 oxonium reagents that are good trifluoromethylation agents of primary, secondary, or aromatic amines such as pyridines, anilines, and indolines (Scheme  24.38) [58]. However, the

747

R

F3CO

R hν

N2+ X–

R N H R′ or R N R″ R′

–99 to –90 °C CD2Cl2

O+ CF3

R = H, MeO, F, tBu X = SbF6, Sb2F11, PF6, BF4

R

R O+ X– CF3 Base

N CF3 R′ or R + N SbF6– R′ CF3 R″

Scheme 24.38  N‐CF3 amines from CF3‐oxonium derivatives.

CF3 N+ SbF6–

70%

X–

+ NMe2CF3

NHCF3

SbF6–

49%

93%

N CF3 68%

NH CF3 74%

24.3  Construction of the N‐CF3 Motif

difficult synthesis and particular reaction conditions have precluded further use of these reagents. In 2015, a new generation of trifluoromethylation reagents based upon hyperva­ lent iodine have been developed by Togni and coworkers [59]. The study of the trifluoromethylation of heteroarenes in acetonitrile led to the discovery of a Ritter‐ type reaction with an azole. Thus, the N‐trifluoromethylation under optimized reaction conditions proceeded in up to 63% isolated yield (Scheme 24.39) [60]. F3 C I

O N

N N H

N

1.0 equiv CH3CN, 3 h Cat. HNTf2, 60 °C 68%

N N

N

N CF3 Mes

N

N N

47% Me

45% Ph

N

N N

N

N CF3

N CF3

N CF3 Ph 47%

N CF3 53%

Scheme 24.39  Synthesis of N‐CF3 imines with the aid of Togni reagent.

In 2012, the same group reported the selective direct trifluoromethylation of substituted electron‐rich heterocycles such as indoles and pyrroles. The heter­ oarenes were first silylated with silica sulfuric acid (SSA) in situ before being treated with the electrophilic trifluoromethylating reagent (Scheme 24.40) [61]. N

R

N H

N R N H

R N

NH

N

R N

N N CF3

(1) SSA cat., HMDS (2)

CF3 I O

1 equiv

2% LiNTf2, 12% HNTf2 1.5 M CH2Cl2, 35 °C

R N

R

N N CF3

N CF3 15–64%

Scheme 24.40  Direct synthesis of N‐CF3 heteroarenes with the aid of Togni reagent.

In 2015, Wang and coworkers studied the trifluoromethylation of NH‐aro­ matic ketimines by in situ generation of a hypervalent iodine intermediate [ArICF3]+ species as donor of “CF3+” [62]. The [ArICF3]+ species was formed via two routes: (i) by using acid Togni’s reagent with copper salt as catalyst in ace­ tonitrile or (ii) by using Ruppert–Prakash reagent and phenyliodine diacetate (PIDA) in the presence of a fluoride donor (KF). The trifluoromethylation of primary ketimines occurs in yields ranging from 40% to 88% (Scheme 24.41). In the case of Togni’s reagent, the copper catalyst increased the electrophilic character of the hypervalent iodine reagent by chelation on the oxygen of the carbonyl. From the Ruppert–Prakash reagent and PIDA, the active species [PhICF3]+[OAc]− was formed in situ. The ketimine was added onto this species resulting in the N‐CF3 ketimine after deprotonation and reductive elimination.

749

750

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

I

Ar

O

O

NH Ar

CF3 Cu(OAc)2 (5%), MeCN, 60 °C N

TMSCF3/KF, PhI(OAc)2, CH3CN, 60 °C, 6 h

Ar

CF3 Ar

40–88%

Scheme 24.41  Electrophilic trifluoromethylation of ketimines.

24.3.4  Nucleophilic Trifluoromethylation In 2012, Inoue and Handa performed the nucleophilic trifluoromethylation of nitroso arenes using TMSCF3 and CsF in 1,2‐dimethoxyethane. The O‐acety­ lated, N‐trifluoromethylated hydroxylamines were obtained and were hydrogen­ ated using Pd/C in tetrahydrofuran (THF) to afford the PhNHCF3. The N‐CF3 aniline was also treated with Ac2O and CF3SO3SiMe3 at 40 °C for six hours to lead to PhNAcCF3 in 78% yield (Scheme 24.42) [63].

Me3SiCF3

(1) ArNO CsF, (MeOCH2)2 (2) Ac2O

CF3 (1) Pd/C, H2 N OAc (2) Ac2O, CF3SO3SiMe3

CF3 N

Ac

Scheme 24.42  Nucleophilic trifluoromethylation of nitroso arenes.

Our group investigated the nucleophilic trifluoromethylation of azodicarboxy­ late derivatives. After exploring different conditions, the best conditions con­ sisted in the use of CF3TMS and di‐tert‐butyl azodicarboxylate in the presence of AcONa as catalyst in DMF at 0 °C. The corresponding N‐CF3 hydrazide was iso­ lated in 30% yield (Scheme 24.43) [64].

BocNNBoc

Me3SiCF3 10% AcONa, DMF

CF3 Boc N N Boc H 30%

Scheme 24.43  Nucleophilic trifluoromethylation of di‐t‐Bu azodicarboxylate.

More recently, the nucleophilic addition of the CF3− anion formed in situ from Ruppert–Prakash reagent has been investigated on the p‐toluenesulfonyl azide (TsN3) to produce azidotrifluoromethane (CF3N3) isolated by distillation with THF in 70–80% (Scheme 24.44). Then, the click reaction (CuAAC) between the solution of trifluoromethyl azide in THF, various alkynes, and a catalytic amount of copper(I) 3‐methylsalicylate at room temperature was conducted. After 18 hours, the corresponding N‐CF3 triazoles were isolated in good yields with the selective formation of the 1,4‐disubstituted triazoles (Scheme 24.44) [65]. Because of the high volatility of CF3N3 (b.p. −28.5 °C), the authors conducted a

24.3  Construction of the N‐CF3 Motif

direct one‐pot, two‐step synthesis of N‐CF3 triazoles. After formation of CF3N3 at −60 °C in DMF, alkyne, aqueous solution of CuSO4 and sodium ascorbate were added. The N‐CF3 triazoles are isolated in reasonable yields comparable with the two‐step procedure, though with a slightly lower regioselectivity (Scheme 24.44).

Me3SiCF3

(1) CsF (2 equiv), TsN3 (1 equiv) DMF, –60 to –30 °C, 4 h

CF3N3 Solution in THF

2) Addition of THF and distillation

70–80%

(1) CsF (2 equiv), TsN3 (1 equiv) DMF, –60 to –30 °C, 4 h

Me3SiCF3

N N R

(2) Alkyne, CuSO4.5H2O Na L-ascorbate, rt, 18 h

N N

Alkyne

N CF3 R CuMeSal (1–5 mol%) 24–90% THF, rt, 18 h R = aryls, esters, alkyls,... R = Ph; 60% (97 : 3) R = Me; 89% (99 : 1) R = 4-CF3Ph; 50% (95 : 5)

N CF3

Scheme 24.44  Synthesis of CF3N3 and CuAAC of CF3N3 with alkynes for synthesis of N‐CF3 triazoles.

In the same vein, the Ramachary–Bressy–Wang enamine [3+2] cycloaddition between the CF3 azide and ketones allowed to prepare a new wide range of sub­ stituted N‐CF3 triazoles (Scheme 24.45) [66]. O F3C N3

+ EWG

N N

Pyrrolidine (cat.) R

EWG

THF, rt, 18 h

N CF3

R

Scheme 24.45  Synthesis of substituted N‐CF3 triazoles.

From these N‐CF3‐1,2,3‐triazoles, different types of transformation have been investigated (Scheme  24.46). A rhodium‐catalyzed trans‐annulation via ring opening followed by cycloaddition with different nitriles, enol ethers, isocy­ anates, and silyl ketene acetals were realized to provide imidazoles, pyrroles, imi­ dazolones, and pyrrolones [67]. Likewise a chemoselective aza‐[4+3]‐annulation with dienes afforded azepine derivatives [68]. R2

R3

R2 N

N CF3 N N R

N CF3

Rh(II) cat.

R1 R1

R2

N CF3

O

N CF3

R1

O

R

Ph

N CF3 R

O N

N CF3

R

N CF3

Scheme 24.46  Transformation of N‐CF3 triazoles into diverse other N‐CF3 heterocycles.

751

752

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

24.4 ­Construction of the N‐CH2CF3 Motif The introduction of a 2,2,2‐trifluoroethyl group on the nitrogen atom of alky­ lamines, arylamines or N‐heterocycles is important in the fields of medicine and agrochemistry [69]. Indeed, the N‐trifluoroethylation of aniline and heterocycles should improve their stability toward oxidative degradation due to the particular properties of the fluoroalkyl groups. For example, the basicity of the N‐trifluoro­ ethylamines is lower than their hydrocarbon counterparts [70], which improve their metabolic stability and decrease their acute toxicity [71]. Accordingly, a number of pharmaceuticals and agrochemicals feature this N‐trifluoroethyl group in their structure as depicted in Figure 24.1 [72–77]. In comparison with the N‐trifluoromethylation methods, the process for N‐ trifluoroethylation have not been so developed. The main approaches to the synthesis of N‐trifluoroethylated amines are based on the reactivity of trif­ luoroethylamine toward alkyl or aryl halides or sulfonates or on the use of fluoroalkyl electrophiles toward nucleophilic amines (Scheme 24.47).

F3C

N H

F3C

R

NH2

or

R X

F3C

R NH2

E

F3C

N H

R

Scheme 24.47  Main approaches to the synthesis of N‐trifluoroethylamines.

24.4.1  Trifluoroethylamine as Nucleophilic Agent This first pathway requires the commercially available 2,2,2‐trifluoroethylamine whose synthesis was first reported by Gilman and Jones in 1943 by reduction of trifluoroacetonitrile under H2 catalyzed by platinum metal [78]. Then various methods have been developed including reduction of trifluoroacetamide [79];

HN

O

O

O

N N

CF3 N

F

N H

N

F O

A

N

N H

Cl

O

B

N

CF3 N

C

E CF3

O

CF3 N

N

CF3

CF3

N

CF3 N

N D

N

N N F3C

O O

N F

N H

N

N

N H

Figure 24.1  Biologically relevant N‐trifluoroethylamino compounds: (A) telcagepant, a CGRP receptor antagonist for the treatment of migraine; (B) halazepam, an anxiolytic benzodiazepine; (C) an orally available tissue‐selective androgen receptor modulator; (D) CYP17A1, a lyase inhibitor for the treatment of castration‐resistant prostate cancer; (E) a stabilizer of tumor suppressor p53‐Y220C mutant; and (F) a PI3 kinase inhibitor.

24.4  Construction of the N‐CH2CF3 Motif

amination of trifluoroethyl halides [80, 81]; fluorination of glycine using HF and SF4 [82]; condensation reaction of trifluoroacetaldehyde hydrate with ammonia hydrate, followed by reduction with NaBH4 or KBH4 [83], and the base catalyzed [1,3]‐proton shift reaction of CF3‐benzylidenimine [84] (Scheme 24.48). O HO

NH2 HF, SF4

O F3C

NaBH4, BF3·Et2O NH2 Pt, H2

″NH3″ F3C

NH2

F3C

X

(1) NH3, H2O (2) NaBH4 OH

F3C

N

F3C

OH

Scheme 24.48  Main approaches to the preparation of 2,2,2‐trifluoroethylamine.

The 2,2,2‐trifluoroethylamine has been widely used in various reactions (nucleo­ philic substitution with alkyl [85, 86] or aromatic halides [87], epoxide ring open­ ing [88, 89], or reductive amination [90]) with some applications in the field of medicinal chemistry. More recently we can cite the exhaustive study of Hartwig and coworker on the palladium catalyzed cross‐coupling reaction between a wide range of aromatic halides and trifluoroethylamine [91] (Scheme 24.49). [Pd(Allyl)Cl]2 cat. AdBippyPhos cat.

X R

+ H N 3

R = alkyl, CN, OMe,... X = Cl or Br

CF3

1.05 equiv KOPh Dioxane, 100 °C 75–100%

H N R

CF3

Scheme 24.49  Palladium‐catalyzed cross‐coupling reaction of 2,2,2‐trifluorethylamine with aryl halides.

24.4.2  Electrophilic Trifluoroethyl Sources The use of trifluoroethyl halides and derivatives seems to be the easiest and most practical way to synthesize trifluoroethylamines, but due to the properties of the fluorine atom, these reagents present a low reactivity toward nucleophilic sub­ stitution. Nevertheless, alkylamines and arylamines in a less extent can react with trifluoroethyl halides [92], tosylates [93], mesylates [17, 94, 95], or o‐nitro‐­ benzenesulfonates [96]. The most reactive trifluoroethyl triflate has been widely used in the design and synthesis of pharmaceuticals under milder conditions (Scheme  24.50a) [97, 98]. In this line, recently Sammis and coworkers have

753

754

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

developed a new strategy based on the one‐pot trifluoroethylation of primary and secondary amines with trifluoroethyl fluorosulfate reagent prepared in situ from appropriate trifluoroethanol and sulfuryl fluoride (Scheme  24.50b) [99]. On the other hand, to circumvent the low reactivity of trifluoromethyl sulfonates, Umemoto and Gotoh developed an stable and effective trifluoroethylating agent based on hypervalent iodine, the (1,1‐dihydrotrifluoroethyl)phenyliodonium tri­ flate, which easily react with aryl and alkylamines (Scheme 24.50c) [100]. F3C R NH2 (a)

or

F 3C

X F3C

NHR

F3C

OSO2R F3C

I

O S O F O

OTf

F3C

OH

R NH2 (b)

SO2F2, DIPEA DMF 31–79%

Ph

(c)

R NH2

Scheme 24.50  Various access to 2,2,2‐trifluoroethylamines from amines.

In the aim to improve the synthesis of N‐trifluoroethylated amines under mild conditions, Khalafi‐Nezhad and coworkers described an efficient method using trifluoroethanol activated by 2,4,6‐trichloro‐1,3,5‐triazine (TCT, cyanuric chloride). This reaction is applicable to various anilines and leads to mono or bis‐N,N‐trifluoroethylated products depending on the amount of 2,4,6‐tris(2,2,2‐­ trifluoroethoxy)‐1,3,5‐triazine (TTFET) (Scheme 24.51) [101]. Aniline/TTFET 1 : 1 N

Cl N

Cl N

Cl

F3C

OH

NaH, THF, 60 °C 6h

F3C

O

O

N N

F3C

N

CF3 THF, rt or DMF, 100 °C

CF3 R

70–92%

N O

CF3

TTFET, 90%

Aniline/TTFET 1 : 0.6 THF, rt

HN

CF3 R

72–76%

Scheme 24.51  Preparation of mono and bis‐N,N‐trifluoroethylanilines.

Alternatively, the preparation of trifluoroethylamino compounds can be achieved via reductive amination based on the formation of a trifluoromethyla­ ldimine (from trifluoroacetaldehyde) or a trifluoroacetyl amide (from trifluoro­ acetic acid or anhydride) in the presence of different reducing agents. Mimura et al. reported the synthesis of trifluoroethylamines in a two‐step procedure by reduction of trifluoroacetaldimines using hydrogenation on Pd–C, or NaBH4 or Pic–BH3 as reducing agent. This strategy has been applied to primary and sec­ ondary alkyl and arylamines in good yields [102]. Some of the general methods for reductive amination starting from carboxylic acids have been applied to the synthesis of trifluoroethylamines. For example, Beller and coworkers described

24.4  Construction of the N‐CH2CF3 Motif

the synthesis of the N‐trifluoroethylaniline using PhSiH3 as hydrogen source in the presence of [Pt] Karstedt’s catalyst and 1,2‐bis(diphenylphosphino)ethane (dppe) [103]. Fu and coworkers used 1 mol% of B(C6F5)3 to catalyze the reduction with polymethylhydrosiloxane as hydrogen source [104]. Song and coworkers reported the N‐trifluoroethylation of aniline with trifluoroacetic acid, in which BH3·NH3 acted as hydrogen source under transition‐metal‐free conditions [105]. Finally, the synthesis of a wide range of trifluoroethylamines has been carried out using trifluoroacetic acid (TFA) as source of fluorine in the presence of PhSiH3 [106]. This methodology was nicely exploited to obtain secondary trifluoroethy­ lamines in a three‐component reaction involving an aldehyde, a primary amine, and TFA (Scheme 24.52). O F3C

O R1–NH2 + R2

H

OH

1.75 equiv

PhSiH3 (2.5 equiv) Toluene, 70 °C, 16 h

F3C

N R1

More than 25 examples 2 R2 R = alkyl, aryl, alcene, ester... R1 = alkyl, allyl, ester.. 29–80%

Scheme 24.52  Synthesis of 2,2,2‐trifluoroethylamines using TFA as a source of fluorine.

From trifluoroacetamides, the catalytic hydrosilylation using tetramethyldisi­ loxane mediated by an electrophilic phosphonium cation catalyst was described by Stephan and coworkers [107]. This strategy is really efficient for the amide derived from N‐phenyl‐2,2,2‐trifluoroacetamide (80–92% yields) but a bit less for the N‐alkyl derivatives (24–64% yields). Recently the combination of BF3·Et2O and of BH3·NH3 in the presence of 2 mol% of B(C6F5)3 allowed the deoxygenative reduction of trifluoroacetyl amides [108]. The 2,2,2‐trifluorodiazoethane prepared from commercially available 2,2,2‐ trifluoroethylamine hydrochloride, according to the method reported by Carreira and coworker [109], can be used as a carbene precursor allowing the N‐trifluoro­ ethylation of anilines. Wang and coworkers reported an elegant synthesis of a wide range of N‐trifluoroethylanilines based on N–H insertion with CF3CHN2 catalyzed by silver (AgSbF6) (Scheme  24.53) [110]. Following these works, Gouverneur and coworkers reported the synthesis of p‐methoxy‐N,N‐bis trif­ luoroethylaniline by N–H insertion of CF3CHN2 catalyzed by copper [111]. NH2 R

+

H N

AgSbF6 (5 mol%)

F3C N2

DCE, 50 °C, air

R

CF3

69–98%

Scheme 24.53  Trifluoroethylation using 2,2,2‐trifluorodiazoethane.

Finally, we can cite an original synthesis of trifluoroethylated alkyl compounds reported by Li and coworkers based on the silver‐catalyzed decarboxylative trifluoromethylation of various primary and secondary alkyl carboxylic acids

755

756

24  Construction of N‐CF2H, N‐CF3, and N‐CH2CF3 Motifs

(Scheme 24.54). The active species responsible for the trifluoromethylation of the alkyl radical is the Cu(CF3)2, which results from the reductive elimination of (bpy)Cu(CF3)3 and subsequent oxidation of the Cu(CF3)2 intermediate [112].

NPhth

CO2H

Ag2+ S2O82–

AgNO3(cat.), K2S2O8 (bpy)Cu(CF3)3, ZnMe2 MeCN/H2O, 40°C, 10 h –H, –CO2

Ag+

R•

NPhth

CF3

86% CuCF3

Cu(CF3)2

[O]

–Cu(CF ) 3 2

Reductive (bpy)Cu(CF3)3 + Elimination ZnMe2

Scheme 24.54  Silver‐catalyzed decarboxylative trifluoromethylation of carboxylic acids.

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55 Bolm, C., Teng, F., and Cheng, J. (2015). Org. Lett. 17: 3166–3169. 56 van der Werf, A., Hribersek, M., and Selander, N. (2017). Org. Lett. 19:

2374–2377.

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64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79

173–181. (b) Sokolenko, T.M., Petko, K.I., and Yagupolskii, L.M. (2009). Chem. Heterocycl. Compd. 45: 430–435. Umemoto, T., Adachi, K., and Ishihara, S. (2007). J. Org. Chem. 72: 6905–6917. Charpentier, J., Früh, N., and Togni, A. (2015). Chem. Rev. 115: 650–682. Niedermann, K., Früh, N., Vinogradova, E. et al. (2011). Angew. Chem. Int. Ed. 50: 1059–1063. Togni, A., Niedermann, K., Früh, N. et al. (2012). Angew. Chem. Int. Ed. 51: 6511–6515. Zheng, G., Ma, X., Li, J. et al. (2015). J. Org. Chem. 80: 8910–8915. Inoue, M. and Handa, M. (2012). O‐acyl‐n‐aryl‐n‐(trifluoromethyl) hydroxylamine derivative and method for producing the same, JP 2012062284A, filed 17 September 2010 and issued 29 March 2012. Mamone, M., Milcent, T., Ongeri, S., and Crousse, B. (2015). J. Org. Chem. 80: 1964–1971. Blastik, Z.E., Voltrovà, S., Matousek, V. et al. (2017). Angew. Chem. Int. Ed. 56: 346–349. Blastik, Z.E., Klepetářová, B., and Beier, P. (2018). ChemistrySelect 3: 7045–7048. Motornov, V., Markos, A., and Beier, P. (2018). Chem. Commun. 54: 3258–3261. Motornov, V., Markos, A., and Beier, P. (2018). J. Org. Chem. 83: 15195–15201. Gillis, E.P., Eastman, K.J., Hill, M.D. et al. (2015). J. Med. Chem. 58: 8315–8359. Morgenthaler, M., Schweizer, E., Hoffmann‐Röder, A. et al. (2007). ChemMedChem 2: 1100–1115. Vorberg, R., Trapp, N., Zimmerli, D. et al. (2016). ChemMedChem 11: 2216–2239. Xu, F., Zacuto, M., Yoshikawa, N. et al. (2010). J. Org. Chem. 75: 7829–7841. Fann, W.E., Pitts, W.M., and Wheless, J.C. (1982). Pharmacother. J. Hum. Pharmacol. Drug Ther. 2: 72–79. van Oeveren, A., Motamedi, M., Mani, N.S. et al. (2006). J. Med. Chem. 49: 6143–6146. Huang, A., Jayaraman, L., Fura, A. et al. (2016). ACS Med. Chem. Lett. 7: 40–45. Bauer, M.R., Jones, R.N., Baud, M.G.J. et al. (2016). ACS Chem. Biol. 11: 2265–2274. Chen, Z., Venkatesan, A.M., Dehnhardt, C.M. et al. (2010). J. Med. Chem. 53: 3169–3182. Gilman, H. and Jones, R.G. (1943). J. Am. Chem. Soc. 65: 1458–1460. Bourne, E.J., Henry, S.H., Tatlow, C.E.M., and Tatlow, J.C. (1952). J. Chem. Soc. (Resumed): 4014–4019.

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80 Elliott, A.J. and Astrologes, G.W. (1986). Preparation of trifluoroethylamine,

US Patent 4 618 718; Chem. Abstr. 110: 192243, filed 14 July 1985 and issued 21 October 1985. 81 Yan, Z., Zhang, L., Huang, K., and Zhou, J. (2016). Preparation method of trifluoroethylamine, Chinese Patent 105906513 (from Faming Zhuanli Shenqing); Chem. Abstr. 165: 353594, filed 26 April 2016 and issued 31 August 2016. 82 Geng, W., Zhou, Q., Wang, S., and Gu, Y. (2013). Method for synthesizing trifluoromethyl amine, Chinese Patent 102875270 (from Faming Zhuanli Shenqing); Chem. Abstr. 158: 215312, filed 24 September 2012 and issued 16 January 2013. 83 Qu, J., Shen, R., Lu, W. et al. (2013). Preparation method of trifluoroethylamine, Chinese Patent 103274947 (from Faming Zhuanli Shenqing); Chem. Abstr. 159: 455239, filed 3 July 2013 and issued 4 September 2013. 84 Soloshonok, V.A., Kirilenko, A.G., Kukhar, V.P., and Resnati, G. (1994). Tetrahedron Lett. 35: 3119–3122. 85 Roberts, L.R., Bryans, J., Conlon, K. et al. (2008). Bioorg. Med. Chem. Lett. 18: 6437–6440. 86 Ye, B., Arnaiz, D.O., Chou, Y.‐L. et al. (2007). J. Med. Chem. 50: 2967–2980. 87 Francotte, P., Goffin, E., Fraikin, P. et al. (2010). J. Med. Chem. 53: 1700–1711. 88 Samoshin, V.V., Zheng, Y., and Liu, X. (2017). J. Phys. Org. Chem. 30: 3689. 89 Letavic, M.A., Bronk, B.S., and Bertsche, C.D. (2002). Bioorg. Med. Chem. Lett. 12: 2771–2774. 90 Zhao, Z., Pissarnitski, D.A., and Huang, X. (2017). ACS Med. Chem. Lett. 8: 1002–1006. 91 Brusoe, A.T. and Hartwig, J.F. (2015). J. Am. Chem. Soc. 26: 8460–8468. 92 Dickey, J.B., Towne, E.B., Bloom, M.S. et al. (1954). Ind. Eng. Chem. 46: 2213–2220. 93 Riss, P.J., Ferrari, V., Brichard, L. et al. (2012). Org. Biomol. Chem. 10: 6980–6986. 94 Kim, S.‐H., Bajji, A., Tangallapally, R. et al. (2012). J. Med. Chem. 55: 7480–7501. 95 Li, Q., Lin, G., Liu, L. et al. (2009). Molecules 14: 777–784. 96 Kuwabara, M., Miura, H., Fukunishi, K. et al. (1986). Nippon Kagaku Kaishi 5: 681–687. 97 For some recent examples see: Come, J.H., Collier, P.N., Henderson, J.A. et al. (2018). J. Med. Chem. 61: 5245–5256. 98 Lu, H., Yang, T., Xu, Z. et al. (2018). J. Med. Chem. 61: 2518–2532. 99 Epifanov, M., Foth, P.J., Gu, F. et al. (2018). J. Am. Chem. Soc. 140: 16464–16468. 100 (a) Umemoto, T. and Gotoh, Y. (1986). J. Fluorine Chem. 31: 231–236. (b) Montanari, V. and Resnati, G. (1994). Tetrahedron Lett. 35: 8015–8018. 101 Haghighi, F., Panahi, F., Haghighi, M.G., and Khalafi‐Nezhad, A. (2017). Chem. Commun. 53: 12650–12653. 102 Mimura, H., Kawada, K., Yamashita, T. et al. (2010). J. Fluorine Chem. 131: 477–486.

­  References

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106 Andrews, K.G., Faizova, R., and Denton, R.M. (2017). Nat. Commun. 8: 15913. 107 Augurusa, A., Mehta, M., Perez, M. et al. (2016). Chem. Commun. 52:

12195–12198.

108 Pan, Y., Luo, Z., Han, J. et al. (2019). Adv. Synth. Catal. 361: 2161. 109 Morandi, B. and Carreira, E.M. (2010). Angew. Chem. Int. Ed. 49: 4294–4296. 110 Luo, H., Wu, G., Zhang, Y., and Wang, J. (2015). Angew. Chem. Int. Ed. 54:

14503–14507.

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112 Tan, X., Liu, Z., Shen, H. et al. (2017). J. Am. Chem. Soc. 139: 12430–12433.

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Part VI Phosphorus‐Linked Fluorine‐Containing Motifs

765

25 Synthesis and Applications of P–Rf ‐Containing Molecules Fa‐Guang Zhang1,2 and Jun‐An Ma 1,2 1

Tianjin University, Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Centre of Chemical Science & Engineering, Weijin Road, Nankai District, Tianjin 300072, China 2 International Campus of Tianjin University, Joint School of NUS & TJU, Changle District, Binhai New City, Fuzhou 350207, China

25.1 ­Introduction Interest in fluorine or fluoroalkyl groups attached to phosphorus atom stems from the possible effect of such substitution on physical, chemical, and biological properties of the resulting phosphorus molecules. Fluorinated organophospho­ rus derivatives have been playing important roles in the fields of chemistry, materials science, pharmaceutical, and agrochemistry. Fluorinated organophos­ phorus compounds involve many kinds of P–Rf‐containing molecules, which were discussed in some books and review papers [1]. This chapter will capture the emerging potential of fluorinated organophosphorus compounds and high­ light recent innovative achievements. The first section is a survey of achiral and chiral fluoro‐organophosphine compounds. The second section presents mono­ fluoromethyl‐, difluoromethyl‐, and trifluoromethylphosphonate reagents. The third section consists of chiral fluorinated aminophosphonic acid derivatives. The fourth section is focused on the synthesis and application of perfluoroalkyl phosphonic and phosphinic acids. The last section describes the development of fluorophosphonium and fluoroalkylphosphonium cations. 25.1.1  Fluoro‐Organophosphine Derivatives Tricoordinate organophosphines have proven to be the most significant class of phosphorus compounds in organic chemistry. They are widely used as Wittig reagents, organocatalysts, and metal ligands for various C─C, C─N, and C─O bond‐forming reactions [2–4].

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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25  Synthesis and Applications of P–Rf ‐Containing Molecules

25.1.2  Achiral Fluoro‐Organophosphines Since the seminal reports of tris(trifluoromethyl)‐phosphine in 1953 [5a] and tris(pentafluorophenyl)‐phosphine in 1960 [5b], a large number of fluoro‐­ organophosphine compounds have been synthesized and investigated in organic synthesis and coordination chemistry. A detailed review on fluoroarylphosphines has been presented by Saunders and coworkers [6]. The synthesis and applica­ tions of fluoroalkenyl‐ and fluoroalkynyl phosphines have been systematically described by Brisdon and coworkers [7]. Four years later, Brisdon and Herbert have also discussed the chemistry of fluoroalkyl phosphines [8]. Several repre­ sentative examples of achiral fluoro‐organophosphines were listed in Scheme 25.1, and researchers who are interested in these subjects are encouraged to read the relevant reviews. Me

Me C6F5

C6F5 P C6F5

P(C6F5)2

P(C6F5)2

P(C6F5)2

P(C6F5)2

(a)

dfppe

dfppm

Ph2PCFCF2

PhP(CFCF2)2

Ph2P

O P(C6F5)2

(C6F5)2P

CF3

PhP(

CF3)2

(b)

PF2

P(CF3)2

P(C2F5)2

PF2

P(CF3)2

P(C2F5)2

(c) dfpe

dfmpe

dfepe

P(CF3)2

CF3

P(CF3)2 PCPH

P(C2F5)2

P(C2F5)2 PCPH

C2F5

Scheme 25.1  Representative examples of achiral fluoro‐organophosphines. (a) Fluoroaryl phosphines. (b) Fluoroalkenyl and fluoroalkynyl phosphines. (c) Fluoroalkyl phosphines.

25.1.3  Chiral Fluoro‐Organophosphines Starting from enantiomerically pure (S)‐2,2′‐binaphthol, a series of chiral monodentate fluoroarylphosphines 1 were prepared by the Beller’s group (Scheme  25.2) [9]. They compared the activity and selectivity of different ligands 1 for the ruthenium‐catalyzed asymmetric hydrogenation of methyl acetoacetate and found that 4‐fluorophenyl ligand exhibited the best selectivity even at 120 °C. Several years later, Togni and coworkers employed (R)‐2,2′‐binaphthol for  the synthesis of chiral diphosphine ligand (R)‐(2′‐(bis(trifluoromethyl) phosphino)‐1,1′‐binaphthyl‐2‐yl)diphenylphosphine 2, which contains a bis(trifluoromethyl)phosphine group. This ligand 2 forms a palladium complex displaying a rather short Pd─P(CF3)2 bond distance. It could be explained by

25.1 Introduction

Me (1) n-BuLi Me TMEDA (2) Cl2PArf

OH (1) Tf2O/Py OH (2) MeMgBr NiCl2(dppp)

P Arf 1

(1) n-BuLi TMEDA (2) Cl2PNEt2

P NEt2

O Me

O

ArfMgCl

HCl

OH O

[Ru(COD)(methallyl)2]/1 (1/2 mol%) OMe

P Cl

MeOH, H2 (60 bar), 60–120 °C, 1–16 h

Me *

OMe

1a, Ar = 2-FC6H4, 80 °C, 16 h: 89% yield and 58% ee 1b, Ar = 4-FC6H4, 120 °C, 1 h: >99% yield and 95% ee 1c, Ar = 3,4,5-F3C6H2, 80 °C, 16 h: 69% yield and 25% ee 1d, Ar = C6F5, 80 °C, 16 h: 25% yield and 6% ee 1e, Ar = 4-CF3C6H4, 100 °C, 16 h: 94% yield and 81% ee

Scheme 25.2  Synthesis of chiral ligands 1 and Ru‐catalyzed hydrogenation of methyl acetoacetate. The [*] indicates a chiral center in the molecular.

the high σ‐character of the P─Pd bond and a possibly strong π‐back‐­donation (Scheme 25.3) [10]. F3C I OH

PH2

OH

OTf

O O

P(CF3)2 OTf

(1) [Ni(dppe)Cl2], Ph2PH, DMF, 100 °C, 1 h 45% (2) Substrate, DABCO, DMF, 100 °C, 40 h CF3

CF3

P Pd P Ph

Cl

Cl Ph

[Pd(COD)Cl2] DCM, rt, 1 h, 92%

P(CF3)2 PPh2 2

Scheme 25.3  Synthesis of chiral ligand 2 and the corresponding Pd complex.

767

768

25  Synthesis and Applications of P–Rf ‐Containing Molecules Me

O

I

Me

O

I

+

Me

O

–78 to –20 oC, 72 h Me {K([18]-crown-6)}(CN)

O

(CF3)2P–P(CF3)2

Me2CO

P(CF3)2

3

P(CF3)2

[Mo(CO)4(NBD)] –NBD CF3 CO P CO O Mo CO O P CO F3C CF3 F3C

Me Me

Scheme 25.4  Synthesis of chiral DIOP analogue 3 and tetracarbonyl–molybdenum complex.

In 2006 Hoge et al. reported the synthesis of chiral 2,3‐O‐isopropylidene‐2,3‐ dihydroxy‐1,4‐bis(diphenylphosphino)butane) (DIOP) analogue 3, in which the phenyl groups at the phosphorus atoms are replaced by strong electron‐with­ drawing trifluoromethyl groups [11]. The reaction of {K([18]‐crown‐6)} P(CF3)2, derived from (CF3)2PP(CF3)2 and {K([18]‐crown‐6)}(CN), with 4,5‐ bis(iodomethyl)‐2,2‐dimethyl‐1,3‐dioxolane in the presence of acetone furnished this bidentate bis(trifluoromethyl)phosphane ligand (Scheme 25.4). The result­ ing high electron‐acceptor strength of the synthesized bidentate (CF3)2P ligand was demonstrated by a structural and vibrational study of the corresponding tetracarbonyl–molybdenum complex. Since its first report, Ugi’s ferrocene amine has exhibited extensive application as a planar chiral synthetic precursor to a large number of metal ligands [12]. Based on the use of (R)‐Ugi’s amine, Togni and coworkers designed and prepared a series of P‐stereogenic ferrocene‐derived (trifluoromethyl)phosphanes 4 [13]. Ligands 4a–c afforded high activities in the asymmetric hydrogenation of dime­ thyl itaconate and allylic alkylation of 1,3‐diphenylallyl acetate. When the ligand 4d was applied in the hydrogenation of a series of 1‐substituted 3,4‐dihydroiso­ quinolinium chlorides, good to excellent yields with variable enantioselectivities were obtained (Scheme 25.5). Independently, the groups of Shen and Sun/You developed stable bis (fluoroalkyl)phosphine‐oxazoline ligands 5 and 6 [14]. It was found that the Pd complexes of these ligands could promote the asymmetric alkylation of mono‐ substituted allyl substrates in good to high yields with excellent regio‐ and enan­ tioselectivities (Scheme 25.6). Control experiments and structure analysis of the Pd‐allyl intermediate demonstrated that the combination of relative steric and strong trans influences presented by the P(Rf )2 moieties gave rise to the excellent selectivity.

25.1 Introduction Me

Me

NMe2 (1) n-BuLi/DMF

Fe

NMe2 OH

Fe

(2) LiAlH4

CF3

OH Ac ion at P HP talliz s (1) y Cr (2)

Fe

Me

PPh2 P Ph CF3 4a (solid)

HPPh2, AcOH 90 °C, 5 h

Crystallization from MeOH Me NMe2 P Ph Fe CF3 (solid)

Me

NMe2 Fe

Fe

(R)-Ugi’s amine

H P Cy P CF3

NMe2 CF3

P

t-BuOK Fe

PR2

R2PH

Fe

P

CF3

Fe

Ph

4c, R = Cy; 4d, R = Xyl

CO2Me

OAc Ph

+

Ph

R3 R2

4a: 100%, 76% ee 4b: 100%, >99% ee 4c: 100%, 97% ee

CO2Me

[Pd2(η3-C3H5)2Cl2]/Ligand

CO2Me

4b: >99%, 90% ee 4c: >99%, 88% ee

R1 Cl

2-Propanol, 100 bar H2 60–99%, 23–96% ee

Cy

CF3

Me Me P Cy P CF3 i-Pr

4b Me

[Rh]/Ligand, H2 (1 atm)

0.5 mol% [Ir(4d)(cod)Cl] NH

P

(1) MeOTf (2) i-PrMgCl

Me

AcOH, 90 °C

Ph

Me

CF3

(1) s-BuLi (2) PhP(CF3)2 Me

MeO2C

NMe2 P Ph CF3

Fe

h 2,

Me

Fe

Me

HBF4·OEt2

(R)-Ugi’s amine

P

Ph

H P

MeO2C

MeO2C Ph

CO2Me

CO2Me Ph

R3 R2

* NH2 R1 Cl

Scheme 25.5  Synthesis of chiral (trifluoromethyl)phosphanes 4 and applications. The [*] indicates a chiral center in the molecular.

769

770

25  Synthesis and Applications of P–Rf ‐Containing Molecules

(a)

(b)

O

CO2H

Br

Br

O

N

P(Rf)2

t-Bu 5 (Rf = CF3, C2F5)

t-Bu

O

O CO2H (a)

Fe

N

N Fe

t-Bu (b)

N

t-Bu

Fe

P(CF3)2 6 (a) (i) Amino alcohol, EDCI, HOBT, rt, 6 h; (ii) TsCl, Et3N, rt, 12 h. (b) (i) s-BuLi, TMEDA, Et2O, –78 °C, (ii) P(OPh)3,–100 °C to rt, 1 h; (iii) CF3TMS/CsF, rt, overnight or C2F5TMS/CsF, 40 °C, overnight. Br

X

R X R

Br

+

CO2Me CO2Me

Pd(dba)2/5 or 6 (2–4 mol%)

MeO2C

CO2Me

BAS, LiOAc or NaOAc R 90–98%, b/l: 81/19–99/1, 64–99.6% ee

Scheme 25.6  The synthesis of bis(fluoroalkyl)phosphine‐oxazoline ligands and its applications. BSA, bis(trimethylsilyl) acetamide.

25.2 ­Phosphorous‐Based Fluoromethylating Reagents The phosphorous‐based fluoromethylating reagents proved to be versatile rea­ gents in modern organic chemistry [1c]. These reagents have been applied suc­ cessfully for the incorporation of monofluoro‐, difluoro‐, and trifluoromethyl moieties into a variety of organic molecules, which are otherwise difficult to prepare. 25.2.1  Monofluoromethylphosphonate Reagents Monofluoromethyl phosphonates 7 could be constructed through many different routes depending on the nature of starting materials. The most common methods include direct reaction of trivalent phosphorus derivatives with fluorohaloalkanes, electrophilic fluorination of phosphonate carbanions, and nucleophilic fluorina­ tion of functionalized phosphonate substrates. Gryszkiewicz‐Trochimowski dem­ onstrated that monofluoromethylphosphonates could be produced from the reaction of CH2ClF with (RO)2P(O)Na in moderate yields (Scheme  25.7a) [15]. Burton and Flynn reported the reaction of trialkyl phosphites and CBr3F for the synthesis of dibromofluoromethylphosphonates (RO)2P(O)CBr2F [16]. Subse­ quently, Savignac and coworkers described a one‐pot conversion of (RO)2P(O) CBr2F into (RO)2P(O)CH2F in the presence of n‐butyllithium and chlorotrimethyl­ silane, followed by treating with absolute ethanol (Scheme 25.7b) [17]. Hamilton

25.2  Phosphorous‐Based Fluoromethylating Reagents

and Roberts found that direct treatment of diethyl (hydroxymethyl)phosphonate with DAST was unsuccessful, whereas the transformation of this alcohol into tri­ flate and further displacement with tetrabutylammonium fluoride (TBAF) proved to be a safe and simple way to the monofluorinated product (Scheme 25.7c) [18]. O RO P RO

Toluene Reflux

(RO)2P(O)Na + CH2ClF (a) (RO)3P + CBr3F (b) O EtO P EtO (c)

F 7

(R = i-Pr, 50%) (R = s-Bu, 36%)

O F O (1) n-BuLi, then TMSCl RO P RO P Br F (2) EtOH, –78 °C RO Br RO >90% 7 (R = Et, i-Pr)

NaH/CF3SO2Cl OH Et2O, –20 °C 80%

O EtO P EtO

OTf

TBAF, THF rt, 1 h 67%

O EtO P EtO 7

F

Scheme 25.7  Syntheses of monofluoromethylphosphonate reagents.

α‐Hydrogen atoms in (RO)2P(O)CH2F are sufficiently acidic to undergo the deprotonation at low temperature. The corresponding lithiated carbanions were found to be rather stable and could be applied to various substitution reactions, including alkylation, acylation, aldol condensation, and toluene sulfonation reactions (Scheme  25.8) [19–21]. More recently, the research group of Sorochinsky presented a general and direct acylation reaction for the synthesis of various diethyl α‐fluoro‐β‐ketophosphonates by using aromatic, heteroaro­ matic, and aliphatic esters as acylating substrates [22]. In comparison with elec­ trophilic fluorination of β‐ketophosphonates [23], this operationally simple method provided an important and complementary strategy for the preparation of α‐fluoro‐β‐ketophosphonates. 1 O R RO P F RO

O RO P RO

O

O i-PrO P i-PrO

R3CHO

R1X or Me2SO4

2 R2 R COCl

F

O RO P RO 7

HO O R3 RO P F RO +

O S F

Tol-p (S)-p-Tol-S(O)OMen*

R3

O RO P RO

F

LDA/THF R4CO2Me

O EtO P EtO

F O

R4 F

Scheme 25.8  Synthetic transformations of monofluoromethylphosphonate reagents. The [*] indicates a chiral center in the molecular.

771

772

25  Synthesis and Applications of P–Rf ‐Containing Molecules

By using (i‐PrO)2P(O)CBr2F, Jubault and coworkers disclosed an electroreduc­ tive cyclopropanation of electron‐deficient olefins in a one‐compartment cell equipped with a magnesium sacrificial anode (Scheme 25.9). α‐Fluorinated cyclo­ propylphosphonamides were obtained in low to good yields and diastereoselecti­ vities [24a]. Further attempts at the asymmetric electrosynthesis of α‐fluorinated cyclopropylphosphonamides using chiral dibromofluoromethylphosphonamides furnished moderate diastereoisomeric excesses [24b]. More recently, this research group reported one example of Zn/LiCl‐promoted cyclopropanation between electron‐deficient alkene and (i‐PrO)2P(O)CBr2F to afford the corresponding monofluorinated cyclopropylcarboxylate in 68% yield [24c]. O i-PrO P i-PrO

F R

EWG

EWG 11–58%, 10–80% de

R

e–, Mg*

O i-PrO P i-PrO

F

EtO2C Br Br Zn /LiC l, TH F

(1) SOCl2/Py (2) diamine, Et3N

Bn N O e–, Mg* F P N CO2Me Bn CO2Me 65%, trans/cis: 95/5, 36%/70% ee

CO2Et

Ph

Ph F

CO2Et

CO2Et (i-PrO)2OP 68%, d.r. 65/35 Bn N O P CBr2F N Bn

Scheme 25.9  Synthesis of fluorinated cyclopropylphosphonates with (i‐PrO)2P(O)CBr2F. The [*] indicates a chiral center in the molecular.

Tetraalkyl fluoromethylene bisphosphonates [(RO)2P(O)]2CHF 8 are interest­ ing monofluoromethylating reagents. The synthesis of these reagents relied on the direct electrophilic fluorination of biphosphonate carbanions in the presence of O–F fluorination reagents (such as FClO3 and AcOF) or N–F fluorination reagents (such as NFSI, NFOBS, and Selectfluor) (Scheme 25.10a) [25]. By using tetraethyl fluoromethylene bisphosphonate (8: R = Et), several research groups reported the Horner–Wadsworth–Emmons (HWE) olefination with chiral α‐amino acid‐derived aldehydes [26]. The corresponding α‐fluorovinylphospho­ nates were hydrogenated to afford α‐fluorinated γ‐aminophosphonates, which could be useful building blocks for the preparation of bioactive compounds and peptide analogues (Scheme 25.10b). 25.2.2  Difluoromethylphosphonate and Difluoromethylphosphonium Reagents Aside from the silicon‐based reagent, the phosphorous‐based difluoromethylat­ ing reagents have also been extensively applied for the facile incorporation of difluoromethyl and difluoromethylphosphonate moieties into various organic molecules.

25.2  Phosphorous‐Based Fluoromethylating Reagents O RO P RO

O P OR OR

NaH or t-BuOK O–F or N–F reagents

O RO P RO

F

O P OR OR

(a) HO2C

H

NPG

R1 (PG = protecting groups)

8 (R = Et)

NPG

O

8: 30–70% yields

O EtO P EtO

F NPG

n-BuLi, THF

R1

R1

O EtO P EtO

(1) Pd/C, H2 (2) Deprotection F NH2 R1

O EtO P EtO

F H N

NH2

R1

O (R1 = Me, i-Bu, s-Bu, Bn) (b)

O HO P HO

R2

(R2 = Bn, Me, i-Pr, i-Bu)

or

OMe Me

Me

F H N

C15H31 O

N

Scheme 25.10  Synthesis of [(RO)2P(O)]2CHF and its application.

25.2.2.1 HCF2P(O)(OR)2

Difluoromethylphosphonates 9 of the type (RO)2P(O)CHF2 could be prepared by the reaction of CHClF2 with dialkyl sodiophosphites (Scheme  25.11a) [27]. The corresponding lithiated carbanions could be easily obtained by the deproto­ nation of (RO)2P(O)CHF2 with lithium diisopropylamide (LDA). These stable intermediates could react with a wide variety of electrophilic species including carbonyl and imine compounds (Scheme 25.11b) [28]. The lithiated carbanions could be also employed as the Michael donors in a series of conjugated additions. In the absence of HMPA, benzylidene, or alkylidine, 1,3‐diones, malononitriles, or malonates as well as nitroalkenes and other Michael acceptors delivered the corresponding products of 1,4‐addition in good to high yields. The addition of HMPA in the reaction system gave rise to an increase of 1,4‐ vs. 1,2‐additions onto α,β‐unsaturated ketones, furnishing the products of conjugated addition in moderate to good yields (Scheme 25.11c) [29]. In 2019, Yamamoto et al. found that the addition of the lithium anion of diethyl (difluoromethyl)phosphonate to 2‐cycloalkenones delivered the corresponding 1,2‐addition products, which were treated with NaOMe/MeOH to induce the phospha‐Brook rearrangement and to give difluoromethyl‐substituted allylic phosphates in good yields. Subsequently, Cu‐mediated reactions of the obtained allylic phosphates with Grignard or aryllithium reagents regioselectively furnished the SN2′ products (Scheme 25.11d) [30].

773

774

25  Synthesis and Applications of P–Rf ‐Containing Molecules

(RO)2P(O)Na + CHClF2

O RO P

THF or pentane 30-35 °C

RO

(a) O RO P (b)

F

O EtO P EtO F

Li

+ R

Li

RO F

EWG

F

9

(EWG)

H R (X = O, NR′)

F

(R = Et, i-Pr, Bu) 49–77%

O RO P RO

THF, –78 °C

O EtO P

(HMPA)

EtO

XH

F F

R

R EWG

F F (EWG)

(R = H, alkyl, aryl; EWG = COR, CO2R, CN, NO2, SOPh, SO2Ph, ...)

(c)

O EtO P

O

( )n (d)

THF, –78 °C

F

RO

F

X

O RO P

LDA

F

Li

EtO F F (n = 0-3)

O OP(OEt)2

HF2C

CF2H

ArMgX + CuI·LiCl (cat.) ( )n

Phospha-Brook rearrangement

or Ar2Cu(CN)Li2

( )n

Ar

SN2′ substitution reaction

Scheme 25.11  Synthesis of (RO)2P(O)CHF2 and applications.

Prakash et  al. described the efficient transformation of diethyl difluoromethylphosphonate into bis(difluoromethylene) triphosphoric acid, which could be further used to synthesize the interesting fluorinated DNA and RNA analogues (Scheme  25.12a) [31]. Cipolla and coworkers designed and synthesized metabolically stable arabinose 5‐phosphate analogues by using the lithium anion of diethyl (difluoromethyl)phosphonate (Scheme  25.12b) [32]. This isosteric (difluoromethyl)phosphonate could be recognized and bound by  the catalytic pocket of the enzyme. The research group of Legault and Martin reported another interesting stereoselective and tunable addition of LiCF2P(O)(OEt)2 or BrMgCF2P(O)(OEt)2 reagents to N‐t‐butanesulfinyl glyco­ sylamines for the synthesis of various 1‐C‐diethylphosphono(difluoromethyl) iminosugars, which could be used as glycosyl phosphate and sugar nucleotide mimics (Scheme 25.12c) [33]. 25.2.2.2 BrCF2P(O)(OR)2

Diethyl bromodifluoromethylphosphonate, (EtO)2P(O)CF2Br, was first pre­ pared in over 90% yield by Burton and Flynn via the Arbuzov reaction from CBr2F2 and (EtO)3P in refluxing ether [16]. Owing to the potential violence of this reaction, Johnson and coworkers demonstrated that its synthesis could be carried out on a molar scale and under safe conditions by slow addition of pure (EtO)3P to a solution of CBr2F2 in refluxing tetrahydrofuran [27d]. Other bromodifluoromethylphosphonates could be prepared via similar process

25.2  Phosphorous‐Based Fluoromethylating Reagents O EtO P (a)

EtO F

O O O P Base P O O P – – O O O O– F F F F OH

Me TsO Base H Cl O N Me + P + F Cl OH

O TfO BnO

O O Me EtO P + EtO F O Me

Li

–

O (EtO)2P

HMPA

F

THF, –78 °C

F

O

O Me

F

O

BnO

O (NaO)2P F

O

Me

OH

F

OH HO Arabinose 5-phosphate analogue

(b)

t-Bu * HO H F F S O N OEt (1) MCF 2P(O)(OEt)2 (M = Li or MgX) O 1 N P OEt 1 H (2) Cyclization, (3) deprotection ( )n 2 O ( )n 2 HO OH 2 2 R O OR Glycosyl-1-phosphate mimic

R 1O

(c)

Scheme 25.12  The application of (RO)2P(O)CHF2 for the synthesis of functional molecules. The [*] indicates a chiral center in the molecular.

[34a–e] (Scheme 25.13a). In addition, Burton et al. found that the reaction of phosphonium bromide [Ph3P+CF2Br]Br− with (EtO)3P resulted in the forma­ tion of (EtO)2P(O)CF2Br in 92% yield [34f ]. In 2009, Zafrani et al. disclosed diethyl bromodifluoromethylphosphonate as a convenient difluorocarbene precursor via a hydrolysis‐based P─C bond cleavage [35]. Bromodi­ fluoromethylphosphonate reacted with hydroxide ion to give the difluorocar­ bene, which was trapped by various phenolate and thiophenolate ions to form the corresponding difluoromethyl aryl ethers/thioethers in high yields (Scheme 25.13b).

(RO)3P

Ether or THF or triglyme

+ CBr2F2

10

(a) O Br F EtO P F EtO (b)

O Br F (R = Me, Et, i-Pr, Bu) RO P 42–100% F RO

XH

XCHF2

KOH, MeCN–H2O

+ Y

(X = O, S) 60–98% yields

Scheme 25.13  Synthesis of (RO)2P(O)CF2Br and its application.

Y

775

776

25  Synthesis and Applications of P–Rf ‐Containing Molecules

In recent years, several research groups developed metal‐catalyzed cross‐­ coupling of bromodifluoromethylphosphonates with various aryl partners for the synthesis of α,α‐difluorobenzylic phosphonates (Scheme  25.14). By using the  directing groups, Zhang and coworkers disclosed the Cu‐catalyzed cross‐­ coupling of bromozincdifluorophosphonate with iodobenzoates or iodo/bromo‐ aryl triazenes (Scheme 25.14a,b) [36]. Qiu and Burton described the Cu‐catalyzed reaction between diethoxyphosphinyldifluoromethylcadmium and aryl iodides (Scheme 25.14c) [37]. Zhang and coworkers further developed the Pd‐catalyzed difluoroalkylation of bromodifluoromethylphosphonate with aryl boronic acids (Scheme  25.14d) [36c]. Using diethyl bromodifluoromethylphosphonate as a precursor of difluoromethyl radical and fac‐Ir(ppy)3 as a photosensitizer, Liu and coworkers reported the direct C–H difluoromethylenephosphonation of arenes and heteroarenes (Scheme 25.14e) [38]. CO2Me I

R (a)

R

N

N

+

N

I/Br

(b)

53–95%

R

Zn (3.0 equiv) Dioxane, 60 °C

Cd/DMF

ArI (EtO)2P(O)CF2CdX CuCl, rt

[Pd(PPh3)4] (5 mol%) O Br R F Xantphos (10 mol%) + EtO P K2CO3, dioxane, 80 °C EtO F

B(OH)2

(d)

O Br F EtO P EtO F (e)

O Br F EtO P + F EtO

CuI (0.1 equiv) 3,4,7,8-Me4-phen (0.2 equiv)

R

CO2Me CF2P (O)(OEt)2

N

N

N

CF2P(O)(OEt)2

Ar

O Br F EtO P F EtO (c)

R

CuI (0.1 equiv) Phen (0.2 equiv) Zn (2.0 equiv) Dioxane, 60 °C

O Br F EtO P F EtO

+

H–Ar

fac-Ir(ppy)3 (3 mol%) 3 W 450 nm LEDs, rt K3PO4 (3 equiv), CH2Cl2

(EtO)2P(O)CF2 55–88%

CF2P(O)(OEt)2 44–89%

O EtO P

Ar

EtO F F 31–90%

Scheme 25.14  Metal‐catalyzed cross‐coupling reactions of (EtO)2P(O)CF2Br with aryl species.

Simultaneously and independently in 2015, the groups of Wang and Liu  reported a substantially similar approach to prepare 6‐difluoromethyl­ enephosphonyl‐phenanthridines through visible light‐driven radical gem‐ difunctionalization of isocyanides with bromodifluoromethylphosphonate

25.2  Phosphorous‐Based Fluoromethylating Reagents

(Scheme 25.15a) [39]. The Pd‐catalyzed Heck‐type reaction of bromodifluoro­ methylphosphonate was developed for the synthesis of various phosphonyldif­ luoromethylated alkenes. Mechanistic studies reveal that a phosphonyl difluoromethyl radical was involved in this reaction (Scheme  25.15b) [40]. Recently, Yi and coworkers presented a transition‐metal‐free, one‐pot three‐ step transformation of thiourea and diethyl bromodifluoromethylphosphonate with electron‐rich heterocycles and arenes. This strategy enabled the introduc­ tion of SCF2H moiety into indoles, pyrroles, and activated arenes, thus deliver­ ing a series of difluoromethyl thioethers (Scheme 25.15c) [41]. R2

BrCF2P(O)(OEt)2 fac-Ir(ppy)3 (1–2 mol%)

R1

3 or 5 W blue LEDs KOAc or K3PO4, rt, 36–60 h

NC

(a)

R1 R (b)

Ar–H

O Br + i-PrO P i-PrO R2

F F

R2 N

K3PO4 (2 equiv), DCE, 120 °C

(3) BrCF2P(O)(OEt)2, rt, 4 h

43–96%

R1

PdCl2(PhCN)2 (5 mol%) Xantphos (10 mol%)

(1) I2, KI, thiourea, dioxane/H2O rt, overnight (2) NaOH/H2, 50 °C, 1 h

CF2P(O)(OEt)2

R1 R

O CF2P(Oi-Pr)2 R2

SCF2H EDG

R

45–95%

SCF2H

or N H

(c)

R1 N H

SCF2H 32–94%

Scheme 25.15  Synthetic applications of (RO)2P(O)CF2Br.

25.2.2.3 TMSCF2P(O)(OR)2

Difluoro(trimethylsilyl)methylphosphonates 11 also provide the CF2‐synthon in organofluorine chemistry, and several procedures have been developed for their syntheses (Scheme  25.16). They were accessed by silylation of LiCF2PO(OR)2, which derived from BrCF2PO(OR)2 [27b, 42] or HCF2PO(OR)2 [34f, 43]. Another approach involved C(sp3)−H chlorination of di‐isopropyl ((methylthio)methyl) phosphonate, chlorine–fluorine exchange (with 3HF–Et3N), activation with n‐ BuLi, and silylation [44]. However, the scope of these preparations was limited to TMSCF2PO(OEt)2 and TMSCF2PO(Oi‐Pr)2. Recently, Prakash and coworkers provided an attractive method for the siladifluoromethylation of dialkyl phos­ phonates and secondary phosphine oxides with TMSCF3 to produce a series of TMSCF2P(O)R2 reagents (R = alkoxy and aryl) [45]. Difluoro(trimethylsilyl)methylphosphonate reagents 11 could provide (dieth­ ylphosphinyl)difluoro‐methyl carbanion under mild conditions with only a ­catalytic amount of initiator. These initiators include fluoride source (CsF, TBAF,

777

778

25  Synthesis and Applications of P–Rf ‐Containing Molecules O EtO P EtO F

THF, –78 °C

THF, –78 °C

F

O RO P 1) SO2Cl2 2) 3HF·NEt3

O i-PrO P i-PrO

SMe

O EtO P

n-BuLi/TMSCl

LDA/TMSCl

H

EtO F

Br F

TMS

RO F F 11

(3) n-BuLi/TMSCl

(1) LiH/LiCl DMF, rt, 10–30 min (2) TMSCF3, rt

O R P H R

Scheme 25.16  Syntheses of (RO)2P(O)CF2TMS.

TMAF, tetrabutylammonium difluorotriphenylsilicate [TBAT]) and oxygen ani­ ons (metal alkoxides, carboxylic acid salts, and carbonates). The in situ generated difluoromethyl carbanion intermediates could be reacted with various alde­ hydes, ketones, imines, and enamines to give the corresponding alcohol and amine derivatives (Scheme 25.17) [28a, 42b, 46, 47]. CF2P(O)(OR)2

Aldehydes Ketones O RO P CF TMS 2 RO 11

O Initiators – P Fluorides RO CF2 RO Alkoxides Carbonates

R1

OH

CF2P(O)(OR)2

Imines Enamines

R2

R3

NHR4

Scheme 25.17  The addition reactions of (RO)2P(O)CF2TMS to aldehydes, ketones, imines, and enamines.

Difluoro(trimethylsilyl)methylphosphonates 11 have gained special attention because both CF2 and phosphonate moieties could be incorporated onto many  molecular scaffolds. In the presence of various metallic complexes, difluoro(trimethylsilyl)methylphosphonates have been extensively used in the cross‐coupling reactions with a variety of partners (Scheme 25.18). These pro­ cedures allow the conversion of aryl boronic acids, aryl iodides, vinyl iodides, allyl halides, aryl diazonium salts, aryl iodonium salts, vinyl iodonium salts, alkynyl iodonium salts, benzyl bromides, and terminal alkynes into the corre­ sponding fluorinated products [48]. As another interesting motif that allowed modifications of the physicochem­ ical properties of a molecule, MesNHSCF2P(O)(OEt)2 was designed and pre­ pared from N‐(cyanosulfanyl)‐aniline and TMSCF2P(O)(OEt)2 by Besset and coworkers [49a]. Under mild and metal‐free conditions, this new reagent reacted with electron‐rich arenes (indoles, aryles, and pyrroles), anilines, thiols, ketones, and β‐ketoesters, thus offering an efficient and operationally simple tool for the construction of C─SCF2PO(OR)2, N─SCF2PO(OR)2, and

25.2  Phosphorous‐Based Fluoromethylating Reagents R R

R

N2 X

B(OH)2

CF2P(O)(OR′)2

–

CF2P(O)(OR′)2 Het

R

R

I

Y I Y I

Br

Ar

Y I Het

H

Ar

R

Ar

Br/I R2

R3

CF2P(O)(OR′)2

O OR′ P CF TMS 11 2 OR′ I 0 [Cu ], [Pd ], [PdII] Cross-coupling

CF2P(O)(OR′)2 CF2P(O)(OR′)2 R R1

R

R1

R

Br

R2 R3

CF2P(O)(OR′)2 CF2P(O)(OR′)2

Scheme 25.18  Metal‐catalyzed cross‐coupling reactions of (RO)2P(O)CF2TMS with various partners.

S─SCF2PO(OR)2 bonds (Scheme  25.19). Subsequently, the same group described the use of MesNHSCF2P(O)(OEt)2 for the BiCl3‐mediated difunc­ tionalization of alkynes and alkenes and for the synthesis of SCF2PO(OEt)2‐ containing alkynes [49b]. Next is the one‐pot two‐step reactions of CuSCN and TMSCF2P(O)(OEt)2 with α‐diazocarbonyl compounds, α‐bromoketones, and aryl diazonium salts (Scheme  25.20). In these reactions, the in situ generation of the thiocyanate intermediates followed in a second step by the introduction of the CF2PO(OEt)2 motif on the latter, according to a Langlois‐type substitution, yielded the corre­ sponding SCF2PO(OEt)2 derivatives [50]. 25.2.2.4 [Ph3P+CF2CO2_] and [Ph3PCF2X]+ Y– (X = H, Cl, Br, I; Y = Cl, Br, I, OTf)

Various difluoromethylphosphonium salts have emerged as very useful reagents for the synthesis of organofluorine compounds. The preparation of the (bro­ modifluoromethyl)triphenylphosphonium bromide 13 was readily accomplished by reaction of triphenylphosphine and CF2Br2 in THF. The salt precipitated could be isolated in 72% yield as a pale yellow solid via filtration in a fritted Schlenk funnel (Scheme  25.21a) [51a–c]. The reaction of Zn(CF3)Br·2CH3CN with triphenylphosphine proceeded in dichloromethane at room temperature to give the corresponding difluoromethyl‐phosphonium bromide 14 in 81% yield (Scheme 25.21b) [51d]. Other difluoromethylphosphonium salts could be pre­ pared from other phosphines and dihalodifluoromethanes. In 2013, Xiao and coworkers demonstrated that difluoromethylene phosphobetaine 15 could be conveniently prepared on 100‐g scale from potassium bromodifluoroacetate and triphenylphosphine (Scheme  25.21c). This compound is an air‐stable solid, which can be shelf‐stored at room temperature for a long time [51e,f ]. Recently,

779

780

25  Synthesis and Applications of P–Rf ‐Containing Molecules Me

O EtO P CF TMS + 2 EtO Me

11

Me

12 (1.2 equiv)

12 (1.2 equiv)

R2

12

(Het)Ar–SCF2P(O)(OEt)2 56–91% H N

R

TFA (1.2 equiv) DCM, 40 °C, 24 h

SCF2P(O)(OEt)2 56–91%

R–SCF2P(O)(OEt)2 55–86%

MsOH (1.2 equiv) DCM, rt, 14 h

O

SCF2P(O)(OEt)2

Me

12 (1 equiv)

R–SH

H N

SCN CuSCN, CsF

TsOH (2.4 equiv) DCM, rt, 2 h

NH2

R1

Me

Me

(Het)Ar–H

R

H N

O

12 (1.8 equiv) AcCl (3 equiv) NMP, 40 °C, 18 h

SCF2P(O)(OEt)2

R1 R2

28–62%

Cl R = TMS, H R

(Het)Ar

12 (1.2 equiv) BiCl3 (1.8 equiv) H2O (1.8 equiv) DCE, 60 °C

R

(Het)Ar

SCF2P(O)(OEt)2 40–89% SCF2P(O)(OEt)2 R = TMS

(Het)Ar

20–86% Cl

R Ar

12 (1.2 equiv)/BiCl3 (1.8 equiv)

R

Ar

SCF2P(O)(OEt)2 31–64%

H2O (1.8 equiv), DCE, 60 oC

Scheme 25.19  Introduction of the SCF2PO(OEt)2 motif into organic molecules. CuSCN (1 equiv) TMSCF2P(O)(OEt)2 (2.5 equiv)

O R2

R1

CsF/H2O, MeCN/NMP, 0 °C to rt

N2

Br

CsF/H2O, MeCN/NMP, 0 °C to rt

–

Ar

N2 BF4

SCF2P(O)(OEt)2 R2

CuSCN (1 equiv) TMSCF2P(O)(OEt)2 (2.5 equiv)

O R

O R1

18–72%

O SCF2P(O)(OEt)2

R

(1) CuSCN (1 equiv)/NaSCN (1.5 equiv) Cs2CO3 (2 equiv), MeCN, rt (2) TMSCF2P(O)(OEt)2 (1.5 equiv), DMF, rt

27–73%

Ar

SCF2P(O)(OEt)2 35–78%

Scheme 25.20  One‐pot incorporation of the SCF2PO(OEt)2 motif into organic molecules.

25.2  Phosphorous‐Based Fluoromethylating Reagents

Dilman and coworkers found that a series of difluoromethylphosphonium salts 16 were obtained by the reaction of difluoromethylene phosphobetaine 15 with  halogenating reagents, as well as arylsulfenyl and arylselenyl chlorides (Scheme 25.21d) [51g]. CF2Br2 + Ph3P (a)

THF or triglyme rt

Zn(CF3)Br·2CH3CN

+ Ph3P

[Ph3PCF2Br] Br 13, 72%

CH2Cl2 rt

–

[Ph3PCF2H] Br

–

14, 81%

(b)

BrCF2CO2K +

Ph3P

DMF, rt

–

[Ph3PCF2CO2] 15, 67%

(c) –

[Ph3PCF2CO2] (d)

15

E (E = Cl, Br, I, ArS, PhSe) MeCN, 50–55 °C, 1–2 h

[Ph3PCF2E] X

–

(X = Cl, Br, I)

16, 61–81%

Scheme 25.21  Preparations of difluoromethylphosphonium salts.

In the presence of an initiator (a base, water, or a photocatalyst) or under heating conditions, these difluoromethylphosphonium salts can deliver dif­ luorocarbene or the CF2H radical, which could be incorporated into organic molecules for the synthesis of difluoroalkylated and trifluoromethylated prod­ ucts. These synthetic transformations include (i) difluoroalkylation of alde­ hydes, ketones, and imines; (ii) difluoroalkylation or trifluoromethylation of alkenes and alkynes, as well as gem‐difluoroalkenation of benzyl halides and diazo compounds; (iii) difluoroalkylation of phenols, thiols, carboxylic acids, and amines; (iv) trifluoromethylthiolation and trifluoromethylselenolation of benzyl halides or aliphatic halides, as well as trifluoromethylation of aromatic iodides [52]. The difluoromethylene ylides generated from these difluoromethylphospho­ nium salts could be captured in situ by aldehydes and ketones to afford a series of the Wittig gem‐difluoroalkene products (Scheme 25.22a) [47b, 51c–f ]. These difluoromethylphosphonium salts under basic conditions can also serve as equivalent of difluoromethyl carbanion in the reactions with aldehydes and ketones (Scheme 25.22b). When this salt is treated with aqueous potassium fluo­ ride/hydroxide, the hydrolysis of C─P bond gave rise to the formation of difluori­ nated alcohols [53a]. The presence of TBAF furnished the trifluoromethylated products [53b]. In addition, gem‐difluorinated phosphonium intermediates could be further involved in light‐mediated addition or substitution reactions [53c,d]. These reagents were also employed for difluoromethylation of imines, iminium ions, and hydrazones to give the corresponding difluorinated amines (Scheme 25.22c) [53e].

781

782

25  Synthesis and Applications of P–Rf ‐Containing Molecules (a)

O

R1

–

R2

+ [R3PCF2CO2] or [Ph3PCF2H] Br

–

NMP, 80–120 °C or DMF, DBU, 50 °C

KF or KOH

(b) R3

R3P CF2 R4

TMSCl (X = O)

–

(c)

OSiMe3 PR3 R3 R4 F F

–

X

R3P CF2

KF or KOH (X = NR')

NHR′ R3

R4

F

F

F

F

R1

R2

OH R3

TBAF

F

R4 F CF3

R3

R4

CH2CHCN OH CN Hantzsch ester 3 ( )2 R 26 W CFL R4 F F CuY OH 400 nm LED 3 (Y = Cl, Br, I) R 4 R F

Y F

Scheme 25.22  The reactions of difluoromethylphosphonium salts with aldehydes, ketones, and imines.

Difluoromethylene phosphobetaine 15 underwent a process of removing CO2 and Ph3P to generate difluorocarbene, which could be readily trapped by various kinds of electron‐rich alkenes to give the difluorocyclopropanated products (Scheme 25.23a) [54a]. Difluoromethylphosphonium salts 13–15 were applied for the hydrodifluoromethylation, bromodifluoromethylation, oxydifluorometh­ ylation, and cyanodifluoromethylation of alkenes to form difluoromethylated alkanes or alkenes (Scheme  25.23a) [53e, 54b–e]. Xiao and coworkers also developed the trifluoromethylation of terminal alkynes and the gem‐difluoro­ cyclopropenation of electron‐rich alkynes (terminal and internal) by using difluoromethylene phosphobetaine 15 (Scheme  25.23b) [55]. The same group demonstrated that a series of benzyl bromides and diazo compounds could react with difluoromethylene phosphobetaine 15 to deliver the corresponding gem‐ difluoro‐olefinated products (Scheme 25.23c) [56]. In the presence of difluoromethylene phosphobetaine 15 as a difluoromethyl­ ene ylide precursor, the reaction of carboxylic acids, phenols, thiols, and amines afforded the difluoromethylated products under simple heating conditions (Scheme  25.24a) [54a, 55b, 57a]. In 2017, Qing and coworkers reported an Ir‐catalyzed and visible light‐induced radical difluoromethylation reaction of aryl‐, heteroaryl‐, and alkylthiols with difluoromethyltriphenylphosphonium tri­ flate [57b], whereas Heine and Studer presented the transition‐metal‐free and light‐initiated radical difluoromethylation of aryl‐ and heteroaryl thiols using (difluoromethyl)triphenylphosphonium bromide [57c] (Scheme 25.24b). In 2015, Liang and Xiao’s group described a facile trifluoromethylthiolation of benzyl halides and aliphatic halides with difluoromethylene phosphobetaine 15 in the presence of elemental sulfur and CsF (Scheme 25.25) [58a]. Subsequently, Xiao and coworkers extended this protocol to α‐bromoketones [58b], secondary

25.2  Phosphorous‐Based Fluoromethylating Reagents –

R3

– [Ph3PCF2CO2]

R2

R1

p-Xylene, 90 °C

R3

F F R1 R1 Ar (a)

X (X = Br OR) – CF2H [Ph3PCF2H] Br Visible light Ir(ppy)3, CuBr2 or ROH R2

[Ph3PCF2H] Br Visible light Ir(ppy)3/CuBr2 then DBU

F

F

(c) Ar

[Ph3PCF2CO2] Cu(MeCN)4PF6 R1 p-Chloranil, KF 18-crown-6, DMF

R2

R1

(2) [Ph3PCF2CO2] Ar

CF2H

CF2H

R1

F

[Ph3PCF2CO2] p-Xylene, 110 °C

F R2

1 (R2 = H, alkyl, aryl) R

N2

Br

(1) Ph3P/tBuOK

CF2H

–

–

–

R1 CF3 2 = H) (R (b)

3

R [Ph3PCF2Br] Br Visible light 1 Ir(ppy)3 (3 mol%)R Ph3P, NaI, KHCO3 – CN [Ph 3PCF2CO2] R2 NaNH3 or NH3 R1 Ir(ppy)3/CuI, blue LED

[Ph3PCF2CO2] R2

CuBr, 70 or 90 °C

F

F

R1

R2

Scheme 25.23  The functionalization of alkenes, alkynes, benzyl bromides, and diazo compounds with difluoromethylphosphonium salts.

RCO2CF2H

R1R2NH

RCO2H

R1R2NCF2H

–

[Ph3PCF2CO2]

(a)

ROCF2H

ROH

p-Xylene, 90 °C or MeCN, 60 °C –

RSCF2H (b)

[Ph3PCF2H] TfO Visible light, fac-Ir(ppy)3

RSH

RSH

[Ph3PCF2H] Br

RSCF2H –

NaH, DMF, 365 nm

ArSCF2H

Scheme 25.24  The functionalization of carboxylic acids, phenols, thiols, and amines with difluoromethylphosphonium salts.

amines [58c], and primary and secondary alcohols [58d] for the synthesis of the corresponding trifluoromethylthiolated products. Furthermore, this sulfuration method was developed into a useful synthetic tool to realize transition‐metal‐ based [18F]trifluoromethylthiolation of α‐bromoketones [58b]. In replacement of elemental sulfur with selenium, a series of benzyl halides could be converted into the trifluoromethylselenolated products [58e]. Interestingly, the same group dis­ closed the trifluoromethylation of aromatic iodides and the trifluoromethylthi­ olation reaction of alkyl halides by using difluoromethylene phosphobetaine 15 as a fluoride and difluorocarbene source [58f–h].

783

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25  Synthesis and Applications of P–Rf ‐Containing Molecules

R–SCF3 43–99%

R1

R SCF3

R–X S8, CsF DMF, 70 °C

Br

O R2 R1 S8, CsF, CuBr2 1 R MeNO2, 60 °C

R–X, S8, Cs2CO3

R1R2NH SCF3 (1) S8, DME, 50 °C N 2 (2) AgF, 80 °C R

R–SeCF3

O

–

SCF3 R2

[Ph3PCF2CO2] Cu(MeCN)4PF6 Ar–I, DBU, DMF

R–X Se, CsF, CuI Ag2CO3, 2,2-bpy 4NCl, DMA, 70 °C

nBu

R1R2CHOH S8, CsF, DMA, 70 °C

SCF3 1

or S8, KF, DMA, 70 °C R 18-crown-6, CuI

R2

Ar– CF3

Scheme 25.25  The trifluoromethyl(thiol)ation of alkyl halides, α‐bromoketones, amines, alcohols, and aromatic iodides with difluoromethylene phosphobetaine 15.

25.2.3  Trifluoromethylphosphonate Reagents In comparison with monofluoromethyl‐ and difluoromethylphosphonate rea­ gents, there has been relatively little investigation on trifluoromethylphospho­ nates. In 1979, Burton and Flynn reported the reaction of CF3I and P(OEt)3 under photolytic conditions to give diethyl trifluoromethylphosphonate 16 in 53% yield (Scheme 25.26) [59a]. Eighteen years later, Nair and Burton disclosed the UV‐irradiated reaction of CF3I with (EtO)2POP(OEt)2 to afford the same product 16 in 63% yield [59b]. Alternatively, the reaction of NaOP(OEt)2 with diphenyl(trifluoromethyl)sulfonium tetrafluoroborate delivered CF3‐phospho­ nate 16 in 70% yield [59c]. Based on the report of Semchenko et  al. [59d], Michalski and coworkers demonstrated that dinucleotide‐derived trifluoro­ methylphosphonates could be prepared by the reaction of TMSCF3 with FP(O) (OR)2 in the presence of catalytic amounts of metal fluoride or by oxidation of CF3P(OR)2 [59e]. P(OEt)3 + CF3I

NaOP(OEt)2

Photolysis

(EtO)2POP(OEt)2 + CF3I

O RO P CF3 16 (R = Et) RO

53%

UV 63%

70%

O RO P F TMSCF3 RO CsF

−

Ph2SCF3 BF4

O KF RO P Cl RO

Scheme 25.26  Syntheses of trifluoromethylphosphonates.

In 2010, Herath et al. found that diethyl trifluoromethylphosphonate 16 could be de‐esterified to provide trifluoromethylphosphonic acid, which was studied as proton conductor for anhydrous proton exchange membranes (Scheme 25.27a) [60a]. In this year, Cherkupally and Beier reported an alkoxide‐induced nucleo­ philic trifluoromethylation of a variety of carbonyl compounds by using diethyl

25.3  Chiral Fluorinated Aminophosphonic Acid Derivatives

trifluoromethylphosphonate 16 [60b]. A series of trifluoromethylated alcohols were obtained in moderate to good yields (Scheme  25.27b). In 2012, Chu and Qing demonstrated that several H‐phosphonates could be trifluoromethylated in 56–90% yields with TMSCF3 in the presence of catalytic amounts of Cu(II) salt and phenanthroline under an air atmosphere (Scheme 25.27c) [60c]. O EtO P CF3 EtO 16 (a)

R (b)

(c)

(2) H2O, rt

85%

O

O O P OEt OEt CF3

O RO P H RO

O HO P CF3 HO

(1) TMSBr, CH2Cl2, rt, overnight

+

RCHO PhOK, DMF 53–86%

TMSCF3

O EtO P CF3 EtO 16

Ar1

Ar2

t-BuOK, DMF

HO CF3 Ar1

Ar2

83–99%

CuX2/phen (30 mol%) (X = OH or OEt) K2CO3, air, DCE, 50 °C

O RO P CF3 RO R = Et, 56%; Pr, 73%; Bu, 87%; i-Bu, 85% (CH2)5Me, 90%; (CH2)4Cl, 70%; Cy, 76%

Scheme 25.27  Transformations of diethyl trifluoromethylphosphonate and the synthesis of analogous dialkyl trifluoromethylphosphonates.

25.3 ­Chiral Fluorinated Aminophosphonic Acid Derivatives Optically active aminophosphonates and aminophosphonic acids serve as isos­ teric or bio‐isosteric analogues of the corresponding amino acids, in which the planar and less bulky carboxylic acid group is replaced by a tetrahedral phospho­ nic acid functionality [61]. The incorporation of fluorine or fluoroalkyl moieties in aminophosphonate derivatives often results in a remarkable change in their physical, chemical, and biological properties. Asymmetric synthesis of enanti­ omerically enriched fluorinated aminophosphonates and aminophosphonic acids has been a subject of growing interest [62]. 25.3.1  Trifluoromethylated Aminophosphonate Derivatives In 2000, Yuan and coworkers employed optically active N‐(−)‐α‐methylbenzyl trifluoroacetimidoyl chloride as chiral substrates for the synthesis of N‐benzyl‐ substituted 1‐imino‐2,2,2‐trifluoroethyl‐phosphonates and 2‐imino‐3,3,3‐trif­ luoropropanephosphonates [63]. Subsequent DBU‐induced [1,3]‐proton shift reaction afforded the Schiff bases with good stereochemical outcome. Finally, Schiff bases were hydrolyzed under mild conditions to give the trifluoromethyl­ ated α‐ and β‐aminophosphonates 17a,b, respectively (Scheme 25.28).

785

786

25  Synthesis and Applications of P–Rf ‐Containing Molecules Ph N Ph

Me

N F3C

R) 3

H Cl

F3C

P(O

Ph

Me H

N

DBU

P(OR)2 O

Me

F3C

H 2 N HCl

H 2N

H

F3C

P(OR)2 O

P(OR)2 O

17a

n

Bu Ph Me Li Ph Me P(O 2 N HCl H2N H O H )(O DBU R) N H O O N P(OR)2 2 F 3C P(OR)2 P(OR)2 17b F3C F3C (R = Et, Pr, i-Pr, Bu, i-Bu)

Me

Scheme 25.28  Asymmetric synthesis of trifluoromethylated α‐ and β‐aminophosphonates 17.

To improve the diastereoselectivity, three research groups of described the highly selective asymmetric synthesis of trifluoromethylated α‐ and β‐ami­ nophosphonates from N‐tert‐butanesulfinyl aldimines and ketimines, which directly constructed a trifluoromethyl‐substituted chiral tertiary carbon center [64]. The corresponding trifluoromethylated aminophosphonates were obtained in good yields with high diastereoselectivities (Scheme 25.29). Sorochinsky’s work t-Bu S O

HN

N

F3C

P(OEt)2 O 68–88% de

t-Bu

t-Bu S O

F3C

HN H

F3C

S O O P(OEt)2

90–95% de

Lu's work t-Bu

t-Bu

O S NH P(OEt) 2 O F3C R

N F3C

t-Bu

S O R

48–90%, 89–99% de

O S NH CH P(OEt) 2 2 O F3C R 72–80%, 89–92% de

Liu's work t-Bu

t-Bu N F3C

S O

HP(O)(OR′)2 rt R

S O HN

P(O)(OR′)2

(1) HCl/Et2O

H2N

O P(OPh)2

(2) aq NaHCO3 F3C F3C R 56–95%, 50–84% de 95%

Ph

Scheme 25.29  Asymmetric synthesis of trifluoromethylated aminophosphonate derivatives.

Recently, Rassukana et  al. found that the enantioselective proline‐catalyzed Mannich reaction of acetone with α‐iminotrifluoroethylphosphonate gave rise

25.3  Chiral Fluorinated Aminophosphonic Acid Derivatives

to the formation of diethyl α‐amino‐α‐trifluoromethyl‐γ‐oxobutylphosphonates with >90% ee (Scheme  25.30 (top)) [65a], whereas Ohshima and coworkers investigated the chiral Rh complex‐catalyzed alkynylation of Cbz‐protected α‐ketiminophosphonate to give the adducts in excellent yields with high enanti­ oselectivities (Scheme 25.30 (bottom)) [65b]. Rassukana’s work P(O)(OEt)2 O

F3C H2N

Me 81%, >90% ee

Actone L-Proline F C 3 DMSO, rt

NH P(O)(OEt)2

P(O)(OEt)2 O

H2N

Actone D-Proline DMSO, rt

F3C

Me

80%, >90% ee

Ohshima’s work Cbz F3C

Cbz

R H Rh-complex

N P(O)(OEt)2

HN

Toluene, MS 4Å, rt

R

O

*

F3C

P(O)(OEt)2

86–99%, 80–93% ee

R′ Me3Si

O

O

N

Rh

N

O

Me

R′

(0.5–5 mol%)

Scheme 25.30  Catalytic enantioselective synthesis of trifluoromethylated aminophosphonates. The [*] indicates a chiral center in the molecular.

25.3.2  Difluoromethylated Aminophosphonate Derivatives Sorochinsky and coworkers also employed enantiomerically pure sulfinimines as chiral building block for the synthesis of α,α‐difluoro‐β‐aminophosphonic acids [66]. The addition reaction of diethyl lithiodifluoromethylphosphonate to chiral sulfinimines in THF afforded the adducts in high diastereoselectivities. The major diastereomer could be readily obtained in optically pure form by crystal­ lization, and its absolute configuration was determined to be (Ss, R) by X‐ray analysis. The N‐sulfinyl group was selectively removed by treatment with trif­ luoroacetic acid in ethanol at 0 °C. Subsequent hydrolysis was carried out by heating under reflux in 10 N HCl to deliver a series of enantiopure α,α‐difluoro‐β‐ aminophosphonic acids 18 in 67–92% yield (Scheme 25.31). O p-Tolyl

S

O

H N

LiCF2P(O)(OEt)2 R

R = Ph, 2-thienyl, R 4-MeOC6H4, 4-CF4C6H4, H 2N F n-C5H11, i-Pr

p-Tolyl

–78 °C, THF

O P(OH)2 F

10 N HCl,

O

>98% ee

S

R

O P(OEt)2

N H F F 82–90% de

Me H2 N

R

O P(OEt)2

F

F

18

Scheme 25.31  Asymmetric synthesis of α,α‐difluoro‐β‐aminophosphonic acids 18.

787

788

25  Synthesis and Applications of P–Rf ‐Containing Molecules

l‐Phosphoserine 19 is an interesting phosphonic amino acid. Therefore, the development of suitable synthetic methodologies for its preparation has been a topic of great interest [67]. Starting from d‐serine and (R)‐isopropylideneglyc­ erol, Berkowitz et al. carried out the triflate displacement approach for the syn­ thesis l‐phosphoserine (Scheme  25.32a,b) [68a]. Both groups of Otaka and Berkowitz have shown that l‐phosphoserine could be prepared by using d‐­ serine‐derived aldehyde and ester (Scheme 25.32c) [68b,c]. Subsequently, Borch and coworkers employed chiral aziridines as starting material for the construc­ tion of l‐phosphoserine (Scheme 25.32d) [68f ]. Unfortunately, the unprotected free l‐phosphoserine appears to undergo slow racemization [68d]. Subsequently, Berkowitz et al. have prepared l‐phosphothreonine and l‐phosphoallothreonine from a common precursor (Scheme 25.32e) [68e]. 4‐(Phosphonodifluoromethyl)‐l‐phenylalanine (F2Pmp), as phosphotyrosine (pTyr) isostere, has emerged as a very important molecular probe in the field of cellular signal transduction [69]. Some studies show that F2Pmp is an efficient inhibitor of protein tyrosine phosphatase because of its lower pKa value relative to that of Pmp. In addition, the mimetic F2Pmp is still capable of acting as hydro­ gen bond acceptor due to its electronegative fluorine atoms. Two enantioselec­ tive preparations of N‐protected 4‐(phosphonodifluoromethyl)‐l‐phenylalanines 20 have been reported. The first approach utilized the DAST‐mediated fluorina­ tion of ketophosphonates, which were formed starting with N‐protected l‐­ tyrosine and l‐serine (Scheme  25.33a,b) [70a,b]. Alternatively, chiral Williams lactone could react with the difluorophosphonate‐based benzyl bromide to afford the imino lactone, which was hydrogenated to the corresponding free amino acid l‐F2Pmp (Scheme 25.33c) [70c]. The abovementioned routes employed excess of DAST as a fluorination source. Therefore, another interesting strategy has been developed by using difluoromethylphosphonate reagents (Scheme  25.34). Kahn and coworkers described the CuCl‐mediated coupling of N‐protected 4‐iodophenylalanyl analogues with a cadmium derivative of bromodifluoromethylphosphonate (Scheme 25.34a) [71]. Recently, Poisson and coworkers reported the CuSCN‐ mediated cross‐coupling of the amino acid‐based iodonium salt with TMSCF2P(O)(OEt)2 for the synthesis of N‐protected 4‐(phosphonodifluoro­ methyl)‐l‐phenylalanine (Scheme 25.34b) [48c]. 25.3.3  Monofluoroalkylated Aminophosphonate Derivatives l‐AP4 is a prototypical competitive agonist of Group III mGluR. Dianionic phos­ phonic moiety is believed to be the key structural element responsible for the Group III selectivity [72a]. The effect of conformational restriction in cyclic ana­ logues of l‐AP4 was examined and revealed that one of the isomers of cyclopro­ pane analogue, (1S,2R)‐APCPr, has a similar activity profile to l‐AP4 [72b,c]. Encouraged by these findings, Jubault and coworkers developed a Rh(II)‐catalyzed diastereoselective cyclopropanation of fluoroalkenes for the preparation of fluorinated cyclic analogues (FAP4) of l‐AP4 [73]. (Z)‐ and (E)‐Stereoisomers of the product were obtained in this diastereoselective cyclopropanation reaction.

25.3  Chiral Fluorinated Aminophosphonic Acid Derivatives O

O BocHN

O

OH

O NH

OBn

BocHN

(a)

CF2P(O)(OEt)2 PDC CO2H DMF 19

Me

O O

BocHN

(b)

NSiMe2t-Bu

OBn

LiCF2P(O)(OEt)2

OTf

O

BocHN

NSiMe2t-Bu CF2P(O)(OEt)2

OH

(EtO)2P(O)CF2

LiCF2P(O)(OEt)2

Me

THF, HMPA, –78 °C Me

CF2P(O)(OEt)2 PDC CO2H DMF

Boc O N H

Me

O

Me

Boc O N OMe

Me

O

(EtO)2P(O)CF2

O

(1) EtOH, Dowex-50

O

(2) TBSCl, imidazole

CF2P(O)(OEt)2

HO TBSO

(EtO)2P(O)CF2 N3

BocHN

TBSO

OH

19

Me

THF, HMPA –78 °C

O

CF2P(O)(OEt)2

OH Me

O

LiCF2P(O)(OEt)2 Me (LiBH4)

Me

Boc OH N CF2 O P(OEt)2 O

O P(OEt)2 CF2 BocHN

CH2OH

CF2P(O)(OEt)2 BocHN

(c)

CO2H

19

(EtO)2(O)PF2C TBSO

(d)

NTs LiCF2P(O)(OEt)2

CF2P(O)(OEt)2

TsHN

THF, HMPA, –78 °C TBSO

BocHN Me

Me Me

(e)

Boc Me OH Boc O MeMgBr Me N N CF2 CF2 O P(OEt)2 O P(OEt)2 Me O O

BocHN

CO2H

19

CF2P(O)(OEt)2 CO2H

L-Phosphothreonine

Me

CF2P(O)(OEt)2

CO2H BocHN L-Phosphoallothreonine

Scheme 25.32  Constructions of l‐phosphoserine derivatives 19.

789

790

25  Synthesis and Applications of P–Rf ‐Containing Molecules O

O O (EtO)2P

OBn NHBoc

L-Tyrosine

TfO

OBn NHBoc O

DAST

O O (EtO)2P

OH NHBoc

F F

(a)

O H2 Pd/C

20a

O (EtO)2P

OBn NHBoc

F F O

I

O (EtO)2P

O (EtO)2P

DAST

F F

O

I

OMe NHR (Ph3P)2PdCl2, DMA–THF IZn

O O (EtO)2P F F

(b)

OH aq LiOH NHR 20a, R = Boc 20b, R = Fmoc

Br O (EtO)2P

O (EtO)2P

OMe NHR

F F

O

O O

+

F F

O

Cbz

N

LiN(TMS)2 Ph

Ph Williams lactone

O (EtO)2P

O Cbz

F F

N

Ph Ph

PdCl2/H2 O O (EtO)2P (c)

F F

OH NHFmoc 20b

O O (EtO)2P

OH NH2

F F

Scheme 25.33  Synthesis of 4‐(phosphonodifluoromethyl)‐l‐phenylalanines 20.

Subsequent transformations (including reduction, chiral separation, hydrolysis, and deprotection) delivered the final four stereoisomers of (−)‐(E)‐FAP4, (+)‐(E)‐ FAP4, (−)‐(Z)‐FAP4, and (+)‐(Z)‐FAP4 (Scheme 25.35). Dolence and Roylance found that the reaction of TBAF with the optically active diethyl N‐(p‐toluenesulfonyl)‐aziridine 2‐phosphonates derived from the

25.3  Chiral Fluorinated Aminophosphonic Acid Derivatives

CdBr +

F F

(a)

OMe NHR

I

O OMe Mes (b)

O

O

O (EtO)2P

NHR

I BF4

CuCl DMF

O (EtO)2P

O (EtO)2P

OMe NHR

F F

(R = Boc, Fmoc) O

TMS

F F CuSCN, CsF MeCN/DMF

O (EtO)2P

OMe NHAc

F F

Scheme 25.34  Syntheses of 4‐(phosphonodifluoromethyl)‐l‐phenylalanines 20 via Cu‐ mediated cross‐coupling reactions.

H2O3P

NH2 L-AP4

+

FAP4

N2

(1S,2S)-APCPr

Rh2(OPiv)4

NH2

H2O3P

NH2

CO2H

F H2O3P

DCM

F CO2H

H2O3P

NH2

(1S,2R)-APCPr

CO2Et

F

F CO2H NH2

H2O3P

CO2H

H2O3P

NH2

NO2

F (EtO)2(O)P

CO2H

H2O3P

CO2H

F

NO2 (1) Separation (2) aq HCl, THF (3) CbzCl, THF (1) Chiral SCF (2) HCl/AcOH

NH2 CO2H

CO2Et

(EtO)2(O)P

(EtO)2(O)P

F

CO2Et NHCbz (Z) or (E)

Scheme 25.35  The synthesis of fluorinated cyclic analogues (FAP4) of l‐AP4.

phosphonoserine enantiomer in THF allowed for the rapid production of β‐ fluoro‐substituted α‐amino phosphonates (Scheme 25.36a) [74a]. Kaźmierczak et al. disclosed a DAST‐mediated preparation of β‐fluoro‐α‐aminophosphonates [26c, 74b]. The mechanism involves the formation of aziridinium ion as the key step of the synthesis (Scheme 25.36b). Subsequently, the same group presented a facile protocol for the preparation of α‐fluoro‐β‐aminophosphonates by the regi­ oselective fluorination of α‐hydroxy‐β‐aminophosphonates [74c]. The fluorina­ tion reactions were mediated by the PyFluor reagent and occurred with retention of configuration (Scheme 25.36c).

791

792

25  Synthesis and Applications of P–Rf ‐Containing Molecules OMs H

OH H H2N

TsHN

P(OEt)2 O

(a)

R

Bn

P(O)(OEt)2

DAST

Bn

(c)

P(O)(OEt)2

PyFluor

N

R

F

TBAF

H

TsHN

P(OEt)2 O

Bn

P(OEt)2 O

NBn2 R

P(O)(OEt)2 F

Bn

F

H P(O)(OEt)2

H

NBn2

N

H P(O)(OEt)2

H − F

OH R

N

R

NBn2

(b)

Ts

P(OEt)2 O

OH

H

NaH

HF–DBU

R

P(O)(OEt)2 NBn2

Scheme 25.36  The synthesis of monofluoroalkylated aminophosphonates.

25.4 ­Perfluoroalkyl Phosphonic and Phosphinic Acids Perfluoroalkyl phosphonates (PFPAs) and perfluoroalkyl phosphinates (PFPiAs) are important subclasses of polyfluorinated compounds (PFCs) [75] and have been widely used as defoamers in pesticide formulations and wetting agents in consumer products [76]. PFPAs are phosphoric acid esters, which possess at least one polyfluoroalkyl group, and have a −2 charge on the hydrophilic head group ( P O O2 2 ). The PFPiAs have two perfluoroalkyl moieties where x and y are usually even numbers and a −1 charge on the hydrophilic head group (P(O) O−) (Scheme 25.37). In particular, the disubstituted polyfluoroalkyl phosphates (diPFPAs) have two polyfluoroalkyl groups that can have the same or different number of perfluorocarbons [77]. It is noteworthy that due to the increasing public concerns over the high persistence, bioaccumulation potential, toxicity, and long‐range transport potential (LRTP) of PFCs, long‐chain PFPAs and PFPiAs have also been the subject of intense scientific and regulatory scrutiny in recent years [78]. In this context, C4/C4 PFPiA and derivatives have been devel­ oped as potential replacements to long‐chain PFCs in certain applications. In the following part, the synthetic routes to PFPAs and PFPiAs will be briefly dis­ cussed, whereas the environmental hazards and human exposure will not be cov­ ered here. F F F

O − O x P − O

PFPA

F F F

O x P O−

F F

F y F

F Fx

PFPiA

Scheme 25.37  Representative examples of PFPAs and PFPiAs.

O O P O O− diPFPA

F F F y

25.5  Fluorophosphonium and Fluoroalkylphosphonium Cations

By employing perfluoroalkyl iodides (PFAIs) as the starting materials, two c­ omplementary synthetic approaches have been frequently used to access PFPAs and PFPiAs. White phosphorus was reacted with PFAIs to produce iodoper­ fluoroalkyl phosphines (Scheme 25.38a). These compounds can either be directly transformed to phosphonates and phosphinates (Scheme  25.38b) or first be ­converted to the chloro and dichloro compounds with freshly prepared and dried AgCl followed by hydrolysis (Scheme  25.38c) [79]. Alternatively, tris (perfluoroalkyl)difluorophosphoranes can also be used as the starting material involving transformations with hydrogen fluoride and water and then produce PFPiAs under heating conditions (Scheme 25.38d) [80]. F F (a) F

Rf (b)

P Rf Rf

Rf (c)

P Rf

I

x

or

P Rf Cl

I

or

I

Rf

or

Rf

P I Rf

P Cl

F F F

P4

+

x

I

P I

[RfPF3]− [5(H2O)H]+ (d)

I

F

x

+

O P

F F

P Rf

I

Rf

+

P I

F F

x

or

F

F

OH Rf

AgCl

Oxidant H 2O

F F

Rf

(Rf)3P

F F

Oxidant H 2O

Cl

P

Heat

+ HF

F F F

F F F

Cl

or

Rf

P Cl

F F x or x O F P F OH

5H2O

Heat

P Rf

I

x

O P OH OH

Cl

F F

x O P OH OH

[RfPF3]− [5(H2O)H]+ F F x x O P F OH

F F +

F

x

H

Scheme 25.38  The syntheses of PFPAs and PFPiAs.

25.5 ­Fluorophosphonium and Fluoroalkylphosphonium Cations Phosphonium cations are an important class of phosphorus compounds that exhibit Lewis acidic reactivity [81]. In 2013, Stephan and coworkers reported the synthesis of two novel highly electrophilic fluorophosphonium cations (FPCs) 21 and 22 [82]. These two compounds were obtained by oxidation of P(C6F5)3 or PhP(C6F5)2 using XeF2 to generate the corresponding difluorophosphorane species and subsequent fluoride abstraction using [SiEt3][B(C6F5)]·2C7H8 (Scheme 25.39). Both the two FPCs could effectively activate alkyl C─F bonds

793

794

25  Synthesis and Applications of P–Rf ‐Containing Molecules

leading to concomitant generation of a carbocation and the difluorophospho­ rane species. As a result, catalytic hydrodefluorination of alkanes was achieved by introducing HSiEt3 as a hydride source and fluoride sink. The authors also demonstrated that the Lewis acidity could be derived from the low‐lying σ* orbital oriented opposite the polar P─F bond [83]. +

F P

C6F5

C6F5 C6F5

or P

Ph

F C6F5

XeF2

C6F5 C6F5

P

F

P C6F5

C6F5

C6F5

or F F P C6F5 Ph C6F5

C6F5 C6F5

[Et3Si] [B(C6F5)4]·2C7H8

– [B(C6F5)4]

21 +

F Ph

P

C6F5 C6F5

[B(C6F5)4] –

22

F R F C6F5

+

Et3SiH

R

R″ + Et3SiF R′

F P C6F5 C6F5 C6F5 F

C6F5

[Et3Si] [B(C6F5)4] –

C6F5 R

H

21 (1 mol%)

Cat.

F P

R″ R′

R″ R′

[B(C6F5)4] –

Et3SiH

Et3SiF

H R

R″ R′

F C6F5

P

C6F5 C6F5

[B(C6F5)4] –

Scheme 25.39  Synthesis of fluorophosphonium cations and proposed reaction mechanism.

The discovery of these electrophilic FPCs provides a new avenue to Lewis acid catalysts and represents a significant improvement in phosphonium catalyst design. Following Stephan’s seminal study, a series of such FPCs (21–37) have been developed over the past few years (Scheme 25.40). For example, the steri­ cally demanding and electron‐withdrawing C6Cl5 fragment has been employed to replace C6F5 groups (23) [84]. The Lewis acidity could be increased by means of using cationic pyridinium substituents, thus generating the unique dicationic salts (30) [85]. A further variant exploited the proximity of two fluorophospho­ nium centers, whereas a related tricationic salt was also reported (31–34) [86]. In this case, the enhanced Lewis acidity is thought to result from the inductive effect of a proximal positive charge rather than by a cooperative effect on the substrate. In the following part, some reactions catalyzed by 21 will be briefly summarized, and then several representative new FPCs and fluoroalkylphospho­ nium cations will also be introduced.

25.5  Fluorophosphonium and Fluoroalkylphosphonium Cations +

F C6F5

P

+

F

C6F5

Ph

C6F5

P

C6F5

C6Cl5

C6F5

P

C6F5

Ph Ph

F

F

Mes F N P Ph N Ph Mes

Ph

P

P

N

Ph

R

R = C6F5, 27 R = C6H5, 28

F3C

F

Me

Ph F Ph P

F P Ph Ph

Ph P Ph

Ph Ph

31

30

P

F

CF3

P

F Ph P Ph

F Ph P Ph

F P Ph Ph

Me N

Ph 34

33 +

Me OTf – Ph

35

+

CF3

32 CF3

+

F3C

29

Fe

Ph Ph

24

F

F

P

Fe

CF3

P

26

25

Ph Ph

F

F3C

F

+

F

23

+

F

F

Ph Ph P F

P

22

21

+

F

+

CF3 Ph

P

Ph OTf Ph

36

+

CF3 –

Ph

P

Ph Ph

37

Scheme 25.40  Examples of fluorophosphonium and fluoroalkylphosphonium cations. [B(C6F5)4] counterions have been omitted for clarity.

By taking advantage of the FPC‐catalyzed hydrodefluorination as the key step, Stephan and coworkers reported the C–C coupling of aryl and alkyl CF3‐conta­ ning compounds with a range of arenes to give CH2–aryl fragments (Scheme 25.41a) [87]. These Friedel–Crafts alkylations could be utilized to implement ring clo­ sure either in an intramolecular or intermolecular manner, thus leading to the  formation of dihydroanthracene and 9‐aryl‐9‐H‐xanthene, respectively. In the case of alkyl–CF3 substrates, only linear products of arene alkylation were observed. The proposed mechanism starts with fluoride abstraction by 21, gen­ erating a difluorocarbocation that effects Friedel–Crafts coupling with the elec­ tron‐rich arenes (Scheme 25.41b). Liberation of the proton from the Wayland intermediate is then believed to react with silane to release H2 while generating a silylium cation that then scavenges fluoride from difluorophosphorane to

795

796

25  Synthesis and Applications of P–Rf ‐Containing Molecules

regenerate the catalyst. Finally, subsequent hydrodefluorination of the transient difluorobenzyl product produces the corresponding diaryl methanes. F

Rn

F

F

F F

+

Ar

H

Rn

21 (1.5 mol%), R3SiH

H Ar

60 °C up to 94% yields

F

H

H

21, i-Pr3SiH 60 °C 68% yield O F F

F F +

O

21, i-Pr3SiH Me 80 °C Me 40% yield

Me

F

Me

H

F F

F Alkyl (a)

F F

Ar

+

Ph Et3SiF

H

C6F5

P

H

Alkyl

80 °C 60–93% yields

Ar

F

+

F H

H

21 (1.5 mol%), R3SiH

C6F5 C6F5

F F

[B(C6F5)4] – + Et3Si Et3SiH

+

Ph F

F Ph

(b)

F F

F

H2

F

H F

+ Et3SiH

C6F5

F P

C6F5 C6F5

Ph F

H F

Scheme 25.41  Consecutive Friedel–Crafts coupling and hydrodefluorination of CF3 derivatives.

Stephan and coworkers also applied this chemistry to the activation of benzyl fluorides and subsequent C─C bond coupling with arenes [88]. This transforma­ tion is effective with a large number of electron‐poor and ‐rich arenes, as well as heterocycles. Importantly, this method was found to be selective for C─F bonds in the presence of benzyl chlorides and benzyl bromides, thus offering a comple­ mentary protocol in contrast to conventional metal‐mediated C–C couplings (Scheme  25.42). Furthermore, the C(sp3)–C(sp3) coupling of benzyl fluoride derivatives with allylic silanes also proved to be workable under mild conditions in the presence of FPC catalyst.

25.5  Fluorophosphonium and Fluoroalkylphosphonium Cations

R1

X F

+

R1

( )n

X

21 (1–3 mol%) Et3SiH, 25–60 °C

R2

Up to 91% yields

( )n

R2 X = C, n = 1 X = O, N, S, n = 0

R3 R1

F

R3 + R2

21 (1 mol%) SiMe3

R2

Et3SiH, 25 °C Up to 84% yields

R1

Scheme 25.42  C–C coupling of benzyl fluorides catalyzed by FPC 21.

In addition to C–F activation, the reactivity of these fluorophosphonium salts was also investigated with olefins and alkynes [89]. In this context, Stephan and coworkers reported the FPC 21‐catalyzed rapid isomerization of 1‐hexene to 2‐ hexene (Scheme  25.43a), the cationic polymerization of isobutylene, and the Friedel−Crafts‐type dimerization of 1,1‐diphenylethylene. In the presence of hydrosilanes, olefins and alkynes undergo efficient hydrosilylation to the alkylsi­ lanes (Scheme  25.43b). Experimental and computational studies revealed that the reaction proceeds via the sequential activation and 1,2‐addition of hydrosi­ lane across the unsaturated C─C bonds. Furthermore, the high Lewis acidity of FPC 21 was also utilized to catalyze the dehydrocoupling of silanes with amines, thiols, phenols, and carboxylic acids to form the Si─E bond (E = N, S, O) with the liberation of H2 (Scheme  25.43c) [90]. Moreover, this reaction can be readily used for in situ transfer hydrogenation of olefins, thus providing an unprece­ dented metal‐free route. In 2018, Stephan and Oestreich demonstrated that the highly electrophilic FPC 21 can also act as effective Lewis acid catalysts in Diels– Alder reactions of cyclohexa‐1,3‐dienes with α,β‐unsaturated ketones and Nazarov cyclizations of activated and unactivated divinyl ketones, respectively (Scheme 25.43d) [91]. On the other hand, to avoid the use of strongly electron‐withdrawing fluoro­ arene substituents while keeping the Lewis acidity, Stephan and cowork­ ers  reported the dicationic imidazolium–phosphonium salt [(SIMes)PFPh2] [B(C6F5)4]2 (29) in 2014 (Scheme 25.44) [92]. Importantly, this species is shown to be more electrophilic than 21 in stoichiometric reactions and acting as an effective Lewis acid catalyst for the hydrodefluorination of fluoroalkanes and the hydrosilylation of olefins. Moreover, the synthetic route to 29 is facile, high yielding, and amenable to structural modifications, thus offering new potential in accessing versatile Lewis acidic fluorophosphonium catalysts. To probe steric influences on electrophilic phosphonium cations, Stephan and coworkers pre­ pared FPC 26 via phosphine oxidation and subsequent fluorine abstraction with [Et3Si(tol)][B(C6F5)4] (Scheme 25.44b) [93]. The Lewis acidity of FPC 26 was pre­ liminary evaluated in the dimerization of 1,1‐diphenylethylene and hydroaryla­ tion of diphenylamine. The collective data shows that FPC 26 is less acidic than

797

798

25  Synthesis and Applications of P–Rf ‐Containing Molecules

F C6F5 Me (a)

Me

P

C6F5 C6F5

[B(C6F5)4] ( )3

R R′

R′ + R3SiH

F P

C6F5

–

21 (1 mol%)

CD2Cl2, rt

R″or R

C6F5 C6F5

[B(C6F5)4]

( )2 [B(C6F5)4] d H H

Me ( ) 2

C6F5

H

R

21 (1.5 mol%) rt 89–99% yields

–

+ R3SiH

E H

+ R3SiH

FPC-21 (1.5 mol%) rt

R3

(E = N, S, O)

E SiR3 50–99% yields R2

R (c)

H

H R3

R1 O R3

R1

R2

R1 C(O)R3

+

C6F5

X

Me

R (X = C or O)

P

R2 Up to 98% yield >95 : 5 d.r.

+

F O

(d)

R′ H

Et Et Et Si δ Me F δ− H P C6F5 C6F5 C6F5

E SiR3 + H–H

1

SiEt3

R′

FPC-21 (1.5 mol%) R2

C6F5

C6F5

R″ or R

(b)

E H

F

SiEt3

Et Et Me Et Si δ F δ− H P C6F5 C6F5 C6F5

Et3SiH

P

–

C6F5 C6F5

[B(C6F5)4]

21 (3 mol%)

–

O X

Me

R up to 82% yield >95 : 5 d.r.

Scheme 25.43  Olefin isomerization, hydrosilylation, dehydrocoupling, Diels−Alder, and Nazarov reactions catalyzed by FPC 21.

25.5  Fluorophosphonium and Fluoroalkylphosphonium Cations

Mes N NH Mes

+ Mes [Et3Si] N F F 2 P Ph [B(C6F5)4]· (C7H8) NH Ph Mes

+ P

Ph

XeF2

Ph

[B(C6F5)4]

–

[B(C6F5)4]

F R″ R′

R

P Ph NH Ph Mes – 29 [B(C6F5)4]

H

29 (1–10 mol%)

Et3SiH

N

+ F

R″ + R′

R

25 °C

Et3SiF

SiEt3

R (a)

+

–

Mes

R″ or R

R′

29 (2 mol%) 45 °C

R′ + Et3SiH

F3C

CF3

CF3

CF3

F3C

CF3

CF3

F3C

F3C

P

F P

F3C

CF3

F

R′

80–96% yields F

XeF2 CH2Cl2

SiEt3

R″ or R R′

CF3

P

F 3C

R

+

F3C [Et3Si(tol)] [B(C6F5)4] Toluene

CF3 CF3

F3C

F3C 26

[B(C6F5)4] – Me Ph

Ph

Ph

+

21 or 26 (1 mol%) Ph

Ph

21, 86% 26, 78%

CH2Cl2, rt Ph Ph Ph Ph

Ph (b)

H N

Ph

+

21 or 26 (1 mol%) Ph

Ph

CH2Cl2, rt

Me Ph

N H

21, >99% 26, 91%

Scheme 25.44  Preparation and applications of fluorophosphonium salts 29 and 26.

799

800

25  Synthesis and Applications of P–Rf ‐Containing Molecules

[(C6F5)3PF][B(C6F5)4] (21), but the improved access to the P center of FPC 26 provides a kinetic acceleration for fluoride exchange and catalysis where the transition states are more sterically demanding. Very recently in 2019, axially chiral FPCs based on dihydrophosphepines with a binaphthyl backbone were prepared and structurally characterized by Stephan and Oestreich (Scheme 25.45) [94]. Both compounds 27 and 28 were active in Si─H bond activation and efficiently mediated the hydrosilylation of ketones, but no enantioinduction was observed. A further mechanistic investigation sug­ gested that chiral phosphonium cations do not serve as actual catalysts but rather initiate the formation of achiral electrophilic species that mediate the hydrosilylation.

P–R

F P–R [Et3Si(C6D6)][B(C6F5)4] C6D6, rt F

XeF2 CH2Cl2, –78 °C

+ P

O R1

OSiEt3

27 or 28 (1 mol%) R2

Et3SiH, rt

R1

R2

F R

[B(C6F5)4]− R = C6F5, 27 R = C6H5, 28

>95% conv., 0% ee

Scheme 25.45  Axially chiral fluorophosphonium cations 27 and 28.

Despite the high Lewis acidity of these FPCs, the presence of the P–F moiety results in limited stability, particularly with respect to water and alcohols. To overcome this daunting challenge, Stephan and coworkers reported a new class of electrophilic phosphonium cations containing α‐CF3 group attached to the phosphorus(V) center (Scheme 25.46) [95]. These species (35–37) were shown to be effective in a variety of Lewis acid catalytic reactions (hydrodefluorination, hydrogenation of ketones and imines, and Mukaiyama aldol reaction) while exhibiting a significant increase in tolerance to ROH relative to other FPCs. These compounds were readily prepared in high yields by quaternization of phosphorus with MeOTf or a Pd(0)‐catalyzed reaction with PhOTf, as well as anion metathesis, respectively. Notably, strong oxidants (XeF2) or highly sensitive silylium cations [Et3Si][BArF] are not required in these procedures, thus offering user‐friendly operational convenience and improved functional group compatibility.

­  References

Ph

P

Me OTf

Ph 35

–

MeOTf CH2Cl2

Ph

P Ph

PhOTf Pd[0], xylene

Ph

P

Ph OTf

Ph 36

–

–

BArF H

+

O

Ph

P

KBArF CH2Cl2

Ph Ph 37

F

Ph

Ph

+

CF3

Ph

+

CF3

CF3

+

CF3

+ R

N H

37 (10 mol%)

Et3SiH

37 (5 mol%)

PhMe2SiH

+

100 °C, 18 h

O +

OMe Me

H O Ph

100 °C, 18 h

OTMS Me

97%

37 (5 mol%)

PhMe2SiH

H

+ Et3SiF

100 °C, 18 h

35 or 36 or 37 (5 mol%) rt, 24 h

R

SiMe2Ph 89–91%

Ph SiMe2Ph H N 76% Ph H OTMS CO2Me Me Me >90%

Scheme 25.46  Fluoroalkylphosphonium cations 35–37.

25.6 ­Conclusion Over the past decades, fluorinated organophosphorus compounds have attracted extensive attention in organic synthesis, medicinal and agrochemical chemistry, and materials science. This chapter summarizes the innovative achievements in the development of Rf–P‐containing ligands, reagents, and catalysts. Notably, some elegant synthetic methodologies allow convenient preparation of a variety of biologically important compounds and special materials. Given the potential of Rf–P‐containing molecules, there is an increasing need for additional research in this area.

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35 36

37 38 39 40 41 42

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47

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809

Index a 1‐acenaphthenone 457 acetoxy‐and amino‐ trifluoromethylthiolation of alkenes 426 achiral fluoro‐organophosphines  766 adamantyl thioperoxide reagent  376 AgSCF3/K2S2O8‐mediated decarboxylative trifluoromethylthiolation 392 air‐stable and recyclable Pd(I) catalyst 354 air‐stable copper trifluoromethylthio complex (bpy)CuSCF3 314 aliphatic ketones  462 aliphatic pentafluorosulfanyl (SF5) alkenes using SF5X photochemical activation 574–575 S2F10 572 SF5Br 572 SF5Cl 572 thermal reactions of  574 triethylborane 577 alkenes using SF6 572 alkenyl compounds  602 β‐haloalkyl‐perfluorosulfanyl compounds aldehydes 581–582 C2‐building blocks  588–601 γ‐SF5‐α,β‐unsaturated aldehydes 586–588 halogen substitution reactions 580–581

vinyl‐SF5 compounds  583–586 oxidation of  606 aliphatic trifluoromethylthioether  374 alkenyl‐SF5 compounds acetylene and dehydrochlorination 602–604 alkyl halides  92, 95–96, 122, 258, 275, 311–312, 434–436, 438, 469, 518 alkylidene(difluoro)cyclopropanes 159 alkyl–Pd(IV)–OCF3 complex  252–253 alkyl triflates  258 alkyl triflones  514–520 applications 517–520 preparation 514–517 alkyl trifluoromethyl (or perfluoroalkyl) sulfoximines 681 alkyl trifluoromethyl sulfoxides [(Alk) S(O)CF3] applications 491–492 preparation 489–491 alkyne‐based aryl iminosulfur oxydifluoride 670 alkynes, difluoromethylation  79–82 alkynyl and vinyl triflones applications 510–513 preparation 510 alkynyl trifluoromethyl selenoethers  705, 711 2‐alkynylnitroarenes 81 2,3‐allenoic acids  396–397, 407 allylic trifluoromethyl sulfides  407 α‐aryl‐β‐(trifluoromethylthio) acrylates 381 α‐trimethylsilyldifluoroacetamides 31

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Jun-An Ma and Dominique Cahard. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

810

Index

α,α‐diaryl allylic alcohols  407 α,α‐difluoro‐β‐aminophosphonic acids 787 α,α‐difluoro β‐carbonyl and β‐enol ether sulfoxides 501 α,α‐difluoro β‐carbonyl or β‐alkyl sulfoxides 503 α,α‐difluorobenzylic phosphonates 776 α,α‐difluoro‐γ‐ aminophosphonates 59 α,β‐unsaturated carboxylic acids  408–410, 535 α–bromoketones  282, 439, 442, 467, 469, 471, 779, 782–784 α‐CF2–alcohols 524 α‐chloro‐β‐fluoroalkylselenolation of alkenes 710–711 α‐chloro‐β‐ trifluoroalkylselenoethers 709 α‐diazoketones  425, 427, 702 α‐fluorinated cyclopropylphosphonamides 772 α‐fluorinated γ‐aminophosphonates 772 α‐fluoro‐β‐aminophosphonates 791 α‐fluoro‐β‐ketophosphonates 771 α‐fluorovinylphosphonates 772 α‐haloketones/α‐diazo esters  698 α‐pentafluorosulfanyl aldehydes 581–582 α‐phenyl‐and α‐methylstyrenes 573 α‐(4‐pyridyl N‐oxide)‐N‐tert‐ butylnitrone (POBN)  246 α‐SCF2PO(OEt)2 ketones  467 α‐SCF3‐β‐substituted carbonyl compounds 421 α‐SCF3‐substituted esters  375, 437 α‐SCF3‐substituted ketones  393, 439 α‐trifluoromethylthio acetophenones  408, 410 α‐trifluoromethylthiolated esters  436 α‐trifluoromethylthiolated ketones  417, 436 α‐(trifluoromethylthio)phosphonium ylides 376

AMBN (2,2’‐azobis(2‐ methylbutyronitrile)) 464 Amii’s method  26 anhydrous proton‐exchange membranes 784 anionic SCF3 reagents  405–411 anthracene 344 anti‐Markovnikov process  393 arenesulfinyl chlorides  678 aromatic and aliphatic trifluoromethylthiolated alkynes 387 aromatic compounds aryl boronic acids  352–354 aryl diazonium salts  347–349 aryl halides  354–357 aryl metallic species  350–351 aryl triflates  349–350 di(hetero)aryl‐λ3‐iodanes 357–358 direct C–H functionalization 343–347 aromatic disulfides  551–552, 554, 556, 558, 611–612 aromatic thiols  451, 554–556 Ar‐SF4‐Ar derivatives  614–615 Ar‐SF4‐R derivatives  615–617 aryl and heteroaryl difluoromethyl sulfones [RSO2CF2H] applications 522–529 preparation 520–522 aryl and heteroaryl halodifluoromethyl sulfones 529–530 aryl 3‐aryl‐2‐propynyl ethers  394, 395 aryl boronic acids  26, 131, 281, 323–324, 343, 352–354, 368, 464, 480, 526, 650–651, 653, 662–663, 704, 776, 778 aryl diazonium salts  26, 237–238, 347–349, 453, 468–469, 471, 653, 778–779 4‐aryl (E)‐but‐3‐enoic acids  428 aryl halides  6–7, 10, 16, 26, 31, 131, 311–312, 316, 343, 347, 350, 354–357, 368, 434, 480, 699, 703, 705–706, 752–753

Index

arylmercaptodifluoromethylacetic acids 292–293 arylmercaptodifluoromethylene radical 293 aryl metallic species  343, 350–351, 368 arylpropynones 393–395 aryl‐SCF2PO(OEt)2 derivatives  468 aryl S–CF3 sulfilimines  676 aryl S–RF sulfilimines  677, 683 aryl sulfonyl fluorides  623, 624, 626, 628–630, 638–641, 643, 649–651 arylsulfurchlorotetrafluorides aryl bis‐and tris(sulfur chlorotetrafluorides) 560 arylsulfur pentafluorides anhydrous HF  561 antimony fluorides  561 Cl/F exchange reaction of  564 Umemoto’s method and KHF2 562 zinc(II) fluoride  561 TCICA  565, 567 trans‐configuration 558 arylsulfur pentafluoride synthesis  553 aryl trichloromethyl thioethers  292 aryl triflates  316, 343, 349–351, 368, 507, 510 aryl triflones [ArSO2CF3] applications 508–509 preparation 505–508 aryltrifluoromethyliodanes (ArICF3X) 294 aryl trifluoromethyl sulfides  304, 344, 347, 479 aryl trifluoromethyl sulfoxides [ArS(O) CF3] application 478–484 preparation 478 aryl trifluoromethyl thioethers  295–296, 348, 482 aryl (trimethylsilyl)difluoromethyl sulfones [ArSO2CF2TMS] 536 atom transfer radical addition (ATRA)  56, 108, 128, 374 aza‐heteroaromatic thiols  728 azidotrifluoromethane (CF3N3) 750

b base‐mediated nucleophilic difluoromethylation 525 benzimidazole  180, 242–243, 726, 732, 737 benzothiophenes  364–365, 469, 631, 709 1,4‐benzoquinone (BQ)  261, 513 benzyltrifluoromethylselenide (BnSeCF3)  708, 709 β‐aminoethane sulfonamides  649 β‐arylethenesulfonyl fluorides  641–642, 647–649, 653–655 β,β‐diarylenals 394 β‐bromo‐α,β‐unsaturated ketones  701 β‐carbonyl difluoromethyl sulfoxides [RS(O)CF2Y] applications 502 preparation 500–502 β‐fluoro‐α‐aminophosphonates 791 β‐, γ‐, δ‐and ε‐trifluoromethylthiolated ketones 409 β,γ‐unsaturated oximes  70, 73, 110 β‐haloalkyl‐perfluorosulfanyl compounds α‐Pentafluorosulfanyl aldehydes 581–582 γ‐SF5‐α,β‐unsaturated aldehydes 586–588 halogen substitution reactions 580–581 SF5‐substituted C2‐building blocks acetic acid derivatives  588–597 difluoro‐pentafluorosulfanyl acetic acid (SF5CF2CO2H) derivatives 597–599 SF5CF2CF2X 599–601 vinyl‐SF5 compounds cycloadditions of  585–586 hydrogen halogenides from β‐halogen‐pentafluorosulfanylalkanes 583–584 β‐ketoesters  97, 101, 125–126, 276–277, 320, 324, 329, 331, 334, 336, 419, 421, 423, 428, 430–433, 455, 456, 458, 469–470, 778

811

812

Index

β‐ketophosphonates 771 β‐sultams 648 β‐trifluoromethylthio‐ trifluoromethylated compounds 413 bidentate (CF3)2P ligand  768 bifunctional squaramide‐catalyzed one‐pot electrophilic trifluoromethylthiolation/ sulfur–Michael/aldol cascade reaction 423 Billard reagents  325, 327 Billard’s trifluoromethanesulfenamide reagents 441 bioactive S‐trifluoromethyl sulfoximines 676 biotin–PEG3–azide 670 2,2’‐bipyridine copper trifluoromethylthiolate ((bpy) CuSCF3) 313–315 bipyridyl ligand dtbpy (4,4’‐di‐tert‐butyl‐2,2’‐ bipyridine) 389 bis‐and tris(pentafluorosulfanyl) benzenes 561 bis‐and tris(sulfur chlorotetrafluorides)  558, 560, 561 1,2‐bis(alkynyl)arenes 384 bis‐cinchona alkaloid organocatalyst 433 1,1’‐bis(diphenylphosphino)ferrocene (dppf )  6, 378, 703 bis(fluoroalkyl)phosphine‐oxazoline ligands  768, 770 bis(fluorosulfuryl)biarenes 649–650 bis‐(2‐methoxyethyl) aminosulfur trifluoride (deoxofluor®) 740 bis(perfluoroalky1)sulfur oxydifluorides 680 bis‐SCF3 allylic acids  407 (bis)sulfilimines 683 bis(sulfonyl)difluoromethanes 539 bistrifluoromethyl disulfide (CF3SSCF3)  309, 317, 404 1,2‐bis(trifluoromethylthio) ethane  375, 378

1,2‐bis(trifluoromethyl)thiolation 350, 351 bistrifluoromethyl peroxide (BTMP)  208, 210, 239 bis(trifluoromethyl) sulfoxide  219, 489–490 bis(trifluoromethylthio)ketene  374, 375 bis(trifluoromethylthio) mercury Hg(SCF3)2  309–310, 434 bis(trifluoromethyl) trioxide  208, 210–211 bis(triflyl)methanide 518 bis(triphenylphosphine) ligated CuSCF3 439 [bmim][SCF3] 435 Borodin–Hunsdiecker reaction  530 boronic acids  26, 59, 131, 228, 281, 320, 323–324, 334, 343, 352–354, 368, 387–389, 430, 458, 460, 463–464, 480, 526, 538, 650–651, 653, 661–663, 704, 706, 711, 776, 778 boron‐mediated Mukaiyama aldol reaction chiral auxiliary, SF5‐acetate 597 of octyl SF5‐acetate with aldehydes  595, 596 BrCF2CH=CH2 89–93 BrCF2CO2Et  11, 31, 37, 38, 49, 66–70, 74, 79, 89–90, 104–106, 270, 469, 731 BrCF2P(O)(OR)2  49, 56, 59, 774–777 bromo‐and iododifluoromethane  726 bromoarenes 362 bromobenzo[d]thiazoles 363 (bromodifluoromethyl) triphenylphosphonium bromide 779 bromodifluoromethyl aryl sulfones  529, 531 bromodifluoromethylphosphonates   271, 774–777, 788 substrate scope  60 bromodifluoromethyl sulfones  530, 532 bromodifluoromethyl thioethers 292–293

Index

bromo‐2‐fluoroethane 574 bromoimidazo[1,2‐a]pyrazines 363 bromoimidazoles 363 bromooxazoles 363 bromopentafluorosulfanylation 574 1‐bromo‐2‐(pentafluorosulfanyl) ethane 574 2‐bromo‐1‐pentafluorosulfanyl propionates 581 1‐bromo‐2‐phenylacetylene 378 3‐bromopyridines  363, 699 4‐bromopyridines 699 bromopyridines  362, 651 bromopyrimidines 363 bromoquinolines 362 bromoquinoxalines 363 Brønsted acid  65 Buchwald–Hartwig aminations aryl fluorosulfates and aniline  664, 666 Buchwald–Hartwig reactions  354 Bunte salt FCH2SSO3Na 465

c calcium bistriflimide–Ca(NTf2)2 643 carbon‐centered nucleophiles  518 1,1’‐carbonyldiimidazole 120 carboxylation of aryl fluorosulfates 664 carboxylic acids  70, 100, 119, 126–127, 152, 178–180, 242, 278, 294, 357, 392, 396, 408–412, 458, 473, 535, 578, 580, 582, 588, 591, 613–614, 664–665, 742, 754–756, 778, 781–783, 785, 797 carfentrazone‐ethyl 726 catalytic metal‐difluorocarbene involved coupling (MeDIC) reaction  3, 10–11 catalytic Togni’s/Umemoto’s reagent 512 catalyzed nucleophilic, aromatics  3 Cbz‐protected α‐ketiminophosphonate 787 C=C double bonds difluoromethylation rearrangements 73–76

subsequent cyclization  69–73 intermolecular difunctionalization BrCF2CO2Et 66–68 BrCF2P(O)(OR)2 56–59 HCF2R (R = CO2H, SO2NHNHBoc) 62–64 Ph3P+CF2CO2– 59–62 selectfluor 65–66 1‐C‐diethylphosphono(difluoromethyl) iminosugars 774 cefazaflur 291 cesium trifluoromethylthiolates (CsSCF3)  315–316, 434, 439 CF2Br2  97, 145–149, 153–155, 292, 716, 743–747, 779 CF2Br2, CF2BrCl 102–103 CF2PO(OEt)2 group  465, 468, 779 CF2R moiety organic substrates  49 synthetic pathways  49 CF3Br 297–301 (3‐CF3)BzOOt‐Bu 408 (CF3CO2)2Xe 301–302 CF3COONa 152 CF3COSR 301 CF3‐donor reagents  297 CF3I/Na/liq. NH3 system  298 CF3S‐containing spiro‐cyclopentanone– thiochromanes 423 CF3SeCl generation‐ trifluoromethylselenolation  709 CF3SeCu–DMF complex  697 CF3Se moiety benzyltrifluoromethylselenide  708–710 CF3SeNMe4 711–712 difluoromethylselenyl motif 714–715 FG‐CF2Se‐molecules 715–716 fluoromethylselenyl motif  715 higher fluorinated homologues 713–714 in situ combination of trifluoromethylation and elemental selenium  705–706

813

814

Index

CF3Se moiety (Contd.) nucleophilic trifluoromethylation 694–695 radical trifluoromethylation 695–696 radical trifluoromethylselenolation  712–713 tetramethylammonium trifluoromethylselenolate (Me4NSeCF3) 701–705 trifluoromethylselenocopper 697–701 trifluoromethylselenotoluene sulfonate (CF3SeTs) 707, 710–711 trifluoromethylselenyl chloride 707–708 CF3SeNMe4 711–712 CF3SO2Na  300–301, 312, 334–337, 346–347, 353, 356, 360–361, 417, 743 (CF3SO2)2O‐promoted reduction  304 CF3SO2SR 301 CF3S‐oxindoles 433 CF3‐substituted organometallic derivatives 164–169 CF3X (X=H, I, TMS) reagents  99 C–H bond difluoroalkylation, DAAS‐Na  31, 33, 41 CH2FBr 131 CH2FI  124, 125, 130–131 CH2FSO2Cl 128–129 CH2FX (X = Cl, Br, I, OTf, OTs, OMs) 125 chiral α‐amino acid‐derived aldehydes 772 chiral diphosphine ligand (R)‐(2’‐ (bis(trifluoromethyl) phosphino)‐1,1’‐binaphthyl‐2‐yl) diphenylphosphine 766 chiral enantiopure N‐SCF3 reagents 331 chiral fluorinated aminophosphonic acid derivatives difluoromethylated aminophosphonate derivatives 787–788

monofluoroalkylated aminophosphonate derivatives 788–792 trifluoromethylated aminophosphonate derivatives 785–787 chiral fluoro‐organo phosphines 765–770 chiral trifluoromethyl substituted dithioketals 322 chiral trifluoromethylthiolated 2,5‐ disubstituted oxazolines  428 2‐chloro‐or 2‐bromo‐1‐ (trifluoromethylthio) alkanes 374 chlorodifluoromethyl aryl sulfone  271, 531 chlorodifluoromethyl phenyl sulfone  530, 733–735 1‐(chloromethyl)‐4‐fluoro‐1,4‐ diazoniabicyclo[2.2.2]octane salt 65 chloropentafluorosulfanylation reactions 577 2‐(chlorotetrafluorosulfanyl) pyridines 562 1‐chloro‐2‐(trifluoromethylthio) alkenes 384 2‐chloro‐3‐(trifluoromethylthio)‐1H‐ indole 303 chloroxyperfluoroalkanes 209 cinchona alkaloid‐catalyzed enantioselective trifluoromethylthiolation 421 cinnamic acids  392, 408, 417 cis‐trifluoromethoxypalladation (FOP) 255 ClCF2COONa  149–152, 155, 165 cobalt‐catalyzed cross‐coupling  33 bromodifluoroacetates 37 Co(III)‐catalyzed hydro‐ difluoromethylthiolation reaction 458 complex (bpy)CuSCF3 314–315 copper‐assisted oxidative bis‐ trifluoromethylthiolation 407 copper‐catalyzed cross‐coupling

Index

α‐silyldifluoroamides 29 bromozinc‐difluorophosphonate 25 bromozinc‐difluorophosphonate with 2‐iodobenzoates 24 iodo/bromo‐aryl triazenes  25 copper‐catalyzed difluoroacetylation bromodifluoroacetates 30 copper‐catalyzed difluoromethylation (DMPU)2Zn(CF2H)2 9 copper‐catalyzed phosphonyldifluoromethylation (hetero)aryl iodides  28 copper‐catalyzed ring‐opening trifluoromethylthiolation of cyclopropanols 415 copper‐catalyzed trifluoromethylselenolation   704, 705 copper‐catalyzed trifluoromethylthiolation 430 of vinyl iodides  379 copper‐free electrophilic method  391 copper(I)‐catalyzed oxydifluoroalkylation of alkenes 72 copper(I) (phenylsulfonyl) difluoromethide 526 copper(I) trifluoromethylselenolate complexes  697, 698 copper(I) trifluoromethylthiolate (CuSCF3)  313, 405, 438, 697 copper‐mediated difluoromethylation aryl iodides, TMSCF2H 4 (hetero)arenediazoniums 5 heteroarenes 6 n‐Bu3SnCF2H 5 copper‐mediated oxidative phosphonyldifluoromethylation TMSCF2PO(OEt)2 28 copper‐mediated oxidative trifluoromethylthiolation reactions 392 copper‐mediated phosphonyldifluoromethylation aryl hypervalent iodides  28 difluoromethylphosphonyl cadmium\ zinc reagents  23

copper (phenylsulfonyl) difluoromethide 538 copper triflate (CuOTf )  237, 682, 705 copper trifluoromethylthiolate (CuSCF3)  312, 313, 437–439 coumarin‐3‐carboxylic acid substrates 392 C‐radical precursors  415 C‐SCF2PO(OEt)2 466 C(sp3)‐centered electrophiles  537 C(sp3)–CF2PO(OEt)2 bonds  56 C(sp3)–SCF3 compounds direct construction of alkyl trifluoromethyl sulfides  403 electrophilic trifluoromethylthiolation reagents 418 via formation of F3CS• radical 415–417 N‐trifluoromethanesulfenamides  419 N‐trifluoromethylthiodibenzenesulfonimide (PhSO2)2NSCF3 425–428 N‐trifluoromethylthiophthalimide 419–423 N‐trifluoromethylthiosaccharin  423–425 N‐trifluoromethylthiosuccinimide 419–423 nucleophilic trifluoromethylthiolation  434–443 O‐SCF3 reagents  428–431 photochemical radical trifluoromethylthiolation under UV irradiation  404–405 via pre‐formation of R• radical 411–415 radical trifluoromethylthiolation with the aid of anionic SCF3 reagents 405–411 silver trifluoromethylthiolate AgSCF3 433 (1S)‐(–)‐N‐trifluoromethylthio‐2,10‐ camphorsultam 428 trifluoromethanesulfonyl chloride (CF3SO2Cl) 432

815

816

Index

C(sp3)–SCF3 compounds (Contd.) trifluoromethanesulfonyl diazo reagent 432 trifluoromethanesulfonyl hypervalent iodonium ylide  431–432 trifluoromethyl diethylaminosulfur difluoride (CF3‐DAST) 432–433 CuCF2PO(OEt)2 reagent  466, 468 4‐cyano‐N‐trifluoromethoxypyridinium triflimide  213, 214 cyanotrifluoromethythiolated compounds 407 cycloalkadienes  576, 601 cycloalkanols  409–410, 415–416, 462 cycloalkenes 576 cyclohexa‐1,4‐dienes 604 cyclohexenyl trifluoromethylthioethers 393 cyclopropanation  152, 157, 160, 177, 180, 772, 788 1,1‐difluoroalkenes  138, 142–143 cyclopropane ring  135, 137, 157–158, 173 CYP17A1 752

d decarboxylative difluorocarbene generation difluorocyclopropyl anion  150 gem‐difluorocyclopropyl, organoboron 151 methylenecyclopropanes 150 Ph3P+CF2CO2–(PDFA) 153 proline derived enecarbamate  151 reagents for  149 decarboxylative fluorination  197, 199–200, 269, 272, 278–279, 285, 292–293 decarboxylative reactions  728–733 dehydroxytrifluoromethylthiolation protocol 437 δ‐sultones 647–649 demethylthiolative fluorination 279–280 density functional theory (DFT)  100, 171–172, 231, 239, 243–244, 255, 379, 579, 591

deoxyfluorination, fluoroformates  198 deoxytrifluoromethylthiolation approach 381 Dess Martin periodinane reagent  701 dialkylsulfamoyl fluorides  633, 635, 638, 669 1,1‐diaryl‐2,2‐difluoroethene 302 2,2‐diaryl‐1,1‐difluoroethenes 526 diaryl selenide  425 1,1‐diaryl‐2,2,2‐ trifluoroethanethiol 302 diaryl trifluoromethyl sulfonium salts  293, 481–482 diastereomerically pure SCF3‐ substituted enamine products 382 dibromodichloromethane 405 1,3‐dibromo‐5,5‐dimethylhydantoin (DBDMH) 255 1,3‐dibromo‐5,5‐dimethylhydantoin (DBH)  198, 741 1,2‐dibromoethane  378, 518 dicationic imidazolium‐phosphonium salt [(SIMes)PFPh2] [B(C6F5)4]2 797 1,1‐dichlorocyclopropanes 140–142 1,1‐dichlorocycloproparene 142 Diels–Alder reaction acrylic acid derivatives  590 cyclopentadiene 585 SF5‐acetylenes 604–605 SF5‐benzyne 569 2‐SF5‐butadiene 586 SF5‐substituted acroleine  585 diethyl α‐amino‐α‐trifluoromethyl‐γ‐ oxobutylphosphonates 787 diethyl α‐fluoro‐β‐ ketophosphonates 771 diethylaminosulfur trifluoride (DAST)  3, 23, 47, 274, 280, 325, 419, 432–433, 538, 740–741, 788, 791 diethyl bromodifluoromethylphosphonate ((EtO)2P(O) CF2Br) 774

Index

diethyl (difluoromethyl) phosphonate 773–774 diethylisopropylamine (DIPEA)  631–632, 659–660 diethyl trifluoromethylphosphonate  297, 694, 784–785 1,1‐difluorination of styrenes  66, 68 difluorination reaction  67 6‐difluoroacetate phenanthridines  78 1,1‐difluoroalkenes, cyclopropanation 142 difluoroalkylated indolino‐3‐ones  82 1‐difluoroalkylated isoquinolines  76, 80 difluoroalkylation electrophilic CF3X (X = H, I, TMS) reagents 99–100 free radical halodifluoroketone or‐amide 107 HCF2I and PhCH2CF2I 107–108 iododifluoroacetates 101–102 (hetero)aromatics catalytic difluoroalkylation  37–39 transition‐metal catalyzed difluoroacetylation 27–33 transition‐metal catalyzed phosphonyl 23–26 nucleophilic BrCF2CO2Et and BrCF2CH=CH2 89–90 silanes 94–95 XCF2PO(OEt)2 89 XCF2SO2Ar 90–93 difluorocarbene  10–11, 149–163, 731 BrCF2CO2H 270 BrCF2P(O)(OEt)2 271 chlorodifluoromethyl aryl ketones 272 Cu‐complex 269–272 FSO2CF2CO2H 270 O–H bond  269 Ph3P+CF2CO2– 269 reagents 97–99

TMSCF2Br 271 difluorocarbene donor reagent (Ph3P+CF2CO2–; PDFA)  270–271, 439, 733 difluorocyclopropanation AuCF3 complexes  170 Bi(CF3)3 169 boc‐protected amino derivatives 161 CF2Br2 146–149 (CF3)2Cd 168 (CF3)2Hg /NaI  167 CF3SiMe3/NaI system  179 CF3SiMe3 178 (CF3)2Zn•2DMPU 168 enolizable ketones with TFDA  162 hexafluoropropene oxide  183 Me3SnCF3/NaI 164 n‐butyl acrylate  177 N‐vinylazoles 181 PhHgCF3/(CF3)2Hg/NaI 167 PhHgCF3/NaI 166 Ph3P+CF2Br Br– 154 phthalimide moiety  160 silyl enolates  174 tertiary amino function  161 difluorocyclopropanation reagent of alkene  143–145 BrCF2P(O)(OEt)2 163 CF2Br2 with Zn  146–149 CF3‐substituted organometallic derivatives 164–169 decarboxylative difluorocarbene generation 149–153 difluorodiazirine 182–183 double bond reactions  185–187 hexafluoropropene oxide  183 Michael‐induced ring closure 183–185 nucleophilic cleavage  153–163 Ruppert–Prakash‐type reagents 169–182 trihalomethyl anions CF2X–(X = Cl, Br) 145–146 difluorocyclopropanes 728 2,2‐difluorocyclopropyl ketones 157–158

817

818

Index

3,3‐difluoro‐3H‐diazirine (DFD) 182–183 difluorohomologation carbonyl compounds  173 ketones 172 1,1‐difluoro‐2‐ hydroxyalkylphosphates 89 difluoromethanesulfonyl chloride (HCF2SO2Cl) 455 difluoromethoxylation  269, 273–275, 285 difluoromethyl aryl ethers  274, 530, 775 difluoromethylated aminophosphonate derivatives 787–788 difluoromethylated isoxazolines  70, 110 difluoromethylated ketones  68 difluoromethylation alkynes  79–82, 85 C=C double bonds intermolecular difunctionalization 56–68 rearrangements 73–76 subsequent cyclization  69–73 electrophilic difluorocarbene reagents  97–99 I(III)‐CF2SO2Ph reagent  100 S‐((phenylsulfonyl)difluoromethyl) thiophenium salts  100–101 free radical CF2Br2, CF2BrCl or TMSCF2Br 102–103 HCF2SO2Cl and HCF2SO2Na/Zn (SO2CF2H)2 108–109 phosphorus‐containing reagents 103–104 sulfones, sulfoximines, thioethers and sulfonium salts  109–111 (hetero)aromatics MeDIC 10–11 radical C–H bond  19–22 transition‐metal catalyzed radical difluoromethylation 12–19 transition‐metal mediated  3–10 isocyanides 76 nucleophilic

cadmium, copper and zinc reagents 90 miscellaneous reagents  96–97 PhSO2CF2H 90–93 reagents 94–95 sulfoximine reagent  96 difluoromethylcadmium  90, 91 difluoromethylcopper 90 difluoromethyl coumarins  527 difluoromethyldiarylsulfoniums 733 difluoro(methylene)cyclopropanes (F2MCPs) 158 difluoromethylene phosphobetaine  731, 743, 779, 781–784 6‐difluoromethylenephosphonyl‐ phenanthridines 776 difluoromethylene ylides  781–782 difluoromethyl phenyl sulfone (PhSO2CF2H)  90, 530 difluoromethyl‐phosphonium bromide 779 difluoromethylphosphonium salts  103, 779, 781–783 difluoromethyl 2‐pyridyl sulfone  19, 93, 522 difluoromethylselenoethers 714 difluoromethylselenyl motif  714–715 1,1‐difluoro‐1‐(methylsulfinyl) alkanes 502 difluoromethyl sulfones [RSO2CF2H] aryl and heteroaryl difluoromethyl sulfones 520–529 aryl and heteroaryl halodifluoromethyl sulfones 529–535 aryl (trimethylsilyl)difluoromethyl sulfones 536–538 other (miscellaneous) aryl difluoromethyl sulfones 539–540 difluoromethyl sulfoxides (RS(O)CF2R) applications 494–498 preparation  493–494, 502–504 and uses  502–504 2‐(difluoromethylsulfonyl) benzothiazole  527, 529

Index

difluoromethylthioester derivatives 460 difluoromethylthiolation reaction electrophilic reagents  453–457 by nucleophilic pathway  453 PhSO2SCF2H 457–462 difluoro‐pentafluorosulfanyl acetic acid (SF5CF2CO2H) derivatives 597–599 difluoro(trimethylsilyl) methylphosphonates 777–778 di(hetero)aryl‐λ3‐iodanes 357–358 dihydroisoquinolinones 709 (1,1‐dihydrotrifluoroethyl) phenyliodonium triflate  754 diiodomethane 405 diisopropylethylamine (DIPEA)  631, 659, 660 dimeric selenolated complexes  698 1,3‐dimesitylimidazol‐2‐ylidene (IMes) 162 1,2‐dimethoxyethane (DME)  154–155, 164–165, 397, 750 dimethoxy‐substituted chiral sulfonamide reagent  428 dimethylacetamide (DMA)  59 1,3‐dimethylbenzene 344 2,4‐dimethylbenzenesulfonyl (DMPs) 254 dimethylformamide (DMF)  59, 491 1,3‐dimethyl‐2‐imidazolidinone (DMI) 184 5,5‐dimethyl‐1‐pyrroline N‐oxide (DMPO) 246 dinitrophenyl disulfides  554, 556 2,4‐dinitro (trifluoromethoxy)benzene (DNTFB) 221 diphenyl disulfide  506, 554 silver difluoride (AgF2) 552 2,2’‐dipyridyl disulfide  553, 562 direct anionic trifluoromethoxylation aryl stannanes and arylboronic acids 230 deoxytrifluoromethoxylation of phenols 228 N‐(hetero) aryl‐N‐hydroxylamines 230

nucleophilic reactions  229 ortho‐trifluoromethoxylated anilide 232 Stern–Volmer quenching  232, 235 trifluoromethyl benzoate  236 direct C–H functionalization  343 direct electrophilic difluoromethylation 269, 272–273 direct radical trifluoromethoxylation CF3OOCF3 239 C–H trifluoromethoxylation  243 C–H trifluoromethoxylation of arenes 247 CW‐EPR studies  248 heteroaryl trifluoromethyl ethers 249 N‐trifluromethoxy pyridine salts 242 Ru(bpy)32+ 245 trifluoromethoxyl radical  239 direct trifluoromethoxylation sp3‐carbon atoms alkyl alcohols and alkyl silanes 259–260 alkyl halides and alkyl triflates 258 α‐diazo esters  263–264 C–H bonds  260–262 of epoxides  262–263 direct trifluoromethoxylation of alkenes Pd(II)‐catalyzed oxidative  252–255 radical trifluromethoxylation 251–252 silver(I)‐catalyzed 255–257 direct trifluoromethoxylation reagents bistrifluoromethyl peroxide  210 bis(trifluoromethyl) trioxide 210–211 chloroxyperfluoroalkanes 209 2,4‐dinitro (trifluoromethoxy) benzene 221 N‐trifluoromethoxy benzimidazole 211–212 N‐trifluoromethoxysaccharin 213 N‐trifluoromethoxy triazolium salts 214–215

819

820

Index

direct trifluoromethoxylation reagents (Contd.) organometallic trifluoromethoxides 217–219 perfluoroalkylsulfurane 219 perfluoroalkylsulfurane oxide 219–220 trifluoromethyl benzoate  222–223 trifluoromethyl hypofluorite 207–209 trifluoromethyl sulfonates  221–222 trifluoromethyl trifluoromethanesulfonate 215–217 direct trifluoromethylation, OCF3 motif 200 di‐t‐butyl azodicarboxylate  750 Doyle–Kirmse rearrangement  469, 472 dtbbpy  17, 70, 76, 79

e

EAS‐type hetArS(O)CF3 synthesis  486 EAS‐type triflinyl heteroarene synthesis 485 (E)‐1,2‐bis(trifluoromethylthio) alkenes  384, 396 electron paramagnetic resonance (EPR)  12, 246, 248 electron‐rich (hetero)arenes  317 electrophilic difluoroalkylation  37, 100 CF3X (X = H, I, TMS) reagents  99 electrophilic difluoromethylating reagents  48, 100, 736 electrophilic difluoromethylation difluorocarbene reagents  97–99 I(III)‐CF2SO2Ph reagent  100 S‐((phenylsulfonyl)difluoromethyl) thiophenium salts  100–101 electrophilic difluoromethylsulfenyl chloride (HCF2SCl) 455 electrophilic fluorophosphonium cation 793 electrophilic hypervalent iodine reagent 428 electrophilic monofluoromethylation

CH2FX (X = Cl, Br, I, OTf, OTs, OMs) 125 monofluoromethyl phosphonium salts 127 monofluoromethylsulfonium ylides 127 monofluoromethylsulfoxinium salts 126 S‐(monofluoromethyl) diarylsulfonium tetrafluoroborate 125–126 of thiophenol  463 electrophilic (PhSO2)2NSCF3 reagent 425 electrophilic SCF3 reagent N‐ (trifluoromethylthio) pyrrolidine‐2,5‐dione 416 electrophilic trifluoroethyl sources 753–756 electrophilic trifluoromethylation  200, 207, 259, 302–303, 351, 376, 419, 482, 681, 743–750 of thiolates or thiols  291, 293–294 electrophilic trifluoromethylthiolating reagent N‐(trifluoromethylthio) phthalimide  344, 384, 391 electrophilic trifluoromethylthiolation  381–391, 403, 488 electrophilic trifluoromethylthiolation reagents 418–433 Billard reagents  325–327 bistrifluoromethyl disulfide (CF3SSSCF3) 317 chiral enantiopure N‐SCF3 reagents 331 Haas reagents  318–319 Lu–Shen reagents  319–321 N‐(trifluoromethylthio)‐ bis(phenylsulfonyl) imide 329–331 N‐(trifluoromethylthio) phthalimide 323–325 N‐trifluoromethylthiosaccharin 328–329 N‐trifluoromethylthiosuccinimide 322–323 Shibata’s reagent  331–334

Index

sodium trifluoromethanesulfonate (CF3SO2Na) 334 trifluoromethanesulfenyl chloride (CF3SCl) 317 trifluoromethanesulfinyl chloride (CF3SOCl) 335–337 trifluoromethanesulfonyl chloride (CF3SO2Cl) 334–335 electrophilic‐type trifluoromethylation 507 elemental fluorine  517, 554–558, 571 employing Billard’s sulfenamide reagent N‐phenyl‐S‐ (trifluoromethyl) thiohydroxylamine 384 enamines  65, 165, 167, 317, 324, 333, 357, 382–383, 419, 421, 456, 537, 751, 778 enantiomerically pure α‐SCF3‐ substituted alcohols  119, 421 enantiomerically pure (S)‐2,2’‐binaphthol 766 enantiomerically pure S–RF sulfoximines 680 enantiopure α,α‐difluoro‐β‐ aminophosphonic acids  787 enantiopure β‐trifluoromethylthiolated ketoesters 421 enantiopure N‐SCF3 reagents  331, 332 enantioselective proline‐catalyzed Mannich reaction  786–787 endothelin (ET‐1) receptor antagonists  662–663, 732 1,6‐enynes  101, 394, 395 ethenesulfonyl fluoride (ESF) derivatives  647–649, 652–655 [[(ethoxycarbonyl)difluoromethyl]thio] phthalimide 469 ethyl 2‐difluoro‐2‐(arylsulfinyl) acetates  2, 502 ethyl 4‐(phenylamino)benzoate  665 ethyl bromodifluoroacetate  728 ethyl iododifluoroacetate  406 Evans‐type chiral lithium imide enolates 421

f

[18F]CF3SePh 694 F3COOOCF3 reactivity  211 FDA  47, 48 difluoromethyl group  48 Fe2O3‐promoted trifluoromethylthiolation of alkenes 414 ferroelectric liquid crystals  137, 155 FG‐CF2Se‐molecules 716 Fischer carbene‐type  177 18 F‐labeled trifluoromethyl thioethers 292 fluorinated cyclic analogs (FAP4)  788, 790, 791 fluorinated cyclopropylphosphonates 772 fluorinated meta‐SF5‐pyridines 563 fluorinated para‐SF5‐pyridines 563 fluorination  140–142, 197–200, 272, 274–275, 278–280, 292–293, 679–680, 739–743 fluorination by bromine trifluoride 742 fluorine/halogen exchange  739 fluoroalkylation  11, 42, 110, 122, 477, 496, 499, 524, 527, 531–532, 536, 659–660 fluorobenzenesulfonimide (NFSI)  272, 329, 628 2‐fluoro‐1,3‐benzodithiole‐1,1,3,3‐ tetraoxide (FBDT)  123 6’‐fluoro[4.3.0]bicyclonucleotides (6’F‐bc4,3‐DNA) 173 fluorobis(phenylsulfonyl) methane 121–122 fluoroform  99, 295, 297, 506, 513, 640–641, 694, 726, 730 fluoroformates, deoxyfluorination 198 fluoroform‐derived CuCF3 297 fluoromalonates 119–120 fluoromethylated spiro[5.5] trienone 83 fluoromethyl phenyl sulfone  119–120 fluoromethyl phenyl sulfoximine  681 fluoromethylselenyl motif  715

821

822

Index

2‐fluoro‐1‐(pentafluorosulfanyl) benzene 569 2‐fluoro‐2‐phenylsulfonylacetophenone 122 fluorophosphonium and fluoroalkylphosphonium cations  765, 793–801 fluorosulfate‐l‐tyrosine (FSY) 668–669 fluorosulfate moiety (–OSO2F) 656, 662, 668 fluorosulfates advantage of  656 C–F bond formation  658–659 C–N bond formation  659, 664–665 dehydration/ dehydrogenation 659–660 sulfur‐fluoride exchange (SuFEx) chemistry 665–668 transition metal‐catalyzed cross‐ coupling reactions C–C bond formation  660–663 C–H bond formation  665 CO or CO2 insertion  663–664 fluorosulfonyldifluoroacetic acid  149, 152, 153, 155, 731–732 (fluorosulfonyl)difluoromethyl sulfoxides 506 2‐fluoro‐2‐sulfonylketone 122–123 fluorosulfurylation  625, 628, 630–631, 633–638, 651, 662, 664–665 free radical difluoroalkylation halodifluoroketone or‐amide  107 HCF2I and PhCH2CF2I 107–108 iododifluoroacetates 101–102 free radical difluoromethylation ArCF2CO2H 112 CF2Br2, CF2BrCl or TMSCF2Br 102 HCF2SO2Cl and HCF2SO2Na/Zn (SO2CF2H)2 108–109 phosphorus‐containing reagents 103 sulfones, sulfoximines, thioethers and sulfonium salts  109–111 TMSCF2CO2Et 112 free radical hydrodifluoroalkylation BrCF2CO2Et 104–106

halodifluoroketone or‐amide  107 free radical monofluoromethylation CH2FSO2Cl 128–129 (H2FCSO2)2Zn (MFMS)  128 monofluoromethyl sulfone  130 (PhSO2)2CFI 128 PhSO(NTs)CH2F 129 Freon 22  726 Freund reaction  138, 140 Friedel–Crafts‐type direct trifluoromethylthiolation 335 5‐18F‐(trifluoromethyl) dibenzothiophenium trifluoromethanesulfonate 294 [18F]trifluoromethylthiolation 441, 783 18 F‐Umemoto reagent  294 furans  29, 30, 358, 364–365, 569

g

γ‐butenolides 396 γ‐fluoroalcohols 129 gem‐difluorinated spiro‐γ‐lactam oxindoles  70, 72 gem‐difluoroalkene  142, 143, 523, 527, 531, 781 intramolecular cyclopropanation 143 gem‐difluorocyclopropanes 656 biological active  136 cyclopropanation 1,1‐difluoroalkenes 142–143 difluorocyclopropanation reagents CF2Br2 with Zn  146–149 CF3‐substituted organometallic derivatives 164–169 decarboxylative difluorocarbene generation 149–153 difluorodiazirine 182–183 double bond reactions  185–187 hexafluoropropene oxide  183 Michael‐induced ring closure (MIRC) 183–185 nucleophilic cleavage  153–163 Ruppert–Prakash‐type reagents 169–182

Index

trihalomethyl anions CF2X–(X = Cl, Br) 145–146 drugs and natural products  136, 137 ferroelectric liquid crystals  137 gem‐difluoro moiety  138, 139 inducible T‐cell kinase (ITK) inhibitor 135 intramolecular Wurtz (Freund) reaction 140 nucleophilic fluorination  140–142 Pd(0)‐catalyzed ring opening  138 potential enzyme inhibitors  136 synthetic approaches  139 synthetic transformation of  138 gem‐difluoroolefins  99, 502, 541 gem‐difluoropropanes 657 (i‐PrO)2P(O)CBr2F 772 gem‐disubstituted chloro trifluoromethyl compounds 336 global warming potential (GWP)  728 Grignard reagents  317, 321, 327, 350, 351, 366, 419, 504, 506, 508, 628, 709, 773

h Haas reagents  318, 319, 322 halazepam 752 halodifluoroketone/amide 107 halodifluoromethyl sulfoxides [RS(O) CF2X] applications 499–500 preparation 498–499 haloforms reaction  145 halophilic reaction  146 Hansch constant  291 Hansch’s hydrophobicity parameter 309 Hantzsch ester (HE)  56, 185 Hass cyclopropane process  138 Hastelloy C  310 HCF2I  90, 107–108 HCF2P(O)(OR)2 773–774 HCF2R (R = CO2H, SO2NHNHBoc) 62–64 HCF2SO2Cl  108–109, 455, 456, 457 HCF2SO2Na/Zn(SO2CF2H)2 108

Heck cross‐coupling reactions 652–653 hemiaminals  297, 694 (hetero)aromatic aldehydes  461 heteroaromatic compounds furans 364–365 imidazo[1,2‐a]pyridines 367 indoles 358–362 isoquinoline 362–364 Knochel–Hauser base  366 1‐phenyl‐5‐iodopyridinones 367 pyrazolin‐5‐ones 368 pyridine 362–364 pyrroles 358–362 quinoline 362–364 tetrafluoropyridazine 366 tetrafluoropyrimidine 366 thiophenes 364–365 (hetero)aromatics difluoroalkylation catalytic difluoroalkylation  33, 37–39 transition‐metal catalyzed phosphonyl 23–26 difluoromethylation catalyzed nucleophilic  3–10 MeDIC 10–11 radical C–H bond  19–22 transition‐metal catalyzed radical difluoromethylation 12–19 transition‐metal mediated  3–10 heteroaryl difluoromethyl sulfones 520–529 heteroaryl triflones preparation 513 uses 514 heteroaryl trifluoromethyl sulfoxides [hetArS(O)CF3] applications 487–489 preparation 484–487 heterocyclic scaffolds  358 hexafluoroacetone hydrate amidinate salt 297 hexafluoropropene oxide (HFPO)  145, 183 hexamethylphosphoramide (HMPA)  172, 393

823

824

Index

(H2FCSO2)2Zn (MFMS)  128 higher fluorinated homologues  695, 696, 713–714 Horner–Wadsworth–Emmons (HWE) olefination  582, 588, 772 HOTf‐promoted reduction of trifluoromethyl sulfoxides  305 Huisgen alkyne–azide cycloaddition  660, 661 Hu–Prakash protocol  175, 176 hydrodifluoroalkylation 102 of alkynes  82, 84 hydrodifluoromethylation of alkenes  62, 63 hydrophobictrifluoromethyl‐λ6‐ tetrafluorosulfanyl (CF3SF4) group 613 hydrophosphonodifluoromethylation 57 plausible reaction pathway  58 3‐hydroxy‐3‐difluoroalkylisoindolin‐1‐ ones 66 1,2‐hydroxydifluoromethylation 64 hypervalent iodine(III)–CF3 reagents  293, 294

i I(III)‐CF2SO2Ph reagent  100 imidazo[1,2‐a]pyridines 367 iminosulfur oxydifluorides  669–671 2‐imino‐3,3,3‐trifluoropropanephosphonates 785 indanone‐based β‐ketoesters 455 indirect trifluoromethylthiolation methods electrophilic trifluoromethylation of thiolates or thiols  293–294 fluorination of polyhalogenalkyl thioethers 292–293 nucleophilic trifluoromethylation 294–298 radical trifluoromethylation 298–302 reduction of trifluoromethyl sulfoxides 303–305 trifluoromethylation of thiones/ thioureas 302–303

indoles  320, 333, 334, 336, 357–362, 367, 450, 455, 456, 459, 465, 469, 472, 487, 488, 504, 513, 749, 777, 778 “innocent” oxidant  345 in situ aromatic selenocyanates  694 in situ combination of trifluoromethylation and elemental selenium  705–706 in situ generated electrophilic species N‐(trifluoromethylthio) succinimide 389 interleukin‐2 inducible T‐cell kinase (ITK) inhibitor  135 intermolecular difunctionalization BrCF2CO2Et 66–68 BrCF2P(O)(OR)2 56–59 HCF2R (R=CO2H, SO2NHNHBoc) 62–64 Ph3P+CF2CO2– 59–62 selectfluor 65–66 internal styrene (E)‐1‐methoxy‐4‐ (prop‐1‐en‐1‐yl)benzene 383 intramolecular OCF3 migration 202–203 intramolecular trifluoromethylthiolation 407, 408 intramolecular Wurtz (Freund) reaction 140 iodine‐free trifluoromethanesulfenate 321 iodine pentafluoride  317, 563, 565, 567 iodoalkyl triflones  520 iododifluoroacetates 101–102 iododifluoromethyl phenyl sulfone  530–531, 534 iododifluoromethylsulfinylarenes 500 iodo‐isoxazoles 513 iodoperfluoroalkyl phosphines  793 3‐iodopyrones 699 Ireland–Claisen rearrangement  159 carboxylic acid  614 of SF5‐acetic acid allyl esters  592 of SF5‐acetic acid cinnamyl esters 593

Index

iron‐catalyzed difluoroalkylation unactivated difluoroalkyl bromides 41 iron‐catalyzed difluoromethylation aryl magnesium reagents  20 aryl zinc reagents  20 iron‐mediated hydrotrifluoromethylthiolation 412–413 isochromenones  469, 709 isocyanides, difluoromethylation 76–79 isoindolin‐1‐ones 65 isolated SCF3‐substituted diarylalkenes 394 isoquinoline  362, 709 isoquinolinediones  362–364, 416, 709 isosteric (difluoromethyl) phosphonate 774

j Johnson–Corey–Chaykovsky reaction 582 Johnson‐type sulfoximinium reagent 496

k {K(18‐crown‐6)}P(CF3)2 768 Knochel–Hauser base  366 Knochel–Hauser base‐promoted reaction 366 Kolomeitsev’s method  234 K2S2O8  261, 301, 336, 391, 393, 394, 407, 408, 411, 414, 415, 460, 462

l Langlois reagent  695, 743 Langlois reagent CF3SO2Na  312, 360 Langlois reagent (NaSO2CF3) 382 laser flash photolytic (LFP)  183 Lewis acid–base adducts (LA‐X)  622 liquid crystalline alkenes  577 lithium fluorocarbenoid (LiCH2F) 124 lithium 2‐phenylpropan‐2‐olate  321 l‐phosphoallothreonine 788 l‐phosphoserine  788, 789

l‐phosphothreonine 788 Lu–Shen reagents  319–321, 353

m MCF3 complex  297, 298 Me3SiCF2X  169, 171 mercaptans 292 2‐mercapto pyridine  522 MesNHSCF2P(O)(OEt)2  778, 779 metabotropic glutamate receptor (mGluR) 135 metal‐catalyst‐free trifluoromethylthiolation 349 metal‐difluorocarbene involved coupling (MeDIC)  3, 10–11, 42 metal‐free trifluoromethylthiolation 361 metallaphotoredox difluoromethylation with bromodifluoromethane  17 (methoxycarbonyl) difluoromethanesulfonamide 469 methoxymethyl (MOM) ethers  438 3‐(4‐methoxyphenyl)propiolic acid  392, 393 1‐methoxy‐4‐(1‐propyn‐1‐yl)‐ benzene 462 methyl chlorodifluoroacetate  153, 728 methylene cyclohexane  576 methylenocyclopropylglycine (MCPG) 150 methyl perfluorooctyl sulfoxide  677 MFDA, difluorocarbene from  156 Michael‐induced ring closure (MIRC)  139, 183–185 Michler’s thioketone  376 miscellaneous reagents  96, 97 mono‐and difluomethyl sulfoximines 686 mono‐and difluoromethyl NH‐ sulfoximines 685 monofluoroalkylated aminophosphonate derivatives 788–792 monofluoromethanesulfinate (MFMS) 128

825

826

Index

monofluoromethylation 275 electrophilic CH2FX (X = Cl, Br, I, OTf, OTs, OMs) 125 monofluoromethyl phosphonium salts 127 monofluoromethylsulfonium ylides 127 monofluoromethylsulfoxinium salts 126 S‐(monofluoromethyl) diarylsulfonium tetrafluoroborate 125–126 free radical CH2FSO2Cl 128–129 (H2FCSO2)2Zn (MFMS)  128 monofluoromethyl sulfone  130 (PhSO2)2CFI 128 PhSO(NTs)CH2F 129 nucleophilic CH2FI 124 2‐fluoro‐1,3‐benzodithiole‐1,1,3,3‐ tetraoxide 123 fluorobis(phenylsulfonyl) methane 121–122 fluoromalonates 119 fluoromethyl phenyl sulfone 119–120 2‐fluoro‐2‐sulfonylketone 122 monofluoromethyl phosphonium salts 124 PhSO(NTBS)CH2F 123–124 TMSCF(SO2Ph)2 (TFBSM)  123 transition‐metal‐catalyzed/mediated CH2FBr 131 CH2FI 130–131 cross‐coupling reactions  130 PhSO2CHFI 131 PTSO2CH2F 132 monofluoromethylation of thiols  463 monofluoromethylphosphonate reagents 770–772 monofluoromethyl phosphonates  770 monofluoromethyl phosphonium salts  124, 127 monofluoromethylselenoethers 715, 716

monofluoromethyl sulfone  130 monofluoromethylsulfonium ylides 127 monofluoromethylsulfoxinium salts 126 monofluoromethylthioesters 464 mono‐or di‐halocubanes  406 2‐monosubstituted 3‐allenoic acids  2, 407 Morita–Baylis–Hillman (MBH) alcohols 436 carbonates 442 Mukaiyama aldol product  592 Munavalli reagent  323

n N‐acyltyrosine 622 NaI/(CF3CO)2O 303 “naked fluoride” method  624 N‐alkenoxypyridinium 436 N‐alkylimidazoles 732 naphthalene 344 N‐arylacrylamides  108, 128, 407, 416 Na2SO3/HCO2Na•2H2O 298 N‐benzoylacrylamides 416 N‐benzyl‐substituted 1‐imino‐2,2,2‐ trifluoroethyl‐ phosphonates 785 N‐bromosuccinimide (NBS)  198, 322, 741 n‐Bu4NI  76, 311, 455 N‐CH2CF3 motif electrophilic trifluoroethyl sources 753–756 trifluoroethylamine 752–753 N‐CF2H azaheterocycles  730 N‐CF2H pyridinones  732 N‐CF2H motif by decarboxylative reactions 728–733 difluoromethyldiarylsulfoniums 733 chlorodifluoromethyl phenyl sulfone 733 from halodifluoromethanes  726 nucleophilic difluoromethylation 737

Index

TMSCF2Br 737 TMSCF2Cl 737 TMSCF3 737 N‐tosyl‐S‐difluoromethyl‐S‐ phenylsulfoximine 736 N‐CF3 amines  747 N‐CF3 benzimidazoles  747 N‐CF3 imidazole and pyrazole  747 N‐CF3 motif electrophilic trifluoromethylation 743 fluorination by bromine trifluoride 742 fluorine/halogen exchange  739 nucleophilic trifluoromethylation 750 oxidative desulfurization– fluorination of dithiocarbamates 741–742 oxidative desulfurization– fluorination of dithiocarbamoyl disulfides 739–740 radical trifluoromethylation  743 via thiocarbamoyl fluoride  743 N‐CF3 triazoles  750, 751 N‐chloro‐N‐(phenylsulfonyl) benzenesulfonamide 330 N‐(cyanosulfanyl)‐aniline 778 N‐difluoromethylation  728, 731–735, 737, 739 N‐difluoromethyl(benz)imidazolin‐2‐ tiones 159 N‐(diphenylmethylidene) 184 N‐difluoromethyl‐2‐pyridones 728, 730 N‐difluoromethyl thioureas  732 Negishi aryl–aryl bond‐forming cross coupling reactions  660 N‐fluorobenzenesulfonimide (NFSI)  272, 329, 628 N‐fluorosulfurylation  633, 634 N‐(gem‐difluorocyclopropyl) azoles 180 N‐(hetero)aryl‐N‐hydroxylamines 202, 230 N‐heterocyclic carbene (NHC)  6, 218, 513, 647, 737

NH sulfoximines  680, 681, 683, 685, 686, 688 Ni‐catalyzed trifluoromethylthiolation 349 nickel‐catalyzed cross‐coupling bromodifluoroacetamides 37 difluoroalkyl bromides  36 nickel‐catalyzed difluoroalkylation difluoroalkylated sulfones  42 unactivated difluoroalkyl bromides 41 nickel‐catalyzed difluoromethylation arylboronic acids, bromodifluoromethane 15 (DMPU)2Zn(CF2H)2 10 iododifluoromethane 18 nickel‐catalyzed reductive difluoromethylation aryl chlorides, bromides  16 1‐nitro‐3‐and 4‐(pentafluorosulfanyl) benzenes 554 1‐nitro‐3‐(pentafluorosulfanyl) benzenes 553 1‐nitro‐4‐(pentafluorosulfanyl) benzene 555 4‐nitrophenyl(phenyl)(trifluoromethyl) sulfonium salt  302 nitroso arenes  743, 750 N‐methylmorpholine (NMM)  512 N‐methyl‐N‐CF3‐aminopyridine 741 N‐methyl‐N,3‐ diarylpropiolamides 395 N‐methyl‐N‐phenyl‐S‐(trifluoromethyl) thiohydroxylamine  385, 387, 389–390 N‐methyl‐N‐phenyl‐ trifluoromethanesulfenamide II 325 N,N‐diethylaminosulfur trifluoride (DAST) 47 N,N’‐dimethylpropyleneurea (DMPU) 172 N,N‐dimethyl‐S‐difluoromethyl‐S‐ phenylsulfoximinium tetrafluoroborate salt  736 N,N,N’,N’‐tetramethyl‐ethane‐1,2‐ diamine (TMEDA)  19

827

828

Index

N‐OCF3 reagents N‐trifluoromethoxy benzimidazole 211 N‐trifluoromethoxy triazolium salts 215 n‐perfluorobutane sulfonyl fluoride (PBSF) 655 N‐phenyl‐2,2,2‐trifluoroacetamide 755 N‐phenyl‐trifluoromethanesulfenamide I 325 N‐protected 4‐ (phosphonodifluoromethyl)‐ l‐phenylalanines 788 [N‐(p‐toluenesulfonyl)imino] phenyliodinane 682 N‐(pyridin‐2‐yl)‐acetamide 728 N‐(2‐pyridyl)indoles 359 N‐SCF3 phthalimide  422 N‐t‐butanesulfinyl glycosylamines 774 N‐t‐butyl‐α‐phenylnitrone (PBN)  246 N‐(tert‐butanesulfinyl)imines 120 N‐tert‐butylsulfinyl ketimines  120 N–Tf S–RF sulfilimine  677 N(TMS)3/Me4NF 295 N‐tosyl‐S‐difluoromethyl‐S‐ phenylsulfoximine  496, 736 N‐trifluoromethanesulfenamides 419 N‐trifluoromethoxy benzimidazole 211 N‐trifluoromethoxy pyridine salts  242 N‐trifluoromethoxysaccharin 213 N‐trifluoromethoxy triazolium salts  214, 216 N‐trifluoromethyl‐N‐ nitrosobenzenesulfonamide (CF3N(NO)SO2Ph) 301 N‐trifluoromethyl‐N‐ nitrosotrifluoromethanesulfonamide (CF3N(NO) SO2CF3) 301 N‐(trifluoromethyl) phthalimide 387 N‐trifluoromethylthioaniline  389, 432 N‐(trifluoromethylthio)‐ bis(phenylsulfonyl) imide 329–330

N‐trifluoromethylthio‐ dibenzenesulfonimide 344, 383–384 N‐trifluoromethylthiodibenzenesulfonimide (PhSO2)2NSCF3 425 N‐trifluoromethylthio‐4‐ nitrophthalimide 421 N‐(trifluoromethylthio) phthalimide  321, 323, 353, 419, 437 N‐trifluoromethylthiosaccharin 320, 328, 344, 383, 387, 423 N‐trifluoromethylthiosuccinimide 322, 345, 419, 423 N‐trimethylsilyl‐ bis(trifluoromethanesulfonyl) imide (TMSNTf2) 245 nucleophilic difluoroalkylation BrCF2CO2Et and BrCF2CH=CH2 89 silanes 94 XCF2PO(OEt)2 90 XCF2SO2Ar 90–93 nucleophilic difluoromethylation  737 cadmium, copper and zinc reagents 90 miscellaneous reagents  96 PhSO2CF2Br 92 PhSO2CF2CO2K 93 PhSO2CF2H 90–92 PhSO(NTBS)CF2H 96 reagents 94 sulfoximine reagent  96 TMSCF2H 94 nucleophilic fluorination  274, 279, 739, 770 pre‐existing ring system  138, 140–142 nucleophilic monofluoromethylation CH2FI 124 2‐fluoro‐1,3‐benzodithiole‐1,1,3,3‐ tetraoxide 123 fluorobis(phenylsulfonyl) methane 121–122 fluoromalonates 119 fluoromethyl phenyl sulfone 119–120

Index

2‐fluoro‐2‐sulfonylketone 122 monofluoromethyl phosphonium salts 124 PhSO(NTBS)CH2F 123–124 TMSCF(SO2Ph)2 (TFBSM)  123 nucleophilic trifluoromethoxylation alkyl alcohols  259–260 alkyl electrophiles  258 nucleophilic trifluoromethylation  295 CF3Se moiety  694 N‐CF3 motif  750 nucleophilic trifluoromethylthiolating reagent 381 nucleophilic trifluoromethylthiolation 378 cesium trifluoromethylthiolate  434 copper trifluoromethylthiolate  437–439 reaction with bis(trifluoromethylthio) mercury Hg(SCF3)2 434 reaction with other nucleophilic SCF3 reagents 439–443 silver trifluoromethylthiolate  435–437 nucleophilic trifluoromethylthiolation reagents 2,2’‐bipyridine copper trifluoromethylthiolate ((bpy) CuSCF3) 313–314 bis‐(trifluoromethylthio) mercury [Hg(SCF3)2] 309–310 cesium trifluoromethylthiolates (CsSCF3) 315 copper trifluoromethylthiolate (CuSCF3) 312–313 silver trifluoromethylthiolate (AgSCF3) 311–312 tetramethylammonium (Me4NSCF3) 315–316

o O‐benzoyl oximes  410 OCFHCH3 group  267, 285 OCF2H group decarboxylative fluorination  272 difluorocarbene into O–H bond 269–272

difluoromethoxylation 273–274 direct electrophilic difluoromethylation 272–273 fluorination 278–280 monofluoromethylation 275–278 nucleophilic fluorination  274 OCF3 motif decarboxylative fluorination 199–200 direct trifluoromethylation 200–202 fluoroformates 198 indirect construction of  198 intramolecular OCF3 migration 202–203 oxidative fluorodesulfurization  198 trifluoromethyl ethers  197–198 OCH2CF3 group trifluoroethoxylation 281–283 trifluoroethylation 283–295 O‐octadecyl‐S‐ trifluorothiolcarbonate 442 optically active diethyl N‐(p‐ toluenesulfonyl)‐aziridine 2‐ phosphonates 790 orally available tissue‐selective androgen receptor modulator 752 organofluorine fragment  654 organometallic trifluoromethoxides 217–219 organophotocatalyst 4CzIPN and BINOL‐based phosphorothiols 413 ortho‐alkynyl functionalized aryl compounds 709 ortho‐lithiation of triflylarenes 509 ortho‐substituted–SCF3 arenes  483 O‐SCF3 reagents in direct C(sp3)–SCF3 bond formation reactions  428 O‐tosyl α‐(phenylsulfonyl) difluoromethyl alcohols  526 O‐triflyl‐2‐(trimethylsilyl)phenols 507 o‐(trimethylsilyl)aryl triflates  349 oxidation of SF5‐aromatics 606

829

830

Index

oxidative desulfurization–fluorination of dithiocarbamates  741–742 of dithiocarbamoyl disulfides 739–740 oxidative difluoromethylation phenanthridines 22 1,10‐phenanthrolines 22 oxidative fluorodesulfurization method 198 oxidative radical intermolecular phosphonotri fluoromethylthiolation 409 oxidative radical intermolecular trifluoromethylthioarylation of styrenes 406 oxindole compounds  415 oxindole‐derived alkenes  381 oxodifluoroalkylation, BrCF2CO2Et 105 oxytrifluoromethylthiolation of α‐diazoketones 427 of alkylsilanes  411 ozone depletion chemical  300 ozone depletion potential (ODP)  728

p palladium‐catalyzed cross‐coupling α,α‐difluoroketones 38 bromides with difluoroenol silyl 37 bromodifluoroacetamides 31 bromodifluoroacetate 31 palladium‐catalyzed decarbonylative difluoromethylation, (DMPU)2Zn(CF2H)2 7 palladium‐catalyzed difluoroacetylation, aryl bromides/triflates  31 palladium‐catalyzed difluoromethylation arylboronic 19 aryl zinc reagents  19 bromodifluoroacetate via a difluorocarbene pathway  8–9 (SIPr)Ag(CF2H) 6 TMSCF2H 7 (TMEDA)Zn(CF2H)2 8

palladium‐catalyzed difunctionalization, alkene 255 palladium‐catalyzed phosphonyldifluoromethylation bromodifluorophosphonate 27 difluorophosphonyl copper reagents 28 p‐(chlorophenyl) derivative  500 Pd‐catalyzed asymmetric Tsuji decarboxylative allylic alkylation 454 Pd‐catalyzed hydrodeoxygenation of phenols 665 Pd(II)‐catalyzed oxidative trifluoromethoxylation, alkenes 252–255 pentafluorosulfanyl (SF5) aliphatic 571–606 aromatics elemental fluorine  554–558 silver difluoride (AgF2) 552–554 xenon difluoride  554 hereroaromatics arylsulfurchlorotetra fluorides 558–565 cis‐isomer 558 2‐fluoro‐1‐(pentafluorosulfanyl) benzene 569 iodine pentafluoride  565 1‐(pentafluorosulfanyl) naphthalenes 569 2‐(pentafluorosulfanyl)pyridines 553, 562 pentafluorosulfanyl‐tetrafluoroethyl derivatives (SF5CF2CF2X) 599–601 perfluoroalkylated sulfoximines  675, 680 perfluoroalkyl iodides (PFAIs)  11, 793 perfluoroalkyl phosphonic and phosphinic acids  765, 792–793 perfluoroalkylsulfurane 219 perfluoroalkylsulfurane oxide 219–220

Index

perhalogenated 3‐dithietanes  1, 502, 505 pharmaceutically important trifluoromethionine 298 phase‐transfer catalyst (PTC)  145, 202, 302, 423 9,10‐phenanthrenequinone (PQ)  5 phenylsulfonyl difluoroacetate salt  93 (phenylsulfonyl)difluoromethyl boronic acid 537–538 phenyl‐tetrazole (PT)  132 phenylthiodifluoromethyltrimethylsilane (PhSCF2TMS) 95 phenyl triazolinone derivatives  726 4‐(phosphonodifluoromethyl)‐l‐ phenylalanine (F2Pmp) 788 phosphonotrifluoromethylthiolation of unactivated alkenes  409, 410 phosphorous‐based fluoromethylating reagents 770–785 phosphorus‐containing reagents 103–104 photocatalyzed cyanodifluoromethylation of alkenes 61–62 photochemical radical trifluoromethylthiolation under UV irradiation  403–405 photoredox catalysis (PC)  16, 49, 56, 71, 104–106, 108, 110, 128, 130, 269, 391, 413, 454, 514, 515, 675 photoredox‐mediated intramolecular carbotrifluoromethylthiolation reaction 416 PI3 Kinase inhibitor  752 Plausible reaction mechanism  79 polar hydrophobicity  612 polyfluoroalkoxylated (hetero) arene 234 polyhalogenalkyl thioethers, fluorination of  292–293 polysulfonates 641–643 (poly‐triflyl)alkanes 519 potassium bis(triflyl)methide  517 P–Rf‐containing molecules

achiral fluoro‐organophosphines  766 BrCF2P(O)(OR)2 774 chiral fluoro‐organophosphines  766–770 difluoromethylated aminophosphonate derivatives 787–788 fluorophosphonium and fluoroalkylphosphonium cations 793–801 HCF2P(O)(OR)2 773 monofluoroalkylated aminophosphonate derivatives 788–792 monofluoromethyl phosphonates 770–772 perfluoroalkyl phosphonic and phosphinic acids  792–793 [Ph3P+CF2CO2–] 779–784 [Ph3PCF2X]+ Y– (X = H, Cl, Br, I; Y = Cl, Br, I, OTf )  779–784 TMSCF2P(O)(OR)2 777–779 trifluoromethylated aminophosphonate derivatives 785–787 trifluoromethylphosphonate reagents 784–785 propiolic acids  392, 393, 397, 408 protein tyrosine phosphate (PTPase) 23 P‐stereogenic ferrocene‐derived (trifluoromethyl) phosphanes 768 p‐toluenesulfonyl azide (TsN3) 750 pyrazole triflones  513 pyrazolin‐5‐ones 368 pyridine‐methyl‐ dithiocarbamate 741 pyridine‐oxazoline (Pyox) ligand 254 pyridinium chlorochromate (PCC)  70, 586

831

832

Index

pyridinyl‐and thionyl‐based fluorosulfates 631 pyridin‐2‐yl fluorosulfates  631

q

quaternary α‐chloro‐α‐ trifluoromethylthiolated aldehydes 423

r radical  3, 11, 16–23, 31, 39, 47, 56, 59, 69, 73, 75, 76, 101–112, 128, 147, 184, 185, 208, 214, 231, 233, 234, 238–248, 251, 260, 272, 298–302, 391–398, 498, 577–580 radical C–H bond difluoromethylation 19–22 radical difluoromethylation heteroarenes with ArI(OCOCF2H)2 21 heteroarenes with HCF2COOH 22 heteroarenes with Zn(SO2CF2H)2 21 radical monofluoromethylation  128–130 radical photocatalytic oxytrifluoromethylthiolation of styrenes 416 radical trifluoromethylation  743 CF3Se moiety  693–713 radical trifluoromethylselenolation 712–713 radical trifluoromethylthiolation with the aid of anionic SCF3 reagents 405–411 methods 391 processes 396 radical trifluoromethoxylation, alkenes 251–252 Ramachary–Bressy–Wang enamine [3+2] cycloaddition  751 (R)‐2,2’‐binaphthol 766 reagents for trifluoromethylthiolation 369 regioselective o,o’‐(bis) trifluoromethylthiolated products 345 reticulated vitreous carbon (RVC)  64

Rh‐catalyzed trifluoromethylthiolation 359 ring‐closing trifluoromethylthiolation 411 R3N+CF2H ammoniums  736 Ru(bpy)3Cl2/TEA 298 Ru(bpy)3Cl2/TMEDA 298 Ruppert–Prakash reagent  145, 169–182, 187, 202, 364, 376, 381, 419, 477, 478, 579, 640, 641, 679, 694, 697, 701, 706, 737, 743, 749, 750

s S‐alkyl S‐phenyl tosylsulfoximines  680 Sandmeyer‐type trifluoromethylthiolation reaction 348 S–aryl sulfoximines  681 S‐(bromodifluoromethyl) diarylsulfonium salts  97 SCF2CO2Et‐containing electron rich (hetero)arenes and ketones  471 SCF2CO2Et cysteine analog  469 SCF3‐containing compounds  291 SCF3‐containing spirocyclopentanone– thiochromanes 322 SCF2H moiety, direct formation of C‐SCF2H bond  453–462 SCF2PO(OEt)2‐containing alkynes  466 SCF3‐substituted alkenes and alkynes electrophilic trifluoromethylthiolation  381–391 via manipulation of SCF3‐containing building blocks  374–376 nucleophilic trifluoromethylthiolation  377–381 radical trifluoromethylthiolation methods 391–398 via S‐trifluoromethylation 376–377 SCF3‐substituted allenes via nucleophilic trifluoromethylation 376 SCF3‐substituted pyrrolidines and piperidines 428 Schotten–Baumann reaction  590 Schwesinger’s superbase (t‐BuP4)  496

Index

S‐(difluoromethyl) benzenesulfonothioate 460 S‐(difluoromethyl)diarylsulfonium tetrafluoroborate reagent  733 SF5‐acetylene 602–605 SF5CF2CF2Br α,β‐unsaturated ketones  601 cycloalkadienes 601 SF4CF3 derivatives aliphatic and olefinic  614 13 C NMR chemical shifts  613 inductive effect  612 S‐(fluoromethyl) benzenesulfonothioate 463 Shen–Lu reagent  319–321, 428 Shen reagent  328–329 Shen’s trifluoromethylsulfenate reagent 431 Shibata’s reagent  331, 333, 334 Shibata’s trifluoromethylsulfonyl hypervalent iodonium ylide reagent  382, 383, 387 Sildenafil  282, 743 silicon‐mediated aldol condensations, of octyl SF5‐acetate with electron‐ rich benzaldehydes  596 silicon‐mediated Mukaiyama aldol reactions, of octyl SF5‐acetate with aldehydes  596 silver(I)‐catalyzed trifluoromethoxylation of alkenes 255 silver difluoride (AgF2) arylsulfur pentafluorides  554 diphenyl disulfide  552 1‐nitro‐3,5‐bis(pentafluorosulfanyl) benzene  552, 553 1‐nitro‐3‐(pentafluorosulfanyl) benzenes 553 nitro‐substituted diphenyl disulfides 552 2‐(pentafluorosulfanyl)pyridine 553 silver(I) trifluoromethylthiolate (AgSCF3)  311, 406, 433, 435 single electron transfer (SET)  11, 147, 213, 231, 239, 269, 383, 391, 397, 411, 512, 527, 696, 728

(SIPr)Ag(SCF2H) 453 S‐(monofluoromethyl)diarylsulfonium tetrafluoroborate 125–126 (1S)‐(–)‐N‐trifluoromethylthio‐2,10‐ camphorsultam  331, 428 sodium 2‐(4‐bromophenyl)‐1,1‐ difluoroethanesulfinate 49 sodium chlorodifluoroacetate (SCDA)  150, 187, 728, 730 sodium perfluoroalkanesulfinates (RfSO2Na) 360 sodium sulfonates  320 sodium triflinate  413, 487, 488, 508, 510, 695, 696, 743 sodium trifluoromethanesulfonate (CF3SO2Na) 334 sodium trifluoromethylsulfinate  507, 510, 695 Sonogashira reactions  660, 661 S‐((phenylsulfonyl)difluoromethyl) thiophenium salts  100–101 S–RF sulfoximines fluorination of S–alkyl sulfoximines 679–680 by imination of sulfoxides  680–682 isolation of S–RF sulfilimines and 686–688 by oxidation of sulfilimines 682–683 post functionalization  688 Stille coupling with vinyl tin reagents 660 S‐(trifluoromethyl) benzenesulfonothioate (PhSO2SCF3) 415 structure‐activity relationship (SAR) 248 3‐substitued silyl aryl triflates  349 substituted N‐CF3 triazoles  751 sulfenamide N‐SCF3 reagent  346 sulfentrazone  726, 728 (phosphadifluoromethyl)sulfinyl indoles 504 sulfonamides  643, 646 sulfonylimidazolium bifluoride product  646, 647

833

834

Index

sulfonyl oxygen–LA interactions  622 sulfuramidimoyl fluorides  669 sulfur‐fluoride exchange (SuFEx)  622, 623, 636, 638, 639, 641–643, 646–650, 665–669 aryl sulfonyl fluorides  623 fluorosulfates 665 N‐acyltyrosine 622 nucleophilic addition/elimination mechanism 621–622 p‐NO2 phenyl sulfonyl fluoride  622 polysulfonates 642–643 sulfonamides 643–647 sulfones 638–641 sulfonic esters  641–643 sulfur (VI) fluorides cross‐coupling reactions, SO2F group 649–654 fluorine and sulfur sources  626–630 fluorosulfates  630–636, 656–668 naked method  624 organofluorine chemistry  654–656 potassium bifluoride approach  624 properties and reactivity of 621–623 in situ sulfonyl chloride formation 625–626 sulfamoyl fluorides  630–636 sulfuramidimoyl fluorides  669 tandem organic reactions  647 sulfur hexafluoride (SF6)  571, 611

t telcagepant 752 temperature‐sensitive trifluoromethoxylating reagent 229 terbinafine 743 terminal alkynes  97, 320, 381, 387–390, 394, 455, 461, 480, 510, 663, 701, 711, 778, 782 tetraalkyl fluoromethylene bisphosphonates [(RO)2P(O)]2CHF 772 tetrabutylammonium fluoride (TBAF)  296, 302, 536, 626, 655, 679, 771

tetrabutylammonium triphenyldifluorosilicate (TBAT)  171, 221, 297 tetrakis(diethylamino)ethylene (TDAE) 500 tetrakis(dimethylamino)ethylene (TDAE)  92, 297, 571, 695, 707 1,1,3,3‐(tetrakistrifluoromethanesulfonyl)propane 519 1‐tetralone 459 tetramethylammonium (Me4NSCF3)  94, 259, 315–316, 381, 441, 701–705 tetramethylammonium trifluoromethylselenolate (Me4NSeCF3) 701–705 2,2,6,6‐tetramethylpiperidine‐N‐oxyl (TEMPO) 230 2,2,6,6‐tetramethylpiperidin‐1‐oxyl (TEMPO) 62 tetra‐n‐butylammonium bromide (TBABr) 391 thermally stable N‐heterocyclic carbene Ag(CF2H) complexes  737 thiocarbamoyl fluoride  740, 742–743 ((2‐phenylpropan‐2‐yl)oxy) (trifluoromethyl) thioether 320–321 thiolates/thiols, electrophilic trifluoromethylation of 293–294 TiCl4‐mediated aldol condensations, of ethyl SF5‐acetate 597 TiCl4‐mediated aldol reactions, of methyl SF5‐acetate 597 Togni reagents  202, 231, 294, 387, 749 toltrazuril  291, 449 toxic trifluoromethanethiol (CF3SH) 404 transition‐metal catalyzed difluoroacetylation 26–33 transition‐metal‐catalyzed/mediated monofluoromethylation CH2FBr 131 CH2FI 130–131

Index

PhSO2CHFI 131 PTSO2CH2F 132 transition‐metal catalyzed phosphonyldifluoromethylation 23–26 transition‐metal catalyzed radical difluoromethylation 11–19 transition‐metal‐catalyzed reactions 252 transition‐metal‐free oxidative (phenylsulfonyl) difluoromethylation 526 1,2,3‐triazole based sulfonamides 646 trichloroacetonitrile (Cl3CCN) 626 trichloroisocyanuric acid (TCICA)  565, 626 2,4,6‐trichloro‐1,3,5‐triazine (TCT cyanuric chloride)  754 triethylamine  298, 591, 643, 662, 663 triethylborane‐mediated radical pentafluorosulfanylation  577–580 triflinyl heteroarenes  485, 487–489 trifluoroacetaldehyde  297, 753, 754 trifluoroacetate salts  295 trifluoroalkylation 659 2,2,2‐trifluorodiazoethane 755 trifluoroethoxylation  267, 280–283, 285 trifluoroethylamine 752–755 2,2,2‐trifluoroethylamine 752–755 trifluoroethylation 283–284 trifluoromethanesulfenamide (CF3SNH2) 317 trifluoromethanesulfenyl acetate (CH3CO2SCF3) 318 trifluoromethanesulfenyl chloride (CF3SCl)  317–318, 404 trifluoromethanesulfenyl trifluoroacetate (CF3CO2SCF3) 318 trifluoromethanesulfinamides 297 trifluoromethanesulfinyl chloride (CF3SOCl)  335, 336, 457, 485, 488, 490 trifluoromethanesulfinyl furan  487 trifluoromethanesulfone (triflone)  675

trifluoromethanesulfonyl chloride (CF3SO2Cl)  334, 432 trifluoromethanesulfonyl diazo reagent 432 trifluoromethanesulfonyl hypervalent iodonium ylide  353, 358, 359, 431–432 trifluoromethoxylated (hetero) arenes 227 trifluoromethoxylated aromatics  225 trifluoromethoxylation alkyl alcohols and alkyl silanes  259 alkyl halides and alkyl triflates  258 α‐diazo esters  263–264 C–H bonds  260–262 of epoxides, nucleophilic  262–263 trifluoromethyl arylsulfonate (TFMS)  237, 238, 255 trifluoromethylated α‐and β‐ aminophosphonates  785–786 trifluoromethylated aminophosphonate derivatives 785–787 trifluoromethylated and trifluoromethylthiolated compounds 353 trifluoromethylated Barton ester 303 trifluoromethylating agents  215, 301 trifluoromethylation of thiones/ thioureas 302–303 trifluoromethylation of thiorenes  302 trifluoromethylation reagent  94, 200, 202, 272, 281, 360, 419, 681, 749 trifluoromethylazosulfonylarenes (CF3N2SO2Ar)  301, 505 trifluoromethyl benzoate (TFBz)  222–223, 234, 236, 237 trifluoromethyl diethylaminosulfur difluoride (CF3‐DAST) 432–433 trifluoromethyl ethers, fluorination 197–198 trifluoromethylphosphonate reagents  765, 784–785 trifluoromethylselenocyanate (CF3SeCN) 708

835

836

Index

trifluoromethylselenoisocyanate (CF3SeNCO) 708 trifluoromethylselenolated α,β‐ unsaturated carbonyl compounds 701 trifluoromethylselenolated alkynes 709 trifluoromethylselenolated benzofuranes 709 trifluoromethylselenotoluene sulfonate (CF3SeTs)  707, 710–711 trifluoromethylsulfinyl (triflinyl) arenes 478 trifluoromethyl sulfonates (TFMS) 221 trifluoromethyl sulfones [RSO2CF3] alkyl triflones  514–517 alkynyl 510 aryl triflones  505–508 heteroaryl triflones  513–514 trifluoromethyl sulfoxides [RS(O)CF3] alkyl trifluoromethyl (or perfluoroalkyl) sulfoxides 489–492 aryl trifluoromethyl sulfoxides 478–484 heteroaryl trifluoromethyl sulfoxides 484–489 trifluoromethylthioarenes 612 trifluoromethylthio lactonization/ lactamization of alkenes  425 trifluoromethylthiolated alkenes  330, 373–398 trifluoromethylthiolated alkynes  381, 387, 391, 396 trifluoromethylthiolated aromatics  368, 373 3‐trifluoromethylthiolated coumarin derivatives 394 trifluoromethylthiolated dithioketals 423 trifluoromethylthiolated functionalized heterocycles 407 trifluoromethylthiolated 2H‐chromenes 381 trifluoromethylthiolated indenones 394

trifluoromethylthiolated oxindoles  416 trifluoromethylthiolated tetrahydronaphthalene skeletons 428 trifluoromethylthiolation/cyclization process 415 trifluoromethylthiolation of α‐diazo esters 441 trifluoromethylthiolation/semi‐pinacol‐ type rearrangement sequence  416, 419 trifluoromethyl trifluoromethanesulfonate (TFMT) 215–217 trifluoromethyltrimethylsilane (TMSCF3)  94, 295, 737 2‐triflyl benzothiazole  513 trihalomethyl anions CF2X–(X = Cl, Br) 145 trimethylsilyl fluorosulfonyldifluoroacetate (TFDA)  655, 732 difluorocarbene from  156 NaF system  156 trimethylsilyltriflate (TMSOTf )  591 trimethylsilyl trifluoromethanesulfonate (TMSOTf ) 415 triphenylphospine‐mediated deoxygenative reduction process 356 tris(perfluoroalkyl) difluorophosphoranes 793 tris(pentafluorophenyl)‐ phosphine 766 tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF)  164, 296, 478, 640, 679 tris(dimethylamino)sulfonium trifluoromethoxide  215, 228 2,4,6‐tris(2,2,2‐trifluoroethoxy)‐1,3,5‐ triazine (TTFET)  754

u Ugi’s ferrocene amine  768 Umemoto reagents  200, 293, 294 Umemoto’s synthesis of SF5 arenes  615

Index

Umemoto‐type diaryl difluoromethyl sulfonium salts  496 unactivated alkenes  105, 108, 112, 409, 412, 413, 458 unactivated internal olefins  428 unsymmetrical diaryl S‐ (bromodifluoromethyl) sulfonium salts  499 UV‐light‐initiated method  278

v vaniliprole 291 vicinal difunctionalized o‐trifluoromethylthiolated iodoarenes 349 Vilsmeier–Haack formylation  182 vinyl boronic acids  387 visible light‐mediated process  391

visible‐light promoted decarboxylative trifluoromethylthiolation 411, 412 visible‐light promoted hydrogen atom transfer HAT‐catalyzed trifluoromethylthiolation  413

w weak base NaOAc mediated reaction 348 Wittig olefination approach  376 Wurtz reaction  138

x XCF2SO2Ar 90–93

z zinc difluoromethylsulfinate  49

837