[1st Edition] 9780128121863, 9780128120835

Table of contents :
Content:
CopyrightPage iv
DedicationPage v
ContributorsPages ix-x
PrefacePage xiPedro J. Pérez
Chapter One - Group 6 Metal Fischer Carbene Complexes: Versatile Synthetic Building BlocksPages 1-150José Barluenga, Enrique Aguilar
Chapter Two - Recent Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions With N-TosylhydrazonesPages 151-219Di Qiu, Fanyang Mo, Yan Zhang, Jianbo Wang
Chapter Three - Oxidative Functionalization of Late Transition Metal–Carbon BondsPages 221-297Anna V. Sberegaeva, David Watts, Andrei N. Vedernikov
Chapter Four - Biaryl Synthesis via C–H Bond Activation: Strategies and MethodsPages 299-399Marco Simonetti, Diego M. Cannas, Igor Larrosa
Chapter Five - Carbon–Nitrogen Bond Formation Through Cross-Dehydrogenative Coupling ReactionsPages 401-481Mattijs Baeten, Bert U.W. Maes
IndexPages 483-495

Citation preview

Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 125 London Wall, London, EC2Y 5AS, United Kingdom First edition 2017 Copyright © 2017 Elsevier Inc. All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-812083-5 ISSN: 0065-3055 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Zoe Kruze Acquisition Editor: Kirsten Shankland Editorial Project Manager: Shellie Bryant Production Project Manager: James Selvam Cover Designer: Christian J. Bilbow Typeset by SPi Global, India

DEDICATION To the memory of Prof. Jose Barluenga (1940–2016), a pillar of the foundation of modern chemistry in Spain. A man, a giant.

v

CONTRIBUTORS Enrique Aguilar Universidad de Oviedo, Oviedo, Spain Mattijs Baeten University of Antwerp, Antwerp, Belgium Jose Barluenga Universidad de Oviedo, Oviedo, Spain Diego M. Cannas School of Chemistry, University of Manchester, Manchester, United Kingdom Igor Larrosa School of Chemistry, University of Manchester, Manchester, United Kingdom Bert U.W. Maes University of Antwerp, Antwerp, Belgium Fanyang Mo Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry; College of Engineering, Peking University, Beijing, China Di Qiu Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing; College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin, China Anna V. Sberegaeva Board on Chemical Sciences and Technology, National Academies of Sciences, Engineering, and Medicine, Washington, DC, United States Marco Simonetti School of Chemistry, University of Manchester, Manchester, United Kingdom Andrei N. Vedernikov University of Maryland, College Park, MD, United States Jianbo Wang Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, China David Watts University of Maryland, College Park, MD, United States

ix

x

Contributors

Yan Zhang Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, China

PREFACE We start a new year for this series of Advances in Organometallic Chemistry with the first volume in 2017, where experts from several areas have prepared five chapters accounting for the use of organometallic species toward practical synthesis. The first chapter corresponds to an invitation to Prof. Barluenga about a year ago. Sadly for the organometallic community, Prof. Barluenga passed away last September 2016. In this chapter, coauthored with Aguilar, a comprehensive update of the use of group 6 Fisher carbene complexes in organic synthesis is provided. N-Tosylhydrazones as carbene source and their use in transition-metalcatalyzed cross-coupling reactions has emerged in the last decade as a synthetic tool. Wang and coworkers have reviewed this area in Chapter 2, according to the nature of the metal center employed in the different catalytic systems described to date. Vedernikov and coworkers have focused in Chapter 3 on a not less important transformation: the oxidative reaction of late transition metal– carbon bonds. With no doubt, this functionalization yet constitutes an area of interest that in spite of decades of study still originates excellent findings year after year. The last two chapters are directed toward one of the probably hottest topic nowadays: the metal-catalyzed coupling reaction, particularly with arylcontaining substrates. Chapter 4 by Larrosa and coworkers are devoted to biaryl formation, whereas in Chapter 5 Maes and coworker focus onto carbon–nitrogen bond formation by means of that strategy. I would like to acknowledge all the authors for having provided such an excellent amount of literature accounted for the always exigent reader of this series. Not less important is the role of the editorial team, Shellie Bryant and James Selvam; without their input, none of this would have been possible. PEDRO J. PEREZ

xi

CHAPTER ONE

Group 6 Metal Fischer Carbene Complexes: Versatile Synthetic Building Blocks
Barluenga, Enrique Aguilar1 Jose Universidad de Oviedo, Oviedo, Spain 1 Corresponding author: e-mail address: [email protected]

We both initiated the preparation and the writing of this review on January 2016, upon Prof. Barluenga received an invitation by Prof. Pedro P
erez. Prof. Barluenga passed away on September 07, 2016.1 This manuscript is dedicated to honor his memory.

Contents 1. 2. 3. 4.

Introduction Synthesis of Group 6 Metal Carbene Complexes Release of the Organic Moiety on FCCs Applications of Alkyl Carbene Complexes in Organic Synthesis (and of Other Carbene Complexes in Reactions Where Only the Carbene Carbon Is Involved) 4.1 Synthesis of Acyclic Compounds 4.2 Synthesis of Three-Membered Carbocycles 4.3 Synthesis of Four-Membered Carbocycles 4.4 Synthesis of Five-Membered Carbocycles 4.5 Synthesis of Six-Membered Carbocycles 4.6 Synthesis of Seven-Membered Carbocycles 4.7 Synthesis of Heterocycles 5. Applications of Alkenyl and Aryl Carbene Complexes 5.1 Synthesis of Acyclic Compounds 5.2 Synthesis of Three-Membered Carbocycles 5.3 Synthesis of Five-Membered Carbocycles 5.4 Synthesis of Six-Membered Carbocycles 5.5 Synthesis of Seven-Membered Carbocycles 5.6 Synthesis of N-Heterocycles 5.7 Synthesis of O-Heterocycles 6. Applications of Alkynyl Carbene Complexes 6.1 Synthesis of Acyclic Compounds 6.2 Synthesis of Four-Membered Carbocycles 6.3 Synthesis of Five-Membered Carbocycles 6.4 Synthesis of Six-Membered Carbocycles Advances in Organometallic Chemistry, Volume 67 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2017.04.001

#

2017 Elsevier Inc. All rights reserved.

2 6 11 13 13 16 20 22 27 29 32 39 40 45 47 54 60 64 70 72 73 74 75 80

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Jos
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6.5 Synthesis of Seven- and Eight-Membered Carbocycles 6.6 Synthesis of Five-Membered N-Heterocycles 6.7 Synthesis of Six-Membered N-Heterocycles 6.8 Synthesis of Seven-Membered N-Heterocycles 7. Nonheteroatom-Stabilized Carbene Complexes (NHSCCs) 7.1 Synthesis of Nonheteroatom-Stabilized FCCs 7.2 Early Chemistry of NHSCCs: Cyclopropanation and Metathesis 7.3 Applications of Alkynyl NHSCCs as Stoichiometric Reagents in Organic Synthesis 7.4 Stoichiometric or Catalytic Transformations Involving NHSCCs as Intermediates Synthesized From M(CO)5L and Conjugated Dienynes or Heterodienynes 8. Conclusions, Summary and Outlook Acknowledgments References

85 87 90 93 95 96 102 107

113 128 131 131

1. INTRODUCTION The concept carbene complex denominates the organometallic species resultant from the formal combination of a carbene and a metallic fragment. The stability of a carbene complex depends on many factors: the metal, its oxidation state, the substituents at the carbene carbon, other ligands attached to the metal … Indeed, some carbene complexes are stable at room temperature and have been synthesized, isolated, and employed as reagents or catalysts in many synthetic transformations; on the other hand, some other, less stable, have been just proposed, detected or, sometimes, even isolated as synthetic intermediates. Group 6 metal carbene complexes are typically divided into two major categories: (a) Schrock-type carbene complexes or Schrock carbenes.2 The major features of these carbenes are: (i) the metal is in high oxidation state, (ii) they are nucleophilic in nature (the carbon atom of the carbene possesses negative charge), and (iii) they have a relatively short bond distance between the metal and the carbene carbon. The most relevant carbene complexes of this type are Mo(VI)- or W(VI)-based carbenes 1 (Fig. 1). Particularly, molybdenum alkylidenes are very powerful olefin metathesis catalysts, even though their sensitivity to air and moisture forces to their handling under glove-box or strict Schlenk techniques. They are usually referred as Schrock catalysts or Schrock alkylidenes and, some of them are widely employed and commercially available (i.e., Schrock catalyst or Schrock–Hoveyda catalyst).

3

Group 6 Metal Fischer Carbene Complexes

X Y

H

M

XR2 (CO)5M

R1

Z

1

R1

2

Schrock carbenes M = Mo, W

Fischer carbenes M = Cr, Mo, W

X = NR2

X = O, N, S

Y = OR3, NR3R4

R1 = alkyl, alkenyl, alkynyl, aryl

Z = alkyl, OR3, NR3R4

R2 = alkyl, aryl, alkanoyl

R1 = alkyl, aryl R2 = alkyl, aryl R3, R4 = alkyl, aryl

Fig. 1 Group 6 metal carbene complexes: general structure and representative examples.

(b) Fischer-type carbene complexes or Fischer carbenes.3 In contrast, for this type of carbene complexes the metal is in low oxidation state [usually they are metal(0) complexes], and the pair of electrons in the π-bonding MO resides mainly on the metal. This, along with the electronegative nature of the X substituent, has the effect of generating a positive charge on the carbon atom and, as a result, they are: (i) electrophilic in nature and (ii) stabilized due to the presence of an electron-donating heteroatom linked to the carbene carbon (2, Fig. 1). The general formulae for Schrock and Fischer carbene complexes (FCCs) are depicted in Fig. 1. Group 6 metal FCCs are the highly valuable reagents in synthetic organic chemistry, probably due to the following reasons: – They are relatively stable organometallic compounds, and in general, their purification and manipulation are rather easy. – They can be prepared in multigram scale and can be stored under inert atmosphere for several months. – The strongly electron-withdrawing pentacarbonylmetal group allows a variety of reactivity patterns, which lead to the construction of a large variety of highly functionalized structures in a regio- and stereoselective manner. Indeed, de Meijere coined the expression “chemical multitalents” to label these versatile complexes.4 Additionally, the metal fragment can be easily removed. – The possibility of placing chiral auxialiaries in different points of the molecule makes FCCs as suitable starting materials for diastereo- and enantioselective synthesis.

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Jos
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Although they have been occasionally proposed as reactive intermediates in catalytic cycles,5 they are usually employed as stoichiometric reagents, probably due to the above-mentioned stability provided by the electrondonating heteroatom. In this sense, chromium complexes have found, by far, the broadest application of group 6 FCCs probably due to their balance of reactivity and stability combined with easy accessibility; moreover, tungsten carbene complexes are usually more stable while molybdenum complexes are more reactive than their chromium analogs. An additional reason may lay in the fact that chromium carbene complexes are more prone toward the insertion of a CO ligand than their tungsten or molybdenum analogs, due mainly to the differences in metal–CO strength through backbonding.6 As a consequence, depending both on their counterparts and on the reaction conditions, the modes of reactivity offered may be either similar or complementary. Stabilization to FCCs is provided by the XR2 group, which most commonly is either an alkoxy or an amino group, and those carbene complexes are usually referred to as alkoxy- or aminocarbenes. There are also examples where acetoxy or thiol derivatives are the stabilizing moieties. Finally, although less frequent, metalloxy groups have also been employed to stabilize metal carbenes and, in this case, differential reactivity has been found.7 Alkoxy FCCs have been by far the most used among all these categories; therefore, for the purposes of this review, we will be referring to them when nothing else is specified. The electrophilicity displayed by FCCs may be evaluated considering the 13C NMR chemical shifts of the carbene carbon,8 as well as the high acidity of the H atoms in α-position to the carbene carbon.9 As shown in Fig. 2, the chemical shift of the carbene carbon decreases as the electron-donating ability of the substituents increases. Also in Fig. 2, the values of pKa of a chromium carbene complex and its analog ester are compared. In general, considering the reactive sites presented by group 6 metal carbene complexes D€ otz has established two major classes of reactions10: (i) those that involve the participation (cleavage) of the metal–carbene bond (metal-templated reactions) and (ii) those occurring at the carbene ligand while the metal–carbene bond remains intact (metal-assisted reactions). Additionally, a third group of transformations is also relevant; these are the ones related to classical coordination chemistry and involve ligand exchange between a carbonyl (or some other) ligand on the metal coordination sphere. Their special interest is based on the fact that many

5

Group 6 Metal Fischer Carbene Complexes

Me Ph

NMe2

OMe

Y

Y Ph

Ph

N Y

Y

N

Ph Me

Y = Cr(CO)5

399.4

352.0

275.6

Y = W(CO)5

357.9

323.9

−

Y=O

196.8

167.0 d (ppm)

170.7

OMe (CO)5Cr pKa (Hα)

206.6 (C6D6) 16.3

OMe O

Me 12.5

219.6 (C6D6)

Me 25

Fig. 2 Properties of carbene complexes vs nonmetallated analogs: shifts (CDCl3) and pKa (Hα).

13

C NMR chemical

metal-templated reactions are initiated by the dissociation of a carbonyl ligand followed by coordination of a new reagent or ligand. General reviews on the chemistry of FCCs have been published rather periodically, updating the knowledge in the field, either by us11 or by others.12 Additionally, we have also written specific reviews covering topics such as, for instance, the synthesis of heterocycles,13 multicomponent14 or cycloaddition reactions,15 or nucleophilic additions.16 On the other hand, other authors have also offered their own perspectives in the chemistry of FCCs, not only on synthetic topics17 attending either to the nature of the products formed (nitrogenated compounds,18 five-membered carbocycles,19 optically active molecules,20 and aromatic compounds21), the type of reactions involved (asymmetric synthesis,22 cyclization reactions,23 and cycloaddition reactions24), or the nature of the FCCs involved (polymetallic FCCs,25 metal glycosylidenes,26 chromium aminocarbene complexes,27 chromium cyclopropylcarbene complexes,28 nitrogen-ylide complexes,29 and imidazolidinone and oxazolidinone chelated carbene complexes30), but also as vehicles for new discoveries.31 Mechanistic32 and theoretical (physical chemistry,33 computational,34 …) reviews have also been published. The aim of this manuscript is to provide an updated, general, and comprehensive overview of the synthetic usefulness of FCCs. To this end, following this introduction, the first two sections of this manuscript will cover both the synthetic procedures employed to prepare different types of FCCs and the methods developed to remove the metal moiety. Then, the

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synthetic usefulness of FCCs will be properly discussed, and it has been organized attending to the nature of the starting carbene complex. Therefore, the subsequent three sections will be dedicated to: (i) alkyl, (ii) alkenyl and aryl, and (iii) alkynyl carbene complexes. Besides alkyl carbene complexes, the first one of these three headings will also include reactions where other FCCs display the same reactivity under the same reaction conditions; usually, they will be reactions that only involve the carbene carbon. Additionally, reactions which are specific for other types of FCCs but only involve the carbene carbon will be included in this section. However, those other reactions that are specific of either alkenyl or aryl FCCs (or both of them), because they involve the double bond or the aromatic ring, will be discussed in the second of those three sections. The same considerations will apply for alkynyl FCCs and the third of those headings. Additionally, specific subheadings have been established attending to the nature of the reaction products: acyclic compounds, carbocycles of different size, and finally, heterocycles, which have been organized according to the type of the heteroatom and to the size of the ring. Finally, the last section before the conclusions will cover the chemistry of nonheteroatom-stabilized carbene complexes (NHSCCs), and will include several subheadings outlining the synthesis of NHSCCs and its reactivity, mainly depending on the way they are generated. Along the whole manuscript, reaction mechanisms will not be discussed in depth in most cases; on the contrary, in general this will be presented in a rather concise manner, and therefore, in many occasions only the most relevant intermediates will be shown, or they will not be analyzed at all.

2. SYNTHESIS OF GROUP 6 METAL CARBENE COMPLEXES The original method (the “Fischer route”)3 is still the simplest and most general approach to Fischer-type metal complexes and it involves the sequential addition of a carbon nucleophile and a carbon electrophile across a metal-coordinated carbon monoxide ligand (Scheme 1, Via A). The carbon nucleophiles are usually organolithium reagents (alkyl-, aryl-, alkenyl-, or alkynyllithium derivatives) which add to hexacarbonyl group 6 metal complexes 3 to afford acyl metallates 4; then, in situ O-alkylation by hard alkylating reagents such as trialkyloxonium tetrafluoroborates,35 alkyl fluorosulfonates,36 or alkyl triflates37 leads to alkoxycarbene complexes 5 in yields typically ranging between 60% and 90%. Softer alkylating reagents, such as alkyl iodides, may be employed under phase transfer conditions.38

7

Group 6 Metal Fischer Carbene Complexes

Via A 1

M(CO)6

R Li

OLi

YR2

(CO)5M 4

3

50%−90%

R1

OR2 (CO)5M

5

Via C R1

R5ZH

ZR5 R34NBr

Via B

R2OH

+

O− NR34 (CO)5M

R4COX

−40°C R1 M = Cr, Mo, W 6 X = Cl, Br YR2 = R23OBF4, R2O3SCF3, R2O3SF,... Z = O, S, NH R1 = alkyl, alkenyl, alkynyl, aryl, R3Si

(CO)5M

O

O R4

(CO)5M

7

R5ZH

R1 8 30%−90%

R1

Scheme 1 Common approaches for the synthesis of group 6 metal FCCs.

In general, the major limitation offered by the Fischer route is related to the accessibility of both the organolithium reagent and the alkylating reagent. The preparation of FCCs with elaborated alkoxy groups requires increasing the nucleophilicity of the acyl metallate species, which may be accomplished by the exchange of the lithium cation by a tetraalkylammonium cation (Scheme 1, Via B). The ammonium acyl metallate 6 is then treated with acyl halides39 to form an acyloxycarbene 7 (unstable over
40°C), which upon addition of the appropriate nucleophile should generate the desired carbene complex.40 It is also possible to prepare amino- and thiocarbene complexes 8 by treatment of alkoxycarbene complexes with the appropriate amine or thiol (Scheme 1, Via C).41 Via A is used mainly for the preparation of alkyl, alkynyl, and aryl alkoxy carbene complexes. Alkoxy alkenyl FCCs can also be prepared by this route, although alternative procedures described below are more commonly used. Via B is used for the synthesis of FCCs bearing alkoxy groups derived from difficult-to-prepare triflates, and also for aminocarbene complexes. Alternatively, chromium alkoxy and amino FCCs, 9 and 10, can be synthesized by reacting sodium (or potassium) pentacarbonylchromate with an acyl halide42 or an amide43 (Hegedus–Semmelhack synthesis, Scheme 2); in the first case, the acylmetallate initially formed is alkylated at a later stage, while in the second case the tetrahedral intermediate is treated with trimethylsilyl chloride at low temperature. Alkenylcarbenes 12 have been prepared taking advantage of the strong acidity of the α-position in alkyl FCCs.44 This procedure is especially useful

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Jos
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O

Na2[Cr(CO)5]

R1

O

Cl

THF, −78°C

2 Na+

R1

Cl

Cr(CO)5

Me3OBF4 H2O, 4°C

O

K2[Cr(CO)5]

R1

O

NR22

THF, −78°C

R1

R1 = alkyl, alkenyl, aryl NR22 = NMe2, NEt2, NPh2, morpholine

2 K+ Cr(CO)5 NR22

Me3SiCl THF, −78°C

OMe (CO)5Cr 1

R 9 14%–65%

NR22 (CO)5Cr 10

R1

20%–93%

Scheme 2 Synthesis of FCCs from pentacarbonylchromates.

for alkoxy alkyl FCCs 11, bearing structurally complex and/or bulky alkoxy groups45; a condensation between FCC 11 and the aromatic aldehyde takes place under mild conditions but with long reaction times (Scheme 3, top). Special conditions are required with enolizable aldehydes; the aldol addition is best performed if the aliphatic aldehyde is precomplexed with a Lewis acid (SnCl4) and the elimination step is achieved by treating adducts 14 with mesyl chloride and triethylamine (Scheme 3, bottom).46 Alkoxy alkynyl FCCs 18 derived from bulky alcohols (either chiral or nonchiral) have been prepared from alkoxy FCCs 16 by addition of lithium alkoxy acetylides 17. The initially formed NHSCCs 19 evolve by 1,3-metal rearrangement into the reaction products. This approach may be applied to all three group 6 metals, including the much elusive molybdenum; it also works efficiently for enolizable carbene complexes (Scheme 4).47 Other strategy, especially useful for the synthesis of allenylidene and cyclic carbene complexes, has been developed taking advantage of the remarkable π-acid properties of pentacarbonyl metal complexes (OC)5ML 20. This type of complexes can be generated by the photochemical cleavage of one carbonyl ligand in hexacarbonylmetal(0) complexes in the presence of weakly coordinated ligands (such as tetrahydrofuran or triethylamine) (Scheme 5, top). For instance, methoxy alkenyl FCCs 22 are formed by photolysis of M(CO)6 (M ¼ Cr, W) in the presence of propargyl alcohols 21 in a methanol:THF solution.48 The proposed mechanism involves the photolytic elimination of one CO ligand and the rearrangement of η2-alkyne intermediate 23 into its η1-hydroxyvinylidene isomer 24. Then, loss of water should form allenylidene intermediate 25 which should be followed by the nucleophilic addition of the methanol to produce the final products (Scheme 5, bottom).

9

Group 6 Metal Fischer Carbene Complexes

OR2

R3CHO, NEt3 ClTMS, 20°C

OR2 (CO)5Cr

(CO)5Cr

12%−85% 11 R2OH = EtOH, menthol, 8-Ph-menthol 3 R = alkenyl, aryl, heteroaryl

(CO)5Cr

12

1) 1 equiv. n-BuLi, −78°C, Et2O 2) 2 equiv. R3CHO/Lewis acid, −78°C, 2 h OMe 3) H O (CO)5Cr 2

OMe OH

MsCl (2 equiv.) Et3N (2.2 equiv.) 0°C, CH2Cl2 (CO)5Cr

OMe

36%−72%

56%−84%

Me

R3

R3

R3 14

13 R3 = Me, n-Pr Lewis acid = AlCl3, TiCl4, SnCl4

15

Scheme 3 Synthesis of alkenyl FCCs by condensation with aldehydes.

OMe (CO)5M

+ R*O

Li

1) THF, −80°C 2) TMSOTf, −80°C 3) −80 to 25°C

OR* (CO)5M

65%−90%

R1 17

16

18

1) THF, −80°C 2) TMSOTf, −80°C

R1

3) −80 to 25°C − (CO)5M

(CO)5M OR*

•

R1

•

+ OR*

R1 19

M = Cr, Mo, W R1 = alkyl (2°), alkynyl, aryl R*OH = trans-2-phenylcyclohexanol, (−)-menthol, (−)-8-phenylmenthol

Scheme 4 Synthesis of alkoxy alkynyl FCCs via nonheteroatom-stabilized carbene complexes.

Other primary saturated and unsaturated alcohols have been employed instead of methanol. Higher yields are usually obtained when the pentacarbonyl species is photogenerated previously. This strategy is especially appropriate for the synthesis of cyclic FCCs by reaction of 20 with terminal acetylenes bearing an adequately placed hydroxyl group.49 Additionally, tungsten pyranylidene FCCs 27 are prepared in moderate to good yields from conjugated enyne-carbonyl compounds [i.e., 1-(alkoxycarbonyl)-2-ethynylcycloalkenes 26] in the presence

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Jos
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hn

M(CO)6

M(CO)5L

THF or Et3N

20

OH R1 R2

+

M(CO)6

21

M = Cr, W R1 = H, Me R2 = Me, alkenyl, aryl

L=THF or Et3N

1) hn 2) rt

OMe (CO)5M

MeOH/THF 24%−73%

22

R1 R2

M(CO)6 hn THF OH

M(CO)5(THF)

R1 R2

(CO)5M OH R2 R1 23

21 H (CO)5M

R1

−H2O

•

OH

(CO)5M

•

MeOH

22

R2

R2 R1 24

•

25

Scheme 5 Synthesis of alkenyl FCCs 22 initiated by photochemical cleavage of a carbonyl ligand.

of stoichiometric amounts of pregenerated W(CO)5THF (Scheme 6). Regarding the reaction scope, a variety of saturated and unsaturated alkyl groups can be placed at the alkoxy position. Moreover, 1-carbamoyl2-ethynylcycloalkenes have also shown to be suitable starting materials for this methodology.50 Amino alkenyl FCCs 30, which are not readily accessible by the abovementioned procedures, can be prepared in a straightforward manner by thermal metathesis of 2-amino-1,3-butadienes 28 with methoxyphenylcarbene complexes 29. The scope of the reaction includes all group 6 metals and moderate to good yields are reached (Scheme 7).51 Additionally, there are many other transformations to prepare specific FCCs from preexisting FCCs, by reactions involving the carbene ligand. Usually, the interest of such transformations resides mainly either in the nature of the transformation or in the structural features of the final products but not in the fact that FCCs are formed. For those reasons, they have not

11

Group 6 Metal Fischer Carbene Complexes

W(CO)5⋅THF

W(CO)5

THF, rt−reflux

( )n O OR1

( )n

0.5−4 h

O

35%−75%

26 R1 = saturated and insaturated alkyl

OR1 27

Scheme 6 Synthesis of pyranylidene FCCs 27 from conjugated enyne-carbonyl compounds.

O N

OMe + (CO) M 5 Ph

R1 R2 28 M = Cr, Mo, W R1 = alkyl, alkoxy R2 = H, alkyl

29

O

Toluene or THF Δ 18%−75%

N (OC)5M R1 30

R2

Scheme 7 Synthesis of amino alkenyl FCCs 22 by thermal metathesis of 2-amino-1,3butadienes.

been included in this section, but many of them will be discussed along this manuscript.

3. RELEASE OF THE ORGANIC MOIETY ON FCCs The reactions of FCCs may be grouped in two types depending on the presence or not of the metal moiety once the reaction is finished. In the first case, one additional step is required to remove the metal fragment (or to release the organic portion) from the reaction products in an efficient manner. There are numerous alternative procedures that allow the transformation of the metal moiety into different functional groups, adding value to these systems (Scheme 8, top). Thus, conversion of FCCs 31 into aldehydes 32 is achieved by acidic treatment (hydrobromic acid or triflic acid)52 whereas base (i.e., pyridine) is employed to obtain enol ethers 33 when the carbene complex bears acidic hydrogen atoms in the α-position.53 Other transformations include methylenation to enol ethers 34 either with

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R1 O 32

OMe

OMe

O

H+ R1

38

R1 33

Base

[O] OMe SnBu3H

OMe

Methylenation

(CO)5M 31

R1

OMe

R1 34

[H] SiMe3H

Bu3Sn

R1

R1 37

MeO

R1

OMe 35

SiMe3 36 R3 N (OC)5Cr R1 39

R2

NaBH4, CF3COOH 0°C 70%−96%

R3 N R2

R1 40

R1 = alkyl, aryl R2 = H, alkyl R3 = alkyl

Scheme 8 Release of the organic moiety on Fischer carbene complexes.

diazomethane53 or Wittig phosphorus ylides54 or hydrogenation leading to saturated compounds 35.53,55 Methylenation of aromatic FCCs can be performed with chloromethyllithium to form methylketones.56 Additionally, the reduction with silicon or tin hydrides leads to silanes 3657 or stannanes 37,58 respectively. However, the most common strategy to remove the metal fragment involves the conversion of alkoxy FCCs into their analogous esters 38 by oxidation either with cerium ammonium nitrate (CAN),59 pyridine N-oxide (PNO),60 dimethyldioxirane,61 dimethylsulfoxide,8 or by air oxidation, which may be promoted by the anion fluoride.62 Most of these reagents also oxidize amino FCCs to amides. Finally, reduction of amino FCCs 39 to amines 40 is achieved with metal hydrides (Scheme 8, bottom).63

13

Group 6 Metal Fischer Carbene Complexes

4. APPLICATIONS OF ALKYL CARBENE COMPLEXES IN ORGANIC SYNTHESIS (AND OF OTHER CARBENE COMPLEXES IN REACTIONS WHERE ONLY THE CARBENE CARBON IS INVOLVED) This section covers the reactions of alkyl carbene complexes as well as transformations involving other types of FCCs, but where only the carbene carbon takes part in the reaction. Some of them are exclusive for specific types of FCCs.

4.1 Synthesis of Acyclic Compounds Hegedus has described that metal-coordinated ketenes are easily generated by photolysis of chromium FCCs64; its subsequent reaction with nucleophiles allows the synthesis of carboxylic acid derivatives. For instance, α-amino esters 4165 (Scheme 9, top) and dipeptides 44 (Scheme 9, bottom) are formed by photolysis of amino FCCs 39 and 42 in the presence of R3 N R2

R3

O hn, CO, MeOH

(CO)5Cr R

N

MeO

45%−98%

1

R2

R1

39 R1 = H, alkyl, aryl R2 = R3 = PhCH2, Me, Et

41

O

Also,

R3 N R2

(CO)5Cr

N

= (CO)5Cr

R1

Me

Bn N , (CO)5Cr

N

N ,

(CO)5Cr

39

( )n

, (CO)5Cr

n = 1, 3, 4, 10 Ph

R3

O

N

O

(CO)5Cr R1

3 + R

H

O 2

OR NH2

hn, 0°C, THF, 50−80 psi CO 55%−88% dr: 74:26 to 98:2

43

42

R1 Ph

N O

OR2

N H O 44

1

R = H, CH2CO2t-Bu, PhCH2, CH2KCH–CH2 R2 = t-Bu, Me R3 = H, Me, Ph, PhCH2, CH3CH(OH), 2-indolyl

Scheme 9 Synthesis of α-amino esters by photolysis of aminocarbene complexes.

14

Jos
e Barluenga and Enrique Aguilar

alcohols and α-amino esters 43, respectively. In the latter case, double stereoselection applies when optically active chromium amino FCCs react in the presence of esters of optically active α-amino acids; the (S)(S) dipeptide is the matched pair while the (R)(S) is the mismatched pair. Excellent yields and good diastereoselectivities are usually obtained.66 In a similar manner, the photochemical reaction of chromium alkoxy FCCs 45 and sulfur ylides 46 leads stereoselectively to 2-acylvinyl ethers 47. Interestingly, the same products are formed in similar E/Z selectivity under thermal conditions but with longer reaction times. MeCN is the optimal solvent as it favors solubility of the reagents and produces cleaner reaction mixtures, although better diastereoselectivities can be obtained with less polar solvents67 (Scheme 10, top). In a related process, the reaction of alkoxy FCCs with α-haloester or α,α-dihaloester lithium enolates 49 at
78°C, followed by quenching with silica gel leads 1:1 to mixtures of Z and E α-substituted enol ethers 50; acid hydrolysis of the enol ether mixtures 50 generates β-keto esters 51 in high yields (75%–90%). However, this approach is restricted to aromatic FCCs68 (Scheme 10, bottom).

OR2 (CO)5Cr

+

OR2

+ − S

R1 45

R3

48%−90% E/Z = 1:1 to 100:0

R1

R3 H 47

46

R2 = alkyl, aryl R1 = Me, PhCH2, R3 = MeO, t-BuO, Ph

O

MeCN, hn

O

Ph ,

,

,

OMe (CO)5Cr 48 +

Ar OLi

1

R

OR2

THF −78°C to rt 73%−95% E/Z = 1:1

OMe O

O OR2

Ar 1

O

H3O+ 75%−90%

R

50

X

49 Ar = aryl, heteroaryl R1 = H, C4H9, Cl R2 = Me, Et X = Cl, Br

Scheme 10 Synthesis of 2-acylvinyl ethers and β-keto esters.

OR2

Ar 1

R 51

15

Group 6 Metal Fischer Carbene Complexes

Tungsten alkoxy FCCs 52 undergo the nucleophilic attack of zincchelated glycine-derived enolates 53 to straightforward produce (E)-βalkoxy-α,β-unsaturated esters 54 in a stereoselective manner (Scheme 11). The reaction works fine for aryl- and alkyl-substituted FCCs; however, the former produce E/Z-diastereomeric mixtures while the latter lead exclusively to the E-isomers.69 Alkoxy aryl FCCs 48 are able to react with 2-unsubstituted benzoxazoles 55 under basic conditions in toluene at high temperatures leading to 2-substituted benzoxazoles 56 through C–H bond functionalization. The reaction should proceed via benzoxazole deprotonation followed by nucleophilic addition to the carbene carbon; noteworthy, the tetrahedral intermediate evolves by loss of the metal fragment rather than the more common alkoxy group elimination. Such behavior is attributed to the presence of an acidic proton in the reaction media70 (Scheme 12). 1,2-Diarylethanones 58 are formed in moderate to good yields by the coupling of aromatic N-tosylhydrazones 57 with chromium alkoxy aryl FCCs 48, under thermal conditions and in the absence of any catalyst. This transformation displays a wide scope regarding the electronic nature of the aromatic groups in both coupling partners; additionally, regarding the sterics, ortho-substitution at the FCC is tolerated71 (Scheme 13).

OR2 (CO)5W

COOR3

+ H 2N

R1 52

53

R1 = alkyl, aryl R2 = Me, Et R3 = Me, t-Bu, Bn, 2-butenyl

LHMDS, ZnCl2 THF −78 to −50°C , 1.5 h 0°C, 1.5 h

R1

63%−77%

CO2R3

R2O

R1 = aryl,

54

E/Z = 1.1:1 to 2.3:1 R1 = alkyl, E/Z = >99:1

Scheme 11 Synthesis of (E)-β-alkoxy-α,β-unsaturated esters from tungsten alkoxy FCCs.

OMe (CO)5Cr

LiOtBu (2 equiv.) toluene, 100°C or 120°C

N +

Ar 48

O

X 55

23%−90%

MeO Ar

N O 56

Ar = aryl, heteroaryl X = alkyl, MeO, F, Cl, Br

Scheme 12 Synthesis of 2-substituted benzoxazoles from alkoxy aryl FCCs.

X

16

Jos
e Barluenga and Enrique Aguilar

OMe (CO)5Cr

+

Ar1

NNHTs

Ar 48

57

1) K3PO4 (2 equiv.) toluene, 90°C or 110°C 2) 2M HCl, THF, 60°C

O Ar1

33%−78%

Ar 58

Ar = aryl, heteroaryl Ar1 = aryl

Scheme 13 Synthesis of 2-substituted benzoxazoles from alkoxy aryl FCCs.

4.2 Synthesis of Three-Membered Carbocycles The development of appropriate conditions for the cyclopropanation reaction has been one of the main objectives in the chemistry of FCCs, since shortly after their discovery.72,73 Indeed, the outcome of the process is highly dependent on the nature of both the olefin and the carbene complex. For instance, regarding the carbene complex, amino FCCs usually do not partake in cyclopropanation reactions because of their inertness, although some exceptions have been reported (vide infra); on the other hand, alkoxy FCCs are involved in most cyclopropanations, and their behavior against electronically different olefins is summarized in Scheme 14. Thus, for electron-deficient olefins and alkoxy FCCs, the reaction requires quite energetic conditions with temperatures in the 80–140°C range, and sometimes the olefin behaves also as solvent. Good yields of cyclopropanes 59 are usually obtained but as mixtures of diastereomers; remarkably, the selectivity depends on the metal employed. This fact suggests that the cyclopropanation occurs within the metal coordination sphere and discards the involvement of free carbene species. Occasionally, olefins 60 and 61 are obtained as by-products; they may be explained by formal insertion into the C–H olefin bond and cyclopropane ring opening. A mechanism to account for the observed results has been proposed.74 More recently, the cyclopropanation of electrondeficient olefins has been achieved at room temperature by using transmetallation to Ni75 or Cu.76 The cyclopropanation of electron-deficient alkenes can be also thermally achieved with chromium alkoxy alkynyl FCCs 65 to form donor–acceptor alkynylcyclopropanes 66 in moderate yield and good diastereoselectivity ratio77 (Scheme 15). The major diastereomers display a cis relationship between the electron-withdrawing group and the triple bond; this fact has been used advantageously to prepare oxepinones and azepinones by gold-catalyzed cycloisomerizations.78

17

Group 6 Metal Fischer Carbene Complexes

R1

Z

OR2

OR2

Z +

Δ

Z 59 (49%−89%)

OR2

Z +

R1 60 (2%−24%)

R1 61 (1%−3%)

OR2 (CO)5M 5

OR2

X

R1

R1 62

35°C

R1 = alkyl, aryl, alkenyl

(46%−62%) R1

X 50°C 100 atm CO

OR2 5

Δ

R1

C

OR2

63

(60%−70%)

R1

C

(CO)5M

X

Z = electron-withdrawing group X = electron-donating group C = nonactivating group

OR2

64 (60%−88%)

1

R = alkenyl, heteroaryl

Scheme 14 Synthesis of cyclopropanes by [2+1]-reaction of FCCs and alkenes.

OMe (CO)5Cr

OMe +

Z

90°C, THF 30%−70% dr = >95:30:1), and complete E-selectivity for unsymmetrical fulvenes (Scheme 19).84

19

Group 6 Metal Fischer Carbene Complexes

Cl ONMe4 (CO)5Cr

O O

R2

R1

−10°C, CH2Cl2

R3

+

R2

O

R3

23%−85%

R1

R4 69

R4 71

70 R2

R1 = alkyl, alkenyl, aryl R2 = H, Me, Bn R3 = H, Bn R4 = H, alkyl, alkenyl

R4

O R3 O

(CO)5Cr R1 72

Scheme 17 Synthesis of 2-oxabicyclo[3.1.0]hexan-3-ones from acyloxyl FCCs.

OMe Fc

(CO)5Cr

DMF, 4% BHT 152°C, 0.5 h

73 Fc = Ferrocenyl

OMe

Bu

88% 97% de

1) O3, CH2Cl2 MeOH, −78°C 2) Me2S, 20°C Fc

H 74

59% 97% de

Bu

OMe

H

CHO 75

Scheme 18 Synthesis of cyclopropane 74 by intermolecular reaction between chromium alkoxy alkenyl FCC 73 and 1-hexene, and its oxidation to cyclopropanecarbaldeyde 75.

R2

OMe (CO)5W

R2

R3

R3

60°C, THF

+

65%−73% exo/endo 3:1 to >30:1

OMe

R1 76

R1

77

78

Scheme 19 Synthesis of alkynylcyclopropanes 78 by reaction between tungsten alkoxy alkenyl FCCs 76 and fulvenes.

The cyclopropanation reaction is rather elusive for amino FCCs, especially against electron-deficient alkenes, because of decomposition of the reaction products to ring-opening species, and also because of the high stability of amino FCCs themselves. Therefore, the strategies employed to achieve cyclopropanation with amino FCCs are based on reducing such stability. For instance, the first example reported involves pyrrolocarbene complex 79, which is more reactive than conventional aminocarbenes because of the delocalization of the unshared pair of electrons at the nitrogen atom through the aromatic pyrrole ring; indeed, FCC 79 produces

20

Jos
e Barluenga and Enrique Aguilar

cyclopropylpyrroles 80 in moderate to good yields and with low diastereoslectivities85 (Scheme 20, top). The pyrrole group has been transformed into a primary amine at a later stage. A second example uses dialkylamino alkoxycarbonyl FCCs 81, where the electron-withdrawing effect of the alkoxycarbonyl group increases the reactivity of the FCC. The corresponding cyclopropanes 82 are formed by reaction with cyclic and acyclic nonconjugated olefins in refluxing toluene in moderate to good yields and usually with high diastereoselectivities86 (Scheme 20, bottom).

4.3 Synthesis of Four-Membered Carbocycles The reactivity of FCCs against olefins changes completely when photoirradiation is applied. Thus, the photolysis of chromium alkoxy FCC 13 in the presence of simple olefins leads to cyclobutanones 83 in excellent yields via photochemically generated ketenes (Scheme 21, top). The high regioselectivity observed corresponds to that resulting from attack of the more nucleophilic olefin carbon on the electrophilic ketene carbonyl carbon. The reaction is also stereoselective; in many cases, a single diastereomer is formed. Additionally, for 1,2-disubstituted alkenes the stereochemistry of the olefin is maintained in the cyclobutanone product. However, the [2+2]cycloaddition does not take place for electron-poor olefins, such as methyl acrylate or acrylonitrile, under the reaction conditions.87 On the other hand,

N

Z

+

Z N

66%−90% dr 1.6:1 to 3.4:1

(CO)5M 79

100°C, THF/DBTH

R1

R1 80

M = Mo, W R1 = Me, Ph Z = CO2Me, CN NR22 (CO)Cr

+

R3

OR1 O 81

111°C, toluene 24−50 h

R3 NR22

35%−70% de >95

R1 82

R1 = Me, t-Bu R2 = Me, Bn; also HNR22 = morpholine R3 = alkyl, aryl

Scheme 20 Cyclopropanation reactions involving group 6 metal amino FCCs.

21

Group 6 Metal Fischer Carbene Complexes

OMe (CO)5Cr

R1

+ Me

MeO Me

MeCN hn (450 W)

R1 13%−96% dr 5:1 to >95:97%

O

O N Ph

87

88

R1 = alkyl (1°, 2°), aryl R2 = Me, PhCH2 R1−R2 = −(CH2)4−

Scheme 21 Synthesis of cyclobutanones from FCCs and olefins.

the employment of cyclic conjugated dienes, such as cyclohexadiene, or of chromium alkoxy FCCs 85 having remote double bonds in the alkoxy group allows the synthesis of bicyclic cyclobutanones 84 or 86 in good yields and in a highly stereo- and regioselective manner88 (Scheme 21, middle). When the photolysis of the chromium FCCs 45 is performed in the presence of optically active (S)-ene-carbamate 87, under 90 psi of CO pressure, optically active cyclobutanones 88 are readily obtained in moderate to good yields and with high control of both the relative and the absolute stereochemistry. This [2+2]-cycloaddition failed for a trans-ene-carbamate but was performed successfully for a gem-disubstituted ene-carbamate89 (Scheme 21, bottom).

22

Jos
e Barluenga and Enrique Aguilar

Usually chromium methoxy FCCs 9 react thermally with silylsubstituted internal acetylenes to produce highly stable silyl vinyl ketenes.90 However, a formal [2+1+1]-cycloaddition occurs when TIPS-substituted furan-2-yl or cyclopropyl acetylenes are employed, and cyclobutenones 89 have been isolated as sole reaction products.91 Silyl vinyl ketenes 90 have been identified as precursors of the reaction products (Scheme 22).

4.4 Synthesis of Five-Membered Carbocycles Transmetallation from group 6 metals to metals of other groups in the periodic table has emerged as a powerful strategy to modulate the reactivity of FCCs.92 Thus, chromium aryl FCCs 48 react with two units of an internal alkyne in the presence of [Ni(cod)2] to provide highly substituted cyclopentadiene derivatives in a [2+2+1] cyclization.93 The electronic properties of the acetylene determine the regiochemistry of the cyclization for nonsymmetrical alkynes. Thus, a sole isomer of unsymmetrical adducts 91 is obtained for 1-phenyl-1-propyne whereas symmetrical cyclopentadienes 92 are formed for methyl 2-butynoate (Scheme 23). On the other hand, chromium cyclopropyl FCC 93 undergo cycloaddition to alkynes leading to cyclopentenone derivatives 94 in good yields (Scheme 24, top).94,95 The reaction tolerates a variety of functional group and proceeds with high regioselectivity being the large substituent at the alkyne placed adjacent to the cyclopentenone carbonyl group. The proposed mechanism should involve the initial elimination of CO, followed subsequently by complexation of the metal carbonyl species to the alkyne and by insertion of the alkyne to form metallacycle 95. This species should open to form alkene-coordinated alkenyl carbene complex 96, which has R2 OMe (CO)5Cr

Benzene, 80°C

+ R

R1 = n-Bu, Me R2 = c-Pr, 2-furyl

R2

MeO

66%–73%

1

9

R1

O

TIPS

TIPS 89

OMe 2

R

R1

O

C

TIPS 90

Scheme 22 Synthesis of cyclobutenones from FCCs and TIPS acetylenes.

23

Group 6 Metal Fischer Carbene Complexes

Ph Me Ph

48%−51%

Ni(cod)2 MeCN

OMe

OMe

Me Ar

Ph

Me 91 Me

Ar −10 to 20°C

(CO)5Cr

MeOOC

Me

MeO2C

48

OMe

51%−56%

Ar

MeOOC

Ar = Ph, 4-methoxyphenyl

Me 92

Scheme 23 Synthesis of cyclopentadienes via [2+2+1]-cycloaddition reactions.

O

RL

Cr(CO)5

Aqueous dioxane RL reflux

+

42%−79% dr = 7:1 to >99:1

OMe RS

93

OCH3

RS 94

RL = alkyl, alkenyl, aryl RS = H, alkyl, aryl RL

Cr(CO)5 +

RL

RS

RL −CO

(CO)4Cr

Cr(CO)4

OMe RS

93 Cr(CO)4 RL RS

MeO

Cr(CO)3 O

RL MeO

RS

MeO 97 O

OMe Cr(CO)3 99

RL RS 98

O

RL

RL RS

RS

95

Cr(CO)4

96 O

MeO

OMe

RL RS OMe Cr(CO)3 100

Cr(0) H2O

94

RS

OMe 101 + ethylene + Cr(0)

Scheme 24 Reaction conditions and mechanism for the synthesis of cyclopentenones.

24

Jos
e Barluenga and Enrique Aguilar

been found to be an intermediate for this reaction.95 Then, a cyclopropane ring opening (i.e., a 1,5-alkyl shift, to 97) should be successively followed by CO insertion (to 98), conversion to dienyl complex 99, and the closure of the ring (to 100). Finally, loss of ethene is proposed to generate cyclopentadienone intermediate 101, which should be transformed into the final cyclopentenone vinylogous ester derivatives 94 by a reduction process, carried out by the low-valent chromium fragment under the aqueous reaction conditions (Scheme 24, bottom). Interestingly, the transformation of metallacyclooctadienone 98 into bicyclic system 100 can be seen as a formal olefin insertion into the metal–carbonyl bond. Intramolecular versions of this reaction have proved to be especially efficient. For instance, good to excellent yields have been reached for cyclopentenones fused to oxygen heterocyclic rings, such as cyclopenta[b] pyran-6(2H)-ones 103 (Scheme 25, top). Indeed, in these intramolecular approaches, the stereochemistry can be controlled by placing a stereogenic carbon in the tether; in any case, the diastereoselectivity strongly depends both on the position of the chiral center and on the ring size of the heterocyclic ring formed.96 This reaction has been employed in a formal total synthesis of ()-vitamin D3.97 Moreover, alkylidenecyclopentenones, such as 104, or alkoxyalkylcyclopentenones are obtained, depending on the leaving group ability of the propargyl substituent, when propargyl alcohols are employed as acetylenes (Scheme 25, bottom).

O R2

Cr(CO)5

Toluene/water reflux

O

62%−72% dr = 50:50 to 94:6

102

R1 H R2

R1

103

R1 = H, Ph, Me R2 = Me, Ph Ph Cr(CO)5 +

O Toluene/water reflux

Ph

65%

OMe 93

O

AcO

104 OCH3

Scheme 25 Synthesis of bicyclic cyclopentenones 103 and alkylidenecyclopentenone 104.

25

Group 6 Metal Fischer Carbene Complexes

Also, chromium ethoxy FCCs 105 react thermally with methylenecyclopropanes 106 to provide functionally substituted cyclopentenones 107 by a [4+1]-cocyclization between methylenecyclopropane and a carbon monoxide ligand, and with incorporation of the carbene ligand as a substituent of the cyclopentenone ring.98 The proposed mechanistic rationale suggests that, after initial dissociation of a CO ligand, a [2+2]-cycloaddition of the methylenecyclopropane 106 to FCC 105 should take place to form 5-chromaspiro[2.3]hexane 108. This species should then undergo a facile cyclopropylmethylmetal to homoallylmetal rearrangement to alkylidenemetallacyclopentane 109, which, after CO insertion followed by reductive elimination of chromium, should yield 110. The final isomerization of 110 to the thermodynamically more stable product 107 has been confirmed by labeling experiments (Scheme 26). In a completely different approach, the successive addition of β-substituted lithium enolates 111 and allylmagnesium bromide to chromium aryl or alkyl FCCs 9 followed by acidic hydrolysis and decoordination of the metal center leads to 1,2,3,3,4-pentasubstituted cyclopentanols 112 or 113 as single diastereoisomers. On the one hand, formation of four new carbon–carbon bonds takes place when an ester enolate (R2 ¼ OMe) is employed to produce O

OEt (OC)5Cr 1 105 R + R3

R2

106

R3 70−110°C, 12−24 h 28%−58%

EtO R1 107

dr: 61/39 to 75/25

O

OEt R1

[Cr] R3

R3

[Cr]

R2

R3

R2

EtO

EtO R2 108

R2

MeOH, H2O

R1 109

R1 110

R1 = Me, Ph R2 = H, Ph, CH2OH R3 = H, Ph, n-C5H11, c-Pr, CO2(t-Bu)

Scheme 26 Synthesis of cyclopentenones from chromium alkoxy FCCs 103 and methylenecyclopropanes 104.

26

Jos
e Barluenga and Enrique Aguilar

1) THF, −78°C or −78 to −55°C 2) OLi

OMe +

(CO)5Cr R1 9

OH R2 = MeO R3 = Me

MgBr

−78 to 20°C 3) 6N HCl, H2O 4) Air, light

R3 R1 OMe 112

73%−87%

R2 R3

R2 = Et, R3 = Me

111

R2

R3

R2−R3 = (CH2)4

1

R = cyclopentyl, aryl, heteroaryl

R1 OMe 113

78%−80%

OMe (CO)5Cr 114 +

Ph

1) THF, −78°C MgBr 2) −78 to 20°C

OMgBr Me

OLi

Ph OMe

OMe 115 [Cr] = (CO)5Cr

OH

[Cr] Li 116

3) [E] 4) HCl, H2O 5) Air, light

OH Me

62%−71%

Ph OMe E

117 [E] = benzaldehyde, styrene, I2

Scheme 27 Synthesis of polysubstituted cyclopentanols from chromium alkoxy FCCs.

1-allylcyclopentanols 112. On the other hand, the participation of ketone lithium enolates (R2 ¼ alkyl group) generates 1-substituted cyclopentanols 113 by a similar process99 (Scheme 27, top). Even more functionalized cyclopentanols 117 have also been prepared from chromium phenyl methoxy FCC 114 by trapping intermediate cyclopentylchromate species 116 with a variety of electrophiles (benzaldehyde, styrene, and iodine)100 (Scheme 27, bottom). N-methoxy-N-methylacetamide (Weinreb amide) has been also employed as a source to generate the enolate. Thus, the successive addition of Weinreb amide-derived enolate 118 and 1-alkoxyallenyllithiums 119 (generated from the corresponding 1-alkoxyallene and BuLi) to chromium alkoxy FCCs 9, followed by quenching with ammonium chloride and decoordination of the metal species, leads regioselectively to 2,4-dialkoxy-2-cyclopentenones 120 in good to excellent yields (Scheme 28).101 The treatment followed after the addition of alkoxyallenyllithium 119 is crucial for the reaction outcome; the reaction regioselectivity and the nature of the reaction products could be controlled

27

Group 6 Metal Fischer Carbene Complexes

1) THF, −78°C 2) OR2 •

OLi

OMe + Me

(CO)5Cr R1 9

N

Li 119 −78 to 20°C 3) NH4Cl, H2O, 20°C

O R2O R1

75%−96%

OMe 118

OMe 120

R1 = alkenyl, alkynyl, aryl, heteroaryl R2 = Me, PhCH2

Scheme 28 Regioselective synthesis of 2,4-dialkoxy-2-cyclopentenones from chromium alkoxy FCCs.

this manner (see below, Scheme 30). Deuteration experiments concluded that the metal adds to the nonsubstituted carbon of the allenyl moiety in the carbometallation/cyclization step.

4.5 Synthesis of Six-Membered Carbocycles The successive addition of β-unsubstituted lithium enolates 121 and allylmagnesium bromide to aryl, heteroaryl, alkyl, or alkynyl chromium FCCs 9 leads diastereoselectively to 1,3,3,5-tetrasubstituted cyclohexane1,4-diols 122 or 123. Thus, five new carbon–carbon bonds are formed when ester lithium enolate 121 (R2 ¼ OEt) is employed to afford 1-allylcyclohexane-1,4-diols 122. Alternatively, the addition of ketone lithium enolates 121 (R2 ¼ Me, Ph) provides 1-substituted cyclohexane-1,4diols 123 in excellent yields in a process that involves the creation of four new carbon–carbon bonds99,100 (Scheme 29). As mentioned above, the outcome of the successive addition of Weinreb amide-derived lithium enolate 118 and 1-alkoxyallenyllithium 124 to chromium aryl alkoxy FCCs 48 can be controlled by the treatment followed after the addition of the alkoxyallenyllithium. Thus, when 5 mL of water is added all at once at
55°C, instantaneous and complete freezing of the reaction mixture occurs; then, after the subsequent addition of NH4Cl and work-up, 2,5-dialkoxy-2-cyclohexenones 125 are obtained in good yields (Scheme 30), instead of the expected cyclopentenones 120 (see Scheme 28). Deuteration experiments pointed out that, under water-freezing conditions, a reverse in the regiochemistry of the intramolecular carbometallation of the unsubstituted double bond of the allene moiety takes place: the metal adds to

28

Jos
e Barluenga and Enrique Aguilar

1) THF, −78°C or −78 to −55°C MgBr 2) −78 to 20°C OMe

R2 = EtO

R1

73%−87%

OMe OH

3) 6N HCl, H2O 4) Air, light

OLi +

(CO)5Cr

OH

122

R2

R1

R2

OH

121

9

R2 = Me, Ph R1 = alkyl (2°), alkynyl, aryl, heteroaryl

R1

80%−91%

OMe OH 123

Scheme 29 Synthesis of polysubstituted cyclopentanols from chromium alkoxy FCCs. 1) THF, −78°C 2) OMe

OLi

OMe + Me

(CO)5Cr Ar 48

Ar = aryl, heteroaryl

N OMe 118

Li • 124 −78 to −55°C 3) H2O (D2O) (5 mL), Freezing −78 to 20°C 4) NH4Cl, H2O, 0°C

O MeO

58%−84%

Ar OMe

H/D 125

Scheme 30 Regioselective synthesis of 2,4-dialkoxy-2-cyclohexenones from chromium aryl alkoxy FCCs.

the internal carbon to produce cyclohexenones 125, while to generate cyclopentenones 120 the metal should add to the unsubstituted carbon.101 On the other hand, the multicomponent coupling of chromium aryl (or heteroaryl) alkoxy FCCs 48, an imide lithium enolate 126 and two units of an initially prepared propargylic organomagnesium reagent 127 allows the enantioselective synthesis of optically pure, highly functionalized 4-hydroxy2-cyclohexenones 128 in moderate to excellent yields102 (Scheme 31). Both enantiomers have been accessed in a highly enantioenriched form; indeed, the removal in situ of the chiral auxiliary group takes place with concomitant generation of a quaternary stereocenter. The three-component coupling of 2-alkynylbenzaldehyde hydrazones 129 with chromium FCCs 9 and electron-deficient alkynes allows the

29

Group 6 Metal Fischer Carbene Complexes

1) THF, −78°C 2) OLi OMe +

(CO)5Cr 48

N

O O

MgBr 127 R1 −78 to 20°C 3) NH4Cl, H2O, 20°C

•

HO R1

50%−84% ee = 97%−99%

Ar Ph

Ar = aryl, heteroaryl R1 = alkyl (1°), aryl

R1

126

Ar OMe O 128

Scheme 31 Synthesis of 4-hydroxy-2-cyclohexenones from chromium alkoxy aryl FCCs.

synthesis of naphthalene derivatives 130 (Scheme 32, top). It is a highly regioselective transformation with unsymmetrical alkynes and involves a three-step sequence with formation of an isoindole derivative, followed by intermolecular Diels–Alder reaction, and nitrene extrusion. The enol ether functionality easily undergoes hydrolysis to produce ketones.103 This approach is closely related to previously developed strategies for the synthesis of five-membered heterocycles (see Section 4.7, Scheme 39), by reactivity of FCCs with enyne-hydrazones or o-alkynylbenzoyl derivatives; indeed, naphthalene derivatives have also been obtained through the analogous isobenzofuran route. Moreover, highly complex structures, such as steroid ring systems 131,104 or tetracyclic frameworks 132 have been prepared by an intramolecular Diels–Alder version of this domino reaction in moderate to good yields105 (Scheme 32, bottom). On the other hand, the reaction can be diverted to stable isoindole derivatives by switching the solvent from dioxane to ethanol, when 2-alkynylbenzaldehyde hydrazones are used.

4.6 Synthesis of Seven-Membered Carbocycles Seven-membered cycloheptadienones 134 are formed in moderate to good yields by treatment of cyclopropyl tungsten FCC 132 with alkynes by a [4+2+1] cyclization (Scheme 33); the suggested mechanism is analogous to the one proposed for the D€ otz benzannulation,106 but incorporating 107 the cyclopropyl ring opening. In general, this sequence proceeds in a regioselective manner both in the alkyne addition step and in the cyclopropyl ring-opening step, and with complete trans-diastereoselectivity. By employing the analogous molybdenum cyclopropyl carbene complex 135, which reacts at lower temperatures than tungsten complex 133, and aromatic phosphines as additives [1,2-bis(diphenylphosphino)benzene for

30

Jos
e Barluenga and Enrique Aguilar

OMe

R2 +

(CO)5Cr

1) Dioxane, 80°C OMe 2) R3 EWG R1

N-NMe2

R2

R1 EWG

72%−95%

9

129

R3

1

R = alkyl, alkenyl, aryl R2 = H, TMS R3 = H, TMS, CO2Me, CO2Et EWG = CO2Me, CO2Et, COPh, –CHKCH–CO2Et

130

O Cr(CO)5 Dioxane, 100°C

MeO +

H

66% dr: 60/40

O

H

H

OH 131 O

Cr(CO)5 MeO + O

Dioxane, 100°C

H

H

64% dr: 58/42 H OH 132

Scheme 32 Synthesis of naphthalene derivatives from chromium alkoxy FCCs.

tungsten complex and triphenylphosphine for molybdenum complex], an increase of the yield of kinetically more stable cycloheptadienone 136 is reached.108 The reaction, however, does not work for terminal alkynes.109 In general, the scope and the limitations of this approach for the preparation of cycloheptadienones are far from optimal; nonetheless, it has been applied also to the synthesis of ferrocenyl-substituted 2,4-cycloheptadienones.110 Therefore, the behavior of cyclopropylcarbene complexes 137 strongly depends on the nature of the metal, as a different process takes place with methoxy cyclopropyl chromium FCC 9, which leads to cyclopentenones as main reaction products. Such distinct behavior should be due to how metallacyclooctadienone intermediate 138 evolves (Scheme 34). On the one hand, a formal olefin insertion followed by elimination of ethylene should occur for chromium (see Scheme 24); the higher tendency to oxidation of chromium vs other group 6 metals together with the aqueous

31

Group 6 Metal Fischer Carbene Complexes

W(CO)5 133 + RL

OMe

Ph2P

PPh2

xylene, 140°C 45%−61%

RS

O RL RS MeO

RL = Pr, Ph RS = Me, Pr, Ph

134

Mo(CO)5

O Ph

135 + Ph

OMe

PPh3, THF, 65°C Ph

65%

Ph

MeO 136

Scheme 33 Synthesis of 2,4-cycloheptadienones from tungsten and molybdenum cyclopropyl methoxy FCCs.

O

M(CO)5 137 OMe 93, M = Cr 133, M = W 135, M = Mo + RL

RS

RL M = Cr (OC)3M O

OMe

RS 94 O

RL RS 138

OMe

RL M = Mo, W RS MeO 134

Scheme 34 Different behavior of chromium and tungsten (or molybdenum) methoxy cyclopropyl FCCs.

reaction conditions should favor the reduction of cyclopentadienone intermediate 101 (Scheme 24) to cyclopentenones 94 making this process irreversible. On the other hand, a reductive elimination to cycloheptadienones 134 should take place for tungsten (or molybdenum), which is favored by the presence of donating phosphines in the nonaqueous reaction medium.

32

Jos
e Barluenga and Enrique Aguilar

4.7 Synthesis of Heterocycles The photochemical reaction of chromium alkoxy FCCs 9 and imines lead to β-lactams 139 in high yield by [2+2]-cycloaddition between the imine and the generated ketene intermediates; the process is of general scope and variations in the structure of both the carbene and the imine are allowed (Scheme 35, top). Very mild reaction conditions (25°C, and THF, Et2O, or CH3CN as solvents) are required and a single diastereomer is obtained in most cases. On the other hand, thermal conditions do not produce β-lactams (iminocarbene chromium complexes are formed instead).111 The analogous synthesis of β-lactones by photolysis of carbene complexes in the presence of aldehydes requires Lewis acid catalysis and has proved to be efficient only for intramolecular cases, such as for cyclopentane-fused lactone 140112 (Scheme 35, bottom). Kerr and Mori developed in the late 1990s the reaction of chromium alkoxy alkyl FCCs 105 with alkynes 141 bearing either a hydroxy group or a tert-butyldimethylsilyloxy group, which leads to ketolactones of four- to seven-membered rings 142 in moderate to excellent yields, after treatment of the crude enol ethers with an oxidizing reagent and work-up (Scheme 36, top). Several γ-lactone natural products, such as (+)-blastmycinone and (+)-antimycinone, have been prepared by this synthetic strategy, using an optically active homopropargylic alcohol derived from (S)-ethyl lactate113 (Scheme 36, middle). Interestingly, this type of cyclization may be thermally promoted,114 induced by ultrasound

R2

OMe +

(CO)5Cr R1

R4 N

R3

hn, Et2O, 16 h 20%−90%

9 R1 = alkyl, aryl R2 = H, Ph R3 = alkenyl, aryl

R3 R2

MeO R1

N R4

O 139

R4 = alkyl, aryl hn, ZnCl2 CO, THF, 20 h

OMe (CO)5Cr

CHO

72% single diast.

H

MeO O O 140

Scheme 35 Photochemical synthesis of β-lactams 139 and bicyclic β-lactone 140.

33

Group 6 Metal Fischer Carbene Complexes

OEt +

(CO)5Cr R1

1) CH3CN, 70°C 2) [FeCl2(DMF)3][FeCl4]

( )n R

3

OR2 141

105

O

n = 0, 30% n = 1, 43%−96%, dr = 52/48 to 98/2 n = 2, 53%−100%, dr = 59/41 to 85/15 n = 3, 63%

R

O

3

O

( )n 142

R1

R1 = alkyl (1°) R2 = H, TBS R3 = H, –(CH2)3–, –(CH2)4–, –(CH2)5–, OTBS O

O

O

O

i-BuCOO

i-BuCOO Et (+)-blastmycinone

OMe (CO)5Cr MeO

HO OMe +

Bu (+)-antimycinone

Ac2O, Et3N, THF Δ, 3.5 h or ))), C6H6, Et3N, 3 h 74% (thermal) 79% (sonication)

O MeO O OMe MeO

Scheme 36 Synthesis of lactones by reaction of chromium FCCs 105 with (protected) alkynols.

techniques,115 (Scheme 36, bottom) or performed under solvent-free conditions, which reduce the reaction time while increasing the yields.116 Five-membered heterocycles of different types, such as substituted furans 145, pyrroles 146, or butenolides 147 are formed, regioselectively and in good yields, by a formal three-component [2+2+1]-cycloaddition obtained by sequential reaction of tungsten FCCs 143 with (i) alkynyllithiums 144 and (ii) aldehydes, sulfonyl aldimines, or carbon dioxide, respectively117 (Scheme 37). An alkynyllithium species 144 is required for the addition step of the sequence; other organolithium reagents do not generate the necessary propargylic intermediate 148, which may evolve by two different routes. On the one hand, it should add to Lewis acid activated sulfonyl imines (or aldehydes or carbon dioxide) to form allenyl intermediate species, such as 149, which should evolve to the final pyrroles 146 by a cyclization (Scheme 38, Via A). Alternatively, a 1,2-migration of the pentacarbonylmetal moiety118 may

34

Jos
e Barluenga and Enrique Aguilar

1) THF, −78°C 2) BF3•OEt2, R3-CHO, −78°C 3) H3O+

OMe + R

(CO)5W

2

Li

O

R1

R3

62%−86%

R1

144 143 R1 = alkyl (1º, 2º), aryl R2 = n-Hex, Ph R3 = Ph, i-Pr, CO2Et, Ph–CHKCH– 1) THF, −78°C 2) BF3•OEt2, R3−CH=NSO2Ph, −78°C OMe 3) H3O+ + R2 Li (CO)5W 64%−85% R1 144 143

R2

145

SO2Ph R

N

1

R3

2 146 R

R1 = alkyl (2°), aryl R2 = n-Hex R3 = Ph, Ph–CHKCH– 1) THF, −78°C 2) CO2, −40°C to −20°C 3) H3O+

OMe + R2

(CO)5W

Li

63%−72%

R1 143

R1 MeO

O

O

2 147 R

144

R = alkyl (1°, 2°), aryl R2 = n-Hex, Ph, SiMe3 1

Scheme 37 Synthesis of substituted furans, pyrroles, and butenolides by reaction of tungsten FCCs 143 with lithium acetylides and different electrophilic reagents.

PhSO2N−

(CO)5W

1) THF, −78°C

+ R2

Li 144

−78°C

R1

143

(CO)5W

R R1 148

•

Via A

2

3) H3O+

R2

R1

SO2Ph

149

−

OMe

R3

MeO

2) BF3•OEt2 R3−CHKNSO2Ph

OMe

Li+

R1

N

R3

+

Li

Via B

2) BF3•OEt2 R3−CHKNSO2Ph −78°C

MeO R1

SO2Ph N

−

146

R2

3) H3O+

R3 Li+ R2

(CO)5W 150

Scheme 38 Possible mechanisms for the synthesis of substituted pyrroles 146.

promote the addition to the electrophile to form metallapyrrolidine intermediate 150, which should undergo an elimination reaction to pyrroles 146 (Scheme 38, Via B). The isobenzofuran cyclization is the formation of the isobenzofurans 152 by the coupling of FCCs with aryl-acetylene-carbonyl compounds

35

Group 6 Metal Fischer Carbene Complexes

O Bu

Bu 1) Dioxane, reflux 2) 5% HCl

OMe (CO)5Cr

+

O

Me

R1

R1

13

O

32%−87% 152

151

H3O+ OMe OMe

OMe

Bu

Bu

Bu – Cr(CO) 4 O+

Cr(CO)4 O R1

O R1 155

R1 154

153 R1 = H, Me, Ph R1 R2

OMe +

(CO)5Cr Me 13 R1 = H, n-Bu R2 = H, n-Bu, Ph

N-NMe2

R3

1) THF, 70°C 2) 3N HCl 36%−74%

O

R1 R2

N-NMe2 H 156

R3 157

R3 = H, Et R2–R3 = –(CH2)4–

Scheme 39 Synthesis of five-membered heterocycles by isobenzofuran cyclization.

151.119,120 The steps of this sequence should involve initially a regio- and stereoselective alkyne insertion to form alkenyl FCC 153 that should be followed by a nucleophilic attack by oxygen to afford carbonyl ylide intermediate 154. Then, the loss of chromium fragment should generate benzofuran derivative 155, which may be converted into isobenzofuryl-derived ketone 152 by a subsequent acid hydrolysis of the enol ether functionality (Scheme 39, top). In an analogous transformation, 1-dimethylaminopyrroles 157 are easily formed by coupling of alkoxy FCC 13 with enyne-hydrazones 156121 (Scheme 39, bottom). In some cases, the three-membered cycloadducts resulting from a cyclopropanation reaction may be unstable and undergo rearrangement

36

Jos
e Barluenga and Enrique Aguilar

in situ. This is, in fact, the case of the reaction of alkenyl and aryl chromium (0) FCCs 9 with α,β-enones and α,β-enals 158 that lead to 2-alkoxy-2,3dihydrofurans 159, in moderate to good yields, by ring expansion of the corresponding formyl or acylcyclopropanes initially generated.122 This process works satisfactorily for alkenyl or aryl FCCs but not for alkyl or alkynyl FCCs, even though neither the aromatic ring nor the double C–C bond of the carbene ligand of complexes 9 partake in the reaction. Conversion of the formed dihydrofurans 159 into furans 160 or into 1,4-diketones 161 is smoothly achieved by acidic treatment (Scheme 40). The successive coupling of an alkoxy aryl FCC of chromium 48 with a ketone lithium enolate 121 and then with a 3-substituted propargylic organomagnesium reagent 127 leads to the selective formation of hydroxy-substituted bicyclic [4.3.0]-γ-alkylidene-2-butenolides 162.123 The substituent at the triple bond results crucial to determine the reaction outcome as it is necessary the participation of the propargylic species through its propargylic (and not allenylic) form to get fused butenolide; otherwise, cyclohexenones may be obtained (see Scheme 31).102 The reaction proceeds efficiently with different aryl and heteroaryl chromium FCCs 48, but lower yields are reached with analogous tungsten FCCs. Significant structural diversity is also provided both by the ketone lithium enolate 121 and by the propargylic organomagnesium reagent 127 (Scheme 41). Racemic and optically active (96%–99% ee) hydroxy- and propargylsubstituted bicyclic [4.3.0]-γ-alkylidene-2-butenolides rac-164, 164 (and also ent-164), are synthesized in 55%–88% yield when an imide lithium enolate 163 is used instead of the ketone lithium enolate and, as a consequence, the addition of one more equivalent of the propargylic R3

HBF4 (54% in Et2O) Et2O, silica gel, rt 55%−94% R3

OMe (CO)5Cr

R

O 1

9 R1 = alkenyl, aryl R2 = H, Me, Ph

THF, 100°C

+ R2

R3 158

R3 = H, Me, Ph, (E)-Et–CHKCH–

38%−94%

R2

160

R1 R2

O

R1 O

OMe

159 0.5N HCl THF, rt R2 = Me; R3 = H 70%−77%

O

R3 R1

R2 O 161

Scheme 40 Synthesis of dihydrofuran derivatives via formal [4+1]-cyclization of α,β-enones and α,β-enals with chromium(0) alkoxy alkenyl and aryl FCCs.

37

Group 6 Metal Fischer Carbene Complexes

1) THF, −78°C MgBr

2) R OMe

127

Ar

R2 121

R2

HO

−78°C to 20°C

3) NH4Cl, H2O, 20°C

+

(CO)5Cr 48

OLi

1

40%−88%

R1

Ar O

O 162 Ar = aryl, heteroaryl R1 = H, Me, TMS, Ph-CH2 R2 = alky(Me, 2°, 3°), alkenyl, alkynyl, aryl, heteroaryl,1,4-benzodioxan-6-yl

Scheme 41 Synthesis of fused 6-5 bicyclic 2-butenolides.

organomagnesium reagent takes place.123 The asymmetric version requires the employment of chiral imide enolates, 126 and ent-126, and propargylic organocerium reagents 165 (Scheme 42). Chromium amino FCCs 166 tethered to dienes undergo efficient formal intramolecular [4+1]-cycloadditions under refluxing toluene to give N-heterocyclic compounds 167. The reaction proceeds in a satisfactory manner for dienes of all three electronic natures, especially with unactivated ones and allows the creation of a quaternary stereocenter. Ligands on chromium have a profound effect on the course of the reaction; for instance, the addition of PPh3 has shown to have a strong influence on both the rate and the outcome of the reaction (Scheme 43, top).124 On the other hand, cyclic enamines 169 or homoenamines 170 may be formed depending on the substitution on the alkene when the chromium aminocarbene is tethered to an olefin, as in 168 (Scheme 43, bottom). This reaction is also of wide scope as it works well with electron-rich, electron-deficient, or unactivated alkenes. The presence of PPh3 is required for the efficiency of the transformation, which should proceed by intramolecular [2+2]-cylcoaddition between the chromium carbene and the alkene moieties, followed by β-hydrogen elimination.125 The coupling of chromium FCC 13 with o-alkynylstyrene epoxides 171 leads to benzoxepinones 172; the reaction should take place via epoxyalkenylcarbene complex 173, followed by CO insertion and cyclization. The substitution pattern of 171 determines the evolution of 17 and therefore the outcome of the reaction; thus, acyclic dienones are formed when epoxides bearing a quaternary stereocenter (having a Me group placed in the carbon linked to the aromatic ring) are employed126 (Scheme 44).

38

Jos
e Barluenga and Enrique Aguilar

1. THF, −78°C 2. OLi OMe

O

N

+

(CO)5Cr

MgBr 127 R −78 to 20°C

3. NH4Cl, H2O, 20°C

O

R1

53%−88%

Ar

48

R1

HO

1

Ar O

163 Ar = aryl, heteroaryl R1 = H, TMS, Ph−CH2CH2

rac-164

O 1. THF, −78°C MgBr•CeCI3 165 R1 −78°C to 20°C

2. OLi OMe

N

+

(CO)5Cr 48

O

3. NH4Cl, H2O, 20°C

O

R1

63%−88% ee = 96%−99%

Ar

Ar O

Ph Ar = aryl, heteroaryl R1 = TMS, Ph−CH2CH2

R1

HO

164

O

126

Scheme 42 Synthesis of hydroxy- and propargyl-substituted bicyclic[4.3.0]-γalkylidene-2-butenolides.

R1

N

( )n

R3 R2

H

R2

Toluene reflux

R3 H

43%−85%

Cr(CO)5

( )n

166 n = 0,1 R1 = Bn, i-Bu, CH2–c–C6H11 R2 = H, Me R3 = H, Ph, CO2Me, CH2OTBDPS, 4-MeO–C6H4–4-MeO2C–C6H4–

N

R1

167

R2 R1 H

N

( )n

R2

Cr(CO)5

Toluene, PPh3 reflux

( )n or

24%−72%

168 n = 0, 1 R1 = Bn, i-Bu, t-Bu, c-C6H11, CH2–c–C6H11 R2 = H, Me, Ph, CO2Me, –CH=CH2,–

R2 ( )n

N

N

R1 169

R1 170

SiMe3

Scheme 43 Synthesis of N-heterocyclic compounds by intramolecular cycloadditions of chromium aminocarbenes.

39

Group 6 Metal Fischer Carbene Complexes

MeO R1 (OC)5Cr

+

Me

R1

Dioxane reflux

OMe

O

O

Me

22%−46%

O

R2

13 171 R = H, TMS

172

1

R2 = H, Me

R2

OMe R1

Me Cr(CO)4 O R2 173

Scheme 44 Synthesis of benzoxepinones by reaction of chromium FCC 13 with o-alkynylepoxides.

A [5+2]-cycloaddition takes place between ethoxy FCCs 174 and vinylaziridines 175 under photochemical conditions and CO pressure to produce 3,4-dihydroazepin-2-ones 176, usually in excellent yields127 (Scheme 45, top). The reaction scope includes the formation of symmetric bis(azepinones). The mechanistic rationale involves the formation of metallated ketene 177 and its subsequent attack by vinylaziridine 175 to generate zwitterionic species 178; then, aziridine ring opening with concomitant C–C bond formation should lead to the reaction products 176. In a similar manner, chromium ethoxy methyl FCC 179 undergo photochemical [6+2]-cycloaddition with vinylazetidines 180, under CO pressure, to synthesize eight-membered ring tetrahydroazocin-2-ones 181 in good to excellent yields (Scheme 45, bottom).

5. APPLICATIONS OF ALKENYL AND ARYL CARBENE COMPLEXES The reactivity of alkenyl and aryl carbene complexes is usually marked by the participation of the double bond and the aromatic ring, being the D€ otz reaction the most representative example. Other important group of

40

Jos
e Barluenga and Enrique Aguilar

hn, Et2O CO (60−70 psi) 16 h

OEt (OC)5M

+ R1

N

O

N

175

R2 N

N

− O M(CO)5

+

• R1

OEt

176

R2

M(CO)5

R1

OEt

177

R2

53%-quant.

R2

174

O R1

175

OEt 178

M = Cr, Mo R1 = Me, alkyl (1°, 2°) R2 = Bn, CH2PMP, PMP, (R)−CH(CH3)Ph hn, Et2O CO (60−70 psi) 16 h

OEt (OC)5Cr

+ Me

179

N R1

R1

O

N

Me OEt

60%−93%

180

181

R1 = alkyl (1°, 2°), Bn, PMPCH2

Scheme 45 Synthesis of azepinone and azocinone derivatives by reaction of ethoxy FCCs with vinylaziridines and vinylazetidines.

reactions is 1,4-additions and, more often, [2+2]-, [3+2]-, or [4+2]-cycloadditions, which may take place in α,β-unsaturated FCCs leading to new carbene complexes. Owing to their activating behavior in these types of reactions, FCCs have been termed as “superesters” or “superamides,” as the adducts or cycloadducts are formed with higher regioselectivity, higher diastereoselectivity, and/or increased reaction rates than with the isolobal ester or amides. Besides those transformations, the most representative reactions developed are described below.

5.1 Synthesis of Acyclic Compounds As mentioned above, FCCs are electrophilic in nature; thus, when the carbene carbon atom is directly linked to an alkenyl group the electron deficiency introduced by the metallic group is extended to the olefin double

41

Group 6 Metal Fischer Carbene Complexes

bond, which will also be prone to undergo nucleophilic attack. Therefore, two positions are amenable of nucleophilic attack: the carbene carbon atom or, via conjugate addition, the β-position of the olefinic double bond. Steric factors and the nature of the nucleophile will play an important role in determining where the attack occurs. In this regard, Casey found that the reaction of chromium (methoxy) (styryl)carbene complex 182 with phenyllithium at
78°C affords, after HCl treatment, a mixture of products: the major component 184 results from the attack of the nucleophile to the carbene carbon atom, while the minor component 183 comes from the attack to the conjugate position (Scheme 46). However, an increased ratio of conjugate addition products (183 and 185) is obtained when lithium diphenylcuprate is employed.128 Barluenga reported in 1994 that alkyl and aryl organolithium reagents undergo smooth and efficient Michael-type addition to chiral, nonracemic chromium carbene complexes derived from (
)-8-phenylmenthol, such as 186,129 affording addition compounds, such as 187, with excellent diastereoselectivity (Scheme 47). The regioselectivity of the process is determined by the bulky alkoxy group linked to the carbene carbon atom. The high diastereoselectivity observed in the reaction has been attributed to an alkene–arene π-stacking effect. Successive removal of the pentacarbonylchromium fragment and of the chiral auxiliary led to optically 1. Ph[M], Et2O, −78°C 2. HCl, −78°C

OMe (CO)5Cr

Ph

OMe Ph Ph

(CO)5Cr

182 Ph[M] = PhLi

Ph[M] = Ph2CuLi

OMe Ph

OMe +

+ Ph

Ph

Ph

183

184

185

9%

17%

0%

30%

6%

8%

Scheme 46 Carbanion addition to methoxy styryl FCC 182. 1) R1Li, THF −78 to 20°C 2) SiO2

OR* (CO)5Cr

Ph

63%−67%

186

OR* (CO)5Cr

1) NaOMe MeOH 2) 1N HCl

R1 Ph

187

40%−62% 80%−90% ee

O

R1 Ph

H 188

R*OH = (−)-8-phenylmenthol R1 = alkyl (1°, 3°), aryI

Scheme 47 Stereoselective Michael addition of organolithium compounds to enantiopure chromium alkoxy alkenyl FCC 182.

42

Jos
e Barluenga and Enrique Aguilar

active β-substituted aldehydes 188 with high enantiomeric excesses. The whole sequence would correspond to an asymmetric Michael addition to an α,β-unsaturated aldehyde. This method has competed advantageously over other asymmetric Michael-type addition reactions to prepare the same kind of compounds130; however, the recent development of organocatalysis has provided more efficient approaches, although they present some limitations.131 The behavior of lithium enolates and organolithium compounds in their reactions with chromium alkenyl FCCs 15 is rather similar, leading to functionalized adducts, such as 189, as a sole distereoisomer in most cases.45,132 However, the reaction course for copper enolates differs than that encountered for lithium enolates,133 as umpolung reactivity of Michael acceptors has been observed. Thus, the anionic species generated after the 1,4-addition of the copper enolate to the carbene complex does not react with electrophiles through the α-position, as it could be expected, but through the initial carbene carbon atom to form demetallated adducts 190 (Scheme 48). The mechanistic rationale for the copper case involves the formation of copper 1-methoxyalkenyl chromate 191 by conjugate addition, which should undergo transmetallation thus transferring the 1-methoxyalkenyl ligand to copper to form 1-methoxyalkenyl copper complex 192; finally, metal complex 192 should react with the electrophile. N-heterocyclic carbenes (NHCs) also behave as nucleophiles against group 6 metal alkenyl FCCs, and the reaction outcome depends mainly on the nature of the alkenyl FCC. Thus, on the one hand, for alkoxy alkenyl FCCs 193, nucleophilic addition of NHCs 194 to the C-β-position is much faster than CO ligand displacement and zwitterionic η1-alkenyl complexes 195 are obtained in quantitative yields (Scheme 49). All compounds 195 reported are stable, quite robust, and can be stored as solids. On the other hand, for amino alkenyl FCCs 196, the nucleophilic attack of NHC 197 is directed to the M(CO)5 fragment, causing the displacement of a CO ligand and the formation of mononuclear mixed biscarbene complexes 198 in good yields; only chromium FCCs undergo this transformation which takes place under rather smooth conditions (room temperature). Aryl and heteroaryl amino carbene complexes 199 may be smoothly lithiated with butyllitium at
78°C, and the lithiated carbene complexes are able to react with electrophiles, such as alkyl halides, aldehydes, ketones, or even to be acylated, to form functionalized amino FCCs 200.134 Lithiated carbene complexes also partake in Negishi cross-coupling reactions to form amino FCCs 201, with satisfactory to good yields in all cases, by a sequence

43

Group 6 Metal Fischer Carbene Complexes

OMe R1 OM

M = Li

(CO)5Cr E

75%

1) OMe THF

R1 15

2)

Et

189

Et

(CO)5Cr

O

H

R1 = 4-Methoxyphenyl E−X = CH2KCH–CH2Br

E−X

OMe R1 M = Cu

O

H

E

53%−82% de >95%

Et 190

R1 = alkenyl, aryl, heteroaryl E−X = H2O, D2O, PhCOCl, MeCOCl, t-BuCOCl, H2CKCHCH2Br, HCCHCH2Br OMe R1 – (CO)5Cr [LCu]

OMe R1

O

H

H

O

LCu + [Cr(CO)5]

Et

Et 192

191

Scheme 48 Normal (M ¼ Li) and umpolung (M ¼ Cu) reactivity of alkenyl FCCs with enolates and electrophiles.

Mes

N

OEt (CO)5M

+

Mes

N

N

Mes

Quant.

R1 193 M = Cr, W R1 = aryl, heteroaryl, MeO

EtO – (CO)5M

194

+ N R1 Mes

H

Pentane, rt

H 195

Mes = 2,4,6-trimethylphenyl NMe2

NMe2 (CO)5Cr

+

Pentane, rt Mes

N

N

Mes

54%−65%

Ar 196 Ar = aryl, heteroaryl

197

Scheme 49 Nucleophilc addition of NHCs to alkenyl FCCs.

(CO)4Cr Mes

N

N 198

Mes

Ar

44

Jos
e Barluenga and Enrique Aguilar

involving transmetallation with zinc bromide, followed by treatment with alkenyl, aryl, or heteroaryl halides in the presence of palladium catalysts.135 Interestingly, FCCs derived from all three group 6 metals tolerate such Negishi coupling conditions (Scheme 50, top). On the other hand,

Y

M(CO)5

1) BuLi, THF, −78°C 2) [E]

X NMe2

Z

29%-quant.

M(CO)5 X NMe2 200

[E] = electrophile

199

M = Cr, W X = S, O, NMe, –CH=CH– Y = H, Br Z = Me, allyl, Br, –CH=O, –COR, –CRR⬘(OH), –CO2Ph

Y

M(CO)5 X NMe2

1) BuLi, THF, −78°C 2) ZnBr2 3) Pd(PPh3)4, R1X, rt

R1

43%−85%

M(CO)5 X NMe2

199

201

M = Cr, Mo, W X = S, O, NMe, –CH=CH– Y = H, Br R1 = alkenyl, aryl, heteroaryl

Br

M(CO)5 X 202

NMe2

R1-ZnBr PdCl2XantPhos

R1

52%−74%

M(CO)5 X NMe2 201

M = Cr, Mo X = S, –CH = CH– R1 = alkyl (1°), aryl, heteroaryl R1-ZnBr Br

M(CO)5 X OEt

Pd(PPh3)4 51%−100%

203

R1

M(CO)5 X OEt 204

M = Cr, Mo, W X = S, O R1 = alkyl (1°), alkenyl, alkynyl, aryl, heteroaryl

Scheme 50 Functionalization of aryl and heteroaryl FCCs by lithiation and Negishi cross-coupling reactions.

45

Group 6 Metal Fischer Carbene Complexes

brominated amino FCCs 202 may act as electrophiles in cross-coupling reactions; thus, in a reverse Negishi coupling they react with organozinc reagents in the presence of PdCl2XantPhos to produce the same amino FCCs 201 mentioned above (Scheme 50, middle). Additionally, brominated alkoxy heteroaryl FCCs 203 also behave as electrophiles in a Negishi cross coupling, leading to functionalized alkoxy heteroaryl FCCs 204 in good to excellent yields. For alkoxy FCCs 203 the coupling with sp-carbon (alkynyltype) nucleophiles is also successful (Scheme 50, bottom).

5.2 Synthesis of Three-Membered Carbocycles The cyclopropanation of the double bond of alkoxy alkenyl FCCs is a strategy to access cyclopropanes complementary to the cyclopropanation of an olefin by a carbene complex. Several approaches have been developed, all of them based on a initial 1,4-addition of a nucleophile followed by reaction with an internal electrophile thus forming the cyclopropane ring. For instance, after the initial 1,4-addition of halomethyllithium to chromium alkenyl FCCs 15, the anionic intermediate evolves by spontaneous γ-elimination leading to trans-substituted methoxy cyclopropyl FCCs 205 in a highly diastereoselective manner136 (Scheme 51). Removal of the metal fragment provides functionalized cyclopropane derivatives. Enantiopure 1,2-disubstituted and 1,2,3-trisubstituted cyclopropanes are formed when enantiomerically pure chromium alkenyl FCCs derived from (
)-8phenylmenthol are employed.137 By a different methodology, but employing the same strategy of 1,4nucleophilic addition followed by reaction with an internal electrophile, Florio and Barluenga prepared functionalized cyclopropanes 208 in moderate diastereoselectivities by addition of lithiated oxazolines 206 to chromium and tungsten alkenyl FCCs 207.138 Only two diastereoisomers (easily separated by column chromatography) were obtained when the chiral auxiliary was placed at the oxazoline ring (Scheme 52). OMe + R1

(CO)5Cr 15

ClCH2I

MeLi, THF/ether −78°C 90%–93%

OMe R1

(CO)5Cr 205

R1 = alkyl, aryl, heteroaryl

Scheme 51 Diastereoselective synthesis of cyclopropylcarbene complexes from alkenyl FCCs and halomethyllithium.

46

Jos
e Barluenga and Enrique Aguilar

1) THF, −80°C to −60°C 2) Air (open flask), sun light or Pyridine N-oxide, THF

R1 N R2

OMe

Me

+

Cl

O

Ar

(CO)5M

Me

50%–60%

COOMe

R1

M = Cr, W Ar = Ph, 4-methoxyphenyl

R1 = i-Pr, MeOCH2 R2 = H, Ph

COOMe trans-208

cis-208

207

Ar

Me

+

Li 206

Ox

Ar

Ox

N

Ox = R

2

O

Scheme 52 Diastereoselective synthesis of cyclopropylcarbene complexes from alkenyl FCCs and lithiated oxazolines.

Ph

O

R2

OMe +

1

R

Li

THF −98°C to rt Ar

(CO)5W

209

R2 R1

W(CO)5

HO

OMe

Ph

59%–81%

Ar 211

210

Ar = aryl, heteroaryl R1, R2 = H, Me, Ph O

(CO)5W

R2 Ph Me Li O

R1

(CO)5W Ph

H

MeO

O

Ph

Ar

Ar

1

Li R2 R 212

Ar

213

H

O W(CO)5 OMe

2

R

R Li 1

214

Scheme 53 Diastereoselective synthesis of cyclopropylcarbene complexes from alkenyl FCCs and lithiated oxirane derivatives.

An additional access to functionalized tungsten cyclopropylcarbene complexes 211 in a diastereoselective manner has been developed by reaction of lithiated oxiranes 209 and tungsten alkenyl FCCs 210 (Scheme 53).139 The bulkiness of tertiary lithiated carbanions employed as nucleophiles explains the preference for the 1,4-addition over the 1,2-addition for these two cases. On the other hand, a model similar to that described by Nakamura for the 1,4-addition of enolates to the same kind of carbene complexes accounts for the observed stereochemical outcome for this reaction.140 Thus, the configurationally stable lithiated oxirane 209 should approach alkenylcarbene complex 210; then, the formed bimetallic complex 212 should control the C–C bond formation on the re face of 210 generating lithiated intermediate

Group 6 Metal Fischer Carbene Complexes

47

213. The favored formation of 213 over 214 is explained by the hindrance between Ar and Ph groups. According to the authors, an appropriate orbital alignment should be present at the obtained lithium derivative 213 to allow the overlap of the carbanion lone pair on the β-carbon (with respect to the oxirane ring) with the antibonding orbital of the oxirane C–O bond; in this manner, the cyclopropanation should take place simultaneously to the oxirane ring opening. On the other hand, the formation of cyclopropylmethanols 211 instead of cyclobutanols has been attributed to kinetic reasons, because of the much closer positions of the carbon atoms involved in the C–C bond-forming step. The oxidation of FCCs 211 leads to cyclopropane-γ-lactones and cyclopropane carboxylates. This strategy has been also extended to optically active α-lithiated aryloxiranes.139 On the other hand, a related reaction consisting in the addition or cycloaddition of sulfur ylides to α,β-unsaturated chromium FCCs leads to mixtures of enol ethers and cyclopropanes, which come from 1,2- and 1,4-additions, being the observed regioselectivity strongly dependent on the nature of the ylide.141

5.3 Synthesis of Five-Membered Carbocycles Even though aryl- and alkenylcarbene FCCs usually react with alkynes to give the [3+2+1]-benzannulation products (see Section 5.4), the cyclopentannulation appears frequently as competing reaction. The cyclopentadiene ring is formed by the coupling of the carbene ligand and the alkyne, without insertion of the CO ligand. Several parameters (metal, solvent, concentration, carbene heteroatom, etc.) affect to the outcome of the reaction but, in general, the cyclopentannulation reaction becomes the major or exclusive reaction pathway in the cases of amino-stabilized aryl FCCs and β-amino-α,β-unsaturated FCCs. For instance, the reaction of morpholinophenylcarbene complex 215 with alkynes gives indene derivatives 216 and/or indenones 217 in very good combined yields (Scheme 54).142 Additionally, the cyclopentannulation becomes also the major or exclusive reaction pathway for β-amino-α,β-unsaturated FCCs 218 leading to 3-alkoxy-5-(dialkylamino)cyclopentadienes 219 (Scheme 55).4,143 Barluenga reported that chromium alkenyl(amino) FCCs 220 bearing an electron-withdrawing group at the β-position144 react with internal alkynes 221, having at least one electron-withdrawing substituent, leading to functionalized cyclopentadiene derivatives 222. A chelate tetracarbonyl

48

Jos
e Barluenga and Enrique Aguilar

R2

O

R2 N + R1

(CO)5Cr

R2

R1 and/or

DMF, 125°C 89%–96%

R1

N O

R1 = H, alkyl (1°), aryl, CO2Et O

R2 = alkyl (1°, 3°), aryl

215

217

216

Scheme 54 Synthesis of indene derivatives via cyclopentannulation of aminophenylcarbene 215 and alkynes. EtO

OEt R1

(CO)5Cr

+

2

R

R

R1

Hexane, 55°C

3

51%–95%

NMe2

R2

NMe2

3

R 219

218 R1 = alkyl (1°, 2°, functionalized) R2 = H, alkyl (1°, 2°), aryl R3 = alkyl (1°, 2°, functionalized), aryl, TMS

Scheme 55 Synthesis of 3-alkoxy-5-(dialkylamino)cyclopentadienes from β-amino alkenyl FCCs and alkynes.

N

N

+

R2

THF, 60°C

CO2R3

CO2R1

(CO)5Cr 220

R1 = Et, (1R,2S,5R)-menthyl R2 = alkyl (1°), aryl, CO2Me, CO2Et R3 = Me, Et

R3O2C

61%–81% R2

221

CO2R1 222 3

R O2C

N

R2 (CO)4Cr CO2R1 223

Scheme 56 Synthesis of cyclopentadiene derivatives from β-(alkoxycarbonyl)alkenylcarbene complexes and internal electron-deficient alkynes.

carbene complex intermediate 223 has been isolated in some cases145 (Scheme 56). However, the reaction of FCCs 220 with unactivated alkynes or terminal electron-poor alkynes leads exclusively to phenols by a D€ otz reaction.

49

Group 6 Metal Fischer Carbene Complexes

Transmetallation has emerged as an strategy to control and to modulate the reactivity of FCCs; for instance, the outcome of the reaction of chromium alkenyl(methoxy) FCCs 15 with alkynes differs in the absence or in the presence of nickel(0) complexes. Phenol derivatives are formed in the first case (D€ otz reaction, see Section 5.4) while cyclopentenones 225 are obtained with internal alkynes in acetonitrile in the presence of a stoichiometric amount of [Ni(cod)2]; hydrolysis of the enol ether moiety takes place during chromatographic purification of the initially formed cyclopentadienes 224.146 The major features of this cyclopentenone annelation are: (i) its wide scope, as neutral and activated alkynes as well as silicon-, boron-, and tin-substituted alkynes are appropriate partners and (ii) its regioselectivity, which is complete for a number of nonsymmetrical alkynes (Scheme 57). On the other hand, an efficient [3+2] cyclization has been reported between alkenyl FCCs of Cr(0) 15 and alkynes in the presence of cationic rhodium(I) complexes providing good yields of cyclopentenone derivatives.147 A cationic rhodium(I) alkoxycarbene complex has been occasionally isolated as reaction intermediate. A formal [3+2] carbocyclization takes place when pentacarbonyl (alkoxyalkenyl)tungsten(0) complexes 226 are treated with either achiral or enantiopure tertiary enamines 227 leading to alkoxycyclopentenes 228 and 229 (Scheme 58).148 Remarkably, enamines 227 derived from aldehydes (R4 ¼ H) and those derived from ketones (R4 6¼ H) generate opposite regiochemistry. Therefore, different mechanisms have been proposed to account for these results; thus, an initial Michael-type 1,4-addition should take place for enamines derived from aldehydes 227 (R4 ¼ H) while ketone-derived enamines 227 (R4 6¼ H) should undergo 1,2-addition to the carbene carbon atom. The initially formed alkoxycyclopentenes 228 and 229 have also been transformed into enantiomerically enriched cyclopentanones and cyclopentenones. OMe + R2

R3

OMe

Ni(cod)2 MeCN

R

R1

(CO)5Cr

SiO2

R3

41%–75% R1

15

O 3

R2 224

R1

R2 225

R1 = Me, alkenyl, aryl, heteroaryl R2 = Me, alkyl (3°), aryl, OEt, CO2Me R3 = Me, t-Bu, CO2Me, PhCH2−, TMS, n-Bu3Sn, PinB (PinB = pinacol boronate)

Scheme 57 Synthesis of cyclopentenones by Ni(0)-mediated reaction of alkenyl FCCs and internal alkynes.

50

Jos
e Barluenga and Enrique Aguilar

OR2

R3 = Me; R4 = Et R3, R4 = –(CH2)5– 88%–95%

R6

2

OR

R1

(CO)5W

+

R4

N

R5 R6 228

R3

R4

R5

OR2

227

R = alkyl (1°, 3°), aryl, heteroaryl R2 = Me, t-Bu R5, R6N =

R1

THF −80°C to rt

R5 N

226

R3

R4 = H

N

1

R4

72%–95% N,

R1

N

R6

R3 229

R3 = i-Pr, n-Hexyl OMe

Scheme 58 Synthesis of cyclopentanone derivatives from tungsten alkenyl FCCs 226 and enamines.

OMe (CO)5Cr

+

OLi R2

X 230

1) −78°C to rt PMDTA 2) H2O 3) Air

OMe X

68%–91% H

121

OH 231

R2

X = CH2, O R2 = Me, alkyl (2°, 3°), alkenyl, alkynyl, aryl, heteroaryl, 4,5-dihydro-4H-pyran-2-yl

Scheme 59 Synthesis of cyclopentanone derivatives from α-substituted alkenylcarbene complexes and lithium methyl ketone enolates.

A related strategy, involving lithium methyl ketone enolates 121 and α-substituted alkenyl FCCs 230 in the presence of three equivalents of N,N,N 0 ,N 0 ,N 00 -pentamethyldiethylenetriamine (PMDTA), has been also developed to diastereoselectively prepare five-membered carbocycles 231 (Scheme 59). Cyclopentenol derivatives 231 are formed as single stereoisomers in very good yields, and bicyclic ketones have also been obtained by hydrolysis of the enol ether group. An initial 1,2-addition of lithium enolates to carbene complexes 230 followed by a cyclization induced by a 1,2-migration of the pentacarbonylchromium group accounts for the observed results.149

Group 6 Metal Fischer Carbene Complexes

51

Allenes have shown to be specially suitable and useful reagents for the synthesis of five-membered carbocycles in their reactions with FCCs.150 Thus, nonactivated allenes react with chromium alkenyl FCCs 232 in the presence of [Ni(cod)2] in toluene at room temperature to produce 3-alkylidenecyclopentanone derivatives 233, an a chemo- and regioselective [3+2]-cyclization151; only the unsubstituted allene C]C is involved in the reaction. Interestingly, when the same type of compounds are reacted in the presence of several rhodium(I) catalysts, such as [(naphthalene)(cod) Rh][SbF6], a complementary chemo- and regioselective [3+2]-cyclization takes place to generate 2-alkylidenecyclopentanone derivatives 234 in good yields143 (Scheme 60, top). Alternatively, compounds 234 have also been obtained by using neutral catalyst [Rh(cod)Cl]2 under a CO atmosphere. For the nickel case, the mechanistic rationale involves an initial chromium–nickel exchange to form a nickel carbene complex, which should insert a single allene unit through the less substituted C]C bond leading to nickelacyclobutane 235 (M ¼ Ni). This species should equilibrate to nickel π-allyl complex 236, which after a reductive elimination should lead to 3-alkylidenecyclopentanone derivatives 233. Moreover, this result also showcases the drastic modification of the reactivity of chromium alkenylcarbene complexes in the presence of Ni(0) complexes (as previously stated for alkynes). Indeed, the thermal reaction of chromium alkenyl FCCs 232 and 1,1-diphenyl or 1,1-dimethyl allenes leads to formation of alkoxysubstituted 1,3-butadienes 237, in the absence of other metal complexes152; in this case, chromacyclobutane intermediate species 235 (M ¼ Cr) should supposedly evolve via a retro-[2+2]-cycloaddition (Scheme 60, middle). For the rhodium-catalyzed transformation, rhodium carbene complexes 238 have been proposed to be the intermediates partaking in this transformation. Indeed, they have been prepared and isolated in good yields (60%–72%) by mixing a solution of stoichiometric amounts of [(naphthalene)(cod)Rh][SbF6] and chromium methoxy complexes 232 at room temperature.137 They should undergo a metalla-Diels–Alder cycloaddition with the allene to form rhodacyclohexane 239, whose evolution by a reductive elimination would generate cyclopentenes 234 (Scheme 60, bottom). This rhodium-catalyzed [3+2]-cyclization reaction works efficiently for a diverse array of activated allenes 240, with outstanding chemospecificity.153 Thus, the [3+2]-cyclization of electron-deficient allenes takes place at the C]C bond placed orthogonally to the electronwithdrawing group, leading to 242, while the [3+2]-cyclization of

52

Jos
e Barluenga and Enrique Aguilar

OMe Ni(cod)2 toluene, 25°C 68%–72%

R2

Ar OMe

•

+ Ar

(CO)5Cr

R1 233 R2

R1

232 Ar = aryl, heteroaryl R1 = R2 = Me, Ph, –(CH2)5– or R1 = Ph, HOCH2CH2 R2 = H, Me

[(naphthalene)(cod)Rh][SbF6] (10 mol%) CH2Cl2, rt

OMe

42%–93%

Ar

R1

R2

234 Ar LnNi

[M] = LnNi

233

R1 MeO

Ar

OMe R2

[M]

236

R1

O

OMe R2

Ar

Ar

235 [M] = (CO)nCr

237 + (CO)nCr

R2 • R1 OMe

OMe Ar Ar

(cod)(CO)Rh 238

[SbF6]

[Rh]

234

R1 R2 239 [Rh] = [(cod)(CO)Rh]+

Scheme 60 Synthesis of alkylidenecyclopentanone derivatives from alkenyl FCCs and allenes in the presence of either Ni(cod)2 or Wender catalyst.

electron-rich allenes proceeds through the heteroatom-substituted C]C bond of the allene leading to 241 (Scheme 61). Therefore, this process is a simple and an effective way to prepare functionalized 3,4-disubstitued 2-alkylidenecyclopentenones due to its efficiency, the high regio- and diastereoselectivity of the cyclization and the ease of the hydrolysis of the obtained cycloadducts.

53

Group 6 Metal Fischer Carbene Complexes

OMe X = OPh, NR R

2 3

47%–99% R , R = –(CH2)3CO– or R2 = Ph, (MeO)2CHCH2 R3 = Ts 2

X

OMe R1

(CO)5Cr 15

+

Rh(I) (5 mol%) CO, CH2Cl2, rt

•

3

R1

X 241

OMe

240 X = COOR

4

R1 = alkyl (2°, 3°), alkenyl, aryl, heteroaryl

X 51%–72% R = Me, Et, t-Bu, PhCH2 4

R1 242

Scheme 61 Synthesis of 2-alkylidenecyclopentanone derivatives from alkenyl FCCs and functionalized allenes in the presence of rhodium(I) catalysts.

Alkenyl FCCs 232 react with methoxycarbonyl-substituted siloxydiene 243 to afford vinylcyclopentene derivatives 244 as unique products, with complete regioselectivity and in good yields (Scheme 62); in contrast, cycloheptadiene derivatives are mainly furnished from electron-rich siloxydienes.154 The formation of the reaction products is explained by a [4+2] cycloaddition, with the electron-poor chromadiene 232 system acting as 4π component, to the electron-rich terminal double bond of siloxydiene 243. Finally, a reductive elimination of the metal fragment in the formed chromacyclohexene intermediate should take place. The overall process is indeed a formal [3+2]-cycloaddition. On the other hand, the reaction between alkoxy(alkenyl) FCCs 15 and neutral 1,3-dienes 245 generates alkenyl cyclopentenes 246 or 247.155 The course of the reaction depends highly on both the temperature and the solvent; different outcomes, such as formal [3+2], [4+1], or even [4+2] cycloadditions, may take place. Thus, [3+2] cycloadducts 246 are formed exclusively when toluene is employed as solvent, whereas heating the reaction in THF at 120°C in a sealed tube leads to [4+1] cycloadducts 247 as unique products; in both cases, 2,6-di-tert-butyl-4-methylphenol (BHT) is used as radical scavenger to inhibit diene polymerization (Scheme 63). The formation of the final products is easily explained by a two-step sequence: a metalla-Diels–Alder reaction followed by reductive elimination of the metal moiety. High enantioselectivities are reached when alkenylcarbene complexes derived from (
)-8-phenylmenthol are employed. However, as the outcome of the reaction between dienes and alkoxy alkenyl

54

Jos
e Barluenga and Enrique Aguilar

OMe

1,2-Dichloroethane 80°C

TBSO + Ar

(CO)5Cr

CO2Me

232

CO2Me

TBSO

OMe

49%–72% Ar

243

244

Ar = aryl, heteroaryl

Scheme 62 Synthesis of cyclopentene derivatives from alkenyl FCCs and siloxydienes.

R2

10% BHT toluene, 80°C R2

OMe

75%–94% R1

+ R1

(CO)5Cr 15

R1 = alkyl (1°), aryl, heteroaryl R2 = H, Me, Me2CKCH(CH2)2–

245

OMe

10% BHT THF, 120°C

246 OMe

R2

R1

30%–31% 247

Scheme 63 Synthesis of cyclopentene derivatives from alkenyl FCCs and neutral dienes.

FCCs depends strongly on the reaction conditions,156 a different behavior, with alkenyl FCCs acting as dienophiles through the double bond in [4+2]cycloadditions, is observed when a deoxygenated diene is used as solvent (see Section 5.4, Scheme 70).157 Finally, alkoxyalkenyl FCCs 207 undergo a smooth and concerted cyclization with 8-methoxyfulvene 248 leading to tetrahydroazulene-derived FCCs 249 in high yields (Scheme 64). Remarkably, four consecutive stereocenters are generated with complete regio- and diastereoselectivity by this all-carbon formal [8+2] cycloaddition; the nature of the observed stereoand regioselectivity has been attributed to both steric and electronic factors.158

5.4 Synthesis of Six-Membered Carbocycles In 1975, the reaction of chromium phenyl carbene complex 250 with tolane to form naphthol 251 was reported for the first time by D€ otz (Scheme 65).159 Since then, the coupling of aryl (or alkenyl) FCCs with alkynes leading to highly substituted naphthols (phenols) has become the most emblematic and useful reaction of FCCs; it is commonly known as the benzannulation reaction or the D€ otz reaction.106 Usually, mild thermal conditions are enough for the reaction to proceed, although photoirradiation or dry-state

55

Group 6 Metal Fischer Carbene Complexes

MeO CH2Cl2 rt, 20 h

OMe + Ar

(CO)5M

MeO

Ar OMe H

63%–89%

207

M(CO)5

248

M = Cr, W Ar = aryl, heteroaryl

249

Scheme 64 Synthesis of tetrahydroazulene-derived alkoxy FCCs by [8+2]-cycloaddition.

Ph

Bu2O, 45°C

+

(CO)5Cr

OMe

Ph

OMe

Cr(CO)3

62% Ph 250

Ph OH 251

€tz reaction. Scheme 65 The Do

absorption conditions have shown to improve the efficiency in some cases. A wide number of theoretical and experimental studies have been carried out to elucidate the mechanism of this reaction, which otherwise has been widely used for the synthesis of molecules of interest. In the benzannulation reaction, a benzene ring is formed by the regioselective assembly of two ligands, carbene, and CO, of the metal complex and the alkyne. In most cases, the regiocontrol is due to steric factors being the bulkiest alkyne substituent placed predominantly at ortho position to the phenolic function. Arene tricarbonylmetal complexes are formed as primary benzannulation products, and they are usually converted into the corresponding metal-free products (and/or into quinones) by oxidative work-up. The scope of the D€ otz reaction regarding to the alkyne counterpart is amazing, but competition studies have shown that terminal alkynes are more reactive than the internal ones.160 In general, the benzannulation reaction of conventional aryl- and alkenyl(amino) FCCs presents more limitations than that of their alkoxy analogs, because the first ones display much lower reactivity, and then cyclopentannulation becomes an important competitive, or even exclusive, reaction pathway due to the higher reaction temperatures required. Nonetheless, alkenyl(dimethylamino)carbene complexes 252 react with terminal

56

Jos
e Barluenga and Enrique Aguilar

NMe2 NMe2 R

(CO)5Cr

2

+

R1

Benzene, 80°C

n-Pr

39%–64%

R1

OH

252

253

R = Me, H R2 = H, Me, Ph R1, R2 = –(CH2)4– 1

+

N (CO)5Cr

R2

n-Pr

CO2Et

R1

R2

N

1) THF, 60°C 2) SiO2

R2

57%–95%

R1

CO2Et OH

254 R1= Et, Bu, Ph, ferrocenyl, 1-cyclopentenyl, CO2Et, COMe R2 = H, Me, Et, Ph

255

€tz reaction: synthesis of phenol derivatives from alkenyl(amino) Scheme 66 The Do FCCs and terminal or internal alkynes.

alkynes, such as 1-pentyne, to give selectively the benzannulation products 253 with moderate yields161 (Scheme 66, top). On the other hand, alkenyl(amino)carbene chromium complex 254, bearing an electronwithdrawing group at the C-β-position, provides polysubstituted 5-(N-pyrrolidinyl)salicylic acid derivatives 255 by benzannulation reaction with an array of alkynes, including internal and electron-deficient alkynes143 (Scheme 66, bottom). Diastereoselective approaches to this reaction have been developed, using three different sources of induction: chiral alkynes and chiral carbene complexes possessing a stereogenic center either in the unsaturated carbene carbon substituent or in the heteroatom-stabilizing substituent. Thus, high stereoinductions are achieved when bulky chiral α-propargylic ethers 257 are used, being the degree of diastereofacial selection strongly dependent on the substituent of the ether moiety. Hunig’s base and TBDMSCl are added to protect the hydroxyl group in the generated arene chromium tricarbonyl complex162 (Scheme 67). The use of FCCs with a stereogenic center in the carbene ligand has also been reported. For instance, menthol-derived aryl FCC 259 provides the higher values of stereoinduction in the reaction with 3,3-dimethyl-1-butyne163; chromium tricarbonyl complexes 260, 261 are

57

Group 6 Metal Fischer Carbene Complexes

OR3

5

OR +

1

R

(CO)5Cr

R4

R2 256

TBDMSCl NEt(i-Pr)2 CH2Cl2, 60°C 32–89 dr: 55/45 to >96/4

257

OR5

TBDMSO R

1

R4

R2 (CO)3Cr

OR3 258

R1 = H, Me R2 = H, Me, t-Bu, TBDMS R3 = Me, i-Pr R4 = Me, n-Pr, Ph R5 = Me, TMS, TBDMS, TIPS, C(Ph)3

€tz reaction involving chiral alkynes. Scheme 67 Diastereoselective Do OTBDMS

OR* 1) t-Bu

(CO)5Cr

OTBDMS

t-Bu

2) TBDMSCl, Et3N 55% de = 82% 259

t-Bu

Cr(CO)3 +

Cr(CO)3

OR*

OR* 261

260

R*OH = (−)-menthol X (CO)5Cr + 262

n-Pr

OTBDMS

TBDMSCl NEt(i-Pr)2 CH2Cl2, 60°C

X = OMe, 50%, 76:24 anti:syn X = NMe2, 39%, 91:9 anti:syn

n-Pr Cr(CO)3 XR 263

€tz reaction involving chiral FCCs. Scheme 68 Diastereoselective Do

isolated by in situ protection with TBDMSCl (Scheme 68, top). Other chiral auxiliaries tested (8-phenylmenthol, borneol, 1-phenylethanol, etc.) were less effective. Unfortunately, the induction provided by the menthol auxiliary is less efficient for alkenylcarbene complexes. However, moderate to high diastereoselectivities are achieved in the reactions of 3-substituted cyclohexenyl carbene complexes 262, leading mainly to antiisomers of 8-substituted tetralin chromium tricarbonyl complexes 263164 (Scheme 68, bottom). On the other hand, the Diels–Alder reaction between 1,3-dienes and activated olefins is one of the most useful and predictable reactions for the synthesis of six-membered carbocycles. In this regard, alkenyl FCCs behave as excellent dienophiles in Diels–Alder reactions in terms of reactivity, regioselectivity, and diastereoselectivity.53,157 For instance, their

58

Jos
e Barluenga and Enrique Aguilar

reaction with isoprene is up to 2  104 faster than that of their organic ester analogs. Also, the regioselectivity of the cycloadditions of alkenyl FCCs, such as 264, with isoprene is comparable (265/266 ¼ 91:9, Scheme 69) to the one observed for Lewis acid-mediated cycloadditions of organic esters analogs with isoprene and much higher than that of their acrylate esters without Lewis acid activation. In addition, the levels of endostereoselectivity in the reactions with cyclopentadiene are significantly higher for FCCs than for the corresponding α,β-unsaturated esters. Moreover, taking into account the easy transformation of the carbene complex cycloadducts into the ester derivatives by oxidative treatment, alkoxy alkenyl FCCs can be considered as α,β-unsaturated ester equivalents in the Diels–Alder cycloaddition. However, as stated before, alkoxy alkenyl FCCs may behave not only as dienophiles but also as dienes (i.e., metalladienes) depending on the reaction conditions leading to five-membered carbocycles (see Section 5.3, Scheme 62). The polarity of the solvent plays an important role in the reaction rate for the Diels–Alder cycloadditions of tungsten alkenyl FCCs, such as 267, with activated dienes, such as 2-amino-1,3-butadiene 268165 (Scheme 70). Thus, at room temperature, no appreciable conversion is observed after 15 days in hexane while a fast reaction takes place in MeOH. Mechanistically, these observations suggest a stepwise process, initiated by nucleophilic attack of the enaminic carbon to the β carbon of the carbene complex and followed by rapid cyclization. In any case, the analysis of the substitution pattern in OMe

C6H6, 25°C

+

W(CO)5

(CO)5W

87%

OMe 265

264

+

W(CO)5 OMe 266

91:9

Scheme 69 [4+2]-Cycloaddition reaction of tungsten alkoxy alkenyl FCC 264 with isoprene. W(CO)5 W(CO)5 +

MeO

MeOH 25°C

MeO

N O

2-Furyl 267

W(CO)5 3N HCl

MeO

268

N

2-Furyl 269

90% O overall yield

O

2-Furyl 270

Scheme 70 Synthesis of cyclohexanone 270 by [4+2]-cycloaddition reaction of aminodiene 268 with tungsten alkoxy alkenyl FCC 267.

59

Group 6 Metal Fischer Carbene Complexes

both diene and FCC in the reaction scope pointed out that the stereochemistry of the reaction products correspond to a formal endo approximation of the related Diels–Alder process, except for a β,β-disubstituted FCC. Hydrolysis of cycloadduct 269 with an aqueous 3 M HCl solution in THF affords the corresponding cyclohexanone derivative 270, which may also be transformed into metal-free organic products by oxidation. Additionally, enantioenriched cycloadducts are obtained by the use of chiral enantiomerically pure dienes derived from 2-methoxymethyl pyrrolidine. Interestingly, seven-membered carbocycles are obtained when chromium FCCs are employed (vide infra, Section 5.5, Scheme 73). The Diels–Alder cycloadditions of amino-functionalized s-cis vinylcarbene complexes 271 bearing a cyclic BF2-chelated structure, with 2-amino-1,3-dienes take place under mild conditions, leading to cyclohexanone-derived carbene complexes. High regioselectivity and exo or endo-selectivity depending on the substitution pattern of the diene are reached.166 Additionally, the usually less accessible exo cycloadducts 273 are obtained with a high level of asymmetric induction when chiral nonracemic 2-aminodienes, such as 272, are employed (Scheme 71). Removal of both the metal fragment and the BF2 group provides an access to α,αbranched β-amino aldehydes or β-amino acids. The thermal reaction between alkenyl FCCs and pentafulvenes leads to substituted indanones and indenes by an uncommon [6+3] carbocyclization.167 For example, the reaction of chromium alkoxy alkenyl FCCs 274 with 6-acetoxyfulvene 275 in acetonitrile at 80°C affords substituted indenes 276 as mixture of isomers (Scheme 72). Moreover,

(CO)5Cr

O

−

R

F

B

+

F

N R1 R1

2

R3

+ N

OR4

1) THF −78°C to rt 2) Silica gel

(CO)5Cr

F − F O B + R1 N R1

23%–60% ee = 11%–93%

R2 R

O 271

272

3

273

R1 = Et, PhCH2– R2 = MeO, PhCH2O, TMSO, CH2KCHCH2O; R3 = Me or R2, R3 = –(CH2)3– R4 = Me, PhCH2–

Scheme 71 [4+2]-Cycloaddition reactions of chelate boroxycarbene complexes 271 with aminodienes.

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1) MeCN, 80°C (X = OR2) or 2 OAc Toluene, 100–200°C (X = NR 2) 2) SiO2

X + R1

(CO)5Cr

X

65%–75% R1

274

275

276

R = aryl, heteroaryl, CO2Et X = OMe, OCH2CH2I, N(CH2)4, NMe2 1

Scheme 72 Synthesis of indene derivatives by [6+3]-cyclization of alkenyl carbene complexes and fulvenes.

the [6+3] cycloadducts obtained in the reaction with alkyl fulvenes furnish indanones in good overall yields, by acidic treatment. The mechanistic course for these [6+3]-cyclization reactions should involve a nucleophilic 1,2-addition of the fulvene to the metal carbene carbon followed by [1,2]-Cr(CO)5-migration with concomitant cyclization.118

5.5 Synthesis of Seven-Membered Carbocycles The reaction of chromium alkenyl FCCs with electron-rich 1,3-butadienes leads to seven-membered carbocycles instead of the initially expected [4+2] cycloadducts157; an enantioselective version of this [4+3]-cyclization has been developed employing enantioenriched 2-aminodienes, such as (S)-2-methoxymethylpyrrolidine-derived 1,3-butadienes 277.168 Acetonitrile as solvent and room temperature are the optimal conditions for the formation of 1-amino-6-methoxycycloheptadienes 278 in a complete regio- and stereoselective manner. The chiral auxiliary is removed under very mild conditions to provide 1,3-cycloheptadiones 279 (Scheme 73, top). The mechanism proposed for the formation of the seven-membered rings involves carbene transfer to form cis-dialkenylcyclopropane derivatives 280, and a Cope rearrangement. The stereochemical results in the asymmetric version of the reaction suggest that the attack on the upside face of the diene is favored over that on the downside face (Scheme 73, bottom). α-Substituted alkenyl FCCs react with lithium methyl ketone enolates to form cyclopentenol derivatives, as stated in Section 5.3.149 However, cycloheptenones 282 are prepared with complete stereoselectivity although in moderate yields (43%–52%), both from chromium and tungsten alkenyl FCCs, when enolates 281 are formed from α,β-unsaturated carbonyl compounds.169 In the proposed mechanism, an initial 1,2-addition of lithium

61

Group 6 Metal Fischer Carbene Complexes

Ar

R2 R

OMe

1

MeCN 25°C

+ Ar

(CO)5Cr

Ar

R2 R2 R1

3N HCl

OMe

R1

N N

OMe

OMe 232

277

40%–55% overall yield

278

O O

ee = 55%–86%

279

Ar = Ph, 2-furyl R1 = Me; R2 = CH3OCH2–, PhCH2OCH2– or R1, R2 = –(CH2)4– (CO)5Cr Ar Favored

MeO R1

OMe

R2

N

N MeO

R2

R1

MeO

Cope rearrangement

278

Ar

Disfavored (CO)5Cr MeO

280 Ar

Scheme 73 Synthesis of cycloheptadione derivatives 279 from amino dienes and chromium alkoxy alkenyl FCCs.

enolates 281 to carbene complexes 232 should lead to bimetallic intermediates 283; then a 1,2-migration of the pentacarbonylmetal group should induce a Michael addition-mediated cyclization to generate sevenmembered intermediates 284. Then, a sequence involving elimination of the metal fragment, hydrolysis, metal decoordination, and double bond isomerization provides 2-cycloheptenones 282 (Scheme 74). Alkenyl FCCs of Cr(0) 15 react with terminal alkynes in the presence of nickel to form cycloheptatriene tricarbonyl chromium(0) complexes 285 (Scheme 75), instead of the a priori expected benzannulation or [3+2] cyclization (as found in the case of internal alkynes, see Section 5.3, Scheme 57). This formal [3+2+2] carbocyclization is completely regio- and stereoselective, the endo isomer being solely formed. The reaction mechanism should involve a four step sequence: (i) initial chromium–nickel exchange, (ii) double alkyne insertion, (iii) intramolecular cyclopropanation to a norcaradiene intermediate, and (iv) isomerization to the final cycloheptatriene ring.75 Additionally, an asymmetric version, which employs chiral binuclear FCCs, leads to chiral nonracemic cycloheptatriene tricarbonyl chromium(0) complexes.170

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OMe +

1. Et2O or THF 0°C to rt 2. H2O

OLi R1

Ar

(CO)5Cr 232

MeO

43%–52%

O

R1

Ar

281

282

Ar = aryl, heteroaryl R1= H, Me, Ph + Li O

O

Me

LiO R1 Ar

− Cr(CO)5

MeO +

−

(CO)5Cr

R1 Ar

283

284

Scheme 74 Synthesis of cycloheptenone derivatives from chromium alkenyl FCCs and enolates derived from α,β-unsaturated carbonyl compounds.

OMe + H

R2

Ni(cod)2, MeCN −10 to 20°C 2h

R1 MeO R2

(CO)3Cr

1

R

(CO)5Cr 15

R1 = alkyl, aryl, heteroaryl R2 = n-Pr, TMS, NC–(CH2)3–

62%–86% R2 285

Scheme 75 Ni-mediated [3+2+2]-cyclization of chromium alkenyl FCCs and terminal alkynes.

The reaction of chromium alkenyl FCCs 15 and allenes in the presence of [Ni(cod)2] in acetonitrile generates 3,4-bis(isopropylidene)cycloheptanone derivatives 287 as only products171 (Scheme 76, top), while a [3+2]-cycloaddition takes place exclusively in toluene, as stated before (see Scheme 60, top).141 This [3+2+2]-cyclization requires the insertion of two units of allene and has been attributed to an enhancement of the half-life of the intermediates generated after the first insertion of the allene, due to Ni-acetonitrile coordination; this fact would allow the insertion of the second allene unit. However, this [3+2+2]-cycloaddition is limited to 1,1-dialkylallenes. Overall, this switch in the outcome indicates that the reactivity of the new carbene complex generated by transmetallation may also be controlled by modification of the coordination sphere of the metal, either by the solvent or by an added ligand.

63

Group 6 Metal Fischer Carbene Complexes

MeO OMe

•

+ R1

(CO)5Cr

Me

O

Ni(cod)2, MeCN −10°C to rt

R1

SiO2

R1

40%–56% overall yield

Me

15 286

R1 = alkyl (1°), aryl, heteroaryl

287 R4

R4 OMe R2 R1

(CO)5Cr

•

+

MeO

[Rh(cod)Cl]2 (10 mol%) CH2Cl2, rt

3

R R2

R3

R4

50%–71%

4

R

R 3

R 289

R3

2M HCl THF, rt >95%

1

288 R1 = alkyl (Me, 1°, 2°, 3°), aryl, heteroaryl R2 = H, Me R3 = R4 = Me, Ph or R3,R4 = –(CH2)5– or R3 = Ph; R4 = H

O

R2 R1

R4 3

R 290

Scheme 76 Synthesis of bis(isopropylidene)cycloheptanone derivatives by Ni-mediated or Rh-catalyzed [3+2+2]-cyclization of chromium alkenyl FCCs and allenes.

In a similar manner, the reaction of chromium alkenyl FCCs 288 and allenes in the presence of 10 mol% of the neutral [Rh(cod)Cl]2 provides 1,3-dialkylidenecycloheptenes 289 with total regioselectivity in moderate yields. These compounds can be hydrolyzed to cycloheptanones 290 in excellent yields (Scheme 76, bottom). The different carbene character displayed by the new carbene complexes generated by chromium-metal exchange (Ni vs Rh) has been taken into consideration to explain the regioselective formation of seven-membered carbocyclic isomers 287 or 290 (head-to-head vs head-to-tail coupling of the allenes). Thus after the formation of π-allyl metallacycles 236 (due to the carbene nature of nickel carbene complexes, see Scheme 60), the insertion of a second allene should take place into the more reactive C(allyl)–Ni bond to afford nickelacyclooctene 291, which should evolve into the observed cycloadducts 287 by reductive elimination (Scheme 77, top). On the other hand, a metalla-Diels–Alder cycloaddition should lead to the formation of metallacyclohexene species 292 because of the low carbene character of rhodium FCCs. Then, a second allene unit should insert giving rise to metallacyclooctene species 293, which upon reductive elimination should provide compounds 290 (Scheme 77, bottom). Chromium alkenyl FCCs 15 also lead to highly functionalized bis1,2-alkylidene cycloheptenes by reaction of with methyl buta-2,3-dienoate in the presence of a rhodium catalyst.172

64

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R2

R1

R2

LnNi R2

OMe R2 236

MeO

287 − LnNi

R2 R2

Ln Rh

R2 = Me

R1

LnNi

OMe 291 R4

R4

R3 R3

MeO

LnRh 290 R4

R2 R1 292

R2

R1 293

− LnRh

R3

Scheme 77 Mechanisms proposed to account for the regioselective formation of methoxycycloheptene isomers 283 or 286 by transmetallation to Ni or Rh.

5.6 Synthesis of N-Heterocycles 1,3-Dipolar cycloadditions between alkenyl FCCs and 1,3-dipoles take place with high regio- and stereoselectivities. For instance, the 1,3-dipolar cycloaddition of alkenyl(alkoxy) chromium FCCs with diazo compounds leads to pyrazoline derivatives173; thus, pyrazolyl FCCs 296 are formed in moderate yields and with high stereoselectivity (>90% de) by reaction of chiral nonracemic chromium FCCs 294 with various diazo derivatives 295174 (Scheme 78). Pyrazoline adducts 296 can be easily transformed into a variety of cyclic and acyclic compounds.175 In a similar manner, (
)-8-phenylmenthol-derived FCCs 294 undergo a 1,3-dipolar cycloaddition with nitrilimines, prepared in situ from hydrazonoyl chlorides 297 and triethylamine, to provide N-phenylpyrazolines in high yields and excellent diastereoselectivies.176 Oxidation of pyrazolinyl FCCs 298 to metal-free pyrazolines is easily achieved with PNO177 (Scheme 78). Additionally, the 1,3-dipolar cycloaddition of enantiopure carbene complexes 294, derived from (
)-8-phenylmenthol, with in situ generated functionalized azomethine ylides 299 provides pyrrolidine carbene complexes 300 with complete stereoselectivity.178 Oxidation and further transformation of cycloadducts 300 give a straightforward entry to pyrrolidine-2-ones. This methodology is useful for the synthesis of pharmaceutically interesting compounds containing a pyrrolidinone ring; for

65

Group 6 Metal Fischer Carbene Complexes

OR*

R*O

Ar

Ar

Cl

(CO)5Cr R1 NHPh N N N N N R CHN2 Ph 297 295 H 298 296 NEt3 −78°C to rt benzene, rt 55%–79% 60%–80% THF >90% de >95% de OR* R1 = H, TMS, Ph, CH2KCH– R1 = Ph, 4-methoxyphenyl, CO2Et Ar (CO)5Cr (CO)5Cr

R1

R1

1

294 R*OH = (−)-8-phenylmenthol Ar = aryl, heteroaryl S S

+ − N

29%–68%

R1 299

>90% de

THF, −50°C

OMe

R*O

Ar O

(CO)4Cr S

N S

300 R1 = Me, PhCH2–

R1

O

N H (+)-Rolipram

Scheme 78 Regio- and stereoselective synthesis of pyrazoline and pyrrolidine derivatives through [3+2]-cyclization of chromium alkenyl FCCs and diazocompounds, nitrilimines, and azomethine ylides.

instance, it has been applied to the synthesis of the antiinflammatory and antidepressant drug (+)-rolipram (Scheme 78). The reaction between chiral nonracemic chromium alkoxyalkenyl FCCs 294 and N-alkylidene glycine ester enolates 301 also allows to access to the pyrrolidine ring with high regio- and diastereoselectivity179 (Scheme 79). A stepwise mechanism involving initial syn 1,4-addition of the enolate to the α,β-unsaturated carbene followed by 5-endo-trig ring closure has been proposed to explain the reaction outcome. Cycloadducts 302 have been transformed into enantiomerically enriched syn-3,4,5trisubstituted prolines. 3-Pyrroline derivatives 304 are also obtained in high yields and with good diastereoselectivities when achiral chromium alkenyl FCCs 303 are treated with aromatic aldimines in the presence of GaCl3 in refluxing

66

Jos
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OR* OR*

1 + R

Ar

(CO)5Cr

OEt

N Li

O

1) THF, −78°C 2) Silica gel

Ar

(CO)5Cr

75%–99% > 95% de

R1

CO2Et

N H

294

301

302

R*OH = (−)-8-phenylmenthol Ar = aryl, heteroaryl R1 = Ph, t-Bu

Scheme 79 Regio- and stereoselective synthesis of pyrrolidine derivatives from chromium alkenyl FCCs and iminoenolates.

OR2

NR3

+ R1

(CO)5Cr

Ar

303

GaCl3 (20 mol%) ClCH2CH2Cl, reflux

R2O

Ar 64%–86% dr = 78/22 to 92/8

R1

N R3 304

R1 = alkenyl, aryl, heteroaryl R2 = Me, Ph–CH2–, i-Pr R3 = aryl, Ph–CH2– Ar = aryl Sn(OTf)2 (20 mol%) NR2 ClCH CH Cl, reflux 2 2

OR* + (CO)5Cr

Ar

R1

R1

294 R*OH = (−)-8-phenylmenthol Ar = aryl, heteroaryl R1, R2 = aryl

R2O

30%–51% dr = 25/75 to 85/15

6M HCl THF, rt Ar

N 2

R 305

85%–98% ee = 96% to >99%

O R1

Ar

N 2

R 306

Scheme 80 Stereoselective synthesis dihydropyrrole derivatives from chromium alkenyl FCCs and imines.

1,2-dichloroethane (Scheme 80, top). The initial [3+2]-cycloadducts 304 can be transformed into 3-pyrrolidinones or 3-alkoxypyrroles.180 However, Sn(OTf )2 is the catalytic Lewis acid of choice to prepare chiral nonracemic dihydropyrroles 305 with good diastereoselectivities when 8-phenylmenthol-derived chromium alkenyl FCCs 294 are used (Scheme 80, bottom). The proposed mechanism involves a metalla-heteroDiels–Alder cycloaddition between the chromadiene system and the iminic double bond followed by reductive elimination. The diastereomers can be readily separated and, therefore, optically pure 2,5-disubstituted3-pyrrolidinone derivatives 306 have been obtained by acid hydrolysis of the major one.181

Group 6 Metal Fischer Carbene Complexes

67

N-containing five- and also six-membered heterocycles fused to a sevenmembered carbocycle ring are obtained by reaction of chromium alkenyl FCCS 15 toward 8-azaheptafulvenes; the nature of the reaction products depends on the substituent at β-position of the FCC. Thus, tetrahydroazaazulene derivatives 308 are readily afforded, with complete regio- and stereoselectivity, when alkyl- and phenyl-substituted chromium alkenyl FCCs 15 and 8-azaheptafulvenes 307 are employed, followed by treatment with PNO. Tungsten carbene complexes provide slighter lower yields of cycloadducts. However, cyclohepta[b]pyridone derivatives 309 are formed by an alternative [8+3] cyclization route when the same reaction protocol is employed with FCCs bearing coordinating groups (heteroaromatic substituents) at the β-position182 (Scheme 81, top). Regarding the mechanistic rationale, in principle the [8+2]-cyclization should be initiated by a 1,4-addition of the heptafulvene N-atom to the activated carbon–carbon double bond of the FCC leading to intermediate 310; it should be followed by cyclization from the endo metal conformation to form kinetic carbene complex cycloadduct 311, which is finally oxidazed to tetrahydroazulene derivatives 308. Alternatively, the formation of the cyclohepta[b]pyridones should involve a 1,2-nucleophilic attack of the nitrogen atom to the metal carbene bond to generate intermediate 312; then, a [1,2]-metal migration would induce a cyclization leading first to zwitterionic species 313 and later to the final reaction products 309, by a two-step sequence involving reductive metal elimination and enol ether hydrolysis. In this scenario, the 1,2-addition step should be assumed as reversible under the reaction conditions; in this manner, the reaction outcome should probably be controlled by the rate of the cyclization of 312–313. Therefore, substituents R1 able of coordinating to the metal would stabilize transition state 314, favoring this pathway, and driving the reaction to the [8+3]-cycloadducts (Scheme 81, bottom). The reaction of chromium alkenylcarbenes 15 and N,N-dimethylaminodiazafulvene 315 produces dihydroimidazo[1,2-a]pyridine cycloadducts 316, with complete regio- and diastereoselectivity via a sequence of 1,2-nucleophilic addition and [1,2]-metal-migration-promoted cyclization.183 The analogous tungsten FCCs lead to cycloadducts 316 in considerably lower yields. Treatment of the initial adducts with concentrated HCl in dichloromethane causes aromatization to imidazopyridines, such as 317, by elimination of dimethylamine (Scheme 82). From a synthetic point of view, this annulation of the pyridine unit onto the preexisting imidazole ring is indeed an unusual approach to the dihydroimidazo[1,2-a]pyridine ring, as

68

Jos
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R1

R2

[8 + 2]

N

O

2) Py-N-oxide

OMe

79%–86% R2

N

OMe

308 R1 = t-Bu, Ph, 4-chlorophenyl, 4-methoxyphenyl, 3-furyl

1) CH3CN, rt

+ R1

(CO)5Cr

O

15

307

R2

2

R = 4-tol, 4-methoxyphenyl

[8 + 3]

N

51%–87%

H

R1

309 R1 = 2-furyl, 2-(N-methylpyrrolyl), 2-thienyl, (E)-Ph–CHKCH–

R2

[8 + 2] route

N

1,4-addition R2

R1

R2

1

N

R

Cr(CO)5

H

H [Cr]

OMe

H

N

Py-N-oxide

308

MeO 310

‡

R2

311

N

307 +

OMe [Cr]

H X

OMe R1

(CO)5Cr

314 OMe

R2 15

N

1,2-addition

H H

R2

OMe

[Cr]

N

309

[Cr] H

[8 + 3] route

R1

R1 312

313

Scheme 81 [8+2] and [8+3] cyclizations of chromium alkenyl carbene complexes and 8-azaheptafulvenes: scope and proposed mechanism.

Me2N

OMe R1

(CO)5Cr

+

15

N

315

Me2N MeCN 25°C N 82%–90%

R1

N N OMe 316

12N HCl CH2Cl2

70% (R1 = 2-furyl)

R1

N N OMe 317

R1 = alkenyl, aryl, heteroaryl

Scheme 82 Synthesis of dihydroimidazo[1,2-a]pyridine derivatives from chromium alkenyl FCCs and diazafulvenes.

69

Group 6 Metal Fischer Carbene Complexes

Ar

NHt-Bu OMe

NHt-Bu

THF

+ Ar

(CO)5Cr

R1 232

NH

52%–91%

N

MeO

318

R1

319

Ar = aryl, heteroaryl R1 = alkyl (1°, 2°), aryl OMe Me OR* (CO)5Cr

320

13 Me

Me

N OH 321

Ph

+ N

87% 322:323 = 70:30

Me

Ph

THF, reflux

+ Ph

(CO)5Cr

322

OR*

N

OR*

323

R*OH = (1R,2S,5R)-menthol

Scheme 83 Diastereoselective synthesis of azepine derivatives from chromium alkenyl FCCs and 4-amino-1-azadienes or oximes.

most general methods leading to this heterocyclic structure involve the building of the imidazole ring from the pyridine nucleus. Alkenyl FCCs 232 react with 4-amino-1-azadienes 318 under unusually mild reaction conditions to afford 4,5-dihydro-3H-azepines 319 with moderate to high yields and with complete regio- and diastereoselectivity184 (Scheme 83, top). NMR monitoring has allowed to establish the reaction mechanism, consists of a two-step sequence: nucleophilic 1,2-addition of the unsubstituted nitrogen of the azadiene and a diastereoselective cyclization promoted by a [1,2]-M(CO)5 migration. In a similar manner, 4,5-disubstituted-4,5-dihydro-3H-azepines are formed in a complete regio- and diastereoselective cycloaddition between alkenyl FCCs and α,β-unsaturated oximes.118 An asymmetric version of this [4+3]-cyclization is achieved using chiral, nonracemic, menthol-derived FCCs. Interestingly, enantiomerically pure azepine derivatives are isolated in about 50% overall yield by crystallization of the major isomers in methanol. Thus, for instance, diastereoisomeric azepines 322 and 323 are obtained in an approximately 70:30 ratio when FCC 320, the oxime of (E)-2-butenal 321, and (1-methoxyethylidene)pentacarbonylchromium 13, which serves as the reducing agent, are refluxed in THF (Scheme 83, bottom). Additionally, highly functionalized 2-azepinones are prepared by reaction of activated 2-azadienes, such as 3-trimethylsilyloxy-2-azadienes, and tungsten alkenylcarbene complexes.185

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5.7 Synthesis of O-Heterocycles Usually, alkynes bearing electron-withdrawing groups have low tendency to partake in benzannulation and pentannulation reactions (for notable exceptions, see Section 5.3, Schemes 56 and 57, and Section 5.4, Scheme 66). For this reason, the reactions of alkoxy chromium FCCs 324 with alkynyl ketones and alkynyl esters 325 afford bicyclic lactones 326 by a von Halban-White186 type double cyclization187 (Scheme 84). Nonetheless, phenols formed by a D€ otz reaction are obtained in some cases as minor products in this reaction. β-Amino or alkoxy alkenyl FCCs 327 react with terminal alkynes to produce cyclopenta[b]pyrans 328 in modest to good yields, instead of the corresponding cyclopentadiene or benzannulation products188 (Scheme 85). The proposed mechanism for the formation of these heterocyclic compounds involves insertion of two molecules of the alkyne into the chromium–carbon bond followed by insertion of a CO ligand and intramolecular [4+2] cycloaddition.189

OMe R1

O +

R2

(CO)5Cr

R4

THF, 50°C

O

O

R5

3

R

R2 R3

R4 33%–93%

324

R5 R1

OMe

325

326

R1 = H, Me R2, R3 = –(CH2)3–, –(CH2)4–, –(CH2)3O– or R2 = Me, R3 = H R4 = Et, Ph, TMS R5 = H, Me, EtO, 1-cyclopentenyl

Scheme 84 Synthesis of fused lactones from chromium alkenyl FCCs and alkynyl ketones.

R2 OEt

X R1

(CO)5Cr 327 X = NMe2, OEt R1 = alkyl (3°), aryl R2 = alkyl (1°), aryl

+

OEt

THF, 52°C R2 17%–59%

O

R1

2

R 328

Scheme 85 Synthesis of cyclopenta[b]pyrans from β-amino or alkoxy chromium alkenyl FCCs and terminal alkynes.

71

Group 6 Metal Fischer Carbene Complexes

Ar 1

3

OR

R

OTMS

R2

OMe

+ Ar

(CO)5Cr 329

1. THF, 90°C, air 2. n-Bu4NF (30 mol%)

O

O R2

330

53%–71%

R1O

R3 Ar 331

Ar = aryl, heteroaryl R1 = Me, I–(CH2)2– R2 = R3 = Me or R2, R3 = –(CH2)5–

Scheme 86 Synthesis of dihydrocumarins from chromium alkenyl FCCs and ketene acetals.

The reaction of chromium(0) alkenyl FCCs 329 with ketene acetals 330 readily produces 4-aryl-3,4-dihydrocoumarins 331 (Scheme 86). Two equivalents of the FCC are incorporated into the final product. This unexpected result is explained by a sequence involving the formation of an isolable alkyne intermediate, generated from the reaction of the ketene acetal, and the carbene complex; then, a benzannulation with another equivalent of the carbene complex and a final lactonization should occur. This transformation represents a route to coumarin derivatives with several points of diversity. Additionally, it may be performed in multigram scale for a combination of model substrates.190 Chromium alkenyl FCCs 332 react with 3-siloxypent-4-en-1-ynes 333 leading to chromenes 334 in a transformation of wide scope for both partners. Moderate to high yields of a variety of 4-alkoxychromenes are reached with mono- and disubstituted alkenyl carbene complexes and mono-, diand tri-substituted 3-siloxypent-4-en-1-ynes.191 Dichloromethane, acetonitrile, and hexane are the tolerated solvents (Scheme 87, top). The cascade sequence starts by a benzannulation reaction that forms a chromium tricarbonyl complexed phenol; then, spontaneous loss of a silanol should generate an o-quinone methide that undergoes an electrocyclic ring closure to the chromene. Oxidative work-up with FeCl3DMF is used to remove complexed chromium tricarbonyl from chromene. This cascade has been applied in a synthesis of vitamin E to prepare both rings in a single step. It has been extended to aryl carbene complexes for the synthesis of 2-Hbenzo[h]-chromenes and lapachenole (Scheme 87, bottom). The reaction of alkenylcarbene complex 335 with o-alkynylheteroaryl carbonyl derivatives 336 produces dienylazaisobenzofuran adducts which are able to partake in a [8+2]-cycloaddition reactions with DMAD in one pot. N-heterocyclic furan-bridged 10-membered ring systems 337 are thus obtained in good to excellent yields (77%–92%)192 (Scheme 88).

72

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R3 OMe (CO)5Cr

+ R2

R1

1. Solvent, 60°C 2. FeCl3·DMF

R4

TBDMSO

MeO R4 R5

5

R 3

47%–88%

R

332

333

R1 = H, alkyl (Me, 3°), aryl R2 = H, Me, TMS or R1, R2 = –(CH2)4– R3 = H, Me R4 = R5 = H, Me or R4 = H, R5 = Me

R2

O

Solvent = CH2Cl2, CH3CN, or hexane

R1 334

MeO HO O O Vitamin E

Lapachenole

Scheme 87 Synthesis of chromenes.

(CO)5Cr

MeO2C Ar

Ar

OMe +

Het

Me

O

1) THF, reflux 2) DMAD, THF, reflux, 2 h

Het

CO2Me

O Me

77%–92%

336 335 Ar = aryl Het = pyridine, pyrimidine, pyrazine

337

OMe

Scheme 88 Synthesis of furan-bridged 10-membered ring systems.

6. APPLICATIONS OF ALKYNYL CARBENE COMPLEXES 1-Alkynyl carbene complexes (1-metalla-1-buten-3-ynes) have experienced growing synthetic application in recent years, taking part in the regio- and/or diastereoselective formation or C–C or C–heteroatom bonds.193 Most reactions involve nucleophilic addition as initial step, where the nucleophile may add to the M]C bond or to the alkyne, whose electrophilic character as a Michael acceptor has been enhanced by the electronwithdrawing properties of the Fischer carbene moiety. Therefore, there will be competition between initial 1,4-addition or 1,2-addition (addition to M]C) which will depend on the nucleophile, the nature of the carbene complex and the reaction conditions. Remarkably, under appropriate conditions, the reaction may be highly diastereo- and regioselective leading to single products.

73

Group 6 Metal Fischer Carbene Complexes

6.1 Synthesis of Acyclic Compounds Usually, 1,4-nucleophilic addition is the prevailing reaction pathway for protic oxygen and sulfur nucleophiles. However, there is a strong temperature dependence for amine nucleophiles: Michael addition to alkoxy alkynyl FCCs is preferred at higher temperatures while aminolysis leading to aminocarbene complexes is favored at low temperatures (Scheme 89, top). For instance, 4-amino-1-chroma-1,3-diene 339 is diastereoselectively formed in almost quantitative yield by addition of a secondary alkyl amine, such as pyrrolidine, to chromium FCC 338 at 20°C (Scheme 89, bottom).194 1,4-Addition has been recently reported for a boradiazaindacene (known as BODIPY)-derived aniline to chromium and tungsten alkoxy alkynyl FCCs in THF at room temperature, to provide β-aminoalkenyl FCCs bearing Z configuration in good to excellent yields.195 NHCs 341 also add to the β-position of alkoxy alkynyl FCCs 340 in pentane at room temperature leading to zwitterionic allenylidene compounds 342 in yields ranging from 81% to quantitative (Scheme 90).196 The employment of 2-oxyfurans (2-methoxyfuran and 2trimethylsilyloxyfuran) as nucleophiles in THF or 1,4-dioxane allows the synthesis of a variety of “push-pull” dienynes.197 Dienyne esters 343 are obtained when 2-methoxyfuran is the oxyfuran partner while dienyne acids 344 are prepared when 2-trimethylsilyloxyfuran is employed instead198 (Scheme 91). The reaction is initiated by a conjugate attack of the 2-oxyfuran to alkynylcarbene 65, followed by formal 1,2-migration of the triple bond and opening of the furan ring. The overall procedure

NMe2

OEt (CO)5Cr

OEt

Me2NH, Et2O

NMe2

(CO)5Cr +

TMS

(CO)5Cr

TMS

TMS T = 20°C T = −100°C OEt (CO)5Cr

+ 338

Ph

43 0

: :

OEt

Et2O, 20°C 5 s–15 min HN

98% E/Z > 99/1

57 100

Ph N

(CO)5Cr 339

Scheme 89 Nucleophilic addition of secondary amines and NHCs to alkoxy alkynyl FCCs.

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OEt (CO)5M

R2 +

R

2

N

N

Pentane, rt 2

R

81%–100%

R1 340

N

+

EtO (CO)5M

−

341

N R2

• R

1

342

M = Cr, W R1 = alkynyl, aryl, heteroaryl R2 = 2,4,6-trimethylphenyl (Mes), 2,6-diisopropylphenyl (IPr)

Scheme 90 Nucleophilic addition of NHCs to alkoxy alkynyl FCCs.

R1 O

OMe

CO2Me

73%–96% OMe (CO)5Cr

THF 0°C to rt

343

MeO R1

R1 65

O

OSiMe3

CO2H

44%–56%

R1 = alkyl (1°, 2°, 3°), alkenyl, alkynyl, aryl, heteroaryl

MeO

344

Scheme 91 Synthesis of push–pull dienynes nucleophilic addition of oxyfurans to alkoxy alkynyl FCCs.

represents both a regioselective olefination at β-position of the alkynyl FCCs 65, and also a direct, flexible, and selective route to substrates useful as building blocks199 for molecular scaffolding (including several dienediynes with a variety of conjugation patterns and functionalities).

6.2 Synthesis of Four-Membered Carbocycles Instead of cyclopropanation reactions, [2+2]-cycloadditions take place between alkynyl FCCs and electron-rich alkenes, such as enol ethers, at room temperature,200 leading to cyclobutenyl carbene complexes, such as 346, with complete regioselectivity (Scheme 92, top). The stability of the cyclobutenes depends both on the nature of the carbene complex and also on the enol ether employed; in some cases, they easily undergo electrocyclic ring opening to form butadienyl FCCs. For instance, cyclobutenyl FCCs

75

Group 6 Metal Fischer Carbene Complexes

OMe OMe (CO)5M

+ O

25°C, neat

(CO)5M

M = Cr, 82% M = W, 97%

Me

Me

O 346

345 M = Cr, W O

OMe (CO)5Cr + R1 65

O Excess

90ºC, THF sealed tube

OMe

R1

16%–52% cis/trans = 84:16 to >95:99% ee

R4

H

N

R3

O

R2 361

R*OH = (−)-8-phenylmenthol R1 = alkyl (2°), aryl R2 = H, Me, PhCH2–, CH2KCH–CH2– R3 = Me, Ph R4 = H, Me, MeO, Br

Scheme 94 Synthesis of cyclopentadienes and cyclopentenones from tungsten alkoxy alkynyl FCCs.

oxygen–tungsten and nitrogen–tungsten bonds have been identified as reaction intermediates. This behavior against enaminones 357 is restricted to [2-(1-cycloalkenyl)ethynyl] FCCs 356; on the contrary, the reaction of alkynyl FCCs with enaminones usually generates heterocyclic compounds (see Section 6.7, Scheme 108). Alternatively, addition of indols 360 to chiral nonracemic alkynyl FCCs 359 provides a simple and efficient route to enantiomerically pure indole C2–C3-fused cyclopentenones 361; moderate yields and excellent enantioselectivities are reached207 (Scheme 94, bottom). Additionally, regioselective addition of enolates 363 to enynyl FCCs, such as 362, followed by further cyclization leads to functionalized cyclopentenoids, such as 364, in a straightforward manner (Scheme 95, top). This method has also been useful for the C2–C3 cyclopentannulation of benzofuran and indole rings. The reaction products have been readily converted cyclopentenones.208 On the other hand, the reaction of alkenyl lithium reagents 365, easily formed from bromoalkenes, and chromium alkynyl FCCs 65 readily leads

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OMe

OEt (CO)5Cr

1) THF, −78°C to rt 2) NH4Cl, H2O

OLi +

MeO2C

OMe CO2Me

76% MeO2C

363 362

364

OMe 4

Li

(CO)5Cr

R

+ R2 R1

65

R3

1) THF, −78°C, 1 h; then rt, 2 h 2) aq. NH4Cl

O R4 R3

50%–85%

R2 R1 rac-366

365

R1 = alkyl (2°), aryl, heteroaryl, TMS R2 = H, Me, Ph; R3 = R4 = Me; R3, R4 = –(CH2)5–; R3 = Ph, R4 = H, Me R2, R3 = –(CH2)3–; R4 = Me, Et R2, R3 = –(CH2)4–; R4 = H, Me 1) THF, −78°C, 1 h; then rt, 2 h

OR* R4

Li

(CO)5W

+ R2

359

R1

R3 365

2) aq. NH4Cl 45%–70% 80 → 99% ee

O R4 R3 R2 R1 366

R*OH = (−)-8-phenylmenthol R1 = aryl R2 = H, R3 = Ph, R4 = Me R2, R3 = –(CH2)3–; R4 = Me, Et R2, R3 = –(CH2)4–; R4 = Me

Scheme 95 Synthesis of cyclopentadienes and cyclopentenones by addition of lithium enolates or alkenyllithiums to alkynyl FCCs.

to polysubstituted cyclopentenones rac-366 in moderate to good yields (Scheme 95, middle). The regiochemistry of the addition depends on the alkenyl lithium 365 employed and, by extension, on the bromoalkene used; therefore, it is completely predetermined. The reaction scope includes tungsten FCCs. Interestingly, enantiopure cyclopentenones 366 have been prepared by this procedure from (
)-8-phenylmenthol-derived tungsten FCCs 359209 (Scheme 95, bottom). Both strategies depicted in Scheme 95 may be considered as complementary to the intermolecular Pauson–Khand reaction.

Group 6 Metal Fischer Carbene Complexes

79

A sequential multicomponent reaction of chromium alkoxy alkynyl FCCs 65 with sterically hindered and strained bicyclic olefins 367, structurally related to norbornene, leads to a broad range of substituted 2-cyclopentenones 368. In these reactions, FCCs 65 react through three positions: the carbene carbon and both acetylenic carbons, in a [2+2+1]/ [2+1] tandem sequence. Polycyclic 2-cyclopentenones 368, which incorporate two units of the same strained bicyclic olefin, are thus prepared although with low stereoselectivity210 (Scheme 96, top). Cyclopropanes are generated as by-products, especially when the reaction is carried out in the absence of CO. Low-yielding procedures to incorporate two different olefins into the final products have also been established; however, good yields of cyclopentenones 370 are achieved when intramolecular [2+1] reactions are involved211 (Scheme 96, middle). The mechanistic rationale for this transformation should first involve a formal [2+2+1]-cycloaddition via (i) [2+2]-addition of strained olefins 367, then (ii) CO insertion (favored under a CO atmosphere), and (iii) a 1,3-metal migration which would lead to a nonstabilized carbene species 371 at a later stage. A final inter or intramolecular cyclopropanation step would generate polycyclic cyclopentenones 368 or 370 (Scheme 96, bottom). Additionally, cyclopentenones were also obtained when the reaction was performed in the presence of alkynes to trap intermediate carbene species 371; however, in this Pauson–Khand reaction the FCC acts just as a donor of CO as the carbene ligand is not incorporated into the final product.212 Barluenga has also reported that chromium alkoxy alkynyl FCCs 65 react with symmetrical internal alkynes in a multicomponent reaction, by consecutive insertions of several acetylene units and carbonyl groups into the metal–carbon bond.213 By controlling the reaction conditions fivecomponent adducts 372 or seven-component adducts 373 can be selectively obtained as major reaction products (Scheme 97, top). The isolated yields are generally low, but still remarkable considering the complexity of the transformation, that involves the creation of four C–C bonds, a σ Cr–C(sp2) bond, and a cyclopentadienyl moiety for organochromium compounds 372 or seven C–C bonds and two five-membered carbocycles for compounds 373. It has been proved that compounds 372 are intermediates in the formation of compounds 373; additionally, compound 374 has been converted into biscyclopentenone 375, cyclopentene-fused cyclopentenone 376 or into spirocyclopentenones 377 (Scheme 97, bottom).

80

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OMe

(CO)5Cr

R1

Toluene CO, 110°C

X

OMe +

X O

32%–75% 65

X

367

R1

368

R1 = alkyl (1°, 3°), aryl, TMS X =

O ,

, HN

, O

MeO2C

N

,

,

OMe

OMe

(CO)5Cr

O +

Toluene 80°C

O

65%–66%

370

369

O

X

367 OMe R1

368

Intermolecular cyclopropanation

X [Cr] O 371 [Cr] = Cr (CO)n

Intramolecular cyclopropanation 370 X=O R1 =

Scheme 96 Synthesis of polycarbocyclic cyclopentenones by [2+2+1]/intermolecular and [2+2+1]/intramolecular [2+1] tandem reaction sequences of alkoxy alkynyl FCCs and stained and sterically hindered alkenes.

6.4 Synthesis of Six-Membered Carbocycles The construction of six-membered carbocycles by Diels–Alder reaction between chromium alkynyl FCCs with 1,3-dienes takes place with the same increased rates that are observed for alkenyl complexes over their ester analogs. For the sake of comparison a representative example is depicted in

81

Group 6 Metal Fischer Carbene Complexes

MeO OMe

R +

R

+

O

OC

R = Et, Pr, Ph

R

CO CO 372 10%−32%

O

TFA toluene

R

R1 Cr

OC

CO

373 16%−34% O

Ph Et

Ph Et

O

R

O

Et Et

R1

Cr

R

R1 = aryl, alkenyl

O

R

R R

65

R

R

80°C DCE

(CO)5Cr

1

R MeO

R

Et

Et

50°C

Sunlight

Et 41%

30%

MeO

375 Et

376 Et

O Et

Ph

Et

Cr OC

(D) H

CO CO 374

Ph

DCE, 110°C sealed vessel

35%−44%

O OMe Et

Et

Et

Et Ph

Ph H (D) 377

Scheme 97 Synthesis of cyclopentenones by multiple alkyne insertion on FCCs.

Scheme 98. Thus, the reaction of FCCs 378 with cyclopentadiene provides norbornadiene derivatives 379 in just 45 min to 2 h at room temperature in 83%–91% yields after purification; on the other hand, the reaction of the same diene with analog esters 380 provides much lower yields of cycloadducts 381 under rather hard conditions.214 Dimethylsulfoxide treatment of norbornadiene FCC 379 (R1 ¼ TMS, R2 ¼ Et) at room temperature allowed confirmation of the structure of the cycloadduct.

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OR2 (CO)5Cr 378 R1

R1

25°C, 45 min to 2 h R1 = R2 = Me, 85% R1 = TMS; R2 = Me, 91% R1 = TMS; R2 = Et, 83%

Cr(CO)5 R2O 379 DMSO, 25°C 82% (R1 = TMS; R2 = Et)

OR2 O 380 R1 150–170°C, 1– 24 h R1 = R2 = Me, 22% R1 = TMS; R2 = Et, 66%

R1

O R2O 381

Scheme 98 Synthesis of six-membered carbocycles by Diels–Alder reaction.

High regioselectivities and stereoselectivities, for unsymmetrical dienynes, are other common advantages for these cycloadditions. All these positive features together with the high regioselectivity in a subsequent annulation (D€ otz reaction) on the obtained alkenyl FCCs have promoted the development of domino reactions from alkynyl FCCs and 1,3-dienes to achieve the selective formation of a large number of carbon–carbon bonds and the construction of complex chemical structures. For example, a tandem [4+2] cycloaddition/benzannulation sequence involving alkoxy alkynyl FCCs, such as 382, a diene 383, and an alkyne (1-pentyne) provides straightforward access to tetrahydronaphthalene derivatives such as 384214 (Scheme 99, top). Also, a one-pot procedure involving the mixing of isobenzofuran 387 [generated in situ by reaction of 1,4-epoxydihydronaphthalenes 385 and 3,6-di(pyridine-20 -yl) s-tetrazine 386] and alkoxy β-alkenyl or β-aryl alkynyl FCCs 388, and the subsequent in situ warming with tert-butyl isocyanide or carbon monoxide leads to a variety of highly polycyclic anthraquinone frameworks 390. The cascade process involves a [4+2] cycloaddition between isobenzofuran 387 and the triple bond of the carbene

83

Group 6 Metal Fischer Carbene Complexes

OMe (OC)5Cr

+

+

OH

Pr 1) THF, 50°C, 36 h 2) SiO2

TMSO

Pr

O

58% 383 382

OMe

SiMe3

384

N N Py

Cr(CO)5

Py N N 386

X

X

388

O X

O X = H, OMe

X

385 X

387 X

t

BuNC, THF rt-60°C, 12 h

O Cr(CO)5 X

OMe

THF, 1 h, rt

THF, 30 min, rt

389

OMe

O

25%–90%

NH-tBu X

OMe 390

Scheme 99 Synthesis of substituted dihydronaphthalene and anthracene derivatives by [4+2]-cycloaddition/benzannulation reactions.

complex followed by benzannulation of the resulting alkenyl FCC cycloadduct 389215 (Scheme 99, bottom). Additionally, a cascade reaction involving the Diels–Alder cycloaddition between alkynyl FCCs and electron-rich dienes followed by a cyclopentannulation allows a direct access to a variety of polycarbocyclic skeletons. This sequence requires an additional double bond in the carbene complex to partake in the cyclopentannulation step; therefore, it only takes place in alkenyl- or aryl-substituted alkynyl FCCs. For instance, the reaction between β-aryl-substituted alkynyl carbene complexes, such as 392, and 2-amino-1,3-butadienes (such as 391) or 1,4-bis(trialkylsilyloxy)-orthoquinodimethanes straightforwardly leads to fluorene derivatives (such as 393)216 or benzo[b]fluorenes217 (Scheme 100, top). On the other hand, excellent yields of polycarbocycle 395 are reached by mixing alkenylsubstituted alkynyl FCCs 394 with 2-aminobuta-1,3-diene 268 in THF at room temperature, by a double tandem [4+2]-cycloaddition/ cyclopentannulation sequence218 (Scheme 100, bottom). The reaction works fine for both chromium and tungsten FCCs but it is slightly faster for the latter ones. Remarkably, this sequence has been extended to

84

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MeO

R1

W(CO)5

R1

OMe

THF, −20°C to rt

+

>95%

N

N O

O 391

393

392

R1 = H, CH2OMe MeO

N

M(CO)5

OMe THF, rt

+

Ph

95%

OMe Ph

N

O O 268

Ph 394

M = Cr, 30 min M = W, 20 min

395

Scheme 100 Synthesis of polycarbocycles by [4+2]-cycloaddition/cyclopentannulation sequences.

synthesize polycycles even larger, which have been prepared by a triple tandem ([4+2] cycloaddition–cyclopentannulation) cascade.219 As pointed out before, 1-metalla-1,3,5-hexatrienes,220 easily prepared either by nucleophilic addition or by cycloaddition involving the triple bond from enynyl FCCs, are suitable substrates for the synthesis of carbopolycycles. Therefore, cyclobutene-containing 1,3,5-metallahexatrienes have been used to prepare cyclobutane-fused o-alkoxyphenol-containing polycyclic systems 399 or 401, through a benzannulation reaction. The cyclobutene may be obtained by two different routes: (i) by a [2+2]-cycloaddition between cyclic enol ethers 397 and chromium or tungsten enynyl FCCs 396,202 (Scheme 101, top) or (ii) by a sequence initiated by nucleophilic addition of carboxylic acids or phenols to 1-tungsten-1,5-hexadiene-3-yne 400 followed by a [4+2]-cycloaddition with another equivalent of the carbene complex (Scheme 101, bottom). The latter approach provides lower cycloadduct yields.221 The cyclobutene moiety is crucial for the benzannulation to occur without the need of carrying out the reaction under a CO atmosphere; alternatively, a cyclopentannulation reaction may take place (as shown in two examples in Scheme 100, where a cyclohexene ring is involved instead of a cyclobutene ring and cyclopentannulation takes place after the [4+2]cycloaddition to form 393 or 395).

85

Group 6 Metal Fischer Carbene Complexes

MeO

O ( )n

M(CO)5

O ( )n

397, neat, rt

OMe

R

1

OH

O ( )n

THF, reflux

R2

40%–93%

R1

OMe

M(CO)5

R2

46%–89% R

1

R2 n = 1, 2

396

398

399

M = Cr, W R1 = Me; R2 = H, Ph, CH2KCH–CH2–O–CH2– or R1, R2 = –(CH2)3–, –(CH2)4– EtO

W(CO)5

OAc

CH3COOH, Et3N, PhH 80°C, 10 h

OEt OH

EtO

400

H 29% 47% (by direct heating of metallahexatriene intermediate)

401

Scheme 101 Synthesis of polycarbocycles from cyclobutene-containing 1,3,5metallahexatriene intermediates.

6.5 Synthesis of Seven- and Eight-Membered Carbocycles Tungsten alkynyl FCCs 402 undergo [4+3]-cyclization with diverse pentafulvenes 77 under CO (20 bar) to form bicyclo[3.2.1]octadien-2-ones 403. Hexane is the solvent of choice for alkyl-, aryl-, and acetoxymonosubstituted fulvenes leading to adducts 403 in good yields (65%– 75%) as E/Z-diastereomeric mixtures. However, the optimal conditions for disubstituted fulvenes include DMF as solvent, CO (20 bar), and heating at 60°C. The presence of CO allows to control the cyclization by inhibiting a side cyclopropanation reaction and facilitates the quantitative recovery of W(CO)6222 (Scheme 102). The reaction between alkoxy alkynyl tungsten FCCs 402 and 1-oxy-orthoquinodimethides provides an entry to different types of seven-membered functionalized benzocarbocycles. Thus, lithium benzocyclobutenoxide 405, formed in situ from benzocyclobutenol 404 and n-butyllithium at
78°C, undergoes an electrocyclic ring opening to ortho-quinodimethide 406 at temperatures below
25°C; its reaction with tungsten alkoxy alkynyl FCCs is high yielding and solvent controlled, leading selectively to benzocycloheptenones 407 in THF (Scheme 103, top) and exclusively to benzocycloheptene ketals 408 in diethyl ether223 (Scheme 103, bottom). However, benzocycloheptene ketals are obtained in THF in moderate yields

86

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R2

OMe (CO)5W

R3

+

R3

R2

1) CO (20 bar), 60°C hexane or DMF 2) SiO2

R1

50%–88% R1 O 403

77

402 1

R = alkenyl, aryl R2 = i-Pr, t-Bu, Ph, 4-methoxyphenyl, AcO; R3 = H or R2 = R3 = Me, Et or R2, R3 = –(CH2)4–

Scheme 102 Synthesis of bicyclo[3.2.1]octadien-2-ones from alkynyl FCCs and pentafulvenes.

OH

BuLi −78ºC, THF

404

OLi

−78 to −25°C

OLi

405

406

OMe (CO)5W O

R1

R1

402 R1

+

43%–97% combined yield

O OMe

OMe 407

408

R1 = alkyl (3°), alkenyl, aryl 1) BuLi, –78°C, Et2O 2) –78 to –25°C OMe (CO)5W 3) OH

402

–25°C to rt

R1 R

1

O 50%–86% 404

408

OMe

R1 = alkyl (3°), alkenyl, aryl

Scheme 103 Synthesis of seven-membered benzocarbocycles from alkynyl FCCs and ortho-quinodimethides.

87

Group 6 Metal Fischer Carbene Complexes

MeO

Cr(CO)5

Cr(CO)5

O , neat, rt

O

OMe R2

40%–93%

R1

MeO R3

H

R3

O

THF, reflux O

57%–71%

R1

R

1

R

2

R2 409

410

411

R1 = Me; R2 = Ph or R1, R2 = –(CH2)3 – R3 = Ph, n-Bu, TBDMSOCH2–, TMS

Scheme 104 Synthesis of eight-membered benzocarbocycles from alkynyl FCCs, enol ethers, and terminal alkynes.

when position 1 of the orthoquinodimethide is substituted; additionally, an alternative reaction pathway is favored by bulky alkoxy groups in the FCC.224 The treatment of chromium enynyl FCCs 409 with dihydrofuran may be followed by a D€ otz-like reaction between the obtained chromium dienyl FCCs 410 and terminal alkynes leading to cyclooctatrienones 411 (Scheme 104). The reaction sequence is regioselective and leads to mixture of diastereoisomers (due to the new stereocenter) in moderate yields (57%– 71%, for the D€ otz-like reaction).225 As a drawback, there are structural limitations regarding both double bonds on the chromium dienyl FCC 410 for this transformation to take place: the internal double bond should be part of a cyclobutene ring while the terminal one should be olefinic, not aromatic.

6.6 Synthesis of Five-Membered N-Heterocycles The [3+2]-cycloaddition of alkynyl FCCs with 1,3-dipolar species has proved to be a successful strategy to prepare five-membered N-heterocycles; usually, as it was pointed out for alkenyl FCCs, those dipolar cycloadditions are faster than the reactions of the analogous propiolates.226 The reaction of alkoxy arylethynyl chromium and tungsten FCCs 412 with aryl-N-alkylnitrones 413 usually leads to high yields of Δ4-isoxazoline complexes 414 as single regioisomers227 (Scheme 105, top). Yields are considerably lower when propiolates are employed. Electron-donating substituents at the nitrone aryl group increase the reactivity, while electronwithdrawing substituents decrease it. In an analogous manner, a [3+2]-annulation of alkoxy alkynyl FCCs 340 with cyclic azomethine imines 415 in THF under mild conditions gives bicyclic pyrazolone–pyrazolo carbene complexes 416 in moderate to good yields228 (Scheme 105, middle). Tungsten FCCs are more reactive

88

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e Barluenga and Enrique Aguilar

OMe OMe Ar1

(CO)5M

+

+ N

H

Ar

(OC)5M

O−

THF, rt

R2

42%–98%

H

O

Ar1

N R2

Ar 412

414

413 R2 = Me, t-Bu, PhCH2– Ar1= Ph, p–X–C6H4–

M = Cr, W Ar = aryl

R2 OEt

R3

(CO)5M

OEt THF, 50°C - reflux

+

N N

O

N

4

R 415

R1 340

R3 416

R2 = H, PhCONH– R3 = H, Ph R4 = aryl, heteroaryl

M = Cr, W R1 = aryl, TMS

R2

OEt

OEt +

Ar1CH2

N3

Neat, 40°C 67%–85%

417 Ar = aryl

N

R4

25%–86%

H

(CO)5W

R1

(OC)5M

O

Ar

Ar

(OC)5W N

N N

418 Ar1 = aryl X = i-Pr, CN, NO2, Me, F

CH2Ar1

419

Scheme 105 Synthesis of five-membered nitrogen heterocycles by dipolar cycloadditions with alkynyl FCCs.

than chromium FCCs in this transformation. Additionally, tungsten aryl-substituted alkynyl FCCs 417 and a variety of benzylic azides 418 provide consistently high yields of triazole carbene complexes 419; this cycloaddition takes place at moderate temperatures (40°C) and in the absence of solvent229 (Scheme 105, bottom). As expected, these two dipolar cycloaddition reactions are completely regioselective due to the polarization of the triple bond of the carbene ligand; however, the latter transformation is too slow to be competitive with a Cu-promoted “click” reaction.230 On the other hand, heterocyclization reactions involving group 6 metal alkynyl FCCs and azafulvenes generate a variety of five-membered heterocyclic compounds. For instance, the reaction of alkynyl FCCs 420 with

89

Group 6 Metal Fischer Carbene Complexes

MeO

M(CO)5 NMe2 + N

OMe

N N

N

70%–90%

R1 420

NMe2

1. THF 2. Pyridine N-oxide

O R1 421

315

M = Cr, W R1 = alkyl (3°), alkenyl, aryl M(CO)5

MeO

N

R2

+

1. THF 2. Pyridine N-oxide 3. SiO2

Ph

R2 N

CO2Me

69%–87%

R1 420

422

307

M = Cr, W R1 = alkyl (2°, 3°), aryl, TMS R2 = 4-Tol, 4-methoxyphenyl

Cr(CO)5

MeO

N

R2

( )n

X 1. THF, −50 to 0°C 2. t-BuNC, 70°C

R2

NtBu N

+

• H

X ( )n

307 424

423 X

( )n

R2

X NH-tBu

N H

X = CH2, O n = 1, 2

Cr(CO)n OMe

OMe

SiO2

R2

( )n NH-tBu

N 82%–89%

425

OMe 426

R2 = 4-Tol, 4-methoxyphenyl

Scheme 106 Synthesis of polycyclic nitrogenated heterocycles.

6-dimethylamino-1,4-diazafulvene 315 in THF, followed by oxidation allows the direct synthesis of imidazole frameworks such as 421231 (Scheme 106, top). Chromium and tungsten FCCs behave in a similar manner in these cyclizations. On the other hand, treatment of alkynyl FCCs with

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N-aryl-8-heptafulvenes 307 provides pyrrole or indole (fused-pyrrole) derivatives, 422 or 426, by reactions or reaction sequences involving [8 +2] cyclizations232 (Scheme 106, middle and bottom). The mechanism proposed to explain the formation of indole derivatives 426 assumes that the [8 +2]-cycloadduct carbene complex intermediates should undergo insertion of carbon monoxide or tert-butyl isocyanate, to form metal heterocumulene species, such as 424 (nonisolated); then, a metal-promoted electrocyclic ring closure should lead to dihydroindole adducts, such as 425. Complete double bond isomerization to aromatic indole derivatives occurs during chromatographic purification over silica gel; therefore, mixtures of cycloheptadiene double bond regioisomers 426 are usually obtained (Scheme 106, bottom).

6.7 Synthesis of Six-Membered N-Heterocycles Alkynyl FCCs undergo hetero-Diels–Alder reactions with azadienes, leading to the formation of six-membered heterocycles. For instance, tungsten FCCs 401 react with simple 1-azadienes 427 or 3-(trimethylsilyloxy)-2aza-1,3-butadienes 429, in THF at room temperature to form 1,4dihydropyridines 428233 or dihydropyridone derivatives,234 in high yields (Scheme 107, top). In the latter case, higher temperatures (60°C) are required when the substituent at the carbene triple bond is a phenyl group; then the initial adduct evolves via cyclopentannulation reaction to form azabenzofluorenones 430 in good yields (62%–84%) (Scheme 107, middle). As expected, the analogous acetylenic ester is much less reactive and the starting materials are recovered after refluxing in toluene for 7 days. Additionally, reaction of chromium or tungsten alkynyl FCCs 420 with 4-amino-1,3-diazadiene 431 in THF at room temperature provides good yields of pyrimidyl FCCs 432235 (Scheme 107, bottom). Tungsten alkynyl FCC 433 reacts with 4-aminopent-3-en-2-ones 434 in hexane at 50°C to give good to excellent yields of 2-aza-bicyclo [3.1.0]hexanes 435 (Scheme 108). Nonpolar solvents and the absence of base are required for this transformation, which proceeds via 1-tungstena1,3,5-trienes 436236; otherwise, the cyclization of 1-metalla-1,3,5-trienes will lead to 1,2-dihydropyridin-2-ylidene and/or pyran-2-ylidene complexes.237 1,3-Dinitrogen systems, such as amidines, guanidines, ureas, or thioureas, undergo addition to both electrophilic positions of alkynyl FCCs leading usually to pyrimidine derivatives in a formal

91

Group 6 Metal Fischer Carbene Complexes

R2

OMe

R2

R3

(CO)5W

THF, 20°C, 5–360 min

+

OMe

65%–89% 4

R

4

R 427

401

R 428 R2 = H, Me, Ph 3 R = H, Me R4 = Et, n-Pr, i-Pr, Ph–CH2–, CH2KCH–CH2–

R1 = alkyl (Me, 1°), aryl, TMS

R1

OMe (CO)5W

R1 THF, 60°C

N

+

O

2

Ph

OMe

HN

62%–84%

TMSO

R2

R 429

392

R1

N

N 1

W(CO)5

R3

430

R1 = Ph, t-Bu R2 = H, Me t-Bu

NMe2

OMe (CO)5M

THF, 25°C

+

M(CO)5

N

A

OMe

54%–72% NH

Cl3C

R1 420

R1

Cl3C 432

431

M = Cr, W R1 = alkyl (2º, 3º), aryl

Scheme 107 Synthesis of six-membered nitrogenated heterocycles by hetero-Diels– Alder reaction.

OEt (CO)5W

R1 +

O NH

O

R1

Hexane, 50°C, 1 h

N

65%–78% Ph

EtO

Ph 433

434

R1 = alkyl (Me, 1°, 2°), aryl

435

R1 NH

Et

O

O (CO)5W Ph 436

Scheme 108 Synthesis of 2-aza-bicyclo[3.1.0]hexanes.

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(CO)5M

X

Me

OEt X

THF, rt

+ MeHN

NHMe

N N Me

(CO)5M

52%–90% Ph

Ph 348

437

438

M = Cr, W X = O, S

Scheme 109 Synthesis of uracil derivatives by reaction with ureas and thioureas.

[3+3]-cycloaddition, while aminolysis products are scarcely observed.238 However, two regioisomers are commonly obtained for nonsymmetric dinucleophiles. The reaction with symmetric N-alkylureas 437 (X]O) or -thioureas 437 (X]S) avoids this problem; the cyclic FCC 438 (X]O) obtained can be transformed into uracil fragments by oxidation239 (Scheme 109). The reaction time can be considerably shortened by microwave activation.240 Interestingly, an intramolecular and efficient synthesis of 1,2-dihydroquinolines has been reported from ortho-aminophenyl alkynyl carbene complexes 439; a two-step process is involved: (i) an initial [1,5]-hydride transfer from the benzylic carbon center to the β-carbon of the triple bond of the alkynyl FCC leading to zwitterionic species 441 and (ii) a cyclization to 1,2-dihydroquinolinyl FCCs 440241 (Scheme 110). Theoretical calculations have determined that the key step is the hydrogen atom migration. The reaction sequence requires temperatures of 70°C or higher. Both reaction time and yield strongly depend on the nature of the substituents on the tertiary amine. This novel pattern of reactivity has served as a starting point for the development of domino reactions. Thus, the reaction between ortho-aminophenyl alkynyl FCCs 439 and alkynes provides 5,6-dihydrophenanthridines 442 and other quinoline derivatives 444, 446, in moderate to good yields by [1,5]-hydride transfer/cyclization/D€ otz benzannulation cascades.241,242 The nature of the alkyne determines the reaction outcome: (i) nonactivated alkynes lead to 5,6-dihydrophenanthridines 442 (Scheme 111, top); (ii) propionaldehyde derivatives 443 yield polycyclic lactones 444 (Scheme 111, middle); and (iii) propiolates 445 generate (1,2-dihydroquinolin-3-ylvinyl) malonates 446 in high yields when the reaction is performed in THF/alcohol (Scheme 111, bottom).

93

Group 6 Metal Fischer Carbene Complexes

OMe

OMe R1

(CO)5Cr

R1

(CO)5Cr R

2

N

R2 N

THF, 90°C sealed tube

63%–98%

R3

R3

439

440

R1 = R2 = aryl or R1 = Ph; R2 = H, t-Bu R3 = H, Me, Cl

R1 R2

H

MeO •

N

(CO)5Cr – R3 441

Scheme 110 Synthesis of 1,2-dihydroquinolines.

6.8 Synthesis of Seven-Membered N-Heterocycles The reaction between chromium indolyl or ortho-aminophenyl alkynyl FCCs 447 or 450 and dihydrofuran leads to azepino[3,2,1-hi]indoles 448, 449 or benzazepines 451, 452 in moderate to good yields (Scheme 112). The reaction starts by an initial [2+2]-cycloaddition step with 2,3-dihydrofuran followed by an intramolecular C–H insertion process.243 The diastereoselectivity for the formation of azepino[3,2,1-hi] indoles depends on the nature of R1; typically only one diastereomer is isolated when R1 ¼ alkenyl, aryl, but low diastereoselectivities are obtained for R1 ¼ OEt. However, for benzazepines 451, 452 moderate diastereoselectivities are reached (3.5/1 to 3.1/1). The reaction of alkoxy alkynyl FCCs 420 with N-unsubstituted pyrrole2-carboxaldehyde-derived imines 453 in hexane at room temperature leads to zwitterionic pyrrolodiazepines 454 in good to excellent yields.244 The reaction mechanism should involve a NH Michael-type addition,

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R5

OMe

OMe R1

1

R

(CO)5Cr

2

R

R N

R4

4

R2 N

THF, 90°C sealed tube

HO

+ R5

R3

42%–72% R3

439

442

R1 = R2 = aryl R3 = H, Me R4 = n-Bu, Et, MeOCH2–, TMS R5 = H, Et OMe R1

(CO)5Cr

R1

MeO R2 R4

N +

N

R4 THF, 90°C, 2 h sealed tube O

R2

OH H

61%–78% CHO

R3 439

R3 444

443

R1 = R2 = aryl R3 = H, Cl R4 = Ph, C5H11, TMS CO2R4

OMe (CO)5Cr

R

R4O2C

1

R1

R2 N

R2

THF/R4OH, 90°C 4 h, sealed tube

N

+ R3 439

CO2R4

R1 = R2 = aryl R3 = H, Me R4 = Me, Et, CH2KCH–CH2–

445

73%–81% R3 446

Scheme 111 Synthesis of 5,6-dihydrophenanthridines and other quinoline derivatives.

followed by intramolecular 1,2-addition of the imine nitrogen and, finally, a [1,3]-migration of M(CO)5. Surprisingly, low yields of cycloadducts (28%–33%) are obtained for indole-2-carboxaldehyde-derived imines, which require THF as solvent (Scheme 113).

95

Group 6 Metal Fischer Carbene Complexes

O OMe R1

(CO)5Cr

MeO

1. , THF, rt, 10 h 2. 90°C, 2 h sealed tube

MeO

R1

O

R1

O N

N

N

+

46%–53% dr = 1.3/1 to >99/1 447 R1 = alkenyl, aryl, EtO

448

449

O OMe (CO)5Cr

MeO

1. , THF, rt, 14 h R1 2. 90°C, 2 h sealed tube R2 N

MeO

R1

O N

N

+ R2

49%–62% dr = 3.1/1 to 3.5/1 450 R1 = R2 = aryl or R1 = Ph; R2 = H

R1

O R2

451

452

Scheme 112 Synthesis of azepine derivatives.

OMe (CO)5M

M(CO)5 N R2

+ N H

Hexane, 25°C 72%–95%

N

N R2

R1

R1 420

453

454

OMe

M = Cr, W R1 = alkyl (1°), aryl R2 = n-Pr, 2-[1-(cyclohexenyl)]ethyl

Scheme 113 Synthesis of pyrrolodiazepines.

7. NONHETEROATOM-STABILIZED CARBENE COMPLEXES (NHSCCs) NHSCCs 455 are a particular type of FCCs lacking the stabilizing hetereoatom245 (Fig. 3). Therefore, they are low-valent metal carbenes and electrophilic in nature; however, they have received much less attention mainly due to their low stability, particularly of those having hydrogen at the Cα carbon. They have been used mainly as stoichiometric reagents; however, relevant contributions to the development of organic chemistry (i.e., alkene metathesis, enyne metathesis) have arisen from their employment as catalysts. This section has been divided into four parts, which cover: (i) methodologies developed for the synthesis of NHSCCs, (ii) early days

96

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R2 (CO)5M R1 455 Nonheteroatom stabilized carbenes M = Cr, Mo, W R1 = alkyl, alkenyl, alkynyl, aryl R2 = H, alkyl, alkenyl, alkynyl, aryl

Fig. 3 Nonheteroatom-stabilized Fischer carbene complexes.

applications of NHSCCs, (iii) the recent reactivity of alkynyl NHSCCs as stoichiometric reagents, and (iv) their behavior, usually as reaction intermediates, when generated from conjugated dienynes or heterodienynes either under stoichiometric or catalytic conditions.

7.1 Synthesis of Nonheteroatom-Stabilized FCCs € Ofele synthesized the first group 6 metal NHSCC, pentacarbonyl(2,3diphenylcyclopropenylidene)chromium(0) 457, a highly stable to air solid which was prepared by treating a 1,1-dichloro-2,3-diphenylcyclopropene 456 with sodium pentacarbonylchromate in THF at
20°C (Scheme 114).246 However, the most commonly employed strategy for the synthesis of group 6 NHSCCs has been by far the nucleophilic substitution of heteroatom-stabilized FCCs. Organolithium reagents, metal hydride complexes, or enamines have been the nucleophiles employed to prepare NHSCCs. The reactions presumably proceed via nucleophilic addition to starting Fischer alkoxy carbene complex 5 leading to tetrahedral intermediate 458, which upon addition of the electrophile evolves with elimination of the E-OR2 moiety to generate NHSCC 459 (Scheme 115). Following this strategy diaryl (or heteroaryl) carbene complexes of chromium or tungsten 461 (Ar1, Ar2 ¼ aryl, heteroaryl) were prepared by Casey247 and Fischer8 by adding aryl or heteroaryllithium reagents to solutions of methoxy aryl (or heteroaryl) carbene complexes 460 at low temperature, followed by an acidic quenching (Scheme 116, top). On the one hand, NHSCCs 461 are moderately air-stable solids although more thermally labile than their methoxy aryl (or heteroaryl) carbene complexes precursors 460. For instance, thermal decomposition of

97

Group 6 Metal Fischer Carbene Complexes

Ph

Ph Cl

THF, −20°C

+ Na2Cr(CO)5 Ph

Cr(CO)5

19.5%

Cl

Ph

456

457

Scheme 114 First synthesis of a nonheteroatom-stabilized group 6 metal carbene complex.

R2O

OR2

Nu-M′ M(CO)5

Nu

R1

M(CO)5 R1

2

1

E-OR M′-LG

R 458

5

Nu

E-LG

M′

M(CO)5

459

Nu-M′ = R3Li, M″HB(OR3) Nu = R3, H E-LG = HCl, TFA, MeOTf, TMSOTf E = H, Me, TMS

Scheme 115 General strategy for the synthesis of nonheteroatom-stabilized carbene complexes via nucleophilic addition to Fischer alkoxy carbene complexes.

MeO M(CO)5

1) Ar2Li, −78°C 2) HCl, −78°C or SiO2/pentane, −30°C

Ar1

Ar2 M(CO)5 Ar1

49%–87%

460 461 M = Cr, W Ar1 = Ph, p-Tol, 2-furyl, 2-thienyl Ar2 = Ph, p-Tol, p-CF3–C6H4, 2-furyl, 2-thienyl, N-Me-pyrrol-2-yl

MeO W(CO)5

1) R1CH2Li, −78°C 2) SiO2/pentane, R1CH 2 −40°C

Ph

R1 W(CO)5

W(CO)5

Ph 462

Ph

463

1

R = H, n-Pr, vinyl

MeO W(CO)5 Ph

1) CH3Li, −78°C 2) HCl, −78°C

CH3

462 −78°C to rt

30 min W(CO)5

W(CO)5 Ph

464 49%–87%

465 deep-red

Ph

466 yellow

+ Ph 47%

Ph

Ph 26%

Scheme 116 Synthesis of nonheteroatom-stabilized diaryl carbene and aryl alkyl carbene complexes.

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pentacarbonyl(diphenylmethylidene) tungsten(0) in heptane was complete in less than 2 h at 100°C leading to W(CO)6, diphenylmethane, and tetraphenylethylene. On the other hand, the metal plays an important role in the stability of the carbene complex; thus, as it happens for heteroatomstabilized FCCs, chromium complexes are more labile than their analogous tungsten ones. The formation of aryl alkyl carbene metal(0) complexes is more problematic as they are highly unstable and can be prepared but not isolated. After addition of alkyllithium to solutions of methoxy phenyl(methylidene) tungsten(0) 462 at
78°C followed by treatment with silica gel, the desired aryl alkyl carbene metal(0) complexes 463 were formed. However, they decomposed even under the low-temperature reaction conditions leading to formation of pentacarbonyl π-olefin tungsten(0) complexes 464, which could be isolated (Scheme 116, middle).248 For instance, phenylethylidenecarbene complex 465 was generated by successive addition of methyllithium and HCl to methoxy phenyl(methylene)tungsten(0) 462 at
78°C but the deep red color attributable to 465 faded within 30 min at that temperature; styrene (47%) and cis- and trans-1-methyl-1,2-diphenylcyclopropane (26%) were obtained upon warming the reaction mixture to room temperature (Scheme 116, bottom).249 Iwasawa found that smooth addition of alkynyllithium species to tungsten FCCs 52 takes place at
78°C leading presumably to tetrahedral intermediate 467, which upon acidic workup with 2 M HCl or TFA produces enynes 469, in moderate to good yields, via NHSCCs 468, when R1 bears acidic hydrogen atoms (R1 ¼ i-Pr, n-Bu) (Scheme 117).116 Interestingly, alkynyllithium addition is preferred to deprotonation even in cases of primary alkyl-substituted carbene complexes. Moreover, the use of alkynyllithium reagents is essential for the success of the addition reaction: no addition products were formed when aryl- or alkyllithium species were employed. Following such pioneering work, Barluenga generated a plethora of chromium or tungsten alkynyl NHSCCs 471 at low temperature in THF, by sequential treatment of alkoxycarbene complexes 470 with various lithium acetylides and trimethylsilyl triflate (TMSOTf ) at
80°C47 (Scheme 118). Metal carbene scaffolds obtained this way are listed according to the number of triple bonds: (i) alkynyl carbene complexes 472, (ii) cross-conjugated diynyl carbene complexes 473, (iii) linearconjugated diynyl carbene complexes 474, and (iv) cross-conjugated triynyl carbene complexes 475.250

99

Group 6 Metal Fischer Carbene Complexes

R2 MeO

Li

THF, −78°C

W(CO)5

OMe R2

W(CO)5

1

Li+

R1

R

52 R1 = n-Bu, i-Pr R2 = Ph, n-Hex

467 R2

R2

2M HCl −78°C

R3 W(CO)5

R4 469 34%–85% R3 = n-Pr, R4 = H R3 = R4 = Me

R1 468

Scheme 117 Synthesis of tungsten NHSCCs 469.

MeO M(CO)5

1) Y Li THF, −78°C 2) TMSOTf −80°C

Y

M(CO)5 X

X

471

470 M = Cr, W X = Ar, alkenyl, alkynyl, alkadiynyl Y = Ar, alkyl, alkynyl, R3Si R2 R2

R2

M(CO)5 R1

R2

M(CO)5

472

473

M(CO)5 R1

474

M(CO)5 475

R1 R1

Scheme 118 Synthesis of nonheteroatom-stabilized alkynyl metal carbene complexes.

The rapid decomposition of alkyl aryl complexes via β-hydride elimination prompted Casey251 and Fischer252 to prepare benzylidene (pentacarbonyl)tungsten(0) and -chromium(0) complexes 478. The sequential procedure involves hydride reduction of stabilized carbene complexes 476 with KHB(O-i-Pr)3 followed by counter-ion exchange

100

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1

R O M(CO)5 Ar1

1) M′HB(OR)3 0°C or −30°C 2) Et4NBr

R1O H Ar1

30%–86%

476

TFA or HBF4·OEt2 −78°C or −110°C

+ M(CO)5 NEt4 477

H M(CO)5 Ar1

M = Cr, Mo, W 478 Ar1 = Ph, p-Tol, p-MeO–C6H4– 50%–80% 1 R = Me, Et M′HB(OR)3 = KHB(O-i-Pr)3, NaHB(OMe)3 H

H W(CO)5

p-MeO-C6H4 479 can be handled at rt

W(CO)5 Ph 480 half life (in solution) 24 min (−56°C) 2 min (0°C)

Scheme 119 Synthesis and stability of group 6 metal benzylidene complexes.

to form tetraethylammonium derivatives 477, which, although moderately air sensitive, can be isolated. Then, addition of TFA or HBF4OEt2 at
78°C leads to carbene complexes 478 in a quantitative manner. Some carbenes can be purified by column chromatography at
70°C followed by recrystallization (Scheme 119, top). Thermal stabilities of complexes 478 are strongly influenced by the nature of substituent R1 and the metal. Thus, for tungsten carbenes, p-anisyl derivative 479 can be handled at room temperature for short periods of time; for phenyl derivative 480, the color in solution stands for several hours at
78°C fading to light orange upon warming to 0°C, or decomposes at
56°C or 20°C in solution with a half-life of ca. 24 min (
56°C) or 2 min (20°C) (Scheme 119, bottom). As expected, benzylidene complex 480 is more stable than methylphenyl carbene tungsten complex 465. In a similar manner, benzylidene complexes of molybdenum have also been prepared, although they are thermally very labile and react rapidly with nucleophiles even at
100°C.253 Zwitterionic metallate complexes 484 are isolated in excellent yields when Fischer alkenyl carbene complexes 482 and enamines 481 are mixed in hexane at room temperature.254 Its formation has been rationalized in terms of a 1,4-addition of the Cα-enamine to the electrophilic alkenyl

101

Group 6 Metal Fischer Carbene Complexes

N 481 N R2O

+

Hexane, rt

N

R

1

OR2

2

OR

M(CO)5 R1

M(CO)5

482

483

M(CO)5 R1 484 94%–98%

M = Cr, W R1 = n-Pr, Ph, 2-furyl, 4-MeO–C6H4 R2 = Me, (1R,2S,5R)-menthyl

O TFA, THF 0°C

N

H2O M(CO)5

R1 485

R1 486 60%–91%

Scheme 120 Nonheteroatom-stabilized metal carbenes by the reaction between alkenyl FCCs and enamines.

carbene complex to produce Michael adduct 483, followed by enamine 1,2addition to the carbene moiety. A sequence involving TFA treatment of 484 at 0°C and hydrolysis lead to [3+3]-cycloadducts 486 in good to excellent yields via NHSCC species 485, generated by R2OH elimination on 484 (Scheme 120). Dry acids (TFA and HBF4) are also effective for such transformation. Compounds 485 are the only examples of group 6 metal dialkyl carbene complexes reported to date. Although not isolated, tungsten complexes (M ¼ W, R1 ¼ Ph, 2-Furyl) are fairly stable at
80°C and they could be characterized by 13C NMR; however, they decompose above
70°C to form imonium salts which are hydrolyzed to 8-bicyclo[3.2.1]octanones 486. Diaryl carbene complexes of chromium can be synthesized by reaction of diaryl diazo compounds 488 with η2-cis-cyclooctene (pentacarbonyl)chromium(0) 487 in mixtures of dichloromethane/hexane at
5°C for 8 h. Crystallization at
78°C followed by chromatographic work-up led to NHSCCs 489 in moderate to good yields, along with the corresponding azines 490 (Scheme 121, top).255

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Jos
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(CO)5Cr 487 + X

CH2Cl2/hexane −5°C, 8 h −N2, −C8H14

Cr(CO)5 + X

X

2

490 0%–46%

489 53%–67%

N2

N

488 X = none, O, CH2CH2, CHKCH Ar1 N2 Ar2 491

+

487

CH2Cl2/hexane −5°C, 8 h

Ar1

−N2, −C8H14

Ar2

Ar1 = Ph, Ar2 = p-MeO–C6H4 Ar1 = Ar2 = p-MeO–C6H4

Cr(CO)5 492 65%–66%

Scheme 121 Synthesis of nonstabilized metal carbene complexes from diazo compounds.

In a similar manner, unbridged diaryl diazo compounds 491 also provided good yields of chromium diaryl NHSCCs 492 under the optimized reaction conditions (Scheme 121, bottom). However, the presence of at least a methoxy group seems to be required to provide further carbene stabilization.256

7.2 Early Chemistry of NHSCCs: Cyclopropanation and Metathesis Group 6 metal NHSCCs have been tested as catalysts for olefin metathesis and cyclopropanation reactions. In fact, in early days, Casey found that both cyclopropanes and new alkenes, coming from metathesis, were formed in reactions of pentacarbonyl(diphenylmethylene) tungsten(0) 493 with alkenes, in variable amounts depending on the nature of the olefin.257 Thus, cyclopropane 494 and 1,1-diphenylethylene were the major products for the reactions with ethyl vinyl ether and isobutylene, respectively (Scheme 122, top). However, 1,1-diphenylethylene and tungsten methoxy FCC 462 (both metathesis compounds) were the main products for the reaction with α-methoxystyrene and only trace amounts of cyclopropane 495 were observed.

103

Group 6 Metal Fischer Carbene Complexes

Ph

EtO 37°C, 3 h

Ph

EtO

494 65%

W(CO)5 Ph

493

+ Ph

Ph

10% Ph

+ Ph

Ph

100°C, 2.5 h

Ph

10%

Ph W(CO)5 Ph 493 32°C + 6h Ph

MeO

Ph

MeO

Ph

495

MeO +

+ Ph

trace

Ph Ph

Ph

W(CO)x R1 R2

Ph

462 24%

Ph

Ph

W(CO)x R1

Ph

W(CO)5

Ph

26%

Ph

496

R2

Ph

Ph

W(CO)x R2

R1

Ph

Ph W(CO)5

Ph

Ph 76%

+

R1

R1 497

R2

2

Ph

+

W(CO)5 Ph

R

Scheme 122 Cyclopropanation and (diphenylmethylene)tungsten(0) 492.

MeO

metathesis

reactions

of

pentacarbonyl

These results gave support to Chauvin’s nonpairwise exchange of alkylidene units mechanism for the metathesis reaction258; indeed, metallacyclobutane 496 appears as a key intermediate in all these transformations. It should be generated by a sequence involving complexation of the alkene to the metal carbene followed by an intramolecular [2+2]-cycloaddition. Then, reductive elimination on metallacyclobutane 496 would lead to cyclopropane 497 while a retro-[2+2]-reaction would give 1,1diphenylacetylene and FCC 462 (Scheme 122, bottom). Katz found that tungsten diphenylcarbene 493 is also an effective initiator for cross metathesis of different types of olefins (terminal, 1,1-disubstituted, or 1,2-disubstituted alkenes) without requiring a Lewis acid cocatalyst.259 Additionally, NHSCC 493 was found to catalyze the ring-opening metathesis polymerization (ROMP) of 1-methylcyclobutene leading to

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Ph W(CO)5 Ph

493

(2.7 mol%), 50°C, 18 h Quantitative Mw = 11,400 Mn = 1400

n

Scheme 123 ROMP of 1-methylcyclobutene catalyzed by carbene complex 493.

polyisoprene of broad molecular weight distribution (Mw ¼ 11,400; Mn ¼ 1400) (Scheme 123). These results also gave support to the role of metal carbene complexes as intermediates in olefin metathesis reactions.260 Interestingly, only cyclopropanes were obtained in the reaction of tungsten benzylidene complex 480 with alkenes, without formation of metathesis products, which is the main difference in reactivity between carbenes 480 and 493. Additionally, cyclopropanation of alkenes with NHSCC 480 takes place rapidly at
78°C while NHSCC 493 requires 40°C to give cyclopropanes and metathesis products in its reactions with alkenes. Phenyl carbene complex 480 is a more electrophilic reagent and is more reactive to the most substituted alkene while diaryl carbene complex 493 displays the opposite behavior.251 The conclusions established regarding the reactivity of alkenes with tungsten phenyl carbene 480 are: (i) cyclopropanes are formed with retention of the stereochemistry of the alkene precursor; (ii) the relative reactivity of alkenes is determined by the number of alkyl groups attached to the more substituted end of the carbon–carbon double bond; and (iii) the relative reactivity of monosubstituted alkenes is sterically controlled: it decreases as the bulk of substituent increases (Scheme 124). Dienes261 or allenes262 undergo cyclopropanation at only one of the double bonds with benzylidene pentacarbonyl complexes 478. Very recently, as an strategy to demonstrate that gold carbene complexes are also reactive species, quantitative cyclopropanation has been achieved by addition of p-methoxystyrene to a solution of gold NHSCC 498 at
78°C followed by warming to room temperature (Scheme 125). NHSCC 498 was obtained from chromium NHSCC 492 by an effective gold-for-chromium exchange.263 Indeed, gold carbene complexes can be readily prepared by transmetallation from group 6 metal FCCs264; however, for NHSCCs some heteroatom-stabilizing effect is required.

105

Group 6 Metal Fischer Carbene Complexes

Ph R1 H W(CO)5

+

R1

H

−78°C

Ph 480

+ Ph

Ph

>

R1 Reactivity order:

Et >

R1

>> t-Bu

i-Pr

>

>

Scheme 124 Cyclopropanation of alkenes with nonheteroatom-stabilized benzylidene tungsten complex 480.

Ar1 Cr(CO)5 Ar1

492 [Cy3PAu]NTf2 CH2Cl2

Ar1 AuPCy3 Ar1

Ar1

Tf2N – +

498 Ar1 = p-MeO–C6H4

Ar1

>95% (GC)

Ar1 499

Ar1

Scheme 125 Cyclopropanation with gold-complexes obtained by transmetallation from a group 6 metal NHSCC.

Katz was also a pioneer on employing metal complexes as catalysts for enyne metathesis and found that several FCCs were able to promote the synthesis of phenanthrene derivatives 501 from enynes 500 by ring-closing metathesis. Both stoichiometric and catalytic conditions were tested.265 Indeed, several tungsten carbene complexes were essayed: among them, both FCC 462 and NHSCC 493 were active catalysts leading to phenanthrenes 501 in moderate yields with moderate to remarkable stereoselectivities, and in loadings as low as 1 mol% (Scheme 126, top). The catalytic cycle is proposed to follow an yne-then-ene pathway, which is the most common one for Mo and W alkylidene complexes (Schrock-type catalysts). Therefore, a [2+2]-cycloadddition should take place between the carbene catalyst species 502 and the triple bond to

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MeO W(CO)5 Ph 462 or Ph W(CO)5 Ph

493

R1

Toluene, 75°C, 18 h

1

R

R2 R2 500 with 462 1 mol% (GLC yields) 100 mol% (isolated yields)

501 with 493

R1 = R2 = H R1 = Me, R2 = H R1 = R2 = Me

31% 18% 26% (78% cis) 19% (95% cis) 24% 24%

R1 = R2 = H R1 = Me, R2 = H

50% 40%

R1

500

W(CO)5

501

51% 40%

R2 502 (or 462 or 493) R2 W

R1

R1 R2 R1

W R1

R2

R2 503

505 R2 R1 W

R1 R2

504

Scheme 126 NHSCC and FCC catalyzed ring-closing metathesis of enynes 500.

produce tungstenacyclobutane 503. Next, a retro-[2+2]-cycloaddition would generate carbene complex 504 which should then evolve by an intramolecular [2+2]-cycloaddition with the remaining double bond to form tungstenacyclobutane 505. The catalytic cycle will finish with

Group 6 Metal Fischer Carbene Complexes

107

the regeneration of the catalyst species 502 by a retro-[2+2]-cycloaddition reaction with concomitant liberation of 9-alkenylphenanthrenes 501 (Scheme 126, bottom).

7.3 Applications of Alkynyl NHSCCs as Stoichiometric Reagents in Organic Synthesis In the last decade, Barluenga developed a series of remarkable synthetic transformations based on alkynyl NHSCCs 506, which were generated following the strategy depicted in Scheme 118. The most relevant results are discussed below attending to the nature of the reaction products, thus starting from acyclic compounds, following with carbocyclic products and ending with heterocycles. NHSCCs 506 undergo low-temperature nucleophile-induced dimerization, with complete chemo-, regio-, and steroselectivity.250 The nature of the nucleophile employed determines the selectivity of the process, and consequently the structure of the endiyne adduct obtained. Thus, high yielding tail-to-tail dimerization of carbene complexes 506 takes place when potassium tert-butoxide is employed. Following this methodology, a variety of di-, tri-, and tetraynylethenes 507 has been accessed (Scheme 127, top). Additionally, this strategy has allowed the synthesis of molecules such as 1,6bis(4-hydroxyphenyl)-3-hexen-1,5-diyne 508, a precursor of compound 509 that self-assembles toward a columnar liquid-crystalline phase and organogels266 (Scheme 127, bottom). In addition to the tail-to-tail dimerization, head-to-tail processes have also been established. Thus, alkenyl-substituted NHSCCs 511 (generated in situ from FCCs 510) undergo dimerization in the presence of 3,5dichloropyridine (3,5-DCP) as nucleophile leading to 3-alkenylocta3,7-dien-1,5-diynes 512 with excellent selectivity250 (Scheme 128). Small amounts of the head-to-head regioisomer have also been observed (headto-tail/head-to-head ratio: 10/1 to >20/1), but separation of both regioisomers and isolation of the major component in pure form is achieved by flash chromatography. A mechanistic proposal for the formation of the two different families of dimeric structures 507 and 512 is shown in Scheme 129. In both cases, a conjugate addition of the nucleophile [t-BuO
or 3,5-DCP] to the electrophilic β-carbon of NHSCCs 506, 511 should be the initial step leading to allenylmetallate species 513, 515. At this point, the reaction should follow two alternative pathways depending on the different nature of these two allenyl intermediates: anionic 513 vs zwitterionic 515. Thus, on the one hand,

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R2 MeO [M]

″tail-to-tail″

1) Li R2 THF, −80°C 2) TMSOTf

R1

[M] R1

16

R1

KOtBu −80 to −40°C 74%–95%

506

R2 R2

507 R1

[M] = Cr(CO)5, W(CO)5 R1 = alkenyl, aryl R2 = alkyl (1°), aryl, TMS RO

OR RO

RO HO

OR OR

O

OH

508

O O

O

OR

O

OR OR

RO RO

509

O

RO

O

O O

RO RO

R = C12H25

O

OR RO

OR OR

Scheme 127 Tail-to-tail dimerization of alkynyl NHSCCs 506.

R1 R2 MeO

R1

"head-to-tail"

R2 1) Li THF, −80°C [M] 2) TMSOTf

510

[M] = Cr(CO)5, W(CO)5 R1 = alkyl (3°), TBDMS R2 = aryl, TMS

R1

[M]

R1

3,5-DCP −80 to −40°C 57%–84%

511

R2 512 R2

3,5-DCP = 3,5-dichloropyridine

Scheme 128 Head-to-tail dimerization of alkynyl NHSCCs 511.

109

Group 6 Metal Fischer Carbene Complexes

R1 – [M]

R1

[M]

R1

R2 tBuO

R2

506

R2

tBuO

513

514

tBuO–

507

R2

– [M]

R1

R1 [M]

3,5-DCP – [M]

Cl

R1

R2

[M]

Cl N

R1 R2

511

R2 R2

512

R2 R1

N Cl

515

– [M]

516 [M] = Cr(CO)5, W(CO)5

R1

Cl

Scheme 129 Proposed mechanisms for the dimerization of alkynyl NHSCCs.

anion 513 should undergo a conjugate addition—through its propargylmetallate structure—to the second equivalent of NSHCCs 506 to form intermediate 514. Then, allenyl species 514 would afford tail-to-tail dimer 507 upon elimination of tert-butoxide and the metal fragment. In the alternative pathway, zwitterionic species 515 should evolve by conjugate attack— through its allenylmetallate form—to NHSCCs 511 leading to bis(allenyl) species 516. Elimination of both 3,5-dichloropyridine and the metal fragment from intermediate 516 would produce head-to-tail dimers 512. Alkynyl chromium NHSCCs 517, in situ synthesized from FCCs 9 as depicted in Scheme 118, react with 2-methoxyfuran to form linear dienyne adducts 518, in good yields (Scheme 130). Alkynyl FCCs also undergo this type of reaction (Scheme 91) but, for NHSCCs 517, it takes place just by allowing the reaction mixture to warm from low temperature to room temperature.198 This strategy has been extended to prepare linear dienediyne adducts 520, from cross-conjugated diyne NHSCCs 519. Remarkably, NHSCCs 517 are also able to react with nonactivated olefins at low temperature to form alkynylcyclopropanes 521 in

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R2 OMe

O MeO Cr(CO)5 R1

Cr(CO)5 R1

9

R2

THF −80°C to rt

CO2Me

74%–86% 517

518

R1 = aryl R2 = aryl, TMS

R1

R2 OMe THF −80°C to rt

R2

O

Cr(CO)5

CO2Me

66%–77% 519

520

R1 R1 = alkyl (1°), aryl, TIPS R2 = aryl

R1

Scheme 130 Synthesis of linear dienynes 518 and diendiynes 520.

good yields and in an almost totally diastereoselective manner267 (Scheme 131). Alkynylspiro[2.3]hexanes, spiro[2.4]heptanes, and spiro [2.5]octanes 522 have also been prepared following this methodology. Additionally, a large family of [3.1.0] bicyclic products 523 is obtained with total regio- and diastereoselectivity in almost quantitative yield by cyclopropanation of one double bond of cyclopentadiene; the endoadducts are formed as single products. All these alkynylcyclopropanes are formed through a nucleophilic attack of the olefinic or dienic partner to the conjugate carbon of the in situ synthesized chromium NHSCC 517. The gold-catalyzed isomerization of bicycles 523 has been recently reported.268 In situ synthesized NHSCCs 506 (M ¼ Cr) react with furfural imines 524 to afford benzofurans 525 in moderate to good yields in a regioselective manner (Scheme 132).269 This procedure is one of the few approaches described for the synthesis of benzofurans by construction of the arene ring; most methodologies involve formation of the furan ring onto a preexisting arene nucleous. As this carbocyclization is highly regioselective, formation of both regioisomeric benzofurans 525 is achieved by exchange of the carbene substituents (R1 and R2). Mechanistically, this reaction should be initiated by conjugate addition of the imine nitrogen to the carbene complex, as stated by a recent theoretical study.270

111

Group 6 Metal Fischer Carbene Complexes

R1

R3 R4 R5 −80 to −40°C

R3 R2

R4

40%–60%

R5 521

R1

( )n

R2

n = 1,2,3

−80 to −40°C Cr(CO)5

30%–98%

( )n

R2

n = 1,2,3

522

R1 517

R1 −80 to −40°C

R1 = aryl

R2

90%–99%

R2 (for alkenes) = alkyl (1°), alkenyl R3, R4 = alkyl (1°), aryl R5 = alkyl

523

R2 (for cyclopentadiene) = alkyl (1°, 2°, 3°), alkenyl, aryl, TMS

Scheme 131 Synthesis of cyclopropanes from in situ generated NHSCCs.

On the other hand, stable 2-azetinyl carbenes 527 are regioselectively afforded by [2+2] cycloaddition reaction of alkynyl-substituted (pentacarbonyl)chromium or -tungsten NHSCCs 506 (M ¼ Cr, W) with imines 526.271 Subsequent reaction of chromium 2-azetinyl carbenes 528 with alkynes allows the preparation of 2,3-dihydrocyclopenta[e]oxazines 529 in moderate to good yields. Azetinyl carbenes 527 can be prepared also from furfural imines, although in competition with the formation of the corresponding benzofurans 525 (vide supra); formation of one or the other product will depend on the electronic nature of the substitution pattern of the NHSCCs 506. An additional family of compounds can be accessed by the reaction of imines with alkynyl NHSCCs. Thus, tungsten alkynyl carbenes 530, bearing an alkyl group at the conjugate position, react with aryl imines 531 under smooth reaction conditions, yielding benzo[c]azepinyl derivatives 532 in good to excellent yields (Scheme 133).272 The reaction occurs with total regioselectivity and it is tolerant to a large variety of functional groups.

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R3

N

NHR3

O

R2

524 R2

O

M = Cr

THF −80°C to rt

M(CO)5 R1 506 R1 = alkyl (2°), alkynyl, aryl R2 = alkyl (1°, 2°), aryl R3 = alkyl, allyl Ar = aryl, heteroaryl

Ar

Bu N R2

(CO)5Cr R1

R1 525

51%–81%

Ar N Bu 526

(CO)5M

M = Cr, W

R5 CH3CN 80°C

R2 R1 527

50%–75%

R4

Bu N

Ar

R1

R2 N

R4

32%–82%

O

Bu Ar

R4 529

528 R1 = alkynyl, aryl R2 = aryl, heteroaryl R4 = alkyl (2°), aryl, heteroaryl, CO2Me Ar = aryl R5 = H, CO2Me

Scheme 132 Synthesis of benzofuran derivatives, 2-azetinylcarbenes, and 2,3dihydrocyclopenta[e]oxazines from NHSCCs 506.

A theoretical analysis of the reaction mechanism has revealed that the presence of an alkyl or aryl group at the conjugate position of the carbene 530 (R2) plays a determining role in terms of sterical hindrance. Thus, after the initial and regioselective imine attack to the conjugate position of NHSCC 530 to form zwitterionic allenylmetallate intermediate 533, the reaction evolves toward a selective formation, through 1,2-pentacarbonylmetal migration, of the benzoazepinyl intermediate 534, avoiding an early closure of the cycle and formation of the azetinyl carbene 527 (vide supra). Finally, a 1,5-hydrogen migration would lead to benzoazepinium tungstate 532. Additionally, several transformations have been performed onto zwitterionic benzoazepinium tungstates 532, taking advantage of both its electrophilic and also its nucleophilic nature; a high number of benzo- and dihydrobenzo[c]azepines with an important degree of substitution have thus been prepared.

113

Group 6 Metal Fischer Carbene Complexes

R3

R2

– (CO)5W

R1

R7 R6

R2 R5

N R3

61%–95%

R1

R3

Ar

531 THF −80°C to rt W(CO)5

N

N

530 Ar

R4 532

531 – (CO)5W

R1

R7

R6 R5

R2

N

(2°), alkynyl, aryl R2 = alkyl (1°, 2°) R3 = n-Bu, allyl R4 = H, Br

R7 H

R6

R2 R5

N

R4

R4

R3

R3 533 R1 = alkyl

R1

– (CO)5W

534 R5 = H,

Me R6 = Me, OMe, OTBDMS, NO2, CO2Me, CN R7 = H, Me

Scheme 133 Regioselective synthesis of benzo[c]azepinyl derivatives from alkynyl NHSCCs and imines.

7.4 Stoichiometric or Catalytic Transformations Involving NHSCCs as Intermediates Synthesized From M(CO)5L and Conjugated Dienynes or Heterodienynes As pointed out above (Section 2, Scheme 5), group 6 metal carbonyl complexes 20 may behave as π-acids with alkynes,273 being able to activate C–C triple bonds by metal coordination. The formed π-complex may evolve by different manners depending on the reaction conditions and on the structure of the alkyne. Dienynes or heterodienynes of general formulae 535 have shown to be appropriate precursors for group 6 metal NHSCCs by reaction with a suitable carbonyl metal complex (Scheme 134). In these transformations, the carbonyl metal complex behaves as a π-acid activating the triple bond, such as in 536, for a subsequent cyclization. This cyclization may occur in different modes (5-exo-dig, 5-endo-dig, or 6-endo-dig) depending on the nature of the starting material and the reaction conditions. Indeed, the generated metal-containing ylides (537–539) may be resonant structures of NHSCCs, which may be isolated (see below), or, in other cases, may react with dipolarophiles to provide new NHSCCs, some of them also isolated.

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Y X Formation of metal ylides 537

M(CO)5 X

5-endo-dig

Y

6-endo-dig X

Y

X M(CO)5L

Y

M(CO)5 538 5-exo-dig

535 M = Cr, Mo, W L = CO, THF X = CH, N Y = CH2, O

X (CO)5M 536

Y

Formation of alkenylidene

(CO)5M X Y

539 M(CO)5

540

Scheme 134 Alternative reaction pathways for metal-activated dienynes or heterodynes.

An additional reaction pathway may take place by formation of an alkenylidene complex 540, which then may evolve by electrocyclization leading to the reactions products; NHSCCs have been proposed as reaction intermediates in these transformations but have neither been detected nor isolated. Most of these reactions take place with catalytic amounts of metal carbonyl complexes 20 although stoichiometric conditions are sometimes required or, in other occasions, have been employed to isolate intermediate carbene complexes. Indeed, three out of these four different possible reaction pathways have been reported for the tungsten carbonyl-mediated cyclization of o-ethynylphenylketone derivatives 541, once generation of tungsten π-activated alkyne complex 542 has been accomplished (Scheme 135): (a) 5-Exo-dig cyclization, to generate tungsten-containing carbonyl ylide 544, which is a resonance form of furyl NHSCC 543. Moreover, 1,2-bis(acetyl)benzene 546 (R1 ¼ Me) was isolated (approx. 50%) when the reaction was performed in the presence of 5 equiv. of H2O.274 Compound 546 is presumably produced by hydrolysis of

115

Group 6 Metal Fischer Carbene Complexes

R1

R1

O

O

R2

O H2 O O

(CO)5W 543

O

(CO)5W 544

546

545 5-exo-dig (fast)

R1

R1

W(CO)5(THF) O THF, rt

O

R1

6-endodig (fast)

O

–

(CO)5W

541

542

R1 O

Alkenylidene formation (slow)

W(CO)5

W(CO)5 547

R3 548 OCH R4 2

550

O

R1

R1 H

O W(CO)5 551

R3 H O R4 H 549

Scheme 135 Alternative reaction pathways for tungsten hexacarbonyl-catalyzed reactions of o-ethynylphenylketones.

NMR-observed methyleneisobenzofuran 545, which comes from 544 by deprotonation from the R1 group and protonation of tungsten– carbon bond. This pathway has been observed also for β-ethynyl α,β-unsaturated ketones (see Scheme 136). (b) 6-Endo-dig cyclization, to generate tungsten carbonyl ylide 547, which may react with enol ethers 548 to form bicyclic compounds 549 (vide infra). (c) Formation of alkenylidene 550, by 1,2-hydrogen shift, which would lead to benzopyranylidene tungsten FCC 551, which has been isolated50 (see Scheme 6). The experimental results suggest that pathways (a) and (b) are faster than (c), which should occur mainly in the absence of the trapping agent (H2O,

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Ar1

Ar1

M(CO)5(THF) (3 equiv.) O THF, rt, 1 h

Ar1

O2, THF O rt, 12 h

52%–59%

O

M(CO)5

552 M = Cr, W 1 Ar = aryl, heteroaryl

O H 554 40%–47% (from 552)

H 553

Ar1

Ar1 O

O –

(CO)5M

H

(CO)5M

555

556 Ph

Ph O +

R1

Cr(CO)5(THF) (5 mol%) THF, rt, 2 h

O

40%–90% cis/trans: 50/50 to >99/1

557

558 OEt R1 =

R1

OTMS O

O-t-Bu ,

OEt ,

Ph ,

Et Ph ,

Et ,

Scheme 136 Synthesis of 2-furyl carbene complexes and their role in catalytic cyclopropanation.

alkene). Additionally, (a) and (b) should be reversible and in equilibrium through metal-complexed species 542 while formation of tungsten FCC 551 makes pathway (c) irreversible. 7.4.1 Initiated by 5-exo-dig Cyclizations 2-Furyl carbene complexes 553 are synthesized in moderate to good yields by reaction of β-ethynyl α,β-unsaturated ketones 552 with chromium and tungsten carbonyls. Regarding the reaction mechanism, the initial coordination of the metal carbonyl to the triple bond should be followed by a 5-exo-dig cyclization by nucleophilic attack of the oxygen of the ketone to the activated triple bond of 555 (Scheme 136, top). As mentioned before,

Group 6 Metal Fischer Carbene Complexes

117

the formed metal carbonyl ylide 556 is indeed a resonant form of carbene complex 553.275 NHSCCs 553 are relatively stable although they slowly decompose leading to furfural derivatives 554. However, in the presence of the electron-rich alkenes and dienes, a catalytic tandem sequence (carbene formation/cyclopropanation) takes place leading to 2-furylcyclopropanes 558 in moderate to excellent yields276 (Scheme 136, bottom). Cr(CO)5(THF) is the best catalyst for this domino reaction, although other group 6 metal carbonyl complexes (as well as catalysts of Rh, Ru, Pd, and Pt) may be employed.

7.4.2 Initiated by 5-endo-dig Cyclizations Iwasawa reported that terminal acetylenic dienol silyl enol ethers 559 cyclize to form different types of nitrogen-containing bicyclic compounds under W(CO)6 catalysis.277 Thus, mixtures of diastereomeric 2-azabicyclo [3.3.0]octane derivatives 560 are synthesized by photoirradiation in the presence of MS4A. Alternatively, isomeric 3-azabicyclo[3.3.0]octanes 561 are obtained when tri-n-butylamine is added under otherwise identical conditions (Scheme 137, top). The selectivity is complete for both rearrangements for substrates bearing an aryl group at the diene terminus, although 2-azabicyclo[3.3.0]octanes appear as by-products in the amine promoted reaction for substrates possessing an alkyl group at that position. A mechanistic rationale considers a dual behavior of the reactants and proposes an equilibrium between π-alkyne metal complex 562 and tungsten alkenylidene 563 (Scheme 137, bottom left). In the absence of tri-nbutylamine, the reaction should start by a 5-endo-dig nucleophilic cyclization to generate zwitterionic tungstate 564; then, a Michael-type addition should produce bicyclic NHSCC 565, which should finally undergo elimination of the metal catalyst to form 2-azabicyclo[3.3.0]octane 560. On the other hand, the addition of the tertiary amine promotes the tautomerization to alkenylidene complex 563. Then, zwitterionic tungstate 566 should be generated by nucleophilic attack of the enol silyl ether to the alkenylidene carbon, and its evolution through a Michael-type addition to the α,β-unsaturated silyloxonium moiety would produce bridged NHSCC 567. Then, a 1,2-alkyl migration should occur to form zwitterionic species 568, helped by electron donation from the nitrogen atom. Finally, elimination of the metal moiety would liberate 3-azabicyclo[3.3.0]octane 561 (Scheme 137, bottom right). Labeling experiments support this mechanistic proposal.

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Ms

TIPSO

N W(CO)6 (3–30 mol%) hn, MS4A toluene rt, 0.5–3 h

Ms

TIPSO R2

N

R2 1

65%–85% R (dr = 60:40 to 40:60)

R1

H

560

TIPSO H

559

n-Bu3N

R1= alkyl (2°), aryl, heteroaryl R2 = H, Me

N Ms H 561

R1

Ms

TIPSO

R2

59%–92%

Ms

TIPSO

N

N

n-Bu3N R1

W(CO)5 H

562

R1

H (OC)5W 563 – W(CO)5

OTIPS Ms N

Ms

TIPSO N

R1

H

–

W(CO)5

R1

564 Ms

TIPSO

566 W(CO)5

N Ms

TIPSO N R1

H

W(CO)5 R1

565

560

567

TIPSO –W(CO) 5 N Ms R1

H

568

561

Scheme 137 Tungsten hexacarbonyl-catalyzed synthesis of 2- or 3-azabicyclo[3.3.0] octane frameworks.

119

Group 6 Metal Fischer Carbene Complexes

TIPSO

R4 R4

R2

W(CO)6 (5–20 mol%) hn, MS4A toluene, rt, 0.5–3 h

R1

67%–81% dr = 75:25 to 20:80 569

TIPSO

4 4 H R R

R2 R1

R3

R3 570

4 4 H R R

TIPSO R2 R1 = H, alkyl (1°, 2°), aryl R2, R3 = H, Me R4 = H, CO2Me

R3

R1

W(CO)5

571 TIPSO

H Z

Z (Z = CO2Me)

Ph

Me

H

572 14%

Scheme 138 Tungsten hexacarbonyl-catalyzed synthesis of bicyclo[3.3.0]octane frameworks.

In a mechanistically related process, a variety of bicyclo[3.3.0]octane derivatives 570 are synthesized with moderate yields and stereoselectivities from the analogous all-carbon skeleton acetylenic dienol silyl ether 569. A mechanism similar to the one depicted in Scheme 137 would explain the formation of the reaction products through NHSCC intermediate 571 (Scheme 138, top). Indeed, the isolation of tricyclic compound 572 as a by-product implicates the presence of a carbene complex intermediate (Scheme 138, bottom).278 This tandem cyclization protocol has been applied to a concise synthesis of the basic carbon skeleton of triquinanes. Iwasawa was able to synthesize tricyclic indole derivatives 574 by photoirradiation of mixtures of N-(o-alkynylphenyl)imines 573, olefins, and W(CO)6 (Scheme 139, top).279 The reaction proceeds with moderate to good yields under stoichiometric conditions or with just a 10 mol% of catalyst. It also works in a satisfactory manner for N-(o-alkynylphenyl)imines derived from internal alkynes, although with moderate diastereoselectivity. After the initial coordination of tungsten carbonyl to the triple bond, the mechanism for this transformation would involve a 5-endo-dig cyclization by nucleophilic attack of the nitrogen to the activated triple bond of

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R1

R2 N +

R4

W(CO)6 (x mol%) hn toluene or benzene, rt

R1

R2

N R4

+

[H3O ] 52%–89% (x = 100) R3 cis/trans = 56/44 to 22/78 (for R1 = H, R3≠ H)

573

55%–68% (x = 10)

O

R1 = H, OMe R2 = Ph, OEt, Me R3 = Me, Pr, Ph

N OTBS

OEt 4

R =

O-t-Bu ,

R1

R3 574

Me ,

R2

O

OEt ,

OMe

,

R1

R1 2

R2

R

N

N

N R3 R3

(CO)5W

R3

W(CO)5

W(CO)5

576

575 R1 R4

R2 1,2-R3migration

N 3

R4

R

Metal elimination

574

W(CO)5 577 Ph N Me

O-t-Bu

W(CO)5 578 12%

Scheme 139 Synthesis of polycyclic indole derivatives by a tungsten carbonylcatalyzed reaction.

575, to form tungsten azomethine ylide 576. Then a [3+2]-cycloaddition should take place leading to NHSCC 577. In a later evolution upon standing, compound 577 is transformed into indole derivative 574 through 1,2-R3 migration and metal elimination (Scheme 139, middle). Indeed,

121

Group 6 Metal Fischer Carbene Complexes

(indolin-3-ylidene)pentacarbonyltungsten complex intermediate 578 has been isolated in 12% yield after careful chromatographic purification on alumina at
20°C (Scheme 139, bottom).280 More recently, time and yield for the reaction with internal alkynes have been improved using PtCl2 or AuBr3 as π-acid catalysts.281 Seven-membered heterocycles 580 may be obtained when the internal alkyne substituent bears a conjugate double bond, as in 579 (Scheme 140, top).282 The proposed tungsten NHSCC intermediate 582 is formed from tungsten-containing azomethine ylide 581 by a [5+2]-cycloaddition reaction; the overall process proceeds satisfactorily even with a 10 mol% of W(CO)6. This transformation was extended to the synthesis of azepino [1,2-a]indole and diazepine derivatives, 583 and 584, either by intramolecular Ph N

OR3 R2

+

OR4

R2 Ph

R1

Ph R1

R2

R1

580 6%–79% (x = 100) 61%–72% (x = 10)

R2

OR3

+ N

O N

then 0.1 M HCl

R1 = H, Me R2 = H, Me, OMe R3 = Et, i-Pr, TIPS R4 = Et, i-Pr R3–R4 = –CH2CH2–

579

–

W(CO)6 (x mol%) hn Et3N, toluene, MS4A, rt, 1.5–24 h

Ph

OR3 OR4

OR4

N

R1

W(CO)5 W(CO)5 582

581 Ph

Me Ph

N

Ph

N N

583 84% (x = 100) 50% (x = 10)

584 85% (x = 100) 72% (x = 10)

Scheme 140 Synthesis of seven-membered heterocycles by tungsten carbonylcatalyzed reactions of N-(o-alkynylphenyl)imine derivatives.

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e Barluenga and Enrique Aguilar

TIPSO

Z

W(CO)6 (5–10 mol%) Et3N (10 mol%) hn MS4A, toluene, rt 1–6 h

Z

R1

TIPSO

R4 R3

R2

585

Z

R1

61%–83% R4

HZ

(Z = CO2Me)

R2 586

R3

R1

Z

H

R1

Z

R3

R4 H

Z

TIPSO

Z

R1

R4 R3

HZ

Z

OTIPS

OTIPS W(CO)5

W(CO)5

587

R4 – R3

588

W(CO)5 589

R1 = i-Pr, Ph =

R4

,

,

,

,

,

,

R2 R3

MeO

OMe

Scheme 141 Tungsten carbonyl complexes-catalyzed stereoselective synthesis of bicyclo[5.3.0]decanes.

approaches or by the employment of imines as dipolarophiles (Scheme 140, bottom). More recently, other metal complexes, such as ReBr(CO)5, AuBr3, or PtCl2, have been found to catalyze this process.283 In another reaction initiated by a 5-endo-dig cyclization, bicyclo[5.3.0] decane derivatives 586 have been prepared in good yields from trienynes 585, bearing 2-silyloxydiene and a conjugate enyne moieties in their structure, by intramolecular W(CO)6-catalyzed reaction284 (Scheme 141). The reaction is stereospecific, highly diastereoselective, and allows a wide range of substituents in the dienol silyl ether skeleton. Moreover, the operating mechanism seems to depend on the silyl enol ether double bond configuration; indeed, for (Z)-enol silyl ether 585, a cyclopropanation on 587 would lead to cis-divinylcyclopropane carbene complex intermediate 588; then a Cope rearrangement should take place to NHSCC 589, and it would account for the configuration of the final product 586. In a similar manner, 1-azabicyclo[5.3.0]decane derivatives 591 have been obtained from thioimidates 590 with catalytic amounts of chromium hexacarbonyl (as low as 2 mol%).285 A varied substitution pattern on the starting thioimidates is allowed for this transformation (Scheme 142, top).

123

Group 6 Metal Fischer Carbene Complexes

RS R3 R1

R2

71%–94%

R4

(R = CH2TMS)

590

N

R1 R5

R2 R5

SR

R3

Cr(CO)6 (2–10 mol%) hn, THF

N

591

R4 R1 = Me, Ph, 2-furyl, TMS, Me-CHKCH, CO2Me R2 = H, Me R3 = H, Me; R1–R3 = –(CH2)4– R4 = H R5 = H, Me; R4–R5 = –(CH2)5– TMS

S

TMS

Cr(CO)6 (30 mol%) hn, toluene Nu

N

S N

Ph

Ph 52%–92% 592

R5 R5 = H, Me NuH = MeOH, CH2 = C(OTBS)OMe

R5

SR R1

8p conrot Δ

N R5 – R4

Cr(CO)5

Nu

593

SR R1 R4 R5

594

Scheme 142 Chromium hexacarbonyl-catalyzed 1-azabicyclo[5.3.0]decane frameworks.

N

Nu

Cr(CO)5

595

stereoselective

synthesis

of

Moreover, an external component can be incorporated when the reaction is performed in the presence of a nucleophile: tricyclic indoles 593 bearing up to three consecutive stereocenters are thus formed (Scheme 142, middle). Methanol or a silyl ketene ketal have been the employed nucleophiles. The reaction sequence has been proposed to occur by conrotatory 1,7electrocyclization of zwitterionic intermediates 594 leading to chromium NHSCCs 595, which evolve into the final 1-azabicyclo[5.3.0]decane derivatives 591 (Scheme 142, bottom). In most cases, only single isomers are obtained; the stereoselective 1,4-addition of the nucleophile takes place by the less hindered face of α,β-unsaturated NHSCC intermediates 595.

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e Barluenga and Enrique Aguilar

7.4.3 Initiated by 6-Endo-dig Cyclizations Several transformations initiated by a 6-endo-dig cyclization and involving group 6 metal NHSCCs as reaction intermediates have also been described. Thus, tungsten-containing carbonyl ylides are involved in the W(CO)6(THF)-catalyzed reaction between o-ethynyl phenyl ketone derivatives 596 and electron-rich alkenes 597 to form polycyclic compounds 598 (Scheme 143). After initial triple bond activation by the tungsten carbonyl π-acid, nucleophilic attack by the oxygen of the carbonyl group causes the previously mentioned 6-endo-dig cyclization leading to tungsten-containing carbonyl ylide 599.286 A [3+2]-cycloaddition should then take place in a concerted manner leading to tungsten NHSCC 600. This intermediate inserts into a C–H bond of the alkoxy group to give product 598 while the tungsten catalyst species is regenerated. Interestingly, the absence of the ketene acetal leads to the formation of a benzopyranylidene complex50 (see Schemes 6 and 135). Intermediate polycyclic NHSCCs in these transformations 600 (Scheme 143) have not been isolated. However, they have been intermolecularly trapped by carrying out the reaction with monosubstituted olefins in the presence of triethylsilane to form polycyclic tetraalkylsilanes 602 in moderate to good yields and with complete regio- and diastereoselectivity (Scheme 144).274 Carbene insertion into the silicon–hydrogen bond of R1 R3

O +

OCH2R4 50%–94% 597 R2 R1 = H, Me, n-Pr, i-Pr R2 = H, Me R3 = H, OEt W(CO)5(THF) R4 = Me, n-Pr 1 R R3

596

O

–

R1

O

R3

H

R2

O

R4 H

598

− W(CO)5(THF) O

R1

OCH2R4 R2

599

W(CO)5(THF) (10 mol%) THF, rt 4 h–1 week

W(CO)5

[3+2]cycloaddition

R3 (OC)5W H

R2

O R4 600

Scheme 143 Synthesis of polycyclic compounds by tungsten carbonyl-catalyzed rearrangement of o-ethynylphenylketones.

125

Group 6 Metal Fischer Carbene Complexes

O +

R1

Et3SiH (10 equiv.) W(CO)5(THF) (10 mol%) THF, rt 44%–78%

O

H

H Et3Si

601 R1 = O-n-Bu, O-t-Bu, OSiMe3, CH2SiMe3, Ph

H 602

H

R1

−W(CO)5(THF) O

Et3Si Si-insertion

O H

H (CO)5W 603

H

R1

H (CO)5W

H

R1

604

Scheme 144 Trapping of NHSCCs intermediate 603 with silanes. Synthesis of polycyclic tetraalkylsilanes.

silanes, described here for a catalytic multicomponent reaction involving NHSCCs, is a well-established reaction of free carbenes or carbene–metal complexes. Indeed, a theoretical study of cycloaddition reactions of tungstencontaining carbonyl ylides depicted in Scheme 143 points out that the [3+2]-cycloaddition proceeds in a reversible and concerted manner, being the endo-mode cycloaddition kinetically favored.287 In a similar manner, a geminal carbofunctionalization of terminal acetylenic dienol silyl enol ethers 605, containing N-Ts or N-Ms component in their tethers, takes place under photoirradiation conditions, leading to 3-azabicyclo[4.3.0]nonane derivatives 606 in moderate yields; equimolar amounts of W(CO)6 are required (Scheme 145, top).278,288 Regarding the mechanistic rationale, the initial 6-endo-dig cyclization on the tungsten carbonyl-activated triple bond should be followed by a Michael-type addition to generate tungsten NHSCC intermediate 607. The overall cascade sequence takes place in a diastereoselective manner. Remarkably, the reaction outcome is catalyst controlled. Thus, by the selection of the appropriate π-acid catalyst 8-azabicyclo[4.3.0]nonane derivatives 608 (cationic gold) or tricyclic compounds 609 and 610 (rhenium) are selectively formed; however, all these products come from 5-exo-dig cyclizations (Scheme 145, bottom).

126

Jos
e Barluenga and Enrique Aguilar

W(CO)6 (100 mol%) MS4A toluene hn, 5–10 min

TIPSO

R1

R2

N TIPSO

605 R1, R2 = Me, Ph X = Ms, Ts

R2

X

N

606 N

N

TIPSO

W(CO)5

R2

H

N

X

R1

608 68%–77% with AuCl(PPh3)/AgSbF6 (10 mol%)

X

H

607 R2

H

R1

R2

H

R1

H

H

37%–52%

X

TIPSO

TIPSO

R1

TIPSO

H

X

R2 N

X

R1

609

610

72% (50/50), R1 = Ph, R2 = Me; X = Ts with ReCl(CO)5 (10 mol%)

Scheme 145 Catalyst-controlled tandem cyclization reactions.

7.4.4 Initiated by Alkenylidene Formation A fourth type of transformations involving group 6 metal NHSCCs as reaction intermediates include those that are initiated by formation of alkenylidene species. Naphthalene derivatives 612 and heteropolyaromatic compounds 616 have been synthesized from benzenes substituted at the ortho-position with ethynyl and alkenyl (611) or heteroaromatic groups (615), usually in good to excellent yields (Scheme 146, top and middle).289 Catalytic or, in some cases, stoichiometric amounts of (CO)5W(THF) are required, depending on the nature of the substrate. The reaction seems to proceed via alkenyldiene intermediates 613, which undergo a 6π electrocyclization to NHSCCs 614. Isomerization, followed by reductive elimination, should lead to the reaction products. Deuterium-labeling experiments support the proposed mechanism. Additionally, cis-1-alkenyl-2-ethynylcyclopropanes 617 undergo rearrangement in the presence of stoichiometric amounts of Cr(CO)5(THF) to provide moderate yields of mixtures of isomeric 1,3,5-cycloheptatrienes

127

Group 6 Metal Fischer Carbene Complexes

R1 R2

R1

(CO)5W(THF) (5–100 mol%) THF, rt, 3–5 days

R2

31%–100% 612

611 R1 = H, Me, OTBS, CO2Me, CO2Et R2 = H, Me, CO2Et R1 R2

R1

6π electrocyclization

R2

W(CO)5 W(CO)5 613

614 Het

(CO)5W(THF) (5–100 mol%) THF, rt, 3–5 days

Het

82%–99% 616

615 Het = 2-furyl, 2-thienyl, 3-thienyl, 2-N-Me-pyrrole (CO)5Cr(THF) (1 equiv.) THF, Et3N rt, 6 h

R1

617 R1 = PhCH2CH2, p-Me–C6H4

R1

R1 +

619 7%–10%

618 24%–34% 1) [1,5]-H 2) Reductive elimination

1) [1,3]-H 2) Reductive elimination R1

R1 [3,3] Cr(CO)5

Cr(CO)5 620

621

Scheme 146 M(CO)5(THF)-catalyzed rearrangements involving alkenylidene formation.

618 and 619 (Scheme 146, bottom).290 The reaction should proceed via formation of alkenylidene chromium complex 620, which should evolve by [3,3]-sigmatropic rearrangement to NHSCC 621. Subsequent [1,5]- or [1,3]-hydrogen shifts in 621, followed by reductive elimination in the

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e Barluenga and Enrique Aguilar

R1

R1 R2

42%–93% (x = 100) 26%–81% (x = 10–20)

I

622

W(CO)5(THF) (x mol%) THF, rt, 15 h

R1 = Me, p-Tol, OTBS, CO2Me R2 = H, Me

R1

R2

I 623

R1 R2

R2

W(CO)5 W(CO)5 I 624

I 625

Scheme 147 Synthesis of iodobenzene or -naphthalene derivatives by tungsten carbonyl-catalyzed rearrangement of 1-iodoalkynes.

generated metallated cycloheptatrienes, would readily explain the formation of regioisomeric reaction products 618 or 619. Tungsten carbonyl complexes also catalyze the transformation of 1-iodoalkynes 622 into iodo-substituted benzene or naphthalene derivatives 623 (Scheme 147). The reaction proceeds satisfactorily not only for o-(iodoethynyl)styrenes but also for nonaromatic dienyne derivatives. Good yields are usually reached when a stoichiometric amount of W(CO)5(THF) is used, but the yield of the catalytic reaction depends on the structure and the substituents of the substrate.291 Regarding the reaction mechanism, after the initial π-activation of the alkyne (see also Scheme 134), an isomerization via 1,2-migration of iodo group occurs to form tungsten iodoalkenylidene 624. The evolution of tungsten alkenylidene 624 by a 6π-electron electrocyclization would lead to NHSCC intermediate 625, which yields the final products by 1,2hydrogen migration and regeneration of W(CO)5(THF).

8. CONCLUSIONS, SUMMARY AND OUTLOOK The work compiled in this review highlights the significant contribution of group 6 metal Fischer carbene complexes (FCCs and NHSCCs) to organic synthesis. Along the review, we hope to have made explicit all

Group 6 Metal Fischer Carbene Complexes

129

the reasons that motivated de Meijere to label these reagents as chemical multitalents. Thus, a small and representative part of the plethora of acyclic, carbocyclic, and heterocyclic products that have been synthesized, taking advantage of the different modes of reactivity of these substrates, has been shown; the ease of switching their chemical behavior by performing the reactions under either thermal or photochemical conditions has been pointed out; the possibilities of tuning their reactivity depending on the nature of the stabilizing group, attending either to the heteroatom (alkoxy, amino), the more or less bulkiness of the heteroatom substituent, and even the option of placing a chiral nonracemic substituent to determine the stereochemistry of the reaction products has been showcased. Moreover, the reactivity of FCCs has been clearly expanded by their ability to insert many types of insaturated species (alkynes, carbonyl ligands, alkenes, dienes, allenes, isocyanates, …), not only once but also several times, which makes FCCs particularly well-suited substrates for multicomponent reactions. The chemistry of FCCs should be considered a rather mature area; it rests on well-established synthetic procedures, most of them of wide scope, which provide multigram quantities of such reagents; moreover, the mechanisms for many reactions and cascades have been clearly determined. Besides other chemists, whose names also appear in this final section, the outstanding contributions made by Wulff, Aumann, Herndon, Sierra, … should be highlighted. On the other hand, there is also a diversity of methods available to efficiently transform FCCs into functionalized metal-free entities. The cyclopropanation reaction stands as the most representative example of a transformation where only the carbene carbon is involved, but it is not the only one. Indeed, the outcome of the reaction between an alkene and a chromium FCC is changed into a four-membered carbocycle just by performing the reaction under photochemical conditions (Hegedus chemistry). Additionally, the carbene ligand can be transferred to produce a variety of acyclic and cyclic structures by formal [n + 1]-cycloadditions. The possibility of expanding the reactivity of FCCs with an additional double bond by employing alkenyl or aryl carbene complexes finds a pivotal point in the D€ otz benzannulation reaction. These types of carbene complexes partake in a widespread repertoire of transformations: C–C couplings, additions, cycloadditions, and multicomponent reactions, in either achiral or enantioselective approaches. Even though it still has a smaller portfolio of reactions, the chemistry of alkynyl FCCs has been greatly expanded, mainly by Barluenga, by involving

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e Barluenga and Enrique Aguilar

such species in a large number of cascade sequences. The in situ formation of 1-metallahexatrienes has been advantageously used as common element in many of them; their further evolution in function of the carbene antagonist(s) has amplified both the molecular complexity of the final products and the diversity of structures accessed. Diverse strategies have been developed to prepare nonheteroatomstabilized group 6 metal carbene complexes (NHSCCs) and the early contributions have been mainly related to the cyclopropanation and the metathesis reactions. The highly relevant findings achieved by pioneers (E.O. Fischer, Casey, Katz, H. Fischer, …) helped to understand the mechanisms involved in those reactions. In the recent times, Barluenga has pointed out that alkynyl NHSCCs are also highly valuable reagents for efficient and selective synthesis. On the other hand, Iwasawa has developed high yielding and atom-economic catalytic cycloisomerizations, cycloadditions, and multicomponent reactions; all of them are based on the ability of group 6 metal carbonyl complexes to coordinate to C–C triple bonds, and on their further evolution involving NHSCCs. But not every aspect of the chemistry of FCCs can be seen through rosecolored glasses. The fact that they are usually employed as a stoichiometric reagents emerges clearly and undoubtedly as their biggest limitation, because of economical and environmental (Green Chemistry) consequences. Anyway, either as stoichiometric reagents or as catalytic intermediates, group 6 metal FCCs offer a direct and highly valuable access to organic structures difficult to be prepared by other routes, and for sure, further developments in the field should be still to come. Indeed, de Meijere in 2004 stated “… The application of chirally modified Fischer carbene complexes in asymmetric synthesis has only begun, and it will probably be an important area of research in the near future.”4 However, 13 years later, such prediction has not been fully accomplished and the role of chiral nonracemic FCCs in asymmetric synthesis is still underexploited. Transmetallation to late transition metals is seen as an opened door to modulate, control and expand the reactivity of group 6 metal FCCs that deserves further efforts. But probably, the development of new reagents, reactions, and strategies capable of mimicking the behavior of group 6 metals in a fully catalytic manner is perceived as the biggest synthetic challenge in the field. Additionally, besides the mentioned developments in organic synthesis, considerable effort is nowadays devoted to study the electrochemical behavior of FCCs, and therefore, new scenarios should become open for them in photophysical applications and material properties.

Group 6 Metal Fischer Carbene Complexes

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ACKNOWLEDGMENTS Authors would like to kindly acknowledge financial support from the Spanish MINECO, the Agencia Estatal de Investigacio´n (AEI), and the Fondo Europeo de Desarrollo Regional (FEDER, EU) (Grants CTQ2013-41336-P and CTQ2016-76794-P). I (E.A.) would like to express my gratitude to Prof. Barluenga for his extraordinary encouraging ability and for his enthusiastic mentoring role along my whole career as a chemist.

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223. Barluenga J, Garcı´a-Garcı´a P, Ferna´ndez-Rodrı´guez MA, Aguilar E, Merino I. Lithium benzocyclobuteneoxide as a precursor of a vinylogous enolate: solvent-controlled synthesis of highly functionalized seven-membered benzocarbocycles. Angew Chem Int Ed. 2005;44:5875. 224. Garcı´a-Garcı´a P, Novillo C, Ferna´ndez-Rodrı´guez MA, Aguilar E. Competitive pathways in the reaction of lithium Oxy-orthoquinodimethanes and Fischer alkoxy alkynyl carbene complexes: synthesis of highly functionalised seven-membered benzocarbocycles. Chem Eur J. 2011;17:564. 225. Barluenga J, Aznar F, Palomero MA. Eight-membered carbocycles from a D€ otz-like reaction. Angew Chem Int Ed. 2000;39:4346. 226. Alcaide B, Casarrubias L, Domı´nguez G, Sierra MA. Reactions of group 6 metal carbene complexes with ylides and related dipolar species. Curr Org Chem. 1998;2:551. 227. Chan KS, Yeung ML, Chan WK, Wang RJ, Mak TCW. Chromium and tungsten pentacarbonyl groups as reactivity and selectivity auxiliaries in [3+2] cycloaddition of alkynyl Fischer carbene complexes with N-alkyl nitrones. J Org Chem. 1995;60:1741. 228. Luo N, Zheng Z, Yu Z. Highly regioselective [3+2] annulation of azomethine imines with 1-alkynyl Fischer carbene complexes to functionalized N,N-bicyclic pyrazolidin3-ones. Org Lett. 2011;13:3384. 229. (a) Chakraborty A, Dey S, Sawoo S, Adarsh NN, Sarkar A. Regioselective 1,3-dipolar cycloaddition reaction of azides with alkoxy alkynyl Fischer carbene complexes. Organometallics. 2010;29:6619. (b) Ponniah SJ, Barik SK, Thakur A, Ganesamoorthi R, Ghosh S. Triazolyl alkoxy Fischer carbene complexes in conjugation with ferrocene/pyrene as sensory units: multifunctional chemosensors for lead(II), copper(II), and zinc(II) ions. Organometallics. 2014;33:3096. 230. Baeza B, Casarrubios L, Ramı´rez-Lo´pez P, Go´mez-Gallego M, Sierra MA. A Cu-catalyzed azide-alkyne cycloaddition approach to the synthesis of bimetallic chromium(0) (Fischer) carbene complexes. Organometallics. 2009;28:956. 231. Barluenga J, Garcı´a-Rodrı´guez J, Martı´nez S, Sua´rez-Sobrino AL, Toma´s M. Facile and versatile annulation of the imizadole ring: single and sequential cyclization reactions of Fischer carbene complexes with 1,4-diazafulvenes. Chem Eur J. 2006;12:3201. 232. Barluenga J, Garcı´a-Rodrı´guez J, Sua´rez-Sobrino AL, Toma´s M. Single and consecutive cyclization reactions of alkynyl carbene complexes with 8-azaheptafulvenes: direct access to polycyclic pyrrole and indole derivatives. Chem Eur J. 2009;15:8800. 233. Barluenga J, Toma´s M, Lo´pez-Pelegrı´n JA, Rubio E. First [4+2] cycloaddition of alkynyl Fischer carbene complexes with heterodienes. Facile synthesis of 1,4dihydropyridines from 1-azadienes. Tetrahedron Lett. 1997;38:3981. 234. Barluenga J, Toma´s M, Ballesteros A, Santamarı´a J, Sua´rez-Sobrino A. Fischer carbene complexes in heterocyclic synthesis. Selective cycloaddition reactions to 2-Aza-1,3butadienes. J Org Chem. 1997;62:1961. 235. Barluenga J, Lo´pez LA, Martı´nez S, Toma´s M. New [4+2] heterocycloaddition of alkynyl Fischer carbene complexes. A facile access to pyrimidyl carbene complexes. Synlett. 1999;219. ohlich R. Homopyrroles by metal-mediated 236. Aumann R, K€ obmeier M, Roths K, Fr€ cycloadditions of (NH)-enamines to alkynylcarbene tungsten complexes via 1-metalla-1,3,5-trienes. Synlett. 1994;1041. 237. Aumann R, Heinen H, Dartmann M, Krebs B. Organische Synthesen mit € Ubergangsmetall-Komplexen, 54. Cyclopentadiene aus 1-Metalla-1,3-dienen und Alkinen durch Cyclisierung Intermedi€arer 1-Metalla-1,3,5-triene (Metall¼Wolfram). Chem Ber. 1991;124:2343. 238. Polo R, Moreto´ JM, Schick U, Ricart S. Reaction of alkynyl alkoxy metal (Cr, W) carbene complexes with 1,3-dinitrogen systems. A direct entry to the pyrimidine skeleton. Organometallics. 1998;17:2135.

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239. D’Acunto M, Tommasone S, Talotta C, et al. Installing tungsten Fischer carbene complexes into a calixarene framework. RSC Adv. 2016;6:75002. 240. Spinella A, Caruso T, Pastore U, Sicart S. Improving methodology for the preparation of uracil derivatives from Fischer carbene complexes. Microwave activation. J Organomet Chem. 2003;684:266. 241. Barluenga J, Fan˜ana´s-Mastral M, Aznar F, Vald
es C. [1,5]-hydride transfer/cyclizations on alkynyl Fischer carbene complexes: synthesis of 1,2-dihydroquinolinyl carbene complexes and cascade reactions. Angew Chem Int Ed. 2008;47:6594. 242. Barluenga J, Fan˜ana´s-Mastral M, Ferna´ndez A, Aznar F. [1,5]-hydride transfer/cyclization of ortho-amino alkynyl Fischer carbene complexes: a useful tool for the synthesis of quinoline derivatives. Eur J Org Chem. 2011;1961. 243. Barluenga J, Fan˜ana´s-Mastral M, Aznar F. C–H insertion processes on stabilized indolyl and ortho-aminophenyl Fischer carbene complexes: synthesis of azepino[3,2,1-hi] indole, benzazepine and indole derivatives. Chem Eur J. 2008;14:7508. 244. Barluenga J, Toma´s M, Rubio E, Lo´pez-Pelegrı´n JA, Garcı´a-Granda S, P
erez Priede M. Unusual [1,2]- and [1,3]-M(CO)5 in Fischer carbene complexes: [4+3] and [3+3] annulation reactions of furan and pyrrole complexes. J Am Chem Soc. 1999;121:3065. 245. (a) Santamarı´a J, Aguilar E. Beyond Fischer and Schrock carbenes: non-heteroatomstabilized group 6 metal carbene complexes—a general overview. Org Chem Front. 2016;3:1561. (b) Iwasawa N. Group 6 metal vinylidenes in catalysis (Cr, Mo, W). In: Bruneau C, Dixneuf P, eds. KGaA, Weinheim: Wiley-WCH Verlag GmbH & Co; 2008:159. Metal Vinylidenes and Allenylidenes for Catalysis. € 246. Ofele K. Pentacarbonyl(2,3-diphenylcyclopropenylidene)-chromium(0). Angew Chem Int Ed. 1968;7:950. 247. (a) Casey CP, Burkhardt TJ. (Diphenylcarbene)pentacarbonyltungsten(0). J Am Chem Soc. 1973;95:5833. (b) Casey CP, Tuinstra HE, Saeman MC. Reactions of (CO)5WC (Tol)2 with alkenes. A model for structural selectivity in the olefin metathesis reaction. J Am Chem Soc. 1976;98:608. (c) Casey CP, Burkhardt TJ, Neumann SM, Scheck DM, Tuinstra HE. (Diphenylcarbene)pentacarbonyltungsten(0). Inorg Synth 1979;19:180. € XC. Pentacarbonyl-Π248. Fischer EO, Held W. Ubergangsmetall-Carben-Komplexe: Olefin-Wolfram(0)-Komplexe durch Reaktion von Pentacarbonyl[methoxy(phenyl)carben]wolfram(0) mit Lithiumalkylen. J Organomet Chem. 1976;112:C59. 249. Casey CP, Albin LD, Burkhardt TJ. Generation and reactions of (phenylmethylcarbene)pentacarbonyltungsten(0). J Am Chem Soc. 1977;99:2533. 250. Barluenga J, de Sa´a D, Go´mez A, et al. Metal carbene dimerization: versatile approach to polyalkynylethenes. Angew Chem Int Ed. 2008;47:6225. 251. (a) Casey CP, Polichnowski SW. In situ generation and reactions of (CO)5WC(C6H5) H with alkenes-role of puckered metallocyclobutanes in determining the stereochemistry of cyclopropane formation. J Am Chem Soc. 1977;99:6097. (b) Casey CP, Polichnowski SW, Shusterman AJ, Jones CR. Reactions of (CO)5WCHC6H5 with alkenes. J Am Chem Soc. 1979;101:7282. 252. Fischer H, Zeuner S, Ackermann K. Electrophilic benzylidene(pentacarbonyl)-chromium(0) and -tungsten(0) complexes: isolation, characterization, and an unusual thermolytic reaction of the tungsten compounds. J Chem Soc Chem Commun. 1984;684. 253. Fischer H, Reindl D. Synthese und Reaktionen von (CO)5Mo[C(Aryl)H]. J Organomet Chem. 1990;385:351. 254. Barluenga J, Ballesteros A, Bernardo de la Ru´a R, Santamarı´a J, Rubio E, Toma´s M. Group 6 heteroatom- and non-heteroatom-stabilized carbene complexes. β,β0 - and α,β,β0 -annulation reactions of cyclic enamines. J Am Chem Soc. 2003;125:1834.

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255. D€ otz KH, Pfeiffer J. Tricyclic pentacarbonyl carbene complexes of chromium: a novel synthetic pathway via diazo precursors and benzannulation. Chem Commun. 1996;895. 256. Pfeiffer J, D€ otz KH. Diarylcarbene complexes of chromium from diazo precursors: synthesis and reaction with electron-rich alkynes. Organometallics. 1998;17:4353. 257. Casey CP, Burkhardt TJ. Reactions of (diphenylcarbene)pentacarbonyltungsten(0) with alkenes. Role of metal–carbene complexes in cyclopropanation and olefin metathesis reactions. J Am Chem Soc. 1974;96:7808. 258. Herrison JL, Chauvin Y. Catalyse de Transformation des Ol
eines par les Complexes du Tungste`ne II. T
elom
erisation des Ol
efines Cycliques en Pr
esence D’ol
efines Acycliques Macromol. Chem Phys. 1970;141:161. 259. McGinnis J, Katz TJ, Hurwitz S. Selectivity in the olefin metathesis of unsymmetrically substituted ethylenes. J Am Chem Soc. 1976;98:605. 260. Katz TJ, McGinnis J, Altus C. Metathesis of a cyclic trisubstituted alkene. Preparation of polyisoprene from 1-methylcyclobutene. J Am Chem Soc. 1976;98:606. 261. Fischer H, Hofmann J. Vinylcyclopropan-Komplexe und Vinylcyclopropane aus Carben-Komplexen und 1,3-Dienen. Chem Ber. 1991;124:981. 262. Fischer H, Bidell W, Hofmann J. Regio- and stereo-selective formation of methylenecyclopropane complexes from allenes and benzylidenepentacarbonyl tungsten. J Chem Soc Chem Commun. 1990;858. 263. Seidel G, F€ urstner A. Structure of a reactive gold carbenoid. Angew Chem Int Ed. 2014;53:4807. 264. Seidel G, Gabor B, Goddard R, Heggen B, Thiel W, F€ urstner A. Gold carbenoids: lessons learnt from a transmetalation approach. Angew Chem Int Ed. 2014;53:879. 265. Katz TJ, Sivavec TM. Metal-catalyzed rearrangement of alkene–alkynes and the stereochemistry of metallacyclobutene ring opening. J Am Chem Soc. 1985;107:737. 266. P
erez A, Serrano JL, Sierra T, Ballesteros A, de Sa´a D, Barluenga J. Control of selfassembly of a 3-hexen-1,5-diyne derivative: toward soft materials with an aggregation-induced enhancement in emission. J Am Chem Soc. 2011;133:8110. 267. Barluenga J, Tudela E, Vicente R, Ballesteros A, Toma´s M. Alkynylcyclopropanes from terminal alkynes through consecutive coupling to Fischer carbene complexes and selective propargylene transfer. Chem Eur J. 2011;17:2349. 268. Barluenga J, Tudela E, Vicente R, Ballesteros A, Toma´s M. Gold-catalyzed rearrangements: reaction pathways using 1-alkenyl-2-alkynylcyclopropane substrates. Angew Chem Int Ed. 2011;50:2107. 269. Barluenga J, Go´mez A, Santamarı´a J, Toma´s M. Regioselective synthesis of 4,6,7trisubstituted benzofurans from furfural imines and nonheteroatom stabilized alkynylcarbene complexes. J Am Chem Soc. 2009;131:14628. 270. Funes-Ardoiz I, Gonza´lez J, Santamarı´a J, Sampedro D. Understanding the mechanism of the divergent reactivity of Non-heteroatom-stabilized chromium carbene complexes with furfural imines: formation of benzofurans and azetines. J Org Chem. 2016;81:1565. 271. (a) Barluenga J, Go´mez A, Santamarı´a J, Toma´s M. Sequential five-component construction of the cyclopenta[e]-[1,3]oxazine skeleton using stable 2-azetine derivatives. Angew Chem Int Ed. 2010;49:1306. (b) Funes-Ardoiz I, Sampedro D. Computational assessment of non-heteroatom-stabilized carbene complexes reactivity: formation of oxazine derivatives. J Org Chem. 2014;79:11824. 272. Gonza´lez J, Go´mez A, Funes-Ardoiz I, Santamarı´a J, Sampedro D. Intermolecular and regioselective Access to polysubstituted benzo- and dihydrobenzo[c]azepine derivatives: modulating the reactivity of group 6 non-heteroatom-stabilized alkynyl carbene complexes. Chem Eur J. 2014;20:7061.

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273. For a seminal review where the concept of π-acid is defined, see: F€ urstner A, Davies PW. Catalytic carbophilic activation: catalysis by platinum and gold π acids. Angew Chem Int Ed. 2007;46:3410. 274. Kusama H, Funami H, Shido M, Hara Y, Tayaka J, Iwasawa N. Generation and reaction of tungsten-containing carbonyl ylides: [3+2]-cycloaddition reaction with electron-rich alkenes. J Am Chem Soc. 2005;127:2709. 275. Miki K, Yokoi T, Nishino F, Ohe K, Uemura S. Synthesis of 2-pyranylidene or (2furyl)carbene–chromium complexes from conjugated enyne carbonyl compounds with Cr(CO)5(THF). J Organomet Chem. 2002;645:228. 276. Miki K, Nishino F, Ohe K, Uemura S. Novel approach for catalytic cyclopropanation of alkenes via (2-furyl)carbene complexes from 1-benzoyl-cis-1-buten-3-yne. J Am Chem Soc. 2002;124:5260. 277. Karibe Y, Kusama H, Iwasawa N. Efficient control of π-alkyne and vinylidene complex pathways for the W(CO)5(L)-catalyzed synthesis of two types of nitrogen-containing bicyclic compounds. J Am Chem Soc. 2008;130:802. 278. Kusama H, Karibe Y, Imai R, Onizawa Y, Yamabe H, Iwasawa N. Tungsten(0)- and rhenium(I)-catalyzed tandem cyclization of acetylenic dienol silyl ethers based on geminal carbo-functionalization of alkynes. Chem Eur J. 2011;17:4839. 279. Kusama H, Tayaka J, Iwasawa N. A facile method for the synthesis of polycyclic indole derivatives: the generation and reaction of tungsten-containing azomethine ylides. J Am Chem Soc. 2002;124:11592. 280. Takaya J, Kusama H, Iwasawa N. Isolation and reaction of (indolin-3-ylidene)pentacarbonyltungsten generated from tungsten-containing azomethine ylide. Chem Lett 2004;33:16. 281. (a) Kusama H, Miyashita Y, Tayaka J, Iwasawa N. Pt(II)- or Au(III)-catalyzed [3+2] cycloaddition of metal-containing azomethine ylides: highly efficient synthesis of the mitosene skeleton. Org Lett. 2006;8:289. (b) Ohyama T, Uchida M, Kusama H, Iwasawa N. Total synthesis of proposed structure of yuremamine and All diastereomers using [3 + 2]-cycloaddition of platinum-containing azomethine ylide. Chem Asian J. 2015;44:1850. 282. Kusama H, Suzuki Y, Tayaka J, Iwasawa N. Intermolecular 1,5-dipolar cycloaddition reaction of tungsten-containing vinylazomethine ylides leading to seven-membered heterocycles. Org Lett. 2006;8:895. 283. Takaya J, Miyashita Y, Kusama H, Iwasawa N. [3+2] cycloaddition of metalcontaining azomethine ylides for highly efficient synthesis of mitosene skeleton. Tetrahedron. 2011;67:4455. 284. (a) Kusama H, Onizawa Y, Iwasawa N. W(CO)5(L)-catalyzed tandem intramolecular cyclopropanation/Cope rearrangement for the stereoselective construction of bicyclo [5.3.0]decane framework. J Am Chem Soc. 2006;128:16500. (b) Onizawa Y, Hara M, Hashimoto T, Kusama H, Iwasawa N. Synthetic studies on and mechanistic insight into [W(CO)5(L)]-catalyzed stereoselective construction of functionalized bicyclo[5.3.0] decane frameworks. Chem Eur J. 2010;16:10785. 285. Karibe Y, Kusama H, Iwasawa N. Chromium(0)-catalyzed tandem cyclization of α,βunsaturated thioimidates containing an enyne moiety. Angew Chem Int Ed. 2012;51:6214. 286. Iwasawa N, Shido M, Kusama H. Generation and reaction of metal-containing carbonyl ylides: tandem [3+2]-cycloaddition–carbene insertion leading to novel polycyclic compounds. J Am Chem Soc. 2001;123:5814. 287. Ito K, Hara Y, Mori S, Kusama H, Iwasawa N. Theoretical study of the cycloaddition reaction of a tungsten-containing carbonyl ylide. Chem Eur J. 2009;15:12408. 288. Grandmarre A, Kusama H, Iwasawa N. W(CO)5(L)-catalyzed cyclization of ω-acetylenic silyl enol ethers for the preparation of nitrogen-containing cyclic compounds. Chem Lett. 2007;36:66.

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289. Maeyama K, Iwasawa N. W(CO)5THF-catalyzed electrocyclizations of aromatic enynes via vinylidene intermediates. J Org Chem. 1999;64:1344. 290. Ohe K, Yokoi T, Miki K, Nishino F, Uemura S. Chromium- and tungsten-triggered valence isomerism of cis-1-acyl-2-ethynylcyclopropanes via [3,3]sigmatropy of (2-acylcyclopropyl)vinylidene–metal intermediates. J Am Chem Soc. 2002;124:526. 291. (a) Miura T, Iwasawa N. Reactions of iodinated vinylidene complexes generated from 1-iodo-1-alkynes and W(CO)5(thf ). J Am Chem Soc. 2002;124:518. (b) Miura T, Murata H, Kiyota K, Kusama H, Iwasawa N. W(CO)5(L)-promoted cyclization of 1-iodo-1-alkynes via iodovinylidene tungsten complexes. J Mol Cat A Chem. 2004;213:59.

CHAPTER TWO

Recent Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions With N-Tosylhydrazones Di Qiu*,†, Fanyang Mo*,‡, Yan Zhang*, Jianbo Wang*,1 *Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing, China † College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin, China ‡ College of Engineering, Peking University, Beijing, China 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Palladium-Catalyzed Coupling Reaction of N-Tosylhydrazones 2.1 Pd-Catalyzed Coupling of N-Tosylhydrazones With Aryl and Alkenyl Halides 2.2 Pd-Catalyzed Coupling of N-Tosylhydrazones With Benzyl Halides 2.3 Pd-Catalyzed Oxidative Coupling of N-Tosylhydrazones 2.4 Pd-Catalyzed Two-Component Cascade Coupling of N-Tosylhydrazones 2.5 Pd-Catalyzed Multicomponent Coupling of N-Tosylhydrazones 3. Copper-Catalyzed Coupling Reaction of N-Tosylhydrazones 3.1 Cu-Catalyzed Coupling of N-Tosylhydrazones With Alkynes 3.2 Cu-Catalyzed Coupling of N-Tosylhydrazones Involving C–H Activation 3.3 Cu-Catalyzed Oxidative Coupling Reaction of N-Tosylhydrazones 4. Rhodium-Catalyzed Coupling Reaction of N-Tosylhydrazones 5. Nickel- and Cobalt-Catalyzed Coupling Reactions of N-Tosylhydrazones 6. Catalytic Intramolecular Cyclization of N-Tosylhydrazones 7. Summary Acknowledgments References

151 152 154 169 170 176 185 193 193 199 201 203 208 210 212 212 212

1. INTRODUCTION The area of transition-metal-catalyzed cross-coupling reactions has experienced considerable growth in the past decades. This strategy has Advances in Organometallic Chemistry, Volume 67 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2017.04.002

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created powerful and indispensable methods for selective constructing carbon–carbon/carbon–heteroatom bond, as well as in synthesizing functional molecules and natural products.1 To expedite synthetic endeavors, chemists have mainly focused on the development of new catalysts for various coupling reactions. On the other hand, the developments toward novel coupling partners also represent the major challenges in organometallic research area. N-Tosylhydrazones, easily synthesized through the condensation of carbonyl compounds with N-tosylhydrazine, are useful and common substrates in organic synthesis. Thus, transition-metal-catalyzed cross-coupling reaction of N-tosylhydrazones not only expands the substrate scope of coupling partners but also furnishes novel and practical methodology for the unconventional modification of carbonyl compounds. Particularly, owing to the reason that the diazo species can be generated in situ via detosylation of N-tosylhydrazones, N-tosylhydrazones have been utilized as the surrogates for unstable diazo compounds or carbene precursors.2 Conceptually, transition-metal-catalyzed cross-coupling reactions of N-tosylhydrazones introduce diazo component or carbene species into cross-coupling systems, providing novel types of C–C, C]C, and carbon– heteroatom bond formation strategies. Mechanistically, the key feature of these coupling processes involves a migratory insertion of the metal-carbene intermediates, which not only constitutes a fresh and novel reaction type of N-tosylhydrazones but also represents a paradigm shift in understanding metal-carbene chemistry. Although several reviews related to transition-metal-catalyzed coupling reactions of N-tosylhydrazones have appeared in the literatures in the past years,3–7 in view of the rapid growth of the field a timely and comprehensive summary of this area is still necessary. This chapter will focus on the recent advances in the area, in particular the cascade transformations involving carbene-coupling process. The reactions are classified according to different transition-metal catalysts (Scheme 1). Due to the space limitation, catalytic C–H, N–H, and O–H insertion processes of N-tosylhydrazones are not included in this contribution.

2. PALLADIUM-CATALYZED COUPLING REACTION OF N-TOSYLHYDRAZONES Palladium-catalyzed coupling reaction of N-tosylhydrazones has been extensively developed and demonstrates many applications in organic

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M

NNHTs R

R′

R

Transition-metal

R′

Cross-coupling of N-tosylhydrazones

R′ R1

R2

Ar

R′

R′ Si

R R3

Ar′

Ar

R

R

R R R1

R3

N

R1

R4

X

R2

• R2

Scheme 1 Transition-metal-catalyzed cross-coupling reactions of N-tosylhydrazones and typical applications in organic synthesis. NNHTs R2

R1

Base N2 Oxidative addition RX

R

PdII

R1

R2

X

Ln 1 Transmetallation

R PdII X R1 R2 2, Palladium carbene

Migratory insertion

R PdIIX R1

3

R2

RM Products

Scheme 2 General reaction pathway of the Pd-catalyzed cross-coupling reaction of N-tosylhydrazones involving migratory insertion.

synthesis.4a–c The general mechanism is shown in Scheme 2. Initially, the carbon-Pd(II) intermediate 1 generates either through transmetalation with other metal species or by oxidative addition from organohalide analogues. Subsequently, decomposition of the in situ-generated diazo species from

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stable N-tosylhydrazone substrates gives rise to the formation of Pd(II)carbene 2 as the key intermediate. Then, a migratory insertion process, in which an “X” ligand of Pd(II) migrates to carbene center, takes place to generate a new carbon-Pd(II) species 3, followed by sequential β-H, β-C elimination or other cascade transformations to afford a variety of functionalized molecules. The Pd-catalyzed cross-coupling reactions of N-tosylhydrazones have established a novel and superior approach toward the selective C–C bond formation, particularly for highly efficient synthesis of polysubstituted alkenes. This content will classify the recent advances according to the various types of the coupling partners.

2.1 Pd-Catalyzed Coupling of N-Tosylhydrazones With Aryl and Alkenyl Halides In 2007, Barluenga group reported the first example of Pd-catalyzed crosscoupling reactions of N-tosylhydrazones (Scheme 3).8 They achieved the catalytic coupling of aryl halides with bench-stable N-tosylhydrazones, which provided a novel route for synthesizing polysubstituted olefins with high efficiency. They proposed that the catalytic cycle of this coupling transformation is initiated by the oxidative addition of aryl halide to Pd(0) species 4, giving rise to aryl palladium(II) complex 5. Then, the reaction of 5 with diazo intermediates, which are generated in situ from N-tosylhydrazones in the presence of a base, occurs affording Pd(II)-carbene species 6. The key feature of this catalytic cycle is the migratory insertion of the aryl group to Pd-carbene center, subsequently delivering the alkyl palladium complex 7. Finally, β-hydrogen elimination of 7 provides the desired arylated olefin along with regeneration of Pd(0) species. In view of the facile condensation of carbonyl compounds with tosylhydrazide into N-tosylhydrazones, this strategy represents a convenient procedure to convert carbonyl compounds into nucleophilic coupling reagents for Pd-catalyzed cross-coupling reactions. This methodology affords a highly efficient way to prepare densely functionalized alkenes with high stereoselectivity and excellent functional group tolerance. Later, Barluenga and Vald
es launched systematic research toward Pd-catalyzed cross-coupling reactions of aryl halides with N-tosylhydrazones derived from divergent carbonyl compounds, proceeding through migratory insertion and β-H elimination to furnish the desired arylated alkenes.9–18 At the first attempt they have carried out Pd-catalyzed coupling reaction of aryl halides with N-tosylhydrazones derived from 4-piperidones (Scheme 4).9 The reaction affords 4-aryltetrahydropyridines in good to excellent yields with

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R

Pd2(dba)3 (1 mol%) Xphos (2 mol%) t-BuOLi (2.2 equiv.)

NNHTs R3 + 1

Ar–X

Mechanism

R3

R1

R2 16 examples 52%–99% yields

dioxane, 70–110°C

R2

Ar

NNHTs

Ar–X Pd(0)L 4

HX

R1 R2 t-BuOLi X Ar–Pd(II)L 5

X H–Pd(II)L Ar

H

R1

R2

N2 R1 R2

Ar

X Ar–Pd(II)L

PdXL H

R1 7

R1

R2

2 6 R

Xphos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Scheme 3 Pd-catalyzed cross-coupling reactions to synthesize substituted alkenes.

TsNHNH2 MeOH 95%

O

N R

Ar–X NNHTs Pd2(dba)3 (1 mol%) XPhos (4 mol%) t-BuOLi (2.3 equiv.) N R

dioxane, 90°C

TsNHNH2, Ar–X Pd2(dba)3 (1 mol%) XPhos (4 mol%) t-BuOLi (2.3 equiv.) dioxane, 90°C

Ar 25 examples 60%–99% yields N R

Scheme 4 Pd-catalyzed one-pot coupling of 4-piperidone, tosylhydrazide, and aryl halides.

good functional group tolerance. Furthermore, the catalytic one-pot procedure was also implemented by using 4-piperidone, tosylhydrazide, and aryl halides as the substrates, leading to the formation of functionalized 4-aryltetrahydropyridines in similarly high yields.

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R

NNHTs Y

R

O

Y Y = OMe, OBn, N

Ph

O

NNHTs OMe +

Ar–X Pd2(dba)3 (2 mol%) XPhos (4 mol%) t-BuOLi, dioxane, 110°C R TsNHNH2, dioxane 70°C, 2 h

Ar

15 examples 70%–99% yields

Y

then Ar–X Pd2(dba)3 (2 mol%) XPhos (4 mol%) t-BuOLi, dioxane, 110°C

Br

1. Pd2(dba)3, XPhos t-BuOLi, dioxane, 110°C, 2 h

NHMe

2. Toluene, HCl aq. MW, 180°C, 1 min

Ph

N Me 94% yield

Scheme 5 Pd-catalyzed one-pot synthesis of enol ethers and enamines.

In 2009, the same group carried out the Pd-catalyzed cross-coupling reaction of aryl halides with α-alkoxy- or α-amino-derived N-tosylhydrazones, achieving the facile and efficient synthesis of enol ethers or enamines (Scheme 5).10 This transformation can be either conducted with the preformed tosylhydrazone substrates or in a one-pot process by using α-functionalized carbonyl compounds and tosylhydrazide. The resulting product of this methodology also demonstrated a potential application in constructing heterocyclic scaffolds. In 2010, the same group also accomplished a simple and straightforward synthesis of 2-arylacrylates compounds by employing the Pd-catalyzed tosylhydrazide-promoted coupling reaction of aryl halides with pyruvate derivatives 8 (Scheme 6).11 Taking into account the great importance of 2-arylacrylates as valuable intermediates and direct precursors for the prophen family of antiinflammatory drugs, this method demonstrates potential usefulness in organic synthesis and medicinal chemistry. In addition, this coupling reaction from N-tosylhydrazones derived from substituted 2-oxoesters can also afford tri- and tetra-substituted functionalized alkenes in a facile manner. The transition-metal-catalyzed coupling reaction has provided a novel approach toward the synthesis of conjugated dienes, which demonstrate great importance in organic synthesis, biochemistry, and materials sciences.12a

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1. TsNHNH2 dioxane, 70°C, 2 h

O OEt O 8

NNHTs

2. Ar–Br Pd2(dba)3 (1 mol%) XPhos (4 mol%) t-BuOLi, 110°C

OEt

CO2Et R2

Me

O 12 examples 60%–99% yields

Ar–Br

1

R

Ar

Ar

Pd2(dba)3 (2.5 mol%) XPhos (10 mol%) t-BuOLi, dioxane, 110°C

CO2H

Prophens

Ar R1

CO2Et R2

7 examples 51%–70% yields

Scheme 6 Synthesis of 2-arylacrylates by Pd-catalyzed coupling reaction from pyruvate with aryl halides.

In 2010, Barluenga and coworkers reported the synthesis of conjugated dienes through two different pathways: the Pd-catalyzed cross-coupling reaction of N-tosylhydrazones derived from α,β-unsaturated ketone with aryl halides, or using alkenyl halide with nonconjugated N-tosylhydrazones (Scheme 7).12b In the latter case, the probable pathway rationalizing the formation of product may involve a hydride elimination of π-allylpalladium intermediate 9. This method provides a novel approach for the synthesis of aryl-substituted conjugated dienes. In 2014, Vald
es successfully expanded the substrate scope of Pd-catalyzed coupling reaction of aryl halides to 1,1,1-trifluoroacetone tosylhydrazones.13 Under the optimized conditions, this transformation affords functionalized α-trifluoromethylstyrenes, which serve as valuable trifluoromethylated synthetic intermediates, in high yields and good functional group tolerance (Scheme 8). This contribution not only represents a novel combination of coupling reaction with fluorine chemistry but also demonstrates potential applications in medicinal chemistry and material sciences. In addition to aryl halides, aryl nonaflates as their analogues have been explored as effective electrophilic reaction partners in Pd-catalyzed crosscoupling of N-tosylhydrazones.14–17 In 2011, Pd-catalyzed coupling reaction of N-tosylhydrazones with aryl nonaflates was described, affording di-, tri-, and tetra-substituted alkenes with good functional group tolerance (Scheme 9).15 Notably, the addition of LiCl in the presence of small amounts of water apparently accelerates this transformation. Under optimized reaction conditions, various olefins are obtained with excellent yields and high stereoselectivity depending on the nature of the coupling partners. Moreover, the success of a single-step synthesis of dihydronaphthalene derivative 10,

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Ar–X

+

Pd2(dba)3 (4 mol%) SPhos or XPhos (16 mol%)

NNHTs R

Ar

R1 R2 R3 12 examples 70%–99% yields

t-BuOLi (2.4 equiv.) dioxane, 110°C

R1 R3

R2

Ar

TsNHNH2 Pd2(dba)3 (2.5 mol%)/XPhos

O

R1

+ Br

t-BuOLi or t-BuONa (2.4 equiv.) dioxane, 110°C

R2

R1

R

R2

Ar

8 examples 40%–61% yields

[Pd]

Mechanism

R

Ar

NNHTs + Br H Ar

R

[Pd] Ar

R [Pd] H

Ar 9

[Pd]–H

R

Scheme 7 Pd-catalyzed coupling reaction for the synthesis of conjugated dienes.

NNHTs R

F3C

Pd2(dba)3 (2 mol%) XPhos (8 mol%) Na2CO3 (2.2 equiv.) +

Ar–Br dioxane, sealed tube, 150°C

R = H, Ph, OBn

CF3 R Ar 17 examples 66%–94% yields

Scheme 8 Pd-catalyzed coupling reaction for the synthesis of α-trifluoromethylstyrenes.

R3

NNHTs

R2

R1

+

Pd2(dba)3 (1–2.5 mol%) XPhos (2–10 mol%) t-BuOLi (2.8 equiv.) H2O (5 equiv.) LiCl (1 equiv.) Ar–ONf dioxane, 110°C

ONf = nonaflate 1. TsNHNH2, EtOH 88% yield Cl

R2

R3

R1

Ar

22 examples 58%–99% yields Cl

Cl Cl

Cl

ONf

O

2.

OH

Pd2(dba)3 (1.5 mol%) XPhos, t-BuOLi LiCl, H2O dioxane, 110°C

Cl

OH 10, 87% yield

NHMe Sertraline

Scheme 9 Pd-catalyzed coupling of N-tosylhydrazones with aryl nonaflates.

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O Ar

Y X N

X +

TsNHNH2, dioxane, 110°C then

Ar

Pd2(dba)3 (3–8 mol%) XPhos (6–16 mol%) t-BuOLi, 110°C

DG X = Br, ONf Y, Z = N, CH

Y X N

DG

22 examples 46%–98% yields X

O Ph

N

X

Br

X

Br

+

TsNHNH2, dioxane 110°C, 7 h then Pd2(dba)3 (8 mol%) XPhos (16 mol%) t-BuOLi, 110°C, 14 h

X

Ph

N

6 examples 52%–96% yields

Scheme 10 Synthesis of (Z)-N-alkenylazoles and pyrroloisoquinolines.

which is the direct precursor of the antidepressant sertraline, demonstrates the practical application of this methodology in organic synthesis. In 2013, Vald
es group reported a one-pot Pd-catalyzed coupling reaction of carbonyl compounds, tosylhydrazine with ortho-substituted aromatic halides or sulfonates (Scheme 10).16 Taking advantage of ortho-stereo-directing effect in the cross-coupling strategy, this method led to the stereoselective synthesis of (Z)-N-alkenylazoles with high yields and selectivity. In addition, they also developed a novel and efficient Pd-catalyzed autotandem catalytic system for C–C/C–C bond formation, affording the biologically relevant pyrroloisoquinolines in an efficient manner. Moreover, Vald
es group described the Pd-catalyzed cross-coupling cascade reaction of α-alkoxy N-tosylhydrazones with ortho-substituted aryl nonaflates to give various heterocyclic compounds (Scheme 11).17 By using sulfonates derived from salicyl aldehydes, the first coupling step leads to protected 1,5-dicarbonyls as the intermediates, followed by the treatment with ammonium hydroxide to generate functionalized isoquinolines in moderate to good yields. Similarly, the employment of ortho-cyanononaflates in the coupling step, followed by subsequent reaction with organolithium reagents, gives rise to 1,2,4-trisubstituted isoquinolines in excellent yields. These two divergent approaches enable a versatile and novel method for the preparation of polysubstituted isoquinolines. In 2015, a facile and effective synthetic method for various 1,1heterodiaryl alkenes was reported by Pd-catalyzed cross-coupling reaction

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Pd2(dba)3 (3 mol%) XPhos (6 mol%) LiOH (1.5 equiv.) NNHTs X O LiCl (3 equiv.) OR3 + R1 dioxane, 110°C ONf R2 H

X

CN + R1 ONf

O R1 R2

Pd2(dba)3 (3 mol%) XPhos (6 mol%) LiOH (3 equiv.) LiCl (3 equiv.)

NNHTs OR3

R2 R1 12 examples 53%–90% yields

110°C OR3 6–24 h

R CN R1

dioxane, 110°C

R2

N

X NH4OH

R2

N

RLi, THF, -78°C

R2 R1 5 examples 54%–99% yields

then rt, 12 h

OR3

Scheme 11 Synthesis of polysubstituted isoquinolines through Pd-catalyzed coupling reaction of α-alkoxy N-tosylhydrazones.

NNHTs Ar

N

N

+ MeO

N N P Br PF6 N

PyBroP

N

Ar

PyBroP (1.3 equiv.) Et3N (2 equiv.) dioxane, rt, 2 h

OH

OMe

then Pd2(dba)3 (5 mol%) t-BuBrettphos (3 mol%) Cs2CO3 (3 equiv.) dioxane, 100°C, 2 h

N MeO

N N

OMe

11 examples 46%–93% yields

OMe N MeO

N N Ar

N P N Pd O N

11

PF6

t-BuBrettphos = 2-(di-t-butylphosphino)-3,6-dimethoxy2′-4′-6′-tri-i-propyl-1,1′-biphenyl

Scheme 12 Pd-catalyzed coupling of heteroarenols with N-tosylhydrazones.

of heteroarenols with N-tosylhydrazones (Scheme 12).18 With the employment of various heteroarenols as the coupling partners, the notable feature of this protocol stands on the mild and viable, economical benign reaction conditions, and the absence of halides or pseudohalides. Proposed mechanism involves in situ C–OH bond activation by using the appropriate phosphonium coupling reagent at first, followed by migratory insertion of the heteroaryl group to Pd(II)-phosphonium-carbene complex 11. Finally, β-hydrogen elimination affords the desired 1,1-heterodiaryl alkenes along with the regeneration of Pd(0) species.

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In 2015, Pd-catalyzed cross-coupling reaction of α-ketoalkylphosphonate-derived N-tosylhydrazones with aryl bromides was demonstrated by Wang group (Scheme 13).19 From easily accessible reagents as the substrates, this catalytic route constitutes a novel strategy to synthesize E-trisubstituted alkenylphosphonates bearing versatile functional groups as well as α-substituted vinylphosphonates. Mechanistically, migratory insertion of palladium carbene is proposed as the key step in this coupling reaction. This methodology utilizes α-keto-alkylphosphonate N-tosylhydrazones as the nucleophilic coupling partner. Furthermore, coupling reaction toward the asymmetric synthesis of chiral functional molecules attracts great attention. In 2010, Barluenga and Vald
es attempted Pd-catalyzed cross-coupling reaction of aryl halides with N-tosylhydrazones derived from α-chiral ketones (Scheme 14).20 As a result, with complete conservation of the stereochemistry at the α-carbon of carbonyl group, a series of aryl-substituted cyclic allylic ethers and allylamines are obtained in high yields. This method not only verifies the cross-coupling

R

NNHTs OMe P OMe R′ O

+

Ar–Br

Pd(PPh3)4 (5 mol%) K2CO3 (2.5 equiv.)

Ar R

dioxane, 90°C, 3 h

R′

OMe P OMe O

12 examples 50%–89% yields

Scheme 13 Synthesis of alkenylphosphonates via Pd-catalyzed coupling of α-ketoalkylphosphonate-derived N-tosylhydrazones with aryl halides.

O N Boc

Ar–X NNHTs Pd2(dba)3, XPhos

TsNHNH2 dioxane

O OMe TsNHNH2 dioxane

N Boc

NNHTs OMe

t-BuOLi, dioxane 110°C

Ar–X Pd2(dba)3, XPhos t-BuOLi, dioxane 110°C

Ar N Boc 6 examples 62%–88% yields >99% ee Ar OMe

4 examples 83%–98% yields >97% ee

Scheme 14 Pd-catalyzed coupling reaction of aryl halides with N-tosylhydrazones derived from α-chiral ketones.

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R3 R3 Br 1

R

O P Ar Ar + R2

NNHTs

Pd(OAc)2 (10 mol%) 12 (20 mol%) t-BuOLi, dioxane

R2

50°C, 24 h

R1

O P Ar Ar

R3 R3 Ar

Ar

O 12 P N O O Ar = 4–FC6H4 Ar Ar O

25 examples 40%–99% yield up to 97% ee

Scheme 15 Pd-catalyzed enantioselective synthesis of axially chiral vinyl arenes.

reaction of chiral N-tosylhydrazones but also keeps the stability of the α-chiral center of carbonyl compounds. In 2016, by using chiral pyrrolidine-based phosphoramidite ligand 12, Gu group reported the first asymmetric catalysis in this field, namely, Pd-catalyzed enantioselective synthesis of axially chiral 1-vinylnaphthalen2-ylphosphine oxides from achiral substrates of aryl bromides with N-tosylhydrazones derived from cyclic ketones (Scheme 15).21 This method combines the asymmetric synthesis with Pd-carbene migratory insertion strategy, opening a superior avenue for the construction of axially chiral biaryl compounds with high yields and excellent enantioselectivity. The advantages of this asymmetric coupling approach include good functional group tolerance and mild reaction conditions. Taking into account that desired products are readily reduced to phosphine derivatives, this methodology provides a novel and alternative way to design and synthesize chiral phosphine ligands. Additionally, Alami and Hamze group have made significant progresses in synthesizing functionalized 1,1-diaryl alkenes by employing the Pd-catalyzed cross-coupling strategy of N-tosylhydrazones with aryl halides or triflates. In particular, they utilized this methodology in the targetoriented synthesis of biochemical active functional molecules. At first, they focused the research topic on the expeditious preparation of 1,1diarylethylenes derivatives through Pd-catalyzed coupling reaction of polyoxygenated N-tosylhydrazones with aryl triflates (Scheme 16).22a They explored this 1,1-diarylethylene scaffold-constructing strategy in the convergent synthesis of iso-combretastatins A (isoCA-4) analogues, which

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Pd(OAc)2 (5 mol%) Xphos (10 mol%) t-BuOLi (2 equiv.)

NNHTs X

Me

X

+ Ar–OTf

Ar

Y

Y

11 examples 52%–97% yield

Z Z R1

MeO

OR2

X

NNHTs +

R1

dioxane, 90°C sealed tube

R3

MeO

OMe

OMe

NNHTs

+

MeO

OMOM OMe

OMe

MeO

OMOM

MeO

OMe

R3

MeO

OMe OMe 10 examples 55%–98% yields

PdCl2(MeCN)2 (5 mol%) dppp (10 mol%) Cs2CO3 (3 equiv.)

X MeO

OR2

PdCl2(MeCN)2, dppp MeO Cs2CO3

PTSA EtOH, 60°C, 2 h

dioxane, 90°C sealed tube

MeO

OH

MeO

OMe 85% yield

OMe OMe isoCA-4, 92%

dppp = 1,3-bis(diphenylphosphino)propane

Scheme 16 Synthesis of polyoxygenated diarylethylenes via Pd-catalyzed coupling reaction with aryl triflates.

demonstrate cytotoxic and antimicotic bioactivity.22b,c This protocol represents a practical application of Pd-catalyzed coupling strategy in biochemistry and medical research. Moreover, by employing this convergent strategy with the coupling of N-tosylhydrazones and aryl iodides under palladium catalysis, they carried out the design and synthesis of an array of benzoxepines derivatives, which served as conformationally restricted isocombretastatin A-4 analogues.22d In addition, 2-α-styrylpyridines derivatives, exhibiting excellent antiproliferative and antimitotic activity, were directly obtained in satisfactory to good yields by Pd-catalyzed coupling with 2-halopyridines (Scheme 17).23 After coupling and subsequent reduction, the desired compound 13, which is found to exhibit excellent antiproliferative and antimitotic activities comparable to isoCA-4, was obtained in simple transformations with good yield.

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Di Qiu et al.

PdCl2(MeCN)2 (5 mol%) dppf (10 mol%) t-BuOLi (2.2 equiv.)

NNHTs

R

MeO

+ ArHet–X

NNHTs

Br

dioxane, 110°C

N

OMe

N

MeO MeO

NO2 OMe

OMe 65% yield

26 examples 45%–98% yields

NO2

PdCl2(MeCN)2 (5 mol%) dppf (10 mol%) t-BuOLi (2.2 equiv.)

OMe

dioxane, 110°C

+

MeO

ArHet

R

Fe/EtOH/HCl aq. 100°C

N

MeO MeO

NH2 OMe

OMe 13, 92% yield

dppf = 1,1′-ferrocenebis(diphenylphosphine)

Scheme 17 Pd(II)-catalyzed coupling of N-tosylhydrazone with heteroaryl halides.

Upon employing the PdCl2(MeCN)2/dppp catalytic system, Alami group also reported the synthesis of tetra-substituted 1,1-diarylethylenes from sterically hindered as well as unhindered N-tosylhydrazones with aryl halides under optimized condition.24a This procedure provides a chemoselective and general synthetic route to a wide range of tetra-substituted olefins, especially for those having a cycloalkylidene unit. Moreover, the challenge of coupling reactions from sterically hindered N-tosylhydrazones could also be solved by using a newly established PdCl2(MeCN)2/Xphos/t-BuONa/fluorobenzene system (Scheme 18).24b This protocol has been applied successfully to the synthesis of a xanthene scaffold. Moreover, they developed the one-pot procedure for the Z-selective synthesis of trisubstituted olefins from arylalkynes with ortho-substituted aryl halides.25a,b This multistep sequence provided a rapid and versatile protocol for the synthesis of 4-arylchromenes 14, thiochromenes, and related heterocycles via a four-step sequence (Scheme 19). In particular, the first three steps involving hydration of alkynes, hydrazone formation, and Pd-catalyzed coupling with ortho-substituted aryl halides furnished Z-trisubstituted olefins stereoselectively without any purification of the intermediates generated in each stage.25a In 2012, the same group also described the one-pot three-step synthetic protocol toward (Z)-trisubstituted olefins from arylalkynes, as well

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n

NNHTs

R1

+ R2

PdCl2(MeCN)2 (5 mol%) dppp (10 mol%) X Cs2CO3 (3 equiv.)

n

R1

R2

dioxane, 90°C 26 examples 62%–95% yields

X = Br, I

n

R2

NNHTs

R1

PdCl2(MeCN)2 (2 mol%) Xphos (4 mol%) X t-BuONa (3 equiv.)

3

R or R

+

R4

R1

R4 R3 or R2

PhF, sealed tube, 100°C

2

X = Br, I

R1

NNHTs

R1

n

R2

R4 3

R 26 examples 40%–97% yields

R3

Scheme 18 PdCl2(MeCN)2-catalyzed coupling reaction of sterically hindered and unhindered N-tosylhydrazones.

R2 1

R

1. TsOH, EtOH OH 2. TsNHNH2 n 3. Pd(MeCN)2Cl2/Xphos R1 t-BuOLi, ArX, dioxane 90°C, 1 h sealed tube

OMOM n OEt 11 examples 52%–94% yields

R2 O

TsOH, EtOH reflux, 1 h R1

11 examples n 52%–100% yields

14

Scheme 19 One-pot multistep synthesis of 4-arylchromenes through Pd-catalyzed coupling of ortho-substituted aryl halides.

as the sequential cyclization process to access 4-aryl-2H-chromenes and 5-aryl-2,3-dihydrobenzo-[b]oxepine.25b In 2015, Alami and Hamze demonstrated the synthetic approach toward benzofulvenes through transition-metal-catalyzed cascade coupling reactions.26 This sequential transformation involves a site-selective Sonogashira coupling reaction of 20 -iodoacetophenone-derived N-tosylhydrazones,

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Di Qiu et al.

Me R

NNHTs + I

Me NNHTs

Ar

Me

Pd(OAc)2 (10 mol%) rac–BINAP (20 mol%) CuI (20 mol%) i-Pr2NH (3 equiv.)

NNHTs

DMSO, rt, 3 h, argon

Ar′–I 1. PdCl2(MeCN)2(10 mol%) XPhos (20 mol%) t-BuONa (3 equiv.), PhF, 100°C 2. PdI2, dppp, Cs2CO3 dioxane,150°C sealed tube, 15 h

R 9 examples 58%–82% yields

Ar′

Ar′

Ar

Ar 5 examples 40%–62% yields

BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Scheme 20 Synthesis of benzofulvenes through Sonogashira and Pd-catalyzed coupling of ortho-ethynyl-N-tosylhydrazones and catalytic cycloisomerization.

Pd-catalyzed cross-coupling of ortho-ethynyl N-tosylhydrazones, and Pd-catalyzed selective 5-exo-digcycloisomerization (Scheme 20). In 2014, the same group established a method to access 3-(α-styryl) benzo[b]thiophene library with a high level of molecular diversity.27 This synthetic sequence is initiated by bromocyclization of methylthiocontaining alkynes using N-methylpyrrolidin-2-one hydrotribromide to obtain 3-bromobenzothiophenes intermediates, followed by a Pd-catalyzed coupling reaction with N-tosylhydrazones, furnishing 2-aryl-3-(α-styryl)benzo[b]thiophene derivatives (Scheme 21). Among them, the coupling product 15 has demonstrated submicromolar cytotoxic activity against the HCT-116 cell line, inhibiting the polymerization of tubulin at micromolar level comparable to that of CA-4. Additionally, the success in the synthesis of 6-methyl-6-phenyl-6H-benzo[4,5]thieno [3,2-c]chromenes with good yields expand the scope of this synthetic method. Furthermore, a concise Pd-catalyzed external ligand-free protocol for the synthesis of 1,1-disubstituted alkenes was reported, allowing for the preparation of heterocyclic arylated alkenes under mild conditions (Scheme 22).28 By using aryl or heteroaryl halides as the substrates, this transformation provides a facile approach to access a variety of heterocyclic compounds, which are difficult to prepare via traditional coupling procedures. In 2015, the Pd-catalyzed cross-coupling reaction of aryl fluorides with N-tosylhydrazones was described by Wang group, which constituted a

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Br

NNHTs Ar

+

Ar′

Me

dioxane, 100°C sealed tube

S

R

MeO

Ar′

PdCl2(MeCN)2 (4 mol%) DavePhos (8 mol%) t-BuOLi (2.2 equiv.)

Ar S 18 examples 65%–97% yields

R

OMe

PTSA

MeO

CH2Cl2/EtOH

Ar′ O Me

OH OMe

R′

S

S

MeO

3 examples 90%–95% yields

15, 70% yield

DavePhos = 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl

Scheme 21 Synthesis of 3-(α-styryl)benzo[b]-thiophene derivatives through Pd-catalyzed coupling of 3-bromobenzothiophenes with N-tosylhydrazones.

NNHTs 2

R

R1

+ Ar–X

Pd(PPh3)2Cl2 (2.5 mol%) t-BuOLi (4 equiv.)

Ar R2

dioxane, 100°C

R1

Ar–X NNHTs 2

1

R

R

TsNHNH2 dioxane 90°C, 2 h

Pd(PPh3)2Cl2 (2.5 mol%) t-BuOLi (4 equiv.) dioxane, 100°C, 2 h

26 examples 68%–95% yields

R2 R1

Ar 3 examples 70%–74% yields

Scheme 22 External ligand-free Pd-catalyzed coupling of N-tosylhydrazones with aryl or heteroaryl halides.

straightforward method for synthesizing di- and trisubstituted arylated olefins (Scheme 23).29 Mechanistically, the reaction is proposed to be initiated by an electron-deficient group-directed SNAr-type process to afford arylpalladium(II) intermediate 16. Notably, this catalytic protocol represents the combination of C–F bond activation and Pd-carbene migratory insertion strategy. Additionally, the Wang group developed a route to 1,3-butadienes through Pd-catalyzed cross-coupling either from cyclopropylmethyl N-tosylhydrazone with aryl halides, or diaryl N-tosylhydrazone with

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NO2

Pd(PPh3)4 (5 mol%) TBAC (20 mol%) Cs2CO3 (3 equiv.)

NNHTs R2

F + R1

DMF, N2, 90°C, 8 h

R

O

N

R2

NO2

R1 R

O

19 examples 36%–78% yields

Pd L F 16

R

TBAC = tetrabutylammonium chloride

Scheme 23 Pd-catalyzed cross-coupling reaction of aryl fluorides with N-tosylhydrazones.

NNHTs

Pd2(dba)3/Xphos + Ar–X

R

t-BuOLi, dioxane, 80°C 14 examples 54%–87% yields

R Ar

NNHTs Ar

R

+

[Pd(allyl)]2/Xphos

X

Cs2CO3, MeCN, 80°C

6 examples 28%–45% yields R PdX Ar 17

β-C cleavage

R

PdX Ar

18

β-H elimination base

R Ar

Scheme 24 Synthesis of 1,3-butadienes through Pd-carbene migratory insertion/β-C/ β-H elimination.

cyclopropyl halides.30 The key process in this transformation is the migratory insertion of cyclopropylmethyl Pd-carbene species. Subsequent cyclopropyl ring opening through β-carbon elimination of 17, which results in the generation of homoallylic species 18, is followed by base-mediated β-H elimination of 18 to give rise to the formation of substituted 1,3butadienes (Scheme 24). These two transformations constitute a novel approach toward the synthesis of arylated 1,3-butadiene derivatives. Subsequently, Yu group reported the synthesis of 1,1-disubstituted 1,3butadienes through PdCl2(MeCN)2-catalyzed cross-coupling reaction by

Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions

169

using cyclopropylmethyl N-tosylhydrazones and aryl halides as the substrates.31 Besides, 1,1,4-trisubstituted 1,3-butadienes can also be accessed with moderate to good yields in the presence of an excess of aromatic bromides catalyzed by Pd(OAc)2. In 2015, the Pd-catalyzed cross-coupling of 2-amino-3-bromo-aromatic and heteroaromatic components with various sulfonylhydrazones was reported.32 This work has reported on the catalytic system as well as on the electronic nature of hydrazones which are necessary for the success of this series of Pd-catalyzed coupling reaction. Pd-catalyzed reductive cross-coupling of aryl halides with diazo species has been performed to construct Csp3–Csp2 single bonds. The Wang group utilized diaryl N-tosylhydrazones as coupling partners in the presence of ammonium formate as the reducing agent, accessing the synthesis of functionalized triarylmethanes as well as heterocyclic analogues.33a Plausible mechanism involves anion exchange of migrated palladium species 19 and sequential decarboxylation to generate Pd–H intermediate 20, followed by reductive elimination to furnish the desired product along with regeneration of Pd(0) species (Scheme 25). Notably, the addition of ammonium acetate significantly suppresses direct reduction of Ar–Pd–X species before diazo decomposition. This coupling strategy constitutes a novel approach toward the efficient synthesis of various triarylmethanes and the corresponding heteroatom-containing analogues from easily available substrates. Recently, Wang and coworkers explored this Pd-catalyzed reductive coupling strategy for the synthesis of di- and triarylmethanes.33b This reaction includes a wide scope of substrates, among which those containing heterocyclic moiety also proceeded well (Scheme 26).

2.2 Pd-Catalyzed Coupling of N-Tosylhydrazones With Benzyl Halides In 2009, the Wang group demonstrated the first example of Pd-catalyzed cross-coupling reaction of benzyl halides with N-tosylhydrazones (Scheme 27).34 This catalytic coupling protocol represents an efficient route to di- and trisubstituted olefins in high yields with excellent stereoselectivity. Mechanistically, the key feature of this transformation is the migratory insertion of benzyl group to the carbenic center of 21 to form intermediate 22, from which β-H elimination affords the desired olefins and regenerates the catalyst with the aid of a base. In 2014, the same group reported the synthesis of a wide range of CF3substituted alkenes and conjugated dienes from Pd-catalyzed coupling

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Pd(OAc)2 (5 mol%) L (15 mol%) HCO2NH4 (1.2 equiv.)

NNHTs Ar1

Ar3–Br

+

Ar2

Ar3 Ar2

Ar1

Cs2CO3 (2.0 equiv.) MeCO2NH4 (1.5 equiv.) t-pentanol, 90°C, 4 h

32 examples 30%–95% yields

L = biphenyl-2yldiphenylphosphine

Mechanism Pd(II) Ar3–X

Ar3 Pd(0)L Ar1

MeCO2

Ar2

suppress the direct reduction Ar3 1

Ar

X

PdHL

HCO2

Ar3–Pd(II)L

2

Ar 20

N2

CO2 + X

Ar1

Ar

PdXL

1

Ar

2

Ar

19

Ar

1

Ar

2

Ar2 Base

X Ar3 Pd(II)L

HCO2 3

Ar3–H

NNHTs Ar1

Ar2

Scheme 25 Pd-catalyzed reductive coupling for synthesizing triarylmethanes.

Pd(OAc)2 (5 mol%)

NNHTs Ar1

R

+

2

Ar –Br

Ar2

PCy3⋅HBF4 (20 mol%) Cs2CO3 (2.0 equiv.) i-PrOH, toluene 80°C, 12 h

Ar1

R

62 examples 30%–95% yields

Scheme 26 Pd-catalyzed reductive coupling to form di- and triarylmethanes.

reaction of CF3-bearing N-tosylhydrazones or diazo compounds with benzyl or aryl halides (Scheme 28).35 Similarly, Pd-carbene migratory insertion is assumed to play a crucial role in these transformations. With the advantages of mild conditions and good functional group tolerance, this methodology displays the potential to find applications in the synthesis of trifluoromethyl-containing complex molecules.

2.3 Pd-Catalyzed Oxidative Coupling of N-Tosylhydrazones In addition to Pd-catalyzed coupling reaction of aryl halides, catalytic oxidative cross-coupling of arylboronic acids with in situ-generated diazo species from N-tosylhydrazones was also developed, involving transmetalation

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NNHTs +

X

Ar

R2

R1

Pd2(dba)3 (2.5 mol%) P(2-furyl)3 (20 mol%) t-BuOLi (3 equiv.)

R2

Ar R1

toluene, 80°C, 3 h

21 examples 67%–96% yields

Mechanism X

Ar

NNHTs

HX

Pd(0) R1

R2

Base t-BuOLi Ar

X Pd(II)L

X

N2

H–Pd(II)L R2

Ar

1

R

R2

R1 X

Ar

H

Pd(II)L

PdXL

Ar R1

R2 22

R1

R2

21

Scheme 27 Pd-catalyzed coupling of benzyl halides with N-tosylhydrazones.

NNHTs + Ar

Ar–Br

R

Br

+

R′

CF3

dioxane, 80°C, 5 h

NNHTs

Pd2(dba)3 (6 mol%) XPhos (24 mol%) t-BuOLi (2.2 equiv.)

CF3 R

Pd2(dba)3 (5 mol%) P(2-furyl)3 (20 mol%) t-BuOLi (3 equiv.)

dioxane, 110°C, 12 h

CF3

Ar R

13 examples 44%–90% yields E/Z = 8:1 to >20:1 R′ R

CF3

Ar 12 examples 48%–80% yields

Scheme 28 Pd-catalyzed coupling to access the synthesis of CF3-substituted alkenes.

between the Pd(II) intermediate with boronic acid to generate aryl-Pd(II) species. In 2010, the Wang group disclosed an example of Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with arylboronic acids in the presence of a Cu(I) salt, affording arylated functionalized olefins with high yields (Scheme 29).36 The success of the selective generation of crosscoupling products indicates that the oxidative homo-coupling of

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Pd(PPh3)4 (5 mol%) CuCl (10 mol%) t-BuOLi (5 equiv.)

NNHTs R

Ar1

Ar2–B(OH)2

+

dioxane, O2, 70°C

R′

R′

Ar1

Ar2

28 examples 30%–84% yields

O2 Mechanism Cu(I)

Ar–B(OH)2 NNHTs

Cu(II)

Pd(II)L 23

Ph

Pd(0)

t-BuOH LiX

t-BuOLi X Ar–Pd(II)L 24

X Ar

R

N2

H–Pd(II)L Ph

Ph X Ar

PdXL H

Ph

Ar–Pd(II)L Ph

26

25

Scheme 29 Pd-catalyzed oxidative cross-coupling of arylboronic acids with N-tosylhydrazones.

arylboronic acids has been largely suppressed under aerobic conditions. The proposed mechanism involves transmetalation of Pd(II) species 23 with arylboronic acid initially to afford aryl-palladium species 24, which decomposes the in situ-generated diazo substrate to give the Pd-carbene complex 25. Subsequently, migratory insertion of aryl group to the carbenic carbon of 25 results in the generation of intermediates 26. Finally, β-H elimination of 26 affords the olefin product with the regeneration of Pd(0) species, which is oxidized by Cu(II) to form Pd(II) species. Furthermore, Wang group described the alkynyl migratory insertion process of Pd-carbene, providing a new synthetic method for stereoselective conjugated enynes through Pd-catalyzed oxidative coupling between N-tosylhydrazones or diazo compounds with terminal alkynes (Scheme 30).37 The key step in this transformation is migratory insertion of the alkynyl group to the metal-carbene center of 27, followed by β-H elimination from 28 to afford enynes. Finally, Pd(0) is oxidized by BQ (benzoquinone) to regenerate Pd(II) species. In 2012, Jiang group demonstrated the C(sp2)–C(sp3) bond formation via Pd-catalyzed oxidative coupling of allylic alcohols with N-tosylhydrazones

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NNHTs Ar

R1

R2

+

Pd(OAc)2 (5 mol%) P(2-furyl)3 (20 mol%) t-BuOLi (3.5 equiv.) BQ (2 equiv.)

R1 18 examples 42%–83% yields

Ar dioxane, 90°C

R2

Mechanism

R2

N2 1

Ar [Pd]

[Pd]

R

R R1

2

R

2

Ar 27

[Pd] R1

Ar 28

Scheme 30 Pd-catalyzed oxidative coupling of N-tosylhydrazones with terminal alkynes.

derived from ketones.38a This reaction is proposed to be initiated by β-H elimination of palladium alkoxide species 29 to generate α,β-unsaturated ketones 30, in which the double bond moiety coordinates to a Pd–H species. Next, olefin insertion into Pd–H bond with sequential diazo decomposition affords alkyl-Pd-carbene intermediate 31. Subsequent migratory insertion of the alkyl group to the Pd-carbene center occurs, facilitated by the coordination of the carbonyl group to Pd species. Finally, β-H elimination of 32 affords the coupling product along with extrusion of Pd(0), which is reoxidized by BQ to regenerate Pd(II) species (Scheme 31). Moreover, in the same year, the Jiang group established a Pd(II)catalyzed alternative coupling reactions of electron-deficient terminal alkenes with N-tosylhydrazones.38b This divergent protocol enables the synthesis of functionalized cyclopropanes from acrylamides, or the chain ketone derivatives from α,β-unsaturated ketones (Scheme 32). The mechanism involves the oxidative cyclometalation of Pd-carbene species 33 with electron-deficient alkene initially to obtain the metallacyclobutane intermediate 34. Sequential β-H elimination occurs to produce linear alkyl-Pd species 35, and second β-H elimination is suppressed by the strong coordination effect. Amide intermediates undergo an alkene insertion to afford cyclopropane structure 36, followed by reduction elimination or protonolysis to furnish cyclopropanes. On the other hand, weaker coordination effect of the ketone results in the unachievable alkene insertion, instead of the formation of chain products via protonolysis in the presence of water. To gain insights into the mechanism, the Bi group carried out a theoretical study toward the mechanism of this water-assisted Pd(II)-catalyzed intriguing cross-coupling of alkenes with N-tosylhydrazones.38c They have

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Pd(OAc)2 (10 mol%) BQ (2 equiv.) t-BuOLi (3 equiv.)

NNHTs

R1

+

R2

R3

R3 R1

MeCN, 90°C, 8 h

OH

R2 O 29 examples 52%-84% yields

Mechanism

R1

R

O HPdX

OPdX

H 1

29

NNHTs

Insertion

R1 30

2

R

OH

O

Base

R1

OH

R3

PdX N2

Pd(II) R2

R3

O R1

OH BQ Pd(0)

R3 31

R3 R2

O

Migratory insertion

–HX

R3 R1

PdX R2

R1

R2 O

XPd 32

Scheme 31 Pd-catalyzed oxidative coupling of N-tosylhydrazones with allylic alcohols involving alkyl group migratory insertion.

clarified the important roles of water, acetate, and t-BuO group in the catalytic cycle. The proposed mechanism is as following: (1) migratory insertion to generate stable five-membered metallacyclic intermediate 37; (2) β-H abstraction by t-BuO, resulting in C]C bond formation; (3) oxidative addition; (4) alkene insertion into Pd–C(sp2) bond; (5) enolization to form Pd–O bond; and (6) hydroxyl hydrogen addition from water to afford final product, along with the generation of Pd–OH species (Scheme 33). Pd-catalyzed oxidative coupling of two molecules of N-tosylhydrazones provided a new route to branched conjugated dienes.39 In 2013, Jiang39a and Prabhu39b reported the Pd-catalyzed oxidative coupling reactions of N-tosylhydrazones under the aerobic condition or using BQ as the oxidant, respectively. These transformations enable the facile, efficient regioselective synthesis of 2,3-substituted-1,3-butadienes from readily available substrates, as well as the preparation of heterocyclic rings. The proposed mechanism involves diazo decomposition by alkenyl-Pd species 38 to generate

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R3 N

NNHTs R1

+

R2

R4

Pd(OAc)2 (10 mol%) t-BuOLi (3 equiv.) H2O (2 equiv.)

R2

MeCN, 90°C, 14 h

R1

O

NNHTs

R2

Mechanism

O 10 examples 70%–81% yields

X NNHTs

Ar

PdLn

[Pd] base

Ar

Ar R2

X = R3

H Pd

O 34

O

O X

Pd Ln

β-H elimination

R3

R1 H

Ar 35

X

O

33

R3

R1

MeCN, 90°C, 14 h

O

R2

R3 N R4

16 examples 59%–76% yields

Pd(OAc)2 (10 mol%) t-BuOLi (3 equiv.) H2O (2 equiv.)

R3

+

R1

O

H

Pd

X= NR3R4

Pd O

O

Ar N R3

Ar

R4

R3 N R4 36

TM

Scheme 32 Pd-catalyzed diverse coupling reaction of N-tosylhydrazones with electron-deficient alkenes.

O

O Pd OH

O

N2 t-BuOH OAc

Et

Ph–H2O, TM

O

O

O t-BuO

Ph

Ph Pd(OAc)2

O

OAc

O

O

Pd O

Ph Oxidative addition Et

O Pd

OH2

Et

O –OAc

Et

Ph Ph

O Pd

O 37

O

t-BuOH

Pd

O Ph

O Pd O

O O

Scheme 33 Proposed mechanism of water-assisted Pd(II)-catalyzed cross-coupling of alkenes with N-tosylhydrazones.

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Jiang⬘s wok NNHTs Ar

Me

Pd(OAc)2 (5 mol%) BQ (20 mol%)

Ar

Ar

DMSO, MS (60 mg), O2 (1 atm.), 90°C

22 examples 41%–87% yields

Mechanism Ar

Me

N2 Pd(II) Ar

Pd(II)

-HX Ar

Me

38

Ar

XPd Pd(II)

Me Ar

39

Ar

Me -HX

Migratory Ar

insertion

-Pd(0)

TM

Prabhu⬘s work NNHTs

Ar

Ar

18 examples 68%–93% yields

Me

Ar

Pd(PPh3)2Cl2 (5 mol%) ligand, BQ, t-BuOLi

or NNHTs

or Me Ar′

Me N H

Ar′

2 examples 56%, 63%

N NNHTs

Scheme 34 Pd-catalyzed oxidative coupling of N-tosylhydrazones to provide branched conjugated dienes.

alkenyl-Pd-carbene intermediate 39. Migratory insertion of alkenyl group with sequential β-H elimination gives rise to the formation of the final product, and Pd(0) is oxidized to regenerate Pd(II) (Scheme 34). Moreover, Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with indoles was carried out, providing an efficient synthetic method for N-vinylindoles40a as well as N-vinylazoles40b with good functional group tolerance (Scheme 35). These transformations are implemented under aerobic conditions or utilized aryl iodide as the oxidant, respectively. Especially, migratory insertion of the indole unit is hypothesized as the key step, followed by β-H elimination to afford N-vinyl-functionalized N-heterocycles.

2.4 Pd-Catalyzed Two-Component Cascade Coupling of N-Tosylhydrazones Furthermore, Pd-catalyzed two-component cascade reaction involving migratory insertion has also experienced considerable growth. This autotandem catalytic strategy by using diazo compounds establishes a novel and facile approach for synthesizing divergent functional molecules. In 2011, Barluenga and Vald
es demonstrated the Pd-catalyzed tandem coupling of N-tosylhydrazones derived from Mannich adducts

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Cui⬘s work

R1

+ N H

R2

Ar

R1

Pd(PPh3)Cl2 (5 mol%) t-BuOLi (2 equiv.)

NNHTs

N Ar

DMF, O2, 80°C R2

26 examples; 45%–99% yields Alami⬘s work R4

R5

N

R2

R1

R2

R1

R2

R1 R3

R3

R3

40 examples 35%–99% yields

N

N

N

Scheme 35 Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with indoles.

TsNHN

NHR1 R2

Pd2(dba)3 (4 mol%) Xphos (16 mol%) t-BuOLi (4.1 equiv.)

Br Cl +

R3 NR1 R2

dioxane/H2O, 150°C (MW)

X

R3

C–C bond formation

X R3 NHR1

Cl

C–N bond formation

17 examples 30%–90% yields

R2 X

Scheme 36 Autotandem Pd-catalyzed C–C/C–N bond formation to obtain quinolines.

with 1,2-dihalogenated arenes, proceeding through aryl group migratory insertion with catalytic amination (Scheme 36).41 This sequential C–C/ intramolecular C–N bond formation protocol provides quinoline derivatives, as well as enantiomerically enriched quinoline scaffold through the combination of organocatalytic Mannich reaction with the Pd-catalyzed coupling reaction. This unprecedented autotandem catalytic transformation opens a new avenue to the development of other appealing coupling cascade transformations. Besides, Wang group utilized the autotandem strategy to access the functionalized acridines from coupling reaction of o-dihalobenzenes with N-tosylhydrazones containing amino group.42 Reaction pathway consists

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Di Qiu et al.

R

X +

R1

R2 H2O (5 equiv.) dioxane, 110°C

Y

NH2

R

Pd2(dba)3 (2.5 mol%) Ruphos (10 mol%) t-BuOLi (4 equiv.)

NNHTs

X, Y = Cl, Br, I, OTf

R2

R1 N 23 examples 30%–98% yields

Ruphos = 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl Pd2(dba)3⋅CHCl3 (2.5 mol%)

R′HN

NNHTs

R I

+ Ar

H

PPh3 (15 mol%) t-BuOLi (3.4 equiv.) BnEt3NCl (1 equiv.) Et3N (2 equiv.) 2-MeTHF, 80°C, 10 min

NR′ Ar R 11 examples 50%–95% yields

Scheme 37 Autotandem Pd-catalyzed C–C/C–N bond formation to afford acridines, pyrrolidine, and piperidine scaffold.

of the aryl group migratory insertion/β-H elimination sequence followed by catalytic intramolecular amination. In addition, Pd-catalyzed coupling reaction between vinyl iodides and N-tosylhydrazones with intramolecular nucleophilic trapping sequence was performed to afford pyrrolidine and piperidine scaffold (Scheme 37).43 Moreover, Pd-catalyzed cross-coupling reaction involving migratory insertion with nucleophilic trapping cascade provided novel and efficient approaches for a wide range of cyclic molecules, including isoindolones 40 (with nitrogen nucleophile),44 dihydronaphthalene 41 and indene 42 (with carbon nucleophile),45 2H-chromenes 43 (with oxygen nucleophile),46 spiroacetal enol ethers 44 (through intramolecular nucleophilic dearomatization),47 1-arylindanes 45 and 1-aryltetralins 46 (with carbon nucleophile),48 allylic sulfones 47 (using N-tosylhydrazone as a double nucleophile),49 and chromeno[4,3-b]chromene 48 (with oxygen nucleophile)50 (Scheme 38). From commercially available aldehydes or ketones and organic halides, these Pd-catalyzed cascade reactions provide facile and straightforward synthesis of divergent building blocks, especially for heterocyclic compounds. In 2016, Huang group reported the Pd-catalyzed cross-coupling reaction of aminals with vinyl N-sulfonyl hydrazones, in which the C–C and C–S bond was simultaneously constructed in a straightforward manner (Scheme 39).51 This process affords aminomethyl-substituted allylic sulfones in moderate to good yields. The key step in this reaction is the

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Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions

Palladiumcatalyzed crosscoupling

NNHTs R–X +

Nucleophilic cascade Target molecules

R2

1

R

R

R

E1 E2

O

R1 N

Ar2 40

R

R2 Ar

Ar1

41

E2

42

O Ar Ar

O

E1 43

44 O

Ts

EWG

R

EWG 45

R1

EWG EWG

Ar

46

Ar

Ar

Ar

R2

47

R3

O

48

Scheme 38 Synthesis of functional molecules through Pd-catalyzed coupling/nucleophilic trapping cascade synthetic strategy.

3

R

+

NNHTs

NBn2 NBn2

3

R

NR22 NR22

MS, n-Bu2O, 100°C, 10 h Pd(II)

Ts NR2

Ar

Ts

Pd(0)

NBn2

R3

MS, n-Bu2O, 100°C, 10 h Pd(DPEPhos)(MeCN)2(OTf)2 (2.5 mol%)

+

NNHSO2R1

Pd(DPEPhos)(MeCN)2(OTf)2 (2.5 mol%)

68% yield

R3

SO2R1 NR22 24 examples 39%–70% yields

NR2 NR2 R2N

Ts Pd 49

Pd Ar

NR2

NR2

Ar Migratory insertion

N2

N2

Ar 50

Pd

NR2

Scheme 39 Pd-catalyzed carbene-coupling reaction of aminals to afford allylic sulfones.

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Di Qiu et al.

migratory insertion of aminomethyl group to form the π-allylpalladium intermediate 50 generated from electrophilic cyclopalladated complex 49, followed by sequential nucleophilic attack to deliver the final product along with the regeneration of active Pd(0) species. In addition, the combination of Pd-catalyzed cross-coupling involving migratory insertion with intramolecular Heck-type reaction has been developed and applied for preparing functional molecules containing C–C double bonds, including spiroamide derivatives 51,52 3-vinylindoles and 3-vinylbenzofurans 52,53 spirocyclic systems 53 (spiro-fluorenes, -dibenzofluorenes, -acridines, and -anthracenes),54 benzofuran-, dihydrobenzofuran-, and indoline-containing alkenes 54,55 indanes and 2,3-disubstituted benzofurans 55,56 polysubstituted indoles 56 and 1,4-dihydroquinolines 560 ,57 as well as various naphtho-fused heterocycles 5758 (Scheme 40). Finally, alkenes are obtained through alkyl group migratory insertion followed by β-H elimination. This reaction represents the first example of the reaction involving neopentyl palladium intermediates with carbenes to form alkenes.52 In 2015, the domino process which converged Pd-carbene migratory insertion with intramolecular Heck reaction was reported, allowing the stereo- and regioselective synthesis of 2-arylidene-3-aryl-1-indanones from readily available N-tosylhydrazones and 20 -iodochalcones (Scheme 41).59 Moreover, the success of one-pot synthesis as well as gram-scale preparation also demonstrates its practical utility in organic synthesis. Mechanistically, this reaction is assumed to proceed via migratory insertion of aryl group, followed by regioselective 5-exo-trig cyclization and β-hydride elimination process. Yin and Jiang group developed an intriguing Pd-catalyzed cross-coupling reaction of furfural tosylhydrazones with 2-iodo-anilines or -thiophenols, respectively, affording polysubstituted indoles or benzothiophenes.60 This transformation is proposed to proceed via aryl migratory insertion to generate 2-furylmethylene palladium species 58. Sequential β-oxygen elimination with concomitant furan ring-opening procedure affords the allene intermediate 59. Subsequently, intramolecular nucleophilic addition, palladium transfer, and β-H elimination occur, leading to the synthesis of indoles or benzothiophenes as ring closure products (Scheme 42). In 2016, an autotandem Pd-catalyzed coupling reaction of alkyne-based aryl iodides with salicyl N-tosylhydrazones was reported (Scheme 43). This convenient method allows the construction of spiro[benzofuran-3,20 chromene] scaffold with good yields and excellent selectivity.61 Mechanistically, this reaction proceeds via initial 5-exo-dig cyclization of 60 to form

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Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions

Palladiumcatalyzed crosscoupling

NNHTs +

R–X

Target molecules

R2

1

R

Heck-type reaction

Ar Me

R4

R1

X R2

R3

O

R1

X

X

N 51 Me

Ar

R3

R

R2

Y

52, X = NAc, O

54, X = NAc, NMe, O

53

Ar Ar

R3 R2

Ar

R

Me

n

X 54ⴕ

O 54ⴖ

55 Ar

Ar

Ar

X

X N Ts

O R2

Me 56

O 55ⴕ

56ⴕ

N R1

X 57, X = O, S, NMe

Scheme 40 Synthesis of functional molecules through Pd-catalyzed cross-coupling of N-tosylhydrazones via intramolecular Heck-type cascade transformations.

O R2 +

1

R

I

Ar

NNHTs

Pd(OAc)2 (10 mol%) PPh3 (30 mol%) K2CO3 (3 equiv.)

H

THF/H2O, 60°C, 2 h

O R1 R2 Ar 40 examples 69%–97% yields

Scheme 41 Synthesis of 2-arylidene-3-aryl-1-indanones through Pd-catalyzed coupling of N-tosylhydrazones with Heck-type cascade reaction.

the vinyl Pd(II) intermediate 61. Then, in situ-generated diazo species reacts with 61 to form Pd-carbene species 62, which undergoes sequential migratory insertion of vinyl group to give benzyl palladium intermediate 63. Finally, intramolecular cyclization of 63 promoted by oxygen as

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Di Qiu et al.

I

R3

1

R + NHEt TsHNN (1 equiv.)

R

O

2

Pd2(dba)3 (5 mol%) dppf (10 mol%) K2CO3 (4 equiv.)

R1 COR2 R3

toluene, 90°C, 6 h

N 19 examples Et 48%–86% yields β-H elimination

Pd transfer

Pd(0) PdI

R1

OPdI

NHEt

R2

R1

N Et

R2

O

H

N2 R1 O I

R1

R2 Migratory insertion

Pd

R1

PdI R O NHEt

•

OPdI

NHEt

R2

2

58

EtHN

59

Scheme 42 Pd-catalyzed coupling of furfural tosylhydrazones with 2-iodoanilines.

R1 4 R3 + R R2

O

R4

Pd(PPh3)4 (5 mol%) K2CO3 (5 equiv.)

OH

I

NNHTs

R1

O

THF, 80°C, 15 h O

R3 R2

23 examples; 50%–86% yields Pd(0) R1 PdI O 60 OH IPd

R1

OH N2

O 61

IPd

OH R1

IPd R1 Migratory insertion

O 62

O 63

Scheme 43 Formation of spiro[benzofuran-3,20 -chromene] derivatives through Pd-catalyzed tandem coupling reaction.

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NNHTs R + O

Ar–X

Pd2(dba)3 (5 mol%) XPhos (10 mol%) Cs2CO3 (2 equiv.)

Ar R 18 examples 45%–80% yields

dioxane, 100°C

O

EWG Ar

Ar

PdX

R

EWG

R O 64

EWG

65

O

H PdX EWG

Scheme 44 Synthesis of benzoxepines through Pd-catalyzed coupling reaction involving carbene insertion and C–C bond cleavage.

nucleophiles affords the spirocyclic skeleton and regenerate Pd species simultaneously. In 2016, Zhou group achieved the regiospecific synthesis of benzoxepines derivatives through Pd-catalyzed coupling reaction of aryl halides with oxabicyclo[4.1.0]heptyl N-tosylhydrazones (Scheme 44).62 Key features of this ring expansion include migratory insertion of the Pd-carbene intermediate to form 64, which undergoes sequential selective C–C bond cleavage to obtain the ring-expanded intermediate 65. Finally, β-H elimination from 65 occurs to deliver benzoxepines containing an aryl group at the 5-position. Moreover, Liang group established divergent Pd-catalyzed decarboxylative coupling of propargylic carbonates with acetophenone-derived N-tosylhydrazones (Scheme 45).63 Migratory insertion from the allenylpalladium carbene 66 with subsequently β-H elimination results in the synthesis of multisubstituted conjugated vinylallenes. Alternatively, formation of propargylic N-sulfonylhydrazones comes from direct nucleophilic attack of the propargyl palladium intermediate 67 with hydrazone salt anion, followed by reductive elimination to furnish propargylic substitution product, accompanying with the regeneration of Pd(0). Furthermore, except for hydrocarbon groups, migratory insertion processes of other heteroatom groups have also been explored. In 2015, Wang group reported the Pd-catalyzed carbene insertion into Si–Si and Sn–Sn bonds, using N-tosylhydrazones as the carbene precursors (Scheme 46).64 This protocol affords geminal bis(silane) and geminal bis(stannane) derivatives with high efficiency under mild conditions. Compared with the traditional insertion process, this reaction is proposed to proceed via oxidative

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Di Qiu et al.

OCO2Me + R2 Ar2 R1

Ar1

NNTs N a

Pd2(dba)3 (10 mol%) BnEt3NCl (1 equiv.) Cs2CO3 (2.2 equiv.) dioxane, 80°C R1

Ar1 •

R2

NNHTs OCO2Me + R2 2 Ar Me R1 via

R2 • R1

Me via

Ar1

Ar1

66

Ar2 14 examples 40%–70% yields

PdOMe

Pd(MeCN)2Cl2 (5 mol%) dppp (10 mol%) Cs2CO3 (2.2 equiv.)

Ar2 N Me

N Ts R2 R1 11 examples 9%–85% yields

Ar1 dioxane, 80°C

Ar

1

67

R1 R2 PdOMe

Scheme 45 Pd-catalyzed decarboxylative synthesis of vinylallenes and propargyl N-sulfonylhydrazones.

SiMe2F

FMe2Si SiMe2F NNHTs R

R⬘

SiMe2F +

or

Pd2(dba)3 (4 mol%) P(OCH2)3CEt (8 mol%) t-BuOLi (3 equiv.)

R⬘ R 28 examples 34%–99% yields or

toluene, 60°C

SnMe3 SnMe3

Me3Sn R

SnMe3 R⬘

23 examples 38%–99% yields

Scheme 46 Pd-catalyzed carbene insertion into Si–Si and Sn–Sn bonds.

addition and migratory insertion of Pd-carbene species as the key steps. This unprecedented reaction shows the generality of metal-carbene migratory insertion process as a new strategy for the construction of carbon– heteroatom bond with high efficiency and good selectivity. In addition, Huang recently reported the first Pd-catalyzed noncarbene cross-coupling reaction of β,γ-unsaturated N-tosylhydrazones with aminals through a catalytic tandem aminomethyl amination/aromatization process (Scheme 47).65 This Pd-catalyzed coupling strategy constitutes a new approach toward the synthesis of β-aminoethylpyrazoles without the need

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Advances in Transition-Metal-Catalyzed Cross-Coupling Reactions

Ts NNHTs

NR2

[Pd(dppp)(MeCN2)](OTf)2 (5 mol%)

NR2

CH2Cl2, 80°C

+

1

R

R2

N N 29 examples 33%–84% yields

R2 Pd

Mechanism NNHTs

NR2

R1

NR2

NR2

Ts

+

N N

NR2

R⬘

NR2

R⬘

[Pd]

72

H–base R2NH NTs HN R⬘ 69

Pd 68 NR2

R⬘ Pd HN N Ts

Base Ts HN N

70

R2N

NR2

R⬘ 71

Scheme 47 Pd-catalyzed coupling of β,γ-unsaturated N-tosylhydrazones with aminals to synthesize β-aminoethylpyrazoles.

of external oxidant and base. The proposed mechanism is assumed to proceed by C–N bond activation initially to afford electrophilic cyclopalladated complex 68. Then, diene 69 which is in situ generated from tosylhydrazones via imine–enamine tautomerization reacts with 68 to give rise to π-allylic palladium complex 70 as the key intermediate. This intermediate then undergoes sequential intramolecular nucleophilic addition to afford 2,3dihydropyrazole intermediate 71. Subsequently, deprotonation of 71 assisted by aminal results in the formation of the azaallylic anion 72, followed by the capture of 68 and final β-H elimination to afford the desired heterocycle derivatives.

2.5 Pd-Catalyzed Multicomponent Coupling of N-Tosylhydrazones Furthermore, Pd-catalyzed multicomponent cascade transformation involving migratory insertion also attracts great attentions. One typical type of this cascade process is Pd-catalyzed autotandem strategy. Recently, Alami and Hamze have disclosed a series of Pd-catalyzed three-component coupling reactions of N-tosylhydrazones with aryl halides with sequential C–C/C– N bond formation, affording various functionalized aromatic compounds with high efficiency.66 In 2013 and 2014, Alami and coworkers reported

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NNHTs R1

X +

R1

NNHTs R3 + 1 R X R2

R2 Y + HN R3

R1 R2 N R3

Ar

PhF, 120°C

1. Pd2(dba)3⋅CHCl3 (2 mol%) PhI (1.2 equiv.) t-BuONa (2.5 equiv.) CPME, reflux N H

R1

Pd(MeCN)2Cl2 (2 mol%) Xphos (4 mol%) t-BuONa (3.5 equiv.)

2. Xphos (8 mol%) t-BuONa (1.2 equiv.) H N (1.2 equiv.) R4 R5

29 examples 35%–93% yields R4 N R5

N

R3

R1 R2 21 examples 45%–83% yields

Scheme 48 Autotandem Pd-catalyzed C–C/C–N bond formation reactions to access nitrogen-containing diarylethylenes and N-vinylindoles.

the one-pot autotandem Pd-catalyzed iterative coupling reactions with sequential C–X bond amination, producing nitrogen-containing diarylethylenes66a and N-vinylindoles66b (Scheme 48). These threecomponent reactions of N-tosylhydrazones, amines, and halogensubstituted aromatic compounds provide facile routes to construct C–C double bond and C–N bond in one-pot fashion. In 2015, the same group developed a Pd-catalyzed one-pot coupling reaction of dihalogenated arenes, N-tosylhydrazones with boronic acids or esters, affording a highly functionalized 1,1-diarylethylene skeleton of the natural product ratanhine with good yields and wide substrate scope (Scheme 49).66c Notably, this iterative cross-coupling strategy, which constructs two distinct C–C bonds in one-pot fashion, allows the facile synthesis of 73 that exhibits antiproliferative activity in the nanomolar concentration range against HCT116 cancer cell lines. In 2016, the same group disclosed a convergent synthesis of arylindole derivatives and (1-arylvinyl)carbazoles through one-pot Pd-catalyzed coupling reaction of 2-nitro-haloarenes with N-tosylhydrazones, followed by a Cadogan–Sundberg reductive cyclization to afford indole scaffold.66d This methodology not only enables facile construction of C–C/C–N bond formation in a single step but also allows efficient synthesis of functional molecules which exhibits antiproliferative activity in low nM range against colon cancer cell lines. Moreover, they developed a new Pd-catalyzed onepot coupling process of N-tosylhydrazones, N-(dihalophenyl)-imidates with amines, affording a library of 5-(1-arylvinyl)-1H-benzimidazoles.66e

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R2

R3

Pd(OAc)2 (4 mol%) R2 SPhos (8 mol%) t-BuOLi (2.4 equiv.) R1 Y CPME, reflux

X +

R1

R–B(OH)2 or R–Bpin

R3

NNHTs X, Y = Cl, Br, I

Y

R2

R3

R1 K3PO4⋅H2O H2O (5 equiv.)

R

28 examples 27%–88% yields

MeO MeO

OMe

OMe Cytotoxicity GI50 = 70 nm 73, 61% yield HCT116 cell lines SPhos = 2-dicyclohexylphosphino-2⬘, 6⬘-dimethoxybiphenyl

Scheme 49 Palladium-catalyzed one-pot coupling reaction of dihalogenated arenes, N-tosylhydrazones with organoborons to form 1,1-diarylethylene derivatives.

NNHTs O2N

R2

R3

+

R1

2. PPh3 (4 equiv.) 160°C, 24 h, sealed tube

Br

2

R

Br

3

R

N

R5

+ 1

R

NNHTs

R4

1. Pd2(dba)3⋅CHCl3 (2.5 mol%) XPhos (10 mol%) t-BuOLi (2.2 equiv.) dioxane, 110°C, 5 h

Cl

OEt

1. Pd2(dba)3⋅CHCl3 (2.5 mol%) DavePhos (10 mol%) t-BuOLi (2.2 equiv.) dioxane, 100°C, 1.5 h 2. H2N-R6 (1.1 equiv.) t-BuOLi (2.2 equiv.) 130°C, 3 h

Scheme 50 One-pot Pd-catalyzed multicomponent N-tosylhydrazones to construct C–C and C–N bonds.

R2

NH

R1

R3

36 examples; 42%–92% yields

R2

R3 N

R1

R5 N R R6 45 examples; 32%–86% yields 4

coupling

reaction

of

A plausible mechanism involves a Pd-carbene migratory insertion process to give substituted alkenes, followed by Pd-catalyzed N-arylation and sequential intramolecular cyclization to verify the construction of one C–C bond and two C–N bonds in the same catalytic cycle (Scheme 50). In 2013, Liang group reported a Pd-catalyzed three-component crosscoupling reaction of vinyl iodide, N-tosylhydrazone (derived from benzaldehydes), and carbon nucleophiles, as well as the one-pot procedure by using the aldehyde compound as the substrate (Scheme 51).67a The proposed mechanism involves migratory insertion of vinyl group to Pd-carbene center, followed by the nucleophilic attack of sodium malonate to the η3-allylpalladium intermediate, resulting in the formation of two distinct C–C bonds.

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NNHTs R

+

+ Ar

I

Pd2(dba)3⋅CHCl3 PPh3, K2CO3

Na EWG

EWG

THF, 2 h

EWG

EWG R

Ar

18 examples 34%–84% yields

Scheme 51 Pd-catalyzed carbene insertion of vinyl halides, N-tosylhydrazones with carbon nucleophiles.

R1 H R2

Pd2dba3⋅CHCl3 (5 mol%) PPh3 (30 mol%) t-BuOLi (3.6–5.4 equiv.) TBAC (1 equiv.)

NNHR⬘ + H

+ I

R

Nu 2-MeTHF, 80°C

R⬘ = Ts or trisyl TBAC = tetrabutylammonium chloride

R1 H R2

Nu

R 14 examples 20%–99% yields

Scheme 52 Pd-catalyzed coupling reaction of vinyl iodides, alkyl aldehyde-derived N-tosylhydrazones, with carbon or nitrogen nucleophile.

In 2015, Van Vranken group described the Pd-catalyzed both intraand intermolecular carbenylative amination and alkylation with vinyl iodides through palladium alkylidene species as the key intermediate (Scheme 52).67b As a result, vinyl iodides are shown to generate η3allylpalladium species, which resists competitive β-H elimination process, preserving the C(sp3) center adjacent to the carbene moiety. This selective multicomponent coupling reaction enables the construction of functionalized alkenes. Wang group have also focused on the Pd-catalyzed multicomponent coupling reaction of N-tosylhydrazones to access the synthesis of functional molecules. In 2010, they carried out the Pd-catalyzed three-component cross-coupling reaction of aryl halides, N-tosylhydrazones, and terminal alkynes as nucleophiles, constructing two separate C–C bonds on a carbenic carbon atom.68 Rather than competitive undesirable Sonogashira products, this C(sp)–C(sp3) coupling reaction provides an efficient method for synthesizing benzhydryl acetylene derivatives (Scheme 53). Especially, transmetalation between the migrated alkylpalladium key intermediate with various transition-metal species opens a new avenue both for carbene chemistry and for cross-coupling reactions. Furthermore, Wang group developed the Pd-catalyzed multicomponent reactions of aryl iodides, allenes with N-tosylhydrazones, or diazo species,

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Ar

NNHTs + Ar⬘ H

Br

Pd2(dba)3 (2.5 mol%) Xphos (10 mol%) CuI (7.5 mol%) t-BuOLi (3.5 equiv.)

+ R

Ar R Ar⬘

toluene, 90°C 21 examples 21%–84% yields

Scheme 53 Pd-catalyzed three-component coupling of N-tosylhydrazone, terminal alkyne with aryl halide.

NNHTs

Ar •

+ Ar⬘–I

+

Ph

Pd2(dba)3 (2.5 mol%) P(2-furyl)3 (15 mol%) t-BuOLi (1.3 equiv.)

Ph

Ar⬘

Ar

Ph

MeCN, Et3N, 80°C

Ph 7 examples; 48%–81% yields

Mechanism Ar

Ar–X

Ar⬘ Pd(0)

R CO2Me R⬘ Ar

Ar⬘ Pd(II)X CO2Me

R R⬘

Ar–Pd(II)X R

76

• R⬘ Ar Ar

R R R⬘

Pd(II)X R⬘

Ar⬘ 75

CO2Me

N2 Ar⬘

Pd(II)X 74

CO2Me

Scheme 54 Pd-catalyzed multicomponent synthesis of 1,3-dienes from aryl iodides, allenes with diazo species.

which is a concise method for synthesizing highly functionalized 1,3dienes.69 Mechanistically, the reaction pathway is assumed to proceed via allene carbopalladation to form 74, with sequential allyl group migratory insertion of Pd-carbene 75 as the key step, resulting in the formation of 76 with an E configuration in the formed double bond (Scheme 54). Moreover, the Pd-catalyzed carbonylation coupling sequence of aryl iodides with diazo compounds was also developed by Wang group.

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The reaction involves acyl group migratory insertion to the carbenic carbon atom (Scheme 55).70a This multicomponent strategy provides a novel route to access α-aryl carbonyl compounds. More importantly, it demonstrates the possibility of the combination of Pd-carbene transformation and catalytic carbonylation. Such transformation involves migratory insertion of an acyl group to Pd-carbene center. In 2011, Wang group reported a Pd(0)-catalyzed carbonylation of N-tosylhydrazone salts or α-diazocarbonyl compounds under atmospheric pressure of CO (Scheme 56).70b Pd-catalyzed carbonylative coupling of in situ-generated diazo species from N-tosylhydrazone salts with various nucleophiles allows the efficient synthesis of esters and amides with high

Ar–I +

Ar⬘

cat. Pd, CO balloon Et3N (2 equiv.) t-BuOLi (2.4 equiv.)

NNHTs R +

Et3SiH

[Pd] Base Ar–Pdl

O

O Ar⬘ +

Ar DCE, 70°C 8 examples R 54%–94% total yields ratio 98:2 to 84:16 dr

R3

Scheme 56 Pd-catalyzed carbonylation of N-tosylhydrazones under atmospheric pressure.

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Pd(PPh3)4 (2 mol%) Cs2CO3 (2 equiv.)

NNHTs R1

R2

+

CNR3 MeCN/H2O = 20:1 60°C

R2 NHR3

R1

33 examples 43%–95% yields

O

N2 1

R R3N

R1

R2

PdLn

R2

R1

R2 PdLn

PdLn R3N

NR3 77

Scheme 57 Pd-catalyzed coupling of N-tosylhydrazones with isocyanides.

yields. Moreover, Staudinger [2+2] reactions are also successfully implemented through the trapping of ketene intermediate with imines, providing aryl or alkenyl substituted β-lactams with high yields and good diastereoselectivity. In this case, ketene-mediated transformation demonstrates great importance in synthesizing functional molecules under mild conditions. In addition to the catalytic carbonylation of N-tosylhydrazones, Pd-catalyzed homologation of in situ-generated diazo species with isocyanides, involving the generation of ketenimine as the key intermediate, has been explored by Cai and coworkers (Scheme 57).71 In 2011, they performed the Pd(0)-catalyzed coupling reaction of N-tosylhydrazones with isocyanides in the presence of a base. The mechanistic hypothesis involves the generation of Pd-carbene species, followed by migratory insertion to form ketenimine intermediate 77, which undergoes sequential nucleophilic addition of water to afford the desired amides. Pd-catalyzed norbornene-mediated coupling reaction (Catellani reaction) of N-tosylhydrazones has also been studied within this field.72 Liang and coworker successfully developed a series of Pd-catalyzed multicomponent norbornene-mediated cascade reactions involving ortho-C–H activation/migratory insertion of aryl group to Pd-carbene center.72a–c Under similar reaction condition, this strategy is applied for the synthesis of polycyclic vinylarenes as well as ortho-aminated analogues (Scheme 58). In addition, these cascade transformations have, respectively, combined intra- or intermolecular alkylation/amination with Pd-carbene migratory insertion strategy. Alternatively, Wang group carried out the Pd-catalyzed three-component reaction of N-tosylhydrazones, norbornene, and aryl halides to obtain arylated double-functionalized norbornenes, proceeding through intermolecular Heck reaction/alkyl group migratory insertion sequence.72d

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Ar Y NNHTs

R + X O

R

Me

Ar

28 examples 42%–93% yields

n

O

n Ar2

I R1

+

NNHTs Pd(OAc)2, PPh3 R1 norbornene, H2O + Cl Me Ar2 Cs2CO3, dioxane R2 80–100°C

Ar1

R2

Ar1 65 examples 46%–96% yields

Ar

I

OBz NNHTs N + + R3 R4 Me Ar

R1

1

R

R2

R3 N

R4 31 examples 16%–88% yields

R2

Scheme 58 Pd-catalyzed norbornene-mediated cascade reactions involving C–H bond activation. Pd(PPh3)4 (5 mol%) Cs2CO3 (2.5 equiv.)

NNHTs Ar–I

+

Pd(0)

Ar⬘

+

R

R Ar⬘

Ar

THF, 60°C, 10 h 23 examples 24%–90% yields

(3 equiv.)

R = H, Me

Base Ar–PdI −Pd(0) N2 Ar IPd

Ar⬘

IPd

Ar

Ar

R

Ar Ar⬘

IPd Ar⬘

R

78

R

Ar⬘ PdI

79

R

Scheme 59 Pd-catalyzed ring opening of norbornene to access methylenecyclopentanes.

In 2015, Liang group developed the Pd-catalyzed three-component domino cascade of aryl iodides, N-tosylhydrazones, and norbornenes (Scheme 59).72e Proceeding through the ring-opening sequence of norbornene, methylenecyclopentane derivatives are obtained with high yields and excellent functional group tolerance under mild reaction conditions. Mechanistically, the reaction pathway is assumed to involve oxidative addition/Heck-type carbopalladium/Pd-carbene 78 migratory insertion to form 79/β-C elimination/β-H elimination sequence to give the desired cyclopentane derivatives.

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R Ar

NNHTs X

N

+ Ar⬘I + X

X = Cl, Br

N R

NHTs X

Ar 24 examples 42%–89% yields

Cul (10 mol%) Ar Cs2CO3 (2.0 equiv.)

NNHTs X +

X⬘

N

Base R

NTs X

−X

N

N

Ts

R 80 , azoalkene

Scheme 60 Pd-catalyzed three-component tosylhydrazones, indoles with aryl iodides.

X

X⬘ N R

PhMe/H2O = 20:1 130°C

N R

R N

Ar⬘

200 mg 4 Å MS PhMe/i-PrOH = 20:1 100°C

X = Cl, Br

Ar

Pd(OAc)2 (10 mol%) dppf (10 mol%) Cs2CO3 (3.4 equiv.)

N

NuH

N R

cascade

5 examples 62%–73% yields

N2

Ts −Ts Nu

reaction

R

of

Nu

α-halo-N-

Furthermore, in 2016 Wang group disclosed a Pd-catalyzed threecomponent cascade reaction of α-halo-N-tosylhydrazones, indoles, with aryl iodides, affording 3-indolyl di- or trisubstituted alkenes with moderate to high yields and good functional group tolerance (Scheme 60).73 This intriguing strategy has been designed by employing indoles as the nucleophiles to react with the azoalkene intermediate 80 generated in situ from the corresponding α-halo-N-tosylhydrazone in the presence of base, which is further subjected to Pd-catalyzed carbene-mediated C–C bond forming reactions with aryl iodides. Furthermore, they also reported the 1,2-H shift procedure of the diazo intermediate by using copper(I) iodide as the catalyst.

3. COPPER-CATALYZED COUPLING REACTION OF N-TOSYLHYDRAZONES 3.1 Cu-Catalyzed Coupling of N-Tosylhydrazones With Alkynes In addition to palladium catalysts, copper complexes have also demonstrated high activity in catalyzing cross-coupling reactions involving migratory insertion. However, the coupling partners as well as the type of transformations are different. In 2011, Wang group developed a novel Cu(I)-catalyzed cross-coupling reaction of terminal alkynes with N-tosylhydrazones as diazo analogues by using rac-bis(oxazoline) 81 as the ligand.74 Highly functionalized trisubstituted allenes were obtained in high yields with good

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R1

R2

+

R3

O

O

Cu(MeCN)4PF6 (5 mol%) 81 (6 mol%) Cs2CO3 (3 equiv.)

NNHTs

R1

N •

R2

dioxane, 90°C

N (±)

R3

81

24 examples 21%–87% yields Mechanism R3

Migratory Cu(I)L 1

R

insertion

R3

R3

2

R 82

Cu(I)L H+ 2

1

R

83

R

R

N2 R1

R2

Base R2

Base

1

R 3

R

• R2

Cu(I)L Cu(I)L

NNHTs R1

H 1

R3

R2 HCO3−

Scheme 61 Cu(I)-catalyzed N-tosylhydrazones.

coupling

R3 + CO32−

reaction

of

terminal

alkynes

with

functional group tolerance (Scheme 61). Mechanistic rationale involves the alkynyl migratory insertion to carbenic center of Cu-carbene intermediate 82 to generate alkyl copper complex 83, followed by the regioselective protonation on the triple bond carbon atom of 83. Since then, this catalytic system for the synthesis of a variety of allenes has been improved and simplified, which employed inexpensive copper(I) iodide and ligands. Functionalized substituted allenes (including 1,3-disubstituted),75a and terminal allenes,75b can be efficiently accessed by Cu-catalyzed crosscoupling reaction of terminal alkynes with divergent N-tosylhydrazones (Scheme 62). Particularly, ethyne has been explored as a coupling partner in Cu-mediated carbene transformations with N-tosylhydrazones or α-diazoacetates.75b These reactions represent a set of concise methods for preparing substituted allenes, which are important structure units that find applications in various areas. On the other hand, Wang group developed a novel and ligand-free C(sp)–C(sp3) bond formation strategy via Cu(I)-catalyzed cross-coupling reaction of N-tosylhydrazones with trialkylsilylethynes.76a Owing to the presence of trialkylsilyl substituents, functionalized alkynes were obtained

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CuI (20 mol%) t-BuOLi (3.5 equiv.)

NNHTs R

1

+

R2

H

R2 26 examples 40%–94% yields

•

dioxane, 90–110°C, 1 h

R1

NNHTs or

H +

H

CuI (1 equiv.) base or ligand

R

Ar

DMF, 60–90°C

N2 R

CO2R⬘

R or • R⬘O2C R 7 examples 28 examples up to 93% yield up to 85% yield Ar

•

Scheme 62 Cu-mediated synthesis of substituted allenes from diazo compounds with terminal alkynes.

CuI (20 mol%) t-BuOLi

NNHTs + R⬘ R

Si

dioxane, 90–110°C

R Si R⬘

41 examples 36%–93% yields

Mechanism Si

Migratory Cu(I)L R

insertion

Si

R⬘

Cu(I)L R

NNHTs Base R

R⬘

N2 R

R⬘ 84 H

R⬘ Si

R Cu(I)L

t-BuOH

Si Cu(I)L

R⬘

Si + t-BuOLi

Scheme 63 Cu(I)-catalyzed cross-coupling reaction of N-tosylhydrazones with trialkylsilylethynes.

in high yields under mild reaction conditions. Mechanistically, the protonation step of alkynyl migrated copper(I) species 84 is crucial for the selectivity of the products (Scheme 63). When changing tert-butyl-substituted alkyne as the coupling partner, this transformation affords allene as the product. Theoretical study indicates that the Cu–C interaction between the tert-butyl-substituted C atom with the copper center, as well as the back-donation from π orbital of the triple bond to σ* antibonding orbital of Si–C, determines the chemoselectivity observed in these studies.76b

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CuI (20 mol%) NaH (6 equiv.) TBAB (20 mol%)

NNHTs R1

R2

+

R3 +

X

dioxane, 90°C,1 h

Base

R1 • R2

34 examples 28%–84% yields R3

–Cu(I)

X

1

N2 R1

Cu R2

R

R3 R2

R1 Cu

R3 R2

Cu

R3 85

TBAB = tetrabutylammonium bromide

Scheme 64 Cu-catalyzed three-component coupling reaction of N-tosylhydrazones, terminal alkynes with allyl halides.

Furthermore, by utilizing the high reactivity of allene moiety, Cu-catalyzed cascade transformations of N-tosylhydrazones with terminal alkynes have been explored for synthesizing a variety of functional molecules. Wang group reported the efficient synthesis of tri- and tetrasubstituted allyl allenes through Cu(I)-catalyzed three-component coupling of N-tosylhydrazones, terminal alkynes with allyl halides (Scheme 64).77 Beyond protonation process, the propargylic Cu(I) species 85, which is generated from Cu(I) carbene migratory insertion, undergoes nucleophilic substitution with allylic iodides. This strategy demonstrates the possibility of incorporating other electrophiles into Cu-catalyzed coupling partners. Phenanthrenes derivatives demonstrate great applications in medicinal chemistry and material research. Wang group has explored the Cu-catalyzed cross-coupling of terminal alkynes with N-tosylhydrazones derived from o-formyl biphenyls for the construction of phenanthrene framework,78a as well as the coupling reaction of 2-alkynyl biphenyls with tosylhydrazones derived from aromatic aldehydes.78b Mechanistically, the reaction is proposed to proceed through Cu-catalyzed coupling/allenylation/6π-electron cyclization of 86/aromatization sequence (Scheme 65). These catalytic transformations provide expeditious synthetic methods for phenanthrenes from readily available starting materials. Moreover, Cu-catalyzed cascade reaction of terminal alkynes with diazo component has been utilized for the construction of a series of heterocyclic scaffolds (Scheme 66). Wang and Zhou reported the efficient synthesis of benzofurans and indoles through Cu(I)-catalyzed ligand-free cross-coupling reaction of terminal alkynes with salicyl N-tosylhydrazones,79a or coupling

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H NNHTs + Ar R′ 18 examples 41%–73% yields

R

cat. CuBr2

Ar

R NNHTs + Ar H R′ 29 examples 48%–80% yields

R

Ar

•

cat. CuI

R′

R′

R

86

Scheme 65 Cu-catalyzed cross-coupling of alkynes with N-tosylhydrazones for synthesizing phenanthrenes.

NNHTs

R

CuBr (10 mol%) Cs2CO3 (3 equiv.)

XH X = O, NH, NAc +

MeCN, 100°C

Cu R⬘

R⬘ R X

XH

20 examples 38%–91% yields

R⬘

+ XH X = O, NTs, NAc

NNHTs CuBr (10 mol%) t-BuOLi (3 equiv.) R1 R2 toluene, 80°C

R1 X

R2

24 examples 62%–95% yields

Scheme 66 Synthesis of benzofurans and indoles from alkynes with N-tosylhydrazones.

of N-tosylhydrazones with o-hydroxy or o-amino phenylacetylenes.79b These two catalytic coupling/allenylation/cyclization strategies lead to the facile and economical preparation of heterocycles by employing easily accessible substrates. Recently, Cu(I)-catalyzed cross-coupling cascade of N-tosylhydrazones with 3-butyn-1-ol has been reported by Wang group.80 This methodology constitutes a new approach toward the synthesis of 2-(diarylmethylene) tetrahydrofurans with moderate to good yields. The proposed mechanism involves the intramolecular cyclization of hydroxy-tethered allenes, which are generated via migratory insertion of alkynyl Cu-carbene species. In 2015, Wang group reported a Cu-catalyzed three-component coupling reaction of N-tosylhydrazones, alkynes, and azides, which constitutes a convenient synthetic route to 1,4,5-trisubstituted 1,2,3-triazoles in an

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Di Qiu et al.

CuI (20 mol%) t-BuOLi (2 equiv.)

NNHTs +

R⬘

N3

N N

R⬘

dioxane, 65°C, 4 h

N

Ar

R

41 examples 37%–97% yields

R

Mechanism TM R

Cu(I)

+ t-BuOLi

t-BuOH t-BuOH N R⬘

N

N

Ar

t-BuOLi +

R [Cu]

89

N N

R⬘

N

Ar

NNHTs

Ar

N2

R

R⬘

N

R

[Cu] H

N3

N N

R⬘ Ar

[Cu]

88

[Cu]

87

R

Scheme 67 Cu-catalyzed three-component reaction of N-tosylhydrazones, alkynes, and azides.

efficient and regioselective manner (Scheme 67).81 Mechanistically, this reaction proceeds through the generation of copper(I) triazolide intermediate 87 initially via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Subsequently, migratory insertion of the triazole group from Cu(I)-carbene 88 occurs to afford alkyl copper complex 89. Finally, sequential protonation of 89 by HO-t-Bu results in the formation of the product along with regeneration of Cu(I) catalyst. This efficient catalytic strategy shows the combination of click chemistry with a metal-carbene migratory insertion process. Moreover, the synthesis of fluorinated 1,3-enynes, which serve as important building blocks in organic synthesis and medicinal research, attracts great attention. Wang group demonstrated the feasibility of the Cu(I)-catalyzed cross-coupling reaction of terminal alkynes with N-tosylhydrazones derived from trifluoromethyl ketones, furnishing functionalized 1,1-difluoro-1,3-enyne derivatives with high efficiency.82 This convenient and facile protocol has combined the Cu-carbene 90 migratory insertion with β-fluoride elimination through a cascade Cu-catalytic cycle (Scheme 68).

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CuI (20 mol%) t-BuOLi (2 equiv.) LiOTf (1 equiv.) TBAC (20 mol%)

NNHTs R1

CF3

+

R

CF2 R1

2

R2

dioxane, 60°C, 2 h

32 examples 25%–88% yields

Cu(I) Cu

F F

R2 Migratory

R1

CF3 90

insertion

Cu

F

Li

β-F elimination –LiF

R1 R2

Scheme 68 Cu-catalyzed synthesis of 1,1-difluoro-1,3-enynes from terminal alkynes with trifluoromethyl ketone N-tosylhydrazones.

3.2 Cu-Catalyzed Coupling of N-Tosylhydrazones Involving C–H Activation Except for terminal alkynes, heterocycles as well as substituted aromatics have also been employed as the nucleophilic coupling partners, proceeding through a C–H bond activation process. In 2011, Wang group reported Cu-catalyzed cross-coupling of N-tosylhydrazones with 1,3-azoles, directly affording 2-benzylated or 2-allylation products.83 Compared with other methods, this strategy provides an efficient avenue for the synthesis of 2-alkylated heterocycles through C–H bond functionalization. For the reaction mechanism, Cu-carbene 91 migratory insertion seems more reasonable rather than the direct carbene C–H insertion (Scheme 69). In 2013, this Cu-catalyzed reaction strategy was expanded to 1,3,4oxadiazoles as the nucleophilic coupling partners, providing an efficient and concise benzylation through direct C–H bond functionalization.84 A series of 2-substituted oxadiazoles could be obtained in high yields (17 examples, 80%–89% yields). Migration of the heteroaryl group to the Cu-carbene center is proposed as the key step. In 2013, Wang group further demonstrated the C–H alkylation of pyridine derivatives through Cu-catalyzed cross-coupling of N-tosylhydrazones with N-iminopyridinium ylides (Scheme 70).85 Using inexpensive CuI catalyst under ligand-free conditions, various ortho-alkylated pyridines were obtained in good yields. The reaction is assumed to proceed via a copper carbene 92 migratory insertion of the pyridyl group, a proposal supported by DFT calculations.

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CuI (10–20 mol%) NNHTs t-BuOLi (2.5 –3.5 equiv.)

N H +

R1

X

R2

toluene or dioxane 110–120°C

R1

Cu

X

R2

H

N2

N

R1

38 examples 30%–86% yields

X = O, S [Cu] Base

N

Migratory insertion

N

R2

Cu X

X

91

R1

R2

N

R1 Cu

X

R2

Scheme 69 Cu-catalyzed cross-coupling of N-tosylhydrazones with 1,3-azoles.

R

R

H

N

+

NNHTs

CuI (20 mol%) t-BuOLi (3.5 equiv.)

R2

toluene, 90°C

1

R

NBz Base

[Cu] Base

N2

R R1 N N

Cu O Ph

R1 N 21 examples 2 NBz R 56%–91% yields H

R

R

R1

R2 N N

Cu O Ph

R1

Migratory R2 insertion

92

N N

R2

Cu O

Ph

Scheme 70 Cu-catalyzed coupling of N-iminopyridinium ylides with N-tosylhydrazones.

Transition-metal-catalyzed C–H alkylation of polyfluoroarenes still remains a challenging problem. Toward this end, Wang group carried out the Cu-catalyzed alkylation of electron-deficient polyfluoroarenes through cross-coupling with N-tosylhydrazones or diazo compounds (Scheme 71).86 This process represents an efficient construction of a C(sp2)–C(sp3) bond of polyfluoroarenes via direct C–H bond alkylation. Mechanistically, migratory insertion of polyfluoroaryl copper carbene species is the key step in the catalytic cycle. In 2014, the Cu(I)-catalyzed cross-coupling of 1,3-azoles with N-tosylhydrazones derived from ferrocenyl ketones was reported, affording secondary alkylated products.87 This method may be used for the synthesis of substituted ferrocenyl-based ligands, as well as 1,10 -disubstituted ferrocenyl bidentate derivatives (Scheme 72).

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CuI (20 mol%) t-BuOLi (3 equiv.) phenanthroline (20 mol%)

NNHTs ArF H +

R⬘

R

dioxane/MeCN = 1:1, 90°C

R

R⬘

cat.CuI or Cu(MeCN)4PF6 t-BuOLi (2–3 equiv.)

N2 ArF H +

R ArF

R⬘

dioxane, 90°C

R ArF

33 examples 37%–88% yields

8 examples 37%–84% yields

R⬘

Scheme 71 Cu(I)-catalyzed alkylation of polyfluoroarenes via C–H functionalization. NNHTs R′

N H +

R X

Fe

N

CuBr (20 mol%) R t-BuOLi (2.5 equiv.)

X Fe

toluene, 120°C 13 examples 48%–89% yields

X = O, S NNHTs R′

N H +

R X X = O, S

R′

Fe

CuBr (50 mol%) t-BuOLi (6 equiv.)

N R

X Fe

toluene, 110°C R′ NNHTs

R′

N R

X

R′ 13 examples 18%–75% yields

Scheme 72 Cu-catalyzed direct alkylation of 1,3-azoles with N-tosylhydrazones bearing ferrocenyl group.

Recently, the Cu(I)-catalyzed regioselective C–H functionalization of azine N-oxides with N-tosylhydrazones was achieved under microwave conditions, giving rise to ortho-alkylated heterocyclic compounds (Scheme 73).88 With readily available substrates and inexpensive copper(I) iodide, a series of 2-alkyl-substituted pyridine, quinoline, and isoquinoline derivatives are easily obtained.

3.3 Cu-Catalyzed Oxidative Coupling Reaction of N-Tosylhydrazones In 2016, Jiang and Wu reported a copper-mediated oxidative coupling reaction of β-ketoesters by using N-tosylhydrazones as two-carbon synthons, affording 2,3,5-trisubstituted furans in moderate to good yields and excellent regioselectivity.89 The proposed mechanism is illustrated in Scheme 74,

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X +

CuI (10 mol%) t-BuOLi (3.5 equiv.)

R′

microwave, toluene, 100°C, 1 h

R

H

N

NNHTs

X

R/R′ = H, alkyl, aryl

O

R

N O

R′

32 examples 62%–93% yields

Scheme 73 Cu(I)-catalyzed coupling of azine N-oxides with N-tosylhydrazones.

Ar

NNHTs +

O

CuCl (1 equiv.) triallylamine (2 equiv.) Zn(OTf)2 (1 equiv.)

O

R1

O R2

R1 OR2

O Ar

O 32 examples 43%–90% yields

DMF/toluene = 3:1 MS, O2, 120°C, 10 h

O2

O R1

Cu

O OR 2

O

Cu0

I

R

Zn(OTf)2

O

1

OR2 95

NNHTs CuI 1/2O CuIIOH 2 Cu(I) Ar Ar base Ar 94 93

II

Cu Ar

Zn(OTf)2 R1

O

96

Path a

TM

Cu

−Cu(0) Ar

II O

R1

–Zn(II)

CO2R2

II

Cu Ar

–Zn(II) CO2R2 O2

R1

CuII O Ar

Path b

CO2R2 O2

TM

Zn(OTf)2 R1 O CO2R2

Scheme 74 Cu/Zn-mediated oxidative coupling of N-tosylhydrazones and β-ketoesters.

which involves the oxidation of Cu-carbene 93 under aerobic conditions to give the vinyl copper(II) complex 94. Then, accelerated by the Lewis acidic nature of the Zn(II) complex, the regioselective radical addition of the dicarbonyl free radical 95 with 94 occurs to generate the radical intermediate 96. Finally, the products are formed through divergent oxidative sequence. This oxidative cyclization strategy represents a unique type of N-tosylhydrazone transformations. Moreover, Jiang group reported the Cu-catalyzed oxidative transformations of ketone-derived N-tosylhydrazones under aerobic conditions, including Glaser homo-coupling, the cross-coupling reaction with an array of halides and terminal alkynes (Scheme 75).90 This protocol affords functionalized internal alkynes and diynes, featured by the use of inexpensive catalytic system,

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NNHTs Me

Ar or 1

R

CuCl (10 mol%) O2 (1 atm.) DABCO (1 equiv.)

NNHTs R2

Ar

Ar

Mechanism NNHTs

18 examples 43%–96% yields or

DMSO, 100°C

R1 R2

R2

R2X

R1

Me

+

or

1

R

Cu(I)

97 R2

R1 Base, O2 –HX, H2O or Cu(II)–OH

14 examples 34%–88% yields

NNHTs

CuX

Base

CuCl (10 mol%) R1 R2 O2 (1 atm.) 18 examples DABCO (1 equiv.) 65%–85% yields or DMSO, 100°C R2

R1

R–X R1

H 98 or

Alkyne

R2

5 examples 55%–75% yields

R1

Cu 100 O2

1

1

R

R2

R

Glaser

(R2 = H)

99

2 (R = H)

2

R

Scheme 75 Cu-catalyzed aerobic oxidative reactions of N-tosylhydrazones to afford various alkynes.

wide substrate scope, and high regioselectivity. Reaction mechanism involves the oxidation and dehydrogenation of in situ-generated Cu-carbene species 97 as the key step, affording the internal (99) or terminal alkyne 98 intermediates. Subsequently, deprotonation of the terminal alkyne 98 assisted by copper coordination gives rise to an alkyne-coordinated copper species 100, which allows the sequential Glaser reaction as well as cross-coupling processes. This method enables the utilization of ketone-derived hydrazones as effective terminal alkyne synthons, providing a new type of alkyne synthetic strategies. In 2016, a Cu-catalyzed oxidative cross-coupling reaction of two different N-tosylhydrazones with elemental sulfur was reported.91 Under aerobic conditions, a series of unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles are obtained in moderate to good yields (Scheme 76). A tentative mechanism proposed the involvement of carbene species and elemental sulfur to afford benzothialdehyde intermediate 101. Thus, nucleophilic attack of N-tosylhydrazone anion with 101 provides the intermediate 102, followed by sequential intramolecular nucleophilic attack to give 103. Final oxidative aromatization by air results in the generation of the desired heterocyclic scaffold.

4. RHODIUM-CATALYZED COUPLING REACTION OF N-TOSYLHYDRAZONES In 2016, Wang group reported a Rh(I)-catalyzed chemoselective crosscoupling reaction of trifluoromethylketone-derived N-tosylhydrazones with

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N N NNHTs +

Ar

R

NNHTs +

S8

Ar

CuI (20 mol%) Cs2CO3 (2 equiv.) Ar

DMAC, 100°C air

R = alkyl (1.2 equiv.)

Ar S < 5% yields

N N R

S

N N

19 examples 41%–62% yields

NNTs

Ar

S

S8 Ar

101

R

S R

Ar

N Ts 102

S

R

< 5% yields

[O] N2

R

R S

N Ar

N 103

N

Scheme 76 Cu-catalyzed multicomponent coupling reaction of two different N-tosylhydrazones with elemental sulfur.

arylboronates, affording 1,1-difluoro-2,2-diarylalkenes with moderate to good yields or 2,2-diaryltrifluoroethanes (Scheme 77).92 Proposed mechanism involves the generation of aryl rhodium species at first through transmetalation with arylboronic acid esters in the presence of a base. This aryl rhodium species then reacts with the in situ-generated diazo compounds to afford the Rh(I)-carbene intermediate, followed by migratory insertion to generate a CF3-substituted alkyl rhodium(I) intermediate. This intermediate can either experience β-fluoride elimination to obtain desired 1,1-difluoroolefin product, or experience protonation of carbon-rhodium bond to afford CF3substituted alkane as a by-product. This transformation illustrates the practical application of trifluoromethylketone-derived N-tosylhydrazones in the concise synthesis of fluorine-containing functional molecules. Apart from the transmetalation process, selective C–C bond cleavage was implemented to efficiently generate carbon-rhodium species, which experienced sequential migratory insertion to perform carbene species functionalization. In 2014, Murakami group reported the Rh-catalyzed asymmetric carbene insertion to C(sp3)–C(sp3) bond of cyclobutanols with N-tosylhydrazones as diazo analogues (Scheme 78).93 With the employment of chiral phosphine ligands, cyclopentanol derivatives are furnished by ring expansion of cyclobutanols with moderate to good yields (up to 77% yield) and excellent enantioselectivities (up to 99% ee). In the reaction mechanism, initially the rhodium alkoxide is formed through the ligand exchange with the substrate. Through β-carbon elimination the four-membered ring rhodium alkoxide is cleaved, affording a γ-keto alkylrhodium intermediate. Then, the reaction of in situ-generated diazo species with alkylrhodium

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CF2

O B O

NNHTs CF3

+

[Rh(COD)Cl]2 (3 mol%) t-BuOLi (2.5 equiv.) Y

MeOH, 70°C

X

Y X 12 examples 34%–70% yields

X = H, OMe Mechanism

Rh(I)Cl diazo b-F elimination species

CF2

Rh(I)F

Ar

Ph

b-F elimination

Rh(I) CF3 Ph

+ t-BuOLi O

(RO)2BOt-Bu

transmetalation

CF3

t-BuOH

Ar

O Ph–B

Ph

Ph–Rh(I)

Ar

NNHTs

by-product Ar Dediazoniation Migratory

t-BuOLi

–N2

N2

insertion Rh–Ar Ph

CF3

Ar

CF3

CF3

Scheme 77 Rh(I)-catalyzed cross-coupling N-tosylhydrazones with arylboronates.

of

trifluoromethylketone-derived

species occurs, giving rise to (alkyl)(carbene)rhodium complex. Migratory insertion of ring-opened alkyl group onto prochiral carbene carbon is proposed as the key step. This Rh-catalyzed enantioselective carbene ringexpansion reaction has created two new chiral centers through the facile selective C–C bond cleavage. Differing from the previous Pd- and Cu-catalyzed N-tosylhydrazones transformations, a typical feature of Rh-catalyzed cross-coupling reaction involving migratory insertion is the combination with the directing-groupassisted C–H activation strategy. Thus, these transformations demonstrate complementary strategy for classic sp2 C–H bond insertion pathway. In contrast to the Rh-catalytic transformations, which are also typically terminated by protonation in the cyclic cycle, the copper-catalyzed reactions also show diverse reaction type. In 2014, Wang group disclosed an efficient synthetic method for ortho-alkenyl phenols through Rh(III)-catalyzed C–H

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R

OH +

Et

Et

[Rh(cod)OH]2 (5 mol%) L (11 mol%) NNHTs t-BuONa (2.5 equiv.) Ar H toluene, 50°C, 24–48 h

R

OH

R

H

Et

H

+

Ar

Et

OH Ar

Et Et 11 examples up to 77% yield up to 99% ee

O O

PPh2 PPh2

O

Ph2P

or

O (R)-SegPhos Mechanism

R

P(t-Bu)2 Fe

H

(R,S)-PPF-P(t-Bu)2 OH

R

OH

–H2O R

ORh H

Et

Et

TM

R

Ar

Et

Et

ORh

+ Rh–OH Et

Et

Et

Et

R

Et Et

R

Et Et

O Rh

R

O Rh H Ar

Et Et

O Rh

t-BuONa NNHTs

N2 Ar

N2

Ar

H

Ar

H

H

Scheme 78 Rh-catalyzed enantioselective carbenoid insertion of cyclobutanols with N-tosylhydrazones.

activation of N-phenoxyacetamides with N-tosylhydrazones or α-diazoesters.94a By employing oxidizing N-oxyacetamide as the directing group, this transformation allows the direct preparation of ortho-alkenyl phenols with high yields and excellent regio- and stereoselectivity. Besides, these reactions proceed under mild conditions and do not need any external oxidants. Mechanistic hypothesis involves the sequence of Rh-carbene 104 migratory insertion to form 105, β-H elimination, reductive elimination, oxidative addition to regenerate active Rh(III) species, instead of direct protonation process (Scheme 79). This methodology has integrated with the

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O R

NHAc

[Cp*RhCl2]2 (2.5 mol%) t-BuOLi (1 equiv.) NaOAc (1 equiv.)

NNHTs +

OH

Ar

R

R′

Ar

R′

25 examples 14%–84% yields

toluene, 90°C, 16 h O

Mechanism TM

NHAc

H

Cp*Rh(OAc)2

C–H activation O

Cp* NHAc Rh (III)

O

[Cp*RhCl2]2

NAc Rh Cp*

Ph Reductive elimination/ oxidative addition

–N2

N2 O

O

N Ac

Rh(III)HCp*

Migratory Ph b-H elimination

O

NAc Rh

Ph

Rh Cp*

Base

104

NNHTs

Ph

insertion

Ph NAc

Ph

Cp*

105

Scheme 79 Rh-catalyzed C–H bond activation of N-phenoxyacetamides with N-tosylhydrazones or α-diazoesters.

C–H bond activation with transition-metal-catalyzed coupling reaction of N-tosylhydrazones. In 2016, Liao and Li implemented a DFT study to examine the mechanism of the above rhodium(III)-catalyzed alkenylation of N-phenoxyacetamide with N-tosylhydrazones.94b The results indicate that the most favorable pathway for the Rh-catalyzed coupling of N-tosylhydrazones involves sequential N–H deprotonation, C–H activation through concerted-metalationdeprotonation process, nitrogen extrusion, Rh(III)-carbene migratory insertion of aryl group, O–N bond cleavage to give a Rh(V) nitrene species, tautomerization, hydrogen migration from the β-C atom to the N atom of the internal oxidant, and acetic-acid-assisted protonation steps (Scheme 80). Alternatively, Rh(I) complexes also emerged as efficient catalysis for C–C double bond formation through coupling reaction of (quinolin8-yl)methanone with N-tosylhydrazones, representing a rare case of C(sp3)–H activation case in this research area.95 In the presence of a base

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O

N

Ac

O

RhIII Cp*

NAc V Rh Cp*

Ph

Ph

Cp* RhIII O NHAc

Cp* RhIII O NAc

Ph

Scheme 80 Probable intermediates for rhodium(III)-catalyzed alkenylation of N-phenoxyacetamide with N-tosylhydrazones.

O

H N

Rh(PPh3)3Cl (10 mol%) Ag2O (0.5 equiv.) NNHTs Cs2CO3 (2 equiv.) + Ar H xylene, 130°C, 48 h

Ar

O N

13 examples 63%–78% yields

(2 equiv.) Ar O O

Rh L

Ar

RhL N 106

Scheme 81 Rh(I)-catalyzed C–H bond activation of (quinolin-8-yl)methanone with N-tosylhydrazones.

and Ag2O, 3-aryl-1-(quinolin-8-yl)prop-2-en-1-one derivatives are obtained in good yields (Scheme 81). A plausible mechanism involves directing-group-assisted C–H metalation at first, followed by migratory insertion as the key step to generate seven-membered rhodacycle 106. This key intermediate experiences sequential β-H elimination to release desired alkenes, accompanying with the regeneration of Rh species. This methodology provides an alternative route for the direct arylvinylation of (quinolin8-yl)methanone by using N-tosylhydrazones.

5. NICKEL- AND COBALT-CATALYZED COUPLING REACTIONS OF N-TOSYLHYDRAZONES In 2012, Miura and coworkers disclosed the direct 2-alkylation process of azoles with N-tosylhydrazones containing unactivated alkyl substituents by employing nickel(II) and cobalt(II) catalysts (Scheme 82).96 In the presence of a base, nickel complexes have emerged as efficient

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+

R

O

2

R

3

R

+ X

2

R

N

O R2 15 examples 34%–86% yields

CoBr2/phen (10 mol%) t-BuOLi (3 equiv.)

3

R

R3

R1

dioxane,100°C, 8 h

NNHTs

N

R1

NiBr2/phen (10 mol%) t-BuOLi (3 equiv.)

NNHTs

N 1

N

R3

X

R2

R1

dioxane, 120°C, 7 h

14 examples 31%–81% yields

X = O, S Mechanism ArHet H

[Ni] base

ArHet Ni –N2

R ArHet Ni R′

R TsHNN R′ R = R′= alkyl

Base –Ts

R N2

R′ ArHet

Ni R R′

H or ArHet H

ArHet

H R R′

Scheme 82 Ni- and Co-catalyzed alkylation of azoles with N-tosylhydrazones.

catalysts for the introduction of secondary alkyl groups into benzoxazole scaffolds. Moreover, straightforward alkylation of 5-aryloxazoles and benzothiazole can be achieved catalyzed by cobalt(II) bromide. The plausible mechanism involves the base-mediated C–H bond metalation process initially, followed by metal-carbene migratory insertion as the key steps. Finally, protonation or ligand exchange with the C–H bond of the starting heteroarene gives rise to the desired heterocycles bearing secondary alkyl side chain. This methodology enables a concise access to azole cores containing unactivated secondary alkyl side chains, which are generally difficult to achieve by using the precedent C–H alkylation strategy. In 2013, Zhang and de Bruin reported a radical-type Co(II)Por (Por ¼ porphyrin)-catalyzed carbene carbonylation with sequential ketene-trapping process by diverse nucleophiles and imines, affording esters, amides, or good diastereoselective trans-β-lactams with high yields in one-pot cascade procedure.97 Consequently, the metalloradical [Co(II) TPP] complex has emerged as an efficient catalyst for the homologation of both N-tosylhydrazone sodium salts and α-diazocarbonyl compounds (Scheme 83).

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N

NNTs Na +

H

R

R′

Ar

DCE, 50°C, 24 h

NNTs Na + R

R′

CoII(Por) (2 mol%) CO (20 bar)

NuH

CoII(TPP) (2 mol%) K3PO4 (3 equiv.) CO (10 bar) toluene, 50°C, 18 h

O

R′ N Ar

R

11 examples 52%–77% yields trans:cis = 85:15 to > 95:5

R′ Nu

R O

15 examples 56%–82% yields

Scheme 83 Co(II)Por-catalyzed carbene carbonylation of N-tosylhydrazone sodium salt with nucleophiles for the synthesis of esters, amides, and β-lactams.

6. CATALYTIC INTRAMOLECULAR CYCLIZATION OF N-TOSYLHYDRAZONES In the past few decades, transition-metal-catalyzed ring-closing metathesis has evolved into a highly efficient and versatile strategy for the intramolecular C]C bond formation. In particular, by employing N-tosylhydrazones or diazo compounds as the carbene precursors, the catalytic carbene dimerization process provides an alternative way to form C]C bonds. However, owing to the instability of diazo species and poor selectivity, this method suffers significant limitation for its use in organic synthesis. In 2012, Wang group successfully disclosed a novel Rh(II)-catalyzed intramolecular carbene dimerization of bis(N-tosylhydrazone)s.98 This catalytic cyclization process, as well as the one-pot procedure from corresponding readily available dicarbonyl substrates, provides a general and highly efficient synthetic method for polycyclic aromatic compounds, including chrysene, helicene, picene, and pentaphenes (Scheme 84). This method is operationally simple and can be served as a general and practical approach to polycyclic aromatic compounds. In addition to the rhodium catalysts, gold complexes have been explored in intramolecular coupling reaction of bis-N-tosylhydrazones. In 2015, Sun group developed a selective and controllable divergent synthetic approach of decomposition of bis-N-tosylhydrazones (Scheme 85).99 Thus, in the presence of gold(I) catalyst and strong base, polysubstituted cyclic olefins are effectively accessed through this Au-catalyzed intramolecular coupling reaction of bis-N-tosylhydrazones. Moreover, the one-pot procedure by using bis-carbonyl compounds as substrates is also employed to access polyaromatic scaffold in a facile and efficient manner. This gold-catalyzed effective approach demonstrates practical applications in synthesizing polycyclic aromatic compounds with good yields.

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R

R

R O

Ar

TsNHNH2

Ar′

NNHTs Rh (OAc) (1.5 mol%) 2 4 t-BuOLi (3 equiv.) Ar′ toluene, MS, 90°C

Ar

R′

3

Chrysene, 91%

Ar′

Ar

TsHNN

O

R′

34 examples 44%–95% yields

R′

[4]helicene, 80%

[5]helicene, 93%

R

R Pentaphene R = H, 85% R = t-Bu, 82%

Picene, 86%

Scheme 84 Rh(II)-catalyzed intramolecular carbene cyclization of bis(N-tosylhydrazone)s.

R1

NNHTs NNHTs

t-BuOLi (3 equiv.) [t-BuXphosAuCl]/NaBArF (2.5 mol%)

R2

DCE, reflux, 12 h

R1 R

2

24 examples 48%–92% yields

O 1. TsNHNH2 (2.2 equiv.), toluene 2. [t-BuXphosAuCl]/NaBArF (2.5 mol%) t-BuOLi (3 equiv.), DCE, reflux Chrysene, 80%

O

O 1. TsNHNH2 (2.2 equiv.), toluene 2. [t-BuXphosAuCl]/NaBArF (2.5 mol%) t-BuOLi (3 equiv.), DCE, reflux

O

Picene, 89% Ph

O Ph

Ts N

Ph

1. TsNHNH2 (2.2 equiv.), MeOH, reflux

O Ph

2. [t-BuXphosAuCl]/NaBArF (2.5 mol%) t-BuOLi (3 equiv.), DCE, reflux 3. DDQ (3 equiv.), toluene, reflux

N Ts 52% total yield

Scheme 85 Au-catalyzed intramolecular coupling of bis-N-tosylhydrazones.

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7. SUMMARY As described in this chapter, the incorporation of transition-metalcatalyzed coupling strategy with N-tosylhydrazones allows toward various novel transformations for C–C bond construction. Serving as readily available substrates, N-tosylhydrazones are widely used in traditional organic transformations, including Bamford–Stevens–Shapiro reaction, Barton–Kellogg reaction, or Julia-type olefination, which have already demonstrated great applications in organic synthesis. Furthermore, the introduction of N-tosylhydrazones in transition-metal-catalyzed crosscoupling reactions not only expands the substrate scope of coupling partners but also makes this coupling strategy practically useful in organic synthesis and other fields. This type of transformation constitutes an unprecedented avenue to construct C–C, C]C, C–X bonds in a selective and efficient manner. Otherwise, various functionalized molecules such as polysubstituted alkenes, allenes, alkynes, aromatic and heterocyclic compounds, can be expeditiously and facilely accessed from N-tosylhydrazones or corresponding carbonyl substrates. Mechanistically, most of these catalytic transformations involve the formation of metal-carbene and subsequent migratory insertion as the key steps. The migratory insertion of metal-carbene has been proved to be general in terms of migrating groups, which include aryl, vinyl, benzyl, acyl, allyl, allenyl, alkynyl, propargyl, and cyclopropyl groups. Although significant achievements have been made in this field, some difficult problems still remain. For example, C(sp3)–H activation combined with migratory insertion, decarboxylative coupling with N-tosylhydrazones, asymmetric carbene transformation, and the coupling catalyzed by early transition-metal are yet challenging goals. With the significant achievements mostly made only in the last 10 years, it would be confident to say that this area is still far from mature and further developments can be expected.

ACKNOWLEDGMENTS The project is supported by the National Basic Research Program of China (973 Program, No. 2015CB856600) and the Natural Science Foundation of China (Grant 21332002, 21472004).

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82. Zhang Z, Zhou Q, Yu W, et al. Cu(I)-catalyzed cross-coupling of terminal alkynes with trifluoromethyl ketone N-tosylhydrazones: access to 1,1-difluoro-1,3-enynes. Org Lett. 2015;17:2474–2477. 83. Zhao X, Wu G, Zhang Y, Wang J. Copper-catalyzed direct benzylation or allylation of 1,3-azoles with N-tosylhydrazones. J Am Chem Soc. 2011;133:3296–3299. 84. Salvanna N, Reddy GC, Rao BR, Das B. Copper-catalyzed direct cross-coupling of 1,3,4-oxadiazoles with N-tosylhydrazones: efficient synthesis of benzylated 1,3,4oxadiazoles. RSC Adv. 2013;3:20538–20544. 85. Xiao Q, Ling L, Ye F, et al. Copper-catalyzed direct ortho-alkylation of N-iminopyridinium ylides with N-tosylhydrazones. J Org Chem. 2013;78:3879–3885. 86. Xu S, Wu G, Ye F, et al. Copper(I)-catalyzed alkylation of polyfluoroarenes through direct C-H bond functionalization. Angew Chem Int Ed. 2015;54:4669–4672. 87. Teng Q, Hu J, Ling L, et al. Copper-catalyzed direct alkylation of 1,3-azoles with N-tosylhydrazones bearing a ferrocenyl group: a novel method for the synthesis of ferrocenyl-based ligands. Org Biomol Chem. 2014;12:7721–7727. 88. Jha AK, Jain N. The microwave-assisted ortho-alkylation of azine N-oxides with N-tosylhydrazones catalyzed by copper(I) iodide. Chem Commun. 2016;52:1831–1834. 89. Huang Y, Li X, Yu Y, Zhu C, Wu W, Jiang H. Copper-mediated [3 + 2] oxidative cyclization reaction of N-tosylhydrazones and β-ketoesters: synthesis of 2,3,5trisubstituted furans. J Org Chem. 2016;81:5014–5020. 90. Li X, Liu X, Chen H, Wu W, Qi C, Jiang H. Copper-catalyzed aerobic oxidative transformation of ketone-derived N-tosylhydrazones: an entry to alkyne. Angew Chem Int Ed. 2014;53:14485–14489. 91. Zhou Z, Liu Y, Chen J, Yao E, Cheng J. Multicomponent coupling reactions of two N-tosylhydrazones and elemental sulfur: selective denitrogenation pathway toward unsymmetric 2,5-disubstituted 1,3,4-thiadiazoles. Org Lett. 2016;18:5268–5271. 92. Zhang Z, Yu W, Zhou Q, Li T, Zhang Y, Wang J. Rh(I)-catalyzed reaction of trifluoromethylketone N-tosylhydrazones and arylboronates. Chin J Chem. 2016;34:473–476. 93. Yada A, Fujita S, Murakami M. Enantioselective insertion of a carbenoid carbon into a C-C bond to expand cyclobutanols to cyclopentanols. J Am Chem Soc. 2014;136:7217–7220. 94. (a) Hu F, Xia Y, Ye F, et al. Rhodium(III)-catalyzed ortho alkenylation of N-phenoxyacetamides with N-tosylhydrazones or diazoesters through C-H activation. Angew Chem Int Ed. 2014;53:1364–1367. (b) Qiu Z, Deng J, Zhang Z, Wu C, Li J, Liao X. Mechanism of the rhodium(III)-catalyzed alkenylation reaction of N-phenoxyacetamide with styrene or N-tosylhydrazone: a computational study. Dalton Trans. 2016;45:8118–8126. 95. Zhang Y, Wang J, Wang J. Rh(I)-catalyzed carbon-carbon double-bond formation by coupling of(quinolin-8-yl)methanone with arylaldehyde tosylhydrazone. Synlett. 2013;24:1643–1648. 96. Yao T, Hirano K, Satoh T, Miura M. Nickel- and cobalt-catalyzed direct alkylation of azoles with N-tosylhydrazones bearing unactivated alkyl groups. Angew Chem Int Ed. 2012;51:775–779. 97. Paul ND, Chirila A, Lu H, Zhang XP, de Bruin B. Carbene radicals in cobalt(II)porphyrin-catalysed carbene carbonylation reactions; a catalytic approach to ketenes. Chem Eur J. 2013;19:12953–12958. 98. Xia Y, Liu Z, Xiao Q, et al. Rhodium(II)-catalyzed cyclization of bis(N-tosylhydrazone) s: an efficient approach towards polycyclic aromatic compounds. Angew Chem Int Ed. 2012;51:5714–5717. 99. Zhu C, Qiu L, Xu G, Li J, Sun J. Base-promoted/gold-catalyzed intramolecular highly selective and controllable detosylative cyclization. Chem Eur J. 2015;21:12871–12875.

CHAPTER THREE

Oxidative Functionalization of Late Transition Metal–Carbon Bonds Anna V. Sberegaeva*,1, David Watts†,1, Andrei N. Vedernikov†,2 *Board on Chemical Sciences and Technology, National Academies of Sciences, Engineering, and Medicine, Washington, DC, United States † University of Maryland, College Park, MD, United States 2 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Group 7 Metals 2.1 Rhenium 3. Group 8 Metals 3.1 Iron 3.2 Ruthenium 3.3 Osmium 4. Group 9 Metals 4.1 Cobalt 4.2 Rhodium 4.3 Iridium 5. Group 10 Metals 5.1 Nickel 5.2 Palladium 5.3 Platinum 6. Group 11 Metals 6.1 Copper 6.2 Silver 6.3 Gold 7. Summary Acknowledgments References

1

222 224 224 230 230 232 233 235 235 240 247 251 251 258 270 279 279 282 283 287 288 288

These authors contributed equally.

Advances in Organometallic Chemistry, Volume 67 ISSN 0065-3055 http://dx.doi.org/10.1016/bs.adomc.2017.03.001

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2017 Elsevier Inc. All rights reserved.

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1. INTRODUCTION In the past two decades, transition metal-mediated oxidative transformations of organic substrates have received an increased attention.1 One of the driving forces behind this trend is the development of new synthetic methods for functionalization of organic substrates that are more atom economical, as compared to traditional methods of organic synthesis. The transition metal-catalyzed oxidative C–H functionalization (Scheme 1) may serve as a good example of such an approach that combines C–H bond activation by transition metal species (step 1) and subsequent M–C bond oxidative functionalization (step 2). Oxidative M–C (M–R) bond functionalization reactions result in the cleavage of the M–C (M–R) bond and formation of derived functionalized organic products R–X: ½M  R + reagent ! “½M” + R  X

(1)

The term “oxidative functionalization” of an M–C (M–R) bond implies an increase of the formal oxidation state of the carbon atom (C) initially attached to the metal. With the Pauling electronegativity of carbon of about 2.62 and the electronegativity values for the transition metals not exceeding 2.4 (see the Pauling electronegativity values for the groups 7–11 metals in Fig. 12), hydrocarbyl ligands are formally “anionic” in the organometallic chemistry classification. Hence, the carbon atom of the C–X bond present in the product of an oxidative functionalization reaction (1) will have an increased formal oxidation state if the electronegativity of X is equal to or

C H

HX Step 1

[M]-X

C [M]

Step 2 C X

Scheme 1

Oxidant, HX

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Oxidative Functionalization

25 26 27 28 29 54.9381 55.845 58.9332 58.6934 63.546

Mn

Fe

Manganese Iron

Co Cobalt

1.6

1.8

Ni Nickel

1.9

Cu Copper

1.9

1.9

43 44 45 46 47 (97.905) 101.07 102.906 106.42 107.868

Tc Technetium

Ru Ruthenium

2.1

Rh Rhodium

2.2

Rd Palladium

2.3

Ag Silver

2.2

1.9

75 76 77 78 79 186.207 190.23 192.217 195.08 196.967

Re Rhenium

1.9

Os Osmium

Ir Iridium

2.2

Pt Rlatinum

2.2

2.2

Au Gold

2.4

Figure 1

greater than that of the hydrocarbyl fragment R itself. For example, the group X in the product of an oxidative functionalization reaction (1) may have a halogen (F, Cl, Br, I), a chalcogen (O, S, Se), a nitrogen, or a carbon atom immediately attached to R. In this chapter, we review the M–C oxidative functionalization reactions involving late transition metals M (groups 8–11) and, arbitrarily, rhenium. While trying to highlight as many examples of stoichiometric oxidative M–C bond functionalization as possible, we will avoid extensive discussion of “old” classical catalytic reactions that involve oxidative M–C bond functionalization steps such as C–C cross-coupling reactions or olefin carbonylation,3 and will place the emphasis on the more recent results appeared in the literature in the 2000s. The inclusion of the platinum group metals and gold in this list is an obvious choice. The platinum metals and, recently, gold are often used in metal-mediated oxidative transformations of organic substrates. The inclusion of the transition metals from the end of the 3d-block series, Fe–Cu, is due to the high and growing interest in the use of these earth-abundant 3d-block transition metals in catalysis instead of, or in addition to, their more rare and more expensive congeners, the noble metals. We thought that we can aid practicing chemists by organizing this chapter according to each particular metal. Whenever possible, additional organization according to the type of hydrocarbyl ligand R involved and the type of new C–X bond formed is also used. Finally, some information available about the mechanisms of these reactions is also provided.

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A C [Mn]

B C [Mn] + [Mn]

Oxidant, X–

Oxidant, X–

X C [Mn+2] X

–[Mn]–X

X C [Mn+1] + [Mn+1]

C X

–2[Mn]

C X

Scheme 2

The last theme is a separate and very interesting topic of current research. One of the well-explored pathways leading to [M]–C bond functionalization involves C–X bond reductive elimination from a high-valent metal species or an oxidative addition–reductive elimination sequence. Both require that the metal atom in an [M]–C transient species can change its oxidation state by either two (Scheme 2A) or, in the case of reactions involving two metal centers, one unit (Scheme 2B). Since such redox reactivity cannot always be possible, exploration of mechanistically different pathways is of current high interest. One such “different” mechanism of M–C functionalization, a Baeyer–Villiger-type oxidation, is common, in particular, for Re(VII) hydrocarbyl complexes discussed in the next section of this chapter.

2. GROUP 7 METALS 2.1 Rhenium Rhenium, with a Pauling electronegativity of 1.9, is one of the more electropositive metals discussed in this chapter. Most of the reactions of Re–C bonds present in Re(VII) or Re(I) complexes discussed later result in the formation of new C–O bonds (oxyfunctionalization). 2.1.1 Re–C(sp3) Bond Oxyfunctionalization Methyltrioxorhenium(VII), MTO (1, Scheme 3), has become the first alkyl rhenium complex studied in the context of M–C bond oxidative functionalization, which results in the formation of a new C(sp3)–O bond. MTO is a commercially available organorhenium compound that is often used as a catalyst in organic oxidation reactions, particularly those utilizing

225

Oxidative Functionalization

Peroxo mechanism δ− R ReO2

+[O]

O δ+

O

O Ox R Re O O R = Me (1, MTO) +YO Ph (2), δ− p-Tol (3), R ReO3 2,4,6-Me3C6H2 (4) O δ+ Y

R

O O Re O O

+H2O

ROH

–HOReO3

–Y

YO = O2H–, PhIO, IO4–

Baeyer–Villiger-type mechanism

Scheme 3

H2O2. The MTO complex is stable against oxygen and water, but in the presence of aqueous hydrogen peroxide, the Re–Me bond can be cleaved to form MeOReO3 and, eventually, methanol in almost quantitative yield, as was discovered in the 1990s4: Me  ReO3 + H2 O2 ! MeOH + HReO4

(2)

Notably, the metal oxidation state remains unchanged in the course of this transformation. Reactions with various oxygen atom donors, H2O2 and nonperoxo compounds, PhIO, pyridine N-oxide, and IO4  in water, have become the object of subsequent mechanistic investigations.5 The efficiency of these oxidants used in 100% excess decreases in the series (MeOH yield after 1 h at 25°C): IO4  (100%) > PhIO (90%) > H2O2 (80%) ≫ PyO (0%). The latter oxidant is unreactive. Two plausible reaction mechanisms were investigated computationally, (i) one involving methyl migration to one of the oxygen atoms of a peroxo intermediate MeReO2(O2) and (ii) one involving methyl migration to the oxygen atom of rheniumcoordinated oxidant (a Baeyer–Villiger, BV, type oxidation mechanism) (Scheme 3). The BV pathway is characterized by lower reaction activation barriers for these oxidants (Y ¼ OH for H2O2 oxidation). The BV mechanism was also supported by isotopic labeling experiments with I18 O4  that showed the formation of exclusively one isotopologue, Me18OH.

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The oxidation of MTO with H2O2 is even more efficient in the presence of flavin-based organocatalysts,6 which are used in some BV-type oxidation reactions of organic substrates.7 In particular, the isoalloxazine derivatives 5–8 provided up to a 600-fold rate enhancement in reaction (2) at pD 3.4 (Scheme 4). The additive 9 was inactive. The role these organocatalysts play in reaction (2) is to convert H2O2 to organic hydroperoxides such as 10 that are more active in BV-type transformations since they give rise to a leaving group Y that is better than OH acting as a leaving group in the reaction with H2O2 alone (Scheme 3). An even more efficient oxygen atom donor for MTO is OsO4.8 When MTO is combined with OsO4 in the presence of aqueous alkali, the reaction proceeds nearly instantaneously even at 40°C to produce methanol (Scheme 5). The base is required for the reaction; the authors found that pyridine bases could also be used instead of alkali metal hydroxides. The DFT calculations and isotope-labeling studies support a mechanism involving activation of MTO by these bases to give [MeReO4]2 with the subsequent rate-determining methyl transfer step involving a five-membered O O

O Me N

X–

N N

N

Ph N

O Me

ClO4–

O

O N N

N

N

O Me

ClO4–

O 7

5, X = ClO4 6, X = Cl

N N

N

N

O Me

BF4–

O 8

Me N

H2O2 5 –HClO4

N

N

CN

N

9 (inactive)

O

N Me O O O 10 H

Scheme 4

O H3C Re O O

H3C OsO4, 3OH– H2O, 22°C

–

ReO4 + OsO2(OH)4

2–

+ CH3OH

O3Os

O 11

Scheme 5

2– ReO3

O

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Oxidative Functionalization

transition state 11. This mechanism is different from that involved in the BV-type oxidation proposed for other oxidants (compare with Scheme 3). An oxygen atom insertion into the MTO’s Re–Me bond leading to methanol can also be achieved by means of electrochemistry using a heterogeneous film electrode (Scheme 6)9 where a Ru(II) complex is covalently attached to tin-doped indium oxide mesoporous nanoparticles. No competing catalytic water oxidation is involved. Results from cyclic voltammetry, chronoamperometry, and controlled potential electrolysis point to the RuIV(OH)3+ species as the catalytically active intermediate in the selective oxidation of MTO to methanol. H/D scrambling and KIE studies suggest that oxygen atom insertion into the Re–C bond is the major pathway. Notably, the advantage of electrocatalysts demonstrated here is the ability to control the involvement of side reactions by the correct choice of the electrode potential. MTO, a Re(VII) methyl complex, is not the only rhenium hydrocarbyl studied in Re–C bond oxidative functionalization. The oxyfunctionalization of Re(I) complexes, (CO)5ReMe, 12, and L2(CO)3ReR (where L2 is a bipyridine ligand), 13–17 (R ¼ Me, Et, n-Pr, Ph, p-Tol, respectively), is also known. Such compounds may serve as a model of some Ir(III) and Ru(II) CH activation products.10 The reaction of 12 with IO4  and PhIO produces methanol in low 20%–30% yields, whereas the periodate oxidation with a catalytic amount of H2SeO3 (10%) can be high yielding in MeOH (80%; Scheme 7). 2+ RuII–OH2

3+

–2e–, –H+

2+

RuIV–OH N where

CH3OH + ReO4– + 2H+

MTO

H2O

RuII–OH2 H

RuII O H3C

2+ =

3+ Electrode surface

ReO3

O P O O

O

O P O

Scheme 6

CO OC CO Re CH3 OC CO 12

Scheme 7

D2SeO3, 10 mol% IO4–, xs 8:2 v/v CD3CN/D2O 12 h, 100°C –[Re]

CH3OD 80%

H2O N

N

RuII

N

N N N

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The role of H2SeO3 is shown to form first the derived alkane(arene) seleninic acids RSe(O)OH; the selenous acid acts as an electrophile in this reaction. The reaction is efficient with the high 90%–95% yield of the seleninic acids (Scheme 8). The latter are oxidized by IO4  to the corresponding RSe(O)2OH, which react with water to form the derived alcohols ROH and H2SeO3 (R ¼ Alk). Phenols could not be produced this way. These results are remarkable because they demonstrate C–Se bond formation as a result of a Re–C bond functionalization. 2.1.2 Re–C(sp2) Bond Oxyfunctionalization Similar to the first examples of Re–C(sp3) bond oxyfunctionalization,4 the first reports on oxygen atom insertion into a Re–C(sp2) bond appeared in the mid-1990s.11 The Re(V) aryl complex featuring the trispyrazolylborate ligand, 18, undergoes reaction with dimethylsulfoxide (DMSO) to give the cationic DMSO adduct followed by oxygen atom insertion into the Re–C bond to give the phenoxy complex 19 and dimethyl sulfide (Scheme 9). Surprisingly, the analogous alkyl complexes 20–22 only gave the corresponding aldehydes upon reaction with DMSO.12 A recent computational study showed that the reactions of alkyl complexes 20–22 involve α-H atom abstraction by the triflate anion. The resulting alkylidene complexes are then reacted with DMSO via oxygen atom insertion into the Re–C bond to produce the aldehydes.13 CO L CO Re + R L CO SeO2

O Se

CD3CN/D2O 9:1

IO4– CD3CN/D2O 9:1

R

HO

O Se R HO O

ROH + SeO2

–[Re] CO N N

CO

CO

MeO N N MeO

Scheme 8

N N

CO Re CH3 CO 13 CO Re Ph CO 16

Re

N N

CO CH3 14

MeO

MeO

CO N N

MeO

CO

MeO CO

Re

CO 15

CO (p-Tolyl)

CO 17

Re

CO

CH3

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Oxidative Functionalization

N N N N

B N H

O OTf Re Ph N

Me2SO

N N N N

B N H

O OSMe2 Re Ph N

TfO N N

Me2SO

N N

B N H

18

TfO

O OSMe2 Re O Ph N

+ SMe2

19

N N N N

B N H

O OTf Re R N

DMSO or PyO

O (Tp)ReO3 + R′

H

R = Me, 20

R′=H

R = Et, 21

R ′ = Me

R = n-Pr, 22

R ′ = Et

Scheme 9

O (Ln)Re

O R

CO, 60 psi C6H6, RT, 3 days

(Ln)Re

R C O

CO CO, 60 psi C6H6, 80°C, 16 h

(Ln)Re

O

R

O R = Me, 23 Bn, 24

C6 F 5 (Ln) =

N N

N C6 F 5

Scheme 10

Similar to MTO, arylrhenium(VII) trioxides 2–4 (Scheme 3; Ar ¼ Ph, p-Tol, 2,4,6-trimethylphenyl, respectively) can also be efficiently oxidized with H2O2 or NaIO4 in THF–water mixtures with the formation of corresponding phenols (e.g., >90% yield for MesOH).14 The thermal instability of 2 and 3 precluded quantitative analysis of their reactions. The use of H18 2 O2 in the reaction with 4 leads to the predominant (>95%) formation of the 18O-labeled organic product, Mes18OH. Interestingly, pyridine N-oxide and DMSO can also react slowly with MesReO3 at 75–100°C, resulting in 15%–20% yield of MesOH. A BV-type mechanism was proposed for these reactions, based on computational analysis and the results of isotopic labeling experiments mentioned earlier. It was also predicted that the fastest reaction is expected when ArReO3 is attacked by hydroperoxide anion, HO2  (OY ¼ O2H in Scheme 3). Finally, CO insertion has also been used in oxidative functionalization of Re–C bonds (Scheme 10).15,16 For example, the alkyl complexes 23 and 24

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react with excess CO to form the corresponding acyl intermediates, which undergo oxygen atom insertion to form the carboxylate derivatives. When R ¼ aryl, the reaction does not proceed, even at a CO pressure of 800 psi and 80°C. Overall, this reaction may represent an important step toward the direct production of acetic acid from syngas.

3. GROUP 8 METALS 3.1 Iron 3.1.1 Oxidative C–C Coupling and Oxyfunctionalization Involving Fe–C(sp3) and Fe–C(sp2) Bonds Iron is a typical “earth-abundant” transition metal, which, from the “chemical sustainability” point of view, would be very desirable to serve as a component of catalysts replacing or complementing scarcer heavier transition metals, particularly the precious platinum group metals. In turn, the relatively low electronegativity of iron (1.8,2 Pauling scale), as compared to most platinum metals (2.2),2 may imply a much higher reactivity of organoiron compounds with respect to various electrophiles. This reactivity, in fact, is reflected in rich organoiron chemistry associated with stoichiometric applications of Collman’s reagent, Na2[Fe(CO)4], 25.17 Some examples of oxidative C–C coupling and oxyfunctionalization of Fe–C(sp3) and Fe–C (sp2) bonds are given in Scheme 11.17 Iron complexes were also among the first catalysts used in catalytic C–C cross-coupling reactions3 that formally may also involve oxidative Fe–C functionalization. Some recent reports18,19 complement this picture. A unique twocoordinate bis(aryl)iron(II) compound 26 (Scheme 12) containing two bulky terphenyl ligands was shown to react with O2 in n-hexane rapidly already at 100°C to form in high yield the corresponding product of the formal oxygen atom insertion into Fe–C bond, paramagnetic high-spin R COOH (1) 0.5 O2, + –[Fe] (2) H –[Fe] Na2Fe(CO)4

RX

R

Fe(CO)4

RC

25

Scheme 11

R′OH

–[Fe]

–[Fe]

RC OR′ O

R′X

R′ O

Fe(CO)3(PPh3) H+

O X2

R

–[Fe]

PPh3

Collman's reagent

R, R′ = Me, 1° Alk, 2° Alk X = OTs, Cl, Br, I

(1) 0.5 O2, (2) H+

X2 R′OH

–[Fe]

RC H O

231

Oxidative Functionalization

Ar

Ar

Ar O2

Fe

Ar O

Fe

O

–100°C Ar

Ar

Ar

Ar 27

26 i-Pr Ar =

i-Pr

Scheme 12

(1) Me3NO, light 20°C, 4d PhOH

Fe

L L

Ph

(2) HCl

+ products of Cp* and L degradation

70%

28 L=

O O

P

O

Scheme 13

d6 bis(aryloxide)iron(II), 27, which was characterized crystallographically.18 Remarkably, no iron(III) products were detected even under excess of O2. No discussion of plausible reaction mechanism was provided. Considering the high reactivity of 26 with respect to O2, it is also surprising to see that the compound does not react with such oxygen atom donor as N2O even at 80°C, 24 h. In another recent report19 a coordinatively saturated bis(phosphite)iron(II) phenyl complex 28, Cp*FeL2(Ph) (Scheme 13), undergoes oxygen atom insertion into Fe–C bond under light when reacted with excess Me3NO. The reaction also leads to the oxidation of the Cp* and both phosphite ligands L. After an acidic workup, phenol can be isolated in about 70% yield. The reaction with Me3NO was studied computationally. It was concluded that the photolytic conditions are required to facilitate Me3NO—for—L substitution (Scheme 14). Subsequent formation of an Fe(IV) oxo intermediate and phenyl group migration are fast and exergonic. Finally, an analogous Fe(II) methyl complex 29, Cp*FeL2(Me), displays a reactivity similar to that of 28, but methanol can be produced only in a low 25% yield.

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hn Fe

L

–L

Ph

L

O O

L=

L

P

O

Fe Ph

28

–Me3N

+Me3NO L Me3N O

Fe Ph

Fe

L O

Ph

Fe

L O

H+

PhOH

Ph

Scheme 14

3.2 Ruthenium 3.2.1 Oxidative C–C Coupling Involving Ru–C(sp3) and Ru–C(sp2) Bonds Ruthenium complexes have an outstanding reputation in the catalytic C–H bond functionalization/oxidative C–C coupling chemistry.3,20 The known reaction types include Ru(0)-catalyzed donor group-directed C(sp2)–H and C(sp3)–H alkylation with olefins (see, e.g., Scheme 15),21 and Ru(II)-catalyzed C(sp2)–H arylation with (hetero)aryl halides ArX (Scheme 16), among others. These reactions are believed to involve Ru(II) or Ru(IV) dihydrocarbyl intermediates resulting from oxidative addition of C–H or C–X bond to Ru(0) or Ru(II) intermediates, respectively. The resulting Ru(II) or Ru(IV) dihydrocarbyls reductively eliminate C–C-coupled products. In spite of the rich catalytic applications of organoruthenium catalysts, stoichiometric Ru–C bond functionalization reactions are poorly explored. One of the reasons behind this fact may be the proposed high reactivity of the ruthenium dihydrocarbyls, resulting from a rate-limiting oxidative addition step; hence, these dihydrocarbyls are unobservable in the corresponding reaction mixtures.22 A particular recent example of a transformation of an isolated trialkyl ruthenium(IV) complex 30 is given in Scheme 17.23 Reaction of 30 with 1,10-phenanthroline in dichloromethane solution at 20°C leads to a product of C(sp3)–C(sp3) reductive elimination and a Ru(II) chloro complex 31. The latter, presumably, results from the reaction of the solvent with the anticipated Ru(II) monoalkyl species resulting from the C–C coupling.

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Oxidative Functionalization

R R′

O

Ru(CO)2(PPh3)3 or Ru3(CO)12

R

or Ru(H)2(CO)(PPh3)2

+

O

110°C R = Me, t-Bu

R′

R′ = H, Alk, Ar, SiMe3, Si(OR″)3

Up to 99%

Scheme 15

[RuCl2(p-cymene)]2 phosphine, K2CO3

N +

N

Ar–X 120°C

Ar

X = Cl, Br, p-TsO

Scheme 16

OTf R

Ru

N R R

PPh3

N

N

CH2Cl2

N N

Ru

PPh3

TfO

+ R–R

Cl N

R = CH2SiMe3 30

31

Scheme 17

3.3 Osmium 3.3.1 Oxidative C–C Coupling Involving Os]C or Os^C Bonds Osmium complexes tend to be more stable in higher oxidation states and form stronger metal–carbon bonds than the other group 8 metals, iron and ruthenium. That is, in particular, true for the complexes containing M]C and M^C bonds. As a result, the α-hydrogen elimination of osmium alkyls having α-CH bonds to give alkylidene and alkylidyne Os complexes is quite common.3 The relative stability of organoosmium complexes having 18-electron count and high metal oxidation states translates to their low reactivity in Os–C bond functionalization chemistry while making organoosmium compounds convenient models for the study of certain stoichiometric transformations. In turn, catalytic applications of osmium complexes are very limited, especially as compared to ruthenium compounds that have outstanding versatility. There is a review on the reactivity of metal complexes containing osmium–carbon double bonds.24

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An interesting class of osmium complexes featuring osmium–carbon multiple bonds are metallacyclic osmabenzene and osmabenzyne complexes, which can be involved in oxidative C–C coupling reactions. An example given in Scheme 18 shows the conversion of an osmabenzyne complex 32, having formally an Os(VI) center, to a chlorocyclopentadienyl Os(II) complex 35.25 The transformation in the scheme was proposed to occur by a carbyne insertion into the Os–C(sp2) bond, leading to a carbene complex 34 with a subsequent carbene ligand insertion into Os–Cl bond and the formation of an η5-coordinated chlorocyclopentadienyl ligand. Overall, the metal oxidation state is reduced by four units. The proposed reaction mechanism was supported by DFT calculations. Computationally, it was also shown that good electron donors favor the osmabenzyne 33 isomer over the chlorocyclopentadienyl complex 35, whereas π-acidic ligands such as CO and PCl3 favor the latter compound type, as was borne out experimentally. The osmabenzyne complexes can be prepared following various routes. In particular, electrocyclization of η3-allenylcarbene Os(IV) complexes 36 leads to functionalized osmabenzynes 37 (Scheme 19).26 Gold and copper alkynyls were used as transmetallating agents to deliver an alkynyl group. Another interesting transformation of a dichloro osmabenzene complex 38 (Scheme 20) occurs in the presence of silver and copper alkynyl transmetallating agents to give functionalized mono- and diphosphonium benzene

PPh3

SiMe3

Cl Os

Me

Cl

SiMe3

PPh3

CO Mo(CO)6

Cl

–Mo(CO)6PPh3

Cl

Os

CO Cl

SiMe3

33

SiMe3 Me

Me

Cl

Cl Cl

SiMe3

PPh3

SiMe3

Me3Si

Os

Me

PPh3

32

SiMe3

Os CO

Ph3P

34

35

Scheme 18

PPh3 Cl Cl Os C Ar

C H PPh3 36 Ar = Ph or p-tollyl

Scheme 19

H C

Ar

(Ph3P)M HNEt3Cl

PPh3

R Cl

Os

Cl Ar R = Ph, SiMe3, p-tolyl, Ph P 3 CH(OEt)2, butyl, M = Au (for all R), 37 Cu (for R = Ph, SiMe3)

R

Ar CH2

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Oxidative Functionalization

PPh3 5 equiv. Ag

t-Bu 96%

CHCl3, 0°C, 5 min Cl

PPh

3

2Cl–

PPh3

t-Bu

–

39

PPh

3

Cl Os Cl PPh

PPh

3

3

38

(1) 5 equiv. Cu CHCl3, RT, 12 h (2) NaBPh4, CH3OH RT, 1 h

PPh3

Ph

2BPh4–

PPh3

BPh4–

+ Ph 40

PPh3 56%

Ph 41

36%

Scheme 20

derivatives 39–41, all characterized by single-crystal X-ray diffraction.27 The reaction does not proceed in dry solvents; the fate of the Os(IV) complex 38 and one of the carbon atoms of the alkynyl reagents remains unknown.

4. GROUP 9 METALS 4.1 Cobalt 4.1.1 Oxidative C–C Coupling Involving Co–C(sp3) or Co–C(sp2) Bonds Recent concerns about the balance of the transition metal supply and demand, environmental concerns, and other considerations28 have led chemists to reevaluation of priorities in the development of new metal-based catalysts. Increased interest has been placed on the first-row transition elements due to their higher natural abundance, lower cost, and, often, lower toxicity as compared to noble metals traditionally used in catalysis. Cobalt is one of the 3d-block elements that has many uses in organometallic catalysis.3 There is however a dearth of well-characterized stoichiometric C–C/C–X oxidative coupling reactions in the literature involving late 3d-block metals and cobalt, in particular. Some reasons behind this situation are the relative weakness of first-row transition metal–carbon bonds, a prevalence of β-hydride elimination (BHE) routes, thermal instability, and multiple available redox pathways including one-electron transformations, as opposed to predominantly two-electron pathways for the noble metals. The one-electron pathways may be especially undesirable when it comes to oxidative C–C coupling. One method proposed for avoiding one-electron pathways and directing the oxidative C–C coupling toward two-electron transformations in a Co(III) platform is to use strong field redox-innocent ligands such as

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phosphine and methyl ligands in the complex 43 (Scheme 21). The latter has been known since 197529 and can be easily synthesized by oxidative addition of methyl iodide to the Co(I) precursor 42.30 Only recently it was found that 43 can undergo selective C–C reductive elimination to form ethane and 44,31 a rare example in cobalt chemistry. Hence, the reaction sequence in Scheme 21 serves as an example of oxidative functionalization of Co–C bond in the complex 42 with methyl iodide acting as an oxidizing agent. A detailed study involving radical trapping, analysis of isotope effects, ligand inhibition, and crossover experiments supports a mechanism involving dissociation of one of the PMe3 ligands, the formation of a five-coordinate intermediate 45 followed by its concerted C–C elimination (Scheme 21). Unexpectedly, the isotopic labeling experiments showed an intermolecular exchange of cobalt-bound methyl ligands between Co(CD3)2(I)(PMe3)3, 43-d6, and 43 (Scheme 22).32 Two plausible mechanisms accounting for these observations are presented in the scheme. In the absence of excess phosphine ligand, dissociation of one PMe3 ligand from 43-d6 produces enough of the five-coordinate intermediate 45-d6 to be engaged in methyl group exchange with the nonlabeled complex 43, which accounts for most of the methyl exchange observed (Scheme 22A). However, excess PMe3 does not completely retard the rate of exchange, suggesting that a second mechanism is at play, which was proposed to be an SN2-type attack of PMe3 on one of the Co-bound methyl groups (Scheme 22B). An even more elegant way to force two-electron redox pathways in C–C coupling reactions is by using appropriately chosen redox noninnocent ligands. For example, two bidentate amidophenolate ligands were used to induce two-electron oxidation of the diamagnetic Co(III) complex 46 upon its treatment with alkyl halides to yield the corresponding Co(III)–R complexes 47 (Scheme 23).33 Each amidophenolate ligand undergoes one-electron oxidation with no net change of the oxidation state of the cobalt center. I

I 2 MeI (PMe3)4CoCH3 42

–Me4PI

Me3P Me3P

Co

CH3

PMe3

Me3P

–PMe3 I Me3P Me3P

Co CH3 45

Scheme 21

Co

CH3-CH3 +

Benzene or Heptane

CH3 43

50°C

CH3

PMe3 PMe3 44

I

A Me3P Me3P

Co

I CD3

PMe3

−PMe3

Me3P

Co

Me3P

CD3

Me3P

Co

I

Co

Co

C CD3 H3

I CD3

PMe3

Me3P

Co

Me PMe3

Me

Me3P

PMe3 –PMe2CD3

P

PMe3 PMe3

PMe3 CH3

I CD3

Me3P

CD3 43-d6

Scheme 22

Me3P

D3 C

45-d6

I Me3P

CD3

Me3P

CD3

43-d6

B

I 43

CD3

Co

Me3P Me 43-d3

Me

CD3

PMe3

I + PMe3

2 Me3P Me3P 43-d3

Co

CH3

CD3

PMe3

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Na t-Bu O t-Bu

CoIII

N

Ph N

t-Bu

t-Bu

t-Bu CoIII

N

RX = MeI, MeOTf, EtBr, EtI, PhCH2Br, PhCH2Cl CH2ClBr, CH2Cl2 Ph N

t-Bu

RZnBr

CoIII

N Ph

t-Bu 46

t-Bu

O

R-X –NaX

O

Ph

O

R

t-Bu

Ph N

t-Bu

O

t-Bu 47

46 + R-Et

O

t-Bu

Ph

R = Ph, hexyl

48

Scheme 23

Rates of addition of different alkyl and benzyl halides and methyl triflate suggest realization of an SN2-type reaction mechanism, as opposed to a radical process. Accordingly, phenyliodide is completely unreactive. Importantly, the ethyl complex 48 demonstrates remarkable stability toward β-hydride elimination and can be involved in subsequent Co–C bond functionalization. Reaction of 48 with RZnX leads to the corresponding R–Et coupling product, albeit in low yield (10%–15%), along with the starting bis-amidophenolate complex 46. Carbonyl insertion into M–C bonds has long been used as a method for establishing new C–C bonds, and this type of reactivity of cobalt complexes is one of the key steps in Co-catalyzed olefin hydroformylation. Notably, Co(II) complexes can also be engaged in Co–C bond carbonylation, but in this case the reaction involves the metal oxidation state change. A series of terphenyl Co(II) complexes 49 react with excess CO to form products of Co–C bond carbonylation, sterically encumbered ketones 50, and Co2(CO)8 (Scheme 24).34 The reaction is selective, but the product type depends on the nature of the aryl groups on 49. When Ar ¼ 1-naphthyl, an ortho-substituted benzophenone 50 is formed, presumably, through carbonyl insertion followed by reductive elimination of the acyl and aryl groups from the Co(II) center. When Ar ¼ mesityl, a more complex transformation is observed wherein double C–H activation of one of the mesityl moieties occurs followed by

239

Oxidative Functionalization

Ar

O

Ar

Ar

Ar

CO, xs Co(OEt2)n

Ar

Ar

O

CO, xs

Et2O, RT, 16 h –Co2(CO)8

hexane RT, 16 h –Co2(CO)8

Ar 2

50

Ar Ar

49

Ar = 1-naphyl

O 51

Ar = 1-naphyl, (n = 1) mesityl, (n = 0)

Ar = mesityl

Scheme 24 Me

Me N

N

N Mes

Mes

CoI Mes

Na(Hg) Cl

THF

Mes Me Me

CoII Mes

N Mes

N

N

N Mes

N2CHCOOAr THF

N Me 55

53 ArNC

CO, xs THF

THF

Me

Me N Mes

I

N

Mes

N

Co CO OC N Mes N

Me

N

Me CoII

Me

O

N CHCOOAr N Mes

Me

Me 52

Me CoII N

N

N

N

Me N

N Ar N Mes

Me

Me 54

56

Scheme 25

C–C reductive elimination. This reactivity is different from that observed for analogous terphenyl Fe(II) complex FeAr2, 26 (Scheme 12), which,18 upon reaction with CO, produces an Fe(II) diacyl complex, Fe(COAr)2. These results suggest that different metals may be used to access different reaction products. Dialkyl complexes of Co(II) featuring NHC ligands were also shown to undergo various Co–C bond insertions, both with and without the metal oxidation state change (Scheme 25).35 The bis-metallacyclic dialkyl Co(II) complex 53, which can be synthesized from 52 via the NHC ligand double C–H activation reacts with CO to form the Co(I) alkyl species 54. The product 54 was characterized by single-crystal X-ray diffraction. The reaction mechanism is poorly understood. Presumably, 53 reacts with CO via initial CO insertion into its Co(II)–C bond and a subsequent C–C reductive elimination. This reaction sequence would produce a Co(0) species. The formation of the Co(I) complex 54, hence, suggests that the reaction proceeds beyond that point.

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TfO Co MePh2P

F

R CF3

57

Me3SiOTf

Co MePh2P

F

R CF2

MePh2P

58

Co CF2RF OTf 59

RF = CF3, CF2CF3

TfO

H 2O –2HF

Co MePh2P

RF CO

Scheme 26

The reactions of 53 with an isonitrile and a diazo compound occur without metal oxidation state change and give the novel cobalt complexes 55 and 56, the products of the Co(II)–C bond oxidative functionalization, resulting from the isonitrile or nitrene insertion into one of the Co(II)–C bonds (Scheme 25). Another example of a carbene insertion into Co(III)–C bond is given in Scheme 26. The reaction involves a transient difluorocarbene complex 58 that was generated via selective fluoride abstraction from a bis(perfluoroalkyl) Co(III) complex 57 with trimethylsilyltriflate.36 Upon generation, 58 quickly undergoes carbene insertion into the Co–C bond to give 59, effectively increasing the perfluoroalkyl chain length by one CF2 unit. The Co(III) complex 58 is sensitive to trace amounts of water and undergoes hydrolysis to release HF, in contrast to similar Co(I)]CF2 carbene complexes, which are hydrolytically more stable.37

4.2 Rhodium 4.2.1 Oxidative C–C Coupling Involving Rh–C(sp3) or Rh–C(sp2) Bonds Rhodium, similar to cobalt, has numerous applications in organometallic catalysis. Many of its catalytic reactions are already the classics of this chemistry, e.g., hydroformylation of olefins or carbonylation of methanol,3 whereas other methods are being rapidly developed.38 Some of the steps in the catalytic cycles of these reactions involve oxidative Rh–C bond functionalization (see, e.g., the catalytic cycle for the Monsanto acetic acid process, the Rh-catalyzed methanol carbonylation in Scheme 27). Due to limitations to the size of this chapter, these reactions will not be discussed here. 4.2.2 Oxidative C–X Coupling (X 5 Cl, Br, I, O, P) Involving Rh–C(sp3) Bonds In the 1990s, it was discovered that dirhodium(II) diporphyrin complexes can activate methane reversibly to produce Rh(III)–H and Rh(III)–CH3

241

Oxidative Functionalization

Me

O C Me

OH OC I

MeOH

Rh

CO I

Me–I RDS

OC I

Rh I

Catalyst resting state

Me

CO I

O C I CO OC I

Rh

Me C I O

Me CO

OC I

Rh

I

C I O

I

Scheme 27 F F

C6F5 F

C6F5

N (F28TPP)Rh CH3 60

PPh3

(F28TPP)Rh + MePPh3 61

F28TPP =

N

F

F

N N

C6F5

F C6F5

F F

Scheme 28

bonds.39 Since then, rhodium compounds have emerged as promising candidates for methane oxidative functionalization, with great interest placed on functionalization of the Rh(III)–Me bond. To facilitate an SN2-type nucleophilic attack of PPh3 at the Rh(III)-bound carbon atom, an electron-deficient porphyrin ligand F28TPP (5,10,15,20-tetrakis-(pentafluorophenyl)-2,3,7,8,12, 13,17,18-octafluoroporphyrin) and the derived methyl Rh(III) complex 60 were used. The reaction results in a methylphosphonium cation MePPh3+ and the Rh(I) anion 61 (Scheme 28).40 The transformation in Scheme 28 was the first example of a nucleophilic displacement at the methyl ligand carbon atom in a neutral organometallic complex. The electron-deficient porphyrin ligand has little effect on the Rh–H/Rh–C bond dissociation energies but affects dramatically the pKa value of the derived Rh(I) anion 61.40 Cationic acac methyl Rh(III) complexes such as 62 can also be readily engaged in SN2-type reaction of their Rh–Me bonds with PPh3 resulting in a methylphosphonium cation MePPh3+ (Scheme 29).41 Treatment of

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BPh4

Me [MePPh3][BPh4]

O

PPh3

PPh3

Rh

CO, xs

PPh3 NCMe

O

Rh(acac)(PPh3)2

PPh3 Rh

O

Inert atmos.

Rh

CH3

O

CH3 CO

O PPh3

PPh3

62

BPh4

PPh3

BPh4 O

O

63

64

Scheme 29

PiPr2 CH3 Rh CO

R = iPr PR2

I CO

Rh

67

PiPr2

I

CH PR2 3

R = tBu

PtBu2

i

R = Pr, 65 t Bu, 66

Rh 68

CO + CH3I

PtBu2

Scheme 30

the same complex 62 with CO produces the acetyl complex 63, which exists in equilibrium with the deinsertion product 64. Neutral five-coordinate rhodium(III) methyl complexes featuring mercoordinating PCP pincer ligands of different steric bulk have been used as scaffolds to investigate Me–I bond elimination. It was found that steric effects dramatically affect the thermodynamics of Me–I elimination from the derived methyl iodo (PNP)Rh(III) complexes 65 and 66 (Scheme 30).42 When 65, featuring isopropyl groups at the phosphorus donor atoms, is treated with CO, no C–I coupling is observed and the expected octahedral Rh(III) carbonyl complex 67 forms. However, when R ¼ tert-butyl, as in 66, treatment with CO leads to facile and irreversible Me–I elimination with concomitant formation of a (PNP)Rh(I) species 68. The result is somewhat surprising since tert-butyl groups are more electron donating than isopropyl groups and would therefore be expected to better stabilize the electron-deficient (PCP)Rh(Me)(I)(CO) complex. The fact that the opposite is observed highlights the role that steric factors can play in M–C functionalization. Isotope-labeling studies support a mechanism involving a concerted reversible formation of a sigma complex (PNP) Rh–(MeI) instead of a two-step reaction sequence involving I dissociation and its subsequent nucleophilic attack at the methyl ligand carbon atom.

243

Oxidative Functionalization

PiPr2 N Rh H3C

L

L N Rh

PiPr2 71

PtBu2

PR2 L X

PR2

H3C i

X

t

R = Pr (69), Bu (70) X = Cl (a), Br (b), I (c)

N Rh

L + CH3–X

PtBu2 72

L = CO, CH3CN, CNC6H3(CH3)2

Scheme 31

The series of analogous cationic five-coordinate [(PNP)Rh(Me)(X)]+ complexes 69 and 70 display similar reactivity (Scheme 31).43 When 69a– 69c are treated with acetonitrile, dimethylphenylisonitrile, or CO (L), the corresponding six-coordinate complexes [(PNP)Rh(Me)(X)(L)]+, 71, are formed. However, once again, when the PNP ligand featuring bulkier tertbutyl groups is used, as in 70a–70c, the reductive elimination of Me–X is observed for all three halogens, X ¼ Cl, Br, and I, with concomitant formation of the derived Rh(I) complexes 72. Treatment of 69a–69c with bulky and virtually noncoordinating P(t-Bu)3 results in the formation of a new P–C bond and the MePðt  BuÞ3+ phosphonium species. Relative rates and ligand inhibition studies support an SN2 reductive elimination mechanism for bromo and iodo complexes 70b and 70c implying an X dissociation followed by SN2 attack of X at the Rh (III)-bound methyl ligand carbon atom. In turn, for the chloro complex 70a a concerted Me–Cl elimination was proposed. A drawback of using steric effects to encourage Me–X elimination is that bulky groups around the metal center can also interfere with C–H activation, a step required in the catalytic oxidative functionalization of alkanes. Therefore, for such applications, it would be beneficial to use the ligand electronic effects to control the C–X bond reductive elimination reactivity. The ligand electronic effects in C–Cl and C–O reductive elimination from Rh(III) methyl complexes were investigated using a terpyridine ligand scaffold with three distal electron-releasing (t-Bu) or electron-withdrawing (NO2) substituents that do not impose steric changes at the Rh(III) center (Scheme 32).44 The Rh(III) methyl chloro iodo complex 73 supported by the terpyridine ligand featuring three tert-butyl groups exhibits no Me–X reductive elimination. However, the electron-deficient trinitro-decorated analog 74 reductively eliminates MeCl and a small amount of MeI upon heating.

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Anna V. Sberegaeva et al.

R MeCl + LRh(I) N R

N

I

Rh N CH3

R = NO2 Cl

90°C CD3NO2

R = tBu No MeX observed

R R = tBu (73), NO2(74)

Scheme 32 R MeA + MeCl + CH4 N R

N

I HA Rh

R = NO2

Cl 150°C

N CH3

R

HA = H2O, AcOH, CF3CO2H

R = tBu CH4

R = tBu (73), NO2 (74)

Scheme 33

The reaction can be made 100% selective in MeCl by adding Bu4NCl salt as a Cl source, which does not affect the overall rate of reaction. The ester MeO2CCF3 can be formed along with MeCl in the presence of Bu4N(CF3CO2) salt as a source of CF3 CO2  anion. The reaction mechanism was proposed to involve halide dissociation from the six-coordinate Rh(III) center followed by an SN2 attack of the appropriate anion at the resulting cationic five-coordinate Rh(III)–Me species. The same electron-deficient complex 74 and its dichloro analog also produce Me–X elimination products (X ¼ Cl, I, CH3CO2, CF3CO2) along with significant amounts of methane when aqueous acetic or trifluoroacetic acids are used as solvents (Scheme 33).45 The electron-richer complex 73 only forms methane. The authors found that the presence of additives of halide ions I or Cl to the reaction media greatly improves the yield of the C–X elimination products MeX. The formation of methane in these experiments suggests that, in contrast to methyl Pt(IV) complexes (see Section 5.3), the less electrophilic methyl

245

Oxidative Functionalization

Rh(III) complexes are not as susceptible to nucleophilic attack at the carbon atom. The reductive elimination of Me–X from Rh(III)–Me species appears also to be the thermodynamically unfavorable step, which competes with the protolytic cleavage of the Rh(III)–Me bond. The susceptibility of Rh(III)–C(sp3) bond to nucleophilic attacks encouraged attempts at the development of a (TPP)Rh(III) hydride (75)mediated “anti-Markovnikov” heterocyclization of unsaturated alcohols and amines (TPP ¼ tetraphenylporphyrin) (Scheme 34).46 Complexes 76, prepared using an “anti-Markovnikov” olefin insertion into Rh–H bond of 75, can be deprotonated and engaged in an intramolecular nucleophilic attack at the Rh(III)-bound primary carbon atom, producing an anionic Rh(I) complex 77 and the heterocycle. The contribution of the competing olefin deinsertion can be controlled by an appropriate choice of solvent and base. The reaction scope is illustrated in Scheme 35. The reaction did not proceed without added base. Both solvent and steric effects around the carbon electrophile strongly imply an SN2-like mechanism. The catalytic conditions were never achieved, but the (TPP)Rh(III)–H reagent with the pKa value of 11 can easily be regenerated from the (TPP)Rh product 77 upon addition of CF3CO2H. H Nu

Ph H Nu Base

(TPP)Rh–H

(TPP)Rh

–H+

H

Nu = N, O, C 75

+ (TPP)Rh– TPP = 77

76

Ph

Ph

N −

Nu N

N

−

N

Ph

Scheme 34

H Nu Base

Nu + (TPP)Rh−

(TPP)Rh O

Nu = O

O

73%a

Ts N

O2N

O >95%a

>95%a

>95%b

69%c

83%c

Reaction conditions: aNMe4OH (3 equiv.), DMSO, 25°C,1 h. bKOtBu (2 equiv.), [18]crown-6 (2 equiv.), Benzene, 25°C, 1 h. cNMe4OH (3 equiv.), 70°C, DMSO, 12 h.

Scheme 35

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Anna V. Sberegaeva et al.

An epoxide-forming reaction is particularly facile and high yielding (Scheme 35). This transformation was chosen to investigate possible reaction mechanisms.47 Using diastereomer 78 of a deuterium labeled 2-hydroxy-1-hexyl Rh(III) complex, it was shown that, after deprotonation of the hydroxy group, the reaction proceeds with no H/D scrambling and with inversion of the configuration of the α-carbon atom Cα (Scheme 36). Thus, additional evidence for an SN2-type mechanism is provided and alternative mechanisms that would involve H/D scrambling or retention of configuration that might be associated with radical chain transformation or precoordination of the alkoxide base can be ruled out. An in-depth study of a reaction similar to that in Scheme 36 was carried out later. A porphyrin ligand featuring four p-sulfonatophenyl groups and 2,5-dihydroxyalkyl ligand at the metal center were employed to improve the solubility of the derived Rh(III) complex 79 in protic solvents (Scheme 37). Through judicious choice of solvent and base additive the reaction can be made selective for intramolecular nucleophilic displacement (IND) to form the epoxide 80, the BHE product, the ketone 81, or the β-oxygen elimination (BOE) product, the alkene 82 (Scheme 37).48 The BHE direction was favored in water as the solvent in the absence of additives. Isotopic labeling studies in H18 2 O suggest the incorporation of 18 the solvent O oxygen atoms into the ketone 81 due to reversible formation OH D

H C4H9

α

H

(TPP)Rh

O

KOtBu

(TPP)Rh– +

18-Crown-6 C6D6, 25°C, 5 min

H C4H9

D H

– No H/D scrambling – Inversion at Cα

78

Scheme 36

IND (TSPP)Rh– +

OH

O 80

KOH/DMSO

BHE OH

(TSPP)Rh

H2O

OH

79 + 2L, BOE

–(TSPP)RhH

NaO3S SO3Na TSPP =

N

N N

N

NaO3S SO3Na

Scheme 37

[L2(TSPP)RhIII]+ + OH– +

OH 82

OH O

81

247

Oxidative Functionalization

of 82 occurring prior to BHE. The reaction rate decreases at higher pH (8.0 ≫ 9 > 10 > 11 > 12). By adding ligands such as pyridine, pyrrolidine, and butylamine, the corresponding (TSPP)Rh(III)(OH) complex could be trapped resulting also in the formation of the alkene 82. Finally, the IND pathway was only favored under strongly basic conditions (KOH/DMSO) with almost immediate formation ( trans-PhCH]CH  Me > Ph. Similar to the complex 89 in Scheme 39, the low reactivity of the phenyl complexes results from the unfavorable conformation of the phenyl ligand that is required for facile C–C coupling (Scheme 40B). The required conformation is unfavorable because of the steric repulsion between the phenyl and the interfering tert-butyl groups at the phosphorus donor atoms. According to DFT calculations, analogous PCP complexes having PH2 groups instead of P(t-Bu)2 show the expected reactivity trend, PhCH]CH > Ph > Me, reflecting the increasing directionality of the C(sp3)–Ir bonds, as compared to the C(sp2)–Ir bonds. A

PtBu2 R R⬘ PtBu2

Ir

Δ

R,R⬘ = (Me, Me), (Me, Ph), (Me, Vin), (Me, CCPh), (Ph, Ph), (Ph, Vin),(Ph, CCPh), (Vin, CCPh), (CCPh, CCPh)

R–R⬘

Vin = trans-PhCH = CH–

90

B

PtBu2

PtBu2

Ir

Ir

Me t

P Bu2

PtBu2 Me

t

P Bu2 C–C elimination requires unfavorable conformation of aryl or vinyl groups

Scheme 40

Ir

Me

PtBu2

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Anna V. Sberegaeva et al.

4.3.2 Functionalization of Ir–C(sp3) and Ir]C Bonds via a Heteroatom (O, N, S) Transfer Combined with alkane C–H activation by Ir(III) complexes,49 oxyfunctionalization of Ir–C(sp3) is another step required for the development of catalytic oxidative functionalization of alkanes (Scheme 1). However, the information available about this type of reactivity of organoiridium complexes is very limited. In particular, recent observations show that the cationic methyl Ir(III) complex [Cp*Ir(III)(NHC)(py)(Me)]+, 91, reacts with O2 in water to yield methanol in up to 75% yield (Scheme 41).54 More detailed isotopic labeling studies of a transformation involving a similar complex 91b generated in dichloromethane solution (Scheme 42) revealed that the reaction produces a dicationic intermediate 93 featuring a μ-oxo-bridged Ir(IV)–O–Ir(IV) fragment. The intermediate can be isolated and was shown to decompose under O2 atmosphere to form MeOH.55 The latter reaction is inhibited by radical traps such as TEMPO and, based on the results of DFT calculations, was proposed to involve reversible formation of a [Cp*Ir(IV)(NHC)(Me)-O]+•, a cation-radical intermediate 92, that produces a methoxo Ir(III) transient, 94, leading to free MeOH. Another report demonstrates a possible coupling of double C–H activation in CH3OCMe3 by a (PNP)Ir(III) dihydride complex 95/norbornene TfO Ir

N

TfO O2, 60 psi HCl or NaCl

Me N

N

Ir

N

H2O, 100°C

Cl

+ MeOH

N

N

91

Scheme 41

BAr F4 Ir

N N

Me ClCH2Cl

BAr F4 0.5O2

Ir

N

BAr F4 91

O Me

Ir

N

Ir

O

N

N 92

91b

93 BArF4

BAr F4 EtOH

Ir

N

OMe N

Scheme 42

MeOH +

Ir

N

solvent N

94

N

Me

Me

N

solvent OEt

2

251

Oxidative Functionalization

O CO2 (PNP)Ir PiPr2 N Ir

H

H PiPr2

+NBE –NBE(H)2 CH3Ot-Bu

95

PiPr2

97 SCO

N Ir OtBu

H

O (PNP)Ir CO +

O OtBu

(PNP)Ir CO

+

(PNP)Ir CO

+

NBE = norbornene NBE(H)2 = norbornane

OtBu

S H

PiPr2 96

H

OtBu NPh

PhNCO

H

OtBu

Scheme 43

combination (Scheme 43) and functionalization of the resulting Fischer carbene 96. The latter reaction leads to Ir]C bond cleavage and an oxygen, sulfur, or nitrene fragment transfer to the carbene carbon when 96 is exposed to CO2, SCO, or PhNCO, respectively.56 The atom transfer reactions result in the formation of formic acid tert-butyl ester or its respective derivatives. The atom transfer to the carbene ligand in 96 was postulated to proceed through four-membered metallacyclic intermediates such as 97.

5. GROUP 10 METALS 5.1 Nickel Nickel is a more electronegative element (1.92 in Pauling scale) as compared to iron and is about equally as electronegative as cobalt. Nickel has a solid reputation in homogeneous catalysis of organic reactions ascending to works by Reppe3 and Kumada–Corriu C–C cross-coupling (X, Y ¼ Cl, Br, I, OTs, etc.)57: Ar  X + R  MgY ! Ar  R + MgXðYÞ

(3)

As compared to its heavier congeners, Pd and Pt, nickel is much more prone to undergo one-electron redox transformations so making Ni–C bond functionalization reactions mechanistically much more complex, as it may become clear from the discussion presented in this section. 5.1.1 Oxidative C–X Coupling (X 5 C, Cl, Br, I, O, P) Involving Ni–C(sp3) and Ni–C(sp2) Bonds Some of the early observations of oxidative Ni(II)–C bond functionalization leading to C–X-coupled organic products (X ¼ O, N) were reported in the 1990s.58,59 The seven-membered metallacyclic alkoxo aryl Ni(II) complex 98 reacts slowly with O2 under ambient conditions to produce the

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corresponding C(sp2)–O-coupled cyclic product, 4,4-dimethylchromane 99, albeit in a low 39% yield (Scheme 44). The same product 99 results from the use of a one-electron oxidant, acetylferrocenium tetrafluoroborate, 100, so implying that the role of the oxidant is, possibly, just to affect a Ni(II)-to-Ni(III) conversion. The resulting high-valent alkoxo aryl Ni species then can be involved in the oxidative C(sp2)–O coupling to form 99. Overall, this reaction requires the use of two equivalents of one-electron oxidant, which formally does not exclude an option of the intermediacy of Ni(IV) species. Similarly, high-yielding oxidative C(sp3)–N and C(sp2)–N bond coupling/ heterocyclization occurs when Ni(II) metallacyclic alkyl (e.g., 101, Scheme 45) or aryl amido complexes (e.g., 102), respectively, supported by 2,20 -bipyridyl (bpy) are treated with either acetylferrocenium tetrafluoroborate, 100, O2, or I2.59 The use of analogous nonmetallacyclic Ni(II) compounds results in much lower yields. The intermediacy of Ni(III) species was proposed.

O2 or (AcC5H4)CpFe+, BF4– Me3P

(100)

Ni O O Ni

PMe3 O 39% 99

98

Scheme 44

(AcC5H4)CpFe+, BF4– (100), 85%

Tol N

Ni(bpy)

I2, 77% O2, 86%

Tol N

101 Ph

(AcC5H4)CpFe+, BF4– (100), 85%

N

I2, 87% O2, 69%

102

Scheme 45

Ni(bpy)

Ph N

253

Oxidative Functionalization

The intermediacy of organonickel(III) and, potentially, organonickel(IV) compounds was also discussed in a series of early works60,61 focusing on oxidative Ni(II)–C(sp2) bond functionalization of aryl nickel(II) compounds such as 103 and 104 to form Ar–X and/or biaryls. The oxidants used are Br2, CuBr2, CuCl2, O2, N–X-succinimides (X ¼ Cl, Br), PhICl2, and N-fluoro-2,4,6-trimethylpyridinium triflate (Scheme 46). The stability of organonickel(III) complexes can be substantially increased when appropriate facially chelating supporting ligands, e.g., pyridinophanes shown in Scheme 47, are used.62–65 Some isolable organonickel(III) complexes 106–109 can be produced by oxidation of corresponding organonickel(II) precursors, e.g., 105, electrochemically or using ferrocenium or silver(I) salts. The resulting Ni(III) compounds demonstrate a variety of C–X coupling reactivities. In particular, C(sp3)–C(sp3),62 C(sp2)–C (sp3),63,64 and C(sp2)–O65 bond formation is observed under mild conditions. Notably, in some cases the 2:1 one-electron oxidant:Ni(II) complex stoichiometry needed to achieve higher yields of C–X coupling products62 may be indicative of the involvement of transient organonickel(IV) species. The facially chelating ligands, hydridotris(pyrazolyl)borate, Tp, and tris(pyrazolyl)methane, CHpz3, are very efficient at stabilizing octahedral d6 metal centers.66 Accordingly, their use enables facile oxidation of metallacyclic dihydrocarbyl nickel(II) complexes 110 and 111 with S-(trifluoromethyl)dibenzothiophenium triflate, 112, and preparation in

N

Ni

N

Br2 or CuBr2 N

Br

Br

79%–89%

103

oxidant N

Ni

+

N

N

N

X X = Cl, Br

104 53%–79% Oxidant = Br2, NBS, CuBr2, PhICl2, NCS, CuCl2

N F

Scheme 46

N

TfO

254

Anna V. Sberegaeva et al.

MeN NMe N

Me

NiII

N

N

+

Fc

N

Me

Me

1 equiv. 100

Me

–[NiII]

NiIII

C2H6, 84%–88%

NMe N Me

105

106

NCH2t-Bu

NCH2t-Bu N

NiIII

Br

N

RR′CHCN

C(R)(R′)CN

Br NCH2t-Bu

KOt-Bu NCH2t-Bu

–[NiII]

107

up to 99%

Nt-Bu N N

NiIII

(p-C6H4F)

Me Nt-Bu

Fc+

F

Me

–[NiII]

up to 72%

108 Nt-Bu

Nt-Bu N

NiIII

N

OMe

OMe Nt-Bu

109

OMe –[NiII]

Nt-Bu

up to 95%

Scheme 47

high isolated yields of the derived trifluoromethylnickel(IV) derivatives, the cationic CHpz3-supported 113, and the neutral zwitterionic Tp-supported 114 (Scheme 48).67 These organonickel(IV) complexes are sufficiently stable for detailed characterization. Remarkably, the cationic Ni(IV) complex 113 undergoes C(sp3)–C(sp2) coupling at 95°C to form quantitatively the dimethylbenzocyclobutene 115. In turn, the reaction of the same Ni(IV) complex 113 with acetate anion leads to a clean formation of a new C(sp3)–O bond and the arylnickel(II) complex 116 resulting from an SN2 attack of the nucleophile at the Ni(IV)-bound C(sp3) carbon atom. The neutral zwitterionic Ni(IV) complex 114 reacts with an even greater variety

255

Oxidative Functionalization

N HE N N

S CF3 112

Ni

N N

E = C (110) = B− (111)

N N 113

Ni CF3

E = C (113) = B− (114)

TfO

N

HC

TfO

N

HE TfO

95°C, 7 h

115 Ni Me4NOAc

CF3

N

HC N N

Ni CF3

OAc

116 N

HB N N

Ni Me4N+

114

CF3

N

HB Me4NX

X = AcO, PhO, PhS, MsN(Me)

N N

Ni

CF3

X

117

(1) n-Bu4NN3 (2) H+ 118

N H N HE = N N

N EH N

E = C (CHpz3) = B− (Tp)

3

Scheme 48

of nucleophiles X ¼ AcO, PhO, PhS, MsN(Me), following an SN2 mechanism to produce arylnickel(II) complexes 117, ionic analogs of 116, in 78%–98% yield. The C(sp3)–X coupling reaction rate increases as the nucleophilicity of the X increases. Interestingly, the use of azide anion as a nucleophile leads to dimethylindoline 118 as a result of a proposed complex reaction sequence.

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The use of Tp-supported Ni(IV) aryl bistrifluoromethyl complexes for C(sp2)–CF3 coupling has also been recently reported (Scheme 49).68 The corresponding anionic aryl trifluoromethyl nickel(II) species 119 can be trifluoromethylated using 112 to form a series of aryl-substituted Ni(IV) compounds 120 (R ¼ H) and 121 (R ¼ p-MeO, p-Me, p-Br, m-CO2Me). Alternatively, 120 can be most efficiently prepared from a bis(trifluoromethyl)nickel(II) complex 122 using a diphenyliodonium salt, [Ph2I]BF4, as a source of phenyl cation. The Ni(IV) complexes 120, 121 undergo clean C(sp2)–CF3 coupling. The elimination is favored by electron-donating substituents in the aryl ligand; a Hammett plot analysis produces a ρ value of 0.91. Available observations also suggest that the reactions of 4,40 -di-tertbutylbipyridine (dtbpy) nickel(II) complexes, (dtbpy)Ni(Ph)CF3, 123,

N nBu N+ 4

HB N N

CF3 112

Ni

119

TfO N N

R

CF3

N

HB

S

CF3

Ni

CF3 120 (R = H) 121 (other R's)

R = p-MeO, p-Me, p-Br, H, m-CO2Me R N

nBu4N+

HB N N

Ph2I+, BF4−

CF3

Ni

N

HB N N

Ni

CF3 CF3

CF3

122

120 77% N

HB

CF3 N N

CF3

Ni

CF3

55°C + "Ni(II)"

MeCN R

120 (R = H) 121 (other R's)

Scheme 49

R

257

Oxidative Functionalization

with 112, and (dtbpy)Ni(CF3)2, 124, with [Ph2I]BF4,68 involve an organonickel(IV) intermediate 125 (Scheme 50). This observation means that the use of strongly stabilizing facially chelating ligands such as Tp and CHpz3 may not be necessary for the transient formation of Ni(IV) species. Hence, the oxidative Ni(II)–C bond functionalization reactions in Schemes 44–46, potentially, may also involve Ni(IV) transients. Another facially chelating ligand, 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3tacn), is one of the most effective when it comes to stabilization of octahedral d6 metal centers.66 There are some indications that oxidation of a Me3tacn-derived dihydrocarbyl nickel(II) complex 126 with O2 in aqueous acetone proceeds with the formation of derived Ni(III) and Ni(IV) species (Scheme 51).69 Finally, two-electron oxidative functionalization of Ni–C bond may not necessarily require the involvement of Ni(IV) transients. An alternative to

112 S CF3

t-Bu N N

Ni CF3

t-Bu

TfO

20°C, 5 min MeCN

123

CF3

t-Bu N N t-Bu 125 t-Bu N N

Ni

t-Bu

CF3 CF3

20°C

Ni CF3

− ''Ni(II)''

NCMe

CF3 57%–67%

observed at −25°C

PhN2+, BF4− 20°C, 5 min MeCN

124

Scheme 50 MeN

MeN

NiII

N Me

Ni(III), Ni(IV) –30°C

126

Scheme 51

t-Bu

20°C

O2/H2O–acetone

+ OH

258

Anna V. Sberegaeva et al.

their involvement may be generation of Ni(III) species and their subsequent bimolecular reductive elimination of a C–C-coupled product.70

5.2 Palladium Palladium has an outstanding reputation in catalytic organic synthesis.71 There are numerous Pd(0)-catalyzed C–C and C–X coupling reactions that include reaction steps which can be classified as Pd–C bond oxidative functionalization.71,72 There are a number of specific reviews focusing on C–X bond formation mediated by high-valent Pd complexes.73,74 This section will focus predominantly on some most recent results dealing with fundamental studies of Pd–C bond oxidative functionalization involving organopalladium(III) and organopalladium(IV) compounds. 5.2.1 Oxidative C–X Coupling (X 5 F, O, N) Involving Pd–C(sp3) Bonds The high reactivity of catalysis-relevant organopalladium(IV) complexes having one or two hydrocarbyl ligands at the metal center and the scarcity of palladium(III) compounds are some of the reasons why the development of this area of organometallic chemistry has been slow. Most of the studies of Pd–C(sp3) bond oxidative functionalization involving high-valent organopalladium complexes focus on the most intriguing last step of this reaction sequence, reductive elimination of an organic product from a high-valent metal center (Scheme 2). Among other high-valent organopalladium complexes, the metallacyclic derivatives of tert-butyl benzene supported by bipyridyl ligand are relatively stable owing to their bis-chelate structure (Scheme 52). For this reason, and since they have both Pd–C(sp3) and Pd–C(sp2) bonds allowing exploration of competitive C(sp2)–X and C(sp3)–X coupling, such complexes have become a popular choice in various model studies of high-valent complexes of lighter group 10 metals. Palladium(IV) complex 128, in particular, is sufficiently stable and can be prepared from its Pd(II) precursor 127 using N-fluoro-2,4,6trimethylpyridinium triflate as oxidant (Scheme 52). This Pd(IV) complex RO

TfO N PdII N

N F

TfO

N PdIV N

MeCN 127

Scheme 52

128

F NCMe

NaOR or Bu4NOR

N

25°C, MeCN

N

PdII

129

F

259

Oxidative Functionalization

dissolved in MeCN accepts attacks of various O-nucleophiles RO, ranging from stronger PhO, AcO, CHF2 CO2  , to weaker NO3  , ðMeOÞ2 PO2  , p-TsO, to produce the corresponding C–O-coupled Pd(II) aryl compounds 129 in high yield.75 The nucleophiles RO can displace the axial nitrile ligand in 128 so complicating the reaction. Hence, no less than 2 equiv. of the nucleophile must be used. The mechanism proposed for the C–O coupling reaction involves an SN2 attack of a nucleophile at the Pd(IV)-bound carbon atom. A close analog of 128, the Pd(IV) complex 131 bearing a tosylamido ligand trans to the alkyl carbon, turned out to be a good model for study of the C(sp3)–N coupling at Pd(IV) center (Scheme 53).76 The reaction of 131 with Me4NNHTs as a nucleophile source in MeCN solution leads to the formation of N-alkylamide derivative 132. A computerized analysis was performed accounting for multiple reaction pathways possible in the system, comprising 131, its isomer 130 that exists in equilibrium with 131, and Me4NNHTs in MeCN solution. The lowest energy path found for this system involves formation of the transient complex 128 followed by an attack of the nucleophile at the Pd(IV)-bound carbon atom in 128 with the concomitant loss of the MeCN ligand. The complex 133, a neutral difluoro derivative of 128, and its ionic pyridine analog 135 (Scheme 54) form products containing new C(sp3)–F TsNH N

N

PdIV

PdIV

N

N

F

130

PdIV

N

F NHTs

NHTs

–MeCN –HF

N

MeCN

N PdII

N

F NCMe

131

128

N Ts

132

Scheme 53 F CH2Cl2

N PdIV N

N PdII

30 min 80°C

F

N

F

133

134

TfO

N

–NC5H5

PdIV N 135

F NC5H5

Scheme 54

F

TfO N PdIV N 136

F

F

Direct C–F elimination

N

+NC5H5

N

TfO PdII NC5H5

137

260

Anna V. Sberegaeva et al.

bonds, 134 and 137, respectively, upon warming at 80°C in CH2Cl2 solutions.77 Surprisingly, no products of C(sp2)–F coupling were observed in these reactions. As opposed to the C(sp3)–O and C(sp3)–N reductive elimination reactions operating by an SN2 mechanism (Schemes 52 and 53), a concerted “direct” C(sp3)–F elimination from the five-coordinate transient 136 was proposed. 5.2.2 Functionalization of Pd(II)–C(sp3) Bonds Using O2 as Oxidant The development of efficient methods for oxidative functionalization of methane, including methane “upgrade” to higher hydrocarbons, would be most viable economically if inexpensive oxidants such as O2 are used. When Pd complexes are used as catalysts in oxidative functionalization of methane, the corresponding catalytic cycles are likely to involve organometallic intermediates with Pd(II)–CH3 bond. These simple considerations inspired a number of research groups to explore the reactivity of various organopalladium(II) complexes toward O2.78 A free-radical chain insertion of O2 into Pd–CH3 bond in the dimethylpalladium(II) bipyridyl complex 138 produces a derived methylperoxopalladium(II) complex 139 in 70% yield (Scheme 55A).79 The proposed radical chain reaction mechanism involves transient formation of hypothetical Pd(III) methyl complexes. A photochemical insertion of O2 into Pd(II)–CH3 bond in the complex 140 operating by a nonradical mechanism leads to another methylperoxopalladium(II) complex 141 which is remarkably stable (Scheme 55B).80 The mechanism of this transformation is being currently explored and may involve the formation of an excited-state triplet dinuclear metal complex responsible for O2 activation. The excited triplet dimer reacts with O2 to form methylpalladium(IV) peroxo transients that reductively eliminate a CH3–O bond to form 141. A photochemical reaction of the methylpalladium(III) complex 142 with O2 in wet MeCN is reported to produce methanol in a low 14% yield along with formaldehyde, formic acid, and a chloropalladium(II) complex 143 (Scheme 55C).81 In the absence of oxygen the photolysis of 142 produces ethane in up to 25% yield along with small amounts of methane and MeCl. A homolytic reaction mechanism was proposed. The use of facially chelating sulfonated dipyridinemethane ligand (dpms) allowed to achieve an efficient photochemical aerobic functionalization of Pd–CH3 bond present in the water-soluble methylpalladium(II) complex (dpms)Pd(Me)OH, 144 (Scheme 56).82

261

Oxidative Functionalization

A N

Me

PdII

N

N

O2

N

Me 138

PdII

Me

O2Me

139

B

SbF6

SbF6

NH2

NH2 N

N

O2, light

N Pd Me

N Pd OOMe

20°C N

N

NH2

NH2 140

141 t-BuN

C

PF6

Nt-Bu N

PdIII N

Cl

Me Nt-Bu

PF6

O2, light MeCN

N

MeOH + CH2O + HCO2H +

N

PdII

Cl NCMe

Nt-Bu 143

142

Scheme 55

H

O O S O N

N

Me Pd OH

(dpms)PdMe(OH)− 144

O2 H2O hv

(dpms)Pd(OH)2− + MeOH + C2H6 + MeOOH

6%–55% 44%–94% 0%–40%

Scheme 56

In general, the reaction can produce a mixture of methanol, ethane, and methylhydroperoxide. By changing the reaction conditions the fraction of each of the three organic products can be varied in a wide range. At pH 10.6 the reaction favors selective formation of ethane in up to 94% yield. At pH 14, methanol becomes the major product (up to 55% yield). At the same pH 14, lowering the concentration of the complex 144 from 13 to 0.7 mM allows one to increase the yield of MeOOH from 4% to 40%. At the same time, MeOOH is not present at pH 10.6 and lower. An unstable

262

Anna V. Sberegaeva et al.

dimethylpalladium(IV) complex 147 (Scheme 57) has been independently synthesized and was found to be responsible for the production of ethane in the overall reaction in Scheme 56. The proposed reaction mechanism is summarized in Scheme 57. The formation of MeOOH results from a photochemical nonchain radical insertion of O2 into Pd–CH3 bond, whereas some MeOH results from the oxygen atom transfer between MeOOH and complex 144. The latter reaction leads to a hypothetic highly reactive methylpalladium(IV) transient 146 involved in electrophilic methyl group transfer to either OH, to form additional O O S O IV Me + OH− N Pd N OH O2H 145

H

H

O O S O N

N

Me Pd OH

O2 H2O hv H

144

H

O O S O N Pd Me N OH

O O S O N Pd O2Me N OH

H2O −(dpms)Pd(OH)2−

O O S O Me N PdIV N OH OH 146

H + MeO2H, H2O −OH−

144 O O S O Me N PdIV N OH X 145 (X = O2H) or 146 (X = OH)

H

+144

OH− SN2

''(dpms)PdII'' + MeOH

−''(dpms)PdII''

O O S O Me N Pd IV N OH Me 147

H

Scheme 57

OH− t1/2 6 min 21°C, H2O

(dpms)Pd(OH)2− + C2H6

+ MeOH

MeOOH

263

Oxidative Functionalization

amounts of MeOH, or the methylpalladium(II) complex 144, to form the Pd(IV) dimethyl derivative 147. Finally, formation of another highly electrophilic methylpalladium(IV) transient 145, a peroxo analog of 146, is expected as a result of direct photochemical oxidation of 144 with O2.82 Notably, a Pd-catalyzed oxidative C–H functionalization utilizing O2 as the oxidant has been proven feasible, although, currently, for a narrow range of substrates, substituted 8-methyquinolines 148 bearing a directing donor group (Scheme 58).83 The reaction utilizes the Pd(II) 2,6pyridinedicarboxylate bis-chelate complexes 149 as catalysts, acetic acid as a solvent, and acetic acid anhydride as a reagent needed to protect the expected reaction by-products, benzylic alcohols, against overoxidation. The reaction results in the corresponding benzylic acetates 151 that form in 48%–79% isolated yield. Analysis of the kinetics of C–H bond activation of a selected R

R 5% 149 + 0.5O2 + Ac2O

+ N

AcOH, 24 h, 80°C

N CH3

AcO

148

CH2 48%–79%

151

R = H, Me, MeO, F, Cl, Br, I, NO2 R 148

N CH3

X X

O

O O

N O

Pd

CH2

O 150

L

X = H, OH, t-Bu L = H2O, DMF, DMSO, AcOH

R

N 151 AcO

Scheme 58

COOH

N

Pd

149

O

N

CH2

R

0.5 O2, Ac2O

AcOH

264

Anna V. Sberegaeva et al.

substrate 148 (R ¼ H) with a selected complex 149 (X ¼ t-Bu, L ¼ DMSO) at 80°C and kinetics of the Pd–C(sp3) bond oxyfunctionalization of the corresponding reaction intermediate 150 (R¼ H, X ¼ t-Bu) with O2 in acetic acid at 22°C have demonstrated, unexpectedly, that the C–H activation step is turnover limiting. The cyclopalladated complex 150 (R ¼ H, X ¼ t-Bu) was prepared independently and was shown to be a kinetically viable reaction intermediate. Its reaction with O2 in AcOH solution produces a mixture of the acetate 151 and the corresponding alcohol with the half-life of 1 h at 22°C. Hence, the oxidative C–H acetoxylation of 148 (Scheme 58) may be considered as a true example of an aerobic catalytic organometallic C–H functionalization. Speaking about oxidative coupling of methylpalladium(II) complexes to produce ethane, it is worth noting the reactions involving dimethylpalladium(II) and methylpalladium(II) dipyridyl complexes.84 Strong oxidants such as K2S2O8, PhI(OAc)2, PhI(O2CCF3)2, (NH4)2[Ce(NO3)6], AgBF4, acetylferrocenium salts, and N-fluoro-2,4,6-trimethylpyridinium triflate can be used in these transformations. Tri- or dimethylpalladium(IV) intermediates observed in these reactions are responsible for ethane elimination. 5.2.3 Oxidative C–X Coupling (X 5 F, Cl, Br, O, N, C) Involving Pd–C(sp2) Bonds Some first observations of Pd–C(sp2) bond oxyfunctionalization involving isolable palladium(IV) aryl complexes date back to 2005.85a Oxidation with PhI(O2CPh)2 of the diarylpalladium(II) precursor 152 produces sufficiently stable Pd(IV) diaryl dicarboxylate 153 that undergoes clean C–O bond reductive elimination in the presence of pyridine additives at 60°C to produce the corresponding arylcarboxylate (Scheme 59). Subsequent detailed

N

N PdII

N

N

PhI(O2CPh)2

−PhCO2−

N

N

PdIV

PdIV O2CPh

152

O2CPh

O2CPh

153

154 +

II

−[Pd ]

N

N O2CPh

N +

N N

Scheme 59

N

PdII O2CPh

Oxidative Functionalization

265

mechanistic studies of this reaction involving a broad range of similar Pd(IV) complexes with varied carboxylate and substituted aryl ligands point to the realization of a two-step process involving dissociation of one carboxylate group to form a five-coordinate Pd(IV) intermediate 154 that undergoes a concerted C–O bond elimination.85b The competing C–C coupling reaction was proposed to occur from the starting five-coordinate species 153. Hence, the use of more polar solvents can favor selective C–O coupling; with acetone as a solvent the ratio of the C–O:C–C-coupled products is as high as 13:1. The first monoarylpalladium(IV) complexes 157–159 that were shown to exhibit clean C(sp2)–O, C(sp2)–Cl, and C(sp2)–Br reductive elimination reactivity, respectively, use a different ancillary ligand platform. They were prepared by oxidation with dilute aqueous H2O2 of the corresponding Pd(II) precursors 155 supported by di(2-pyridyl)ketone (dpk) ligand. The role of the dpk ligand is twofold. First, it forms a hydroperoxoketal complex 156 where the oxidizing OOH fragment is brought to a close proximity to the reducing Pd(II) center. Second, the hydrated and singly deprotonated form of dpk acts as a good facially chelating anionic ligand stabilizing the octahedral Pd(IV) center. The Pd(IV) hydroxo complexes 157 resulting from the H2O2 oxidation can be subsequently converted to their chloro and bromo analogs, 158 and 159, respectively, using HCl or HBr (Scheme 60).86 Remarkably, both experimental and computational (DFT) studies point to the realization of concerted C–X reductive elimination directly from the six-coordinate Pd(IV) species 157–159. This mechanistic feature appears to be common for dpk-derived Pd(IV) monohydrocarbyl complexes. The first-order rate constants for all of the C–X reductive elimination reactions in Scheme 60 fall in a very narrow range of (1.6–2.5)  105 s1 at 22°C. Using the same ligand platform, the first isolable monoaryl amido Pd(IV) complexes 162 that demonstrate clean and high-yielding C(sp2)–N coupling reactivity were prepared by oxidation with dilute H2O2 of the dpk-supported amido aryl Pd(II) precursors 160. The oxidation is possible in THF, MeOH, MeCN, or AcOH used as a solvent (Scheme 61).87 Some of the intermediate hydroperoxoketal-derived Pd(II) complexes 161 and aryl amido Pd(IV) complexes 162 were characterized by single-crystal X-ray diffraction. The C(sp2)–N reductive elimination of the aryl amido Pd(IV) complexes 162 produces the corresponding N-substituted carbazoles 163 in high yield. The reaction rates are faster for Pd(IV) complexes incorporating electronricher amido ligands (R, MeSO2 > CF3SO2 > CF3CO), which corresponds

X

OH R

N PdII OAc− N

155

excess H2O2

water, 0°C N 1h Pd II OAc−

R

N N HO2

N O

R = MeO, Me, H, F

N PdIV

R

N ON

OH 156

OH

157 water, 20°C 2 days

HX

N PdIV

Me

OAc−

X−

N ON

X = Cl, Br

158 (X = Cl) 159 (X = Br)

OH

water, 20°C 2 days

R Me −

OAc

N

O Pd N N

>95% HO OH

Scheme 60

N X + (dpk)PdX2

267

Oxidative Functionalization

Pd N

H2O2

NR N

− “(dpk)PdII”

OH NR Pd N N O

NR Pd N N

20 − 60°C

N R

>95% O

HO

OH

OOH

161

160

162

163

R=SO2CH3, SO2CF3, COCF3

Scheme 61

F N Pd FN

150°C

N

DMSO SO2

F N

− “Pd(II)” NO2

L = MeCN 165

CH2Cl N 2BF4 N F (Selectfluor)

Pd N

MeCN

N

166

Me4NF BF4 F N Pd LN

50°C N MeCN − “Pd(II)”

SO2 SO2

N

NO2

L = MeCN NO2

F

164

166 F

N N t-Bu

N

XeF2

Pd F

XeF2

t-Bu

F

t-Bu

N t-Bu 167

F

80°C

F

PhNO2 −“Pd(II)”

F

Pd F HF

F 168

Scheme 62

to higher pKa values of the parent N–H acids for the more reactive complexes. Notably, no competing C–O coupling was observed. Isolable monohydrocarbyl Pd(IV) complexes exhibiting clean C(sp2)–F coupling reactivity have been known since 2008.88 Two such complexes, 165 and 167, can be prepared by fluorination of the corresponding Pd(II) precursors with Selectfluor® or XeF2 (Scheme 62). The C(sp2)–F bond

268

Anna V. Sberegaeva et al.

elimination from the isolated 165 requires high temperature, but its more labile cationic monofluoro analog 164 reacts under much milder conditions to produce the same arylfluoride 166. Both experimental and computational analysis suggest that these reactions proceed via five-coordinate Pd(IV) species resulting from the dissociation of one fluoride (165) or acetonitrile ligand L (164). The trifluoropalladium(IV) aryl complex 167 appears to be highly oxidizing; high-yielding reductive elimination of the corresponding arylfluoride 168 is only possible in the presence of excess fluorinating agent such as XeF2. Some of the first isolated aryl chloro Pd(IV) complexes, diaryl 16989 and monoaryl Pd(IV) species 170,90 are shown in Scheme 63. Both compounds can be prepared by chlorination of the corresponding Pd(II) precursors. The diaryl complex 169 eliminates the corresponding arylchloride and, competitively, the C–C-coupled diaryl product in up to 7:1 ratio. Reductive elimination of a more reactive monoaryl complex 170 proceeds under milder conditions to form selectively the derived arylchloride in a form of a Pd(II) complex 171. Considering many currently known examples of C(sp2)–C reductive elimination reactions of aryl Pd(IV) complexes,91–95 it is worth mentioning the transformations involving CF3 ligand. Such reactions are more challenging than other C(sp2)–C coupling transformations.93–95 In particular, the success of the oxidative coupling of an aryl and the CF3 ligands present in the Pd(II) complex 172 depends strongly on the nature of the oxidant (Scheme 64).94 Neither N-chlorosuccinimide nor PhI(OAc)2 is efficient in this reaction, whereas the use of N-fluoro-2,4,6-trimethylpyridinium triflate allows for a high-yielding Ar–CF3 coupling. The reaction intermediate, the aryl

N N

Pd

PhICl2

N

N

80°C

Cl

AcOH

Pd IV

−PhI

Cl 152

N

Cl and N 7:1

169

N N

Pd i-Pr

PhICl2

O N

MeCN

O

N

N 170

Scheme 63

N

−[Pd ] II

Cl

33°C

Cl

MeCN

Pd NiPr

Cl N

Pd

Cl 75%

i-Pr

O N N

171

269

Oxidative Functionalization

F

F

t-Bu N N

F

Pd

t-Bu 172

CF3

F

t-Bu

N TfO

N N t-Bu

CF3

80°C, 3 h

F

PhNO2 − “Pd(II)”

Pd OTf

CF3

173

77% −TfO

− “Pd(II)”

F

t-Bu CF3

N N t-Bu

Pd F

174

Scheme 64

trifluoromethyl Pd(IV) complex 173, could be isolated at 22°C. The latter complex reductively eliminates the derived trifluoromethylarene in 77% yield when exposed to the same conditions that are used in the oxidative coupling reaction. Subsequent mechanistic studies and computational analysis of the reductive elimination of 173 suggest the prior formation of a five-coordinate Pd(IV) transient 174 resulting from reversible dissociation of the triflate ligand with subsequent concerted C–C elimination from 174.95 Interestingly, based on results of the computational analysis, at the coupling step the CF3 ligand acts as an electrophilic component, whereas the aryl ligand acts as a nucleophilic one. Recently, various Pd-catalyzed oxidative C–H functionalization reactions have been developed that involve the C(sp2)–F, C(sp2)–Cl, C(sp2)–O, or C(sp2)–C oxidative coupling step (Scheme 65).1 The mechanistic analysis of these catalytic reactions raises the question whether or not the reactions involve the corresponding Pd(IV) aryl complexes as catalytically competent reaction intermediates. To answer this question detailed kinetics studies are required. However, even the kinetics studies may not be informative when the oxidation of organometallic intermediates is not the catalyst turnoverlimiting step (Scheme 65, step 2). The Pd-catalyzed oxidative C–H chlorination with N-chlorosuccinimide96 and oxidative C–H arylation with [Ar2I]BF497 are examples of reactions where the oxidation step is turnover limiting. Detailed kinetics and computational98 studies of these reactions show that the reactions

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C H

HX Step 1

C

[M]-X

[M] Oxidant, HX

C X X

Step 3 C

Step 2

[M]

Scheme 65

involve catalytically competent dinuclear PdIII species. In particular, the mechanism of the C–H chlorination of benzo[h]quinoline with N-chlorosuccinimide96 involves catalytically active isolable dinuclear Pd(II) species 175 and the bisaryl dipalladium(III) intermediate 176. The latter could be generated independently and was shown to cleanly eliminate 10-chlorobenzo[h] quinolone 177 under the catalytic reaction conditions (Scheme 66). Acetato-bridged dinuclear organopalladium(III) complexes, analogs of 176, were first prepared and their C(sp2)–Cl and C(sp2)–O reductive elimination reactivity characterized in 2009.99

5.3 Platinum 5.3.1 Oxidative C–X Coupling (X 5 C, Cl, I, O, N) Involving Pt–C(sp3) Bonds Platinum holds a special place among the metals discussed in this chapter. Platinum(II) complexes were the first transition metal compounds that were reported in the late 1960s to the early 1970s100 to activate the alkane C–H bonds and catalyze their oxidative transformations. A recent historical review of this chemistry is available.101 The key reaction sequence involved in the oxidative Pt(II)–CH3 bond functionalization in the original catalytic system is presented in Scheme 67A. The methylplatinum(II) species 178 are oxidized to form methylplatinum(IV) intermediates 179, which is accomplished in the original catalytic methane oxidation system by the action of PtCl6 2 .100 The methylplatinum(IV) intermediate 179 is electrophilic enough to accept SN2 attacks of various nucleophiles Nu, e.g., Cl, or HNu, e.g., H2O, and form the corresponding products of oxidative Pt(II)–CH3 bond functionalization, CH3–Nu, 180. The reaction

271

Oxidative Functionalization

OC

CO N Cl

O

N OC

CO

Pd

N

N

Cl

CO

OC N H

O O Pd N N O O

O

OH

N

N

Me

N

Pd

O

O O Pd N

Cl

N

N

N

Pd

O O N

OAc

O

O + AcOH

175

Pd

Turnover-limiting oxidation

176

Cl N

N 177

Scheme 66

A X

oxidant PtII

X

CH3

178

PtIV

+ CH3-Nu + X−

PtII

CH3

(or HX)

Nu− (or HNu)

179

B

180

PtIV II

Pt H D

D

H

D

+H2O, −H+

D

H

Cl− OH

−PtII

H

Cl OH

H 181

Scheme 67

D

PtCl62−

182

183

D H

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mechanism requires that the ligand trans to CH3 in the intermediate 179 is a good leaving group. The mechanism of the last step of the Pt(II)–C bond functionalization sequence in Scheme 67 was studied using isotopically labeled 2-hydroxyethyl Pt(IV) chloro complexes, such as 182 derived from trans1,2-dideuterioethylene complex 181 (Scheme 67B), as a model. The nucleophilic attacks at 182 by Cl or water used as a solvent lead to the formation of new C(sp3)–Cl (chloroethanol) or C(sp3)–O bonds (1,2-ethanediol), respectively. Importantly, the reaction of 182 with Cl was found to include an inversion of the configuration of the PtIV-bound carbon atom (compare 182 and 183), as expected for an SN2 mechanism.102 Two series of model complexes, (dppe)PtMe3(OR) (R ¼ Ac, p-Tol, 184) and (dppbz)PtMe3(OR) (R ¼ H, Ac, p-Tol, 187), were used to demonstrate the ability of model Pt(IV) methyl complexes to reductively eliminate C–Ocoupled products MeOR. These products formed predominantly (88%–98%) in weakly polar solvents such as benzene and THF (Scheme 68).103,104 In more polar acetone and nitrobenzene the reactions are much faster, but they produce predominantly ethane, the product of the C–C coupling. Similarly, thermolysis of analogous sulfonylamido complexes, (dppbz) PtMe3(NHSO2R) (R ¼ Me, p-Tol, p-C6H4(n-C4H9), 188), produces Ph2 P benzene or THF

Ph2 Me P Me PtIV Me P Ph2 X

Ph2 Me P Me PtIV Me P Ph2 X acetone 186 or PhNO2

X = AcO, p-TolO (184) = I (185)

Ph2 P

Ph2 Me P Me PtIV Me P Ph2 X

benzene or THF

acetone or PhNO2

X = OH, AcO, p-TolO (187) = NHSO2Me, NHSO2(p-C6H4Me), NHSO2(p-C6H4C4H9) (188)

Scheme 68

P Ph2

Ph2 P P Ph2

P Ph2 Ph2 P P Ph2

Me PtII Me

+ Me–X

X PtII Me

+ Me–Me

Me PtII Me

+ Me–X

X PtII Me

+ Me–Me

Oxidative Functionalization

273

C(sp3)–N-coupled products, N-methylsulfonylamides, and, concurrently, ethane.105 Finally, (dppe)PtMe3(I), 185, showed a competitive C(sp3)–I and C–C coupling, leading to MeI and ethane, respectively.106,107 The reactions in Scheme 68 have been proposed to proceed via initial dissociation of the corresponding anionic ligands X to form fivecoordinate intermediates such as 186. In the case of the C–X coupling, this step is followed by SN2-type nucleophilic attack of X at the methyl ligand of 186 situated trans to the coordination vacancy. The same five-coordinate intermediates 186 are involved in the C–C coupling. The ability of 186 to concurrently react with X is diminished severely in more polar solvents due to stronger ionic solvation of X that negatively impacts the reactivity of the ionic nucleophiles. The role of five-coordinate polymethyl Pt(IV) intermediates in the C–C reductive elimination of ethane was also elucidated in the thermal decomposition of some trimethyl as well as tetramethylplatinum(IV) complexes. The rate of these reactions leading to ethane was analyzed as a function of the chelating diphosphine bite angle108 and the ability of the monodentate ligands present in the metal coordination sphere to dissociate.109,110 When the formation of five-coordinate intermediates is not too energetically costly, the reactions proceed via five-coordinate intermediates. The subsequent reductive elimination of these five-coordinate transients is much more facile than directly from the six-coordinate reactants. The five-coordinate intermediates may not be readily available when rigid-chelating ligands are used and the formally anionic ligands such as methyl or hydride are not able to readily dissociate. In such cases, direct reductive elimination from six-coordinate Pt(IV) complexes takes place. To make the Pt(II)–C bond functionalization sequence in Scheme 67 more attractive and potentially suitable for practical use in oxidative functionalization of inexpensive hydrocarbons, the cost of the oxidant should be minimal. Oxygen is considered as one of the ideal candidates for this role. Earlier works reported radical chain insertion of O2 into Pt(II)–Me bond of complex 189 to produce a methylperoxo Pt(II) species 190 in high yield (Scheme 69A).111 A nonradical photochemical insertion of O2 into Pt(II)–CH3 bond of complex 191 was also reported to form effectively a methylperoxo Pt(II) species 192 (Scheme 69B). The latter product decomposes to form formaldehyde and a Pt(II) hydroxo complex. The reaction of 191 with oxygen was proposed to involve an excited-state dinuclear metal species that reacts with O2 to form an η2-peroxo Pt(IV) transient. The latter undergoes subsequent C–O elimination to form 192.80

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A t-Bu

t-Bu P

t-Bu

Me Pt Me

N

5 stm.O2

t-Bu P

20°C N

189

Me Pt OOMe

190

B SbF6

SbF6 NH2

NH2 N

N N Pt Me

O2, light

N Pt OOMe

20°C N

N

NH2

NH2 191

192

Scheme 69

The use of semilabile facially chelating sulfonated dipyridinemethane ligands such as dpms (Scheme 70) provides an opportunity for clean aerobic Pt(II)–C(sp3) bond functionalization and formation of functionalized alkane derivatives in protic media.112 Most of the reactions in Scheme 70 are virtually quantitative and sufficiently fast when they are run in aqueous solutions under air at 20°C. The reactions allow, in particular, for efficient aerobic functionalization of the Pt(II)–C(sp3) but not Pt(II)–C(sp2) bond112b in such complexes as 193 and 196 to form methanol,113 dimethyl ether,114 olefin oxides,115,116 or aminoalcohols.117 The transformations are two steps. In the first step, Pt(IV) alkyl hydroxo complexes 194 or 197 are produced that do not readily eliminate C–O-coupled products and are often isolable. The requirement to have a good leaving group, the sulfonate in this case, trans to the alkyl ligand translates to faster C–O elimination reactivity of their isomers such as 195, which have the required ligand arrangement. The mechanism of the aerobic oxidation of (dpms)PtMe(H2O) was studied computationally118 and experimentally using kinetics and isotopic labeling techniques.119

SO3

HC

HC

0.5O2 PtII R (HX) 20°C H2O or MeOH 193

N N

N N

60–90°C

194

Scheme 70

N N

+

20°C

2+ OH2 PtII OH2

O

SO2 O

0.5O2

N N

20°C H2O

HO 20−90°C

O H+

OH

O

HN

or O

= (t-Bu)N

HC SO3

NH2R'

or

PtIV C X

197

O

H

R = Me, C2H4OH X = OH, OMe

196 C X

PtIV OH X

195

HC

PtII C X H

HC SO3 MeOH, Me2O or

+

R

OH

SO3 N N

N N

PtIV R X

R = Me, Ph, C2H4OH HX = H2O, MeOH

HC

SO2 O

HC

SO2 O

+

N N

2+ OH PtII OH2 2

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5.3.2 Oxidative C–X Coupling (X 5 Br, O) Involving Pt(III)–C(sp3) Bonds The two-step functionalization of Pt(II)–C(sp3) bond discussed earlier is not the only option for oxidative C(sp3)–X coupling. Remarkably, some “paddlewheel”-type alkyl Pt(III) complexes such as 198 were considered as intermediates in aerobic epoxidation of some olefins (Scheme 71A).120 The Pt(III)–C(sp3) bond cleavage was proposed to result from an SN2 attack of a nucleophile (H2O, MeOH) at the Pt(III)-bound carbon atom. Interestingly, the mononuclear bromoplatinum(III) alkyl complex 199 that is stable enough to be isolated and fully characterized eliminates a C–Br bond to form 201 in the absence of oxidants, as a result of its disproportionation into a Pt(II) and Pt(IV) species, presumably, 200.121 The latter, highly reactive transient also results from reaction of 199 with Br2 at 78°C. The Pt(IV) complex 200 eliminates a C(sp3)–Br bond readily upon warming up to 20°C. 5.3.3 Oxidative C–X Coupling (X 5 C, F, Br, I) Involving Pt–C(sp2) Bonds Oxidative functionalization of Pt(II)–Ar bonds in (di)arylplatinum(II) complexes leading to competitive or exclusive formation of C(sp2)–C(sp2) and/ or C(sp2)–X-coupled products (X ¼ F, Br, I) has been recently reviewed.122 Free halogens, Br2 and I2, and XeF2 can be used as oxidants in these reactions. Iodination of bis(aryl)platinum complexes, (dmpe)Pt (p-C6H4F)2, 202, and (dmpbz)Pt(p-C6H4F)2, 204, with I2 produces trans-diiodo derivatives 203 and 205, respectively (Scheme 72).123 A gentle heating of 203 leads to a competitive C–I and C–C coupling, whereas 205, containing a more rigid-chelating ligand dmpbz, forms exclusively the C–I-coupled product. It was proposed that the C–C coupling reaction requires prior formation of five-coordinate Pt(IV) transients and is accompanied by the formation of cis-isomeric complexes such as 206, whereas the C–I coupling occurs as a direct elimination from tight ion pairs closely resembling the six-coordinate precursors. Notably, the cis-isomeric complex 206 can only be engaged in a C–C coupling. Hence, avoidance of the trans-/ cis-isomerization of 203 allows for suppression of C(sp2)–C(sp2) coupling and more selective C–I elimination. The factors that disfavor the isomerization are the absence of light, the use of more polar solvents (DMF vs benzene), and the use of a more rigid-chelating ligand (dmpbz vs dmpe); their effect was analyzed computationally (DFT). A similar approach was used to direct Pt(II)–C(sp2) bond functionalization toward selective formation of C(sp2)–Br vs C(sp2)–C(sp2) bond (Scheme 73).124 When a rigid bulky chelating quinoxaline-derived diphosphine ligand is used, bromination of the corresponding

A n NO3 H3N H3N H3N H3N

RO

2+

Pt

O O

Pt

N N

n

ROH

NO3

3+

H3N H3N

Pt

N N

n

60°C

+ “[Pt(II)]2”

RO

H3N H3N

R = H, Me n = 1, 2

Pt

O O

ROH OR O

O HN

N

B i-Pr

i-Pr N

N

i-Pr

i-Pr

BArF4

N

N

Br 0.5Br2

i-Pr Br Pt

Pt i-Pr

−78°C Br

BArF4

i-Pr

i-Pr N

N

20°C Br

Pt

L

L

L

199

200

201

i-Pr L=

N i-Pr

Scheme 71

t-Bu

=

198

i-Pr N i-Pr

i-Pr Br

BArF4

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Me2 P Ar Pt Ar P Me2

Me2 I P Ar Pt Ar P Me2 I

l2

Me2 P Pt P Me2

DMF, dark

Ar + Ar–I I

203 trans-(dmpe)PtAr2(I)2 205 trans-(dmpbz)PtAr2(I)2

202 (dmpe)PtAr2 204 (dmpbz)PtAr2 Ar = p-C6H4F

isomerization (photo- or thermal) Me2Ar P I Pt Ar P Me2 I

Me2 P Pt P Me2

I + Ar–Ar I

206 cis-(dmpe)PtAr2(I)2

Scheme 72

Me t-Bu P C6F5 Pt Ar P N t-Bu Me N

Br2

207

Me t-Bu MeCN Br P C6F5 80°C Pt P Br Ar N t-Bu Me N

Me t-Bu P C6F5 Pt + Ar–Br Br P N t-Bu Me N

208 Ar = p-C6H4F

Scheme 73

diarylplatinum(II) complex 207 produces trans-dibromoplatinum(IV) complex 208 exclusively. Heating 208 in MeCN leads to a clean C–Br elimination of p-BrC6H4F favoring the more electron-rich p-C6H4F aryl ligand over the electron-poorer C6F5. The fluoride ligand has a reputation of being one of the least reactive simple anionic ligands when it comes to C(sp2)–X coupling. To exclude the possibility of competitive C–C coupling a series of monoaryl Pt(IV) complexes 209–211 were used, all having very bulky 2-bis(1-adamantyl)phosphinophenoxide ligand (Scheme 74).125 Xenon difluoride was employed as a fluorinating agent. While 209 and 210 with relatively “compact” p-C6H5F and 3,5-F2C6H3 ligands failed to produce arylfluorides, the most sterically hindered mesityl complex 211 produced mesitylfluoride in quantitative yield. A two-step mechanism was proposed. In the first step, the ratedetermining dissociation of the pyridine ligand produces a five-coordinate Pt(IV) transient 212 that is involved in a subsequent fast C(sp2)–F coupling. The aryl steric bulk appears to be the critical factor facilitating pyridine dissociation.

279

Oxidative Functionalization

py

Ar

py

py

XeF2 O

Pt PAd2

Ar

O –30°C CH2Cl2

Pt

F F

PAd2

Ar= 4-FC6H4 (209) 3,5-F2C6H3 (210) 2,4,6-(Me)3C6H2 (211)

60–100°C O toluene Ar = Mes

F

Pt

+ Mes–F

PAd2

Ar = Mes

–py Ar O

Pt

F F

PAd2 212

Scheme 74

6. GROUP 11 METALS 6.1 Copper The success and versatility of Pd-catalyzed oxidative functionalization of organic substrates involving high-valent organopalladium species raised interest in the exploration of other transition metals with accessible higher oxidation states. The organometallic transients resulting from activation of suitable organic substrates by low-valent metal compounds can, potentially, be intercepted by strong oxidants to produce the respective high-valent organometallic derivatives. Similar to organopalladium(IV) chemistry, such studies may promise new discoveries and success when developing new organic synthetic methodologies. Copper is one of the metals that has recently become involved in such exploration. The inorganic high-valent Cu(III) compounds are known to be accessible, although with more difficulty than high-valent Pd(IV) complexes. Importantly, the application of copper compounds in catalysis has a long story beginning with the Ullmann C(sp2)–X coupling reaction (X ¼ O, N, S).126 This section of the chapter will present some of the recent results exploring the oxidative functionalization of the Cu–C bond, mostly involving organocopper(III) complexes. 6.1.1 Oxidative C–X Coupling (X 5 F, O, N) Involving Cu–C(sp2) Bonds One of the early discoveries, the facile C(sp2)–H activation of macrocyclic arenetriamines 213 by Cu(II) salts to form macrocyclic organocopper(III) compounds 214–216 along with Cu(I) species also containing coordinated

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ligand 213, dates back to the early 2000s (Scheme 75).127 The assignment of the +3 oxidation state of the metal in the complexes 214–216 is based on analysis of their Cu K-edge X-ray absorption spectra. The copper(III) center features a square planar arrangement of the donor atoms. Interestingly, in the presence of halide anions, Cl, Br, I, the geometry of the metal coordination unit changes to square pyramidal with one halide ligand in the axial position.128 The yield of the Cu(III) complexes 214–216, based on the macrocycles 213, was initially only 50% because of the formation of a Cu(I) by-product with coordinated 213. Running the reaction in DMF under air to allow for reoxidation of Cu(I) back to Cu(II) allows to improve the yield of Cu(III) products up to 92%.128 Building on the successful preparation and the availability of organocopper(III) compounds 214–216, a study of their C(sp2)–X coupling reactivity has been undertaken. Reaction of the arylcopper(III) complexes 216 and its p-methyl and p-nitro analogs, 217 and 218, respectively, with various sufficiently N–H acidic (pKa  17) nitrogen nucleophiles HNu in MeCN leads to a facile C(sp2)–N coupling and formation of the corresponding macrocyclic N-aryl derivatives 219 in quantitative yield along with the Cu(I) complex [Cu(NCMe)4]ClO4 (Scheme 76).129 The more acidic substrates HNu react more rapidly. In turn, the electron-poorer nitro-substituted organocopper(III) complex 218 was the most reactive in the series of complexes studied. Interestingly, heating 216 at 50°C in MeCN results in the product of intramolecular C(sp2)–N coupling, 220. No Cu(III) reaction intermediates were detected in these experiments. Two reaction mechanisms were proposed, one involving direct attack of deprotonated nucleophiles at the Cu(III)-bound carbon, and one involving coordination of a nucleophile to the metal center with subsequent concerted C–N reductive elimination. 2+ 2ClO4– NH

Cu(ClO4)2

NH

MeCN 20°C

R N n 213 n = 0, 1 R = H, Me

Scheme 75

HN

Cu

NH

RN n 214 (n = 0; R = H) 215 (n = 1; R = H) 216 (n = 1; R = Me)

+ “Cu(I)”

281

Oxidative Functionalization

R

HNu :

R Nu Me N

NH

2+

+ HNu

NH

O

2ClO4 HN

–[Cu(NCMe)4]ClO4

NH

Cu

O C NH

–

219

MeN

SO2NH2

R=H 216 (R = H) 217 (R = Me) 218 (R = NO2)

NH C O

MeCN 50°C

ClO4– NH MeN⊕

R′ R′ = H, Me, MeO

NH

220

Scheme 76 HNu :

2+ 2ClO4– + HNu HN

Cu

NH

MeN 216

–[Cu(NCMe)4]ClO4

NH

Nu Me N

O

O

O

OH

OH

OH

CF3CH2OH

CBr3CH2OH

Me3COH

NH O

OH OH

OH

221 R R = H, Me, MeO, CF3, NO2

R′ R′ = H, MeO, F, Cl, CF3, CN, NO2

Scheme 77

In a related study the reactivity of the Cu(III) complex 216 toward various O-nucleophiles was investigated (Scheme 77).130 The selected nucleophiles HNu react with 216 in MeCN solution at 15–50°C to form the corresponding C(sp2)–O-coupled macrocycles 221 and a Cu(I) complex [Cu(NCMe)4]ClO4. As in the case of N–H acids (Scheme 76), the more acidic substrates react at faster rates. No Cu(III) intermediates were detected, as in the case with the N–H acids.129 Notably, the oxidative C–H functionalization of the macrocycle 213 (n ¼ 1, R¼ Me) could be performed when this compound was combined with a catalytic (10%) amount of Cu(ClO4)2 or CuBr2 in methanol solution. The products 219 or 221 resulting from a combination of reactions in

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Schemes 75 and 76 (HNu ¼ 2-pyridone) or Schemes 75 and 77 (HNu ¼ MeOH), respectively, formed in high 72%–84% yields. Neither the expected Cu(III) intermediates 216 nor the derived five-coordinate adduct with bromide ion were detected in the reaction mixtures so pointing to the viability of the organocopper(III)-mediated oxidative C–H functionalization.128 In the absence of specific highly Cu(III)-stabilizing ligands such as 213 the chances to detect organocopper(III) species are low. As a result, the involvement of organocopper(III) intermediates is often suggested and even supported by DFT calculations. For example, the involvement of organocopper(III) intermediates was suggested in enantioselective benzylic C–H bond cyanation using bis(benzenesulfonyl)fluoramine and trimethylsilyl cyanide,131 fluorination of arylstannanes and aryltrifluoroborates with N-fluoro-2,4,6-trimethylpyridinium triflate,132 and fluorination of aryltrifluoroborates with KF as the fluorine source and Cu(OTf )2 as the oxidant and the mediator for the C(sp2)–F coupling.133 A computational (DFT) study of Cu-catalyzed C(sp2)–F coupling of diaryliodonium triflates and KF also points to the involvement of arylcopper(III) species.134

6.2 Silver Various inorganic silver(I) compounds are often encountered in organic synthetic preparations and, particularly, in Pd-catalyzed C–H functionalization reactions, as additives playing the role of a base or an one-electron oxidant. Recently a few reports have appeared pointing to the ability of phosphineligated Ag(I) carboxylates such as AdCO2Ag(PPh3) (Ad ¼ 1-adamantyl), 223,135 or t-BuCO2Ag(L), 224,136 to break some relatively acidic aromatic C(sp2)–H bonds (Scheme 78). The organic substrates that are used to demonstrate this reactivity are a substituted benzenetricarbonylchromium(0) complex 222 and pentafluorobenzene.136 In both cases an efficient silvermediated H/D exchange was observed between the aromatic substrate and D2O. The resulting arylsilver(I) compounds may then be involved in aryl transmetallation to a Pd(II) center in the reactions utilizing such Ag(I) carboxylates in combination with Pd(0) phosphine complexes.135,136 Me

F H Cr(CO)3 222

Scheme 78

D2O, PhMe 70°C, 2 h

Me

D

AdCO2Ag(PPh3) (223)

F

Cr(CO)3 75%

283

Oxidative Functionalization

Surprisingly, some of such reactions are zero order in Pd catalyst,135 so implying that the rate-determining step does not involve the Pd species. Based on these reports, one can expect that the role of silver(I) compounds in organometallic catalysis may be more significant than that of bases or oxidants assigned to them traditionally.

6.3 Gold Organogold chemistry has received a great deal of attention in the past two decades after it was discovered that gold can efficiently mediate a variety of transformations involving olefin and allene C]C and alkyne C^C bonds making them more susceptible to nucleophilic attacks.137,138 Both Au(I) and Au(III) compounds are often used in these reactions as Lewis acids. At the same time, until recently the use of the AuI/AuIII and AuI/AuII (dinuclear complexes with Au–Au bond) redox couples in organic synthesis remained somewhat limited. In this section, we will focus on the Au–C oxidative functionalization involving high-valent gold compounds. There is a recent review summarizing progress in the field of organogold chemistry.138 6.3.1 Oxidative C–X Coupling (X 5 Cl, Br, I, C, P) Involving Au–C(sp2) Bonds Various phosphine (L)-ligated aryl, vinyl, and alkylgold(I) complexes (L)AuR, 226 (L ¼ PPh3), can be readily prepared starting from the corresponding (L) AuCl precursors 225 and boronic acids (Scheme 79).139 The resulting compounds 226 contain a two-coordinate gold atom with the P–Au–C angle close to 180 degrees, often showing a 3- to 5-degree Cs2CO3 Ph3P Au Cl + RB(OH)2 225

i-PrOH, 50°C 24 h

Ph3P Au R 226

R= NO2 O C2H5

Scheme 79

CHO

Me

Me O

CHO

OMe

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Anna V. Sberegaeva et al.

X-halogenating agent Au(PPh3) 227

X-halogenating agents:

X –“(Ph3P)Au(I)”

228

O C NX C O (X = Cl, Br, I)

Scheme 80

deviation from linearity due to packing effects in the crystals. The low coordination number of the metal makes the metal atom readily accessible for attacks by various agents. In particular, reactions of the vinylgold(I) complex 227 with N–X–succinimides (X ¼ Cl, Br, I) lead to the corresponding vinyl halides 228 in 88%–96% yield (Scheme 80).139 Reactions of the arylgold(I) complexes 226 shown in Scheme 79 with N–X–succinimides (X ¼ Cl, Br, I) also produce the corresponding halides R–X in yields exceeding 95%.140 In turn, the use of Selectfluor® or N-fluorobenzenesulfonimide enables the exclusive formation of the corresponding diaryls.140 A more detailed picture of reactivity of organogold(I) compounds in Au–C 2 (sp ) bond oxidative functionalization reactions was obtained in another study where PhICl2 was used as an oxidant at 78°C (Scheme 81).141,142 First, organogold(III) complexes were produced. Second, the study revealed that the type of organogold(III) products resulting from oxidation of (R3P)Au(Ar) complexes is very sensitive to the nature of the phosphine ligand employed, PR3. Oxidation with PhICl2 of the complex (Ph3P)Au(p-C6H4F), 230, supported by triphenylphosphine ligand leads to the formation of the diarylgold(III) compound 231 already at 78°C (Scheme 81A). It is speculated that the oxidation of Au(I) to Au(III) occurs at a much slower rate than the subsequent aryl ligand transmetallation from Au(I) to Au(III).142 As a result, 50% of the starting material 230 is consumed in the transmetallation reaction and is converted to the chlorogold(I) compound 225. The use of a bulkier and more donating tricyclohexylphosphine ligand instead of PPh3 slows down transmetallation and results in the quantitative oxidation of 232, the PCy3 analog of the arylgold(III) complex 230, to form the aryldichlorogold(III) complex 233 (Scheme 81B).141

285

Oxidative Functionalization

A 2 Ph3P Au Ar

+ PhICl2 – PhI

Ar Ph3P Au Ar

–78°C

230

+

Ph3P Au Cl

Cl

231

225

Ar = p-C6H4F B Cy3P Au Ar

+ PhICl2 – PhI

Ar Cy3P Au Cl Cl 233

20°C

232 Ar = p-C6H4F

Scheme 81

Ar

A

Ar

–PPh3

231

Cl