[1st Edition] 9780128119938, 9780128119730

Table of contents :
Content:
Advances in Heterocyclic ChemistryPage i
Editorial Advisory BoardPage ii
Front MatterPage iii
CopyrightPage iv
ContributorsPage vii
PrefacePage ixChris Ramsden, Eric Scriven
Chapter One - Recent Developments in the Chemistry of 3-Arylisoxazoles and 3-Aryl-2-isoxazolinesOriginal Research ArticlePages 1-41P. Vitale, A. Scilimati
Chapter Two - Diketene as Privileged Synthon in the Syntheses of Heterocycles Part 1: Four- and Five-Membered Ring HeterocyclesaOriginal Research ArticlePages 43-114M.M. Heravi, B. Talaei
Chapter Three - Synthesis of Heterocycles From AmidrazonesOriginal Research ArticlePages 115-139A.A. Aly, M. Ramadan, H.M. Fatthy
Chapter Four - 2-Pyridone Methides (2-Methylene-1,2-dihydropyridines) and Benzo-Fused Analogs—Part 1: SynthesisOriginal Research ArticlePages 141-189G. Fischer
Chapter Five - Synthesis of Piperidines and Dehydropiperidines: Construction of the Six-Membered RingOriginal Research ArticlePages 191-244M.M. Nebe, T. Opatz
Chapter Six - The Literature of Heterocyclic Chemistry, Part XIV, 2014Original Research ArticlePages 245-301Leonid I. Belen'kii, Yu B. Evdokimenkova
IndexPages 303-323

Citation preview

VOLUME ONE HUNDRED AND TWENTY TWO

ADVANCES IN HETEROCYCLIC CHEMISTRY

EDITORIAL ADVISORY BOARD A. T. Balaban Galveston, Texas, United States of America A. J. Boulton Norwich, United Kingdom M. Brimble Auckland, New Zealand D. L. Comins Raleigh, North Carolina, United States of America J. Cossy Paris, France J. A. Joule Manchester, United Kingdom P. Koutentis, Cyprus V. I. Minkin Rostov-on-Don, Russia B. U. W. Maes Antwerp, Belgium A. Padwa Atlanta, Georgia, United States of America A. Schmidt Clausthal, Germany V. Snieckus Kingston, Ontario, Canada B. Stanovnik Ljubljana, Slovenia C. V. Stevens Ghent, Belgium J. A. Zoltewicz Gainesville, Florida, United States of America

VOLUME ONE HUNDRED AND TWENTY TWO

ADVANCES IN HETEROCYCLIC CHEMISTRY Editors

ERIC F. V. SCRIVEN Department of Chemistry, University of Florida, Gainesville, FL, USA

CHRISTOPHER A. RAMSDEN Lennard-Jones Laboratories, Keele University, Staffordshire, United Kingdom

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 125 London Wall, London EC2Y 5AS, United Kingdom The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, 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: 978-0-12-811973-0 ISSN: 0065-2725 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Zoe Kruze Acquisition Editor: Poppy Garraway Editorial Project Manager: Shellie Bryant Production Project Manager: Surya Narayanan Jayachandran Senior Cover Designer: Mark Rogers Typeset by TNQ Books and Journals

CONTRIBUTORS A.A. Aly Minia University, Minia, Egypt Leonid I. Belen’kii N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation Yu B. Evdokimenkova Library for Natural Sciences, Russian Academy of Sciences, Moscow, Russian Federation H.M. Fatthy Al-Azhar University, Assiut, Egypt G. Fischer Leipzig, Germany M.M. Heravi Alzahra University, Tehran, Iran M.M. Nebe University of Mainz, Mainz, Germany T. Opatz University of Mainz, Mainz, Germany M. Ramadan Al-Azhar University, Assiut, Egypt A. Scilimati Department of Pharmacy-Pharmaceutical Sciences, University of Bari “A. Moro”, Bari, Italy B. Talaei Alzahra University, Tehran, Iran P. Vitale C.I.N.M.P.I.S. – Interuniversity Consortium for Innovative Methodologies and Processes for Synthesis, Bari, Italy; Department of Pharmacy-Pharmaceutical Sciences, University of Bari “A. Moro”, Bari, Italy

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PREFACE The opening chapter by Professor Paola Vitale and Antonio Scilimati (C.I.N.M.P.I.S., Bari, Italy) covers recent developments in the chemistry of 3-arylisoxazoles and 3-aryl-2-isoxazolines. Chapter 2 by Professor Majid M. Heravi and Bahareh Talaei from Alzahra University, Tehran, Iran, deals with diketene as a privileged synthon in the synthesis of four- and five-membered ring heterocycles. In the next chapter, Professor Ashraf A. Aly (Minia University, Egypt) and colleagues Mohamed Ramadan and Hazem M. Fatthy from Al-Azhar University, Egypt describe recent methods for the synthesis of heterocycles from amidrazones. In Chapter 4, Professor Gunther Fischer (Leipzig, Germany) presents the latest developments in the synthesis of 2-pyridone methides (2-methylene1,2-dihydropyridines) and benzo-fused analogs. Professor Till Opatz and Marco M. Nebe from the University of Mainz review, in Chapter 5, the synthesis of piperidines and dehydropiperidines, particularly construction of the six-membered ring. In the final chapter, Professor Leonid Belen’kii (Zelinsky Institute, Moscow, Russian Federation) and Yu. B. Evdokimenkova (Russian Academy of Sciences, Moscow, Russian Federation) present The literature of heterocyclic chemistry, part XIV, 2014. Chris Ramsden and Eric Scriven October, 2016.

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CHAPTER ONE

Recent Developments in the Chemistry of 3-Arylisoxazoles and 3-Aryl-2-isoxazolines P. Vitale*, x, 1, A. Scilimatix *C.I.N.M.P.I.S. e Interuniversity Consortium for Innovative Methodologies and Processes for Synthesis, Bari, Italy x Department of Pharmacy-Pharmaceutical Sciences, University of Bari “A. Moro”, Bari, Italy 1 Corresponding author: E-mail: [email protected]

Contents 1. Introduction 2. 3-Arylisoxazoles 2.1 Synthesis of 3-Arylisoxazoles

2 2 2

2.1.1 1,3-Dipolar Cycloadditions 2.1.2 Cyclization of Oxime Derivatives

3 9

2.2 Synthesis of Pharmacologically Active Isoxazoles 2.3 Spectroscopic Techniques and Density Functional Theory Calculations 2.4 Reactions of 3-Arylisoxazoles 3. 3-Aryl-2-isoxazolines 3.1 Synthesis of 3-Aryl-2-isoxazolines 3.1.1 1,3-Dipolar Cycloaddition 3.1.2 Cyclization of Oxime Derivatives

15 18 20 25 25 26 29

3.2 Structure 3.3 Reactions of 3-Aryl-2-isoxazolines 3.4 Pharmacological Active 3-Aryl-2-isoxazolines References

30 32 34 35

Abstract 3-Arylisoxazoles and 3-aryl-2-isoxazolines are versatile building blocks in organic chemistry. They are components of a wide number of pharmaceutical products and biologically active molecules. This chapter describes developments in the chemistry of these heterocycles, focusing on synthetic methods and reactivity studies published in the years 2005e2016. Particular attention is given to the regioselectivity of synthetic methods and their application to the preparation of pharmacological active compounds.

Keywords: 3-Aryl-2-isoxazolines; 3-Arylisoxazoles; 4,5-Dihydroisoxazoles; Isoxazole synthesis; Isoxazoline synthesis; Pharmacological activity. Advances in Heterocyclic Chemistry, Volume 122 ISSN 0065-2725 http://dx.doi.org/10.1016/bs.aihch.2016.10.001

© 2017 Elsevier Inc. All rights reserved.

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1. INTRODUCTION Isoxazoles and isoxazolines are five-membered heterocycles widely used as versatile building blocks in preparative organic chemistry due to the easy cleavage of their NeO bond; they are a masked form of dicarbonyl compounds, which are useful in the synthesis of other heterocycles (1990AHC139). 2-Isoxazolines and isoxazoles are also important scaffolds, as a moiety of the chemical structure of a wide number of drugs and biological active molecules (2005COC925) that act as herbicides, fungicides, analgesics, gamma-aminobutyric acid (GABA)antagonists, antiviral (2010CBD461), antibacterials, and antiinflammatory drugs (2000JMC775). The chemistry of isoxazoles has been the subject of numerous papers, patents, thematic issues, and books chapters. Their synthesis and reactivity, (2012THC(26)261) structure and spectroscopic characteristics, and physicochemical properties have been extensively summarized (2009HC170(P2), 1999THS301, 2008CHECIII365). Isoxazole and isoxazoline chemistry of the last decades has also been collected in chapters of The Chemistry of Heterocyclic Compounds (1999HC49(P2), 2009HC170(P2)), Progress in Heterocyclic Chemistry (1996PHC(8)192, 1997PHC(9)207, 1998PHC(10)209, 1999PHC(11)213, 2000PHC(12)219, 2001PHC(13)217, 2002PHC(14)235, 2003PHC(15)261, 2005PHC(17) 238, 2007PHC(18)288, 2009PHC(21)308), and Comprehensive Heterocyclic Chemistry (1984CHEC(6)1, 1996CHEC-II(3)221, 2008CHECIII365). Among the five-membered ring heterocycles, 3-arylisoxazoles and 3-aryl-2-isoxazolines are stable, versatile compounds (2013S2940), widely present in the scaffolds of pharmacologically active compounds. This chapter highlights the synthesis and the chemistry of aryl-substituted isoxazoles and 2-isoxazolines reported in the years 2005e2016, with reference to their preparation, structural characterization, reactivity, and also their biological in vivo activity.

2. 3-ARYLISOXAZOLES 2.1 Synthesis of 3-Arylisoxazoles In general, isoxazoles can be prepared by [3 þ 2] cycloaddition reaction between nitrile oxides and dipolarophiles (alkenes, alkynes, enolates), by reacting hydroxylamine with a carbonyl derivative or by other

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lesser known approaches (2004TL5991, 2005JCR(S)677). New methodologies developed in the last 10 years to synthesize 3-arylisoxazoles are described in the following paragraphs, and attention is also given to reaction mechanisms. 2.1.1 1,3-Dipolar Cycloadditions 1,3-Dipolar cycloaddition is a notable route for the synthesis of isoxazoles and isoxazolines (2015ASC2583, 2012EJO3043, 2005JOC7761). Among the most used synthetic approaches, isoxazoles have been prepared from nitrile oxides (RCNO) and alkenes, alkynes, enolates, or by reaction of hydroxyiminoyl chlorides with dipolarophiles such as alkynes, enolates of b-ketoesters or b-ketoamides formed in the presence of bases (2009HC170(P2)). Isoxazoles can be isolated from reactions of ArCNO and alkenes after an oxidation/aromatization step (2005JMC723, 2001JCS(P2)1168). Such an approach has been found to be highly regioselective when electron-poor alkenes 1 are initially brominated, affording, after reaction with nitrile oxides, 5,5-disubstituted bromo-2-isoxazolines 2. These are easily transformed into the corresponding 3,5-disubstituted isoxazoles 3 by a dehydrohalogenation reaction with Et3N (Scheme 1). Various 5-sulfone, 5-sulfoxide, and 5-carbonyl isoxazoles have been prepared in reasonable to good isolated yields by this one-pot procedure (2008SL0919). Activated cyclopropene 1,1-diesters (e.g., 4) have been found to act as dipolarophiles in 1,3-dipolar cycloadditions with arylnitrile oxides. The resulting strained cyclopropylisoxazolines intermediates, in the presence of imidazole/basic conditions, have been used for the synthesis of polyfunctionalized 3,4,5-trisubstituted arylisoxazoles 5 (Scheme 2). The best results (88% yield) are obtained when m- or p-substituted benzohydroxyiminoyl

Scheme 1 A one-pot multistep synthesis of 5-carbonyl 3-arylisoxazoles.

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Scheme 2 Proposed mechanism for the reaction between ArCNO and cyclopropene 1,1-diester.

chlorides, imidazole and electron-poor cyclopropenes react in dichloromethane (DCM). Other commonly used solvents provide lower product yields (2009T9146). Recently, very mild and ecosustainable conditions for the synthesis of 5-substituted-3-arylisoxazoles have been described and some examples are noteworthy. Nitrile oxides have been obtained from their corresponding hydroxyiminoyl halides in mildly acidic aqueous solutions by a metal/ catalyst free reaction, through a dehydrohalogenation elimination mechanism that start with chlorine loss, followed by hydroxyiminoyl deprotonation. The presence of water is essential for the reaction, and it has been suggested that the driving force of this process is the nitrile oxide solubility in water (2016AC3997). Another example is the reaction in water of benzaldoximes 6 with alkynes in the presence of potassium chloride and OxoneÒ (potassium peroxymonosulfate), where the in situ generated hypochlorous acid allows the formation of nitrile oxide intermediates 7 (Scheme 3) (2014TL2308). A one-pot three-step formation of 3,5-disubstituted isoxazoles 10 from aromatic aldehydes 8 and arylacetylenes 9 has been performed in deep

Scheme 3 Synthesis of isoxazoles mediated by KCl/Oxone in water.

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Scheme 4 One-pot three-step synthesis of 3,5-disubstituted isoxazoles in deep eutectic solvents (DESs).

eutectic solvents (DESs) (Scheme 4), where aldoximes are prepared in situ by adding NH2OH∙HCl and solid NaOH to the DES-solution of aromatic aldehydes. N-Chlorosuccinamide (NCS) is then added to the reaction mixture, affording the imidoyl chloride, and conversion into the nitrile oxide is favored by the presence of urea. Finally a 1,3-dipolar cycloaddition to the alkyne gives the product 10. DES containing choline chloride (ChCl)/urea (1:2) provides the best yields and is also responsible for the nitrile oxide stabilization through hydrogen bonding with urea and through electronic interactions with the choline moiety. Moreover, dipolar cycloaddition of ethynylbenzenes with activated nitroalkenes also proceeds in good yield in acetylcholine chloride (AcChCl)/urea as a dissolving DES, affording ethyl 5-substituted isoxazole3-carboxylates in good yields after 24 h. In this case, the DES seems to favor the nitro-tautomerization of the nitroalkene into the nitrile oxide (2015ASC2343). By applying a previously reported methodology consisting of a cycloaddition between arylnitrile oxides and enolates (1987T2191, 2002T2659), 4,5-disubstituted 3-arylisoxazoles 13 have been produced in high yields by reacting appropriately substituted arylnitrile oxides with different substituted enolates 11 (Scheme 5). As described in Section 3.1.1, 3-aryl-5-substituted isoxazoles can be obtained in general by formation of stable 5-hydroxy-3aryl-2-isoxazoline intermediates 12 (Scheme 5) (2007T12388, 2015S807, 2005T11270), although the presence of an electron-withdrawing group (EWG) on the aryl moiety enables the direct formation of isoxazoles by spontaneous dehydration of the 5-hydroxy-2-isoxazolines intermediates

Scheme 5 Synthesis of 3-aryl-5-substituted isoxazoles 13 from 3-aryl-5-hydroxy-2isoxazolines intermediates 12.

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(2004JMC4881, 2008T11198). Valuable 3-aryl-5-vinylisoxazoles can also be prepared by formation of stable 3-aryl-5-hydroxy–5-vinyl-2-isoxazoline intermediates by the reaction of arylnitrile oxides with the enolate ion of methyl vinyl ketone (see below). The 1,3-dipolar cycloaddition of arylnitrile oxides to enolate anions is also successful for the preparation of 5-substituted 3,4-diarylisoxazole derivatives 16, which are precursors of pharmacologically active compounds (2004JMC4881). The starting materials for the ring construction (N-hydroxyiminoyl chlorides and phenylacetone or its substituted derivatives) are easily accessible (Scheme 6). By generating the ketone enolates under thermodynamic control conditions at 0  C, the methylene deprotonation affords a “thermodynamic” enolate 14, which in turn reacts with different arylnitrile oxides. The reaction outcome depends on the base used for the ketone deprotonation. If lithium diisopropylamide (LDA) is used for the deprotonation of the ketone, the 3,4-diaryl-5-methyl-5-hydroxy-2-isoxazoline intermediates 15 are regioselectively isolated in high yields (Scheme 6) and can then be converted into the corresponding isoxazoles 16 under mild basic environment. Conversely, the one-pot formation of the target 3,4-diaryl-5methylisoxazole is observed when the sodium enolate of the phenylacetone (e.g., 14-Na) is used, due to the spontaneous dehydration/aromatization of the isoxazoline derivatives. When the lithium phenylacetonitrile 17 is used, instead of a lithium enolate of a ketone, 5-amino-3-aryl-4-phenylisoxazoles 18 are obtained, although in moderate yield (w40%), by a one-pot methodology through cycloaddition with arylnitrile oxides (Scheme 7) (2014EJM606). In a similar way, 4-alkyl-5-amino-3-arylisoxazoles have been prepared by nucleophilic addition of a-anions of nitriles to a-chloroximes, and the

Scheme 6 3,4-Diaryl-5-alkyl-5-hydroxy-2-isoxazoline precursors of 3,4,5-trisubstituted isoxazoles.

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7

Scheme 7 Synthesis of 5-amino-3-aryl-4-phenylisoxazoles 18 by cyclization of ArCNO and PhCHLiCN 17.

scope and limitations of this reaction have been studied by varying the nature of the nitrile and chloride oxime (2006OL3679). The reaction between alkynes and nitrile oxides has in general a low regioselectivity, but an appropriate choice of alkynes, nitrile oxide substituents, or controlled reaction conditions can overcome the drawbacks of such an approach. In this context, metal-catalyzed cycloadditions are useful alternatives leading to more regioselective reactions. A series of novel 3,5- and 3,4-disubstituted isoxazoles have been prepared by investigating transition-metal-catalyzed [3 þ 2] cycloadditions (2005JA210, 2005JOC7761, 2008AGE825, 2002MI1361). Among such methodologies, an easy heterogeneous nanocatalyzed cycloaddition of alkynes to in situ generated nitrile oxides has been reported to give 5disubstituted-3-arylisoxazoles. The catalyst (Cu/aminoclay/reduced graphene oxide nanohybrid) is cheap and stable, can be removed by filtration and washed with water and acetone to be efficiently reused several times (2015JCR683). Cu(II)/montmorillonite clay catalyzed the synthesis of 3,5-disubstituted isoxazoles by reacting aldehydes and terminal alkynes. This reaction has an excellent functional group compatibility and was optimized in aqueous medium, through a cheap and efficient one-pot domino multicomponent reaction, without the isolation of harmful and unstable hydroxyimoyl chloride intermediates (2013TL3558). Copper (5%) or iron (10%) alone have been found to catalyze the reaction of benzohydroxyiminoyl chloride and phenylacetylene, affording 3,5-diphenylisoxazole in high yields (71e79%) via in situ nitrile oxide generation, whereas the beta-enaminone as a product of the isoxazole reductive ring opening can be promoted in the presence of Cu/Fe mixtures (2013T8987). Complexation with aluminum increases nitrile oxides electrophilicity, despite the dipole character. Hence, alkynyl oximes have been obtained from the reaction of aluminum acetylide and reacted with in situ generated nitrile oxides. A tandem addition/intramolecular 5-endo-dig metalative

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cyclization mechanism, in the presence of 20% AlMe3 in the reaction mixture, affords regioselectively 4-alumino-isoxazoles 19 in 60e70% yields (Scheme 8). These intermediates are found to be very versatile for the synthesis of 3,4,5-trisubstituted isoxazoles 20 by further reaction with electrophiles (2011OL5664). This methodology is also efficient for the preparation of other heterocycles. Alternative methods for nitrile oxide preparation have been reported, often allowing easier one-pot multistep approaches toward 3-arylisoxazoles. In particular, CrO2 and MnO2 have been found to be valuable oxidants of oximes leading to in situ generation of nitrile oxides for 1,3-dipolar cycloaddition reactions. CrO2 is a good reagent from the perspective of industrial or scale-up procedures, because it can be easily recovered either by simple decantation or by magnetic removal from the reaction solvent. The oxime oxidation to nitrile oxide can be attributed to a metal-induced tautomeric equilibrium between a nitroso and an oxime intermediate (2010T9582). Similarly, oxidation of aldoximes to nitrile oxides can be catalyzed by hypervalent iodine/Oxone in the presence of hexafluoroisopropanol in aqueous methanol solution (2013OL4010). Hindered trisubstituted 3-arylisoxazoles atropoisomers, containing at C-4 an acyl or amide substituent, have been prepared in 50e94% yields from arylnitrile oxides and beta-dicarbonyl enolates, and the methodology appears to be particularly useful for the preparation of antitumor isoxazoles (2012T10360). Recently reported solid-phase organic syntheses of 3-aryl- and 5substituted-3-arylisoxazoles are notable for their excellent performance together with the high purity of the products (2013SC303). Starting from polymer-supported selenyl bromide, vinyl selenides have been prepared in the presence of tBuOK from beta-bromoethyl selenide. These vinyl derivatives react by 1,3-dipolar cycloaddition with nitrile oxides, prepared in situ from the corresponding aldoximes, to give polymer-supported isoxazolinyl-selenides with high regioselectivity. The 3-arylisoxazoles are finally produced in high yields upon selenide oxygenation using hydrogen

Scheme 8 Synthesis of 3,4,5-trisubstituted isoxazoles by reaction of an aluminum acetylide and in situ generated nitrile oxides.

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peroxide (2006S2293). Similarly, 3-arylisoxazoles 23 have been obtained in high yields by reaction between arylnitrile oxides and polystyrene-supported vinyl sulfone resin 22 (Scheme 9). When polystyrene-supported hydroxyethyl sulfone resin 21 was acetylated in the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), the vinyl-sulfone 22 was prepared by a formal beta-elimination of acetic acid. The formation of the arylnitrile oxides occurs in situ by reacting the desired aldoxime with NaOCl/CH2Cl2. The final cleavage, achieved in the presence of tBuOK, releases the polymersupported phenylsulfinic acid (2013SC303) together with the 3-arylisoxazole. 2.1.2 Cyclization of Oxime Derivatives Substituted-3-arylisoxazoles are often prepared from a,b-unsaturated oximes, in the presence of a metal catalyst or particular leaving groups that allow the cyclization. N-Alkoxycarbonyl-O-propargylic hydroxylamines 24 have been used for the construction of the isoxazole ring by electrophilic cyclization in the presence of iodine, acting as both an iodinating and an oxidizing agent (2011JOC3438). A plausible mechanism proposed for the formation of isoxazoles 27 consists of the electrophilic addition of halonium ion to precursor 24 (Scheme 10), followed by electrophilic 5-endo-dig cyclization of iodonium ion giving a 2,5-dihydroisoxazole intermediate 25. Under the acidic reaction conditions [N-iodosuccinimide (NIS)/BF3∙Et2O], iodonium addition to the ene-carbamate moiety followed by elimination of HI affords the N-alkoxycarbonyl isoxazolium salts 26 that give the final products 27 after aqueous-workup (Scheme 10) (2011JOC3438). Similarly, the iodocyclizations of 2-alkyn-1-one O-methyl oximes (2005OL5203, 2007JOC9643, 2008JCC658) and O-propargylic N-tosyl hydroxylamines (2007TL647) have been found to proceed under mild conditions, affording 4-iodoisoxazoles in good yields.

Scheme 9 3-Arylisoxazoles preparation from arylnitrile oxides and polystyrenesupported vinyl sulfone resin 22.

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Scheme 10 Synthesis of isoxazoles 27 by iodocyclization of alkynes 24.

3,5-Disubstituted isoxazoles have also been prepared in good yields from a,b-unsaturated oximes by a mild, nontoxic approach, in the presence of cheaply available manganese dioxide. The limitations of this synthetic methodology are also evidenced when the used oximes are derived from a,b-unsaturated aldehydes or aliphatic ketones (2007SC585). From the reactions of trans-1-(b-aroylvinyl)pyridinium bromides with hydroxylamine hydrochloride, 3-substituted arylisoxazoles have been isolated but with poor regioselectivity. The reaction proceeds by formation of an oxime intermediate, followed by intramolecular nucleophilic addition at the double bond, and elimination of pyridine (2015RJC1078). Similarly, 3- and 5-arylisoxazoles (29 and 30) have been obtained simply by combining b-dimethylaminovinyl aromatic ketones 28 and NH2OH hydrochloride (Scheme 11). The reaction regioselectivity strongly depends on the starting enaminone used, as well as the reaction conditions (2008JHC879). When the reaction is carried out in the presence of pyridine, a mixture of isoxazoles 29 and 30 is obtained. The 3-substituted isomers 30 have been smoothly isolated with high yields and regioselectivity when Ar is 4-ClC6H4, 4-NO2C6H4, or a furan-2-yl substituent. Conversely, the regioisomeric 5-substituted arylisoxazoles 29 were obtained via 5-hydroxyisoxazoline intermediates in the absence of pyridine in the reaction medium, due to the higher reactivity of the enaminone as a Michael acceptor (Scheme 11). By a similar approach, 3,5-disubstituted isoxazoles 34 have been prepared in good to high yields with high regioselectivity by a multistep

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Scheme 11 3- and 5-arylisoxazoles from b-dimethylaminovinyl aromatic ketones and NH2OH.

synthesis employing a 5-exo-trig cyclization of b-(N-hydroxyamino)vinyl ketones 32, obtained from the Michael-type addition of hydroxylamine to an a-alkynyl ketone 31 (Scheme 12). Subsequent acidic dehydration (p-TsOH) of the 3,5-disubstituted-5-hydroxy-2-isoxazoline intermediates 33 leads to the products 34 (2014JOC2049). Different substituted alkynyl ketones 31 have been obtained by addition of lithium acetylides to aromatic

Scheme 12 3,5-Disubstituted isoxazoles 34 from alkynyl ketones 31 and hydroxylamine.

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Scheme 13 Regioselective access to 3- and 3,5-disubstituted arylisoxazoles 36 by reaction of N-hydroxy-4-toluenesulfonamide and a,b-unsaturated aldehydes or ketones 35.

aldehydes, followed by the oxidation of the obtained propargyl secondary alkoxide intermediates with iodine and K2CO3 in t-BuOH (Scheme 12) (2014JOC2049). A versatile, regioselective access to 3- and 3,5-disubstituted isoxazoles 36 starting from N-hydroxy-4-toluenesulfonamide (TsNHOH) and a,bunsaturated aldehydes or ketones 35 has been described (Scheme 13) (2009OL3982). The reaction affords the best results under very mild conditions (K2CO3 in MeOH/H2O at room temperature) in the presence of less hindered or EWG-substituted enals as substrates. Higher temperatures and longer reaction time are required when enones are reacted with TsNHOH to afford 3,5-disubstituted isoxazoles 36. Like water, solventless systems and room temperature ionic liquids (ILs) are of current interest as green reaction mediums that are environmentally friendly alternatives to volatile conventional organic solvents. An efficient one-pot synthesis of 3,5-disubstituted isoxazoles starting from b-diketones and hydroxylamine hydrochloride in reusable butylmethylimidazolium salt-based ILs at room temperature, using NaOH as a base, has been reported (2009JHC108). Also, a hydroxy(tosyloxy)iodobenzene (HTIB) (Koser’s reagent) mediated synthesis of tricyclic isoxazole derivatives from substituted 2-propargyloxybenzaldoximes under “on-water” conditions has recently been described (2010GC1090). Among metal-catalyzed cyclizations, an efficient gold(I)-catalyzed tandem cyclizationefluorination has been developed by reaction of (Z)-2-alkynoneO-methyl oxime 37 at room temperature in the presence of (iPr)AuCl/ AgOTs and Selectfluor (Scheme 14). This affords 4-fluoroisoxazoles 38 in

Scheme 14 Au-catalyzed synthesis of 3-aryl-4-fluoroisoxazoles from 2-alkynone Omethyl oximes.

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high yield and with high selectivity by a one-pot approach (2014JOC6444). A plausible Au(I)/Au(III) catalytic cycle mediated by the external oxidant (Selectfluor) explains the obtained results. A number of other gold-catalyzed processes have also been reported (2010SL777, 2011ASC2708, 2010OL2594, 2011OL2746). Among these, cyclometalated gold (III) complexes were found to be efficient as catalysts in the cycloisomerization of a,b-acetylenic oximes 39, allowing the formation of isoxazoles 40 in good to excellent yields, and up to 96% of reagent conversion (2013ASC2055). In this study, different five- and six-membered gold-complexes 41 have been mixed with the oxime in the presence of AgOTf under mild reaction conditions, at room temperature and under air, without the use of dried solvent (Scheme 15). Moreover, a simple one-pot oxyboration reaction of alkynyl-oximes has been developed. The presence of iPrAuTFA under mild conditions allows the regioselective formation of 4-borylated isoxazoles building blocks in good yields (2016OL480). During optimization of this reaction, some activated substrates were found to undergo noncatalyzed transformations into the desired 4-boro-isoxazoles, although after longer reaction times and higher temperatures. Different functional groups, sensitive to alternative borylation routes, were found to be compatible with the reaction conditions of oxyborylation (2016OL480), and the optimized methodology was efficient in a gram-scale synthesis of building blocks for valdecoxib antiinflammatory drug preparation. Like boron-derivatives, highly versatile building blocks, such as 4organoselenylisoxazoles 42, are easily prepared in the presence of FeCl3/ R2SeSeR2 from the alkynone (Z)-O-methyloxime derivatives 41 at room temperature, under an air atmosphere, and using very short reaction times (2013JOC1630). This methodology has been found to be highly versatile, since the optimized reaction conditions are compatible with the presence of many different substituents on the isoxazole and arylselenide moieties (Scheme 16).

Scheme 15 3-Arylisoxazoles from gold-catalyzed cycloisomerization of a,b-acetylenic oximes 39.

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Scheme 16 4-Organoselenylisoxazoles 42 from alkynone (Z)-O-methyloxime 41 in the presence of FeCl3/R2SeSeR2.

Concerning the one-pot procedures useful for the cyclization of the propargyl derivatives 43, a synthesis of 3,5-disubstituted isoxazoles 45 in 51e88% yields was optimized from simple starting reagents (aromatic aldehydes, alkynes, and tosylhydroxylamine) and metal-free conditions, by a tetra-n-butylammonium fluoride (TBAF) mediated detosylative 5-endodig cyclization of propargylic N-hydroxylamines 44. The hydroxylamines 44 were obtained by p-toluenesulfonic acid (p-TSA) catalyzed N-propargylation of N-tosyl-hydroxylamines (Scheme 17) (2012EJOC5767).

Scheme 17 Tetra-n-butylammonium fluoride (TBAF)emediated detosylative 5-endodig cyclization of propargylic N-hydroxylamines.

Heteropolyacids (HPA) such as Preyssler, Dawson, and Keggin-types have been found to be efficient green catalyst for the synthesis of 3,5-disubstituted isoxazole derivatives (Scheme 18). These catalysts are reusable, because they can easily be removed from the reaction media by filtration (2008SC135).

Scheme 18 Heteropolyacids (HPA) for the synthesis of 3,5-disubstituted isoxazole derivatives.

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The reaction of 1,3-diphenyl-propane-1,3-dione and NH2OH hydrochloride has been studied as a reaction model. Because of the importance of the interactions between the polarized polyanion and the substrate in this catalytic process, the effect of various solvents/catalysts was explored. Isoxazoles 47 were obtained in high yields, and good selectivities from the corresponding b-dicarbonyl-compounds 46 in the presence of H3PW11CuO40 as a green catalyst, which successfully gave the desired products in high yields in up to three consecutive runs (Scheme 18). 3-Arylisoxazoles have also been obtained, even if in low yields, when 3azido-substituted a,b-unsaturated aldehydes lose a nitrogen molecule at room temperature and undergo a ring closure to 2-formyl-azirines (2005TL6575). Although the isoxazoles were not the major isolated product, this represents a novel approach starting from acyclic halo a,b-unsaturated aldehydes.

2.2 Synthesis of Pharmacologically Active Isoxazoles Isoxazole is the core ring in the structure of several bioactive compounds, drugs, and agrochemicals (2005COC925). Many herbicides, hypoglycemics, antibiotics, antiinflammatory, and analgesic agents contain the isoxazole ring (e.g., isoxaflutole, sulfamethoxazole, acivicin, lefunamide (1999THS301, 2009EJMC3898)). In detail, the 3-arylisoxazole moiety is important for the biological activity of antibacterials (cloxacillin, dicloxacillin, oxacillin (2014OL5266)), cyclooxygenase inhibitors (valdecoxib (2000JMC775), mofezolac (1998PLM245), P6 and its analogues (2004JMC4881)), antihyperglycemic agents (2009BMC5285), HIV-inhibitory drugs (2010CBD461), and glutamate receptor antagonists (2005BMC5391). Representative structures are shown in Fig. 1.

Figure 1 Pharmacologically active compounds containing 3-arylisoxazole moieties.

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Valdecoxib is a preferential cyclooxygenase-2 (COX-2) inhibitor belonging to the nonsteroidal anti-inflammatory drug (NSAID) class named Coxibs, used in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, dysmenorrheal, and as an adjuvant in some chronic and oncological diseases. Since its commercialization, different synthetic procedures for valdecoxib preparation have been reported. Some are based on the dipolar cycloaddition of nitrile oxides and ketone enolates (2004JMC4881), enamines as alkene equivalents (2012SC639), or by oxime cyclization/Suzuki coupling (Scheme 19) (2002ASC1146, 2014OL5266) or electrophilic cyclization (2007JOC9643). Various 3,4-disubstituted isoxazole 4-boronates and 3-aryl-5substituted isoxazole 4-boronic esters 49 have been easily and regioselectively prepared in high yields from the alkynylboronate 48, and then efficiently transformed into valdecoxib and some of its analogues 50, after Suzuki coupling with p-bromobenzene sulfonamide (Scheme 20) (2005T6707). Valdecoxib and its 3,4-diaryl-5-alkylisoxazole analogues have been isolated in high yields by a one-pot procedure in which the sodium enolate of 1-aryl2-propanones undergo a 1,3-dipolar cycloaddition to suitably substituted arylnitrile oxides, followed by a spontaneous dehydration/aromatization

Scheme 19 Synthesis of valdecoxib by oxime cyclization/Suzuki coupling.

Scheme 20 Synthesis of valdecoxib (50; Ar ¼ Ph) and some of its analogues from the boronic esters 49.

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reaction of the 5-hydroxyisoxazoline intermediates (2009US0181970). By using this highly versatile approach, selective COX-1 and COX-2 inhibitors were obtained, allowing structureeactivity relationship (SAR) studies for the identification of the chemical groups determinant the inhibitory activity (2013JMC4277). Interestingly, different antiplatelet 5-substituted 3-pyridylisoxazoles have been prepared by 1,3-dipolar cycloaddition of 2-pyridyl-, 3-pyridyl, and 4-pyridyl carbonitrile oxides to alkynes. Such 3-(pyridyl)isoxazoles were evaluated for in vitro antiaggregation activity in the human platelet-rich blood plasma model, where they suppressed completely the platelet aggregation induced by arachidonic acid, without affecting cyclooxygenase, thromboxane synthase, or thrombin activity (2014RCB2092). Regarding the synthesis of pharmacologically active anticancer drugs, different 3-arylisoxazole-based compounds have been prepared (2014BMC1349). The synthesis of novel 5-(3-alkylquinolin-2-yl)-3-aryl isoxazoles 54 and their cytotoxic activity has been reported, together with SAR studies. The synthetic methodology is a multistep procedure, where the isoxazole ring derives from the 1,3-dipolar cycloaddition of propargyl alcohol 51 to aromatic nitrile oxides, generated in situ from aldoxime and NaOCl in DCM at room temperature. The obtained 3-arylisoxazol5-yl methanols 52 were in turn oxidized to the aldehydes 53, further converted in the corresponding Schiff’s base with aniline, and finally producing 5-(3-alkylquinolin-2-yl)-3-aryl isoxazoles 54 in high yield by reaction with aldehydes in the presence of iodine (Scheme 21). The in vitro cytotoxicity of 5-(3-alkylquinolin-2-yl)-3-arylisoxazoles 54, evaluated by MTT assay in A549, COLO 205, MDA-MB 231, and PC-3 human cancer cell lines, revealed that the presence of a fluoro or CF3 substituent at the para position of the 3-aryl-substituted isoxazoles is important for the biological activity, compared to 3-tolyl- or unsubstituted

Scheme 21 Synthesis of antitumor 5-(3-alkylquinolin-2-yl)-3-arylisoxazoles 54.

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3-phenyl derivatives, and with respect to the anticancer drug doxorubicin used as a positive control. The scaffold of 3,5-diarylisoxazoles was used to design disubstituted fivemembered heteroaromatic antihyperglycemic agents. The designed isoxazoles 57 were easily obtained by Williamson type O-alkylation of the 5-methoxy-2-(3-phenylisoxazol-5-yl)phenol 56 used as a parent compound (Scheme 22) and isolated in 45% yields by reaction of the appropriately substituted benzoyl diketone 55 with NH2OH∙HCl. The antihyperglycemic action was assessed in various in vitro models of type-2 diabetes such as DPP-4, PTP1B, and PPARg, and some of the new isoxazoles were found to be promising in vivo as antihyperglycemic agents, being endowed with moderate lipid-lowering activity. Finally, among pharmacologically active compounds recently reported, different 3,4,5-trisubstituted isoxazoles have been obtained by the classical 1,3-dipolar cycloaddition of arylnitrile oxides to chalcone derivatives and tested for their antibacterial and antifungal activity. Many of the synthesized compounds were moderate antibacterial agents, whereas some derivatives bearing chloro, nitro, or methyl substituents on the aromatic rings were endowed with good antifungal activity against Candida albicans strains (2014IJC214).

2.3 Spectroscopic Techniques and Density Functional Theory Calculations The spectroscopic characteristics of the isoxazole present in both simple and complex molecules have been studied to define the regiochemistry of cycloaddition reactions used for their preparation (2001TL1057, 2002S1663). Multinuclear magnetic resonance is an important tool for structure/reactivity investigations by chemical shifts/coupling constants correlations, as summarized and collected in book series chapters (2009HC170(P2), 2008CHECIII365). Among recent contributions, para-substituted 3-phenylisoxazoles were prepared and their structures studied by multinuclear magnetic resonance (15N and 13C NMR). Particular attention was given to chemical shifts

Scheme 22 Synthesis of 3,5-diarylisoxazole antihyperglycemic agents.

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correlation with the electronic features and position of the arylsubstituents, also to better understand the influence of a specific chemical structure on its biological activity. The assignment of 15N and 13C NMR signals of the isoxazole ring have been reported and compared with density functional theory (DFT) calculated 15N and 13C chemical shifts. The results of these studies suggest that the C(3) chemical shift is not sensitive to the electronic effects of the para-substituents. Conversely, the N atom was found to be significantly down-shielded by EWGs (less negative values) and upfielded in the presence of electron-donating groups (EDGs) (more negative values) (Fig. 2) (2006MRC851). A computational study qualitatively and quantitatively predicted an unexpected regiospecific Cu(I)-catalyzed synthesis of 3,5-disubstituted isoxazoles. Despite both isoxazole regioisomers usually being observed in nitrile oxide cycloadditions to alkynes, a single regioisomer was obtained in 74e92% yields in copper(I)-catalyzed reactions. This is due to a stepwise mechanism involving Cu(I)-acetylides, as demonstrated by comparison with the higher activation barrier energy calculations for the hypothesized concerted mechanism (2005JA210). Similarly, DFT calculations performed at the B3LYP level of theory have been performed to study the reaction of arylnitrile oxides with the lithium enolate of methyl vinyl ketone (MVK) at 78  C (2015S807). Specifically, the 5-hydroxy-3-aryl-5-vinyl-2-isoxazolines were formed in high yields in the presence of EWG-substituted or unhindered arylnitrile oxides. By comparing the activation energies for the reactions of Li-enolate of MVK with o-, m-, p-chlorobenzonitrile oxides, a two-step ionic mechanism was hypothesized because of the high bond polarization of both reactants, demonstrating, by considering the differences of the calculated transition states energies, the high importance of steric effects in the reaction, in accord with the experimental results (2015S807). Reagent reactivity and regiochemistry of these reactions were investigated using activation energy calculations and DFT-based reactivity indexes.

Figure 2 15N NMR: down-shield of electron-withdrawing groups (EWGs) and up-field of electron-donating groups (EDGs) present on para position of the 3-arylisoxazoles.

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The theoretical 13C NMR chemical shifts of the cycloadducts, obtained by Gauge-Invariant Atomic Orbital (GIAO) methods, were comparable with the observed values (2011SAA1375).

2.4 Reactions of 3-Arylisoxazoles Isoxazole rings are widely used as masked forms of dicarbonyl compounds, which can be obtained by ring-opening in the presence of reducing reagents or in a basic environment, due to the easy cleavage of NeO bond. Due to the labile isoxazole NeO bond, a carbenoidic or carbenemediated one-atom isoxazole ring expansion can be achieved by reaction of isoxazoles with diazo compounds. Initially formed isoxazolium N-ylides 58 easily undergo ring opening to (3Z)-1-oxa-5-azahexa-1,3,5-trienes 59. The reaction conditions which permit a 6p-electrocyclization to give 2H-1,3-oxazines 60 (Scheme 23) have been investigated by DFT calculations at the B3LYP/6-31G(d) level (2014BJC1896). Isoxazole ring-opening by NeO bond cleavage, through UV irradiation at 300 nm, is a key step in a photochemical one-pot three-component synthesis of substituted imidazoles 65. This transformation involves reaction of an aldehyde 61, an a-aminonitrile 62, and an azirine intermediate 64, formed in situ from the appropriate isoxazole 63 (Scheme 24). The reaction

Scheme 23 Isoxazole ring expansion to 2H-1,3-oxazines 60.

Scheme 24 Imidazoles from aldehydes, a-aminonitriles, and in situ formed azirines.

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occurs without undesired oxazoles or other by-products formation (2014OL5430). A short-lived vinylnitrene intermediate 67 was identified as an intermediate in the laser flash photolysis of 3,5-diphenylisoxazole 66. TD-DFT calculations at the B3LYP level and with the 6-31Gþ(d) basis set have been performed to establish the relative energies of the hypothesized optimized transition states and intermediates (2013JOC11349). When the photolysis occurred in an oxygen-saturated solvent, the vinylnitrene, with 1,3-biradical character, was intercepted by oxygen to form benzoic acid 68 and benzamide 69 (Scheme 25). Alkylated enaminoketones, b-enaminothioesters, lactams, and bis-blactams have been isolated starting from 3-arylisoxazoles by using different bases, to obtain further functionalized compounds. When 3-phenylisoxazole 70 reacts with t-BuLi, PhCN and Li-ethynolate are obtained as the main products of the ring fragmentation, following a C(5)eH deprotonation. Less hindered alkyllithiums (n-BuLi, EtLi, MeLi) react with isoxazole 70 by a deprotonation/ring-opening/nucleophilic addition route, affording alkylated enaminones 72, together with aryl ketones 71 (Scheme 26). These products are formed by addition of RLi to benzonitrile, in turn formed by fragmentation of the iminoketene intermediate. Small amounts of 2 -alkyl-4,6-diphenylpyrimidines 73 have also been detected in the reactions of 3-phenylisoxazole with EtLi and MeLi (2005T2623). When 3-arylisoxazoles (e.g., 70; Ar ¼ Ph) were reacted with lithium amides, such as LDA, LHMDS, and LTMP, no products of nucleophilic addition were isolated. Instead, syn bis-azetidinones 75 (e.g., Ar ¼ Ph) were isolated in high yields by isoxazole deprotonation and ring-opening,

Scheme 25 Proposed mechanism for the trapping of a vinylnitrene intermediate with oxygen.

Scheme 26 Reactivity of 3-phenylisoxazole 70 with alkyllithiums.

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followed by a dimerization of an azetinone anion Li-intermediate 74 (Scheme 27) (2007T12388). The substituent on the aryl moiety plays an important role for the reaction outcome. EWGs are favorable to the dimerization reaction, despite the competitive fragmentation of the iminoketene anions mainly observed with EDGs functionalized 3-arylisoxazoles (Scheme 27). Moreover, the size of the substituent is also important; the dimerization reaction occurs to a lesser extent in the presence of hindered groups on the ortho position, which favor fragmentation (2008T11198). Liþ chelation played an important role for the stereoselective formation of the syn bis-azetidinone, since low yields of the product are obtained by reacting 3-phenylisoxazole with NaHMDS or KHMDS. By reacting 3-arylisoxazoles with an excess of LDA in the presence of PhSH at 98  C, N-unsubstituted b-enaminothioesters 76 were isolated in high yields (Scheme 28). These are useful synthons for the preparation of N-unsubstituted b-enaminoacyl derivatives (e.g., b-ketoamides, b-enaminoesters, b-enaminoamides) (2011T6944). 4-Lithiumisoxazoles (e.g., 78), obtained by the lithiation of 4-organoselenylisoxazoles (e.g., 77) with n-BuLi, are suitable intermediates for a further functionalization in good yields by reaction with electrophiles, furnishing the functionalized isoxazoles 79. The 4-organoselenylisoxazoles are also

Scheme 27 Reactivity of 3-arylisoxazoles with lithium amides.

Scheme 28 Reactivity of 3-arylisoxazoles with lithium phenylthiolate in excess of LDA.

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useful to prepare 4-bromoisoxazoles (e.g., 80) via Br/Se exchange reactions (Scheme 29) (2013JOC1630). Similarly, 4-boron isoxazoles derivatives (e.g., 81) have been found to be efficient building blocks for isoxazole ring functionalization, especially in the presence of functional groups sensitive to lithiation methodologies. The valdecoxib analogues 82 have been obtained in high isolated yield by Suzuki cross-coupling reaction of the 4-pinacol boronate building block with p-bromobenzenesulfonamide (Scheme 30) (2016OL480). 3-Aryl-5-alkylisoxazoles can be regioselectively functionalized by side chain metalation with lithium amides, followed by quenching with electrophiles (2002T2659). In the presence of a double bond linked to C(5), an interesting possibility for bis-functionalization has been explored. When a strong nucleophile like n-BuLi reacted with 3-phenyl-5-vinylisoxazole 83, the product of alkyllithium addition to the C]C bond (i.e., 84) was isolated to a lesser extent. The main product 85 is formed by further reaction with the double bond of a second molecule of the vinylisoxazole 83 (Scheme 31) (2006T16170). In the same study, it was found that starting from the vinylisoxazole 83, the isoxazolyl-oxirane 86 is formed by reaction with m-CPBA, and the isoxazole 87 is obtained by reaction with benzonitrile oxide.

Scheme 29 4-Phenylselenylisoxazole 77: a useful precursor of 4-substituted isoxazoles 79.

Scheme 30 4-Organoboron isoxazole 81 is an efficient precursor for valdecoxib analogues preparation e.g., 82.

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Scheme 31 Side chain functionalization of 3-aryl-5-vinylisoxazole 83.

The solvent-free synthesis of novel bis(indolyl)methanes containing an isoxazole moiety 90 has been accomplished in excellent yields (94e99%) by microwave irradiation of 3-arylisoxazole-5-carbaldehydes 89 in the presence of SiO2, a commercially available, inexpensive, and efficient catalyst. The starting isoxazolyl-carbaldehydes 89 are obtained by oxidation of the corresponding isoxazolyl-methanol substrates 88 (Scheme 32) using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and solid iodine for 10e12 h at room temperature (2015CP470). An interesting ortho-deuteration of 3-arylisoxazoles has been reported. It occurs with high incorporation of deuterium (>80%) under very mild reaction conditions, by a CeH activation and hydrogen isotope exchange in the presence of homogeneous iridium(I) complexes bearing an NHC/phosphine ligand sphere (2015T1924). Direct functionalization of the aryl moiety also constitutes an efficient Pd-catalyzed regioselective CeH activation of 3,5-diarylisoxazoles 91 to afford the ortho-aroylation products 92 or acetoxylation products 93 (2014RA8588). The sp2 isoxazole C(4)eH bond does not react under these conditions, whereas among the two ortho-hydrogens that can be palladated near N- and O-directing atoms, only the proton proximal to the N atom

Scheme 32 Synthesis of bis(indolyl)methanes 90 from indole and 3-substituted isoxazole-5-carbaldehydes 89.

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Scheme 33 Pd-catalyzed regioselective CeH activation of 3,5-diarylisoxazoles to afford ortho-aroyl and acetoxy derivatives.

of 3,5-diarylisoxazole undergoes catalytic functionalization to form a new CeC or CeO bond (Scheme 33).

3. 3-ARYL-2-ISOXAZOLINES D2-Isoxazolines are an important class of five-membered heterocycles. They are a fundamental scaffold of numerous biologically active molecules and are frequently used to prepare building blocks for natural products synthesis, chiral ligands for asymmetric synthesis, (1999OL1795, 2001JA2907), or to produce a variety of bifunctional synthons by selective ring opening (e.g., a,b-unsaturated ketones, g-amino alcohols, betahydroxyketones (2008JOC9181, 2008OL1695), b-hydroxy nitriles (1982JA4023), acids or esters, b-aminoacids). 3-Aryl-2-isoxazolines are also important as a moiety of antidepressants, antipsychotics, and anxiolytics structures (Fig. 3) (2007BMC3649).

3.1 Synthesis of 3-Aryl-2-isoxazolines Some synthetic strategies toward 3-aryl-2-isoxazolines formation are described below and grouped by their ring-construction methodologies.

Figure 3 Pharmacologically active 3-aryl-2-isoxazolines.

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3.1.1 1,3-Dipolar Cycloaddition Several substituted 3-aryl-2-isoxazolines, interesting from a synthetic and structural point of view, have been obtained by classical [3 þ 2] cycloaddition between nitrile oxides and alkenes. A number of 3-aryl-2-isoxazoline carbocyclic nucleoside analogues and 3-arylisoxazoline g-lactams (2011T1907), precursors of g-amino acids, have been easily prepared (Scheme 34) starting from azabicyclic 3-aryl-2isoxazolines 95. The adducts 95 are obtained, in turn, from arylnitrile oxides and the olefinic azabicyclic derivatives 94 (2006T7370, 2008T3541, 2008T7312, 2009T10679, 2012T1845, 2012T1384). A very efficient synthesis of isoxazolines employs water-assisted nitrile oxide formation under catalyst-free conditions. The pH of the aqueous solution influences the yield of the cycloaddition, with the optimum values ranging between pH 4 and 5. The substituents on the starting hydroxyimoyl chlorides are important for the reaction outcome. EWGs on the aryl moiety enhance the yields, and excellent stereoselectivity has been obtained by reaction of substituted alkenes and terpene-derivatives, such as a-pinene and (1R)-myrtenol, affording enantiomerically pure isoxazolines (2016AC3997). Often, the differences between the various known methodologies used to synthesize isoxazolines resides in the methods used to prepare the nitrile oxide (2008SC2392, 2008S711, 2006BMC4361, 2005S3423, 2005JMC2054) such as the oxidation of aldoximes, dehydrohalogenation of hydroxyiminoyl chlorides, dehydration of nitroalkanes, activation of (Het)aryl alkynes by copper nitrate (2015AC8795), etc. Using 1,3-dipolar cycloaddition reaction conditions, 3-aryl-5-nitro- and 5-acetyl-3-aryl-2-isoxazolines have been prepared from arylhydroxamic

Scheme 34 Synthesis of isoxazoline-fused carbocycles.

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chlorides and either nitroethylene (2007CHE362) or methyl vinyl ketone (2005T11270) dipolarophiles. Versatile building blocks have been obtained by a simple combination of suitably substituted arylnitrile oxides with a substituted alkene. This is illustrated by the preparation of 3-aryl-5-phenylthio-2-isoxazolines 97 (2010S3195), regioselectively isolated in 56e90% yields by reaction of arylnitrile oxides with commercially available phenyl vinyl sulfide 96 (Scheme 35). By applying a previously reported methodology (1987T2191, 2002T2659), substituted 3-arylisoxazolines have been produced in high yields by reacting substituted arylnitrile oxides with substituted enolates. Valuable 3aryl-5-hydroxy-5-vinyl-2-isoxazolines 99 have been prepared by reaction of arylnitrile oxides with the enolate ion of methyl vinyl ketone 98, formed at low temperature (78  C) with an excess of LDA (2015S807, 2005T11270). The optimized reaction conditions allowed the minimization of the competitive formation of 5-acetyl-3-aryl-2-isoxazolines 100 (Scheme 36). The 3-aryl-5-hydroxy-5-vinyl-2-isoxazoline intermediates 99 are obtained in fair to good yields when EWG or less-hindered substituents are present on the aryl moiety of arylnitrile oxides. The corresponding 3-aryl5-vinylisoxazoles can easily be obtained by quantitative dehydration of the 5-hydroxyisoxazolines using BF3∙Et2O in CH2Cl2. Substituted 3-aryl-5-hydroxy-2-isoxazolines have been produced in high yields by reacting suitably substituted arylnitrile oxides with the lithium enolate of acetaldehyde (2007T12388). The same synthetic scheme has been used for the preparation of 3-(5chlorofuran-2-yl)-5-methylisoxazole as building block in the preparation

Scheme 35 3-Aryl-5-phenylthio-2-isoxazolines 97 from arylnitrile oxides and phenyl vinyl sulfide.

Scheme 36 A route to 5-hydroxy-3-aryl-5-vinyl-2-isoxazolines.

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of pharmacologically active pyrazoles. The 3-heteroarylisoxazole was obtained in 72% overall yield by reaction of 5-chlorofuran carbonitrile oxide and the lithium enolate of the acetone, prepared by reaction of LDA and dry acetone at 78  C for 2 h (2012CMC629), followed by the quantitative dehydration/aromatization of the 3-(5-chlorofuran-2-yl)-5hydroxy-5-methyl-2-isoxazoline intermediate under mild basic conditions. The 1,3-dipolar cycloaddition of arylnitrile oxides to the enolate anions 101 has also been successfully used for the preparation of variously substituted 5-hydroxy-3,4-diarylisoxazoles 102, which are precursors of pharmacologically active compounds (2004JMC4881). The methodology is versatile, since the starting materials are easily accessible aldehydes and ketones (Scheme 37). Moreover, different ketone enolates can be obtained from the ketones under thermodynamic control at 0  C (2004JMC4881) or under kinetic control at 78  C (2002T2659). Among novel methodologies, 3,4-diaryl-5-hydroxy-2-isoxazol-5-yl carboxylic acids have been obtained by 1,3-dipolar cycloaddition of arylnitrile oxide to the Li-dianion of phenylpyruvic acid, prepared at 0  C by deprotonation with two equivalents of LDA, followed by an acidic quenching with HCl (2013JMC4277). The hydroxy-derivative was found to be particularly stable, and all attempts to carry out the dehydration/ aromatization transformation to the corresponding aromatic isoxazole derivative under basic (or acid) conditions failed (see Section 3.3). N-Chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 3,3dimethyldioxirane (DMDO), NaOCl, ceric ammonium nitrate (CAN), N-chlorobenzotriazole (NCBT), MagtrieveÔ , KI/I2, and chloramine-T oxidizing agents are efficient reagents for the oxidation of aldoximes. They have been used alone and also in combination, as in the case of NaIetBuOCl, for the in situ generation of hypoiodite oxidative species (2010GC1090). Several hypervalent iodine reagents (diacetoxyiodo)

Scheme 37 Synthesis of 3-aryl-5-hydroxy-2-isoxazolines 102 from ArCNO and Li-enolates.

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benzene (DIB), PhIO/cetyltrimethylamonium bromide (CTAB), PhICl2, iodosylbenzene, [hydroxy(tosyloxy)]iodobenzene have also been frequently used. For the best environmentally safe approaches and green synthetic protocols, [hydroxy(tosyloxy)iodo]benzene (HTIB (Koser’s reagent) (2010GC1090), NaOCl (2005S3423), PhIO/CTAB (2008JOC7775), and organocatalytic KI/OxoneÒ (2013CC4800) have been used as oxidizing agent in aqueous media for aldoximes oxidation to nitrile oxides. However, some limitations are due to the presence of reactive functional groups, longer reaction times necessary to get an acceptable yield, or the need to use other toxic components. Worthy of note is the efficient and catalytic one-pot/three-step synthesis of isoxazolines 106 from aldehydes 103, performed in the presence of a catalytic amount of iodobenzene. This involves the in situ oxidation of the initially formed aldoximes 104 to nitrile oxides 105, which then react with alkenes (Scheme 38) (2014S503). Moderate to good yields of the 3-aryl-2isoxazolines 106 were obtained by this simple and mild procedure. According to the proposed mechanism, meta-chloroperbenzoic acid (mCPBA) oxidises iodobenzene to a hypervalent intermediate that is able to perform the oxidation of the aldoxime to the nitrile oxide. This regenerates iodobenzene which can be reoxidized to the hypervalent iodine by mCPBA (Scheme 38). 3.1.2 Cyclization of Oxime Derivatives An interesting transition-metal-free synthesis of isoxazolines was accomplished by a TEMPO-mediated oxidative sp3 CeH activation approach, starting from the oximes 107 (Scheme 39) (2013OL3214). The mechanism involves the O-radical intermediates 108 that undergo 1,5-H-radical abstraction to generate the less stable C-radicals 109. The radicals 109 may then undergo ring closure forming the substituted isoxazolines 110 (Scheme 39).

Scheme 38 A one-pot arylisoxazoline formation from oximes, PhI, and mCPBA.

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Scheme 39 Isoxazolines from the cyclization of remote C-radical oximes intermediates.

This reaction was optimized by using polar aprotic solvents (DMSO, DMF, and DMA) at 140  C and by addition of two equivalents of K2CO3. An investigation of the scope and limits of the reaction revealed that the best results (59e82%) can be achieved when aromatic and heteroaromatic rings are bonded to the oxime(C) and the b (C) atoms (2013OL3214). Similarly, a direct radical-mediated aliphatic sp3 CeH bond activation results in an efficient transition-metal-free approach toward the formation of the D2-isoxazolines 112 in good yields from the oximes 111 (Scheme 40) under milder conditions at 45 or 80  C. This reaction occurs in the presence of SelectfluorÒ and Bu4NI (2015EJO5084). The proposed mechanism involves the formation of an N-O-I intermediate, which is the precursor of a b-iodooxime that cyclizes to the 2-isoxazoline by intramolecular nucleophilic substitution (Scheme 40).

3.2 Structure The spectroscopic characteristics of isoxazoles and isoxazolines have been widely studied (1989T6517), and 2-isoxazolines have been widely prepared by 1,3-dipolar cycloadditions of nitrile oxides with various alkenes (1974T3765). Through elucidation of the possible forming isomer structures, the regiochemistry of these cycloadditions have been thoroughly investigated and reviewed. Recently, the reactivity of 4-nitrobenzonitrile oxide has been studied in the presence of different dipolarophiles, such as methyl methacrylate,

Scheme 40 D2-Isoxazolines from direct sp3 CeH bond activation of oximes 111.

3-Arylisoxazoles and 3-Aryl-2-isoxazolines

31

allyl bromide, and acrylonitrile. New substituted 3-aryl-5-substituted-2isoxazolines and 3-aryl-4-cyano-2-isoxazoline were prepared, and the GIAO method (1990JA8251) was used to study the regioselectivity of these 1,3-dipolar cycloaddition. HOMO/LUMO energies, electronic chemical potential, global and local electrophilicity and nucleophilicity were calculated for dipole and dipolarophile, and the favorable interactions were determined. DFT-based activation energy calculations and reactivity indexes are useful for predicting the 13C NMR chemical shifts of the cycloadducts and aid structure determination by comparison with the observed experimental data (2011SAA(79)1375). The NMR and X-ray characterization is also useful to explain the high stereospecificity of the oxidative-based cyclization of branched 2-allyloxybenzaldoximes in high yields, where only the syn product is obtained by a hypothesized synchronous [3 þ 2] mechanism (2010GC1090). Moreover, these techniques were fundamental in the structural characterization of enantiomerically pure antimycobacterial di- and trispiroheterocycles, obtained by 1,3-dipolar cycloaddition of arylnitrile oxides to (R)-1-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)pyridinones 113 (Scheme 41) (2010TA1315). The structures of the products, derived from the reaction of nitrile oxide to C]C bonds of both dibenzylidene functions, and/or by addition to the C]O bond, were confirmed by 1D and 2D NMR experiments. For some compounds X-ray determined structures were used when the 1H and 13C chemical shifts of diasteromeric bis-dispiro-adducts were found to be very similar.

Scheme 41 Synthesis of enantiomerically pure antimycobacterial spiroheterocycles.

32

P. Vitale and A. Scilimati

3.3 Reactions of 3-Aryl-2-isoxazolines 2-Isoxazolines are particularly reactive in the presence of either reductive or oxidant agents. The reductive isoxazoline NeO bond cleavage has been efficiently used to prepare a number of highly functionalized cyclic amino acid derivatives, which are useful intermediates in medicinal chemistry (2012S1951). In 3-aryl-5-substituted-2-isoxazolines, the proton at C(4) is generally more acidic than the proton at C(5), with the exception of 5-substituted derivatives bearing an EWG. In this case the increased acidity of H-C(5) results in deprotonation at both the 5 and the 4 positions in the presence of a strong base, such as organometallic compounds. When the 5-substituent is an EWG and is also a good leaving group, the removal of proton H-C(4) occurs, and aromatization is the sole reaction observed. At the same time, when the strong base favors the formation of the C(5)-anion of the isoxazoline, a 1,5-ring opening may occur, with formation of stable nitriles. In general, the most reported reactivity of substituted 3-aryl-2isoxazolines is related to the presence of functional groups that are able to act as leaving groups (LG: halogens, sulfides, ethers, esters) at the C(4) or C(5) positions (Scheme 42). In this way, 4- or 5-substituted-3-aryl-2isoxazolines, e.g., 114, can be valuable precursors of the corresponding isoxazoles, e.g., 115, by b-eliminations, both in acidic or basic conditions (1991HC203(P1), 2008JHC879, 2008SL0919, 2010S3195). The 5-hydroxy-2-isoxazolines can be quantitatively dehydrated into their corresponding isoxazoles by treatment with base, plausibily through a E1cB mechanism (2002ASC1146, 2002T2659, 2009CH587, 2004JMC4881); this dehydration does not occur with strong bases because of the prevalent competitive hydroxyl hydrogen abstraction (1987T2191). Different behaviors can be obtained if other functional groups are bonded to the carbinol carbon atom. The formation of the 3,4diarylisoxazole-5-carboxylic acids 118 from the corresponding 5-hydroxy3,4-diaryl-2-isoxazolinyl-5-carboxylic acids 116 under basic or acid

Scheme 42 Aromatization of 2-isoxazolines in the presence of good leaving groups (LG) at C(5).

3-Arylisoxazoles and 3-Aryl-2-isoxazolines

33

conditions does not occur until the carboxyl group at C(5) is converted into its corresponding methyl ester 117 (Scheme 43) (2013JMC4277). In the presence of a vinyl group at C(5), sodium alkoxides, or RLi used as bases undergo nucleophilic addition to 5-hydroxy-5-vinyl-2-isoxazolines, e.g., 119, through the formation of a a,b-unsaturated ketone intermediate (Scheme 44) (2005T11270, 2006T16170). When 3-aryl-5-nitroisoxazolines 120 (R]NO2) are reacted with KSelectride, the corresponding isoxazoles 121 are isolated in good yields, together with benzonitriles 123 or benzamides 122, as products of 1,3-cyclodecomposition of the isoxazoline (2007CHE362). Conversely, 5-acetyl-3-aryl-2-isoxazolines 120 (R ¼ Ac) react with the same reducing agent through a complete reduction of the carbonyl moiety, affording the corresponding alcohols. Although 2-isoxazolines usually undergo complexation with Mo(CO)6 together with NeO bond cleavage and 1,3-cyclodecomposition (1985BCJ991), aromatization is the main reaction of 3-aryl-5-nitroisoxazolines and 5-acetyl-3-aryl-2-isoxazolines 120 with molybdenum hexacarbonyl at 70  C (Scheme 45) (2007CHE362).

Scheme 43 Synthesis of 3,4-diarylisoxazole-5-carboxylic acids.

Scheme 44 Reactivity of 3-aryl-5-hydroxy-5-vinyl-2-isoxazolines in the presence of bases.

Scheme 45 Reactivity of 3-aryl-5-nitro-2-isoxazolines and 5-acetyl-3-aryl-2-isoxazolines with K-Selectride or molybdenum hexacarbonyl.

34

P. Vitale and A. Scilimati

3.4 Pharmacological Active 3-Aryl-2-isoxazolines The isoxazoline ring is present in a number of commercially available and clinically useful drugs, as well as in other biological active compounds, acting as antibacterial, antitubercular, and antidepressant agents (2009EJMC3898). Most of the recently synthesized isoxazolines were prepared as antibacterial and antifungal compounds. 3-(2-Aryl-1H-indol-3-yl)-4-aroyl-5-arylisoxazolines 124 have been prepared by 1,3-dipolar cycloaddition of indolylnitrile oxides with chalcones and tested as antibacterials against Staphylococcus aureus and Escherichia coli and as fungicidal agents against Aspergillus flaws and Aspergillus niger. SAR studies revealed that the enhanced antibacterial and antifungal activity of the more active compound can be attributed to the presence of OMe and F substituents in the aromatic substituents of the indolylisoxazoline structure (Scheme 46) (2008OPPI493). 3-(5-Substituted-benzimidazol-2-yl)-5-arylisoxazolines 126 have been prepared in good yields by reaction of 1-(1H-benzimidazol-2-yl)-3(substituted-phenyl)prop-2-en-1-ones 125 with NH2OH. The purified compounds have been evaluated against Bacillus subtilis, S. aureus, E. coli, and Klebsiella pneumoniae, by using streptomycin and benzyl penicillin as references. The antifungal activity was assayed against Fusarium oxysporum and A. niger in comparison to fluconazole. The newly synthesized 3-(5substituted-benzimidazol-2-yl)-5-arylisoxazolines 126 exhibit interesting biological activity against F. oxysporum; a few are also antibacterials (Scheme 47) (2010CCL1145). Novel enantiomerically pure di- and trispiroheterocycles, obtained by the 1,3-dipolar cycloaddition of arylnitrile oxides to the C]C and the

Scheme 46 Synthesis of 3-(2-aryl-1H-indol-3-yl)-4-aroyl-5-arylisoxazolines from indolylnitrile oxides and chalcones.

3-Arylisoxazoles and 3-Aryl-2-isoxazolines

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Scheme 47 Synthesis of 3-(5-substituted-benzimidazol-2-yl)-5-arylisoxazolines.

C]O double bonds of (R)-1-(1-phenylethyl)-3,5-bis[(E)-arylmethylidene] tetrahydro-4(1H)-pyridinones 113 (see Section 3.2), have been screened in vitro against Mycobacterium tuberculosis H37Rv (MTB) and multidrugresistant M. tuberculosis (MDR-TB) (2010TA1315). All of the diastereomeric bis-spirocycloadducts showed good to excellent in vitro activity against MTB (MIC values ranging from 0.5 to 40.5 mM). A number of them were found to be excellent antimicotics, being more potent than ethambutol (MIC ¼ 7.6 mM), and ciprofloxacin (MIC ¼ 4.7 mM) used as control, respectively.

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2009US0181970 2010CBD461 2010GC1090 2010OL2594 2010S3195 2010SL777 2010T9582 2010TA1315 2010CCL1145 2011ASC2708 2011JOC3438 2011OL2746 2011OL5664 2011SAA1375 2011T1907 2011T6944 2012CMC629 2012EJO3043 2012EJOC5767 2012S1951 2012SC639 2012T10360 2012T1384 2012T1845 2012THC(26)261 2013ASC2055 2013CC4800

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CHAPTER TWO

Diketene as Privileged Synthon in the Syntheses of Heterocycles Part 1: Four- and Five-Membered Ring Heterocyclesa M.M. Heravi1, B. Talaei Alzahra University, Tehran, Iran 1 Corresponding author: E-mail: [email protected]

Contents 1. Introduction 2. Syntheses of Four-Membered Heterocycles 3. Synthesis of Five-Membered Heterocycles 3.1 Containing One Heteroatom

45 48 57 57

3.1.1 Oxygen 3.1.2 Nitrogen 3.1.3 Sulfur

57 68 92

3.2 Containing Two Heteroatoms

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3.2.1 Nitrogen and Oxygen Atoms 3.2.2 Nitrogen and Sulfur Atoms

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3.3 Syntheses of Five-Membered Heterocycles in the Solid Phase 4. Conclusion Acknowledgments References

105 107 108 108

Abstract 4-Methyleneoxetan-2-one (Diketene or DK) consists of a four-membered lactone ring adjacent to a methylene function. It can be used as a versatile precursor for the syntheses of wide range of heterocycles including fused and spiral biheterocycles. In this chapter, we try to cover the structural features and reactivity of DK, and underscore its applications as a flexible and useful synthon in the syntheses of four- and fivemembered heterocycles as well as a wide variety of fused or spiro heterocycles. This chapter as part 1 is divided in accordance with the ring sizes and subdivided according to types, numbers, and arrangements of heteroatoms.

a

Dedicated to Professor A.A. Alizadeh, who has promoted the chemistry of diketene, in recent years, in Iran.

Advances in Heterocyclic Chemistry, Volume 122 ISSN 0065-2725 http://dx.doi.org/10.1016/bs.aihch.2016.10.003

© 2017 Elsevier Inc. All rights reserved.

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Keywords: b-Lactams; Azetidin-2-ones; Diketene; Furans; Indoles; Isoxazoles; Oxazoles; Pyrroles; Thiadiazoles; Thiazoles; Thiophenes

List of Abbreviations D AIBN aq. Binap BQ CyNC a-CPA DAM DBA DBN DCC DCM Dim. DMAP DMF dr E ee eq. h hv IR LDA MCPBA min MW MCR Nu NBS NMR Ph PhMe PPA RT TBAF TBS TFA TFAA THF TMOF TMS Ts p-TSA UVeVIS

Heat, reflux Azobisisobutyronitrile Aqueous 2,20 -Bis(diphenylphosphino)-1,10 -binaphthyl Benzoquinone Cyclohexenyl isocyanide a-Cyclopiazonic acid Di-(p-Anisyl)Methy Dibenzoylacetylene 1,5-Diazabicyclo[4.3.0]non-5-ene Dicyclohexylcarbodiimide Dichloromethane Dimerization 4-Dimethylaminopyridine Dimethylformamide Diastereoselectivity Electrophilic Enantiomeric excess Equivalent(s) Hour Light (photochemistry) Infrared Lithium Diisopropylamide m-Chloroperbenzoic acid Minute(s) Microwave Multicomponent reaction Nucleophilic N-Bromosuccinimide Nuclear Magnetic Resonance Phenyl Toluene Polyphosphoric Acid Room Temperature Tetra-n-Butylammonium Fluoride tert-Butyldimethylsilyl Trifluoroacetic acid Trifluoroacetic anhydride Tetrahydrofuran Triethylorthoformate Trimethylsilyl Tosyl p-Toluenesulfonic acid UltravioleteVisible

Diketene as Privileged Synthon in the Syntheses of Heterocycles

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1. INTRODUCTION 4-Methyleneoxetan-2-one or diketene (DK) 1 is an organic compound with the formula (CH2CO)2. It is commonly prepared by dimerization of ketene. DK is a relatively safe colorless liquid. In spite of its high reactivity as an alkylating agent, and unlike its analogues blactones, such as propiolactone and b-butyrolactone, it is not carcinogenic, probably due to the instability of its DNA adducts and its high chemical reactivity as alkylating agent with nucleophilic and electrophilic reagents such as alcohols, aldehydes, amines, and ketones and it is commonly used for the production of acetoacetic esters and amides as well as substituted 1-phenyl-3-methylpyrazolones (2008CRT1964). DK is a member of the oxetane family, consisting of a four-membered lactone ring with an exocyclic methylene function, and can also be considered as an anhydride of acetoacetic acid. It is highly reactive, and readily hydrolyses in water-generating acetoacetic acid. Its half-life in deionized water is approximately 45 min at 25 C (2009JPO438). DK is an important and common industrial intermediate and its derivatives have a wide variety of applications, including the manufacture of agrochemicals, dyes, pigments, pharmaceuticals (including vitamins), and stabilizers for PVC and polyester. The latter are used in the syntheses of dyestuffs and pigments at the industrial level. Ketene can be easily dimerized to DK which exists in a b-lactone or cyclobutandione structure. The dimer obtained is a highly strained ring system, thus it readily undergoes ring-opening. The strain energy of DK was found being 94.2 kJ/mol, resulting in a highly exothermic ring opening. DK is an enol lactone of acetoacetic acid, thus its most common reaction is acylation of a nucleophile affording an acetoacetic acid derivative. Typical reactions of DK are the addition reactions with simultaneous ring-opening of the b-lactone. DK is easily ring-opened in situ by amines at ambient temperature. This typical reaction provides a divergent building block or used in the construction of various N-heterocycles. DK has both electrophilic (E) and nucleophilic (Nu) sites, which undergo typical reactions with numerous substrates to afford functionalized heterocycles (Scheme 1). Nucleophiles usually react at the carbonyl carbon leading to lactone ring-opening whereas electrophilic reagents initially react at the terminus of the exocyclic alkene motif without ring-opening at the lactone moiety.

46

M.M. Heravi and B. Talaei

Scheme 1

DK reacts readily with a wide range of nucleophiles such as alcohols, thiols, amines, phenols, carboxylic acids, amides, ureas, thioureas, urethanes, sulfonamides, cyanoacetic esters, etc. to give the corresponding acetoacetyl derivatives via a nucleophilic reaction route (Scheme 2). Suitable acetoacetyl derivatives can be converted to the corresponding heterocycles under appropriate conditions (2007JOC9761). DK has been found as a privileged synthon in the syntheses of several heterocyclic systems, owing to its high chemical activity toward the nucleophiles. Typically reactions proceed via the formation of 1,3-dicarbonyl

Scheme 2

Diketene as Privileged Synthon in the Syntheses of Heterocycles

47

compounds, which undergo subsequent reactions. Thus, the reaction of hydrazine derivatives with DK is an efficient approach toward the construction of the pyrazoles. In this way, hydrazones afford pyrazolin-3-ones, hydroxylamines give isoxazolones or isomers, hydroxamic acids produce oxazoles, and a-hydroxyketones and a-hydroxy acids furnish butenolides or furanones, respectively (Scheme 2). Moreover, DK can react with imidates, cyanamides, carbodiimides, and isocyanates to make several approaches available for the construction of six-membered heterocyclic systems. DK has also been used to obtain heterocycles such as cyclopropanespiro-b-lactones, benzofurans, pyrazolidines, pyrido[2,3-d] pyrimidines, and condensed isoquinoline analogs. Multicomponent reactions (MCRs) are convergent reactions in which three or more starting materials react to form one product. In an MCR, a product is assembled according to a cascade of elementary chemical reactions. Using DK as a starting material, five-, six- and seven-membered heterocycles may be synthesized efficiently via variety of MCRs. DK has also been used in the total syntheses of natural products and multistep syntheses of some complex molecules in a key step (1964JA5654, 1978JA4225). For instance, the enantioselective addition of DK to aldehydes resulted in the formation of optically active 6-substituted pyridyls (2001IJ241). Four stereoisomers of nodulisporacid A can be synthesized efficiently via a three-component reaction involving DK (2010TL2765). In addition, initial acetoacetylation of resins with DK gives the polymer-bound acetoacetamide, which can be used in the solid-phase version of some important name reactions such as Biginelli multicomponent reaction, Hantzsch cyclocondensation (1998BMCL2381), and Knoevenagel reaction (1999S1961). In 1986, the chemistry of DK was comprehensively reviewed (1986CRV241). Clemens endeavored to index every type of synthetic transformation, including those leading to the syntheses of heterocycles, that involves DK providing an all-inclusive coverage of the publications that appeared from 1907 till early 1985. A literature survey from 1986 to date revealed a huge number of publications on the application of DK as a privileged synthon in the syntheses of various heterocycles. Although a few brief sections involving the chemistry of DK can be found in some text books (B-2010MI01, B-1992MI173), no comprehensive review has appeared in the literature since 1986. We are interested in heterocyclic chemistry (2014AHC(111)95, 2014AHC(112)1, 2014AHC(112)183, 2014AHC(113)1, 2015AHC(114)

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M.M. Heravi and B. Talaei

77, 2015AHC(117)261, 2016CUOC1591, 2010H1979, 2015JMOCA(402)100, 2014JMOC-A(394)74) particularly, heterocycles showing relatively high biological activity (2015MI577, 2014T7). We have recently published three chapters regarding the applications of ketenes as synthons in the syntheses of three- and four-membered heterocycles, Part 1 (2014AHC(113)143), five-membered heterocycles, Part 2 (2015AHC(114) 147) and six-membered heterocycles, Part 3 (2016AHC(118)195), respectively. In this chapter, we wish to underscore the applications of DK as a privileged synthon in the syntheses of various four- and five-membered heterocycles. The applications of DK in construction of six-membered rings will be discussed in a separate chapter.

2. SYNTHESES OF FOUR-MEMBERED HETEROCYCLES Highly enantioselective hydrogenation of DK was achieved, using catalytic systems RuCl[(S)- or (R)-binap](benzene)Cl and triethylamine or with Ru2C14[(S)- or (R)-binap]2(NEt3) in THF, for the hydrogenation of DK to obtain (R)-4-methyloxetan-2-one 2 in high enantiomeric excess and also high selectivity (up to 92%) (Scheme 3) (1992JCS(CC)1725). Upon photolysis, DK reacts with various ketones such as acetone and acetophenone to afford the corresponding spirocompounds. Notably, the heterolytic addition of DK to ketones affords cycloadducts such as 2,2disubstituted 6-methyl-1,3-dioxan-4-ones. For example, benzophenone reacts with DK when they are exposed to ultraviolet light to give a mixture containing b-lactone 4 (25%), 4-diphenylhydroxymethyl-2,5dihydrofuran-2-one 5 (25%) and 1,1,6,6-tetraphenyl-2,5-dioxaspiro[3.3] heptane 7 (9%) were obtained. When the reaction was performed under nitrogen, a small quantity of 2,2-diphenyl-4-diphenylmethylenoxetane 8 was detected along with 4, 5, and 7 (Scheme 4) (1975CPB365). The generation of such products can be explained as follows: photocycloaddition of the benzophenone carbonyl to the olefinic double bond of DK produces the spirooxetane derivative 4. In fact, the attack of the

Scheme 3

Diketene as Privileged Synthon in the Syntheses of Heterocycles

49

electron-deficient oxygen atom of the carbonyl np* excited state to the olefinic moiety of DK produces a biradical intermediate 3, which is cyclized to the spirooxetane compound 4. Upon isomerization following route a (by either radical or ionic reaction), the isomer 5 is formed. On the other hand, upon decarboxylation following route b, compound 4 affords 2,2-diphenyl3-methylenoxetane as an intermediate 6. The latter then can be added to another molecule of benzophenone to produce 7 (Scheme 4). Spirooxetane 7 was an already known compound, and was synthesized via the photoaddition of benzophenone to allene (1968JOC2774, 1966CC813). Upon decomposition and under special conditions, DK can be converted to allene (1957USP2818456). This offers another possible approach to the syntheses of 7. By elimination of a molecule of formaldehyde from 7, compound 8 is formed (Scheme 4). Upon exposure to UVeVIS laser irradiation, DK as an enol-lactone partner can react with p-benzoquinone (BQ) to provide a complex mixture 9 even if the reaction is performed under an argon atmosphere resulting in

Scheme 4

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M.M. Heravi and B. Talaei

Scheme 5

the oxetane 10 as chief product along with the spirocyclobutanone 13 and spirodioxetane 14 as minor products. When this reaction was conducted under an oxygen atmosphere and VIS-laser irradiation, similar results were obtained except that the spiroacetal 11 was also generated, and no trioxanes (oxygen trapping) were detected. Actually, it was found that the spirocyclobutanone 13 is a secondary photolysis product of the acetal-type oxetane regioisomer generated by photodecarboxylation as well as photorearrangement. Spiroacetal 11 possesses an additional oxygen atom compared to the starting DK, thus it was reasoned that compound 11 was the product of the secondary photolysis of an oxygen-trapped product (Scheme 5) (1988LA869). DK reacts with N-bromosuccinimide (NBS) to afford 3-bromo-4methylene-2-oxetanone 15, which can be captured by ethanol at low temperature to give ethyl 2-bromoacetoacetate 16 in moderate yield (Scheme 6) (1948JA29). Similarly, DK was chlorinated in the 3-position using N-2,4trichloroaniline to afford 3-chloro-4-methylene-2-oxetanone17 (Scheme 7). 2-Bromoacetoacetate 16 is generally less stable than chloroacetoacetate 18 and thus is scarcely used as a reagent in organic syntheses. Nevertheless, the

Scheme 6

Diketene as Privileged Synthon in the Syntheses of Heterocycles

51

Scheme 7

thiolactam 19, obtained from ethyl ()-pyroglutamate, upon the reaction with ethyl 2-bromoacetoacetate in the presence of NaHCO3 in refluxing CH2Cl2 afforded the alkylidenepyrrolidine 20 in satisfactory yield. The latter after several steps including protection-deprotection of groups was hydrogenated to afford the two diastereoisomeric 2-[2-(p-nitrobenzyloxycarbonyl)-5pyrrolidinyl]butanoic acids 21. Upon dehydration using l-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride 22 as a dehydrating agent, the pnitrobenzyl ()-6b-ethylcarbapenam-3-carboxylate 23 was obtained (Scheme 8) (1983JOC1439). The [2 þ 2] cycloaddition of DK to imines is recognized as a general approach for generating b-lactams (Scheme 9). For the syntheses of carbapenem antibiotics such as 25, this reaction was carried out using an appropriate chiral imine to provide requirement for chiral induction to obtain an

Scheme 8

Scheme 9

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M.M. Heravi and B. Talaei

optically active intermediate (1988T2149). When optimizing the conditions for the [2 þ 2]-cycloaddition reaction of DK with imine, it was found that the polarity of solvent plays the key role in the stereoselectivity of the reaction. Toluene as solvent provided the best selectivity. Thus, upon the reaction of 24 with DK in toluene, 25 (S-R-R) and 25 (R-S-R) were formed in a ratio of 7.7:1 however, the chemical yield was poor (18%). Chen et al. reported an efficient and highly stereoselective synthesis of (2R,3R)-3-[(1R)-1-[tert-butyl(dimethyl)siloxy]ethyl]-4-oxoazetidin-2-yl acetate 29. The key steps are a [2 þ 2] cycloaddition of DK to the chiral imine 27 (which was prepared from 26 and relatively bulky (diphenylmethyl)amine). This highly stereoselective [2 þ 2] cycloaddition reaction was performed in the presence of imidazole in five to one equivalent ratio of DK in anhydrous THF at 15 C for a relatively long reaction time. A mixture of (3S,4S)-b-lactam 28a and (3R,4R)-b-lactam 28b was obtained in 78% yield and a 4.7:1 ratio (Scheme 10) (2011S555). The stereochemistry of 26 was determined as 3,4-trans on the basis of 1H-NMR coupling constant between H-3 and H-4. This coupling constant can be attributed to epimerization at C-3 forming the cis-isomer 28a predominantly, which was converted into more thermodynamically stable trans-isomer 28b mediated by imidazole. Asymmetric titanium tetrachloride catalyzed reduction of 28a to afford the respective alcohol 29a with S-configuration, which upon Mitsunobu inversion gave the desired R-configured alcohol 29b (Scheme 11) (2011S555). Similarly, [2 þ 2] cycloaddition reaction of DK with imine 30 containing an l-menthyl moiety afforded the (4S)-isomer 31 as the chief product. The asymmetric reduction of 31 using a di-isopropylamine-borane complex mediated by magnesium trifluoroacetate afforded a mixture of 32a and 32b

Scheme 10

Diketene as Privileged Synthon in the Syntheses of Heterocycles

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Scheme 11

(4:1). Next, upon alkaline hydrolysis, compound 32 was converted into the carboxylic acid 33 (Scheme 12) (1992CPB1094). In 1985, the successful synthesis of N-protected azetidin-2-ones 37 was reported by Simig et al. Initially, N-arylated or N-benzylated N-(3oxobutyryl)aminomalonate diethyl esters 36 were prepared. These esters were equilibrated with pyrrolidine-2-ones 35 and the mixture was treated with NaOEt in the presence of I2 to afford 37aec (Scheme 13) (1985T479).

Scheme 12

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M.M. Heravi and B. Talaei

Scheme 13

This approach for building up the azetidin-2-one skeleton from N-(3oxobutyryl) aminomalonate esters 36 possessing a chiral auxiliary on nitrogen is operationally convenient owing to its simplicity. It is widely used in asymmetric syntheses of chiral azetidine-2-one and has found application in the total syntheses of natural products (2009T9742). For instance, Onomura and co-workers reported a convenient syntheses of azetidin-2-ones 37d, which possesses an acetyl group at the 3-position and two alkoxy carbonyl groups at the 4-position, with high diastereoselectivity. Conversion to 38, which possesses two chiral centers, was achieved by reduction using NaBH4. Finally 38 was converted into enantiomerically pure 4-methoxy3-(10-silyloxyethyl)azetidin-2-one 39 in several steps involving various functional group transformations. Interestingly, in this protocol, the conversion of 35d to 37d was accomplished electrochemically (Scheme 14) (2009T9742).

Scheme 14

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Acetoacetamides are useful precursors for the synthesis of b-lactams. A research group at Beecham Laboratories has successfully carried out the reaction of acetoacetylated perhydrooxazine with DK to obtain compound 40. The latter was subjected to diazo exchange with toluene-p-sulphonyl azide and Et3N, which then upon exposure to irradiation was cyclized to provide solely the trans-substituted b-lactam 41. The latter was used as a versatile intermediate for the synthesis of thienamycin derivative 42 (Scheme 15) (1979JCS(CC)846, 1981USP4245089, 1980TL5071, 1978JA313). Using a chiral oxazine, the reaction proceeded to completion stereospecifically (1984TL2913). It is worthy of mention that pyrrolidinone 44, obtained from the acid-catalyzed reaction of DK with the protected

Scheme 15

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aminomalonate 43, can be converted into thienamycin 42 by a completely different reaction pathway (1985T479). Upon heating in an aprotic solvent, DK reacts smoothly with 3aminobut-2-enamide 45 to afford 3-(1-iminoethyl)-4-hydroxy-2-pyridone 46, which subsequently upon acid hydrolysis provides the corresponding acetyl derivative 47. Based on the facile preparation of 47, the Katagiri group designed a synthetic approach toward compound 53 using 47 as starting material. They successfully prepared 1-benzyl-3-(1-hydroxyethyl)4-methoxy-2-pyridone 49a and its 6-methyl derivative 49b starting from 3-acetyl-4-hydroxy-2-pyridones 47a,b. They initially methylated 47a,b to obtain the methyl ethers 48a,b, followed by reduction with NaBH4 to furnish 1-benzyl-3-(1-hydroxyethyl)-4-methoxy-2-pyridone 49a. This was then converted into the azetidin-2-one 52a in three steps in satisfactory overall yield (35%) albeit as a mixture of diastereomers. This diastereomeric mixture can be converted into 53a by Karady’s method (magnesium trifluoroacetate in ether (5 eq.)/diisopropylamine-borane (2 eq.)/0 C) (Scheme 16) (1981JA6765, 1986JCS(P1)1289).

Scheme 16

Diketene as Privileged Synthon in the Syntheses of Heterocycles

57

3. SYNTHESIS OF FIVE-MEMBERED HETEROCYCLES 3.1 Containing One Heteroatom 3.1.1 Oxygen Five-membered heterocycles are generally formed from initial condensation of DK with acetoacetylates in an intramolecular condensation process. aHydroxyketones 54, 57, and 60 are commonly submitted to a sequential acetoacetylation/condensation reaction affording the corresponding fivemembered rings such as the butenolide 55, 58, and 61, respectively (Scheme 17) (1954JCS822, 1985AP190). These butenolides are readily transformed into furan-3-carboxylic acids (e.g., 56 and 59) (1954JCS822). Furanones such as 63 are important intermediates in the total synthesis of several naturally occurring compounds (1988TL4807). They are commonly obtained from a-hydroxyacids by the previously mentioned conventional pathway (Scheme 18) (1954JCS832). To find and secure optimal reaction

Scheme 17

Scheme 18

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M.M. Heravi and B. Talaei

conditions, initially, the S-ketoester was treated with diisopropylamino magnesium iodide, which led only to the recovery of 62a; no expected cyclized product 63 was isolated or even not detected. It was assumed that the cyclization is sensitive and dependent on the nature of substitution in the a-alkoxyacetate motif. As a matter of fact, now, it is well established that the reaction is actually sensitive to the metal counterion (1954JCS832, 1983TL5143, 1976JCS(P1)1485). (S)-Carlosic acid 70, the chief precursor of (R)-carlosic acid 71 in Penicillium charlesii, was prepared from the reaction of dimethyl (S)-malate 64 and DK (Scheme 19) (1974JOC113). The cyclization of 65 to 66 had to be conducted at a low temperature otherwise the undesired dimethyl fumarate was generated (with simultaneous liberation of CO2 and generation of acetone). Upon treatment of 65 with t-BuOK/t-BuOH at the freezing point, compound 66 was obtained in 39% yield. The bromination of 66 to 67 had to be performed rapidly, as otherwise the HBr generated during the reaction affected the ester function. The catalytic reduction of 67 to 68 was conducted in a similar way to that for a-bromo-(S)-7-methyltetronic acid. Treatment of 68 with butyryl chloride, TiCl4, and PhNO2 gave the ester 69, which was then transformed to 70 by gentle saponification (Scheme 19) (1974JOC113). On the other hand, the transesterification of functionalized tert-butyl acetothioacetates 72 proceeds smoothly to give carlosic acid 70 (1983TL5143). The utilization of tetrabutylammonium fluoride as a suitable catalyst effectively promoted the cyclization of g-substituted-a-acyltetronic acids (1987JCS(P1)121, 1977JCS(CC)609, 1980BCJ2046). Upon treatment of DK with VO(OEt)Cl2 and a-methylstyrene 73a in EtOH, ring expansion occurred to afford the ring-enlarged dihydrofuran 74a. When a trimethylsilyl moiety is present at the a-position of styrene, further oxidation can occur. For example, upon VO(OR2)Cl2-induced reaction of DK with a-trimethylsilylstyrene 73e, the furan 75 was obtained via desilylative aromatization (Scheme 20) (1991JOMC1). A proposed mechanism for such a reaction is illustrated (Scheme 21). According to it, initially, the oxovanadium alkoxide attacks DK with subsequent ring-opening via one-electron oxidation to afford a radical intermediate 76, which isomerizes to 77 the more stable radical, which is able to form a new CeC bond with 73. The oxovanadium species could generate a complex with 77 or with 77 and 73 in a similar manner as has already been reported for Mn(III)-based oxidation. The reaction with olefin is apparently supported by the VO(OR2)Cl2-induced oxidation of a-methylstyrene to

Diketene as Privileged Synthon in the Syntheses of Heterocycles

Scheme 19

Scheme 20

59

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M.M. Heravi and B. Talaei

R

Scheme 21

Scheme 22

acetophenone in the absence of DK. Upon cyclization, 78 is transformed into the dihydrofuran 74. Most probably, the VO(OR2)Cl2 species is promoting the desilylative process leading to aromatization of 74 into 75 through oxidation of the oxovanadiumedihydrofuran complex (1991JOMC1). The condensation of N-methoxyacetocetamide 79 with an a-acetoxy aldehyde proceeds smoothly to give the corresponding 2,5-dimethylfuran derivative 80 (Scheme 22) (1980USP4240973). DK can be used as a basic reagent in a pseudo-five-component reaction in one-pot reaction to afford a highly efficient synthesis of substituted bisfuramides (Scheme 23). The reaction of DK with a suitable diamine,

Scheme 23

Diketene as Privileged Synthon in the Syntheses of Heterocycles

61

Scheme 24

dibenzoylacetylene (DBA), mediated by triphenylphosphine in dichloromethane proceeded smoothly at 25 C to give furamides 81 spontaneously (2008S3742). In this approach, ring-opening of DK takes place under mild reaction conditions in the absence of catalyst. Satisfactory yields have been reported for these MCRs (2008S3742). A facile three-component reaction involving an amine, DK, and dibenzoylacetylene catalyzed by triphenylphosphine occurred in a onepot fashion N3-(alkyl)-2-methyl-4-(2-oxo-2-phenylethyl)-5-phenyl-3furamide derivatives 82 resulted (Scheme 24) (2007T8083). A plausible mechanism of this reaction using N-alkyl-3-oxobutanamide is suggested (Scheme 25). Based on the chemistry of nucleophilic trivalent phosphorus, it is logical to assume that 82 is generated from initial addition of triphenylphosphine to dibenzoylacetylene followed by protonation of the 1:1 adduct by the N-alkyl-3-oxobutanamide as Bronsted acid. Next,

Scheme 25

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M.M. Heravi and B. Talaei

the positively charged phosphorus can be attacked by the conjugate base to give phosphorane 83, which is then converted to betaine 84. Upon cyclization of the betaine 84 followed by elimination of triphenylphosphine oxide, 82 is formed (Scheme 25) (2007T8083). Four possible stereoisomers of nodulisporic acid A 88 were synthesized efficiently via a three-component reaction in one-pot leading to the construction of the whole scaffold. Mukaiyama et al. reported that by addition of large excess of ethanol or methanol to a premixture of aldehyde 85, DK, and TiCl4 in dichloromethane, compound 86 was exclusively produced in good yield as a sole isomer (configuration not determined). Then, in the next stage and in the same pot, 86 was successively treated with tetra-n-butylammonium fluoride (TBAF) and HCl resulting in the construction of the whole scaffold in 51% yield. Upon complete deprotection, HCl was added, which led to the formation of enol ether. Then, the methyl ester of (4S,40 S,60 S)-87 upon hydrolysis gave (4S,40 S,60 S)-88 as a 1:1 mixture of (E)- and (Z)-isomers (Scheme 26). In a similar way, only

Scheme 26

Diketene as Privileged Synthon in the Syntheses of Heterocycles

63

Scheme 27

by changing the combination of stereoisomers 85 and dimethyl malate, methyl esters 87 of 88 were synthesized as stereoisomeric forms (2010TL2765). A nitrile group can be added as an ester enolate in an intramolecular fashion to give 90. The required precursor is an alpha acyloxy nitrile 89, which is simply prepared from the reaction of a cyanohydrin with DK (Scheme 27) (1987BCJ2139). 2-Chloroacetoacetate 91 is prepared easily from the reaction of DK and Cl2 in EtOH. 2-chloroacetoacetates are commonly used in synthesis of a number of heterocyclic systems. For example, 2-chloroacetoacetic acid derivatives are frequently used as intermediates for the synthesis of fivemembered heterocyclic systems such as oxazoles, imidazoles, and thiazoles. In such reactions, heterocyclizations often occur by displacement of the halogen at C2 with the subsequent reaction of the carbonyl group at C3. Aminofuran 93 was synthesized from the reaction between ethyl 2chloroacetoacetate and acetoacetonitrile as its sodium salt 92. Compound 93 then upon treatment with ammonia was converted into cyanopyrrole 94 (Scheme 28) (1978JOC3821). 4-chloroacetoacetate 91 derived from DK is a versatile intermediate for the synthesis of tetronic acid 97. It can initially be converted into

Scheme 28

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M.M. Heravi and B. Talaei

2,4-dichloroacetoacetates 98, 4-alkoxy 95 and 4-hydroxyacetoacetate 96 intermediates via heterocyclization (Scheme 29) (1982EUP67408). In this type of heterocyclization, the halogen is converted into a hydroxyl group, which upon lactonization under different reaction conditions gave a tetronic acid. Upon treatment with SOCl2, 91 is converted into dihaloacetoacetate 98, which upon heating gave 3-chlorotetronic acid 99 as a water-insoluble intermediate. This water-insoluble intermediate was separated from salts and then upon hydrogenation on Pd in water provided the final desired product 97 (1987C73). Similarly, the asymmetric synthesis of ()-4hydroxypyrrolidin-2-one 100, a natural product isolated from Amanita muscaria, was achieved. Treatment of 91 with baker’s yeast gave intermediate A, which upon treatment with NH3 provided the desired natural product 100. The spectroscopic and physical data for this synthetic compound were identical to those already obtained from natural product. Isocyanides (2011T2707, 2016MI53203) react with DK, catalyzed with a tertiary base, to give highly functionalized butenolides 101, which have been found to be useful as aging inhibitors for rubber (1972GEP2222405) (Scheme 30).

Scheme 29

Diketene as Privileged Synthon in the Syntheses of Heterocycles

65

Scheme 30

The reactive exocyclic bond of DK reacts with carbenes and carbenoids obtained from various common sources such as diazo compound/metal catalyst or diazo compound/photochemical decomposition (hv) and phenyl(trihalomethyl)mercury frequently resulted in the formation of 5-oxo4-oxaspiro[2,3]hexanes in acceptable yields. For example, reaction of DK with diazoacetophenone 102 (R ¼ OEt) as expected afforded two isomeric spiro compounds, trans- and cis-2-benzoyl-1-hydroxycyclopropaneacetic acid b-lactone 103. These reactions provided an adduct in which the blactone ring remained intact (1973CPB729). Upon the rearrangement via either path a or b then affords isomer 104 (R ¼ QEt) or 105 (R ¼ OEt), respectively. Under the reaction conditions, probably compound 106 is also generated (Scheme 31) (2000JCS(P1)2109, 1994TL6737, 1973CPB729). Simple thermal rearrangement is excluded in this case since compound 103 is stable both in refluxing toluene and at more elevated temperatures. When it is heated at 180 C under pressure in a sealed tube, it gives a mixture that does not contain any of the furanones. By contrast, upon heating and in the presence of any of a broad range of metals, e.g., copper powder, copper(II) acetylacetonate, rhodium(II)acetate, etc., 103 is transformed to a mixture of the furanones. It is assumed that their formation takes place during the cyclopropanation reaction. Thus, it was proposed that a soluble metal compound generated in the reaction simultaneously catalyzes the rearrangement of spirolactone to furanone (1994TL6737). A plausible

Scheme 31

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M.M. Heravi and B. Talaei

mechanism involves the generation of the species by reaction of the metal and diazo compound, which acts as an active catalyst. Therefore, apparently the spirolactone to furanone rearrangement is in fact a metal catalyzed process (Scheme 32). The reaction of cyclic 2-diazo-1,3-dicarbonyl compounds 107 with DK affords the products generated from either insertion of the metal species into the OeC bond of the b-lactone ring or from cyclopropanation of the exocyclic double bond, or equally the results of both processes. The reaction finally leads to the formation of the benzofurans 108 and 109 (Scheme 33). Products bearing exocyclic double bonds 111 could be generated via thermal liberation of CO2 (Scheme 34) from a dioxaspirooctenone 110 (Path a) or via 1,3-dipolar cycloaddition reaction (Path b) (2000JCS(P1) 2121, 1997JCS(P1)1, 2016CUOC1591). DK reacts with acyl dimethylsulfonium methylides 112 and 116 to give furan 115 and spirocyclic furanone 117, respectively (Scheme 35) (1975USP3869480, 1968BCJ1738).

Scheme 32

Diketene as Privileged Synthon in the Syntheses of Heterocycles

Scheme 33

Scheme 34

Scheme 35

67

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M.M. Heravi and B. Talaei

Alkylthiols were reacted with DK in the presence of azobisisobutyronitrile (AIBN) as a catalyst to afford g-alkylthio-b-butyrolactones 118. Free radicals have been suggested as reactive intermediates in these reactions (Scheme 36) (1972JOC1837). In general, b-lactones undergo polymerization to give 3-hydroxypropionic acid polyesters, while in this case the rearrangement during polymerization takes place due to the presence of the sulfur atom in the alkyl chain. Postulation of intermediate 119 is justified as the electron pair on sulfur is well known to assist in the ring-opening of the lactones. The reaction of 119 via path a attack of carboxylate anion on the secondary carbon of the episulfonium ion is ineffective and results in the recovery of starting material. Reaction via path b ring-opening of the episulfonium ion on the primary carbon affords the rearranged lactone 120. The consecutive intermolecular opening of the episulfonium ion at the primary carbon gives the polyester 122. Decomposition via path c, 120 gives the alkyl allyl sulfide 121 and along with liberation of CO2 (Scheme 36) (1972JOC1837). 3.1.2 Nitrogen The most direct strategy for the synthesis of the 3-acyltetramic acids 123 is the acetoacetylation of amino acid esters using DK with subsequent cyclization promoted by sodium methoxide, followed by treatment with methanolic ammonia at 100 C to give the corresponding 3-(1-iminoethyl) tetramic acid derivatives 124 (Scheme 37) (1980CPB2494). Copper complexes were prepared by treatment of 3-acyl and 3-(1-iminoethyl)tetramic acid derivatives using copper(II)acetate in aqueous ethanol. It is noteworthy that the nature of the substituent at the 5-position shows an effect on the antimicrobial activity. Moreover, it was found that some of the copper(II)

Scheme 36

Diketene as Privileged Synthon in the Syntheses of Heterocycles

69

Scheme 37

complexes exhibited higher potency than their parent compounds (1980CPB2494). The attempted conversion of the tetramic acid 123 into the 3-acetyl-5benzyl-3-pyrrolin-2-one 128 by selective catalytic hydrogenation of the enolic double bond followed by the removal of water from the resulting hydroxyketone failed. Thus, 2-amino-3-phenylpropanal diethyl acetal 126, obtained by reduction of the a-aminoester 125, was reacted with DK to give the condensed acetoacetic amide 127. Upon hydrolysis of the acetal group in the latter by 1% hydrochloric acid in aqueous THF resulted in the free aldehyde 128 (Scheme 38). This was subsequently treated with 2N aqueous NaOH in a CH2Cl2/Et2O mixture at ambient temperature, to afford compound 129 in satisfactory yield by a smooth intramolecular Knoevenagel/Cope condensation (Scheme 38) (1980HCA121).

Scheme 38

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M.M. Heravi and B. Talaei

Scheme 39

The reaction of 125a (R ¼ COCH3) with DK failed to give the expected tetramic acid derivative 123. Instead, cyclization occurred affording 3-acetyl-5-carbethoxy-2-hydroxy-4-methyl-pyrrole 130. Thus, when 125a was treated with DK in excess in the presence of NaOAc, 3-acetyl5-carbethoxy-2-hydroxy-4-methylpyrrole 130 and 2,5-dimethyl-3,6dicarbethoxy- pyrazine 131 were isolated, no product corresponding to the compound 123 was detected. Upon catalytic reduction using PtO2, 130 was converted into 132 (Scheme 39) (1971CPB292). In another approach to tetramic acids, DK was reacted with aaminoketones in a sequential acetoacetylation/condensation to afford pyrrolidinones such as 132 and 133 (1971CPB292). However, when using a-amino acids and their esters (1954JCS850, 1967YZ1219), only pyrrolidinediones 132 were obtained (Scheme 40) (1980HCA121, 1980CPB2494, 1984CPB4197). A number of these substituted tetramic acids showed interesting biological properties and are used as plant growth regulators

Scheme 40

Diketene as Privileged Synthon in the Syntheses of Heterocycles

71

Scheme 41

(1979ABC1641) and antibiotics (1984CPB4197). This sequential strategy involving acetoacetylation/condensation has been employed in synthesis of the antibiotic Holomycin (1964JA5654) and the mycotoxic cyclopiazonic acids (1984JA6873, 1977MI125). B€ uchi et al. reported the concise total synthesis of the antibiotic Holomycin 144 (Scheme 41) (1964JA5654). Initially, S-benzyl-L-cysteine ethyl ester 134 was acylated using DK to afford the N-acetoacetyl derivative 135, which upon cyclization prompted by NaOEt gave the racemic 3-acetyl4-hydroxy-5-(S-benzylthio)methyl-3-pyrrolin-2-one 136. Upon treatment of the latter with thionyl chloride in benzene at ambient temperature, a yellow crystalline compound was isolated. It was identified as a reduced product 3-acetyl-4-hydroxy-5-(S-benzylthio)methylene-3-pyrrolin-2-one 139. It is assumed that the latter is generated from the putative chlorosulfite 137. Upon decomposition and extrusion of SO, the latter is converted into another intermediate 138. Condensation of the ketone 139 with NH2-OH gave oxime 140 as a sole product. The latter was submitted to rearrangement in the presence of p-toluenesulfonyl chloride and NaOH to give a 3-pyrrolin2-one 141. The latter upon tosylation and subsequent treatment with sodium

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benzyl mercaptide gave 142. Upon removal of the two benzyl groups from the latter, using lithium in liquid ammonia followed by air oxidation gave 143 as crude material. Treatment of this crude in HCl/MeOH gave the desired target Holomycin 144. It was found to be identical with the compound isolated from natural product in every respect (Scheme 41). Upon treatment of 145 with one equivalent of NaOEt/EtOH, the free base is obtained, which was reacted with DK at 5 C, affording the expected l-acetoacetyl-2-carbocthoxy-pyrrolidine 146. When the latter was refluxed in NaOMe/MeOH/benzene, intramolecular condensation occurred to give 147. Upon the hydrolysis of 147, with 0.1N HCl, a nonbasic residue was obtained that upon crystallization provided 149. The proposed pathway to 149 involves the generation of 148, which underwent acid-catalyzed intermolecular condensation (Scheme 42) (1973MI132).

Scheme 42

Diketene as Privileged Synthon in the Syntheses of Heterocycles

73

Scheme 43

Substituted pyrrolidine-2,4-diones, e.g., 150 have been employed as precursors in the total synthesis of antibiotics, streptolydigin, and tirandamycin. It was obtained from the reaction of DK with diethyl N-methylDL-aspartate. Compound 150 was reacted with methylamine to afford enamine 151. Upon treatment with 0.2N HCl, the latter gave 1-methyl2,4-pyrrolidione-5-(N-methylacetamide) 152, which in several steps was converted into the desired natural product streptolydigin (Scheme 43) (1978JA4225). Naturally occurring tetramic acid 155 can be synthesized in two steps starting from L-tyrosine methyl ester 153. Acylation of by 153 by DK gave under LaceyeDieckmann reaction conditions, 154 which was converted into the desired naturally occurring compound 155 in satisfactory yield (Scheme 44) (2010EJO5402). DK readily reacts with bromine and N,O-diprotected tyrosine derivatives 156 in the presence of Et3N to give the corresponding bromoacetoacetamide 157. Upon base catalysis and under LaceyeDieckmann reaction

Scheme 44

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M.M. Heravi and B. Talaei

condensations, the latter concurrently undergoes MichaeliseBecker reaction using excess potassium diethyl phosphite to give the intermediate 158. Removal of activated phosphonates from 158 and reaction with aldehydes followed by WittigeHornereEmmons reaction provided the desired N,Odiprotected tetramic acids 159 in a one-pot MCR (Scheme 45) (2010EJO5402). a-Aminoamides and a-aminonitriles can also be utilized for the synthesis of pyrrolidinone derivatives. The reaction of a-aminoamides 160 with DK resulted in the formation of anilides 161, with aromatic and aliphatic N-substituents which upon treatment with NaOMe were converted into different products 162 and 163, respectively (Scheme 46) (1972YZ1507). When N0 -methyl-DL-aspartimide 164 was treated with distilled DK, acetoacetamidoimide 165 was obtained, which upon treatment with small excess of NaOMe underwent rearrangement to give 3-acetyl-2,4pyrrolidione-5-(N-methylacetamide) 166 as a tetramic acid derivative in moderate yield (Scheme 47) (1978JA4237). N-Benzylaminoacetonitrile 167a and N-methylaminoacetonitrile 167b, which upon cyclo-condensation with DK in the presence of lithium enolates in refluxing glyme gave the corresponding N-alkyl-a(acetoacetamido)acetonitriles 3-acetyl tetramic acids 163a and 163b, respectively (Scheme 48) (1978JA4225, 1972YZ1515).

Scheme 45

Diketene as Privileged Synthon in the Syntheses of Heterocycles

75

Scheme 46

Scheme 47

A fused ring system 171 was obtained in 84% yield from the reaction of azahomoadamantane 168 with DK in the presence of Et3N. The reaction proceeds via initial base-catalyzed cyclization of 169 to give 170. The latter tautomerizes to the desired fused ring system 171 at room temperature (Scheme 49) (1981JOC4474). The reaction of aminotropone 172a (R ¼ H) and aminotropolone 172b (R ¼ OH) with DK have attracted much attention thus it was studied extensively (1965BCJ306). DK reacted readily with aminotropone 172a and aminotropolone 172b to give the corresponding acetoacetamidotropones 173a and tropolones 173b, respectively. 2-Acetoacetamidotropones

Scheme 48

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M.M. Heravi and B. Talaei

Scheme 49

Scheme 50

173a can undergo ring closure to afford cyclohepta[b]pyrrole derivatives 174a, an aldose reductase inhibitor (Scheme 50) (1982USP4337265). 2-Amino-7-bromotropone 172c (R ¼ Br) reacted with DK under similar conditions to afford the corresponding N-acetoacetyl derivatives 175 while 2-amino-3-bromotropone was quite unreactive under the reaction conditions. Treatment of 2-acetoacetamido-7-bromotropone 175 with alkali gave 3-acetyl-4-hydroxycarbostyril 176 (Scheme 51) (1965BCJ306). With excess DK, mixtures of pyrone 177 and pyridone 178 derivatives are formed as a result of further condensation of the 4-aminotropolone with DK (1966BCJ281, 1967YZ1351); the composition of the product mixtures

Scheme 51

Diketene as Privileged Synthon in the Syntheses of Heterocycles

77

Scheme 52

was found to be dependent on basicities of the NH group of starting aminotropones (1971CPB1477); that is, the aminotropones that have relatively high pKa values (2.07e3.42) tend to afford pyridone derivatives 178, while those with lower pKa values increase the tendency to form pyrone derivatives 177 (Scheme 52). Nitrenes, generated from irradiation of acyl azides or from ethyl azidoformate in dichloromethane with a high-pressure mercury lamp, also add to the exocyclic double bond of DK to give the spirocyclic intermediates 179, which when produced rapidly rearrange to afford the pyrrolinone derivatives 180 in low yield (Scheme 53) (1978CL697, 1979CPB1181). The low yields of the pyrrolinones 180 are attributable to photo-Curtius rearrangement of the acyl azides to the isocyanates. Without irradiation, reaction of DK with benzoyl azide did not occur, and starting DK was recovered (Scheme 53) (1979CPB1181). This preparation of tetramic acids has been used to introduce the pyrrolinone ring (C) during a total synthesis of althiomycin (Scheme 54) (1982MI137). Initially, the thiazoline carboxyazide 181 was coupled with DK under irradiation using a 100 W high-pressure mercury lamp with a quartz filter at 0 C (HALOS PIH-100). The coupled product was then methylated using diazomethane to obtain the desired product 182. Aldol condensation of the latter with formalin (35%) in DMSO at ambient temperature gave hydroxymethylated product A. Then, the hydroxymethyl derivative A was deprotected using anhydrous HF in the presence of anisole at 0 C, and finally the resultant was coupled with the oxime of thiazole

Scheme 53

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M.M. Heravi and B. Talaei

Scheme 54

carboxyazide B in the presence of potassium carbonate in DMF as solvent at ambient temperature to give althiomycin (1982MI137). DK combines with C-benzoyl-N-phenylazomethine oxide 183 to form the intermediate spiro compound 184. Elimination of carbon dioxide follows the addition to give the intermediate alkylideneisoxazolidine 185, which was not isolated. Intramolecular rearrangement of 185 gives 5benzoyl-1-phenylpyrrolidin-3-one 186. Unchanged DK acts on 186 as an acetoacetylating agent at C-2 to afford 187. C-2 is activated by the 3keto-functionality and the ring nitrogen atom, and is favored over C-5 because of the steric hindrance of the benzoyl group (Scheme 55) (1972JCS(P1)222).

Scheme 55

Diketene as Privileged Synthon in the Syntheses of Heterocycles

79

Scheme 56

Reaction of isoquinolinium bis(ethoxycarbonyl)methylide 188 with DK undergoes ring closure via the carbon terminus of the enolate intermediate to afford 189, which on hydrolysis with dilute hydrochloride acid afforded 190 and 191 (Scheme 56) (1976JHC461). Acetoacetamides have been nitrosated and converted into aaminoacetoacetamides, which were used for the preparation of a series of herbicidal pyrroles 192 (Scheme 57); conversely, the acetoacetic ester could be nitrosated and reductively condensed with an acetoacetamide (1973GEP2235811). The aromatic amines, for instance substituted anilines, were reacted with DK to afford the amides 193, which upon treatment with tosyl azide in the presence of Et3N or NaH in THF gave the a-diazoanilides 194. Upon heating in benzene at reflux temperature and in the presence of catalytic amounts

Scheme 57

80

M.M. Heravi and B. Talaei

Scheme 58

of Rh2OAc4, the latter were converted into 3-acetylindoles 195 (Scheme 58) (1990JOC1093). Worthy to mention that this strategy showed some limitations. For example, N-unsubstituted indoles 195 (R ¼ H) could not be synthesized directly by this route. Various primary amines, DK, and nitrostyrene were reacted in CH2Cl2 at room temperature in a one-pot four-component reaction to afford highly functionalized 1H-pyrrole-3-carboxamide derivatives 196 (Scheme 59) (2008S725). It was suggested that in this MCR, initially, amine A is reacted with DK to give the N-alkyl-3-oxobutanamide, which subsequently reacted with the primary amine B to give the reactive enamine 197. The latter then was treated with nitrostyrene to afford a betaine 198, which upon rearrangement gave intermediate 198. Cyclization followed by loss of a nitrite anion, 198 generated a new intermediate 200. Finally, 200 was oxidized under the reaction conditions to provide 196 (Scheme 60) (2014JMOC-A(392)173, 2014JICS209). In addition, this reaction can be performed under neutral conditions also in a one-pot fashion without any activation or modification of starting materials. Therefore, this highly effective and simple strategy is usually chosen as an attractive alternative to the tedious multistep protocol for the preparation of furan derivatives (2008S725). Moreover, an effective and simple four-component reaction involving two different primary amines, DK and dibenzoylacetylene, proceeds smoothly in a one-pot fashion leading to the formation of a wide variety of 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives 201 (Scheme 61) (2008T351). It is proposed that the formation of 201 occurs by initial addition of an amine to DK resulting in the formation of N-alkyl-3-oxobutanamide with

Scheme 59

Diketene as Privileged Synthon in the Syntheses of Heterocycles

81

Scheme 60

Scheme 61

the subsequent reaction of the 1:1 adduct with a second primary amine to afford 197. Then, 197 reacts with dibenzoylacetylene to afford intermediate 202, which is rapidly converted to intermediate 203 and subsequently to furan derivative 201 (Scheme 62) (2008T351).

Scheme 62

82

M.M. Heravi and B. Talaei

Scheme 63

In a one-vessel four-component reaction involving dibenzoylacetylene as an electron-deficient acetylene compound, isoquinoline, water, and DK in dry dichloromethane react at ambient temperature to give a yellow crystalline solid 204. 1,2-Dihydroisoquinoline derivatives 205 are apparently formed from the enolization and cyclization of intermediate 206 (Scheme 63) (2008HCA844). 1,2,3,10b-Tetrahydropyrrolo[2,1-a]isoquinoline-1-carboxamide derivatives 207 were prepared from the reaction between isoquinoline, an amine, DK, and dibenzoylacetylene in CH2Cl2 (Scheme 64) (2008S429). Based on the well-recognized behavior of isoquinoline as a nucleophile, it is logical that 207 is actually the result of the addition of nucleophilic isoquinoline to dibenzoylacetylene followed by protonation of the 1:1 adduct 208 by the acidic OH present in N-alkyl-3-oxobutanamide. As a result, the positively charged ion is susceptible to attack by the conjugate base of the acidic OH to generate the intermediate 209, which in turn can be transformed into enol 210. Ultimately, upon cyclization, the enol 210 is converted into the desired target 207 (Scheme 65) (2008S429). A highly efficient approach was reported for the synthesis of the mycotoxin DL-b-cyclopiazonic acid 212. This approach starts from DK,

Scheme 64

Diketene as Privileged Synthon in the Syntheses of Heterocycles

83

Scheme 65

which reacted with a-amino ester 211 in the presence of base (1977MI125). It is worthy to mention that the synthesis of a-cyclopiazonic acid 214 makes use of DK in a similar fashion (Scheme 66) (1984JA6873, 1985H1111, 1977MI125). Compound 212 is initially converted into 213. The final step involves the oxidative cyclization of b-cyclopiazonic acid in the presence of Et3N. A concise total synthesis of indolic terpene alkaloid, a-cyclopiazonic acid 214 has been achieved and reported. Starting from indole-4-methanol, the

Scheme 66

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M.M. Heravi and B. Talaei

total synthesis was achieved in 11 steps. In this total synthesis, the key step is a carbocationic cascade reaction, terminated by a 4-nitrosulfonamide group and reinitiated by direct benzylic carbocation generation from the intermediate 215, which provides the tetracyclic product 216 in high yield. While removing the nosyl group using thioglycolate, the indolic tosyl function was also cleaved, and the fully deprotected pyrrolidino-indole 217 was obtained in an excellent yield. Completion of the synthesis followed with treatment of the fully deprotected indole 217 with DK in the presence of t-BuOK and CH2Cl2 to form a-CPA 214 (Scheme 67) (2005JCS(CC)3162). When intermediate 218 was exposed to methanolic sodium methoxide in benzene and the resulting enolate mixture brought to pH of 4, a-CPA 214 was isolated (Scheme 68) (1984JA6873). Notably, to date, just three different total synthesis of a-CPA 214 have been reported. It is worthy of

Scheme 67

Diketene as Privileged Synthon in the Syntheses of Heterocycles

85

Scheme 68

mention that in these three syntheses the tetramic acid residue was constructed from the reaction of pyrrolidine-2-carboxylate with DK via a Dieckmann cyclization action (1984JA6873, 1985H1111). DK reacts with bifunctional nucleophiles such as hydrazine derivatives offering a methodology for the construction of the pyrazole ring. The reaction of hydrazines with acetoacetate esters is usually used to form pyrazolones. However, pyrazolones can also be directly synthesized from the reaction of hydrazines with DK. In this approach, hydrazine hydrate is reacted with DK in MeOH to give N-acetoacetylhydrazine, which is simultaneously cyclized via intramolecular formation of enamine to give 5-methyl-3-pyrazolone 219 in excellent yield (Scheme 69). Pyrazolone 219 has also been synthesized from the reaction of DK with acetyl hydrazides (1960NKZ305). Thus, methylhydrazine reacts with DK to give 2,5-dimethyl-3-pyrazolone 220 in an excellent chemical yield. Notably, the other alkyl pyrazolones can similarly be synthesized (1963YZ741).

Scheme 69

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Scheme 70

The herbicidal pyrazole 222 has been synthesized from the in-situ reaction of 4-substituted acetoacetates 221 and methylhydrazine and dimethylcarbamic chloride (Scheme 70) (1978GEP2644588). In this reaction, it is assumed that the halide was replaced prior to cyclization. Phenylhydrazine on treatment with DK yields 223, which upon treatment with excess DK gives 2-phenyl-3-pyrazolone 224 (Scheme 71). Apparently, this additional DK eliminates phenylhydrazine from the equilibrium rapidly. This assumption is based on the fact that HCl-initiated cyclization without the addition of DK gives 1-phenyl-3-pyrazolone 225 (1944JA1959). Thus, either of the two 3-pyrazolone isomers (224e225) can be synthesized selectively from a common intermediate (Scheme 71). Upon heating with excess phenylhydrazine, compound 224 is readily converted to bis-pyrazolonyl 226 (Scheme 72).

Scheme 71

Scheme 72

Diketene as Privileged Synthon in the Syntheses of Heterocycles

87

Scheme 73

5-Methyl-2-aryl-3-pyrazolones 227 easily can be synthesized by the reaction of DK with 4-hydrazinylbenzene sulfonic acid under mild reaction conditions in water (Scheme 73) (1935USP2017815, 1985GEP3416205). The arylpyrazolones obtained were easily coupled with diazonium salts to provide the pyrazolone 228, which is the commercially available colorant Pigment Yellow 10 (Scheme 74). Several molecules having NeN bonds also react with DK to provide useful chemicals. For example, hydrazobenzene in the presence of Et3N can combine with DK to afford 1,2-diphenyl-5-methyl-3-pyrazolone 225 (Scheme 75) (1975CPB456). It is assumed that initially fairly unstable acetoacetyl derivatives 229 are generated and thus undergo intramolecular ring closure to give the corresponding pyrazolone derivatives. This cyclization could have taken place during recrystallization. The presumed intermediate on further heating at reflux readily undergoes ring closure to yield the pyrazolone 225 in good yield. Zetenin et al. reported the synthesis of unknown b-ketohydrazides 230a,b. Their approach involved a simple reaction of DK with an

Scheme 74

Scheme 75

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equivalent amount of the respective hydrazide 230a,b at ambient temperature. A characteristic feature of 230a,b, and their oxygen analogs 230cee is their propensity for ring-chain tautomerism 230 to 231. Compounds 230a,b,e were isolated entirely in the linear form 230 in dimethyl sulfoxide, whereas tautomerization 230 to 231 occurred in CDCl3 or other nonpolar solvents. By contrast, the 5hydroxyisoxazolidinones 230c,d are obtained in the equilibrium with the linear form 230 in dimethyl sulfoxide, and exist as the cyclic form 231 in CDCl3 (Scheme 76) (1991CHE232). Unpredictably, reaction of DK with N-phenyl-N-methylhydrazine and then with polyphosphoric acid (PPA) gave the fused heterocyclic system 235 (Scheme 77) (1980JOC30). Reaction of DK with 2 mol of a-methylphenylhydrazine afforded 232. The latter was converted to indole hydrazide 233 via HCl-catalyzed Fischer indole synthesis in EtOH. The unexpected conversion in the final step 233 to 235 deserves some additional discussion. This transformation can be rationalized as an arylation with simultaneous NeN bond cleavage under acidic conditions, reminiscent of the benzidine rearrangement. The betaine form of 233 is envisaged as a vinyl analogue of hydrazobenzene, which on rearrangement resulted in the generation of intermediate indolecarboxamide 234. The latter when subjected to intramolecular acylation under acidic conditions afforded 235 (Scheme 77) (1980JOC30). Treatment of phenylhydrazones of aromatic ketones and aldehydes with DK in refluxing acetic acid gave pyrazolin-3-ones 233 (Scheme 78). Alkaline hydrolysis of the latter led to 234, which on treatment with acetic anhydride furnished 235. Significantly, the phenylhydrazones derived from most aliphatic carbonyl compounds give products that have similar structure to 236 (1970CPB2269).

Scheme 76

Diketene as Privileged Synthon in the Syntheses of Heterocycles

89

Scheme 77

Scheme 78

Cyclic hydrazones (pyrazolines) were treated with DK under neutral conditions to give the corresponding fused piperidine-2,4-diones 237 (Scheme 79) (1966MI1441937). The interaction of DK with N-alkyl- and N-arylhydrazones of less crowded ketones upon treatment with DK gave the corresponding 2,5,5trisubstituted 4-acetylpyrazolidine-3-ones 238 (Scheme 80). The latter contain a set of four cyclic tautomers comprising two diastereoisomers C and D and two enol forms E and F. Noticeably, the form C is the main

Scheme 79

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Scheme 80

product whereas form F is only formed in polar solvents, owing to stabilization by solvation effects. Treatment of N-alkyl- and N-arylhydrazones of aldehydes with DK resulted in the formation of open-chain Nacetoacetyl-N-alkyl-(aryl)-hydrazones 239 (Scheme 80) (2003MI94, 1999CHE748). Reaction of l-iminopyridinium 240 and l-iminoquinolinium ylides with DK afforded the fused bicyclic ring systems 245 (Scheme 81)

Scheme 81

Diketene as Privileged Synthon in the Syntheses of Heterocycles

91

Scheme 82

(1975CPB452). Formally, the product of reaction is a [3 þ 2] cycloadduct, 244. However, on further study another mechanism was proposed (Scheme 81). According to this, first, N-imines 240 are formed from 1-amino quaternary ammonium iodide. These intermediates are then reacted with DK as nucleophiles to generate another N-acylated dipolar intermediate 241. It can also have another accepted structure 242. The latter can then be tautomerized to structure 243. In fact, tautomer 243 is the insoluble intermediate acetoacetylated ylide which can be cyclized. However, for the cyclization of 243, two different routes are possible: (path a) Initially, 3,9-dihydropyrazolo [1,5-a]pyridine 244 is formed which upon oxidation gives the corresponding pyrazolo[1,5-a]pyridine type derivative 245; (path b) Initially, the stable N-imine 246 is formed which then upon treatment with sodium ethoxide is transformed into 247. In a one-pot three-component reaction involving DK, aryl azides, and the appropriate amines in acetonitrile mediated with Et3N, 248 were synthesized in high yields (Scheme 82). It was found that yields increased significantly when amines with higher basicity were used (2009JCO481). This protocol is operationally simple, since in most cases the products are separable by just cooling it to room temperature yielding the corresponding amides in pure form (2009JCO481). A reasonable mechanism for this reaction is depicted in Scheme 83 (2009JCO481, 2014MI647). A highly efficient copper-free synthesis of 5-methyl-1H-1,2,3-triazolemodified peptidomimetics has been achieved. This strategy makes use of a

Scheme 83

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combination of Ugi four-component reaction with a three-component cycloaddition. Following the Ugi four-component reaction, pazidobenzoic, aniline, benzaldehyde, and isocyanide were reacted in MeOH at ambient temperature to give intermediate 249. Then, in onepot aniline (1eq), DK, and Et3N (1eq) were refluxed for 48h. This resulted in the formation of the 5-methyl-1H-1,2,3-triazole-modified peptidomimetics 250 in 38% yield (Scheme 84) (2012MI309). An alternative route for triazole-modified peptidomimetics 250 is shown (Scheme 84). In this route, a mixture of DK, p-azidobenzoic acid, and aniline was heated in the presence of Et3N (2eq) to generate the intermediate 251. Upon protonation of the latter by two equivalents of HCl/MeOH in the same vessel aniline, benzaldehyde, and isocyanide (CyNC) were added resulting in the formation of 250 in 33% yield (2012MI309). 3.1.3 Sulfur In the presence of NaH, ethyl 4-bromoacetoacetate reacted with 2cyanoethene1,1-dithiol disodium salt 252 to give 253 (Scheme 85) (1983CPB2480).

Scheme 84

Diketene as Privileged Synthon in the Syntheses of Heterocycles

93

Scheme 85

Upon treatment of 1,1-dithiol disodium salt derivatives with an equivalent amount of methyl iodide, initially, the S-monomethylated derivative was generated as an intermediate that reacted further with ethyl 4bromoacetoacetate to afford another intermediate 254. Intramolecular cyclization of 254 involving the S-methylene and nitrile carbons afforded a 3-imino-2,3-dihydrothiophene derivative, which cyclized to 255 (Scheme 86) (1983CPB2480).

3.2 Containing Two Heteroatoms 3.2.1 Nitrogen and Oxygen Atoms Under optimized conditions, DK reacted with hydroxylamine to afford acetoacetic acid oxime, which was converted slowly into 3-methylisoxazol5-one 256. The latter was transformed into 3,30 -dimethyl-5-hydroxy-4,50 bisisoxazole 257 upon treatment with Et3N (Scheme 87) (1965CPB248, 1972CPB1368). Isoxazolinone 256, left over in an acidic medium at ambient temperature, was sluggishly converted into the unknown compound 258. It was found that 256 was converted to the compound 258 by elimination of hydroxylamine and liberation of CO2. Upon treatment of 256 with ammonia with subsequent condensation of the second isoxazolinone, compound 259 was formed, and 259 in the presence of AcOH gives compound 260 (1965CPB248). However, it has been reported that isomeric 3-hydroxy-5methylisoxazole 261 can be synthesized from the reaction of DK and hydroxylamine by carefully controlling the pH between 9 and 10 (1984CJC1940). When the hydroxylamine hydrochloride solution was

Scheme 86

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M.M. Heravi and B. Talaei

Scheme 87

buffered with a twofold excess of Na2CO3 (pH ¼ 10e11), a mixture of 256 and 261 resulted in almost equivalent amounts while changing from carbonate to bicarbonate (pH ¼ 8) resulted in the sole obtention of 256. The prevailing species at pH ¼ 10 was the neutral hydroxylamine molecule. These species are nucleophilic due to the lone pair of nitrogen atoms, which attacks DK with the formation of either the oxime 262 or the hydroxamic acid 263. It is suggested that at pH around 10, hydroxamic acid 263 may be generated as the main intermediate, which upon fast acidification gives 261 while approaching higher pH provides a condition for generation of the deprotonated hydroxylamine (NH2O). In this way, the oxygen atom becomes the nucleophile resulting in the generation of different intermediates unable to form 261. Generation of 256 requires the cleavage of the CeN bond in 263. Therefore, hydrolysis of 263 results in the formation of acetoacetic acid 264. The latter in acidic media could react with the generated hydroxylamine to give an oxime 265 and 256 (Scheme 88) (1984CJC1940). Compound 261 is a useful plant protection agent marketed as Tachigaren or Hymexazol. Thus, several synthetic strategies have been developed for its synthesis. A highly efficient approach to 3-hydroxy-5methylisoxazole 261 has been reported. In this approach, the uncatalyzed reaction of DK with 266 gave N-acetoacetyl-O-benzylhydroxylamine

Diketene as Privileged Synthon in the Syntheses of Heterocycles

95

Scheme 88

267 in a satisfactory yield (Scheme 89). In the following, debenzylation through catalytic reduction of the latter using Raney nickel gave acetoacetamide and benzyl alcohol. Nevertheless, by substituting Pd/C with Raney nickel, 267 was converted into an oily material that was identified as 268. Upon treatment of the latter with dry HCl in glacial acetic acid, 3-hydroxy5-methylisoxazole 261 was obtained (1972CPB1368). The synthesis of this commercial agrochemical has been improved by the use of tert-butyl group as an acid-labile blocking moiety on the oxygen. An attempt to use an O-acyl protecting group gave Lossen rearrangement of the generated intermediate acetoacetamide leading to the construction of oxazol-2-one 269 in satisfactory yield, which makes the production of this agrochemical economically feasible (Scheme 90) (1979H1297).

Scheme 89

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Scheme 90

Scheme 91

N,O-Bis(trimethylsily1)hydroxylamine 270 reacted with DK providing the corresponding acetoacetate cyclized under acidic conditions to afford 3hydroxy-5-methylisoxazole 261 (Scheme 91). The dianion of isoxazole 261 was easily provided by the treatment of the latter with 2 eq of lithium diisopropylamide (LDA) in THF at 10 C. The dianion generated attacks isoamyl nitrite (2:l stoichiometry) to give 3-hydroxyisoxazole-5-carboxaldehyde oxime 271 as a mixture of geometrical isomers in a satisfactory yield (Scheme 91). The latter upon acetylation gave the diacetate 272 with subsequent total reduction using BH3/THF to afford muscimol 273, a natural product isolated from the mushroom Amanita muscaria (1983JOC4307). When N,O-bis(trimethylsilyl)hydroxylamine was treated with DK, O,O0 -bis(trimethylsilyl)acetoacetohydroxamic acid was obtained as a mixture of E and Z isomers, ((E)-275 and (Z)-275). The first intermediate of this 1:1 condensation was considered to be 274 (Scheme 92) generated by nucleophilic attack of HeN on OeC(O), tautomerization of the enol to the ketone

Scheme 92

Diketene as Privileged Synthon in the Syntheses of Heterocycles

97

Scheme 93

led to the isolated product is a mixture of (E)-275 and (Z)-275 isomers with hydroximic structure. These hydroxamic acid analogues when treated with HCl, cyclized to 5-methyl-3-isoxazolol 261 (2004CCC1472). DK acts as an acetoacetylating agent when it is treated with N-substituted hydroxylamines. Acetoacetylation takes place on the nitrogen, which is then cyclized rapidly to give tertiary alcohols 276. The latter can be N-methylated or dehydrated to give the expected products (Scheme 93) (1980JHC727). N-Phenylacetoacetohydroxamic acid 277 was obtained from the reaction of N-phenylhydroxylamine and DK, 277 then underwent facile cyclization mediated by BF3 to give the oxazole 278 (Scheme 94) (1963GEP1146494). Reaction of 277 with aroyl chlorides led to cyclization and acylation in a one-pot fashion resulting in the synthesis of 279, which is effective as a herbicide (1982MI8270878). Upon treatment with DK, N-hydroxylsulfonamides 280 was converted into 3-methyl-2-sulfonylisoxazolones 281 (Scheme 95) (1965CPB248).

Scheme 94

Scheme 95

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M.M. Heravi and B. Talaei

It is known that in almost every instance of heterocyclization in which (Z)-chloroacetoacetic acid is involved, the carbons at the 2-and 3-position are merged into the heterocyclic nucleus, thus the resulting product holds a pendant methyl group. Bearing this in mind, the oxazole 282 was obtained on treatment of the 2-chloroacetoacetamide with formic acid/formamide at moderate temperature (1978USP4093654). Further heating led to the formation of imidazoles 283 from the same precursors (Scheme 96). It is worth mentioning that this procedure for the synthesis of imidazole has been modified for the production of antisecretory compounds such as cimetidine (1975USP3876647, 1948HCA32, 1979GEP2905134). When both aliphatic and aromatic amidoximes 284 are treated with a small excess of DK in toluene under reflux, acetonylated 1,2,4-oxadiazoles 286a,b are obtained in satisfactory yields (Scheme 97) (1982M781). Upon treatment of 284 with DK in acetic acid or in pyridine at ambient temperature, a ring-opened product 285 is obtained, which easily undergoes cyclization by refluxing in toluene to give compound A. However, if the reaction is carried out in the presence of a strong base such as diethyl sodiomalonate as, NaOMe, NaH or LiH, compound 285 loses acetone to give 1,2,4-oxadiazol-5-one 287 (1969BCJ3008, 1982CPB336). Benzamide oxime 284b when treated with g-bromoacetoacetyl bromide 288 in basic media or just by refluxing in a solvent gave a resinous compound. On the other hand, reaction of two mol equivalents of 284b with g-bromoacetoacetyl bromide at 0e5 C gave benzamides 289 and

Scheme 96

Diketene as Privileged Synthon in the Syntheses of Heterocycles

99

Scheme 97

290 in 73% and 3% yields, respectively. When, 289 was refluxed in toluene, 5-(3-bromo-2-oxopropyl)-3-phenyl-1,2,4-oxadiazole 291 is obtained in reasonable yield (Scheme 98) (1982CPB3987). The outcome of the reaction can be influenced by the nature of acetoacetic acid derivative employed. The difference in reactivity of the ester 292 and the acid bromide 288 with benzohydroxamide has been taken advantage of and results in the synthesis of two entirely different products (Scheme 99) (1982CPB3987).

Scheme 98

100

M.M. Heravi and B. Talaei

Scheme 99

Allylamine can be transformed easily into N-allylacetoacetamide 293 upon treatment with DK (1951USP2561205). The resulting adduct then can be cyclized readily into 2-acetonyloxazoline 294 (Scheme 100a). Other amines react likewise to produce substituted oxazolines. On the other hand, isopropanolamine 295 upon treatment with DK gives N-(2-hydroxypropyl) acetoacetamide 296, which in refluxing in thionyl chloride and subsequent treatment with methanolic potassium hydroxide is cyclized into oxazoline 297 in good yield (Scheme 100b) (1969CPB2405). Acetoacetylated aziridines were also rearranged to oxazolines (Scheme 100c) (1971YZ384). Heterocycles, e.g., analgesic 298 bearing NeO bonds, can be synthesized starting from acetoacetanilide (Scheme 101) (1981USP4284786). Furazan 299, an antihypertensive agent, can also be synthesized from an acetoacetamide (1982USP4356178). Ketene typically can undergo 1,3-dipolar cycloaddition reactions with representative 1,3-dipoles such as nitrones and N-oxides to give the corresponding isoxazolone derivatives. In general, ketene is created by the pyrolysis of DK. Thus, thermal 1,3-dipolar cycloaddition of 5-nitrofuran2-carbohydroxamoyl chloride 300 with DK in toluene gave a crystalline product 302. During this reaction, hydrogen chloride gas is evolved. Here, upon thermal treatment, the predicted intermediate adduct 301 was generated, which upon the elimination of CO2 gave an isoxazole derivative 302 instead of isoxazolone (Scheme 102) (1969BCJ258).

Scheme 100

Diketene as Privileged Synthon in the Syntheses of Heterocycles

101

Scheme 101

d’Alontres et al. achieved the successful 1,3-dipolar cycloaddition of DK to benzonitrile oxide 303 to afford 3,30 -diphenyl-5,50 -spiro[2-isoxazoline] 306 in moderate yield (1967RS750). A substance containing a b-lactone ring such as 304 is proposed as a probable intermediate. The latter can be decarboxylated to 305, which upon addition of another molecule of 303 affords 306 (Scheme 103). In this reaction, the exomethylene of DK can be considered as a dipolarophile. Upon acetoacetylation with DK at N-2,5-phenyltetrazole is converted into 307. When nitrogen is eliminated from this intermediate, intermediate 308 is obtained, which is converted into another undisputed structure 309. The latter then is subjected to intramolecular cyclization via the amide oxygen to provide 1,3,4-oxadiazoles 310. Notably, in this reaction, a byproduct 311 was detected, which can be formed by further condensation of 310 with DK (Scheme 104) (1976CPB2549). When the reaction was

Scheme 102

102

M.M. Heravi and B. Talaei

Scheme 103

performed in refluxing CH3COOH, 2-methyl-5-phenyl-1,3,4-oxadiazole 312 and 1,1-diacetyl-2-benzoylhydrazine 313 were formed. Compound 312 is formed because initially DK reacts with acetic acid to give acetic anhydride through the mixed anhydride. Upon acetylation with either acetic anhydride or the mixed anhydride, the same 1,3-dipolar intermediate 315 (B, R ¼ CH3) is obtained, which is converted into the compound 312 by path a. Then, addition of acetic acid to the 1,3-dipolar intermediate 314 (R ¼ CH3) gives the enol acetate intermediate 316, which upon acetyl migration gives compound 313 (Scheme 105). 3.2.2 Nitrogen and Sulfur Atoms Degradation of vitamin B1 gives the thiazole 317, which can also be prepared from the reaction of 2-chloroacetoacetate esters and thioformamide (Scheme 106) (1935JA1876). Another thiazole 318 can be prepared by using DK. It is patented as an antisecretory agent acting similarly to cimetidine and ranitidine (1982USP4363813). DK is extensively used in the synthesis of substituted acetoacetamido side chains for b-lactam antibiotics. Thus, 4-(bromoacetoacetamido)

Scheme 104

Diketene as Privileged Synthon in the Syntheses of Heterocycles

103

Scheme 105

Scheme 106

cephalosporanic acid 320 was formed via a one-pot three-component reaction of bromine, DK, and 7-aminocephalosporanic acid 319 (7-ACA) (Scheme 107). Compound 320 shows modest antibiotic potency. More active antibiotics can be prepared by side chain displacement or cyclization of the resulting adducts (e.g., 321) (1980USP4239758, 1979USP4172891).

Scheme 107

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M.M. Heravi and B. Talaei

Scheme 108

Displacement of the halogen of 4-haloacetoacetate esters followed by conversion of 4-haloacetoacetamido side chains into aminothiazoles with thiourea by ring closure on the carbonyl group (C3) provides antibiotics with outstanding activity (c.f. 322) (Scheme 108) (1983USP4421912, 1981USP4260607, 1981USP4254260, 1983USP4391979). Another common b-lactam side chain (c.f. 323) is prepared via nitrosation of the active methylene group of 4-haloacetoacetamides prior to cyclization with thiourea (1981USP4264595, 1979USP4179502). The functionalized aminothiazole 324, prepared from 4-haloacetoacetates, has been claimed to be a post-emergent herbicide (1978USP4120690, 1980USP4232163). It should be noted that the 4-bromoacetoacetate intermediate, used to make 324, was prepared by the facile thermal isomerization of the 2-bromo isomer (Scheme 109).

Scheme 109

Diketene as Privileged Synthon in the Syntheses of Heterocycles

105

3.3 Syntheses of Five-Membered Heterocycles in the Solid Phase DK is involved in the first step of the solid-phase preparation of pyrrole-3carboxamides from enaminones and a-alkyl-a-nitroalkenes. Thus, rink Amide S resin was acetoacetylated by DK, which upon treatment with primary amines is transformed into polymer-bound enaminones 325. The reaction conditions for the subsequent cyclization with nitroalkenes can be performed via two- or three-component reactions (1998TL8263). The best reaction conditions for the synthesis of pyrroles 326 were found to be reaction in a mixture of DMF/EtOH 1:1 at 60 C for 2 h. Upon the cleavage of the latter with 20% TFA/DCM, pyrrole-3-carboxamides 327 were obtained by Method A (Scheme 110). A one-pot three-component reaction involving an aromatic aldehyde, a nitroalkane and piperidine as catalyst for the Henry reaction leads to the in-situ formation of the nitroalkene (Method B in Scheme 110) conducted in DMF/EtOH 1:1 at 70 C for 5 h, which also gives 327 via 326. Jung et al. have reported the solid-phase synthesis of pyrroles. They used inexpensive and commercially available DK for acetoacetylation under mild reaction conditions. Polymer-bound enaminones were reacted with a-bromoketones under Hantzsch reaction conditions to give the corresponding pyrroles. After cleavage with 20% TFA in dichloromethane,

Scheme 110

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M.M. Heravi and B. Talaei

Scheme 111

the corresponding pyrrole-3-carboxamides 327 were obtained in pure forms (Scheme 111) (1998BMCL2381). Upon acetoacetylation of ArgoPore1-Rink-NH2 resin with DK, polymer-bound acetoacetamide can be obtained. It can be used in a key step for solid-phase synthesis. In this regard, the solid-phase Nenitzescu indole synthesis of 5-hydroxyindole-3-carboxamides was accomplished. The polymer-bound acetoacetamide in the presence of a primary amine and triethyl formate gave the corresponding enaminone 328. Upon 1,4addition of benzoquinones to the latter and TFA-mediated cleavage from the resin, the respective indole 329 was obtained (Scheme 112) (2000TL6253). The Jung research group also used polymer-bound enones as substrates for the synthesis of the two important heterocycles, namely pyrazoles and pyridines. In their approach to pyrazoles, these frameworks were constructed from the reaction of alkylidene- and arylidene-b-oxo esters 330 (Scheme 113). Initially, resin-bound b-oxo esters were synthesized through DMAP-catalyzed acetoacetylation using DK in dichloromethane.

Scheme 112

Diketene as Privileged Synthon in the Syntheses of Heterocycles

107

Scheme 113

These resin-bound esters then underwent Knoevenagel reaction with aliphatic and aromatic aldehydes, which led to the formation of 2alkylidene-331 and 2-arylidene-b-oxo esters 332. The latter was subjected to cyclocondensation with phenylhydrazine hydrochlorides followed by TFA/CH2Cl2 (1:3) induced cleavage to afford trisubstituted pyrazole-4carboxylic acids 333 and 334 (1999S1961).

4. CONCLUSION Diketene (DK) and its derivatives are important and versatile compounds in organic chemistry. In addition, they are used as intermediates in the manufacture of a wide range of polymers, pharmaceuticals, agrochemicals, and dyes. They are particularly useful as synthons in the convergent synthesis of heterocycles. DK is easily prepared from inexpensive commercially available compounds. Nowadays, DK itself is a commercially available feedstock. The chemistry of DK still offers good prospects for new findings in the future. It is hoped that this chapter has provided a background in the chemistry of DK and has provided some new ideas. Undoubtedly, the most important reaction of DK is addition that can be categorized as follows: (1) addition reaction that results in acetoacetyl derivatives; (2) addition reaction that leads into cyclic (chiefly heterocyclic) compounds, and (3) addition reaction of the C]C double bond of DK, which gives O-butyrolactone derivatives. The first two modes of reaction (1) and (2) frequently proceed via ionic species while the last (3) often involves the generation of a free radical as an intermediate.

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ACKNOWLEDGMENTS The authors are grateful to the Department of Chemistry of Alzahra University for the encouragements and Alzahra University Research Council for partial financial support. We are also grateful to Leila Talaei and Katayun Jahedinia for their kind assistance. MMH is also thankful to Iran National Science Foundation (INSF) for the granted individual research chair.

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Diketene as Privileged Synthon in the Syntheses of Heterocycles

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CHAPTER THREE

Synthesis of Heterocycles From Amidrazones A.A. Aly*, 1, M. Ramadanx, H.M. Fatthyx *Minia University, Minia, Egypt x Al-Azhar University, Assiut, Egypt 1 Corresponding author: E-mails: [email protected] and [email protected]

Contents 1. Introduction 2. Synthesis of Five-Membered Rings With Two Heteroatoms 2.1 Pyrazoles 3. Synthesis of Five-Membered Rings With Three Heteroatoms 3.1 Triazoles 3.1.1 By Reaction of Amidrazones With

116 116 116 118 118 118

3.2 Thiadiazoles

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3.2.1 Reactions of Dithioesters 3.2.2 Reaction of Amidrazones With

127 128

4. Synthesis of Five-Membered Rings With Four Heteroatoms 4.1 Thiatriazoles 5. Synthesis of Fused Five-Membered Rings 5.1 Indazoles 6. Synthesis of Six-Membered Rings With One Heteroatom 6.1 Pyridines 7. Synthesis of Six-Membered Ring With Two Heteroatoms 7.1 Pyrimidines 8. Synthesis of Six-Membered Rings With Three Heteroatoms 8.1 1,2,4-Triazines

129 129 129 129 130 130 130 130 131 131

8.1.1 Reaction of Imidrazones With

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9. Synthesis of Seven-Membered Rings With Three Heteroatoms 9.1 1,3,4-Oxadiazepines 9.2 1,2,4-Triazepines 9.2.1 Reaction of Imidrazones With

136 136 136 136

References

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Abstract Amidrazones have the structure R1NC(R2) ¼ NNHR3. The ease of forming CeN and C]N bonds is reflected in their extensive use for the preparation of heterocycles. While the terminal nitrogen atom of the hydrazone moiety in amidrazones Advances in Heterocyclic Chemistry, Volume 122 ISSN 0065-2725 http://dx.doi.org/10.1016/bs.aihch.2016.11.001

© 2017 Elsevier Inc. All rights reserved.

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j

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(C]NeNH2) is the most powerful nucleophilic center, the other two nitrogen atoms can also act as nucleophiles and thus complete cyclization processes. In this chapter, we update the utility of amidrazones in heterocycles synthesis.

Keywords: Amidrazones; Nitrogen heterocycles; Pyrazoles; Synthesis; Triazepines; Triazines; Triazoles

1. INTRODUCTION The amidrazones can be regarded as the reaction products of acidic thioamides with hydrazine and its derivatives. These compounds have basic character that is attributed to the amide nitrogen atom (1966OCNC173; 1966SOCN529). Amidrazones are weak monoacid bases characterized by the structures Ia-e (Fig. 1). Amidrazone derivatives are also considered as an important class of amidines (1970CR151). The carbonenitrogen bonds are polarized, which makes the amidrazone carbon atom a low electron density center. Such configuration enables reactions with nucleophilic reagents. Therefore amidrazones are important precursors in the synthesis of various classes of heterocycles.

2. SYNTHESIS OF FIVE-MEMBERED RINGS WITH TWO HETEROATOMS 2.1 Pyrazoles Aly et al., synthesized mercaptopyrazoles 3a-e using the reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate (2) with amidrazones 1a-e in absolute ethanol (EtOH) catalyzed by triethylamine (Et3N) (Scheme 1) (2015JSC502). They also, synthesized pyrazole derivatives 5a-e from the reaction of amidrazones 1a-e with diaminomaleonitrile (4) in dry dimethylformamide (DMF). The products obtained were formed in poor yields using Method 1, whereas when the reaction was carried out under microwave irradiation (MW, Method 2), the yields of products were good and the

Figure 1 Various amidrazone structures Ia-e.

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Synthesis of Heterocycles

Scheme 1

reaction time was shorter compared with Method 1 (Scheme 2) (2016JHC00). In 2003, pyrazole hydrochloride derivatives 8a-f were prepared in good yields (82e89%) from the reaction of picolinimidohydrazide 6 with b-methoxyvinyltrifluoromethyl ketones 7a-f in presence of HCl/EtOH (Scheme 3) (2003JFC159). It was shown that electron withdrawing groups as in the case of 9d-f gave higher yields compared with those having electron donating groups as in the case of 9a-c.

Scheme 2

Scheme 3

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The free bases of 3-aryl-5-trifluoromethyl-1H-1-picolinoylpyrazoles 9a-f were obtained by addition of equivalent amounts of Et3N to 8a-f (Scheme 3) (2003JFC159).

3. SYNTHESIS OF FIVE-MEMBERED RINGS WITH THREE HETEROATOMS 3.1 Triazoles 3.1.1 By Reaction of Amidrazones With 3.1.1.1 Aryl Halides

Staben et al., reported that one-pot reaction of amidrazones 10a-c with aryl halides in the presence of carbon monoxide and Pd(OAc)2/Xantphos (Xantphos ¼ 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene) afforded 1,2,4-triazoles 11a-c directly (Scheme 4) (2010ACIE325). It was reported that aryl bromides were also effective reactants in this one-pot fourcomponent process. For example, compound 11 was generated in 58% and 50% yield from the corresponding aryl iodide and aryl bromide, respectively (2010ACIE325). 3.1.1.2 Aldehydes and Ketones

Nakka et al. reported that a convenient and efficient ceric ammonium nitrate catalyzed synthesis of 3,4,5-trisubstituted 1,2,4-triazoles 12a,f was achieved by oxidative cyclization of amidrazones 1a,f with benzaldehyde in polyethylene glycol (PEG) (Scheme 5) (2015S517).

Scheme 4

Scheme 5

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Synthesis of Heterocycles

Scheme 6

In 2002, Drutkowski et al. reported that triazole derivatives 14a-e were obtained from reaction of amidrazones 13a-e with acetone under acidic conditions (Scheme 6) (2002T5317). 3.1.1.3 Itaconic Anhydride

A series of 1,2,4-triazole derivatives 16h-j containing a methacrylic acid moiety was synthesized in moderate yields by the reaction of N 3-substituted amidrazones 1h-j with itaconic anhydride (15) in refluxing diethyl ether (Scheme 7) (2015BMCL2664). 3.1.1.4 2-(1,3-Dioxoindan-2-ylidene)malononitrile

In 2006, Aly and coworkers reported that 1,2,4-triazole derivatives 18a-d,j were prepared in good yields from the reaction of amidrazones 1a-d,j with 2-(1,3-dioxoindan-2-ylidene)-malononitrile (CNIND, 17) in dry ethyl acetate (Scheme 8) (2006ZN1239). They have also synthesized triazoles 20a-c,e by the reaction of amidrazones 1a-c,e with 2-(2-oxoindolin-3-ylidene)malononitrile (19) in dry ethyl acetate (Scheme 9) (2010JCR200).

Scheme 7

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Scheme 8

Scheme 9

3.1.1.5 Aminal

Ellis and Arias-Wood have reported that when amidrazone 21 and aminal 22 were refluxed in toluene the protected derivative of triazole was obtained. The protecting group was removed by trifluoroacetic acid/ dichloromethane (TFA/DCM) to yield triazole 23 (Scheme 10) (2011SC1703). 3.1.1.6 Trifluoroacetic Anhydride

Roberts et al. showed that the reaction of amidrazones 24a,b with trifluoroacetic anhydride at room temperature afforded the trifluoromethyltriazoles 25a,b (Scheme 11) (2011BMCL6515).

Scheme 10

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Scheme 11

3.1.1.7 Cyclic Anhydride

Amidrazone derivatives 1h-j with cis-1,2-cyclohexanedicarboxylic anhydride (26) were dissolved in anhydrous diethyl ether at ambient temperature and allowed to stand for 14 days. Reaction led to different types of structures 27e29 depending on the starting amidrazone substituents (Scheme 12) (2012ADP486). Similarly, the reaction of amidrazone derivatives 1a,m-o with maleic anhydride (30) in anhydrous diethyl ether at room temperature for 48 h afforded triazole derivatives 31a,m-o in moderate to good yield (Scheme 13, 2004JMC873). 3.1.1.8 Dimethyl Acetylenedicarboxylate

The reaction of N3-substituted amidrazones 1m,n with dimethyl acetylenedicarboxylate (DMAD, 32) afforded compounds 33m,n (2005JAUMCSC11) (Scheme 14). Cyclization of 33m,n carried out in methanol solution in the presence of Et3N gave triazin-5-ones 34m,n. In contrast, when cyclization of 33m,n was performed in boiling, n-butanol,

Scheme 12

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Scheme 13

Scheme 14

triazoles 35m,n and 1,2,4-triazin-5-ones 36m,n were formed (Scheme 14) (2005JAUMCSC11). 3.1.1.9 Imidates

Mangarao et al. have reported that the reaction of amidrazones 1a,h,l with 2,2,2-trichloro-ethylimidates 37 in PEG as a solvent and p-toluenesulfonic acid (PTSA) as a catalyst at 80 C afforded triazoles 38a,h,l (Scheme 15) (2014TL177). The reaction of 2-hydrazinopyridine with ethyl benzimidate (39) under mild acidic conditions at 50 C afforded the amidrazone 40 in a few minutes. Subsequent cyclization of 40 to triazole 41 was completed after heating in ethanol (Scheme 16) (2013TL5721).

Scheme 15

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Scheme 16

Zarguil and coworkers found that when a variety of imidates 42 and 45 were treated with hydrazine derivatives, the reaction proceeded by substitution of the ethoxy group with the hydrazines giving intermediates 43 and 46, which then rapidly gave 1,2,4-triazoles 44 and 47, respectively (Scheme 17) (2008TL5883). 3.1.1.10 Triethyl Orthoformate and Ethyl Chloroformate

Previously, it had been reported that amidrazones 48a-d when treated with triethyl orthoformate yielded the corresponding 1,2,4-triazole derivatives 49a-c (Scheme 18) (1990JIAS174).

Scheme 17

Scheme 18

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However, when amidrazone 48d in pyridine was treated with ethyl chloroformate and the mixture was heated under reflux for 6 h, triazol-5one 49d was obtained (Scheme 18) (1990JIAS174). In the same manner, the reaction of amidrazone 50 with triethylorthoformate in the presence of PTSA gave 1,2,4-triazole 51 (Scheme 19) (2015BMC9). Hamzaoui et al. treated bisamidrazones 52a-g with two equivalents of ethyl choloroformate in anhydrous ethanol with pyridine as a catalyst in the cold to afford bistriazol-5-ones 53a-g (Scheme 20) (2012MJC246). 3.1.1.11 Excess of Ammonia

The reaction of hydrazonyl chlorides 54 with excess of ammonia in presence of Et3N as a proton acceptor gave dimer 55, which decomposes on heating or recrystallization to afford the triazole derivatives 56 (Scheme 21) (2012TL4507). 3.1.1.12 Diphenyl N-Cyanimidocarbonate

Kurz and coworkers showed that irradiation of amidrazones 57a,b 0 in DCM with 1,1 -thiocarbonyldiimidazole 58 for 2e3 min, afforded 1,2,4-triazolium 59a,b (Scheme 22) (2008EJOC6029).

Scheme 19

Scheme 20

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Scheme 21

Scheme 22

3.1.1.13 Phthaloyl Chloride

Recently, triazolium dihydrochloride salts 60a-e were obtained from the reaction of amidrazones 1a-e with phthaloyl chloride in dry ethanol and catalyzed with a few drops of Et3N under reflux conditions (Scheme 23) (2016JHC00). High yields of products were formed when the aryl moiety carried electron donating substituents (Scheme 23). 3.1.1.14 Ethyloxalyl Chloride

When amidrazone 50 was treated with ethyloxalyl chloride, the reaction afforded ethyl-1-(5-methyl-2-nitrophenyl)-3-(4-methoxyphenyl)-1,2,4triazole-5-carboxylate (61). After reduction and cyclization, 62 was obtained (Scheme 24) (2005JMC7932). Brooker et al. reported that condensation of thioamide 63 with a hydrazide in n-butanol afforded N3-substituted N1-acylamidrazones 64 as

Scheme 23

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Scheme 24

Scheme 25

intermediates, which cyclized after a few hours to give triazole derivatives 65a,b (Scheme 25) (2004EJOC3422). 3.1.1.15 Silylation of Amidrazones

The silylation of amidrazones 66 was carried out with trimethylsilyl chloride in Et3N. The disilylated esters 67 were then cyclized by heating at 90 C in chlorobenzene in the presence of a catalytic amount of trifluoromethanesulfonic acid to afford triazoles 68 (Scheme 26) (1994SC3055). 3.1.1.16 Synthesis of Triazole From C-Glucosyl Amidrazones

Recently, Bokor et al. reported that a boiling solution of C-glucosyl amidrazone 69 in m-xylene afforded triazol-5-one 70 in low yield (37%). However, cyclization of C-glucosyl amidrazone 71 in boiling DMF gave

Scheme 26

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Synthesis of Heterocycles

Scheme 27

triazolone 72a (69% yield). Reaction of tosyl-amidrazone 73 with ethyl chloroformate produced the tosylated triazolone 72b in 70% yield (Scheme 27) (2016CR128). 3.1.1.17 Synthesis of Triazole From Chlorohydrazones

El Kaim et al. reported that chlorination of hydrazone 74 using Nchlorosuccinimide in DCM gave 75 (Scheme 28). Chlorohydrazone 75 was then treated with n-butylamine and Et3N in DMF under oxygenation condition to afford the corresponding triazole 76 in 77% yield (Scheme 28) (2010S1771). It appears that the second step (i.e., from 75 into 76) involved the formation of an amidrazone moiety (Scheme 28) (2010S1771).

3.2 Thiadiazoles 3.2.1 Reactions of Dithioesters Orlewska et al. showed that dithioesters 77a-d rapidly eliminate ammonia when treated with dilute hydrochloric acid to form 5-methylthio-1,3,4thiadiazoles 78a-d (Scheme 29). Refluxing dithioesters 77a-d in alcoholic potassium hydroxide gave 1,2,4-triazoles 79a-d (Scheme 29). Thioesters 77a-d were cyclized to thiadiazoles 80a-d on treatment with sec-amines (Scheme 29) (2006PSS737).

Scheme 28

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Scheme 29

3.2.2 Reaction of Amidrazones With 3.2.2.1 p-Phenylenediisothiocyanate

The reaction of N1-substituted amidrazones 1m,p with p-phenylenediisothiocyanate (78) in ethanol gave compounds 79m,p, which upon refluxing in glacial acetic acid afforded 80m,p. On the other hand when the reaction mixture was refluxed in an aqueous solution of sodium hydroxide, 81m,p were formed. Whereas, carrying out the reaction in xylene or butanol, triazolethione derivatives 82m,p were obtained (Scheme 30) (2000APPDR199). 3.2.2.2 Sulfinyl-bis-2,4-dihydroxybenzenethioyl

Modzelewska-Banachiewicz et al. reported that amidrazones 1a,m reacted with sulfinyl-bis-2,4-dihydroxybenzene to give 84a,m. The insoluble precipitate in methanol was purified by crystallization from isopropanol to give 85a,m (Scheme 31) (2001EJMC75).

Scheme 30

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Synthesis of Heterocycles

Scheme 31

4. SYNTHESIS OF FIVE-MEMBERED RINGS WITH FOUR HETEROATOMS 4.1 Thiatriazoles The reaction of thionyl chloride (2eq) and bisamidrazones 50a-g (1eq) in DCM and anhydrous pyridine afforded the thiatriazole products 86a-g (Scheme 32) (2013ADP321).

Scheme 32

5. SYNTHESIS OF FUSED FIVE-MEMBERED RINGS 5.1 Indazoles Aly et al., found that amidrazones 1a-e surprisingly reacted with 2,3dichloro-1,4-naphthoquinone (DCHNQ, 87) in dry DMF, and the reaction afforded 3-phenyl-1H-benzo[f]indazole-4,9-dione (88) in 80% yield (Scheme 33) (2007Ark41).

Scheme 33

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6. SYNTHESIS OF SIX-MEMBERED RINGS WITH ONE HETEROATOM 6.1 Pyridines Zarguil et al. (2008TL5883) and Altuna-Urquijo et al. (2005TL6113) reported that the reaction of a,b-diketoester derivatives 89q,r with amidrazones 1q,r afforded triazines 90q,r (Scheme 34). An aza-DielseAlder reaction of these triazines 90q,r using 2,5-norbornadiene (91) gave pyridine derivatives 92q,r. The substituted pyridines 92q,r could also be obtained in a one-pot reaction directly from 89 and 91 in ethanol solution at reflux without isolating the triazines 90q,r (Scheme 34).

Scheme 34

7. SYNTHESIS OF SIX-MEMBERED RING WITH TWO HETEROATOMS 7.1 Pyrimidines When bisacetylenic ketones 94 were treated with N-boc phenylamidrazones 93 under mild neutral conditions and short reaction time, the pyrimidine derivatives 95 were formed in 82e91% yield (Scheme 35) (2005JOC3307). Recently, Aly et al. reported that amidrazones 1a-f surprisingly reacted with 2,3-diphenylcyclopropenone (96) to give 3-aryl-2,5,6-triphenylpyrimidin4(3H)-ones (2016JCR637) (Scheme 36). This was ascribed to nucleophilic

Scheme 35

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Synthesis of Heterocycles

Scheme 36

hydrazine addition of 1 to 96, followed by further conjugate additions and finally extrusion of ammonia to give 97 (Scheme 36) (2016JCR637).

8. SYNTHESIS OF SIX-MEMBERED RINGS WITH THREE HETEROATOMS 8.1 1,2,4-Triazines 8.1.1 Reaction of Imidrazones With 8.1.1.1 Diketones

The reaction between imidazol-1-ylcarboxamidrazone 98 and 1,10phenanthroline-5,6-dione (99) in isopropyl alcohol with stirring and heating for 20 min afforded 1,2,4-triazine 100 in 68% yield (Scheme 37) (2013CHC1728). The reaction of 2-pyridylamidrazone 6a with 3,3,6,6-tetrachloro-1,2cyclohexanedione 101 afforded unexpectedly bis-hemiaminal 102 instead of the corresponding ketodiazene, subsequent dehydration gave 103 that was converted into 104 (78% yield) by dehydro-chlorination under basic conditions (Scheme 38) (2013TL1542). In the same manner, the reaction of amidrazones 6b with 1,2-diketones 105 in refluxing EtOH-THF (7:3) afforded triazine 106 in 50% yield (Scheme 39) (2015RCB897).

Scheme 37

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Scheme 38

Scheme 39

8.1.1.2 1,4-Benzoquinone and 1,4-Naphthoquinone

Aly et al., synthesized fused 1,2,4-triazines 108a-d and 110a-d from the reaction of amidrazones 1a-d with 1,4-benzoquinone 107 (2eq) and 1,4naphthoquinone 109 (Scheme 40) (2007Ark41). 8.1.1.3 a-Haloesters

Reaction of amidrazones 109a-c with a-haloesters 110a-b in tetrahydrofuran under reflux gave 1,2,4-triazin-6-ones 111a-c (Scheme 41) (2007TJC141).

Scheme 40

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Synthesis of Heterocycles

Scheme 41

8.1.1.4 Alkynes

Interestingly, reaction of amidrazone 112 with ethyl propionate 113 in refluxing ethanol afforded triazine 114 in 70% yield (Scheme 42) (2012JHC1009). The reaction of amidrazone 1 with alkyne derivatives 115a-f in presence of N-iodosuccinimide and PTSA in dimethyl sulfoxide (DMSO) at 110 C afforded triazines 116a-f (Scheme 43) (2013RSC1). 8.1.1.5 Ketoamides

The reaction of amidrazone hydroiodide 117 with primary ketoamide 118 yielded 1,2,4-triazin-5-one 119 (Scheme 44) (2003TL5657). 8.1.1.6 a-Ketoesters

Stoltz and coworkers reported the reaction of amidrazone 120 with ketoester 121 in the presence of magnesium sulfate in methanol followed

Scheme 42

Scheme 43

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Scheme 44

Scheme 45

by reflux in DMF to give anti-triazin-5-one 122a (17%) and syn-triazin-6one 122b (71%, Scheme 45) (2005TL1997). On the other hand, reaction of benzamidrazone 123 with 2-oxobutyric acid ethyl ester 124 led to the formation of triazin-5-one ring 125 (Scheme 46) (2013TL474). 8.1.1.7 a-Hydroxyketones

The condensation reaction of amidrazone 126 with a-hydroxyketone 127 in ethanolic solution afforded 128. Subsequent oxidative cyclocondensation of 128 by heating in toluene solution in the presence of manganese dioxide led to the isolation of triazine 129 in 70% yield (Scheme 47) (2009JOC8343). 8.1.1.8 Acetic Anhydride

Stepanov and coworkers reported that condensation of amidrazone 130a-c with glyoxal produced 1,2,4-triazine 131a-c (Scheme 47). While the

Scheme 46

135

Synthesis of Heterocycles

Scheme 47

reaction of amidrazones 130a-c with acetic acid and nitrous acid afforded tetrazoles 132a-c (Scheme 48). Interestingly, the reaction of amidrazones 130a-c with acetic anhydride and sulfuric acid gave a 1,2,4-triazole 133 (Scheme 48) (2015CHC350). 8.1.1.9 Formaldehyde

The reaction of amidrazone 134 with formaldehyde in the presence of PTSA afforded triazin-5-one 135 (Scheme 49) (2009Ark150). Amidrazones 136a,b reacted with DMF dimethylacetal (DMFDMA) in xylene to yield triazines 137a,b. When products 137a,b were dissolved in glacial acetic acid heating at reflux afforded pyrazolo[3,4-e][1,2,4]triazines 138a,b (Scheme 50) (2010MOL3302).

Scheme 48

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Scheme 49

Scheme 50

9. SYNTHESIS OF SEVEN-MEMBERED RINGS WITH THREE HETEROATOMS 9.1 1,3,4-Oxadiazepines Recently, it was demonstrated that amidrazones 1a-e reacted with 2acetylcyclopentanone (139) at room temperature to give cyclopenta[e-1,3,4]oxadiazepines (140, 2016JHC00) (Scheme 51) in 70e79% yield.

9.2 1,2,4-Triazepines 9.2.1 Reaction of Imidrazones With 9.2.1.1 Dicyanonaphthoquinone

Aly et al., synthesized 4-aryl-5-imino-3-phenyl-1H-naphthol[1,2,4] triazepine-6,11-diones 142a,b,e,s, in 68e80% yields, from the reaction

Scheme 51

137

Synthesis of Heterocycles

Scheme 52

of amidrazones 1a,b,e,s with dicyanonaphthoquinone 141 in dry ethyl acetate (Scheme 52) (2008ZNB223). 9.2.1.2 Arylidines

Omran et al. reported that the reaction of amidrazone 143 with arylidines 144a-c in ethanol catalyzed by Et3N gave triazepines 145a-c (Scheme 53) (2006SC3647).

Scheme 53

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A.A. Aly, M. Ramadan, A.M. Mohamed, and E.A. Ishak, J. Heterocycl. Chem., 49, 1009 (2012). S. Hamzaoui, A. Ben Salem, A. Ben Hsouna, N. Chaari, M. Trigui, M. Mourer, and M. Kossentini, Mediterr. J. Chem., 1, 246 (2012). P. Frohberg, I. Schulze, C. Donner, and F. Krauth, Tetrahedron Lett., 53, 4507 (2012). D. Tang, J. Wang, P. Wu, X. Guo, H.J. Li, and S. Yang, R. Soc. Chem., 1 (2013). T. Olszewska, P.E. Gajewska, and J.M. Milewska, Tetrahedron Lett., 49, 474 (2013). A.M. Schmidt and X. Qian, Tetrahedron Lett., 54, 5721 (2013). S.A. Bunev, V.E. Sukhonosova, E.V. Statsyuk, I.G. Ostapenko, and P.P. Purygin, Chem. Heterocycl. Compd., 48, 1728 (2013). S. Hamzaoui, K. Hamden, A. Ben Salem, M. Mourer, J.B. RegnoufDe-Vains, and M. Kossentini, Arch. Pharm., 346, 321 (2013). A. Guirado, L.I.J. Sanchez, R. Moreno, and J. Galvez, Tetrahedron Lett., 54, 1542 (2013). M. Nakka, B.M. Gajula, R. Tadikonda, S. Rayavarapu, P. Sarakula, and S. Vidavalur, Tetrahedron Lett., 55, 177 (2014). A.A. Aly, A.B. Brown, A.A. Hassan, M.A.-M. Gomaa, and F.M. Nemr, J. Sulf. Chem., 36, 502 (2015). M. Nakka, R. Tadikonda, S. Rayavarapu, P. Sarakula, and S. Vidavalur, Synthesis, 47, 517 (2015). R. Paprocka, M. Wiese, A. Eljaszewicz, A. Helmin-Basa, A. Gzella, B. Modzelewska-Banachiewicz, and J. Michalkiewicz, Biorg. Med. Chem. Lett., 25, 2664 (2015). D. Catarzi, F. Varano, D. Poli, L. Squarcialupi, M. Betti, L. Trincavelli, C. Martini, D. Dal Ben, A. Thomas, R. Volpini, and V. Colotta, Biorg. Med. Chem., 23, 9 (2015). S.D. Kopchuk, V.N. Chepchugov, A.G. Kim, V.G. Zyryanov, S.I. Kovalev, L.V. Rusinov, and N.O. Chupakhina, Russ. Chem. Bull., 64, 897 (2015). A.I. Stepanov, V.S. Sannikov, D.V. Dashko, A.G. Roslyakov, A.A. Astrat’ev, and E.V. Stepanova, Chem. Heterocycl. Compd., 51, 350 (2015). E. Bokor, Z. Szeles, T. Docsa, P. Gergely, and L. Somsak, Carbohydrate. Res., 429, 128 (2016). A.A. Aly, A.A. Hassan, M.A.-M. Gomaa, S. Br€ase, and F.M. Nemr, Reaction of Amidrazones with Diaminomaleonitrile: Synthesis of 4Amino-5-Iminopyrazoles, J. Heterocycl. Chem., 00, 00 (2016). http:// dx.doi.org/10.1002/jhet.2607. A.A. Aly, A.A. Hassan, S. Br€ase, M.A.-M. Gomaa, and F.M. Nemr, Reaction of Amidrazones with Phthaloyl ChloridedSynthesis of 1,2,4-Triazolium Salts (Part I), J. Heterocycl. Chem., 00, 00 (2016). http://dx.doi.org/10.1002/jhet.2643. A.A. Aly, M. Ramadan, M. Abd Al-Aziz, H.M. Fathy, S. Br€ase, A.B. Brown, and M. Nieger, J. Chem. Res., 40, 637 (2016). A.A. Aly, E.A. Ishak, M. Ramadan, N.A.A. Elkanzi, and A.A.M. ElReedy, Amidrazones and 2-Acetylcyclopentanone in the Synthesis of Cyclopenta[e][1,3,4]-Oxadiazepines, J. Heterocycl. Chem., 00, 00 (2016). http://dx.doi.org/10.1002/jhet.2727.

CHAPTER FOUR

2-Pyridone Methides (2-Methylene-1,2dihydropyridines) and BenzoFused AnalogsdPart 1: Synthesis G. Fischer Leipzig, Germany E-mail: gunther_fi[email protected]

Contents 1. Introduction 1.1 General Survey 1.2 Scope and Limitation 1.3 Nomenclature 2. Occurrence and Synthesis 2.1 Survey 2.2 Natural Occurrence 2.3 Synthesis of N-Unsubstituted Methides 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5

142 142 143 143 143 143 144 144

From Pyridine Bases and Benzologs From N-Oxides By Ring Formation By Ring Transformation or Cleavage By Other Reactions

144 153 155 162 162

2.4 Syntheses of Anhydrobases 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5

162

From Pyridine Bases and Benzologs From Quaternary Pyridinium Salts and Benzologs By Ring Formation By Ring Transformation By Other Reactions

162 164 177 182 182

References

182

Abstract The review (Part 1) deals with the synthesis of 2-pyridone methides and benzo-fused analogs. Methides that are unsubstituted at the nitrogen atom are mainly synthesized from the corresponding pyridine bases by reactions at o- or a-positions, from N-oxides or by Advances in Heterocyclic Chemistry, Volume 122 ISSN 0065-2725 http://dx.doi.org/10.1016/bs.aihch.2016.07.001

© 2017 Elsevier Inc. All rights reserved.

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j

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G. Fischer

ring formation or transformation. N-Substituted so-called anhydrobases mostly originate from quaternary salts either by deprotonation or by reactions at o- or a-positions.

Keywords: 2-Methylenepyridines; Anhydrobases; Dihydropyridines; Heterocycles; Isoquinolines; Nitrogen heterocycles; Organic chemistry; Pyridines; Pyridinium salts; Quinolines

List of Abbreviations cond. DBU DMAD DMAP eq Hal min Mst NMM NMO NMP spec. SSA Ts y

conditions 1,5-diazabicyclo[5,4,0]undec-5-ene dimethyl acetylenedicarboxylate 4-dimethylaminopyridine equivalent(s) halide minutes mesityl N-methylmorpholine N-methylmorpholine N-oxide N-methyl-2-pyrrolidone specially silica sulfuric acid p-toluenesulfonyl yield

1. INTRODUCTION 1.1 General Survey 2-Pyridone methide series compounds have been studied for more than 110 years (cf. 61HC(14/2)1). One has to distinguish between derivatives of N-unsubstituted parent substance 1a- (NH type, Scheme 1) and N-substituted 1b-type compounds. The first type is formally a tautomer of 2-picoline (2a), the latter type belongs to the class of anhydrobases, 4 5

3

+ N R

2

6

N1 R

N

CH2 α

2a

1a (R = H) 1b (R = alkyl, aryl, etc.)

N R

CH3

2b

N

CH2

CH2

3

4

Scheme 1

R

_ CH3 OH

2-Pyridone Methides (2-Methylene-1,2-dihydropyridines)

143

that is, formal products of dehydrating, for instance, quaternary 2picolinium hydroxide (2b). Results, mostly gained in the field of anhydrobases, have partly been compiled in Weissberger’s (cited earlier) and Rodd’s handbooks (57RCC(IVA)488, 76RCC2(IVF)27, 87SRC(IVF)1) as well as Katritzky’s Comprehensive Heterocyclic Chemistry (84CHEC(2)315) and a review (82CHE217).

1.2 Scope and Limitation The present chapter (Parts 1 and 2) covers literature from about 1960 through 2015 together with some work published in 2016. The coverage is generally restricted to derivatives of 2-pyridone (1), 2-quinolone (3), and 1-isoquinolone methides (4) and, in the case of anhydrobases, to Ncarbosubstituted compounds. The exocyclic methylene group must not be a part of an additional fused ring in a nitrogen-bridged bicyclic system. In consequence, the huge group of indolizines (cf. 61HC(15)) as well as pyrido[1,2-a]azepines (11AHC(103)61) will at best be mentioned as products of methide reactions. The same restriction applies to the large area of cyanines (cf. 63HC(18)) and to other dyes, such as squaraines (cf. 09CC6339) or pyro- and quinophthalones (cf. 07T9172).

1.3 Nomenclature In this chapter the pyridone methide moiety is, for consistency, as far as possible drawn and numbered as shown in Formula 1. The exocyclic methylene carbon atom is termed a (cf. 90SAA803). Pyridone methides were occasionally termed pyridmethines (63AHC(1)339, p. 426; 72AJC1549) or pyridomethenes (10OL4010, 15JMC(A)16831).

2. OCCURRENCE AND SYNTHESIS 2.1 Survey NH-Type methides (1a) mainly form (1) from the corresponding pyridine bases either by reactions at an a-carbon atom or by substitution of o-positioned halogen, (2) from N-oxides, and (3) by ring formation or transformation. Though such methides are tautomerizable in principle, examples described in the synthetic sections of this chapter, as a rule, have been claimed to exist substantially or exclusively in the methide form. (The possibility to form hydrogen-bridge bonds is favorable to NH-type methide tautomers.) Anhydrobases (1b), on the other hand, are mainly accessible from quaternary salts, either by deprotonation by means of basic substances, by an attack on the a-position, or by the replacement of an o-positioned leaving group.

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G. Fischer

O O N Me

Ac

O O

5

Scheme 2

2.2 Natural Occurrence Among recently found natural products, highly fused alkaloid 6ketenesanguinarine (5, Scheme 2) is worth mentioning (14MI3).

2.3 Synthesis of N-Unsubstituted Methides 2.3.1 From Pyridine Bases and Benzologs 2.3.1.1 Reactions at an a-Positioned Carbon Atom

2.3.1.1.1 Acylation The reaction has nearly exclusively been applied to quinaldine and its derivatives, because the corresponding quinolone methides are relatively stable (cf. Part 2, Section 3.6). They are usually synthesized from the quinaldyl anion and esters or from quinaldine and acyl chlorides or anhydrides. The reaction products, being gathered, in an exemplary fashion, in Schemes 3e6, contain, if at all, only small amounts of nonmethide tautomers (cf. Part 2, Section 3.5). Thus, the acylation of 2,3-dimethylquinoline or quinaldine (8) in the presence of different basic reagents (Scheme 3)1 gives quinolone methides 6, 72, 9, and 10 (88T3319, 91JCS(P1)2831). Similar reactions lead to products 11a (10AXE1746), 11b (01JPO201), and 12 (00JCS(P2)1259). Other examples (Scheme 4) involve the formation of enolic bisquinoline compounds 14 and 15 by the condensation of quinaldyl lithium (13) and diethyl oxalate (03CEJ2710) or carbonate (09JST(930)78), respectively, as well as fluorine derivative 16 (06JICS173). The use of nitriles (instead of esters) enables the formation of imines, such as 18, which may be either isolated (13JST(1032)138) or hydrolyzed in situ to give aforementioned acyl derivatives, for instance, 19 (13ICA(401)38). Corresponding aroyl compounds (e.g., 19b) can be obtained by another, solvent-free method from quinolines and aroyl chlorides in the presence of catalyst silica gel under microwave irradiation (01TL4363). 1

In the captions beneath the formulas, substituents (R or X) in parentheses refer, in the order given, to substructures a, b, c etc. of the respective formula or all formulas of the reaction. 2 Hydrogen-bridge bonding is, as a rule, no longer depicted.

145

2-Pyridone Methides (2-Methylene-1,2-dihydropyridines)

1. NaH, N2 2. RCOOMe, 65 °C

N

N H O

EtOK (COOEt)2

N H

N 8 O

7

R

6a-c (R = iPr, tBu, Ph)

COOEt (CX3CO)2O Et3N, 25 °C, N2

1.iPr2NLi 2.BrCH2COOEt -78 °C

N H

N H O

O CX3 10a, b (X = F, Cl)

CH2Br

9

N H

N H O R 11a, b (R = COOEt, CH=CHPh)

O 12

F

Scheme 3

2-Quinolylacetonitrile (20) and analogs behave similarly to quinaldine (Scheme 5): The treatment with acyl chlorides affords quinolone methides 21a (97CHE445), 21b (10CHE887), and 22a and b (11JHC1149). aBenzoyl derivatives 23aec are examples of isoquinolone methides (06EJO2817). The condensation of 2-picoline or quinaldine (8) and several aromatic (mostly cyclic) anhydrides (Scheme 6) leads to pyrophthalones 25e28 or analogous quinophthalones, respectively (07T9172). A milder procedure of preparing quinophthalone 29 has been described (09MI2). 2.3.1.1.2 Other Carbon-Carbon Bond-Forming Reactions The treatment of quinaldine derivatives 30, 32, and 35 (Scheme 7) with dimethyl acetylenedicarboxylate (DMAD) results in the formation of a-vinyl-type 1:1 adducts 31 and 33 and 1:2 adduct 36, respectively (79JCS(P1)2171). Different a-vinyl structures, this time in the pyridine series (e.g., 38), arise

N H

O

O

(COOEt)2 14

H N

2 N

CH2Li

13

CO(OEt)2 35 °C

N

13

O

H

H

N

15

CHF2-COOEt 35 °C, Argon AcOH, Br2 or < [email protected]>.

2. GENERAL SOURCES AND TOPICS 2.1 General Books and Reviews 2.1.1 Textbooks and Handbooks Heterocyclic chemistry: 14MI1. Green syntheses: 14MI2, 14MI3. Ionic liquids in organic synthesis: 14MI4. Applied Stereochemistry of Biologically Active Products: 14MI5. 2.1.2 Annual Reports Three-membered ring systems: 14PHC55. Four-membered ring systems: 14PHC85. Thiophenes and Se/Te derivatives: 14PHC115. Pyrroles and benzo analogs: 14PHC151. Furans and benzofurans: 14PHC193. Five-membered ring systems with more than one N atom: 14PHC237. Five-membered ring systems with N and S (Se) atoms: 14PHC279. Five-membered ring systems with O and S (Se, Te) atoms: 14PHC303. Five-membered ring systems with O and N atoms: 14PHC319. Pyridines and benzo derivatives: 14PHC349. Diazines and benzo derivatives: 14PHC395. Triazines and tetrazines: 14PHC449. Six-membered ring systems with O and/or S atoms: 14PHC463. Seven-membered rings: 14PHC521. Eight-membered and larger rings: 14PHC573. 2.1.3 Specialized Reports Devoted to Several Recent Years Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides (since 2011): 14CC12434.

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Progress of the synthesis of condensed pyrazole derivatives (from 2010 to mid-2013): 14EJMC(85)311. 2.1.4 History of Heterocyclic Chemistry, Biographies Baking, aging, diabetes: A short history of the Maillard reaction: 14AG(E) 10316. History and applications of quinones as dienophiles in total synthesis: 14AG(E)2056. 2.1.5 Bibliography of Monographs and Reviews The literature of heterocyclic chemistry, Part XII, 2010e11: 14AHC(111)147.

2.2 General Topics by Reaction Type 2.2.1 General Sources and Topics Problems of heteroaromaticity: 14AHC(113)111, 14CRV6383. Structure, bonding, and reactivity of heterocyclic compounds: 14THC(38)1. The [3 þ 3] cycloaddition alternative for heterocycle syntheses: 14ACR1396. Hetero-cycloreversions mediated by photoinduced electron transfer: 14ACR1359. Mechano heterocyclic chemistry: grinding and ball mills: 14AHC(112) 117. Triazole-, imidazolium, and triazolium CH donor groups as anion receptors: 14CSR6198. Self-assembly of intramolecular charge-transfer compounds: 14ACR1186. 2.2.2 Structure and Stereochemistry 2.2.2.1 Stereochemical Aspects

Additive effects on asymmetric hydrogenation of N-heteroaromatics: 14H(88)103. Anionic chiral tridentate N-donor pincer ligands in asymmetric catalysis: 14ACR3162. Applications of chiral auxiliaries: 14MI6. Asymmetric iodolactonization: 14EJOC3051.

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C]N-Containing azaarenes as activating groups in enantioselective catalysis: 14JOC831. Helical-chiral small molecules in asymmetric catalysis: 14EJOC21. Recent applications of C1-symmetric bis(oxazoline) ligands in asymmetric catalysis: 14S722. Regio- and stereoselectivity in the lithiation reactions of small-ring heterocycles: 14EJOC5397. Transition metal-catalyzed asymmetric hydrogenation of heteroaromatics: 14TCC(343)145. 2.2.2.2 Betaines and Other Unusual Structures

General aspects of N-heterocyclic carbene chemistry: 14N(510)485, 14MI7, 14MI8, 14CRV5215, 14CRV8747. N-Heterocyclic silylene complexes in catalysis: 14ICF134. 2.2.3 Reactivity 2.2.3.1 General Topics

Adventures in ring-contraction reactions: 14SL466. Arenes and hetarenes in reactions with unsaturated nitro compounds: 14KGS648. Baker’s-yeast-mediated reduction of sulfur-containing compounds: 14EJOC3737. 1,3-Dinitro alkanes in one-pot construction of carbo- and heterocyclic systems: 14EJOC1805. Domino reactions: 14MI9. Heterocyclic ketene aminals: Scaffolds for heterocycle molecular diversity: 14EJOC1129. Methods and applications of cycloaddition reactions: 14MI10. Preparation of functionalized heteroaromatics using an intramolecular Wittig reaction: 14OBC4044. Side reactions in aromatic substitutions: 14MI11. Ynamides in ring forming transformations: 14ACR560. 2.2.3.2 Reactions With Electrophiles and Oxidants

Aerobic oxidations of alcohols and amines with copper/TEMPO and related systems: 14AG(E)8824. Trifluoromethylation reactions with electrophilic trifluoromethylating reagents: 14CEJ16806.

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2.2.3.3 Reactions With Nucleophiles and Reducing Agents

Metal free CeH functionalization of aromatics. Nucleophilic displacement of hydrogen: 14THC(37)1. Organic electron donors as powerful single-electron reducing agents in organic synthesis: 14AG(E)384. 2.2.3.4 Reactions Toward Free Radicals, Carbenes etc.

Aerobic oxidation catalysis with stable radicals (primarily nitroxyl radicals): 14CC4524. Catalytic access to a-oxo gold carbenes, particularly, useful in heterocyclizations: 14ACR966. Catalytic reactions with N-mesityl-substituted N-heterocyclic carbenes: 14MI12. Low-valent cobalt catalysis (N-heterocyclic carbene as ligand) for CeH functionalization: 14ACR1208. The mechanism of N-heterocyclic carbene-catalyzed reactions involving acyl azoliums: 14ACR696. Radical addition to iminium ions and cationic heterocycles: 14M16190. Scavenging of organic C-centered radicals by nitroxides: 14CRV5011. 2.2.3.5 Cross-Coupling and Related Reactions

CeH bond functionalization in hetarenes catalyzed by group 3e5 metal alkyl complexes: 14DT2331. Ru-catalyzed alkyne annulations by CeH/HeteH bond functionalizations: 14ACR281. The cross-dehydrogenative coupling of C-sp3eH bonds for CeC bond formations: 14AG(E)74. Metal-catalyzed annulation reactions for p-conjugated polycycles: 14CEJ3554. Metal-mediated cross-coupling reactions: 14MI13, 14MI14. Transition-metal-catalyzed CeS activation: From thioester to (hetero) aryl thioether: 14ACSC280. 2.2.3.6 Heterocycles as Intermediates in Organic Synthesis

Advances in the ring opening of small-ring heterocycles with organoboron derivatives: 14SL1817. Enabling the use of heterocyclic arynes in chemical synthesis: 14JOC846.

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2.2.3.7 Organocatalysts

A general overview of the organocatalytic intramolecular aza-Michael reaction: 14CSR7430. N-Heterocyclic carbenes in asymmetric organocatalysis: 14COCT13. Hydrogen-bonding in aminocatalysis: From proline and beyond: 14CEJ358. Organocatalytic Lewis base functionalization of carboxylic acids, esters, and anhydrides via C1-ammonium or azolium enolates: 14CSR6214. Small heterocycles in multicomponent reactions: 14CRV8323. 2.2.4 Synthesis 2.2.4.1 General Topics and Nonconventional Synthetic Methodologies

2-Alkynylbenzaldoxime: a versatile building block for the generation of N-heterocycles: 14OBC9045. Amino acids as a tool for asymmetric synthesis of heterocycles: 14OBC6297. Artificial enzyme mimics: 14CSR1734. Azabicycles construction: The transannular ring contraction with Nprotected nucleophiles: 14OBC6570. Comprehensive organic synthesis: 14MI15. Economic synthesis of heterocycles: 14MI16. Enantioselective synthesis of spiroacetals: 14OBC5324. Lithium compounds in organic synthesis: 14MI17. Mesostructured hybrid organic-silica materials containing N-heterocyclic carbene ligands as ideal supports for heterogeneous organometallic catalysts: 14ACSC1458. Nazarov-like cyclization reactions (2009e13): 14OBC5331. Nitroalkenes in the synthesis of 3e5-membered O-, N-, and S-heterocycles: 14RSCA48022. Olefin metathesis: 14MI18. Preparation and structure classification of heteraspiro[mn]alkanes: 14S1957. Recent developments in the synthesis of cyclic guanidine alkaloids: 14PHC1. (Section 2.4.2.2). Synthesis and applications of copper N-heterocyclic carbene complexes: 14WHX20. Synthesis of N-heterocycles from nitroarenes: 14KGS704. Transition metal-mediated direct CeH arylation of heteroarenes involving aryl radicals: 14ASC645.

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The use of silyl-protected enoldiazoacetates for heterocyclic syntheses: 14AJC365. 2.2.4.2 Synthetic Strategies and Individual Methods

2.2.4.2.1 General Problems CeH bond functionalization through intramolecular hydride transfer: 14AG(E)5010. Dual gold catalysis and, particularly, its role in formation of heterocycles: 14ACR864. Enzymes as biocatalysts for organic synthesis: 14AG(E)3070. Gold-catalyzed reactions of methylidene- and vinylidenecyclopropanes to give heterocycles: 14ACR913. Gold-catalyzed cyclizations (including heterocyclizations) of allenol and alkynol derivatives: 14ACR939. A Complete Toolbox for Nanostructured Carbon Materials:14PHC29. (Section 2.2.5.7). 2.2.4.2.2 Synthetic Application of Photo Reactions and Alternative Energy Input Non-biaryl atropisomers for stereospecific phototransformations: 14CL1816. Photoinduced electron transfer-initiated cyclization reactions and asymmetric transformations of (Z)-b-dehydroamino acid derivatives: 14H(89)579. Heterocyclization of oxime-based heteroradicals under the incisive EPR action: 14ACR1406. Use of microwave heating in the synthesis of heterocycles from carbohydrates: 14COC417. 2.2.4.2.3 Synthetic Application of Metal-Catalyzed Reactions CeH nitrogenation and oxygenation of (hetero)arenes by ruthenium catalysis: 14CC29. CeIII salts promoted construction of heterocycles by bond forming reactions: 14CSR779. Copper-catalyzed asymmetric synthesis: 14MI19. Direct heteroaromatic coupling reactions by transition-metal catalysis: 14BCJ751. Direct metal-catalyzed regioselective functionalization of enamides in synthesis of N-heterocycles: 14CEJ7548.

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Ethylene oligomerization using Fe complexes and the discovery of bis(imino)pyridine ligands: 14CC1398. Heterocyclic synthesis by p-acidic metal catalyzed reactions via NeO bond cleavage: 14H(89)845. Heterocyclization via transition metal-catalyzed isomerization of O- and N-allylic systems: 14CEJ8832. Iron-catalyzed synthesis of heterocycles (since 2006): 14T4827. Recent developments in transition metal-catalyzed spiroketalization: 14OBC7423. Syntheses of chiral heterocycles via Zr-catalyzed asymmetric carboalumination of alkenes: 14H(88)845. Synthesis of heterocycles via transition-metal-catalyzed hydroarylation of alkynes: 14CSR1575. Synthesis of multiply arylated heteroarenes via Pd-catalyzed direct CeH arylation: 14S2833. 2.2.4.2.4 Synthesis of Heterocycles via Cycloaddition and Multicomponent Reactions Asymmetric 1,3-dipolar cycloadditons of stabilized azomethine ylides with nitroalkenes: 14CTMC1271. Cycloaddition of 1,3-butadiynes: Efficient synthesis of carbo- and heterocycles: 14M13788. 1,4-Dipolar cycloadditions and related reactions: 14T3085. Intermolecular gold(I)-catalyzed cycloadditions of alkynes and allenes: 14CAJ3066. Microwave-assisted cycloaddition reactions in carbo- and heterocyclic chemistry: 14COC2139. Selectivity in 1,3-dipolar cycloadditions of nitrilimines with functionalized dipolarophiles: 14COC598. Biocatalytic or organocatalytic enantioselective multicomponent reactions: 14EJOC2005. Boron-substituted 1,3-heterodienes as key elements in multicomponent processes: 14BJOC237. Cascades involving catalysis and sigmatropic rearrangements: 14AG(E) 2556. Domino reactions based on Knoevenagel condensation in the synthesis of heterocycles: 14T551. Recent progress in metal-assisted multicomponent syntheses of heterocycles: 14H(89)869.

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Synthesis of oxazolo-, thiazolo-, pyrazolo-, and imidazo-fused heterocycles by multicomponent reactions: 14COS471. Synthesis of pyrido- and pyrimido-fused heterocycles by multicomponent reactions: 14COS835. Ugi and Passerini reactions as successful models for investigating multicomponent reactions: 14COC719. The Ugi-Smiles and Passerini-Smiles couplings: Phenols in isocyanidebased multicomponent reactions: 14EJOC7749. 2.2.4.2.5 Miscellaneous Methods Dehydrogenative Heck annulations of internal alkynes: 14S1555. Heterocycles from donor-acceptor interactions: 14AHC(112)145. Heterocycles from the reaction of thione groups with acetylenic bonds: 14AHC(113)245. Recent advances and applications of reductive desulfurization in organic synthesis: 14T8983. Recent advances in the electrochemical construction of heterocycles: 14BJOC2858. Stereoselective carbo- and heterocyclization reactions under phasetransfer catalysis: 14T1935. Synthesis of heterocycles via nucleophilic substitution of hydrogen in nitroarenes: 14H(88)75. Synthetic approaches for nitrogen bridgehead heterocyclic systems: 14H(89)1125. 2.2.4.3 Versatile Synthons and Specific Reagents

Acid hydrazides, potent reagents for synthesis of O-, N-, and/or S-heterocycles: 14CRV2942. Acyl Meldrum’s acid derivatives: Application in organic synthesis: 14UK620. a-Amidoalkylating agents: Structure, synthesis, reactivity and application: 14AHC(111)43. Chemistry of pent-4-yne-1,3-diones as precursors for heterocycles: 14AHC(113)67. Dimethyl acetylenedicarboxylate: A versatile tool in organic synthesis: 14AHC(113)1. Diversity-oriented approach to heterocycles via methyl 2-acetamidoacrylate and its congeners: 14T5361.

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Formation and reactivity of 5-aminopenta-2,4-dienals as precursors for N-heterocycles: 14AHC(111)1. Hydrazines and azo-compounds in the synthesis of heterocycles comprising NeN bond: 14H(88)129. Iron(III) chloride promoted cyclization as an approach to polycyclic heteroaromatics: 14SL313. Ketenes as synthons in the syntheses of three- and four-membered heterocycles: 14AHC(113)143. Sequential addition and cyclization of a,b-ynones and -ynoates bearing proximate nucleophiles: 14S687. Sulfur monochloride in organic synthesis: 14UK225. Synthesis and reactivity of heterocyclic hydroxylamine-O-sulfonates: 14HC133. Synthesis of heterocyclic systems based on mono- and dicarbonyl adamantane derivatives: 14UK377. 2.2.4.4 Ring Synthesis From Nonheterocyclic Compounds

Advances in the synthesis of iodoheterocycles via iodocyclization of functionalized alkynes: 14COC341. Aza-DielseAlder reaction as an efficient approach for construction of heterocycles: 14COC1586. The conversion of allenes to strained three-membered heterocycles: 14CSR3136. Cyclization reactions of bis(allenes) for the synthesis of polycarbo(hetero) cycles: 14CSR3106. Heterocycles via transition metalecatalyzed CeH functionalization and Ceheteroatom bond formation: 14COC2049. Heterocycles from a-aminonitriles: 14CEJ13064. Metaleorganic frameworks as solid catalysts for the synthesis of N-heterocycles: 14CSR5750. PaaleKnorr reaction in the synthesis of heterocyclic compounds: 14AHC(111)95. Heterocycles via Ag- and Pt-catalyzed addition of OeH and NeH bonds to allenes: 14CSR3164. 2.2.5 Properties and Applications (Except Drugs and Pesticides) 2.2.5.1 Dyes and Intermediates

Arylazoazines and arylazoazoles as interesting disperse dyes: 14EJC192.

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Anchoring groups attached on porphyrins as potential dyes for dye-sensitized solar cells: 14RSCA21379. Indocyanine green: Photosensitizer or chromophore? Still a debate: 14CMC1871. Marine natural pigments: Chemistry, distribution, and analysis: 14DP124. Previous and recent advances in pyranoanthocyanins equilibria in aqueous solution: 14DP190. Pyridinium N-phenolate betaine dyes: 14CRV10429. 2.2.5.2 Substances With Luminescent and Related Properties

Benzobisoxazole cruciforms as fluorescent sensors: 14ACR2074. 1,3-Bis(2-pyridylimino)isoindoline-based chromophores and fluorophores: 14EJIC4715. Locking r-conjugated and heterocyclic ligands with boron(III) in luminescent materials: 14AG(E)2290. Near-infrared emitting lanthanide complexes of porphyrin and BODIPY dyes: 14CCR(273)87. Materials containing N-heterocycles for highly efficient phosphorescent OLEDs: 14JMC(C)9565. Photoluminescence and applications of N-heterocyclic carbene metal complexes: 14CSR3551. Progress in the fluorescent probe based on spiro ring opening of xanthenes: 14CJOC1. Redox- and photochemistry of bis(terpyridine)ruthenium(II) amino acids and their amide conjugates: 14EJIC5468. 2.2.5.3 Organic Conductors and Photovoltaics

Dipyrromethene-based materials and their applications in organic photovoltaic devices: 14CSR3342. Design and synthesis of molecular donors for solution-processed efficient organic solar cells: 14ACR257. Efficient photovoltaic polymers based on two-dimensional conjugated benzodithiophene: 14ACR1595. Functional naphthalene diimides as potential semiconductors and photovoltaics: 14AG(E)7428. Molecular materials for organic photovoltaics (mainly, oligothiophenes): 14AM3821. b-Oligofurans as an emerging class of conjugated oligomers for organic electronics: 14AG(E)2546.

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Organic photovoltaics: 14MI20. Poly(3,4-ethylenedioxyselenophene) and its derivatives: Novel organic electronic materials: 14ACR1465. 2.2.5.4 Coordination Compounds

2,6-Bis(1,2,3-triazol-4-yl)pyridine (btp) as a new versatile ligand: 14CSR5302. Design, synthesis, and excited-state properties of mononuclear Ru(II) complexes of tridentate heterocyclic ligands: 14CSR6184. Pyridine coordination chemistry for molecular assemblies on surfaces: 14ACR3407. Structural modification strategies for the rational design of red/NIR region BODIPYs: 14CSR4778. 2.2.5.5 Polymers

Coordination polymers with nucleobases. Structural aspects and potential applications: 14CCR(276)34. Design, synthesis, and structure-property relationships of isoindigo-based polymers: 14ACR1117. Entropically driven ring-opening polymerization of strainless organic macrocycles: 14CRV2278. 4,20 :60 ,400 -Terpyridines as building blocks in coordination polymers and metallomacrocycles: 14DT6594. 2.2.5.6 Ionic Liquids

Advances in functionalized ionic liquids as reagents and scavengers in organic synthesis: 14COC2530. Development of ionic nanoparticle networks as ionic liquid based materials: 14CC10929. Energy storage materials synthesized from ionic liquids: 14AG(E)13342. Extractive desulfurization of fuel oils using ionic liquids: 14RSCA35302. Imidazolium-based ionic liquids grafted on solid surfaces: 14CSR7171. Ionic liquids and ultrasound in combination: Synergies and challenges: 14CSR8132. Ionic liquid-based green processes for energy production: 14CSR7838. Ionic liquids as catalysts and reaction media in oleochemical raw materials processing: 14COC2797. Ionic liquids for energy, materials, and medicine: 14CC9228. Ionic liquids in heterocyclic synthesis (Update 1): 14CRV(PR1). The microwave-assisted ionic-liquid method: A promising methodology in nanomaterials: 14CAJ2378.

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Point-functionalization of ionic liquids: An overview of synthesis and applications: 14EJOC6120. Recent trends of ionic liquid chemistry in the field of synthetic organic chemistry: 14YGK518. Synthesis and transformations of nitrogen heterocycles in ionic liquids: 14KGS690. The use of supported acidic ionic liquids in organic synthesis: 14M8840. 2.2.5.7 Miscellaneous

Self-assemblies based on the “outer-surface interactions” of cucurbit[n] urils: 14ACR1386. Solvent-assisted linker exchange instead of synthesis of metal-organic hybrid materials: 14AG(E)4530. Spiropyran-based dynamic materials: 14CSR148. Zeolitic imidazolate framework composite membranes and films: synthesis and applications: 14CSR4470.

2.3 Specialized Heterocycles 2.3.1 Nitrogen Heterocycles (Except Alkaloids) Chalcones as versatile synthons for the synthesis of 5- and 6-membered N-heterocycles: 14COC2750. Synthesis of saturated N-heterocycles: 14JOC2809. Transformation of saturated N-heterocycles by microorganisms: 14AMB1497. 2.3.2 Oxygen Heterocycles Synthesis of 5- and 6-membered cyclic organic peroxides and their transformations into peroxide ring-retaining products: 14BJOC34. Synthesis of saturated oxygenated heterocycles I: 5- and 6-membered rings: 14THC(35)1. Synthesis of saturated oxygenated heterocycles II: 7- to 16-membered rings: 14THC(36)283. 2.3.3 Sulfur Heterocycles Catalytic asymmetric a-sulfenylation as a new pathway to access chiral CeS bonds: 14MROC424. Intramolecular thioleene “click” reactions for the synthesis of S-heterocycles: 14M19137. Sulfur heterocyclization from p-electron deficient quinones via chargetransfer interaction: 14PSS440.

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2.4 Natural and Synthetic Biologically Active Heterocycles 2.4.1 General Sources and Topics 2.4.1.1 Biological Functions of Natural and Synthetic Bioactive Heterocycles

Chemistry and biology of neurotrophic natural products: 14AG(E)956. 2,8-Diheterabicyclo[3.2.1]octane ring systems: Natural occurrence, synthesis, and properties: 14SL1643. Natural lactones and lactams: 14MI21. Natural products with anti-Bredt and bridgehead double bonds: 14AG(E)13664. Natural product synthesis at the interface of chemistry and biology: 14CEJ10204. 2.4.1.2 General Approaches to Syntheses of Biologically Active Heterocycles

The asymmetric hetero-DielseAlder reaction in the syntheses of bioactive compounds: 14AG(E)11146. Catalytic enantioselective 1,3-dipolar cycloadditions of azomethine ylides: 14ACR1296. Constraining cyclic peptides to mimic protein structure motifs: 14AG(E) 13020. Diastereoselective In promoted allylation of chiral N-sulfinyl imines: 14EJOC485. Direct Rh-catalyzed 1,3-transpositions of allylic alcohols and their silyl ethers in natural product synthesis: 14CSR4381. Harmicine, a tetracyclic tetrahydro-b-carboline, its synthesis, isolation, and use: 14KGS1488. Heterogeneous catalysis as a versatile tool for the synthesis of bioactive heterocycles: 14MI22. High-pressure transformations in natural product synthesis: 14S1279. Metal-catalyzed cross-coupling reactions of halomaleic anhydrides and halomaleimides: 14S281. Morita-Baylis-Hillman reaction in the synthesis of natural products and drugs: 14COC3078. Natural product synthesis via the Rh-carbenoid mediated cyclization of a-diazo carbonyl compounds: 14AJC343. Nitroso DielseAlder reaction in the functionalization of diene-containing natural products: 14OBC7445. The orthoester Johnson-Claisen rearrangement in the synthesis of bioactive molecules: 14EJOC2833.

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Pfitzinger reaction in the synthesis of bioactive compounds: 14MROC225. Protecting group-free syntheses of natural products and biologically active compounds: 14T8183. Strategies for the construction of tetrahydropyran rings in the synthesis of natural products: 14OBC3323. Syntheses of bioactive natural and related compounds based on their key structural units: 14SL1953. Synthetic approaches to heterocyclic guanidines with biological activity: 14COC2711. 2.4.1.3 Total Syntheses of Natural Products

Applications of BartoneMcCombie reaction in total syntheses: 14COS787. Applications of Mannich reaction in total syntheses of natural products: 14COC2857. Cu-mediated aromatic amination and its use in the total synthesis of natural products: 14CC13650. Highly selective synthetic methodologies in total synthesis of bio natural products: 14CPB1045. Lactonizations mediated by 2-methyl-6-nitrobenzoic anhydride (MNBA) with acyl-transfer catalyst in the total synthesis of natural products: 14BCJ196. Synthetic methodologies and applications of phthalides and phthalans in the total synthesis: 14CRV6213. Total synthesis of diterpenoid pyrones: nalanthalide, sesquicillin, candelalides A-C, and subglutinols A, B: 14SNP(43)1. The total synthesis of isodon diterpenes: 14AG(E)10588. Transannular reactions employed in asymmetric total synthesis: 14T9461. 2.4.2 Alkaloids 2.4.2.1 General

Alkaloids: A treasury of poisons and medicines: 14MI23. Alkaloids as inhibitors of monoamine oxidases and their role in the central nervous system: 14SNP(43)123. Electrochemical behaviour of alkaloids: Detection and interaction with DNA and proteins: 14H(88)879.

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2.4.2.2 Synthesis

Approaches to the total synthesis of quinolizidine alkaloid (þ)-epiquinamide and its isomers: 14COS627. Gold approaches to polycyclic indole alkaloids: 14CL572. Heathcock-inspired strategies for the synthesis of fawcettimine-type lycopodium alkaloids: 14CEJ42. Synthesis of alkaloids using transition-metal-catalyzed intramolecular amination reactions: 14SL179. Synthetic strategies toward hetidine and hetisine-type diterpenoid alkaloids: 14OBC1846. Total syntheses of the pyrrolidine alkaloid hygrine: 14COS889. 2.4.2.3 Individual Groups of Alkaloids

Alkaloids from the tribe Bocconieae (Papaveraceae): A chemical and biological review: 14M13042. Cinchona alkaloid catalysis for enantioselective carbon-nitrogen bond formation reactions: 14CTMC224. Dimeric pyrrole-imidazole alkaloids: synthetic approaches and biosynthetic hypotheses: 14CC8628. Important classes of bioactive alkaloids from marine ascidians: 14CTMC207. The indoloquinoline alkaloid neocryptolepine, a unique bioactive natural product: 14EJOC7979. Isolation, biological perspectives and synthesis of piperidine alkaloid conhydrin: 14S2551. Isoquinoline alkaloids with drug-like properties from the genus Corydalis: 14RSCA15900. Lauraceae alkaloids: 14RSCA21864. Progress in asymmetric synthesis of galanthamine-type alkaloids: 14CJOC852. Synthesis, reactivity, and applications of ()-cytisine and its derivatives: 14CRV712. 2.4.3 Antibiotics Thiopeptide antibiotics: Retrospective and recent advances: 14MDR317. 2.4.4 Vitamins Photo, thermal, and chemical degradation of riboflavin: 14BJOC1999. Riboflavin interactions with oxygendA survey from the photochemical perspective: 14CEJ15280.

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2.4.5 Drugs 2.4.5.1 General

Alkaloids as scaffolds in drugs against cancer, tuberculosis, and smoking cessation: 14CTMC239. Analysis of the structural diversity, substitution patterns, and frequency of N-heterocycles among US FDA-approved pharmaceuticals: 14JMC10257. Conjugates of natural products with nitroxyl radicals as a basis for creation of new drugs: 14CMC2839. Design of bioactive small molecules targeting RNA: 14OBC1029. Ferrocene modification of organic compounds for medicinal applications: 14IZV26, 14IZV2405. Fluorine-containing drugs introduced to the market in the last decade (2001e11): 14CRV2432. Functionalized organozinc reagents in medicinal chemistry: Discovery of novel drug candidates: 14S430. Fungal metabolites as pharmaceuticals: 14AJC827. Perspectives of Colchicaceae alkaloids in medicinal chemistry: 14CTMC274. Recent development of benzotriazole-based medicinal drugs: 14MC640. Supramolecular photochemistry of drugs in biomolecular environments: 14CSR4051. Synthetic approaches to the 2012 new drugs: 14BMC2005. Thiopeptide engineering as a multidisciplinary effort towards future drugs: 14AG(E)6602. Use of click-chemistry in the development of peptidomimetic enzyme inhibitors: 14CMC1467. 2.4.5.2 Definite Types of Activity

The chemistry and biology of theta defensins as antimicrobial agents and scaffolds for peptide drug design: 14AG(E)10612. The evolving role of chemical synthesis in antibacterial drug discovery: 14AG(E)8840. Advances in copper complexes as anticancer agents: 14CRV815. Antibody-drug conjugates as an emerging concept in cancer therapy: 14AG(E)3796. Anti-cancer palladium complexes: A focus on PdX2L2, palladacycles and related complexes: 14CSR4751.

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MetaleN-heterocyclic carbene complexes as anti-tumor agents: 14CMC1220. Thiazolidine-2,4-diones as multi-targeted scaffold for potential anticancer agents: 14EJMC(87)814. Benzimidazole: An emerging scaffold for analgesic and antiinflammatory agents: 14EJMC(76)494. Antimalarials in development in 2014: 14CRV11221. A comprehensive review on synthetic approach for antimalarial agents: 14EJMC(85)147. Fruitful decade for antileishmanial compounds from 2002 to late 2011: 14CRV10369. Natural product based leads to fight against leishmaniasis: 14BMC18. Recent approaches to chemical discovery and development against malaria and the neglected tropical diseases human African trypanosomiasis and schistosomiasis: 14CRV11138. Recent developments in drug discovery for leishmaniasis and African trypanosomiasis: 14CRV11305. SAR analysis of new anti-TB drugs currently in pre-clinical and clinical development: 14EJMC(86)335. Synthesis and medicinal chemistry of selected antitubercular natural products: 14RSCA15180. Natural antiviral compounds: 14SNP(42)195. Natural small molecules as potential and real drugs of Alzheimer’s disease: 14SNP(42)153. Non-adenosine nucleoside inosine, guanosine and uridine as antiepileptic drugs: 14MRMC1033. Benzimidazole derivatives as kinase inhibitors: 14CMC2284. Biologically driven synthesis of pyrazolo[3,4- d]pyrimidines as protein kinase inhibitors: 14CRV7189. Natural sulfonium-ion glucosidase inhibitors and their derivatives as antidiabetic agents: 14ACR211. Sulfonyl-containing modulators of serotonin 5-HT6 receptors and their models: 14UK439. Chromones and their derivatives as radical scavengers: A remedy for cell impairment: 14CTMC2552. Combretastatin analogues as tubulin binding agents: 14COC2462. Heart regeneration: novel chemical and therapeutic methods or agents: 14AG(E)4056. Quinazolines: New horizons in anticonvulsant therapy: 14EJMC(80)447.

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Selected heterocyclic compounds as antioxidants. Synthesis and biological evaluation: 14CTMC2462. Trends in research of antitrypanosomal agents among synthetic heterocycles: 14EJMC(85)51. Triglyceride-lowering agents: 14BMC3551. Use of guanidine-substituted heterocycles in the treatment of neglected tropical diseases: 14COC2572. 2.4.5.3 Individual Substances and Groups of Compounds

Benzocoumarins: Isolation, synthesis, and biological activities: 14MRMC603. Chromone as a valid scaffold in medicinal chemistry: 14CRV4960. Comprehensive review in current developments of imidazole-based medicinal chemistry: 14MRR340. Coumarin hybrids as novel therapeutic agents: 14BMC3806. 1,4-Dihydropyridines: A class of pharmacologically important molecules: 14MRMC282. Flavones: An important scaffold for medicinal chemistry: 14EJMC(84)206. Furanocoumarins: Biomolecules of therapeutic interest: 14SNP(43)145. Heteroaryl chalcones and their therapeutic potential: 14BPN451. Tetraoxanes as antimalarials: Harnessing the endoperoxide: 14MRMC123. 1,3,5-Triazine-based analogues of purine as privileged scaffolds in medicinal chemistry: 14EJMC(85)371. 1,3,5-Triazines (2000e13) as antimicrobial, anti-TB, anti-HIV and antimalarial compounds: 14MRMC768. The use of spirocyclic scaffolds in drug discovery: 14BMCL3673. 2.4.6 Miscellaneous 2.4.6.1 Enzymes, Coenzymes, and Their Models

Copper complexes of N-donor ligands as artificial nucleases: 14EJIC2597. Metallo-b-lactamases and their biomimetic complexes: 14EJIC2869. 2.4.6.2 Amino Acids and Peptides

Chemistry, self-assembly and biological use of amino acid N-carboxyanhydrides and synthetic polypeptides: 14CC139. “Click” reaction as a versatile toolbox for the synthesis of peptideconjugates: 14CSR7013.

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Cyclic peptides as inhibitors of amyloid fibrillation: 14CEJ2410. Design, synthesis, conformational analysis and use of indolizidin-2-one dipeptide mimics: 14OBC5052. Peptide nanotubes: 14AG(E)6866. Synthesis of the biologically active natural cyclodepsipeptides apratoxin A and its analogs: 14CPB735. Synthesis of carbocyclic and heterocyclic b-aminocarboxylic acids: 14CRV1116. 2.4.6.3 Plant Metabolites

Chemical constituents of plants from the genus Neolitsea: 14HC61. 2.4.6.4 Heterocycles Produced by Marine Organisms

Cerebrosides from marine organisms: 14SNP(42)59. Heme in the marine environment: From cells to the iron cycle: 14MTM1107. Indole alkaloids from marine sources as potential leads against infectious diseases. Macrolactins: Antitumor antibiotics as marine drug lead: 14COC804. Marine toxins in Italy: 14EJOC1357. Marine toxin structure elucidation by mass spectrometry: 14COC812. Research of apratoxin A: A marine cyclic depsipeptide with significant anti-cancer activity: 14CJOC475. Terpenoids from the sea: Chemical diversity and bioactivity: 14COC840. The potential biomedical application of cyclopeptides from marine natural products: 14COC918. (þ)-Saxitoxin, the shellfish paralytic agent, its chemistry and chemical biology: 14AG(E)5760. Synthesis of imidazole alkaloids originated in marine sponges: 14SNP(42)33. 2.4.6.5 Other Topics

Aflatoxins: 14MI25. Tetrapyrrole compounds of Cyanobacteria: 14SNP(42)341. The use of UPLC-MS in food analysis: 14MI24.

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3. THREE-MEMBERED RINGS 3.1 General Topics The chemistry of transition metals with three-membered ring heterocycles: 14CRV8153. Organocatalytic asymmetric epoxidation and aziridination of olefins and their synthetic use: 14CRV8199.

3.2 One Heteroatom 3.2.1 One Nitrogen Atom 3.2.1.1 Reactivity of Azirines and Aziridines

Regio- and stereoselective functional group transformations of aziridine2-carboxylates: 14AJOC1020. Optically pure aziridinyl ligands as useful catalysts in the stereocontrolled synthesis: 14COC3045. Synthesis and reactivity of 2-(carboxymethyl)aziridine derivatives: 14CRV7954. 3.2.1.2 Synthesis of Aziridines

Recent advances in the stereoselective synthesis of aziridines: 14CRV7881. Synthesis and applications of vinylaziridines and ethynylaziridines: 14CRV7784. 3.2.2 One Oxygen Atom 3.2.2.1 Reactivity of Oxiranes

Stereoselective epoxide polymerization and copolymerization: 14CRV8129. Synthesis of cyclic carbonates from CO2 and epoxides (ionic liquids and related catalysts): 14CST1513. Vinyl epoxides in organic synthesis: 14CRV8037. 3.2.2.2 Synthesis of Oxiranes

Asymmetric organocatalytic epoxidations: 14AG(E)7406. Biomimetic iron-catalyzed asymmetric epoxidations: 14ASC261. Catalytic asymmetric Darzens reactions: 14COS361.

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Enantioselective epoxidation of unfunctionalized olefins with chiral Mn(III)-salen complexes: 14COS204. Hydrogen bond directed epoxidation: 14OBC4544.

3.3 Two Heteroatoms Advances in the chemistry of oxaziridines: 14CRV8016. Asymmetric catalytic routes to dialkyl peroxides and oxaziridines: 14ACSC1234. Catalytic diamination of olefins via NeN bond activation in di-tertbutyldiaziridinone and its analogs as nitrogen sources: 14ACR3665. Diazirine-based photoprobes for affinity-based elucidation of proteine ligand interaction: 14H(89)2697.

4. FOUR-MEMBERED RINGS 4.1 General Topics Four-membered ring-containing spirocycles: Synthetic strategies and opportunities: 14CRV8257. 4.1.1 One Nitrogen Atom Asymmetric catalysis and other advances in chemical synthesis of b-lactams: 14CRV7930. The chemistry and biological potential of azetidin-2-ones: 14EJMC(74) 619. Copper-promoted synthesis of four-membered azacycles: 14RSCA1689. Four-membered rings from isocyanides: Developments since the mid 1980s: 14ARK(2)406. Recent trends in the design, synthesis and biological exploration of blactams: 14CMC393. 4.1.2 One Oxygen or Sulfur Atom Catalytic asymmetric nucleophilic openings of 3-substituted oxetanes: 14OBC6028. Alkynyl silyl sulfides as thioketene equivalents, particularly, for b-thiolactam synthesis: 14SL2415.

4.2 Two Heteroatoms Tetrafluoroethane b-sultone derived di- and trifluoromethylation reagents: 14CCR(261)28.

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5. FIVE-MEMBERED RINGS 5.1 General Topics Synthesis of energetic nitro derivatives of pyrazoles, imidazoles, triazoles and tetrazoles: 14CJOC304. Synthesis of g-butenolides and a,b-unsaturated g-butyrolactams by addition of vinylogous nucleophiles to Michael acceptors: 14T2595. Synthesis of g-lactams and g-lactones via intramolecular Pd-catalyzed allylic alkylations: 14ACR3439. N-ylides of 1,2,3-triazoles and tetrazoles: 14H(89)2053.

5.2 One Heteroatom 5.2.1 One Nitrogen Atom Transition-metal-catalyzed asymmetric allylic dearomatizations in pyrrole and indole series: 14ACR2558. 5.2.1.1 Monocyclic Pyrroles

C-Ethynylpyrroles: synthesis and reactivity: 14UK475. Pyrrole chemistry: 14MI26. Reactions of acetylenes in superbasic media, in particular, synthesis of pyrroles: 14UK600. Recent advances (2009e13) in the synthesis of pyrroles by multicomponent reactions 14CSR4633. Recent developments in the synthesis of dipyrromethanes: 14OPP183. 5.2.1.2 Hydropyrroles

1,3-Carbon DeA strategy for [3 þ 2] cycloadditions/annulations with imines: Synthesis of functionalized pyrrolidines and related alkaloids: 14RSCA16397. Organocatalytic synthesis of pyrrolidines via cycloaddition reactions of azomethine ylides: 14COC1073. (S)-(þ)-1-(2-Pyrrolidinylmethyl)pyrrolidinedAn effective catalyst for asymmetric synthesis: 14ZOF(1)3. Recent progress towards transition metal-catalyzed synthesis of g-lactams: 14OBC1833. Synthesis of g-lactams starting from acyclic or cyclic precursors: 14COC1373.

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5.2.1.3 Porphyrins and Related Systems

Chlorins: Natural sources, synthetic developments and main applications: 14COS42. Glycoconjugates of porphyrins with carbohydrates: syntheses and biological activity: 14UK523. Meso-substituted porphyrins for dye-sensitized solar cells: 14CRV12330. Metalloporphyrins immobilized on silica as catalysts in heterogeneous processes: 14COS67. Metalemetalloporphyrin frameworks: A resurging class of functional materials: 14CSR5841. Microwave-assisted synthesis and reactivity of porphyrins: 14COS89. Multiporphyrinic cages: Architectures and functions: 14CRV8542. Porphyrinoids: Synthesis, modifications, and applications: 14THC(33)1; 14THC(34)1. Strategies toward the synthesis of amphiphilic porphyrins: 14T6685. Synthesis and functionalization of corroles; their nonlinear optical absorption properties: 14COS29. Tetrabenzotriazaporphyrins: synthesis, properties and application: 14UK657. 5.2.1.4 Indoles, Carbazoles, Related Systems, and Hydrogenated Derivatives

Alkylideneindoleninium ions and alkylideneindolenines: Key intermediates for the asymmetric synthesis of 3-indolyl derivatives: 14AJOC1036. Applications of Bartoli indole synthesis: 14CSR4728. Chiral Broensted acid-catalyzed Friedel-Crafts reaction of indoles: 14COC2108. 4,7-Dihydroindole: A synthon for the preparations of 2-substituted indoles: 14COS167. A photoinduced CeH activation of the indole system using the Witkop cyclization: 14AG(E)1208. Recent advances in the synthesis of biologically active spirooxindoles: 14T9735. Recent developments in the synthesis and applications of isatins: 14OPP317. Synthetic routes towards benzofuro[2,3-b]pyrroles and benzofuro[2,3-b] indoles: 14H(89)2029. Synthesis of spirooxindoles via organocatalytic asymmetric assembly reactions: 14ACSC743.

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Synthetic approaches to 3-(2-nitroalkyl) indoles and their use to access tryptamines and related bioactive compounds: 14CRV7108. 5.2.1.5 Isoindoles (Including Phthalocyanins and Porphyrazines)

Glycosylated metal phthalocyanines: 14COS59. Modern syntheses of sophisticated phthalocyanine-based photoactive systems: 14CAJ2676. Quadruple-decker phthalocyanines: 14JPP615. Subphthalocyanines, subporphyrazines, and subporphyrins: Nonplanar aromatic systems: 14CRV2192. Synthetic approaches to glycophthalocyanines: 14T2681. 5.2.1.6 Polycyclic Systems Including Two or More Heterocycles

1,4-Dihydropyrrolo[3,2-b]pyrrole and its p-expanded analogues: 14CAJ3036. Indolizine: a biologically active moiety: 14MCR3593. 5.2.2 One Oxygen Atom 5.2.2.1 Furans

Catalytic alkylation of furans by p-activated alcohols: 14KGS860. Chemical-catalytic approaches to the production of furfurals from biomass: 14TCC(353)41. Furans and singlet oxygen as a synthetic tool: 14CC15480. Furan-type compounds from carbohydrates via heterogeneous catalysis: 14COC547. Ionic liquids in catalytic conversion of starch-based biomaterials to hydroxymethylfurfural: 14COC1149. Synthetic strategy for multisubstituted-fused furans using main-group metal reagents: 14SL2099. The versatility of furfuryl alcohols and furanoxonium ions in synthesis: 14CC7223. 5.2.2.2 Hydrofurans

Transition metal mediated oxidative cyclization of 1,5-dienes towards cis-2,5-disubstituted tetrahydrofurans: 14OBC9492. 5.2.2.3 Annulated Furans

Catalytic asymmetric synthesis of chiral benzofuranones: 14ASC1172. Methods for the synthesis and modification of linear anthrafurandiones: 14KGS193.

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The sequential homobimetallic catalysis in the synthesis of benzofuran derivatives: 14KGS182. Synthesis and transformations of naphtho[2,3-b]furans: 14KGS674. 5.2.2.4 Five-Membered Lactones

Synthetic applications of g-hydroxybutenolides: 14COS244. 5.2.3 One Sulfur Atom Advances in the synthesis of thiophene derivatives by cyclization of functionalized alkynes: 14M15687. Photochromism of diarylethene molecules and crystals: Memories, switches, and actuators: 14CRV12174.

5.3 Two Heteroatoms 5.3.1 Two Nitrogen Atoms 5.3.1.1 Pyrazoles and Annulated Pyrazoles

Chemistry of pyrazole-3(5)-diazonium salts: 14KGS1318. Synthesis of nitropyrazoles: 14HAC872. Environment-friendly synthesis of bioactive pyrazoles: 14COC115. Pyrazolopyrimidines: synthesis, chemical reactions and biological activity: 14IJAR474. 5.3.1.2 Imidazoles and Annulated Imidazoles

Advances in the synthesis of imidazo[1,5-a]- and imidazo[1,2-a]quinoxalines: 14UK820. Advances in the synthetic methods of benzimidazoles: 14CJOC495. Synthesis and reactions of safe diazo-transfer reagent: Guanidino diazonium salt (azide imidazolinium salt): 14YGK14. Synthesis and bioactivity of fluorinated benzimidazoles and [a]- and [b] annulated benzimidazoles: 14KGS831. Radziszewski reaction as efficient method to synthesise imidazoles: 14COS824. 5.3.2 One Nitrogen and One Oxygen Atom 5.3.2.1 1,2-Heterocycles

Construction of N,O-heterocycles via copper-free click reactions of nitrile oxides: 14CJOC1092.

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5.3.2.2 1,3-Heterocycles

Chiral oxazolidine catalyst for asymmetric synthesis: 14H(89)1. Progress in the synthesis of 2-substituted benzoxazoles: 14CJOC1048. Synthesis and reactivity of oxazol-5-(4H)-ones as 1,3-dipoles: 14COC2691. Transition metalemediated synthesis of oxazoles: 14H(89)2479. 5.3.3 One Nitrogen and One Sulfur Atom A biocompatible, efficient 2-cyanobenzothiazole-based click reaction and its applications: 14OBC865. Electron-transfer processes in highly correlated electron systems of thiazyl radicals: 14BCJ234. 4-Oxothiazolidines with exocyclic C]C bond(s): Synthesis, structure, reactions and bioactivity: 14COC1108. The progress in the chemistry and biological activity of the 4-thiazolidinones: 14EJMC(72)52. Recent advances in the synthesis of 2-substituted benzothiazoles: 14RSCA60176. Synthesis and biological activity of oxoindolinylidene derivatives of thiazolidin-4-ones: 14KGS1649. Thiazolothiadiazoles and thiazolooxadiazoles: Synthesis and biological applications: 14S1709. 5.3.4 Two Sulfur Atoms Development of p-electron systems based on M(dmit)(2) (M ¼ Ni and Pd; dmit: 1,3-dithiole-2-thione-4,5-dithiolate) anion radicals: 14BCJ355.

5.4 Three Heteroatoms 5.4.1 Three Nitrogen Atoms 5.4.1.1 Monocyclic Systems

Catalysis by 1,2,3-triazole- and related transition-metal complexes: 14CCR(272)145. Current developments in the syntheses of 1,2,4-triazole compounds: 14COC359. Progresses in syntheses and applications of bis-1,2,3-triazoles: 14CJOC92. Progress of 3-azido-1,2,4-triazole and its derivatives: 14HAC100. Reactions of metallocarbenes derived from N-sulfonyl-1,2,3-triazoles: 14CSR5151.

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Recent applications of click reaction in the syntheses of 1,2,3-triazoles: 14COS647. Supramolecular chemistry of click linear oligo- and poly(amide-triazole) s: 14SL2246. Supramolecular interactions of 1,2,3-triazoles: 14CSR2522. 1,2,3-Triazole fragment formation as the source of biological activity using 1,3-dipolar cycloaddition: 14EJOC3289. 5.4.1.2 Annulated Triazoles

Direct routes to thiazolo[3,2-b]- and -[2,3-c]triazoles by cyclization: 14PSS157. 5.4.2 Two Nitrogen Atoms and One Oxygen, Sulfur or Selenium Atom The synthetic routes to azolyloxadiazoles: 14JHC1215. Recent advances in the chemistry and synthetic applications of amino1,3,4-thiadiazoles: 14JHC1558. Recent developments in the synthesis and applications of 1,2,5-thia- and selenadiazoles: 14OPP475. 1,3,4-Thiadiazole. Synthesis, reactions, and applications: 14CRV5572.

5.5 Four Heteroatoms Mercaptoalkanoic acids as versatile synthons in the syntheses of thiasteroid analogues and selenathiadiazoles: 14PSS6. Tetrazoles as carboxylic acid isosteres: chemistry and biology: 14JIP15.

6. SIX-MEMBERED RINGS 6.1 General Nitroalkenes in 14RSCA51794.

the

synthesis

of

6-membered

heterocycles:

6.2 One Heteroatom 6.2.1 One Nitrogen Atom 6.2.1.1 Pyridines

Enantioselectively-catalyzed reactions with (E)-2-alkenoylpyridines, their N-oxides, and the corresponding chalcones: 14CRV6081. Metal complexes with pyridyl azolates: Design, preparation and applications: 14CCR(281)1.

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Metal-free multicomponent syntheses of pyridines: 14CRV10829. Research progress on the synthesis of energetic pyridines: 14CJOC1288. 6.2.1.2 Pyridinium Compounds, Ylides, Pyridine N-Oxides

Progress of 3-aminopyridinium-based synthetic receptors in anion recognition: 14RSCA20114. 6.2.1.3 Applications of Pyridines

Synthetic nicotinamide cofactor analogs for redox chemistry: 14ACSC788. 6.2.1.4 Bipyridines and Related Systems

Application of bipyridyl complexes in coupling reactions: 14CJOC693. 6.2.1.5 Hydropyridines

2,3-Dihydropyridin-4(1H)-ones and 3-aminocyclohex-2-enones: Synthesis, functionalization, and applications to alkaloid synthesis: 14SL2536. Optically active 3-substituted piperidines by ring expansion of prolinols and derivatives: 14CEJ4516. Reactions of 1,2- and 1,4-dihydropyridines: 14COC1159. 2,2,6,6-Tetramethylpiperidine 1-oxyl radical (TEMPO) and its derivatives: Synthesis and applications. 14COC459. 6.2.1.6 Pyridines Annulated with Carbocycles

Bischler-Napieralski reaction in the syntheses of isoquinolines: 14AHC(112)183. Carbonecarbon bond activation with 8-acylquinolines: 14TCC(346)85. Come-back of phenanthridine and phenanthridinium derivatives in the 21st century: 14BJOC2930. Doebner, Doebnerevon Miller, and KnoevenageleDoebner reactions in quinoline syntheses: 14COS701. Metal complex catalysis in the synthesis of quinolines: 14JOM(768)75. Recent advances in the synthesis of quinolines: 14RSCA24463. Recent syntheses of 1,2,3,4-tetrahydroquinolines, 2,3-dihydro-4(1H)quinolinones and 4(1H)-quinolinones using domino reactions: 14M204. The Povarov catalytic asymmetric aza-DielseAlder synthesis of 1,2,3,4tetrahydroquinolines: 14S135.

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6.2.1.7 Pyridines Annulated With Heterocycles

Functionalization of imidazo[1,2-a]pyridines by metal-catalyzed crosscoupling reactions: 14EJOC5119. Malononitrile as a key reagent in multicomponent reactions for the synthesis of pharmaceutically important pyridines: 14COC2513. Synthesis and properties of thiazolo- and oxazolo[3,2-a]quinolinium systems and their hydrogenated derivatives: 14KGS992. 6.2.2 One Oxygen Atom 6.2.2.1 Pyrans and Hydropyrans

N-Heterocyclic carbene catalysis for access to the 3,4-dihydropyran-2one skeleton: 14EJOC5631. 6.2.2.2 Annulated Pyrans

Chromenes, fused chromenes, and dihydrobenzo[h]chromenes in organic synthesis: 14CRV10476. Pechmann reaction in the synthesis of coumarin derivatives: 14AHC(112)1. Synthesis and transformation of halochromones: 14COS317. Synthesis of pyranopyrans from carbohydrates: 14COC1686. The use of ortho-quinone methides, particularly, in diastereocontrolled syntheses of benzopyran derivatives: 14ACR3655.

6.3 Two Heteroatoms 6.3.1 Two Nitrogen Atoms 6.3.1.1 1,3-Heterocycles: Monocyclic Pyrimidines and Hydropyrimidines (Except Pyrimidine Nucleoside Bases and Nucleosides)

Barbituric acids in the construction of coordination and supramolecular compounds: 14CCR(265)1. Catalytic asymmetric Biginelli reaction for the enantioselective synthesis of 3,4-dihydropyrimidinones: 14COC687. 6.3.1.2 Annulated Pyrimidines (Except Purines)

Advances in metal-catalyzed cross-coupling reactions of halogenated quinazolinones and their quinazoline derivatives: 14M17435. Recent advances in 4(3H)-quinazolinone synthesis: 14RSCA12065. Synthesis of fused pyrimidine derivatives using NCNCC þ C approach: 14ZOF(3)3. Synthesis, reactions, and applications of pyranotriazolopyrimidines: 14EJC681.

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6.3.1.3 Pyrimidine Nucleoside Bases and Purines

Microwave synthesis of guanine and purine analogs: 14CMW155. 6.3.1.4 Nucleotides and Nucleosides

Bioactive carbocyclic nucleoside analogsdSyntheses and properties of entecavir: 14COC2808. Multicomponent reactions in nucleoside chemistry: 14BJOC1706. Pd-catalyzed Suzuki reaction of unprotected nucleosides and nucleotides in aqueous solvents: 14RSCA18558. Recent developments in the synthesis of substituted purine nucleosides and nucleotides: 14COC2072. Recent progress in the syntheses of carbocyclic nucleosides: 14CJOC2202. Synthesis and biological properties of azanucleoside derivatives (nucleoside analogs where the furanose ring is replaced by a nitrogen-containing ring or chain): 14EJOC2201. 6.3.1.5 Nucleic Acids

Quinone methides and their biopolymer conjugates as reversible DNA alkylating agents: 14COC44. mRNA display: from basic principles to macrocycle drug discovery: 14DDT388. Recognition of mismatched (non-Watson-Crick) base pairs in DNA by small molecules: 14CSR3630. 6.3.1.6 1,4-Heterocycles: Pyrazines and Hydropyrazines

Quinoxaline macrocycles: 14AHC(112)51. Synthesis of pyrazino[2,3-d]pyrimidine (pteridine) derivatives from different heterocycles: 14PHCH194. 6.3.2 One Nitrogen and One Oxygen or Sulfur Atom Synthesis of 3,4-dihydro-2H-1,4-benzoxazines and their oxo derivatives: 14COS676. Fused 1,4-benzothiazine ring systems from o-aminothiophenol and its derivatives: 14IJHC223.

6.4 Three Heteroatoms Privileged s-triazines: Structure and pharmacological applications: 14FMC463. Supramolecular assembly of melamine and its derivatives: 14RSCA1708.

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7. RINGS WITH MORE THAN SIX MEMBERS 7.1 Seven-Membered Rings 1,5-Benzothiazepines: 14JGT1769. Fused 1,4-benzothiazine ring systems as versatile synthons to construct 1,5-benzothiazepines: 14ACS651. Microwave-assisted synthesis of benzo-fused seven-membered azaheterocycles: 14MROC55. Recent advances in dibenzo [b,f][1,4]oxazepine synthesis: 14HC251.

7.2 Medium Rings The aminoacyl incorporation reaction in the synthesis of medium-sized ring heterocycles: 14KGS166. Importance and synthesis of benzannulated medium-sized and macrocyclic rings: 14RSCA43241.

7.3 Large Rings 7.3.1 General Problems 7.3.1.1 Structure, Stereochemistry, Reactivity, Design

Chemical consequences of mechanical bonding in catenanes and rotaxanes: isomerism, modification, catalysis and molecular machines for synthesis: 14CC5128. Cyclic [4]rotaxanes containing two parallel porphyrinic plates: Toward switchable molecular receptors and compressors: 14ACR633. A perspective to resorcinarene crowns: 14T1111. Progress on covalently bonded calixarene-tetrathiafulvalene supramolecules: 14CJOC1992. Recent developments in the thiamacrocyclic chemistry of the latter dblock elements: 14CCR(280)176. Recent developments of thiacalixarene based molecular motifs: 14CSR4824. Triptycene-derived calixarenes, heterocalixarenes, and analogues: 14JIP261. 7.3.1.2 Synthesis

Calixarene-based chemosensors by means of click chemistry: 14CAJ2344. Progress in the synthesis and exploitation of catenanes since the millennium: 14CSR4658.

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Synthesis and use of fluorous and highly fluorinated macrocyclic and spherical molecules: 14JFC(157)84. 7.3.1.3 Applications

Calixarenes and calix[4]resorcinarenes as chiral NMR solvating agents: 14JIP1. Sixteen-membered macrolides: Chemical modifications and future applications: 14H(89)281. Transition-metal-complexed catenanes and rotaxanes: From dynamic systems to functional molecular machines: 14TCC(354)35. 7.3.2 Crown Ethers and Related Compounds Crown ether chemistry of polydentate complexing for lithium isotope separation: 14CJOC316. Direct and indirect single electron transfer (SET)-photochemical approaches for the preparation of novel phthalimide and naphthalimidebased lariat-type crown ethers: 14BJOC514.

8. HETEROCYCLES CONTAINING UNUSUAL HETEROATOMS 8.1 Phosphorus Heterocycles 8.1.1 Chemistry of Individual Classes of P-Heterocycles Highly enantioselective hydroformylation of alkenes by rhodium-diazaphospholane catalysts: 14AA29. Phosphinate-containing heterocycles: 14BJOC732. Pyridyl-functionalized, low-coordinate phosphorus heterocycles: 14CL1390. 8.1.2 Synthesis Syntheses of heteraphosphacyclanes: 14EJOC905. Microwave-assisted synthesis of P-heterocycles: 14PSS1266.

8.2 Boron Heterocycles Chalcogenocarboranes: A family of multifaceted sterically demanding ligands: 14CCR(258)72. Generation and reactivity of o-carborynes (1,2-dehydro-o-carboranes): 14DT4925.

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8.3 Silicon, Germanium, Tin, and Lead Heterocycles Research progress in benzosilole-containing organic compounds: 14CJOC1061. Synthesis of siloles and germoles that exhibit the aggregation-induced emission effect: 13MI1.

8.4 Selenium and Tellurium Heterocycles Organoselenium chemistry: 14MI27. Selenophene electronics: 14IJC440.

8.5 Other Unusual Heterocycles Chemistry of organoiron compounds (general monograph): 14MI28. 8.5.1 Metallacycles The applications of palladacycles as transition-metal catalysts in organic synthesis: 14SL2686. The chemistry of aromatic osmacycles: 14ACR341. Coordination-induced skeletal rearrangements of zirconacyclobutenesilacyclobutene fused complexes: 14CCR(270e271)2. Fused-ring metallabenzenes: 14CCR(270e271)151. Progress in synthesis and applications of bis(cyclopentadieny)titanacycles: 14CJOC865. Progresses of ring expansion reaction of small transitional metallacyclic compounds: 14CJOC1471. 8.5.2 Metal Chelates and Related Complexes Dynamic heteroleptic metal-phenanthroline complexes: from structure to function: 14DT3815. Ferrocenylimidazoles and unsymmetrically 1,10 -disubstituted ferrocenes, bearing a triazole ring directly linked to the redox unit, behave as efficient ion-pair recognition receptors: 14DT18. Fischer carbene complexes as favourite targets and vehicles for new synthetic approaches: 14DT16959. Group 13 metal (Al, Ga, In, Tl) complexes supported by heteroatombonded carbene ligands: 14CCR(275)63. Ruthenium pincer complexes: Ligand design and complex synthesis: 14CCR(276)112.

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Self-assembled M2L4 coordination cages: Synthesis and potential applications: 14CCR(275)19. Transition metal complexes with charge-compensated dicarbollide ligands: 14JOM(751)221.

APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx. doi.org/10.1016/bs.aihch.2016.09.002.

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INDEX ‘Note: Page numbers followed by “f” indicate figures and “t” indicate tables.’

A 7-ACA. See 7-Aminocephalosporanic acid (7-ACA) AcChCl. See Acetylcholine chloride (AcChCl) Acetic anhydride, 134e135 Acetoacetamides, 55e56, 79 2-Acetoacetamido-7-bromotropone, 76 Acetoacetamido-tropones, 75e76 Acetoacetamidoimide, 74e75 Acetoacetic acid oxime, 93 N-Acetoacetyl derivatives, 76 1-Acetoxyacetyl-2-carbethoxypyrrolidine, 72 N-Acetoacetyl-N-alkyl-(aryl)-hydrazones, 89e90 N-Acetoacetyl-O-benzylhydroxylamine, 94e95 Acetoacetylation, 97 of ArgoPore1-Rink-NH2 resin, 106 N-Acetoacetylhydrazine, 85 Acetonylated 1,4-oxadiazoles, 2, 98e99 2-Acetonyloxazoline, 100 Acetoxylation products, 24e25 5-Acetyl-3-aryl-2-isoxazolines, 27, 33 3-Acetyl-4-hydroxy-2-pyridones, 56 3-Acetyl-4-hydroxy-5-(S-benzylthio) methyl-3-pyrrolin-2-one, 71e72 3-Acetyl-4-hydroxy-5-(S-benzylthio) methylene-3-pyrrolin-2-one, 71e72 3-Acetyl-5-benzyl-3-pyrrolin-2-one, 69 3-Acetyl-5-carbethoxy-2-hydroxy-4methyl-pyrrole, 70 3-Acetylamino-3-(2-vinylphenyl) acrylamides, 180e181 Acetylcholine chloride (AcChCl), 5 a,b-Acetylenic oximes, 13 3-Acetylindoles, 79e80 4-Acetylpyrazolidine-3-ones, 89e90 Acid bromide, 99

Acidic thioamides, 116 Activated methylene compounds, 160e161 Activated pyridinium salt, 169 Acyl dimethylsulfonium methylides, 66e67 O-Acyl protecting group, 95 N-Acylated dipolar intermediate, 90e91 Acylation, 144e145 a-Acylation, 169 3-Acyltetramic acids, 68e69 ADA reaction. See Aza-DielseAlder reaction (ADA reaction) (S)-AgTRIP, 216e217 AIBN. See Azobisisobutyronitrile (AIBN) Aldehydes, 17, 20e21, 29, 118e119 Aldimines, 196e197 Aldoximes, 29 Alkali hydroxide, 164e165 Alkaloids, 261e262 6-ketenesanguinarine, 144 individual groups of, 262 synthesis, 262 Alkenes, 3 4-Alkoxy, 63e64 N-Alkoxycarbonyl isoxazolium salts, 9e10 N-Alkoxycarbonyl-O-propargylic hydroxylamines, 9e10 4-Alkyl-substituted 4,5dehydropiperidines, 225 N-Alkyl-a-(acetoacetamido)acetonitriles 3-acetyl tetramic acids, 74e75 N3-(Alkyl)-2-methyl-4-(2-oxo-2phenylethyl)-5-phenyl-3furamide derivatives, 61 2-Alkylidene, 106e107 Alkylidene-b-oxo esters, 106e107 Alkylideneisoxazolidine, 78 5-(3-Alkylquinolin-2-yl)-3-arylisoxazoles, 17e18

303

j

304 g-Alkylthio-b-butyrolactones, 68 Alkylthiols, 68 Alkynes, 133 Alkynone (Z)-O-methyloxime derivatives, 13 (Z)-2-Alkynone-O-methyl oxime, 12e13 Alkynyl ketones, 10e12 N-(Alkynyl)alkenamines, 212e213 Alkynylboronate, 16 2-Alkynylpiperidines, 199e200 N-Allyl 3-alkynylamines, 218 N-Allylacetoacetamide, 100 Allylamine, 100 Allylic cyclization, 205e208 4-Alumino-isoxazoles, 7e8 Amide nitrogen atom, 116 Amidoximes, 98e99 Amidrazone hydroiodide, 133e134 Amidrazones, 116e117, 116f, 119 aldehydes, 118e119 aminal, 120 aryl halides, 118 cyclic anhydride, 121 DCM, 124 2-(1,3-dioxoindan-2-ylidene) malononitrile, 119 DMAD, 121e122 ethyl chloroformate, 123e124 ethyloxalyl chloride, 125e126 excess of ammonia, 124 imidates, 122e123 itaconic anhydride, 119 ketones, 118e119 p-phenylenediisothiocyanate, 128 phthaloyl chloride, 125 silylation of amidrazones, 126 sulfinyl-bis-2,4-dihydroxybenzenethioyl, 128 synthesis of triazole from C-glucosyl amidrazones, 126e127 from chlorohydrazones, 127 triethyl orthoformate, 123e124 trifluoroacetic anhydride, 120 Aminal, 120 Amino acids, 265e266 a-Amino ester, 82e83

Index

5-Amino-3-aryl-4-phenylisoxazoles, 6e7 2-Amino-3-phenylpropanal diethyl acetal, 69 2-Amino-7-bromotropone, 76 u-Amino-vinyl iodides, 206 d-Aminoacrylates, 220 Aminoalcohols, 195e196, 220 1,3-syn-1,5-Aminoalcohols, 195e196 Aminoaldehydes, 211e212, 220e221 a-Aminoamides, 74e75 3-Aminobut-2-enamide, 56 7-Aminocephalosporanic acid (7-ACA), 102e103 a-Aminoester, 69 Aminofuran, 63 Aminohydroxydisilanes, 223 a-Aminonitriles, 20e21 b-(3-Aminopropyl)styrenes, 205 Aminothiazole, 104 Aminotropolone, 75e76 Aminotropone, 75e76 Ammonia, excess of, 124 Analgesic, 100e101 Anhydrobases, syntheses of benzologs, 162e177 pyridinium bases, 162e163 quaternary pyridinium salts, 164e177, 166t reactions, 182 by ring formation, 177e180 by ring transformation, 182 Anilide, 172 Anilines, 233e234 Annulated furans, 271e272 (RS,R,S)-Anti-adducts, 196e197 (RS,S,R)-Anti-adducts, 196e197 Anti-triazin-5-one, 133e134 Antibiotics, 262 Aromatic aldehydes, 4e5 Aromatic nucleophilic substitution reaction, 151 Aromatization, 32 Aryl bromides, 118 Aryl halides, 118 Aryl moiety, 22 3-Aryl-2-cyano-1-methylpiperidines, 213e214

305

Index

3-Aryl-2-isoxazolines, 2, 23, 25e35 pharmacologically active, 25f, 34e35 reactions, 32e33 structure, 30e31 synthesis, 25e30 1,3-dipolar cycloaddition, 26e29 oxime derivatives cyclization, 29e30 N-Aryl-2-methylpiperidines, 203 3-Aryl-2,5,6-triphenylpyrimidin-4(3H)ones, 130e131 2-Aryl-3-bromopiperidines, 205 4-Aryl-5-imino-3-phenyl-1H-naphthol [1,2,4]triazepine-6,11-diones, 136e137 3-Aryl-5-nitroisoxazolines, 33 3-Aryl-5-phenylthio-2-isoxazolines, 27 3-Aryl-5-substituted isoxazole 4-boronic esters, 16 3-Aryl-5-trifluoromethyl-1H-1picolinoylpyrazoles, 117e118 3-(2-Aryl-lH-indol-3-yl)-4-aroyl-5arylisoxazolines, 34 4-Aryl-substituted 4,5dehydropiperidines, 225 3-Aryl-substituted isoxazoles, 17e18 Arylacetylenes, 4e5 N-Arylated N-(3-oxobutyryl) aminomalonate diethyl esters, 53e54 Arylidene-b-oxo esters, 106e107 Arylidines, 137 3-Arylisoxazol-5-yl methanols, 17 3-Arylisoxazole-5-carbaldehydes, 24 3-Arylisoxazoles, 2, 8e9 pharmacologically active isoxazoles, synthesis of, 15e18, 15f reactions of, 20e25 3-aryl-5-vinylisoxazole side chain functionalization, 24 bis(indolyl)methanes synthesis, 24 imidazoles, 20 isoxazole ring, 20 with lithium amides, 22 with lithium phenylthiolate, 22 4-organoboron isoxazole, 23 Pd-catalyzed regioselective C-H activation, 25

3-phenylisoxazole reactivity, 21 4-phenylselenylisoxazole, 23 trapping of vinylnitrene intermediate, 21 spectroscopic techniques and DFT calculations, 18e20 synthesis of, 2e15 1,3-dipolar cycloadditions, 3e9 oxime derivatives, cyclization of, 9e15 a-Arylmethylidene-b-keto esters, 232 7-Arylpyrazolo[1,5-a]pyridines, 162e163 Arylpyrazolones, 87 6-Arylpyridone methides, 156, 158 (2-Arylpyrrolidin-1-yl)acetonitriles, 213e214 2-Arylpyrrolidines, 213e214 Aspergillus flaws (A. flaws), 34 Aspergillus niger (A. niger), 34 Asymmetric organocatalysis, 199 Au catalysts, 199e200 Auxiliary-based strategies, 196e197 Aza-DielseAlder reaction (ADA reaction), 130, 227e228 Aza-Prins reactions, 224e225 Azabicyclic 3-aryl-2-isoxazolines, 26 3-Azabicyclo[4.1.0]heptenes, 216e217 2-Azabicyclo[4.2.0]oct-1-enes, 212e213 1-Azadienes, 228e229 Azahomoadamantane, 75e76 Azetidin-2-ones, 54 Azetidines, 209 reactivity of, 267 synthesis of, 267 Aziridines, 195e196 Aziridinium intermediate, 208e209 Azirines, reactivity of, 267 Azobisisobutyronitrile (AIBN), 68 a-Azolylmethides, 173, 175

B Benzaldimines, 195e196 Benzaldoximes, 4 Benzamide oxime, 98e99 Benzamides, 21, 98e99 1-(1H-Benzimidazol-2-yl)-3-(substitutedphenyl)prop-2-en-1-ones, 34e35

306 Benzo-fused analogs general survey, 142e143 nomenclature, 143 occurrence and synthesis natural, 144 survey, 143 scope and limitation, 143 syntheses of anhydrobases, 162e182 N-unsubstituted methides synthesis, 144e162 Benzoic acid, 21 Benzologs, 144e153 from pyridinium bases and, 162e163 from quaternary pyridinium salts and attack at unsubstituted 2-position, 176e177 a-carbon atom reaction, 169e172 treatment with basic agents, 164e169 photochemical tautomerization, 152e153 a-positioned carbon atom reactions, 144e150 replacement of leaving groups at 2position, 172e176 halogen substituents, 172e174, 174t substituents, 174e176 replacement of ortho-halogen substituents, 151e152 Benzonitrile oxide, 101e102 p-Benzoquinone (BQ), 49e50 1,4-Benzoquinone, 132 Benzoyl derivatives, 145e146 Benzoyl diketone, 18 C-Benzoyl-N-phenylazomethine oxide, 78 Cis-2-Benzoyl-1hydroxycyclopropaneacetic acid b-lactone, 65 5-Benzoyl-1-phenylpyrrolidin-3-one, 78 a-Benzoylquinolone methide-type, 169 u-Benzoylstyrenes. See Chalcones N-Benzyl-2-ethenylpiperidine, 206e207 1-Benzyl-3-(1-hydroxyethyl)-4methoxy-2-pyridone, 56 S-Benzyl-L-cysteine ethyl ester, 71e72 N-Benzylaminoacetonitrile, 74e75

Index

N-Benzylated N-(3-oxobutyryl) aminomalonate diethyl esters, 53e54 Benzylidene derivative, 161e162 Bicyclic piperidine, 209e210 Bipyridines and related systems, 275 Bis-pyrazolonyl, 86 Bis-pyridinylidene, 177, 179 Bis-triazol-5-ones, 124 2,2 0 -Bis(di-p-tolylphosphino)-1, 1 0 -binaphthyl (TolBINAP), 216 N,O-Bis(trimethylsilyl)hydroxylamine, 96e97 Bisamidrazones, 129 N-Boc phenylamidrazones, 130 N-Boc-2-vinylpiperine, 207e208 1,2-Bonds, reactions forming, 229e235 ADA reaction, 227e228 aza-Prins reactions, 224e225 Mannich reactions, 222e223 miscellaneous, 226e229 2,3-Bonds, reactions forming, 235e236 aza-Prins reactions, 224e225 Mannich reactions, 222e223 miscellaneous, 226e227 3,4-Bonds, reactions forming ADA reaction, 227e228 miscellaneous, 228e229 4,5-Bonds, reactions forming, 229e231 5,6-Bonds, reactions forming, 231e233, 235e236 6,1-Bonds, reactions forming, 233e235 4-Boron isoxazoles, 22e23 BQ. See p-Benzoquinone (BQ) 5-(3-Bromo-2-oxopropyl)-3-phenyl1,2,4-oxadiazole, 98e99 Bromo-4-methylene-2-oxetanone, 50 4-Bromo-iodopiperidines, 224e225 4-(Bromoacetoacetamido) cephalosporanic acid, 102e103 2-Bromoacetoacetate, 50e51 4-Bromoisoxazoles, 22e23 N-Bromosuccinimide (NBS), 28e29, 50 Brønsted acidecatalyzed hydroalkylation of ynamides, 221e222 Brønsted-and Lewis acids, 224

307

Index

btp. See 2,6-bis(1,2,3-Triazol-4-yl) pyridine (btp) (RS)-tert-Butanesulfinamide, 196e197 n-Butanol triazoles, 121e122 Butenolides, 57, 64e65 4,6-di-tert-Butyl-3-hydroxy-1,2-quinone, 150

C CAN. See Ceric ammonium nitrate (CAN) Carbazoles, 270e271 a-Carbon atom reaction a-acylation, 169 formation of dyes, 169e170 formation of a-vinyl compounds, 170e172 CarboneCarbon bond-forming reaction, 145e148 Carbonenitrogen bonds, 116 a-(Carboxybenzoyl)quinolone methide, 148e150 S-Carlosic acid, 58e59 (R)-Carlosic acid, 58e59 Ceric ammonium nitrate (CAN), 28e29 Cetyltrimethylammonium bromide (CTAB), 28e29 Chalcones, 159e160 CHEC. See Comprehensive Heterocyclic Chemistry (CHEC) Chiral epoxides, 195e196 Chiral imidate (RS), 196e197 Chiral phosphoric acid, 199 2-Chloro compounds, 175e177 3-Chloro-4-methylene-2-oxetanone, 50e51 2-Chloro-6-methylthio analog, 175e177 4-Chloro-iodopiperidines, 224e225 Chloroacetoacetate, 50e51 2-Chloroacetoacetate, 63 4-Chloroacetoacetate, 63e64 N-Chlorobenzotriazole (NCBT), 28e29 Chlorohydrazones, triazole synthesis from, 127 2-Chloropyridinium salt, 169, 173 2-Chloroquinoline, 151e153 N-Chlorosuccinamide (NCS), 5, 28e29

3-Chlorotetronic acid, 63e64 Choline chloride (ChCl), 5 Cleavage, 162 CNIND. See 2-(1,3-Dioxoindan-2ylidene)-malononitrile (CNIND) Comprehensive Heterocyclic Chemistry (CHEC), 143 R-Configured alcohol, 52e53 Coordination compounds, 258 COX-2. See Cyclooxygenase-2 (COX-2) Coxibs, 16 a-CPA. See a-Cyclopiazonic acid (a-CPA) C-radicals, 29e30 CrO2, 8 N-Crotyl-2-vinylpiperine, 207e208 Crown ethers and related compounds, 279 CTAB. See Cetyltrimethylammonium bromide (CTAB) Cyano ester, 160e161 Cyanoacetamide, 151e152 2-Cyanoethene1,1-dithiol disodium salt, 92e93 Cyclic anhydride, 121 Cyclic hydrazones, 89 Cyclization, 121e122 Cyclocondensation of precursors, 159 Cis-1,2-Cyclohexanedicarboxylic anhydride, 121 Cyclohexanedione, 174e175 1,3-Cyclohexanedione, 154, 156 Cyclohexanone-derived b-dicarbonylcompounds, 234 Cyclooxygenase inhibitors, 15 Cyclooxygenase-2 (COX-2), 16 Cyclopenta[e-1,3,4]-oxadiazepines, 136 Cyclopentadienes, 174e175 a-Cyclopiazonic acid (a-CPA), 82e85 Cyclopropene 1,1-diesters, 3e4

D DBA. See Dibenzoylacetylene (DBA) DBH. See 1,3-Dibromo-5,5dimethylhydantoin (DBH) DBU. See 1,8-Diazabicyclo [5.4.0]undec7-ene (DBU)

308 DBA (Continued ) DCHNQ. See 2,3-Dichloro-1,4naphthoquinone (DCHNQ) DCM. See Dichloromethane (DCM); Diphenyl N-cyanimidocarbonate (DCM) Deep eutectic solvents (DESs), 4e5 Dehydropiperidines, 214 2,3-Dehydropiperidines, 221e222 Density functional theory (DFT), 18e19 calculations, 18e20 15 N NMR, 19f Deprotonated dithianes, 195e196 DESs. See Deep eutectic solvents (DESs) DFT. See Density functional theory (DFT) Di-tert-butyl-1,2-quinone, 150e151 Diacetate, 96 Diacetoxyiodo benzene (DIB), 28e29 1,1-Diacetyl-2-benzoylhydrazine, 101e102 Diaminomaleonitrile, 116e117 3,4-Diaryl-2-isoxazolinyl-5-carboxylic acids, 32e33 3,4-Diaryl-5-alkylisoxazole analogues, 16e17 3,4-Diaryl-5-hydroxy-2-isoxazol-5-yl carboxylic acids, 28 3,4-Diaryl-5-methyl-5-hydroxy-2isoxazoline intermediates, 6 3,4-Diarylisoxazole-5-carboxylic acids, 32e33 3,5-Diarylisoxazoles, 18, 24e25 Diastereoisomeric 2-[2-(pnitrobenzyloxycarbonyl)-5pyrrolidinyl]butanoic acids, 50e51 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU), 8e9 2-Diazo-1,3-dicarbonyl compounds, 66e67 Diazoacetophenone, 65 DIB. See Diacetoxyiodo benzene (DIB) a,a-Dibenzoyl methide, 169e170 Dibenzoylacetylene (DBA), 60e61 N,a-Dibenzoylisoquinolone methide, 165, 167 1,3-Dibromo-5,5-dimethylhydantoin (DBH), 205

Index

Dicarbonyl compounds, 14e15, 155, 161e162 2,3-Dichloro-1,4-naphthoquinone (DCHNQ), 129 2,4-Dichloroacetoacetates, 63e64 Dichloromethane (DCM), 3e4, 120 Dicyanonaphthoquinone, 136e137 Dienes, 210e211 3,3-Diethoxypropan-1-amine, 211e212 Diethynylpyridine, 162e164 4,5-Dihydro-1H-pyrrol-3-carboxamide derivatives, 80e81 1,2-Dihydroisoquinoline derivatives, 82 3,9-Dihydropyrazolo [1,5-a]pyridine, 90e91 Dihydropyridines, 210e211, 228 1,2 0 -Diisoquinolyl derivative, 166e169 Diketene (DK), 45e46, 131 acetoacetylation, 101e102 acting as acetoacetylating agent, 97 alkylthiols reacting with, 68 of ArgoPore1-Rink-NH2 resin with, 106 as basic reagent in pseudo-fivecomponent reaction, 60e61 cyclic hydrazones reacting with, 89 [2 + 2] cycloaddition, 51e53 enantioselective hydrogenation, 48 enol-lactone partner, 49e50 interaction with N-alkyl-and Narylhydrazones, 89e90 isocyanides reacting with, 64 one-pot three-component reaction, 91 phenylhydrazine on treatment with, 86 polymer-bound acetoacetamide, 47 as privileged synthon, 46e47 reaction with acetic acid, 102 with acyl dimethylsulfonium methylides, 66 with 3-aminobut-2-enamide, 56 with bifunctional nucleophiles, 85 with bromine, 73e74 with hydroxylamine, 93 with 2 mol of amethylphenylhydrazine, 88 with nucleophiles, 46 reactive exocyclic bond, 65

Index

in solid-phase preparation, 105 in synthesis of substituted acetoacetamido side chains, 102e103 a,b-Diketoester derivatives, 130 1,2-Diketones, 131e132 Dimedone, 154, 156 Dimethyl acetylenedicarboxylate (DMAD), 121e122 2,5-Dimethyl-3-pyrazolone, 85 2,5-Dimethyl-3,6-dicarbethoxy- pyrazine, 70 3,3 0 -Dimethyl-5-hydroxy-4,5 0 biisoxazole, 93e94 l-[3-(Dimethylamino) propyl]-3ethylcarbodiimide hydrochloride, 50e51 b-Dimethylaminovinyl aromatic ketones, 10e11 3,3-Dimethyldioxirane (DMDO), 28e29 2,5-Dimethylfuran derivative, 60 2,3-Dimethylquinoline, 144e145 2-(2, 4-Dinitrobenzyl)pyridine, 152e153 1,5-Diols, 233e234 2-(1,3-Dioxoindan-2-ylidene)malononitrile (CNIND), 119e120 Diphenyl N-cyanimidocarbonate (DCM), 124 2,2-Diphenyl-4diphenylmethylenoxetane, 48e49 1,2-Diphenyl-5-methyl-3-pyrazolone, 87 3,3 0 -Diphenyl-5,5 0 -spiro[2-isoxazoline], 101e102 2,3-Diphenylcyclopropenone, 130e131 4-Diphenylhydroxymethyl-2,5dihydrofuran-2-one, 48e49 3,5-Diphenylisoxazole, 21 Dipiperidine, 214e215 Dipiperidine alkaloids virgidivarine, 214e215 1,3-Dipolar cycloaddition, 3e9, 26e29, 148 5-amino-3-aryl-4-phenylisoxazoles synthesis, 7 3-aryl-5-phenylthio-2-isoxazoline, 27 3-aryl-5-substituted isoxazoles synthesis, 5 3-arylisoxazoles preparation, 9 5-carbonyl 3-arylisoxazoles synthesis, 3

309 3,5-disubstituted isoxazoles synthesis, 5, 8 5-hydroxy-3-aryl-5-vinyl-2-isoxazolines, 27 isoxazoles synthesis, 4 isoxazoline-fused carbocycles synthesis, 26 one-pot arylisoxazoline formation, 29 precursors of 3,4,5-trisubstituted isoxazoles, 6 reaction between ArCNO and cyclopropene 1,1-diester, 4 1,3-Dipolar intermediate, 102e103 Dipolarophiles, 2e3 Dipolarophiles, 30e31 1,3-Dipoles, 100 N,O-Diprotected tyrosine derivatives, 73e74 Disilylated esters, 126 3,5-Disubstituted isoxazoles, 10e12 3,4-Disubstituted 2-hydroxy-5nitropiperidines, 228e229 2,3-Disubstituted 2-piperidinones, 197e198 2,4-Disubstituted 3-(chloromethyl)-3,4dehydropiperidines, 224e225 4,5-Disubstituted 3-arylisoxazoles, 5e6 3-Disubstituted arylisoxazoles, 12 3,5-Disubstituted arylisoxazoles, 12 5,5-Disubstituted bromo-2-isoxazolines, 3 3,4-Disubstituted isoxazole 4-boronates, 16 3,5-Disubstituted isoxazoles, 3e5, 10e11 1,1-Disubstituted olefin, 195e196 (E)-1,2-Disubstituted olefins, 195e196 (Z)-1,2-Disubstituted olefins, 195e196 2-or 2,2-Disubstituted pent-4-en-1amines, 204 2,5-Disubstituted piperidin-4-ols, 201 2,3-trans-Disubstituted piperidines, 195e196 2,6-trans-Disubstituted piperidines, 215 2,3-Disubstituted piperidines, 196e197, 212e213 2,4-trans Disubstituted piperidines, 195e196 2,4-Disubstituted piperidines, 219e220

310 2,6-cis-Disubstituted piperidines, 222e223, 234e235 2,6-Disubstituted piperidines, 199e200, 207e208 3,4-trans-Disubstituted piperidines, 220e221, 225e226 2,3-Disubstituted tetrahydropyridines, 232 2,6-Disubstituted-4methylenepiperidines, 223 3,5-Disubstituted-5-hydroxy-2isoxazoline intermediates, 10e12 Dithioesters, 127e128 reactions, 127 DK. See Diketene (DK) DMAD. See Dimethyl acetylenedicarboxylate (DMAD) DMDO. See 3,3-Dimethyldioxirane (DMDO) DMF. See Dry dimethylformamide (DMF) DMF dimethylacetal (DMFDMA), 135 Drugs, 263e265 alkaloids, 263 substances and groups of compounds, 265 types of activity, 263e265 Dry dimethylformamide (DMF), 116e117 Dyes formation, 169e170

E EDGs. See Electron-donating groups (EDGs) Electrocyclization, 210e211 Electron-donating groups (EDGs), 18e19 Electron-withdrawing group (EWG), 5e6 Electrophilic (E), 45 b-Enaminothioesters, 22 Enol acetate intermediate, 102e103 Enolate anions, 28 Enolates, 5e6 Enyne, 214e215 Enyne cyclization, 216e219 Escherichia coli (E. coli), 34 Ester, 99, 151e152 Ethanol (EtOH), 116e117 2-Ethenyl-6-hydroxymethylpiperidin-5ols, 206e207 2-Ethenyl-6-methylpiperidin-4-ols, 206e207

Index

Ethyl 2-bromoacetoacetate, 50 Ethyl 2-cyano-3,3-bis(methylthio) acrylate, 116e117 Ethyl benzimidate, 122e123 Ethyl chloroformate, 123e124 Ethyl propionate, 133 Ethyl-1-(5-methyl-2-nitrophenyl)-3-(4methoxyphenyl)-1,2,4-triazole-5carboxylate, 125e126 Ethyloxalyl chloride, 125e126 EtOH. See Ethanol (EtOH) EWG. See Electron-withdrawing group (EWG) Exocyclic methylene group, 143

F Five-membered heterocycles, synthesis of containing one heteroatom, 57e93 containing two heteroatoms, 93e104 in solid phase, 105e107 Five-membered lactones, 272 Five-membered rings, 269e274. See also Four-membered rings; Sixmembered rings; Threemembered rings four heteroatoms, 274 heterocycles, 2 one heteroatom, 269e272 synthesis of energetic nitro derivatives, 269 synthesis with four heteroatoms thiatriazoles, 129 synthesis with three heteroatoms thiadiazoles, 127e128 triazoles, 118e127 synthesis with two heteroatoms, 116e118 three heteroatoms, 273e274 two heteroatoms, 272e273 4-Fluoroisoxazoles, 12e13 3-Fluoropiperidines, 204 Formaldehyde, 135 Four heteroatoms, 274 five-membered rings synthesis with, 129 Four-membered heterocycles, syntheses of, 48e56 acetoacetamides, 55e56 enantioselective hydrogenation of DK, 48

Index

synthesis of N-protected azetidin-2-ones, 53 UVeVIS laser irradiation, 49e50 Four-membered rings, 268. See also Fivemembered rings; Six-membered rings; Three-membered rings one nitrogen atom, 268 one oxygen atom, 268 one sulfur atom, 268 spirocycles, 268 two heteroatoms, 268 Furamides, 60e61 Furanones, 57e58 Furans, 271 Furazan, 100e101 Fused bicyclic ring systems, 90e91 Fused five-membered rings synthesis indazoles, 129 Fused ring system, 75e76

G Gauge-Invariant Atomic Orbital methods (GIAO methods), 19e20 Germanium heterocycles, 280 C-Glucosyl amidrazones, triazole synthesis from, 126e127 Gold-catalyzed asymmetric cycloisomerization of 1, 6-enynes, 216e217

H Haloamination, 203e205 a-Haloesters, 132 Halogen of 4-haloacetoacetate esters, 104 Halogen substituents, 172e174, 174t 2-Halopyridinium salts, 174, 176 Herbicidal pyrazole, 86 Herbicidal pyrroles, 79 Heterocycle(s), 100 construction, intermolecular reactions forming 1,2- and 2,3-bonds, 222e227 reactions forming 1,2- and 3,4-bonds, 227e229 reactions forming 1,2- and 4,5-bonds, 229e231

311 reactions forming 1,2- and 5,6-bonds, 231e233 reactions forming 1,2- and 6,1-bonds, 233e235 reactions forming 2,3- and 5,6-bonds, 235e236 containing unusual heteroatoms boron heterocycles, 279 germanium heterocycles, 280 lead heterocycles, 280 metal chelates and related complexes, 280e281 metallacycles, 280 other unusual heterocycles, 280e281 phosphorus heterocycles, 279 selenium heterocycles, 280 silicon heterocycles, 280 tellurium heterocycles, 280 tin heterocycles, 280 nitrogen heterocycles, 259 oxygen heterocycles, 259 sulfur heterocycles, 259 Heterocycles synthesis from amidrazones five-membered rings synthesis with four heteroatoms, 129 with three heteroatoms, 118e128 with two heteroatoms, 116e118 fused five-membered rings synthesis, 129 seven-membered synthesis rings with three heteroatoms, 136e137 six-membered rings synthesis with one heteroatom, 130 three heteroatoms, 131e135 with two heteroatoms, 130e131 1,2-Heterocycles, 272 1,3-Heterocycles, 273 N-Heterocyclic carbenes, 230 Heterocyclic chemistry books and reviews, 248e249 five-membered rings, 269e274 four-membered rings, 268 heterocycles, specialized nitrogen heterocycles, 259 oxygen heterocycles, 259 sulfur heterocycles, 259 heterocycles containing unusual heteroatoms

312 Heterocyclic chemistry (Continued ) boron heterocycles, 279 germanium heterocycles, 280 lead heterocycles, 280 phosphorus heterocycles, 279 selenium heterocycles, 280 silicon heterocycles, 280 tellurium heterocycles, 280 tin heterocycles, 280 unusual heterocycles, 280e281 monographs and reviews, 247 natural and synthetic biologically active heterocycles alkaloids, 261e262 antibiotics, 262 drugs, 263e265 miscellaneous, 265e266 sources and topics, 260e261 vitamins, 262 publishing volume, 248 rings with more than six members large rings, 278e279 medium rings, 278 seven-membered rings, 278 six-membered rings, 274e277 supplementary data, 281 three-membered rings, 267e268 topics by reaction type, 249e259 properties and applications, 256e259 reactivity, 250e252 structure and stereochemistry, 249e250 synthesis, 252e256 a-Heterocyclyl methides, 148 Heteropolyacids (HPA), 14 Holomycin, 71e72 Homoallylamine, 224e225 Homoallylic alcohols, 195e196 N-Homopropargyl amides, 212e213 HPA. See Heteropolyacids (HPA) HTIB. See Hydroxy(tosyloxy) iodobenzene (HTIB) Hydrazone, 127 Hydrazonyl chlorides, 124e125 Hydroamination, 201e203 Hydrofurans, 271 Hydrogenated derivatives, 270e271

Index

Hydropalladation, 212e213 Hydropyrans, 276 Hydropyrazines, 277 Hydropyridines, 275 Hydropyrimidines, 276 Hydropyrroles, 269 Hydroxamic acid, 94e95 5-Hydroxy-2-isoxazolines, 32 5-Hydroxy-3-aryl-2-isoxazoline intermediates, 5e6 5-Hydroxy-3-aryl-5-vinyl-2-isoxazoline intermediates, 27 5-Hydroxy-3-aryl-5-vinyl-2-isoxazolines, 27 5-Hydroxy-3, 4-diarylisoxazole derivatives, 28 N-Hydroxy-4-toluenesulfonamide (TsNHOH), 12 3-Hydroxy-5-methylisoxazole, 94e95 5-Hydroxy-5-vinyl-2-isoxazolines, 33 Hydroxy(tosyloxy)iodobenzene (HTIB), 12 4-Hydroxyacetoacetate, 63e64 b-(N-Hydroxyamino)vinyl ketones, 10e12 Hydroxyethyl sulfone resin, 8e9 2-Hydroxyethylpiperidines, 199 a-Hydroxyketones, 57, 134e135 Hydroxylamines, 14 Hydroxylaminoenoates, 226 N-Hydroxylsulfonamides, 97 N-(2-Hydroxypropyl) acetoacetamide, 100 (e)-4-Hydroxypyrrolidin-2-one, 63e64 Hypervalent iodine reagents, 28e29

I ILs. See Ionic liquids (ILs) Imidates, 122e123 Imidazol-1-ylcarboxamidrazone, 131 Imidazoles, 20e21, 98 and annulated imidazoles, 272 Imidrazones reaction acetic anhydride, 134e135 alkynes, 133 arylidines, 137 1,4-benzoquinone, 132

313

Index

dicyanonaphthoquinone, 136e137 diketones, 131 formaldehyde, 135 a-haloesters, 132 a-hydroxyketones, 134 ketoamides, 133 a-ketoesters, 133e134 1,4-naphthoquinone, 132 N-Imines, 90e91 Iminium ion, 221e222 3-Imino-2,3-dihydrothiophene derivative, 93 a-Iminoesters, 235e236 3-(1-Iminoethyl)-4-hydroxy-2-pyridone, 56 l-Iminopyridinium, 90e91 Indazoles, 129 Indoles, 270e271 Indoline, 181e182 Inflammatory diseases, 16 Intermolecular heterocycle construction reactions forming 1,2- and 2,3-bonds, 222e227 reactions forming 1,2- and 3,4-bonds, 227e229 reactions forming 1,2- and 4,5-bonds, 229e231 reactions forming 1,2- and 5,6-bonds, 231e233 reactions forming 1,2- and 6,1-bonds, 233e235 reactions forming 2,3- and 5,6-bonds, 235e236 Intramolecular pathways via ring-closing reactions ring-closing reactions forming 1,2-bond, 195e211 ring-closing reactions forming 2,3-bond, 211e214 ring-closing reactions forming 3,4-bond, 214e222 4-Iodopiperidines, 224e225 N-Iodosuccinamide (NIS), 9 Ionic liquids (ILs), 12, 258e259 Ir-catalyzed coupling of vinyl aziridines, 201

Iridium-catalyzed allylic amination, 206e207 Isocyanides, 64 Isoindoles, 271 Isolable blue methide, 152e153 (4S)-Isomer, 52e53 Isomeric 3-hydroxy-5-methylisoxazole, 93e95 (E)-Isomers, 96e97 (Z)-Isomers, 96e97 Isopropanolamine, 100 Isoquinoline N-oxide, 155 Isoquinolinium bis(ethoxycarbonyl) methylide, 79 Isoquinolone series, 180e181 Isothiocyanate reaction, 150 Isoxazole(s), 2, 6, 10e11, 13e15, 18, 20e24, 32e33 moiety, 24 rings, 20 Isoxazolines, 2, 29e30 D2-Isoxazolines, 25, 30 Isoxazolium N-ylides, 20 Isoxazolyl-carbaldehydes, 24 Isoxazolyl-methanol substrates, 24 Isoxazolyl-oxirane, 23e24 Itaconic anhydride, 119

J Jørgensen’s catalyst, 199

K Ketene, 45, 100 6-Ketenesanguinarine, 144 2-(2 0 -Ketoalkyl)piperidines, 199e200 Ketoamides, 133 3-Ketoenamines, 156 Ketoester, 133e134, 150 b-Ketohydrazides, 87e88 Ketones, 118e119 Kr€ ohnke-Mukaiyama salt, 169

L LaceyeDieckmann reaction, 73e74 (3R,4R)-b-Lactam, 52 (3S,4S)-b-Lactam, 52

314 b-Lactone, 48e49, 68 ring, 101e102 Lansoprazole, 163e164 Large rings, 278e279 LDA. See Lithium diisopropylamide (LDA) Lead heterocycles, 280 Leaving groups (LG), 32 Li+ chelation, 22 Lithium diisopropylamide (LDA), 96 Lithium phenylacetonitrile, 6e7 4-Lithiumisoxazole, 22e23

M Maleic anhydride, 121e122 Mannich reactions, 222e223 Mannich-type intramolecular cyclization of aminoallylsilanes, 223 Marine organisms, heterocycles produced by, 266 mCPBA. See metachloroperbenzoic acid (mCPBA) MCRs. See Multicomponent reactions (MCRs) MDR-TB. See Multidrugresistant M. tuberculosis (MDR-TB) Medium rings, 278 8-Membered homologue, 209e210 Mercaptoalkanoic acids, 274 Mercaptopyrazoles, 116e117 metachloroperbenzoic acid (mCPBA), 29 Metal chelates and related complexes, 280e281 Metal-catalyzed reactions, 253e254 Metallacycles, 280 Metathesis reactions, 214e215 Methides, 151e152 5-Methoxy-2-(3-phenylisoxazol-5-yl) phenol, 18 4-Methoxy-3-(10-silyloxyethyl)azetidin2-one, 54 N-Methoxyacetocetamide, 60 N-Methoxyquinolinium salt, 154, 157 b-Methoxyvinyltrifluoromethyl ketones, 117e118 6-Methyl derivative, 56 Methyl ester, 32e33

Index

b-Methyl substituted aminoaldehyde, 220e221 Methyl vinyl ketone (MVK), 19, 27 5-Methyl-1H-1,2,3-triazole-modified peptidomimetics, 91e92 5-Methyl-2-aryl-3-pyrazolones, 87 3-Methyl-2-sulfonylisoxazolones, 97 1-Methyl-2, 4-pyrrolidione-5(N-methylacetamide), 73 5-Methyl-3-isoxazolol, 96e97 5-Methyl-3-pyrazolone, 85 2-Methyl-5-phenyl-1,3,4-oxadiazole, 101e102 2-Methyl-5,5-diphenylpiperidine, 202e203 N 0 -Methyl-DL-aspartimide, 74e75 N-Methylaminoacetonitrile, 74e75 C-Methylated products, 166e169 N-Methylated products, 166e169 Methylenecyclopropane, 209e210 4-Methyleneoxetan-2-one, 45 6-Methylidene-1,3-oxazinane, 212e213 3-Methylisoxazol-5-one, 93e94 (R)-4-Methyloxetan-2-one, 48 a-Methylphenylhydrazine, 88e89 2-Methylpiperidine, 202e203 4-Methylthioquinolinium salt, 176e177, 179 Michael addition, 195e201 application of intramolecular nucleophilic substitution, 195 asymmetric intramolecular aza-Michaeladdition, 199 chiral sulfinamides, 197e198 propargylic alcohols, 199e200 Rh-catalyzed enantioselective C-arylation, 201 MichaeliseBecker reaction, 73e74 Microwave irradiation (MW irradiation), 116e117 MnO2, 8 Monoamide, 169, 173 Monocyclic pyrimidines, 276 Monocyclic pyrroles, 269 MTB. See Mycobacterium tuberculosis (M. tuberculosis)

Index

Multicomponent reactions (MCRs), 47 Multidrugresistant M. tuberculosis (MDRTB), 34e35 Multinuclear magnetic resonance, 18 Muscimol, 96 MVK. See Methyl vinyl ketone (MVK) MW irradiation. See Microwave irradiation (MW irradiation) Mycobacterium tuberculosis (M. tuberculosis), 34e35 Mycotoxin DL-b-cyclopiazonic acid, 82e83

N NaBArF. See Sodium tetrakis[3,5bis(trifluoromethyl)phenyl]borate (NaBArF) 1,8-Naphthalimide derivative, 148e149 1,4-Naphthoquinone, 132 N-Naphthoyl-(S)-tert-leucinate (NTTL), 209e210 Natural active heterocycles alkaloids, 261e262 antibiotics, 262 drugs, 263e265 miscellaneous, 265e266 amino acids and peptides, 265e266 enzymes, coenzymes, and models, 265 heterocycles produced by marine organisms, 266 other topics, 266 plant metabolites, 266 sources and topics, 260e261 vitamins, 262 NBS. See N-Bromosuccinimide (NBS) NCBT. See N-Chlorobenzotriazole (NCBT) NCS. See N-Chlorosuccinamide (NCS) NIS. See N-Iodosuccinamide (NIS) Nitrenes, 77 Nitrile group, 63 Nitrile oxide(s), 3, 29 intermediates, 4 Nitro compound, 164e165 Nitrobenzylidene derivative, 160e161 5-Nitrofuran-2-carbohydroxamoyl chloride, 100e101

315 Nitrogen, 68e92 acetoacetamides, 79 arylpyrazolones, 87 condensation of ketone, 71e72 conversion of tetramic acid, 69 copper-free synthesis, 91e92 DK reaction, 73e74 with bifunctional nucleophiles, 85 four-component reaction, 80 fused ring system, 75 heterocycles, 259 interaction of DK, 89e90 nitrenes, 77 one-pot three-component reaction, 91 and oxygen atoms, 93e102 acetoacetylation with DK, 101e102 O-acyl protecting group, 95 allylamine, 100 benzamide oxime, 98e99 1,3-dipolar cycloaddition reactions, 100 DK acting as acetoacetylating agent, 97 DK attacks, 94 DK reacting with acetic acid, 102 plant protection agent, 94e95 and sulfur atoms, 102e104 treatment of phenylhydrazones, 88 1-Nitrogen-substituted 2-picolinium salts, 170e172 Nitroolefins, 228e229 3-Nitropiperidines, 228e229 Nitroso-DielseAlder adducts, 215 Nonconventional synthetic methodologies, 252e253 2,5-Norbornadiene, 130 NTTL. See N-Naphthoyl-(S)-tertleucinate (NTTL) Nucleophilic hydrazine addition, 130e131 Nucleophilic sites (Nu sites), 45 Nucleophilic substitution, 195e201 application of intramolecular nucleophilic substitution, 195 chiral sulfinamides, 197e198 Rh-catalyzed enantioselective C-arylation, 201

316 Nucleophilic substitution (Continued ) synthesis of disubstituted piperidines, 195e196 Nucleophilic vinyl substitution, 156

O Olefinic azabicyclic derivatives, 26 One heteroatom, 57e93. See also Three heteroatoms; Two heteroatoms five-membered rings one nitrogen atom, 269e271 one oxygen atom, 271e272 nitrogen, 68e92 oxygen, 57e68 six-membered rings one nitrogen atom, 274e276 synthesis, 130 sulfur, 92e93 three-membered rings, 267e268 one nitrogen atom, 267 one oxygen atom, 267e268 One nitrogen atom five-membered rings carbazoles, 270e271 1,2-heterocycles, 272 1,3-heterocycles, 273 hydrogenated derivatives, 270e271 hydropyrroles, 269 indoles, 270e271 isoindoles, 271 monocyclic pyrroles, 269 one oxygen atom and, 272e273 one sulfur atom and, 273 porphyrins and related systems, 270 four-membered rings, 268 six-membered rings applications of pyridines, 275 bipyridines and related systems, 275 hydropyridines, 275 one oxygen atom and, 277 one sulfur atom and, 277 pyridines, 274e275 pyridines annulated with carbocycles, 275 pyridines annulated with heterocycles, 276

Index

pyridinium compounds, ylides, pyridine N-oxides, 275 three-membered rings aziridines, synthesis of, 267 azirines and aziridines, reactivity of, 267 One oxygen atom five-membered rings annulated furans, 271e272 five-membered lactones, 272 furans, 271 1,2-heterocycles, 272 1,3-heterocycles, 273 hydrofurans, 271 two nitrogen atoms and, 274 four-membered rings, 268 six-membered rings annulated pyrans, 276 pyrans and hydropyrans, 276 three-membered rings reactivity of oxiranes, 267 synthesis of oxiranes, 267e268 One sulfur atom five-membered rings, 272 four-membered rings, 268 two nitrogen atoms and, 274 One-pot multistep approaches, 8 One-vessel four-component reaction, 82 Organic conductors, 257e258 Organic synthesis, heterocycles as intermediates in, 251 Organocatalysts, 252 4-Organoselenylisoxazoles, 13e14, 22e23 Ortho-aroylation products, 24e25 Ortho-halogen substituents replacement, 151e152 Ortho-hydrogens, 24e25 Orthoester, 196e197 (3Z)-1-Oxa-5-azahexa-1,3,5-trienes, 20 1,3,4-Oxadiazepines, 136 1,3,4-Oxadiazoles, 101e102 2H-1,3-Oxazine, 20 Oxazol-2-one, 95e96 Oxazole, 97e98 Oxetane, 49e50 N-Oxides, 153e155 Oxime acid, 94e95

Index

Oxime derivatives cyclization, 9e15, 29e30 Au-catalyzed synthesis of 3-aryl-4fluoroisoxazoles, 12 3,5-disubstituted arylisoxazoles, 11 gold-catalyzed cycloisomerization, 13 HPA, 14 4-organoselenylisoxazoles, 14 regioselective accessing, 12 3-and 5-substituted-arylisoxazoles, 11 synthesis of isoxazoles, 10 TBAF, 14 Oximes, 29e30 Oxiranes reactivity of, 267 synthesis of, 267e268 3-Oxobutanamines, 222e223 2-Oxobutyric acid ethyl ester, 134 N-(3-Oxobutyryl) aminomalonate esters, 54 2-(2-Oxoindolin-3-ylidene) malononitrile, 119e120 Oxone, 4 Oxygen, 57e68 DK, 60e61 facile three-component reaction, 61 heterocycles, 259 b-lactones, 68 reactive exocyclic bond of DK, 65 S-carlosic acid, 58 stereoisomers of nodulisporic acid A, 62e63 Oxygen trapping, 49e50

P PEG. See Polyethylene glycol (PEG) Penicillium charlesii (P. charlesii), 58 Peptides, 265e266 Pharmacological active 3-aryl-2isoxazolines, 34e35 Pharmacologically active isoxazoles synthesis, 15e18, 15f 5-(3-alkylquinolin-2-yl)-3-aryl isoxazoles synthesis, 17 3,5-diarylisoxazole antihyperglycemic agents synthesis, 18 valdecoxib synthesis, 16

317 2-Phenacylthiopyridinium salts, 166, 168 1,10-Phenanthroline-5,6-dione, 131 Phenyl vinyl sulfide, 27 3-Phenyl-1H-benzo( f )indazole-4,9dione, 129 N-Phenylacetoacetohydroxamic acid, 97 Phenylacetone, 6 p-Phenylenediisothiocyanate, 128 (R)-1-(1-Phenylethyl)-3,5-bis[(E)arylmethylidene]tetrahydro4(1H)-pyridinones, 31, 34e35 Phenylhydrazine, 86 Phenylhydrazones treatment, 88 N-Phenylhydroxylamine, 97 3-Phenylisoxazole, 21 3-(Phenylsulfanyl)piperidines, 205 N-2,5-Phenyltetrazole, 101e102 Phenylthiophthalimide (PhthSPh), 205 Phosphomolybdic acid (PMA), 224 Phosphorane, 61e62 Phosphorus heterocycles, 279 Photo reactions, 253e254 Photochemical reactions, 148e150 Photochemical tautomerization, 152e153 Photochromic 2-benzyl-3benzoylqunolones, 181e182 Photovoltaics, 257e258 Phthaloyl chloride, 125 PhthSPh. See Phenylthiophthalimide (PhthSPh) 2-Picoline, 142e143 Piperidin-4-ols, 222e223 2,4,6-cis-Piperidin-4-ols, 212e213 Piperidine, 195e196 methods for synthesis, 194 moiety, 193 ring, 194e195 2-Piperidinone, 215 Plant metabolites, 266 PMA. See Phosphomolybdic acid (PMA) PMP-protected homoallylamine, 224e225 Polyethylene glycol (PEG), 118 Polymer-bound acetoacetamide, 47 Polymers, 258 Polyphosphoric acid (PPA), 88 Porphyrins and related systems, 270

318 a-Positioned carbon atom reactions acylation, 144e145 carbonecarbon bond-forming reaction, 145e148 photochemical reactions, 148e150 reduction, 148 side-chain ring formation, 150 thermal reactions, 148e150 PPA. See Polyphosphoric acid (PPA) L-Proline, 208e209 L-Proline-derived Jørgensen-type catalyst, 230e231 Propargyl alcohol, 17 Propargyl derivatives, 14 Propargylic alcohols, 199e200 Propargylic N-hydroxylamines, 14 N-Protected amines, 225 Pyrans, 276 2-Pyranylpyridine, 148e150 Pyrazines, 277 Pyrazole(s), 106e107, 116e118 and annulated pyrazoles, 272 hydrochloride derivatives, 117e118 Pyrazolin-3-ones, 88e89 Pyrazolines. See Cyclic hydrazones Pyrazolo[1,5-a]pyridine type derivative, 90e91 Pyrazolo[3,4-e][1,2,4]triazines, 135e136 Pyrazolone, 85, 87 3-Pyrazolone isomers, 86 Pyridine(s), 130, 274e275 annulated with carbocycles, 275 annulated with heterocycles, 276 applications, 275 bases a-positioned carbon atom reactions, 144e150 photochemical tautomerization, 152e153 replacement of ortho-halogen substituents, 151e152 Pyridinium bases, anhydrobases syntheses, 162e163 Pyridinium compounds, ylides, pyridine N-oxides, 275 Pyridinium salt, 148e149 Pyridmethines, 143

Index

Pyrido[1,2-a]azepines, 143 Pyrido[1,2-a]azepine series, 162 Pyridomethenes, 143 Pyridone, 76e77 2-Pyridone methide series compounds, 142e143 Pyridone methide(s), 153e154, 162e163 2-Pyridone methides(2-methylene-1,2dihydropyridines) general survey, 142e143 nomenclature, 143 occurrence and synthesis natural, 144 survey, 143 scope and limitation, 143 syntheses of anhydrobases, 162e182 N-unsubstituted methides synthesis, 144e162 2-Pyridylacetate ester, 163e164 2-Pyridylamidrazone, 131e132 Pyrimidines, 130e131 Pyrone, 76e77 Pyrophthalones, 145, 147 1H-Pyrrole-3-carboxamide derivatives, 80 Pyrrole-3-carboxamides, 105e106 Pyrroles, 105 Pyrrolidine-2-ones, 53e54 Pyrrolidine-2,4-diones, 73 Pyrrolinones, 77

Q Quaternary 2-picolinium hydroxide, 142e143 Quaternary pyridinium salts, 166t a-carbon atom reaction, 169e172 replacement of leaving groups at 2-position, 172e176 halogen substituents, 172e174, 174t substituents, 174e176 treatment with basic agents, 164e169 unsubstituted 2-position, 176e177 Quinaldinium salt, 172 Quinaldyl lithium, 144, 146 Quinine-based catalyst, 199 Quinoline-1-oxide, 154e155 Quinolines, 144 Quinolone methides, 144e145

319

Index

2-Quinolone, 142e143 Quinolyl acetate ester and phenacyl bromide, 166e169 2-Quinolyl-b-tropolone, 149e150 2-Quinolylacetonitrile, 145e146 Quinophthalone, 145, 147

R Rac-porantheridine, 215 Racepihalosaline, 215 O-Radical intermediates, 29e30 RCM. See Ring-closing metathesis (RCM) Reductive amination, 195e201 application of intramolecular nucleophilic substitution, 195 chiral sulfinamides, 197e198 Rh-catalyzed enantioselective Carylation, 201 Ring expansion reactions, 208e210 Ring formation anhydrobases syntheses, 177e180 N-unsubstituted methides synthesis, 155e162 Ring rearrangement reactions, 208e210 Ring synthesis, 256 Ring transformation anhydrobases syntheses, 182 N-unsubstituted methides synthesis, 162 Ring-chain tautomerism, 87e88 Ring-closing metathesis (RCM), 214 Ring-closing reactions forming 1,2-bond allylic cyclization, 205e208 electrocyclization, 210e211 haloamination, 203e205 hydroamination, 201e203 Michael addition, 195e201 nucleophilic substitution, 195e201 reductive amination, 195e201 ring expansion reactions, 208e210 ring rearrangement reactions, 208e210 sulfenoamination, 203e205 forming 2,3-bond, 211e214 forming 3,4-bond enyne cyclization, 216e219 metathesis reactions, 214e215

miscellaneous, 220e222 Ring-rearrangement metathesis (RRM), 214e215 Rings with more than six members large rings, 278e279 medium rings, 278 seven-membered rings, 278 RRM. See Ring-rearrangement metathesis (RRM)

S SAR. See Structureeactivity relationship (SAR) SchotteneBaumann benzoylation, 169 Selenium heterocycles, 280 two nitrogen atoms and, 274 Semisquaraine, 169e171 SET. See Single electron transfer (SET) Seven-membered rings, 278 synthesis with three heteroatoms 1,3,4-oxadiazepines, 136 1,2,4-triazepines, 136e137 Side-chain ring formation, 150 Silicon heterocycles, 280 Silylation of amidrazones, 126 Single electron transfer (SET), 279 Six-membered rings, 274e277. See also Five-membered rings; Fourmembered rings; Threemembered rings intermolecular heterocycle construction, 222e236 intramolecular pathways via ring-closing reactions, 195e222 intramolecular ring-closing reactions, 194e195 methods for piperidine synthesis, 194 nitroalkenes, 274 one heteroatom, 274e276 one oxygen atom, 276 piperidine ring, 194e195 synthesis with one heteroatom, 130 synthesis with three heteroatoms, 131e135 synthesis with two heteroatoms, 130e131 pyrimidines, 130e131

320 Six-membered rings (Continued ) three heteroatoms, 277 two heteroatoms, 276e277 Sodium tetrakis[3,5-bis(trifluoromethyl) phenyl]borate (NaBArF), 216 Solid phase, synthesis of five-membered heterocycles, 105e107 Solvatochromic vinylogous a-pyridones, 165, 167 Spectroscopic techniques, 18e20 15 N NMR, 19f Spiroacetal, 49e50 Spirocyclic furanone, 66e67 Spirocyclobutanone, 49e50 Spirodioxetane, 49e50 Stabilized methide, 169 Staphylococcus aureus (S. aureus), 34 Stereoisomers of nodulisporic acid A, 62e63 Strong base, 32 Structureeactivity relationship (SAR), 16e17 2-Styrylpiperidines, 206 5-Substituted 3,4-diarylisoxazole derivatives, 6 2-Substituted 4-chloro-4,5dehydropiperidines, 224e225 2,4-cis-Substituted 4-chloropiperidines, 224e225 4-Substituted acetoacetates, 86 N1-Substituted amidrazones, 128 N3-Substituted amidrazones, 119, 121e122 5-Substituted arylisoxazoles, 10e11 N3-Substituted N1-acylamidrazones, 125e126 2-Substituted piperidines, 199e200 4-Substituted-3-aryl-2-isoxazolines, 32 5-Substituted-3-aryl-2-isoxazolines, 32 3-(5-Substituted-benzimidazol-2-yl)-5arylisoxazoline, 34e35 Sulfenoamination, 203e205 Sulfinyl-bis-2,4-dihydroxybenzene, 128e129 N-Sulfonylaldimines, 232 Sulfonylpiperidinecarbimidates, 196e197 Sulfur, 92e93

Index

heterocycles, 259 syn bis-azetidinones, 21e22 Synthesized triazoles, 119e120 Synthetic biologically active heterocycles alkaloids, 261e262 antibiotics, 262 drugs, 263e265 miscellaneous, 265e266 amino acids and peptides, 265e266 enzymes, coenzymes, and models, 265 heterocycles produced by marine organisms, 266 other topics, 266 plant metabolites, 266 sources and topics, 260e261 vitamins, 262 Synthetic methodology, 17 Synthetic strategies, heterocyclic chemistry, 253e255 metal-catalyzed reactions, 253e254 photo reactions, 253e254 problems, 253 synthesis of heterocycles, 254e255

T u-TA. See u-Transaminase (u-TA) Tautomer, 90e91 Tautomeric methide, 148e150 TBAF. See Tetra-n-butylammonium fluoride (TBAF) TBD. See Triazabicyclodecene (TBD) O-TBS-protected 2-hydroxysulfinamides, 197e198 Tellurium heterocycles, 280 TEMPO. See 2,2,6,6-Tetramethyl-1piperidinyloxy (TEMPO) Terpene-derivatives, 26 Tert-butyl acetothioacetates, 58e59 (2R,3R)-3-[(1R)-1-[Tert-butyl(dimethyl) siloxy]ethyl]-4-oxoazetidin-2ylacetate, 52 Tetra-n-butylammonium fluoride (TBAF), 14, 62e63 Tetrachloro 1,2-quinone, 150e151 3,3,6,6-Tetrachloro-1,2cyclohexanedione, 131e132 Tetracyano derivatives, 160

Index

Tetrahydro-2H-pyran-2,6-diol, 232 1,2,3,10b-Tetrahydropyrrolo[2,1-a] isoquinoline-1-carboxamide derivatives, 82 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO), 24 N,N,N 0 ,N 0 -Tetramethylnaphthalene-1,8diamine, 208e209 Tetramic acid, 69 1,1,6,6-Tetraphenyl-2,5-dioxaspiro[3.3] heptane, 48e49 Tetrasubstituted (dehydro)piperidines, 221e222 Tetrazoles, 134e135, 274 TFA. See Trifluoroacetic acid (TFA) Thermal reactions, 148e150 Thiadiazoles, 127e128 reaction of amidrazones, 128 reactions of dithioesters, 127 Thiatriazoles, 129 Thiazole, 102e103 Thiazoline carboxyazide, 77e78 Thioamide, 125e126 1,1 0 -Thiocarbonyldiimidazole, 124e125 Thioesters, 127e128 Thiolactam, 50e51 ThorpeeIngold effect, 201e202 Three heteroatoms. See also One nitrogen atom; Two heteroatoms five-membered rings One oxygen, sulfur or selenium atom, 274 synthesis, 118e128 three nitrogen atoms, 273e274 two nitrogen atoms, 274 six-membered rings, 277 synthesis, 131e135 Three nitrogen atoms annulated triazoles, 274 monocyclic systems, 273e274 Three-membered rings, 267e268. See also Five-membered rings; Fourmembered rings; Six-membered rings one heteroatom, 267e268 transition metals, 267 two heteroatoms, 268

321 Tin heterocycles, 280 TolBINAP. See 2,2 0 -Bis(di-ptolylphosphino)-1,1 0 -binaphthyl (TolBINAP) p-Toluenesulfonic acid (p-TSA), 14, 122 N-Tosyl aminoallenes, 224e225 N-Tosyl homoallylamine, 224e225 Tosyl-amidrazone, 126e127 N-Tosylhydrazones, 206 N-Tosylimines, 231 N-Tosyleprotected homoallyl amines, 225e226 Trans-2-benzoyl-1hydroxycyclopropaneacetic acid b-lactone, 65 u-Transaminase (u-TA), 235 Transformation, 150 Triarylisoquinolone methide, 178e181 Triazabicyclodecene (TBD), 206e207 Triazepines, 137 1,2,4-Triazepines, 136e137 reaction of imidrazones, 136e137 1,2,4-Triazin-5-ones, 121e122, 133e134 1,2,4-Triazin-6-ones, 132e133 Triazines, 130 1,2,4-Triazines, 131e135 2,6-bis(1,2,3-Triazol-4-yl)pyridine (btp), 258 Triazol-5-one, 123e124 Triazole(s), 209e210 derivatives, 119 by reaction of amidrazones with, 118e127 aldehydes, 118e119 aminal, 120 aryl halides, 118 cyclic anhydride, 121 DCM, 124 2-(1,3-dioxoindan-2-ylidene) malononitrile, 119 DMAD, 121e122 ethyl chloroformate, 123e124 ethyloxalyl chloride, 125e126 excess of ammonia, 124 imidates, 122e123 itaconic anhydride, 119 ketones, 118e119

322 Triazole(s) (Continued ) phthaloyl chloride, 125 silylation of amidrazones, 126 synthesis of triazole from C-glucosyl amidrazones, 126e127 synthesis of triazole from chlorohydrazones, 127 triethyl orthoformate, 123e124 trifluoroacetic anhydride, 120 synthesis from C-glucosyl amidrazones, 126e127 triazole-modified peptidomimetics, 91e92 1,2,4-Triazoles, 118e120, 123e124 Triazolium dihydrochloride salts, 125 1,2,4-Triazolium, 124e125 Triazolophthalazine, 160 Tributylphosphine-catalyzed (4+2)annulation of allenes, 231 4-(Tributylstannyl)butanamines, 226e227 2,2,2-Trichloro-ethylimidates, 122 2,4,5-Trienal Schiff base, 177e178, 180 Triethyl orthoformate, 123e124 Triethylamine (Et3N), 116e117 Trifluoroacetic acid (TFA), 120 Trifluoroacetic anhydride, 120 a-Trifluoromethylated 4-piperidinone derivatives, 222e223 Trifluoromethyltriazoles, 120e121 1,2,3-Trimethylindole, 181e182 2,5,5-Trimethylpiperidine, 202e203 3,4,5-Trisubstituted 1,2,4-triazoles, 118 2,3,6-Trisubstituted 3,4dehydropiperidines, 231 3,4,5-Trisubstituted arylisoxazoles, 3e4 3,4,5-Trisubstituted isoxazoles, 7e8 2,4,5-Trisubstituted piperidines, 220 2,4,6-Trisubstituted piperidines, 195e196 4,5,6-Trisubstituted-1,4,5,6tetrahydropyridines, 228e229 Tropolones, 75e76 Tropone, 236 p-TSA. See p-Toluenesulfonic acid (p-TSA) TsNHOH. See N-Hydroxy-4toluenesulfonamide (TsNHOH)

Index

Two heteroatoms. See also One nitrogen atom; Three heteroatoms five-membered rings one nitrogen and one sulfur atom, 273 one nitrogen atom and one oxygen atom, 272e273 synthesis, 116e118 two nitrogen atoms, 272 two sulfur atoms, 273 four-membered rings, 268 nitrogen and oxygen atoms, 93e102 nitrogen and sulfur atoms, 102e104 six-membered rings one nitrogen atom and one oxygen atom, 277 one nitrogen atom and one sulfur atom, 277 synthesis, 130e131 two nitrogen atoms, 276e277 three-membered rings, 268 Two nitrogen atoms, 272 annulated pyrimidines, 276 1,3-heterocycles, 276 1,4-heterocycles, 277 imidazoles and annulated imidazoles, 272 nucleic acids, 277 nucleotides and nucleosides, 277 one oxygen and, 274 one selenium atom and, 274 one sulfur atom and, 274 pyrazoles and annulated pyrazoles, 272 pyrimidine nucleoside bases and purines, 277 Two sulfur atoms, five-membered rings, 273 Type-2 diabetes, 18 L-Tyrosine methyl ester, 73

U a,b-Unsaturated aldehydes, 199 a,b-Unsaturated carbonyl complex, 199e200 a,b-Unsaturated ketones, 199 N-Unsubstituted indoles, 79e80 N-Unsubstituted methides synthesis from N-oxides, 153e155

323

Index

from pyridine bases and benzologs, 144e153 reactions, 162 by ring formation, 155e162 by ring transformation, 162

V Valdecoxib, 16 analogues, 23 Versatile synthons, 255e256

a-Vinyl compounds formation, 170e172 Vinyl sulfone resin, 8e9 Vinyl-sulfone, 8e9 Vinylisoxazole, 23e24 Vinylnitrene intermediate, 21 Virgiboidine, 214e215

Y Ynimines, 210e211