Advances in Heterocyclic Chemistry. Volume 133 [133] 9780128209851

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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

VOLUME ONE HUNDRED AND THIRTY THREE

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 1650, San Diego, CA 92101, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 125 London Wall, London, EC2Y 5AS, United Kingdom First edition 2021 Copyright © 2021 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: 978-0-12-820985-1 ISSN: 0065-2725 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Zoe Kruze Acquisitions Editor: Jason Mitchell Editorial Project Manager: Shellie Bryant Production Project Manager: James Selvam Cover Designer: Alan Studholme Typeset by SPi Global, India

About the editors Eric F.V. Scriven Eric Scriven was educated in the UK and appointed lecturer in organic chemistry at the University of Salford in 1971. He joined Reilly Industries in 1979, and was Head of Research & Development 1991-2003. He is now Publishing Editor of Arkivoc and is based at the Department of Chemistry, University of Florida in Gainesville. His research interests are in heterocyclic chemistry, especially pyridines. He has over 100 publications and patents in heterocyclic chemistry. He has also published and consulted in the field of technology management. He was a founding editor (with Hans Suschitzky) of Progress in Heterocyclic Chemistry now in its 25th year. He has collaborated with Alan Katritzky and others as an Editor-in-Chief of Comprehensive Heterocyclic Chemistry 2nd and 3rd editions. He has edited two other works, Azides and Nitrenes (1984), and Pyridines (2013).

Affiliations and expertise Publishing Editor of Arkivoc, Department of Chemistry, University of Florida, Gainesville, USA

Christopher A. Ramsden Chris Ramsden was born in Manchester, UK in 1946. He is a graduate of Sheffield University and received his PhD in 1970 for a thesis entitled ‘Meso-ionic Compounds’ (W. D. Ollis) and a DSc in 1990. Subsequently he was a Robert A. Welch Postdoctoral Fellow at the University of Texas (with M. J. S. Dewar)(1971-3), working on the development and application of semi-empirical MO methods, and an ICI Postdoctoral Fellow at the University of East Anglia (with A. R. Katritzky)(1973-6), working on the synthesis of novel heterocycles. In 1976 he moved to the pharmaceutical industry and was Head of Medicinal Chemistry (1986-1992) at Rhone-Poulenc, London. He moved to Keele University as Professor of Organic Chemistry in 1992, where he is now Emeritus Professor. His research interests include the structure and preparation of novel heterocycles, three-centre bonding in the context of the chemistry of betaines and hypervalent species, and the properties of the enzyme tyrosinase and related ortho-quinone chemistry. He was an Editor-inChief of ‘Comprehensive Heterocyclic Chemistry III’ and a co-author of ‘The Handbook of Heterocyclic Chemistry, 3rd Edn, 2010.

Affiliations and expertise Professor of Organic Chemistry, Keele University, Staffordshire, UK

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Table of contents 1. Organosilicon azoles: Structure, silylotropy and NMR spectroscopy Lyudmila I. Larina 2. Recent advances in the Nenitzescu indole synthesis (1990–2019) Florea Dumitrascu and Marc A. Ilies 3. One-pot reactions of three-membered rings giving N,O,S-heterocycles Vitalii A. Palchykov and Oleksandr Zhurakovskyi

1

65

159

4. Organometallic complexes of functionalized chelating azines: Part 2 Alexander P. Sadimenko

225

Index

289

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Contributors Florea Dumitrascu Center for Organic Chemistry “C. D. Nenitzescu” Romanian Academy, Bucharest, Romania Marc A. Ilies Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, United States Lyudmila I. Larina A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Irkutsk, Russian Federation Vitalii A. Palchykov Research Institute of Chemistry and Geology, Oles Honchar Dnipro National University, Dnipro, Ukraine; Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, United States Alexander P. Sadimenko Department of Chemistry, University of Fort Hare, Republic of South Africa Oleksandr Zhurakovskyi Pharmaron UK, Hoddesdon, Herts, United Kingdom

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Preface Volume 133 of Advances in Heterocyclic Chemistry is composed of four chapters. Chapter 1 by Lyudmila Larina (A.E. Favorsky Irkutsk Institute of Chemistry, Irkutsk, Russian Federation) reviews the structure and silylotropy rearrangements of organosilicon azoles (pyrazoles, imidazoles, thiazoles, 1,2,3- and 1,2,4-triazoles, tetrazoles, and benzazoles) using multinuclear 1 H, 13C, 15N, and 29Si NMR spectroscopy. Special emphasis is given to studies employing dynamic NMR spectroscopy and a critical analysis of literature data on the structure of silicon-containing azoles is presented. In Chapter 2, Florea Dumitrascu (“C. D. Nenitzescu” Romanian Academy, Bucharest, Romania) and Marc Ilies (Temple University, Philadelphia, USA) describe recent advances in the Nenitzescu synthesis of 5- and 6-hydroxyindoles, 5-hydroxyindazoles, and 5-hydroxybenzofurans from suitably substituted quinones and β-enamines. The simple working procedures, mild reaction conditions, and easily accessible and structurally diverse starting materials provide convenient access to structurally diverse compounds with biological properties of potential interest. In Chapter 3, Vitalii Palchykov (Oles Honchar Dnipro National University, Dnipro, Ukraine and University of Texas at Dallas, USA) and Oleksandr Zhurakovskyi (Pharmaron UK, Hoddesdon, UK) survey, for the period 2014–19, the one-pot formation of N,O,S-containing heterocyclic products from three-membered precursors, especially “spring-loaded” epoxides and aziridines. The literature is conveniently arranged according to ring size, heteroatom type, and the number of heteroatoms in the ring. The volume is completed by the second part of a survey of organometallic complexes of functionalized chelating azines by Alexander Sadimenko (University of Fort Hare, Republic of South Africa). The review includes the synthesis and coordination modes of chelating azines containing thienyl, indolyl, carbazolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, and N-heterocyclic carbene functionalities, as well azines annulated to other heterocycles. The role of the discussed compounds in catalysis, materials chemistry, photochemistry, and microbiology is highlighted. ERIC F.V. SCRIVEN Department of Chemistry, University of Florida, Gainesville, FL, United States CHRISTOPHER A. RAMSDEN Lennard-Jones Laboratories, Keele University, Staffordshire, United Kingdom ix

CHAPTER O NE

Organosilicon azoles: Structure, silylotropy and NMR spectroscopy Lyudmila I. Larina* A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Irkutsk, Russian Federation *Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Some problems of the chemistry of trialkylsilylazoles 2.1 The application and reactivity of C- and N-trimethylsilylazoles 2.2 The structure and physico-chemical properties of trialkylsilylazoles 2.3 The silylotropic transformation of N-trialkylsilylazoles 3. NMR spectroscopy of C- and N-trimethylsilylazoles 3.1 The structure of the C- and N-trimethylsilylazoles 3.2 The silylotropic rearrangement of 4-substituted N-trimethylsilylpyrazoles 4. Catalysis of silylotropy in azoles 4.1 N-Trimethylsilylpyrazole derivatives 4.2 Tetramethyl-1,3-bis(3-R-pyrazolyl)disiloxanes 5. Structure of trimethylsilylation product of 1,2,3-triazole 6. Silylotropic rearrangement of other N-trimethylsilylazoles 7. The structure of trimethylsilylation products of 1,2,4-triazole-5-one derivatives and products of subsequent trans-silylation by dimethyl(chloromethyl) chlorosilane 7.1 The silylation products of 1-methyl- and 4-methyl-1,2,4-triazole-5-one 7.2 The silylation products of 3-nitro-1,2,4-triazole-5-one and its 1-methyl derivatives 7.3 The structure of silylation products of 3-chloro-1,2,4-triazole-5-one 7.4 The structure of the silylation products of 1,2,4-triazole-5-one 8. Conclusion Acknowledgments References Further reading

2 5 5 9 18 20 20 26 28 28 33 35 38

42 43 47 48 49 52 53 53 62

Abstract The present review summarizes comprehensive data (from the author’s work and the literature) on structure and silylotropy rearrangements of organosilicon azoles (pyrazoles, imidazoles, thiazoles, 1,2,3- and 1,2,4-triazoles, tetrazoles and benzazoles) and related compounds by multinuclear 1H, 13C, 15N and 29Si NMR spectroscopy. Special Advances in Heterocyclic Chemistry ISSN 0065-2725 https://doi.org/10.1016/bs.aihch.2019.08.001

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2019 Elsevier Inc. All rights reserved.

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Lyudmila I. Larina

emphasis is given to studies of silylated azoles by dynamic NMR spectroscopy. The structure of C- and N-trimethylsilyl derivatives of azoles, their bistrimethylsilyl analogs, and bicyclic organosilicon derivatives of azoles are discussed. The influence of the nature of the heterocycle and substituent on the equilibrium constants and the values of free activation energy of silylotropic transformations are analyzed. The catalytic effect of halogens and trimethylhalogensilanes on the silylotropy processes in N-trimethylsilylazoles is covered in detail. Critical analysis of literature data on structure of silicon-containing azoles is presented. Keywords: Organosilicon azoles, C- and N-trimethylsilylazoles, Structure and tautomerism, Silylotropic transformation, Catalytic silylotropy, Dynamic NMR, Multinuclear NMR spectroscopy

1. Introduction Organosilicon compounds occupy an important place in the organic chemistry. Silicon-containing materials have found a wide application in various fields of industrial chemistry, agriculture, and medicine [1978MI1, 1980MI1, 2000MI1, 2000EJO807, 2003MI1, 2003MI2, 2004EOD1149, 2004OM4468, 2006EJO311, 2006JA8479, 2006RMC1169, 2007DDR 156, 2009CSR1002, 2007BMC354, 2007CDD654, 2011CMC1509, 2011JMC2529, 2012JA7978, 2013JMC388, 2014MI, 2016RCB1034, 2017RCB2290, 2018CHE100, 2018DT9608]. Their unique properties and specific biological activity attract considerable attention of research community. Over the last few years interest in organosilicon chemistry has been steadily increasing. These studies have greatly contributed to synthetic, theoretical, medicinal, and applied chemistry. The presence of a silicon atom in an organic molecule provides for ample possibilities for medicinal applications. The medicinal prospects of silicon-containing compounds are especially interesting because of diverse chemical properties of organosilicon molecules. This diversity furnishes a potential for specific interactions between an organosilicon molecule and a biological macromolecule [2013JMC388]. The insertion of a silicon atom into an organic compound leads to the chemical and physical differences promoted by the silyl group. It can impart unique properties to the compounds. There are several important chemical properties of organic silicon that are relevant for medicinal chemistry [2000MI1, 2013JMC388, 2018AP1700297], for example: (1) The larger

Organosilicon azoles

3

size and covalent radius of the silicon atom compared to the carbon atom can dramatically affect the conformation and reactivity of ring structures containing a silicon center. (2) The enhanced lipophilicity of silicon-containing molecules often promote cell and tissue penetration and changes the potency and selectivity of the silicon structure relative to the carbon structure. (3) A silicon atom has different bonding capability compared to carbon based on the availability of 3d orbitals and lowest Si–C or Si–X antibonding orbitals for hyper conjugation. (4) The electropositive nature of silicon atoms compared to C, N, O atoms contributes to an electron-deficient center in a molecule and reversed bond polarization relative to the corresponding carbon bonds. In medicinal chemistry, this property intensifies hydrogen-bonding abilities, increases the acidity of silanols, and may also influence metabolic processes. (5) Si–OC and Si–N bonds are thermodynamically stable but kinetically labile in aqueous and acidic media based on the steric environment around the silicon atom. This property is valuable for synthetic protecting groups and prodrug approaches. Silicon-containing molecules are widely used as synthons and silylation agents in organic synthesis [1993MI1, 1994CSR111, 2009CR2455, 2005ARK377, 2013 BOC3, 2013MI1, 2015AC51, 2017RCB2264, 2017RCB2283, 2017T 3160, 2018AHC(126)55, 2018JCR297, 2018MC439]. Such a broad use of organosilicon compounds necessitates an understanding their chemical and spectral properties, tautomeric rearrangements and electronic structure peculiarities. Numerous methods have been developed for the synthesis of new organosilicon compounds with potentially useful properties [2000OM3486, 2003OM916, 2004MI1, 2009MI1, 2007MI1, 2013MI2, 2016MI1, 2016RCB1027, 2016RCB1067, 2017RCB2199, 2018AHC(124)175, 2018CEJ848, 2018CEJ944, 2018JOC2198, 2018MC 418, 2018PSS488, 2018RGC1639]. In the chemistry of azoles and related compounds, silicon-containing derivatives hold a special position. The results of our studies of various azole derivatives are published in monographs [2003DISS, 2009MI2] and several reviews dedicated to tautomerism of azoles [2018AHC(124)233], the chemistry of five-membered nitroazoles [1994RHC27, 1994ROC1141], and their benzanalogs [2006THS321, 2005THS327], the chemistry of siliconcontaining azoles [2001ROC149], Nuclear magnetic resonance (NMR) spectroscopy and mass-spectrometry of nitroazoles [1996MI1, 1998THS443], and electronic effects of five-membered nitrogen-containing aromatic heterocycles [1986RCR411]. Our on-going research is devoted to the chemistry, structure, and application of organosilicon azoles and related silicon-containing materials

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[1998JOMC129, 1998RCB1418, 2001ROC1891, 2002ROC344, 2003 ROC1393, 2003ROC1522, 2004ROC1804, 2006RGC1023, 2007MRC 661, 2007RGC2145, 2010ROC1675, 2011JOMC1964, 2011ROC298, 2014CHE967, 2014CHE1332, 2014ROC1377, 2015CHE381, 2015 MC34, 2015MCP227, 2015MI1, 2015RCB2261, 2015RGC2304, 2016MC 326, 2016MC426, 2016RCB1081, 2016ROC1229, 2017MC175, 2017MC 352, 2017RCB2253, 2017ROC413, 2017ROC1066, 2017ROC1510, 2018 MI1, 2019DP336, 2019ROC352]. The synthesis and structure of siloxane derivatives of azoles (1,2,4triazoles, benzimidazoles, benzotriazoles, benzothiazole), [2014CHE1332, 2014ROC1377, 2015RCB2261, 2017MC352], acetylenic silylderivatives of benzimidazole [2015RGC2304], organosilicon cyclophanes of benzimidazole and benzotriazole [2016MC426], silanes and siloxanes of imidazoles [2017ROC413, 2017ROC1066], silicon-containing derivatives of 1,2,3-triazoles, oxazoles, isoxazoles and imidazoles [2003ROC1507, 2015OL1826, 2017MC175, 2017RCB2253, 2017T3979], organosilicon macroheterocycles [2017RCB2339] have been studied. Organosilicon azoles represent a unique place in heterocyclic chemistry. The chemistry, structure, and biological activity of trimethylsilyl ethers of thiazole derivatives possessing antiinflammatory activity and cytotoxicity have been discussed [2007MI1]. In the synthesis of complex functional nitrogen-containing heterocyclic systems, their use, instead of N-unsubstituted substrates, often provides for smoother reactions and easier separation of the products. Despite the widespread application of silylated azoles in organic synthesis, silylotropy processes are poorly covered in the literature. Systematic research in this area has not been conducted, and the literature contains scant information. The above has prompted the writing of this review covering the available literature and our own data on tautomerism, structure and properties of silicon-containing azoles, and their functional derivatives from the viewpoint of NMR spectroscopy. NMR spectroscopy, in particular, 15N and 29Si NMR provides one of the most effective and fast tools for the investigation of the electronic structure and tautomeric transformations of silicon-containing nitrogen heterocycles. 15N and 29Si NMR methods have considerably extended the analytical arsenal of organic chemistry. The suitability of 15N NMR for these studies is attributed to the wide range of chemical shifts (900 ppm) and its great sensitivity to structural and environmental changes (tautomerism, H-bonds, protonation). Due to the rapid progress in experimental techniques, investigations on low abundant 13C, 15N, 17O, 29Si nuclei

Organosilicon azoles

5

are of key importance for functionalized azoles, previously very difficult, now have become a routine procedure. Even minor changes in tautomeric equilibrium constants and conformation of a molecule, temperature variations, or solvent replacement can markedly change the nuclei shielding not always in line with the degree of electron redistribution [2003DISS, 2009MI2, 2018AHC(124)233]. Modern experimental NMR data with computational methods can aid to the chemical shift assignments especially in the case of crystalline materials (so-called NMR crystallography) [2012MI1]. Therefore, the majority of investigations are devoted to the problem of prototropic tautomerism in heterocycles. This confirms the topicality of investigations in this area. Nevertheless, the literature data on silylotropy rearrangements in organosilicon containing azoles are scarce and so systematic examinations in this area have not been performed.

2. Some problems of the chemistry of trialkylsilylazoles 2.1 The application and reactivity of C- and N-trimethylsilylazoles Azoles containing a trialkylsilyl group are widely used in medicine and as synthons in synthetic organic chemistry. Their chemistry has been discussed [2001ROC149]. Trimethylsilylazoles (TMS-azoles) may be divided into two large classes: 1. C-Trimethylsilylazoles (C-TMS-azoles), substituted azoles, and their benzannelated analogs containing a trimethylsilyl group attached to one or several carbon atoms. 2. N-Trimethylsilylazoles (N-TMS-azoles), one of which nitrogen is bonded with Si-Me3 group. Since the properties, structure, and especially chemical reactions of C- and N-trimethylsilylazoles are considerably different, they are treated separately below. Many N-substituted trialkylsilylazoles are broadly used as silylation agents in fine organic synthesis, including peptide synthesis [1993T6195, 1997T14381, 2000CTL245, 2001ROC149, 2002PCJ16, 2003DISS, 2009 MI3, 2012 OL58, 2013MI3, 2013MI4, 2013ROC934, 2018MI1]. N-Trimethylsilylazoles, mainly 1-trimethylsilylimidazole and 1-trimethylsilyl1,2,4-triazole are extensively applied in organic synthesis to protect a hydroxyl group [1993SC2191, 1997T14381, 1998TL5473, 2001ROC 149, 2009MI2, 2015CHE395, 2018MI1]. 1-(tert-Butyldimethylsilyl)imidazole has been successfully used in the synthesis of optically active compounds [1998AC180, 1998CEJ311, 2001ROC149, 2003DISS].

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N-TMS-imidazole is employed for the quantitative determination of monosaccharides, including in milk, and also to protect the hydroxyl group of hydrocortisone [2001ROC149, 2003DISS, 2014FC743]. Azole nucleoside analogs were obtained on the basis of N-trimethylsilylazoles. The nucleosides of 1,2,4-triazole series (virazole, ribamidil) have antiviral activity [2000JCS(P1)829, 2001ROC149, 2016MI2]. Penetrating through the cell membrane, it is metabolized, becoming a mono- or triphosphate. This drug is a competitive inhibitors of dehydrogenase inosinmonophosphate, inhibits the synthesis of viral RNA and DNA, not acting at the same time on the host cells. Some N-substituted trimethylsilylazoles are used in the synthesis of herbicides, as components of initiating polymerization systems and polyoxymethylene stabilizers [2001ROC149, 2003DISS]. Thus, N-trimethylsilylazoles in synthetic organic chemistry are used as synthons, trimethylsilylation agents, as well as for the introduction of various functional groups onto the heterocyclic nitrogen atom [2001ROC149, 2003DISS] (Scheme 1):

Scheme 1 The possible ways of functionalization of N-trimethylsilylazoles.

Organosilicon azoles

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C-Trimethylsilylazoles, in particular Dondoni reagent—2trimethylsilylthiazole (1), have proven themselves effective in asymmetric synthesis (Scheme 2) [1996CHEC3, 1998S1681, 2004CR2557, 2010OBC 3366, 2012OS323, 2013MI2].

Scheme 2 The mechanism of 2-trimethylsilylthiazole interaction with aldehydes.

Sequential asymmetric synthesis of a number of α-chiral aldehyde homologs became possible using the Dondoni reagent. The mechanism of its interaction with aldehydes is represented in Scheme 2 [1998S1681, 2004CR 2557, 1988JOC1748, 1990PAC643, 1993JOC3196, 1987T3533, 1996JOC 1922, 1997JOC6261]. Special interest in this reaction arose when it was found that reaction of 2-trimethylsilylthiazole, 2-trimethylsilylbenzothiazole, and 2-trimethylsilyl-4-methyloxazole with α-chiral aldehydes led to formation of products which incorporate a (C-2)–Si bond with high stereoselectivity (Scheme 3):

Scheme 3 The reaction of C-trimethylsilylazoles with α-chiral aldehydes.

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This reaction is used for the stereoselective homologization of D-glyceric aldehyde [1993OS21, 1987JOC3413, 1985TL5477]. The greatest degree of diastereoselectivity (
95%) was observed when using 2-trimethylsilylthiazole (Table 1) [1985TL5477, 1988S685]. This explains the great interest in the latter. The ability to control the diastereomeric structure of the final products is illustrated in Table 1. The nature of the heterocycle has a significant effect on the yield and diastereomeric purity of the reaction products.

Table 1 The ratio of diastereomers in the reaction products of 2-trimethylsilylazole with α-chiral aldehyde [1985TL5477, 2004CR2557]. TMS-azole Aldehyde The ratio A:B (yield %)

1

33:66 (70)

1

73:27 (73)

1

>95:185 >24

45

Me3Si 7.62, 7.60 148.01 115.04 139.04 13.4 2.0

46

H

7.55, 7.73 143.0 106.30 133.64 14.2 16.2 >185 23.1b

47

Cl

7.54, 7.59 141.77 110.88 131.69 17.1 4.1

165

24.0

48

Br

7.56, 7.60 143.60 94.10 133.80 17.0 3.5

159

23.8

c

49

I

7.65, 7.68 147.36 57.68 137.86 17.2

50

NO2

8.15, 8.41 138.78 137.61 133.96 22.1 23.4 >185 >24

δ Si (C-Si) ¼ 11.1 ppm. [1971JOMC185], Δν ¼ 2.2 Hz, tc ¼ 140°C, the resonance frequency of the NMR spectrometer 60 MHz. c Under heating partly decomposes (see later). a 29 b

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δ

29

Si, ppm NO 2

22

20

18 Br 16 Ph H

14

CH 3 12

9

10

11

12

13

14

15

pKa

Fig. 2 Correlation of the 29Si chemical shifts of 4-substituted 1-trimethylsilylimidazole and pKa values of 4-substituted pyrazoles. Table 6 The parameters of the correlation equation δ29Si ¼ aX + bY + d. XY a b d R

S

n

σ Iσ R

10.17  0.31

8.07  0.39

14.08  0.07

0.995

0.25

7

FR

5.94  0.18

7.31  0.81

14.07  0.06

0.994

0.25

7

A direct correlation is also observed between δ29Si of 4-substituted N-TMS-pyrazoles and δ1H (NH) values of 4-substituted pyrazoles [1996MI2, 2001ROC149, 2003DISS, 2018AHC(124)233]. A similar relationship in amines and amides and their N-TMS derivatives has been reported [1977ZN163]. The results of correlation of the 29Si chemical shift values with the substituent constants (σI, σR and F , R) show that the substituent effects from position 4 of the pyrazole ring (43–50) are transmitted on the silicon atom with approximately equal contributions from the induction (field) and resonance components (Table 6) [1996MI2, 2003DISS, 2018AHC(124)233]. The results of the correlation equation practically do not depend on the choice of the substituent parameters (σI σR, F R).

3.2 The silylotropic rearrangement of 4-substituted N-trimethylsilylpyrazoles The most common type of tautomerism is prototropy where rearrangement is carried out as the result of proton transfer. Proton migration differs from all other types of tautomerism—elementotropy, metallotropy, acylotropy and

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methylotropy—because the proton has small size, so is not sensitive to steric effects. The amplitude of the activation energy change of elementotropy (1,2-migration of a proton or group of atoms) in pyrazoles (А ! B) has been discussed [1998MRC110, 2000AHC(76)2, 2000AHC(76)159, 2003DISS, 2009MI2, 2018AHC(124)233] (Scheme 11, Table 7).

Scheme 11 The elementotropic migration in pyrazoles.

The value of the activation energy of proton exchange is lower, than other groups, except for some metals (Hg, Sn) capable of the formation of intermolecular associates. The barriers of the silylotropy process in pyrazoles have substituent values of 22–25 kcal/mol [1998MRC110, 2001ROC149, 2003DISS, 2018AHC(124)233]. Argentotropy in iridium complexes with pyrazole ligands has been studied by multinuclear dynamic NMR spectroscopy (ΔH* ¼ 7.6–8.3 kcal/mol, ΔS* ¼ 13eu  20 eu) [1994IC2196]. The exchange silylotropic rearrangements of 4-substituted N-trimethylsilylpyrazoles (43–50) are slow enough on the NMR time scale, therefore, the observation of the dynamic processes of Me3Si group migration is possible only with increasing temperature. At room temperature, the positions 3 and 5 in the N-TMS-pyrazoles (Table 5) are not equivalent in contrast to N-H-pyrazoles. Therefore, their NMR spectra (43–50) are separated signals of the protons (and carbons) in position 3 and 5. With increasing temperature the rate of the Me3Si group migration increases, the position 3 and 5 became equivalent and the spectra have a signal Н-3,5 (or C-3,5). Lowering the temperature to room leads again to the separation of these signals. Thus, there is a reversible silylotropy exchange of trimethylsilyl groups between the nitrogen atoms (N-1 and N-2). 6 The barriers of silylotropy exchange of Me3Si-group (ΔG¼ c ) in 4-substituted N-trimethylsilylpyrazoles (43–50) have been determined by Table 7 Activation energy values of elementotropy in N-substituted pyrazoles. Y Ph Me COR SiR3 GeR3 H HgR2 SnR3

ΔG#c , kcal/mol a

Argentotropy.

>40

35

30

22–25

20

10–15

10

5

Aga

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the dynamic 1H NMR method on the equation Oki (3) (Table 5). According to dynamic 1H NMR spectroscopy data, the values of free activation energy of TMS-group 1,2-migration change in range 22–25 kcal/mol for most 4-substituted N-trimethylsilylpyrazoles (43–50) and depend in a complex way on the nature of the substituent (Table 5). We are faced with an unexpected phenomenon—the barriers of tautomeric processes for some compounds were too large to be measured by NMR spectroscopy. The study of 1-trimethylsilylpyrazole (46), 1,4-bistrimethylsilylpyrazoles (45), and 1-trimethylsilyl-4-nitropyrazole (50) under the same conditions did not lead to the expected result—we could not achieve the coalescence of the proton signals H-3 and H-5, even at a temperature of 185°C (at 90 MHz). Apparently, these compounds require a higher temperature, which is practically (technically) impossible [2003DISS, 2018AHC(124)233]. It should be noted that the authors [1971JOMC185] were able to achieve coalescence of the H-3 and H-5 signals in N-trimethylsilylpyrazole (46) only because they worked on the spectrometer with a lower operating frequency (60 MHz). The barrier value of silylotropy in the N-trimethylsilylpyrazole calculated by us from data [1971JOMC185] of temperature-dependent NMR spectrum, comparable (23.1kcal/mol) with the values of barriers for the studied compounds (22–25 kcal/mol) (Table 5).

4. Catalysis of silylotropy in azoles 4.1 N-Trimethylsilylpyrazole derivatives We were able to detect an unexpected acceleration of formally silylotropic transformations of N-TMS-azoles in the presence of halogens or trimethylhalogensilanes. First we have discovered the catalysis of silylotropic rearrangement in a series of 4-substituted 1-trimethylsilylpyrazoles (43–50). Annular prototropic tautomerism in azoles is described by the general equation of acid–base catalysis [2000AHC(76)2, 2000AHC(76)159, 2001ROC149, 2003DISS]. At the same time, the catalysis of elementotropy in the azoles (migration other groups than a proton) has not been observed to date. Known cases only involve irreversible migration, for example, such as alkyl and phenacyl groups in the molecule of 1,2,4-triazole under the action of catalytic quantities of alkyl—and phenacylhalogenides [1990CL347]. At the heating of 4-substituted N-TMS-pyrazole (43–48, 50) to a temperature 159–165°С the coalescence of the proton signals in position

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3 and 5 of the pyrazole cycle occurs, while at the cooling temperature of the sample to room, the signals are again separated. As an example, the signals of H-3 and H-5 of temperature-dependent 1H NMR spectrum of 4-chloro-1-trimethylsilylpyrazole (47) are shown in Fig. 3 [2001ROC149, 2003DISS]. Temperature transformation of 1H NMR spectrum of 4-iodo1-trimethylsilylpyrazole (49) was absolutely extraordinary (Fig. 4) [1996RCB2861, 1996MI2, 1996MI3, 1996MI4, 2001ROC149, 2003 DISS]. The initial coalescence of the H-3 and H-5 signals occurs at a temperature of over 100°С (δ1Н ¼ 7.65 ppm). However, the subsequent cooling of the sample to room temperature does not lead to the expected separation of signals. Decoalescence of these signals occurs only at low temperatures up to 45°С. The complete separation of the signals is recorded at –(70–90)°С (Table 5). The calculation results show that the reversible process of 1,2-migration of the TMS group (silylotropy) in 4-iodo-1- trimethylsilylpyrazole (49) has a fairly low barrier transition—ΔG6c¼ ¼ 12.2 kcal/mol (CD2Cl2) [1996RCB2861, 2003DISS]. Thus, heating of 4-iododerivatives (49) leads to unpredictable sudden lowering of 1,2-migration barrier of the Me3Si group. A detailed study of

+27°C H-3

H-5

+120°C

+165°C

H-3,5

+27°C H-3

H-5

Fig. 3 Temperature-dependent 1H NMR spectra of 4-chloro-1-trimethylsilylpyrazole (47).

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H-3

H-5

+27°C

+140°C

+27°C

H-3

H-5

–70°C

Fig. 4 Temperature-dependent 1H NMR spectra of 4-iodo-1-trimethylsilylpyrazole (49).

the reasons of this unusual phenomenon has led to the following conclusion. Heating of 4-iodo-1-trimethylsilylpyrazole is accompanied by partial decomposition. The most probable decomposition mechanism is reduced to the thermolysis of C–I bond with elimination of free iodine (Scheme 12). The interaction of the latter with a molecule 49 leads to the formation of Me3SiI. Trimethyliodosilane in turn, acting as a catalyst, accelerates the exchange of the trimethylsilyl group between the nitrogen atoms of compound 49.

Scheme 12 The decomposition mechanism of 4-iodo-1-trimethylsilylpyrazole.

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31

The phenomenon of the catalytic acceleration of the silylotropy transformation, which we found by the example of 4-iodo-N-TMS-pyrazole is of a general nature. Special experiments have shown that the addition of small quantities of iodine almost immediately and without any heating leads to the coalescence of H-3 and H-5 signals in 1H NMR spectra of N-trimethylsilylpyrazoles. Bromine and chlorine show a less active: to achieve the same effect need time or heat of the sample (60–80°С). The mechanism of the catalytic influence of halogens on the migration of trimethylsilyl group include the generation of trimethylhalogensilanes with the subsequent formation and dissociation of the corresponding 1,2bis-TMS-pyrazolium salts (Scheme 13).

Scheme 13 The formation of 1,2-bis-(trimethylsilyl)pyrazolium halogenides.

The addition of a small amount of trimethylchlorosilane to trimethylsilylpyrazole leads to the coalescence of the H-3 and H-5 signals in NMR spectra. In this case, Me3SiCl, as expected, shows less activity— the coalescence of H-3 and H-5 signals occurs either after some period of time (over 30 min), or when heated (80°C). By mixing equimolar quantities of 1-trimethylsilypyrazole and Me3SiBr we were able to isolate and identify by NMR bromide 1,2-di(trimethylsilyl)pyrazole (57) (Table 8) [1996RCB2861, 2001ROC149, 2003DISS]. The resonance signals of protons of heterocycle and Me3Si group in the pyrazolium bromide 57 (Table 8) are shifted in a low field in comparison with the neutral molecule, which is characteristic of onium forms (N,N 0 -bisalkylated and N-protonated heterocyclic molecules) [1981OMR1, 2002 JMT165, 2003DISS].

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Table 8 1H, 13C and 29Si NMR chemical shifts of 1,2-bis(trimethylsilyl) pyrazolium bromide (57) (ppm, CDCl3). δ13С δ1Н Compound

Н-3,5

Н-4

SiMe3

С-3,5

С-4

SiMe3

δ29Si

7.84

6.48

0.59

136.76

106.07

2.34

24.3

Thus, the silylotropic transformations of 4-substituted N-trimethylsilylpyrazoles are catalyzed by trimethylhalogensilanes due to the intermediate formation of N,N 0 -bis(trimethylhalogensilyl)pyrazolium salts. The fast degenerate exchange between the initial of N-trimethylsilylpyrazole and the resulting salts dramatically reduces the barrier of silylotropy: from 22–25 kcal/mol (in the absence of a catalyst) to 12 kcal/mol. In the interaction of equimolar amounts of N-TMS-pyrazoles with Me3SiBr; the equilibrium is shifted toward the formation of salt. The process of 1,2-migration of the trimethylsilyl group between the N-1 and N-2 atoms in pyrazole can be considered as a special case of the addition–elimination reaction. The formation of analogous N,N 0 -bis (trimethylsilyl)imidazolium salts and their participation in exchange processes have been reported [1986JCS(P2)221, 1986JCS(P2)227] (Scheme 14). Imidazolium salts have been studied by NMR (Table 9), X-ray analysis (Table 2) and conductometric titration.

Scheme 14 The generation of N,N0 -bis-(trimethylsilyl)imidazolium salts.

According to X-ray analysis, the crystalline 1:1 adduct obtained by interaction of N-trimethylsilylimidazole with Me3SiI is N,N 0 -bis(trimethylsilyl) imidazolium iodide (12) (Tables 2 and 9) [1986JCS(P2)227]. As mentioned earlier, the N–Si bond length in cations is larger than in the neutral molecule (Table 2). The conductivity of solutions of imidazolium cations determined

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Table 9 1H 13C and 29Si NMR chemical shifts of N,N0 -bis(trimethylsilyl)imidazolium salts (11, 12, 13, 13a) (CD2Cl2, ppm) [1986JCS(P2)221]. δ13С δ 1Н Compound

X

Н-2

Н-4,5

Si(CH3)3

С-2

С-4,5

Si(CH3)3

δ29Si

11

Br

9.79

7.48

0.72

144.1

124.5

0.0

26.3

12

I

9.34

7.52

0.75

143.0

124.5

0.0

26.9

13

CF3SO3

8.63

7.42

0.64

141.0

124.1

0.8

26.9

13a

ClO4

8.52

7.39

0.64

143.3

124.9

0.69

26.1

by the method of conductometric titration, increases in the following series of anions: Х ¼ Cl < Br < I < CF3SO3 [1986JCS(P2)221]. The shift of the resonance signals of 1H and 13C NMR of protons and carbons in position 2 of the imidazole ring in a high field increases in the same order changes ion Х, while δ29Si almost independent of the nature of the anion (Table 9). The rate of exchange reaction of N,N0 -bis(trimethylsilyl)imidazolium salts with electrophilic silanes (Me3SiX) decreases in the following order: X ¼ Cl > Br > CF3SO3 > I, ClO4. The equilibrium constants of formation of these salts fall almost in reverse order [1986JCS(P2)227]: ClO4 > OSO2CF3 > I > Br > Cl Thus, the barriers of silylotropy exchange of Me3Si-group in N-trimethylsilylpyrazole derivatives change in the range 22–25 kcal/mol and depend in a complex way on the nature of the substituent. Silylotropy in N-trimethylsilylpyrazoles in the presence of halogens or trimethylhalosilanes is believed to proceed through formation of N,N0 -bis(trimethylsilyl) pyrazolium salts, the barrier of silylotropy in pyrazoles being markedly reduced.

4.2 Tetramethyl-1,3-bis(3-R-pyrazolyl)disiloxanes Catalytic exchange processes are observed for other silicone derivatives of azoles. The interaction of 1-trimethylsilylpyrazole (46) and its 3-methyl derivatives (54) with 1,3-dichlorotetramethyldisiloxane (ClMe2Si)2O has been studied by multinuclear NMR method (Scheme 15) [2001ROC149, 2003DISS].

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Scheme 15 The interaction of 1-trimethylsilylpyrazoles with 1,3-dichlorotetramethyl disiloxane. Table 10 1H and 29Si NMR chemical shifts of tetramethyl-1,3-bis(3-R-pyrazolyl-10 )disiloxanes (58, 59) (ppm) [2001ROC149, 2003DISS]. δ1H Compound

R

H-3,5

H-4

Si(CH3)3

δ29Si

58

H

7.64 7.69

6.23 6.32

0.41 0.48

6.4 6.8

59

CH3

7.47

6.02

0.39

5.5

Solvent а

CDCl3

CDCl3

а

Without solvent (neat liquid).

It was expected that this may lead to either the corresponding derivatives of pentacoordinated silicon atom (46a, 54a), or pyrazolium chlorides, (46b, 54b), or products of bimolecular condensation 58 (R ¼ H), 59 (R ¼ CH3) (Scheme 15). We found that the reaction product is tetramethyl-1,3-bis-(10 -pyrazolyl)disiloxane (58) or the corresponding methylated analog (59). 1H and 29Si NMR chemical shifts of 58 and 59 compounds are presented in Table 10. As can be seen, chemical equivalence of protons and carbons shifts in positions 3 and 5 of the pyrazole ring is observed in the spectra of 1H and 13C NMR for compound 58. This is due to the rapid silylotropic exchange of siloxane fragment between the nitrogen atoms of the pyrazole ring. The silylotropic process is catalyzed by traces of trimethylchlorosilane which can be located in the system (Scheme 16) [1996MI5, 2001ROC149, 2003DISS].

Scheme 16 The silylotropic exchange of siloxane fragment in the pyrazole.

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35

The discovery of catalytic silylotropy in trimethylsilylazoles (in the presence of halogens or trimethylchlorosilanes) gives reason to (revise) reconsider many literature data and, in addition, to explain some results of researchers. For example, the authors [1995RCB2190] showed that, under the action of trimethylchlorosilane on silver salt of 1-hydroxybenzotriazole3-oxide (60), 1-trimethylsiloxybenzotriazole-3-oxide (61) was isolated (Scheme 17).

Scheme 17 The trimethylsilylation of 1-hydroxybenzotriazole-3-oxide.

The multiplicity and number of the signals and their broadening in NMR spectra of compound 60 indicate equilibrium between two structures containing the OSiMe3 group in position 1 and 3, respectively. To explain this fact the authors [1995RCB2190] proposed to consider 1,3-O,O-shift of the SiMe3 group as two consecutive 1,2-O,N—and 2,3-N,O-shift. The mechanism of this reaction has not been proven. In our opinion, it is likely that the traces of trimethylchlorosilane remaining in the system, have a catalytic action and the intermediate of silylotropy is 2-trimethylsilyl-1-trimethylsiloxybenzotriazolium-3-oxide chloride [2001ROC149, 2003DISS].

5. Structure of trimethylsilylation product of 1,2,3-triazole There are contradictory data on the structure of N-trimethylsilyl-1,2,3triazole. For example, Birkofer and coworkers [1966CB2512] suggested that the trimethylsilyl group in the N-trimethylsilyl-1,2,3-triazole quickly exchanged between neighboring nitrogen atoms N-1 and N-2. According to other data [1976JOMC285], 1-trimethylsilyl-1,2,3-triazole, obtained in the result of the interaction of 2,5-norbornadiene with trimethylsilylazide, isomerized into 2-trimethylsilyl-1,2,3-triazole.

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To clarify the dynamic behavior of N-trimethylsilyl-1,2,3-triazole the trimethylsilylation reaction of 1,2,3-triazole by hexamethyldisilazane has been studied (Scheme 18) [1998MRC110, 2001ROC149, 2003DISS]. The multinuclear 1H, 13C, and 29Si NMR data proved that the interaction of 1,2,3-triazole with hexamethyldisilazane leads to a mixture of 1- (62) and 2-trimethylsilyl-1,2,3-triazole (63) in the ratio 1:5 (Scheme 18) [1998MRC110, 2001ROC149, 2003DISS]. NMR data indicate that the nature of solvent (CDCl3 solution or neat liquid—100% liquid) has no effect on the ratio of 1-trimethylsilyl- (62) and 2-trimethylsilyl-1,2,3-triazole (63) in the mixture (Table 11).

Scheme 18 The trimethylsilylation of 1,2,3-triazole.

Table 11 1H, 13C, and 29Si NMR chemical shifts of 1-trimethylsilyl- (62) and 2-trimethylsilyl-1,2,3-triazole (63) in CDCl3 and neat liquid (values in parentheses) (ppm)a. δ 13С δ 1Н H-4

H-5

SiMe3

C-4

C-5

SiMe3

δ 29Si

62

7.92 (7.07)

7.92 (6.98)

0.58 (0.25)

132.70

126.59

1.10

20.2

63

7.82 (7.40)

7.82 (7.40)

0.58 (0.21)

135.62

135.62

1.32

22.0

Compound

a

The ratio of isomers determined by 13C NMR using the technique NNE (with decoupling from protons without Overhauser effect).

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37

Attempts to convert one form of compound to another by heating the mixture (up to 65°C in chloroform and 200оС in a neat liquid) have not led to the transformation of the spectra. Consequently, the free energy of activation of mutual transitions 62Ð63 is much more than 25 kcal/mol, and the molecules should not be attributed to tautomers, but to N-TMS1,2,3-triazole isomers (Scheme 19) [1998MRC110, 2001ROC149, 2003DISS].

Scheme 19 N-trimethylsilyl-1,2,3-triazole isomers.

Protons H-4 and H-5 of 1-TMS-1,2,3-triazole 62 in CDCl3 medium are chemically equivalent. This indicates high rate of exchange of trimethylsilyl groups between the atoms N-1 and N-3 in this solvent at room temperature (Table 11). The most likely cause of the acceleration of silylotropy process 62 may serve as a catalytic action of Me3SiCl formed by the interaction of 1-TMS-1,2,3-triazole with traces of HCl in chloroform. Introduction of trimethylsilyl group into the 1,2,3-triazole cycle has little effect on the shielding constants of the nuclei of the triazole cycle— Δδ13C ¼ 5 ppm (Scheme 20).

Scheme 20 13C NMR chemical shift values of C-4,5 of 1,2,3-triazole and 2-trimethylsilyl1,2,3-triazole.

As a result of our studies it becomes evident that the authors of [1966CB2512], apparently, observed not 1Ð2 the exchange of TMS-group

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in N-trimethylsilyl-1,2,3-triazole, and a mixture of 1- and 2-TMS-1,2,3triazole, with a larger population of the latter. To further confirm this conclusion, we estimated values of total energy 1-TMS and 2-TMS-1,2,3 -triazole by the ab initio (MP2/6-311++G*) method. The calculation data predict that 1-trimethylsilyl-1,2,3-triazole in the gas phase should be more favorable (stable) (4.8 kcal/mol). In this case the calculated values of the dipole moments of isomers 62 and 63 are equal to 4.77 and 0.57 D, respectively. Based on the experimental values of the dipole moment of N-trimethylsilyl-1,2,3-triazole (1.54 D [1966CB2512]) and the theoretical values obtained for each isomer, we evaluated the ratio (population), which is equal to 1:3 (0.23:0.77), respectively for 90 and 91. This is consistent with our results obtained by NMR data. Thus, we were able to show that trimethylsilylation of 1,2,3-triazole formed two isomers—1-trimethylsilyl- and 2-trimethylsilyl-1,2,3-triazole in a ratio of 1:5, which indicates regioselectivity of trimethylsilylation process. In addition, for 1-TMS-1,2,3-triazole there is a process 1Ð3 degenerate tautomeric rearrangement (migration) of trimethylsilyl group.

6. Silylotropic rearrangement of other N-trimethylsilylazoles The analysis of literature data [1974CB3070, 1974JOMC347, 1976IC3054, 1977ZN163, 1989NAR853] shows that the migration barrier of trimethylsilyl groups in N-trimethylsilyl derivatives of imidazole and benzimidazole is lower than in other N-trimethylsilylazoles. In the proton spectra of N-trimethylsilylimidazole, even at room temperature, coalescence of the H-4 and H-5 signals is observed (Table 12). Similarly, coalescence of the H-4 and H-7 signals, as well as H-5 and H-6 signals is observed in the 1H NMR spectrum of N-trimethylsilylbenzimidazole (Table 13). The broadening of C-4 and C-5 signals of N-trimethylsilylimidazole and C-5, C-6 and C-4, C-7 signals of similar benzimidazoles in the carbon spectra is detected (Tables 12 and 13). In the solid state N-trimethylsilylbenzimidazole does not undergo silylotropy transformation: all the signals of carbon atoms in the 13C NMR spectra solid state are separated [1983H1713, 1988MRC134]. We found that the 29Si chemical shift of the silicon atom of the trimethylsilyl group in the N-trimethylsilylazoles is sensitive to the nature

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Table 12 1H, 13С and 29Si NMR chemical shifts (δ, ppm) and coupling constants (J, Hz) of N-trimethylsilylazoles (CDCl3). δ13С (δ1H) C-3 (Н-3) or C-2 (Н-2)

C-4 (Н-4)

C-5 (Н-5)

δ29Siа

Refs

64

140.62 (7.65) 140.1 (7.56) 139.7 (7.60)

128.65 (7.11) 125.5 (7.06) 129.9 brs (7.60)

128.65 (7.11) 125.5 (7.06) 120.7 brs (7.10)

13.16

[1974JOMC347]b [1974JOMC347]b [1976IC3054]c [1976IC3054]c [1988MRC134] [1989NAR853]d

65

148.0

124.6 (6.87)

124.6 (6.87)

46

142.85 (7.73) 143.5 (7.80) (7.77)

106.71 (6.28) 106.3 (6.40) (6.32)

133.29 (7.56) 134.0 (7.65) (7.59)

14.6 14.4

[2003DISS] [2003DISS] [1988MRC134] [1989NAR853]c

66

154.2 (8.2)

148.4 (7.9)

17.1

[1988MRC134] [1989NAR853]d

Compound

[1976IC3054]c [1976IC3054]c

а

100% Liquid (neat liquid) [1977ZN163], δ29Si of 1-trimethylsilylpyrrole—11.1 ppm. 100% Liquid. c In CН2Cl2. d In CCl4. b

of the heterocycle (Tables 12 and 13). With an increase of the electronegativity of the heterocycle (the nature of the heteroatom, the increase in the number of heteroatoms and their location in the azole ring), the shielding constant of the 29Si nucleus increases. This means that the electronegativity of the azolyl ring increases in the following sequence: pyrrole, imidazole, pyrazole, 1,2,3-triazole (Table 12), and of the benzazolyl ring—in the next sequence: indole, benzimidazole, indazole, benzoxazole, benzotriazole (Table 13).

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Table 13 13C (CDCl3) and 29Si (neat liquid) NMR chemical shifts of some N-trimethylsilylbenzazoles (ppm). δ13С [1988MRC134] Compound

C-4

C-5

C-6

C-7

C-8

C-9

δ29Sia

115.8b

122.0c

122.0c

115.8b

139.2b

139.2b

12.8

119.8

123.4

126.0

111.1

137.8

146.6

18.1

111.5

122.3

123.5

109.5

145.3

133.7

16.8e

δ Si (ppm) [1977ZN163]: 1-trimethylsilylindole—10.7, 1-trimethylsilylindazole—14.5. Broad signal. c1 J ¼ 191.7, 2J ¼ 13.8 Hz. d 13 δ С and δ29Si (CDCl3) from [1981RGC1096]. e The authors [1981RGC1096] assigned erroneously the value 16.8 ppm to the structure 69A a 29 b

. 14

N NMR data [1974CB3070] also indicate fairly fast (on the NMR time scale) silylotropic exchange in the N-TMS-imidazole (Scheme 21):

Scheme 21

14

N NMR chemical shift values of nitrogen atoms in N-trimethylsilylazoles.

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The acceleration of the exchange process in N-TMS-imidazole and N-TMS-benzimidazole is most likely due to the catalytic effect of trimethylchlorosilane that many researchers used either as catalyst in the reaction of trimethylsilylation of azoles by hexamethyldisilazane ([1974JOMC347 and references in 2001ROC149]) or as silylation agent ([1976IC3054, 1990ACS1050 and references in 2001ROC149]). The second factor explaining the rapid silylotropic rearrangement may be associated with a higher basicity of the pyridine nitrogen atom in the imidazole and benzimidazole than pyrazole. For example, Torocheshnikov et al. [1974JOMC347] failed to slow the migration of the TMS-group in N-(trimethylsilyl)imidazole even at 80оС and they suggested that involvement of a difficult intermolecular exchange process. In fact, the synthesis of N-(trimethylsilyl)imidazole [1974JOMC347] was carried out in the presence of Me3SiCl, which accelerates, in our opinion, the migration process of trimethylsilyl group. Other researchers [1976IC3054] found themselves in a similar situation. N-TMS-imidazole and its 2-methyl derivatives were obtained by silylation of corresponding imidazoles using as silylated agent trimethylchlorosilane. O’Brien with colleagues [1971JOMC185] found that the activation energy for N-(trimethylsilyl)pyrazoles determined from analysis of line shape in diluted aqueous solutions of diphenyl ether is unusually low (3–6 kcal/mol), whereas the activation energy for neat liquids—24–32 kcal/mol. The presence of water in dilute solutions leads to hydrolysis of the N-trimethylsilylpyrazole derivatives, and the formed products can catalytically accelerate the exchange process. Undoubtedly, participation of catalysts in an exchange process indicates the intermolecular nature of the silylotropic rearrangements in the N-TMS-imidazole and N-TMS-benzimidazole. Silylotropic rearrangement of 4-substituted N-trimethylsilylpyrazole (neat liquids) [1998MRC110, 2001ROC149, 2003DISS] is also intermolecular in nature, with the only difference that this is due to the formation of associates of the type: ...TMS-Azole....TMS-Azole... Thus, the results of our research provided an opportunity to critically evaluate some of the literature data, revise the interpretation of the findings (conclusions) of earlier works in this area, clarify the existing views on the processes of elementotropy in azoles, and carry out some generalization of the results of these studies.

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7. The structure of trimethylsilylation products of 1,2,4-triazole-5-one derivatives and products of subsequent trans-silylation by dimethyl(chloromethyl)chlorosilane 1,2,4-Triazole-5-ones, in particular, 3-nitro-1,2,4-triazole-5-one are high-energy compounds and widely used as explosives. The structure, tautomeric properties and thermal stability of high-energy explosive 1,2,4triazolone, 3-nitro-1,2,4-triazole-5-one (NTO), and its derivatives has been intensively studied [2003DISS, 2009MI2, 2006CEP9, 2016CHE948, 2016CR3919, 2017TA655, 2018AHC(124)233, 2018EP200, 2018 CEC6252, 2018MI2]. The structural features of the substituted 1,2,4triazolinones and their analogs showing wide applications in different research disciplines. At the same time, azolones used to produce a wide range of substituted ribonucleosides, wherein the intermediate products are used trimethylsilylated azolones. We have studied the trimethylsilylation of 1,2,4-triazole-5-one (70), 3-nitro- (71) and 3-chloro- (72), and their N-methylated analogs 73–75 [1996MI6, 1998MI2, 2001MI1, 2003DISS] by 1H, 13C, 15N and 29Si NMR spectroscopy. The study of structural features of the 1,2,4-triazolone is complicated by their annular and keto-enol tautomerism (Schemes 22 and 23). However, as a rule, tautomeric equilibrium in 1,2,4-triazolinone shifted toward the azolinone form.

Scheme 22 The prototropy and keto-enol tautomerism in 1,2,4-triazole-5-ones.

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Scheme 23 The prototropy and keto-enol tautomerism in N-methyl-1,2,4-triazole5-ones.

7.1 The silylation products of 1-methyl- and 4-methyl-1,2,4triazole-5-one To facilitate the identification of products of 1,2,4-triazole-5-ones trimethylsilylation, silylation products of model (methylated) compounds (73, 75) were studied. The interaction of 4-methyl-1,2,4-triazolone-5 (75) with (Me3Si)2NH leads to a single product of trimethylsilylation—NTMS-derivative (Scheme 24). The formation of 4-methyl-1-trimethylsilyl1,2,4-triazolone-5 (76) is indicated by the presence of a signal in 29Si NMR spectrum at 16.2 ppm (N–Si), and as well as the presence in the proton spectrum of signals at 7.54 (H-3), 3.26 (CH3) and 0.45 (Me3SiN) ppm. There are four signals in the 13C NMR spectrum: δ ¼ 159.26 (C-5), 139.56 (C-3), 28.16 (CH3), 1.33 (NSiMe3), and in the 15N NMR spectrum there are three: δ ¼ 204.4, 111.3, 244.5 (N-1, N-2 and N-4, respectively) (Table 14) [1998MI2, 2001MI1].

Scheme 24 The trimethylsilylation of 4-methyl-1,2,4-triazole-5-one.

ARTICLE IN PRESS 44 Table 14

Lyudmila I. Larina

13

C, 15N and 29Si NMR chemical shifts (ppm) of 1,2,4-triazole derivatives. δ15N δ 13C

Compound

C-3

C-5

N-1

N-2

N-4

δ29Si

76

139.56

159.26

204.4

111.3

244.5

16.2

77

147.79

157.22

216.6

103.6

163.8

29.0

78

136.02

156.11

204.8

163.8

230.8

14.1

79

135.38

153.55

242.4

104.9

219.7

24.9

80

135.26

153.86

245.0

214.2

245.7

11.2

81

157.87

155.53

194.6

94.9

167.6  23.8a

33.9

82

144.20

152.31

247.9

197.6

214.6

25.6

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Organosilicon azoles

Table 14 cont’d

13

C, 15N and 29Si NMR chemical shifts (ppm) of 1,2,4-triazole derivatives.— δ15N

δ 13C Compound

C-3

C-5

N-1

N-2

N-4

δ29Si

83

161.73

162.06

194.9

94.8

167.4  23.2a

32.2 22.2

85

164.20

160.40

98.3

109.0

247.9  33.4a

24.6

86

163.66

160.53

202.3

139.6

154.0

27.4 14.2

87

162.42

150.72

134.0

103.3

190.0

29.5 23.5

88

146.88

167.69

187.2

103.1

197.0

15.2 15.9

89

150.91

162.42

229.5

150.6

162.0

16.2

90

139.01

162.42

94.8

126.2

202.2

24.5 12.8

δ N (NO2).

a 15

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At the same time, silylation of 1-methyl-1,2,4-triazole-5-one (73) leads to a mixture of two products 77 and 78, and according to 1H NMR data the ratio is 1:1.5, respectively (Scheme 25).

Scheme 25 The formation of methyl-1,2,4-triazolium chloride.

5,5-trimethyl-3,4-dihydro-5-silaoxazolo[2,3-d]-1-

There are two silicon signals (29.0 and 14.1 ppm) in the 29Si NMR spectra related to OSi- and NSi-group in 77 and 78 compound, respectively. Three pairs of 15N NMR signals are assigned, respectively, to atoms N-1, N-2 and N-4 of minor 77 (216.6, 103.6 and 163.8 ppm) and the major 78 (204.8, 163.8 and 230.8 ppm) isomers [1998MI2, 2001MI1, 2003DISS]. The reaction of 76 with dimethyl(chloromethyl)chlorosilane leads to previously unknown bicyclic salt (80)— 4,4-dimethyl-5H-4-silaoxazolo[2,3-e]-4methyl-1,2,4-triazolium chloride (Scheme 26), while the mixture 77 and 78 forms a new isomeric product (79)— 5,5-trimethyl-3,4-dihydro-5silaoxazolo[2,3-d]-1-methyl-1,2,4-triazolium chloride (Scheme 25).

Scheme 26 The formation of 4,4-dimethyl-5H-4-silaoxazolo[2,3-e]-4-methyl-1,2,4triazolium chloride.

The most informative in establishing the bicyclic structures are the 1H NMR signals of methylene protons and the 29Si NMR signals. The proton signals of the CH2 group of compound 80 is shifted to downfield by about 0.4 ppm (due to proximity to the oxygen atom) compared to 79, and the 29Si resonance signals of the fragment Me2SiN (80) are in a more upfield than Ме2ЅіО (79) (14 ppm).

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47

The proposed mechanism of the reaction of TMS-derivatives 76, 77 and 78 with ClMe2SiCH2Cl includes the stage of trans-silylation with elimination of Me3SiCl, intramolecular N- or O-silylmethylation with intermediate formation of pentacoordinated silicon compound and heterocyclization into the bicyclic ionic products [1998MI2, 2001MI1, 2003DISS].

7.2 The silylation products of 3-nitro-1,2,4-triazole-5-one and its 1-methyl derivatives The trimethylsilylation of the 1-methyl-3-nitro-1,2,4-triazole-5-one 74 occurs exclusively on the oxygen atom with the formation of 81 (Scheme 27), as indicated by the value of δ29Si ¼ 33.9 ppm, belonging to the OSiMe3 group.

Scheme 27 The formation of 5,5-dimethyl-3,4-dihydro-5-silaoxazolo[2,3-d]-1-methyl-3-nitro-1,2,4-triazolium chloride.

3-Nitro-1,2,4-triazole-5-one (71), interacting with hexamethyldisilazane, is converted into the bis-silylation product—1 -trimethylsilyl-3-nitro-5-trimethylsiloxy-1,2,4-triazole (83) (Scheme 28).

Scheme 28 The formation of 5,5-dimethyl-3,4-dihydro-5-silaoxazolo[2,3-d]-3-nitro-1,2,4triazole.

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Of the two possible structures 83 and 84, preference is given to the first, since the position of the signals in the 15N NMR spectrum of 83 coincides with that for the model compound 81. 29Si NMR signals at 32.2 and 22.2 ppm relevant to OSiMe3 and NSiMe3 groups, respectively (Scheme 28) (Table 14) [1998MI2, 2001MI1, 2003DISS]. The shielding value of magnetically active nuclei in compounds 81 and 83 is close enough, which indicates the similar electronic effects of N-substituents—CH3 and Me3Si. Trans-silylation reaction of 81 and 83 according to NMR spectroscopy leads to new bis-cyclic compounds—5,5-dimethyl-3,4-dihydro-5-silaoxazolo [2,3-d]-1-methyl-3-nitro-1,2,4-triazolium chloride (82) (Scheme 27) and 5,5-dimethyl-3,4-dihydro-5-silaoxazolo[2,3-d]-3-nitro-1,2,4-triazole (85) respectively (Scheme 28) (Table 14).

7.3 The structure of silylation products of 3-chloro-1,2,4triazole-5-one 3-Chloro-1,2,4-triazole-5-one (72) in the same conditions is silylated with the formation of two isomers (86, 87) (Scheme 29). The 13C NMR spectrum of the products of trimethylsilylation of 3-chloro derivative 72 by hexamethyldisilazane contains two sets of low-field resonance signals of the ring carbons of different intensity (δ 162.47 and 150.77 ppm—major; δ 163.71 and 160.61—minor) (Table 14).

Scheme 29 The trimethylsilylation of 3-chloro-1,2,4-triazole-5-one.

The 29Si NMR spectrum contains four signals of TMS-groups: 29.6, 27.4 ppm (OSiMe3) and 23.8, 14.3 ppm (NSiMe3). The 15N NMR spectrum has six nitrogen signals and 1H NMR spectrum has two sets of signals (OSiMe3 and NSiMe3) with ratio of the integrated intensity of 1:2. These data prove the structure of the two bis-silylated isomers 86 and 87 (1:2) (Table 14).

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49

7.4 The structure of the silylation products of 1,2,4triazole-5-one The silylation of 1,2,4-triazole-5-one (70) by excess of hexamethyldisilazane leads to the formation of a mixture of three products 1:1.5:2 (88–90) from the four possible (88–91) (Scheme 30). We managed to identify these products by NMR spectroscopy (Table 14).

Scheme 30 The generation of bicyclic organosilicon azoles.

The presence in the proton spectrum of the three signals at low field (δ 7.85, 7.28 and 7.51 ppm—in order of increasing intensities 1:1.5:2) and six signals of protons of Me3Si group (δ 0.34, 0.39, 0.43, 0.45, 0.46, 0.47 ppm) at high field suggests the existence of three isomers, each of which contains two TMS groups (88–91). In this case the first two signals in this region belong to the OSiMe3 group (δ 0.34—low intensive, δ 0.39—more intense), and four signals, respectively, to the group NSiMe3 (δ 0.43, 0.45, 0.46 and 0.47 ppm). The spectrum of 29Si NMR is detected two sets of signals: in a low field there are two signals (27.3 and 23.9 δ), which can be attributed to the OSiMe3 groups, and four signal (15.8, 15.6, 14.9, 12.5 δ), related to NSiMe3 groups. The ranges of the chemical shifts of 29 Si atoms are characteristic for OSiMe3 and NSiMe3 [1988MC457, 2003DISS, 2008MI1]. The 13C NMR spectrum in the region of high field includes 5 signals (because of the coincidence of two signals of the six expected) relating to

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Lyudmila I. Larina

the carbon of trimethylsilyl groups. The signals 0.73 and 0.93 δ belong to the carbon atoms of OSiMe3 groups, and when 1.58, 1.91 and 2.17 δ—to the carbon NSiMe3 groups. In the low field region of the 13C spectrum six signals belong to the atoms C-5 (169.85, 164.52 and 164.3 δ) and the atoms C-3 (153.01, 149.56 and 141.43 δ) proposed three isomers. Recording of NMR spectra with 13C decoupling from protons, but without the Overhauser effect (gate-decoupling), allowed us to estimate the approximate ratio of isomers is 1:1.2:1.5—N,O- N,N- and N,O-isomers, respectively (Scheme 30). The mixture of isomers 88–91 after treatment by ClCH2SiMe2Cl transforms, respectively, into the bicyclic products: 4,4-dimethyl-5H-4-siloxano [2,3-d]-1,2,4-triazole (88а), 4,4-dimethyl-5H-4-seroxat-lo[2,3-e]-1,2,4triazole (88b), 5,5-dimethyl-3,4-dihydro-5-siloxano[2,3-C]-1,2,4-triazole (89a) and 5,5-dimethyl-3,4-dihydro-5-siloxano[2,3-b]-1,2,4-triazole (90a) (Scheme 31, Scheme 32). The last have identified on the basis of the analysis of NMR data of model methylated isomers, 3-substituted analogs and related compounds [2002TA187, 2003DISS, 2008MI1]. Bis N,N-silylated product 88 with ClCH2SiMe2Cl forms two bicyclic products 88a and 88b. The isomer 89 transforms into bicyclic compound 89a, while products 90 and 91 give only one and the same heterocycle 90a (Scheme 31, Scheme 32).

Scheme 31 The mechanism of formation of bicyclic organosilicon azoles.

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51

Thus, the results of studies of trimethylsilylation products of azoles indicate a significant influence of the substituents on the process of silylation: 1,2,4-triazolone in the interaction with hexamethyldisilazane forms three TMS-silylation products, 3-chloro derivative—2 products and 3-nitroisomer—only single product.

Scheme 32 The formation of 5,5-dimethyl-3,4-dihydro-5-siloxano[2,3-b]-1,2,4-triazole.

The authors [1982JOC474] after trimethylsilylation of 1,2,4triazolinone obtained a mixture in which two TMS-products were proposed (Scheme 33).

Scheme 33 Trimethylsilylation products of 1,2,4-triazole-5-one.

In addition, authors [1982JOC474] showed that trimethylsilylation of imidazole-2-one by hexamethyldisilazane (using the catalytic amount of trimethylchlorosilane) results 1-trimethylsilyl-2-(trimethylsilyloxy)imidazole (Scheme 34).

Scheme 34 The trimethylsilylation of imidazole-2-one.

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Lyudmila I. Larina

The chemical equivalence of the protons H-4 and H-5 in proton NMR spectra [1982JOC474] indicates rapid exchange of trimethylsilyl groups between the atoms N-1 and N-3 in the imidazole cycle (at room temperature). In our opinion, the rapid exchange (or low barrier) of 1Ð3 migration of trimethylsilyl group in the 1-trimethylsilyl-2-(trimethylsilyloxy)imidazole [1982JOC474] is due to the catalytic effect of trimethylchlorosilane used by the authors to catalyze the trimethylsilylation reaction [1996RCB2861, 2001ROC149, 2003DISS] (Scheme 34). As mentioned earlier, the lactim-lactam tautomerism (AÐB) of trimethylsilylbenzoxazolone (69) which is observed along with the ring-chain rearrangement has been studied by NMR in [1981RGC1096] (Table 13). The 29Si NMR chemical shift value (16.8 ppm) in the compound 69 was assigned to the fragment O-SiMe3, thus, the authors [1981RGC1096] believe that the tautomeric form 69A prevails (Scheme 35).

Scheme 35 The ring-chain rearrangement and lactim-lactam tautomerism of trimethylsilylbenzoxazolone.

However, based on the results of our studies of TMS-1,2,4-triazoles containing N-SiMe3 and O-SiMe3 groups (Table 14) and data of work [1988MC457] it is possible to assume that the value of δ29Si 16.8 ppm refers to the group N-SiMe3 but not O-SiMe3-group (Table 14). The value of δ29Si silicon atom of O-SiMe3-group is significantly greater (20–23 δ) then those of the N-SiMe3 groups. The results of our studies of compounds containing N-SiMe3 and O-SiMe3 groups have allowed us to make corrections of some literature reports on the determination of structure of silicon-containing heterocyclic compounds.

8. Conclusion Methods of multinuclear and dynamic NMR spectroscopy (1H, 13C, N, Si) and quantum chemistry have systematically established structural features and tautomeric transformations of a wide series of C- and N-organosilicon substituted azoles (pyrazoles, imidazoles, 1,2,3-triazoles,

15

29

ARTICLE IN PRESS 53

Organosilicon azoles

1,2,4-triazolones and their benzanalogs) and their model derivatives, as well as the structure of previously unknown reactions of some of them with a number of organic and organosilicon compounds promising for practical use. Thus, the barriers of silylotropy exchange of Me3Si-group in N-trimethylsilylazole derivatives change in range 22–25 kcal/mol and depend in a complex way on a nature of the substituent. Silylotropy in N-trimethylsilylpyrazoles in the presence of halogens or trimethylhalosilanes is believed to proceed through formation of N,N0 -bis(trimethylsilyl) pyrazolium salts, the barrier of silylotropy in pyrazoles being markedly reduced. The results of our examinations of the structure and tautomerism (silylotropy) of organosilicon derivatives of nitrogen heterocycles (azoles) and a generalization of the data available on this subject made it possible to take a fresh look at some aspects of tautomerism and to reveal erroneous results and conclusions of previous works. The high efficiency of using 29Si and 15N NMR spectroscopy in resolving structural issues of the chemistry of functionally substituted heterocyclic systems (organosilicon azoles) has been shown.

Acknowledgments I thank Igor Grushin for support and kind help with translation of this manuscript. This review would certainly not have seen a light without the loving encouragement and tolerance contributed over the many years by my big and friendly family: daughter Polina, son Sergei, parents Polina and Ivan, sister Tatyana, brother Aleksei, daughter-inlaw Maria, son-in-law Boris, and also all the grandchildren Mikhail, Anastasiya, Anna, Stepan, Alexander, Leonid, Anatoly, Alena, and Arina.

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A.W. Brown, Adv. Heterocycl. Chem., 126, 55 (2018). N.F. Lazareva, V. Baryshok, and I. Lazarev, Arch. Pharm., 351, 1700297 (2018). J. Li, S. Jin, G. Lan, X. Ma, J. Ruan, B. Zhang, and L. Li, Cryst Eng Comm., 20, 6252 (2018). C.R.W. Reinhold, Z. Dong, J.M. Winkler, H. Steinert, M. Schmidtmann, and T. Meller, Chem. A Eur. J., 24, 848 (2018). M.H. Habicht, F.F. Wossidlo, T. Bens, E.A. Pidko, and C. Meller, Chem. A Eur. J., 24, 944 (2018). S.V. Basenko and A.S. Coldatenko, Chem. Heterocycl. Compd., 54, 100 (2018). M.N. Khrizanforov, S.V. Fedorenko, A.R. Mustafina, K.V. Kholin, I.R. Nizameev, S.O. Strekalova, V.V. Grinenko, T.V. Gryaznova, R.R. Zairov, R. Mazzaro, V. Morandi, A. Vomiero, and Y.H. Budnikova, Dalton Trans., 47, 9608 (2018). R. Khatiwada, L. Abrell, G. Li, R.A. Root, R. Sierra-Alvarez, J.A. Field, and J. Chorover, Environ. Pollut., 240, 200 (2018). D. Ren, H. Liu, Y. Huang, X. Fu, and X. Li, J. Chem Res., 42, 297 (2018). C. Frota, E.C. Polo, H. Esteves, and C.R.D. Correia, J. Org. Chem., 83, 2198 (2018). Y.S. Vysochinskaya, A.A. Anisimov, S.A. Milenin, A.A. Korlyukov, F.M. Dolgushin, E.G. Kononova, A.S. Peregudov, M.I. Buzin, O.I. Shchegolikhina, and A.M. Muzafarov, Mendeleev Commun., 28, 418 (2018). A.V. Astakhov, K.Y. Suponitsky, and V. Chernyshev, Mendeleev Commun., 28, 439 (2018). M.V. Pletneva and L.O. Belova, Application of N-Trimethylsilylimidazole as a Highly Effective Silylating Reagent, MIREA, Russian Technol. Univer.: Moscow: (2018)(russ). D.S. Viswanath, T.K. Ghosh, and V.M. Boddu, Emerging Energetic Materials: Synthesis, Physicochemical, and Detonation Properties, Springer: New-York: (2018), 477. Z. Han, K. Xie, X. Ma, and X. Lu, Phosphorus Sulfur Silicon Relat. Elem., 5, 488 (2018). B.A. Gostevskii and N.F. Lazareva, Russ. J. Gen. Chem., 58, 1639 (2018). V.М. Annenkov, V.A. Palshin, S.N. Zelinski, L.I. Larina, and E.N. Danilivtseva, Dyes Pigments, 160, 336 (2019). N.O. Yarosh, L.V. Zhilitskaya, L.G. Shagun, I.A. Dorofeev, and L.I. Larina, Russ. J. Org. Chem., 55, 352 (2019).

Further reading 1988CB895 1996AFC815 1996JOC2934

A. Boettcher, T. Debaerdemaeker, J.G. Radziszewski, and W. Friedrichsen, Chem. Ber., 121, 895 (1988). E. Troyano, M. Villamiel, A. Olano, J. Sanz, and I. Martinez-Casrto, J. Agric. Food Chem., 44, 815 (1996). P.F. Pagoria, A.R. Mitchell, and D. Schmidt, J. Org. Chem., 61, 2934 (1996).

ARTICLE IN PRESS Organosilicon azoles

1997MI1

1997RCJ73 2008T1753 2018PMP71

63

P.F. Pagoria, A.R. Mitchell, R.D. Schmidt, and L.E. Fried, Chemistry & Materials Science Progress Report: Summary of Selected Research and Development Topics, Lawrence Livermore, Univer.: California: (1997)28preprint UCID-20622-97. M.S. Pevzner, Russ. Chem. J., 41, 73 (1997). M. Morita, Y. Hari, T. Iguchi, and T. Aoyama, Tetrahedron, 64, 1753 (2008). N.N. Vlasova, E.N. Oborina, L.I. Belousova, and L.I. Larina, Prot. Met. Phys. Chem. Surf., 54, 71 (2018).

CHAPTER TWO

Recent advances in the Nenitzescu indole synthesis (1990–2019) Florea Dumitrascua,*, Marc A. Iliesb a

Center for Organic Chemistry “C. D. Nenitzescu” Romanian Academy, Bucharest, Romania Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, United States *Corresponding author: e-mail address: [email protected] b

Contents 1. Introduction 2. Mechanism and intermediates 2.1 Mechanism 2.2 Intermediates 3. Starting materials 3.1 1,4-Benzoquinones 3.2 1,4-Naphthoquinones 3.3 Heterocyclic benzoquinones 3.4 Enamines 3.5 Enamino benzoquinone hybrids 3.6 Quinoneimines and quinonediimines 4. Improvements and modifications of the Nenitzescu reaction 5. Impact of reaction conditions 6. Products of the Nenitzescu synthesis 6.1 5-Hydroxyindoles 6.2 6-Hydroxyindoles 6.3 4,5-Dihydroxyindoles 6.4 Other indolic structures as byproducts 7. Nonindolic compounds of the Nenitzescu reaction 7.1 5-Hydroxybenzofurans and annelated derivatives 8. Unexpected products of the Nenitzescu reaction 9. Applications Acknowledgments References

2 4 4 9 12 12 18 24 32 66 67 70 72 74 74 75 76 77 78 78 80 80 83 83

Abstract This review, based on the literature published since 1990, highlights recent advances in the Nenitzescu 5-hydroxyindole synthesis—one of the most useful methods for obtaining of the 5-hydroxyindoles starting from 1,4-benzoquinones and β-enamines. The 5-hydroxyindole skeleton is an important component of many biologically active Advances in Heterocyclic Chemistry ISSN 0065-2725 https://doi.org/10.1016/bs.aihch.2020.03.001

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2020 Elsevier Inc. All rights reserved.

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natural products, drug-like compounds and has high potential for advanced material applications, as demonstrated recently. Another significant feature of the Nenitzescu reaction is the formation of 5-hydroxybenzofurans. The extension of the Nenitzescu reaction, through variations in the structure of the quinone and/or the enamine used, has also proved a useful procedure for obtaining compounds incorporating the 5-hydroxyindole moiety, 6-hydroxyindoles, 5-hydroxyindazoles, and other structures. The ongoing interest for 5-hydroxyindole synthesis from 1,4-benzoquinone and enamines is due to the simple working procedures, mild reaction conditions, and easily accessible and structurally diverse starting materials. Also, the interesting biological properties observed for Nenitzescu reaction products and for their congeners obtained through subsequent modifications make 5-hydroxyindoles privileged structures in the quest to achieve structurally diverse compounds with unique biological properties. Keywords: Nenitzescu indole synthesis, 5-Hydroxyindoles, 1,4-Benzoquinones, β-Enamines, 5-Hydroxybenzofurans, 6-Hydroxyindoles, 4,5-Dihydroxyindoles, Condensed indoles, 5-Hydroxyindazoles, Biological activities, Arbidol (umifenovir), Antiinfluenza, Antimicrobial, Anticancer

1. Introduction Ninety years ago, Nenitzescu (1929BSCR37) discovered the generation of 5-hydroxyindole derivatives through the reaction between 1,4benzoquinones and ethyl 3-aminocrotonates. The reaction is currently known in the literature as the Nenitzescu reaction or the Nenitzescu indole synthesis and has been proved to be a general procedure for accessing 5-hydroxyindoles bearing different substitution patterns. The archetypal Nenitzescu 5-hydroxyindole synthesis implies the condensation between 1,4-benzoquinone 1 and ethyl β-aminocrotonate 2 to form ethyl 5hydroxy-2-methylindole-3-carboxylate 3 (Scheme 1) (1929BSCR37). The reductive cyclization of the o,β-dinitrostyrenes 4 (Scheme 1) is another synthesis of indoles, published by Nenitzescu in 1925 (1925BER1063), which allowed the synthesis of indoles of type 5 (Scheme 1). However, its synthetic potential is somewhat lower as compared to the Nenitzescu 5-hydroxyindole reaction, due to limited accessibility of dinitroderivates 4 and a rather difficult work-up procedure. The Nenitzescu reaction also allows access to 6-hydroxyindoles, 5-hydroxybenzofurans, 5-hydroxyindazole, and other more diverse structures that are difficult to access through other pathways (1973OR337, 1993PCJ413, 2008COC691). An extension of the Nenitzescu reaction via different quinones, enamines and diverse reaction conditions has proved

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Nenitzescu indole synthesis (1990–2019)

O CO2Et

+

Acetone

CO2Et

HO

Ethanol H2N

O 1 1,4-Benzoquinone

N H

Me 2 3-Aminocrotonic ester

Me

3 5-Hydroxyindole

Nenitzescu 5-hydroxyindole synthesis 1929 R

NO2 NO2

R Fe/AcOH EtOH

4

N H 5

Nenitzescu indole synthesis 1925 Scheme 1 The original Nenitzescu indole syntheses.

to be a fruitful synthetic method for accessing new fused heterocyles incorporating the 5-hydroxyindole or 5-hydroxybenzofuran backbone, such as pyrido[2,3-b]indole (2008JHC1517), benzocarbazoles (1994APH137, 2005BMC819, 2017ADV24813), furo[3,2-h]indole (2003CHC872), furo [2,3-g]indole (2003CHC872), imidazo[4,5-g]indole (2003CHC61), dihydrobenzo[g]indole (2005T9129), pyrrolo[2,3-h]quinoline (2004CH C16), and others. Thus, the Nenitzescu indole synthesis is a simple, straightforward and versatile method for preparation of compounds with potential biological activities, starting with easily accessible synthons. The 5hydroxyindole substructure is present in natural compounds such as the neurotransmitter serotonin 6, hormone melatonin 7, 5-hydroxytryptophan 8, and the alkaloid bufotenin 9, which have biological properties of great significance (Fig. 1). The antiinflammatory agent indomethacin 10 and antiviral arbidol 11 are another two synthetic drugs presenting a 5-hydroxyindole moiety. Other 5-hydroxyindole containing derivatives are the marine alkaloids hainanerectamines A, B (12, 13), hyrtiosins A, B (14, 15), hyrtinadine A, among others, which have been isolated, synthesized and investigated for their biological activities (Fig. 1) (2015MD4814). Developments in the synthetic and mechanistic aspects, and toward applications of the Nenitzescu indole synthesis, have been reviewed previously in reports dedicated to this reaction (1973OR337, 1993PCJ413, 2008COC691) or in reviews covering the synthesis and reactivity of indoles

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(CH2)2NH2

HO

(CH2)2NHCOMe

MeO

COOH

HO

7 Melatonin

6 Serotonin (CH2)2NMe2

HO

8 5-Hydroxytryptophan

MeO

NMe2

CH2COOH

HO

Me

Br

N

N H

CO2Et N

COC6H4Cl-p

9 Bufotenin

OHC

CH2SPh

Me

10 Indometacin O

NH2

N H

N H

N H

11 Arbidol H

COCH2OH

HO

CH2COMe HO

HO

Me OH N H 12 Hainanerectamine A O

N H

N H 13 Hainanerectamine B

14 Hyrtiosin A N

O

HO

HO

OH

OH N H

15

N H

Hyrtiosin B

N

N H

N H 16 Hyrtinadine A

Fig. 1 Natural and synthetic representatives of the 5-hydroxyindole family having biologic activity.

(1972MI413, 1992RC506, 2000JCSP(1)1045, 2005MI145, 2006CR2875, 2010MI2042, 2014CHC1400, 2016MI188, 2019RCR99) and enamines (1996AHC207, 1998AHC283).

2. Mechanism and intermediates 2.1 Mechanism Two mechanisms have been proposed for the formation of 5-hydroxyindoles through the Nenitzescu reaction between 1,4-benzoquinones and enamines. The two mechanisms differ essentially by the way the enamine reacts with the quinone in the first step of the reaction. Chronologically, the first mechanism was reported by Steck and coworkers in 1959 and implies as key step the generation of a CdN bond through the 1,2-addition of the amine group from the enamine to the C]O group of the quinone giving 1,4-benzoquinone hemiaminal 17

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(Scheme 2) (1959JO1750). Elimination of water from tautomer 18 gives the N-substituted 4-aminophenol 19, which cyclizes to generate the expected 5-hydroxyindole 3. O CO2Et H2N

Me

N H

HO

O 1

2

CO2Et

HO

CO2Et

O

1,2-Addition

+

Me

HO –H2O

CO2Et

HO

Me

N H

Me

18

17 CO2Et

N H

HO

Me

N H 3

19

Scheme 2 Steck’s mechanism proposed for the Nenitzescu indole synthesis.

Steck’s mechanism implies the 1,2-addition at the carbonyl group of the quinone, which is not sustained by experimental evidence. In this context, instead of the intermediate 17, a related 1,2-adduct of type 21, generated by addition of the α-carbon of the aminocrotonic ester to the carbonyl group, has been proposed as the intermediate in the synthesis of 6-hydroxyindoles 23 starting from benzoquinone and enaminoesters (Scheme 3). The bicyclic intermediates of type 22 resulting from the condensation reaction have been isolated, characterized and their chemical and biological properties were investigated (2014GC4359, 2015T4084). O

OH

CO2Et

CO2Et 1,2-Addition

+ Me

O

NHR

O 1

21

20 OH

HO

N R 22

Me

RHN

CO2Et

CO2Et Me

–H2O

HO

N

Me

R 23

Scheme 3 Access to 6-hydroxyindoles through Nenitzescu synthesis via a 1,2C-addition to the carbonyl group of the quinone.

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The second mechanism proposed for the formation of 5-hydroxyindoles is the so-called Nenitzescu–Allen mechanism, which is the generally accepted mechanism for this reaction (Scheme 4) (1965RRC339, 1966JA2536). This mechanism differs from the Steck’s mechanism (Scheme 2) and involves the formation of enamino hydroquinone 25 by the reaction of benzoquinone with enamino ester 2 in the first step of the mechanism, which leads to a new CdC bond between the α-enaminic carbon atom and the C]C bond of the quinone. The reaction mechanism is complex and the key role played by intermediate 25 (Scheme 4) in the formation of 5-hydroxyindoles was proposed by its discoverer in 1929 (1929BSCR37). It must be emphasized that the first mechanism proposed by Raileanu and Nenitzescu in 1965 and then strengthened in 1971 was based on experimental evidence including the isolation of some reaction intermediates and their transformation to the corresponding indoles (1965RRC339, 1971T5031). A similar mechanism was proposed by Allen in 1966 (1966CIL117, 1966JA2536, 1968JO198) and substantiated by experimental evidence arising from further studies (1966JO2669, 1972T5251, 1973T921, 1975T1631, 1978LA129). O CO2Et

CO2Et –

O

+ Me

O

Me OH

O 24

2 CO2Et

HO

CO2Et NH

HO

26 CO2Et

O +

27

O

25b CO2Et Me

N H 28

Me

NH2

NH2

OH

N H

O

OH

25a

HO

CO2Et Me Oxidation

Me

O

+

NH2

–

Me

NH2

O 1

CO2Et

+

NH2

Me

CO2Et

HO Reduction N H

Me

3

Scheme 4 Raileanu-Nenitzescu/Allen mechanism for accessing 5-hydroxyindoles.

The Nenitzescu–Allen mechanism (Scheme 4) is nowadays unanimously accepted as the reaction mechanism for the Nenitzescu indole synthesis (1965RRC339, 1971T5031, 1966CIL117, 1966JA2536, 1968JO198, 1972T5251, 1973T921, 1975T1631, 1978LA129, 1980APH582, 1980APH697), although the Steck mechanism (Scheme 1) cannot be

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completely dismissed. The most important steps and intermediates are as follows: initial Michael 1,4-addition of enamine 2 to 1,4-benzoquinone 1 gives the imino derivative 25a, which by tautomerization leads to enamino hydroquinone 25b. Oxidation of 25b to the corresponding quinone 26 in the presence of unreacted benzoquinone followed by cyclization of enamino quinone 26 to carbinolamine 27 and subsequent elimination of water to give quinonium intermediate 28. Reduction of the intermediate 28 by unreacted enamino hydroquinone 25b gives the final 5-hydroxyindole 3. Beer (1953JCS1262), Monti (1966JO2669), Grinev (1962ZOB1948), Kucklander (1972T5251, 1973T921, 1975T1631, 1978LA129), and other researchers also contributed significantly to a better understanding of the Nenitzescu 5-hydroxyindole mechanism either by isolation of certain intermediates or by studying their chemical transformation. Also, an intermediate resulting through an electron bimolecular transfer between 25b and 27 species was suggested as key intermediate in the indole synthesis (1979TL4009). It was demonstrated that the reaction mechanism implying an oxidation–reduction process has a crucial role to direct the reaction toward 5-hydroxyindoles instead of benzofurans or other byproducts (1965RRC339, 1971T5031, 1966CIL117, 1966JA2536, 1990CHC274). Thus, the generally accepted Nenitzescu–Allen mechanism involves an oxidation–reduction pathway. The formation of indoles in solvents of low polarity and in the presence of Lewis acid catalysts such as ZnCl2, ZnI2, AlCl3, and BF3
Et2O was explained on the other hand in terms of a nonredox mechanism (Scheme 5) (2006JHC873, 2008TL7106,

+O

_ ZnCl2

_ ZnCl2

CO2Et

O

CO2Et

H

+ Me O 29

O

O+

O

_

CO2Et + N

H H _ ZnCl2 32

Me

HO

Me

NH2

ZnCl2 31

30

H

CO2Et

H

HO

Me

NH2 2

HO

+

NH2

H

CO2Et

N H O+ H _ ZnCl2 33

Me

CO2Et

HO –H2O –ZnCl2

N H

Me

3

Scheme 5 The nonredox mechanism of the Nenitzescu reaction in the presence of Lewis acids such as ZnCl2.

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2016EJMC466). The best results were obtained with Zn (II) salts as catalysts, which is explained by the high affinity of Zn(II) to coordinate the oxygen, compared to other Lewis acids. The authors proposed as the first step of the reaction the formation of zinc complex 29 through coordination of the oxygen atom of benzoquinone with Zn(II) ion (Scheme 5). In the next step of the mechanism the zinc complex 29 reacts with enamine to give intermediate 30, which after tautomerization to 31 undergoes cyclization leading to 32 and 33 complexes. The final reaction product 3 is generated by elimination of water and zinc chloride from the intermediate 33. The Nenitzescu indole synthesis in the presence of Lewis acids such as ZnCl2 was extended with good results to enaminones (Scheme 6). Thus, starting from quinone 1 and bis-enaminones 34, the symmetric 5,50 dihydroxydiindoles 35a–c could be obtained (2008TL7106). The formation of bisindoles 35 in the presence of ZnCl2 implies in the first step the generation of the complex bis-enamineone-ZnCl2 36A (Scheme 6), which HO

OH

O Me

Me

+

ZnCl2 COR

RCO

N H

O

C H2

NH n

N

CH2Cl2

RCO Me

34a–c R = Me, Ph, OEt

1

Zn

COR Me

35 R = OEt; n = 2 R = Me, Ph, OEt; n = 6

Me

Me 36B

36A Ce(IV)

5-Hydroxyindole N

N Me

Me

+1

Zn

N

N

O

O

Et3N

H H

Me

Me

Me O

O

O

N

Cl

Cl Me

n

NHR

Ce(IV) RNH O

R N –Ce(IV) –H2O

O 37

OH OH 38

39

Scheme 6 Examples of Nenitzescu indole syntheses proceeding through a nonredox mechanism, via catalytic action of Lewis acids ZnCl2 or Ce(IV).

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9

was isolated and characterized by X-ray analysis. This complex failed to react with 1,4-benzoquinone but in the presence of triethylamine is deprotonated to complex 36B, which in the next step reacts with 1,4-benzoquinones giving indoles 35 (Scheme 6) (2008TL7106). On the basis of this result a similar mechanism was proposed for synthesis of indoles in the presence of Lewis catalysts. It was supposed that the formation of complexes of type 36B is due to enamine basicity. Another nonredox mechanism was proposed for the synthesis of 5-hydroxybenzo[g]indoles from 1,4-naphthoquinone, primary amines, and β-dicarbonyl compounds, using as catalyst ceric(IV) ammonium nitrate (CAN) (Scheme 6) (2010OBC3426, 2013T5401). The proposed mechanism includes the formation of the complex 37 from 1,4-naphthoquinone and CAN, which in the next step reacts with enamine to give cerium(IV) complex 38, followed by its transformation into 5-hydroxybenzo[g]indole 39 (Scheme 6).

2.2 Intermediates The enamino hydroquinones of type 25b, enamino quinones of type 26 and carbinolamines of type 27 have been isolated and fully characterized. They proved to be veritable intermediates because under special reaction conditions they could be converted into the corresponding 5-hydroxyindole (Scheme 4). The formation of transient intermediates 24 and 28 was also suggested but these compounds were not isolated. The proposed imino intermediate structure of type 25a, isolated from reaction between benzoquinone and ethyl 3-amino-3-methylcrotonate, was later revised as being a dihydrobenzofuran derivative (1953JCS1262, 1971T5031). The formation of other transient intermediates in the Nenitzescu reaction has also been proposed by other authors (1979TL4009). 2.2.1 Enamino hydroquinones Enamino hydroquinones 40 (Scheme 7) are considered as key intermediates in the indolization process (Scheme 4) but also in the formation of benzofuran derivatives 42 (Scheme 7). Substituted hydroquinones 40 were isolated in many instances as sole reaction products or in mixtures with indoles, benzofurans or other nonindolic products (1953JCS1262, 1961ZOB2303, 1965RRC339, 1971CHC309, 1971T5031, 1973T921, 1980JO1493, 1981JO4197, 1992CHC299, 1992PCJ523, 1999RCB160, 2003CHC1013, 2006JHC873). The formation of enamino hydroquinones is strongly influenced by factors such as the structure and ratio of reactants

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and nature of the solvent used. The cyclization of enamino hydroquinones to the corresponding 5-hydroxyindoles 43 requires special reaction conditions (1962ZOB1948, 1965RRC339, 1966JA2536, 1968JO198, 1971CHC309, 1971T5031, 1973T921, 2003CHC1013, 2006JHC873) and only one case of direct transformation of enamino hydroquinone to corresponding indole has been reported (1970ABC724). However, enamino hydroquinones 40 can undergo cyclization to indoles 43 (Scheme 7) in the presence of acetic acid and an oxidizing reagent such as the starting quinone (1965RRC339, 1966CIL117, 1968JO198). R3 O

R R

NHR O

1

HO 1

Oxidation

41

O

2

R NHR

Enamino quinones

–ROH 1

42 3

–H2O

R = CO2alk

Cyclization 40

R3

O

5-Hydroxy-benzofuran-2-one

OH Indolization

NHR

Cyclization

3

R HO

HO

2

2

1

–R NH2

R

HO

3

2

N

R

O

R

2

1

R

43 5-Hydroxyindoles

44 5-Hydroxybenzofurans

Scheme 7 Chemical transformations of enamino hydroquinone intermediates 40 toward indoles and other structures.

In the absence of an oxidizing agent, the isolated enamino hydroquinones 40 cyclises to 5-hydroxybenzofuran derivatives 42 or 44 (1965RRC339, 1971T5031, 1990CHC1194). The 5-hydroxybenzofurans 44 are obtained from enamino hydroquinones 40 by cyclization and subsequent elimination of an amine (Scheme 7). If the R3 substituent in the enamino hydroquinones 40 is a highly reactive group R3 (e.g., CO2R) the cyclization process takes place between R3 and OH groups giving a 2-cumaranone derivative 42 (Scheme 7). The nature of substituents grafted on to the enamino moiety in the hydroquinones 40 can also lead by cyclization to other structures (1999RCB160). 2.2.2 Enamino quinones Enamino quinone intermediates of type 41 have been isolated from the reaction mixture and in a few cases they were converted into the corresponding 5-hydroxyindoles 43 (1962ZOB1948, 1966JO2669, 2005T11866). On the other hand, enamino hydroquinones 40 were transformed into

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Me

Br COR O

2

NHR

R

3

COR O Me 46

1

45

O

O

O

O

NHR

2

N H

O

CN

O

47

48 Me

X CF3

N H

Me

CN

O

1

COR

O

COC6H4Me-p

HO

O R X

N OH H

R

49 (R = H, Me; X = H, Cl)

X X

NH

N OH

N OH

N

n

50

51

Fig. 2 Enamino quinones and carbinolamine as intermediates in the Nenitzescu reaction.

the correponding quinones 41 through the use of an oxidizing reagent (1990CHC274). The enamino 1,4-naphthoquinones 45 and 46 (Fig. 2), together with 5-hydroxybenzo[g]indoles and benzo[f]indole-4,9-diones, were isolated in many instances from the reaction of the corresponding 1,4-naphthoquinones with primary amines and β-dicarbonyl compounds (2010OBC3426, 2013T5401). The enamino quinones 47 and 48 were also isolated from reaction of cyclic enamine with 1,4-benzoquinone and 2-methyl-benzoquinone (1970ABC724, 1971ABC282). 2.2.3 Carbinolamines The presence of carbinolamines (hemiaminals) of type 27 (Scheme 4) as intermediates in the Nenitzescu reaction was suggested by Raileanu (1965RRC339) and Allen (1966JA2536). The isolation and investigation of the chemical behavior of carbinolamines was performed by Kucklander (1972T5251, 1973T921, 1975T1631, 1978LA129, 1980APH582, 1980APH697) and by other researchers (1999RCB160). For example, the enamino quinone 52 obtained by Grinev et al. (1962ZOB1948) from condensation of benzoquinone and ethyl N-methyl-β-methylaminocrotonate gives upon standing in ethanol a compound formulated as stereoisomeric enamino quinone 53 (Scheme 8). Its structure was reinvestigated by Kucklander (1972T5251) and revised as being carbinolamine 54. The carbinolamine was transformed into the corresponding indole 55 via treatment with hydroquinone in acetic acid at room temperature. In the absence of hydroquinone no reaction occurred. Grinev et al. (1962ZOB1948) obtained a similar result by catalytic hydrogenation of the compound supposed to be quinone 53.

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CO2Et

O O

CO2Et

CO2Et NHMe

O

NHMe

Me

+ Me

O

O

NHMe

O 1

53

52 CO2Et

O

Me

CO2Et

HO Hydroquinone

HO

N

Me

Me 54

AcOH

N

Me

Me 55

Scheme 8 The isolation of carbinolamine 54 as intermediate in the Nenitzecu reaction and its transformation into indole 55.

Fused carbinolamines 49, 50 (Fig. 2) were obtained in good yields by Nenitzescu reaction between tetrahalogenated benzoquinones with cyclic enamines or heterocyclic ketene aminals (1970JA3470, 2015T4084). It should be noted that the tetracyclic compound 51 (Fig. 2), resulting from condensation between 2-methyl-1,4-naphthoquinone and a heterocyclic ketene aminal, probably has a carbinolamine structure similar to that of compounds 50 (2014GC4359).

3. Starting materials 3.1 1,4-Benzoquinones The availability of quinones and enamines as starting materials in the Nenitzescu synthesis make this reaction one of the most attractive methods for obtaining 5-hydroxyindoles. The most useful quinone for 5hydroxyindole synthesis is 1,4-benzoquinone 1, together with 2-substituted, 2,3-disubstituted, 2,5-disubstituted, 2,6-disubstituted, trisubstituted, and tetrasubstituted 1,4-benzoquinones (Fig. 3). These substituted quinones are used frequently to obtain indoles substituted at the benzene ring. The use of 1,4-naphthoquinone and their substituted derivatives (Fig. 3) has proved to be a good route to prepare benzo[g]indoles (2010OBC3426, 2010TL5160, 2011T8747, 2013T5401, 2016EJMC466). 1,4-Benzoquinones condensed with an aromatic heterocyclic ring constitute a class of quinones that have been shown to be valuable for the generation of condensed heterocyclic systems containing a 5-hydroxyindole moiety (1997T15005, 2000CHC1276, 2002CHC586, 2003CHC61,

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O R

R R

R

R

R

R

R O

O

O

O

O

O

R

R

R R O

O

O

O

O

R

R

Substituted 1,4-benzoquinones O

O

O

O R

O

O

R Het R

O

O

O

O

O

O

Annelated 1,4-benzoquinones

Fig. 3 Quinones that can be used as starting materials in the Nenitzescu indole synthesis.

2003CHC872, 2004CHC16, 2004SL1039, 2005CHC221, 2005S2414, 2009JMC3474, 2006BMC7282). Noteworthy, as mentioned above, the structure of the enamine is essential for the process of indolization toward 5-hydroxyindoles or in accessing nonindolic products (vide supra). 3.1.1 Monosubstituted benzoquinones The condensation between substituted quinones and enamines is regioselective and this is mainly determined by electronic and steric effects of the substituents attached at the quinone ring (Schemes 9 and 10). In a few cases, it has been also shown that the structure of the enamine can also play an important role in the regioselectivity of the reaction. O

O

O R

O +2

R

R

O

O R = Me, Et, Ph R = Cl, Br, I

+ 2 R = F, OH, OMe R = SBn, 3-indolyl

+ 2 R = CO2Me, CF3 R

CO2Et

HO

CO2Et

HO

+ R

N H 6-Substituted

Me R

N H

7-Substituted

CO2Et

HO R

N H 6-Substituted

Me

CO2Et

HO N H

Me

4-Substituted

Scheme 9 The influence of quinone substitution on the regioselectivity of the Nenitzescu indole synthesis.

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O

CO2Me CO2Me

HO

+

OH CO2Et

59% 57

OH NH2

COMe

+ Me

N H

OH O 58

O

59

Me

CHCl3 N OH

2

Me

COMe

CO2Et

O

CO2Et

HO

+

NH

OH Me

O 56

CO2Me

Me

NH2

2

60

CO2Me

+ 56

Me

61 (71%)

Scheme 10 Regioselectivity of the Nenitzescu indole synthesis is affected by reactive substituents on the quinone ring.

Thus, the condensation between 2-substituted quinones with enamines is well documented and shown to be completely or partially regioselective and depends on the electronic effects of the substituents on the quinone ring (Scheme 9). In the case of monosubstituted quinones the reaction is completely regioselective for quinones bearing carboethoxy (1968JO198, 2005BMC819) and trifluoromethyl (1968JO2064) groups, yielding the corresponding 4-substituted 5-hydroxyindoles (Scheme 9). 6-Substituted5-hydroxyindoles have been reported to be generated from the reaction between enamine and quinones substituted at the 2-position with OH, OMe, F, SBn, and 3-indolyl groups (1959JO1750, 1965CIL2096, 1968JO2064, 2016MOL638). In the case of 2-Me-, 2-Et, 2-Ph-, 2-Cl-, 2-Br-, and 2-I-quinone the reaction gives mixtures of 6- and 7substituted 5-hydroxyindoles with the major product in all cases being the 6-substituted indole (Scheme 9) (1965CIL2096, 1966JA2536, 1966JO2669, 1968JO2064). However, in few cases it was reported that condensation of enamines with 2-methy-, 2-phenyl- and 2-biphenyl-1,4quinone affords only 6-substituted 5-hydroxyindoles (2005BMC819, 2001JO4457). On the other hand, substituents (R ¼ CO2Et, COMe) with high reactivity at the quinone ring lead to different products, generated via intramolecular cyclization of enamino hydroquinones to form new hetrocyclic compounds (1968JO198). For example, starting from 2-carbomethoxy benzoquinone 56 and ethyl β-aminocrotonate 2 one can isolate enamino hydroquinone 57, which by subsequent treatment with a small amount of starting benzoquinone in acetic acid affords the corresponding indole 59 and isocarbostyryl derivative 58 (Scheme 10) (1968JO198). Similarly, the

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condensation of 2-acetyl-p-benzoquinone 60 and β-aminocrotonate 2 results exclusively in the formation of the substituted isoquinoline derivative 61 (Scheme 10) (1968JO198). 3.1.2 Disubstituted benzoquinones 2,3-Disubstituted benzoquinones (R ¼ Me, Cl, OMe) in reaction with enamines of type 2 afford the expected 6,7-disubstituted indoles, which in some cases can be accompanied by enamino hydroquinones or other byproducts (1958BER2253, 1971CHC309, 1971T5031, 2005T9129). 2,5-Disubstituted benzoquinones with identical substituents on the quinone ring generate 4,7-disubstituted 5-hydroxyindoles. In the case of 2,5disubstituted quinones with different substituents, the regioselectivity of the reaction is strongly influenced by the electronic effects of the substitutents (Scheme 11). Hence, for the condensation of 2-chloro-5-alkyl-1,4benzoquinone and 2-chloro-5-trifluoromethyl-1,4-benzoquinone with ethyl β-aminocrotonate 2, it was was found that the reaction is completely regioselective and yields exclusively the 4-chloro-7-alkyl indole isomer (1968JO2064, 1970JO1190, 1973JMC757, 1990CHC274). On the other hand, the 2-methoxy-5-trifluoromethyl-1,4-benzoquinone (Scheme 11) generates a mixture of two 5-hydroxyindole indoles (1968JO2064). O

O

O CF3

MeO

Cl

Cl O

CO2Et

+2

+2

OMe

CF3

O

O

+2

HO

CF3

CF3

CF3 CO2Et

HO

HO

CO2Et

HO

Me

Cl

CO2Et

+ OMe

N H

Me CF3

N H

Me Cl

N H

CF3

N H

Me

Scheme 11 The influence of electronic effects on the regioselectivity of the Nenitzescu reaction.

Many examples are also available in the case of Nenitzescu indole syntheses starting with 2,6-disubstituted benzoquinones (1992PCJ523, 1995PCJ636, 2002MC15, 2002RCB1886, 2018AJOC2094). Thus, condensation of 2,6-dibromo-1,4-benzoquinone 62 with enamino esters of type 20 (five examples), performed in methanol, acetic acid under reflux,

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or by heating in a mixture of AcOH/Ac2O, leads to the formation of the corresponding enamino hydroquinones 63 with yields in the range 10%–99% (Scheme 12) (1992PCJ523). It was found that condensation of benzoquinone 62 with a substituted nitrodienamine derivative afforded a benzofuran derivative (1995PCJ636). Also, reacting 2,6-dibromo benzoquinone 62 with 3-oxocaprolactam piperidine enamine 64 in acetone, or in ethanol, at room temperature, yielded dihydro-furo[2,3-c]azepinone 65 (Scheme 12), which in acetic acetic, under reflux, subsequently generated a mixture of the expected furo[2,3-c]azepinone 66 and, unexpectedly, the chromene[3,4-b]pyridine-5-one derivative 67 (2002MC15, 2002RCB1886). A similar behavior has been observed in the case of reactions between enamines 64 or 3-piperidino-5,6-dihydropyridin-2-one 68 and 1,4-benzoquinone and 2-chloro-1,4-benzoquinone, respectively (Scheme 12) (2002RCB1886). O Br

Br

CO2Et

+ Me O 62

NHR

a: AcOH/Ac2O

CO2Et

Br HO

b: AcOH

Me

c: MeOH/–15°C OH

Br 63

20 Br HO

62

+

AcOH

EtOH HN

RT

N

Br

O NO

O 64

reflux

N H 65

Br

Br

HO

NH

HO

+ Br

NHR

N H

O

Br

O

O 66

67

O

;

HN

N O 68

Scheme 12 The Nenitzescu reaction of 2,6-dibromobenzoquinone with various enamines.

Moreover, the condensation of 2,6-dibromobenzoquinone 62 with 3-morpholino-6-ethoxycarbonylcyclohexen-5-one 69 as enamine under Nenitzescu reaction conditions leads to the dibenzobenzofuran derivative

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70, together with the generation of the unexpected spirobenzofuran derivative 71 (Scheme 13) (1997PCJ612). The unsubstituted 1,4-benzoquinone yielded similar results, whereas 2-phenylthio-1,4-benzoquinone afforded only the spiro compound (1993MC40, 1997PCJ612). Alternatively, the reaction of enaminoketones 72a,b having a phenyl group with 1,4benzoquinone afforded no spiro compound, with dibenzofuran 73a and carbazole 73b being the main products (Scheme 13) (1997PCJ612). 2,6Dichloro-, 2,6-dimethyl, and 2,6-dimethoxy-1,4-benzoquinonequinone have also been used as reactants in the Nenitzescu reaction with azaenamines (2018AJOC2094).

Br

Br

R

O Br

R

O

HO

Br CO2Et

HO

+ EtO2C

+ Br

O O 62

O

69

O

R = 4-morpholinyl

Br

O

O

71

70

O

O Ph

R

HO

CO2Et

+ EtO2C O 1

O 72a,b a: R = 4-morpholinyl b: R = NHC6H4OMe-p

Scheme 13 Regioselectivity of ethoxycarbonylcyclohexen-5-ones.

X

Ph

73a,b a: X = O; b: X = NC6H4OMe-p

Nenitzescu

indole

synthesis

with

3.1.3 Trisubstituted benzoquinones 3-Hydroxy-2,5-dimethyl-1,4-benzoquinone reacts with ethyl β-aminocrotonate in alcohol under reflux to give ethyl 5,6-dihydroxy2,4,7-trimethylindole-3-carboxylate in 45% yield (1951JCS2029). The reaction of 2,3-dimethoxy-6-methyl-1,4-benzoquinone with ketene aminals leads to condensed 5-hydroxy-2-aminoindoles in good yields (2010S3536). 3.1.4 Tetrasubstituted benzoquinones The investigation of the condensation under the conditions of the Nenitzescu reaction between 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and secondary enamines leads to the formation of unexpected 2-azaspiro[4,5]decatrienes 75 (Fig. 4) by Michael addition followed by

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Florea Dumitrascu and Marc A. Ilies

CN

O

NH

Cl

N R3

Cl

2 COR1 R

74

CN

Cl

F NH N R

O

Cl

F

OH

OH

3

HO

O

COR 1 R

NH

HO

O

NH

Cl

F 2

75

R 76

77

Fig. 4 Different heterocyclic compounds accessible through Nenitzescu indole type synthesis from tetrasubstituted benzoquinones.

cyclization (2011BMC2666). Similarly, 2-azaspiro[4,5]decatrienes 74 (Fig. 4) were obtained (three examples) in the reaction with secondary enamines by replacing DDQ with 2,3-dicyano-1,4-benzoquinone (2011BMC2666). The reaction of DDQ with several tertiary and secondary enamines leads to 3-aminobenzofuran derivatives (2011BMC2666). The reaction of tetrahalogenated 1,4-benzoquinones (X ¼ F, Cl, Br) and cyclic ketene aminals represents a good method to obtain fused polyhalogeno7a-hydroxy-[1,2-a]indol-5-one derivatives 50 (2015T4084). An efficient synthesis of 8,9,11-trihalo-5H-benzofuro[3,2-c]carbazol-10-ols 76, 77 (Fig. 4) has been developed by treating 2,3-dihydro-1H-carbazol-4(9H)one with tetrafluoro- and tetrachloro-1,4-benzoquinones (2017TL3979). In order to explain the generation of benzofuro[3,2-c]carbazole derivatives the authors proposed a different mechanism to that generally accepted by researchers for the formation of indoles and furans starting from benzoquinones and enamines (2017TL3979). A possible ionic mechanism proposed for the formation of benzofuro-carbazoles 76 and 77 implies in the first step the nucleophilic attack of the starting 2,3-dihydro-1Hcarbazol-4(9H)-one tautomer to the C]O quinone carbon atom giving an intermediate adduct that undergoes cyclization and aromatization (2017TL3979).

3.2 1,4-Naphthoquinones The structure of the compounds generated through the reaction between enamine and 1,4-naphthoquinone 78 or their derivatives (Fig. 3) is strongly dependent on the enamine structure but also on the electronic effects of the substituents on the 1,4-naphthoquinone ring. The reaction conditions can also influence the structure of the final product (1955ZOB1355, 1958ZOB447, 1993PIAS189, 1998CHC651, 2003CHC61, 2003 SC2285, 2004PCJ146, 2005RCB774, 2005S2414, 2005T9129,

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2005T11866, 2006BMC7282, 2009JMC3474, 2010OBC3426, 2010RCB1639, 2010TL5160, 2011JHC355, 2011T8747, 2013T5401, 2014ASC421, 2014GC4359, 2014LOC188, 2016EJMC466, 2017ADV24813, 2018EJMC946). In the most cases, the intermediates obtained via condensation between enamines and 1,4-naphthoquinone 78 lead to the generation of 5-hydroxy-1H-benzo[g]indole derivatives 79 as a result of an indolization process. A typical example for reaction between 1,4-naphthoquinone and esters of 3-aminocrotonic acid is illustrated in Scheme 14. Interestingly, the condensation of ester of β-aminoacrylic 81 with 1,4-naphthoquinone in acid acetic and under oxygen atmosphere provides 9,10-anthraquinone derivatives 82 along with 2-enamino 1,4naphthoquinones instead of the expected benzo[g]indole derivatives (2014ASC421). Under optimized reaction conditions, both 1,4naphthoquinone 78 and 1,4-anthraquinone 80 react with of β-aminoacrylic esters to give only 9,10-anthraquinones and 5,12-tetracenedione derivatives 82 (Scheme 14). O

CO2R

HO

CO2Et

+ Me

Me

NR

NHR

O 78

79 O

20 O CO2R

+ NHR

AcOH O2

CO2R O

O 80 NO2

HO

81

82

Me R2N

O

Me NO2

R2N

Me

COAr

HO COAr O

78 AcOH Four examples

83

CO2R

O

Me

COAr NMe2

MeO

COPh +1

Me2NCH(OEt)2 84

COAr 85

84 MeO

COPh

MeO

Me

CH2COMe

HO

+

O O

O

Me2N 86

87

88

HO

Scheme 14 5-Hydroxy-1H-benzo[g]indole from 1,4-naphthoquinone via Nenitzescu indole synthesis reaction conditions.

Through the use of tertiary enamino ketones or nitroenamines as enaminic component in the reaction with 1,4-naphthoquinone (Scheme 14) Lyubchanskaya et al. (1998CHC651, 2003CHC61) obtained

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3-nitro-5-hydroxynaphtho[1,2-b]furan 83 (yield 23%–58%) and 3-aroyl-5hydroxynaphtho[1,2-b]furans 84. In the case of reaction of enaminoketones, the formation of naphtho[1,2-b]furan 84 is accompanied by the generation of trisubstituted naphthalenes 85 (1998CHC651). In a similar manner, 1,4naphthoquinone reacts with a tertiary N-hetarylenaminone yielding the corresponding naphtho[1,2-b]furan derivative (2011JHC355). The naphthofuran 84 (R ¼ Ph) was methylated to the OH group to give compound 86 (Scheme 14), which, under the action of dimethylformamide diethylacetal, was transformed into the heterocyclic tertiary enamine 87 (1998CHC651). Subsequent condensation of 87 with 1,4-benzoquinone yielded benzofuran-naphthofuran hybrid 88, which preserves the dimethylamino group on the benzofuran moiety (1998CHC651). It is important to note that when primary bis-ketoenamines 89a,b (Scheme 15) were reacted with 1,4-naphthoquinone, an unexpected 3acetyl-5-hydroxy-2-methylnaphtho[1,2-b]furan 90 was obtained in good yield (2003SC2285). Therefore, it can be stated that condensation between cyclic enamines and 1,4-naphthoquinone is a useful method to prepare polycyclic compounds containing a 5-hydroxyindole moiety (2004PCJ146, 2014GC4359, 2014LOC188, 2005RCB774). Moreover, it was found that the condensation between 6-aminouracil 91 and 78 in nitromethane or acetic acid leads to the expected benzopyrimidoindole derivative 92 and to the bis Michael adduct 93 (Scheme 15), formed by a Me O HN

+

COMe

CH2

n

HN

COMe

COMe

HO AcOH n = 2, 4

O

Me

O Me 78

90

89a,b

O H2N O 78

HO N

+ H2N

N

Me O

N

MeNO2 AcOH

N H

N

N

Me

+

O

O

N

OH H2N

92

93

Me

Me

O

Me

Me 91

N

OH

O

N

Me O

Me

Scheme 15 Nenitzescu reaction of 1,4-naphthoquinone with bis-ketoenamines and 6-aminouracil.

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double addition of aminouracil to naphthoquinone moiety (2004PCJ146). The formation of secondary products in the condensation between 78 and enamines during the Nenitzescu reaction was reported by Kucklander (1971TL157, 1978LA129). The 1,4-anthraquinone 94 reacts with enamines 20, in the same way as 1,4-naphthoquinone, to yield the expected naphtho-condensed 5-hydroxyindoles 95 (Scheme 16), whereas condensation of 2-chloro1,4-anthraquinone 96 with enaminoketones 97 afforded carbinolamines 98 in low yields (7% and 8% yield) (2006BMC3599). A similar result was obtained in the reaction of 1,4-anthraquinone 94 with a cyclic enamine.

OH

O CO2Et

AcOH/RT

+

RT Me

NHR

O

29%–49% Five examples

R

N

95

20

94

CO2R Me OH

O COMe

+ Me

Cl

NHR

AcOH/RT

Cl

Two examples

HO

O

R

96

98

97

N

COMe Me HO

O

O R1

+ Me O

OH

O

NHR

O

a. AcOH

HCl

b. MeOH

MeOH

2

OH N R2

O 100

Me 101

OH CO2Et O

Me

N 1

R1 99

O

R Azonines

Scheme 16 Heterocyclic compounds generated from anthraquinones and related congeners via Nenitzescu indole synthesis reaction conditions.

On the same framework, 1,4,9,10-anthradiquinone 99 reacted with enamines 100 (11 congeners) in methanol or glacial acetic acid under typical Nenitzescu reaction conditions (Scheme 16). Unexpectedly, the products were spirocyclic compounds 101, which were converted to dibenzo[c,f] azonine derivatives (four examples) in the presence of HCl at room temperature (2006BMC3599). Substituted 1,4-naphthoquinones react with several enamines such as enamine esters, aminoporfirin nickel complex, and trimethoxyaniline in

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conditions of the Nenitzescu synthesis in a complex manner (2005T11866, 2011T8747, 2017ADV24813). Thus, condensation of 2-acyl-1,4naphthoquinones with 3,4,5-trimethoxyaniline gives benzophenanthridinequinone, benzocarbazole, and 2-acyl-3-(3,4,5-trimethoxyanilino)-1, 4-naphthoquinone derivatives (2017ADV24813). 2,3-Dicarboethoxy-1,4-naphthoquinone 102 is a disubstituted 1,4naphthoquinone that reacted with N-substituted β-enamine esters 20 (R ¼ Me, Bn, 4-tolyl) yielded 5-oxo-1,5-dihydro-benzo[g]indole derivatives 103a–c (Scheme 17) (2005T9129). These compounds were obtained in 23%–56% yield and resulted by rearrangement of one ethoxycarbonyl group of the postulated adduct intermediates (2005T9129). The indolones 103a–c are unstable in acetic acid under reflux and, after elimination of an ethoxycarbonyl group, afforded benzo[g]indoles 104a–c (Scheme 17). In the case of reaction between 1,4-naphthoquinone 102 and β-aminocrotonic ester 2 indolone 105 was isolated and gave the benzo[g]indole derivative 104d under reflux in acetic acid (Scheme 17). When β-aminocrotonitrile was the enamine used in the same reaction, a mixture of three compounds 106–108 was obtained. Structures 106 and 107 are similarly with those CO2Et O CO2Et

CO2Et

+

CO2Et

Me

O 102

+

Me

NH2

O RT

CN

N H

N

Me

CO2Et

+ NMe2

AcOH

O

CO2Et

C H2 OH

EtO2C

108 EtO2C CO2Et

O

CO2Et

OH CO2Et

CO2Et

+

+

RT

Me

CN O EtO2C

HO

107 CO2Et

N H 104d

CN

Me

104a–c CO2Et

HO

reflux

CO2Et

HO

EtO2C

Me

AcOH

105 CO2Et

106

102

CO2Et Me

N

2

N H CO2Et

R = Me, Bn, p-tolyl CO2Et

AcOH

CO2Et O

R

103a–c CO2Et

Me

N

reflux

CO2Et

EtO2C

102

Me

NR

RT

20

CO2Et

CO2Et

HO AcOH

AcOH

NHR

CO2Et

CO2Et

O

CO2Et

NMe2

NMe2

OCOMe 109

110

CO2Et

111

Scheme 17 Compounds generated from 2,3-dicarboethoxy-1,4-naphthoquinone via Nenitzescu indole synthesis reaction conditions.

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resulted from N-substituted β-enamines 20 (R ¼ Me, Bn, 4-tolyl), whereas 108 (structure confirmed by X-ray analysis) was the result of condensation between indolone 106 and 2,3-dicarboethoxy-1,4-naphthoquinone 102 (Scheme 17). When condensation between 2,3-dicarboethoxy-1,4naphthoquinone 102 and enamines was extended to a tertiary enamine ester, no compound incorporating a benzo[g]indole skeleton was found. Instead, reaction of naphthoquinone 102 with tertiary enamine yielded two dihydrocyclopenta[a]naphthalene isomers 109 and 110, which can undergo intercorvension (Scheme 17). Additionally, the naphthalene derivative 111 was isolated in 12.6% yield from the reaction medium (Scheme 17). For comparison, 2,3-dicarbomethoxybenzoquinone 112 was reacted with β-enamine esters 20a–c (R ¼ Me, Bn, 4-tolyl). The N-alkyl enamine esters 20a,b (R ¼ Me, Bn) and 112 lead to benzofuran derivative 113 in 59% yields (2005T9129). Unexpectedly, N-aryl enamine ester 20c (R ¼ 4-tolyl) afforded the pyrroloindole derivative 114 in 26% yield (Scheme 18). EtO2C

O CO2Et

CO2Me

+ CO2Me

Me Me

NHR

MeO2C

O

Me

N

N

Me

CO2Me

CO2Me

O 112

CO2Et

CO2Et

HO

20a–c

113

Me

114

Me

Scheme 18 Heterocyclic compounds generated from 2,3-dicarboethoxybenzoquinone via Nenitzescu indole synthesis reaction conditions.

The synthesis of 5-hydroxybenzo[g]indoles from 1,4-naphthoquinones has been accomplished in good yield by modified or improved Nenitzescu reaction conditions (2010OBC3426, 2010TL5160, 2011T8747, 2013 T5401, 2016EJMC466). The three-component reaction between 1,4naphthoquinone, primary amines 115, and β-dicarbonyl derivatives 116 (Scheme 19), in ethanol, under reflux, and in the presence of CAN (5 mol%) as catalyst, generated 5-hydroxybenzo[g]indoles 117 (17 congeners) in yields ranging between 53% and 96% (2010OBC3426). It is noteworthy that at room temperature the three-component reaction of 1,4-naphthoquinone 78 with primary amines 115 and β-ketoesters 116 affords a mixture of 5-hydroxybenzo[g]indoles 117 and enamino 1,4-naphthoquinones 45 (2010OBC3426, 2013T5401). By a similar three-component procedure (Scheme 19) 2-bromo-1,4-naphthquinone 118 condenses with amines 115 and ketoesters 119 to yield benzo[f]indolequinones 120 (nine examples) accompanied by enamino 2-bromo-1,4-naphthoquinone 46 (five examples;

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Fig. 2). The syntheses imply in situ generation of enamine reactant, followed by its Michael addition to quinone. For the formation of final reaction products, a nonredox reaction mechanism was suggested (Scheme 6). A versatile method to prepare 5-hydroxybenzo[g]indoles 122 (13 examples, 52%–80% yield) was demonstrated by one-pot three-component reactions of 1,4naphthquinone with β-aminoketones 121 and urea, as a source of nitrogen (Scheme 19) (2010TL5160). The synthesis of substituted benzo[g]indoles 122 was performed under microwave action for 5 min, in presence of boron trifluoride etherate as Lewis catalyst.

3

COR

HO

O R

1

+

R NH2

78 O

3

2

+

R O

O

CAN(5%)

2

R1 117

116

115

R

N

EtOH/reflux

O

O

+

R

1

R NH2

+

Br

COR

2

Me CAN(5%–15%)

+

EtOH/reflux

O

O

O

O 118

115

119

46

Me

N R

120

O

N

HO

n

X

Et2O-BF3

+ O 78

H2NCONH2

+

ArCOCH2

N

n

X

N H

MW

Ar

n = 0,1; X = C, O 121

122

Scheme 19 Products of modified/improved reaction conditions of the Nenitzescu indole synthesis, using naphthoquinone or substituted naphthoquinones.

3.3 Heterocyclic benzoquinones Replacement of substituted 1,4-benzoquinones with various heterocyclic quinones such as benzofuranquinone (2003CHC872), indazolequinone (2000CHC1276), benzimidazolequinone (2003CHC61) (Scheme 20), benzothiazolequinone (2005CHC221), and quinolinedione and isoquinolinedione (2002CHC586) represents an extension of the Nenitzescu indole synthesis that generates tricyclic systems containing benzofuran and/or indole rings, including new annelated heterocyclic hybrid systems. The structures of compounds resulting from the interaction of heterocyclic

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quinones with enamines are strongly influenced by changes in the structure of enamine and by the solvent used as reaction medium. Additionally, an asymmetric starting quinone can direct the reaction toward the formation of either a single product or two regioisomers. In this context, the reaction of asymmetric 3-methylbenzofuranquinone (3-methyl-4,7-dioxobenzofuran) 123 with β-aminocrotonic esters 2 and 20a,b,d (R ¼ Me, Bn, 4MeOC6H4) has been investigated in acetic acid medium at 20°C for 20 h (2003CHC872). The authors have shown that condensation of 3-methylbenzofuranquinone 123 with N-methyland Nbenzylaminocrotonic esters 20a,b in acetic acid yields the furo[2,3-g] indole derivatives 124a,b as main reaction products (Scheme 20). NMR analysis of the crude reaction product, as well as the mother solution left after crystallization of 124, indicated the presence of furo[3,2-g]indole isomers 125a,b in amounts up to 10%. Under similar conditions, benzofuroquinone 123 reacts with ethyl esters of β-aminocrotonic 2 and N-3-(4methoxyphenyl)crotonic 20d to generate furo[2,3-g]indole derivatives 124c,d in yields ranging from 30% to 40%, along with furo[2,3-g] benzofuran 126 (Scheme 20). However, only furoindoles 124c,d were CO2Et

CO2Et HO

HO H

Me RNH

Me O

CO2Et

Me 124a,b

AcOH

Me

+

Me

Me

CO2Et

CO2Et

H

RNH

CO2Et

Me NR

O

2, 20d

125a,b

R = Me, Bn

HO

HO

O

NR

Me O

20a,b

O

NR

Me

+

O

Me O

O 123

Me Me BnNH 127a,b

H

124c,d

COMe

R

HO

HO Me

a: R = COMe, b: R = NO2

126

R = H, MeOC6H4

R

O

O Me 128a,b

Me

+

NBn

O Me 129

Scheme 20 Products generated via Nenitzescu indole synthesis-type reaction conditions from asymmetric quinones.

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Florea Dumitrascu and Marc A. Ilies

isolated in pure form. The ratios between the two types of compounds were determined by NMR analysis as 72:28 for 124c/126 and of 60:40 for 124d/126. In this context, it is worth mentioning that the reaction between quinone 123 and enamine 127a having an acetyl group at the β-position leads to benzodifuran derivative 128a and indole 129 in a ratio of 9:1. In the case of β-nitroenamine 127b, the hydroxybenzofuran 128b has been obtained as the sole reaction product (2003CHC872). In the same framework, indazolequinone 130, generated from azaNenitzescu synthesis (1997T15005), can serve as quinone reagent in the Nenitzescu indole synthesis and reacts with a variety of enamines yielding interesting heterocyclic structures. Thus, through the reaction of indazolequinone 130 with N-methylamino crotonic ester 20a, using a mixture of acetic acid and acetic anhydride at 20°C, an indolization process was observed with the formation of pyrrolo[3,2-e]indazole 131a in 54% yield (Scheme 21) (2000CHC1276). Similarly, the condensation between enamines 20a,b and indazoloquinone 130 yielded the corresponding pyrrolo[3,2-e]indazole 131b,c and up to 8% from the corresponding furo

CO2Et O

HO Ph

N O

N

+ Me

Ph 130

Me

CO2Et AcOH/Ac O 2

NR

Ph N NPh

NHR

131a–c: R = H, Me, Bn

2; 20a,b

CO2Et 130

CO2Et

+ Me

CO2Et

HO

HO Me

AcOH/Ac2O

NHC6H4OMe-p

N NPh

20d

Me

+

N

Ph

O

Ph

C6H4OMe-p

N NPh

131d

132 1

COR 1 130

+ Me

NHR

2

133a–c

COR

COR HO

AcOH/Ac2O

1

HO Me NR2

Ph

+

Me O

Ph

N NPh

N NPh

134a–c

135a,b

Scheme 21 Products generated via Nenitzescu indole synthesis-type reaction conditions from indazolequinone 130.

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[2,3-e]indazoles of type 132 (Scheme 21). In the case of N-arylenamine 20d a mixture of pyrrolo[3,2-e]indazole 131d and furo[2,3-e]indazole 132 has been obtained in a ratio of 60:40, determined on the basis of NMR spectroscopy. The annelated indazoles 131b,c and 132 were separated by column chromatography and their structures were established via NMR spectroscopy. Under similar reaction conditions, enamino ketones 133a–c and indazolequinone 130 lead to a mixture of pyrroloindazoles 134a–c and furoindazoles 135a,b (Scheme 21). The ratios of annelated indazoles, determined by NMR spectroscopy of the crude reaction product, were found to be as follows: 134a/135a 20:80, 134b/135b 30/70, and 134c/135b 33/77, respectively. Based on the NMR data, the formation of a furan ring can be considered to be favored to the indolization process. Benzimidazolequinone 136 has also been used as a heterocyclic quinone in reactions with β-aminocrotonic acid derivatives 20a,b,d (2003CHC61). These condensation reactions were carried out in nitromethane, at reflux, and found to yield exclusively the imidazo[4,5-g]indoles 137a–c in good yields (48%–68%) (Scheme 22). When acetic acid was used as reaction medium for the condensation process between enamine 20a (R ¼ H) and quinone 136, the imidazo[4,5-g]indole only 137a was obtained in 12% yield.

CO2Et

O

HO Me

N

H

+ N H

O 136

RNH

CO2Et 20a,b,d

MeNO2

Me NR

HN N 137a–c

137a: R = Me, 137b: R = Bn, 137c: R = 4-MeOC 6H4

Scheme 22 Products generated via Nenitzescu indole synthesis- type reaction conditions from benzimidazolequinone 136.

The condensation of various enamines with 2-methyl-4,7dioxobenzothiazole 138—another nonsymmetrical 1,4-quinone—was also found to be strongly influenced by the nature of the solvent and enamine structure; factors that can direct the reaction process to the generation of both indolic and/or nonindolic compounds (2005CHC221). Thus, when

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reactions between quinone 138 and enamino ketones 139a–d were performed in acetic acid, the major products were furo[2,3-e]benzothiazole derivatives 140a,b. The formation of the furobenzothiazole isomers 141a,b as side products in the condensation reaction was detected via NMR spectroscopy in the solid residue obtained after the evaporation of acetic acid (Scheme 23). On the other hand, it has been found that the condensation of benzothiazolequinone 138 with the enamino ketones 139a,d in nitromethane affords as main reaction products the pyrrolo[2,3-e]benzothiazoles 142a,b as a consequence of an indolization process. Additionally, based on NMR analysis, the furo[2,3-e]benzothiazole derivatives 140a,b were confirmed to be present in the reaction mixture in minor amounts (Scheme 23). When the condensation of quinone 138 with β-aminocrotonic esters 20b,d has been conducted in acetic acid or nitromethane, only the indolization process was evidenced. The pyrrolo[2,3-e] benzothiazoles 143a,b were isolated and characterized from the reaction mixture, whereas the pyrrolo[3,2-g]benzothiazoles isomers were only detected by NMR spectroscopy 144a,b as minor products (Scheme 23).

COR

COR

O

HO

HO COR

N

+ Me

S

NHC6H4X

S Me R = Me, Ph

Me 140a,b

139a–d

O

N

N

O 138

+

O

S Me

Me

Me

AcOH

141a,b

139 a: R = Me, X = 4-Me; b: R = Me, X = 4-OMe; c: R = Ph; X = 4-Me: d: R = Ph, X = 4-OMe O COR COR HO MeNO N 2 Me

+

S

Me

Me

NHC6H4X

S

O 138

139a,d

O

142a,b CO2Et

CO2Et

HO

HO N S O 138

Me

MeNO2 or AcOH R = Bn, 4-MeOC6H4

Me

Me

RNH(Me)C = CHCO2Et NR

S

140a,b

C6H4X

N Me

+

N

+

NR

N S

N Me

Me 143a,b

144a,b

Scheme 23 Products generated via Nenitzescu indole synthesis- type reaction conditions from 2-methyl-4,7-dioxobenzothiazole 138.

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Along the same lines, the condensation of 2-methoxycarbonyl4-oxo-5,8-quinolinedione 145 with enamino ketones 146a–e in acid acetic has been investigated (Scheme 24). It was been found that the reaction is regioselective and generates the annelated benzofuran 147a,b, with a yield of 59% for 147a and 37% for 147b (2004CHC16). By replacing enamino ketones 146a–e with an enamine presenting a weaker electron-withdrawing substituent at the β-position, such as N-benzyl-β-aminocrotonic ester 20b, an unexpected pyrrolo[2,3-h]quinoline 148 was obtained in 13% yield, which incorporates in its structure the 6-hydroxyindole moiety (Scheme 24). The synthesis of compound 148 was accomplished by heating the two components in acetic acid at 60–65°C for 10 min. The authors highlighted that the changing of quinone in the Nenitzescu reaction is not responsible for the formation of 6-hydroxyindoles instead of expected 5-hydroxyindoles. Mention must be made that the formation of 6hydroxyindoles in the Nenitzescu indole synthesis has been usually described to take place with N-arylamines or enamines having strong electron acceptors such as cyano and nitro groups at the β-position. Due to the poor solubility in usual NMR solvents the structures of furo[2,3-f]quinolines 147a,b and pyrrolo[2,3-h]quinoline 148 were assigned by NMR spectroscopy of their acetylated derivatives.

Me O

O

O Me

+ O

N H

CO2Me

AcOH

H

1

R N

COR

O

R3

3

CO2Me N H OH 147a,b; R3 = Me, Ph

R2 146a–e

145

O

a: R1 = H, R2 = R 3 = Me; b:R1 = H, R2 = 4-MeC 6H4, R3 = Me c: R1 = R2 = Me, R3 = Ph; d: R1 = H, R 2 = Bn, R3 = Ph; e: R1 = H,R 2 = 4-MeOC 6H4, R3 = Ph OH O O O H Me

+ O

N H 145

BnNH

CO2Et

CO2Me 20b

PhCH2

N H

N

CO2Me

CO2Et

Me 148

Scheme 24 Products generated via Nenitzescu indole synthesis- type reaction conditions from 2-methoxycarbonyl-4-oxo-5,8-quinolinedione 145.

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OH O

CO2Et

CO2Et

Me

Me

+

N O

Me R

H

N H

O

AcOH

CO2Et

or MeNO2

O

Me

Me 20a–d

149 O

CO2Et H

Me

+

N

1

R Me

Me

150 OH CO2Et Me

Me

O

N

EtO

N H

O

AcOH

N

2

2

COR

R

O

Me

Me 149

151 R1

= Me, Ph, 4-MeC6H4, 4-MeOC6H4,

152a,b R2 = Me

R2 = Me, Ph

R1 = Ph, 4-MeC6H4, 4-MeOC6H4, R2 = Ph

Scheme 25 Products generated via Nenitzescu indole synthesis- type reaction conditions from 4-ethoxycarbonyl-1,3-dimethylisoquinolin-5,8-dione 149.

The reaction of 4-ethoxycarbonyl-1,3-dimethylisoquinoline-5,8-dione 149 with enamino esters 20 in glacial acetic acid has been found to be completely regioselective (2002CHC586) and to lead exclusively to the furo[3,2-h]isoquinoline derivative 150, with yields in the range of 30%–50% (Scheme 25). Interestingly, the formation of pyrrolo[3,2-h] isoquinoline through an indolization process has not been observed using nitromethane as solvent. When enamino esters 20 were replaced with enamino ketones 151 (7 examples) only furo[3,2-h]isoquinolines 152a,b were obtained. Moreover, when ethyl N,N-dimethylaminocrotonate was used in the condensation with quinone 149 no reaction occurred. The Nenitzescu reaction of the heteroaromatic quinones 153–155 (quinoline-5,8-dione, quinoxaline-5,8-dione, quinazoline-5,8-dione) with the primary ketene aminal 156, in ethanol at room temperature, was shown to afford aza-annulated 2-aminoindole-3-carboxylates 157–159 in moderate yields (Scheme 26) (2005S2414). In the case of nonsymmetrical quinones 153 and 155 the reaction is regioselective. The structure of the regioisomer obtained was established utilizing the nuclear overhauser effect (NOE). The ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-pyrrolo [2,3-f]quinolin-3-carboxylate 161 (Scheme 26) was obtained by Nenitzescu indole synthesis between quinoline-5,8-dione 153 and ketene aminal 160, under reflux in dichloromethane and in the presence of ZnI2 (2009JMC3474).

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O

O

O

N

N

N N

N O

O

O 155

154

153 H2N

CO2Et

H2N

156

EtOH

CO2Et

HO N

NH2

N H

N N

157 (47%)

N 159 (14%)

Cl

O

NH2

N H

158 (45%)

CO2Et

HO

N

H N

+ 153

N

NH2

N H

CO2Et

HO

CO2Et

HO

CO2Et

Cl

CH2Cl2/ZnI2 N

N H

N H

H2N

O

161

160

Scheme 26 Products generated via Nenitzescu indole synthesis- type reaction conditions from heteroaromatic quinones 153–155 (quinoline-5,8-dione, quinoxaline-5, 8-dione, quinazoline-5,8-dione).

In order to evaluate the cytotoxic activity of various pyrimido[4,5-b] indoles, the aza-annelated pyrimido[4,5-b]indoles 163–165 (Scheme 27) were prepared in moderate yields from the 2-aminopyrimidine 162 and heterocyclic benzoquinones 153–155 (2004SL1039). NMe2 N H2N

N

NMe2 AcOH; EtOH

162 AcOH; EtOH +154 AcOH; EtOH

+153

N

HO

HO

163

N

NMe2

N

N

N N H

NMe2

NMe2

NMe2 HO

+155

N N

N H

N

NMe2

N

N H

N

NMe2

N 164

165

Scheme 27 Annelated pyrimido[4,5-b]indoles from heteroaromatic quinones 153–155 and aromatic enamine 162.

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Similarly annelated pyrimido[4,5-b]indoles 167 and 168 (Scheme 28) have been obtained, in yields of 10.9% and 19%, respectively, from 2-(pyrrolidin-1-yl)pyrimidine-4,6-diamine 166 and from quinoline-5,8dione 153 and quinoxaline-5,8-dione 154 (2006BMC7282). The structures of the new pyrimido[4,5-b]indoles 166 and 167 were assigned by spectroscopic methods (IR, H-NMR, C-NMR, MS, UV) and via NOE experiments. NH2

NH2

O N

HO

H2N

N

N

AcOH, EtOH

N

+

N

N

O

NH2

NH2

O N H2N

N

N

N

AcOH, EtOH N

N N

O 154

HO

N

+

N

167

166

153

N

N H

166

N

N H

N

168

Scheme 28 Annelated pyrimido[4,5-b]indoles via Nenitzescu reaction.

3.4 Enamines The electronic and steric effects and the number of substituents attached the nitrogen or carbon atoms from of the enamine molecule have a crucial role because they can direct the Nenitzescu reaction to formation of either the expected indole or the nonindolic products. For example, nitro enamines (R1 ¼ NO2) or tertiary enamine 171 in the reaction with 1,4benzoquinones provided a fruitful method for 5-hydroxybenzofuran preparation rather than 5-hydroxyindoles (1990CHC503, 1993MC146, 1995MC68, 1997T177, 2003CHC707). A classification of enamines (Fig. 5) is useful for a better understanding of the substituents influence on the reaction course in order to predict the structure of the final products. The acyclic enamines 169–171 can be classified according to the degree of substitution of the nitrogen atom as primary, secondary, and tertiary. A similar classification can be applied for ketene aminals 175–177. Another group of enamines are cyclic enamines 172–174 possessing an endocyclic or exocyclic nitrogen atom as well as the cyclic ketene aminals 178. The aromatic compound 179 and the heterocyclic amines 180 can also be considered as cyclic enamines in the reaction with 1,4-benzoquinones

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R

1

R

R

NH2

R

R

NH R

169 Primary

1

2

2

2

R

1

R

N

3

R

n

NH

3

N

R

R

R 174

NHR 173

172

171 Tertiary

170 Secondary

n

n

3

Cyclic enamines

R1 = alk, aryl, heteroaryl, O-Alk, CO2R, NO2,CH = CHR, R2 = CO2R, COR, CN, CONHR, R H2N

NH2 H2N

175 Primary

R

1

NH HN 2 2 R R

R

1

R

NH R

H2N

N R R2 177

2

Tertiary

Het 180 Heterocyclic amines

NH

2

R 178 n = 1,2,3 Cyclic ketene aminals R

NH2

NH2

179 Aromatic amines

n

HN

176 Secondary Ketene aminals

R

1

N

NHR 181 Azaenamine

Fig. 5 Types of enamines used in the Nenitzescu reaction.

(2017CSE5110). By using in the Nenitzescu reaction of cyclic enamines, aromatic, or heterocyclic enamines complex fused indoles have been synthesized. Replacing enamines with hydrazones 181 in the condensation with 1,4-benzoquinone was proved to be an interesting method to obtain 5-hydroxyindazole derivatives. This synthesis of 5-hydroxyindazoles from 1,4-benzoquinones and azaenamines is known as the aza-Nenitzescu reaction (2018AJOC2094). 3.4.1 Acyclic enamines Ethyl β-aminocrotonate 2 (Scheme 1), an acyclic enamine of type 169, was the first enamine used in the Nenitzescu 5-hydroxyindole synthesis (1929BSCR37). Enamino esters of type 169 and 170 (R1 ¼ Me, Alk; R2 ¼ COOR) are the most productive and frequently used to prepare indole derivatives because they present high reactivity and as a consequence indolization process takes place straightforwardly (1990CHC274, 1993 PIAS189, 1995JCSP(1)2667, 1996JO9055, 1998JMC4755, 2003CHC61, 2003CHC872, 2004CHC16, 2004JCHEMO183, 2006BMC3599,

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2006JHC873, 2006JMC4327, 2008TL7106, 2009JMC3474, 2009TL4182, 2010OBC3426, 2010PCJ296, 2010RCI975, 2011APP49, 2011JHC733, 2011OBC1317, 2011T8747, 2013BKCS2968, 2013T5401, 2014CHC489, 2014BMCL1944, 2015CHC978, 2016EJMC466, 2016TL5653, 2017BMC327, 2017CRCU365, 2017CSE5110, 2018EJMC946). The β-aminocynamic nitrile 169 (R1 ¼ Ph, R2 ¼ CN) and 1,4-benzoquinone in AcOH gave in 32% yield the corresponding 3-cyano-5-hydroxyindole whereas in chloroform no reaction occurred. It was reported that the condensation of 3-methylcrotonanilides 182a–d (R ¼ H, Me, Et, Bn) and 1,4-benzoquinone (Scheme 29) gives the expected indole 183 only in the case of crotonanilide 182b (R ¼ Me) but for methylcrotonanilides 182a,c,d (R ¼ H, Et, Bn) the reaction stopped at the Michael adducts 184a,c,d (1961ZOB2303). The same authors also stated that the cyclization reaction of substituted hydroquinones 184a,c,d in acid medium afforded 3-acetyl-2-hydroxyindole 185 (1961ZOB2303). The lack of evidences regarding the structure of compound 185 determined Panisheva et al. (2003CHC1013) to reconsider the structure of these compounds resulted by interaction of 3-methylcrotonanilides 182a–d and 1,4benzoquinone. Under similar reaction conditions described by Grinev et al. (1961ZOB2303) all 3-methylcrotonanilides 182a-d give the Michael adducts 184a–d. The cyclization of hydroquinone adducts 184a–d in acetic acid and in the presence of sulfuric acid resulted in the formation of the benzofuranone derivatives 186 and/or 187 (Scheme 29). The formation Me

O

HO

PhHNOC

+ RHN

Me

Me

reflux OH

O 1

HO

CONHPh

Cl(CH2)2Cl

–PhNH2

187b,d R = H, Et

R = Me

CONHPh

HO N Me 183

Me

O

O

NHR

184a–d

182a–d

NHR

+

186

R = Me, Et, Bn

+PhNH2 heating Me

COMe

HO

HO N

NHPh

OH

Ph

O

185

186

O

Scheme 29 Nenitzescu reaction employing 3-amino crotonanilides 182 as enamines.

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of the compound 186 from hydroquinones 184a,c was explained by involvement of the NHCOPh group in the reaction process by cyclization followed by elimination of one molecule of aniline. The isolation of benzofuranones 186 containing NHPh group along with expected compounds 187 was explained by their reamination with the aniline eliminated at the formation of 187. This was demonstrated by heating compounds 187b,d with aniline when benzofuranone 186 has been obtained (Scheme 29). β-(N0 -benzoyl-N-hydrazino)crotonate 188 has been used in reactions with 1,4-benzoquinone and 1,4-naphthoquinone to obtain N-benzoyl1-amino-5-hydroxyindole 189 in 26% yield and N-benzoyl-1-amino5-hydroxybenzo[g]indole 190 (Scheme 30) in 36% yield (1993PIAS189). O CHCl3

+ Me

Me

N

reflux

NHNHCOPh

NHCOPh

O 1

188

189 O

CO2Et

HO

CO2Et AcOH

+ Me

CO2Et

HO

CO2Et

N

50–60 oC

NHNHCOPh

Me

NHCOPh O

188

78

190

Scheme 30 Synthesis of N-amino-5-hydroxyindole derivatives by Nenitzescu reaction of β-(N0 -benzoyl-N-hydrazino)crotonate with 1,4-benzoquinones.

Usually, tertiary enamines 171 in the reaction with 1,4-benzoquinones (Scheme 14) lead to the formation of benzofurans or condensed benzofurans (1990CHC503, 1990CHC739, 1993MC146, 1993PCJ136, 1994PCJ893, 1995MC68, 1995PCJ631, 1995PCJ636, 1995PCJ640, 1997T177, 1998 CHC651, 2000CHC410, 2003CHC61, 2003CHC707, 2007JCC906, 2011BMC2666, 2011JHC355). The condensation of acyclic enamino ketones (R2 ¼ COR) with various 1,4-benzoquinones (Scheme 14) has a more complex output giving 5-hydroxyindoles and/or 5-hydroxyfurans,

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or other nonindolic products (1993PCJ136, 1998CHC651, 2011 EJOC4635). The structure of the final products is influenced by the degree of substitution of the nitrogen atom, by electronic effects and reaction conditions. The influence of the enamines structure on the course of the Nenitzescu reaction is illustrated in Schemes 14 and 20 . The reaction of 1,4-benzoquinone with secondary enamino ketone 151 in glacial acetic acid gave only benzofuran 191 (Scheme 31) whereas by using nitromethane as solvent a mixture of indole 192 and benzofuran 193 was obtained (2011EJOC4635). A study of the reaction between various enamino ketons 151 and 1,4-benzoquinone (Scheme 31) evidenced the influence of the solvents and enamine substituents on the formation of indoles 193, 194 and benzofurans 191, 195 (1993PCJ136). O COMe

HO

AcOH Me

O

Me

O COMe

+ Me

NHR

+ 191 Me

N

NHMe

Me

O 1

191 (53%)

COMe

COMe MeNO HO 2

+

151

192 COMe

HO Various

+

solvents

N

COMe

HO O

Me

Me

R O 1

193a–d

151

191

R = H, Me, Ph,4-MeOC6H4 O COPh

+

solvents Me

NHR

COPh

HO Various

+ N

Me

COPh

HO O

Me

R O 1

194a–f 151 R = H, Me, Bn, Ph, 4-MeC6H4, 4-MeOC6H4

195

Scheme 31 The output of the Nenitzescu reaction giving either indoles or benzofurans as a consequence of the enamine substituents effect or reaction medium.

3.4.2 Nitro enamines Primary, secondary, and tertiary nitro enamines have been employed as enamine component in condensation with 1,4-benzoquinones under conditions of the Nenitzescu reaction and it has been found that in many instances the formation of 5-hydroxybenzofurans prevailed in spite of 5-hydroxyindoles (1990CHC503, 1992CHC34, 1992CHC299, 1995 MC68, 1995PCJ631, 1995PCJ636, 2003CHC61, 2005S2414). In the case of tertiary nitro enamines such as 1-nitro-2-dimethylamino-ethylenes

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196a,b the formation of 5-hydroxyindoles is not possible (1990 CHC503). It is noteworthy that by comparison with β-aminoacrylate, nitro enamine 196a without a hydrogen atom in the β-position react with 1,4benzoquinones (R ¼ H, O2NC6H4, SPh, 2,3-dichloro), in acetic acid medium and in the presence of p-toluenesulfonic acid as catalyst, to give exclusively 3-nitro-5-hydroxybenzofurans 197a–d (R ¼ H, SPh, O2NC6H4, 2,3-dichloro) in 19%–68% yields (Scheme 32). In the case of monosubstituted benzoquinones (R ¼ SPh, O2NC6H4) only the 7substituted benzofurans 197b,c were isolated. 1-Nitro-2-dimethylamino2-methyl-ethylene 196b presents higher reactivity than nitro enamine 196a in the reaction with 1,4-benzoquinones (R ¼ H, 2,3-dichloro). The formation of 3-nitrobenzofurans 197e,f from 1,4-benzoquinones (R ¼ H, 2,3-dichloro) and enamine occurs in acetic anhydride-acetic acid medium in the absence of catalyst. Some chemical transformations of benzofurans 197 have been performed (Scheme 32). Thus, the reduction of nitrofuran 197a (R ¼ H) with Zn in a mixture of acetic acid/acetic anhydride yields 3-acetamido-5-acetoxybenzofuran 198 (Scheme 32).

O NO2

HO NO2

R

+

Me2N O R = H, O2NC6H4, SPh, 2,3-Cl2

196a

AcOH/Ac2O

O

R

NHAc

AcO

Zn

AcOH/TsOH

O 198

197a–d

O Me

NO2

+

Me2N

AcOH/Ac2O

R

R = H, 2,3-Cl2

196b NO2

197e,f NO2

HO MeI

Me

O

EtONa

O

NMe2

HO

OH

O

NO2

HO

+ H –H

R R

OH

R

+

O H

202

Me

200

+H+

R 201

NO2

AcO

Me

NO2 + NMe2

NO2

R

Ac2O

197e

199

HO

Me

O

R

O

MeO

NO2

HO

197

R –Me2NH NMe2

203

Scheme 32 Synthesis and chemical transformation of the Nenitzescu reaction products obtained by nitroenamines and quinones.

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Florea Dumitrascu and Marc A. Ilies

2-Methyl-3-nitro-5-hydroxybenzofuran 197e was O-alkylated to 5methoxybenzofuran 199 using methyliodide in the presence of sodium ethoxide. By acylation of 5-hydroxybenzofuran 197e with acetic anhydride in the presence of a catalytic amount of H2SO4, 2-methyl-3-nitro5-acetoxybenzofuran 200 has been obtained (Scheme 32; 1990CHC503). The mechanism for the benzofurans formation involves tautomerization of the Michael adducts 201 to the iminotautomers 202 followed by protonation and cyclization to the 2,3-dihydrobenzofurans 203. The dihydroderivatives 203 eliminate dimethylamine giving the final reaction products 197 (Scheme 32). 1,4-Naphthoquinone reacts in AcOH with primary, secondary, and tertiary (Scheme 14) nitro enamines giving only 5-hydroxy-2-methyl-3-nitronaphtho [1,2-b]furan 83 (Scheme 14) in yields of 23%–48% (2003CHC61). Unexpectedly, the condensation in acetic acid in the presence of acetic anhydride of secondary β-nitro enamines 204b–g with 1,4-benzoquinone (Scheme 33) yields 3-nitro-6-hydroxyindoles 205 along with 3-nitro-furan derivative 197e (1992CHC34). Condensation of primary enamine 204a with benzoquinone affords exclusively 2-methyl-3-nitro-5-hydroxybenzofuran 197 in 57% yield. In the case of secondary nitroenamines 204b,c substituted at nitrogen with methyl and benzyl groups in the mixtures obtained by Nenitzescu reaction the formation of 3-nitrobenzofurans 197 prevails instead of the indole (Scheme 33). In the case of the N-aryl nitroenamines 204d–g the 6-hydroxyindoles 205 are obtained in yields of up to 52%.

O Me

+ RHN O 1

NO2

NO2

AcOH

NO2

HO

+ HO

Me

N R 205a–g

204a–g

R=H R = H, Me, Bn, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4 R = Me R = Bn R = Ph R = MeC6H4 R = MeOC6H4 R = ClC6H4

7% 16% 38% 39% 52% 36%

O

Me

197e 57% 67% 50% 7%

Scheme 33 Reaction of benzoquinone with β-nitroenamines towards either indole or benzofuran derivatives.

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Nenitzescu indole synthesis (1990–2019)

It has been found that the structure of the products resulting from condensation of secondary cyclic nitro enamines 206–208 with 1,4benzoquinone in acetic acid/acetic anhydride is strongly influenced by the size of the enamine ring (1992CHC299). The reaction between 2-(2nitromethylene)pyrrolidine 206 and benzoquinone leads to a mixture of benzofuran derivatives 209 and 2,5-disubtituted hydroquinone 210 in a total yield of 54% (Scheme 34). In the case of 2-(2-nitromethylene)piperidine 207, the benzofuran derivative 211, 2,5-disubtituted hydroquinone 212, the expected 3-nitro-5-hydroxy-1,2-pentamethyleneindole 213 (Scheme 34), and the N-acetylated starting enamine were identified in the reaction mixture based on NMR spectroscopy. 2-(2-Nitromethylene) hexahydroazepine 208 and 1,4-benzoquinone under similar reaction conditions lead to a complex mixture, six compounds being identified based on NMR analysis as 5-hydroxyindole 214, the most representative, 6-hydroxyindole 215s and monoacetylated 4,5-dihydroxyindoles 216 and 217 (Scheme 34). OH HO

+

NO2

NO2

N

+ OH 210 (20%)

209 (34%)

n=1

NO2

N

(CH2)3NHAc

O

1

OH n

+1

HN

NO2

HO

206–208

N

N

O2N

+

n=2 O2N

O

(CH2)4NHAc

NO

HO

NO2

+

N

OH

+1 211 (16%) n=3

+

N

214

OH(Ac)

NO2

NO2

HO

213

212 (8%)

HO

3%

NO2

(Ac)HO

+

N

N

215

216, 217

Scheme 34 Reactions of cyclic nitroenamines with p-benzoquinone;the influence of the ring size.

Nitrodieneamines and 1,4-benzoquinones under the conditions of the Nenitzescu reaction give a mixture of compounds (Schemes 35–37) including also benzofuran derivatives (1995MC68, 1995PCJ631, 1995PCJ636).

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Florea Dumitrascu and Marc A. Ilies

O NO2

HO

NMe2

O O

NMe2

+

Me2N O 220 (9%)

219 (10%)

ClCH2CH2Cl

+

NMe2

+

OH

O

80°C

NO2

NMe2

Me2N O

+

NO2

1

Me2N

218

OH

O

222 (1%)

221 (8%) O

Me2N H

H

–HNO2

H

NMe2

+Me2NH

–Me2NH Me2N O2N

O

O NMe2

O

220

Me2N

Me2N

OH

O 224

223

225

Scheme 35 Nenitzescu reaction vs Diels–Alder reaction pathways in the case dienediamines used as enamine component.

NMe2

O Br

Br

Br

+

Me2N

O 218

62

NO2

HO

MeOH

Br

NMe2

O

NO2

226 Me2NCH(OEt)2 Br

NO2

NO2

HO NMe2

1+

O

Me 196b

Me

Br2

NO2

HO Br

O

Me

227

197e

Scheme 36 Steric hindrance eludes Diels–Alder adduct formation and leads to the brominated benzofuran 227 by the Nenitzescu reaction route.

O

NMe2

O 1

NO2

MeNO2

+ p-MeOC6H4 N H 228

NO2

20°C 24 h

O

NMe2

229 (48%)

Scheme 37 Nenitzescu reaction between benzoquinone and a nitrodienediamine leading to a benzofuran derivative.

ARTICLE IN PRESS Nenitzescu indole synthesis (1990–2019)

41

3.4.3 Dienediamines It is known that the interaction between enamino dienes and 1,4benzoquinones takes place either by 4 + 2 Diels–Alder cycloaddition giving 1,4-naphththoquinones or by a double Diels–Alder cycloaddition affording substituted 9,10-anthraquinones (1942BER232, 1966BER934). Lyubchanskaya et al. (1995MC24, 1995PCJ631, 1997CHC282) synthesized and investigated for the first time the behavior of substituted 1,3diene-2,4-diamines under Nenitzescu reaction conditions (1995MC68, 1995MC69, 1995PCJ636, 1995PCJ640). The reaction between dienediamine 218 [2,4-bis(dimethylamino)-1-nitrobuta-1,3-diene] and p-benzoquinone has been studied in several solvents, including dichloromethane, nitromethane, acetone, and methanol (1995MC68). Dienediamine 218 in the reaction with benzoquinone 1 can act as enamine in the Nenitzescu synthesis or dienophile in Diels–Alder cycloaddition reaction. The condensation of these compounds in dichloroethane at 80° C gave a mixture of four reaction products (Scheme 35). Benzofuran 219 has been obtained as a result of the Nenitzescu reaction whereas 1,4naphthoquinone 220 and 9,10-anthraquinone derivative 221 are Diels–Alder cycloadducts. The formation of traces of the nitrohydroquinone 222 is explained by generation of nitrous acid in the course of the reaction followed by a complex reduction–oxidation process of the starting benzoquinone. The structure of the reaction products was assigned based on NMR spectroscopy and by comparison with literature data for compounds having similar structures. The proposed mechanism for formation of the 2,7-disubstituted 1,4naphthoquinone 220 involves a 4 + 2 cycloaddition reaction between benzoquinone and diene to form intermediate tetrahydro-1,4-naphthoquinone 223 followed by elimination of dimethylamine and HNO2 giving 6-dimethylamino-1,4-naphthoquinone 224 (1995PCJ636). Subsequently 1,4-addition of dimethylamine to naphthoquinone 224 leads to adduct 225, which under the reaction conditions undergoes dehydrogenation to compound 222 (Scheme 35). The formation of the anthraquinone derivative 221 was explained by a double Diels–Alder reaction between 2 moles of dienediamine 218 and a mole of 1,4-benzoquinone. Interestingly, dienediamine 218 and 2,6-dibromo-1,4-benzoquinone 62 (Scheme 36) lead exclusively to 2-(2-dimethylaminovinyl)-3-nitro-4,6dibromo-5-hydroxybenzofuran 226 (1995PCJ636). 2,6-Dibromoquinone 62 was chosen due to the steric constrains of the two bromine atoms, which prevent the formation of Diels–Alder cycloadducts. The structure of dibromobenzofuran 226 was determined on the basis NMR data and

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Florea Dumitrascu and Marc A. Ilies

confirmed by an independent synthesis (Scheme 36) implying condensation of dimethylformamide diacetal with 2-methyl-3-nitro-4,6-dibromo-5hydroxybenzofuran 227 (1995PCJ636). The dibromobenzofuran 227 was prepared by the Nenitzescu reaction between benzoquinone and nitroenamine 196b to produce 3-nitrobenzofuran 197e followed by its bromination to give benzofuran 227 (Schemes 32 and 36). Secondary nitrodienediamine 228 (Scheme 37) having an arylamino group instead of dimethylamino group when reacting with p-benzoquinone gives as sole product the benzofuran derivative 229 in 48% yield (1995MC68). The formation of the expected indole was detected only by mass spectrometry whereas the presence of the Diels–Alder 1,4cycloadduct has not been observed. The best yield is obtained when the reaction between benzoquinone and enamine 228 is carried out in nitromethane. Interestingly, when keto dienediamino 230a,b were used in reactions with p-benzoquinone, the indolyl-benzofurans 232a,b (Scheme 38) resulted in yields of 17% and 28% by a double Nenitzescu synthesis (1995MC69). It has been found that 1-aroyl-2-arylamino-4-dimethylamino-1,3-butadienes 230c,d lead also to 3-(indolyl-2)-2-dimethylaminobenzofuran derivatives 232c,d in yield of 24% (1995PCJ640). O

NMe2

+

COPh

HO

+1

OH

NAr

ArNH O 1

COPh

HO AcOH

COPh

20°C 24 h

NMe2

NAr

230a,b

Me2N

O 232a,b

231a,b A r = Ph, 4-MeOC6H4

O

NMe2

COAr

HO AcOH

+ HN O 1

1

Ar

20°C 2

COAr

230c,d

1

OH

N Ar 2 Me2N

O 232c,d

c: Ar1 = Ph, Ar2 = 4-ClC 6H4; d: Ar1 = Ar 2 = 4-MeOC6H4

Scheme 38 The doube Nenitzescu cascade reaction towards indole-benzofuran hybrid compounds.

It was established that the best yields were obtained when the reaction was carried out in acetic acid at room temperature and at a quinone/enamine ratio of 2:1. The reaction mechanism implies the formation of 5hydroxyindole intermediates 231 which act as an enamine in the reaction with another molecule of benzoquinone to form the benzofuran ring attached at the 2-position of indole. It is interesting to note that the presence

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Nenitzescu indole synthesis (1990–2019)

of a dimethylamino group in the benzofuran moiety is not usual because the formation of the benzofuran ring from quinones and enamines take place in the most cases by elimination of NHR and NHR2 groups. The conservation of the dimethylamino group has been explained by stereoelectronic factors that prevent the dimethylamino group elimination and facilitate the dehydrogenation by the quinone excess. The structure of compound 232b was confirmed by an independent synthesis (Scheme 39) of its O,O-dimethylated derivative 237 which was obtained in turn by dimethylation of 232b (1995MC69, 1995PCJ640). The synthesis of 237 started from 5-hydroxyindole 233 which was subjected in the first step to O-methylation giving the corresponding 5-methoxyindole 234 (Scheme 7). The methylation has been achieved with dimethyl sulfate in alkaline medium and in the presence of benzyltriethylammonium chloride (BTAC). In the next step the 5-methoxyindole 234 (Scheme 39) was transformed by condensation with dimethylformamide diethylacetal into the indole enamine 235, which by condensation with p-benzoquinone in the Nenitzescu reaction conditions led to benzofuran 236. Finally, by O-methylation with dimethyl sulfate in the presence of BTAC, compound 237, was obtained. It is interesting to note that 2-methyl-3-benzoyl5-hydroxyindole 233 has also been prepared by the Nenitzescu reaction between p-benzoquinone and corresponding enamine (1993PCJ136). It is noteworthy that nitrodienediamine 238 (Scheme 39) having cyano and ethoxycarbonyl substituents on nitrogen does not undergo Nenitzescu reaction with p-benzoquinone (1997CHC282).

COPh

HO

Me2SO4 Me

N

Me2NCH(OEt)2

BTAC

N

DMF

235

COPh OH

NAr Me2N

COPh

MeO

+1/AcOH

NMe2

Ar

Ar 234

233

Nenitzescu reaction

Me

N

Ar

MeO

COPh

MeO

COPh

MeO

Me2SO4 BTAC

O

OMe

NAr Me2N

O 237

236 EtO2C NO2

N NC

NHC6H4OMe-p 238

Scheme 39 Parallel synthetic pathway to demonstrate the indolo-benzofuran structure of derivatives of type 232.

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Florea Dumitrascu and Marc A. Ilies

3.4.4 Ketene aminals The reaction of ketene aminals (ketene N,N-acetals) 175–178 (Fig. 5) with p-benzoquinone under Nenitzescu reaction conditions has been shown to be a useful method for synthesis of 5-hydroxy-2-aminoindoles and condensed 5-hydroxyindole (1981S157, 1999RCB160, 2005S2414, 2006JMC4327, 2009JMC3474, 2010S3536, 2015T4084, 2016MOL638). From the reaction of benzoquinones with ketene and heterocyclic ketene aminals 2-aminobenzofuran derivatives (1981S157), an unexpected 1,3oxadiazole derivative (1999RCB160), 7a-hydroxy-[1,2-a]indol-5-ones (2015T4084), and 3a-hydroxy-indol-6-ones (2014GC4359) have also been obtained. The reaction in acetic acid under reflux between benzoquinone and ketene N,N-acetals (ketene aminals) 176a–d (Scheme 40) gave 5-hydroxy-2-aminoindoles 239a–d in yield of 21%–70% along with corresponding 2-aminobenzofurnas 240a–d in yield of 6%–29% (1981S157). From the ketene aminals 176e,f and 1,4-benzoquinone only the benzofurans 240e,f were isolated in yield of 26% and 27% (Scheme 40). By condensation of cyclic ketene aminal 241 with 1,4-benzoquinone (Scheme 40) was isolated the imidazoindole 242 in 9% yield (1981S157). O

1 H R N

+

R2 AcOH

1

R

HO

2

R

HO

2

+

R N H

1

O

O

NHR

N

NHR

1

1

1

R 239a–d

176a–f

240a–f

a: R1 = Ph, R2 = NO2; b: R1 = Et, R2 = NO2; c: R1 = Ph, R2 = COPh; d: R1 = Ph, R2 = Et; e: R1 = Ph, R2 = 4-BrC6H4CO; f: R1 = Et, R2 = 4-BrC6H4 O H N

AcOH

+ N H O 1

COPh

HO

COPh

241

N

NH

242

Scheme 40 Nenitzescu reaction between 1,4-benzoquinone and ketene aminals.

Alekseeva et al. (1999RCB160) investigated the interaction between 1,4-benzoquinone and acetyl ketene aminals 243 and 246 (Scheme 41) and found that the structure of the resulting product is determined by the enamine structure. The acetyl ketene aminal 243 and benzoquinone in acetone, at reflux, affords the 5-hydroxyaminal 244 with an indole skeleton, which is similar to the intermediate postulated in the Nenitzescu synthesis (1972T5251). The high stability of compound 244 was explained by

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Nenitzescu indole synthesis (1990–2019)

electronic effects and its transformation to 6-chloroindole 245 was accomplished by using acetyl chloride in presence of pyridine. In the case of N-benzoylated aminal 246 its interaction with 1,4-benzoquinone in nitromethane and in the presence of p-toluenesulfonic acid leads to hydroquinone Michael adduct 247 in 91% yield (Scheme 41). Treatment of the hydroquinone 247 under the action of an oxidizing reagent, such as benzoquinone or 2,6-dichloro-3,5-dicyanobenzoquinone (DCQ), unexpectedly affords 1,3-oxazole derivative 248 instead of the corresponding 1,4benzoquinone (1999RCB160). O

+

H2N Ph

O

N H

1

243

COMe

O

COMe

OH

pyridine

Cl

N

Ph 245

MeCONH

HO H PhCO N

COMe

+

COMe NHCOPh

MeNO2 TsOH

N H

Ph

NH2

Ph

244

O

O 1

NH2

N

COMe

HO

MeCOCl

Acetone

N DCQ

HO

O

Ph

NHPh OH

OH

246

248

247

Scheme 41 The structure of the ketene aminals in reaction with p-benzoquinone directs the Nenitzescu reaction pathway.

The proposed reaction mechanism for the formation of 1,3-oxazole derivative 248 is shown in Scheme 42 (1999RCB160). The first step is addition of 1,4-benzoquinone followed by oxidation of the cyclic form 249 of the Michael adduct 247 to give spiro compound 250. The elimination of a hydroquinone molecule from tricyclic compound 250 leads to spiro oxazole 251 followed by furan ring opening to 1,3-oxazole 252 and subsequent intramolecular acetylation to the final reaction product 248 (Scheme 42). H N

H2N HO

NHCOPh

247

Me

+1

O

Ph

Me OH

250

249 N

HN HO –C6H4(OH)2

OC6H4OH O

Oxidation cyclization

OH

O

HN HO

Ph O

O

H2N

N Ph

HO

O

248

Me OH

251

OCOMe 252

Scheme 42 Proposed mechanism for the formation of the oxazole derivative 248.

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Florea Dumitrascu and Marc A. Ilies

The synthesis of 2-aminoindoles from ketene aminals and 1,4benzoquinones was extended to primary ketene aminals 253 having electronic-withdrawing groups (2005S2414). The best results were obtained at room temperature when ethanol was used as solvent (Scheme 43). Probably due to the electronic effect of the nitro group, 2-nitroethene-1,1-diamine 253e reacts with benzoquinone to give 2-amino-5-hydroxyindole 254e only under reflux in methanol for 1 h. From ketene aminals 253a–f the 2-aminoindoles 254a–f were prepared in yields varying between 21% and 49% (Scheme 43). The cyanoketene aminal 253d has been found to be too unstable and was generated in situ by ammonolysis of enamine 255 but its reaction with benzoquinone leads to low yield of indole 254d (R ¼ CN). The authors proposed for indole 254d an alternative synthetic procedure implying in the first step the preparation of N-allylaminal 256 from 255 and allyamine (Scheme 43). The ketene aminal 256 condensation with benzoquinone affords 2-allylaminoindole 257, which was transformed into the final compound 254d by action of methanesulfonic acid in the presence of Pd/C (Scheme 43). O H2N

+

R

EtOH RT

H2N O 1

R

HO

NH2

N H

253a–f

254a–f

R = CO2Et, COPh, COCF3, CN, NO2, CONH2 EtO

H2N

CN Allylamine

H2N

N H

CN

+1 EtOH

CN

HO

MeSO3H N

NH

254d

Pd/C

H 255

256

257

Scheme 43 2-Aminoindole synthesis employing primary ketene aminals as enamine components in the Nenitzescu reaction.

2-Amino-benzo[g]indole derivative 258 (Scheme 44) was synthesized in ethanol at room temperature in a yield of 19% from ketene aminal 156 and 1,4-naphthoquinone (2005S2414). N-Aryl aminal 160 (Scheme 44) and 1,4-naphthoquinone condensation lead to 2-amino-5-hydroxybenzo[g] indole 259 in 35% yield (2006JMC4327). When the reaction is performed in the presence of zinc iodide using dichloromethane as solvent, the aminoindole is obtained predominantly (2006JMC4327). Also, aza- and diaza-1,4-naphthoquinones 153–155 (Scheme 26) have been proved to

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Nenitzescu indole synthesis (1990–2019)

CO2Et

HO H2N O

H2N

CO2Et

NH2

N H

156 EtOH/RT

258 (19%)

O

H m-ClC6H4 N

78

CO2Et

CH2Cl2/reflux

160 N H

ZnI2 R

CO2Et Amine

NHC6H4Cl-m

259 (35%)

2

R N

CO2Et

CO2Et

HO

1

EtO

CO2Et

HO

H2N

+1

1

H2N

EtOH 13 examples

H2N 260

261

N H

N R 2 R

262

Scheme 44 Benzoquinones in Nenitzescu reaction with ketene aminals giving the expected 2-aminoindole derivatives.

be useful reagents in the reaction with aminals 156 and 160 giving the corresponding azabenzo[g]indole derivatives 157–159, 161 (2005S2414). Landwehr et al. (2006JMC4327) synthesized a library of 2-amino-5-hydroxyindoles from 1,4-benzoquinone and primary-secondary and primary-tertiary ketene aminals (Scheme 44) and investigated their biological activity. The two components were stirred in ethanol at room temperature in a benzoquinone/aminal ratio of 1.2/1 to afford 2-aminoindoles 262 in 28%–82% yields. Ketene aminals 261 were prepared by reacting 3-ethoxy-3-aminoacrylate 260 with primary and secondary amines in ethanol under reflux (Scheme 44). Heterocyclic ketene aminals (HKAs) are useful intermediates in the Nenitzescu reaction for the synthesis of fused 5-hydroxindoles (1981S157, 2010S3536). The condensation between 1,4-benzoquinone and the cyclic ketene aminal 241, described previously by Aggarwal et al. (1981S157) (Scheme 45), has been extended by Yang et al. (2010S3536) in the case of three types of heterocyclic ketene aminals, such as imidazolidin-2-ylidene 263, tetrahydropyrimidin-2(1H)-ylidene 264 and 1,3-diazepan-2-ylidene derivatives 265 (Scheme 45). By using 1,4benzoquinone 1 and 2,3-dimethoxy-6-methyl-1,4-benzoquinone 266 condensed 5-hydroxyindoles 267–269 have been obtained in yields of

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Florea Dumitrascu and Marc A. Ilies

H N

H N

COR

H N

COR

264 R = OEt, Ar

+ 1, 266

+ 1, 266

Dioxane/AcOH

Dioxane/AcOH

2

R

R

COR

HO

N H 265 R = OEt, Ar

N H

N H 263 R = OEt, Ar

+ 1, 266 Dioxane/AcOH 2

2

R COR

HO

1

1

N R

NH

R

1

COR

HO

1

R

COR

N 1

R

R 268

267

H N

N

R

NH

1

269

R1 = R2 = H or R1 = OMe, R2 = Me; 17 examples

Scheme 45 Cyclic ketene aminals as enamine components in Nenitzescu reactions.

78%–93% by a simple procedure involving heating heterocyclic ketene aminals with 1,4-benzoquinones at reflux in dioxane and in the presence of acetic acid as catalyst (2010S3536). Bisindoles are important compounds due to both their presence in nature and their potent biological activities. As a consequence new synthetic strategies have been developed for their synthesis. Condensation of 2-(1Hindol-3-yl)benzoquinone derivatives 270 with heterocyclic ketene aminals 263–265 (Scheme 46) in ethanol at room temperature, and in the presence of triethylamine (0.1 equiv.), generated a library of 3,70 -bisindole derivatives 271–273 (2016MOL638). By optimization of the reaction conditions COR

HO H N

O 3

COR

R

EtOH/Et3N

+

N n H

N R

n = 1,2,3

23 examples

2

1

N

3

R

R

O

R = Ar

270

COR

X

X

X

X

+ n

N H

O n = 1,2,3 263–265

R 1

R 271–273 X

O H N

2

N n = 1,2,3

263–265

NH n

acetone/RT 27 examples R = Ar

COR

O X

N X

NH

OH n

X = F, Cl, Br 274a–c

50 (n = 1,2,3)

Scheme 46 Applications of the Nenitzescu reaction to substituted bioactive indoles.

ARTICLE IN PRESS Nenitzescu indole synthesis (1990–2019)

49

bisindoles 271–273 were obtained in yields of 65%–91% and their structure was assigned based on NMR and IR spectroscopy. The synthesis of 2-(1Hindol-3-yl)benzoquinones 270 was performed at room temperature by simple mixing of 3-unsubstituted indoles with 1,4-benzoquinone in water (2006EJOC869). Twenty seven trihalogened 7a-hydroxy[1,2-a]indol-5-ones 275–277 (Scheme 46) have been synthetized in good yields (71%–92%) from tetrahalogenated benzoquinones 274a–c (X ¼ F, Cl, Br) and cyclic ketene aminals 263–265 (2015T4084). The best reaction conditions for the synthesis of fused carbinolamines 50 (n ¼ 1,2,3) were obtained by using acetone as the solvent, at room temperature. The structures of the 7a-hydroxy-[1,2-a] indol-5-ones were deduced by NMR and IR spectroscopy and the unexpected formation of such carbinolamines was confirmed by X-ray diffraction for the representative compound 264 (n ¼ 2, X ¼ Cl, Ar ¼ 4-MeOC6H4). The isolation of carbinolamines having similar structure to those reported in the literature and proposed as intermediates in the Nenitzescu indole synthesis confirmed the proposed reaction mechanism (1972T5251, 1999RCB160). The steps of the suggested reaction mechanism are similar to that for the Nenitzescu synthesis and include Michael addition followed by the imine–enamine tautomerization, HX elimination, and intramolecular cyclization to final product (2015T4084). Interestingly, the condensation of benzoquinones with heterocyclic ketene aminals 263–265 in ethanol at room temperature gives 3ahydroxy-indol-6-one derivatives 275 (Scheme 47) in very good yields (2014GC4359). The quinones used in this reaction were 1,4-benzoquinone 1, 1,4-naphthoquinone 78, 2-methyl-1,4-naphthoquinone 276, and 1,4anthraquinone 94. Noteworthy, the same HKAs 263–265 gave with benzoquinone and 2,3-dimethoxy-5-methylbenzoquinone in ethanol/Et3N (Scheme 45) the expected condensed 5-hydroxyindoles 267–269 (2010S3536). Moreover, the formation of carbinolamines 267–269 from HKAs 263–265 and 1,4-benzoquinone was also a result of a Nenitzescu indole synthesis (Scheme 9). The formation of carbinolamines (7a-hydroxyindol-5-one) 267–269 was the result of Nenitzescu indole synthesis whereas the formation of carbinolamines (3a-hydroxy-indol-6-one) 275 was named by the authors as an anti-Nenitzescu reaction. The yields decreased for quinones in the order benzoquinone > naphthoquinone > 1,4-anthraquinone, this being a consequence of the steric effects determined by the size of the quinone. The steric effect of a methyl group at the 3-position in naphthoquinone leads to a competition

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between Nenitzescu and anti-Nenitzescu reaction. Thus, the crude product resulting from reaction of 2-methylnaphthoquinone 276 with cyclic aminal 263 (n ¼ 1, Ar ¼ 4-MeC6H4) was analyzed by HPLC and it was found that the ratio between Nenitzescu and anti-Nenitzescu products was of 23:56. Two anti-Nenitzescu reaction products 279a,b (Scheme 47) were subjected to chemical transformation with the aim of eliminating the OH group and synthesize products with a 6-hydroxyindole skeleton. Indeed, by heating compound 279a (Ar ¼ 4-ClC6H4) under reflux in methanol, and in the presence of sodium methoxide, the tetracyclic compound 281 having a 6-hydroxyindole substructure was obtained (Scheme 47). The hydroxyl group was eliminated from compound 279b (Ar ¼ 4-MeOC6H4) in dioxane under reflux and in presence of triethylamine to give tetrahydrobenzo[e] pyrimido[1,2-a]indol-5(8H)-one 280 (Scheme 47). O H N

OH R

COAr

+

O

30 min/RT

N H

n

COAr

EtOH NH

N R

21 examples

O

n

275

263–265

Me O

H N

Me

COAr

COAr

+

+ n

N H

O

263 n = 1, Ar = 4-MeC6H4

277

N

N

OH

N

N

reflux O Ar = 4-MeOC6H4

278 Nenitzescu product

Anti-Nenitzescu product

COAr Et N/dioxane 3

280

OH

NH

N Me

O 276

O

COAr

HO

OH

COAr

COAr MeOH/MeONa reflux

N

NH

HO

N

NH

Ar = 4-ClC6H4 279a,b

281

Scheme 47 Nenitzescu and anti-Nenitzescu reactions.

The proposed mechanism for the formation of the compounds 275 is shown in Scheme 48. The initial aza-ene addition of enamine to the carbonyl group of the quinone gives adduct 282. Imine–enamine tautomerization gives 283 which undergoes intramolecular indolization to the tricyclic compound 284. The final 3a-hydroxy-indol-6-one derivatives 275 result from oxidation in the reaction conditions of keto–enol tautomer 285 of the compound 284.

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O H N

COAr

OH Tautomerism

1,2-addition

N H

COAr

COAr

Aza-ene

+ n

OH

O

O

NH

N

NH

HN

O

n

n

1

263–265 n = 1,2,3

282 OH

OH

283 COAr

COAr Tautomerism

HO R

H

N

NH

COAr

Oxidation O R

H

N

NH n

n

284

OH

O

NH

N R n

285

275

Scheme 48 The anti-Nenitzescu reaction pathway by aza-ene addition of enamine to carbonyl group.

3.4.5 Aza enamines. The aza-Nenitzescu reaction The condensation of aldehyde hydrazones with 1,4-benzoquinones can proceed either by addition of the azomethine carbon atom to the C]C bond of the 1,4-benzoquinone giving the aza-Michael adducts or by NH group. By analogy with the original Nenitzescu indole synthesis (1929BSRC37) the bonding of an azomethine carbon from hydrazones to quinones giving 5-hydroxyindazoles was named the aza-Nenitzescu reaction (1997T15005, 1999CHC570). The condensation between phenylhydrazones 286 (so-called azaenamines) and p-benzoquinone (Scheme 49) represents a new synthesis of 5-hydroxyindazoles 289 and/or 4,7-indazolediones 290. The azaNenitzescu synthesis is a complex reaction and it is worth highlighting that by reacting hydrazones with p-benzoquinone in acetic acid medium the stable aza-Michael adduct 287 has been isolated and its cyclization to the expected 5-hydroxyindazole or indazolediones has been achieved under the action of potassium ferricyanide as oxidizing reagent. Usually, in the Nenitzescu reaction the formation of Michael adducts and their oxidative cyclization into indole take place in one step. 5-Hydroxyindazoles 289 result from aza-Michael adducts 287 by oxidation to quinone intermediates 288 followed by cyclization, as in the original Nenitzescu reaction. For the formation of 4,7-indazole quinone 290 the proposed mechanism implies the addition of the hydrazone NH group to the quinone ring of intermediates 288 (1997T15005, 1999CHC570).

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O

OH H

+

C6H4R

C6H4R

AcOH

O

N

N

C6H4R

K3[Fe(CN)6]

N

NHPh

NHPh

PhNH O

OH

O

287a–d

286a–d

1

288a–d O

C6H4R

HO N

N

C6H4R

+ N

Ph

O

N

Ph

289a–d 290a–d R = H, 4-NO2, 4-Br, 4-OMe

Scheme 49 The aza-Nenitzescu reaction to indazoles when phenylhydrazones are replacing enamines.

The aza-Nenitzescu reaction is strongly influenced by the nature of the substituents. It has been observed that the presence of a nitro substituent gives the hydroquinone adduct and the corresponding 5-hydroxyindazole, even in the absence of an oxidizing reagent. By oxidation of aza-hydroquinone adducts 287a–d with potassium ferricyanide the following results have been obtained: compounds 287a,b give a mixture of 5-hyroxyindazoles 289a,b and 4,7-indazolequinones 290a,b, whereas 287c gives only indazolequinone 290c. The adduct 287d was obtained in 7% yield and its oxidation gave only traces of indazolequinone 290d. Under similar reaction conditions the interaction between 2-chloro-1,4benzobenzoquinone 291 and benzaldehyde phenylhydrazone 286a (Scheme 50) is regioselective yielding azaenamine hydroquinone 292 (1997T15005).

OH

O H

Cl

Ph

[O]

Ph

Cl

N

+

N

NHPh

PhNH O 291

N O

OH 292

286a

N

Ph 293

O

O H

+

C6H4R

C6H4R N

PhNH O 78

O

Ph

Cl

286a,d

N

N

O Ph 294a,b R = H, 4-OMe

Scheme 50 Substituted indazole derivatives formed by aza-Nenitzescu reaction.

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By action of potassium ferricyanide on hydroquinone 292, indazolequinone 293 (Scheme 50) was formed in poor yield (5.6%), whereas the formation of the corresponding 5-hydroxyindazole was evidenced only by mass spectrometry (1997T15005, 1999CHC570). In conclusion, the reaction of aldehyde phenylhydrazones with quinones gives, in two steps, via aza-Nenitzescu synthesis, 5-hydroxyindazoles in low yields, with the main reaction products being 4,7-indazolequinone derivatives. The replacement of p-benzoquinones with 1,4-naphthoquinone 78 in aza-Nenitzescu reaction (Scheme 50) afforded no aza-Michael adduct. No 5-hydroxy-benzo[g]indazole has been obtained either. The products isolated were 4,9-dioxobenzoindazole 294a (yield 6%) and 294b in yield of 23% (1999CHC570). When the aza-Nenitzescu reaction was performed with 1,4naphthoquinone 78 and N-methylhydrazones 295a–d as azaenamines (Scheme 51) the reaction products were the adducts 296a–d. The compounds 296 resulted in 44%–72% yields by addition of the NH group from N-methylhydrazone at the C]C naphthoquinone bond (2000T5137). The adducts 296a–d were cyclized to benzoindazole quinones 297a–d by heating them at the melting point or in boiling xylene for 2–5 days (Scheme 51). The condensation of hydrazones 295 with 1,4-benzoquinone and 2,3-dimethylbenzoquinone proceeds as in the case of 1,4naphthoquinone, affording N-adducts having similar structure with compounds 295a–d. 2-Acetylnaphthoquinone 298 and N-methylhydrazones 295a,e gave in good yields compounds 299a,e, having similar structures to 296a–d (Scheme 51). In contrast to adducts 296a–d, the transformation O

O

O H

MeOH

+

xylene

N

N

N

MeNH O

O 296a–d

295a–d

78

R

R

R

reflux

N

N O

Me

Me

297a–d

a: R = Ph; b: 4-MeOC6H4 ; c: R = 2,5-(MeO) 2C6H4; d: R = CH = CHPh; e: R = COMe O

O H

COMe

+

N

N N O

295a,e

Me R AcOH

MeNH O 298

O COMe

R

Me 299a,e

–RCHO

N O

N

Me 300

Scheme 51 Indazole synthesis by the adduct formation between phenylhydrazone and 1,4-naphthoquinones and subsequent cyclization to benzoindazole quinones.

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of compounds 299 to the benzoindazole quinone 300 occurs under mild reaction conditions by simply stirring the hydrazones in acetic acid at room temperature (Scheme 51). The condensation of N,N-disubstituted hydrazones with 2-acetyl-1,4-naphthoquinone 298 has been reported to give C-adducts of type 45 and 46 (Fig. 2; 2000T5137). Recently, the interaction between aldehyde hydrazones and 1,4benzoquinones has been reinvestigated (Scheme 52) through a systematic screening of the reaction parameters and by using palladium catalysts and acids as additives (2018AJOC2094). Initially, the reaction between 1,4benzoquinone (1.2 equiv.) and 1-benzylidene-2-phenylhydrazine 286a (1 equiv.) was performed in the presence of Pd(OAc)2 (5 mol%) and trifluoroacetic acetic (TFA) (3.5 equiv.) under an O2 atmosphere and in 1,2-dichloroethane at 75°C. By this working procedure the expected 1,3-diphenyl-5-hydroxyindazole was obtained in 41% yield. However, the best results were obtained when the reaction was carried out in the presence of TFA and under a nitrogen atmosphere; the yield of 1,3-diphenyl5-hydroxyindazole increasing to 69%. This strategy has been demonstrated to be highly effective for various 1,4-benzoquinones and hydrazones (27 examples). The yields for 5-hydroxyindazoles were in the range 41%–74%. In the case of 2-methyl-1,4-benzoquinone and 2-chloro-1,4benzoquinone the reaction is regioselective because only 5-hydroxyindazole substituted at the 6-position was isolated. When 1,4-benzoquinones were replaced by 1,4-naphthoquinone the synthesis, under similar reaction conditions, gives the corresponding 5-hydroxybenzoindazole only in traces. By chemical transformation of 5-hydroxyindazole derivatives 302 compounds presenting interesting photoluminescence properties both in the solid state and in solution were obtained (2018AJOC2094). Based on aza-Nenitzescu synthesis of 5-hydroxyindazole 302 and the methods for benzofuran syntheses, such as condensation between phenols and olefins, intramolecular cyclization of suitably substituted phenols and hydroquinone intermediates results in the Nenitzescu synthesis. Janardhanan et al. (2019NJC10166) elaborated a procedure for obtaining 3H-benzofuro[3,2-e]indazoles 303 (Scheme 52). This synthetic strategy implied either annulation of 5-hydroxyindazoles 303 or a domino cyclization process starting from p-benzoquinones and hydrazones (Scheme 52). It has been established that obtaining 3H-benzofuro[3,2-e]indazoles 303 is possible by varying the ratio between 1,4-benzoquinone and hydrazone. To a ratio p-benzoquinone/hydrazones of 1.2/1 only 5-hydroxyindazoles 302 (Scheme 52) were obtained in 32%–74% yield (2018AJOC2094). By using two equivalents of p-benzoquinone and one equivalent of

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Nenitzescu indole synthesis (1990–2019)

O H

Pd(OAc)2 (5 mol %)

2

Ar

HO

2

TFA (3.5 equiv.)

+

R

Ar

HN

N

ClCH2CH2Cl

Ar 1

O 1.2 equiv.

N

N2/75°C/6 h

1 equiv. 301

Ar 302

27 examples

N 1

OH

O H R

Ar

2

Pd(OAc)2 (5 mol %) TFA (28 equiv.)

+ HN O 3 equiv.

N

ClCH2CH2Cl

Ar 1

N2/75°C/6 h

1 equiv.

16 examples

Ar

O

N 303

301

Ar

2

N 1

O Ph

HO

TFA (14 equiv.)

+ O 2 equiv.

N

N

Ph 1 equiv. 302 (Ar1 = Ar 2 = Ph)

303 (Ar1 = Ar 2 = Ph) ClCH2CH2Cl N2/75°C/6 h

Scheme 52 Aza-Nenitzescu reactions used to obtain small libraries of indazoles and benzofuroindazoles.

benzaldehyde phenylhydrazone a mixture of 5-hydroxyindazoles 302 (Ar1 ¼ Ar2 ¼ Ph) and benzofuro[3,2-e]indazole (Ar1 ¼ Ar2 ¼ Ph) was isolated (2019NJC10166). The optimal reaction conditions for synthesis of angular fused benzofuro[3,2-e]indazoles 303 have been achieved by using three equivalents of p-benzoquinones, 28 equivalents of TFA, palladium catalyst, and a nitrogen atmosphere (Scheme 52). The yields for hybrid heterocycles 303 using a series of 16 hydrazones and 1,4-benzoquinone are in the range of 36%–63% (Scheme 52). The versatility of the method and the influence of substituents were investigated by testing a series of substituted p-benzoquinones. Thus, the reaction of 2-methyl-1,4-benzoquinone with three hydrazones leads to the expected benzofuroindazole derivatives of type 303 (yields 48%–69%) whereas 2,6-dimethyl-1,4-benzoquinone affords only 5-hydroxyindazole. Also the condensation of 2-chloro-1,4-benzoquinone with benzaldehyde phenylhydrazone 286a gives 5-hydroxyindazole derivative in 36% yield, but for 2-bromo-1,4-benzoquinone only traces of indazole derivative was detected. By using as reactants 2,5-dimethyl, 2,6-dichloro and 2,6dimethoxy-1,4-benzoquinones neither the 5-hydroxyindazole 302 nor benzofuroindazole 303 were obtained. It has been established that the 5-hydroxyindazole 302 (Ar1 ¼ Ar2 ¼ Ph) with 2 equivalents of

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p-benzoquinone in the presence of 14 equivalents of TFA, and in the absence of Pd(OAc)2, gives the corresponding benzofuroindazole derivative 303. These control experiments proved that the stoichiometry of reactants has a determinant role in the yield and structure of the final reaction products. Also, it has been concluded that Pd(OAc)2 is only implicated in the formation of aza-Nenitzescu 5-hydroxyindazoles 302, the formation of benzofuroindazoles 303 taking place simultaneously under the action of TFA. The investigation of physicochemical properties of the new benzofuroindazoles 303 showed their highly fluorescent properties in the solution state. 3.4.6 Nitro enehydrazines Granik et al. (2004MC73, 2004RCB2834) investigated for the first time the condensation of 1,4-benzoquinone with a nitro enehydrazine 304 under Nenitzescu reaction conditions. When N-aminoenamine 304 reacts with p-benzoquinone instead of a Nenitzescu reaction product the iminoderivative 305 (Scheme 53) is obtained as a result of water elimination between keto and NH2 groups (2004MC73). In order to circumvent this condensation N-aminoenamine 304 was transformed by interaction with benzaldehyde into the enehydrazine 306 (Scheme 53). By treatment of enamine 306 with p-benzoquinone in AcOH and in the presence of p-toluenesulfonic acid the 6-hydroxyindole 307 is obtained in 24% yield (2004MC73, 2004RCB2834). The position of the hydroxyl group on the indole ring for compound 307 was assigned on the basis of NMR data and confirmed by X-ray diffraction of its O-acetyl derivative 308 (2004RCB2834). The formation of 6-hydroxyindoles from secondary 3-nitroenamines and p-benzoquinone under the conditions of the Nenitzescu reaction and mechanistic considerations has been described in the earlier literature (1992CHC34). When 6-hydroxyindole 307 is O-acylated, using acetic anhydride in the presence of a catalytic amount of sulfuric acid, the diacylated 6-hydroxyindole 309 along with trisubstituted benzene 310 were obtained (Scheme 53). The diacylated indole 309 has been obtained from 307 by simultaneous O-acylation and hydrolysis of the Schiff base followed by N-acylation whereas the compound 310 resulted from 307 by pyrrole ring opening (Scheme 53). The compounds 309 and 310 were transformed into 1-acetylamino-6-hydroxy-2methyl-3-nitroindole 311 which was deacetylated by acid hydrolysis giving 1-amino-6-hydroxy-2-methyl-3-nitroindole 312 in 86% yield (Scheme 53).

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H

NO2

N

O H

NO2

NO2

NH2

AcOH

+

AcO Me

Me

N

NHNH2

N = CHPh O

O 1

304

305

PhCHO

308

Ac2O reflux

H

NO2

NO2 AcOH

1

+

Me

NH

HO

N = CHPh

N

Me

N = CHPh

306

O2N

NO2 Ac2O

OAc

+

H2SO4 AcO RT

N

Me

N Ac

AcO

NHAc

N = CHPh 310

309

307 (24%)

Me

H2O/HCl

HCl H2O/EtOH

NO2 HO

N NH2 312

Me

NO2

H2O/BuOH HCl

HO

N

Me

NHAc 311

Scheme 53 Reaction of p-benzoquinone with an enehydrazine under Nenitzescu conditions.

3.4.7 Cyclic enamines Cyclic enamines are a category of enamines including compounds having structures 172–174 (Fig. 5), heterocyclic cyclic aminals 178 (Fig. 5), aromatic amines 179, and heterocyclic amines 180 (Fig. 5). Cyclic enamines in the reaction with quinones furnish condensed 5-hydroxyindoles, condensed 5-hydroxybenzofurans, or nonindolic compounds (1956ZOB1449, 1970JA3470, 1993MC40, 1994APH137, 1994PCJ119, 1997PCJ612, 2001JO4457, 2002MC15, 2002RCB1886, 2005BMC819, 2005JMC635, 2005RCB774, 2005T9129, 2006RCB1659, 2011RJOC731). Grinev et al. (1956ZOB1449) reported for the first time a reaction between 1.4-benzoquinone and 3-amino-cyclohexen-1-one 313a as cyclic enamine. The reaction between 3-amino-2-cyclohexen-1-one 313a as well as its 5,5-dimethyl derivative 313b with various 1,4-benzoquinones (2-trifluoromethyl-, 2-methoxy-, 2-acetyl-, 2-carbomethoxy-, 2-chloro5-trifluoromethyl-1,4-benzoquinone) is complex and was investigated by Allen et al. (1969CC1144, 1970JA3470). The structures of the products are influenced by reaction solvent, temperature, reaction time, and electronic effect of quinone substituents. Thus, from 2-trifluoromethyl- and 2-chloro5-trifluoromethyl-1,4-benzoquinone in AcOH at room temperature, the carbinolamines 49 (Fig. 2) were isolated. 2-Methoxy-1,4-benzoquinone

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and cyclic enamines 313a,b (R ¼ H, Me) afford only one regioisomer 314a or 314b (Scheme 54; 1970JA3470). Treatment of enamine 313b with 2-acetyl-1,4-benzoquinone gives the phenanthridine derivative 315 whereas with 2-carbomethoxy-1,4-benzoquinone the phenanthridinone derivative 316 was obtained along with the carbazolone 317 (Scheme 54) (1970JA3470). The dihydro pyrrolo[1,2-a]indoles 319, related to antitumor mitosenes and antibiotic mitomycin, have been synthesized by condensation of cyclic enamine 318 (Scheme 54) with 1,4-benzoquinone or 2-methyl-1,4benzoquinone (1971ABC282). The reaction of enamine 318 with p-toluquinone gives mixture of 6-methyl- and 7-methyl pyrrolo[1,2-a] indole derivatives. Kucklander et al. investigated intensively Nenitzescu 5-hydroxyindole synthesis and it was found that the reaction between various cyclic enamines 320 and 1,4-benzoquinones provides a lucrative procedure for obtaining annelated 5-hydroxyindoles 321 (Scheme 54; 1981APH379, 1981BER2238, 1987APH308, 1987APH312, 1994APH137), annelated benzofurans (1983BER152), or unexpected compounds (1986BER3847, 1988BER577). O OH

O

O HO

Me Me

Me R

R H2N

O OH

Me

MeO

R

N H

OH R = H, Me

313a,b CO2Me

NH

N R

314a,b

OH

Me

O

316

315

O

CO2Et

HO

HO

NH

Me N H

+ p-Quinone

318

317

N

R

CO2Et

Me

319 (R = H, 6-Me, 7-Me)

O HO n

O

n

+

NHR 320 (n = 1–3)

R O

N R

O

321 (n = 1–3)

Scheme 54 Cyclic enamines used in Nenitescu indole methodology.

The product structures (Scheme 55) resulting from reaction of 1,4benzoquinone and cyclic enaminones 322 are dependent on the reaction time, reactants ratio, quinone structure, and temperature (1994APH137,

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O

O

HO

O

HO

4 equiv.

1 equiv.

+ AcOH/RT N R

air

O

NHR

AcOH/RT

324

O MeO2C HO

O 325

O NHR

Scheme 55 Nenitescu enaminone 322.

HO CO2Me

1 equiv.

+

AcOH 80°C

OH

R

322

1

323

N

Argon

O

CO2Me

1 equiv. 322

AcOH/RT air

O

N OH

R 326

reactions

between

benzoquinones

and

the

cyclic

2005BMC819). When the condensation of p-benzoquinone and 2-aminomethylene-1-indanones 322 was performed in a ratio of 1:1 in AcOH at room temperature for 30 min, and under an argon atmosphere, 2,6-dihydroxy-benzo[b]carbazole derivatives 324 (2 examples) resulted in 56% yield (2005BMC819). Under the same reaction conditions from stoichiometric amount of 2-carbomethoxy-1,4-benzoquinone and enaminone 322 the 2,6-dihydroxy-5H-benzo[b]carbazole-1-carboxylates 326 (10 examples) having similar structure with compounds obtained from benzoquinone resulted (Scheme 55). The reaction is regioselective and as a consequence the carbomethoxy group is bonded at the 4-position of the indole ring, which is similar to the 5-hydroxyindoles obtained from acyclic enamines. The condensation in AcOH at room temperature for 16 h between 1,4-benzoquinone and 322 affords benzo[g]carbazole-diones 323 (10 examples). The diols 326 by comparison with their analogues 324 are stable in air and were transformed into the corresponding diones by oxidation in alkaline medium. Interestingly, 2-carbomethoxy-1,4benzoquinone and enaminone 322 in AcOH at 80°C for 2 h leads to 2,3dihydro-spirobenzofurans 325 (four examples, Scheme 55). Cyclic tertiary enamines 64, 68, 69, and 72a (Schemes 12 and 13, Fig. 6) and 1,4-benzoquinones lead to annelated benzofurans and spirobenzofurans (1993MC40, 1995PCJ636, 2002MC15, 2002RCB1886). Secondary cyclic enamines 327–332 (Fig. 6) and 1,4-benzoquines under Nenitzescu reaction conditions result in the formation of the corresponding annelated 5-hydroxyindoles (1994PCJ119, 2005JMC635, 2005RCB774, 2006 RCB1659, 2010PCJ296, 2011RJOC731).

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N R

O

O

OH

CO2Et

n

COR

NH

N

N

O

ArHN

64 (n = 2) 68 (n = 1) NC

CN

MeO

R NH

MeO

1

Me

2

NH

NH

EtO EtO

3

NC

EtO

Me

R

329

NHBn

328

327

69 (R = CO2Et)

ArHN

O

RO

O

ROC EtO

330

331

332

Fig. 6 Examples of cyclic tertiary enamine structures.

For example, tetrahydroisoquinoline enaminones 333 (R1 ¼ Me, Ph) with benzoquinone (Scheme 56) in nitromethane at room temperature furnish the indolo[2,1-a]isoquinoline derivatives 334 (R1 ¼ Me, Ph) (2001JO4457). Under identical conditions, p-toluquinone and acetylenaminone 333 (R1 ¼ Me) give only one regioisomer 334 (R2 ¼ Me) (Scheme 56). The condensation of N-substituted 4-aminocoumarins with 1,4-naphthoquinones (Scheme 56) in the presence of the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]) and KHSO4 as catalyst takes place by an indolization process affording hydroxybenzo[g]chromeno[4,3-b]indole in yields of 35%–76% (eight examples) (2014LOC188). O MeO

MeO

2

R NH

MeO

+

O

MeNO2

MeO RT Three examples

N R

O

2

O 1

R

R 333 R1 = Ph, Me

R2 = H,Me

1

OH 334 OH

O NHR

O

KHSO4

+

[bmim]BF4/toluene O

335

O

O

78

N

O

R

336

Scheme 56 Polycyclic indoles containing structures from cyclic enaminones in reaction with 1,4-benzoquinones.

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R R

R OH

1

R

2 1

R

NH2

1

1

1

R

1

R

HO

NH2

R R

R

2

HO N H

2

1

N H

OH

R

1

2

337a (11%); 337b (7%); 337c ( 9%)

R 338a (31%); 338b (21%); 338c (29%)

339a (12%); 339b (17%); 339c (9%)

a: R1 = H, R2 = NO2; b; R1 = Me, R2 = NO2 ; c: R1 = Me, R2 = CN

Fig. 7 Compounds resulted via the Nenitzescu reaction starting with aromatic amines and 1,4-benzoquinone.

The heterocyclic ketene aminals 241, 263–265 (Schemes 40, 45–47) act in the reactions with 1,4-benzoquinones and their homologues as cyclic enamines giving fused 5-hydroxindoles (1981S157, 2010S3536), 7a-hydroxy-[1,2-a]indol-5-ones (2015T4084), and 3a-hydroxy-indol-6ones (2014GC4359). 3.4.8 Aromatic and heteroaromatic amines The use of aromatic and heterocyclic amines as the enamine component in the Nenitzescu reaction is a valuable method to prepare in one step 3-hydroxycarbazole derivatives and other fused heterocyclic systems. The first example is the reaction between quinones and aromatic amines reported in 1980 by Bernier et al. (1980JO1493) with the aim of obtaining analogues of the alkaloid ellipticine, known as a DNA intercalator. From the reaction between 1,4-benzoquinone and aromatic amines containing electron-withdrawing groups, such as nitro and cyano, performed by heating of components under reflux in acetic acid for 4 h or in trifluoroacetic acid for 30 min (Fig. 7) were isolated three types of compounds: 3-hydroxycarbazoles 337, the hydroquinones 338, and the diarylamines 339 (Fig. 7). The structures of the products were assigned on the basis of their spectral properties. The main disadvantage of this reaction is that the expected 3-hydroxycarbazoles 337a–c are obtained in low yields along with the byproducts 338 and 339 (Fig. 7). Pushkarskaya et al. (2016TL5653) developed a simple procedure for the synthesis of highly functionalized 3-hydroxycarbazoles implying annulation of electron-rich N-substituted anilines with various quinones (Scheme 57). The reaction performed in PhMe/AcOH (4:1) at room temperature generated in moderate yields a library of 3-hydroxycarbazoles

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(19 examples). Quinones used in this synthesis were 2-substituted 1,4-benzoquinones (R ¼ Me, t-Bu, Ph, OMe), 2,3-substituted 1,4benzoquinones (R ¼ Me, OMe), 1,4-naphthoquinone 78 and their 6,7-dimethyl and 5,8-dimethoxy derivatives. O

OMe

OMe HO

2

+

PhMe/AcOH

R

RT

NHR 1

MeO

O

N

R2

19 examples

R 341

340

OMe 1

Scheme 57 Carbazole synthesis by Nenitzescu reaction of aromatic amines and different 1,4-benzoquinones.

Bernier and Henichart (1981JO4197) extended the Nenitzescu reaction by replacing anilines with 1,3-dimethyl-6-aminouracil 91 which can act as a cyclic enamino ketone. The condensation between 1,4-benzoquinone 1 and aminouracil 91 (Scheme 58) was achieved in nitromethane or acetic acid medium and represents the one-step synthesis for pyrimido[4,5-b] indole derivatives (Scheme 58). The reaction was carried out under reflux and pyrimido[4,5-b]indole 342 was obtained along with hydroquinone Michael adducts 343 and 344 (Scheme 58). The structures of the products were determined on the basis of their spectral properties, and in the case of pyrimido[4,5-b]indole 342 the structure was confirmed by an independent synthesis. The best results for 6-hydroxypyrimido[4,5-b]indole 342 have been obtained in nitromethane (yield 41%) whereas in acetic acid the yield was only 8%. The formation of the products is in accordance with the general mechanism for the Nenitzescu indole synthesis and its adaptation to the reactions of 1,4-benzoquinone with anilines and heterocyclic amine has been presented (1980JO1493, 1981JO4197). Reaction of 1,4naphthoquinone with dimethyl-6-aminouracil 91 (Scheme 15) results in the formation of annelated benzo[g]indole 92 and enamine bisadduct 93 (2004PCJ146). O O

O 1 + 91

A. MeNO2 B. AcOH

HO

N

OH

Me

N

N

H2 N

Me

OH 342: A (41%); B (8%)

343: A (trace) B (25%)

O N

N

+

N

O

Me

H 2N

O

Me

OH

N Me

Me N

NH2

Me

O

+ N H

OH

Me

O 344: A (17%); B (15%)

Scheme 58 Pyrimidinoindole and Michael adducts obtained by the Nenitzescu reaction of aminouracil with benzoquinone.

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2,4,6-Triaminopyrimidines 345a–g (R1, R2 ¼ amino, cycloalkylamino, dialkylamino) have been used as enamines in reactions with 1,4benzoquinone to afford a library (Scheme 59) of 2,4-diamino-9H-pyrimido [4,5-b]indol-6-ols 346 (2004SL1039). The synthesis was performed in ethanol or glacial acetic acid under reflux giving pyrimido[4,5-b] indole derivatives 346 in yields of 23%–55%. Similarly, the condensation between 1,4-benzoquinone and 2,6-diamino-4-hydroxypyrimidine 347, N,N-dimethylated 348 and O-methylated 349 derivatives in ethanol gives the corresponding pyrimido[4,5-b]indoles 346 whereas for 2methoxypyrimidine 350 no reaction has been observed in ethanol or acetic acid (Scheme 59). In order to investigate biological activity for a wide variety of pyrimido[4,5-b]indoles (22 examples) the method was extended for the synthesis of two new series of 9H-pyrimido[4,5-b]indol6-ols of type 346 (2006BMC7282, 2018JEI1). Interestingly, the 2,6diamino-4-hydroxypyrimidine 348 with 1,4-benzoquinone in ethanol under reflux gives in 23% yield the expected pyrimido[4,5-b]indole 351 (Scheme 59) but in acetic acid 6-hydroxy-pyrimido[4,5-b]indole 352 containing substructure 347at the 5-position was obtain in yield of 35% (2004SL1039). 1

O

R

R

N

+ N

H2N

HO

AcOH R

N

or EtOH

2

N

N H

O 1

1

345a–g

R

2

346a–g

a: R1 = R2 = NH2; b: R1 = NMe2, R2 = NH2; c: R1 = NH2, R2 = NMe2; d: R1 = R2 = NMe2 ; e: R1 = 4-morpholinyl, R 2 = NMe 2; f: R1 = NH2; R2 = 1-pyrrolidinyl; g: R1 = R2 = pyrrolidinyl O

NH H2N

OMe

O

N

N

NH

NH2 H N 2

NMe2 H2N

N

N

N NH2

N

H2N

349

348

347

NH2

OMe

350 NH2

HN

O HO

NH

O

N NH2

O

HO N H

N

NH

NH2

N

N H 351

NH2

352

Scheme 59 Nenitzecu reaction as a versatile method for obtaining libraries of bioactive pyrimido[4,5-b]indols using various aminopyrimidines.

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The replacement of p-benzoquinone by 1,4-naphthoquinone 78 in the reaction with 2,4,6-triaminopyrimidines (Scheme 60) provides a facile way to obtain benzo[g]pyrimido[4,5-b]indoles 354 (2004SL1039, 2006BMC7282). Similarly, condensation of azanaphthoquinones 153– 156 with 2,4,6-triaminopyrimidines (Schemes 27 and 28) gives new policyclic heterocyclic systems (2004SL1039, 2006BMC7282). R R

O

HO

N

AcOH, EtOH

N

+ N

H2N

2

2

R

N

N H

reflux 6 h

1

R

1

O 354a–e

353a–e

78

a: R1 = R2 = NH2; b: R1 = 4-morpholinyl, R2 = NH2; c: R1 = 4-methylpiperazinyl, R2 = NH2 ; d: R1 = 1-pyrrolidinyl, R2 = NH2; e: R1 = NH2, R2 = 4-morpholinyl

Scheme 60 By replacing benzoquinone with naphthoquinone fused polycyclic pyrimidinoindoles are accessible by Nenitzescu reaction with aminopyrimidines.

2,4,6-Triaminopyridine 355 can act as an enamine in the reaction with 1,4-benzoquinone and the structure of the final products is determined by the ratio of reactants (2008JHC1517). When 2,4,6-triaminopyridine 355 was treated with an excess of benzoquinone (1.2 equiv.) in boiling ethanol pyrido[2,3-b]indole derivative 356 (Scheme 61) possessing the 5-hydroxyindole subunit was obtained in 17% yield (2008JHC1517). Unexpectedly, one equivalent of 2,4,6-triaminopyridine 356 in ethanol

O

NH2

NH2 EtOH

+ H2N O 1

N

NH2

HO

1:1 mole

N H 356

355

N

NH2 OH

NH2 EtOH 1 + 355

2:1 mole

HO

HN

OH N H

N

357

N H

+

HO N H

N

NH2

358

Scheme 61 The Nenitzescu reaction of triaminopyridines gives facile access to polycyclic fused azacarbazole-like structures.

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and two equivalents of 1,4-benzoquinone mixture gives a linear and an angular pyridodiindole derivative 357 and 358 via a double Nenitzescu reaction (Scheme 61). Attempts to generate pyridodiindoles 357 or 358 from the α-carboline derivative 356 and benzoquinone have not been successful. Another synthesis for a γ-carboline derivative from a pyridine enamine, namely 5-methyl-4-aminopyridin-2-one, and p-benzoquinone was reported in a synthesis of congeners of the alkaloid ellipticine (1987T527). The synthesis represented a new method to access compounds having a γ-carboline scaffold. (2-Amino-5,10,15,20-tetraphenylporphyrinato)nickel(II) 359 was used as the enamine component in reactions with 1,4-benzoquinone, 1,4naphthoquinone and 2-hydroxy-1,4-naphthoquinone (2005T11866). The reaction between the nickel complex of porphyrin 359 and 1,4benzoquinone was performed in tetrahydrofuran (THF) under reflux and in the presence of a catalytic amount of concentrated sulfuric acid and gave compound 360 with a 5-hydroxyindole substructure in 65% yield (Scheme 62). When the reaction was carried out in THF at room temperature the porphyrin indole 360 was obtained in 54% yield along with the byproducts 361–363. NH2

Ph

H N

Ph

OH

O THF

N

N

+

Ph

Ni

Ph

reflux

N

N

N

N

Ph

Ni

Ph

N

N O Ph

Ph 1

359

360 (65% / 54%) O

O

O N

Ph

Ph

Ni

Ph

N

N

N

N

N

N

Ni

Ph

N

N

Ph Ph 361 (11%)

O

NH2

Ph

362 (4%)

N

Ph

O Ph

N

N Ni

Ph

O Ph

N

N

Ph 363 (28%)

Scheme 62 Grafting indole substructures onto the porphyrin core by Nenitzescu reactions of benzoquinone with a porphyrin complex acting as an enamine-like component.

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O O

O

NH2

Ph

N

Ph N

Ph

N Ni

Ph N

N

N

OH

N

N

Ph

Ni

Ph

N

N

N

N

O Ph

N

Ph

Ni

Ph

N

Ph Ph

Ph 366 (25%)

365 (70%)

364 (4%) O

O O

Ph HN

Ph HN O

N

N Ni

Ph

N Ph

Ni

Ph

N

N

N

Ph 367 (12%)

Ph N

N

Ph 368 (71%)

Fig. 8 1,4-Naphthoquinone used in Nenitzescu reactions with porphyrins acting as enamine-like components.

Stirring 1,4-naphthoquinone and (2-amino-5,10,15,20tetraphenylporphyrinato)nickel(II) 359 leads, under similar reaction conditions to those described for benzoquinone (20 min at room temperature in THF), to a mixture of three compounds 364–366 (Fig. 8). The resulting compounds 364 and 365 are benzoanalogues of those ones resulting from the interaction between (2-amino-5,10,15,20tetraphenylporphyrinato)nickel(II) 359 and 1,4-benzoquinone, namely 361 and 362, respectively. In the case of 2-hydroxy-1,4-naphthoquinone the interaction with aminoporphyrin 359 requires a long time (3 days at room temperature or 10 h at reflux in THF) by comparison with 1,4benzoquinone and 1,4-naphthoquinone. From the reaction mixture the compounds 367 and 368 were isolated by TLC and their structures were assigned by MS spectrometry and NMR spectroscopy (2005T11866). The proposed mechanism for the formation of both compounds implies the addition of the amino group to the quinone moiety.

3.5 Enamino benzoquinone hybrids The unstable 1,4-benzoquinone-enamine hybrids 369 (n ¼ 1, n ¼ 2) were generated by oxidation of the corresponding hydroquinones and their chemical transformation investigated (1994APH143). It has been

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established that the ambident enamino quinones 369 (n ¼ 1) are not stable in solution and no compound was isolated. The hybrids 369a–c (n ¼ 2) on standing in ethanol give, unexpectedly, the tricyclic methano-cyclopent[c] azocin-6,9-diones 370a–c in 44%–58% yield (Scheme 63). It was deduced on the basis NMR spectroscopy that by standing in CDCl3 over 12 h the tricyclic compounds 370 are in equilibrium with the corresponding spiro dihydroquinones 371 (Scheme 63). O

O

O n

O

O

EtOH Me

Me O

Me

RT

O

371a–c

COMe

HO

COMe

AcOH N

NHR

O

R

O

Me

Me

R = Me, Bn, 4-tolyl

O

Me

NHR Me

370a–c

369 n = 2; R = Me, Bn, 4-tolyl

COMe

RT

N HO

NHR

O

CDCl3

Me

; Me

Me

N

Me

R O

372b–e

373b–e

374

Scheme 63 Unstable enamino quinone derivatives and their reactivity.

The enamino quinones hybrids 372b–e (R ¼ Me, Bn, 4-MeC6H4, 4-MeOC6H4) undergo intramolecular cyclization to the dihydro spiropyrroles 373b–e (Scheme 63; 2000JPC17); these transformations were achieved in 50% yield in AcOH or alcohol in the presence of perchloric acid. The enamino quinone 372a (R ¼ H) leads to 3-acetyl-6-hydroxy-quinoline 374 in 44% yield (Scheme 63).

3.6 Quinoneimines and quinonediimines Quinoneimines and quinonediimines are derivatives of 1,4-benzoquine that can act as components in the Nenitzescu reaction with enamine to form 5-aminoindoles, 5-aminoenzofurans or N-substituted 4-aminophenol derivatives. The product structures resulting from interaction between N-substituted 1,4-quinoneimines and diimines with enamines is strongly dependent on the solvent, the enamine substituents and, to a lesser degree, by the N-substituent of the quinone imine (2005RCB1690, 2007RJOC414, 2011RJOC1169, 2017RJOC525). By comparison with 1,4-benzoquinone, quinoneimines and diimines have a higher reactivity

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and as a consequence enamines do not require the presence of an electronwithdrawing group on the enamine (1962JA837). The interaction between N-arenesulfonyl-1,4-benzoquinoneimines with various enamines has been investigated by Titov et al. (1972 CHC789, 1973CHC1311). On reacting N-arylsulfonylimines with derivatives of 3-alkyl- and 3-cycloalkylaminocrotonic acids they obtained N-arylsulfonyl-4-aminophenol derivatives, resembling the Michael adducts isolated from 1,4-benzoquinone and enamines (1973CHC1311). The reaction of N-arylsulfonyl-2,6-dichloro-1,4-benzoquinoneimines with 3-alkylaminocrotonates proceeds with displacement of the arylsulfonyl group and formation of a substituted 6-hydroxyindole (1976CHC411). The condensation between N-sulfonyl quinoneimines 375 was carried out in several solvents in order to establish the solvent influence on the structure of the reaction products (2011RJOC1169, 2017RJOC525). Thus, in chloroform or dichloromethane was formed 5-aminoindoles 376, in acetic acid 5-aminobenzofurans 377 and in dichloroethane, depending of enamine structure, was isolated either adduct 378 or 5-aminophenol 379 (Scheme 64; 2011RJOC1169). The condensation between nitroenamines 204c,h with quinoneimine 375 (Ar ¼ 4-MeC6H4) gives 5-aminobenzofuran derivative 380 and 6-hydroxyindoles 205c,h (2005RCB1690). 6-Hydroxy-3-nitroindole 205c (R ¼ Bn) has been also synthesized from 1,4-benzoquinone and nitroenamines 204c (1992CHC34).

NSO2Ar

COR

ArSO2NH

CHCl3

+

R

CH2Cl2

Me

N

R

COR Me

Ar

O 375

376 Me PhSO2NH

(CH2Cl)2 OH Me

EtO2C

NHAr

377 Me2CO

OH

OMe

R 379

NSO2Ar

+ Me O 375 Ar = 4-MeC6H4

NHR

Me

R = Me, OEt

378 NO2

O

R

ArSO2NH

N H

COR

ArSO2NH

AcOH

AcOH

+ O

TsOH

204c,h R = Bn, CHMe2

NO2

NO2

ArSO2NH

Me

380 Ar = 4-MeC6H4

HO

N

Me

R 205c,h R = Bn, CHMe2

Scheme 64 Nenitzescu reaction synthesis of 5-aminoindoles or 5-aminobenzofurans by employing benzoquinoneimines instead of benzoquinones.

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The compounds 381–383, resulting from condensation of N-tosyl-1,4naphthquinone imine with enamines in various solvents (Scheme 65), are benzo analogues of the products 376–378 obtained when 1,4-quinoneimines and N-arylenamines are used as starting materials (2011RJOC1169). The influence on the course of reaction of the enamine structure was also demonstrated by interaction of nitroenamines with N-sulfonyl quinoneimines 375 (Scheme 64) when a mixture of 5-aminobenzofuran derivative 377 and 6-hydroxyindole 205 derivatives was obtained (2005RCB1690). Based on the reaction between quinoneimines and enamines a synthesis of the antiarrhythmic drug dronedarone 386 (Scheme 65) in 47% yield starting from N-methanesulfonyl quinoneimine 384 and bisenamine 385 was developed (2011WO107705A1).

CO2Et

TsNH OH Me

TsNH

COR

TsNH O

Me

N

Me

Ar EtO2C

R

N H

R = Me, OEt 382

381 Solvent: NSO2Me

+

Bu

AcOH

COC6H4R-p

p-RC6H4CO NH

HN

Bu

AcOH

COC6H4R-p

MeSO2NH O

O 384

383

CHCl3: (CH2Cl)2

Acetone

385; R = (CH 2)3NBu2

Bu

386; R = (CH 2)3NBu2

Scheme 65 Different reaction products of Nenitzescu reaction using quinone imines and different enamines and reaction conditions.

One of the first examples of a reaction between quinone diimines and enamines was reported by Kuehne (1962JA837) and it was found to give carbazoles. Later, Domschke et al. (1966BER939) extended the synthesis to acyclic and cyclic enamines obtaining indole and carbazole derivatives. A regiospecific formation of indoles from substituted quinone diimine has been reported (1990JO1379). N-Arylsulfonyl-1,4-quinone diimines on reacting with N-aryl-3-aminocrotonates at room temperature in acetone proceeds with cleavage of an arenesulfonamide to give the corresponding 5-arenesulfonamidoindoles (1974CHC1327). More recently the formation of indoles and fused indoles from the condensation of N,N0 -disubstituted quinondiimines with cyclic and acyclic enamines has been reported (2007RJOC414, 2011RJOC1169).

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4. Improvements and modifications of the Nenitzescu reaction Despite the low to moderate yields, the simplicity and the straightforwardness of the Nenitzescu reaction and the potential for biological applications of 5-hydroxyindoles has encouraged improvements of the reaction. This includes challenging the competition between the two paths of the Nenitzescu reaction leading either to indoles or benzofurans and directing the reaction more selectively. The use of nitromethane at room temperature as solvent for the Nenitzescu synthesis increases the yields for 5-hydroxyindoles and, for example, made possible the generation of a library of indole derivatives (1979TL4009). One-pot synthesis of 5-hydroxyindoles has been accomplished in 73%–95% yields by the in situ generation of enamines from amines and β-ketoesters (10 examples) in the presence of montmorillonite KSF clay followed by reaction with 1,4-benzoquinones (Scheme 66). 1,3Dicarbonyl compounds, such as acetylacetone, 1,3-indandione, and dimedone, lead to the corresponding indoles or annelated indoles (2013BKCS2968). One-pot reaction of 1,4-naphthoquinone with aniline and ethyl acetoacetate in the presence of catalyst affords the corresponding benzo[g]indole. The effect of various catalysts on the indole yields has shown that the best results are obtained by using montmorillonite. Ethyl 5-hydroxy-1-methyl-2-(trans-2-phenylcyclopropyl)-1H-indole-3carboxylate 388 as an analogue of antiviral umifenovir was synthesized in 28% yield by one-pot reaction of β-ketoester 387, methylamine, and 1,4-benzoquinone (2014CHC489). A series of 5-hydroxybenzo[g]indoles 117 (Scheme 19) were synthesized by one-pot three-component reaction starting from 1,4-naphthoquinone, 1,3-dicarbonylic compounds, and primary amines in the presence of CAN (2010OBC3426, 2013T5401). A variation of the Nenitzescu reaction for synthesis 5-hydroxybenzo[g] indoles 122 (Scheme 19) implying a one-pot three-component procedure starting from 1,4-naphthoquinone, β-aminoketones, and urea under microwave (2010TL5160). An improved procedure for obtaining 5-hydroxyindoles and 5-hydroxybenzo[g]indoles from quinones and enamines in good yields was developed by using a Lewis catalyst (2006JHC873, 2008TL7106, 2011OBC1317, 2016EJMC466). By comparison with other Lewis acids the most efficient catalysts proved to be ZnI2 or ZnCl2 (Scheme 6) and when

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O

CO2Et

HO OEt

Me

+

R NH2

+ O

O

Cl(CH2)2Cl Me

N

catalyst reflux

R

O 10 examples O

+

Me

NH2

AcOH/EtOH

+

N

reflux 16 h

Ph O

CO2Et

HO

COCH2CO2Et

Me 387

Ph

388

Scheme 66 One-pot multicomponent Nenitzescu reaction by in situ generation of enamines.

synthesis was performed in dichloromethane. The use of ZnBr2 as a catalyst in the Nenitzescu reaction was used for the preparation of 2-phenyl-3carboethoxy-5-hydroxyindole from the corresponding enaminoester generated in situ and p-benzoquinone (2011OBC1317). 5-Hydroxyindole-3-carboxamides 392 (14 examples) were obtained by a solid-phase process implying a sequential process (2000TL6253). Thus, the acetoacylation with diketene of ArgoPore1-Rink-NH2 resin gives the N-acetoacetyl derivative 389 which by condensation with primary amines forms the enamine-resins 390. Condensation of the enamines 390 with various 1,4-benzoquinones gives the indoles 391 linked by resin support which by treatment with TFA generate indoles 392 in 2195% yields (Scheme 67). 1

Resin NH2 +

Resin NHCOCH2COMe

O

R NH2

Resin N H

CO

Me

O

389 R O

NHR

390

1

2

O

CONH-resin

HO

TFA R

Me

N R

1

391

14 examples

CONH2

HO

R2

Me

N R

1

392

Scheme 67 Solid supported Nenitzescu reactions facilitating access to a library of 5-hydroxyindoles.

Interestingly, by condensation of carboxymethyl cyclohexadienones and amines, a library of 6-hydroxyindoles was synthesized in good yields (2017JO8426). The formation of 6-hydroxyindoles was explained by

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formation of an enamine intermediate which undergoes subsequent cyclization to 6-hydroxyindole. The annelation with p-benzoquinones of the spasmolytic agent drotaverine 332 possessing enamine structure was performed both in solution and in the solid state by simple fusion of reactants (2005RCB774, 2006CHC1352).

5. Impact of reaction conditions The yields and structures of the products resulting from the Nenitzescu reaction are largely determined by structure of the starting materials and the reaction conditions such as solvent, catalyst, ratio of reactants, temperature, and reaction time. The solvent nature has a significant role in directing the reaction between 1,4-benzoquinones and enamines toward the indolization process and in some cases significantly influences the yield of indole derivatives, which is in the range 5%–95%. The reactions of enamines with quinones have been carried out with good results in acetone (2006RCB1659, 2017CRCU365, 2017DPS1, 2019O17910), nitromethane (1979TL4009, 1996JO9055, 2005CHC221, 2005JMC635, 2005RCB774, 2009TL4182, 2011 EJOC4635, 2014BMCL1944), acetic acid (1990CHC274, 1997T177, 1998JMC4755, 2003SC2285, 2004CHC16, 2004PCJ146, 2004SL1039, 2005BMC819, 2005CHC221, 2005T9129, 2006BMC3599, 2006BMC7282, 2010RCB1639, 2010RCI975, 2011BMC2666, 2011RJOC731, 2015CHC978), ethanol (2005JMC635, 2005S2414, 2006JMC4327, 2008JHC1517, 2009JMC3474, 2010OBC3426, 2016MOL638), 1,2-dichloroethane (2011APP49, 2013BKCS2968), dichloromethane (1995MC68, 2006JHC873, 2008TL7106, 2009JMC3474, 2011JHC733, 2016EJMC466, 2018EJMC946), benzene (2006JHC873, 2010PCJ296), THF (2005T9129, 2011JHC733), and water (2006 EJOC869). It was found that nitromethane and acetic acid are suitable solvents to obtain 5-hydroxyindole derivatives. Also the solvent mixtures can be used in the obtaining of 5-hydroxyindoles in good yields (1995JCSP(1) 2667, 2004SL1039, 2009CJM116, 2010S3536, 2014CHC489). Polyethylene glycol-400 is an eco-friendly solvent for obtaining of new isoxazolyl indole-3-carboxylic acid esters (2017CSE5110). The solvent effect of various solvents on the indole yield was investigated in the process of synthesis optimization of 5-hydroxyindoles required for biological evaluation or other studies (1995JCSP(1)2667, 1996JO9055, 2010RCI975, 2010TL5160). A systematic study regarding the influence of concentration,

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ratio of reactants, solvent, temperature, and reaction time on the reaction between ethyl 3-aminocrotonate and 1,4-benzoquinone showed that solvents used should have a high polarity and a relatively low polarizability (2004JCHEMO183). The role of solvent on the course of Nenitzescu reaction is briefly depicted in Schemes 31 and 65. The influence of the solvent on the product structure was also studied (Scheme 68) by the discoverers of this reaction (1965RRC339, 1971T5031, 1988RRC953). Thus, condensation of 1,4-benzoquinone with ethyl 3-aminocinnamate in AcOH gave the expected 5-hydroxyindole 393 in 46% yield. When the reaction was performed in benzene or chloroform at room temperature or under reflux the enamino hydroquinone 394 in 25% yield along with quinone 395 (ca. 3.5%) and hydroquinone were obtained. The compound 394 in acetic acid in the presence of a catalytic amount of 1,4-benzoquinone was cyclized to indole 393. Interestingly, when the reaction was performed in 1-butanol under reflux the result was a yellow compound 397 (20% yield) and 4-enamine-5-hydroxyindole

E

HO

E = COOEt Ph

N H AcOH

393 AcOH

reflux

+1

Ph OH

NH2

O

Ph

NH2

O E

+ Ph

E

CHCl3

NH2

C6H6

E

+

OH

O

E H2N

394

Ph

O

395

BuOH

1 NH2 E

reflux Ph

E

O

Ph

H

E

O

H N

Ph

Ph E

HO N H 396

Ph

+

HN Ph

H N H E

O

397a (Proposed structure)

HN O H

E

H

397b (Revised structure)

Scheme 68 Solvent influence in Nenitzescu reaction and the reinvestigation of the structure of the 2,8-diazaheptalenedione derivative structure revised to the pyrrole–azepine hybrid structure by X-ray diffraction analysis.

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396 (15% yield) (1988RRC953). For the yellow compound, the 2,8diazaheptalenedione structure 397a was assigned based on IR and NMR spectroscopy. A reinvestigation by X-ray analysis of the yellow compound revealed a pyrrole–azepine hybrid structure for 397b having the two heterocyclic rings connected by a double bond (2020RCXXX). The reactants ratio can influence in many cases the structure (Schemes 55 and 61) and the yield of the reaction products (2008JHC1517, 2004JCHEMO183, 2005BMC819, 2010RCI975). Usually, the Nenitzescu synthesis takes place in mild conditions but there are some cases when the temperature and reaction time (Scheme 55) are factors which change the course of the reaction (2004JCHEMO183, 2005BMC819, 2005T11866, 2010RCI975). The yield of 5hydroxyindoles and annelated 5-hydroxyindoles can be increased using various catalysts such as ZnCl2, ZnBr2, ZnI2, AlCl3, BF.3Et2O, KHSO4, and montmorillonite (2006JHC873, 2008TL7106, 2011JHC733, 2013 BKCS2968, 2014LOC188, 2016EJMC466, 2016MOL638).

6. Products of the Nenitzescu synthesis 6.1 5-Hydroxyindoles The Nenitzescu 5-hydroxyindole synthesis is renowned for easy access to 5-hydroxyindoles and annelated 5-hydroxyindoles. However, the reaction between enamines and quinones is complex because reactants can interact in different ways and, as a consequence, the formation of nonindolic compounds is frequent. 5-Hydroxyindole derivatives are usually obtained as final reaction products but in some cases Michael adduct intermediates are converted into indoles (1990CHC274, 1993PCJ136, 1993PIAS189, 1995JCSP(1)2667, 1996JO9055, 1997T177, 1998JMC4755, 1999RCB160, 2000TL6253, 2004JCHEMO183, 2005S2414, 2006JHC873, 2006JMC4327, 2008JHC1517, 2008TL7106, 2009JMC3474, 2009TL4182, 2010OBC3426, 2010RCB1639, 2010RCI975, 2011APP49, 2011JHC733, 2011OBC1317, 2011T8747, 2013BKCS2968, 2013T5401, 2014BMCL1944, 2014CHC489, 2015CHC978, 2016EJMC466, 2016TL5653, 2017BMC327, 2017CRCU365, 2017CSE5110, 2017DPS1, 2018EJMC946, 2019IJPBS517). The synthesis of annelated 5-hydroxyindoles is also frequent and it is possible when the starting materials are condensed 1,4-benzoquinone and/or cyclic enamines (1992CHC299, 1994APH137, 1994PCJ119,

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1997PCJ612, 1998CHC651, 2000CHC1276, 2003CHC872, 2003SC2285, 2003CHC61, 2004CHC16, 2004PCJ146, 2004SL1039, 2005BMC819, 2005CHC221, 2005JMC635, 2005RCB774, 2005S2414, 2005T9129, 2006BMC3599, 2006BMC7282, 2006RCB1659, 2010PCJ296, 2010S3536, 2011RJOC731, 2013BKCS2968, 2014LOC188, 2016EJMC466, 2016MOL638, 2016TL5653, 2017ADV24813, 2018EJMC946, 2019O17910).

6.2 6-Hydroxyindoles The formation of 6-hydroxyindoles is not usual (Schemes 3, 24, 33 and 34, 53) in the Nenitzescu reaction but has been described in some cases (1965ZOR2051, 1971APH57, 1976CHC411, 1979APH515, 1992CHC34, 1992CHC299, 2004MC73, 2004RCB2834). Factors that influence the formation of 6-hydroxyindoles include enamine structure and reaction conditions. It was found that an aryl substituent on the nitrogen atom of the enamine favors formation of 6-hydroxyindoles vs 5-hydroxyindoles, the first report being due to Grinev et al. (1965ZOR2051). The presence of β-nitro substituents in the structure of enamines results in 3-nitro-6-hydroxyindoles along with benzofurans or 5-hydroxyindoles (Schemes 33, 34, and 53) (1992CHC34, 1992 CHC299, 2004MC73, 2004RCB2834). The nature of the solvent seems (Scheme 69) to be an important factor that can afford 6-hydroxyindoles (1971APH57, 1973CHC1225, 1979APH515). The condensation of N-arylaminocrotonates with p-benzoquinone in acetone generates 5-hydroxyindoles 398 whereas in acetic acid the result is the formation of 6-hydroxyindoles 399. Another example is reaction between 1,4benzoquinone and substituted N-arylaminocrotonates in propionic acid at 15°C which gives 6-hydroxyindoles in a mixture with 5-hydroxyindoles, 4-hydroxy-5-propionyloxyindoles, and 5-hydroxybenzofurans (1979 APH515). The reaction in acetone of N-arylaminocrotonates of annelated benzoquinone 145 and N-benzyl-β-aminocrotonic ester 20b yields in acetic acid condensed 6-hydroxyindole derivative 148 (Scheme 24; 2004CHC16). A mechanism for 6-hydroxyindoles formation through Nenitzescu synthesis by addition of enaminic carbon atom to the carbonyl group of the quinone to give intermediate 21 (Scheme 3) has been proposed. It was found that β-nitroenamines react with benzoquinoneimines (Scheme 64) to give a mixture of 6-hydroxyindoles and 5hydroxybenzofurans (2005RCB1690). The influence of steric factors was

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O CO2Et

HO

CO2Et

acetone N

+

Me

20%

Me

NHAr

CO2Et AcOH AcOH/Cl(CH2)2Cl HO

N

20

1

398

Me

Ar

O

Ar

399

Ar = Ph, 10%; Ar = 4-MeC 6H4 , 13%, Ar = 4-ClC6H4, 20% yield NSO2Ar Cl

Cl

CO2Et

+ Me O 400

NHR

Acetone R = Me, Et

CO2Et

Cl HO

N Cl

20

Me

R 401

Scheme 69 6-Hydroxyindoles formation by Nenitzescu reaction; Influence of the reactants substitution or reaction conditions.

evidenced in the formation of 6-hydroxyindoles from benzoquinoneimine 400 (Scheme 69). The condensation reaction in acetone between Naryl-sulfonyl-2,6-dichloro-1,4-benzoquinoneimine with N-methyl and N-ethyl β-aminocrotonic esters proceeds with elimination of the arylsulfonyl group giving 5,7-dichloro-6-hydroxyindoles 401 in 30% and 20% yield, respectively (1976CHC411). Under similar reaction conditions 2,6dichloro-1,4-benzoquinone and ethyl N-methyl-β-aminocrotonate afford the expected 4,6-dichloro-5-hydroxyindole derivative (1976CHC411). It was found that condensation between HKAs and 1,4-benzoquinone in ethanol follows the pathway for 6-hydroxyindoles synthesis but stops at 3a-hydroxy-indol-6-one derivatives 275 (Schemes 47 and 48; 2014GC4359). In one case the 3a-hydroxy-benzoindolone derivative 279a (Ar ¼ 4-ClC6H4) was converted into tetracyclic compound 281 (Scheme 47) including a 6-hydroxyindole moiety (2014GC4359).

6.3 4,5-Dihydroxyindoles Mono O-acylated 4,5-dihydroxyindoles and 4,5-dihydroxybenzo[g]indoles are byproducts in the Nenitzescu synthesis that were isolated from the reaction mixture in low yield (2%–35%) when the reaction between enamine and 1,4-benzoquinones was performed in acetic or propanoic acid (1971APH602, 1971TL157, 1972T5251, 1975T1631, 1978LA129, 1979APH515, 1992CHC299, 2015CHC978). The formation of O-acylated 4,5-dihydroxyindoles was investigated by Kucklander et al. (1971APH602, 1971TL157, 1972T5251, 1975T1631, 1978LA129, 1979APH515) who established that 4,5-dihydroxyindoles result from nucleophilic addition of acetate ion to carbinolamine intermediates (Scheme 70). This mechanism is sustained by formation of 5-acetoxy-4-hydroxyindoles from carbinolamine on standing in acetic acid

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at room temperature (1972T5251). More recently by reacting in acetic acid a twofold molar excess of 1,4-benzoquinone with enaminoester 402 (Scheme 70) was obtained a mixture consisting of the expected 5-hydroxyindole 403 and 5-acetoxy-4-hydroxy-substituted as byproduct 404 (2015CHC978). The representative steps of the Kucklander proposed mechanism for obtaining acylated 4,5-dihydroxyindole are shown in Scheme 70 (1993PCJ413). First the addition of acetic acid to carbinolamine 405 affords 4-acetyloxy carbinolamine 406,which undergoes indolization process to 4,5-dihydroxyindole acetylated at 4-OH group 407. Under the reaction conditions, rearrangement of the acetyl group attached to the 5-OH yields the final by product 408. Schols et al. (2015CHC978) proposed an alternative mechanism that only differs from the one suggested by Kucklander in that the addition of the acetate ion takes place to the enamino quinone intermediate of type 26 not carbinolamine 405. OH

O

CO2Et

+

Me

16 h/RT

N

Ph

1

OAc

N

405

OH

OAc

HO

AcO

HO HO

406

N

Me

Ph 404; 10%

Ph

AcOH HO

N

Me

403; 23%

402

O

CO2Et

AcO

+

AcOH

NH

O

CO2Et

HO

N

N

407

408

Scheme 70 Synthesis of 4,5-dihydroxyindoles by the Nenitzescu reaction.

6.4 Other indolic structures as byproducts 4-Enamine 5-hydroxyindoles 409, 410 (1973T921; Fig. 9), 396 (1988RRC953; Scheme 68), and annelated 4-enamine indole 352 (2004SL1039; Scheme 59) have been isolated as byproducts in the Nenitzescu synthesis in yields up to 11%. Kucklander and coworkers (1971TL2093, 1972T5251, 1973T921) isolated from the reaction mixture formed by 1,4-benzoquinone with enamines the bisindoles 411–413 (1971TL2093, 1972T5251, 1973T921) and the pyrroloindoles 414 and 415 (1973T921). Synthesis of pyrrolo [2,3-f]indole 415 was accomplished by condensation of enamine ester 20 and the enamino quinone 53 (1980APH582). Other byproducts resulting from the reaction between 2,4,6-triaminopyridine 356 and two equivalents of 1,4-benzoquinone are pyridodiindole derivatives 357 and 358 (Scheme 60; 2008JHC1517).

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Bn

R NH2 E

NHMe E

Me E

HO

N

Me E

HO

HO HO

Me

N

N

Me

E

E

E

E

Me N

Me

HO

Me

410

E

Me

N Bn

R 409

Me

N

HO

Me

412

411: R = Me, Bn

Me E N

Me Me

Me

Me E

N

HO

Me E

HO

N

E

E

N

Me N

Me

Me

Me N

Me

Me 413

414

415

Fig. 9 Indole and bisindole structures obtained by the Nenitzescu reaction.

7. Nonindolic compounds of the Nenitzescu reaction 7.1 5-Hydroxybenzofurans and annelated derivatives The formation of 5-hydroxybenzofurans under Nenitzescu reaction conditions is quite similar in frequency to the formation of 5-hydroxyindoles. As a consequence, the condensation of 1,4-benzoquinones and enamines to yield 5-hydroxybenzofurans can be considered as a general method for their preparation (1990CHC503, 1990CHC739, 1990CHC1194, 1992CHC34, 1992CHC299, 1993MC146, 1993PCJ136, 1994PCJ893, 1995MC68, 1995MC69, 1995PCJ636, 1995PCJ640, 1997CHC1245, 1997PCJ612, 1997T177, 1998CHC651, 1999RCB160, 2000CHC410, 2003CHC707, 2003CHC1013, 2003SC2285, 2005BMC819, 2005PCJ636, 2005RCB1690, 2005T9129, 2006JHC873, 2007JCC906, 2011BMC2666, 2011EJOC1947, 2011EJOC4635, 2011JHC355, 2011OBC1317, 2017ADV14562, 2017RJOC525, 2017T7282, 2017TL3979, 2018BMC4330). Annelated 5-hydroxybenzofurans are also formed under Nenitzescu reaction conditions if a cyclic enamine or a condensed 1,4-benzoquinone are used (1993MC40, 1994PCJ119, 1994PCJ893, 1997PCJ612, 1997T177, 2000CHC1276, 2002CHC586, 2002MC15, 2002RCB1886, 2003CHC61, 2003CHC872, 2003CHC1013, 2003SC2285, 2004CHC16, 2005BMC819, 2005 CHC221, 2011EJOC4635).

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The generation of either 5-hydroxyindoles or 5-hydroxybenzofurans or mixtures of both comes from the common intermediates that are enamine hydroquinones, the so-called Michael adducts 40 (Schemes 7 and 32). These Michael adducts have been isolated in many cases and converted either to 5-hydroxyindoles or to 5-hydroxybenzofurans (Schemes 7 and 32). When Michael adducts undergo oxidation, the indolization process takes place. In the absence of oxidizing agent cyclization of the Michael adducts of type 201 results in a dihydro benzofuran, such as 203, which by dehydrogenation or elimination of a leaving groups (e.g., NMe2) leads to the corresponding 5-hydroxybenzofuran (1971PCJ27, 1997T177, 2002MC15, 2002RCB1886; Schemes 12, 32, and 71). In a few cases 1,2-dihydrobenzofurans (Scheme 71) have been isolated and their stereochemistry assigned based on NMR data and X-ray diffraction (1966 JPC144, 1971PCJ27, 1994JMS203, 1997JCSPT(2)1811). The 1,2dihydrobenzofuran derivatives were converted into the corresponding 5-hydroxybenzofurans on heating with dilute HCl (1966JPC144, 1971PCJ27). The reaction of phenylsulfonyl-1,4-benzoquinone 416 with ethyl β-aminocrotonate esters is regioselective giving 2,3dihydrobenzofurans 417 having a phenylsulfonyl group at the 4-position of the benzofuran ring. On heating compounds 417b (R ¼ Me) in the presence of HCl elimination of the alkylamino group takes place to form 5-hydroxybenzofuran 418 (Scheme 71). Under similar reaction conditions the dihydroderivatives 417a,c,d undergo hydrolysis, and decarboxylation of the ester group. The condensation in chloroform of 2,3dimethoxy-1,4-benzoquinone with ethyl α-methyl-β-aminocrotonate results in the formation of two stereoisomers of 2,3-dihydrobenzofurans cis-419 and trans-419 (Scheme 71; 1971T5031).

O

SO2Ph CO2Et

SO2Ph

+ Me

NHR

Cl(CH2)2Cl

HO

SO2Ph H

Me

or AcOH

O

35%–66%

O 416

CO2Et

HCl

CO2Et

HO

R = Me

Me

O

NHR

R = H, Me, Et, Ph 417a–d

418

O Me

OMe

CO2Et

+ OMe O 112

CHCl3

HO

Me

CO2Et Me

Me

NH2

MeO

O OMe cis-419

Me

HO

O

MeO NH2

CO2Et

+ OMe trans-419

Scheme 71 Synthesis of benzofurans through the Nenitzescu reaction.

NH2 Me

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8. Unexpected products of the Nenitzescu reaction The complexity of the reaction between 1,4-benzoquinones and enamines is revealed by formation as major products of a series of unexpected structures. Among these unanticipated structures are spirobenzofurans (Schemes 13 and 55), (1993MC40, 1997PCJ612, 1995PCJ636, 2002MC15, 2002RCB1886, 2005BMC819), 2-azaspiro [4,5]decatrienes 74, 75 (2011BMC2666; Fig. 4), spiropyrroles 373b–e (Scheme 63; 1994APH143, 2000JPC17, 2011BMC2666), 5-oxo-1,5dihydro-benzo[g]indole (2005T9129), naphtho[2,3-d]indol-1-carboxylate derivatives 101 (Scheme 16; 2006BMC3599), methano-cyclopent[c] azocin-6,9-diones 370a–c (Scheme 63, 1994APH143), pyrrole–azepine hybrid 395 (Scheme 68; 1971T5031, 2020RCXXX), and 6-hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones (2011T8747).

9. Applications The discovery of natural 5-hydroxyindole derivatives with significant physiological action, such as serotonin 6, melatonin 7, 5-hydroxytryptophan 8 (Fig. 1), has been followed by an increasing interest in the Nenitzescu indole synthesis. The main advantages of the Nenitzescu synthesis in obtaining of 5-hydroxyindoles are due to the commercially available or easily accessible starting materials and mild reaction conditions. During this time new naturally occurring 5-hydroxyindoles have been isolated (Fig. 1) and have been found to present various biological activities (2015MD4814). Moreover, the 5-hydroxyindoles formed by Nenitzescu synthesis have been converted by chemical transformation into new compounds that were evaluated as potentially biologically active molecules. An interesting feature of the Nenitzescu reaction is also the facile access to 5-hydroxybenzofurans and condensed 5-hydroxybenzofurans as final reaction products, which have also been shown to present interesting biological activities (1994PCJ893, 2005PCJ636, 2018BMC4330). The antimicrobial activity of 5-hydroxyindoles and condensed 5hydroxyindoles and their derivatives has been tested against a number of Gram-negative and Gram-positive bacteria and were found to show weak, moderate, or high activity. (1993PIAS189, 1994PCJ103, 1999IJC(B)156,

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1999IJC(B)690, 1999IJC(B)1070, 1999IJC(B)1226, 1999IJHC131, 2001RRC99, 2003IJC(B)2023, 2005IJC(B)1470, 2005IJC(B)1663, 2005IJC(B)1679, 2005IJC(B)2594, 2007IJC(B)690, 2011APP49, 2017DPS1, 2019IJPBS517). A series of indole derivatives obtained by functionalization of the 5-hydroxyindoles core structures were evaluated for their antifungal potential (1999IJC(B)156, 1999IJC(B)690, 1999IJC(B) 1226, 1999IJHC131, 2003IJC(B)3108, 2007IJC(B)690, 2010PCJ296). Several 5-hydroxyindoles and 5-hydroxybenzofurans substituted with imidazole rings obtained via Nenitzescu reaction revealed weak antimicrobial and anesthetic activity (1994PCJ103). Compounds with a 5-hydroxyindole skeleton formed from benzoquinones and enamines are potent inhibitors of enzymes such as 5-lipoxygenase, phospholipase A2 (PLA2s) and other enzymes that are implied in an inflammatory response of a wide range of diseases (1996JO9055, 2006JMC4327, 2009JMC3474, 2011BMCL456, 2011 CBDD314, 2014EJMC492, 2014PLOe87708, 2016EJMC466, 2018 EJMC946). The first selective PLA2s inhibitor, known as LY311727 (Scheme 72), was obtained starting from 5-hydroxyindole 420, which in turn was prepared by Nenitzescu reaction (1996JO9055). Benzo[g]indoles derivatives present a selective inhibition of pro-inflammatory prostaglandin (PG)E2 that diminish inflammatory reactions in the carrageenan induced mouse paw edema and rat pleurisy tests (2009BMC7924). It is noteworthy that 5-hydroxyindole-isoxazole hybrids exhibit both antiinflammatory and analgesic activity comparable with that of commercial drugs (2017 CSE5110). Antiinflammatory activity was also observed for other 5-hydroxyindole derivatives [1973JMC757, 2003IJC(B)2023]. A series of analogues of antiinflammatory drug indomethacin were synthesized and investigated for their biological activity (2001BMC745). Compounds including a 5-hydroxyindole moiety have been found to possess antitumor activity when tested on various cancer cell lines (1994APH137, 1995JCSP(1)2667, 1998JMC2720, 1998JMC4755, 2001 JMC3311, 2005BMC819, 2005T9129, 2006BMC3599, 2006BMC7282, 2007APH424, 2008JHC1517, 2015CRCU372, 2017CRCU365, 2018JEI1, 2019CCL2157). Apaziquone known also as EO9 (Scheme 72) is an indolequinone derivative which was obtained on large scale using the Nenitzescu reaction and evaluated in phase III clinical trials for the treatment of nonmuscle invasive bladder cancer (1995JCSP(1)2667, 1999JSO401, 2017EOD783). Apaziquone is structurally related to the

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CO2Me

HO

P

O

CH2CONH2

O OH

OH N

N

Me

CH2CH3

CH2Ph

CH2Ph 420

LY311727 O CO2Et

HO

CH2OH

N N

Me

N H

O

3

CH2OH

Me EO-9

HO N

CH2NMe2

CO2Et

HO

Me

Br

R 3, 55 (R = H, Me)

CO2Et N

CH2SPh

Me 11 (Arbidol)

Scheme 72 Indoles with significant biological activity obtained via Nenitzescu reaction.

well-known chemotherapeutic agent mitomycin C and as a consequence a library of structural analogues to EO9 indolequinone were synthesized and evaluated for their anticancer activity (1998JMC2720, 2001JCSP(2)843). 5-Hydroxyindoles and their derivatives display antiviral activity against several viruses such as influenza (1993PCJ81, 2004CCL1039, 2004 CJMC219, 2017BMCL3744), hepatitis B (2006BMC911, 2006 BMC2552, 2006CRCU577, 2010CRCU272), HIV (2007OPRD241, 2015CHC978), and chikungunya (2017BMC327) viruses. (1991PCJ391, 1993PCJ75, 2011JMM1831, 2014CHC489, 2014PCJ571). Arbidol 11 is a synthetic 5-hydroxyindole antiviral drug (umifenovir) that inhibits viral DNA and RNA synthesis and has been used in the treatment of influenza virus in Russia, China and to a lesser extent in western countries (1993PCJ75, 1993PCJ81, 2014AVR84, 2014PCJ636, 2015PCJ151, 2017BMCL3744, 2018RCR509). The production process for arbidol was developed in Russia starting from indoles 3 and 55 (Scheme 72) that were obtained via Nenitzescu reaction of 1,4benzoquinone with corresponding β-enaminoesters. A more complicated reaction pathway to arbidol published in 2011 (2011CN102351778A)

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stands as a proof of the versatility and simplicity of the Nenitzescu reaction for such purposes. It has been found that arbidol presents a broad-spectrum antiviral activity and is important in the treatment and prevention of influenza virus and other acute respiratory viral infections (2008CMC997, 2018VIR184, 2019JVe02185). Also, arbidol proved to possess immunestimulating and antiinflammatory properties. As a consequence new structural analogues based on arbidol or other 5-hydroxyindole derivatives have been synthesized and evaluated for their antiviral activities (1991PCJ391, 1991PCJ238, 1992PCJ676, 2004CCL19, 2014CHC489, 2015CHC978, 2017BMCL3744, 2019BP109359). Pyrazino[1,2-a]indoles obtained from 5-hydroxyindole have been synthesized and their antidepressant properties evaluated and compared to those of the drug pyrazidol (1992PCJ750). Some indoles resulting from Nenitzescu synthesis have been used as key intermediates for obtaining benzoxazine isoquinolines which were investigated for their potential as selective M4 muscarinic receptor antagonists (1998BMCL1991, 2002JMC3094). Additional applications of the Nenitzescu reaction in medicinal chemistry include synthesis of delta-opioid receptor antagonists (2005JMC635), of bexarotene prodrugs (2014BMCL1944), and of 2-oxo[1,4]oxazino[3,2-e] indoles as heteroanalogues of angelicin—a photoactivable DNA intercalator (2009TL4182). The most applications of Nenitzescu reaction are devoted to the synthesis and biological activities of 5-hydroxyindoles. However, several uses of the Nenitzescu reaction in the field of materials science have also been recently reported (2010RCB1639, 2011EJOC1947, 2011EJOC4635, 2014RCB109, 2018AJOC2094, 2019NJC10166).

Acknowledgments This work was supported in part by a grant from NIH (R03EB026189) to M.A.I., which is gratefully acknowledged.

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CHAPTER THREE

One-pot reactions of three-membered rings giving N,O,S-heterocycles Vitalii A. Palchykova,b,∗, Oleksandr Zhurakovskyic a

Research Institute of Chemistry and Geology, Oles Honchar Dnipro National University, Dnipro, Ukraine Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, United States c Pharmaron UK, Hoddesdon, Herts, United Kingdom ∗ Corresponding author: e-mail addresses: [email protected]; [email protected] b

Contents 1. Introduction 2. Synthesis of five-membered rings 2.1 Tetrahydrofurans, γ-lactones and dioxolanes 2.2 Furans and benzofurans 2.3 Pyrrolidines and their carbonyl-containing analogs (pyrrolidinones) 2.4 Pyrroles and indoles 2.5 1,3-Oxazolidines 2.6 1,3-Oxazolines and oxazoles 2.7 1,3-Oxazolidin-2-ones and 1,3-oxazolidin-4-ones 2.8 1,3-Thiazolidines, 1,3-thiazolines, 1,3-thiazolidin-2-ones, 2-imino-1,3-thiazolidines, 1,3-oxathiolanes, and 1,3-oxathiolane-2-thiones and related Compounds 2.9 Imidazoles (benzimidazoles) and related heterocycles 2.10 1,2,3-Triazoles 3. Synthesis of six-membered rings 3.1 Pyrans, partially hydrogenated pyrans and δ-lactones 3.2 Piperidines, pyridines, and their partially hydrogenated analogs 3.3 1,4-Dioxanes, 1,4-oxathian-2-ones, 1,4-oxathian-3-imines, thiomorpholines, piperazines, and tetrahydropyrimidines 3.4 Morpholines, their aryl-fused- and carbonyl-containing analogs (morpholones) 4. Synthesis of seven-membered and larger rings 4.1 Oxepanes 4.2 2,5-Dihydrooxepines 4.3 Azepanes and related heterocycles 4.4 Oxazepanes and their sulfur-containing analogs 4.5 Other large rings 5. Concluding remarks Acknowledgments References Advances in Heterocyclic Chemistry ISSN 0065-2725 https://doi.org/10.1016/bs.aihch.2020.04.001

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2020 Elsevier Inc. All rights reserved.

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Vitalii A. Palchykov and Oleksandr Zhurakovskyi

Abstract Three-membered heterocycles, such as epoxides and aziridines, are “spring-loaded” for ring opening and thus undergo facile conversion into open-chain and cyclic derivatives. This review covers syntheses of various N,O,S-containing heterocyclic products from three-membered precursors, published between 2014 and 2019. The literature is arranged according to the ring size, heteroatom type, and the number of heteroatoms in the ring.

Keywords: Epoxides, Aziridines, Furans, Oxazolines, Pyrroles, Imidazoles, Pyrans, Oxazolidines, Oxazoles, Pyrrolidines, Tetrahydrofuranes, Morpholines, Piperidines, Pyridines

1. Introduction Three-membered heterocycles, such as epoxides, aziridines and oxaziridines, combine high reactivity with widespread availability and reasonable benchtop stability. Because of this, they serve as convenient

One-pot reactions of three-membered rings

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entry points to open-chain and cyclic derivatives. A great body of work, and a number of reviews, has been published in this area. Among these, a comprehensive monograph by Yudin (2006AEOS495) stands out, which became a desktop reference for many practitioners in the field. It was published in 2006 and has since been superseded by later works, such as a special issue of Chemical Reviews, “Small heterocycles in synthesis” (2014CRV7783). The present review covers the most important recent developments (2014–2019) in the field of one-pot transformations of three-membered heterocycles—epoxides, aziridines, and oxaziridines—into larger congeners. This is a focused update of the authors’ earlier account (2018AOS147). Further recent reviews include Singh’s work on aziridines (2018ARK50, 2019AHC245) and Corr^ea’s review on multicomponent heterocyclizations of epoxides and aziridines (2019MOL630). There is unavoidable overlap between these works; however, the authors felt it was necessary for providing the context of the state-of-the-art research. The authors chose to focus on the most novel, useful, or otherwise interesting papers, citing relevant topical reviews where appropriate. Also, we will not discuss the well-known CO2/CS2 addition to epoxides and aziridines which gives cyclic carbonates and 1,3-oxazolidin-2-ones (2012EJO6479, 2012CCL107, 2019ASC265, 2012PAC581, 2013RSCA 11385, 2013JCO2U49, 2015COC681, 2016CR1337, 2017COC698, 2017GC3707, 2019CL985).

2. Synthesis of five-membered rings Epoxides and aziridines are inherently strained small heterocycles and this allows for facile ring expansion (2013JOC9533, 2013ACSC272, 2018MOLD447). The (3 + 2)-cycloaddition of aziridines was reviewed in 2012 (2012EJO6479) and 2016 (2016ACSC6651).

2.1 Tetrahydrofurans, γ-lactones and dioxolanes Tetrahydrofurans (THFs) are frequently found in natural products and pharmaceuticals, and as such their syntheses have been reviewed on several occasions (2007T261, 2016T5003). Five-membered oxygen heterocycles can be prepared by the acid- or, more rarely, base-promoted ring opening of epoxides (2013JOC9533, 2013ACSC272, 2019EJO1092). Typically, an epoxide is activated by a Lewis or Brønsted acid and undergoes an attack by a pendant oxygen

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nucleophile. If the attacking group is itself an epoxide, a cascade synthesis of poly-THF compounds 1 becomes possible (Scheme 1) (2009AGE5250). The control of endo- vs exo-ring opening is of great importance in these reactions, and often influenced by traces of water.

Scheme 1 All-exo polyepoxide ring opening.

An example of such epoxide opening is the 2018 synthesis of cis-solamin by Miyaoka, who cyclized bisepoxide 2 into bis-THF 3 under acid catalysis in the presence of water (Scheme 2) (2018OBC3018). An attempted cyclization of epoxide 4 by Goswami, in their synthesis of cytospolide Q, led to a mixture of products, highlighting the importance of preorganization of the substrate (2018ACSO7350). In an interesting base-promoted cyclization, bisepoxide 5 was treated with KOH in water and converted into the THF 6 along with some unidentified isomer (2015CC15696). The reaction is thought to proceed by the Payne rearrangement mechanism.

Scheme 2 Epoxide ring opening in the synthesis of natural products.

Solvent choice can have a large effect on the reaction outcome even under otherwise identical conditions. ScIII-promoted cyclization of spiroepoxides 7 proceeded in a stereodivergent fashion depending on the choice of solvent—THF vs dichloromethane (DCM) (Scheme 3) (2014OL2474).

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Scheme 3 Stereodivergent cyclization of spiroepoxides 7.

The reaction of epoxide 8 with the Baylis–Hillman adduct 9 furnished spirolactone 10 through a radical cyclization followed by an in situ lactonization. This reaction proceeds through a tandem radical cyclization, in which Cp2TiCl acts as the radical initiator, to give the product 10 in a satisfactory yield (Scheme 4) (2014EJO2980). Very recently, a Cp2TiClpromoted radical cyclization was proposed as a strategy for the syntheses of iridoid monoterpenes and spirooxindole based tetrahydrofuran/lactone derivatives 11, 12 (2018JOC6086, 2018S3006, 2019JOC16124).

Scheme 4 Synthesis of spirocompounds 10–12.

D’hooghe reported the synthesis of β-lactam-fused tetrahydrofurans 13 (Scheme 5) by an intramolecular ring opening of the epoxides 14 under basic conditions (2016OBC11279).

Scheme 5 Intramolecular epoxide ring opening to form tetrahydrofurans 13.

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Intermolecular couplings are also widely used (Scheme 6). Both alkynyl (2016TL415) and vinyl lithium (2016T6025) species can be used as nucleophiles, leading to butyrolactones 15 or hemiacetals 16, respectively. A mixture of rac/meso-17 was resolved using a Co-salen catalyst, delivering R,R-18 in good yield and with excellent enantioselectivity (2014TL3569).

Scheme 6 Synthesis of THF derivatives 16, 18, and γ-lactones 15 by the ring opening of epoxides.

Hydrolysis of the epoxy alcohol 19 with hot water delivered triol 20 which upon treatment with tetra-n-butylammonium fluoride (TBAF) underwent unexpected 5-exo-trig cyclization to the tetrahydrofuran 21 (Scheme 7, path b) instead of the desired tetrahydropyran 22 (2017TL1037).

Scheme 7 Two-step one-pot synthesis of the tetrahydrofuran 21 from epoxy alcohol 19.

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A (3 + 2)-cycloaddition of epoxides with alkenes allows the preparation of polysubstituted THF rings 23–27 with varying degrees of selectivity (Scheme 8). These reactions have been catalyzed by Pd (2018CC13143), Sc (2016EJO3335), and Cu (2018JST276). Enantioselective Ni-catalyzed variants are known (2014CC11480, 2016JOC1237).

Scheme 8 Synthesis of THF derivatives by the cycloaddition of epoxides.

Interestingly, the cycloaddition between an epoxide and a cyclopropane ring (both being three-atom units) also leads to five-membered products, e.g., 28 (Scheme 9) (2017EJO1647). These reactions are catalyzed by indium and proceed with a hydride shift from Ca to Cb (2015EJO2517). Moderate enantioenrichment (e.r. 66:34) was observed with C2-symmetric bisoxazoline ligands.

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Scheme 9 Synthesis of tetrahydrofurans 28 by the cycloaddition between cyclopropanes and epoxides.

Conjugated allenes undergo cycloaddition onto epoxides at the internal double bond. Pd-catalyzed cycloaddition of 29 gave chiral THF 30 with high yields and selectivity (Scheme 10). The use of chiral N-heterocyclic carbene (NHC) ligand 31 was key to obtaining good enantiomeric excess (ee) (2018OL4773).

Scheme 10 Synthesis of furans 30.

2-Amino dihydrofurans 32 have been obtained by the reaction of alkynyl epoxides 33 with activated nitriles under copper catalysis (Scheme 11). The process can be seen as a formal cycloaddition between epoxides 33 and the tautomeric ketenimines (2019OCF245).

Scheme 11 Synthesis of dihydrofurans 32.

Synthesis of γ-lactones from aziridines is less precedented. In one example, microwave-assisted hydrolysis of nitriles 34 under basic conditions gave lactones 35 (Scheme 12). The reaction is thought to proceed via an intermediate carboxylate which attacks the aziridine (2015OBC2716).

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Scheme 12 Synthesis of lactones 35.

In 2014, the first catalytic approach to the nucleophilic addition of silyl ketene acetals 36 to epoxides 37 was reported (Scheme 13) (2014OL5721). The protocol is metal-free and catalyzed by TBAF or 1,3-dimethylimidazolium fluoride (2017MOL1385).The reaction proceeds under ionic-liquid- or even solvent-free-conditions allowing γ-lactones 38 to be obtained directly with high regioselectivities and yields.

Scheme 13 Synthesis of lactones 38.

A simple combination of an ester, acyl pyrrole, or α-epoxy 2-nitrophenyl hydrazone, with a base (potassium (KHMDS) or lithium bis(trimethylsilyl) amide (LiHMDS)) leads to the highly diastereoselective synthesis of β,γ-fused bicyclic γ-lactones 39 (dr up to >25:1), including those with quaternary centers. Conveniently, both syn- and antifused bicyclic systems can be generated stereoselectively by simply changing the base counterion (Scheme 14) (2018C2228).

Scheme 14 Synthesis of lactones 39.

Cyclopropane-fused γ-lactone 40 was prepared as the key intermediate in a protecting group-free total synthesis of sesquiterpenoid phellilane L (Scheme 15) (2017JOC12377). Another lactone 41 was used in the synthesis of photo-mycolactones (2015TL3220).

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Scheme 15 Synthesis of lactones 40, 41.

The first example of a manganese-catalyzed C–H transformation using an oxygen-directing group is described in a borane-mediated synthesis of isobenzofuranones 42 from esters and oxiranes (Scheme 16) (2016OL304).

Scheme 16 Synthesis of isobenzofuranones 42.

A convenient and efficient method for the copper-catalyzed Ullmann synthesis of (Z)-aurones 43 by an intramolecular tandem reaction of (2-halogenphenyl)(3-phenyloxiran-2-yl)methanones was reported by Su (Scheme 17) (2014JOC4218).

Scheme 17 Synthesis of aurones 43.

Five-membered cyclic peroxides 44 were prepared in one step from readily accessible β,γ-epoxy ketones and H2O2 (Scheme 18). The reaction proceeded via a tetrahydrofuran intermediate, which converted into the thermodynamically favored 1,2-dioxolane 44. The product contains a leaving group, which can be displaced to synthesize analogs of the plakinic acid (2014OL2650).

Scheme 18 Synthesis of dioxolanes 44.

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FeOx-pillared bentonite is a highly effective catalyst for the conversion of epoxides to acetonides, as described by Chavasiri (2014CCAOAC104). The reaction furnishes 2,2-dimethyl-4-phenyl-1,3-dioxolanes 45 in excellent yields under mild conditions (Scheme 19).

Scheme 19 Synthesis of dioxolanes 45.

A cationic indium catalyst has been developed for the conversion of epoxides and lactones into spiroorthoesters, a family of expanding monomers (Scheme 20). The reaction of ε-caprolactone with 1,2-epoxy-7octene resulted in the formation orthoesters 46a,b with full conversion of both components (2018CCC3219).

Scheme 20 Synthesis of trioxaspiro[4.6]undecanes 46a,b.

The use of gold catalysis allows the convertion of activated alkynes 47 into acetals 48 upon reaction with disubstituted epoxides (Scheme 21) (2015T2280).

Scheme 21 Synthesis of dioxolanes 48.

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2.2 Furans and benzofurans The literature on the synthesis and further conversion of furans is rich and vast. The topic is therefore frequently overviewed. The reader is directed to two excellent reviews, from Wu and Gevorgyan. Numerous reports on furan synthesis and reactivity are present in the literature and subjected to periodic reviews. The book by Wu, “Transition Metal Catalyzed Furans Synthesis,”, has a chapter that covers, inter alia, the conversion of epoxides into furans by metal-catalyzed cyclizations (2016TMCFS39). Gevorgyan wrote a comprehensive review on the synthesis of monocyclic aromatic heterocycles, with 40 pages dedicated to furans (2013CRV3084). Perhaps, the most common way to convert an epoxide into a furan is to treat epoxy alkynes 49 with a Lewis or Brønsted acid (Scheme 22). The use of Pd(OAc)2, Pd(dba)2, AuCl3, AgOTf, or LAuOTf (2013CEJ12512, 2015AGE15506, 2018ACSC8290) have been reported. The reaction is generally robust and scalable (2015AGE15506). Furans with up to three substituents are typically prepared by this method. The remaining carbon atom in the furan is bound to the transition metal in the reaction intermediate and undergoes protonation during workup.

Scheme 22 The common way of converting epoxides 49 into furans.

In an interesting application of this reaction, B(MIDA)-containing epoxide 50 can be selectively converted into 2- or 3-borylated furans in an Au-promoted cyclization (Scheme 23). The location of the boron substituent in the product is dictated by the choice of the catalyst ligand—IPrAuSbF6 or (2,4-di-t-BuPh)AuOTf (2014JA13146). In 2018, Zhang and Zhu performed a detailed computational study of this process. They showed that the counterion and the ligand of the gold catalyst play a less important role during the ring expansion, but they are crucial for the subsequent hydride shifts: TfO
counterion with (ArO)3P favors the 1,2-H migration, leading to the formation of a 3-borylated furan, whereas SbF
6 with the IPr ligand promotes the 1,2-boron migration, supporting the predominant formation of 2-borylated furan (2018ACSC9252).

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Scheme 23 Divergent synthesis of B(MIDA)-substituted furans.

Ha et al. developed a new synthetic method for highly substituted furans 51 from 2-(aziridin-2-ylmethylene)malonate using aziridine ring opening by the internal carbonyl oxygen with the assistance of BF3OEt2 followed by aromatization (Scheme 24) (2017ACSO7525).

Scheme 24 Synthesis of furans 51.

The required furan 52 can be prepared in situ by the oxidation of the appropriate alkene with m-CPBA, as shown by George and coworkers (Scheme 25) (2015OL4228).

Scheme 25 Synthesis of annulated furan 52 from in situ generated epoxide.

A one-pot three-component reaction of aromatic amines, 4-hydroxycoumarin and α,β-epoxy ketones under solvent-free conditions in the presence of ZnO-ZnAl2O4 nanocomposite furnished furo[3,2-c] chromen-4-ones 53 (Scheme 26) (2018HEC19).

Scheme 26 Synthesis of furochromenones 53.

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Irradiation of the benzoyl oxiranes 54 resulted in a facile and efficient synthesis of the benzofurooxepine derivatives 55 (Scheme 27) (2014JPPC31).

Scheme 27 Synthesis of benzofurooxepines 55.

A direct Catellani reaction between aryl iodides and epoxides under palladium/norbornene (Pd/NBE) cooperative catalysis afforded 2,3dihydrobenzofuran derivatives 56 in 44%–99% yields (Scheme 28) (2018OCF3108).

Scheme 28 Synthesis of dihydrobenzofurans 56.

A route to 3-amino-2,3-dihydrobenzofurans 57 that utilizes microwaveassisted organic synthesis to rapidly generate flavonoid analogues has been developed by Aldrich and coworkers (Scheme 29) (2018CEJ4509).

Scheme 29 Synthesis of dihydrobenzofurans 57.

2.3 Pyrrolidines and their carbonyl-containing analogs (pyrrolidinones) Synthesis of pyrrolidines from epoxides or aziridines has been reviewed on several occasions, covering both the basic methods (2011RJOC1609) and various recent alternatives (2007CRV2080, 2012EJO6479, 2013M9650, 2013JOC9533, 2014CRV7784, 2015THC49, 2016ACSC6651). Perhaps, the most straightforward way to convert an epoxide into a pyrrolidine is to subject it to an intramolecular attack by a nitrogen nucleophile. Some specific examples of this process (synthesis of pyrrolidines 58, 59) are shown on Scheme 30 (2014RSCA2482, 2014OBC7389).

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Scheme 30 Formation of pyrrolidines 58, 59 from protected epoxyamines.

Enyne-containing epoxides 60 can be converted into a range of pyrrolidines, e.g., 61–63, under effectively identical conditions using [Rh(NBD)2]+ BF4
catalysis. The specific product in this study was determined by fine-tuning the substitution pattern and electronic factors in precursor 60 (Scheme 31) (2017ACSC1533).

Scheme 31 Synthesis of pyrrolidines 61–63.

Feng and Zhang further extended this chemistry to a highly enantioselective and diastereoselective [3 + 2] cycloaddition of vinyl aziridines with silyl enol ethers, providing an efficient approach to functionalized pyrrolidines 64 (Scheme 32) (2018CC2401).

Scheme 32 Synthesis of pyrrolidines 64.

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Difluorinated pyrrolidines 65 have been obtained by a straightforward double substitution of bromo epoxides 66 with alkyl amines. Both reactions occur in the same pot providing the products in moderate to excellent yields (Scheme 33) (2017JOC3270).

Scheme 33 Synthesis of difluoropyrrolidines 65.

Hydroxy aziridines can be easily converted into ring-expanded products 67a,b by the action of dimethylsulfonium methylide, obtained in situ from NaH and (Me3SO)+ I
(Scheme 34) (2014OBC7389).

Scheme 34 Pyrrolidines 67a,b from aza-Payne rearrangement aziridinols.

The alkylation of a 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with ω,ω0 -dihaloalkanes leads to 2-CF3-pyrrolidines 68, 2-CF3-piperidines 69, and 3-CF3-azepanes 70 (Scheme 35). A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles reacted in this ring rearrangement (2014CEJ10650).

Scheme 35 Synthesis of CF3-heterocycles 68–70.

A Lewis acid-catalyzed (3 + 1 + 1) cycloaddition between aliphatic isocyanides and azomethine ylides, generated in situ from the aziridines 71, led to pyrrolidine derivatives 72 (2014T6623). This reaction can also be modified to employ aromatic isocyanides, thus generating azetidines 73 (Scheme 36).

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Scheme 36 Synthesis of pyrrolidines 72 and azetidines 73.

Synthesis of alkaloid-like 3-(aminomethyl)pyrrolizidines 74 by an intramolecular In(OTf )3-mediated ring rearrangement of aziridines 75 has been developed by D’hooghe (Scheme 37) (2017S2215).

Scheme 37 Synthesis of pyrrolizidines 74.

Compound 76 was as an intermediate en route to (+)-lentiginosine: acidcatalyzed ring opening followed by a one-pot cyclization gave pyrrolidinone 77 (Scheme 38) (2014TA497).

Scheme 38 One-pot conversion of aziridine 76 into pyrrolidinone 77.

Biocatalysis has also found use in the transformation of aziridines. Treatment of nitriles 78a,b with nitrilase gave pyrrolidinones 79a,b, 80a,b with good selectivities and complete conversion (Scheme 39) (2015OBC2716).

Scheme 39 Biocatalytic conversion of aziridines 78a,b into pyrrolidinones 79a,b and lactones 80a,b.

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A dramatic tandem annulation controlled by the N-substituent was observed in reactions of sulfonylaziridines with 1,3-dicarbonyl compounds (Scheme 40) (2018OL5680). N-Tosyl aziridines underwent a sequence of ring opening, nucleophilic substitution, and lactamization to provide hexahydrobenz[e]isoindoles 81 in good yields with good diastereoselectivity. By contrast, 3-benzazepine compounds 82 were formed in good yields when the N-substituent was a 4-nitrobenzenesulfonyl group (Ns).

Scheme 40 Synthesis of compounds 81, 82.

A convenient method was reported for the synthesis of tricyclic and tetracyclic cage-like lactams 83–88 by treatment of the strained systems 89 with Grignard reagents, their N-analogs, or phenyl lithium (Scheme 41) (2018JHC2381).

Scheme 41 Synthesis of lactams 83–88.

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(3 + 2)-Cycloaddition between an aziridine and an alkene or an alkyne is a powerful way to prepare pyrrolidines. It offers the possibility of installing multiple substituents in the resulting heterocycle, with varying degrees of regio- and stereoselectivity (2012EJO6479, 2015THC49, 2016ACSC6651). Depending on the reaction conditions and the substrate structure, the aziridine can open either at the CdC or CdN bond. The reactions are typically catalyzed by classical Lewis or Brønsted acids, as well as transition metals: Pd(PPh3)4 (2017CEJ268), Pd2(dba)3 (2015AGE1604, 2015JOC1414, 2016CEJ6243, 2016OL3370, 2016CSI2302, 2017JA12141). Scheme 42 highlights some recent examples of the synthesis of pyrrolidines 90–92 (2017CEJ268, 2017JA12141, 2018ACSC10261).

Scheme 42 Synthesis of pyrrolidines 90–92 by the (3 + 2)-cycloaddition of aziridines with alkenes.

Radical-mediated reactions offer a complementary approach. A thiylcatalyzed (3 + 2)-cycloaddition of N-tosyl vinylaziridines 93 with alkenes gave vinyl pyrrolidines (Scheme 43) (2016AGE8081).

Scheme 43 Synthesis of pyrrolidines by thiyl-radical-catalyzed cyclization reaction.

The power of this approach is demonstrated in a recent enantioselective synthesis of cyclopiazonic acids by Aggarwal, in which aziridine 94 underwent a stereospecific intramolecular (3 + 2)-cycloaddition onto a

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pendant alkene to give all-substituted pyrollidine 95 (2018AGE1346). The reaction of trans-94 was exceedingly faster than that of cis-94; 10 min at
55°C (trans-94) vs 14 h at 23°C (cis-94) (Scheme 44). Only the products of NdCa bond cleavage were observed.

Scheme 44 Aggarwal synthesis of pyrrolidines by an intramolecular aziridine-alkene cycloaddition.

Scheme 45 shows more examples of intramolecular aziridine 96–98 cycloadditions (2014OBC7482, 2016ASC3093, 2017CEJ17862).

Scheme 45 Intramolecular reactions of aziridines 96–98.

The use of the donor–acceptor aziridines 99–101 lowers the reaction barrier and such compounds have often been used in cycloadditions (Scheme 46). The reactions are catalyzed by Lewis acids. Alkynes (2016OL4614), enol ethers (2017ACSC3934), and ketene imines (2018OCF2020) have been reported as the reaction partners.

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Scheme 46 Synthesis of pyrrolidines from 2,20 -diester aziridines 99–101.

Oxaziridines having α-proton-bearing substituents on the nitrogen atom can be converted into the pyrrolidine derivatives 102 through a MgI2-mediated (3 + 2)-cycloaddition (Scheme 47) (2016OL4940). Banerjee and coworkers disclosed a clever annulation reaction of N-tosyl aziridinedicarboxylate and various donor–acceptor cyclopropanes in the presence of MgI2, which provided access to 2H-furo[2,3-c]pyrroles 103 in moderate yields (2015JOC7235).

Scheme 47 Pyrrolidines 102, 103 by the (3 + 2)-cycloaddition of oxaziridines/aziridines to cyclopropanes.

Aziridine-alkyne cycloadditions leading to dihydropyrroles 104–107 and catalyzed by transition metals are summarized in Scheme 48 (2016JA2178, 2017CJOC1165).

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Scheme 48 Synthesis of dihydropyrroles 104–107 from N-Ts/Ns/Ms-aziridines.

The use of allenes as the coupling partners allows access to the vinyl substituted pyrrolidines 108–109 under Rh catalysis (Scheme 49) (2016AGE10844).

Scheme 49 Synthesis of vinylpyrrolidines 108, 109.

2.4 Pyrroles and indoles Pyrroles are an important class of heterocycles frequently present in natural products. Being nitrogen-containing heterocycles, pyrroles can be obtained

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by the ring expansion of aziridines (2007CRV2080, 2010T7337, 2013CRV3084, 2014CRV7784, 2015THC49, 2016ACSC6651); however, epoxides 110, 111 have also been used for this purpose (Scheme 50) (2014CEJ1818, 2018JOC14733).

Scheme 50 Synthesis of indoles using epoxides 110 and 111.

Transition-metal-catalyzed cycloisomerization of propargylic aziridines has been a popular method for the synthesis of substituted pyrroles for the past 10 years (2011CRV1657, 2015CRV9028). Acyl aziridines have been shown to react with activated allenes to give the pyrroles 112, 113. The reaction takes place in supercritical carbon dioxide (scCO2) or toluene (under microwave conditions) (Scheme 51) (2016JOC9028).

Scheme 51 Synthesis of pyrroles 112 and 113 in supercritical сarbondioxide and toluene.

Cu-catalyzed (3 + 2)-cycloaddition of acyl aziridines 114 gives acylsubstituted pyrroles 115 (Scheme 52). The reaction is thought to proceed via an intermediate azomethine ylide (2014OBC1351).

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Scheme 52 Synthesis of pyrroles 115 by the copper acetate-catalyzed (3 + 2)cycloaddition of aziridines and nitroalkenes.

If the reacting C]C bond is part of an aromatic ring, indoles are formed instead of the pyrroles. For example, treatment of haloaryl aziridines 116 with PhSH, followed by Cu-catalyzed cyclization, gave 2-substituted indoles 117 (Scheme 53) (2015JОC12659).

Scheme 53 Synthesis of indoles 117.

In 2017, a reaction of 2-naphthols with aziridines through a formal (3 + 2)cycloaddition was reported. The reaction allows access to functionalized benzoindolines 118, and tolerates a broad range of functional groups (2017CC8219). A preliminary study of the mechanism indicates an SN1-type ring-opening of the aziridines (Scheme 54).

Scheme 54 Synthesis of benzoindolines 118.

A Pd/norbornene-catalyzed domino procedure has been developed to give the indoline derivatives 119 (2018CC3407). This reaction provides an efficient access to indolines 119 by employing aryl iodides with aziridines as new electrophiles for “Catellani-type” chemistry (Scheme 55).

Scheme 55 Synthesis of indolines 119.

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2.5 1,3-Oxazolidines The synthesis of 1,3-oxazolidines has been reviewed on several occasions (2011RJOC797, 2015THC49, 2016CRV15235). Oxaziridines are useful starting materials towards oxazolidines and their use has been summarized in two reviews (2013THC39, 2014CRV8016). Synthesis of 1,3-oxazolines by (2 + 3)-cycloaddition of carbonyl compounds with azomethine ylides, generated in situ from aziridines, has been reviewed (2016MOL935, 2012EJO6479). Oxazolidines 120 were efficiently constructed by this approach in the presence of Pd2(dba)3 (Scheme 56) (2016CSI2302).

Scheme 56 Synthesis of oxazolidines 120.

A direct one-pot synthesis of oxazolidines 121 was achieved by the addition of formaldehyde to a mixture of aziridines and formic acid in a 1:1:1 ratio under catalyst- and solvent-free conditions (Scheme 57) (2018CS10509).

Scheme 57 Synthesis of oxazolidines 121.

In a heteroatom reversal of this approach, a novel enantioselective (3 + 2)-cycloaddition of epoxides with imines has been achieved. Bis(guanidino)iminophosphorane 122 is a chiral super base that enabled reaction of β,γ-epoxysulfones with imines owing to its high basicity and stereocontrolling ability, and provided enantioenriched 1,3-oxazolidines 123 (Scheme 58) (2018AGE6299).

Scheme 58 Synthesis of oxazolidines 123.

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A Co(II)-catalyzed stereospecific coupling of N-methylanilines or tetrahydroisoquinoline with styrene oxides can furnish the 1,3-oxazolidines 124 and 125 by a tandem CdN and CdO bond formation in the presence of tert-butyl hydroperoxide (TBHP). The reaction is stereospecific (Scheme 59) (2018CC11813).

Scheme 59 Synthesis of oxazolidines 124 and 125.

A novel (3 + 2)-annulation of trisubstituted ketene imines with metallocarbonyl ylides (obtained by a Lewis-acid-catalyzed CdC bond cleavage of oxiranes) is shown in Scheme 60. This protocol allowed for the efficient production of a variety of highly functionalized oxazolidines 126 under mild conditions (2018OCF2020).

Scheme 60 Synthesis of oxazolidines 126.

Banerjee et al. recognized that epoxides can be used as masked aldehydes (through the Meinwald rearrangement) and achieved the synthesis of 1, 3-oxazolidines 127a,b by the reaction of aziridines with epoxides (Scheme 61) (2016ASJOС360).

Scheme 61 Synthesis of oxazolidines 127a,b.

2.6 1,3-Oxazolines and oxazoles The synthesis, biology, and biomedical applications of 1,3-oxazolines and oxazoles have been reviewed previously (1994T2297, 2009AGE7978, 2011RJOC797, 2014IJPSR4601). Chiral oxazoline-containing ligands have found widespread application in asymmetric catalysis, and thus have been subject to numerous reviews (2004CRV4151, 2007ADDR1504, 2009CRV 2505). Here, we discuss only the recent developments in this vast area.

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N-Acyl aziridines 128 were stereoselectively converted in oxazolines 129 under Pd catalysis with a chiral ligand (Scheme 62). Trans-aziridines 130 underwent a similar reaction to give 131, catalyzed by Fe(NO3)3 (2014JHC1659, 2016ACSC4694). Antioxazolines 132 and oxazoles 133 can be prepared from keto-aziridines 134 by a one-pot acylation/ recyclization sequence (2015JICS2031). These reactions can be viewed as heteroatom variants of the vinylcyclopropane rearrangement.

Scheme 62 The use of aziridines 128, 130, and 134 in the synthesis of oxazolines.

In recent years, oxazoles (for example, compounds 135–139) are more often prepared from 2H-azirines as opposed to aziridines (Scheme 63) (2015OL4070, 2016OL3646, 2017OL3370, 2017JOC6313).

Scheme 63 Synthesis of oxazoles 135–139 starting from 2H-azirines.

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Oxazoles 140 were obtained in quantitative yields by simple thermolysis of starting azirines 141 in o-dichlorobenzene (2019JOC15567). In just 1 min, compound 142 converted to the desired product 143 at room temperature in acetone (2018BJOC506) (Scheme 64). Depending on conditions, azirines 144 can be transformed in oxazoles 145 or pyrroles 146 (2018JOC3177). A gold(III)-catalyzed C,O-selective annulation of isocyanates with 2H-azirine 147 has been achieved (2019CEJ4093). Various oxazole derivatives, e.g., 148, 149, were obtained from both aryl and aliphatic isocyanates in moderate to excellent yields.

Scheme 64 Synthesis of oxazoles 140, 143, 145, 148, and 149 and pyrroles 146 from azirines 141, 142, 144, and 147.

2.7 1,3-Oxazolidin-2-ones and 1,3-oxazolidin-4-ones In view of the great practical applications of oxazolidinones as antimicrobials (2005CRV529, 2012ADD271, 2013BMC577, 2016EOTP591) and chiral auxiliaries (2016RSCA30498), methods for their synthesis are constantly improving. One of the best known and well-documented syntheses of 1, 3-oxazolidin-2-ones involves the cycloaddition of CO2 to aziridines, which is 100% atom-efficient and often eco-friendly (solvent and catalyst free). Experimental and theoretical investigations on to this approach were extensively reviewed in 2012 (2012CCL107, 2012PAC581, 2012EJO6479), 2013 (2013RSCA11385), and 2017 (2017COC698). Numerous catalysts have

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been developed for this reaction; among the most recent are (salen)CrIIICl (2015CSI1293), sugarcane bagasse/KI (2015ACSSCE147), mesoporous zirconium phosphonates (2015GC795). Several papers from 2014 to 2018 discuss in silico studies of the mechanism of CO2 cycloaddition to aziridines (2014RSCA17236, 2014STC1245, 2018JPOe3735). A simple stereoselective method for the synthesis of trans-2hydroxymethyl-N-alkyl-1,3-oxazolidin-2-ones 150 was reported by Besbes (2018SC2242). The synthesis involves the reduction of trans-aziridine2-carboxylates with lithium aluminum hydride (LAH), followed by a ring opening and a cyclization in the presence of methyl chloroformate to afford the target trans-oxazolidinones 150 in a completely regio- and stereoselective process (Scheme 65). A plausible reaction mechanism has been proposed that involves an SN1 pathway. A detailed computational study has been reported.

Scheme 65 Synthesis of oxazolidinones 150.

Selective procedures for the ionic-liquid-mediated synthesis of 1, 3-oxazolidin-2-ones 151, 152a,b, and 153 from epoxides and carbamates have been developed (Scheme 66) (2014CCC278, 2015RSCA71765, 2016EJO3650).

Scheme 66 Synthesis of 1,3-oxazolidin-2-ones 151, 152a,b, 153.

The use of oxaziridines instead of aziridines and epoxides allows access to oxazolidin-4-ones (Scheme 67). Smith reported an isothiourea-catalyzed reaction starting with symmetric anhydrides 154 to give antioxazolidin4-one products 155 (2015CEJ10530). The reactions are stereospecific with

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respect to the oxaziridine carbon. However, only the use of symmetric anhydrides 154 was reported. Enantioenriched oxazolidin-4-one products 156 were prepared by the reaction of α-aroyloxyaldehydes 157 with oxaziridines under NHC redox catalysis (2017TA125).

Scheme 67 Lewis-base-catalyzed reactions for the stereoselective synthesis of oxazolidin-4-one derivatives 155 and 156.

2.8 1,3-Thiazolidines, 1,3-thiazolines, 1,3-thiazolidin-2-ones, 2-imino-1,3-thiazolidines, 1,3-oxathiolanes, and 1,3-oxathiolane-2-thiones and related Compounds 1,3-Oxathiolanes are typically prepared by reacting epoxides with dithioesters 158 or with CS2 (2014S1815) (Scheme 68). The latter reaction can be catalyzed by alkali alkoxides, with t-BuOLi showing the best reactivity (2016OBC7480).

Scheme 68 Synthesis of 1,3-oxathiolanes and 1,3-oxathiolane-2-thiones from epoxides.

Samzadeh–Kermani reported complementary syntheses of oxathiolanes and thiazolidines starting from epoxides 159 and aziridines 160, respectively (Scheme 69). The substrate is reacted with a carbon nucleophile

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(alkyne or malononitrile) and a sulfur source (CS2, PhNCS or S8) (2015SL643, 2016M761). Recently, a similar copper-catalyzed reaction toward thiazolidine derivatives 161 was developed (2019M1085).

Scheme 69 Synthesis of alkylidene 1,3-oxathiolanes and thiazolidines.

Lewis acid-catalyzed SN2-type ring-opening of aziridines 162 followed by a concomitant 5-exo-dig cyclization furnished 2-iminothiazolidine derivatives 163 in excellent yields (Scheme 70) (2016JOC6433).

Scheme 70 Synthesis of 2-iminothiazolidines 163.

N-Phenyl aziridine-2-carboxylates 164 undergo catalyst-free ring expansion into imidazolidin-2-ones 165 upon reaction with alkyl isocyanates (Scheme 71). On the other hand, reactions of aryl isocyanates give oxazolidin-2-imines 166 (2015TL1837).

Scheme 71 Synthesis of imidazolidin-2-ones 165 and oxazolidin-2-imines 166.

Thiazoles can be prepared by the reactions of epoxides with thioamides or thioureas (Scheme 72). For example, simple treatment of nitro epoxides 167 (prepared in situ from the corresponding nitrostyrenes) with phenyl thioamide gave thiazoles 168 in good yield (2011OBC3457). Similarly, reactions of the electron-deficient epoxides 169 with thioureas 170 led to thiazolidinones 171 (2015JHC1269).

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Scheme 72 Synthesis of thiazolines and thiazoles from epoxides 167, 169.

2-Acyl aziridines 172 were converted into 2-aminothiazoles 173 when treated with ammonium thiocyanate in the presence of RuCl3 catalyst (Scheme 73) (2014JICS69).

Scheme 73 Conversion of aziridines 172 into thiazolines 173.

Thiazolines can also be obtained from thiiranes. However, the latter suffer from stability issues and this has limited the number of successful reactions. Reaction of thiirane 174 with bromoimidazole gave fused product 175 in a double nucleophilic substitution process (Scheme 74) (2017BMCL2583). Thiirane 176 was treated with cyclic imines to give triazolines 177, 178 (2014СНС550).

Scheme 74 Synthesis of thiazolines 175, 177, 178 from thiiranes 174 and 176.

Klen and Khaliullin have reported a number of thiazoline syntheses. Imidazole-substituted thiirane 179 was treated with a range of nucleophiles to give the fused products 180 (2014RJOC271) (Scheme 75).

Scheme 75 Synthesis of fused thiazolines 180 from thiiranes by Klen and Khaliullin.

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Nonactivated 2-(thiocyanatomethyl)aziridines with diverse substitution patterns were used as substrates in a LAH-promoted thia-aza-Payne rearrangement to provide access to functionalized thiiranes (Scheme 76). Subsequent exposure of the intermediates to triphosgene resulted in the formation of thiazolidin-2-ones 181 (2017EJO3229).

Scheme 76 Synthesis of thiazolidin-2-ones 181.

A variety of oxazaheterocycles 182–185 was obtained from keto epoxides 186 upon ring opening with suitably substituted nucleophiles (Scheme 77) (2017ASJC2679).

Scheme 77 Synthesis of imidazolidines 182, pyrazoles 183, oxazoles 184, and oxazolidinones 185.

2.9 Imidazoles (benzimidazoles) and related heterocycles Both epoxides and aziridines can be converted into imidazoles. Typically, epoxides (a two-carbon component) react with some kind of bisnitrogen nucleophile, whereas aziridines can contribute its own nitrogen toward the resulting ring (thus being a CdCdN component). Synthesis of imidazoles from aziridines by (3 + 2)-cycloadditions was reviewed in 2012 (2012EJO6479). Reaction of nitro epoxides 187 with amidines gave imidazoles 188 under basic conditions (Scheme 78) (2015RSCA51559). In a conceptually similar approach, 187 was treated with mixtures of a primary amine and cyanamide (presumably forming the amidine in situ) to give aminoimidazoles 189 (notably in the absence of additional base) (2015OL1157).

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Scheme 78 Synthesis of imidazoles 188 and 189 from nitroepoxides 187.

The bisnitrogen nucleophile can be part of an aromatic ring (Scheme 79). For example, treatment of epoxides 190 with 2-aminopyridines in the presence of strong acid gives fused imidazo-pyridinones 191 (2014SL1692).

Scheme 79 Synthesis of imidazole derivatives 191 from activated epoxides 190.

Some recent examples of the synthesis of imidazolidines from aziridines are depicted on Scheme 80. Compounds 192 were produced by a dehydrogenative (2 + 3)-cyclization of glycine derivatives with N-sulfonyl aziridines (2018OL92). Enantioenriched imidazolidines 193 can be accessed by a rhodium-catalyzed intermolecular (3 + 2)-cycloaddition of chiral vinyl aziridines with oxime ethers. Notably, both aldoximes and ketoximes are suitable substrates, affording chiral imidazolidines 193 in high yields and with good stereoselectivity (2018OL3587). The synthesis of the cyclic imidazolidines 194

Scheme 80 Synthesis of imidazolidines 192–194.

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by CdN bond forming sequences was reported in 2018 (2018OL1444, 2018T6497). Here, a (3 + 2)-cycloaddition of vinyl aziridines with cyclic N-sulfonyl imines was catalyzed by palladium. Interestingly, the use of LiCl as an additive improved the diastereoselectivity with less encumbered substrates. Fullerene-substituted aziridine 195 (fullerene ring removed for clarity) can be converted into both imidazolines 196 and sulfamides 197 by reaction with an appropriate nucleophile (Scheme 81). Interestingly, the N-Ts fragment is lost in both cases (2014JOC11744).

Scheme 81 Conversion of fullerene aziridines 195 into derivatives 196 and 197.

2.10 1,2,3-Triazoles Synthesis of 1,2,3-triazoles by the (3 + 2)-cycloaddition of azides with alkynes (2009CRV4207, 2016CRV3086) has been known for well over a century. Discovered by Dimroth, it was then popularized by Huisgen (hence the “Huisgen cycloaddition”) in 1950s. Sharpless et al. developed a copper-catalyzed modification that became immensely popular among both chemists and biochemists due to the high reaction rate (even under extreme dilutions) and improved regioselectivity. It is often referred to as the “click reaction” (2002AGE2596, 2003DDT1128). Addition of an epoxide to the reaction mixture adds a spin to the reaction, leading to in situ ring opening and formation of triazoles 198 or 199 (Scheme 82). The process is catalyzed by copper in a number of forms: CuI (2016JOC9757, 2017RCI4175), CuI-phosphorated SiO2 (2014NJC5429), CuI-pyrrolidinyl-oxazolo-carboxamide complex (2015NJC3973), and immobilized CuI in [bmim]Br (2015CRC1257).

Scheme 82 General conversion of epoxides into 1,2,3-triazoles 198, 199 by a threecomponent reaction.

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3. Synthesis of six-membered rings 3.1 Pyrans, partially hydrogenated pyrans and δ-lactones The synthesis of pyrans, tetra- and dihydropyrans, and their carbonylcontaining analogs, from epoxides has been reviewed on several occasions (2004BCJ2129, 2009AGE5250, 2009CSR3175, 2010MD763, 2010T7337, 2013RSCA11385, 2017ASJOC243). Treatment of (R)-benzyl glycidyl ether 200 with the stabilized carboanion 201 bearing a masked ketone led to the formation of the dihydro- and tetrahydropyrans 202 and 203, depending on the nature of the workup (Scheme 83) (2016AGE232).

Scheme 83 Preparation of cyclic systems utilizing (R)-benzyl glycidyl ether 200.

The epoxyalkynes 204 were converted into the keto-substituted dihydropyran products 205 and 206 by the action of boron trifluoride etherate (Scheme 84). Notably, the activation of the alkyne moiety proceeds without any added transition metal (2014JOC4119).

Scheme 84 Synthesis of 3,6/5,6-dihydropyrans and 3,4-dehydropiperidines 205, 206 from epoxides.

A similar intermolecular coupling of epoxides 207 required the addition of large amounts of NbCl5 (Scheme 85) (2017ASJC614).

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Scheme 85 Nb-catalyzed ring opening of epoxides 207 into dihydropyrans.

Epoxy alcohol 208, obtained by Sharpless asymmetric epoxidation of alkene 209, stereoselectively converted into the cis-tetrahydropyran (goniothalesdiol A) 210 (Scheme 86). No five-membered isomer was detected (2017TL1037).

Scheme 86 Synthesis of goniothalesdiol A 210.

A facile and efficient synthesis of 4-isochromanones 211 has been achieved by copper-catalyzed intramolecular reaction of epoxides with electron-deficient alkenes, with dimethyl sulfoxide (DMSO) acting as the oxidant. The process involves a sequential oxidative ring opening of the epoxides and an oxa-Michael addition (Scheme 87) (2018EJO926).

Scheme 87 Synthesis of 4-isochromanones 211.

One-pot CdH activation/epoxide ring opening of 212/213 catalyzed by Pd(II) gave substituted isochroman-1-ones 214 (Scheme 88) (2015JA6140). Compounds 215 and 216 are formed under conceptually similar conditions: a carbonyl directing group promotes ortho-C–H activation by Pd(II) (2015JA10950) or Ni(II) (2018AGE11797) followed by the epoxide ring opening. Notably, the nickel-catalyzed formation of cis-215 is completely stereoselective and proceeds on a gram scale.

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Scheme 88 Synthesis of fused tetrahydropyranones 214–216 from epoxides.

Tungstated zirconia (WOx/ZrO2) allows performing a three-component coupling of styrene oxide with two equivalents of 2-naphthol (or sesamol) leading to xanthene derivative 217 (Scheme 89) (2017CCAOAC5).

Scheme 89 Synthesis of xanthene derivatives 217.

In 2018 the Catellani reaction was employed for the synthesis of isochroman scaffolds 218 (Scheme 90) (2018AGE3444).

Scheme 90 Synthesis of isochromanes 218.

3.2 Piperidines, pyridines, and their partially hydrogenated analogs Piperidines are an immensely important class of compounds medicinally: the piperidine ring is the most common heterocyclic subunit among FDA approved drugs (2014JMC10257). Their synthesis from epoxides and aziridines was reviewed in 2011 (2011RJOC1609). Scheme 91 shows one of the direct ways to access piperidines from epoxides. Treatment of alcohol 219 with Ts2O (which is often used in preference

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to TsCl with sensitive substrates) followed by an intramolecular SN2 attack gives aziridinium ion 220. The latter can be cleaved by an external nucleophile to yield either piperidines 221 or pyrrolidines 222 depending on the conditions (2014CAJ1060, 2018OBC796).

Scheme 91 Synthesis of piperidines 221 or pyrrolidines 222.

Scheme 92 summarizes piperidine synthesis by reductive transformation of the carbonyl-containing aziridines 223–225 (2014TA1246, 2015RSCA50580, 2016OBC6426). These impressive reactions proceed through a one-pot regioselective ring cleavage at the marked CdN bond, alkyne/alkene reduction, cyclization, debenzylation and, in the case of 223/224—imine reduction (albeit the order of these events was not reported).

Scheme 92 Synthesis of piperidine derivatives by the reduction of functionalized aziridines 223–225.

Ring opening of the N-tosyl aziridine 226 with benzyl amine gives a mixture of piperidine and pyrrolidine products (Scheme 93) (2017EJO4235).

Scheme 93 Synthesis of piperidines and pyrrolidines by aminolysis of aziridine 226.

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In 2015, Palchikov reported that a range polycyclic piperidine products 227a,b/228a,b is accessible from bisepoxide 229. In this two-step one-pot process the more sterically epoxide undergoes a catalyst-free intermolecular aminolysis followed by another intramolecular ring opening (2015EAPCNs96). The method offers access to the 2-azabicyclo[3.3.1] nonane (2-ABN, shown in bold) core. Morphan, an important 2-ABN-containing pharmacophore, is found in more than 300 natural products (e.g., morphine and strychnine) (2011S993) (Scheme 94).

Scheme 94 Synthesis of 2-ABN subunits 227a,b by the domino aminolysis of dicyclopentadiene diepoxide 229.

The structurally diverse piperidine and pyrrolidine derivatives 230–232 were prepared by a base-promoted aminolysis of keto epoxides (Scheme 95) (2015JOC2781).

Scheme 95 Synthesis of fused azaheterocycles 230–232.

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Treatment of the keto epoxides 233 with BF3Et2O gives ketone intermediates, which intramolecularly cyclize to quinolin-4-ones 234 (Scheme 96) (2016T7025).

Scheme 96 Synthesis 3-arylquinolin-4(1H)-ones 234.

Recent syntheses of tetrahydroisoquinolines 235–237 are presented in Scheme 97 (2014TL6787, 2016ASC532, 2018AGE10980).

Scheme 97 Synthesis of tetrahydroisoquinolines 235–237.

Fused piperidines 238 were accessed from vinyl indoles and N-activated aziridines in good yields and with great diastereoselectivity (Scheme 98). The reaction is catalyzed by LiClO4 and proceeds through a FriedelCrafts alkylation followed by aza-Michael addition (2017JOC2364). 3-Spiropiperidino indolenines 239 can be synthesized by a Lewis acidcatalyzed SN2-type ring opening of activated aziridines followed by Pd-catalyzed dearomative spirocyclization with propargyl carbonates (2018CC8583).

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Scheme 98 Synthesis of indole piperidines 238 and 239.

Diastereo- and enantioselective catalytic (3 + 3)-cycloaddition of donor–acceptor aziridines with N,N-dialkyl-3-vinylanilines has been reported under Lewis acid catalysis (Scheme 99). The reaction yields tetrahydroisoquinolines 240 or 241 in good yields and selectivity (2018T3671, 2019ASJOC1621).

Scheme 99 Synthesis of tetrahydroisoquinolines 240 and 241.

Pyridines 242 were obtained in Kr€ ohnke synthesis upon heating of epoxides 243 with appropriately substituted oximes under solvent-free conditions and in the absence of any catalyst (Scheme 100) (2014TL3844). The use of anilines instead of oximes under similar conditions, but in the presence of MeSO3H/Al2O3, led to the formation of quinolines 244 (2017BJOC1977). Notably, the latter reaction proceeded at room temperature, as opposed to

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200°C required for the former. The use of aziridines in the synthesis of quinolines is much less precedented. The first report of such a reaction was published in 2018; here, activated N-sulfonyl aziridines were treated with azido aldehydes 245 under acidic catalysis (2018OCF3488).

Scheme 100 Synthesis of pyridines and quinolines.

3.3 1,4-Dioxanes, 1,4-oxathian-2-ones, 1,4-oxathian-3-imines, thiomorpholines, piperazines, and tetrahydropyrimidines Dioxanes are typically prepared from epoxides upon reaction with an oxygen-containing nucleophiles. For example, treatment of epoxides with diazoketoesters 246 gave 1,4-dioxenes 247 (Scheme 101). The reaction is catalyzed by a [CpRu(CH3CN)3][BArF]/phenanthroline system (2014AGE6140).

Scheme 101 Synthesis of 1,4-dioxenes 247 from epoxides and with α-diazo-β-keto esters.

Sulfur- and nitrogen-containing products are also accessible. Epoxides can undergo a rapid one-pot reaction with ethyl mercaptoacetate furnishing 1,4-oxathian-2-ones 248 in the presence of a catalytic amount of eco-friendly Triton B (Scheme 102) (2018HEC187). In situ generated silver acetylide was employed as a nucleophile in reactions with isothiocyanates and epoxides to form the 1,4-oxathian-3-imine derivatives 249 (2016T5301).

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A similar reaction leads to thiomorpholines 250 from N-Ts-aziridines 251 under copper catalysis (2019JHC450).

Scheme 102 Synthesis of 1,4-oxathian-2-ones 248, 1,4-oxathian-3-imines 249 and thiomorpholines 250.

Piperazines 252 were obtained from N-activated aziridines in a one-pot process involving ring-opening to bisamines 253 and addition-substitution with vinylsulfonium salts 254 (Scheme 103) (2017S2488).

Scheme 103 Synthesis of trifluoromethylated piperazines 252 in one pot.

A simple and efficient one-pot three-component synthesis of highly substituted piperazines 255 was achieved by SN2-type ring-opening of N-activated aziridines by anilines, followed by a Pd-catalyzed annulation with propargyl carbonates (Scheme 104) (2019JOC1757). Alternatively, a stereospecific Cu-catalyzed nucleophilic ring opening of N-sulfonylaziridines and hydroamination led to the piperazines 256. When R1 ¼ H, piperazines 256 undergo a C¼C bond migration to furnish pyrazines 257 (2018OL4444). Annulation of p-quinamine with N-tosylaziridines 258 has been reported as a convenient route to piperazines 259 with exclusive diastereoselectivity up to 100:1 (2019OL10115).

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Scheme 104 Synthesis of piperazines 255–257, 259.

Pd-catalyzed coupling of allylic epoxides 260 with diamines gave intermediate amines 261, which were subjected to an intramolecular Michael addition in one pot to give the benzpiperazine derivatives 262 (Scheme 105) (2015OL4576).

Scheme 105 Synthesis of benzpiperazines 262.

Aziridine aldehyde dimers 263, amino acids and isocyanides undergo a “disrupted” Ugi reaction to yield piperazinone derivatives 264a,b (Scheme 106) (2014JOC9948, 2016JOC5209).

Scheme 106 Synthesis of piperazinone derivatives 264a,b.

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An efficient Cu-catalyzed formal (3 + 3)-cycloaddition of isocyanoacetates with aziridines provide a practical access to valuable 1,4,5,6-tetrahydropyrimidine derivatives 265. In particular, the use of enantiopure aziridines delivers disubstituted tetrahydropyrimidines 266 bearing a 1,3-diamine unit in good yields and excellent selectivity (Scheme 107) (2018OL5112).

Scheme 107 Synthesis of tetrahydropyrimidines 265, 266.

An expedient route to structurally diverse 1,4,5,6-tetrahydropyrimidines 267 by domino ring-opening cyclization of activated aziridines with α-acidic isocyanides is shown in Scheme 108 (2018OL2925). The transformation proceeds through a Lewis-acid-mediated SN2-type ring opening of activated aziridines with α-carbanion of the TosMIC-type isocyanides, followed by a concomitant 6-endo-dig cyclization in good to excellent yields.

Scheme 108 Synthesis of tetrahydropyrimidines 267.

3.4 Morpholines, their aryl-fused- and carbonyl-containing analogs (morpholones) The morpholine ring consists of two two-carbon units, a nitrogen atom and an oxygen atom. This system easily lays itself to a retrosynthetic disconnection to either aziridine or epoxide starting materials, and this has resulted in a plethora of reported approaches. The methods for morpholine synthesis were covered in comprehensive reviews by Kourounakis (2020CMC392), Cossy (2019EJO7513), Palchykov (2013RJOC787, 2019CHC324), and Kikelj (2012S3551), and before that by Rutjes (2004S641). Ring opening of aziridines by various nucleophiles followed by cyclization to form morpholine

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derivatives has been reviewed by Singh (2018ARK50). To avoid unnecessary repetition, only the latest or most important methods are discussed here. General approaches to morpholines 268 and their carbonyl-containing analogs 269–271 starting from aziridines and epoxides are summarized in Scheme 109.

Scheme 109 General approaches to morpholines 268 and their carbonyl-containing analogs 269–271 starting from aziridines and epoxides.

Feng and Liu have developed a new asymmetric catalytic strategy for high order (8 + 3)-cycloaddition of tropones with meso-aziridines through a desymmetrization/annulations process. The chiral N,N0 -dioxide/ Mg(OTf )2 complex exhibited excellent performance in the reactions, affording the tricyclic heterocycles 272 in up to 98% yield, and with excellent diastereo- and enantioselectivity (Scheme 110) (2018CEJ13428).

Scheme 110 Synthesis of tetrahydrocyclohepta[b][1,4]oxazines 272.

Spiromorpholines 273 were synthesized by regio- and stereoselective aziridine ring opening with 2-bromophenols and a subsequent tandem cyclization (2019JOC10412). A transition-metal-free (3 + 3) annulation provides a rapid high yield access to fused bicyclic morpholines 274a,b with a tetrasubstituted carbon center (Scheme 111) (2019OL10115).

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Scheme 111 Synthesis of morpholines 273 and 274a,b.

The aziridinooxazolidine 275 is easily converted into morpholines 276 and 277 by the action of nickel acetate or lithium aluminum hydride, respectively (Scheme 112) (2019CEJ1456).

Scheme 112 Synthesis of benzoxazines 276 and 277.

Convenient access to polysubstituted morpholin-2-ones 278 has been achieved by the epoxide-mediated Stevens rearrangement of α-amino-acidderived tertiary allylic, propargylic, and benzylic amines (Scheme 113) (2019CEJ5169).

Scheme 113 Synthesis of morpholinones 278.

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4. Synthesis of seven-membered and larger rings 4.1 Oxepanes The synthesis of oxepanes like 279 by epoxide ring opening (Scheme 114) has been widely covered in the review literature. The reader is directed to the excellent reviews by the group of Jamison who has written extensively on the topic (2009AGE5250, 2009CSR3175, 2010MD763).

Scheme 114 All-endo polyepoxide opening cascade leading to oxepanes 279.

In 2015, Jamison showed that the use of [Rh(CO)2Cl]2 instead of more conventional Lewis or Brønsted acids fascilitated the conversion conjugated epoxides 280 into oxepanes 281 with high selectivity and in excellent yield (Scheme 115) (2015JA6941).

Scheme 115 Rh-catalyzed epoxide ring-opening into oxepanes 281.

4.2 2,5-Dihydrooxepines Polyfunctional epoxides 282 can be selectively converted into dihydrooxepines 283 or alkenes 284a,b depending on the reaction conditions (Scheme 116). The original catalyst (RhCl(IPr)(COD)/AgSbF6) led primarily to mixtures of the alkenes; however, [Rh(NBD)2]+ BF4
proved to be more selective and compound 283 was obtained in 72% yield (2017ACSC1533).

Scheme 116 Synthesis of 2,5-dihydrooxepine 283.

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4.3 Azepanes and related heterocycles Azepines, being nitrogen-containing analogs of oxepines, can be made by using the conditions from Scheme 116 and applying them to aziridines, as opposed to epoxides. Thus, treatment of enyne aziridines 285 with [Rh(NBD)2]+ BF4
in DCE gave the fused azepines 286 (Scheme 117). The E/Z geometry of the starting materials is reflected in the syn/ antiorientation of the products. A switch to diene aziridines 287 resulted in the formation of the monounsaturated products 288 (2015AGE15854, 2015JA3787).

Scheme 117 Synthesis of azepine derivatives 286, 288.

The alkene and the alkyne do not necessarily have to be in the same molecule for the (5 + 2)-cycloaddition to take place. Intermolecular reaction of vinylaziridines 289 with alkynes 290 in the presence of a rhodium catalyst give the cycloadducts 291 (Scheme 118) (2016JA2178). Interestingly, similar products 292 were obtained from amino epoxides 293, when the latter was treated with BF3OEt2 in the presence of catalytic FeCl3 and two equivalents of an alkyne (2016AGE10423).

Scheme 118 Synthesis of azepines 291 and 292.

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Further alteration of the reaction partners enables azepine synthesis by (4 +3)-cycloaddition of aziridines 294 with electron-rich dienes (Scheme 119) (2017AGE1351). Interestingly, the alkene component of 295 remains unaltered in the reaction, in stark difference to the previous method.

Scheme 119 Synthesis of azepine derivatives 295.

Pushing the limits even further, a trimolecular reaction of an aziridine with two alkynes has been reported (Scheme 120). The process is catalyzed by HSbF6, and works with terminal alkynes and nonactivated aziridines, furnishing the azepine derivatives 296 in moderate to good yields (2014AGE4196).

Scheme 120 Synthesis of azepine derivatives 296.

Another azepine synthesis (compound 297) by cycloaddition has been reported starting from diynes 298 and 2H-azirines 299 (Scheme 121). It proceeds with an unprecedented metal-catalyzed CdC bond cleavage of the azirines at room temperature (2016AGE2861).

Scheme 121 Synthesis of azepine derivatives 297.

An alkyldiphenylphosphine-promoted (4 + 3)-cycloaddition of allenoates with aziridines has been achieved under mild conditions, providing the biologically interesting functionalized tetrahydroazepines 300a,b (Scheme 122) (2019RSCA1214). Dihydropiperidines 301 were isolated as minor products.

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Scheme 122 Synthesis of azepine derivatives 300a,b.

Reaction of enantioenriched aziridines 302 with N-bromosuccinimide (NBS) and 4-nitrobenzenesulfonylamine (NsNH2) led to stereospecific cyclization into azepanes 303 (Scheme 123) (2014OL2134).

Scheme 123 Synthesis of azepanes 303.

Irradiation of the oxaziridines 304 promotes a photochemical ring expansion into azepanes 305, with varying levels of stereoselectivity (Scheme 124) (2016OPRD1533).

Scheme 124 Synthesis of compounds 305.

4.4 Oxazepanes and their sulfur-containing analogs Synthesis of oxazepanes and thiazepanes from three-membered precursors is reasonably well precedented; however, the question of stereoselectivity often remains unanswered. Reaction of the triazoles 306 with hydroxy epoxides 307 under rhodium and magnesium catalysis gives oxazepanes 308 in moderate yields (Scheme 125) (2016OL6432).

Scheme 125 Synthesis of oxazepanes 308 from epoxides 307.

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Treatment of epoxides 309 with boron trifluoride led to mixtures of morpholines and oxazepanes (Scheme 126) (2016T690).

Scheme 126 Conversion of epoxides 284 into mixtures of morpholines and oxazepanes.

Imidazoazepines 310 have been obtained serendipitously by an SN2-type ring-opening of N-activated aziridines with 2-bromobenzylamine (Scheme 127). The initial reaction is followed by an unprecedented cascade sequence comprising a Cu-catalyzed cross dehydrogenation, a C–N coupling, and an Ullmann-type C–C bond formation. The benzoxazepine and benzothiazepine derivatives 311 have also been synthesized by the ringopening of aziridines with 2-bromobenzyl alcohols and mercaptans, respectively, followed by a Cu-catalyzed N-arylation (2014JOC6468). The N-tosyl-aziridine 312 was used to prepare oxazepane 313 upon treatment with an aryldiazonium salt (2019OCF1832).

Scheme 127 Syntheses of imidazo-, oxa-, and thiazepine ring systems.

An Ir-catalyzed (4 + 3)-cyclization of vinyl aziridines with para-quinone methide derivatives led to benzoxazepine scaffolds 314 in moderate to high yields (40%–96%) and considerable levels of selectivity (dr. 70:30 to >95:5) (Scheme 128) (2018ACSC10234).

Scheme 128 Synthesis of benzoxazepine scaffolds 314.

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4.5 Other large rings Sulfonylaziridines 315 have been converted into a number of 7-, 10-, or 11-membered heterocycles by treatment with amines or amino alcohols, in a two-step one-pot process (Scheme 129) (2015JOC9926).

Scheme 129 Synthesis of other large rings from sulfonylaziridines 315.

Diketone epoxides 316 undergo ring expansion into medium-sized lactones 317 upon treatment with a Lewis acid and an azide or bromide source (Scheme 130) (2018CEJ2080).

Scheme 130 Ring expansion of epoxides 316 into lactones 317.

Recently, the Catellani reaction was employed for the synthesis of 13- and 14-membered macrocycles 318 and 319 starting from epoxides 320 (Scheme 131) (2018AGE3444).

Scheme 131 Synthesis of macrocycles 318, 319.

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The novel cryptands 321 were obtained by the reaction of terminal bisepoxides 322 with bisthiols 323 (Scheme 132) (2019S2214). The free hydroxyl group in 321 can be tosylated, thus allowing for further modification of these macrocycles.

Scheme 132 Synthesis of macrocycles 321.

5. Concluding remarks Strained three-membered heterocycles are a convenient entry point to larger ring systems. The common reactivity pattern of epoxides and aziridines is their ability to undergo various (3 + 2)-cycloadditions, which lead to five-membered heterocycles (tetrahydrofurans, pirrolidines, imidazoles and other rings). Increasing amounts of attention have been given to the synthesis of six-membered rings such as pyrans, piperidines, morpholines, piperazines, etc. On the other hand, there is only a small set of methods to convert aziridines and epoxides into seven-membered and larger heterocyclic systems (oxepanes, dihydrooxepines, azepanes, azepines, oxazepanes, thiazepines, benzoxazepines, and related compounds). In this review, the authors aimed to provide a snapshot of the recent work on one-pot transformations of small heterocycles. We hope it will both seed further research and serve as a one-stop guide to the available transformations.

Acknowledgments V.A.P. would like to express profound gratitude to Prof. Vladimir Gevorgyan (University of Texas at Dallas, USA), in whose group he worked during 2020, for providing unlimited access to modern chemical literature, databases, and valuable discussions.

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CHAPTER FOUR

Organometallic complexes of functionalized chelating azines: Part 2 Alexander P. Sadimenko* Department of Chemistry, University of Fort Hare, Republic of South Africa *Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Five-membered monoheterocycles 3. Pyrazole functionalities 4. Imidazole, triazole, and tetrazole functionalities 5. Other heterocyclic functionalities 6. Azines annulated with the other heterocycles 7. Conclusions References

225 226 230 242 273 274 281 282

Abstract Organometallic compounds of the chelating azines containing thienyl, indolyl, carbazolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, N-heterocyclic carbene functionalities, as well azines annulated to the other heterocycles, are reviewed. Material on their synthesis and coordination modes, the role of the discussed compounds in catalysis, materials chemistry, photochemistry, and microbiology is highlighted. Keywords: Carbazolyl, Chelates, Coordination mode, Cyclometalation, Dithienyl, Imidazol-2-ylidene, Imidazolyl, Indolyl, Ligands, Phthalazine, Pyrazine, Pyrazolyl, Pyridazine, Pyrimidine, Quinoxaline, Supramolecular chemistry, Thienyl, 1,3,5-Triazine, 1,2,3-Triazolyl

1. Introduction Previously attention has been paid to the organometallic complexes of azines (2018AHC51) and chelate-forming azines (six-membered pyridinetype heterocycles with two or more heteroatoms), a special group is made up of azines together with pyridines along with biazines (bipyridazines, Advances in Heterocyclic Chemistry, Volume 133 ISSN 0065-2725 https://doi.org/10.1016/bs.aihch.2020.05.001

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2021 Elsevier Inc. All rights reserved.

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bipyrimidines, and bipyrazines), as well as their benzannulated derivatives (2019AHC315). Organometallic chemistry of chelating azines also includes complexes of azines with carbonyl, hydroxyl, thiol, selenol, amino, imino, phosphino, and some other functionalities, and they were described recently in Part 1 of this survey (2020AHC293). However, the range of chelating azines also includes thienyl, indolyl, carbazolyl, imidazolyl, 1,2,3-triazolyl, N-heterocyclic carbene moieties, and annulated azines with some other heterorings which constitute the subject of the present chapter. Analysis of the existing data shows that they form a group of organometallic compounds of special theoretical and applied interest. They are interesting as luminescent, fluorescent, phosphorescent, near-infrared emissive, antimicrobial, and bioactive materials, and also materials for biological imaging, anticancer materials, and sensitizers for solar cells. Many representatives of complexes under discussion are catalysts for Suzuki–Miyaura, Negishi, Pauson-Khand, Kumada–Corriu, Heck cross-coupling, Grignard reactions, hydrogenation, transfer hydrogenation, alkylation, dehydrogenative alkylation, α-olefination, arylation, hydroarylation, hydroboration, hydrosilylation, multicomponent synthesis of pyridines, and also electrocatalysts for carbon dioxide reduction.

2. Five-membered monoheterocycles Two homoleptic iridium(III) complexes contain extended π-conjugated 1,4-di(thiophen-2-yl)benzo[g]phthalazine or 1-(2,4-bis (trifluoromethyl)phenyl)-4-(thiophen-2-yl)-benzo[g]phthalazine groups and are characterized by a near-infrared emission with high photoluminescence (Eq. 1) (2017CM4775).

ð1Þ

3-(2,6-Dimethylphenoxy)-6-(thiophen-2-yl)pyridazine, 1-(2,6-dimethylphenoxy)-4-(thiophen-2-yl)phthalazine (Eq. 2), and 9-(4-(thiophen-2-yl) phthalazin-1-yl)-9H-carbazole (Eq. 3) give triscyclometalated iridium(III) complexes with valuable electroluminescent properties (2010SM2231).

Organometallic complexes of functionalized chelating azines

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ð2Þ

ð3Þ

A 4,6-dithienyl pyrimidine derivative constitutes a new type of cyclometalating ligand in an iridium(III) complex and has phosphorescent properties (Eq. 4) (2016D6949).

ð4Þ

9-(4-(4-Chlorophenyl)phthalazin-1-yl)-9H-carbazole gives a triscyclometalated iridium(III) complex, where carbazole does not participate in cyclometalation (Eq. 5), but its presence is valuable for the quality of this component for organic light-emitting diode (OLED) devices (2009OE618).

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ð5Þ

A biscyclometalated iridium(III) complex based on 3-(4-(9Hcarbazol-9-yl)phthalazin-1-yl)-9-ethyl-9H-carbazole and 2-picolinic acid is a red phosphorescent emitter in polymer light-emitting diodes (Eq. 6) (2013DP(97)43).

ð6Þ Phosphorescent yellow-to-orange iridium(III) complexes containing 2-thienylquinazolines as cyclometalating ligand and picolinate as ancillary NO ligand have been reported (Eqs. 7 and 8) (2015RSC97841). Bulky substituents at the 4-position of the quinazolyl ring not only allow tuning of their optoelectronic properties but also lead to the change of the position of the coordinating nitrogen atom of the quinazolyl ring.

ð7Þ

Organometallic complexes of functionalized chelating azines

229

ð8Þ

Cyclorhodation (Eq. 9) and cyclopalladation (Eq. 10) occurs for 1-(2-pyridyl)- and 1-(2-pyrimidyl)indole (1998POL533).

ð9Þ

ð10Þ

The rhodacycle intermediate of type 1 has been postulated in the rhodium-catalyzed C2-difluoroalkylation of N-pyrimidylindole with 2, 2-difluorovinyl mesityl sulfonate (2017CC9482).

3,6-Bis(2-thienyl)-1,2,4,5-tetrazine undergoes double cyclometalation to yield a dinuclear platinum(II) double CN-chelate (Eq. 11) (2008JOM1703).

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ð11Þ

4-Thienylpyrimidines give dinuclear palladium(II) CN-chelates with bridging acetate groups (Eq. 12) (2015POL(100)89).

ð12Þ

3. Pyrazole functionalities 3,6-Bis(3,5-dimethylpyrazol-1-yl)pyridazine gives chromium(0), molybdenum(0), tungsten(0), and manganese(I) mono-NN-chelates (Eq. 13) (1991D1557).

ð13Þ

2,4,6-Tris(pyrazol-1-yl)pyrimidine, 2,4,6-tris(4-methylpyrazol-1-yl)pyrimidine, and 2,4,6-tris(3,5-dimethylpyrazol-1-yl)pyrimidine, depending on the ratio of the reagents, yield mono- or dinuclear NN-chelated rhenium(I) complexes, and the monochelates have been characterized by fluxionality in solution (Eq. 14) (1996D3065). Similar trends are observed for 2,4,6-tris(4-methylpyrazol1-yl)-1,3,5-triazine or 2,4,6-tris

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(3,5-dimethylpyrazol-l-yl)-1,3,5-triazine and their rhenium(I) mono- and dinuclear NN-chelated complexes (Eq. 15) (1996D3371).

ð14Þ

ð15Þ

2-Bromo-5-(1H-pyrazol-1-yl)pyrazine gives a monometallic octahedral NN-chelate (Eq. 16) (2019NJC2449). With trifluoroacetic acid, protonation occurs on the uncoordinated nitrogen atom.

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ð16Þ

3-Chloro-6-(pyrazolyl)pyridazine (Eq. 17), 3,6-bis(pyrazolyl)pyridazine (Eq. 18), and their methyl-substituted derivatives form mononuclear cationic ruthenium(II) NN-chelates (2009JOM2618).

ð17Þ

ð18Þ 3-Chloro-6-(3,5-dimethylpyrazolyl)pyridazine (Eq. 19), 3,6-bis (pyrazolyl)pyridazine (Eq. 20), and some of their substituted derivatives give NN-chelates of ruthenium(II), osmium(II), rhodium(III), and iridium(III) (2010ICA2287).

ð19Þ

ð20Þ

Organometallic complexes of functionalized chelating azines

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3-Сhloro-6-(3-pyridyl-1-pyrazolyl)pyridazine gives a range of mononuclear chelates and 3,6-bis(3-pyridyl-1-pyrazolyl)pyridazine forms both mononuclear and dinuclear products (Eqs. 21 and 22) (2012JCS565, 2014 JCS1143), where the pyridazine ring does not participate in coordination.

ð21Þ

ð22Þ

Pyrimidine-based thiophene pyrazoles, depending on the ratio of the reactants, give mono- or bischelates ruthenium(II), rhodium(III), and iridium(III) possessing antibacterial properties (Eq. 23) (2020JOM121155).

ð23Þ

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2-(Pyrazol-1-yl)pyrimidine (Eq. 24), 2-(3,5-dimethylpyrazol-1-yl) pyrimidine, and 4,6-bis(pyrazol-1-yl)-pyrimidine (Eq. 25) give ruthenium(II) NN-chelates (2001NJC1050).

ð24Þ

ð25Þ

HOOC

CF3

HOOC

CF3 N

N N

N H + HOOC

N

N

N RuCl 3

KOAc

N

HOOC

Ru

N N

N N

CF3

N

HOOC

N

HOOC

CF3

ð26Þ 4-(3-Trifluoromethylpyrazol-5-yl)-2-(3-trifluoromethyl)phenylpyrimidine (Eq. 26) and substituted 4-(6-(3-trifluoromethylpyrazol-5-yl) pyridin-2-yl)-2-trifluoromethylpyrimidines (Eq. 27) are used as cyclometalating ligands to couple with 4,40 ,400 -triethoxycarboxy-2,20 :60 , 200 -terpyridine ruthenium(III) chloride (2014JMA(A)5418). Bistridentate Ru(II) have been used as sensitizers for solar cells.

Organometallic complexes of functionalized chelating azines

235

ð27Þ 2,3-Bis(pyrazol-1-yl)quinoxaline in methylene chloride gives a cationic ruthenium(II) NN-chelate, in which only the nitrogen heteroatoms of the pyrazolate rings are involved (Eq. 28) (2009ICA4486). In methanol partially methanolyzed ligand is generated and NN-coordination embraces both pyrazolate and pyrazine nitrogen heteroatoms. 2,3-Bis(pyrazol-1-yl)pyrazine (Eq. 29) and 3,6-bis(3,5-dimethylpyrazol-1-yl)pyridazine (Eq. 30) both give mono-NN-cationic chelates in which azine and pyrazolate nitrogens are involved irrespective of the reaction medium. All the products are catalysts for transfer hydrogenation.

ð28Þ

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ð29Þ

ð30Þ 4,6-Bis(3,5-dimethylpyrazol-1-yl)pyrimidine, 3,6-bis(3,5dimethylpyrazol-1-yl)pyridazine, and 3-(3,5-dimethyl-pyrazol-1-yl)-6chloropyridazine readily form rhodium(I) [(Rh(Cl)(diolefin))2(L)] complexes (1984POL213). These react with carbon monoxide to yield the related carbonyl derivatives. 2-Chloro-3-(3-(2-pyridyl)pyrazolyl)quinoxaline with ruthenium(II), rhodium(III), and iridium(III) precursors gives cationic NN-chelates, and only the pyrazolyl and pyridyl rings participate in coordination (Eq. 31) (2016ICA(441)95).

ð31Þ 3,6-Bis(3,5-dimethylpyrazolyl)-1,2,4,5-tetrazine gives a dinuclear ruthenium(II) cationic NN-bischelate with a bridging tetrazine ligand (Eq. 32) (2016D12532).

Organometallic complexes of functionalized chelating azines

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ð32Þ 4,6-Bis(pyrazolyl)pyrimidine and substituted derivatives give ruthenium(II), rhodium(III), and iridium(III) mono- and bis-NN-chelates depending on the ratio of the reactants (Eq. 33) (2010JOM495).

ð33Þ 2-Chloro-3-(pyrazolyl)quinoxaline gives cationic ruthenium(II), osmium(II), rhodium(III), and iridium(III) NN-chelates (Eq. 34) (2010JMS205).

ð34Þ

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2-Chloro-3-((3-furanor 3-thiophene-2-yl)-1H-pyrazol-1-yl) quinoxaline (Eq. 35) and 2,3-bis((3-furan- or 3-thiophene-2-yl)-1Hpyrazol-1-yl)quinoxaline (Eq. 36) give ruthenium(II), rhodium(III), and iridium(III) cationic NN-chelates (2018ICA(476)101).

ð35Þ

ð36Þ

A bis(3,4-dimethylpyrazolyl)-2,4,6-triazine derivative serves as an ancillary and 2-phenylpyridine as cyclometalating ligand in a cationic iridium(III) complex characterized by fluorescent emission and can be applied as a biological imaging probe (Eq. 37) (2018EJI4533).

ð37Þ 3-Chloro-6-(3,5-dimethylpyrazol-1-yl)pyridazine gives a pyrazinium salt that enters into oxidative addition with [Pd(PPh3)4] to yield a palladium(II) carbene product (Eq. 38) (2012OM8537).

Organometallic complexes of functionalized chelating azines

239

ð38Þ

Pyrazolyl-pyrimidine ligands give neutral and cationic palladium(II) NN-chelates (Eq. 39); the cationic complexes are catalysts for copolymerization (2008JOM1269).

ð39Þ

4,6-Bis(pyrazol-1-yl)pyrimidine and 4,6-bis(4-methylpyrazol-1-yl) pyrimidine give cationic and neutral mono- and dinuclear palladium NN-chelates and bischelates (Eq. 40) (2000IC1152). Such complexes are catalysts for carbon monoxide/alkene terpolymerization (2005ASC839, 2015JOM(800)90). 2-(4-Methyl-1H-pyrazol-1-yl)pyrimidine and 2(4-bromo-1H-pyrazol-1-yl)pyrimidine yield cationic allylpalladium(II) NN-chelates characterized by two types of fluxional processes: allyl rotation and interchange of the pyrimidine protons (Eq. 41) (2005EJI100).

ð40Þ

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ð41Þ

2,4,6-Tris(4-methylpyrazol-1-yl)-1,3,5-triazine and 2,4,6-tris(4-bromopyrazol-1-yl)-1,3,5-triazine give dicationic palladium(II) bis-NN-chelates, which are partially hydrolyzed to the cationic bis-NN-chelate of 4,6-bis (4-methyl- or 4,6-bis(4-bromo)pyrazol-1-yl)-1,3,5-triazin-2-olate (Eqs. 42 and 43) (1996CB589, 1998IC6606, 2004EJI549). 2-Methoxy-4,6-bis (4-methylpyrazol-1-yl)-1,3,5-triazine with palladium(II)-allyl precursor reacts in steps yielding cationic monochelates, then dicationic bischelate, and finally the cationic product of partial hydrolysis (Eq. 44). This ligand with a palladium(II) pentafluorophenyl precursor gives only the neutral monochelate (Eq. 45).

ð42Þ

ð43Þ

Organometallic complexes of functionalized chelating azines

241

ð44Þ

ð45Þ

2,4,6-Tris(3,5-dimethylpyrazol-1-yl)-1,3,5-triazine forms palladium(II) NN-monochelates that have a dynamic behavior and are characterized by three metallotropic processes (Eq. 46) (2003IC885).

ð46Þ

2-(1-Pyrazolyl)pyrimidine and 2-(1-(3,5-dimethyl)pyrazolyl)pyrimidine give neutral and cationic NN-chelates; the latter are catalysts for copolymerization of styrene with carbon monoxide (Eq. 47) (2001JOM(619) 287, 2001NJC1050).

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ð47Þ

4. Imidazole, triazole, and tetrazole functionalities 2,3-Bis(1-methylimidazol-2-yl)quinoxaline gives a seven-membered molybdenum(0) tetracarbonyl NN-chelate (Eq. 48) (2011OM6441).

ð48Þ

N-Ethyl-N0 -2-pyrimidylbenzimidazolium bromide gives a manganese CN-carbene-chelate, which is an electrocatalyst for carbon dioxide reduction (Eq. 49) (2016IC9509).

ð49Þ

3-Substituted-1-(2-pyrimidine)imidazolium chlorides in a transmetalation reaction give rhenium(I) CN-carbene-chelates characterized by emissions in the range 515–570 nm (Eq. 50) (2013ICA(394)488). ð50Þ

Organometallic complexes of functionalized chelating azines

243

1-Methyl-3-pyrimidylbenzimidazolium hexafluorophosphate gives a rhenium(I) CN-carbene-chelate, which is a mediator for electrocatalytic conversion of carbon dioxide (Eq. 51) (2016IC3136).

ð51Þ

Bis(1,2,3-triazole)pyrimidines give rhenium(I) bis-NN-chelates, which in the solid state show hydrogen or halogen bonding (Eq. 52) (2015JOM (792)206).

ð52Þ

2,6-Bis(imidazol-1-yl)pyrazines (Eq. 53), a 2,5-bis(imidazol-1-yl) pyrimidine (Eq. 54), and a 2,6-bis(1H-benzo[d]imidazol-1-yl)pyrazine (Eq. 55) give iron(II) dicationic bis-CNC-carbene-pincers, which, compared to the pyridine analogs, are characterized by stabilized excited states, a real prospect for photo-sensitizing applications (2019D10915).

ð53Þ

ð54Þ

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ð55Þ 2-(4H-1,2,4-Triazol-30 -yl)-pyrazine, 3-(4-methylphenyl)-pyrazin-2-yl1,2,4-triazole, and 3-(4-methoxyphenyl)-pyrazin-2-yl-1,2,4-triazole (Eq. 56) form ruthenium(II) mono-NN-chelates (2006ICA736).

ð56Þ

3,6-Di(3-((1-Ethyl-5-methylpyrazol-3-yl)methyl)-1-imidazolium) pyridazine dihexafluorophosphate in a transmetalation reaction affords a dicationic ruthenium(II) complex represented by two CN-carbene-chelates, one formed by the nitrogen atom of the pyrazolyl ring and carbene center of the imidazol-2-ylidne moiety and another by the nitrogen atom of the pyridazine ring and carbene center of another imidazol-2-ylidene ring (Eq. 57) (2017EJI616). The product is characterized by anticancer properties.

ð57Þ

Pyrimidine-functionalized imidazolium salts in a transmetalation process give cationic iridium(III) and ruthenium(II) CN-carbene-chelates, which are catalysts for transfer hydrogenation and alkylation (Eq. 58) (2009 CRV3612, 2009OM321).

Organometallic complexes of functionalized chelating azines

245

ð58Þ

3-Methyl-1-(pyrimidin-2-yl)imidazol-2-ylidene, depending on the ratio of the reactants, gives dicationic ruthenium(II) CN-bis- or monocarbenechelates (Eq. 59) (2015BJOC1786). The monochelate substitutes one acetonitrile ligand for triphenylphosphine or two such ligands for 1, 10-phenanthroline.

ð59Þ 3-Methyl-4-phenyl-1-(pyrimidin-2-yl)-1H-1,2,3-triazolium salts in a transmetalation reaction give cationic ruthenium(II) and osmium(II) CN-carbene-chelates, which are catalysts for transfer hydrogenation (Eq. 60) (2016D15983).

ð60Þ

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Alexander P. Sadimenko

3,6-Bis(N-(pyridylmethyl)imidazolylidenyl)pyridazine gives a ruthenium(II) dinuclear tetracarbene-chelate with bridging chloride ligand, a dinuclear palladium(II) allyl biscarbene chelate, in which the pyridazine ring is out of coordination, and a trinuclear copper(II) complex with a triangular unit bound by three 3-(N-(pyridylmethyl)-imidazolylidenyl)6-(N-(pyridylmethyl)-imidazolylonyl)-pyridazines, where one imidazolylidene is oxidized to imidazolone (Eq. 61) (2012OM6614, 2014MI4). If preparation of the palladium(II) or nickel(II) dinuclear allyls occurs in the presence of methanol, CN cleavage between the pyridazine and the imidazole ring or methoxylation of the pyridazine ring occurs. This is followed by formation of either a palladium(II) complex with the bridging μ-η2(NN)bridging pyridylmethyl imidazolyl ligands or a nickel(II) biscarbene-chelate, in which methoxylated pyridazine does not participate in coordination (Eq. 62). The ruthenium(II) product is a catalyst for oxidation.

ð61Þ

Organometallic complexes of functionalized chelating azines

247

ð62Þ

Bispyrimidylimidazolium salts with a methylene spacer either in a transmetalation reaction or using metal powder under air give dicationic iron(II), cobalt(II), and nickel(II) bis-CN-carbene-chelates (Eq. 63) (2009AGE5513).

ð63Þ 0

N-Methyl-N -(2-pyrimidinyl)imidazolium hexafluorophosphate gives a cationic cobalt(III) C,N-carbene-chelate (Eq. 64). N-Picolyl-(2-pyrimidinyl) imidazolium hexafluorophosphate yields a dicationic cobalt(III) triscarbenechelate, in which one of the pyridine rings is not coordinated (Eq. 65). Bis(N-2-Pyrimidylimidazolylidenyl)methane dihexafluorophosphate affords first a cobalt(III) cationic triscarbene-chelate, of which two chelate rings are CN and the third is CC, and subsequently a tricationic cobalt(III) tetrachelate (2CN + 2CC), in which two pyrimidine rings are not coordinated (Eq. 66) (2009D7008). The products are catalyst precursors for Kumada–Corriu cross-coupling and Grignard reactions.

ð64Þ

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ð65Þ

ð66Þ

3,6-Bis(N-methylimidazolium)pyridazine dichloride and 3,6-bis(N-nbutylimidazolium)pyridazine dichloride (2007TL8366) give dinuclear silver tetracarbenes and by a transmetalation reaction ruthenium(II), rhodium(III), and iridium(III) CN-monocarbene-chelates (Eq. 67). In these chelates one of the arms remains uncoordinated and protonated (2012POL(34)176).

ð67Þ

A 1,2,4-triazolium salt containing a pyrimidyl functional group gives an iridium(I) monocarbene and at the next stage the cationic CN-carbene chelate, which is a catalyst for hydrogenation (Eq. 68) (2007OM855).

Organometallic complexes of functionalized chelating azines

249

ð68Þ

1,3-Bis(pyrimidine-2-yl)-imidazolium bromide in solution gives coexisting iridium(I) monocarbene and CN-monocarbene-chelate products (Eq. 69) (2012IC12767).

ð69Þ

1-Methyl-3-(50 -pyridmidyl), or 1-methyl-3-(50 -pyridimidyl-20 trifloromethyl) benzimidazolium and imidazolium iodides are ancillary ligands, and 2-(2,4-difluorophenyl)pyridine is a cyclometalating ligand in iridium(III) neutral blue or greenish-blue phosphorescent complexes (Eq. 70) (2015IC161).

ð70Þ

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2-(1H-Tetrazol-5-yl)pyrazine is an ancillary and 2-phenylpyridine is a cyclometalating ligand in a heteroleptic iridium(III) complex that is characterized by red emission (Eq. 71) (2008IC10509).

ð71Þ

2-Phenylpyridine, 2-(2,4-difluorophenyl)pyridine (Eq. 72), or 1-benzyl-4-phenyl-1,2,3-triazole (Eq. 73) are cyclometalating and 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole, 1-benzyl-4-(pyrimidin-2-yl)-1,2, 3-triazole, or 1-benzyl-4-(pyrazin-2-yl)-1,2,3-triazole are ancillary ligands in the cationic phosphorescent iridium(III) complexes, and pyrimidine-based complex exhibits dual emission (2020IC1785).

ð72Þ

ð73Þ 1-(Pyrimidin-2-yl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) propyl)-1H-imidazol-3-ium bromide yields cationic silver(I) biscarbene and gold(I) monocarbene, but ruthenium(II) cationic and palladium(II) neutral CN-monocarbene-chelates (Eq. 74) (2015D7139).

Organometallic complexes of functionalized chelating azines

251

ð74Þ 2,6-Bis(alkylimidazol-2-ylidene)pyrazine ligands give ruthenium(II) dicationic tetra-CN-carbene-chelates (Eq. 75) (2012OM4980, 2016 D1299, 2016TOC45). Protonation using perchloric acid (not shown) and methylation using methyl triflate occur at the uncomplexed pyrazine nitrogen atoms.

ð75Þ

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2,4-Di(1H-imidazol-1-yl)-6-methoxy-1,3,5-triazine substitutes pyridine in monocobaloxime to yield a ligand-bridged bicobaloxime (Eq. 76) (2013ICC(27)1).

ð76Þ

Ligands based on pyridazines with two imidazolium groups tethered to the 3- and 6-positions of the azine ring give a palladium(II) allyl monocarbene, which is a precatalyst for Heck CdC coupling (Eq. 77) (2008CEJ5112). However, if the salt is taken not as the chloride but the tetrafluoroborate or hexafluorophosphate, and if the monocarbene is reacted with silver tetrafluoroborate or hexafluorophosphate, a palladium CN-carbene chelate is afforded. Moreover, these salts serve as precursors for the mercury(II) dicationic biscarbene, which can in turn be the source for the palladium(II) CN-carbene-chelate. The palladium(II) monocarbene slowly rearranges to the dinuclear palladium(II) complex, in which one palladium-allyl moiety is coordinated to a carbene center and another to the pyridazine nitrogen atom and subsequently to the trinuclear complex containing a CN-carbene bischelate. The other two palladium sites are

Organometallic complexes of functionalized chelating azines

253

abnormally coordinated to the imidazol-2-ylidene rings through the C4-carbon sites.

ð77Þ 3,6-Bis(N-n-butylimidazolium)pyridazine dichloride with silver(I) oxide gives a biscarbene where the azine ring is out of coordination (Eq. 78) (2008OM4166). The same salt as the dihexafluorophosphate with palladium(II) acetate or a combination of silver(I) and palladium(II) agents gives two different products of CdN cleavage and forms two different palladacycles. They consist of a Pd2C2N2 core and anionic imidazoles coordinated in an NC5- or NC2-fashion. In the case of palladium acetate, the CdN bond cleavage and palladation are accompanied by addition of the CdH bond of the imidazole ring to the CN triple bond of acetonitrile. Both palladacycles are catalysts for Heck-Mizoroki and Suzuki coupling.

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ð78Þ 3-Substituted 1-(pyrimidin-2-yl)imidazolium salts give a wide variety of nickel(II) products depending on the nature of the substituent and anion (2009OM1336). The 3-methyl hexafluorophosphate gives a fivecoordinate dicationic product consisting of a bis-CN-carbene-chelate and C-coordinated third carbene ligand (Eq. 79). 3-Ethyl, 3-benzyl, and 3-nbutyl hexafluorophosphates give five-coordinate cis-bis-CN-carbene-chelates coordinating acetonitrile, whereas 3-isopropyl hexafluorophosphate gives a trans-analog (Eq. 80). If the reaction sequence involves isolation of the silver biscarbene, then the n-butyl hexafluorophosphate yields the six-coordinate dicationic product, a tris-CN-carbene-chelate. 3-(Pyridin-2-ylmethyl)-1(pyrimidin-2-yl)imidazolium hexafluorophosphate yields the four-coordinate dicationic nickel(II) cis-bis-CN-carbene-chelate, in which pyrimidinyl moieties are not engaged in coordination (Eq. 81). 3-(20 ,60 -Diisoprylphenyl)- and 3-mesityl hexafluorophosphates afford hexacoordinate dicationic nickel(II) trans-CN-carbene-chelates carrying two acetonitrile or one acetonitrile and one water ligand, respectively (Eq. 82). Finally, the N-isopropyl chloride forms a four-coordinate cationic nickel(II) trans-CN-carbene chloride (Eq. 83).

Organometallic complexes of functionalized chelating azines

255

ð79Þ

ð80Þ

ð81Þ

ð82Þ

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ð83Þ

1-n-Butyl-3-(2-pyrimidyl)imidazolium hexafluorophosphate gives a silver(I) cationic biscarbene and by transmetalation a five-coordinate palladium(II) CN-biscarbene-chelate (Eq. 84) (2008D4015, 2009CRV 3561, 2014MI2). 1-(2-Picolyl)-3-(2-pyrimidyl)imidazolium hexafluorophosphate gives dinuclear dicationic silver complexes, in which one silver is in a biscarbene environment and another is NN-coordinated to the opposite pyridine heteroatoms, whereas the pyrimidine ring is not coordinated (Eq. 85). Transmetalation leads to a square planar dicationic palladium(II) cis-CN-carbene chelate again without involvement of the pyrimidine ring. Both palladium(II) products are catalysts for Heck coupling.

ð84Þ

ð85Þ

Organometallic complexes of functionalized chelating azines

257

3-Substituted-1-(pyrimidin-2-yl)imidazolium salts, depending on the nature of the 3-substitutent, give cis- (methyl) or trans- (benzyl) dicationic or trans-monocationic (ethyl) palladium pentacoordinate bis-CNcarbene-chelates (Eq. 86) (2009D7045). The same salts with benzyl and mesityl substituents but with a chloride anion give neutral palladium(II) mono-CN-carbene-chelates, which are catalysts for Suzuki and Hiyama coupling (Eq. 87).

ð86Þ

ð87Þ 2-(Pyrimidine-2-yl)imidazo[1,5-a]pyridin-4-ylium hexafluorophosphate affords a cationic palladium(II) mixed monocarbene and CN-carbene chelate, which is a catalyst for Suzuki–Miyaura CdC coupling (Eq. 88) (2014ICA(411)165).

ð88Þ

1-(2-Pyrimidyl)-3-substituted imidazolium chlorides give various palladium(II) CN-carbene-chelates by either transmetalation or direct interaction of components (Eqs. 89 and 90) (2016BJO1557). When the threesubstituent is methyl and the salt is taken as hexafluorophosphate, the cationic palladium(II) carries two ligands; one is CN-chelated and the other coordinated as a monocarbene (Eq. 91) (2017ACS(CAT)3004).

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ð89Þ

ð90Þ

ð91Þ

N-Methyl-N-(2-pyrimidinyl)imidazolium hexafluorophosphate gives a platinum(II) CN-carbene cationic bischelate (Eq. 92); bis(N-2pyrimidylimidazol)methane dihexafluorophosphate yields a dicationic triscarbene-chelate (Eq. 93) (2010D4198). The products are catalyst precursors for hydrosilylation.

ð92Þ

ð93Þ

N-2-Pyrimidyl imidazolium salts give cationic silver(I) biscarbenes and palladium(0) CN-carbene-chelates, which are catalysts for transfer hydrogenation (Eq. 94) (2010OM4555).

Organometallic complexes of functionalized chelating azines

259

ð94Þ Bis(2-pyrimidylimidazolium)methylene dihexafluorophosphate gives a heterotrimetallic cluster featuring a linear silver–platinum–silver array (Eq. 95) (2014ICC(47)45).

ð95Þ

1-Aryl-3-pyrimidylimidazolium hexafluorophosphates, depending on the nature of the aryl substituents, produce either complexes in which one ligand is bidentately CN-coordinated and another is bound in a monodentate fashion (Eq. 96), or, for aryl substituents with higher steric demand, complexes in which both ligands form CN-carbene-chelates (Eqs. 97 and 98) (2018D16638). All the products are catalysts for hydroarylation.

ð96Þ

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Alexander P. Sadimenko

ð97Þ

ð98Þ

1-(1-Hydroxy-4-methylpentan-2-yl)-3-(pyrimidin-2-yl)-1H-imidazol-3ium chloride, and 1-(1-hydroxy-3-phenylpropan-2-yl)-3-(pyrimidin-2-yl)1H-imidazol-3-ium chloride give palladium(II) CN-carbene-chelates, which are catalysts for arylation (Eq. 99) (2015RSC107601). ð99Þ Raney nickel is a carbene-transfer agent in a number of preparations of carbenes and carbene chelates (2012OM282). 3-Pyrimidyl-1-(pyridin-2ylmethyl)imidazolium hexafluorophosphate yields nickel(II) and palladium(II) CN-biscarbene-chelates where the pyrimidine ring is out of coordination, but a ruthenium(II) monocarbene bis CNN-carbene-pincer where both nitrogen heteroatoms of the pyridine and pyrimidine ring participate in coordination (Eq. 100).

ð100Þ

Organometallic complexes of functionalized chelating azines

261

A dinuclear platinum complex of a pyrimidin-2-yl derivative is dicationic and follows from the metal transfer (Eq. 101) (2011IC8671).

ð101Þ 2-(3-Mesitylimidazolium)pyrimidine chloride in a direct reaction gives a palladium(II) CN-monocarbene chelate or a silver(I) monocarbene (Eq. 102) (2008JOM3273, 2009CRV3561). The latter serves as a precursor in a series of transmetalation reactions affording: (i) another palladium(II) CN-monocarbene chelate; (ii) a cationic palladium(II) CN-biscarbenechelate; (iii) a dinuclear dicationic nickel(II) CN-biscarbene-chelate with chloride bridges; and (iv) a tetracationic adduct of dinuclear nickel(II) CN-biscarbene-chelate with iodide bridges and a mononuclear nickel(II) CN-biscarbene-chelate.

ð102Þ

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1-(2-Pyrimidyl)-3-(aryl or alkyl) imidazolium chlorides give silver(I) monocarbenes and in a transmetalation reaction palladium(II) CN-carbene-chelates (Eq. 103) (2009OM2142, 2015MI1). For a small substituent (e.g., methyl) there are two ligands in the coordination sphere of the cationic palladium(II) complex with carbene and CN-carbene chelate type of coordination (Eq. 104). These products are catalysts for Mizoroki-Heck coupling.

ð103Þ

ð104Þ

1-(2-Pyrimidyl)-3-methylimidazolium chloride in a transmetalation reaction gives a silver(I) monocarbene and subsequently a cationic platinum(II) coordinated to two ligands, one as monocarbene and the other as a CN-carbene chelate (Eq. 105) (2012JOM(701)56). Ligand precursors with bulkier substituents in the 3-position (cyclohexyl, mesityl, 2,6-diisopropylphenyl) give exclusively neutral platinum(II) CN-carbenechelates (Eq. 106).

ð105Þ ð106Þ

Organometallic complexes of functionalized chelating azines

263

Unsymmetrical NCN-pincer forming ligands consist of 1,2,3-triazole, imidazolium or benzimidazolium, and pyrimidine arms (2017D586). In the case of imidazolium precursors cationic NCN nickel(II) pincers are formed (Eq. 107). In the case of a benzimidazolium chloride, depending on the ratio of the reactants, mono- or bis-NCN-nickel(II) pincers are afforded (Eq. 108). The monocationic benzimidazole-2-ylidene pincer is noted for catalytic activity in Suzuki–Miyaura coupling.

ð107Þ

ð108Þ

4-(2-Dialkylamino)pyrimidinyl functionalized 3-mesitylimidazolium chlorides give silver(I) monocarbenes and in a transmetalation reaction palladium(II) CN-carbene-chelates (Eq. 109) (2017CEJ14563). In a direct reaction of the imidazolium salts with palladium(II) chloride, pyridine CC-carbene-chelates are afforded. The reactivity of the piperidinyl CCcarbene-chelate includes reversible dissociation to yield dinuclear palladium(II) bis-CC-carbene-chelates with chloride bridges and association occurring upon heating. Hydrochloric acid at pH 4 gives a palladium(II) monocarbene coordinated to pyridine which at pH 2 yields a palladium(II) CN-carbene-chelate. All palladium products are catalysts for Suzuki– Miyaura cross-coupling.

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ð109Þ 2,6-Bis(N-methylimidazolium)pyrazine dichloride (and 2,6-bis (N-methylbenzimidazolium)pyrazine dichloride) gives a tetranuclear palladium(II) complex, in which two terminal PdCl2(DMSO)2 units are η1(C)-coordinated via the carbene centers. The remaining part of each ligand comprising pyrazine and the second imidazol-2-ylidene moiety form μ2-η1(N):η1(C) bridges between the central palladium(II) sites (Eq. 110) (2012ICA(383)83). Both the imidazolium and benzimidazolium products are catalysts for Suzuki coupling.

ð110Þ

Organometallic complexes of functionalized chelating azines

265

N-(3-Chloro-2-quinoxalinyl)-N0 -arylimidazolium salts afford zwitterionic palladium(II) complexes with η1(C)-coordination mode and the imidazolium counterpart intact (Eq. 111) (2017D8598). They are catalysts for Suzuki–Miyaura cross-coupling.

ð111Þ

Pyridazine-bridged imidazolium-pyrazole hexafluorophosphate initially gives a silver(I) biscarbene (Eq. 112) (2011EJI3340). At the next stage the dinuclear complex, in which additional silver(I) coordinates to the two pyrazole rings, rearranges to a product in which each silver ion is bound to the pyrazole nitrogen and carbene carbon with secondary bonding to pyridazine nitrogens. Finally a trinuclear complex, in which a third silver(I) ion is accommodated between the pyridazine nitrogens, results.

ð112Þ

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3,6-Bis(N-(pyridylmethyl)imidazolium)pyridazine hexafluorophosphate forms a hexanuclear silver(I) cluster in which six silver atoms are bridged by four carbene ligands but the pyridazine heteroring remains uncoordinated (Eq. 113) (2007OM3660).

ð113Þ

3-(3-(2,4,6-Trimethylphenyl)-3H-imidazolium-1-yl)-6-(3,5-dimethylpyrazol-1-yl)-pyridazine gives silver(I) and gold(I) biscarbenes in transmetalation reactions (Eq. 114) (2012OM5025). At the next stage biscarbene bis-NN-chelates for the heterodinuclear gold(I)-copper(I) or silver(I) complexes are formed. Another product is a heterotrinuclear tricationic complex, in which gold(I) is in a biscarbene environment, one silver (I) is bis-NN-chelated and one silver is sandwiched between pyridazine nitrogen heteroatoms.

Organometallic complexes of functionalized chelating azines

267

ð114Þ

4,6-Bis(1-substituted-imidazolium-3-yl)-1,3,5-triazine-2-ol salts give zwitterionic dinuclear silver biscarbenes of the type di-4,6-bis (1-substituted-imidazol-2-ylidene-3-yl)-5H-1,3,5-triazin-2-one-5-ide disilver, which are deep-blue emitters (Eq. 115) (2011OM6674). The di (4,6-bis(1-tert-butylimidazol-2-ylidene-3-yl)-5H-1,3,5-triazin-2-on-5-ide) silver complex can be transmetalated to yield an identical gold(I) product (2012OM3431).

ð115Þ

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Tri-imidazolium salts linked by 1,3,5-triazine give tricationic trinuclear silver(I) biscarbenes (Eq. 116) (2018AGE15767).

ð116Þ

Imidazolium 1,3,5-triazines bearing piperidine and morpholine substituents give silver(I) monocarbenes with antimicrobial and antifungal activity and gold(I) mono- and biscarbenes (Eq. 117) (2013D12370).

ð117Þ

Organometallic complexes of functionalized chelating azines

269

1,10 -(2,6-(4-Diethylaminotriazinyl))di(3-n-butylbenzimidazolium) bis (hexafluorophosphate) gives a dinuclear dicationic silver(I) tetracarbene and, by a transmetalation reaction, a dinuclear dicationic gold(I) tetracarbene along with minor amounts of the tetranuclear dicationic gold(I) hexacarbene (Eq. 118) (2016D1484). Transmetalation of the silver complex with a palladium(II) complex yields the mononuclear cationic palladium(II) CNC-carbene-pincer. Triazinyl-containing silver and gold complexes adopt a twisted, helical conformation.

ð118Þ

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3,5-Bis(N-pyrimidylimidazoliummethyl)pyrazolate) hexafluorophosphate yields a tetranuclear tetracopper(II) complex with two bridging hydroxides, which is a catalyst for arylation (Eq. 119). (2010OM1457).

ð119Þ

2-(1-Methylimidazolium-2-yl)pyrimidine (Eq. 120) and 3,6-bis (1-methylimidazolium-3-yl)pyridazine hexafluorophosphates (Eq. 121) produce helical mono- and dinuclear mercury(II) carbenes (2001JOM(617)364).

ð120Þ

ð121Þ

3,6-Bis(imidazolium-3-yl)pyridazine dications give dinuclear tetracationic mercury(II) tetracarbenes with double helical bimetallic arrangements (Eq. 122) (2006ICA4891). Nitrogen heteroatoms do not participate in the coordination.

Organometallic complexes of functionalized chelating azines

271

ð122Þ 1-Acetamido-3-(2-pyrazinyl)-imidazol-2-ylidene (Eq. 123) and 1-acetamido-3-(2-pyrimidyl)-imidazol-2-ylidene (Eq. 124) give dicationic mercury(II) cis-biscarbenes, whereas the pyrimidyl ligand yields a cationic silver(I) trans-biscarbene (Eq. 125) (2007CEC278).

ð123Þ

ð124Þ

ð125Þ

3,6-Bis(4,5-dihydro-4-isopropyloxazol-2-yl)pyridazine gives palladium (II) mono- and bis-NN-chelates depending on the ratio of the reactants (Eq. 126) (2001JOM(627)121).

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ð126Þ

2,3-Bis((1-n-propylbenzimidazolium)methyl)quinoxaline dihexafluorophosphate gives silver (I) and mercury(II) dicationic tetracarbenes and donor sites of the azine ring are not engaged in coordination (Eq. 127) (2013OM3493). 2,3-Bis((1-pyridylbenzimidazolium)methyl)quinoxaline dihexafluorophosphate also gives a silver(I) dicationic tetracarbene, but with NiCl2 gives a nickel(II) dicationic bis-CN-carbene-chelate in which the pyridine ring nitrogens are involved (Eq. 128).

ð127Þ

Organometallic complexes of functionalized chelating azines

273

ð128Þ

5. Other heterocyclic functionalities 2-(Benzothiazole)-2,3-dihydro-1H-perimidine forms an NN-rhenium(I) tricarbonyl chelate (Eq. 129) (2016POL(117)755). 2-Pyrimidylbenzothiazole ligands as potential chemotherapeutics have been reviewed (2020ICA119302).

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ð129Þ

6. Azines annulated with the other heterocycles 1,2,4-Triazolo[1,5-a]pyrimidine and 5,7-dimethyl-1,2,4-triazolo [1,5-a]pyrimidine with diorganotin dichlorides give addition compounds with organotin: ligand stoichiometry 1:2 and 1:1, depending on the steric bulk of the substituents at the tin atom, and coordinate to tin through the nitrogen atom of the azole ring (Eq. 130) (2006JOM693).

ð130Þ

1,2,4-Triazolo-[1,5-a]pyrimidine gives a rhenium(I) complex where two ligands are monodentately coordinated via nitrogen atoms of the triazole rings (Eq. 131) (2009POL2571).

ð131Þ

7-Hydroxy-5-methyl[1,2,4]triazolo[1,5-a]pyrimidine gives an N-coordinated ruthenium(II) complex through a nitrogen of the triazole ring (Eq. 132) (2010POL1023).

Organometallic complexes of functionalized chelating azines

275

ð132Þ

[(η6-Biphenyl)Ru(en)]2+ binds only to N7 of guanosine (2), to N7 and N of inosine (3–5), and to N3 of thymidine (6) (2002JA3064, 2003JA173). 1

1,2,4-Triazolo[1,5-a]pyrimidines give monodentately N-coordinated ruthenium(II) complexes (Eq. 133) (2016POL(109)33).

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ð133Þ

Ruthenium(II) arene acetylacetonate complex has a high affinity toward derivatives of guanosine coordinating them via the nitrogen atom of the imidazole ring (Eq. 134) and with respect to adenosine when coordination is possible via the nitrogen atom of both the imidazole and pyrimidine ring (Eq. 135) (2004CEJ5173, 2018EJI3522).

ð134Þ

ð135Þ

Polycyclic fused imidazolium salts featuring a dibenzo[a,c]phenazine moiety give rhodium(I) and iridium(I) monocarbenes (Eq. 136) (2014 JOM(749)134).

ð136Þ

1,3,7,9-Tetramethyl-6-oxopurinediium bistriflate gives rhodium(I) biscarbenes where both imidazol-2-ylidene and pyrimidin-2-ylidene carbene centers are engaged (Eq. 137) (2015EJI2416).

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ð137Þ

Pyridazine annulated bis(N-heterocyclic carbene) ligand as a dicationic salt gives rhodium(I) CC biscarbene-chelates, and in the case of the di-npropyl precursor the process of deprotonation of the imidazolium rings is stepwise (Eq. 138) (2012OM7532). The products are catalysts for transfer hydrogenation.

ð138Þ

The pyridazine-based bisimidazolium salt (2010MI1) with silver(I) oxide or copper(I) oxide gives binuclear biscarbenes and by transmetalation a gold(I) biscarbene (Eq. (139) (2012OM739). With a rhodium(I) precursor, a mononuclear rhodium(I) CC-carbene chelate results.

ð139Þ

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The range of such complexes can be extended to biscarbenes of copper(I), silver(I), and gold(I) prepared from the benzyl substituted pyridazine annulated bisimidazolium salt (Eq. 140) (2012OM7893).

ð140Þ The iridium(III) cyclometalated complex of 2-phenylpyridine forms an adduct with 9-ethylguanine coordinated via the nitrogen heteroatom of the imidazole counterpart, which has anticancer properties (Eq. 141) (2011IC5777).

ð141Þ

Caffeine with cobalt(I) complex [Co(Me)(PMe3)4] undergoes CdH activation to yield 8-caffeinyl cobalt(I), which with phenyl or 2-pyridyl bromide affords a cobalt(II) bromide (Eq. 142) (2013ICC(30)139).

ð142Þ

Organometallic complexes of functionalized chelating azines

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A caffeine-derived imidazolium triflate gives rhodium(I) and ruthenium (II) monocarbenes, of which the rhodium(I) complex has anticancer properties (Eq. 143) (2016D13161).

ð143Þ Quinoxalino-annulated imidazol-2-ylidenes form rhodium(I) monocarbene and silver(I) biscarbene (Eq. 144) (2006CC640, 2007CCR642). Two similar annulated structures have the same composition (Eq. 145) (2004OM1928, 2007CCR884).

ð144Þ

ð145Þ

The purines 8-chlorocaffeine (Eq. 146) or 8-bromo-9-methyladenine (Eq. 147) oxidatively add platinum(0) tetrakis-triphenylphosphine to the C8  halide bond to yield platinum(II) protic carbenes through the stage of C-bound ylidene with further protonation (2014JA7841).

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ð146Þ

ð147Þ 8-Bromo-20 -deoxy-30 ,50 -di- and tri-O-acetylguanosine (Eq. 148) as well as 8-bromo-20 -deoxy-30 ,50 -di- and tri-O-acetyladenosine (Eq. 149) enter into C8  Br oxidative addition with palladium(0) precursor to give the C8-palladated azolates (2018OM4181).

ð148Þ

ð149Þ

Imidazo[1,5-b]pyridazin-7-amines form iridium(I) PN-chelates, which are catalysts for alkylation (Eq. 150) (2014CEJ13279). The amido group is deprotonated and the negative charge is spread over the PNCN framework.

ð150Þ

A 1,3,5-Triazine annulated nitrogen heterocyclic carbene possesses weak σ-donor and pronounced π-acceptor properties in its adducts and chelates

Organometallic complexes of functionalized chelating azines

281

(2015OM5335). In the silver adduct and in the rhodium(I) diene and dicarbonyl it functions as a monodentate ligand (Eq. 151). In the cationic complex it forms a CN-chelate. In the dicationic complex three bridging ligands coordinated to the rhodium sites group in the solid state around the BF 4 anion, and the resultant dication is stabilized by anion—π-interactions.

ð151Þ

7. Conclusions 1. Thienyl, dithienyl, indolyl, and carbazolyl substituted azines give mono-, bis-, and triscyclometalated complexes, and when dinuclear complexes are formed, the coordination situation may be supplemented by the bridging chloride, carbon monoxide, or acetate bridging groups. Pyrazolyl substituted azines form mono- and bis-NN-chelates, dinuclear complexes with one or two such chelates; NN-chelation may occur along with cyclometalation to afford CNN-pincers. In the case of one azine core and two pyrazolyl groups, NN-chelation may be over pyrazolyl nitrogen atoms only or one pyrazolyl and one azinyl nitrogen. For combination of pyrazolyl, azinyl, and pyridyl moieties, only

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pyrazolyl and pyridyl functionalities participate in NN-coordination. Imidazolyl- or 1,2,3-triazolyl substituted azines form NN-chelates. Imidazol-2-ylidene substituted azines give CN-mono-, bis-, tris-, and tetracarbene-chelates, and when there are two such substituents, CNC-carbene-pincers are generated. For a combination of pyrazolyl, imidazol-2-ylidene, an pyridazine two types of CN-carbene-chelates co-exist, pyrazolyl-carbene and pyridazine-carbene. Tetracarbene chelation is often combined with the chloride bridge formation. In the presence of pyridyl groups, pyrazine may be out of coordination. Chemical transformations observed in the organometallic azine chelates include oxidation of imidazol-2-ylidene into imidazolone, methoxylation of the azine ring, cleavage of the CdN bond between azine and imidazole ring, notably in the case of palladacycle formation. Monocarbene formation is possible but often in combination with chelation. There are specific examples of CC-coordinated cyclometalating ligands or CC-carbene-chelates. Dinuclear complexes often contain μ2-η1(N):η1(C)-bridges. Complexes of coinage metals often contain only carbene functions, although cases are known when silver is accommodated between two pyridazine nitrogens. 2. In most cases when 1,2,4-triazole is annulated to pyrimidine, coordination is over the nitrogen atom of the azole counterpart. The same occurs in guanosine but in adenosine both rings appear to be active. If in the annulated proligand, one of the counterparts is an imidazolium ring, in the complex the only donor center is the carbene carbon. If, however, both azole and azine rings work as carbenes, coordination via the carbene centers takes place in both rings.

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Index Note: Page numbers followed by “f ” indicate figures, “t” indicate tables, and “s” indicate schemes.

A 3-Acetamido-5-acetoxybenzofuran, 100–102, 101s 1-Acetamido-3-(2-pyrazinyl)imidazol-2-ylidene, 271 1-Acetamido-3-(2-pyrimidyl)imidazol-2-ylidene, 271 3-Acetyl-5-hydroxy-2-methylnaphtho [1,2-b]furan, 84–85, 84s 3-Acetyl-6-hydroxy-quinoline, 131, 131s Acyclic enamines, 97–100 Aggarwal synthesis, 177–178, 178s All-endo polyepoxide opening cascade reaction, 207, 207s All-exo polyepoxide ring opening reaction, 161–162, 162s 2-Allylaminoindole, 110, 110s Allylpalladium(II) NN-chelates, 239–240 2-Amino-benzo[g]indole, 110–111, 111s 1-Amino-6-hydroxy-2-methyl3-nitroindole, 120, 121s Aminoimidazoles, 191, 192s Annelated 5-hydroxybenzofurans, 142 Annelated 5-hydroxyindoles, 138–139 Annelated pyrimido[4,5-b]indoles, 95–96, 95–96s Anti-Nenitzescu reaction, 113–114, 114–115s Apaziquone, 145–146, 146s Arbidol, 66–67, 68f, 146–147, 146s Aromatic amines, 125–130 1-Aryl-3-pyrimidylimidazolium hexafluorophosphates, 259–260 3-Arylquinolin-4(1H)-ones, 199, 199s Aurones, 168, 168s 2-Azabicyclo[3.3.1] nonane (2-ABN), 198, 198s Azaenamine hydroquinone, 116, 116s Aza enamines, 115–120 Aza-Nenitzescu reaction, 115–120 Azepanes, 210

Azepines, 208–209 Azetidines, 174, 175s

B Benzofurans, 143, 143s, 170–172 3H-Benzofuro[3,2-e]indazoles, 118–120, 119s Benzofurooxepines, 172, 172s Benzo[g]pyrimido[4,5-b]indoles, 128, 128s Benzoindolines, 182, 182s 1,4-Benzoquinones, 76–82 2-(Benzothiazole)-2,3dihydro-1H-perimidine, 273–274 Benzoxazepine, 211s, 212 Benzoxazines, 206, 206s N-Benzoyl-1-amino-5-hydroxybenzo[g] indole, 99, 99s N-Benzoyl-1-amino-5-hydroxyindole, 99, 99s Benzpiperazines, 203, 203s Bicyclic organosilicon azoles, 49–50, 49–50s 1,3-Bis(pyrimidine-2-yl)-imidazolium bromide, 249 Bisindoles, 72–73, 72s, 112–113 Bis(2-pyrimidylimidazolium)methylene dihexafluorophosphate, 259 2,6-Bis(N-methylimidazolium)pyrazine dichloride, 264 3,5-Bis(N-pyrimidylimidazoliummethyl) pyrazolate) hexafluorophosphate, 270 3,6-Bis(3,5-dimethylpyrazol-1-yl) pyridazine, 230 3,6-Bis(4,5-dihydro-4-isopropyloxazol2-yl)pyridazine, 271–272 3,6-Bis(N-(pyridylmethyl)imidazolylidenyl) pyridazine, 246–247 3,6-Bis(imidazolium-3-yl)pyridazine dications, 270–271 3,6-Bis(N-(pyridylmethyl)imidazolium) pyridazine hexafluorophosphate, 266 289

290 3,6-Bis (1-methylimidazolium-3-yl) pyridazine hexafluorophosphates, 270 Bis(1,2,3-triazole)pyrimidines, 243 2,3-Bis(1-methylimidazol-2-yl) quinoxaline, 242 2,3-Bis((1-n-propylbenzimidazolium) methyl)quinoxaline dihexafluorophosphate, 272–273 3,6-Bis(2-thienyl)-1,2,4,5-tetrazine, 229–230 3,6-Bis(3,5-dimethylpyrazolyl)-1,2,4,5tetrazine, 236–237 4,6-Bis(1-substituted-imidazolium-3-yl)1,3,5-triazine-2-ol salts, 267 1,2-Bis-(trimethylsilyl)pyrazolium halogenides, 31, 31s Brominated benzofuran, 104s, 105–106 2-Bromo-5-(1H-pyrazol-1-yl)pyrazine, 231–232 Bufotenin, 66–67, 68f 1-n-Butyl-3-(2-pyrimidyl)imidazolium hexafluorophosphate, 256–257

C Carbazoles, 125–126, 126s Carbinolamines, 75–76 Catellani reaction, 212 CF3-heterocycles, 174, 174s Chelating azines, organometallic complexes of annulation, 274–281 five-membered monoheterocycles, 226–230 imidazole functionalities, 242–273 pyrazole functionalities, 230–242 tetrazole functionalities, 242–273 triazole functionalities, 242–273 3-Chloro-6-(3,5-dimethylpyrazol-1-yl) pyridazine, 238–239 9-(4-(4-Chlorophenyl)phthalazin-1-yl)9H-carbazole, 227–228 2-Chloro-3-(pyrazolyl)quinoxaline, 237 3-Chloro-6-(3-pyridyl-1-pyrazolyl) pyridazine, 233 2-Chloro-3-(3-(2-pyridyl)pyrazolyl) quinoxaline, 236 N-(3-Chloro-2-quinoxalinyl)-N0 arylimidazolium salts, 265

Index

3-Chloro-1,2,4-triazole-5-one, 48 4-Chloro-1-trimethylsilylpyrazole, 28–29, 29f Click reaction, 193 CN-carbene-chelates, 282 Cobalt(III) C,N-carbene-chelate, 247–248 Cyclic enamines, 121–125, 122s Cyclic tertiary enamines, 123, 124f

D Dehydropiperidines, 194, 194s 4-(2-Dialkylamino)pyrimidinyl functionalized 3-mesitylimidazolium chlorides, 263–264 5,7-Dichloro-6-hydroxyindoles, 139–140, 140s Diels–Alder reaction pathways, 104s, 105 Dienediamines, 105–107 1,10 -(2,6-(4-Diethylaminotriazinyl)) di(3-n-butylbenzimidazolium) bis(hexafluorophosphate), 269 Difluoropyrrolidines, 174, 174s Dihydrobenzofurans, 170, 174–175s 2,3-Dihydrobenzofurans, 100–102, 101s, 143, 143s Dihydrofurans, 166, 166s 2,5-Dihydrooxepines, 207, 207s Dihydropyrans, 194, 194–195s Dihydropyrroles, 179, 180s 4,5-Dihydroxyindoles, 140–141 5,5-Dimethyl-3,4-dihydro-5-silaoxazolo [2,3-d]-1-methyl-3-nitro-1,2,4triazolium chloride, 47s, 48 5,5-Dimethyl-3,4-dihydro-5-silaoxazolo [2,3-d]-3-nitro-1,2,4-triazole, 47s, 48 5,5-Dimethyl-3,4-dihydro-5-siloxano[2,3b]-1,2,4-triazole, 50–51, 51s 4,4-Dimethyl-5H-4-silaoxazolo[2,3-e]-4methyl-1,2,4-triazolium chloride, 46, 46s 5,7-Dimethyl-1,2,4-triazolo[1,5-a] pyrimidine, 274 Dioxanes, 201 4,9-Dioxobenzoindazole, 116s, 117 Dioxolanes, 161–169 3,6-Di(3-((1-ethyl-5-methylpyrazol-3-yl) methyl)-1-imidazolium) pyridazine dihexafluorophosphate, 244

291

Index

Disubstituted benzoquinones, 79–81 δ-lactones, 194–196 Doube Nenitzescu cascade reaction, 106, 106s Dronedarone, 133, 133s

E 4-Enamine 5-hydroxyindoles, 141, 142f Enamines, 96–130 Enamino benzoquinone hybrids, 130–131 Enamino hydroquinones, 73–74 Enamino quinones, 74–75 EO9. See Apaziquone Ethyl 2-(3-chlorobenzyl)-5hydroxy-1H-pyrrolo[2,3-f]quinolin3-carboxylate, 94, 95s Ethyl 5,6-dihydroxy-2,4,7trimethylindole-3-carboxylate, 81 Ethyl 5-hydroxy-2-methylindole3-carboxylate, 66, 67s

F Five-membered monoheterocycles, 226–230 Furans, 170–172 Furochromenones, 171, 171s Furo[3,2-h]isoquinolines, 94, 94s Fused azaheterocycles, 198, 199s Fused carbinolamines, 75f, 76 Fused imidazo-pyridinones, 192, 192s Fused tetrahydropyranones, 195, 196s Fused thiazolines, 190, 190s

G

γ-lactones, 161–169 Gold(I) biscarbene, 266–267 Gold(I) hexacarbene, 269 Goniothalesdiol A, 195, 195s

H Hainanerectamine A, 66–67, 68f Hainanerectamine B, 66–67, 68f Heterocyclic amines, 125–130 Heterocyclic benzoquinones, 88–96 Heterocyclic ketene aminals (HKAs), 111–112 5-Hydroxybenzofurans, 142–143

Hydroxybenzo[g]chromeno[4,3-b]indole, 124, 124s 5-Hydroxybenzo[g]indoles, 72s, 73, 87–88, 88s 1-Hydroxybenzotriazole-3-oxide, trimethylsilylation of, 35, 35s 3-Hydroxycarbazoles, 125–126, 126s 5-Hydroxy-1H-benzo[g]indole, 83–84, 83s 5-Hydroxyindole-3-carboxamides, 135, 135s 5-Hydroxyindoles antimicrobial activity, 144–145 antiviral activity, 146 natural and synthetic representatives, 66–67, 68f synthesis, 138–139 6-Hydroxyindoles, 135–136, 139–140, 140s 7-Hydroxy-5-methyl[1,2,4]triazolo[1,5-a] pyrimidine, 274–275 6-Hydroxy-pyrimido[4,5-b]indole, 127, 127s 5-Hydroxytryptophan, 66–67, 68f Hyrtinadine A, 66–67, 68f Hyrtiosin A, 66–67, 68f Hyrtiosin B, 66–67, 68f

I Imidazoazepines, 211, 211s Imidazo[1,5-b]pyridazin-7-amines, 280 Imidazo[4,5-g]indoles, 91, 91s Imidazoindole, 108, 108s Imidazole-2-one, trimethylsilylation of, 51, 51s Imidazoles, 191, 192s Imidazolidines, 192–193, 192s Imidazolidin-2-ones, 189, 189s 2-Iminothiazolidines, 189, 189s 4,7-Indazole quinone, 115, 116s Indole piperidines, 199–200, 200s Indoles, 180–182, 181–182s Indolines, 182, 182s Indolyl-benzofurans, 106, 106s Indometacin, 66–67, 68f 4-Iodo-1-trimethylsilylpyrazole, 29, 30f Iridium(III) CN-carbene-chelates, 244–245 Iridium(I) monocarbene, 249 Isochromanes, 196, 196s 4-Isochromanones, 195, 195s

292

K Ketene aminals, 108–114

L Lactams, 176, 176s Lewis-base-catalyzed reactions, 187–188, 188s LY311727, 145, 146s

M Manganese CN-carbene-chelate, 242 Melatonin, 66–67, 68f Mercury(II) carbenes, 270 Mercury(II) cis-biscarbenes, 271 Mercury(II) tetracarbenes, 270–271 2-(3-Mesitylimidazolium)pyrimidine chloride, 261 2-(1-Methylimidazolium-2-yl)pyrimidine, 270 3-Methyl-4-phenyl-1-(pyrimidin-2-yl)1H-1,2,3-triazolium salts, 245 3-Methyl-1-(pyrimidin-2-yl)imidazol-2ylidene, 245 1-Methyl-3-pyrimidylbenzimidazolium hexafluorophosphate, 243 1-Methyl-1,2,4-triazole-5-one, 43–47 4-Methyl-1,2,4-triazole-5-one, 43–47 N-Methyl-1,2,4-triazole-5-ones, 42, 43s Michael adducts, 126, 126s, 143 Molybdenum(0) tetracarbonyl NN-chelate, 242 Monoacetylated 4,5-dihydroxyindoles, 103, 103s Monometallic octahedral NN-chelate, 231–232 Monosubstituted benzoquinones, 77–79 Morphan, 198 Morpholines, 204–206, 206s Morpholinones, 206, 206s

N 1,4-Naphthoquinones, 82–88 Nb-catalyzed ring opening reaction, 194, 195s Nenitzescu indole synthesis antiinflammatory activity, 145 antitumor activity, 145–146

Index

antiviral activity, 146–147 applications, 144–147 improvements, 134–136 indolic structures, 141 medicinal chemistry, 147 modifications, 134–136 Nenitzescu–Allen mechanism, 70, 70s nonindolic compounds, 142–143 nonredox mechanism, 71–73, 71–72s reactants ratio influence, 138 solvent influence, 136–138, 137s Steck’s mechanism, 68–69, 69s unexpected products, 144 Nickel(II) CN-biscarbene-chelates, 260 Nickel(II) dicationic bis-CN-carbenechelate, 272–273 Nitro enamines, 100–104 Nitro enehydrazines, 120 3-Nitro-6-hydroxyindoles, 102, 102s 3-Nitro-1,2,4-triazole-5-one, 47–48 NN-chelation, 281 N,O,S-containing heterocyclic products five-membered rings, 161–193 seven-membered rings, 207–213 six-membered rings, 194–206

O O-acylated 4,5-dihydroxyindoles, 140–141 One-pot multicomponent Nenitzescu reaction, 134, 135s Organic silicon, chemical properties of, 2 Osmium(II) CN-carbene-chelate, 245 1,4-Oxathian-3-imines, 201–202 1,4-Oxathian-2-ones, 201–202 1,3-Oxathiolanes, 188–189, 188–189s 1,3-Oxathiolane-2-thiones, 188, 188s Oxazepanes, 210–211 Oxazepines, 211, 211s Oxazoles, 184–186 1,3-Oxazolidines, 183–184 Oxazolidin-2-imines, 189, 189s Oxazolidinones, 186–188 1,3-Oxazolines, 184–186 Oxepanes, 207, 207s

P Palladium(II) bis-NN-chelates, 240–241, 271–272

293

Index

Palladium(II) CN-biscarbene-chelates, 260 Palladium(II) CN-carbene-chelates, 257–258, 261–264 Palladium(II) CN-chelates, 230 Palladium(II) mono-NN-chelates, 241, 271–272 Partially hydrogenated pyrans, 194–196 Piperazines, 202, 202–203s Piperazinones, 203 Piperidines, 196–197, 197s Platinum(II) CN-carbenechelates, 262 Platinum(II) double CN-chelate, 229–230 Polycyclic fused imidazolium salts, 276 Polycyclic indoles, 124, 124s Polyethylene glycol-400, 136–137 Pyrazino[1,2-a]indoles, 147 Pyridazine-bridged imidazolium-pyrazole hexafluorophosphate, 265 Pyridines, 200–201, 201s Pyrimidine-based thiophene pyrazoles, 233 Pyrimidine-functionalized imidazolium salts, 244–245 2-(Pyrimidine-2-yl)imidazo[1,5-a]pyridin4-ylium hexafluorophosphate, 257 1-(Pyrimidin-2-yl)-3-(3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) propyl)-1H-imidazol-3-ium bromide, 250–251 Pyrimido[4,5-b]indole, 126, 126s N-2-Pyrimidyl imidazolium salts, 258–259 3-Pyrimidyl-1-(pyridin-2-ylmethyl) imidazoliumhexafluorophosphate, 260 1-(2-Pyrimidyl)-3-substituted imidazolium chlorides, 257–258 Pyrroles, 181, 181–182s Pyrrolidines, 172–174, 173–175s, 177–179, 177–179s, 196–197, 197s Pyrrolidinones, 175, 175s Pyrrolizidines, 175, 175s Pyrrolo[2,3-e]benzothiazoles, 91–92, 92s Pyrrolo[3,2-e]indazole, 90–91, 90s Pyrrolo[2,3-h]quinoline, 93, 93s

Q Quinolines, 200–201, 201s Quinonediimines, 131–133 Quinoneimines, 131–133

Quinoxalino-annulated imidazol-2ylidenes, 279

R Rhenium(I) bis-NN-chelates, 243 Rhenium(I) CN-carbene-chelates, 242–243 Ruthenium(II) cationic NN-bischelate, 236–237 Ruthenium(II) CN-carbene-chelates, 244–245 Ruthenium(II) dicationic tetra-CNcarbene-chelates, 251–252 Ruthenium(II) dinuclear tetracarbenechelate, 246–247 Ruthenium(II) mono-NN-chelates, 244 Ruthenium(II) NN-chelates, 232, 234–236

S Serotonin, 66–67, 68f Silver(I) biscarbenes, 265–268 Silver(I) monocarbenes, 261–264, 268 Silver(I) tetracarbene, 269 Solid supported Nenitzescu reactions, 135, 135s Spiro dihydroquinones, 130–131, 131s Spiromorpholines, 205, 206s Steck’s mechanism, 68–69, 69s Stereodivergent cyclization reaction, 162, 163s 4-Substituted 5-hydroxyindoles, 77s, 78 4-Substituted N-trimethylsilylpyrazoles, 26–28 3(5)-Substituted pyrazoles, 23, 23s 3-Substituted-1-(2-pyrimidine) imidazolium chlorides, 242 3-Substituted 1-(pyrimidin-2-yl) imidazolium salts, 254–256

T Tetrahydrobenzo[e]pyrimido[1,2-a]indol-5 (8H)-one, 113–114, 114s Tetrahydrocyclohepta[b][1,4]oxazines, 205, 205s Tetrahydrofurans, 161–169 Tetrahydroisoquinolines, 199–200, 199–200s Tetrahydropyrimidines, 204, 204s

294 Tetramethyl-1,3-bis(3-R-pyrazolyl) disiloxanes, 33–35 1,3,7,9-Tetramethyl-6-oxopurinediium bistriflate, 276–277 Tetrasubstituted benzoquinones, 81–82 Thiazepines, 211, 211s Thiazoles, 189, 190s Thiazolidines, 188–189, 189s Thiazolidin-2-ones, 191, 191s Thiazolines, 189–190, 190s 4-Thienylpyrimidines, 230 Trans-silylation reaction, 48 Trialkylsilylazoles physico-chemical properties, 9–18 silylotropic transformation, 18–20 structure, 9–18 1,2,4-Triazole-5-one, 49–52 1,2,3-Triazoles, 193, 193s 1,2,4-Triazolo-[1,5-a]pyrimidine, 274–276 Tricyclic methano-cyclopent[c]azocin6,9-diones, 130–131, 131s Trifluoromethylated piperazines, 202, 202s Trihalogened 7a-hydroxy[1,2-a]indol5-ones, 112s, 113 8,9,11-Trihalo-5H-benzofuro[3,2-c] carbazol-10-ols, 81–82, 82f 5,5-Trimethyl-3,4-dihydro-5-silaoxazolo [2,3-d]-1-methyl-1,2,4-triazolium chloride, 46, 46s

Index

3-(3-(2,4,6-Trimethylphenyl)-3Himidazolium-1-yl)-6(3,5-dimethylpyrazol-1-yl)pyridazine, 266–267 Trimethylsilylazoles, 5–9 application, 5–9 functionalization, 5, 6s, 9, 9s interatomic distances, 11–17t NMR spectroscopy, 20–28 physico-chemical properties, 9–18 reactivity, 5–9 silylotropic rearrangement of, 38–41 silylotropic transformation, 26–28, 38–41 structure, 20–26 Trimethylsilylbenzoxazolone, 52, 52s N,N 0 -bis-(Trimethylsilyl)imidazolium salts, 32, 32s N-Trimethylsilylpyrazole, 28 1-Trimethylsilyl-1,2,3-triazole, 36, 36s 2-Trimethylsilyl-1,2,3-triazole, 36–37, 36–37s N-Trimethylsilyl-1,2,3-triazole, 37, 37s 1-Trimethylsilyl-2-(trimethylsilyloxy) imidazole, 51, 51s Trioxaspiro[4.6]undecanes, 169, 169s 2,4,6-Tris(3,5-dimethylpyrazol-1-yl)1,3,5-triazine, 241 Trisubstituted benzoquinones, 81

V Vinylpyrrolidines, 180, 180s