Metal and Nonmetal Assisted Synthesis of Six-Membered Heterocycles 0128202823, 9780128202821

Table of contents :
Cover
Metal- and Nonmetal-Assisted
Synthesis of
Six-Membered
Heterocycles
Copyright
Contents
About the author
Preface
1 Six-membered N-heterocycles
1.1 Introduction
1.2 Metal- and nonmetal-assisted synthesis of six-membered N-heterocycles
1.2.1 Aluminum-assisted synthesis
1.2.2 Antimony-assisted synthesis
1.2.3 Bismuth-assisted synthesis
1.2.4 Cerium-assisted synthesis
1.2.5 Cesium-assisted synthesis
1.2.6 Indium-assisted synthesis
1.2.7 Iodine-assisted synthesis
1.2.8 Iridium-assisted synthesis
1.2.9 Iron-assisted synthesis
1.2.10 Lanthanum-assisted synthesis
1.2.11 Lithium-assisted synthesis
1.2.12 Magnesium-assisted synthesis
1.2.13 Manganese-assisted synthesis
1.2.14 Molybdenum-assisted synthesis
1.2.15 Rhodium-assisted synthesis
1.2.16 Samarium-assisted synthesis
1.2.17 Scandium-assisted synthesis
1.2.18 Silicon-assisted synthesis
1.2.19 Tin-assisted synthesis
1.2.20 Ytterbium-assisted synthesis
1.2.21 Zinc-assisted synthesis
1.2.22 Zirconium-assisted synthesis
References
2 Six-membered fused N-heterocycles
2.1 Introduction
2.2 Metal- and nonmetal-assisted synthesis of six-membered N-heterocycles fused with other heterocycles
2.2.1 Aluminum-assisted synthesis
2.2.2 Calcium-assisted synthesis
2.2.3 Cerium-assisted synthesis
2.2.4 Cesium-assisted synthesis
2.2.5 Iodine-assisted synthesis
2.2.6 Iridium-assisted synthesis
2.2.7 Iron-assisted synthesis
2.2.8 Lithium-assisted synthesis
2.2.9 Manganese-assisted synthesis
2.2.10 Mercury-assisted synthesis
2.2.11 Molybdenum-assisted synthesis
2.2.12 Neodymium-assisted synthesis
2.2.13 Nickel-assisted synthesis
2.2.14 Rhenium-assisted synthesis
2.2.15 Rhodium-assisted synthesis
2.2.16 Ruthenium-assisted synthesis
2.2.17 Scandium-assisted synthesis
2.2.18 Thallium-assisted synthesis
2.2.19 Tin-assisted synthesis
2.2.20 Titanium-assisted synthesis
2.2.21 Ytterbium-assisted synthesis
2.2.22 Zinc-assisted synthesis
2.2.23 Zirconium-assisted synthesis
References
3 Six-membered fused N-polyheterocycles
3.1 Introduction
3.2 Metal- and nonmetal-assisted synthesis of six-membered N-polyheterocycles fused with other heterocycles
3.2.1 Aluminum-assisted synthesis
3.2.2 Arsenic-assisted synthesis
3.2.3 Bismuth-assisted synthesis
3.2.4 Cesium-assisted synthesis
3.2.5 Indium-assisted synthesis
3.2.6 Iodine-assisted synthesis
3.2.7 Iron-assisted synthesis
3.2.8 Lanthanum-assisted synthesis
3.2.9 Lithium-assisted synthesis
3.2.10 Magnesium-assisted synthesis
3.2.11 Manganese-assisted synthesis
3.2.12 Molybdenum-assisted synthesis
3.2.13 Nickel-assisted synthesis
3.2.14 Promethium-assisted synthesis
3.2.15 Rhenium-assisted synthesis
3.2.16 Rhodium-assisted synthesis
3.2.17 Scandium-assisted synthesis
3.2.18 Tin-assisted synthesis
3.2.19 Tungsten-assisted synthesis
3.2.20 Ytterbium-assisted synthesis
3.2.21 Zinc-assisted synthesis
References
4 Six-membered N,N-heterocycles
4.1 Introduction
4.2 Metal- and nonmetal-assisted synthesis of six-membered heterocycles with two nitrogen atoms
4.2.1 Aluminum-assisted synthesis
4.2.2 Bismuth-assisted synthesis
4.2.3 Cerium-assisted synthesis
4.2.4 Copper-assisted synthesis
4.2.5 Gold-assisted synthesis
4.2.6 Indium-assisted synthesis
4.2.7 Iodine-assisted synthesis
4.2.8 Iridium-assisted synthesis
4.2.9 Iron-assisted synthesis
4.2.10 Lanthanum-assisted synthesis
4.2.11 Lithium-assisted synthesis
4.2.12 Magnesium-assisted synthesis
4.2.13 Manganese-assisted synthesis
4.2.14 Molybdenum-assisted synthesis
4.2.15 Nickel-assisted synthesis
4.2.16 Niobium-assisted synthesis
4.2.17 Rhodium-assisted synthesis
4.2.18 Ruthenium-assisted synthesis
4.2.19 Samarium-assisted synthesis
4.2.20 Scandium-assisted synthesis
4.2.21 Selenium-assisted synthesis
4.2.22 Silicon-assisted synthesis
4.2.23 Silver-assisted synthesis
4.2.24 Tin-assisted synthesis
4.2.25 Titanium-assisted synthesis
4.2.26 Tungsten-assisted synthesis
4.2.27 Ytterbium-assisted synthesis
4.2.28 Zinc-assisted synthesis
4.2.29 Zirconium-assisted synthesis
References
5 Six-membered N,N-polyheterocycles
5.1 Introduction
5.2 Metal- and nonmetal-assisted synthesis of six-membered polyheterocycles with two nitrogen atoms
5.2.1 Aluminum-assisted synthesis
5.2.2 Barium-assisted synthesis
5.2.3 Bismuth-assisted synthesis
5.2.4 Cobalt-assisted synthesis
5.2.5 Copper-assisted synthesis
5.2.6 Gold-assisted synthesis
5.2.7 Iodine-assisted synthesis
5.2.8 Iridium-assisted synthesis
5.2.9 Iron-assisted synthesis
5.2.10 Lithium-assisted synthesis
5.2.11 Manganese-assisted synthesis
5.2.12 Molybdenum-assisted synthesis
5.2.13 Nickel-assisted synthesis
5.2.14 Rhodium-assisted synthesis
5.2.15 Ruthenium-assisted synthesis
5.2.16 Scandium-assisted synthesis
5.2.17 Silicon-assisted synthesis
5.2.18 Tin-assisted synthesis
5.2.19 Titanium-assisted synthesis
5.2.20 Zinc-assisted synthesis
References
6 Six-membered O-heterocycles
6.1 Introduction
6.2 Metal- and nonmetal-assisted synthesis of six-membered oxygen containing heterocycles
6.2.1 Aluminum-assisted synthesis
6.2.2 Barium-assisted synthesis
6.2.3 Bismuth-assisted synthesis
6.2.4 Cerium-assisted synthesis
6.2.5 Cesium-assisted synthesis
6.2.6 Chromium-assisted synthesis
6.2.7 Cobalt-assisted synthesis
6.2.8 Copper-assisted synthesis
6.2.9 Europium-assisted synthesis
6.2.10 Indium-assisted synthesis
6.2.11 Iodine-assisted synthesis
6.2.12 Iron-assisted synthesis
6.2.13 Lanthanum-assisted synthesis
6.2.14 Molybdenum-assisted synthesis
6.2.15 Nickel-assisted synthesis
6.2.16 Osmium-assisted synthesis
6.2.17 Platinum-assisted synthesis
6.2.18 Rhodium-assisted synthesis
6.2.19 Silver-assisted synthesis
6.2.20 Titanium-assisted synthesis
6.2.21 Tungsten-assisted synthesis
6.2.22 Ytterbium-assisted synthesis
6.2.23 Zinc-assisted synthesis
References
7 Six-membered O,O-heterocycles
7.1 Introduction
7.2 Metal- and nonmetal-assisted synthesis of six-membered oxygen-containing polyheterocycles
7.2.1 Aluminum-assisted synthesis
7.2.2 Antimony-assisted synthesis
7.2.3 Barium-assisted synthesis
7.2.4 Bismuth-assisted synthesis
7.2.5 Cerium-assisted synthesis
7.2.6 Cesium-assisted synthesis
7.2.7 Chromium-assisted synthesis
7.2.8 Cobalt-assisted synthesis
7.2.9 Copper-assisted synthesis
7.2.10 Hafnium-assisted synthesis
7.2.11 Iodine-assisted synthesis
7.2.12 Iron-assisted synthesis
7.2.13 Lithium-assisted synthesis
7.2.14 Molybdenum-assisted synthesis
7.2.15 Nickel-assisted synthesis
7.2.16 Platinum-assisted synthesis
7.2.17 Rhodium-assisted synthesis
7.2.18 Scandium-assisted synthesis
7.2.19 Selenium-assisted synthesis
7.2.20 Silver-assisted synthesis
7.2.21 Titanium-assisted synthesis
7.2.22 Tungsten-assisted synthesis
7.2.23 Zinc-assisted synthesis
7.2.24 Zirconium-assisted synthesis
References
8 Six-membered O,N-heterocycles
8.1 Introduction
8.2 Metal- and nonmetal-assisted synthesis of six-membered O,N-heterocycles
8.2.1 Aluminum-assisted synthesis
8.2.2 Bismuth-assisted synthesis
8.2.3 Copper-assisted synthesis
8.2.4 Gold-assisted synthesis
8.2.5 Iodine-assisted synthesis
8.2.6 Iron-assisted synthesis
8.2.7 Lithium-assisted synthesis
8.2.8 Mercury-assisted synthesis
8.2.9 Nickel-assisted synthesis
8.2.10 Palladium-assisted synthesis
8.2.11 Platinum-assisted synthesis
8.2.12 Rhodium-assisted synthesis
8.2.13 Ruthenium-assisted synthesis
8.2.14 Silver-assisted synthesis
8.2.15 Tin-assisted synthesis
8.2.16 Titanium-assisted synthesis
8.2.17 Ytterbium-assisted synthesis
8.2.18 Zinc-assisted synthesis
References
9 Six-membered S-heterocycles
9.1 Introduction
9.2 Metal- and nonmetal-assisted synthesis of six-membered heterocycles with sulfur heteroatom
9.2.1 Aluminum-assisted synthesis
9.2.2 Bismuth-assisted synthesis
9.2.3 Calcium-assisted synthesis
9.2.4 Cesium-assisted synthesis
9.2.5 Copper-assisted synthesis
9.2.6 Gold-assisted synthesis
9.2.7 Iodine-assisted synthesis
9.2.8 Iron-assisted synthesis
9.2.9 Lead-assisted synthesis
9.2.10 Lithium-assisted synthesis
9.2.11 Phosphorus-assisted synthesis
9.2.12 Platinum-assisted synthesis
9.2.13 Rhodium-assisted synthesis
9.2.14 Ruthenium-assisted synthesis
9.2.15 Silver-assisted synthesis
9.2.16 Tin-assisted synthesis
9.2.17 Ytterbium-assisted synthesis
9.2.18 Zinc-assisted synthesis
References
Index
Back Cover

Citation preview

Metal- and N,onmetal­ Assisted Synthesis of Six-Membered Heterocycles

DR. NiA,VJEET MUiR Department of Qleminry. Bananllall Vidyapith, Banasthali, Rajastnan, IndEa

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2020 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. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-820282-1 For Information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Susan Dennis Acquisitions Editor: Anneka Hess Editorial Project Manager: Liz Heijkoop Production Project Manager: Vignesh Tamil Cover Designer: Christian Bilbow Typeset by MPS Limited, Chennai, India

Contents About the author Preface

vii ix

1. Six-membered N-heterocycles

1

1.1 Introduction 1.2 Metal- and nonmetal-assisted synthesis of six-membered N-heterocycles References

2. Six-membered fused N-heterocycles 2.1 Introduction 2.2 Metal- and nonmetal-assisted synthesis of six-membered N-heterocycles fused with other heterocycles References

3. Six-membered fused N-polyheterocycles 3.1 Introduction 3.2 Metal- and nonmetal-assisted synthesis of six-membered N-polyheterocycles fused with other heterocycles References

4. Six-membered N,N-heterocycles 4.1 Introduction 4.2 Metal- and nonmetal-assisted synthesis of six-membered heterocycles with two nitrogen atoms References

5. Six-membered N,N-polyheterocycles 5.1 Introduction 5.2 Metal- and nonmetal-assisted synthesis of six-membered polyheterocycles with two nitrogen atoms References

6. Six-membered O-heterocycles 6.1 Introduction

1 1 48

65 65 66 108

121 121 121 169

183 183 183 229

243 243 244 284

295 295

v

vi

Contents

6.2 Metal- and nonmetal-assisted synthesis of six-membered oxygen containing heterocycles References

7. Six-membered O,O-heterocycles 7.1 Introduction 7.2 Metal- and nonmetal-assisted synthesis of six-membered oxygen-containing polyheterocycles References

8. Six-membered O,N-heterocycles 8.1 Introduction 8.2 Metal- and nonmetal-assisted synthesis of six-membered O,N-heterocycles References

9. Six-membered S-heterocycles 9.1 Introduction 9.2 Metal- and nonmetal-assisted synthesis of six-membered heterocycles with sulfur heteroatom References Index

296 338

351 351 352 398

413 413 414 447

459 459 460 491 505

About the author Dr. Navjeet Kaur was born in Punjab, India. She received her BSc from Punjab University, Chandigarh (Punjab, India) in 2008. In 2010 she completed her MSc in chemistry from Banasthali Vidyapith. She was awarded with her PhD in 2014 by the same university, under the supervision of Prof. D. Kishore. Presently, she is working as an assistant professor in the Department of Chemistry, Banasthali Vidyapith and has entered into a specialized research career focused on the synthesis of 1,4-benzodiazepine-based heterocyclic compounds (Organic Synthetic and Medicinal Chemistry). With 9 years of teaching experience, she has published over 150 scientific research papers, review articles, book chapters, and monographs in the field of organic synthesis in national and international reputed journals. She has published two books, “Palladium Assisted Synthesis of Heterocycles” and “Metals and Non-metals: Five-Membered N-Heterocycle Synthesis” with CRC Press, Taylor & Francis Group. She was presented with the Prof. G.L. Telesara Award in 2011 by Indian Council of Chemists (Agra, Uttar Pradesh) at Osmania University (Hyderabad), and the Best Paper Presentation Award in National Conference on “Emerging Trends in Chemical and Pharmaceutical Sciences” (Banasthali Vidyapith, Rajasthan). She has attended about 40 conferences, workshops, and seminars. Apart from all these, she has been working as NSS Program Officer since 2016, member of UBA (Unnat Bharat Abhiyan) since 2018 and has delivered numerous radio talks. Dr. Navjeet finds interest in Sikh literature and has completed a 2-year Sikh Missionary course from Sikh Missionary College (Ludhiana, Punjab). Dr. Navjeet Kaur is currently guiding 5 research scholars- Meenu Devi, Yamini Verma, Pooja Grewal, Pranshu Bhardwaj, and Neha Ahlawat - as their PhD supervisor.

vii

Preface

A wide variety of biological activities are exhibited by nitrogen-, oxygen-, and sulfur-containing heterocycles and recently many reports have appeared for the synthesis of these heterocycles. The synthesis of heterocycles with the help of metals and nonmetals has become a highly rewarding and important method in organic synthesis. New strategies have been developed for the preparation of heterocycles in recent decades. The largest classical divisions of organic chemistry are constituted by heterocycles. Heterocycles are of immense importance biologically, industrially, and for the functioning of human society. Heterocycles are present in many pharmaceutically active compounds and natural products. Transition metal-catalyzed reactions are the most attractive protocols among a number of new synthetic methodologies because multiple substituted molecules are constructed directly under mild conditions from easily available starting substrates. The development of newer transformations for heterocycle syntheses using atomically economical and efficient pathways is a popular research area currently. There is a need for the development of a rapid, efficient, and versatile strategy for the synthesis of heterocyclic rings. Metal- and nonmetal-involving methods have gained prominence because traditional conditions have disadvantages such as long reaction times, harsh conditions, and limited substrate choices. Heterocycles have been synthesized under conventional and traditional conditions for use in industry, because these reactions are robust, reliable, and economically effective. However, these reactions also create waste by-products. Many efficient strategies have been developed for the synthesis of heterocycles, however the search for improved methods has continued unabated. One of the major research endeavors in synthetic organic chemistry is the development of new synthetic protocols toward heterocycles, aiming at achieving better functional group compatibilities and greater levels of molecular complexity in atomically economical and convergent ways under mild reaction conditions using easily available starting substrates. The synthesis of heterocyclic compounds in the presence of metal and nonmetal complexes has become increasingly common because a metalcatalyzed reaction can form complicated molecules directly from easily ix

x

Preface

available starting materials under mild conditions. In metal- and nonmetalassisted tools, small unreactive molecules, such as CO2, CO, or ethylene, have been efficiently utilized for the synthesis of heterocycles. Despite the significant progress that has been made with metal and nonmetal chemistry of heterocycles, there remains a high demand for efficient, general, and sustainable strategies for the construction of these molecules. In this book, the author has focused on the utilization of metals and nonmetals for the synthesis of several six-membered heterocyclic compounds.

CHAPTER 1

Six-membered N-heterocycles 1.1 Introduction Heterocycles and implicit nitrogen-containing heterocycles are becoming very important in all aspects of pure and applied chemistry [1a,b]. Development of new synthetic methodology, isolation from natural sources, finding modern applications of various heterocycles in the pharmaceutical field, in industry, chemistry, or medicine are the subjects intensively studied by chemists, biologists, and researchers [2a,b]. Heterocycles are not only important due to their abundance in organic chemistry but they are also very important for their chemical, biological, and technological applications [3]. For many decades, N-heterocycles have been used as medicinal compounds, and form the basis for various drugs like morphine (analgesic), captopril (hypertension), and vincristine (cancer chemotherapy) [4a
i,5a
h]. The six-membered heterocyclic compounds are pharmaceutical actives. Six-membered heterocycles like substituted pyridines possess a wide range of pharmacological activity. They are used to modulate anginapectoris, antidiabetic, hypertension, antitumor, act as Ca21 channel blockers, and heptaprotective properties. In addition, pyridine derivatives are also used as organic bases and organocatalysts in organic synthesis. The fused quinoline functionality is also present in a number of naturally occurring and biologically active compounds [6a
h,7a
g,8a,b,9a,b,10a, b,11a,b,12a,b,13a
d,14a
e,15a,b,16].

1.2 Metal- and nonmetal-assisted synthesis of sixmembered N-heterocycles 1.2.1 Aluminum-assisted synthesis A multicomponent reaction of malononitrile, aromatic aldehydes, and thiophenols was used for the one-pot synthesis of highly functionalized pyridines (Scheme 1.1) [17
21]. The reaction was catalyzed with potassium fluoride impregnated alumina. Good yields were obtained in the Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00001-4

© 2020 Elsevier Inc. All rights reserved.

1

2

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

case of benzaldehydes, as they have both electron-withdrawing and electron-donating substituents. It was reported that heterocyclic or aliphatic aldehydes did not undergo a reaction with satisfactory yields. For comparison, the reactions were also performed in ethanol using an oil bath under conventionally heated reflux conditions. The microwaveassisted reactions consistently provided better results (62%
93% yields) when compared to the reactions under conventional reflux conditions in ethanol (56%
82% yields) [22].

Scheme 1.1

The N-tosyl iodopiperidines were obtained in good yields by iodocyclization of unsaturated tosylamides with oxone oxidation in potassium iodide. A simple, new method was developed for the transformation of alcohols to tosylamides (Scheme 1.2) [23].

Scheme 1.2

After the cyclization of substrates bearing a prenyl ene functionality, the fate of analogous substrates possessing a crotyl moiety was investigated under similar reaction conditions. However, this reaction provided a mixture of products, each in low yields, which indicated that the substrate was not good for this reaction (Scheme 1.3) [24,25].

Six-membered N-heterocycles

3

Scheme 1.3

Various 4-aza-1,7-dienes bearing activated enophile underwent thermal or Lewis acid-catalyzed ene cyclization to form the ene cyclization product, substituted piperidines, along with bicyclic lactones, formed via a competing hetero-Diels
Alder reaction (Schemes 1.4 and 1.5). A thermal ene cyclization was facilitated upon activation of the enophile with a single ester, but the reaction was not amenable to Lewis acid catalysis. It was reported that the Lewis acid-catalyzed reaction was facile with other activating groups on the enophile, although there was a fine balance between the competing hetero-Diels
Alder reaction and the desired ene cyclization, with the product distribution being influenced by the nature of the ene component, the activating group on enophile, and the Lewis acid [25,26].

Scheme 1.4

4

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.5

The pyridine derivative was formed from acylaminoketone and nitrile by microwave-assisted reaction. Good yields of 3,5,6-trisubstituted 2-aminopyridine derivative were obtained after the elimination of acyl residue. The high-energy-molecule ketene was formed as a side product produced by an electrocyclic reaction (Scheme 1.6) [27,28].

Scheme 1.6

Novel Mannich bases N-(2-(R)-1-(Z)-2-(1-(4-methylpiperazin-1-yl) methyl)-2-oxoindolin-3-ylidene)hydrazinyl)-1-oxopropan-2-ylamino)-2oxoethyl)-4-(5-oxo-4-(2-phenylhydrazono)-3-(trifluoromethyl)-4,5-dihydro1H-pyrazol-1-yl)benzamide were prepared. The N-(2-oxo-2-(R)-1oxo-1-(Z)-2-(2-oxoindolin-3-ylidene)hydrazinyl)propan-2-ylamino)ethyl)4-(5-oxo-4-(2-phenylhydrazono)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-yl)benzamide were synthesized by condensation of (R)-N-(2-(1hydrazinyl-1-oxopropan-2-ylamino)-2-oxoethyl)-4-(5-oxo-4-(2-phenylhydrazono)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)benzamide with isatin. The N-(2-oxo-2-(R)-1-oxo-1-(Z)-2-(2-oxoindolin-3-ylidene) hydrazinyl)propan-2-ylamino)ethyl)-4-(5-oxo-4-(2-phenylhydrazono)3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-yl)benzamide was subjected to

Six-membered N-heterocycles

5

Scheme 1.7

Mannich reaction with cyclic secondary amine like morpholine/piperidine/ N-methyl piperidine in DMF in the presence of formaldehyde to afford the excellent yields of Mannich base N-(2-(R)-1-(Z)-2-(1-(4-methylpiperazin1-yl)methyl)-2-oxoindolin-3-ylidene)hydrazinyl)-1-oxopropan-2-ylamino) -2-oxoethyl)-4-(5-oxo-4-(2-phenylhydrazono)-3-(trifluoromethyl)-4,5dihydro-1H-pyrazol-1-yl)benzamide. The yield was improved to 90% under microwave irradiation. Further steps involved simple reaction conditions and good yield procedure (Scheme 1.7) [29].

6

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

1.2.2 Antimony-assisted synthesis Thibaudeau and coworkers [30] reported a rapid transformation of several amides and N,N-diallylic amines to fluorinated piperidines in superacid, HFeSbF5, by a novel cyclization-fluorination process (Scheme 1.8) [25].

Scheme 1.8

1.2.3 Bismuth-assisted synthesis Thiols underwent oxidative coupling in the presence of Bi(NO3)3  5H2O to afford the disulfides. The heteroaromatic thiol 2-pyridinethiol was reacted in this method to synthesize the 2,20 -dipyridine disulfide in 93% yield (Scheme 1.9) [31,32].

Scheme 1.9

The classical Hantzsch reaction is one of the most economical and simplest methods for the preparation of pharmacologically useful and biologically important 1,4-dihydropyridine derivatives. Bismuth nitrate pentahydrate acted as a very efficient catalyst under MWI for a one-pot three-component preparation of 1,4-dihydropyridines (1,4-DHPs) in excellent yields from diverse aldehydes, amines/ammonium acetate, and 1,3-dicarbonyl compounds under solvent-free conditions within 1
3 min. The extreme rapidity and excellent yield of reaction was due to a concurrent effect of MWI and catalyst. An extremely fast and easy method was reported for the synthesis of 1,4-DHPs in catalytic amounts of bismuth nitrate under solvent-free conditions and MWI. This idea was extended to the reaction on carbonyl compounds (both 1,3
dicarbonyl compounds and aldehydes) with a suitable NH3 source under solvent-free conditions in the presence of catalytic amounts of bismuth nitrate. Many bismuth salts such as bismuth triflate, bismuth chloride, bismuth bromide,

Six-membered N-heterocycles

7

bismuth subnitrate, bismuth nitrate, and bismuth iodide pentahydrate were screened using ethyl acetoacetate, benzaldehyde, and ammonium acetate as a model reaction under automated CEM MWI conditions (300 W, 1 min, 50 °C). The reaction occurred in 52% yield within a min without any catalyst (only MWI). A series of 1,4-DHPs was prepared using diverse 1,3
diketo compounds, aldehydes, and ammonium acetate/ amines under MWI in the presence of bismuth nitrate pentahydrate (5 mol%) as catalyst (Scheme 1.10) [33].

Scheme 1.10

Anderson and coworkers [34] developed an intramolecular cyclic ene reaction of parent aldehyde in the presence of Bi(OTf)3  xH2O catalyst for the synthesis of two 3,4-disubstituted piperidines (Scheme 1.11) [32].

Scheme 1.11

The aza-Prins-type cyclization of epoxides and N-protected homoallyl amines in the presence of bismuth chloride (Lewis acid) provided various trans-4-chloro-2-substituted piperidines under mild reaction conditions (Scheme 1.12) [32,35].

Scheme 1.12

8

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The Bi(OTf)3  xH2O or bismuth chloride-catalyzed aza-Diels
Alder reaction of imines with Danishefsky’s diene synthesized various dihydropyridin-4-ones in high yields (Scheme 1.13) [32,36].

Scheme 1.13

1.2.4 Cerium-assisted synthesis Nair and coworkers [37] synthesized functionalized piperidines by stereoselective intramolecular cyclization of epoxypropyl cinnamylamines with ceric ammonium nitrate (Scheme 1.14). The epoxide ring underwent a single-electron transfer oxidation by ceric ammonium nitrate to provide a radical cation and the cerium(III) was oxidized to cerium(IV) [25].

Scheme 1.14

A three-component one-step reaction of primary amine, 1,3-dicarbonyl compound, and α,β-unsaturated aldehyde was reported by Menéndez et al. [38]. This protocol was established using CAN as a Lewis acid catalyst. This method has excellent substrate tolerance and furnished 1,4-dihydropyridines at room temperature with moderate-togood yields. The β-ketothioesters were efficiently used as dicarbonyl component to provide the 1,4-dihydropyridines bearing a reactive thioester group (Scheme 1.15) [39].

Six-membered N-heterocycles

9

Scheme 1.15

1.2.5 Cesium-assisted synthesis Cycloadditions were evaluated on acid-labile polystyrene supports such as HMPB
AM resin, Wang resin, and syringaldehyde-based resin. All steps (i.e., linking, cycloaddition, and cleavage) of solid phase were performed under both controlled MWI and thermal conditions. Generally, the reaction rate increased significantly and reaction times decreased from hours or days to minutes when conducted under high-temperature MW conditions (Scheme 1.16) [40
44].

Scheme 1.16

1.2.6 Indium-assisted synthesis To examine the benefit of iron as compared to other typical metal halides used in the aza-Prins cyclization, a few runs were carried out using indium halides as catalysts (Scheme 1.17) [45
49]. It was reported that both indium bromide and indium chloride also induced the

10

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

cyclization of aldehydes and homopropargyl tosylamine to provide the tetrahydropyridines. However, the yields were lower and the reaction rates were slower.

Scheme 1.17

1.2.7 Iodine-assisted synthesis Khan et al. [50] prepared highly functionalized piperidine derivatives by an iodine-catalyzed one-pot five-component reaction (Scheme 1.18). The β-keto esters were reacted with amines for in situ generation of enamine that underwent Mannich-type reaction with iodine-activated Schiff ’s base to afford an intermediate. The formed intermediate reacted with aldehydes to produce the compound that tautomerized in the presence of iodine. The formed compound underwent intramolecular Mannich-type reaction to afford the compound that tautomerized to provide the corresponding products [51].

Scheme 1.18

Six-membered N-heterocycles

11

Akbari and coworkers [52] synthesized 1,4-DHPs by multicomponent reactions of 1,3-dicarbonyl compounds, aldehydes, and ammonium acetate in the presence of iodine (30 mol%) (Scheme 1.19). The cyclized products were obtained from 1,3-dicarbonyl compounds [51].

Scheme 1.19

Zolfigol and coworkers [53] developed a reaction for the preparation of Hantzsch N-hydroxyethyl-1,4-DHPs under mild reaction conditions (Scheme 1.20) [51].

Scheme 1.20

Ren and Cai [54] reported a one-pot Hantzsch reaction under solvent-free conditions for the synthesis of 2,4,6-triarylpyridines (Scheme 1.21). Enol attacked the iodine-activated aldehydes to afford the β-hydroxy keto intermediate that reacted with NH3. The imino-keto intermediate was produced by nucleophilic attack of another molecule of enol. The 2,4,6-triarylpyridines were obtained when imino-keto intermediate underwent intramolecular cyclization followed by loss of water and subsequent oxidation [51].

12

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.21

Kumar and coworkers [55] reported an iodine-catalyzed three-component reaction of substituted anilines, cinnamaldehydes, and 2-keto esters in methanol to afford the N-aryl-1,4-DHPs (Scheme 1.22). Antioxidant and antidyslipidemic activities of 1,4-DHPs were evaluated in vitro and in vivo. Anilines and cinnamaldehydes were reacted to synthesize the Schiff’s base that underwent 1,4-addition with enol to produce an intermediate. The N-aryl-1,4-DHPs were formed by elimination of H2O followed by intramolecular cyclization and subsequent loss of proton [51].

Scheme 1.22

The (diacetoxyiodo)benzene, [bis(trifluoroacetoxy)iodo]benzene (BTI), and [hydroxyl(tosyloxy)iodo]benzene are extensively used in many cationic cyclizations that are important for the construction of heterocyclic compounds [56
77]. Tellitu and coworkers [78
81] reported a series of BTI-promoted intramolecular amidation reactions (Scheme 1.23) to provide several five-, six-, and seven-membered heterocyclic compounds. The ionic mechanism was proposed on the basis of experimental evidences; this mechanism involved the formation of Nacylnitrenium intermediates by initial reaction of the amide with hypervalent iodine reagent [82].

Six-membered N-heterocycles

13

Scheme 1.23

1.2.8 Iridium-assisted synthesis The sulfoxonium ylides were used as a carbene source in the presence of simple and commercially available iridium catalyst for many inter- and intramolecular X
H bond insertions such as a practical ring-expansion protocol for lactams. The sulfoxonium ylides were recommended as preferable surrogates to traditional diazo esters and ketones due to stability and safety (Scheme 1.24) [83].

Scheme 1.24

Fujita and coworkers [84] used [Cp IrCl2]2 for N-heterocyclization, and it was employed for the reaction of aniline and benzylamine with several diols to afford five-, six-, and seven-membered cyclic amines. The borrowing hydrogen protocol was used for the transformation of primary amines into nitrogen-containing heterocycles via a double alkylation with suitable diols (Scheme 1.25) [85,86].

Scheme 1.25

1.2.9 Iron-assisted synthesis An iron-catalyzed thermodynamic equilibration of 2-alkenyl 6-substituted piperidines was a key step in the ecofriendly and highly diastereoselective preparation of substituted cis-2,6-piperidines that allowed the isolation of enriched mixtures of the most stable cis-isomers (Scheme 1.26) [87].

14

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.26

The amide derivatives of piperidines were synthesized in complete stereoselectivity and good yields by interesting application of this reaction (Scheme 1.27) [88,89].

Scheme 1.27

Among different examined solvents (acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, nitromethane, carbon tetrachloride, 1,2-dichloroethane, and dichloromethane) the best conditions were using 1,2-dichloroethane and dichloromethane. A similar solvent effect to the oxa-alkyne Prins cyclization was reported. The chlorovinyl derivative was formed in a mixture with the bromovinyl compound when the reaction was performed with dichloromethane as solvent and ferric bromide as catalyst (Scheme 1.28) [49,90].

Scheme 1.28

The N-sulfonyl iminium ion was produced when homopropargyl tosylamine was reacted with an aldehyde in the presence of ferric halide. The formed intermediate afforded tetrahydropyridine (Scheme 1.29) [49].

Six-membered N-heterocycles

15

Scheme 1.29

The dimer 2-alkyl-4-chloro-1-tosyl-1,2,5,6-tetrahydropyridine was synthesized from noncommercial and more elaborated aldehyde (Scheme 1.30) [49,91,92].

Scheme 1.30

Although the cycloaddition reaction needed low catalyst loading, the alkyne cyclotrimerization products and pyridine product were formed. An ironpentamethyl(cyclopentadienyl)acetonitrile sandwich complex was synthesized by Ferré and coworkers [93] for the successful synthesis of pyridine product in 73% yield. However, this cycloaddition reaction was limited to one activated alkyne and needed the iron-complex in stoichiometric amounts (Scheme 1.31) [94].

Scheme 1.31

In the past iron was used for the synthesis of pyridine. Sir William Ramsay [95] reported this very first example in 1876. He prepared pyridine in traces upon passing acetylene and hydrocyanic acid through a red hot iron tube [96]. Knoch and coworkers [97] reported a cycloaddition of nitriles and alkynes using an iron-phosphoranecyclooctadiene complex for the preparation of pyridine derivatives. Although the cycloaddition reaction needed low catalyst loading, significant cyclotrimerization of alkyne was also reported together with the desired pyridine products (Scheme 1.32).

16

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.32

1.2.10 Lanthanum-assisted synthesis The original method for aza-Diels
Alder reactions was limited to either activated aldehydes like glyoxylates or the simplest aldehyde, formaldehyde [98
103]. The Ln(OTf)3-promoted aza-Diels
Alder reactions in water were compatible with substrates that were difficult to employ under standard conditions. For instance, propanal, hexanal, and phenylethanal reacted in the presence of Ln(OTf)3 to afford the good yields. Less reactive dienes such as 2-methyl-1,3-butadiene, 2,3-dimethyl-1,3-butadiene, and 1,3-cyclohexadiene did not react with higher aldehydes using this method; however, they reacted smoothly with L-phenylalanino ester and formaldehyde (Scheme 1.33) [104]. Aza-sugars were synthesized using this protocol [105]. Unlike carbon Diels
Alder reactions, most of the available protocols were auxiliary-based and enantioselective aza-Diels
Alder reactions were far less studied [106
108].

Scheme 1.33

Molander and coworkers [109] reported that the diastereoselective intramolecular hydroamination of aminoalkene was used not only for the synthesis of (2)-pinidiol but also for the synthesis of its (1)- and (2)-isomers (Scheme 1.34). The lanthanocene catalyst displayed good catalytic

Six-membered N-heterocycles

17

activity but low diastereoselectivity, which was improved when the reaction was performed in the presence of a threefold excess of n-propylamine relative to the aminoalkene substrate. Also, sterically more open ansalanthanocenes showed higher diastereoselectivities. The synthetic validity of this reaction was demonstrated for the preparation of pinidinol with excellent cis/trans diastereoselectivity [110].

Scheme 1.34

1.2.11 Lithium-assisted synthesis Paravidino and coworkers [111] reported a new diastereoselective fourcomponent reaction where nitriles, phosphonate, isocyanoacetates, and aldehydes were combined to synthesize the functionalized cis-3-isocyano3,4-dihydro-2-pyridones. Heteroaromatic, aromatic, and α,β-unsaturated aldehydes and nitriles afforded reasonable to excellent yields of desired products cis-3-isocyano-3,4-dihydro-2-pyridones. However, primary aliphatic nitriles were avoided because they were less efficient in the synthesis of azadiene (Scheme 1.35) [112].

Scheme 1.35

The base-catalyzed hydroamination reaction of styrenes and monobenzylated piperazine was reported by Beller et al. [113] as a key step for the preparation of N-(heteroarylcarbonyl)-N0 -(arylalkyl)piperazines, which are CNS (central nervous system) active compounds. Thus styrenes were reacted with N-benzylpiperazine at 65 °C
120 °C in the presence of

18

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

n-BuLi (0.1
0.2 eq.) to afford the N-benzyl-N0 -(2-arylethyl)piperazines in good yields. The reaction also occurred in similar or even better yields at room temperature than at higher temperatures, when carried out in a 2:1 olefin/amine ratio (Scheme 1.36). A variant involved prior isomerization of allylbenzene to methylstyrene [110].

Scheme 1.36

1.2.12 Magnesium-assisted synthesis Kadouri-Puchot and coworkers [114] developed a much improved variation of ene-iminium cyclization using a chiral pool starting compound. Enantiomerically pure (S)-phenylglycinol was reacted with butyraldehyde to afford the oxazolidine (Scheme 1.37). The β-aminoalcohol was obtained with high diastereoselectivity when oxazolidine was reacted with organolithium species. Oxazolidine exists in equilibrium with the ring-opened imine tautomer with E-geometry. A highly ordered, chelated transition state was formed in the presence of organolithium reagent. The β-aminoalcohol was reacted with glyoxal to form an imine that was cyclized to give the hemiacetal. The ene-iminium cyclization occurred with complete facial discrimination as the phenyl substituent hindered the Re face and therefore the concerted process proceeded to form the bicyclic intermediate. Completion of the synthesis involved oxidative cleavage of terminal alkene, followed by Swern oxidation of hemiacetal to afford the lactone. The ketone was reduced with Kselectride diastereoselectively to install the 4-hydroxy substituent. Finally, trans-6-substituted-4-hydroxypipecolic acid was formed in almost quantitative yield by hydrogenolysis. A 27% overall yield was achieved in seven steps.

Six-membered N-heterocycles

19

Scheme 1.37

Bartoli et al. [115] reported an unconventional multicomponent reaction of two 1,3-dicarbonyl compounds, ethyl propiolate, and primary amines for the synthesis of 1,4-dihydropyridines where ethyl propiolate acted as electrophile (Scheme 1.38) [39].

Scheme 1.38

1.2.13 Manganese-assisted synthesis Pyridines were formed when vinyl azides were reacted with monocyclic cyclopropanols in the presence of Mn(acac)3, whereas 2-azabicyclo[3.3.1] non-2-en-1-ol derivatives were obtained from bicyclic cyclopropanols using a catalytic amount of Mn(acac)3 (Scheme 1.39) [116].

20

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.39

Enantiopure nitrone, obtained from protected D-glyceraldehyde, was subjected to allylation conditions to afford either the syn- or anti-product on the basis of Lewis acid used (Scheme 1.40). The selectivity was efficiently tuned to provide the antidiastereomer using boron trifluoride and the syn-diastereomer with zinc bromide in excellent yields. The Z-nitrone was produced quantitatively when the syn-product was oxidized with manganese dioxide. The nitrone possessing tethered alkene was subjected to thermal cycloaddition conditions to afford the cycloadduct as a major diastereomer via an endo-type transition state. The dioxolane of bicyclic intermediate was cleaved oxidatively to provide an aldehyde, then oxidized to a carboxylic acid and then esterified to synthesize the fused 2,6-disubstituted piperidine. The 4-hydroxypipecolic acid skeleton was constructed in good yield by zinc-promoted reduction of the nitrogen
oxygen bond. The substituted pipecolic acid was converted into orthogonally protected product in two steps that provided the N-heterocycle in 23% overall yield in nine steps [117].

Scheme 1.40

Six-membered N-heterocycles

21

1.2.14 Molybdenum-assisted synthesis Trost and Andersen [118] synthesized orally bioavailable human immunodeficiency virus inhibitor tipranavir. The key chiral intermediate was prepared by asymmetric allylic alkylation starting from carbonate. The product was formed in 94% yield using 15 mol% chiral ligand and 10 mol% Mo precatalyst with 2 eq. of sodium dimethylmalonate as the additive. The reaction was performed at 180 °C under sealed-vessel MW heating for 20 min. Thermal heating under reflux (67 °C) required 24 h and afforded the same chemical yield of intermediate in higher enantiomeric purity (96% enantiomeric excess). A similar method involving a Mo-catalyzed microwave-driven asymmetric allylic alkylation (6 min, 160 °C, tetrahydrofuran) as the key step was elaborated by Moberg et al. [119] for the synthesis of (R)-baclofen. Other enantioselective reactions carried out by MW heating included asymmetric Heck reactions [120] and ruthenium-catalyzed asymmetric hydrogen transfer processes (Scheme 1.41) [121].

Scheme 1.41

The coniine is a neurotoxin found in the hemlock plant. The synthesis of enantiomerically enriched coniine represents the utility of catalytic transformations. As shown in Scheme 1.42, the unsaturated piperidine was formed in 83% yield by Mo-catalyzed ring-closing metathesis of benzylamine in the presence of chiral molybdenum catalyst (5 mol%). The poisonous alkaloid was constructed by a two-step sequence [122,123].

Scheme 1.42

22

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

During the search for an efficient chiral complex that would promote the ring-closing metathesis of triene, en route to quebrachamine, a class of chiral catalysts was investigated that initiated the requisite process enantioselectively and efficiently than other existing chiral or achiral molybdenum- or ruthenium-based catalysts [124]. Ring-closing metathesis of triene in the presence of only 1 mol% rac-molybdenum-complex proceeded with .98% conversion within 1 h to provide the desired product in 79% yield (Scheme 1.43). The reaction was far less efficient with achiral molybdenum alkylidene. Various achiral ruthenium carbenes deliver 35% to .98% conversion at 5 mol% loading after 6 h. The by-products were formed in significant amounts by Ru-catalyzed transformations; desired product was obtained only in 36%
65% yield. The desired tetracyclic diene was obtained in 83% yield only when 7.5 mol% of a more efficient ruthenium complex was used [125]. A chiral catalyst offered reactivity patterns that were substantially different from those offered by achiral variants. In other words, chiral catalysts were relevant to cases other than those where the goal was achieving high enantioselectivity [123].

Scheme 1.43

The enantioselective synthesis of Aspidosperma alkaloid quebrachamine was developed. That is, the total synthesis was principally conceived to challenge the current state-of-the-art olefin metathesis catalysts and served as a springboard for catalyst development. As shown in Scheme 1.44, the late-stage ring-closing metathesis needed ring-closure onto one of two sterically hindered vinyl groups at a congested all-carbon quaternary center [126] in the presence of a Lewis basic tertiary amine. To identify an effective catalyst for enantioselective and efficient ring-closing metathesis of starting material and to address the aforementioned shortcomings, a new class of stereogenic molybdenum complexes, represented by monopyrrolide, was introduced. The design of more active chiral molybdenum-based catalysts was largely based on mechanistic considerations. One such principle is that,

Six-membered N-heterocycles

23

in any olefin metathesis process the metal center was fluxional: it underwent repeated inversion through intermediacy of square pyramidal or trigonal bipyramidal complexes. The energetic barriers reduced in the absence of a rigid bidentate ligand that accompanied such transformations within the catalytic cycle and enhanced the catalyst activity. On the basis of studies by Eisenstein et al. [127,128], the stereogenic at molybdenum complexes were outfitted with one relatively weaker electron-donating and a relatively stronger electron-donating ligand. Theoretical investigations suggested that the presence of an electron donor ligand increased the rate of metallacyclobutane cycloreversion as well as controlled and facilitated the stereochemical course of olefin coordination. The validity of above hypotheses was strongly supported by experimental evidences: stereogenic at molybdenum complexes, produced in situ from an eq. of chiral aryl alcohol (catalyst isolation not required) and achiral molybdenum bis-pyrrolide readily promoted the difficult ring-closing metathesis. The desired tetracyclic diene bearing an all-carbon quaternary stereogenic center was obtained with exceptional enantioselectivity and yield (84%) [123,129
137].

Scheme 1.44

1.2.15 Rhodium-assisted synthesis The reaction of triazoles with triethylsilane was investigated in the presence of a catalytic amount of Rh(II) acetate to evaluate the feasibility of using triazoles as precursors of rhodium carbenoids, which was a method developed by Doyle et al. [137] for the efficient trapping of rhodium carbenoids. Not surprisingly, under these reaction conditions pyridotriazoles behave differently. While the 7-H derivative remained unaffected, the 7chlorosubstituted compound was smoothly transformed, product of carbenoid insertion, into Si
H bond. These processes have clearly indicated that 7-halo-substituted pyridotriazoles can indeed serve as convenient substrates of rhodium carbenoids (Scheme 1.45) [138].

24

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.45

The 1-(3-aminopropyl)vinylarenes underwent a [Rh(COD)(DPPB)] BF4-catalyzed intramolecular anti-Markovnikov hydroamination to afford the high yield of 3-arylpiperidines. The 3,5-disubstituted piperidines were formed with high diastereomeric excess from reactants with substituents β to the amino group, whereas enamines and isomerized starting materials were obtained from substituents in α and γ positions (Scheme 1.46) [139].

Scheme 1.46

Until recently, there were no convenient protocols toward C-3 imino-substituted cyclopropenes, potentially useful building blocks for organic chemistry [140
142]. Recently, it was reported [143] that 7halo-substituted N-fused triazoles served as surrogates for imino diazo compounds [144] in rhodium(II)-catalyzed chemoselective reaction with terminal alkynes to afford the 3-(2-pyridyl)cyclopropenes or indolizines, depending upon catalyst source. The presence of halogen substituent in N-fused triazoles was important, as no reaction proceeded with triazoles containing alkyl or H groups at C-7. Although the direct rhodium(II) perfluorobutyrate-catalyzed transannulation of triazoles afforded a convenient and rapid protocol toward indolizines, it was not without limitations (Scheme 1.47) [145,146].

Scheme 1.47

Six-membered N-heterocycles

25

The ring-opening by heteroatomic nucleophiles also occurred in an intramolecular manner that led to new heterocyclic compounds. For example, vinyl epoxide underwent 6-endo-cyclization under extremely mild conditions in the presence of Rh catalyst to provide the trans-hydroxypiperidine derivative. The olefinic functionality was crucial, as the reaction occurred through the initial coordination of π-bond and nitrogen lone pair, followed by formation of π-allyl or enyl intermediate. This double coordination was believed to govern both the stereoselectivity and regioselectivity of reaction (Scheme 1.48) [147].

Scheme 1.48

A chelation-assisted carbon-hydrogen activation of α,β-unsaturated ketoximes occurred in the presence of Rh catalyst and then the reaction with alkynes provided highly substituted pyridine derivatives (Scheme 1.49) [148].

Scheme 1.49

Rapoport and coworkers [149] reported the effect of ring size on N-H insertions. A series of substrates was prepared (Scheme 1.50) where the carbamate N-H bond undergoing insertion was tethered to diazo ketoester with carbon chains of several lengths.

Scheme 1.50

26

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The viability of one-pot examples encouraged to combine the ringclosing metathesis and carbenoid N
H insertion reactions in a one-pot protocol for the preparation of nitrogen-containing heterocycles of varying functionality and sizes (Scheme 1.51) [150]. Several factors were considered to ensure the success of their chosen tandem process. For example, the initial N
H insertion had to be chemoselective with minimal equivalents of the trapping agent at low catalyst loadings to avoid side reactions. Also, the reaction conditions of each step in the sequence had to be tuned carefully in order to avoid the suppression in each subsequent step in the sequence and to minimize the formation of by-products.

Scheme 1.51

Various acyclic enynes were converted to their cyclic diene isomers with endo-selectivity by Rh-catalyzed cycloisomerization. Two different catalyst systems were reported that were effective for the promotion of carbon
carbon bond-forming cyclization of enynes to afford the good-toexcellent yield of hetero- and carbocyclic compounds (Scheme 1.52) [151].

Scheme 1.52

A highly enantioselective Rh-catalyzed arylation of aliphatic N-tosylaldimines occurred in high yield with combination of an active Rh hydroxide complex, chiral bicyclo[3.3.0]octadiene ligands, and neutral reaction conditions. This protocol was applied for the one-pot enantioselective preparation of chiral 2-aryl-piperidines (Scheme 1.53) [152].

Six-membered N-heterocycles

27

Scheme 1.53

The five- and six-membered products were formed in excellent yields by mild, Rh-catalyzed hydroaminations of unactivated olefins with primary and secondary alkylamines. Various functional groups like halo, hydroxyl, carboalkoxyl, and cyano were tolerated (Scheme 1.54) [153].

Scheme 1.54

Ingrossio and coworkers [154] demonstrated the earliest example of the use of rhodium in the synthesis of pyridines by cycloaddition reactions wherein RhCp(C2H4)2 was used in the cycloaddition of propionitrile and 1-hexyne. This protocol provided pyridine products in an almost equal mixture of regioisomers albeit in moderate yields. The yield of pyridine products [155] increased to 67% by switching to RhCp (C2H4)2. However, for the cycloaddition reaction high reaction temperatures were necessary. Tanaka and coworkers [156] synthesized pyridines when diynes were reacted with nitriles and only 3 mol% rhodium-based catalyst. The pyridine product was obtained in quantitative yields when activated nitriles were used. However, when unactivated nitriles were used in the cycloaddition reaction the yields dropped significantly. In another example, the pyridine product was formed as a single regioisomer when activated aryl ethynyl ethers were reacted with nitriles in the presence of rhodium catalyst [157] (Schemes 1.55
1.57).

Scheme 1.55

28

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.56

Scheme 1.57

Hanzawa and coworkers [158] synthesized piperidine ring system with three contiguous stereocenters by [RhCl(cod)]2-catalyzed 1,4-conjugate addition of alkenylzirconocene chloride to a bis-enone derivative (Scheme 1.58) [25].

Scheme 1.58

Bates and Lim [159] reported a highly diastereoselective preparation of piperidine derivative via double-bond reduction of the allylamine followed by intramolecular reductive amination in the presence of Wilkinson’s catalyst (Scheme 1.59).

Scheme 1.59

Six-membered N-heterocycles

29

The ammonium ylides underwent [1,2]-shift similar to sulfonium and oxonium ylides. Benzyl group was a preferentially migrating group. West et al. [160
167] reported a sequence of intramolecular formation of ammonium ylide and subsequent rearrangement for the preparation of cyclic amines. Diazo ketone was reacted with rhodium acetate catalyst to afford an ammonium ylide that underwent [1,2]-shift to produce the piperidine derivatives (Scheme 1.60).

Scheme 1.60

Oshitari and Mandai [168] reported the preparation of a neurokinin substance P receptor antagonist (1)-CP-99,994, involving the synthesis of piperidine ring from allylamine via rhodium-assisted hydroformylation (Scheme 1.61) [25].

Scheme 1.61

This method was employed for the short total synthesis of prosopinine using Rh-BIPHEPHOS-catalyzed aminocarbonylation as a key step (Scheme 1.62) [169].

30

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.62

Ojima and coworkers [170,171] reported the cyclohydrocarbonylation reaction for the preparation of enantiopure derivatives of homokainoids or kainic acid, which were conformationally rigidified (S)-glutamic acids as depicted in Scheme 1.63. The cyclohydrocarbonylation reaction provided a key intermediate in quantitative yields that afforded the desired homokainic acid.

Scheme 1.63

Chiou and coworkers [172] prepared enantiopure 3-hydroxypiperidine derivatives in 91% yield using cyclohydrocarbonylation reaction; following a direct methoxy enamide adduct using a boron trifluoride reductivecleavage of etherate complex and a hydrosilane following the cyclohydrocarbonylation reaction (Scheme 1.64).

Scheme 1.64

The highly substituted pyridine derivatives were synthesized from α,β-unsaturated N-benzyl ketimines and aldimines and alkynes by a convenient one-pot carbon
hydrogen alkenylation/electrocyclization/aromatization sequence. The reaction occurred through the formation of dihydropyridine intermediates (Scheme 1.65) [173,174].

Six-membered N-heterocycles

31

Scheme 1.65

Highly functionalized pyridines were generated by a concise one-pot method involving a formal insertion of Rh vinylcarbenoids into the nitrogen
oxygen bond of isoxazoles. Rh vinylcarbenoids were derived from diazo compounds. The insertion products underwent a rearrangement upon heating to afford the 1,4-DHPs. 2,3-Dichloro-5,6-dicyanobenzoquinone oxidation provided the good yield of pyridines (Scheme 1.66) [175
178].

Scheme 1.66

Following the use of linear selective ligand BIPHEPHOS by Buchwald [176], Ojima and coworkers [178] developed an efficient cyclohydrocarbonylation of vinylglycine derivates toward pipecolic acid derivatives as depicted in Scheme 1.67. Quantitative yield of protected-pipecolate adduct was obtained by cyclohydrocarbonylation reaction.

Scheme 1.67

In the case of trimethoxy substrate the addition of trifluoracetic acid was detrimental to the reaction, it was likely to either cause degradation to the starting material or the product. The dimethoxy substrate was reacted under similar conditions (Scheme 1.68) [177].

32

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.68

Allyldipropargylamine (i.e., 1,6-enediyne) was reacted with a hydrosilane in the presence of a rhodium-cobalt or rhodium catalyst under carbon monoxide atmosphere and underwent another type of silylcarbocyclization involving only 1,6-diyne functionality to afford the high yield of exo-methylene-4-piperidinone (Scheme 1.69) [178,179].

Scheme 1.69

Valdez and Leighton [180] synthesized 3-substituted-4-oxopipecolic acid derivatives by a tandem asymmetric aza-Darzens reaction with nucleophilic ring-opening in situ. A chiral silane-containing Lewis acid was used to facilitate the subsequent nucleophilic opening of aziridine and activate both the imine for aza-Darzens reaction. A sulfonium ylide was produced from diphenylsulfide and ethyl diazoacetate by a rhodium acetate-catalyzed one-pot process (Scheme 1.70). The ylide attacked the acylhydrazone, which was complexed with enantiomerically pure silane, followed by elimination of diphenylsulfide to form the chiral aziridine. The silane remained complexed to aziridine that activate it for nucleophilic attack of chloride liberated from the silane and provided a single regioisomer of aminohalide with excellent ee and in good yield. To produce the N-heterocyclic core, aminohalide was reacted with acrolein to give the aldehyde. Deprotonation of thiazolium salt furnished

Six-membered N-heterocycles

33

N-heterocyclic carbene that reacted with aldehyde functionality to give an enol [181]. Subsequent cyclization of enol via a nucleophilic substitution reaction with inversion of stereogenic center formed 4-oxopipecolic acid analogue with retention of enantiopurity in good yield.

Scheme 1.70

Many different formats and supports were used in microwave-assisted synthesis apart from traditional cross-linked polystyrene resins. These included tentagel resins [182], cellulose membranes [183,184], cellulose beads [185], and glass surfaces [186]. Janda et al. [187] used JandaJel as a support in solid-phase synthesis of oxazoles. The resin-bound α-acylamino-β-ketoesters were treated with Burgess’s reagent to produce the oxazoles, which were cleaved from the resin with diversity-building amidation reaction. The best conditions used for the key cyclization step were 20 eq. of pyridine and 3 eq. of Burgess’s reagent in chlorobenzene (15 min, 100 °C). Interestingly, conventional thermal heating for 4 h at 80 °C was used for the synthesis of final library since it afforded conversions as high as the 15 min MW run (Scheme 1.71).

Scheme 1.71

34

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The triazole was treated with phenylacetylene in the presence of Rh(II) acetate to test the hypothesis regarding the annulation of amino diazo compounds with alkynes to form a pyrrole ring. This reaction occurred smoothly to form a mixture of indolizine and cyclopropene with yields of 28% and 68% of isolated product, respectively. Surprisingly, under these reaction conditions cyclopropene did not undergo further isomerization into indolizine [138]. Throughout the reaction the ratio of these products remained constant, suggesting an independent path for the synthesis of indolizine (Scheme 1.72).

Scheme 1.72

1.2.16 Samarium-assisted synthesis Hydroamination/cyclization of aminoallenes was faster than the reaction of (terminal) aminoalkenes, but slower (by a factor of 5
20) than aminoalkynes [188,189]. The cyclization followed two different routes providing two possible regioisomers (Scheme 1.73). A mixture of products was obtained from mono-substituted, terminal allenes; however, synthesis of cyclic imine through the endocyclic pathway was favored. However, while this was true for the hexadienylamine, cyclization of homologous heptadienylamine provided tetrahydropyridine exclusively. The mode of synthesis of tetrahydropyridine was not known, because it involved either an allene to alkyne isomerization of aminoallene starting material prior to the hydroamination/ cyclization step or cyclization of heptadienylamine through exocyclic pathway, followed by an isomerization of allylamine [110].

Scheme 1.73

Six-membered N-heterocycles

35

A variety of alkaloid frameworks [190
201] and pharmaceutically relevant targets [202] were generated by intramolecular hydroamination. Marks and coworkers [203] synthesized (1)-coniine starting from aminodiene in a few steps using chiral octahydrofluorenyl samarocene complex (S)-Sm (Scheme 1.74) [110].

Scheme 1.74

1.2.17 Scandium-assisted synthesis The acyl-α-lactam and amino thioester derivatives were formed stereoselectively in high yields by Sc(OTf)3-catalyzed four-component coupling reactions of α,β-unsaturated thioesters, silyl enol ethers, amines, and aldehydes (Scheme 1.75) [143,204].

Scheme 1.75

Sc(OTf)3 was found to be an efficient catalyst in aza-Diels
Alder reactions [205
207]. The substituted N-benzylideneaniline was reacted with 2-trans-1-methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky’s diene) in the presence of 10 mol% Sc(OTf)3 to give the imino-Diels
Alder adducts (a tetrahydropyridine derivative in this case) quantitatively (Scheme 1.76) [143].

Scheme 1.76

36

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Amines are the most widely used and easily available amino sources in organic synthesis. They were frequently used as amine component in the classical Hantzsch reaction. Similarly, amines were also favorable amino sources in the devisal of new multicomponent synthesis of 1,4-dihydropyridines. For example, α,β-unsaturated aldehydes, amines, and 1,3-dicarbonyl compounds were reacted for the synthesis of unsymmetrical 1,4-dihydropyridines. During the synthesis of 1,4-dihydropyridines by two-component condensation of α,β-unsaturated aldehydes and β-enamino esters, Renaud and coworkers [208] performed tentative investigations on direct three-component reaction of amines, 1,3-dicarbonyl compounds, and α,β-unsaturated aldehydes to afford the 1,4-dihydropyridines with Lewis acid catalyst. The reactions were conducted in a stepwise manner to afford the moderate-to-excellent yields (Scheme 1.77) [39].

Scheme 1.77

The 2,6-unsubstituted 1,4-dihydropyridines were synthesized by a multicomponent reaction using electron-rich alkenes as precursors of enaminone intermediates. Use of Lewis acid Sc(OTf)3 afforded 1,4-dihydropyridines in fair-to-good yields. However, this method has disadvantages such as the presence of side products and 2
19 days of reaction time (Scheme 1.78) [39,209].

Scheme 1.78

The condensation of aldehydes and amines afforded imines. Direct use of amines, aldehydes, and propiolates has been a well-established method for the preparation of 1,4-dihydropyridines. Interestingly, Fukuzawa and coworkers [210] reported a three-component reaction of two molecules

Six-membered N-heterocycles

37

of propiolates and imines to afford the 1,4-dihydropyridines in the presence of 10 mol% Lewis acid catalyst Sc(OTf)3. In these reactions, one key step was the decomposition of imines to amines and aldehydes. The products were obtained in only low-to-moderate yields by this reaction with imines obtained from the condensation of aromatic aldehydes with aliphatic/aromatic amines (Scheme 1.79) [39].

Scheme 1.79

1.2.18 Silicon-assisted synthesis The radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates comprised a novel protocol to 2,4-disubstituted piperidines. The diastereoselectivity enhanced by employing tris(trimethylsilyl)silane in place of tributyltin hydride (Scheme 1.80) [211].

Scheme 1.80

The azabicyclo[2.2.2]octan-5-ones were synthesized by a highly diastereoselective three-component aza-Diels
Alder reaction of anilines, benzaldehydes, and cyclohexenone (Scheme 1.81) [212]. A strong heteropoly acid H4[SiW12O40] catalyzed the reaction. The bicyclic products were formed with excellent diastereoselectivities (up to . 99:1) in moderate yields [22].

Scheme 1.81

38

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The cyanide derivatives like malonitrile were frequently used as reactive substrates for the preparation of 1,4-dihydropyridines in amine, NH3 or enaminone by multicomponent reactions. In these reactions amine, enamione, or NH3 acted as amino source to produce the heterocyclic backbone while cyano groups were mainly involved as the donor of electrophilic carbons in multicomponent reactions. Interestingly, in some reactions, it was also possible to directly employ the nitrogen atom in cyano group as the amino source of 1,4-dihydropyridines. Fustero et al. [213] reported a three-component reaction involving alkyl propiolates, fluorinated nitriles (cyanides), and chiral allyl p-tolyl sulfoxide for the preparation of 1,4-dihydropyridines (Scheme 1.82) [39].

Scheme 1.82

1.2.19 Tin-assisted synthesis The triphenylpyridine was prepared from phenylacetylene, chloroanhydride of benzoic acid, and ammonia in the presence of tin(IV) chloride catalyst (Scheme 1.83) [44,214
216].

Scheme 1.83

Gowrisankar and coworkers [217] reported a reaction of allylamines involving an allyltributylstannane-mediated vinyl radical cyclization as key step for the stereoselective syntheses of two types of regioisomeric methyl 5-methylenepiperidine-3-carboxylates (Schemes 1.84 and 1.85). The reaction involved sequential 5-exo-trig cyclization followed by 1,2-aryl migration [25,218
222].

Six-membered N-heterocycles

39

Scheme 1.84

Scheme 1.85

1.2.20 Ytterbium-assisted synthesis The reaction was carried out using imines linked through the nitrogen atom to a Rink amide resin, an aminomethyl polystyrene-based resin. The product was cleaved from Rink linker with trifluoracetic acid. This protocol can even convert the ketones into 2,2-disubstituted dihydropyridones (Scheme 1.86) [223
225].

Scheme 1.86

Aminomethylated polystyrene resin was used as the immobilized amine component of a solid-phase aza-Diels
Alder reaction. Direct combination of resin, an aldehyde, a diene, and lanthanide(III) triflate furnished a tetrahydropiperidine ring smoothly. The [4 1 2] adducts were cleaved efficiently from the solid support employing a traceless release protocol involving N-dealkylation of the tertiary amine via treatment of the resin-bound product with 1-chloroethyl chloroformate and subsequent methanolic decomposition of the formed carbamate. The piperidine derivatives were formed with purity in reasonable to excellent yields (Scheme 1.87) [226].

40

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 1.87

The β-ester acetals served as C-nucleophile sources and precursors of β-enamino esters for the synthesis of 1,4-dihydropyridines. The starting acetals and aromatic amines produced β-enamino esters in situ that reacted with aldehydes in homocondensation to afford the 1,4-dihydropyridines in the presence of Lewis acid Yb(OTf)3 by heating at 90 °C in dioxane (Scheme 1.88) [39,227].

Scheme 1.88

1.2.21 Zinc-assisted synthesis The 2-amino-3,5-dicarbonitrile-6-thio-pyridines [228] were synthesized in better yields (45%
77%) by zinc chloride-catalyzed one-pot threecomponent reaction under microwave or conventional heating (Scheme 1.89) when compared to reports [229] using base catalysts such as Et3N or 1,4-diazabicyclo[2.2.2]octane (20%
48%) and conventional heating methods.

Scheme 1.89

Six-membered N-heterocycles

41

This protocol used Danishefsky’s diene to prepare the peptidomimetic opioids, which were derived from N-alkyl-2-alkyl-2,3-dihydro-4-pyridone. This was the central reaction with easily available building blocks under mild conditions, showing the use of [4 1 2]-cyclocondensation in the preparation of novel, complex heterocyclic compounds (Scheme 1.90) [230].

Scheme 1.90

The 2,3-dihydro-4-pyridones were synthesized on a soluble polymer support, where poly(ethylene glycol)-supported aldehyde or amine was used to produce the imine component (Scheme 1.91) [231a,b].

Scheme 1.91

Barluenga and coworkers [232] reported a reaction using a chiral diene for an asymmetric cycloaddition to form the highly functionalized 4oxopipecolic acid derivatives. A Lewis acid-catalyzed Diels
Alder reaction of chiral diene and N-silylaldimine was performed (Scheme 1.92). Basic hydrolysis cleaved the nitrogen-silicon bond and the formed enamine of chiral auxiliary afforded piperidone in excellent ee. Several reactions were performed to protect the amine selectively with 2,2,2-trichloroethyloxycarbonyl chloride (TrocCl). The protecting group reactions

42

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

were followed by oxidation of the alcohol to give the carboxylic acid and subsequent esterification provided the pipecolic acid motif. Finally, deprotection of the Troc-protecting group furnished (2R,3S,6S)-4-oxopipecolic acid analogue in 99% yield.

Scheme 1.92

The 2-alkyl-4-methylpyridines were obtained in high selectivity and yields (90%) by interaction of dimethylethynylcarbinol with ammonia and carboxylic chloroanhydrid3es in the presence of zinc chloride under mild conditions (40 °C) (Scheme 1.93) [44,233,234].

Scheme 1.93

The reactions were performed [233,235] for the synthesis of di-, tri-, and tetraalkylpyridines. The 1,2-dialkyl-l,3-enines were reacted with carboxylic chloroanhydrides to afford only 2,3,4-trialkylpyridines, while 2,4dialkyl-l,3-enines provided 2,3,4,6-tetraalkylsubstituted pyridines in high selectivity (Scheme 1.94) [44].

Scheme 1.94

Six-membered N-heterocycles

43

The aluminum(III) chloride was changed to zinc chloride to obtain a target product with 100% selectivity and in 95% yield (Scheme 1.95) [44,236].

Scheme 1.95

The change of t-butanol with isobutylene confirmed the supposition experimentally [237,238]. The reaction provided high yield (88%) of 2,4,6-trimethylpyridine. The alkyl-substituted pyridines were synthesized from chloroanhydrides of carboxylic acids in the presence of indium chloride, zinc chloride, and tin(IV) chloride (Scheme 1.96) [44,239,240].

Scheme 1.96

The L-mannonic γ-lactone provided (S)-2,3-di-O-benzylglyceraldehyde in six steps in 44% yield that was reacted with (R)-α-methylbenzylamine to afford the chiral imine (Scheme 1.97). The unsaturated (2S)-piperidone was formed with complete diastereoselectivity by a Lewis acid-catalyzed hetero-Diels
Alder reaction of imine with Danishefsky’s diene. Concurrent reduction of the ketone and the enamine functionality with sodium borohydride provided a single diastereomer with the desired (4R)-4-hydroxy stereochemistry. An intermediate was produced by acetylation of hydroxyl group and selective hydrogenation of N-benzyl group in the presence of Boc anhydride. The (2S,4R)-4-hydroxypipecolic acid was obtained by hydrogenation of both O-benzyl protecting groups followed by oxidative cleavage. Further steps were needed to transform the pipecolic acid into a suitably functionalized key intermediate for the preparation of palinavir. This reaction reported by Gálvez and coworkers [241] was highly efficient. The key hetero-Diels
Alder reaction and

44

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

subsequent reduction were high yielding and completely stereoselective. Access to both (2R)- and (2S)-carboxylic acid substituents was possible using either (R)- or (S)-configurations of starting material, respectively. The opposite stereochemistry of hydroxyl group was obtained with Lselectride. The disadvantage of this method was that seven linear steps were required to synthesize the starting imine.

Scheme 1.97

Gálvez and coworkers [241] performed an asymmetric heteroDiels
Alder reaction using an enantiomerically pure imine to produce the 4-oxopipecolic acid. Danishefsky’s diene was reacted with a chiral imine obtained from benzylamine and 2,3-dibenzyl-D-glyceraldehyde, catalyzed by zinc chloride to afford the piperidone core with excellent diastereoselectivity in moderate yield (Scheme 1.98). The desired product was synthesized using L-selectride to reduce the alkene and then protection of the ketone as a ketal to afford the intermediate. The carboxylic acid was produced by hydrogenolysis of benzyl protecting groups then Boc protection of the nitrogen, followed by oxidation of diol. Finally, the unnatural enantiomer of 4-oxopipecolic acid was formed upon removal of the protecting groups under acidic conditions.

Six-membered N-heterocycles

45

Scheme 1.98

Ji and coworkers [242] synthesized a series of pyridine-substituted 3,6diazabicyclo[3.2.0]heptanes that acted as selective agonists for a nicotinic acetylcholine receptor (Scheme 1.99). The bicyclic core of these compounds was constructed from an allylamine, which underwent [1,3]dipolar cycloaddition reaction to synthesize the isoxazolidine. This isoxazolidine was cleaved to furnish a product, which after chiral resolution and cyclization afforded a required subunit [25].

Scheme 1.99

46

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

A mixture of intermediate and pyridine derivative was obtained when propylenemalononitrile derivative was treated with trimethyl o-acetate. The substituted pyridone was yielded upon demethylation of pyridine by Olah’s protocol (Scheme 1.100). The substituted pyridone was used as the C
D ring unit for the generation of streptonigrin analogues [243]. Streptonigrin has a pyridyl substituted quinoline system and acts as an antitumor and antibiotic [244].

Scheme 1.100

The isocyanoacetamides were involved in these Passerini-type heterocyclizations. Thus isocyanoacetamides reacted smoothly with aliphatic carbonyl compounds in the presence of R3SiCl and Zn(OTf)2 as a Lewis acid to afford the good yields of protected 2-hydroxyalkyl oxazole derivatives [245]. Benzaldehyde provided a by-product in significant amount by a second condensation of benzaldehyde at the 4-position of oxazole. The by-products became dominant products (yield 61%) when 2 eq. of benzaldehyde was used. The 4-position in oxazoles was highly reactive toward electrophilic attack and offered useful opportunities for further modifications (Scheme 1.101) [112,246].

Six-membered N-heterocycles

47

Scheme 1.101

Salehi and Guo [247] synthesized 1,4-DHPs in H2O under MWI employing tetrabutylammonium bromide as a phase-transfer catalyst by the reaction of ethyl/methyl acetoacetates, aldehydes, and ammonium acetate (Scheme 1.102). The reactions were completed in 3
10 min. In the absence of microwaves, even at 100 °C, did not result in significant yields in 10 min. Terephthalaldehyde, a dialdehyde, was used as a substrate for the bifunctional compounds possessing two units. Sivamurugan and coworkers [248] performed a Lewis acid Zn[(L)proline]2-catalyzed onepot synthesis of Hantzsch 1,4-DHPs under MWI and solvent-free conditions [249].

Scheme 1.102

1.2.22 Zirconium-assisted synthesis The allylamines were used as precursors for the synthesis of 4arylpiperidines (Scheme 1.103) [25,250].

Scheme 1.103

The zirconium-catalyzed reaction of EtMgCl with imines under selected conditions furnished C,N-dimagnesiated compounds that were further trapped with electrophiles. The overall transformation constituted

48

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

a new pathway to cyclic or bifunctional nitrogen-containing compounds like pyrrolidines, 1-azaspirocyclic γ-lactams, and azetidines (Scheme 1.104) [251].

Scheme 1.104

Ahari et al. [252] reported an efficient method for the synthesis of enantiomerically pure trans-2,3-disubstituted piperidines from substituted allylamines. The allylamines were formed from starting material by sequential hydrozirconation, iodination, and base-mediated ring-closure reactions (Scheme 1.105) [25].

Scheme 1.105

Takahashi et al. [133] reported an intermolecular cycloaddition reaction of two different alkynes and a nitrile for the preparation of pyridines (Scheme 1.106).

Scheme 1.106

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CHAPTER 2

Six-membered fused N-heterocycles 2.1 Introduction Diverse compounds such as alkaloids, antibiotics, essential amino acids, vitamins, hemoglobin, and hormones and various synthetic drugs and dyes contain heterocycles as core skeletons [1a
e]. The ability of heterocyclic nuclei to act both as biomimetics reactive and pharmacophores has largely contributed to their unique value as traditional key elements of many drugs constituting the main structure of a number of natural products and exhibit a wide range of biological activities. Due to their importance in biological areas, the development of synthetic methods for nitrogen heterocyclic compounds and their fused scaffolds with a high degree of diversity has become a leading focus in modern drug design and discovery [2
4]. This chapter covers the preparation of many fused six-membered N-heterocycles because a number of biological properties are associated with them. They are valuable building blocks in pharmaceuticals and are known for exhibiting many biological properties like antimicrobial, antiinflammatory, antiasthmatic, antioxidants, anticancer, anti-HIV, antileishmanial, and antituberculosis. Natural quinine as well as synthetic chloroquine and their analogues are some of the quinoline-based antimalarials that are used for the treatment of malaria. They act by interfering hemoglobin digestion in the blood stages of malaria parasite’s lifecycle. Norfloxacin, ciprofloxacin, and levofloxacin are some of the important antibiotics based on a quinoline-based antioxidant used as a food preservative (E324) as well as pesticide and is sold under fluoroquinolones. Oxamniquine is a tetrahydroquinoline-based drug that is effective anthelmintic with schistosomicidal activity against Schistosoma mansoni. Martinellic acid and martinelline alkaloids with fused tetrahydroquinoline are isolated from the roots of Martinella iquitosensis that are used as an eye medication in South America. L-689560 serves as a very potent N-methyl-D-aspartate antagonist. Ethoxyquin is used as a preservative to Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00002-6

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

prevent the rancidification of fats in pet foods. It is also used as a rubber stabilizer. Some substituted quinolines exhibit potent antibreast cancer activity. 4-Carboxyl quinoline derivative acts as a selective cyclooxygenase inhibitor with greater potency than reference drug celecoxib. The hydrazones based on quinoline show excellent antibacterial and antituberculosis activities [5
16].

2.2 Metal- and nonmetal-assisted synthesis of six-membered N-heterocycles fused with other heterocycles 2.2.1 Aluminum-assisted synthesis The thiazolo[4,5-b]pyridines were synthesized under solid-phase conditions on the basis of successful solution-phase synthetic conditions. The thiazole resin with diversity element was reacted with ketones under optimized Friedlander reaction conditions (microwave irradiation and aluminum(III) chloride). This reaction afforded thiazolo[4,5-b]pyridine resin. The resin was treated with m-chloroperoxybenzoic acid in dichloromethane to afford the resin-bound sulfone intermediate. Finally, the sulfone group on resin was displaced with amines by a desulfonative substitution reaction in tetrahydrofuran and spontaneous cleavage from the resin to synthesize the thiazolo[4,5-b]pyridine [17,18]. The solidphase synthesis of thiazolo[4,5-b]pyridines used appropriate ketones, bromoacetophenones, and amines as diversity elements and key building blocks. The thiazolo[4,5-b]pyridine resin was produced efficiently by this reaction. This method was accompanied by concurrent cleavage from the resin to provide the final thiazolo[4,5-b]pyridine derivatives (Scheme 2.1) [19].

Scheme 2.1

Six-membered fused N-heterocycles

67

The alkyl-substituted pyridines were synthesized by a reaction of t-butanol with gaseous NH3 and acetylchloride in the presence of aluminum(III) chloride as condensing agent [20]. The reaction occurred unselectively to afford a mixture of 4-acetonyl-2,6-dimethylpyridine, 2,4,6-trimethylpyridine, and 1,3,6,8-tetramethyl-2,7-naphthyridine in common 85% yield (Scheme 2.2).

Scheme 2.2

A cascade three-component reaction was developed for the preparation of fused heterocyclic 1,4-dihydropyridines using aldehydes, 2-chlorophenyl functionalized thioamides, and malonitrile. The 1,4-dihydropyridines were prepared efficiently through intramolecular cyclization of intermediates under microwave irradiation (MWI) in the presence of potassium fluoride/ neutral aluminum oxide catalysts with poly(ethylene glycol)-6000 (Scheme 2.3) [21,22].

Scheme 2.3

68

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 2.4

A variety of 4-aza-1,7-dienes bearing activated enophile underwent thermal or Lewis acid-catalyzed ene cyclization to synthesize the substituted piperidines, the ene cyclization product, along with bicyclic lactones, formed via a competing hetero-Diels
Alder reaction (Schemes 2.4 and 2.5). A thermal ene cyclization was facilitated upon activation of the enophile with a single ester, but the reaction was not amenable to Lewis acid catalysis. The Lewis acid-catalyzed reaction was facile with other activating groups on the enophile, although there was a fine balance between the competing hetero-Diels
Alder reaction and the desired ene cyclization, the product distribution was influenced by the nature of ene component, the activating group on the enophile, and the Lewis acid used [23,24].

Scheme 2.5

Six-membered fused N-heterocycles

69

Kim and coworkers [25] reported radical cyclization of enamide derivatives to afford the dihydropyrido[2,1-a]isoindolone derivatives. The enamide derivatives were in turn synthesized from the allylamines with o-haloaryl substituents at the rear position (Scheme 2.6) [24].

Scheme 2.6

De Kimpe and coworkers [26] reported a tributyltin hydride and azobisisobutyronitrile-mediated radical cyclization using bromoalkane as radical precursor for the conversion of 1-allyl- and 1-(3-phenylallyl)-substituted 4-(2-bromo-1,1-dimethylethyl)azetidin-2-ones into 3-substituted 7-alkoxy5,5-dimethyl-1-azabicyclo[4.2.0]octane-8-ones in good diastereomeric excess (Scheme 2.7). Bromoalkane was in turn produced when allylamine was reacted with 3,3-dimethyl-1-bromopropanal [24].

Scheme 2.7

70

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

2.2.2 Calcium-assisted synthesis The monomorine is an indolizidine alkaloid isolated from the pharaoh ant. This reaction was used for the synthesis of monomorine

Scheme 2.8

(Scheme 2.8) [27]. The key steps involved were an intramolecular 1,6conjugate addition of a hydroxylamine, followed by a tandem double hydrogenation-cyclization.

2.2.3 Cerium-assisted synthesis The more-complex diversification processes became possible by ready access to solid-supported hydroformylation products, as shown for the Hantzsch synthesis of pyridines from an allylic alcohol. After the hydroformylation in scCO2, the solid-supported aldehydes were subjected without further purification and directly to multicomponent coupling with methyl 3-aminocrotonate and methyl acetoacetonate. The two isomeric pyridines were formed in 99% yield by aromatization with ceric ammonium nitrate and subsequent cleavage of the anchoring group with trifluoracetic acid (Scheme 2.9) [28].

Scheme 2.9

72

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Heterogeneous gold on nanocrystalline CeO2 was used [29]. The effect of functional groups [30] and sterically demanding substituents [31] was investigated in-depth. This reaction occurred effectively also with gold(I) [32] and platinum(II) [33] catalysts. The versatile method was applied for the construction of a variety of five- and six-membered ring fused phenols [34,35], enantiomerically pure tetrahydroisoquinolines [36], bis-phenols [37], and oxepins [38]. The [(Ph3PAu)2Cl][BF4]- or gold(III) chloride-catalyzed hydroarylation of sylilated γ-alkynylfurans was reported (Scheme 2.10) [39,40]. The phenols with a silyl group were formed with PtCl2(MeCN)2 [41].

Scheme 2.10

2.2.4 Cesium-assisted synthesis Cycloaddition reactions were performed on acid-labile polystyrene supports such as 4-(hydroxymethyl)phenoxyacetic acid (HMPB)-AM resin, Wang resin, and syringaldehyde-based resin. All steps (i.e., linking, cycloaddition, and cleavage) under solid-phase were performed under both controlled MWI and thermal conditions. The reaction times decreased from hours or days to minutes and significant rate enhancements were observed under high-temperature microwave (MW) conditions (Scheme 2.11) [42].

Scheme 2.11

Six-membered fused N-heterocycles

73

2.2.5 Iodine-assisted synthesis Lingam et al. [43] reported an I2-induced Pictet
Spengler reaction for the synthesis of many 1,1-disubstituted tetrahydro-β-carbolines [44] (Scheme 2.12). I2 catalyzed the reaction upon coordinating with carbonyl oxygen of ketones that was then attacked by the amino group of tryptamine to produce an intermediate. The formed intermediate underwent an intramolecular Friedel
Crafts cyclization followed by loss of proton to afford the desired products [45].

Scheme 2.12

The ketone was reacted using O-methyl hydroxylamine hydrochloride to produce the oxime in 85% yield. The starting material was treated with 1 eq. of EtN(i-Pr)2 and 5 eq. of I2 in 1,2-dicholoethylene at room temperature to provide a mixture of products (Scheme 2.13) [46].

Scheme 2.13

Yamamato et al. [47] reported a general protocol for the preparation of highly substituted isoquinolines from o-alkynyl benzyl azides (Scheme 2.14). I2 coordinated with the carbon
carbon triple bond of compound and activated it toward nucleophilic ring-closure of azide. The isoquinolines were formed by subsequent elimination of H1 and nitrogen [45].

Scheme 2.14

74

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

This method [48] was employed for the preparation of pyrralopyridines where I2-mediated electrophilic cyclization of 2-alkynyl-1-methylene azide aromatics occurred (Scheme 2.15) [45].

Scheme 2.15

The unsaturated bromo-substituted alkyne as well as the alkyne was well suited for the synthesis of annulated pyridines [49
54]. The bromo-substituted alkyne was reacted with t-butyllithium (2 eq., 1 h, 278 °C) to afford the lithium intermediate that readily added p-TolCN (1.3 eq., 1 h, 278 °C) to lithiated pyridine derivative via a remarkably fast 6-endo-dig ringclosure [55]. The poly-functional annulated pyridine was formed in 60% yield after iodolysis (Scheme 2.16).

Scheme 2.16

An intermediate was produced by lithiation of 3-alkynylbenzofuran in 2 position employing n-butyllithium (1.1 eq., 4 h, 255 °C) followed by addition of p-TolCN (1.3 eq., 2 h, 240 °C). The products were formed in 62% and 55% yields after addition of iodine or bromine (Scheme 2.17) [56].

Six-membered fused N-heterocycles

75

Scheme 2.17

Shibahara et al. [57] synthesized several 2-aza-indolizines from N-2pyridylmethyl thioamides via an I2-mediated, oxidative desulfurization [58,59] promoted cyclizations (Scheme 2.18). An intermediate was generated by deprotonation of the N-2-pyridylmethyl thioamides with pyridine, followed by double iodination at sulfur. The 2-aza-indolizines were prepared by intramolecular substitution by the pyridine nitrogen of intermediate and subsequent aromatization of the formed intermediate [45].

Scheme 2.18

A convenient method was accomplished via regioselective iodocyclization reaction to synthesize the novel selenium-β-lactams like 3-selena-1dethiacephems (Scheme 2.19) [60a,b]. The key starting compounds, alkyne-selenoureas, were readily synthesized under basic conditions by N-alkylation reaction of propargyl-azetidinones with a variety of isoselenocyanates. Firstly, the reaction of β-alkyne-selenourea was examined with 1.05 eq. of sodium iodide symporter (NIS) or I2 at room temperature in tetrahydrofuran. The reaction highly depends on the type of electrophile used. With NIS, the desired 3-selena-1-dethiacephem was obtained along with 3-aza-4-oxo-1-dethiacephem and 3-aza-4-selenoxo-1-dethiacephem. The decomposition of 3-aza-4-selenoxo-1-dethiacephem provided 3-aza-4-oxo-1-dethiacephem. However, the desired 3-selena-1dethiacephem was exclusively obtained in good yield (84%) with

76

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

byproducts only in trace amounts (as indicated by thin layer chromatography) when the reaction was performed using 1.05 eq. of I2. Different reaction conditions were screened to improve the yield of cyclization. The best solvent for cyclization reaction was dichloromethane. The reaction was strongly affected by the amount of I2 added, and the 1.25 eq. of I2 provided the best result (92% yield). Therefore the iodocyclization of other alkyne-selenoureas was performed with 1.25 eq. of I2 at room temperature in dichloromethane. Good-to-excellent yields of various 3-selena-1dethiacephems were obtained. The nature of substituent on selenourea had very little effect on the product yields or reaction rate. Arylsubstituted selenoureas provided slightly higher yield as compared to alkyl-substituted selenoureas. The aryl substitution at alkynes was also well accommodated and furnished the excellent yields of cyclized products. The reaction showed high regioselectivity for six-membered ring selenacephems. Seven-membered ring products were never formed under these reaction conditions.

Scheme 2.19

2.2.6 Iridium-assisted synthesis Sames et al. [61] reported that alkene-amide substrates underwent an oxidative intramolecular cyclization reaction under catalytic and neutral conditions. This overall conversion needed tandem sp3 carbon
hydrogen bond activation at the position adjacent to the carbon
carbon and amide nitrogen bond formation. For example, pyrrolidine substrate was transformed to indolizidinone and pyrrolizidinone products in 17% and 66% yield, respectively, in the presence of [Ir(COE)2Cl]2 with hydrogen acceptor norbornene or tert-butylethylene and carbene ligand N,N’-bis

Six-membered fused N-heterocycles

77

(2,6-diisopropylphenyl)imidazolyl carbene (IPR) (N,N 0 -bis(2,6-diisopropylphenyl)imidazolyl carbene) (Scheme 2.20) [62].

Scheme 2.20

2.2.7 Iron-assisted synthesis Wan et al. [63] developed a cycloaddition of diynes and unactivated nitriles in the presence of iron catalyst. The pyridine product was formed in excellent yields. However, for the cycloaddition reaction a large excess of nitrile was needed. The authors developed an iron catalyst system to prepare the pyridines and expanded the scope of existing substrate in the cycloaddition of alkynes and alkynenitriles (Scheme 2.21).

Scheme 2.21

Asymmetric induction in this ene reaction was performed by using a combination of a chiral bis-oxazoline ligand and Fe(acac)3 and triethyl aluminum as the catalyst [64]. No asymmetric induction occurred, but high 1,3-stereoinduction was reported. Heterobicycles were synthesized. While the catalyst was poisoned with an excess of ligand, it was rather surprising that amine with substrates underwent cyclizations. Whereas starting material was cyclized to provide indolizidines in a 25:75 ratio (mixture of Z and E isomers) with bipyridine ligand, the utilization of chiral BOX ligand mainly provided product exclusively in 95% yield as racemate with E configuration at the enol ether double bond (Scheme 2.22) [65]. Oxobicycles and quinolizidines can also be prepared employing similar processes [66,67].

Scheme 2.22

Modified Michael reactions were performed for the preparation of highly substituted pyridines using α,β-unsaturated oximes as acceptors in the presence of ethyl acetoacetate [67,68]. To obtain the product very high temperature was required even under iron catalysis. Nevertheless, the method was synthetically interesting because of its operational simplicity (Scheme 2.23).

Scheme 2.23

The efficiency of iron-catalyzed cycloaddition reactions to produce the benzannulated compounds prompted researchers to investigate the cycloaddition of alkynes and alkynenitriles for the synthesis of pyridines. The pyridines were prepared from diynes with difficulty due to the limited reactivity of nitrile to undergo cycloaddition reactions. Therefore the nitrile and alkyne were tethered to promote the initial cycloaddition of nitrile, alkyne, and Fe catalyst functionalities. Decyne and alkynenitrile were subjected to 40 mol% ligand and 30 mol% iron acetate, and zinc dust at 80 °C in dimethylaniline (DMA). Many phosphines, amines, and Rh(I)-N-heterocyclic carbine (NHCs) were used based on their successful use as ligands in other cycloaddition reactions involving iron [69
78]. However, the use of NHCs or phosphines as ligands did not result in the synthesis of desired cycloaddition pyridine product (Scheme 2.24).

Scheme 2.24

The iron catalytic system was also effective in intramolecular cycloaddition of dialkynenitriles. The substrate was reacted upon the addition of 20 mol% Fe(OAc)2 to provide the tricyclic product in 74% yield (Scheme 2.25) [79a,b].

Six-membered fused N-heterocycles

79

Scheme 2.25

The trifluoromethyl group at β-position toward the heterocyclic nitrogen atom in azines was involved in irreversible enzyme inhibition [80], which makes it reasonable for the search of cytotoxic antitumor agents among 3-trifluoromethyl substituted pyridines. The synthesis of fused 3-CF3-substituted pyridines was reported only in one publication [81] where 3,3,3-trifluoro-2-methoxy-2-arylpropyonitrile provided 3-CF3substituted pyridines. The methods were developed to synthesize the compounds with aromatic moieties where 1-aryl-4-(trifluoromethyl)thieno[3,2-с]pyridines were formed using 3,3,3-trifluoro-1-nitropropene and trifluoroacetylthiophen as key reagent for the preparation of 1-aryl-4-trifluoromethyl-β-carbolines (Scheme 2.26) [82].

Scheme 2.26

80

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Efforts to isolate Fe(OAc)n complex were unsuccessful. However, the analogous ferrous bromide complex [83] was produced and used as a catalyst for the cycloaddition of decyne and alkynenitrile. The iron-ligand complex catalyzed the coupling and provided 58% yield of pyridine. For comparison, reactions performed with 10 mol% ferrous bromide, in lieu of ferrous acetate, afforded pyridine in 54% yield (Scheme 2.27) [77].

Scheme 2.27

2.2.8 Lithium-assisted synthesis The Friendlader synthesis of 1,8-napthyridine using MR44 was performed in the presence of lithium chloride as an efficient catalyst. Lithium chloride was added to a mixture of appropriate active methylene compound and 2-amino nicotinaldehyde, mixed thoroughly and irradiated in a microwave oven (Scheme 2.28) [84].

Scheme 2.28

Wang and coworkers [85] reported a sequential I
Li exchange in vinyl iodide followed by intramolecular nucleophilic acyl substitution of aminoalkenyllithium ester for the synthesis of alkylidene aza-cycloketones with defined olefin geometry (Scheme 2.29). This key reaction was used to carry out a concise total synthesis of allopumiliotoxin [24].

Scheme 2.29

Six-membered fused N-heterocycles

81

2.2.9 Manganese-assisted synthesis The cyclization/oxidation sequence of different amides obtained from tryptamine was reported under optimized conditions. Surprisingly, no carboline products were observed. However, the cyclization step occurred only after the reaction of amides with diphosphonium analogue when heated for about 30 min at 130 °C. Subsequent oxidation with manganese (IV) oxide afforded carboline products in 65% to 88% yields. It was reported that this reaction provided an effective pathway to synthesize the carboline natural products (Scheme 2.30) [86,87].

Scheme 2.30

2.2.10 Mercury-assisted synthesis Dhavale and coworkers [88] reported that sugar-derived β-hydroxy-alkenylamines underwent an intramolecular aminomercuration reaction for the synthesis of sugar-substituted pyrrolidines (Scheme 2.31). The sugar-derived β-hydroxy-alkenylamines were prepared from allylamines. The pyrrolidines were elaborated for the preparation of polyhydroxylated indolizidine alkaloids such as 1-epi-castanospermine, castanospermine, and 8-epicastanospermine [24].

Scheme 2.31

82

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

2.2.11 Molybdenum-assisted synthesis Optically enriched small- and medium-ring unsaturated cyclic amines and N-fused bicyclic amides were prepared in up to 98% enantiomeric excess by molybdenum-catalyzed desymmetrization of easily available achiral polyene substrates. The effects of olefin substitution, catalyst structure, ring size, and positioning of Lewis basic functional groups were evaluated (Scheme 2.32) [89].

Scheme 2.32

Martin and coworkers [90] synthesized a series of bicyclic ring systems (Scheme 2.33). Grubbs and Fu [91] used ring-closing metathesis (RCM) for the preparation of dihydropyrroles that was applied for the synthesis of fused aza-heterocycles (found in a number of alkaloids) in the presence of Schrock's catalyst. Thus it was reported that RCM can be used to synthesize a number of fused nitrogen heterocycles such as indolizidine, pyrrolizidine, and quinolizidine alkaloid scaffolds [92].

Scheme 2.33

2.2.12 Neodymium-assisted synthesis This protocol provided tricyclic and tetracyclic alkaloidal skeletons [93]. Particularly high diastereoselectivities were reported in the synthesis of benzo[a]quinolizine and pyrido[2,1-a]isoindolizine ring systems. Remarkably, electron-donating methoxy substitution of aromatic ring did not sequester selectivity and catalyst activity to a significant extent (Scheme 2.34) [94].

Six-membered fused N-heterocycles

83

Scheme 2.34

2.2.13 Nickel-assisted synthesis A number of variations on catalytic reactions involving carbon
carbon triple and double bonds have been reported. For instance, the nickel-catalyzed coupling of aldehydes and 1,3-dienes with HSiEt3 is shown in Scheme 2.35 [95]. The nickel NHC complex was produced in situ by addition of BuLi to a mixture of imidazolium salt and NiCl2. The (Z)-alkene was formed in moderate-to-high yield. Interestingly, the (E)-alkene was formed when a phosphane ligand was used instead of NHC. Jamison et al. [96,97] used an in situ mixture of IPr (1,3-(2,6-diisopropylphenyl)imidazol-2-ylidene) and Ni(COD)2 to catalyze the coupling of terminal olefins with isocyanates and olefins with aldehydes to afford the acrylamides. Similar conditions were employed to couple two isocyanates with alkynes to provide the pyrimidine diones [98]. The reaction of diynes with nitriles was catalyzed by in situ prepared nickel NHC complex under basic conditions to give a variety of substituted pyridines. Vinyl cyclopropanes were successfully isomerized to cyclopentenes upon addition of a mixture of a Ni(0) precursor. Other reactions with C
C double bonds used nickel NHC complexes for the polymerization of styrene [99] and dimerization of ethane [100
103]. Various imines were treated with NaOi-Pr in catalytic amounts of Ni(0) and IMes to form the amines by transfer hydrogenation [104]. A reaction of catalytic amounts of Ni(0) and a triazol-5-ylidene with H3NBH3 led to the rapid synthesis of dihydrogen gas by dehydrogenation, which, interestingly, was shown to proceed through hydrogen transfer of ammonia-borane to the carbene carbon, followed by C
H activation by the nickel species [105].

Scheme 2.35

Dipropargyl amines [106] with gem-dialkyl groups were easily transformed in the presence of cobalt(II) chloride/manganese catalytic system.

Scheme 2.36

The reaction temperature was decreased to 80 °C and yield of dihydropyrrolopyridines increased up to 90%
98% with the presence of gem-dialkyl groups in initial diacetylene (Scheme 2.36) [107]. Cook and coworkers [108,109] synthesized the opioid agonistic alkaloid mitragynine, through the formation of allylamine intermediate, which in turn was produced via an asymmetric Pictet-Spengler reaction and a Ni (COD)2-mediated cyclization as the key steps (Scheme 2.37) [24].

Scheme 2.37

Six-membered fused N-heterocycles

85

2.2.14 Rhenium-assisted synthesis During the studies on the catalytic Beckmann rearrangement of oximes with p-toluenesulfonic acid and tetrabutylammonium perrhenate [110], it was reported that phenethyl ketone oximes cyclized on the oxime nitrogen atom with phenyl group. The phenethyl ketone oximes were transformed to quinolines upon treatment with tetrabutylammonium perrhenate in catalytic amounts (Scheme 2.38) [111,112].

Scheme 2.38

2.2.15 Rhodium-assisted synthesis Tanaka et al. [113] prepared pyridones and axially chiral pyridones in good yields by reacting isocyanates and diynes using a cationic rhodium catalyst (Schemes 2.39 and 2.40) [114].

Scheme 2.39

Scheme 2.40

The alkene tethered isocyanates and internal, symmetrical alkynes underwent three-component [2 1 2 1 2] metal-catalyzed cycloadditions. The complex produced from a triarylphosphine ligand and [Rh (C2H4)2Cl]2 was reported to catalyze the desired cycloaddition initially. The pyridones were prepared by cycloaddition of diynes or alkynes and

86

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

isocyanates as noted in all these cycloadditon reactions so far. If one of the alkyne functionalities were to be substituted for an alkene, the product thus obtained would be a lactam. Lactams are present in highly important pharmacologically active and structurally important compounds [115,116]. Yu and Rovis [117] reported that cyclization of an alkyne and an alkenylisocyanate in the presence of a rhodium catalyst provided lactam products and a vinylogous amide. High selectivity of .20:1 was reported favoring the vinylogous amide product. This protocol was also extended for the construction of structural cores of lasubine alkaloids (Scheme 2.41).

Scheme 2.41

Until recently, there were no convenient protocols for the synthesis of C-3 imino-substituted cyclopropenes, potential building blocks for organic chemistry [118
120]. Recently, it was reported [121] that 7-halo-substituted N-fused triazoles were used as surrogates for imino diazo compounds [122] in chemoselective reaction with terminal alkynes and rhodium(II)-catalyst to afford the 3-(2-pyridyl)cyclopropenes or indolizines, depending upon catalyst source. No reaction proceeded with triazoles containing alkyl or H groups at C-7 therefore the presence of halogen substituent in N-fused triazoles was crucial. Although the direct rhodium(II) perfluorobutyrate-catalyzed transannulation of triazoles afforded a convenient and rapid protocol toward indolizines, it has limitations (Scheme 2.42) [123].

Scheme 2.42

Saito and coworkers [124] reported the use of in situ produced cationic rhodium(I) catalyst (from [RhCl(cod)]2 and AgSbF6 in HFIP) for the synthesis of annulated pyridines from alkynylvinyl oximes (Scheme 2.43) [24].

Six-membered fused N-heterocycles

87

Scheme 2.43

Inagaki and Mukai [125] reported that allylamines underwent [RhCl (CO)2]2-catalyzed intramolecular [2 1 2 1 1]-cycloaddition reactions to afford the azabicyclo[5.3.0]dec-1(10)-en-9-ones and azabicyclo[4.3.0]non1(9)-en-8-ones (Scheme 2.44). This protocol provided a new entry for the generation of bicyclo[4.3.0]-non-1(9)-en-8-one framework bearing an alkyl appendage at the ring junction, which was hardly formed in satisfactory yield by Pauson
Khand reaction of enynes [24].

Scheme 2.44

Several naturally occurring indolizine derivatives were synthesized by Rh (II)-catalyzed reactions using N-pyrrolyl-α-diazoketones as carbenoid precursors [126
129]. Nevertheless there are few examples about the insertion of α-keto carbenoids into C
3H bond of pyrroles [130]. The C-3 substituted bicyclic ketones were produced rapidly as the only isolable products in 50%
70% yields when several α-diazoketones and α-diazo-β-ketoesters derived from 2-pyrrolylpropionic and 2-pyrrolylacetic acids were reacted in the presence of catalytic amounts of Rh(II) acetate at room temperature in CH2Cl2 or 1,2-dichloroethane at reflux. On the other hand, the α-diazobutanone provided a mixture of ketones derived from intramolecular insertion into the nitrogen
hydrogen and C
3H bonds of pyrrole ring. The product ratio was independent of both the catalyst concentration and the reaction temperature (Scheme 2.45).

Scheme 2.45

88

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Silicon stabilized the nucleophile species and the enol species [131]. Many well-known reactions such as Claisen
Schmidt, aldol, and Mannich reactions involved enol nucleophiles. These neutral carbon nucleophiles were used to construct the izidine alkaloids bicyclic core (Schemes 2.46 and 2.47) where a cyclohydrocarbonylation reaction furnished N-acyliminium species that was subsequently trapped by one of the carbon nucleophile systems.

Scheme 2.46

Scheme 2.47

Amide was reacted under cyclohydrocarbonylation reaction conditions. The strongly acidic conditions were employed where N-acyliminum ion was trapped with enols in a stepwise manner [131]. Thus acetic acid was chosen as the acid source and solvent based on the positive results obtained with acetic acid as solvent. Mass analysis showed a molecular weight corresponding to the hydrogenated enamide and a mass corresponding to the desired product, which also has the same molecular weight as the enamide byproduct. Three peaks in approximately 1:1:1 were confirmed by HPLC analysis, which confirmed the results observed by mass indirectly (Scheme 2.48).

Scheme 2.48

In the case of trimethoxy substrate the addition of trifluoracetic acid was detrimental to the reaction, it was likely to either cause degradation to the starting material or the product. The dimethoxy substrate was reacted under similar conditions (Scheme 2.49) [132].

Scheme 2.49

The search of the best conditions for the cyclohydrocarbonylation reaction began having two substrates in hand. The successful conditions for the heteroatomic nucleophiles, using catalytic amount of p-TSA and Rh(acac)(CO)2 with BIPHEPHOS, were chosen as the starting points for condition screening [133]. The synthesis of N-acyliminium ion was facilitated when sodium sulfate was added as a dehydrating agent. A mixture of desired product and enamide was observed by mass spectrometry and NMR analysis when the starting compound was subjected to cyclohydrocarbonylation conditions (Scheme 2.50).

Scheme 2.50

90

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The starting substrate was subjected to cyclohydrocarbonylation conditions employing p-TSA as an additive (Scheme 2.51). The reaction provided two major adducts, the predicted cyclized hydrogenated product in 10.8 mg and uncyclized enamide product not quantified but reported by mass and NMR spectrometry analyses of crude reaction mixture [134].

Scheme 2.51

Efforts to continue the development of this reaction stopped following the discovery in a publication by Taddei and Mann [135]. This paper reported the optimized conditions for the allylsilane trapping of cyclohydrocarbonylation to generate the N-acyliminium ion as shown in Scheme 2.52.

Scheme 2.52

Brummond and Yan [136a] reported a Rh(I)-catalyzed allenic Alder-ene reaction of alkynyl allenamides (Scheme 2.53). Various cross-conjugated triene with heterocyclic compounds were formed in good-to-excellent yields. The reaction generated complex tricycles with moderate diastereoselectivity in a Pauson
Khand manner when the atmosphere was changed from argon to carbon monoxide [136b].

Scheme 2.53

Six-membered fused N-heterocycles

91

The enols were used as nucleophilic trapping agents of N-acyliminium ions [137]. Thus obviously the cyclohydrocarbonylation reaction was performed using these nucleophiles as trapping agents (Scheme 2.54).

Scheme 2.54

Wang and coworkers [138] synthesized piperidine-fused cyclooctenones from ene-vinylcyclopropanes via a rhodium(I)-catalyzed two-component [5 1 2 1 1]-cycloaddition reaction (Scheme 2.55) [24].

Scheme 2.55

Ingrossio and coworkers [139] demonstrated the earliest example using rhodium for the synthesis of pyridines by cycloaddition reactions wherein RhCp(C2H4)2 was used in the cycloaddition of propionitrile and 1-hexyne. Pyridine products were formed in an almost equal mixture of regioisomers albeit in moderate yields. The yield of pyridine products increased to 67% when switched to RhCp (C2H4)2. However, for the cycloaddition reaction high reaction temperatures were necessary. Tanaka and coworkers [140] reported that pyridines were prepared with only 3 mol% rhodium-based catalyst by reacting diynes with nitriles. The quantitative yields of pyridine product were obtained when activated nitriles were used. However, when unactivated nitriles were used in the cycloadddition reaction the yields dropped significantly. In another example, activated aryl ethynyl ethers were reacted with nitriles in the presence of rhodium catalyst [141] to afford the pyridine product as a single regioisomer. A regio- and chemoselective [2 1 2 1 2]-cycloaddition of a variety of nitriles and alkynes was catalyzed with cationic Rh(I)/modified-BINAP

92

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

complexes to afford the highly functionalized pyridines under mild reaction conditions (Scheme 2.56).

Scheme 2.56

Macrocyclic skeletons were constructed using a cobalt catalyst system. Tanaka [141] synthesized 2-aminopyridines using a cationic rhodium catalyst. However, the reaction was applied to only one example albeit in low yield (Scheme 2.57) [142].

Scheme 2.57

After reporting that alkenes participated in three-component coupling, the reaction was rendered asymmetric and included more ubiquitous terminal alkynes. Under catalytic conditions, yields were low with terminal alkynes due to a competing alkyne dimerization [143]. Chiral phosphoramidites prevented the dimerization and were the most efficient ligands for the promotion of enantioselective Rh-catalyzed [2 1 2 1 2]-cycloaddition. Commercially available MonoPhos provided poor yields, while the best enantioselectivities and yields were obtained with TADDOL (α,α,α0 ,α0 -tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol)-based phosphoramidites (Scheme 2.58). The enantioselectivity was optimized further upon manipulation of the amine portion of phosphoramidite [144
146].

Scheme 2.58

Six-membered fused N-heterocycles

93

As the substrate scope was flushed out, it was reported that the electronics and sterics of the alkyne have a marked influence on product selectivity. Sterically large terminal, aryl alkynes favor vinylogous amide. However, selectivity eroded and lactam was formed in increased amounts as aryl alkynes become more electron-deficient. In contrast, alkyl alkynes afforded lactam ordinarily, but shift to vinylogous amide as their steric bulk was increased. The product selectivity favored the lactam with TADDOL-based phosphoramidite ligands and alkyl alkynes. Poor results were reported with commercially available MonoPhos (19%, 67% enantiomeric excess), but the product selectivity favored vinylogous amide. The product ratio (1:3.6) was improved further with 3,3'-disubstituted-trimethylsilyl BINOL. Ultimately, the highest ratio in favor of vinylogous amide (1:6.2) and excellent enantioselectivity (91% enantiomeric excess) were obtained with 3,3'-disubstituted tert-butylbiphenyl phosphoramidite (Scheme 2.59) [147].

Scheme 2.59

The ability to predict and control product selectivity with terminal alkynes in a highly enantioselective manner allowed the quick synthesis of various natural products. The indolizidine and (1)-lasubine II [147] were synthesized rapidly by Rh-catalyzed [2 1 2 1 2]-cycloaddition as the key step. The cycloadditions occurred with excellent enantioselectivities and moderate to good yields. For (1)-lasubine II, hydrogenation of quinolizinone reduced both the carbonyl and the vinylogous amide to give the quinolizidine (Scheme 2.60).

Scheme 2.60

94

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The tetra-substituted stereocenters found in natural products such as FR901483 and cylindricines A, C, F were generated using substitution on the tethered alkene as substituted olefins. The desired cycloadducts were formed in good selectivity and yield when various 1,1-disubstituted olefins were used [148]. Ligand was found to afford the best enantio- and product selectivity for lactam with alkyl alkynes. A number of different alkyl olefin substitutions were tolerated; however, sterically bulky substituents disfavored the migratory insertion of alkene, resulting in increased 2-pyridone formation and lower yields. The desired cycloadduct was formed in 19% yields with cyclohexyl substitution while butenyl- and methyl-substituted olefins afforded upward of 75% yield. Nevertheless, the size of substituent does not diminish enantioselectivities, which remain greater than 87% (Scheme 2.61).

Scheme 2.61

Various symmetrical, internal alkynes were used in this approach. Unsymmetrical alkynes participated in a predictable and highly regioselective manner [149]. A number of alkynes were explored (Scheme 2.62), and it was found that electron-donating groups were beta in the products and electron-withdrawing substituents were alpha to the carbonyl. The vinylogous amide was formed almost exclusively as major product with unsymmetrical, internal alkynes. Substitution on olefin was well tolerated, even with sterically bulky groups. A significant increase in enantioselectivity was also observed with 1,1-disubstituted alkenes. The regioselectivity arises from stabilization of the forming partial positive charge by the more electron-donating group. Mayr’s scale of nucleophilicity [150,151] afforded a convenient method for the prediction of alkyne insertion.

Scheme 2.62

Six-membered fused N-heterocycles

95

Chiou et al. [152] reported that N-allylic amides of arylacetic acids underwent rhodium-catalyzed cyclohydrocarbonylation-bicyclization to afford the tricyclic aza-heterocyclic structures such as tricyclic indolizidine alkaloids, crispine A and its analogues as well as the tetracyclic β-carboline alkaloid, harmicine (Schemes 2.63 and 2.64) [24].

Scheme 2.63

Scheme 2.64

One of the challenges to improve the substrate scope of reaction was the synthesis of lactam using aryl alkynes [153]. Exchange of isocyanate for the carbodiimide biases oxidative cyclization toward metallacycle, allowing for selective lactam formation even with vinylogous amidefavoring aryl alkynes (Scheme 2.65). Electron-rich alkynes were able to partially override this preference. These amidine products were modified

96

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

by reduction of the imine to the amine or hydrolysis to provide the lactam, showing their synthetic utility.

Scheme 2.65

The asymmetric cycloadditions of diarylalkynes (tolanes) were examined with the advent of GuiPhos. It was reported that the enantioselectivities varied as a function of alkyne electronics in a nonlinear manner. It was hypothesized that with excess of alkyne, the alkyne coordinated to the octahedral Rh(III) metallacycle and altered the enantioselectivity of alkene insertion. This hypothesis was tested by investigating a number of weakly coordinating additives that did not participate in the reaction to standardize enantioselectivities [154]. The best additive found was methyl nicotinate, and many examples showed a leveling of enantioselectivities (Scheme 2.66). The exogenous ligand bind to the octahedral Rh(III) species and favored over the other diastereomeric transition states for the olefin insertion. The composition of alkyne no longer played a role in the enantioselective step of catalytic cycle due to the additive.

Scheme 2.66

An azomethine functionalized with a 2-furanyl group was used to define the scope of azomethine substrate (Scheme 2.67). Significant substrate effects were observed and furo[2,3-c]pyridine was isolated and identified as a result of N
N cleavage and carbon
hydrogen olefination. Azomethines with aryl- and alkyl-substituted furans coupled smoothly with acrylates (68%
81%). The azomethine was not limited to C2-substitution in the furan ring. Thus a C3-substituted substrate underwent C2
H bond cleavage under same conditions with high selectivity and only a single isomeric product was formed. Furthermore, an indolefused pyridine was obtained in good yield when indole-functionalized

Six-membered fused N-heterocycles

97

azomethine was coupled smoothly with n-butyl acrylate. These fused heterocyclic compounds are present as the cores of natural products [155,156]. The preparation of these less accessible heterocyclic compounds through carbon
hydrogen activation was unprecedented.

Scheme 2.67

The cyclization of benzimidazole derivative was catalyzed with Rh(I)N-heterocyclic carbine (NHC) complex at the same rate. Furthermore, the zero-order [157] and first-order [158,159] reaction was indicated by kinetic investigation of the cyclization of benzimidazole derivative in the presence of coinplex rhodium(I)-N-heterocyclic carbine (NHC) complex catalyst. These results were consistent with a mechanism in which the resting state of catalyst contains a single molecule of bound substrate. Carbene coinplex was formed at lower temperature than that at which cyclization occurred and was observed throughout the reaction, leading to the conclusion that NHC complex was the resting state of catalyst (Scheme 2.68) [160
162].

Scheme 2.68

Bates and Lim [163] reported a highly diastereoselective preparation of piperidine derivative via double-bond reduction of allylamine in the presence of Wilkinson’s catalyst followed by intramolecular reductive amination (Scheme 2.69). The piperidine derivative was used as a substrate to construct the Nuphar alkaloid, nupharamine, and the bicyclic heterocyclic

compound. The saturated analogue was delivered upon reduction of bicyclic heterocyclic compound with lithium aluminum hydride [24].

Scheme 2.69

Mizoguchi and coworkers [164] developed a divergent synthetic method comprised of four steps to afford the fused skeletons, which appear in transtangolide and aspidoplytine. The three-step processing of allylamine provided branched precursor. This involved Ugi condensation of amine with tert-butyl isonitrile, 3-indolecarbaldehyde, and a terminal olefin and installation of diazoimide followed by rhodium-catalyzed reaction of allylamine involving a 1,3-dipolar cycloaddition of ylide intermediate with terminal olefin to provide a separable 1:1 diastereomeric mixture of fused skeletons (Scheme 2.70) [24].

Scheme 2.70

Diversity oriented synthesis (DOS) is a powerful method for the preparation of small molecules that exhibit important biological activity. The DOS protocol was based on using a pivotal substrate that was subjected to different reaction conditions to provide skeletally unique products. The novel conjugated triene and Pauson
Khand ring systems were synthesized. The [5,5], [5,6], and [5,7] ring systems were formed in good yields when [Rh(CO)2Cl]2 catalyst was used under carbon monoxide or nitrogen atmosphere (Scheme 2.71) [165].

Scheme 2.71

2.2.16 Ruthenium-assisted synthesis Bates and Lu [166] reported the transformation of 1,3-amino alcohol. The 1,3-amino alcohol was in turn synthesized from allylamine by sequential cross-metathesis and hydrogenation. A formal synthesis of porantheridine was achieved (Scheme 2.72) [24].

Scheme 2.72

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Hong and Yamazaki [167] synthesized pyridines by a metal-catalyzed [2 1 2 1 2] reaction where isocyanates and alkynes coupled. Hoberg and Oster [168,169] advanced the field of metal-promoted cycloadditions greatly with nickel-catalyzed and -mediated transformations using a combination of carbon dioxide, isocyanates, alkynes, or alkenes to synthesize the various carbocycles and heterocyclic compounds. Earl and Vollhardt [170] showed the ability to control the regioselectivity of cycloadditions of tethered alkynes for the synthesis of pyridone products and found that this selectivity was affected by alkyne electronics. Takahashi et al. [171] reported that both ruthenium and nickel worked effectively to prepare the bicyclic pyridones. Tanaka et al. [172,173] developed the first asymmetric synthesis of pyridones by exploiting a cationic Rh/bidentate phosphine catalyst to form the atropisomers of 2-pyridones with good enantioselectivity (Schemes 2.73 and 2.74).

Scheme 2.73

Scheme 2.74

2.2.17 Scandium-assisted synthesis Nüchter and Ondruschka [174] reported the parallel construction of a 36-member library of Biginelli dihydropyrimidines in a suitable multivessel rotor placed inside a dedicated multimode MW reactor. The modern multimode MW reactors operated with specifically designed 96-well plates under sealed-vessel conditions, the parallel protocol offered a considerable higher throughput than the automated sequential technique, albeit at the cost of having less control over the reaction parameters for each individual vessel/well. One additional limitation of the parallel approach was that all reaction vessels were exposed to same irradiation

Six-membered fused N-heterocycles

101

conditions in terms of MW power and reaction time during library production, thus not allowing specific needs of individual building blocks to be addressed by varying the temperature or time (Scheme 2.75) [175,176].

Scheme 2.75

The α-carboline was formed in moderate yield by Sc(OTf)3-catalyzed in situ formation of acyliminium ion from methoxyindolone and subsequent cyclization (Scheme 2.76) [177]. Cu(OTf)2 also mediated the same reaction in a better yield [178].

Scheme 2.76

The α-carboline derivative was formed in excellent yield when a solution of tryptamine and methyl 2-(1,1-dimethoxyethyl)benzoate was heated in toluene in the presence of 10 mol% Sc(OTf)3 and MS 4A (Scheme 2.77) [178,179]. The desired product was obtained as a single diastereomer by a similar reaction with ethyl ester of tryptophane.

Scheme 2.77

Sc(OTf)3 was found to be an efficient catalyst in aza-Diels
Alder reactions [180
182]. Substituted N-benzylideneaniline was reacted with 2-trans-1-methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky’s diene)

102

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

in the presence of 10 mol% Sc(OTf)3 to provide the quantitative yields of imino-Diels
Alder adducts (a tetrahydropyridine derivative in this case). On the other hand, the reaction course between cyclopentadiene and substituted N-benzylideneaniline under the same conditions was changed, and tetrahydroquinoline derivative was formed as the sole product (Scheme 2.78). The cyclopentadiene acted as a dienophile and aromatic imines as azadienes in this reaction [183
185]. However, a mixture of tetrahydroquinoline and tetrahydropyridine derivatives was obtained with 2,3-dimethylbutadiene. Other dienophiles including vinyl ethers, vinyl sulfide, and silyl enol ether were used to provide the high yields of tetrahydroquinoline derivatives [178,186
192].

Scheme 2.78

Perfluoroalkanesulfonyl protected hydroxybenzaldehydes were reacted with isonitriles and 2-aminopyridines for a three-component condensation reaction to afford the imidazo[1,2-a]pyridine ring system. The imidazo [1,2-a]pyridine was obtained when condensed products were used for palladium-catalyzed cross-coupling reactions with boronic acids or thiols (Schemes 2.79 and 2.80) [193].

Scheme 2.79

Six-membered fused N-heterocycles

103

Scheme 2.80

2.2.18 Thallium-assisted synthesis The palladium intermediate was used in the synthesis of a number of β-carboline analogues as well as the halogenation of indole-2-position, through the insertion of carbon monoxide or isocyanides into the Pd
C2 bond of cyclopalladated complex (Scheme 2.81) [194]. The formation of N-heterocycle was facilitated in stoichiometric amount of palladium. The indole-based N-heterocycles were prepared using only a catalytic amount of palladium.

Scheme 2.81

2.2.19 Tin-assisted synthesis The 2-azetidinone-tethered azide underwent an allenic hydroamination reaction for stereocontrolled synthesis of 4-hydroxypipecolic acid analogue with a bicyclic β-lactam moiety [195]. A complex reaction mixture was formed when azide was reduced using triphenylphosphine method. Fortunately, the bicyclic 4-hydroxypipecolic acid analogue was synthesized in a totally regioselective fashion through 6-exo-dig aminocyclization with concomitant acetate cleavage when 2-azetidinone-tethered azidoallenic acetate was treated with triphenyltin hydride at room temperature in benzene solution (Scheme 2.82) [196].

104

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 2.82

2.2.20 Titanium-assisted synthesis The 1,4-diketo-alkyne was reacted with titanium
nitrogen complex and indolizidines were formed in 20% and 10% yields, respectively, along with pyrrole derivative in 11% yield. The structures were determined by nuclear Overhauser effect experiments. The ester group of indolizine was converted into nitrile group using titanium
nitrogen complex to afford the indolizine (Scheme 2.83) [197a,b,198].

Scheme 2.83

Since many heterocyclic compounds were synthesized from dry air as a nitrogen source, synthesis of natural products using titanium
nitrogen complex was evaluated. At first, the natural product monomorine I [199] was synthesized from indolizine derivative. The retro synthetic analysis of monomoline I employing this protocol is depicted in Scheme 2.84. Monomorine I was formed by hydrogenation of indolizine because hydrogen on the catalyst approached from the backside of substituents. Indolizine was formed from triketone using present nitrogenation. The triketone was formed in 85% yield by ozonolysis of starting compound [200] followed by treatment with Me2S. A tetrahydrofuran solution of titanium
nitrogen complex (2 eq.) and triketone, prepared from lithium, titanium(IV) chloride, and TMSCl under dry air, was refluxed for 24 h.

Six-membered fused N-heterocycles

105

The desired indolizine derivative was formed in 22% yield after the usual work-up. The monomorine I was formed as a main product in 32% yield along with indolizidine in 4% yield by hydrogenation of indolizine derivative with rhodium on alumina (20 atm) [201,202]. Thus, titanium
nitrogen complex prepared from dry air as a nitrogen source was used for short-step synthesis of monomorine I and indolizidine [198,203].

Scheme 2.84

2.2.21 Ytterbium-assisted synthesis The tetrahydro-β-carbolines were constructed by Pictet
Spengler’s reaction under microwave/ionic liquid conditions. It was reported that the ionic liquid [bmim]BF4 had moderated activity, while [bmim]AlCl4 was a very active catalyst, affording higher steroselectivity (cis/trans, 1.6:1). The MW reaction was completed in 30 min, using both aromatic and aliphatic amines and 50 mol% de [bmim]Cl-AlCl3, (N 5 0.5) and 10 mol% Yb (PTf)2, producing the tetrahydro-β-carbolines in yields higher than 85% in one-step, even when amines with low nucleophilic character were used (Scheme 2.85) [204].

Scheme 2.85

106

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

2.2.22 Zinc-assisted synthesis The cycloaddition reaction of alkynes and alkynenitriles was performed in the presence of tantalum. However, this cycloaddition reaction was employed to only one substrate and the reaction was stoichiometric in tantalum hexachloride (Scheme 2.86) [205].

Scheme 2.86

A one-pot synthesis of substituted triazolopyridines was performed by tying aerobic double dehydrogenative nitrile synthesis to various heterocyclization processes (Scheme 2.87) [206]. Generally, the reagents for heterocyclizations were added after a full transformation of nitrile had been achieved.

Scheme 2.87

The ethynylcarbinols and substituted methyl- and vinyleneacetylenes were reacted with carboxylic chloroanhydrides and ammonia to afford the intermediates through the formation of pyrylium salts and opened a perspective way to the directed synthesis of substituted pyridines in high selectivity and yields [207,208a,b]. The studies in a field of directed synthesis of bicyclic pyridine bases from carboxylic chloroanhydrides and 1-ethynylcycloalkanes were the logical continuation of the reaction. The cyclic ethynylcarbinols were interacted with bromo-, chloro-, and iodoanhydrides of carboxylic acids under mild conditions (1 h, 20 °C) in the presence of two-component catalysts zinc chloride-phosphorusoxy trichloride (1:1) and subsequently the mixture was treated with ammonium hydroxide at 0 °C to afford the 2-alkyl-3,4-cycloalkenopyridines. The synthesis of 2-alkyl-3,4-cycloalkenopyridines by other methods was very difficult (Scheme 2.88).

Six-membered fused N-heterocycles

107

Scheme 2.88

The epoxy-β-lactam was opened reductively with titanocene(III) chloride to afford a benzyl radical that was trapped by intramolecular π systems to synthesize the tricyclic 2-azetidinone (Scheme 2.89) [60b,209].

Scheme 2.89

The desired intramolecular cascade reaction was carried out successfully under several reaction conditions, such as heating with a mixture of triethylamine, TMSCl, and zinc chloride, treatment with TBSOTf in triethylamine [210], treatment with TMSI in (TMS)2NH, and treatment with Bu2BOTf in (TMS)2NH [211]. For example, indole compound was treated with TBSOTf at room temperature in the presence of triethylamine to give the two diastereoisomers (Scheme 2.90) [212]. The rate of reaction increased when dichloroethane was used in place of CH2Cl2 as a solvent [213].

Scheme 2.90

108

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

2.2.23 Zirconium-assisted synthesis The zirconocene-assisted intermolecular coupling reaction of one molecule of Si-tethered diyne with three molecules of nitriles provided 5-azaindoles when the reaction mixture was hydrolyzed [214]. It was reported that the reaction integrating all the five components together was very unpredictable and interesting [215
217]. Recently, it was found that the one-pot preparation of 5-azaindoles was performed from four different components including one alkyne and three different nitriles [218
221]. Complicated reactive intermediates were isolated and characterized. Further synthetic applications of these intermediates have also been achieved (Scheme 2.91).

Scheme 2.91

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551.

CHAPTER 3

Six-membered fused N-polyheterocycles 3.1 Introduction N-Heterocycles are a special group of organic compounds found in various pharmacologically active natural and synthetic products. Nature has provided us countless chemical substances that are structurally and biologically relevant [1a
f]. Among these heterocyclic compounds tetrahydroquinolines exhibit significant biological activity with different therapeutic targets. They have many uses in diverse fields like pharmaceuticals, agrochemistry, and industry. They are also found in natural sources displaying insecticidal, plant growth regulation, pigment, and antibacterial functions[2
6]. Fused six-membered nitrogen-containing heterocycles like benzimidazoquinazolines and benzimidazoisoquinolines are potent antitumor agents. Benzimidazo[2,1-b]quinazolines are potent immuno-suppressors and the benzimidazo[2,1-b]benzo[f]isoquinoline ring system is present in pharmacologically active compounds [7
9]. Due to the importance of this motif in the field of alkaloid synthesis and medicinal chemistry, control of enantioselective synthesis of substituted six-membered nitrogen heterocycles has been the subject of much attention [10]. The importance of these compounds lies in their uses in drug industries and it has been established that they are biologically active in many aspects. These results have encouraged many researchers to pay attention to modification of these compounds for the purpose of using them in treatment of different diseases [11
16].

3.2 Metal- and nonmetal-assisted synthesis of six-membered N-polyheterocycles fused with other heterocycles 3.2.1 Aluminum-assisted synthesis Hammond et al. [17] reported a method for the transformation of dienes into 4,4-difluoroisoquinolin-3-ones by reaction with maleimide (Scheme 3.1). The dienes were in turn produced by ring-closing metathesis (RCM) of difluorinated 1,7-enyne carbonyl compounds [18]. Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00003-8

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121

122

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.1

Callier
Dublanchet et al. [19] reported that hydrazone, an oxime ether, and imine bearing an unsaturated amide or ester underwent radical addition
cyclization
elimination reaction when treated with azobisisobutyronitrile (AIBN) and tributyltin hydride for the synthesis of N-norpyrroloquinoline as a major product (Scheme 3.2) [18]. As substrates in the domino approach, the enol acetate for the homoerythrina skeleton and the enol acetate for the erythrina were used, which were obtained from the known ketoesters and ketones [20], respectively, by reaction with isopropenyl acetate in catalytic amounts of p-toluene sulfonic acid in 93% and 86% yield. The erythrina skeleton was constructed when a mixture of amine, enol acetate, and trimethylaluminum was kept in benzene for 1 h at room temperature and then heated at reflux for 5 h to provide the 79% yield of erythrina skeleton. The ketoesters were reacted with trimethylaluminum and amines under identical conditions but not provided the desired homoerythrina and erythrina skeleton, respectively (Scheme 3.3) [21].

3.2.2 Arsenic-assisted synthesis Mestroni et al. [22] synthesized phenanthroline ligands using similar electrophilic aromatic substitution protocol (Scheme 3.4). By employing a

Six-membered fused N-polyheterocycles

123

Scheme 3.2

Scheme 3.3

Scheme 3.4

Doebner
Miller quinoline synthesis [23], nitroaniline and enal were condensed to synthesize the α,β-unsaturated iminium. This intermediate was cyclized to produce the quinoline, which was advanced to the chiral ligand. The reactions of quinoline, addition and substitution reactions were similar to pyridine and naphthalene. Like in pyridine, the nitrogen atom of quinoline underwent protonation, alkylation, acylation, and oxidation

124

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.5

Scheme 3.6

with peroxyacids to afford the N-oxide. Nucleophilic substitution reactions occur on the ring C-atoms, preferentially on those of the more activated benzene moiety. As the amino component can be varied in many ways, the Skraup synthesis was widely used in the preparation of polyheterocycles and for the synthesis of quinolines. This was shown by the preparation of 1,10phenanthroline (Scheme 3.5) starting from 8-aminoquinoline using chelating ligand [24]. The microwave-assisted syntheses of quinoline derivatives were carried out in the resonance cavity of a dynamic MW power system employing MWI at power levels and variable duty cycles. A mixture of glycerol, 2,6diaminotoluene, arsenic pentoxide, and H2SO4 was irradiated for the Skraup synthesis of 7-amino-8-methylquinoline [25,26]. Even though the reaction yield was not improved, an important decrease in reaction time was achieved. The 7-amino-8-methylquinoline was condensed with ethyl-(ethoxymethylene)-cyanoacetate on silica gel solid support to afford a dramatic decrease of reaction time along with an increase of reaction yield (Scheme 3.6) [27].

3.2.3 Bismuth-assisted synthesis The 2,2,4-trimethyl-1,2-dihydroquinoline derivative was formed in 83% yield when 5-amine-1,3-benzodioxol was reacted with 2,2-dimethoxypropane in the presence of Bi(OTf)3  xH2O catalyst (Scheme 3.7) [28,29].

Six-membered fused N-polyheterocycles

125

The N-acyliminium ions served as important intermediates in organic synthesis [30], and Bi(OTf)3  xH2O-catalyzed intra- and intermolecular amidoalkylation reactions were reported. The intramolecular amidoalkylation reaction provided tetrahydroisoquinoline derivatives in good yields when 3-acetoxy-2-phenethylisoindolin-1-one (Scheme 3.8), (4R,5S)-4,5diacetoxy-1-phenethylpyrrolidin-2-one (Scheme 3.9) and 5-acetoxy-2,5dihydro-3-methyl-1-phenethyl-1H-pyrrol-2-one (Scheme 3.10) were used. Only one diastereomer was obtained in the case of (4R,5S)-4,5-diacetoxy1-phenethylpyrrolidin-2-one [28
32]. Sabitha and coworkers [33] reported that the reaction of aromatic amines with N-allyl derivatives of o-aminobenzaldehydes (Scheme 3.11) or S-allyl derivatives of pyrazole aldehydes (Scheme 3.12) generated

Scheme 3.7

Scheme 3.8

Scheme 3.9

Scheme 3.10

126

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.11

Scheme 3.12

aldimines in situ by bismuth chloride-catalyzed intramolecular heteroDiels
Alder reaction [34]. This protocol provided a simple reaction for the preparation of hexahydrodibenzo[b,h][1,6]naphthyridines, obtained as a mixture of cis- and trans-diastereoisomers in 1:1 ratio, and hexahydropyrazolo[40 ,30 :5,6]thiopyrano[4,3-b]quinolines (only the cis products), respectively, in good-to-high yields. A similar cycloaddition reaction of aromatic amines occurred with either an O-allyl derivative of a sugarderived aldehyde (Scheme 3.13) [35] or N-prenylated sugar aldehyde (Scheme 3.14) with bismuth chloride catalyst. Furo[20 ,30 :5,6]pyrano[4,3-b] quinoline derivatives (mainly as the trans-isomer) and benzo-annelated decahydrofuro[3,2-h][1,6]naphthyridine derivatives (trans-fused products only) [36] were obtained, respectively [28,29]. The pyrano[3,2-c]quinoline derivatives were synthesized in high yields by BiCl3-catalyzed aza-Diels
Alder reaction of N-aryl aldimines with nucleophilic olefins (Scheme 3.15) [28,29,37]. The aryl amines and hydroxy-α,β-unsaturated aldehydes underwent tandem Michael and intramolecular Friedel
Crafts-type cyclization in the presence of Bi(OTf)3  xH2O at 80 °C in acetonitrile to provide a new class of chiral pyran-tetrahydroquinolines, in high stereoselectivity and good yields. This straightforward method was a convenient way to synthesize the

Six-membered fused N-polyheterocycles

127

Scheme 3.13

Scheme 3.14

Scheme 3.15

unusual benzo-fused heterobicycles in one-step operation (Scheme 3.16) [38]. The pyranoquinoline is present in alkaloids like oricine, flindersine, and veprisine and several derivatives exhibiting a wide range of biological activities such as antiallergic, psychotropic, estrogenic, and antiinflammatory [28,29].

128

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.16

Scheme 3.17

A diene obtained from optically active citranellal underwent Bi(NO3)3catalyzed and MW-induced intramolecular Diels
Alder reaction for the construction of a tricyclic system. Perhaps the most important reaction for the synthesis of polyheterocyclic and polycarbocyclic compounds is Diels
Alder reaction. Acidic reagents accelerated this cyclization reaction extensively. The reaction of citranellal and aromatic amine provided diene using molecular sieves. After filtration, the crude diene was irradiated in a CEM MW and treated with Bi(NO3)3 for 10 min (temperature 50 °C and power levels 300 W) using tetrahydrofuran as the solvent. This method provided tricyclic system (Scheme 3.17). Two isomers (cis and trans) were present in a ratio of 20:80 as indicated by NMR analysis. This protocol was mild and simple as compared to other methods for the preparation of these compounds. This product was produced without MWI. However, for the complete consumption of starting material more time (2 h) was required. No reaction occurred without Bi(NO3)3. The excess amount of Bi(NO3)3 was problematic since under acidic conditions the starting imine was not very stable. For the successful reaction, appropriate concentration of substrate and catalyst in tetrahydrofuran was necessary. From a few experiments, 10 mol% catalyst was needed for this reaction when performed with 1 mmol of substrate in 10 mL of tetrahydrofuran [28,39].

3.2.4 Cesium-assisted synthesis The alcohol products were formed from silylprotected aryl iodides that were compatible under the reaction conditions and were deprotected in

Six-membered fused N-polyheterocycles

129

situ (Scheme 3.18). Notably, annulated pyrrole was obtained in excellent yield from aryl iodide (Scheme 3.19). This compound is present in the core of pharmacologically active compounds like lamellarin and lettowianthine [40
43]. The unsubstituted bromoalkyl pyrroles were reacted with a number of aryl iodides using palladium chloride as catalyst. Blaszykowski et al. [43] extended the Pd-catalyzed norbornene-assisted sequential coupling reaction to the annulation of pyrroles. Good-to-excellent yields of annulated pyrroles were obtained from electron-poor aromatics, which contain one blocking group ortho to the iodide moiety. The desired annulated pyrroles, although in somewhat lower yields, were obtained using electron-rich aromatics (Scheme 3.20). Zhu et al. [44] used an aryne annulation while maintaining an alternative protocol from functionalized oximes. The role of palladium was not clear in the reaction; maybe it assisted in N-O bond cleavage after the hetero-Diels
Alder reaction to afford the core of product (Scheme 3.21). Nandi and Ray [45] synthesized fused tetrahydropyridine derivatives via 6-exo-trig cyclization of N-aryl allylamines with palladium(0). However, cyclopropa[d]-fused isoquinoline derivatives were obtained via

Scheme 3.18

Scheme 3.19

Scheme 3.20

130

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.21

Scheme 3.22

a domino sequence when N-methallylated derivatives were subjected to Heck reaction under the same reaction conditions (Scheme 3.22) [18]. While palladium-assisted aryne annulation reactions are relatively rare, Zhang et al. [46] prepared indolophenanthridines by an intramolecular palladium-mediated protocol (Scheme 3.23). The palladium
phosphine catalyst conducted an oxidative addition into the aryl bromide, and added across an aryne eq. to produce the aryl palladium intermediate. Ringclosure occurred from carbopalladation of palladium to forge the C-C bond between the indole and the arene and provided the product. Rawal et al. [47] reported an intramolecular arylation of phenolates employing cesium carbonate and Herrmann’s catalyst in dimethylaniline (Scheme 3.24). Many biaryl compounds possessing various linkages between the two aryl groups were formed in good-to-excellent yields under these conditions. Indoles as a classical C-nucleophilic species were used as building blocks in Cu-catalyzed cascade heterocyclic compound preparation,

Six-membered fused N-polyheterocycles

131

Scheme 3.23

Scheme 3.24

especially for the generation of fused cyclic systems. Liu and Wan [48] reported cuprous iodide-catalyzed tandem reactions utilizing indoles and o-bromoarylalkynes possessing a free NH group. Under catalytic conditions, intermediates were formed by oxidative addition or hydroamination of indoles to o-bromoarylalkynes. The fused polycyclic products were formed in moderate-to-good yields by a subsequent carbon
carbon coupling of C2 in the indole unit and the arene
halide bond. The other potential isomeric products, which might have been given via carbon
nitrogen coupling initiated intermediate, were not observed in the experiments (Scheme 3.25). Grigg et al. [49a] rendered the anion capture part of their intramolecular cascade (Scheme 3.26). The reaction was initiated through carbopalladation/cyclization and the Pd π-allyl complexes were formed but followed by their interception, via an intramolecular nucleophilic addition, the polycyclic isoquinolones were obtained [49b]. Yamada et al. [50] used an intramolecular amination reaction for the total synthesis of two aporphine alkaloids, 7,70 -bis-dehydro-O-methylisopiline and O-methyl-dehydroisopiline, employing a ligand-free method reported by Fürstner and Mamane [51]. Simply heating a mixture of aminoarylbromide with cesium acetate and copper iodide in dimethylsulfoxide resulted in a high-yielding and smooth intramolecular amination that allowed

132

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.25

Scheme 3.26

the completion of first total synthesis of 7,70 -bis-dehydro-O-methylisopiline and O-methyl-dehydroisopiline, the former being formed by coppermediated oxidative dimerization of the latter (Scheme 3.27) [52]. Lamaty and coworkers [53] reported a new method for the preparation of 4-amino-1-methyl-4-1H-pyrrolo-[3,2-c]quinoline and 4-aryl-1-methyl4-1H-pyrrolo[3,2-c]quinoline derivatives from allylamine under MWI. The key steps involved RCM of N,N-bis-allylamine, and base-catalyzed

Six-membered fused N-polyheterocycles

133

Scheme 3.27

aromatization and intramolecular lactamization to afford the lactam. The phosphorusoxy trichloride-mediated chlorination of lactam provided imidoyl chloride. The imidoyl chloride through amination or palladiumcatalyzed cross-coupling under MW conditions furnished pyrrolo[3,2-c] quinolines in good yields (Scheme 3.28) [18,54]. The easily available amides were transformed into pyrrolo[1,2-b]isoquinolines in 75%
81% yield under standard conditions (Scheme 3.29). Milder conditions were employed for amide substrate. Thus the amide was heated at 80 °C for 5 h in the presence of palladium acetate (5 mmol %) to provide the heterocyclic compound in 79% yield. The oxidized naphthyl derivative was also present in the crude reaction mixture (Scheme 3.30) [55]. Interestingly, o-acrolyl- and o-acyl anilines reacted effectively with arynes produced from o-silyl aryl triflates, to give the variously substituted acridines as products (Scheme 3.31). Huang and Zhang [56] and Larock et al. [57] have independently demonstrated this reactivity. They have been particularly interested in annulation processes, which afforded biologically interesting ring systems rapidly by simple tandem processes. For example, the salicylates and in situ formed arynes reacted readily to construct the heteroatom ring systems, such as thioxanthones, xanthones, and acridones [58,59a,b]. The N-acylpyrrolamides were transformed into tricyclic compounds in 74%
85% yield under usual conditions (Scheme 3.32) [60].

134

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.28

Scheme 3.29

The cross-coupling and carbon
hydrogen activation compound was formed in 89% yield from 3-methyloxyl benzeneboronic acid. The desired product was also formed in 59% yield when the dibromo substrate was treated with 3-methyloxyl benzeneboronic acid under these conditions (Scheme 3.33) [61]. The ene was easily synthesized from 5-methyl-2-cyclohexenone [62]. Ketalization of ene followed by hydroboration afforded the high yield of alcohol. The hydroxyl group of alcohol was converted into carboxyl group with the usual protocol to provide an intermediate compound, which furnished the product when treated with diethyl phosphorochloridate. The tetrahydrofuran solution of the obtained product and

Six-membered fused N-polyheterocycles

Scheme 3.30

Scheme 3.31

Scheme 3.32

Scheme 3.33

135

136

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.34

titanium
nitrogen complex (derived from Ti(Oi-Pr)4, TMSCl, and lithium under dry air) was refluxed for 36 h to provide the lactam in 40% yield together with stereoisomers in 7% yield. Lactam was formed in 39% yield when the reaction was performed using nitrogen gas. Dry air served as nitrogen source instead of nitrogen gas. The melting point of lactam was in complete agreement with that reported in the literature [63
69]. The tetracyclic compound was formed when lactam was treated with H3PO4 in formic acid as per Stork’s protocol. Thus a formal total synthesis of ( 6 )-lycopodine was performed utilizing titanium
nitrogen complex obtained from dry air (Scheme 3.34) [70,71]. Hesse and Kirsch [72] reported the amination of β-chloroacroleins using palladium-2,20 -bis(diphenylphosphino)-1,10 -binaphthyl catalytic system. However, without catalyst, under the same conditions, the condensation reaction of amine occurred with aldehyde [73], to provide a mixture of imine and the coumarin derived from the intramolecular cyclization of imine (Scheme 3.35) [74]. Ozaki et al. [75] synthesized six-membered ring. The ring-closure product was formed smoothly in 75% yield when the compound was heated under standard conditions (Scheme 3.36). The carboamination reactions were extended to N-protected γ-aminoalkenes that allowed the synthesis of interesting compounds that

Six-membered fused N-polyheterocycles

137

Scheme 3.35

Scheme 3.36

Scheme 3.37

could not be accessed employing transformations of γ-N-(arylamino) alkenes. For example, tetrahydropyrroloisoquinolin-5-one was generated in good diastereoselectivity and yield when a palladium-catalyzed carboamination of substrate was performed with methyl-2-bromobenzoate, which afforded intermediate in 73% yield. The formed intermediate was treated with acid/base to provide the tetrahydropyrroloisoquinolin-5-one in 95% yield (Scheme 3.37) [76
82]. In addition to the protocols of multicomponent synthesis, cycloaddition, and dipolar addition, some new methods to structures of higher complexity have been developed. For instance, Hsung et al. [83] reported a method for the construction of tricyclic piperidyl ring systems through an aryne intermediate (Scheme 3.38). In this example, a formal [2 1 2]cycloaddition reaction of vinyl enamine and aryne, derived from silyl aryl triflate, furnished benzocyclobutenyl intermediate. The benzocyclobutenyl intermediate underwent a 4π electrocyclic ring-opening to reveal the

138

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

o-quinone dimethide that reacted with pendant olefin via [4 1 2]-cycloaddition, affording the core of product. While not technically a benzannulated bicycle, the piperidine formed within tricycle could not be formed without the direct participation of aryne intermediate during the course of reaction cascade.

3.2.5 Indium-assisted synthesis Raghunathan and coworkers [84
86] used N-prenylated aliphatic aldehydes for the synthesis of hexahydropyrrolo[3,4-b]quinolines in the presence of indium chloride (Scheme 3.39) [18].

3.2.6 Iodine-assisted synthesis Verma et al. [87] reported a solvent-controlled and iodine-mediated selective synthesis of o-alkynyl esters and iodopyrano[4,3-b]quinolines from o-alkynyl aldehydes under mild reaction conditions (Scheme 3.40). The o-alkynyl aldehydes were reacted with iodine in dichloromethane to afford the iodoirenium intermediate. The pyrano[4,3-b]quinolines were formed upon nucleophilic attack of alcohols on carbonyl carbon followed by cyclization. However, using alcohols as a nucleophile as well as solvent, o-alkynyl esters

Scheme 3.38

Scheme 3.39

Six-membered fused N-polyheterocycles

139

were formed via hypoiodide intermediate that subsequently underwent electrophilic iodocyclization to afford the pyranoquinolones [88]. Fei and coworkers [89] reported that N-propargylaminoquinones underwent 6-endo-dig cyclization for the generation of azaanthraquinone skeletons (Scheme 3.41). Iodine coordinated with the carbon
carbon triple bond of N-propargylaminoquinones to afford an iodoirenium intermediate which by 6-endo-dig cyclization and subsequent oxidative aromatization furnished azaanthraquinones [88]. Parvatkar et al. [90] reported a one-pot protocol for the preparation of many indoloquinolines via sequential imination, nucleophilic addition, and annulation in the presence of iodine (Scheme 3.42). Electrophilic attack of iodine on Schiff's base formed 3-iodo-indolinium cation. Schiff's base was formed in situ by the reaction of anilines with indole-3caroxyaldehyde. The 2-N-phenyl substituted indole was formed via nucleophilic attack by the amino group of another molecule of anilines on intermediates. The dihydroindoloquinoline intermediates were produced by intramolecular electrophilic substitution followed by expulsion of anilines and subsequent departure of iodine. Finally, the dihydroindoloquinoline intermediates were oxidized to afford the desired indoloquinolines. This reaction was useful for aryl amines containing heterocyclic

Scheme 3.40

Scheme 3.41

Scheme 3.42

140

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

amines and electron-donating groups. However, the reaction did not occur with aryl amines bearing electron-withdrawing groups [88]. The starting compound underwent aza-Prins cyclization with benzaldehyde in the presence of 20 mol% iodine to provide a mixture of diastereomers in 60% yield that was structurally similar to populene D (Scheme 3.43) [88,91]. Wang et al. [92] developed an efficient protocol for the generation of 1,3-diarylbenzo[f]quinolines via three-component reaction of naphthalene-2-amine, aromatic aldehydes, and 2-halogenated acetophenone in the presence of 5 mol% I2 catalyst (Scheme 3.44). Enol attacked the iodine-activated Schiff's base to afford a compound that underwent Friedel
Crafts cyclization to produce an intermediate. The 1,3-diaryl benzoquinoline was obtained by opening of oxirane ring with iodine and subsequent loss of H2O [88]. Lin and coworkers [93] reported an efficient protocol for the synthesis of 1,2,3,4-tetrahydroquinolines under mild reaction conditions via an iodine-assisted domino reaction of anilines with cyclic enol ethers (Scheme 3.45). The cyclic enol ethers were reacted with anilines for in situ formation of 2-azadienes that underwent iodine-assisted (a mild Lewis

Scheme 3.43

Scheme 3.44

Six-membered fused N-polyheterocycles

141

acid) aza-Diels
Alder reaction with another molecule of cyclic enol ethers for the synthesis of tetrahydroquinolines as a mixture of endo/exo-isomers. This protocol was applied to anilines having alkyl, alkoxy, and halo moieties [88]. Yan et al. [94] developed an iodine-mediated aza-Diels
Alder reaction for the synthesis of tetrahydroquinolines (Scheme 3.46). The tetrahydroquinoline derivatives were formed as a mixture of cis- and trans-isomers when imine was reacted with acyclic ether or cyclic ethers. The reaction worked well with aryl amines containing electron-withdrawing as well as electrondonating groups [88]. The aromatized compounds were formed in high yields when acyclic vinyl ether such as n-butylvinyl ether was used instead of tetrahydroquinoline as formed in the case of aniline as shown in Scheme 3.47. The vinyl ether attacked the iodine-activated Schiff’s base to produce an intermediate. The aromatized 3-arylbenzo[f]quinolines were generated by intramolecular Friedel
Crafts cyclization followed by expulsion of butanol induced by iodine and subsequent air oxidation [88,95]. Subba Reddy and Grewal [96] reported a facile protocol for the preparation of tetrahydrofuro-[3,2-c]quinoline derivatives via aza-Diels
Alder reaction of N-(methyl-N-trimethylsilyl)methylaniline and dihydrofurran

Scheme 3.45

Scheme 3.46

142

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

with 10 mol% iodine (Scheme 3.48). The N-(methyl-N-trimethylsilyl) methylaniline produced aza-diene in the presence of a catalytic amount of molecular iodine. In situ produced aza-diene underwent [4 1 2]-cycloaddition with electron-rich ether dihydrofurran to provide the desired products with cis slelectivity. The catalytic activity of iodine was superior as compared to other Lewis acids such as bismuth chloride, tin(III) chloride, ferric chloride, and zinc chloride. Many angularly fused quinolines were prepared by this reaction [88]. Halim and coworkers [97] reported an iodine-induced tandem cyclization of N-(o-alkynylphenyl)imines for the synthesis of a series of angular dihydrofuroquinolines (Scheme 3.49). Intermediate formed by rapid and reversible single electron extraction from imine by I2 may convert to its rotomer. Intermediate eliminated 2 eq. of hydrogen iodide to provide the respective products [88]. Wu et al. [98] reported an efficient one-pot protocol for the synthesis of 4-aryl-3-methyl-1H-benzo[h]pyrazolo[3,-b]quinoline-5,10-diones via three-component condensation of aldehydes, 3-methyl-1-phenyl-1H-pyrazol-5-amine, and 2-hydroxynaphthalene-1,4-dione using 10 mol%

Scheme 3.47

Scheme 3.48

Scheme 3.49

Six-membered fused N-polyheterocycles

143

Scheme 3.50

Scheme 3.51

iodine in H2O (Scheme 3.50). Dione was in equilibrium with its keto form that provided an intermediate and then tautomerized to afford an intermediate. The desired products were formed upon nucleophilic attack of intermediate on iodine-activated carbonyl carbon of aldehydes followed by intramolecular cyclization and subsequent oxidation [88]. Wang et al. [99] synthesized thiopyranoquinoline, pyranoquinoline, naphtho[2,7]naphthyridine, and thienoquinoline derivatives (Scheme 3.51). In the presence of iodine, the ketone was in equilibrium with the enol form that immediately attacked the in situ produced Schiff's base to afford an intermediate. The desired aromatized compounds were obtained by intramolecular Friedel
Crafts cyclization followed by dehydration and oxidation [88]. Zeng and Cai [100] reported a domino reaction for the preparation of benzo[h]quinolinyl and benzo[f]quinolinyl acetamides (Scheme 3.52). In situ produced intermediate reacted with iodine-activated Schiff's base to afford an intermediate rather than more favorable intermediate. Intramolecular cyclization of intermediate followed by elimination of water and subsequent aromatization furnished the good yields of benzo[f]quinolinyl acetamides [88].

3.2.7 Iron-assisted synthesis The [1,4]diazepino[5,6-b]quinolin-2-ones were synthesized from differently protected allylamines. In the case of tosyl-protected amine, the nitro moiety

144

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.52

Scheme 3.53

Scheme 3.54

was reduced with iron-acetic acid to afford the 2-aminoquinoline, which was converted into [1,4]diazepino[5,6-b]quinolin-2-ones via sodium hydridemediated intramolecular cyclization. However, the cyanamide of allylamines was treated with iron-acetic acid to provide the [1,4]diazepino[5,6-b]quinolin2-one in one-pot reaction (Schemes 3.53 and 3.54) [18,101]. Different routes were developed for the preparation of 1,4-diazepin-2one fused polycyclic systems from allylamines [102]. The β-carbolines were produced via Pictet
Spengler reaction of allylamines with benzaldehyde. The β-carbolines underwent intramolecular reductive cyclization when heated with Fe
AcOH at 120 °C to provide the 2-aminoquinoline, which furnished the final compound upon treatment with sodium hydride in tetrahydrofuran (Scheme 3.55) [18].

Six-membered fused N-polyheterocycles

145

Scheme 3.55

Scheme 3.56

The 3-aminoxanthone by the Skraup method afforded xanthone annelated with a pyridine ring (Scheme 3.56) [103,104]. Previous research [105] has established that coupling of electron-rich aryl bromides with a boronic acid, which was prone to protodeboronation, would be difficult to achieve under conventional conditions. Therefore this cross-coupling reaction was investigated under MWI conditions. According to the optimized protocol, [106
110] styrene and boronic acid were reacted with [Pd(PPh3)4] as catalyst and sodium bicarbonate as base in a 1:1 mixture of H2O and dimethylformamide at 150 °C and 150 W (maximum irradiation power). The reaction was completed in 15 min and biaryl compound was formed in 84% (an excellent yield) with a negligible degree of proto-deboronation, and no homo-coupling products were reported. The trimethoxy analogue was formed in 82% yield from styrene and boronic acid by the same procedure. However, the subsequent reduction of nitro group of trimethoxy and biaryl intermediates was problematic as all common

146

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

reduction protocols, [111] using either granular tin or tin(II) chloride, failed, even after prolonged heating (Scheme 3.57). Although the use of iron in refluxing ethanol with either 6 N ammonium hydroxide or with hydrogen chloride was found to reduce the nitro group, a complex mixture was obtained, containing, for example, the phenanthridines. Attempts to perform catalytic hydrogenation with palladium/ carbon (10 mol%) in methanol were unsuccessful to afford the target anilines in any substantial amount [112]. Tilve and coworkers [113] reported a double-reductive cyclization as a key step for the direct synthesis of target compound (Scheme 3.58). The condensation of o-nitrophenylacetic acid and o-nitrobenzaldehyde, followed by esterification, provided the stilbene. The stilbene was reduced with iron and acetic acid in hydrochloride acid to give an intermediate in 74% yield. The compound was synthesized in 80% yield by regioselective methylation. This method provided overall yield of 42% over four steps, which was the highest yield obtained so far.

Scheme 3.57

Scheme 3.58

Six-membered fused N-polyheterocycles

147

3.2.8 Lanthanum-assisted synthesis The tricyclic hexahydrocyclopenta[ij]isoquinoline was formed with exclusive trans-diastereoselectivity and high regiospecificity starting from trivinylbenzene, when this reaction sequence was combined with a bicyclization step (Scheme 3.59). The high trans-diastereoselectivity was explained similar to diastereoselective hydroamination/cyclization of substituted aminoalkenes [114
116].

3.2.9 Lithium-assisted synthesis Friendlader synthesis of 1,8-napthyridine was performed using LiCl (efficient catalyst) and MR44. Lithium chloride was added to a mixture of appropriate active methylene compound and 2-amino nicotinaldehyde, mixed thoroughly and irradiated in a MW oven (Scheme 3.60) [117]. The 2-lithiopyridines were generated by iodo
lithium exchange in formylation reactions [118]. In addition, the halogen
lithium exchange was used in the 2-metalation of quinoline derivatives [119,120], and in the intramolecular cyclization of 2-quinolidyl- and 2-pyridyllithium reagents, produced from the bromoquinoline, leading to the indolizonebased compound (Scheme 3.61) [121,122]. A three-component reaction of o-aminocinnamate (amine and dienophile in a single component) provided tetracyclic tetrahydroquinolines. The reaction was based on the reaction of an amine, an aldehyde, and an isocyanoacetamide in toluene employing stoichiometric amount of

Scheme 3.59

Scheme 3.60

148

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

lithium bromide as promoter. Two pairs of diastereomers were formed in 95% yield out of 16 possible isomers under these conditions [123]. A mixture of two pairs of diastereomers was cleanly transformed to 4,5-phenanthroline in 71% yield under carefully controlled conditions (Scheme 3.62) [124,125]. Intermolecular aryne annulations were performed on a variety of substrates. Pawlas and Begtrup [126] synthesized phenanthridines when aryl nitriles were reacted with 2 eq. of aryne through the activated nitrilium zwitterions (Scheme 3.63). Dominguez et al. [127] reported a palladium-catalyzed direct arylation of aryl-substituted pyrazoles for the synthesis of pyrazolophenanthridines

Scheme 3.61

Scheme 3.62

Scheme 3.63

Six-membered fused N-polyheterocycles

149

(Scheme 3.64). The resulting cyclization utilizing potassium carbonate, palladium acetate, n-Bu4Br, and lithium chloride in a sealed tube produced pyrazolophenanthridines in 42%
65% yields in dimethylformamide at 110 °C. Organotin reagents RSnMe3 and RSnBu3 comprise a valuable source of complexity and diversity. They were easily synthesized and stable and can be readily interfaced with relay switch reagents. Tris-cyclization-anion capture is shown in Scheme 3.65. The mechanism of the reaction involved a Pd-catalyzed [2 1 2 1 2]-cycloaddition followed by oxidative addition of palladium(0), an intermediate common to both cascades [128,129]. The aromatic Finkelstein reaction was used only once in the natural product synthesis by Furstner and Kennedy [130] for the construction of cytotoxic Tylophora alkaloids antofine and cryptopleurine. The Suzuki coupling of 1-bromo-2-iodo-4-methoxybenzene afforded an intermediate and then a bromide
iodide exchange occurred using either a Buchwald’s procedure or standard lithiation
iodination sequence with excess sodium iodide together with diamine and CuI to provide the more reactive iodide

Scheme 3.64

Scheme 3.65

150

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

that was used for the synthesis of antofine and cryptopleurine (Scheme 3.66). Although comparable yields were reported for both procedures, the standard lithiation was, however, preferred because long reaction times were needed in the second case. The bromide underwent vinylic Finkelstein reaction to afford the 1-iodo-2-methylpropene during synthetic studies toward the total synthesis of kaitocephalin [52,131]. The benzyl N-[2-(2,4-cyclohexadienyl)ethyl]carbamate underwent an intramolecular 1,4-chloroamidation reaction and was exploited as an important step toward the total synthesis of lycorane alkaloid (Scheme 3.67) [132,133]. Following various reports of 1,10 -bi-2-naphthol-based ligands in asymmetric allylic alkylation, Chapsal and Ojima [134,135] successfully used their novel phosphoramidite biphenol-based ligands to two asymmetric allylic substitution reactions. The first example lycorane, reported involved the key step in the total synthesis of alkaloid following the key allylic alkylation step, was obtained in .99% ee (Scheme 3.68).

Scheme 3.66

Scheme 3.67

Six-membered fused N-polyheterocycles

151

Scheme 3.68

Scheme 3.69

Sanz et al. [136] extended a variation of Barluenga’s indole synthesis to complete the total synthesis of N-methylcrinasiadine. Aryne formation and lithiation of aryl bromide were followed by cyclization of aryl anion onto the reactive triple bond and proton quench of the formed intermediate with an eq. of methanol (Scheme 3.69). Desroy et al. [137] reported a one-pot enyne metathesis and Diels
Alder reaction for the synthesis of new tricyclic β-lactams (Scheme 3.70). The combination of RCM and Diels
Alder reaction sequences was a useful synthetic pathway for the asymmetric synthesis of novel polycyclic carbacephem derivatives [138]. The enyne metathesis of monocyclic 2-azetidinone provided the bicyclic compound. This diene then underwent a Diels
Alder reaction with dimethyl acetylenedicarboxylate as dienophile to afford the high yield of tricyclic β-lactam [139a,b].

3.2.10 Magnesium-assisted synthesis Chiba et al. [140] developed a facile synthetic protocol for phenanthridine derivatives starting from Grignard reagents and biaryl-2-carbonitriles under an oxygen atmosphere via copper-catalyzed carbon
nitrogen bond

152

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.70

Scheme 3.71

formation on the aromatic carbon
hydrogen bond. The conversion was performed by a sequence of nucleophilic addition of Grignard reagents to biaryl-2-carbonitriles to form the N
H imines and their copper-catalyzed carbon
nitrogen bond formation on the aromatic carbon
hydrogen bond, where molecular oxygen was a prerequisite to achieve the catalytic process (Scheme 3.71) [141].

3.2.11 Manganese-assisted synthesis A common nucleophile for intramolecular cyclizations was aryl ring that acted through an electrophilic aromatic substitution reaction (Scheme 3.72). Kessar et al. [142] developed this reaction in the transformation of aryl bromide to fused isoquinoline intermediate in the total synthesis of chelerythrine chloride. The mechanism of ring-closure involved amineassisted intramolecular addition to the aryne by aminonaphthyl functional group. The isoquinoline product was obtained by oxidation in the next step.

Six-membered fused N-polyheterocycles

153

Scheme 3.72

Scheme 3.73

3.2.12 Molybdenum-assisted synthesis Pérez
Castells et al. [143] developed an intramolecular Pauson
Khandtype reaction of allenamide in the presence of Mo(MeCN)3(CO)3 to afford a tricycle in 43% yield, although the original conditions were not effective (Scheme 3.73) [49b].

3.2.13 Nickel-assisted synthesis Mori and coworkers [144] reported the total synthesis of erythrocarine by employing RCM of dienyne as the key step and a number of important reaction sequences. The starting compound was reacted with trimethylsilylacetylene in the presence of palladium catalyst to afford an alkyne that was then condensed with nitromethane to provide the nitro derivative. The alkyne was formed when nitro derivative was treated with lithium
aluminum hydride followed by Boc-protection. The alkyne provided RCM precursors applying a number of reaction sequences. The cyclized product was formed in almost quantitative yield when dienyne hydrochloride in CH2Cl2 was treated with Grubbs’ first-generation catalyst (10 mol%) for 18 h at rt. The cyclized product was treated with potassium carbonate in methanol to give the alcohol, erythrocarine (Scheme 3.74) [139].

3.2.14 Promethium-assisted synthesis The 3-aminoquinoline reacted with butyric aldehyde under optimum conditions to synthesize the N-(2-ethylhexenyl-2)-3-aminoquinoline, 2-propyl-3-ethyl-5,6-benzo-l,7-naphthyridine, and condensation products,

154

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.74

initial aldehyde (content of no more than 8%) in total .95% yield (Scheme 3.75) [145,146]. The substituted naphthyridines were formed in 40% yield and initial quinoline in 55% yield when 4-aminoquinoline was interacted with C4
C7 by aliphatic aldehydes. The common amount of side products such as dimers and trimers of butyric aldehyde and alkylquinolines was not more than 10% (Scheme 3.76) [146]. The 3-ethyl-4-phenyl- and 2-phenyl-3-ethyl-5,6-benzo-l,7naphtyridine and N-aryl-substituted 3-aminoquinolines were formed in total 98% yield by a mixed liquid-phase condensation of 3aminoquinoline with benzaldehyde and butyric aldehyde (1:1:1 ratio, 6 h, 150 °C, PrCl 3 -triphenylphosphine-dimethylformamide, toluene) (Scheme 3.77) [147].

Six-membered fused N-polyheterocycles

155

Scheme 3.75

Scheme 3.76

Scheme 3.77

A mixture of 2-propyl-3-ethyl- and 2-phenyl-3-ethyl-l,10-phenanthrolines was obtained in 1:1 ratio in total yield of 45% by a mixed condensation of 8-aminoquinoline with benzaldehyde and butyric aldehyde using PrCl3-triphenylphosphine-dimethylformamide catalyst (Scheme 3.78) [146,147]. According to analogous Schemes 3.79 and 3.80 substituted 1,7-, 1,10-, and 4,7-phenanthrolines were prepared by liquid-phase condensation of o-, m-, and p-phenylenediamines with butyric aldehyde that opened a prospective and simple protocol to construct the hardly available substituted phenanthrolines, starting from available aromatic diamines [148]. The reaction was

156

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.78

Scheme 3.79

Scheme 3.80

studied on the example of various C4
C6 aliphatic aldehydes and high yields (B60%) of phenanthrolines were obtained under reaction conditions (5 mol % catalyst PrCl3-triphenylphosphine-dimethylformamide, 8 h, 180 °C). In contrast to the traditional protocol of a synthesis of unsubstituted phenanthrolines according to the Skraup method based on a condensation of acrolein and glycerin with phenylenediamine in the presence of concentrated nitric acid or sulfuric acid, [149] it was found that when the reaction was performed in the presence of mixed catalyst PrCl3
palladium chloride
zinc chloride-triphenylphosphine-dimethylformamide in a ratio of 1:1:2:1:1 at 100 °C
120 °C, the yields of 1,7-, 1,10-, and 4,7-phenanthrolines raised from 50% to 90% [146].

Six-membered fused N-polyheterocycles

157

3.2.15 Rhenium-assisted synthesis The formation of carbon
nitrogen bond on the nitrogen atom of oxime was extremely unusual and its reaction mechanism was not known. Therefore chemists focused on the synthesis of quinolines using rhenium reagents. It needed polar solvents like nitromethane for the catalytic Beckmann rearrangement. However, it was reported that only quinolines were formed when a nonpolar solvent like 1,2-dichloroethane was used in this reaction. Furthermore, when n-Bu4NReO4 was used in an equimolar amount in the reaction, approximately 60% yield was obtained. Later on it was reported that this low yield was due to the reduction of perrhenic acid by the first product dihydroquinoline. The reaction occurred in the presence of chloranil as an oxidant, quinoline was obtained in high yield even after reducing the amount of n-Bu4NReO4 to 20 mol% (Scheme 3.81) [150].

3.2.16 Rhodium-assisted synthesis This method was simply extended to the assembly of DE-ring system of yohimbine framework (Scheme 3.82) and was started by the synthesis of tryptophyl-substituted amide in three steps by sequential alkylation [151], acylation, and Boc-protection [152] of tryptamine. The cycloaddition of tryptophyl-substituted amide occurred in the presence of nickel catalyst to afford the quinoline in 88% yield at room temperature, while the alternative thermal protocol needed a temperature of 150 °C, caused cleavage of Boc protecting group, and provided only a 45% yield of 1,4-cyclohexadiene product. The pentacyclic 19,20-didehydroyohimban was formed in 86% yield upon elaboration of the formed product by selective hydrogenation of sterically less encumbered olefin, protiodesilylation [153] of vinylsilane with concomitant removal of the Boc protecting group, and Bischler
Napieralski closure of the C-ring. The structure of 19,20-didehydroyohimban was

Scheme 3.81

158

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.82

established by its catalytic hydrogenation over PtO2 to afford the alloyohimban and yohimban in a 1:1 ratio [154
156]. The alkaloids lycopodine were synthesized using isomunchnone dipole approach [157]. As shown in Scheme 3.83, 5-methylcyclohexenone was transformed into diazo imide in seven steps. The desired tandem ylide cycloaddition products were formed in 97% yield as a 3:2 diastereomeric mixture upon diazo decomposition of diazo imide with Rh2(pfb)4 at 25 °C in dichloromethane. This mixture was treated with BF3.2AcOH to give the tetracyclic amide in 71% yield as a mixture of diastereomers (4:1). There are many well-known reactions that involve enol nucleophiles such as Claisen
Schmidt, aldol, and Mannich reactions [158]. Various neutral carbon nucleophiles were used to construct the izidine alkaloids bicyclic core as depicted in Schemes 3.84 and 3.85 where a cyclohydrocarbonylation reaction provided an N-acyliminium species that was trapped by one of the carbon nucleophile systems [159]. The N-acyliminium ion was produced by cyclohydrocarbonylation to reproduce the reaction and yield (Scheme 3.86). However, only modest isolated yields of 46% and 52% were obtained under these conditions. Furthermore, no secondary product was detected on analysis of the crude reaction mixture by LC
MS. It was necessary to continue screening conditions to provide the good-to-excellent yield of desired product [159].

Six-membered fused N-polyheterocycles

Scheme 3.83

Scheme 3.84

Scheme 3.85

Scheme 3.86

159

160

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Chiou et al. [160] reported that N-allylic amides of arylacetic acids afforded tricyclic aza-heterocyclic structures such as tricyclic indolizidine alkaloids, crispine A and its analogues as well as the tetracyclic β-carboline alkaloid, harmicine, by rhodium-catalyzed cyclohydrocarbonylation-bicyclization (Schemes 3.87 and 3.88) [18]. The allylsilane system (Scheme 3.89) afforded a facile access to 6-6-6 alkyl quinolizidine alkaloids. However, the synthesis of precursor was a synthetic challenge and not provided the ideal scenario for reaction condition screening [161,162]. Grigg et al. [163] reported a rhodium(I)-catalyzed [2 1 2 1 2]-cycloaddition followed by a Pd-catalyzed direct arylation of newly formed aromatic moiety for the synthesis of phenanthrene-type heterocyclic compounds (Scheme 3.90).

Scheme 3.87

Scheme 3.88

Six-membered fused N-polyheterocycles

161

Scheme 3.89

Scheme 3.90

3.2.17 Scandium-assisted synthesis The Sc(OTf)3 catalyst worked efficiently in aza-Diels
Alder reactions [164
166]. The substituted N-benzylideneaniline and 2-trans-1-methoxy-3trimethylsiloxy-1,3-butadiene (Danishefsky’s diene) were reacted in the presence of 10 mol% Sc(OTf)3 to provide the imino-Diels
Alder adducts (a tetrahydropyridine derivative in this case) quantitatively. On the other hand, the reaction course between cyclopentadiene and substituted N-benzylideneaniline under same conditions was changed, and tetrahydroquinoline derivative was formed as the sole product (Scheme 3.91). In this reaction, the cyclopentadiene acted as a dienophile and aromatic imines as azadienes [167
169]. However, a mixture of tetrahydroquinoline and tetrahydropyridine derivatives was obtained with 2,3-dimethylbutadiene. Other dienophiles, like vinyl ethers, vinyl sulfide, and silyl enol ether, were used to provide the high yields of tetrahydroquinoline derivatives [170
177]. The substituted N-methylacridones were synthesized from 2-(Nmethyl-N-phenylamino)benzaldehydes via dehydrogenative cyclization. This reaction involved two primary processes: first the aldehyde was

162

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

coordinated with Sc(OTf)3 and induced the aromatic electrophilic substitution reaction to afford the active intermediate N-methyl-acridin-9-ol that was oxidized quickly in situ to form the acridones. Furthermore, the involved protocol was both atom efficient and environmental friendly; water was the only by-product in this reaction. Herein, a scandium(III)catalyzed single step reaction afforded N-methylacridones by intramolecular dehydrogenative cyclizations. This transformation was very different than other transition metal-catalyzed aromatic carbon
hydrogen activation of aldehydes (Scheme 3.92) [178
189a,b]. The intramolecular kinetic isotope effect experiment was performed with deuterium-labeled substrates (Scheme 3.93). No kinetic isotope effect was reported (the intramolecular kH/kD 5 1.0 in the different reaction times), which has indicated that the carbon
hydrogen bond activation did not occur in this reaction [189,190]. However, when this occurred, the aromatic electrophilic substitution reaction provided the active intermediate N-methylacridin-9-ol. The intermediate alcohol was detected by GC
MS. The reaction of deuterated aldehyde was also conducted to further affirm this analysis (Scheme 3.94). The deuterated alcohol of C-d2 was observed. On the basis of these results, it was concluded that this transformation was a result of Friedel
Crafts alkylation reaction [191
193].

Scheme 3.91

Scheme 3.92

Scheme 3.93

Six-membered fused N-polyheterocycles

163

Scheme 3.94

Scheme 3.95

3.2.18 Tin-assisted synthesis The pyrroloquinolines were formed in preference to the pyrrolobenzoazepines by tin(IV)-catalyzed cyclization and rearrangement of 1-arylγ-hydroxylactams via an intermediate iminium ion (Scheme 3.95) [194]. Stille reaction is very tolerant of many functional groups that make it effective for the synthesis of complex pyridine derivatives [195]. It was possible to produce the organostannane in situ via Pd-assisted reaction of a pyridyl triflate or halide with hexamethylditin (Scheme 3.96) [196,197]. The ( 6 )-epi-zephyrathine was synthesized by incorporation of the carbonyl group within the tether [198]. The oxabicyclic cycloadduct was formed easily in high yield at rt and was used to complete the synthesis of ( 6 )-epi-zephyrathine. The oxabicyclic cycloadduct was subjected to a Lewis acid-induced ring-opening in acetone to afford the acetonide (Scheme 3.97). This was followed by reaction with a substituted benzoyl chloride after N-Boc-deprotection. The target molecule was formed in 15% overall yield in seven steps by a subsequent radical cyclization, reduction, and acidic workup. The cycloaddition involving indole systems is shown in Scheme 3.98 and has much synthetic potential as it offers an efficient and rapid entry into the tetracyclic core found in Strychnos and Aspidosperma alkaloids [198,199]. The ketone was reduced to provide a single isomer, which was protected as tert-butyldimethylsilyl ether. An intermediate was formed in 68% yield upon bromination with N-bromosuccinimide in triethylamine. The final ring was formed under radical cyclization conditions, and this completed the generation of the framework of Aspidosperma alkaloids.

164

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.96

Scheme 3.97

The benzo-fused tricyclic β-lactams such as benzocarbacephems as well as benzocarbapenems were synthesized by an approach (racemic and asymmetric), through intramolecular aryl radical cyclization of 2-azetidinone-tethered haloarenes [200]. The desired benzocarbacephems and benzocarbapenems were obtained in good yields as single diastereomers after chromatographic purification when haloaryl β-lactams were reacted with AIBN and tributyltin hydride at reflux in benzene (Schemes 3.99
3.101) [139b]. The 5-methyl-5,6-dihydrobenzimidazo[2,1-a]benzo[f]isoquinolines were prepared conveniently in three steps (Scheme 3.102). The 1-bromo-2naphthoic acid was heated with o-phenylenediamines in polyphosphoric

Six-membered fused N-polyheterocycles

165

Scheme 3.98

Scheme 3.99

Scheme 3.100

Scheme 3.101

acid to give the 2-(1-bromo-2-naphthyl)-1H-benzimidazoles which underwent N-allylation with 3-bromoprop-1-ene and sodium hydride in tetrahydrofuran to afford the 1-allyl-2-(1-bromo-2-naphthyl)benzimidazoles in 68%
88% yield. The 5-methyl-5,6-dihydrobenzimidazo[2,1-a]benzo[f]

166

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.102

Scheme 3.103

isoquinolines were prepared by Bu3SnH-assisted cyclization of 1-allyl-2-(1bromo-2-naphthyl)benzimidazoles in refluxing toluene [201
203]. The aryl-2-azetidinone-tethered haloarenes were reacted for the regiocontrolled synthesis of fused tetracyclic biaryl-2-azetidinones that were considered as β-lactam-biaryl hybrids via aryl-aryl radical cyclization [204]. The trans-β-lactams were treated with AIBN and tributyltin hydride at reflux in benzene under high dilution conditions to synthesize the condensed tetracyclic biaryl-2-azetidinones as single trans-diastereomers in good yields after chromatographic purification (Scheme 3.103) along with reduced starting material in small amounts [139b]. In contrast, symmetrical benzamides containing an appropriate electrophile on the aromatic ring underwent intramolecular cyclizations very effectively (Scheme 3.104). In these substrates, rapid rotation of aromatic ring facilitated the capture of α-amido radical before its demise, affording benzoquinolizidinone and benzoindolizidinone in good yield [205,206].

3.2.19 Tungsten-assisted synthesis The [1,2]-alkyl-migrated products were formed along with a small amount of formal [4 1 2] cycloadducts by the reaction of substrates,

Six-membered fused N-polyheterocycles

167

Scheme 3.104

Scheme 3.105

possessing an internal triple bond, in the presence of a stoichiometric amount of tungsten complex (Scheme 3.105) [207].

3.2.20 Ytterbium-assisted synthesis The resins ArgoGel and ArgoPore were efficiently loaded with leucine methyl ester and then acetylated. Functional group transformations afforded the formyl group, which reacted subsequently with substituted aniline. The formed adduct was then subjected to Diels
Alder cycloaddition. ArgoGel furnished final products in higher purity and yield after cleavage with 95% aqueous trifluoracetic acid. Cleavage of basic tetrahydroquinoline from the resin was difficult with trifluoracetic acid but occurred smoothly upon acylation of the basic nitrogen with trifluoroacetic anhydride (Scheme 3.106) [208]. Kiselyov et al. [209] connected the 4-nitrophenylalanine to Wang resin by esterification in the first example of the Grieco three-component condensation. The amino group was deprotected, acylated, and the nitro group was reduced to the amine. Grieco three-component condensation of aldehyde, amine, and diene afforded the desired tetrahydroquinoline derivative after the cleavage with trifluoracetic acid (Scheme 3.107).

168

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 3.106

Scheme 3.107

3.2.21 Zinc-assisted synthesis Mamada and coworkers [210] reported a solvent-free “green” reaction for the synthesis of polycyclic benzimidazole derivatives based on heating the arylene diamines and carboxylic acid anhydrides in solid state in the

Six-membered fused N-polyheterocycles

169

Scheme 3.108

Scheme 3.109

presence of Zn(OAc)2. Products were obtained and purified directly by train sublimation of the crude reaction mixtures (Scheme 3.108). The diarylamines were reacted with carboxylic acids under MWI for several min in the presence of zinc chloride to afford the good yield of 9-substituted acridines (Scheme 3.109) [211].

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1311.

CHAPTER 4

Six-membered N,N-heterocycles 4.1 Introduction Heterocyclic chemistry is the most interesting branch of organic chemistry and of utmost practical and theoretical importance. As a result of this a great deal of research conducted in chemistry is devoted to heterocyclic chemistry [1a
f]. Heterocycles are widely distributed in nature. It is an expanding and vast field of chemistry due to obvious use of compounds derived from heterocycles in pharmacy, medicine, agriculture, plastics, polymers, and other areas. Due to their biological activities heterocycles are employed in the treatment of infectious diseases. Various heterocycles prepared in laboratories are successfully used as clinical agents [2
5]. Six-membered aromatic rings possessing two nitrogen atoms including phthalazinones, quinazolinones, pyrimidines, and pyrimidinones exhibit a wide spectrum of pharmacological properties and therefore are interesting target compounds in pharmaceutical and medicinal chemistry. The pathways for the transformation of hydrocarbon substrates into nitrogencontaining products with the assistance of metal catalysts are the focus of investigation in synthetic organic chemistry [6
10]. Over 90% of pharmaceuticals have at least one nitrogen atom in their structure and out of seven about one reaction in the pharmaceutical industry involves the formation of a C
N bond. The N-heterocycles occur in a variety of biologically active and natural compounds. Efficient protocols for the preparation of N-containing heterocycles are of fundamental importance and represent a major challenge in synthetic chemistry [11
16].

4.2 Metal- and nonmetal-assisted synthesis of sixmembered heterocycles with two nitrogen atoms 4.2.1 Aluminum-assisted synthesis Wang and coworkers [17] reported an efficient synthesis of 5-unsubstituted-3,4-dihydropyrimidin-2(1H )-ones via Fe(III)-catalyzed Biginelli-like cyclocondensation of urea with ketones and aldehydes in acetonitrile. Sandhu and coworkers [18] developed a facile synthesis of Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00004-X

© 2020 Elsevier Inc. All rights reserved.

183

184

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

these compounds by one-pot condensation of urea, aldehydes, and enolizable ketones (Scheme 4.1) using bimetal system potassium iodide and AlCl3 under reflux in acetonitrile. Some combinations of catalytic systems were examined and the most effective combination was found to be AlCl3 and KI systems [19].

Scheme 4.1

The condensation of 2-amino-3-ethylcarboxylate-4,5-diphenylfuran with mono-substituted thioureas under microwave irradiation (MWI) on alumina support provided a series of novel 2-thioxo-5,6-diphenyl-furo [2,3-d]pyrimidin-4(1H )-ones in excellent yield (92%) within 8 min of reaction time period. The condensation of benzoin and cyanoethyl acetate over basic alumina under MWI furnished 2-amino-3-ethylcarboxylate4,5-diphenylfuran efficiently. The furopyrimidines were synthesized when 2-amino-3-ethylcarboxylate-4,5-diphenylfuran was reacted with monosubstituted thioureas under microwave irradiation for 7
8 min. Under conventional conditions the same reaction took 4
5 h to afford only 57%
65% yield. The solid-supported microwave (MW) chemical reactions occurred in short duration with greater ease of manipulation to provide the product in excellent yields (Scheme 4.2) [20].

Scheme 4.2

Six-membered N,N-heterocycles

185

The substituted ethyl 1,2,3,6-tetrahydro-4-methyl-2-thioxo/oxo-6phenyl-1-(4,5-diphenyl-1H-imidazol-2-yl)pyrimidine-5-carboxylates were prepared. In connection with using microwaves, various imidazolylpyrimidines were generated in minimum time and minimum solvent under MWI (Scheme 4.3). A simple protocol was reported for the synthesis of 4,5-diphenyl imidazolyl pyrimidine derivatives during the programmed study on the development of green approach toward the synthesis of new organic molecules, in which two aryl rings were located at C-4 and C-5 on the opposite faces of the planar imidazole ring. The substituted ethyl-1-formyl-l,2,3,6-tetrahydro-4-methyl-6-phenyl-2-oxo/ thioxopyrimidine-5-carboxylates and benzil were condensed with ammonium acetate using four drops of glacial acetic acid and acidic alumina for 8 min under solvent-free MWI for the synthesis of substituted ethyl 1,2,3,6-tetrahydro-4-methyl-2-thioxo/oxo-6-phenyl-l-(4,5-diphenyl-1Himidazol-2-yl)pyrimidine-5-carboxylates [21].

Scheme 4.3

Two simple, benign, solvent-free, rapid, and versatile MW energy transfer systems for the preparation of quinoxalines (i.e., 2,3-diphenyl4a,5,6,7,8,8a-hexahydroquinoxaline, 2,3-diphenylquinoxaline and its

186

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

derivatives, and 2-phenylquinoxaline and also 2,3-dihydro-5,6-diphenylpyrazine and pyridine-2,3-diamine) have been used. The first approach used mineral supports for the reaction of α-hydroxyketone (acyloin) or 1,2-dicarbonyl (benzil) with 1,2-diamines. Among the mineral supports, the efficiency of acidic alumina as catalyst was clearly proved (80%
86%). Moreover, it has an oxidative role in the tandem oxidation of acyloin to the 1,2-dicarbonyl compound. The second approach used a polar paste system for the reaction of 1,2-dicarbonyl (benzil) with 1,2-diamines. By far, the most common protocol relied on the condensation of an aryl 1,2-diamine with a 1,2-dicarbonyl compound in refluxing acetic acid or ethanol for 2
12 h. For example, in the literature quinoxaline was formed in yields ranging from 34% to 85% depending on the reaction conditions of condensation of 1,2-diaminobenzene with benzyl (PhCOCOPh). The microwave-assisted condensation was performed between phenylglyoxal monohydrate and dicarbonyls like benzil and also acyloin with many diamines like 4methylbenzene-1,2-diamine, benzene-1,2-diamine, 4-nitrobenzene-1,2diamine, 4,5-dimethylbenzene-1,2-diamine, ethylene-1,2-diamine, cyclohexane-1,2-diamine, and pyridine-2,3-diamine. It was found that acidic alumina was a good catalyst in a new, microwave-assisted solventfree reaction for the synthesis of products (Scheme 4.4) [22].

Scheme 4.4

An environmentally benign method was reported for the preparation of 2-substituted-4,6-diarylpyrimidines using inorganic solid supports as an energy transfer medium as well as its catalytic role. The reaction eliminated the use of solvent during the reaction. The yield increased and reaction time was brought down from hours to minutes. The high yield and rate enhancement was attributed to the coupling of microwaves with solventfree conditions. Further, the role of base was studied in the reaction and it was concluded that MW-assisted basic alumina-catalyzed reaction was the best in terms of reaction time as well as catalysis and yield. Many synthetic modes of pyrimidines were reported starting from thiobarbituric acid (TBA) [23], chalcones [24], and thioureas [25]. But these generally provided

Six-membered N,N-heterocycles

187

pyrimidinone derivatives. The 4,6-diaryl-2-(4-morpholinyl/1-piperidinyl/ 1-pyrrolidinyl)-pyrimidines were synthesized under microwave and solidsupported method. Classically [26], the α,β-unsaturated ketones were refluxed with S-benzylthiouronium chloride (SBT) and heterocyclic secondary amines in ethanol (20 mL) for 10
18 h to afford the 2,4,6-trisubstituted pyrimidines. Different experimental trials were performed to standardize the reaction under microwaves. The heterocyclic secondary amine (morpholine/piperidine/pyrrolidine) was added to S-benzylpyrimidine derivative, adsorbed over basic alumina and irradiated under microwave. The product was obtained within 3 min in 85% yield. The adsorbed reaction mixture of chalcone and SBT was irradiated over neutral/basic alumina to afford the S-benzyl derivative. Further the formation of final cyclized product as well as the precursor over neutral/basic alumina prompted to attempt one-pot synthesis of required pyrimidine derivative from the reactants such as SBT, chalcone, and heterocyclic secondary amines. This one-pot synthesis minimized the energy and yield loss, and limited the necessity of solvent. Basic alumina under microwave provided the best result in terms of reaction time and yield. This was attributed to the requirement of basic conditions for the nucleophilic displacement of Sbenzyl group by heterocyclic secondary amine. These solid supports acted as both energy transfer media as well as catalysts. The effect was not purely thermal [27] and it was obvious from the fact that for similar product yield longer time periods are required using oil-bath at the same temperature of 110 °C
120 °C (Scheme 4.5) [28,29].

Scheme 4.5

4.2.2 Bismuth-assisted synthesis Khosropour and coworkers [30] synthesized pyrimidinones using 3.5 mol % tetrabutylammonium bromide. This Biginelli reaction used ketoesters, primary alcohols (instead of aldehydes), and bismuth nitrate. The one-pot oxidation-cyclocondensation was carried out without the isolation of an intermediate aldehyde (Scheme 4.6). The primary benzyl alcohols,

188

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 4.6

containing either electron-donating or electron-withdrawing groups, were treated to afford the pyrimidinones in short reaction times and high yields. Another important aspect was that many moieties, like halide, ether, and nitro, survived under these reaction conditions. The same reaction was performed in acetonitrile as solvent, where the reaction yield was about 80% and the time was 40 min [31]. Khodaei and coworkers [32] reported a direct synthesis of these compounds that involved a three-component condensation using benzyl halides instead of aldehydes and Bi(NO3)3  5H2O in tetrabutylammonium fluoride as catalyst and an in situ oxidant (Scheme 4.7). It was an in situ, one-pot oxidation-cyclocondensation and the advantage of this reaction was that several commercially available alkyl halides were used rather than aldehydes and the intermediate aldehydes did not need isolation. The preparation of 3,4-dihydropyrimidin-2(1H )-ones [33] at 100 °C was promoted in the presence of 1,1,3,3-tetramethylguanidinium trifluoroacetate as a room temperature ionic liquid (RTIL) [19,34].

Scheme 4.7

The 4,6-diarylpyrimidin-2(1H )-ones were synthesized by an efficient single step Bi(OTf)3-TCT or Zn(OTf)2-TCT promoted method under solvent-free MWI conditions (Scheme 4.8) [34,35].

Six-membered N,N-heterocycles

189

Scheme 4.8

The 4,6-diarylpyrimidin-2(1H )-ones were prepared by one-pot method in catalytic amount of Bi(TFA)3 immobilized on n-butylpyridinium tetrachloroferrate, [nbpy]FeCl4, as a RTIL. This protocol allowed the generation of many 4,6-diarylpyrimidin-2(1H )-ones in high yields. The catalytic system was recycled and reused (Scheme 4.9) [34,36].

Scheme 4.9

A straightforward and simple one-pot cyclocondensation of a ketoester, an aldehyde, and urea was reported under acidic conditions (Biginelli reaction) [37]. The Lewis acids like several bismuth(III) compounds were studied in this reaction. Thus the use of bismuth chloride [38], Bi (OTf)3  xH2O [39], BiONO3 [40], Bi(NO3)3  5H2O [41], and BiOClO4  xH2O [42] was reported for this reaction. A polyanilinebismoclite complex (PANI-BC) was used successfully as an efficient catalyst in this reaction. The catalyst was easily recovered and reused after completion of the reaction [43]. A simple and fast Bi(NO3)3-catalyzed microwave-assisted synthesis of 3,4-dihydropyrimidin-2(1H )-ones was reported under solvent-less conditions (Scheme 4.10) [34,44].

Scheme 4.10

190

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

4.2.3 Cerium-assisted synthesis The 5-phenyl-7-thioxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine2,4-(1H,3H)-dione and 5-phenyl-5,8-dihydropyrimido[4,5-d]pyrimidine2,4,7(1H,3H,6H)-trione derivatives were synthesized when a mixture of proper aromatic aldehyde, barbituric acid, and urea (or thiourea) was reacted in catalytic amount of ceric ammonium nitrate in water under mild reaction conditions (Scheme 4.11). Thus a variety of substituted aldehydes, urea (or thiourea), and barbituric acid were treated in the presence of ceric ammonium nitrate catalyst to synthesize the pyrimidopyrimidinones. The pyrimidopyrimidinones were formed in excellent yields by performing the reaction at refluxing temperature for 5
15 min in water as a solvent. This reaction tolerated a variety of other functional groups of aromatic aldehydes under reaction conditions. Both electrondeficient and electron-rich aldehydes worked well to afford the products in high yields [45
51].

Scheme 4.11

The Biginelli reaction is very important for the synthesis of biologically active DHPMs. It involved the acid-catalyzed condensation of CH-acidic carbonyl components, aldehydes, and urea-type building blocks. Matloobi and Kappe [52] made great contributions in the area of microwaveassisted Biginelli reactions. They combined MWI with click chemistry [53], parallel library-generation, and solution- (Scheme 4.12) and solidphase combinatorial (Scheme 4.13) chemistry based on this Biginelli reaction. Kappe and coworkers [54] reported an efficient five-step linear method involving an initial Biginelli multicomponent reaction for the synthesis of a variety of 2-substituted pyrimidines in comparatively short reaction time and high yields. The lanthanum chloride Biginelli catalyst

Six-membered N,N-heterocycles

191

was modified by impregnation of lanthanum chloride on graphite support [55] that reduced the reaction time from 5 h for conventional heating in ethanol to 8 min under MWI for the formation of dihydropyrimidines thione. A high speed MW method was performed using Biginelli MMS to synthesize the 2-amino-4-(het)aryl-pyrimidine, present in important pharmaceuticals. The dihydropyrimidine-2-thione was obtained in 65% yield that was elaborated into 2-amino-4-arylpyrimidines when an inexpensive mediator/catalyst trimethylsilylchloride was used under MW heating (10 min, 120 °C).

Scheme 4.12

Scheme 4.13

192

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

4.2.4 Copper-assisted synthesis Rajitha and coworkers [56] reported a Biginelli reaction in the presence of bismuth oxide perchlorate and bismuth subnitrate catalyst for the synthesis of 3,4-dihydropyrimidinones. They also developed [57] a one-pot condensation reactions of β-keto esters, aldehydes, and thiourea or urea using copper dipyridine dichloride as a catalyst (Scheme 4.14). Aliphatic aldehydes were not used in both of these protocols to give the dihydropyrimidinones [19].

Scheme 4.14

The arylation of heterocyclic compounds with aryl halides is now also a powerful synthetic tool due to the introduction of ligand-assisted methods and recent developments, even if a bit harsher conditions were required in most cases than those in the case of Chan
Lam coupling reactions. An interesting example was reported for the synthesis of AMN (Nilotinib) [58], a compound currently undergoing phase II/III clinical trials for chronic myelogenous leukemia. The aromatic imidazole was synthesized regioselectively in 75% yield by arylation of 4-methylimidazole with aryl bromide and without any competing self-arylation of bromoaniline (Scheme 4.15) [59].

Scheme 4.15

Six-membered N,N-heterocycles

193

Enamides being important intermediates, the vinylation of amides in the presence of copper catalyst also served for the synthesis of important intermediates in the synthesis of natural products that do not necessarily incorporate an enamide moiety in their framework, as exemplified by the total synthesis of barenazines by Focken and Charette [60]. The key step involved in the synthesis of these naturally occurring hexahydropyridinopyrazines was diastereoselective reduction of 5-amino-2,3-dihydro-1Hpyridin-4-one that was dimerized to the core structure of barenazines. The 5-amino-2,3-dihydro-1H-pyridin-4-one was conveniently synthesized in excellent yield using a cross-coupling of tert-butylcarbamate and cyclic iodo-aminoenone (Scheme 4.16). This reaction was especially straightforward and interesting because although iodo-aminoenones were easily accessible by iodination of aminoenones, the synthesis of their amino derivatives, such as 5-amino-2,3-dihydro-1H-pyridin-4-one, was usually a lengthy process [59].

Scheme 4.16

Two three-atom building blocks were used and pyrazine was obtained by the condensation of 2-aminoethanol and N
C
C building block (Scheme 4.17) [61].

Scheme 4.17

194

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Antonchick et al. [62] used chiral catalyst (derived from Cu(CH3CN)4PF6 and N,P-ferrocinyl ligand) for the synthesis of spiro-pyrrolidineoxindoles in 98% enantiomeric excess and up to 97% yield. The organocatalytic asymmetric cycloaddition of 3-methylene-2-oxindoles to azomethine ylides from glycyl imine methyl esters resulted in the synthesis of pentacyclic spirotryprostatin A scaffold with an all carbon quaternary stereocenter [63]. The 1,3-dipolar cycloaddition of N-unsubstituted 3-methylene-2-oxindoles containing electron-donating and electron-withdrawing groups and a variety of mono- and poly-substituted glycyl imine esters catalyzed by a Cu (CH3CN)4PF6 (5 mol%) and ferrocene-based ligand at ambient temperature, followed by N-acylation provided the spiro-N-acylpyrrolidine-oxindole products in good ee and yields. The diastereoselectivity was high except for osubstituted azomethine ylides. The pentacyclic scaffold of spirotryprostatin A was synthesized by acylation of amino group in the spiro-pyrrolidine ring, however, (L)-Fmoc-ProCl and deprotection of Fmoc group resulted in an immediate triggering of diketopiperazine cyclization (Scheme 4.18). The yields (18%
21%) of products decreased when both the substrates contain electron-withdrawing group [64].

Scheme 4.18

Azodicarboxylates served as dienophiles in hetero-Diels
Alder reactions. The 1,3-cyclopentadiene was reacted with {[(2-oxo-1,3-oxazolidin-3-yl)carbonyl]diazenyl}formate. The hetero-Diels
Alder adduct was formed in high yield (92%) but in low ee (B20%) when (R,R)-Cu(OTf)2 (10 mol%) catalyst was used. The enantioselectivity was not improved when the chiral ligand was changed to a more sterically hindered ligand (Scheme 4.19) [65,66].

Scheme 4.19

Six-membered N,N-heterocycles

195

The pyrido[30 ,20 :5,6]pyrimido[1,2-a]benzimidazol-5(6H)-one was formed by copper-catalyzed cyclocondensation of 2-aminobenzimidazole and 2-bromobenzoic acid in dimethylformamide and potassium carbonate at reflux. The pyrido[30 ,20 :5,6]pyrimido[1,2-a]benzimidazol-5(6H)-one was treated with sulfur and phosphorus in refluxing pyridine to give the 5-thione analogue. The 5-thione analogue was treated with hydrazine in refluxing ethanol followed by nitrosation to afford the fused hexaazapentacyclic system (Scheme 4.20) [67,68].

Scheme 4.20

Fu et al. [69] synthesized nitrogen heterocycles by an efficient copper-catalyzed aerobic oxidative intramolecular alkene carbonhydrogen amination. This method used easily available substituted 3-methyleneisoindolin-1-ones as the starting materials, Cu(OTf)2 as the catalyst, and air as the oxidant for the construction of nitrogen heterocycles in good-to-excellent yields (Scheme 4.21) [70].

Scheme 4.21

Karpov and Muller [71,72] developed a catalytic access to the class of alkynones on the basis of Sonogashira protocol: terminal acetylenes were converted by the reaction with acid chlorides in only 1 eq. of amine base and produced highly electrophilic ynones concomitantly consigning an

196

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

essentially neutral reaction medium. Subsequent Michael additions can now selectively address the unsaturated functionality with a broad number of nucleophiles. The pharmacologically important class of pyrimidines was constructed when amidinium salts were reacted as amidine precursors in the presence of an excess of Na2CO3. Interestingly, “notorious” trimethylsilyl alkynones were successfully synthesized and transformed under mild conditions to afford the disubstituted derivatives as a result of trimethylsilyl cleavage. An alternative catalytic three-component access to ynones was performed by carbonylative alkynylation of alkynes, aryl iodides, and carbon monoxide. Poly-substituted pyrimidines were synthesized upon subsequent addition of an amidinium salt in the sense of a four-component reaction (Scheme 4.22) [73,74].

Scheme 4.22

An intriguing entry to functionalized nitrogen-containing heterocycles was provided by carbon monoxide insertion into intermediate aminopalladium adducts. Tamaru et al. [75
77] performed interesting experiments under Wacker-type conditions and exploited various unsaturated ureas and carbamates as nitrogen nucleophiles to afford the pyrimidinones, imidazolidinones, and related N-heterocycles (Scheme 4.23). In particular, both the nitrogen atoms acted as nucleophiles when urea derivatives were used as substrates. Among nitrogen nucleophiles, endo-carbamates displayed a distinctive reactivity and needed addition of sodium acetate as buffered conditions to react [78].

Scheme 4.23

Six-membered N,N-heterocycles

197

4.2.5 Gold-assisted synthesis The pursuit of synthetic efficiency stimulated the development and design of innovative synthetic strategies and new concepts by implementing reaction cascades. The vast majority of reported cascade sequences use a single starting substrate possessing multiple functional groups strategically positioned along a chain, terminating with an alkyne moiety. Au(I)-catalyzed cyclization of alkynoic acids was the first step in a sequence leading to an N-acyl iminium ion cyclization that resulted in the synthesis of complex multiring heterocyclic products of the general structure [79]. Indeed, keto amide was formed in 71% yield when a toluene solution of 1 mol% AuPPh3Cl/AgOTf was treated with alkynoic acid (1 eq.), followed by pyrrolyl ethyl amine. The subsequent conversion from keto amide to final compound by gold(I) needed higher temperatures to surmount the activation barrier to the N-acyliminium ion (Scheme 4.24) [80].

Scheme 4.24

Toste and coworkers [81] developed a [3 1 3]-annulation of azomethine imines with propargyl esters in the presence of Au(III) catalyst. The β-position of pyrazolidinone was substituted to afford the bicyclic product with high cis selectivity, which was determined during ring-closing rather than in the synthesis of allyl-Au intermediate (Scheme 4.25) [82].

Scheme 4.25

198

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Fused tricyclic xanthines have potential activities as anticonvulsants to treat chemically induced seizures and are selective and potent antagonists of human A2A adenosine receptors. A convenient, simple, and green synthetic protocol was developed for the construction of diverse fused tricyclic xanthines via Ag(I)-catalyzed isomerization-hydroamination or Au(I) complex-catalyzed intramolecular hydroamination of terminal alkynes in water under MWI (Scheme 4.26) [83].

Scheme 4.26

4.2.6 Indium-assisted synthesis Indium(III) chloride was explored as a powerful Lewis catalyst affording high chemo- and regioselectivity in many chemical transformations. Ranu et al. [84] synthesized dihydropyrimidn-2(1H )-ones in the presence of indium chloride catalyst. Various substituted aliphatic, aromatic, and heterocyclic aldehydes were subjected to this very efficient condensation. The dihydropyrimidin-2(1H )-thiones were obtained with similar success when thiourea was used (Scheme 4.27).

Scheme 4.27

4.2.7 Iodine-assisted synthesis Sarma and coworkers [85] developed a quick protocol for the condensation reaction of an ethyl acetoacetate, aldehyde, and thiourea or urea to

Six-membered N,N-heterocycles

199

prepare the substituted 3,4-dihydropyrimidin-2(1H )-ones using iodinealumina as the catalyst under solvent-free and MWI conditions (Scheme 4.28). The method was quick (1 min) with various substituted aromatic, aromatic, and heterocyclic aldehydes; however, no aliphatic aldehyde was used. Mirza-Aghayan and coworkers [86] synthesized 3,4-dihydropyrimidinones from an aldehyde, urea or thiourea, and a keto ester under microwaves and solvent-free conditions using ferric chloride hexahydrate as a catalyst.

Scheme 4.28

Noguchi et al. [87a] reported that iodine promoted the cyclization of allenamides via 6-endo-trig pathway (Scheme 4.29). It was proposed that the iodonium intermediates were produced selectively at the terminal olefin to afford the bicyclic guanidines [87b].

Scheme 4.29

Ren and Cai [88] synthesized 3,4-dihydro-4,6-diphenylpyrimidin-2 (1H )-one by one-pot, three-component reaction via Biginelli-like reaction (Scheme 4.30). Urea attacked the iodine-activated aldehydes to provide the intermediate, which underwent intramolecular cyclization and subsequently eliminated the molecule of water to deliver the products [89].

Scheme 4.30

200

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Zalavadiya and coworkers [90] reported a three-component domino reaction for the preparation of dihydropyrimidines from 1,3-dicarbonyl compounds, aromatic aldehydes, and N-(3-chloro-4-fluorophenyl)urea using 5 mol% iodine (Scheme 4.31) and these were evaluated for their in vitro antimycobacterial activity. In the presence of iodine, 1,3-diketone was in equilibrium with its enol form that attacked the iodine activated N-acylinium ion intermediate to afford an intermediate whose intramolecular cyclization followed by dehydration afforded the dihydropyrimidines [89].

Scheme 4.31

Bakavoli et al. [91] synthesized a series of pyrazolo[3,4-d]pyrimidine derivatives by one-pot iodocyclization reaction (Scheme 4.32) and screened their antibacterial activity. In situ produced Schiff's base underwent intramolecular cyclization and subsequent oxidation to afford the good-to-excellent yields of products [89].

Scheme 4.32

Zeng and Cai [92] developed a convenient multicomponent protocol for the generation of diverse tetrazolopyrimidines (Scheme 4.33). In situ generated enols reacted with aldehydes to afford the chalcones.

Six-membered N,N-heterocycles

201

1,4-Addition of free amino group of 5-aminotetrazole followed by intramolecular cyclization provided intermediate. The tetrazolopyrimidines were formed upon elimination of water and subsequent isomerization of double bond [89].

Scheme 4.33

One-pot synthesis of 3,4-dihydropyrimidin-2(1H )-ones was performed using iodine as a catalyst [93,94]. A cadmium chloride-catalyzed Biginelli reaction has also been developed [95]. Jenner [96] reported the effect of high pressure on Biginelli reactions. Bose and coworkers [97,98] reported a simple green protocol for Biginelli reaction catalyzed by p-toluenesulfonic acid using grindstone chemistry (Scheme 4.34). This method was time-saving, convenient, and also useful for kilogram-scale operation. The same group also reported water-based biphasic reaction media using p-toluenesulfonic acid catalyst for the large-scale preparation of dihydropyrimidinones. Jin and coworkers [99] developed a methanesulfonic acidcatalyzed efficient one-pot reaction of β-keto esters, aldehydes, and urea in ethanol for the synthesis of 3,4-dihydropyrimidin-2(1H )-ones [19].

Scheme 4.34

4.2.8 Iridium-assisted synthesis 1,2-Diols are more abundant than 1,2-diamines and ethylene glycol reacted with benzylamine to synthesize the piperazine in high yield. Diol was reacted with 2 eq. of amine to form a diamine that was reacted with different diol to produce a piperazine (Scheme 4.35). This method did

202

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

indeed work, and two 1,2,4-trisubstituted piperazines were synthesized from readily available starting substrates. The lower yield was obtained from incomplete conversion in the first step that afforded a mixture of products [100].

Scheme 4.35

The diol intermediate was not formed in acceptable yield when the reaction was carried out with two eq. of ethylene glycol and one eq. of benzylamine (Scheme 4.36). The ethylene glycol was oxidized more easily than the 2-aminoethanol intermediates, and provided the desired intermediate that was converted into unsymmetrically 1,4-disubstituted piperazines [101].

Scheme 4.36

The unsymmetrically substituted piperazines with different N-substituents were synthesized as shown in Scheme 4.37. Chiral ethanolamines are easily available from amino acids and are a good starting point for the preparation of chiral piperazines. Furthermore, this method afforded a system possessing one free and one alkylated nitrogen, which was useful for further modifications [102].

Scheme 4.37

Six-membered N,N-heterocycles

203

Various additional substrates were tested (Scheme 4.38
4.40), but only trace amounts of product were observed in most cases by GC
MS. The benzylamine and 1-phenylethane-1,2-diol furnished mono-aminated intermediate in 67% yield that did not react further. The substrates decomposed at higher reaction temperatures [103].

Scheme 4.38

Scheme 4.39

Scheme 4.40

4.2.9 Iron-assisted synthesis The dihydropyrimidine derivatives were synthesized by Biginelli reaction and excellent results were obtained under MWs (Scheme 4.41) [104].

Scheme 4.41

Brantenko and coworkers [105] reported a cyclocondensation of 3aryl(heteroaryl)pyrazole-4-cabaldehyde with urea and ethyl acetoacetate in the presence of FeCl3  6H2O to afford the 3-aryl (heteryl)-4-(4-pyrazolyl)-1,2,3,4-tetrahydropyridine-2-ones (Scheme 4.42).

204

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 4.42

The pyridine products were formed when alkynenitriles with and without Thorpe
Ingold assistance underwent cycloaddition reactions. This method afforded five- and six-membered bicyclic pyridines [106]. However, this strategy did not provide greater than six-membered tethered bicyclic systems. Exogenous alkynes containing secondary amino or free hydroxyl groups were not tolerated under these reaction conditions. Efforts to understand the reactivity pattern of different pyridyl bis-imine ligands in the cycloaddition reaction are currently underway. Alkynenitriles and other coupling partners were also tested using a similar iron catalyst system in order to discover the new reaction methodologies. The 2-aminopyrimidines [107] are present in many biologically active compounds and structurally important cores (Scheme 4.43).

Scheme 4.43

The cyclopentadienyliron dicarbonyl dimer behaved in the same manner as group VI metal carbonyls. However, the metal carbonyl was converted to the dimer of cyclopentadienone (Scheme 4.44) [108].

Scheme 4.44

Six-membered N,N-heterocycles

205

4.2.10 Lanthanum-assisted synthesis The reaction conditions were optimized in terms of catalyst type/concentration (lanthanum chloride/12 mol%), solvent (ethanol), temperature (140 °C), and MW reaction time (30 min) for the Biginelli MMS of the mitotic kinesin Eg5 inhibitor monastrol in racemic form in 82% yield (Scheme 4.45). Significant improvement was observed in yield as Biginelli reactions typically provided low yields [109].

Scheme 4.45

4.2.11 Lithium-assisted synthesis Resin-bound enaminone was obtained by immobilization of the needed dioxolane-protected 4-lithioacetophenone, deprotection with pyridinium para-tolylsulphonate, and condensation with Bredereck’s reagent. The suitability of resin for library preparation was verified by a trial condensation with acetamidine hydrochloride followed by electrophilic ipso-degermylative cleavage using trifluoroacetic acid. This protocol afforded 2-methylpyrimidine (Scheme 4.46) [110].

Scheme 4.46

206

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

4.2.12 Magnesium-assisted synthesis Salehi and Guo [111] synthesized dihydropyrimidinones by a magnesium bromide-catalyzed efficient and facile one-pot synthesis under solvent-free conditions (Scheme 4.47). Besides β-ketoesters, β-diketones were used and N-methylurea was also used to afford the dihydropyrimidinones, which are very important from a biological activity point of view [19].

Scheme 4.47

4.2.13 Manganese-assisted synthesis The reaction of various aldehydes with β-keto ester and urea to afford the THPM derivatives was first discovered by Biginelli [112], thus all these multifunctionalized pyrimidines are called as Biginelli compounds. In recent years, tetrahydropyrimidines have become increasingly important due to their pharmacological and therapeutic properties, because they exhibit a wide range of biological activities, and nearly every day additional new structures are added to this list [113]. A series of tetrahydropyrimidines was synthesized via one-pot condensation reaction of quinolinecarboxaldehydes using excess amount of both urea and ester in the presence of manganese(III) acetate (Scheme 4.48).

Scheme 4.48

4.2.14 Molybdenum-assisted synthesis Both organometallic catalysts and reagents were used for affecting the ring cleavage of small ring systems [114]. By comparison with the extensive thermal and photochemical studies of the 2H-azirine ring system, its behavior toward organometallic reagents has been relatively unexplored.

Six-membered N,N-heterocycles

207

Alper and Wollowitz [115] reported that group VI metal carbonyls [M(CO)6, M 5 Cr, Mo, W] were useful reagents for the conversion of 2-aryl azirines to pyrazines. The chemical reactivity of 2H-azirines [116a,b,117] would be of interest to further investigate the reactions of various 2-phenyl-3-vinyl substituted 2H-azirines in the presence of transition metal catalyst. The commonly used Grubbs’ catalyst induced a clean rearrangement that occurred via carbon
nitrogen bond cleavage of 2H-azirine ring. However, when the reaction was performed using Wilkinson’s catalyst [Rh(PPh3)3Cl] in an alcoholic solvent, the only product α,β-unsaturated oxime was obtained in high yield (Scheme 4.49).

Scheme 4.49

4.2.15 Nickel-assisted synthesis The allylamines were used to furnish the substituted imidazo[1,2-a]pyrimidin-2-ones in a sequential Raney-Ni-assisted reduction of the nitrile group to afford the diamines followed by intramolecular cyclization via reaction with CNBr (Scheme 4.50) [118,119].

Scheme 4.50

Many variations on catalytic reactions involving C
C triple and double bonds were applied. For instance, the nickel-catalyzed coupling of aldehydes and 1,3-dienes with HSiEt3 is shown in Scheme 4.51 [120]. The nickel NHC complex was produced in situ by addition of BuLi to a mixture of imidazolium salt and NiCl2. The moderate-to-high yield of (Z)-alkene was obtained. The reaction provided (E)-alkene when a phosphane ligand was used instead of NHC. Jamison et al. [121,122] used an in situ mixture of IPr (1,3-(2,6-diisopropylphenyl)imidazol-2-ylidene) and Ni(COD)2 to catalyze the coupling of terminal olefins with isocyanates and olefins with aldehydes to afford the acrylamides. Similar conditions

208

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

were used to couple two isocyanates with alkynes to give the pyrimidine diones [123]. Vinyl cyclopropanes were successfully isomerized to cyclopentenes upon addition of a mixture of Ni(0) precursor and other reactions with C 5 C double bonds in which nickel NHC complexes were used for the polymerization of styrene [124] and dimerization of ethane [125,126]. Various imines were treated with NaOi-Pr in the presence of catalytic amounts of Ni(0) and IMes to afford the amines by transfer hydrogenation [127]. The catalytic amounts of Ni(0) and a triazol-5-ylidene were reacted with H3NBH3 leading to rapid synthesis of dihydrogen gas by dehydrogenation, which occurred through hydrogen transfer of ammonia-borane to the carbene carbon, followed by C-H activation by nickel species [128].

Scheme 4.51

This method was extended for the preparation of hexahydro-pyrimido [1,2-a]pyrimidin-2-ones from bis-allylamines (Scheme 4.52). These compounds showed significant antileishmanial activity [119,129].

Scheme 4.52

An alternative protocol to multicomponent heterocyclic compound involved the use of palladium catalysis for the synthesis of keto-alkynes for cycloaddition reactions. For example, the coupling of acid chlorides with terminal alkynes in the presence of palladium catalyst afforded bis (hydroxymethyl)azetidine-1-yl-pyrimidine nucleosides. This substrate was trapped to provide routes to aromatic heterocyclic compounds. As an example, the addition of amidines afforded a multicomponent synthesis of pyrimidines (Scheme 4.53) [130]. This same substrate was formed via carbonylative coupling of aryl halides with terminal alkynes, affording a

Six-membered N,N-heterocycles

209

Scheme 4.53

four-component preparation of pyrimidines. Bis(hydroxymethyl)azetidine-1-yl-pyrimidine nucleosides were used in 1,3-dipolar cycloaddition reactions. For example, cycloaddition of hydroximinoyl chlorides afforded a concise synthesis of isoxazaoles, while addition of 1,3-dipolar 1-(2-oxyethyl)pyridinium salts provided indolizines [131].

4.2.16 Niobium-assisted synthesis Yadav et al. [132] reported a condensation reaction of a β-keto ester, an aldehyde, and thiourea or urea under ambient conditions for an efficient niobium(V) chloride-catalyzed synthesis of 3,4-dihydropyrimidinones (Scheme 4.54). The study of this reaction using other Lewis acids like cerium(III) chloride, indium(III) chloride, tantalum(V) chloride, gadolinium(III) chloride, and yttrium(III) chloride revealed that niobium(V) chloride was superior in terms of reaction time and conversion. The advantage of this catalyst was that the reaction occurred at room temperature whereas other Lewis acids needed reflux conditions. A novel L-prolinecatalyzed Biginelli reaction was also reported under solvent-free conditions by same group [133]. The advantages were participation of β-diketones also in the reaction and short reaction times at room temperature under solvent-free conditions [19]. Mabry and Ganem [134] used L-proline methyl ester hydrochloride as a catalyst for the synthesis of dihydropyrimidinones via Biginelli reaction.

Scheme 4.54

210

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

4.2.17 Rhodium-assisted synthesis An Ugi MCR is used to produce the central piperazine unit in Merck’s improved synthesis of the important HIV protease inhibitor indinavir (crixivan) (Scheme 4.55) [135]. While these MCRs were generally effective and very elegant at producing complexity, they often have to be performed in multiple discrete steps and they also suffer from poor atom economy.

Scheme 4.55

The intramolecular alkylation reaction was applied for the construction of complex bioactive compounds. For example, the potent N-terminal lunase inhibitor, originally synthesized in 6% overall yield and 14 linear steps [136], was prepared in 13% overall yield and 11 linear steps by relying on carbon
hydrogen functionalization reaction as a key step in the sequence (Scheme 4.56) [137a,b]. More highly substituted derivatives that were very difficult to synthesize by alternative protocols were readily prepared rapidly in 15% and 17% overall yields, and resulted in the identification of even more potent inhibitors. This protocol was used in the total synthesis of alkaloids ( 6 )-strychnofoline [138] and ( 6 )-horsfiline [139]. Carreira and Meyers [140] constructed the spiro-cyclopropaneoxindole by cyclopropanation of

Six-membered N,N-heterocycles

211

Scheme 4.56

pyperilene using carbenoid, produced from a Rh(II)-catalyzed decomposition of 3-diazoisatin, and performed ring-expansion employing imine to afford the spiro-pyrrolidine-oxindole that was used for the preparation of spirotryprostatin B (Scheme 4.57) [64].

Scheme 4.57

212

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

4.2.18 Ruthenium-assisted synthesis De and Gibbs [141] developed a one-pot synthesis of 3,4-dihydropyrimidin-2(1H )-ones using ruthenium(III) chloride catalyst under solvent-free conditions (Scheme 4.58). By employing this protocol, monastrol, a potent anticancer drug and a mitotic kinesin Eg5 motor protein inhibitor, was prepared in 65 min in 89% yield. The same group has also reported [142] the synthesis of these compounds via the reaction of a β-keto ester, an aldehyde, and urea using scandium(III) triflate as a reusable catalyst in refluxing acetonitrile. Blacquiere and coworkers [143] prepared novel boron-possessing dihydropyrimidinones via the addition of formylphenylboronic acid derivatives to ethyl acetoacetate and urea without an additional Lewis acid catalyst [19].

Scheme 4.58

The borrowing hydrogen protocol was applied to the transformation of primary amines into nitrogen heterocycles via a double alkylation process with suitable diols. The diamine underwent cyclization with ethylene glycol to afford the piperazine product [144]. Ruthenium-catalyzed reactions of diamines with diols have also been reported [145,146] as well as cyclization reactions of diols, which possess additional heteroatoms [147,148]. These diols afforded piperazines, as shown in the conversion of various amines with diols leading to the cyclization products. The ruthenium catalysts used included cationic complexes with terdentate PNP ligands as well as RuCl2(PPh3)3 (Scheme 4.59) [149].

Scheme 4.59

The catalytic hetero-Diels
Alder reaction allowed a convenient access to six-membered heterocyclic compounds (Scheme 4.60). The hetero-

Six-membered N,N-heterocycles

213

Diels
Alder reaction was classified into two groups: (1) [4 1 2]-cycloaddition of 1,3-dienes with a heteroatom-heteroatom or carbon-heteroatom double bond and (2) [4 1 2]-cycloaddition of α,β-unsaturated carbonyl compounds with olefins [150
153].

Scheme 4.60

Hammond et al. [154] reported a method for the transformation of dienes into 4,4-difluoroisoquinolin-3-ones by reaction with maleimide (Scheme 4.61). The dienes in turn were obtained by ring-closing metathesis of difluorinated 1,7-enyne carbonyl compounds [119].

Scheme 4.61

214

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

4.2.19 Samarium-assisted synthesis Shen et al. [155] synthesized dihydropyrimidinones by one-pot Biginelli reaction under solvent-free conditions using samarium diiodide as a catalyst (Scheme 4.62). However, low yields were obtained when cinnamaldehyde and methoxy or hydroxy substituted benzaldehydes were used. Steric effects of aliphatic aldehydes in reaction with ethyl acetoacetate and urea influenced the yield of reaction [19].

Scheme 4.62

4.2.20 Scandium-assisted synthesis Keung and coworkers [156] synthesized α-aminoamidines by a scandium (III) triflate-assisted three-component Ugi condensation involving amines, aldehydes, and isonitriles (Scheme 4.63) [19]. Pirrung and Sarma [157,158] synthesized β-lactams via a method of accelerating the Ugi reaction of β-keto acids in aqueous solution.

Scheme 4.63

4.2.21 Selenium-assisted synthesis Synthesis occurred through the oxidation of acetophenone, by SeO2 with subsequent ring-closure by reaction of the racemic 2,3-diaminopropionic acid, in methanolic NaOH solution. The isomers were separated and the required isomer was reacted with morpholine after conversion to the acid chloride and subsequent reaction with 4-methoxyphenyllithium. Twofold demethylation using hydrobromic acid afforded the final compound (Scheme 4.64) [159,160].

Six-membered N,N-heterocycles

215

Scheme 4.64

4.2.22 Silicon-assisted synthesis The catalyst used here was noncorrosive and reusable without any loss of activity even after five runs. Tajbakhsh et al. [161] also reported a natural heulandite type of zeolite-catalyzed method for the preparation of these compounds (Scheme 4.65). In this case also the catalyst was reusable up to five times retaining the same activity as that of fresh catalyst without appreciable changes in yield. Aliphatic aldehydes provided products in longer reaction times (12 h) and lower yields (44%
46%) as compared to aromatic aldehydes that took 4
5 h and give 60%
87% yields [19].

Scheme 4.65

Martins and coworkers [162] reported a one-pot synthesis of trichloromethylated tetrahydropyrimidinones via Biginelli-type condensation of aromatic aldehydes and chlorinated 1,3-dicarbonyl compounds with thiourea in the presence of InBr3 catalyst. Pan et al. [163] used

216

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

trimethylsilylchloride as an efficient and facile reagent for one-pot condensation of 1,3-dicarbonyl compounds, aldehydes, and thiourea at room temperature to provide the dihydropyrimidinones (Scheme 4.66). The advantages were that aliphatic aldehydes also provided products in good yields and a simple work-up by filtration. The same group [164,165] also reported Biginelli-type condensation reaction of urea (or thiourea), cycloalkanones, and aldehydes using trimethylsilylchloride as a Lewis acid and also the synthesis of two families of spiro-fused fused and heterobicyclic heterobicyclic compounds. The 5-unsubstituted-3,4-dihydropyrimidin-2(1H )-ones were synthesized by an iodotrimethylsilane-catalyzed Biginelli-like reaction of ketones with aldehydes and urea [19,166].

Scheme 4.66

Furthermore, different active methylene nitriles were evaluated in the reaction. The reaction route depends on the nature of nitrile. Thus compounds [167] were obtained starting from benzoylacetonitriles, while cyanoacetic acid amides provided hitherto unknown pyrimidopyrimidines (Scheme 4.67).

Scheme 4.67

Six-membered N,N-heterocycles

217

A green strategy was reported for the preparation of morpholinopyrimidines, starting from 1-(4-morpholinophenyl)ethanone, benzaldehyde, and guanidine hydrochloride in the presence of catalytic amount of a heterogeneous NaHSO4  SiO2 catalyst (Scheme 4.68) [168]. The (E)-1(4-morpholinophenyl)-3-arylprop-2-en-1-one was produced by the condensation of three components, which was followed by its rearrangement to morpholinophenyl pyrimidines.

Scheme 4.68

Various aldehydes, N-arylthioureas, and 1,3-dioxocompounds were easily condensed for the synthesis of dihydropyrimidines using chlorotrimethylsilane as dehydrating agent. This was the first successful example of Biginelli reaction with N-arylthioureas (Scheme 4.69) [168].

Scheme 4.69

The dihydropyrimidines were synthesized using hetarylacetophenones as oxomethylenes (Scheme 4.70) [168].

218

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 4.70

The β-keto esters, aldehydes, and urea underwent trimethylsilyl triflate-mediated one-pot cyclocondensation reaction in acetonitrile at room temperature with shorter reaction times as reported by Bose and coworkers [169] (Scheme 4.71). This method provided a mitotic kinesin Eg5 inhibitor monastrol within 15 min in 95% yield. One mol% triethylsilyl triflate was also used as a catalyst at room temperature in acetonitrile. Ghosh and coworkers [170] used indium(III) triflate (2 mol%) catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H )-ones. Su and coworkers [171] also used strontium(II) triflate as a reusable catalyst for Biginelli reaction under solvent-free conditions [19].

Scheme 4.71

4.2.23 Silver-assisted synthesis The reaction conditions were optimized using (E)-5-(2-benzylidene-1tosylhydrazinyl)-2-methylpent-3-yn-2-yl acetate. The optimal reaction conditions, as shown in Scheme 4.72, were use of water (1 eq.) as an additive and AgSbF6 (10 mol%) as a catalyst at room temperature in dry CH2Cl2 [172a,b]. Lee and Chung [173] evaluated the tolerance of Ag (I)-catalyzed tandem cyclization of several hydrazones under optimized conditions. All reactions occurred smoothly to provide the products in 30%
88% yields.

Six-membered N,N-heterocycles

219

Scheme 4.72

In addition to amides and carbamates, the imino group was another functional group frequently used in these kinds of cyclizations. For example, benzothiazoles, 2-(propargylamino)benzoxazoles, and benzoselenazoles (Scheme 4.73) were reacted in the presence of a catalytic amount of Ag salt to afford the dihydropyrimidinones (DHPMs). The benzene ring with an electron-donating group accelerated the ring-closure, while it was retarded with an electron-withdrawing group [174,175].

Scheme 4.73

Yamamoto and Kawasaki [176,177] reported a highly regio-, enantio-, and diastereoselective azo-hetero-Diels
Alder reaction of 2-azopyridine and acyclic silyloxydiene using silver(I)-2,20 -bis(diphenylphosphino)-1,10 binaphthyl catalyst (Scheme 4.74). The formed pyridazine derivatives could be effectively converted to 1,4-diamines, which are biologically important compounds [175].

Scheme 4.74

220

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The 3,4-dihydropyrimidin-2(1H )-ones were synthesized [178] using silica gel-supported sodium bisulfate as a heterogeneous catalyst. Yadav and coworkers [179] reported a green reaction for the Biginelli reaction (Scheme 4.75) using Ag salt of heteropolyacid (i.e., Ag3PW12O40) in water. This catalyst was superior in terms of reaction times and conversion when compared to other solid acid catalysts like acid resin (Amberlyst15), KSF clay, and acid-washed silica gel (sulfuric acid-silicon oxide). The reuse of catalyst in an ecofriendly solvent like water was an added advantage [19].

Scheme 4.75

The 3,4-dihydropyrimidinones (Biginelli condensation) were prepared using Ag3PW12O40 as a recyclable water-tolerant heteropolyacid (Scheme 4.76) [175,180].

Scheme 4.76

4.2.24 Tin-assisted synthesis After initial loading of Wang resin with Fmoc-protected amino acid and subsequent Fmoc removal, the resin-bound amine was treated with 3 eq. of 4,6-dichloro-5-nitropyrimidine, in the presence of Hunig’s base, to cleanly load the pyrimidine on resin. The resin-bound chloropyrimidine was then further functionalized with a variety of amino acid methyl esters and subsequently reductively cyclized, using SnCl2, and cleaved with trifluoroacetic acid, to afford the desired dihydropteridinones in good yield and purity (Scheme 4.77) [181].

Six-membered N,N-heterocycles

221

Scheme 4.77

4.2.25 Titanium-assisted synthesis The o-alkynylbenzaldehydes acted as suitable building blocks for isoquinoline. The domino imination/annulation reaction was promoted efficiently under microwave heating (Scheme 4.78). This method was also extended to 2-acetyl-N-propargylpyrroles for the preparation of pyrrolo[1,2-a]pyrazine. The reaction occurred well with analogous 2-acetyl-N-propargylindoles [182a,b] only in the presence of TiCl4.

Scheme 4.78

Abbiati et al. [182a,b] reported the synthesis of pyrazino[1,2-a]indole nucleus from 2-carbonyl-N-propargylindoles by sequential imination/ annulation in the presence of ammonia in MeOH. The reaction worked well with N-propargylindole-2-carbaldehydes, but selectivities and yields were unsatisfactory using 2-acetyl-N-propargylindoles. The reaction failed with 2-benzoyl-N-propargylindoles. These disadvantages overcome when MW heating and 3 eq. of TiCl4 were used, which improved both selectivities and yields in the reactions of these less reactive substrates with reduction of reaction times (Scheme 4.79) [183,184a,b].

222

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 4.79

4.2.26 Tungsten-assisted synthesis Heravi et al. [185] developed a one-pot cyclocondensation of an aldehyde, a 1,3-dicarbonyl compound, and urea using 12-tungstophosphoric acid as a recyclable catalyst for the synthesis of 3,4-dihydropyrimidin-2 (1H )-ones (Scheme 4.80) [19].

Scheme 4.80

Decatungstodivanadogermanic acid (H6GeW10V2O40  22H2O) was prepared and used as a novel, green heterogeneous catalyst for the construction of spiro-fused heterocyclic compounds in high yields by a one-pot three-component cyclocondensation of aldehyde, cyclic ketone, and urea under solvent-free condition and MWI at 80 °C. This catalyst was efficient not only for cyclic ketones, but also for cyclic β-diester, β-diketones, and β-diamide derivatives like dimedone, cyclohexanone, and barbituric acid or Meldrum’s acid derivatives. The cyclic β-ketoesters [186] and β-diamides, barbituric acid or Meldrum’s acid derivatives were reacted with 2 eq. of aldehydes and 1 eq. of urea in the presence of H6GeW10V2O40  22H2O as a catalyst at 80 °C under solvent-free conditions to give a family of σ symmetric spiroheterobicyclic compounds in good yields (Scheme 4.81). The reaction occurred very efficiently with electron-withdrawing p-substituted benzaldehydes and benzaldehyde, but it proceeded only up to Knoevenagel adducts, when electron releasing p-substituted benzaldehydes were used. This investigation was extended to cyclic ketones such as cyclohexanone (Scheme 4.82). No desirable product was obtained when the mixture was reacted without H6GeW10V2O40  22H2O, which indicated that the catalyst was necessary. As compared to other catalysts, the use of 3 mol%

Six-membered N,N-heterocycles

223

H6GeW10V2O40  22H2O resulted in 80% yield under MWI (600 W) for 7 min. The best result was obtained with 3 mol% H6GeW10V2O40  22H2O, although other factors were not yet optimized.

Scheme 4.81

Scheme 4.82

4.2.27 Ytterbium-assisted synthesis Biginelli reaction was applied for the synthesis of bromophenyl-substituted derivatives of dihydropyrimidines on a 1 and 40 mmol reaction scale using single- and multimode MW reactors respectively. The same experimental conditions of reaction temperature and time were applicable to both MW reactors, affording similar product yields (Scheme 4.83) [187].

Scheme 4.83

Yang et al. [188] prepared different dihydropyrimidines using different inorganic salts as a catalyst and the yields of one-pot Biginelli reaction increased from 20%
50% to 81%
99%, while the reaction time decreased from 18
4 h to 20 min. This reaction disclosed a simple and

224

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

new modification of the Biginelli-type reaction under solvent-free conditions using ytterbium chloride and Yb(OTf)3 as a catalyst. The catalyst was easily recovered and reused (Scheme 4.84).

Scheme 4.84

Biginelli three-component cyclocondensation reaction of aldehydes, CH-acidic carbonyl compounds, and urea synthesized dihydropyrimidinones under strongly acidic conditions. Many improved methods used Lewis acids instead of traditional mineral acids under MW heating. Thus recent reports used montmorillonite KSF clay under solvent-free conditions (MW heating in a household oven for 5
17 min (1200 W) vs 6 h oil-bath at 110 °C) [189], and catalytic amounts (10 mol%) of iodine adsorbed on neutral alumina (90 °C, 1 min) and N-bromosuccinimide in N,N-dimethylacetamide (600 W, 3
6 min) [190,191]. Alternatively, lanthanide catalysts lanthanum chloride or Yb(OTf)3 were used by Kappe and Stadler [192a,b] in an automated sequential microwave-assisted preparation of a 48-membered dihydropyrimidine library via Biginelli reaction. The cyclocondensation with urea was catalyzed by Yb(OTf)3, while in the case of thioureas lanthanum chloride was the superior catalyst. This reduced the reaction time from 4 to 12 h (under reflux conditions) to 10
20 min [193]. This rendered the sequential generation of a 48membered library feasible within 12 h. The library was produced by MW synthesizer. Consequently, to ensure the complete dissolution of starting components the solvents (ethanol:acetic acid, 1:3) were chosen. The proper choice of solvents made the work-up efficient and simple as the formed products precipitated many times directly from the reaction mixture after the completion of reaction (Scheme 4.85). Yield reduced to 50% when the reaction was performed at 130 °C, therefore, higher temperatures should be avoided.

Scheme 4.85

Six-membered N,N-heterocycles

225

4.2.28 Zinc-assisted synthesis Li and coworkers [194] developed a solvent-free ZnCl2-catalyzed method for the synthesis of 3,4-dihydropyrimidin-2(1H )-ones by the condensation of a 1,3-dicarbonyl compound, an aldehyde, and urea at 80 °C in shorter reaction times (Scheme 4.86). The 2-furaldehyde afforded the expected products in 10 min in 94%
95% yields, which normally gives low yields [19]. Zhang and Li [195] used Zn sulfamate as a catalyst for one-pot condensation reaction of β-keto esters, aromatic aldehydes, and urea in refluxing ethanol.

Scheme 4.86

Anand and Rao [196] synthesized 2-methyl pyrazine using Znmodified ferrierite catalysts (Scheme 4.87).

Scheme 4.87

The dihydropyrimidinones are synthesized due to their diverse pharmacological activities [197]. Following the recent work [198,199] on dihydropyrimidinones based on the Biginelli reaction, here an efficient and convenient one-pot synthesis of acyclic C-nucleosides having indene-1,3-dione and dihydropyrimidinone bases is reported. Thus the 2,2-dimethyl-[1,3]dioxolan-4-carbaldehyde [200] was treated with ethyl acetoacetate and urea in the presence of triflate catalyst (TMSTMf) at 65 °C under microwave irradiation to provide the (R and S)-pyrimidone derivative (41%) resulting from the formation of stereocenter at C-4 of the dihydropyrimidines ring. Alternatively, (R and S)-pyrimidone derivative was formed in better yield (36%) under the same conditions but using natural phosphate doped with zinc chloride instead of the triflate catalyst. Interestingly, the (R and S)-pyrimidone derivative was treated with

226

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

sodium methoxide in methanol at 100 °C under microwave irradiation for 5 min to afford a product (6-(1,2-dihydroxyethyl)-pyrimidin-2-one) in 45% yield. The spectrum was also characterized by elimination of CO2Et group at C-5 of (R and S)-pyrimidone derivative, indicative of H-4 abstraction by action of methoxide ion and simultaneous loss of water, leading to the formation of 6-(1,2-dihydroxyethyl)-pyrimidin-2one (Scheme 4.88) [201].

Scheme 4.88

An efficient and simple protocol was reported for the preparation of 2-substituted-4,6-diarylpyrimidines by one-pot three-component reaction of SBT, 4-hydroxy-3,5-dinitro substituted chalcones, and heterocyclic secondary amines (morpholine/pyrrolidine/piperidine) in the presence of 15 mol% zinc oxide as a heterogeneous catalyst. This method has several advantages such as simple procedure, short reaction time, and excellent yields. The catalyst was stable, inexpensive, and was easily recycled and reused for several cycles with consistent activity. The reaction was optimized for various reaction parameters such as solvent, temperature, and catalyst loading. When the reaction was done at room temperature the chalcones remain unconsumed. The effect of temperature was monitored on the yield of product from 60 °C to 120 °C. However, yield not increase further on increasing the temperature from 100 °C to 120 °C [202a,b]. Hence, the optimum reaction temperature was chosen to be 100 °C. Yields were very low when the reaction was catalyzed in the absence of solvent. Among the various solvents studied, dimethylformamide was found to be the best solvent and provided the maximum yield of desired product. Catalyst concentration was optimized by varying its concentration from 5 to 20 mol%. Increase in product yield was observed from 5 to 20 mol% of catalyst amount. Hence 15 mol% was considered as an optimum catalyst concentration (Scheme 4.89) [203].

Six-membered N,N-heterocycles

227

Scheme 4.89

Huang and Cao [204] synthesized an eleven-member library of uracils in three steps. Resin-bound selenium bromide was reacted sequentially with unsaturated esters and primary amines in a one-pot, two-step procedure to afford the substituted amino ester resins that reacted with various isocyanates in the presence of K2CO3 to provide the polymer-supported 1,3,6-trisubstituted-5,6-dihydrouracils. The target compounds were released using hydrogen peroxide (Scheme 4.90).

Scheme 4.90

Although it has been known for more than a century, it was still the most important protocol for the synthesis of such class of compounds. Since 1893, the preparation of dihydropyrimidine nucleus was extensively

228

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

explored by Biginelli reaction [205
207]. Many catalysts [208
212] were reported for the generation of dihydropyrimidines, either by development of novel multistep strategies or by modification in classical Biginelli reaction. In addition, many catalysts like H3PW12O40 (Scheme 4.91) [213], SbCl3/Al2O3 (Scheme 4.92) [214], and zinc iodide (Scheme 4.93) [215] were used for reaction under MWI. However, limitations like expensive catalyst, use of toxic solvents, laborious work-up procedures, requirement of excess reagents/catalysts, etc., restrict the practical synthetic utility of this chemistry. The potentiality of microwave/ionic liquid synergetic couple uniquely has not been explored much for the synthesis of Biginelli compounds. Therefore a microwave/ionic liquids protocol would be ideally suitable for the preparation of this privileged heterocyclic compound.

Scheme 4.91

Scheme 4.92

Scheme 4.93

Six-membered N,N-heterocycles

229

4.2.29 Zirconium-assisted synthesis The three-component cyclocondensation of β-dicarbonyl compounds, substituted aromatic aldehydes, and urea/thiourea in the presence of reusable sulfated zirconia (ZrO2/SO422) acid catalyst was reported for the synthesis of 3,4-dihydropyrimidin-2(1H )-ones and -thiones in moderateto-good yields (Scheme 4.94) [216]. The catalyst was recycled up to eight times. Although the catalyst was still active during the 8th run, its activity dropped to almost 50% of the original reactivity.

Scheme 4.94

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488.

CHAPTER 5

Six-membered N,N-polyheterocycles 5.1 Introduction The range of application of heterocyclic compounds is very wide. They are of specific importance as they are associated with a wide variety of physiological activities. A significant number of compounds synthesized in the industrial sector are heterocyclic in nature [1a
e]. A large number of synthetic heterocyclic compounds are predominant among all types of agrochemicals, pharmaceuticals, and veterinary products. Some of the synthetic heterocycles are used as rocket propellants and in photography. Pyrimidine and quinozoline derivatives are used as tyrosine kinase inhibitors. A series of substituted 2-(aminopyrimidinyl)- and 2-(aminopyridyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by hyperproliferation of stem cells, followed by their subsequent differentiation into peripheral white blood cells. Imatinib is the blockbuster drug used for the treatment of CML [2]. Imatinibmysilate is marketed under the brandname Gleevec. The quinazoline derivative drugs like lapatinib and erlotinib are also important tyrosine kinase inhibitors. Among the heterocyclic compounds, quinoxalines are important chemotherapeutic agents and have found wide clinical applications as anticancer, antimicrobial, anti-AIDS, antiviral, sedative/hypnotic/antiepileptic, antitubercular, cardiac agents, as well as analgesics, diuretics, antibiotics, metabolic electrolytes, etc. Quinoxalines display a broad spectrum of biological [3] and pharmacological [4] activities such as fungicides, insecticides, anthelmintics, herbicides, antibacterial [5], antiprotozoal, antimycobacterial, antibiotic, and anticancer properties [6]. Quinoxaline derivatives have found applications in dyes [7], electron luminescent materials [8], and chemically controllable switches [9] as building blocks for the synthesis of anion receptors [10], cavitands [11], dehydroannulenes [12], Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00005-1

© 2020 Elsevier Inc. All rights reserved.

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244

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

organic semiconductors [13], and as electron transport materials in multilayer organic light-emitting diodes [14]. A number of synthetic strategies have been developed for the preparation of substituted quinoxalines, including condensation of aryl-1,2-diamines with α-functionalized ketones, usually dicarbonyl compounds or their equivalents [15,16].

5.2 Metal- and nonmetal-assisted synthesis of sixmembered polyheterocycles with two nitrogen atoms 5.2.1 Aluminum-assisted synthesis A novel radical preparation of bicyclic guanidines was developed. A radical domino reaction was initiated upon slow addition of azobisisobutyronitrile and Bu3SnH to a solution of azide-substituted N-acyl cyanamide at reflux in benzene to afford the diazepine fused system (Scheme 5.1) [17]. Larraufie and coworkers [18] developed a radical cascade reaction of

Scheme 5.1

N-acyl cyanamide. The domino reaction involving the formation of a carbon
nitrogen and a carbon
carbon bond afforded annulated quinazolinone derivative (Scheme 5.2). The key step involved the radical migration of carbon substituents or hydrogen atoms triggered by rearomatization of a cyclohexadienyl radical produced by radical addition to the aromatic ring [19].

Scheme 5.2

Six-membered N,N-polyheterocycles

245

The benzisoxazole bearing antipsychotic risperidone is the most prescribed therapeutic for schizophrenia. For this molecule the benzisoxazole ring was synthesized via an intramolecular nucleophilic aromatic substitution between the adjacent aromatic ring and an in situ produced oxime [20]. The carbonyl derivative precursor was formed by a Friedel
Crafts acylation of the difluoroaromatic (the acetate N-protecting group was presumably lost in the workup). Finally, the piperidine ring was alkylated under Finkelstein conditions to complete the synthesis of risperidone (Scheme 5.3) [21].

Scheme 5.3

The condensation of formamide and substituted 1,3-cyclohexadienes under microwaves using inorganic solid supports afforded different 3,4dihydrobenzo[2,3-d]pyrimidine derivatives. Pharmaceutical interest in benzopyrimidines has insisted to prepare a series of new 3,4-dihydrobenzo [2,3-d]pyrimidines under microwave irradiation (MWI) and acidic conditions in dry media by the cyclization of 1,3-cyclohexadiene derivatives with formamide (Scheme 5.4). Malononitrile and benzoin were condensed on a solid support, either montmorillonite K10 clay or basic alumina or silica gel, under MWI to provide the good yield of 2-amino3-cyano-4,5-diphenylfuran. A 1,3-cyclohexadiene derivative was formed via an intermediate in high yield after a short reaction time when 2-amino-3-cyano-4,5-diphenylfuran was treated with a unsaturated ketone under MWI. The 3,4-dihydrobenzo[2,3-d]pyrimidine derivatives were obtained when 1,3-cyclohexadiene derivatives were cyclized with

246

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

formamide under MWI on an acidic alumina solid support. The reaction was completed only in 4
5 min in 87% yield by the present method as compared to 6
7 h reaction time with 65% yield by the literature method [22]. These observations demonstrated that this method was facile, expeditious, and environmentally benign for organic synthesis.

Scheme 5.4

Niementowski reaction was extended to prepare the 3-substituted/ 2,3-disubstituted-4(3H)quinazolinones instead of 2-substituted derivatives. 3-Methyl-1H-pyrazolones were generated from substituted hydrazides under MWI using various solid supports. Inspired by the high yields obtained using formic acid, a further study of 4(3H)quinazolinones synthesis, as a possible Niementowski reaction, was performed using different heteroaromatic and aromatic carboxylic acid, carboxylic acid, and amine were mixed and irradiated under microwaves to afford the 2,3-disubstituted-4(3H)quinazolinones. Good yields were obtained in less irradiation time compared to the conventional procedure [23] requiring acetyl chloride, 5-substituted anthranilic acid, amino acids, and pyridine and long refluxing time. The hydrazide was prepared from the corresponding acid using hydrazine hydrate. The 4-(6-bromo-2-methyl-4-oxoquinazolin-3 (4H)-yl)benzohydrazide was reacted, by conventional technique using ethyl acetoacetate in EtOH solvent and using different solid supports as neutral alumina, to synthesize the 6-bromo-2-methyl-3-[-4-[3-methyl5-oxo-2,5-dihydro-1H-pyrazol-1-yl)carbonyl]phenyl}quinazoline-4(3H)one (Scheme 5.5) [24].

Six-membered N,N-polyheterocycles

247

Scheme 5.5

5.2.2 Barium-assisted synthesis Carpenter and coworkers [25] reported a reaction of o-phenylenediamines and o-aryl isothiocyanate esters for the synthesis of benzimidazo[2,1-b]quinazolin-12(5H)-ones in 91%
98% yield via tandem N,N0 -diisopropylcarbodiimide-mediated benzimidazole cyclization and microwave-assisted benzimidazoquinazolinone cyclization with barium hydroxide (Scheme 5.6). Common methods employed for the synthesis of benzimidazo[2,1-b] quinazolin-12(5H)-ones required 200 °C and provided low yields or sometimes with byproduct.

Scheme 5.6

5.2.3 Bismuth-assisted synthesis Perimidines (peri-naphtho-fused pyrimidine systems) constitute an important class of synthetic and natural products, many of which exhibit important biological activities such as cytotoxicity [26,27]. Bismuth chloride catalyzed the reaction of aromatic and aliphatic ketones and

248

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

naphthalene-1,8-diamine for the synthesis of several pyrimidine derivatives in high yield (Scheme 5.7). Other Bi(III) salts like bismuth bromide and Bi(NO3)3  5H2O also catalyzed this reaction [28].

Scheme 5.7

Antoniotti and Duñach [29] reported a one-pot bicatalyzed condensation of epoxides with ene-1,2-diamines for the synthesis of various mono- and disubstituted quinoxaline derivatives in good yields (Scheme 5.8). This reaction occurred in dimethylsulfoxide in the presence of catalytic amounts of bismuth(0) powder and triflic acid or Cu triflate as additives under molecular oxygen. Later on it was reported that the reaction was catalyzed by a bismuth(III) active species produced in situ from Bi powder [30]. Quinoxaline-based compounds exhibit a variety of biological activities such as antifungal, antimicrobial, antihelmintic, and antitumoral [31].

Scheme 5.8

One-pot condensation of trimethyl o-formate, anthranilic acid, and primary amines provided several 4(3H)-quinazolinones. The reaction occurred in catalytic amount of Bi(TFA)3 in n-butylpyridinium tetrachloroferrate and furnished the desired heterocyclic compounds in high-to-excellent yields (Scheme 5.9) [32]. Khosropour and coworkers [33] developed a method where the immobilization of Lewis acids in ionic liquids provided 4(3H)-quinazolinone by condensation reaction of trimethyl o-formate, anthranilic acid, and primary amines in catalytic amount of Bi(TFA)3 in [NBP][FeCl4] as a room-temperature ionic liquid. The reactions were performed for 5
20 min at 60 °C by reacting a 1:1.2:1.2 molar ratio mixture of anthranilic acid, trimethyl o-formate, and primary amines, respectively, in the presence of 5 mol% Bi(Tfa)3 in [NBP][FeCl4] to

Six-membered N,N-polyheterocycles

249

afford the high-to-excellent yields (79%
98%) of desired products. The ionic liquid was recovered and reused three times without any appreciable decrease in yield. Interestingly, it was reported that the combination of Bi (Tfa)3-[NBP][FeCl4] was crucial for this reaction. The products were not obtained when the reaction was performed without either of these catalysts, and only the starting materials were isolated. The product was obtained in 75% yield and the addition of 30% hydrogen peroxide and sodium hydroxide under reflux for 1 h was necessary when this reaction was carried out in molecular solvent ethanol [31,34
38].

Scheme 5.9

5.2.4 Cobalt-assisted synthesis When indazolone was reacted with carbon monoxide in the presence of a catalytic amount of Co2(CO)8 at elevated temperature (230 °C), 3-phenyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (product of carbonylation of the N
N bond) was obtained in quantitative yield (Scheme 5.10) [39a,b,40].

Scheme 5.10

5.2.5 Copper-assisted synthesis Willis et al. [41] used (o-haloalkenyl)aryl halide as precursors for the synthesis of unusual heterocyclic products, cinnolines (Scheme 5.11). The intermediate dihydrocinnoline derivatives were formed when N-nucleophile was replaced with a N,N-disubstituted hydrazine in the presence of Cu catalyst. A simple deprotection and in situ aerial oxidation were employed to provide the desired cinnoline products. Moderate-toexcellent yields of cinnolines were obtained [42].

250

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.11

The o-halo aryl amines resemble to o-hydroxyl halides in terms of reactivity. Intermolecular nucleophilic displacement, intramolecular N-arylation, and elimination processes of methylsulfonamide protected o-halo aryl amines and 2-haloamides provided products under the catalysis of cuprous iodide and assistance of 1,10-phenanthroline as well as base (cesium carbonate and potassium carbonate) (Scheme 5.12) [43,44].

Scheme 5.12

As compared to seven-membered ring matrix, the six-membered hetero ring system was easier to synthesize theoretically. Tanimori and coworkers [45] synthesized six-membered heterocycles from amino acids. The key factor for this synthesis was the use of o-bromoaniline, which introduced various optically pure amino acids to afford the quinoxalin-2-ones. A notable characteristic of this protocol was that no loss of optical purity was observed on the products after the reaction (Scheme 5.13) [44].

Scheme 5.13

Six-membered N,N-polyheterocycles

251

The 2-formyl pyrroles were reacted with o-iodide anilines to provide the tricyclic products. The reactions in the presence of sparteine ligand and cuprous iodide occurred at 130 °C and consisted of a two-step tandem conversion of carbon
nitrogen coupling and imine condensation (Scheme 5.14) [44,46].

Scheme 5.14

Bao et al. [47] reported a copper-catalyzed carbon
sulfur coupling for the synthesis of 2H-benzo[b][1,4]thiazin-3(4H)-ones. The AcSH was used as a novel sulfur source and 2-halopheyl masked 1-haloamides as building blocks. A class of 2H-benzo[b][1,4]thiazin-3(4H)-ones was generated in moderate-to-excellent yields by a reaction sequence of tandem nucleophilic displacement and intramolecular carbon
sulfur coupling reactions. The quinoxalin-2(1H)-ones were obtained when TsNH2 was used as nucleophile (Scheme 5.15) [44].

Scheme 5.15

Azo compounds were involved in hetero-Diels
Alder reactions and reacted as dienophiles. A 1/1 complex diene/CuOTf was formed in which both the vinyl groups appeared to be complexed to the copper(I) ion when diene was treated with Cu trifluoromethane sulfonate (CuOTf). The N-phenyl triazolinedione was treated with complex diene/CuOTf to afford the same cycloadduct that was formed when diene was reacted with N-phenyl triazolinedione in the absence of Cu(OTf). From these results, it was not clear if N-phenyltriazoline dione reacted directly with diene or with complex diene/CuOTf (Scheme 5.16) [48,49].

252

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.16

Along with the use in one-pot synthesis of heterocyclic products, o-haloaromatic amines were also capable of acting as starting substrates for the synthesis of fused heterocyclic compounds [50]. The 2halotrifluoroacetanilides were reacted with pyrrole-2-carboxylate esters in the presence of cuprous iodide and L-proline to afford a class of fused pyrrolo[1,2-a]quinoxalines (Scheme 5.17) [44].

Scheme 5.17

Although amides, amines, azoles, or hydrazines were used as nitrogen sources in most of the copper-catalyzed cascade reactions involving carbon
nitrogen coupling process, some unconventional N-containing moieties like amidines served as nitrogen source to afford many heterocyclic motifs via copper-catalyzed transformation. Fu et al. [51] carried out a comprehensive and pioneering exploration of this subject (Scheme 5.18). The cuprous iodide was able to catalyze tandem reactions of o-halo aromatic ketones, aldehydes, or esters as reaction partners of amidines, to afford the quinazolinones and quinazolines with the assistance of base and L-proline, the chemoselectivity was manipulated via modifying reaction temperature and specific functional groups [44].

Scheme 5.18

Six-membered N,N-polyheterocycles

253

The cuprous iodide-catalyzed cascade reaction of 2-bromobenzylamines with amides afforded quinazolinone type of products while cuprous iodidecatalyzed reactions of methyl masked 2-iodide aryl amines with amides provided purine derivatives that bear analogous architecture to benzimidazoles (Schemes 5.19
5.20) [52]. These results strongly exemplified the tremendous diversity of copper-catalyzed tandem reactions for the synthesis of heterocyclic compound [44].

Scheme 5.19

Scheme 5.20

All methods for the synthesis of heterocycle do not use electrophilic aromatic substitution to create bonds. Many approaches use transition metal catalysts to form the substituted heterocycle regioselectively [53]. Fu et al. [54] used this aspect to develop an efficient preparation of substituted quinazolines through an Ullman-type coupling of amide and o-bromo benzylamine (Scheme 5.21).

Scheme 5.21

The angular 8H-thiazolo[5,4-f]quinazolin-9-one ring was prepared using Appel’s salt (4,5-dichloro-1,2,3-dithiazoliumchloride). The commercially available 2-amino-5-nitrobenzonitrile afforded thiazolo-quinazoline ring in six steps [55]. Under MWI, as compared to conventional heating (oil or metal bath), the reactions were cleaner, the overall time for the

254

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

synthesis reduced considerably, and the products were purified rapidly. Unfortunately, the route described in this case was not well adapted for easy introduction of various substituents onto the skeleton (Scheme 5.22) [56].

Scheme 5.22

5.2.6 Gold-assisted synthesis In some cases electron-rich arenes served as good nucleophiles [57,58]. Jurberg and Gagosz [59] reported a hydroarylation of N-propargyl-Narylhydrazines for the construction of cinnoline derivatives using gold complex [XPhosAu(NCCH3)SbF6] as a catalyst. An alkynyl ether functionality triggered a new reaction mode of furanyne cyclization with gold complex [Mes3PAu]NTf2 and provided a new class of tetracyclic system rather than a phenol (Scheme 5.23) [60,61].

Scheme 5.23

Six-membered N,N-polyheterocycles

255

During the studies on an efficient synthesis of potential bioactive fused heterocyles, a highly efficient [Au{P(t-Bu)2(o-biphenyl)}{CH3CN}]SbF6catalyzed cascade cycloisomerization was developed to afford the pyrrolo [2,1-a][1,3]quinazoline (Scheme 5.24) [62] and benzo[e]indolo[1,2-a]-pyrrolo[2,1-c][1,4]diazepine-3,9-diones (Scheme 5.25) [63]. These reactions occurred through the formation of an initial enol lactone intermediate via an intramolecular cycloaddition [64]. This reaction afforded efficient and straightforward synthesis of tricyclic lactam from simple starting materials in which several C
N and C
C bonds were formed in a one-pot reaction [61,65].

Scheme 5.24

Scheme 5.25

Encouraged by the successful use of NaAuCl4  2H2O as a catalyst for the preparation of 1,5-benzodiazepines, it was expected that quinoxalines would be formed if o-phenylenediamine was reacted with α-bromo ketones. Indeed, quinoxalines were produced in high yields when 1 eq. of o-phenylenediamine was treated with 1.2 eq. of α-bromo ketones in EtOH under similar reaction conditions. The quinoxalines (33%) were obtained in much lower yield without gold catalyst. The generality and scope of reaction was established by a variety of aromatic ring-tethered α-bromo ketones, and quinoxalines were produced in good-to-excellent yields in all cases in the presence of NaAuCl4  2H2O under mild reaction conditions. In the reaction, gold catalyst acted as a bifunctional catalyst;

256

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

namely, it served as a Lewis acid catalyst in the cyclization process via activation of the carbonyl group [66] as well as an oxidative catalyst for the dehydrogenation of in situ produced dihydroquinoxalines with dioxygen (Scheme 5.26) [67,68a-b].

Scheme 5.26

Broggini et al. [69a] reported intramolecular hydroamination of allenamides in the presence of gold(III) catalyst to afford the 2-vinyl-4quinazolinones (Scheme 5.27) [69b].

Scheme 5.27

Gold-catalyzed synthesis of polycyclic heterocyclic compounds has attracted the attention of chemists and many efficient protocols have been developed by research groups [70
74]. As part of ongoing efforts into the synthesis of potential bioactive polycyclic compounds via transition metalcatalyzed cascade reactions [75
77] a facile and efficient gold-catalyzed cascade reaction was presented for the preparation of highly substituted benzo[4,5]imidazo[1,2-c]pyrrolo[1,2-a]quinazolinones (Scheme 5.28).

Scheme 5.28

Six-membered N,N-polyheterocycles

257

The stereochemical outcome of this reaction was affected by substitution at the propargylic position. The double migratory cascade reaction of 1,4-bis-propargylic acetates afforded dienes, which were hydrolyzed to form the unsymmetrical 1,2-diketones. The quinoxalines were formed in good yields by a one-pot cascade double migration-hydrolysis followed by condensation with aromatic 1,2-diamines (Scheme 5.29) [78a,b].

Scheme 5.29

5.2.7 Iodine-assisted synthesis Majumdar et al. [79] reported an efficient method for the preparation of 1,2,3,4-tetrahydroquinoxaline derivatives (Scheme 5.30). The carbon
carbon double bond of compound was activated with I2 to produce an iodoiranium intermediate that underwent 6-exo-trig cyclization to synthesize the products [80].

Scheme 5.30

The cyclohexane-1,4-dione was reacted with two molecules of o-amino compound to synthesize the dispirocyclic compounds possessing quinazolin-4-(1H)-one derivatives (Scheme 5.31) [80].

Scheme 5.31

258

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

El-Shaieb et al. [81] synthesized 2,3-dihydroquinazolines by a facile one-pot method (Scheme 5.32). The amino group of compound attacked the I2 activated aldehydes to produce the intermediate that furnished imine upon elimination of water molecule. The desired products were obtained by intramolecular cyclization of imine [80].

Scheme 5.32

Wang et al. [82] synthesized quinazoline-4-(1H)-one derivatives in high yields in the presence of I2 catalyst in ionic liquid (Scheme 5.33). Intramolecular nucleophilic attack of the nitrogen of amide group on I2 activated Schiff’s base formed the cyclized product [80].

Scheme 5.33

Argade et al. [83] reported a general method for the synthesis of various quinazolinones via hexamethyldisilazane (HMDS)/iodine-induced intramolecular dehydrative cyclization (Scheme 5.34). The products were not formed in the absence of either iodine or HMDS and I2 was required in catalytic amount to induce the first silylation of the more reactive amide carbonyl group that underwent intramolecular cyclization (ringclosure with deoxysilylation) to afford the quinazolinones [80].

Scheme 5.34

Six-membered N,N-polyheterocycles

259

Zhang and coworkers [84] reported a novel tandem reaction for the preparation of several 2-phenylquinazolines (Scheme 5.35). In situ produced Schiff’s base was oxidized to afford an intermediate via sp3 carbonhydrogen functionalization [85,86]. The 2-phenylquinazoline derivatives were obtained by intramolecular cyclization of Schiff’s base and subsequent oxidation of the formed intermediate. A variety of benzylamines and 2-amino-4-substituted ketones were successfully used [80].

Scheme 5.35

Wang and Zeng [87] synthesized 3,4-dihydroquinazolin-4-ones via one-pot three-component reaction of o-esters, anthranilic acids, and amines under solvent-free conditions using 5 mol% I2 (Scheme 5.36). I2 facilitated the formation of imidic ester intermediate by reacting anthranilic acids with o-esters that reacted rapidly with amines to produce an amidine intermediate. The cyclized products were yielded by intramolecular attack of the amino group at I2 activated carbonyl carbon. A variety of aryl amines with electron-withdrawing and electron-donating groups were successfully used [80].

Scheme 5.36

5.2.8 Iridium-assisted synthesis The reaction was carried out with equimolar amounts of ( 6 )-trans-1,2diaminocyclohexane and ethylene glycol (Scheme 5.37). Since the desired reaction was closely related to the N-heterocyclization reported by Yamaguchi and coworkers [88], the same reaction conditions and catalyst were chosen for the test reaction. The reaction was conducted in a sealed heavy-walled flask to ensure that hydrogen was not liberated from the reaction mixture.

260

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.37

Aromatic diamines like quinazolines are another group of biologically significant heterocycles. The quinazolines were synthesized by condensation of an aldehyde and a 2-aminobenzylamine followed by oxidation. This oxidation was accomplished using 2,3-dichloro-5,6-dicyanobenzoquinone [89,90], air/activated carbon, or air/trifluoroacetic acid [91,92]. A primary alcohol was treated with iridium catalyst to form an aldehyde that condensed in situ with 2-aminobenzylamine to afford the 1,2,3,4-tetrahydroquinazoline. The 1,2,3,4-tetrahydroquinazoline was oxidized to quinazoline by aid of the catalyst or by air (Scheme 5.38).

Scheme 5.38

The acetamidine hydrochloride and 2-iodobenzoic acid were selected as model substrates for the optimization of reaction conditions including ligand, catalyst, temperature, base, solvent, and time. Only a trace product was formed in the ligand- and catalyst-free reaction. The desired product was formed in 75% yield without ligand in the presence of ferric chloride (10% mmol) in dimethylformamide under microwave MW heating at 100 °C for 30 min. Thus this reaction was also performed in a ligand-free catalytic system. The L-proline (20 mol%) ligand was used in order to obtain higher yields. As expected, the product yield improved to 84%, which indicated the important role of ligand. This catalytic system was selected to examine the effect of bases, and cesium carbonate was found to be more effective than sodium tert-butoxide or 1,8-diazabicyclo[5.4.0] undec-7-ene. The results showed that the combination of N,N0 -dimethylethylenediamine and Fe2(acac)3 also provided high yield (85%). In order to obtain greener protocols, the reaction was performed in water with the combination of L-proline and ferric chloride under MW heating at 100 °C for 30 min. The desired product was formed in 73% yield. It also provided good yields up to 78% without ligands when the reaction was conducted in water (Scheme 5.39) [93].

Six-membered N,N-polyheterocycles

261

Scheme 5.39

5.2.9 Iron-assisted synthesis The reaction occurred easily and the products were quite stable so that different reductants with a wide activity range allowed the synthesis of phenazine and its substitution products (Scheme 5.40). No dihydrophenazines were formed as intermediates and there was reasonable doubt that this type of deoxygenation reaction of nitroaromatics involved a nitrene intermediate [94
96]. Suschitzky and Feuer [97] suggested that an uncatalyzed cyclization reaction occurred via an aci-form of the nitro derivative, which eliminated water. The formed N-oxide intermediate was reduced further to the final product.

Scheme 5.40

The benzimidazo[1,2-c]quinazoline was formed in 46% yield upon reductive cyclization of 1-acetyl-2-(2-nitrophenyl)benzimidazole in the presence of hydrogen chloride and iron powder in refluxing ethanol (Scheme 5.41) [98,99].

Scheme 5.41

The traditional protocol to prepare the quinoxalines took 6 h of heating and cooling (reflux), today it is completed without using organic solvents in about 30 min. The benefit of not using any organic solvent emphasizes the new concern for the environment referred to as green

262

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

chemistry. The acid adducts were formed under MW heating in 30 min. The quinoxalines were also synthesized in one and half hour as compared to 6 to 12 h of convectional heating (Scheme 5.42) [100].

Scheme 5.42

Das and coworkers [101] reported the use of Amberlyst-15 or silica chloride as a heterogeneous catalyst for the preparation of furano- or pyranoquinolines via coupling of benzaldehydes, anilines, and 2,3-dihydrofurans or 3,4-dihydro-2H-pyrans. The same reaction was also reported [102] using two reusable solid acids (HY-zeolite and Fe31-K10 montmorillonite clay) for the one-pot synthesis of furano- and pyranoquinolines. A solvent-free protocol was also developed for the one-pot preparation of 4(3H)-quinazolinones (Scheme 5.43) [103] via coupling reaction of o-esters, anthranilic acid, and amines using Amberlyst-15 or silicasupported sodium hydrogen sulfate as a heterogeneous catalyst. The products were formed in shorter reaction times (5
15 min). Most of the reactions occurred at room temperature, but in the case of anilines with a nitro group, the products were formed by heating the reaction mixture at 60 °C for more time (15 min). For 2,5-dimethoxyaniline heating of reaction mixture for 10 min was necessary. The Amberlyst-15 catalyst was recovered and reused [104].

Scheme 5.43

Six-membered N,N-polyheterocycles

263

5.2.10 Lithium-assisted synthesis Initially, Boc-protected amino acids were coupled to p-methylbenzhydrylamine resin. Selective N-alkylation of amide bond was performed to form an intermediate in order to add additional potential diversity to the compounds being synthesized. The cleavage of Boc-protecting group and tritylation were carried out upon treatment with lithium t-butoxide and addition of an alkyl halide. Removal of trityl protecting group, coupling of appropriate anthranilic acid, and acetylation at room temperature afforded compound that was cyclized to afford the resin-bound quinazolinone by heating at 200 °C in sulfolane for 4 h. Synthesis of styrylquinazolinones was completed by treatment with sodium methoxide and reaction with the desired aromatic aldehyde. The products were cleaved from the resin using anhydrous hydrogen fluoride in the presence of anisole (Scheme 5.44) [105].

Scheme 5.44

5.2.11 Manganese-assisted synthesis Methods for the preparation of 2,3-disubstituted piperazines involved the reduction of pyrazine, and substitution of a suitably substituted alkyl halide via reductive amination and via Brønsted acid/Mn(0)-mediated radical cyclization reaction (Scheme 5.45) [106
110].

264

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.45

5.2.12 Molybdenum-assisted synthesis Many synthetic protocols are known for the synthesis of substituted quinoxalines. The classic method for the preparation of quinoxaline was the condensation of 1,2-dicarbonylic compound with 1,2-diamino compound. In general, this method required the use of a strong acid catalyst, high temperature, and long reaction times. The heterogeneous system was applied for the synthesis of quinoxalines in the presence of Keggin heteropolyoxometalates (AlFeMoVP and AlCuMoVP) as reusable catalyst. The synthesis of quinoxaline involved the reaction of 1,2-diketones and substituted o-phenylenediamines. Before attempting detailed catalytic work, a noncatalytic reaction of benzyl, o-phenylenediamine, and toluene was examined and it was reported that no formation of quinoxaline was detected under the experimental conditions, indicating that from a practical point of view the reaction did not occur without catalyst. The experimental conditions were 1 mmol of o-phenylenediamine, 100 mg of catalyst, 7 mL of toluene, and 1 mmol of benzyl, 2 h at 25 °C. Under these conditions, quinoxaline was obtained with a selectivity of 100% for both catalysts. A very slight increase in yields of azlactone was reported with increasing the amount of AlCuMoVP (Scheme 5.46) [111].

Scheme 5.46

5.2.13 Nickel-assisted synthesis Beylin and coworkers [112] reported an intramolecular reductive cyclization of Michael addition product of nitromethane to enantiomerically

Six-membered N,N-polyheterocycles

265

enriched aminoenoate for the preparation of chiral lactam, side-chain of the potent antibacterial agents and gyrase/topoisomerase inhibitors, amino-quinazolinediones (Scheme 5.47) [19].

Scheme 5.47

High yield of benzimidazo[1,2-c]quinazolines was obtained when 2(2-nitrophenyl)benzimidazole was reduced to afford the 2-(2-aminophenyl)benzimidazole that reacted with aldehydes in EtOH/CH3COOH mixture (Scheme 5.48) [93,113].

Scheme 5.48

The phenazine derivatives were synthesized by one-step reductive cyclization of substituted 2,2’-dinitrodiphenyl amines in alkaline media under mild reduction conditions [114]. Raney nickel or ruthenium/carbon [115] was used as catalyst. The 1,6-dimethoxy-phenazines [116] were also prepared in a similar way (Scheme 5.49).

266

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.49

5.2.14 Rhodium-assisted synthesis One can easily envision why N-acyliminium cyclizations are more facile. Therefore iminium-cyclizations are still used. Campi et al. [117] in 1995 reported that 2-(N-allylaminomethyl)aniline underwent aminocarbonylation in the presence of rhodium catalyst for the synthesis of quinazoline skeleton (Scheme 5.50).

Scheme 5.50

Mizoguchi and coworkers [118] developed a divergent synthetic method involving four steps to afford the fused skeletons, which are present in transtangolide and aspidoplytine. The three-step processing of allylamine provided branched precursor. This involved Ugi condensation of amine with tert-butyl isonitrile, 3-indolecarbaldehyde, and a terminal olefin and installation of diazoimide followed by rhodium-catalyzed reaction of branched precursor involving a 1,3-dipolar cycloaddition of ylide intermediate with terminal olefin to give a separable 1:1 diastereomeric mixture of fused skeletons (Scheme 5.51) [19].

Scheme 5.51

Six-membered N,N-polyheterocycles

267

Acrylates were coupled smoothly with azomethine under conditions A (Scheme 5.52), and products were obtained as major products in 68%
88% yield, whereas the diolefination product was formed in 56%
79% yields under conditions B. Acrylonitrile was also a viable coupling partner, but only for monoolefination/cyclization. The scope of azomethine substrate was explored using benzyl or n-butyl acrylate. Electronwithdrawing, electron-donating, and halogen groups present at the para position of benzene ring were well tolerated under both sets of conditions. When the ortho position was blocked by fusion with an extra ring or a halogen group, selective monoolefination/cyclization occurred. Azomethines with substituents in the meta position were well-tolerated and the carbon
hydrogen functionalization occurred preferentially at the less hindered site. Moreover, a gem-diethyl analogue smoothly reacted with comparable selectivity and reactivity. In contrast to the smooth reactions of these activated olefins, styrene and N,N-dimethylacrylamide were less effective and reacted with different selectivity. Dihydrophthalazines and phthalazines are known to be potentially bioactive [119
121]. Dihydrophthalazines are less accessible, and are typically synthesized by nucleophilic addition to phthalazines [122,123a,b].

Scheme 5.52

The sequencing of second olefination and the scission of pyrazolidinone ring was subjected to conditions (benzyl acrylate), but no reaction occurred. The proposed o-olefinated azomethine intermediate was

268

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

probed next. The 1,2-dihydrophthalazine was formed in high yield by Rhcatalyzed one-pot reaction of aldehyde with 5,5-dimethylpyrazolidinone (Scheme 5.53), which indicated the intermediacy of an o-olefinated azomethine. The Rh catalyst was necessary in this reaction, as omission of the catalyst provided a mixture of unidentifiable products, which also suggested that the Rh catalyst promoted the scission of pyrazolidinone ring and/or the subsequent Michael cyclization. Hydrazone was smoothly cyclized to 1,2-dihydrophthalazine (68% yield) even in the absence of catalyst (Scheme 5.54). This result supported the intermediacy of hydrazone as well as indicated that the scission of pyrazolidinone ring was Rhmediated. Additional information on the catalytic cycle was obtained from deuterium-labeling studies using n-butyl acrylate (Scheme 5.55). The observed loss of deuterium in the ortho position of the product agreed with reversible cyclometalation, and this metalation/proto-(deutero) demetalation was faster than any subsequent reactions [123b
125].

Scheme 5.53

Scheme 5.54

Scheme 5.55

Six-membered N,N-polyheterocycles

269

The azomethine ylides of (hetero)arylaldehydes are suitable substrates for carbon
hydrogen activation under chelation assistance although carbon
hydrogen activation of these substrates has not been reported. Furthermore, the possible cleavage of carbon
nitrogen, C 5 N, and carbon
carbon bonds in the pyrazolidinone ring was coupled with carbon
hydrogen activation, providing unique and versatile products. The rich chemistry of rhodium(III)-catalyzed oxidative carbon
hydrogen olefination of azomethine imines has been reported, where the cleavage of all of these bonds involved under different conditions. The conditions were screened for the coupling of (hetero)arylaldehydes with benzyl acrylate in the presence of [RhCp-(MeCN)3](SbF6)2 catalyst. Cu(OAc)2 was proved to be a less effective oxidant, and two functionalized 1,2-dihydrophthalazines were formed in low yields. In contrast, silver acetate was proved to be effective oxidant and monoolefination/cyclization product was formed in 88% yield when the reaction was optimized using a slight excess of the oxidant and the olefin. In contrast, only [3 1 2]-dipolar addition occurred upon omitting the Rh catalyst (Scheme 5.56) [80,123b].

Scheme 5.56

5.2.15 Ruthenium-assisted synthesis Watanabe and coworkers [126] reported the potential of various transition metal complexes in reductive cyclization reactions. In particular, the N(2-nitrobenzoil)amides were effectively transformed into 4-(3H)-quinazolinone derivatives with ruthenium catalysts (Scheme 5.57).

270

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.57

The antibiotic tryptanthrine was synthesized by this reaction as shown in Scheme 5.58 [127].

Scheme 5.58

The insertion into a saturated methylene occurred albeit in low yield (9%). All of these reactions were thought to occur through the formation of metal-bound nitrene intermediate (Scheme 5.59) [128,129].

Scheme 5.59

Among the alternative protocols for the synthesis of nitrogen heterocycles, Cho et al. [130,131] developed an interesting strategy for the construction of quinolines using many ruthenium catalysts. Alcohol reacted with acetophenone (and a variety of other ketones) employing Grubbs first-generation catalyst (Scheme 5.60). The quinoline was obtained by an oxidative process with formal loss of hydrogen. Alternative ruthenium [132
134] and iridium [135] catalysts were used for the same transformation, in some cases starting from an alcohol rather than a ketone. The o-phenylenediamine was reacted with diol under ruthenium-catalyzed oxidative conditions to form the quinoxaline [136,137].

Six-membered N,N-polyheterocycles

271

Scheme 5.60

The protected (4S)-4-hydroxy-L-proline was oxidized with ruthenium (IV) oxide to form the lactam (Scheme 5.61). The lactam was reduced to give an aminal, which was in equilibrium with aminoaldehyde. A onepot Horner
Wadsworth
Emmons (HWE) reaction produced α,β-unsaturated amide and then an intramolecular conjugate addition reaction afforded good yield of amide. The stereochemistry arises by selective attack of amine on the less hindered face to form an amide as a single diastereomer. Weinreb amide was treated with methylmagnesium bromide to form the methyl ketone. The methylenation of ketone with Tebbe’s reagent followed by Boc deprotection afforded amine. Reductive deamination using samarium diiodide as a one-electron reducing agent cleaved the carbon
nitrogen bond of proline derivative to afford an intermediate, which was spontaneously cyclized in situ with expansion of the ring to form the piperidone in excellent yield. Reduction of piperidone with lithium aluminum hydride and simultaneous removal of

Scheme 5.61

272

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

hydroxy-protecting group followed by protection of secondary amine provided 3-hydroxypiperidine. Many transformations were needed to convert the piperidine into the desired product, (1)-febrifugine [138].

5.2.16 Scandium-assisted synthesis The 2,3-dihydroquinazolinones were synthesized enantioselectively using a readily available Sc(III)-inda-pybox catalyst via a metal-catalyzed asymmetric intramolecular amidation of an imine (Scheme 5.62) [139].

Scheme 5.62

The quinazolinobenzodiazepine natural products such as circumdatins H, E, and J, benzomalvin A, asperlicin C, and schlerotigenin and analogues have been the target of much synthetic endeavor [140
144]. A noteworthy example is the total syntheses of circumdatin F, asperlicin C, and schlerotigenin and other fused quinazolines by microwave and scandium(III) triflate-promoted double cyclization of anthranilate possessing tripeptides (Scheme 5.63) [145].

Scheme 5.63

Nüchter and Ondruschka [146] reported a parallel construction of a 36-member library of Biginelli dihydropyrimidines in a suitable multivessel rotor placed inside a dedicated multimode MW reactor. The modern multimode MW reactors operated with specifically

Six-membered N,N-polyheterocycles

273

designed 96-well plates under sealed-vessel conditions; the parallel approach offered a considerable higher throughput than the automated sequential technique, albeit at the cost of having less control over the reaction parameters for each individual vessel/well [147]. The limitation of the parallel approach was that all reaction vessels during library production were exposed to the same irradiation conditions in terms of MW power and reaction time and not allowed specific needs of individual building blocks to be addressed by varying the temperature or time (Scheme 5.64) [148].

Scheme 5.64

5.2.17 Silicon-assisted synthesis Salehi et al. [149] developed a novel method for the one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones (Scheme 5.65) via condensation reaction of isatoic anhydride, ammonium carbonate, or primary amine, and an aromatic aldehyde using silica sulfuric acid as a catalyst in refluxing EtOH. The catalyst was reused several times without any loss of product yields. Aliphatic amines provided the products in shorter reaction times as compared to aromatic ones. Aliphatic aldehydes underwent aldol condensation under these reaction conditions and thus were not used for this reaction. The same group [150] also developed an efficient protocol for the synthesis of a series of mono- and disubstituted quinazolin-4(3H)-ones via silica sulfuric acid-catalyzed, one-pot reaction of an o-ester and isatoic anhydride with ammonium acetate (or a primary amine) under solvent-free conditions [98].

Scheme 5.65

274

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

5.2.18 Tin-assisted synthesis Unlike Dieterle, Ullmann [151] and King [152] reported the preparation of 3,4-benzocinnoline by a two-stage reduction of 2,20 -dinitrodiphenyl through the formation of 3,4-benzocinnoline N-oxide as intermediate. The first reduction step to the 3,4-benzocinnoline N-oxide was performed with sodium sulfide and then the intermediate, 3,4-benzocinnoline N-oxide was reduced with stannous chloride in acidic conditions (or by electrochemical reduction) to the final product (Scheme 5.66).

Scheme 5.66

Thomson et al. [153] used acetic acid and Zn dust as reducing agents during the second step; LiAlH4 was also used to perform both reductions, including the reduction step of intermediate 3,4-benzocinnoline N-oxide to provide the final product. Eckert and Steiner [154] reported the cyclization reaction of 1,10 -nitroanthrimide; they observed that oxyanthrimide was formed via ammonia elimination by reduction under basic conditions while indanthrene derivatives were formed under acidic conditions. Eckert and Steiner [155] also prepared phenazine using 2,20 -dinitrodiphenyl amine as starting compound. The 2,2’-dinitrodiphenyl amine was first reduced with tin(II) chloride and then the formed reaction mixture was oxidized with H2O2 or other oxidative reagents (ferric chloride, potassium permanganate, and manganese(IV) oxide); 2,20 -diaminodiphenyl amine was not isolated (Scheme 5.67).

Scheme 5.67

Six-membered N,N-polyheterocycles

275

ˇ et al. [156] synthesized tetrahydroquinoxalines and quinoxaKrchnák linones. The starting point for both syntheses was 4-(4-formyl-3-methoxyphenoxy)butyryl AM resin. The synthesis of quinoxalinones followed a pathway consisting of RA with an amino acid ester, nucleophilic fluorine displacement by reaction of o-fluoronitrobenzene with BAL secondary amine, and reduction of nitro group with SnCl2 to the amine, which resulted in spontaneous cyclization to the dihydroquinoxalinone. The amide moiety was then alkylated before the structures were cleaved from the linker with trifluoroacetic acid (or hydrogen fluoride or hydrogen chloride), which caused air oxidation to the quinoxalinone (Scheme 5.68).

Scheme 5.68

The 4-fluoro-3-nitro-benzoic acid was used for the acylation of resinbound secondary amine. The common intermediate o-nitroaniline was formed upon displacement of the fluorine with primary amine. The 4hydroxy-quinoxalin-2-one was generated when ethyl oxalyl chloride was reacted at 40 °C in toluene followed by tin chloride reduction and resin cleavage (Scheme 5.69) [157].

276

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.69

The isatins were reacted with 2-nitrobenzamides in the presence of Sn (II) chloride to provide the spiroquinazolinone-oxindoles (Scheme 5.70) [158]. The Sn(II) served both as a reducing agent for transformation of nitro group in amides to an amino group and, together with the oxidized Sn(IV), as an activator of the C-3 carbonyl group of isatin. The formed isatin imine underwent intramolecular cyclization with amide to provide the final product. The products were formed in excellent yields by reaction with different types of substituents on amides and on isatin. This protocol, however, remained unexplored for isatins containing activating groups on the phenyl ring or for N-substituted isatins. These products were formed earlier [159,160] by a three-component reaction of amines, isatins, and isatoic anhydride.

Six-membered N,N-polyheterocycles

277

Scheme 5.70

Makino and coworkers [161] reported a cycloaddition of anthranilamides with o-formates for the synthesis of various quinazolines. The solidsupport was treated with p-nitrobenzoic acid. The amine was obtained by reduction of nitro group and amine was transformed to the amide with acid chloride. The quinazolines were formed in very high purities after cyclocondensation and cleavage of the solid support (Scheme 5.71).

Scheme 5.71

Makino and coworkers [162] synthesized quinazolines using a cyclocondensation. In the first step, nitro acids were connected onto Wang resin by etherification. The nitro group was reduced to amine and then a cycloaddition occurred with 2-methoxycarbonyl phenylisothiocyanate. A mixture of products was obtained upon cleavage of the resin with trifluoroacetic acid depending on the acid concentration, which was due to the fragmentation of linker. However, the S-allyl quinazoline was synthesized cleanly after the S-allylation of quinazoline (Scheme 5.72).

278

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.72

The dihydroquinazoline derivatives were synthesized by a novel method under solid-phase conditions. Polymer-bound 4-bromomethyl-3nitrobenzoate and the amide were used as versatile substrates that underwent nucleophilic displacement with amines followed by reduction and cyclocondensation reactions to give the structurally diverse dihydroquinazolines in excellent purity and yield (Scheme 5.73) [163]. The 2,3-dihydrooxazolo[2,3-b]quinazolin-5-ones and 2-cyanoquinazolin-4(3H)-ones were prepared in four-steps using polymer-bound anthranilic acid derivatives through the formation of dithiazole resins (Scheme 5.74) [164]. The 3,4-dihydro-2(1H)-quinazolinones were prepared under the best conditions upon treatment of intermediates with N,N0 -disuccinimidyl carbonate in N-methylpyrrolidine overnight at room temperature. For the synthesis of 3,4-dihydroquinazolines, the use of trifluoroacetic acid was avoided to prevent the premature cleavage from the resin. This cyclocondensation proceeded well overnight using 2.5% acetic acid in trimethyl o-formate/N-methyl-2-pyrrolidone (1:4) at 65 °C. In the case of 2-substituted dihydroquinazolines, the ring formation occurred successfully using an aldehyde/2,3-dichloro-5,6-dicyano-p-benzoquinone combination at room temperature in N-methyl-2-pyrrolidone overnight (Scheme 5.75) [165].

Six-membered N,N-polyheterocycles

Scheme 5.73

Scheme 5.74

279

280

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 5.75

The 5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinoxalin-6-ones with three points of diversity were synthesized under solid-phase conditions. Primary amines attached to 2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene reacted with 1,5-difluoro-2,4-dinitrobenzene followed by displacement of second fluorine with amino acid ester, reduction of nitro groups, acylation, and ring-closure (Scheme 5.76) [166].

Scheme 5.76

Six-membered N,N-polyheterocycles

281

Quinoxaline derivatives form a group of generally less investigated compounds. However, recently more efforts have been made to prepare and characterize these compounds. The 4-amino-3-nitrophenol was reduced with stannous chloride in hydrochloric acid to afford the 3,4-diaminophenol. The reaction of o-phenylenediamine and pyruvic acid under MW heating in the presence of 6 N hydrochloric acid afforded 3-methylquinoxaline-2(1H)-one. The 3-methylquinoxaline-2(1H)-one was reacted with 4-aminobenzoic acid and formaldehyde employing Mannich reaction to provide the 4-{[-3-methyl-2-oxoquinoxaline-1(2H)methyl] amino}benzoic acid. The 1-({[4-(1H-benzimidazol-2-yl)phenyl]amino}methyl)-3-methylquinoxaline-2(1H)-one was formed when 4-{[3methyl-2-oxoquinoxaline-1(2H)methyl]amino}benzoic acid was reacted with o-phenylenediamine (Scheme 5.77) [167].

Scheme 5.77

5.2.19 Titanium-assisted synthesis Quinazolines exhibit a variety of biological activities and have attracted the attention for a few decades. Particular attention has been paid to methoxy and amino derivatives that possess cancerogenic and antimalaria properties and are used to develop medicines against hypertension [168a
c]. The 4-amino-8-hydroxy-2-phenylquinazoline derivatives were synthesized from well-known compounds: N-(2-methoxyphenyl)benzamide and N-(2-hydroxyphenyl)benzamide. The synthesis consists of converting N-(2-R1-oxyphenyl)benzamide derivatives to the appropriate

282

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

benzimidoyl chlorides with phosphorus pentachloride. Such chlorides reacted with cyanamide derivatives to afford the acyclic linear products that underwent cyclization to final 8-R1-oxyquinazolines using titanium (IV) chloride. Unfortunately, the unsubstituted N-(2-hydroxyphenyl)benzamide reacted with phosphorus pentachloride in anhydrous toluene providing 2-phenyl-1,3-benzoxazole mainly. It was necessary to protect the hydroxy group in amide using Ph3CCl to avoid such side reaction and then converted the protected amide into the benzimidoyl chloride and finally to quinazoline. Considering the fact that biological activity of compounds is also greatly dependent on their ability to acid
base interactions, the pKa values of the synthesized compounds have also been determined (Scheme 5.78).

Scheme 5.78

The o-alkynylbenzaldehydes served as suitable building blocks for the construction of isoquinoline nucleus. Microwave heating promoted the domino imination/annulation reaction efficiently (Scheme 5.79). This reaction was also extended to 2-acetyl-N-propargylpyrroles for the generation of pyrrolo[1,2-a]pyrazine. The reaction of 2-acetyl-N-propargylindoles worked well only in the presence of TiCl4 [169a,b]. The benzoxazinone (kind of a mixed anhydride) was reacted to syn-

Scheme 5.79

thesize the quinazolinone in 55% yield [170]. The synthesis of heterocyclic compounds using titanium isocyanate complex was reported and novel nitrogenation protocol was developed. It was observed that dry air can be used as a nitrogen source for the preparation of heterocyclic compounds (Scheme 5.80) [171
174].

Six-membered N,N-polyheterocycles

283

Scheme 5.80

The cyclocondensation reaction of 2-(2-aminophenyl)benzimidazole with o-esters under MWI in dimethylacetamide afforded benzimidazo [1,2-c]quinazoline derivatives in high yields [175]. The benzimidazo[1,2-c] quinazoline derivatives were also prepared when 2-(2-nitrophenyl)benzimidazole derivative was treated with triethyl-o-formate in the presence of TiCl4
Zn (Scheme 5.81) [176,177].

Scheme 5.81

5.2.20 Zinc-assisted synthesis The dihydroquinazolines were obtained in high yields (72%
94%) when carbonyl compounds and 2-(aminoaryl)alkanone O-phenyl oximes were irradiated under microwaves in toluene solution with [emim]PF6 as ionic liquid at 160 °C for 30 min. Portela-Cubillo et al. [178] reported this reaction (Scheme 5.82). The quinazolines were obtained instead when

Scheme 5.82

284

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

0.3 eq. of zinc chloride was introduced in the mixture. Except the cupric chloride-catalyzed reaction of aldehydes with anthranilamide, protocols of synthesizing the quinazoline ring either needed multistep preparations of special reactants/reagents or give moderate yields. The zinc chloride-catalyzed annulation of oxime ethers with aldehydes under microwaves provided substituted quinazolines (Scheme 5.83). Quinazolines were obtained in high yields with aromatic and aliphatic aldehydes containing electron-withdrawing substituents in the 4-position. The lower yields were obtained using aldehydes with electron-donating substituent. Dihydroquinazolines were formed in poor yields using ketones as carbonyl compounds [179,180].

Scheme 5.83

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34.

CHAPTER 6

Six-membered O-heterocycles 6.1 Introduction The rich activity of heterocyclic compounds in biological systems is important for agricultural, pharmaceuticals, and natural products. Heterocyclic compounds have provided a platform for the rapid exchange of research in the areas of pharmaceutical, organic, medicinal, and analytical chemistry [1a
c]. In the pharmaceutical industry over 75% of the top 200 branded drugs have heterocyclic fragments in their structures. Heterocyclic building blocks also have practical uses as components in antioxidants, dyestuffs, bases, copolymers, and ligands. Most of the organic compounds containing heterocyclic compounds show better biological activity than nonnitrogen compounds [2
5]. Pyran derivatives constitute a useful class of heterocyclic compounds, which are widely distributed in nature [6]. The fused pyran ring skeleton is a well-known heterocycle and an important core unit in a number of natural products. Pyran and fused pyran derivatives have attracted a great deal of interest due to their association with various kinds of biological properties. Substituted benzo(b)pyran derivatives exhibit anticancer activities against three human cell lines even at very low concentrations [7
10]. A number of 2-amino-4H-pyrans are used as pigments, photoactive materials, and potentially biodegradable agrochemicals [11
13]. Naphthopyrans are a class of photochromic compounds and the molecules have the ability to generate a yellow color on being irradiated with ultraviolet light. Pyranochalcones have been reported to exhibit antimicrobial, antimutagenic, antitumor, and antiulcer activities [14,15]. Pyrans and fused pyran derivatives have attracted a great deal of interest due to their association with various kinds of biological properties. The pyran heterocycles embedded with other heterocyclic moiety either in the form of a substituent or as a fused component changes its properties and converts it into a novel heterocyclic derivatives [16a,b]. This chapter focused on the use of metal and nonmetal for the construction of various six-membered heterocyclic compounds with oxygen heteroatom. Metal and nonmetal-mediated synthesis of different Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00006-3

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

heterocycles is classified into the following categories based on the type of metal and nonmetal.

6.2 Metal- and nonmetal-assisted synthesis of sixmembered oxygen containing heterocycles 6.2.1 Aluminum-assisted synthesis As depicted in Scheme 6.1, bis(vinyl) silane was treated with s-butyllithium for metal
halogen exchange followed by treatment with alkyl iodide to provide the advanced intermediate. The last two steps were double oxycarbenium ion/vinyl silane cyclization to synthesize the tetrahydropyran ring followed by deprotection to furnish the natural product [17,18].

Scheme 6.1

Hsung et al. [19,20] applied successful allenamide chemistry in the formal total synthesis of (1)-zincophorin via an inverse electron-demand hetero-[4 1 2]-cycloaddition of chiral allenamide (Scheme 6.2). Chiral allenamide and heterodiene underwent highly stereoselective cycloaddition to provide the pyran as a single isomer. Pyran underwent highpressure hydrogenation, which was not trivial, and the ensuing tin(IV) bromide-promoted crotylation with concomitant removal of the chiral urea group give the key intermediate. In this entire sequence, the chiral auxiliary of allenamide served to afford stereochemical control for the cycloaddition and hydrogenation, and in return, the new stereocenters would dictate the selectivity of the final crotylation and removal (and recovery) of the auxiliary. Pyran was subsequently transformed into intermediate, which spectroscopically matched Miyashita’s advanced intermediate, thereby constituting a formal total synthesis of (1)-zincophorin.

Six-membered O-heterocycles

297

Scheme 6.2

For the preparation of lactones, 2-nitro-cycloalkanones were reacted with several enones, providing adducts (Scheme 6.3) [21]. The three synthetic operations such as retro-Claisen cleavage, reduction, and nitronate formation were performed on adducts in a single step using sodium borohydride in a mixture of H2O
MeCN (2:3). The spiroketals were synthesized by quick acidic hydrolysis of nitronate intermediate.

Scheme 6.3

This versatile method allowed rapid synthesis of 1,6-dioxaspiro[4.6] undecane systems. The nitroalkenes were prepared directly by an efficient nitro-aldol (Henry) reaction of nitro-alcohol and O-protected hydroxyaldehydes under heterogeneous conditions (Scheme 6.4) [22]. The reduction of nitroalkene double bond was coupled with the formation of nitronate anion that upon acidification underwent a tetrahydropyran deprotection, Nef reaction, and ketalization to afford the spiroketals [23,24].

298

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.4

6.2.2 Barium-assisted synthesis Oxocarbenium ions served as reactive intermediates in various important synthetic transformations such as Prins-pinacol cyclizations, glycosylation, and oxa-Pictet
Spengler reactions. A highly enantioselective variant of acyl-Pictet
Spengler reaction was reported where N-acyliminium ions underwent cyclization in the presence of a chiral thiourea catalyst. This strategy was extended to reactions involving oxocarbenium ions for the development of an enantioselective oxa-Pictet
Spengler reaction. Using a chiral thiourea catalyst, enantioenriched tetrahydropyranoindoles (found in bioactive compounds) were synthesized (Scheme 6.5) [24].

Scheme 6.5

6.2.3 Bismuth-assisted synthesis Dihydropyrans and tetrahydropyrans are examples of cyclic ethers widespread in nature. These structures are found in many compounds like scytophycin C [25], (2)-centrolobine, (2)-mucocin, and (1)-bistramide C among others [26,27]. Various bismuth-based synthetic protocols were reported for the synthesis of dihydropyrans and tetrahydropyrans. The 2H-pyrans were obtained in good yield by bismuth chloride-catalyzed Diels
Alder reaction of various dienes with electrophiles such as ethyl mesoxalate [28]. The Bi(OTf)3  xH2O-catalyzed reaction of glyoxylic acid [29], diethyl mesoxalate, or ethyl glyoxylate [30] with various dienes

Six-membered O-heterocycles

299

also provided [4 1 2] adducts (Scheme 6.6). Lian and Kinckle [31] reported that triethylsilyloxyvinyltrimethylsilanes underwent bismuth bromide-catalyzed tandem addition/silyl-Prins reaction with a variety of aldehydes. The cis-2,6-disubstituted dihydropyrans were formed in goodto-excellent yields by this reaction (Scheme 6.7).

Scheme 6.6

Scheme 6.7

The bismuth chloride-assisted cross-cyclization between homoallylic alcohols and epoxides provided various benzyl tetrahydropyran derivatives. The reaction afforded good yields of desired products and occurred under mild conditions (Scheme 6.8) [32].

Scheme 6.8

The stereoselective intramolecular reductive tandem etherification reactions of ketones and trialkylsilyloxy aldehydes in the presence of various trialkylsilyl nucleophiles and catalytic bismuth bromide furnished trans- and cis-2,6-di- and trisubstituted tetrahydropyrans (Scheme 6.9) [33].

Scheme 6.9

300

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The antibiotic (2)-centrolobine (Scheme 6.10) [34], the antitumor agent (2)-mucocin (Scheme 6.11) [35,36], and other biologically interesting compounds were synthesized.

Scheme 6.10

Scheme 6.11

Evans and Andrews [37] reported an efficient and mild intramolecular oxa-conjugate addition of tethered triethylsilyloxy substituted α,β-unsaturated ketones in the presence of Bi(NO3)3  5H2O catalyst. The cis-2,6-disubstituted tetrahydropyrans were synthesized stereoselectively (Scheme 6.12).

Scheme 6.12

Six-membered O-heterocycles

301

This protocol afforded good-to-high yields of hexahydrodibenzo[b,h] [1,6]naphthyridines, as a mixture of cis and trans diastereoisomers (1:1) [38], and hexahydropyrazolo[40 ,30 :5,6]thiopyrano[4,3-b]quinolines (only the cis products) [39], respectively. The aromatic amines underwent a similar cycloaddition reaction with O-allyl derivative of a sugar-derived aldehyde (Scheme 6.13) [40] in the presence of bismuth chloride as catalyst. Furo[20 ,30 :5,6]pyrano[4,3-b]quinoline derivatives (mainly as the trans isomer) [41] were formed.

Scheme 6.13

The aza-Diels
Alder reaction of N-aryl aldimines with nucleophilic olefins was catalyzed with bismuth(III) chloride for the synthesis of pyrano [3,2-c]quinoline derivatives in high yields (Scheme 6.14) [41,42].

Scheme 6.14

The Prins reaction of homoallylic alcohols with aldehydes afforded an alternative method for the preparation of tetrahydropyrans. 4Chlorotetrahydropyrans were synthesized with the help of bismuth

302

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

chloride under microwave irradiation (Scheme 6.15). However, the more interesting 4-tetrahydropyranol derivatives were formed when Bi (OTf)3  xH2O was used in either [bmim]PF6 or acetonitrile [43,44].

Scheme 6.15

The 4-chlorotetrahydropyrans were synthesized under microwave radiation in the presence of bismuth chloride [45]. However, 4tetrahydropyranol derivatives were synthesized using Bi(OTf)3  xH2O in acetonitrile (Scheme 6.16) [41,46].

Scheme 6.16

The rapid and stereoselective synthesis of various interesting substituted tetrahydropyrans was carried out by an intramolecular Sakurai cyclization of homoallylic alcohols in the presence of Bi(OTf)3  xH2O (Scheme 6.17) [41,47,48].

Scheme 6.17

6.2.4 Cerium-assisted synthesis The addition of protonated formaldehyde (derived from paraformaldehyde-hydroxy ketone and poly(styrenesulfonic acid)/H2O under MW exposure) to ketone occurred. Then addition of another protonated formaldehyde molecule occurred to afford a diol that in turn attacked the third formaldehyde molecule to provide adduct that yielded the final product 1,3-dioxane after dehydration. Tetrahydropyrans are present in natural products such as polyether antibiotics, carbohydrates,

Six-membered O-heterocycles

303

and marine toxins. The direct stereoselective synthesis of tetrahydropyranol derivatives in ionic liquid was achieved using an aldehyde and a simple homoallyl alcohol in the presence of a catalytic amount of cerium triflate (Scheme 6.18) [49].

Scheme 6.18

6.2.5 Cesium-assisted synthesis This strategy was employed for the synthesis of epoxysilanes that were useful in α-lithiation reactions [50], formation of vinyl siloxanes under basic conditions [51
56], and also in ring-opening reactions using lithium diphenylphosphide [57], Grignards [58,59], or hydrides [60]. Silyl epoxides produced by epoxidation were also used in oxidation reactions to afford the aldehydes [61] and SN20 reactions in the case of silylated vinyloxiranes [62]. Trimethylsilylated epoxides containing a three methylene and tethered hydroxy group were used in boron trifluoride-promoted internal cyclizations to give the tetrahydropyrans [63]. Interestingly, when Lewis acid was used, diepoxide was obtained in a ladder polyether fashion, whereas the more interesting natural product bearing tetrahydropyran dyad was produced after treatment of compound with cesium carbonate (Scheme 6.19) [64]. The triepoxides also underwent boron-trifluoride epoxide oxacyclization to afford the bis-oxepanes [65].

Scheme 6.19

6.2.6 Chromium-assisted synthesis Paterson and Tudge [66,67] synthesized leucascandrolide A using Jacobsen’s asymmetric hetero-Diels
Alder reaction with aldehyde and siloxydiene, forming 2,6-cis-tetrahydropyran-4-one that was reduced with sodium borohydride to afford the C5 equatorial alcohol (Scheme 6.20).

304

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.20

The C9 and C11 stereochemistry was controlled with a boron-assisted aldol reaction through 1,5-anti stereoinduction. Instead of setting the requisite C17-(R) alcohol stereochemistry in the natural product, subjecting the ketone to LiAlH(Ot-Bu)3 resulted in the synthesis of C17-(S) alcohol with superior stereocontrol ( . 32:1 dr). Later, Mitsunobu macrolactonization occurred effectively to set the C17-(R) configuration via inversion.

6.2.7 Cobalt-assisted synthesis The tetrahydronaphthyridines were prepared by reacting dialkynenitriles under microwaves in the presence of CpCo(CO)2 catalyst. Interestingly, tantalum [68] was used in cycloaddition reaction of alkynes and alkynenitriles to form the pyridines. However, this cycloaddition reaction was used for only one substrate and the reaction needed tantalum hexachloride in stoichiometric amounts. With all these transition metals being used in the cycloaddition reactions, there was a need to use environmentally

Six-membered O-heterocycles

305

less-toxic, cost-effective, and easily available metal salts. Therefore an effective and mild catalyst system for the cycloaddition of alkynenitriles and alkynes was highly desired (Scheme 6.21).

Scheme 6.21

6.2.8 Copper-assisted synthesis Evans and coworkers [69] reported the first examples of heteroDiels
Alder reaction of unsaturated carbonyl compounds like acyl phosphonate with electron-rich heterodienophiles in the presence of chiral bis (oxazolines)/copper(II) complex catalyst. Dihydrofuran and its enantiomer were, respectively, formed in 93% ee using either the (S,S)-Cu(SbF6)2 or (S,S)-Cu(SbF6)2 catalysts (Scheme 6.22) [70].

Scheme 6.22

Fuerstner and Stimson [71] prepared aza-bicycles from starting material via the cyclization of α,β-unsaturated carbonyl with alkyne in the presence of copper(I) catalyst under hetero-Diels
Alder reaction conditions (Scheme 6.23) [72].

306

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.23

The hetero-Diels
Alder reaction of various types of electron-rich alkenes and various unsaturated acyl phosphonates afforded cycloadducts with excellent enantio- and stereoselectivities and in high yields when bis (oxazoline)/copper(II) catalysts were used. Generally, better ee’s and endo/ exo-selectivities were obtained using bis(oxazoline)/Cu(OTf)2 catalysts than with bis(oxazoline)/Cu(SbF6)2 catalysts (Scheme 6.24) [70,73].

Scheme 6.24

These enantioselective reactions were catalyzed with (S,S)-Cu(SbF6)2 and their stereochemical course accounted for the intermediacy of a distorted square planar bis(oxazoline)/copper(II)/substrate complex rather than by a tetrahedral bis(oxazoline)/copper(II)/substrate complex. The substrate undergoing activation must be capable of bidentate coordination to the chiral Lewis acid for the achievement of high enantioselectivity (Scheme 6.25) [70,74].

Scheme 6.25

The hetero-Diels
Alder reaction of acyl phosphonates was carried out with silyl enol ethers obtained from acetophenone. A mixture of Michael adduct and dihydropyrans was formed upon cycloaddition of crotylphosphonate with ene. The endo-isomer was formed preferentially using (S, S)-Cu(SbF6)2. In contrast to the results obtained with mono-substituted

Six-membered O-heterocycles

307

enol ethers, the same major enantiomers were obtained with (S,S)-Cu (SbF6)2 catalysts. While alteration of reaction conditions (temperature, solvent) did not influence the product distribution, the change of silyl group in silyl enol ether, such as the exchange of a trimethylsilyl group to a tertbutyldimethylsilyl group, modified the ratio of Michael adduct and cycloadducts (Scheme 6.26) [70,75].

Scheme 6.26

When the bulkier silyl group (i.e., tert-butyldimethylsilyl group) was used, the silyl transfer to a putative copper(II) enolate retarded and the formal cycloaddition pathway became dominant. This result implicated a nonconcerted process for the cycloadditions of this heterodienophile (Scheme 6.27) [70,75].

Scheme 6.27

Evans and coworkers [75] developed an inverse electron demand hetero-Diels
Alder reaction of α,β-unsaturated carbonyl compounds with

308

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

ethyl vinyl ether in the presence of C2- symmetric bis(oxazoline)
copper (II) complex to give the chiral dihydropyrans in high enantio- and diastereoselectivities (Scheme 6.28).

Scheme 6.28

This hetero-Diels
Alder reaction was extended to unsaturated ketoester with various electron-rich dienophiles. In catalytic hetero-Diels
Alder reactions, unsaturated ketoesters were somewhat more reactive than unsaturated acyl phosphonates [76]. Generally, high enantio- and diastereoselectivities and good yields were obtained for the hetero-Diels
Alder adducts in the presence of (S,S)-Cu(OTf)2 catalyst (Schemes 6.29
6.33) [70].

Scheme 6.29

Scheme 6.30

Scheme 6.31

Six-membered O-heterocycles

309

Scheme 6.32

Scheme 6.33

The α,β-unsaturated keto-ester and dienophile were reacted in the presence of catalysts such as (1R,2S)-Cu(OTf)2 to synthesize the dihydropyrans in high ee’s (Scheme 6.34) [70,77].

Scheme 6.34

The dienophile supported on solid-phase and the (1R,2S)-Cu(OTf)2 complex afforded the adducts in good-to-excellent ee’s (86%
98%) (Scheme 6.35) [70,77].

Scheme 6.35

310

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Carbohydrates possessing nitrogen atoms were prepared from γ-amino-protected unsaturated keto esters. The hetero-Diels
Alder adduct, precursor to aminosugars, was synthesized with high enantio- and diastereoselectivity in good yield and with full control of the stereocenter bearing the amino group from starting substrate and alkene in the presence of (S,S)-Cu(OTf)2 (Scheme 6.36) [70,78].

Scheme 6.36

A library of substituted dihydropyrans was constructed for proteinbinding assays by hetero-Diels
Alder reaction of unsaturated ketoesters catalyzed by (R,R)-Cu(OTf )2. Furthermore, both the C35
C40 fragment and the E ring of the (1)-azaspiracid-1 were prepared by a heteroDiels
Alder reaction of electron-rich olefin using (S,S)-Cu(OTf)2  2H2O complex as the catalyst to produce the pyran with good enantio- and diastereoselectivity (Scheme 6.37) [70,79].

Scheme 6.37

Unsaturated ketooxazolidinones were not considered as good dienes, as when electron-rich olefin and unsaturated keto-oxazolidinones were treated with (S,S)-Cu(SbF6)2, adduct was formed in only 6% yield; the Mukaiyama
Michael product was the major compound (79% yield) (Scheme 6.38) [70,80].

Six-membered O-heterocycles

311

Scheme 6.38

Hetero-Diels
Alder reactions were performed in an intramolecular manner. Wada and coworkers [81,82] published many articles on this subject. The hetero-Diels
Alder compounds with an effective kinetic resolution were obtained by an enantioselective reaction of methyl (E)-4methoxy-2-oxo-(3-butenoate) with (rac)-6-methyl-5-hepten-2-ol. At 278 °C, high enantioselectivities (97%) and high diastereoselectivities (de) (86%) were observed in the presence of molecular sieves 5 Å and (S,S)Cu(SbF6)2 (Scheme 6.39) [70].

Scheme 6.39

The N-arylimines reacted with nucleophilic olefins in heteroDiels
Alder reactions to provide easy access to substituted tetrahydroquinolines. The hetero-Diels
Alder reaction of N-benzylidene-anilines and dihydropyran occurred in the presence of cupric bromide as a Lewis acid at room temperature in acetonitrile to synthesize the pyranotetrahydroquinoline adducts in poor-to-good yields (46%
76%). Mixtures of trans- and cis-isomers were obtained in ratios that varied from 38/62 to 21/79 depending on the substituents (Scheme 6.40) [70,83].

312

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.40

Elaiolide is the aglycon of elaiophylin, a 16-membered macrolide with antihelminthic and antimicrobial activities isolated from cultures of Streptomyces melanosporus. Mono-substituted vinyltin derivatives underwent Cu-mediated coupling reactions for the total syntheses of complex natural products. Natural products containing a C2 symmetric structure were efficiently synthesized by Cu-mediated cyclodimerization as reported by Paterson as early as 1997, in the first report on the use of CuTC in the context of total synthesis (Scheme 6.41) [84]. The macrocyclic C2 symmetric core of elaiolide was prepared by CuTC-mediated cyclodimerization of vinylstannane, which simultaneously created C3C4 and C30 C40 bonds in high yield for 15 min at room temperature. The effect of concentration was observed as more dilute conditions (0.01 M) provided higher selectivity in favor of the cyclodimer [85,86].

Scheme 6.41

Six-membered O-heterocycles

313

The majority of hetero-Diels
Alder reactions involving aldehydes have concentrated on asymmetric catalysis. Johannsen and Jørgensen [87] reported that chiral C2-symmetric bis(oxazoline)/copper(II) complexes served as efficient catalysts for hetero-Diels
Alder reaction of alkyl glyoxylates and 1,3-dienes to afford the ene compounds and heteroDiels
Alder adducts in high yields, with excellent ee’s. The ene product/ hetero-Diels
Alder adduct ratio depends on the chiral ligands bound to Cu. For example, the methyl glyoxylate was reacted with 2,3-dimethylbutadiene at 20 °C in the presence of Cu(OTf)2 catalyst to afford the ene adduct and hetero-Diels
Alder adduct in a ratio of 1/0.6 to 1.0/1.8 (Scheme 6.42) [70].

Scheme 6.42

A diverse array of substituted cyclic and noncyclic conjugated 1,3dienes was involved in hetero-Diels
Alder reactions with alkyl glyoxylates. In the case of noncyclic substituted dienes, the heteroDiels
Alder adducts were formed with good ee’s and in modest yields along with ene-adducts when the hetero-Diels
Alder reaction was catalyzed by complexes of copper(II). In contrast, the yields of heteroDiels
Alder adducts were good and the ene-adducts were not formed in the case of cyclic 1,3-dienes such as 1,3-cyclohexadienes (Scheme 6.43) [87]. Most of the studies of oxa-Diels
Alder reactions involved 1,3-cyclohexadiene [70]. Paterson [88] reported a remarkably efficient CuTC-promoted intermolecular coupling of substrate with complex vinyl iodide for the total synthesis of concanamycin F (Scheme 6.44). The desired 1,3-diene was formed in an excellent yield (89%) under mild reaction conditions, in contrast to palladium(0)-catalyzed conditions (20%) [86].

314

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.43

Scheme 6.44

The vinyltin motif was substituted by a heteroatom, such as sulfur. Joule and coworkers [89,90] reported that the vinyltin derivative was cross-coupled to 6-iodopteridin-4-one in the presence of CuTC promoter to afford an intermediate in moderate yield (Scheme 6.45). The intermediate was converted into pyran, the (masked and protected) organic ligand of oxomolybdoenzymes cofactor [86].

Six-membered O-heterocycles

315

Scheme 6.45

6.2.9 Europium-assisted synthesis Resin-bound dienophiles i.e., carboxypolystyrene-bound vinyl ether of 1,4-butanediol and heterodienes containing trifluoromethyl, methyl ester, and p-tolylsulfinylmethyl groups at the C-2 position underwent an efficient, endo-selective hetero-Diels
Alder reaction under Lewis acid conditions. The supported adducts were cleaved reductively to afford the functionalized dihydropyrans, which are particularly interesting for combinatorial synthesis (Schemes 6.46
6.48) [91].

Scheme 6.46

316

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.47

Scheme 6.48

Koch and coworkers [92] first developed solid-phase synthesis of 3,4-dihydropyran, which involved the Knoevenagel transformation of a polystyrene resin-linked acetoacetate into an α,β-unsaturated ketone (an oxabutadiene) that underwent inverse electron demand Diels
Alder cycloaddition. The resin-bound heterodiene was formed by esterification of the free hydroxyl groups of a Wang resin with benzylidenepyruvic acid in diisopropylcarbodiimide. The formed resinbound heterodiene was reacted with various soluble electron-rich dienophiles in Eu(fod)3-catalyzed [4 1 2]-heterocycloadditions. The epimeric mixtures of primary allylic alcohols endo- (major epimer) and exo-products were formed in high overall yields by reductive cleavage of heterocycloadducts using lithium aluminum hydride in ether/tetrahydrofuran at 20 °C, followed by mild hydrolysis with aq. sodium sulfate (Scheme 6.49).

Six-membered O-heterocycles

317

Scheme 6.49

6.2.10 Indium-assisted synthesis One-pot multicomponent reactions have recently gained steady and considerable increasing economic, academic, and ecological interest because they address fundamental principles of reaction design and synthetic efficiency [93
95]. Additionally, the prospect of extending one-pot reactions into SPS and combinatorial [96] promised many opportunities for developing novel lead structures for catalysts and pharmaceuticals. In continuation of it on indium(III) chloride-catalyzed reactions [97
100] and surface solid state reactions coupled with microwave irradiation, [101,102] an efficient and simple protocol for the synthesis of new spiropyran-based indolines through the three-component condensation of malononitrile, isatin, and α-naphthol/β-naphthol/1-phenyl-3-methylpyrazolon-2-one/4-hydroxy coumarin using indium trichloride impregnated silica gel as a catalyst under solvent-free conditions was reported (Scheme 6.50).

Scheme 6.50

6.2.11 Iodine-assisted synthesis The Claisen
Schmidt condensation of 3-acetyl-tropolone and terephthalaldehyde provided the substrate. The cyclization of 3,30 -{1,4-phenylenebis

318

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

[(1E)-3-oxoprop-1-ene-1,3-diyl]} bis(tropolone) iodine/dimethylsulfoxide/ sulfuric acid system afforded a facile synthesis of 1,4-phenylene bridged bispyrano-fused tropone compounds (Scheme 6.51) [103].

Scheme 6.51

Mohapatra et al. [104] synthesized trans-2,6-disubstituted-3,4-dihydropyrans when δ-hydroxy-α,β-unsaturated aldehydes were treated with allyltrimethyl silane in the presence of 10 mol% I2 (Scheme 6.52). The oxonium intermediate was formed upon nucleophilic attack of hydroxyl group on activated carbonyl carbon followed by expulsion of trimethyl silyl hydroxide. The final products were produced by initial attack on the trimethyl silyl group to provide a nucleophile that attacked the oxonium intermediate [105].

Scheme 6.52

Xie et al. [106] synthesized poly-substituted 3-iodopyrans from alkynyl carboxamides (Scheme 6.53). The products were formed by formation of iodoirenium intermediate followed by intramolecular nucleophilic attack of the oxygen of carboxamide group in 6-endo-dig fashion and subsequent de-protonation. The yields increased significantly and the reaction times decreased when electron-withdrawing groups were present on N-aromatic ring [105].

Six-membered O-heterocycles

319

Scheme 6.53

Larock et al. [107] reported 6-endo-dig and 5-exo-dig cyclization, respectively, from o-alkynylbenzyl alcohols for the synthesis of five- and six-membered iodo heterocycle (Scheme 6.54). The iodoirenium intermediate was formed when iodine coordinated with carbon
carbon triple bond. Nucleophilic attack by the hydroxyl group occurred by 6-endo-dig and 5-exo-dig cyclization to afford an intermediate [105].

Scheme 6.54

Yadav et al. [108] synthesized 4-iodotetrahydropyran derivatives by I2mediated Prins cyclization (Scheme 6.55). The diastereomers were afforded in excellent yields when homoallylic alcohols were treated with aldehydes in the presence of I2. The synthesis of products was explained by the formation of hemiacetal by hydrogen iodide produced in situ during the reaction and subsequent dehydration followed by Prinscyclization. The cis-homoallylic alcohols provided products with all cis configuration while trans-homoallylic alcohols afforded products with trans-trans-configuration. The reaction worked very well with a variety of aldehydes such as cyclic, aliphatic, and aromatic. The unsubstituted homoallylic alcohols also give the corresponding products [105].

Scheme 6.55

320

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

This method [109] is simple for the synthesis of 4-iododihydropyrans using silylalkyne-Prins cyclization [110
112]. The reaction was initiated via an acetal formation by hydrogen iodide produced in situ that was attacked by homopropargylic alcohols to afford an oxocarbenium ion intermediate. The oxocarbenium ion intermediate underwent Prinscyclization to afford the β-carbocation that was subsequently trapped by iodide ion to produce the 4-iododihydropyrans (Scheme 6.56) [105].

Scheme 6.56

Jung and coworkers [113] reported a one-pot I2-mediated domino Knoevenagel-6π-electrocyclization reaction of 1,3-dicarbonyl compounds and 3-methyl-2-butenal for the synthesis of 2H-pyrans. The angular products were formed in good-to-excellent yield (Scheme 6.57) [105].

Scheme 6.57

6.2.12 Iron-assisted synthesis A small amount of regioisomers and/or [4 1 2] ene products was formed in these reactions. The trans-disubstituted cyclopentanes were formed regardless of the stereochemistry at C-2 when 2-substituted triene esters were used [114]. In addition, when substituted triene ethers were used in order to generate three contiguous chiral centers, the reaction showed excellent stereocontrol [115,116]. Only [4 1 4] reaction occurred with starting substrate and a tetrahydropyran with trans configuration was obtained. Other cis and trans isomers were present in less than 1% each (Scheme 6.58). The selectivity of this reaction depends on the substrate configuration and on the ligand. With (E,E) isomer of starting substrate, a

Six-membered O-heterocycles

321

mixture of trans products resulting from [4 1 4] and [4 1 2] reactions were obtained with the latter as major product (6:94). An inversion of selectivity was observed (Scheme 6.59) [117].

Scheme 6.58

Scheme 6.59

A nonasymmetric hetero-Diels
Alder reaction was performed. Among all the iron-carboxylate complexes tested, Fe(III) 2ethylhexanoate was found to be the most efficient one (Scheme 6.60) [118,119].

Scheme 6.60

An iron-catalyzed thermodynamic equilibration of 2-alkenyl 6-substituted tetrahydropyrans was the key step of highly diastereoselective and an ecofriendly synthesis of substituted cis-2,6-tetrahydropyrans that allowed the isolation of enriched mixtures of the most stable cis-isomers (Scheme 6.61) [120].

Scheme 6.61

322

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

6.2.13 Lanthanum-assisted synthesis After solving the issue of 5-exo-selective hydroalkoxylation, the more intricate heterocyclizative problem associated with tuning of the regioselectivities of allenols was next examined. One of the challenges for modern synthesis was to create distinct types of complex molecules from identical substrates based solely on catalyst selection. The allenol was subjected to an lanthanide amide-catalyzed approach to afford the dihydropyran (Scheme 6.62), and the nucleophilic attack occurred at the central allene carbon atom via 6-endo-cyclization [121
123]. In addition, partial epimerization was reported through the isolation of epim.

Scheme 6.62

The 6-endo-mode of cyclization was preferred over the favored 5-exomode in the presence of both La(OTf)3 and H2O to afford the tetrahydropyrans mainly [124,125]. Anhydrous La(OTf)3 or BF3.OEt2 provided tetrahydrofuran as the sole product. CeCl3 increased the synthesis of tetrahydropyran, albeit in low yield, and the major product was ring-opened product by chloride. However, the selectivity for La(OTf)3-promoted reaction was reversed and tetrahydropyran was dominant at a longer reaction time in the presence of H2O (1.1
2.2 eq.). The influence of H2O was less pronounced in solvents other than dichloromethane. Biomimetic successive ring-closure reactions also proceeded under similar reaction conditions (Schemes 6.63 and 6.64) [126]. The α-alkoxy alcohols were formed with high stereo- and regioselectivity in good-to-high yields by Yb(OTf)3-catalyzed intermolecular ring-opening reactions of epoxides with alcohols [127,128].

Six-membered O-heterocycles

323

Scheme 6.63

Scheme 6.64

6.2.14 Molybdenum-assisted synthesis Grubbs et al. [129,130] evaluated the limitation and scope of this reaction and synthesized five-, six-, and seven-membered ring unsaturated O-heterocycles from acyclic dienes (Scheme 6.65) [117].

Scheme 6.65

324

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The development of chiral olefin metathesis catalysts is one of the most important advances in this field. Hoveyda and coworkers [131
135] developed a chiral molybdenum-catalyzed asymmetric olefin metathesis. For example, the enantioselective olefin metathesis of allyl cycloalkenyl ethers in the presence of chiral molybdenum catalyst afforded unsaturated cyclic tertiary ethers in high chemical yields with very high enantiomeric excess values (Scheme 6.66) [136].

Scheme 6.66

Two more recent instances, where chiral olefin metathesis catalysts act to address issues other than product enantiomeric purity, are shown in Schemes 6.67 and 6.68. Chiral complex rac promoted the ring-closing metathesis of enyne readily to provide the diene exclusively [137], no five-membered ring diene was formed predominantly by reactions with Ru carbene [138
140]. In another example, an exceptionally Z-selective ( . 98: , 2 Z:E) ROCM of oxabicycle and styrene was promoted with chiral molybdenum complex [141,142].

Scheme 6.67

Scheme 6.68

Six-membered O-heterocycles

325

6.2.15 Nickel-assisted synthesis The oxa-, carbo-, and azacycles as products were formed efficiently in high yields from unsaturated alkyl halides by a convenient and mild freeradical cyclization of organohalides in the presence of a nickel chloride  dimethoxyethane/pybox complex as a catalyst and Zn powder in methanol (Scheme 6.69) [143].

Scheme 6.69

Firstly Inoue et al. [144
146] and further Tsuda et al. [147
152] developed a Ni/phosphine-catalyzed coupling of two alkynes with carbon dioxide to provide the pyrones. These reactions generally required elevated temperatures and high pressures of carbon dioxide. In addition, only a limited number of diynes were successfully converted into pyrone. As with many cycloaddition reactions, oligomerization of diyne was a major side reaction. These obstacles overcome when IPr was used as a ligand in lieu of phosphines [153]. The oligomerization of diyne was suppressed with the steric bulk of this ligand. As a result, high yields of various bicyclic pyrones were obtained. Notably, all pyrones were formed using relatively low reaction temperatures and ambient pressures. Nickel/IPr served as a general catalyst system for the coupling of diynes and carbon dioxide. To date, this catalyst has not provided pyrones from either sterically hindered diynes or terminal diynes. Terminal diynes oligomerized at a faster rate than carbon dioxide incorporation. In contrast, sterically hindered diynes did not react under any conditions (elevated pressure and temperature). Asymmetrical diynes, including diynes bearing one sterically demanding substituent, underwent clean conversion into pyrones [154]. However, one isomer was preferentially formed and the regioselectivity of reaction improved as the relative difference increased between the two terminal groups. Furthermore, only one regioisomer was afforded when a diyne possessing a very bulky group (such as trimethylsilyl or tert-butyl) and a methyl group was used (Scheme 6.70).

326

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.70

An efficient catalytic protocol was developed for the preparation of condensed thiazolo[5v,4v:50 ,60 ]pyrano[40 ,30 :3,4]furo[2,3-b]indole and spiro[indoline-3,40 -pyrano[2,3-c]thiazolecarbonitriles derivatives by a one-pot three-component reaction involving activated methylene reagent, substituted 1H-indole-2,3-diones, and 2-thioxo-4thiazolidinone under microwave irradiation. This reaction described the synthesis of novel condensed and spiro indole derivatives using NiO nanoparticles as catalyst in absolute ethanol by Knoevenagel condensation followed by Michael addition. The reaction was performed in the absence of any catalyst in order to confirm the effective involvement of NiO nanoparticles. Without NiO nanoparticle, the reaction was incomplete even after 30 min of microwave irradiation, although a small amount of compound was observed. The reaction was conducted under conventional heating without any catalyst to verify the specific effect of microwaves. The compound was formed in 25%
35% yields by refluxing for 30 h while the compound was obtained in 32%
40% yields under microwave irradiation for 30 min (Scheme 6.71) [155].

Scheme 6.71

Six-membered O-heterocycles

327

6.2.16 Osmium-assisted synthesis Leighton and Kozmin generated a molecule using consecutive cyclizations on a linear precursor. Myers' alkylation of iodide with (2)-pseudoephedrine propionamide set the C12 methyl stereocenter. The methyl stereocenter was treated with acid to afford a lactone that was subsequently converted to aldehyde. Coupling of aldehyde and enol ether, which was prepared from 3-(tri-iso-propylsilyloxy)propanal in eight steps, with BF3  Et2O in the presence of 2,6-di-tert-butylpyridine as a proton scavenger resulted in simultaneous formation of intermediate with moderate diastereoselectivity (5.5:1 ratio of C9 alcohols). A cis-tetrahydropyran ring was formed exclusively when intermediate oxocarbenium ion was trapped internally with allylsilane in a Prins-type reaction. The final product was obtained by a series of straightforward transformations including a stereoselective reduction of C5 ketone (Scheme 6.72) [156,157].

Scheme 6.72

6.2.17 Platinum-assisted synthesis The heterocyclic compounds were constructed when simple enynes were reacted with platinum chloride catalyst in alcohol or H2O (Scheme 6.73)

328

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

[158,159]. In most cases, this reaction occurred preferentially to the Pt (II)-catalyzed addition of MeOH to the alkyne to synthesize the ketones or acetals [160
166].

Scheme 6.73

Blum et al. [167] synthesized oxabicyclo[4.1.0]heptene in 97% yield upon treatment of enyne with 5 mol% platinum(IV) chloride (Scheme 6.74). The product was formed as a single diastereomer. The X-ray crystallography of naphthyl-substituted cycloisomerization product confirmed its relative stereochemistry and structure. The relative stereochemistry corresponded to a stereospecific cyclopropanation of E-alkene. Indeed, a 4:1 mixture of cyclopropanes was obtained when a 4:1 mixture of E:Z-alkene isomers was subjected to reaction conditions [168].

Scheme 6.74

The course of reaction was affected dramatically depending on the substitution pattern of enyne. Substituted enynes delivered cyclopropanes and Alder-ene product without any enyne metathesis products (Scheme 6.75) [169].

Scheme 6.75

Six-membered O-heterocycles

329

6.2.18 Rhodium-assisted synthesis Tanaka and coworkers [170] reported that the intermolecular [2 1 2 1 2]cycloaddition of N-tethered 1,6-enynes with electron-deficient ketones in the presence of cationic rhodium(I)-(R)-H8-BINAP complex catalyst afforded fused dihydropyrans possessing two quaternary carbon centers with excellent diastereo-, regio-, and enantioselectivity (Scheme 6.76). The o-functionalized aryl ketones were obtained with excellent enantioand regioselectivity when electron-rich aryl ketones were reacted with 1,6-enynes in the presence of same catalyst [72].

Scheme 6.76

Andrus and Argade [171] synthesized tetrahydropyran in a single step from starting material by hydroformylation (Scheme 6.77). This extraordinarily facile method afforded lactol in 90% yield [172,173]. The formed intermediate was exposed to bismuth bromide and allyl trimethylsilane at room temperature to produce the tetrahydropyranyl alcohol in nearly quantitative yield as a single stereoisomer within 20 min.

Scheme 6.77

330

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The hydroacylation product was formed as suggested by time-resolved NMR experiments and mass spectrometry, but dimerized quickly (most probably via an intermolecular hetero-Diels
Alder reaction) [174] to form the target compound, especially at elevated temperatures (Scheme 6.78). The ability of these compounds to dimerize was what led to the development of the tandem hydroacylation-Michael addition reaction initially.

Scheme 6.78

Lopez-Herrera and Sarabia-Garcia [175] prepared 2-deoxy-α-KDO involving Rh-catalyzed intramolecular O
H insertion of intermediate as a key step, which afforded the final product in 96% yield (Scheme 6.79).

Scheme 6.79

Various acyclic enynes were converted to their cyclic diene isomers with endo-selectivity by Rh-catalyzed cycloisomerization. Two different catalyst systems were evaluated, which were effective for the promotion of carbon
carbon bond-forming cyclization of enynes to afford the hetero- and carbocyclic compounds in good-to-excellent yield (Scheme 6.80) [176].

Six-membered O-heterocycles

331

Scheme 6.80

6.2.19 Silver-assisted synthesis Gallagher [177] reported a highly diastereoselective preparation of cis-2,6disubstituted tetrahydropyrans involving a probable transition state chair conformation of substituted δ-allenic alcohols (Scheme 6.81) [178].

Scheme 6.81

Inter- and intramolecular alkyne-carbonyl coupling was reported using cationic Ag (AgSbF4) as a catalyst (Scheme 6.82) [179].

Scheme 6.82

Gore et al. [180] reported an elegant preparation of perhydrofuropyrans or perhydrofurofurans from allenic diols. One or the other bicyclic ketal was formed as single cis diastereoisomers depending on the chain length between the allenic moiety and the hydroxyl group (Scheme 6.83). However, the dihydropyrans were also produced, indicating that coordination and thus cyclization also occurred on the other (terminal) double bond for such allenes [178].

Scheme 6.83

332

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Various natural products and analogs were synthesized by silverassisted cyclization of allenic alcohols. Citreoviridin, verrucosidin, and their metabolite citreal were generated from dihydroxyallene via silverpromoted stereoselective cyclization (Scheme 6.84) [178,181].

Scheme 6.84

As a first strategy toward the construction of cembranoid eunicin, Agmediated cyclization of a suitably functionalized allene was used for controlling the stereochemistry in the synthesis of tetrahydropyran ring (Scheme 6.85). The trans bicyclic dihydro-2H-pyran present in the

Scheme 6.85

Six-membered O-heterocycles

333

tricyclic framework of eunicins was prepared from 3-ethynylglucose derivative after diastereoselective synthesis of an allene through addition of pentenylmagnesium bromide, and AgNO3-promoted cyclization [178,182]. The silver-catalyzed cyclization of phosphonato-allenic alcohols provided unsaturated analogues of nucleosides (Scheme 6.86) [183]. Either a mixture of dihydropyrans and furans or dihydropyrans was formed depending on the substitution of allenic moiety [178].

Scheme 6.86

The o-alkynyl formylquinolines were cyclized in the presence of various Ag salts. Surprisingly, either the 6-endo-product or the 5-exo-dig product or both were formed depending on the Ag counterion (Scheme 6.87) [178,184].

Scheme 6.87

A hydroxylated ynone was cyclized in the presence of Ag triflate for the synthesis of a trioxadispiroketal unit of phosphatase inhibitor spirastrellolide A (Scheme 6.88) [185]. The modest yield was obtained and a side reaction occurred on another part of the molecule, affording a furan sidechain [178].

334

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 6.88

Intramolecular additions of carboxylic acids and alcohols to inert olefins occurred with Ag triflate. δ-Alkenyl alcohols provided 5-exo-trig product as the only or the major product, except with terminal phenylalkenes and trisubstituted alkenes, the reaction following 6-endo-trig process (Scheme 6.89). For alkenyl acids, the cyclization mode depends on the substituents and the chain length. This process offered one of the simplest methods to form the lactones or cyclic ethers in good yields. The Ag-mediated addition of nucleophiles to alkenes has been much less studied, as the reaction with inactivated alkenes has only been achieved with good yields in recent years. The addition of nucleophiles to alkenes activated with I2 or selenium compounds is also known, as is the Agmediated addition of nucleophiles to alkenes with an allylic leaving group. Intramolecular additions of carboxyl or hydroxyl groups to inert olefins in the presence of Ag(I) triflate catalyst in 1,2-dicholoethylene is one of the newest and simplest protocols to form the lactones or cyclic ethers using Ag-mediated chemistry [186,187].

Scheme 6.89

Olsson and Claesson [188] synthesized 2,5-dihydrofurans and 5,6dihydropyrans by 5-endo-trig cyclization of allenic alcohols and 6-endo-trig cyclization of allenic alcohols, respectively (Schemes 6.90 and 6.91). On the other hand, γ0 -allenic diols were converted into an equimolecular mixture of dihydropyrans when R1 was hydrogen and were selectively converted into dihydropyrans when R1 was an alkyl group (Scheme 6.92) [187,189].

Six-membered O-heterocycles

335

Scheme 6.90

Scheme 6.91

Scheme 6.92

The 2,5-disubstituted tetrahydrofurans were synthesized with a high degree of stereocontrol by ring-contraction of bromotetrahydropyrans in the presence of Ag tetrafluoroborate in acetone (Scheme 6.93) [190,191]. The opposite transformation was also described, as in the treatment of dihydrofuran with silver carbonate to afford the final product [187,192].

Scheme 6.93

336

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

6.2.20 Titanium-assisted synthesis The carbo- and heterocycles possessing quaternary centers adjacent to tertiary or secondary centers were generated by an intramolecular iodo-aldol cyclization of prochiral α-substituted enoate ketones and aldehydes. The reactions proceeded in good yields and were highly trans-selective with iodomethyl and hydroxyl groups on opposite faces of the ring system (Scheme 6.94) [193].

Scheme 6.94

6.2.21 Tungsten-assisted synthesis Many photochemically supported tungsten carbonyl-catalyzed reactions have been reported. The alkyne derivative was converted either into the metal carbine or into the metal vinylene intermediates (Scheme 6.95). These compounds afforded cyclic enolether, which was further converted into substructures of altromycin B, a pluramycin antibiotic [194,195].

Scheme 6.95

6.2.22 Ytterbium-assisted synthesis The Yb(OTf)3 efficiently catalyzed the carbonyl-ene reactions of simple alkenes and glyoxylates [196,197]. Other Ln(OTf)3 were also effective catalysts, while lanthanide(III) chlorides and alkoxides did not promote

Six-membered O-heterocycles

337

the reaction. 2-Methyl-1,3-butadiene (isoprene) reacted with glyoxylate to form an ene product and a hetero-Diels
Alder product [198]. The hetero-Diels
Alder adduct was obtained as a major product by Yb (OTf)3-catalyzed reaction of isoprene with a glyoxylate in CH3CN (Scheme 6.96). In contrast, the ene product was formed preferentially in dichloromethane. Chiral ytterbium catalysts formed from chiral ligands (pybox derivatives or 1,1'-bi-2-naphthol derivatives) and Yb(OTf)3 were used in an asymmetric carbonyl-ene reaction [128].

Scheme 6.96

6.2.23 Zinc-assisted synthesis Biologically active molecules like insect [199] or mammal [200] pheromones are constructed conveniently by intermolecular Diels
Alder reactions of chiral 3-sulfinyloxabutadienes. Indeed, when opposed to electron-rich dienophiles, this new type of heterodienes formed dihydropyran adducts that provided glycoside analogues. Wada and coworkers [201] developed a strategy for the synthesis of various heterodienes in good yields. Inverse electronic demand Lewis acid-catalyzed [4 1 2]cycloadditions using vinyl ethers and sulfides provided dihydropyran adducts with moderate facial selectivity and good endo-selectivity. The adducts containing an allylic sulfoxide underwent [2,3]-sigmatropic rearrangement in the presence of a thiophilic agent like piperidine to afford the stable methylenehydroxypyrans. The hydroboration of methylenehydroxypyrans give 2,3-dideoxy-3-alkylglycosides. Moreover, some alkylidene pyruvic acid esters and heterodienes have been successfully tested with solid-supported vinyl ether under Lewis acid conditions (Scheme 6.97).

Scheme 6.97

338

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Allylic Zn species were successfully employed in intramolecular “Znene” reactions. After the transmetalation of an appropriate allylic magnesium derivative with zinc bromide, Klumpp et al. [202] prepared various N- and O-heterocycles (Scheme 6.98).

Scheme 6.98

This reaction was used for the synthesis of different heterocyclic compounds. Thus the cyclic organozinc species were formed by lithium chloride-mediated direct Zn insertion to allylic chloride at 25 °C within 40 h. Likewise, tetrahydro-2H-pyran derivative was generated from allylic chloride in 65% yield (dr 5 93:7) (Scheme 6.99) [203,204].

Scheme 6.99

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[181] J.A. Marshall, K.G. Pinney, Stereoselective synthesis of 2,5-dihydrofurans by sequential SN2' cleavage of alkynyloxiranes and silver(I)-catalyzed cyclization of the allenylcarbinol products, J. Org. Chem. 58 (1993) 7180
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1884. [183] V.K. Brel, V.K. Belsky, A.I. Stash, V.E. Zadovnik, P.J. Stang, Synthesis and molecular structure of new unsaturated analogues of nucleotides containing sixmembered rings, Eur. J. Org. Chem. 3 (2005) 512
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4556. [187] M. Alvarez-Corral, M. Munoz-Dorado, I. Rodriguez-Garcia, Silver-mediated synthesis of heterocycles, Chem. Rev. 108 (2008) 3174
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938. [199] P. Hayes, C. Maignan, Ready access to the 6,8-dioxabicyclo[3.2.1]octane ring system using asymmetric heterocycloaddition induced by a chiral sulfoxide: application to the total synthesis of the Mus musculus pheromone, Tetrahedron: Asymmetry 10 (1999) 1041
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[201] E. Wada, W. Pei, H. Yasuoka, U. Chin, S. Kanemasa, Exclusively endo-selective Lewis acid-catalyzed hetero-Diels-Alder reactions of (E)-1-phenylsuifonyl-3-alken2-ones with vinyl ethers, Tetrahedron 52 (1996) 1205
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1753.

CHAPTER 7

Six-membered O,O-heterocycles 7.1 Introduction Chromene derivatives are an important class of heterocycles, and are the chief components of many naturally occurring products. Generally, chromenes are used as cosmetic agents, food additives, and potential biodegradable agrochemicals [1a
c,2,3]. Recently, the synthesis of chromene derivatives has drawn more attention due to their pharmacological and biological applications. The chromene derivatives show various pharmacological properties such as anticancer, anticoagulant, anti-HIV, diuretic, antimalarial, antitumor, antibacterial, antileukemic, antimalarial, and antianaphylactic activities [4
12a
c]. Moreover chromene derivatives are components of several natural products like calanone, calanolides, and calophyllolides [13a
c]. In addition, they can be used as cognitive enhancers for the treatment of neurodegenerative disease, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, AIDS-associated dementia, and Down syndrome as well as for the treatment of myoclonus and schizophrenia. A number of chromene derivatives are valuable as photoactive materials [14]. Coumarin is a chemical compound found in many plants. It is appetite suppressant, bitter in taste, and is probably produced by plants as a defense chemical to discourage predation. Coumarin is used in the pharmaceutical industry as a precursor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to dicoumarol, notably warfarin and some even more potent rodenticides. All of these agents were historically discovered by analyzing sweet clover disease. Coumarin has clinical medical value by itself, as an edema modifier. Coumarin and other benzopyrones, such as 1,2-benzopyrone, 5,6-benzopyrone, diosmin, and others are known to stimulate macrophages to degrade extracellular albumen, allowing faster resorption of edematous fluids. Coumarin is also used as a gain medium in some dye lasers [15]. Coumarin and coumarin-related compounds have proved for many years to have significant therapeutic potential. They come from a wide variety of natural sources and new coumarin derivatives are being discovered or synthesized on a regular basis. Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00007-5

© 2020 Elsevier Inc. All rights reserved.

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Coumarin is a simple molecule and many of its derivatives have been known for more than a century. However, their vital role in plant and animal biology has not been fully exploited. It is evident from the research described that coumarin and coumarin-related compounds are a plentiful source of potential drug candidates in relation to its safety and efficacy [16].

7.2 Metal- and nonmetal-assisted synthesis of sixmembered oxygen-containing polyheterocycles 7.2.1 Aluminum-assisted synthesis The spirocyclic compounds are present in a number of pharmacologically relevant natural products having a spiro center that exhibit various biological activities; therefore their synthesis has become an interesting target [17
19]. Because of continuing interest in the preparation of naphtho [2,3-b]pyranoquinones with useful biological properties [20a,b], here some new derivatives with spiro center at C-2 of the heterocyclic ring were prepared. The 2,6-dihydroxyacetophenone was reacted with cyclopentanone employing Kabbe’s method [21] to provide the 2-spirochromanone in 80% yield. The 2-spirochromanone was reduced with lithium aluminum hydride and oxidized with (diacetoxyiodo)benzene to give the benzopyranoquinone (60%). The Diels
Alder reaction of quinone with piperylene, 1-(trimethylsilyloxy)-1,3-butadiene, and 1-methoxy-1,3cyclohexadiene afforded aromatized cycloadducts in 44%
65% yield (Scheme 7.1).

Scheme 7.1

The Lewis acid-catalyzed or thermal ene cyclization of various 4-aza1,7-dienes with activated enophile afforded the ene cyclization product, substituted piperidines, along with bicyclic lactones, formed via a competing hetero-Diels
Alder reaction (Schemes 7.2 and 7.3). A thermal ene cyclization was facilitated upon activation of enophile with a single ester, but the reaction was not amenable to Lewis acid catalysis. It was reported

Six-membered O,O-heterocycles

353

Scheme 7.2

Scheme 7.3

that the Lewis acid-catalyzed reaction was facile with other activating groups on the enophile, although there was a fine balance between the competing hetero-Diels
Alder reaction and the desired ene cyclization, with the product distribution being influenced by the nature of the ene component, activating group on the enophile, and the Lewis acid [22,23]. The 2-aminochromenes were synthesized from aromatic aldehydes, 1-naphthol, and malononitrile under microwave and solvent-free conditions employing catalytic efficacy of magnesium/aluminum hydrocalcite (Scheme 7.4) [24].

Scheme 7.4

7.2.2 Antimony-assisted synthesis The perfluoro-2-(but-2-en-2-yl)benzoic acid was obtained as a mixture of Z- and E-isomers when perfluoro-3-ethylindan-1-one was heated with SbF5 at 70 °C and then the reaction mixture was treated with water. A solution of salts of perfluoro-4-ethyl-1H-isochromen-1-yl cations and perfluoro-3,4-dimethyl-1H-isochromen-1-yl was obtained when the

354

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

reaction temperature was increased to 125 °C (7 h) [23]. The solution of salts was hydrolyzed to afford the perfluoro-4-ethyl-isochromen-1-one and perfluoro-3,4-dimethylisochromen-1-one, respectively. The formation of solution contained only a salt of cation perfluoro-3,4-dimethyl1H-isochromen-1-yl upon increasing the reaction time (86 h). Reaction of perfluoro-1-ethylindan as well as ketone with excess of silicon oxide at 75 °C in SbF5 medium formed a solution of a salt of 4-fluorocarbonylperfluoro-3-methyl-1H-isochromen-1-yl cation. The 4-fluorocarbonylperfluoro-3-methyl-1H-isochromen-1-yl cation was hydrolyzed to give the acid. A separate experiment has shown that a salt of cation practically did not react with silicon oxide even at 125 °C (Scheme 7.5).

Scheme 7.5

7.2.3 Barium-assisted synthesis An efficient protocol was developed for the synthesis of 3-arylidenechromen4-ones using a grinding technique under solvent-free conditions. The 3-arylidenechroman-4-ones were formed in high yield upon grinding of variously substituted chroman-4-ones with aromatic aldehydes at room temperature in the presence of anhydrous barium hydroxide. Products were formed by just acidification of the reaction mixture in ice cold water. Reaction in solid state, with high selectivity, enhanced rate, and manipulative simplicity were the attractive features of this environmentally benign

Six-membered O,O-heterocycles

355

method. The chroman-4-one derivatives needed for this reaction were obtained by polyphosphoric acid-catalyzed cyclization of phenoxypropanoic acids under MWI. The synthesis of 3-arylidenechroman-4-ones involved the condensation of chroman-4-ones with aromatic aldehydes in the presence of basic or acidic reagents. But for the condensation the use of acidic reagents was preferred usually as the chroman-4-one ring was more stable to acidic reagents. Use of bases like alcoholic sodium hydroxide, potassium hydroxide, piperidine, sodium methoxide, and acetic anhydride was also reported for the synthesis of these compounds. In a recent approach Amberlyst-15 was reported for this reaction under microwave irradiation. Ring-closure of an acrylic acid derivative with trifuoroacetic anhydride in CH2Cl2 medium was also a pathway for the preparation of 3arylidenechroman-4-ones. The chroman-4-ones needed for this reaction were prepared by a modified route involving the polyphosphoric acid-catalyzed cyclization of phenoxypropanoic acid under MWI (Scheme 7.6) [25].

Scheme 7.6

The flavanones were synthesized upon cyclization of 2-hydroxychalcones using triethylamine, a mild base, under MWI. The microwave energy accelerated the organic reactions and has many advantages over conventional heating. The substituted chalcones (precursors of flavanones) were prepared when suitable acetophenone was reacted with substituted benzaldehyde under MWI conditions using barium hydroxide as base. The flavanones were obtained by cyclization of these chalcones in the presence of triethylamine base under MWI (Scheme 7.7). For comparison, these flavanones were also synthesized by the usual conventional method. The

356

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.7

flavanones were formed within a few seconds upon microwave irradiation and otherwise were usually formed after 2
3 h by conventional method. The reaction rate enhanced considerably by this method, and provided products with improved yields (50% to 95%) and brought down the reaction time from hours to seconds [26].

7.2.4 Bismuth-assisted synthesis The Prins reaction of several styrenes and paraformaldehyde occurred with an efficient catalyst Bi(III) triflate. The reaction occurred at reflux in acetonitrile and furnished 1,3-dioxanes in good yields (Scheme 7.8) [27
29].

Scheme 7.8

The lactone group is an important moiety [30] present in several drugs like camptothecin, lovastatin, and other compounds, namely bufadienolides [31]. The intramolecular dehydrated six-membered lactone was formed in high yield by bismuth chloride/zinc-catalyzed Grignard-type addition of allyl bromide to 5-oxohexanoic acid (Scheme 7.9) [27,29,32]. Synthetic pathways to coumarins included the Knoevenagel reaction, the Pechmann reaction, and the Wittig reaction. The Pechmann reaction is the most common as it involves the use of readily available substrates, as

Six-membered O,O-heterocycles

357

Scheme 7.9

is the case of ketoesters and phenols, in the presence of acidic condensing agents. The bismuth chloride or Bi(NO3)3  5H2O [33] was used under thermolytic conditions [34] or in combination with ultrasounds [35] (Scheme 7.10). This method was fast and provided high yield of various coumarins [27,29].

Scheme 7.10

Flavanones exhibit biological activities including their action as cholagogues, antioxidants, hepatoprotectors [36,37], and anticancer agents [38,39]. Ahmed and Ansari [40] isomerized the 2ʹ-hydroxychalcones utilizing a silica-supported-bismuth chloride catalyst. The flavanones (chroman-4-one derivatives) were obtained in good-to-excellent yields by this reaction that occurred under dry conditions (Scheme 7.11) [27,29].

Scheme 7.11

The 4-arylbutyric acids underwent intramolecular Friedel
Crafts reaction in the presence of Bi(NTf2)3 catalyst to afford the 1-tetralones. This reaction with 3-phenoxypropionic acid provided 2,3-dihydro-1-benzopyran-4-one (chroman-4-one) (Scheme 7.12) [27,29,41]. The Baeyer
Villiger oxidation of indanone with m-chloroperoxybenzoic acid using Bi(OTf)3  xH2O catalyst furnished another chromanone

358

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.12

derivative, 3,4-dihydro-1-benzopyran-2-one (chroman-2-one) in 65% yield (Scheme 7.13) [27,29,42].

Scheme 7.13

The Baeyer
Villiger oxidation of cyclopentanone occurred with m-chloroperoxybenzoic acid in the presence of Bi(OTf)3  xH2O and MCBi(OTf)3 catalyst to afford the lactone in 90% yield (Scheme 7.14) [27,29,43].

Scheme 7.14

The coumarin is synthesized by a most important reaction (i.e., Pechman reaction). The cyclization reaction between an active dicarbonyl compound and phenol was performed using acidic reagents. The reaction of ethylacetoacetate and phenol was carried out in the presence of 5 mol % Bi(NO3)3 under solvent-free conditions in a domestic MW oven for 8
10 min. This reaction provided coumarin in 80%
85% yields (Scheme 7.15) [44].

Scheme 7.15

Six-membered O,O-heterocycles

359

7.2.5 Cerium-assisted synthesis The ready access to solid-supported hydroformylation products makes more-complex diversification processes possible, as shown for the Hantzsch synthesis of pyridines from an allylic alcohol. After the hydroformylation in scCO2, the solid-supported aldehydes were reacted directly without purification in multicomponent coupling with methyl 3aminocrotonate and methyl acetoacetonate. The two isomeric pyridines were formed in 99% yield upon aromatization with ceric ammonium nitrate and subsequent cleavage of the anchoring group with trifluoroacetic acid (Scheme 7.16) [45].

Scheme 7.16

The benzofuran was synthesized from 1,3-cyclohexanedione. Annelation of 1,3-cyclohexanedione occurred by Strandtmann method through the formation of β-keto sulfoxide intermediate, which reacted with several benzaldehydes to give the furo[2,3-h]flavones that were previously isolated from natural sources: lanceolatin B [46], isopongaglabol methyl ether [47], isopongaglabol, pongaglabrone [48], millettocalyxin C [49], and pongol [50] (Scheme 7.17).

360

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.17

7.2.6 Cesium-assisted synthesis The salicylates and in situ produced arynes reacted readily to construct the heteroatom ring systems, like thioxanthones, xanthones, and acridones (Scheme 7.18) [51]. Here, a novel coupling reaction occurred between o-(trimethylsilyl)aryl triflates and o-hydroxychalcones in a simple one-step process for the preparation of 9-substituted xanthenes under very mild reaction conditions [52a,b,53].

Scheme 7.18

7.2.7 Chromium-assisted synthesis The hetero-Diels
Alder reaction of Danishefsky’s diene occurred with several aldehydes using chromium
salen complex containing DIANANE (endo, endo-2,5-diaminonorbornane). The reaction provided 2-substituted 2,3-dihydro-4H-pyran-4-ones in high enantioselectivities and yields (Scheme 7.19) [54].

Six-membered O,O-heterocycles

361

Scheme 7.19

7.2.8 Cobalt-assisted synthesis Kamiya et al. [55]. reported a carbonylation of tetrahydrofuran in the presence of catalytic amounts of cobalt acetate using carbon monoxide and H2 to afford the 8-valerolactone in 35%
45% yield (Scheme 7.20) [56].

Scheme 7.20

7.2.9 Copper-assisted synthesis A three-component reaction of allenic esters, dialkylzinc, and unactivated ketones in the presence of catalytic amounts of Cu (OAc)2
DIFLUORPHOS complex provided highly functionalized δ-lactones. This catalytic asymmetric multicomponent reaction formed one tetra-substituted chiral center and two carbon
carbon bonds simultaneously (Scheme 7.21) [57].

Scheme 7.21

The yields and rates for cyclization reactions of o-(alkynyl)benzoates improved upon addition of a catalytic amount of Cy2NH  HX in the presence of Cu(II)halide in stoichiometric amount to afford the 4haloisocoumarins. Various 4-haloisocoumarins were formed in good yield under standard reaction conditions (Scheme 7.22) [58]. The 4-arylcoumarins were formed in high yields after the acidic work-up when arylpropionic acid methyl esters bearing a methoxymethyl-protected hydroxy group at the ortho position underwent

362

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.22

hydroarylation with several arylboronic acids at ambient temperature in methanol in the presence of a catalytic amount of CuOAc (Scheme 7.23) [59].

Scheme 7.23

The polycyclic ethers with high diastereoselectivity were obtained by Cu-catalyzed [2,3]-shift of oxonium ylides [60]. The polycyclic ether was formed in 80% yield as a single diastereomer when a diazocarbonyl compound with an allyl ether was reacted in the presence of Cu(II) trifluoroacetylacetate (Cu(tfacac)2) (Scheme 7.24). The reaction occurred through the formation of oxonium ylide, and subsequent [2,3]-shift of an allyl group to give a polycyclic ether [61].

Scheme 7.24

The indolodioxane was synthesized enantioselectively using hydrazines as reaction partners for carbon
nitrogen bond formation. This tricyclic molecule is a potent antihypertensive agent among the derivatives of nonnatural hybrid of three 5-hydroxytryptamine receptor 1A receptor binding molecules: spiroxatrine, 5-hydroxytryptamine, and pindolol. The indole core was constructed from aryl iodide using a three-step sequence. The Cu-catalyzed formation of N-aryl N-Boc hydrazide proceeded smoothly

Six-membered O,O-heterocycles

363

to afford an intermediate in 74% yield (Scheme 7.25); this substrate was then used in Fischer’s indole synthesis to form the conveniently substituted, fully elaborated, indole derivative [62,63].

Scheme 7.25

The heterocyclic compounds with two heteroatoms in a 1,3-position were constructed by carbonylative ring-expansion. The 1,3-dioxolane was reacted in the presence of sulfuric acid and cuprous oxide to afford the 1,4-dioxan-2-one in 90% yield. This reaction is also applicable to the expansion of six- to seven-membered rings (Scheme 7.26) [56,64].

Scheme 7.26

The hetero-Diels
Alder adducts were formed with good enantioselectivity when nonactivated aldehydes were reacted with Brassard’s diene in the presence of chiral Cu(II) Schiff base complex catalyst. The 5methyl α,β-unsaturated δ-lactones were formed in good diastereoselectivities (anti/syn) (95/5), modest-to-good yields, and good-to-excellent ee’s when oxa-Diels
Alder reaction was carried out with diene and aldehydes in the presence of Cu(OTf)2, followed by treatment with trifluoroacetic acid (Scheme 7.27) [65,66]. The heterocycles containing a quaternary center were generated by hetero-Diels
Alder reactions with ketones. The challenge, for chemists, is to control this quaternary center [66
68]. Most of the heteroDiels
Alder reactions of ketones involve dienes like more electron-rich

364

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.27

dienes such as Brassard’s or Danishefsky’s dienes or 1,3-cyclohexadiene derivatives. The ene or Mukaiyama aldol reactions can compete with oxa-Diels
Alder reaction depending on the diene. In hetero-Diels
Alder reactions involving ketones, the chirality comes from the catalyst or from the substrate. The starting material reacted diasteroselectively to afford the final compound in 53% yield in the presence of 1,10-phenanthroline/Cu (OTf)2 (10 mol%) catalyst (Scheme 7.28) [69].

Scheme 7.28

The first example of enantioselective catalytic hetero-Diels
Alder reaction of activated ketones with activated dienes was reported in 1997 [70]. The ethyl pyruvate was reacted with trans-1-methoxy-3-(trimethylsilyloxy)buta-1,3-diene (Danishefsky’s diene). The catalyst influenced the ee and yield of hetero-Diels
Alder adduct. Different C2-symmetric bis(oxazoline) ligands were tested, and the best ee’s and yields were obtained with (S,S)-Cu(OTf)2 (10 mol%) catalyst, which provided heteroDiels
Alder adduct in 99% ee (dichloromethane, 240 °C) and 78% yield (Scheme 7.29). The diene has to approach the si face of the ketone to form the (S) hetero-Diels
Alder adduct. It was assumed that both the ethyl pyruvate and chiral ligand were coordinated to the Cu(II) center, with the substrate and the ligand in the same plane affording a complex in which the carbonyl re face of ethyl pyruvate was shielded by the tert-butyl

Scheme 7.29

Six-membered O,O-heterocycles

365

groups of the ligand. As usual, when Danishefsky’s diene was used, a traditional Mukaiyama aldol condensation and/or a hetero-Diels
Alder reaction occurred, but the dihydropyranones were exclusively obtained after the acidic treatment of reaction mixture [66]. The hetero-Diels
Alder reaction was performed using Danishefsky’s diene and ethyl pyruvate. Cu(OTf)2 provided the best results (Scheme 7.30) [71]. The copper(II)/ligand stoichiometry was critical for reactivity and selectivity. Whereas a 1/1 ratio of cyclohexylidine ligand derived from cyclohexanone, (2)-diphenyl ethylamine, and Cu(OTf)2 furnished hetero-Diels
Alder adduct in 92% enantiomeric excess, from Danishefsky’s diene and ethyl pyruvate, only 73% enantiomeric excess was reported in hetero-Diels
Alder adduct upon increase in the copper (II)/ligand ratio to 2/1. Furthermore, the catalytic activity of complex was inhibited when a two-fold molar excess of ligand relative to copper(II) salt was used. The ee of cycloadduct increased to 94% upon decreasing the ring size of ketone component from six to four carbon atoms [66].

Scheme 7.30

Spirolactones were synthesized starting from cyclic ketoesters. For example, the spirolactone was formed in modest yield when Danishefsky’s diene and starting substrate were reacted by a hetero-Diels
Alder reaction in the presence of copper-complex catalyst. The (S,S)-Cu(OTf)2 catalyst afforded the best ee of spirolactone (Scheme 7.31) [66,72].

Scheme 7.31

The dicarbonyl compounds like α-diketones underwent heteroDiels
Alder reactions. For example, the hetero-Diels
Alder reaction of Danishefsky’s diene and diketone was conducted in the presence of (S,S)Cu(OTf)2, and the cycloadduct was formed in excellent ee (94%) and

366

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

good yield. Both the ee and yield were not affected upon lowering the amount of catalyst from 10 to 0.05 mol% (Scheme 7.32) [66,73].

Scheme 7.32

The O-nucleophiles are much lower in reaction diversity as compared to N-nucleophiles due to the lower valence of O-atom. Therefore the tandem reactions initiated by copper-catalyzed carbon
oxygen coupling are also less than those initiated by carbon
nitrogen coupling. Actually, presently reports are available only on sole copper-catalyzed carbon
oxygen coupling intrigued tandem reactions dealing with heterocyclic compound synthesis. Interestingly, research in copper-catalyzed tandem reactions began from the copper-catalyzed domino reactions involving coupling reaction of O-nucleophiles. Initially, epoxides served as precursors of nucleophiles to react with o-iodophenols. Satisfactory yields of 2,3-dihydro-1,4-benzodioxines were obtained through the formation of ring-opening intermediates with cuprous oxide catalyst and 1,10-phenanthroline/cesium carbonate. Except the major products, side products were also produced in some entries due to steric hindrance with good regioselectivity (Scheme 7.33) [74,75].

Scheme 7.33

Ranu et al. [76]. used aluminum-supported copper(II) catalyst system, and this system was expanded to similar reactions of arizidines with o-iodophenols to afford the 3,4-dihydro-2H-1,4-benzooxazines. The structure of starting materials was revised for improving the regioselectivity of carbon
oxygen coupling initiated tandem reactions, and designed a new copper-catalyzed domino reaction to synthesize the 2,3-dihydro-1,4-benzodioxine derivatives.

Six-membered O,O-heterocycles

367

Epoxide group was reacted with the hydroxyl group of phenol matrix, and the elaborated backbone underwent nucleophilic attack of another phenol in cuprous bromide-catalyzed conditions to afford the 2,3-dihydro-1,4-benzodioxines. The theoretically possible byproducts were not formed due to the instability of seven-membered fused ring system (Scheme 7.34) [75,77].

Scheme 7.34

The 3,6-dichloro-2-(4-fluorophenyl)-7-methyl-4H-chromen-4-one was formed in good yield upon oxidative cyclization of 3-(3,4-disubstituted-phenyl)-1-(2-hydroxy-3,4,5-trisubstituted phenyl)prop-2-en-1-ones using cupric chloride at reflux in dimethylsulfoxide. The 3-(3,4-disubstituted-phenyl)-1-(2-hydroxy-3,4,5-trisubstituted phenyl)prop-2-en-1-ones were in turn prepared via Claisen
Schmidt condensation of aromatic aldehydes and various substituted acetophenones in the presence of ethanol/potassium hydroxide. The 1,5-benzothiazepines were obtained in good yield when chalcones were treated with o-aminothiophenol in ethanol at reflux condition under the influence of glacial acetic acid for 6 h (Scheme 7.35) [78a,b].

Scheme 7.35

368

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

A highly effective and simple carbon
oxygen carboxylic intramolecular coupling reaction was reported for the preparation of benzopyranones in the presence of Cu(I) catalyst by cyclization of 20 -halobiaryl-2-carboxylic acids. The reaction was effected best using stoichiometric amounts of Liebes kind promoter CuTC and without ligand at 200 °C in dimethylformamide for 20 min under MWI. Excellent yields of benzopyranones were obtained from carboxylic aryl bromides, chlorides, and triflates under these conditions. The reaction was extended for the synthesis of coumestans and indolactones but failed to afford the simpler lactones from nonaromatic carboxylic acids (Scheme 7.36). The aryloximes and aryloxyamines were obtained when N-hydroxyphthalimide underwent cross-coupling with phenylboronic acids [79] and aromatic oximes with aryl halides [63,80].

Scheme 7.36

The functionalized optically active six-membered oxygenated heterocyclic compounds were synthesized using electron-rich dienes, particularly Danishefsky-type dienes. Ghosh and coworkers [81] developed a heteroDiels
Alder reaction in the presence of chiral constrained bis(oxazolines)/ Cu(OTf)2 catalyst such as (1R,2S)-Cu(OTf)2. A hetero-Diels
Alder reaction was carried out between Danishefsky’s diene and ethyl glyoxylate in order to compare the properties of the above catalyst with (S,S)-Cu (OTf)2 and (S,S)-Cu(OTf)2. The reaction was completed and provided a mixture of pyranone and Mukaiyama
aldol product that was treated with TFA to afford the pyranone. The best ee and yield of pyranone were obtained with (1R,2S)-Cu(OTf)2, as pyranone was formed with 72% ee and in 70% yield at
78 °C versus 17%
44% ee and 27%
42% yield when (S,S)-Cu(OTf)2 and (S,S)-Cu(OTf)2 were used. A decrease in ee of pyranone (50% at 23 °C vs 76% at
78 °C) was reported using (1R,2S)Cu(OTf)2 at 23 °C (Scheme 7.37) [66]. The C4
C13 fragment of laulimalide was constructed by oxaDiels
Alder reaction of Danishefsky’s diene and aldehyde with (1S,2R)Cu(OTf)2 catalyst. The dihydropyranone was formed in good ee and yield using chiral constrained complex (1S,2R)-Cu(OTf)2. Dihydropyranone

Six-membered O,O-heterocycles

369

Scheme 7.37

was converted into C4
C13 fragment of laulimalide by Ferrier rearrangement, and the latter compound provided laulimalide after a few steps (Scheme 7.38) [66,82].

Scheme 7.38

Jørgensen and coworkers [83] reported a catalytic oxa-Diels
Alder reaction of prochiral N-oxy-pyridine aldehydes. The electron-rich dienes and N-oxy-pyridine-2-carboxaldehyde derivatives underwent catalytic asymmetric oxa-Diels
Alder reaction in the presence of chiral copper(II) complex catalyst to give the oxa-Diels
Alder adducts upon treatment with trifluoroacetic acid. The Mukaiyama
aldol products were also formed in this reaction. The oxa-Diels
Alder adducts were formed with excellent ee’s and in moderate to good yields. Different catalysts such as (S,S)-Cu(OTf)2 were tested in different solvents in the case of heteroDiels
Alder reaction of 5-bromo-N-oxy-pyridine-2-carbaldehyde. When the reaction was performed in the presence of (4R,5S)-Cu(OTf)2 in a mixture of toluene/dichloromethane (4/1), the best ee of final compound was obtained (Scheme 7.39) [66].

370

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.39

Different N-oxy-pyridine-2-carboxaldehyde derivatives underwent (4R,5S)-Cu(OTf)2-catalyzed oxa-Diels
Alder reaction with Danishefsky’s diene. The ee’s of hetero-Diels
Alder adducts were good-to-excellent and yields were modest-to-good (Scheme 7.40) [66,83].

Scheme 7.40

Thasana and coworkers [84] developed an intramolecular arylation of carboxylic acids for the construction of isolamellarins. The bromoaryl benzoic acids were cyclized upon treating with 2 eq. of Liebeskind catalyst CuTC at 200 °C in dimethylformamide under MWI to afford the desired polycyclic targets in 86% and 95% yield (Scheme 7.41). An alternative method using Pb(OAc)4 for the synthesis of lactone ring started from a debrominated analogue of bromoaryl benzoic acid and provided the desired lactone but in a disappointing yield (7%) [63].

Scheme 7.41

Different isochromenone derivatives were synthesized upon aromatic substitution by activated methylene compounds (1,3-diketones) with stoichiometric amounts of Cu(I) catalyst and base depending on the pressure, temperature, and nature of the activating methylene groups (Scheme 7.42).

Six-membered O,O-heterocycles

371

The isochromene was formed as the main product after acidification under standard reflux conditions (Cu1, NaH) in tetrahydrofuran whereas it was the minor product and deacylated isochromene was the main product (55%
70%) due to the cleavage of acyl group in the high-temperature water media under MWI (Cu1 and potassium hydroxide) at 100 °C
150 °C in water (3
14 bar) [85].

Scheme 7.42

7.2.10 Hafnium-assisted synthesis The hydrophobic ionic liquids were used to enhance the activity of metal triflates dramatically in Friedel
Crafts alkenylations of aromatic compounds with several aryl- and alkyl-substituted alkynes (Scheme 7.43) [86].

Scheme 7.43

7.2.11 Iodine-assisted synthesis Menezes and coworkers [87] reported a simple reaction for the synthesis of various flavones under MWI using 20 mol% iodine (Scheme 7.44). In situ produced iodoiranium intermediate underwent intramolecular cyclization to afford an intermediate that readily eliminated hydrogen iodide to provide the flavones. The liberated hydrogen iodide was oxidized to iodine to complete the catalytic cycle [88].

Scheme 7.44

372

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The reaction conditions were tuned in the case of hetero-1,3-diyne to achieve a single or double cyclization (Scheme 7.45). Thus unsymmetrical as well as symmetrical, bis-heterocyclic units with dihalide moiety were readily accessible. The dihalo compounds were used as precursors for the construction of more complex fused heterocyclic compounds that exhibit potential applications as organic field effect transistors [89,90].

Scheme 7.45

Gao and coworkers [91] synthesized a variety of 2-aryl-4,9-dihydrocyclohepta[b]-pyran-4,9-diones from 3-cinnamoyltropones utilizing iodine/ dimethylsulfoxide/sulfuric acid system (Scheme 7.46) [88].

Scheme 7.46

Yadav et al. [92]. reported a simple protocol for the preparation of 1,3-dioxane derivatives in excellent yield via an I2-mediated Prins cyclization (Scheme 7.47). The olefin was treated with activated aldehyde to give the key intermediate. The 1,3-dioxane derivatives were formed by O-alkylation of key intermediate with another molecule of aldehydes followed by attack of oxygen anion on carbocation. The protocol was

Six-membered O,O-heterocycles

373

Scheme 7.47

applicable to styrene derivatives as well as to aliphatic olefins. However, aromatic aldehydes failed to give the products [88]. This reaction exhibited high chemoselectivity in the presence of either other oxidizable moieties or secondary alcohols and a very high degree of selectivity for the oxidation of primary alcohols to aldehydes, without any noticeable overoxidation to carboxylic acids [93,94]. This protocol was used for the oxidation of (fluoroalkyl)alkanols to respective aldehydes [95] by one-pot selective oxidation/olefination of primary alcohols utilizing (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl or TEMPO DAIB-(2,2,6,6tetramethylpiperidin-1-yl)oxyl system and stabilized phosphorus ylides [96], and in the chemo-enzymatic oxidationhydrocyanation of γ,δ-unsaturated alcohols [97]. The TEMPO-catalyzed oxidations were also performed using (dichloroiodo)benzene in the presence of pyridine as a stoichiometric oxidant instead of DAIB [98]. On the basis of the ability of DAIB
TEMPO system to selectively oxidize primary alcohols to aldehydes in the presence of secondary alcohols, Forsyth and coworkers [99] reported a selective oxidative conversion of various highly functionalized 1°,2°-1,5-diols into δ-lactones. A representative example for the conversion of substrate to δ-lactone is shown in Scheme 7.48. The asymmetric total synthesis of antitumor (1)-eremantholide A was performed using a similar DAIB
TEMPO-promoted γ-lactonization [100a,b,101].

Scheme 7.48

7.2.12 Iron-assisted synthesis The carbonylation reaction was applicable to a variety of 2-vinyloxiranes and the nature of product was controlled by the nature of metal complex. For instance, the α,β-unsaturated lactone was formed from

374

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

2-vinyloxiranes and Fe(CO)5 whereas the catalytic carbonylation of 2-vinyloxiranes with carbon monoxide and [Rh-(COD)Cl2] regiospecifically afforded unsaturated lactone in good yield (Scheme 7.49) [56,102].

Scheme 7.49

Sabitha et al. [103] synthesized (S)-5-hexadecanolide from 2,3-epoxy chloride. The epoxy chloride provided an alkynol upon base-induced ring-opening followed by alkylation. An aldehyde was formed when secondary hydroxyl group of alkynol was protected as benzyl ether and tetrahydropyranyl protection was removed selectively followed by oxidation of the formed primary alcohol. The obtained aldehyde underwent Horner
Wadsworth
Emmons reaction to give an α,β-unsaturated ester, which on hydrogenation underwent a sequence of reactions and provided the target molecule (S)-5-hexadecanolide (Scheme 7.50).

Scheme 7.50

7.2.13 Lithium-assisted synthesis This transformation proved to be amenable to asymmetric catalysis. Various preliminary attempts were made, and the best result thus far was reported with stoichiometric lithium acetate as base and commercially available carbene precursor H (Scheme 7.51) [104]. The keto-esters were transformed to known chiral δ-valerolactones intermediates and used for the preparation of natural products that exhibit a wide variety of pharmacological activities. For this, a silicon-directed

Six-membered O,O-heterocycles

375

Scheme 7.51

stereoselective reduction [105] of ketones with sodium borohydride afforded very good yield of an inseparable mixture of diastereoisomeric alcohols (Scheme 7.52). The diastereoisomeric hydroxy ester mixture in each case was then hydrolyzed and the intermediate hydroxy acids underwent a smooth cyclization to afford the major δ-lactones. The dimethyl (phenyl)silyl group in δ-lactones was transformed to hydroxy group following Fleming oxidation utilizing peracetic acid and potassium bromide with retention of configuration affording hydroxy lactones [106
110].

Scheme 7.52

The key tetrahydrocorticosterone (THB) intermediate was synthesized as shown in Scheme 7.53. 1,3-Dimethoxybenzene was lithiated and added

Scheme 7.53

376

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

to ethyl formate. The formed alcohol was oxidized to the tetramethyl protected THB. Many protocols of demethylation resulted in incomplete demethylation; the reaction mixture still contained mono-, di-, and trimethylated THB after prolonged reaction time. The methoxy intermediate was treated with BBr3 to afford the cyclized compound 2,8-dihydroxyxanthone (DHX). No desired product was formed using a known reaction [109] to open the parent DHX. The β-silylaldehydes are the building block of chiral lactams and lactones. The aldehyde was transformed to a six-membered lactam and lactone and then to a piperidine framework [110]. Lactone was methylated to provide the lactone (Scheme 7.54). The lactone was obtained by converting the silyl group to hydroxy group with retention of configuration. Lactone is the antipode of natural simplactone B [111].

Scheme 7.54

Both the absolute and relative configurations of major diastereoisomer were assigned by converting it to (1)-simplactone B, the antipode of a natural and known valerolactone (Scheme 7.55) [110,111]. For this,

Scheme 7.55

adduct was reduced with sodium cyanoborohydride followed by hydrolysis with LiOH. The formed substituted malonic acid intermediate was heated at 110 °C, which resulted in decarboxylation and concomitant lactonization to afford the desired lactone. The dimethyl(phenyl)silyl group

Six-membered O,O-heterocycles

377

in lactone was transformed to a hydroxy group following the Tamao
Fleming oxidation [112] using peracetic acid and potassium bromide with retention of configuration leading to (1)-simplactone B. The (S)-5-hexadecanolide was isolated from the mandibular glands of oriental hornet, Vespa orientalis [113], as a pheromone to stimulate the workers to construct the queen cell. This lactone is also found in some fruits like peaches and apricots. The 5-hexadecanolide has important physiological activities and thus a number of synthetic procedures are reported in the literature. A mannitol-derived aldehyde provided (S)-5-hexadecanolide. The (R)-acetonide, synthesized from mannitol, was treated with 1-bromodecane in the presence of naphthalene and lithium to afford the alcohol. This alcohol was converted to a chiral epoxide in four steps. The ring-opening of epoxide afforded hydroxyl acetal that was converted to an unsaturated δ-lactone. The desired (S)-5-hexadecanolide was obtained by hydrogenation of the double bond in δ-lactone (Scheme 7.56) [103,114,115].

Scheme 7.56

7.2.14 Molybdenum-assisted synthesis Trost and Andersen [116] employed this concept in their approach to the orally bioavailable HIV inhibitor tipranavir. The key chiral intermediate was formed by asymmetric allylic alkylation starting from carbonate. The product was obtained in 94% yield using 15 mol% chiral ligand and 10 mol% molybdenum precatalyst with 2 eq. of sodium dimethylmalonate as the additive. The reaction was performed under sealed-vessel MW heating for 20 min at 180 °C. Thermal heating under reflux needed 24 h and provided the intermediate in the same chemical yield, albeit in slightly higher enantiomeric purity (96% enantiomeric excess). Moberg et al. [117] elaborated on a similar pathway involving a MW-driven

378

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

molybdenum-catalyzed asymmetric allylic alkylation (6 min, 160 °C, tetrahydrofuran) as a key step for the synthesis of muscle relaxant (R)-baclofen. Other enantioselective reactions conducted under MW heating included asymmetric Heck reactions [118] and ruthenium-catalyzed asymmetric hydrogen transfer processes (Scheme 7.57) [119].

Scheme 7.57

Tipranavir is a molecule active against the HIV protease enzyme. The chiral catalyst was able to rearrange a simple achiral molecule to a valuable chiral one in high enantiomeric purity that finds an application for the synthesis of tipranavir [120]. The achiral substrate was treated with an appropriate chiral catalyst to provide a chiral product that was otherwise difficult to access in the nonracemic form (Scheme 7.58). Synthesis of chi-

Scheme 7.58

ral product underlines the ability of catalytic enantioselective olefin metathesis to deliver the molecules not easily prepared with enantiomerically enriched substrates and achiral catalysts [121]. The latter approach required an efficient protocol for enantioselective synthesis of O-substituted quaternary carbon stereogenic center. In spite of recent advances,

Six-membered O,O-heterocycles

379

facile and efficient methods, particularly of the catalytic variety, affording the tertiary alcohols in high enantiomeric purity has remained largely unavailable [122
132]. Site-selective allylic oxidation (dichloromethane, pyridinium chlorochromate, 80 °C) of cyclic allylic ether allowed for a Rh-catalyzed hydrogenation [3 mol% ClRh(PPh3)3] to produce the desired lactone and the n-propyl side-chain, respectively.

7.2.15 Nickel-assisted synthesis A novel cycloaddition reaction of alkynes and phthalic anhydride to provide isochromones was reported; the key intermediate, nickelacycle, was formed via decarbonylation [133]. Analogously, thiophthalic anhydride and phthalic imide provided the heterocyclic compounds via addition to alkynes under nickel catalysis [134,135]. When o-acyloxybenzonitrile was treated with a bulky Lewis acid and nickel(0) catalyst, methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide), in the presence of alkynes, a coumarine derivative was formed efficiently. The reaction occurred via nickelacycle, which was formed by elimination of aryl cyanide. The cleavage of two carbon
carbon bonds furnished the key intermediate (Scheme 7.59) [136].

Scheme 7.59

Tsuda et al. [137
139] reported a coupling of two alkynes with carbon dioxide in the presence of Ni/phosphine catalyst to afford the pyrones (Scheme 7.60). These reactions generally required elevated temperatures and high pressures of carbon dioxide. Only a limited

Scheme 7.60

380

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

number of diynes were converted into pyrone. Oligomerization of diyne was a major side reaction as with many cycloaddition reactions. These obstacles were overcome when IPr was used as a ligand in lieu of phosphines. The oligomerization of diyne was suppressed with steric bulk of this ligand. As a result, high yields of various bicyclic pyrones were obtained. Notably, all pyrones were synthesized using relatively low reaction temperatures and ambient pressures. The diynes were coupled with carbon dioxide in the presence of an Ni/IPr general catalyst system. To date, this catalyst has not provided pyrones from either sterically hindered diynes or terminal diynes. Terminal diynes oligomerized at a faster rate than carbon dioxide incorporation [140
142]. The traditional halogen
metal exchange using magnesium turnings afforded 2-thienylmagnesium bromide that was used as nucleophile in addition reactions to give the decahydroisoquinoline-derived aldehyde [143], vinylogous acyl triflates [144], or lactones [145]. This heteromagnesium reagent was also used in Cu-catalyzed ring-opening of azabicyclic alkenes [146], as well as metalated counterpart in cobalt-catalyzed crosscoupling with alkyl halides [147,148]. In addition, some alkylated derivatives and 2-thienylmagnesium bromides underwent cross-coupling reactions with haloarenes using palladium [149], or nickel catalysts [150
152] for the synthesis of highly conjugated compounds with electro-optical properties. Scheme 7.61 shows some applications of

Scheme 7.61

these couplings involving 2-thienylmagnesiums. Other metalation protocols were more convenient when other moieties were present. The thienyl Grignard reagent was prepared from 2,3-dihydrothieno[3,4-b] [1,4]dioxine by lithium
magnesium transmetalation. Another example

Six-membered O,O-heterocycles

381

was the nickel-catalyzed coupling of thienyl Grignard reagent with aryl dibromide to afford the bis-thiophene [153,154]. Louie and coworkers [155] developed a hetero-[2 1 2 1 2]-cycloaddition of carbon dioxide with diynes in the presence of nickel catalyst. The reaction of diynes with carbon dioxide occurred under atmospheric pressures in the presence of N-heterocyclic carbine ligand and bis(1,5-cyclooctadiene)nickel to afford the pyrones in high yields (Scheme 7.62).

Scheme 7.62

The bicyclic pyrones were synthesized by cycloaddition of substituted diynes with CO2 [156
158] or aldehydes [159] in the presence of Ni(0)phosphine catalysts (Scheme 7.63) [160].

Scheme 7.63

The mechanism of this transformation involved initial [2 1 2]-cycloaddition of an alkyne and CO2, followed by the insertion of second unsaturation and subsequent reductive elimination to form a carbon
oxygen bond. The hindered alkynes did not react under these conditions. In contrast, the reaction of asymmetrically substituted diynes showed that the regioselectivity of reaction depends on the N-heterocyclic carbene ligand of choice as well as on the terminal group size [161]. In all cases, the major product formed presented the larger substituent of the diyne precursor in the formed pyrone product (Scheme 7.64) [162].

Scheme 7.64

382

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Takahashi et al. [163] developed a halogen-dependent catalytic reaction of alkynes with halopropenoates, where (Z)-3-iodopropenoate afforded pyrones and (Z)-3-bromopropenoate provided cyclopentadienes (Scheme 7.65) [164].

Scheme 7.65

7.2.16 Platinum-assisted synthesis The acetylenic alcohols underwent carbonylative cyclization with CO, one of the most straightforward protocols of forming methylenelactones. In particular, the synthesis of five-membered lactones from acetylenic alcohols by carbonylation has been studied intensively; however, only very limited data are available for the synthesis of six-membered lactone rings by carbonylative routes [165,166]. The previously explained reaction of Pt(PPh3)4-catalyzed carbonylation of alkynes with carbon monoxide and thiols can be employed for the carbonylative cyclization of acetylenic alcohols to lactones [167]. The ((phenylthio)methyl)-α-lactone was obtained selectively in good yield when the carbonylation of 5-hydroxy1-pentyne was carried out with thiophenol in the presence of 3 mol% Pt (PPh3)4 catalyst at 120 °C under carbon monoxide (30 atm) for 4 h. Since the product would be formed by Michael addition of thiophenol to methylene-α-lactone, cyclocarbonylation was evaluated without thiophenol to afford the desired methylenelactone in only 39% yield along with a few byproducts. Consequently, the cyclocarbonylation reaction with 10 mol% thiophenol resulted in selective formation of methylenelactone in 67% yield (Scheme 7.66) [168].

Scheme 7.66

Six-membered O,O-heterocycles

383

7.2.17 Rhodium-assisted synthesis The α,β-unsaturated carbonyl compounds with hydroxyl group were interesting bifunctional substrates in terms of possibility of this domino process to provide the oxygen heterocycles like 3,4-dihydrocoumarins. The reaction of starting substrate occurred smoothly with several arylboroxines to afford the good yields of 3,4-dihydrocoumarins (Scheme 7.67). In comparison to amino-substituted substrates, hydroxyl-bearing substrates needed

Scheme 7.67

longer reaction times to complete the second cyclization step of conjugate addition intermediate, which was reported on thin-layer chromatography during the reaction progress and isolated if the reaction was stopped midway, probably due to the lower nucleophilicity of hydroxyl group [169]. Among ring rearrangements, ring contractions are a group of reactions for the preparation of less common azetidines [170
183]. The electrocyclic ring-contraction [184] of l-aza-2,4,6-cyclooctatriene provided benzofused azetidines (7-azabicyclo[4.2.0]octadienes) through a Rh(II)-catalyzed intramolecular domino reaction of vinyldiazomethanes substituted pyrroles (Scheme 7.68) [185].

Scheme 7.68

Hodgson et al. [186
188] reported that unsaturated diazo keto esters underwent one-pot cross-metathesis in tandem with carbonyl ylide formation/intramolecular cycloaddition (Scheme 7.69). The olefin crossmetathesis occurred in the presence of dicarbonyl-stabilized diazo moiety, which allowed the formation of many unsaturated diazo compounds. The diazo moiety, left intact during the cross-metathesis reaction, was subsequently used for carbonyl ylide formation, which ultimately underwent intramolecular cycloaddition with the newly formed olefin.

384

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.69

Kitagaki et al. [189,190] reported an intramolecular reaction of carbonyl compound and dimethyl acetylenedicarboxylate. High enantioselectivity (68%
92% enantiomeric excess) was achieved over a range of diazo substrates with dirhodium(II) tetrakis[N-benzene-fused phthaloyl(S)-valinate] [Rh2(S-BPTV)4]. The high level of enantiocontrol provided conclusive evidence that chiral rhodium(II) catalyst was associated with ylide in the cycloaddition step (Scheme 7.70).

Scheme 7.70

Suga et al. [191,192] developed an alternative protocol for asymmetric catalysis in 1,3-dipole cycloaddition. The achiral 1,3-dipole was produced in the rhodium acetate-catalyzed diazo decomposition of o-methoxycarbonyl-diazoacetophenone by intramolecular reaction of rhodium(II) carbene complex with an ester carbonyl oxygen (Scheme 7.71).

Scheme 7.71

Six-membered O,O-heterocycles

385

The asymmetric induction in subsequent cycloaddition to C5N and C5C bond was achieved by chiral Lewis acid ytterbium(III)-pybox-Ph or scandium(III)-pybox-i-Pr, which activated the dipolarophile through complexation. With this approach, up to 96% enantiomeric excess for C5C bond addition and 95% enantiomeric excess for C5O bond addition were obtained, respectively. Cyclohydrocarbonylation has particular utility in the synthesis of these alkaloids because it is a one-pot reaction and requires environmentally benign solvents. The heteroatom nucleophiles acted as excellent diastereoselective trapping agents in cyclohydrocarbonylative reaction (Scheme 7.72) for the preparation of azabicyclo[2.2.0]alkane amino acids [193].

Scheme 7.72

The products were treated with LiAlH4 to afford the complex tetracyclic products with N,O-acetal moiety. Tanaka et al. [194] reported a cationic rhodium-catalyzed intermolecular [4 1 2]-annulation of isatins and 2-alkynylbenzaldehydes in the presence of [Rh((R,R)12O)]BF4 to synthesize the spirobenzopyranone-oxindoles in excellent enantioselectivity (up to 99%) and yields (Scheme 7.73) [195].

Scheme 7.73

Neesaon and Stevenson [196] used Wilkinson’s catalyst for the total synthesis of sesquiterpenoid calomelanolactone. A fully intramolecular trimerization of triyne in the presence of Wilkinson’s catalyst afforded compound in 86% yield that was further elaborated to the required natural product sesquiterpenoid calomelanolactone (Scheme 7.74) [197].

386

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.74

The vinyloxiranes underwent carbonylative ring-expansion in the presence of catalytic amounts of [Rh(COD)Cl]2 and carbon monoxide to afford the α,β-unsaturated valerolactones [102]. Isoprene oxide was reacted with carbon monoxide to yield the final compound in 75% yield (Scheme 7.75) [56].

Scheme 7.75

The tetrahydrofuran was carbonylated using [Rh(COD)Cl2] catalyst [198]. Different products were obtained depending on the promoter (Scheme 7.76). The major product was valeroladone when iodide ion was

Scheme 7.76

used (lithium iodide, methyl iodide, or hydrogen iodide). The α-methylbutyrolactone was obtained as the major product when iodine was used in the reaction. In all cases, however, due to the polymerization of lactones the yield of carbonylated products did not exceed 15%. Under these conditions, the Co(OAc)2  4H2O was less efficient than Rh catalyst [56].

7.2.18 Scandium-assisted synthesis The effect of Lewis acids on asymmetric hetero-Diels
Alder reaction of Danishefsky’s diene and chiral 3-(p-tolylsulfinyl)-2-furaldehyde was

Six-membered O,O-heterocycles

387

studied [199
201]. A 1:1 mixture of diastereomers was produced with zinc chloride. On the other hand, Ln(OTf)3 and lanthanide chloride acted as effective promoters and provided high diastereomeric excesses and yields. Among them, the triflates showed better selectivities. A catalytic enantioselective hetero-Diels
Alder reaction of Danishefsky’s diene and butyl glyoxylate was reported [202a]. The reaction was catalyzed with a chiral yttrium bis-trifluoromethane sulfonamide (bis-triflamides) produced from chiral bis-triflamides and Yb(OTf)3 (Scheme 7.77). Less satisfactory results were obtained with Yb(OTf)3 and Sc(OTf)3 [202b].

Scheme 7.77

7.2.19 Selenium-assisted synthesis Ring transformations using hydrogen peroxide/selenium oxide resulted in the ring-contraction of cycloalkanones to norcycloalkane carboxylic acids [203,204], and related rearrangements in acyclic ketones [205
207] as well as 3-ketosteroids [208,209]. Moreover, it was reported that ketal was rapidly converted into enollactone in high yield. The formation of enollactone involved acid-catalyzed hydrolysis of ketal protecting group, followed by a Baeyer
Villiger type oxidation of intermediate ketone. The reaction was extended to other 2-alkylidenecycloalkanones affording enol lactones (Scheme 7.78) [210,211].

Scheme 7.78

7.2.20 Silver-assisted synthesis β-Allenic acids were cyclized using silver salts as reported in a short asymmetric total synthesis of (2)-malyngolide. The optically active substituted allenic acid was subjected to substoichiometric quantity of soluble amine and catalytic silver nitrate for the construction of δ-lactone motif of this natural product (Scheme 7.79). Interestingly, the

388

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.79

chirality of allenic functionality was preserved in this reaction. The 6-endo-trig process was surprisingly preferred to the 5-exo-trig cyclization; probably a more stable transition state was evoked leading to the δ-lactone compared to its homologue leading to furanone, the developing positive charge at the disubstituted allene terminus enhanced the stabilization. Allenic acids were used for the synthesis of δ-lactones. Electrophilic activation of trisubstituted allene engaged the carboxylic acid in a 6-endo-trig cyclization. This route was preferred to the competitive 5-exo-dig pathway, due to the enhanced stabilization provided by the developing positive charge at disubstituted allene terminus in transition state, and eventually leading to δ-lactone. This reaction belongs to an efficient asymmetric synthesis of naturally occurring antibiotic (2)-malyngolide [212,213]. Dalla and Pale [214] trapped the organosilver intermediate, formed upon cyclization, with bromine. The Z-bromoenol lactones were formed stereoselectively but in modest yields, except when Thorpe
Ingold effect favored the cyclization (Scheme 7.80) [213].

Scheme 7.80

Conjugated enynoic acids reacted readily with Ag salts to afford the pyranones and/or furanones depending on the substituents and the salt [215]. The best catalyst in this case was Ag2CO3 and led to Z-5-alkylidenefuran-2(5H)-ones stereoselectively in excellent yields. A small fraction of 2H-pyran-2-ones was nevertheless produced, and as already reported [216,217], the role of Ag counterion was critical for privileging the 5-exodig over the 6-endo-dig cyclization (Scheme 7.81). The zinc dibromide promoted the opposite situation and provided 2H-pyran-2-ones as the major product with this catalyst [213].

Six-membered O,O-heterocycles

389

Scheme 7.81

The benzo analogues, o-alkynylbenzoic acids, were transformed to isocoumarins and/or alkylidenebenzofuranones, through Ag catalysis. Surprisingly, the 5-exo-dig cyclization was favored using silver powder in warm dimethylformamide as the most selective conditions. Bellina et al. [218] studied different catalysts to cyclize the o-alkynylbenzoic acids; it was found that silver nitrate favored the 6-endo-process (as palladium catalysts did) whereas phthalides were formed with silver (Scheme 7.82) [213].

Scheme 7.82

The higher furanone/pyranone ratios were obtained, depending on the substrate, either with silver in dimethylformamide and high dilutions, with silver iodide, or with silver carbonate in dimethylformamide (Schemes 7.83 and 7.84) [114,219,220].

Scheme 7.83

Scheme 7.84

The formation of six-membered lactone was not favored via endo-type lactonization (Scheme 7.85). At this point, factors affecting the pyranone/ furanone ratio were not yet very clear, although it was known that the

390

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.85

ratio between two products strongly depends on the nature of silver salts, the substrate structures, and the solvents [114,221]. Castañer and Pascual [222] reported that phenylpropargylidene malonic acid was transformed into γ-benzylidene-R-carboxibutenolide either more smoothly, in the presence of Ag salt at room temperature or by thermal isomerization (Scheme 7.86). The reaction was applicable to other aliphatic and aromatic propargylidene malonic acids, and although compounds with aromatic substituent always provided butenolides, their alkyl analogues furnished mixtures of pyrones and butenolides in a variable ratio [114,223].

Scheme 7.86

Various well-stereodefined five-membered lactones are isolated from natural sources, and many of them exhibit a variety of biological activities. Therefore their syntheses have attracted the attention of chemists, and many organometallic protocols have been reported utilizing Ag and other metals. For example, the cyclization of alkynoic acid (Scheme 7.87) was

Scheme 7.87

carried out in catalytic amounts of silver or silver iodide to provide the natural product ligustilide in excellent stereo- and regioselectivities and good yield [224]. Lissoclinolide, an antibiotic butenolide, was also synthesized stereoselectively by a reaction sequence in which silver(I)-catalyzed lactonization of alkyne was the key step [225]. The same approach was applied for the synthesis of ligustilide starting from a structurally close alkyne [114,226].

Six-membered O,O-heterocycles

391

The Ag-assisted addition of nucleophiles to alkenes has been much less studied as the reaction with inactivated alkenes has only been achieved with good yields in recent years. The addition of nucleophiles to alkenes activated with I2 or selenium compounds is also known, as is the Ag-assisted addition of nucleophiles to alkenes with an allylic leaving group. Intramolecular additions of carboxyl or hydroxyl groups to inert olefins in the presence of Ag(I) triflate catalyst in 1,2-dicholoethylene was one of the newest and simplest protocols to form the lactones or cyclic ethers (Scheme 7.88) utilizing Ag-assisted chemistry [114,227].

Scheme 7.88

The N,N-disubstituted lactone hydrazones were formed from ω-chloroalkanohydrazides upon treating with AgBF4 [228]. This reaction with enantiomerically pure 1-amino-2-(methoxymethyl)pyrrolidine hydrazides afforded appropriate substrates for the synthesis of 2-alkylsubstituted six-membered lactones in high enantiomeric purities (Scheme 7.89) [114,229].

Scheme 7.89

The S-glycosidic silyl enol ethers were treated with Ag triflate for the synthesis of bicyclic C-glycosides [230
232] as single, cis-fused diastereomers for both the five- and six-membered templates, and also for the preparation of ketooxetanes (Scheme 7.90) [114].

Scheme 7.90

392

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

7.2.21 Titanium-assisted synthesis Johnson et al. [233] synthesized an analogue of mevinoline from the acetal. The acetal and 1,3-bis(trimethylsilyloxy)-1-methoxybuta-1,3-diene were coupled to afford the alcohol. The chiral auxiliary was removed to give the aldol product, which was reduced to diol. Saponification and lactonization afforded the desired lactone (Scheme 7.91).

Scheme 7.91

Bonini et al. [234] synthesized mevinoline analoge from aldol product. The key step involved the enzymatic resolution of syn-diol. The direct aldol reaction of acetoacetate with aldehyde provided an aldol product (Scheme 7.92). The formed aldol product was reduced selectively to give the syn-diol. The desired lactone was obtained by enzymatic lactonization of syn-diol.

Scheme 7.92

Evans [235] synthesized 6-deoxyerythronolide B, which served as an exact key intermediate to provide the desired fragment where subsequent olefination and auxiliary cleavage provided fragment (Scheme 7.93). Another potential preparation was adapted from Curran’s synthesis of discodermolide and related analogs where aldol and hydroboration chemistry, similar to Evans’ route, led to desired fragment.

Six-membered O,O-heterocycles

393

Scheme 7.93

7.2.22 Tungsten-assisted synthesis Decatungstodivanadogermanic acid was prepared and used as a novel, green heterogeneous catalyst for the generation of spiro-fused heterocyclic compounds by a three-component one-pot cyclocondensation reaction of aldehyde, cyclic ketone, and urea in high yields under solvent-free condition and MWI at 80 °C. This catalyst was efficient not only for cyclic ketones, but also for diester, cyclic diketones, and diamide derivatives like dimedone, cyclohexanone, and barbituric acid or Meldrum’s acid derivatives. The reaction of cyclic ketoesters [236] and diamides, barbituric acid, or Meldrum’s acid derivatives with 2 eq. of aldehydes and 1 eq. of urea in the presence of decatungstodivanadogermanic acid as a catalyst afforded a family of symmetric spiroheterobicyclic compounds in good yields under solvent-free conditions at 80 °C. The reaction was extended to various p-substituted benzaldehydes in the presence of barbituric acid and Meldrum’s acid to explore the scope and limitations of this reaction (Scheme 7.94).

Scheme 7.94

7.2.23 Zinc-assisted synthesis A BINOLate-zinc complex was produced in situ from 3,30 -dibromo-1, 10 -bi-2-naphthol and diethyl zinc which was an efficient catalyst for the

394

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

enantioselective hetero-Diels
Alder reaction of aldehydes and Danishefsky’s diene to afford the 2-substituted 2,3-dihydro-4H-pyran-4-ones in 98% enantiomeric excess and up to quantitative yield (Scheme 7.95) [237].

Scheme 7.95

The Evan’s aldol reaction with propionaldehyde and acylated auxiliary provided the ketone. Subsequently, imide was formed by Parikh
Doering oxidation. The alcohol was obtained in 86% yield based on recovered starting material by the formation of titanium enolate of imide and addition to methacrolein. Alcohol was reduced stereoselectively via chelation strategy with Zn(BH4)2 that was freshly prepared from sodium borohydride and zinc chloride. The formed syn-alcohol was tied up with an acetonide protecting group and then oxidized under antiselective 9-BBN hydroboration conditions (Schemes 7.96) [238].

Scheme 7.96

Six-membered O,O-heterocycles

395

Enantioenriched α,β-unsaturated lactones served as a key structural subunit of many natural products. During the preparation of pironetin, a protocol was reported to produce the unsaturated lactone fragment from lactone. The unsaturated lactones obtained by this reaction underwent 1,4-addition to prepare the heteroatom (N, S)-containing lactone library (Scheme 7.97) [239].

Scheme 7.97

The tetrahydrochromen-5-one was prepared under MWI in the presence of zinc chloride/montmorillonite K-10 (Scheme 7.98). The excellent yield of 2,4-diphenyl-4H-chromen-5-one was obtained [240].

Scheme 7.98

Rossing protocol was used for the preparation of 2-acylphenoxyacetic acids under nitrogen atmosphere with phase transfer catalyst to afford the either 2-acetyl benzofurans or benzofurans. The structural features of substrates and solvent affected the selective synthesis of 2-acetyl benzofurans and benzofurans. The ethylfuro[2,3-h]chromone-8-carboxylates were formed in good yields when a mixture of 8-formyl-7-hydroxy chromones was reacted with ethyl bromo acetate under nitrogen atmosphere in potassium carbonate as phase transfer catalyst (Scheme 7.99) [241]. Liu et al. [242] synthesized xanthone derivative with extended π-systems and some other structurally perturbed analogues (Scheme 7.100). These formed derivatives work as α-glucosidase inhibitors. The xanthone derivative with least conjugated system was less effective, thus it

396

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 7.99

Scheme 7.100

was proved that extended conjugation played a crucial role in the inhibition process [243].

7.2.24 Zirconium-assisted synthesis Various chiral catalysts like vanadium, titanium, chromium, manganese, copper, cobalt, zirconium, zinc, palladium, rhodium, samarium, lanthanum, ytterbium, and europium bearing a chiral ligand have been developed for asymmetric hetero-Diels
Alder reaction. Yamashita and coworkers [244] used a chiral zirconium catalyst for asymmetric transselective hetero-Diels
Alder reaction. The 1,3-diene was reacted with aldehydes smoothly in the presence of chiral zirconium complex, obtained from Zr(O-t-Bu)4, n-propanol, the 1,1'-bi-2-naphthol derivative, and water, and the pyranone derivatives were formed with high trans-selectivities and enantioselectivities in high yields (Scheme 7.101). The asymmetric synthesis of (1)-prelactone C was performed using a chiral ligand (Scheme 7.102) [245].

Six-membered O,O-heterocycles

397

Scheme 7.101

Scheme 7.102

The ZrOCl2  8H2O displayed high catalytic activities for the preparation 3-subsituted coumarins via Knoevenagel condensation under MW heating and solvent-free conditions. This method has several advantages such as high yields, low loading of catalyst, clean reaction, and use of various substrates that made it attractive protocol for the generation of 3substituted coumarins (Scheme 7.103) [246,247].

Scheme 7.103

Many asymmetric syntheses of exo- and endo-brevicomin have been reported but the development of a short synthetic pathway with good yield is lacking and therefore of interest. The epoxide was formed in 85% yield and 99.5% enantiomeric excess using Sharpless asymmetric epoxidation reaction. The ring-opening of epoxide was performed with Grignard reagent derived from 2-(2-bromoethyl)-2-methyl-1,3-dioxolane. Takano’s synthesis of exo-brevicomin in 78.5% enantiomeric excess and 29% overall yield required 6 steps and also started with same epoxide. The syn-diol was afforded in 80% yield upon ring-opening of epoxide in the presence of cuprous iodide at 78 °C. The diol was treated with zirconium chloride under MWI in MeOH to provide the (1R,5S,7S)-5-methyl-7-vinyl-6,8dioxabicyclo[3.2.1]octane in 86% yield through the formation of (S)-1((2R,6S)-6-methoxy-6-methyltetrahydro-2H-pyran-2-yl)prop-2-en-1-ol,

398

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

which was also recovered in 12% yield. Acetal (S)-1-((2R,6S)-6methoxy-6-methyltetrahydro-2H-pyran-2-yl)prop-2-en-1-ol was treated with zirconium chloride in methanol under MWI to form the required compound (1R,5S,7S)-5-methyl-7-vinyl-6,8-dioxabicyclo[3.2.1] octane quantitatively. The (p)-endo-brevicomin was formed in enantiomeric excess 98.5% and 95% yield when (1R,5S,7S)-5-methyl-7-vinyl6,8-dioxabicyclo[3.2.1]octane was hydrogenated in catalytic amount of 5 mol% palladium/carbon in an autoclave at 10 bar of pressure (Scheme 7.104) [248].

Scheme 7.104

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5761.

CHAPTER 8

Six-membered O,N-heterocycles 8.1 Introduction Oxazines and their derivatives are heterocyclic compounds containing one oxygen and one nitrogen. Oxazine heterocycles have special interest because they constitute an important class of nonnatural and natural products and show useful biological activities [1
4]. The 1,4-oxazine scaffold is a structural subunit of many synthetic and naturally occurring bioactive compounds and exhibit diverse biological activities such as sedative, antiulcer, antipyretic, analgesic, antitubercular, anticonvulsant, antimalarial, antitumor, antihypertensive, antimicrobial, anticancer, antifungal, and antithromobotic compounds [5
9]. 1,3-Oxazines have generated great interest as antipsychotic agents and as possible effectors for serotonin and dopamine receptors. Oxazines are an important group of organic dyes that are generally π-conjugated systems, with interesting photophysical and lasing properties [10
12]. Oxazine derivatives are an important class of heterocycles, and have attracted much synthetic interest due to their wide range of biological activities. These days, development of drug resistance is a major problem and to overcome this situation, it is necessary to synthesize new classes of compounds [13]. Synthesis of compounds containing oxygen and nitrogen in a ring is of growing importance by virtue of their presence in numerous biologically important compounds. Therefore the design and synthesis of new diverse polycyclic heterocycles with potential medicinal and biological activity from readily available starting materials in a time- and cost-effective manner has received significant attention in research on combinatorial, organic, and medicinal chemistry. The development of simple synthetic routes to widely used organic compounds using readily available reagents is one of the main objectives of organic synthesis [14
16].

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00008-7

© 2020 Elsevier Inc. All rights reserved.

413

414

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

8.2 Metal- and nonmetal-assisted synthesis of six-membered O,N-heterocycles 8.2.1 Aluminum-assisted synthesis The nitroalkene underwent tandem cycloaddition. A racemic version was first investigated to ensure the success of this process. There were two major purposes of this endeavor. The first was to gain insights into the stereoselectivity of cycloaddition events and to simplify the stereochemical outcome. The achiral vinyl ether was used to reduce the possible number of formed diastereomers. The second purpose was to optimize the reaction conditions, which were directly applied to the asymmetric synthesis. Therefore n-butyl vinyl ether was used in [4 1 2]-cycloaddition reaction with nitroalkene and trimethylaluminum as the Lewis acid promoter (Scheme 8.1). This reaction was highly facile and excellent yields of nitronate were obtained [17].

Scheme 8.1

Only desired thiazepines were formed in excellent yield when β-benzoyl arylic acid was reacted with 2-chloroacetyl chloride over basic alumina (as inorganic solid support) under microwave irradiation and solvent-free conditions in 5
6 min. The yield was improved to 30% if a solution of 2-chloroacetyl chloride in benzene was added drop wise into a solution of triethylamine and benzothiazepine in benzene. The desired azeto[2,1-d][1,5]benzothiazepines were not formed upon using 3 eq. of 2chloroacetyl chloride to improve the yield; but the yield of byproduct 1,3-oxazine derivative was improved slightly. In another trial first the diketenes were formed through addition of triethylamine to a solution of 2-chloroacetyl chloride in benzene and subsequently 1,5-benzothiazepine was added into the resulting reaction mixture to give only 1,3-oxazine derivative in low yield. On the other hand, the desired azeto[2,1-d][1,5]benzothiazepine was formed under MWI with good yield as the only product (Scheme 8.2) [18a,b].

8.2.2 Bismuth-assisted synthesis The benzoxazine derivatives were synthesized using bismuth triflate catalyst. The Bi(OTf)3  xH2O-catalyzed intramolecular cationic cyclization of

Six-membered O,N-heterocycles

415

Scheme 8.2

3-acetoxy-2-(phenoxymethyl)-isoindolin-1-one and 3-acetoxy-2-[(3,5dimethoxyphenoxy)methyl]-isoindolin-1-one provided 6,12b-dihydroisoindolo[1,3-c][1,3]-benzoxazin-8-one and its 1,3-dimethoxy derivative in 65% yield (Scheme 8.3) [19
21].

Scheme 8.3

The preparation of piperidine derivatives is of major importance. The 2-cyano-l-azadienes possessing an electron-rich enol ether dienophile component underwent cycloaddition to afford the oxazinopiperideines. This reaction was catalyzed by bismuth chloride and the trans-isomer was formed as a major reaction product (Scheme 8.4) [20,21].

Scheme 8.4

416

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

8.2.3 Copper-assisted synthesis A microwave-assisted method was developed for the fast preparation of 2H-1,4-benzoxazin-3-(4H)-ones via a cascade reaction with a nucleophilic substitution followed by a cuprous iodide/1,8-diazabicyclo[5.4.0] undec-7-ene-catalyzed coupling-cyclization (Scheme 8.5). This approach involved short reaction time, simple reaction conditions, a broad substrate scope, and moderate-to-good yields [22]. Bao et al. [23] reported coppercatalyzed tandem reactions for the preparation of 2H-1,4-benzoxazin-3(4H)-ones using easily available 2-haloamides and o-hydroxylaryl halides. The reactions were carried out successfully employing cuprous iodide/ cesium carbonate/1,10-phenanthroline systems at 90 °C in dioxane. Simultaneously, Liu and Wan [24] synthesized the same target products using 1,8-diazabicyclo[5.4.0]undec-7-ene and identical starting materials under MWI.

Scheme 8.5

2-Cyano-1-azadienes containing either N-phenyl or N-acyl substituent reacted under thermal conditions with both electron-poor (HOMO azadiene-controlled) and electron-rich (LUMO azadiene-controlled) dienophiles [25
27]. The Cu(OTf)2-catalyzed intramolecular Diels
Alder reaction of 2-cyano-1-azadiene, bearing an electron-rich enol ether dienophile component, underwent cycloaddition to afford the oxazinopiperidines with a cis/trans ratio of 1/3.7 in 60% yield (Scheme 8.6) [28]. The asymmetric intramolecular cycloaddition in the presence of Cu (OTf)2 catalyst was not efficient as oxazino-piperidines were formed with an ee of 8%. This result has suggested that reaction occurred via singlepoint diene/catalyst complex and the cyano group was not coordinated to the copper cation [29].

Scheme 8.6

Six-membered O,N-heterocycles

417

Various nitroso compounds, which were very reactive heterodienophiles, underwent hetero-Diels
Alder reactions at low temperatures [29
31]. The disproportionation of Boc
NHOH to form the Boc
N5O was activated by copper catalyst CuBr  Me2S, and the formed Boc
N5O was involved in hetero-Diels
Alder reaction with 1,3-dienes. The 1,3-cyclohexadiene and Boc
NHOH were treated with 10 mol% CuBr  Me2S to provide the acylnitroso that was trapped efficiently to synthesize the hetero-Diels
Alder adduct. The heteroDiels
Alder adduct was formed in 41% yield after 65 h. The efficiency of hetero-Diels
Alder cycloaddition was improved dramatically when the reaction was performed at 20 °C within a few hours with cuprous chloride as catalyst using a stoichiometric oxidant hydrogen peroxide (Scheme 8.7) [32].

Scheme 8.7

Wilson and coworkers [33] prepared optically active cycloadducts from 1,3-dienes and arylnitroso derivatives. The oxidizing agent used was enantiomerically pure complex cupric chloride. Unfortunately, no enantioselectivity was reported. The dissociation of acylnitroso from the chiral metal complex occurred before the [4 1 2]-cycloaddition (Scheme 8.8) [29].

Scheme 8.8

The (2Z,4E)-3-trimethylsilyloxy-2,4-hexadiene was reacted with (S)(SEGPHOS)/CuPF6  (MeCN)4 [(S)-LI/CuPF6(MeCN)4] to give the hetero-Diels
Alder adduct with complete regioselectivity [34
38] but in very low ee (16%). However, the size of silyl group was increased (trimethylsilyl , tert-butyl(dimethyl)silyl , TIPS) to improve the low enantioselectivity. Furthermore, the ee of hetero-Diels
Alder adduct was increased to 99% [39] using diene and (S)-DIFLUORPHOS/ CuPF6(MeCN) (Scheme 8.9) [29].

418

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.9

Minatti and Buchwald [40] developed a copper-catalyzed annulation of functionalized aryl iodides by introducing primary amines to afford the benzoxazines, and the structure of functionalized aryl iodides was modified to produce the corresponding homologues (Scheme 8.10). The reaction comprised tandem carbon
nitrogen coupling and intramolecular SN2 displacement as demonstrated by designed experiments [24].

Scheme 8.10

As an active reactant containing both nucleophilic and electronic sites, aziridine derivatives were found as good precursors for the preparation of N-heterocycles via copper-catalyzed ring-opening/carbon
nitrogen coupling reactions. Seker and coworkers [41] have done this type of representative work. o-Halophenols were used as reaction partners of aziridines to initiate the reaction. The trans-fused tricyclic products 3,4-dihydro-2Hbenzo[b][1,4]oxazines [42] were synthesized in good-to-excellent yields using cuprous iodide, ligand as well as base (Scheme 8.11) [24].

Scheme 8.11

Schöllkopf and Jentsch [43] reported a ring-opening of oxirane with lithiated 2-isocyanopropionate. The oxirane acted as an alkylating agent in this reaction. Later on asymmetric epoxides were used in this reaction.

Six-membered O,N-heterocycles

419

The optically active epoxides were treated with lithiated tert-butyl ester and boron trifluoride to provide the good yields of γ-hydroxy-isocyanoacetates. The oxazine derivatives, starting substrates for the total synthesis of structural analogues of cephalosporins, were easily prepared from γ-hydroxy-isocyanoacetates upon heating with Cu2O in toluene (Scheme 8.12) [44,45].

Scheme 8.12

The use of an organic solvent under high pressures of oxygen was a potential safety hazard. This issue was addressed by diluting oxygen with an inert gas, like nitrogen, to ensure that the mixture remained outside of flammability limits of the solvent [46,47]. Such conditions were applied in a one-gram scale oxidative cyclization of intermediate, which was featured in five-step synthesis of the unprotected benzomorpholine product from easily available substrates (Scheme 8.13). The aerobic oxidative cyclization step occurred under these modified conditions to afford the quantitative yield [48].

Scheme 8.13

8.2.4 Gold-assisted synthesis The alkynyl-β-lactams underwent regiocontrolled Au/Brønsted acid cocatalyzed bis-heterocyclization for the efficient synthesis of optically pure tricyclic bridged acetals containing 2-azetidinone [49,50]. The terminal alkyne was treated with gold(III) chloride/p-toluenesulfonic acid (PTSA)

420

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

catalytic system to afford the desired ketal. The alkyne hydration also provided polar ketone in appreciable amounts. The [AuClPPh3]/AgOTf/ PTSA system displayed better activity. Interestingly, the 6,8-dioxabicyclo [3.2.1]octane derivative was formed by metal/acid cocatalyzed reaction of terminal alkynyl dioxolane; on the other hand, this reaction provided alkynyl dioxolanes as sole products (Scheme 8.14) through an exclusive 7endo/5-exo-bis-oxycyclization by initial attack of oxygen atom on the external alkyne carbon. Competition between the initial 7-endo- and 6exo-oxycyclizations appeared to favor the former, despite the fact that this was energetically more demanding [51].

Scheme 8.14

The furan analogues were constructed by an effective intramolecular addition of a hydroxy group to C
C triple bond. The Au(I)-catalyzed cyclization of monoallylic diols is an efficient method for the synthesis of tetrahydropyran analogs (Scheme 8.15) [52
54].

Scheme 8.15

A different reaction mode was reported with internal alkynes. The sixmembered 1,3-oxazine heterocyclic compounds were obtained by a 6endo-dig cyclization. With N-heterocyclic carbene (NHC) ligand, the intermediate was deprotonated by a base to afford a vinylgold species in good yields (Scheme 8.16); the same reaction failed with a phosphane ligand [55,56]. They are true intermediates of reaction and they also acted as catalysts in the presence of acid [57]. In order to devise efficient synthesis of potential bioactive fused heterocyles, a highly efficient [Au{P(t-Bu)2(o-biphenyl)}{CH3CN}]SbF6catalyzed cascade cycloisomerization was developed for the synthesis of

Six-membered O,N-heterocycles

421

Scheme 8.16

pyrrolo/pyrido[2,1-b]benzo[d][1,3]oxazin-1-ones (Scheme 8.17) [58], pyrrolo/pyrido[2,1-a][1,3]benzoxazinones (Scheme 8.18) [59], and benzo[e] indolo[1,2-a]-pyrrolo[2,1-c][1,4]diazepine-3,9-diones (Scheme 8.19). These cascades occurred from an initial enol lactone intermediate via an intramolecular cycloaddition [60]. The observed products were obtained by a subsequent intermolecular hydroamination of the intermediate, followed by a cyclization. The strategy provided an efficient and straightforward synthesis of tricyclic lactam molecular architectures in which several C
N and C
C bonds were formed from simple starting materials in a one-pot reaction [54,61].

Scheme 8.17

Scheme 8.18

Mixtures of 3,6-dihydro-1,2-oxazines and 4,5-dihydroisoxazoles were obtained from allenic hydroxylamine ethers with exchanged positions of the hetero atoms under these conditions. The regioselectivity was shifted

422

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.19

in favor of isoxazoles when cationic Au(I) complexes Ph3PAuBF4 were used (Scheme 8.20) [62,63]. On the contrary, a selective 6-endo-cyclization occurred to afford the oxazines when N-Boc-protected hydroxylamine ethers were treated with Au(I) chloride. This protocol was particularly versatile because allenic hydroxylamine ethers (precursors) of heterocyclic compounds were formed by Mitsunobu reaction in a stereoselective manner from the same hydroxyallenes [64a,b].

Scheme 8.20

In intramolecular hydroamination of alkynes with imine derivatives, Shin and coworkers [65] reported that homopropargylic trichloroacetimidates underwent 6-exo-trig cyclizations under mild conditions (0 °C) in the presence of Ph3PAuBF4. They had success with both internal and terminal alkynes, and the anti-addition product was formed exclusively in all cases (Scheme 8.21). The Au(I)-catalyzed intramolecular hydroamination of trichloroacetimidates obtained from homopropargyl and propargyl alcohols has been reported [66]. A variety of trichloroacetimidates underwent efficient hydroamination in the presence of 2
5 mol% cationic gold (I) complex under exceptionally mild conditions. An orthogonality of

Six-membered O,N-heterocycles

423

Scheme 8.21

Au-catalyzed protocol using a stoichiometric electrophile has been demonstrated [67]. Dixon and coworkers [68] developed an interesting Au(I)-catalyzed reaction of primary amines and alkynoic acids. Good yields of multiring heterocyclic products were obtained. The alkynoic acids will form enol lactone intermediates, which reacted subsequently with primary amines to afford the N-acyl iminium intermediates. The multiring heterocyclic products were constructed when tethered electron-rich heterocyclic compounds attacked the iminium. Internal and terminal alkynes were suitable for additions. To probe the nature of active catalyst for final two steps in the sequence, control experiments were performed using HOTf and/or a phosphorine base (2-tert-butylimino-2-diethylamino-1,3dimethylperhydro-1,3,2-diazaphosphorine), which confirmed that indeed a Lewis acid and Brønsted acid assistance was responsible for this part of the reaction (Scheme 8.22) [66].

Scheme 8.22

Kimber and coworkers [69a] reported a gold(I)-catalyzed intramolecular hydroarylation of allenamides for the synthesis of α-vinyl-substituted tetrahydroisoquinolines (Scheme 8.23). When R 5 Boc, the hydroarylation reaction impeded maybe due to the steric hindrance of bulky Boc group [69b].

Scheme 8.23

424

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

8.2.5 Iodine-assisted synthesis The 1,2,4,5-thiaoxadiazines were formed in 61%
80% yields when 1,5diacyl thiocarbohydrazides were cyclized with iodine [70]. The color of iodine disappeared gradually upon addition of iodine solution in ethanol with continuous stirring. The iodine was added continuously until it was in slight excess indicated by the persistence of its violet color. The reaction mixture was kept overnight to provide the granular solids that were identified as dihydroiodo-1,2,4,5-thiaoxadiazines, which upon basification with dilute ammonium hydroxide afforded free base (Scheme 8.24) [71].

Scheme 8.24

Majumdar et al. [72] reported an efficient protocol for the preparation of 3,4-dihydro-2H-1,4-benzoxazine derivatives (Scheme 8.25). The carbon
carbon double bond of compound was activated with iodine to produce an iodoiranium intermediate that underwent 6-exo-trig cyclization to afford the products [73].

Scheme 8.25

8.2.6 Iron-assisted synthesis Loudon and coworkers [74
76] synthesized indole and quinolone derivatives readily by the interaction of aromatic nitro groups and ortho-sidechains. On the other hand, the displacement of an ortho-substituent occurred frequently when a diaryl derivative with two ortho nitro groups was reduced in an alkaline solution. The 2,2-dinitrodiphenyl amine was transformed into phenazine with sodium sulfide [77]. Similarly, phenothiazine was formed in one-step when 2,20 -dinitrodiphenyl sulfide was reacted with hydrazine (Scheme 8.26) [78]. The 4-methylphenoxazine was reacted with ferrous oxalate to provide the 40 -methyl-2-nitrodiphenyl ether [79].

Six-membered O,N-heterocycles

425

Scheme 8.26

8.2.7 Lithium-assisted synthesis The tetracyclic tetrahydroquinolines were synthesized by a threecomponent reaction based on the o-aminocinnamate (amine and dienophile in a single component). An amine, aldehyde, and an isocyanoacetamide were reacted in toluene employing lithium bromide as promoter in stoichiometric amount. Under these conditions, two pairs of diastereomers were formed in 95% yield out of 16 possible isomers [80]. Under controlled conditions, the mixture of diastereomers was cleanly transformed into 4,5-phenanthroline in 71% yield (Scheme 8.27) [45].

Scheme 8.27

Various benzo-fused six-membered hetero- and carbocycles were synthesized from simple starting substrates via intramolecular aryne-ene reaction. The reaction was highly diastereoselective, and its scope included conventional substituted benzynes as well as extended to intriguing hetero-aryne systems. The out-competing external nucleophilic attack on aryne intermediate affected the success of this reaction. This was accomplished by tuning the polarity of aryne triple bond via substituent

426

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

inductive effects. Another aspect of this reaction was the use of aryne-ene reaction in the total synthesis of (1/ 2 )-crinine (Scheme 8.28) [81].

Scheme 8.28

The applications and synthesis of stabilized oxiranyllithium reagents have been reviewed [82,83]. The lithiated aryloxiranes were used for the asymmetric synthesis of cyclopropanes from the reaction of α,β-unsaturated Fischer carbene complexes and oxiranyllithiums [84], or the use of oxazolidine ring for fixing and directing the stereoselectivity of lithiation, as commented in the case of aziridinyllithium reagents. A recent example of the latter protocol was that enantiomerically pure oxazolidinyl-substituted arylepoxide underwent diastereoselective lithiation to produce the organolithium reagent (Scheme 8.29) [85]. This chiral oxiranyllithium species reacted with nitrones to synthesize the 1,6-dioxa-4,7-diazaspiro[4.5]decane derivative, which was converted into γ-butyrolactones or γ-amino acid derivatives after some transformations [86].

Scheme 8.29

8.2.8 Mercury-assisted synthesis Harding and coworkers [87,88] reported a method for the synthesis of substituted 1,3-oxazines. In Scheme 8.30, the unsaturated carbamate was transformed into a 3:1 cis/trans mixture of diastereomers [89].

Scheme 8.30

The reactivity of 1,3-diamino-1,3-butadienes was investigated in order to expand the scope of available dienophiles in Diels
Alder reactions.

Six-membered O,N-heterocycles

427

Surprisingly, few studies have been reported on these potentially highly reactive and useful dienes as substrates in Diels
Alder reactions. Gompper and Heinemann [90] developed the in situ synthesis of 1,3-bis(dimethylamino)-1,3-butadiene from vinamidinium salt and its subsequent Diels
Alder reaction with dimethyl acetylenedicarboxylate to provide the modest yield (43%) of poly-substituted aromatic ring. Other vinamidinium salts containing additional functional groups behaved similarly with this dienophile. Barluenga et al. [91] reported the synthesis of 1,3-dimorpholino-2-methyl-1,3-butadiene and its reactions with various dienophiles. However, the protocol used to synthesize this diamino diene was not generally applicable to a variety of diamino dienes and needed toxic mercury salts (Scheme 8.31) [89,92].

Scheme 8.31

A mixture of five- and six-membered rings was formed depending on the substituents present on starting unsaturated carbamate. A mixture of heterocycles was obtained by mercuration-demercuration of compounds (Schemes 8.32 and 8.33) [89,93,94].

Scheme 8.32

Scheme 8.33

428

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The structure of final heterocyclic compound was fixed by the unsaturated chain in starting material. The mercuration-demercuration of compounds afforded benzo-fused bicycles as major products (12:1 diastereomer ratio), and the stereochemistry depends on the size of newly formed ring (Schemes 8.34 and 8.35) [89,95,96].

Scheme 8.34

Scheme 8.35

The heterocyclic compounds were synthesized by double addition to dienic compounds using primary carbamates, and the reaction was highly stereoselective as compared to the aminomercuration. Thus either 1,5- or 1,4-hexadiene afforded the cis-pyrrolidine as only reaction product isolated after the final reduction (Scheme 8.36) [97]. The same protocol was applied to diallylether to afford the trans-morpholine exclusively. However, a 1:1 mixture of two possible bicycles was formed in the case of 1,5-cyclooctadiene [89].

Scheme 8.36

8.2.9 Nickel-assisted synthesis The N-allyl anhydride [98,99] was synthesized from 4-benzyloxy-3methoxybenzoic acid [100] in six steps (Scheme 8.37). The esterification of 4-benzyloxy-3-methoxybenzoic acid provided methyl ester that was nitrated with fuming nitric acid to give the methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate in 83% yield. Sodium borohydride cleanly reduced the nitro group of methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate using

Six-membered O,N-heterocycles

429

Scheme 8.37

nickel(II) chloride catalyst to form an aniline, which was transformed to acid by hydrolysis. The 7-benzyloxy-6-methoxyisatoic anhydride was obtained as a solid after simple filtration when sodium salt of acid was treated with a phosgene-toluene solution. The 7-benzyloxy-6methoxyisatoic anhydride was treated with sodium hydride followed by allyl bromide in N,N-dimethylacetamide to afford the desired N-allyl anhydride [101,102]. The commercially available 2-aminophenols underwent a regioselective one-pot reaction for the synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines under MW heating. The acyclic intermediates were produced by base-mediated regioselective O-alkylation with 2-bromoalkanoates. A subsequent intramolecular amidation reaction provided good yields of desired products (Scheme 8.38) [103].

Scheme 8.38

8.2.10 Palladium-assisted synthesis Substituted benzoxazinone derivatives are present in many natural and biologically active compounds [104a,b]. Petricci et al. [105] reported a cyclohydrocarbonylation reaction utilizing acyl chlorides and 2iodoaniline for the synthesis of benzoxazinones (Scheme 8.39). Tietze and coworkers [106,107] reported domino-Wackercarbonylation and Wacker
Mizoroki
Heck reactions for the conversion of substituted allylamine derivatives into perhydro-1,4-oxazines (Schemes

430

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.39

8.40 and 8.41). This protocol was based on an efficient palladiumcatalyzed domino reaction, initiated by a Wacker oxidation and subsequent insertion of the palladium-species formed into the π-bonds of carbon monoxide, esters, and α,β-unsaturated ketone [108].

Scheme 8.40

Scheme 8.41

The challenge of synthesizing six-membered rings via Wacker-type oxidative cyclization was illustrated with substrate, a precursor to 3vinylmorpholine derivative. This substrate was cyclized with two of the most versatile catalyst systems that have been reported previously: Larock and Hightower [109] and Hiemstra et al. [110] introduced palladium acetate in dimethylsulfoxide and palladium acetate/pyridine in toluene as solvent. These catalysts were used to produce the diverse pyrrolidine derivatives, but they have shown limited success in the synthesis of sixmembered rings. Only trace yields of 3-vinylmorpholine derivative were obtained when substrate was reacted with these catalysts (Scheme 8.42) [48,111
115].

Scheme 8.42

Six-membered O,N-heterocycles

431

The substrates under reaction conditions afforded 3-methylenedihydrobenzoxazines instead of the usual dihydrobenzoxazole ring system and did not confirm the hypothesis that propargyl derivative reacted via allene intermediate (Scheme 8.43) [116
118].

Scheme 8.43

The formation of allylic amide products in predominant amounts raises the possibility that these reactions could proceed via an allylic carbon
hydrogen activation pathway, rather than via aminopalladation of alkene (Scheme 8.44). Chen and White [119] reported allylic amination reactions using palladium(II) catalysts in dimethylsulfoxide and they are of particular relevance in this context [120,121]. The homoallyl ether substrate was subjected to oxidative cyclization conditions to distinguish between two mechanisms. The major product of reaction was a sevenmembered ring as expected from an aminopalladation pathway. The allylic carbon
hydrogen activation product was detected in only small amounts; however, this product was formed probably by aminopalladation, which was formed in situ via isomerization of homoallyl ether substrate. Collectively, these observations have suggested that product was formed predominantly by aminopalladation pathway [48].

Scheme 8.44

CO insertions catalyzed by metal are important reactions in organic synthesis. This reaction was catalyzed efficiently with palladium [122]. However, carbon monoxide carbonylations with metal carbenes in the presence of metal catalyst are rare and proceed only under high pressures

432

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

and/or temperatures. Zhang et al. [123] reported carbon monoxide carbonylation of diazocarbonyl compounds with palladium catalyst under more mild conditions. This reaction pathway was demonstrated by trapping the palladium-bound ketene intermediate with alcohols and amines to afford the good yields of dicarbonyl compounds. Additionally, using imines, interesting six-membered heterocyclic compounds were formed in 65%
93% yield (Scheme 8.45).

Scheme 8.45

The enantiopure N-allyl aminoalcohols provided optically active morpholine-type acetals in high yields with slight changes in the Li2PdCl4/cupric chloride reagent system (Scheme 8.46) [124,125].

Scheme 8.46

The cyclic chloromethyl derivatives were formed in high yields when amino alcohols were reacted in the presence of cupric chloride as oxidant, Li2PdCl4 as catalyst, and tetrahydrofuran as solvent (Scheme 8.47) [124,125].

Scheme 8.47

Six-membered O,N-heterocycles

433

The aminocarbonylation of allenic N-tosylcarbamates was performed with palladium catalytic system under buffered conditions to afford the 1,3-oxazin-2-ones possessing an acrylate side-chain. The reaction proceeded with high stereoselectivity and provided only trans-4,5-disubstituted heterocyclic compounds (Scheme 8.48) [125
127].

Scheme 8.48

Merck research group optimized the reaction conditions for reductive cyclization and contributed some mechanistic insights by experiment [128] and computation. Although Diels
Alder adducts were not obtained for the cyclization reaction upon adding 2,3-dimethylbutadiene, an oxazine was obtained from 2,3-dimethylbutadiene and o-nitrobenzene under reductive carbonylation conditions (Scheme 8.49). This result showed that intramolecular cyclization of o-nitrostyrenes was faster than intermolecular cycloaddition with dienes and that aromatic nitro groups were reduced to nitroso species under these conditions. Also, a linear correlation was obtained in a plot of the log of the rate ratio (kX/kH) versus the reduction potential of the substituted nitrostyrenes. It has been suggested that the rate/turnover limiting step was likely the initial reduction of substrate, which involved an electron transfer to the nitroarene [129
131].

Scheme 8.49

Various six-membered ring biaryl compounds containing both electron-withdrawing and electron-donating substituents were synthesized in excellent yields (Scheme 8.50). The nitrogen- and alkyl-containing tethers were tolerated but needed higher catalyst loadings to ensure the complete conversion [132].

434

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.50

While the catalytic system was extremely effective for the direct arylation of aryl bromides, no reaction occurred or poor yields of cyclized products were obtained for aryl chlorides. Fagnou and coworkers [133] reported new conditions using electron-rich NHC ligands [134]. Various functionalized five- and six-membered rings were synthesized in excellent yields with varying tethers such as amine, ether, alkyl, and amide functionalities using potassium carbonate and 1
3 mol% catalyst at 130 °C in dimethylaniline (Scheme 8.51).

Scheme 8.51

This reaction was limited to aryl bromides, no reaction occurred with aryl chlorides. However, upon using an electron-rich NHC ligand, various functionalized five- and six-membered rings were synthesized in excellent yields with varying tethers such as amine, ether, alkyl, and amide moieties (Scheme 8.52) [135].

Scheme 8.52

The palladium hydroxide/carbon was reported to be very effective for intramolecular direct arylation of aryl bromides and aryl iodides to synthesize the five- and six-membered carbo- and heterocyclic ring systems (Scheme 8.53) [136].

Six-membered O,N-heterocycles

435

Scheme 8.53

Fagnou and coworkers [137] reported an intramolecular direct aryation of aryl bromides, chlorides, and iodides with an efficient general catalyst system (Scheme 8.54) to produce various five- and six-membered heteroand carbocyclic biaryl compounds.

Scheme 8.54

8.2.11 Platinum-assisted synthesis The reactivity was diminished and the regioselectivity of cycloisomerization reaction was changed when an electron-withdrawing substituent was present in the para position of aromatic ring. Thus 2.5:1 ratio of the 7endo-product to the 6-exo-product was observed in the case of p-CF3. The ratio between the 7-endo-dig enol ether and the 6-exo-dig enol ether was the same as for the final products (2.5:1), which supported the hypothesis that these enol ethers were indeed intermediates in the formation of fused bicyclic acetals. The reaction proceeded much more slowly with the strongly electron-withdrawing nature of the p-nitro group and, notably, the fused bicyclic acetal product was isolated in a major amount arising from a 6-exo-cyclization. However, the formation of several unidentified side products was observed in this reaction. Encouraged by these results this reaction explored whether the platinum catalyst could directly convert the butane diacetal (BDA)-protected substrate into the desired bicyclic acetal product by a domino de-protectionhydroalkoxylation sequence. Since acetal protecting groups can generally be removed by acid treatment, the Lewis acid catalyst should be capable of cleaving the BDA group and generating the diol in situ, [138
141] which then should undergo a double intramolecular hydroalkoxylation reaction of the triple bond. Indeed, after some experimentation it was

436

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

reported that 2 mol% platinum(IV) chloride in acetic acid resulted in complete conversion of the starting material into bicyclic acetal. Although other Lewis acids were able to form the diol and cleave the BDA, only gold(III) chloride and platinum(IV) chloride could catalyze the subsequent hydroalkoxylation reaction. Other solvent systems were not as effective for the domino sequence. In particular, the addition of excess water (5% v/v) led to no conversion of the starting material and complete deactivation of the catalyst. Faster conversion was reported upon addition of trifluoroacetic acid to the reaction mixture. Any conversion of starting material was not reported with acetic acid alone, which clearly suggested that the platinum catalyst was necessary for both steps of the domino reaction (Scheme 8.55).

Scheme 8.55

8.2.12 Rhodium-assisted synthesis Olson and Du Bois [142] reported rhodium-catalyzed carbon
hydrogen activation in unsaturated sulfamate derivatives for the synthesis of oxathiadiazinanes (Scheme 8.56). They proposed that such carbon
hydrogen amination provided a new general pathway to carbon
nitrogen bond formation. These oxathiadiazinanes served as precursors of differentially protected vicinal diamines [108].

Scheme 8.56

Chiou and coworkers [143] synthesized 1-azabicyclo[4.3.0]alkane amino acid derivatives and their congeners by rhodium-BIPHEPHOScatalyzed extremely regioselective cyclohydrocarbonylation of allylamides

Six-membered O,N-heterocycles

437

under mild conditions. The reaction involved two consecutive cyclization steps, first step provided the cyclic N-acyliminium key intermediate via cyclohydrocarbonylation, whereas the second step produced the 1-azabicyclo[4.3.0] system with high diastereoselectivity (Scheme 8.57) [108].

Scheme 8.57

The carbonylation of isoxazolidines occurred with insertion of carbon monoxide into nitrogen
oxygen bond with [Rh(COD)Cl]2 catalyst to provide the tetrahydro-1,3-oxazin-2-ones in 20%
82% yield (Scheme 8.58). However, in the presence of iridium trichloride catalyst, the carbonylation proceeded and was followed by hydrogen transfer from another molecule of substrates. The cyclohexene was used as an external hydrogen source for Ir-catalyzed conversion [144,145].

Scheme 8.58

Du Bois and coworkers [146] extended this reaction to sulfamate esters as aminating agents. The sulfamates were more active toward amination as shorter reaction times and lower Rh catalyst loadings afforded the oxathiazinanes in good yields (Scheme 8.59).

Scheme 8.59

Zalatan and Du Bois [147] performed the same enantioselective reaction with dimeric Rh(II) complex. Analogous to Blakey’s Ru(II)-pybox system, Du Bois’ Rh2(S-nap)4 complex, along with 3 Å molecular sieves and iodosobenzene, catalyzed the cyclization of benzylic sulfamate esters efficiently with good-to-excellent enantioinduction (Scheme 8.60). This

438

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

new Rh(II) system was also highly chemoselective for allylic C
H bond amination over olefin aziridination. This reversal in selectivity was highlighted with an allylic substrate where amination occurred to form a five-membered ring; aziridination was favored with Rh2(OAc)4, but amination was favored with Rh2(S-nap)4. While the enantioselectivities suffer for trans-olefinic and terminal substrates (12%
54% enantiomeric excess), allylic amination of cis-olefinic substrates resulted in good asymmetric induction (82% and 84% enantiomeric excess). These results were in contrast to the Ru(II)-pybox system where the reverse selectivities were observed, thus providing evidence for different mechanisms between Ru and Rh catalysts. Data from a cyclopropane clock experiment for Du Bois’ system is consistent with a concerted, nitrene-type amination.

Scheme 8.60

8.2.13 Ruthenium-assisted synthesis Michael addition was involved with this catalytic system (Scheme 8.61). It was reported that the compounds used in palladium chemistry, with a t-Boc protected hydroxylamine, as well as their higher homologues, underwent cross-metathesis with electron-poor alkenes, like methyl acrylate, followed by subsequent intramolecular conjugate addition. Unfortunately, the attack of ruthenium on the nitrogen
oxygen bond complicated the cross-metathesis, which resulted in low yields of desired cross-metathesis product, catalyst deactivation, and, in one case, isolation of a curious ketone. On the other hand, cross-metathesis of phthaloylprotected hydroxylamines occurred very efficiently, even with only 0.5 mol% Grubbs second-generation catalyst. The isoxazolidines with poor stereoselectivity and tetrahydro-[1,2]-oxazines selectively as their trans-isomers were formed by subsequent dephthaloylation resulting in tandem intramolecular Michael addition [148].

Scheme 8.61

Six-membered O,N-heterocycles

439

Blakey and coworkers [149] reported amination of allylic and benzylic C-H bonds intramolecularly with high levels of enantiocontrol and good yields using a nonporphyrin-based Ru catalyst (Scheme 8.62). This Ru (II)-pybox process was intriguing as this catalytic system was highly selective for the C-H bond amination of allylic sulfamates that was not the case with the analogous Rh-catalyzed process where olefin aziridination [150] hampered the efficient C-H bond amination. Based on this chemoselectivity and previous work with Ru porphyrin complexes, it was suggested that the reaction occurred via bis(imido)Ru(VI) species and a hydrogen abstraction/radical rebound mechanism was in play.

Scheme 8.62

Besides Rh(II) dimers, Ru porphyrin complexes [151
156] were also effective catalysts for this stereospecific sulfamidate-forming reaction in 89% yield. This reaction occurred through the formation of iminoiodanes that interacted with catalyst to produce a bis(imido)Ru(VI) complex. The C-H bond insertion was also asynchronous and the hydrogen abstraction involved short-lived radical intermediates. Che and coworkers [157] for the first time used a chiral porphyrin ligand and an enantioselective intramolecular C-H bond amination occurred with enantiomeric excesses up to 88% (Scheme 8.63) [158,159].

Scheme 8.63

Piscopio and Robinson [160] reported that the first step in this synthesis was the protection of 2-aminophenol using Boc protecting group. This reaction occurred at room temperature for 18 h after which the crude product was washed with carbon tetrachloride and dried to provide the white crystals of product in 64% yield (Scheme 8.64). The resulting compound underwent an allylation reaction with allyl bromide at 60 °C using potassium carbonate as base in acetone as solvent. The O-monoallylated compound was isolated in 92% yield after purification by column

440

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.64

chromatography. This monoallylated compound was further allylated under the same conditions but did not afford the desired diallylated compound; the monoallylated starting material was re-isolated instead. Then, a stronger base, NaH, was used in the presence of allyl bromide with tetrahydrofuran as solvent. The reaction was carried out at room temperature for 18 h and provided 64% yield of diallylated compound after column chromatography. The diallylated compound was then isomerized with ruthenium catalyst at 95 °C for 18 h to provide an isomerized compound in 81% yield. The desired six-membered compound was formed in good yield (76%) when isomerized compound was treated with Grubbs II catalyst for 48 h at 60 °C. Small-to-medium size ring heterocyclic compounds were synthesized by isomerization
ring-closing metathesis (RCM) strategy. van Otterlo [161] used this protocol for the synthesis of benzo-fused six-membered heterocyclic compounds from starting aminophenol in the presence of Grubbs’ catalyst II. However, benzo-fused eight-membered heterocycles were synthesized from starting compound using Grubbs’ catalyst II (5 mol%) (Scheme 8.65).

Scheme 8.65

The 4H-benzo-[1,4]-oxazines were formed in good yields by isomerization of diallyl compounds followed by RCM reaction, although RCM reaction on the substrates bearing electron-rich vinylic olefins in the

Six-membered O,N-heterocycles

441

presence of Grubbs’ catalyst was problematic. One of the most interesting disclosures concerning the enyne metathesis was the formation of 2,3,4tri- and 2,3-disustituted furans from 1,2-dioxines [162,163]. The strategy was based on the enyne-RCM/Diels
Alder reaction sequence. The 1,2dioxines were converted into furans under reaction conditions as shown in Scheme 8.66. The substituted furan was formed by cycloaddition reaction of dienes with singlet oxygen followed by FeSO4-catalyzed reaction.

Scheme 8.66

The borrowing hydrogen protocol was applied to the transformation of primary amines into nitrogen heterocycles via a double alkylation process with suitable diols. Such diols provided morpholines, as shown in the transformation of various amines with diols affording cyclization products [164
169]. The ruthenium catalysts used included cationic complexes with terdentate 2,6-bis(diphosphino)pyridine ligands as well as RuCl2(PPh3)3 (Scheme 8.67) [170a,b].

Scheme 8.67

Ruth and Stark [171] reported a reaction for the transformation of intermediate Ru complex, derived from in situ produced ruthenium tetraoxide and bis-allylamines, into morpholine derivatives via [3 1 2]-cycloaddition (Scheme 8.68) [108].

Scheme 8.68

442

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

8.2.14 Silver-assisted synthesis The tert-butyldimethylsilyl carbamates containing (E)-allyl chloride were treated with silver fluoride to afford the cyclic carbamates. The silver fluoride played a dual role in this method (Scheme 8.69). The reactive carboxylate intermediate was unmasked with fluoride ion by desilylation, while silver ion activated the allyl chloride unit [172,173].

Scheme 8.69

The cyclization mode was highly dependent on the oxime stereochemistry, the E isomer afforded cyclic vinyl nitrone, while the Z isomer underwent O-cyclization and give vinyl oxazines (Scheme 8.70) [173
175].

Scheme 8.70

The N-benzoyl allenic aminoacids were treated with silver tetrafluoroborate or silver nitrate that resulted in O-cyclization instead of the desired N-cyclization (Scheme 8.71) [173,176].

Scheme 8.71

As for allenes, carbamates were also involved in the Ag-catalyzed heterocyclization of aminoalkyne derivatives. The NH-part of O-propargylcarbamates reacted with acetylenic functionality after activation with a strong base (potassium tert-butoxide) and silver isocyanate to deliver the methylene oxazolidinones (Scheme 8.72). The same reaction was also promoted by copper chloride. In this case, a strong (potassium tert-butoxide) or a mild

Six-membered O,N-heterocycles

443

Scheme 8.72

base (triethylamine) was needed depending on the nature of the group carried by nitrogen atom [173,177]. The acetylenic isoureas afforded oxazines or oxazolidines upon treating with silver triflate (Scheme 8.73). No yield was reported in this publication [173,178].

Scheme 8.73

The yield of cyclization step was determined by the nature of substituent present on the nitrogen atom. The reaction was facilitated with electron-withdrawing groups. The cyclization occurred smoothly in the presence of silver salt and Et3N (10 mol% each) when the substituent was toluenesulfonyl. The trans-isomer was formed preferentially when the transition state was free from gauche repulsion [85]. The O-3,4-pentadienyl carbamates underwent aminocyclization to afford the 4-vinyltetrahydro1,3-oxazin-2-ones. The trans-selectivity was preferred in the formation of 4-vinyltetrahydro-1,3-oxazin-2-ones (Scheme 8.74) [179,180].

Scheme 8.74

A disilver(I) complex produced in situ from a terpyridine (t-Bu3tpy) ligand and AgNO3 catalyzed the reaction (along with sulfamate substrates) with similar selectivities and efficiencies to Du Bois’ [146] system albeit at high temperature (Scheme 8.75). Mass spectrometry studies supported the intermediacy of disilver(I) complex and amination occurred via

444

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.75

silver-nitrene as evident by the retention of configuration in the oxazolidinone products.

8.2.15 Tin-assisted synthesis The inverse electron demand [4 1 2]-cycloaddition where dienol ether reacted as a dienophile and nitroalkene as a heterodiene finds no precedent. However, this mode of reaction was effected between a cyclic 1,3diene and a nitroalkene. As depicted in Scheme 8.76, tin tetrachloride promoted the cycloaddition of 2-nitrostyrene and 1,3-cyclohexadiene to provide only nitronate product [181]. This transformation indicated that the desired periselectivities may be garnered by the proper choice of diene and Lewis acid activator.

Scheme 8.76

8.2.16 Titanium-assisted synthesis The 1,3-butadienol ether was compatible with TiCl2(Oi-Pr)2. However, while during the reaction of dienol ether with nitrostyrene both components were consumed, no useful products were formed, maybe due to the decomposition of obtained nitronate in the presence of TiCl2(Oi-Pr)2. A mixture of diastereomers was formed when nitroalkene was used (Scheme 8.77). Conversion of nitroalkene did not occur when tin(IV) chloride was used most likely due to the rapid unproductive consumption of dienol ether [182].

Scheme 8.77

Six-membered O,N-heterocycles

445

Dienol ether was compatible with TiCl2(Oi-Pr)2, Me3Al, and SnCl4, an ideal substrate to see the effect of these three Lewis acids in parallel. Dienol ether was then reacted with nitroalkene. Only Diels
Alder product nitrocyclohexene was formed in the presence of SnCl4 or Me3Al, while the nitronate as well as nitrocyclohexene were formed with TiCl2(Oi-Pr)2 (Scheme 8.78) [183].

Scheme 8.78

The dienol ether was reacted with nitroalkene in the presence of different Lewis acids (Scheme 8.79). Unfortunately, only α-cycloadduct was obtained in the presence of either TiCl2(Oi-Pr)2 or Me3Al [184].

Scheme 8.79

This method is focused on N,O-acetals where nitrogen contain an electron-withdrawing group. This reaction was needed as the isoxazolidines failed to undergo reaction with secondary alkyl sulfonates, in contrast to the successful reaction of primary alkyl halides. The N,O-acetals, under Lewis acidic conditions, opened to iminium ions that were trapped with appropriate nucleophiles [185,186]. The N,O-acetals were easily synthesized from N-protected amino alcohols and, in most cases, underwent clean and smooth ring-opening in the presence of a strong Lewis acid such as tin(IV) chloride or titanium(IV) chloride on exposure to allyltrimethylsilane (Scheme 8.80) [148].

446

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 8.80

8.2.17 Ytterbium-assisted synthesis The dipolar cycloaddition of alkoxy-substituted donor-acceptor cyclobutanes and cyclopropanes continue to be an active area of research. These strained carbocycles underwent [4 1 2]- or [3 1 2]-cycloadditions with dipolar substrates under Lewis acidic conditions to afford a number of intriguing hetereocyclic compounds. Various heterocycles were synthesized by these cycloadditions, proceeding at times with a high degree of regiochemistry and stereoselectivity, and providing the good yield of products, allowing for their use in the synthesis of natural products. Originally, this was centered on alkoxy-activated donor
acceptor cyclopropanes and their applications in natural product synthesis. They underwent a [4 1 2]-cycloaddition with aldehydes, imines, and, more recently, nitroso arenes (Scheme 8.81) [186].

Scheme 8.81

8.2.18 Zinc-assisted synthesis The cyclohexanone was used as a carbonyl component that afforded oxazoles (64% yield) along with substituted 2H-1,4-oxazin-2-one. The 2H1,4-oxazin-2-one was formed where the initially formed nitrilium ion was trapped with a second molecule of isocyanide. An intermediate was produced by cyclization of ethoxycarbonyl group. Subsequent deprotonation provided 2H-1,4-oxazin-2-one. The yield of 2H-1,4-oxazin-2-one increased up to 45% when 3 eq. of isocyanoacetate was used (Scheme 8.82) [45,187]. The hydroamination of gem-dialkyl-activated aminoalkenes and aminoalkynes was catalyzed by aminotroponiminato [188
190] and

Six-membered O,N-heterocycles

447

Scheme 8.82

aminotroponate [191] zinc alkyl complexes at elevated temperatures (80 °C
120 °C). The addition of anilinium borate [PhNMe2H][B (C6F5)4] as cocatalyst resulted in significantly higher catalyst activities. The role of catalyst was therefore most likely that of a Lewis acid, rather than a lanthanide-like mechanism involving insertion of the unsaturated carbon
carbon bond in a metal amide bond. The catalysts tolerated many functional groups such as sulfonamides, amides, furans, (thio)ethers, pyridines, thiophenes, and thioacetals, because they lack a reactive metal-alkyl bond. The 1,4-oxazines were formed by cyclization of secondary amine propargyl ethers due to a facile double-bond migration of the initial hydroamination product leading to thermodynamically favored vinyl ether (Scheme 8.83) [89].

Scheme 8.83

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3734.

CHAPTER 9

Six-membered S-heterocycles 9.1 Introduction Thiopyran structure refers to a six-membered ring with one sulfur heteroatom singly bonded in a cyclic system of two double bonds and one tetrahedral atomic center. The pyrans and thiopyrans can be synthesized using acyclic or cyclic precursors that indicate if a pyran ring-closure does or does not occur during synthesis. Reactions such as (1) disproportionation, (2) oxidation, (3) desulfurization of thiopyrans, (4) hydrogenation and reduction, (5) ring-opening reactions, (6) isomerization, (7) substitution reactions, and (8) conversion to carbocyclic systems outline the chemical properties of pyrans and thiopyrans. Pyrans are very rare as natural products. Only some 2H-pyrans have been isolated from plants [1,2]. The heterocyclic compounds that contain sulfur and nitrogen have enormous significance in the field of medicinal chemistry. Thiazines are a group of heterocyclic organic compounds that are still largely unexplored for their pharmacological activities. There are different available methods for the synthesis of thiazine derivatives in the literature. Many thiazine derivatives are biologically active and play an important role in the treatment of various diseases and show promising results of varying degrees, where they act as antifungal, antibacterial, antitumor, antipsychotic, antineoplastic, antimalarial, antiinflammatory, antiviral, analgesic, and anticancer agents and thus represent an interesting class of heterocyclic medicinal compounds worthy of further exploration [3
9]. Thiazines are a group of heterocyclic organic compounds that are still largely unexplored for their pharmacological activities. Heterocyclic thiazine derivatives are important because they are biological constituents of many biomolecules and drugs [10
13]. The thiazine derivatives are synthesized by various methods, including microwave irradiation, solvent-free reactions, one-pot synthesis, and other environmentally friendly methods that should be adapted easily in different biomedical and pharmaceutical research. Moreover, the study of thiazine has attracted the interest of medicinal chemists and biochemists up to

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles DOI: https://doi.org/10.1016/B978-0-12-820282-1.00009-9

© 2020 Elsevier Inc. All rights reserved.

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

a great extent and showed that this potent molecule has capabilities for designing potential bioactive agents [14,15a,b,16].

9.2 Metal- and nonmetal-assisted synthesis of sixmembered heterocycles with sulfur heteroatom 9.2.1 Aluminum-assisted synthesis The 2-chlorophenyl functionalized thioamides, aldehydes, and malonitrile were used in a cascade three-component reaction for the synthesis of fused heterocyclic 1,4-dihydropyridines. The 1,4-dihydropyridines were synthesized efficiently through the intramolecular cyclization of intermediates in the presence of potassium fluoride/neutral aluminum oxide catalysts with poly(ethylene glycol)-6000 under MWI (Scheme 9.1) [17,18].

Scheme 9.1

The chloro, flouro-2-acetyl benzimidazole were synthesized by microwave-assisted reaction of lactic acid and 3-chloro-4-fluorobenzene1,2-diamine, followed by oxidation with aluminum oxide and potassium permanganate. The chalcone derivatives of chloro, fluoro-2-acetyl benzimidazole were produced by condensation with different aldehydes and the formed compounds were cyclized with thiourea to give the thiazine derivatives of chloro, fluoro-benzimidazole. The synthesized 3-chloro-4fluoro aniline underwent four-step reaction involving acetylation, nitration, hydrolysis, and reduction for the generation of 3-chloro-4-fluoro phenylene diamine. 3-Chloro-4-fluoro phenylene diamine served as starting material to prepare various benzimidazole chalcone derivatives. The key intermediate 1-(7-chloro-6-fluoro-1H-benzimidazol-2-yl)ethanone [2-acetylbenzimidazole], needed for the synthesis of the title compounds, was prepared when 1-(7-chloro-6-fluoro-1H-benzimidazol-2-yl)ethanol was oxidized with potassium permanganate in the presence of aluminum oxide. Various benzimidazolyl chalcone derivatives were synthesized by condensation of 2-acetylbenzimidazole with various aromatic aldehydes. A mixture of thiourea and chalcone derivatives dissolved in ethanolic

Six-membered S-heterocycles

461

sodium hydroxide was stirred for 3 h using magnetic stirrer and then poured into cold water with continuous stirring. This was kept in a refrigerator for 24 h. The precipitate obtained was fluoro, chloro-2-substituted benzimidazole thiazine derivatives (Scheme 9.2) [19].

Scheme 9.2

1,4-Benzothiazine is a molecule of interest to biologists and chemists as it is a precursor in many synthetic transformations leading to biologically active heterocyclic molecules and also is a subunit of various tissues like feathers and mammalian hair [20]. Many protocols have been reported for the preparation of 1,4-benzothiazine like synthesis from 2-aminothiophenol by a reductive cyclization of R-(4-nitrophenylthio) acids [21] and 2-aminophenyl disulfides [22]. While investigating the use of ionic liquids in cyclization reactions for the preparation of macrocyclic chelating agents, Tandon and coworkers [23] reported the transformation of alkylsulfanylphenylamines into 3-oxo-1,4-benzothiazines as sole product (Scheme 9.3). The benefit of this reaction was that the product was separated by solid-supported heterogeneous base. Interestingly, the alkylsulfanylamines bearing smaller alkyl groups were converted to benzothiazines in higher yields and in shorter time as compared to those with larger alkyl groups. This was due to the steric factor involved at the time of cyclization with nucleophilic substitution at the thio group. The ionic liquid was used in a molar ratio of 1:10, and it was recovered and reused three times without any decrease in yield. This reaction in molecular solvents was rarely reported in the literature. Some examples used dimethylsulfoxide as a molecular solvent under reflux for 30
40 min with 62%
72% yields [24,25].

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 9.3

9.2.2 Bismuth-assisted synthesis The discovery of lactam compounds as clinically useful antibiotic agents was a landmark in modern chemotherapy of infectious diseases. Therefore the past few decades have witnessed remarkable growth in this field. The need for more effective lactamase inhibitors as well as more effective and potent lactam antibiotics has motivated medicinal and synthetic organic chemists to design and synthesize new interesting compounds [26
28]. 3-Hydroxycephems are versatile intermediates for the synthesis of several orally active cephalosporin antibiotics with heteroatom substituents or hydrogen attached directly to the C3 position of 3-cephem skeleton. Tanaka and coworkers [29,30] synthesized 3-hydroxycephems by intramolecular reductive carbon
sulfur bond formation utilizing a bismuth chloride
tin redox system in dimethylformamide/pyridine (Scheme 9.4) [31].

Scheme 9.4

Sabitha and coworkers [32
34] reported that in situ generated aldimines, derived from the reaction of aromatic amines with S-allyl derivatives of pyrazole aldehydes, underwent bismuth chloridecatalyzed intramolecular hetero-Diels
Alder (HDA) reaction (Scheme 9.5). This protocol afforded a simple synthesis of hexahydropyrazolo [40 ,30 :5,6]thiopyrano[4,3-b]quinolines (only cis products) in good-tohigh yields [31].

Six-membered S-heterocycles

463

Scheme 9.5

9.2.3 Calcium-assisted synthesis Tanaka et al. [35a] used α-acylated β-lactam-derived allenamides for the preparation of a series of antibiotics 3-norcephems (Scheme 9.6). The key step involved was calcium chloride-assisted 1,4-addition of nucleophiles to the central allenic carbon of allenamides as reported in the intermediate complex. Although this could be considered also as an umpolung phenomenon, with the α-acyl group in allenamides, this is more in line with a classical 1,4-addition. An ensuing cyclization via vinylogous enolate addition afforded 3-norcephems [35b].

Scheme 9.6

Thioacetals like 1,3-dithianes and 1,3-dithiolanes were used as protecting groups for carbonyl compounds, due to their high yielding, facile synthesis, and stability to both basic and acidic conditions [36]. For example, 1,3-dithiane was used to protect a ketone in the late-stage macrocyclization of intermediate for the preparation of (S)-zearalenone dimethyl ether (Scheme 9.7) [37
40].

464

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 9.7

9.2.4 Cesium-assisted synthesis The chloroacetyl chloride, substituted 2-chlorobenzenethiol, and primary amine underwent a fast 1:1:1 addition reaction in the presence of cesium carbonate in dry dimethylformamide at 150 °C under MW for less than 20 min to afford the benzo[b][1,4]-thiazin-3(4H)-ones. The results were excellent in terms of yields. The outcome of reaction was not interfered by position of chloro at aromatic ring. The presence of an aryl or alkyl substituent at amine not influenced the reaction to any significant extent. The cesium carbonate/dimethylformamide exhibited a good system, while either using potassium carbonate instead of cesium carbonate or decreasing the ratio of cesium carbonate only caused the incompletion of reaction. This method provided an efficient and convenient pathway for synthesizing a variety of benzo[1,4]thiazin-3(4H)-ones. Representative primary amines containing a branched-chain alkyl group, straight-chain alkyl group, aryl group, and tetrahydrofuran group reacted with substituted chlorobenzenethiols to provide the high yields of benzo[1,4]thiazin-3 (4H)-ones (Scheme 9.8) [41].

Scheme 9.8

Six-membered S-heterocycles

465

Annulations afforded biologically important ring systems rapidly by simple tandem reactions. For example, salicylates and in situ produced arynes readily reacted to synthesize the heteroatom ring systems like thioxanthones, xanthones, and acridones (Scheme 9.9) [42,43a,b]. The o-hydroxychalcones and o-(trimethylsilyl)aryl triflates were coupled for the preparation of 9-substituted xanthenes under very mild reaction conditions in a simple one-step process [44].

Scheme 9.9

9.2.5 Copper-assisted synthesis Kant and Farina [45] developed a related conjugate addition of organocuprates to allenamides (Scheme 9.10). Subsequent cyclization, through the formation of intermediates, afforded cephams.

Scheme 9.10

1,3-Thiazines served as convenient precursors and were synthesized by a fast MW-assisted three-component reaction of aldehydes, thioamides, and alkenes. This three-component HDA reaction consisted of in situ condensation of aminothiocarbonyl compound with an aldehyde to afford the N-thioacyl imine heterodiene, which reacted with an alkene to provide the 1,3-thiazine cycloadduct. This reaction was promoted by a Brønsted acid or a Lewis acid. The nature of catalyst [Cu(OTf)2, trifluoroacetic acid, p-toluenesulfonic acid, and BF3.OEt2], solvent (dichloromethane, chloroform, toluene, dichloroethane), water-adsorbent agent (molecular sieves or magnesium sulfate), temperature (room temperature to 100 °C), and reaction stoichiometry were varied. Finally, the best result (98% yield) was obtained for a 1:1.2:1.2 ratio of aldehyde/thioamide/

466

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

alkene with 2 eq. of BF3.OEt2 at 50 °C in dichloromethane in the presence of magnesium sulfate. The main disadvantage was that the reaction took too long reaction time (5 days). In this reaction MWI worked efficiently. The cycloaddition of N-thioacyliminium dienes was regioselective, but the endo/exo-selectivity of HAD can vary with the structure of the substrate. In this first example, thiazine was obtained in a 1:1 endo/exo ratio. The styrene adduct was formed with high endo-selectivity and the product was isolated in good yield (94%). This was explained by the synthesis of Meerwein’s alkylating reagent Et3O.BF4 from BF3.OEt2. However, due to the competing formation of valerolactone by intramolecular hydrocarboxylation, the yield was lower. Then, cyclic cis-alkenes such as cyclooctene, cyclohexene, and norbornene were used. A mixture of exo- and endo-diastereoisomers was formed for thiazines in a 1:1.3 and 1:1.6 ratio, respectively (Scheme 9.11) [46].

Scheme 9.11

As an active reactant containing both nucleophilic and electronic sites, aziridine derivatives were found to be good substrates for the preparation of N-heterocycles via copper-catalyzed ring-opening/carbon
nitrogen coupling cascade reactions. Seker and coworkers [47,48] performed this type of work. o-Halothiophenols and o-halophenols were used as reaction partners of aziridines to initiate the reaction. The trans-fused tricyclic products 3,4-dihydro-2H-benzo[b][1,4]thiazines and 3,4-dihydro-2H-benzo [b][1,4]oxazines were synthesized in good-to-excellent yields using cuprous iodide as a ligand as well as base (Scheme 9.12) [49].

Six-membered S-heterocycles

467

Scheme 9.12

Porter and coworkers [50] explained the nucleophilicity of 1,3oxathiolanes toward copper carbenes for the preparation of 1,4-oxathianes (Scheme 9.13).

Scheme 9.13

Bao et al. [51] synthesized 2H-benzo[b][1,4]thiazin-3(4H)-ones by cascade reactions involving copper-catalyzed carbon-sulfur coupling. The tactic used AcSH as a novel sulfur source and 2-halopheyl masked 1-haloamides as building blocks. A class of 2H-benzo[b][1,4]thiazin-3 (4H)-ones was formed in moderate-to-excellent yields by reaction sequence of tandem nucleophilic displacement and intramolecular carbon
sulfur coupling reactions. Analogous transformations have been found to be practical by using TsNH2 as nucleophile, which provides quinoxalin-2(1H)-ones (Scheme 9.14) [49].

Scheme 9.14

468

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The trans-1,2,3,4,4a,10a-hexahydrophenoxathiine was prepared from cyclohexeneoxide with o-bromothiophenol by a base-mediated domino SN2 epoxide ring-opening reaction followed by Ullmann coupling cyclization in the presence of 1,1-binaphthyl-2,2-diamine and 20 mol% cuprous iodide in acetonitrile at 120 °C in sealed tube. The pure product trans-1,2,3,4,4a,10a-hexahydrophenoxathiine was formed in 12% yield in 80 h. The best ligand for the preparation of 1,4-phenoxathiine in 62% yield was 1-(2-hydroxynaphthalen-1-yl)naphthalen-2-ol. Without ligand, the coupling product trans-1,2,3,4,4a,10a-hexahydrophenoxathiine was not formed even in trace amounts, which indicated that ligand was crucial for this reaction. The reaction was optimized with different Cu salts, bases, solvents, and different ratios of copper salt. Although the reaction was catalyzed by several copper salts, cuprous iodide was found to be the best copper salt in terms of yield. Among the tested solvents acetonitrile was the best solvent; cesium carbonate was the best base. The yield reduced drastically upon decreasing the cuprous iodide catalyst loading from 20 to 10 mol%. The reaction did not provide even a trace amount of coupling product in the absence of cuprous iodide. Both ligand and copper salt were important for the coupling reaction. The reaction did not proceed in the absence of base (Scheme 9.15) [52].

Scheme 9.15

Despite its promising utility, the asymmetric HDA reaction of thiocarbonyl compounds has attracted less attention than aza- and oxaDiels
Alder reactions. A few reports exist on the thia-Diels
Alder reaction [53
56]. At first, the enantioselective thia-Diels
Alder was achieved with oxazolidinone as the dienophile and thiabutadiene as the heterodiene using Lewis acid bis(imine)/Cu(OTf)2 complexes in stoichiometric amount [57]. Among the different bis(imine)/Cu(OTf)2 complexes tested, Cu(OTf)2 was found to be the best catalyst. The amount of catalyst was decreased to 10 mol% upon adding molecular sieves 4Å in the reaction media, and the HDA adduct, dihydrothiopyran, was formed, from oxazolidinone and thiabutadiene, with a high endo/exo ratio of 96/4, in 94% enantiomeric excess and in good yield (91%) for the endo-adduct. Other catalysts, like Cu(OTf)2, were also tested, and it was reported that the

Six-membered S-heterocycles

469

HDA adducts dihydrothiopyrans were formed, at room temperature, with an endo/exo ratio of 70/30. The ee was excellent as the major endo-compound dihydrothiopyran was isolated with an ee of 98% when Cu(OTf)2 was used (Scheme 9.16) [58].

Scheme 9.16

Although amides, amines, azoles, or hydrazines were used as nitrogen sources in most copper-catalyzed cascade reactions involving carbon
nitrogen coupling process, some unconventional N-containing moieties like amidines also served as nitrogen source to afford the various heterocyclic motifs via copper-catalyzed transformation. Fu et al. [59
61] performed a comprehensive and pioneering exploration of this subject (Scheme 9.17). 2-Halobenzenesulfonamides were used for the synthesis of 1,2,4-benzothiadiazine-1,1-dioxide derivatives, and the results obtained from these experiments have suggested that the N-arylation step was the first intermediate [62,63]. This reaction was properly elaborated to aliphatic reactants [49].

Scheme 9.17

This method was creative as a synthetic strategy based on a brand-new consideration, and was also highly useful for providing the versatile pharmaceutical backbone of phenothazine. Unlike the reactions based on the double-coupling reactions occurring at two sp2 C
X bonds in one reagent, the reactions involving the double-coupling process, respectively,

470

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

happening at C
X bonds of two different starting compounds was a scarcely mentioned and different approach. Ma et al. [64] established the tandem reactions of o-bromothiophenols and o-iodoanilines successively. The carbon
sulfur coupling occurred as the first transformation in the tandem reaction process through the catalysis of cuprous iodide in the presence of potassium carbonate and L-proline to afford the intermediates that provided phenothiazine derivatives efficiently through the intramolecular carbon
nitrogen coupling (Scheme 9.18) [49].

Scheme 9.18

Hetero-Diels
Alder adducts were produced when N-sulfinyl derivatives were reacted with acyclic 1,3-dienes. The unsymmetrical and symmetrical 1,3-dienes were also involved in HDA reactions with sulfoximines. Sulfoximine was reacted with 1,3-diene to provide the trans-adduct and the cis-adduct in 93% yield in a ratio of 5/95. The cis-adduct was obtained with an ee of 77% when the reaction was carried out with 10 mol% (S,S)-Cu(OTf)2 (Scheme 9.19) [65
79].

Scheme 9.19

9.2.6 Gold-assisted synthesis Nolan and coworkers [80] described that dithioacetals and propargylic sulfides rearrange to afford the indenes through pentannulation of aromatic rings as shown by Wang and coworkers [81]. A putative Au carbenoid intermediate was formed in the first step upon 1,3-nucleophilic attack of thioether to alkyne (Scheme 9.20) [82].

Six-membered S-heterocycles

471

Scheme 9.20

Reliable and rapid MW applications are advantageous for Au(I)-catalyzed inter- and intramolecular hydroamination of unactivated alkenes and provided an important pathway for high-throughput synthesis (Scheme 9.21) [83,84]. The use of MW radiation as a heat source allowed convenient access to the temperature needed to complete the reaction in a much shorter time than that needed under conventional thermal conditions. Various phosphine
Au(I) complexes have been shown to be efficient catalysts for intramolecular hydroamination reactions of alkenes to provide the heterocyclic compounds [85].

Scheme 9.21

This reaction was employed for the preparation of dihydrothiopyranone and dihydrothiophenone products. The reaction tolerated precursor alkynes capped with aryl unit, proton, or electron-withdrawing group. The dichloro(pyridine-2-carboxylato) Au(III) precatalyst was used for the internal alkynes whereas platinum chloride catalyst was used with terminal alkynes. Allylic inversion was reported and the reaction tolerated ketones, vinyl halides, and aromatic functionalities. This method allowed the immediate precursor to afford the ylide that was incorporated into a molecule at an early stage of the synthesis rather than immediately prior to the ylide formation as was the case with standard approaches and provided greater synthetic flexibility. The iso-thiochroman-4-ones were synthesized upon incorporation of an aromatic unit in the linker between sulfoxide and alkyne following the same strategy (Scheme 9.22) [86].

472

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 9.22

Liu and coworkers [87] reported that diynes underwent intramolecular cycloaddition with tethered arenes in the presence of Au catalyst. The deuterium-labeling has indicated that the first reaction step was intramolecular arylation of one alkyne to form the vinyl Au(I), which underwent either a Nazazov cyclization or 5-exo-dig addition to provide the final product (Scheme 9.23) [82].

Scheme 9.23

The allenes containing nucleophilic substituents in the α- or β-position underwent Au-catalyzed endo-cycloisomerization for the synthesis of various five- and six-membered heterocyclic compounds. Key features of these reactions were the high reactivity of allene in the presence of carbophilic Au(I) or Au(III), Lewis-acidic catalysts, and the chirality transfer from the allenic axis of chirality to the new stereogenic center in the cyclization product. The chirality transfer using σ-donor ligands to Au, and applications in the total synthesis of natural products such as β-carboline alkaloids (2)-isochrysotricine and (2)-isocyclocapitelline were optimized. Based on continued interest in the stereoselective synthesis and transformation of functionalized allenes [88
91], a program was started dedicated to the development of new synthetic applications of allenes using homogeneous Au catalysis. In contrast to other research groups who have studied Au-catalyzed intermolecular additions to allenes [92,93] or exo-selective cyclizations [94
98], they have concentrated their efforts on endo-cycloisomerizations of chiral allenes containing a nucleophilic substituent in the homoallylic (β) or allylic (α) position (Scheme 9.24). These reactions occurred with perfect atom economy [99
101].

Six-membered S-heterocycles

473

Scheme 9.24

9.2.7 Iodine-assisted synthesis Mayer et al. [102] prepared a small library of 10H-phenothiazines with novel substitution patterns around the ring system in order to evaluate the structure-activity relationship for the binding of phenothiazine derivatives to human immunodeficiency virus-1 TAR RNA (Scheme 9.25). The synthesis occurred in acceptable-to-moderate yields by an I2-catalyzed reaction of diarylamines with sulfur at 190 °C in doubly distilled water within 20 min. Because of the hydrophobicity of 10H-phenothiazine products, they directly precipitated upon cooling and could be isolated by filtration.

Scheme 9.25

Biehl [103,104] used thiourea derivatives as starting materials to form the unprecedented structures with completely unknown properties (Scheme 9.26). The formation of benzothiazines, by cyclization of benzyne with thiourea derivatives, was controlled by fluoride stoichiometry to such an extent that isothiazine products were favored.

Scheme 9.26

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Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

The 1,2,4,5-thiaoxadiazines were formed in 61%
80% yields when 1,5-diacyl thiocarbohydrazides were cyclized with I2 (Scheme 9.27) [105]. Iodine solution in ethanol was added with continuous stirring; the color of I2 disappeared gradually. The addition of I2 was continued until it was in slight excess indicated by the persistence of its violet color. The granular solids were obtained after keeping the reaction mixture overnight; the solid was found to be dihydroiodo-1,2,4,5-thiaoxadiazines, which on basification with dilute ammonium hydroxide afforded the free base [106].

Scheme 9.27

Davies and coworkers [107] reported an efficient entry into polysubstituted thiomorpholine derivatives by conjugate addition of homochiral lithium N-allyl-N-(methylbenzyl)amide to tert-butyl cinnamate followed by enolate trapping by various electrophilic sulfur sources, conversion of the S-alkyl functionality into a disulfide, and reduction with Lalancette’s reagent (Scheme 9.28) [108].

Scheme 9.28

Six-membered S-heterocycles

475

The cyclic thioether was synthesized by thionation of diphenyl-type compounds employing zeolite and elemental sulfur [109]. Phenothiazine was synthesized very efficiently by thionation of diphenylamine with elemental sulfur utilizing hydrothermally treated HY zeolites as catalysts. The nature of active sites of zeolites played an important role in this thionation reaction (Scheme 9.29) [110].

Scheme 9.29

The N-alkyl- and N-acyldioxolo[4,5-b]phenathiazines were synthesized regioselectively by Bernthsen’s thionation [111,112] using I2 and elemental sulfur as a reagent (Scheme 9.30) [113]. The reaction mixture of N-(4-alkylphenyl)[1,3]benzodioxol-5-amine, one I2 crystal, and sulfur was refluxed in dry o-dichlorobenzene under nitrogen during 6 h. Then, the mixture was extracted with diethylether. The formed oil was chromatographed on silica gel with toluene to elute first the solvent (o-dichlorobenzene), and next a product as a red powder. The thionation reaction was regioselective and afforded single isomer, the linear dioxolo[4,5-b]phenothiazine. The reaction of chloro derivative under the same conditions was unsuccessful and provided many side products of polymerization [110].

Scheme 9.30

The 4-hydroxy benzaldehyde was condensed with acetophenone by Claisen
Schmidt reaction to afford the 1-(4-phenyl)-3-(4-hydroxyphenyl)-2-propen-1-one. Heterocyclic ring formation, aromatic nucleophilic substitution, and heterocyclic ketones or aldehydes condensation reactions were carried out under solvent-free reaction conditions or on solid support. The acetophenone was reacted with 4-hydroxy benzaldehyde in the presence of 40 mol% sodium hydroxide to provide the starting compound 1-(4-phenyl)-3-(40 -hydroxyphenyl)-2-propen-1-one that was treated with substituted aniline to give the 1-(4-phenyl)-3-(40 -aminophenyl)

476

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

aryl-2-propen-1-one that underwent cyclization with sulfur in the presence of I2 catalyst to afford the 2-(propen-1-one) aryl-3-substituted phenothiazine (Scheme 9.31). All these reactions were performed under MWI [114].

Scheme 9.31

Chatel and coworkers [115] used Bernthsen’s thionation for the synthesis of N-acyl- and N-alkyldioxinophenothiazine and acridinone derivatives. The substituted dioxino[b]- and [c]phenothiazines or acridinones were synthesized. The N-arylation of [1,4]benzodioxin-6-amine with organobismuth or organolead reagents afforded N-aryl-2,3-dihydro-1,4-benzodioxin-6-amine; subsequent Bernthsen thionation provided phenothiazine ring, followed by N-acylation. On the other hand, [1,4]benzodioxin-6-amine was N-alkylated and the formed alkylamines were N-phenylated before Bernthsen thionation to afford the tetracyclic phenothiazines. Alternative arylation with chlorobenzoic acid followed by cyclization under acidic conditions provided dioxinoacridinones, which were successfully alkylated (Scheme 9.32) [110].

Scheme 9.32

9.2.8 Iron-assisted synthesis Loudon and coworkers [116
118] reported that indole and quinolone derivatives were synthesized readily by the interaction of aromatic nitro

Six-membered S-heterocycles

477

groups and ortho-side-chains. In contrast to this, the displacement of an ortho-substituent frequently occurred when a diaryl derivative possessing two ortho nitro groups was reduced in an alkaline solution. The 2,2-dinitrodiphenyl amine was transformed to phenazine with sodium sulfide [119]. Similarly, the reaction of 2,20 -dinitrodiphenyl sulfide with hydrazine and ferrous oxalate afforded phenothiazine in one step (Scheme 9.33) [120,121].

Scheme 9.33

9.2.9 Lead-assisted synthesis The thionation of N-arylindazoles provided pyrazolo[3,4-b]- and pyrazolo [4,3-c]phenothiazine derivatives [122]. Copper acetate-catalyzed reaction of 6-amino-3-chloroindazole (derived from 6-nitroindazole) with p-tolyl lead triacetate furnished 3-chloro-6-(p-tolylamino)-1H-indazole, which on Bernthsen’s thionation with S8 and iodine give pyrazolo[4,3-c]phenothiazine (Scheme 9.34) [110].

Scheme 9.34

9.2.10 Lithium-assisted synthesis The thiophthalan was reacted with lithium and catalytic amount of 4,40 di-tert-butylbiphenyl at 278 °C in tetrahydrofuran to give the intermediate and products, after condensation with different electrophiles at the same temperature and final hydrolysis with water (Scheme 9.35) [123]. The thiolactone was directly isolated after workup when carbon dioxide was used as electrophile. In addition, the use of carbonyl compounds as electrophiles provided hydroxy thiols, which were cyclized easily with

478

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

85 mol% phosphoric acid to produce the products, which were homologues of starting substrate [124].

Scheme 9.35

Yadav and Rai [125] reported a green pathway for the preparation of several potentially useful bicyclic hetereocycles from easily available substrates under MWI and solvent-free conditions (Scheme 9.36) [126].

Scheme 9.36

The 2-lithiothiophenes were used as nucleophiles in formylation reactions [127,128], achieved even using a 2,5-dilithiated thiophene in a synthesis of oligothienylenevinylenes [129]. Sulfur was used as electrophile, allowing the synthesis of dithienothiophene [130] and annulated oligothiophene derivatives [131]. The introduction of sulfur atom utilizing 2-thienyllithium reagents is shown in Scheme 9.37 where the 2-thienyllithium was reacted with sulfur and subsequently the formed

Six-membered S-heterocycles

479

thiolate salt was in situ treated with α-(bromomethyl)acrylic acid to give the sulfanylated thiophene, which was converted into dihydrothiopyran upon heating [132]. The 2-lithiated thiophenes were treated with chlorodiphenylphosphane to give the 2-thienyl-derived phosphanes [133]. The 2-thienyllithium was also used for substitution reactions to dialkyldichlorosilanes providing bis(2-thienyls)silanes that acted as precursors of arylsilanediols [134]. In addition, the benzo[b]thiophene was lithiated similarly at C-2, being used as nucleophile, for instance, in alkylations [135] and azidations [136], as well as in reactions with Weinreb amides in the synthesis of agonists for the α-nicotinic acetylcholine receptor [137]. Furthermore, 2-iodotellurophenes and 2-iodoseleniophenes were obtained by direct 2-lithiation of chalcogenophenes and subsequent reaction with I2 [138,139].

Scheme 9.37

Mukherjee and Biehl [140] reported a new direction in intramolecular aryne aminocyclization protocols. The alkylated 2-bromo thiophenol derivatives containing pendant amines underwent a ring-closure to produce the thiazyl heterocylces in a variety of sizes using low-temperature conditions with tert-butyllithium. Kurth et al. [141] reported a solidsupported preparation of similar benzannulated heterocyclic compounds utilizing bulky alkoxide bases to form the arynes from nitroarenes (Schemes 9.38 and 9.39).

Scheme 9.38

Resin was swollen in dichloromethane. The sulfonamide resin was formed from swollen resin by reacting with t-BuOLi (base) and benzylsulfonyl chloride. The sulfonamide resin was then reacted with appropriate alcohols under Mitsunobu conditions (diisopropyl azodicarboxylate, triphenylphosphine,

480

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 9.39

room temperature, tetrahydrofuran). Cyclization reaction of resin with sodium hydride in dimethylformamide afforded thiazolo[4,5-c][1,2]thiazine resin. The resin was treated with m-chloroperoxybenzoic acid in dichloromethane to form the resin-bound cyclic sulfonamide. Finally, the thiazolo[4,5-c][1,2]thiazines were cleaved from the resin with amines (Scheme 9.40) [142
162].

Scheme 9.40

Six-membered S-heterocycles

481

9.2.11 Phosphorus-assisted synthesis The thionation of benzil aryl imines with phosphorus pentasulfide in refluxing xylene or toluene provided benzothiazines [163
170]. Thionation of benzyl monoarylimines proceeded easily to give the 2H-benzo-1,4-thiazines via annulation reactions. Subsequently, oxidation of 2H-benzo-1,4-thiazines afforded benzothiazoles (Scheme 9.41) [110].

Scheme 9.41

A series of tetrathiafulvalene derivatives was prepared from 1,8-diketones employing P4S10 as a thionating reagent. A detailed study of the reactions of Lawesson’s reagent and phosphorus pentasulfide with a series of 4,5-bis(RCOCH2S)-1,3-dithiole-2-thiones was reported [171]. These reactions led to the fusion of either a thiophene or an unsaturated 1,4dithin ring to the dithio; the latter in higher yield, while the former was a significant product in the reactions with Lawesson’s reagent; small amounts of minor products were also produced (Scheme 9.42) [110].

Scheme 9.42

9.2.12 Platinum-assisted synthesis The simple enynes were reacted with platinum chloride catalyst in the presence of water or alcohols to synthesize the heterocyclic compounds [172,173]. In most cases, this reaction occurred preferentially to the Pt (II)-catalyzed addition of CH3OH to the alkyne to form acetals or ketones (Scheme 9.43) [174
180].

Scheme 9.43

482

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

9.2.13 Rhodium-assisted synthesis The addition of nitrenes to olefins is the widely used method for the synthesis of aziridines. Along these lines, sulfonamides served as convenient nitrene precursors that were converted in the presence of various transition metal catalysts utilizing commercially available iodobenzene diacetate. The highyielding aziridination of styrene occurred with good enantioselectivity using Cu(I) catalyst derived from chiral bis(oxazoline) ligand [181]. Chang et al. [182] reported a Cu-catalyzed variant that need no external ligand. Instead, a pyridyl nitrogen moiety served as an internal ligand that increased the efficiency of aziridination. Many unsaturated sulfonamides underwent an intramolecular aziridination to provide the tricyclic aziridines in the presence of a rhodium catalyst (Scheme 9.44) [183,184].

Scheme 9.44

Olson and Du Bois [185] synthesized oxathiadiazinanes by rhodiumcatalyzed carbon
hydrogen activation in the unsaturated sulfamate derivatives (Scheme 9.45). This carbon
hydrogen amination afforded a new general pathway to carbon
nitrogen bond formation. These oxathiadiazinanes acted as precursors of differentially protected vicinal diamines [108].

Scheme 9.45

Zalatan and Du Bois [186] reported this enantioselective reaction with a newly developed dimeric Rh(II) complex. Analogous to Blakey’s Ru(II)pybox system, Du Bois’ Rh2(S-nap)4 complex, along with 3 Å molecular sieves and iodosobenzene, catalyzed the cyclization of benzylic sulfamate esters efficiently with good-to-excellent enantioinduction. This new Rh(II) system was also highly chemoselective for allylic C
H bond amination over olefin aziridination. This reversal in selectivity was highlighted with an allylic substrate where amination occurred to form a five-membered ring;

Six-membered S-heterocycles

483

aziridination was favored with Rh2(OAc)4, but amination was favored with Rh2(S-nap)4. While the enantioselectivities suffer for trans- and terminal olefinic substrates (12%
54% enantiomeric excess), allylic amination of cis-olefinic substrates resulted in good asymmetric induction (82% and 84% enantiomeric excess). These results were opposite to Ru(II)-pybox system where reverse selectivities were observed (Scheme 9.46), thus providing evidence for different mechanisms between Ru and Rh catalysts. Data from a cyclopropane clock experiment for Du Bois’ system was consistent with a concerted, nitrene-type amination.

Scheme 9.46

Du Bois and coworkers [187] reported the use of sulfamate esters as aminating agents. The sulfamates were more active toward amination as shorter reaction times and lower Rh catalyst loadings provided the good yields of oxathiazinanes (Scheme 9.47).

Scheme 9.47

Besides Rh(II) dimers, Ru porphyrin complexes [188
193] were also effective catalysts for the stereospecific sulfamidate-forming reaction in yields up to 89%. The reaction occurred through the formation of iminoiodanes that interacted with catalyst to form a bis(imido)Ru(VI) complex. The carbon
hydrogen bond insertion was also asynchronous and concerted but the hydrogen abstraction was believed to involve short-lived radical intermediates. Che and coworkers [194] used a chiral porphyrin ligand for the first time and an enantioselective intramolecular carbon
hydrogen bond amination occurred with enantiomeric excesses up to 88% (Scheme 9.48) [195,196].

Scheme 9.48

484

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

9.2.14 Ruthenium-assisted synthesis Yamamoto and coworkers [197] synthesized dithiopyrone or thiopyranimine, respectively by ruthenium-catalyzed cycloaddition of 1,6-diyne with carbon disulfide or isothiocyanate (Scheme 9.49) [198].

Scheme 9.49

The borrowing hydrogen protocol was used for the conversion of primary amines into nitrogen-containing heterocycles via a double alkylation process with suitable diols. Ru-catalyzed reactions of diamines with diols [199,200] as well as cyclization reactions of diols, which possess additional heteroatoms, have also been reported [201,202]. Such diols provided piperazines and morpholines, as shown in the transformation of various amines with diols affording the cyclization products. The Ru catalysts RuCl2(PPh3)3 as well as cationic complexes were used with terdentate PNP ligands (Scheme 9.50) [203].

Scheme 9.50

An estradiol-like skeleton was constructed in a two-step sequence from aromatic enynes [204]. Homoallyl and allyl ethers reacted to about 50% conversion with one portion of catalyst. Higher yields were obtained upon addition of 10 mol% catalyst divided into four portions, with filtering between additions. This afforded greater than 90% conversion to dienes formed in good isolated yield. Allyl amides were excellent substrates for ring-closing ene-yne metathesis. Silyl protection of the alcohol and attempted five-membered ring-closing ene-yne metathesis was unsuccessful, but the six- and seven-membered rings were formed in good yields (Scheme 9.51) [205].

Six-membered S-heterocycles

485

Scheme 9.51

Blakey and coworkers [206] used a nonporphyrin-based Ru catalyst for the amination of allylic and benzylic carbon
hydrogen bonds intramolecularly with high levels of enantiocontrol and good yields (Scheme 9.52). The Ru(II)-pybox-catalyzed reaction was intriguing as this catalytic system was highly selective in carbon
hydrogen bond amination of allylic sulfamates that was not the case with the analogous Rh-catalyzed reaction where olefin aziridination [207] hampered the efficient carbon
hydrogen bond amination. Based on this chemoselectivity and previous work with Ru porphyrin complexes, the authors suggested that this reaction occurred via a bis(imido)Ru(VI) species and a hydrogen abstraction/radical rebound mechanism was in play.

Scheme 9.52

The sulfone possessing heterocyclic compounds were prepared by ring-closing metathesis. Although principally interested in ring-closing alkene-alkene metathesis, Yao [208] reported that the ring-closure of enyne afforded high yield of sulfone bearing diene employing firstgeneration Grubbs’ complex (Scheme 9.53) [209].

Scheme 9.53

Many interesting S-heterocycles with biological potential are synthesized by ring-closing metathesis [210
214]. This protocol was designed to

486

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

provide the sultams bearing multiple handles as attractive scaffolds for potential library synthesis with the ultimate goal of uncovering interesting biological leads. A stereogenic center was installed at C3 using a key Mitsunobu alkylation reaction. The key allyl sultam building blocks were yielded using ensuing metathesis as a cyclization event. All subsequent reactions leading to more complex building blocks occurred with high levels of diastereoselectivity to provide the good yields of enantiopure δ-sultams. This reaction started with the multigram synthesis of allylsulfonyl chloride. The sulfonamide was formed in good yields by subsequent amination with anhydrous NH3 [215]. Mono-protection with Boc2O [216] afforded sulfonamide (93%), with an acidic proton (N
H) suitable for Mitsunobu alkylation (Scheme 9.54). Mitsunobu reaction with chiral, nonracemic alcohol, obtained from epoxide utilizing Christie protocol [217], provided the good yield (78%) of ring-closing metathesis precursor. Initial attempts to form the sultam via ring-closing metathesis in the presence of second-generation Grubbs catalyst [218] in refluxing dichloroethane or dichloromethane failed. The sultam was formed in good yield when toluene was used as a solvent under refluxing conditions. Alternatively, the δ-sultam was formed in excellent yield by Boc-removal in diene using trifluoroacetic acid, followed by ring-closing metathesis in refluxing dichloromethane [219].

Scheme 9.54

Six-membered S-heterocycles

487

9.2.15 Silver-assisted synthesis The 1,1-dioxo-2H-1,2-benzothiazines were formed selectively when benzenesulfonamides were cyclized with silver salts (Scheme 9.55). In ethanol or dimethylformamide yields were higher than 80% and no O-cyclization occurred. Silver fluoride, nitrate, and hexafluoroantimonate were better catalysts as compared to Cu(I) salts. The AgSbF6 associated with triethylamine reduced the reaction time remarkably without any influence on the efficiency of reaction [220,221].

Scheme 9.55

A disilver(I) complex formed in situ from AgNO3 and a terpyridine (t-Bu3tpy) ligand catalyzed the reaction (along with sulfamate substrates) with similar selectivities and efficiencies albeit at high temperature (Scheme 9.56) [187]. The intermediacy of disilver(I) complex was suggested by mass spectrometry and proposed that amination proceeded via silver
nitrene as evident by the retention of configuration in oxazolidinone products.

Scheme 9.56

9.2.16 Tin-assisted synthesis Schwarz et al. [222] reported that the fluoronitro resin was reacted with solutions of thiocarboxylic acids. This reliable solid-phase nucleophilic aromatic substitution provided o-nitroethers. The o-nitroethers were

488

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

exposed to standard nitro group reduction conditions, but did not furnish the desired o-alkylthioanilines or the corresponding 1,4-benzothiazin-3ones (Scheme 9.57) [223].

Scheme 9.57

9.2.17 Ytterbium-assisted synthesis The asymmetric HDA reaction of 2,4-diphenyl-1-thiabuta-1,3-diene and (S)-N-acryloxyl-4-benzyl-1,3-oxazolidin-2-one in the presence of Yb (OTf)3 provided the adduct with moderate endo/exo-selectivity, and excellent enantioselectivity of endo-isomer (3R,4R-isomer) (Scheme 9.58) [224]. The opposite endo-enantiomer (3S,4S-isomer) was formed when the same reaction was performed in the absence of Yb(OTf)3. The stoichiometric reaction with Yb(OTf)3 and coordinating solvents such as dimethylsulfoxide, tetrahydrofuran, and dimethylformamide also favored the (3S,4S)-endo-isomer. For hetero cycloaddition of N-acylimines with chiral vinyl ethers, Yb(OTf)3 activation caused dominant decomposition of N-acylimines [225,226].

Scheme 9.58

Six-membered S-heterocycles

489

Blechert and coworkers [227] reported that Ru alkylidene catalyst acted as a precatalyst for dihydroxylation reactions. This sequential tandem reaction relied on Grubbs I-catalyzed ring-closing metathesis followed by a subsequent in situ oxidation of the Ru source with NaIO4/ YbCl3  6H2O to afford an active dihydroxylation catalyst. This catalyst was used for a cis-dihydroxylation of newly formed double bond to afford many cyclic compounds (Scheme 9.59).

Scheme 9.59

9.2.18 Zinc-assisted synthesis A five-step synthesis scheme provided a series of some new phenothiazine derivatives. The 6-substituted-benzothiazolyl-2-diazonium chlorides were formed by diazotization of 2-amino-6-substituted-benzothiazoles. The 6-substituted-benzothiazolyl-2-diazonium chlorides were reacted with cold solution of naphthol in dilute sodium hydroxide to yield the 2-diazo-6-substituted-benzothiazolyl-sodionaphthoxides that provided 2-diazo-6-substituted-benzothiazolyl-naphthols on acidification with concentrated hydrogen chloride. The 2-diazo-6substituted-benzothiazolyl-naphthols were reacted with p-substituted anilines to give the 2-diazo-6-substituted-benzothiazolyl-p-substituted aniline naphthalenes. This synthesis was also attempted under MWI by using conventional methods. The 2-diazo-6-substitutedbenzothiazolyl-6-substituted-[2,3-b]benzophenothiazines were synthesized when benzothiazolyl-p-substituted-anilinenaphthalenes were fused with sulfur in the presence of I 2 (Scheme 9.60) [228].

490

Metal- and Nonmetal-Assisted Synthesis of Six-Membered Heterocycles

Scheme 9.60

The phenothiazine derivatives were synthesized by environmentally benign protocol under MWI. Generally, phenothiazine derivatives were prepared in six steps by conventional method involving the Smiles rearrangement. In first three steps 2-aminobenzenethiol was formed from aromatic amines and three further steps were needed for the synthesis of phenothiazines. Therefore the conventional approach was lengthy, laborious, low yield provider, and time consuming with respect to starting material, aromatic amines. Therefore efforts were made to design a new environmentally benign protocol for the synthesis of bioactive title compounds to make available these compounds for pharmacological aspects. Finally, a new MW-assisted reaction was explored for the synthesis of substituted phenothiazine derivatives. The reaction yield of the final product improved drastically and the reaction time was lowered with respect

Six-membered S-heterocycles

491

to the initially used amines as compared to the conventional Smiles rearrangement. The reported new method has two steps instead of the six-step conventional method. In the first step, a mixture of o-substituted aniline derivatives and p-substituted phenol dissolved in minimum quantity of absolute ethanol and zinc chloride as catalyst was exposed under MWI to provide the biphenyl amino derivative. The phenothiazine was prepared in the second step via thionation of biphenyl amino derivative in the presence of I2 catalyst under MWI. The overall reaction was favored when an electron-withdrawing group was present at o/p-position of hydroxyl group in phenols. The 5,5-dioxide derivatives of formed phenothiazines were obtained by oxidation with 30% hydrogen peroxide in glacial acetic acid in ultrasound bath (Scheme 9.61) [229].

Scheme 9.61

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1775.

Index Note: Page numbers followed by “f” refer to figures.

A Acid-labile polystyrene, 9 Alkyl-substituted pyridines, 43 Alkyne cyclotrimerization, 15 Aluminum-assisted synthesis fused six-membered N-heterocycles, 66f, 67f, 68f, 69f alkyl-substituted pyridines, 67 bromoalkane, 69 cascade three-component reaction, 67 Friedlander reaction conditions, 66 hetero-Diels Alder reaction, 68 Lewis acid-catalyzed reaction, 68 solution-phase synthetic conditions, 66 fused six-membered N-polyheterocycles, 121 122, 122f, 123f six-membered N-heterocycles, 1 5, 2f, 4f, 5f six-membered N,N-heterocycles, 183 187, 184f, 185f, 186f, 187f six-membered N,N-polyheterocycles, 244 246, 244f, 245f, 246f, 247f six-membered O-heterocycles, 296 297, 296f, 297f, 298f six-membered O,N-heterocycles, 414, 414f, 415f six-membered O,O-heterocycles, 352 353, 352f, 353f six-membered S-heterocycles, 460 461, 460f, 461f, 462f 2-Amino-3,5-dicarbonitrile-6-thiopyridines, 40 Anilines, 12 Antimony-assisted synthesis six-membered N-heterocycles, 6, 6f six-membered O,O-heterocycles, 353 354, 354f Aromatic aldehydes, 1 2 Aromatic diamines, 260

Arsenic-assisted synthesis, 122 124, 123f, 124f Aspidosperma alkaloid quebrachamine, 22 23 Aza-Diels Alder reactions, 16 Aza-Prins cyclization, 7, 9 10, 140

B Barium-assisted synthesis six-membered N,N-polyheterocycles, 247, 247f six-membered O-heterocycles, 298, 298f six-membered O,O-heterocycles, 354 356, 355f, 356f Benzimidazolyl chalcone derivatives, 460 461 Bicyclic lactones, 3 Biginelli reaction, 190 191 Bismuth-assisted synthesis fused six-membered N-polyheterocycles, 124 128, 125f, 126f, 127f, 128f six-membered N-heterocycles, 6 8, 6f, 7f six-membered N,N-heterocycles, 187 189, 188f, 189f six-membered N,N-polyheterocycles, 247 249, 248f, 249f six-membered O-heterocycles, 298 302, 299f, 300f, 302f six-membered O,N-heterocycles, 414 415, 415f six-membered O,O-heterocycles, 356 358, 356f, 357f, 358f six-membered S-heterocycles, 462, 462f, 463f Boc-protected amino acids, 263 Burgess’s reagent, 33

C Calcium-assisted synthesis

505

506

Index

Calcium-assisted synthesis (Continued) fused six-membered N-heterocycles, 70, 70f six-membered S-heterocycles, 463, 463f, 464f Carbon nucleophile systems, 88 Cerium-assisted synthesis fused six-membered N-heterocycles, 70 72, 71f, 72f six-membered N-heterocycles, 8, 8f, 9f six-membered N,N-heterocycles, 190 191, 190f, 191f six-membered O-heterocycles, 302 303, 303f six-membered O,O-heterocycles, 359, 359f, 360f Cesium-assisted synthesis fused six-membered N-heterocycles, 72, 72f fused six-membered N-polyheterocycles, 129f, 130f, 132f, 133f, 134f, 135f, 136f, 137f, 138f annulation process, 133 biaryl compounds, 130 bromoalkyl pyrroles, 129 carboamination reactions, 136 137 copper-mediated oxidative dimerization, 131 132 electron-rich aromatics, 129 hetero-Diels Alder reaction, 129 ketalization, 134 136 3-methyloxyl benzeneboronic acid, 134 multicomponent synthesis, 137 138 palladium-assisted aryne annulation reactions, 130 polycyclic isoquinolones, 131 titanium-nitrogen complex, 134 136 six-membered N-heterocycles, 9, 9f six-membered O-heterocycles, 303, 303f six-membered O,O-heterocycles, 360, 360f six-membered S-heterocycles, 464 465, 464f, 465f Chalcone derivatives, 460 461 4-Chlorotetrahydropyrans, 301 302 Chromium-assisted synthesis

six-membered O-heterocycles, 303 304, 304f six-membered O,O-heterocycles, 360, 361f Cinnamaldehydes, 12 Claisen-Schmidt reaction, 475 476 Cobalt-assisted synthesis six-membered N,N-polyheterocycles, 249, 249f six-membered O-heterocycles, 304 305, 305f six-membered O,O-heterocycles, 361, 361f Copper-assisted synthesis six-membered N,N-heterocycles, 192 196, 192f, 193f, 194f, 195f, 196f six-membered N,N-polyheterocycles, 249 254, 250f, 251f, 252f, 253f, 254f six-membered O-heterocycles, 305 314, 305f, 306f, 307f, 308f, 309f, 310f, 311f, 312f, 314f, 315f six-membered O,N-heterocycles, 416 419, 416f, 417f, 418f, 419f six-membered O,O-heterocycles, 361 371, 361f, 362f, 363f, 364f, 365f, 366f, 367f, 368f, 369f, 370f, 371f six-membered S-heterocycles, 465 470, 465f, 466f, 467f, 468f, 469f, 470f Copper-catalyzed cascade reactions, 469 Coumarin, 351 352, 356 358 Cyclization-fluorination process, 6 Cycloaddition reaction, 15 1,3-Cyclohexadiene derivatives, 245 246 Cyclohydrocarbonylation reaction, 30

D N,N-Diallylic amines, 6 Diastereoselective intramolecular hydroamination, 16 17 Dihydroquinazoline derivatives, 278 Dimer 2-alkyl-4-chloro-1-tosyl-1,2,5,6tetrahydropyridine, 15 Diversity oriented synthesis (DOS), 99

Index

E Electrocyclic reaction, 4 Enantiopure nitrone, 20 Epoxypropyl cinnamylamines, 8 Europium-assisted synthesis, 315 316, 315f, 316f, 317f

F 2-Formyl pyrroles, 251 Friedel Crafts cyclization, 140, 143 Friedlander reaction conditions, 66 Fused six-membered N-heterocycles biological properties, 65 66 4-carboxyl quinoline derivative, 65 66 ethoxyquin, 65 66 hemoglobin digestion, 65 66 martinellic acid and martinelline alkaloids, 65 66 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis. See Aluminum-assisted synthesis calcium-assisted synthesis, 70, 70f cerium-assisted synthesis, 70 72, 71f, 72f cesium-assisted synthesis, 72, 72f iodine-assisted synthesis. See Iodineassisted synthesis iridium-assisted synthesis, 76 77, 77f iron-assisted synthesis, 77 80, 77f, 78f, 79f, 80f lithium-assisted synthesis, 80, 80f manganese-assisted synthesis, 81, 81f mercury-assisted synthesis, 81, 81f molybdenum-assisted synthesis, 82, 82f neodymium-assisted synthesis, 82, 83f nickel-assisted synthesis, 83 84, 83f, 84f rhenium-assisted synthesis, 85, 85f rhodium-assisted synthesis. See Rhodium-assisted synthesis ruthenium-assisted synthesis, 99 100, 99f, 100f, 101f scandium-assisted synthesis, 100 102, 101f, 102f, 103f thallium-assisted synthesis, 103, 103f tin-assisted synthesis, 103, 104f

507

titanium-assisted synthesis, 104 105, 104f, 105f ytterbium-assisted synthesis, 105, 105f zinc-assisted synthesis, 106 107, 106f, 107f zirconium-assisted synthesis, 108, 108f oxamniquine, 65 66 quinoline-based antioxidant, 65 66 Fused six-membered N-polyheterocycles benzimidazo[2,1-b]quinazolines, 121 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 121 122, 122f, 123f arsenic-assisted synthesis, 122 124, 123f, 124f bismuth-assisted synthesis, 124 128, 125f, 126f, 127f, 128f cesium-assisted synthesis, 128 138, 129f, 130f, 132f, 133f, 134f, 135f, 136f, 137f, 138f indium-assisted synthesis, 138, 138f iodine-assisted synthesis, 138 143, 139f, 140f, 141f, 142f, 143f, 144f iron-assisted synthesis, 143 146, 144f, 145f, 146f lanthanum-assisted synthesis, 147, 147f lithium-assisted synthesis, 147 151, 147f, 148f, 149f, 150f, 151f, 152f magnesium-assisted synthesis, 151 152, 152f manganese-assisted synthesis, 152, 153f molybdenum-assisted synthesis, 153, 153f nickel-assisted synthesis, 153, 154f promethium-assisted synthesis, 153 156, 155f, 156f rhenium-assisted synthesis, 157, 157f rhodium-assisted synthesis, 157 160, 158f, 159f, 160f, 161f scandium-assisted synthesis, 161 162, 162f tin-assisted synthesis, 163 166, 163f, 164f, 165f, 166f, 167f tungsten-assisted synthesis, 166 167, 167f ytterbium-assisted synthesis, 167, 168f zinc-assisted synthesis, 168 169, 169f

508

Index

G Gold-assisted synthesis six-membered N,N-heterocycles, 197 198, 197f, 198f six-membered N,N-polyheterocycles, 254 257, 254f, 255f, 256f, 257f six-membered O,N-heterocycles, 419 423, 420f, 421f, 422f, 423f six-membered S-heterocycles, 470 472, 471f, 472f, 473f

H Hafnium-assisted synthesis, 371, 371f Hantzsch reaction, 6 7, 11 Hetero-Diels Alder reaction, 3, 43 44, 308, 311, 313 Horner Wadsworth Emmons (HWE) reaction, 271 272 Hydrogenolysis, 18 Hydroxycephems, 462

I Indium-assisted synthesis fused six-membered N-polyheterocycles, 138, 138f six-membered N-heterocycles, 9 10, 10f six-membered N,N-heterocycles, 198, 198f six-membered O-heterocycles, 317, 317f Iodide-catalyzed cascade reaction, 253 Iodine-assisted synthesis, 73f, 74f, 75f, 76f alkyl-substituted selenoureas, 75 76 3-alkynylbenzofuran, 74 Friedel Crafts cyclization, 73 fused six-membered N-polyheterocycles, 138 143, 139f, 140f, 141f, 142f, 143f, 144f isoquinolines, 73 regioselective iodocyclization reaction, 75 76 six-membered N-heterocycles, 10 12, 10f, 11f, 12f, 13f six-membered N,N-heterocycles, 198 201, 199f, 200f, 201f six-membered N,N-polyheterocycles, 257 259, 257f, 258f, 259f

six-membered O-heterocycles, 317 320, 318f, 319f, 320f six-membered O,N-heterocycles, 424, 424f six-membered O,O-heterocycles, 371 373, 371f, 372f, 373f six-membered S-heterocycles, 473 476, 473f, 474f, 475f, 476f sodium iodide symporter (NIS), 75 76 unsaturated bromo-substituted alkyne, 74 Iodine-catalyzed one-pot five-component reaction, 10 Iridium-assisted synthesis fused six-membered N-heterocycles, 76 77, 77f six-membered N-heterocycles, 13, 13f six-membered N,N-heterocycles, 201 203, 202f, 203f six-membered N,N-polyheterocycles, 261 262, 261f, 262f Iron-assisted synthesis fused six-membered N-heterocycles, 77 80, 77f, 78f, 79f, 80f fused six-membered N-polyheterocycles, 143 146, 144f, 145f, 146f six-membered N-heterocycles, 13 15, 14f, 15f, 16f six-membered N,N-heterocycles, 203 204, 203f, 204f six-membered N,N-polyheterocycles, 259 260, 260f, 261f six-membered O-heterocycles, 320 321, 321f six-membered O,N-heterocycles, 424, 425f six-membered O,O-heterocycles, 373 374, 374f six-membered S-heterocycles, 476 477, 477f Iron-catalyzed cycloaddition reactions, 78 Iron-phosphoranecyclooctadiene complex, 15 Irreversible enzyme inhibition, 79

L Lanthanum-assisted synthesis

Index

fused six-membered N-polyheterocycles, 147, 147f six-membered N-heterocycles, 16 17, 16f, 17f six-membered N,N-heterocycles, 205, 205f six-membered O-heterocycles, 322, 322f, 323f Lead-assisted synthesis, 477, 477f Lewis acid catalyst, 8 Lewis acid-catalyzed ene cyclization, 3 Lithium-assisted synthesis fused six-membered N-heterocycles, 80, 80f fused six-membered N-polyheterocycles, 147 151, 147f, 148f, 149f, 150f, 151f, 152f six-membered N-heterocycles, 17 18, 17f, 18f six-membered N,N-heterocycles, 205, 205f six-membered N,N-polyheterocycles, 263, 263f six-membered O,N-heterocycles, 425 426, 425f, 426f six-membered O,O-heterocycles, 374 377, 375f, 376f, 377f six-membered S-heterocycles, 477 480, 478f, 479f, 480f

M Macrocyclic chelating agents, 461 Magnesium-assisted synthesis, 151 152, 152f fused six-membered N-polyheterocycles, 151 152, 152f six-membered N-heterocycles, 18 19, 19f six-membered N,N-heterocycles, 206, 206f Malononitrile, 1 2 Manganese-assisted synthesis fused six-membered N-heterocycles, 81, 81f fused six-membered N-polyheterocycles, 152, 153f

509

six-membered N,N-heterocycles, 206, 206f six-membered N,N-polyheterocycles, 263, 264f Mannich-type reaction, 10 Mercury-assisted synthesis fused six-membered N-heterocycles, 81, 81f six-membered O,N-heterocycles, 426 428, 426f, 427f, 428f Michael cyclization, 267 268 Microwave-assisted benzimidazoquinazolinone cyclization, 247 Mo-catalyzed microwave-driven asymmetric allylic alkylation, 21 Modified Michael reactions, 78 Molybdenum-assisted synthesis fused six-membered N-heterocycles, 82, 82f fused six-membered N-polyheterocycles, 153, 153f six-membered N-heterocycles, 21 23, 21f, 22f, 23f six-membered N,N-heterocycles, 206 207, 207f six-membered N,N-polyheterocycles, 264, 264f six-membered O-heterocycles, 323 324, 324f six-membered O,O-heterocycles, 377 379, 378f

N Neodymium-assisted synthesis, 82, 83f Nickel-assisted synthesis fused six-membered N-heterocycles, 83 84, 83f, 84f fused six-membered N-polyheterocycles, 153, 154f six-membered N,N-heterocycles, 207 209, 207f, 208f, 209f six-membered N,N-polyheterocycles, 264 265, 265f, 266f six-membered O-heterocycles, 325 326, 325f, 326f

510

Index

Nickel-assisted synthesis (Continued) six-membered O,N-heterocycles, 428 429, 429f six-membered O,O-heterocycles, 379 382, 379f, 380f, 381f, 382f Niementowski reaction, 246 2-Nitro-cycloalkanones, 297 Nitrogen-containing heterocycles, 26

O Osmium-assisted synthesis, 327, 327f Oxamniquine, 65 66 Oxazines, 413 Oxazolidine, 18 Oxobicycles, 77 Oxocarbenium ions, 298

P Palladium-assisted synthesis six-membered O,N-heterocycles, 429 435, 430f, 431f, 432f, 433f, 434f, 435f Pauson Khand ring systems, 99 2-Phenylquinazoline, 259 N-Phenyl triazolinedione, 251 Phosphorus-assisted synthesis, 481, 481f Pictet-Spengler’s reaction, 105 Platinum-assisted synthesis six-membered O-heterocycles, 327 328, 328f six-membered O,N-heterocycles, 435 436, 436f six-membered O,O-heterocycles, 382, 382f six-membered S-heterocycles, 481, 481f Promethium-assisted synthesis, 153 156, 155f, 156f N-Propargylaminoquinones, 139 Pyridines, 4, 19

Q Quebrachamine, 22 23 Quinolizidines, 77 Quinoxalines, 243 244, 248, 255 256

R Rhenium-assisted synthesis

fused six-membered N-heterocycles, 85, 85f fused six-membered N-polyheterocycles, 157, 157f Rhodium-assisted synthesis, 85f, 86f, 87f, 88f, 89f, 90f, 91f, 92f, 93f, 94f, 95f, 96f, 97f, 98f, 99f alkyne dimerization, 92 N-allylic amides, 95 aryl ethynyl ethers, 91 92 azomethines, 96 97 benzimidazole derivative, 97 carbon nucleophile systems, 88 cyclohydrocarbonylation reaction, 88 89 diarylalkynes, 96 dimethoxy substrate, 89 diversity oriented synthesis (DOS), 99 electron-donating groups, 94 electron-rich alkynes, 95 96 fused six-membered N-heterocycles. See Rhodium-assisted synthesis fused six-membered N-polyheterocycles, 157 160, 158f, 159f, 160f, 161f indolizine derivatives, 87 isocyanates and diynes, 85 lactams, 85 86 lasubine alkaloids, 85 86 nucleophilic trapping agents, 91 Pauson Khand ring systems, 99 pyridine products, 91 92 six-membered N-heterocycles, 24f, 25f, 26f, 27f, 28f, 29f, 30f, 31f, 32f, 33f acyclic enynes, 26 allyldipropargylamine, 32 aziridine, 32 33 Burgess’s reagent, 33 carbenoids, 23 chiral 2-aryl-piperidines, 26 cycloaddition reactions, 27 cyclohydrocarbonylation reaction, 30 diazo ketone, 29 3,5-disubstituted piperidines, 24 7-halo-substituted pyridotriazoles, 23 heteroatomic nucleophiles, 25 hydroformylation, 29

Index

intramolecular reductive amination, 28 nitrogen-containing heterocycles, 26 pyridine derivatives, 25 six-membered N,N-heterocycles, 210 211, 210f, 211f six-membered N,N-polyheterocycles, 266 269, 266f, 267f, 268f, 269f six-membered O-heterocycles, 329 330, 329f, 330f, 331f six-membered O,N-heterocycles, 436 438, 436f, 437f, 438f six-membered O,O-heterocycles, 383 386, 383f, 384f, 385f, 386f six-membered S-heterocycles, 482 483, 482f, 483f TADDOL-based phosphoramidites, 92 tetra-substituted stereocenters, 94 Wilkinson’s catalyst, 97 98 Ruthenium-assisted synthesis fused six-membered N-heterocycles, 99 100, 99f, 100f, 101f six-membered N,N-heterocycles, 212 213, 212f, 213f six-membered N,N-polyheterocycles, 269 272, 270f, 271f six-membered O,N-heterocycles, 438 441, 438f, 439f, 440f, 441f six-membered S-heterocycles, 484 486, 484f, 485f, 486f

S Samarium-assisted synthesis six-membered N-heterocycles, 34 35, 34f, 35f six-membered N,N-heterocycles, 214, 214f Scandium-assisted synthesis fused six-membered N-heterocycles, 100 102, 101f, 102f, 103f fused six-membered N-polyheterocycles, 161 162, 162f six-membered N-heterocycles, 35 37, 35f, 36f, 37f six-membered N,N-heterocycles, 214, 214f

511

six-membered N,N-polyheterocycles, 272 273, 272f six-membered O,O-heterocycles, 386 387, 387f Selenium-assisted synthesis six-membered N,N-heterocycles, 214, 215f six-membered O,O-heterocycles, 387, 387f Silicon-assisted synthesis six-membered N-heterocycles, 37 38, 37f, 38f six-membered N,N-heterocycles, 215 218, 215f, 216f, 217f, 218f six-membered N,N-polyheterocycles, 273, 273f Silver-assisted synthesis six-membered N,N-heterocycles, 218 220, 219f, 220f six-membered O-heterocycles, 331 335, 331f, 332f, 333f, 334f, 335f, 336f six-membered O,N-heterocycles, 442 444, 442f, 443f, 444f six-membered O,O-heterocycles, 387 391, 388f, 389f, 390f, 391f, 392f six-membered S-heterocycles, 487, 487f Single-electron transfer oxidation, 8 Six-membered N-heterocycles. See also Fused six-membered Nheterocycles medicinal compounds, 1 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 1 5, 2f, 4f, 5f antimony-assisted synthesis, 6, 6f bismuth-assisted synthesis, 6 8, 6f, 7f cerium-assisted synthesis, 8, 8f, 9f cesium-assisted synthesis, 9, 9f indium-assisted synthesis, 9 10, 10f iodine-assisted synthesis, 10 12, 10f, 11f, 12f, 13f iridium-assisted synthesis, 13, 13f iron-assisted synthesis, 13 15, 14f, 15f, 16f

512

Index

Six-membered N-heterocycles (Continued) lanthanum-assisted synthesis, 16 17, 16f, 17f lithium-assisted synthesis, 17 18, 17f, 18f magnesium-assisted synthesis, 18 19, 19f molybdenum-assisted synthesis, 21 23, 21f, 22f, 23f rhodium-assisted synthesis. See Rhodium-assisted synthesis samarium-assisted synthesis, 34 35, 34f, 35f scandium-assisted synthesis, 35 37, 35f, 36f, 37f silicon-assisted synthesis, 37 38, 37f, 38f tin-assisted synthesis, 38, 38f, 39f ytterbium-assisted synthesis, 39 40, 39f, 40f zinc-assisted synthesis. See Zincassisted synthesis zirconium-assisted synthesis, 47 48, 47f, 48f organocatalysts, 1 Six-membered N,N-heterocycles hydrocarbon substrates, 183 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 183 187, 184f, 185f, 186f, 187f bismuth-assisted synthesis, 187 189, 188f, 189f cerium-assisted synthesis, 190 191, 190f, 191f copper-assisted synthesis, 192 196, 192f, 193f, 194f, 195f, 196f gold-assisted synthesis, 197 198, 197f, 198f indium-assisted synthesis, 198, 198f iodine-assisted synthesis, 198 201, 199f, 200f, 201f iridium-assisted synthesis, 201 203, 202f, 203f iron-assisted synthesis, 203 204, 203f, 204f lanthanum-assisted synthesis, 205, 205f lithium-assisted synthesis, 205, 205f

magnesium-assisted synthesis, 206, 206f manganese-assisted synthesis, 206, 206f molybdenum-assisted synthesis, 206 207, 207f nickel-assisted synthesis, 207 209, 207f, 208f, 209f niobium-assisted synthesis, 209, 209f rhodium-assisted synthesis, 210 211, 210f, 211f ruthenium-assisted synthesis, 212 213, 212f, 213f samarium-assisted synthesis, 214, 214f scandium-assisted synthesis, 214, 214f selenium-assisted synthesis, 214, 215f silicon-assisted synthesis, 215 218, 215f, 216f, 217f, 218f silver-assisted synthesis, 218 220, 219f, 220f tin-assisted synthesis, 220, 221f titanium-assisted synthesis, 221, 221f, 222f tungsten-assisted synthesis, 222 223, 222f, 223f ytterbium-assisted synthesis, 223 224, 223f, 224f zinc-assisted synthesis, 225 228, 225f, 226f, 227f, 228f zirconium-assisted synthesis, 229, 229f niobium-assisted synthesis, 209, 209f Six-membered N,N-polyheterocycles chronic myelogenous leukemia (CML), 243 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 244 246, 244f, 245f, 246f, 247f barium-assisted synthesis, 247, 247f bismuth-assisted synthesis, 247 249, 248f, 249f cobalt-assisted synthesis, 249, 249f copper-assisted synthesis, 249 254, 250f, 251f, 252f, 253f, 254f gold-assisted synthesis, 254 257, 254f, 255f, 256f, 257f iodine-assisted synthesis, 257 259, 257f, 258f, 259f

Index

iridium-assisted synthesis, 261 262, 261f, 262f iron-assisted synthesis, 259 260, 260f, 261f lithium-assisted synthesis, 263, 263f manganese-assisted synthesis, 263, 264f molybdenum-assisted synthesis, 264, 264f nickel-assisted synthesis, 264 265, 265f, 266f rhodium-assisted synthesis, 266 269, 266f, 267f, 268f, 269f ruthenium-assisted synthesis, 269 272, 270f, 271f scandium-assisted synthesis, 272 273, 272f silicon-assisted synthesis, 273, 273f tin-assisted synthesis, 274 281, 274f, 275f, 277f, 279f, 280f, 281f titanium-assisted synthesis, 281 283, 282f, 283f zinc-assisted synthesis, 283 284, 283f, 284f pyrimidine and quinozoline derivatives, 243 quinoxalines, 243 244 Six-membered O-heterocycles biodegradable agrochemicals, 295 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 296 297, 296f, 297f, 298f barium-assisted synthesis, 298, 298f bismuth-assisted synthesis, 298 302, 299f, 300f, 302f cerium-assisted synthesis, 302 303, 303f cesium-assisted synthesis, 303, 303f chromium-assisted synthesis, 303 304, 304f cobalt-assisted synthesis, 304 305, 305f copper-assisted synthesis, 305 314, 305f, 306f, 307f, 308f, 309f, 310f, 311f, 312f, 314f, 315f europium-assisted synthesis, 315 316, 315f, 316f, 317f indium-assisted synthesis, 317, 317f

513

iodine-assisted synthesis, 317 320, 318f, 319f, 320f iron-assisted synthesis, 320 321, 321f lanthanum-assisted synthesis, 322, 322f, 323f molybdenum-assisted synthesis, 323 324, 324f nickel-assisted synthesis, 325 326, 325f, 326f osmium-assisted synthesis, 327, 327f platinum-assisted synthesis, 327 328, 328f rhodium-assisted synthesis, 329 330, 329f, 330f, 331f silver-assisted synthesis, 331 335, 331f, 332f, 333f, 334f, 335f, 336f titanium-assisted synthesis, 336, 336f tungsten-assisted synthesis, 336, 336f ytterbium-assisted synthesis, 336 337, 337f zinc-assisted synthesis, 337 338, 337f, 338f naphthopyrans, 295 pyran derivatives, 295 pyranochalcones, 295 Six-membered O,N-heterocycles metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 414, 414f, 415f bismuth-assisted synthesis, 414 415, 415f copper-assisted synthesis, 416 419, 416f, 417f, 418f, 419f gold-assisted synthesis, 419 423, 420f, 421f, 422f, 423f iodine-assisted synthesis, 424, 424f iron-assisted synthesis, 424, 425f lithium-assisted synthesis, 425 426, 425f, 426f mercury-assisted synthesis, 426 428, 426f, 427f, 428f nickel-assisted synthesis, 428 429, 429f palladium-assisted synthesis, 429 435, 430f, 431f, 432f, 433f, 434f, 435f platinum-assisted synthesis, 435 436, 436f

514

Index

Six-membered O,N-heterocycles (Continued) rhodium-assisted synthesis, 436 438, 436f, 437f, 438f ruthenium-assisted synthesis, 438 441, 438f, 439f, 440f, 441f silver-assisted synthesis, 442 444, 442f, 443f, 444f tin-assisted synthesis, 444, 444f titanium-assisted synthesis, 446, 446f ytterbium-assisted synthesis, 446 zinc-assisted synthesis, 446 447, 447f oxazines, 413 Six-membered O,O-heterocycles chromene derivatives, 351 coumarin, 351 352 metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 352 353, 352f, 353f antimony-assisted synthesis, 353 354, 354f barium-assisted synthesis, 354 356, 355f, 356f bismuth-assisted synthesis, 356 358, 356f, 357f, 358f cerium-assisted synthesis, 359, 359f, 360f cesium-assisted synthesis, 360, 360f chromium-assisted synthesis, 360, 361f cobalt-assisted synthesis, 361, 361f copper-assisted synthesis, 361 371, 361f, 362f, 363f, 364f, 365f, 366f, 367f, 368f, 369f, 370f, 371f hafnium-assisted synthesis, 371, 371f iodine-assisted synthesis, 371 373, 371f, 372f, 373f iron-assisted synthesis, 373 374, 374f lithium-assisted synthesis, 374 377, 375f, 376f, 377f molybdenum-assisted synthesis, 377 379, 378f nickel-assisted synthesis, 379 382, 379f, 380f, 381f, 382f platinum-assisted synthesis, 382, 382f rhodium-assisted synthesis, 383 386, 383f, 384f, 385f, 386f scandium-assisted synthesis, 386 387, 387f

selenium-assisted synthesis, 387, 387f silver-assisted synthesis, 387 391, 388f, 389f, 390f, 391f, 392f tungsten-assisted synthesis, 392, 393f zinc-assisted synthesis, 393 396, 394f, 395f, 396f zirconium-assisted synthesis, 361f, 362f, 396 398 Six-membered S-heterocycles metal- and nonmetal-assisted synthesis aluminum-assisted synthesis, 460 461, 460f, 461f, 462f bismuth-assisted synthesis, 462, 462f, 463f calcium-assisted synthesis, 463, 463f, 464f cesium-assisted synthesis, 464 465, 464f, 465f copper-assisted synthesis, 465 470, 465f, 466f, 467f, 468f, 469f, 470f gold-assisted synthesis, 470 472, 471f, 472f, 473f iodine-assisted synthesis, 473 476, 473f, 474f, 475f, 476f iron-assisted synthesis, 476 477, 477f lead-assisted synthesis, 477, 477f lithium-assisted synthesis, 477 480, 478f, 479f, 480f phosphorus-assisted synthesis, 481, 481f platinum-assisted synthesis, 481, 481f rhodium-assisted synthesis, 482 483, 482f, 483f ruthenium-assisted synthesis, 484 486, 484f, 485f, 486f silver-assisted synthesis, 487, 487f tin-assisted synthesis, 487 488, 488f ytterbium-assisted synthesis, 488 489, 488f zinc-assisted synthesis, 489 491, 490f, 491f thiazine derivatives, 459 Sulfoxonium ylides, 13

T Tetrahydronaphthyridines, 304 305 Tetrahydropyrans, 302 303 Tetrathiafulvalene derivatives, 481

Index

Thallium-assisted synthesis, 103, 103f Thioacetals, 463 Thiomorpholine derivatives, 474 Thiophenols, 1 2 Tin-assisted synthesis fused six-membered N-heterocycles, 103, 104f fused six-membered N-polyheterocycles, 163 166, 163f, 164f, 165f, 166f, 167f six-membered N-heterocycles, 38, 38f, 39f six-membered N,N-heterocycles, 220, 221f six-membered N,N-polyheterocycles, 274 281, 274f, 275f, 277f, 279f, 280f, 281f six-membered O,N-heterocycles, 444, 444f six-membered S-heterocycles, 487 488, 488f Titanium-assisted synthesis fused six-membered N-heterocycles, 104 105, 104f, 105f six-membered N,N-heterocycles, 221, 221f, 222f six-membered N,N-polyheterocycles, 281 283, 282f, 283f six-membered O-heterocycles, 336, 336f six-membered O,N-heterocycles, 446, 446f Tosylamides, 2 N-Tosyl iodopiperidines, 2 Tungsten-assisted synthesis fused six-membered N-polyheterocycles, 166 167, 167f six-membered N,N-heterocycles, 222 223, 222f, 223f six-membered O-heterocycles, 336, 336f six-membered O,O-heterocycles, 392, 393f

U Ullmann coupling cyclization, 468

W Wilkinson’s catalyst, 97 98

515

Y Ytterbium-assisted synthesis fused six-membered N-heterocycles, 105, 105f fused six-membered N-polyheterocycles, 167, 168f six-membered N-heterocycles, 39 40, 39f, 40f six-membered N,N-heterocycles, 223 224, 223f, 224f six-membered O-heterocycles, 336 337, 337f six-membered O,N-heterocycles, 446 six-membered S-heterocycles, 488 489, 488f

Z Zinc-assisted synthesis, 168 169, 169f fused six-membered N-heterocycles, 106 107, 106f, 107f six-membered N-heterocycles, 40f, 41f, 42f, 43f, 44f, 45f, 46f, 47f 2-alkyl-4-methylpyridines, 42 alkyl-substituted pyridines, 43 2-amino-3,5-dicarbonitrile-6-thiopyridines, 40 carboxylic acid, 44 2,3-dihydro-4-pyridones, 41 hetero-Diels Alder reaction, 43 44 isocyanoacetamides, 46 Lewis acid-catalyzed Diels Alder reaction, 41 42 Olah’s protocol, 46 oxidative cleavage, 43 44 Passerini-type heterocyclizations, 46 tetrabutylammonium bromide, 47 six-membered N,N-heterocycles, 225 228, 225f, 226f, 227f, 228f six-membered N,N-polyheterocycles, 283 284, 283f, 284f six-membered O-heterocycles, 337 338, 337f, 338f six-membered O,N-heterocycles, 446 447, 447f six-membered O,O-heterocycles, 393 396, 394f, 395f, 396f

516

Index

Zinc-assisted synthesis (Continued) six-membered S-heterocycles, 489 491, 490f, 491f Zirconium-assisted synthesis fused six-membered N-heterocycles, 108, 108f

six-membered N-heterocycles, 47 48, 47f, 48f six-membered N,N-heterocycles, 229, 229f six-membered O,O-heterocycles, 361f, 362f, 396 398