Novel synthesis of indole and quinoline derivatives

By Mayur Desai

The book is really good source of information on synthesis of heterocycles. The book covers synthetic aspects of indole and quinoline derivatives. Wittig olefination - Claisen rearrangement protocol is used for the synthesis of these heterocycles. The adopted methodology has shown to implement on 8 different starting materials in
each chapter. The protocol can be used for synthesis of other heterocyclic compounds also.

• Language: English
• Publisher: Mayur Desai
• Release date: Feb 3, 2021
• ISBN: 9781393728306

Mayur Desai

Dr. Mayur Desai completed his doctoral work in Pune University. His research area of interest is heterocyclic chemistry. He published his research work in 11 reputed journals like European Journal of Organic Chemistry, Tetrahedron Letters and Beilstein Journal of Organic Chemistry. Also he has programmed 4 stereochemistry softwares.

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Acknowledgement

It gives me immense pleasure to express my thanks to all those who have been there all the while during my research period, readily lending their help in every possible way.

I take this opportunity to express my deep sense of gratitude to my research guide, Prof. M. G. Kulkarni, for his unfailing attention, inspiring guidance, constant support and constructive criticism at every point of time. He is more than a teacher to me.

I am grateful to Prof. D. D. Dhavale, head of the department for providing necessary facilities.

It is indeed a great pleasure to acknowledge to the teaching and non-teaching staff of the department of chemistry, who helped me in several ways during the tenure of my work.

The immense help extended to me by my labmates Dr. Dnyaneshwar, Dr. sanjay, Dr. Ajit, Dr. Atrimuni, Yunus, Vijay, Deekshaputra, Ramesh, Dhatrak sir, Kishor and shashi is difficult to express in words. Their friendship, love and affection made my lab work memorable.

Wholehearted co-operation extended by my friends Mahendra, Datta, Vilas, Manojkumar, Shreekar, Momin, Naveen, Purushottam, Sanjay Chavan, Vishwas, Raju-Pune University, is greatly acknowledged.

Thanks are due to our scientific staff, Mrs. J. P. Chaudhari for NMR spectra and Basaveshwar for microanalysis and IR spectra.

I would like to thank M. K. Sul, Garud and Nitin for their co-operation. Co-operation from technical section, account section and stores is gratefully acknowledged.

I can not even imagine where I would have been today, had it not been a handful of my friends, who were always there with me in times of joy and stress. Heartful thanks to Vinay Sapre, Govind Sane, Amit Kulkarni and Amar Bhagwat for helping me to survive in the roughest patch of my research endeavor. Sincere thanks to the Dr. Amey Mulay for his timely support, encouragement and valuable suggestions.

Word falls short to thank Sumant Bhide who has always stood beside me in all my ups and downs with his optimism and endless patience. The concern and motivation which I have received from him in darkest hour of need are beyond my words to express.

My family members (Baba, Aai, brother, sisters, wife and kids - Bravim and Maitreyee) need a special mention for their tolerance and encouragement. Their patience, love and affection have given me the strength to go through the rigors and vigors of life with more enthusiasm and zeal.

Finally I wish to thank UGC, New Delhi for the award of JRF and SRF during the tenure of this work.

Date:    (Mayur Prabhakar Desai)

Abbreviations

The following abbreviations are used in this thesis-

Boc      tert-butyloxycarbonyl

DMAP      4-dimethylaminopyridine

TBAF      Tetrabutyl ammonium fluoride

PPTS      pyridinium para-toluenesulfonate

DMF      Dimethyl formamide

KOH      Potassium hydroxide

NAN3      Sodium azide

AcOH      Acetic acid

p-TSA      para-toluene sulfonic acid

NBS      N-bromo succinamide

LAH      Lithium aluminium hydride

9-BBN      9-Bora bicyclo [3.3.1] nonane

DIBAL-H     Diisobutyl aluminium hydride

m-CPBA     meta-chloroperoxy benzoic acid

THF      Tetrahydro furan

Yb(OTf)2     Ytterbium triflate

NaH      Sodium hydride

CS2      Carbon disulfide

TLC      Thin layer chromatography

SnCl2      Tin chloride

AIBN      Azo bis-isobutyronitrile

Li2CO3      Lithium carbonate

DCM      Dichloromethane

n-BuLi      n-butyl lithium

DCE      Dichloroethane

NMR      Nuclear Magnetic Resonance

Abstract

The thesis is divided into three chapters.

Chapter 1:  Wittig olefination – Claisen rearrangement protocol for the synthesis of 3-(but-3-en-2-yl)-1H-indoles

This chapter deals with the synthesis of 3-(but-3-en-2-yl)-1H-indoles, which have been found as an important intermediates in biologically active compound, such as an indole alkaloids, indole 3-acetic acid and its secondary metabolites known as plant growth hormones. In animals, serotonin (5-hydroxytryptamine) is known as a crucial neurotransmitter in the central nervous system. The potent physiological properties of these indole derivatives led to vast research of their use as medicines in the field of pharmaceutical chemistry. That is why intensive investigations on the indoles for both, the reactivity and the development of the synthetic way have been done. There is still sustained interest for the development of new strategies for the construction of indoles, especially the 3-substituted indoles.

An efficient two-step synthesis of 3-(but-3-en-2-yl)-1H-indoles 42a-h from several o-nitro aldehydes 40a-h using Wittig-olefination followed by insitu Claisen rearrangement and reductive cyclization was developed. (Scheme 18)

Scheme 18

CHAPTER 2: Synthesis of 3-methyl quinoline-4-carbaldehydes

Quinoline aldehydes are important synthetic intermediates in the synthesis of heterocyclic compounds which are used in the manufacture of dyes, pharmaceuticals, fragrances and flavours etc. 3-substituted and 2, 3-di-substituted quinoline-4-carbaldehyde derivatives are used in the synthesis of immunosuppressant KF20444 and 5-HT3 receptor antagonists. Quinoline mevalonolactones, prepared from 3-methyl quinoline-4-carbaldehyde, act as inhibitor of HMG-CoA reductase. 3-substituted quinoline-4-carbaldehyde derivatives are used in the development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). These derivatives are exploited in the synthesis of DNA binders, anti-tumor agents and for the treatment of viral and parasite infectionsand macrolides. Derivatives of quinoline-4-carbaldehyde are also used in the preparation of colouring agents for keratin containing fibres.

Though there are a number of quite efficient methods for the preparation of quinoline-4-carbaldehydes, only two methods are available for the preparation of 3-methyl quinoline-4-carbaldehyde derivatives which is the essential moiety present in quinoline mevalonolactones. We developed the synthesis of highly substituted 3-methyl quinoline-4-carbaldehyde ring 61a-h using a Wittig olefination-Claisen rearrangement methodology.

Scheme 27

CHAPTER 3: synthesis of 3-methylfuro[2,3-b]indoles

Furo[2,3-b]indole occurs naturally in the calabar bean alkaloid Physovenine and other natural products. This framework is of importance as it is a part of many natural products like the anti-cholinergic calabar bean alkaloids physovenine. This underlines the importance of developing novel routes to substituted furo[2,3-b]indoles. Though there are many routes to this heterocyclic ring system, there was no route found for the preparation of substituted 3-methyl furo[2,3-b]indoles.An efficient synthesis of furoindoles 211a-h were developed by using Wittig olefination-Claisen rearrangement methodology followed by five step reaction sequence in overall good yields (Scheme 66).

SCHEME 66

Chapter 1

Wittig olefination – Claisen rearrangement protocol

for the synthesis of 3-(but-3-en-2-yl)-1H-indoles

Introduction

Indoles are one of the most widely distributed heterocyclic compounds in nature. ¹ The indole ring appears in tryptophan, an essential amino acid, and metabolites of tryptophan are important in the biological chemistry of both, plants and animals. In plants, the structural variety of indole alkaloids including indole-3-acetic acid and its secondary metabolites are known as a plant growth hormone. In animals, serotonin (5-hydroxytryptamine) is known as a crucial neurotransmitter in the central nervous system. ² The potent physiological properties of these indole derivatives led to vast research on their use as medicines in the field of pharmaceutical chemistry. Among the successful examples as drugs are indomethacin, ³ one of the first nonsteroidal anti-inflammatory agents, sumatriptan, which is used in the treatment of migraine headaches, and pindolol, ⁴ one of the â -adrenergic blockers. Several naturally occurring indoles also have clinical importance. Vincristine, ⁵ a dimeric indole alkaloid, and closely related compounds were the first of the anti-mitotic class of chemotherapeutic agents for cancer. The mitomycins ⁶ and derivatives of ellipticine ⁷ are other examples of compounds having antitumor activity. That is why intensive investigations on the indoles for both the reactivity and the development of the synthetic way have been done. There is still sustained interest for the development of new strategies for the construction of indoles, especially the 3-substituted indoles.

W. E. Billups⁸ and co-workers have conducted allylation of indole 1 with allyl acetate 2, palladium acetylacetonate and triphenylphosphine (ligand/catalyst = 1) in glacial acetic acid. On heating this mixture at 75oC for 5 h; 3-allylindole 3 (54%), 1-allylindole 4 (7%), and 1,3-bisallylindole 5 (11%) were obtained. The product formation and rate of reaction was dependent on the ratio of ligand and catalyst. Altering the ligand/catalyst ratio to 1:3, resulted in the formation of the 1-allylindole as major product, however the overall rate of the reaction became significantly slow (Scheme 1).

Scheme 1

JOHN A. MURPHY⁹ and co-workers reported that treatment of 1,4-Pentadienyl-3-sulfonamides 6 with tributyltin hydride in presence of AIBN giving 3-allylindole 3 alongwith compound 7 and compound 8   ( Scheme 2).

Scheme 2

J. S. YADAV¹⁰ and co-workers have reported zinc mediated Barbier reaction for the synthesis of 3-allyl indole. Treatment of indole 1 with allyl bromide 9 in the presence of zinc dust in aqueous THF gave 3-allyl indole 10 in excellent yield. The scope of reaction was tested by treating several substituted indoles with different alkyl halides to give respective 3-alkyl derivatives in high yields. (Scheme 3)

Scheme 3

SHIN KAMIJO¹¹ et al. reported that the palladium-catalyzed three-component coupling reaction (TCCR) of aryl isocyanides 11, allyl methyl carbonate 12, and trimethylsilyl azide was conducted in the presence of Pd2(dba)3.CHCl3(2.5 mol %) and dppe(1,2-bis(diphenylphosphino)ethane) (10 mol %) at 40-60oC, allyl aryl cyanamides 13 was obtained in excellent yield, whereas at higher temperature (100oC), the reaction gave N-cyanoindoles 14 in good to moderate yields. (Scheme 4)

Scheme 4

SHIN KAMIJO¹² et al. reported synthesis of substituted indoles by using bimetallic as well as duel role catalyst. Reaction was carried out by treating 2-(alkynyl)phenylisocyanates 15 with allyl carbonates 12 in the presence of Pd (PPh3)4

(1 mol %) and CuCl (4 mol %) giving substituted 3-allyl indole 16 in excellent yield. On the other hand, treatment of (alkynyl)phenylisocyanates 15 with alcohols 17 in presence of Na2PdCl4 (5 mol %) or PtCl2 (5 mol %) gave N-(alkoxycarbonyl)-indole 18 in excellent yield. Most likely Pd(0) acts as a catalyst for the formation of a δ allylpalladium alkoxide intermediate and CuI behaves as a Lewis acid to activate the isocyanate, and the cyclization step proceeds with a co-operative catalytic activity of Pd and Cu. Pd(II) or Pt(II) catalyst exhibits a dual Lewis acidity. On one hand, it accelerates the addition of alcohols to isocyanates and on the other hand, it acts as a typical transition-metal catalyst to activate the alkyne for the subsequent cyclization. (Scheme 5)

Scheme 5

ACHILLE UMANI-RONCHI¹³ and co-workers reported mild palladium catalyzed alkylation of indole via nucleophilic allylic substitution. The reaction involves treatment of indole 1 with allyl carbonate 19, in the presence of palladium catalyst (5 mol %), in low coordinating solvent DCM and base Li2CO3 giving 3-alkylated product 20 in excellent yield along with a trace of N-alkylated product 21. The regioselectivity of the reaction could be controlled by the proper choice of base and reaction media. (Scheme 6)

Scheme 6

MASANARI KIMURA¹⁴ and co-workers have reported the synthesis of C-3 selective allylation of indole. The reaction involves treatment of indole 1 with allyl alcohol 22 in the presence of catalyst Pd(PPh3)4 (5 mol %) and triethyl borane

(30 mol %) as a promoter under inert atmosphere, when 3-allyl indole 3 was obtained in excellent yield after the flash chromatography purification. The scope of methodology was further tested by variation in indole as well as allyl alcohol. (Scheme 7)

Scheme 7

BARRY M. TROST¹⁵ et al. have developed methodology for the enantioselective C-3 allylation of 3-methyl indole 23. The reaction involves treatment of 3-methyl indole 23 with allyl alcohol 22 in the presence of Pd2(dba)3.CHCl3 , chiral ligand and 9-BBN as a promoter in the presence of dichloromethane to give 3-allyl-3-methyl indolenine 24 in excellent yield with 82 % ee. The utility of this methodology was further explored by applying the methodology to the synthesis of oxindole family natural products like, (-) Phenserine and (-) Esermethole. (Scheme 8)

Scheme 8

EIICHI NAKAMURA¹⁶ and co-workers have reported synthesis of 2,3-disubstituted indole and benzofurans. The reaction involves treatment of 2-ynylanilines 25 with n-BuLi and ZnCl2 giving 3-zincisobenzoheterole intermediates. These intermediates have been transmetalated to corresponding cuprate by using CuCN.2LiCl mixture. These cuprate intermediate were then allowed to react with allyl bromide 26 to give corresponding indole 27 in excellent yields (Scheme 9).

Scheme 9

DIPAK PRAJAPATI¹⁷ et al. reported that treatment of indole 1 with allyl bromide 26 in the presence of gallium metal and tetrabutylammonium bromide as an additive in aqueous DMF at room temperature, gave 3-allyl indole 3 in excellent yields. The versatility of methodology was checked by using substituted indoles and alkyl halides in the reaction (Scheme 10).

Scheme 10

ALBERT S. C. CHAN¹⁸ and co-workers reported that reaction of indole 1 with 1,3-diphenyl-2-propenyl acetate 28 in presence of 0.3 mol % of palladium catalyst and 2.5 mol % of chiral  ligand and potassium carbonate in acetonitrile at 40 oC gave C-3 alkylated product 29 in good yield with 96 % ee. The scope of reaction was checked for the various substituted indoles. (Scheme 11)