Indole based multicomponent reactions towards functionalized heterocycles

This short review offers a non-exhaustive panorama of the


Introduction
Multicomponent reactions (MCR-s) have recently emerged as valuable tools in the preparation of structurally diverse chemical libraries of drug-like heterocyclic compounds. 1The multicomponent reaction story began as far back as 1850 by the publication of the Strecker reaction, 2 arriving nowadays at its apogee.During this one and a half century period, some notable achievements include the discovery of the Biginelli, 3 the Mannich, 4 and the Passerini 5 reactions culminating in 1959 when Ugi published 6 probably the most versatile MCR based on the reactivity of isocyanides. 7In view of the increasing interest for the preparation of large heterocyclic compound libraries, the development of new and synthetically valuable multicomponent reactions remains a challenge for both academic and industrial research teams. 8lthough functionalized indole ring systems have been found frequently in biologically active molecules, indole derivatives as MCR partners are rather under-represented.This review offers a short and non-exhaustive summary of the synthesis of functionalized heterocyclic systems by multicomponent strategies involving indole derivatives as reaction partners.

Scheme 1
In this process, in the absence of an amine component, a simple multicomponent approach employing an equimolar mixture of ethyl 2-indolylacetate 1a, benzaldehyde and Nmethylmaleimide resulted in the formation of 4 in 74% yield.

MCR-s involving isocyanides-Ugi reaction
Despite the importance of Ugi-type reactions in the synthesis of heterocyclic compounds, only scant attention has been paid to the incorporation of indoles as multicomponent reaction partners.For example, the indole nucleus has a secondary role in a recently published preparation of pyrrolo[2,1-a]isoquinoline derivatives.Mironov et al. have found a new MCR between isoquinoline 5, geminal diactivated olefins 6, and isocyanides 7, for the synthesis of dihydro-10H-pyrrolo[2,1-a]isoquinolines (Scheme 2). 15From a mechanistic point of view, the key step is the formation of zwitterion 8, which was attacked by isocyanide affording the final product 9.

Scheme 2
The β-carboline core is a frequently occurring structural motif in natural products and biologically active substances.For the preparation of a pentacyclic β-carboline structure Dömling et

MCR-s with boronic acids-Petasis reaction
In the '90-s, a new synthetic method, involving vinyl boronic acids as nucleophiles in Mannich type reactions was developed by Petasis for the preparation of various allylamines. 17Later on, this approach was extended to the preparation of non-natural amino acids.Thus, a trimolecular condensation involving diverse 3-indolyl boronic acids 19, glyoxalic acid 20, and a chiral amine 21 allowed the preparation of N-substituted-indolylglycines 22 (Scheme 5) with excellent diastereoselectivity (de>99%).

Multicomponent reactions combined with domino cyclisation
Domino reactions 21 involving the formation of several chemical bonds in one sequence without isolating the intermediates, have proven to be economically and environmentally favourable procedures for the preparation of complex molecules.A successful combination of domino reactions with the multicomponent approach tends towards the ideal organic synthesis concept.Following this idea, a three component condensation domino Knoevenagel-hetero Diels-Alder pathway was worked out by Tietze et al. for the preparation of indole alkaloid derivatives (30 and 34, respectively) of the Corynanthe (Scheme 7) and Valesiachotamine (Scheme 8) groups. 22n both reactions, high diastereoselectivity was observed and the configuration of the newly formed stereogenic centres can be reversed by changing the tosyl group (27a) at the indole nitrogen into hydrogen (27b) or vice-versa.With an aim towards constructing the central isoquinoline based tricyclic core of the anticancer alkaloids manzamine (Scheme 9), Markó et al. have proposed a novel cascade anionic polycyclisation method. 24

Scheme 9
Their procedure is situated somewhere on the borderline between multicomponent and domino reactions.Substituted gramines 35, in the presence of t-BuOK reacted with acrolein and functionalized β-keto phosphonates via a multicomponent condensation, followed by base catalyzed polycyclisation cascade of 36 to afford highly substituted decahydro-isoquinoline type compounds 37 (Scheme 10).This highly chemo-and diastereoselective process allowed the control of up to four chiral centres.

Yonemitsu-reaction
Meldrum's acid 31 appears to be an attractive reagent in organic syntheses owing to its high acidity, steric rigidity and high reactivity. 25n When, at beginning of the '90-s, we were interested in the preparation of non-natural βsubstituted tryptophan derivatives for the synthesis of modified CCK-4 analogs 28 , the Yonemitsu reaction attracted our attention.Stable, high-yield isolated products with the readily cleavable dioxanedione appendage seemed to be valuable intermediates for our purposes.

Scheme 12
Solvolysis of 39 with alcohols gave a diastereomeric mixture of acid esters 42 (Scheme 13).For the transformation of the carboxylic acid function into carbamate, the well-known domino acylazide 43 formation-Curtius rearrangement-benzylalcohol mediated solvolysis of the isocyanate intermediate 44 procedure was utilized.Separation of the diastereomeric carbamates 45 (syn/anti), followed by classical deprotection completed the synthesis of β-substituted tryptophans 46 (syn/anti). 31

Synthesis of heterocycle-fused tryptamines
The tetrahydro-β-carboline core, present in numerous alkaloids (Vinca-, Rauwolfia-, Harmanalkaloids) and synthetic products with valuable biological properties, is accessible from tryptamine via the well-known Pictet-Spengler 33 and Bischler-Napieralski reactions.Some 3,4annulated (tetrahydro)-β-carbolines were reported to be potent benzodiazepine antagonists or tyrosine kinase inhibitors. 34Heterocycle fused tryptamines are considered as useful precursors for the preparation of functionalized, conformationally restricted serotonin and melatonin analogs.
A multicomponent pathway, using masked nucleophile containing aldehydes, was proposed for the preparation of new 3,4-heterocycle fused (tetrahydro)-β-carbolines. Following a chemoselective deprotection, an internal nucleophilic ring opening of the Meldrum's acid moiety could be envisaged and the resulting carboxylic acid function was to be relayed toward the targeted tryptamine and β-carboline compounds.
In a preliminary study, 35 the trimolecular adducts 49 were prepared by using Cbz (CO 2 Bn) masked 2-hydroxy-48a or 2-aminoacetaldehydes 48b,c as aldehyde partners (Scheme 14).Deprotection of 49 and subsequent internal nucleophilic attack allowed the isolation of furanone 50a (90 %), and pyrrolidinone 50b (80 %), as sole products.In both cases, we observed the exclusive formation of 3,4-trans disubstituted ring systems, resulting from a decongested transition state in which the bulky indole ring, being remote from the Meldrum's acid moiety, favours an equatorial attack.Conversion of the carboxylic acid function to amine followed the classical pathway providing heterocycle-fused trans tryptamines 51a or 51b.

Scheme 16
Simple functional group transformations completed the synthesis of chiral pyrrolidinonefused tryptamine (-)-61. 38In both series, the chirality of the Garner's aldehyde ensured a complete and predictible control of the two newly created stereocentres.Although our initial investigations to reproduce Bailey's results failed, multicomponent reactions between 2-substituted indoles 1, benzaldehyde and Meldrum's acid 31 were carried out in the presence of one equivalent of triethylamine affording stable, crystalline adduct salts 64 in 60-78 % yield. 40It is noteworthy that 64 are obtained stricto sensu in tetramolecular reaction processes (Scheme 18).When in situ formed azides 66, prepared via the well-known path from 65, were heated in toluene, a diastereomeric mixture of spirocyclic pyrrolidinone-indolines 68 was isolated via 67 resulting from a Curtius rearrangement, followed by a thermal spirocyclisation process.

Preparation of spiro[pyrrolidinone-indolines]
Indoline-2-one (oxindole) 70 also proved to be a reactive nucleophile under modified Yonemitsu conditions.Condensation of 70 with aromatic aldehydes, Meldrum's acid 31 and triethylamine afforded adduct salts 71 in moderate yields.A successful application of the previous domino process on 72 allowed the isolation of functionalized spiro-oxindole derivatives 73. 41It is important to note that the spiro-oxindole core is present in various alkaloids, for example horsfiline or spirotyprostatines, of biological interest.

Conclusions
This short review describes the main synthetic methods that have been published in the field of indole based multicomponent reactions during the last three decades.In spite of some recent progress, particularly concerning the Yonemitsu reaction, multicomponent methodology with the

15, tryptamine 16, and isocyanide 17 as
16arting materials, has been worked out by Zhang et al. for the synthesis of various, including indole containing, polycyclic lactams 18 (Scheme 4).16
27 ISSN 1424-6376 Page 214 © ARKAT USA, Inc carbazoles Scheme 11 6.1.Synthesis of β-substituted tryptophans Tryptophan is an important essential amino acid present in various biologically active peptides.Its replacement by conformationally constrained β-substituted analogs has been used commonly in peptide-receptor affinity studies.