Four-component heterocyclization

Recently, a completely new four-component heterocyclization of pyranopyrazoles 193 has been designed (09RCB2362,09JCO914) (Scheme 73). It consists in the simultaneous mixing of aldehydes 28, MN 27b, ketoesters 36, and hydrazine hydrate. Domino-type heterocyclization proceeds very regioselectively, probably, via formation of a pyrazolone 194 and UN 30in situ. The method is very facile and facilitates preparation of a broad variety of pyranopyrazoles 193. 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R1 = PhCH R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular IV-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

K. Paulvannan, Preparation of Tricyclic Nitrogen Heterocycles via Tandem Four-Component Condensation/ Intramolecular Diels-Alder Reaction , Tetrahedron Lett. 1999, 40,1851-1854. 

In this section I refer to a number of cycloadditions which cannot be categorized into the above-described types. For example, Murai and colleagues reported the four-component coupling of alkyne, hydrazone, hydrosilane and CO. Here, the [Ir4(CO)i2]-catalyzed reaction proceeded under pressurized CO conditions at high temperature, whereby a seven-membered nitrogen heterocycle was obtained (Scheme 11.37) [48]. 

Rikimaru K, Yanagisawa A, Kan T, Fukuyama T (2007) A versatile synthesis of a-amino acid derivatives via the Ugi four-component condensation with a novel convertible isonitrile. Heterocycles 73 403 17... 

Paulvannan K (1999) Preparation of tricyclic nitrogen heterocycles via tandem four-component condensation/intramolecular Diels-Alder reaction. Tetrahedron Lett 40 1851-1854... 

It should be noted that carbonyl compounds, more often aldehydes, are usual second reagent in both the groups. Other building-blocks in these multicomponent processes, leading to the formation of five-, six-, and seven-membered heterocycles, can be numerous acids and their derivatives, p-dicarbonyl compounds or other CH-acids, isocyanides, etc. At this, three-component reactions of ABC and ABB types [32] are the most typical for aminoazole, although some four-component ABCC processes were also published. 

Lipson et al. in several publications [91-93] in the reactions of dimedone and aromatic aldehydes with 2-aminobenzimidazole, 3,5-diamino-l,2,4-triazole, and 3-amino-5-methyltio-l,2,4-triazole described a formation of angular tri- and four-cyclic heterocycles as minor reaction products. However, aldehydes did not participate in these MCRs and the solvent (DMF) acted as a carbonyl component... 

The chemo- and regiospecific palladium-catalyzed four-component reaction of aryl iodides followed by incorporation of carbon monoxide, a polymer-supported allene, and a range of secondary cyclic amines has been reported as a short and high-yielding route to complex heterocycles with three points of diversity, such as 7 <2000CC2241>. 

The use of palladium-based chemistry continues to generate methods for heterocyclic synthesis. In a four-component reaction, ring-fused pyridines can be synthesized in one pot, referred to as a coupling-isomerization-enamine addition-cyclocondensation sequence (Scheme 106) <2005EJ01834>. 

In particular, the consecutive one-pot four-component reaction of (hetero)aroyl chlorides 7, aUcynes 4, tryptamine derivatives 73 as primary amines and a,p-unsam-rated acid chlorides 71 to form tetrahydro-p-carbolines 74 most clearly demonstrates the potential of this concept and methodology for the rapid construction of highly-substituted, complex heterocycles. Five new CT-bonds and four new stereocenters can be installed in a sequence of consecutive one-pot transformations (Scheme 42). 

An elegant safety-catch linker fhat is activated by derivatization of a benzamide with a Boc group has been reported. The compounds can then be released by various nucleophiles, which, in turn, lead to different heterocyclic systems [195]. This linker was developed in connection with an Ugi four-component condensation, for which the starting isonitrile was formed directly on the sohd support 174 (Scheme 80). 

Multicomponent condensations such as the Ugi reaction [44] and the Big-inelli condensation [45] are especially useful for the creation of diverse chemical libraries on the solid phase. Four-component condensations have been reviewed by Mjalli and Toyonaga [46] for the synthesis on the solid phase of small-ring heterocycles [47]. For example, the one-pot condensation of an amine (derived from amino acids) and an aldehyde, followed by the addition of an isocyanide and a carboxylic acid, provides a dipeptidomimetic iV-alky 1-A-acyl- a-amino amide 10 that can serve as a useful starting point for the synthesis of imidazoles 11 and pyrroles 12, which are pharmaceutically useful compounds (Fig. 4). 

Myriad examples are known of oxindoles reacting to form indoles without prior carbonyl activation. Given (he vast scope of this subject, only a few early examples will be cited in addition to recent studies. Several groups have annulated oxindoles to access fused-indole heterocycles. Ila, Junjappa, and coworkers prepared pyrido[2,3-( ]indoles [61, 62] and 67/-indolo[2,3-fc]quinolines [63] using this approach (Scheme 9, equation 1). Adib and colleagues reported a simple synthesis of 9/7-pyrimido[4,5-Z ]indoles from oxindoles (eqnation 2) [64], and Bazgir and coworkers described a four-component one-pot a-carboUne synthesis... 

An efficient method for the synthesis of dihydrothiophene ureidoformamides 149 from commercially available materials in a four-component domino process was reported by Cai et al. [82] (Scheme 12.58). The reaction efficiently assembled aromatic aldehydes 69, malodinitrile 71a, 1,3-thiazolidinedione 148, and anitines 102 with high yields by conducting the reaction in a cosolvent mixture of polyethylene glycol (PEG) 400/H2O (1 1) at 80 °C. Under optimized conditions, a wide range of aldehydes and amines were converted into the desired heterocycles with yields ranging from 27% to 90%. 

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