Synthetic multicomponent reactions

A library of 800 substituted prolines of type 112 was described using a similar synthetic approach. The [3 + 2] cycloaddition occurred via a multicomponent reaction of a-amino esters, aldehydes, and maleimides (Scheme 38). 

Other multicomponent reactions are exemplified in the following two schemes. A new highly diastereoselective four-component reaction was developed for the synthesis of dihydropyridones 191 substituted with an isocyanide functionality <06OL5369>, thereby generating a synthetically useful complex isocyanide for use in further reactions. In this strategy, a phosphonate, a nitrile, and an aldehyde are used to generate an azadiene intermediate 192, which is trapped by an isocyanoacetate in the same pot. 

Also reactions that rapidly create more diversity are sought after. In recent years, more and more multicomponent reactions (MCRs) have been developed and combined with modern synthetic methods such as RCM or Pd couplings to provide rapid access to complex, natural product-like structures in solution. 

The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

Many of the recent advances in synthetic applications of allylic boron reagents have focused on the use of these reagents as key components of tandem reactions and one-pot sequential processes, including multicomponent reactions. The following examples briefly illustrate the range of possibilities. Most cases involve masked allylboronates as substrates, and the tandem process is usually terminated by the allylboration step. 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

Unlike amidines, the multicomponent reaction of a,(3-unsaturated ketones 96 (aliphatic [94] or aromatic [95, 96]) with carbonyl compounds 97 and ammonia, which are the synthetic precursors of amidines, yielded 1,2,5,6-tetrahydropyrimidines 98 instead of dihydroheterocycles. When R3 is not the same as R4 tetrahydropyrimidines 98 were mixtures of diastereomers A and B, in which the relative configurations of stereogenic centers were also established [95, 96]. In contrast to conventional mechanical shaking requiring about 48 h [95], sonicated reactions were completed within 90 min at room temperature and provided the target heterocycles in high yields and purities [96]. Ultrasonic irradiation also significantly expanded the possibilities of such three-component reactions (Scheme 3.29). 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

In term of diversity-oriented strategies, multicomponent reactions (MCR) represent an attractive and rapid access to libraries of macrocycles inspired by biologically active natural products. Combined with Passerini and Ugi reactions, M-RCM has already shown promising synthetic potential, as illustrated by the pioneering work of Domling and coworkers [46]. Condensation of isocyanide 69 with carboxylic acid 70 in the presence of paraformaldehyde leads to bis-olefin 71, which is subsequently submitted to RCM in the presence of G1 and titanium isopropoxide to give the 22-membered macrocycle 72 (Scheme 2.27). 

Abstract How to access efficiently the macrocyclic structure remained to be a challenging synthetic topic. Although many elegant approaches/reactions have been developed, construction of diverse collection of macrocycles is stiU elusive. This chapter summarized the recently emerged research area dealing with multi-component synthesis of macrocycles, with particular emphasis on the approach named multiple multicomponent reaction using two bifunctional building blocks . 

Abstract Heterocyclic structures are an integral part of numerous drugs and natural products and there is a considerable interest in efficient methods for their S3mthesis. A variety of multicomponent reactions (MCRs) provide access to heterocychc structures such as isocyanide based MCRs, dicarbonyl derivative and cycloaddition MCRs. MCR-derived heterocycles are typically prepared in few, versatile and atom efficient synthetic steps and exhibit anticancer, antioxidant and antimicrobial properties. 

One of the most prominent class of multicomponent reactions involves the use of isocyanides [5] and many synthetic methods have been developed to access heterocycles from isocyanide-based chemistry [6, 7]. There are a number of reviews covering the applications of isocyanide-based MCRs in drug discovery [8, 9]. fii this review, we will focus on the most recent developments in the field. 

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