Van Leusen three-component reaction

The first MCR involving the explicit use of a-acidic isonitriles was reported in 1998 by Sisko [131]. The reaction involves the cycloaddition of aTosMIC derivative (8) to an (in situ-generated) imine (10) followed by the elimination of p-toluenesulfinic acid (TsH) as described in 1977 by van Leusen for preformed imines (Fig. 5, scaffold P) [119]. Although several potential pitfalls for the conversion of the traditional van Leusen [3 + 2] cycloaddition to the so-called van Leusen three-component reaction (vL-3CR) of imidazoles were expected by the author, simply stirring the aldehyde and amine for 20 min followed by addition of the TosMIC derivative and base resulted in the isolation of the corresponding imidazole (9) in high yield [131]. 

Despite the chemical complexity of multicomponent reactions (MCRs), the dawn of MCRs was fairly early in the history of organic chemistry. The first MCR was the so-called Strecker reaction discovered in 1850 [1, 2], which generates amino acids via a three-component reactiOTi between amines, aldehydes (or ketones), and hydrogen cyanide (Scheme 1). Since then, organic chemists have devoted much effort to the discovery of additional MCRs. Thus, we now can find a number of MCRs, including the Biginelli reaction [3], the Gewald reaction [4], the van Leusen three-component reaction [5], the Hantzsch reaction [6], the Mannich reaction [7], the Kabachnik-Fields reaction [8, 9], the Passerini reaction [10], the Ugi reaction [11, 12] and numerous variations thereof [13]. 

A convenient method of synthesis of pharmacologically attractive imidazoquinoxaline derivatives 75a-g has been described (DeMoliner and Hulme 2012b). The method involves the three-component reaction of A-Boc-o-phenylenediamines 76a-d with glyoxylic acid derivatives, namely, with ethyl glyoxylate (see Sect. 4.4) and benzylglyoxylamide 77, with the participation of tosylmethyl isocyanides. The reaction is carried out under microwave irradiation [the Van Leusen and Van Leusen modification (2012)]. It is likely that, first, the condensation of aldehyde at the free amino group of compounds 76a-d leads to imines 78a-d, which are... 

Isocyanide derivatives are undoubtedly the most important reactants in MCRs because they show both nucleophilic and electrophilic characters within a single functionality. For example, IMCRs include the Ugi four-component reaction (Ugi-4CR) [11, 12], the Passerini three-component reaction (Passerini-3CR) [10], the Groebke-Blackbum-Bienayme reaction [44—46], the van Leusen three-... 

Three-component condensation of A -Boc-l,2-DABs 76, ethyl glyoxylate and substituted tosyl isocyanates in the presence of potassium carbonate on heating and under microwave irradiation (the Van Leusen strategy mentioned above) has been described (DeMoliner and Hulme 2012b). The reaction proceeds as a one-pot process, but in two stages cyclization of intermediates 106 leads to imidazo[l,5-a] quinoxalin-4-ones 107a-g (Scheme 4.48). 

---