Imidazoles, 2-acyl 2-cyano

There have also been a few examples of ring expansions involving azetines. One such instance, which follows a pericyclic mechanism, is the thermolysis of 4-cyano-l-t-octyl-3-t-octylamino-2-t-octyliminoazetine (160), producing the 4-amino-5-cyanoimidazole (Scheme 89). Such azetine species have been implicated as intermediates in the photolysis of enaminonitriles to imidazoles (Section 4.08.1.1.1 Scheme 17). In strongly basic medium the azetidinone (161), which possesses a lactam group, is ring expanded to the 4H-imidazolinone (163), probably via the anionic acylic species (162 Scheme 89) <80AHC(27)241>. 

Replacing the carbonyl group in the ketoamides with a cyano group leads to N-acylated a-aminonitriles (see Section 4.02.9.1(i)). These compounds, such as 1219, react with ammonium acetate at high temperature to give cyclized products, imidazoline 1220 and li7-imidazol-5(4//)-imine 1221 (Scheme 298) <1996H(43)937, 1997T5359>. 

Reactions of A(-acyl- or iV-cyano-imidates with primary amines, hydrazines, or hydrazides have been used on occasion. The latter two reagents adapt the process to the synthesis of 1-amino-imidazoles (210) <87HCA187, 93AHC(57)i>. Nucleophilic attack by the amino group displaces the morpholine function in the first step. A related synthesis has provided the best method yet for making... 

Friedel-Crafts acylations are unknown for the azoles, clearly because of interaction between the basic nitrogen and the Lewis acid catalyst. It is, however, possible to 2-aroylate 1-alkylimidazoles" or indeed imidazole itself by reaction with the acid chloride in the presence of triethylamine, the substitution proceeding via an N-acylimidazolium ylide as shown below. It is similarly possible to introduce cyano to the 2-position by reaction with Af-cyano-4-dimethylaminopyridinium chloride." In the reverse sense, 2-acyl substituents can be cleaved by methanolysis, the mechanism again involving the imidazolium ylide." ... 

In this manuscript we disclose new synthetic methodology to prepare a member of a class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves a thiazolium catalyzed cross acyloin-type condensation of a pyridinealdehyde with an iV-acylimine. The pyridinealdehyde was prepared in 3 steps and 68% yield from 2-chloro-4-cyano pyridine. The tosylamide precursor to the iV-acyl imine was prepared in two steps and 93% yield from isonipecotic acid. We have demonstrated the scope and some preliminary mechanistic studies concerning this new reaction. The resulting a-keto-amide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in 6 steps and 38% overall yield. 

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