2-Methyl-imidazoles, side-chain reactions

A benzisoxazole moiety provides the nucleus of an anticonvulsant agent whose structure differs markedly from the traditional agents in this class. The synthesis starts with a compound (61-1) that incorporates a preformed benzisoxazole. Bromination proceeds on the position adjacent to the carboxylic acid (61-2). This intermediate loses carbon dioxide on heating, leaving behind the bromomethyl derivative (61-3). Displacement of the halogen with the ion from the reaction of imidazole with sodium hydride yields the alkylation product (61-4). The short side chain is then methylated by successive treatment with a base and methyl idodide to afford zoniclezole (61-5) [64]. 

Large rate accelerations have been observed in the metal ion-promoted hydrolysis of some lactams and these reactions are considered in Section 61.4.10. Other investigations have dealt with divalent metal ion-catalyzed hydrolysis of p-nitrophenyl picolinate in the presence of imidazoles and pyridines having hydroxyl groups in their side chains,226 the zinc(II)-facilitated hydrolysis of esters of 2-hydroxy acids227 and the metal ion-promoted hydrolysis of methyl 2-( JV-acetylhydrazono) propanoate.228... 

Lateral metalation can be a complication, and this occurs in compounds such as 1,2-dimethyl- and 1-benzyl-imidazoles, and with 2-methyl- and 2-benzyl-benzimidazoles. Subsequent reactions of these compounds take place at the side-chain carbanion centre (73JOC4379, 74JOC2301). 

Silylation with silyl chlorides or silyl triflates is performed in the presence of auxiliary bases, e.g. pyridine, TEA, imidazole, etc., in solvents such as CH2CI2, CHQ3, DMF, or As milder reagents A-methyl-G-(trimethylsilyl)acetamide and preferably A,C)-bis(trimethylsilyl)acetamide (BTMSA, 136) (Scheme 72) are used for such purposes. Since the acetamide that results from this reaction is difficult to remove from the reaction medium, cyanotrimethylsilanet or l-(trimethylsilyl)imidazole (137).t l may be used as alternatives. For quantitative silylation of amino acids containing additional side-chain functionalities, excess silylating agent is required. 

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