MULTIFUNCTIONALIZATION OF IMIDAZOLE VIA SEQUENTIAL HALOGEN-METAL EXCHANGE - A NEW ROUTE TO PURINE-RING ANALOGS

A new method for the synthesis of purine-ring analogs based upon the sequential halogen-metal exchange functionalization of 1-[(benzyloxy)methyl]-2,4,5-triiodoimidazole (1) has been developed and is illustrated by the synthesis of (1H)-imidazo[4,5-d]pyridazin-4(5H)-one (2-aza-3-deazahypoxanthine, 8). Treatment of 1 with BuLi followed by quench with PhSSPh afforded the 2-(phenylthio) derivative, which upon treatment with BuLi followed by quench with DMF gave the 5-carboxaldehyde. This aldehyde was converted into its ethylene acetal, which was treated with BuLi followed by quench with ClCO2CH3 to afford a 4-(methoxycarbonyl)imidazole. Removal of the phenylthio group with Al(Hg) and the (benzyloxy)methyl and ethylene acetal protecting groups concomitantly with 3 M HCl afforded methyl 5(4)-formylimidazole-4(5)-carboxylate, which underwent cyclo-condensation with ethanolic NH2NH2 to give target 8. This synthetic approach was found amenable to modification by efficient ''one-pot'' multistep transformations. Thus, treatment of 1 with (a) BuLi, (b) (CH3)3SiCl, (c) BuLi, (d) (CH3)2NN(CH3)CHO, (e) BuLi, and (f) (CH3OCO)2O afforded the N-protected 4-(methoxycarbonyl)-imidazole-5-carboxaldehyde (13) in 25% yield directly from 1. Imidazole 13 was then elaborated to 8 in two steps. 1-Formyl-1,2,2-trimethylhydrazine is a recommended replacement for DMF as a tandem formylating/ortho-metalation directing agent.