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Paper | Regular issue | Vol 36, No. 5, 1993, pp.971-985
Published online, 1st January, 1970
DOI: 10.3987/COM-92-6224
Site Selective Alkoxymethylation of Imidazo[4,5-b]pyridines: Structural Analysis by High Field NMR Methods

Malvinder P. Singh, Yadagiri Bathini, and J. William Lown*

*Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada


The alkylation reactions of 2-aryl-1(3)H-imidazo[4,5-b]pyridines (eauivalent to 1-deazapurines) with alkoxymethyl chlorides and bromoacetonitrile are described. The structural assignments of the products were made by the use of two-dimensional 1H-1H NOE (NOESY) and selective INEPT (INAPT) 13C nmr experiments utilizing polarization transfer from carbon-bound hydrogens in the alkyl side chains to selected 13C resonances via long-range 3JCH couplings. Although three isomeric N-alkyl derivatives could arise from a single heterocycle based on considerations of tautomeric equillibria, however, the reactions exhibit marked site selectivity even under quite different reaction conditions. Thus, N-3 alkyl derivatives are produced exclusively in basic (Et3N/NaH) nonpolar media following and an SE2cB mechanism. Solvent effects are evident in a loss of N-3 vs N-1 selectivity for alkylation when the polar aprotic solvent DMF is used. Under neutral conditions direct alkylation occurs at the N-4 position following an SE2’ mechanism. The overall site selectivity appears to be governed by the relative reactivity of individual nucleophilic sites rather than the tautomeric composition in solution.