Regioselective N-alkylation of imidazo[4,5-b]pyridine-4-oxide derivatives: an experimental and DFT study |
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Authors: | Wael Zeinyeh Sylvie Radix Nadia Walchshofer |
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Affiliation: | a Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, INSERM U863, IFR 62, F-69373 Lyon cedex 08, France b Université de Lyon, Université Lyon 1, ISPB-Faculté de Pharmacie, F-69373 Lyon cedex 08, France c Laboratoire de Chimie Théorique, Université Pierre et Marie Curie, Paris VI, UMR-CNRS 7616, 4 Place Jussieu, 75252, Paris cedex, France |
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Abstract: | Regioselectivities were determined for N-alkylations of imidazo[4,5-b]pyridine-4-oxide and 2-methyl-imidazo[4,5-b]pyridine-4-oxide with benzyl bromide or benzyl iodide at RT using K2CO3 in DMF as a base. Experimental attempts have shown that N-1/N-3 ratios slightly varied according to the substitution on C-2 position. This was confirmed by DFT calculations in solvent phase. This computational study has shown first that this N-benzylation reaction passed through a SN2 mechanism. Moreover, regioselectivity of N-benzylation has appeared essentially governed by ‘steric approach control’. It explained that opposite N-1/N-3 ratios were obtained with imidazo[4,5-b]pyridine-4-oxide and its 2-methyl-substituted analog. Finally, regioselectivities slightly varied with the nature of benzyl halide. |
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Keywords: | N-alkylation DFT calculations Imidazo[4,5-b]pyridine Regioselectivity SN2 mechanism Tautomerism |
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