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The indazole scaffold represents a promising pharmacophore, commonly incorporated in a variety of therapeutic drugs. Although indazole-containing drugs are frequently marketed as the corresponding  N -alkyl 1 H - or 2 H -indazole derivative, the efficient synthesis and isolation of the desired  N -1 or  N -2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of  N -1 alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for  N -1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we observed > 99%  N -1 regioselectivity for 3-carboxymethyl, 3- tert -butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on  N -1/ N -2 regioisomeric distribution. For example, employing C-7 NO 2  or CO 2 Me substituted indazoles conferred excellent  N -2 regioselectivity (≥ 96%). Importantly, we show that this optimized  N -alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate electrophiles, while maintaining a high degree of  N -1 regioselectivity.

beilstein journal of organic chemistry

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution