Regioselective <i>N</i>-alkylation of the 1<i>H</i>-indazole scaffold; ring substituent and <i>N</i>-alkylating reagent effects on regioisomeric distribution
Ryan M. Alam, J. J. Keating
Abstract
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.