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 1H- or 2H-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 NO₂ or CO₂Me 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.

中文翻译：

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1H-吲唑支架的区域选择性N-烷基化；环取代基和N-烷基化试剂对区域异构分布的影响


吲唑支架代表了一种有前途的药效团，通常掺入多种治疗药物中。尽管含吲唑的药物经常以相应的N-烷基 1 H-或 2 H-吲唑衍生物的形式销售，但所需N -1 或N -2 烷基吲​​唑区域异构体的有效合成和分离通常具有挑战性，并对产品产率产生不利影响。因此，作为关注生物活性吲唑衍生物合成的更广泛研究的一部分，我们旨在开发用于合成N -1 烷基吲唑的区域选择性方案。各种条件的初步筛选表明，氢化钠（NaH）与四氢呋喃（THF）（在烷基溴存在下）的组合代表了一种有前途的N -1 选择性吲唑烷基化系统。例如，在检查的 14 种 C-3 取代吲唑中，我们观察到 3-羧甲基、3-叔丁基、3-COMe 和 3-甲酰胺吲唑的N -1 区域选择性 > 99%。这种优化的（THF 中的 NaH）方案进一步扩展到各种 C-3、-4、-5、-6 和 -7 取代的吲唑，突出了空间和电子效应对N -1/ N -2 区域异构体分布的影响。例如，使用C-7 NO ₂或CO ₂ Me取代的吲唑赋予优异的N -2 区域选择性（≥96%）。重要的是，我们表明，这种优化的N -烷基化程序可以耐受多种结构的烷基化试剂，包括伯烷基卤化物和仲烷基甲苯磺酸盐亲电子试剂，同时保持高度的N -1 区域选择性。