Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

Herein, we report a pair of regioselective N ¹- and N ² -alkylations of a versatile indazole, methyl 5-bromo-1H-indazole-3-carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N ¹- and N ²-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N ¹-substituted products when cesium is present and other non-covalent interactions (NCIs) drive the N ²-product formation. Methyl 1H-indazole-7-carboxylate (18) and 1H-indazole-3-carbonitrile (21) were also subjected to the reaction conditions and their mechanisms were evaluated. The N ¹- and N ²-partial charges and Fukui indices were calculated for compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways.