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-1 H -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 1 H -indazole-7-carboxylate ( 18 ) and 1 H -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.