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

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