A Computational Study on the Addition of HONO to Alkynes toward the Synthesis of Isoxazoles; a Bifurcation, Pseudopericyclic Pathways and a Barrierless Reaction on the Potential Energy Surface

Homopropargyl alcohols react with <i>t-</i>BuONO to form acyloximes which can be oxidatively cyclized to yield ioxazoles. The mechanism for the initial reaction of HONO with alkynes to form acyloximes (e.g., <b>13c</b>) has been explored at the B3LYP/6-31G­(d,p) + ZPVE level of theory. The observed chemoselectivity and regioselectivity are explained via an acid-catalyzed mechanism. Furthermore, the potential energy surface revealed numerous surprising features. The addition of HONO (<b>8</b>) to protonated 1-phenylpropyne (<b>18</b>) is calculated to follow a reaction pathway involving sequential transition states (<b>TS6</b> and <b>TS8</b>), for which reaction dynamics likely play a role. This reaction pathway can bypass the expected addition product <b>21</b> as well as transition state <b>TS8</b>, directly forming the rearranged product <b>23</b>. Nevertheless, <b>TS8</b> is key to understanding the potential energy surface; there is a low barrier for the pseudopericylic [1,3]-NO shift, calculated to be only 8.4 kcal/mol above <b>21</b>. This places <b>TS8</b> well below <b>TS6</b>, making the valley-ridge inflection point (VRI or bifurcation) and direct formation of <b>23</b> possible. The final tautomerization step to the acyloxime can be considered to be a [1,5]-proton shift. However, the rearrangement in the case of <b>17h</b> to <b>13c</b> is calculated to be barrierless, arguably because the pathway is pseudopericyclic and exothermic