Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions

Abstract

Efficient syntheses of 4,5-, 5,6-, and 6,7-indolyne precursors beginning from commercially available hydroxyindole derivatives are reported. The synthetic routes are versatile and allow access to indolyne precursors that remain unsubstituted on the pyrrole ring. Indolynes can be generated under mild fluoride-mediated conditions, trapped by a variety of nucleophilic reagents, and used to access a number of novel substituted indoles. Nucleophilic addition reactions to indolynes proceed with varying degrees of regioselectivity; distortion energies control regioselectivity and provide a simple model to predict the regioselectivity in the nucleophilic additions to indolynes and other unsymmetrical arynes. This model has led to the design of a substituted 4,5-indolyne that exhibits enhanced nucleophilic regioselectivity.

Analyzing Reaction Rates with the Distortion/Interaction‐Activation Strain Model

“…The relative reactivities are controlled by these distortion energies. The distortion/interaction‐activation model also successfully predicted the regioselectivities observed experimentally for other cases 43a–43f. The more linear side of the aryne is also the favored site of nucleophilic attack experimentally.…”

“…The distortion/interaction‐activation strain model proved to be a reliable way to understand and predict the products of these reactions. The study by Cheong and co‐workers led to the breakthrough in this area,43a and it demonstrated the potential of this model to explain regioselectivities as well as reactivities. …”

Understanding and Modulating Indolyne Regioselectivities

“…26,27 Thus, we had ready access to indolyne precursors 12-14 ( Figure 3). Trapping of the indolyne intermediates with nucleophilic agents and cycloaddition partners provided access to a number of 4-, 5-, 6-, and 7-substituted indoles (e.g., 25-…”

Transfer Hydrogenation vs Nucleophilic Addition: Aryne Reaction with Alcohols

“…This novel mode of reactivity is firstorder with respect to the alcohol and is calculated to proceed via a concerted, asynchronous mechanism (Figure 2). The aryne ring in the transition state is quite distorted [13,14] and the H-C(OH) bond cleavage is more advanced than the cleavage of the O-H bond. Both findings support a minor contribution of a hydridic nature of the transferred hydrogen H at the carbinol atom within the concerted mechanism frame (a real carbocation mechanism is excluded).…”