Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions

Abstract

The 6,7-indolyne shows remarkable regioselectivity in its cycloaddition with 2-substituted furans. Electron-donating groups give predominantly the more sterically crowded product, while electron-withdrawing groups display the opposite regioselectivity. By contrast, 4,5- and 5,6-indolynes show no regioselectivity. Optimized electronic structure calculations using the M06-2X density functional and 6-311+G(2df,p) basis set revealed that the 6,7-indolynes are highly polar structures and that their cycloadditions have substantial electrophilic substitution character that leads to the observed preference for contrasteric products.

Insertion of Arynes into N-Halo Bonds: A Direct Approach to o-Haloaminoarenes

“…Additionally, a heteroaryne was also a viable substrate, providing the chloroaminated indole derivatives in a 8:1 ratio of two isomers (entry 14). Note that the observed regioselectivity in our studies is consistent with with that reported for nucleophilic additions of unsymmetrical arynes, 7c,16 suggesting the insertion may occur in a polar pathway directed by steric and electronic effects of both arynes and N–X bonds. 17 …”

Cycloaddition of Arynes and Cyclic Enol Ethers as a Platform for Access to Stereochemically Defined 1,2‐Disubstituted Benzocyclobutenes

“…[10] Recently, computational methods have been utilized to better understand how cycloaddition and nucleophilic addition reactions to arynes are influenced by aryne structures. [11,12] In these computations, both the bond angle and the charge at each triply bonded aryne carbon atom have been considered.…”

Applications and validations of the Minnesota density functionals

“…Garr et al [83] applied M06-2X with a continuum solvation model to the 4 + 2 Diels-Alder cycloadditions of indole arynes and thioindole arynes to 2-substituted furans to study the unusual regioselectivity that sometimes leads to the more crowded product. The density functional calculations explained the results by showing that the 6,7-indolynes are highly polar structures and that the cycloadditions have substantial electrophilic substitution character such that the synchronicity of the reaction path and the preference for contrasteric products are sensitive to the electronwithdrawing or electron-donating character of the 2-substituent.…”