DFT computations reproduce the surprisingly high regioselectivities in nucleophilic additions and cycloadditions to 4,5-indolynes, and the low regioselectivities in reactions of 5,6-indolynes. Transition state distortion energies control regioselectivities, activating the 5 and 6 positions over 4 and 7 positions, leading to high preferences for 5 and 6-substituted product from 4,5-and 6,7-indolynes, respectively. Orbital and electrostatic interactions have only minor effects, producing low regioselectivities in reactions of 5,6-indolynes. The distortion model predicts high regioselectivities with 6,7-indolynes; these are verified experimentally. The regioselectivities found with other benzynes are explained on the basis of distortion energies that are reflected in reactant geometries.The indole motif is ubiquitous among bioactive natural products and medicinal agents. 1 Indolynes are highly reactive derivatives that have shown promise in the synthesis of indole alkaloids and substituted indole derivatives. [2][3][4] In contrast to the inherent nucleophilic reactivity of indoles, indolynes are electrophilic. This umpolung of the indole heterocycle, coupled with the high reactivity of arynes, render indolyne methodology a powerful tool for the preparation of novel and synthetically challenging indole derivatives. 3 Previous studies have shown that nucleophilic additions to 4,5-indolynes can occur with significant regioselectivity. 3 We now report quantum mechanical calculations that provide a surprising explanation of the origins of this regioselectivity as well as the reported regioselectivities for other substituted arynes, reported in our laboratories and those of Buszek. 4 We have now predicted and verified experimentally the regioselectivities of nucleophilic additions to 5,6-and 6,7-indolynes. We show that control of regioselectivity arises from the unsymmetrical bending distortion of arynes, and the attendant differential distortion energies required to achieve regioisomeric transition state geometries. The intimate relationship between distortion energies 5 and activation barriers has been demonstrated previously in 1,3-dipolar 6 and Diels-Alder cycloadditions. 7 After submission of our manuscript, an experimental and computational study of furan cycloadditions to indolynes from Buszek and Cramer came to a related conclusion. 8 We previously reported that the generation of 4,5-indolynes from silyl triflates produces aryne intermediates that are trapped to give 5-substituted adducts preferentially ( The results of density functional computations (B3LYP/6-31G(d)) 9 are shown in the last column. Transition states were located for a variety of nucleophilic additions. The results are supported by computations with larger basis sets, other functionals (e.g., see SI for MO6-2X results), and MP2 calculations that will be reported in a full paper. The B3LYP results on the competing transition structures (TSs) reproduce the trends in regioselectivity, while the magnitudes are usually exaggerated. Activation...

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.

We report an experimental and computational study of 3-silylarynes. The addition of nucleophiles yield ortho-substituted products as a result of aryne distortion, but meta-substituted products form predominately when the nucleophile is large. Computations correctly predict the preferred site of attack observed in both nucleophilic addition and cycloaddition experiments. Nucleophilic additions to 3-t-butylbenzyne, which is not significantly distorted, give meta-substituted products.

We report the design and synthesis of an indolyne that displays a reversal in regioselectivity, in both nucleophilic addition and cycloaddition reactions, compared to typical 4,5-indolynes. Our approach utilizes simple computations to predict regioselectivity in reactions of unsymmetrical arynes. With this methodology, novel benzenoid-substituted indoles can be accessed with significant regiocontrol. Furthermore, the technology provides an unconventional tactic for the synthesis of C4-substituted indole alkaloids, as demonstrated by a synthesis of indolactam V.

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