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The regioselectivity in addition of nucleophiles to the p-benzyne intermediates derived from unsymmetrical aza-substituted enediynes via Bergman cyclization was studied. Computational studies [using UB3LYP/6-31G(d,p) level of theory] suggest that the p-benzyne intermediate retains its similar electrophilic character at the two radical centers even under unsymmetrical electronic perturbation, thus supporting the predicted model of nucleophilic addition to p-benzyne proposed by Perrin and co-workers (Perrin et al. J. Am. Chem. Soc. 2007, 129, 4795-4799) and later by Alabugin and co-workers (Peterson et al. Eur. J. Org. Chem. 2013, 2013, 2505-2527). However, observed experimental results suggest that there was small but definite regioselectivity (∼5-25%), the extent varying with the electronic nature of the substituents. Differential solvated halide ion concentrations around the vicinity of two radical centers arising due to surrounding surface electrostatic potential (computationally calculated) may be one of the possible factors for such selectivity in some of the examined p-benzynes. However, other complicated dynamical issues like the trajectory of the attacking nucleophile to the radical center which can be influenced by electronic and/or steric perturbation of starting enediyne conformation cannot be ruled out. The overall yield of the anionic addition was in the range of 80-99%.

Inducing high regioselectivity in nucleophilic addition to p-benzynes, first reported by Perrin and O’Connor et al. (J. Am. Chem. Soc.200712947954799) has been a challenge as the reaction involves a very fast barrier-less addition of nucleophile. On the other hand, achieving a high degree of regioselectivity is important as that will make the reaction synthetically useful. Recently, a study has been reported from our group (J. Org. Chem.20188377307740), whereby it was shown that nucleophilic addition to p-benzynes derived from unsymmetrical N-substituted cyclic enediynes proceeds with low extent of selectivity by incorporation of groups with divergent electronic characters. Herein, we report that excellent regioselectivity (>99%) can be achieved keeping an ortho alkoxy group in unsymmetrical 1,2-dialkynylbenzene in the form of a cyclic enediyne in quantitative yields. High regioselectivity (∼84%) is also shown by pyridine based enediynes where the pyridine nitrogen is in a 1,3-relationship with the impending radical center, expanding the synthetic scope of this nucleophilic addition. The regioselectivity can be explained in terms of computed electrostatic potentials which are substantially different around two radical centers arising due to the “ortho effect” (conformational alignment of lone pair of the ortho alkoxy oxygen or the nitrogen in pyridine systems).

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