How To Achieve High
Regioselectivity in Barrier-less
Nucleophilic Addition to p‑Benzynes Generated
via Bergman Cyclization of Unsymmetrical Cyclic Azaenediyne?
posted on 2019-01-28, 00:00authored byEshani Das, Shyam Basak, Anakuthil Anoop, Santanu Chand, Amit Basak
Inducing high regioselectivity
in nucleophilic addition to p-benzynes, first reported
by Perrin and O’Connor
et al. (J. Am. Chem. Soc. 2007, 129, 4795−4799) 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. 2018, 83, 7730−7740), 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).