Experimental and Theoretical Studies on Rhodium-Catalyzed Coupling of Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Fluorinated Heterocycles

Fluorinated heterocycles play an
important role in pharmaceutical
and agrochemical industries. Herein, we report on the synthesis of
four types of fluorinated heterocycles via rhodium­(III)-catalyzed
CH activation of arenes/alkenes and versatile coupling with
2,2-difluorovinyl tosylate. With N-OMe benzamide
being a directing group (DG), the reaction delivered a monofluorinated
alkene with the retention of the tosylate functionality. Subsequent
one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1­(2H)-ones and 5-fluoropyridin-2­(1H)-ones.
When NOPiv benzamides were used, however,
[4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1­(2H)-ones. Synthetic applications have been demonstrated and
the ready availability of both the arene and the coupling partner
highlighted the synthetic potentials of these protocols. Mechanistically,
these two processes share a common process involving NH deprotonation,
CH activation, and olefin insertion to form a 7-membered rhodacycle.
Thereafter, different reaction pathways featuring β-F elimination
and CN bond formation are followed on the basis of density
functional theory (DFT) studies. These two pathways are DG-dependent
and led to the open chain and cyclization products, respectively.
The mechanistic rationale was supported by detailed DFT studies. In
particular, the origins of the intriguing selectivity in the competing
β-F elimination versus CN bond formation were elucidated.
It was found that β-F elimination is a facile event and proceeds
via a syn-coplanar transition state with a low energy
barrier. The CN bond formation proceeds via a facile migratory
insertion of the RhC­(alkyl) into the Rh­(V) amido species.
In both reactions, the migratory insertion of the alkene is turnover-limiting,
which stays in good agreement with the experimental studies.