Anodic Olefin Coupling Reactions: Mechanistic Insights that Guide the Development of New Synthetic Methods

Intramolecular anodic olefin coupling reactions provide a powerful method for the synthesis of organic molecules. They enable the construction of carbocyclic and heterocyclic ring systems, the formation of tetrasubstituted carbons, and the generation of polycyclic structures while either maintaining or increasing the functionality of a substrate.

     The reactions also allow for the systematic study of radical cation intermediates. These investigations provide insight into the chemical reactivity of the intermediates, as well as the factors that control the chemo-, regio-, and stereoselectivity of reactions that involve them. For example, consider the reaction profile for a  competition study illustrated in Scheme 1.¹

      In this experiment, a sulfonamide anion was oxidized to form the N-based radical 1. The radical (1) could partition along two possible pathways. Either, it could cyclize onto an electron-rich olefin or it could accept an electron from the olefin to regenerate the sulfonamide anion and form an olefinic radical cation (2). The resulting radical cation would then either undergo a reverse electron-transfer to form 1, be trapped by the sulfonamide anion, or be trapped by a competing alcohol nucleophile. A combination of computational studies and experimental rates was used to determine that N-based products from the reaction were derived from a N-radical addition to the olefin. It was also found that the electron-transfer reaction did occur, and that the event led to cyclic ether formation. Alcohol trapping of the radical cation intermediate was found to be reversible and afford the kinetic product of the overall reaction. The N-radical based cyclization afforded the thermodynamic product of the reaction.

     Studies of this nature do not just provide interesting information to satisfy our curiosity. They also provide insights that help shape the design and development of future synthetic efforts. In the case above, two pieces of information gained from the study have proven critical for subsequent synthetic studies; the fact that alcohol cyclizations are reversible and the idea that N-based radicals can be readily generated and trapped.

     An understanding that alcohol trapping of a radical cation can be reversible has had an immediate impact on efforts to develop rapid routes to C-glycosides,² novel approaches to lactone intermediates,³ and tandem cyclization strategies that avoid the decomposition reactions that often compete with slower cyclizations.⁴ The understanding that the N-cyclization products were derived from a N-based radical led to the development of new methods for amidyl-radical synthesis and the study of subsequent trapping reactions.⁵

     In the talk to be presented, the mechanistic findings highlighted in Scheme 1 will be discussed along with ongoing efforts to use those findings to expand the scope and utility of oxidative cyclization reactions.

References:

1. Campbell, J. M.; Xu, H. –C.; Moeller, K. D.  J. Am. Chem. Soc. 2012, 134, 18338.

2. Smith, J. A.; Moeller, K. D. Org. Lett. 2013, 15, ASAP.

3. Redden, A.; Perkins, R. J.; Moeller, K. D. Angew. Chem. Int. Ed. 2013, 52, ASAP.

4. Perkins, R. J.; Xu, H. –C.; Campbell, J. M. Beilstein J. Org. Chem.  2013, 9, 1630.

5. Unpublished results with Hai-Chao Xu and John Campbell.