A New Reaction; Direct Intermolecular Alfa-Arylation of Ketones via Umpolung

Arylation of ketones is an important transformation in organic synthesis. It has seen numerous applications in the synthesis of medicinal compounds as well as in the total synthesis of natural products. It is generally carried out by the transition metal catalyzed reaction of enolates with aryl-halides (Scheme 1). An alternative is the reaction of enolates with an electrophilic aryl reagent such as e.g. diaryliodonium salt (Scheme 1). A common factor in these approaches is the use of a functionalized aryl donor.

We report on a novel direct arylation of ketone enolates that does not require such a functionalized aryl donor, but allows the use of feedstock heteroaromatic and aromatic compounds. This unprecedented metal free reaction^1,2 proceeds via the umpolung of a ketone enolate into an electrophilic enolonium species³ by the action of a hypervalent iodine reagent (Scheme 1c). The reaction is of broad scope with respect to heteroaromatic compounds and also allows reaction with electron-rich benzene derivatives. It should prove useful for applications both in industry and academia.

References

1) Shimon Maksymenko, Keshaba N. Parida, Gulab Pathe, Yuriy Lipisa, Atul A. More, Alex M. Szpilman* Org. Lett. 2017, In Press

2) For a Copper mediated reaction of indole and pyrrole with enolates see a) P. S. Baran, J. M. Richter, J. Am. Chem. Soc., 2004, 126, 7450–7451 b) P. S. Baran, J. M. Richter, D. W. Lin, Angew. Chem. Int. Ed. 2005 , 44 , 609 –612

3) S. Arava, J. N. Kumar, S. Maksymenko, M. A. Iron, K. N. Parida, P. Fristrup, A. M. Szpilman, Angew. Chem. Int. Ed. 2017, 56, 2599-2603