Palladium-Catalyzed Directed C(sp³)-H Arylation of Saturated Heterocycles at C-3 Using a Concise Optimization Approach.

Affron, Dominic P.; Bull, James A.

Saturated heterocycles, such as THFs, pyrrolidines, piperidines and THPs, are essential components of many biologically active compounds. Examples of C-H functionalization on these important ring systems remain scarce, especially at unactivated positions. Here we report the development of conditions for the palladium-catalyzed stereoselective C(sp3)-H arylation at unactivated 3-positions of 5- and 6-membered N- and O-heterocycles with aminoquinoline directing groups. Subtle differences in substrate structures altered their reactivity significantly; and different conditions were required to achieve high yields in each case. Successful conditions were developed using a short empirical optimization approach to cover reaction space with a limited set of variables. Excellent cis-selectivity was achieved in all cases, except for the THP substrate where minor trans-products were formed through a different palladacyclic intermediate. Here, differences in reactivity and selectivity with other directing groups were examined.

HETEROCYCLIC compounds synthesis; PIPERIDINE; ALIPHATIC amine synthesis; STEREOSELECTIVE reactions; MATHEMATICAL optimization; ARYLATION

European Journal of Organic Chemistry, 2016, Vol 2016, Issue 1, p139

1434-193X

Academic Journal

10.1002/ejoc.201501300