New general method for regio- and stereoselective allylic substitution with aryl and alkenyl coppers derived from Grignard reagents.

Allylic substitution with sp(2)-carbon reagents (aryl and alkenyl anions) was realized by using allylic picolinates and copper reagents derived from RMgBr and CuBr x Me(2)S to afford anti S(N)2' products regio- and stereoselectively. Steric and electronic factors in the reagents and the size of the methylene substituents around the allylic moiety marginally affected the selectivity. The reaction system was compatible with alkyl reagents as well.

Synthesis of the active form of loxoprofen by using allylic substitutions in two steps.

High regioselectivity for allylic substitution of the cyclopentenyl picolinate 5 with benzylcopper reagent was attained with ZnBr(2), and the finding was applied to the p-BrC(6)H(4)CH(2) reagent. The cyclopentene moiety in the product was reduced to the cyclopentane, and the p-BrC(6)H(4) was converted to the "Cu"C(6)H(4) for the second allylic substitution with picolinate 8 to furnish the title compound after oxidative cleavage of the resulting olefin moiety.

Picolinoxy group, a new leaving group for anti SN2' selective allylic substitution with aryl anions based on Grignard reagents.

The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr and CuBr*Me2S. The substitution proceeds with anti SN2' pathway and with high chirality transfer. The electron-withdrawing effect of the pyridyl group and chelation to MgBr2 are likely the origin of success.