Reversing the Regioselectivity of Halofunctionalization Reactions through Cooperative Photoredox and Copper Catalysis

Abstract

Halofunctionalization of alkenes is a classical method for olefin difunctionalization. It gives rise to adducts which are found in many natural products and biologically active molecules, and offers a synthetic handle for further manipulation. Classically, this reaction is performed with an electrophilic halogen source and leads to regioselective formation of the halofunctionalized adducts. Herein, we demonstrate a reversal of the native regioselectivity for alkene halofunctionalization through the use of an acridinium photooxidant in conjunction with a copper cocatalyst.

Keywords: cooperative catalysis; halofunctionalization; organocatalysis; photoredox catalysis; radicals.

Figure 1

Alkene Halofunctionalization – Catalytic Reversal of Regioselectivity

Figure 2

Alkene Halofunctionalization – Initial Mechanistic Proposal

Chart 1

Scope of the Alkene Halofunctionalization Reaction Products isolated as single regioisomers except where noted. ^a10 mol% CuCl₂/phen, 1 equiv. NCP, ^b10 mol% CuBr₂/bpy, 1 equiv. DEBM ^c10 mol% CuCl₂/phen,1 equiv. NCS ^d10 mol% CuBr₂/phen, 1 equiv. NBP, ^ewith 5.0 equiv. AcOH, ^fwith 10 mol% 2,6-Lutidine. Boc=tert-butoxycarbonyl Ms=methanesulfonyl NCP=N-Chlorophthalimide. DEBM=Diethyl bromomalonate. NCS=N-Chlorosuccinimide. NBP=N-bromophthalimide