Acetate Facilitated Nickel Catalyzed Coupling of Aryl Chlorides and Alkyl Thiols

Abstract

We report a mild, fast, and convenient catalytic system for the coupling of aryl chlorides with primary, secondary, as well as previously challenging tertiary alkyl thiols using an air-stable nickel(II) precatayst in combination with the low-cost base potassium acetate at room temperature. This catalytic system tolerates a variety of functional groups and enables the generation of thioethers for a wide range of substrates, including pharmaceutical compounds in excellent yields. Chemoselective functionalization of disubstituted substrates was demonstrated. Kinetic and NMR studies, as well as DFT computations support a Ni(0)/Ni(II) catalytic cycle and identify the oxidative addition product as the resting state. Acetate coordination and subsequent acetate facilitated formation of a thiolate complex via internal deprotonation play a key role in the catalytic cycle.

Recent Metal-Catalyzed Methods for Thioether Synthesis

“…Scheme 18 Coupling of aliphatic thiols facilitated by acetate base. 60 Among other substrates, sulfonates have been rarely investigated as electrophiles. In the above mentioned study by our group, triflates were the most and tosylates the least reactive substrates.…”

Transition Metal CatalysedC‐SCross‐Coupling Reactions at Room Temperature.

“…Acetate facilitated formation of a thiolate complex via internal deprotonation play a key role in the catalytic cycle (Scheme 27). [54] It is noteworthy that, addition of additives to the reaction accelerates product formation.…”

C−S Cross‐Coupling Reactions Catalyzed by Well‐Defined Copper and Nickel Complexes

“…[104] Furthermore, POCOP-, PNP-and POP-Ni(II) pincer complexes have showed a great performance in CÀ S cross-couplings of aryl halides and aryl-thiols (Scheme 20). [111][112][113] The catalytic reactions are usually carried out in DMF for 2-6 h at 80 °C in the presence of KOH, obtaining yields from 76 % to > 99 %. These catalytic conditions tolerate functional groups such as methoxy, cyano, heterocycles and CF 3 .…”

“…Although this drawback can be circumvented by the correct choice of the catalyst and base. Actually, using a xanphos-Ni(II) pincer complex (17-Ni) and potassium acetate [K(CH 3 COO) 2 ] the reaction proceeds at room temperature in only 2 h. [113] In a comparative study, using chlorobenzene, bromobenzene and iodobenzene the yields were similar (81 %, 89 % and 85 %, respectively), in fact using phenyl triflate allowed to reach 96 % yield of the desired product. Besides, primary, secondary and a variety of sterically challenging alkyl thiols were coupled with chloro-arenes.…”