Pd‐ and Ni‐Catalyzed Cross‐Coupling Reactions of Functionalized Organozinc Reagents with Unsaturated Thioethers

Abstract

A variety of unsaturated thioethers have been subjected to cross-coupling reactions with functionalized zinc reagents in the presence of a transition-metal catalyst. Three different catalytic systems based on Pd(OAc)(2) or [Ni(acac)(2)] and the ligands S-Phos or DPE-Phos gave the best results. N-Heterocyclic thioethers based on a pyridine, pyrimidine, pyrazine, pyridazine, triazine, benzothiazole, benzoxazole, pyrrole, or quinazoline ring, as well as thiomethylacetylenes, serve as electrophiles in this cross-coupling reaction. Aryl-, heteroaryl-, benzylic, and alkylzinc halides with sensitive functionalities, such as ester, nitrile, or ketone groups react at ambient temperature with unsaturated thioethers using a Ni catalyst. The corresponding Pd-catalyzed reactions require slightly higher temperatures. Large-scale cross-coupling experiments (10-20 mmol) with N-heterocycles are also reported.

Carbon–Carbon Bond Forming Reactions Mediated by Organozinc Reagents

“…The formation of 393 is illustrative (Scheme 4.91). Interestingly, the Pd-catalyzed variant involving the same partners proceeds equally well but requires slightly higher temperatures [146]. The same Ni(acac) 2 /DPEPhos (174) system also catalyzes the coupling of aryl and heteroaryl bromides, chlorides, and tosylates with primary and secondary aminoalkylzinc reagents prepared by transmetallation from the parent Grignard reagents.…”

“…Aside from organic halides, other electrophilic coupling partners have been employed. Thiomethylated aryl-and heteroaryl derivatives are excellent partners that can be cross-coupled with a wide range of aryl-and heteroarylzinc reagents in THF at rt in the presence of Ni(acac) 2 and DPEPhos (174) [146,201], as illustrated by the preparation of 255 (Scheme 4.57). Similarly, the thiomethylated oxazole 257 undergoes cross-coupling with several zinc reagents in the presence of NiCl 2 (PPh 3 ) 2 , but heating to 60 • C is required [202].…”

“…Thiomethylated alkynes are also well suited, but in this case, superior results are obtained using bis-[2-(diphenylphosphino)phenyl]ether (DPEPhos) (174) (5 mol%) as ligand[144][145][146] (Scheme 4.38). The formation of thiophenyl ethynylpyridine 173 is illustrative.…”

“…The formation of thiophenyl ethynylpyridine 173 is illustrative. Pd-catalyzed cross-coupling or aryl-and hetarylzinc reagents with sulfur electrophiles[143][144][145][146].…”

“…of NaOH) and brine. After drying (Na 2 SO 4 ), the solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/EtOAc 6 : 4) to afford 155 (89.1 mg, 82%) as a colorless solid, mp 75-77 • C. mol%) were dissolved in THF (1 ml) (Scheme 4.38)[146]. The mixture was stirred for 10 min, and 2-thienylzinc iodide (1.5 mmol) was added dropwise.…”