Safe, Scalable, Inexpensive, and Mild Nickel‐Catalyzed Migita‐Like C−S Cross‐Couplings in Recyclable Water

Abstract

A new approach to C−S couplings is reported that relies on nickel catalysis under mild conditions, enabled by micellar catalysis in recyclable water as the reaction medium. The protocol tolerates a wide range of heteroaromatic halides and thiols, including alkyl and heteroaryl thiols, leading to a variety of thioethers in good isolated yields. The method is scalable, results in low residual metal in the products, and is applicable to syntheses of targets in the pharmaceutical area. The procedure also features an associated low E Factor, suggesting a far more attractive entry than is otherwise currently available, especially those based on unsustainable loadings of Pd catalysts.

Assembly of (hetero)aryl thioethers via simple nucleophilic aromatic substitution and Cu-catalyzed coupling reactions with (hetero)aryl chlorides and bromides under mild conditions

“…13 Interestingly, most successful coupling reactions have resulted from electron-deficient (hetero)aryl halides except for those in Fu's and Oderinde's studies. 9,10 The same reactivity trend was also observed in Baran's studies on DEL synthesis via Ni-catalyzed C-S bond formation 14 and Lipshutz's Ni-catalyzed migita-like C-S cross-coupling in recyclable water 15 that were disclosed very recently (Fig. 1).…”

“…During the past two decades, great efforts have been directed to the development of catalytic systems for coupling of (hetero) aryl halides with thiols and their equivalents [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] to assemble (hetero)aryl thioethers of high prevalence in bioactive molecules 16 and synthetic intermediates. 17 Because of their abundance, relatively low cost but low reactivity, the utilization of (hetero)aryl chlorides as coupling partners has become a reference point to assess the efficiency of newly developed catalytic systems.…”

“…18f These reactions were believed to go through an S N Ar mechanism and require a strong electron-withdrawing group in the substrate to proceed under mild conditions. The requirement of relatively harsh reaction conditions for less reactive electron-deficient aryl halides triggered intensive studies on the assembly of (hetero)aryl thioethers via metal-and photo-catalyzed coupling of thiols and aryl halides, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] as well as S N Ar reactions using more reactive electrophiles, 19 through microwave irradiation 20 or in some special solvents. 21 Recently, we attempted to discover more powerful oxalic diamides for Cu-catalyzed arylation of thiols and identified that N,N′-bis(2-phenylpropyl)oxalamide (BPPRO, L1) and N,N′bis(naphthalen-1-ylmethyl)oxalamide (BNMO, L2) were more effective ligands than those reported by Lee's group 5g (for detailed studies on reaction condition screening, see the ESI †), which enabled the complete coupling of (hetero)aryl chlorides at 130 °C with satisfactory reaction scope at relatively low catalytic loadings (1-5 mol%, Scheme 1), and the coupling with (hetero)aryl bromides to proceed smoothly at 70 °C with only 1 mol% Cu 2 O and ligand.…”

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

“…Thus, Lipshutz and co-workers demonstrated that the well-defined complex of the type [Ni(phen) 2 Br 2 ] is more catalytically active than the plain mixing of [NiBr 2 ] and phen. [103] Furthermore, the [Ni(phen) 2 Br 2 ] complex catalyzes the CÀ S cross-coupling reactions in water in the presence of DL-αtocopherol methoxypolyethylene glycol succinate (TPGS-750-M), which acts as surfactant. Remarkably, the synthesis of a key intermediate for the Pfizer's antitumor agent axitinib was achieved in gram scale, and more important, was the fact that the residual nickel found in the axitinib precursor was 9.8 ppm, which is a value below the FDA accepted guidelines of � 25 ppm.…”

“…Phen type ligands form robust catalysts when they are coordinated to Ni(II). Thus, Lipshutz and co‐workers demonstrated that the well‐defined complex of the type [Ni(phen) 2 Br 2 ] is more catalytically active than the plain mixing of [NiBr 2 ] and phen [103] . Furthermore, the [Ni(phen) 2 Br 2 ] complex catalyzes the C−S cross‐coupling reactions in water in the presence of DL‐α‐tocopherol methoxypolyethylene glycol succinate (TPGS‐750‐M), which acts as surfactant.…”