Article pubs.acs.org/OPRD
Development of Multigram Scale Synthesis of Trifluoromethylthiolating Reagent: (bpy)CuSCF3 Yunxiao Zhang, Kangji Gan, and Zhiqiang Weng* State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350108, China S Supporting Information *
ABSTRACT: A practical and reproducible procedure for the efficient preparation of (bpy)CuSCF3 (1), a copper reagent for trifluoromethylthiolation reaction, is reported. All reaction parameters were optimized, and reagent 1 was synthesized in 26 g scale. Finally, the utility of the reagent 1 was highlighted in the synthesis of a Toltrazuril intermediate on a preparative scale.
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INTRODUCTION The incorporation of fluoroalkyl moieties in organic scaffolds often deeply modifies the chemical and physicochemical properties of organic molecules.1,2 Among the fluorinated functional groups, the trifluoromethylthio substituent (SCF3) possesses a highest Hansch parameter (π = 1.44).3−5 The trifluoromethylthio functionality is widely present in pharmaceuticals, in agrochemicals, as well as in functional materials.6,7 The most popular and general methods for the generation of aryl trifluoromethyl thioethers (ArSCF3) involve the nucleophilic and radical trifluoromethylation of aryl sulfides, disulfides, sulfenyl chlorides, and thiocyanates8−18 and reaction of trifluoromethylthiolate with aryl halides.19−23 However, these classical approaches suffer from inherent drawbacks; for example, some of reactions reported are of limited substrate scope with respect to the electron-poor aromatic groups, or rely on the use of expensive and/or toxic reagents under harsh reaction conditions. Based on this, the transition metalmediated or catalyzed trifluoromethylthiolation has recently emerged as a promising strategy to produce aryl trifluoromethyl thioethers.6,24−26 The use of trifluoromethylthiocopper (CuSCF3) for the trifluoromethylthiolation has also proven to be very effective for the formation of the trifluoromethylthiolated products. Generally, this copper reagent was prepared by heating a mixture of bis(trifluoromethylthio)mercury with copper power in an autoclave (Scheme 1a),20,27 by the reaction of trifluoromethylthiosilver with copper bromide (Scheme 1b),28 or by the reaction of bis(trifluoromethyl) disulfide with copper power (Scheme 1c).29,30 Very recently, a novel method for the synthesis of CuSCF3 by a deoxygenative reduction of Langlois’
reagent CF3SO2Na was reported by Yang and Vicic, and coworkers (Scheme 1d).31 Though these methods effectively access this versatile reagent, they suffer some limitations, such as the use of highly toxic bis(trifluoromethyl) disulfide and mercury reagent, and the requirement of prerequisite synthesis of trifluoromethylthio derivatives of silver or mercury. In this regard, the development of an alternative novel approach with readily available starting materials is highly desirable. Recently, our group has developed a strategy for the synthesis of the diimine-ligated copper(I) trifluoromethylthiolate complexes from readily available, inexpensive materials (Scheme 1e).32,33 These complexes reacted with aryl and heteroaryl halides and alkyl halides to afford the corresponding trifluoromethyl thioethers in good to excellent yields.34−41 To further investigate the reactivity and application of this class of reagent, we required a synthetic process which would produce large amounts of the desired copper(I) trifluoromethylthiolate complexes. Described herein is a modified synthetic route now capable of providing multigram quantities (ca. 26 g) of (bpy)CuSCF3 (1; bpy =2,2′-bipyridine).
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RESULTS AND DISCUSSION Our procedure for the synthesis of (bpy)CuSCF3 (1) was accomplished in a combination strategy starting from CuF2, elemental sulfur, SiMe3CF3, and bpy (Scheme 2). In a Scheme 2. Synthesis of (bpy)CuSCF3 (1)
resealable Schlenk tube possessing a Teflon screw valve under nitrogen, the reaction of CuF2, S8, with SiMe3CF3 in MeCN at 80 °C for 10 h produced a dark-brown reaction mixture whose 19 F NMR spectrum showed a resonance at −27.5 ppm, characteristic of CuSCF3 species.42 The reaction mixture was then filtered through Celite. The addition of a 2,2′-bipyridine to the filterate led to the formation of 1 in 60% yield (19F NMR). Slow diffusion of Et2O into the MeCN solution at −25 °C
Scheme 1. Methods for Synthesis of Trifluoromethylthiocopper (CuSCF3)
Received: February 22, 2016 Published: March 15, 2016 © 2016 American Chemical Society
799
DOI: 10.1021/acs.oprd.6b00052 Org. Process Res. Dev. 2016, 20, 799−802
Organic Process Research & Development
Article
Table 1. Copper Source Screen for the Synthesis of 1a MeCN
bpy
[Cu] + SiMe3CF3 + S8 ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ CuSCF3 ⎯⎯⎯→ (bpy)CuSCF3 80 ° C, 10 h
1
entry
copper source
yield of 1 (%)b
1 2 3 4 5 6 7 8 9
CuI CuBr CuCl CuCN CuSCN CuF2 Cu(TFA)2 Cu(OTf)2 Cu(MeCN)4PF6
0 0 0 0 0 60 0 0 0
a Reaction conditions: [Cu] (0.50 mmol), SiMe3CF3 (1.5 mmol), S8 (0.50 mmol), bpy (0.50 mmol), CH3CN (1.5 mL), 80 °C, 10 h, N2. bThe yield was determined by 19F NMR spectroscopy with PhOCF3 as internal standard.
Table 2. Solvent Screen for the Synthesis of 1a Solvent
bpy
CuF2 + SiMe3CF3 + S8 ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ CuSCF3 ⎯⎯⎯→ (bpy)CuSCF3 80 ° C, 10 h
1
entry
solvent
yield of 1 (%)b
1 2 3 4 5 6 7 8 9 10
MeCN acetone CH2Cl2 Diglyme THF dioxane DMF DMSO NMP toluene
60 0c 0c 0 0 0 2 0
