New Electrophilic Bromodifluoromethylation and Pentafluoroethylation Reagents

Abstract

S-(fluoroalkyl)diphenylsulfonium salts have been successfully synthesized from the reaction between fluoroalkylsul­finates and triflic anhydride in dichloromethane through a one-pot procedure. These S-(fluoroalkyl)diphenylsulfonium salts have been demonstrated to be effective reagents to fluoroalkylate C-nucleophilic substrates. Ionic substitution and radical or halogenophilic mechanism might be all involved in the reactions.

Key words

fluorine - nucleophiles - sulfoxides - S-(fluoroalkyl)diphenylsulfonium salts - fluoroalkylation

References and Notes

• 1a Chambers RD. In Fluorine in Organic Chemistry   John Wiley and Sons; New York: 1973. 
• 1b In Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum Press; New York: 1994. 
• 1c In Fluorine-Containing Amino Acids, Synthesis and Properties   Kukhar VP. Soloshonok VA. John Wiley and Sons; Chichester: 1995. 
• 1d Matsnev A. Noritake S. Nomura Y. Tokunaga E. Nakamura S. Shibata N. Angew. Chem. Int. Ed.  2010,  49:  572 
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• 6b Umemoto T. Kuriu Y. Shuyama H. Miyano O. Nakayama S.-I. J. Fluorine Chem.  1986,  31:  37 
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• For the preparation of sodium fluoroalkylsulfinates, see:
• 15a Huang W.-Y. Zhang H.-Z. Chin. J. Chem.  1992,  10:  274 
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CCDC 759656 contains the supplementary crystallographic data for the compound 1a. This data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

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Typical Procedure for the Preparation of 1a-d
Under nitrogen atmosphere, benzene (7.5 mL, 84.0 mmol) and trifluoromethanesulfonic anhydride (6.0 mL, 35.5 mmol) were added into a suspension of sodium pentafluoro-ethanesulfinate^¹5 (3.18 g, 15.4 mmol) in CH₂Cl₂ (5 mL), which was well cooled by ice bath. After vigorously stirring at 0 ˚C for 2 h, the reaction mixture was warmed to r.t. and continued to react for 4 d. Then the reaction mixture was diluted with CH₂Cl₂ (60 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using CH₂Cl₂-MeCN (4:1) as the eluent. After recrystallization from pentane-EtOAc, 1.40 g of 1b (20%) was obtained as a white solid. ^¹H NMR (300 MHz, CDCl₃): δ = 7.84 (t, J = 7.7 Hz, 2 H), 7.95 (t, J = 8.2 Hz, 1 H), 8.34 (d, J = 8.2 Hz, 2 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -94.5 (s, 2 F), -75.7 (s, 3 F), -76.8 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 137.4, 133.9, 132.3, 120.7 (q, J = 318.5 Hz, CF₃), 117.0. ESI-MS: m/z = 305.0 [M⁺]. IR (KBr): 3067, 1477, 1455, 1331, 1288, 1254, 1234, 1160, 1128, 1031, 938, 757, 639, 517, 504 cm^-¹. Anal. Calcd for C₁₅H₁₀F₈O₃S₂: C, 39.65, H, 2.22. Found: C, 39.64, H, 2.51.

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Typical Procedure for the Fluoroalkylation of 2a-d,g To a 25 mL round-bottomed flask, 1-ethynylbenzene (50 mg, 0.49 mmol) and anhyd THF (4 mL) were added and maintained under a N₂ atmosphere at -78 ˚C. n-BuLi (0.22 mL of a 2.5 mol L^-¹ solution in hexane, 0.55 mmol) was added, and the reaction mixture was stirred at -78 ˚C for 30 min. Then 1b (226 mg in 2 mL of anhyd THF, 0.50 mmol) was added. After 1 h, the cooling bath was removed, and the reaction was warmed naturally to r.t. Then the reaction mixture was poured into H₂O (30 mL), extracted with Et₂O (30 mL), washed with brine (3 × 20 mL), and dried over anhyd Na₂SO₄. Et₂O was evaporated under reduced pressure, and the residue was purified by column chroma­-tography on silica gel using pentane as the eluent; 28 mg of 2g (25%) was obtained as a colorless liquid. ^¹H NMR: δ = 7.57 (d, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 2 H). ^¹9F NMR: δ = -101.2 (q, J = 4.2 Hz, 2 F), -85.3 (t, J = 4.2 Hz, 3 F).

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Typical Procedure for the Fluoroalkylation of 2e-f,h
To a 25 mL round-bottomed flask, ethyl 2-methyl-3-oxobutanoate (70 mg, 0.49 mmol) was dissolved in anhyd DMF (4 mL). NaH (24 mg, 56%, 0.56 mmol) was added under a N₂ atmosphere. The reaction mixture was stirred at r.t. for 30 min then cooled to -50 ˚C. Compound 1b (226 mg in 2 mL of anhyd DMF, 0.50 mmol) was added, and the cooling bath was removed. After warming naturally to r.t., the reaction mixture was poured into H₂O (30 mL), extracted with Et₂O (30 mL), washed with brine (3 × 20 mL), and dried over anhyd Na₂SO₄. The ether layer was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using PE-EtOAc (10:1) as the eluent; 42 mg of 2h (33%) was obtained as a colorless liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 4.29 (q, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 1.61 (s, 3 H), 1.30 (t, J = 7.3 Hz, 3 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -113.5 (dd, AB, ^² J _FF  = 282.5 Hz, 2 F), -78.8 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 197.1, 166.1, 63.3 (t, J = 19.5 Hz), 62.8, 27.9, 15.6, 13.7. MS (EI): m/z = 43 (100), 44 (5.3), 73 (3.0), 77 (2.9), 105 (7.3), 123 (6.1), 192 (3.4), 220 (7.3). IR (KBr): 2988, 2942, 1734, 1466, 1389, 1365, 1338, 1260, 1209, 1107, 1004, 745 cm^-¹. HRMS: m/z calcd for C₉H₁₁O₃F₅: 262.0628; found: 262.0625.