Acetonitrile-Hexane Extraction Route to Pure Sulfonium Salts.

A rapid, simple procedure is described for synthesizing trialkyl, dialkylaryl, and alkyldiaryl sulfonium salts that features a selective extraction procedure to access analytically pure sulfonium salts. Alkylation of dialkylsulfides, alkylarylsulfides, and diarylsulfides followed by partitioning between acetonitrile and hexanes efficiently separates nonpolar reactants and byproducts, the usual impurities, to afford analytically pure crystalline and noncrystalline sulfonium salts. The method is efficient, general, and particularly well suited for the preparation of oily sulfonium salts that are otherwise extremely difficult to purify.

Introduction

Sulfonium salts are valuable reagents whose diverse applications range from electrolytes in solar cells,[1] to photocationic polymerization catalysts,[2] to alkylating agents in living cells.[3] In synthetic organic chemistry, sulfonium salts have featured prominently as precursors to sulfur ylides and as activated alkylating agents.[4] Recently, sulfonium salts have been harnessed as stable, charged reagents capable of driving alkyl or aryl transfer processes[5] through the release of benign, neutral dialkylsulfides for trifluoromethylation,[6] radiofluorination,[7] photoredox catalysis,[8] and cross-coupling reactions.[9]

Alkylaryl sulfonium salts are readily accessed via direct alkylation of sulfides.[10] Sulfide alkylations are reversible, which is minimized or prevented using polar solvents or through the addition of metal salts to remove potentially nucleophilic anions.[11] The main impurities are residual nonpolar reactants. Crystalline sulfonium salts may be purified by recrystallization, though improved purity is not guaranteed because of thermal instability, hygroscopy, and decomposition in solvents of low polarity.[12] Sulfonium salts that form oils are particularly challenging to access in pure form, which has prompted in situ deployment without purification.[9c]

Results and Discussion

Selective, liquid–liquid solvent extraction appeared to be an ideal method for rapidly purifying sulfonium salts. Separation using biphasic acetonitrile–hexanes is attractive because acetonitrile is an effective solvent for the synthesis of sulfonium salts and has a very low solubility in hexanes.[10] Biphasic acetonitrile–hexane has been widely employed for selective extractions, particularly for analytical analyses, but has not been used for the purification of sulfonium salts.[13]

After some optimization, sulfonium salts were readily prepared by treating acetonitrile or 1,2-dichloroethane solutions of dialkylsulfides with alkyl halides in the presence of a silver salt. Upon completion, the reaction mixture was filtered through a pad of Celite to remove the insoluble silver halide salt, concentrated, and then partitioned between a mixture of acetonitrile/hexanes (1:3). The acetonitrile layer was collected, extracted three times with hexanes, and then concentrated to afford the pure sulfonium salt.

The method was applied to the synthesis of a variety of trialkyl, dialkylaryl, and alkyldiaryl sulfonium salts (Table ). The alkylations are equally effective with activated electrophiles such as ethyl iodide and benzyl bromide as with less reactive alkyl iodides (cf. Table , entries 1–3). The alkylations are uniformly efficient with dialkyl-, arylalkyl-, or diarylsulfides affording pure sulfonium salts from electron-rich, neutral, or electron-deficient aromatics (Table , entries 1–3, 4–11, and 12, respectively). Varying the non-nucleophilic counterion of the silver salt provides a robust, selective synthesis of sulfonium salts with facile control over the counterion. The method is simple and efficient on milligram or gram scale to afford the corresponding sulfonium salts in very good yield.

Table 1

Synthesis of Sulfonium Salts from Sulfides

Conclusions

The alkylation of dialkyl, alkylaryl, and diarylsuflides followed by partitioning the crude reaction mixture between biphasic acetonitrile and hexanes provides a rapid effective method of accessing pure sulfonium salts. The protocol overcomes the previous challenge of purifying trialkyl, dialkylaryl, and alkyldiaryl sulfonium salts that are either oils or crystalline and are otherwise challenging to crystallize.

Experimental Section

All reactions were performed in oven-dried glassware under ambient atmosphere wrapped with aluminum foil. All chemicals were purchased from commercial vendors and used as received unless otherwise specified. ACS grade acetonitrile, 1.2-dichloromethane, hexanes, and acetone were used as solvents and used as received without drying. Reactions were magnetically stirred and monitored using glass-backed, 250 μm thickness, F254 hard layer SiliaPlate thin-layer chromatography (TLC) plates purchased from Silicycle. 1H and 13C nuclear magnetic resonance spectra were recorded at room temperature on a Varian Mercury Plus 400 (400 MHz/101 MHz) or a Varian Unity Inova 500 (500 MHz/126 MHz) spectrometer. Chemical shifts were referenced to either CDCl3 (δ 7.26) or dimethyl sulfoxide (DMSO)-d6 (δ 2.50) for 1H NMR and CDCl3 (δ 77.16) or DMSO-d6 (δ 39.52) for 13C NMR. High-resolution mass spectra were obtained on a Thermo-Electron LTQ-FT 7T FFTICR-MS with an Ion Max Source (positive electrospray ionization).

General Sulfide Synthesis Procedure

Neat alkyl halide (1 equiv) was added to a rt, acetone suspension (0.1 M) of the corresponding thiol (1 equiv) and K2CO3 (1.5 equiv). The reaction was stirred at room temperature or heated to reflux until completion of the reaction as judged by TLC analysis. The crude reaction mixture was filtered and concentrated to afford the corresponding sulfide that was used without further purification.

General Procedure for the Synthesis and Purification of Sulfonium salts

Neat alkyl halide (2 equiv) was added to an acetonitrile solution (0.13–0.2 M) of sulfide (1 equiv) and AgOTf (1 equiv). After 16 h, the mixture was filtered through a pad of Celite to remove the precipitated silver halide salt. The pad of Celite was washed with MeCN (3 × 10 mL), the filtrate was concentrated, and then the crude mixture was partitioned between MeCN/hexanes (1:3, by volume). The phases were separated, the hexane layer was removed, and then the MeCN layer was washed two more times with hexanes (2×). The resulting MeCN phase was concentrated in vacuo to afford the pure sulfonium salt. If necessary, the sulfonium salt can be subjected to further MeCN/hexane extractions to remove residual impurities. For the synthesis of tetrafluoroborate, hexafluoroantimonate, and hexafluorophosphate salts, the general procedure was modified by employing 1,2-dichloroethane as the solvent and the corresponding silver salt in place of AgOTf (1 equiv), and after completion, the crude mixture was partitioned between MeCN/hexanes (1:3, by volume) and vigorously stirred for 4 h. The phases were then separated and extracted as in the general procedure.

Butyl(2-methoxyphenyl)sulfide (1b)

The general sulfide synthesis employed 2-methoxybenzenethiol (1 g, 1.15 mL, 7.13 mmol), K2CO3 (1.48 g, 10.7 mmol), and bromobutane (0.77 mL, 7.13 mmol) in acetone (40 mL, 0.1 M). The mixture was heated to reflux for 20 h to afford, after filtration, 1.39 g (99%) of 1b as a clear pale-yellow liquid that was used without further purification. The spectral data was identical to that of the previously characterized material.[14]

Butyl(4-fluorophenyl)sulfide (1c)

The general sulfide synthesis employed 4-fluorothiophenol (1 g, 1.15 mL, 7.13 mmol), K2CO3 (1.48 g, 10.7 mmol), and bromobutane (0.77 mL, 7.13 mmol) in acetone (40 mL, 0.1 M). The mixture was heated to reflux for 20 h, cooled to rt, filtered to remove excess K2CO3, and then concentrated. The crude material was dissolved in CH2Cl2 (30 mL) and then washed with water (150 mL). The phases were separated, the aqueous phase was extracted with CH2Cl2 (3 × 30 mL), and then the combined organic phases were washed with brine (100 mL), dried (Na2SO4), and concentrated to afford 1.43 g of 1c (99%) as a clear pale-yellow liquid that was used without further purification. The spectral data was identical to that of the previously characterized material.[15]

1-Methyltetrahydro-1H-thiophen-1-ium Trifluoromethanesulfonate (2a)[16]

The general procedure employed tetrahydrothiophene (0.25 mL, 2.84 mmol), AgOTf (728 mg, 2.84 mmol), and methyl iodide (0.35 mL, 5.67 mmol) in acetonitrile (14 mL, 0.2 M) to afford, after extraction, 659 mg (92%) of 2a as a white solid: MP (decompn): 207–211 °C; IR (ATR): 3028, 2930, 1150, 1028 cm–1; 1H NMR (500 MHz, DMSO-d6) δ 3.47–3.43 (m, 2H), 3.29–3.24 (m, 2H), 2.75 (br s, 3H), 2.28–2.20 (m, 2H), 2.15–2.07 (m, 2H); 13C NMR (126 MHz, DMSO-d6) δ 44.3, 27.7, 25.0; HRMS (+ESI) m/z [M+] calculated for C5H11S 103.0576; found 103.0575.

1-Butyltetrahydro-1H-thiophen-1-ium Trifluoromethanesulfonate (2b)[16]

The general procedure employed tetrahydrothiophene (0.25 mL, 2.84 mmol), AgOTf (728 mg, 2.84 mmol), and butyl iodide (0.64 mL, 5.67 mmol) in acetonitrile (14 mL, 0.2 M) to afford, after extraction, 720 mg (86%) of 2b as a clear, slightly viscous liquid: IR (ATR): 2965, 2878, 1251, 1026 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.72–3.65 (m, 2H), 3.47–3.41 (m, 2H), 3.29–3.26 (m, 2H), 2.48–2.30 (m, 4H), 1.80–1.73 (m, 2H), 1.57–1.48 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 43.3, 42.1, 28.6, 27.2, 21.4, 13.3; HRMS (+ESI) m/z [M+] calculated for C8H17S 145.1045; found 145.1045.

1-Benzyltetrahydro-1H-thiophen-1-ium Trifluoromethanesulfonate (2c)[17]

The general procedure employed tetrahydrothiophene (0.25 mL, 2.84 mmol), AgOTf (728 mg, 2.84 mmol), and benzyl bromide (0.67 mL, 5.67 mmol) in acetonitrile (14 mL, 0.2 M) to afford, after extraction, 821 mg (88%) of 2c as an off-white solid: MP: 115–117 °C; IR (ATR): 3008, 2990, 2947, 1150, 1028 cm–1; 1H NMR (500 MHz, DMSO-d6) δ 7.57–7.55 (m, 2H), 7.48–7.45 (m, 3H), 4.55 (d, J = 1.8 Hz, 2H), 3.50–3.45 (m, 2H), 3.40–3.35 (m, 2H), 2.27–2.20 (m, 2H), 2.18–2.11 (m, 2H); 13C NMR (126 MHz, DMSO-d6) δ 130.4, 129.8, 129.5, 129.4, 45.0, 42.6, 28.1; HRMS (+ESI) m/z [M+] calculated for C11H15S 179.0889; found 179.0887.

Benzyl(butyl)(2-methoxyphenyl)sulfonium Trifluoromethanesulfonate (2d)

The general procedure employed butyl(2-methoxyphenyl)sulfide (1b) (1 g, 5.09 mmol), AgOTf (1.31 g, 5.09 mmol), and benzyl bromide (1.21 mL, 10.19 mmol) in acetonitrile (39 mL, 0.13 M) to afford, after extraction, 2.14 g of 2d (96%) as a viscous, amber oil: IR (ATR) 1589, 1028, 756 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.70 (ddd, J = 8.5, 7.5, 1.6 Hz, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.31–7.21 (m, 5H), 7.17 (dd, J = 8.5, 1.1 Hz, 1H), 7.13 (td, J = 8.0, 7.5, 1.1 Hz, 1H), 5.04 (ABq, Δν = 77 Hz, J = 12.2 Hz, 2H), 3.96 (s, 3H), 3.94–3.81 (m, 2H), 1.68–1.51 (m, 2H), 1.49–1.40 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.1, 137.1, 133.5, 130.4, 129.8, 129.1, 127.5, 125.6 (1J(C–F) = 318 Hz), 122.7, 122.4 (1J(C–F) = 318 Hz), 119.2 (1J(C–F) = 318 Hz), 116.0 (1J(C–F) = 318 Hz), 113.1, 105.8, 56.7, 47.9, 40.6, 26.7, 21.2, 13.2; HRMS (+ESI) m/z [M + H] calculated for C18H23OS+ 287.1464; found 287.1477.

Butyl(ethyl)(2-methoxyphenyl)sulfonium Trifluoromethanesulfonate (2e)

The general procedure employed butyl(2-methoxyphenyl)sulfide (1b, 1 g, 5.09 mmol), AgOTf (1.31 g, 5.09 mmol), and ethyl iodide (819 mmL, 10.19 mmol) in 1,2-dichloroethane (17 mL, 0.3 M) to afford, after extraction, 1.65 g (87%) of 2e as a viscous, amber oil: IR (ATR) 1590, 1028 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.83–7.75 (m, 2H), 7.26 (td, J = 7.7, 1.1 Hz, 1H), 7.22 (dd, J = 8.5, 1.1 Hz, 1H), 4.05 (s, 3H), 3.89–3.75 (m, 4H), 1.75–1.39 (m, 4H), 1.33 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.2, 137.3, 133.8, 122.9, 113.4, 105.7, 56.8, 41.6, 37.2, 26.6, 21.2, 13.2, 9.6; HRMS (+ESI) m/z [M+] calculated for C13H21OS+ 225.1307; found 225.1308.

Butyl(ethyl)(2-methoxyphenyl)sulfonium Tetrafluoroborate (2f)

The general procedure employed butyl(2-methoxyphenyl)sulfide (1b, 500 mg, 2.55 mmol), AgBF4 (496 mg, 2.55 mmol), and ethyl iodide (410 mmL, 5.09 mmol) in 1,2-dichloroethane (8.5 mL, 0.3 M) to afford, after extraction, 663 mg (83%) of 2f as a viscous, amber oil: IR (ATR) 1590, 1028 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.80–7.73 (m, 2H), 7.24 (tt, J = 7.8, 1.2 Hz, 1H), 7.21 (dt, J = 7.7, 1.1 Hz, 1H), 4.05 (s, 3H), 3.91–3.67 (m, 4H), 1.72–1.41 (m, 2H), 1.33 (br t, J = 7.4 Hz, 3H), 0.90 (br t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.3, 137.3, 133.9, 122.9, 113.4, 105.7, 56.8, 41.6, 37.1, 26.7, 21.3, 13.3, 9.7; HRMS (+ESI) m/z [M+] calculated for C13H21OS+ 225.1307; found 225.1308.

Butyl(ethyl)(2-methoxyphenyl)sulfonium Hexafluorostibate(V) (2g)

The general procedure employed butyl(2-methoxyphenyl)sulfide (1b, 250 mg, 1.27 mmol), AgSbF6 (438 mg, 1.27 mmol), and ethyl iodide (205 mmL, 2.55 mmol) in 1,2-dichloroethane (4.3 mL, 0.3 M) to afford, after extraction, 530 mg (90%) of 2g as a viscous, amber oil: IR (ATR) 1590, 1012 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.80 (ddd, J = 8.8, 7.6, 1.6 Hz, 1H), 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.28–7.20 (m, 2H), 4.06 (s, 3H), 3.84–3.74 (m, 2H), 3.68–3.51 (m, 2H), 1.73–1.42 (m, 4H), 1.35 (t, J = 7.3 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 160.3, 137.7, 134.2, 122.9, 113.6, 105.3, 56.8, 41.7, 37.2, 26.8, 21.4, 13.3, 9.8; HRMS (+ESI) m/z [M+] calculated for C13H21OS+ 225.1307; found 225.1308.

Hexafluoro-l6-phosphane, Butyl(ethyl)(2-methoxyphenyl)sulfonium Salt (2h)

The general procedure employed butyl(2-methoxyphenyl)sulfide (1b, 500 mg, 2.55 mmol), AgPF6 (644 mg, 2.55 mmol), and ethyl iodide (410 mmL, 5.09 mmol) in 1,2-dichloroethane (8.5 mL, 0.3 M) to afford, after extraction, 810 mg (86%) of 2h as a viscous, amber oil: IR (ATR) 1590, 1012 cm–1; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 8.0, 1.5 Hz, 1H), 7.81 (tt, J = 8.0, 1.0 Hz, 1H), 7.41 (dt, J = 7.7, 1.0 Hz, 1H), 7.30 (tt, J = 7.7, 1.0 Hz, 1H), 3.98 (s, 3H), 3.80–3.60 (m, 4H), 1.59–1.47 (m, 2H), 1.39 (sextet, J = 7.3 Hz, 2H), 1.21 (t, J = 7.3 Hz, 2H), 0.87 (t, J = 7.3 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 160.2, 137.4, 133.8, 122.8, 113.5, 105.3, 56.7, 41.4, 37.0, 26.6, 21.1, 13.2, 9.6; HRMS (+ESI) m/z [M + H] calculated for C13H21OS+ 225.1307; found 225.1308.

Butyl(ethyl)(4-fluorophenyl)sulfonium Tetrafluoroborate (2i)

The general procedure employed butyl(4-fluorophenyl)sulfide (1c, 500 mg, 2.71 mmol), AgBF4 (528 mg, 2.71 mmol), and ethyl iodide (436 mmL, 5.43 mmol) in 1,2-dichloroethane (9 mL, 0.3 M) to afford, after extraction, 750 mg (92%) of 2i as a viscous, amber oil: IR (ATR) 1589, 1031 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.09–7.99 (m, 2H), 7.45–7.39 (m, 2H), 3.89–3.67 (m, 4H), 1.74–1.39 (m, 4H), 1.36–1.31 (m, 3H), 0.91–0.88 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 166.4 (d, J = 258.8 Hz), 134.4 (d, J = 9.8 Hz), 119.1 (d, J = 22.8 Hz), 115.8 (d, J = 3.3 Hz), 43.5, 39.4, 26.3, 21.2, 13.2, 9.3; HRMS (+ESI) m/z [M+] calculated for C12H18FS+ 213.1108; found 213.1108.

Diethyl(phenyl)sulfonium Tetrafluoroborate (2j)[18]

The general procedure employed ethylphenylsulfide (1d, 500 mg, 3.62 mmol), AgBF4 (704 mg, 3.62 mmol), and ethyl iodide (582 mmL, 7.23 mmol) in 1,2-dichloroethane (9 mL, 0.3 M) to afford, after extraction, 815 mg (89%) of 2j as a viscous, amber oil: IR (ATR) 1479, 1045 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.00–7.95 (m, 2H), 7.84–7.70 (m, 3H), 3.87–3.67 (m, 4H), 1.34 (t, J = 7.4 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 135.0, 131.4, 131.3, 120.0, 38.5, 9.3; HRMS (+ESI) m/z [M+] calculated for C10H15S+ 167.0889; found 167.0888.

Ethyldiphenylsulfonium Tetrafluoroborate (2k)[18c,19]

The general procedure employed diphenylsulfide (1e, 500 mg, 2.68 mmol), AgBF4 (523 mg, 2.68 mmol), and ethyl iodide (432 mmL, 5.37 mmol) in 1,2-dichloroethane (8.5 mL, 0.3 M) to afford, after extraction, 700 mg (86%) of 2k as a viscous, amber oil with spectral data that was identical to that of the previously characterized material.