1,3-Sulfanyl Group Migration: Formation of Unexpected Trifluoromethyl-Containing Bridged Heterocycles

Abstract

Concentrated sulfuric acid promoted the intramolecular dehydration and 1,3-sulfanyl migration of 1,1,1-trifluoro-4,4-bis(arylthio)butane-2,2-diol; this afforded, in addition to the expected unsaturated ketone, an unexpected trifluoromethyl-containing bridged heterocycle.

4-ethoxy-1,1,1-trifluorobut-3-en-2-one - thio nucleophiles - indium trichloride - Michael addition - dehydration

References and Notes

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14

Typical Procedure and Spectroscopic Data of Compounds 2 and 3
4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (1, 0.336 g, 2 mmol) was added into a 10 mL flask containing thiol (4 mmol), which was stirred at r.t.; TLC analysis was used to monitor the reaction progress. After 2-4 d, the reaction was deemed complete, and the reaction mixture was purified by column chromatography on silica gel (hexane-EtOAc, 200:3) to give the products 2 or 3.
1,1,1-Trifluoro-4,4-bis(phenylthio)butane-2,2-diol (2a) Yellow solid, mp 62-63 °C; yield 72%. ¹H NMR (300 MHz, CDCl₃): δ = 7.54-7.28 (10 H, m, 2 C₆H₅), 4.92 (1 H, t, ³ J _HH = 7.0 Hz, CH), 4.68 (2 H, br, OH), 2.37 (2 H, d, ³ J _HH = 7.0 Hz, CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 42.63 (CH₂), 51.97 (CH), 115.17 (q, ¹ J _CF = 233.3 Hz, CF₃), 129.91 (Ph), 130.14 (q, ² J _CF = 43.6 Hz, CF₃C), 130.69 (Ph), 135.05 (Ph), 135.38 (Ph). ¹⁹F NMR (298 MHz, CDCl₃): δ = -87.38 (s, CF₃). MS: m/z (%) = 360 (2.57) [M⁺], 342 (15.59) [M⁺ - H₂O], 251 (28.10) [M⁺ - SPh], 233 (100) [M⁺ - H₂O - SPh], 109 (46.63) [SPh], 69 (5.42) [CF₃]. IR: ν = 3421, 3062, 1766, 1538, 1211, 1144, 1063 cm^-1. Anal. Calcd for C₁₆H₁₅F₃O₂S₂ (%): C, 41.32; H, 4.20. Found: C, 41.39; H, 4.20.
4-(4-Chlorophenylthio)-4-ethoxy-1,1,1-trifluorobutane-2,2-diol (3) Yellow solid; mp 106-107 °C; yield 64%. ¹H NMR (300 MHz, CDCl₃): δ = 7.43-7.28 (4 H, m, C₆H₄Cl), 5.69 (1 H, br, OH), 5.22 [1 H, dd, ³ J _HH = 3.0 Hz, 11 Hz, CH(OH)OEt], 4.21-4.16 (1 H, m, OCH₂), 3.67-3.62 (1 H, m, OCH₂), 3.38 (1 H, br, OH), 2.32-2.27 (1 H, m, CH₂), 2.13-2.08 (1 H, m, CH₂), 1.32 (3 H, t, ³ J _HH = 7.0 Hz, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 36.87 (CH₃), 42.84 (CH₂), 51.31 (OCH₂), 51.90 (CH), 117.27 (q, ¹ J _CF = 234.0 Hz, CF₃), 128.78 (C₆H₄Cl), 129.26 (C₆H₄Cl), 132.95 (q, ² J _CF = 82.0 Hz, CF₃C), 133.34 (C₆H₄Cl), 133.64 (C₆H₄Cl). ¹⁹F NMR (298 MHz, CDCl₃):
δ = -87.15 (s, CF₃). MS: m/z (%) = 330 (1.36) [M⁺], 312 (2.22) [M⁺ - H₂O], 285 (0.53) [M⁺ - OEt], 267 (3.21) [M⁺ - H₂O - OEt], 187 (45.82) [M⁺ - SC₆H₄Cl], 169 (74.74)
[M⁺ - H₂O - SPhCl], 141 (100) [M⁺ - SC₆H₄Cl - EtOH], 143 (44.78) [SC₆H₄Cl], 69 (34.39) [CF₃]. IR: ν = 3354, 1417, 1189, 1117, 1083, 1053 cm^-1. Anal. Calcd for C₁₂H₁₄F₃O₃SCl (%): C, 43.58; H, 4.27. Found: C, 43.56; H, 4.26.

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Typical Procedure and Spectroscopic Data for Diols
4,4-Diethoxy-1,1,1-trifluorobutane-2,2-diol (5, 0.1 g, 0.5 mmol) was added into a 10 mL flask containing thiol (2 mmol), which was stirred at r.t.; TLC analysis was used to monitor the process. After 3 d, the reaction finished, and the reaction mixture was purified by column chromatography on silica gel (hexane-EtOAc, 100:1) to give the products 2d or 2e.
4,4-Bis(4-chlorophenylthio)-1,1,1-trifluorobutane-2,2-diol (2d)
Yellow solid, mp 66-67 °C; yield 73%. ¹H NMR (300 MHz, CDCl₃): δ = 7.41 (4 H, d, ³ J _HH = 6.0 Hz, C₆H₄), 7.34 (4 H, d, ³ J _HH = 6.0 Hz, C₆H₄), 4.83 (1 H, t, ³ J _HH = 6.0 Hz, CH), 4.53 (2 H, s, OH), 2.31 (2 H, d, ³ J _HH = 8.0 Hz, CH₂). ¹⁹F NMR (298 MHz, CDCl₃): δ = -86.99 (s, CF₃). MS: m/z (%) = 268 or 266 (27.12 or 97.86) [M⁺ - H₂O - p-ClC₆H₄S⁺], 250 or 248 (25.14 or 58.83) [M⁺ - 2H₂O - p-ClC₆H₄S⁺], 119 or 197 (28.55 or 58.47) [M⁺ - 2H₂O - CF₃ - p-ClC₆H₄S⁺], 146 or 144 (23.92 or 55.17) [p-ClC₆H₄SH], 108 or 106 (100) [M⁺ - 2H₂O - 2p-ClC₆H₄S⁺], 69 (52.11) [CF₃]. IR: ν = 3823, 3753, 1477, 1168, 814 cm^-1. Anal. Calcd for C₁₆H₁₃F₃O₂S₂ (%): C, 44.77; H, 3.05. Found: C, 44.83; H, 3.01.

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Typical Procedure and Spectroscopic Data for Bridged Cyclic Compounds
Compound 2 was added to the cold concd H₂SO₄ (3 mL) with efficient stirring. The temperature of the reaction during the addition was kept below 10 °C and the reaction mixture was stirred at 0 °C for 1 h. Then it was poured to the chipped ice and set aside for 2 h in the refrigerator. The aqueous acid solution was extracted with CH₂Cl₂ (3 × 10 mL). The solvent was evaporated in vacuum to give the crude products, which were purified by recrystallization (CH₂Cl₂-hexane) to give the final product 4 and/or 6.
Compound 4a: white solid, mp 169-171 °C; yield >99%. ¹H NMR (300 MHz, CDCl₃): δ = 7.45-7.14 (8 H, m, 2 C₆H₄), 4.48 (1 H, s, CH), 2.61 (2 H, d, ³ J _HH = 4.0 Hz, CH₂). ¹⁹F NMR (298 MHz, CDCl₃): δ = -73.73 (s, CF₃). ¹³C NMR (75 MHz, CDCl₃): δ = 135.03 (C₆H₄), 130.33 (C₆H₄), 129.67 (C₆H₄), 127.56 (q, ¹ J _CF = 286.0 Hz, CF₃), 127.41 (C₆H₄), 126.62 (C₆H₄), 125.81 (C₆H₄), 39.40 (CF₃C), 31.75 (CH), 29.71 (CH₂). MS: m/z (%) = 324 (100) [M⁺], 255 (31.34)
[M⁺ - CF₃], 215 (63.32) [M⁺ - Ph], 69 (7.29) [CF₃]. IR: ν = 1470, 1440, 1270, 1176, 1156, 760 cm^-1. HRMS: m/z calcd for C₁₆H₁₁F₃S₂: 324.030; found: 324.027.
X-ray Crystal Data: C₁₆H₁₁F₃S₂: FW = 324.37; 293 (K); monoclinic, P2/c; λ = 0.71 Å; a = 9.482(9) Å, b = 16.180(19) Å, c = 9.482(9) Å, α = 90°, β = 109.203(10)°, γ = 90°; V = 1373.8(2) Å3; Z = 4, D _c = 1.568 mg/m³; absorption coefficient 0.410 mm^-1; F(000) = 664; size 0.501 × 0.290 × 0.078 mm; 2.27 < θ < 26.99; reflections collected 7979; Absorption correction Empirical; transmission 1.00 mix-0.741 min; goodness of fit on F2 0.98; final R indices R1 = 0.0491, wR2 = 0.1190.
4-(4-Chlorophenylthio)-1,1,1-trifluorobut-3-en-2-one (6d)
Yellow solid; mp 79-81 °C; yield 78%. ¹H NMR (300 MHz, CDCl₃): δ (E-isomer) = 8.22 (d, ³ J _HH = 15.0 Hz, =CH), 7.48-7.40 (m, C₆H₄), 6.25 (d, ³ J _HH = 15.0 Hz, =CH). ¹⁹F NMR (298 MHz, CDCl₃): δ (E-isomer) = -77.71 (s, CF₃). ¹H NMR (300 MHz, CDCl₃): δ (for Z) = 7.80 (d, ³ J _HH = 10.0 Hz, =CH), 7.48-7.40 (m, C₆H₄), 6.67 (d, ³ J _HH = 10.0 Hz, =CH). ¹⁹F NMR (298 MHz, CDCl₃): δ (for Z) = -78.10 (s, CF₃). MS: m/z (%) = 266 (36.22) [M⁺], 197 (100) [M⁺ - CF₃], 143 (53.24) [M⁺ - ⁺SC₆H₄Cl], 69 (28.63) [CF₃]. IR: ν = 1675, 1516, 1306, 1151, 1069, 898. Anal. Calcd for C₁₀H₆ClF₃OS (%): C, 45.04; H, 2.27. Found: C, 44.84; H, 2.24.

17

Single-crystal X-ray structural data for 4a have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 644817.