Chemo- and Regioselective Addition of Carboxylic Acid to the Alkylthio-­Activated Enyne Triple Bond in the Absence of Catalysts

Abstract

A series of methyl 3-acetoxy-2-(1,3-dithiolane-2-ylidene)but-3-enoate derivatives has been synthesized by the chemo- and regioselective addition of carboxylic acids to the alkyl­thio-activated terminal alkynes in moderate to high yields in the ­absence of catalysts.

Key words

alkyne - additon reaction - enol esters - regioselectivity

References and Notes

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17

Preparation of 2b3 as a Typical Procedure. The reaction of Boc-glycine (1.2 mmol, 210 mg) and alkyne 1b (1.0 mmol, 200 mg) was carried out in MeCN under reflux temperature for 30 h. After alkyne 1b was consumed (monitored by TLC), the reaction mixture was poured into cold sat. NaHCO₃ solution (50 mL) and extracted with Et₂O (3 × 10 mL). The combined organic extracts were dried over anhyd MgSO₄, filtered and concentrated under reduced pressure to yield the crude product, which was purified by chromatography over silica gel column using Et₂O-hexane (1:3) as eluent to give 300 mg (80%) of 2b3 as a white crystalline solid.
Methyl 3-[2-( tert -Butoxycarbonyl)acetoxy]-2-(1,3-dithian-2-ylidene)but-3-enoate ( 2b3).
Mp 99-101 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (s, 9 H), 3.34-3.37 (m, 2 H), 3.47-3.50 (m, 2 H), 3.76 (s, 3 H), 4.00 (s, 2 H), 5.01 (br s, 1 H), 5.14 (d, J = 2.0 Hz, 1 H), 5.35 (d, J = 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.22 (3 C), 36.38, 39.38, 42.37, 51.96, 79.94, 108.63, 111.62, 149.42, 155.50, 165.03, 168.05, 169.35. IR (KBr): 3376, 2980, 2937, 1762, 1716, 1690, 1518, 1368, 1270, 1150, 1001 cm^-1. MS (EI): m/z = 398 [M + 23]⁺. Anal. Calcd for C₁₅H₂₁O₆S₂N: C, 47.98; H, 5.64; N, 3.73. Found: C, 47.82; H, 5.60; N, 3.62.
3-(1,3-Dithiolan-2-ylidene)-4-methoxy-4-oxobut-1-en-2-ylbenzoate ( 2b2).
Colorless liquid. ¹H NMR (500 MHz, CDCl₃): δ = 3.36-3.39 (m, 2 H), 3.47-3.50 (m, 2 H), 3.73 (s, 3 H), 5.21 (d, J = 1.5 Hz, 1 H), 5.45 (d, J = 1.5 Hz, 1 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.56 (q, J = 7.0 Hz, 1 H), 8.06 (q, J = 7.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 36.75, 39.64, 52.29, 108.88, 112.42, 128.70 (2 C), 129.91, 130.29 (2 C), 133.58, 150.34, 164.50, 165.66, 169.37. IR (KBr): 3065, 2944, 1734, 1695, 1597, 1499, 1248, 1214, 1088, 999, 886 cm^-1. MS (EI): m/z = 323 [M + 1]⁺. Anal. Calcd for C₁₅H₁₄O₄S₂: C, 55.88; H, 4.38. Found: C, 55.81; H, 4.33.
3-(1,3-Dithiolan-2-ylidene)-4-methoxy-4-oxobut-1-en-2-yl-4-nitrobenzoate ( 2b4).
White crystal; mp 146-148 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.40 (t, J = 6.0 Hz, 2 H), 3.51 (t, J = 6.0 Hz, 2 H), 3.73 (s, 3 H), 5.27 (s, 1 H), 5.49 (s, 1 H), 8.24 (d, J = 9.0 Hz, 2 H), 8.30 (d, J = 9.0 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 36.80, 39.71, 52.29, 109.33, 111.83, 123.87 (2 C), 131.36 (2 C), 135.40, 150.09, 150.95, 162.60, 165.41, 170.13. IR (KBr): 3105, 2957, 1738, 1688, 1526, 1281, 1217, 1099 cm^-1. MS (EI): m/z 368 [M + 1]⁺. Anal. Calcd for C₁₅H₁₃O₆NS₂: C, 49.04; H, 3.57; N, 3.81. Found: C, 49.00; H, 3.68; N, 3.69.
3-(1,3-Dithiolan-2-ylidene)-4-methoxy-4-oxobut-1-en-2-yl-4-methoxybenzoate ( 2b5). White crystal; mp 124-126 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.38 (t, J = 6.5 Hz, 2 H), 3.50 (t, J = 6.5 Hz, 2 H), 3.74 (s, 3 H), 3.88 (s, 3 H), 5.20 (s, 1 H), 5.44 (s, 1 H), 6.93 (d, J = 8.5 Hz, 2 H), 8.03 (d, J = 8.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 36.72, 39.58, 52.21, 55.69, 108.55, 112.72, 113.93 (2 C), 122.28, 132.39 (2 C), 150.39, 163.89, 164.18, 165.69, 168.94. IR (KBr): 2953, 2929, 1717, 1683, 1607, 1499, 1286, 1257, 1223, 1166, 1082, 997 cm^-1. MS (EI): m/z = 353 [M + 1]⁺. Anal. Calcd for C₁₆H₁₆O₅S₂: C, 54.53; H, 4.58. Found: C, 54.48; H, 4.50.
Methyl 3-(2-Chloroacetoxy)-2-(1,3-dithiolan-2-ylidene)but-3-enoate ( 2b6). White crystal; mp 74-76 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.37 (t, J = 6.5 Hz, 2 H), 3.51 (t, J = 6.5 Hz, 2 H), 3.76 (s, 3 H), 4.14 (s, 2 H), 5.19 (d, J = 1.0 Hz, 1 H), 5.39 (d, J = 1.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 36.69, 39.74, 41.19, 52.26, 109.26, 111.55, 149.85, 165.07, 165.27, 170.21. IR (KBr): 3020, 2950, 1766, 1687, 1633, 1507, 1439, 1267, 1222, 1159, 1082, 961 cm^-1. MS (EI): m/z = 296 [M + 1]⁺. Anal. Calcd for C₁₀H₁₁ClO₄S₂: C, 40.75; H, 3.76. Found: C, 40.86; H, 3.81.
3-(1,3-Dithian-2-ylidene)-4-methoxy-4-oxobut-1-en-2-yl Benzoate ( 2a2). Colorless liquid. ¹H NMR (500 MHz, CDCl₃): δ = 2.18-2.21 (m, 2 H), 2.96-3.02 (m, 4 H), 3.71 (s, 3 H), 5.10 (d, J = 2.0 Hz, 1 H), 5.55 (d, J = 2.0 Hz, 1 H), 7.45 (q, J = 7.5 Hz, 2 H), 7.56 (d, J = 7.5 Hz, 1 H), 8.05 (quint, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.91, 29.60, 30.06, 52.19, 109.89, 121.13, 128.70, 128.75, 129.93, 130.27, 130.43, 133.59, 147.95, 164.44, 164.64, 164.88. IR (KBr): 2989, 1736, 1694, 1500, 1453, 1248, 1215, 1084, 885 cm^-1. MS (EI): m/z = 337 [M + 1]⁺. Anal. Calcd for C₁₆H₁₆O₄S₂: C, 57.12; H, 4.79. Found: C, 57.24; H, 4.89.
Methyl 3-[2-( tert -Butoxycarbonyl)acetoxy]-2-(1,3-dithian-2-ylidene)but-3-enoate ( 2a3). White crystal; mp 104-106 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (s, 9 H), 2.17-2.21 (m, 2 H), 2.95-3.00 (m, 4 H), 3.75 (s, 3 H), 3.97 (s, 2 H), 4.97 (br s, 1 H), 5.02 (d, J = 2.0 Hz, 1 H), 5.45 (d, J = 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 23.52, 28.25 (3 C), 29.25, 29.68, 42.47, 51.83, 79.98, 109.51, 120.32, 147.18, 155.49, 164.30, 164.49, 167.99. IR (KBr): 3380, 2933, 1779, 1695, 1513, 1455, 1426, 1223, 1135, 1084 cm^-1. MS (EI): m/z = 412 [M + 23]⁺. Anal. Calcd for C₁₆H₂₃O₆S₂N: C, 49.34; H, 5.95; N, 3.60. Found; C, 49.49; H, 6.06; N, 3.67.
3-(1,3-Dithian-2-ylidene)-4-methoxy-4-oxobut-1-en-2-yl-4-nitrobenzoate ( 2a4). White crystal; mp 144-146 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.17-2.22 (m, 2 H), 2.99-3.02 (m, 4 H), 3.72 (s, 3 H), 5.15 (s, 1 H), 5.58 (s, 1 H), 8.22 (d, J = 7.5 Hz, 2 H), 8.29 (d, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.84, 29.62, 30.06, 52.14, 110.23, 120.46, 123.86 (2 C), 131.33 (2 C), 135.44, 147.80, 150.94, 162.53 (2 C), 164.66. IR (KBr): 3446, 1740, 1695, 1527, 1457, 1277, 1248, 1097 cm^-1. MS (EI): m/z 382 [M + 1]⁺. Anal. Calcd for C₁₆H₁₅NO₆S₂: C, 50.38; H, 3.96; N, 3.67. Found: C, 50.44; H, 3.88; N, 3.72.
3-(1,3-Dithian-2-ylidene)-4-methoxy-4-oxobut-1-en-2-yl-4-methoxybenzoate(2a5). White crystal; mp 122-123 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.15-2.19 (m, 2 H), 2.94-3.00 (m, 4 H), 3.69 (s, 3 H), 3.85 (s, 3 H), 5.06 (s, 1 H), 5.51 (s, 1 H), 6.90 (d, J = 7.5 Hz, 2 H), 7.99 (d, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 23.84, 29.48, 29.93, 52.00, 55.62, 109.36, 113.87 (2 C), 121.42, 122.26, 132.28 (2 C), 147.97, 163.70, 163.83, 164.03, 164.84. IR (KBr): 893, 1032, 1165, 1213, 1263, 1457, 1494, 1605, 1694, 1719, 2948 cm^-1. MS (EI): m/z = 367 [M + 1]⁺. Anal. Calcd for C₁₇H₁₈O₅S₂: C, 55.72; H, 4.95. Found: C, 55.81; H, 5.02.

18

General Procedures for the Preparation of Compounds 2a1 and 2b1.
To a solution of alkyne 1 (2.00 mmol) in AcOH (10 mL) was stirred at r.t. for 4 h. After alkyne 1 was consumed (monitored by TLC), the reaction mixture was poured slowly into cold sat. NaHCO₃ solution (50 mL), extracted with Et₂O (3 × 10 mL). The combined organic extracts were washed with H₂O (2 × 10 mL), dried over anhyd MgSO₄. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography using Et₂O-hexane (1:8) as eluent to give the corresponding product 2a1 or 2b1.
Methyl 3-Acetoxy-2-(1,3-dithiolan-2-ylidene)but-3-enoate ( 2b1). Colorless liquid. ¹H NMR (500 MHz, CDCl₃): δ = 2.12 (s, 3 H), 3.33-3.36 (m, 2 H), 3.47-3.49 (m, 2 H), 3.76 (s, 3 H), 5.12 (d, J = 1.5 Hz, 1 H), 5.29 (d, J = 1.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.46, 36.73, 39.70, 52.30, 108.71, 112.50, 149.91, 165.53, 168.63, 169.03. IR (KBr): 2949, 1757, 1685, 1507, 1271, 1197, 1085, 1018 cm^-1. MS (EI): m/z 261 [M + 1]⁺. Anal. Calcd for C₁₀H₁₂O₄S₂: C, 46.14; H, 4.65. Found: C, 46.27; H, 4.57.
Methyl 3-Acetoxy-2-(1,3-dithian-2-ylidene)but-3-enoate ( 2a1).
Colorless liquid. ¹H NMR (500 MHz, CDCl₃): δ = 2.11 (s, 3 H), 2.17-2.20 (m, 2 H), 2.95-2.99 (m, 4 H), 3.74 (s, 3 H), 5.00 (s, 1 H), 5.38 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.54, 23.90, 29.57, 30.02, 52.15, 109.61, 121.15, 147.59, 164.04, 164.73, 168.56. IR (KBr): 2927, 1756, 1691, 1509, 1427, 1373, 1228, 1199, 1083 cm^-1. MS (EI): m/z = 275 [M + 1]⁺. Anal. Calcd for C₁₁H₁₄O₄S₂: C, 48.16; H, 5.14. Found: C, 48.10; H, 5.21.