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DOI: 10.1055/s-2005-869855
Efficient Solid-Phase Synthesis of 1,3,4-Trisubstituted β-Thiolactams
Publication History
Publication Date:
07 June 2005 (online)
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Abstract
An efficient solid-phase synthesis of a series of 1,3,4-trisubstituted β-thiolactams is described. The key reaction, a direct thionation of polymer-supported β-lactams, was carried out using the Lawesson’s reagent to give β-thiolactams in good overall yields.
Key words
solid-phase synthesis - β-thiolactams - Lawesson’s reagent - β-lactams - combinatorial chemistry
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References
Gel-phase 13C NMR spectra were recorded in a conventional 200 MHz NMR apparatus.
15
Typical Procedure for the Solid-Phase Synthesis of β-Thiolactams.
Resin-bound β-lactam 7a (157 mg, theoretical loading 0.58 mmol/g, 0.091 mmol) was suspended in anhyd toluene (3 mL) under nitrogen atmosphere. Lawesson’s reagent (6, 55.4 mg, 0.137 mmol, 1.5 equiv) was previously dried in a vacuum desiccator over phosphorus pentoxide for 2 h, and then added to the suspension. The reaction mixture was stirred at 95 °C for 2 h. The resin was washed with CH2Cl2 (3 × 2 mL), ETOAc (3 × 2 mL), MeOH (3 × 2 mL) and CH2Cl2 (2 mL), and finally drying in vacuo to afford resin-bound β-thiolactam 8a. A suspension of resin 8a (147 mg, theoretical loading 0.57 mmol/g, 0.084 mmol) in 10% TFA in CH2Cl2 (3 mL) was stirred at r.t. for 50 min. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL) and treated with a diazomethane solution in Et2O at 0 °C. After methylation was completed, solvent was evaporated and the crude product was subjected to flash chromatography using hexane-EtOAc (80:20) to give 4-(4-chlorophenyl)-1-(methoxycarbonyl)methyl-3-phenoxy-2-thioxoazetidine (9a, 13.4 mg, 41%).
4-(4-Chlorophenyl)-1-(methoxycarbonyl)methyl-3-phenoxy-2-thioxoazetidine (9a): IR (film): 1747, 1492, 1223 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.70 (d, J = 17.6 Hz, 1 H), 3.75 (s, 3 H), 4.90 (d, J = 17.6 Hz, 1 H), 5.44 (d, J = 4.1 Hz, 1 H), 5.71 (d, J = 4.1 Hz, 1 H), 6.78-6.96 (m, 4 H), 7.16-7.28 (m, 5 H). 13C NMR (50 MHz, CDCl3): δ = 43.08, 52.54, 70.55, 81.14, 115.69, 122.30, 128.66, 129.19, 129.81, 129.94, 135.21, 156.55, 166.80, 200.89. MS (DEI): m/z (%) = 361 (28) [M+], 230 (92), 212 (23), 167 (15), 121 (100). HRMS: m/z calcd for C18H16ClNO3S [M+]: 361.0539; found: 361.0539.
1-(Methoxycarbonyl)methyl-3-phenoxy-2-thioxo-4-(4-
p
-tolyl)azetidine (9b): IR (film): 1748, 1494, 1225 cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.30 (s, 3 H), 3.69 (d, J = 17.6 Hz, 1 H), 3.74 (s, 3 H), 4.89 (d, J = 17.6 Hz, 1 H), 5.42 (d, J = 4.1 Hz, 1 H), 5.68 (d, J = 4.1 Hz, 1 H), 6.78-6.88 (m, 3 H), 7.09-7.25 (m, 6 H). 13C NMR (50 MHz, CDCl3): δ = 21.08, 42.99, 52.42, 71.23, 81.42, 115.87, 122.07, 128.01, 128.55, 129.07, 139.11, 156.65, 166.90, 200.99. MS (DEI): m/z (%) = 341 (52) [M+], 239 (11), 210 (100), 192 (50), 121 (20). HRMS: m/z calcd for C19H19NO3S [M+]: 341.1086; found: 341.1095.
1-(Methoxycarbonyl)methyl-3-phenoxy-4-phenyl-2-thioxoazetidine (9c): IR (film): 1741, 1487, 1219 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.71 (d, J = 17.5 Hz, 1 H), 3.75 (s, 3 H), 4.91 (d, J = 17.5 Hz, 1 H), 5.45 (d, J = 4.1 Hz, 1 H), 5.71 (d, J = 4.1 Hz, 1 H), 6.76-6.92 (m, 2 H), 7.09-7.17 (m, 2 H), 7.31 (s, 6 H). 13C NMR (50 MHz, CDCl3): δ = 43.10, 52.46, 71.30, 81.31, 115.83, 122.12, 128.37, 128.56, 129.08, 129.16, 131.20, 156.72, 166.90, 201.01. MS (DEI): m/z (%) = 327 (33) [M+], 239 (3), 196 (100), 178 (39), 167 (17), 121 (52). HRMS: m/z calcd for C18H17NO3S [M+]: 327.0929; found: 327.0925.
4-(4-Bromophenyl)-1-(methoxycarbonyl)methyl-3-phenoxy-2-thioxoazetidine (9d): IR (film): 1748, 1492, 1225 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.69 (d, J = 17.8 Hz, 1 H), 3.75 (s, 3 H), 4.89 (d, J = 17.8 Hz, 1 H), 5.43 (d, J = 4.1 Hz, 1 H), 5.69 (d, J = 4.1 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 2 H), 6.88-6.95 (m, 1 H), 7.11-7.25 (m, 4 H), 7.45 (d, J = 8.4 Hz, 2 H). 13C NMR (50 MHz, CDCl3): δ = 43.10, 52.52, 70.64, 81.14, 115.78, 122.33, 123.42, 129.20, 130.22, 130.39, 131.67, 156.59, 166.77, 200.93. MS (DEI): m/z (%) = 405 (36) [M+], 274 (86), 256 (31), 167 (16), 121(100). HRMS: m/z calcd for C18H16BrNO3S [M+]: 405.0034; found: 405.0045.
4-(2-Bromophenyl)-1-(methoxycarbonyl)methyl-3-phenoxy-2-thioxoazetidine (9e): IR (film): 1750, 1489, 1224 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.78 (s, 3 H), 3.81 (d, J = 17.5 Hz, 1 H), 4.94 (d, J = 17.5 Hz, 1 H), 5.47 (d, J = 4.2 Hz, 1 H), 6.21 (d, J = 4.2 Hz, 1 H), 6.85-6.95 (m, 3 H), 7.12-7.35 (m, 5 H), 7.49 (d, J = 7.8 Hz, 1 H). 13C NMR (50 MHz, CDCl3): δ = 43.62, 52.58, 70.21, 81.55, 116.14, 122.34, 123.80, 127.35, 128.91, 129.10, 130.21, 131.20, 132.96, 156.80, 166.55, 201.63. MS (DEI): m/z (%) = 405 (9) [M+], 326 (100), 274 (73), 256 (12), 167 (29), 121(83). HRMS: m/z calcd for C18H16BrNO3S [M+]: 405.0034; found: 405.0026.
3-Methoxy-1-(methoxycarbonyl)methyl-2-thioxo-4-(4-
p
-tolyl)azetidine (9f): IR (film): 1747, 1487, 1207 cm-1. 1H NMR (200 MHz, CDCl3): δ = 2.37 (s, 3 H), 3.26 (s, 3 H), 3.63 (d, J = 17.6 Hz, 1 H), 3.72 (s, 3 H), 4.62 (d, J = 4.1 Hz, 1 H), 4.82 (d, J = 17.6 Hz, 1 H), 5.49 (d, J = 4.1 Hz, 1 H), 7.20 (s, 4 H). 13C NMR (50 MHz, CDCl3): δ = 21.14, 42.75, 52.36, 57.94, 70.72, 84.58, 128.44, 128.53, 129.25, 139.13, 166.94, 202.72. MS (DEI): m/z (%) = 279 (63) [M+], 192 (45), 148 (100), 133 (23), 105 (56). HRMS: m/z calcd for C14H17NO3S [M+]: 279.0929; found: 279.0936.
3-Methoxy-1-(methoxycarbonyl)methyl-4-phenyl-2-thioxoazetidine (9g): IR (film): 1750, 1489, 1209 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.25 (s, 3 H), 3.65 (d, J = 17.6 Hz, 1 H), 3.72 (s, 3 H), 4.64 (d, J = 4.1 Hz, 1 H), 4.84 (d, J = 17.6 Hz, 1 H), 5.53 (d, J = 4.1 Hz, 1 H), 7.26-7.41 (m, 5 H). 13C NMR (50 MHz, CDCl3): δ = 42.84, 52.39, 57.94, 70.87, 84.58, 128.46, 128.53, 129.14, 131.71, 166.92, 202.71. MS (DEI): m/z (%) = 265 (31) [M+], 178 (26), 134 (100), 118 (10), 91 (52). HRMS: m/z calcd for C13H15NO3S [M+]: 265.0773; found: 265.0767.
4-(4-Bromophenyl)-3-methoxy-1-(methoxycarbon-yl)methyl-2-thioxoazetidine (9h): IR (film): 1750, 1489, 1209 cm-1. 1H NMR (200 MHz, CDCl3): δ = 3.28 (s, 3 H), 3.63 (d, J = 17.6 Hz, 1 H), 3.73 (s, 3 H), 4.63 (d, J = 4.1 Hz, 1 H), 4.81 (d, J = 17.6 Hz, 1 H), 5.49 (d, J = 4.1 Hz, 1 H), 7.19 (d, J = 8.5 Hz, 2 H), 7.53 (d, J = 8.5 Hz, 2 H). 13C NMR (50 MHz, CDCl3): δ = 42.83, 52.44, 58.10, 70.20, 84.42, 123.42, 130.18, 130.66, 131.76, 166.82, 202.68. MS (DEI): m/z (%) = 343 (23) [M+], 256 (20), 212 (77), 169 (17), 118 (64), 88 (100). HRMS: m/z calcd for C13H14
81BrNO3S [M+]: 344.9857; found: 344.9860.
1-(Methoxycarbonyl)methyl-3-methyl-4-phenyl-2-thioxoazetidine (9i): IR (film): 1749, 1488, 1208 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.47 (d, J = 7.2 Hz, 3 H), 3.10 (q, J = 7.2 Hz, 1 H), 3.64 (d, J = 17.8 Hz, 1 H), 3.73 (s, 3 H), 4.79 (d, J = 17.8 Hz, 1 H), 4.94 (d, J = 1.5 Hz, 1 H), 7.30-7.38 (m, 5 H). 13C NMR (50 MHz, CDCl3): δ = 14.60, 43.33, 52.33, 57.74, 71.75, 126.52, 129.09, 135.64, 167.24, 208.27. MS (DEI): m/z (%) = 249 (33) [M+], 190 (2), 178 (18), 118 (100), 91 (23). HRMS: m/z calcd for C13H15NO2S [M+]: 249.0823; found: 249.0813.
1-(Methoxycarbonyl)methyl-4-phenyl-3-(3-phenyl-propyl)-2-thioxoazetidine (9j): IR (film): 1747, 1485, 1207 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.82-2.04 (m, 4 H), 2.63 (t, J = 7.2 Hz, 2 H), 3.08 (br t, J = 5.9 Hz, 1 H), 3.62 (d, J = 17.9 Hz, 1 H), 3.70 (s, 3 H), 4.79 (d, J = 17.9 Hz, 1 H), 5.00 (d, J = 1.7 Hz, 1 H), 7.12-7.42 (m, 10 H). 13C NMR (50 MHz, CDCl3): δ = 28.31, 29.87, 35.66, 43.26, 52.28, 62.67, 70.20, 125.74, 126.46, 128.25, 129.13, 135.74, 141.70, 167.24, 207.05. MS (DEI): m/z (%) = 353 (53) [M+], 320 (49), 231 (15), 178 (28), 160 (66), 131 (51), 117 (65), 91 (100). HRMS: m/z calcd for C21H23NO2S [M+]: 353.1449; found: 353.1461.
4-(4-Bromophenyl)-1-(methoxycarbonyl)methyl-3-(3-phenylpropyl)-2-thioxoazetidine (9k): IR (film): 1750, 1489, 1210 cm-1. 1H NMR (200 MHz, CDCl3): δ = 1.79-2.03 (m, 4 H), 2.63 (t, J = 7.1 Hz, 2 H), 3.03 (br t, J = 5.9 Hz, 1 H), 3.61 (d, J = 17.8 Hz, 1 H), 3.71 (s, 3 H), 4.76 (d, J = 17.8 Hz, 1 H), 4.97 (d, J = 1.4 Hz, 1 H), 7.13-7.26 (m, 7 H), 7.52 (d, J = 8.2 Hz, 2 H). 13C NMR (50 MHz, CDCl3): δ = 28.28, 29.82, 35.62, 43.22, 52.37, 62.73, 69.49, 123.01, 125.80, 128.14, 128.26, 132.32, 134.83, 141.56, 167.14, 206.93. MS (DEI): m/z (%) = 431 (11) [M+], 398 (10), 293 (35), 231 (10), 160 (59), 149 (100). HRMS: m/z calcd for C21H22BrNO2S [M+]: 431.0555; found: 431.0567.