Subscribe to RSS
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)
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
-
1a
High Throughput Screening
Devlin JP. Marcel Dekker, Inc.; New York: 1997. -
1b
Obrecht D.Villalgordo JM. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries Elsevier Science Ltd.; New York: 1998. -
1c
Terrett NK. Combinatorial Chemistry Oxford University Press; Oxford: 1998. -
1d
Combinatorial Chemistry
Fenniri H. Oxford University Press; Oxford: 2000. -
1e
Combinatorial Library Design and Evaluation
Ghose AK.Viswanadhan VN. Marcel Dekker, Inc.; New York: 2001. -
2a
Seneci P. Solid-Phase Synthesis and Combinatorial Technologies Wiley and Sons; New York: 2000. -
2b
Solid-Phase Organic Synthesis
Burgess K. John Wiley and Sons; New York: 2000. -
2c
Solid-Phase Organic Synthesis
Czarnik AW. John Wiley and Sons; New York: 2001. -
2d
Zaragoza-Dörwald F. Organic Synthesis on Solid Phase 2nd ed.: Wiley-VCH; Weinheim: 2002. - 3
Mazur S.Jayalekshmy P. J. Am. Chem. Soc. 1979, 101: 677 -
4a
Dolle RE. J. Comb. Chem. 2001, 3: 477 -
4b
Dolle RE. J. Comb. Chem. 2002, 4: 369 -
4c
Dolle RE. J. Comb. Chem. 2003, 5: 693 -
4d
Dolle RE. J. Comb. Chem. 2004, 6: 623 - 5 For a review see:
Kidwai M.Sapra P.Bhushan KR. Curr. Med. Chem. 1999, 6: 195 - 6
Konaklieva MI. Med. Chem. Rev. - Online 2004, 1: 133 ; and references cited therein -
7a
Tsang WY.Dhanda A.Schofield CJ.Page MI. J. Org. Chem. 2004, 69: 339 -
7b
Tsang WY.Dhanda A.Schofield CJ.Frere JM.Galleni M.Page MI. Bioorg. Med. Chem. Lett. 2004, 14: 1737 - 8
Murphy BP.Pratt RF. Biochem. J. 1988, 256: 669 -
9a
Wojkowski PW.Dolfini JE.Kocy O.Cimarusti CM. J. Am. Chem. Soc. 1975, 97: 5628 -
9b
Commercon A.Ponsinet G. Tetrahedron Lett. 1983, 24: 3725 -
9c
Verkoyen C.Rademacher P. Chem. Ber. 1985, 118: 653 -
9d
Förster WR.Isecke R.Spanka C.Schaumann E. Synthesis 1997, 942 -
10a
Mata EG. Tetrahedron Lett. 1997, 38: 6335 -
10b
Delpiccolo CML.Mata EG. Tetrahedron: Asymmetry 1999, 10: 3893 -
10c
Delpiccolo CML.Mata EG. Molecules 2000, 5: 537 -
10d
Delpiccolo CML.Mata EG. Tetrahedron: Asymmetry 2002, 13: 905 -
10e
Delpiccolo CML.Fraga MA.Mata EG. J. Comb. Chem. 2003, 5: 208 -
10f
Delpiccolo CML.Mata EG. Tetrahedron Lett. 2004, 45: 4085 -
10g
Delpiccolo CML.Méndez L.Fraga MA.Mata EG. J. Comb. Chem. 2005, 7: 331 -
11a
Scheibye S.Kristensen J.Lawesson SO. Tetrahedron 1979, 20: 1339 -
11b
Cava MP.Levinson MI. Tetrahedron 1985, 41: 5061 -
11c
Jesberger M.Davis TP.Barner L. Synthesis 2003, 1929 - 13 Nishio et al. have established a reactivity order towards LR: alcohol > amide > ketone > ester; see:
Nishio T.Ori M. Heterocycles 2000, 52: 111 - 14
Rauchfuss TB.Zank GA. Tetrahedron Lett. 1986, 27: 3445 - 16
Schaumann E.Nieschalk J.Isecke R.Spanka C.Mrotzek H.Förster W.-R. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120-121: 349 - 17
Ruhland B.Bombrun A.Gallop MA. J. Org. Chem. 1997, 62: 7820 - 18
Rosenblum SB.Huynh T.Afonso A.Davis HR.Yumibe N.Clader JW.Burnett DA. J. Med. Chem. 1998, 41: 973 ; and references cited therein
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.