Efficient Solid-Phase Synthesis of 1,3,4-Trisubstituted β-Thiolactams

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.

solid-phase synthesis - β-thiolactams - Lawesson’s reagent - β-lactams - combinatorial chemistry

References

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 

12

Gel-phase ¹³C NMR spectra were recorded in a conventional 200 MHz NMR apparatus.

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 

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.

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