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Synlett 2006(20): 3484-3488  
DOI: 10.1055/s-2006-956479
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of Bicyclic α-Hydroxy-α-trifluoromethyl-γ-lactams

Norio Shibata*, Hiroyuki Fujimoto, Satoshi Mizuta, Shinichi Ogawa, Yumi Ishiuchi, Shuichi Nakamura, Takeshi Toru*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa, Nagoya 466-8555, Japan
Fax: +81(52)7355442; e-Mail: nozshiba@nitech.ac.jp; e-Mail: toru@nitech.ac.jp;
Further Information

Publication History

Received 25 September 2006
Publication Date:
08 December 2006 (online)

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Abstract

A facile method for the synthesis of bicyclic 3-hydroxy-3-trifluoromethyl-γ-lactams using a variety of enamines and ethyl trifluoropyruvate with or without a catalyst was examined.

Key words

fluorine - tandem reactions - bicyclic compounds - heterocycle - green chemistry

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Although a literature survey on SciFinder® reveals the types of compounds 1 as being registered, surprisingly, neither references nor the synthetic information on them is available.

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Compound 1a: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 2.02-2.18 (m, 2 H), 2.26-2.66 (m, 4 H), 4.37 (br s, 1 H), 4.65 (d, J = 15.8 Hz, 1 H), 4.89 (d, J = 15.8 Hz, 1 H), 7.15-7.20 (m, 2 H), 7.31-7.42 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.1 (s, 3 F). IR (KBr): 3128, 1763, 1632, 1601, 1413, 1359, 1263, 1183, 1158, 1075, 1026, 960, 945, 737, 712, 568, 499 cm-1. MS (EI): m/z = 325 [M+].
Compound 1b: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 2.09-2.22 (m, 2 H), 2.36-2.68 (m, 4 H), 4.48 (br s, 1 H), 7.19-7.25 (m, 2 H), 7.45-7.56 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.4 (s, 3 F). IR (KBr): 3424, 1767, 1651, 1613, 1496, 1399, 1255, 1191, 1086, 1015, 849, 744, 715, 552 cm-1. MS (EI): m/z = 311 [M+].
Compound 1c: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.75-1.97 (m, 4 H), 2.10-2.35 (m, 1 H), 2.34-2.50 (m, 1 H), 2.86-3.04 (m, 2 H), 3.62 (ddd, J = 14.0, 7.6, 5.6 Hz, 1 H), 3.87 (dt, J = 14.0, 6.2 Hz, 1 H), 4.34 (d, J = 4.2 Hz, 1 H), 7.08-7.14 (m, 2 H), 7.27-7.32 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.0 (s, 3 F). IR (KBr): 3250, 2960, 1764, 1638, 1593, 1458, 1433, 1366, 1336, 1277, 1256, 1184, 1161, 1072, 985, 946, 841, 755, 708, 562, 499 cm-1. MS (EI): m/z = 339 [M+].
Compound 1d: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.05 (s, 3 H), 1.07 (s, 3 H), 2.24 (d, J = 16.6 Hz, 1 H), 2.35 (s, 2 H), 2.38 (d, J = 16.6 Hz, 1 H), 4.26 (br s, 1 H), 4.66 (d, J = 16.0 Hz, 1 H), 4.89 (d, J = 16.0 Hz, 1 H), 7.13-7.18 (m, 2 H), 7.31-7.41 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.0 (s, 3 F). IR (KBr): 3201, 2961, 1756, 1625, 1599, 1421, 1267, 1191, 1173, 1062, 956, 701 cm-1. MS (EI): m/z = 353 [M+].
Compound 1e: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.12 (s, 3 H), 1.14 (s, 3 H), 2.29 (d, J = 18.6 Hz, 1 H), 2.23 (d, J = 16.4 Hz, 1 H), 2.41 (d, J = 18.6 Hz, 1 H), 2.45 (d, J = 16.4 Hz, 1 H), 4.44 (br s, 1 H), 7.17-7.22 (m, 2 H), 7.47-7.53 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.0 (s, 3 F). IR (KBr): 3398, 3222, 2962, 1766, 1647, 1615, 1496, 1400, 1244, 1192, 1163, 1074, 1048, 897, 742, 715, 571, 505, 449 cm-1. MS (EI): m/z = 339 [M+].
Compound 1f: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 0.85 (s, 3 H), 0.95 (s, 3 H), 1.67 (d, J = 18.2 Hz, 1 H), 1.80 (d, J = 18.2 Hz, 1 H), 2.10 (d, J = 16.4 Hz, 1 H), 2.22 (d, J = 16.4 Hz, 1 H), 2.80-3.03 (m, 2 H), 3.60 (ddd, J = 14.0, 7.8, 5.6 Hz, 1 H), 3.89 (dt, J = 14.2, 6.0 Hz, 1 H), 4.28 (br s, 1 H), 7.10-7.14 (m, 2 H), 7.31-7.34 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -77.8 (s, 3 F). IR (KBr): 3200, 2962, 1755, 1642, 1605, 1422, 1263, 1189, 1167, 1068, 701, 497 cm-1. MS (EI): m/z = 367 [M+].
Compound 5g: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.31 (t, J = 7.2 Hz, 3 H), 1.75-1.93 (m, 2 H), 2.27-2.37 (m, 2 H), 2.47-2.62 (m, 2 H), 4.17-4.34 (m, 2 H), 5.76 (d, J = 6.4 Hz, 1 H), 6.06 (s, 1 H), 7.21-7.42 (m, 10 H), 7.69 (d, J = 6.4 Hz, 1 H). 19F NMR (188 MHz, CDCl3): δ = -76.1 (s, 3 F). IR (KBr): 3321, 2953, 1747, 1565, 1432, 1373, 1281, 1193, 1034, 991, 946, 744, 704, 550 cm-1. MS (EI): m/z = 447 [M+].
Compound 1g: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.86-2.06 (m, 3 H), 2.18-2.54 (m, 3 H), 4.20 (br s, 1 H), 6.81 (s, 1 H), 7.15-7.20 (m, 4 H), 7.33-7.45 (m, 6 H). 19F NMR (188 MHz, CDCl3): δ = -78.1 (s, 3 F). IR (KBr): 3400, 3064, 3033, 2954, 1759, 1647, 1603, 1243, 1191, 1165, 1076, 1013, 741, 715, 700, 612, 512, 418 cm-1. MS (EI): m/z = 401 [M+].
Compound 1h: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 0.93 (s, 3 H), 1.01 (s, 3 H), 1.89 (d, J = 18.2 Hz, 1 H), 2.09 (d, J = 18.2 Hz, 1 H), 2.16 (d, J = 16.4 Hz, 1 H), 2.31 (d, J = 16.4 Hz, 1 H), 4.29 (br s, 1 H), 6.83 (s, 1 H), 7.17-7.21 (m, 4 H), 7.34-7.41 (m, 6 H). 19F NMR (188 MHz, CDCl3): δ = -77.9 (s, 3 F). IR (KBr): 3390, 2962, 1765, 1646, 1600, 1424, 1405, 1356, 1266, 1225, 1193, 1161, 1078, 1067, 904, 743, 702, 567, 447 cm-1. MS (EI): m/z = 429 [M+].
Compound 1i: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 2.13-2.24 (m, 2 H), 2.32-2.62 (m, 4 H), 4.41 (br s, 1 H), 4.68 (d, J = 16.4 Hz, 1 H), 5.09 (d, J = 16.4 Hz, 1 H), 7.64 (s, 2 H), 7.87 (s, 1 H). 19F NMR (188 MHz, CDCl3): δ = -63.0 (s, 6 F), -78.3 (s, 3 F). IR (KBr): 3545, 1764, 1645, 1612, 1408, 1353, 1281, 1184, 1133, 1081, 957, 708, 684 cm-1. MS (EI): m/z = 461 [M+].
Compound 1j: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 2.02-2.16 (m, 2 H), 2.29-2.59 (m, 4 H), 4.39 (br s, 1 H), 4.88 (d, J = 16.8 Hz, 1 H), 5.12 (d, J = 16.8 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H). 19F NMR (188 MHz, CDCl3): δ = -60.1 (s, 3 F), -78.0 (s, 3 F). IR (KBr): 3126, 2813, 1760, 1645, 1612, 1409, 1319, 1263, 1157, 1110, 1080, 1039, 967, 946, 878, 770, 709, 657, 426 cm-1. MS (EI): m/z = 393 [M+].
Compound 1k: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.79-1.98 (m, 4 H), 2.63-2.71 (m, 4 H), 4.65 (d, J = 16.2 Hz, 1 H), 4.97 (d, J = 16.2 Hz, 1 H), 5.99 (s, 1 H), 7.13-7.17 (m, 2 H), 7.29-7.40 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.1 (s, 3 F). IR (KBr): 3384, 3011, 2948, 2883, 1761, 1590, 1403, 1320, 1259, 1207, 1171, 1039, 944, 743, 710, 627, 525, 463 cm-1. MS (EI): m/z = 339 [M+].
Compound 1l: brown oil. 1H NMR (200 MHz, CDCl3): δ = 2.23 (s, 3 H), 4.79 (d, J = 16.0 Hz, 1 H), 4.87 (d, J = 16.0 Hz, 1 H), 7.10-7.17 (m, 2 H), 7.30-7.36 (m, 3 H). 19F NMR (188 MHz, CDCl3): δ = -78.6 (s, 3 F). IR (neat): 3341, 2220, 1748, 1633, 1402, 1352, 1267, 1181, 1139, 1083, 1032, 953, 742, 716, 614, 557 cm-1. MS (EI): m/z = 296 [M+].
Compound 4: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.80 (br s, 1 H), 4.65 (d, J = 15.8 Hz, 1 H), 5.10 (d, J = 15.8 Hz, 1 H), 5.65 (br s, 1 H), 6.34 (d, J = 7.6 Hz, 1 H), 6.65 (d, J = 8.4 Hz, 1 H) 7.15-7.40 (m, 6 H). 19F NMR (188 MHz, CDCl3): δ = -78.1 (s, 3 F). IR (KBr): 3592, 3471, 3338, 3239, 1721, 1618, 1471, 1388, 1352, 1281, 1174, 1123, 1038, 948, 788, 702 cm-1. MS (EI): m/z = 323 [M+].
Compound 5m: colorless crystals. 1H NMR (200 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H), 2.43-2.48 (m, 1 H), 2.58-2.65 (m, 2 H), 4.25-4.38 (m, 2 H), 4.51 (d, J = 6.0 Hz, 2 H), 7.20-7.25 (m, 2 H), 7.31-7.43 (m, 3 H), 8.01 (br d, 1 H), 9.76 (s, 1 H). 19F NMR (188 MHz, CDCl3): δ = -78.7 (s, 3 F). IR (KBr): 3375, 2986, 2715, 1759, 1648, 1558, 1453, 1433, 1341, 1240, 1192, 1158, 1038, 970, 737, 665, 461 cm-1. MS (EI): m/z = 357 [M+].