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DOI: 10.1055/s-2007-967989
Synthesis of Optically Active Substituted 3-Fluoropiperidines from Prolinols by Using DAST
Publication History
Publication Date:
24 January 2007 (online)
Abstract
The treatment of optically active prolinols with DAST produces optically active 3-fluoropiperidines via aziridinium intermediates.
Key words
ring expansion - fluorine - rearrangements - piperidine - aziridinium
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References and Notes
General Procedure for the Ring Expansion of Prolinols 1-5 and 19-23.
To a stirred solution of prolinol (0.5 mmol) in THF or CH2Cl2 (5 mL) at 0 °C, DAST (0.7 mmol) was added dropwise. After 1 h, the cooling bath was removed and the reaction mixture was stirred at r.t. for 1 h. The reaction was worked up by cooling to 0 °C followed by careful addition of a sat. NaHCO3 solution (10 mL). The mixture was extracted twice with EtOAc (30 mL). The crude product was purified by flash chromatography on silica gel using cyclohexane-Et2O (9:1) as eluant.
Compound 12: [α]D 20 -6.7 (c 0.135, CHCl3). IR (neat): 2921, 1460, 1252, 1153, 1090, 835, 776, 739, 699 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.40-7.15 (m, 5 H), 4.80 (dm, J = 47.2 Hz, 1 H), 4.06 (dddd, J = 9.5, 9.5, 4.5, 4.5 Hz, 1 H), 3.64 (d, J = 13.4 Hz, 1 H), 3.52 (d, J = 13.4 Hz, 1 H), 2.92-2.79 (m, 2 H), 2.29-1.99 (m, 3 H), 1.59-1.36 (m, 1 H), 0.83 (s, 9 H), 0,03 (s, 3 H), 0,01 (s, 3 H). 13C NMR: δ = 137.5 (s), 129.0 (d), 128.3 (d), 127.1 (d), 87.9 (dd, ¹ J C-F = 171.2 Hz), 65.1 (d), 62.3 (t), 60.2 (t), 56.0 (dt, 2 J C-F = 20.2 Hz), 38.8 (dt, 2 J C-F = 20.2 Hz), 25.8 (q), 18.1 (s), -4.8 (q). MS (EI): m/z (relative intensity) = 323 (2) [M+], 308 (3), 303 (2), 290 (2), 266 (31), 246 (4), 232 (2), 192 (3), 191 (4), 190 (3), 134 (11), 102 (2), 100 (2), 92 (9), 91 (100), 77 (3), 75 (4), 73 (10), 65 (3), 59 (3). HRMS: m/z calcd for C18H31NFOSi [MH]+: 324.2159; found: 324.2151.
17Compound 14: [α]D 20 +37.6 (c 0.35, CHCl3). IR (neat): 3069, 2930, 2856, 2800, 1588, 1471, 1427, 1360, 1154, 1105, 1027, 976, 821, 738, 698 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.65-7.58 (4 H), 7.43-7.21 (11 H), 4.83 (ddddd, J = 47.7, 5.0, 5.0, 2.5, 2.5 Hz, 1 H), 4.13 (dddd, J = 8.0, 8.0, 4.0, 4.0 Hz, 1 H), 3.50 (s, 2 H), 2.74-2.58 (m, 2 H), 2.40 (ddd, J = 29.1, 12.1, 2.0 Hz, 1 H), 2.15 (m, 1 H), 1.98 (m, 1 H), 1.67 (m, 1 H), 1.04 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 137.6 (s), 135.7 (d), 134.2 (s), 134.0 (s), 129.7 (d), 129.6 (d), 129.0 (d), 128.2 (d), 127.7 (d), 127.6 (d), 127.1 (d), 87.7 (dd, J = 170 Hz), 66.2 (dd, J = 3 Hz), 62.2 (t), 59.6 (t), 56.3 (dt, J = 21 Hz), 38.5 (dt, J = 20 Hz), 27.0 (q), 19.2 (s). MS (EI): m/z (relative intensity) = 447 (1) [M+], 414 (2), 392 (7), 391 (27), 390 (82), 370 (4), 225 (3), 222 (3), 201 (8), 199 (10), 192 (7), 191 (6), 183 (9), 181 (6), 170 (5), 135 (7), 92 (8), 91 (100), 65 (3). HRMS: m/z calcd for C28H35NFOSi [MH]+: 448.2472; found: 448.2473.
19Compound 28: [α]D 20 +6.6 (c 0.35, CHCl3). IR (neat): 2930, 2856, 2786, 1460, 1427, 1384, 1252, 1180, 1106, 1083, 1048, 936, 888, 821, 776, 739, 700 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.67-7.63 (m, 4 H), 7.42-7.33 (m, 6 H), 4.12 (dddd, J = 10.1, 10.1, 5.0, 5.1 Hz, 1 H), 2.90-2.83 (m, 1 H), 2.79-2.73 (m, 1 H), 2.22 (s, 3 H), 2.11-2.03 (m, 1 H), 2.00-1.78 (m, 2 H), 1.63-1.51 (m, 3 H), 1.06 (s, 9 H), 0.89 (t, J = 7.5 Hz, 3 H). 13C NMR: δ = 135.7 (d), 134.1 (s), 129.7 (d), 127.6 (d), 95.1 (ds, 1 J C-F = 172 Hz), 66.4 (d), 62.3 (t), 61.7 (dt, 2 J C-F = 21.2 Hz), 45.8 (q), 41.4 (dt, 2 J C-F = 22.0 Hz), 31.4 (dt, 2 J C-F = 22.7 Hz), 27.0 (q), 19.2 (s), 7.10 (q). MS (EI): m/z (relative intensity) = 399 (2) [M+], 379 (12), 364 (9), 343 (28), 342 (100), 322 (15), 225 (7), 201 (11), 199 (13), 183 (18), 181 (10), 144 (18), 124 (30), 122 (23), 94 (11), 58 (12).
20The ee values were determined by HPLC: OJ-H, hexane, 0.3 mL/min.