Synthesis of Optically Active Substituted 3-Fluoropiperidines from Prolinols by Using DAST

Abstract

The treatment of optically active prolinols with DAST produces optically active 3-fluoropiperidines via aziridinium intermediates.

ring expansion - fluorine - rearrangements - piperidine - aziridinium

References and Notes

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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.

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<A NAME="RG06106ST-16">16</A>

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.

<A NAME="RG06106ST-17">17</A>

Compound 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.

<A NAME="RG06106ST-18">18</A> Seebach D. Boes M. Naef R. Schweizer WB. J. Am. Chem. Soc.  1983,  105:  5390 

<A NAME="RG06106ST-19">19</A>

Compound 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).

<A NAME="RG06106ST-20">20</A>

The ee values were determined by HPLC: OJ-H, hexane, 0.3 mL/min.

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Benzyl and allyl neighboring groups are reported to participate in DAST reactions in the absence of internal nucleophile, for examples, see:

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