Rearrangement of 2-Hydroxyalkylazetidines into 3-Fluoropyrrolidines

Abstract

Upon treatment with DAST (diethylaminosulfur trifluoride) enantiopure 2-hydroxyalkylazetidines rearrange into 3-fluoropyrrolidines. The reaction is stereospecific and involves a bicyclic 1-azoniabicyclo[2.1.0]pentane intermediate which is regioselectively opened by a fluoride anion.

Key words

fluorination - DAST - pyrrolidines - azetidines

References and Notes

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16

Crystal structure has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 676883.

17

The kinetic control invoked here is also supported by the chemical stability of 36, which does not rearrange when heated at 100 °C in toluene for 8 h.

18

General Procedure for the Reaction of Azetidinols with DAST: To a solution of the required 2-hydroxyalkyl-
azetidine (1 mmol) in anhyd CH₂Cl₂ (7 mL) cooled at 0 °C under argon was added dropwise diethylaminosulfur trifluoride (245 µL, 2 mmol). The resulting solution was allowed to reach r.t. (1 h) and was stirred for 1 h. The reaction mixture was then basified with 1 M NaOH (5 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). Drying over MgSO₄, filtration, and evaporation of the solvent under reduced pressure gave a residue that was purified by flash chromatography.
Selected data: Compound 26: yield (from 10): 81%; colorless oil; R _f 0.75 (EtOAc); [α]_D ²⁵ -46.1 (c = 0.57, CHCl₃). ¹H NMR (300 MHz): δ = 1.40 (d, J = 6.6 Hz, 3 H, Me), 1.80-2.15 (m, 2 H, H4, H4′), 2.50-3.75 (m, 3 H, H2, H5, H5′), 2.79 (dd, J = 12.0, 30.0 Hz, 1 H, H2′), 3.21 (q, J = 6.6 Hz, 1 H, CHMe), 5.13 (dt, ² J _HF = 54.0 Hz, ³ J _HH = 6.0 Hz, 1 H, H3), 7.13-7.28 (m, 5 H, Ar). ¹³C NMR (75 MHz): δ = 23.1 (Me), 32.8 (d, ³ J _C-F = 23.0 Hz, C2), 50.9 (C4), 59.6 (d, ³ J _CF = 23.0 Hz, C4), 65.4 (CHMe), 92.5 (d, ² J _CF = 176.0 Hz, C3), 127.0, 128.1, 128.4 (CHAr), 145.1 (CqAr). ¹⁹F NMR (188 MHz): δ = -168.2 [qd (false hept), ² J _HF = 80.7 Hz, ³ J _HF = 30.0 Hz, 1 F]. MS (CI, NH₃ gas): m/z = 194 (100) [MH⁺]. Compound 30: yield (from 14): 79%; colorless solid; mp 69 °C; R _f 0.85 (EtOAc-pentane, 1:9); [α]_D ²⁵ +119.8 (c = 0.5, CHCl₃). ¹H NMR (300 MHz): δ = 1.29 (d, J = 6.0 Hz, 3 H, Me), 2.48-2.72 (m, 2 H, H2, H5), 3.16 (ddd, ³ J _HH = 3.0, 9.0 Hz, ³ J _HF = 36.0 Hz, 1 H, H5′), 3.27 (d, J = 12.0 Hz, 1 H, NCHHPh), 3.35 (dd, ³ J _HH = 12.0 Hz, ³ J _HF = 21.0 Hz, 1 H, H3), 4.22 (d, J = 12.0 Hz, 1 H, NCHHPh), 5.10 (dm, ² J _HF = 57.0 Hz, 1 H, H4), 7.22-7.41 (m, 10 H, Ar). ¹³C NMR (75 MHz): δ = 16.0 (Me), 57.4 (NCH₂Ph), 60.3, 60.8 (d, ³ J _CF = 23.0 Hz, C3, C5), 67.2 (d, ⁴ J _CF = 2.2 Hz, C2), 98.3 (d, ² J _CF = 182.0 Hz, C4), 127.1, 127.2, 127.4, 128.1, 128.4, 128.8, 128.9 (CHAr), 138.4, 140.5 (CqAr). ¹⁹F NMR (188 MHz):
δ = -164.4 to -165.2, (m, 1 F). MS (ESI, +ve): m/z = 270.3 (100) [MH⁺].