Ring Expansion of 2-Alkenyl Azetidines into Unsaturated Azocanes

Abstract

Enantiomerically pure 2-alkenyl azetidines undergo a ring expansion into N-alkyl-1,2,3,6-azocines upon reaction with activated alkynes (ethyl propiolate or ethynyl p-tolyl sulfone). The scope of this ring enlargement, which provides a new entry to functionalized eight-membered ring nitrogen heterocycle, is discussed.

Key words

azetidines - ring expansion - azocanes

References and Notes

• For general reviews on the synthesis of azetidines prior to 2000, see:
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17

Typical Procedure for the Ring Expansion of 2-Alkenyl Azetidines into Unsaturated Azocanes: The following procedure for the preparation of azocane 8 is representative. To a solution of azetidine 9 (800 mg, 3.03 mmol) in absolute EtOH (30 mL), was added in one portion, ethyl propiolate (0.62 mL, 6.06 mmol). The reaction mixture was stirred for 5 days and concentrated under reduced pressure. The crude residue was purified by flash chromatography (Pentane-Et₂O, 75:25 + 0.1% Et₃N) to afford 8 as a colourless oil (911 mg, 82%).
Compound 8: R _f  = 0.30 (Pentane-Et₂O, 75:25); [α]_D ^²5 -957 (c 0.95, CH₂Cl₂); ^¹H NMR (300 MHz): δ = 0.95 (d, J = 6.7 Hz, 3 H, Me), 1.17 (t, J = 7.1 Hz, 3 H, OCH₂CH ₃), 2.95 (dd, J = 12.0, 6.5 Hz, 1 H, H7), 3.41-3.60 (m, 2 H, H4), 4.08 (q, J = 7.1 Hz, 2 H, OCH ₂), 4.27 (d, J = 15.8 Hz, 1 H, NCHH), 4.43 (d, J = 15.8 Hz, 1 H, NCHH), 4.64 (m, 1 H, H8), 5.39 (dd, J = 11.1, 6.5 Hz, 1 H, H6), 5.56 (m, 1 H, H5), 7.03 (d, J = 7.9 Hz, 1 H, Ar), 7.11-7.27 (m, 9 H, Ar), 7.57 (s, 1 H, H2); ^¹³C NMR (75 MHz): δ = 14.6 (CH₃CH₂), 18.7 (CH₃), 25.1 (C4), 53.3 (NCH₂), 56.0, 57.6 (C7, C8), 59.7 (OCH₂), 94.9 (C3), 125.2, 126.8, 127.5, 128.4, 128.5, 128.6, 132.0 (C5, C6, CHAr), 139.1, 141.2 (CqAr), 151.9 (C2), 170.0 (C=O); MS (ESI): m/z (%) = 385.3 (20) [M + Na⁺], 362.2 (100) [M + H⁺]. Compound 7: white solid; mp 74 ˚C; R _f  = 0.25 (Pentane-Et₂O, 75:25); [α]_D ^²5 -548 (c 3.3, CH₂Cl₂); ^¹H NMR (300 MHz): δ = 1.07 (d, J = 6.5 Hz, 3 H, Me), 2.47 (s, 3 H, Me), 3.02-3.16 (m, 2 H, H4, H7), 3.74 (dd, J = 16.2, 7.5 Hz, 1 H, H4′), 4.44 (d, J = 15.8 Hz, 1 H, NCHH), 4.58 (d, J = 15.8 Hz, 1 H, NCHH), 4.64 (m, 1 H, H8), 5.24 (m, 1 H, H5), 5.50 (m, 1 H, H6), 7.03 (m, 2 H, Ar), 7.19-7.44 (m, 10 H, Ar), 7.64 (s, 1 H, H2), 7.72 (d, J = 6.7 Hz, 2 H, Ar); ^¹³C NMR (75 MHz): δ = 18.7 (CH₃), 21.5 (CH₃), 25.4 (C4), 53.2 (NCH₂), 56.3, 57.7 (C7, C8), 102.5 (C3), 123.2, 125.5, 127.0, 127.2, 127.3, 127.6, 127.8, 128.3, 128.5, 128.7, 128.8, 129.4, 133.0 (C2, C5, C6, CHAr), 138.8, 139.9, 140.6, 142.4 (CqAr), 149.9 (C2); MS (ESI):
m/z (%) = 466.3 (100) [M + Na⁺].