Intramolecular Ring-Opening Reactions of 1-(2-Methoxyphenyl)-6-oxabicyclo[3.2.0]heptanes: Spirocyclic Dihydrobenzofurans from Fused Bicyclic Oxetanes

Abstract

Treatment of fused oxetanes with Et₂AlCl, TMSCl, acetyl chloride, or ethereal hydrochloric acid leads to the formation of spirocyclic dihydrobenzofurans through intramolecular attack of an oxygen atom of a proximal phenolic methyl ether.

cyclizations - heterocycles - Lewis acids - neighboring-group effects - spiro compounds

References and Notes

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In taxoids, the close proximity of the C-2 hydroxy group with the oxetane ring allows for a particularly facile intramolecular S_N2 displacement at C-20 leading to the formation of tetrahydrofurans:

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14

Typical Experimental for Oxetane Ring-Opening Reaction with HCl To a solution of oxetane 1a (50 mg, 0.18 mmol) in Et₂O (5 mL) at 0 °C HCl (1 M in Et₂O, 1.80 mL, 1.80 mmol) was added over a period of 10 min. The resulting solution was stirred for 18 h at r.t. The resulting mixture was poured into H₂O (10 mL) and the aqueous layer was extracted with Et₂O (2 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over MgSO₄, filtered and concentrated in vacuo. The crude product was purified via column chromatography (hexane-EtOAc, 8:2) to furnish spirocycle 8a as a colorless oil (37 mg, 78%). R _f = 0.2 (hexane-EtOAc, 8:2); mp 88-90 °C. IR (neat): ν_max = 3445, 2945, 2865, 1651, 1497, 1466, 1199 cm^-1. ¹H NMR (360 MHz, CDCl₃): δ = 6.65 (1 H, s, CCHCOCH₃), 6.58 (1 H, s, CH₂OCCHCCH₃), 5.07 (1 H, dd, J = 6.8, 1.8 Hz, CHOH), 3.93 (1 H, d, J = 11.0 Hz, COCH₂C), 3.79 (3 H, s, ArOCH₃), 3.65 (1 H, d, J = 11.0 Hz, COCH₂C), 2.19 (3 H, s, ArCH₃), 2.16-2.11 (1 H, m, HOCHCH ₂CH₂), 1.97-1.94 (1 H, m, HOCHCH ₂CH₂), 1.61-1.50 (1 H, m, HOCHCH₂CH ₂), 1.49-1.44 (1 H, m, HOCHCH₂CH ₂), 1.26 (1 H, br, OH), 1.07 [3 H, s, C(CH₃)₂], 1.03 [3 H, s, C(CH₃)₂]. ¹³C NMR (100 MHz, CDCl₃): δ = 17.0 (q), 24.6 (q), 26.7 (q), 32.2 (t), 40.9 (t), 44.9 (s), 56.9 (q), 64.9 (s), 65.2 (t), 92.8 (d), 108.6 (d), 111.7 (d), 125.3 (s), 128.2 (s), 152.1 (s), 156.1 (s). ESI-HRMS: m/z calcd for C₁₆H₂₂O₃Na: 285.1461; found: 285.1457; LRMS (EI): m/z (%) = 262 (100) [M⁺], 231 (5), 205 (33), 192 (6), 175 (33), 163 (9).

15

Typical Experimental Procedure for Oxetane Ring-Opening Reaction with AcCl To a solution of oxetane 1a (50 mg, 0.18 mmol) in DCE (10 mL) at r.t., AcCl (0.13 mL, 1.80 mmol) was added. The resulting solution was stirred overnight at r.t. poured into H₂O (10 mL) and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic phases were dried over MgSO₄, filtered, and reduced in vacuo. The crude product was purified via column chromatography (hexane-EtOAc, 9:1) to furnish spirocycle 9a as a colorless oil (45 mg, 81%). R _f = 0.2 (hexane-EtOAc, 9:1). IR (neat): ν_max = 2950, 2869, 2252, 2105, 1739, 1651, 1490, 1464, 1223, 1047 cm^-1. ¹H NMR (360 MHz, CDCl₃): δ = 6.66 (1 H, s, CCHCOCH₃), 6.54 (1 H, s, CH₂OCCHCCH₃), 4.96 (1 H, dd, J = 6.8, 1.6 Hz, CHOCOCH₃), 4.45 (1 H, d, J = 11.1 Hz, COCH₂C), 4.16 (1 H, d, J = 11.2 Hz, COCH₂C), 3.77 (3 H, s, ArOCH₃), 2.18 (3 H, s, ArCH₃), 2.15-2.12 (1 H, m, COCHCH ₂CH₂), 1.97 (3 H, s, OCOCH₃), 1.99-1.91 (1 H, m, COCHCH ₂CH₂), 1.63-1.55 (1 H, m, COCHCH₂CH ₂), 1.52-1.48 (1 H, m, COCHCH₂CH ₂), 1.10 [3 H, s, C(CH₃)₂], 1.06 [3 H, s, C(CH₃)₂]. ¹³C NMR (125 MHz, CDCl₃): δ = 16.5 (q), 20.9 (q), 24.6 (q), 26.4 (q), 31.9 (t), 39.6 (t), 44.9 (s), 56.4 (q), 61.7 (s), 67.1 (t), 92.3 (d), 109.0 (d), 111.2 (d), 125.9 (s), 127.3 (s), 151.4 (s), 154.8 (s), 171.0 (s). ESI-HRMS: m/z calcd for C₁₈H₂₄O₄Na: 327.1567; found: 327.1562. LRMS (EI): m/z (%) = 304 (100) [M⁺], 262 (21), 175 (66), 160 (8), 115 (8), 91 (7), 69 (5), 43 (16).

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