Regiochemical and Stereochemical Studies of the Intramolecular Dipolar Cycloaddition of Nitrones Derived from Quaternary Aldehydes

Abstract

Three aldehydes each with a quaternary α-carbon stereocentre bearing an alkenyl, a phenyl, and a methyl ester group were treated with N-methylhydroxylamine. In each case bicyclic isoxazolidine products were formed by condensation to give intermediate nitrones that undergo intramolecular dipolar cycloaddition. The stereoselectivity was influenced by the α-carbonyl substituent, possibly by a hydrogen bond between CO and a nearby CH of the nitrone in the transition state (supported by DFT and X-ray studies), and the regioselectivity was affected by the length of the tether and by the presence of an ester on the alkene dipolarophile.

Key words

cycloaddition - diastereoselectivity - domino reaction - fused-ring systems - heterocycles

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• 9 Dimethyl 1-Methyl-7-phenyloctahydrobenzo[c]isoxazole-3,7-dicarboxylate (14a) The aldehyde 13 (100 mg, 0.33 mmol), N-methylhydroxylamine hydrochloride (30 mg, 0.36 mmol), and DIPEA (0.12 mL, 0.66 mmol) in toluene (4 mL) was heated at 110 °C. After 2 h, the solvent was evaporated. Purification by column chromatography, eluting with PE–EtOAc (7:2), gave the cycloadducts 14a and 14b (67 mg, 61%) as a mixture (ratio 5:1 by ¹H NMR spectroscopy) from which isomer 14a was isolated by crystallization from CH₂Cl₂–hexane (1:1) as amorphous solid; mp 98–100 °C; R_f = 0.28 [PE–EtOAc (7:2)]. IR (film): ν_max = 2950, 1750, 1725, 1435 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.38–7.34 (2 H, m), 7.31–7.26 (3 H, m), 4.13 (1 H, s), 3.79 (3 H, s), 3.67 (3 H, s), 3.57 (1 H, d, J = 4 Hz), 3.23–3.19 (1 H, m), 2.46–2.38 (1 H, m), 2.35–2.26 (1 H, m), 1.97–1.87 (5 H, m), 1.74–1.59 (1 H, m), 1.37–1.26 (1 H, m). ¹³C NMR (400MHz, CDCl₃): δ = 175.1, 172.9, 140.7, 128.8, 127.7, 126.3, 80.4, 70.5, 53.2, 52.4, 52.2, 48.1, 47.8, 26.9, 26.5, 22.2. HRMS (ES): m/z calcd for C₁₈H₂₃NO₅ [MH⁺]: 334.1649; found [MH⁺]: 334.1646. LRMS (ES): m/z (%) = 334 (100) [MH⁺]. X-ray crystal structure analysis (see Supporting Information): CCDC 1422381.