Mild Cleavage of N–O Bond of 3,6-Dihydro-1,2-oxazines by Condensation of Aldehydes in Aqueous Media

Abstract

The nonreductive cleavage of a model 3,6-dihydro-1,2-oxazine by condensation of 2,2-dimethoxyacetaldehyde under aqueous conditions is investigated. Depending on the pH of the solution, the reaction leads either to the N-acylated 1,4-amino alcohol or to the corresponding stable hemiaminal. The formation of the former is believed to proceed through iminium to oxaziridine rearrangement and not through enamine formation, as confirmed by the use of nonenolizable aldehydes. This procedure allows a very mild, nonreductive cleavage of N–O bonds.

Key words

nitrogen - imines - ring opening - aldehydes - heterocycles

• References and Notes

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• 14 Typical Experimental ProcedureTo a solution of 3,6-dihydro-1,2-oxazine (2, 51 mg, 0.46 mmol) in aq pH 3 buffer solution (2 mL) was added aq 2,2-dimethoxyacetaldehyde solution (60% solution, 0.16 mL, 1.05 mmol, 2,3 equiv). The solution was stirred in an open flask at 50 °C for 48 h, then cooled and concentrated in vacuo. The residue was triturated with CH₂Cl₂ (5 mL). After filtration and concentration, the residue was purified by chromatography (10% MeOH–CH₂Cl₂).
• 15 Data for Hemiaminal 5 Yellow oil, mixture of stereoisomers, yield 33% (33 mg, 0.15 mmol). ¹H NMR (360 MHz, CDCl₃): δ = 6.76–6.65 (1 H, br s, NH), 5.96 (1 H, d, J = 10.0 Hz), 5.75 (1 H, dt, J = 10.0, 3.2 Hz), 4.57 (1 H, d, J = 3.2 Hz), 4.49 (1 H, m), 4.23 (1 H, q), 4.12 (1 H, d, J = 3.2 Hz), 3.53 (3 H, s), 3.52 (3 H, s), 2.00–1.60 (4 H, m) ppm. ¹³C NMR (62.5 MHz, CDCl₃): δ = 132.9, 131.6, 130.2, 127.2 (stereoisomers), 104.8 and 99.9 (stereoisomers), 71.9 and 71.7 (stereoisomers), 68.4 and 68.3 (stereoisomers), 56.5, 56.3, 53.9, 53.3 ­(stereoisomers), 48.6 and 44.7 (stereoisomers), 28.9, 25.2, 24.6, 2.31 (stereoisomers) ppm. ESI-HRMS: m/z calcd for ­C₁₁H₁₉NO₅Na [MNa⁺ – MeOH + AcOH]: 268.1161; found: 268.1154.
• 16 Data for Amide 6 Brown oil, yield 33% (33 mg, 0.15 mmol). ¹H NMR (360 MHz, CDCl₃): δ = 6.73–6.57 (1 H, br s, NH), 5.95 (1 H, ddd, J = 10.0, 3.3, 2.0 Hz), 5.74 (1 H, dd, J = 10.0, 2.0 Hz), 4.71 (1 H, s), 4.49 (1 H, m), 4.23 (1 H, m), 3.42 (3 H, s), 3.41 (3 H, s), 1.98–1.83 (2 H, m), 1.81–1.67 (2 H, m), 1.63 (1 H, br s) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 167, 133.1, 130.0, 99.9, 64.3, 53.8, 53.7, 44.3, 28.9, 25.2 ppm. ESI-HRMS: m/z calcd for C₁₁H₁₇NO₅Na [MNa⁺ – MeOH + AcOH]: 266.1034; found: 266.1030.
• 17 Data for Amide Epimer 7 Colorless oil, yield 33% (33 mg, 0.15 mmol). ¹H NMR (360 MHz, CDCl₃): δ = 7.20–7.00 (1 H, br d, J = 6.0 Hz, NH), 5.93 (1 H, dt, J = 10.0, 3.5 Hz), 5.85 (1 H, m), 4.73 (1 H, s), 4.12 (1H, br t), 4.08 (1 H, m), 3.42 (3 H, s), 3.41 (3 H, s), 2.19 (2 H, m), 1.87 (1 H, br s), 1.84–1.78 (2 H, m) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 167, 131.8, 127.1, 99.9, 64.9, 53.9, 53.6, 48.6, 24.7, 23.0 ppm. ESI-HRMS: m/z calcd for C₁₁H₁₇NO₅Na [MNa⁺ – MeOH + AcOH]: 266.1034; found: 266.1029.