Intramolecular Oxidative Pd(II)-Catalyzed Alkoxylation of 3-Aza-5-alkenols with O₂ as Sole Oxidant: Mild Conditions for the Synthesis of 1,4-Oxazine Derivatives

Abstract

Synthesis of 1,4-2H-oxazine derivatives was performed by Pd(II)-catalyzed aerobic oxidative cyclization of 3-aza-5-al­kenols, prepared from easily available 1,2-amino alcohols. The ­reaction proceeds in very mild conditions with a simple catalytic system consisting of PdCl₂(MeCN)₂ in THF at room temperature with molecular oxygen as the sole stoichiometric oxidant.

palladium - heterocycles - alkenols - alkoxylation - molecular oxygen

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Experimental Procedure
A solution of 4 (1.0 mmol), PdCl₂(MeCN)₂ (0.05 mmol, 13 mg), in THF (5 mL) was stirred under oxygen atmosphere for 5 h at r.t.. The solvent was evaporated under reduced pressure. The crude mixture was diluted with brine (10 mL) and extracted with CH₂Cl₂ (2 × 25 mL). The organic layer was dried over Na₂SO₄ and the solvent removed under reduced pressure. The residue was chromatographed on a silica gel column with light PE-EtOAc (5:1) as eluent to give 5 (75%).
Data for 4-Acetyl-6-methyl-3,4-dihydro-2 H -1,4-oxazine (5) Colourless oil. IR (nujol): 1676 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.75 (3 H, s), 2.12 (3 H, s), 3.48 (2 H, t, J = 4.7 Hz), 3.55 (2 H, t, J = 4.7 Hz), 5.89 (1 H, s). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.9 (q), 22.0 (q), 43.1 (t), 64.1 (t), 98.9 (d), 137.9 (s), 163.7 (s). MS: m/z = 141 [M⁺]. Anal. Calcd for C₇H₁₁NO₂: C, 59.56; H, 7.85; N, 9.92. Found C, 59.33; H, 7.96; N, 9.88.

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Reaction conditions used to attempt the isomerization process: (i) PdCl₂ (10 mol%) in H₂O-MeOH (1:1) at 80 ˚C for 24 h; (ii) PdCl₂(TMEDA) (10 mol%) in H₂O-MeOH (1:1) at 80 ˚C for 24 h; (iii) PdCl₂(MeCN)₂ (10 mol%) in CH₂Cl₂ at r.t. for 24 h.