Synthesis of N,O-Heterocycles by Intramolecular Conjugate Addition of a Hydroxylamine

Abstract

Isoxazolidines and tetrahydro-1,2-oxazines were produced by a tandem deprotection-intramolecular Michael addition of hydroxylamines. For tetrahydrooxazine formation, high stereoselectivity was observed, even when a quaternary centre was formed.

Keywords

Michael addition - hydroxylamine - oxazine

References and Notes

• 1 Perlmutter P. Conjugate Addition Reactions in Organic Synthesis   Pergamon Press; Oxford: 1992. 
• 2 For some examples of isoxazolidines, see: Bates RW. Sa-Ei K. Tetrahedron  2002,  58:  5957 
• 3 Bates RW. Sa-Ei K. Org. Lett.  2002,  4:  4225 
• 4a Janza B. Studer A. Synthesis  2002,  2117 
• 4b Tiecco M. Testaferri L. Marini F. Sternativo S. Santi C. Bagnoli L. Temperini A. Tetrahedron: Asymmetry  2001,  12:  3053 
• 5a Connon SJ. Blechert S. Angew Chem. Int. Ed.  2003,  42:  1900 
• 5b Vernall AJ. Abell AD. Aldrichimica Acta  2003,  36:  93 
• For applications of this combination of reactions to the synthesis of tetrahydropyrans, see:
• 6a Bressy C. Allais F. Cossy J. Synlett  2006,  3455 
• 6b Bates RW. Song P. Tetrahedron  2007,  63:  4497 
• 7 Grochowski E. Jurczak J. Synthesis  1976,  682 
• 8 This is considered to be much lower than typical loadings: Namba K. Wang J. Cui S. Kishi Y. Org. Lett.  2005,  7:  5421 
• 12 For a discussion of cross-metathesis of different classes of alkenes, see: Chatterjee AK. Choi TL. Sanders DP. Grubbs RH. J. Am. Chem. Soc.  2003,  125:  11360 
• 13 Banwell MG. Bui CT. Pham HTT. Simpson GW. J. Chem. Soc., Perkin Trans. 1  1996,  967 

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Typical Procedure: A solution of alkene 5 (207 mg, 0.67 mmol), Grubbs second generation catalyst (11 mg, 2 mol%) and methyl acrylate (182 µL, 2.02 mmol) in CH₂Cl₂ (2 mL) was heated at reflux under nitrogen for 3 h. The mixture was then cooled and the volatiles were removed under reduced pressure. The mixture was purified by column chromatography on silica gel eluting with 10-20% EtOAc in hexane to give the ester 7a as a solid (237 mg, 97%). ¹H NMR (300 MHz, CDCl₃): δ = 7.65 (m, 4 H, Ar), 7.39 (m, 2 H, Ar), 7.26 (m, 3 H, Ar), 6.99 (dt, J = 6.5, 15.5 Hz, 1 H, H3), 5.87 (d, J = 15.5 Hz, 1 H, H2), 5.31 (t, J = 6.5 Hz, 1 H, H6), 3.72 (s, 3 H, OMe), 2.32 (m, 3 H, H4, H5), 2.00 (m, 1 H, H5).

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Typical Procedure: Hydrazine hydrate (78 µL, 1.6 mmol) was added to a solution of phthalimide 7a (195 mg, 0.53 mmol) in CH₂Cl₂ (2 mL). The mixture was stirred for 15 min, and then filtered through a pad of celite to remove the copious colourless precipitate. The filtrate was evaporated to give the oxazine 10a as an oil (122 mg, 98%). ¹H NMR (300 MHz, CDCl₃): δ = 7.23 (m, 5 H, Ph), 5.30 (br s, 1 H, NH), 4.55 (dd, J = 11.2 Hz, 1 H, H6), 3.70 (s, 3 H, OMe), 3.44 (m, 1 H, H3), 2.45 (dd, J = 16.8, 4.7 Hz, 1 H, CHHCO₂Me), 2.37 (dd, J = 16.8, 8.5 Hz, 1 H, CHHCO₂Me), 1.50-2.00 (m, 4 H, H4, H5). Compound 10c was prepared analogously. ¹H NMR (300 MHz, CDCl₃): δ = 7.80 (m, 2 H, Ar), 7.50 (m, 3 H, Ar), 7.20 (m, 5 H, Ar), 6.40 (br s, 1 H, NH), 4.59 (dd, J = 10.7, 2.3 Hz, 1 H, H6), 3.59 (ddt, J = 10.9, 8.8, 2.8 Hz, 1 H, H3), 3.14 (dd, J = 14.5, 9.0 Hz, 1 H, CHHSO₂Ph), 3.03 (dd, J = 14.5, 3.0 Hz, 1 H, CHHSO₂Ph), 1.50-1.90 (m, 4 H, H4, H5).

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The corresponding alcohol is prepared by the reaction between styrene oxide and vinyl magnesium bromide in Et₂O. We thank Professor David Knight, University of Cardiff, for this procedure.