Synlett 2008(7): 1042-1044  
DOI: 10.1055/s-2008-1072650
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Roderick W. Bates*a, Robert H. Snella, SusAnn Winbushb
a Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
e-Mail: roderick@ntu.edu.sg;
b Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
Further Information

Publication History

Received 20 August 2007
Publication Date:
28 March 2008 (online)

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.

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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.