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Synlett 2003(6): 0805-0808
DOI: 10.1055/s-2003-38732
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical Route for the Preparation of Substituted 6-oxo-2-Hexenoate Derivatives

Marta Freiríaa, Andrew J. Whiteheadb, William B. Motherwell*a
a Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon St., London, WC1H 0AJ, UK
b Chemical Development Division, GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Fax: +44(207)6797524; e-Mail: w.b.motherwell@ucl.ac.uk;
Further Information

Publication History

Received 21 February 2003
Publication Date:
17 April 2003 (online)

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Abstract

Reaction of 2-hydroxy-3-butenoates with a series of carbonyl derivatives gives substituted 6-oxo-2-hexenoates in good yields under mild acid conditions via Claisen rearrangement of the allyl alkenyl ether intermediate.

Key words

Claisen rearrangement - substituted hexenoates - aldehydes - β-keto esters - tandem Michael-aldol

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Typical Experimental Procedure: The 2-hydroxy-3-butenoate (20 mmol) and aldehyde (30 mmol) were dissolved in dry toluene (15 mL) at r.t. in the presence of a catalytic amount of p-toluenesulfonic acid (10 mg). The reaction was refluxed for 48 h using a Dean-Stark trap for the removal of water. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by flash chromatography [typically petroleum ether (bp 30-40 °C)-EtOAc, 80:20] to give the desired product. All new compounds exhibited spectral (1H NMR, 13C NMR, IR, MS) and analytical (HRMS) data fully consistent with the assigned structures.
Spectral Data for Methyl ( E )-5,5-dimethyl-6-oxo-2-hexenoate: Rf 0.20 [Petroleum ether (bp 30-40 °C)-EtOAc, 80:20]. 1H NMR (300 MHz, CDCl3): δ = 1.14 [s, 6 H, C(CH 3)2], 2.41 (dd, 2 H, J = 7.8 Hz, J = 1.4 Hz, CH 2), 3.79 (s, 3 H, OCH 3), 5.93 (dt, 1 H, J = 15.6 Hz, J = 1.4 Hz, =CHCO2CH3), 6.93 (dt, 1 H, J = 15.6 Hz, J = 7.8 Hz, CH=CHCO2CH3), 9.60 (s, 1 H, CHO). 13C NMR (75.5 MHz, CDCl3): δ = 21.8 [C(CH3)2], 39.7 (CH2), 46.2 [C(CH3)2], 51.9 (OCH3), 124.6 (=CHCO2CH3), 144.2 (CH=CHCO2CH3), 166.8 (CO2CH3), 205.0 (CHO). FT-IR (NaCl): ν = 1803, 1730, 1645 cm-1. LRMS (EI+): m/z = 171 (50) [M+ + 1], 139 (100), 109 (79), 81 (73), 41 (33). HRMS (EI+) calcd for C9H14O3 [M+] 170.09429. Found: 170.09400.