Acetic Acid → Methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate

Participants

Reaction Steps

A solution of 6-iodochroman (13.8 g, 53.1 mmol) in tetrahydrofuran (THF) (143 mL) was cooled to −78° C. in a dry ice/acetone bath and then treated with n-BuLi, 2.5M solution in hexanes (23.35 mL, 58.4 mmol). The mixture was stirred for 10 minutes before being treated with N,N-dimethylformamide (6.16 mL, 80 mmol) and the resultant was warmed to ambient temperature and stirred for 10 minutes. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude chroman-6-carbaldehyde as a yellow solid which was used without further purification. LC/MS (m/z) ES+=163.22 (M+1). A solution of the crude chroman-6-carbaldehyde, methyl 3-oxobutanoate, piperidine (0.263 mL, 2.66 mmol) and AcOH (0.152 mL, 2.66 mmol) in Benzene (113 mL) was refluxed (DS-trap) overnight. The mixture was concentrated and diluted with ethyl acetate. The dilution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-30% hexanes/ethyl acetate) the afford methyl 2-(chroman-6-ylmethylene)-3-oxobutanoate (mixture of E and Z isomers, 8.352 g, 32.08 mmol, 60.47% yield) as a thick yellow oil. 1H NMR (400 MHz, CHLOROFORM-d, major isomer) δ ppm 7.48 (s, 1 H), 7.22-7.12 (m, 2 H), 6.78 (d, J=8.6 Hz, 1 H), 4.27-4.18 (m, 2 H), 3.92-3.81 (m, 3 H), 2.77 (t, J=6.3 Hz, 2 H), 2.39 (s, 3 H), 2.06-1.99 (m, 2 H); 1H NMR (400 MHz, CHLOROFORM-d, minor isomer) δ ppm 7.58 (s, 1 H), 7.16-7.08 (m, 2 H), 6.79-6.71 (m, 1 H), 4.23-4.18 (m, 2 H), 3.84-3.78 (m, 3 H), 2.76 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.03-1.96 (m, 2 H); LC/MS (m/z) ES+=261.2 (M+1).

Provenance & Evidence