Heck Reactions of Crotonaldehyde

Abstract

A direct method for the synthesis of β,β-disubstituted-α,β-unsaturated aldehydes via Heck reaction of aryl halides with crotonaldehyde and related substrates has been developed. The reaction provides rapid access to products usually prepared via multistep sequences. The power of the method in combination with an organocatalytic transfer hydrogenation is illustrated with a short asymmetric synthesis of (S)-Florhydral^®.

Key words

Heck reaction - unsaturated aldehydes - palladium - arylations - cross-coupling - crotonaldehyde

References and Notes

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11

Representative Experimental Procedure for the Heck Reaction of Crotonaldehyde (Table 1, Entry 2)
4-Bromotoluene (256.4 mg, 1.5 mmol), TBACl (438 mg, 1.57 mmol), and NaOAc (148 mg, 1.80 mmol) were suspended in NMP (8 mL). Palladium acetate (6.8 mg, 0.03 mmol) in NMP (4 mL) was added, followed by croton-aldehyde (250 µL, 3 mmol). Oxygen was removed by two cycles of freeze-pump-thaw. The mixture was then heated at an oil-bath temperature of 90 °C for 75 min. After being cooled, the reaction mixture was poured into a half-concentrated aqueous solution of NaHCO₃ (80 mL) and extracted three times with CH₂Cl₂ (120 mL in total). The combined organic fractions were washed with brine once, dried over MgSO₄, and concentrated under reduced pressure. The resulting solution in NMP was directly loaded onto a column packed with silica gel and eluted with Et₂O-pentane (15:85, v/v) to yield the product in fractions of pure E- and Z-isomers (70% combined yield).