Synthesis of 2,5-Dimethoxy-4-methyl-propenylbenzene
(a) With 1 Equiv of Base.
Ethyltriphenylphosphonium bromide (11.10 g, 0.03 mol) in 50 mL of dry THF was stirred under a N2 atmosphere with 3.36 g (0.03 mol) of commerical potassium tert-butoxide. The mixture was stirred for 2 h, resulting in an orangered colored solution. A solution of 2,5-dimethoxy-4-methylbenzaldehyde (5.40 g, 0.03 mol) in 25 mL of dry THF was added dropwise to the reaction mixture. As the addition proceeded, the color changed to bright yellow. The mixture was stirred a t room temperature for 0.5 h and refluxed overnight under an N2 atmosphere. The reaction mixture was filtered, diluted with water, and extracted three times with CHCl3 The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was taken up into a minimum of Et20, and the solution was decanted to remove triphenylphosphine oxide, which separated as a solid. The solid was washed with ether, and the combined ether solutions were concentrated and passed through a short silica gel column eluted with ethyl acetate-hexane (l:l), to remove remaining traces of triphenylphosphine oxide. The required olefin, along with some unreacted aldehyde, was rapidly eluted from the column. Concentration of this material gave a residue, which was taken up into 10 mL of EtOH and treated with 10 mL of saturated NaHSO, solution. The bisulfite adduct was removed by filtration and was repeatedly washed with ether. The combined filtrate and washings were concentrated to give the required product as a yellow liquid: yield 3.56 g (62%); bp 110-125°C (0.15 mm); GC analysis indicated the product to be 72% Z isomer and 28% E isomer.
(b) With 2 Equiv of Base.
The Wittig reaction was repeated as above but using 2 equiv of potassium tert-butoxide. Thus, 5.4g (0.03 mol) of the aldehyde and 11.1 g (0.03 mol) of ethyltriphenylphosphonium bromide with 6.72 g (0.06 mol) of potassium tert-butoxide yielded, after distillation, 2.89 g (50%) of the pure olefin, bp 105-110°C (0.05 mm). GC analysis showed it to be 97% E and 3% Z.
Reference: J. Med. Chem. 25, 526-530 (1982)