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Recently, we have reported on the synthesis of anisole derivatives from 4-alkylidene-2-cyclohexene-1-ones with iodine in methanol. 4-Alkylidene-2-cyclohexene-1-ones could be synthesized from the reaction of Baylis-Hillman acetates and 2,4-pentanedione according to the reported procedure by Chamakh and Amri. We and other groups have reported the selective introduction of nucleophiles at the secondary benzylic position of the Baylis-Hillman acetates via the corresponding DABCO salts. Thus, we envisioned that we could prepare 4-methylene-2-cyclohexenone skeleton and para-methoxymethyl anisoles by combining the DABCO salt concept and the aromatization reaction with iodine in methanol. Suitably substituted anisoles are useful as the starting materials for the fragrances, dyes and pesticides, as antioxidants in oils and fats, or as stabilizers of plastics. Moreover, paramethoxymethyl anisoles have been used for the kinetic acetalization of diol or amino alcohol systems in the presence of DDQ during the synthesis of (+)-FR900482, taxotere side chain, cyclopropyl lactone oxylipins, and erythromycin A. Our synthetic scheme for the synthesis of 4-methylene-2cyclohexenone skeleton and para-methoxymethyl anisole is shown in Scheme 1 by using 4a and 5a as the representative examples. The reaction of the Baylis-Hillman acetate 1a and DABCO in aqueous THF gave the corresponding DABCO salt 2a instantaneously as reported. The reaction of the DABCO salt 2a and 2,4-pentanedione afforded the intermediate 3a in moderate yield (44%). During the synthesis of 3a, some side products were produced (including dihydropyran skeleton), which diminished the yield of 3a. With the compound 3a in our hand, we examined the next conversion toward 4-methylene-2-cyclohexeneone 4a by using the Amri’s conditions (K2CO3 in ethanol) and we could prepare 4-methylene-2-cyclohexenone 4a in good yield (72%). The synthesis of 4a was tried by using the modified conditions in order to improve the yield of 4a as follows. In situ generation of the DABCO salt 2a in ethanol and the following reaction with 2,4-pentanedione in the presence of K2CO3 gave 4a in a similar isolated yield (47%) (Scheme 1). The use of ethyl acetoacetate instead of 2,4-pentanedione also gave 4a in lower yield (not shown in Scheme 1). The structure of 4a was confirmed as shown in Table 1 by NOE experiments. As an example, irradiation of the methyl group (δ = 2.11 ppm) of 4a showed increments of the proton at the 2-position (δ = 6.00 ppm) and one of the methylene protons (δ = 5.51 ppm) in 0.6 and 0.7%, respectively. As the final step, the reaction of 4a and iodine (1.1 equiv.) in methanol (40-50 C) afforded methoxymethyl anisole 5a in good yield (84%). Similarly, 5c and 5e were synthesized in good yields from 4b and 4c. As shown in Table 1, the use of ethanol as the solvent afforded the ethoxymethyl phenetole derivatives

Synthesis of 4-Methylene-2-cyclohexenones and Their Aromatization Reaction toward para-Methoxylmethyl Anisole Derivatives