A Practical and Stereoselective Synthesis of Cinnamyl Alcohols Bearing α-Cyano or α-Ester Functional Group from Baylis-Hillman Adducts

Abstract

Cinnamyl alcohols bearing ester, acid, or nitrile functional group at the 2-position are very useful synthons for the synthesis of various biologically important compounds. Synthesis of cinnamyl alcohol derivatives from the BaylisHillman adducts has been reported by us and other groups. The conversion can be carried out directly by using 20% aqueous sulfuric acid (for the Baylis-Hillman adducts derived from acrylonitrile) or trifluoroacetic acid (for the Baylis-Hillman adducts derived from acrylates). Recently, Basavaiah and coworkers have reported the two-step, onepot conversion method: TMSOTf-assisted conversion of Baylis-Hillman alcohol into the corresponding primary acetate with acetic anhydride and the following partial hydrolysis with K2CO3 in methanol. In the above chemical transformation, the conversion of secondary acetate into the primary one is the key step. Rearrangement of secondary acetate into the primary one was conducted by following reaction conditions such as DABCO/THF/reflux, montmorillonite K10 clay/microwave, and TMSOTf (cat.)/CH2Cl2. Direct conversion of BaylisHillman alcohol into the corresponding primary acetate can be carried out by the Basavaiahs method: acetic anhydride in the presence of TMSOTf. However, TMSOTf is a moisturesensitive and somewhat expensive reagent. During the preparation of Baylis-Hillman acetate, we found that the use of acetic anhydride in the presence of a catalytic amount of sulfuric acid in CH2Cl2 afforded directly the corresponding primary acetate in excellent yield. In these regards we envisioned that we could develop the more convenient and practical method to convert the BaylisHillman alcohol into the primary acetate or eventually to primary alcohol (Scheme 1 and Table 1). The reaction of Baylis-Hillman adducts with acetic anhydride (1.5 equiv.) in the presence of sulfuric acid (10 mol%) gave the corresponding rearranged cinnamyl acetates quantitatively in dichloromethane at room temperature within 30 min (Actually, the cinnamyl acetate derivatives could be isolated in 92-95% yields.). In order to obtain the corresponding cinnamyl alcohols in a one-pot we tried some reaction conditions for the next partial hydrolysis. Addition of water to the reaction mixture (two-phase system) afforded the hydrolyzed cinnamyl alcohols in trace amounts. The use of THF instead of CH2Cl2 showed better results in the hydrolysis step. However, neither the acetylation in THF nor the subsequent acidic hydrolysis in aq. THF was efficient. As a next choice, we used methanol as solvent after the formation of rearranged acetate in CH2Cl2 and added K2CO3. However, this process showed incomplete reaction and produced some side products. Thus, we finally adapted the two-step procedure involving the well-known hydrolysis protocol, K2CO3 in methanol, after simple workup process of the primary acetates (vide infra). The representative examples are shown in Table 1. As shown in Table 1, the method can be applicable to both of the Baylis-Hillman adducts derived from acrylates or acrylonitrile. The yields are higher than the reported in all cases. The formation of the cinnamyl alcohols is highly stereoselective (E for the ester and acetyl derivatives and Z for the nitrile analogs) as reported. The method has some advantages over the previous methods: (1) higher yields in