Remarkable Rate Acceleration of Baylis-Hillman Reaction of Notorious α,β-Unsaturated Aldehydes Catalyzed by Proton Donor

The Baylis-Hillman reaction is an efficient carbon-carbon bond-forming reaction between aldehyde and α,β-unsatu-rated carbonyl compound catalyzed by a tertiary amine such as DABCO.1 However, the reaction has suffered from low reaction rates and yields in many aldehydes.2,3 Especially the Baylis-Hillman reaction of cinnamaldehyde and its derivatives is notorious.2 As an example, the highest yield of Baylis-Hillman adduct of cinnamaldehyde is at best 66% even though a variety of ways have been examined.2a-f The situation is more severe for the Baylis-Hillman adducts of α-substituted cinnamaldehyde, crotonaldehyde, and β-sub-stituted crotonaldehyde. The yields in these entries remained extremely low (13-31%) until now.2b,f,g During our recent studies, various Baylis-Hillman adducts were required of α,β-unsaturated aldehydes.4 However, the reaction of α-methylcinnamladehyde under normal condi-tions (cat. DABCO, rt) with methyl acrylate did not produce any trace amounts of the desired Baylis-Hillman adduct even after 7 days. Similarly, the reactions of p-methoxy-cinnamaldehyde and β-phenylcinnamaldehyde were very sluggish. Thus we decided to develop an efficient protocol for the Baylis-Hillman reaction of cinnamaldehyde and its derivatives. The rate-determining step of the Baylis-Hillman reaction is the reaction between the ammonium enolate I and the aldehyde,5a,d-f as shown in Scheme 1. Thus, increasing the amount of the enolate, activation of the aldehyde, or stabili-zation of the zwitterion II would increase the reaction rate. In this context, various proton donors5,6 and Lewis acids5i-k have been known to increase the reaction rate by stabilizing the zwitterion II. Thus, we carried out the reaction of α-methylcinnam-aldehyde (1a) with methyl acrylate in the presence of DABCO (50 mol %) and various proton donors, as shown i