FULL PAPER DOI: 10.1002/ejoc.200701112 First Evidence of Proline Acting as a Bifunctional Catalyst in the Baylis– Hillman Reaction Between Alkyl Vinyl Ketones and Aryl Aldehydes Michelangelo Gruttadauria,* [a] Francesco Giacalone, [a] Paolo Lo Meo, [a] Adriana Mossuto Marculescu, [a] Serena Riela, [a] and Renato Noto [a] Keywords: Aldehydes / Baylis–Hillman reactions / Organocatalysis / Proline / Reaction mechanisms / Semi-empirical calculations Proline in the presence of sodium hydrogen carbonate has been found to be an effective catalyst for the Baylis–Hillman reaction between methyl or ethyl vinyl ketone and aryl alde- hydes. Screening of several amine catalysts showed that an ionizable carboxylic function directly linked to the secondary amine catalyst plays an important role in the synthesis of the desired product in good yield. The data obtained has allowed us to suggest, for the first time, that proline, sarcosine, pipec- Introduction The Baylis–Hillman reaction is a versatile and atom-eco- nomical carbon–carbon bond-forming reaction which has attracted huge interest in the scientific community. [1–6] This reaction involves the amine- (or phosphane-)catalysed [7] ad- dition of an aldehyde to an activated alkene, such as alkyl vinyl ketones, alkyl (aryl) acrylates, acrylonitrile and vinyl sulfones. Scheme 1 shows the commonly accepted mecha- Scheme 1. DABCO-catalysed Baylis–Hillman reaction. [a] Dipartimento di Chimica Organica “E. Paternò”, Università di Palermo, Viale delle Scienze, Pad. 17, 90128, Palermo, Italy Fax: +39-091-596825 E-mail: mgrutt@unipa.it Supporting information for this article is available on the WWW under http://www.eurjoc.org or from the author. Eur. J. Org. Chem. 2008, 1589–1596 © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1589 olinic acid and homoproline may act as bifunctional catalysts via a bicyclic enaminolactone species as intermediate. Quan- tum-mechanical calculations (PM3/COSMO and ab initio 3- 21G/COSMO) support this mechanism and give more insight into the role of hydrogen carbonate. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) nism for the model Baylis–Hillman reaction between methyl vinyl ketone and benzaldehyde in the presence of DABCO as catalyst. The first step involves the reversible conjugate addition of the nucleophilic amine to the α,β-unsaturated ketone to generate an enolate. The second step involves the nucleo- philic attack of the enolate on the aldehyde to generate a zwitterionic intermediate. Finally, proton migration (step 3) and elimination (step 4) afford the product and regenerate the amine catalyst. Protic solvents are known to accelerate the reaction, whereas in the absence of any proton donor the reaction shows autocatalysis. [8] It has been proposed that the product can act as a hydrogen-bond donor. Thus, in the initial stage of the reaction, step 3 is the rate-limiting step. As the product concentration increases, the proton- transfer mechanism becomes efficient and step 2 becomes rate-limiting. Aggarwal et al. proposed that in the presence of a protic species (product or solvent) the zwitterionic in- termediate is involved in a proton-transfer reaction that fa- cilitates the formation of the product (Scheme 2). [9] Scheme2. Role played by protic solvents in the Baylis–Hillman re- action. [9]