METAL-ACCELERATED AND LIGAND-ACCELERATED CATALYSIS OF THE BAYLIS-HILLMAN REACTION

The Baylis-Hillman reaction, the coupling of an unsaturated carbonyl c ompound/nitrile with aldehydes, is a valuable reaction but is limited in its practicality by poor reaction rates. We have endeavored to acce lerate the reaction using Lewis acids and found that while conventiona l Lewis acids gave reduced rates group III, and lanthanide triflates ( 5 mol %) gave increased rates. The optimum metal salts were La(OTf)(3) and Sm(OTf)(3), which gave rate accelerations (k(rel)) of approximate ly 4.7 and 4.9, respectively, in reactions between tert-butyl acrylate and benzaldehyde when using stoichiometric amounts of DABCO. At low l oadings of DABCO (up to 10 mol %), no reaction occurred due to associa tion of DABCO with the metal. Use of additional ligands to displace th e DABCO from the metal was studied, and the rate of reaction was found to increase further in most cases. Of the ligands tested, at 5 mol %, (+)-binol gave one of the largest rate accelerations (3.4-fold) and w as studied in more detail. It was found that reactions occurred even a t low DABCO concentration so that here the Lewis base and Lewis acid w ere able to promote the reaction without interference from each other. While the (+)-binol (and other chiral ligands) failed to provide any significant asymmetric induction, a substantial nonlinear effect was o bserved with binol. Thus, use of racemic binol gave no effect on the r ate. In seeking to maximize the rate attainable, more soluble (liquid) ligands were studied. Diethyl tartrate and triethanolamine gave rate enhancements of 5.2x and 3.5x at 50 mol %, respectively, versus 1.5x a nd 2.3x at 5 mol %. The best protocol was to use 100 mol % DABCO, 50 m ol % triethanolamine, and 5 mol % La(OTf)(3). This gave overall rate a ccelerations of between 23-fold and 40-fold depending on the acrylate and approximately 6-fold for acrylonitrile. A simple acid wash removed the reagents, leaving the product in the organic phase. While trietha nolamine accelerated the reaction without the lanthanum triflate (18-2 2-fold at 80 mol %), the reaction in the presence of the metal salt wa s faster. The system was tested synthetically on various substrates an d found to give good rate accelerations with both activated (benzaldeh yde and p-nitrobenzaldehyde) and less activated aldehydes (anisaldehyd e and cyclohexanecarboxaldehyde) with acrylates. The limited amount of dimerized acrylate in the latter reactions is noteworthy and should e xtend the range of substrates that can be made by the Baylis-Hillman r eaction using our optimum conditions.