Solvent effects Baylis-Hillman reactions

In a different study, based on the reaction rate data collected in aprotic solvents, the Morita-Baylis-Hillman reaction has been found to be second order in aldehyde and first order in DABCO and acrylate. On the basis of these data, a new mechanism has been proposed, involving a hemiacetal intermediate (110). The proposed mechanism is further supported by two different kinetic isotope effect experiments.145... 

A related reaction known as Baylis-Hillman reaction, which also has a large negative activation volume, was found to be greatly accelerated in water, compared with usual organic solvents. The first step is the conjugate addition of a tertiary amine (l,4-diazabicyclo[2.2.2]octane DABCO) to acrylonitrile (Scheme 2) which is fast in water. The second step, which is rate-determining, is accelerated via a process wherein the hydrophobic effect could be involved. Other structured solvents also enhance the Baylis-Hillman reaction, but to a small extent [75]. 

Leadbeater, N.E. and van der Pol, C. (2001) Development of catalysts for the Baylis-Hillman reaction the application of tetramethylguanidine and attempts to use a supported analogue. Journal of the Chemical Society - Perkin Transactions 1, 2831-2835 Graunger, R.S., Leadbeater, N.E. and Pamies, M.A. (2002) The tetramethylguanidine catalysed Baylis-Hillman reaction effects of co-catalysts and alcohol solvents on reaction rate. Catalysis Communications, 3, 449-452. 

The Baylis-Hillman reaction of optically pure azetidine-2,3-diones [235, 236] with methyl vinyl ketone in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) in acetonitrile at 20°C for 1 h have been reported to give functionalized allylic alcohols, having the (3-lactam scaffold, in good yields (80%) and complete diastereoselectivity [237]. In terms of achieving good yields with a reasonable rate of reaction, 50 mol% of DABCO seemed to be the catalyst amount of choice for this reaction. No significant solvent effect was observed in the overall yield (Scheme 108). 

The Baylis-Hillman reaction involves the reaction of an aldehyde with an a,fi-unsaturated ketone in the presence of a tertiary amine. This results in the aldehyde adding at the a-position of the carbon-carbon double bond. The reaction is conventionally carried out without a solvent however this causes problems if the starting materials are solids. Hence the reaction was investigated in ionic liquids such as [BMIM][BF4] and [BMIMjjPFe] [210]. The reaction of methyl acrylate with ben-zaldehyde proceeded 11 to 34 times faster in the ionic liquids than in the solvent acetonitrile. Various Lewis acidic additives had little effect on the reaction, with the exception of lithium perchlorate, which gave a 53 times rate enhancement. This reaction is shown in Scheme 5.2-85. 

The kinetics of the aza-Morita-Baylis-Hillman reaction have been studied for a range of imine substrates in various solvents, using triphenylphosphine as catalyst, and p-nitrophenol as a Brpnsted acid co-catalyst. The effects of varying the phosphineiphenol catalyst ratio on the rate indicate interdependence between them. This and the solvent effects support reversible protonation of zwitterionic intermediates within the mechanism. ip-NMR and quantum calculations also support such a route. 

The catalytic effect of alkylmethylimidazolium ionic liquids as solvents for the Baylis-Hillman reaction has been investigated by DFT, using benzaldehyde, substrate and DABCO as base. 3-Substituted 3-hydroxy-2-oxindoles (76, n = 0, 1) have been prepared in water via an MBH reaction of unprotected isatins with cyclic enones. Bicyclic imidazolyl alcohol (77) is a particularly good catalyst, with its hydroxyl group proposed to stabilize the betaine intermediate. 

Baylis-Hillman reaction of an aldehyde with an a.y -unsaturated carbonyl compound is catalysed by l,4-diazabicyclo[2.2.2]octane (DABCO) a zwitterionic intermediate (60) is proposed. Lithium perchlorate is found to accelerate the reaction further (in diethyl ether solvent), presumably through further stabilization of such a species. The effect is not seen with most other metal salts, presumably because they cannot act as efficient, independent co-catalysts in the presence of a tertiary amine. 

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