Efficient Baylis−Hillman Reaction Using Stoichiometric Base Catalyst and an Aqueous Medium

Abstract

A practical and efficient set of conditions were developed using stoichiometric base catalyst, 1,4-diazabicyclo[2,2,2]octane (DABCO), and an aqueous medium to overcome problems commonly associated with the Baylis--Hillman reaction, such as low reaction yields and long reaction time. These simple modifications to the classical conditions, using more base catalyst and an aqueous medium, proved to be successful in converting a variety of aliphatic and aromatic aldehydes to their corresponding Baylis--Hillman products. The inclusion of environmentally friendly water in the reaction solvent was critical for achieving the high yield of Baylis--Hillman adducts. Our deuterium-exchange experiments suggest that the Michael addition adduct formed between DABCO and methyl acrylate is the active intermediate for the Baylis--Hillman reaction in aqueous conditions, and its hydrolysis, a nonproductive side reaction facilitated by the quaternary ammonium ion, leading to the formation of a stable betaine product, consumes both the catalyst and methyl acrylate, making it necessary to add more base catalyst and methyl acrylate.

Biosynthesis of Violacein, Structure and Function of l-Tryptophan Oxidase VioA from Chromobacterium violaceum

“…IEA and racemic IAA were synthesized from indole and methyl 2-(bromomethyl)acrylate (1) following a procedure from Holzapfel et al (27). Methyl 2-(bromomethyl) acrylate was obtained in two steps from methyl acrylate and paraformaldehyde, followed by bromination with PBr 3 (28,29). Reduction of the methylene group was performed using magnesium in MeOH, and saponification of the corresponding esters 2 and 4 led to the desired products in good yields (Fig.…”

Novel aprotic polar solvents for facile Baylis-Hillman reaction

“…Indeed, the rate of reaction of aldehydes 3 and 4 with a and the yields of the products were found to be much higher in sulpholane than in an aqueous medium. 6 Importantly, the hydrolysis of acrylate and its excess usage was avoided by employing these reaction conditions.…”

“…7 However, recent conditions employing DABCO in aqueous conditions 6 or protic solvent (MeOH) under the influence of microwave 13 or novel base 14 resulted in moderate to high yields of adducts, but only with select aldehydes. Since N-methylmorpholine is commercially used as a solvent apart from other uses, 11 reaction of acrylamide with aldehydes (2, 5, 7, 9-13) in N-methylmorpholine as solvent catalyzed by standard base (DABCO) at room temperature is conceived as an attractive proposition.…”

“…Particularly to bring the less reactive aldehydes like aliphatic aldehydes into the purview of this reaction, dioxane:water 6 solvent system played a crucial role. Similarly, towards this endeavor, sulpholane 7 was another important addition from our laboratories.…”

The Baylis-Hillman reaction of substituted aminomethylbenzotriazoles

“…hydroxyl (or amino), alkene, and electron-withdrawing groups, make Baylis-Hillman adducts valuable intermediates in Friedel-Crafts [6][7][8] and Heck reactions, 9,10 hydride addition, 11,12 hydrogenation, [13][14][15][16] aminohydroxylation, 17 radical 18,19 and photochemical reactions 20 and 1,3-dipolar cycloaddition. 21 Numerous chemical and physical methods have been developed [22][23][24][25][26][27] to accelerate the BaylisHillman reaction, overcoming traditional slow reaction rates (weeks or months). 28 [35][36][37][38] Aminomethylbenzotriazoles 1 are useful synthetic intermediates 39 in which the methylene carbon is highly electrophilic because of equilibrium with the benzotriazolide-iminium ion pair 2 (Scheme 1).…”