Baylis-Hillman Reaction on the Solid Phase

Prien et al. [18] have synthesized 3-hydroxy-2-methylidene propionic acids on hydrox-yethyl resin via a Baylis-Hillman reaction by using aldehydes bearing electron-withdrawing groups, for example nitrobenzaldehyde, trifluoromethylbenzaldehyde and pyridine-carboxaldehyde. 

In the solid-phase Baylis-Hillman reaction developed in our group [19] resin-bound acrylic ester reacted with aldehydes to form 3-hydroxy-2-methylidene-propionic acids, or with aldehydes and sulfonamides in a three-component reaction to form 3-aminoaryl-2-methylidene sulfonylpropionic acids [20] (Fig. 6.4). 

We chose 2-chlorotrityl chloride resin for the attachment of acrylic acid, because in solution-phase chemistry the best results have been obtained by using aryl acrylates or (erf-butyl acrylates [21], In addition to DABCO (1,4-diazabicyclo [2.2.2]octane) - the most common tertiary cyclic amine for this type of reaction - we also used the more reactive 3-quinuclidinol (3-hydroxy-quinuclidine, 3-HQN) for the Baylis-Hillman reaction with aldehydes. We used 26 different aldehydes and obtained good to excellent purities, as determined by analytical HPLC. 

The three-component Baylis-Hillman reaction was also performed on 2-chlorotrityl chloride resin by treating polymer-bound acrylic acid with aldehydes and sulfonamides in dioxane at 70 °C for 16 h under DABCO catalysis (Fig. 6.4). Both scaffolds, 3-hydroxy-2-methylidene propionic acids as well as 2-methylidene-3-aminoarylsulfonyl-propionic acids, are precursors for the synthesis of MCSLs. 

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