Tailoring Activators for the Selective Reactions of Ethyl 2-(Trimethylsilyl)acetate Under Batch and Continuous Flow Conditions

The use of silicon-based reagents in organic synthesis has received significant attention and has been an ever-growing area of focus in recent years. Since Hosami and Sakurai first described the fluoride-initiated reaction of allytrimethylsilane to aldehydes, there have been several advancements in the field. Alternative sources of silicon activation have been developed such as tBu-P4 and proazaphosphotrane bases as well as work completed by my research group into the tetrabutylammonium controlled addition to aldehydes under mild conditions for a wide variety of substituted trimethylsilanes.

It was recognized that these reaction conditions could be further developed through the tailoring of tetrabutylammonium activators for use with specific trimethylsilane substrates, to provide mild and efficient routes to β-hydroxy esters and α,β-unsaturated esters. Conditions for tetrabutylammonium controlled addition and olefination reactions of ethyl 2-(trimethylsilyl)acetate were developed under both batch and continuous flow conditions, employing catalytic amounts of activator at ambient temperature.

The synthesis of a diverse range of β-hydroxy esters was achieved through the addition reactions of various aromatic, heteroaromatic, aliphatic aldehydes and ketones to ethyl 2-(trimethylsilyl)acetate using of catalytic amounts of Bu4NOAc. In parallel, conditions for the batch synthesis of the corresponding α,β-unsaturated esters using catalytic amounts of Bu4NOTMS were developed by another member of my research group. A stepwise reaction pathway to the α,β-unsaturated ester was demonstrated via formation of the silylated β-hydroxy ester and subsequent elimination reaction. The use of a specific tetrabutyl ammonium activator was key to the desired product formation. The weaker acetate activator was unable to effect the elimination, whereas it’s trimethylsilyloxide counterpart effectively completed the elimination reaction to provide α,β-unsaturated esters.

In both cases, the tetrabutylammonium counterion was shown to play a vital role in the effectiveness of the reaction. The synthesis of these β-hydroxy esters and α,β-unsaturated esters were achieved using mild conditions without the specialized precautions associated with other organometallic synthesis.

To further develop these conditions, the reactions were transferred from traditional batch style synthesis methods to continuous flow. The time required to achieve full conversion was significantly reduced for both addition and olefination reactions, from the one hour required for batch to one minute for continuous flow, while maintaining the employment of catalytic amounts of activator and the use of ambient temperature. Teaming this reduction in reaction time with the improved process safety that flow chemistry offers, highlights the significant benefits of adapting pharmaceutical synthesis from batch to continuous flow.