Tailoring Activators for the Selective Reactions of Ethyl 2-(Trimethylsilyl)acetate Under Batch and Continuous Flow Conditions
2020
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.
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