Executive Summary : | Fluorination is an important tool in fine-tuning the pharmacokinetic and pharmacological properties of drugs and lead compounds due to the comparable size of fluorine with hydrogen but with the highest electronegativity. Despite the increasing demand for fluorinated organic molecules, there are very limited methodologies are known so far for the incorporation of trifluoromethyl group in organic molecules. Trifluoromethylation of α,β-unsaturated ketones, esters, thioesters, and amides have been studied so far. However, to the best of our knowledge, trifluoromethylation of α,β-unsaturated aldehydes is not known in the literature. As compared to the other α,β-unsaturated compounds, α,β-unsaturated aldehydes provide easy access to multiple functionalizations and the simplicity in the functional group interconversion such as to alcohol (using NaBH₄) and to carboxylic acid (using NaClO₂). Hence, we propose to study the reaction of α,β-unsaturated aldehydes with trifluoromethylation reagent such as Togni’s reagent to achieve trifluoromethylated α,β-unsaturated aldehydes. Although there is a possibility of multiple regioisomeric products in this reaction, our preliminary result shows the formation of β-trifluoromethylated product. As the unoptimized preliminary reaction resulted in the β-trifluoromethylated saturated aldehyde in 30% yield, we propose to optimize the reaction to improve the product yield and enantioselectivity by employing different catalysts, solvents, and temperature. We also propose to synthesize a cascade bis-trifluoromethylated products from α,β-unsaturated aldehydes. As the β-trifluoromethylation may proceed via SOMO activated species, we propose to study the cascade α-heteroarylation of β-trifluoromethylated aldehydes via SOMO catalysis. We also propose to study a cascade β-trifluoromethylation followed by α-amination of α,β-unsaturated aldehydes to achieve the β-trifluoromethylated α-aminated aldehydes. This synthetic methodology is proposed to apply for the synthesis of β-amyloid inhibitor and 4,4,4-trifluorovaline. |