AmericanChemicalSociety.com

Based on our earlier findings we have made further progress on the asymmetric hydrogenation of trifluoromethyl imines, and the synthesis of chiral trifluoromethyl amines.

As the commercially available trifluoroketones were limited, we prepared some trifluoromethyl ketones. Benzaldehydes were treated with trimethyltrifluoromethyl silane in the presence of tetrabutyl ammonium fluoride. The reaction mixture was then treated with hydrochloric acid and extracted with dichloromethane and washed several times with water to give the crude secondary trifluoromethylated alcohol. The trifluoromethylated benzylalcohol was then directly oxidized by Dess-Martin’s periodinone at 0 °C to give the desired trifluoromethylated ketones.

These and other commercially available CF₃-ketones were treated with both enantiomers of a-methylbenzyl amines, respectively, in the presence of montmorillonite K-10 in toluene and heated at 130 °C. The crude imines were isolated after filtration and solvent removal in vacuum. The general conversion to the imines was excellent. The crude chiral imines were directly used in the next hydrogenation step without further purification.

The chiral imines were reduced by hydrogenation in the presence of palladium on barium carbonate (Pd/BaSO₄) in tetrahydrofuran as solvent under ambient temperature to give the secondary amines. The hydrogen pressure had no effect on the diastereoselectivities at lower pressures (30 bars). These secondary amines were then treated with a solution of dilute hydrochloric acid under hydrogen atmosphere in the presence of palladium on barium carbonate (Pd/BaSO₄) at 70 °C which resulted in hydrogenolysis and gave the desired chiral amines.

Based on our own earlier investigations the hydrogenolysis of the diastereomeric secondary amines occurred with different rates. In all cases, the (R, R)-diastereomer reacted faster than the (R, S)-diastereomer. This type of secondary kinetic resolution was earlier reported independently by other groups. In order to ensure the formation of products of high enantiomeric excess, the reaction was continuously monitored and usually to be stopped at 50 – 60% conversion, when a large majority of the (R, R)-diastereomer already underwent hydrogenolysis. Until this conversion the overwhelming majority of the (R, S)-amines remain unreacted. We have optimized the experimental conditions to obtain the best possible yields and optical purity. Under the optimized conditions we were able to synthesize ten chiral trifluoromethyl amines to show the scope of the reaction. While the enantiomeric excesses varied from 40-97%, the majority of the products were isolated in good to excellent optical yields.

I feel that the generous support from ACS-PRF through the current grant made a significant positive impact on my career. We were able to clarify a 25 years old problem in heterogeneous asymmetric catalytic hydrogenations. Further the mechanistic findings we made a breakthrough in the target reaction, and produced the product with 99+% enantiomeric excess. The impact of the grant, however, is perhaps even greater on the early career of my undergraduate students who have participated in the project. As UMB is the major minority and economically disadvantaged student serving institution in the greater Boston, Eastern New England area several of my students were (and still are) the first in their family to attend college. To see these students to beat the odds and graduate with excellent GPA, and even get accepted to chemistry graduate schools gives me great satisfaction. Several students already graduated and went on to obtain their PhD in Chemistry. Others are still working in the PI’s lab and their graduation is forthcoming in this and the next academic year. It is my sincere hope that after graduation these students will also enter either graduate school, or research oriented careers.