The study of the catalytic asymmetric addition of Alkylzinc to form fluorinated tertiary alcohol

Abstract

Chiral fluorinated products have a huge importance in the fine chemical synthesis, and their synthesis is one of the most important challenges nowadays, due to its outstanding bioactive properties: they are widely used in numerous agrochemicals and pharmaceuticals, product classes that move trillion dollars, save lives and help in the humanity progress. Our group has a much interest in this kind of compound, and uses our expertise in 19F NMR to study them. This work is focused on the alkylation of fluorinated ketones using alkylzincs to generate fluorinated chiral tertiary alcohols as a building block to be used to synthetize other molecules with different bioactive properties; for example, the chiral molecule p-(HO2C)-C6H4 C(CF3)(CH3)OH, which is a precursor of a product’s family that is being really effective in the obesity and type II diabetes treatment. We have studied the addition reaction with different ligands and ketones and figured out some tendencies. For instance, the difference in reaction of different ketones is a relation between the steric hindrance and the LUMO orbital’s energy of the ketones. When diethylzinc was used, the more hindered the ligand more important the steric hindrance of the ketone and with the more hindered ketones the steric hindrance of the ligand gains more importance in the reaction’s rate. After this study, which took most of the time due to the labour to synthetize the ligands, came the more exciting part of the project. Dimethylzinc is more interesting than diethylzinc, due to its lack of β-elimination and to the fact the precursor target be methylated and not ethylated. For that reasons, and the modest results in the literature (up to 83% of e.e.) we decided to study the methylation using L* and, to our surprise, it behave differently than with diethylzinc. It led us to find an outstanding condition, which gives one virtually enantiomeric pure addition product and a great reaction scope. Gratifyingly, three out of four ketones tested in this work; presented more the 95% of enantiomeric excesses. In addition, at the same time we were doing this study, we tried to synthetize a stable Zn(CF3)2, and we have done it successfully by stabilizing it with a ligand. This compound was stable enough to be characterized by crystallography x-ray diffraction and its reactivity will be tested in the next future.