Pyrazole derivatives are considered as a prime scaffold for medicinal, agricultural, supramolecular as well as materials sciences. 3/5-Trifluoromethylpyrazoles, well-known examples of pyrazole derivatives, which are key privileged fragment widely existed in many agrochemicals, and pharmaceuticals.<br/>In our thesis, we will present a new, high yielding, and practical synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole provides the key intermediates in kilo scales for important MedChem and AgroChem relevant building blocks. Starting from 4-ethoxy-1,1,1-trifluoro-3-buten-2-one one-step procedure for the regioisomeric mixture synthesis with followed separation by distillation has been developed. Based on these compounds the efficient strategy to regioisomeric building blocks bearing CF3-group at 3-d and 5-th positions was elaborated. A set of 1-methyl-3-(trifluoromethyl)-1H-pyrazoles bearing functional group, including aldehyde, acid, boron pinacolate, lithium sulfinate, and sulfonyl chloride, were synthesized based on flow lithiation of 1-methyl-3-(trifluoromethyl)-1H-pyrazole. The mild conditions of the bromination by NBS of both 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole was proposed. The introduction of the functional group into the 4-th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was illustrated by the optimized synthesis of corresponding aldehyde and acid-based on Br-Li exchange in 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole with n-BuLi. Alternatively, the introduction of the functional group (acid and boron pinacolate) into 5-th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was made based on DoM reaction 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole with LDA and further debromination by catalytic hydrogenation.

Practical, kilo scale synthetic method for functionalized 1-methyl-3/5-(trifluoromethyl)-1H-pyrazoles

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.