Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine

Scale-Up and Optimization of a Continuous Flow Carboxylation of N-Boc-4,4-difluoropiperidine Using s-BuLi in THF

“…This result was quite remarkable since side reactions could have arisen, such as the elimination of HF from the CF 2 group or intramolecular displacement of fluorine leading to cyclopropane formation (as observed following lithiation with 4-chloropiperidine). , The lithiated piperidine was subsequently trapped with CO 2 to afford 2 in 54% isolated yield when 5 g was used (condition A, Scheme ). , O’Brien and co-workers reported an α-carboxylation of N -Boc-pyrrolidines with s -BuLi, replacing the TMEDA/Et 2 O combination used in Beak’s protocol by THF …”

“…This simpler protocol was also applied to 1 , this time providing 2 in 64% isolated yield (condition B, Scheme ). Decomposition of the lithiated piperidine could be responsible for the moderate yield of this transformation, as recently disclosed by O’Brien on the pyrrolidine system …”

Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates

“…Finally, an alternative route to selected trans -isomers would be the use of Beak's α-lithiation-trapping methodology, 18 a ,19 with which we have much experience. 11 a ,20 For this, it was envisaged starting with N -Boc methyl piperidines 7 and carrying out α-lithiation (using s -BuLi/TMEDA) and subsequent trapping with carbon dioxide (followed by methylation) to give methyl pipecolinates trans - 5 (Scheme 1). For N -Boc 2-methyl piperidine 7a , equatorial lithiation from the lowest energy conformation with an axial 2-methyl group (to avoid unfavourable A 1,3 -type strain) should give the 2,6- trans isomer.…”