A Piperidino Phase Switching Functional Group Tag

KiloMentor blog articles have emphasized of having intermediate substances that are easy to purify in a synthetic scheme.  An intermediate that acts as a base and can be extracted into an aqueous phase as a salt and subsequently taken back into an organic solvent in its free base form will usually be easier to separate and purify. This is consistent with the teaching of Dennis P. Curran who first drew attention to the importance of phase switching in purification and isolation.

R. A. Olofson and Duain E. Abbott wrote a paper, Tests of a Piperidino Mask for the Protection of Functionalized Carbon Sites in Multistep Synthesis, J. Org. Chem., 49, 2795-2799 (1984) which I believe needs more consideration. It teaches that a piperidine functionality attached to carbon at a primary or secondary carbon within a complex structure can be converted, in their respective cases, into a primary chloride or secondary chloride/ alkene in high yield and good selectivity.  To quote from the paper, “…. advantages can be envisioned in schemes using this mask for multistep protection. First, acid-base extraction methods are readily adapted for the isolation of process intermediates. Second, the formation of readily crystallized amine salts can further facilitate the purification of these intermediates.”

The reagent that affects this loss of a piperidine group from a complex molecule and its replacement by chlorine is α-chloroethyl chloroformate {Cl-CO-O—CHCl-CH₃; called ACE-Cl}. The conversion can be pictured as:

The reason the cleavage is so clean with the piperidine ring moiety unopened is that competition between S_N1 (E1) and S_N2 cleavages of the intermediate quaternary salt is occurring with relative rates such that ArCH2, allyl, t-alkyl >> sec-alkyl >methyl > primary 

alkyl >> piperidine ring opening. That is, the piperidino ring 

functionality is cleaved much more slowly than anything else!

Treatment with methanol hydrogen chloride removes the ACE protection liberating the piperidine.