Synthesis and Structural Elucidation of 1,2‐Disubstituted 3‐Fluoropiperidines

The work described details the reaction between Selectfluor® and a series of 1‐carbonyloxy and 1‐sulfonyl 2‐piperidines in order to generate 3‐fluoro‐2‐methoxypiperidines 3a–f. Their subsequent reaction with allyltrimethylsilane, in the presence of BF3 and TiCl4, is then reported. Studies involving a combination of single‐crystal X‐ray crystallography and NMR spectroscopy indicate that the allylation process is cis‐selective for both carbamate and sulfonamide variants and that optimal levels of diastereoselectivity are obtained using the N‐2‐nitrobenzene sulfonyl (2‐Ns) group. In this manner, the synthesis of a series of 2‐allyl 3‐fluoro‐substituted piperidines (5a, c–f) was achieved. The conversion of both the cis and trans‐N‐tosyl adducts (5d) into 3‐fluorinated analogues of the natural products pelletierine (10) and coniine (11) is subsequently detailed. Electrophilic fluorination of a range of N‐protected 2‐piperideines, followed by Lewis‐acid mediated functionalization affords the corresponding 3‐fluoropiperidines. When X = allyl, these reactions were found to be cis‐selective. This was particularly marked in the case of R = 2‐Ns. 19F NMR spectroscopy and X‐ray crystallography were used to understand the stereochemical outcomes of these processes.