Ring Contraction of 3‐Hydroxy‐3‐(trifluoromethyl)piperidines: Synthesis of 2‐Substituted 2‐(Trifluoromethyl)pyrrolidines

Abstract

A ring contraction of 3-hydroxy-3-(trifluoromethyl)piperidines was achieved via an aziridinium intermediate. This contraction facilitates the synthesis of a series of 2-substituted 2-(trifluoromethyl)pyrrolidines incorporating a quaternary center at the C2 position.

Synthetic Applications of Aziridinium Ions

“…Most cases with diethylaminosulfur trifluoride (DAST) have yielded enlarged fluorinated piperidine ring compounds (50) from hydroxymethylpyrrolidine (49) via fluorine-driven ring opening in a stereoselective manner [71,72]. This reaction, generation, and ring opening of a bisaziridinium ion (52) from 3-hydroxy-3-trifluoromethyl piperidine (51) with removal of the hydroxy group could also be applicable for the synthesis of biologically important α-trifluoromethyl pyrrolidines (53) (Scheme 14) [73,74].…”

“…Subsequent alkenylborate attack with ring opening to the activated three-membered aziridinium ion afforded a stable boronated alkenyl piperidine resonance between (75) and (76), as shown in Scheme 20 [82]. Recently, an interesting reaction was developed to generate a reactive zwitterionic aziridinium intermediate (74) from the reaction of N-propargyltetramethylpiperidine (73) with trans-alkenyl-B(C6F5)2 compounds via trans-1,2-amine/borane addition to a carboncarbon triple bond. Subsequent alkenylborate attack with ring opening to the activated three-membered aziridinium ion afforded a stable boronated alkenyl piperidine resonance between (75) and (76), as shown in Scheme 20 [82].…”

“…Figure 5. Representative examples of Scheme 13 following pathway "a" or "b" to prepare various aza-cyclic valuables.This reaction, generation, and ring opening of a bisaziridinium ion (52) from 3hydroxy-3-trifluoromethyl piperidine (51) with removal of the hydroxy group could also be applicable for the synthesis of biologically important α-trifluoromethyl pyrrolidines (53) (Scheme 14)[73,74].…”

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

“…Besides the overwhelming number of examples dealing with 1‐azoniabicyclo[3.1.0]hexane‐interceded pyrrolidine‐to‐piperidine transformations, ring‐contraction reactions from 3‐substituted piperidines to 2‐substituted pyrrolidines, involving analogous bicyclic intermediates, are known in the literature as well. Recently, Cossy and co‐workers have developed a general protocol for the ring contraction of 3‐hydroxy‐3‐(trifluoromethyl)piperidines 137 into a broad library of 2‐substituted 2‐(trifluoromethyl)pyrrolidines 139 , using a variety of halogen, nitrogen, oxygen, carbon and sulfur nucleophiles to trigger this ring transformation (Scheme ) . Herein, treatment of 3‐hydroxypiperidines 137 with 1.5 equiv.…”

Synthesis of Optically Active α-Trifluoromethylamines by Rearrangement of β-Amino-α-trifluoromethyl Alcohols

“…In the context of our studies on ring expansion and ring contraction of heterocycles containing nitrogen and on the rearrangement of β-amino alcohols, via aziridinium ion intermediates, we would like to report here that optically active functionalized α-trifluoromethylamines A can be obtained from β-amino-α-trifluoromethyl alcohols B with good diastereo- and enantioselectivity by regioselective ring opening of an aziridinium ion intermediate C by a variety of nucleophiles under kinetic conditions (Scheme ).…”