RCM-Mediated Synthesis of Trifluoromethyl-Containing Nitrogen Heterocycles

Abstract

A ring-closing metathesis mediated pathway to trifluoromethyl-containing piperidines is detailed. This involves the development of a synthetic route to a new (trifluoromethyl)allylating reagent via a Diels-Alder/retro-Diels-Alder strategy, its application in the synthesis of a series of trifluormethyl-substituted diolefin precursors for ring-closing metathesis, and eventually the successful cyclization of these precursor molecules into the corresponding functionalized piperidines.

An Improved Ring‐Closing Metathesis Approach to Fluorinated and Trifluoromethylated Nitrogen Heterocycles

“…[8,9] (Scheme 3). The sequence proceeded via initial alkylation of tert-butyl tosylcarbamate [14] with tosylate 5 [8] in refluxing acetonitrile, followed by TFA-mediated liberation of sulfonamide 31 in good overall yield.…”

“…[8,9] (Scheme 3). The sequence proceeded via initial alkylation of tert-butyl tosylcarbamate [14] with tosylate 5 [8] in refluxing acetonitrile, followed by TFA-mediated liberation of sulfonamide 31 in good overall yield. Compound 31 was alkylated under Mitsunobu conditions (triphenylphosphane, diethyl azodicarboxylate, toluene, 50°C) with several unsaturated alcohols in generally good yields to provide the RCM precursors 32-35, which in turn, were subjected to the aforementioned RCM conditions ( Table 2).…”

“…This is exemplified by work of the Brown group who successfully applied ring-closing metathesis (RCM) on vinyl fluoride-containing substrates to prepare fluorinated analogues of seven-membered heterocyclic HIV protease inhibitors, [5] and related work from the Haufe group. [6] At the same time, we were developing a similar RCM approach to prepare small libraries of fluorinated [7] and trifluoromethylated [8] nitrogen heterocycles, including the development of a route to a new trifluoromethyl-containing allylating reagent. [9] Inspired by these successful approaches, we aimed to extend this methodology to a complementary pathway, which is retrosynthetically outlined in Scheme 1.…”

Synthesis of non-natural cyclic amino acids from available unsaturated tertiary amines

“…This method provides a possibility to carry out a synthesis of complex molecules containing a large number of various functional groups [2]. In certain cases cyclic amino acids were obtained by olefi ns metathesis in suffi ciently large yields [3][4][5]. However in these procedures a serious problem consisted in the synthesis of compounds that were the precursors of the metathesis reaction.…”

1-(Trifluoromethyl)vinyllithium

“…The reaction of 1-(trifluoromethyl) vinyllithium with imines for the preparation of 2-(trifluoromethyl) allylamines has been reported. 1, 12 The reaction of N-benzylimine can be promoted by BF 3 ·OEt 2 to furnish the desired amine in 81% yield (eq 12). Under similar conditions, N-benzoyl and Ntosylimine have been applied as reactive electrophiles to afford the corresponding N-allylamides in 97 and 90% yield, respectively (eqs 13 and 14).…”