Direct and Stereoselective Synthesis of Diversely Substituted 2,4‐trans‐(NH)‐Pyrrolidines by Copper(I)‐Catalyzed Radical Cyclization at Low Temperature

Abstract

This work describesasuccessfulc opper(I)catalyzed radical cyclization of b-haloethylallylamines bearing an unprotected NH-group while retaining catalyst-redox activity.T he cyclization occurs regio-and diastereoselectively at 0 8 8Ca nd furnishes diversely substituted 1,3-trans-(NH)-pyrrolidinesd irectly in high isolated yields.A ni nvolvement of the bulky copper complex in the cyclization step as the possible reason for the diastereoselectivity was proposed. Synthetica pplications of the productsi nt he preparation of useful 4-chloro-NH-pyrrole in as ingle step,h as also been demonstrated. Aq uick, mild and generalm ethod involving simple addition of trichloroacetic acid/dimethyl sulfoxide (CCl 3 CO 2 H-DMSO) solution to readily accessible N-allylaldimines and ketimines tolerating acid-sensitive and highly deactivating substituents was developed to access the amine precursors.

β,β,β‐Trichloroethyl‐NH‐Enamine as Viable System for 5‐Endo‐trig Radical Cyclization via Multifaceted CuI−CuII Redox Catalysis: Single Step Synthesis of Multi‐Functionalized NH‐Pyrroles

“…PMDETA was the most effective ligand in terms of the product yield (74%) (Table , entry 1 – 4 ). Only the Cu(I)/PMDETA complex could effectively retain its redox activity, unaffected by deactivating N H‐groups of the enamine 20 a and/or pyrroles 21 a formed during progress of the radical reaction …”

“…Advantageously, this Cu(I)/PMDETA‐catalyst uses overall lesser amount of PMDETA and lesser reaction time (Table , entry ‐ 5 ) than required for the aromatization of an isolated halogenated pyrrolidine in the next aromatization reaction. Thus, it shortens the synthetic operations and reaction time for, otherwise a multi‐step synthetic protocol …”

“…This previously known 2,2,2‐trichloroethylamine 19 g was prepared by reduction of trichloroacetonitrile with LiAlH 4 according to a method reported as reported in our previous article …”

“…Secondly, there is a greater geometric constraint in the transition state of the N H‐enamine 8 than N ‐substituted enamine 4 as the nitrogen atom in 8 is not pre‐substituted with any group or functionality acting as a cyclization auxillary . Thirdly, a free N H‐group in an enamine can bind to a Cu(I)‐catalyst to form an inactive Cu(I)‐ N H complex causing the loss of catalyst‐redox activity essential to perform the radical reactions . Despite all these challenges, a single step synthesis of a N H‐pyrrole from a N H‐enamine is advantageous over multisteps N ‐preprotection post deprotection dependent protocols usually suffering with the loss of the yields …”

“…Our previous experiences with substrate‐ and catalyst‐controlled radical cyclization reactions prompted us to investigate roles of enamine‐structures, radical initiators, additives and reaction conditions in a “disfavored” 5‐ endo ‐mode of radical cyclization in an enamine system. This led to a discovery of an efficient approach to convert a “disfavored mode 5 to a favored mode 9 ” of a 5‐ endo ‐ trig radical cyclization to form pyrrolidine radical 10 which spontaneously converts to N H‐pyrrole 11 having a 4‐halo‐and the carbonyl functionalities at 2‐ and 3‐positions (Scheme ).…”