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Transition‐Metal‐Free Multiple Functionalization of Piperidines to 4‐Substituted and 3,4‐Disubstituted 2‐Piperidinones
Author(s) -
ChamorroArenas Delfino,
NolascoHernández Alejandro A.,
Fuentes Lilia,
Quintero Leticia,
SartilloPiscil Fernando
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201905262
Subject(s) - surface modification , chemistry , electrophile , cationic polymerization , reactivity (psychology) , conjugated system , trimethylsilyl , transition metal , combinatorial chemistry , lewis acids and bases , organic chemistry , catalysis , polymer , medicine , alternative medicine , pathology
Remote and multiple functionalization of piperidines without the use of transition‐metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two‐step protocol that enables the multiple functionalization of piperidines to either 4‐substituted or trans ‐3,4‐disubstituted 2‐piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent‐radical form, a novel multiple C(sp 3 )‐H oxidation of piperidines to α,β‐unsaturated 2‐piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2‐piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.