Transition‐Metal‐Free Multiple Functionalization of Piperidines to 4‐Substituted and 3,4‐Disubstituted 2‐Piperidinones

Abstract

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(sp3)‐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.

Transition-Metal-Free Functionalization of Saturated and Unsaturated Amines to Bioactive Alkaloids Mediated by Sodium Chlorite

“…Coupling this triple C(sp 3 )-H oxidation with a carbon-based nucleophilic addition-electrophilic trapping reaction permitted to produce trans-3,4-disubstituted piperidines, important frameworks present in pharmaceutical alkaloids. 39 We then tackled the intrinsic low reactivity of the ,unsaturated lactams toward the conjugated additions of Grignard reagents by employing TMSCl as carbonyl activating agent. Good yields were obtained when carbon-based electrophiles, instead of common aqueous quenching media, were used obtaining a variety of trans-3,4-disubstituted 2-piperidinones.…”

Palladium‐Catalyzed Cascade Carbonylation to α,β‐Unsaturated Piperidones via Selective Cleavage of Carbon–Carbon Triple Bonds

“… [8c] Thus, several methodologies have been established towards their synthesis in recent years. [9] Main approaches to this class of compounds include C−H oxidation reactions[ 9a , 9b , 9c ] and intramolecular cyclization reactions (Scheme 1 b ). [ 9d , 9e , 9f , 9g , 9h ] Despite these significant advances, still limitations exist with respect to substrate scope and the use stoichiometric amounts of oxidants or additives.…”

Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines

“…Asymmetric chemical synthetic approaches f or the preparation of 3-substituted and 3,4-disubstituted piperidines include those based on metalation/cross-coupling (11)(12)(13)(14), Grignard Michael addition (15), ring-closure (16), and transition-metal-catalyzed dearomatization of pyridines (17)(18)(19)(20). However, limitations are associated with all of these approaches, including high reaction temperatures, sensitivity to moisture, lack of availability of starting materials and the use of expensive non-commercial chiral ligands (11,21).…”