On the Reaction Mechanism of the Selective C(sp3)–H Functionalization of N-Benzylpiperidines Mediated by TEMPO Oxoammonium Cation

Abstract

The selective and dual C(sp3)−H oxidation of N-heterocycles to their corresponding 3-alkoxyamino lactams mediated by TEMPO oxoammonium cation (TEMPO+) is turning into a convenient non-metallic strategy for the rapid functionalization of piperidines and pyrrolidines to bioactive alkaloids. Mechanistic proposal suggests that TEMPO+ prefers to oxidize endocyclic C−H bond of either N-substituted-piperidines or pyrrolidines to their corresponding endocyclic iminium intermediates, which are transformed into enamine intermediates, and then trapped by oxoammonium cation. Although the product formation seems to be in concordance with this mechanistic rationale, neither experimental evidence nor theoretical calculations have been reported. Accordingly, the current investigation provides computational findings explaining that the origin of the selective C−H oxidation is attributed to an unprecedented C−H… interaction between two hydrogen atoms of TEMPO+ with the aromatic ring of piperidine benzyl group. To prove the existence of the enamine intermediate, we developed an unprecedented transition-metal-free tetra C−H oxidation of two N-benzyl-4-methylenepiperidines. Accordingly, the existence of the elusive enamine intermediate was attained by generating a transitory dienamine intermediate, which is trapped by TEMPO+ and NaClO2 to their corresponding 4-(alkoxyaminomethyl)-3,4-epoxy-2-piperidone

Transformation of (allo)securinine to (allo)norsecurinine via a molecular editing strategy

“…Our synthesis commenced with regioselective double oxidation of C5 and C6 carbons of allosecurinine ( 1 ) to produce lactam 20 in 60% yield as a 4:1 diastereomeric mixture ( Scheme 2 ). In 2016, Sartillo-Piscil and coworkers reported a double sp 3 C−H oxidation of cyclic amines to α-alkoxyamine lactams ( Osorio-Nieto et al, 2016 ; Romero-Ibañez et al, 2023 ). In the instance of allosecurinine ( 1 ), the oxoammonium cation of TEMPO ( 15 ) selectively abstracted the C6 hydridic α-hydrogen from the amine moiety due to its greater steric accessibility consistent with Sartillo-Piscil’s reports ( Osorio-Nieto et al, 2016 ; Romero-Ibañez et al, 2023 ).…”

“…In 2016, Sartillo-Piscil and coworkers reported a double sp 3 C−H oxidation of cyclic amines to α-alkoxyamine lactams ( Osorio-Nieto et al, 2016 ; Romero-Ibañez et al, 2023 ). In the instance of allosecurinine ( 1 ), the oxoammonium cation of TEMPO ( 15 ) selectively abstracted the C6 hydridic α-hydrogen from the amine moiety due to its greater steric accessibility consistent with Sartillo-Piscil’s reports ( Osorio-Nieto et al, 2016 ; Romero-Ibañez et al, 2023 ). This led to the formation of the iminium ion intermediate 16 , which subsequently underwent tautomerization, resulting in the formation of enamine 17 .…”

Ferrier Glycosylation Mediated by the TEMPO Oxoammonium Cation

“…Intrigued by this unprecedented reactivity of 1 , we explored several possible paths to explain our results. First, an addition–elimination pathway (Scheme a) was considered, based on the well-known electrophilicity of the R 2 N + O bond in 1 . , Accordingly, the electron-rich double bond of glycal 4 might be attacked by 1 to initially form 3-alkoxyamine oxocarbenium cation I , followed by a concerted 1,2-elimination to give key vinylic oxocarbenium intermediate II , which could be further attacked by nucleophiles. However, if this mechanism were to operate, I could also undergo nucleophilic attacks to form 19 .…”

“…In this context, over the past eight years, our research group has been interested in expanding the use and mechanistic findings of TEMPO + 1 beyond the C–H oxidation of hydroxyl groups. An important feature of the chemistry of 1 is that it readily reacts with piperidines to form transient enamine intermediates, which are attacked by an additional 1 equiv of 1 to form a key iminium intermediate A and finally the corresponding 3-alkoxyaminolactam B (Scheme a)…”

β-Alkenylation of Saturated N-Heterocycles via a C(sp3)–O Bond Wittig-like Olefination

“…Since the latter protocol visualizes the C4 and C3 positions as dipolar synthons ( 3 ), nucleophiles and electrophiles were incorporated in a tandem fashion ( 5 → 6 ) ( Scheme 1 , eq 2). 5 Unlike the transition-metal catalyzed reactions, in which the directing group is majorly responsible for the reaction success (e.g., A ), in the TMF version, the benzyl group of piperidine 3 has been proposed to act as a pseudodirecting group ( B ) 6 for the selective dual C–H oxidation mediated by oxoammonium cation (TEMPO + ) to the transitory intermediate alkoxyamino lactam 4a, which is crucial for the third C–H functionalization ( 5 ), and thus to access to 3,4-disubstituted-2-piperidones 6 in only two-steps from simple piperidines.…”