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

Julio Romero-Ibañez; Jacinto Sandoval-Lira; Silvano Cruz-Gregorio; Julio M. Hernández-Pérez; Leticia Quintero; Fernando Sartillo-Piscil

doi:10.1055/a-2053-9558

Synthesis, Inhaltsverzeichnis

Synthesis 2023; 55(21): 3662-3669
DOI: 10.1055/a-2053-9558

special topic

C–H Bond Functionalization of Heterocycles

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

Julio Romero-Ibañez‡

^aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, México

,

Jacinto Sandoval-Lira‡

^bDepartamento de Ingeniería Ambiental, TecNM, Instituto Tecnológico Superior de San Martín Texmelucan, Camino a la Barranca de Pesos, C.P. 74120 San Martín Texmelucan, Puebla, México

,

Silvano Cruz-Gregorio

^aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, México

,

Julio M. Hernández-Pérez

^aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, México

,

Leticia Quintero

^aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, México

,

Fernando Sartillo-Piscil ∗

^aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP), 14 Sur Esq. San Claudio, Col. San Manuel, 72570 Puebla, México

› Institutsangaben

Abstract

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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 nonmetallic strategy for the rapid functionalization of piperidines and pyrrolidines to bioactive alkaloids. Mechanistic proposal suggests that TEMPO⁺ prefers to oxidize the endocyclic C–Hα 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–Hα oxidation can be attributed to an unprecedented C–H···π interaction between two hydrogen atoms of TEMPO⁺ with the aromatic ring of the 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 was trapped by TEMPO⁺ and NaClO₂ to give the corresponding 4-(aminooxymethyl)-3,4-epoxy-2-piperidone.

Key words

selectivity - C–H oxidation - alkoxyamino lactams - oxoammonium salt of TEMPO - sodium chlorite

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Referenzen

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