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. 2025 Aug 29;90(34):12226-12239.
doi: 10.1021/acs.joc.5c01742. Epub 2025 Aug 18.

Selective endo-Cyclic α-Functionalization of Saturated N-Alkyl Piperidines

Rachel C Phillips  1 , John C K Chu  1 , Alex A Rafaniello  1 , Matthew J Gaunt  1
Affiliations

Selective endo-Cyclic α-Functionalization of Saturated N-Alkyl Piperidines

Rachel C Phillips et al. J Org Chem. .

Abstract

Saturated N-alkyl heterocycles are among the most significant structural motifs in natural products, small-molecule biological probes, and pharmaceutical agents, as evidenced by their prevalence in FDA-approved drugs. Substituted derivatives of these cyclic tertiary alkylamine scaffolds often exhibit markedly different physicochemical and biological properties compared to their unsubstituted counterparts. Consequently, methods for the selective functionalization of these scaffolds would greatly facilitate the optimization of biological activity, physicochemical properties, and systematic evaluations of structure-activity relationships. In this work, we present a robust platform for the late-stage α-functionalization of N-alkyl piperidines through a sequential process involving iminium ion formation followed by nucleophilic functionalization. Key to this strategy is the selective formation of endo-iminium ions from six-membered N-heterocycles, achieved via α-C-H elimination of cyclic tertiary alkylamine N-oxides. This approach provides exceptional endo-selectivity, enabling efficient further functionalization. The method allows for the in situ addition of diverse carbon-based nucleophiles to the iminium intermediates, demonstrated across a range of piperidine-based systems; alkylation, azinylation, and trifluoromethylation are successfully demonstrated through a variety of activation modes. Furthermore, the formal C-H functionalization sequence has been successfully applied to the late-stage modification of complex bioactive molecules, underscoring the potential of this methodology to expand drug-like chemical space.

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Figures

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1
Evolution of a strategy for endo-cyclic α-selective C–H functionalization of N-alkyl piperidines.
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2
Overview of the optimization for selective endo-cyclic iminium ion formation. Condition A: 2.5 equiv acetylating agent, CD2Cl2 [0.3 M], 0 °C, 3 h. Condition B: 6.6 equiv acetylating agent, CD2Cl2 [0.3 M], −78 °C to rt, 5 h. (A) Effect of counteranion released from the acylating agent. (B) Effect of steric factors in the acylating reagent.
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Preliminary evaluation of iminium selectivity across a range of cyclic tertiary alkylamines. Reactions were performed on a 0.2 mmol scale using 6.6 equiv of PivCl unless otherwise specified. AY = assay yield determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard.
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Single-point energies of the exo- and endo-cyclic α-C–H elimination transition states. Calculations were performed at the wB97XD/6-311++g­(d,p) level of theory.
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1. Optimal Conditions for Different Classes of Alkyl Halides
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(A) Alkyl iodide and (B) cyclic tertiary alkylamine scope for the one-pot α-alkylation transformation. Reactions were performed on a 0.2 mmol scale using 2.5 equiv PivCl. AY = assay yield determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. IY = isolated yield. *N-(4-Phenylbenzyl) piperidine N-oxide 7a was used as the amine component. a1.5 equiv of copper perchlorate was added to the reaction mixture.
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(A) α-Methylation conditions via Grignard addition and scope. (B) α-Trifluoromethylation conditions and scope. (C) α-Heteroarylation conditions and scope with respect to the heteroaryl iodide component. All reactions were performed on a 0.2 mmol scale using 2.5 equiv PivCl. AY = assay yield determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. IY = isolated yield.
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(A) Regioselectivity in the α-functionalization of N-benzyl-2-methylpiperidine via Zn-mediated and Grignard-based alkylation. (B) Diastereoselectivity observed in the α-functionalization of N-benzyl 4-methylpiperidine via Zn-mediated and Grignard-based alkylation. (C) Poorly selective alkylation of N-benzyl tetrahydroisoquinoline under Zn-mediated conditions. (D) Highly selective α-functionalization of N-benzyl tetrahydroisoquinoline under Grignard-based alkylation and trifluoromethylation. All reactions were performed on a 0.2 mmol scale using 2.5 equiv PivCl. AY = assay yield determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. IY = isolated yield.
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(A) Late-stage α-functionalization of dextromethorphan and (B) late-stage α-trifluoromethylation scope with respect to the complex cyclic tertiary alkylamine component. All reactions were performed on a 0.2 mmol scale using 2.5 equiv PivCl. AY = assay yield determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. IY = isolated yield. aIsolated as the TFA salt.
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