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. 2019 Mar 15;84(6):3249-3259.
doi: 10.1021/acs.joc.8b03162. Epub 2019 Feb 27.

A 5 + 1 Protic Acid Assisted Aza-Pummerer Approach for Synthesis of 4-Chloropiperidines from Homoallylic Amines

Rene Ebule  1 , Sagar Mudshinge  1 , Michael H Nantz  1 , Mark S Mashuta  1 , Gerald B Hammond  1 , Bo Xu  2
Affiliations

A 5 + 1 Protic Acid Assisted Aza-Pummerer Approach for Synthesis of 4-Chloropiperidines from Homoallylic Amines

Rene Ebule et al. J Org Chem. .

Abstract

We report that HCl·DMPU induces the formation of (thiomethyl)methyl carbenium ion from DMSO under mild conditions. Homoallylic amines react with this electrophile to generate 4-chloropiperidines in good yields. The method applies to both aromatic and aliphatic amines. The use of HCl·DMPU as both non-nucleophilic base and chloride source constitutes an environmentally benign alternative for piperidine formation. The reaction has a broad substrate scope, and the conditions offer good chemical yields with high functional group tolerance and scalability.

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Conflict of interest statement

Notes

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Examples of piperidine-containing natural products and drug molecules.
Figure 2
Figure 2
Failed substrates.
Figure 3
Figure 3
ORTEP representation of (2n) with thermal ellipsoids shown at the 50% probability level.
Scheme 1
Scheme 1
Literature background.
Scheme 2
Scheme 2
Gram scale reaction and mechanistic study.
Scheme 3
Scheme 3
Proposed mechanism.
See this image and copyright information in PMC

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