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Review
. 2014 Sep 19;18(9):1097-1104.
doi: 10.1021/op500224x. Epub 2014 Aug 29.

Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C-H Functionalization Sequences

Tehetena Mesganaw  1 , Jonathan A Ellman  1
Affiliations
Review

Convergent Synthesis of Diverse Tetrahydropyridines via Rh(I)-Catalyzed C-H Functionalization Sequences

Tehetena Mesganaw et al. Org Process Res Dev. .

Abstract

A Rh-catalyzed C-H bond activation/alkenylation/electrocyclization cascade reaction provides diverse 1,2-dihydropyridines from simple and readily available precursors. The reaction can be carried out at low (<1%) Rh-catalyst loadings, and the use of the robust, air-stable Rh precatalyst, [RhCl(cod)]2, enables the cascade reaction to be easily performed on the benchtop. The 1,2-dihydropyridine products serve as extremely versatile synthetic intermediates for further elaboration often without isolation. The addition of electrophiles under kinetic or thermodynamic conditions provides a wide range of iminiums. Subsequent addition of a nucleophile then generates a diverse array of differently substituted piperidine products. Additionally, [3 + 2] and [4 + 2] cycloadditions of the 1,2-dihydropyridine intermediate provides access to bridged bicyclic structures such as tropanes and isoquinuclidines. These concise reaction sequences enable the formation of highly substituted piperidines in synthetically useful yields with excellent diastereoselectivity.

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Figures

Figure 1
Figure 1
Representative drugs that incorporate the piperidine motif.
Figure 2
Figure 2
Rh-catalyzed activation/alkenylation/electrocyclization.
Figure 3
Figure 3
Piperidines generated via kinetic and thermodynamic iminiums.
Scheme 1
Scheme 1. Preparative scale synthesis of tetrahydropyridines
Scheme 2
Scheme 2. Preparative scale synthesis of tetrahydropyridines using a silyl alkyne
Figure 4
Figure 4
Synthesis of cyclopropyl pyrrolidines.
See this image and copyright information in PMC

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