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. 2022 Feb 11;24(5):1224-1227.
doi: 10.1021/acs.orglett.2c00018. Epub 2022 Jan 31.

Synthesis of Polycyclic Isoindolines via α-C-H/N-H Annulation of Alicyclic Amines

Anirudra Paul  1 , Camille Vasseur  1 , Scott D Daniel  1 , Daniel Seidel  1
Affiliations

Synthesis of Polycyclic Isoindolines via α-C-H/N-H Annulation of Alicyclic Amines

Anirudra Paul et al. Org Lett. .

Abstract

Relatively unstable cyclic imines, generated in situ from their corresponding alicyclic amines via oxidation of their lithium amides with simple ketone oxidants, engage aryllithium compounds containing a leaving group on an ortho-methylene functionality to provide polycyclic isoindolines in a single operation. The scope of this transformation includes pyrrolidine, piperidine, azepane, azocane, and piperazines.

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Figures

Scheme 1.
Scheme 1.
Overview of methods for amine α-C–H/N–H annulation
Scheme 2.
Scheme 2.. Scope of the reaction.
Reactions were performed with 0.5 mmol of 1. Yields correspond to isolated yields of chromatographically purified product. A mixture of ether (1 mL) and THF (1 mL) was used for the lithiation of 1. Cyclic imines were prepared in situ by adding n-BuLi (2 equiv) to a solution of the corresponding cyclic amine (2 equiv) in ether (1 mL) at −78 °C, followed by the addition of trifluoroacetophenone (2.05 equiv). a A mixture of ether (1.8 mL) and THF (0.2 mL) was used for the lithiation of 1. b THF (1 mL) was used for the lithiation and cyclic imine was prepared in situ by adding n-BuLi (2 equiv) to a solution of cyclic amine (2 equiv) in ether (1.5 mL) at −78 °C, followed by the addition of trifluoroacetophenone (2.05 equiv) in 1 mL of ether.
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