Novel, Versatile Three-Step
Synthesis of 1,2,3,4,10,10a-Hexahydro­pyrazino[1,2-a]indoles by Intramolecular
Carbene-Mediated C-H Insertion

Niels Krogsgaard-Larsen; Mikael Begtrup; Matthias M. Herth; Jan Kehler

doi:10.1055/s-0030-1258967

PAPER

Novel, Versatile Three-Step Synthesis of 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indoles by Intramolecular Carbene-Mediated C-H Insertion

Niels Krogsgaard-Larsen^a, Mikael Begtrup^a, Matthias M. Herth^a, Jan Kehler*^b
^a Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark
^b H. Lundbeck A/S, Department of Medicinal Chemistry, 9 Ottiliavej, 2500 Valby, Denmark
Fax: +45 36438237; e-Mail: jke@lundbeck.com;

Abstract

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Abstract

A new convenient three-step synthesis of the privileged CNS scaffold 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles has been developed. The method makes use of an intramolecular carbene-mediated C-H insertion in phenylpiperazine-derived tosylhydrazones made from 2-fluorobenzaldehydes. Notably, the piperazine can be replaced with other cyclic nitrogen bases and the methodology is successfully extended to pyrrolidine, piperidine, azepane, morpholine, and homopiperazine.

Key words

1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles - C-H insertion - phenylpiperazine - carbene - cyclization

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Novel, Versatile Three-Step Synthesis of 1,2,3,4,10,10a-Hexahydro­pyrazino[1,2-a]indoles by Intramolecular Carbene-Mediated C-H Insertion

Novel, Versatile Three-Step Synthesis of 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indoles by Intramolecular Carbene-Mediated C-H Insertion