Design and Synthesis of (2-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)cyclopropyl)methanamine as a Selective Serotonin 2C Agonist

Jianjun Cheng; Patrick M Giguere; Wei Lv; Bryan L Roth; Alan P Kozikowski

doi:10.1016/j.tetlet.2015.01.060

Design and Synthesis of (2-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)cyclopropyl)methanamine as a Selective Serotonin 2C Agonist

Tetrahedron Lett. 2015 Jun 3;56(23):3420-3422. doi: 10.1016/j.tetlet.2015.01.060.

Authors

Jianjun Cheng¹, Patrick M Giguere², Wei Lv¹, Bryan L Roth², Alan P Kozikowski¹

Affiliations

¹ Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
² National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC 27599, United States.

Abstract

A conformationally restricted analog of a selective cyclopropane-bearing serotonin 2C agonist was designed and synthesized. A 2,2-dimethyl-2,3-dihydrobenzofuran scaffold was investigated as a constrained variant of a biologically active isopropyl phenyl ether. Construction of the required dimethyl-2,3-dihydrobenzofuran intermediate began using a procedure that relied on a microwave-assisted alkylation reaction. The synthesis of the designed compound as its HCl salt is reported in a total of 12 steps and 17% overall yield. Biological evaluation revealed the constrained analog to be a selective serotonin 2C agonist with modest potency.

Keywords: Agonist; Benzofuran; Cyclopropylmethanamine; Serotonin 2C.

Grants and funding

R01 MH099993/MH/NIMH NIH HHS/United States