Synlett 2007(14): 2257-2261  
DOI: 10.1055/s-2007-985574
LETTER
© Georg Thieme Verlag Stuttgart · New York

Direct Uncatalyzed Amination of 2-Chloropyridine Using a Flow Reactor

Bruce C. Hamper*, Eden Tesfu
Pfizer Inc., Global Research & Development, Medicinal Chemistry, 700 Chesterfield Parkway West, Chesterfield, MO 63017, USA
e-Mail: bruce.c.hamper@pfizer.com;
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Publikationsverlauf

Received 3 April 2007
Publikationsdatum:
13. August 2007 (online)

Abstract

Chloropyridines are efficiently converted into 2-amino­pyridines by uncatalyzed nucleophilic aromatic substitution (SNAr) in NMP using a continuous-flow reactor. A variety of secondary amines undergo SNAr with both electron-rich and electron-deficient 2-chloropyridines to afford 2-aminopyridines in good to excellent yield. The flow reactor, which provides a short reaction time and high temperatures up to 300 °C, can overcome the activation barrier for reactions with unactivated substrates. Short reaction times result in fewer side products and can afford milligram to multigram ­quantities of product using continuous flow.

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In addition, the reactions we wished to investigate required pressures and temperatures beyond the range of commercially available chip-based devices.