Synthesis 2022; 54(22): 5055-5063
DOI: 10.1055/s-0037-1610786
special topic
Aryne Chemistry in Synthesis

Regioselective Amination or Alkoxylation of Halogenated Amino-, Thio- or Alkoxypyridines via Pyridyne Intermediates

Benjamin Heinz
a   Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Dimitrije Djukanovic
a   Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Fiona Siemens
a   Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Mohamed Idriess
a   Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
,
Benjamin Martin
b   Novartis Pharma AG, Chemical Development, Fabrikstraße, 4056 Basel, Switzerland
,
Paul Knochel
a   Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany
› Author Affiliations
We thank the DFG and Novartis (Basel) for generous financial support.


Abstract

The treatment of 3-halopyridines (Cl, Br) bearing an R-substituent in position 2 (R = OEt, NEt2, N-piperidyl, or SEt) or in position 5 (R = OMe, OEt, SEt, NMe2, NEt2, or aryl) with KHMDS and an amine at 25 °C for 12 hours in THF provided regioselectively 3- and 4-aminated pyridines in 56–90% yields. The reaction of 3-bromo-2-diethylaminopyridine with various alcohols in the presence of t-BuOK/18-crown-6 in THF at 80 °C for 20–60 hours gave various 4-alkoxy-2-diethylaminopyridines in 61–81% yields. These substitution reactions were proposed to proceed via pyridyne intermediates.

Supporting Information



Publication History

Received: 15 September 2021

Accepted after revision: 29 September 2021

Article published online:
11 November 2021

© 2021. Thieme. All rights reserved

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