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

Benjamin Heinz; Dimitrije Djukanovic; Fiona Siemens; Mohamed Idriess; Benjamin Martin; Paul Knochel

doi:10.1055/s-0037-1610786

Synthesis, Table of Contents

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

^aLudwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany

,

Dimitrije Djukanovic

^aLudwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany

,

Fiona Siemens

^aLudwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany

,

Mohamed Idriess

^aLudwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany

,

Benjamin Martin

^bNovartis Pharma AG, Chemical Development, Fabrikstraße, 4056 Basel, Switzerland

,

Paul Knochel ∗

^aLudwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5–13, Haus F, 81377 München, Germany

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Abstract

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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.

Key words

potassium bases - pyridines - amination - alkoxylation - pyridynes

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References

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