Regioselective difunctionalization of pyridines via 3,4-pyridynes |
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Authors: | Benjamin Heinz Dimitrije Djukanovic Paolo Filipponi Benjamin Martin Konstantin Karaghiosoff Paul Knochel |
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Institution: | Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstraße 5-13, 81377 Munich Germany.; Novartis Pharma AG, Chemical Development, Fabrikstraße, 4002 Basel Switzerland, |
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Abstract: | A new regioselective 3,4-difunctionalization of 3-chloropyridines via 3,4-pyridyne intermediates is reported. Regioselective lithiation of 3-chloro-2-ethoxypyridine and a related 2-thio-derivative followed by treatment with aryl- and alkylmagnesium halides as well as magnesium thiolates at −78 °C produced 3,4-pyridynes during heating to 75 °C. Regioselective addition of the Grignard moiety in position 4 followed by an electrophilic quench in position 3 led to various 2,3,4-trisubstituted pyridines. This method was adapted into a continuous flow set-up. As an application, we have prepared a key intermediate for (±)-paroxetine.A regioselective 3,4-difunctionalization of pyridines was performed. Lithiation and transmetalation with arylmagnesiums gave 3,4-pyridyne intermediates. Addition of magnesium species led to 3-pyridylmagnesiums which were quenched with electrophiles. |
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