Organic Chemistry, Sponsor Lecture
OC-021

Recent Case Study by Janssen R&D

S. Wagschal1
1Janssen Pharmaceutica -

Simon Wagschal,[a] Diego Broggini,[a] Tobias Strittmatter,[a] Trung Duy Chi Cao,[a] Luca Perego,[a] Pascal Schleiss,[a]Kristian Paun,[a] Jessica Steiner,[a] Anna-Lena Merk,[a] Joachim Harsdorff,[a] Sven Hock,[a] Elena Cosimi,[a] Stefan Schirling,[a] Jan Dijkmans,[b] Brecht Egle,[b] Sébastien Lemaire,[b] Ferdinand H. Lutter,[c] Lucie Grokenberger,[c] Paul Knochel[c] and Roger Fässler[a]

[a] Discovery Product Development and Supply, Janssen Pharmaceutica, Hochstrasse 201, 8200 Schaffhausen (Switzerland), [b] Discovery Product Development and Supply, Janssen Pharmaceutica, Turnhoutseweg 30, B-2340 Beerse (Belgium), [c] Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5-13, Haus F, 81377 München (Germany)

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1,2,3-1H-triazoles and other related heterocycles with sterically hindered metal amide bases. We report here a room-temperature and highly regioselective ortho magnesiation of several aryl azoles using a new tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

[1] F. H. Lutter, L. Grokenberger, L. A. Perego, D. Broggini, S. Lemaire, S. Wagschal, P. Knochel, submitted.