Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model

Abstract

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and trisubstituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines were hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. After trapping of the pyridynes generated in situ, the neighbouring directing groups may be removed or exploited using versatile metal-catalysed cross-coupling reactions. This methodology now renders 3,4-pyridynes as useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle.

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Figure 1: Pyridine-containing drugs, pyridyne isomers and previous examples of pyridynes.
Figure 2: Design of 3,4-pyridynes with controllable regioselectivity.
Figure 3: Synthesis of silyltriflates 20, 22 and 25.
Figure 4: Competition between steric interactions and electronic effects in transition states for nitrone cycloadditions.
Figure 5: Derivatization of adducts 26 and 30.

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Acknowledgements

The authors are grateful to Boehringer Ingelheim, DuPont, Eli Lilly, Amgen, AstraZeneca, Roche, the A. P. Sloan Foundation, the University of California, Los Angeles, the ACS Division of Organic Chemistry (fellowship to A.E.G.) and the Foote Family (fellowship to A.E.G.) for financial support. Jordan Cisneros (University of California, Los Angeles) is acknowledged for experimental assistance and thanks Pfizer for financial support. These studies were supported by shared instrumentation grants from the National Science Foundation (CHE-1048804) and the National Center for Research Resources (S10RR025631).

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A.E.G. planned and carried out the experimental work. A.E.G. and N.K.G. conceived the project, co-wrote the manuscript and commented on the manuscript.

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Correspondence to Neil K. Garg.

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Goetz, A., Garg, N. Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model. Nature Chem 5, 54–60 (2013). https://doi.org/10.1038/nchem.1504

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