Regioselective Reactions of 3,4-Pyridynes Enabled by the Aryne Distortion Model

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 tri-substituted 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 have been hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The newly developed 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. Following trapping of in situ-generated pyridynes, the neighboring directing groups may be removed or exploited using versatile metal-catalyzed cross-coupling reactions. This methodology now renders 3,4-pyridynes useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle.

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