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Synthesis

Pyridines Yield To Diels-Alder

by Bethany Halford
July 18, 2005 | APPEARED IN VOLUME 83, ISSUE 29

ORGANIC SYNTHESIS

With the help of a little electronic tug from tungsten, chemists from the University of Virginia have managed to persuade pyridines to undergo a Diels-Alder reaction (J. Am. Chem. Soc. 2005, 127, 10568). The reaction methodology offers synthetic chemists a promising new route to the complex isoquinuclidine core common to a number of medicinally relevant compounds, according to the report.

Diels-Alder reactions with pyridines are virtually unknown because the heterocycles' aromatic stabilization makes them inert to this type of cycloaddition reaction. Chemistry professor W. Dean Harman, grad students Peter M. Graham and David A. Delafuente, and coworkers reasoned that a -basic metal, like tungsten, could coordinate one of the heterocycle's double bonds and disrupt its aromaticity, effectively making the pyridine into a diene.

Harman previously used this strategy to coax benzene into undergoing Diels-Alder reactions. Pyridines, however, present an additional obstacle: Metals tend to coordinate to the heterocycle's nitrogen atom rather than its double bonds. Harman's group gets around this problem by using 2-substituted pyridines, such as 2-(dimethylamino)pyridine and 2,6-lutidine. "We played the trick of blocking the nitrogen from binding to the metal," Harman explains.

After coordinating to a -basic tungsten complex, the once-inert pyridines undergo cycloaddition with electron-deficient alkenes under mild conditions. Harman's group observed that only one regioisomer of the bicyclic product is formed and that the reaction is somewhat stereoselective.

The new methodology may lead to many new reactions with p-bound heterocycles, Harman points out. His group is currently trying to make the reaction general for all pyridines. "I expect that we're going to have access to a number of reactions with heterocycles that haven't been observed before," he says.

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