Catalytic flow synthesis: a new and efficient method to achieve pyrrolidine nitroxides

Palladium catalyzed reductions play an important role in many organic synthetic processes. When combined with flow chemistry, they offer an efficient approach for modifying reduction-sensitive functional groups. The preparation and modification of pyrrolidine-based paramagnetic building blocks require more vigorous conditions than their unsaturated analogues, and yields are generally low. The objective of this study is to demonstrate that flow-chemical reduction provides a viable method for obtaining nitroxide stable free radicals with saturated rings from their unsaturated counterparts. Because reduction of the nitroxide group is unavoidable during palladium catalyzed hydrogenation, a second aim is to investigate the behavior of the nitroxide group under varying pressure and temperature conditions in flow systems. While saturation of the carbon–carbon double bond in pyrroline aldehydes or esters and reduction of the nitroxide to the corresponding hydroxylamine occur readily under mild conditions, conversion of the nitroxide to the amine in significant quantities requires elevated temperatures. This suggests that pressure can be used to control secondary functional group reductions while avoiding overreduction of the nitroxide. We anticipate that this work will contribute to the selective synthesis of pyrrolidine- and piperidine-type nitroxide stable free radicals using a green methodology.