2-Pyridone-Enabled Manganese-Catalyzed ortho-Selective Deuteration of Aromatic Amides with D₂O

Abstract

We present a highly efficient and regioselective methodology for the synthesis of ortho-deuterated aromatic amides, utilizing Mn(CO)₅Br as the catalyst, 2-pyridone as the CMD base, and D₂O as the deuterium source. This approach exhibits a broad substrate scope and exceptional functional group tolerance, enabling the late-stage deuteration of complex molecules with high yields and substantial deuterium incorporation. Mechanistic investigations suggest that 2-pyridone plays a critical role in the success of the reaction, acting as an endogenous base that facilitates reversible C−H activation and subsequent hydrogen-deuterium exchange. Deuterium-labeled compounds have become indispensable tools in a wide array of scientific domains[1], including mechanistic investigations of organic reactions[2], the development of deuterated drugs[3], and quantitative mass spectrometry analyses[4]. Consequently, the synthesis of deuterium-labeled organic compounds has attracted significant research attention. Aromatic carboxylic acids and their derivatives, as fundamental structural units, play a pivotal role in drug development and are commonly incorporated into the molecular frameworks of a wide variety of pharmacologically active compounds[5], such as Procainamide[6], Amisulpride[7], and Nemonapride[8]. Among these, benzamide derivatives have garnered substantial interest due to their broad spectrum of biological and pharmacological activities. Therefore, the design and development of selective synthetic methodologies for site-specific deuterated amide compounds is of considerable academic importance and holds significant potential for both theoretical advancements and practical applications in pharmaceutical chemistry. The direct hydrogen-deuterium (H/D) exchange of amide compounds is typically facilitated under catalytic conditions that involve acids, bases, or transition metals (such as Pd, Pt, Ru, Rh, and Ir)[9]. The use of directing groups to promote these exchanges has been extensively studied. For example, Yu et al. demonstrated efficient ortho-deuteration of aromatic amides using a palladium catalyst and 8-aminoquinoline as a directing group (Scheme 1a)[10]. More recently, our group developed an alternative methodology utilizing Ni(OTf)2 or CuO as catalysts to achieve efficient ortho-deuteration of benzamide derivatives[11]. However, these approaches often rely on costly deuterium sources and HFIP as the solvent, which reduces the theoretical deuterium incorporation and limits their broader applicability, as well as their potential for further functionalization.