Selective Reduction of Barbituric Acids Using SmI2/H2O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adducts**

Since the 1864 landmark discovery by Adolf von Baeyer, barbituric acids have played a prominent role in medicine and organic synthesis. The barbituric acid scaffold occurs in more than 5000 pharmacologically active compounds, including commonly used anticonvulsant, hypnotic, and anticancer agents (Figure 1a). Moreover, as an easily accessible feedstock material, it is an extremely useful building block for organic synthesis. However, despite the fact that barbiturates have been extensively studied for over a century, the general monoreduction of barbituric acids remains unknown, even though it would have considerable potential for the production and discovery of pharmaceuticals, materials, and polymers. Interestingly, the barbiturate monoreduction products would formally constitute a new class of tetrahedral intermediates of amide bond addition reactions, only few of which have been successfully isolated to date because of their transient nature. Single-electron-transfer reactions open up unexplored reaction space charted with chemoselectivity and reactivity levels difficult to access by ionic reaction mechanisms. The generation of ketyl-type radicals with SmI2 is particularly valuable in this regard because of the excellent chemoselectivity imparted by the reagent and the potential to effect polarity reversal of the carbonyl group through a singleelectron-reduction event (Figure 1b). However, the selective reduction of amide carbonyls with SmI2 is challenging and no general method to achieve this highly desirable transformation is currently available. Herein, we demonstrate that the SmI2/H2O reagent [10] can perform the selective monoreduction of barbituric acids to the corresponding hemiaminals (Figure 1c). To our knowledge these are the first general examples of monoreduction of such systems as well as the reduction of amide-type carbonyls with SmI2. [7,8] The hemiaminal products are analogous to tetrahedral intermediates derived from amide addition reactions. Moreover, the radical intermediates formed by the one-electron reduction have been utilized in intramolecular additions to alkenes. For the first time in any SmI2-mediated cross-couplings of acyl-type radicals, [11] these additions proceed with full control of diastereoselectivity. Furthermore, experimental evidence is provided for the isomerization of vinyl radical intermediates under SmI2/H2O reaction conditions. This discovery opens the door for the use of SmI2/H2O in cascade reductive processes employing Ccentered radicals. Overall, these studies provide a basis for multiple methodologies to form versatile hemiaminal products (cf. hemiacetals) by a formal amide polarity reversal event. We hypothesized that single-electron reduction of barbituric acids (cyclic 1,3-diimides) to their respective radical anions could provide a benchmark for the development of a general system for the reduction of a wide range of amide functional groups. We considered that 1) in the barbituric acid system the reduction of one of the imide carbonyls would be Figure 1. a) Examples of pharmacologically active barbiturates. b) Polarity inversion strategy using SET approach. c) This study.