Michal Szostak

Beyond samarium diiodide: Vistas in reductive chemistry mediated by lanthanides(II)

Reactions proceeding through open-shell, single-electron pathways offer attractive alternative outcomes to those proceeding through closed-shell, two-electron mechanisms. In this context, samarium diiodide (SmI(2)) has emerged as one of the most important and convenient-to-use electron-transfer reagents available in the laboratory. Recently, significant progress has been made in the reductive chemistry of other divalent lanthanides which for many years had been considered too reactive to be of value to synthetic chemists. Herein, we illustrate how new samarium(II) complexes and nonclassical lanthanide(II) reagents are changing the landscape of modern reductive chemistry.

Selective Reductive Transformations Using Samarium Diiodide-Water

Samarium diiodide (SmI(2)) is one of the most important reductive electron transfer reagents available in the laboratory. Key to the popularity of SmI(2) is the ability of additives and co-solvents to tune the properties of the reagent. Over the last decade water has emerged as a particularly valuable additive, opening up new chemical space and leading to the discovery of unprecedented selectivity and new reactions promoted by SmI(2). In this Feature Article we review recent progress in the application of SmI(2)-H(2)O systems, with an emphasis on mechanistic considerations and the development of new transformations.

Electron transfer reduction of unactivated esters using SmI2–H2O

The reduction of unactivated esters using samarium diiodide is reported for the first time. The optimised protocol allows for the reduction of primary, secondary and tertiary alkyl esters in excellent yields and is competitive with reductions mediated by metal hydrides and alkali metals.

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,1 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 1 a).2 Moreover, as an easily accessible feedstock material, it is an extremely useful building block for organic synthesis.3 However, despite the fact that barbiturates have been extensively studied for over a century, the general monoreduction of barbituric acids remains unknown,4 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.5

A general electron transfer reduction of lactones using SmI2–H2O

Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI(2)-H(2)O and a Lewis base to tune the redox properties of the complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.

Uncovering the Importance of Proton Donors in TmI2‐Promoted Electron Transfer: Facile CN Bond Cleavage in Unactivated Amides

The amide bond is one of the most ubiquitious functional groups in chemistry and biology.1 To date, the majority of strategies to functionalize amide bonds have focused on activation of the carbonyl group towards nucleophilic addition,2 however only few examples of the selective activation of σ C–N bonds in amides have been reported. In this regard, the cleavage of a σ C−N bond in amides was achieved in several highly innovative but very specialized bridged lactams, in which one of the C−N bonds was sufficiently distorted from planarity (Figure 1 a).3 Functionalization of the C−N bond in electronically activated phthalimides has also been described.4 However, a general method for the activation of σ C−N bonds in amides is unknown despite its considerable potential to advance the synthetic application of amide linkages in chemistry and biology.

On the Role of Pre‐ and Post‐Electron‐Transfer Steps in the SmI2/Amine/H2O‐Mediated Reduction of Esters: New Mechanistic Insights and Kinetic Studies

The mechanism of the SmI2-mediated reduction of unactivated esters has been studied using a combination of kinetic, radical clocks and reactivity experiments. The kinetic data indicate that all reaction components (SmI2, amine, H2O) are involved in the rate equation and that electron transfer is facilitated by Brønsted base assisted deprotonation of water in the transition state. The use of validated cyclopropyl-containing radical clocks demonstrates that the reaction occurs via fast, reversible first electron transfer, and that the electron transfer from simple Sm(II) complexes to aliphatic esters is rapid. Notably, the mechanistic details presented herein indicate that complexation between SmI2, H2O and amines affords a new class of structurally diverse, thermodynamically powerful reductants for efficient electron transfer to carboxylic acid derivatives as an attractive alternative to the classical hydride-mediated reductions and as a source of acyl-radical equivalents for C=C bond forming processes.