Highly chemoselective direct reduction of primary, secondary, and tertiary amides to alcohols using SmI2/amine/H2O is reported. The reaction proceeds with C–N bond cleavage in the carbinolamine intermediate, shows excellent functional group tolerance, and delivers the alcohol products in very high yields. The expected C–O cleavage products are not formed under the reaction conditions. The observed reactivity is opposite to the electrophilicity of polar carbonyl groups resulting from the nX → π*C═O (X = O, N) conjugation. Mechanistic studies suggest that coordination of Sm to the carbonyl and then to Lewis basic nitrogen in the tetrahedral intermediate facilitate electron transfer and control the selectivity of the C–N/C–O cleavage. Notably, the method provides direct access to acyl-type radicals from unactivated amides under mild electron transfer conditions.

Mechanistic details pertaining to the SmI2–H2O-mediated reduction and reductive coupling of 6-membered lactones, the first class of simple unactivated carboxylic acid derivatives that had long been thought to lie outside the reducing range of SmI2, have been elucidated. Our results provide new experimental evidence that water enables the productive electron transfer from Sm(II) by stabilization of the radical anion intermediate rather than by solely promoting the first electron transfer as originally proposed. Notably, these studies suggest that all reactions involving the generation of ketyl-type radicals with SmI2 occur under a unified mechanism based on the thermodynamic control of the second electron transfer step, thus providing a blueprint for the development of a broad range of novel chemoselective transformations via open-shell electron pathways.

Structural characterisation and reactivity of new tetrahedral intermediates based on a highly modular barbituric acid scaffold, formed via chemoselective electron transfer using the SmI2–H2O reagent, are reported. Lewis acid promoted cleavage of bicyclic α-amino alcohols affords vinylogous N-acyliminium ions, which undergo selective (>95:5, 1,4 over 1,2) capture with a suite of diverse nucleophiles in a practical sequence to biologically active uracil derivatives.

Lewis acid promoted cleavage of α-amino alcohols derived from barbituric acids via chemoselective Sm(II)-mediated electron transfer affords a wide range of C6-substituted 5,6-dihydrouracils. The reaction involves the first generation of N-acyliminium ions directly from the versatile barbituric acids and proceeds with excellent stereoselectivity. The products are shown to be active in generic transition metal catalyzed reactions, thus providing a modular and highly practical sequence to the biologically significant uracil derivatives.

The first general reduction of nitriles to primary amines under single electron transfer conditions is demonstrated using SmI2 (Kagan’s reagent) activated with Lewis bases. The reaction features excellent functional group tolerance and represents an attractive alternative to the use of pyrophoric alkali metal hydrides. Notably, the electron transfer from Sm(II) to CN functional groups generates imidoyl-type radicals from bench stable nitrile precursors.

The mechanism of a recently reported first mono-reduction of cyclic 1,3-diesters (Meldrum's acids) to β-hydroxy acids with SmI2–H2O has been studied using a combination of reactivity, deuteration, kinetic isotope and radical clock experiments. Most crucially, the data indicate that the reaction proceeds via reversible electron transfer and that water, as a ligand for SmI2, stabilizes the radical anion intermediate rather than only promoting the first electron transfer as originally proposed.

Samarium(II) iodide–water complexes are ideally suited to mediate challenging electron transfer reactions, yet the effective redox potential of these powerful reductants has not been determined. Herein, we report an examination of the reactivity of SmI2(H2O)n with a series of unsaturated hydrocarbons and alkyl halides with reduction potentials ranging from −1.6 to −3.4 V vs SCE. We found that SmI2(H2O)n reacts with substrates that have reduction potentials more positive than −2.21 V vs SCE, which is much higher than the thermodynamic redox potential of SmI2(H2O)n determined by electrochemical methods (up to −1.3 V vs SCE). Determination of the effective redox potential demonstrates that coordination of water to SmI2 increases the effective reducing power of Sm(II) by more than 0.4 V. We demonstrate that complexes of SmI2(H2O)n arising from the addition of large amounts of H2O (500 equiv) are much less reactive toward reduction of aromatic hydrocarbons than complexes of SmI2(H2O)n prepared using 50 equiv of H2O. We also report that SmI2(H2O)n cleanly mediates Birch reductions of substrates bearing at least two aromatic rings in excellent yields, at room temperature, under very mild reaction conditions, and with selectivity that is not attainable by other single electron transfer reductants.

Recently, samarium(II) iodide reductants have emerged as powerful single electron donors for the highly chemoselective reduction of common functional groups. Complete control of the product formation can be achieved on the basis of a judicious choice of a Sm(II) complex/proton donor couple, even in the presence of extremely sensitive functionalities (iodides, aldehydes). In most cases, the reductions are governed by thermodynamic control of the first electron transfer, which opens up new prospects for unprecedented transformations via radical intermediates under mild regio-, chemo- and diastereoselective conditions that are fully orthogonal to hydrogenation or metal-hydride mediated processes.

Substrate-directable reactions play a pivotal role in organic synthesis, but are uncommon in reactions proceeding via radical mechanisms. Herein, we provide experimental evidence showing dramatic rate acceleration in the Sm(II)-mediated reduction of cyclic esters that is enabled by transient chelation between a directing group and the lanthanide center. This process allows unprecedented chemoselectivity in the reduction of cyclic esters using SmI2–H2O and for the first time proceeds with a broad substrate scope. Initial studies on the origin of selectivity and synthetic application to form carbon–carbon bonds are also disclosed.

Structural characterisation and reactivity of new tetrahedral intermediates based on a highly modular barbituric acid scaffold, formed via chemoselective electron transfer using the SmI2–H2O reagent, are reported. Lewis acid promoted cleavage of bicyclic α-amino alcohols affords vinylogous N-acyliminium ions, which undergo selective (>95:5, 1,4 over 1,2) capture with a suite of diverse nucleophiles in a practical sequence to biologically active uracil derivatives.

The mechanism of a recently reported first mono-reduction of cyclic 1,3-diesters (Meldrum's acids) to β-hydroxy acids with SmI2–H2O has been studied using a combination of reactivity, deuteration, kinetic isotope and radical clock experiments. Most crucially, the data indicate that the reaction proceeds via reversible electron transfer and that water, as a ligand for SmI2, stabilizes the radical anion intermediate rather than only promoting the first electron transfer as originally proposed.

Recently, samarium(II) iodide reductants have emerged as powerful single electron donors for the highly chemoselective reduction of common functional groups. Complete control of the product formation can be achieved on the basis of a judicious choice of a Sm(II) complex/proton donor couple, even in the presence of extremely sensitive functionalities (iodides, aldehydes). In most cases, the reductions are governed by thermodynamic control of the first electron transfer, which opens up new prospects for unprecedented transformations via radical intermediates under mild regio-, chemo- and diastereoselective conditions that are fully orthogonal to hydrogenation or metal-hydride mediated processes.