Preparation and Use of Samarium Diiodide (SmI₂) in Organic Synthesis: The Mechanistic Role of HMPA and Ni(II) Salts in the Samarium Barbier Reaction

Abstract

Although initially considered an esoteric reagent, SmI 2 has become a common tool for synthetic organic chemists. SmI 2 is generated through the addition of molecular iodine to samarium metal in THF.1,2-3 It is a mild and selective single electron reductant and its versatility is a result of its ability to initiate a wide range of reductions including C-C bond-forming and cascade or sequential reactions. SmI 2 can reduce a variety of functional groups including sulfoxides and sulfones, phosphine oxides, epoxides, alkyl and aryl halides, carbonyls, and conjugated double bonds. [2][3][4][5][6][7][8][9][10][11][12] One of the fascinating features of SmI-2 -mediated reactions is the ability to manipulate the outcome of reactions through the selective use of cosolvents or additives. In most instances, additives are essential in controlling the rate of reduction and the chemo-or stereoselectivity of reactions. [13][14] Additives commonly utilized to fine tune the reactivity of SmI 2 can be classified into three major groups: (1) Lewis bases (HMPA, other electron-donor ligands, chelating ethers, etc.), (2) proton sources (alcohols, water etc.), and (3) inorganic additives (Ni(acac) 2 , FeCl 3 , etc). 3Understanding the mechanism of SmI 2 reactions and the role of the additives enables utilization of the full potential of the reagent in organic synthesis. The Sm-Barbier reaction is chosen to illustrate the synthetic importance and mechanistic role of two common additives: HMPA and Ni(II) in this reaction. The Sm-Barbier reaction is similar to the traditional Grignard reaction with the only difference being that the alkyl halide, carbonyl, and Sm reductant are mixed simultaneously in one pot. 1,15 Examples of Sm-mediated Barbier reactions with a range of coupling partners have been reported, 1,3,7,10,12 and have been utilized in key steps of the synthesis of large natural products. 16,17 Previous studies on the effect of additives on SmI 2 reactions have shown that HMPA enhances the reduction potential of SmI 2 by coordinating to the samarium metal center, producing a more powerful, [13][14]18 sterically encumbered reductant 19-21 and in some cases playing an integral role in post electrontransfer steps facilitating subsequent bond-forming events. 22 In the Sm-Barbier reaction, HMPA has been shown to additionally activate the alkyl halide by forming a complex in a pre-equilibrium step. 23Ni(II) salts are a catalytic additive used frequently in Sm-mediated transformations. [24][25][26][27] Though critical for success, the mechanistic role of Ni (II) was not known in these reactions. Recently it has been shown that SmI 2 reduces Ni(II) to Ni(0), and the reaction is then carried out through organometallic Ni(0) chemistry. 28These mechanistic studies highlight that although the same Barbier product is obtained, the use of different additives in the SmI 2 reaction drastically alters the mechanistic pathway of the reaction. The protocol for running these SmI 2 -initiated reactions is described. Video LinkThe video comp...

Solvent-Dependent Substrate Reduction by {Sm[N(SiMe3)2]2(THF)2}. An Alternative Approach for Accelerating the Rate of Substrate Reduction by Sm(II)

“…THF was purified using an air-free solvent purification system. Samarium diiodide (SmI 2 ) was prepared by standard methods, and iodometric titration was employed to verify concentration prior to use. , {Sm[N(SiMe 3 ) 2 ] 2 (THF) 2 } was prepared and purified by the method reported by Evans . In all subsequent experiments KI-free {Sm[N(SiMe 3 ) 2 ] 2 (THF) 2 } was used as a free-flowing powder.…”

“…Samarium(II)-based reductants have become important reagents in organic synthesis due to their ability to initiate a wide variety of reductions and bond-forming reactions that proceed through radical and anionic intermediates. − The most commonly utilized Sm(II)-based reductant is samarium diiodide (SmI 2 ). In part, the utility of SmI 2 is a consequence of its straightforward preparation and storage in tetrahydrofuran (THF) under an inert atmosphere. , One important feature of reactions employing SmI 2 is the addition of oxygen-containing Lewis bases (predominantly HMPA) or proton donors (alcohols, glycols, and water) that compete with bound solvent (THF) for coordination to the oxophilic Sm(II) center, significantly altering the reactivity and selectivity of the reagent. , Although additives can impact the reactivity of the reagent through the production of a thermodynamically more powerful reductant − or through the stabilization of Sm(III), the key feature in many of these processes is the displacement of THF or iodide ligands creating open sites for substrate coordination . Given the oxophilicity of the reagent, and the importance of oxygen donor molecules in facilitating reactions of SmI 2 , several questions come to mind: (1) Do coordinating oxygen-containing solvents inhibit substrate access to the metal?…”

“…In part, the utility of SmI 2 is a consequence of its straightforward preparation and storage in tetrahydrofuran (THF) under an inert atmosphere. 6,7 One important feature of reactions employing SmI 2 is the addition of oxygen-containing Lewis bases (predominantly HMPA) or proton donors (alcohols, glycols, and water) that compete with bound solvent (THF) for coordination to the oxophilic Sm(II) center, significantly altering the reactivity and selectivity of the reagent. 8,9 Although additives can impact the reactivity of the reagent through the production of a thermodynamically more powerful reductant 10−12 or through the stabilization of Sm(III), 13 the key feature in many of these processes is the displacement of THF or iodide ligands creating open sites for substrate coordination.…”