Substrate-Directable Electron Transfer Reactions. Dramatic Rate Enhancement in the Chemoselective Reduction of Cyclic Esters Using SmI₂–H₂O: Mechanism, Scope, and Synthetic Utility

Abstract

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.

Reversed Electron Apportionment in Mesolytic Cleavage: The Reduction of Benzyl Halides by SmI2

“…These two substituents differ from the others by two features. The first is that these two substituents are capable of delocalizing the negative charge from the benzylic position onto themselves, and the second is that they are capable of binding to the samarium cation 10a. 25 Although it is unlikely that the electron‐withdrawing power of the p ‐CN and p ‐CO 2 Me substituents alone is sufficient to overcome the electronegativity of Cl and Br, their pairing with the triply charged samarium cation, apparently results in more efficient negative charge stabilization on the benzylic fragment than by its localization on the nucleofuge.…”

Highly Chemoselective Reduction of Amides (Primary, Secondary, Tertiary) to Alcohols using SmI2/Amine/H2O under Mild Conditions

“…In all cases, only alcohol products were formed, suggesting that chelation does not override the inherent reaction pathway. 16 We also found that amides featuring substituents known to afford mixtures of C–N/C–O cleavage products with other reagents 2a were amenable to the Sm(II) reduction protocol and that useful levels of chemoselectivity were obtained with these substrates (entries 13 and 14). We note, however, that N , N -diisopropylamide was unreactive under our reaction conditions (entry 15).…”

Highly Chemoselective Synthesis of Indolizidine Lactams by SmI2‐Induced Umpolung of the Amide Bond via Aminoketyl Radicals: Efficient Entry to Alkaloid Scaffolds

“…[16] The positioningo fa na lkene tether at the apositiontothe carbonyl group in a1,3-arrangement with achelating substituent enabled efficient reductive cyclization by adirecting group mechanism. [17] Mechanistically,t he cyclization proceeds by electron-transferr eduction of the imide carbonyl to generate an electron-rich aminoketyl radical, [18] which added to the p acceptor (cf. reduction of the acceptora nd anionic addition).…”

“…[22] To our knowledge this result represents ar are example of aS mI 2 -induced cyclization of an N-tethered unactivated olefin. [2a] With optimized conditions in hand, the scope of the reaction was next explored.S pecifically,t he examples were selected to cover the range of functional group tolerance with the highly discriminating SmI 2 /H 2 Or eagent [2l] and comparet he directing group effect [17] on the cyclization efficiency ( Table 2). As shown, the method readily accommodates ar ange of functional groups reductively removed with other lanthanide reagents, [1,2] including ethers (entry 2), benzyl fluorides (entry 3), aryl bromides (entry 4), naphthalenes (entry 5), and heterocycles (entry 6).…”