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

Michal Szostak,Malcolm Spain,David J Procter

doi:10.1002/anie.201303178

Michal Szostak, Malcolm Spain + Show 1 more

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https://doi.org/10.1002/anie.201303178

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Abstract

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.

Highlights

The amide bond is one of the most ubiquitious functional groups in chemistry and biology.[1]
We considered that highly reducing nonclassical lanthanide(II) iodides that are activated by proton donors, could potentially permit productive electron transfer to amide carbonyls, a functional group that has been traditionally resistant to single-electron-transfer reductants, as a result of nN!p*C=O conjugation.[1]
On the basis of this experiment and the known propensity of nonclassical LnI2 to cleave CÀO bonds in ethers,[15] we propose that the mechanism of the TmI2-mediated cleavage involves a direct insertion of TmII into the CÀN amide bond; a mechanism involving fragmentation of an initially-formed ketyl-type radical seems to be operating in some cases as suggested by the correlation of the reaction efficiency with thermochemical stabilization energies (SE) of the fragmenting radical in the series: tBu (71 %, SE = 4.35 kcal molÀ1) > iPr (29 %, SE = 2.57 kcal molÀ1) > Me (< 2 %, SE = À1.65 kcal molÀ1).[16]