Bond-Weakening Catalysis: Conjugate Aminations Enabled by the Soft Homolysis of Strong N–H Bonds

Abstract

The ability of redox-active metal centers to weaken the bonds in associated ligands is well precedented, but has rarely been utilized as a mechanism of substrate activation in catalysis. Here we describe a catalytic bond-weakening protocol for conjugate amination wherein the strong N–H bonds in N-aryl amides (N–H bond dissociation free energies ~100 kcal/mol) are destabilized by ~33 kcal/mol upon by coordination to a reducing titanocene complex, enabling their abstraction by the weak H-atom acceptor TEMPO through a proton-coupled electron transfer process. Significantly, this soft homolysis mechanism provides a method to generate closed-shell, metalated nucleophiles under neutral conditions in the absence of a Brønsted base.

Catalytic N-radical cascade reaction of hydrazones by oxidative deprotonation electron transfer and TEMPO mediation

“…7 ). Taken together, although we could not completely exclude the concerted proton-coupled electron transfer mechanism at the current stage 24 38 39 , the above results are more consisted with an ODET activation mechanism involving sequential deprotonation of hydrazone substrates by the K 2 CO 3 and visible-light photocatalytic single-electron transfer (SET) oxidation.…”

“…1b , several major challenges would probably be encountered, such as the controlled formal homolysis of the recalcitrant N–H bond for the formation of the neutral N-centred hydrazonyl radical, regioselectivity of the N-radical cyclization step (for example, 6- endo and 5- exo , path a versus path b) 34 35 and selective homolytic activation of aza-allylic C–H bond in C-centred radical intermediate. Notably, it has been recently documented by MacMillan 36 37 , Knowles 24 38 39 and our group 28 40 that the addition of a suitable Brønsted acid, Lewis acid or base could facilitate some otherwise inaccessible photocatalytic event by weakening chemical bonds of reactants and co-catalysts or modulating their redox potential. It has also been demonstrated by López and Gómez that complete 6- endo -selectivity over 5- exo ring closure in radical cyclization of C-centred radicals can be controlled by the radical property, substitution pattern at C-5 or ring strain of substrate 34 35 .…”

O–H hydrogen bonding promotes H-atom transfer from α C–H bonds for C-alkylation of alcohols

“…We questioned whether the basic principles of PRC could be integrated into a catalytic system for the selective activation of alcohol α-C–Hbonds in the presence of a wide range of other C–H bonds (such as α-C=O, α-ether, or allylic or benzylic C–H) (11, 12). Specifically, we postulated that the selective C-alkylation of alcohols could be achieved via a photoredox-catalyzed, H-bond–assisted bond activation strategy (Fig.…”

Identification of Bond‐Weakening Spirosilane Catalyst for Photoredox α‐C−H Alkylation of Alcohols

“…Coordination-induced bond-weakening of NÀ H and OÀ H bonds by lowvalent metals have been studied in the field of inorganic chemistry. [8] A coordination-induced bond-weakening strategy using low-valent metals, however, would be problematic in combination with the strongly oxidative PC-HAT hybrid catalysis for targeting CÀ H bonds. [7,8] Knowles and co-workers reported pioneering work on NÀ H bond-weakening catalysis in organic synthesis.…”