Rhodium-Catalyzed C–H Activation of Phenacyl Ammonium Salts Assisted by an Oxidizing C–N Bond: A Combination of Experimental and Theoretical Studies

Abstract

Rh(III)-catalyzed C-H activation assisted by an oxidizing directing group has evolved to a mild and redox-economic strategy for the construction of heterocycles. Despite the success, these coupling systems are currently limited to cleavage of an oxidizing N-O or N-N bond. Cleavage of an oxidizing C-N bond, which allows for complementary carbocycle synthesis, is unprecedented. In this article, α-ammonium acetophenones with an oxidizing C-N bond have been designed as substrates for Rh(III)-catalyzed C-H activation under redox-neutral conditions. The coupling with α-diazo esters afforded benzocyclopentanones, and the coupling with unactivated alkenes such as styrenes and aliphatic olefins gave ortho-olefinated acetophenoes. In both systems the reactions proceeded with a broad scope, high efficiency, and functional group tolerance. Moreover, efficient one-pot coupling of diazo esters has been realized starting from α-bromoacetophenones and triethylamine. The reaction mechanism for the coupling with diazo esters has been studied by a combination of experimental and theoretical methods. In particular, three distinct mechanistic pathways have been scrutinized by DFT studies, which revealed that the C-H activation occurs via a C-bound enolate-assisted concerted metalation-deprotonation mechanism and is rate-limiting. In subsequent C-C formation steps, the lowest energy pathway involves two rhodium carbene species as key intermediates.

Computational Studies of Heteroatom‐Assisted CH Activation at Ru, Rh, Ir, and Pd as a Basis for Heterocycle Synthesis and Derivatization

“…A related study by Huang and Chen on the Rh(OAc) 2 Cp*-catalyzed coupling of PhC(O)NHOR (OR = OPiv, OMe) with both cyclohexylallene and 1,1-dimethylallene was recently reported[79]. M06(MeOH)//B3LYP calculations confirm the observed regioselectivities: with cyclohexylallene, the 430 Rh-catalyzed lactam formation from N-acetoxybenzamide and 331 Rh-catalyzed benzocyclopentanone formation from benzophenone ammonium salts and α-diazoesters (R = CO 2 i Pr)[80]. (cf.Figure 1.30)is favored, but with 1,1-dimethylallene, greater steric hindrance in the insertion transition state drives the formation of the 3-isomer.…”

“…Ammonium groups can also act as internal oxidants, with C-N bond cleavage resulting in loss of an amine and formation of carbocyclic products. Lan, Wan, Li, and coworkers used M06(MeCN) and B3LYP-D3(MeCN) calculations to model Rh(OAc) 2 Cp*-catalyzed benzocyclopentanone formation from benzophenone ammonium salts and α-diazoesters(Figure 1.31)[80]. Initial deprotonation and loss of HOAc forms an enolate intermediate from which C-H activation proceeds preferentially from the C-bound form (ΔG ‡ calc : M06 = 27.2 kcal mol −1 , B3LYP-D3 = 26.3 kcal mol −1 ); barriers via the O-bound isomer were 2-3 kcal mol −1 higher.…”

Enaminones as Synthons for a Directed C−H Functionalization: RhIII‐Catalyzed Synthesis of Naphthalenes

“…However, in spite of tremendous progress, only five-membered carbocycles have been obtained thus far. [7] To enable the construction of an alternative scaffold, the six-membered naphthalene ring structure, a weaker directing group, an alkene moiety, is positioned one carbon atom away from the phenyl ring to eliminate the five-membered-ring synthetic pathway (Scheme 1 b). [8] Using a weakly coordinating alkene group, however, translates to, inevitably, several major drawbacks associated with that Pd II -based catalytic system: 1) required use of a strong acid for the generation of a highly electrophilic Pd II species, 2) no synthetically useful functionalities integrated into the target framework during the ring-forming process, 3) poor regioselectivity associated with the alkyne coupling partner, and 4) incompatibility with synthetically useful handles such as bromo and iodo substituents.…”

Rh(III)- and Ir(III)-Catalyzed C–C Bond Cross Couplings from C–H Bonds

“…Many mechanistic studies combining experimental and theoretical investigations have been undertaken [140,[158][159][160][161][162][163]. Certainly, in a near future, even more efforts will be devoted to rationalize the observed exciting reactivity, and hopefully, in a near future, a more rational design of new transformations and more powerful catalytic systems will be made possible.…”