Rhodium(III)-Catalyzed Heterocycle Synthesis Using an Internal Oxidant: Improved Reactivity and Mechanistic Studies

Abstract

Directing groups that can act as internal oxidants have recently been shown to be beneficial in metal-catalyzed heterocycle syntheses that undergo C-H functionalization. Pursuant to the rhodium(III)-catalyzed redox-neutral isoquinolone synthesis that we recently reported, we present in this article the development of a more reactive internal oxidant/directing group that can promote the formation of a wide variety of isoquinolones at room temperature while employing low catalyst loadings (0.5 mol %). In contrast to previously reported oxidative rhodium(III)-catalyzed heterocycle syntheses, the new conditions allow for the first time the use of terminal alkynes. Also, it is shown that the use of alkenes, including ethylene, instead of alkynes leads to the room temperature formation of 3,4-dihydroisoquinolones. Mechanistic investigations of this new system point to a change in the turnover limiting step of the catalytic cycle relative to the previously reported conditions. Concerted metalation-deprotonation (CMD) is now proposed to be the turnover limiting step. In addition, DFT calculations conducted on this system agree with a stepwise C-N bond reductive elimination/N-O bond oxidative addition mechanism to afford the desired heterocycle. Concepts highlighted by the calculations were found to be consistent with experimental results.

Combined Experimental and Computational Investigations of Rhodium- and Ruthenium-Catalyzed C–H Functionalization of Pyrazoles with Alkynes

“…13 In the present case NH and CH activation proceed with an overall barrier of 15. As the barrier to migratory insertion is similar with both approaches (ca.…”

“…12 In their computational study, Guimond et al considered isoquinolone formation via the reaction of PhC(O)NH(OAc) with acetylene at a simple Rh(OAc) 2 Cp model catalyst. 13 More recently Xia and coworkers revisited this system for dihydroquinolone formation via coupling of PhC(O)NH(OR) (R = Me, C(O)tBu) and ethene at Rh(OAc) 2 Cp*. 14 Here we report synthetic and mechanistic studies on the highly efficient CH functionalisation of 3-phenylpyrazoles with alkynes at a {RhCp*} centre and show similar reactivity at {Ru(p-cymene)}.…”

Synthesis of Heterocyclic Compounds through Palladium-Catalyzed C–H Cyclization Processes

“…During the process, the use of a large excess of reoxidants may inhibit the undesired N-O bond cleavage in which palladium and/or copper salt(s) involve. [41][42][43] The results of the tandem process affording 2-quinolinones via the formation of symmetrical 3,3-diarylacrylamides are summarized in Table 3. Reactions of substrates with a methyl group or a halogen atom at the para-position of the benzene rings proceeded efficiently (entries 1-3), whereas that of cinnamamide 12e, which possesses a methoxy group at the same position, resulted in the formation of the desired 2-quinolinone 14ee in only 12% yield, along with the recovery of the starting 12e in 85% yield (entry 4).…”

Synthesis of Isoquinolinones via Regioselective Palladium-Catalyzed C–H Activation/Annulation

“…The coordination of the metal center to the heteroatom-containing functional group-such as benzamides [33][34][35][36], aryl imines [37], and anilides [38][39][40]-directs and facilitates selective cleavage of Csp 2 -H bond to form the metallacycle. Migratory insertion of an alkene or alkyne forms the advanced intermediates, which undergo the subsequent reductive elimination to afford the heterocyclic product.…”