Steric Effect of Carboxylate Ligands on Pd‐Catalyzed Intramolecular C(sp²)–H and C(sp³)–H Arylation Reactions

Abstract

A bulky carboxylic acid bearing three cyclohexylmethyl substituents at the α-position, namely, tri(cyclohexylmethyl)acetic acid, is demonstrated to act as an efficient ligand source in Pd-catalyzed intramolecular C(sp )-H and C(sp )-H arylation reactions. The reactions proceed smoothly under mild reaction conditions, even at room temperature due to the steric bulk of the carboxylate ligands, which accelerates the rate-determining C-H bond activation step in the catalytic cycle.

C−H Activation and Cross‐Coupling of Acyclic Aldonitrone

“…A significant improvement could be achieved using carboxylic acids 3 – 6 additives (Figure 1), bulkier than PivOH (Table 1, entries 16–20). Particularly, acid 6 has been reported to have extraordinary effect on Pd‐catalyzed arylation yields, [32] and it was so in our case as well: 2 a was obtained in 72 % yield using 6 instead of PivOH (Table 1, entry 19). Unlike PivOH, decreasing the amount of 6 to 10 mol % increased the yield to 81 % (Table 1, entry 20).…”

“…If the coordinating nitrone has configuration E , the next, key reaction step can occur which is activation of the nitrone C(sp 2 )−H by an arylpalladium complex, probably via a concerted metalation‐deprotonation pathway similar to the mechanism postulated for Pd‐catalyzed arylation of N ‐oxides [34] . Such reaction course explains the need for a bulky carboxylate ligand [32] and is analogous to the mechanism proposed for Pd‐catalyzed C−H arylation of aldoxime ethers in the presence of silver acetate [17] . Subsequent reductive elimination provides ketonitrone 2 with retention of configuration around the C=N double bond.…”

Base‐Assisted C−H Bond Cleavage in Cross‐Coupling: Recent Insights into Mechanism, Speciation, and Cooperativity

“…A preliminary indication of where the break over point may reside comes from a recent study on intramolecular direct arylation by Tsuji . A series of large carboxylic acid additives were tested for their impact on yield in the cyclization illustrated in Figure b.…”

Palladium-Catalyzed Synthesis of Fluorenes by Intramolecular C(sp2)–H Activation at Room Temperature

“…A carboxylic acid bearing three long alkyl chains 1e 10 was not a good ligand for the reaction. The use of a bulkier carboxylic acid 1f, which was the best carboxylate ligand source for intramolecular C(sp 2 )-H bond-arylation reactions, 9 gave only 7% of 3a. Thus, we established that 1c is the best carboxylate ligand source under the reaction conditions.…”

“…Actually, we recently reported that a bulky carboxylic acid bearing three cyclohexylmethyl moieties in the position can operate as an efficient carboxylate ligand source in palladium-catalyzed intramolecular C(sp 2 )-H bond-arylation reactions (Scheme 1c). 9 It is notable that these reactions proceed at room temperature. After evaluating various carboxylic acids in the fluorene synthesis, commercially available pivalic acid was found to be the best source of the carboxylate ligand, and the desired reactions proceeded efficiently at room temperature (Scheme 1d).…”