Rubén Vicente

Assisted ruthenium-catalyzed C-H bond activation: carboxylic acids as cocatalysts for generally applicable direct arylations in apolar solvents.

Catalytic amounts of aromatic carboxylic acid MesCO H enabled efficient ruthenium-catalyzed direct arylations in apolar solvents with unparalleled broad scope via a concerted deprotonation-metalation mechanism.

Ruthenium-Catalyzed Regioselective Direct Alkylation of Arenes with Unactivated Alkyl Halides through CH Bond Cleavage†

Direct arylation of arenes by C H bond cleavage, which is attractive because of its ecologically and economically benign nature, is an increasingly viable alternative to conventional cross-coupling reactions with stoichiometric amounts of organometallic reagents. 2] However, while the development of stabilizing ligands allowed for the use of unactivated alkyl halides in traditional cross-coupling chemistry, generally applicable methodologies for intermolecular regioselective direct alkylations of arenes with alkyl halides by C H bond cleavage have proven elusive. Recently, we reported on the beneficial effect of carboxylic acids as additives in ruthenium-catalyzed direct arylation 11] with aryl bromides, chlorides, or tosylates. Given the significantly improved activity of the in situ generated catalytic system, we became interested in exploring its use for unprecedented ruthenium-catalyzed direct alkylations with unactivated alkyl halides 15] as electrophiles. Herein, we report our findings on the development of such C H bond functionalization reactions, which allowed for the efficient conversion of primary and secondary alkyl halides and proved applicable to neopentyl-substituted electrophiles. At the outset of our studies, we probed various additives in the ruthenium-catalyzed direct alkylation of 2-pyridyl benzene (1a), employing unactivated alkyl bromide 2 a in NMP as solvent (Table 1). Different phosphines did not significantly affect the outcome of the envisioned reaction (Table 1, entries 1–4). On the contrary, more promising results were obtained when catalytic amounts of carboxylic acids were used as additives (Table 1, entries 5–9). The alkylsubstituted, sterically hindered acid 1-AdCO2H gave the best results (Table 1, entry 9). Reactions performed in toluene as solvent proceeded less efficiently (Table 1, entry 10), and other solvents, such as THF, 1,4-dioxane, DMSO, or N,N-dimethylacetamide, gave considerably lower yields of desired product 3a. As an economically attractive alternative, RuCl3·n H2O [17] could be employed as catalyst precursor (Table 1, entry 11). Importantly, direct alkylation of pyridine derivative 1a could be performed at reaction temperatures as low as 60 8C with comparable efficiencies (Table 1, entries 13–15). Finally, the use of independently prepared carboxylic ester 1-AdCO2(nHex) clearly indicated that its formation was not relevant to the generation of the catalytically active ruthenium species (Table 1, entry 16). We then explored the scope of the optimized catalytic system in the direct alkylation of pyridine derivatives 1 (Table 2). A variety of unactivated alkyl bromides bearing bhydrogen atoms enabled regioselective direct alkylations (Table 2, entries 1–8). While an alkyl iodide also led to an acceptable yield of product 3a (Table 2, entry 9), the corresponding alkyl chloride turned out to be a more challenging substrate (Table 2, entry 10). Notably, our in situ generated catalytic system was not limited to the use of primary alkyl halides but also enabled the conversion of sterically more congested secondary alkyl halides, albeit with lower yield (Table 2, entry 11). Importantly, neopentyl bromide also served as starting material for a direct alkylation (Table 2, entry 12), which indicated that mechanisms relying on either a Table 1: Optimization of ruthenium-catalyzed direct alkylation.

Ruthenium-Catalyzed Direct Arylations Through C–H Bond Cleavages

Stoichiometric cycloruthenation reactions of substrates containing Lewis-basic functionalities set the stage for efficient ruthenium-catalyzed C-H bond functionalization reactions. Thereby, selective addition reactions of C-H bonds across alkenes or alkynes enabled atom-economical synthesis of substituted arenes. More recently, ruthenium-catalyzed direct arylation reactions were examined, which display an unparalleled scope and, hence, represent economically and environmentally benign alternatives to traditional cross-coupling chemistry.

Mechanistic Insight into Direct Arylations with Ruthenium(II) Carboxylate Catalysts

Mechanistic studies revealed ruthenium-catalyzed direct arylations to proceed through reversible C-H bond activation and subsequent rate-limiting oxidative addition with aryl halides, which led to the development of widely applicable well-defined ruthenium(II) carboxylate catalysts.

Carboxylate-Assisted Ruthenium-Catalyzed Direct Alkylations of Ketimines

The mechanism of carboxylate-assisted ruthenium(II)-catalyzed direct alkylations of ketimines with unactivated alkyl halides was probed through experimental studies. The remarkable chemoselectivity of the broadly applicable catalyst also enabled direct alkylations among others on H(2)O or under solvent-free reaction conditions.

Metal-Free Direct Arylations of Indoles and Pyrroles with Diaryliodonium Salts

Direct arylations of indoles and pyrroles with differently substituted diaryliodonium salts were shown to efficiently proceed in the absence of metal catalysts.

Catalytic direct arylations in polyethylene glycol (PEG): recyclable palladium(0) catalyst for C-H bond cleavages in the presence of air.

Two protocols for ruthenium- or palladium-catalyzed direct arylations in user-friendly polyethylene glycol (PEG) were devised, which set the stage for the development of user-friendly palladium(0)-catalyzed C-H bond functionalizations in the presence of air with a recyclable phosphine ligand-free palladium complex.

Cu(I)-catalyzed regioselective synthesis of polysubstituted furans from propargylic esters via postulated (2-furyl)carbene complexes.

Polysubstituted furan derivatives are regioselective obtained from (bis-alkynyl)methyl carboxylates in the presence of catalytic amounts of copper(I) salts. This multistep process is consistent with the intermediacy of a copper(I) (2-furyl)carbene complex which is intercepted by suitable trapping reagents.

Ruthenium‐Catalyzed Direct Arylations of N‐Aryl 1,2,3‐Triazoles with Aryl Chlorides as Electrophiles

Ring ring ring: Ruthenium-catalyzed direct arylations of N-aryl 1,2,3-triazoles with chlorides as arylating reagents proceed efficiently with an in situ generated complex derived from phosphane PCy(3) in N-methyl-2-pyrrolidone (NMP) as solvent.

Air-Stable Secondary Phosphine Oxide as Preligand for Palladium-Catalyzed Intramolecular α-Arylations with Chloroarenes

A palladium catalyst derived from air-stable secondary phosphine oxide (1-Ad)(2)P(O)H enabled efficient intramolecular alpha-arylations of amides with aryl chlorides, which allowed for the synthesis of diversely substituted (aza)oxindoles.