Concerted Metalation-deprotonation Pathway Research Articles

Regio- and Chemoselective Palladium-Catalyzed Additive-Free Direct C─H Functionalization of Heterocycles with Chloroaryl Triflates Using Pyrazole-Alkyl Phosphine Ligands.

A series of new pyrazole-alkyl phosphine ligands with varying cycloalkyl ring sizes that enable additive-free regio- and chemoselective C─H arylation of heterocycles are reported. Excellent α/β selectivity of various heterocycles such as benzo[b]thiophene, thiophene, furan, benzofuran, and thiazole can be achieved using these ligands, along with excellent chemoselectivity of C─Cl over C─OTf of chloroaryl triflates. Mechanistic studies supported by both experimental findings and density functional theory calculations indicate that the pyrazole phosphine ligands with optimal ring sizes allow the reaction to proceed with a lower energy barrier via a concerted metalation-deprotonation pathway.

Electronically controlled regioselective hydroarylation of gem-difluoroallenes

All-carbon quaternary centers are ubiquitous structural motifs in natural products, bioactive molecules, and pharmaceuticals. The formation of these crowded carbon centers is well known to be challenging, and methods to access them remain in high demand. Transition-metal-based strategies have emerged as a powerful approach to quaternary carbons, primarily relying on cross-coupling reactions and olefin arylation processes. Herein is presented a straightforward method to create benzylic all-carbon quaternary centers employing gem -difluoroallenes. Features of this method include room temperature C–H functionalization, excellent regioselectivity in the insertion of gem -difluoroallenes, and generation of gem -difluoroalkene products, which have widespread applications in synthesis and pharmaceutical sciences. Mechanistic studies support a turnover limiting rhodium-catalyzed C–H cleavage that likely proceeds via a concerted metalation deprotonation pathway. Regioselective insertion of the gem -difluoroallene is controlled by electronic effects. • Efficient and facile construction of all-carbon quaternary benzylic centers • Preparation of versatile gem -difluoroalkenes via hydroarylation is shown • Regioselective insertion of 1,1-difluoroallene is controlled by electronic effects • Gram-scale synthesis and diverse synthetic transformations are observed Efficient construction of all-carbon quaternary centers is vital owing to their ubiquity in natural products, bioactive molecules, and drugs. Here, Wang et al. develop an example of hydroarylation of gem -difluoroallenes to prepare versatile gem -difluoroalkenes with an all-carbon quaternary center.

Insights into the C[sbnd]H activation mechanism in the Rh(I)-Catalyzed alkenylation of ketone with alkyne

The mechanisms of the Rh(I)-catalyzed alkenylation reaction were investigated by density functional theory (DFT) calculations. Our results show that the CH activation of this reaction occurs through the metal hydride pathway rather than the general concerted metalation deprotonation (CMD) mechanism. The favorable metal–hydride pathway involves CH oxidative addition, alkyne migratory insertion into RhH and CC reductive elimination. Moreover, the consecutive migratory insertion into the RhH and CC reductive elimination is kinetically more favorable than the alkyne migratory insertion into RhC and CH reductive elimination. The CMD pathway is kinetically unfavorable due to the considerably higher barrier of several elementary steps. The improved mechanistic understanding will enable design of novel couplings between hydrocarbons and CH bonds.

Mechanistic Investigation of Palladium-Catalyzed meta-C-H Bond Activation of Arenes with a Carboxyl Directing Group.

The mechanism of Pd(II)-catalyzed meta-C-H bond olefination of arenes with a carboxyl directing group (DG)-containing template has been investigated with density functional theory. The reaction includes three major steps: C-H bond activation, alkene insertion, and β-hydride elimination. The C-H activation step, which proceeds via a concerted metalation-deprotonation pathway, is found to be the rate- and regioselectivity-determining step. We proposed a mono-N-protected amino acid (MPAA)/DG-assisted C-H activation model, in which the carboxyl DG coordinates with the Pd center and delivers it to the meta-position of arene, and the bidentate dianionic MPAA acts as a base for deprotonation. There is a hydrogen bonding interaction between the carboxyl DG and the carboxylate group of MPAA. An alternative Pd(OAc)2-catalyzed mechanism without involvement of MPAA is also operative. The template is conformationally flexible, and multiple low-energy transition-state conformations contribute to the regioselectivity.

Palladium Nitrosyl Complexes as Highly Versatile Catalysts for C−H/C−H Oxidative Coupling of Arenes: Application Area and Insight into Mechanism

AbstractPalladium nitrsosyl carboxylates Pd3(NO)2(CX3CO2)4(ArH)2 (I: X=Cl, Ar=Ph; II: X=F, Ar=Tol) are found to be effective catalysts for C−H/C−H oxidative homocoupling of arenes bearing electron‐donor as well as electron‐withdrawing groups (EWG). Trifluoroacetate complex II is found to be more promising due to higher stability under the reaction conditions. Complex II also shows high performance in intramolecular coupling in diarylsulfides, diarylethers and diarylamines giving corresponding dibenzothiophenes, dibenzofurans and carbazoles with yields ranged from moderate to high. The plausible mechanism is studied by DFT computational analysis basing on Pd3 linear complexes as major active species. It was found that two deprotonation steps proceed in two different ways: for the first deprotonation SEAr is most probable pathway while for the second one concerted metalation‐deprotonation (CMD) is preferable. That can explain high tolerance of the system to different substrates: SEAr is favorable in the presence of electron donor group and EWG facilitate CMD. NO group was found to be involved into the CMD pathway and that is the rate‐determining step with the highest activation barrier.

Cooperative Au/Ag Dual-Catalyzed Cross-Dehydrogenative Biaryl Coupling: Reaction Development and Mechanistic Insight.

An operationally simple and highly selective Au/Ag bimetallic-catalyzed cross-dehydrogenative biaryl coupling between pyrazoles and fluoroarenes has been developed. With this reaction, a wide range of biheteroaryl products can be obtained in moderate to good yields with excellent functional group compatibility. The exact role of silver salts, previously overlooked in most gold-catalyzed transformations, has been carefully investigated in this biaryl coupling. Insightful experimental and theoretical studies indicate that silver acetate is the actual catalyst for C-H activation of electron-poor arenes, rather than the previously reported gold(I)-catalyzed process. An unprecedented Au/Ag dual catalysis is proposed, in which silver(I) is responsible for the activation of electron-poor fluoroarenes via a concerted metalation-deprotonation pathway, and gold(III) is responsible for the activation of electron-rich pyrazoles via an electrophilic aromatic substitution process. Kinetic studies reveal that ArFnAu(III)-mediated C-H activation of pyrazoles is most likely the rate-limiting step.

Computational Exploration of Mechanistic Avenues in C-H Activation Assisted Pd-Catalyzed Carbonylative Coupling.

The detailed mechanism of the intermolecular Pd-catalyzed carbonylative coupling reaction between aryl bromides and polyfluoroarenes relying on C(sp2)-H activation was investigated using state-of-the-art computational methods (SMD-B3LYP-D3(BJ)/BS2//B3LYP-D3/BS1). The mechanism unveils the necessary and important roles of a slight excess of carbon monoxide: acting as a ligand in the active catalyst state, participating as a reactant in the carbonylation process, and accelerating the final reductive elimination event. Importantly, the desired carbonylative coupling route follows the rate-limiting C-H activation process via the concerted metalation-deprotonation pathway, which is slightly more feasible than the decarboxylative route leading to byproduct formation by 1.2 kcal/mol. The analyses of the free energies indicate that the choice of base has a significant effect on the reaction mechanism and its energetics. The Cs2CO3 base guides the reaction toward the coupling route, whereas carbonate bases such as K2CO3 and Na2CO3 switch toward an undesired decarboxylative path. However, K3PO4 significantly reduces the C-H activation barrier over the decarboxylation reaction barrier and can act as a potential alternative base. The positional influence of a methoxy substituent in bromoanisole and different substituent effects in polyfluoroarenes were also considered. Our results show that different substituents impose significant impact on the desired carbonylative product formation energetics. Considering the influence of several ligands leads to the conclusion that other phosphine and N-heterocyclic carbene, such as P nBuAd2 and IMes, can be used as an efficient alternative than the experimentally reported P tBu3 ligand exhibiting a clear preference for C-H activation (ΔΔ⧧ GLS) by 7.1 and 10.9 kcal/mol, respectively. We have also utilized the energetic span model to interpret the experimental results. Moreover, to elucidate the origin of activation barriers, energy decomposition analysis calculations were accomplished for the critical transition states populating the energy profiles.

Rhodium(III)-Catalyzed Selective Monoarylation of β or γ C(sp3)-H Bonds Assisted by a Trimethylpyrazole Group.

The selective arylation of unactivated β or challenging γ primary and secondary β-C(sp3)-H bonds has been developed with a Cp*Rh(III) catalyst assisted by a trimethylpyrazole group. A rarely reported six-membered rhodacycle has been identified in rhodium-catalyzed C(sp3)-H activation reactions. Preliminary mechanistic studies have revealed that a concerted metalation-deprotonation pathway might be involved in the C-H activation step.

Palladium-Catalyzed, Site-Selective Direct Allylation of Aryl C-H Bonds by Silver-Mediated C-H Activation: A Synthetic and Mechanistic Investigation.

We describe a method for the site-selective construction of a C(aryl)-C(sp3) bond by the palladium-catalyzed direct allylation of arenes with allylic pivalates in the presence of AgOPiv to afford the linear (E)-allylated arene with excellent regioselectivity; this reaction occurs with arenes that have not undergone site-selective and stereoselective direct allylation previously, such as monofluorobenzenes and non-fluorinated arenes. Mechanistic studies indicate that AgOPiv ligated by a phosphine reacts with the arene to form an arylsilver(I) species, presumably through a concerted metalation-deprotonation pathway. The activated aryl moiety is then transferred to an allylpalladium(II) intermediate formed by oxidative addition of the allylic pivalate to the Pd(0) complex. Subsequent reductive elimination furnishes the allyl-aryl coupled product. The aforementioned proposed intermediates, including an arylsilver complex, have been isolated, structurally characterized, and determined to be chemically and kinetically competent to undergo the proposed elementary steps of the catalytic cycle.

Cp*Co(III)-Catalyzed C(sp3)–H Bond Activation: A Highly Stereoselective and Regioselective Alkenylation of 8-Methylquinoline with Alkynes

Efficient, atom-economical, highly regioselective C(sp3)–H bond alkenylation of 8-methylquinoline catalyzed by (Cp*)Co(III) is reported. A well-defined, air-stable, molecular cobalt catalyst, Cp*Co(III), is employed for the first time in C(sp3)–H bond activation. The developed methodology is broadly applicable and tolerates a variety of functional groups, under mild conditions. Experimental and density functional theory (DFT) results suggest that the initial cyclometalation was occurred via an external-base-assisted concerted metalation deprotonation pathway.

ChemInform Abstract: Palladium‐Catalyzed Annulation of Alkynyl Aryl Ethers with Isocyanates Through o‐C—H Cleavage. Synthesis of Solid‐State Emissive 2‐Methylidene‐2H‐1,4‐benzoxazin‐3(4H)‐ones.

Abstract The title transformation can be achieved by the o-C–H cleavage of alkynyl aryl ethers, which is easily derived from phenols, followed by the insertion/annulation with isocyanates in the presence of a palladium catalyst. Various alkynyl aryl ethers and arylisocyanates are applied to this transformation to give the corresponding cyclic products. Mechanistic study indicates that the C–H cleavage is effected reversibly by the concerted metalation-deprotonation pathway. The products exhibit solid-state luminescence upon irradiation of UV light. Fluorescent maxima and quantum yields can be controlled by the substituents at appropriate sites in the products.

Palladium-catalyzed annulation of alkynyl aryl ethers with isocyanates through o-C–H cleavage. Synthesis of solid-state emissive 2-methylidene-2H-1,4-benzoxazin-3(4H)-ones

The title transformation can be achieved by the o-C–H cleavage of alkynyl aryl ethers, which is easily derived from phenols, followed by the insertion/annulation with isocyanates in the presence of a palladium catalyst. Various alkynyl aryl ethers and arylisocyanates are applied to this transformation to give the corresponding cyclic products. Mechanistic study indicates that the C–H cleavage is effected reversibly by the concerted metalation-deprotonation pathway. The products exhibit solid-state luminescence upon irradiation of UV light. Fluorescent maxima and quantum yields can be controlled by the substituents at appropriate sites in the products.

A Robust and Efficient Catalyst Possessing an Electron‐Deficient Ligand for the Palladium‐Catalyzed Direct Arylation of Heteroarenes

AbstractThe exploration of the direct arylation capacity of a unique, thermally stable, and air‐stable Pd0–phosphine catalyst is reported. Besides decisively contributing to catalyst robustness, the electron‐deficient trifluoromethyl‐substituted triphenylphosphine ligands make the palladium center more electron‐deficient and accelerate the direct arylation step. The combination of only 0.5–2 mol‐% of the catalyst and a substoichiometric quantity of pivalic acid generates an efficient system to promote biaryl‐forming reactions of a broad range of electronically varied hetarenes and aryl bromides. The observed regioselective arylations suggest that a concerted metalation–deprotonation pathway is involved in the C–H activation step.

Mechanistic Analysis of Iridium(III) Catalyzed Direct CH Arylations: A DFT Study

In a recent experimental work the Ir complex [Ir(cod)(py)(PCy(3))](PF(6)) (that is, Crabtree's catalyst) has been shown to catalyze the C-H arylation of electron-rich heteroarenes with iodoarenes using Ag(2)CO(3) as base. For this process, an electrophilic metalation mechanism, (S(E)Ar) has been proposed as operative mechanism rather than the concerted metalation-deprotonation (CMD) mechanism, widely implicated in Pd-catalyzed arylation reactions. Herein we have investigated the C-H activation step for several (hetero)arenes catalyzed by a Ir(III) catalyst and compared the data obtained with the results for the Pd(II)-catalyzed C-H bond activation. The calculations demonstrate that, similar to Pd(II)-catalyzed reactions, the Ir(III)-catalyzed direct C-H arylation occurs through the CMD pathway which accounts for the experimentally observed regioselectivity. The transition states for Ir(III)-catalyzed direct C-H arylation feature stronger metal-C((arene)) interactions than those for Pd(II)-catalyzed C-H arylation. The calculations also demonstrate that ligands with low trans effect may decrease the activation barrier of the C-H bond cleavage.

Retraction: Facile Palladium‐Catalyzed Arylation of Heterocycles and Nonactivated Arenes with Aryl Chlorides

Retraction: Facile Palladium‐Catalyzed Arylation of Heterocycles and Nonactivated Arenes with Aryl Chlorides

Modulating Reactivity and Diverting Selectivity in Palladium-Catalyzed Heteroaromatic Direct Arylation Through the Use of a Chloride Activating/Blocking Group

Through the introduction of an aryl chloride substituent, the selectivity of palladium-catalyzed direct arylation may be diverted to provide alternative regioisomeric products in high yields. In cases where low reactivity is typically observed, the presence of the carbon-chlorine bond can serve to enhance reactivity and provide superior outcomes. From a strategic perspective, the C-Cl bond is easily introduced and can be employed in a variety of subsequent transformations to provide a wealth of highly functionalized heterocycles with minimal substrate preactivation. The impact of the C-Cl functional group on direct arylation reactivity has also been evaluated mechanistically, and the observed reactivity profiles correlate very well with that predicted by a concerted metalation-deprotonation pathway.