Bond Functionalization Reactions Research Articles

Recent Advances in the Nickel-Catalyzed Alkylation of C-H Bonds.

Functionalization of C-H bonds has emerged as a powerful strategy for converting inert, nonfunctional C-H bonds into their reactive counterparts. A wide range of C-H bond functionalization reactions has become possible by the catalysis of metals, typically from the second row of transition metals. First-row transition metals can also catalyze C-H functionalization, and they have the merits of greater earth-abundance, lower cost and better environmental friendliness in comparison to their second-row counterparts. C-H bond alkylation is a particularly important C-H functionalization reaction due to its chemical significance and its applications in natural product synthesis. This review covers Ni-catalyzed C-H bond alkylation reactions using alkyl halides and olefins as alkyl sources.

Recent advances in ruthenium‐catalysed aromatic C−H bond oxygenation, nitrogenation and halogenation

AbstractThe transition metal‐catalysed C−H bond functionalization has emerged as a powerful tool for accessing numerous organic compounds in greener manner with step and atom economy. Remarkable progress has been made in the metal‐catalysed C−H bond functionalization during the past decades and the trend is continuing as new reactions are being added. In the transition metal‐catalysed C−H bond functionalization, a growing attention has been paid on ruthenium, particularly, the stable ruthenium(II) as it allows several C−H bond functionalization reactions to perform in water with high selectivity. The ruthenium‐catalysed C−H bond functionalization reactions, such as arylation, alkenylation, annulation, cyanation, amination and silylation just to mention some have been well documented in numerous published papers, book chapters and review articles. However, as ruthenium‐catalysed C−H functionalization has been growing rapidly, a comprehensive review is necessary from time to time to highlight the progress made in this ever expanding field. In view of this, the manuscript presents the ruthenium‐catalysed direct C−O, C−N and C‐halogen bond forming reactions involving aromatic C−H bond covering oxygenation, amination, amidation, imidation, nitration and halogenation reported from 2012 to 2022.

Sustainable Aerobic Allylic C-H Bond Oxidation with Heterogeneous Iron Catalyst.

Emerging techniques are revolutionizing the realm of chemical synthesis by introducing new avenues for C-H bond functionalization, which have been exploited for the synthesis of pharmaceuticals, natural compounds, and functional materials. Allylic C-H bond oxidation of alkenes serves as possibly the most employed C-H bond functionalization reaction. However, sustainable and selective approaches remain scarce, and the majority of the existing conditions still hinge on hazardous oxidants or costly metal catalysts. In this context, we introduce a heterogeneous iron catalyst that addresses the above-mentioned concerns by showcasing the aerobic oxidation of steroids, terpenes, and simple olefins to the corresponding enone products. This novel method provides a powerful tool for the arsenal of allylic C-H bond oxidation while minimizing the environmental concerns.

A Simple Access to γ- and ε-Keto Arenes via Enzymatic Divergent C─H Bond Oxyfunctionalization.

Performing divergent C─H bond functionalization on molecules with multiple reaction sites is a significant challenge in organic chemistry. Biocatalytic oxyfunctionalization reactions of these compounds to the corresponding ketones/aldehydes are typically hindered by selectivity issues. To address these challenges, the catalytic performance of oxidoreductases is explored. The results show that combining the peroxygenase-catalyzed propargylic C─H bond oxidation with the Old Yellow Enzyme-catalyzed reduction of conjugated C─C triple bonds in one-pot enables the regio- and chemoselective oxyfunctionalization of sp3 C─H bonds that are distant from benzylic sites. This enzymatic approach yielded a variety of γ-keto arenes with diverse structural and electronic properties in yields of up to 99% and regioselectivity of 100%, which are difficult to achieve using other chemocatalysis and enzymes. By adjusting the C─C triple bond, the carbonyl group's position can be further tuned to yield ε-keto arenes. This enzymatic approach can be combined with other biocatalysts to establish new synthetic pathways for accessing various challenging divergent C─H bond functionalization reactions.

Esterification of Thioamides via Selective N-C(S) Cleavage under Mild Conditions.

Herein, we report an exceedingly mild method for the direct, transition-metal-free esterification of thioamides through the selective generation of tetrahedral intermediates. The method represents the first transition-metal-free approach to the thioamide to thionoester transformation in organic synthesis. This reactivity has been accomplished through N,N-Boc2-thioamides that engage in ground-state destabilization of the nN → π*C═S conjugation. The ground-state destabilization of "single-atom" bioisosteric thioamides will expand the arsenal of valuable amide bond functionalization reactions.

C-H Borylation of Benzophenones Using Hydrazone as the Traceless Directing Group.

C-H borylation is one of the powerful C-H bond functionalization reactions. In this context, a metal-free C-H borylation of benzophenones using hydrazone as the traceless directing group has been reported. The dibromoboron intermediates can be obtained in excellent yields, and the corresponding arylboronic esters are generated in moderate to excellent yields. Furthermore, the borylated compounds can be transformed in a one-pot method, avoiding the loss of overall yield caused by the separation of the arylboronic esters.

Direct Cyclopalladation of Fluorinated Benzyl Amines by Pd3(OAc)6: The Coexistence of Multinuclear Pdn Reaction Pathways Highlights the Importance of Pd Speciation in C-H Bond Activation.

Palladacycles are key intermediates in catalytic C-H bond functionalization reactions and important precatalysts for cross-couplings. It is commonly believed that palladacycle formation occurs through the reaction of a substrate bearing a C-H bond ortho to a suitable metal-directing group for interaction with, typically, mononuclear "Pd(OAc)2" species, with cyclopalladation liberating acetic acid as the side product. In this study, we show that N,N-dimethyl-fluoro-benzyl amines, which can be cyclopalladated either ortho or para to fluorine affording two regioisomeric products, can occur by a direct reaction of Pd3(OAc)6, proceeding via higher-order cyclopalladated intermediates. Regioselectivity is altered subtly depending on the ratio of substrate:Pd3(OAc)6 and the solvent used. Our findings are important when considering mechanisms of Pd-mediated reactions involving the intermediacy of palladacycles, of particular relevance in catalytic C-H bond functionalization chemistry.

Transition-Metal-Catalyzed C-H Bond Activation for the Formation of C-C Bonds in Complex Molecules.

Site-predictable and chemoselective C-H bond functionalization reactions offer synthetically powerful strategies for the step-economic diversification of both feedstock and fine chemicals. Many transition-metal-catalyzed methods have emerged for the selective activation and functionalization of C-H bonds. However, challenges of regio- and chemoselectivity have emerged with application to highly complex molecules bearing significant functional group density and diversity. As molecular complexity increases within molecular structures the risks of catalyst intolerance and limited applicability grow with the number of functional groups and potentially Lewis basic heteroatoms. Given the abundance of C-H bonds within highly complex and already diversified molecules such as pharmaceuticals, natural products, and materials, design and selection of reaction conditions and tolerant catalysts has proved critical for successful direct functionalization. As such, innovations within transition-metal-catalyzed C-H bond functionalization for the direct formation of carbon-carbon bonds have been discovered and developed to overcome these challenges and limitations. This review highlights progress made for the direct metal-catalyzed C-C bond forming reactions including alkylation, methylation, arylation, and olefination of C-H bonds within complex targets.

Catalytic asymmetric silicon-carbon bond-forming transformations based on Si-H functionalization

In view of the exciting advancement on silicon-carbon bond-forming transformations achieved in the past decade, this review intends to show a unified illustration of the recent findings on enantioselective Si-H bond functionalization aided by asymmetric catalysis. Accordingly, this review describes the enantioselective silicon-carbon bond-forming Si-H bond functionalization, focusing on the reactivity and stereoselectivity in catalytic asymmetric hydrosilylation, carbene Si-H insertion, Si-H silylation, and Si-C bond-forming cross-coupling reactions that were achieved with high enantioselectivity in the presence of transition-metal catalyst systems. This review highlights recent and representative examples of the enantioselective Si-H bond functionalization, discusses the origins of silicon-involving stereoselectivities, and evaluates the substrate scopes and limitations in these catalytic asymmetric Si-H bond functionalization reactions due to the special reactivity of different hydrosilanes.

Pd-Catalyzed Asymmetric Oxidative C-H/C-H Cross-Coupling Reaction between Ferrocenes and Azoles.

The asymmetric C-H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein, our work discovered a Pd-catalyzed asymmetric oxidative C-H/C-H cross-coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Mono-N-protected amino acid as chiral ligands with palladium(II) has been demonstrated as an effective catalytic system in a weakly azine-directed asymmetric C-H bond functionalization reaction. This method offers a powerful strategy for constructing various substituted planar chiral ferrocenes via a dual C-H bond activation pathway in medium yields (up to 70%) with good enantioselectivity (up to 95.3:4.7 er) under mild conditions.

Understanding Precatalyst Activation and Speciation in Manganese-Catalyzed C-H Bond Functionalization Reactions.

An investigation into species formed following precatalyst activation in Mn-catalyzed C-H bond functionalization reactions is reported. Time-resolved infrared spectroscopy demonstrates that light-induced CO dissociation from precatalysts [Mn(C^N)(CO)4] (C^N = cyclometalated 2-phenylpyridine (1a), cyclometalated 1,1-bis(4-methoxyphenyl)methanimine (1b)) in a toluene solution of 2-phenylpyridine (2a) or 1,1-bis(4-methoxyphenyl)methanimine (2b) results in the initial formation of solvent complexes fac-[Mn(C^N)(CO)3(toluene)]. Subsequent solvent substitution on a nanosecond time scale then yields fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)], respectively. When the experiments are performed in the presence of phenylacetylene, the initial formation of fac-[Mn(C^N)(CO)3(toluene)] is followed by a competitive substitution reaction to give fac-[Mn(C^N)(CO)3(2)] and fac-[Mn(C^N)(CO)3(η2-PhC2H)]. The fate of the reaction mixture depends on the nature of the nitrogen-containing substrate used. In the case of 2-phenylpyridine, migratory insertion of the alkyne into the Mn-C bond occurs, and fac-[Mn(C^N)(CO)3(κ1-(N)-2a)] remains unchanged. In contrast, when 2b is used, substitution of the η2-bound phenylacetylene by 2b occurs on a microsecond time scale, and fac-[Mn(C^N)(CO)3(κ1-(N)-2b)] is the sole product from the reaction. Calculations with density functional theory indicate that this difference in behavior may be correlated with the different affinities of 2a and 2b for the manganese. This study therefore demonstrates that speciation immediately following precatalyst activation is a kinetically controlled event. The most dominant species in the reaction mixture (the solvent) initially binds to the metal. The subsequent substitution of the metal-bound solvent is also kinetically controlled (on a ns time scale) prior to the thermodynamic distribution of products being obtained.

Advances in Transition-Metal-Catalyzed Keto Carbonyl-Directed C—H Bond Functionalization Reactions

Advances in Transition-Metal-Catalyzed Keto Carbonyl-Directed C—H Bond Functionalization Reactions

Application of Ligands in Cp*Rh(III)-Catalyzed C—H Bond Functionalization Reaction

Application of Ligands in Cp*Rh(III)-Catalyzed C—H Bond Functionalization Reaction

Synthesis of 3‐Arylacetamides Substituted Maleimide Via Weakly Coordinating Acetamide Assisted Cross‐dehydrogenative Coupling and Their Photophysical Studies

AbstractMaleimides serve as an important synthetic precursor for various organic transformation reactions. However, maleimides have been rarely employed as coupling partners for the direct synthesis of 3‐aryl substituted maleimides via oxidative Heck‐type reaction, due to the lack of β‐hydrogen at the syn‐periplanar position. Therefore, herein, we report an efficient and highly selective synthesis of 3‐arylacetamide incorporated maleimides through the cross‐dehydrogenative coupling process using the simple and native primary acetamide as a weakly directing group with Pd(II)‐catalysis conditions. This reaction furnishes 3‐arylated maleimide derivatives in good yields with high functional group tolerance. Furthermore, 3‐arylated maleimides were transformed into synthetically important derivatives. Based on preliminary control experiments, a probable reaction mechanism has been proposed for the distal C−H bond functionalization reaction. Interesting photophysical properties of the synthesized products were also observed.

Tris(ortho-carboranyl)borane: An Isolable, Halogen-Free, Lewis Superacid.

The synthesis of tris(ortho-carboranyl)borane (BoCb3 ), a single site neutral Lewis superacid, in one pot from commercially available materials is achieved. The high fluoride ion affinity (FIA) confirms its classification as a Lewis superacid and the Gutmann-Beckett method as well as adducts with Lewis bases indicate stronger Lewis acidity over the widely used fluorinated aryl boranes. The electron withdrawing effect of ortho-carborane and lack of pi-delocalization of the LUMO rationalize the unusually high Lewis acidity. Catalytic studies indicate that BoCb3 is a superior catalyst for promoting C-F bond functionalization reactions than tris(pentafluorophenyl)borane [B(C6 F5 )3 ].

Tris(ortho‐carboranyl)borane: An Isolable, Halogen‐Free, Lewis Superacid

AbstractThe synthesis of tris(ortho‐carboranyl)borane (BoCb3), a single site neutral Lewis superacid, in one pot from commercially available materials is achieved. The high fluoride ion affinity (FIA) confirms its classification as a Lewis superacid and the Gutmann‐Beckett method as well as adducts with Lewis bases indicate stronger Lewis acidity over the widely used fluorinated aryl boranes. The electron withdrawing effect ofortho‐carborane and lack of pi‐delocalization of the LUMO rationalize the unusually high Lewis acidity. Catalytic studies indicate that BoCb3is a superior catalyst for promoting C−F bond functionalization reactions than tris(pentafluorophenyl)borane [B(C6F5)3].

The Renaissance of Organo Nitriles in Organic Synthesis.

In the arena of functional group-oriented organic synthesis, nitrile or cyano functionality is of immense importance. The presence of nucleophilic N-atom, π-coordinating ability of the triple bond, and electrophilic C-center imparts unique and interesting reactivities. Owing to the ability of the nitrile to transform into various other functional groups or intermediates, the chemistry is very rich and diverse. In particular, the involvement of nitrile in numerous organic reactions such as inter- or intramolecular alkyne insertion, [2+2+2] cycloaddition with alkynes, [3+2] cycloaddition with azides, [4+2] cycloaddition with dienes allow the synthesis of many important carbo- and heterocycles. Furthermore, the nitrile serves as a directing group in many C-H bond functionalization reactions to introduce diverse functionalities and participate as a radical acceptor in radical cascade strategies to obtain a large variety of functional molecules. This review mainly focuses on the reactivity and diverse synthetic application of the nitrile including C-H bond functionalization, alkyne insertion, cycloaddition, and thermal or photochemical cascade strategy. The objective of the current review aims at bringing out the striking collection of various nitrile-triggered organic transformations.

Recent Advances in Transition-Metal-Catalyzed C-H Functionalization of Ferrocene Amides.

During the past decades, in synthetic organic chemistry, directing-group-assisted C-H functionalization is found to be a key tool for the expedient and site-selective construction of C-C and hybrid bonds. Among C-H functionalization of ferrocene derivatives, the directed group strategy is undoubtedly the most commonly used method. Compared to the other directing groups, ferrocene amides can be synthesized easily and are now recognized as one of the most efficient tools for the selective functionalization of certain positions because its metal centre permits fine, tuneable and reversible coordination. The family of amide directing groups mainly comprises monodentate and bidentate directing groups, which are categorized on the basis of coordination sites. In this review, various C-H bond functionalization reactions of ferrocene using amide directing groups are broadly discussed.

Rieske Oxygenase Catalyzed C–H Bond Functionalization Reactions in Chlorophyll b Biosynthesis

Rieske oxygenases perform precise C–H bond functionalization reactions in anabolic and catabolic pathways. These reactions are typically characterized as monooxygenation or dioxygenation reactions, but other divergent reactions are also catalyzed by Rieske oxygenases. Chlorophyll(ide) a oxygenase (CAO), for example is proposed to catalyze two monooxygenation reactions to transform a methyl-group into the formyl-group of Chlorophyll b. This formyl group, like the formyl groups found in other chlorophyll pigments, tunes the absorption spectra of chlorophyllb and supports the ability of several photosynthetic organisms to adapt to environmental light. Despite the importance of this reaction, CAO has never been studied in vitro with purified protein, leaving many open questions regarding whether CAO can facilitate both oxygenation reactions using just the Rieske oxygenase machinery. In this study, we demonstrated that four CAO homologues in partnership with a non-native reductase convert a Chlorophyll a precursor, chlorophyllidea, into chlorophyllideb in vitro. Analysis of this reaction confirmed the existence of the proposed intermediate, highlighted the stereospecificity of the reaction, and revealed the potential of CAO as a tool for synthesizing custom-tuned natural and unnatural chlorophyll pigments. This work thus adds to our fundamental understanding of chlorophyll biosynthesis and Rieske oxygenase chemistry.

Stereoselective synthesis of δ-fluorinated isoleucines exploiting consecutive C(sp3)-H bond activations

Fluorinated α-amino acids are important building blocks for pharmaceutical and agrochemical industries, as well as in protein NMR and material science. We optimized a synthetic route to generate 5-fluoro-l-isoleucine (1) and 5,5-difluoro-l-isoleucine (2) from l-alanine by leveraging two consecutive C(sp3)-H bond functionalization reactions and developed a new oxidation protocol to facilitate directing and protecting group removal without α-epimerization of the amino acid or trigger other side reactions.