Bond-forming Reactions Research Articles

Nickel-Carbon Bond Oxygenation with Green Oxidants via High-Valent Nickel Species.

Described herein is the synthesis of the NiII complex (tBuMe2tacn)NiII(cycloneophyl) (tBuMe2tacn = 1-tert-butyl-4,7-dimethyl-1,4,7-triazacyclononane, cycloneophyl = -CH2CMe2-o-C6H4-) and its reactivity with dioxygen and peroxides. The new tBuMe2tacn ligand is designed to enhance the oxidatively induced bond-forming reactivity of high-valent Ni intermediates. Tunable chemoselectivity for Csp2-O vs Csp2-Csp3 bond formation was achieved by selecting the appropriate solvent and reaction conditions. Importantly, the use of cumene hydroperoxide and meta-chloroperbenzoic acid suggests a heterolytic O-O bond cleavage upon reaction with (tBuMe2tacn)NiII(cycloneophyl). Mechanistic studies using isotopically labeled H2O2 support the generation of a high-valent Ni-oxygen species via an inner-sphere mechanism and subsequent reductive elimination to form the Csp2-O bond. Kinetic studies of the exceptionally fast Csp2-O bond-forming reaction reveal a first-order dependence on both (tBuMe2tacn)NiII(cycloneophyl) and H2O2, and thus an overall second-order reaction. Eyring analysis further suggests that the oxidation of the NiII complex by H2O2 is the rate-determining step, which can be modulated by the presence of coordinating solvents. Moreover, computational studies fully support the conclusions drawn from experimental results. Overall, this study reveals for the first time the ability to control the oxidatively induced C-C vs C-O bond formation reactions at a Ni center. Importantly, the described system merges the known organometallic reactivity of Ni with the biomimetic oxidative transformations resembling oxygenases and peroxidases, and involving high-valent metal-oxygen intermediates, which is a novel approach that should lead to unprecedented oxidative catalytic transformations.

Enantioselective Sequential Catalytic Arylation-Fukuyama Cross-coupling of 1,1-Biszincioalkane Linchpins.

1,1-Bis(iodozincio)alkanes are used as dinucleophilic linchpins in an enantioselective double cross-coupling reaction sequence involving aryl iodides and then thioesters. The two catalytic C-C bond-forming reactions are achieved in the same pot through two distinct palladium-based catalytic systems: a first non-enantioselective one delivering configurationally labile secondary benzylzinc species from an achiral precursor, and a second enantioconvergent one that operates a highly efficient dynamic kinetic resolution of the racemic intermediates. This strategy, new in the area of asymmetric synthesis through two consecutive electrophilic substitution reactions of geminated C(sp3 )-organodimetallics, provides useful methodology to access in a modular fashion acyclic α-disubstituted ketone products with very high enantiomeric purity.

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.

Diverse Synthetic Transformations Using 4-Bromo-3,3,4,4-tetrafluorobut-1-ene and Its Applications in the Preparation of CF2 CF2 -Containing Sugars, Liquid Crystals, and Light-Emitting Materials.

Organic molecules with fluoroalkylene scaffolds, especially a tetrafluoroethylene (CF2 CF2 ) moiety, in their molecular structures exhibit unique biological activities, or can be applied to functional materials such as liquid crystals and light-emitting materials. Although several methods for the syntheses of CF2 CF2 -containing organic molecules have been reported to date, they have been limited to methods using explosives and fluorinating agents. Therefore, there is an urgent need to develop simple and efficient approaches to synthesize CF2 CF2 -containing organic molecules from readily available fluorinated substrates using carbon-carbon bond formation reactions. This personal account summarizes the simple and efficient transformation of functional groups at both ends of 4-bromo-3,3,4,4-tetrafluorobut-1-ene and discusses its synthetic applications to biologically active fluorinated sugars and functional materials, such as liquid crystals and light-emitting molecules.

Mechanistic Insight into the TBHP-Mediated Decarboxylative Condensation of α-Ketoacids: Reaction Development and Application to Oligopeptide Synthesis.

With the aim of achieving the convergent elongation of peptide chains, an amide bond formation reaction that enables a peptide fragment coupling has long been pursued. The decarboxylative amidation recently reported by our group is a potential solution to this problem. In this article, a mechanistic analysis of the t-butyl hydroperoxide (TBHP) mediated-decarboxylative amidation of α-ketoacids that results in a significant advance in convergent peptide synthesis is described. Despite the observation of epimerization with low bulk substrates in preliminary studies, a systematic examination and understanding of the reaction mechanism enabled the development of a modified epimerization-free reaction whereby peptide fragment couplings using peptide α-ketoacids were successfully achieved.

Co(III) Intermediates in Cobalt-Catalyzed, Bidentate Chelation Assisted C(sp2)-H Functionalizations

The C-H bond activation and functionalization is a powerful tool that provides efficient access to various organic molecules. The cobalt-catalyzed oxidative C-H bond activation and functionalization has earned enormous interest over the past two decades. Since then, a wide diversity of synthetic protocols have been published for C-C, C-Het, and C-Hal bond formation reactions. To gain some insights into the reaction mechanism, the authors performed a series of experiments and collected evidence. Several groups have successfully isolated reactive Co(III) intermediates to elucidate the reaction mechanism. In this review, we will summarize information concerning the isolated and synthesized Co(III) intermediates in cobalt-catalyzed, bidentate chelation assisted C-H bond functionalization and their reactivity based on the current knowledge about the general reaction mechanism.

Cu-Mediated Thianthrenation and Phenoxathiination of Arylborons.

Great success in synthetic chemistry is motivated by the development of novel and reactive linchpins for carbon-carbon and carbon-heteroatom bond formation reactions, which has dramatically altered chemists' approach to building molecules. Herein, we report the ready synthesis of aryl sulfonium salts, a versatile electrophilic linchpin, via a novel Cu-mediated thianthrenation and phenoxathiination of commercially available arylborons with thianthrene and phenoxathiine, providing a series of aryl sulfonium salts in high efficiency. More importantly, by leveraging the sequential Ir-catalyzed C-H borylation and Cu-mediated thianthrenation of arylborons, the formal thianthrenation of arenes is also achieved. The Ir-catalyzed C-H borylation with undirected arenes normally occurred at the less steric hindrance position, thus providing a complementary method for thianthrenation of arenes in comparison with electrophilic thianthrenation. This process is capable of late-stage functionalization of a series of pharmaceuticals, which might find wide synthetic applications in both industry and academic sectors.

Photoinduced Palladium-Catalyzed 1,2-Difunctionalization of Electron-Rich Olefins via a Reductive Radical-Polar Crossover Reaction

Palladium-catalyzed cross-coupling reactions belong to the most important transformations for the construction of C–C or C-heteroatom bonds. More recently, the photochemical activation of palladium complexes emerged as a key strategy to leverage palladium catalysis at room temperature beyond the scope of conventional cross-coupling chemistry. Herein, we report on the photoinduced palladium-catalyzed 1,2-difunctionalization reaction of electron-rich olefins. Mechanistic experiments and computational studies reveal that this reaction proceeds via the addition of an alkyl radical, followed by the oxidation of a radical intermediate to access carbocation intermediates, which are inaccessible via classic thermal reaction conditions. The carbocation can then be applied to a variety of secondary C–C or C–N bond-forming reactions. This strategy now allows a general approach toward densely functionalized unsymmetric 1,1-bis(heterocyclyl)alkanes.

Structure-property relationship studies of photoactive tridentate ligands and their applications in sensing of Cu(II) and Fe(II) ions

A series of tridentate polypyridyl N^N^N/N^C^N-coordinating ligands (R1, R2, L1, L2) were synthesized by palladium-catalyzed Suzuki-Miyaura C–C bond-forming and N-methylation reactions in good-to-excellent yields (70–97%). These ligands were characterized by a set of analytical techniques including NMR, HRMS and single-crystal XRD. The electrochemical and photophysical properties of these ligands were examined using cyclic voltammetry, UV–vis absorption and luminescence spectroscopies. Theoretical calculations at the level of DFT and TD-DFT were also performed for the detailed studies of the optoelectronic properties of these compounds. These ligands displayed either an admixture of singlet ligand-centered (1LC) and singlet charge-transfer (1CT) transitions or pure 1LC/1CT luminescence in some cases. Ligands (L3 and L4) which are charged in nature were further used as selective chemosensors for the detection of Cu(II) and Fe(II) ions with a “turn-off” fluorescence behavior in a binding stoichiometry of 2:1 = ligand:M(II) [M = Fe(II)/Cu(II)] and a limit of detection up to 4.66–21.71 ppm level.

Iridium/Zinc-Co-Catalyzed Ring-Opening Reactions of Oxabicyclic Alkenes with Indole Nucleophiles: A Combined Experimental and Theoretical Study

An experimental and theoretical investigation on the iridium/zinc-co-catalyzed ring-opening reactions of oxabicyclic alkenes with indole nucleophiles is reported. The reaction affords trans-3-indolyl-1,2-dihydronaphthalen-1-ol products in good yield with no N-alkylated products observed. The C–C bond-forming reaction does not require prior functionalization and is entirely atom-economic. The mechanism and origins of selectivity in the iridium-catalyzed ring-opening reaction have been examined at the M06-D3/Def2TZVPP level of theory. Orbital analysis and natural population analysis charges demonstrate that the Cα site of the π-allyliridium intermediate is the most electrophilic site of attack. Distortion/interaction analysis reveals that the chemoselectivity likely originates from an earlier-stage transition state between Cα and C3, which requires less distortion energy compared to Cα–N1 during the rate-determining intermolecular nucleophilic attack. Moreover, conceptual density functional theory was used to conceptualize the preferential reactive sites of the nucleophiles probed. The C–C bond-forming step is speculated to proceed through a Friedel–Crafts-type reaction.

Engineering C-C Bond Cleavage Activity into a P450 Monooxygenase Enzyme.

The cytochrome P450 (CYP) superfamily of heme monooxygenases has demonstrated ability to facilitate hydroxylation, desaturation, sulfoxidation, epoxidation, heteroatom dealkylation, and carbon-carbon bond formation and cleavage (lyase) reactions. Seeking to study the carbon-carbon cleavage reaction of α-hydroxy ketones in mechanistic detail using a microbial P450, we synthesized α-hydroxy ketone probes based on the physiological substrate for a well-characterized benzoic acid metabolizing P450, CYP199A4. After observing low activity with wild-type CYP199A4, subsequent assays with an F182L mutant demonstrated enzyme-dependent C-C bond cleavage toward one of the α-hydroxy ketones. This C-C cleavage reaction was subject to an inverse kinetic solvent isotope effect analogous to that observed in the lyase activity of the human P450 CYP17A1, suggesting the involvement of a species earlier than Compound I in the catalytic cycle. Co-crystallization of F182L-CYP199A4 with this α-hydroxy ketone showed that the substrate bound in the active site with a preference for the (S)-enantiomer in a position which could mimic the topology of the lyase reaction in CYP17A1. Molecular dynamics simulations with an oxy-ferrous model of CYP199A4 revealed a displacement of the substrate to allow for oxygen binding and the formation of the lyase transition state proposed for CYP17A1. This demonstration that a correctly positioned α-hydroxy ketone substrate can realize lyase activity with an unusual inverse solvent isotope effect in an engineered microbial system opens the door for further detailed biophysical and structural characterization of CYP catalytic intermediates.

Stereodefined polymetalloid alkenes synthesis via stereoselective boron-masking of polyborylated alkenes

Polyborylated-alkenes are valuable polymetalloid reagents in modern organic synthesis, providing access to a wide array of transformations, including the construction of multiple C–C and C–heteroatom bonds. However, because they contain similar boryl groups, many times their transformation faces the main challenge in controlling the chemo-, regio- and stereoselectivity. One way to overcome these limitations is by installing different boron groups that can provide an opportunity to tune their reactivity toward better chemo-, regio- and stereoselectivity. Yet, the preparation of polyborylated-alkenes containing different boryl groups has been rare. Herein we report concise, highly site-selective, and stereoselective boron-masking strategies of polyborylated alkenes. This is achieved by designed stereoselective trifluorination and MIDA-ation reactions of readily available starting polyborylated alkenes. Additionally, the trifluoroborylated-alkenes undergo a stereospecific interconversion to Bdan-alkenes. These transition-metal free reactions provide a general and efficient method for the conversion of polyborylated alkenes to access 1,1-di-, 1,2-di-, 1,1,2-tris-(borylated) alkenes containing BF3M, Bdan, and BMIDA, a family of compounds that currently lack efficient synthetic access. Moreover, tetraborylethene undergoes the metal-free MIDA-ation reaction to provide the mono BMIDA tetraboryl alkene selectively. The mixed polyborylalkenes are then demonstrated to be useful in selective C–C and C–heteroatom bond-forming reactions. Given its simplicity and versatility, these stereoselective boron-masking approaches hold great promise for organoboron synthesis and will result in more transformations.

Organobase-catalyzed Mannich reaction of cyclic N-sulfonyl imines and 1,2-diketones: A sustainable approach to 4-(3-arylquinoxalin-2-ylmethyl)sufamidates

A convenient, eco-friendly, organobase-catalyzed one-pot two-step sequential approach to a fascinating class of various 4-(3-arylquinoxalin-2-ylmethyl)-substituted sulfamidates in good to high yields is reported. This CC/CN bond-forming reaction proceeds via a Mannich reaction of cyclic N-sulfonyl aldimines with 1-aryl-2-alkyl-1,2-diketones catalyzed by triethylamine, followed by the aza-cyclization of in situ formed 1,2-dicarbonyl precursors with ortho-diaminoarenes in PEG-400 as a natural, reusable, and benign solvent at room temperature. In addition, this 100% carbon atom-economic approach could be viable for gram-scale synthesis and tolerates various synthetically resourceful functionalities under mild conditions.

Organic Field Effect Transistors Comprising Copolymers Synthesized without Structure-Directing Moieties with Enhanced Carrier Mobility

Conjugated materials are synthesized by C–C bond formation reactions. Trimethyltin and boronic acid are two widely used structure-directing moieties. While using the ethynyl moiety as a part of the monomer, additional structure-directing moieties are not needed. However, ethynylene will be part of the conjugated material. Often, the polymers with an ethynylene moiety negatively impact the polymers’ properties. However, the ethynylene moiety could minimize the dihedral angle if the monomer has steric functionalities. For example, BODIPY is an attractive monomer due to its high molar extinction coefficient, partial quinoidal character, and high quantum yield. However, materials based on BODIPY exhibited poor charge carrier mobility due to steric hindrance generated by four methyl groups. Herein, we copolymerize BODIPY with ethynylene comprising i-indigo and thieno-i-indigo. The copolymer with thieno-i-indigo showed increased molecular weight and significantly reduced band gap compared to the copolymer with i-indigo. The copolymer with i-indigo showed immeasurably low hole transport mobility. On the other hand, the copolymer with thieno-i-indigo exhibited 0.003 cm2V–1 s–1. These measurements were made using field effect transistors. We also measured the charge carrier mobility using the space charge-limited current method. Both copolymers exhibited a mobility of 10–3 cm2 V–1 s–1.

Exploring Guanidinium Organocatalysts for Hypoiodite-Mediated Reactions.

This account describes our recent work on developing guanidinium hypoiodite- catalysts for oxidative carbon-nitrogen and carbon-carbon bond-forming reactions. These reactions proceeded smoothly using guanidinium hypoiodite generated in situ by treating 1,3,4,6,7-hexahydro-2H-pyrimido[1,2-a]pyrimidine hydroiodide salts with an oxidant. In this approach, the ionic interaction and hydrogen bonding ability of the guanidinium cations enable bond-forming reactions that have been difficult with conventional methods. Enantioselective oxidative carbon-carbon bond-forming reaction was also achieved by using a chiral guanidinium organocatalyst.

N-(Morpholine-4-dithio)phthalimide: A Shelf-Stable, Bilateral Platform Molecule Enabling Access to Diverse Unsymmetrical Disulfides.

Synthetic methods for unsymmetrical disulfides are greatly needed owing to their applications in drug discovery, linker chemistry, and materials sciences. In this study, a new shelf-stable and easy-to-prepare bilateral disulfurating platform molecule, N-(morpholine-4-dithio)phthalimide, has been developed for the divergent synthesis of unsymmetrical disulfides. The amino and imide leaving groups of this reagent can be orthogonally transformed. Under acidic conditions, the amino moiety undergoes selective protonation and thus can be displaced by various carbon nucleophiles, such as allyl trimethylsilanes, alkynyl silanes, and electron-rich arenes, leaving the phthalimide moiety untouched. Meanwhile, the phthalimide leaving group is amenable to substitution under basic or neutral conditions. The combination of these transformations provides rapid access to diverse unsymmetrical disulfides through two C-S bond-forming reactions.

Covalent Organic Frameworks as Porous Pigments for Photocatalytic Metal-Free C-H Borylation.

Covalent organic frameworks (COFs) are highly promising as heterogeneous photocatalysts due to their tunable structures and optoelectronic properties. Though COFs have been used as heterogeneous photocatalysts, they have mainly been employed in water splitting, carbon dioxide reduction, and hydrogen evolution reactions. A few examples in organic synthesis using metal-anchored COF photocatalysts were reported. Herein, we report highly stable β-keto-enamine-based COFs as photocatalysts for metal-free C-B bond formation reactions. Three different COFs have been availed for this purpose. Their photocatalysis performances have been monitored for 12 different substrates, like quinolines, pyridines, and pyrimidines. All the COFs showcase moderate-to-high yields (up to 96%) depending upon the substrate's molecular functionality. High crystallinity, a large surface area, a low band gap, and a suitable band position result in the highest catalytic activity of TpAzo COF. The thorough mechanistic investigation further highlights the crucial role of light-harvesting capacity, charge separation efficiency, and current density during catalysis. The light absorbance capacity of the COF plays a critical role during catalysis as yields are maximized near the COF's absorption maxima. The high photostability of the as-synthesized COFs offers their reusability for several (>5) catalytic cycles.

Room-Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design.

Ullmann-type C-N coupling reactions represent an important alternative to well-established Pd-catalyzed approaches due to the differing reactivity and the lower cost of Cu. While the design of anionic Cu ligands, particularly those by Ma, has enabled the coupling of various classes of aryl halides and alkyl amines, most methods require conditions that can limit their utility on complex substrates. Herein, we disclose the development of anionic N1,N2-diarylbenzene-1,2-diamine ligands that promote the Cu-catalyzed amination of aryl bromides under mild conditions. Guided by DFT calculations, these ligands were designed to (1) increase the electron density on Cu, thereby increasing the rate of oxidative addition of aryl bromides, and (2) stabilize the active anionic CuI complex via a π-interaction. Under optimized conditions, structurally diverse aryl and heteroaryl bromides and a broad range of alkyl amine nucleophiles, including pharmaceuticals bearing multiple functional groups, were efficiently coupled at room temperature. Combined computational and experimental studies support a mechanism of C-N bond formation that follows a catalytic cycle akin to the well-explored Pd-catalyzed variants. Modification of the ligand structure to include a naphthyl residue resulted in a lower energy barrier to oxidative addition, providing a 30-fold rate increase relative to what is seen with other ligands. Collectively, these results establish a new class of anionic ligands for Cu-catalyzed C-N couplings, which we anticipate may be extended to other Cu-catalyzed C-heteroatom and C-C bond-forming reactions.

Structure–Property Relationship in the Lanthanum Grafted Zeolite and Its Application as an Efficient Acido-Basic Catalyst for C–C/C–O Bond Formation Reactions

Structure–Property Relationship in the Lanthanum Grafted Zeolite and Its Application as an Efficient Acido-Basic Catalyst for C–C/C–O Bond Formation Reactions

Multimetallic-Catalyzed C-C Bond-Forming Reactions: From Serendipity to Strategy.

The use of two or more metal catalysts in a reaction is a powerful synthetic strategy to access complex targets efficiently and selectively from simple starting materials. While capable of uniting distinct reactivities, the principles governing multimetallic catalysis are not always intuitive, making the discovery and optimization of new reactions challenging. Here, we outline our perspective on the design elements of multimetallic catalysis using precedent from well-documented C-C bond-forming reactions. These strategies provide insight into the synergy of metal catalysts and compatibility of the individual components of a reaction. Advantages and limitations are discussed to promote further development of the field.