Transition Metal-catalyzed Cross-coupling Reactions Research Articles

Remote Migratory Reductive Arylation of Unactivated Alkenes Enabled by Electrochemical Nickel Catalysis.

Transition metal-catalyzed cross-coupling reaction between organometallic reagents and electrophiles is a potent method for constructing C(sp2)-C(sp3) bonds. Given the characters of organometallic reagents, cross-reductive coupling is emerging as an alternative strategy. The resurgence of electrochemistry offers an ideal method for electrochemical reductive of cross-coupling electrophiles. Inspired by the mechanism of electrochemical metal hydride, our study proposed that Ni-H electrochemically catalyze the hydroarylation coupling of unactivated alkenes with aryl halides. 1,1-Diarylalkanes can be produced effectively. This method have advantages including mild conditions, excellent regioselectivity, and satisfactory yields.

Perfect Partners: Biocatalytic Halogenation and Metal Catalysis for Protein Bioconjugation.

Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH2 in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.

Photosensitized Reductive Elimination of Gold(III) to Enable Esterification of Aryl Iodides with Carboxylic Acids.

Compared to the well-established transition metal-catalyzed cross-coupling reactions, Au(I)/Au(III)-catalyzed cross-coupling reactions have lagged behind. Despite some advancements, achieving gold-catalyzed C-O coupling with carboxylic acids via an Au(III) carboxylate intermediate remains challenging due to the thermal unfavorability of the critical reductive elimination step. Here, we present the first photosensitized reductive elimination of gold(III) to enable esterification of aryl iodides with carboxylic acids. In the presence of a (P, N)-gold(I) catalyst and a photosensitizer benzophenone under blue LED irradiation, esterification derivatives were obtained from aryl iodides with both aryl and alkyl (1°, 2°, 3°) carboxylic acids. Mechanistic and modeling studies support that energy transfer (EnT) from a photosensitizer produces an excited-state gold(III) complex that couples aryl iodides with carboxylic acids. This photoinduced energy-transfer strategy has been applied in several other photosensitized gold catalysis reactions, indicating its potential for further applications.

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis.

Aryl radicals play a pivotal role as reactive intermediates in chemical synthesis, commonly arising from aryl halides and aryl diazo compounds. Expanding the repertoire of sources for aryl radical generation to include abundant and stable organoboron reagents would significantly advance radical chemistry and broaden their reactivity profile. While traditional approaches utilize stoichiometric oxidants or photocatalysis to generate aryl radicals from these reagents, electrochemical conditions have been largely underexplored. Through rigorous mechanistic investigations, we identified fundamental challenges hindering aryl radical generation. In addition to the high oxidation potentials of aromatic organoboron compounds, electrode passivation through radical grafting, homocoupling of aryl radicals, and decomposition issues were identified. We demonstrate that pulsed electrosynthesis enables selective and efficient aryl radical generation by mitigating the fundamental challenges. Our discoveries facilitated the development of the first electrochemical conversion of aryl potassium trifluoroborate salts into aryl C-P bonds. This sustainable and straightforward oxidative electrochemical approach exhibited a broad substrate scope, accommodating various heterocycles and aryl chlorides, typical substrates in transition-metal catalyzed cross-coupling reactions. Furthermore, we extended this methodology to form aryl C-Se, C-Te, and C-S bonds, showcasing its versatility and potential in bond formation processes.

Carbene-Assisted Arene Ring-Opening.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex molecules and fused ring compounds. This chemistry expands the horizons of carbene chemistry and provides a novel pathway for arene ring-opening.

Enantioselective Synthesis of the 1,3-Dienyl-5-Alkyl-6-Oxy Motif: Method Development and Total Synthesis.

The 1,3-dienyl-5-alkyl-6-oxy motif is widely found in various types of bioactive natural products. However, present synthesis is mainly non-asymmetric which relied upon different olefination or transition metal-catalyzed cross-coupling reactions using enantioenriched precursors. Herein, based upon a newly developed enantioselective α-alkylation of conjugated polyenoic acids, a variety of 1,3-dienyl-5-alkyl-6-oxy motif (with E-configured internal olefin) was generated as the corresponding α-adducts in a highly enantioselective and diastereoselective manner. Utilizing 1,3-dienyl-5-alkyl-6-oxy motif as key intermediates, we further demonstrated their synthetic potential by expedient total syntheses of three types of natural products (glutarimide antibiotics, α-pyrone polyketides and Lupin alkaloids) within 4-7 steps.

Mechanistic studies of transition metal-catalyzed cross-coupling reactions

Mechanistic studies of transition metal-catalyzed cross-coupling reactions

Synthesis, Antimicrobial and Computational Studies of New Branched Azaphenothiazinones Derivatives

In a continued search for new medicinally active nonlinear phenothiazines, novel angular chloroazaphenothiazinone derivatives have been synthesized via transition metal-catalyzed cross-coupling reactions. The structural elucidation of the synthesized compounds was established by a combined spectroscopic and elemental analysis. The synthesized compounds were tested for their antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Enterococusfaecalis, Escherichia coli, Candida albican,and Aspergillus niger isolates by the convectional agar-well dilution method and compounds 5c and 8cdisclosed excellent in vitro activity against some of the tested microorganisms. In silico,the study showed that the synthesized compounds possessed promising physichemical properties and fit well in the active site of a Biotin-Protein Ligase (BPL) forming essential hydrogen bonding and hydrophobic interactions.

Precise control of conjugated polymer synthesis from step-growth polymerization to iterative synthesis

Conjugated polymers with excellent optoelectronic properties, easy processability, and flexible physical properties are versatile in various applications. In recent years, the precise synthesis of conjugated polymers has attracted much attention due to the close relationship between structure and property. From the perspective of the polymerization mechanism, the synthetic methods of conjugated polymers can be classified into step-growth polymerization, chain-growth polymerization, and iterative synthesis. From step-growth polymerization to iterative synthesis, polymer synthesis becomes more controllable. In this review, we introduce these three synthetic approaches to prepare conjugated polymers with controllable structures based on transition metal-catalyzed cross-coupling reactions and further reveal the control over chemical structures, including length, regioregularity, sequence, and topology. The precise control over the synthesis of conjugated polymer is of great significance for the synthesis of functional polymer with a specific structure, which paves a way for fabricating high-performance devices.

Aldol condensation-enabled acceptor-acceptor type bithiophene imide polymer semiconductors for n‐type field-effect transistors

While the development of high-performing n-type polymer semiconductors remains a challenge, the involving of costly transition-metal catalysts and even toxic reagents during the preparation of these materials might also cause serious environmental issues. Herein, by devising two new aldehyde-functionalized bithiophene imide (BTI)-type building blocks, we designed and synthesized two acceptor-acceptor type n-type polymers, BTI-BD and BTI2-BD, on the basis of an environmentally benign, transition metal-free and thus cost-effective aldol condensation. The resulting polymers exhibited planar and rigid backbone conformations and low-lying LUMO energy levels close to −4.0 eV, thus leading to unipolar n-type tranport character with a highest electron mobility of 1.35 × 10−3 cm2 V−1 s−1 in organic field-effect transistors for the BTI2-BD polymer which features a higher molecular ordering in solid state. Our results demonstrate that the aldol polycondensation strategy could serve as a cheaper and more ecofriendly alternative to the convential transition metal-catalyzed cross-coupling reactions for constructing n-type acceptor-acceptor polymers with unipolar n-type charge transport characteristics.

Progress on the Transition Metal-catalyzed Cross-coupling Reaction of Thioesters

Progress on the Transition Metal-catalyzed Cross-coupling Reaction of Thioesters

Cu/SaBox-Catalyzed Photoinduced Coupling of Acylsilanes with Alkynes.

The transition metal-catalyzed cross-coupling reaction with Fischer metal carbene intermediates bearing an electron-rich alkoxyl or siloxyl group remains a big challenge due to the lack of readily available corresponding carbene precursors. Herein, we report the coupling of alkynes with the Fischer-type copper carbene species bearing a α-siloxyl group, which could be in situ generated from acylsilanes catalytically under photoirradiation and redox-neutral conditions. The side-arm modified bisoxazoline (SaBox) ligands prove to be crucial for this coupling reaction, which provides the corresponding alkynyl alcohol in high yields with remarkable heterocycle tolerance and broad substrate scope.

Iron‐Catalyzed Alkoxycarbonylation of Alkyl Bromides via a Two‐Electron Transfer Process

Transition metal-catalyzed carbonylative cross-coupling reactions are some of the most widely used methods in organic synthesis. However, despite the obvious advantages of iron as an abundant and low toxicity transition metal catalyst, its practical application in carbonylation reaction remains largely unexplored. Here we report our recent study on Fe-catalyzed alkoxycarbonylation of alkyl halides. Mechanistic studies indicate that the reaction is catalyzed by an in situ generated Fe2- complex. This low-valent iron species activates alkyl bromides via a distinctive two-electron transfer (TET) process, whereas it proceeds via a single electron transfer (SET) process for alkyl iodides which is consistent with literature.

Gram-scale synthesis of the N-phenyl phenothiazine photocatalyst by benzyne addition

N-phenyl phenothiazine is one of the most reducing photoredox catalysts. Its synthesis commonly requires transition metal-catalyzed cross-coupling reactions. Here, we show the syntheses of four aryl phenothiazines via a benzyne route, including a multigram-scale synthesis of N-phenyl phenothiazine. While yields are modest, the simplicity, low cost, and lack of requirement for cross-coupling catalysts in this synthesis will be attractive to users of this photocatalyst.

Catalytic Desymmetric Dicarbofunctionalization of Unactivated Alkenes.

The construction of multi-stereocenters by a transition metal-catalyzed cross-coupling reaction is a major challenge. The catalytic desymmetric functionalization of unactivated alkenes remains largely unexplored. Herein, we disclose -a desymmetric dicarbofunctionalization of 1,6-dienes via a nickel-catalyzed reductive cross-coupling reaction. The leverage of the underdeveloped chiral 8-Quinox enables the Ni-catalyzed desymmetric carbamoylalkylation of both unactivated mono- and disubstituted alkenes to form pyrrolidinone bearing two nonadjacent stereogenic centers in high enantio- and stereoselectivitives with broad functional-group tolerance. The synthetic application of pyrrolidinones allows the rapid access to complex chiral fused-heterocycles.

Iron-catalyzed cross-couplings of propargylic substrates with Grignard reagents

One of the main challenges of modern chemical industry is the inevitable transition to greener, more sustainable manufacturing processes that utilize raw materials more effectively, minimize waste streams, and avoid the use of toxic and hazardous materials. The development of new iron-based catalytic systems can eliminate the need for the currently widely used, costly and potentially toxic heavy metal catalysts in industrially relevant chemical reactions. Prominent examples of such processes include transition metal-catalyzed cross-coupling reactions for formation of carbon-carbon (CC) bonds. This minireview outlines recent developments in the area of iron-catalyzed cross-coupling chemistry during the last couple of decades, with special emphasis on the use of propargylic substrates and Grignard reagents as coupling partners.

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions.

In this review, the incorporation of a cyclobutyl substituent in molecules, by transition metal-catalyzed cross-coupling, is described by only considering the formation of C-C bonds. Three main strategies are used to introduce a cyclobutyl substituent in molecules by involving either electrophilic or nucleophilic cyclobutane derivatives.

Developments in Organocatalyzed C(Ar)- C(Ar) Bond formation Reactions Involving Single Electron Transfer Mechanism: An Overview

The formation of new bonds through C-C bond formation is of utmost importance in the synthesis of biologically privileged scaffolds and therapeutic drugs. In recent years, extensive efforts has been done to improve the intermolecular and intramolecular cross-coupling reaction in the simple, mild, efficient, economical, and eco-friendly manner via transition metal-free or organocatalytic direct C-H bond activation methodology. The traditional cross-coupling era continuously shifted to metal-free, organocatalytic, or metal-free cross-dehydrogenative coupling strategies to fast-track the reactions and diminishing the typical purification processes. Therefore, recent advances on the transition-metal-free, organocatalytic inter- and intra-molecular cross-coupling reactions have been introduced and discussed in the present article. In view of the reaction mechanism, organocatalytic cross-coupling reactions undergo through radical pathways, radical anionic intermediate which is completely different from traditional transition metal-catalyzed reactions. The exploration of transition metal-free organocatalyzed cross-couplings for direct C-H arylation of arenes has grown significantly, thereby, improving the formation of a wide range of aryl-aryl /arylheteroaryl/ heteroaryl-heteroaryl compounds. In the survey, transition metal-free/organocatalytic cross-coupling reactions showed a higher efficiency under simple and mild conditions than the comparative transition metal-catalyzed cross-coupling reactions. However, the higher regioselectivity and chemoselectivity are still far ahead in organocatalytic cross-coupling reactions due to their specific intrinsic mechanistic pathway. The tuning of many parameters such as oxidative states, ligands coordination, and counter anions, etc., which results in the specific direct C-H functionalization with flexible methodology are missing in the transition metal-free cross-coupling reactions. The highly systematic transition metal-catalyzed chemistry is still playing a dominant role over transition metal-free chemistry in organic synthesis. The organocatalyzed transition-metal-free conditions should be more efficient, chemoselective, and regioselective for further potential development and applications in organic synthesis. For the endless pursuit of sustainable chemistry and green chemistry, such transition-metal-free/organocatalytic reactions should be never ceased. Additional curious attention and interest have been developed so far, and chemists are showing their eagerness and talents to uncover the hidden treasure of green chemistry. In this review article, we highlighted the developments of various transition metal-free/organocatalytic C-H bond activation reactions which further encourages the advancement in the development of sustainable C-C coupling reactions and their further applications towards the synthesis of biologically privileged scaffolds and drug molecules.

Editorial Catalysts: Special Issue on Transition Metal Catalyzed Cross-Coupling Reactions

Transition metal catalyzed cross-coupling reactions have proved to be powerful tools for carbon–carbon as well as carbon–heteroatom bond formation in the development of synthetic methodologies for applications ranging from pharmaceuticals to materials [...]

C(sp2)-H functionalization in non-aromatic azomethine-based heterocycles.

Direct C(sp2)-H functionalization of the endocyclic azomethine and aldonitrone moieties in non-aromatic azaheterocycles has established itself as a promising methodology over the last decade. Transition metal-catalyzed cross-coupling reactions, α-metalation-electrophile quenching protocols, and (metal-free) nucleophilic substitution of hydrogen reactions (SNH) are the major routes applied on cyclic imines and their derivatives. In this overview, we show the tangible progress made in this area during the period from 2008 to 2020.