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A Co(acac)3/PN precatalyst was developed and optimized for catalytic Kumada coupling of aryl Grignard reagents to sterically encumbered alkyl halides. The substrate scope demonstrates excellent yie...

International audience; This chapter describes recent developments in the manganese-catalyzed crosscoupling reactions for the formation of CC or C-heteroatom bonds, including C-N, CO , C-S and C-B bonds. The nature of the organic halide and the organometallic coupling partner (organolithium, Grignard or organostannyl reagents) are important parameters in these reactions. Mechanistic studies are discussed as well as the recently arisen question about the influence of trace-metal contamination in certain reactions.

Transition-metal-catalyzed cross-coupling has emerged as one of the most powerful and useful tools for the formation of C–C and C–heteroatom bonds. Given the shortage of resources of precious metals on Earth, the use of Earth-abundant metals as catalysts in developing cost-effective strategies for cross-coupling is a current trend in synthetic chemistry. Compared with the achievements made using first-row nickel, iron, cobalt, and even manganese catalysts, the group 6 metal chromium has rarely been used to promote cross-coupling. This perspective covers recent advances in chromium-catalyzed cross-coupling reactions in transformations of chemically inert C(aryl)–O, C(aryl)–N, and C(aryl)–H bonds, offering selective strategies for molecule construction. The ability of low-valent Cr with a high-spin state to participate in two-electron oxidative addition is highlighted; this is different from the mechanism involving single-electron transfer that is usually assigned to chromium-mediated transformations.1 Introduction2 Chromium-Catalyzed Kumada Coupling of Nonactivated C(aryl)–O and C(aryl)–N Bonds3 Chromium-Catalyzed Reductive Cross-Coupling of Two Nonactivated C(aryl)–Heteroatom Bonds4 Chromium-Catalyzed Functionalization of Nonactivated C(aryl)–H Bonds5 Conclusions and Outlook

Polythiophene derivatives synthesized by Kumada catalyst-transfer polycondensation (KCTP) have been intensively studied as potential candidates for low-cost organic solar cells (OSCs) due to their capability of scalable production. However, the power conversion efficiency (PCE) is still unsatisfactory so far. In this work, two regioregular polythiophene derivatives, P3SHT and PTST with thioalkyl chains, were prepared by KCTP. Compared to the analogue P3HT with alkyl chains, the new polymers show stronger absorption and downshifted energy levels due to the role of sulfur as a π-acceptor. The non-covalent interaction induced by sulfur also improves the crystallinity of the relevant polymers. However, the photovoltaic properties of P3SHT with thioalkyl chains are inferior to those of P3HT due to the severe phase separation in OSCs. PTST with alternating alkyl and thioalkyl chains exhibits the strongest crystallinity among these polymers since it mitigates the steric hindrance of sulfur atoms while retaining the merit of thioalkyl chains. More importantly, PTST is able to hierarchically pre-aggregate in solution, and then form a favorable morphology in OSCs, consequently yielding a superior PCE to P3HT.

Biaryl compounds are an important class of aromatic compounds used for the synthesis of antiviral, antihypertensive, and antifungal drugs. The familiar methods for the synthesis of biaryl compounds are Pd-, Ni-catalyzed couplings reactions, such as Suzuki, Negishi and Kumada reactions. Hypertension is a medical condition in which the blood pressure against artery wall is high enough to increase the risk of heart disease and stroke. Angiotensin receptor blockers (ARBs) are one of the most effective and commonly prescribed antihypertensive agents. o-Tolyl benzonitrile (OTBN) is the common building block for the synthesis of the sartan series of drug molecules (ARBs), such as candesartan, irbesartan, losartan, tasosartan, and valsartan. The classical methods for the synthesis of OTBN are Pd-catalyzed, Ni-catalyzed Suzuki coupling reactions. The other high yield methods for the synthesis of OTBN are Ni-catalyzed Kumada coupling, and desulfinating cross-coupling using Pd-catalyst. The Ni-catalysts could be an alternative to the expensive Pd-catalyst, as cost is a factor for bulk manufacturing of this building block. Although there are few reports of OTBN synthesis using desulfinating cross coupling, this method has opened a new avenue.

Suzuki–Miyaura catalyst transfer polymerization (SM CTP) is a versatile method to prepare conjugated polymers with control over molecular weight, sequence, and dispersity. This perspective aims to highlight some of the progress in using Suzuki–Miyaura coupling to prepare well-defined conjugated polymers via a chain-growth mechanism. We detail some of the advantages and challenges of this coupling to make aromatic polymers from monomers bearing two functional groups. The advances in arene borylation over the last twenty years are briefly highlighted, as these strategies should serve to diversify monomer scope in the future. The proposed mechanism for transmetalation in Suzuki–Miyaura polymerization is discussed, as it is different from the more typical Kumada coupling. We describe the versatility of the organoboron group used for this reaction and how it can be used tune polymerization behavior. Finally, some of the advances in catalyst design to prepare conjugated polymers using SM CTP are noted.

New PCNPy pincer nickel complexes have been synthesized through a short synthetic route. Incorporating pyridine as the nitrogen side arm facilitated the C–H activation in the PCN ligand and allowed the cyclometallation with nickel to take place at room temperature. Pyridine also enhanced the stability of β-hydrogen-containing alkyl complexes. Also, the symmetric NCN nickel complex with pyridine side arms was successfully obtained giving a rare example of such type of complexes to be prepared through direct C–H activation. Furthermore, preliminary results showed that the (PCNPy)Ni–Br is active in Kumada coupling reactions particularly the coupling of aryl halides with aryl Grignard reagents.

A new series of 3,3ʹ-disubstituted chiral (S)-BINOL derivatives 6a–6k has been synthesized via the Kumada and Suzuki–Miyaura coupling reactions using (S)-BINOL as the initial compound. The Kumada coupling has been found to be superior in terms of yields and reaction time. All the synthesized compounds have been screened for their antibacterial activity against Gram-positive and Gram-negative organisms using Penicillin and Streptomycin as standards. The most potent antibacterial activity has been determined for compounds 6a,6b, 6c, and 6d with MIC values ranging from 1.17 to 4.68 μg/mL against all bacterial strains tested. Molecular docking studies has presented an insight into the binding pattern of the top active ligands with the respective target protein.

A series of ester-functionalized benzimidazolium salts 2a–c were prepared by quaternization of 1-{(ethoxycarbonyl)methyl}benzimidazole (1) with 3,5-dimethylbenzyl bromide, 2,5-dimethylbenzyl chloride and 3-methoxybenzyl chloride, respectively. Refluxing 2a–c with nickelocene in THF yielded the neutral cyclopentadienyl NHC nickel(II) complexes 3a–c. Their structures were defined by NMR, IR and elemental analysis techniques. Molecular weights of 3a–c were affirmed by MALDI-TOF mass spectrometry. Catalytic tests of 3a–c were performed in Kumada coupling of some aryl chlorides with phenylmagnesium bromide at 25 °C.

1,3‐Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo[1.1.1]pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues., 1,3‐C‐disubstituted bicyclo[1.1.1]pentanes (BCPs) are accessed from 1‐iodo‐BCPs by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This represents the first general use of iodo‐BCPs as cross‐coupling electrophiles, and the first Kumada coupling of tertiary iodides in general. Benefiting from short reaction times, mild conditions, and broad scope, it enables the synthesis of a wide range of BCPs including drug analogues.

A series of nickel complexes in varying oxidation states were evaluated as precatalysts for the stereospecific cross-coupling of benzylic ethers. These results demonstrate rapid redox reactions of precatalysts, such that the oxidative state of the precatalyst does not dictate the oxidation state of the active catalyst in solution. These data provide the first experimental evidence for a Ni0 -NiII catalytic cycle for a stereospecific alkyl-alkyl cross-coupling reaction, including spectroscopic analysis of the catalyst resting state.

A supramolecular catalytic ensemble HP-T@Au-Fe3O4 supported by highly branched assemblies of hexaphenylbenzene (HPB) derivatives has been developed. The as-prepared HP-T@Au-Fe3O4 nanohybrid material serves as an efficient catalytic system to prepare biaryl derivatives through the Kumada cross-coupling reaction using aryl chlorides as one of the coupling partners under mild reaction conditions (visible light irradiation, aqueous media, aerial conditions, short reaction time). Through the cooperative effect of Au NPs and Fe3O4 NPs, dual activation of aryl chlorides for the generation of aryl radical intermediates is achieved. On the other hand, oligomeric assemblies contributed significantly to the enhancement of the reaction rate and yield of the product by facilitating the reductive elimination step. Different mechanistic studies confirm the involvement of Au NPs, Fe3O4 NPs and oligomeric assemblies in the synergistic and balanced operation of HP-T@Au-Fe3O4 nanohybrid materials in the efficient completion of the catalytic cycle of the Kumada coupling reaction. Being magnetic, the catalytic ensemble could be recycled for up to five catalytic cycles. The as-prepared supramolecular photocatalytic ensemble also works efficiently in Heck coupling reactions involving aryl chlorides and aryl iodides as the coupling partner.

X.-J.W., I.A., J.A., and T.N. would like to acknowledge the European Union for a Marie Curie ITN Grant (Photo4Future, Grant No. 641861). C.S. acknowledges the European Union for a Marie Curie European post-doctoral fellowship (FlowAct, Grant No. 794072). We would like to thank the Engineering and Physical Sciences Research Council for financial support (EP/M02105X/1). C. L. thanks the Prof. & Mrs Purdie Bequests Scholarship and AstraZeneca for his PhD Studentship. A continuous‐flow, visible‐light‐promoted method has been developed to overcome the limitations of iron‐catalyzed Kumada–Corriu cross‐coupling reactions. A variety of strongly electron rich aryl chlorides, previously hardly reactive, could be efficiently coupled with aliphatic Grignard reagents at room temperature in high yields and within a few minutes’ residence time, considerably enhancing the applicability of this iron‐catalyzed reaction. The robustness of this protocol was demonstrated on a multigram scale, thus providing the potential for future pharmaceutical application. Publisher PDF

Ni-catalyzed C(sp(3))-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetallation with the Grignard reagent and syn reductive elimination produces the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic C-O bond cleavage and transmetallation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular S(N)2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp(3))-O bond activation.

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes. Access to all-carbon disubstituted BCPs via cross coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3-C-disubstituted BCPs from 1-iodo-bicyclo[1.1.1]pentanes (iodo-BCPs) by direct iron-catalyzed crosscoupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodoBCPs as electrophiles in cross-coupling, and of Kumada coupling of tertiary iodides in general. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3-C-disubstituted BCPs including various drug analogues.

A nanoparticle (NP)-based precatalyst has been developed for organic synthesis: sulfur-modified Au-supported Fe (SAFe). The SAFe was easily prepared through a three-step procedure involving simultaneous in situ metal NP and nanospace organization (PSSO). This method avoids the need for preformed templates for immobilizing and stabilizing the metal nanoparticles. On account of the relative safety and enormous earth abundance of iron, SAFe potentially represents an ideal precatalyst for carbon–carbon bond-forming cross-coupling reactions. As such, it has been applied as a precatalyst to Kumada coupling under ligand-free conditions, proving to be capable of being recycled and used repeatedly for this reaction. Analysis of SAFe and of reaction mixtures suggested that the active species in these reactions are produced in situ by assemblies of iron-based NPs.

Heterodinuclear transition metal complexes with a direct metal–metal interaction offer the potential of unique reactivity compared with mononuclear catalysts. Heterodinuclear Co–Zr complexes with phosphinoamide ligands bridging Co and Zr metal centers are effective precatalysts for Kumada C–C bond coupling reactions between alkyl halides and alkyl Grignards. In contrast, the analogous mononuclear Co tris(phosphinoamine) complex without Zr provides very inefficient catalysis. Here we describe density functional theory calculations that reveal the mechanistic and reactivity impact of the Co–Zr metal–metal interaction and phosphinoamide ligands on alkyl halide–alkyl Grignard Kumada coupling catalysis. The Co–Zr interaction enables two-electron reduction of the precatalyst to form an active catalyst, which then promotes a low-energy electron-transfer alkyl halide oxidative addition mechanism. The Co–Zr interaction and the phosphinoamide ligands bridging the metal centers provide a dialkyl intermediate with a ...

A systematic study of the widely used, titled name reaction transition-metal-catalyzed cross-coupling reactions with attention to context with the directed ortho metalation (DoM) is reported. In general, the Suzuki–Miyaura and Negishi protocols show greater scope and better yields than the Corriu–Kumada variant, although the latter qualitatively proceeds at fastest rate but has low functional group tolerance. The Negishi process is shown to be useful for substrates with nucleophile and base-sensitive functionality and it is comparable to the Suzuki–Miyaura reaction in efficiency. The link of these cross-coupling reactions to the DoM strategy lends itself to the regioselective construction of diversely substituted aromatics and heteroaromatics.

We report here the chromium-catalyzed regioselective Kumada arylative cross-coupling of C(aryl)-O bonds at ambient temperature. By using a simple and low-cost chromium(II) chloride salt as a precatalyst, accompanied by a 2-pyridyl ligation, the catalytic cleavage and arylative coupling of C(aryl)-O bonds were achieved with a traceless activation strategy, overcoming the regioselectivity obstacle when several C-O bonds coexist in the Kumada coupling system.

The electron-rich silylene Co(I) chloride 5 was obtained through the reaction of CoCl(PMe3)3 with chlorosilylene. Complex 5 reacted with 1,3-siladiazole HSiMe(NCH2PPh2)2C6H4 to give the silylene Co(III) hydride 6 through chelate-assisted Si–H activation. To the best of our knowledge, complex 6 is the first example of Co(III) hydride supported by N-heterocyclic silylene. Complexes 5 and 6 were fully characterized by spectroscopic methods and X-ray diffraction analysis. Complex 6 was used as an efficient precatalyst for Kumada cross-coupling reactions. Compared with the related complex 3 supported by only trimethylphosphine, complex 6 as a catalyst supported by both chlorosilylene and trimethylphosphine exhibits a more efficient performance for the Kumada cross-coupling reactions. A novel catalytic radical mechanism was suggested and experimentally verified. As an intermediate silylene cobalt(II) chloride 6d was isolated and structurally characterized.

The synthesis and catalytic properties in Kumada C C coupling of the [Ni(BIPHEP)X2] complexes, X = Cl (1), Br (2), are described. The crystal structures of the BIPHEP ligand and 2 are also presented and compared with previously reported crystal structures of atropisomeric bidentate phosphine ligands (P,P) and related [M(P,P)X2] complexes (M = Ni, Pd, Pt). BIPHEP crystallizes in the C2/c space group, with both enantiomers present in the unit cell. This is consistent with BIPHEP being a “tropos” ligand. Complex 2 crystallizes in the P21/a space group. There are two symmetry-independent molecules in the asymmetric unit, namely 2a and 2b, in which the BIPHEP ligand adopts the S or the R configuration, respectively. Complexes 2a and 2b exhibit a severely tetrahedrally-distorted square planar NiP2Br2 coordination sphere, with a PNiP bite angle of 93.3° and 94.7°, respectively. The observed catalytic behavior of complexes 1 and 2 in the Kumada coupling between p-tert-butyl-halogenobenzene and p-tolylmagnesium chloride is benchmarked against that of [Ni(dppp)Cl2], dppp = 1,3-bis(diphenylphoshpino)propane. However, all three complexes are catalytically inactive in the Suzuki-Miyaura coupling reaction.