Bond Coupling Reactions Research Articles

Base‐Promoted Tandem Reaction towards Conjugated Dienone or Chromone Derivatives with a Cyano Group: Insertion of Alkynes into C–C σ‐Bonds of 3‐Oxopropanenitriles

AbstractBase‐promoted insertion reactions of alkynes into the C–C σ‐bonds of α‐cyano ketones were established to construct highly functionalized conjugated olefins or chromone derivatives via transition metal‐free tandem reactions. These reactions are initialized through the nucleophilic attack of α‐cyano ketones to alkynones followed by intramolecular nucleophilic addition/ring‐opening to furnish the cyano‐containing alkenes. In the cases of alkynones bearing an ortho‐halide‐substituted aryl ring, a further C–O bond coupling reaction occurs to afford chromone derivatives in good to high yields. Various alkynones bearing alkyl or aryl substituents were compatible in the reaction. This reaction has the potential to become a general synthetic protocol for the preparation of cyano‐substituted olefins and chromones due to the abundance of easily accessible starting materials possessing diverse substituent groups.magnified image

Synthesis of 1‐Vinyl/Arylbenzotriazole 3‐Oxides through a Copper‐Mediated C–N Bond Coupling Reaction

AbstractAn efficient synthesis of 1‐vinyl/arylbenzotriazole 3‐oxides via the copper‐promoted coupling of N‐hydroxybenzotriazoles with alkenyl‐ or arylboronic acids is reported. This strategy features mild reaction conditions, good functional group tolerance, broad substrate scope and rapid introduction of benzotriazole N‐oxide moieties into molecules. Density functional theory calculations revealed that the formation of the favored N‐coupling product depends on the kinetically more favorable C–N bond formation pathway.magnified image

Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis proceeds through a catalytic shunt pathway

CYP121, the cytochrome P450 enzyme in Mycobacterium tuberculosis that catalyzes a single intramolecular C-C cross-linking reaction in the biosynthesis of mycocyclosin, is crucial for the viability of this pathogen. This C-C coupling reaction represents an expansion of the activities carried out by P450 enzymes distinct from oxygen insertion. Although the traditional mechanism for P450 enzymes has been well studied, it is unclear whether CYP121 follows the general P450 mechanism or uses a different catalytic strategy for generating an iron-bound oxidant. To gain mechanistic insight into the CYP121-catalyzed reaction, we tested the peroxide shunt pathway by using rapid kinetic techniques to monitor the enzyme activity with its substrate dicyclotyrosine (cYY) and observed the formation of the cross-linked product mycocyclosin by LC-MS. In stopped-flow experiments, we observed that cYY binding to CYP121 proceeds in a two-step process, and EPR spectroscopy indicates that the binding induces active site reorganization and uniformity. Using rapid freeze-quenching EPR, we observed the formation of a high-spin intermediate upon the addition of peracetic acid to the enzyme-substrate complex. This intermediate exhibits a high-spin (S = 5/2) signal with g values of 2.00, 5.77, and 6.87. Likewise, iodosylbenzene could also produce mycocyclosin, implicating compound I as the initial oxidizing species. Moreover, we also demonstrated that CYP121 performs a standard peroxidase type of reaction by observing substrate-based radicals. On the basis of these results, we propose plausible free radical-based mechanisms for the C-C bond coupling reaction.

A bioinspired and biocompatible ortho-sulfiliminyl phenol synthesis

Synthetic methods inspired by Nature often offer unique advantages including mild conditions and biocompatibility with aqueous media. Inspired by an ergothioneine biosynthesis protein EgtB, a mononuclear non-haem iron enzyme capable of catalysing the C–S bond formation and sulfoxidation, herein, we discovered a mild and metal-free C–H sulfenylation/intramolecular rearrangement cascade reaction employing an internally oxidizing O–N bond as a directing group. Our strategy accommodates a variety of oxyamines with good site selectivity and intrinsic oxidative properties. Combining an O–N bond with an X–S bond generates a C–S bond and an S=N bond rapidly. The newly discovered cascade reaction showed excellent chemoselectivity and a wide substrate scope for both oxyamines and sulfenylation reagents. We demonstrated the biocompatibility of the C–S bond coupling reaction by applying a coumarin-based fluorogenic probe in bacterial lysates. Finally, the C–S bond coupling reaction enabled the first fluorogenic formation of phospholipids, which self-assembled to fluorescent vesicles in situ.

Formation of Alkanes by Aerobic Carbon–Carbon Bond Coupling Reactions Catalyzed by a Phosphovanadomolybdic Acid

The valorization of alkanes is possible via carbon–carbon coupling reactions. A series of dialkyl cobalt complexes [(RCH2)2CoIII(bpy)2]ClO4 (R = H, Me, Et, and Ph) were reacted with the H5PV2Mo10O40 polyoxometalate as a catalyst, leading to a selective oxidative carbon–carbon bond coupling reaction. The reaction is initiated by electron transfer from [(RCH2)2CoIII(bpy)2]+ to H5PVV2Mo10O40 to yield an intermediate [(RCH2)2CoIV(bpy)2]2+–H5PVIVVVMo10O40, as identified by a combination of EPR and X-ray photoelectron spectroscopy experiments. The reaction is catalytic with O2 as terminal oxidant representing an aerobic C–C bond coupling reaction.

C–N Bond Coupling Reactions of Ammonia with Acetone Promoted by Iridium and Rhodium Complexes: Experimental and DFT Studies

Treatment of acetone solutions of the known chlorido‐bridged complexes [{M(µ‐Cl)(cod)}2] (M = Ir, Rh; cod = 1,5‐cyclooctadiene) under an ammonia atmosphere afforded the cationic complexes {M(cod)[κN,κN‐NH2–C(CH3)2–CH2–C(CH3)=NH]}Cl [M = Ir (3), Rh (4)]. The molecular structures of 3 and 4 showed the formation of six‐membered metallacycles due to the presence of a 4‐imino‐2‐methylpentan‐2‐amine‐κN,κN‐chelated ligand. Alternatively, the cations [M(cod)(NCCH3)2]BF4 (M = Ir, Rh) reacted with gaseous ammonia at atmospheric pressure affording bis(ammine) complexes [M(cod)(NH3)2]BF4 [M = Ir (5), Rh (6)], which were found to react with acetone, forming cations [M(cod)(κN,κN‐NH2–C(CH3)2–CH2–C(CH3)=NH)]BF4 [M = Ir (7), Rh (8)]. DFT studies reveal that the transformation of 6 into 8 is mediated by NH3 molecules acting as an external base. The reaction is triggered by deprotonation of an ammonia ligand forming a amido–metal intermediate, which further transforms into an acetimino ligand through aldol condensation. The terminal methyl group of one acetimino ligand is deprotonated by NH3 yielding an enamine ligand, which can react with the imine ligand through concerted nucleophilic addition to afford the metallacycle, which is stabilized by protonation.

Boron-mediated sequential alkyne insertion and C-C coupling reactions affording extended π-conjugated molecules.

C–C bond coupling reactions illustrate the wealth of organic transformations, which are usually mediated by organotransition metal complexes. Here, we show that a borafluorene with a B–Cl moiety can mediate sequential alkyne insertion (1,2-carboboration) and deborylation/Csp2–Csp2 coupling reactions, leading to aromatic molecules. The first step, which affords a borepin derivative, proceeds very efficiently between the borafluorene and various alkynes by simply mixing these two components. The second step is triggered by a one-electron oxidation of the borepin derivative, which results in the formation of a phenanthrene framework. When an excess amount of oxidant is used in the second step, the phenanthrene derivatives can be further transformed in situ to afford dibenzo[g,p]chrysene derivatives. The results presented herein will substantially expand the understanding of main group chemistry and provide a powerful synthetic tool for the construction of a wide variety of extended π-conjugated systems.

Copper-Catalyzed Cascade Amination Route to N-Aryl Benzimidazoquinazolinones.

An efficient one-pot Cu-catalyzed C-H functionalization/two-fold C-N bond formation protocol for the syntheses of N-aryl benzimidazoquinazolinones is being reported. This strategy involves a Cu-catalyzed C-N bond coupling reaction between N-anilinoquinazolinones and aryl/heteroaryl halides followed by acetate ligand-assisted intramolecular C-H amination.a This reaction is high-yielding and straightforward for the synthesis of anti-cancer drug analogues of benzimidazoquinazolinones.

Stereoselective Metal-Catalyzed C–C Bond Coupling Reactions by Stereoconvergence, Dynamic Kinetic Asymmetric Transformation, or Dynamic Kinetic Resolution

The development of stereoselective metal-catalyzed cross-coupling reactions over the past 30 years has revolutionized the way in which C–C, C–N, and C–X bonds are formed in an enantiomerically pure form. In particular asymmetric reactions that transform racemic substrates into enantioenriched products in high, ideally quantitative, yields are particularly appealing. Consequently, many deracemization processes have been developed, implying conceptually diverse strategies such as dynamic kinetic asymmetric transformation (DYKAT), dynamic kinetic resolution (DKR), and stereoconvergence. In this review the most recent achievements in dynamic metal-catalyzed cross couplings of racemic substrates are collected and discussed according to the nature of the deracemization step. 1 Introduction 2 Deracemization by Dynamic Kinetic Resolution (DKR)/Dynamic Kinetic Asymmetric Transformation (DYKAT) 2.1 DKR towards the Control of Central Chirality 2.2 DYKAT towards the Control of Central Chirality 2.3 DKR/DYKAT towards the Control of Axial Chirality 3 Deracemization Involving a Stereoconvergent Transformation 4 Conclusion

ChemInform Abstract: Activated Nanostructured Bimetallic Catalysts for C—C Coupling Reactions: Recent Progress

AbstractReview: 127 refs.

Reactivity of 3-Imino-Functionalized Indoles with Rare-Earth-Metal Amides: Unexpected Substituent Effects on C–H Activation Pathways and Assembly of Rare-Earth-Metal Complexes

The reactivities of different 3-imino-functionalized indoles with rare-earth-metal amides [(Me3Si)2N]3RE(μ-Cl)Li(THF)3 were studied to reveal unexpected substituent effects on C–H bond activation pathways, leading to the formation of unusual rare-earth-metal complexes. The reactions of 3-(tert-butylimino)indole with [(Me3Si)2N]3RE(μ-Cl)Li(THF)3 produced tetranuclear rare-earth-metal complexes {[η1:(μ2-η1:η1):η1-3-(tBuN═CH)C8H4N]RE2(μ2-Cl)2(THF)[N(SiMe3)2](η1:η1-[μ-η5:η2-3-(tBuN═CH)C8H5N]2Li)}2 (RE = Ho (1a), Er (1b)), incorporating a unique indolyl-1,2-dianion through sp2 C–H activation bonded with the central metal in η1:(μ2-η1:η1) mode. The reactions of 3-(phenylimino)indole with [(Me3Si)2N]3RE(μ-Cl)Li(THF)3 afforded novel binuclear complexes formulated as {3-[PhNCH(CH2SiMe2)N(SiMe3)]C8H5NRE(THF)(μ2-Cl)Li(THF)2}2 (RE = Y (2a), Sm (2b), Dy (2c), Yb (2d)) through an unexpected sp3 C–H bond activation with subsequent C–C bond coupling reactions. Treatment of 3-(2-methylphenylimino)indole or 3-(4-methylphenylimino)indole with [(Me3Si)2N]3Yb(μ-Cl)Li(THF)3 generated the corresponding dinuclear rare-earth-metal amido complexes {3-[(2-MePh)NCH(CH2SiMe2)N(SiMe3)]C8H5NYb(THF)(μ2-Cl)Li(THF)2}2 (3) and {3-[(4-MePh)NCH(CH2SiMe2)N(SiMe3)]C8H5NYb(THF)(μ2-Cl)Li(THF)2}2 (4), following the same pathway for the formation of complexes 2a–d. Treatment of 3-(4-tert-butylphenylimino)indole with [(Me3Si)2N]3RE(μ-Cl)Li(THF)3 afforded new hexanuclear rare-earth-metal complexes {3-[(4-tBu-Ph)NHCH(CH2SiMe2)N(SiMe3)]C8H5NREN(SiMe3)2}6 (RE = Dy (5a), Ho (5b), Er (5c)) via sp3 C–H bond activation followed by C–C bond coupling reactions. In contrast, under the same conditions as those for the preparation of 5, the reaction with the corresponding yttrium complex provided the new heterohexayttrium complex {3-[(4-tBu-Ph)NCH(CH2SiMe2)N(SiMe3)]C8H5NYN(SiMe3)2Li(THF)}6 (6), having a 4-tBu-anilido moiety. All of these complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray structure analysis. Plausible pathways for the formation of these different rare-earth-metal complexes were proposed.

Competitive intramolecular C-C vs. C-O bond coupling reactions toward C6 ring-fused 2-pyridone synthesis.

An interesting competitive C-C vs. C-O bond coupling reaction on N,3,5-trisubstituted pyridones is reported. These coupling reactions provided selective access to C- or O-ring-fused pyridones, both at the challenging C6-pyridone position. 1,6-C-Annulated pyridones were generally achieved in good yields with excellent chemoselectivity under Pd(0) conditions. On the other hand, full C6-regioselective Csp(2) aryloxylation was achieved under oxidative coupling promoted by silver salts to access 5,6-O-annulated pyridones. Based on various experiments and observations, mechanistic evidence of these competitive reactions was provided and it was proposed that C-O bond formation proceeded through radical cyclization. These processes were performed under mild reaction conditions and offer an efficient and attractive methodology to selectively access a large scope of C-arylated and O-arylated pyridones of biological interest.

Non-covalent organocatalysis in asymmetric oxidative C(sp3)–H bond functionalization – broadening C–H bond coupling reactions

In this highlight, the design of cooperative non-covalent organocatalysis for the development of novel asymmetric oxidative C–H bond functionalization reactions is presented.

Activated nanostructured bimetallic catalysts for C–C coupling reactions: recent progress

This minireview highlights the recent progress made in the last decade towards the development of activated bimetallic alloy nanoparticle catalysts for C–C coupling reactions, including asymmetric C–C bond coupling reactions.

ChemInform Abstract: Gas‐Phase Studies of Metal Catalyzed Decarboxylative Cross‐Coupling Reactions of Esters

AbstractReview: 91 refs.

Prying open a Reactive Site for Allylic Arylation by Phosphine-Ligated Geminally Diaurated Aryl Complexes

Gas-phase ion–molecule reaction experiments, theoretical kinetic modeling, and computational chemistry were used to examine the role of a second gold center in promoting allylic arylation. Geminally diaurated complexes [(L)nAu2Ph]+ are demonstrated to participate in C–C bond formation reactions with allyl halides, CH2═CHCH2X (X = Cl, Br, and I), given a favorable phosphine ligand architecture. Thus, while [(Ph3P)2Au2Ph]+, 1, is unreactive toward the allyl halides, [(dppm)Au2Ph]+, 2 (where dppm = bis(diphenylphosphino)methane, (Ph2P)2CH2), reacts via C–C bond coupling to produce [(dppm)Au2X]+. The reaction kinetics (efficiencies) follows the expected leaving group ability, X = I (58%) > Br (2%) > Cl (0.02%). DFT calculations were carried out to examine the potential mechanism for the C–C bond coupling reactions of 2 with each of the three allyl halides. The most favorable mechanism for C–C bond coupling of 2 requires the active participation of both gold centers in a redox couple mechanism wherein the ally...

ChemInform Abstract: Gas Phase Studies of the Pesci Decarboxylation Reaction: Synthesis, Structure, and Unimolecular and Bimolecular Reactivity of Organometallic Ions

AbstractReview: 67 refs.

Gas-phase studies of metal catalyzed decarboxylative cross-coupling reactions of esters

Abstract Metal-catalyzed decarboxylative coupling reactions of esters offer new opportunities for formation of C–C bonds with CO2 as the only coproduct. Here I provide an overview of: key solution phase literature; thermochemical considerations for decarboxylation of esters and thermolysis of esters in the absence of a metal catalyst. Results from my laboratory on the use of multistage ion trap mass spectrometry experiments and DFT calculations to probe the gas-phase metal catalyzed decarboxylative cross-coupling reactions of allyl acetate and related esters are then reviewed. These studies have explored the role of the metal carboxylate complex in the gas phase decarboxylative coupling of allyl acetate proceeding via a simple two-step catalytic cycle. In Step 1, an organometallic ion, [CH3ML]+/– (where M is a group 10 or 11 metal and L is an auxillary ligand), is allowed to undergo ion-molecule reactions with allyl acetate to generate 1-butene and the metal acetate ion, [CH3CO2ML]+/–. In Step 2, the metal acetate ion is subjected to collision-induced dissociation to reform the organometallic ion and thereby close the catalytic cycle. DFT calculations have been used to explore the mechanisms of these reactions. The organometallic ions [CH3CuCH3]–, [CH3Cu2]+, [CH3AgCu]+ and [CH3M(phen)]+ (where M = Ni, Pd and Pt) all undergo C–C bond coupling reactions with allyl acetate (Step 1), although the reaction efficiencies and product branching ratios are highly dependant on the nature of the metal complex. For example, [CH3Ag2]+ does not undergo C–C bond coupling. Using DFT calculations, a diverse range of mechanisms have been explored for these C–C bond-coupling reactions including: oxidative-addition, followed by reductive elimination; insertion reactions and SN2-like reactions. Which of these mechanisms operate is dependant on the nature of the metal complex. A wide range of organometallic ions can be formed via decarboxylation (Step 2) although these reactions can be in competition with other fragmentation channels. DFT calculations have located different types of transition states for the formation of [CH3CuCH3]–, [CH3Cu2]+, [CH3AgCu]+ and [CH3M(phen)]+ (where M = Ni, Pd and Pt). Of the catalysts studied to date, [CH3Cu2]+ and [CH3Pd(phen)]+ are best at promoting C–C bond formation (Step 1) as well as being regenerated (Step 2). Preliminary results on the reactions of [C6H5M(phen)]+ (M = Ni and Pd) with C6H5CO2CH2CH=CH2 and C6H5CO2CH2C6H5 are described.

Alkali metal mediated C-C bond coupling reaction.

Metal catalyzed carbon-carbon (C-C) bond formation is one of the important reactions in pharmacy and in organic chemistry. In the present study, the electron and hole capture dynamics of a lithium-benzene sandwich complex, expressed by Li(Bz)2, have been investigated by means of direct ab-initio molecular dynamics method. Following the electron capture of Li(Bz)2, the structure of [Li(Bz)2](-) was drastically changed: Bz-Bz parallel form was rapidly fluctuated as a function of time, and a new C-C single bond was formed in the C1-C1' position of Bz-Bz interaction system. In the hole capture, the intermolecular vibration between Bz-Bz rings was only enhanced. The mechanism of C-C bond formation in the electron capture was discussed on the basis of theoretical results.

Gas phase studies of the Pesci decarboxylation reaction: synthesis, structure, and unimolecular and bimolecular reactivity of organometallic ions.

CONSPECTUS: Decarboxylation chemistry has a rich history, and in more recent times, it has been recruited in the quest to develop cheaper, cleaner, and more efficient bond-coupling reactions. Thus, over the past two decades, there has been intense investigation into new metal-catalyzed reactions of carboxylic substrates. Understanding the elementary steps of metal-mediated transformations is at the heart of inventing new reactions and improving the performance of existing ones. Fortunately, during the same time period, there has been a convergence in mass spectrometry (MS) techniques, which allows these catalytic processes to be examined efficiently in the gas phase. Thus, electrospray ionization (ESI) sources have been combined with ion-trap mass spectrometers, which in turn have been modified to either accept radiation from tunable OPO lasers for spectroscopy based structural assignment of ions or to allow the study of ion-molecule reactions (IMR). The resultant "complete" gas-phase chemical laboratories provide a platform to study the elementary steps of metal-catalyzed decarboxylation reactions in exquisite detail. In this Account, we illustrate how the powerful combination of ion trap mass spectrometry experiments and DFT calculations can be systematically used to examine the formation of organometallic ions and their chemical transformations. Specifically, ESI-MS allows the transfer of inorganic carboxylate complexes, [RCO2M(L)n](x), (x = charge) from the condensed to the gas phase. These mass selected ions serve as precursors to organometallic ions [RM(L)n](x) via neutral extrusion of CO2, accessible by slow heating in the ion trap using collision induced dissociation (CID). This approach provides access to an array of organometallic ions with well-defined stoichiometry. In terms of understanding the decarboxylation process, we highlight the role of the metal center (M), the organic group (R), and the auxiliary ligand (L), along with cluster nuclearity, in promoting the formation of the organometallic ion. Where isomeric organometallic ions are generated and normal MS approaches cannot distinguish them, we describe approaches to elucidate the decarboxylation mechanism via determination of their structure. These "unmasked" organometallic ions, [RM(L)n](x), can also be structurally interrogated spectroscopically or via CID. We have thus compared the gas-phase structures and decomposition of several highly reactive and synthetically important organometallic ions for the first time. Perhaps the most significant aspect of this work is the study of bimolecular reactions, which provides experimental information on mechanistically obscure bond-formation and cross-coupling steps and the intrinsic reactivity of ions. We have sought to understand transformations of substrates including acid-base and hydrolysis reactions, along with reactions resulting in C-C bond formation. Our studies also allow a direct comparison of the performance of different metal catalysts in the individual elementary steps associated with protodecarboxylation and decarboxylative alkylation cycles. Electronic structure (DFT and ab initio) and dynamics (RRKM) calculations provide further mechanistic insights into these reactions. The broad implications of this research are that new reactions can be discovered and that the performance of metal catalysts can be evaluated in terms of each of their elementary steps. This has been particularly useful for the study of metal-mediated decarboxylation reactions.