Oxidative Cross-coupling Reaction Research Articles

Palladium catalyzed cross-dimerization of terminal acetylenes and acrylates

A palladium catalyzed oxidative cross-coupling reaction between terminal alkynes and acrylates was developed. In the presence of palladium catalyst and copper(II) acetate as oxidant, the cross dimerization products with were formed. This protocol provides a novel method to construct the tetrasubstituted functionalized alkenes.

C-H Acidity and Arene Nucleophilicity as Orthogonal Control of Chemoselectivity in Dual C-H Bond Activation.

We discovered a cooperative gold/silver catalysis mechanism in the oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole, using DFT calculations. A silver(I)-catalyzed CMD mechanism is responsible for the C-H activation of 1,2,4,5-tetrafluorobenzene, and C-H acidity determines the chemoselectivity. A gold(III)-catalyzed SE2Ar mechanism is responsible for the C3-H activation of N-TIPS-indole, and arene nucleophilicity determines the chemo- and regioselectivity. The orthogonal chemoselectivity control provides a mechanistic guide for dual C-H activation reactions.

Copper-Catalyzed Oxidative Cross-Coupling Reactions for the Synthesis of β-Acyl-α-amino Acid Derivatives in Aqueous Medium

Copper-Catalyzed Oxidative Cross-Coupling Reactions for the Synthesis of <i>β</i>-Acyl-<i>α-</i>amino Acid Derivatives in Aqueous Medium

Direct C-H/C-H cross-coupling of benzimidates with heteroarenes to access biheteroaryl-2-carbonitriles.

A Rh-catalyzed C-H/C-H oxidative cross-coupling reaction of benzimidates with heteroarenes is developed, yielding biheteroaryl-2-carbonitriles directly after in situ dealcoholization. This protocol features high atom- and step-economy, and a broad substrate scope with good functional group tolerance.

General rhodium-catalyzed oxidative cross-coupling reactions between anilines: synthesis of unsymmetrical 2,2'-diaminobiaryls.

Described herein is a dual chelation-assisted RhCl3-catalyzed oxidative C-H/C-H cross-coupling reaction of aniline derivatives. The highlight of this methodology is the chemo- and regioselective cross-coupling between electronically similar substrates, which represents a highly challenging task in oxidative Ar-H/Ar-H cross-coupling reactions. Furthermore, this Cp*-free catalytic reaction tolerates a range of functional groups and requires only a low molar ratio of coupling partners. These features expedite the synthesis of unsymmetrical 2,2'-diaminobiaryls.

Palladium-catalyzed oxidative cross-coupling for the synthesis of α-amino ketones.

A novel oxidative cross-coupling reaction for the synthesis of α-aryl α-amino ketones in the presence of palladium catalysts using T+BF4− as an oxidant has been developed. This transformation was achieved by direct C–H oxidation of α-aminocarbonyl compounds and arylation. The mild reaction has a broad reaction scope and gives desired α-aryl α-amino ketones in moderate to excellent yields.

Visible-light-promoted oxidation/condensation of benzyl alcohols with dialkylacetamides to cinnamides.

Oxidative cross-coupling reactions of benzyl alcohols with N,N-dialkylacetamides were developed only employing oxygen as the terminal oxidant, efficiently providing a new, novel protocol for the construction of multifunctionalized cinnamides with the synergistic effects of KOH, organic photocatalyst eosin Y, and visible light irradiation at room temperature. A broad substrate scope and mild reaction conditions are the prominent features of this transformation.

Oxidative and Reductive Cross-Coupling Reactions Catalyzed by an Anionic “Ligandless” Palladium Complex

The anionic complex [NBu4][Pd(DMSO)Cl3], which can be synthesized on a gram scale in a single step starting from commercially available starting materials, has been shown to be an active catalyst in the Mizoroki–Heck reaction of aryl halides. We present two new catalytic applications of this complex: the base-free oxidative Heck reaction and the reductive homodimerization of aryl halides. This complex outperformed other palladium salts. In the latter reaction, the catalyst loading could be reduced to 0.01 mol %. The scope of the reactions has been explored, demonstrating the potential of the anionic palladium complex in these catalytic transformations.

Upgrading Cross-Coupling Reactions for Biaryl Syntheses.

Transition-metal catalyzed cross-coupling reactions have emerged as a powerful tool for constructing biaryl compounds. Aryl halides and aryl metallic reagents (typically prepared from aryl halides) are used as coupling partners. It would be desirable to replace either aryl halide or aryl metallic reagents used in cross-couplings reactions with more readily available surrogates. Oxidative dehydrogenative cross-coupling between two different "inert" aryl C-H bonds represents an ideal system that would revolutionize cross-coupling chemistry. Furthermore, cross-coupling reactions might be improved by developing new catalytic protocols based on cheap transition-metal catalysts or even transition-metal-free systems to decrease costs and avoid the use of heavy metal and noble transition metals. It would be desirable to promote both catalytic systems and replace either or both coupling partners. We have used different strategies to improve cross-coupling reactions for constructing biaryls, which we categorized into four groups as follows. First, we focused on developing methodologies to be applied to easily produced and naturally abundant arenol-based electrophiles in cross-coupling via C-O activation. We have extended coupling partners to aryl carboxylates and arenols. Direct application of arenes as surrogates for organohalides and organometallic reagents avoids the tedious preparation of these reagents from arenes and considerably reduces the cost of starting materials. We have also explored cross-coupling reactions of arenes with various organometallic reagents, such as arylboronic acids, arylsilanes, and aryl Grignard reagents. Second, we summarize oxidative cross-coupling reactions based on C-H activation with aryl metallic reagents. On the basis of the reactivity patterns of different organometallic reagents, we adapted different catalytic systems to achieve effective cross-coupling reactions. Third, we improved a well-developed cross-coupling between arenes and organohalides through a strategy of replacing one coupling partner and using a new catalytic system. We have applied earth-abundant transition metals, such as Fe, and Co, and even developed transition-metal-free catalytic systems. Finally, our ultimate goal is to construct biaryls by cross dehydrogenative arylation between two different arenes. Owing to the structural similarity of both arenes, in particular two substituted benzenes, the greatest challenges are not only achieving regio- and chemo-selective C-H activation reactions but also matching both the reactivities and selectivities of both substrates to avoid homocouplings of either arene. Through our efforts, we have developed and applied four different strategies by introducing directing groups, controlling electronic and steric properties, and using dual directing strategies. We hope our studies will stimulate interest and new thinking on cross-couplings reactions for building carbon-carbon bonds from readily available and inexpensive chemicals from basic petroleum chemistry and nature.

Inside Cover: Regioselective Metal‐ and Reagent‐Free Arylation of Benzothiophenes by Dehydrogenative Electrosynthesis (Angew. Chem. Int. Ed. 40/2018)

Electrochemical “welding” serves as a powerful tool for the arylation of benzo[b]thiophenes in position 2 or 3. S. R. Waldvogel and co-workers report in their Communication on page 13325 ff. the first electro-organic dehydrogenative synthesis of 2- or 3-(hydroxyphenyl)benzo[b]thiophenes by oxidative cross-coupling reactions. The direct use of electricity as a reagent eliminates the necessity of leaving groups, metal catalysts, stoichiometric oxidizers, or reducing agents. Therefore, the reaction enables a sustainable synthetic pathway to these scaffolds and can be considered as ”green chemistry”.

I2-Catalyzed Oxidative Cross-Coupling Reaction of Methyl Ketones and 2-(2-Aminophenyl) Benzimidazole: Facile Access to Benzimidazo[1,2-c]quinazoline.

A general and efficient iodine-catalyzed metal-free oxidative cross-coupling reaction of methyl ketones with 2-(1H-benzo[d]imidazol-2-yl)aniline has been established. This is a new synthetic strategy for the synthesis of benzimidazo[1,2-c]quinazoline derivatives involving C(sp3)–H oxidation, condensation, and cyclization processes.

Mechanistic Study on Cu(II)-Catalyzed Oxidative Cross-Coupling Reaction between Arenes and Boronic Acids under Aerobic Conditions.

Substantial attention has been given to modern organocopper chemistry in recent years since copper salts are naturally abundant, cheap, and less toxic in comparison to precious metals. Copper salts also exhibit versatility in catalyzing and mediating carbon-carbon and carbon-heteroatom bond forming reactions. Despite the wide applications of copper salts in catalysis, reaction mechanisms have remained elusive. Using azacalix[1]arene[3]pyridine, an arene-embedded macrocycle, and its isolated and structurally well-defined ArCu(II) and ArCu(III) compounds as molecular tools, we now report an in-depth experimental and computational study on the mechanism of a Cu(II)-catalyzed oxidative cross-coupling reaction between arenes and boronic acids with air as the oxidant. Stoichiometric reaction of organocopper compounds with p-tolylboronic acid validated arylcopper(II) rather than arylcopper(III) as a reactive organometallic intermediate. XPS, EPR, 1H NMR, HRMS, and UV-vis spectroscopic evidence along with the isolation and quantification of all products and copper speciation, combined with computational analysis of the electronic structure and energetics of the transient intermediates, suggested a reaction sequence involving electrophilic metalation of arene by Cu(II), transmetalation of arylboronate to ArCu(II), the redox reaction between the resulting ArCu(II)Ar' and ArCu(II) to form respectively ArCu(III)Ar' and ArCu(I), and finally reductive elimination of ArCu(III)Ar'. Under aerobic catalytic conditions, all Cu(I) ions released from reductive elimination of ArCu(III)Ar' and from protolysis of ArCu(I) were oxidized by oxygen to regenerate Cu(II) species that enters into the next catalytic cycle. The unraveled reactivity of arylcopper(II) compounds and the catalytic cycle would enrich our knowledge of modern organocopper chemistry and provide useful information in the design of copper-catalyzed reactions.

Stereoselective Synthesis of Optically Pure 2-Amino-2'-hydroxy-1,1'-binaphthyls.

Direct entry to optically pure 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives by an iron-catalyzed stereoselective oxidative cross-coupling reaction between 2-naphthol and 2-aminonaphthalene with a labile chiral auxiliary is reported. This efficient method offers entry to tailor-designed ( R a)- and ( S a)-NOBINs that are not accessible by any other means.

Boric Ester and Thiourea as Coupling Partners in a Copper-Mediated Oxidative Dehydrosulfurative Carbon-Oxygen Cross-Coupling Reaction.

A copper-mediated oxidative dehydrosulfurative carbon-oxygen cross-coupling reaction with boric ester and six-membered cyclic thiourea for single-step production of densely substituted 2-alkoxypyrimidines incorporated in a privileged scaffold is described. This is the first demonstration of boric ester acting as an alkoxy donor in a metal-catalyzed coupling reaction to produce ether. The reaction method offers a shortcut for producing 2-alkoxypyrimidine derivatives with rapid diversification and expands the utility of boric ester and the scope of Liebeskind-Srogl-type reactions.

An oxidative cross-coupling reaction of 4-hydroxydithiocoumarin and amines/thiols using a combination of I2 and TBHP: access to lead molecules for biomedical applications.

A metal-free I2/TBHP induced highly atom economic and operationally simple oxidative cross-coupling reaction has been developed for the direct synthesis of sulfenamides/sulfanes/disulfides from the reaction of 4-hydroxydithiocoumarin and amines/thiols. The novelties of the present protocol are unprecedented S-C bond formation in addition to S-N and S-S bonds, shorter reaction time, mild and environmentally benign reaction conditions, functional group tolerance and moderate to excellent yields. Moreover, the four newly synthesized compounds namely 4q, 6d, 6e and 7a exhibit anti-proliferative activity against the breast cancer cell line MCF7, and may be lead molecules for future drug development.

Direct C-4 alkylation of quinazoline N-oxides with ethers via an oxidative cross-coupling reaction under metal-free conditions.

A novel and efficient protocol for the direct C-4 alkylation of quinazoline-3-oxides via radical oxidative coupling between quinazoline 3-oxides and ethers in the presence of TBHP was developed. The reaction proceeded smoothly under metal-free conditions, which provided quinazoline-containing heterocyclic molecules in moderate to good yields.

Selectfluor-induced C(sp2)-O coupling reaction of N-substituted anilines with hydroxylamine derivatives.

A novel avenue of C-O bond construction was facilely achieved via Selectfluor-induced oxygenation of C(sp2)-H bonds of N-substituted anilines by reacting with N-hydroxyphthalimide or N-hydroxymaleimide without any metal catalyst. A variety of N-aryloxyimide derivatives were prepared from N-acyl or sulfonyl anilines in moderate to excellent yields with good functional-group tolerance under mild conditions, which are of great interest in the field of phenol or benzofuran derivative synthesis. Besides, the method is effective on the gram scale, which highlights the practicality of this transformation.

Metal-free oxidative coupling of quinoxalin-2(1H)-ones with arylaldehydes leading to 3-acylated quinoxalin-2(1H)-ones

A facile TBHP-mediated direct oxidative coupling of quinoxalin-2(1H)-ones with arylaldehydes has been developed under metal-free conditions. This method provided a convenient and efficient approach to various 3-acylated quinoxalin-2(1H)-ones from readily available starting materials with excellent regioselectivity. This reaction proceeded efficiently under mild conditions over a broad range of substrates and with functional group tolerance.

Oxidative cross-coupling reaction of catechols with active methylene compounds in an aqueous medium using an AlPO4-supported Ru catalyst

A green oxidative coupling reaction of catechols with active methylene compounds was achieved using an AlPO4-supported Ru catalyst, where O2 and H2O were used as the ideal oxidant and solvent, respectively.

Selective aerobic oxidation of halides and amines with an inorganic-ligand supported zinc catalyst.

A practical, efficient and environmentally benign catalytic protocol for the oxidative cross-coupling reaction of halides with amines, oxidative self-coupling of amines and oxidation of halides was developed with inorganic-ligand supported ZnPOM (NH4)4[ZnMo6O18(OH)6] using molecular oxygen. This method mainly utilizes an inorganic polymolybdate ligand to support the Zn2+ ion, avoiding the use of complicated organic ligands.