Iron‐Catalyzed Direct Oxidative Alkylation and Hydroxylation of Indolin‐2‐ones with Alkyl‐Substituted N‐Heteroarenes

Presented herein is the first direct alkylation and hydroxylation reaction between two different C(sp³)?H bonds, indolin‐2‐ones and alkyl‐substituted N‐heteroarenes, through an oxidative cross‐coupling reaction. The reaction is catalyzed by a simple iron salt under mild ligand‐free and base‐free conditions. The reaction is environmentally benign, employs air (molecular oxygen) as the terminal oxidant and oxygen source for the synthesis of O‐containing compounds, and produces only water as the byproduct.     

Iron(III) Chloride Catalyzed Oxidative Coupling Reaction of 1,2‐Diarylethylene Derivatives

A nontoxic FeCl₃ catalyzed intramolecular oxidative coupling reaction was developed for mild synthesis of a series of phenanthrenes with different substituents. The method involves cross dehydrogenative coupling of a variety of 1,2‐diarylethylene derivatives with di‐tert‐butylperoxide (DTBP) as a sole oxidant at room temperature in CH₂Cl₂/TFA (9:1 V/V) to yield phenanthrenes in good to excellent yields.     

Cobalt‐Catalyzed Oxidative C−H/C−H Cross‐Coupling between Two Heteroarenes

The first example of cobalt‐catalyzed oxidative C?H/C?H cross‐coupling between two heteroarenes is reported, which exhibits a broad substrate scope and a high tolerance level for sensitive functional groups. When the amount of Co(OAc)₂?4 H₂O is reduced from 6.0 to 0.5 mol %, an excellent yield is still obtained at an elevated temperature with a prolonged reaction time. The method can be extended to the reaction between an arene and a heteroarene. It is worth noting that the Ag₂CO₃ oxidant is renewable. Preliminary mechanistic studies by radical trapping experiments, hydrogen/deuterium exchange experiments, kinetic isotope effect, electron paramagnetic resonance (EPR), and high resolution mass spectrometry (HRMS) suggest that a single electron transfer (SET) pathway is operative, which is distinctly different from the dual C?H bond activation pathway that the well‐described oxidative C?H/C?H cross‐coupling reactions between two heteroarenes typically undergo.     

Copper‐Complex‐Catalyzed Asymmetric Aerobic Oxidative Cross‐Coupling of 2‐Naphthols: Enantioselective Synthesis of 3,3′‐Substituted C1‐Symmetric BINOLs

A novel chiral 1,5‐N,N‐bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross‐coupling of 2‐naphthols. Air serves as an external oxidant and generates a series of C₁‐symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3‐ and 3′‐substituents. A preliminary investigation using one of the obtained C₁‐symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α‐alkylation of amino esters.     

Cs2CO3‐Catalyzed Aerobic Oxidative Cross‐Dehydrogenative Coupling of Thiols with Phosphonates and Arenes

An efficient Cs₂CO₃‐catalyzed oxidative coupling of thiols with phosphonates and arenes that uses molecular oxygen as the oxidant is described. These reactions provide not only a novel alkali metal salt catalyzed aerobic oxidation, but also an efficient approach to thiophosphates and sulfenylarenes, which are ubiquitously found in pharmaceuticals and pesticides. The reaction proceeds under simple and mild reaction conditions, tolerates a wide range of functional groups, and is applicable to the late‐stage synthesis and modification of bioactive molecules.     

Copper‐Catalyzed C(sp3)−H/C(sp3)−H Cross‐Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2‐Trifluoromethyl‐Substituted Dihydropyrrol‐2‐ols

The first oxidative C(sp³)−H/C(sp³)−H cross‐dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper‐catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2‐trifluoromethyldihydropyrrol‐2‐ol derivatives in a highly diastereoselective manner by cascade C(sp³)−C(sp³) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.     

Lanthanides Mediated Oxidative Cross Coupling of Benzylalcohol and Various Amines to Form Corresponding Imines

Herein, a new and efficient approach towards the oxidative cross‐coupling of benzylalcohol and various aromatic amines to form corresponding imines with high degree conversion (>80 %) and chemo‐selectivity using lanthanide salts as pre‐catalysts is presented. The catalyzed oxidative cross‐coupling reaction using La(NO₃)₃ · 6H₂O as pre‐catalyst displayed a broad substrate scope. The reaction afforded various substituted imines from the reaction of benzylalcohol with ample variety of amines in good yields.     

Oxidant‐Controlled Catalytic Transformations of Phenols with Unexpected Cleavage of Aromatic Rings

Oxidative transformations of phenols have attracted significant attention of chemists due to their importance in biological process and organic synthesis. In contrast to the relatively well‐developed oxygenation and coupling reactions of phenols, the highly efficient and selective oxidative ring cleavage of phenols is under‐represented. This work describes a novel CuCl‐catalyzed tandem homocoupling/skeletal rearrangement of phenols that realizes the cleavage of the phenol ring by using air or Ag₂CO₃ as the oxidant. Interestingly, simply changing the oxidant to K₂S₂O₈ results in the oxidative coupling/cyclization of phenols to give dibenzofurans. These results set an important precedent of oxidant‐controlled catalytic transformations of phenols.     

Transition‐Metal‐Free BF3‐Mediated Oxidative and Non‐Oxidative Cross‐Coupling of Pyridines

We report a BF₃‐mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross‐coupling). Moreover, we have developed a novel transition‐metal‐free cross‐coupling method between alkylmagnesium reagents and 4‐substituted pyridines, such as isonicotinonitrile and 4‐chloropyridine, by employing BF₃?OEt₂ as a promoter. The combination of these methods enabled us to efficiently prepare a range of di‐, tri‐, and tetrasubstituted pyridines.     

Ruthenium‐Catalyzed Cross‐Dehydrogenative ortho‐N‐Carbazolation of Diarylamines: Versatile Access to Unsymmetrical Diamines

The dehydrogenative C–N cross‐coupling of unprotected, secondary anilines through ortho‐N‐carbazolation has been achieved using a Ru catalytic system with O₂ as the terminal oxidant. The reactions proceed in an intermolecular fashion, selectively in the ortho position. Implications for the field of organic synthesis are discussed.     

Highly selective oxidative cross‐coupling polymerization with copper(I)‐bisoxazoline catalysts

The asymmetric oxidative coupling polymerization of methyl 6,6′‐dihydroxy‐2,2′‐binaphthalene‐7‐carboxylate with the copper‐diamine catalysts under an O₂ atmosphere was carried out. As is the case with the CuCl‐2,2′‐(S)‐isopropylidenbis(4‐phenyl‐2‐oxazoline) [(S)IPhO] catalyst, a polymer with a high cross‐coupling selectivity of 96% was obtained in 71% yield, whose THF‐soluble part had a number‐average molecular weight of 4.5 × 10³. To estimate the enantioselectivity with respect to the cross‐coupling linkage in the obtained polymer, the model asymmetric oxidative cross‐coupling reaction with CuCl‐(S)IPhO was also conducted, and the products showed a 94% cross‐coupling selectivity and enantioselectivity of 31% ee (S). © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 6287–6294, 2005     

Cobalt(III)‐Catalyzed Intramolecular Cross‐Dehydrogenative C−H/X−H Coupling: Efficient Synthesis of Indoles and Benzofurans

An efficient cobalt(III)‐catalyzed intramolecular cross‐dehydrogenative C?H/N?H coupling of ortho‐alkenylanilines has been developed utilizing O₂ as a terminal oxidant. The developed reaction tolerates various reactive functional groups and allows the synthesis of diverse indole derivatives in good to excellent yields. The method was successfully extended to the synthesis of benzofurans through the intramolecular cross‐dehydrogenative C?H/O?H coupling of ortho‐alkenylphenols.     

Oxidative Cyclization Reaction of 2‐Aryl‐Substituted Cinnamates To Form Phenanthrene Carboxylates by Using MoCl5

The oxidative cyclization reaction of 2‐aryl cinnamates and derivatives thereof can be easily performed with MoCl₅ as the oxidant. This powerful reagent allows oxidative coupling reactions for which other reagents fail. The best results are obtained when the 2‐phenyl substituent of the cinnamate is equipped with two methoxy groups. Even iodo moieties in the bay region of phenanthrene are tolerated under the reaction conditions. If naphthalene moieties are involved, a rearrangement of the skeleton occurs, providing an elegant route to highly functionalized angular arenes. The cyclization is demonstrated for 15 example substrates with isolated yields of up to 99 % for the phenanthrene derivative. The broad scope of the reaction underlines the usefulness of MoCl₅ and MoCl₅/TiCl₄ in the oxidative coupling reaction.     

Organo‐Iodine(III)‐Catalyzed Oxidative Phenol–Arene and Phenol–Phenol Cross‐Coupling Reaction

The direct oxidative coupling reaction has been an attractive tool for environmentally benign chemistry. Reported herein is that the hypervalent iodine catalyzed oxidative metal‐free cross‐coupling reaction of phenols can be achieved using Oxone as a terminal oxidant in 1,1,1,3,3,3‐hexafluoropropan‐2‐ol (HFIP). This method features a high efficiency and regioselectivity, as well as functional‐group tolerance under very mild reaction conditions without using metal catalysts.     

Palladium‐Catalyzed Oxidative Cross‐Coupling of α‐Cyanoketene Dithioacetals with Olefins

Efficient palladium‐catalyzed cross‐coupling reactions of the internal olefins α‐cyanoketene dithioacetals with a variety of olefins were achieved in dioxane/HOAc/DMSO (9:3:1 v/v/v) under air atmosphere or by means of AgOAc as the terminal oxidant. Electron‐deficient terminal olefins reacted to form the linear diene derivatives with air as the oxidant. Styrenes underwent the cross‐coupling to give both the linear and branched dienes when using AgOAc as the oxidant. Unactivated cyclic and linear internal olefin substrates both reacted in the presence of a catalytic amount of benzoquinone in air to produce skipped dienes. The typical products were structurally confirmed by X‐ray crystallography.     

Cooperative Reductive Elimination: The Missing Piece in the Oxidative‐Coupling Mechanistic Puzzle

The reaction between benzoic acid and methylphenylacetylene to form an isocoumarin is catalyzed by Cp*Rh(OAc)₂ in the presence of Cu(OAc)₂(H₂O) as an oxidant and a leading example of oxidative‐coupling reactions. Its mechanism was elucidated by DFT calculations with the B97D functional. The conventional mechanism, with separate reductive‐elimination and reoxidation steps, was found to yield a naphthalene derivative as the major product by CO₂ extrusion, contradicting experimental observations. The experimental result was reproduced by an alternative mechanism with a lower barrier: In this case, the copper acetate oxidant plays a key role in the reductive‐elimination step, which takes place through a transition state containing both rhodium and copper centers. This cooperative reductive‐elimination step would not be accessible with a generic oxidant, which, again, is in agreement with available experimental data.     

Nickel Catalysis Enables Oxidative C(sp2)–H/C(sp2)–H Cross‐Coupling Reactions between Two Heteroarenes

Nickel can be used to promote oxidative C(sp²)?H/C(sp²)?H cross‐coupling between two heteroarenes. The reaction scope can be extended to aromatic carboxamides as the coupling partner. The reaction exhibits high functional‐group compatibility and broad substrate scope. The silver oxidant can be recycled to reduce costs and waste, which is very useful for practical applications.     

Synthesis of Functionalized o‐, m‐, and p‐Terphenyl Derivatives by Consecutive Cross‐Coupling Reactions of Triazene‐Substituted Arylboronic Esters

Triazene‐substituted arylboronic esters were prepared readily from the corresponding aryl magnesium derivatives and shown to function as a new class of donor–acceptor‐substituted coupling reagents. The selective functionalization of these aromatic derivatives led to a wide variety of terphenyl derivatives in which the original bifunctional unit (often further substituted with another functional group) formed the central aromatic ring. The functionalized terphenyl derivatives were formed in two efficient cross‐coupling steps from the triazene‐substituted boronic esters: Suzuki cross‐coupling with an aryl halide was followed by BF₃?OEt₂‐induced palladium‐catalyzed coupling of the diazonium salt generated in situ from the triazene with an arylboronic acid.     

Kinetic Studies on the Palladium(II)‐Catalyzed Oxidative Cross‐Coupling of Thiophenes with Arylboron Compounds and Their Mechanistic Implications

Reaction orders for the key components in the palladium(II)‐catalyzed oxidative cross‐coupling between phenylboronic acid and ethyl thiophen‐3‐yl acetate were obtained by the method of initial rates. It turned out that the reaction rate not only depended on the concentration of palladium trifluoroacetate (reaction order: 0.97) and phenylboronic acid (reaction order: 1.26), but also on the concentration of the thiophene (reaction order: 0.55) and silver oxide (reaction order: ?1.27). NMR spectroscopy titration studies established the existence of 1:1 complexes between the silver salt and both phenylboronic acid and ethyl thiophen‐3‐yl acetate. A low inverse kinetic isotope effect (k_H/k_D=0.93) was determined upon employing the 4‐deuterated isotopomer of ethyl thiophen‐3‐yl acetate and monitoring its reaction to the 4‐phenyl‐substituted product. A Hammett analysis performed with para‐substituted 2‐phenylthiophenes gave a negative ρ value for oxidative cross‐coupling with phenylboronic acid. Based on the kinetic data and additional evidence, a mechanism is suggested that invokes transfer of the phenyl group from phenylboronic acid to a 1:1 complex of palladium trifluoroacetate and thiophene as the rate‐determining step. Proposals for the structure of relevant intermediates are made and discussed.     

Copper‐Catalyzed Dehydrogenative Cross‐Coupling Reaction between Allylic CH Bonds and α‐CH Bonds of Ketones or Aldehydes

A dehydrogenative cross‐coupling reaction between allylic C?H bonds and the α‐C?H bond of ketones or aldehydes was developed using Cu(OTf)₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ‐unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)₂ as a Lewis acid catalyst was also proposed (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Tf=trifluoromethanesulfonate).