Copper‐Catalyzed Three‐Component Coupling of Terminal Alkyne,Dihalomethane and Amine to Propargylic Amines

The direct C H and C halogen activation for C C bond formation is one of the most interesting reactions in organic chemistry. C C bond formation using alkynes as a carbon nucleophilic source is a very useful method in synthesis. Herein, a copper(I) chloride catalyzed three‐component coupling reaction of alkynes, dihalomethanes and amines through C H and C halogen activation to form propargylic amines under mild conditions has been established. The reaction can be conducted in water, in neat or in common organic solvents and it was applicable to both aromatic and aliphatic alkynes with good functional groups tolerance. It represents an excellent example of multi‐component reactions (MCRs), provides an elegant method for the synthesis of propargylic amines which are frequent skeletal components and synthetically versatile key intermediates for the preparation of many nitrogen‐containing biologically active compounds. From the mechanism point of view, this chemistry offers not only a new approach to propargylic amines with new C C and C N bonds formation through C H and C halogen activation, but also provides valuable mechanistic insight into the novel multi‐component reactions.     

Copper‐Catalyzed Cascade Reactions of Substituted 4‐Iodopyrazolecarbaldehydes with 1,2‐Phenylenediamines and 2‐Aminophenols

A new approach for the synthesis of novel annulated‐pyrazoles is presented. This protocol includes an intermolecular condensation followed by a copper‐mediated intramolecular C N or C O coupling reaction. The method is applied to a range of substituted 4‐iodopyrazolecarbaldehydes which react with 1,2‐phenylenediamines or 2‐aminophenols to yield substituted 2,4‐ or 1,4‐dihydrobenzo[b]pyrazolo[4,3‐e][1,4]diazepines or substituted‐2H‐ or 1H‐benzo[b]pyrazolo[3,4‐f][1,4]oxazepines, respectively.     

Palladium‐Catalyzed Direct Arylations of 1,2,3‐Triazoles with Aryl Chlorides using Conventional Heating

Generally applicable, palladium‐catalyzed direct arylations of 1,2,3‐triazoles with aryl chlorides were accomplished through conventional heating at reaction temperatures of 105–120 °C. Thereby, intra‐ and intermolecular C H bond functionalizations were achieved with a variety of differently substituted chlorides as electrophiles, bearing numerous valuable functional groups.     

Iridium‐Catalyzed Selective Synthesis of 4‐Substituted Benzofurans and Indoles via Directed Cyclodehydration

A directed cyclization‐dehydration cascade of α‐aryloxy ketones and α‐arylamino ketones was efficiently catalyzed by a cationic iridium‐BINAP complex, which afforded various types of 4‐substituted benzofurans and indoles in high yields with complete regioselectivity. The newly developed protocol also enabled the enantioselective preparation of chiral 4‐acetyloxindole using a chiral iridium catalyst.     

Mechanistic Studies on the Palladium‐Catalyzed Direct C‐5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium

An in‐depth mechanistic study on the palladium‐catalyzed direct arylation of imidazoles at the C‐5 position is presented. The interactions of triphenylphosphine (PPh₃)‐ligated aryl‐Pd species with 1,2‐dimethyl‐1H‐imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine‐ligated organo‐Pd species are not active and the reaction proceeds through imidazole‐ligated organo‐Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim‐ligated Pd(0) species have been characterized in a Pd(dba)₂/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)₂X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)₃]⁺ is also reported. The ability of these species to effect the C H arylation of dmim at room temperature in the presence of acetate is also demonstrated.

     

Ruthenium‐Catalyzed Oxidative Homo‐Coupling of 2‐Arylpyridines

A ruthenium‐catalyzed oxidative homo‐coupling reaction of 2‐arylpyridines via C H activation was developed. The reaction could tolerate various functional groups on both the aryl and the pyridyl rings to afford a series of dimerized products with iron(III) chloride (FeCl₃) as a stoichiometric oxidant. A tentative mechanism was proposed for this oxidative C H/C H homo‐coupling.     

Copper‐Mediated ortho‐Arylation of Benzamides with Arylboronic Acid

The copper‐mediated direct ortho C H bond arylation of benzamide derivatives with arylboronic acids was achieved by employing an 8‐aminoquinoline moiety as the bidentate directing group. Various biaryls were synthesized in good yields with excellent regioselectivity. The reaction shows good functional group compatibility and proceeds in a highly selective manner at the ortho‐position of the benzamides. Deuterium‐labelling experiments indicated that the ortho C H bond cleavage of benzamide was involved in the rate‐determining step of the arylation.

     

Palladium‐Catalyzed and Hybrid Acids‐Assisted Synthesis of [60]Fulleroazepines in One Pot under Mild Conditions: Annulation of N‐Sulfonyl‐2‐aminobiaryls with [60]Fullerene through Sequential C‐H Bond Activation,C‐C and C‐N Bond Formation

An extraordinarily efficient hybrid acids‐assisted, palladium‐catalyzed and chelating‐group‐assisted C H bond activation of N‐sulfonyl‐2‐aminobiaryls and their annulations with [60]fullerene via sequential C C and C N bond formation at room temperature to afford [60]fulleroazepines is demonstrated. The formation of [60]fulleroazepines is highly regioselective and tolerant to both electron‐withdrawing and electron‐donating groups on the aryl moiety and the reaction gives monofunctionalized fullerenes in good yields (up to 54% isolated yield and 92% based on converted C₆₀).     

Sulfonic Acid‐Catalyzed Autoxidative Carbon‐Carbon Coupling Reaction under Elevated Partial Pressure of Oxygen

An aerobic organocatalytic oxidative C C bond formation reaction of benzylic C H bonds with various C‐nucleophiles is described. The coupling reaction proceeds by simply stirring the substrates under elevated partial pressure of oxygen in the presence of a sulfonic acid catalyst at room temperature. Elevation of the pressure enables the reaction of a broad scope of nucleophile substrates otherwise showing poor reactivity at ambient pressure. The benzylic C H bonds of xanthene, acridanes, isochromane and related heterocycles could be functionalized with nucleophiles including ketones, 1,3‐dicarbonyl compounds and aldehydes. Electron‐rich arenes could be utilized as nucleophiles at elevated temperatures. The reactions are believed to proceed via autoxidation of the benzylic C H bonds to the hydroperoxides and subsequent nucleophilic substitution catalyzed by sulfonic acids.     

Nickel‐Catalyzed Coupling of Fluoroarenes and Amines

The combination of bis(cyclooctadiene)nickel [Ni(COD)₂] and 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene hydrochloride (IPr⋅HCl) effectively catalyzes coupling of fluoroarenes with amines in the presence of sodium tert‐butoxide (t‐BuONa). Activated, unactivated and deactivated fluoroarenes as well as fluoropyridines can react with cyclic or acyclic aliphatic amines. The reactions tolerate various functional groups in the fluorides including PhC(O), C(O)NEt₂, CF₃, OMe and vinyl groups.

     

Palladium‐Catalyzed Intermolecular C‐2 Alkenylation of Indoles Using Oxygen as the Oxidant

A general and efficient palladium‐catalyzed intermolecular direct C‐2 alkenylation of indoles using oxygen as the oxidant has been developed. The reaction is of complete regio‐ and stereoselectivity. All products are E‐isomers at the C‐2‐position with no Z‐isomers and 3‐substituted products were detected.

     

One‐Pot Palladium‐Catalyzed Synthesis of Selectively Substituted Phenanthridines by Sequential Aryl‐Aryl and Heck Couplings,Aza‐Michael and Retro‐Mannich Reactions

A catalytic synthesis of selectively substituted phenanthridines is achieved through a reaction sequence involving palladium/norbornene‐catalyzed unsymmetrical aryl‐aryl and Heck couplings followed by aza‐Michael and retro‐Mannich reactions. In spite of the many steps involved the method is very simple and allows the formation of selectively substituted phenanthridines under mild conditions in a straightforward one‐pot reaction starting from readily available aryl iodides and bromides.     

Nickel‐Catalyzed Suzuki–Miyaura Coupling of a Tertiary Iodocyclopropane with Wide Boronic Acid Substrate Scope: Coupling Reaction Outcome Depends on Radical Species Stability

We describe a nickel‐catalyzed Suzuki–Miyaura arylation of a tertiary iodocyclopropane with arylboronic acids; this is an efficient and convergent strategy for providing various enantioenriched arylcyclopropanes with a quaternary stereogenic center. This is the first metal‐catalyzed coupling between a tertiary alkyl electrophile and a wide range of aromatics, including heteroaromatics. We found that the outcome of the Ni‐catalyzed coupling with halides as electrophiles was dependent on the stability of the radical species formed during the reaction. The use of tert‐butyl alcohol (t‐BuOH) as the reaction solvent was very effective, because of its stability under the radical‐generating reaction conditions.

     

Copper‐Catalyzed Cyanation of Aryl Iodides with Malononitrile: An Unusual Cyano Group Transfer Process from C(sp3) to C(sp2)

An unusual copper‐catalyzed cyanation of aryl iodides to form aryl nitriles by cyano group transfer from C(sp³) to C(sp²) carbon atoms is reported and proceeds to give yields of up to 86%.     

Convenient and Reliable Routes Towards 2‐Aminothiazoles: Palladium‐Catalyzed versus Copper‐Catalyzed Aminations of Halothiazoles

Two efficient methods for the amination of 2‐halothiazoles are presented here. A first protocol requires a Pd/L system. Several 2‐aminothiazoles were synthesized under optimized conditions and isolated in good yields. The first palladium‐catalyzed C N coupling reactions between 2‐halothiazoles and primary alkylamines are presented. In a second part, ligand‐free copper‐catalyzed aminations of 2‐halothiazoles by alkylamines and aniline in a green solvent have been developed. The protocol is very effective for primary and secondary amines and perfectly tolerates the presence of another halide moiety on the 2‐halothiazole. The reaction occurs under the assistance of microwave irradiation, which drastically decreases the reaction time. The reaction leads to the formation of 2‐aminothiazoles, key molecules in pharmaceutical research.

     

Copper(I)‐Catalyzed Dehydrogenative Amidation of Arenes Using Air as the Oxidant

The copper(I) bromide‐catalyzed intermolecular dehydrogenative amidation of arenes via C H bond activation assisted by a 2‐pyridyl or 1‐pyrazolyl chelating group using air as the terminal oxidant has been achieved at 140 °C. N‐Aryl amides, N‐alkyl amides, benzamide derivatives, imides, and lactams all are good coupling partners to obtain moderate to excellent yields. The amount of solvent is critical for the transformation: both increasing and decreasing the amount of solvent decreased the yield. Notably, the amidation of bimolecular 2‐phenylpyridine with the dual N H bonds of a primary amide proceeded smoothly in one‐pot to afford a good yield under the same conditions. The amidation can be performed with a good yield at the gram scale.

     

Iron‐Catalyzed Nitrogen‐Directed Coupling of Arene and Aryl Bromides Mediated by Metallic Magnesium

2‐Arylpyridines, 2‐alkenylpyridine, and aromatic imines can be coupled with aryl bromides in the presence of an iron catalyst, metallic magnesium, a diamine ligand and an organic dihalide oxidant at 0 °C. The use of a 1:1 mixture of tetrahydrofuran and 1,4‐dioxane is essential for this C H bond activation reaction. The reaction has wider scope of the substrate compared with the reaction using a separately prepared Grignard reagent, and proceeds with lower catalyst loading (2.5 mol%).     

Copper‐Catalyzed N‐Alkylation of Sulfonamides with Benzylic Alcohols: Catalysis and Mechanistic Studies

The N‐alkylation of sulfonamides with alcohols is efficiently performed in the presence of easily available copper catalysts via hydrogen borrowing methodology. Applying a copper acetate/potassium carbonate system the reaction of sulfonamides and alcohols gave the corresponding secondary amines in excellent yield. In situ HR‐MS analysis indicated that bissulfonylated amines are formed under air atmosphere, which act as self‐stabilizing ligands for the catalytic system. UV‐visible measurements suggest the interaction between the copper centre and the bissulfonylated amine. Reactions of benzyl alcohol‐d₇ with p‐toluenesulfonamide, N‐benzyl‐p‐toluenesulfonamide or N‐benzylidenetoluenesulfonamide revealed that the reaction proceeds via a transfer hydrogenation mechanism and the whole process is micro‐reversible. Competitive reactions of benzyl alcohol and benzyl alcohol‐d₇ with p‐toluenesulfonamide revealed a kinetic isotope effect (kH/kD) of 3.287 (0.192) for the dehydrogenation of benzyl alcohol and 0.611 (0.033) for the hydrogenation of the N‐benzylidene‐p‐toluenesulfonamide intermediate, which suggests that dehydrogenation of the alcohol is the rate‐determining step.     

Base‐Mediated Direct Arylation of Pyrrole Derivatives

It appears that transition metal catalysts are not necessary to perform the direct arylation of electron‐rich heterocycles with aryl iodides and bromides. Lithium tert‐butoxide in DMF promotes this reaction for a variety of N‐alkyl‐ and N‐arylpyrroles as well as for benzofuran and some other electron‐rich aromatic compounds and provides the desired products in moderate to high yields. In contrast to all previous reports on the Pd‐catalyzed direct arylation of indolizine, the reaction mediated by lithium tert‐butoxide proceeds selectively at position 5.     

Copper‐Catalyzed Selective Oxidative Acylation of Secondary Anilines with Ethyl Glyoxalate: Domino Synthesis of Indoline‐2,3‐diones

A novel, easy and useful copper‐catalyzed selective acylation of secondary anilines with ethyl glyoxalate has been developed, and the corresponding indoline‐2,3‐dione derivatives were prepared. The procedure comprises the sequential intermolecular copper‐catalyzed selective oxidative ortho‐site aromatic acylation of the NH group in secondary anilines and intramolecular nucleophilic attack of the NH group to the ester. The inexpensive, easy and efficient method should provide a new strategy for synthesis of dicarbonyl compounds.