Copper‐Catalyzed Domino SN2′/Coupling Reaction: A Versatile and Facile Synthesis of Cyclic Compounds from Baylis–Hillman Acetates

A variety of substituted quinoline/pyridine, thiochromene and naphthalene derivatives, which might be of biological and medicinal value, were synthesized by copper‐catalyzed domino S_N2′/coupling, S_N2′/deacylation/coupling and S_N2′/coupling/elimination reactions. The method provides a general and convenient approach to the synthesis of various substituted cyclic compounds from the corresponding Baylis–Hillman (B‐H) acetates and N‐/S‐/C‐nucleophiles.     

Copper‐Catalyzed Decarboxylation of Aromatic Carboxylic Acids: En Route to Milder Reaction Conditions

The copper‐catalyzed decarboxylation of carboxylic aromatic acids has been advantageously achieved by using aliphatic amines like tetramethylethylenediamine (TMEDA) or hexamethylenetetraamine (HMTA) as ligands instead of the aromatic heterocyclic amines (quinoline, phenanthroline) used until now. The improvement is significant since the reaction can be performed at a lower temperature (ca. 50 °C less) and the reaction time is clearly shorter (15 min instead of 12 to 24 h).     

Copper‐Catalyzed Trifluoromethylation of Acrylamides Coupled with Indole Dearomatization: Access to Trifluoromethyl‐Substituted Spiro[indole‐3,3′‐pyrrolidine] Derivatives

A copper‐catalyzed cascade reaction involving trifluoromethylation of acrylamides coupled with ring closure and indole dearomatization is reported. This facile transformation was highly regioselective and proceeded under mild conditions, allowing efficient access to trifluoromethyl‐substituted spiro[indole‐3,3′‐pyrrolidine] derivatives, which are of increasing interest to the pharmaceutical industry.

     

Copper‐Catalyzed Divergent Trifluoromethylation/Cyclization of Unactivated Alkenes

Most of the precedent copper‐catalyzed trifluoromethylation reactions of unactivated alkenes concern terminal alkenes, and these processes are terminated in elimination, or nucleophilic addition, or semipinacol rearrangement, or C H bond functionalization steps. In this study, we develop a trifluoromethylation method for both unactivated terminal and internal alkenes to enable divergent late‐stage radical cyclization and achieve high molecular complexity. These cyclizations are well consistent with Baldwin’s rule. Furthermore, a kinetic isotope effect (KIE) study and control reactions were conducted, and a plausible mechanism is proposed.

     

Highly Selective Copper‐Catalyzed Monoarylation of Aniline

A series of mono‐, bi‐ and tridendate ligands was investigated in the copper‐catalyzed monoarylation of aniline with p‐chloronitrobenzene. Excellent selectivities at high conversions were observed when bridged bisimidazolidenes as well as biphenyl‐bisalkylphosphines were employed. The X‐ray crystal structure of bis(tert‐butyl)biphenylphosphine‐copper complex indicates a significant binding of the metal center to the aryl moiety and, thus, an almost bidendate coordination mode. Chelating bisphosphines, glycol, phenanthroline or other mono‐ to tridendate ligands led to less selective or productive catalysts.     

Ligandless Copper‐Catalyzed Coupling of Heteroaryl Bromides with Gaseous Ammonia

A range of different N‐ and S‐containing heterocyclic bromides can be efficiently coupled with gaseous ammonia in the presence of copper(II) acetylacetonate [Cu(acac)₂] as catalyst and in the absence of additional ligands. Unstable aminothiophenes and aminobenzothiophenes can be further reacted in situ to afford functionalized derivatives.     

Efficient Copper‐Catalyzed Synthesis of N‐Alkylanthranilic Acids via an ortho‐Substituent Effect of the Carboxyl Group of 2‐Halobenzoic Acids at Room Temperature

We have developed an efficient copper‐catalyzed method for the synthesis of N‐alkylanthranilic acids. The protocol uses inexpensive copper(I) iodide/racemic 1,1′‐binaphthyl‐2,2′‐diol (rac‐BINOL) as the catalyst/ligand system, readily available 2‐halobenzoic acids and aliphatic amines as the starting materials, the coupling reactions were performed at room temperature, and various functionalities in the substrates were tolerated.     

Copper‐Catalyzed Trifluoromethylation and Bicyclizations of 1,7‐Enynes Leading to Fused Polycycles

A series of trifluoromethyl‐containing heterocycles, like indene and dihydroquinolinone or dihydrocoumarin‐fused tetracyclic compounds have been prepared using copper‐catalyzed cascade reaction of benzene‐tethered 1,7‐enynes. A study of the mechanism indicated that radical trifluoromethylation and sequential 6‐exo‐dig/5‐endo‐trig bicyclization processes were involved in this protocol. Moreover, some selected products showed certain fungicidal activities against 14 kinds of plant fungi which means that these functionalized tetracyclic compounds might be used in the agrochemical field.

     

Efficient Synthesis of 2‐Fluoromethylated Quinolines via Copper‐Catalyzed Alkynylation and Cyclization of Fluorinated Imidoyl Iodides

2‐Fluoromethylated quinolines were synthesized through the reaction of N‐aryl‐fluorinated imidoyl iodides with terminal alkynes in good yields by the catalysis of copper(I) iodide (CuI) alone.     

Metal‐Free Trifluoromethylation and Arylation of Alkenes: Domino Synthesis of Oxindole Derivatives

A novel, simple and highly efficient method for the synthesis of 3‐(trifluoromethyl)‐indolin‐2‐one derivatives has been developed. The protocol uses readily available N‐alkyl‐N‐phenylacrylamides as the starting materials, inexpensive and easily stored Langlois reagent (sodium trifluoromethanesulfinate) as the trifluoromethyl source, and iodobenzene diacetate [PhI(OAc)₂] as the oxidant. The procedure involves a metal‐free domino trifluoromethylation and arylation of alkenes. The methods did not need mediation of any transition metal which avoided contaminations of toxic metals in the products.

     

Practical Methods for the Synthesis of Trifluoromethylated Alkynes: Oxidative Trifluoromethylation of Copper Acetylides and Alkynes

Two practical and complementary methods are reported for the synthesis of trifluoromethylated alkynes. The first one, a mix‐and‐stir process, is based on the oxidative trifluoromethylation of readily available and bench‐stable copper acetylides while the second one, which displays a broad substrate scope and has several advantages over existing procedures, is based on the oxidative copper‐catalyzed direct trifluoromethylation of terminal alkynes. Both reactions provide user‐friendly processes for the synthesis of trifluoromethylated acetylenes which can be easily obtained from readily available starting materials.

     

A Simple Copper‐Catalyzed Cascade Synthesis of 2‐Amino‐1H‐indole‐3‐carboxylate Derivatives

We have developed a simple and efficient copper‐catalyzed method for the synthesis of 2‐amino‐1H‐indole‐3‐carboxylate derivatives via cascade reactions of substituted N‐(2‐halophenyl)‐2,2,2‐trifluoroacetamide with alkyl 2‐cyanoacetate or malononitrile under mild conditions, and the method is of wide practical application.     

Trifluoromethylation of 1‐Aryl‐3,3‐diisopropyltriazenes

A new method for the trifluoromethylation of functionalized aromatic diisopropyltriazenes is described. In a facile two‐step, one‐pot synthesis, various functionalized trifluoromethyl‐substituted arenes are accessible in mostly good yields by using methyl iodide as iodination agent and the trifluoromethylation system (trifluoromethyl)trimethylsilane/potassium fluoride/copper iodide. This concept could be expanded to perfluoroethylation as well as ethoxycarbonyldifluoromethylation reactions.     

Simple N‐Heterocyclic Carbenes as Ligands in Ullmann‐Type Ether and Thioether Formations

A simple N‐heterocyclic carbene (NHC) derived from 1‐methyl‐3‐ethylimidazolium tetrafluoroborate was found to be an efficient ligand for a range of copper‐catalyzed cross‐coupling reactions, leading to the formation of aromatic ethers and thioethers.

     

Copper‐Catalyzed Coupling of (E)‐Bromostilbene with Phenols/Azole: ESI‐MS Detection of Intermediates by Using an Ionically‐Tagged Ligand

A system based on copper/1,10‐phenanthroline efficiently promotes the coupling between phenols or pyrazole with (E)‐bromostilbene. (E)‐1‐Aryloxy‐1,2‐diphenylethenes were obtained from the coupling with phenols in good to excellent yields (69–90%). The exception was the reaction involving a phenol containing an electron‐withdrawing cyano group that required a longer reaction time and gave only 49% yield. Kinetic studies indicated the participation of the vinyl halide in the rate‐determining step. Under the conditions employed, the activation of the vinyl halide via a radical pathway was discarded using a radical scavenger test. By using an ionically‐tagged 1,10‐phenanthroline derivative as the ligand, various copper‐based ions were detected through ESI(+)‐MS. These ions suggested that formation of the active species [phenCuOAr(HOAr)₂] precedes the vinyl halide activation.     

Synthesis of 2‐Aminobenzothiazoles via Copper(I)‐Catalyzed Cross‐Coupling with Part‐Per‐Million Catalyst Loadings

An efficient protocol has been developed for the preparation of 2‐aminobenzothiazoles via a copper(I)‐catalyzed tandem reaction of 2‐iodoanilines with isothiocyanates at very low catalyst loadings [typically 50 ppm of copper(I) iodide (CuI)]. A variety of 2‐iodoanilines could be cross‐coupled with isothiocyanates, affording 2‐aminobenzothiazoles in moderate to good yields (49–93%) under the given conditions. The turnover number (TON) of this reaction reaches 67,000 and the reaction could be scaled up, at least, to the gram‐scale.     

Synthesis of Chiral Amino Acid Anilides by Ligand‐Free Copper‐Catalyzed Selective N‐Arylation of Amino Acid Amides

An atom‐economic, practical and cost‐effective protocol for synthesis of chiral amino acid anilides via ligand‐free copper‐catalyzed selective C N cross coupling of chiral amino acid amides and aryl halides, hetereoaryl halides and a vinyl bromide has been developed. No racemization occurred during the C N coupling. A plausible mechanism is proposed.     

Efficient and General Synthesis of 3‐Aminoindolines and 3‐Aminoindoles via Copper‐Catalyzed Three‐Component Coupling Reaction

An efficient three‐component coupling (TCC) reaction toward a variety of 3‐aminoindoline and 3‐aminoindole derivatives has been developed. This cascade transformation proceeds via the copper‐catalyzed coupling reaction between 2‐aminobenzaldehyde, a secondary amine, and an alkyne leading to a propargylamine intermediate which, under the reaction conditions, undergoes cyclization into the indoline core. The latter, upon treatment with a base, smoothly isomerizes into the indole. Alternatively, the indole can directly be synthesized in a one‐pot sequential reaction.     

Palladium‐ and Copper‐Catalyzed Site Selective Monoamination of Dibromobenzoic Acid

The carboxylate anion has been used as a directing group in the aromatic amination of electronically equivalent aryl bromides to afford selective ortho‐substituted derivatives (>99:1 selectivity; 60–80% yield) in the case of copper(I) catalysis. The solvent, base and equivalents of base were important factors in the success of this reaction. Complementary selectivity was achieved with palladium catalysis where the para‐substituted derivatives were produced selectively (>99% selectivity, 70–80% yield).