Metal-free intermolecular oxidative C-N bond formation via tandem C-H and N-H bond functionalization

The development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both a N-H and C-H bond, is described. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. Mechanistic investigations indicate that the reaction proceeds via nucleophilic attack of the phthalimide on an aromatic radical cation, as opposed to the electrophilic aromatic amination that has been reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted aniline derivatives is demonstrated.     

Rhodium-Catalyzed Amination of Aromatic Olefins [1]

Summary.  The oxidative amination of styrene with secondary amines in the presence of cationic rhodium catalysts yields regiospecifically the corresponding anti-Markovnikov enamines. Styrene as the hydrogen acceptor gave concomitantly ethylbenzene. In the presence of 1,5-cyclooctadiene (cod) preferential reduction to cyclooctene takes place. The addition of cod reduces the rate of the reaction, but also the amount of ethylbenzene produced. Here, for the first time the ratio of enamine: ethylbenzene is > 1, which is favourable in case of more expensive styrene derivatives. A screening of various ligands for oxidative amination reveals that hemilabile 2-(ω-phosphino-n-alkyl)-pyridines are superior ligands for this reaction compared to simple alkyl and aryl phosphines. Received May 30, 2000. Accepted July 11, 2000     

Regioselective copper-catalyzed amination of chlorobenzoic acids: synthesis and solid-state structures of N-aryl anthranilic acid derivatives

[reaction, structure: see text] A chemo- and regioselective copper-catalyzed cross-coupling reaction for effective amination of 2-chlorobenzoic acids with aniline derivatives has been developed. The method eliminates the need for acid protection and produces a wide range of N-aryl anthranilic acid derivatives in up to 99% yield. The amination was found to proceed with both electron-rich and electron-deficient aryl chlorides and anilines and also utilizes sterically hindered anilines such as 2,6-dimethylaniline and 2-tert-butylaniline. The conformational isomerism of appropriately substituted N-aryl anthranilic acids has been investigated in the solid state. Crystallographic analysis of seven anthranilic acid derivatives showed formation of two distinct supramolecular architectures exhibiting trans-anti and unprecedented trans-syn dimeric structures.     

Microwave-accelerated methodology for the direct reductive amination of aldehydes

[chemical reaction: see text]. An improved procedure for the direct reductive amination of aldehydes was developed which uses dibutyltin dichloride as catalyst in the presence of phenylsilane as reductant. Rapid reaction is promoted by the use of microwave conditions with anilines, secondary and primary amines being suitable reactants.     

Towards Uniform Iodine Catalysis: Intramolecular C−H Amination of Arenes under Visible Light

A photochemical catalytic amination of arenes is presented. The reaction proceeds under benign iodine catalysis in the presence of visible light as the initiator and provides access to a range of differently substituted arylamines. A total of 29 examples demonstrate the broad applicability of this mild oxidation method. The scope of the reaction could further be expanded to silyl‐tethered derivatives, which undergo intramolecular amination upon formation of seven‐membered heterocycles. Cleavage of the silicon tether provides access to the corresponding 3‐substituted anilines.     

Palladium‐Catalyzed Amination of Aryl Sulfides with Anilines

A combination of a palladium–NHC catalyst and potassium hexamethyldisilazide enables the amination of aryl sulfides with anilines to afford a wide variety of diarylamines. The reaction conditions are versatile enough for the reaction of even bulky ortho‐substituted aryl sulfides. This amination can be applied to the modular synthesis of N‐aryl carbazoles from the corresponding ortho‐bromothioanisoles. As aryl sulfoxides undergo extended Pummerer reactions to afford ortho‐substituted aryl sulfides, the Pummerer products are thus useful substrates for the amination to culminate in efficient syntheses of a 2‐anilinobenzothiophene and an indole as proof‐of‐principle of the utility of the extended Pummerer reaction/amination cascade.     

Skeleton-Reorganizing Coupling Reactions of Cycloheptatriene and Cycloalkenones with Amines

Skeletal reorganization reactions have emerged as an intriguing tool for converting readily available compounds into complicated molecules inaccessible by traditional methods. Herein, we report a unique skeleton-reorganizing coupling reaction of cycloheptatriene and cycloalkenones with amines. In the presence of Rh/acid catalysis, cycloheptatriene can selectively couple with anilines to deliver fused 1,2-dihydroquinoline products. Mechanistic studies indicate that the retro-Mannich type ring-opening and subsequent intramolecular Povarov reaction account for the ring reorganization. Our mechanistic studies also revealed that skeleton-reorganizing amination between anilines and cycloalkenones can be achieved with acid. The synthetic utilization of this skeleton-reorganizing coupling reaction was showcased with a gram-scale reaction, synthetic derivatizations, and the late-stage modification of commercial drugs.     

An efficient silane-promoted nickel-catalyzed amination of aryl and heteroaryl chlorides

A new silane-promoted nickel-catalyzed amination of aryl chlorides with 0.5 mol % of Ni(acac)2, 1 mol % of 3,5,6,8-tetrabromo-1,10-phenanthroline, and polymethylhydrosiloxane was developed. A broad range of aryl and heteroaryl chlorides can be coupled with secondary amines and anilines to give the desired (het)arylamines in good to excellent yields. The reaction is sensitive to the nature and amount of the silane promoter.     

Acid-catalyzed ortho-alkylation of anilines with styrenes: an improved route to chiral anilines with bulky substituents

[reaction: see text] Reaction of para-substituted anilines with styrene derivatives at elevated temperatures, when catalyzed by CF3SO3H, results in highly chemoselective ortho-alkylation of the aniline. When R = H, dialkylation can be achieved by varying the ratio of styrene to aniline. Several different substituted anilines and styrenes were examined, and good yields (42-87%) were obtained, except in the case where electron-withdrawing substituents are present on the styrene.     

Efficient [5 + 1]-strategy for the assembly of 1,8-naphthyridin-4(1H)-ones by domino amination/conjugate addition reactions of 1-(2-chloropyridin-3-yl)prop-2-yn-1-ones with amines

A facile synthetic approach for the synthesis of 1,8-naphthyridine-4(1H)-one derivatives via a catalyst free and Pd-supported tandem amination sequence is developed and described. In a case of aliphatic amines reaction proceeds in a catalyst free mode, however anilines demand Pd-supported reaction conditions.     

Synthesis of 2,3-dihydroindoles, indoles, and anilines by transition metal-free amination of aryl chlorides

Aliphatic and aromatic amines react with 2- and 3-chlorostyrene in the presence of potassium tert-butoxide to give N-substituted 2,3-dihydroindoles in good yields. The combination of this domino-amination protocol with a suitable dehydrogenation reaction gives access to pharmacologically interesting indoles in a one-pot procedure. Overall product yields of N-substituted indoles >50% are obtained by this method starting from commercially available substrates. In addition to the intramolecular base-promoted amination of aromatic C-Cl bonds, metal-free intermolecular aminations of aryl chlorides with primary and secondary amines are described. The use of potassium tert-butoxide as base allows the synthesis of various anilines in good to excellent yields. Due to the formation of aryne intermediates, either N-substituted anilines or meta-substituted anilines are produced with excellent selectivities.     

Iron-promoted tandem reaction of anilines with styrene oxides via C-C cleavage for the synthesis of quinolines

A novel iron-promoted tandem reaction of anilines with styrene oxides via C-C cleavage and C-H activation has been developed. The reaction utilizes an inexpensive FeCl(3) as promoter and is suitable for forming a variety of 3-arylquinolines from the simple and readily available starting materials.     

Direct, metal-free amination of heterocyclic amides/ureas with NH-heterocycles and N-substituted anilines in POCl3

A POCl(3)-mediated, direct amination reaction of heterocyclic amides/ureas with NH-heterocycles or N-substituted anilines is described. Compared to the existing methods, this operationally simple protocol provides unique reactivity and functional group compatibility because of the metal-free, acidic reaction conditions. The yields are generally excellent.     

Catalytic C-H amination with aromatic amines

Aniline joins the club: A β-diketiminato copper(I) catalyst enables C-H amination of anilines employing low catalyst loadings to preclude oxidation to the diazene ArN=NAr. Electron-poor anilines are particularly resistant towards diazene formation and participate in the amination of strong and unactivated C-H bonds. N-alkyl anilines also take part in C-H amination.     

Synthesis of hindered anilines: copper-catalyzed electrophilic amination of aryl boronic esters

No longer a hindrance: copper-catalyzed electrophilic amination of aryl boronic esters is accomplished under mild reaction conditions using 2.5-5.0 mol % of a catalyst derived from copper tert-butoxide and Xantphos ligand. The reaction tolerates a wide range of functional groups and can be used to prepare some of the most hindered anilines made to date.     

Palladium-catalyzed amination of aryl nonaflates

The first detailed study of the palladium-catalyzed amination of aryl nonaflates is reported. Use of ligands 2-4 and 6 allows for the catalytic amination of electron-rich and -neutral aryl nonaflates with both primary and secondary amines. With use of Xantphos 5, the catalytic amination of a variety of functionalized aryl nonaflates resulted in excellent yields of anilines; even 2-carboxymethyl aryl nonaflate is effectively coupled with a primary alkylamine. Moderate yields were obtained when coupling halo-aryl nonaflates with a variety of amines, where in most cases the aryl nonaflate reacted in preference to the aryl halide. Overall, aryl nonaflates are an effective alternative to triflates in palladium-catalyzed C-N bond-forming processes due to their increased stability under the reaction conditions.     

Ligand-Promoted Rhodium(III)-Catalyzed ortho-C−H Amination with Free Amines

Ligand development for rhodium(III)-catalyzed C−H activation reactions has largely been limited to cyclopentadienyl (Cp) based scaffolds. 2-Methylquinoline has now been identified as a feasible ligand that can coordinate to the metal center of Cp*RhCl to accelerate the cleavage of the C−H bond of N-pentafluorophenylbenzamides, providing a new structural lead for ligand design. The compatibility of this reaction with secondary free amines and anilines also overcomes the limitations of palladium(II)-catalyzed C−H amination reactions.     

High turnover number and rapid, room-temperature amination of chloroarenes using saturated carbene ligands

[equation--see text] A catalytic system for the mild amination of aryl chlorides is described. This system consists of a Pd(0) precursor and a dihydroimidazoline carbene ligand, which is generated in situ from its protonated tetrafluoroborate salt (2). Using this catalyst, aryl and heteroaryl chlorides react with secondary amines and anilines within hours at room temperature. Turnover numbers as high as 5000 are obtained at elevated temperatures for reaction of morpholine with an unactivated aryl chloride.     

From furans to anilines: toward one-pot two-step amination/diels-alder sequences

Selective metal-free amination and Diels-Alder reactions are described in the furan series, leading to polysubstituted anilines or to stable oxabicyclic adducts in high yield. Interestingly, anilines are conveniently prepared through a novel one-pot, two-step amination/Diels-Alder procedure from commercially available 5-bromo-2-furaldehyde.     

Mechanistic studies of copper(I)-catalyzed allylic amination

The reactions of nitrosobenzene and N,N'-diethyl-4-nitrosoaniline with [Cu(CH3CN)4]PF6 provide novel Cu(I) complexes, [Cu(PhNO)3]PF6 (1) and [Cu(Et2NPhNO)3]PF6 (2); in 2 the copper atom is N-coordinated to the nitrosoarenes in a distorted trigonal planar geometry. Complex 1 is strongly implicated as a reactive intermediate in the Cu(I)-catalyzed allylic amination of olefins based on (i) its isolation from the catalytic reaction, (ii) its stoichiometric regioselective allylic amination of alpha-methyl styrene (AMS), (iii) the non-involvement of free PhNO in its amination of AMS, and (iv) its function as a catalyst for the amination of alkenes from phenylhydroxylamine. The reaction between AMS and 1 (80 degrees C, dioxane) is first order in both alkene and 1. Relative rate studies of the reaction of 1 with para substituted AMS derivatives gives a Hammett rho value of -0.035. Alkene adducts isolated from the reaction of 1 with styrene and alpha-methylstyrene are formulated as [(PhNO)3Cu(eta(2)-alkene)]PF6 (7,8) on the basis of spectroscopic characterization and thermolysis. PM3 and DFT MO calculations support the role of [(alkene)Cu(RNO)3]+ and (eta(1)- or eta(3)-allyl)Cu(RNO)2(RNHOH)+ complexes as probable catalytic intermediates and address the origin of the distinctive reaction regioselectivity. A mechanistic scheme is proposed which is consistent with the accumulated experimental and computational results.