Hosseinzadeh and coworkers reported a variant of this protocol that involves the use of KF/Al2O3 as base in the presence of CuI (10 mol%) and 1,10‐phenanthroline (10 mol%) as ligand in refluxing toluene. The reactions of unactivated aryl chlorides with primary arylamines, like the reactions with secondary arylamines, require catalysts generated from alkylphosphine ligands or carbenes (equation 26). The scope of the couplings with heteroaromatic compounds was further expanded by using vinylboronic acids292. A palladacycle formed from X‐phos has also been shown to couple aniline with activated and unactivated aryl chlorides in water98. General mechanism of copper‐catalyzed amination reactions with hypervalent organometallic reagents. (%)aa A mild method for the N‐arylation of both aromatic amines and cyclic secondary aliphatic amines using aryl iodonium salts was reported by Kang and coworkers359. For example, the amination of aryl chlorides with cyclic or acyclic amines ran to completion at room temperature within 15 minutes70. It was speculated that the active arylating agent in the studies with arylboronic acids might be the anhydride form and not the free acid. Copper‐Mediated Reactions of ArI and ArBr with Aromatic Amines Aryl iodides are the most common aryl halide used in copper‐mediated coupling reactions that form CN bonds. Yamashita and Hartwig isolated three‐coordinate arylpalladium amido complexes with the bulky phosphines P(Bu‐t)3, Q‐phos and FcP(Bu‐t)2188. The amination of aryl chlorides catalyzed by the combination of Pd2dba3 and 13 (Figure 5) occurred at 80°C with 0.5 mol% catalyst66. This step is thought to be rate‐limiting, and the intramolecular attack would lower the activation energy to accelerate the reaction. The resulting species undergoes oxidation with dioxygen to generate a Cu(III) complex; reductive elimination generates a Cu(I) species; and the Cu(I) species is then oxidized to Cu(II). The reactions of aryllead reagents with aliphatic amines formed anilines in low yields348, but a number of heteroarylamines, such as aminoindazole317, 351, aminobenzodioxole352 and aminobenzodioxane331, 353, reacted with aryllead reagents to form the N‐aryl heteroarylamines in moderate to good yields. Although lying outside the scope of the synthesis of anilines, we note that numerous copper‐catalyzed or copper‐mediated methods have been published for the coupling of NH containing heterocycles with aryl halides to form N‐aryl heterocycles269-276. Reactions with Unactivated Aryl Chlorides Typically, unactivated aryl chlorides react with amines in palladium‐catalyzed reactions using third‐generation electron‐rich, sterically hindered monophosphines or carbenes as ligands (equation 13). Consequently, most examples of the coupling of aryl halides with arylamines have been reported with ArI and ArBr, and the majority of these reactions have been conducted with aryl iodides. Anilines don’t undergo Freidel crafts reaction because they react with ferric chloride of the reaction mixture which acts as catalyst for the reaction. Usually, electron‐rich arenes will react at the ortho or para position while electron‐poor arenes will react at the meta position. Addition of phenyl bromide to (BINAP)2Pd(0), conducted with high ratios of aryl bromide to free phosphine, were close to zero order in phenyl bromide.178 Under these conditions, dissociation of phosphine is the major contributor to the rate of the oxidative addition process. This primary amine shows two N–H stretches (3442, 3360); note the shoulder band, which is an overtone of the N–H bending vibration. No strong correlation was observed between the basicity of the amine or the electron‐donating property of the arylboronic acids and the reaction yields. The isolated palladium complex Pd[P(Bu‐t)3]2 catalyzed the amination of unactivated or activated aryl chloride with primary aryl amines in water using sodium hydroxide or potassium hydroxide as the base and cetyltrimethylammonium bromide as phase‐transfer agent69. Potential mechanisms for copper‐catalyzed amination reactions with low‐valent organometallic reagents. Catalysts containing ligand 11 (Figure 4) provide good yields for some aminations with dialkyl amines. Buchwald and coworkers further developed this chemistry by surveying a variety of diols for amination of aryl iodides with catalytic amounts of CuI263, 264. Triethylamine also promoted the copper(II)‐mediated organobismuth N‐arylations of amides312, whereas pyridine more successfully promoted the analogous N‐arylation of imides and sulfonamides. Later, a range of anionic O‐donor ligands (66-79) were screened to improve the N‐arylation of primary alkyl amines using aryl b romides as substrates (Scheme 9)265. The dimeric palladium(I) complex [{PdBrL}2] (L = P(1‐Ad)(Bu‐t)2, P(Bu‐t)3) catalyzed reactions of aryl chlorides under mild conditions. A few examples of the coupling of aryl bromides with these catalysts have also been reported. Complexes of the N‐heterocyclic carbene IPr 23 and SIPr 24 (Figure 7) couple aniline with unactivated aryl chlorides, even at room temperature in excellent yields68, 75, 85, 88-90. The first example of a palladium‐catalyzed amination of an aryl chloride, albeit the reaction of a highly activated aryl chloride at a high temperature, was catalyzed by trans‐di(μ‐acetato)bis[o‐(di‐o‐tolylphosphino)benzyl] dipalladium(II) 38. para‐Trifluoromethyl chlorobenzene coupled with piperidine in 98% yield to form a 13:1 mixture of para and meta regioisomers from a combination of palladium‐catalyzed coupling and reactions through benzyne intermediates. They also concluded that oxidative addition of PhI to complexes of the bulkier phosphines (n = 0–1) proceed after dissociation of ligand to generate PdL. Third, the rate of reductive elimination is strongly dependent on the nucleophilicity of the heteroatom and electrophilicity of the palladium‐bound aryl group187. The imidazole then coordinates to 102 to form another copper(II) complex (103). However, m‐chloronitrobenzene did not react under these conditions, presumably due to the weaker stabilization of the charged intermediate. Use of an ionic liquid also improved the yields of the reaction of unactivated aryl chlorides with cyclohexylamine and cyclopentyl amine when air‐ and moisture‐stable complexes [PdCl2(N‐heterocyclic carbene)2] were used as catalyst110. Mechanism of copper‐catalyzed amination of aryl halides. For example, reactions of unactivated aryl halides with diethylamine, N‐ethylaniline or cyclohexyl ethylamine occurred in yields ranging from 73–90%. The hindered mesitylamine formed only 25% of the arylation product (Figure 19)343. Anilines undergo the usual electrophilic reactions such as halogenation, nitration and sulphonation. For reactions that employ weak bases, it is likely, although not experimentally verified, that the resting state is the arylpalladium halide. The ligand precursor imidazolium salts are simple to prepare and are now commercially available. Faster rates for reactions of indole and pyrrole with aryl halides were observed when the reactions were catalyzed by palladium complexes formed by combining a 1:1 ratio of Pd(dba)2 and P(Bu‐t)3 (equation 40) than when catalyzed by complexes of DPPF68. While reactions of electron‐rich and electron‐neutral aryl triflates proceeded with high yields, poor results were obtained for electron‐deficient aryl triflates, even with the weak bases K3PO4 or Cs2CO3. An atom of nitrogen holds a positive charge. For example, reaction of 2‐bromotoluene with 3‐methylindole occurred with high yields. Iodobenzene reacts by associative displacement of a phosphine, bromobenzene reacts by rate‐limiting dissociation of phosphine, and chlorobenzene reacts by reversible dissociation of phosphine, followed by oxidative addition. Josiphos ligand that generates highly active catalysts for the coupling of primary alkylamines with aryl chlorides, Phanephos, similar to BINAP, synthesized for amination by primary alkylamines. The observation of the alkoxide complex in this reaction strongly suggests the intermediacy of the alkoxide complex in the catalytic reactions125. Support for the proposed mechanism comes from the observation that the L‐phenylaniline–Cu(II) complex reacted with bromobenzene in the presence of K2CO3 under N2 to yield the product in 43% yield after 48 h, despite low solubility of the complex in the solvent DMA. For example, nearly quantitative yields were achieved in the presence of a palladium complex of DPPF as the catalyst103. The chelating biscarbene ligand (63) and the biarylphosphine ligand (12, Figure 5) shown in Figure 17 were the most effective256. Presumably, during the oxidation of Cu(II) to Cu(III), hydrogen peroxide would also be produced, and this hydrogen peroxide could lead to the oxidation of ArB(OH)2 to ArOH397. Instead, β‐hydrogen elimination from amides may be slower169.