Arylation of amines

Arylation of amines in combinatorial synthesis has been achieved by nucleophilic aromatic substitution or by metal-catalyzed amine/halogen exchange (Table 3.5). 

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Arylation of amines or alcohols catalyzed with copper are well documented (Fig. 3). 

If, instead of a palladium catalyst, a nickel catalyst, such as the bipyridylnickel(II) bromide, is used for the arylation of amines (Fig. 7), the reduction of the aryl halide into the corresponding aromatic hydrocarbon is still present for the primary or secondary benzylamines but, the arylation into substituted anilines is the main reaction even most often the only one, for the other types of amines. 

Hartwig and Buchwald have developed a new methodology for arylation of amines or phenols with aryl halides and palladium catalysts.17 This reaction provides a very useful strategy for the preparation of various heterocyclic compounds such as phenazines, as shown in Scheme 9.4.18... 

Arylations of amines and nitrogen-containing heterocycles require the presence of a copper catalyst, usually 10% copper(ll) acetate. For example, the reaction of 4-MeC6H4Pb(OAc)3 with the benzimidazole 20 affords the arylation product 21 in 98% yield.39 40 Similarly, the arylation of the amino groups of heteroaromatic compounds 22 and 23 gives rise to the corresponding products 24a and 25 in good to excellent yields (Equations (7)-(9)).41 42... 

Scheme 3.34. Alkylation or arylation of amines by treatment of organocopper reagents with amines [119].

N-Arylations of amines have also been realized with support-bound heteroaromatic halides (Entries 9-11, Table 10.4). Several examples of the synthesis of substituted 1,3,5-triazines [83-85], purines [78,85-93], and pyrimidines [77,85,94—96] have been reported. The reactivity of these arylating agents depends strongly on their precise substitution pattern, and generally increases with decreasing electron density of the het-eroarene. Illustrative examples are given in Table 10.4. The arylation of amines with simultaneous cleavage of the product from the support is discussed in Section 3.8. 

Arylation of amines by the direct displacement of aryl halides is possible when the halogen is activated by strong electron-withdrawing groups in the ortho and para positions. For example, 2,4-dinitrobenzenamine can be prepared by heating 2,4-dinitrochlorobenzene with ammonia ... 

Thus, the transition metal catalyzed arylation reactions of amines and alcohols would constitute powerful tools for synthetic chemists. We have been developing practical procedures for the palladium-catalyzed arylation of amines and alcohols with aryl halides or sulfonates. During the course of our investigations [9] as well as those of John Hartwig and co-workers [10] the substrate scope of these transformations has been incrementally expanded. With each cycle of this catalyst improvement process, advances in mechanistic understanding and ligand design have also been made. 

General Procedure for the Palladium-Catalyzed Arylation of Amines with Aryl Bromides using BINAP/Pd (Excerpted with permission from [27]. 2000 American Chemical Society) An oven-dried Schlenk flask was charged with... 

Representative for the Palladium-Catalyzed Arylation of Amines with Aryl Chlorides using (f-BuljP/Pd (Reproduced with permission from [50]. 1999 American Chemical Society) In a dry box, aryl halide, amine, Pd(dba)j, (t-BuljP, and sodium fert-butoxide were weighed directly into a screw cap vial. A stir bar was added followed by 1.0-2.0 ml of toluene to give a purple mixture. The vial was removed from the dry box, and the mixture was stirred at room temperature. After 5.5 h, the reaction mixture was adsorbed onto sihca gel and chromatographed with 50% toluene/hexanes to give 242 mg (90%) of N-(4-cyano-phenyl)diphenylamine as a white solid. 

Representative Procedure for the Palladium-Catalyzed Arylation of Amines with Aryl Bromides using DPPF/Pd (Excerpted with permission from [29]. 1996 American Chemical Society) In an inert atmosphere dry box, DPPFPdClj and 3.0 equiv. of DPPF/Pd were added to a solution of 20 equiv of bromoben-zophenone and 25 equiv of sodium ferf-butoxide in 8 ml of anhydrous THF. The reaction tube was sealed with a cap containing a PTFE septum and removed from the dry box. Butylamine (25 equiv) was added to the reaction mixture by syringe, and the mixture was heated to 100 °C for 3 h. The reaction was cooled to room temperature, the volatile materials were removed by rotary evaporation, and the product was isolated by either sublimation or silica-gel chromatography (20 1 hexane/EtOAc or 10 1 hexane/Et20 followed by 4 1 hexane Et20). 

Kang, S.-K., Lee, S.-H., Lee, D. Copper-catalyzed N-arylation of amines with hypervalent iodonium salts. Synlett 2000, 1022-1024. 

In this case, the second A-arylation was slow and required 1.5 equivalents of bismuth reagent and 1 equivalent of copper diacetate. For example, the first arylation of (5)-valine took place in 1 day at room temperature to yield 85% product, but the second A-arylation required 14 days at room temperature to yield 69% product. However, no racemization of the amino acid ester was detected, and for this reason, this procedure offers an advantage over the palladium-mediated arylation of amines that racemize amino acids342. 

Arylation of amines. Rapid transfer of an aryl group from ArjBifOAclj to amines is catalyzed by copper(II) pivalate (9 examples, 45-100%). 

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