Anilines Buchwald-Hartwig amination

The first examples utilising A-heterocyclic carbenes as ligands in the Buchwald-Hartwig amination involved the in situ formation of the catalyst from the corresponding imidazolium salt and a Pd(0) source. Nolan reported IPr-HCl/PdjCdbalj as a catalytic system for the amination of aryl chlorides in excellent yields, using different types of amines, anilines, and also imines or indoles [142,143] (Scheme 6.46). Hartwig showed later that in some cases the reactions could be performed at room temperature and without anhydrous conditions even for aryl chlorides [ 144]. This was later shown for the less challenging bromides and iodides [145,146]. 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

Many other examples from the literature have used the Buchwald-Hartwig amination to rapidly access bioactive anilines. S. Morita formed aripiprazole 32 and its metabolite by distinguishing between an aryl chloride and bromide during the amination... 

In papers published back-to-back in 1996, Hartwig and Buchwald reported amination chemistry with palladium complexes of DPPF and BINAP as catalysts [50,86]. These palladium complexes provided animations of aryl bromides and iodides with primary alkyl amines, with cyclic secondary amines, and with anilines. It is ironic that the amination chemistry was first discovered by using a particularly labile phosphine, but was dramatically improved by the use of chelating ligands. 

Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethyl-amine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazi-nones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for NIO-vinylation. The boronic acids can be replaced with siloxanes or starmanes. The mild condition of this reaction is an advantage over Buchwald-Hartwig s Pd-catalyzed cross-coupling. The Chan-Lam C-X bond cross-coupling reaction is complementary to Suzuki-Miyaura s C-C bond cross-coupling reaction. 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

In 2012, T2ik2ihashi et al. [30] reported the catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone derivatives using the Buchwald-Hartwig reaction with a (i )-MOP-Pd2(dba)3 catalyst. This reaction involved the 1,4-addition of aniline to an ynone, followed by an intramolecular Buchw2ild-Hartwig amination. An enantioselectivity as high as 72% ee could be achieved (Scheme 2.4). 

Arylation of Anilines. It was demonstrated that la, as well as other diphenyliodonium salts with other non-nucleophiUc counterions, can efficiently arylate aniline to AliV-diphenylamine (2) (eq 1). Salts Ig-i bearing halide counterions were found to be completely ineffective. A similar copper-catalyzed Buchwald-Hartwig-type phenylation of both alkyl and aryl amines using [Ph2l]BF4 (If) and its analogs has been reported. ... 

In another example, the Buchwald-Hartwig A)-arylation conditions were applied to the cross-coupling reaction of 3,7-dibromo-10-hexyl-10f/-phenothiazine with a variety of primary and secondary anilines and amines, including carbazole, leading to 3,7-diaminophenothiazine derivatives in excellent yields (eq 17). ... 

Benzylamines and the chloro or bromo substituted anilines cannot be applied in the Buchwald Hartwig reaction and this is another limitation. These limitations can be overcome by triazene-linked anilines. On one hand, the amine could be benzylated by reductive alkylation with benzaldehydes, or on the other hand, be used for an inverse Buchwald-Hartwig reaction, e.g. with dichlorobenzenes for the assembly of chloroanilines. 

Metal-catalyzed N-arylation of amines with haloarenes (Buchwald-Hartwig coupling) has been developed since the 1990s and provided more efficient access to carbazoles. Nozaki et al. reported the palladium-catalyzed double N-arylation of primary amines with 2,2 -dihalobiphenyls [8], A variety of dihalobiphenyls 10 and anilines 11 with electron-donating or electron-withdrawing substituent(s) are applicable to give multisubstituted carbazoles 12 in moderate to high yields (Scheme 23.4). 

The palladium-catalyzed intramolecular C-H arylation of aromatic C-H bonds with haloarenes (Ar-H/Ar-X coupling, where X is halogen) is effective for the synthesis of carbazole alkaloids with amine linkers, as reported by Bedford and coworkers in 2006 (Scheme 16.16a) [34]. Buchwald-Hartwig coupling of an aryl bromide and an aniline derivative generated aryl chloride 91 in situ, which was easily cyclized under palladium catalysis to give clausine P in 80% yield. They also... 

Buchwald s XPhos ligand (L7) works well to catalyze the amination of 5-bromopyrimidine with anilines and secondary cyclic amines.67 Buchwald also found that ligands L20 and L21 were the best ligand for the palladium-catalyzed amination of benzothiazoles with secondary amines and anilines. Hartwig reports that (r-Bu)3P was excellent for the catalytic amination of 2-chloroheteroaryl compounds with secondary amines and anilines.35,68 As with other examples using bulky mono-dentate phosphines, primary aliphatic amines were not reported. 

Both Buchwald and Hartwig have explored the use of palladium-catalyzed amination for the synthesis of dendrimers and polyanilines. Dendrimers, such as 48, can be easily assembled through sequential aiylation of aminoanilines.89 These dendrimers are useful in creating metal-organic frameworks and often can exhibit interesting electronic effects, such as diradicals, and as optical materials. Polymeric anilines 49 are of intense interest due to their unique electrical conducting properties. Using the... 

The tremendous utility of catalytic C-0 and C-N bond formation processes, pioneered by Buchwald and Hartwig, is largely based on the efficiency of palladium-catalyzed systems. However, efficient nickel-catalyzed processes have also been reported for this important class of transformations. The catalytic coupling of aryl chlorides with primary or secondary amines is a particular niche where utility of the nickel-catalyzed process was found. A representative sampling of aniline derivatives prepared by the activity of Ni(cod)2/dppf as the pre-catalyst is depicted below (Figure 3-3). 

Aniline and N-methylaniUne derivatives are the most reliable substrates for the Hartwig-Buchwald coupling, and they experience a high level of functional group tolerance. Similar to the coupling of primary amines, the double arylation of aniline can be a competing side reaction. A slight excess of the amine relative to the aryl component usually diminishes this side reaction. 

In addition, this reaction is also applicable for combinatorial chemistry. Thus, the heterofunctionalization of haloarenes on a solid support is a versatile method to create small-molecule libraries of high diversity. Starting with simple resins, aryl amines can be prepared in good to excellent yield by amination of polymer-bound aryl halides employing either the Hartwig or the Buchwald protocol (BINAP or P(o-Tol)j, /BuONa for a review, see refPrimary and secondary alkylamines and anilines can be employed in the case of cyclic amines, BINAP was found to be the optimal ligand for the arylation. ... 

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