Aryl chloride, Buchwald-Hartwig amination

More challenging are the (hetero)aryl chlorides, since they are cheaper and more widely available than the corresponding bromides and iodides. Maes et al. published the first examples of microwave-assisted Buchwald-Hartwig aminations on (hetero)aryl chlorides in a commimication in 2003 [99]. The substrates 2- and 3-chloropyridine as well as 2-chloroquinoline were smoothly coupled with N-methylaniline and p-toluidine within only 10 min using a catalyst loading of only 1 mol% (Schemes 96 and 97). The diazine... 

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]. 

Scheme 6.61 Buchwald-Hartwig amination reactions of aryl chlorides.

Proazaphosphatrane ligands in combination with Pd2(dba)3 also generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides, e.g. (132) from (130) and (131). The PAP ligand with R = Bu was particularly effective and the catalyst performed extremely well with sterically hindered substrates. ... 

Buchwald-Hartwig Amination Reactions with Aryl Chlorides Using 7... 

As stated previously, Q-phos shows perhaps the broadest scope for the Buchwald-Hartwig amination.45 Aryl chlorides are efficiently animated by all amine classes. The only coupling which gave poor yields was between ortho substituted aryl chlorides and acyclic secondary aliphatic amines. Typically, reaction temperatures of 70-100 °C are required and base sensitive aryl chlorides can be animated by replacing NaO/-Bu with K3PO4. 

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... 

Nolan and coworkers reported on the excellent activity of 4 as precatalyst for the Buchwald-Hartwig amination reaction, displaying high efficiency for the coupling of numerous (hetero)aryl chlorides, at room temperature or at extremely low catalyst loading as low as 0.025 mol% [26]. 

The GooBen group developed palladium-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides using a bench-stable, commercially available A -heterocycle-based catalyst (Experimental Procedure below). ... 

However, the Buchwald-Hartwig reaction with NHCs as hgands is not limited to palladium. Nickel has also been successfully employed in this catalytic amination. In situ procedures have been described for the coupling of aryl chlorides [163] and tosylates [164] and, more interestingly, anisoles [165]. The use of well-defined Ni(0) catalysts has also been studied [166] (Scheme 6.49). 

Independent investigations by Maes and coworkers have involved the use of commercially available and air-stable 2-(dicydohexylphosphanyl)biphenyl (ligand B) as a ligand system for the successful and rapid coupling of (hetero)aryl chlorides with amines under microwave Buchwald-Hartwig conditions (0.5-2 mol% palladium catalyst) [129, 130]. Both methods provide very high yields of products within an irradiation time of 10 min. 

The Buchwald-Hartwig aryl amination methodology cited above in this section was engaged by Hartwig and others to synthesize N-arylindoles 377 [469]. Carbazole can be N-arylaied under these same conditions with p-cyanobromobenzene (97% yield). Aryl chlorides also function in this reaction. The power of this amination method is seen by the facile synthesis of tris-carbazole 378 [469c]. 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

Concurrently with this contribution from Buchwald and co-workers, the Hartwig group reported that the P(t-Bu)3P/Pd-catalyst system first reported by Koie and co-workers [36] is sufficiently active to couple aryl bromides with secondary amines at room temperature [50]. For example, 2-bromotoluene is efficiently aminated with morpholine at in 96% yield, Eq. (19). This catalyst is capable of the room temperature coupling of acyclic secondary amines and aryl bromides as well as the coupling of aryl chlorides at elevated temperatures. 

Concurrently with this report from Hartwig, Buchwald and co-workers reported that the system based on commercially available ligand 4 is an excellent catalyst for the coupling of aryl chlorides and primary aliphatic amines, Eq.(103) [42]. 

The synthesis of 7-azaindoles is a challenging task and there are few efficient routes to substituted derivatives. In the laboratory of C. Thibault, the concise and efficient synthesis of 4-fluoro-1/-/-pyrrolo[2,3-jb]pyridine was achieved. The fluorination was carried out using the Balz-Schiemann reaction. The aromatic amine precursor was prepared via the Buchwald-Hartwig coupling of the aryl chloride with A/-allylamine followed by deallylation. The diazonium tetrafluoroborate intermediate was generated at 0 C and it decomposed spontaneously in 48% HBF4 solution to afford the desired aromatic fluoride. 

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