Buchwald-Hartwig amination aryl chloride coupling

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... 

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. 

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]. 

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. 

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. 

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). 

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... 

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