Buchwald-Hartwig C-N bond and

The Buchwald-Hartwig C—N bond and C—O bond formation reactions 1.7.1 Pd-catalyzed C—N bond formation... 

Buchwald-Hartwig C-N bond and C-O bond formation reactions... 

The Buchwald-Hartwig amination reaction has become a most efficient method for forming a new C-N bond, and it is mediated by a Pd catalyst. Onr group reported on the nse of 1 to catalyze amination reactions of aryl triflates with very good results (Table 14.5). ... 

The Harmata group s initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731 OOJOC169> for sulfoximine N-arylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. 

In 1995, Buchwald and Hartwig independently discovered the direct Pd-catalyzed C—N bond formation of aryl halides with amines in the presence of stoichiometric amount of base [93, 94], This field is becoming rapidly mature and many reviews covering the scope and limitations of this animation have been published since 1995 [95-102]. In the context of heteroaryl synthesis, one example is given to showcase the utility and mechanism of this reaction. Applications to individual heterocycles may be found in their respective chapters. 

Amines are generally prepared by nucleophilic amination, which is a coupling of carbon electrophiles with a nucleophilic amination reagent, NR2, and Ni and Pd catalyzed reaction of aryl halides with arylamines (Hartwig-Buchwald amination) . Thus, the direct C—N bond formation between carbon nucleophiles and electrophilic nitrogen functionality R2N+ constitutes an example of the umpolung methodology. 

Palladium-catalyzed amination of aromatic halides, developed independently by Buchwald and Hartwig, is a useful tool for the construction of C—N bonds. Caravieilhes and coworkers reported using a microreador for aromatic amination [35]. With the use of CPC CYTOS Lab System, the reaction of p-bromotoluene with piperidine gave the desired coupling produd in quantitative yields with a residence time of 7.5 min (Scheme 4.24). 

During (he last few years, a novel Pd(O)-catalyzed method for C-N bond formation from amines and aryl halides has emerged largely due to contributions from the Buchwald and Hartwig groups [120, 121]. In one application, an intramolecular C-N bond linkage was realized using classic palladium catalysis condition in Buchwald s synthesis of tetrahydropyrroloquinoline... 

In the total synthesis of naturally occurring indole alkaloids, applications of n-allylpalladium intermediate and C-N bond formation are developing areas (126]. With the advent of new methodologies in these fields, especially with the successes of the Buchwald and Hartwig s chemistry, more syntheses using those strategies are to be expected. 

Other Metal Catalysts Palladium catalysts are most widely used for C—N bond formation, particularly in Buchwald-Hartwig coupling reactions [48], Halides or pseudohalides are generally used. Recently, direct aminationof C— H bonds has been developed with palladium catalysts. Pd(0)-catalyzed diamination of terminal olefins at allylic and homoallylic carbons takes place via formal sp3 C—H activation under solvent-free conditions [49]. More recently, an asymmetric version of allylic and homoallylic diamination has been successfully achieved using di-tert-butyldiaziridi-none as the nitrogen source (Equation 11.21) [50]. 

The seminal work by the groups of Hartwig and Buchwald in 1994 on aryl amina-tion chemistry has spurred substantial research on C-N bond formation in general and aryl-nitrogen bond formation in particular [114]. Catalytic aryl amine couplings are usually slow processes, especially when copper catalysis is used, often... 

One of the most versatile approaches to highly functionalized carbazoles is the sequential palladium-catalyzed C-N/C-C coupling for assembly of the central pyrrole moiety. Many total syntheses of naturally occurring carbazole alkaloids are following this route. The initial C-N bond formation by a palladium(0)-cata-lyzed Buchwald-Hartwig amination of aryl halides or triflates 94 with arylamines 31 affords the diarylamines 95 (Scheme 24) [139,140]. Oxidative cyclization of the diarylamines 95 to the carbazoles 32 proceeds via a double C-H bond activation and is achieved in the presence of palladium(ll) compounds. 

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 annus mirahilis of the palladium-catalyzed C—N bond formation was 1995, when Buchwald and Hartwig reported, independently, two milestone events -Buchwald the amination of aryl bromides with different amines using [ P(o-Tol)3 2PdCl2] and NaOt-Bu as base [24], and Hartwig a similar procedure using LHMDS as base (Scheme 3.3) [25]. 

Several tandem reaction sequences have been developed for indole synthesis featuring a Buchwald-Hartwig aryl amination as one component. For instance, a tandem double JV-arylation of substrate 5 leads to indoles 6 through a cascade of C-N bond forming reactions. A range of structurally and electronically diverse amines can be used successfully in this transformation. 

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