Palladium-catalyzed aromatic Hartwig-Buchwald amination

The palladium-catalyzed amination of aryl halides and sulfonates has emerged as a valuable method for the preparation of aromatic amines [2], Numerous ligands and catalysts have been reported to effect this type of cross-coupling. This reaction, known as the Hartwig-Buchwald amination, is shown in Eq. (1). 

Palladium-catalyzed aromatic amination of aryl halides, developed independently by Buchwald and Hartwig, is a useful tool for the construction of C—N bonds. Caravieilhes and coworkers examined this aromatic amination using a microreactor [16]. When the reaction of p-bromotoluene and piperidine with Pd(OAc)2/ biarylphosphine as a catalyst system and sodium tert-pentoxide as a base in xylene was carried out using a CPC CYTOS Lab System, the desired coupling product was obtained in quantitative yield with a 7.5 min residence time (Scheme 6.5). 

The reaction conditions are similar to the palladium-catalyzed Buchwald-Hartwig amination (see Chapter 3) with one distinct advantage when the base NaOt-Bu used in the Buchwald-Hartwig procedure is replaced with KOt-Bu, the reaction proceeds without the need for a palladium catalyst. Primary and secondary amines, as well as aromatic and aliphatic amines, undergo the amination smoothly however, only meto-substituted aniUnes can be obtained. 

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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