Buchwald-Hartwig amination applications

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

Scheme 3 Applications of the Buchwald-Hartwig Amination Involving C-H Activation...

In 2008, Application of CyclopaUadated Compounds as Catalysts for Heck and Sonogashira Reactions, by Najera and Alonso [110], Palladacyclic Precatalysts for Suzuki Coupling, Buchwald-Hartwig Amination and Related Reactions Bedford [111]... 

Indoles can be synthesized via a palladium-mediated intramolecular amination reaction of an appropriately substituted haloarene. This is a specific application of the Buchwald-Hartwig amination reaction that has found use in the synthesis of biologically active natural products. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Many other industrial applications at large scale are known. This subject has been comprehensively reviewed by Busacca et al. [37], and we will highlight one example here, the case of torcertrapib - which is a powerful cholesteryl ester transfer protein (CETP) inhibitor invented by Pfizer [38]. The key step in this synthesis - which can be scaled-up to multi-kilograms - is a Buchwald-Hartwig reaction involving very cheap l-chloro-4-trifluoromethylbenzene and a chiral amine in the presence of PdfOAcj and DavePhos (Scheme 2.8). Interestingly, PhB(OH)2 was added in order to activate the catalyst. 

Aryl amination, also known as Buchwald-Hartwig coupling, is one of the most important transformations in organic synthesis, due to its versatility and the ubiquitous nature of nitrogen-containing molecules in therapeutically active compounds.There have been numerous studies on catalytic applications of NHC-Pd complexes to aryl amination, sometimes with impressive results. 

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 first application of the single-step procedure to the synthesis of azacafix-arenes was laimched by Ito et al., who prepared a series of azacafix[ ]arenes 4a-f with different ring sizes (w = 3 to 8) [16,17]. As shown in Scheme 2, starting from the N-methylation of 3-bromoaniline (2) in 3 steps, the resultant 3-bromo-N-methylaniline (3) was subjected to the Buchwald-Hartwig aryl amination reaction to yield azacaUxarenes 4a-f, which were isolated by medium-pressure liquid chromatography. 

Another application of the single-step procedure tvas made by Miyazaki et al, who utilized the Buchwald-Hartwig aryl amination reaction for the preparation of azacalix[6]pyridine 7d [18], in which all the benzene rings of the above azacalix[6]arene 4d were replaced by pyridine rings (Scheme 3). Azacalix[ ]pyridines 8a-f (n = 3-8) with tolyl groups on the nitrogen bridges... 

Although one of the more recent additions to the armamentarium of these palladium-catalysed reactions, the Buchwald-Hartwig cross-coupling of amines with aiyl halides already has found applications in macrocycle synthesis. In the first example, Iqbal et al used this coupling as the cyclization step in the synthesis of constrained tri- or tetra-peptidomimetics with a biaiyl linker (Scheme 11.13 illustrates a tripeptidomimetic (112)). Fair to moderate yields were obtained for products containing 16- to 22-membered rings. 

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. 

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... 

The application of transition metal catalysis for aryl amination was reported and developed primarily by the groups of Buchwald and Hartwig in the late 1990s and presented a mild and broadly applicable method for amination of aryl bromides and chlorides by use of palladium(II) and BINAP, tol-BINAP, or... 

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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