Palladium catalysts Buchwald-Hartwig amination

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 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). ... 

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. 

The Buchwald-Hartwig amination is an exceedingly general method for generating any type of aromatic amine from an aryl halide or aryl sulfonates.1,2 The key feature of this methodology is the use of catalytic palladium modulated by various electron-rich ligands. Strong bases, such as sodium ferf-butoxide, are essential for catalyst turnover. 

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). 

Hartwig and Buchwald have developed a new methodology for arylation of amines or phenols with aryl halides and palladium catalysts.17 This reaction provides a very useful strategy for the preparation of various heterocyclic compounds such as phenazines, as shown in Scheme 9.4.18... 

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. 

In certain cases, when the palladium or nickel catalyzed coupling is not efficient or fails completely, an alternate solution is provided by the use of copper based catalyst systems. The 5-iodouracil derivative shown in 7.77. was unreactive towards imidazole using either the Buchwald-Hartwig conditions or the copper(I) triflate promoted the carbon-nitrogen bond formation reported by Buchwald98 These latter conditions, however, were effective in coupling the iodouracil with a series of other amines (7.77.), The optimal catalyst system consisted of copper(I) triflate, phenantroline and dibenzylideneacetone (dba).99... 

In papers published back-to-back in 1996, Hartwig and Buchwald reported amination chemistry with palladium complexes of DPPF and BINAP as catalysts [50,86]. These palladium complexes provided animations of aryl bromides and iodides with primary alkyl amines, with cyclic secondary amines, and with anilines. It is ironic that the amination chemistry was first discovered by using a particularly labile phosphine, but was dramatically improved by the use of chelating ligands. 

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. 

An amine can be coupled with an aryl bromide, iodide or triflate in the presence of a palladium catalyst, a base, typically KOBu or CSCO3, and a ligand such as the bidentate phosphine BINAP. These reactions are known as Buchwald or Buchwald-Hartwig reactions (Scheme 10.24). A catalytic cycle is again involved, with the amine displacing X from Ar-Pd -X to form Ar-Pd -NHR2. Abstraction of a proton by the base produces Ar-Pd -NRj, which undergoes a reductive elimination. 

The mechanisms and catalysts used in this Buchwald-Hartwig chemistry mirror those of coupling reactions involving oxidative addition, transmetallation, and reductive elirruna-tion. The first step, as usual, is oxidative insertion of Pd(0) into the aryl-halogen bond. The Pd(ll) complex now adds the amine so that both coupling partners find themselves bonded to the same palladium atom. The base eliminates H—1 from the complex and reductive elimination forms the Ar—N bond. 

Besides the Hartwig-Buchwald reaction, amination can be achieved by a Pd-catalyzed variant of the Ullmann reaction in the presence of copper salts. Though the scope of this reaction is much narrower, it does not require expensive phosphine ligands and thus is more economical. The arylation of diphenylamine with water-insoluble aryl iodides can be achieved in aqueous microemulsions in the presence of phosphine-free palladium catalyst and copper(I) iodide (Scheme 58). 

Solid-supported versions of the Buchwald-Hartwig reaction are known too. In 2012, Al-Amin et al. [42] reported a stable heterogeneous sulfur-modified gold-supported palladium material (SAPd), which was used for the amination of aryl bromides and chlorides. The catalyst was employed at a loading of about 0.2 mol%, and can be used for a minimum of 10 reaction cycles without loss of catalytic activity, affording very good yields for a large cross-section of substrates. 

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