Heck reaction, Buchwald-Hartwig amination

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. 

Verkade s P,N-ligand L13 also catalyzes the Heck reaction of aryl iodides. It was thus shown that the Buchwald-Hartwig amination could be appended to a Heck reaction using Pd/L13.47 The operation is performed by first adding an aryl iodide to the catalyst solution and an aminostyrene 10 at 60 °C. This gives an intermediate N-aryl aminostyrene 11 to which 2 equiv of a second aryl iodide is added at 110 °C. This gives a second aryiation of the aminostyrene as well as the Heck arylation of the olefin (12). 

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]... 

Indole is one of the most important heterocyclic scaffolds for drug discovery. Approaches for indole synthesis using hydroamination as a key step in their syntheses has been an ongoing area of investigation over the past several years [329, 330]. Early examples focused on one-pot intermolecular hydrohydrazination followed by the Lewis-acid-catalyzed Fischer indole synthesis [331, 332] (Scheme 15.102) or one-pot intermolecular hydroamination followed by cross-coupling to either form a C-N bond (via the Buchwald-Hartwig amination) [333] (Scheme 15.103) or a C-C bond (via a Heck reaction) [334, 335] (Scheme 15.104). Alternatively, o-alkynylanilines can be used directly as substrates for intramolecular hydroamination (Scheme 15.105) [198, 200, 336-340]. These approaches have been thoroughly reviewed [10]. 

To overcome the ring closure of intermediate 10 giving rise to by-product 8 that was particularly encountered with secondary alkyl halides. Tautens and coworkers [22] developed conditions that favor the oxidative addition of alkyl hahdes. The methodology was widely applied to the intramolecular (Scheme 19.12) and intermolecular ortho alkylation of aromatic C-H bonds with secondary alkyl iodides and bromides [23]. Depending on the terminating reactions employed (the Heck reaction, direct arylation of heterocycles, and the Buchwald-Hartwig amination), a variety of valuable heterocydes were efficiently prepared. It should be pointed out that the reaction of enantioenriched substrates occurred with... 

Equation 14.4 shows how a Buchwald-Hartwig amination can be combined with a Mizoroki-Heck reaction in a tandem sequence... 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

The Hartwig-Buchwald arylation of amines can also be favorably combined with the Heck reaction [383, 384]. For example, the intramolecular palladium-catalyzed N-arylation of immobilized dehydro(halophenyl)alaninate was found to proceed smoothly to form indolecarboxylates. The method was successfully combined with the Heck reaction to constitute a one-pot indole synthesis in the form of a palladium-catalyzed cascade C,N-arylation reaction (Scheme 8.58) [383, 384]. 

The Heck cyclization proceeds via methylene indolenines (83) (isolable in the presence of Ag salts) and migration of their exocyclic double bond to the internal enamine position under the reaction conditions. A variety of 3-methylindoles (84) is accessible directly from 2-bromoiodobenzenes by a Pd-catalyzed aryl amination (Hartwig-Buchwald reaction)/Heck cyclization cascade [172]. 

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