Intramolecular reactions Buchwald-Hartwig indole synthesis

The mechanism of the direct intramolecular Buchwald-Hartwig indole synthesis is that of a traditional palladium-catalyzed cross-coupling reaction and begins with loss of a ligand on palladium. Oxidative addition of an appropriately substituted Z-vinylhaloarene (1) generates intermediate 2. Deprotonation of 2 and displacement of a halide ligand sets up a reductive elimination on 3 to yield indole 4. 

Indole systan 168 has been prepared from a ring closure reaction of dihydroisoqui-noline derivative 167 catalysed by a NHC-Pd system (Scheme 5.44) [49], The product 168 was prepared from an intramolecular Buchwald-Hartwig coupling and was used in the total synthesis of rac-mangochinine 169. 

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],... 

A less direct strategy for indole synthesis (58) is the intramolecular Buchwald-Hartwig amination of an enamine 57 catalyzed by (DPPF)PdCl2.99 It is necessary to use the Z-enamine isomer 57 that was set by a Homer-Wadsworth-Emmons reaction. 

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). 

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. 

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]. 

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]. 

---