Indoles Buchwald-Hartwig synthesis

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],... 

The first total synthesis of (-)-fumiquinazoline A and B was accomplished by B.B. Snider and co-workers using a Buchwald-Hartwig Pd-catalyzed cyclization of an iodoindole carbamate to construct the imidazoindolone moiety. In order to set up the stereochemistry at the benzylic position of the indole fragment, the double bond was oxidized with the saccharine-derived Davis oxaziridine in the presence of methanol to give the major diastereomer in 65% yield. 

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). 

Palladium-Catalyzed Indole Ring Synthesis Buchwald-Hartwig 621... 

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 Buchwald-Hartwig amination reaction has also been applied to the synthesis of A -arylhydrazones, which can then be transformed into indoles via the Fisher indole synthesis. Since this reaction sequence does not use a Buchwald-Hartwig amination reaction directly in the synthesis of indoles, it will not be a focus of this chapter. 

The Buchwald-Hartwig amination reaction can facilitate the synthesis of nitrogen-containing heterocycles. For instance, Buchwald demonstrated that the amination reaction could be used to prepare N-arylhydrazones from hydrazones and aryl halides. Acid-catalyzed condensation of the hydrazone with a ketone then yielded the desired indoles.Hartwig described a similar arylhydrazone formation with DPPF as a ligand and CS2CO3 as a base."... 

Buchwald quickly parlayed this transformation into a versatile indole synthesis via oxidation of intermediate indolines prepared using the above intramolecular Buchwald-Hartwig amination. Variations leading directly to indoles and related nitrogen-containing heterocycles quickly followed and are described below. 

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. 

Substituted indoles can be prepared using the Buchwald-Hartwig N-arylhydrazone synthesis provided that a functionalization of the intermediate A -arylhydrazone is carried out before the Fisher indole synthesis synthesis step. Both A -alkyl and A -aryl indoles may be prepared in this manner. For instance, an A -methylindole was prepared as a mixture of regioisomers by first methylating an arylhydrazone. 

Several tandem reaction sequences have been developed for indole synthesis featuring a Buchwald-Hartwig aryl amination as one component. For instance, a tandem double JV-arylation of substrate 5 leads to indoles 6 through a cascade of C-N bond forming reactions. A range of structurally and electronically diverse amines can be used successfully in this transformation. 

The Buchwald-Hartwig indole synthesis has been used successfully to prepare complex natural products featuring functionalized indoles. One of the earliest examples was a transformation carried out by Hartwig and coworkers to prepare 18, an intermediate in the synthesis of damirone B, a topoisomerase II inhibitor. " ... 

The examples presented illustrate two of the common ways Buchwald-Hartwig indolizations are run. Both are from the applications to natural product synthesis described above. 

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