Buchwald indole synthesis

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],... 

Most recently, Wagaw, Yang, and Buchwald published a full account of the synthesis of indoles using the palladium-catalyzed amination process [185]. From the standpoint of catalysis, new results included improved turnover numbers and rates when Xantphos was used as ligand. Moreover, this ligand allowed diarylation of the hydrazone, including a one-pot sequential diarylation to provide mixed diaryl hydrazones. A procedure for the alkylation of N-aryl hydrazones was also reported. These procedures allow the formation of N-aryl and N-alkyl indoles after subjecting the products to Fischer conditions for indole synthesis. 

The Buchwald group exploited the Pd-catalyzed hydrazone synthesis for the efficient preparation of indoles. While removal of the benzophenone moiety and isolation of the free hydrazine did not proceed cleanly, the MIT workers found that Fischer indole synthesis could be effected by in situ exchange of the ketone group. The desired indoles could thus be isolated in good to excellent yield over two steps,Eq. (149) [121]. 

An alternative indole synthesis was reported by the Buchwald group where initial displacement of the primary bromide by benzylamine is followed by a Pd-catalyzed cyclization, Eq. (173) [139]. After deprotection, the desired indole was obtained in 54 % yield over two steps. 

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. 

Hartwig and Tan reported a simple indole synthesis from an oxime acetate involving C-H functionalization (Scheme 3, equation 1) [22]. Buchwald described an excellent versatile carbazole synthesis that also involved C-H activation (equation 2) [23], as did Youn [24], Antonchick [25], Gault [26], and Shi [27], who synthesized 4-deoxy-carbazomycin B (equation 3). 

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. 

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. " ... 

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