Dehydrogenative indole synthesis

Scheme 12.39 Traditional indole S5mthesis vs. dehydrogenative indole synthesis.

A large number of carbazole syntheses have involved the preparation and dehydrogenation of hydrocarbazoles, mainly 1,2,3,4-tetrahydrocarbazoles, which are 2,3-disubstituted indoles. These, in turn, are usually prepared by the Fischer indole synthesis or the Bischler synthesis. This section will not deal with the preparation of the tetrahydrocarbazole, because... 

Zeolites are known to catalyze the formation of various nitrogen-containing aromatic ring systems. Examples include the synthesis of pyridines by dehydrogenation / condensation / cyclization of C -Cg precursors [1], the formation of methylpyridines by high-temperature isomerization of anilines [2], the amination of oxygen-containing heterocyclic compounds [3] and the Fischer indole synthesis [4,5]. The latter synthesis consists (see Scheme 1) of a condensation towards a phenylhydrazone followed by an acid-catalyzed cyclization with elimination of ammonia. The two reaction steps are usually combined in a one-pot procedure. 

The fact that indoline - 2,3-dihydroindole - is only a simple dehydrogenation step to indole, this conversion represents an obvious and important indole synthesis. 

An extremely important and versatile indole synthesis is the dehydrogenation (oxidation) of indolines (2,3-dihy-droindoles), as we have already seen in several previous chapters. This method of indole ring generation is presented here in full. For an excellent summary of the early methods, see Sundberg [1]. 

Fischer indole synthesis to cyclohexanone-2-troponylhydrazone and dehydrogenation of the product to indolo[2,3-h]tropone the 8- and 10-isopropyl-, and 7-bromo-analogues, were also prepared. Treatment of the 2-troponylhydrazones of cyclo-heptanone and JV-benzylpiperidinone with acid gave analogous products. Tndolo[2,3-h]tropone was converted into benzo[h]-l-aza-azulene. ... 

Indole-2,3-quinodimethanes have also been exploited as the key intermediates in indolo[2,3-a]caibazole synthesis, allowing the preparation of several interesting systems. Thus, when the starting materials 74a-b (obtained from the condensation of protected indole-2-carboxaldehydes with 2-aminostyrene) underwent treatment with methyl chloroformate in hot chlorobenzene, the carbamates 75a-b were obtained, and could subsequently be dehydrogenated into the aromatic compounds 76a-b (Scheme 11). However, all functionalization attempts of the methyl... 

A synthesis of an indolo[3,2-fl]carbazole (2) was reported in 1951—the first preparation of a compound belonging to this class (Scheme 13). This was accomplished commencing with cyclohexanone, via conversion to the bishydrazone 108, which underwent Fischer indolization in glacial acetic acid to furnish the octahy-dro derivative 109. After a final dehydrogenation step, the desired product 2 was obtained (51JCS809). 

The 2-aminophenethyl alcohols resulting from condensation of ort/io-nitrotoluenes are good precursors for preparation of indoles. Watanabe and coworkers have developed ruthenium-catalyzed dehydrogenative iV-heterocyclization for synthesis of indoles and other heterocycles from 2-aminophenethyl alcohols or 2-nitrophenylethyl alcohols (Eq. 10.52). 69a The oxidative cycli-zation of 2-aminophenethyl alcohols are also catalyzed by Pd-based catalysts.69... 

JPS 62,490(1973) gives an indoline synthesis which can be carried one step further (dehydrogenation described in this chapter) to give DMT derivatives. See JOC 41,1118(1976) for indoles from betaketosulfoxides. 

Using a modification of Sakamoto s indole benzannulation protocol (see Scheme 5.59), Beccalli et al. reported the synthesis of the 3-methoxycarbazole alkaloids hyellazole (245) and 6-chlorohyellazole (246) (540) (Scheme 5.61). Unlike Sakamoto s methodology, this method requires a good leaving group at the 2-position of the indole moiety of the 3-(l,3-butadienyl)indoles 692 to facilitate the aromatization of the intermediate dihydrocarbazole by eliminating the dehydrogenation step. 

The method that has been most utilized for the preparation of aromatic carbazoles from noncarbazole precursors is the dehydrogenation of a tricyclic indole, usually a 1,2,3,4-tetrahydrocarbazole. The synthesis of the latter s is outside the scope of this article. The next most used precursors are biphenyls with an ortho nitrogen substituent, and the next, diphenylamines the synthesis of these precursors is also not dealt with in detail here. Finally, a variety of approaches utilizing precursor indoles have been described some of these have been used only once, whereas others have been used often enough that they can be described as general. 

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