Indole substitution patterns

In contrast, Cozzi and Umani-Ronchi found the (salen)Cr-Cl complex 2 to be very effective for the desymmetrization of meso-slilbene oxide with use of substituted indoles as nucleophiles (Scheme 7.25) [49]. The reaction is high-yielding, highly enantioselective, and takes place exclusively at sp2-hybridized C3, independently of the indole substitution pattern at positions 1 and 2. The successful use of N-alkyl substrates (Scheme 7.25, entries 2 and 4) suggests that nucleophile activation does not occur in this reaction, in stark contrast with the highly enantioselective cooperative bimetallic mechanism of the (salen)Cr-Cl-catalyzed asymmetric azidolysis reaction (Scheme 7.5). However, no kinetic studies on this reaction were reported. 

Figure 9 Indole Substitution Patterns Found in Aldrich Catalog...

Meanwell NA, Wallace OB, Fang H et al (2009) Inhibitors of HIV-1 attachment. Part 2 an initial survey of indole substitution patterns. Bioorg Med Chem Lett 19 1977-1981... 

Aroylindoles bind to the colchicine site of p-tubulin, however, and in contrast to colchicine (1), vincristine (2a), nocodazole (13) or taxol (3), they showed no significant influence on the GTPase activity up to 10 pM [48,49]. In addition, angiogenesis in the chick embryo chorioallantoic membrane (CAM) assay was inhibited by D-64131 and analogue. Since 2-aroylindoles are easy to synthesise (Scheme 2), the role of the indole substitution pattern was studied in more detail. 

Boron trichloride, usually in conjunction with an additional Lewis acid, effects o-chloroacetylation of anilines. The resulting products are converted to indoles by reduction with NaBH4.[l], The strength of the Lewis acid required depends upon the substitution pattern on the ring. With ER substituents no additional... 

Full -polarization in diradicals can give rise to zwitterionic products. First examples were studied in detail by Carpenter and coworker who investigated solvent effects on rates and product distribution in Myers-Saito cyclizations.64 Polar solvents and substitution patterns that stabilize either positive or negative charges (or both) favor the zwitterionic products. For example, the presence of a dimethylamino group leads to stabilization of cations and isolation of pyrrolo-quinolines, rather than pyrido-indoles from eneyne-carbodiimides, as reported by Wang and coworkers (Scheme 14).65... 

Syntheses of category Ilac can properly be called the most important category of indole synthesis. Fundamentally, the reason for this is the use of aniline or its derivatives as starting materials. Besides the easy availability of many aniline derivatives, the aromatic starting material is monofunctional whereas many other annelation procedures require a specific ortho substitution pattern in the aromatic starting material. 

Higa, T., Ichiba, T., and Okuda, R. K., Marine indoles of novel substitution pattern from the acorn worm Glossobalanus sp. Experientia, 41, 1487, 1985. 

The Fischer method is the main way of making indoles, but it is not suitable for them all. We need now to study its applicability to various substitution patterns. If the carbonyl compound can enolize on one side only, as is the case with an aldehyde, then the obvious product is formed. 

The substitution pattern of the first example is particularly important as the neurotransmitter hi serotonin is an indole with a hydroxyl group in the 5-position, and many important drugs follow that pattern. Sumatriptan (marketed as Imigran), is an example that we can also use to show that substituted phenylhydrazines are made by reduction of diazonium salts (Chapter 23). The first stage of the synthesis is nitrosation of the aniline and reduction with SnCl2 and HC1 to give the salt of the phenylhydrazine. 

There are many other indole syntheses but we will give a brief mention to only one other and that is because it allows the synthesis of indoles with a different substitution pattern in the benzene ring. If you like names, you may call it the Reissert synthesis, and this is the basic reaction. 

We can contrast the types of indole made by the Fischer and by the Reissert syntheses by the different ideal positions for substituents. These are, of course, notthe only possible substitution patterns.. 

Indoles treated with dimethyl diazomalonate under catalysis by rhodium(II) acetate undergo GH and NH insertion reactions depending on the substitution pattern on the indole moiety (e.g., Scheme 84) <2002JOC6247>. 

New approaches to the indole nucleus are continuously developed, providing aceess to indoles which are difficult to prepare using the well established reactions, such as the Fischer indole synthesis. Nevertheless, this classic reaction is still often used for constructing more complex systems, as exemplified by the preparation of 2-(pyrimidin-4-yl)indoles <03CPB975>, or indolo[3,2-i)]carbazoles possessing new substitution patterns <03T1265>. 

Transition-metal catalyzed reactions are now common and attractive routes to exotic indoles with substitution patterns which are otherwise difficult to realize. Using an intramolecular Heck reaction, the precursors 94 were converted to a number of 3-aryl-3-alkenyl oxindoles 95 in good yield and with good ee. The requisite compounds 94 are available in three steps from IV-benzylbenzoxazolin-2-one using palladium-based chemistry <03JA6261>. 

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