3- indoles, preparation

A mild and effective method for obtaining N- acyl- and N- alkyl-pyrroles and -indoles is to carry out these reactions under phase-transfer conditions (80JOC3172). For example, A-benzenesulfonylpyrrole is best prepared from pyrrole under phase-transfer conditions rather than by intermediate generation of the potassium salt (81TL4901). In this case the softer nature of the tetraalkylammonium cation facilitates reaction on nitrogen. The thallium salts of indoles prepared by reaction with thallium(I) ethoxide, a benzene-soluble liquid. 

Table 1 Selected indoles prepared by the Hemetsberger-Knittel route...

The Fischer indole synthesis is commonly recognized as one of the most powerful and versatile tools for construction of indoles, as reflected by the amount of recent publications in which it has been used successfully. The usual approach involves initial preparation of a phenylhydrazone 323 from a suitable phenylhydrazine and an enolizable carbonyl compound, followed by an acid-induced cyclization to the target indole 324, featuring a [3,3]-sigmatropic rearrangement as the key step (Scheme 38). Some selected new examples of indoles prepared using standard Fischer conditions are collected in Table 2. 

Table 2 Selected examples of Indoles prepared using the Flsoher Indole synthesis...

Table 3 Examples of indoles prepared according to the Bartoli route...

The total synthesis of aspidophytine (1) commenced with the preparation of the key tryptamine building block 9, as shown in Scheme 3. Although we have already confronted a typical means of indole preparation in Woodward s total synthesis of strychnine, namely the Fischer indole synthesis, in this context an alternative approach based on reductive cyclization was employed instead to fashion this heterocycle. Starting from known intermediate 14, ... 

A collection of pharmacologically active indoles prepared via Fischer indolization is listed in Table 6 [240-268], along with their putative biological target and the disease(s) that are associated with that target. In several cases the compound shown is selected from a large collection of equally active compounds. 

Bailey and Liebeskind independently discovered the anionic cycUzation shown in Scheme 1 [1, 2] that leads to indoUnes and, by subsequent oxidation, to indoles. Both methods are virtually identical, involving bromine-lithium exchange followed by quenching of the aryllithium species with an electrophile (equations 1 and 4). The Af-allylindole can be deallylated with palladium (equation 2) [3], and the indohne is easily oxidized to the corresponding indole (equation 3). A selection of indoles prepared this way by Liebeskind and Zhang is shown (1-6) [2], The yields are overall for the two steps. These workers also employed chloranil (f-BuOMe, rt) to oxidize indohnes to indoles. An excellent review by Bailey and Mealy is available [4]. Bailey s related indoline synthesis via arynic cycUzation is presented in the later chapter on NucleophiUc CycUzation of Arynes (Chapter 65). 

The chemistry described by Saegusa, Kobayashi, and others (Sehemes 1 to 4 and Table 1) is reminiscent of the earlier work by Zeeh (Scheme 5) [16-18]. These Lewis acid-catalyzed reactions of isocyanides with ketones are shown in equation 3. The A/-/crt-butyl group in 37 is removable by boron trifluoride etherate. A suggested pathway is illusttated in equation 3 and is initiated by BE3 activation of the aryl ketone (38). Some indoles prepared by Zeeh are 39-41 [17]. The elegant free-radical cyclization of aryl isocyanides developed by Fukuyama is presented in Chapter 49. 

Scheme 3 Indoles Prepared by Iron/Acetic Acid in the Nenitzescu Indole Synthesis...

The Leimgruber-Batcho indole synthesis was quickly adopted by several groups for the synthesis of 2,3-unsubsti-tuted indoles. A tabulation of indoles prepared in this... 

Buchwald and his colleagues have made extensive use of the titanium reductive ring closure in an indolization as summarized in Scheme 8, equations 1 and 2 [76]. A small selection of indoles prepared using these methodologies is shown. 

A selection of additional indoles prepared by Fukuyama via the corresponding u-isocyanostyrene is shown in Scheme 2. 

---