Dihydroindole, from indole

For the preparation of 2,3-dihydroindoles (8) from indoles (7), two reduction methods are known. In the column Reduction Method in the table, the one indicated A represents use of EtsSiH in TFA (79JOC4809) and the other, indicated B, employs NaBHsCN in AcOH (77S859, 88JMC1746). Although both methods are applicable, the former is generally superior to the latter. In some cases, depending on the substrates structures, the reverse cases are also observed. Examples are the reactions marked B in the column. 

Whereas the dehydrogenation of pyrroles to indoles has been described sporadically in preceding chapters, the present chapter covers those examples from tetrahydroindoles, such as the often encountered 4-keto-4,5,6,7-tetrahydroindole. The dehydrogenation of indoUnes (2,3-dihydroindoles) to indoles is covered in a later chapter. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

Because of the previous inaccurate botanical determination of the Madagascan periwinkle, the alkaloids of this plant were formerly considered as Vinca alkaloids, an erroneous subclassification for alkaloids isolated from a plant belonging to the genus Catharanthus. It also should be noted that the alkaloids of C. roseus containing two different (most commonly indole and dihydroindole) alkaloid building blocks were, and sometimes still are, referred to as dimeric indole alkaloids. It is more accurate to use the term binary or bisindole alkaloids, since chemically these alkaloids are not dimers of two equal subunits, but rather comprised of two (bis) different alkaloid building blocks. 

Examination of the C-NMR spectra of roseadine (23) (Table XI) through comparison with vindoline (3) and leurosine (11) permitted the assignment of all carbons of the dihydroindole unit. The carbons of the indole nucleus were assigned by comparison with vinblastine (1), and the presence of three deshielded carbons, a methine carbon at 8 142.9 and two quaternary carbons at 8 133.2 and 169.2, were observed. The latter was assigned to the methoxycarbonyl carbon, which is shielded somewhat from its characteristic chemical shift of 8 174 1 ppm in the vinblastine series by attachment of an olefinic unit. The other two deshielded carbons at 8 133.2 and 142.9 could be assigned as C-18 and C-17, respec-... 

Vinblastine (4) and vincristine (5) are closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus roseus (L.) G. Don (formerly known as Vinca rosea L.), the Madagascar periwinkle. Both of these anticancer agents, known as vinca alkaloids in the medical literature, are specific binders of tubulin, leading to tubulin depolymerization and cell cycle arrest in the metaphase stage. 

A new method for the benzannulation of indole involving the thermal cyclization of 3-buta-l,3-dienylindoles (560 and 561) was described for the synthesis of 3-methoxycarbazole alkaloids 562 (538-540). Contrary to earlier benzannulation procedures, this method involves the ring closure of a 3-buta-l,3-dienylindole without the loss of the methoxy group at the 3-position of the carbazole nucleus. The 3-buta-l,3-dienylindole required for this method was obtained by Sakamoto s procedure (538,539) starting from l-acetyl-2-methoxy-l,2-dihydroindole-3-one by... 

Indolines are produced in good yield from 1-benzenesulfonylindoles by reduction with sodium cyanoborohydride in TFA at 0°C (Equation 5) (89TL6833). If acyl groups are present at C-2 or C-3 in the substrate, they are reduced to alkyl groups. Indole is also reduced to 2,3-dihydroindole by sodium cyanoborohydride and acetic acid or triethylamineborane and hydrochloric acid. An alternative method for preparing indolines involves treatment of indoles with formic acid (or a mixture of formic acid and ammonium formate) and a palladium catalyst (82S785). Reduction of the heterocyclic ring under acidic conditions probably involves initial 3-protonation followed by reaction with hydride ion. 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

N-Methyl- and N-phenyl-2-vinylpyrroles 20a,b react with DMAD at reflux temperature in chloroform to give, in moderate yields, the dihydroindoles 22 via a 1,3-H shift from the Diels-Alder intermediate 21 (55-75%) (80JOC4515). These adducts were readily converted into the corresponding indoles 23 with Dichlorodicyanoquinone (DDQ). 2-Vinyl-pyrrole failed to give [4 + 2]-cycloadducts with acetylenic esters (80JOC4515). Spectroscopic analysis of the product mixtures indicated the presence of polymeric compounds resulting from Michael addition reactions. 

Intermediate samarium enolates derived from ketones 1522 or 1525 could stereoselectively be trapped with allyl halides, leading to tricycles 1524 and 1526. The intramolecular alkylation by the chloroalkyl terminus of compound 1527 led to tetracyclic compound 1528 with satisfactory efficiency. These cascade reactions selectively generate three continuous stereogenic centers, including a quaternary carbon atom at the 3-position of the dihydroindole moiety, a structural motif of many indole alkaloids. 

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