Indole 7-bromo-, ring synthesis

Hegedus also described an efficient synthesis of 4-bromoindoIe (10) and 4-bromo-l-(4-toluenesulfonyl)indole (11) starting from 2-amino-6-nitrotoluene (9) [20]. The synthesis is lengthy but yields are good, and the method involves the Hegedus indole ring synthesis discussed later in this chapter. 

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... 

The cyclization of A-allyl-o-haloaniJines was adapted to the sohd phase for both indoles [309, 310] and oxindoles [311]. For example, as illustrated below (310), a library of l-acyl-3-alkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [309]. Zhang and Maryanoff used the Rink amide resin to prepare iV-benzylindole-3-acetamides and related indoles via Heck cyclization [310], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-A-acryloylanilines [311]. This latter cyclization route to oxindoles is presented later in this section. Caddick has described Heck indole ring syntheses from 2-chloroanilines using Pd/imidazolium salts [312], and Anslyn uses the Heck cyclization of 299 to 300 as a fluorescence sensor [313]. 

In synthesis of eletriptan (Relpax), Pfizer s triptan for the treatment of migraine, Macor again used the Mori—Ban indole synthesis as the key operation to assemble the indole ring. Jeffrey s conditions were once again employed to transform the o-bromo-A allylaniline into the indole core. 

Li and Tu have described an innovative three-component domino reaction for the synthesis of multifunctionalized tetracyclic indeno[l,2-h]indole derivatives (Scheme 6.30) [59]. Ninhydrin 205 was used to test the allyUc esterification, but the desired product 208 was not observed during this process. Indeed, a novel polysubstituted tetracyclic indeno[l,2-fc]indole derivative 207 was obtained. Li and Tu tested then the best conditions and found out that the reaction proceeds nicely in acetic anhydride under microwave conditions in 20-32min with 63-87% yield (Scheme 6.30a). Electron-withdrawing substituents like fluoro, chloro, and bromo in the para-position of the benzene ring as well as electron-donating substituents (Me, OMe) are well tolerated in this reaction. Bulky residues do not cause any problems. 

Zembower and co-workers explored the double Heek reaetion in one-pot and completed the synthesis of DG-041 1, EPj receptor antagonist [18]. A practically reliable catalytic system Pd(OAc)2/(o-tolyl)3 afifeeted both the transformations, intramolecular Heck reaction of bromo intermediate 38 to form indole ring, as well as intermolecular Heck coupling of resulting indole intermediate with acrylic acid 39 to give 40, en route to 41 (Seheme 9.10). 

The most studied approaches to ring closure reactions is the S j l substitution of aromatic substrates that have an appropriate substituent in a position ortho to the leaving group. An important example of this approach is the synthesis of substituted indoles by the photoinduced substitution reaction of o-haloanilines (bromo, iodo) with carbanions from ketones, followed by spontaneous ring closure in the reaction media ... 

Such a reversible blocking of the 2-position by sulfenylation was of particular interest in the synthesis of bromo-derivatives of indolyl-3-propionic acid. Specific bromination or nitration of the benzene ring of an indole is normally difficult to achieve, since the pyrrole ring also will react with electrophilic reagents. As an example, 5-bromoindole-3-propionic acid has been prepared using this reversible protection, that is by bromination of the 2-sulfenylated compound and removal of the arylthio group by the two consecutive reactions with NBS and NaBKi (727). 

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