Indole bromination

Halo-, and even more so, 2-halo-indoles are unstable and mnst be utilised as soon as they are prepared A -acyl- or A -sulfonyl-haloindoles are much more stable. A variety of methods are available for the p-halogenation of indoles bromine or iodine (the latter with potassium hydroxide) in dimethylformamide give very high yields pyridinium tribromide works efficiently iodination and chlorination tend to... 

Reactions with electrophilic reagents take place with substitution at C-3 or by addition at the pyridine nitrogen. All the aza-indoles are much more stable to acid than indole (cf. 20.1.1.9), no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards other electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Maniuch and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quatemisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. Acylation at C-3 in all four systems can be carried out at room temperature in the presence of excess aluminium chloride. ... 

One type of o-aminobenzyl anion synthon is a mixed Cu/Zn reagent which can be prepared from o-toluidines by / i.s-trimethylsilylation on nitrogen, benzylic bromination and reaction with Zn and CuCN[l]. Reaction of these reagents with acyl halides gives 2-substituted indoles. 

Ha.logena.tlon, 3-Chloroindole can be obtained by chlorination with either hypochlorite ion or with sulfuryl chloride. In the former case the reaction proceeds through a 1-chloroindole intermediate (13). 3-Chloroindole [16863-96-0] is quite unstable to acidic aqueous solution, in which it is hydroly2ed to oxindole. 3-Bromoindole [1484-27-1] has been obtained from indole using pytidinium tribromide as the source of electrophilic bromine. Indole reacts with iodine to give 3-iodoindole [26340-47-6]. Both the 3-bromo and 3-iodo compounds are susceptible to hydrolysis in acid but are relatively stable in base. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

Most of the substitution reactions of di-, tetra, and hexa-hydro-carbolines and of their oxo derivatives are similar to those of the parent indole or indolenine derivatives. Nitration and bromination of harma-line (l-methyl-3,4-dihydro-j8-carbolme) are referred to in Section IV, A, 1. Sulfonation and azO COupling ° proceed as expected for indole derivatives. The preparation of chlorinated and iodinated derivatives of 6-nitroharmaline has been reported,but their structures have not been established. 

Vilsmeier-Haack and Friedel-Crafts reactions, bromination, debromination, debenzylation in indole series and their synthetic application 99YZ35. 

Bromination of the diphenyl indole derivative 316 with bromine in DMF or trimethylammonium bromide afforded the 7-bromo derivative 317. Reaction with allyl bromide or its derivatives gave A-allyl derivatives 318 that upon cyclization with palladium acetate gave 7,9-dimethoxy-l,2-diphenylpyrrolo[3,2,l-// ]quinoline derivatives 319 (92T7601) (Scheme 57). 

When 1-methyl-, 1,2- and 1,3-dimethyl-indoles were oxidized on a platinum electrode in methanolic ammonium bromide solution, in addition to the oxidation products, products of nuclear bromination at the 3-and 5-positions were observed. 1,2- Dimethylindole (20) gave 3-bromo-1,2-dimethylindole (81CCC3278) [bromine in chloroform gave the same product (85CHE786)]. In acidic conditions the amidinium cation formed from 20 was brominated in the 5-position (Scheme 14). Acylated 2-aminoindoles reacted similarly in neutral media to give 3-bromo derivatives and when protonated to give 5-bromo products. Bromine in chloroform transformed l-methyl-2-dimethylaminoindole (21) into the 3-bromo derivative (85CHE782) (Scheme 15). 

The use of mixtures of trimethylbromosilane and dimethyl sulfoxide to brominate indoles is more successful than analogous chlorinations since the bromine atom increases the rate of transformation of Me2S+OSiMe3 to Me2S+Br and shows a stronger electrophilic character than the chloro intermediate. Sulfonium products do not form in such reactions [89JCR(S)182],... 

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