Indoles chlorination

As with the pyrroles, N-chloroamides have been widely employed in indole chlorination [66JOC2627 80H( 14)867 81JOC2054]. Chloroindolen-ines may be isolated under controlled conditions [80H( 14)867 81JOC2054], 2-Phenyl-, l-methyl-2-phenyl-and 3-methyl-2-phenyl-indoles were converted by 1-chloroisatin (NCI) into the 3-chloro derivatives... 

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. 

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. 

The structure of ( )-169 is determined to have a ( )-3a,3a -bispyrrolo[2,3-(j] indole skeleton by carrying out X-ray single crystallographic analysis of its derivative 252 (99H1237). Compound 252 is obtained from ( )-169 by the following sequence of reactions (1) alkaline hydrolysis of ( )-169 to 249 (88%), (2) conversion of 249 to 251 (71%) by treatment with NaH and chloroacetyl chloride, (3) substitution of chlorine on the chloroacetyl group for acetate 252 (93%) by the reaction with NaOAc. 

At high copper(II) chloride indole ratios the pyrrole ring of 2-methylindole was chlorinated in yields approaching 92%. This reaction is believed to involve radical cations of indoles formed in an electron-transfer process. At low copper(ll) chloride indole ratios dimers were formed [86JCS(P 1)2305]. 

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],... 

Standing at 0°C Me2SCl2 1277 is formed, which chlorinates the indoles to 3-chloroindole 1296 [76] (Scheme 8.30). 

Chlorination with N-chlorosuccinimide at the activated indole 2-position gives the corresponding chloro... 

The pyrido[3, 4 4,5]furo[3,2-A]indole 24 can be prepared by Curtius rearrangement of 3-[5-(2-nitrophenyl)-2-furyl]-propenoic azide 25, followed by reduction of the nitrophenyl functionality of the product 26, chlorination of the tetracyclic product (PCI5), then reduction (Zn/AcOH) to give the parent compound 24 <1987CCC192> (Scheme 7). 

Chlorination of yohimbine (74) at the (3 position of the indole moiety with tert-butyl hypochlorite and treatment of the resulting chloride (539) with base in... 

Early syntheses of haloindoles involved direct reactions of indoles with chlorine, bromine, or iodine. In some cases, this approach was reasonably successful, but the instability of the resulting 3-haloindoles made product isolation and further chemistry difficult. For example, although attempted preparations of 3-chloro-, 3-bromo-, and 3-iodoindole were described in the early 1900 s [2], only recently have practical syntheses of these compounds and their N-protected derivatives become available. For example, 3-bromoindole (2) can be prepared in... 

The incorporation of an indole ring system often leads to an improvement in the light fastness. A suitable example is Cl Acid Blue 123 (6.177), which is derived from 4,4 -dichlorobenzophenone. Condensation with l-methyl-2-phenylindole in the presence of phosphorus oxychloride produces the triarylmethane ring system. Replacement of the chlorine atoms with p-phenetidine, followed by sulphonation, gives the dye. 

Cbemical/Physical. The aqueous chlorination of indole by hypochlorite/hypochlorous acid, chlorine dioxide, and chloramines produced oxindole, isatin, and possibly 3-chloroindole (Lin and Carlson, 1984). 

A related approach, developed almost simultaneously by Neuss and co-workers at Eli Lilly (25) and by Kutney et al. in Vancouver (26), utilized as coupling substrate the chloroindoline alkene 17, which, through equilibrium with the corresponding chloroindolenine, was readily prepared by chlorination of dihydrocleavamine 18. Condensation with the 17-deacetyl-16-carboxyhydrazide derivative of vindoline (19) gave a binary indole-indoline product (20) (Scheme 4). The undesired C-16 con-... 

The required chirally substituted indoloazepine 219 was prepared by reaction of (5)-l-(l-naphthyl)ethylamine with the methiodide of 4-piper-idone (223), followed by a Fischer indole reaction leading to the V-carboline 224 (Scheme 56). Chlorination and reaction with thallium dimethylmalonate, followed by decarbomethoxylation of the resulting in-... 

The chlorine atom in the 3-chloromethyl derivatives (87) (R = H and Pr") undergoes displacement with 3-(4-piperidyl)indoles in the presence of sodium bicarbonate giving (88) (Equation (13)) <88JAP(K)63301881>. 

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