4-Chloroindoles

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. 

Indole and its derivatives in organic solvents (hydrocarbons, CH2C12, CHCI3, and CCI4) and aqueous sodium hypochlorite yield 1-chloroindoles 5, 1,3-dichloroindoles 6, and 3-H-3-chloroindole 7 [75JCS(CC)842 78 JOC2639 81JOC2054] (Fig 1). 

Acetamido-2-(7-chloroindol-3-ylmethyl)propanedioic acid dimethyl ester[6]... 

Nitroindole (ARf 40—45), 5-chloroindole (jiRf 60 — 65) and indole QiRf 70—75) yielded orange-yellow chromatogram zones on a pale yellow background. If the chromatogram was exposed to ammonia vapor for 15 s the color was intensified. The detection limits were 10 ng substance per chromatogram zone. 

Fig. 1 Reflectance scan of a chromatogram track with 80 ng substance per chromatogram zone 5-nitroindole (1), 5-chloroindole (2) and indole (3).

Nucleophilic processes that generate chloroindoles are largely confined to the displacements of oxy functions and Sandmeyer reactions of diazo-nium salts [81 H( 15)547]. A low yield of 2-chloroindole was obtained by a reaction sequence that involved treatment of oxindole with phosphoryl chloride, and then treatment of the Vilsmeier salt with sodium bicarbonate [66JOC2627 86H(24)2879]. It is, however, much better to prepare this compound from 2-lithioindole (92JOC2495). With phosphoryl chloride and dimethylformamide ethyl l-hydroxyindole-2-carboxylate failed to give the expected 3-formyl derivative. Instead there was a 50% yield of the 3-chloro derivative (84CPB3678). Diazonium salts have been used as precursors in... 

Preparation of bromoindoles by replacement of metallic substituents have included oxidation of indolylmagnesium bromide by p-nitrobenzoic acid to give 3-bromoindole (67BSF1294), thallation procedures (illustrated in Scheme 18 also applied to the synthesis of chloroindoles) [85H(23)3113 86H(24)3065 87CPB3146, 87H(26)2817 89H(29)1163], and the use of lithium derivatives. The thallation reactions provide access particularly to 4- and 7-bromoindoles. Quenching the protected 2-lithium derivative of indole with 1,2-dibromotetrachloroethane gave an 87% yield of 2-bromoindole (92JOC2495). 

When TCS 14 is added slowly to a mixture of indole or 1-methylindole in DMSO and MeCN at 0°C the sulfonium salts 1295 a and 1295b are isolated in 87% in 71% yield, respectively [76]. If however, TCS 14 reacts for 30 min at 0°C with DMSO in MeCN before addition of indole the sulfonium salt 1295 a is isolated in 37% yield only, with 35% 3-chloroindole 1296a . The authors assume that the initially formed intermediate 789 gives the sulfonium salt 1295, whereas on... 

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

Jensen JB, H Egsgaard, H van Onckelen, BU Jochknsen (1995) Catabolism of indole-3-acetic acid and 4- and 5-chloroindole-3-acetic acid in Bradyrhizobium japonicum. J Bacterial 111 5762-5766. 

An alternative route to an intermediate similar to 139 has been reported by Molina and coworkers [94]. Indole 143 (Fig. 40) was prepared in several steps starting from 3-acetyl-2-chloroindole, the nitrogen at C-2 being introduced... 

Erickson extended these reactions to useful preparations of both 3-chloroindole and several 2,3-dihaloindoles, many of which occur naturally [5], When the C-3 position is already substituted, halogenation usually occurs at C-2. A summary of these halogenations is shown below. Erickson was able to improve Piers synthesis of 2 to a yield of 82%. Interestingly, the action of sulfuryl chloride on 3-iodoindole gives the ipso product 3-chloroindole in 84% yield. 

The notoriously unstable 2-chloroindole was first synthesized in pure form by Powers [6], and this procedure was later extended to the preparation of 2-bromoindole by Erickson [5], The method involves reaction of oxindole with either P0C13 or POBr3 but yields are very low in both cases (26% for 2-chloroindole and 15% for 2-bromoindole). Powers also synthesized the more stable l-benzyl-2-chloroindole from JV-benzyloxyindole and POCI3, but discontinued all work in this area after developing a severe skin rash from these haloindoles. This toxicity is consistent with the role of natural halogenated indoles in chemical defense by marine organisms. 

Rearrangements of TV-chloro compounds in heterocyclic systems have been studied. TV-Chloroindole 51 gives62 the 3-chloro isomer 52. With pyrrole (53) there are two... 

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). 

In the same year, Hibino et al. reported a total synthesis of furostifoline (224) employing a new type of electrocyclic reaction (636). This cyclization proceeds through a 2-alkenyl-3-allenylindole intermediate, which is derived from 2-(fur-3-yl)-3-propargyUndole 1128. Compound 1128 was prepared starting from 2-chloroindole-3-carbaldehyde (891), furan-3-boronic acid (1124), and ethynylmagnesium bromide. 

In the following year, this method was also applied to the total synthesis of tjipanazole FI (371) (784). For this synthesis, the required bisindole 1444 was obtained starting from 5-chloroindole (1440) in three steps and 47% overall yield. Acylation of 1440 with oxalyl chloride led to the glyoxylic acid chloride 1441. Transmetalation of indolylmagnesium bromide with zinc chloride, followed by addition of the acid chloride, provided the ot-diketone 1443. Exhaustive reduction of 1443 with lithium aluminum hydride (LiAlFl4) afforded the corresponding bisindolylethane 1444. Executing a similar reaction sequence as shown for the synthesis of tjipanazole F2 (372) (see Scheme 5.243), the chloroindoline (+ )-1445 was transformed to tjipanazole FI (371) in two steps and 50% overall yield (784) (Scheme 5.244). 

The palladium based catalyst systems were also effective in the construction of carbon-nitrogen bonds on benzannulated five membered heterocycles. The 4-chloroindole derivative shown in 6.78. was coupled with piperazine in excellent yield, using a ferrocene based ligand.109 The analogous 5-bromo-benzimidazole derivative gave similar results (6.79.),110... 

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