2-Iodoindole

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. 

Iodine in the presence of morpholine converted 1-methoxyindole into the 3-iodo derivative in 27% yield (85CPB5147). When treated with diio-doacetylene, an indolylmagnesium halide gave 3-iodoindole in 83% yield (54CB1148). 

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... 

A vast improvement for the synthesis of both 3-bromo- and 3-iodoindole by using DMF as solvent was described by Bocchi and Palla, as summarized below [4], This appears to be the method of choice for the preparation of simple 3-bromo- and 3-iodoindoles. 

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. 

In comparison to 2-trialkylstannylindoles, the synthesis of 3-trialkylstannylindoles is more complicated since the halogen-metal exchange process usually leads to rapid isomerization to the corresponding 2-lithioindole species. In contrast, the Pd-catalyzed reaction of 3-iodoindole and... 

Interestingly, with only slight difference in the imidazole N-protection, an anomalous Stille reaction occurred for the stannane 43 [29]. When the protecting group of the 5-stannylimidazole was changed from methyl into 1-ethoxymethyl, the reaction between 3-iodoindole 44 and 1-ethoxymethyl-5-bromo-2-methylthioimidazole (46) gave not only the normal ipso product 47 but also the cine product 48. 

Treatment of 3-trimethylsilylethoxymethyl(SEM)-2(37f)-oxazolone 258 with ferf-BuLi at —78 °C, followed by the addition of tributyltin chloride gives the stannyloxazolones 259. Cross-coupling of 259 with 2-formyl-3-iodoindole in the presence of Pd(PPh3)4 catalyst affords a 1 1 mixture of isomeric 4- and 5-(3-indolyl)-2(3//)-oxazolones 260. These compounds can be further transformed into the tetracyclic carbazoles 262 (Fig. 5.63). ... 

A Pd-catalyzed alkoxycarbonylation of 2-chloropyridine 117 to ester 118 was reported in the synthesis of camptothecin analogs <97JOC6588>. Another Pd-catalyzed alkoxycarbonylation was the central feature in Hibino s total synthesis of oxopropaline G (121), a P-carboline isolated from Streptomyces sp G324 <98TL2341>. Triflate 119 was prepared from 2-foimyl-3-iodoindole in seven steps. The Pd-catalyzed alkoxycarbonylation of 119 provided the key intermediate, l-methoxycarbonyl-4-methylcarboline 120, which was then transformed to oxopropaline G (121) in four additional steps. 

The analogous transformation of 2-formyl-3-iodoindole derivatives and phenylacetylene gave /3-carbolincs in good yield (4.35.), The efficiency of the procedure was moderately influenced by the nature of indole s N-substituent.43... 

A substance described as ethyl 2,3-dihydro-5,6-dihydroxy-3-iodoindole-2-carboxylate (24), but which is probably the corresponding 7-iodo compound (25) (see Section IV, E), has been prepared by reduction of the ethyl ester of iododopachrome (26), and this is readily reoxidized in air to the corresponding aminochrome (shown spectroscopically).104... 

Palladium-catalyzed coupling reactions of the Heck type have in many instances involved indole and pyrrole derivatives. Although the mechanisms are complex, organopalladium species are implicated (84H(22)1493). Vinylation of A-substituted-3 -iodoindoles with amidoacrylate groups provides a useful functionalization of indoles (Scheme 81) (90JOM(39l)C23). Yields are improved in intramolecular reactions, e.g. (406 — 407) and (408 — 409) <92H(34)219,91CPB2830). 

In contrast with the relatively facile nucleophilic substitution reactions at the 2-position of the indole system, only 3-iodoindole has been reported to react with silver acetate in acetic acid to yield 3-acetoxyindole (59JOC117). This reaction is of added interest as 3-iodo-2-methylindole fails to react with moist silver oxide (72HC(25-2)127). It is also noteworthy that the activated halogen of ethyl 3-bromo-4-ethyl-2-formylpyrrole-5-carboxylate is not displaced during the silver oxide oxidation of the formyl group to the carboxylic acid (57AC(R)167>. 

A 3-lithioindole has been obtained by the reaction of l-benzenesulfonyl-3-iodoindole with f-butyllithium at -100 °C, but on allowing the reaction mixture to come to room temperature, it is found that the 3-lithio derivative has isomerized to give the thermodynamically more stable 2-lithioindole (82JOC757). The reaction of l-benzenesulfonyl-3-iodoindole with LDA yields l-benzenesulfonyl-3-iodo-2-lithioindole. 

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