3- Bromo-2-iodoindole

The lithiation of 3-haloindoles represents an excellent method for the preparation of other 2,3-dihaloindoles. For example, treatment of 4 with LDA followed by quenching with CNBr affords 2,3-dibromoindole 7 in good yield [13], and quenching with iodine furnishes 3-bromo-2-iodoindole 8 [14],... 

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. 

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. 

An excellent synthesis of 5-bromo- (18) and 5-iodoindole (19) involves protecting the indole double bond as sulfonate 16, acetylation to 17, and halogenation [27]. Indoline itself undergoes bromination at C-4 and C-7 [28]. 

Martin prepared 5-trimethylstannylindole and effected coupling with bromobenzene to give 5-phenylindole [125], In a search for new cAMP phosphodiesterase inhibitors, Pearce prepared the furylindole 190 from 5-bromoindole and 5-ferr-butoxy-2-trimethylstannylfuran [196a], Benhida and co-workers explored Stille couplings of 6-bromo- and 6-iodoindole, and methyl 6-iodoindol-2-ylacetate with a variety of heteroarylstannanes and vinylstannanes [196b]. 

Somei and co-workers made extensive use of the Heck reaction with haloindoles in their synthetic approaches to ergot and other alkaloids [26, 40, 41, 240-249]. Thus, 4-bromo-l-carbomethoxyindole (69%) [26], 7-iodoindole (91%) (but not 7-iodoindoline or l-acetyl-7-iodoindoline) [40, 41], and l-acetyl-5-iodoindoline (96%) [41] underwent coupling with methyl acrylate under standard conditions (PdlOAc /PhsP/EtjN/DMF/100 °C) to give the corresponding (E)-indolylacrylates in the yields indicated. The Heck coupling of methyl acrylate with thallated indoles and indolines is productive in some cases [41, 241, 246]. For example, reaction of (3-formylindol-4-yl)thallium bis-trifluoroacetate (186) affords acrylate 219 in excellent yield [241], Similarly, this one-pot thallation-palladation operation from 3-formylindole and methyl vinyl ketone was used to synthesize 4-(3-formylindol-4-yl)-3-buten-2-one (86% yield). 

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. 

Reduction of the 7-iodoaminochromes70 with zinc and dilute acid was usually accompanied by virtually complete elimination of the iodine atom,109,155 except in the case of 7-iodonoradrenochrome (42), where, although the main product was 5,6-dihydroxyindole (29), traces of 5,6-dihydroxy-7-iodoindole (56) were also detected.156 Only partial debromination was observed when 7-bromoadrenochrome (57) was reduced with this system 7-bromo-5,6-dihydroxy-.V-methylindole (58) and 5,6-dihydroxy-iV-methylindole (28) were both obtained in significant quantities.155... 

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>. 

Lithiation of indole followed by application of CC13CC13, BrCCl2CCl2Br or ICH2CH2I results in the formation of 2-chloro-, 2-bromo- and 2-iodoindole, respectively917. 

Likewise, quenching the 2-lithro species derived from 6 with CNBr gives 2-bromo-3-iodo-l-(phenylsulfonyl)indole in 80% yield. Lithiation of A-(phenylsulfonyl)indole (3) with LDA followed by quenching with CNBr or benzenesulfonyl chloride gives the corresponding 2-bromo and 2-chloro derivatives in 82 and 93% yields, respectively [15]. Similar lithiation methods have been used to prepare 2-iodo-l-methylindole [16] and l-Boc-2-iodoindole, the latter of which can be converted to 2-iodotryptamine, and its... 

Direct 2-bromination of 3-substituted indoles can be carried out using N-bromosuccinimide in the absence of radical initiators. 2-Bromo- and 2-iodoindoles can be prepared very efficiently via a-lithiation (section 17.6.1) 2-haloindoles are also available from the reaction of oxindoles with phosphoryl halides. Bromination of methyl indole-3-carboxylate gives a mixture of 5- and 6-bromo derivatives. ... 

Bromo- and -iodoindoles, and the similarly reactive 2- and 3-triflates, " undergo palladium-catalysed couplings as normal aryl halides. Since 2- and 3-haloindoles are unstable it is expedient to employ their A -acyl derivatives. Halogen and triflate on the benzene ring of indoles take part unexceptionally in coupling reactions. 

When an organometallic derivative of indole is required for a coupling reaction, boronic acids are to be preferredalthough 2-zinc and 2-stannyl derivatives can be used. The palladium-catalysed coupling of 6-bromo or 6-iodoindoles with allyl and heteroaryltin compounds does not require masking of the indole iV-hydrogen. ... 

Despite the merit of pioneering the biomimetic approach to 5,6-dihydroxyindole synthesis, some of these papers contained incorrect structural conclusions that were highlighted in revisions by subsequent workers. Thus, for example, Heacock and co-workers (63JA1825) provided unambiguous proof that in iodo- and bromo-aminochromes the halogen occupies the 7- and not the 2-position, as previously believed. Independent total syntheses of 5,6-dimethoxy-7-iodoindole and of... 

Bromo and -iodoindoles can be prepared very efficiently via a-lithiation (section 17.6.1) 2-haloindoles are also available from the reaction of oxindoles with phosphorus oxyhalides. ... 

Scheme 6, equation 2) [12], The key step in Clive s sequence is the Hoftnann rearrangement of amide 17 to amine 18, followed by oxidation to quinone 19 with phenyliodme(ni) bis(triacetate). In like fashion, 4-bromo-5-hydroxyindole, 5-hydroxy-4-iodoindole, and 5-hydroxy-4-iodo-3-methylindole were prepared in this study. Nishiyama and coworkers adopted an electrochemical oxidation of diaryl amides to carbazoles (equation 3 and 21-22) [13]. 

Additional halogenation of 78 and 81 exhibits interesting results [28]. Bromination (1.3-mol eq.) of the former in AcOH provides methyl 6-bromo-5-iodoindole-3-carboxylate (82, 56%) and the corresponding carboxylic add (83, 18%). On the other hand, bromination of the latter gives complex mixtures of products under various reaction conditions. Relatively clean reaction takes place with Br2 (1.3-mol eq.) in AcOH at 100 °C providing methyl 6-bromo- (84, 17%), methyl 2-bromo-5-iodo-l-methoxyindole-3-carboxylates (85, 33%), 5-iodo-l-methoxyindole-3-carboxylic acid (86, 7%),... 

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