Iodination of indoles

In common with a number of heterocyclic iodinations, kinetic effects are found in the iodination of indole and 2-methylindole [68AC(R)1435], When the substituent effects for the reaction are examined it is clear that any resonance effects from the fused benzene ring are only poorly relayed to the reactive 3-position, and the rates appear to be controlled by inductive effects. A 5-methyl group was more activating than 5-methoxy [69AC(R)799]. 

A review of methods of synthesis of aromatic iodo compounds has appeared offering considerable information of potential value to research chemists wishing to prepare iodoheterocycles (84RCR343). Iodination differs from chlorination and bromination in that a much less reactive electrophile (and a much larger one) is involved. The second step of the reaction is usually at least partially rate-determining. Isotope effects are noted in the iodination of indole [68AC(R) 1435], and the transition state resembles the Wheland intermediate more than in chlorination and bromination. 

The kinetics of iodination of indole and some of its derivatives in aqueous ethanol have been studied over a wide range of iodide ion concentration (4 x 10-4 to 10-1 M) and at different pH values (6.50-7.86).107-109 The observed second-order rate constants are inversely... 

Bromination and iodination of indoles in DMF at 25 °C result in a highly selective formation of 3-haloindoles in almost quantitative yield1051. This procedure is a considerable improvement in comparision to former methods where reagents such as pyridinium or dioxane perbromides1052 and 2,4,4,6-tetrabromocyclohexane-2,5-dienone1053 have been used. 

Sulfenylation of indoles can be carried out with sulfenyl halides[7], disulfides[7-9] or with A -methylthiomorpholine[10]. With disulfides the indoles are converted to lithium[8] or zinc[9] salts prior to sulfenylation. Thiophenols and iodine convert indoles to 3-(arylthio)indoles[l 1]. 

Coupling reactions of indole-3-acetic acid derivatives have also p ovided convenient routes to indolo[2,3-a]carbazoles (Scheme 5). An iodine-p-omoted coupling... 

Introduction of an iodine to C-2 of indole can be accomplished using lithium derivatives. Since direct iodination tends to give mixtures it is essential to activate the 2-position at the expense of the inherently more reactive 3-position. This has been done by lithiating 1-f-butoxycarbonylin-doles (25) and then converting them into iodo derivatives before deprotection (85JHC505) (Scheme 19). Alternatively carbon dioxide can be used... 

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... 

Negishi methodology can also be used to achieve the 3-acylation of indoles. Thus, Faul used this tactic to prepare a series of 3-acylindoles 83 from indole 82 [107], Indole 82 could also be iodinated cleanly at C-3 with iV-iodosuccinimide (78%). 

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

The Merck process group in Rahway has developed two syntheses of rizatriptan (4) utilizing palladium catalyzed indolization reactions (Schemes 19 and 20). Both routes start from the iodoaniline 51, which was prepared by reaction of 47 with iodine monochloride in the presence of CaCOa. " Palladium catalyzed coupling of iodoaniline 51 with bis-triethylsilyl protected butynol in the presence of NaaCOa provided a mixture of indoles 52a and 52b. This mixture was desilylated with aqueous HCl in MeOH to furnish the tryptophol 53 in 75% yield from 51. Protection of the alkyne prevented coupling at the terminal carbon of the alkyne and tnethylsilyl (TES) was found to be optimal because it offered the correct balance between reactivity (rate of coupling) and... 

JHC993). The analogous reaction of the diacetoxythallium derivative of 3-acetylindole provides the one example of electrophilic iodination of the benzenoid ring of indole (Scheme 21) (79JHC993). 

The iodination of cross-linked polystyrene has been achieved using iodine under strongly acidic reaction conditions [55] or in the presence of thallium(III) acetate [61], but this reaction does not proceed as smoothly as the bromination. More electron-rich arenes, such as thiophenes [45,62-64], furans [46], purines [65], indoles [66], or phenols [67,68] are readily halogenated, even in the presence of oxidant-labile linkers (Figure 6.2). Polystyrene-bound thiophenes have also been iodinated by lithiation with LDA followed by treatment with iodine [64],... 

A number of related reactions are worthy of mention. Benzanilide (334) is converted into phenanthridone (335) by irradiation in benzene in the presence of iodine.362 Cyclodehydrogenation is also observed in the anilides of indole-2-carboxylic acid and indole-3-carboxylic acid on irradiation in acetone.363 Irradiation of diphenyl-amine304 and certain of its JV-substituted derivatives365 yields the corresponding carbazole. The mechanism of this reaction differs from... 

A new iodine-catalysed, remarkably simple Michael reaction of indoles with enones, e.g. PhCH=CHCOR, has been developed.183 The Sml3-catalysed reaction of indoles with electron-deficient alkenes (e.g. enones) afforded the corresponding Michael adducts in high yields. As in the previous case, the substitution on the indole nucleus occurred exclusively at the 3-position and A-alkylation products have not been observed.184... 

There are no quantitative studies to permit direct comparison of the reactivity of indole in electrophilic substitution with that of pyrrole. However, the available data indicate that the reactivity at position 3 of indole does not differ very much from that of the 2-position of pyrrole. For instance, indole is reported to be 50 times more reactive than aniline in the iodination reaction.107... 

Amat di San Filippo and De Fabrizio109 studied the effects of several substituents in the benzene ring on the reactivity at C-3 of indole on iodination. The effects of a methyl group at positions 1 and 2 were also studied. The results are summarized in Table XXVII. There is no possibility of resonance interaction between a substituent in position 5 (or 6) and the reaction center in 3. Heteronuclear nonconjugative ... 

Fig. 15. Plot of log k/ko vs. oepi constants for the iodination of substituted indoles. Data from Amat di San Filippo and De Fabrizio.109...

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

In an elegant synthesis of indole derivatives, regioselective introduction of oxygen has been achieved by first introducing iodine into the aryl system followed by displacement with methoxide (equation 27)242,243. Also, aryl polyethers have been synthesized by reaction of bis-aryl chlorides with bis-phenols (equation 28)244. 

An interesting approach to the synthesis of indoles is the combination of directed orr/w-lithiation followed by an S l reaction324. Thus, the selective or o-lithiation of 2-fluoropyridine (262) by LDA followed by iodination afforded 2-fluoro-3-iodopyridine (263) in high yield (75%). Substitution of the 2-fluorine atom under S Ar conditions is a convenient synthesis of 2-substituted 3-iodopyridines (264) (equation 169), which can react with acetone or pinacolone enolate ions in liquid ammonia, followed by acidic treatment, to give the corresponding substituted 7-azaindoles (265) [R = H, R = Me (75%), R = t-Bu (78%) R = Me, R = f-Bu (70%), R = Me (95%)] (equation 170). 

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