4- Iodoindoles

Synthesis of camptothecin (163) is another example[133]. The iboga alkaloid analog 164 has been synthesized smoothly by the intramolecular coupling of iodoindole and unsaturated ester to form an eight-membered ring. Af-Methyl protection of the indole is important for a smooth reaction[134]. An efficient construction of the multifunctionalized skeleton 165 of congeners of FR900482 has been achieved[135]. 

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). 

Nitrophenyl esters of thymidine are substrates for staphylococcal nuclease and ribonucleotide 5 -(5-iodoindol-3-ol) (3) and 5 -(4-methyl-coumarin-7-ol) (4) esters have been used for the histochemical demon-... 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

OH-indoles from substituted phenylethylamines TL 723(1970) 4-Alkylindoles from 4-Br or iodoindoles BER 104,2027(1971) Indoles from cyclohexanones and allylamines C.R. Acad. Sci. Paris 272,1509(1971)... 

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. 

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],... 

Conventional aryldiazonium salt chemistry on 4-aminoindole provides 4-iodo-l-(4-toluenesulfonyl)indole (13), 4-iodoindole (14), and l-(fm-butyldimethylsilyl)-4-iodoindole (15) in excellent yields as shown [25, 26],... 

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]. 

Widdowson expanded his hexacarbonylchromium chemistry to the synthesis and lithiation of Cr(CO)3-Af-TIPS indole (29), leading to 4-iodoindole 30 after oxidative decomplexation [37]. Stannylation at C-4 could also be achieved using this method (62% yield), and comparable chemistry with 3-methoxymethylindole leading to C-4 substitution was described. 

Another general approach to benzene-ring haloindoles involves thallation chemistry. Hollins and co-workers demonstrated that C-4 thallation occurs readily in a series of 3-acylindoles 31, affording 4-iodoindoles 32 following treatment of the thallated intermediates with KI [38]. 

Somei improved this methodology by quenching the appropriate thallated intermediate with 12/CuI/DMF to give 4-iodoindole-3-carboxaldehyde in 94% yield [39], and he extended this method to achieve efficient syntheses of C-7 haloindoles [40, 41], For example, 7-iodoindole (33) was prepared in good overall yield from A-acetylindoline as illustrated. Thallation at C-5 is a minor (5%) pathway. 

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). 

Gilchrist examined the cyclization of Af-alkenyl-2-iodoindoles with palladium [268, 269], For example, reaction of A-pentenylindole 244 under Heck conditions affords a mixture of 245 and 246 in very good yield. In the absence of TIOAc, 246 is the major product. Further exposure of 245 to Pd(OAc)2 gives 246. Reaction of l-(4-butenyl)-2-iodoindole under similar conditions affords the pyrrolo[l,2-a]indole ring system in modest yield (35%). 

Herbert and McNeil have shown that the appropriate 2-iodoindole can be carbonylated in the presence of primary and secondary amines to afford the corresponding 2-indolecarboxamides in 33-97% yield. Further application of this protocol leads to amide 319, which is a CCK-A antagonist (Lintitript) [420]. 

Fukuyama employed a vinyltin derivative in the carbonylation of 3-carbomethoxymethyl-2-iodoindole to afford 320 [176]. Buchwald effected the carbonylation of 4-iodoindole 321 to give lactam 322 [136], and a similar carbonylation reaction on 4-iodoindole malonate 125 gives ketone 323 in 68% yield. 

Although examples are sparse, a Pd-catalyzed carbon-sulfur bond formation leading to 379 was the penultimate reaction in a synthesis of ( )-chuangxinmycin [470, 194], Earlier, Widdowson described the thiolation of 3-acetyl-4-iodoindole (Me02CCH2SsnMe3/Pd(Ph3P)4/83%) [471]. 

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... 

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