Indole, 2-bromo-5-iodo

A variety of 3-substituted P- and y-carbolines have been synthesized from N-substituted 3-iodo-l//-indole-2-carbal-dehydes and 2-bromo(iodo)-l//-indole-3-carbaldehydes, respectively (Schemes 163 and 164) <2002JOC7048>. The coupling of these aldehydes with various terminal acetylenes with PdChlPPhala/CuI as the catalyst readily affords the corresponding alkynylindole carbaldehydes, which have subsequently been converted to the corresponding /-butyl-imines and cyclized to P- and y-carbolines either a copper-catalyzed or a thermal process. 

Scope and Limitations. Carbonyl Component. For practice purposes this reaction is limited to aromatic aldehydes, of which a wide variety has been studied, and to a,/3-unsaturated aliphatic aldehydes. The sub-stitutents on the ring of the aromatic aldehydes include alkyl, fluoro, chloro, bromo, iodo, hydroxyl, alkoxy, acyloxy, carbethoxy, nitro, and various combinations of two or more of these groups. Aldehydes of the naphthalene, pyrene, biphenyl, thiophene, furmi, pyrrole, indole, chro-mane, coumarane, and thiazole series also have been employed. 

The most studied approaches to ring closure reactions is the S j l substitution of aromatic substrates that have an appropriate substituent in a position ortho to the leaving group. An important example of this approach is the synthesis of substituted indoles by the photoinduced substitution reaction of o-haloanilines (bromo, iodo) with carbanions from ketones, followed by spontaneous ring closure in the reaction media ... 

Bromo-3-iodo-l-(4-methylphenylsulfonyl)indole (0.476 g, 1.00 mmol), methyl acrylate (0.108 g, 1.25 mmol), EtjN (0.127 g, 1.25 mmol) and Pd(OAc)2 (11 mg, 0.050 mmol) were mixed in a tube, purged with argon and the tube was sealed and heated to 100°C for 1 h. After cooling, it was opened and mixed with CH2CI2 (50 ml). The solution was washed with water and dried (Na SOJ. The residue was purified by chromatography on silica using 1 3 benzene-hexane for elution. The yield was 0.350 g (81%). 

Standard Heck conditions were used to introduce the dchydroalanine side-chain with 4-bromo-3-iodo-l-(4-methylphenylsulfonyl)indole[12]. Using 4-fluoro-3-iodo-l-(4-methylphenylsulfonyl)indole as the reactant, Merlic and Semmelhack found that addition of 2 eq, of LiCl or KCl improved yields in reactions carried out with 10% Pd/C as the catalyst[13]. The addition of the dehyroalanine side chain can also be done by stoichiometric Pd-mediated vinylation (see Section 11.2). A series of C-subslituled dehydro tryptophans was prepared in 40-60% yield by this method[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. 

Both 3-bromo- and 3-iodo-indoles have been selectively prepared by titrimetric addition to the heterocycle of the halogen dissolved in dimethylformamide. The mildly basic solvent is probably responsible for trapping the generated hydrogen halide (82S1096). 

A novel route to indoles and quinolines has been developed by sequential Wiltig and Heck reactions <96CC2253>. Thus, treatment of o-bromo- or iodo-lV-lrifluoroaceiylanilines (86) with a stabilized phosphorane affords the corresponding enamines 87 as a mixture of isomers. Cyclization to 88 is effected by heating with palladium acetate, tri phenyl phosphine, and bu.se. 

An entirely different approach to 3-haloindoles involves a mercuration/iodination sequence, which has been adopted by Hegedus to prepare 4-bromo-3-iodo-l-(4-toluenesulfonyl)indole for use in the synthesis of ergot alkaloids [20,21], We will discuss this chemistry later. 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Chloroindole has been prepared from indole and sulfuryl chloride (66JOC2627) and 3-bromo- and 3-iodo-indole have been obtained by direct halogenation in DMF (82S1096). 2-Methylindole reacts with sodium hypochlorite in carbon tetrachloride to give a 2 1 mixture of 1,3- and 3,3- dichloro derivatives (81JOC2054). 3-Substituted indoles are halogenated to yield 3-haloindolenium ions which react in a variety of ways, as illustrated by the reaction of 3-methylindole with NBS in aqueous acetic acid (Scheme 12). 

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>. 

Aniline, JV-alkyl-o-allyl-indole synthesis from, 4, 321 Aniline, N-allyl-indole synthesis from, 4, 326 Aniline, AT-allyl-o-bromo-indole synthesis from, 4, 327 Aniline, N-allyl-o-iodo-indole synthesis from, 4, 327 Aniline, o-bromo-in indole synthesis, 4, 340 Aniline, o-halo-cyclization, 4, 340 Aniline, m-nitro-in indole synthesis, 4, 338 Aniline black, 3, 197 Anilines... 

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... 

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