Indole 7-bromo

Rudisill and Stille developed a two-step procedure in which 2-bromo-or 2-trifluoromethanesulfonyloxyacetanilides were coupled with tri-n-butyl-stannylacetylenes in the presence of Pd(PPh3)4.[l], Cyclization was then effected with PdCl2(CH3CN)2. The conditions are compatible with a variety of carbocyclic substituents so the procedure can provide 2-substituted indoles with carbocyclic substituents. The reported yield ranges from 40% to 97% for the coupling and from 40% to 82% for cyclization. 

A -(2 2-Diethoxyethyl)anilines are potential precursors of 2,3-unsubstituted indoles. A fair yield of 1-methylindole was obtained by cyclization of N-inethyl-M-(2,2-diethoxyethyl)aniline with BFj, but the procedure failed for indole itself[2], Nordlander and co-workers alkylated anilines with bromo-acetaldehyde diethyl acetal and then converted the products to N-trifliioro-acetyl derivatives[3]. These could be cyclized to l-(trifluoroacetyl)indoles in a mixture of trifluoroacetic acid and trifluoroacetic anhydride. Sundberg and... 

Phenylsulfonyl)indol-2-ylzinc chloride 2-Bromo-4-methylpyridine, Pd(PPh3)2Cl2 92 [5]... 

A mixture of l-(r-Boc)indol-2-yl-tri- -butylstannanc (1.2 mmol) and 4-bromo-benzonitrile (1.0 mmol) and Pd(PPh3)2C , (0.02 mmol) in dry dioxane (5 ml) was heated at I00°C overnight under nitrogen. The reaction mixture was cooled, diluted with EtOAc and stirred for 15 min with 15% aq. KF. The precipitate was removed by filtration and washed with EtOAc. The EtOAc layer was separated, washed with brine, dried (Na2S04) and concentrated. The residue was purified by chromatography on silica. The yield was 66%. 

There are also palladium-catalysed procedures for allylation. Ethyl 3-bromo-l-(4-methylphenylsulfonyl)indole-2-carboxylate is allylated at C3 upon reaction with allyl acetate and hexabutylditin[27], Ihe reaction presumably Involves a ir-allyl-Pd intermediate formed from the allyl acetate, oxidative addition, transmetallation and cross coupling. 

Bromo-l-(4-methylsulfonyl)indole Methyl a-(t-butoxycarbonylamino)acrylate. 87 [8]... 

C Vinyl stannane coupling 9 3-Bromo-l-(methanesulfonyl)indole Pd(OAc)2, chloranil Z-(2-Etho,xy vinyl)tri-n-butylstannane, Pd(PPh3)2Cl2 83 [9]... 

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]. 

Heck type vinylation of 4-bromo-l-(4-methylphenylsulfonyl)-indole proceeds in good yield with such alkenes as methyl acrylate, styrene and N-vinylphthalimide using Pd(OAc)2 (5 mol%) and tri-o-tolylphosphine as the... 

The Suzuki coupling of arylboronic acids and aryl halides has proven to be a useful method for preparing C-aryl indoles. The indole can be used either as the halide component or as the boronic acid. 6-Bromo and 7-bromoindolc were coupled with arylboronic acids using Pd(PPh3)4[5]. No protection of the indole NH was necessary. 4-Thallated indoles couple with aryl and vinyl boronic acides in the presence of Pd(OAc)j[6]. Stille coupling between an aryl stannane and a haloindole is another option (Entry 5, Table 14.3). 

A mixture of 4-bromo-l-(4-methylphenylsulfonyl)indole (88 mg, 0.25 mmol), methyl a-acetamidoacrylate (91 mg, 0.64 mmol), PdCl2(PPh3)2 (16 mg, 0.023 mmol) and NaOAc (82 mg, 0.98 mmol) in EtjN (0.8 ml) and DMF (0.4 ml) was heated to 120°C in a sealed tube for 2 h. The tube was opened and the contents diluted with EtOAc and filtered through Celite. The EtOAc was washed successively with 10% HCl, sat. NaHC03 and brine and then dried (MgS04). The residue was purified by elution through silica gel with 10 1 benzene-EtOAc to give the product as a yellow solid (93 mg, 90%). 

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. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

Substituted indoles can be prepared from o-bromo or o-iodoanilines by paHadium-cataly2ed cycli2ation of AJ-aHyl derivatives (31). 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Indole-2-carboxylic acid, 5-bromo-l-hydroxy-tautomerism, 4, 197-198 Indolecarboxylic acid chloride synthesis, 4, 288... 

Zenitz obtained the analogous compounds 237 and 238 by the action of the corresponding a-cyano-w-bromo-w-alkanes on 2-methylindolyl magnesium bromide in ether. Eiter and Svierak prepared a-(3-indolyl)propionitrile (239) by the action of a-bromopropionitrile on indole magnesium iodide in anisole. ... 

The oxidation of indole magnesium bromide and its 2- and 3-methyl derivatives at room temperature with p-nitroperbenzoic acid, in the absence of light and air, results in the formation of 3-bromoindole (370), 3-bromo-2-methylindole (371), and 2-bromo-3-methylindole (372), respectively. ... 

Under conditions more similar to those of the Reimer-Tiemann reaction 3-bromopyridine was obtained from pyrrole and bromo-form. Treatment of pyrrole with chloroform and aqueous alkali gave pyrrole-2-aldehyde curiously, the formation of 3-chloropyridine under these conditions does not appear to have been reported, in spite of being frequently quoted. However, indole gave both indole-3-aldehyde and 3-chloroquinoline under these conditions [Eq. (10)]. 

Bromination of the diphenyl indole derivative 316 with bromine in DMF or trimethylammonium bromide afforded the 7-bromo derivative 317. Reaction with allyl bromide or its derivatives gave A-allyl derivatives 318 that upon cyclization with palladium acetate gave 7,9-dimethoxy-l,2-diphenylpyrrolo[3,2,l-// ]quinoline derivatives 319 (92T7601) (Scheme 57). 

Perhydropyrido[l,2-c]pyrimidine was N-arylated with 6-bromo-l-(2-propyl)indole in the presence of DBU, NaO/-Bu, (/-Bu)3P, and Pd(OAc)2 in boiling xylene (01MIP6). 

Soderberg and coworkers have developed a palladium-phosphine-catalyzed reductive iV-het-eroannuladon of 2-nitrostyrenes forming indoles in good yields For example, reaction of 6-bromo-2-nitrostyrene with carbon monoxide in the presence of a catalytic amount of palladium diacetate (6 mol% and triphenylphosphine 124 mol% in acetonitrile at 30 gives 4-bromoindole in 86% yield fEq 10 62 Several functional groups, such as esters, ethers, bromides, tnflates, and additional nitro groups, have been shown to be compatible with the reaction conditions... 

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). 

When 1-methyl-, 1,2- and 1,3-dimethyl-indoles were oxidized on a platinum electrode in methanolic ammonium bromide solution, in addition to the oxidation products, products of nuclear bromination at the 3-and 5-positions were observed. 1,2- Dimethylindole (20) gave 3-bromo-1,2-dimethylindole (81CCC3278) [bromine in chloroform gave the same product (85CHE786)]. In acidic conditions the amidinium cation formed from 20 was brominated in the 5-position (Scheme 14). Acylated 2-aminoindoles reacted similarly in neutral media to give 3-bromo derivatives and when protonated to give 5-bromo products. Bromine in chloroform transformed l-methyl-2-dimethylaminoindole (21) into the 3-bromo derivative (85CHE782) (Scheme 15). 

Bromination of 4//-furo[3,2-b]indole (50) occurred at the 2-position and was assisted by prior N-benzylation with the 4-benzoyl compound a 61% yield of the 2-bromo derivative was obtained. Thus, a-attack in the furan moiety predominates (78JHC123). When the pyrazolofuran (51) was treated with one molar equivalent of bromine, a mixture of the 2-bromo... 

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

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