Indole derivatives, benzene

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

It has been reported that the reaction of 2-(2-pyridyl)indole with benzene-sulphonyl chloride, under phase-transfer catalytic conditions, yields three products, which have been recorded as being the 3-, 4- and 6-benzenesulphonylindoles [56], or 3-chloro-l-benzenesulphonyl-2-(2-pyridyl)indole, as the major product, with the 1-benezenesulphonyl- and l,3-bis(benzenesulphonyl) derivatives, as the minor products [55]. In the light of the earlier discussion, the latter structural assignments appear to be more likely to be correct. 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

Indoline-2-thiones undergo desulphurization to the corresponding indole derivatives on irradiation in benzene,... 

Irradiation of the benzoazanorbornadiene (69) does not follow the conventional route for such photochemically active systems. The reaction, affords 1-chloronaphthalene, by deamination, as well as two thermally labile indole derivatives (70, 71) by the route shown in Scheme 5. These are formed by 1,3-nitrogen migrations within the azanorbornadiene. A detailed study of the rearrangement of the cyclopropanonaphthalene (72) has identified the products shown in Scheme 6. The reaction is solvent dependent and is more rapid in non polar solvents, such as benzene, than in polar solvents. The isomeric cyclopropanonaphthalene (73), a product of the rearrangement shown in Scheme 6, yields 1-cyanonaphthalene as the principal product on irradiation. ... 

In the case of indole derivatives, 3-phenylindole (64) was formed in the reaction of indole (63) with tetraphenylbismuthonium trifluoroacetate or tetraphenylbismuthonium p-toluenesulfonate in benzene under reflux under neutral conditions. But 3,3-diphenyl-i/f-indole (65) was obtained by treatment of the sodium salt of indole with tetraphenylbismuthonium p-toluenesulfonate. A related example is the 2-phenylation of -tetramethyl-p-phenylenediamine which was realized with triphenylbismuth... 

The oxidative coupling reactions of benzofuran and N-substituted indoles with benzene and derivatives have also been achieved using oxygen as an oxidant (Equation 11.37) [76]. This methodology for synthesizing heterocoupled biaryls... 

HMO calculations on cycl[3.2.2]azine (240)26-26 attributed substantial DE to the molecule and more recently Dewar and Trinajstic462 calculated a value for the Dewar resonance energy of 18.9 kcal mole-1. The aromaticity of 240 is reflected in the PMR spectrum101 which shows proton resonances in the region 7.20 to 7.86 ppm. Paudler and Shin463 examined an isomer of 240, viz., pyrrolo[3,2,1-/, i]indole (241), and from a comparison of the benzene-induced shifts of the proton resonances in both 241 and 7-methylindole suggested that there is no loss of aromaticity in 241 relative to the indole derivative. A further comparison of the proton chemical shifts in 241 and its dihydro derivative 242 led the authors to suggest that the former is the more aromatic. 

Aromatic substances are oxidized to hydroxyderivatives and dihydroxy-derivatives. Benzene (1) is converted through an instable epoxidic form (2) to phenol (3) which is further oxidized to form pyrocatechol (4) or hydro-quinone (5). The muconic acid (6) is the terminal oxidation degree, being formed by opening the benzene ring. In this way, not only monocyclic but also polycyclic hydrocarbons are oxidized, such as quinoline, indol and coumarins. Some substances are even oxidized to water and carbon dioxide... 

There are many synthetic examples involving intramolecular Diels-Alder reactions. In the Grieco and Kaufman synthesis of eburnamonine, indole derivative 227 was treated with 0.5 equivalents of LiC104 in refluxing benzene, and an 81% yield of 228 was obtained. Interestingly, simply heating 227 on Florisil in... 

Prenylations and ferf-prenylations of indole most frequently occur at positions Nl, C2 and C3 (Sects. 2-4), with fewer indole alkaloids prenylated in the benzene section (Sect. 5). There are no indole derivatives with prenylated or ferf-prenylated bridge head positions C3a or C7a. Regioselective introduction of prenyl or tert-prenyl groups at the indole ring can be challenging, depending on the position. Certain cases are simple, such as N-prenylation, others are still not reported, such as... 

In the 1980s Muratake and Natsume (202) in a number of reports presented a new, interesting approach to the synthesis of substituted indole derivatives that focused on their use as intermediates in the preparation of a variety of clavine alkaloids and mycotoxins. The method elaborated by the authors consisted of constructing the specifically substituted benzene portion of the indole nucleus, with 1-methoxycarbonylpyrrole being the starting material. The functionalized 4-alkylindole thus obtained was transformed to a tricyclic indole derivative which appeared to be a common intermediate for the synthesis of several ergot alkaloids, as exemplified by the synthesis of ( )-dihydrosetoclavine (203-205) (Scheme 42). Recently, the application of this method was extended by the authors (206) to the syntheses of a series of marine alkaloids, the hapalindoles. Most of these alkaloids have a tetracyclic framework made up of 3,4-substituted tryptamine and two isoprene units. 

Another strategy for annelation of pyrroles and indoles involves cycloaddition reactions. Because the heteroaromatic rings have substantial aromatic stabilization, the C2—C3 bond is not very reactive toward cycloaddition and there are only a few examples of the heterocycles acting as dienophiles. The carbocyclic ring of indole, like benzene, is unreactive toward cycloaddition. However, vinylpyrroles and indoles are quite reactive and react as electron-rich dienes because of the electron-donating nature of the ring. Other cycloaddition reactions involve the 2,3-dimethylene derivatives of pyrrole and indole, the so-called quinodimethanes, which are very reactive dienes. These intermediates, and more stable synthetic equivalents, are useful in cycloadditions with a variety of dienophiles. 27/-Isoindole, which itself can be thought of as a quinodimethane, is a very reactive diene. 

Finally, the reaction of C-benzoyl-W-phenylnitrone (185) with indole derivatives in benzene at room temperature for several days gives, among other products, small amounts of the isoxazolines 187. These isoxazolines were presumably produced from the oxidation of the intermediate cycloadduct indo-lines 186 [83] (Scheme 52). 

Heterocycles were synthesized by arylation of vinylogous amides, followed by Heck reaction. Monoarylation of the vinylogous amide 54 with 1, 2-dibromo-benzene afforded 55. The indole derivative 56 was obtained by intramolecular... 

Most AFC alkylation reactions are focused on relatively reactive furans, pyrroles, and indoles, whereas benzene derivatives are much less explored. The Wang group reported the organocatalytic asymmetric synthesis of chromane and dihydrobenzopyrane derivatives 121 from readily available 1-naphthols and a,p-unsaturated aldehydes by the AFC alkylation/cyclization cascade reaction (Scheme 6.49). The process appeared to have a broad substrate... 

Isatins are indole derivatives with broad use in synthetic dye production and are intermediates in the synthesis of other heterocyclic molecules/ They also possess a variety of biological activities/ Aksenov et al. reported a one-pot synthesis of isatins using ethyl nitroacetate with substituted benzenes such as anisole (159) in polyphosphoric acid fScheme 5.38)/ The process for isatin formation likely includes a hybrid between the Nef and Vilsmeier reactions of anisole 159 and nitro ester 160 to form the oxime intermediate 161, which then undergoes a Beckmann rearrangement to give the anilide 162. Subsequent intramolecular acylation yields isatin 163. 

Arcyriarubin-A has been synthesised starting from indolylmagne-sium bromide and 3,4-dibromo-iV-methylmaleimide (Scheme 80) 623). By heating these compounds together in benzene a mixture of the indole derivatives (514) and (515) was formed which could be conveniently separated by chromatography. Hydrolysis of (515) with aqueous sodium hydroxide followed by heating with ammonium acetate afforded... 

Li and Tu have described an innovative three-component domino reaction for the synthesis of multifunctionalized tetracyclic indeno[l,2-h]indole derivatives (Scheme 6.30) [59]. Ninhydrin 205 was used to test the allyUc esterification, but the desired product 208 was not observed during this process. Indeed, a novel polysubstituted tetracyclic indeno[l,2-fc]indole derivative 207 was obtained. Li and Tu tested then the best conditions and found out that the reaction proceeds nicely in acetic anhydride under microwave conditions in 20-32min with 63-87% yield (Scheme 6.30a). Electron-withdrawing substituents like fluoro, chloro, and bromo in the para-position of the benzene ring as well as electron-donating substituents (Me, OMe) are well tolerated in this reaction. Bulky residues do not cause any problems. 

Methoxy, chloro, ester, and methyl substitution were tolerated at the 5- and 6-positions of the indole moiety. Additionally, other arenes such as benzene, o-xylene, p-xylene, and 1,2-dichlorobenzene could serve as coupling partners to access the C2-arylated indole derivative in moderate to excellent 5uelds and with good selectivities (eq 30). 

R. Jain, K. Sharma, D. Kumar, A greener, facile and scalable synthesis of indole derivatives in water reactions of indole-2,3-diones with 1,2-difunctionalized benzene. Tetrahedron Lett. 53 (2012) 6236-6240. 

Indole derivatives can be chromatographed on paper in various solvent systems we choose them according to the substituents present on the indole nucleus if they are hydrophilic (—COOH), ammoniacal solvent mixtures, as, for example, isopropanol —cone, ammonia—water (8 1 1) (135), or acid mixtures, such as chloroform—acetic acid (100 2) or benzene— propionic acid—water are suitable for derivatives of more lipophilic character the systems light petroleum—methanol (100 4) or formamide/he-xane can be employed (136). 

A novel [3-I-3]-benzannulation process occurs in the coupling of alkynylcarbene complexes (e.g., 160, Scheme 17.27) and heteroaromatic aldehyde-derived imines (e.g., 201) [83]. Furan, benzofuran, and N-substituted indole derivatives led to benzannulation products, heteroaromatic-fused benzenes (e.g., 204). The mechanism proposed involves electrophilic aromatic substitution at the 3-position of the heterocyclic ring, resulting in the complex 202, followed by a simultaneous 1,2-shift of the metal and nucleophilic addition to the iminium salt. 

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