Indoles ozonolysis

The final step can involve introduction of the amino group or of the carbonyl group. o-Nitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from o-aminophcnyl-acetonitriles by partial reduction of the cyano group. 

TV-Acyl indoles derived from amides have been employed for the conversion of lactones into protected hydroxyacids. Thus, (chloromethyl)alumi-num 2-(2-propenyl)anilide reacts (120) with 1,4- and 1,5-lactones, as for example per-O-terZ-butyldimethylsilyl-D-ribono-1,4-lactone (104), to afford hydroxyamides. After protection of the free hydroxyl group, these amides were converted by ozonolysis into TV-acyl indoles, 105, which were readily saponified to the acid 106. 

The procedure was proved to be general for the preparation of protected hydroxy acids from lactones (121). This apparently trivial process is often difficult to carry out, as the attempted derivatization of y or J-hydroxyacids frequently results in relactonization rather than hydroxyl protection. The method was applied to several aldonolactones to produce the corresponding intermediate hydroxyamides. Protection using [(2-trimethylsilyl)-ethoxy]methyl chloride, methoxymethyl chloride, ter/-butylchlorodimeth-ylsilane, or zm-butylchlorodiphenylsilane followed by ozonolysis gave the protected N-(y- or <5-hydroxyacyl)indole derivatives. Mild saponification gave indole and the acetal- or silyl-protected hydroxy acids. 

The quinoline 88 has been transformed into the intermediate 89, which was subsequently ring-opened by ozonolysis, followed by base-induced ring closure to the indole-2-carboxaldehyde 90 (Scheme 60) <2002TL5295>. Several useful 4-substituted indoles have also been prepared by ring-contraction of A-alkyl-5-aminoisoquinolinium salts with the system NaHS03/Na2S03 <2000JHC1293, CHEC-III(3.0340)333>. 

EtOH), were first isolated in 1872 and 1877, respectively (14). Quin-amine was observed to give indole color reactions (7, 15), and 2,3-dimethylindole was a result of zinc dust distillation of the alkaloid (15). With chromic acid (9), the quinuclidine carboxylic acid (III) was obtained, and with nitric acid 3,6,8-trinitro-4-hydroxyquinoline was isolated (15, 16). This quinoline is a consequence of fission of the indole and recyclization, with nitration preceding and following these steps [cf. ozonolysis of yohimbine to furnish a 2,3-disubstituted 4-hydroxy-quinoline (17)]. 

A novel procedure for the oxidative cleavage of indole carbon double bonds in the presence of H2O2 using plant cell cultures, as a catalytic system, led to benzazonine diones 297 (Scheme 54) <2004TL8061>. 177-Benzo[ ][l,4]diazonines 298 were obtained in a highly substituted form and in high yields by ozonolysis of 1,2,3,4-tctrahydro-9//-pyrido[3,4- indole derivatives 296 (X = NAc) <2000JME3518>. 

Hunig bases, polymeric = animated cbloro-methylated ethenylbenzene homopolymers deprotonation with of ketones, 11 or phosphonium salts, 32 removal of acids with, 32 Hybrid plasmids, 243-245 Hydration. See Alkenes or Alkynes Hydrazine hydrazinolysis with of esters, 239-240,331 of phthaloyl-protected amines, 162,163 reduction of ketones with, 97-98,109 Hydrazines, cyclic oxn., N3 extrusion, 35,331 Hydrazones WolfF-Kishner redn. of, 109 —, aryl- indole synth. with, 151-152, 296, 307 —, dialkyl-, lithiated alkylation, 12, 18, 25-26 enantioselective (SAMP-hydrozones), 25-26 ozonolysis of, 26... 

Diazepines.—Formation. There is a report on the formation of the C=N bond in l,4-benzodiazepin-2-ones and in l,2-dihydropyrazin-2-ones by the intramolecular reaction of aldehyde groups or keto-groups with iminophos-phoranes the process had earlier been described in the patent literature. 1,4-Benzodiazepin-2-ones have also been prepared from indoles by ozonolysis followed by reductive cyclization with hydrazine hydrate. A new simple syn-... 

An alternative route involves ozonolysis of 6-nitrosafrole followed by reductive conversion to an aldehyde which is converted into indole 18 by reduction, with or without prior conversion to a gfcm-diacetate (Scheme 9). Alternatively, 6-nitrosafrole can be reduced to the corresponding amine which is trifluoroacetylated, ozonized and allowed to cyclize by removal of the protecting group with diethylene triamine (86% yield of 18). This latter step is particularly clean, high yielding and easy to work up. 

Carbonyl groups can also be introduced by ozonolysis. This approach has been used to obtain 4-substituted indoles starting with 1,4-dihydronaphthalenes (Equation (7)) <76LA1475,85JA2943). 

The core skeleton of geissoschizine, an important biosynthetic precursor to numerous polycyclic indole scaffolds, was the target of a nickel-catalyzed alkylative coupling strategy. Cyclization precursor 13 was prepared by ozonolysis and double reductive amination of cyclopentene 12 (Scheme 8.13) [35]. Nickeldeprotection/oxidation sequence followed, and chromatography led to complete inversion of the C3 stereocenter. A Fisher indole synthesis followed to afford ( )-deformyl-isogeissoschizine, the core skeleton of geissoschizine. 

Ozonolyses of tetrahydro-lH-pyrido-[4,3-fe]-indoles resulted in the formation of a nine-membered keto-lactam, which could either be isolated or in situ cyclized to dihydropyrrolo[3,2-( ]quinolones, which can be derivatized by electrophilic aromatic substitution, selectively on the pyrrole moiety. In the ozonolysis reaction, alkyl cin-noline betaines were formed as side products, most likely via Cl side products. ... 

Another of the arylalanines, L-tryptophan, was used at the same laboratories [81] for the synthesis of novel benzazepines (56) as dual inhibitors of ACE and thromboxane synthase (Scheme 5.25). Ozonolysis of 7V-acetyl l-tryptophan to effect scission of the indole ring followed by 7V-protection gave the 4-keto acid (57) as a cyclization precursor. Downstream transformations included diastereoselective reduction of the ketone functionality and reductive alkylation of the amine substituent with ethyl 2-oxo-4-phenyl-butanoate. 

Tryptophan cleavage with NBS can be blocked by reaction of the tryptophan peptide or protein with 2-hydroxy-5-nitrobenzyl bromide the Koshland reagent (see Section III.4.) or by ozonolysis of tryptophan residues to formylkynurenine (313, 419). These modification reactions of the indole nucleus restrict NBS cleavage to tyrosyl and histidyl peptide bonds. 

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