Indoles from aldehydes

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. 

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)]. 

The second method leads to the formation 3-alkyl- and 3-arylindoles from the reaction of indole with aldehydes in the presence of alkali metal tetra-carbonylhydridoferrate (Scheme 40).67 It is possible that this novel process may occur via reduction of intermediate 3-alkylidene- or 3-arylidene indolenines. 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

Substituted Indoles from Pyrrolyl Aldehydes J. Prakt. Chem. 315,295(1973)... 

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

TL1759) from indole, the aldehyde RCHO, and Meldrum s acid could arise from a nucleophilic attack of Meldrum s acid upon the 3-indolylcarbinol by a mechanism analogous to that outlined in Scheme 69. However, it is more probable that the aldehyde reacts initially with Meldrum s acid and that (294) results from a Michael-type addition of indole to the activated ethylene. 

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

An intramolecular cycloaddition reaction is also a vital feature of Oppolzer s synthesis (Scheme 5).336 Here the cycloaddition reaction occurs on an unsaturated nitrone ester (39) (not isolated). Again, the aldehyde derived from oxidation of the diol (40) gave entirely the ( )-olefin on reaction with crystalline a-methoxy-carbonylethylidenetriphenylphosphorane, which allowed the synthesis of (+)-chanoclavine I (34) to be completed in an overall yield of 14% from indole-4-aldehyde. In contrast, the Horner-Emmons reaction on the aldehyde from... 

Aldehyde oxidase purified from maize coleoptiles is a multicomponent enzyme that contains a molybdenum cofactor, nonheme iron, and flavin adenine dinucleotide (FAD) as prosthetic groups.111 When substrate specificity of the aldehyde oxidase was tested, good activity was detected with IAAld, indole-3-aldehyde, and benzaldehyde among others. The addition of NADP and NADPH did not change the activity. In contrast, in maize endosperm, tryptophan-dependent IAA biosynthesis was dependent on an NADP/NADPH redox system, which may mean that the two tissues of maize are utilizing different pathways or different redox systems for IAA biosynthesis.112... 

The common route to bis(indoyl)methanes is via condensation of indoles with aldehydes or ketones in the presence of either protic or Lewis acids. The reaction has been evaluated in tetrafluoroborate and hexafluorophosphate ionic liquids and of the metal salts tested best results were obtained with In(OTf)3 and FeCl3-6H20. Although In(OTf)3 is somewhat more active, its higher price makes the use of iron(III)chloride more attractive. Furthermore, whereas the activity of In(OTf)3 decreases quickly upon recycling, ionic liquid solutions of FeCl3 remain reasonably active for at least four runs.[62] It was found that in hydrophilic ionic liquids the reaction did not proceed at all, whereas fast conversion was observed with the [PF6] -anion, see Scheme 9.17. As water is produced in the course of the reaction it is possible that elimination of the water from the reaction medium helps to protect the catalyst, however, it cannot be excluded that at least some of the catalytic activity is due to the formation of HF. While the... 

One type of compound generated by pyrolysis of simple peptides consists of small molecules similar to those obtained from the pyrolysis of component amino acids such as hydrocarbons (aromatic hydrocarbons from peptides containing Phe orTyr), aldehydes, pyrrole, pyrroline, indole (from peptides containing TRP), some aliphatic amines, etc. 

Fischer indole synthesis Preparation of indoles from arylhydrazones of ketones and aldehydes in the presence of protic or Lewis acid catalyst. 172... 

Amines via condensations. Tryptophan derivatives are obtained by reaction of indoles with A-substituted aziridinecarboxylic esters at 0° or room temperature. Stoichiometric amount of Sc(OTf)3 is required. By SclOTfjj catalysis the Strecker-type synthesis from aldehydes, amines, and BujSnCN can be carried out either in organic solvents or in water. Pictet-Spengler reaction is directly accomplished using acetals. ... 

Indoles are an important class of fine chemicals derivatives find application as fragrance chemicals. The indole nucleus is present in many biologically active molecules including plant-growth regulators, proteins and pharmaceuticals. The selective synthesis of indole derivatives constitutes an important area of drug research. The well-known Fischer indole synthesis provides a versatile method for synthesizing substituted indoles from the arylhydrazones of aldehydes or ketones... 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

Quinazolin-2-one was obtained quantitatively by fusing 2-aminobenzaldehyde with urea (10 min at 150°C).76,91 Similarly, 2-amino-3-formylpyridine and urea (15 min at 160°C) gave an excellent yield of pyrido[2,3-d]pyrimidin-2-one (see 3).92 Finally, as an example from jt-excessive chemistry, 2-amino-indole-3-aldehyde was converted to its 2-benzyloxycarbonyl derivative, which benzylamine quantitatively converted to 3-benzyl-9f/-pyrimidino-[4,5- >]indol-2-one (87)93... 

It was noted above that the photolysis of indole and aldehydes in the solid state leads to diindolymethanes by a mechanism postulated to involve an oxetane intermediate (Scheme 14). The reaction also proceeds when aromatic aldehydes and indole or 2-methylindole are irradiated with UV light in acetonitrile solution (Scheme 28) [61]. Under these circumstances, it has been proposed that light-induced electron transfer from the indole to the aldehyde yields a ketyl radical anion and the indole radical cation. Proton transfers, coupling, and elimination of water can then yield an electrophilic alkylidene indolenine 65 which can react with indole thermally to give the observed product. 

---