Triethylbenzylammonium Chloride as a Useful and Efficient Catalyst for the Alkylation of Indole/substituted Indoles in Water: A Comparative Study between Conventional and Microwave Irradiation

A green and facile method for the alkylation of indole/substituted indole in water using a phase Transfer catalyst (Triethylbenzylammonium Chloride, TEBA) to synthesise bis‐indolyl methanes (BIMs) and Michael addition of indole to α,β‐unsaturated carbonyl compounds is reported. The substitution of indoles occurred exclusively at the 3‐position and products of N‐alkylation has not been observed. However, for 3‐substituted indoles, reactions were found to occur at the 2‐position. A comparative study between conventional heating and microwave irradiation has also been reported.     

Scope and mechanism of the Pd(II)-catalyzed arylation/carboalkoxylation of unactivated olefins with indoles

Treatment of 1-methyl-2-(4-pentenyl)indole (5) with a catalytic amount of [PdCl2(MeCN)2] (2; 5 mol %) and a stoichiometric amount of CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature for 30 min gives methyl (9-methyl-2,3,4,9-tetrahydro-4-carbazolyl)acetate (6), which was isolated in 83% yield. A number of 2- and 3-alkenyl indoles undergo a similar palladium-catalyzed cyclization/carboalkoxylation to give the corresponding polycyclic indole derivatives in moderate to excellent yields with excellent regio- and diastereoselectivity. Under similar conditions, vinyl arenes undergo intermolecular arylation/carboalkoxylation with indoles to give 3-(1-aryl-2-carbomethoxyethyl) indoles in moderate yield with high regioselectivity. Stereochemical analyses of the palladium-catalyzed cyclization/carboalkoxylation of both 2- and 3-alkenyl indoles are in agreement with mechanisms involving outer-sphere attack of the indole on a palladium-olefin complex followed by alpha-migratory insertion of CO and methanolysis of the resulting acyl palladium intermediate. CuCl2 functions as the terminal oxidant in this palladium-catalyzed cyclization/carboalkoxylation of alkenyl indoles and also significantly increases the rate of reaction of 2 with the alkenyl indole to form the corresponding acyl palladium complex. Spectroscopic studies are in agreement with the intermediacy of a heterobimetallic Pd/Cu complex as the active catalyst in this reaction.     

Reactions of indoles with nitrogen dioxide and nitrous acid in an aprotic solvent

The reaction of 2-phenyl- and 1-methyl-2-phenylindole with nitrogen dioxide or with nitrous acid (NaNO2-CH3COOH) in benzene leads mainly to the formation of the isonitroso and 3-nitroso indole derivatives, respectively. When reacted with nitrous acid, 1-methyl-2-phenylindole gives also the corresponding azo-bis-indole in good yields. The reaction of indole with nitrogen dioxide leads to 2-(indol-3-yl)-3H-indol-3-one as the main product together with small amounts of 2-(indol-3-yl)-3H-indol-3-oxime; whereas the major product obtained when the same indole is reacted with nitrous acid is represented by 2-(indol-3-yl)-3H-indol-3-oxime. The reaction of 3-alkyl substituted indoles with nitrogen dioxide is rather complex and results in the formation of different nitro indoles, whereas nitrosation is observed when nitrous acid is used. Crystal structures of 2-(indol-3-yl)-3H-indol-3-one and of 4-nitro-N-acetyltryptamine have been determined by X-ray analysis.     

Bromination of 2, 3-dimethylindole

In bromination of indoles, the bromine atom will most probably enter at position 2 or 3. For example, indole and 2-methylindole [1] brominate at position 3, while some 3-substituted indoles [2] brominate at position 2. In the case of 2, 3-dimethylindole it was shown [3], that bromine does not enter the benzene ring, as would have been expected, but adds to the active 2, 3 (double) bond of the indole.     

Stereoselective synthesis of both enantiomers of N-aryl indoles with axially chiral N-C bonds

N-Aryl indoles with axially chiral N-C bonds were synthesized by stereoselective nucleophilic aromatic substitution reactions of planar chiral tricarbonyl(2,6-disubstituted-1-fluorobenzene)chromium complexes. The stereochemistry of the products is highly dependent on the position of the substituent in the indole. When indoles devoid of a substituent at the 2-position were used, N-aryl indole chromium complexes having anti orientation with respect to the tricarbonylchromium fragment were obtained diastereoselectively. In contrast, 2-substituted indoles gave the N-aryl indoles with syn orientation between the tricarbonylchromium fragment and the benzene ring of the indole. These results demonstrate that we have succeeded in synthesizing both enantiomers of N-aryl indoles utilizing an identical planar chiral arene chromium complex.     

Synthesis of fused indoles by sequential palladium-catalyzed Heck reaction and N-heteroannulation

A route to 3,4-fused indoles via two consecutive palladium-catalyzed reactions; an intramolecular Heck reaction followed by a reductive N-heteroannulation is described. Using this route, a number of indoles have been prepared having a variety of ring sizes anchored to the 3- and 4-position of the indole nucleus. Furthermore, a number of functional groups, both carbon and heteroatom substituents can be introduced in (and on) the additional ring without any detrimental effects on the two reactions.     

Introduction of the pyrazolidine ring into the pyrrole ring of indole

The reaction of indoles with 1-acyl-5-hydroxypyrazolidines under heterogeneous catalysis conditions leads, depending on the structure of indole, to 2- and/or 3-(1-acyl-5-pyrazolidinyl)indoles. Thus, the formation of 2-pyrazolidinylindoles is the results of an unco-substitution at the 3-position of the indole, followed by migration of the pyrazolidine ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1207–1213, September, 1990.     

Synthetic applications of 3‐(cyanoacetyl)indoles and related compounds

Various synthetic applications of 3‐(cyanoacetyl)indoles, as well as syntheses of some related indoles, have been investigated. Diethyl 2‐(1H‐indol‐3‐yl)‐2‐oxoethylphosphonate and a methyl derivative thereof have been prepared in one step from indole. Moreover, it was demonstrated that 3‐(cyanoacetyl)indoles are useful starting materials for the preparation of for example 3‐(1H‐indol‐3‐yl)‐3‐oxopropanamides, 3‐heteroarylindoles or 3‐heteroaroylindoles.     

Regioselective Rh-catalyzed direct carbonylation of indoles to synthesize indole-3-carboxylates

Rh-catalyzed C-H carbonylation of indoles under 1 atm of CO has been achieved. Various substituted indoles and indole with free N-H could be carboxylated with linear- and/or cyclic-alcohol to give the desired indole-3-carboxylates with up to 92% yield. A mechanism involving Rh(III) initiated C-H metallation is proposed.     

Synthesis of pyrazole‐fused azepino[5,4,3‐cd]indoles

The synthesis of some new pyrazolo[3′,4′:6,7]azepino[5,4,3‐cd] indoles (10a‐c) was achieved via regios‐elective cyclization of the respective 3‐(4‐acylaminopyrazol‐5‐yl)indoles (9a‐c) under Bischler‐Napieralski reaction conditions. The latter compounds were obtained by acylation of the corresponding 3‐(4‐aminopyra‐zol‐5‐yl)indoles (8a,b) which, in turn, were prepared by reduction of the 3‐(4‐nitropyrazol‐5‐yl)indoles precursors (7a,b) . The latter synthons were accessible from the reaction of indolylzinc chlorides (5a,b) with 5‐chloro‐1,3‐dimethyl‐4‐nitropyrazole. Ms and nmr spectral data of 10a‐c are in agreement with the assigned azepino‐indole structure as determined for 10a by X‐ray crystal measurements which demonstrate that the azepine ring is almost completely planar with the indole and pyrazole rings.     

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

An unprecedented tandem N‐alkylation–ionic aza‐Cope (or Claisen) rearrangement–hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N‐alkylation and subsequent microwave‐irradiated ionic aza‐Cope rearrangement–hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2‐reverse quaternary‐centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza‐Cope rearrangement reaction proceeds highly regioselectively to give the quaternary‐centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2‐reverse prenylated indoles, such as indolines, indole‐fused sultams and lactams, and the natural product bruceolline D.     

Synthesis and properties of 1,2-dihydropyridazino[4,5-b]indole II

The possibility of the synthesis of substituted 1,2-dihydropyridazino[4,5-b]indoles by the reaction of 1-methyl-2-carbomethoxy-3-(α-halobenzyl)indole or 1-methyl-2-carbomethoxy-3-(α-acetoxybenzyl)indole with hydrazines was demonstrated. The oxidation, reduction, and acylation reactions of the resulting 1,2-dihydropyridazino[4,5-b]indoles were studied.     

Asymmetric Friedel-crafts reaction of indoles with imines by an organic catalyst

In this communication, we report an asymmetric Friedel-Crafts reaction of indoles with imines catalyzed by a bifunctional cinchona alkaloid catalyst. This is the first efficient organocatalytic asymmetric Friedel-Crafts reaction of indoles with imines. This reaction is operationally simple and, unprecedentedly, affords high enantioselectivity for a wide range of indoles and both aryl and alkyl imines. This establishes a direct, convergent, and versatile approach to optically active 3-indolyl methanamines, a structural motif embedded in numerous indole alkaloids and synthetic indole derivatives.     

Platinum-catalyzed multistep reactions of indoles with alkynyl alcohols

PtCl2 effectively catalyzes the multistep reaction of N-methyl indole (1 a) with pent-3-yn-1-ol (2 a) in THF at room temperature for 2 h to give indole derivative 3 a, which contains a five-membered cyclic ether group at C3 in 93% yield. Under similar reaction conditions, various substituted N-methyl indoles 1 b-h and indole (1 i) reacted efficiently with 2 a to afford the corresponding indole derivatives 3 b-h and 3 i in 48-91 and 72% yields. The results showed that N-methyl indoles with electron-donating substituents were more reactive affording higher product yields than those with electron-withdrawing groups. Likewise, various substituted but-3-yn-1-ols 2 b-e and other longer chain alkynyl alcohols 2 f-i also underwent a cyclization-addition reaction with N-methyl indole (1 a) to provide the corresponding cyclization-addition products 3 j-m and 3 a, 3 j, and 3 n-o in good to excellent yields. The present platinum-catalyzed cyclization-addition reaction can be further extended into N-methyl pyrrole. Mechanistically, the catalytic reaction proceeds by an intramolecular hydroalkoxylation of alkynyl alcohol to afford cyclic enol ether followed by the addition of the C--H bond of indole to the unsaturated moiety of cyclic enol ether providing the final product. Experimental evidence to support this proposed mechanism is provided.     

Facile synthesis of azocino[4,3-b]indoles by ring-closing metathesis

The azocino[4,3-b]indole system, tricyclic substructure of the indole alkaloids apparicine and ervaticine, is efficiently assembled by ring-closing metathesis of 2-allyl-3-(allylaminomethyl)indoles. The metathesis sites are introduced into the indole nucleus by reductive amination of a 3-formyl derivative with allylamine, followed by α-lithiation with subsequent electrophilic trapping with acrolein.     

Photophysics and photocatalytic behavior of composite CdS-purine nanoparticles in the presence of certain indoles

The photophysics of purine-capped Q-CdS has been examined in the presence of certain indoles. The addition of indole does not modify electronic spectrum of purine-capped Q-CdS but it forms a fluorescing charge-transfer intermediate with illuminated CdS, which has an emissive peak at 495 nm. The intensity and the lifetime of this intermediate are enhanced initially with an increase in concentration of indole. In the presence of other indoles, the fluorescence is simply quenched in a dynamic process without forming any fluorescing intermediate. In contrast, emissive CT intermediate is not formed in the presence of indole or any of its derivatives with adenine-capped Q-CdS. In all the cases the quenching of fluorescence, monitored by steady state and time-resolved methods, follows the Stern-Volmer relationship and takes place with a bimolecular rate constant of approximately 10(10) dm(3)mol(-1)s(-1). Purine-capped Q-CdS sensitizes the reactions of the investigated indole(s)-O2 couple much more efficiently than adenine-capped Q-CdS. The differences in quenching of fluorescence and reactivity of holes between purine-capped Q-CdS and adenine-capped Q-CdS are explained by the difference in the binding of indole to the particle. In the case of purine-capped Q-CdS, specific channels for the binding of the solutes are created through the H-bond with the surface-capped purine.     

PMA-SiO2–Mediated MCR in PEG-400: A Greener aza-Friedel–Crafts Reaction Leading to 3-Arylmethyl/Diarylmethyl Indoles

A greener approach for the synthesis of 3-arylmethyl/diarylmethyl indoles has been achieved via a PMA-SiO₂-mediated three-component reaction (the aza-Friedel–Crafts reaction) involving indoles, aldehydes, and N,N-disubstituted anilines in PEG-400. A variety of indole derivatives were prepared by using this operationally simple and straightforward methodology in acceptable yields.     

Synthesis of indoles via 6pi-electrocyclic ring closures of trienecarbamates

A new method for the preparation of indoles from readily available alpha-haloenones and alpha-(trialkylstannyl)enecarbamates is described. Following a Stille coupling, trienecarbamate 2 is electronically activated to undergo a facile 6pi-electrocyclic ring closure and subsequent oxidation to afford protected aniline 4. Upon deprotection and reductive amination, acid 5 underwent clean cyclization to N-acetylindole 6 (Ac2O, NEt3, 130 degrees C). This method has been used to construct a variety of substituted indoles that are not easily prepared by conventional indole annelation methods.     

Spectrophotometric determination of indoles using a modification of the ehrlich colour reaction

A sensitive spectrophotometric method for the determination of indole (1 μg/ml) in aqueous solution is described. It is also applicable to certain 3-substituted indoles. The method employs p-dimethylaminobenzaldehyde in aqueous trifluoracetic acid. With indoles this reagent gives stable colours which are more intense than those obtained in the conventional Ehrlich reaction. Factors affecting fading of the indole colour are discussed.     

Pathways of Electrochemical Oxidation of Indolic Compounds

The electrochemical behaviour of indole and a group of indole‐containing compounds with a substituent at the C3 position, indol‐3‐acetamide (IAM), tryptamine, gramine, indole acetic acid (IAA), indole propionic acid (IPA), indole butyric acid (IBA) and tryptophan, was investigated at a glassy carbon electrode, in order to determine their oxidation pathways. Indole undergoes one irreversible pH dependent oxidation, whereas the oxidation process of indole derivatives was more complex, a two step, the oxidation at C2 position on the pyrrole ring followed by the hydroxylation at the C7 position of the benzene moiety of indoles, irreversible pH dependent oxidation.