A novel intramolecular Ugi 3CC for the synthesis of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides

An intramolecular Ugi reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid with aryl amines and isocyanides has been developed to produce a novel class of N-alkyl-3-oxo-2-aryl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-1-carboxamides in good yields. This is the first report on intramolecular Ugi three component reaction of 2-(2-formyl-1H-indol-1-yl)acetic acid, aryl amine, and isonitrile.     

New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

Synthesis of 1-{4a,6-dimethyl-4a,9a-dihydropyrano-[3,4-<Emphasis Type="Italic">b</Emphasis>]indol-9(1<Emphasis Type="Italic">H</Emphasis>)-yl}ethanone

Heating of the bromination product of 4-methyl-3,6-dihydro-2H-pyran with 4-toluidine or 2-bromo-4-methylamiline in triethylamine gave 4-methyl-N-(4-methylphenyl)- and N-(2-bromo-4-methylphenyl)-4-methyl-3,6-dihydro-2H-pyran-3-amines which were converted into the corresponding amides by reaction with bromo- or chloroacetyl chloride. 1-{4a,6-Dimethyl-4a,9a-dihydropyrano[3,4-b]indol-9(1H)-yl} ethanone was synthesized in good yield by heating N-(2-bromo-4-methylphenyl)-N-(4-methyl-3,6-dihydro-2Hpyran-3-yl)acetamide in boiling toluene in the presence of palladium(II) acetate, triphenylphosphine, copper(II) acetate, triethylamine, and potassium carbonate.     

Synthesis,structures, and photochromic properties of 3-[(<Emphasis Type="Italic">E</Emphasis>)-alk-1-enyl]-4-(1-alkyl-5-methoxy-2-methyl-1<Emphasis Type="Italic">H</Emphasis>-indol-3-yl)furan-2,5-diones

New hetarylethenes, viz., 3-[(E)-alk-1-enyl]-4-(1-alkyl-5-methoxy-2-methyl-1H-indol-3-yl)furan-2,5-diones, exhibiting photochromic properties in solution were synthesized. The molecular and crystal structure of 3-(5-methoxy-1,2-dimethyl-1H-indol-3-yl)-4-[(E)-prop-1-enyl]furan-2,5-dione was determined by X-ray diffraction. The initial and photoinduced forms of hetarylethenes are characterized by thermal stability. The open-ring isomers of furandiones exhibit fluorescence with quantum yields of up to 0.1.     

Synthesis and structure of new 6-substituted 5-methyl-5,6-dihydrocyclohepta[<Emphasis Type="Italic">b</Emphasis>]indole-9,10-dicarboxylic anhydrides

Reactions of (2-chloro-1-methyl-1H-indol-3-yl)-2-oxoacetyl chloride with alk-3-enoic acids gave the corresponding 6-substituted 5-methyl-5,6-dihydrocyclohepta[b]indole-9,10-dicarboxylic anhydrides which showed fluorescent properties.     

Thermische Lactonisierung von Estern γ-Brom-α, β-ungesättigter Carbonsäuren zu Δα-Butenoliden. Direkte γ-Bromierung von α, β-ungesättigten Säuren

By heating with iron powder at 120–150° some γ-bromo-α, β-unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ^7alpha;-butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ-bromocrotonate ( 1c ) and the corresponding acid ( 1d ) to Δ^α-butenolide ( 8a ), methyl γ-bromotiglate ( 3c ) and the corresponding acid ( 3d ) to α-methyl-Δ^α-butenolide ( 8b ), a mixture of methyl trans- and cis-γ-bromosenecioate ( 7c and 7e ) and a mixture of the corresponding acids ( 7d and 7f ) to β-methyl-Δ^α-butenolide ( 8c ). The procedure did not work with methyl trans-γ-bromo-Δ^α-pentenoate ( 5c ) nor with its acid ( 5d ). Most of the γ-bromo-α, β-unsaturated carboxylic esters ( 1c, 7c, 7e and 5c ) are available by direct N-bromosuccinimide bromination of the α, β-unsaturated esters 1a, 7a and 5a ; methyl γ-bromotiglate ( 3c ) is obtained from both methyl tiglate ( 3a ) and methyl angelate ( 4a ), but has to be separated from a structural isomer. The γ-bromo-α, β-unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β-unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine-carrying carbon anti to the carboxylic ester group; an exception is methyl γ-bromo-senecioate, for which the two isomers (cis, 7e , and trans, 7d ) have about the same stability. The N-bromosuccinimide bromination of the α,β-unsaturated carboxylic acids 1b , 3b , 4b , 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ-bromocrotonic acid ( 1 d ), γ-bromotiglic acid ( 3 d ), trans- and cis-γ-bromosenecioic acid ( 7d and 7f ) as well as trans-γ-bromo-Δ^α-pentenoic acid ( 5d ) have been prepared. Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond. α-Methyl-Δ^α-butenolide ( 8b ) was converted to 1-benzyl-( 9a ), 1-cyclohexyl-( 9b ), and 1-(4′-picoly1)-3-methyl-Δ^α-pyrrolin-2-one ( 9 c ) by heating at 180° with benzylamine, cyclohexylamine, and 4-picolylamine. The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.     

Synthesis and comparative study of reactivities of δ-lactone,estor group and oxazinone ring in coumarin derivatives towards carbon or nitrogen nucleophiles

Condensation of methyl 7-methylcoumarin-4-acetate ( 2 ) with primary amines and with anthranilic acid gave 7-methyl-2-oxo-N-aryl-2H-[1]-benzopyran-4-acetamide ( 4a—d ) and (7), respectively. Compound 7 underwent cyclization to give 2-(7-methyl-2-oxo-2H-[1]-benzopyran-4-yl)-methyl-4H-3,1-benzoxazin-4-one ( 3 ). The reaction of 3 with aromatic amines gave the corresponding quinazolone derivatives 5 which tautomerises to the thermodynamically more stable isomer 6 , whereas its reaction with Grignard reagents and aromatic aldehydes gave 8a, 8b , and 9a, 9b , respectively.     

Synthesis of 3-(aminooxoethyl)-6-methyl-1-(thiethan-3-yl)-pyrimidine-2,4-(1H,3H)-diones

A new approach to prepare 2-chloroacetamides has been developed, based on the reaction of chloroacetyl chloride with excess of secondary amines. Alkylation of 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione with the synthesized 2-chloroacetamides in the presence of potassium carbonate has afforded N ³-acetamido-substituted 6-methyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-diones.     

Synthesis of Nitrogen‐Containing Derivatives of (18α,19β)‐19‐Hydroxy‐2,3‐secooleanane‐2,3,28‐trioic Acid 28,19‐Lactone

The object of this study is the interaction of the cyclic anhydride 2 of (18α,19β)‐19‐hydroxy‐2,3‐secooleanane‐2,3,28‐trioic acid 28,19‐lactone ( 1 ) with primary and secondary amines. It was shown that the products of steric control (the corresponding 2‐amino‐2‐oxo‐3‐oic acids=2‐amides) were formed solely upon the opening of the anhydride cycle by secondary amines (Scheme 2), whereas the interaction with primary amines yielded a mixture of isomeric amides (Scheme 10). In the latter case, the solvent provided a noticeable effect on the reaction selectivity, which was demonstrated in the case of 4‐methoxybenzylamine. The interaction between the resulting 3‐amides and oxalyl chloride yielded the corresponding cyclic imides, whereas under these conditions, 2‐amides formed spiropyrrolidinetriones (Scheme 4).     

Reactions of <Emphasis Type="Italic">N</Emphasis>-and <Emphasis Type="Italic">C</Emphasis>-Alkenylanilines: VII. Synthesis of Indole Heterocycles from Products of Reaction between <Emphasis Type="Italic">N</Emphasis>-Mesyl-2-(1-alken-1-yl)anilines and Halogens

N-Mesyl-2-(1-methyl-1-butenyl)-6-methylaniline reacted with Br₂ to afford N-mesyl-2-(3-bromo-1-penten-2-yl)aniline that under treatment with NH₃ or amines underwent cyclization into N-mesyl-7-methyl-3-methylene-2-ethylindoline. The reaction of N-mesyl-2-(1-methyl-1-buten-1-yl)-4-methyl- and 2-(1-methyl-1-buten-1-yl)aniline with Br₂ gave rise to the corresponding N-mesyl-2-(2-bromo-1-methyl-1-buten-1-yl)anilines. Under the similar conditions N-tosyl-2-(1-cyclohexen-1-yl)aniline was converted into N-tosyl-2-(6-bromo-1-cyclohexen-1-yl)aniline that under treatment with NH₃ furnished N-tosyl-1,2,3,9a-tetrahydrocarbazole. The reaction of N-mesyl-1,2,3,9a-tetrahydrocarbazole with CuBr₂ in MeOH afforded N-mesyl-4-methoxy-1,2,3,4-tetrahydrocarbazole. N-Mesyl-6-methyl-2-(1-cyclopenten-1-yl)aniline in reaction with Br₂ in the presence of NaHCO₃ was oxidized into the corresponding cyclopentenone, and with NBS it gave N-mesyl-2-(2-bromo-1-cyclopenten-1-yl)aniline.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 730–737.Original Russian Text Copyright © 2005 by Gataullin, Sotnikov, Spirikhin, Abdrakhmanov.     

Synthesis and photochromic and fluorescence properties of 3-(1-benzyl-5-methoxy-2-methylindolyl)-4-thienyl-substituted furan(pyrrole)-2,5-diones

New nonsymmetrical dihetarylethenes, 3-(1-benzyl-5-methoxy-2-methyl-1H-indol-3-yl)-4-(3-thienyl)furan-2,5-dione and 1-alkyl- and (1-aryl)-3-(1-benzyl-5-methoxy-2-methyl-1H-indol-3-yl)-4-(3-thienyl)-1H-pyrrole-2,5-dione, exhibiting photochromic properties in solutions were synthesized. Noncyclic isomers of dihetarylethenes show fluorescence with quantum yields up to 0.13.     

N-Arylation of a hindered indoline as a route to 2-(2-methyl-1-(4-oxo-3,4-dihydrophthalazin-1-yl)-1H-indol-3-yl)acetic acid derivatives

A convenient synthesis of 2-(2-methyl-1-(4-oxo-3,4-dihydrophthalazin-1-yl)-1H-indol-3-yl)acetic acid derivatives is described using a microwave-promoted multi-step S_NAr reaction. The desired products were found to exhibit atropisomerism.     

Favorskii Rearrangement in the Reaction of 3-(1-Adamantyl)-1-chloro-2-propanone with Amines

The reaction of 3-(1-adamantyl)-1-chloro-2-propanone with amines [diethylamine, (1-adamantyl)methylamine, p-toluidine, and piperidine] in diethyl ether at room temperature involves the Favorskii rearrangement and yields N,N-disubstituted amides of 3-(1-adamantyl)propanoic acid.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid derivatives via thiazolones

2-Alkoxy-4-heteroarylaminomethylene-5(4H)-thiazolones 4 were converted with various nucleophiles into β-heteroarylamino-α,β-dehydro-α-amino acid derivatives 11, 14, 15, 16, 17, 18 , and 19 . Reduction of 4 with sodium borohydride in ethanol saturated with gaseous ammonia afforded the corresponding β-heteroaryl-amino substituted alanyl amides 20 . Thiazoledione derivative 7a was transformed with sodium methoxide in methanol into 1-(4,6-dimethylpyrimidinyl-2)-4-mercaptocarbonylimidazol-2(3H)-one ( 8a ).     

β-Carbolines derived from β-methyltryptophan and a stereoselective synthesis of (2RS,3SR)-β-methyltryptophan methyl ester

The methyl ester of isomer A of β-methyltryptophan (2SR,3RS; 2A ) was stereoselectively prepared by an efficient modified method through the reaction of a-methyl-N-(1-Methylethyl)-1H-indole-3-methanamine ( 3 ) with methyl nitroacetate to give the desired nitro compound as a mixture of two racemates 5A , and 5B. During the recrystallization process epimerization occurred and only racemate 5A crystallized out. Catalytic hydrogenation of 5A in the presence of acid stereoselectively yielded the desired amino acid ester 2A. Pictet-Spengler condensation of 2A with aldehydes under aprotic conditions followed by dehydrogenation gave excellent yields of β-carbolines 7a-i , (R = methyl, ethyl, acetyl, phenyl, pyridine-2-yl, furan-2-yl, quinoline-2-yl, styryl, phenethyl). Also β-carbolines 7a,b,i were synthesized by the Pictet-Spengler condensation of (3-meth-yltryptophan under acidic aqueous conditions followed by esterification and dehydrogenation.     

Five-membered dioxoheterocycles: XCIX. Reaction of 1-aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones with indoles. Crystal and molecular structure of substituted 2-(indol-3-yl)pyrrole

1-Aryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones react with indole and 2-methylindole with the formation of methyl 1-aryl-3-aroyl-4-hydroxy-2-(1H-indol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates. Crystal and molecular structure of methyl 3-benzoyl-4-hydroxy-2-(2-methyl-1H-indol-3-yl)-5-oxo-1-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylate was examined.     

Synthesis and Evaluation of 2-{[(2-Oxo-1H-quinolin-8-yl)oxy]methyl}-Substituted α-Methylidene-γ-butyrolactones

O-Alkylation of 8-hydroxy-1H-quinolin-2-one ( 1 ) afforded 8-(2-oxopropoxy)-1H-quinolin-2-one ( 2 ) which was immediately cyclized to form the tricyclic 2,3-dihydro-3-hydroxy-3-methyl-5H-pyrido[1,2,3-de][1,4]benzoxazine,-5-one ( 3). The Reformatsky-type condensation of 3 furnished antiplatelet 8-[(2,3,4,5-tetrahydro-2-methyl-4-methylidene-5-oxofuran-2-yl)melhoxy]-1H-quinolin-2-one ( 4 ). Its counterparts 7a – f , Ph-substituted at C(2) of the furan ring, were obtained from 1 via alkylation and the Reformatsky-type condensation. Although compound 4 was less active against platelet aggregation than 7a – f , it was the only compound which exhibited significant inhibitory activity on high-K⁺ medium, Ca²⁺-induced vasoconstriction and was more active than most of its Ph-substituted counterparts against norepinephrine-induced vasoconstrictions.     

Regioselective addition of aromatic amines at the exocyclic C=C bond of 2-(2-Oxo-2,3-dihydro-1H-indol-3-ylidene)acetic acid esters

Methyl and ethyl 2-(2-oxo-2,3-dihydro-3H-indol-3-ylidene)acetates react with aromatic amines to give products of regioselective addition at the α-position of the activated exocyclic C=C bond, methyl and ethyl 2-arylamino-2-(2-oxo-2,3-dihydro-1H-indol-3-yl)acetates.     

Reaction of indoles with ethyl bromopropynoate over Al<Subscript>2</Subscript>O<Subscript>3</Subscript> surface

1H-Indole and 2-methyl-1H-indole reacted with ethyl 3-bromopropynoate over aluminum oxide to give mixtures of the corresponding ethyl 3-(1H-indol-3-yl)propynoates and ethyl 3,3-bis(1H-indol-3-yl)-acrylates, the latter prevailing.     

Ultrasound-assisted synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones by novel core-shell bio-based nanocatalyst anchoring sulfonated L-histidine on magnetized silica (SO3H-L-His@SiO2-nano Fe3O4)

An efficient synthesis of 3-(1-(2-(1H-indol-3-yl)ethyl)-2-aryl-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)indolin-2-ones is reported via a one-pot three-component reaction of 3-phenacylidenoxindoles, tryptamine, and dimedone under ultrasound irradiation using a newly prepared core-shell nanostructure. The utilized nanocatalyst is obtained by anchoring sulfonated L-histidine amino acid shell, as the bio part, on silica-nanomagnetite core (SO₃H-L-His@SiO₂-nano Fe₃O₄) and characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy (¹H NMR), field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, thermogravimetric/differential thermal analysis, vibrating sample magnetometer measurements, transmission electron microscopy, and back-titration. The protocol contains several advantages, such as relatively short reaction times, simple work-up procedure by separation of the catalyst with an external magnet, the use of economical and environmentally friendly ultrasonic waves, and reusability and recoverability of the core-shell nano-promoter for three runs without significant activity loss.