Efficient PhB(OH)2-catalyzed one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones under solvent free conditions

An efficient and practical one-pot synthesis of 3-substituted isoindolin-1-ones and isobenzofuran-1(3H)-ones has been developed under solvent free-conditions using non-toxic and cheap phenylboronic acid as excellent catalyst. This strategy involves the sequential two-step Mannich/lactamization cascade reaction of inexpensive 2-formylbenzoic acid with primary amines and a wide variety of ketones, and an aldol/lactonization cascade reaction of 2-formylbenzoic acid with a broad range of ketones.     

2-Aminothiophene derivatives in a novel synthesis of phthalimidines

New aminophthalides were synthesized from o-formylbenzoic acid and substituted 2-aminothiophenes. Two of these compounds underwent recyclization in boiling Ac₂O to give the previously unknown 3-acetoxy-2-(3-cyano-4,5-dimethylthiophen-2-yl)-1,3-dihydroisoindol-1-one and 3-acetoxy-2-(3-cyano-4,5-tetramethylenethiophen-2-yl)-1,3-dihydroisoindol-1-one. The possible reaction mechanism and factors preventing the recyclization, in particular, the formation of intramolecular hydrogen bonds in the starting phthalides, were discussed. Some reactions of the resulting compounds with C-nucleophiles in trifluoroacetic acid were investigated. Two derivatives containing 4-hydroxy-3,5-di-tert-butylphenyl substituents were studied by X-ray diffraction.     

A novel one-pot pseudo-four-component isocyanide-based reaction: an unexpected approach for the synthesis of tetrahydrodiisoindoloquinoxalines and tetrahydrobenzodiisoindoloquinoxalines

A novel isocyanide based one-pot pseudo-four-component strategy for the synthesis of tetrahydrodiisoindoloquinoxaline and tetrahydrobenzodiisoindoloquinoxaline derivatives via the reaction of 1,2-diamines, 2-formylbenzoic acid, and an isocyanide at room temperature in good yields without using any catalyst and activation, is described.     

Synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the one-pot reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate

We describe a new one-pot synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate in acetic acid under reflux conditions and in the absence of a catalyst.     

Synthesis of zwitterionic salts via three component reactions of nitrogen-containing heterocycles, acetylenedicarboxylate and cyclic 1,3-dicarbonyl compounds

A practical synthetic procedure for the preparation of the charge-separated pyridinium-Meldrum acid zwitterionic salts was developed through a unique one-pot three component reaction of pyridine, acetylenedicarboxylate and Meldrum acid. Other nitrogen-containing heterocycles such as N-methylimidazole, 2-picoline, quinoline, isoquinoline and other cyclic 1,3-dicarbonyl compounds such as 1,3-cyclopentanedione, 1,3-cyclohexanedione, barbituric acid also took part in the reaction to give corresponding zwitterionic salts in moderate yields, respectively. In one case an unusual isoquinolinium 1,3-cyclopentanedionate was obtained. A feasible explanation is given for this novel one-pot tandem reaction and the formation of different kinds of products.     

A novel sulfonic acid functionalized ionic liquid catalyzed multicomponent synthesis of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives in water

Three-component reactions of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl compounds were prompted by novel sulfonic acid functionalized ionic liquids 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl)imidazolidine-1,3-diium hydrogen sulfate ([DMDBSI]·2HSO₄) in water at reflux temperature to provide a novel series of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives for the first time in high yields.     

A facile domino protocol for the stereoselective synthesis of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines

A facile protocol for the stereoselective construction of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines from the reactions of 2,2′-sulfonylbis(1,3-diarylprop-2-en-1-ones) with cyclic 1,3-diketones, viz. cyclohexane-1,3-diones, barbituric acid, and 2-thioxodihydropyrimidine-4,6(1H,5H)-dione in the presence of DBU in ethanol is described. This transformation presumably occurs via domino Michael addition-proton exchange-annulation via intramolecular displacement sequence.     

A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives under Pd(OAc)2/HCOOH system

A facile and efficient method for the synthesis of N-substituted isoindolin-1-one derivatives from 2-formylbenzoic acid and amine under Pd(OAc)₂/HCOOH system has been described. The whole process is carried out in ligand-free conditions and furnished the desired products by reductive intramolecular cyclization. Furthermore, this procedure is applied successfully for the modification of natural products, such as vindoline and estrone.     

Condensation of fluorosubstituted benzaldehydes with amines and cyclic 1,3-diketones

Condensation of fluorosubstituted benzaldehydes with 2-naphthyl or 6-quinolylamine and cyclic β-diketones (,3-cyclohexanedione, dimedone, and 1,3-indandione) provided new fluoroderivatives of benzo[a]-acridine, 4,7-phenanthroline, and benzo[f]indeno[1,2-b]quinoline. Forming in the course of the reaction fluorophenylmethylene-2-naphthyl-(or 6-quinolyl)amines, arylbis(cyclohexane-1,3-dion-2-yl)methanes, and 2-(fluorophenylmethylene)-1,3-indandiones were isolated.     

Catalyst-free synthesis of 3-hydroxyimidazo[1,2-a]pyridine zwitterion derivatives via the three-component reaction of ethyl glyoxalate, 2‑aminopyridines and cyclic 1,3-dicarbonyls

The three-component reaction of ethyl glyoxalate, 2-aminopyridines, and cyclic 1,3-dicarbonyl compounds such as 4-hydroxycoumarin, N,N-dimethylbarbituric acid and 4-hydroxy-6-methyl-2H-pyran-2-one is described for the synthesis of 3-hydroxyimidazo[1,2-a]pyridine zwitterion derivatives.     

Solid-phase synthesis of isoindolinones and naturally-occurring benzobutyrolactones (phthalides) using a cyclative-cleavage approach

Starting from Merrifield resin, 2-formylbenzoic acids were immobilized on solid supports. Reactions between immobilized 2-formylbenzoic acids and different organometallic reagents (Grignard reagents, zinc reagents, allyl silanes via Sakurai type reactions) furnished secondary alcohols which cyclized depending on the metal counter ion and reaction conditions, forming benzoannelated lactones. Asymmetric synthesis was possible on the resin using chiral [2.2]paracyclophane ligands. While the reaction of immobilized ortho-carboxy benzaldehydes with primary amines at elevated temperatures yielded 3-hydroxyisoindolinones, a reaction at ambient temperature allowed imine formation, which underwent 1,2-addition-cleavage reaction with various nucleophiles, yielding isoindolinones with three points of diversity.     

Synthesis of imidazolidin-4-one and 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-dione derivatives of primaquine: scope and limitations

The synthesis of imidazolidin-4-one derivatives of primaquine as potential antimalarial agents is described. The target compounds were synthesized in three steps: (i) condensation of (±)-primaquine with N^α-protected amino acids, (ii) removal of the N^α-protecting group, and (iii) reaction of the N-acylprimaquine with a carbonyl compound: acetone, three cyclic ketones and veratraldehyde. Using 2-formylbenzoic acid in the third step afforded 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. All products were isolated in good to excellent yields. Whereas imidazolidin-4-ones were formed as mixtures of all possible diastereomers in equal amounts, 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones were produced in a stereoselective fashion. The compounds hydrolyse very slowly (t_1/2 5-30 d) in pH 7.4 buffer to release primaquine. These primaquine derivatives are being submitted to biological assays, and preliminary results of their antimalarial activity are quite encouraging.     

Acetals and ethers-xiii Reaction products of 2-butenal with ethylene glycol

The unsaturated cyclic acetal, 2-(1-propenyl)-1,3-dioxolane (2), has been found as an intermediate product in the p-toluenesulfonic acid catalysed reaction of 2-butenal with an excess of ethylene glycol. The final product consisted of 2-[2-(2-hydroxyethoxy)-propyl]-1,3-dioxolane (3), and a small amount of geometric isomers of cis- and trans-5-(2-hydroxyethoxy)-7-methyl-1,4-dioxepane (4a and 4b, respectively).     

Facile approach to diverse range of 1,3-diaza-heterocycles: angular/linear selectivity paradigm and a remarkable intramolecular methyl migration

Starting from cyclic anhydrides and tert-butyl 2-aminobenzylcarbamate, simple and efficient synthesis of diverse range of kinetically controlled angular and thermodynamically controlled linear tricyclic and tetracyclic 1,3-diaza-heterocycles have been described via the intramolecular cyclizations of the corresponding imides/anilic acid esters. The effect of imide stability on the angular/linear product selectivity has also been described. The kinetically controlled angular products were successfully transformed to the corresponding thermodynamically controlled linear products by refluxing in methanol or methanol and acetic acid mixture. An interesting in situ 1,2-intramolecular methyl group migration has also been described.     

Isocyanide-based multicomponent reactions: synthesis of 2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)-N-alkylbenzamide and 1,7-diazaspiro[4,4]nonane-2,4-dione derivatives

A four-component reaction between 2-formylbenzoic acid, malononitrile, isocyanides, and primary alkyl amines has been developed for an efficient preparation of 2-(1-(alkylcarbamoyl)-2,2-dicyanoethyl)-N-alkylbenzamide and 1,7-diazaspiro[4,4]nonane-2,6-dione derivatives under two different conditions. It is shown that simply by changing the reaction solvent from ethanol to dichloromethane and controlling the order of the addition of reagents, two completely different products can be obtained. These multicomponent reactions showed high atom economy.     

Regioselective synthesis of mono- and bis-decahydrobenzocarbazoles via tandem reactions of α-diazo ketones

Regioselective intermolecular 1,3-dipolar cycloaddition reactions of rhodium generated carbonyl ylides with indoles are reported in this paper. Intermolecular 1,3-dipolar cycloaddition reactions of five-membered-ring cyclic carbonyl ylides with indole and substituted indoles afforded hexahydro-2H-carbazol-2-ones in a regioselective manner. Similarly, reactions of cyclic carbonyl ylides were carried out to afford decahydrobenzo[c]carbazoles or decahydrocyclopenta[c]carbazoles with high regioselectivity. Interestingly, the other possible regioisomer decahydrobenzo[a]carbazoles were also obtained by the reaction of cyclic carbonyl ylides and indoles having electron withdrawing substituents. The structure and stereochemistry of regioisomers 6,11c-epoxy-1,2,3,4,4a,5,6,6a,11b,11c-decahydro-4a-methyl-5-oxo-7H-benzo[c]carbazole and 11-benzenesulfonyl-6,11b-epoxy-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-4a-methyl-5-oxo-1H-benzo[a]carbazole were unequivocally corroborated by single-crystal X-ray analyses. To advance this study, regioselective double 1,3-dipolar cycloaddition reaction of five-membered-ring cyclic carbonyl ylides has been demonstrated for the first time with biindoles having various aryl and alkyl spacers. This process constructed up to eight stereocenters, four carbon-carbon and two carbon-oxygen bonds in a single step with an excellent molecular complexity and stereoselectivity.     

The unprecedented C-alkylation and tandem C-/O-alkylation of phenanthrolinium salts with cyclic 1,3-dicarbonyl compounds

N-p-Nitrobenzyl- or N-phenacylphenanthrolinium bromides reacted with a series of cyclic 1,3-dicarbonyl compounds in acetonitrile in the presence of triethylamine as base catalyst to give the unprecedented C-alkylated products and tandem alkylated/intramolecular O-alkylated oxazabicyclic compounds according to the structure of cyclic 1,3-dicarbonyl compounds.     

New Synthesis of 3-(2-Furyl)phthalides

3-(2-Furyl)phthalides were synthesized for the first time by the reaction of 2-formylbenzoic acids with furan derivatives in the presence of an acidic catalyst. It was found that the reaction of 2-formylbenzoic acids and 2-alkylfurans in aqueous dioxane in the presence of perchloric acid leads to a mixture of 2-carboxyaryldifurylmethanes and 3-furylphthalides, which can be separated easily by preparative column chromatography. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1302–1304, September, 2005.     

A new method for enol lactone synthesis by a Michael addition/cyclization sequence

Reactions of cyclic 1,3-dicarbonyl compounds with 1-(2-alkenoyl)-4-bromo-3,5-dimethylpyrazoles under the double catalytic activation conditions using both catalytic amounts of Lewis acid and amine catalysts provide a new direct synthetic route to enol lactones. Thus, 1,3-cyclohexanedione is allowed to react with 4-bromo-1-crotonoyl-3,5-dimethylpyrazole, in tetrahydrofuran at room temperature in the presence of both catalytic amounts (10 mol% each) of nickel(II) perchlorate hexahydrate and 2,2,6,6-tetramethylpiperidine, to give 4,7,7-trimethyl-3,4,5,6,7,8-hexahydrobenzopyran-2(H),5-dione in a good yield. This reaction does not proceed or is too slow under the reaction conditions other than the double catalytic activation conditions.     

Construction of 4-substituted 2-(pyrrolidine-3-yl)acetic acid derivatives as cyclic γ-aminobutyric acid analogues employing intermolecular [2+2]-photocycloaddition as key steps

The synthesis of new 2-(pyrrolidine-3-yl)acetic acid derivatives as cyclic γ-aminobutyric acid analogues, which are additionally substituted at the 4-position, is reported. A de Mayo reaction, i.e. a combination of an intermolecular [2+2]-photocycloaddition of 1,3-dioxinones with N-protected 3-pyrroline and a fragmentation reaction of the resulting cyclobutane moiety, represent the key steps.