Reaction of N,N'-Di(methoxycarbonyl)-p-benzoquinonediimine with Meldrum's Acid and its Analogs

Reactions of 2,2-dimethyl-4,6-dioxo-1,3-dioxane (Meldrum's acid), 2,2-tetramethylene-4,6-dioxo-1,3-dioxane and 2,2-pentamethylene-4,6-dioxo-1,3-dioxane in the presence of MeONa gave rise instead of expectable products of Michael 1,4-addition the corresponding N,N'-di(methoxycarbonyl)-p-benzoquinonediimines substituted in the ring.     

Investigation of reactions of the organozinc reagents prepared from zinc and dialkyl dibromomalonates with the derivatives of 2-arylmethyleneindan-1,3-dione and 5-arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-dione

Organozinc compounds prepared from dialkyl dibromomalonates and zinc react with 2-arylmethyl-eneindan-4,6-diones, 5-arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-diones, as well as with 2-[4-(1,3-dioxoindan-2-ylidenemethyl)phenyl]methyleneindan-1,3-dione and 5-[4-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-2-ylidenemethyl)phenyl]methylene-2,2-dimethyl-1,3-dioxane-4,6-diones to form dialkyl 3-aryl-1′3′-dioxaspiro(cyclopropane-2,2′-indan)-1,1-dicarboxylates, dimethyl 3-aryl-6,6-dimethyl-5,7-dioxa-4,8-dioxaspiro[2,5]octan-2,2-dicarboxylates, dialkyl 2-{4-[3,3-bis (alkoxycarbonyl)-1′,3′-dioxaspiro(cyclopropane-2,2′-indan)-1-yl]phenyl}-1′,3′-dioxaspiro[cyclopropane-2,2′-indan]-1,1-dicarboxylates, and dialkyl 2-{4-[2,2-bis(alkoxycarbonyl)-6,6′-dimethyl-4,8-dioxo-5,7-dioxaspiro[2,5]oct-1-yl]phenyl}-6,6-dimethyl-4,8-dioxo-5,7-dioxaspiro[2,5]octan-1,1-dicarboxylate respectively.     

Study of Nitrogen- and Sulfur-Containing Heterocycles. 57. Synthesis and Conversion of 4′-Substituted 5-(5-Amino-6-Pyrimidylthio)-2,2-Dimethyl-4,6-Dioxo-1,3-Dioxanes

By reaction of 4-substituted 5-amino-6-mercaptopyrimidines with 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, we have obtained 4′-substituted 5-(5-amino-6-pyrimidylthio)-2,2-dimethyl-4,6-dioxo-1,3-dioxanes. We have studied diazotization of these compounds by isoamyl nitrite. In the case of 4′-methoxy- and 4′-dimethylamino-substituted derivatives, we have obtained derivatives of novel heterocyclic systems: pyrimido[5,4-e][1,3,4]thiadiazine and pyrimido[5,4-e][1,3,4]thiadiazine-7-spiro-5′-1,3-dioxane, and in the case of the 4′-isopropylamino-substituted derivative we obtained 4-isopropyl-7-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1,2,3-triazolo[5,4-d]pyrimidin-7-ylidene.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 613–623, April, 2005.     

New thiourea organocatalysts and their application for the synthesis of 5-(1H-indol-3-yl)methyl-2,2-dimethyl-1,3-dioxane-4,6-diones a source of chiral 3-indoylmethyl ketenes

The stereoselective properties of modified thiourea organocatalysts were tested in the Friedel–Crafts alkylation of indole with 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones, which produces chiral 5-((1H-indol-3-yl)(aryl)methyl)-2,2-dimethyl-1,3-dioxane-4,6-diones. Based on a tentative reaction mechanism for ((S)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethylbutanamide organocatalysts, modifications were applied in four selected regions. Systematic structure-stereoselectivity relationship study allowed designing the best efficient organocatalyst for the investigated Friedel–Crafts alkylation of indole with 5-arylidene-2,2-dimethyl-1,3-dioxane-4,6-diones.     

Synthesis and Dynamic NMR Study of New Stable Ylides Derived from the Reaction of Triphenylphosphine,Dialkyl Acetylenedicarboxylates,and 5-ACYL Meldrum’s Acid

Abstract

Triphenylphosphine and dialkyl acetylenedicarboxylate react smoothly in the presence of 5-acyl Meldrum's acid in dichloromethane at room temperature and lead to synthesis of new stable ylide derivatives of dimethyl (5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-3-(triphenyl-λ⁵-phosphanylidene) succinate. Dynamic NMR study results of rotamers are reported and compared with the previous-related reports.     

Reactions of Bisazomethines of the Naphtalene Series with 1,3-Diketones

Bisazomethines prepared from aromatic dialdehydes and 2-naphthylamine were for the first time reacted with the following diketones: 1,3-cyclohexanedione, 5,5-dimethyl-1,3-cyclohexanedione, 5-phenyl-1,3-cyclohexanedione, indandione, and 2,2-dimethyl-1,3-dioxane-4,6-dione was studied. The reactions with 1,3-diketones of the cyclohexane series yield benzophenanthridine derivatives. The reactions with indandione, depending on conditions, give either bisarylideneindandiones or bisdihydrobenzo[f]indenoquinoline. As evidenced by the ^13C NMR and IR spectra, in the case of biphenyl-4,4'-dicarbaldehyde bis[N-(2-naphthyl)imine] and 2,2-dimethyl-1,3-dioxane-4,6-dione, 4,4'-bis(3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-1-yl)biphenyl is formed.     

Reaction of N,N-dimethylazidochloromethyleniminium chloride (azidophosgeniminium chloride) with 1,3-dimethyl-4-aminouracils. A new “one pot” synthesis of 3-aryl-(and 3-alkyl)-4,6-dimethyl-5,7-dioxo-1,2,3-triazolo[4,5-d]pyrimidines (8-azatheophyllines) via a diazo group transfer process

N,N-Dimethylazidochloromethyleniminium chloride (azidophosgeniminium chloride) ( 1 ) reacts by diazo group transfer with 1,3-dimethyl-4-aryl-(and alkyl)aminouracils 4 to give, under mild “one pot” reaction conditions, a very good yield of 3-aryl-(and 3-alkyl)-4,6-dimethyl-5,7-dioxo-1,2,3-triazolo[4,5-d]pyrimidines (8-azatheophyllines) 8 . That reaction proceeds, very likely, through formation of non-isolated 4-imino-5-diazouracils 6 .     

Three-component condensation of Meldrum’s acid with 2-naphthylamine and esters derived from vanillin

Three-component condensation of Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) with 2-naphthylamine and esters derived from vanillin involves intermediate formation of N-arylmethylidene-2-naphthylamines which are cleaved with Meldrum’s acid to give 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones and arylmethylideneketenes. Reaction of the latter with 2-naphthylamine leads to formation of 2-methoxy-4-(3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-1-yl)phenyl carboxylates.     

Reactions of some pyranylidene esters with amines

The reactions of 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2,6-diphenyl-4H-pyran ( 1 ) with primary amines gave the corresponding 1-substituted 1,4-dihydropyridine derivatives. The related benzo derivative of 1 (12) and primary amines gave 3-substituted 3,4-dihydro-2-phenyl-5H-[1]benzopyrano[3,4-c] pyridine-4,5-dione derivatives. With secondary amines, 12 gave 2-phenyl-4H,5H-pyrano[3,4-c] [1]benzopyrane-4,5-dione, and with isopropylamine, N,N-dimethylhydra-zine, and methanolic potassium hydroxide, 12 gave 4-phenacylcoumarin. Some reaction intermediates were isolated which indicate probable reaction paths. The reactions with amines were extended to a naphtho derivative of 1 (19) and to a thia homolog of 12 (24).     

H NMR studies on the reductively triggered release of heterocyclic and steroid drugs from 4,7-dioxoindole-3-methyl prodrugs

Hypoxia is a feature of several disease states, including cancer and rheumatoid arthritis. Prodrug systems which, after bioreduction, selectively release active drugs in these tissues may be important in therapy. An improved preparation of 1,2-dimethyl-3-hydroxymethyl-5-methoxyindole-4,7-dione was developed. Mitsunobu coupling with (5-substituted) isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) gave 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and N-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethyl)isoquinolin-1-ones. Similar coupling with the anticancer drug pentamethylmelamine gave its potential prodrug 1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N-methylaminomethyl)-5-methoxyindole-4,7-dione. Treatment of sodium prednisolone hemisuccinate with 3-chloromethyl-1,2-dimethyl-5-methoxyindole-4,7-dione gave an analogous candidate prodrug of the anti-inflammatory drug prednisolone. In a chemical model system for bioreduction, SnCl₂ in CDCl₃/CD₃OD triggered rapid stoichiometric release of isoquinolin-1-ones from the O-linked prodrugs but not from the N-linked analogues. Use of this system allowed the release process to be monitored in situ by ¹H NMR spectroscopy. Diethyl hydrazine-1,2-dicarboxylate was found to reduce Sn^IV to Sn^II, making the overall reductive release catalytic in tin. The reduced (hydroquinone) prodrug may have a short lifetime under these reductive conditions, meaning that only good leaving groups are expelled. Thus 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and analogues may be useful as reductively triggered prodrugs.     

New Chiral Diamines of the Dioxolane Series: (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylaminomethyl)- 1,3-dioxolane and (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(methyl- aminomethyl)-1,3-dioxolane

The reaction of sodium diphenylamide with 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane gave (+)-(4S,5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane, which was brought into complex formation with cobalt chloride. Treatment of 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane with sodium N-methylanilide resulted in cleavage of the SÄO bond in the p-toluenesulfonate moiety with formation of N-methyl-N-phenyl-p-toluenesulfonamide and 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane disodium salt. Diethyl (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate reacted with methylamine to give the corresponding dicarboxamide which was reduced with lithium aluminum hydride to (4S,5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane having chiral carbon and nitrogen atoms.     

无外加催化剂条件下芳香醛与活性亚甲基化合物的缩合反应和迈克尔加成反应

在DMF溶剂中，不外加催化剂使芳香醛(1)与2,2-二甲基-1,3-二氧六环-4,6-二酮(2)发生缩合反应生成2,2-二甲基-5-芳亚甲基-1,3-二氧六环-4,6-二酮(3a～f)。在同样条件下，芳香醛与5,5-二甲基-1,3-环己二酮(4)则发生缩合和迈克尔加成反应生成2,2'-芳亚甲基双(3-羟基5,5-二甲基-2-环己烯-1-酮)(5a～h)。用单晶X-射线分析法确定了产物5b的晶体结构。     

Synthesis, spectroscopic and DFT investigation of dimethyl-2-(5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(triphenylphosphinylidene)succinate

Dimethyl-2-(5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-(triphenylphosphinylidene)succinate has been synthesized and characterized by elemental analysis, FT-IR and ¹H, ¹³C and ³¹P NMR. The vibrational wavenumbers, gauge including atomic orbital (GIAO) ¹H and ¹³C chemical shift values of title compound in the ground state have been computed with density functional theory method (DFT) and the B3LYP functional. The basis sets used are 6-311G(d,p) and 6-31G(d). The harmonic vibrational wavenumbers have been computed and the scaled values have been compared with the experimental FT-IR spectra. The complete assignments have been performed on basis of the total energy distribution (TED) of the vibrational modes, calculated with scaled quantum mechanics (SQM) method. Most of the computed wavenumbers are found to be in good agreement with the observed spectrum.     

Preparative synthesis of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione (2-trifluoroacetyl Meldrum's acid) and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one and their synthetic usefulness as (trifluoroacetyl)ketene precursors

A simple and reliable method for the preparation of 2,2-dimethyl-5-(trifluoroacetyl)-1,3-dioxane-4,6-dione and 2,2-dimethyl-6-(trifluoromethyl)-4H-1,3-dioxin-4-one on a multigram scale was developed. These (trifluoroacetyl)ketene precursors were used in the hetero-Diels-Alder reaction with dialkylcyanamides and 1-ethoxyprop-1-yne, as well as in some reactions with nucleophiles.     

Reactions of dialkyl 4-bromo-2,2-dimethyl-3-oxohexane-1,6-dioates,-heptane-1,7-dioates with zinc and aromatic aldehydes

Zinc enolates generated from dimethyl 4-bromo-2,2-dimethyl-3-oxohexane-1,6-dioate and zinc reacted with aromatic aldehydes giving methyl 2,2-dimethyl-3-oxo-3-(5-oxo-2-aryltetrahydrofuran-3-yl)propanoates. The reaction of zinc enolates obtained from dimethyl 4-bromo-2,2-dimethyl-3-oxoheptane-1,7-dioate and zinc with aromatic aldehydes depending on the synthesis conditions led to the formation either methyl 2,2-dimethyl-3-oxo-3-(6-oxo-2-aryltetrahydropyran-3-yl)propanoates or 3-(5,5-dimethyl-4,6-dioxo-2-aryltetrahydropyran-3-yl)propanoates. The compounds synthesized formed as a single diastereomer of E-configuration.     

2,2-Dimethyl-5-(5-R-furfurylidene)-1,3-dioxane-4,6-diones. 3. Selective hydrogenation of the exocyclic double bond and three-dimensional structures of the reaction products

The reaction of 2,2-dimethyl-5-(5-R-furfurylidene)-1,3-dioxane-4,6-diones with sodium borohydride in alcohol leads exclusively to products of hydrogenation of the exocyclic double bond. The three-dimensional structure of one of them — 2,2-dimethyl-5-(5-methyl-furfuryl)-1,3-dioxane-4,6-dioxane — was investigated by x-ray diffraction analysis (XDA).See [1] for Communication 2.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1201–1207, September, 1989.     

Enyne Meldrum´s acid derivatives: synthesis and Michael reactions with amines and thiols

Russian Chemical Bulletin - The Knoevenagel condensation of arylpropynals with Meldrum´s acid in the presence of Et3N affords 5-(3-arylprop-2-yn-1-ylidene)-2,2-dimethyl-1,3-dioxane-4,6-diones...     

Synthesis,anticancer, and computational studies of 1, 3, 4-oxadiazole-purine derivatives

Theophylline-7-acetic acid (acefylline) ( 3 ) and its derivatives are pharmacologically active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of 2-((5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)-N-arylacetamides ( 10a-j ) has been reported. All the synthesized derivatives ( 10a-j) were structurally verified by FT-IR, ¹H NMR, ¹³C NMR and evaluated for their anti-cancer (using MTT assay), hemolytic and thrombolytic potential. N-(4-Chlorophenyl)-2-(5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)acetamide ( 10g ) was found to be the most active against human liver cancer cell lines (Huh7) having cell viability 53.58 ± 1.28 using 100 μg/mL concentration of compound which was further in-silico modelled to describe the possible mechanistic insights for its anti-proliferative activity. The results of hemolytic and thrombolytic activities indicated that these derivatives were less toxic and hold considerable potential as a drug candidate. 2-(5-((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(2-fluorophenyl)acetamide ( 10c ) of the series was found to be least toxic with 0.1% hemolysis relative to ABTS (95.5%) as positive control. 2-(5-((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(tetrahydro-2H-pyran-4-yl)acetamide ( 10j ) exhibited potent clot lysis activity (90%) as compared to negative control DMSO (0.57%).     

Condensation of 2-naphthylamine or N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexane-3-carboxylate

Condensation of 2-naphthylamine with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate afforded depending on the reaction conditions methyl 9,9-dimethyl-11-oxo-8,9,10,12-tetrahydro-7H-benzo[a]acridine-10-carboxylate or 4-alkoxymethyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??Hspirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylate. The condensation of N-benzyl-2-naphthylamines with formaldehyde and methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate provided with the quantitative yield the corresponding methyl 4-benzyl-1,4-dihydro-2??,6??-dioxo-4??,4??-dimethyl-2??H,3H,6??H-spirobenzo[f]quinoline-2,1??-cyclohexyl-3??-carboxylates.     

1,4,4a,10b-Tetrahydro-N,N-dimethyl-4-phenanthridinamines and 1,4,4a,5,6,10b-hexahydro-N,N-dimethyl-4-phenanthridinamines

Synthetic procedures to prepare the title compounds are described. Diels-Alder cycloaddition of β-nitrostyrene derivatives 5 to N,N-dimethyl-1,3-butadien-1-amine, 6 , gave 5-aryl-N,N-dimethyl-6-nitro-2-cyclohexen-1-amines 7. Reduction of 7 with zinc in acetic acid gave the diamino derivatives 8 . Schotten-Baumann acylation of 8 gave amides 9 . Treatment of 8 with alkyl isocyanates gave the aminourea derivatives 10 . Bischler-Napieralski cyclodehydration procudure of 9 and 10 gave 1,4,4a,10b-tetrahydrophenanthridinamines 3 and N⁶-alkyl-1,4,4a,10b-tetrahydro-N⁴,N⁴-dimethyl-4,6-phenanthridinediamines 11 , respectively. Condensation of diamines 8 with aryl aldehydes under azeotropic conditions gave imines 12 which on treatment with acids yielded 6-aryl-1,4,4a,5,6,10b-hexahydro-N,N-dimethyl-4-phenanthridinamines 4 . The stereochemistry of these materials is assigned from the proton magnetic resonance studies.