New highlights in the synthesis and reactivity of 1,4-dihydropyrazine derivatives

In the course of our investigations on the synthesis of original nitrogen heterocyclic derivatives, we were interested in the synthesis and study of original 1,4-dihydropyrazine rings. To this aim the desired bisvinylphosphate derivative was prepared from N-Boc piperazine-2,5-dione and then was engaged in palladium catalyzed reactions (reduction, Suzuki and Stille cross-coupling reactions). The 1,4-dihydropyrazine and the corresponding 2,5-disubstituted derivatives were obtained in fair to good yields and were then functionalized under anionic conditions. Aromatization into 1,4-pyrazines was investigated in a second stage.     

Reduction of nitronate adducts from RMgX and 1-hethoxy-4-nitronaphthalene to oximes or amines by trivalent phosphorus reagents

The reduction of nitronate adducts from 1-methoxy-4-nitronaphthalene and Grignard reagents (CH₃ MgX, PhCH₂CH₂HgX, i-C₃H₇ MgX, c-C₆H₁₁MgX and t-C₄H₉MgX) with hexamethyl phosphorous triamide and phosphorous trichlorlde is reported. With the former reagent the reaction is chemio and stereoselective and only the E-oxime is recovered being the E-2-alkyl-4-methoxy-1(2H)naphthalenone oximes and the E-2-alkyl-2,3-dihydro-1,4-naphthoquinone-1-oximes obtained after quenching with NH₄Cl and HCl respectively. Oxime stereochemistry is assigned by LIS values caused by Eu(dpm)₃ on ¹³C signals of 2-methyl-4-methoxy-1-(2H)naphthalenone oxime and 2-methyl-2,3-dihydro-1,4-naphthoquinone-1-oxime. Complete reduction to amines is obtained with phosphorous trichloride.     

Diastereoselective protocols for the synthesis of 2,3-trans- and 2,3-cis-6-methoxy-morpholine-2-carboxylic acid derivatives

Two diastereoselective and straightforward protocols for the high-yielding synthesis of 2,3-trans- and 2,3-cis-6-methoxy-3-substituted morpholine-2-carboxylic esters were realized in few steps, through the condensation between 5,6-diethoxy-5,6-dimethyl-1,4-dioxan-2-one and an appropriate imine, which is the key reaction to control the C2-C3 relative stereochemistry, followed by a methanolysis/ring-closure tandem reaction sequence. In particular, 2,3-trans-morpholines derive from the R*,S*-product of the acid condensation of N-functionalized alkylimines with the silylketene acetal of the above lactone, whereas 2,3-cis-morpholines derive from the R*,R*-product of basic condensation of an N-tosylimines with the lactone.     

Synthesis and amination of 5- and 8-amino derivatives of 2-phenylnaphtho[2,3-d]-1,3-thiazole-4,9-dione

5- and 8-Amino-2-phenylnaphtho[2,3-d]-1,3-thiazole-4,9-diones were obtained by treatment of 3,5-diamino-2-chloro- and 2,5-diamino-3-chloro-1,4-naphthoquinones with sodium sulfide followed by condensation with benzaldehyde. Thermal and photochemical butylamination and CoCl{in2}-promoted arylamination of 5-amino-2-phenylnaphthothiazole-4,9-dione in position 8 was carried out.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2203–2206, December, 1994.     

Thermochemical study of three dimethylpyrazine derivatives

The standard (p ⁰=0.1 MPa) molar enthalpies of formation, in the gaseous phase, at T-298.15 K, for 2,5-dimethylpyrazine (2,5-DMePz) and for the two dimethylpyrazine-N,N′-dioxide derivatives, 2,3-dimethylpyrazine-1,4-dioxide (2,3-DMePzDO) and 2,5-dimethylpyrazine-1,4-dioxide (2,5-DMePzDO), were derived from the measurements of standard massic energies of combustion, using a static bomb calorimeter, and from the standard molar enthalpies of vaporization or sublimation, measured by Calvet microcalorimetry. The mean values for the molar dissociation enthalpy of the nitrogen-oxygen bonds, 〈DH _m⁰〉(N-O), were derived for both N,N′-dioxide compounds. These values are discussed in terms of the molecular structure of the two N,N′-dioxide derivatives and compared with 〈DH _m⁰〉(N-O) values previously obtained for other N-oxide derivatives.     

Fast atom bombardment mass spectrometry of new polydentate schiff bases. 2. The case of mono- and bisaldimines containing pyridine groups

The mass spectrometric behaviour of seven polydentate Schiff bases derived from the condensation of formyl or diformyl precursors (2,3-dihydroxy- or 2,5-dihydroxy-benzaldehyde, 3-metoxy- or 3-ethoxy-salicylaldehyde, 3-formyl-salicyclic acid, 4-methoxy- or 4-chloro-2,6-diformylphenol) with 2-aminomethylpyridine have been investigated by fast atom bombardment mass spectrometry and metastable ion studies.     

Heterocyclic analogs of 5,12-naphthacenequinone. 4. Synthesis of 4,11-dimethoxy-anthra[2,3-d]isoxazole-5,10-dione

A preparative synthetic method has been developed for 3-chloro-2-formyl-1,4-dimethoxyanthraquinone starting from available 2-methylquinizarine. The condensation of the α-chloroaldehyde obtained with acetone oxime gives 4,11-dimethoxyanthra[2,3-d]isoxazole-5,10-dione. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1421–1427, September, 2006.     

Synthesis and properties of dipyridinium betaines of derivatives of 1,4-benzoquinone and tetracyanoquinodimethane

Reaction of chloranil with excess pyridine gives the poorly stable 2,5-di(N-pyridinium)-3,6-dichloro-1,4-benzoquinone dichloride which is readily hydrolyzed to give the bisbetaine of 2,5-di(N-pyridinium)-1,4-benzoquinone-3,6-dioxide. Treatment with acid gives its mono- and bisprotonated derivatives as the perchlorate and dibromide and bromination gives the betaine 2-bromo-2,5-di(N-pyridinium)-5-cyclohexene-1,3,4-trione-6-oxide perbromide. The reaction of malonodinitrile with 2,5-di(N-pyridinium)-3,6-dichloro-1,4-benzoquinone dichloride in situ gives the poorly stable bisbetaine of 2,5-di(N-pyridinium)-7,7,8,8-tetracyanoquinodimethane-3,6-dioxide.Riga Technical University, Riga LV-1048. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 346–349, March, 1998.     

Synthesis and absorption spectra of 2-substituted 5,8-dimethoxy-4H-1-benzothiopyran-4-one 1,1-dioxides

2,3-Dibromo-5,8-dimethoxy-4H-1-benzothiopyran-4-one (thiochromone) 1,1-dioxide which was a starting material to prepare sulfone analogues of 1,4-naphthoquinone dyes was easily prepared from 5,8-dimethoxythiochroman-4-one by oxidation and bromination. The reactions of 2,3-dibromo-5,8-dimethoxythiochromone 1,1-dioxide 4 with aliphatic and aromatic amines in ethanol below 20° gave 2-substituted derivatives 12a-e and at higher reaction temperature the amination gave 2-arylamino derivatives 13c-e debrominated at C -3. The visible absorption spectra of these derivatives were investigated by the PPP MO method.     

Oxidation of 1,1,2-trisubstituted hydrazines and 1,1-dimethylhydrazones stable 1,4-hydropyrazine and 1,2-dihydropyridazine systems

3-(N,N-Dimethylhydrazono)propionic acid and 1,4-bis-(dimethylamino)-3,5-dicyano-1,4-dihydropyrazine derivatives, 4,5-disubstituted 1,2-bis(dimethylamino)-1,2-dihydropyridazines, methyl -(2,2-dimethylhydrazino)acrylate, bis[N,N-dimethyl-2,3-(2,2-dimethylhydrazono-methyl) succinamide], and dimethyl 1,4-(2,2-dimethylhydrazino)-1,3-butadiene-2,3-dicarbox-ylate were obtained by oxidation of 2'-substituted 1,1-dimethyl-2-ethylhydrazines.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 396–401, March, 1976.     

Approaches to phenazine-derived N-isosteres of anthracyclinones

1-Hydroxyphenazine 5,10-dioxide showed antitumor properties against mouse leukemia P388. It also participated in biochemical mechanisms of quinoid antitumor agents, as indicated by inhibition of radiolabeled DNA-RNA precursors in cultured leukemia L1210 cells and by stimulation of oxygen consumption in mammalian microsomes. This suggests that the isosteric di-N-oxide system may be a biologically active substitute for 1,4-quinone, and that di-N-oxides of tetrahydrobenzo[b]phenazines can be explored as anthracyclinone N-isosteres. As potential synthetic intermediates, 7,8,9,10-tetrahydro-6,11-dihydroxybenzo[b]-phenazines have been prepared by 1) Diels-Alder addition of phenazine-1,4-quinone and 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene to give isolable but labile adducts and 2) condensation of 6,7-diamino-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxy-2-naphthoic acid with 3-methoxy-1,2-quinone. Attempts at N-oxidation gave instead oxidation of the 6,11-hydroquinone ring to quinone, regardless of hydroxyl protection. Despite previous literature indications, we have been unable to synthesize the 1,4-dihydroxyphenazine 5,10-dioxide system. We conclude that this hydroxyl substitution pattern (1,4) in an adjacent ring must be avoided in the redesign of anthracyclinone isosteres that have di N-oxide in place of quinone.     

Ionic Liquid-Mediated Facile Synthesis and Antimicrobial Study of Thiazolo [2,3-b]Benzo[h]Quinazolines and Thiazino[2,3-b] Benzo-[h]Quinazolines

Abstract

8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione, obtained by the condensation of 2-benzylidene-6-methoxy-3,4-dihydronapthalene-1(2H)-one with thiourea, on reaction with chloroacetic acid and 3-chloropropanoic acid in the presence of the ionic liquid N-methylpyridinium tosylate furnishes 3-methoxy-7-phenyl-7,10-dihydro-5H- benzo[h]thiazolo[2,3-b]quinazoline-9(6H)-one and 3-methoxy-7-phenyl-5,6,10,11-tetrahydro- benzo[h][1,3]thiazino[2,3-b]quinazoline-9(7H)-one. Further, condensation of the thione with 1,2-dibromoethane and 1,3-dibromopropane yields 3-methoxy-7-phenyl-6,7,9,10-tetrahydro-5 H-benzo[h]thiazolo[2,3-b]quinazoline and 3-methoxy-7-phenyl-5,6,7,9,10,11-hexahydrobenzo [h][1,3]thiazino[2,3-b]quinazoline respectively. Arylidene derivatives have been obtained by two routes. The structures of the cyclized compounds have been established on the basis of elemental analysis and spectroscopic data. The synthesized compounds were screened for antimicrobial activity. Some of the compounds showed promising antimicrobial activities.     

Attempted synthesis of ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐3‐carboxylate and 3‐acetate derivatives

Ethyl 3,4‐dihydro‐2H‐1,4‐benzoxazine‐3‐carboxylate derivatives 2 were obtained and isolated in low yields from the condensation of 2‐aminophenol and ethyl 2,3‐dibromopropanoate. They can be obtained by hydrogenation of ethyl 2H‐1,4‐benzoxazine‐3‐carboxylate in satisfactory yield. Using 2‐iminophenol did not direct the condensation with ethyl 2,3‐dibromopropanoate towards 2 but was fruitfull for the preparation of ethyl 2‐(4‐benzyl‐3,4‐dihydro‐2H‐1,4‐benzoxazin‐3‐yl)acetate from ethyl bromocrotonate.     

Reactions of 2,5-diphenyl-1,4 dithin sulfones with sodium azide

A number of unanticipated transformations were observed when various 2,5-diphenyl-1,4-dithiin sulfones were treated with sodium azide. These include a fragmentation to give 1,2-dicyano-1,2-diphenylethen, the formation of 2,5-dipehnyl-1,4-thiazine-1,1-dioxide, and the rearrangement of 3-bromo-2,5-diphenyl-1,4-dithiin-1,1-dioxide to its 2-bromo- isomer. Possible mechanism for these unusual reactions are discussed.     

Interaction of 1,2-bishyroxylamines with 1,2-dicarbonyl compounds. Isolation and properties of 2,3-dihydropyrazine-1,4-dioxides

The condensation of 1,2-bishydroxylamines with 1,2-dicarbonyl compounds led to the isolation of derivatives of 2,3-dihydropyrazine-1,4-dioxide. The 2,3-bis(bromomethyl)-4a,5,6,7,8,8a-hexahydroquinoxaline reacts readily with O- and N-nucleophiles; condensed pyrazines are formed by interaction with o-phenylenediamine, phenylhydrazine, and tert-butylamine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 514–522, April, 1993.     

Synthesis of New Substituted 2,3-Dihydro-1,4-dioxin-2-ones and 1,4-Dioxan-2-ones

3-Alkyl-6-methyl-2,3-dihydro-1,4-dioxin-2-ones reacted with acetyl chloride in the presence of zinc(II) chloride to give the corresponding 3-alkyl-5-acetyl-6-methyl-2,3-dihydro-1,4-dioxin-2-ones. Oxidation of the latter with hydrogen peroxide in formic acid, followed by treatment with magnesium bromide, afforded 3-alkyl-6-methyl-1,4-dioxane-2,5-diones. Successive chlorination and dechlorination of 6-hydroxymethyl-1,4-dioxan-2-ones yielded 6-methylene-1,4-dioxan-2-ones.     

Synthesis and electroconductivities of poly(2-methoxy-5-methythio-1,4-phenylene vinylene) and copolymers

Poly(2-methoxy-5-methylthio-1,4-phenylene vinylene), PMTPV, and copolymers containing both unsubstituted or 2,5-dimethoxy-substituted and 2-methoxy-5-methylthio-1,4-phenylene vinylene units were prepared in thin films from their water-soluble, sulfonium salt precursor polymers. Doping of drawn and undrawn films of PMTPV with I₂ vapor led to conductivities of 10^?4–10^?3 S cm^?1, which is significantly lower than those reported for poly(2,5-dimethoxy-1,4-phenylene vinylene). Conductivity of I₂-doped copolymer films ranges from 10^?3–10⁰ S cm^?1 depending on composition.     

Synthesis of New Substituted 2,3-Dihydro-1,4-dioxin-2-ones and 1,4-Dioxan-2-ones

3-Alkyl-6-methyl-2,3-dihydro-1,4-dioxin-2-ones reacted with acetyl chloride in the presence of zinc(II) chloride to give 5-acetyl-3-alkyl-6-methyl-2,3-dihydro-1,4-dioxin-2-ones. Oxidation of the latter with hydrogen peroxide in formic acid, followed by treatment with magnesium bromide, afforded 3-alkyl-6-methyl-1,4-dioxane-2,5-diones. Chlorination of 6-hydroxymethyl-1,4-dioxan-2-ones with thionyl chloride and subsequent dehydrochlorination led to formation of 6-methylene-1,4-dioxan-2-ones.     

Catalytic synthesis of dihydrofurans (review)

Various methods for the preparation of 2,3-dihydrofuran, 2,5-dihydrofuran, 2-methylenetetrahydrofuran, and their alkyl and aryl derivatives are examined. The most promising method for the preparation of 2,3-dihydrofuran is the conversion of 1,4-butanediol on cobalt catalysts. 2,5-Dihydrofuran is obtained by dehydration of 2-butene-1,4-diol on Al₂O₃, cobalt-containing and other catalysts, while 2-methylenetetrahydrofuran is obtained by dehydrohalogenation of tetrahydrofurfuryl halides. The various methods for the isomerization of 2,5-dihydrofuran to 2,3-dihydrofuran are discussed. Examples of the application of dihydrofurans in organic synthesis are presented.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1299–1311, October, 1982.     

Syntheses of pyrimidine and purine analogs derived from 1,2,6-thiadiazine 1,1-dioxide

5-Amino-3-oxo-2H, 4H-1,2,6-thiadiazine 1,1-dioxide and the monopotassium salt of 3,5-dioxo-2H, 4H,6H-1,2,6-thiadiazine 1,1-dioxide was obtained by condensation of sulfamide and ethyl cyanacetate and diethyl malonate, respectively. 7-Oxo-1H,4H,6H-imidazo[2,3-c]-1,2,6-thia-diazine 5,5-dioxide was prepared by a multi-step reaction sequence from 5-amino-3-oxo-2H, 4H-1,2,6-thiadiazine 1,1-dioxide.