The Use of 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one as “Masked” α-Bromo-α'-Hydroxy Ketone in the Synthesis of Heterocyclic Systems

4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one was obtained on the basis of the readily obtainable 4-methylene-5,5-dimethyl-1,3-dioxolan-2-one. It forms 2-imidazo[1,2-a]pyridin-2-yl-2-propanol with 2-aminopyridine, 11a-hydroxy-1,1-dimethyl-3-oxo-1,5,11,11a-tetrahydro[1,3]oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium bromide with 2-(aminomethyl)pyridine, and the corresponding derivative of 4-hydroxyoxazolidin-2-one with 2-(3,4-dimethoxyphenyl)ethylamine. The last product was converted by intramolecular amidoalkylation without isolation into 10b-(bromomethyl)-8,9-dimethoxy-1,1-dimethyl-1,5,6,10b-tetrahydro[1,3]oxazolo[3,4-a]isoquinolin-3-one.     

1-(2-Quinoxalyl)-, 1-[3,5-Di(trifluoromethyl)phenyl]-, 1-(2-Carboxyphenyl)-, and 1-Ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydroindazoles

The corresponding 1-(2-quinoxalyl)-, 1-[3,5-di(trifluoromethyl)phenyl]-, and 1-ethoxycarbonyl-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles have been obtained from reactions of 2-acetyl-1,3-cyclohexanedione, its 5,5-dimethyl and 5-(2-furyl) derivatives, with 2-hydrazinoquinoxaline, 3,5-di(trifluoromethyl)phenylhydrazine, and ethoxycarbonylhydrazine. On interaction with ethoxycarbonylhydrazine the intermediate 2-[1-(-ethoxycarbonyl)hydrazino]ethylidene-1,3-cyclohexanediones were also isolated. From the potassium salt of 2-formyldimedone and 2-carboxyphenylhydrazine hydrochloride, 2-(2-carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione was obtained, the cyclization of which in ethanol in the presence of HCl led to 1-(2-carboxyphenyl)- and 1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole.     

Synthesis of Some New Thiazoles and Pyrazolo[1,5-a]pyrimidines Containing an Antipyrine Moiety

Ethyl 2-{2-[4-(2,3-dimethyl-5-oxo-1-phenyl-3-(pyrazolin-4-yl)]-2-cyano-1-(phenylamino)vinylthio}-acetate, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl-(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]2-(4-oxo-3-phenyl-(1,3-thiazoilidin-2-ylidene))ethanenitrile, 2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]-2-(4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))ethanenitrile, 2-(5-acetyl-4-methyl-3-phenyl(1,3-thiazolin-2-ylidene))-2-[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]ethanenitrile, and ethyl 2-(cyano(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)methylene)-2,3-dihydro-4-methyl-3-phenylthiazole-5-carboxylate were synthesized by treatment of 2-(4-(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-mercapto-3-(phenylamino)-acrylonitrile with appropriate halo ketones or halo esters. Also, 4-{2-[5,7-dimethyl-2-(phenylamino)(7a-hydropyrazolo[1,5-a]pyrimidin-3-yl](1,-thiazol-4-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one derivatives were synthesized via reaction of 4-{2-[5-amino-3-(phenylamino)pyrazolin-4-yl](1,3-thiazol-2-yl)}-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one with β-diketone or β-keto ester. All synthesized compound were established by elemental analysis, spectral data, and alternative synthesis whenever possible.     

Synthesis of 3-(2-guanidinoethyl) and 3-[2-(S-methylisothioureidoethyl)] analogs of 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate as a respective releaser of nitric oxide and inhibitor of nitric oxide synthase

The Hantzsch condensation of 2-azidoethyl acetoacetate with 2,3-dichlorobenzaldehyde and isopropyl 3-aminocrotonate afforded 3-(2-azidoethyl) 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate ( 7 ). Reduction of the 3-(2-azidoethyl) moiety of 7 using 5% palladium-on-calcium carbonate and hydrogen gas gave the 3-(2-aminoethyl) derivative 8 , which was subjected to guanylation using 1H-pyrazole-1-carboxamidine hydrochloride to yield the target 3-(2-guanidinoethyl) analog 9 . The 3-(2-aminoethyl) product 8 was elaborated to the title compound 3-[2-(S-methylisothioureidoethyl)] 5-isopropyl 2,6-dimethyl-1,4-dihydro-4-(2,3-dichlorophenyl)pyridine-3,5-dicarboxylate hydrochloride ( 12 ) via the intermediate 3-(2-thioureidoethyl) compound 10 . The 3-(2-guanidinoethyl 9 and 3-[2-(S-methylisothioureidoethyl)] 12 compounds were about 116- and 23-fold less potent calcium channel antagonists, respectively relative to the reference drug nifedipine.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

新型树形化合物1,3,5-三-[7-(7-甲基-2,2-二-(2,2-二羟甲基-3-羟基丙氧基羰基)-6,8-二氧杂螺[3.5]-壬基)]苯的合成

以丙酮和甲酸乙酯为原料, 在醇钠的作用下合成了1,3,5-三乙酰基苯(1). 1与二溴新戊二醇在酸的作用下发生缩酮化反应, 制成1,3,5-三-(1-甲基-2,6-二氧杂-4,4-二溴甲基环己基)苯(2). 2与5,5-二甲基-4,6-二氧杂-1,3-环己二酮在乙醇钠的作用下合成了1,3,5-三-[7-(7-甲基-2,2-二-乙氧羰基-6,8-二氧杂螺[3.5]-壬基)]苯(3). 将3在氯仿中与季戊四醇进行酯交换反应得到产物1,3,5-三-[7-(7-甲基-2,2-二-(2,2-二羟甲基-3-羟基丙氧基羰基)-6,8-二氧杂螺[3.5]-壬基)]苯(4). 收率为47.7%. 标题化合物及中间产物使用IR, ¹H NMR和MS或元素分析进行了表征.     

Cyclodimerization of 1-(Dimethoxyniethyl)-5,6-dimethylidene-7-oxa-bicyclo[2.2.1]hept-2-ene Induced by Nonacarbonyldiiron. Crystal Structure of (1RS, 2SR, 3RS, 4RS, 4aRS, 9aSR)- Tricarbonyl[C, 2,3, C-η-(1,4-epoxy-1,5-bis(dimethoxymethyl)-2,3-dimethylidene-1,2,3,4,4a,9,9a,10-octahydroanthracene)]iron

The transition-metal-carbonyl-induced cyclodimerization of 5,6-dimethylidene-7-oxabicyclo[2.2.1]hept-2-ene is strongly affected by substitution at C(1) While 5,6-dimethylidene-7-oxabicyclo[2.2.1]hept–2-ene-l-methanol ( 7 ) refused to undergo [4 + 2]-cyclodimerization in the presence of [Fe₂(CO)⁹] in MeOH, 1-(dimethoxymethyl)-5,6-di-methylidene-7-oxabicyclo[2.2.1]hept-2-ene ( 8 ) led to the formation of a 1.7:1 mixture of ‘trans’ ( 19, 21, 22 ) vs. ‘cis’ ( 20, 23, 24 ) products of cyclodimerization together with tricarbonyl[C, 5,6, C-η-(l-(dimethoxymethyl)-5,6-di-methylidenecyclohexa-1,3-diene)]iron ( 25 ) and tricarbonyl[C,3,4, C-η-(methyl 5-(dimethoxymethyl)-3,4-di-methylidenecyclohexa-1,5-diene-l-carboxylate)]iron ( 26 ). The structures of products 19 and of its exo ( 21 ) and endo ( 22 ) [Fe(CO)₃(1,3-diene)]complexes) and 20 (and of its exo ( 23 ) and endo (24) (Fe(CO)₃(1,3-diene)complexes) were confirmed by X-ray diffraction studies of crystalline (1RS, 2SR, 3RS, 4RS, 4aRS, 9aSR)-tricarbonyl[C, 2,3, C-η-(1,4-epoxy-1,5-bis(dimethoxymethyl])-2,3-dimethylidene-1,2,3,4,4a,9,9a,10-octahydroanthracene)iron ( 21 ). In the latter, the Fe(CO)₃(1,3-diene) moiety deviates significantly from the usual local C_s symmetry. Complex 21 corresponds to a ‘frozen equilibrium’ of rotamers with η-alkyl, η³-allyl bonding mode due to the acetal unit at the bridgehead centre C(1).     

Chemistry of iminofurans: V. Synthesis,structure, and cyclization of 4-R-4-oxo-2-[2-(2-oxo-1,2-diphenylethylidene)hydrazino]but-2-enoic acids

Reactions of 1,2-diphenylethane-1,2-dione hydrazone with 4-aryl-2-hydroxy-4-oxobut-2-enoic and 2-hydroxy-5,5-dimethyl-4-oxohex-2-enoic acids provided 4-aryl-4-oxo-2-[2-(2-oxo-1,2-diphenylethylidene) hydrazino]but-2-enoic and 5,5-dimethyl-4-oxo-2-[2-(2-oxo-1,2-diphenylethylidene)hydrazino]hex-2-enoic acids. The acids derivatives can exist in solutions as Z- and β-enehydrazino-or β-ketohydrazone forms, and under the treatment with acetic anhydride they undergo cyclization into 5-aryl- and 5-tert-butyl-3-[2-(2-oxo-1,2-diphenylethylidene)hydrazono]-2,3-furandiones.     

Azoles and Azines: CXIX. Alkylation of 5,5'-(4-Nitrobenzylidene)bis(2-thiobarbituric) Acid and 5-(4-Nitrophenyl)-2,8-dithioxo-5,7,8,9-tetrahydro-2H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H)-dione with Haloacetic Acids and Their Esters

5,5'-(4-Nitrobenzylidene)bis(2-thiobarbituric) acid and 5-(4-nitrophenyl)-2,8-dithioxo-5,7,8,9-tetrahydro-2H-pyrano[2,3-d:6,5-d']dipyrimidine-4,6(1H,3H)-dione, similar to unsubstituted 2-thiobarbituric acid, readily react with haloacetic acids and their esters to form regioselectively the S-alkylation products. The alternative routes fo 5,5'-(4-nitrobenzylidene)bis[(4-hydroxy-6-oxo-1,6-dihydropyrimidine-5,2-diyl)sulfanyl]diacetic acids, based on condensation of 4,6-dihydroxypyrimidin-2-ylthioacetic acid with carbonyl compounds followed by cyclodehydration to [(5-(4-nitrophenyl)-4,6-dioxo-3,5,6,7-tetrahydro-4H-pyrano[2,3-d:6,5-d']dipyrimidine-2,8-diyl)di(sulfanyl)]diacetic acid derivatives, are less efficient. Alkylation of 2-thiobarbituric acid with ethyl bromoacetate in ethanol in the presence of alkali yields 5-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-2-thiobarbituric acid.     

Synthesis of 1-[3-methyl-2(3H)-benzazolon-5- or 6-yl]-4-{4-[cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methyleneoxyphenyl}piperazines

Reactions of 3-methyl-6-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzoxazolone, 3-methyl-6-[4-(4-hydroxy-phenyl)-1-piperazinyl]-2(3H)-benzothiazolone and 1,3-dimethyl-5-[4-(4-hydroxyphenyl)-1-piperazinyl]-2(3H)-benzimidazolone with cis-{[2-(2,4-dichlorophenyl) -2-(1H-imidazol-1-ylmethyl)]-1,3-dioxolan-4-yl}methyl meth-anesulfonate in the presence of sodium hydride furnish the title compounds.     

Enantioselective syntheses of no-carrier-added (n.c.a.) (s)-4-chloro-2-[f] fluorophenylalanine and (s)-(α-methyl) -4-chloro-2-[f]fluorophenylalanine

(S)-4-Chloro-2-fluorophenylalanine and (S)-(α-methy)-4-chloro-2-fluorophenylalanine were synthesized and labeled with no carrier added (n.c.a.) fluorine-18 through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro-2-[¹⁸F]fluorobenzyl iodide and the lithium enolate of (2S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-4-chloro-2-[¹⁸F]fluorophenylalanine and (2S,5S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3,5-dimethyl-1,3-imidazolidine-4-one for (S)-(α-methyl) -4-chloro-2-[¹⁸F] fluorophenylalanine. Quantities of about 20–25 mCi were obtained at the end of sy nthesi s, ready for injection after hydrolysis and high performance liquid chromatography (HPLC) purification, with a radiochemical yield of 17%–20% corrected to the end of bombardment after a total synthesis time of 90–105 min from [¹⁸F] fluoride. The enantiomeric excesses were shown to be 97% or more for both molecules without chiral separation and the radiochemical and chemical purities were 98% or better.     

Rearrangements of 5-acetyl-3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-2H-pyran-2-one and 3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-5-ethoxycarbonyl-2H-pyran-2-one into 1-aminopyridine,pyrano[2,3-b]pyridine and isoxazole derivatives

Rearrangements of 5-acetyl-3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-2H-pyran-2-one ( 1 ) and 3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-5-ethoxycarbonyl-2H-pyran-2-one ( 7 ) in the presence of N-nucleophiles, such as ammonia, hydrazine, and hydroxylamine, into 1-aminopyridine, pyrano[2,3-b]-pyridine, and isoxazole derivatives 5, 11 , and 15 is described. In the reaction of compounds 1 and 7 with C-nucleophiles, such as 5,5-dimethyl-1,3-cyclohexanedione and barbituric acid, only substitution of the dimethylamino group is taking place to give the compounds 17, 18 , and 20 .     

Reactions of 1-[Benzoyl(2-hetaroyl)]-2,2-dimethyhydrazines with 1,3-Dibromopropyne, 2-Propynyl Bromide,and Allyl Bromide

Reactions of 1-[benzoyl(2-hetaroyl)]-2,2-dimethyhydrazines with 1,3-dibromopropyne in MeOH at 50°C afforded 2-phenyl(heteryl)-6-bromomethylidene-4,4-dimethyl-5H-1,3,4-oxadiazinium bromides. Reactions of 1-[benzoyl(2-hetaroyl)]-2,2-dimethyhydrazines with propargyl bromide and allyl bromide gave rise to 1,1-dimethyl-1-(2-propyn-1-yl)- and 1,1-dimethyl-1-(2-propen-1-yl)-2-benzoyl(hetaroyl)hydrazinium bromides. On treating these compounds with NaOH solution the corresponding imides were obtained.     

Reactions of 5-[3-(trifluoromethyl)-phenyl]furan-2-carbaldehyde

The Knoevenagel condensations of 5-[3-(trifluoromethyl)phenyl]furan-2-carbaldehyde with seven compounds containing an active methyl or methylene group have been studied. The compounds used were: methyl 2-cyanoacetate, malononitrile, 2-furylacetonitrile, acetophenone, 2-thioxo-1,3-thiazolidin-4-one (rhodanine), 5,5-dimethylcyclohexane-1,3-dione (dimedone), and methyl 2-azidoacetate. The effect of microwave irradiation on the condensation reactions was studied and compared with “’classical”’ conditions. Thermolysis of methyl 2-azido-3-{5-[3-(trifluoromethyl)phenyl]-2-furyl}propenoate afforded methyl 2-[3-(trifluoromethyl)phenyl)]-4H-furo[3,2-b]pyrrole-5-carboxylate. (2E)-3-{ 5-[3-(Trifluoromethyl)phenyl]-2-furyl}propenoic acid was converted to the corresponding azide, which was cyclized on heating into 2-[3-(trifluoromethyl)phenyl)]-4,5-dihydrofuro[3,2-c]pyridin-4-one. The latter after successive action of POCl₃ and NH₂NH₂-Pd/C gave 2-[3-(trifluoromethyl)-phenyl]furo[3,2-c]pyridine. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 825–831, June, 2006.     

Uncommon transformations of methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate initiated by bases

Methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate prepared in two stages from D-ribose acetonide underwent a series of uncommon transformations under the treatment with bases providing the following different products depending on the base applied: methyl 3-(5-acetyl-2,2-dimethyl-1,3-dioxol-4-yl)propionate (DBU), methyl 2,3-isopropylidenedioxy-7-oxabicyclo[2.2.1]heptane-6-carboxylate (t-BuOK), methyl {(5R)-2,2-dimethyl-5-[(2R)-oxiranyl]-1,3-dioxolan-4-ylidene}propionate and methyl-(E)-3-{(4S,5R)-2,2-dimethyl-5-[(1R)-(2-oxiranyl)]-1,3-dioxolan-4-yl}-2-propenoate (t-BuOK and LDA).     

5-(2-hydroxyphenyl)-1,2-dimethyl(1-methyl-2-vinylaryl)-1H-1,3,4-triazoles and their complexes with Zn(II)

The interaction of 2,3-dimethyl-4-oxo-1,3-benzoxazinium and 2-[β-(4-bromophenylvinyl)]-3-methyl-4-oxo-1,3-benzoxazinium perchlorates with hydrazine hydrate has afforded the corresponding triazoles that have been used as ligands for the synthesis of zinc complexes L₂Zn. Luminescent properties of the prepared complexes have been studied.

     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.     

Salze der Tris[1,2-äthandiolato(2-)]- und der Tris[2,3-butandiolato(2-)]arsensäure

Salts of the Tris[1.2-ethanediolato(2-)]- and of the Tris[2.3-butanediolato(2-)] Arsenic Acid Salts of tris[1.2-ethanediolato(2-)]arsenic acid and of tris[2,3-butanediolato(2-)]-arsenic acid are obtained by ester interchange of As(OCH₃)₅ with 1.2-diols in the presence of various amines.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

Reactions of 3-[N-chloroacetylamino-N-(4-nitrophenyl)]-2-formylindole with alkylamines

The reactions of 3-[N-chloracetylamino-N-(4-nitrophenyl)]-2-formylindole (1a) with 2-(N, N-dialkylamino)ethylamines afford complex condensation products 7b,c consisting of two similar but not identical diazepinoindole fragments. For the reaction of compound 1a with 3-(N,N-diethylamino)propylamine, the process occurs in a different manner, and the predominant product is 4-ethylaminopropyl-1-(4-nitrophenyl)-2-oxo-1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole hydrocloride (14). Two routes of these unexpected transformations were proposed. The structures of the synthesized products were proved by the ¹sH and ¹³C NMR, HMBC, and HSQC (direct proton-carbon correlation) spectra. Dedicated to Academician V. A. Tartakovsky on the occasion of his 75th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1536–1542, August, 2007.