Syntheses of various 5-(3′-substituted phenyl)uracils

The Suzuki Pd(0)-catalysed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium has been used for the preparation of 5-(3′-chlorophenyl)-, 5-(3′-iodophenyl)-, 5-(3′-aminophenyl)-, 5-(3′-azidophenyl)-, 5-(3′-methylthiophenyl)- and 5-(3′-styryl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4 di-t-butoxy-5-pyrimidineboronic acid and the six different aryl halides that were used as coupling partners, only 1-azido-3-bromobenzene did not give satisfactory yields, 18%. The other five aryl halides gave the desired 5-(3′-substituted phenyl)-2,4-di-r-butoxypyrimidines in 41–92% yield. Dealkylation of these five 5-(3′-substituted phenyl)-2,4-di-t-butoxypyrimidines in 2.5M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields. 5-(3′-Azidophenyl)uracil was prepared in 43% yield directly from 5-(3′-aminophenyl)-2,4-di-r-butoxypyrimidine.     

Brominated trimetrexate analogues as inhibitors of pneumocystis carinii and toxoplasma gondii dihydrofolate reductase

Five previously undescribed trimetrexate analogues with bulky 2′-bromo substitution on the phenyl ring were synthesized in order to assess the effect of this structure modification on dihydrofolate reductase inhibition. Condensation of 2-[2-(2-bromo-3,4,5-trimethoxyphenyl)ethyl]-1,l-dicyanopropene with sulfur in the presence of N,N-diethylamine afforded 2-amino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methyl-thiophene-3-carbonitrile ( 15 ) and 2-amino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethyl]thiophene-3-car-bonitrile ( 16 ). Further reaction with chloroformamidine hydrochloride converted 15 and 16 into 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-4-methylthieno[2,3-d]pyrimidine ( 8a ) and 2,4-diamino-4-[2-(2′-bromo-3′,4′,5′-trimethoxyphenyl)ethylthieno[2,3-d]pyrimidine ( 12 ) respectively. Other analogues, obtained by reductive coupling of the appropriate 2,4-diaminoquinazoline-6(or 5)-carbonitriles with 2-bromo-3,4,5-trimethoxyaniline, were 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)-5-chloro-quinazoline ( 9a ), 2,4-diamino-5-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 10 ), and 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxyanilinomethyl)quinazoline ( 11 ). Enzyme inhibition assays revealed that space-filling 2′-bromo substitution in this limited series of dicyclic 2,4-diaminopyrimidines with a 3′,4′,5′-trimethoxyphenyl side chain and a CH₂, CH₂CH₂, or CH₂NH bridge failed to improve species selectivity against either P. carinii or T. gondii dihydrofolate reductase relative to rat liver dihydrofolate reductase.     

Synthesis of aryl ω-(1-methyl-5-imidazolyl and 1H-5-tetrazolyl)alkyl ketones

Successful syntheses of 2,4-dichlorophenyl 2-(1-methyl-5-imidazolyl)ethyl and 2,4-dichlorophenyl 3-(1-methyl-5-imidazolyl)propyl ketones are described. In addition, syntheses of 2,4-dichlorophenyl and 4-chlorophenyl 3-(1-methyl-1H-5-tetrazolyl)propyl ketones are reported.     

Picryl derivatives of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one

Treatment of 5-nitro-2,4-dihydro-3H-1,2,4-triazol-3-one ( 1 ) with picryl fluoride (PkF) in 1-methyl-2-pyrrolidinone (NMP) gave a mixture of a monopicryl and a dipicryl derivative of 1 in a ratio of 2 :1 , respectively, regardless of the initial concentrations of 1 and PkF. The products were identified as 5-nitro-2-picryl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 2 ) by X-ray crystallography and 5-nitro-2,4-dipicryl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 4 ) by ¹⁵N labeling experiments.     

Photochemische reaktionen von übergangsmetall-organyl-komplexen mit olefinen XI. Photochemisch induzierte C---C-verknüpfung von tricarbonyl-η-2,4-dimethyl-2,4-pentadien-1-yl-mangan mit 1-dimethylamino-2-propin—Synthese eines η-7-dimethylamino-N-2,4-heptadien-1-yl-chelatkomplexes

UV irradiation of tricarbonyl-η⁵-2,4-dimethyl-2,4-pentadien-1-yl-manganese (2) in THF at 208 K yields solvent-stabilized dicarbonyl-η⁵-2,4-dimethyl-2,4-pentadien-1-yl-tetrahydrofurane-manganese (3), which reacts in situ with two equivalents of 1-dimethylamino-2-propyne (4) to dicarbonyl-1–5-η-2,4-dimethyl-(6-dimethylaminomethyl-N)-10-dimethylamino-deca-2,4,6,8- tetraen-1-yl-manganese (5). The crystal and molecular structure was determined by an X-ray diffraction analysis. Complex 5 crystallizes in the monoclinic space group P2₁/c, A = 1109.9(2) pm, B = 836.0(2) pm, C = 2156.9(4) pm, β = 93.23(3)°, V = 1.9982(7) nm³, Z = 4. Complex 5 was also studied in solution by IR and NMR spectroscopy. A possible formation mechanism of 5 will be discussed.

Zusammenfassung

UV-Bestrahlung von Tricarbonyl-η⁵-2,4-dimethyl-2,4-pentadien-1-yl-mangan (2) in THF bei 208 K liefert solvenstabilisiertes Dicarbonyl-η⁵-2,4-dimethyl-2, 4-pentadien-1-yl-tetrahydrofuran-mangan (3), welches in situ mit zwei Äquivalenten 1-Dimethylamino-2-propin (4) zu Dicarbonyl-1–5-η-2,4-dimethyl-(6-dimethylaminomethyl-N)-10-dimethylamino-deca-2,4,6,8-tetraen-1-yl-mangan (5) reagiert. Seine Kristall- und Molekülstruktur wurde durch eine Röntgenbeugungsanalye bestimmt. Komplex 5 kristallisiert in der monoclinen Raumgruppe P2₁/c, A = 1109.9(2) pm, B = 836.0(2) pm, C = 2156.9(4) pm, β = 93.23(3)°, V = 1.9982(7)_ nm³, Z = 4. Komplex 5 wurde auch in Lösung IR- und NMR-spektroskopisch untersucht. Ein möglicher Bildungsmechanismus von 5 wird diskutiert.     

The synthesis of 3H-pyrazol-3-one derivatives containing a 9H-xanthene ring

2,4-Dihydro-5-methyl-2-phenyl-4-(9H-xanthen-9-yl)-3H-pyrazol-3-one ( 3 ) was prepared by the condensation of phenylhydrazine and ethyl α-acetyl-9H-xanthene-9-acetate ( 2 ), or 9H-xanthen-9-ol ( 1 ) and 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one ( 4 ). 5-Amino-2,4-dihydro-2-phenyl-4-(9H-xanthen-9-yl)-3H-pyrazol-3-one ( 6 ) was obtained by the condensation of 1 and 5-amino-2,4-dihydro-2-phenyl-3H-pyrazol-3-one ( 5 ).     

Synthesis of new thietanylpyrimidine and thietanylimidazole derivatives

New thietanyl-substituted derivatives of pyrimidine-2,4(1H,3H)-dione and imidazole were synthesized. The alkylation of 6-methylpyrimidine-2,4(1H,3H)-diones with 2-chloromethylthiirane in water involved the N¹ atom of the pyrimidine ring and afforded 6-methyl-1-(thietan-3-yl)-pyrimidine-2,4(1H,3H)-diones. Under analogous conditions 6-aminopyrimidine-2,4(1H,3H)-dione gave rise to 6-(thietan-3-ylamino)pyrimidine-2,4(1H,3H)-dione. Unsymmetrically substituted 2-methyl-4(5)-nitro- and 5(4)-bromo-2-methyl-4(5)-nitro-1H-imidazoles reacted with 2-chloromethylthiirane to produce mixtures of isomeric 2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles and 5(4)-bromo-2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles.     

Pyrimidine derivatives. IX . Synthesis of bromosubstituted 5-nitro-2,4(1H,3H)-pyrimidinedione derivatives

The following 5-nitro-2,4(1H,3H)-pyrimidinediones possessing bromo substituted side chains at the 1- and 6-positions were prepared by bromination of 3,6-dimethyl-1-(ω-hydroxyalkyl)-5-nitro-2,4(1H,3H)-pyrimidinediones 4a and 4b and its nitrates 2a and 2b . The three of mono-bromo derivatives are: 1-(ω-acetoxyalkyl and ω-hydroxyalkyl)-6-bromomethyl-3-methyl. 6a, 6b, 7a and 7b and 1-(ω-bromoalkyl)-3,6-dimethyl-2,4(1H,3H)- pyrimidinediones 8a and 8b . The one type dibromo derivatives are: 1-(ω-bromoalkyl)-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinediones 5a and 5b .     

Pyrimidine derivatives. VI. Synthesis of mono-, di-, tri-, and tetrabromo-substituted pyrimidine derivatives

The following bromo-2,4(1H,3H)-pyrimidinediones possessing a bromo substituent at the 5-position and side chains at the 1- and 6-positions were prepared. The three types of mono-bromo derivatives are: 1-(bromoalkyl)-3,6-dimethyl- 3a-d , 5-bromo-3,6-dimethyl-1-(hydroxyalkyl)- 4a-d , and 1-(acetoxyalkyl)-5-bromo-3,6-dimethyl-2,4(1H,3H)-pyrimidinediones 11a-d . The three types of dibromo derivatives are: 5-bromo-1-(bromoalkyl)-3,6-dimethyl- Sa-d , 1-(acetoxyalkyl)-5-bromo-6-bromomethyl- 8a, 8c , and 8d , and 5-bromo-6-bromomethyl 1-(hydroxyalkyl)-2,4(1H,3H)-pyrimidinediones 9a, 9c , and 9d . Likewise one group of tribromo and one group of tetrabromo derivatives are: 5-bromo-1-(bromoalkyl)-6-bromomethyl -7a-d and 5-bromo-1-(bromoalkyl)-6-dibromomethyl-2,4(1H,3H)-pyrimidinediones 6a-d .     

A Synthesis of Phosphorylated 2,4-Dioxothiazolidine Derivatives

Abstract

The zwitterionic 1:1 intermediates generated from trialkyl phosphites and dialkyl acetylenedicarboxylates are trapped by 2,4-thiazolidinedione and 5-arylidene- 2,4-thiazolidinediones to produce dialkyl 2-(2,4-dioxothiazolidin-3-yl)-3-(dialkoxyphosphoryl) succinates and dialkyl 2-(5-arylidene-2,4-dioxothiazolidin-3-yl)-3-(dialkoxyphosphoryl) succinates in good yields.

GRAPHICAL ABSTRACT     

Syntheses of various 5-(bromoaryl)-substituted uracils

The Suzuki Pd(0)-catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium, previously further developed by us, has been used for regioselective preparation of 5-(2′-bromo-5′-furyl)-, 5-(2′-bromo-4′-furyl)-, 5-(2′-bromo-5′-thienyl)-, 5-(2′-bromo-4′-thienyl)-, 5-(4′-bromo-2′-thiazolyl)-, 5-(3′-bromophenyl)-, 5-(6′-bromo-2′-pyridyl)- and 5-(4′-bromo-2′-pyrimidyl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4-di-t-butoxy-5-pyrimidineboronic acid and the nine different aryl dibromides that were tried as coupling partners, only the 2,4- and 2,5-dibromothiazoles did not give satisfactory yields, 15% and 0%, respectively. The other seven aryl dibromides gave the desired 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 58-89% yield. Attempts to synthesise 2,4-di-t-butoxy-5-(2′-bromo-4′-thienyl)pyrimidine from 2-bromo-4-iodothiophene failed. Dealkylation of the 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 2.5 M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields.     

Spectral and thermal studies on ruthenium carbonyl complexes with 5-trifluoromethyl-2,4-dihydropyrazol-3-one ligands

Reactions of the cluster compound [Ru(3)(CO)(12)] with 5-trifluoromethyl-2,4-dihydropyrazol-3-one (HL(1)), 4-(2,4-dichlorophenylhydrazono)-5-trifluoromethyl-2,4-dihydropyrazol-3-one (H(2)L(2)), 4-(3-fluorophenylhydrazono)-5-trifluoromethyl-2,4-dihydropyrazol-3-one (H(2)L(3)), 4-(3-trifuoloromethyl-phenylhydrazono)-5-trifluoromethyl-2,4-dihydropyrazol-3-one (H(2)L(4)) and 4-(3-nitrophenylhydrazono)-5-trifluoromethyl-2,4-dihydropyrazol-3-one (H(2)L(5)) have been carried out in benzene and under reduced pressure. The structures of the isolated complexes were elucidated using elemental analyses, IR, UV-vis, mass and NMR spectroscopy. All the complexes are diamagnetic and have trigonal bipyramidal structures with general formulae [Ru(CO)(4)(HL(1))] and [Ru(CO)(3)(H(2)L(2-5))]. The thermal decompositions of the complexes were studied in correlation with the mass spectral fragmentation patterns.     

New method for the annelation of a pyridine ring on derivatives of imidazole and benzimidazole

The interaction of (Z)-1,3-diaryl-4-bromo-2-buten-1-ones with 1-substituted (benz)imidazoles in benzene gave (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-imidazolium bromides and (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-benzimidazolium bromides which readily cyclize in the presence of base to form derivatives of 7,9-diarylpyrido[1,2-a]benzimidazole and 6,8-diarylpyrimidazo[1,2-a]pyridine. The effects of the nature of substituents in the benzene ring of the diarylbutenones and the substituent at N(1) in the (benz)imidazoles on the alkylation and cyclization reactions has been studied. The optimum conditions for the synthesis of the 5-R-4-hydroxy-2,4-diphenyl-4,5-dihydro-1H-pyrido[1,2-a]benz-imidazol-10-ium, 5-R-2,4-diaryl-4-hydroxy-4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium, and 5-R-2,4-diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium have been found.     

Synthesis of 3H-pyrazol-3-one derivatives containing a 9H-thioxanthene ring

2,4-Dihydro-5-methyl-2-phenyl-4-(9H-thioxanthen-9-yl)-3H-pyrazol-3-one ( 3 ) was prepared by condensing 9H-thioxanthen-9-ol ( 1 ) with 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one ( 2 ), or by cyclizing ethyl α-acetyl-9H-thioxanthene-9-acetate ( 4 ) with phenylhydrazine. 2,4-Dihydro-5-methyl-2-phenyl-4-(9H-thioxan- then-9-yl)-3H-pyrazol-3-one 10,10-dioxide ( 8 ) was prepared by cyclizing ethyl α-acetyl-9H-thioxanthene-9-acetate 10,10-dioxide ( 7 ) with phenylhydrazine. Compound 8 was also obtained by oxidizing 3 with hydrogen peroxide in acetic acid. 5-Amino-2,4-dihydro-2-phenyl-4(9H-thioxanthen-9-yl)-3H-pyrazol-3-one ( 10 ) was obtained by condensing 1 with 5-amino-2,4-dihydro-2-phenyl-3H-pyrazol-3-one ( 9 ).     

Synthesis and Pharmacological Evaluation of Chlorinated N-Alkyl-3- and -5-(2-hydroxyphenyl)pyrazoles as CB1 Cannabinoid Ligands

The syntheses of several new 3- and 5-(4-chloro-2-hydroxyphenyl)-5- and -3-(2,4-dichlorophenyl)-1-alkylpyrazoles are reported. These syntheses started from simple chlorophenols, 2,4-dichlorobenzaldehyde or ethyl 2,4-dichlorobenzoate in order to prepare pyrazoles bearing three and four chloro substituents in certain positions. The affinity of these compounds towards the CB ₁ type cannabinoids receptors was then evaluated in human brain tissues (frontal cortex). The results showed that some of the compounds exhibit affinity towards this kind of receptors in the micromolar range.     

Reactions of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with Electrophiles

 Treatment of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with haloalkanes yielded oxadiazole S-alkyl derivatives, whereas its reaction with formaldehyde and amines resulted in formation of oxadiazole N(3)-aminomethyl derivatives. The alkylation of 2-alkylsulfanyl-5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazoles with methyl bromoacetate proceeded at the N(1)-position of pyrimidine to give 2-alkylsulfanyl-5-(1-methoxycarbonylmethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazoles, whereas aminomethylation, bromination, or nitration took place at position 5 of pyrimidine ring and afforded the corresponding 5-pyrimidine substituted derivatives.     

含一价铜配合物的新型双金属钼氧簇合物[5-(4-Br-Ph)-2,4'-Hbpy]2·[CuⅠ(5-(4-Br-Ph)-2,4'-bpy)2]2[Mo8O26]的水热合成及晶体结构

采用水热法合成出一种含一价铜配合物的新型双金属钼氧簇合物[5-(4-Br-Ph)-2,4'-Hbpy]2[Cu(5-(4-Br-Ph)-2,4'-bpy)2]2[Mo8O26],并通过X射线单晶结构分析、红外光谱分析、元素分析以及X射线粉末衍射分析对该化合物的结构进行了表征.结果表明,该化合物属单斜晶系,P21/c空间群,晶胞参数a=1.4411(3)nm,b=1.3924(3)nm,c=2.5183(5)nm,β=99.06(3)°,V=4.990(17)nm3,Z=2;该化合物是由一价铜配合物{Cu(5-(4-Br-Ph)-2,4'-bpy)2}+与{β-Mo8O26}4-簇通过共价配位键连接形成的新型多金属钼酸盐,其中游离的质子化配体作为抗衡阳离子.     

Synthesis of tetronic acid enamine. Dienamine derivatives from 3-(2H)furanones

The synthesis of 5-aryl (or alkyl) aminomethylene-3-(1-amino or 1-alkylaminoethylidene)-2,4-dioxo-(3H,5H)furans and 5-arylaminomethylene-3-(1-hydroxyethylidene)-2,4-dioxo-(3H,5H)furans (new 3-acetyltetronic acid derivatives) are described. The stereochemistry of these compounds from the ¹H nmr data is discussed.     

Synthesis and Pharmacological Evaluation of Chlorinated <Emphasis Type="Italic">N</Emphasis>-Alkyl-3- and -5-(2-hydroxyphenyl)pyrazoles as <Emphasis Type="Italic">CB</Emphasis><Subscript>1</Subscript> Cannabinoid Ligands

Summary. The syntheses of several new 3- and 5-(4-chloro-2-hydroxyphenyl)-5- and -3-(2,4-dichlorophenyl)-1-alkylpyrazoles are reported. These syntheses started from simple chlorophenols, 2,4-dichlorobenzaldehyde or ethyl 2,4-dichlorobenzoate in order to prepare pyrazoles bearing three and four chloro substituents in certain positions. The affinity of these compounds towards the CB ₁ type cannabinoids receptors was then evaluated in human brain tissues (frontal cortex). The results showed that some of the compounds exhibit affinity towards this kind of receptors in the micromolar range.     

Synthesis of 1-halophenyl 4-(2-imidazolyl)-1-butanones and 5-(2-imidazolyl)-1-pentanones and their ketalization with glycerol

An alternate synthesis of 1-(2,4-dichlorophenyl)-4-(2-imidazolyl)-1-butanones 5d is presented after 1-[(dimethylamino)methyl- and 1-methyl]-2-lithioimidazole failed to be substituted satisfactorily by 2-(2,4-dichlorophenyl)-2-(3-iodopropyl)-1,3-dioxolane ( 3b ). The Pinner addition of ethanol to 2-(2,4-dichlorophenyl)-2-(3-cyanopropyl)-1,3-dioxolane yielded the corresponding imidate which was reacted with 1-amino-2,2-dimethoxyethane to form an amidine. Hot dilute hydrochloric acid converted this ami-dine to the 2-imidazolyl ketone 5b . Syntheses of homologous 1-(4-chloro- and 2,4-dichlorophenyl)-4-(2-imidazolyl)-1-pentanones 20 are described. Ketalizations of 5 and 20 with glycerol formed imidazolyl 1,3-dioxolanyl alcohols. Selective N- and O-alkylations of some of these imidazolyl alcohols are described.