Structure and reactions of a thiazolino[3,2-a]pyrimidine carbinolamine

Ethyl 4-chloroacetoacetate condenses with 4-amino-6-hydroxy-2-pyrimidinethiol to yield ethyl 3-hydroxy-5-oxo-7-aminothiazolino[3,2-a]pyrimidin-3-acetate ( 3 ), and not ethyl 3-hydroxy-5-amino-7-oxothiazolino[3,2-a]-pyrimidin-3-acetate, as previously reported. This compound reacts with ammonia to produce ethyl 4-(6′-amino-4′-oxo-2′-pyrimidinethiol)-3-aminocrotonate ( 8 ), the open chain structure of which accounts for the cyclization of 3 to the poly-cyclic lactam, 6a-hydroxy-5,6,6a,7-tetrahydro-8-thia-1,4-diazacycl[3.3.2]azine-2,5-dione, rather than the sterically more favorable lactone, when 3 was treated with triethylamine. Some other reactions of 3 are described, and the structures of 3 and 8 were comfirmed by single crystal X-ray diffraction analysis.     

The synthesis of 3-deazapyrimidine nucleosides related to uridine and cytidine and their derivatives

Condensation of 2,4-bis(trimethylsilyloxy)pyridine ( 1 ) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2 ) gave 4-hydroxy-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 3 ). Deblocking of 3 gave 4-hydroxy-1-β-D-ribofuranosyl-2-pyridone (3′-deazauridine) ( 4 ). Treatment of 4 with acetone and acid gave 2′,3′-O-isopropylidene-3-deazauridine ( 6 ). Reaction of 4 with diphenylcarbonate gave 2-hydroxy-1-β-D-arabinofuranosyl-4-pyridone-O₂←2′-cyclonucleoside ( 7 ) which established the point of gylcosidation and configuration of 4 . Base-catalyzed hydrolysis of 7 gave 4-hydroxy-1-β-D-arabinofuranosyl-2-pyridone (3-deazauracil arabinoside) ( 12 ). Fusion of 1 with 3,5-di-O-p-toluyl-2-deoxy-D-erythro-pentofuranosyl chloride ( 5 ) gave the blocked anomeric deoxynucleosides 8 and 10 which were saponified to give 4-hydroxy-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazauridine) ( 11 ) and its α anomer ( 9 ). Condensation of 4-acetamido-2-methoxypridine ( 13 ) with 2 gave 4-acetamido-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 14 ) which was treated with alcoholic ammonia to yield 4-acetamido-1-β-D-ribofuranosyl-2-pyridone ( 15 ) or with methanolic sodium methoxide to yield 4-amino-1-β-D-ribofuranosyl-2-pyridone (3-deazacytidine) ( 16 ). Condensation of 13 and 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride ( 17 ) gave the blocked nucleoside 22 which was treated with base and then hydrogenolyzed to give 4-amino-1-β-D-arabinofuranosyl-2-pyridone (3-deazacytosine arabinoside) ( 23 ). Fusion of 13 with 5 gave the blocked anomeric deoxynucleosides 18 and 20 which were deblocked with methanolic sodium methoxide to yield 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazacytidine) ( 21 ) and its a anomer 19 . The 2′-deoxy-erythro-pentofuranosides of both 3-deazauracil and 3-deazacytosine failed to obey Hudson's isorotation rule but did follow the “quartet”-“triplet” anomeric proton splitting pattern in the ¹H nmr spectra.     

Synthesis of certain 1,2,4-triazole nucleoside derivatives

The syntheses of 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and its 2′-deoxy analog 8b as well as 5-amino-2-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-3-one ( 12 ) have been accomplished. Compounds 8a and 8b were synthesized via glycosylation of 3-bromo-5-nitro-1,2,4-triazole which was followed by replacement in three steps of the 3-bromo function to yield 3-nitro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 4a ) and its 2′-deoxy analog 4b . Compounds 4a and 4b were methylated at N², hydrogenated and deblocked to give 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and the 2′-deoxy analog 8b . Compound 12 was synthesized by glycosylation of 3-amino-1-methyl-1,2,4-triazolin-5(2H)-one ( 10 ). The structures of 8b and 12 were confirmed by single crystal X-ray diffraction analysis.     

Building libraries of skeletally diverse scaffolds from novel heterocyclic active methylene compound through multi-component reactions

Libraries of skeletally diverse potential bioactive polycyclic/spirocyclic heterocyclic compounds; 2-amino-7,9-dimethyl-5-oxo-4-aryl-4,5,6,7-tetrahydropyrano[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile, 2′-amino-7′,9′-dimethyl-2,5′-dioxo-6′,7′-dihydro-5′H-spiro[indoline-3,4′-pyrano[2,3-d]pyrazolo[3,4-b]pyridine]-3′-carbonitrile, and 5,5′-(arylmethylene)bis(4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) have been synthesized through a multi-component reaction using novel heterocyclic active methylene compound 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one as one of the building blocks. This protocol can be considered to be an efficient and eco-friendly strategy for diversity oriented synthesis.     

Synthesis of derivatives of <Emphasis Type="Italic">o</Emphasis>-aminoacetophenone and <Emphasis Type="Italic">o</Emphasis>-aminobenzyl alcohol

Oxidation of 2′-hydroxy-8-methylspiro[4H-benz-1,3-oxazin-2-one-6,1′-cyclopentane] or N-mesyl-2-(cyclopent-1-en-1-yl)-6-methylaniline provided the corresponding ketones. The rearrangement of these ketones oximes under treatment with thionyl chloride gave rise to nitriles of 5-(2-amino-3-methylphenyl)-5-oxopentanoic or 5-(2-methanesulfamido-3-methylphenyl)-5-hydroxypentanoic acids. By heating 5-(2-acetylamido-3-methylphenyl)-5-oxopentanoic acid with LiH in THF3-(2,8-dimethylquinol-4-on-3-yl)propanoic acid was obtained.     

New Monoterpene-Substituted Dihydrochalcones from Piper aduncum

Five New unusual monoterpene-substituted dihydrochalcones, the adunctins A–E (1″S)-1-{2′-hydroxy-4′-methoxy-6′-[4″-methyl-1″-(1?-methylethyl)cyclohex-3″ -en-1″ -yloxy]phenyl}-3-phenylpropan-1-one ( 1 ), (5aR*,8R*,9aR*)-3-phenyl-1-[5′,8′,9′,9′a-tetrahydro-3′-hydroxy-1′-methoxy-8′-(1″-methylethyl)-5′-a-methyldibenzo-[b,d]furan-4′-yl]propan-1-one ( 2 ), (2′R*,4″S*)-1-{6′-hydroxy-4′-methoxy-4″-(1?-methylethyl)spiro[benzo[b]-furan-2′(3′H),1″ -cyclohex-2″ -en]-7′-yl}-3-phenylpropan-1-one ( 3 ), (2′R*,4″R*)-1-{6′-hydroxy-4′-methylethyl-4″-(1?-methylethyl)spiro[benzo[b]furan-2′(3′H),1″-cyclohex-2″-en]-7′-yl}-3-phenypropan-1-one ( 4 ), and (5′aR*,6′S*, 9′R*,9′aS*)-1-[5′a,6′,7′,8′,9′a-hexahydro-3′,6′-methoxy-6′-methyl-9′-(1″-methylethyl)dibenzo[b,d]-furan-4′-yl]-3-phenylpropan-1-one ( 5 ) were isolated from the leaves of Piper aduncum (Piperaceae) by preparative liquid chromatography. In addition, (?)-methyllindaretin ( 6 ), trans-phytol, and α-tocopherol ( = vitamin E) were also isolated and identified. The structures were elucidated by spectroscopic methods, including 1D- and 2D-NMR spectroscopy as well as single-crystal X-ray diffraction analysis. The antibacterial and cytotoxic potentials of the isolates were also investigated.     

Synthesis of naphthyridinone derivatives as potential antimalarials

In this paper we present the synthesis of 8-(4′-amino-1′methyl-butylamino)-5-(β,β,β-trifluoroethoxy)-1,6-naphthyridine ( 4 ), 8-(4′-amino-1′methylbutylamino)-6-methyl-1,6-naphthyricline-5-one ( 5 ), two 1-alkyl-3-(4′-amino-1′-methylbutylamino)-7-methyl-1,8-naphthyridin-4-ones ( 20a ) and 20b ), 3-(1′-amino-4′-methylbutyl-amino)-l-ethyl-7-methyl-l,8-naphthyridin-4-one (20c), and 4-(4′-diethylamino-1′-methylbutylamino)-7-methyl-1,7-naphthyridin-8-one ( 28 ). The compounds were evaluated for antimalarial activity in the Plasmodium berghei screen and found to be inactive.     

Five-membered 2.3-dioxo heterocycles: LXVIII. Three pathways in the reaction of methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with 3-amino-5,5-dimethylcyclohex-2-en-1-one

Methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 3-amino-5,5-dimethylcyclohex-2-en-1-one having no substituent on the nitrogen atom to give 3-aroyl-4-arylamino-6′,6′-dimethyl-6′,7′-dihydro-5H-spiro[furan-2,3′-indole]-2′,4′,5′(1′H,5′H)-triones or methyl 12-aroyl-11-aryl-9-hydroxy-5,5-dimethyl-3,10-dioxo-8,11-diazatricyclo[7.2.1.0^2,7]dodec-2(7)-ene-1-carboxylates. The latter underwent thermal recyclization to 3′-aroyl-1′-aryl-4′-hydroxy-6,6-dimethyl-6,7-dihydrospiro[indole-3,2′-pyrrole]-2,4,5′(1H,1′H,5H)-triones.     

Synthesis of 2-[3′-(trifluoromethyl)anilino] -5-hydroxynicotinic acid

2-[3′-(Trifluoromethyl)anilino]-5-hydroxynicotinic acid (2) was synthesized by two routes: a) by direct hydroxylation of 2-[3′-(trifluoromethyl)anilino]nicotinie acid (1) ; and b) by the following sequence starting from 2-chloro-3-methyl-5-nitropyridine (3) via 5-amino-2-chloro-3-methylpyridine (4) , 2-ehloro-5-hydroxy-3-methylpyridine (6) , 5-acetoxy-2-chloro-3-methylpyridine (7) , 5-acetoxy-2-chloronicotinie acid (8) , and 2-chloro-5-hydroxynicotinic acid (9). The correlation of 2 with one of the metabolites of 1 has been accomplished, and the identities of both compounds have been proven.     

Various approaches to the use of 3-acetyl-2-amino-4-hydroxy-1,3-pentadienecarbonitrile in heterocyclic synthesis

Two approaches to the use of 3-acetyl-2-amino-4-hydroxy-1,3-pentadienecarbonitrile (1) in heterocyclic synthesis are considered. A method for preparing 3-acetyl-4-amino-5-cyano-2-methylpyridine directly from1 andN,N-dimethylformamide dimethylacetal (DMF DMA) was proposed, together with a synthetic route to 2-(2-amino-3-cyano-6-hydroxy-phenyl)-8-cyano-5-hydroxy-4-methylquinoline based on the transformation of hydroxyvinyl ketone1 into its diphenylboron chelate and condensation of the latter with DMF DMA. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 127–130, January, 1997.     

Two new xanthones from the pericarp of Garcinia mangostana

Two new xanthones, designated garcimangosxanthone F (1) and garcimangosxanthone G (2), were isolated from the EtOAc-soluble fraction of ethanolic extract from the pericarp of Garcinia mangostana. Their structures were established as 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6′,6′-dimethylpyrano[2′,3′:3,2]xanthone and 1,6,7-trihydroxy-5-(3-methylbut-2-enyl)-8-(3-hydroxy-3-methylbutyl)-6′,6′-dimethyl-4′,5′-dihydropyrano[2′,3′:3,2]xanthone, respectively, on the basis of their 1D, 2D NMR and MS data interpretation.     

Enantioselective synthesis of both enantiomers of the neuroexcitant 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA)

The preparation of both enantiomers of 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), 1, an analogue of the neuroexcitant 2-amino-3-(3-hydroxy-5-methyl-4-yl) propanoic acid (AMPA) is described. The enantiomerically pure glycine derivative tert-butoxycarbonyl-2-(tert-butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (BOC-BMI) was coupled with 4-bromomethyl-2-methoxymethyl-5-tert-butylisoxazolin-3-one 6 to give the intermediates (2R,5R)-8 and (2S,5S)-8. These alkylated products were hydrolyzed under mild conditions to give enantiopure (R)-1 and (S)-1 with e.e.'s in excess of 99% in 33% overall yield.     

SYNTHESIS OF NEW 8-METHOXY-4-METHYL-3-(N-[2′-AMINO-(1′,3′,4′)THIA/OXA-DIAZOL-5′-YL]-SUBSTITUTED METHYL)-AMINO THIOCOUMARINS

8-Methoxy-4-methyl-3-(N-[2′-amino-(1′, 3′,4′)thia/oxa-diazol-5′-yl] substituted methyl)-amino thiocoumarins 6(a–f) and 7(a–f), were synthesized by using the unreported 8-methoxy-4-methyl-3-[N-(2′-oxo-2′-methoxy-1′-substituted ethan-1′-yl) amino thiocoumarins as key intermediates.     

Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

基于羟苯基苯并咪唑的Zn2+比率荧光探针

通过羰基将两分子2-(4-氨基-2-羟苯基)苯并咪唑(4-AHBI)连接,合成了结构高度对称的新化合物N,N′-二-[3-羟基-4-(2-苯并咪唑)苯基]脲(C27H20N6O3,1),测试了不同溶剂条件下1的紫外吸收和荧光发射光谱,研究了1对Zn2+的选择性识别作用。结果表明,随着溶剂极性的增大,1的紫外吸收峰发生蓝移,激发态分子内质子转移(ESIPT)荧光发射峰明显增强。与4-AHBI相比,1在乙腈溶液中的紫外吸收强度增强约3.5倍,最大吸收峰红移8 nm,荧光发射增强8倍多。1在乙腈溶液中的Zn2+荧光响应行为表明1与Zn2+的结合将导致1在445 nm处的荧光强度不断降低,而在395 nm处出现的新峰的荧光强度不断增强,具有比率荧光探针的特点,而且检测范围较宽,可达1×10-6-1×10-2 mol.L-1。     

Studies in spiroheterocycles. Part XVII. synthesis of novel fluorine containing spiro[indole-pyranobenzopyran] and spiro[indenopyran-indole] derivatives

An elegant one-step synthesis of two novel spiro ring systems viz: spiro[3H-indole-3,4′-(2′-amino-3′-carbonitrile-[4′H]-pyrano[3,2-c]benzopyran)]-2,5′(1H)-dione8 and spiro[(2-amino-3-carbonitrile-indeno[1,2-b]pyran)-4(5H)>3′-[3H]indole]-2′,5(1′H)-diones in 80–85% yields is described. The spiro heterocycles were prepared by the reactions of fluorine containing 3-dicyanomethylene-2H-indol-2-ones with 4-hydroxy-2H-1-benzopyran-2-one and 1H-indene-1,3(2H)-dione respectively. The synthesized compounds have been characterized on the basis of elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral data.     

Streptonigrin and related compounds III. Synthesis and microbiological activity of destrioxyphenylstreptonigrin and analogues

Synthesis of three tricyclic analogues of streptonigrin, based on the 2-(2′-pyridyl)quinoline-5,8-dione system and with the characteristic substitution pattern of rings A and C of streptonigrin is described. The C-ring precursor, in the form of a substituted 2-acetylpyridine was condensed with either 3-hydroxy-5-methoxy-2-nitrobenzaldehyde or 3-hydroxy-4-methoxy-2-nitrobenzaldehyde, followed by reductive cyclization and oxidation to the corresponding quinones 12 and 29 . The 7-amino substitution was introduced in 12 via bromination and azidation. The 6-amino substitution was introduced through direct reaction of 29 with sodium azide. Destrioxyphenylstreptonigrin 2 was twice as active and the 6-amino-7-inethoxy analogue 4 was as active as streptonigrin in a microbiological assay. A 4′-bromo analogue of 2 was 60% as active as streptonigrin.     

Hydrolytic cleavages of 7-nitro-2-phenyl-1,2-benzisoxazol-3-one. Evidence for the occurrence of a benzidine-like rearrangement of N,O-diphenylhydroxylamines

Preparation of the title compound 1 is described. Its treatment with base caused hydrolysis of the amide bond and subsequent benzidine-like rearrangement to give 4′-amino-3-carboxy-4-hydroxy-5-nitrobiphenyl (4) . Acid treatment caused cleavage of the nitrogen-oxygen bond and rearrangement to 7-nitro-3-phenylbenzoxazol-2-one (6) .     

Pseurotin, a new metabolite of Pseudeurotium ovalis Stolk having an unusual hetero-spirocyclic system.

The structure and absolute configuration of pseurotin ( 1 ), a new metabolite, isolated from culture filtrates of Pseudeurotium ovalis STOLK (Ascomycetes), has been shown to be 2-[1′(S), 2′ (S)-dihydroxhex-3′-ene-yl]-3-methyl-8(S)-methoxy-8-benzoyl-9(R)-hydroxy-(5S)-1-oxa-7-aza-spiro[4.4]non-2-ene-4, 6-dione ( 1 ), by spectral data and chemical transformations, and by X-ray analysis of its dibromo derivative 2 [1].     

Regioselective conversion of 3-cyano-6-hydroxy-2-pyridones into 3-cyano-6-amino-2-pyridones

The reaction of a tautomeric mixture of 1-butyl-1,2-dihydro-6-hydroxy-4-methyl-2-oxopyridine-3-carbonitrile and its 2-hydroxy-6-oxo analog with phosphorus oxychloride gave 1-butyl-6-chloro-1,2-dihydro-4-methyl-2-oxopyridine-3-carbonitrile (68%) and 1-butyl-2-chloro-1,6-dihydro-4-methyl-6-pyridine-3-car-bonitrile (3%). Both chloropyridones were converted to their corresponding aminopyridones by reaction with liquid ammonia. Strong support for the molecular structure of 6-amino-1-butyl-1,2-dihydro-4-methyl-2-oxopyridine-3-carbonitrile was obtained on the basis of nmr techniques.