Synthesis of 1,8- and 2,8-dihydrocycloheptapyrazol-8-one derivatives by the reactions of 3-acetyltropolone and its methyl ethers with phenylhydrazine

3-Acetyltropolone ( 1 ) reacted with phenylhydrazine to give 3-acetyltropolone phenylhydrazone ( 3 ) and 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one ( 4 ). The former ( 3 ) cyclized to afford the latter ( 4 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) with phenylhydrazine gave 4 , 3-methyl-2-phenyl-2,8-dihydrocyclo-heptapyrazol-8-one ( 5 ), and 3-methyl-2-phenyl-2,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 6 ). The compound ( 5 ) reacted with phenylhydrazine to afford 6 . The reaction of 7-acetyl-2-methoxytropone ( 2b ) with phenylhydrazone gave 7-acetyl-2-methoxytropone phenylhydrazone ( 7 ), 7-acetyl-2-(N′-phenylhydrazino)-tropone phenylhydrazone ( 8 ), 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 9 ), and 6 . The compound ( 7 ) was heated to afford 4 and reacted with phenylhydrazine to afford 8 and 9 . The compound ( 8 ) was also refluxed to give 9 .     

Synthesis of novel acyclonucleosides. Reactions of 1-(1-bromo or 3-bromo-2-oxopropyl)pyridazin-6-ones

Reaction of 1-(3-bromo-2-oxopropyl)pyridazin-6-ones 1 and 2 with sodium azide at room temperature gave the corresponding 1-(3-azido-2-oxopropyl)pyridazin-6-ones 3 and 4 , whereas reaction of 1-(1-bromo-2-oxo-propyl)pyridazin-6-ones 5 and 6 with excess sodium azide afforded 4-azido-5-chloropyridazin-6-one 7 and 4,5-diazido-3-nitropyridazin-6-one 8 by dealkylation. Some 1-(2-hydroxypropyl)pyridazin-6-ones 9, 10, 11 were synthesized from the corresponding 1-(2-oxopropyl) derivatives 1, 2, 3 . 4,5-Dichloro-1-(2,3-dihydroxypropyl)-pyridazin-6-one 13 was also prepared from compound 9 via the corresponding 2,3-epoxypropyl derivative 12 . Treatment of compound 5 with thiourea gave 4,5-dichloro-1-(2-amino-4-methylthiazol-5-yl)pyridazin-6-one 14 . Reaction of compounds 1 and 2 with thiourea at 20° afforded the corresponding 3-formamidinylthio-2-oxo-propyl derivatives 15 and 16 , whereas treatment of compound 1 with thiourea at 45° gave 4,5-dichloro-1-[(2-aminothiazol-5-yl)methyl]pyridazin-6-one 17 . Compound 17 was also prepared from compound 15 by refluxing in ethanol.     

Synthetic and structural study of 4-phosphacyclohexanones and 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones

The synthesis of bicyclic phosphorus–nitrogen (PN) compounds containing the rigid bicyclo[3.3.1]nonan-9-one framework was attempted using the Mannich condensation reaction of four different phosphorinanone classes with amines and aldehydes. Three different isomers of 4-tert-butyl-2,6-di(methoxycarbonyl)-3,5-bis(p-dimethylaminophenyl)-4-phosphacyclohexanone were obtained from the Michael addition reaction of tert-butylphosphine with 2,4-di(methoxycarbonyl)-1,5-bis(p-dimethylaminophenyl)penta-1,4-dien-3-one. The reaction of the all-equatorial isomer with methylamine and formaldehyde produced the bicyclic PN compound 7-tert-butyl-1,5-di(methoxycarbonyl)-6,8-bis(p-dimethylaminophenyl)-3-methyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one. The identical Mannich reaction of the enol tautomer also yielded the same product, as well as the PN compound 4-tert-butyl-6-methoxycarbonyl-5-(p-dimethylaminophenyl)-2-methyl-2-aza-4-phosphacyclohexanone and the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2-propenoate. The newly synthesised 3-aza-7-phosphabicyclo[3.3.1]nonan-9-one PN compound adopts a chair–chair conformation both in solution and the solid state.     

1,4-二硝基-2,3-二硝胺基哌嗪的合成

本文以乙二胺, 乙二醛和脲为原料, 通过Mannich反应, 合成出2,5,7,9-四氮杂双环[4.3.0]壬-8-酮盐酸盐(1); 化合物1 亚硝化给出2,5-二亚硝基-2,5,7,9-四氮杂双环[4.3.0]壬-8-酮(2); 硝化化合物2制得2,5,7,9-四硝基-2,5,7,9-四氮杂双环[4.3.0]壬-8-酮(3); 化合物3水解制得1,4-二硝基-2,3-二硝胺基哌嗪(4).     

New functionalization opportunities for <Emphasis Type="Italic">peri</Emphasis>-hydroxynaphthoyl and <Emphasis Type="Italic">peri</Emphasis>-fused heterocyclic compounds

A capability was studied of hydrogenated α-pyrone heterocycle in 7-methoxy-4-(4-methoxy-phenyl)-3,4-dihydro-2H-benzo[h]chromen-2-one to undergo aminolysis under the treatment with hydrazine hydrate, primary and secondary aliphatic and aromatic amines. A new approach was developed to the preparation of perihydroxyketone of naphthalene series containing a specific functional substituent in the ortho-position with respect to hydroxy group. The effect was revealed of an acetyl group in the position 9 of 7-methoxy-4-(4-methoxyphenyl)-3,4-dihydro-2H-benzo[h]chromen-2-one on the reaction of this compound with aliphatic amines and hydrazine hydrate. 9-Methoxy-1-(4-methoxyphenyl)-6-methyl-3H-benzo[de]pyrido[3,2,1-if]cinnolin-3-one [9-methyl-6-methoxy-3-(4-methoxyphenyl)-10,10a-diazapyren-1-one] was obtained, a new bis-peri-fused heteroaromatic system.     

含肟醚的新型三唑并嘧啶衍生物的合成及除草活性研究

2-巯基-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶(6)与氯乙醛或氯丙酮反应生成5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-硫丙酮(硫乙醛) (7). 中间体7与O-烷基(芳基)羟胺(5)反应得到目标化合物1-(5,7-二甲基-1,2,4三唑[1,5-a]嘧啶-2-硫)乙醛-O-烷基肟醚(9), 2-(5,7-二甲基-1,2,4三唑[1,5-a]嘧啶-2-硫)丙酮O-烷基肟醚(10). 初步生物活性测试结果表明部分化合物具有较好的除草活性.     

Constructing conformationally constrained macrobicyclic musks

To investigate the structure-odor correlation of musks, (12R)-12-methyl-13-tridecanolide (1), a macrocyclic musk, and 13-tridecanolide, its non-musky demethyl analogue, were conformationally constrained by introduction of methylene bridges between C-3 and C-8 or C-9. These [7.5.1]- and [8.4.1]-macrobicycles were synthesized starting from bicyclo[5.3.1]undec-8-en-9-one (3) and bicyclo[4.3.1]dec-7-en-8-one (8), respectively, by a sequence consisting of catalytic hydrogenation, alpha-alkylation with a TBS-protected (tert-butyldimethylsilyl) hydroxy halide, acid-catalyzed cyclization, oxidative cleavage of the formed enol ether double bond, and subsequent reduction of the carbonyl group via its tosylhydrazone. The compound (1R,6R,9R)-(+)-6-methyl-4-oxa-bicyclo[7.5.1]pentadecan-3-one (22) was found to possess the most pronounced musk odor, and this was rationalized by a superposition analysis with the polycyclic aromatic musk odorant (4S,7R)-Galaxolide (2). In its (1S,6R,9S)-(+)-stereoisomer 23 as well as in (1S,6R, 10R)-(+)-6-methyl-4-oxabicyclo[8.4.1]-pentadecan-3-one (18) the (6R)-methyl group seems to hinder the interaction with the musk receptor, while the demethyl compounds 7 and 12 showed only very faint odors.     

Microbial transformation of diosgenin by Syncephalastrum racemosum (Cohn) Schroeter

<正>Microbial transformation of diosgenin(1) by Syncephalastrum racemosum yielded five new polar metabolites,which wereidentified as(25R)-spirost-5-en-3β,7α,9α-triol-12-one(2),(25R)-spirost-5-en-3β,9α,12α-triol-7-one(3),(25R)-spirost-5-en-3β,9α-diol-7,12-dione(4),(25R)-spirost-4-en-9α,12β,14α-triol-3-one(5),and(25S)-spirost-4-en-9α,14α,25β-triol-3-one(6).Compounds 1-6 exhibited moderate cytotoxicity against K562 cells and among them compounds 2,3,and 6 were more potentthan the parent compound 1.     

Synthesis of optically active (+)-19-nortestosterone by asymmetric bis-annulation reaction

Michael reaction of 1,7-pctadien-3-one with 2-methylcyclopentane-1,3-dione, followed by intramolecular aldol condensation promoted by L-amino acids produced the optically active (+)-4-(3-butenyl)-7a-methyl-5,6,7,7a-tetrahydroindane-1,5-dione in high chemical and optical yields. The PdCl₂-catalyzed oxidation of the terminal double bond gave the methyl ketone, which had 76% optical purity and was made 100% optically pure by recrystallization. Then aldol condensation afforded the tricyclic ketone, which was alkylated with 3-butenyl iodide to afford (?)-3β-t-butoxy-2,3,3a,4,5,7,8,9,9aβ,9bα-decahydro-6-(3-butenyl)-3aβ-methyl-1H-benz[e]inden-7-one. The synthesis of this compound means the total synthesis of (+)-19-nortestosterone.     

Cyclisation of 4-[2-Cyclofentenyl]-3-Hydroxy [1] Benzopypan-2-One

4-[2-cyclopentenyl]-3-hydroxy [1] bonzopyran-2-one(3) was cyclised to the bicyclie coumar in-1,3-ethano-2-bromo-1,2-dihydro-3H-pyrano [2,3-c] [1] benzopyran-5-one (6) by a sequence of reactions viz. acetylation of 3, addition of bromine to cyclopenteny double bond and treating the resulting acetyldibromo compound (5) with 4% alcoholic KOH, Cyclisation of compound (3) with mercuric acetate in methanol gave condensed furan derivative 7 which on reductive demercuration with zinc borohydride in dimethoxyethane gave the 1,3-propano-1,2-dihydrofuro [2,3-c] [1] benzopyran-4-one, 8. Cyclisation of compound 2 with come. H₂SO₄ furnished a mixture of bicyclic derivative 9 ad furo coumarin derivative 8.     

New taxane derivatives: synthesis of baccatin[14,1-d]furan-2-one nucleus and its condensation with the norstatine side chain

New taxanes 15 and 18, containing the unsaturated and saturated baccatin[14,1-d]furan-2-one nucleus, respectively, were prepared starting from the readily available 13-oxo-7-Tes-baccatin III (3). Sequential formation of the enolate of 3 and reaction with ethyl glyoxylate gave the 13-oxo-7-Tes-baccatin[14,1-d]-3,4-dehydrofuran-2-one 4. The reduction of 4 can result in the formation of a mixture of compounds corresponding to 13-hydroxy alcohol 5 and 13-enol derivative 6. Both 5 and 6 were transformed into 13-oxo-7-Tes-baccatin[14,1-d]furan-2-one 8 by treatment with a base. Further reduction of 8 gave 13-hydroxy compound 9. Esterification of 6 and 9 with N,O-protected norstatine 12, followed by deprotection, gave the new promising anticancer taxanes 15 and 18, respectively.     

Syntheses of substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles

Starting from readily available ethyl-4-nitropyrrole-2-carboxylate ( 1 ), substituted 1-methyl-2-(1,3,4-thiadiazol-2-yl)-4-nitropyrroles and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-4-nitropyrroles were prepared. The reaction of 1 with diazomethane gave ethyl 1-methyl-4-nitropyrrole-2-carboxylate ( 2 ). Reaction of compound 2 with hydrazine hydrate afforded the corresponding hydrazide 3 . The reaction of 3 with formic acid yielded 1-(1-methyl-4-nitropyrrole-2-carboxyl)-2-(formyl)hydrazine ( 7 ). Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 6 in 40% yield. Reaction of compound 7 with phosphorus pentoxide afforded compound 9 . Reaction of compound 3 with 1,1′-carboxyldiimidazole in the presence of triethylamine yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-oxadiazoline-4(H)-5-one ( 11 ). Refluxing compound 3 with cyanogen bromide in methanol gave compound 12 . Compound 13 could be obtained through the reaction of compound 3 with carbon disulfide in basic medium. Alkylation of compound 13 afforded the correspanding alkylthio derivative 14 . Reaction of 1-methyl-4-nitropyrrole-2-carboxylic acid ( 15 ) with thiosemicarbazide and phosphorus oxychloride gave 2-amino-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 16 ). Sandmeyer reaction of compound 16 yielded 2-chloro-5-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazole ( 17 ). Refluxing of the latter with thiourea afforded 2-(1-methyl-4-nitro-2-pyrrolyl)-1,3,4-thiadiazoline-4(H)-5-thione ( 18 ). Alkylation of compound 18 gave the corresponding alkylthio derivative 19 . Oxidation of the latter with hydrogen peroxide in acetic acid yielded 2-(1-methyl-4-nitro-2-pyrrolyl)-5-methylsulfonyl-1,3,4-thiadiazole ( 20 ).     

Synthesis and molecular structure of 6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one

The title compound 6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][1,2,4]-triazin-8(7H)-one (4), molecular formula C(11)H(10)N(6)OS, was obtained by the reaction of 3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5(2H)-one (3) with carbon disulfide in a water/pyridine mixture. Compound 4 can also be synthesized by reacting 6-amino-3(2H)mercapto-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one (7) with benzyl bromide in methanolic ammonia water. The compound crystallizes in the monoclinic space group P2(1)/c with a = 7.2926(15), b = 14.456(2), c = 11.436(2) A, beta = 105.30(2) degrees , V= 1162.9(4) A(3) and Z = 4, resulting in a density Dcalc of 1.567 g/cm(3). Molecules of 4 are linked by extensive intermolecular N-H...N and N-H...O hydrogen bonding [graph set R(2)(2 )(9)]. The structure is further stabilized by pi-pi stacking interactions.     

An approach to acyclo-1-deazathymidine c-nucleosides via 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one.

An approach to the synthesis of acyclo-1-deazathymidine nucleosides is described. Diels-Alder reaction of 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one with acetylenic compounds 4 and 5 yielded the 3-[(tetrahydropyran-2-yl)oxy]-methyl- and 3-bromomethyl-5-methyl-2,6-dichloropyridine intermediates 7 and 8. The bromomethyl group of compound 8 underwent easy substitution with the appropriate nucleophiles, permitting the introduction of acycLo sugar moieties. The resulting 3-substituted 2,6-dichloro-5-methyl pyridines 9a,b - precursors for some acyclo pyridine-C-nucleosides - were treated with sodium phenylmethoride to afford 2,6-dibenzyloxypyridines 10a,b. Debenzylation using a palladium-strontium carbonate catalyst gave the unstable C-nucleosides 2a,b of the 6-hydroxy-1H-pyridin-2-one type. A stable 6-hydroxy-1H-pyridin-2-one 2c, exempt from benzylic oxygen, was obtained via cycloaddition of THP-protected 6-hydroxy-1-hexyne.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Synthesis and Crystal Structure of（9S,13R,14S）-7,8-Dehydro-4-（4′-bromobenzyloxy）-3,7-dimethoxy-l7-methyl-morphinan-6-one Monohydrate

The title compound(9S,13R,14S)-7,8-dehydro-4-(4'-bromo-benzyloxy)-3,7-dime-thoxy-17-methyl-morphinan-6-one monohydrate(O-4-bromobenzylsinomenine) was synthesized by the reaction of(9S,13R,14S)-7,8-dehydro-4-hydroxy-3,7-dimethoxy-17-methyl-morphinan-6-one with 4-bromobenzyl alcohol.Its chemical structure was determined by X-ray single-crystal diffraction.The crystal belongs to the monoclinic system,space group P21 with a = 8.890(2),b = 14.757(4),c = 9.205(2) ,β = 91.577(4)°,C26H30BrNO5,Mr = 516.42,μ = 1.740 mm-1,V = 1207.2(5)3,Z = 2,Dc = 1.421 mg/m3,F(000) = 536,R = 0.0785 and wR = 0.1889.     

Synthesis of analogues of the 2,3,6,-triazaphenothiazine ring system

Treatment of 2,3-dichloroquinoxalines with 2-amino-6-picoline-3-thiol gave a mixture of 2,3-bis(2-amino-6-picolinyl-3-thio)quinoxalines ( 16 , R = H, CI) and 2,3-bis (N,N-dimethylamino)quinoxalines ( 15 , R = H, CI) separated by fractional crystallization. A similar reaction of 3-amino-6-methoxypyridine-2(1H)-thione ( 9 ) with 4,5-dichloropyridazin-3(2H)-one ( 21 ) gave 4-chloro-5-(3-amino-6-methoxypyridyl-2-thio)pyridazin-3(2H)-one ( 22 ). Concentrated hydrochloric acid-catalysed cyclization of 22 gave the non-rearranged 7-methoxy-2,3,6-triazaphenothiazin-1(2H)-one. The action of compound 22 in refluxing glacial acetic acid gave, on the other hand, 7-methoxy-2,3,6-triazaphenothiazin-4(3H)-one via a Smiles rearrangement. These cyclized compounds are the first known derivatives of the new 2,3,6-triazaphenothiazine ring system.     

Reactions of 3-acetyltropolone and its methyl ethers with hydroxylamine. Formation of 8H-cyclohept[d]isoxazol-8-one and 8H-cyclohept[c]isoxazol-8-one

The reaction of 3-acetyltropolone ( 1 ) with hydroxylamine under the acidic condition gave 3-methyl-8H-cyclohept[d]isoxazol-8-one ( 4 ) and its oxime ( 5 ), and under the neutral condition gave 4 and 3-acetyltropolone oxime ( 6 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) with hydroxylamine under the acidic condition gave 4, 5 , and 4-methyl-1H-2,3-benzoxazin-1-one ( 7 ), and under the neutral condition gave 4, 7 , 3-methyl-8H-cyclohept[c]isoxazol-8-one ( 8 ), and its oxime ( 9 ). The reaction of 7-acetyl-2-methoxytropone ( 2b ) with hydroxylamine under the acidic condition gave 4 and 5 , and under the neutral condition gave 5, 7 , and 9 .     

Synthesis and Crystal Structure of (9S,13R,14S)-7,8-Dehydro-4-(4'-bromobenzyloxy)-3,7-dimethoxy-17-methyl-morphinan-6-one Monohydrate

The title compound (9S,13R,14S)-7,8-dehydro-4-(4'-bromo-benzyloxy)-3,7-dime- thoxy-17-methyl-morphinan-6-one monohydrate (O-4-bromobenzylsinomenine) was synthesized by the reaction of (9S, 13R, 14S)-7,8-dehydro-4-hydroxy-3,7-dimethoxy- 17-methyl-morphinan-6-one with 4-bromobenzyl alcohol.Its chemical structure was determined by X-ray single-crystal diffraction.The crystal belongs to the monoclinic system, space group P2<,1> with a = 8.890(2), b = 14.757(4), c = 9.205(2) (A), β = 91.577(4)°, C<,26>H<,30>BrNO<,5>, M<,r> = 516.42,μ = 1.740 mm<'-1>, V = 1207.2(5) (A)<'3>, Z = 2, D<,c> = 1.421 mg/m<'3>, F(000) = 536, R = 0.0785 and wR = 0.1889.     

(±)-19-去甲基-4(18),8,11,13-四烯-松香烷-7-酮的全合成

以间异丙基溴苯1为起始原料,通过进攻环氧乙烷及溴代两步制得溴化物3.溴化物3与Hagemann′s酯发生偶联反应,水解后生成偶联产物5.再以路易斯酸BF3·Et2O催化化合物5进行分子内环化为关键步骤得到反式稠合中间体6,最后通过与三苯基膦碘甲烷季盐发生Wittig反应及氧化,合成了(±)-19-去甲基-4(18),8,11,13-四烯-松香烷-7-酮[19-nor-abieta-4(18),8,11,13-tetraen-7-one](8).