Synthesis of 4‐hydroxyquinolin‐2(1H)‐one analogues and 2‐substituted quinolone derivatives

A versatile synthetic method for preparing 4‐hydroxyquinolone and 2‐substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates were keto esters 4a‐e , which could be transformed to 4‐hydroxyquinolones 5a,b or 2‐substituted quinolone ethyl esters 6a‐c depending on the reaction conditions. 4‐Hydroxyquinolone analogues were prepared and investigated for N‐methyl‐D‐aspartate (NMDA) activity in vitro. Among these derivatives, 6,7‐difluoro‐3‐nitro‐4‐hydroxyquinolin‐2(1H)‐one ( 9 ) exhibited moderate activity.     

2-取代氨基-5-去氢枞基-1,3,4-噁二唑衍生物的合成及除草活性

以去氢枞酸为原料,经酰化后与水合肼反应合成去氢枞酰肼3,再与芳基异硫氰酸酯反应,得到中间体1-去氢枞酰基-4-取代基氨基硫脲4,4在Hg(OAc)2/EtOH条件下关环,合成得到一系列新型2-取代氨基-5-去氢枞基-1,3,4-噁二唑化合物5.采用IR,MS,1HNMR,13C NMR和元素分析等方法对中间体4和目标产物5进行了分析和表征.初步的除草活性测试表明,化合物4和5对油菜的胚根生长以及对稗草的幼苗生长有一定的抑制作用,其中化合物4d在浓度为100mg/L时对油菜胚根生长的抑制率达88.2％.     

Studies on the Reaction of α‐Chloroformylarylhydrazine Hydrochloride with Imidazole and 1,2,4‐Triazole

α‐Imidazolformylarylhydrazine 2 and α‐[1,2,4]triazolformylarylhydrazine 3 have been synthesized through the nucleophilic substitution reaction of 1 with imidazole and 1,2,4‐triazole, respectively. 2,2′‐Diaryl‐2H,2′H‐[4,4′]bi[[1,2,4]‐triazolyl]‐3,3′‐dione 4 was obtained from the cycloaddition of α‐chloroformylarylhydrazine hydrochloride 1 with 1,2,4‐triazole at 60 °C and in absence of n‐Bu₃N. The inducing factor for cycloaddition of 1 with 1,2,4‐triazole was ascertained as hydrogen ion by the formation of 4 from the reaction of 3 with hydrochloric acid. 4 was also acquired from the reaction of 3 with 1 and this could confirm the reaction route for cycloaddition of 1 with 1,2,4‐triazole. Some acylation reagents were applied to induce the cyclization reaction of 2 and 3.1 possessing chloroformyl group could induce the cyclization of 2 to give 2‐aryl‐4‐(2‐aryl‐4‐vinyl‐semicarbazide‐4‐yl)‐2,4‐dihydro‐[1,2,4]‐triazol‐3‐one 6. 7 was obtained from the cyclization of 2 induced by some acyl chlorides. Acetic acid anhydride like acetyl chloride also could react with 2 to produce 7D . 5‐Substituted‐3‐aryl‐3H‐[1,3,4]oxadiazol‐2‐one 8 was produced from the cyclization reaction of 3 induced by some acyl chlorides or acetic acid anhydride. The 1,2,4‐triazole group of 3 played a role as a leaving group in the course of cyclization reaction. This was confirmed by the same product 8 which was acquired from the reaction of 1 , possessing a better leaving group: Cl, with some acyl chlorides or acetic acid anhydride.     

The pyridine ring of NAD is formed by a nonenzymatic pericyclic reaction

The biosynthesis of quinolinate 3, the precursor to the pyridine ring of NAD, is still poorly understood. Two pathways have been identified, one involving the direct formation of quinolinic acid from aspartate and dihydroxyacetone phosphate, the other requiring a five-step degradation of tryptophan. The final step in this degradation is catalyzed by the non-heme Fe(II)-dependent enzyme 3-hydroxyanthranilate-3,4-dioxygenase (HAD). This enzyme catalyzes the oxidative ring opening of 3-hydroxyanthranilate (1) to 2-amino-3-carboxymuconic semialdehyde (ACMS, 2) which then cyclizes to quinolinate (3). In this communication, we demonstrate the following: (1) cyclization of ACMS to 3 is not HAD catalyzed, (2) the most stable form of ACMS in solution is an all trans isomer which undergoes facile cis to trans isomerization about the C2-C3 and C4-C5 double bonds via transient formation of its enol tautomer (6), (3) a model study on the ring opening of N,N-dimethylcarbamoylpyridinium with hydroxide and methoxide suggests that the cyclization of ACMS occurs by an electrocyclization reaction of its enol tautomer 6. Thus, the biosynthesis of quinolinic acid, by the tryptophan pathway, is likely to be a member of a growing family of natural products whose biosynthesis involves a pericyclic reaction.     

Quantification of D/L-aspartic acids in Aplysia californica central nervous system by beta-cyclodextrin modified micellar electrokinetic chromatography.

In presence of an organic modifier (e.g. methanol), separation of amino acid enantiomers tagged with naphthalene-2,3-dicarboxaldehyde by beta-cyclodextrin modified micellar electrokinetic chromatography was dramatically improved. Coupled with laser-induced fluorescence detection, the method was well suited for analysis of D/L-amino acid enantiomers present in mass/volume-limited biological samples such as cell clusters. The five major ganglia dissected from the central nervous system of Aplysia californica, a widely used neuronal model, were analyzed to determine D- and L-aspartic acid enantiomers both free and bound in proteins/tissue matrix. The analyses revealed high levels of free D-aspartic acid ranging from 0.13 to 0.82 micromol/g wet tissue (or 6.0-21.2% of the total free aspartic acid) in all of the five ganglia. However, no D-aspartic acid was detected bound in protein/tissue matrix. The content of free D-aspartic acid in the liver tissue was also found below the detection limit of the method, which was 1 x 10(-8) M.     

Synthesis and crystal structure of some 3,5-pyrazolidinediones

Syntheses of various derivatives of 3,5-pyrazolidenedione are reported. This includes 4-arylidene (alkylidene or aralkylidene)-3,5-pyrazolidinediones, which on epoxidation gave unreported oxiranes. The syntheses of these derivatives were based on either the Knoevenagel reaction of carbonyl derivatives with 3,4-pyrazolidinedione or cyclization of arylidene (alkylidene) malonic acid hydrazide with glacial acetic acid. 4-Arylazo-3,5-pyrazolidinedione derivatives were also prepared by coupling of aryldiazonium salts with 3,5-pyrazolidinedione or cyclization of arylazomalonic acid hydrazide. Reduction of 4-benzylidene derivatives gave the corresponding benzyl derivatives. The structure of the new products was confirmed by elemental and spectral analyses and X-ray crystallography.     

Synthesis, properties, and oxidizing ability of 9,11-dimethylbenzocyclohepta[6,7-b]pyrimido[5,4-d]furan- 10(9H),12(11H)-dionylium tetrafluoroborate

Convenient preparation of novel 9,11-dimethylbenzocyclohepta[6,7-b]pyrimido[5,4-d]furan-10(9H),12(11H)-dionylium tetrafluoroborate 11*BF4- consisted of a condensation reaction of benzo[d]tropone with dimethylbarbituric acid and following oxidative cyclization reaction by using DDQ-Sc(OTf)3 or photoirradiation under aerobic conditions. Alternative synthesis of 11*BF4- was also accomplished by a condensation reaction of 2-methoxybenzo[d]tropone with dimethylbarbituric acid and a subsequent cyclization reaction by using 42% aq HBF4. The X-ray crystal analysis and MO calculation were carried out to clarify the structural characteristics. Properties of the cation 11 were studied by the pKR+ value (4.7) and reduction potentials (-0.46 and -1.07 V vs Ag/AgNO3) as well as the reaction with some nucleophiles. The oxidizing ability of 11*BF4- toward alcohols in the autorecycling process was demonstrated as well.     

Domino reaction of 1,3-bis(trimethylsilyloxy)-1,3-dienes with oxalyl chloride: general and stereoselective synthesis of gamma-alkylidenebutenolides

The Lewis acid catalyzed cyclization of oxalyl chloride with 1,3-bis(trimethylsilyloxy)-1,3-dienes 3, derived from 1,3-dicarbonyl compounds 1, provides a new and general approach for the synthesis of gamma-alkylidenebutenolides 4, a pharmacologically and synthetically important class of substances. A variety of butenolides were efficiently prepared in good yields and with very good regio- and stereoselectivities. An up-scaling of the reaction was possible. The use of the Lewis acid trimethylsilyl-trifluoromethanesulfonate (TMSOTf) proved to be superior to other activation conditions. Sterically undemanding gamma-alkylidenebutenolides could be prepared alternatively by reaction of the corresponding 1,3-dicarbonyl dianions with N,N'-dimethoxy-N,N'-dimethylethanediamide (2d). In contrast to the dianion method, the Lewis acid catalyzed reaction also facilitated the cyclization of sterically hindered, base-labile, cyclic and functionalized substrates. From a methodology viewpoint, the dianion reaction represents the first cyclization of a bis-Weinreb amide and the first cyclization of an oxalic acid-synthon with an ambident dianion. The TMSOTf-catalyzed reactions are both the first cyclizations of 1,3bis(trimethylsilyloxy)-1,3-dienes with a C2 dielectrophile and the first cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-dienes with a carboxylic acid dichloride or a related dielectrophile.     

研究硅酸聚合反应的新途经

用高分子反应统计理论研究了硅酸聚合反应.利用三甲基硅烷化-气相色谱法跟踪测定了聚合反应过程中各低聚态硅酸的含量变化,得到了分子数量分数分布.该分布符合含有内环化因子校正的A₁型缩聚反应统计理论,内环化反应是硅酸聚合反应的重要特征.     

Synthesis of 4H-1,3-benzoxazin-4-onium salts and 4-H-1,3-benzoxazin-4-ones

Salicylamide and its substituted derivatives react with aliphatic carboxylic acid anhydrides and perchloric acid to give 4H-1,3-benzoxazin-4-onium salts. These same compounds were obtained by acidic cyclization of O- and N-acylsalicylamides. The synthesized salts are converted to 2-substituted 4H-1,3-benzoxazin-4-ones by the action of triethylamine and are hydrolyzed by water to N-acylsalicylamides. The probable reaction scheme is examined.     

Synthesis of 2-amino-5-chloro-3-(trifluoromethyl)benzenethiol and conversion into 4H-1,4-benzothiazines and their sulfones

The synthesis of 2-amino-5-chloro-3-(trifluoromethyl)benzenethiol was achieved by hydrolytic cleavage of 2-amino-6-chloro-4-(trifluoromethyl)benzothiazole which was prepared by cyclization of 4-chloro-2-(trifluoromethyl)phenylthiourea by bromine in chloroform, the phenylthiourea was prepared by the reaction of 4-chloro-2-(trifluoromethyl)aniline with ammonium thiocyanate in hydrochloric acid. Condensation and oxidative cyclization of 2-amino-5-chloro-3-(trifluoromethyl)benzenethiol with β-diketones/β-ketoesters provided 4H-1,4-benzothiazines. Fluorinated sulfones were obtained by oxidation of the corresponding benzothiazines with 30% hydrogen peroxide in glacial acetic acid. The structures of the newly synthesized compounds were confirmed by spectral studies.     

Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1- fluoromethyl-4-oxo-4H-[1,3thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives

A series of 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H- [1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives (2a-1) was prepared and evaluated for antibacterial activity. These compounds were obtained by deacylation of 4-benzoyloxy-2-(1-chloro-2-fluoroethyl)thio-6,7- difluoroquinoline-3-carboxylate (10) and subsequent intramolecular cyclization followed by substitution with cyclic amines and then hydrolysis. The intramolecular cyclization reaction of 18, one of the diastereomers (17, 18) revealed that the cyclization reaction proceeded through an inversion to afford (-)-11a in good chemical and optical yield. The enantiomers of 2a were prepared from the enantiomers of 11a, which were obtained by the optical resolution of the racemate using high-performance liquid chromatography (HPLC). Compounds 2a,b showed excellent in vitro and in vivo antibacterial activity against both gram-negative and gram-positive bacteria including quinolone and Methicillin-resistant Staphylococcus aureus.     

Clean and Convenient One-Pot Synthesis of 4-Hydroxycoumarin and 4-Hydroxy-2-quinolinone Derivatives

A simple, efficient, and environmentally friendly procedure has been developed for the reaction of Meldrum's acid with phenol, substituted phenols, aniline, or substituted anilines with Eaton's reagent (phosphoric anhydride + methylsulfonic acid) as cyclization reagent. 4-Hydroxycoumarins and 4-hydroxy-2-quinolinones were synthesized in moderate yields by carrying out the reaction in solvent-free, convenient, and clean one-pot preparation.     

富马酸奈拉西坦的合成工艺改进

报道了一种合成富马酸奈拉西坦(7)的新工艺。以衣康酸二甲酯和苄胺为起始原料,经Michael加成和分子内环合反应制得1-苄基-5-氧代吡咯烷-3-羧酸甲酯(3); 3经NaBH₄还原得1-苄基-4-羟甲基-吡咯烷-2-酮(4); 4经甲磺酰化反应得1-苄基-5-氧代吡咯烷-3-羧酸甲磺酸酯(5); 5经氨解得奈拉西坦(6); 6与富马酸经成盐反应合成7,总收率78.4%,其结构经¹H NMR确证。     

Cyclization of 4,5‐Diamino Pyrazole Derivatives and Their Antibacterial Activities

A convenient synthesis of intermediate 4,5‐diamino‐3‐aryl‐1‐phenylpyrazoles 4a – 4c was reported. The different cyclization reactions were carried out with chalcone, 2‐mercaptoacetic acid and p‐anisialdehyde, ethyl chloroformate, glyoxal and thiourea to afford different N and S containing heterocycles. The reaction conditions were compared by conventional heating and microwave irradiation. The structures of the cyclization products were determined by analytical and spectroscopic data. All the synthesized compounds were screened for antibacterial activities in vitro.     

Stereoselectivity of superacid-catalyzed Pictet-Spengler cyclization reactions

[reaction: see text] High stereoselectivities were found in a wide range of superacid-catalyzed Pictet-Spengler cyclization reactions. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed under the superacid conditions as compared with the corresponding weak acid (TFA)-catalyzed (monocationic) cyclization reaction of the N-benzylidene-2-(3',4'-dimethoxy)phenethylamines that bear electron-donating groups on the cyclizing aromatic ring. The computational study also supported the energetic favorability of the cyclization of the N,N-diprotonated imine and revealed a significantly early transition-state structure.     

Study of Cyclization of Chelating Compounds Using Electrospray Ionization Mass Spectrometry

Electrospray ionization mass spectrometry (ESI-MS) was used for the study of cyclization of organic chelating compounds (chelators). Four chelating compounds were studed: Symmetrical ethylenediaminediacetic acid (s-EDDA), Unsymmetrical ethylenediaminediacetic acid (u-EDDA), N-(2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), and N-(2-hydroxyethyl)iminodiacetic acid (HEIDA). The chelators were cyclized with treatments of acids and heating. The open and cyclized form of the chelators were semi-quantified by both positive and negative ion modes ESI-MS. The kinetics of chelator cyclization was studied as a function of reaction temperature and the pH of the matrix. The cyclization of s-EDDA was found to be a pseudo-first order reaction in s-EDDA and overall second order. The cyclizations of HEIDA and HEDTA are reversible reactions. Higher temperature and lower pH favors cyclization.     

合成5-氯-1-甲基-4-硝基咪唑的工艺改进

以草酸二乙酯为原料,经酰胺化、环合、成盐及硝化反应合成了5-氯-1-甲基-4-硝基咪唑,总收率61.3%,其结构经1H NMR, IR和MS表征.本方法有两点改进: (1)在酰胺化反应中用30%～40%甲胺水溶液代替甲胺气体; (2)在成盐反应中直接向环化产物的丙酮溶液加硝酸析出5-氯-1-甲基咪唑硝酸盐晶体.     

Carbopyronine荧光染料中间体的有效合成方法

在非质子路易斯酸的辅助下高收率的合成了Carbopyronine荧光染料中间体2,7-双二甲氨基-9,10-二氢-9,9-二甲基蒽环。反应关键步骤是路易斯酸辅助下的环化反应,考查了几种路易斯酸的效果。确立了环化反应的最佳条件为： 2.5mol的路易斯酸与1mol的叔醇2在0 ˚C反应6 h,再于室温下反应10 h。     

3－芳基－6－三氯甲基－1，2，4－三唑并[3,4-b]-1,3,4-噻二唑的合成与波谱表征

首次报道3－芳基－4－氨基－5－巯基－1，2，4－三唑与三氯乙酸在三氯氧磷 存在下关环，合成了3－芳基－6－三氯甲基－1，2，4－三唑并[3,4-b]－1，3，4 －噻二唑，标题化合物结构经元素分析、红外光谱、核磁共振氢谱、碳谱与质谱确 证。