HALOACETYLATED ENOL ETHERS: 16[5] REGIOSPECIFIC SYNTHESIS OF 5-TRICHLOROMETHYL-PYRAZOLES

ABSTRACT

The regiospecific synthesis and isolation of three series of 5-trichloromethyl-pyrazoles 2f–j, 3a–j and 4a–j from the cyclocondensation of 1,1,1-trichloro-4-alkoxy-3-alken-2-ones (1a–f) or trichloroacetyl containing β-diketones (1g–j) with dry hydrazine and phenyl-hydrazine is reported. It was established by ¹H- and ¹³C-NMR spectroscopy that the 5-hydroxy-5-trichloromethyl-4,5-dihydro-1H-pyrazole intermediates 2a–j were formed quantitatively.     

Potassium–Tertiary Butoxide–Assisted Addition of Thioglicolic Acid to Chalcone Derivatives Under Solvent-Free Conditions

A series of chalcone derivatives containing thioglicolic acid (4a–j) was prepared by addition of thioglicolic acid to the chalcones (3a–j) in the presence of KOt-Bu under solvent-free conditions. The mechanistic pathway of the reaction can be explained by the Michael-type addition of thioglicolic acid to chalcone derivatives (3a–j).     

Junjappa–Ila (JI) Heteroaromatic Annulation: A New General α‐Oxoketene Dithioacetals Mediated Inverse Method for Synthesis of Substituted Benzothiazoles

3‐(Methylthio)‐5‐oxo‐2‐(2‐phenyl‐1,3‐thiazol‐4‐yl)‐4,5‐substituted‐pent‐2‐enenitriles 3a–j were obtained in good yields by condensation of (2‐phenyl‐1,3‐thiazol‐4‐yl)‐acetonitrile (1) with various α‐oxoketene dithioacetals 2a–j in the presence of sodium hydride. The intermediates 3a–j underwent smooth cyclization in the presence of PTSA to afford the corresponding benzothiazoles 4a–j in moderate yields.     

Sydnones as Masked Hydrazines for the Synthesis of 4‐Arylazo‐1,2‐dihydro‐pyrazol‐3‐one Derivatives

A simple and convenient one‐pot synthesis of 4‐(4‐chlorophenylazo)‐5‐methyl‐2‐aryl‐1,2‐dihydro‐pyrazol‐3‐ones (4a–j) has been carried out from 3‐arylsydnones (3a–j) by reaction with 2‐(4‐chlorophenyl)‐hydrazono‐3‐oxo‐butyric acid ethyl ester (2b). The 3‐arylsydnones are used as masked hydrazines in this reaction. Similarly, the 4‐arylazo‐2‐(7‐hydroxy‐4‐methyl‐2‐oxo‐2H‐chromen‐8‐ylmethyl)‐5‐methyl‐1,2‐dihydro‐pyrazol‐3‐ones (7a–j) were synthesized from 3‐[(7‐acetoxy‐4‐methyl‐8‐methylene)coumaryl]sydnone (5). All the newly synthesized compounds exhibited antimicrobial activity greater than the reference drugs used.     

Synthesis and Screening Antimicrobial Activities of Novel 1,3-Diaryl-3- (Phenylthio)Propan-1-One Derivatives

Abstract

In this study, a series of novel β-mercapto carbonyl derivatives (3a–j) was prepared by addition of thiophenol (2) to chalcones (1a–j) in the presence of catalytic amount of iodine (10 mol%) in CH₂Cl₂. Antibacterial and antifungal in vitro properties of the synthesized compounds were tested against some human pathogenic microorganisms by employing the disk diffusion technique. For the most active compounds, also minimum inhibitory concentrations (MICs) were determined.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Asymmetric synthesis and biological activities of natural product (+)-balasubramide and its derivatives

The natural product (+)-balasubramide (3j) and its derivatives (3a–3i) were synthesized using a two-step asymmetric synthesis, and the biological activities of 3a–3j were determined in vitro. Methyl (2S,3R)-(+)-3-phenyloxirane-2-carboxylate (1h), the asymmetric synthesis of which was described in a previous paper, was selected as the starting material. Compounds 3a–3j were evaluated for their neuroprotective, antioxidative, and anti-neuroinflammatory effects. (+)-Balasubramide and its derivatives with different electronegative groups in the 6-phenyl ring produced little neuroprotection and antioxidation, but induced potent anti-neuroinflammatory effects in BV-2 microglial cells (with the exception of 3g). Compound 3c, with a trifluoromethyl group in its 6-phenyl ring, was a particularly potent anti-neuroinflammatory agent. These results demonstrated that the electronegativity of the 6-phenyl ring of (+)-balasubramide is an important determinant of its inhibitory effect on neuroinflammation. More electronegative substituents result in more potent anti-neuroinflammatory effects. Moreover, cytotoxicity assays indicated no significant effects of the tested compounds.     

Improved Synthesis of (–)-Agelastatin A

Optimization of key steps in the synthesis of the architecturally unique tetracyclic antitumor alkaloid (–)-agelastatin A (1) improved the overall yield of the 11-step process (eight operations) from 9% to 23%. Changing the solvent and using a more efficient N-benzyl deprotecting-group procedure enhanced the yields of the C-ring and D-ring intermediates, (–)-4 and (–)-7, respectively. Bromination of (–)-7 with 1,3-dibromo-5,5-dimethylhydantoin, rather than N-bromosuccinimide (NBS), increased the yield of (–)-1 from 69% to more than 94% yield.     

Synthesis of New β,β′-Diketodithioethers via Swern Oxidation and Study of Their Hydrazone Formation Rate

The synthesis of β,β′-diketodithioethers 4b–j from corresponding β,β′-dihydroxydithioethers 3b–j was carried out by a Swern oxidation using DMSO-oxalyl chloride as oxidizing agent. β,β′-Dihydroxydithioethers 3b–j were prepared by the reaction of two molar equivalents of epoxides 1b–j with dimercaptoethane 2 in the presence of a saturated aqueous solution of potassium carbonate. The reactivity behavior of imine formation of the β,β′-diketodithioethers 4b–j by 2,4-dinitrophenylhydrazine was also investigated, and a mechanism was proposed by using molecular orbital (MO) calculations. To confirm the proposed mechanism, the role of the thia function to activate hydrazone formation by measuring HOMO-LUMO energy levels was also demonstrated.     

SYNTHESIS OF 2-(4-CHLOROBENZOYLAMIDO)-5-ARYLOXYMETHYL-1,3,4-OXADIAZOLES UNDER MICROWAVE IRRADIATION

2-(4-Chlorobenzoylamido)-5-aryloxymethyl-1,3,4-oxadiazoles (IIa–j) are synthesized by cyclization of 1-aryloxyacetyl-4-(4- chlorobenzoyl)-thiosemicarbazides (Ia-j) in the presence of mercuric acetate under the condition of microwave irradiation.     

Synthesis and Characterization of Novel Quinazoline-Substituted 1,3,4-Thiadiazolium-5-thiolates

Abstract

Novel 3-[4-(6-bromo-4-oxo-2-phenylquinazolin-3(4H)-yl)benzoyl]-2-substituted-1,3,4-thiazolium-5-thiolate 7(a–j) and 3-{4-[(6-bromo-2-phenylquinazolin-4-yl)amino] benzoyl}-2-substituted-1,3,4-thiadiazolium-5-thiolate 12(a–j) were synthesized from 6-bromo-2-phenyl-4H-3,1-benzoxazin-4-one (1). The structures of the newly synthesized compounds were confirmed by spectral data and elemental analysis.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

GRAPHICAL ABSTRACT     

Synthesis and biological evaluation of 1,2,4-oxadiazole linked 1,3,4-oxadiazole derivatives as tubulin binding agents

As an aspect of our ongoing research in search of new anticancer agents, a series of novel analogs of 1,3,4-oxadiazole embedded with 1,2,4-oxadiazole moieties (11a–j) were synthesized. The structure of the final compounds was confirmed by ¹H NMR, ¹³CNMR and mass spectroscopic techniques and evaluated for their in vitro anticancer activity against three human cancer cell lines (lung, breast). Among the synthesized compounds, 11?b, 11?g, 11?h, and 11i showed potent anticancer activity with IC₅₀ values within the range of 0.34?±?0.025 to 2.45?±?0.23?μM against three human cancer cell lines. Further, these compounds (11a–j) were investigated for molecular docking studies. Among them, compound 11?h showed strong binding affinity on binding sites of target protein EGFR (PDB ID: 4hjo) with highest docking score (-7.028). It revealed that 11?h was a strong tubulin binding agent.     

含2-三氟甲基苯并咪唑的双噁二唑硫醚及其亚砜衍生物的合成

芳甲酰肼和氯乙酸在二甲苯中反应生成了一系列的2-芳基-5-氯甲基-1,3,4-噁二唑(1a～1j), 继而与2-(2-三氟甲基苯并咪唑-1-亚甲基)-5-巯基-1,3,4-噁二唑(2)在乙醇-水的溶液中反应得到了一系列的含2-三氟甲基苯并咪唑的双噁二唑硫醚3a～3j, 再用硝酸氧化得到相应的亚砜衍生物4a～4j. 化合物的结构经元素分析, IR, ¹H NMR确证.     

Herstellung von 6,14-Ethenomorphinan-Derivaten

Zusammenfassung Dihydronorthevinon (2b) wurde aus Dihydrothevinon (2a) mit Azodicarbonsäurediethylester (DEAD) hergestellt und zu einigen neuen N-substituierten Dihydronorthevinon-Derivaten (2c–2g) umgesetzt. Es wurdenGrignard-Reaktionen dieser Verbindungen mit Methylmagnesiumiodid bzw.tert-Butylmagnesiumchlorid durchgeführt. O-Demethylierungen von3a–3j ergaben die entsprechenden N-substituierten Buprenorphin- bzw. Diprenorphin-Analoga4a–4j.

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Preparation of 6,14-ethenomorphinan derivatives

Summary Dihydronorthevinone (2b) was prepared from dihydrothevinone (2a) with diethyl azodicarboxylate (DEAD) and transformed into a number of new N-substituted dihydronorthevinone derivatives (2c–2g).Grignard reactions of the new compounds with methylmagnesium iodide andtert-butyl-magnesium chloride were studied. O-Demethylation of3a–3j resulted in the corresponding N-substituted buprenorphine and diprenorphine analogs4a–4j.

     

KHSO4-Assisted Michael Addition–Elimination Reactions of Indole with 3-Dimethylamino-1-phenylprop-2-en-1-ones in Water: An Environmentally Friendly Synthesis of Novel 3-Indolylchalcones

KHSO₄-assisted Michael addition–elimination reactions of 2-methylindoles and 1,2-dimethylindoles with 3-dimethylamino-1-phenylprop-2-en-1-ones (2) in water, leading to the formation of 3-(2-methyl-1H-indol-3-yl)-1-arylpropenones (3a–e) and 3-(1,2-dimethy-1H-lindol-3-yl)-1-arylpropenones (3f–j) respectively in good to excellent yields have been reported. However, cyclodehydration of adducts 3a–f to give carbazoles 4 failed to take place under the reaction conditions.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Microwave Assisted Synthesis of Biologically Active α-Aminophosphonates Catalyzed by Nano-BF3·SiO2 under Solvent-Free Conditions

Abstract

An efficient and high-yield synthesis of a class of new α-aminophosphonate derivatives as diethyl α-aryl/2-thienyl-α-[2-(phenylthio)phenylamino]methylphosphonates 6a–j in short reaction times from three component coupling reactions (Kabachnik-Fields reaction) of 2-aminodiphenylsulfide 3, substituted phenyl/heterocyclic aldehydes 4a–j, and diethyl phosphite 5 is reported. The reaction proceeds smoothly in the presence of the catalyst, nano-silica-supported boron trifluoride (BF₃·SiO₂) without using solvent under microwave irradiation. The title compounds were tested for in vitro antibacterial and antifungal activities at concentrations of 100 and 200 μg/disc. Minimum inhibitory concentrations (MICs) were also examined.

Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures and tables.     

Expression of theSU(2) rotation matrices D( j ) in terms of normalized irreducible tensorial matrices

TheSU(2) rotation matricesD ^(j), specified in terms of axis and angle of rotation, are expressed as linear combination of normalized irreducible tensorial matricces (NITM) of rankl = 0 to 2j rotated to the polar angles of the axis. The rotated NITM are constructed from spherical harmonics of the same rank. Since this formulation requires no matrix products, it may be computationally more efficient than Euler angle formulas, particularly for largej. Rotated NITM and formulas for theD ^(j) withj = 1/2 andj = 1 are written out explicitly. A formula for the structure constants of the products of conformable NITM is also given in terms of 3-j and 6-j symbols.     

Synthesis of Some Novel α-Cyanoketene-N,S-acetals Derived from Secondary Aliphatic Amines and Their Use in Pyrazole Synthesis

New α-cyanoketene-N,S-acetals 2(a–g) and β-dialkylamine-α-cyanoacrylates 3(g–i) were synthesized in good to excellent yields by the reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate 1 with secondary aliphatic amines (i.e., N-methylalkyl- and N-ethylalkylamines), and pyrrolidine, in the presence of triethylamine, under reflux in ethanol, for 1–16 h, depending on the amine used. Five N-methylalkyl amines and pyrrolidine yielded exclusively mono-substituted N,S-acetals 2(a–f) in good yields. On the other hand, N-ethylbenzylamine gave a mixture of monosubstituted products including N,S-acetal 2g in 35% yield and the unexpected product ethyl 3-[benzyl(ethyl)amino]-2-cyanoacrylate 3g in 50% yield. N-Ethylcyclohexylamine and N-ethylbutylamine did not produce N,S-acetals and gave only the unexpected products ethyl 2-cyano-3-[cyclohexyl(ethyl)amino]acrylate 3h and ethyl 3-[butyl(ethyl)amino]-2-cyanoacrylate 3i in good yields. The α-cyanoketene-N,S-acetals 2(a–f), 2j, and 2k underwent cyclization with the binucleophile hydrazine in ethanol under reflux to afford substituted pyrazoles 4(a–f), 4j, and 4k in good yields.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resources: Full experimental and spectral details.]     

Synthesis of New 4,5-Dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-amine–Derived Ureas and Their Anticancer Activity

A new series of 1,2,4-triazolo[4,3-a]-quinoline derivatives were designed and synthesized to meet the structural requirements essential for anticancer activity. N-1-(5-Methylisoxazol-4-yl/4-fluoro-2,3-dihydro-1H-inden-1-yl/aryl)-N’-3-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl) urea derivatives were accomplished in good yields by the reaction of 4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-amine with 3-(3-chloro-5-fluoro-2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylic acid, 4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid, and various simple aromatic carboxylic acids in the presence of diphenyl phosphoryl azide (DPPA). All the newly synthesized title compounds were characterized by elemental and spectral data. Furthermore, anticancer activity was screened for the title compounds (12a–j) in vitro against human neuroblastoma cell lines (SK N SH) and human colon carcinoma cell lines (COLO 205) by using the MTT cell viability method. A few of them (12a and 12b) possess significant cytotoxicity, and some other compounds 12d-f and 12j displayed moderate cytotoxicity against both cell lines.     

Synthesis of Some Prospective Bioactive Azeto[2,1-d][1,5]benzothiazepinones

Ten azeto[2,1-d][1,5]benzothiazepinone derivatives 6a–j were synthesized starting from 4-acetyl-2-phenyl-1,2,3-triazole 1. First, condensation of 1 with various aldehydes 2a–e afforded α,β-unsaturated carbonyl compounds 3a–e, which subsequently underwent cyclization with o-aminothiophenol to yield the corresponding 2,4-disubstituted-1,5-benzothiazepines 4a–e. Treatment of 4a–e with chloroacetyl chloride 5a or phenoxyacetyl chloride 5b by [2+2] cycloaddition reaction gave the title compounds 6a–j. The assignment of the structures of 6a–j was made by ¹H NMR, MS, and elemental analyses.     

溴代芳香碳糖苷的高效合成方法

首先在三氟乙酸银和无水四氯化锡体系中合成芳香碳糖苷2-(2,3,4,6-四-O-乙酰基-β-D-吡喃糖)-1,4-二甲氧基苯(4a和4b), 再以弱路易斯酸硝酸铵为催化剂, 使用N-溴代丁二酰亚胺(NBS)在温和条件下溴化4a和4b, 高产率地得到2-(2,3,4,6-四-O-乙酰基-β-D-吡喃糖)-5-溴-1,4-二甲氧基苯(1a和1b); 讨论了NBS和硝酸铵的用量对溴化反应的影响, 并对产物的NMR进行了解析.