Synthesis,psychotropic and anticancer activity of 2,2‐dimethyl‐5‐[5′‐trialkylgermyl(silyl)‐2′‐hetarylidene]‐1,3‐dioxane‐4,6‐diones and their analogues

A series of 2,2‐dimethyl‐5‐(5′‐R‐hetarylidene)‐1,3‐dioxane‐4,6‐diones has been synthesized for examing a structure–activity relationship. Furyl and thienyl derivatives of Meldrum's acid possess neurotropic activity comprising both depriming and activating components. Comparison of acute toxicity of carbon, silicon and germanium analogues in the furan series of the compounds has demonstrated that the germanium derivative is 11.5 times less toxic than the carbon analogue and four times less toxic than the silicon derivative. 2,2‐Dimethyl‐5‐(5′‐triethylsilyl‐2′‐thenylidene)‐1,3‐dioxane‐4,6‐dione has moderate toxicity with the highest neurotropic and cytotoxic activity Copyright © 2003 John Wiley & Sons, Ltd.     

Embryotoxicity studies of tri‐n‐butyltin(IV) complexes of 5‐[(E)‐2‐(aryl)‐1‐diazenyl]‐2‐hydroxybenzoic acid and 2‐[(E)‐2‐(3‐formyl‐4‐hydroxyphenyl)‐1‐diazenyl] benzoic acid on sea urchin development

The toxicity studies of free 5‐[(E)‐2‐(aryl)‐1‐diazenyl]‐2‐hydroxybenzoic acid and 2‐[(E)‐2‐(3‐formyl‐4‐hydroxyphenyl)‐1‐diazenyl]benzoic acid and their tri‐n‐butyltin(IV) complexes were evaluated by using sea urchin early developmental stages as recommended model organisms for toxicity tests. The novel complexes, as the parent tri‐n‐butyltin(IV) chloride (TBTCl), caused mitosis block and induced high embryonic mortality in sea urchin. Copyright © 2005 John Wiley & Sons, Ltd.     

The Synthesis of 2‐(Chromon‐2/3‐yl)‐3‐(5‐thione‐4‐hydro‐1,3,4‐thiadiazol‐2‐yl)‐4‐oxo‐thiazolidine

2‐Formylchromones and 3‐formylchromones as the first materials singly reacted with 2‐amino‐5‐mercapto‐1,3,4‐thiadiazole to give the corresponding Schiff bases, which on cyclocondensation with mercapto‐acetic acid in 1,4‐dioxane yielded target compounds named 4‐oxo‐thiazolidines. The structures of all the synthetic compounds were confirmed by elemental analysis and IR, ¹H NMR, LC‐MS (ESI) spectral data.     

Synthesis of 3‐[5‐methyl‐1‐(4‐methylphenyl)‐1,2,3‐triazol‐4‐yl]‐6‐substituted‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazoles

Several 3‐[5‐methyl‐1‐(4‐methylphenyl)‐1,2,3‐triazol‐4‐yl]‐6‐substituted‐1,3,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazoles have been synthesized and the structures of these compounds were established by elemental analysis, MS, IR and ¹H NMR spectral data.     

Heterocyclic Systems Containing Bridged Nitrogen Atom: Synthesis and Antibacterial Activity of 3‐(2‐Phenylquinolin‐4‐yl)/3‐(1‐p‐Chlorophenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazine Derivatives

The condensation of 4‐amino‐5‐mercapto‐3‐(2‐phenylquinolin‐4‐yl)/3‐(1‐p‐chlorophenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazoles 1a‐b with chloroacetaldehyde 2a‐b , ω‐bromo‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenone 3a‐b , chloranil 4a‐b , 2‐bromocyclohexanone 5a‐b , 2,4′‐dibromoacetophenone 6a‐b and 2‐bromo‐6′‐methoxy‐2′‐acetonaphthone 7a‐b are described. The structures of the compounds synthesized were confirmed by elemental analyses, IR, 1H NMR and mass spectra. The antibacterial activities were also evaluated.     

Synthesis of (4Z)‐4‐(Arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones by the Reaction of Ethyl (2Z)‐3‐Aryl‐2‐isothiocyanatoprop‐2‐enoates with Organolithium Compounds

A convenient one‐pot method for the preparation of (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones 2 and 3 from ethyl (2Z)‐3‐aryl‐2‐isothiocyanatoprop‐2‐enoates 1 , which can be easily prepared from ethyl 2‐azidoacetate and aromatic aldehydes, has been developed. Thus, these α‐isothiocyanato α,β‐unsaturated esters were treated with organolithium compounds, including lithium enolates of acetates, to provide 5‐substituted (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones, 2 , and 2‐[(4Z)‐(4‐arylmethylidene)‐5‐ethoxy‐2‐thioxo‐1,3‐oxazolidin‐5‐yl]acetates, 3 .     

Syntheses of 4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones from Sydnone Derivatives and Their Fragments

4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 11 and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 13 have been obtained from a‐chloroformylarylhydrazine hydrochloride 2 . Moreover, the intermediates, including 3, 4 , 9 and 10 , in this study are synthetically informative and valuable. It is also noteworthy that three reactants, 1, 2 and sydnonecarbaldehydes, were prepared from sydnone derivatives and their fragments. The oxidative cyclizations of sydnonecarbaldehyde semicarbazones 9 and carbazones 10 with two different oxidizing agents (Cu(ClO₄)₂ and Fe(ClO₄)₃) have been extensively examined. The reaction time and the yields of cyclizations were affected by the substituents of semicarbazones 9 and carbazones 10.     

Synthesis and Fungicidal Activity of (E)‐5‐[1‐(2‐Oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐4‐one Derivatives

The novel fungicidal agents, (E )‐5‐[1‐(2‐oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐ 4‐one derivatives, were designed and synthesized in moderate to excellent yields in four steps using α ‐hydroxyketone and diketene as raw materials and characterized by HR‐ESI‐MS , ¹H NMR and X‐ray diffraction. The preliminary bioassay showed that some of these compounds, such as 5e , 6a , 6e , and 7 h exhibit 87.8%, 91.3%, 89.9% and 87.8% inhibition rates against Sclerotinia scleotiorum , 3b , 3c , 4c and 7 h exhibit 96.4%, 92.5%, 90.3% and 76.9% inhibition rates against Phytophthora capsici at the concentration of 50 µg/mL , respectively. These compounds exhibited significant fungicidal activities against S. scleotiorum and P. capsici with EC₅₀ values of 2.56–11.60 µg/mL , and compounds 6e and 7 h exhibited weak inhibition against the spore germination of S. scleotiorum , while the spore germination of P. capsici was strongly inhibited by compound 7 h solution. Scanning electron microscopy (SEM ) and transmission electron microscopy (TEM ) observation indicated that compound 7 h had a significant impact on the structure and function of the hyphal cell wall of P. capsici mycelium.     

Highly Diastereoselective Total Syntheses of (+)‐7‐Epigoniodiol, (−)‐8‐Epigoniodiol,and (+)‐9‐Deoxygoniopypyrone

An expedient concise total synthesis of (+)‐7‐epigoniodiol, (?)‐8‐epigoniodiol, and (+)‐9‐deoxygoniopypyrone is accomplished. The key transformations include a catalytic hydroxylation and base‐mediated N‐(acetyl)oxazolidinone addition reactions, which could set the consecutive OH motif that is either syn,syn or syn,anti with high diastereoselectivity. Moreover, this approach envisioned to facilitate the synthesis of other representatives of the family with structural and stereochemical variation.     

Synthesis of Some Novel 3,6‐Bis(1,2,3‐triazolyl)‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazole Derivatives

The cyclization of 1‐amino‐2‐mercapto‐5‐[1‐(4‐ethoxyphenyl)‐5‐methyl‐1,2,3‐triazol‐4‐yl]‐1,3,4‐triazole which was synthesized from p‐ethoxyaniline with various triazole acid in absolute phosphorus oxychloride yields 3,6‐bis(1,2,3‐triazolyl)‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazole derivatives 9a?j , and their structures are established by MS, IR, CHN and ¹H NMR spectral data.     

The Synthesis of Some New N‐[1‐(2,5‐Dichlorophenyl)‐5‐Methyl‐1,2,3‐Triazol‐4‐yl]‐Carbamic Acid Ester Derivatives

The synthesis of some new N‐[1‐(2,5‐dichlorophenyl)‐5‐methyl‐1,2,3‐triazol‐4‐yl]‐carbamic acid ester derivatives are reported in this paper. The yielded products 6a‐l were confirmed by Elemental analyses, NMR, MS, and IR spectra.     

Hydriodic Acid‐Mediated Cyclization of α‐Substituted Secondary 2‐Ethenylbenzamides: Synthesis of 2‐Substituted 2,3‐Dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones and 3,3‐Disubstituted (E)‐1‐(Arylimino)‐1,3‐dihydroisobenzofurans

A new and facile method for the preparation of 2‐substituted 2,3‐dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones 3 and 3,3‐disubstituted (E)‐1‐(arylimino)‐1,3‐dihydroisobenzofurans 6 has been developed. Thus, treatment of N‐alkyl(or aryl)‐2‐(1‐methylethen‐1‐yl)benzamides 2 with concentrated hydriodic acid (HI) in MeCN at room temperature afforded 3 . Similar treatment of N‐aryl‐2‐(1‐phenylethen‐1‐yl)benzamide 5 with concentrated HI at 0° afforded 6 .     

Synthesis and Cytotoxicity of 6‐Pyrrolidinyl‐2‐(2‐Substituted Phenyl)‐4‐Quinazolinones

In our continuing search for potential anticancer candidates, 2‐(3‐methoxyphenyl)‐6‐pyrrolidinyl‐4‐quinazolinone ( JJC‐1 ) was selected as the lead compound. Starting 5‐pyrrolidinyl‐2‐aminobenzamide was prepared using standard methodology from 5‐chloro‐2‐nitrobenzoic acid by reaction with SOCl₂, NH₃, pyrrolidine, and H₂. The starting benzamide then was reacted with 2‐substituted benzaldehyde or benzoyl chloride in N,N‐dimethylacetamide (DMAC) in the presence of NaHSO₃ at 150 °C. Thermal cyclodehydration/dehydrogenation gave the target 6‐pyrrolidinyl‐2‐(2‐substituted phenyl)‐4‐quinazolinones ( 15–22 ). These target compounds were assayed for their cytotoxicity in vitro against six cancer cell lines, including human monocytic leukemia cells (U937), mouse monocytic leukemia cells (WEHI‐3), human hepatoma cells (HepG2, Hep3B) and human lung carcinoma cells (A549, CH27). Most of them exhibited significant cytotoxic effect toward U937 and WEHI‐3 cells, with EC₅₀ values ranging from 0.30 to 10.10 μM. Compound 19 was investigated further for its action mechanisms. Preliminary findings indicated that compound 19 induced G2/M arrest and apoptosis on U937 cells.     

Transformations of Methyl 2‐[(E)‐2‐(Dimethylamino)‐1‐(methoxycarbonyl)ethenyl]‐1‐methyl‐1H‐indole‐3‐carboxylate

A simple and efficient synthesis of novel 2‐heteroaryl‐substituted 1H‐indole‐2‐carboxylates and γ‐carbolines, compounds 1 – 3 , from methyl 2‐(2‐methoxy‐2‐oxoethyl)‐1‐methyl‐1H‐indole‐3‐carboxylate ( 4 ) by the enaminone methodology is presented.     

A Convenient Synthesis of 2,3‐Dihydro‐4H‐thiopyrano[2,3‐b]‐, ‐[2,3‐c]‐, or ‐[3,2‐c]pyridin‐4‐ones by the Reaction of the Corresponding 1‐(Chloropyridinyl)alk‐2‐en‐1‐ones with NaSH

2,3‐Dihydro‐4H‐thiopyrano[2,3‐b]pyridin‐4‐ones 4 were prepared by a three‐step sequence from commercially available 2‐chloropyridine ( 1 ). Thus, successive treatment of 1 with ⁱPr₂NLi (LDA) and α,β‐unsaturated aldehydes gave 1‐(2‐chloropyridin‐3‐yl)alk‐2‐en‐1‐ols 2 , which were oxidized with MnO₂ to 1‐(2‐chloropyridin‐3‐yl)alk‐2‐en‐1‐ones 3 . The reactions of 3 with NaSH?n H₂O proceeded smoothly at 0° in DMF to provide the desired thiopyranopyridinones. Similarly, 2,3‐dihydro‐4H‐thiopyrano[2,3‐c]pyridin‐4‐ones 8 and 2,3‐dihydro‐4H‐thiopyrano[3,2‐c]pyridin‐4‐ones 12 were obtained starting from 3‐chloropyridine ( 5 ) and 4‐chloropyridine ( 9 ), respectively.     

One‐Pot Synthesis of 4‐(Alkylamino)‐1‐(arylsulfonyl)‐3‐benzoyl‐1,5‐ dihydro‐5‐hydroxy‐5‐phenyl‐2H‐pyrrol‐2‐ones via a Multicomponent Reaction

An effective route to novel 4‐(alkylamino)‐1‐(arylsulfonyl)‐3‐benzoyl‐1,5‐dihydro‐5‐hydroxy‐5‐phenyl‐2H‐pyrrol‐2‐ones 10 is described (Scheme 2). This involves the reaction of an enamine, derived from the addition of a primary amine 5 to 1,4‐diphenylbut‐2‐yne‐1,4‐dione, with an arenesulfonyl isocyanate 7 . Some of these pyrrolones 10 exhibit a dynamic NMR behavior in solution because of restricted rotation around the C? N bond resulting from conjugation of the side‐chain N‐atom with the adjacent α,β‐unsaturated ketone group, and two rotamers are in equilibrium with each other in solution ( 10 ? 11 ; Scheme 3). The structures of the highly functionalized compounds 10 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS), by elemental analyses, and, in the case of 10a , by X‐ray crystallography. A plausible mechanism for the reaction is proposed (Scheme 4).     

Synthesis of 3‐Aryl‐2‐methoxyinden‐1‐one (Z)‐Phenylhydrazones via Hydrobromic Acid‐Mediated Cyclization of 2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehyde Phenylhydrazones

2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehydes 2 , obtained by successive treatment of 1‐(1‐aryl‐2‐methoxyethenyl)‐2‐bromobenzenes 1 with BuLi and 1‐formylpiperidine, were transformed to the corresponding phenylhydrazones 3 on treatment with PhNHNH₂. When these hydrazones were allowed to react with conc. HBr, cyclization, followed by dehydrogenation with air occurred, furnished 3‐aryl‐2‐methoxyinden‐1‐one (Z)‐phenylhydrazones 4 .     

Synthesis of 1,3‐Dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates via Intramolecular Cyclization of 2‐[2‐(Dimethoxymethyl)phenyl]‐ 2‐hydroxyalkanoates Followed by Oxidation

A novel and efficient method for the preparation of 1,3‐dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates 4 under mild conditions has been developed. Thus, the reaction of [2‐(dimethoxymethyl)phenyl]lithiums, generated easily from 1‐bromo‐2‐(dimethoxymethyl)benzenes 1 , with α‐keto esters gives the corresponding 2‐[2‐(dimethoxymethyl)phenyl]‐2‐hydroxyalkanoates 2 . The TsOH‐catalyzed cyclization of these hydroxy acetals is followed by the oxidation of the resulting cyclic acetals 3 with PCC to give the desired products in satisfactory yields. The reaction of [2‐(dimethoxymethyl)‐4,5‐dimethoxyphenyl]lithium with (MeOC?O)₂, followed by treatment with NaBH₄ or organolithiums, affords 2‐[2‐(dimethoxymethyl)‐4,5‐dimethoxyphenyl]‐2‐hydroxyalkanoates 6 , which can similarly be transformed into the corresponding 1,3‐dihydro‐3‐oxo‐2‐benzofuran‐1‐carboxylates 7 in reasonable yields.     

Synthesis of (−)‐3‐Carene‐2,5‐dione via Allylic Oxidation of (+)‐3‐Carene

Activated carbon‐supported CuCl₂ (CuCl₂/AC) is a heterogeneous catalyst for the liquid‐phase selective allylic oxidation of (+)‐3‐carene with tert‐butyl hydroperoxide (TBHP) and O₂ to produce (?)‐3‐carene‐2,5‐dione. The possible reaction mechanism and the effects of different factors on the allylic oxidation were investigated. The optimal conditions are as follows: reaction temperature, 45 °C; molar ratio of CuCl₂ to (+)‐3‐carene, 1%; volume ratio of (+)‐3‐carene to TBHP, 1:3; and reaction time, 12 h. Under the optimal conditions, the conversion of (+)‐3‐carene reached 100%, whereas the selectivity for (?)‐3‐carene‐2,5‐dione reached 78%. The CuCl₂/AC catalyst was characterized via X‐ray diffraction, and the chemical structure of the target compound was identified via infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectrometry, and optical analysis.     

Synthesis of 3‐(Pyridin‐4‐Ylmethyl)‐4‐Substituted‐1,2,4‐Triazoline‐5‐Thione

The reaction of the hydrazide of pyridine‐4‐acetic acid with isothiocyanate gave thiosemicarbazide derivatives respectively. Further cyclization with 2% NaOH led to the formation of 4‐substituted 3‐(pyridin‐4‐ylmethyl)‐1,2,4‐triazoline‐5‐thione and 3‐(pyridin‐4‐ylmethyl)‐1,2,4‐triazoline‐5‐thione. The structures of all new products were confirmed by analytical and spectroscopic methods.