Preparation of Partially Hydrogenated 4,6‐Dimethyldibenzothiophenes

The synthesis of three key intermediates of the hydrogenation pathway in the hydrodesulfurization of 4,6‐dimethyldibenzothiophene (4,6‐DM‐DBT; 1 ) is described. The hydrogenated derivatives 1,2,3,4‐tetrahydro‐4,6‐dimethyldibenzothiophene (= 4,6‐dimethyl‐1,2,3,4‐tetrahydrodibenzothiophene; 4,6‐DM‐TH‐DBT; 2 ), 1,2,3,4,4a,9b‐hexahydro‐4,6‐dimethyldibenzothiophene (= 4,6‐dimethyl‐1,2,3,4,4a,9b‐hexahydrodibenzothiophene; 4,6‐DM‐HH‐DBT; 3 ), and dodecahydro‐4,6‐dimethyldibenzothiophene (= 4,6‐dimethylperhydrodibenzothiophene; 4,6‐DM‐PH‐DBT; 4 ) were prepared by direct hydrogenation of 1 . The reactions were carried out in continuous and batch reactors by using metal sulfide as well as noble‐metal catalysts. The influence of the reaction conditions on the formation of the products and the distribution of their stereoisomers was studied in detail. The isomers of the main products were isolated and characterized by NMR, GC/MS/MS, and X‐ray crystal‐structure diffractometry.     

Synthesis of 4,6-dimethyl-tetrahydro- and hexahydro-dibenzothiophene

2-Bromo-3-methylcyclohexanone was synthesized by conjugate addition of trimethylaluminium to 2-bromo-2-cyclohexen-1-one with copper bromide as catalyst, coupled with 2-methylthiophenol and annulated with the aid of polyphosphoric acid to 4,6-dimethyl-1,2,3,4-tetrahydrodibenzothiophene. The latter was hydrogenated to 4,6-dimethyl-1,2,3,4,4a,9b-hexahydrodibenzothiophene, another intermediate in the hydrodesulfurization of 4,6-dimethyldibenzothiophene, by zinc and trifluoroacetic acid, and dehydrogenated to 4,6-dimethyldibenzothiophene.     

Total Synthesis of the Biologically Active,Naturally Occurring 3,4‐Dibromo‐5‐[2‐bromo‐3,4‐dihydroxy‐6‐(methoxymethyl)benzyl]benzene‐1,2‐diol and Regioselective O‐Demethylation of Aryl Methyl Ethers

3,4‐Dibromo‐5‐[2‐bromo‐3,4‐dihydroxy‐6‐(methoxymethyl)benzyl]benzene‐1,2‐diol ( 2 ), a natural product, has been synthesized for the first time starting from (3‐bromo‐4,5‐dimethoxyphenyl)methanol ( 5 ) in five steps and with an overall yield of 34%. The reaction of some methoxymethyl‐substituted aryl methyl ethers with BBr₃, followed by the addition of MeOH, afforded the corresponding methoxymethyl‐substituted arylphenols in high yields.     

A Facile Synthesis of 1‐Substituted 3‐Alkoxy‐1H‐isoindoles Based on the Reaction of 2‐(Dialkoxymethyl)phenyllithiums with Nitriles,Followed by Acid‐Catalyzed Cyclization

A two‐step synthesis of 1‐substituted 3‐alkoxy‐1H‐isoindoles 4 has been developed. Thus, the reaction of 2‐(dialkoxymethyl)phenyllithium compounds, which are easily generated in situ by Br/Li exchange between 1‐bromo‐2‐(dialkoxymethyl)benzenes 1 and BuLi in THF at ?78°, with nitriles afforded [2‐(dialkoxymethyl)phenyl]methanimines 2 , which were treated with a catalytic amount of TsOH?H₂O in refluxing CHCl₃ to give the desired products in reasonable yields. Similarly, 3‐aryl‐1‐ethoxy‐1‐methyl‐1H‐isoindoles 7 have been prepared starting from 1‐bromo‐2‐(1,1‐diethoxyethyl)benzenes 5 .     

Reaction of 3‐Hydroxyquinoline‐2,4‐diones with Isocyanates and Thermally Induced Transformation of the Reaction Products

3‐Hydroxyquinoline‐2,4‐diones 1 react with isocyanates to give novel 1,2,3,4‐tetrahydro‐2,4‐dioxoquinolin‐3‐yl (alkyl/aryl)carbamates 2 and/or 1,9b‐dihydro‐9b‐hydroxyoxazolo[5,4‐c]quinoline‐2,4(3aH,5H)‐diones 3 . Both of these compounds are converted, by boiling in cyclohexylbenzene solution in the presence of Ph₃P or 4‐(dimethylamino)pyridine, to give 3‐(acyloxy)‐1,3‐dihydro‐2H‐indol‐2‐ones 8 . All compounds were characterized by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, as well as by EI mass spectrometry.     

Synthesis of 6‐Alkylidene‐5,6‐dihydro‐4H‐1,3‐thiazine Derivatives via the Cyclization of N‐3‐Bromo‐3‐alkenylthioamides

By the treatment of N‐3‐bromo‐3‐alkenylthioamides with sodium hydroxide in DMF‐H₂O in the presence of tetra‐butylammonium bromide, series of 6‐alkylidene‐5,6‐dihydro‐4H‐1,3‐thiazine derivatives were prepared in moderate to good yields. The cyclization is supposed to proceed via both the intramolecular vinylic nucleophilic substitution and the elimination‐addition mechanisms (formation of acetylenic intermediates) in a competitive manner.     

Two‐Step Synthesis of 1,3‐Disubstituted 3,4‐Dihydro‐4‐thioxoquinazolin‐2(1H)‐ones from 1‐Bromo‐2‐fluorobenzenes

An efficient synthesis of 3‐alkyl‐3,4‐dihydro‐4‐thioxobenzoquinazolin‐2(1H)‐ones 3 has been accomplished in two steps and in satisfactory yields from 1‐bromo‐2‐fluorobenzenes 1 . Thus, the reaction of 1‐fluoro‐2‐lithiobenzenes, generated by the Br/Li exchange between 1 and BuLi, with alkyl isothiocyanates, gives N‐alkyl‐2‐fluorobenzothioamides 2 , which, in turn, react with a series of isocyanates in the presence of NaH to give the desired products 3 .     

Regioselective Synthesis of 6‐[Chloro(difluoro)methyl]salicylates by [3+3] Cyclocondensations of 1,3‐Bis(trimethylsilyloxy)buta‐1,3‐dienes with 1‐Chloro‐1,1‐difluoro‐4‐(trimethylsilyloxy)pent‐3‐en‐2‐one

The TiCl₄‐mediated [3+3] cyclocondensation of various 1,3‐bis(trimethylsilyloxy)buta‐1,3‐dienes with 1‐chloro‐1,1‐difluoro‐4‐(trimethylsilyloxy)pent‐3‐en‐2‐one provides a regioselective access to novel 6‐(chlorodifluoromethyl)salicylates (=6‐(chlorodifluoromethyl)‐2‐hydroxybenzoates) with very good regioselectivity. For selected products, it was demonstrated that the CF₂Cl group can be transformed to CF₂H and CF₂(Allyl) by free‐radical reactions.     

Synthesis of 3‐(ω‐Hydroxyalkoxy)isobenzofuran‐1(3H)‐ones by Trifluoroacetic Acid‐Mediated Lactonization of tert‐Butyl 2‐(1,3‐Dioxol‐2‐yl)‐ or 2‐(1,3‐Dioxan‐2‐yl)benzoates

An efficient two‐step method for the preparation of 3‐(2‐hydroxyethoxy)‐ or 3‐(3‐hydroxypropoxy)isobenzofuran‐1(3H)‐ones 3 has been developed. Thus, the reaction of 1‐(1,3‐dioxol‐2‐yl)‐ or 1‐(1,3‐dioxan‐2‐yl)‐2‐lithiobenzenes, generated in situ by the treatment of 1‐bromo‐2‐(1,3‐dioxol‐2‐yl)‐ or 1‐bromo‐2‐(1,3‐dioxan‐2‐yl)benzenes 1 with BuLi in THF at ?78°, with (Boc)₂O afforded tert‐butyl 2‐(1,3‐dioxol‐2‐yl)‐ or 2‐(1,3‐dioxan‐2‐yl)benzoates 2 , which can subsequently undergo facile lactonization on treatment with CF₃COOH (TFA) in CH₂Cl₂ at 0° to give the desired products in reasonable yields.     

Ultrasound‐Assisted Synthesis of 6‐Methyl‐1,2,3,4‐tetrahydro‐N‐aryl‐2‐oxo/thio‐4‐arylpyrimidine‐5‐carboxamides Catalyzed by Uranyl Nitrate Hexahydrate

An efficient and simple method developed for the synthesis of 6‐methyl‐1,2,3,4‐tetrahydro‐N‐aryl‐2‐oxo/thio‐4‐arylpyrimidine‐5‐carboxamide derivatives ( 4a‐o ) using UO₂(NO₃)₂.6H₂O catalyst under conventional and ultrasonic conditions. The ultrasound irradiation synthesis had shown several advantages such as milder conditions, shorter reaction times and higher yields. The structures of all the newly synthesized compounds have been confirmed by FT‐IR, ¹H NMR, ¹³C NMR and mass spectra.     

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.     

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 .     

Liquid‐Phase Synthesis of 2‐Methyl‐2‐Aryloxypropanoic Acid Derivatives from Polyethylene Glycol) Supported 2‐Bromo‐2‐Methylpropanoate

An efficient liquid‐phase synthesis of 2‐methyl‐2‐aryloxypropanoic acid derivatives with good yields and high purity on soluble polyethylene glycol (PEG) has been developed by treatment of PEG‐bound 2‐bromo‐2‐methylpropanoate with phenoxides in the presence of a catalytic amount of NBu₄I and KI, and subsequent cleavage from the PEG.     

Synthesis of 8‐Oxoberbines and Related Benzolactams by Pd(OAc)2‐Catalyzed Direct Aromatic Carbonylation

A variety of alkoxy‐substituted benzolactams with a berbine or yohimbane skeleton were prepared from 1‐benzyl‐1,2,3,4‐tetrahydroisoquinolines or 1‐benzyl‐1,2,3,4‐tetrahydro‐β‐carbolines by a phosphine‐free Pd(II)‐catalyzed direct aromatic carbonylation in a Pd(OAc)₂‐Cu(OAc)₂ catalytic system. The site selectivity was compared with that of the carbonylation with Pd(OAc)₂ or Pd(OAc)₂·2 PPh₃, respectively.     

1,2,3,4‐Tetrasubstituted Cyclopentadienes and Their Applications for Metallocenes: Efficient Synthesis through Zirconocene‐ and CuCl‐Mediated Intermolecular Coupling of Two Alkynes and One Diiodomethane

1,2,3,4‐Tetrasubstituted cyclopentadienes and indene derivatives with identical or different substituents were obtained in good to excellent isolated yields through a zirconocene‐ and CuCl‐mediated intermolecular coupling process. This synthetic procedure involved three organic partners, including one CH₂I₂, and two different or identical alkynes. Two alkynes or one diyne undergo Cp₂Zr^II‐mediated (Cp=η⁵‐C₅H₅) pair‐selective reductive coupling to afford the corresponding zirconacyclopentadiene derivatives, which react, in the presence of CuCl and 1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1 H)‐pyrimidinone (DMPU), with CH₂I₂ through intermolecular followed by intramolecular coupling to afford the cyclopentadiene derivatives. An application of the prepared tetrasubstituted cyclopentadiene derivatives was demonstrated by the facile synthesis of the corresponding zirconocene complexes [(^4RCp)₂ZrCl₂] and [(^4RCp)₂ZrR′₂] (R′=Me, Et, or nBu). The unique 1,2,3,4‐tetrasubstituted cyclopentadiene ligands and the corresponding metallocenes are expected to have further applications in organometallic chemistry and organic synthesis.     

Synthesis of (+) or (-)-2-(8′-Diphenylphosphino-1′-naphthyl)oxazoline Ligands and Their Application in Pd-Catalyzed Allylic Alkylation Reaction

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Synthesis of alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates for evaluation as calcium channel antagonists

The Bigenelli acid catalyzed condensation of 2‐pyridylcarboxaldehyde ( 1 ), urea ( 2 ) and an alkyl acetoacetate ( 3 ) afforded the respective alkyl (Me, Et, i‐Pr, i‐Bu, t‐Bu) 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates ( 4a‐e ). The most potent calcium channel antagonist ethyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylate ( 4b , IC₅₀ = 1.67 × 10^?5 M) wasa much weaker calcium channel antagonist than the reference drug nifedipine (Adalat®, IC₅₀ = 1.40 × 10^?8 M) on guinea pig ileal longitudinal smooth muscle (GPILSM). The alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates did not show any inotropic effect on heart since no increase, or decrease, in the contractile force of guinea pig left atrium was observed. These structure activity studies show that the alkyl 6‐methyl‐4‐(2‐pyridyl)‐1,2,3,4‐tetrahydro‐2H‐pyrimidine‐2‐one‐5‐carboxylates ( 4a‐e ) are partial bioisosteres of nifedipine with respect to calcium channel antagonist activity on guinea pig ileal longitudinal smooth muscle (GPILSM).     

Synthesis of 4-(4-Methylsulfonylphenyl)-3-phenyl-2(3H)-thiazole Thione Derivatives as New Potential COX-2 Inhibitors

Synthesis of novel 4-（4-methylsulfonylphenyl）-3-phenyl-2（3H）-thiazole thione derivatives with functionalized diarylheterocycle pharmacophore as potential COX-2 inhibitors was described. The title compounds were synthesized by cyclocondensation of corresponding dithiocarbamate and 2-bromo-1-（4-methylsulfonylphenyl）ethanone, followed by dehydration with H2SO4. All of the target compounds were characterized by ^1H NMR, IR and mass spectral data.     

Synthesis and Structures of Two Isomeric 4‐Diazo‐2,3,4,5‐tetrahydrofuran‐3‐ones

The two regioisomeric 4‐diazo‐2,3,4,5‐tetrahydrofuran‐3‐ones 6 and 7 were prepared via the common intermediate 2,3,4,5‐tetrahydro‐2,2‐dimethyl‐5,5‐diphenylfuran‐3‐one ( 8 ). Diazo transfer with 2,4,6‐triisopropylbenzenesulfonyl azide yielded 6 , whereas 7 was obtained via oxidation of the monohydrazone 12 , which was prepared selectively from tetrahydrofuran‐3,4‐dione 11 . The crystal structures of 6 and 7 have been established by X‐ray crystallography.     

Tautomeric behaviour and isotopic multiplets in the 13C NMR spectra of partially deuterated 5‐arylazo‐pyrimidine (1H,3H,5H)‐2,4,6‐triones and 5‐arylazo‐2‐thioxo‐pyrimidine (1H,3H,5H)‐4,6‐diones—evidence for elucidation of tautomeric forms

NMR spectra of the synthesized azo dyes, 5‐arylazo‐pyrimidine (1H,3H,5H)‐2,4,6‐triones (5a–g), 1,3‐dimethyl‐5‐arylazo‐pyrimidine (1H,3H,5H)‐2,4,6‐triones (6a–g), and 5‐arylazo‐2‐thioxo‐pyrimidine (1H,3H,5H)‐4,6‐diones (7a–g) were studied in (CD₃)₂SO (three drops of CD₃OD were added into solutions of the dyes in two different concentrations). All dyes showed intramolecular hydrogen bonding. Dyes 5a–7a showed bifurcated intramolecular hydrogen bonds. Tautomeric behaviours of some of N‐methylated azo dyes (6a‐g) were studied in two different concentrations. The solvent–substrate proton exchange of dyes 5a–d, 6a and 7a–e was examined in presence of three drops of CD₃OD. The dyes which were soluble in (CD₃)₂SO containing CD₃OD showed isotopic splitting (β‐isotope effect) in the ¹³C NMR spectra. Copyright © 2009 John Wiley & Sons, Ltd.