Reaction of Zinc and Sodium Enolates of 3-Alkyl-6-aryl-5,5-dimethyl-2,3,5,6-tetrahydropyrane-2,4-diones with Acyl Chlorides or Benzyl Bromides

Zinc enolates of 3-alkyl-6-aryl-5,5-dimethyl-2,3,5,6-tetrahydropyrane-2,4-diones react with acyl chlorides to form O-acylation products, 4-acyloxy-3-alkyl-6-aryl-5,5-dimethyl-5,6-dihydropyrane-2-ones. Sodium enolates of these pyranediones react in DMSO with substituted benzyl bromides to give mainly C-alkylation products, 3-alkyl-6-aryl-3-(4-R-benzyl)-5,5-dimethyl-2,3,5,6-tetrahydropyrane-2,4-diones, as single geometric isomers. In some cases, O-alkylation products, 4-alkoxy-3-alkyl-6-aryl-5,5-dimethyl-5,6-dihydropyrane-2-ones, are formed as by-products (10-15%).     

Synthesis of cycloalkenopyrylium salts

Acylation of cyclopentylidenecyclopentanone, cyclohexenylcyclohexanone, and cycloneptenylcycloheptanone with anhydrides of aliphatic acids in the presence of 70% perchloric acid is studied. A simple method of synthesis of 2-alkyl-3, 4; 5, 6-bicycloalkenopyrylium salts is given. Treatment of the pyrylium salts with ammonia gives 2-alkyl-3, 4; 5, 6-bicyclopenteno- and cycloheptenopyridine in good yields.     

A convenient synthesis of 3-alkyl-2,3-dihydro-2,4-dioxo-6-phenyl-, 3-alkyl-2,3-dihydro-4-oxo-6-phenyl-2-thioxo-, and 3-alkyl-2-arylimino-2,3-dihydro-4-oxo-6-phenyl-4H-1,3-thiazines

The reactions of 1-alkylamino-1-alkylthio-3-phenylpropene-3-thiones 3 with thiophosgene and phosgene in toluene, followed by treatment of the reaction mixture with triethylamine gave 3-alkyl-2,3-dihydro-4-oxo-6-phenyl-2-thioxo- 4 , 3-alkyl-2,3-dihydro-2,4-dioxo-6-phenyl-4H-1,3-thiazines 5 , respectively in good to excellent yields. Similarly treatment of compounds 3 with N-arylimidoyl dichloride in benzene at room temperature gave 3-alkyl-2-arylimino-2,3-dihydro-4-oxo-6-phenyl-4H-1,3-thiazines 6 in excellent yields. The reactions of compounds 3 with oxalyl chloride in toluene gave also 5 in good yields.     

Synthesis of 6-substituted 1-alkoxy-5-alkyluracils

Synthesis of 6-substituted 1-alkoxy-5-alkyluracils 2a-c have been achieved from readily accessible 2-alkyl-3,3-di(methylthio)acryloyl chlorides 4a,b in high overall yields. Treatment of 4a,b with silver cyanate followed by reaction of the resulting isocyanates 5a,b with an appropriate alkoxyamine afforded N-alkoxy-N′-[2-alkyl-3,3-di(methylthio)acryloyl]ureas 6a,b in 85–88% yields. Cyclization of 6a,b in acetic acid containing methanesulfonic acid followed by oxidation with 3-chloroperoxybenzoic acid gave high yields of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils 9a,b. Nucleophillic addition-elimination reaction of 9a,b with sodium azide, phenylthiol, or phenylselenol produced 6-azido-1-butoxythymine ( 2a , 98%), 5-ethyl-1-(2-phenoxyethoxy)-6-(phenylthio)uracil ( 2b , 95%), or 5-ethyl-1-(2-phenoxyethoxy)-6-(phenylselenenyl)uracil ( 2c , 91%).     

A study on ester formylhydrazones

A series of ester formylhydrazones 2 were synthesized from the reaction of alkyl imidate hydrochlorides 1 with formylhydrazine. Treatment of 2 with hydrazine hydrate, ethyl carbazate and tert-butyl carbazate led to the formation of 3-alkyl-4-amino-, 3-alkyl-4-ethoxycarbonylamino- and 3-alkyl-4-tert-butoxycar-bonylamino-4H-1,2,4-triazoles 3–5 , respectively. Reaction of compounds 2 with formylhydrazine gave N,N'-diformylhydrazine 6 . Compounds 2 were reacted with 2,5-dimethoxytetrahydrofuran to afford 3-alkyl-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazoles 8 .     

Investigation of 2,3'-Biquinolyl. 11. Regioselectivity in the Hydroxylation of 1-Alkyl-3-(2-quinolyl)quinolinium Halides

The hydroxylation of 1-alkyl-3-(2-quinolyl)quinolinium halides by an alkaline solution of K₃[Fe(CN)₆] in aqueous 1,4-dioxane leads to a mixture of 1-alkyl-3-(2-quinolyl)-1,2-dihydro-2-quinolones and 1-alkyl-3-(2-quinolyl)-1,4-dihydro-4-quinolones with predominance of the former. The use of the system of K₃[Fe(CN)₆]/Mg(OH)₂ in aqueous 1,4-dioxane leads to the regiospecific formation of 1-alkyl-3-(2-quinolyl)-1,4-dihydro-4-quinolones.     

Nucleophilic substitution in 1-alkyl-4,5-dichloro-3-nitropyridazin-6-ones

Treatment of 1-alkyl-4,5-dichloro-3-nitropyridazin-6-one with C-nucleophiles and with ambident nucleophiles (2-azahetarylacetonitriles) leads to a selective substitution of a chorine atom by the quaternary carbon atom of the carbanion formed from a substituted acetonitrile. The pK_a of the CH-acid 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)malononitrile was determined by potentiometric titration. Reaction of 2-(1-alkyl-5-chloro-3-nitro-6-oxo-1,6-dihydro-4-pyridazinyl)-2-hetarylacetonitriles with primary amines gives 6,7-dihydro-1H-pyrrolo[2,3-d]pyridazin-7-ones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 556–564, April, 2006.     

A one-step synthesis of 2-Alkyl-5-hydroxychromones and 3-Alkoyl-2-alkyl-5-hydroxychromones

2-Alkyl-5-hydroxychromones (2-alkyl-5-hydroxy-4-oxo-4H-1-benzopyran) and 3-alkoyl-2-alkyl-5-hydroxychromones (3-alkoyl-2-alkyl-5-hydroxy-4-oxo-4H-1-benzopyran) were prepared in one-step and one pot reaction by condensation of 2',6'-dihydroxyacetophenone with an alkoyl chloride in the presence of K2CO3.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

1,2-silyl-migrative cyclization of vinylsilanes bearing a hydroxy group: stereoselective synthesis of multisubstituted tetrahydropyrans and tetrahydrofurans(1)

Acid-catalyzed intramolecular addition of a hydroxy group to alpha-alkylated vinylsilanes has been studied. Treatment of (Z)-5-alkyl-5-silyl-4-penten-1-ols 1 (R = alkyl) with 5 mol % TiCl(4) in CHCl(3) gave trans-2-alkyl-3-silyltetrahydropyrans 2 exclusively (trans/cis = >99/1 to 97/3). The cyclization efficiency and rate strongly depended on the geometry of the C-C double bond and the silyl group. The use of (E)-vinylsilanes resulted in lower yields with poor cis-selectivity. In the cyclization of (Z)-1 (R = Bu), the silyl group used, the reaction time, and the yield of 2 were as follows: SiMe(2)Ph, 9.5 h, 75%; SiMe(3), 7.5 h, 66%; SiMePh(2), 24 h, 58%; SiMe(2)-t-Bu, 0.75 h, 85%; SiMe(2)Bn, 1.5 h, 78%. This 1,2-silyl-migrative cyclization could be applied to stereoselective synthesis of trisubstituted tetrahydropyrans. The acid-catalyzed reaction of 1-, 2-, or 3-substituted (Z)-5-silyl-4-nonen-1-ols 8 gave r-2,t-3,c-6-, r-2,t-3,t-5-, or r-2,t-3,c-4-trisubstituted tetrahydropyrans with high diastereoselectivity, respectively. (Z)-4-Alkyl-4-silyl-3-buten-1-ols 5 as well as 1 underwent the 1,2-silyl-migrative cyclization to give 2-alkyl-3-silyltetrahydrofurans 6 with high trans-selectivity. This silicon-directed cyclization was also available for the stereoselective synthesis of tri- and tetrasubstituted tetrahydrofurans.     

An unusual synthetic way to 2-methyl-3-alkyl-6-ethoxy-heptan-2-ols from 2-ethoxy-5-alkyl-3,4-dihydro-2H-pyrans

A simple and swift preparation of 2-methyl-3-alkyl-6-ethoxyheptan-2-ols may be accomplished in two steps starting from 2-ethoxy-5-alkyl-3-,4-dihydro-2H-pyrans via chlorination of the heterocyclic compounds and subsequent reaction with MeMgBr.     

Heterocyclic compounds from 3,3-dimercapto-1-aryl-2-propen-1-ones. Note 3. Condensation with N-methyl-o-phenylenediamine and N-benzyl-o-phenylenediamine

Two seven-membered ring compounds and three five-membered ring compounds were obtained by reaction in hot xylene of 3,3-dimercapto-l-phenyl-2-propen-1-one (1) with N-alkyl-o-phenylenediamines (2) . Compounds isolated were the 4-phenyl-5-alkyl-1,5-dihydro-2H-1,5-benzodiazepine-2-thiones (3) the 1-alkyl-4-phenyl-1,3-dihydro-2H-1,5-benzodiazepine-2-thiones (4) , the 1-alkyl-2-phenacylbenzimidazoles (5) , the 1-alkyl-2-phenylbenzimidazoles (6) and the 1-alkyl-2-methylbenzimidazoles (7) . The structures of these compounds were elucidated from their chemical reactivity and their nmr and ir spectra.     

An Improved Method for γ-Carboxylation of β-Diketones. Synthesis of 4-Alkyl-3,5-Dioxohexanoic Acids and 5-Alkyl Derivatives of Triacetic Acid Lactone

γ-Carboxylation of β-diketones, 1, can be improved using samples containing 100% of ketoenol tautomers, 3, prepared by mild hydrolysis of the corresponding copper(II) complexes 2. Cyclization of the so formed 4-alkyl-3,5-dioxohexanoic acids, 4, affords 5-alkyl-4-hydroxy-6-methyl-2-pyrones, 5.     

Facile Synthesis of Nicotinic Acid Derivatives with Unsymmetrical Substitution Patterns

Abstract

Two novel methods for synthesis of nicotinic acid derivatives with unsymmetrical substitution patterns were presented via ketene dithioacetals. The ketene N,S-acetals 2 reacted with β-ketoesters or β-cyanoesters to give 4-amino-5-cyano-2-alkyl-6-methylthio-nicotinic acid derivatives 3 or 2,4-diamino-5-cyano-6-methylthio-nicotinic acid ethyl ester 4. However, 6-amino-5-cyano-2-alkyl-4-methylthio-nicotinic acid esters 6 were obtained by the reaction of the ketene dithioacetals 1 and β-amino-crotonates.     

Cyanoacetylene and Its Derivatives: XXVIII. Reactions of 2-Mercaptobenzothiazole with Nitriles of αα,ββ-Acetylene γγ-Hydroxyacids and with 3-Phenyl-2-propynonitrile

Nucleophilic addition of 2-mercaptobenzothiazole to 4-alkyl-4-hydroxy-2-alkynonitriles at 1:1 ratio in the presence of 4-6 wt% of Et₃N occurs regio- and stereospecifically to afford (Z)-4-alkyl-3-(benzothiazolyl-2-thio)-4-hydroxy-2-alkenonitriles (yield 40-51%). In the presence of 1.3 wt% of Dabco the thiazole and 4-hydroxy-4-methyl-2-pentynonitrile (1:1) give rise to a mixture of 2-alkenonitrile and 2-(3,3,6,6-tetramethyl-2-cyanomethyl-5-cyanomethylene-1,4-oxathian-2-yl)thiobenzothiazole. At the use of 4-6 wt% of LiOH arises an intractable mixture containing 1,4-oxathiane, benzothiazol-2-one, 2-[1-(5,5-dimethyl-2-cyanomethyl)-4-cyanomethylene-1,3-oxathiolan-2-yl)-1-methylethyl]thiobenzothiazole, bis(2,2,5,5-tetramethyl-6-cyanomethyl-3-cyanomethylene-1,4-oxathian-6-yl) disulfide, bis[1-(5,5-dimethyl-2-cyanomethyl-4-cyanomethylene-1,3-oxathiolan-2-yl)-1-methylethyl] disulfide, and 3-[1-(5,5-dimethyl-2-cyanomethyl-4-cyanomethylene-1,3-oxathiolan-2-yl)-1-methylethyl]benzothiazol-2-one (according to ¹H and ¹³C NMR data). 2-mercaptobenzothiazole adds to 3-phenyl-2-propynonitrile in the presence of 7 wt% of KOH with regio- and stereospecific formation of (Z)-3-(benzothiazolyl-2-thio)-3-phenyl-2-propenonitrile (88%).     

A novel synthesis of 4,5-diaryl-6-arylamino-2,3-benzo-1,3a,6a-triazapentalenes

Treatment of N-alkyl- and N-aryl-imines of 2,3-diaryl- and 2-alkyl-3-aryl-3-(benzotriazol-1-yl)propenals with trifluoroacetic anhydride in THF at room temperature gave 5-alkyl-4-aryl-6-[N-alkyl (and aryl)-N-trifluoroacetyl]amino-2,3-benzo-1,3a,6a-triazapentalenes in moderate to good yields. On heating triazapentalenes having R²=aryl in MeOH at reflux, detrifluoroacetylation of triazapentalene occurred to give title compounds in good yields. However, the same treatment of triazapentalenes having R²=alkyl did not give the corresponding detrifluoroacetylation product. The title compounds and 5-alkyl-4-aryl-6-(N-alkyl-N-trifluoroacetyl)amino-2,3-benzo-1,3a,6a-triazapentalenes were found to be good precursors for the synthesis of 1-(o-aminophenyl)-3-arylamino-4-alkyl (and aryl)-5-arylpyrazoles and 1-(o-aminophenyl)-3-(N-alkyl-N-trifluoroacetyl)amino-4-alkyl (and aryl)-5-arylpyrazoles, respectively.     

Syntheses and reactions of some 1-substituted-7-alkyl-2-thioxopurines: X-Ray structure of 6-methylamino-7-nonyl-2-thioxopurine

Several 1-substituted-7-alkyl-2-thioxopurines 8,9,10 were synthesized by the reaction of isothiocyanates with 1-alkyl-4-amino-5-cyanoimidazoles 3 . Treatment of 3 with methyl isothiocyanate gave the Dimroth rearranged product 6-methylamino-7-alkyl-2-thioxopurines 11 . The structure of 11 was unambiguously defined by X-ray crystallography.     

A novel conversion of acetylenic 1,2,4-triazoles into 3-alkyl-5-arylpyridazines

Bromination of 2-aryl-1-[1,2,4]triazol-1-ylalk-3-yn-2-ols gives 6-bromo-7-hydroxy-5-alkyl-7-aryl-7,8-dihydro-[1,2,4]triazolo[1,2-a]pyridazin-4-ylium salts, which are converted by treatment with strong alkali into novel 3-alkyl-5-arylpyridazines.     

Fluorocinnoline derivatives. II. Synthesis and antibacterial activity of fluorinated 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic acids

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-1,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alkyl-6,8-difluoro- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17-35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin.     

Reactions of 4-dicyanomethylenepyrans with hindered primary amines

The reaction of 2,6-dimethyl- and 2,6-diphenyl-4-dicyanomethylene-4H-pyran with hindered primary amines such as isopropylamine and cyclohexylamine gave 1-alkyl-2-amino-3-cyano-6-rnethyl(or phenyl)-4-acetonylidene (or phenacylidene)-1,4-dihydropyridine derivatives. The 6-methyl-4-acetonylidene examples underwent a facile thermal rearrangement to give 1-alkyl-2,6-dimethyl-4-dicy anomethy lene-1,4-dihydropy ridines. Several reactions of the acylidene derivatives are described.