Heterocycles: 2—Regiospecific addition of methylhydrazine to acetylenic ketones

The reaction of 1-p-methoxyphenyl-3-phenyl-2-propen-1-one and 3-p-methoxyphenyl-1-phenyl-2-propen-1-one with methylhydrazine gave 1-methyl-3-p-methoxyphenyl-5-phenylpyrazoline and 1-methyl-3-phenyl-5-p-methoxyphenylpyrazoline, respectively. These compounds, on oxidation, gave 1-methyl-3-p-methoxyphenyl-5-phenylpyrazole(2) and 1-methyl-3-phenyl-5-p-methoxyphenylpyrazole, respectively. When methyl-hydrazine was made to react with 1-p-methoxyphenyl-3-phenyl-2-propyn-1-one, a pyrazole was obtained which proved to be identical with 2. Confirmatory evidence for this identity was obtained from their spectral data.     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Synthesis of enantiomerically pure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol present in the liver oil of cartilaginous fish

Synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol 1, the principal methoxylated glyceryl ether found in Nature, is described by a highly convergent five-step process taking place in 27% overall yield. The synthesis is based on an ether bond formation between the chiral synthon (R)-2,3-O-isopropylidene-sn-glycerol and (Z)-(R)-1-chlorohexadec-4-en-2-ol employing ground potassium hydroxide and tetra-n-butylammonium bromide as a catalyst under solvent free conditions.     

Unusual result of the reaction of 4-(1-methyl-1H-imidazol-2-yl)methylene-substituted 2-alkylthioimidazol-5(4H)-one with copper(ii) chloride

A reaction of potassium ({(4Z)-4-[(1-methyl-1H-imidazol-2-yl)methylene]-5-oxo-1-phenyl-4,5-dihydro-1H-imidazol-2-yl}thio)acetate with copper(II) chloride in methanol leads to bis(5-anilino-7-methoxycarbonyl-1-methyl-1H-imidazo[1,2-c]pyrimidin-4-ium) tetrachloro-cuprate(II), whose structure was confirmed by the X-ray diffraction studies.     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Furopyridines. XIII. Reaction of 2-methylfuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridines with lithium diisopropylamide

Lithiation of 2-methylfuro[2,3-b]- 1a , -[2,3-c]- 1c and -[3,2-c]pyridine 1d with lithium diisopropylamide at ?75° and subsequent treatment with deuterium chloride in deuterium oxide afforded 2-monodeuteriomethyl compounds 2a, 2c and 2d , while 2-methylfuro[3,2-b]pyridine 1b gave a mixture of 1b, 2b , 2-methyl-3-deuteriofuro[3,2-b]pyridine 2′b and 2-(1-proynyl)pyridin-3-ol 5 . The same reaction of 1a at ?40° gave 3-(1,2-propadienyl)pyridin-2-ol 3 and 3-(2-propynyl)pyridin-2-ol 4 . Reaction of the lithio intermediates from 1a, 1c and 1d with benzaldehyde, propionaldehyde and acetone afforded the corresponding alcohol derivatives 6a, 6c, 6d, 7a, 7c, 7d, 8a, 8c and 8d in excellent yield; while the reaction of lithio intermediate from 1b gave the expected alcohols 6b and 8b in lower yields accompanied by formation of 3-alkylated compounds 9, 11, 12 and compound 5 . While reaction of the intermediates from 1a, 1b and 1d with N,N-dimethylacetamide yielded the 2-acetonyl compounds 13a, 13b and 13d in good yield, the same reaction of 1c did not give any acetylated product but recovery of the starting compound almost quantitatively.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of N,N-disubstituted 4-amino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides and of 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 3-amino-2-methyl-1-phenyl-2-propen-1-ones (I) and 3-amino-1,2-diphenyl-2-propen-1-ones (II) occurred in good to moderate yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides. Polar 1,4-cycloaddition of dichloroketene to I and II occurred only in the former case, giving in good to moderate yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-5-methyl-6-phenyl-2H-pyran-2-ones which were dehydrochlorinated with DBN to N,N-disubstituted 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones. In the reaction of 2-methyl-1-phenyl-3-diphenylamino-2-propen-1-one with dichloroketene, a product was isolated which was proven by uv, ir, nmr and chemical evidence to be the dipolar ion VI, the supposed intermediate of the polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted enaminones.     

Reaction of sulfene and dichloroketene with N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones. Synthesis of 1,2-oxathiino[6,5-E] indole and of pyrano[2,3-e] indole derivatives

The 1,4-cycloaddition of sulfene to N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones afforded N,N-disubstituted 3,4,5,6-tetrahydro-8-methyl-7-phenyl-7H-1,2-oxathiino[6,5-e]indol-4-amine 2,2-dioxides only in the case of aliphatic N-substitution. The 1,4-cycloaddition of dichloroketene occurred normally only in the case of 1,5,6,7-tetrahydro-2-methyl-1-phenyl-5-piperidinomethyleneindol-4-one to give 3,3-dichloro-3,4,5,6-tetrahydro-8-methyl-7-phenyl-4-piperidino-7H-pyrano[2,3-e]indol-4-one. Attempted recrystallisation, dehydro-chlorination or treatment with palladium on carbon of this adduct, as well as reaction of similar enaminoketones with dichloroketene, gave instead the same product, namely 3-chloro-8-methyl-7-phenyl-7H-pyrano[2,3-e]indol-4-one, as a result of dehydrochlorination, dehydrogenation and subsequent hydrogenolysis of the C-NR₂ bond in the primary adduct.     

Synthesis of N-alkoxy-substituted 2H-benzimidazoles

Treatment of 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines with potassium tert-butoxide in tert-butanol followed by the addition of an electrophile affords N-alkoxy-2H-benzimidazoles. Electrophiles including methyl iodide, allylic bromides, propargylic bromides, benzyl bromide, and acetyl chloride gave good to excellent yields of product while 1-iodo- and 2-iodo-butane afforded very low yields.     

Synthesis of 7-iodo(arylsulfanyl)methyl-7,8-dihydro-[1,3]thiazolo[2,3-i]purinium pentaiodide (perchlorates) and their transformation into 4-amino-5-(1,3-thiazol-2-yl)imidazole derivatives

Intramolecular electrophilic cyclization of 6-allylsulfanylpurine by the action of iodine and arenesulfenyl chlorides gave 7-iodomethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium pentaiodide and 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates, respectively. 7-Iodomethyl-7,8-dihydro-[1,3]thiazolo[2,3-i]purin-6-ium iodide reacted with sodium and potassium alkoxides to produce alkyl N-[5-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-4-yl]formimidates, and its reaction with secondary cyclic amines afforded 5-(4-methyl-1,3-thiazol-2-yl)-N-[morpholin-4-yl(or piperidin-1-yl)methylidene]-1H-imidazol-4-amines. Successive treatment of 7-arylsulfanylmethyl-7,8-dihydro[1,3]thiazolo[2,3-i]purin-6-ium perchlorates with sodium acetate and morpholine led to the formation of 5-(4-arylsulfanylmethyl-4,5-dihydro-1,3-thiazol-2-yl)-N-(morpholin-4-ylmethylidene)-1H-imidazol-4-amines.     

11. Anil-Synthese. 16. Mitteilung. Über die Herstellung von styryl-derivaten des 2-phenyl-imidazo [1,2-a]pyridins

Preparation of styryl derivatives of 2-phenyl-imidazo [1, 2-a]pyridine 2-(p-Tolyl)-imidazo [1, 2-a]pyridines and 7-methyl-2-phenyl-imidazo [1,2-a]-pyridines can be converted, in dimethylformamide, on reaction with anils of aromatic aldehydes in the presence of potassium hydroxide or potassium t-butoxide, into the corresponding 2-(stilben-4-yl)- and 2-phenyl-7-styry1-imidazo [1, 2-a]-pyridines (‘Anil-Synthesis’). The 2-(p-tolyl)-imidazo [1,2-a]pyridines react far less readily than the 7-methyl-2-phenyl-imidazo[1,2-a]pyridines.     

A highly enantio- and diastereoselective 1,3-dimethylallylation of aldehydes

A highly enantio- and diastereoselective pentenylation of aldehydes is described. The homoallylic alcohol derived from 1,3-dimethylallylation of (-)-menthone undergoes an efficient allyl-transfer reaction with a wide range of aliphatic aldehydes in the presence of an acid catalyst to give rise to the corresponding 4-methyl-2(E)-penten-4-yl-5-ol products in good yields with high enantio- and 4,5-syn-selectivities.     

Eine neue Synthese von 8-Hydroxy-2-methyl-1,2,3,4-tetrahydroisochinolin

A new Synthesis of 8-Hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline Vilsmeier formylation of N-[2-(3,5-dimethoxyphenyl)ethyl]-trifluoroacetamide ( 5 ) yielded the aldehyde 6 , which under mild basic conditions was hydrolyzed to 7 and cyclized to 6,8-dimethoxy-3,4-dihydroisoquinoline ( 3 ). Methylation of 3 and reduction of the double bond in 10 afforded 6,8-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline ( 11 ). The methoxyl group at C(6) was selectively demethylated and the free hydroxyl group in 12 was phosphorylated to give 13 . Reduction of the latter with potassium in liquid ammonia yielded 8-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline ( 2 ), which was demethylated to the title compound 1 .     

Syntheses on the basis of 2H-chromen-2-one and 2H-chromene-2-thione

4-Hydroxy-2H-chromen-2-one and 4-hydroxy-2H-chromene-2-thione reacted with allyl bromide, 1,1,3-trichloroprop-1-ene, and 1,3-dichlorobut-2-ene to give the corresponding ethers, which were oxidized to (2-oxo-2H-chromen-4-yloxy)acetic acid with potassium permanganate, and various derivatives of that acid were obtained. 3-(3,3-Dichloroprop-2-enyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,3-dichloroprop-2-enyl)-7-hydroxy-4-methyl-2H-chromene-2-thione were synthesized, and some their transformations were studied.     

Temperature- and Pressure-induced Structural Transition of Binary Clathrate Hydrates

We discover new structure II (sII) hydrate forming agents of two C₄H₈O molecules (2-methyl-2-propen-1-ol and 2-butanone) and report the abnormal structural transition of binary C₄H₈O+CH₄ hydrates between structure I (sI) and sII with varying temperature and pressure conditions. In both (2-methyl-2-propen-1-ol+CH₄) and (2-butanone+CH₄) systems, the phase boundary of the two different hydrate phases (sI and sII) exists at the slope change of the phase-equilibrium curve in the semi-logarithmic plots. We confirm the crystal structures of two hydrates synthesized at low (278 K and 6 MPa) and high (286 K and 15 MPa) temperature and pressure conditions by using high-resolution powder diffraction and Raman spectroscopy. 2-Methyl-2-propen-1-ol and 2-butanone can occupy the large cages of sII hydrate at low temperature and pressure conditions; however, they are excluded from the hydrate phase at high temperature and pressure conditions, resulting in the formation of pure sI CH₄ hydrate.     

Microwave assisted synthesis of some new thiazolopyrimidine, thiazolodipyrimidine and thiazolopyrimidothiazolopyrimidine derivatives with potential antioxidant and antimicrobial activity

Biginelli reaction of ethyl acetoacetate, thiourea and the appropriate aromatic aldehyde was used to produce ethyl 4-aryl-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylates, that reacted with bromomalononitrile to give ethyl 3-amino-5-aryl-2-cyano-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylates rather than the isomeric 7H-thiazolo[3,2-a]pyrimidines. Thiazolopyrimidine derivatives reacted with carbon disulphide to yield ethyl 9-aryl-7-methyl-2,4-dithioxo-2,3,4,9-tetrahydro-1H-thiazolo[3,2-a:4,5-d']dipyrimidine-8-carboxylates, that reacted with phenacyl bromide to produce ethyl 8-methyl-10-(4-methoxyphenyl)-3-substituted-5-thioxo-2(un)subatituted-10H-thiazolo[3',2':1',2']pyrimido[4',5':4,5]thiazolo[3,2-a]pyrimidine-9-carboxylates. The aforementioned reactions were carried out using both conventional chemical methods and with the assistance of microwave irradaition. Comparison between both methods showed that the microwave assisted method is preferable because of the time reduction and yield improvements achieved. The new compounds were tested for their biological activity as antioxidants, antibacterial or antifungal agents. Some of the new compounds were found to have moderate to good antioxidant and antimicrobial activities.     

Nitropyrazoles: XII. Transformations of the 4-Methyl Group in 1,4-Dimethyl-3,5-dinitropyrazole and Cyclization of the Transformation Products

A preparative procedure for the synthesis of 1,4-dimethyl-3,5-dinitropyrazole by nitration of 1,4-dimethylpyrazole was developed. The reaction of 1,4-dimethyl-3,5-dinitropyrazole with dimethoxymethyl- (dimethyl)amine (N,N-dimethylformamide dimethyl acetal) gave (E)-N,N-dimethyl-2-(1-methyl-3,5-dinitropyrazol- 4-yl)ethenylamine. Acid hydrolysis of the latter afforded (1-methyl-3,5-dinitropyrazol-4-yl)acetaldehyde, and the reaction with sodium nitrite in hydrochloric acid led to formation of 2-hydroxymino-2-(1-methyl- 3,5-dinitropyrazol-4-yl)acetaldehyde. The corresponding O-methyloxime and phenylhydrazone reacted with K₂CO₃ to give 6-methyl-4-nitropyrazolo[4,3-d]isoxazole-3-carbaldehyde O-methyloxime and 1-methyl-3-nitro-4-(2-phenyl-2H-1,2,3-triazol-4-yl)pyrazol-5-ol, respectively. Treatment of (1-methyl-3,5-dinitropyrazol-4-yl)-acetaldehyde with benzenediazonium chloride gave (1-methyl-3,5-dinitropyrazol-4-yl)acetaldehyde phenylhydrazone which underwent intramolecular cyclization with replacement of the 5-nitro group by the action of K₂CO₃ in acetonitrile; in the reaction with K₂CO₃ in ethanol, the 5-nitro group was replaced by ethoxy.     

Methyl (E)-2-(2-phenylcyclopropylidene)acetate: Synthesis, isomerization, and reaction with 1,3-diphenyl-2-benzofuran

Treatment of 3-methyl-2-phenylcycloprop-2-ene-1-carboxylic acid with potassium tert-butoxide induced its isomerization into trans-2-methylidene-3-phenylcyclopropane-1-carboxylic acid which was converted into methyl ester, and heating of the latter for 1 h in toluene gave methyl (E)-2-(2-phenylcyclopropylidene)acetate. Thermal isomerization of methyl (E)-2-(2-phenylcyclopropylidene)acetate on prolonged heating in toluene afforded 5-methoxy-3-methyl-2-phenylfuran, and the reaction with 1,3-diphenyl-2-benzofuran resulted in [4 + 2]-cycloaddition at the exocyclic double bond.     

Acyclo analogs of formycin a

Starting from 7-chloro-3-methyl-1H-pyrazolo[4,3-d]pyrimidine ( 1 ) by reaction with methanol/hydrogen chloride, subsequent methylation and reaction with N-bromosuccinimide 3-bromomethyl-7-methoxy-1-methyl-1H-pyrazolo[4,3-d]pyrimidine ( 6 ) is prepared. Treatment with ethylene glycol in the presence of potassium carbonate/potassium iodide and subsequent reaction with ethanolic ammonia afforded 7-amino-3-(2-hydroxyethoxymethyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine ( 11 ) an acyclo analog of formycin A.     

Reaction of 4,5-diaminopyrimidine and ethyl acetoacetate: Synthesis and chemistry of isomeric dihydropyrimido[4,5-b][1,4] diazepinones

Depending upon reaction conditions, 4,5-diaminopyrimidine and acetoacetic ester gave a variety of condensation products, including the two isomeric dihydropyrimido[4,5-b][1,4]-diazepinones. Under conditions leading to bicyclic products, the formation of 1,5-dihydro-4-methyl-2H-pyrimido[4,5-b][1,4]diazepin-2-one ( 2 ) was strongly favored. The isomeric 3,5-dihydro-2-methyl-4H-4-one compound ( 4 ) was best obtained by cyclization of ethyl 3-(4-amino-5-pyrimidylamino)crotonate ( 3 ) under base catalysis. Thermal rearrangement of 2 and 4 proceeded, in each instance, with loss of the isopropenyl moiety and gave 8-purinone. Compound 4 underwent ring contraction under the influence of alkoxide to yield a product which was shown to be the 7-isopropenyl-8-purinone ( 6 ).