Bromination of methyl substituted 1,2,5-thiadiazoles with N-bromosuccinimide

Bromomethyl-1,2,5-thiadiazoles 2a-c were prepared by bromination of methyl-1,2,5-thiadiazoles 1a-c by NBS in refluxing carbon tetrachloride. When bromination of 1a and 1b was carried out under irradiation of tungusten lamp, mixtures of cis -5a and b and trans-1,2-dibromo-1,2-bis(1,2,5-thiadiazol-3-yl)ethylene ( 6a and b ) were obtained.     

Reactions of 2-aryl-4-methoxy-9-oxocyclohepta[b]pyrylium perchlorates with hydroxylamine and hydrazines

2-Aryl-4-methoxy-9-oxocyclohepta[b]pyrylium perchlorates 1a-c reacted with hydroxylamine hydrochloride and hydrazine sulfate in the presence of triethylamine to afford 2-aryl-4,9-dihydrocyclohepta[b]pyran-4,9-dione 4-oximes 3a-c and 4-hydrazones 4a-c in good yields, respectively. On the other hand, the reactions with methylhydrazine and phenylhydrazine gave respectively 1-methyl- and 1-phenyl-substituted 5-aryl-3-(3-tropolonyl)pyrazoles 5a-c and 6a-c in excellent yields. Treatment with 4-nitrophenylhydrazine gave 2-aryl-4,9-dihydrocyclohepta[b]pyran-4,9-dione 4-(4-nitrophenyl)hydrazones 7a-c in good yields.     

Reduction of the 1,2,5-thiadiazole ring of 3,6:12,15-di-1,4-benzo[6.6](3,4)-1,2,5-thiadiazolo- and 3,5:11,13-di-1,3-benzo-[6.6](3,4)-1,2,5-thiadiazolocyclophanes. Selective preparation of cis- and trans-[23]cyclophane-1,2-diacetoamide

The effect of the [2.2.2]cyclophane ring structure on the reduction of 1,2,5-thiadiazole ring incorporated in cyclophanes 1a-c and 2a-c was investigated. When reduced by sodium metal in ethanol followed by acetylation, para[2³]cyclophane 1 gave a mixture of the expected cis- and trans-diamides, 3 and 4 , in which 4 was the major product. On the other hand, reduction of 1 with lithium aluminum hydride proceeded in a cis-selective manner and gave 3 as a major product after a treatment of the reduced products with acetic anhydride. The reduction of metacyclophane 2 , which is less strained than 1 , proceeded exclusively in cis-fashion and a subsequent treatment of the reduction product with acetic anhydride gave only cis-diamide 6 .     

Reduction of 4,7-diphenyl-1,2,5-thia(oxa)diazolo[3,4-c]pyridines affording 2,5-diphenyl-3,4-diaminopyridines and ring closure of the diamines to fluorescent azaheterocycles

Reduction of 4,7-diphenyl-1,2,5-thia- ( 1a-i ) and 1,2,5-oxadiazolo[3,4-c]pyridines ( 3a and c-e ) gave 3,4-diamino-2,5-diphenylpyridines ( 2a-g ), which were converted into the fluorescent triazolo[4,5-c]-( 5 ), 1,2,5-selenadiazolo[3,4-c]- ( 6 ), imidazolo[4,5-c]pyridines ( 8 ), and pyrido[5,6-c]pyridines ( 11 ). In the reduction of 3a, c and e , 4,5-dihydro[1,2,5]oxadiazolo[3,4-c]pyridines ( 4a-c ) were obtained.     

A novel synthesis of precocenes. Efficient synthesis and regioselective O-alkylation of dihydroxy-2,2-dimethyl-4-chromanones

The reactions of trihydroxybenzenes 1a-c and 3-methylbut-2-enoic acid ( 2 ) in a zinc chloride/water/phosphoryl chloride system afford either the new trihydroxyphenylbutenone derivatives 3b,c or dihydroxy-2,2-dimethyl-4-chromanones 4a-c in good yields. Compounds 3b,c can be cyclized in high yields to 4b,c in 5% sodium hydroxide solution. Regioselective O-alkylation of 4a-c leads to 5a-f in good yields. O-Alkylation of 5a-f , followed by reduction and dehydration, results in the formation of precocene 3 ( 7d ) and its regioisomer 7a-c,e,f . Methylation of 4a-c gives 6g-i . Subsequent reduction and dehydration affords precocene 2 ( 7h ) and its regioisomers 7g,i .     

A convenient synthesis of 2-amino-4H-1,3,4-oxadiazino[5,6-b]-quinoxaline derivatives

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 5 with a 2-fold molar amount of ethyl chloroglyoxalate gave ethyl 8-chloro-4-methyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline-2-carboxylate 6 , whose reaction with hydrazine hydrate afforded the C₂-hydrazinocarbonyl derivative 7 . The reaction of compound 7 with nitrous acid provided the C₂-acylazide derivative 8 , which was converted into the C₂-amino 9 , C₂-carbamate 11a-c, 12a,b , and C₂-ureido 13a-c, 14 derivatives. The mass spectral fragmentation patterns were examined for compounds 10–14 , wherein the molecular ion peak did not appear in the mass spectra of compounds 10c, 11a-c, 12a,b, 13c , and 14.     

Synthesis and antimicrobial activity of new 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,thiopyrane, thiazolidinone,and azepine derivatives

4-oxo-4-phenylbutanehydrazide 3 was reacted with aryl or alkyl isothiocyanates to give the corresponding N-substituted-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide 4a-c . Cyclization of thiosemicarbazides 4a-c with sodium hydroxide led to the formation of 3-(4-sub-5-thioxo-1,2,4-triazol-3-yl)-propanone 5a-c . Desulfurization of thiosemicarbazides 4a-c by mercuric oxide afforded 3-(5-(sub-amino)-1,3,4-oxadiazol-2-yl)-propanone 6a-c . The reaction of 4a-c with phosphorus oxychloride gave 3-(5-(sub-amino)-1,3,4-thiadiazol-2-yl)-propanone 7a-c . Treatment of 4a-c with ethyl-bromoacetate or α-bromopropionic acid gave N′-(3-sub-thiazolidin-2-ylidene)-butanehydrazide 8a-c and (N′-(3-sub-oxothiazolidin-2-ylidene)-butanehydrazide 9a-c . Chlorination of oxothiazolidine-hydrazide 9a-c by phosphorus oxychloride afforded N-(3-sub-4-oxothiazolidine)-butane-hydrazonoyl-chloride 10a-c . The reaction of 10a-c with mercaptoacetyl-chloride yielded 2-((4-benzoyl-thiopyrane) hydrazono)-3-sub-thiazolidinone 11a-c . Also, reacted of 10a-c with hydrazine hydrate afforded N″-(3-sub-oxothiazolidine)-butane-hydrazon-hydrazide 12a-c . The 3-sub-2-((pyridazine) hydrazono) thiazolidinone 13a-c was obtained by cyclization of 12a-c via refluxing in DMF. The reaction and cyclized of 9a-c with chloroacetyl-chloride in ethanolic KOH afforded 1-((3-sub-4-oxothiazolidine) amino)-azepine-dione 14a-c . The chemical structures of the new compounds have been confirmed by diverse spectroscopy analyses such as IR, NMR, MS, and elemental analysis. The synthesized compounds were tested for their antimicrobial activity and these compounds were considered (Pyridazin-hydrazono-thiazolidinone 13a-c , oxothiazolidin-azepinedione 14a-c , N-thiazolidin-hydrazon-hydrazide 12a-c , and thiopyran-hydrazono-thiazolidinone 11a-c ) the most effective as antimicrobial activity.     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

Synthesis and reactions of heterocyclic methyl 2-propenoates and 2,3-epoxypropanoates with nucleophiles

Reaction of 2-(3-,4-)pyridinecarboxaldehydes 5 with carbomethoxymethylene triphenylphosphorane afforded predominantly E-methyl-3-(pyridinyl)-2-propenoates 7. Oxidation of 7a-c with m-chloroperbenzoic acid gave methyl E-3-(1-oxidopyridinyl)-2-propenoates 8a-c in high yield. The Darzen's reaction of 5a-c with methyl bromoacetate yielded a mixture of stereoisomers cis- 9a-c and methyl trans-3-(pyridinyl)-2,3-epoxy-propanoates 10a-c in a ratio of 2:1. Oxidation of cis- 9a-c and trans- 10a-c afforded the corresponding cis- 11a-c and methyl trans-3-(1-oxidopyridinyl)-2,3-epoxypropanoates 12a-c in good yield. The reaction of 11a and 12a with cyclic amines as piperidine gave the respective threo- 13 and methyl erythro-2-(1-piperidino)-3-hydroxy-3-(1-oxido-2-pyridino)propanoate 14. The sodium borohydride reduction of the N-alkoxylcarbonyl pyridinium salts of 9c and 10c afforded the corresponding N-alkoxycarbonyl-1,2-dihydropyridyl derivatives 15 and 16. A number of selected compounds ( 7a-c , 9a-c , 10a , 10c , 11a-c and 12a , 12c ) were found to be inactive in the P388 Lymphocytic screen. Compounds 9-12 did not react with the model nucleophile ethanethiol in phosphate buffer at 37°.     

Reactions of 3-isopropenyltropolones with bromine and N-bromosuccinimide: Formation of 8H-cyclohepta[b]furan-8-one derivatives

3-Isopropenyltropolones 1a-c were treated with bromine in carbon tetrachloride to give 3-methyl-8H-cyclohepta[b]furan-8-ones 2a-c and their corresponding 7-bromo-substituted compounds 3a-c , while reactions in acetic acid gave the bromo-substituted compounds 3a-c . On the other hand, bromination of 1a-c with N-bromosuccinimide afforded 7-bromo-3-(2-bromo-1-methylethenyl)tropolones 5a-c . The compound 2a was treated with bromine to give 2-bromo-3-methyl-8H-cyclohepta[b]furan-8-one ( 4 ). The tropolones 5a-c were heated in the presence of potassium carbonate to give the cyclized compounds 3a-c .     

Ylides of heterocycles. VII.. I-, N-, P- and S-ylides of pyrimidones

The reaction of pyrimidone derivatives 1a-d with iodosobenzene prepared in situ from diacetoxyiodobenzene or dichloroiodobenzene afforded the iodonium-ylides 2a-d in good yields. Their thermal rearrangement produced 5-iodo-4-phenoxy-pyrimidin-6(1H)-ones 3a-c . Reductive deiodination of 3 gave the corresponding 4-phenoxypyrimidin-6(1H)-ones 4a-c . Acid catalized treatment of the iodonium-ylides 2a-d with nucleophiles such as pyridine, nicotinamide, isoquinoline, or triphenylphosphine produced the corresponding N- or P-ylides 7, 8, 9 , and 10 , respectively. The thiophanium-ylides 11a,c were obtained from the iodonium-ylides 2 without the use of a catalyst. The pyridinium-ylides 7 have been also prepared from the 5-halopyrimidones 5 or 6 which in turn could be obtained from the reactive iodonium-ylides 2 with hydrochloric or hydrobromic acid, respectively.     

Preparation of [23]cyclophane-1,2-diones by the reaction of 3,6;12,15-Di-1,4-benzo[6.6](3,4)-1,2,5-thiadiazolocyclophanes with grignard reagents

3,6;12,15-Di-1,4-benzo[6.6](3,4)-1,2,5-thiadiazolocyclophanes 1a-c were prepared starting from 3,4-di-p-tolyl-1,2,5-thiadiazole 3 and converted into [2³]cyclophane-1,2-diones 2a-c by the reaction with Grignard reagents.     

Synthesis and Photochemistry of syn- and anti-9,10-Epoxy-1, 4-dihydro-1,4-ethanonaphthalene-2,3-diones

The title epoxydiketones were prepared stereoselectively, direct epoxidation of 3a-c with MCPBA produced syn isomers la-c whereas epoxidation of 4a-d followed by saponification of the spirolactone rings gave anti isomers 2a-c. The stereochemistry of 1a and 2a was established by X-ray diffraction, whereas that of the remaining epoxydiketones was determined from the correlation of visible, ¹H, and ¹³C NMR spectral data; the differences between spectra of the corresponding syn and anti isomers are explained in terms of through-space interaction and steric effects. Photolysis of syn isomers 1a-c afforded the corresponding naphthalenes 8a-c in almost quantitative yields; in contrast, irradiation of anti isomers 2a-c gave complicated mixtures. The quantum yield of disappearance of 1a was 52 times that of 2a. Reaction mechanisms are proposed to account for the product formation. The differences in the photochemical behavior of the title syn and anti isomers are rationalized in terms of stereoelectronic effects of the epoxy rings in the syn isomers.     

Synthesis of cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives by use of the [2 + 8] cycloaddition reaction of indolizines and dimethyl acetylenedicarboxylate

The reaction of 1-ethoxycarbonylmethylpyridinium bromides 5a-k with nitro ketene dithioacetal, 1,1-bis-(methylthio)-2-nitroethylene ( 2 ), in the presence of triethylamine in ethanol gave the desired ethyl 2-methyl-thioindolizine-3-carboxylates 3a-k in good yields, along with ethyl 2-methylthio-1-nitroindolizine-3-carboxyl-ates 4a-d . Deesterification of 3 using sodium hydroxide in methanol followed by treatment with polyphosphoric acid gave the corresponding 2-methylthioindolizines 5a-d in good yields. The desulfurization of 5 with Raney-nickel in ethanol occurs smoothly to give the 1,2,3-unsubstituted indolizines 6a-c (a , parent indolizine; b , 8-methylindolzine; c , 6,8-dimethylindolizine). Similarly, pyrrolo[2,1-a]isoquinoline ( 19 ) was also synthesized. These indolizine and pyrrolo[1,2-a]isoquinoline derivatives were allowed to react with dimethyl acetylene to give the corresponding cycl[3.2.2]azine and benzo[g]cycl[3.2.2]azine derivatives in good results.     

Polycondensed nitrogen heterocycles. XXII. A new synthesis of 5,6-dihydro-7H-pyrazolo[1,5-d][1,4]benzodiazepin-6-ones

A new synthesis of 2-methyl-9-R'-10-R-5,6-dihydro-7H-pyrazolo[1,5-d][1,4]benzodiazepin-6-ones ( 4a-c ) is deserved. Reaction of ethyl hydrazinoacetate hydrochloride with 1,3-diketones 1a-c gave both 3-methyl-5-(4R'-5-R-2-nitrophenyl)pyrazol-1-yl-acetate acids ( 2a-c ) and the corresponding ethyl esters 3a-c . Reduction with the appropiate reducing agent of compounds 2a-c and 3a-c directly gave the title compounds. Compound 4a showed insecticidal properties against the house fly.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Ring-transformation reactions of 5-hydroxy-2-oxabicyclo[3.2.0]-heptan-4-ones and 5-hydroxy-2-oxabicyclo[3.2.0]hept-6-en-4-ones

Dehydrochlorination of chlorinated 5-hydroxy-2-oxabicyclo[3.2.0]heptan-4-ones, 3a-c, which were obtained from the photo[2+2]cycloadditions between 4-hydroxy-3(2H)-furanone 1 and chloroethylenes, with triethylamine gave 2-ethenyl-3(2H)-furanones 4a,b or 2-(2-cyanoethyl)-3(2H)-furanone 4c. 2-Oxa-bicyclo[3.2.0]hept-6-en-4-ones 7 being [2+2]cycloadducts between 1 and acetylenes gave 2,3-dihydro-3-oxooxepin derivatives 8 by electrocyclic rearrangement.     

Synthesis,structure, and oxidation of 3,4-dihydro-1,2,5-benzotrithiepins

Stable benzene-fused polysulfide compounds, 3,4-dihydro-1,2,5-benzotrithiepins ( 1a-c ), have been prepared, and the structure of 1a has been determined by X-ray crystallographic analysis. While the electrophilic oxidation of compounds 1 with m-chloroperbenzoic acid gave the corresponding 3,4-dihydro-1,2,5-benzotrithiepin 5-oxides ( 2 ) in moderate yields, the oxidation of 1 with N-bromosuccinimide afforded a mixture of 5-oxides 2 , unexpected, inseparable 3,4-dihydro-1,2,5-benzotrithiepin 2,2-dioxides ( 3 ), and 3,4-dihydro-1,2,5-benzotrithiepin 1,1-dioxides ( 4 ). Semiempirical PM3 calculations were carried out, and the computed HOMO of 1a suggested a significant favoring of electrophilic reactions at the sulfur atom at the 5-position. The treatment of 5-oxides 2 with acetyl bromide or oxalyl dibromide as halogenating reagents gave 2,2-dioxides 3 and 1,1-dioxides 4 , suggesting that an intramolecular halogen transfer from the 5-position (sulfide moiety) to the 1- and 2-positions (disulfide moiety) took place in the reactions.     

Reactions of O-methyl o-quinone monoximes with methyl-, methylene- and methine- substituted aromatic compounds. Synthesis of benzo[d]oxazole and 1,4-benzoxazine derivatives

O-Methyl o-quinone monoxime 1 reacts thermally with compounds 2a-d or 6a,b or 7a,b to give mainly the corresponding 2-substituted phenanthroxazoles 3a-c and 8 . The reaction of 1 with aromatic methylene compounds lOa-c affords the ketones 13a-c in moderate to high yields. Similar products are also obtained from the reaction of monoximes 15a,b with some of the above reactants. The unexpected products 5 and 20 are obtained from the reaction of 1 with 2-methylimidazole ( 2d ) and with phenyloxirane ( 19 ) respectively, while the 4H-1,4-oxazine derivative 23 is obtained from the reaction of 1 with indene ( 21 ).     

Asymmetric Synthesis of 3-Hydroxyprolines by Photocyclization of N-(2-Benzoylethyl)glycinamides

The chiral N-(2-benzoylethyl)-N-tosylglycinamides 1a-c were prepared from the C₂-symmetric pyrrolidines 5a-c . Irradiation of these ketones 1a-c gave cis-3-hydroxyprolinamides 10-12 in moderate to good yields (Scheme 3). The de of the photocyclizations depended on the size of the substituents in positions C(2) and C(5) of the chiral pyrrolidine auxiliaries. In addition, the de varied with the reaction temperature, allowing the determination of activation-parameter differences. The structure of products 10-12 were established by NMR and X-ray analyses.