Oxidation of heterocyclic nitrogen ylids to nitro heterocycles. Comparison of dimethyldioxirane with peracids

Oxidation of 3-amino-4-(4-chlorophenyl)furazan ( 1 ) and its phosphine imine derivative, 3-(4-chlorophenyl)-4-trioctylphosphiniminofurazan ( 3 ), with dimethyldioxirane (DMD) gave 3-(4-chlorophenyl)-4-nitrofurazan ( 4 ) as the exclusive product. However, the sulfilimine derivative, 3-(4-chlorophenyl)-4-dimethylsulfiliminofurazan ( 2 ), was converted by DMD to the sulfoximine, 3-(4-chlorophenyl)-4-dimethylsulfoximinofurazan ( 6 ). These results contrast dramatically with the oxidations of these compounds with peracids.     

Synthesis of pyridazino[4,5-b]indole derivatives from 2-(3-carboxy-1-methylindole)acetic acid anhydride

2-(3-Carboxy-1-methylindole)acetic acid anhydride ( 1 ) reacts with aryldiazonium salts to give 85–95% of the corresponding α-hydrazono anhydrides 2 . Treating 2 with boiling hydrazine hydrate in xylene, the respective 2-aryl-4-carbohydrazido-5-methyl-1-oxo-1,2-dihydro-5H/-pyridazino[4,5-b]indoles 3 were obtained (47–67%), and these compounds characterized as the respective benzylidene derivatives 4 . Compounds 2 react with amines (aniline, morpholine, piperidine) to give the respective 2-(3-carboxy-1-methylindole)aceta-mide 5 or the respective 2-aryl-4-carboxamido-5-methyl-5H-pyridazino[4,5-b]indole 6 , the product obtained depending on the structure of the aryl substituent. Boiling 2b (aryl = 4-chlorophenyl) with 5% sodium hydroxide gave (80%) 2-(3-carboxy-1-methylindole)acetic acid ( 7 ). Hydrolysis of 2b gave a mixture of 7 and 2-(3-carboxy-1-methylindolyl)-2-(4-chlorophenylhydrazono)acetic acid ( 8 ).     

Reaction of 3-(o-chlorobenzylidene)-2,4-dioxopentanoic acid with hydroxylamine hydrochloride. Revised structure tor azeto[3,2-d]isoxazoline

Reaction of 3-(o-ehlorobenzylidene)-2,4-dioxopentanoic acid (1) with hydroxylamine hydro-chloride in acetic acid gave 5-(o-chlorophenyl)-3-methyl-4-(α-hydroxyimino)isoxazolineglyo-xylic acid (5) and 3-(o-chlorobenzylidene)-4-hydroxyimino-2-oxopentanoic acid (2) in 57% and 7% yields. Pyrolysis of 5 afforded 5-(o-chlorophenyl)-3-methylisoxazole-4-carbonitrile (8), cis- and trans-5-(o-chlorophenyl)-3-methylisoxazoline-4-carbonitriles (9,10), and 5-(o-chloro-phenyl)-3-methylisoxazoline-4-carboxamide (11).     

A new synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines via a Key Intermediate

The chlorination of the α-hydrazonoester 4 with phosphoryl chloride/pyridine gave 3-[α-(o-chlorophenylhydrazono)methoxycarbonylmethyl]-2-chloroquinoxaline 5 , whose cyclization with 1,8-diazabicyclo[5,4,0]-7-undecene afforded 3-methoxycarbonyl-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 6 . The reaction of 6 with hydrazine hydrate provided 3-hydrazinocarbonyl-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 7 , whose reactions with methyl and allyl isothiocyanates furnished 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1-(o-chlorophenyl)-1H-pyrazolo[3,4-b]quinoxaline 2 and 3-(4-allyl-2,3-dihydro-3-thioxo-4H-1,2,4-triazol-5-yl)-1-(o-chloropheny)-1H-pyrazolo[3,4-b]quinoxaline 8 , respectively. Moreover, the reactions of 7 with triethyl orthoformate and orthoacetate gave 1-(o-chlorophenyl)-3-(1,3,4-oxadiazol-5-yl)-1H-pyrazolo-[3,4-b]quinoxaline 9a and 1(o-chlorophenyl)-3-(2-methyl-1,3,4-oxadiazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 9b , respectively.     

Synthesis of Hexa- and Octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine.     

Friedel-crafts cyclisation—IV: Intramolecular vs intermolecular acylation with β-aryl derivatives of propionyl chloride in aromatic substrates

Studies on the aluminium chloride-catalysed behaviour of β-phenylpropionyl, β,β-diphenylpropionyl, and β,β,β-triphenylpropionyl chlorides in anisole and some other aromatic stubstrates under standardised conditions are discussed. β,β-Diphenylpropionyl chloride gave yields of up to 27% 3-phenylindan-1-one in anisole and is one of the most easily cyclised acid chlorides so far reported. β,β,β-Triphenylpropionyl is less easily cyclised in anisole to 3,3-diphenylindan-1-one and its transformation product 2,3-diphenylind-1-one. The expected open-chain ketone is completely decomposed into products of αβ-ketonic cleavage and a subsequent redox reaction. Differences in ratios of intermolecular to intramolecular acylation (now called o/c ratios) are discussed.In benzene, β-bis-(p-chlorophenyl)propionyl chloride gave, in addition to the previously noted β-bis-(p-chlorophenyl)propiophenone (48%), the folloowing compounds: 6-chloro-3-(p-chlorophenyl)indan-1-one (4%) (the intramolecular acylation product), β-(p-chlorophenyl)-β-phenylpropiophenone (2·3%), ββ-diphenylpropiophenone (0·5%), 3-(p-chlorophenyl)-indan-1-one (5·2%). The transformation processes are discussed. Aluminium chloride-catalysed β-aryl exchange in acid chlorides is reported for the first time, but β-aryl exchange does not occur in ββ-(or 3,3-)di-aryl derivatives of indan-1-one.     

Synthesis of 1,8-, 1,6- and 3,6-dichloro-9H-thioxanthen-9-ones

Cyclization of 2-chloro-6-[(3-chlorophenyl)thio]benzoic acid ( 2 ) gave a mixture of 1,8-, 3 , and 1,6-dichloro-9H-thioxanthen-9-ones 4 . The mixture was converted to 1,8-diamino- 7 , and 1-amino-6-chloro-9H-thioxanthen-9-ones 8 , from which 3 and 4 were prepared separately, respectively. From a mixture of 4 and 3,6-dichloro-9H-thioxanthen-9-one ( 11 ) obtained by cyclizing 4-chloro-2-[(3-chlorophenyl)thio]benzoic acid ( 10 ) was separated 11 by conversion of 4 to 8 .     

Reactions of 2-isocyanatobenzoyl chloride and 2-carbomethoxyphenyl isocyanate with 5-aminotetrazole

Treatment of 2-isocyanatobenzoyl chloride ( 4 ) with 5-aminotetrazole (5-AT) gave 3-(5-tetrazolyl)quinazoline-2,4(1H,3H)-dione ( 1 ) directly. Treatment of 2-carbomethoxyphenyl isocyanate ( 5 ) with 5-AT gave 2-[((5-amino-1H-tetrazol-1-yl)carbonyl)amino]benzoic acid methyl ester ( 6 ) as a kinetic product, which was thermally isomerized to 2-[((1H-tetrazol-5-ylamino)carbonyl)amino]benzoic acid methyl ester ( 7 ), the thermodynamically more stable urea. Cyclization of 7 with polyphosphoric acid gave 2-(1H-tetrazol-5-ylamino)-4H-3,1-benzoxazin-4-one ( 2 ). Urea 6 was quite labile in solution, as shown by nmr, and readily reacted with methanol to give 2-[(methoxycarbonyl)amino]benzoic acid methyl ester ( 10 ).     

Photochemical and thermal transformations of azomethine imines

The thermal and photochemical fragmentations of a few bisazoalkenes have been investigated. 2-Phenyl-4,5-disubstituted-1, 2,3-triazoles were obtained both in the thermolysis and photolysis of 1, 2-bisphenylazo-(4, 4′-dichloro) stilbene, 1, 2-bisphenylazo(4, 4′-dimethoxy)stilbene, 1, 2-bisphenylazocyclohexene and o-(phenylazo) phenyldiazocyanide. Both 2, 3-bisphenylazo-2-butene and 1, 2-bisphenylazoethylene failed to undergo either photolysis or thermolysis in the expected manner. However, 2, 3-bisphenylazo-2-butene underwent an acid-catalysed valence isomerisation to anhydro 1-phenylimino-2-phenyl-4, 5-dimethyl-1, 2, 3-trizolium hydroxide, which on photolysis gave 2-phenyl-4, 5-dimethyl-1, 2, 3-triazole. The same iminotriazolium intermediate gave a cycloadduct, 2, 6-diphenyl-3, 3a-dimethyl-4, 5-dicarbomethoxypyrazolino [2.3.c][1.2.3] triazole, on treatment with dimethyl acetylenedicarboxylate, whereas treatment with carbon disulphide gave 2-phenyl-4, 5-dimethyl-1, 2, 3-triazole. Both photolysis and thermolysis of C-biphenylene-N^α(4-chlorophenyl)-N^β-cyanoazomethine imine gave 9-fluorenone-N- (4-chlorophenyl) anil. Photolysis of 1, 2-bisphenylazoacenaphthylene in methanol gave acenaphthenequinone monophenylhydrazone.     

Oxidations of 3,6-diamino-1,2,4,5-tetrazine and 3,6-bis(s,s-dimethylsulfilimino)-1,2,4,5-tetrazine

Oxidation of 3,6-diamino-1,2,4,5-tetrazine ( 1 ) with most peracids gave 3,6-diamino-1,2,4,5-tetrazine 1,4-dioxide ( 3 ) as the major product; however, treatment of 1 with peroxytrifluoroacetic acid (PTFA) gave 3,6-diamino-1,2,4,5-tetrazine 1-oxide ( 4 ) as the major product along with a small amount of 3-amino-6-nitro-1,2,4,5-tetrazine 2,4-dioxide ( 5 ). Oxidation of 3,6-bis(S,S-dimethylsulfilimino)-1,2,4,5-tetrazine ( 6 ) with 3-chloroperoxybenzoic acid (MCPBA) gave 3-S,S-(dimethylsulfilimino)-6-nitroso-1,2,4,5-tetrazine ( 7 ), which was oxidized further with dimethyldioxirane to 3-(S,S-dimethylsulfoximino)-6-nitro-1,2,4,5-tetrazine ( 8 ). All attempts to obtain 3,6-dinitro-1,2,4,5-tetrazine ( 2 ) by further oxidation of 7 or 8 failed.     

Synthesis and properties of some aryl-s-triazines

The synthesis and reactions of several substituted s-triazines were studied in attempts to prepare 4,6-bis(4-chlorophenyl)-s-lriazine-2-carboxylie acid ( 2 ) and 2-aldehyde ( 8 ). The 4,6-bis-(4-chlorophenyl)-s-triazine derivatives were surprisingly inert to a variety of reagents. 4,6-Bis-(4-chlorophenyl)-2-methyl-s-triazine ( 1 ) could not be oxidized with any of a variety of oxidants. On bromination 1 gave 4,6-bis(4-chlorophenyl)-2-dibromomethyl-s-triazine ( 4 ) which was resistant to hydrolysis but on oxidation with selenium dioxide gave 2 . Compound 2 was also prepared by the oxidation of 4,6-bis(4-chlorophenyl)-2-hydroxymethyl-s-triazme ( 7 ) with potassium permanganate. Other reagents did not oxidize 7 to 8 . 4,6-Bis(4-chloroanilino)-2-mcthyl-s-triazine ( 3 ) was also resistant to oxidizing agents. 2-Diazomethy1-4,6-dichloro-s-triazine ( 11 ) on reaction with 4-chloroaniline gave 4,6-bis(4-chloroanilino)-2-chloromethyl-s-triazine ( 12 ). All efforts to prepare 8 were unsuccessful.     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

Studies on imidazole derivatives and related compounds. I. Synthesis of novel antineoplastic derivatives of 4-carbamoylimidazolium-5-olate

Acylation of 4-carbamoylimidazolium-5-olate ( 2 ) with a variety of acid chlorides produced 4(5)-carbamoyl-1H-imidazol-5-(4)yl acid carboxylates ( 3a-j ). Treatment of esters 3a,c with sodium hydroxide gave imides, 4a,c . Methylation of 3a and 2 with diazomethane gave the N-3 methyl derivative ( 6 ) and a mixture of the N-3, O-dimethyl derivative ( 9 ), the N-1, N-3-dimethyl derivative ( 10 ) and the O-methyl derivative ( 11 ), respectively. 5-Carbamoyl-1-methylimidazolium-4-olate ( 7 ) and its 4-carbamoyl isomer ( 16 ) were prepared from 2-aminopropanediamides 8 and 15 , respectively. Treatment of the imidazolium compound ( 10 ) with aqueous potassium hydroxide gave the recyclized product, 1-methyl-5-methylcarbamoylimidazolium 4-olate ( 18 ). Methyl derivatives 6, 7 , and 9 except 16 demonstrated the complete lack of antitumor activity against Lewis lung carcinoma or sarcoma 180 in mice.     

On the mechanism of hydrolysis of the triazolobenzodiazepine,triazolam. Spectroscopic study

The hydrolysis of 8-chloro-6-(2′-chlorophenyl)-1-methyl-4H[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (Triazolam) at room temperature, involves a reversible mechanism. The intermediate is a protonated species and the final product is the ring-opened compound resulting from the reversible scission of the imine bond. The two compounds were determined simultaneously as a function of pH with pmr and cmr spectrometry. Spectral data of the benzophenone derivative II (ir, cmr, pmr) are reported.     

Synthesis of 1, 5- and 1, 7-dichloro-9H-thioxanthen-9-ones

1, 5-Dichloro-9H-thioxanthen-9-one ( 2 ) was prepared by cyclization of 2-chloro-6-[(2-chlorophenyl)thio]-benzoic acid ( 10 ) obtained from 2-chloro-6-iodobenzoic acid ( 9 ) and 2-chlorobenzenethiol. Similarly, 1, 7-di-chloro-9H-thioxanthen-9-one ( 6 ) was prepared from 9 via 2-chloro-6-[(4-chlorophenyl)thio]benzoic acid ( 11 ). Compound 6 was also obtained by condensation of 2-chloro-6-mercaptobenzoic acid ( 12 ) with chlorobenzene in the presence of sulfuric acid.     

Synthesis of potential impurities of cloxacillin sodium drug substance

The present work describes the synthesis and characterization of six related compounds of cloxacillin sodium ( 1 ) viz penicilloic acid of cloxacillin (2) , (3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl) glycine (Glycine analogue of cloxacillin) (3), CMICAA adduct of cloxacillin (4) , (4S)-2-(carboxy(3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido) methyl)-3-(2-ethylhexanoyl)-5,5-dimethylthiazolidine-4-carboxylic acid (N-2-ethylhexanoyl penicilloic acid of cloxacillin) ( 5 ), N-Acetylated penicilloic acid of cloxacillin ( 6 ), and Cloxacillin Penicillamide (7) . These related compounds are very essential in the process development of cloxacillin sodium and are used as reference standards to determine the quality of the drug substance.     

Synthesis and reactions of 4-(arylhydrazino)coumarins

The interaction of 4-hydroxycoumarin with phenyl-, 2-chlorophenyl- and 4-bromophenyhydrazine hydrochlorides in the presence of triethylamine led in all cases to the corresponding 4-(arylhydrazino)-coumarins and 1-aryl-3-(2-hydroxyphenyl)-2H-pyrazolin-5-ones. 4-(Arylhydrazino)coumarins reacted with 4-chlorobenzaldehyde in the presence of piperidine acetate to give the corresponding 2-aryl-3-(4-chlorophenyl)[1]benzopyrano[4,3-b]pyrazol-4-ones. The reaction of 4-(4-bromophenylhydrazino)-coumarin with 4-chlorobenzaldehyde in the presence of piperidine acetate and an excess of piperidine gave 2-(4-bromophenyl)-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-4-(piperidinocarbonyl)pyrazole, but the reaction of phenyl- and 4-(2-chlorophenylhydrazino)coumarins with 4-chlorobenzaldehyde gave 1-aryl-5-(4-chlorophenyl)-3-(2-hydroxyphenyl)-4-(1-piperidino)carbonyl-4,5-dihydropyrazoles.     

新型含噻唑和三唑环的亚胺类化合物的合成及生物活性研究

设计合成了一系列新型含有噻唑和三唑环的亚胺类化合物, 其结构经元素分析、1H NMR和X射线晶体衍射确证. 生物活性测试结果表明, 部分化合物在50 μg/L浓度下对苹果轮纹菌具有一定的杀菌活性.     

Reactions of 6-Amino-5-Cyano-3-Methyl-1,4-Diphenyl-1H 4H-Pyrano[2,3-C]Pyrazole and its Methanimidate

Reaction of 6-amino-5-cyano-3-methyl-1,4-diphenyl- 1H,4H-pyrano[2,3-c]pyrazole 1 with triethyl orthoformate in acetic anhydride gave its methanimidate 2, which reacts with primary aliphatic and aromatic amines to give 4,6-dihydro-3-methyl-1,4-diphenyl-6- (alkyl)pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5(lH)- imine 3 and the starting compound 1 , respectively. Treatment of 1 with o-aminophenol gave 5-(2-benzoxalyl)- 1,4-dihydro-3-methyl-1,4-diphenylpyrano[2,3-c]pyrazol- 6-amine 9.     

Reactions of zinc enolates derived from 1-aryl-2-bromo-alkanones and 1-aryl-2-bromo-2-phenylethanone with 3-aroyl-6-bromochromen-2-ones and 2-benzoylbenzo[f]chromen-3-one

3-Aroyl-6-bromochromen-2-ones and 2-benzoylbenzo[f]chromen-3-one reacted with zinc enolates derived from 1-aryl-2-bromoalkanones and 1-aryl-2-bromo-2-phenylethanone to give, respectively, 4-(1-alkyl-2-aryl-2-oxoethyl)-3-aroyl-6-bromochroman-2-ones and 1-(2-aroyl-1-methyl-2-oxoethyl)-2-benzoyl-1,2-dihydrobenzo[f]chromen-3-ones as a single stereoisomer. Treatment with acetic anhydride of the intermediate product obtained from 3-benzoyl-6-bromochromen-2-one and [1-(4-chlorophenyl)-2-phenylethen-1-yloxy]-zinc(II) bromide resulted in the formation of 3-(1-acetoxy-1-phenylmethylidene)-6-bromo-4-[2-(4-chlorophenyl)-2-oxo-1-phenylethyl]chroman-2-one.