Synthesis of 1,8- and 2,8-dihydrocycloheptapyrazol-8-one derivatives by the reactions of 3-acetyltropolone and its methyl ethers with phenylhydrazine

3-Acetyltropolone ( 1 ) reacted with phenylhydrazine to give 3-acetyltropolone phenylhydrazone ( 3 ) and 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one ( 4 ). The former ( 3 ) cyclized to afford the latter ( 4 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) with phenylhydrazine gave 4 , 3-methyl-2-phenyl-2,8-dihydrocyclo-heptapyrazol-8-one ( 5 ), and 3-methyl-2-phenyl-2,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 6 ). The compound ( 5 ) reacted with phenylhydrazine to afford 6 . The reaction of 7-acetyl-2-methoxytropone ( 2b ) with phenylhydrazone gave 7-acetyl-2-methoxytropone phenylhydrazone ( 7 ), 7-acetyl-2-(N′-phenylhydrazino)-tropone phenylhydrazone ( 8 ), 3-methyl-1-phenyl-1,8-dihydrocycloheptapyrazol-8-one phenylhydrazone ( 9 ), and 6 . The compound ( 7 ) was heated to afford 4 and reacted with phenylhydrazine to afford 8 and 9 . The compound ( 8 ) was also refluxed to give 9 .     

1,6- and 1,7-naphthyridines. II. Synthesis from acyclic precursors

A number of 8-hydroxy-6-methyl-1,6-naphthyridin-5(6H)-one-7-carboxylic acid alkyl esters 3 and the isomeric 5-hydroxy-7-methyl-1,7-naphthyridin-8(7H)-one-6-carboxylic acid alkyl esters 4 were synthesized from acyclic precursors obtained starting from quinolinic anhydride 5. Thus, methanolysis of 5 afforded the hemiester 6 which treated with oxalyl chloride and sarcosine ethyl ester gave 3-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-2-carboxylic acid methyl ester 8. Compound 8 was cyclized to naphthyridines 3a-e with sodium alkoxides. The isomeric naphthyridines 4a-c were obtained by cyclization of the open intermediary 2-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-3-carboxylic acid methyl ester 9 obtained by a route that involves treatment of 5 with sarcosine ethyl ester and esterification with diazomethane. Spectroscopic properties (¹H nmr, uv, ir) of compounds 3 and 4 are discussed and confirmed the proposed structures.     

Synthesis of 4,5-dihydro-4-methyl-1-phenyl-1,4,5-benzotriazocine-2,3,6(1H) triones

The title compounds, 7a and its 9-chloro analog 7b , were prepared in three steps from methyl N-phenylanthranilates. Thus, methyl N-phenylanthranilate ( 3a ) was treated with oxalyl chloride to yield 2-[(2-chloro-1, 2-dioxoethyl) phenylamino]benzoic acid methyl ester ( 4a ). Treatment of 4a with methylhydrazine gave 2-([2-(1-methylhydrazino)-1,2-dioxoethyl]phenylamino) benzoic acid methyl ester ( 6a ), which was cyclized with sodium hydride in dimethylformamide to produce 7a . Alkylation of 7a and 7b with iodomethane afforded the respective 5-methyl derivatives 8a and 8b . A survey of the known literature benzotriazocines is presented.     

Ringschlussreaktionen mit 2-(β-Styryl)benzylaminen 5-Phenyl-1H-2-benzazepine. 23. Mitteilung über siebengliedrige Heterocyclen

Cyclization reactions with 2-(β-styryl)benzylamines 5-Phenyl-1H-2-benzazepines Cyclization of the urea derivative 3 with POCl₃ to give 2-(4-methyl-1-piperazinyl)-4-phenylquinoline ( 4 ) was carried out in analogy to the quinoline synthesis of Foulds & Robinson. This reaction was used for the preparation of 2-benzazepines. The trisubstituted ureas 6 and 8 , derived from the 2-(β-styryl)-benzylamines 5 , were cyclized with POCl₃ to yield the 3-amino-5-phenyl-1H-2-benzazepines 7 and 9 , respectively. Similarly, cyclization of the corresponding acetyl-derivatives 10 gave the 3-methyl-5-phenyl-1H-2-benzazepines 12 . On the other hand, the disubstituted urea 15 , cyclized under the same conditions to the 1-methyl-1-phenylisoindoline derivative 16 , and 2-(β-styryl)benzylamine ( 5a ) on treatment with phosgene gave the isoindoline 17 in an analogous manner.     

Synthesis of [1,5-A]Pyrimidinone Ring Derivatives

Cyclodehydrogenation of the benzalhydrazino derivatives 5 and 6 gave 6-cyano-7-(4-methoxyphenyl)- 2-phenyl-5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (8) and 6-cyano-7-(4-methoxyphenyl)-4-methyl-2-phenyl- 5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (9) respectively. Melhylation, acetylation and benzylation of 8 gave the corresponding N-methyl, acetyl and benzyl derivatives 10-12 . Methylation of 5 with dimethylsulfate gave 2-benzalhydrazino-5-cyano-3-methyl-6-(4-methoxyphenyl)-3,4-dihydropyrimidin-4-one (6) , of which the reaction with acetic anhydride in pyridine afforded the N-acetylbenzalhydrazino derivative 15 . The latter was also prepared from acetylation of 5 followed by medthylation with iodomethane. Acetylation of 5 with boiling acetic anhydride afforded the diacetyl derivative 16 , whereas its benzylation gave the mono-N-benzyl derivative 14 .     

Chinazolincarbonsäuren. VII. Mitteilung. Ein einfacher Zugang zu (4-Oxo-3,4-dihydrochinazolin-3-yl)-alkansäuren, (4-Oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)-alkansäuren und deren Estern

Quinazoline Carboxylic Acids. An Easy Route to (4-Oxo-3,4-dihydroquinazolin-3-yl)-alkanoic Acids, (4-Oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)-alkanoic Acids and their Esters A new route was found for the synthesis of (4-Oxo-3,4-dihydroquinazolin-3-yl)-alkanoic acids ( 8 ) and (4-Oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)-alkanoic acids ( 6 ) by cyclization of the N-(2-aminobenzoyl)amino acids 5 with HCOOH or HNO₂. 2H-3,1-Benzoxazine-2,4(1H)-diones ( 1 ) reacted with glycine esters to 2 , which were cyclized by HNO₂ to the esters 4 . Ester 4 was hydrolyzed to 6 (X = CH₂). Diones 1 reacted with the most common amino acids (as the ammonium salt of tertiary amine) to amino-alkanoic acids 5 , which were cyclized with orthoformate to 7 or 8 depending on the reaction conditions.     

Synthesis of 2,3-dihydro-3-hydroxy-2-(pyrrol-1-ylmethyl)-1H-isoindol-1-one. An intermediate for the synthesis of tetracyclic systems

N-Chloromethylphthalimide 1 and the potassium salt of pyrrole gave N-(pyrrol-1-ylmethyl)pbthalimide 2 . Reduction of 2 led to the hydroxyisoindolone 3 . This hydroxylactam cyclized under acidic conditions to lead to a pyrroloimidazoloisoindolone 4 via an acyliminium ion. Transformation of 3 with acetic acid derivatives provided 5, 7 and 9 which gave by intramolecular cyclization, tetracyclic compounds 6, 10 and 11 .     

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.     

Reactions of 3-acetyltropolone and its methyl ethers with aminoguanidine

3-Acetyltropolone ( 1 ) reacted with aminoguanidine to afford its guanylhydrazone ( 3 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) gave 4-methyl-1(2H)-phthalazinone ( 5 ), while the reaction of 7-acetyl-2-methoxytropone ( 2b ) gave its guanylhydrazone ( 6 ) and 3-methyl-1,8-dihydrocycloheptapyrazol-8-one ( 4 ). The guanylhydrazones ( 3 and 6 ) were easily cyclized to 4 by heating in acetic acid.     

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 .     

Asymmetric Synthesis of α-Amino Acids and α-N-Hydroxyamino Acids from N-Acylbornane-10,2-sultams: 1-chloro-1-nitrosocyclohexane as a practical [NH] equivalent

Successive treatment of N-acylsultams 3 with sodium hexamethyldisilazide, 1-chloro-1-nitrosocyclohexane ( 1 ), and aq. HCl gave diastereoisomerically pure, crystalline N-hydroxyamino-acid derivatives 5 . These were converted into various amino acids 7 , N-hydroxyamino acids 8 , and an N-Boc-amino acid 9 . (S, S)-Isoleucine ( 17 ) and (S, S)-2-acetamido-3-phenylbutyric acid ( 23 ) were obtained from N-crotonoylsultam 15 via 1,4-addition of an organomagnesium or organocopper reagent followed by enolate ‘amination’ with 1 .     

3,4-Dihydro-2-phenyl-2H-pyrano[2,3-b]pyridines. Novel aza analogs of flavans

Complementary approaches to the synthesis of the title compounds 1 are described. Metallation of 3,5-di-bromo-2-methoxypyridine ( 5b ) by bromine/lithium exchange gave selectively the 3-lithio intermediate 6 which was trapped with substituted cinnamaldehydes 7 , providing allylic alcohols 8 in good yields. Methyl ether cleavage and concomitant cyclization occurred on exposure to concentrated hydrobromic acid in hot acetic acid. The resulting 2-phenyl-2H-pyrano[2,3-b]pyridines were hydrogenated over Raney nickel to the title compounds which had antiviral activity. Alternatively, 1 were synthesized by Heck reaction of appropriately substituted 3-halo-2-methoxypyridines ( 5 or 24 ) with vinyl carbinol 15 to furnish ketones 16 or 26 which, upon reduction of the carbonyl group, were cyclized directly to 1 .     

Synthesis of nitrogen-containing heterocycles. 7 Reaction of aliphatic diaminomethylenehydrazones with hindered ethoxymethylenecyanoacetate

Aliphatic diaminomethylenehydrazones 1 were reacted with ethyl 2-cyano-3-ethoxy-2-pentenoate 2 to give a number of heterocycles in low to moderate yields, according to the substitution pattern and the size of substituent. When 1 carried a single methyl group on the terminal nitrogen, it gave preferentially 6-oxo-1,6-dihydropyrimidines 4 incorporating N(4) into the ring. In contrast, the reaction between 1c or 1d and 2 led to 6-imino- and 6-oxo-1, 6-dihydropyrimidines 7 and 8 along with 3 . When the alkylidene moiety was bulky, 1e and 1f , the similar reaction gave 3 in high yields without any cyclized product. Upon exposure to acid, compound 3 yielded 6-oxo-1,6-dihydropyrimidines 6 , [1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate 5 and N-alkenyl-1,2,4-triazoles 9 in addition to 7 and 8 in proportions dictated by the nature of the substituents of 1 . The structural assignment and reaction mechanism are discussed.     

Easy preparation,characterization and reactions of new 8-chloro-7-formyl-4-oxo-2-phenyl-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile

8-Chloro-7-formyl-4-oxo-2-phenyl-4H-pyrimido[1,2-a]pyrimidine-3-carbonitrile ( 3 ) is constructed using N-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) acetamide ( 2 ) via Vilsmeier-Haack formylation reaction. Compound 3 reacted with 3-(triethoxysilyl)propan-1-amine under different conditions. Condensation of pyrimidopyrimidine 3 with thiosemicarbazone derivative gave Schiff base 8 , which upon treating with Vilsmeier-Haack reagent afforded pyrazole carbothioamide 9 . Cyclocondensation of compound 3 with some binucleophiles namely thiocarbohyrazide, hydrazine carbodithioic acid, benzyl hydrazinecarbodithioate and/or 2-thioxopyrimidinone was investigated. Structures of the new synthesized compounds were confirmed by their analytical and spectral data.     

A study of the Claisen rearrangement of 7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one derivatives

Summary The Claisen rearrangement of 7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one (2 a) gave 7-hydroxy-8-(1-phenyl-2-propenyl)-3-phenyl-(4H)-1-benzopyran-4-one (3 a) and 2,3-dihydro-2,6-diphenyl-3-methyl-(7H)furo[2,3-h]-1-benzopyran-7-one (7 a). 2-Methyl-7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one (2 b) afforded4 b and7 b. 8-Methyl-7-(3-phenyl-2-propenyloxy)-3-phenyl-(4H)-1-benzopyran-4-one (12) gave only the alkali soluble product 7-hydroxy-8-methyl-6-(1-phenyl-2-propenyl)-3-phenyl-(4H)-1-benzopyran-4-one (13).3 a,4 b, and13 were further cyclized in acidic medium to9 a,10 b, and14 followed by dehydrogenation.This paper is dedicated to Dr. F. M. Dean, Department of Organic Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool, U. K., on his retirement     

Preparation of 2-[1-Phenyl-1H-pyrazol-5-yl]benzoic Acids from Dilithiated C(α),N-Phenylhydrazones and Methyl Hydrogen Phthalate

Select C(α),N-phenylhydrazones were dilithiated with excess lithium diisopropylamide to their dianion-type intermediates followed by condensation with methyl hydrogen phthalate. The resulting C-acylated hydrazones were not isolated but acid cyclized directly to afford new substituted 2-(1-phenyl-1H-pyrazol-5-yl)benzoic acids.     

A facile and improved synthesis of tubercidin and certain related pyrrolo[2,3-d]pyrimidine nucleosides by the stereospecific sodium salt glycosylation procedure

A simple synthesis of tubercidin ( 1 ), 7-deazaguanosine ( 2 ) and 2′-deoxy-7-deazaguanosine ( 14 ) has been accomplished using the sodium salt glycosylation procedure. Reaction of the sodium salt of 4-chloro- and 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine, 3 and 4 , respectively, with 1-chloro-2,3-0-isopropylidene-5-0-(t-butyl)dimethylsilyl-α-D-ribofuranose ( 5 ) gave the corresponding protected nucleosides 6n and 7 with β-anomeric configuration. Deprotection of 6 provided 8 , which on heating with methanolic ammonia gave tubercidin ( 1 ) in excellent yield. Functional group transformation of 7 , followed by deisopropylidenation gave 2-aminotubercidin ( 10 ) and 2-amino-7-β-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-4(3H)-thione ( 11 ). Treatment of 7 with 1N sodium methoxide followed by exposure to aqueous trifluoroacetic acid, and ether cleavage furnished 7-deazaguanosine ( 2 ). 2′-Deoxy-7-deazaguanosine ( 14 ) and 2′-deoxy-7-deaza-6-thioguano-sine ( 18 ) were also prepared by using similar sequence of reactions employing 4 and 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 15 ).     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

A facile and novel synthesis of 1,6-naphthyridin-2(1H)-ones

A new and convenient procedure for the synthesis of 1,6-naphthyridin-2(1H)-ones and their derivatives is described. In the first scheme 5-acetyl-6-[2-(dimethylamino)ethenyl]-1,2-dihydro-2-oxo-3-pyridinecarbonitrile ( 4 ) obtained by the reaction of N,N-dimethylformamide dimethyl acetal with 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile ( 3 ) was cyclized to 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile ( 5 ) by the action of ammonium acetate. Thermal decarboxylation of acid 7 obtained from the hydrolysis of nitrile 5 led to a mixture of 5-methyl-1,6-naphthyridin-2(1H)-one ( 8 ) and its dimer 9 . Hydrazide 11 obtained from nitrile 5 in two steps was converted to 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one ( 12 ) by the Curtius rearrangement. The amino group of 12 was readily replaced by treatment with aqueous sodium hydroxide to yield 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one ( 13 ). In the second scheme, Michael reaction of enamines of type 20 with methyl propiolate, followed by ring closure gave 5-acyl(aroyl)-6-methyl-2(1H)-pyridinones ( 21 ) which in turn were treated with Bredereck's reagent to produce 5-acyl(aroyl)-6-[2-(dimethylamino)ethenyl]-2(1H)-pyridinones ( 22 ). Treatment of 22 with ammonium acetate led to the formation of 1,6-naphthyridin-2(1H)-ones 23 .     

Reaction of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succininc anhydride

Reactions of 2-(phenylamino)benzoic and 2-(phenylamino)- and 2-methyl-6-phenylpyridine-3-carboxylic acid hydrazides with succinic anhydride in organic solvents at room temperature gave the corresponding 4-(2-aroylhydrazinyl)-4-oxobutanoic acids. The reactions in boiling acetic acid afforded N-(2,5-dioxopyrrolidin-1-yl)benzamide or N-(2,5-dioxopyrrolidin-1-yl)pyridine-3-carboxamide.