Reaction of ethyl N-(6-ethoxycarbonyl-2-methylthiothieno[2,3-d]-pyrimidin-5-yl) formimidate with alkyl- and arylhydrazines: Formation of modified thieno[2,3-d]pyrimidines and thieno[2,3-d:4,5-d]dipyrimidin-4-ones

The reaction of ethyl N-(6-ethoxycarbonyl-2-methyl-thiothieno[2,3-d]pyrimidin-5-yl)formimidate ( 1 ) with methyl-hydrazine, N,N′-dimethyl- and N,N′-diphenylhydrazines separately in refluxing ethanol resulted in hydrolysis of formimidate group to give ethyl 5-amino-2-methylthiothieno[2,3-d] pyrimidine-6-carboxylate ( 2 ). The reaction on 1 with methyl-hydrazine without solvent afforded ethyl 5-amino-2-(1-methyl-hydrazino)thieno[2,3-d]pyrimidine-6-carboxylate ( 3 ), which underwent hydrazone formation with p-nitrobenzaldehyde to give 4 . Treatment of 1 with N,N-dimethylhydrazine afforded a mixture of 3-dimethylamino-7-methylthiothieno[2,3-d:4,5-d']dipyrimidin-4(3H)-one ( 5 ) and 2 . Displacement of methylthio group in 5 with morpholine, piperidine and 4-methylpiperazine gave the corresponding 7-substituted derivatives 6a-c . The reaction of 1 with para-substituted phenylhydrazines resulted in the formation of 3-(p-substituted phenylamino)7-methylthiothieno[2,3-d:4,5-d']dipyrimidin-4 (3H)ones ( 7a-c ).     

Synthesis of pyrazolo[4′,3′:5,6]pyrazino[2,3-c]pyrazoles and pyrazolo[4′,3′:5,6]pyrazino[2,3-d]pyrimidines and their application to polyester fibres

4-Nitroso-1-phenyl-3-methyl-5-aminopyrazole ( 1 ) was condensed with ethylcyanoacetate ( 2 ), malononitrile ( 4a ) and 2-cyanomethylbenzimidazole ( 4b ) to yield 6-hydroxy-5-cyano, 6-amino-5-cyano and 6-amino-5-(benzimidazol-2-yl)-3-methylpyrazolo [3,4-b]pyrazines 3, 5a and 5b , respectively. 5-Cyano-6-chloro derivative 6 obtained from 3 was converted to 3-aminopyrazolo[4′,3′:5,6]pyrazino[2,3-c]pyrazoles 8a and 8b by the treatment with hydrazin hydrate ( 7a ) and phenylhydrazine ( 7b ), respectively. Compound 5a was treated with formamide ( 9a ), urea ( 9b ) and thiourea ( 9c ) to give 4-aminopyrazolo[4′,3′:5,6]pyrazino[2′3′-d]pyrimidines 10a–10c. With refluxing acetic anhydride compounds 8a, 8b and 10a gave corresponding acetamido derivatives 8c, 8d and 10d. Compound 5a was treated with ethylorthoformate ( 11 ), acetic anhydride ( 12 ) or benzoylchloride ( 13 ) to give fused benzimidazopyrazolo[4′,3′:5,6]pyrazino[2′,3′-d]pyrimidines, viz., benzimidazol[1,2-c]pyrazolo[4,3-g]pteridines ( 14a–14c ). Some of the compounds 8, 10 and 14 were applied to polyester as disperse dyes and their fastness properties were studied.     

Synthese von 6-(pyrid-4-yl)-substituierten Pyrido[: 3-d]pyrimidinen und 1,8-Naphthyridinen

Synthesis of 6-(4-pyridinyI)-substituted Pyrido[2,3-d]pyrimidines and 1,8-Naphthyridinms A series of new 6-(4-pyridinyl)-substituted pyrido-[2,3-d]pyrimidines 2 – 4 and 1,8-naphthyridines 6 , respectively, is described. Cyclisation of 2-amino-5-(4-pyridinyl)-pyridinm-3-carboxamide 1a with diethyl oxalate gives the pyrido-[2,3-d]pyrimidinm 2a . Alkylation of( 2a ) yields the 3-ethylaminoxyrido[2,3-d]pyrimidine derivative 2b . Saponification of 2a , b gives the corresponding carboxylic acids 3a , b , which are decarboxylated by heating above the melting point to give 4a , b . The 2-amino-5-(4-pyridinyl)-pyridinm carboxylic acid derivatives 1 b – e react with ethylmalonylchloridm and diethyl malonate to afford the 1,8-naphthyridines 6b – e . The 1-oxide 7 in a similar reaction gives 8 and the oxdiazole( 9 ) which is converted by ring transformation to the 1,8-naphthyridine 10 .     

Cyclisierungen mit Cyanthioacetamid in Gegenwart von Schwefel

Cyclizations of Cyanothioacetamide in the Presence of Sulphur Cyanothioacetoamide 1 reacts with sulphur in the presence of triethylamine to form the 2,5-diamino-thiophene derivative 3 and in the presence of sodium ethoxide the 1,4-dihydropyridine derivative 2 , respectively. 3 easily undergoes ring opening to yield the butadiene derivative 6 . Catalyzed by amine from 1 , cyclic ketones, and sulphur the 2-spiro[thieno[2,3-d]pyrimidine-4-thiones] 8 arise. Analogously to other cyanoacetic acid derivatives 1 react with sulphur and isothiocyanates to form the 4-amino-Δ⁴-thiazoline-2-thiones 9 and with sulphur and carbon disulfide to yield the 5-amino-1,2-dithiol-3-thione derivative 12 . Among the o-amino-thiocarboxamides 3 , 9 , 12 the compounds 3 and 9 can be converted into the 5,6-heterocondensed pyrimidine-4-thiones 4 and 10 .     

Reactions with 5,6-Diphenyl-2,3-dihydro-imidazo[2,1-b]thiazol-3-ones and 6,7-Diphenyl-2,3-dihydro-4H-imidazo[2,1-b]1,3-thiazin-4-one

2-Methyl-5,6-diphenyl-2,3-dihydro-imidazo[2,1-b]thiazol-3-one 5 and 6,7-diphenyl-2,3-dihydro-4H-imidazo[2,1-b]1,3-thiazin-4-one 6 are prepared from 4,5-diphenyl-2-mercapto-imidazole 1 . Compounds 5 and 6 react with amines or hydrazines to give the 2-(4,5-diphenyl-imidazol-2-ylthio)acet(or propan) amides (hydrazides) 7a – g and the 3-(4,5-diphenyl-imidazol-2 ylthio) propanamides(hydrazides) 8a – e , respectively. The hydrazides 7a, 7b and 8a are condensed with aromatic aldehydes to the hydrazones 9a – h and 10a – d . Compound 5 couples with aryldiazonium salts to give 2-arylazo-2-methyl-5,6-diphenyl-2,3-dihydro-imidazo[2,1-b]thiazol-3-ones 11a – d .     

Push-pull-Butadiene. XII. Darstellung von Hetrocyclen aus 2,6-Bis[bis(alkylthio)methylen]cyclohexylidenmalononitrilen

Preperations of Heterocycles by using of 2,6-Bis[bis(alkylthio)methylene]cyclohexylidenemalononitriles . 2,6-Bis[bis(alkylthio)methylene]cyclohexylidenemalonitriles 1 react with alkanethioles to give 1,3-bis(alkylthio)-5-[bis(alkylthio)methylene]-5,6, #7,8-tetrahydro-isoquinoline-4-carbonitriles 2 . Treatment of 1 with hydrogen bromide yields 4,6,7,9-tetrakis(alkylthio)-2,3-dihydro-5,8-diaza-phenalenes 3 . On the other hand, 1 can be converted with bromine to 6,9-bis(alkylthio)-4,7-dibromo-2,3-dihydro-5,8-diaza-phenalenes 5 . However, the reaction of 1 and N-bromosuccinimide afforded 2,6-bis[bis(alkylthio)methylene]-3-bromo-cyclohexylidenemalononitriles 8 .     

A novel synthesis of indeno[2',1': 5,6] pyrido[2,3- d ][1,2,4]triazolo[4,3- a ]pyrimidines

Reaction of 5-(4-chlorophenyl)-2-thioxo-2,3-dihydro-1H-indeno[2',1':5,6] pyrido[2,3-d]pyrimidine-4,6-dione with hydrazonoyl chlorides gave 1,2,4-triazolo[4,3-a]pyrimidine derivatives regioselectively in good yields. The structures of the newly synthesized compounds are established on the basis of chemical and spectroscopic evidence as well as their synthesis by alternative methods.     

2,3-Heterokondensierte Thiophene aus substituiertem 2-Aminothiophen-3-thiol

2,3-Heterocondensed Thiophenes from Substituted 2-Aminothiophen-3-thiole Ethyl 5-amino-4-mercapto-3-methyl-thiophen-2-carboxylate ( 2 ), obtainable from the appropriate thienylthiocyanate 1 by reduction, undergoes reactions in analogy to the 2-aminobenzenthiole. Thus, with formic acid or trimethylorthoacetat the thieno [2,3-d]thiazoles 4 and 5 are formed. Aromatic aldehydes yield the thieno[2,3-d]thiazolines ( 6 ) which can be dehydrogenated by sulphur to form 9 . From carbon disulfide and 2 the thieno[2,3-d]thiazol-2-thione ( 7 ) is formed. With phenacylbromide or ethyl bromoacetate 2 can be converted into the thieno[3,2-b] thiazine derivatives 11 or 12 . Diazotation of 2 yields the thieno[2,3-d]1,2,3-thiadiazole derivative ( 14 ).     

Amino-thieno[2,3–c]pyrazole und Amino-thieno[2,3–b]pyrrole

Amino-thieno[2,3–c]pyrazoles and Amino-thieno[2,3–b]pyrroles The synthesis of thieno[2,3–c]pyrazoles and thieno[2,3–b]pyrroles is described. From the dithioliumsalt ( 1 ) and potassium hydroxide the potassium-(2,2-dicyan-1-methylthio-ethen-1-yl)-thiolate ( 2 ) is formed. This reacts with hydrazine hydrate to form the 3-amino-5-thioxo-pyrazol-4-carbonitrile ( 3 ) S-Alkylation with α-chlorocarbonyl compounds yielding ( 6a–c ) leads via Thorpe-Ziegler-cyclization to 3,4-diamino-thieno[2,3–c]pyrazoles ( 9 ) if the position 1 is alkylated ( 8 ). Acetyl acetone yields 2-mercapto-pyrazolo[1,5–a]pyrimidine ( 5 ). After S-alkylation ( 10a–d ) are immediately cyclized to thieno [2′,3′:3,4]pyrazolo[1,5-a]pyrimidine ( 11a–d ). The ketone ( 6a ) can be cyclized to the pyrazolo [5,1–b]thiazole ( 12 ). 3 reacts with oxalyl chloride to form the 2,3-dioxo-6-thioxo-imidazo[1,2-b]pyrazole ( 13 ) of which S-phenacyl derivative ( 14 ) because the NH-proton cannot be cyclized. The 5-amino-3,4-dicyano-pyrrol-2-thiolate ( 16 ) shows the analogous behaviour. The S-alkylation is followed by cyclization, and 3,5-diamino-thieno[2,3–b]pyrroles ( 18a–b ) arise. Reaction of 5-amino-2-alkylthio-pyrrol-3,5-dicarbonitrile ( 17 ) with acetyl acetone provides pyrrolo[1,2-a]pyrimidine ( 20a–c ) which can be cyclized to form thieno[3′,2′:4,6]pyrimidines ( 21a–c ) very easily.     

Reactions with Thiazolo[3,2-b]-s-triazol-3(2H)-ones

5-Aryl-3-carboxymethylthio-1,2,4-triazoles 2 are cyclised to 6-arylthiazolo[3,2-b]-s-triazol-3(2H)-ones 3 . This structural assignment has been based on IR and NMR spectra. 2-Arylmethylene-6-arylthiazolo[3,2-b]-s-triazol-3(2H)-ones 7 were prepared by several methods. Compounds 3 coupled with diazotised anilines to give 2,3-dihydro-6-arylthiazolo[3,2-b]-s-triazole-2,3-dione 2-arylhydrazones 8 . The action of amines on 3a opens the thiazolone ring with the formation of substituted (5-phenyltriazol-3-ylthio)-acetamides 9 .     

Two Syntheses of [2.2.2] (1,2,3)Cyclophane

Two syntheses are presented for [2.2.2] (1,2,3)cyclophane (7), the remaining member of the symmetrical [2_n]cyclophanes whose preparation has not previously been described. The first method involved the dimerization of 2,6-bis (4′, 4′-dimethyl-2′-oxazolinyl)toluene ( 1 ) to give 2 which, on hydrolysis, produced the tetracarboxylic acid 3 . Conversion of 3 , via the acid chloride ( 4 ), to the tetraol 5 , followed by treatment with phosphorus tribromide yielded the tetrabromide 6 . The overall scheme was then completed by reaction of 6 with phenyllithium to give [2.2.2] (1,2,3) cyclophane ( 7 ). An alternate, more convenient, method began with the pyrolysis of 2,6-bis (chloromethyl)toluene ( 8 ) to give 3-chloromethylbenzocyclobutene ( 9 ). Formation of the Grignard of 9, followed by reaction with ferric chloride, yielded the dimer 10 . Pyrolysis of 10 then gave [2.2.2] (1,2,3)cyclophane (7).     

A facile synthesis of some novel fused [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol derivatives

A series of novel 3-[6-(4-substituted phenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-ylmethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives (7a–7h) have been synthesized from 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (1) through a multi-step reaction sequence. The key intermediate (6) on condensation with various substituted aromatic carboxylic acids in the presence of phosphorus oxychloride afforded the series of title compounds (7a–7h). The structures of all newly synthesized compounds were established on the basis of their IR, ¹H-NMR, ¹³C-NMR and liquid chromatography mass spectrometry spectral data.     

Substituierte 4-Amino-thieno[2,3-c]isothiazole und 4-Amino-thieno[3,2-d]isothiazole

Substituted 4-Amino-thieno[2,3-c]isothiazoles and 4-Amino-thieno[3,2-d]isothiazoles The alkylation of disodium-(4-cyanisothiazole-3,5)-dithiolate 1 with α-chloro carbonyl compounds followed by THORPE -ZIEGLER -cyclization yields the substituted 4-amino-thieno[3,2-d]isothiazoles 3 , which can be converted into the thieno-isothiazolo-1,4-thiazepine derivatives 4, 5 . The successive alkylation of 1 with dimethylsulfate and α-chloro carbonyl compounds yields the 5-methylthio-isothiazole-4-carbonitriles 11 which are cyclized to form the substituted 4-amino-3-methylthio-thieno[3,2-d]isothiazoles 13 . The inverse alkylation procedure leads to the isomeric 4-amino-3-methylthio-thieno[2,3-c]isothiazoles 20 . Successive alkylation of the 3-hydroxy-5-mercapto-4-cyanoisothiazoles 14 with α-chloro carbonyl compounds and diazomethane followed by cyclization yields the 4-amino-3-methoxy-thieno[3,2-d]isothiazoles 17 . From 13 and 20 the isothiazole-thieno-pyrimidines 21, 22 and the isothiazolo-thieno-oxazinone 25 are synthesized.     

Neue Synthese von substituierten 4-Amino-chinazolinen und deren Heteroanalogen

New Synthesis of Substituted 4-Amino-quinazolines and Their Heteroanaloga N-Chloracetyl-anthranilonitriles react with potassium thiocyanate in the presence of alcohol to the (4-aminoquinazolin-2-yl-thio)-acetic acid ester ( 5 ). In the presence of water or primary amine the acetic acid derivative ( 6 ) or the acetic acid amide derivatives ( 7 ) are obtained. 2,4-Diaminoquinazolines ( 8 ) arise if vigorous reaction conditions are employed. With 2-chloracetylamino-cyclopent-1-en-carbonitrile as starting material the pyrimidines ( 11 ) are formed from the reaction with potassium thiocyanate. Analogously, (4-pyrimidyl-2-yl-seleno)-acetic acid ester ( 12 ) and (thiazolo[4,5-d]pyrimid-2-yl-seleno)-acetic acid derivatives ( 16 ) can be prepared with potassium selenocyanate. N-Chloracetyl derivatives of 5-membered heterocycles with enamino-nitrile structure ( 13 , 15 , 18 , 20 ) react with potassium thiocyanate to yield thieno[2,3-d]-, thiazolo[4,5-d]-, pyrrolo[2,3-d]-, furo[2,3-d]- and pyrazolo[4,3-d]pyrimidines ( 14 , 16 , 19a , 19b , 21 ).     

Reactions with β-ketodianilides. I. New synthesis of Pyrido[3,4-c]pyridine Derivatives

Acetonedicarboxylic acid dianiline reacted with malononitrile, ethyl cyanoacetate or benzoylacetonitrile to give (6-amino-5-cyano-1,2-dihydro-2-oxo-1-phenylpyrid-4-yl)-acetanilide ( 3 ), (3-cyano-2,6-dioxo-1-phenyl-1,2,5,6-tetrahydropyrid-4-yl)acetanilide ( 8 ) or (3-cyano-1,6-dihydro-1,2-diphenyl-6-oxopyrid-4-yl)acetanilide ( 9 ). Compounds 3 and 8 could be cyclised into 8-amino-1,6-diphenyl-1,2,4,5,6,7-hexahydro-7-iminopyrido[3,4-c]pyridine-2,5-dione ( 4 ) and 7-amino-1,2,3,5,6,8-hexahydro-1,6-diphenylpyrido[3,4-c]pyridine-2,5,8-trione ( 10 ) respectively by heating their solutions in dimethylformamide in the presence of triethylamine. Each of 3 and 4 coupled with arenediazonium chlorides to give the corresponding arylhydrazone derivatives ( 5a–d ) and ( 6a–c ), respectively. Condensation of 4 with p-nitrosodimethylaniline yielded 8-amino-4- (p-dimethylaminophenylimino)-1,6-diphenyl-1,2,4,5,6,7-hexahydro-7-iminopyrido[3,4-c]pyridine2,5-dione ( 7 ).     

Über neue Pyrazolverbindungen. IV Darstellung und Cyclisierungsverhalten einiger akzeptorsubstituierter N-(Pyrazol-3-yl)-thioharnstoffe

New Pyrazol Derivatives. IV. Preparation and Cyclization of Some Acceptor-Substituted N-(Pyrazol-3-yl)-thioureas . 3-Aminopyrazol-4-carboxylic acid derivatives ( 1 , 2 ) were transformed by reaction with different isothiocyanates R²NCS to N-(pyrazol-3-yl)-N^. -substituted thioureas ( 5 , 6 ). Ethyl 3-amino-1-benzylpyrazol-4-carboxylate reacts with CSCl₂ to form ethyl 1-benzyl-3-isothiocyanatopyrazol-4-carboxylate ( 3 ) which yields with amines the corresponding N-(pyrazol-3-yl)-N^. -substituted thioureas ( 5 ). As a byproduct in the reaction with CSCl₂ N,N^. -di-(pyrazol-3-yl)-thiourea ( 4 ) is formed. With hydrazine or phenylhydrazine N-(pyrazol-3-yl)-thiosemicarbazides ( 7a , b ) are obtained. The thioureas ( 5 , 6 ) can be cyclized in basic solution to 4,5,6,7-tetrahydropyrazolo[3,4-d]pyrimidin-4-on-6-thiones ( 8 ) which on alkylation form 6-alkylthio-4,5-dihydropyrazolo[3,4-d]pyrimidin-4-ones ( 9 ). Methyl-N-(pyrazol-3-yl)-N^.-benzoylisothiourea ( 10 ) reacts with ethylamine to form N-benzoyl-N^. -ethyl-N^‥-(pyrazol-3-yl)-guanidine derivative ( 11 ) which on treatment with NaH in dimethylformamide yields 6-benzoylamino-5-ethyl-4,5-dihydropyrazolo[3,4-d]pyrimidin-4-one ( 12 ). By treatment with sulfuric acid the N-(pyrazol-3-yl)-thiourea derivatives ( 5 , 6 ) form new 6-amino substituted pyrazolo[3,4-d][1,3]thiazin-4-ones ( 13 ).     

A One‐Pot Synthesis of [1,2,4]Triazino[4,3‐b]‐[1,2,4,5]tetrazines

Reactions of hydrazonoyl halides 6 with either 4‐amino‐2,3‐dihydro‐6‐substituted‐3‐thioxo‐[1,2,4]‐triazin‐5(4H)ones 1 ( 2 ) or 4‐amino‐3‐methylthio‐6‐substituted‐[1,2,4]‐triazin‐5(4H)ones 3 ( 4 ) gave [1,2,4]‐triazino‐[4,3‐b][1,2,4,5]tetrazine derivatives 9 ( 10 ), respectively. The mechanism of the reactions studied is discussed.     

萘并吡喃并[2,3-d]嘧啶-4(3H)-酮衍生物的合成与表征

通过氮杂Wittig反应合成了7种萘并吡喃并[2,3-d]嘧啶-4(3H)-酮衍生物。首先用2-萘酚、氰乙酸乙酯和芳醛通过Knoevenagl-Cope缩合得到2-氨基萘并吡喃(Ⅰ),(Ⅰ)再与三苯基膦反应得到膦亚胺中间体(Ⅱ)。(Ⅱ)与芳基异氰酸酯采用aza-Wittig反应得到碳二亚胺(Ⅲ)。(Ⅲ)再分别与胺、醇、酚反应合成了萘并吡喃并[2,3-d]嘧啶-4(3H)-酮Ⅳ(a-g)。目标化合物结构经1H-NMR、MS和IR进行了表征。试验考察了亲核试剂及反应条件对产品收率的影响。结果表明,亲核试剂空间位阻小反应速度较快,收率高;若有吸电子基团时,反应时间缩短。     

含噻二唑环噻吩并[2,3-d]嘧啶类含氟衍生物的合成及抗肿瘤活性

通过2-氨基-3-氰基噻吩与三氟乙酸、三氯氧磷反应"一锅法"制得2-三氟甲基-4-氯噻吩并[2,3-d]嘧啶,收率为60%,再与2-氨基-5-(取代苄硫基)-1,3,4-噻二唑发生芳香族亲核取代反应合成10个含噻二唑环噻吩并[2,3-d]嘧啶类含氟衍生物,收率为64%~75%。目标化合物的结构经红外光谱、核磁共振氢谱、质谱与元素分析表征,并采用MTT法对其进行初步的体外抗肿瘤活性筛选。结果表明,化合物Ⅳc和Ⅳf对Hep G2和BGC-823细胞的抑制活性高于对照样吉非替尼。     

2-Arylamino-thiophen-3-carbonsäurederivate

2-Arylamino-thiophene-3-carboxylic Acid Derivatives The title compounds 3 are synthesized by reaction of 2-amino-thiophene-3-carboxylic acid derivatives 1 with anilines. The nucleophilic 5-position in 3 allowed the synthesis of 5-aryliden-Δ³-thiolen-2-one-imines 5 , 6 and the oxidative coupling to yield the azo compound 7 . 1-Aryl-thieno-[2,3-d]pyrimid-4-ones 9 , the thieno[2,3-b]chinolin-4-one 10 and the 4-chloro thieno[2,3-b]chinolines 10 , 11 can be obtained from 3 .