Synthesis and tuberculostatic activity of novel N′‐methyl‐4‐(pyrrolidin‐1‐yl)picolinohydrazide and N′‐methylpyrimidine‐2‐carbohydrazide derivatives

The synthesis of N′‐methyl‐4‐(pyrrolidin‐1‐yl)picolinohydrazide and N′‐methyl‐pyrimidine‐2‐carbohydrazide derivatives ( 5a and 5b ) was carried out. These compounds were used as starting materials to obtain methyl N′‐methylhydrazinecarbodithioates 6a and 6b , which, on reaction with either triethylamine or hydrazine, gave corresponding 1,3,4‐oxadiazioles 7a and 7b or 1,2,4‐triazoles 9a and 9b with the free NH₂ group at the N‐4 position, respectively. Compounds 8a – e , particularly containing cyclic amines at N‐4 of the 1,2,4‐triazole ring, were also obtained. Synthesized compounds were tested in vitro for their activity against Mycobacterium tuberculosis. The structure–activity relationship analysis for obtained compounds was done. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:223–230, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21008     

Synthesis of novel N‐alkyl/aryl‐N′‐(4‐arylthiazol‐2‐yl)‐N″‐xylosyl guanidines

The reaction of 2,3,4‐tri‐O‐acetyl‐β‐D‐xylopyranosyl isothiocyanate ( 1 ) and 2‐amino‐4‐arylthiazoles ( 2 ) gave xylosylthioureas 3 . These thiourea derivatives reacted with alkyl/aryl amine in the presence of HgCl₂ to give a new series of N‐alkyl/aryl‐N″‐(4‐arylthiazol‐2‐yl)‐N″‐xylosyl guanidines 4 . Some of the synthesized guanidines were screened for their biological activity. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:688–694, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20379     

Reactivity of 3‐(benzothiazol‐2‐yl)‐3‐oxopropanenitrile: A facile synthesis of novel polysubstituted thiophenes

The reaction of 3‐(benzothiazol‐2‐yl)‐3‐oxopropanenitrile 1 with active methylene reagents 2a–d and sulfur afforded polysubstituted thiophenes 3a–c . The synthetic potential of the β‐enaminonitrile moiety in 3a was explored. The reaction of 3a with active methylene reagents 2a–e afforded thieno[2,3‐b]pyridine derivatives 6–8. Refluxing of 3a with acetic anhydride alone, with acetic anhydride/pyridine mixture, or with carbon disulfide in pyridine afforded the acetamido 9, thieno[2,3‐d]pyrimidine 10, and pyrimidinedithiol 11 derivatives, respectively. The pyrimidinedithiol 11 was alkylated smoothly with methyl iodide to give the bis(methylthio) derivative 12. Also, compound 3a reacted with trichloroacetonitrile to give the thieno[2,3‐d]pyrimidine derivative 14. Compound 3a reacted with triethyl orthoformate or formamide to give the ethoxymethylideneamino 15 and thieno[2,3‐d]pyridine 16, respectively. Compound 15 reacted with hydrazine to afford thieno[2,3‐d]pyridine 17, which reacted with various reagents such as chloroacetyl chloride, ethyl cyanoacetate, diethyl oxalate, or chloroethylformate to give 1,2,4‐triazolo[1,5:1,6]pyrimidino‐[4,5‐b]thiophene derivatives 18a–c and 19, respectively. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:94–101, 2000     

Study on the reaction of methyl N‐Methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates with sodium alkoxides

Methyl N‐methyl‐N‐(6‐substituted‐5‐nitropyrimidin‐4‐yl)glycinates ( 4a‐n ), obtained from 6‐substituted‐4‐chloro‐5‐nitropyrimidines and sarcosine methyl ester (methyl 2‐(methylamino)acetate), in the reaction with sodium alkoxides underwent transformations to give different products. N‐methyl‐N‐(5‐nitropyrimidin‐4‐yl)glycinates ( 4a,i,j ) bearing amino and arylamino groups in the position 6 of the pyrimidine ring gave corresponding 6‐substituted‐4‐methylamino‐5‐nitrosopyrimidines ( 5a,i,j ). In the reaction of N‐(6‐alkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4b,f‐h ) with sodium alkoxides the corresponding 6‐alkylamino‐4‐methylamino‐5‐nitrosopyrimidines ( 5b,f‐h ) and 5‐hydroxy‐8‐methyl‐5,8‐dihydropteridine‐6,7‐diones ( 6b,f‐h ) were formed. The main products of the reaction of N‐(6‐dialkylamino‐5‐nitropyrimidin‐4‐yl)‐N‐methylglycinates ( 4c‐e,k,l ), after work‐up, were the corresponding 6‐dialkylamino‐9‐methylpurin‐8‐ones ( 7c‐e,k,l ) and 8‐alkoxy‐6‐dialkylamino‐9‐methylpurines ( 9c,1,10c,l ). Methyl N‐methyl‐N‐{[6‐(2‐methoxy‐oxoethyl)thio]‐5‐nitropyrimidin‐4‐yl}glycinate ( 4n ) under the same conditions gave methyl 7‐methylaminothiazolo[5,4‐d]pyrimidine‐2‐carboxylate ( 13 ). Mechanisms of the observed transformations are discussed.     

Synthesis of α‐alkylidene‐γ‐butyrolactones via Ring‐cleavage/recyclization of 2‐Amino‐4,5‐dihydro‐3‐furancarboxamides

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarboxarnides 1a,b with cyanomethylene compounds (such as alkyl cyanoacetates and malononitrile) gave the corresponding ring‐opened products 2a‐f. Compounds 2a‐d reacted with methanesulfonic acid to give the corresponding α‐alkylidene‐γ‐butyrolactones 3a‐d. On the other hand, treatment of 2e,f with methanesulfonic acid yielded 3‐pyridinecarbonitrile derivatives 4a,b.     

The behavior of 2‐thioxo‐4‐thiazolidinones toward organophosphorus reagents

The reaction of 2‐thioxo‐4‐thiazolidinone ( 1a ) with phosphorus ylides 2a and 2b afforded compounds 5 and 6. On the other hand, formylmethylenetriphenylphosphorane (2c) reacts with 1a and its N‐methyl derivative 1b to give the new complicated phosphonium ylides 7a,b, respectively. Reactions of 1b with ylides 2a and 2d gave rise to the olefinic compound 8 and the new phosphorane product 9. Moreover, dialkyl phosphites 3a,b and trialkyl phosphites 4a–c react with 1a to give both the alkylated products 10a–c and the dimeric compounds 11,12. A mechanism is proposed to explain the formation of the new products.© 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 337–341, 1999     

Synthesis and Anticancer Evaluation of Some Novel Quinazolin‐4(3H)‐one Derivatives

A new series of quinazolinone derivatives bearing pyridine, pyrimidine, pyrazole, or pyran moieties were synthesized for the purpose of anticancer cell line evaluation. Synthesis of these derivatives was achieved by the reaction of the ketone 2 with the appropriate aldehydes in the presence of either ethylcyanoacetate or malononitrile and ammonium acetate in one‐pot reaction. Chalcones 6 reacted also with hydrazine hydrate to give the corresponding pyrazolines 7 and reacted with urea or thiourea to give the 2‐oxopyrimidines or the 2‐thioxopyrimidines 8 , respectively. Evaluation of some representative examples of the newly synthesized compounds against cancer cell lines showed promising activity as anticancer agents.     

Metallation reactions. XXXIV. Synthesis of 2‐(1‐hydroxy‐1‐arylethyl)‐1,3‐benzoxathiol‐3‐oxide derivatives

The reaction of benzoxathiole‐3‐oxide with lithiumdiisopropylamide in tetrahydrofuran gave an anion, which was reacted with various aryl‐methyl‐ketones to give 2‐(1‐hydroxy‐1‐arylethyl)‐1,3‐benzoxathiol‐3‐oxide derivatives. The reaction was carried out in different temperature conditions: at ‐88 °C the trans addition stereoisomers to the sulfoxide oxygen atom were the main products.     

Synthesis of 1‐methyl‐, 4‐nitro‐, 4‐amino‐and 4‐iodo‐1,2‐dihydro‐3H‐pyrazol‐3‐ones

4‐Aminopyrazole‐3‐ones 4b, e, f were prepared from pyrazole‐3‐ones 1b‐d in a four‐step reaction sequence. Reaction of the latter with methyl p‐toluenesulfonate gave 1‐methylpyrazol‐3‐ones 2b‐d . Compounds 2b‐d were treated with aqueous nitric acid to give 4‐nitropyrazol‐3‐ones 3b‐d. Reduction of compounds 3b‐d by catalytic hydrogenation with Pd‐C afforded the 4‐amino compounds 4b, e, f. Using similar reaction conditions, nitropyrazole‐3‐ones derivatives 2c, d were reduced into aminopyrazole‐3‐ones 5e, f. 4‐Iodopyrazole‐3‐ones 7a, 7c and 8 were prepared from the corresponding pyrazol‐3‐ones 2a, 2c and 6 and iodine monochloride or sodium azide and iodine monochloride.     

One‐pot Synthesis of 1,2,3,4‐Tetrahydropyrimidin‐2(1H)‐thione Derivatives and their Biological Activity

2‐Thioxo/oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate derivatives 2a , 2b , 2c , 2d were prepared by the reaction of ethyl acetoacetate and thiourea or urea with aldehydes using NH₄Cl as a catalyst. Compounds 2a and 2c reacted with mono and bihalogenated compounds such as ethyl iodide, chloroacetonitrile, epichlorohydrin, acetyl chloride, ethyl bromoacetate, chloroacetic acid, chloroacetylchloride, and/or oxalyl chloride to afford compounds 3 , 4a , 4b , 5 , 6a , 6b , 7 , 8 , 9 and 10 , respectively. Compounds 2a , 2c , and 7 were allowed to react with p‐fluorobenzaldehyde to yield the corresponding products 11a , 11b , and 12 , respectively. Oxidation of 2a and 2c gave 2b , 13a , 13b , 14 , 15 , 16 dependent on the oxidizing agent used. Vilsmeiere‐Haack formylation of 2a and 2b with POCl₃/DMF afforded 17a and 17b . Chlorination of 2b and 2d gave the chlorinated derivative 18a and 18b , which reacted with thiourea to give thioureidopyrimidine 19a and 19b . Reactions of 2a with hydrazine monohydrate, semicarbazide hydrochloride, and sodium hydroxide gave compounds 20 , 21 , 22 , respectively. The cytotoxicity and in vitro anticancer evaluation of some prepared compounds have been assessed against two different human tumor cell lines including breast adenocarcinoma MCF‐7 and human hepatocellular carcinoma HepG2. Antimicrobial and antioxidant activities of some compounds were investigated. The newly synthesized compounds were characterized by IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data.     

Studies on the reaction of N‐(3‐carbethoxy‐4,5,6,7‐tetrahydrobenzo[b]thien‐2‐yl)‐N′‐phenylthiourea with hydrazine hydrate (Part 1)

The reaction of N‐(3‐carbethoxy‐4,5,6,7‐tetrahydrobenzo[b]thien‐2‐yl)‐N′‐phenylthiourea ( 1 ) with hydrazine hydrate in 1‐butanol afforded a mixture of compounds 2, 3 and 4 . Treatment of 3 and 4 with nitrous acid gave 6 and 8 respectively, while reactions of 3 with acetylacetone gave 7 . Synthesis of tetracyclic compounds 9a‐f and 11 from the reactions of 3 with ethyl orthoformate or appropriate acids, acid chloride, carbon disulphide and/or ethyl chloroformate. Also its reaction with isothiocyanate derivatives gave the corresponding thiosemicarbzides 12a,b which on, refluxing in alcoholic KOH gave the unexpected tetracyclic products 14a,b . Similarly the tetracyclic compounds 16a‐e and 19 were obtained by cyclization of 4 and 18 respectively.     

Synthesis of Some New [1,8]Naphthyridine,Pyrido[2,3‐d]‐Pyrimidine,and Other Annulated Pyridine Derivatives

2‐Aminopyridine‐3‐carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3 , 5 , 8 , 11 , and 14 , respectively. Further annulations of 3 , 5 , and 8 gave the corresponding pyrido[2,3‐b][1,8]naphthyridine‐3‐carbonitrile derivative 17 , pyrido[2,3‐h][1,6]naphthyridine‐3‐carbonitrile derivatives 18 and 19 , respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4‐isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a , b , 21 , 22a , b , and 26 , respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27 . Compound 27 reacted with 4‐chlorobenzaldehyde and 1H‐indene‐1,3(2H)‐dione to give the pyridopyrimidine derivative 28 and spiro derivative 30 , respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34 . Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35 . The structures of the newly synthesized compounds were established by elemental and spectral data.     

Syntheses of some new azolopyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidines

Diethyl 2‐[(ethoxythioxomethyl)amino]‐4,5,6,7‐tetrahydrothieno[2,3‐c]‐pyridine‐3,6‐dicarboxylate 2 , prepared from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine‐3,6‐dicarboxylate 1 by boiling in anhydrous ethanol, was converted into pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidine derivatives 3, 4 by treatment with hydrazine hydrate. The tetracyclic systems imidazo[1,2‐a]pyrido‐[4′,3′:4,5]thieno[2,3‐d]pyrimidine 9 and pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo‐[3,2‐a]pyrimidine 10 were synthesized by the reaction of 2 with 1,2‐diaminoethane and aminoethanethiol, respectively. The hydrazino derivative 4 underwent cyclization reactions with orthoesters and nitrous acid to give the corresponding pyrido[4′,3′:4,5]thieno[2,3‐d][1,2,4]triazolo[1,5‐a]pyrimidines 5, 6 and pyrido[4′,3′:4,5]thieno[3,2‐e][1,2,3,4]tetrazolo[1,5‐a]pyrimidine 8 , respectively. Moreover, reactions of 3 with cyanogen bromide, N‐carbethoxyhydrazine, carbon disulfide, and ethylchloroformate resulted in the formation of the new pyrido[4′,3′:4,5]thieno[2,3‐d][1,3,4]thiadiazolo[3,2‐a]pyrimidine derivatives 12–15 . © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:280–286, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10030     

Photochemical Reactions of N‐(2‐Halogenoalkanoyl) Derivatives of Anilines

The photochemical reactions of 2‐substituted N‐(2‐halogenoalkanoyl) derivatives 1 of anilines and 5 of cyclic amines are described. Under irradiation, 2‐bromo‐2‐methylpropananilides 1a – e undergo exclusively dehydrobromination to give N‐aryl‐2‐methylprop‐2‐enamides (=methacrylanilides) 3a – e (Scheme 1 and Table 1). On irradiation of N‐alkyl‐ and N‐phenyl‐substituted 2‐bromo‐2‐methylpropananilides 1f – m , cyclization products, i.e. 1,3‐dihydro‐2H‐indol‐2‐ones (=oxindoles) 2f – m and 3,4‐dihydroquinolin‐2(1H)‐ones (=dihydrocarbostyrils) 4f – m , are obtained, besides 3f – m . On the other hand, irradiation of N‐methyl‐substituted 2‐chloro‐2‐phenylacetanilides 1o – q and 2‐chloroacetanilide 1r gives oxindoles 2o – r as the sole product, but in low yields (Scheme 3 and Table 2). The photocyclization of the corresponding N‐phenyl derivatives 1s – v to oxindoles 2s – v proceeds smoothly. A plausible mechanism for the formation of the photoproducts is proposed (Scheme 4). Irradiation of N‐(2‐halogenoalkanoyl) derivatives of cyclic amines 5a – c yields the cyclization products, i.e. five‐membered lactams 6a , b , and/or dehydrohalogenation products 7a , c and their cyclization products 8a , c , depending on the ring size of the amines (Scheme 5 and Table 3).     

A Novel Synthesis of 4‐Pyridazineacetic Acids via Ring Expansion of N‐Cyanomethylated 3‐Pyrazoline‐4‐acetic Acids

A novel synthetic route to 4‐pyridazineacetic acids 10 – 12 has been achieved by the ring‐expansion reaction of N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 – 9 . 1H‐Pyrazole‐4‐acetic acids 1 – 3 were reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the corresponding C‐cyanomethylated 1H‐pyrazole‐4‐acetic acids 4 – 6 as major products together with N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and 3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the corresponding N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 9 as major products. Thermal treatment of 7 – 9 with sodium hydride in N,N‐dimethylformamide caused ring expansion to yield the corresponding 4‐pyridazineacetic acids 10 – 12 .     

Synthesis of Some New 1,2,3,4‐Tetrahydropyrimidine‐2‐thione and Their Thiazolo[3,2‐a]pyrimidine,Thiazino and Benzothiazepine Derivatives

The starting N‐(2‐pyridyl)‐6‐methyl‐4‐phenyl‐2‐thioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxamide ( 4 ) was used as a key intermediate for the synthesis of new 1,2,3,4‐tetrahydropyrimidine‐2‐thione and their thiazolo[3,2‐a]pyrimidine, thiazino and benzothiazipen derivatives. The reaction of 4 with haloketones in ethanol catalyzed by base afforded the corresponding thiophenopyrimidine and pyrimidothiazipine derivatives 5 , 6 , 7 , 8 , 9 , 10 . Methylation and formylation of 4 led to the pyrimidine derivatives 15 and 16 , respectively. The preventative compounds were established on the basis of elemental and spectral data.     

Synthesis and Structure of Novel Thieno[2, 3‐d]Pyrimidine Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

The reaction of 5‐(1‐pyrrolyl)‐4‐methyl‐2‐phenylthieno[2, 3‐d]pyrimidine carbohydrazide 5 with CS₂ in the presence of pyridine afforded the 6‐(2, 3‐dihydro‐2‐mercapto‐1, 3, 4‐oxadiazol‐5‐yl)‐4‐methyl‐5‐(1‐pyrrolyl)‐2‐phenylthieno[2, 3‐d]pyrimidine 6 , which reacted with methyl iodide in the presence of sodium methoxide to yield the 6‐(2‐methylthio‐1, 3, 4‐oxadiazol‐5‐yl)‐4‐methyl‐5‐(1‐pyrrolyl)‐2‐phenyl‐thieno[2, 3‐d]pyrimidine 7. The 6‐(2‐substituted‐1, 3, 4‐oxadiazol‐5‐yl)‐2‐phenylthieno[2, 3‐d]pyrimidine derivatives 9, 11 and 13 were obtained by the condensation of 6‐(2‐methylthio‐1, 3, 4‐oxadiazol‐5‐yl)‐2‐phenylthieno[2, 3‐d]pyrimidine 7 with appropriate secondary amines. The structure of the new compounds was substantiated from their IR, UV‐vis spectroscopy, ¹H NMR, mass spectra, elemental analysis and X‐ray crystal analysis.     

Polycyclic N‐Heterocyclic Compounds. 56 Reaction of N‐(5,6‐Dihydro[1]benzoxepino[5,4‐d]pyrimidin‐4‐yl)amidine or Its Amide Oxime Derivatives with Hydroxylamine Hyrdochloride

The reactions of N‐(5,6‐dihydro[1]benzoxepino[5,4‐ d]pyrimidin‐4‐yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.     

Reactivity of (2‐methylsulfanyl‐4‐oxo‐6‐phenyl‐4h‐pyrimidin‐3‐yl)‐acetic acid methyl ester towards hydrazine hydrate and benzylamine

The title ester 1 reacted with hydrazine hydrate to give hydrazide 2 , which underwent intramolecular cyclization to yield 1‐amino‐7‐phenyl‐1H‐imidazo[1,2‐a]pyrimidine‐2,5‐dione ( 3 ) or took place in a substitution reaction with benzylamine to form N‐benzyl‐2‐(2‐benzylamino‐4‐oxo‐6‐phenyl‐4H‐pyrimidin‐3‐yl)‐acetamide ( 4 ). The reaction of ester 1 with benzylamine gave corresponding amide 7 , disubstituted derivative 4 or 1‐benzyl‐7‐phenyl‐1H‐imidazo[1,2‐a]pyrimidine‐2,5‐dione ( 8 ) depending on the reaction conditions.     

Synthesis of 4‐fluoroalkyl‐2H‐pyrido [1, 2‐a] pyrimidin‐2‐ones from 2, 2‐dihydropolyfluoroalkanoic acids

In the presence of N, N′‐dicyclohexylcarbodiimide, 2‐aminopyridine and its derivatives (2) condensed with 2, 2‐di‐hydropolyfluoroalkanoic adds (1) to give the corresponding amides. Subsequent intramolecular Micheal addition‐elimination reactions of the fluorine‐containing amides under basic conditions gave 4‐fluoroalkyl‐2H‐pyrido[1,2‐a]pyrimidin‐2‐ones (3) in good yields.