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.     

Facile Synthesis and Anticancer Activity Study of Novel Series of Substituted and Fused Coumarin Derivatives

Various new substituted and fused coumarin analogues have been synthesized via different synthetic pathways. Among which are variable substituted coumarin derivatives bearing either biologically active side chains or rings at 5, 6, and 3 positions of the coumarin nucleus as indicated in compounds 10 , 12 , 13 , 16–19 , 21 , 23–32 , 38 , and 42–45 . In addition, different pyranocoumarin derivatives either substituted as in compounds 2 , 3 , and 6 or fused as compounds 33–36 , pyranoxanthene analogues such as compounds 4 and 46 , coumarinotriazolothiadiazine derivative 8 , coumarinonaphthodiazocin analogue 39 and coumarinopyrazolone derivative 40 were synthesized. Thirty‐eight of the synthesized compounds were subjected to in vitro anticancer screening against mammalian liver carcinoma HepG2 and breast carcinoma MCF7 cell lines using Cisplatin as a standard reference. The anticancer activity screening results revealed that, among the tested compounds, compounds 16 , 40 , and 43 bearing 4‐chlorophenyl‐2‐aminopyridine‐3‐carbonitrile attached to C₆ position, fused pyrazolone ring or attached to 4‐chlorophenyl‐2‐oxo‐dihydropyridine‐3‐carbonitrile at C₃ position of the coumarin nucleus, respectively, exhibited moderate to strong activity against both cell lines.     

A facile synthesis of 8-(β-D-ribofuranosyl)-4-thioxo-3H-pyrazolo[1,5-a]-1,3,5-triazine and its α-anomer

A versatile intermediate 2 for C-nucleoside synthesis was treated with thiosemicarbazide to obtain thiosemicarbazone 6 , which was then converted to 3-aminopyrazol-2N-thiocarboxamide derivatives 7 and 8 by the reaction of 6 and sodium ethoxide. 4-Thioxo-4H-pyrazolo[1,5-a]-1,3,5-triazine C-nucleosides 11 and 12 were obtained by the ring closure reaction of 7 and 8 with triethyl orthoformate. Brief treatment of 11 and 12 with 10% methanolic hydrogen chloride afforded C-nucleosides 4 and 13 , respectively, without anomerization. Identification of compounds 4 and 13 was made on the basis of ¹H nmr and uv spectra, as well as chemical conversion to known compounds with established configurations. Model compounds were also synthesized in order to confirm the heterocyclic moieties.     

Generation and cyclization of thiocarbonyl S‐ylides by reaction of diazocompounds with C‐sulfonyldithioformates

The unexpected 1,3‐benzodithiine derivatives 5b,c were obtained from the reactions of trimethylsilyldiazomethane 2 with C‐sulfonyldithioformates, bearing pentachlorophenylthio group, 1b,c via unprecedented cyclization of the transient thiocarbonyl ylides 4b,c . While the corresponding reaction with C‐sulfonyldithioformates, bearing phenylthio group, afforded 5a via [2 + 3]‐cycloadditive dimerization of a transient thiocarbonyl ylides 4a . Under the same reaction condition, C‐sulfonyldithioformates 1d–f react with diazomethane and/or phenyldiazomethane to afford the unsymmetrical 1,3‐dithiolane 7d,e and thiirane 8e,f derivatives, respectively. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:28–33, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20246     

Synthesis of pyrido[2,3-d]pyrimidines from aminopyrimidinecarbaldehydes

2-Methoxy-4-amino-5-pyrimidinecarbaldehyde ( 2a ) as well as its 6-methyl 2b and 6-phenyl derivatives 2c were prepared by reduction of the corresponding aminopyrimidinecarbonitriles 1 . Catalytic hydrogenation of 1a, 1b gives 5-hydroxymethylpyrimidines 3a, 3b ; under the same conditions 1c afforded 5-aminomethylpyrimidine 4 . Condensation of 2 with carbonitriles, ketones and polyfunctional carbonyl compounds bearing the -CH₂CO- moiety afforded the pyrido[2,3-d]pyrimidines and pyrimido-[4,5-b]quinoline derivatives.     

The structure of the diazonium coupling products of phenacyl thiocyanate and phenacyl selenocyanate with diazotized 3-phenyl-5-aminopyrazole

The reaction of diazotized 3-phenyl-5-aminopyrazole with phenacyl thiocyanate 1a and phenacyl selenocyanate 1b afforded directly 2-imino-3-(3-phenyl-5-pyrazolyl)-5-benzoyl-2,3-dihydro-1,3,4-thiadiazole monohydrate 9a and 2-imino-3-(3-phenyl-5-pyrazolyl)-5-benzoyl-2,3-dihydro-1,3,4-selenadiazole monohydrate 9b , respectively. The products 9a and 9b were also obtained from the reaction of C-benzoyl-N-(3-phenyl-5-pyrazolyl)formohydrazidoyl bromide 10 with potassium thiocyanate and potassium selenocyanate, respectively. Acetylation, benzoylation, and nitrosation of 9 afforded the corresponding diacetyl, dibenzoyl, and nitroso derivatives 11-13 , respectively. Cyclization of C-benzoyl-N-(3-phenyl-5-pyrazolyl)-nitrilimine 6 was shown to give the pyrazolo [5,1-d]triazole 8 and not the pyrazolo[5,1-c]-as-triazine derivative 7 , as previously reported.     

Synthesis of heterocyclic compounds from 2-phenyl-1,2,3-triazole-4-formylhydrazine

2-Phenyl-1, 2, 3-triazole-4-formylhydrazine (2) was prepared by hydrazinolysis of the corresponding ester 1. Reaction of 2 with CS₂/KOH gave the oxadiazole derivatives (3) which via Mannich reaction with different dialkyl amines furnished 3-N, N-dialkyl derivatives (4a–c). Also, condensation of 2 with appropriate aromatic acid in POCI₃ yielded oxadiazole derivatives (5a–c), or with aldehydes and ketones afforded hydrazones (6a–c). Cyclization of (6a–c) with acetic anhydride gave the desired dihydroxadiazole derivatives (7a–c). On the other hand, reaction of dithiocarbazate (8) with hydrazine hydrate gave the corresponding triazole derivative (9) which on treatment with carboxylic acids in refluxing POCI₃ yielded s-triazole [3, 4–b]-1, 3, 4-thiadiazole derivatives (10a–b). The structures of all the above compounds were confirmed by means of IR, ¹H NMR, MS and elemental analysis.     

Synthesis of new 2-pyridinone and thiazole derivatives containing coumarin moiety

Coumarin has shown considerable therapeutic potency because of its versatile biological prosperities. Also, pyridines have been adopted in medicinal chemistry as potent ring. Moreover, several investigations reported the potency of thiazole-containing compounds. So, during this research, new functionalized 2-pyridinone and thiazole derivatives bearing coumarin moiety were aimed to synthesize. Many trials to obtain the 6-amino-2-oxo-pyridine-3,5-dicarbonitriles through the condensation of cyanoacetohydrazone of 3-acetyl coumarin with 2-(arylidene)malononitriles were carried out using different reaction conditions. In all cases, the reaction gave none of the corresponding 2-pyridinone derivatives except the reaction with 2-(benzylidene)-malononitrile afforded product in few yield. Moreover, the reaction of another cyanoacetanilide with the 2-(arylidene)-malononitrile afforded the unexpected arylidene derivatives rather than the expected pyridin-2-one derivatives. Finally, new thiazoles bearing coumarin moiety were synthesized using 3-acetylcoumarin N-(2,4-dimethoxyphenyl)-thiosemicarbazone. Cyclization of thiosemicarbazone derivative with ethyl 2-chloroacetate, chloroacetone or phenacyl bromide afforded in high yields the corresponding derivatives of thiazolidin-4-one, 4-methylthiazole or 4-phenylthiazole, respectively.     

Modified Riemschneider Reaction of 3‐Thiocyanatoquinolinediones

The Riemschneider reaction of 3‐thiocyanatoquinoline‐2,4(1H,3H)‐diones with conc. H₂SO₄ was investigated. Using different reaction conditions, 13 types of reaction products were isolated. Compounds bearing a Me, Et, or Bu group at C(3) afforded mainly [1,3]thiazolo[5,4‐c]quinoline‐2,4‐diones and 1,9b‐dihydro‐9b‐hydroxythiazolo[5,4‐c]quinoline‐2,4‐diones. In the case of the 3‐Bu derivatives of the starting compounds, C‐debutylation was also observed. If a Bn group is present at C(3), rapid C‐debenzylation of the starting thiocyanates occurred, yielding [1,3]oxathiolo[4,5‐c]quinoline‐2,4‐diones, and mixtures of mono‐, di‐, and trisulfides derived from 4‐hydroxy‐3‐sulfanylquinoline‐2‐ones. The reaction mechanism of all of the transformations is discussed. All new compounds were characterized by IR, ¹H‐ and ¹³C‐NMR, and EI and ESI mass spectra, and in some cases, ¹⁵N‐NMR spectra were also used to characterize new compounds.     

Synthesis of Unique Ceramides and Cerebrosides Occurring in Human Epidermis

The sphingolipids 1a , b and 2a , b which play important roles in epidermal barrier function, were synthesized by N-acylation of C₁₈-sphingosine 3 and 1-O-glucosylated C₁₈-sphingosine 6 , respectively, with ω-acyloxy-substituted fatty acids 4 and 5 (Scheme 1). These fatty acids were obtained from ω-hydroxy-substituted fatty acids 8 and 9 by esterification with linoleic acid ( 7 ). The C₃₄-fatty acid 8 was prepared as follows: C₂₅-Compound 18 was obtained by means of a Wittig reaction of C₁₃-aldehyde 13 with C₁₂-phosphonium salt 15 or of C₁₂-aldehyde 24 with C₁₃-phosphonium salt 21 , respectively, and subseqent hydrogenation and O-deprotection (Scheme 2). Alternatively, 8 was prepared via 30 by copper-catalyzed coupling of C₁₃-alkyl halide 19 with the Grignard reagent derived from C₁₂-alkyl bromide 14 (Scheme 2). Oxidation of 18 to aldehyde 39 and Wittig reaction with C₉-phosphonium salt 41 furnished the desired ω-hydroxy-substituted fatty acid 8 , after O-deprotection (Scheme 3). Similarly, Wittig reaction of C₁₁-phosphonium salt 22 with C₁₂-aldehyde 24 furnished C₂₃-aldehyde 40 , after hydrogenation, O-deprotection, and oxidation; Wittig reaction with compound 41 and subsequent deprotection afforded the desired C₃₂-fatty and 9 (Scheme 3). an alternative strategy furnished compound 8 by a coupling reaction of alkyne 53 with ω-bromo-substitued fatty acid 52 , obtained from compounds 24 and 47 by Wittig reaction, hydrogenation, and introduction of bromide (Scheme 4). Hydrogenation (Lindlar's catalyst) of the resulting C₃₄-alkyne 54 and deprotection furnished 8 .     

Synthesis of Some Novel 2‐Anilinothiophene, 2,3′‐Bithienyl and Thienylthiopyridine Derivatives Resistance to Penicillium Digitatum Effect the Fruit

Reaction of benzotriazol‐1‐yl acetone 1 with phenyl isothiocyanate followed with α‐chloroacetone or ethyl‐α‐chloroacetate afforded 2‐anilinothiophenes 3 or 4 , respectively. Treatment of 3 with malononitrile at different reaction conditions afforded 6 or 7 . Reaction of 1 with CS₂ in DMF and phenacylbromide afforded S‐alkylated thiophene 10 . Reactions of the latter compound with different active methylene nitriles afforded thienylthiopyridine derivatives 14 and 15 . Condensation of 10 with hydrazine hydrate afforded hydrazon derivative 16 . Reaction of thiophene 17 with formamide in DMF afforded 19 which converted to N‐thienylpyrimidine 20 when treated with malononitrile. The structure of the newly synthesized compounds has been established on the basis of their analytical and spectral data. The compounds were also investigated for antibacterial and antifungal activities.     

Synthesis and reactions of 2-chloro-3,4-dihydrothienopyrimidines and -quinazolines

Reaction of 2,4-dichlorothienopyrimidines and -quinazolines 1 with sodium borohydride gave the corresponding 2-chloro-3,4-dihydro derivatives 2. Some nucleophilic substitutions of 2b afforded 2-substituted derivatives 3b-7b and reaction of 2g,h with ethyl bromoacetate yielded selectively the corresponding 3-substituted compounds 8g,h which were derived to imidazo[2,1-b]quinazolin-2-ones 9g,h .     

Carboboration Reactions of 1,2‐Bis[(diarylphosphino)ethynyl]benzenes with Tris(pentafluorophenyl)borane

The 1,2‐bis[(diarylphosphino)ethynyl]benzene derivatives 1a (R=Ph) and 1b (R=o‐tolyl) undergo 1,1‐carboboration at one of their acetylene units upon treatment with (C₆F₅)₃B at elevated temperature to give the products 5a and 5b , respectively. At room temperature, we observed the formation of the corresponding phosphireniumborate zwitterions, 7a and 7b , respectively, which may be intermediates of the 1,1‐carboboration reactions. The reaction of the more bulky 1,2‐bis[(dimesitylphosphino)ethynyl]benzene 1c with (C₆F₅)₃B takes a different course. At 110°, we observed the complete conversion to the benzopentafulvene derivative 8 which is probably formed in a typical carbocation rearrangement sequence after the initial (C₆F₅)₃B Lewis acid‐addition step. The compounds 5a, 5b, 7b , and 8 were characterized by X‐ray crystal‐structure analyses.     

A new approach to the synthesis of benzofuro[3,2‐b]quinolines,benzothieno[3,2‐b]quinolines and indolo[3,2‐b]quinolines

Treatment of 2‐hydroxy‐, 2‐mercapto‐, and 2‐ethoxycarbonylamino‐benzonitriles 12 with 2‐fluoro‐ or 2‐nitrophenacylbromides 13 under alkaline conditions provided the corresponding benzofuran, benzothiophene, and indole intermediates 10 , respectivelly. Nucleophilic cyclization of these compounds led to the corresponding tetracyclic quinolinones 7a, 7b , and 3. Denitrocyclization reaction of compounds 10 (R = NO₂) was found especially useful. Compounds 7a, 7b , and 3 were converted to their chloro derivatives 14a‐c , which were reduced with hydrogen and a catalyst to the corresponding compounds 8a, 8b , and 2. The presented pathway represents a new method of preparation of quindoline 2 and its O and S analogs 8. Chloro derivatives 14 are reactive enough to provide the corresponding methoxy derivatives 15 and dimethylamino derivatives 16. Methylation of compounds 7a and 7b with iodomethane providing mixtures of major N‐methyl derivatives 17 and minor O‐methyl derivatives 15 were also studied.     

Synthesis of Novel Benzofuran‐Gathered C‐2,4,6‐substituted Pyrimidine Derivatives Conjugated by Sulfonyl Chlorides: Orally Bioavailable,Selective, Effective Antioxidants and Antimicrobials Drug Candidates

In the present study, we have made an effort to develop the novel synthetic antioxidants and antimicrobials with improved potency. The novel benzofuran‐gathered C‐2,4,6‐substituted pyrimidine derivatives 5a , 5b , 5c , 5d , 5e , 5f , 6a , 6b , 6c , 6d , 6e , 6f , 7a , 7b , 7c , 7d , 7e , 7f , 8a , 8b , 8c , 8d , 8e , 8f , 9a , 9b , 9c , 9d , 9e , 9f were synthesized by simple and efficient four‐step reaction pathway. Initially, o‐alkyl derivative of salicylaldehyde readily furnish corresponding 2‐acetyl benzofuran 2 in good yield, upon the treatment with potassium tertiary butoxide in the presence of molecular sieves. Further, Claisen–Schmidt condensation with aromatic aldehydes via treatment with thiourea followed by coupling reaction with different sulfonyl chlorides afforded target compounds. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, mass, and elemental analysis and further screened for their antioxidant and antimicrobial activities. The results showed that the synthesized compounds 8b , 8e , 9b , and 9e produced significant antioxidant activity with 50% inhibitory concentration higher than that of reference, whereas compounds 7d and 7c produced dominant antimicrobial activity at concentrations 1.0 and 0.5 mg/mL compared with standard Gentamicin and Nystatin, respectively.     

Synthesis and Reactions of Some Heterocyclic Candidates Based on 2‐Amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene Moiety as Anti‐Arrhythmic Agents

In continuation of our previous work, a series of novel thiophene derivatives 4 , 5 , 6 , 8 , 9 , 9a , 9b , 9c , 9d , 9e , 10 , 10a , 10b , 10c , 10d , 10e , 11 , 12 , 13 , 14 , 15 , 16 were synthesized by the reaction of ethyl 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carboxylate ( 1 ) or 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile ( 2 ) with different organic reagents. Fusion of 1 with ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N‐thienylmalimide derivative 5 , respectively. Acylation of 1 with chloroacetylchloride afforded the amide 6 , which was cyclized with ammonium thiocyanate to give the corresponding N‐theinylthiazole derivative 8 . On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the corresponding thiourea derivatives 9a , 9b , 9c , 9d , 9e , which were cyclized by the action of sodium ethoxide to afford the corresponding N‐substituted thiopyrimidine derivatives 10a , 10b , 10c , 10d , 10e . Condensation of 2 with acid anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11 , 12 , 13 . Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester derivatives 14 , 15 , 16 , respectively. The structures of newly synthesized compounds were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data, LD₅₀, and pharmacological activities of the synthesized compounds are reported.     

Synthesis and Reactions of New Thiazoles and Pyrimidines Containing Sulfonate Moiety

Treatment of 2‐tosyloxybenzylidinethiosemicarbazone ( 2 ) with active halo compounds afforded thiazoles 3 – 5 . Moreover, reaction of compound 2 with acetic anhydride or dimethylformamide dimethylacetal gave N,N diacetyl 6 and dimethylamino derivatives 7 , respectively. Cyclization of thiazole derivatives 3 with some arylidenemalononitriles yielded thiazolo[2,3‐d]pyrans 8 – 12 . Multicomponent reaction of 2‐tosyloxybenzaldehyde ( 1 ) with urea, thiourea, or compound 2 and ethyl acetoacetate or acetylacetone afforded pyrimidines 13 – 14 . The structures of compounds were elucidated by elemental and spectral analyses.     

Furopyridines. XIII. Reaction of 2-methylfuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridines with lithium diisopropylamide

Lithiation of 2-methylfuro[2,3-b]- 1a , -[2,3-c]- 1c and -[3,2-c]pyridine 1d with lithium diisopropylamide at ?75° and subsequent treatment with deuterium chloride in deuterium oxide afforded 2-monodeuteriomethyl compounds 2a, 2c and 2d , while 2-methylfuro[3,2-b]pyridine 1b gave a mixture of 1b, 2b , 2-methyl-3-deuteriofuro[3,2-b]pyridine 2′b and 2-(1-proynyl)pyridin-3-ol 5 . The same reaction of 1a at ?40° gave 3-(1,2-propadienyl)pyridin-2-ol 3 and 3-(2-propynyl)pyridin-2-ol 4 . Reaction of the lithio intermediates from 1a, 1c and 1d with benzaldehyde, propionaldehyde and acetone afforded the corresponding alcohol derivatives 6a, 6c, 6d, 7a, 7c, 7d, 8a, 8c and 8d in excellent yield; while the reaction of lithio intermediate from 1b gave the expected alcohols 6b and 8b in lower yields accompanied by formation of 3-alkylated compounds 9, 11, 12 and compound 5 . While reaction of the intermediates from 1a, 1b and 1d with N,N-dimethylacetamide yielded the 2-acetonyl compounds 13a, 13b and 13d in good yield, the same reaction of 1c did not give any acetylated product but recovery of the starting compound almost quantitatively.     

4‐Toluenesulfonamide as a Building Block for Synthesis of Novel Triazepines,Pyrimidines, and Azoles

N‐{(E)‐(dimethylamino)methylidenearbamothioyl}‐4‐toluenesulfonamide ( 2 ) was obtained by reaction of N‐carbamothioyl‐4‐toluenesulfonamide ( 1 ) with dimethylformamide dimethylacetal or alternatively by the reaction of 1‐(dimethylamino)methylidenethiourea with tosyl chloride. Compound 2 was reacted with substituted anilines to yield anilinomethylidine derivatives 3a , 3b , 3c , 3d , 3e , 3f , 3g . Treatment of 3a , 3b , 3c , 3d , 3e , 3f , 3g with phenacyl bromide gave triazepines 4a , 4b , 4c , 4d , 4e , 4f , 4g and imidazoles 5a , 5b , 5c , 5d , 5e , 5f , 5g . Esterification of compound 3e afforded ester derivative 6 , which was subjected to react with hydrazine to yield hydrazide derivative 7 . Oxadiazole 8 was obtained by reaction of 7 with CS₂/KOH. Compound 3e was treated with o‐aminophenol or o‐aminothiophenol to give benzazoles 9a , 9b . N‐(Diaminomethylidene)‐4‐toluenesulfonamide ( 10 ) reacted with enaminones to yield pyrimidines 11 , 12 , 13 , respectively. The structures of the compounds were elucidated by elemental and spectral analyses. Some selected compounds were screened for their in vitro antifungal activity. In general, the newly synthesized compounds showed good antifungal activity.     

Synthesis of Some Pyrimidine 2-Oxo(Thio)-4,6-Dione Derivatives

5-Arylidenes 1a and 1b, on reaction with ethyl cyanoacetate and diethyl malonate in the presence of ammonium acetate under Michael condensation, yield pyridine derivatives 2 and 3, respectively. Cyclopentapyrimidine derivative 4 can also be obtained by the reaction of 1a with malononitrile in the presence of piperidine. The reaction of 5-arylidene lb with monochloroacetic acid in an alkaline medium gives the thiazol derivative 5. Also, spiro-[3′, 5′]cyclohexenyl pyrimidine derivative 6 could be obtained from the reaction of 1d with maleic anhydride. On the other hand, 5-arylidene 1e reacts with maleic anhydride to give 2-thiobarbituric acid derivative 7. The condensation reaction of 2-thiovioluric acid 8 with some hydrazines affords the triazole derivatives 9a-d. Finally, barbituric acid condenses with isatin to give 5-arylidene 1f, which can be cyclized with phosphorous pentoxide to afford 10.