4-Cyano-2-oxo-1,2,4-oxadiazolo[2,3-a]quinoxaline 5-N-oxides. New synthetic method and reaction with alcohols. Potential cytotoxic activity

Several quinoxaline 1,4-di-N-oxides have been shown to be efficient and selective cytotoxins for hypoxic cells. We present now a series of 4-cyano-2-oxo-1,2,4-oxadiazolo[2,3-a]quinoxaline 5-N-oxides 2a-2k . They were prepared starting from 3-amino-2-quinoxalinecarbonitrile 1,4-di-N-oxides 1a-1k and 2-chloroethyl isocyanate in dry dioxane at 100–110°. A reaction mechanism is proposed. The treatment of 1a with phenyl isocyanate afforded 2a . Reaction of 2c with silica gel yielded 1c . Compounds 2a-2g were heated in the presence of ethanol and 2-propanol giving the corresponding carbamates 3a-3g and 4a-4g . Compound 2d was already obtained by heating a mixture of 1d and ethyl chloroformiate. Compound 2b was prepared when the carbamate 3b was heated at 150°. Quinoxalines were tested as cytotoxic agents both in oxic and hypoxic cells. The most interesting compounds were 3g and 4g .     

Microwave‐assisted synthesis of new regioisomeric 6,7‐dihydroindeno[1,2‐e]pyrimido[4,5‐b][1,4]diazepin‐5(5aH)‐ones

Novel 11‐amino‐6‐aryl‐6,7‐dihydroindeno[1,2‐e] pyrimido[4,5‐b][1,4]diazepin‐5(5aH)‐ones 4a‐f were prepared regioselectively by the tricomponent reaction of 4,5,6‐triaminopyrimidine 1, 1,3‐indandione 2 and aromatic aldehydes 3a‐f. The bicomponent approach, using 2,4,5,6‐tetraaminopyrimidine 5 and 2‐aryl‐ideneindandiones 6a‐f as reagents, afforded 9,11‐diamino‐6‐aryl‐6,7‐dihydroindeno[1,2‐e]pyrimido[4,5‐b]‐[1,4]diazepin‐5(5aH)‐ones 7a‐f in good yields and the regioisomeric 8,10‐diamino derivatives 8a‐c in lower yields. Both, bi‐ and tricomponent approaches were performed by microwave irradiation and all products were fully characterized by detailed NMR measurements.     

Synthesis of some sulfur-containing spiro-pyrimidinetriones,pyrazolidinediones, and isoxazolidinediones

Novel sulfur-containing spiro compounds such as 7,11-diaryl-9-thia-2,4-diazaspiro [5,5] undecane-1,3,5-trione 9,9-dioxides ( 2 ), 6,10-diaryl-8-thia-2,3-diazas-piro[4,5]decane-1,4-dione-8,8-dioxides ( 3 ) and 6,10-diaryl-2-oxo-8-thia-3-azaspiro [4,5] decane-1,4-dione-8,8-dioxides ( 5 ) have been prepared by the condensation of 4-dimethoxycarbonyl/diethoxycarbonyl-3,5-diaryl-1-thiane 1,1-dioxides ( 1 ) with urea, hydrazine hydrate, and hydroxylamine hydrochloride, respectively. The N-substituted derivatives ( 4 and 6 ) of 3 and 5 have also been prepared by acylation and nitrosation. The structures of 2, 3 , and 5 were established by IR, ¹H NMR, and ¹³C NMR spectral studies, respectively.     

Synthesis of fluorine containing N‐benzyl‐1,2,3‐triazoles and N‐methyl‐pyrazoles from conjugated alkynes

1, 3‐Dipolar‐cycloaddition reaction of fluoro substituted 3‐aryl‐propynenitriles 1 with benzyl azide 2 afforded the expected 3‐benzyl‐5‐aryl‐3H‐[1,2,3]triazole‐4‐carbonitrile 3 and 1‐benzyl‐5‐aryl‐1H‐[1,2,3]‐triazole‐4‐carbonitrile 4 in good yield. However, 1,3‐dipolar cycloaddition of diazomethane 5 with 3‐aryl‐propynenitriles 1 resulted in the exclusive formation of N‐methyl‐pyrazole derivatives 6 and 7 .     

Synthesis of quinoxaline 1,4-dioxides from 4,5(6,7)-dimethylbenzofuroxan

In this study, novel substituted quinoxaline 1,4-dioxides were synthesized from novel substituted benzofuroxan. 4,5(6,7)-Dimethylbenzofuroxan 3 was prepared by the thermal decomposition of 2,3-dimethyl-6-nitrophenylazide 2 . Novel quinoxaline 1,4-dioxides derivatives were obtained using compound 3 and the enolic form of 1,3-diketones 4 catalyzed by silica gel or molecular sieves. These reactions gave isomeric quinoxaline 1,4-dioxides 5 and 6 . These reactions of compound 3 may involve tautomers 4,5-dimethylbenzofuroxan 3a , 6,7-dimethylbenzofuroxan 3b on the surface of a solid catalyst.     

Solid-phase syntheses of heterocycles containing the 2-aminothiophenol moiety

Efficient and general procedures have been developed for the solid-phase preparation of substituted benzothiazoles (1), 3, 4-dihydro-1,4-benzothiazines (2), 3,4-dihydro-1,4-benzothiazine-1, 1-dioxides (3), 3,4-dihydro-3-oxo-1,4-benzothiazines (4), and 3, 4-dihydro-3-oxo-1,4-benzothiazine-1,1-dioxides (5). All five classes of compounds were prepared from a common intermediate, resin-bound 2-amino-4-carboxythiophenol, in a minimal number of steps. This intermediate was generated by (i) coupling 4-fluoro-3-nitrobenzoic acid onto Wang resin, or onto an amino acid bound to the resin, (ii) substitution of the aryl fluoride with a protected thiol, (iii) reduction of the nitro group, and (iv) removal of sulfur protection. Reaction with the appropriate substrates and reagents to effect cyclization gave the substituted core structures, which were modified further to introduce additional point(s) of diversity. Following cleavages from the solid support, the compounds were obtained in high initial purities and good isolated yields after purification.     

New liquid crystalline compounds based on 2-arylthiophenes and 2-(biphenyl-4-yl)thiophenes

A general and versatile route to the 2-alkyl-5-(4'-cyanophenyl)thiophenes was established, involving the condensation of an aryl vinyl ketone with an aldehyde in the presence of a thiazolium catalyst (Stetter procedure) to give a 1,4-diketone which with Lawesson's reagent undergoes ring-closure to give the corresponding arylthiophene. In the final step the exchange of a bromo substituent on the phenyl ring for a cyano group is accomplished by copper(I) cyanide in N,N-dimethylforamamide at reflux. The same sequence afforded 2-alkyl-5-(4'-cyanobiphenylyl)thiophenes. Several of the 1,4-diketones were obtained by conjugate addition of nitroalkanes to aryl vinyl ketones, and treatment of the γ-nitroketones with silica gel-supported potassium permanganate. Three alkyl 5-(4-cyanophenyl)thiophene-2-carboxylates were prepared by condensing β-chlorovinylaldehydes with thioglycolates. The cyanophenylthiophenes exhibited only monotropic phases, but incorporation of an additional phenyl ring provided cyanobiphenylylthiophenes of wide nematic ranges. Transition temperatures of binary mixtures of the cyanophenylthiophenes with 4-n-pentyl-4'-cyanobiphenyl were measured, and extrapolated virtual nematic-isotropic transition temperatures were determined.     

Polyesters derived from 1,4-oxathian-2-ones

1,4-Oxathian-2-one ( 1a ) was prepared in high yield by oligomerization of methyl(2-hydroxyethyl)mercaptoacetate ( 3 ) followed by catalytic depolymerization in vacuo. A similar sequence starting with methyl(2-hydroxyethyl)sulfonylacetate ( 5 ) afforded the corresponding sulfone, 1,4-oxathian-2-one-4,4-dioxide ( 1c ), however, 1,4-oxathian-2-one-4-oxide ( 1b ) could not be obtained by this procedure. Ring opening melt polymerization of 1a and 1c afforded low molecular weight crystalline polyesters 2a and 2c . Oxidation of 2a with m-chloroperoxybenzoic acid produced the corresponding polyester 2b containing sulfoxide groups. Thermogravimetric analyses and visual observations indicated 2b to be thermally unstable relative to 2a and 2c .     

Synthesis and reactivity of 4-substituted-2,3-dihydrobenzo-1,4-thiazines

A series of derivatives of 4H-2,3-dihydrobenzo-1,4-thiazine has been prepared. 4-Acetyl-2,3-dihydrobenzo-1,4-thiazine undergoes self-condensation by n-butylmagnesium bromide affording the corresponding 4-aceto-acetyl-2,3-dihydrobenzo-1,4-thiazine, which, is converted to 5H-1,4-thiazino[2,3,4-if]quinolin-5-one. Halogena-tion of the acetyl derivative takes place at the position 2 of the heterocyclic ring and oxidation leads to 1-oxides and 1,1-dioxides.     

Preparation of some substituted imidazo[1,2-a]pyridine derivatives

2-Bromopyridine derivatives 2a-2c were prepared. Compounds 2b and 2c and ammonia yielded aminopyridines 3b and 3c which were converted to imidazo[1,2-a]pyridine derivatives 4b and 4c . Compound 4b was nitrated giving the analogue 5b of metronidazole 1 .     

A new approach for the synthesis of some 1,4-benzoxathiin 4,4-dioxide derivatives

A series of 1,4-benzoxathiin 4,4-dioxide derivatives have been prepared by a new synthetic route. The reactions of 2-chloro-4-nitrobenzenethiol 1 with l-aryl-2-chloroethanones 2 in the presence of sodium hydroxide give l-aryl-2-(2-chloro-4-nitrophenylthio)ethanones 3 which on oxidation with 30% aqueous hydrogen peroxide afford l-aryl-2-(2-chloro-4-nitrophenylsulfonyl)ethanones 4. By the reactions of compounds 4 with 2-[3 or 4-(bromomethyl)phenyl]benzoxazole in the potassium carbonate, triethylbenzyl-ammonium chloride and dimethylformamide system, 2-aryl-3-arylmethyl-7-nitro-1,4-benzoxathiin 4,4-dioxides 5 or 6 are obtained via a tandem alkylation-cyclization process.     

Furopyridines. IX. Syntheses and properties of 3-ethoxy derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

Reaction of ethyl 3-ethoxycarbonylmethoxyfuropyridine-2-carboxylates 2a-2d with sodium ethoxide afforded 3-ethoxy derivatives 3a-3d which converted to 3-ethoxyfuropyridines 5a-5d by hydrolysis and decarboxylation of the ester group. Vilsmeier reaction of 5a and 5b gave 2-formyl-3-ethoxy derivatives 6a and 6b and 2-formyl-3-chloro derivatives 7a and 7b , while 5c and 5d did not give any formyl compound. Bromination of 3-ethoxyfuropyridines with 1 equivalent mole of bromine gave 2-bromo-3-ethoxyfuropyridines 9a-9d , whereas reaction with 3 equivalents of bromine yielded 2,2-dibromo-3,3-diethoxy-2,3-dihydrofuropyridines ( 10a and 10b ) and/or 2-bromo-3,3-diethoxy-2,3-dihydrofuropyridines 11b , 11c and 11d . Treatment of compounds 5a-5d with n-butyllithium in hexane-tetrahydrofuran at ?70° and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 6a-6d .     

Synthesis of Arylnaphthoquinones and Their Reactions with o‐Substituted Primary Aromatic Amines

Cycloaddition reaction of 2‐aryl‐1,4‐benzoquinones 1a‐d with a number of different dienes, namely 2,3‐dimethylbutadiene; 1,4‐diphenylbutadiene and anthracene yield 2‐aryl‐6,7‐dimethyl‐1,4‐ naphthoquinones 3a,b ; 2,5,8‐triphenyl‐1,4‐naphthoquinone 4 and 2‐aryl‐1,4,9,10‐tetrahydro‐9,10‐o‐benzoanthracene‐1,4‐dione 5 , respectively were investigated. In addition, the cycloaddition reaction of 2‐aryl‐1,4‐benzoquinones 1d,e with 2,3‐dimethylbutadiene was also investigated to yield 2‐aryl‐5,8‐dihydro‐6,7‐dimethyl‐1,4‐naphthohydroquinones 2a,b . Cyclocondensation reactions of Diels‐Alder adducts 2b, 3b, 5a with ethylenediamine, o‐substituted primary aromatic amines gave quinoxaline, phenazine, phenoxazine and phenothiazine ocyclic derivatives 6–14.     

Studies on 4‐Thiazolidinones: Scope of the Reactions of 3‐Aryl‐2‐thioxo‐1,3‐thiazolidin‐4‐ones with Cyanide and Cyanate Ions

Treatment of 3‐aryl‐2‐thioxo‐1,3‐thiazolidin‐4‐ones 1 with CN^? and NCO^? effected the ring cleavage providing [(cyanocarbonothioyl)amino]benzenes 4 and arylisothiocyanates 5 , respectively. Similar treatment of 5‐(2‐aryl‐2‐oxoethyl) derivatives 2 afforded 2,4‐bis(2‐aryl‐2‐oxoethylidene)cyclobutane‐1,3‐diones 6 along with each of the preceding products. Treatment of the respective (E,Z)‐5‐(2‐aryl‐2‐oxoethylidene) analogues 3b and 3c with CN^? gave 4b and 4c and 2‐(arylcarbonyl)‐2‐methoxy‐4‐oxopentanedinitriles 7b and 7c , in addition to 3,6‐bis[2‐(4‐chlorophenyl)‐1‐methoxy‐2‐oxoethylidene]‐1,4‐dithiane‐2,5‐dione 8c , which has been generated from 3c . Reactions of 3c or 3d with NCO^? provided 5c or 5d , together with 8c or 8d as pure isomers. In the formation of the MeO products 7 and 8 , the solvent (MeOH) has participated. Structures of these products are based on microanalytical and spectroscopic data. Rationalizations for the above transformations are given.     

Synthesis and antimicrobial activity of 2‐(acyl or carboxyalkyl)‐3‐(H or alkyl or aryl)‐5 (or ‐6 or ‐8)‐monochloro, 7‐fluoro‐substituted‐4H‐1,4‐benzothiazines

A series of 2‐(acyl or carboxyalkyl)‐3‐(H or alkyl or aryl)‐5 (or ‐6 or ‐8)‐monochloro, 7‐fluoro‐substituted‐4H‐1,4‐benzothiazines 3a‐x were prepared to investigate their potential biological activity. In this work the 3a‐w structures are supported with physical and analytical data and the results of their in vitro antimicrobial activity against some strains Gram positive, Gram negative, and Fungi are reported. It was found that compounds 3a, 3d displayed interesting antibacterial activity, whereas compound 3f displayed interesting antifungal activity.     

Synthesis and Antimicrobial Activity of New Pyridothienopyrimidines and Pyridothienotriazines

5‐Acetyl‐3‐amino‐4‐aryl‐6‐methylthieno[2,3‐b]pyridine‐2‐carboxamides ( 5a,b ) were reacted with triethyl orthoformate or nitrous acid to give the corresponding pyrimidinones 6a,b and triazinones 7a,b . The reaction of 5a,b with acetic anhydride was carried out and its products were identified as a mixture of 8‐acetyl‐9‐aryl‐2,7‐dimethylpyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐4(3H)‐one ( 9a,b ) and related 5‐acetyl‐4‐aryl‐3‐biacetylamino‐6‐methylthieno[2,3‐b]pyridine‐2‐carbonitrile ( 10a,b ). Reaction of 7a with some halocompounds afforded the N‐alkylated triazinones 8a‐c . Chlorination of 6a,b and 9a,b with phosphorus oxychloride produced 4‐chloropyrimidines 11a‐d which were used as precursors for the rest of the target heterocycles. Some of the prepared compounds were tested in vitro for their antimicrobial activities.     

2H-1,2,4-benzothiadiazine 1,1-dioxides 2. A condensation of 2-aminobenzenesulfonamide with chloroalkyl isothiocyanates

A reaction of 2-aminobenzenesulfonamide ( 1 ) with 2-chloroethyl or 3-chloropropyl isothiocyanate in isopropanol afforded 2-(2′-chloroethylthioureido)- and 2-(3′-chloropropylthioureido)benzenesulfonamides ( 2a,b ) in 67% and 55% yield respectively. Treatment of 2a,b with triethylamine in methanol at room temperature furnished 3-(2′-aminoethylthio)- and 3-(3′-aminopropylthio)-2H-1,2,4-benzothiadiazine 1,1-dioxides ( 9a,b ) in quantitative yield. Heating 2b to reflux in methanol under neutral conditions gave 9b but in the form of the hydrochloride 8b which could be converted into the free base 9b by treating with ammonia water. When compounds 2a,b were treated with triethylamine in methanol at elevated temperature, 3-(2′-mercaptoethylamino)- and 3-(3′-mercaptopropylamino)-2H-1,2,4-benzothiadiazine 1,1-dioxides ( 10a,b ) were obtained in good yield. Alternatively, 10a,b could also be prepared from 9a,b in 95% and 77% yield respectively.     

Preparation of trifluoromethylated pyrazoles and 1,4-thiazine 1,1-dioxides from trifluoromethylated sulfone derivatives

Trifluoromethylated sulfones, 3-amino-2-arylsulfonyl-4,4,4-trifluoro-3-hydroxybutanenitrile ( 3 ) and 3-(aroylmethyl)sulfonyl-1,1,1-trifluoropropane-2,2,-diols 12 , were prepared and cyclized to 4-arylsulfonyl-5-trifluoromethyl-3-hydrazinopyrazoles 9 and 5-arylsulfonyl-3-trifluoromethyl-3-hydroxy-2,3-dihydro-4H-1,4-thiazine 1,1-dioxides 13 , respectively.     

Synthesis of pyrimido[4,5-e][1,4]oxazepin-5-ones

Eighteen novel pyrimido[4,5-e][1,4]oxazepin-5-ones were prepared directly via the reaction of either ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate (Ia) or ethyl 4-chloro-2-m-chlorophenyl-5-pyrimidinecarboxylate (Ib) with a variety of substituted 2-(alkylamino)ethanols. A typical example was the preparation of 8,9-dihydro-9-methyl-2-phenylpyrimido[4,5-e][1,4]-oxazepin-5(7H)-one (IIa) from the reaction of Ia with 2-(methylamino)ethanol. Hydrolytic cleavage of the lactone ring in IIa with sodium hydroxide solution, followed by acidification with hydrochloric acid afforded 4-[(2-hydroxyethyl)methylamino]-2-phenyl-5-pyrimidinecarboxylic acid (IV). Reactions of IIa with concentrated ammonium hydroxide or hydrazine also caused cleavage of the lactone ring, giving the corresponding amide (V) or hydrazide (VI), respectively. Structural assignments were supported by infrared and nuclear magnetic resonance spectra.     

Synthesis Of 1,8‐dioxa‐dibenzo[e,h]azulenese

A novel synthetic route to 2‐methyl‐1,8‐dioxa‐dibenzo[e,h]azulenes [1] via cyclisation of the corresponding 1,4‐dicarbonyl compound is described. 1,4‐Dicarbonyl compounds were synthesized by the alkylation reaction of the 11H‐dibenzo[b,f]oxepine‐10‐one while analogous alkylation of 11H‐dibenzo[b,f]thiepine‐10‐one resulted in formation of O‐alkylated products. Selective oxidation of 2‐methyl group afforded 1,8‐dioxa‐dibenzo[e,h]azulenes with formyl and hydroxymethyl functionality at C(2) position.