Synthesis of 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-aryl-4,5-dihydro-1H-pyrrole-3-carboxylates, a new triazafulvalene system

(2E,3Z)-2-(1-Methyl-2,5-dioxoimidazolidin-4-ylidene)-3-[(arylamino- or heteroarylamino)methylene]succinate 5 obtained by [2+2] cycloaddition of (5Z)-5-[(dimethylamino)methylene]-3-methylimidazolidine-2,4-dione (1) and dimethyl acetylenedicarboxylate (2) followed by substitution of the dimethylamino group with aromatic or heteroaromatic amines, afforded by heating in ethanol in the presence of potassium hydroxide, potassium salts 6. Acidification of 6 with hydrochloric acid afforded mixtures of (E)- and (Z)-isomers of methyl 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates. On the other hand, alkylation of compounds 6 with methyl iodide or benzyl bromide produced the corresponding methyl (E)-4-(2-methoxy- or 2-benzyloxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates 9, derivatives of a new triazafulvalene system.     

Synthesis,Structure and Cytotoxicity Testing of Novel 7-(4,5-Dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives

The appropriate 1-arylhydrazinecarbonitriles 1a–c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a–c, which are subsequently converted into the corresponding amides 4a–e, 8a–c, sulfonamides 5a–n, 9, ureas 6a–I, and thioureas 7a–d. The structures of the newly prepared derivatives 3a–c, 4a–e, 5a–n, 6a–i, 7a–d, 8a–c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1′-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC₅₀ values in the range of 2.38–3.77 μM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.     

Reaction of acetylenedicarboxylic acids esters with 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-1-carbothioamides and 3,4,5,6-tetrahydro-2<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazepine-3-thiones

The reactions of dimethyl acetylenecarboxylate with 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones and 4,5-dihydro-1H-pyrazole-1-carbothioamides are convenient methods for the synthesis of 7,8-dihydrothiazolo[3,2-b][1,2,4]triazepin-3-ones derivatives and methyl esters of (2Z)-[2-(4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acids, respectively. The reaction of methyl propynoates with 4,5-dihydro-1H-pyrazole-1-carbothioamides or with 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione gives 2-(4,5-dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones.     

Synthesis of 1-phenyi-1H-tetrazolo[4,5-d]tetrazole and 5-aryl-1-(4-bromophenyl)-1,2,4-triazolo[4,3-d]tetrazoles

l-Phenyl-lH-tetrazol-5-yIhydrazine (2) was reacted with nitrous acid to yield 1-phenyl-lH-tetrazolo[4,5-d]tetrazole (3). l-Arylidene-2-(l-phenyl-lH-tetrazol-5-yl)hydrazines (4) were generally reactive towards electrophilic reagents. When treated with bromine in acetic acid, 4 yielded mixtures of 1-arylidene-2-[1-(4-bromophenyl)-lH-tetrazol-5-yl]hydrazines (5a-d) and 2-[1-(4-bromophenyl)-lH-tetrazol-5-yl]hydrazidic bromides (6a-d). Solvolysis of 6a-d in aqueous acetone yielded 5-aryl-1-(4-bromophenyl)-1,2,4-triazolo[4,3-d]tetrazoles (7a-d). The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR and ¹H NMR data.     

Tetrazoles: XLIX. Alkylation of tetrazoles with tetrakis(chloroacetoxymethyl)methane

Alkylation of 1-aryl-4,5-dihydro-1H-tetrazol-5-ones and 1-phenyl-4,5-dihydro-1H-tetrazole-5-thione with tetrakis(2-chloroacetoxymethyl)methane in boiling acetonitrile in the presence of potassium bromide and triethylamine gives tetrakis[2-(4-aryl-5-oxo-4,5-dihydro-1H-tetrazol-1-yl)acetoxymethyl]-methanes and tetrakis[2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)acetoxymethyl]methane, respectively. The alkylation process is considerably accelerated under microwave irradiation.     

A novel reaction of (2a7-trinito-9H-fluoren-9-ylidene)-propanedinitrile with N-arylisoindolines

N-Arylisoindolines 1a-c reacted with (2,4, 7-trinitro-9H-fluoren-9-ylidene)propanedinitrile ( A ) in pyridine with admission of air via a net α-H-atom abstraction and formation of [3-(2-aryl-3-arylimino-2,3-dihydro- 1H-isoindol-1-ylidene)-2-aryl-2,3-dihydro-1H-isoindol-1-ylidene]propanedinitriles 2a-c , N-[2-aryl-3-(2-aryl-3-arylimino-2,3-dihydro-1H-isoindolyl-1-idene)-2,3-dihydro-1H-isoindol-1-ylidene]arenamines 3a, b , N, N'-[2-aryl-1H-isoindole-1,3(2H)-diylidene]bisarenamines 4a, b and N-arylphthalimides 5a-c in moderate yields. 2,4,7-Trinitro-9-fluorenone as well as one reduction product each of the latter and of A, namely compounds 6 and 7 , respectively, are also found. The structure of 2b has been unambiguously confirmed by an X-ray crystal structure analysis. A rationale for the conversions observed is presented. These involve dehydrogenation and oxidative couplings of 1a-c as well as transfer of N-aryl fragment from 1a-c to intermediate products.     

Facile one pot multicomponent synthesis of novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives

An efficient base catalyzed one pot multicomponent reaction of aryl/hetryl chalcones, thiosemicarbazide and 1-(benzofuran-2-yl)-2-bromoethan-1-one was developed to synthesize the novel 4-(benzofuran-2-yl)-2-(3-(aryl/heteryl)-5-(aryl/heteryl)-4,5-dihydro-1H-pyrazol-1yl)thiazole derivatives.     

Synthesis of Stable Atropisomers of Dialkyl-4-Ethoxy-1-(8-((2-ethoxy-2-oxoacetyl)-amino)-1-naphthyl)-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates

Summary.  Protonation of the reactive 1:1-intermediate produced in the reaction between triphenylphosphine and dialkyl acetylenedicarboxylates with diethyl N,N′-(naphthalene-1,8-diyl)-dioxamate leads to a vinylphosphonium salt which undergoes an intramolecular Wittig reaction to produce dialkyl-4-ethoxy-1-(8-((2-ethoxy-2-oxoacetyl)-amino)-1-naphthyl)-5-oxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates in good yields. The title compounds exist as stable rotamers as a result of restricted rotation around the single bond linking the naphthalene moiety and the heterocyclic system. The calculated free energy of activation for interconversion of the atropisomers amounts to about 102±2 kJ · mol⁻¹. Corresponding author. E-mail: isayavar@yahoo.com Received February 5, 2002. Accepted March 19, 2002     

Synthesis of novel N-aryl-N-(1H-tetrazol-5-yl)benzenesulfonamides in water

N-Aryl-N-(1H-tetrazol-5-yl)benzenesulfonamides were synthesized via an eco-friendly protocol using ZnBr₂-catalyzed [2 + 3] cycloaddition reaction of N-cyano-N-arylbenzenesulfonamides and sodium azide under reflux conditions in water. The products were obtained in excellent yields via an easy work-up procedure.     

Synthesis of some newer 5-(5-aryl-2H-tetrazol-2-ylmethyl)-4-substituted-s-triazole-3-thiols as possible antiinflammatory agents

Several 1-(5-aryl-2H-tetrazol-2-ylacetyl)-4-substituted thiosemicarbazides and 5-(5-aryl-2H-tetrazol-2-yl-methyl)-4-substituted-s-triazole-3-thiols were synthesized as possible antiinflammatory agents. These compounds were characterized by their elemental, infrared and nuclear magnetic resonance analysis.     

Synthesis of 7,8-dihydro-6H-pyrazolo[3,4-b]quinolin-5-ones and related derivatives

This paper describes the synthesis of a new series of 4-amino-1-(unsubstituted and chloro or fluoro substituted benzyl)-7,8-dihydro-6H-pyrazolo[3,4-b]quinolin-5-ones 8 and the corresponding 7,8-dihydro-6H,9H-pyrazolo[3,4-b]quinoline-4,5-diones 13 . The derivatives obtained by reaction of these compounds with sodium azide in concentrated sulfuric acid are also reported.     

An unexpected aminolysis in the synthesis of 5-substituted 3-(1H-tetrazol-5-yl)pyrazolo[1, 5-a]quinazolines

A synthetic route to 5-substituted 3-(1H-tetrazol-5-yl)pyrazolo[1, 5-a]quinazolines is described. An unexpected displacement of a 4-morpholinyl group from the 5-position of this system occurred during tetrazole formation by the ammonia produced by in situ generation of hydrazoic acid from ammonium chloride and sodium azide.     

The photolysis of 1-(4,5-dihydro-1H-imidazol-2-yl)benzotriazole

1-(4,5-Dihydro-1H-imidazolo-2-yl)benzotriazole was photolyzed at 254 nm yielding 1,2-dihydro-4H-imidazo-[1,2-a]benzimidazole.     

Development of a new synthesis of 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone,sodium salt via an amidine intermediate

A new synthesis of the recently reported 3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone, sodium salt ( 1 , MDL-427), an experimental mediator release inhibitor, was developed from: (1) reaction of 5-aminotetrazole 3 and triethyl orthoformate 6 to give ethyl N-(1H-tetrazol-5-yl)formimidate 8 , (2) reaction of methyl anthranilate and imidate 8 to give amidine 11 , and (3) treatment of 11 with base to give 1 . Investigation of each of these steps independently led to a significantly more efficient, facile and higher-yielding 1-pot process. A brief examination of anthranilic acid 13 and its salts and derivatives 14 to 17 in this process found them to have dissimilar reactivities. The formation of amidine 11 as an isolable intermediate was unusual, as was its failure to cyclize under standard neutral or acidic conditions. The absolute requirement for base to effect cyclization of 11 appears to be unprecedented.     

From Levulinic Acid to Biheterocycles: Synthesis of 1-[(5-Hydroxy-5-trifluoromethyl-3-substituted-4,5-dihydro-1H-pyrazol-1-yl)-3-(5-trifluoromethyl-1H-pyrazol-3-yl)propan-1-ones

We develop an efficient method to synthesize novel propionyl-spaced bisheterocyclic compounds. It entails cyclocondensation of 3-(5-trifluoromethyl-1H-pyrazol-3-yl)propanoyl hydrazide obtained from levulinic acid, with 1,1,1-trifluoro-4-methoxy-3-alken-2-ones proceeding regiospecifically to 1-[(5-trifluoromethyl-5-hydroxy-3-substituted-4,5-dihydro-1H-pyrazol-1-yl)-3-(5-trifluoromethyl-1H-pyrazol-3-yl)propan-1-one derivatives.     

Eine überraschende Ringerweiterung von 3-(Dimethylamino)-2,2-dimethyl-2H-azirin zu 4,5-Dihydropyridin-2(3H)-on-Derivaten

An Unexpected Ring Enlargement of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine to 4,5-Dihydropyridin-2(3H)-one Derivatives The reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine ( 1a ) and 4,4-disubstituted 2-(trifluoromethyl)-1,3-oxazol-5(4H)-ones 7 in MeCN at 70° afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 10 (Scheme 4), whereas no reaction could be observed between 1a and 2-allyl-4-phenyl-2-(trifluoromethyl)-1,3-oxazol-5(2H)-one ( 8a ) or 4,4-dibenzyl-2-phenyl-1,3-oxazol-5(4H)-one ( 9 ). The formation of 10 is rationalized by a mechanism via nucleophilic attack of 1a onto 7 . The failure of a reaction with 9 shows that only activated 1,3-oxazol-5(4H)-ones bearing electron-withdrawing substituents do react as electrophiles with 1a . The amino-azirine 1a and 2,4-disubstituted 1,3-oxazol-5(4H)-ones 2b – e in refluxing MeCN undergo a novel ring enlargement to 4,5-dihydropyridin-2(3H)-ones 11 (Scheme 5). Several side products were observed in these reactions. Two different reaction mechanisms for the formation of 11 are proposed: either 1a undergoes a nucleophilic addition onto the open-chain ketene tautomer of 2 (Scheme 6), or 2 reacts as CH-acidic compound (Scheme 7).     

Synthesis of 1-(5-phenyl-2H-tetrazol-2-ylacetyl)-4-substituted thiosemicarbazides as possible antiinflammatory agents

A series of 1-(5-phenyl-2H-tetrazol-2-ylacetyl)-4-substituted thiosemicarbazids were prepared as possible antiinflammatory agents. Their antiproteolytic activity was reported.     

Studies on quinazolinones. 2. Synthesis of 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3–6]quinazolin-5-one and -2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one

To search for novel antihypertensive heterocycles in the condensed quinazoline series, two representative compounds were synthesized via a suitable reaction sequences. Treating anthranilonitrile with allyl isocyanate gave 2-(allylureido)benzonitrile ( 10 ) in a quantitative yield. Compound 10 was cyclized to 3-allylquinazoline-2(1H, 4(3H)-dione ( 11 ). Bromination of 11 in carbon tetrachloride converted it into the corresponding 3-(2,3-dibromopropyl) derivative ( 12 ) in 92% yield. Ring closure of 12 was effected by the action of alkali to afford 2-bromomethyl-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 13 ). The title compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 7 ) could be obtained by a reaction of either 12 or 13 with 1-benzylpiperazine respectively. Starting from the readily available 3-allyl-2H-thioxoquinazolin-4(3H)-one ( 16 ) via the analogous reactions gave the 2-bromomethyl-2,3-dihydro-5H-thiazolo[2,3-b]-quinazolin-5-one ( 19 ) in good yield. However, the reaction of 19 with 1-benzylpiperazine provided another target compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 8 ) only in poor yield (8%). As major product, the dehydrobrominated compound, 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 22 ) was isolated. A preliminary pharmacological evaluation revealed that both compounds 7 and 8 are devoid of the antihypertensive activity.     

5-phenyl-2H-tetrazol-2-ylmethyl ketones in the synthesis of tetrazolylalkanols and tetrazolyl(hydroxy)alkylphosphonates

The reduction of 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone with sodium tetrahydridoborate gave 1-(5-phenyl-2H-tetrazol-2-yl)propan-1-ol and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanol, respectively. Only 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one was reduced with baker’s yeast with an appreciable yield. 1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone reacted with diethyl phosphonate in the presence of potassium fluoride to produce the corresponding diethyl [hydroxy(5-phenyl-2H-tetrazol-2-yl)alkyl]phosphonates.     

2,6-Dithiodecahydro-1H,5H-Diimidazo[4,5,-b:4′,5′-e]Pyrazine and related dioxo- and diimino-decahydrodiimidazopyrazines

Thiourea condensed with 1,4-diformyl-2,3,5,6-tetrahydroxypiperazine 2 in the presence of hydrochloric acid to give 2,6-dithiodecahydro-1 H,5H-diimidazo[4,5,-b:4′,5′-e]pyrazine 5 isolated as the dihydrochloride salt. The salt 5 . 2HCl was converted to the free base 5 by lithium hydroxide, to the dinitrate salt 5 . 2HNO₃ by silver nitrate, degraded to 2-thio-2,3,4,7-tetrahydro-1 H-imidazo[4,5-b]pyrazine 6 in a reaction with tert-butyl amine, and converted to 4,8-dihydro-4,8-dinitro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine-2,6- disulfonic acid 9 by nitric acid (100%) at −40°C. Denitration of the dinitramine 9 to give 4,8-dihydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 11 was brought about by methanolic hydrogen chloride in ether. In one run nitration without oxidation converted the salt 5 · 2HCl to the dinitrate salt of the 4,8-dinitro derivative 10 ; treatment with triethyl amine liberated the free base 10 from the salt. Degradation of 2,6-dioxo-1,3,4,5,7,8-hexanitrodecahydro-1H,5H-diimidazo[4,5-b:4′,5′-e]pyrazine 12 to 2-oxo-2,3-dihydro-1,3-dinitro-1H-imidazo[4,5-b] pyrazine 13 was brought about by hydrochloric acid. Treatment with lithium hydroxide also liberated 2,6-dioxodecahydro-1H,5H-diimidazo [4,5-b:4′,5′-e]pyrazine 3 from its dihydrochloride salt. Attempts to liberate 2,6-diiminodecahydro-1H, 5H-diimidazo[4,5-b:4′,5′-e]pyrazine 4 from its tetrahydrochloride salt led instead to intractable mixtures. The tetrahydrochloride salt 4 · 4HCl was converted to the dihydrochloride salt 4 · 2HCl in a reaction with tert-butyl amine.