Synthesis of 2-Aryl-3-hydroxy-4,9-dihydrocyclohepta[b]pyran-4,9-diones

3-(2-Bromoacetyl)tropolone ( 1 ) reacted with benzaldehydes 2a-g in the pressence of alkali at low temperature to give 2-aryl-3-hydroxy-4,9-dihydrocyclohepta[b]pyran-4,9-diones 3a-g in good yields.     

A New and simple synthesis of 2-aryl-4,9-dihydrocyclohepta[b]pyran-4,9-diones

3-Acetyltropolone ( 1 ) reacted with 2-methoxybenzaldehyde ( 2a ) in the presence of ethyl orthoformate and perchloric acid to afford 2-(2-methoxyphenyl)-4,9-dihydrocyclohepta[b]pyran-4,9-dione ( 3a ). The reactions with 3,4-dimethoxybenzaldehyde ( 2b ), vanillin ( 2c ), and piperonal ( 2d ) gave respectively the corresponding products 3b-d . The reaction with benzaldehyde ( 2e ) gave uncyclized 3-cinnamoyltropolone ( 4 ).     

Synthesis and reactions of 1,3-dicarbonyl-substituted troponoids: Conversion to tropolones having an isoxazole or a pyrazole ring

3-Acetyltropolone ( 1 ) was treated with diethyl oxalate in the presence of sodium ethoxide to afford 3-(2-ethoxalyl-1-oxoethyl)tropolone ( 2 ) as a minor product and its cyclized 2-ethoxycarbonyl-4,9-dihydrocyclohetpa[b]pyran-4,9-dione ( 3 ) as the major one. The former was readily converted to the latter. Then, as a stable synthon bearing a 1,3-dicarbonyl group, 2-(2-ethoxalyl-1-oxoethyl)-7-methylaminotropone ( 5 ) was prepared. The reactions of compound 5 with hydroxylamine, hydrazine, and methylhydrazine were carried out to give troponoids possessing an isoxazole or a pyrazole ring. The parent compounds, 3-(3-pyrazolyl)tropolone ( 13 ) and 3-(1-methylpyrazol-3-yl)tropolone ( 21 ), were obtained via hydrolysis and decarboxylation. Similarly, 2-ethoxycarbonyl-4,9-dihydrocyclohepta[b]pyran-4,9-dione ( 3 ) reacted with hydroxylamine, hydrazine, and methylhydrazine to yield troponoids possessing a heterocyclic ring.     

Synthesis and reactions of halo-, nitro-, and arylazo-substituted 3-cinnamoyltropolones. Formation of styryl-substituted heterocycle-fused troponoid compounds

3-Cinnamoyltropolone ( 1 ) reacted with bromine to afford 7-bromo- ( 2 ), 5,7-dibromo-3-cinnamoyltropolone ( 3 ), and 6,8-dibromo-4,9-dihydrocyclohepta[b]pyrane-4,9-dione ( 4 ) according to amount of the reagent. Iodination and nitration of 1 gave respectively 7-iodo- ( 5 ) and 5-nitro-3-cinnamoyltropolone ( 6 ). Azo-coupling reactions gave 5-arylazo-3-cinnamoyltropolones 7a-f . Compounds 1, 2, 3 and 5 reacted with hydroxylamine to give 3-styryl-8H-cyclohept[d]isoxazol-8-ones 10-13 , while 6 and 7a gave 5-nitro-3-styryl-8H-cyclohept[d]-isoxazol-8-one oxime ( 14 ) and 2-cinnamoyl-7-methoxy-4-phenylazotropone ( 15 ), respectively. The reactions of 1,3 , and 5 with phenylhydrazine gave 3-styryl-1,8-dihydrocycloheptapyrazol-8-ones 16-19 .     

Nucleophilic substitutions of 2-chloronaphtho[2,3-b]furan-4,9-dione with amines

2-Chloronaphtho[2,3-b]furan-4,9-dione 4 was allowed to react with pyrrolidine to produce 2-(1-pyrrolidinyl)naphtho[2,3-b]furan-4,9-dione 8 in 64% yield. In a similar manner, the reaction of 4 with cyclic amines (piperidine, morpholine, 4-substituted piperazines, etc.) gave the desired compounds. 2-Dimethylaminonaphtho[2,3-b]furan-4,9-dione 20 and 2-propylaminonaphtho[2,3-b]furan-4,9-dione 23 were obtained from the reactions of 4 with amines in 67% and 48% yields, respectively. Furthermore, the reactions of 4 with acyclic amines (diethylamine, dipropylamine, isopropylamine, butylamine, etc.) gave the desired compound. Compound 4 was treated with sodium azide to give 2-azidonaphtho[2,3-b]furan-4,9-dione 28 in 42% yield. All these nucleophilic substitutions were carried out at room temperature. It was found that 4 showed high reactivity for amines. Unexpectedly, 2-morpholinonaphtho[2,3-b]furan-4,9-dione 13 was obtained from the reaction of 4 with 1-morpholino-1-cyclohexene.     

A new synthetic route to 2-substituted naphtho[2,3-b]furan-4,9-dione2-Substituted Naphtho[2,3-b]furan-4,9-dione

4,9-Dimethoxynaphtho[2,3-b]furan 9 was obtained in 91% yield via the reductive methylation of naphtho[2,3-b]furan-4,9-dione 2 . After treatment of 9 with butyllithium, the mixture was allowed to react with N,N-dimethylacetamide, followed by oxidization with cerium(IV) diammonium nitrate to give 2-acetylnaphtho[2,3-b]furan-4,9-dione 1 . 2-Formylnaphtho[2,3-b]furan-4,9-dione 13 and 2-trimethylsilyl-naphtho[2,3-b]furan-4,9-dione 14 were also obtained from 9 by a similar method. The halodesilylations of 14 easily gave 2-iodonaphtho[2,3-b]furan-4,9-dione 16 , 2-bromonaphtho[2,3-b]furan-4,9-dione 17 , and 2-chloronaphtho[2,3-b]furan-4,9-dione 18 in 82%, and 93% and 83% yield, respectively. Furthermore, the nitrodesilylation of 14 gave 2-nitronaphtho[2,3-b]furan-4,9-dione 3 in 77% yield.     

3-methylthio-1,2-dithiolylium salts : Reaction with 4-hydroxy-6-methyl-2H-pyran-2-one and 4-hydroxycoumarin

The reaction of 4- and 5-aryl-3-methylthio-1,2-dithiolylium iodides with 4-hydroxy-6-methyl-2$\text{H}$-pyran-2-one and 4-hydroxycoumarin has been studied. 4-Substituted salts yielded 3-aryl-7-methyl-2-thioxo-2$\text{H}$,5$\text{H}$-pyrano [3,2-c]pyran-5-ones and 3-aryl-2-thioxo-2H,5H-pyrano[3,2-c]benzo[e]pyran-5-ones, respectively, whereas 5-substituted salts gave rise to 3-(5′-aryl-1′,2′-dithiol-3′-ylidene)-6-methyl-2$\text{H}$-pyran-2,4-diones and 3-(5′-aryl-1′,2′-dithiol-3′-ylidene)-2$\text{H}$-benzo [b]-pyran-2,4-diones.     

A facile synthesis of novel 1-aryl-1H-pyrazolo[3,4-b]quinoxalines

The reactions of 3-methyl-2-oxo-1,2-dihydroquinoxaline 3 with chlorophenyl diazonium salts afforded the hydrazones 4a-c , whose chlorinations with phosphoryl chloride gave the dichlorides 5a-c . Refluxing of the dichlorides 5a-c and base in N,N-dimethylformamide provided the 1-aryl-1H-pyrazolo[3,4-b]quinoxalines 6a-c .     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones VII. Synthesis of 2H,5H-[1]benzothiopyrano[4,3-b]pyran and 2H,5H-thiopyrano[4,3-b]pyran derivatives

The dipolar 1,4-cycloaddition of dichloroketerie to N,N-disubslituled 3-aminomethylene-2,3-dihydro-4-thiochromanones and 3-aminomethylenetelrahydro-4-thiopyranones gave N,N-disubstituted 4-amino-3,3-diehloro-3,4-dihydro-2H,5H-[1]benzolhiopyrano[4,3-b]pyran-2-ones and 4-amino-3,3-dichloro-3,4,7,8-tetrahydro-2H,5H-thiopyrano[4,3-b]pyran-2-ones, respectively, only in the ease of aromatic or strong hindering aliphatic N-substitution. The adducts gave N,N′-disubstituted 4-amino-3-chloro-2H,5H-[1]benzothiopyrano[4,3-b]pyran-2-ones and 4-amino-3-chloro-7,8-dihydro-2H,5H-thiopyrano[4,3-b]pyran-2-ones, respectively, by dehydro-chlorination with DBN. By chromatography on neutral alumina, 3-(2,2-dichloroethylidene)-2,3-dihydro-4-thiochromanone was isolated as an unstable liquid from the reaction between dichloroketerie and 3-diethylaminornethylene-2,3-dihydro-4-thiochromanone.     

A convenient synthesis of 3-aryl-4H- Benzopyrano[3,4-d]isoxazol-4-ones

Regioselective 1,3-dipolar cycloaddition of nitrile oxides 5a-c to ethyl o-hydroxycinnamate (3) gave the corresponding ethyl trans-3-aryl-4,5-dihydro-5-(2-hydroxyphenyl)-4-isoxazolecarboxylates 6a-c . Their structure was confirmed by reductive cleavage to 1 and compounds 9a-c . Compounds 6a-c afforded upon heating in the presence of pyridine the 3-aryl-4H-[1]benzopyrano[3,4-d]isoxazol-4-ones 11a-c . Compound 10c was also isolated from 6c and transformed thermally into 11c .     

Photocyclization of 2-[1]benzothien-3-yl)-3-phenylpropenoic acids

Photocyclization of the substituted 2-([1]benzothien-3-yl)-3-phenylpropenoic acids 3a-c in the presence of iodine and air in a benzene-cyclohexane mixture afforded a separable mixture of three compounds, benzo[b]naphtho[2,1-d]thiophene-6-carboxylic acids 4a-c , 6H-benzo[b]naphtho[2,3-d]thiopyran-6-ones 5a-c , and 10-methoxy-2-methyl-6H-benzo[b]naphtho[2,3-d]pyran-6-one ( 6 ).     

Three-Component Spiro Heterocyclization of Pyrrolediones with Malononitrile and Cyclic Enols

Ethyl 4,5-dioxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates reacted with malononitrile and five-membered cyclic enols, indan-1,3-dione and cyclopentane-1,3-dione to give 1-substituted ethyl 2-amino-3- cyano-2′,5-dioxo-5′-phenyl-1′,2′-dihydro-5H-spiro[indeno[1,2-b]pyran-4,3′-pyrrole]-4′-carboxylates and ethyl 2-amino-3-cyano-2′,5-dioxo-5′-phenyl-1′,2′,6,7-tetrahydro-5H-spiro[cyclopenta[b]pyran-4,3′-pyrrole]-4′-carboxylates, respectively.     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

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.     

Synthesis of new furopyrans and angularly fused furopyranochromenes from 3-arylmethylidenefuran-2-ones

Reactions of 5-aryl-3-arylmethylidenefuran-2-ones with malononitrile gave 6-amino-2,4-diaryl-4Hfuro[2,3-b]pyran-5-carbonitriles and 2-aryl-5-imino-5H,11bH-furo[3′,2′: 5,6]pyrano[3,4-c]chromen-6-amines as potentially biologically active substances.     

Reactions of 3-acetyltropolone with benzaldehydes in trimethyl orthoformate in the presence of perchloric acid: Synthesis of 2-aryl-4-methoxy-9-oxocyclohepta[b]pyrylium perchlorates

3-Acetyltropolone ( 1 ) reacted with benzaldehydes in trimethyl orthoformate in the presence of perchloric acid to afford 2-aryl-4-methoxy-9-oxocyclohepta[b]pyrylium perchlorates 3a-c in 25–37% yields. From the filtrates, 3-(3,4-diaryl-3-butenoyl)tropolones 4a,b and 3-(2-methoxycinnamoyl)tropolone ( 5 ) were also isolated.     

Design and synthesis of novel quinoline derivatives bearing oxadiazole,isoxazoline, triazolothiadiazole,triazolothiadiazine, and piperazine moieties

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1 , which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4 , 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c , respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7 . Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c . Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 , 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c . Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.     

A facile synthesis of 2-acetylnaphtho[2,3-b]furan-4,9-dione

Reaction of the parent naphtho[2,3-b]furan-4,9-dione 2 with various electrophilic reagents was difficult, and only nitration of 2 gave small amounts of 2-nitronaphtho[2,3-b]furan-4,9-dione 4 . Then 2-acetylnaphtho[2,3-b]furan-4,9-dione 1 was not obtained by the acetylation of 2 . On the other hand, compound 1 that is isolated from Tabebuia Cassinoides and has cytotoxic activity, was obtained from 3-lithiofuran in five steps.     

Condensed Isoquinolines. 15. Synthesis of 5,10-Dihydro[1,2,4]triazolo[1,5-b]isoquinolines and Related Spiranes

Condensation of o-bromomethylphenylacetonitrile with arylcarbohydrazides gave, depending on the reaction conditions, 2-arylcarboxamido-1,4-dihydroisoquinoline-3(2H)-imine hydrobromides or 2-aryl-5,10-dihydro[1,2,4]triazolo[1,5-b]isoquinolines. Analogous condensation of 4-(2-bromomethylphenyl)tetrahydro-2H-pyran-4-carbonitrile and 1-(2-bromomethylphenyl)-1-cyclopentanecarbonitrile with arylcarbohydrazides gave respectively 2-aryl-2,3,5,6-tetrahydrospiro[4H-pyran-4,10'(5'H)-[1,2,4]triazolo[1,5-b]isoquinolines and 2-arylspiro[1,2,4]triazolo[1,5,b]isoquinoline-10(5'H)-1'-cyclopentanes, derivatives of new spirane heterocycles. The reaction with condensing agents of 3-imino-2,2',3,3'5',6'-hexahydrospiro[isoquinoline-4(1H),4'-4H-pyran]-2-amine and 3-imino-2,3-dihydrospiro[isoquinoline-4(1H),1'-cyclopentane]-2-amine hydrobromides, synthesized from the corresponding bromo nitriles and hydrazine, may serve as an alternative route for the synthesis of these compounds. The structure of obtained triazoloisoquinolines was established from IR, ¹H and ¹³C NMR spectra. An X-ray crystallographic study of 2-phenylspiro[1,2,4]triazolo[1,5-b]isoquinoline-10(5H),1'-cyclopentane was carried out.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVII. Synthesis of 2H-[1]benzothiepino[5,4-b]pyran derivatives

1,4-Cycloaddition of dichloroketene to a number of N,N-disubstituted (E)-4-amino methylene-3,4-dihydro-[1]benzothiepin-5(2H)-ones gave in excellent yield N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-[1]benzothiepino[5,4-b]pyran-2-ones III, which are derivatives of the 2H-[1]benzothiepino[5,4-b]pyran system. Dehydrochlorination of III with DBN afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-[1]-benzothiepino[5,4-b]pyran-2-ones, generally in excellent yield.