Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Control of electron demand in the cycloadditions of 2(H)-1,4-oxazin-2-ones

3-Methoxy-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one 4, 3-methoxy-5-chloro-6-phenyl-2(H)-1,4-oxazin-2-one 5, 3-phenylsulfenyl-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one 6, and 3-phenylsulfenyl-5-chloro-6-phenyl-2(H)-1,4-oxazin-2-one 7, are ambident dienes and undergo Diels-Alder cycloadditions with electron neutral, rich and deficient dienophiles.     

Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.     

Design and synthesis of boron containing 2,4-disubstituted-phthalazin-1(2H)-one and 3,7-disubstituted-2H-benzo[b][1,4] oxazine derivatives as potential HGF-mimetic agents

We synthesized boron containing 2-(4-methoxybenzyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioaborolan-2-yl)phenyl) phthalazin-1(2H)-one 3 and 7-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-benzo[b][1,4] oxazine 8. The reaction of compound 2 with B₂pin₂ using potassium acetate as the base and Pd(PPh₃)₂Cl₂ as the catalyst, produced the corresponding boron-containing derivative 3 as a white solid in 65% yield. Alternatively, we have synthesized compound 8 as a yellow solid in 59% yield using the Miyaura borylation reaction. The potassium trifluoro(4-(-methyl-2H-benzo[b][1,4]oxazine-3-yl)phenylborate 9 was then obtained after treatment of 8 with aqueous solution of KF₂H in methanol as white solid product in 60% yield. The biological activities of the synthetic compounds are currently being evaluated.     

A non-catalytic regioselective approach to the synthesis of (E)-stilbenes from suitably functionalized 2H-pyran-2-ones

Highly functionalized (E)-stilbenes 3a-m and 4-aryl-6-styryl-pyran-2-ylidineacetonitriles 4a-b have been prepared and delineated through the ring transformation of 6-aryl-3,4-disubstituted-2H-pyran-2-ones 1 with commercially available (E/Z)-4-phenyl-3-buten-2-one 2 without the use of any catalyst.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Synthesis of 2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones by the domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates

2-Alkoxyiminoimidazolidines 2-3 react with acetylene dicarboxylates and ethyl phenylpropiolate to give 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones C, which subsequently undergo a sterically induced multihetero-retro-ene fragmentation to give imidazo[1,2-a]pyrimidin-5(1H)-ones 4-7 together with formaldehyde or benzaldehyde. On the other hand, a similar reaction of 2-3 with ethyl propiolate gives corresponding 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones 8-10. The unsubstituted imidazo[1,2-a]pyrimidin-5(1H)-one 11 can be prepared by retro-ene reaction of 9 upon prolonged heating in refluxing ethanol. A direct synthetic approach to 1-formyl-7-phenyl-imidazo[1,2-a]pyrimidine-5(1H)-one 14 is reported using DMF/sulfonyl chloride as a new Vilsmeier-type N-formylating reagent.     

A convenient one-pot synthesis of 2-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one derivatives and their further transformations

The trifluoromethyl containing heterocycles, 2-hydroxy-4-aryl-3-(thien-2-oyl)-2-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one derivatives 4, were synthesized via a one-pot three-component reaction of aldehyde 1 with 1,3-cyclohexanedione 2 and 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione 3 in the presence of a catalytic amount of Et₃N. The effect of bases and solvents on the reaction efficiency and yield was briefly investigated. Treatment of 4 with an excess amount of NH₄OAc in ethanol afforded 2-trifluoromethyl-1H-quinolin-5-one derivatives 5. Refluxing of 4 with TsOH in CHCl₃ gave the corresponding dehydrated products 8.     

Tri-component reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones: synthesis of 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino-[4,5-b:4,5-e]-4H-thiopyran-1,6-dione and 2-(4-cyanophenoxy) pyrimidine

Reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones with p-cyanophenol and 2-mercaptopyrimidine in the presence of base gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones 4-9, 2-(4-cyanophenoxy)pyrimidine (10) and 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]-4H-thiopyran-1,6-diones 11 as a novel heterocycle.     

Synthesis of substituted 3-(3-chloro-1H-pyrazol-5-yl)quinoxalin-2(1H)ones

Synthetic strategies to gain access to all four isomers of 3-(3-chloro-1H-pyrazol-5-yl)quinoxalin-2(1H)ones with monosubstituted benzo core (i.e., compounds 8a–d) are described. Preparation of these heterocyclic compounds succeeded starting from only two different substituted 2-nitroanilines (i.e., 3-methoxy- and 4-methoxy-2-nitroaniline) in three or five steps, respectively.     

Efficient stepwise and one pot three-component synthesis of 2-amino-4-(2-oxo-2H-chromen-3-yl)thiophene-3-carbonitriles

Environmentally benign conditions have been developed for the synthesis of 2-amino-4-(2-oxo-2H-chromen-3-yl)thiophene-3-carbonitriles (3) starting from 3-acetyl-2H-chromen-2-one (1) through the intermediacy of 2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)malononitrile (2) using the Knoevenagel condensation followed by the Gewald reaction. Alternatively, 3 could also be prepared in a one pot method by treating equimolar amounts of 1, malononitrile, and elemental sulfur. The merits of this preparation are mild reaction conditions, easy work-up procedure, and good yields.     

A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

Cycloaddition of methyl 2-(2,6-dichorophenyl)-2H-azirine-3-carboxylate to electron-rich 2-azadienes

tert-Butyldimethylsililoxy-2-aza-1,3-butadienes react with 2H-azirine 3 leading to Diels-Alder cycloadducts in moderate yields. The reactions are endo- and regioselective with the azirine being added by its less hindered face. There is only one product in the case of 1b, 4b. There are two isomers (4 and 5) from 1a, 1c and 1d. A different result was obtained with the diene 1e. Diene 1e formed products 4e and 8. Some of compounds 4 and 5 have been hydrolysed leading to functionalised aziridines 7. Compound 8 gave aziridine 9.     

Efficient synthesis of new 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones

The synthesis of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones 5, 6a-d from 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d is reported. The 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d were obtained from regiospecific bromination of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 1, 2a-d with molecular bromine. The NMR and X-ray diffraction data showed that 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones were brominated at 4-position in the pyrrolidin-2-one ring.     

A novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indoles and its application in the synthesis of Rizatriptan

In this study, a novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-indoles (8) is presented starting from (1H-1,2,4-triazol-1-yl)methanol (5) and indolines (6) under 98% H₂SO₄ at room temperature for 4–24 h, followed by deacetylation and dehydrogenation. Based on this finding, a novel route to synthesize Rizatriptan starting from tryptamine was designed and accomplished with 48.5% overall yield in 6 steps. Compared with operational art, the new route afforded higher yield and more pure products requiring no chromatographic purification, which may further be applied in industrialization.     

Reaction of (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile with N-arylisoindolines

In a multistep reaction, 3,3′-(2-aryl-2H-isoindol-1,3-ylene)-di-(1,4-naphthoquinone-2-carbonitriles) 13a-f have been formed in 25-61% yield from a series of N-arylisoindolines 8a-f with (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile (1) in aerated pyridine. The structure of one of these products (13f) has been unambiguously confirmed by a single crystal X-ray structure analysis. Under otherwise the same conditions, 2-(3-methoxyphenyl)-isoindoline (8g) and 1 gave 38% of [4-(2,3-dihydro-1H-isoindol-2-yl)-2-methoxyphenyl]-1,3-dioxoindan-2-ylidene)acetonitrile (15). Rationales for these conversions involving the known rearrangement of the radical anion of 1 into the radical anion of 1,4-naphthoquinone-2,3-dicarbonitrile (3) are presented.     

The reaction of 2-(1-hydropolyfluoro-1-alkenyl)-4H-3,1-benzoxin-4-ones with dinucleophilic reagents: a convenient route to fluoroalkylated nitrogen-containing tricyclic compounds

The reactions of 2-(1-hydropolyfluoro-1-alkenyl)-4H-3,1-benzoxin-4-ones (2) with hydrazine hydrate and phenyl hydrazine were investigated. The reaction of 2 with hydrazine hydrate in ethanol under reflux condition readily gave 2-fluoroalkyl-4H-pyrazolo[5,1-b]quinazolin-9-ones (3) in high yields. The reaction of 2 with phenyl hydrazine, however, resulted in the formation of 2-(2-phenyl-5-fluoroalkyl-2H-pyrazol-3-yl) benzoic acids (7). Further treatment of 7 with PPA gave 1-phenyl-4,9-dihydro-3-fluoroalkyl-1H-pyrozolo[3,4-b]quinolin-4-ones (4) in 65-80% overall yields.     

Unexpected dimerization during hydrogenation of 2-(2-pyridylmethylene)-3(2H)-benzofuran-3-ones

Palladium catalyzed hydrogenation of 2-(2-pyridylmethylene)-3(2H)-benzofuran-3-ones (1-3) gave besides the expected 2,α-dihydro products 8-10 pentacyclic dimers formed by an attack of a semihydrogenated species on the substrate.     

Regioselective synthesis of 3,4,6,7-tetrahydro-3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones through ascorbic acid catalyzed three-component domino reaction

An efficient, three-component domino reaction of dimedone 1, aromatic aldehydes (2a–o), and 1,3-cyclohexanedione 1a in the regio-selective synthesis of 3,3-dimethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-diones (3a–o) is reported. The desired product, 3 is efficiently promoted by ascorbic acid as an organo catalyst.