Synthesis, reactions and biological evaluation of some new naphtho[2,1-b]furan derivatives bearing a pyrazole nucleus

Vilsmeier formylation of 2-(1-phenylhydrazonoethyl)naphtho[2,1-b]furan (2) gave 3-naphtho[2,1-b]furan-2-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (3), which was reacted with C- and N-nucleophiles to afford naphthofuranpyrazol derivatives 4-8. Treatment of 2-[(3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene]-malononitrile (4a) with reactants having active hydrogen and Et?N gave the corresponding pyrazoline, pyran and chromene addition product derivatives 10, 12 and 13, consisting of three different connected heterocyclic moieties. Reaction of 1-((3-(naphtho[2,1-b]furan-2-yl)-1-phenyl-1H-pyrazol-4-yl) methylene)-2-phenylhydrazone (6b) with AcONa and ethyl bromoacetate or chloroacetone afforded the thiazolidinone and methylthiazole derivatives 14 and 15, respectively. In addition, intramolecular cyclization of 6d with Ac?O afford the corresponding 1,3,4-thiadiazol-2-yl acetamide derivative 16. The structures of the synthesized compounds were confirmed by IR, 1H-NMR/13C-NMR and mass spectral studies. Compound 14 showed promising effects against the tested Gram positive and negative bacteria and fungi.     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Structure,synthesis, and voltammetric investigation of 1-(quinolin-2-yl)-2-(pyran-2-yl)ethane-1,2-dione derivatives

By the XRD analysis the structure was established of 1-(7,8-dimethyl-4-chloroquinolin-2-yl)-2-[3,5-di(tert-butyl)-6-oxo-6H-pyran-2-yl]ethane-1,2-dione formed as a result of the oxidation of 3,5-di(tert-butyl)-6-[(Z)-2-(quinolin-2-yl)-1-hydroxyethen-1-yl]pyran-2-ones. By the cyclic voltammetry the oxidation of 1-(quinolin-2-yl)-2-(pyran-2-yl)ethane-1,2-dione derivatives was shown to proceed in two stages.     

Intramolecular capture of pummerer rearrangement intermediates. I. Synthesis of pyrrolo[2,1-c][1,4]benzothiazines

Treatment of 1-(2-alkylsulfinylphenyl)pyrroles with trifluoroacetic acid in refluxing toluene gives 4-substituted pyrrolo[2,1-c][1,4]benzothiazines in good yield when the alkyl group bears an electron withdrawing substituent on the α-carbon. In the absence of such a group, starting material is recovered. The sulfoxides are prepared by oxidation (mCBPA) of the corresponding sulfide. The sulfides are prepared from 2-aminobenzenethiol either by S-alkylation followed by conversion to the pyrrole using 1,4-dimethoxytetrahydrofuran in glacial acetic acid or by S-alkylation of 1-(2-phenylmercapto)pyrrole followed by oxidation to the sulfoxide.     

Bacterial dioxygenase- and monooxygenase-catalysed sulfoxidation of benzo[b]thiophenes

Asymmetric heteroatom oxidation of benzo[b]thiophenes to yield the corresponding sulfoxides was catalysed by toluene dioxygenase (TDO), naphthalene dioxygenase (NDO) and styrene monooxygenase (SMO) enzymes present in P. putida mutant and E. coli recombinant whole cells. TDO-catalysed oxidation yielded the relatively unstable benzo[b]thiophene sulfoxide; its dimerization, followed by dehydrogenation, resulted in the isolation of stable tetracyclic sulfoxides as minor products with cis-dihydrodiols being the dominant metabolites. SMO mainly catalysed the formation of enantioenriched benzo[b]thiophene sulfoxide and 2-methyl benzo[b]thiophene sulfoxides which racemized at ambient temperature. The barriers to pyramidal sulfur inversion of 2- and 3-methyl benzo[b]thiophene sulfoxide metabolites, obtained using TDO and NDO as biocatalysts, were found to be ca.: 25-27 kcal mol(-1). The absolute configurations of the benzo[b]thiophene sulfoxides were determined by ECD spectroscopy, X-ray crystallography and stereochemical correlation. A site-directed mutant E. coli strain containing an engineered form of NDO, was found to change the regioselectivity toward preferential oxidation of the thiophene ring rather than the benzene ring.     

Synthesis and antimicrobial activity of some new pyrazole, fused pyrazolo[3,4-d]-pyrimidine and pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidine derivatives

Hydrazonyl bromides 2a,b reacted with active methylene compounds (dibenzoylmethane, acetylacetone, ethyl acetoacetate, phenacyl cyanide, acetoacetanilide, ethyl cyanoacetate, cyanoacetamide and malononitrile) to afford the corresponding 1,3,4,5- tetrasubstituted pyrazole derivatives 5-12a,b. Reaction of 12a,b with formamide, formic acid and triethyl orthoformate give the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4- d]pyrimidin-4(3H)one and 5-ethoxymethylene-aminopyrazole-4-carbo-nitrile derivatives 13-15a,b, respectively. Compounds 15 a,b reacted with benzhydrazide and hydrazine hydrate to afford pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine and [4-iminopyrazolo- [3,4-d]pyrimidin-5-yl]amine derivatives 16 a,b and 17 a,b. Reactions of compounds 17 a,b with triethyl orthoformate and carbon disulfide give the corresponding pyrazolo[4,3-e]- [1,2,4]triazolo[1,5-c]pyrimidine derivatives 18a,b and 19 a,b, respectively.     

Parallel solution-phase synthesis of 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines

A simple and straightforward methodology for the parallel, solution-phase synthesis of novel 4-dialkylamino-2-methylsulfonyl-6-vinylpyrimidines 9a-j has been developed. Starting from 2-methylthio-6-[2-(p-toluensulfonyloxy)ethan-1-yl]-4(3H)-pyrimidinone (6), a three-step procedure (namely, tosylate substitution by amines, base-catalyzed rearrangement, and sulfide to sulfone oxidation) using a Buchi Sincore synthesizer gave the final products in high yield after simple ethyl acetate extraction and without further purification. Interestingly, when the final oxidation step was performed on 4-arylpiperazine derivatives 8g-j, the corresponding highly polar piperazine N-oxides 9g-j were obtained, which conversely needed chromatographic purification in order to give the pure products.     

Features of the reaction of 4-bromobut-2-enylphosphonium salts with monosubstituted hydrazines

(4-Bromobut-2-en-1-yl)triphenylphosphonium bromide reacted with phenylhydrazine at 2°C in the presence of sodium carbonate to form triphenyl[4-(2-phenylhydrazinylidene)but-2-en-1-yl]phosphonium bromide in 62% yield. The obtained N-phenylhydrazine derivatives cyclized into the corresponding pyrazoline derivatives of phosphonium salts. Unlike phenylhydrazine, ethylhydrazine reacted with (4-bromobut-2-ene-1-yl)triphenylphosphonium bromide under the same conditions to afford triphenyl[(1-ethyl-4,5-dihydro-1Hpyrazol-3-yl)methyl]- and -[(1-ethyl-1H-pyrazol-3-yl)methyl]phosphonium bromides in yields of 60 and 40%.     

Synthesis of 7-azabicyclo[2.2.1]heptane and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives by base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides, investigating the effect of the nitrogen protecting group and the relative configuration of the leaving group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11, 13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been carried out to rationalize the formation of the different adducts.     

Synthesis of New 4,5-Dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-amine–Derived Ureas and Their Anticancer Activity

A new series of 1,2,4-triazolo[4,3-a]-quinoline derivatives were designed and synthesized to meet the structural requirements essential for anticancer activity. N-1-(5-Methylisoxazol-4-yl/4-fluoro-2,3-dihydro-1H-inden-1-yl/aryl)-N’-3-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl) urea derivatives were accomplished in good yields by the reaction of 4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-amine with 3-(3-chloro-5-fluoro-2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylic acid, 4-fluoro-2,3-dihydro-1H-indene-1-carboxylic acid, and various simple aromatic carboxylic acids in the presence of diphenyl phosphoryl azide (DPPA). All the newly synthesized title compounds were characterized by elemental and spectral data. Furthermore, anticancer activity was screened for the title compounds (12a–j) in vitro against human neuroblastoma cell lines (SK N SH) and human colon carcinoma cell lines (COLO 205) by using the MTT cell viability method. A few of them (12a and 12b) possess significant cytotoxicity, and some other compounds 12d-f and 12j displayed moderate cytotoxicity against both cell lines.     

Synthesis, docking studies and biological evaluation of benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives on 5-HT1A serotonin receptors

A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl)-propan-1-one derivatives 6a-f, 7a-f and their corresponding alcohols 8a-f were synthesized and evaluated for their affinity towards 5-HT(1A) receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl)-3-(4-(pyridin-2-yl)piperazin-1-yl)propan-1-one (7e) displayed micromolar affinity (K(i) = 2.30 μM) toward 5-HT(1A) sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.     

Modifications of 5,12-dihydroindolo[3,2-a]carbazole scaffold via its regioselective C2,9-formylation and C2,9-acetylation

The effective approaches for regioselective double formylation and acetylation of 5,12-dialkyl-6,7-diaryl-substituted 5,12-dihydroindolo[3,2-a]carbazoles by their treatment with dichloromethyl methyl ether in the presence of SnCl₄ or with acetyl chloride in the presence of AlCl₃ to afford the 2,9-diformyl or 2,9-diacetyl derivatives, respectively, were developed. Furthermore, new 2,9-bis(2,2-dicyanovinyl) derivatives were synthesized by the Knoevenagel condensation of diformyl-containing substrates with malononitrile, when new 2,9-bis(quinoxaline-2-yl)- and 2,9-bis(benzo[g]quinoxaline-2-yl) derivatives were formed via microwave-promoted oxidation of diacetyl-containing substrates with SeO₂ to the corresponding diglyoxals, followed by the reaction of these intermediates with o-phenylendiamine or 2,3-diaminonaphthalene, respectively. The basic optical and electrochemical properties of some 5,12-dihydroindolo[3,2-a]carbazoles were investigated.     

Synthesis of soluble and thermally stable polyimides from unsymmetrical diamine containing 2,4,5-triaryl imidazole pendent group

A novel unsymmetrical diamine monomer containing triaryl imidazole pendant group, 4-[4-(4,5-diphenyl-1H-imidazol-2-yl)phenoxy] benzene-1,3-diamine (DAI), was successfully synthesized via aromatic substitution reaction of 1-chloro-2,4-dinitrobenzene with 4-(4,5-diphenyl-1H-imidazol-2-yl)phenol, followed by palladium-catalyzed hydrazine reduction. The diamine monomer DAI polymerized with commercial available dianhydrides such as benzophenone tetracarboxylic dianhydride (BTDA), pyromellitic dianhydride (PMDA) and bicyclo[2.2.2]-oct-7-ene-2,3,5,6-tetracarboxylic dianhydride (BCDA) by using two step synthetic methods to obtain corresponding polyimides (PIs). PIs had inherent viscosity of 0.42-0.51 dL/g and exhibited excellent solubility in aprotic polar solvents such as N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), pyridine and methyl sulfoxide (DMSO). PIs showed high glass transition temperatures between 230 and 320 °C, and they were fairly stable up to a temperature above 300 and 450 °C depending on the dianhydride monomer used for the PIs preparation.     

Elongation of the pi-system of phthalocyanines by introduction of thienyl substituents at the peripheral beta positions. Synthesis and characterization

1,4,8,11,15,18,22,25-octabutoxyphthalocyanines ((OBu)8Pcs) having eight 2-thienyl (1) and [2,2'-bithiophene]-5-yl (2) groups at beta positions and their zinc(II) and cobalt(II) derivatives were prepared from 2-thienyl- (3) or [2,2'-bithiophene]-5-yl (4)-substituted phthalonitriles in moderate to good yields. The electronic absorption spectra of the Pcs showed red-shifted Q-bands relative to beta-unsubstituted (OBu)8Pcs. The longer substituent, the [2,2'-bithiophene]-5-yl group, is more effective than the 2-thienyl group in enlarging the pi-conjugated system of the Pcs. The ring oxidation potential obtained by cyclic voltammetry shifted cathodically with increasing chain length, indicating destabilization of the HOMOs. Due to the shift of the Q-band, 2-thienyl- and [2,2'-bithiophene]-5-yl-substituted Pcs exhibit a remarkable color change from the original green color.     

One-pot synthesis and characterization of a chromophore--donor--acceptor assembly

The acid-functionalized tris-heteroleptic chromophore--donor--acceptor assembly [RuII(bpyCOOH)(bpyCH2PTZ)(bpyCH2MV2+)](PF6)4]4+ (1) (bpyCOOH = 4'-methyl-2,2'-bipyridine-4-carboxylic acid; bpyCH2PTZ = 10-((4'-methyl-2,2'-bipyridin-4-yl)methyl)phenothiazine; bpyCH2MV2+ = 1-((4'-methyl-2,2'-bipyridin-4-yl)methyl)-1'-methyl- 4,4'-bipyridinediium) was synthesized in a one-pot reaction by careful selection of the order of ligand addition to RuCl2(DMSO)4 (DMSO = dimethyl sulfoxide). The success of this method was based upon separation and isolation of 1 from mixtures containing ligand-scrambled products by cation exchange chromatography. Metal-to-ligand charge-transfer (MLCT) excitation in acetonitrile at 464 nm was followed by intramolecular electron transfer to give a redox-separated state [RuII(bpyCOOH)(bpyCH2PTZ.+)(bpyCH2MV.+)]4+ with an efficiency of eta RS = 0.35 +/- 0.05.     

Synthetic studies directed towards asmarines; construction of the tetrahydrodiazepinopurine moiety by ring closing metathesis

Asmarines are tetrahydro[1,4]diazepino[1,2,3-g,h]purine derivatives isolated from marine sponges (Raspailia sp). They possess profound cytotoxic activity towards cancer cell lines, and are thus attractive synthetic targets. The tetrahydrodiazepinopurine ring skeleton has been prepared employing the RCM reaction on Boc-protected 6-allylamino-7-(propen-1-yl)purine as the key step for the construction of the seven-membered ring. 7-(Propen-1-yl)purines were formed by a novel rearrangement of 7-allylpurines under basic conditions. Boc-protected N⁶,7-diallylpurine also participated in RCM to give the eight-membered ring analog of the diazepinopurine.     

Synthesis and transformations of 1-(1,3-butadien-1-yl)benzotriazoles

1-[α-(Phenylthio)alkyl]benzotriazoles were converted into the corresponding 1-(1,3-butadien-1-yl)benzotriazoles in good yields by one-pot sequential reactions with (i) lithium diisopropylamide, (ii) allyl bromide or cinnamyl chloride, and (iii) potassium t-butoxide. Diels-Alder and hetero [4 + 2] cycloadditions of 1-(1,3-butadien-1-yl)benzotriazoles and some transformations of their α-lithio derivatives were studied.     

The homologous tert-amino effect: a route to fused 2-benzazepine derivatives

2-Cyano- and 2-carbethoxy-3-[2-(pyrrolidin-1-ylmethyl)phenyl]acrylonitriles were prepared through either amination of appropriate 3-[2-(bromomethyl)phenyl]acrylonitriles with pyrrolidine or condensation of 2-(pyrrolidin-1-ylmethyl)benzaldehyde with malononitrile and ethyl cyanoacetate. These acrylonitrile derivatives were shown to undergo easy mutual interconversion with 1-(pyrrolidin-1-yl)indane-2-carbonitriles driven by solvent polarity. Upon heating at 140-150 °C both acrylonitrile and indane derivatives were found to give 2,3,5,10,11,11a-hexahydro-1H-pyrrolo[1,2-b][2]benzazepine-11-carbonitriles. All transformations observed were rationalized in the terms of reactions related to the tert-amino effect. Furthermore, the corresponding piperidin-1-yl and azepan-1-yl analogs of the above acrylonitriles and indanes were obtained similarly. By analogy their heating afforded 1,2,3,4,6,11,12,12a-octahydropyrido[1,2-b][2]benzazepine-12-carbonitriles and 7,8,9,10,11,11a, 12,13-octahydro-5H-azepino[1,2-b][2]benzazepine-12-carbonitriles.     

Efficient Synthesis of Novel 3-[5-(1H-Benzimidazol-2-Ylmethanesulfonyl)-4-Phenyl-4H-(1,2,4)Triazol-3-Yl]-1H-(1,8)Naphthyridin-4-One Derivatives

Abstract

of 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbohydrazide (4) with substituted phenyl isothiocyanates (5) in ethanol under reflux for 30 min gave thiosemicarbazide derivatives 6, which on cyclization in 2N NaOH under refluxing conditions for 1 h resulted in 3-(5-mercapto- 4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (7). Alternatively, 7 could also be prepared from following sequence of reactions, i.e., 4 → 8 → 7. In another sequence of reactions, condensation of 7 with chloroacetic acid in dimethylformamide (DMF) and K₂CO₃ as a mild base at 120 °C for 2 h resulted in 2-((5-(1,4-dihydro-4-oxo-1,8-naphthyridin-3-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl)acetic acid (10). The latter, on reaction with substituted o-phenylenediamine (11) in 6N HCl for 4 h yielded 3-(5-((1H-benzo[d]imidazol-2-yl)methylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)-1,8-naphthyridin-4(1H)-one (12). Alternatively, 12 could also be prepared by reacting 7 with 13 in DMF and K₂CO₃ as a mild base at 120 °C for 2 h, followed by oxidation with H₂O₂ resulting in the corresponding sulfonyl derivatives 14.     

Synthesis of 6H-pyrrolo[3',4':2,3][1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H)-diones using 3-bromo-4-(indol-1-yl)maleimide scaffold

Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)maleimides and bis(indol-1-yl)maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-1-yl)maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.