Regioselective cyclocondensation of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates with thiazolylhydrazines

Ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates reacted in a regioselective fashion with thiazolylhydrazines to give the corresponding ethyl 1-thiazolyl-5-fluoroalkyl-1H-pyrazole-4-carboxylates. The product structure was determined on the basis of NMR and X-ray diffraction data.     

A new synthetic route to substituted 1-fluoro-1-cyclopropanecarboxylates

Substituted 6-fluoro-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylates were obtained as a mixture of the exo- and endo-isomers by reaction of substituted 6,8-dioxo-2,3,7-triazabicyclo[3.3.0]oct-3-en-4-carboxylates with N-fluoropyridinium tetrafluoroborate.     

Reactivity of 2-halo-2H-azirines. Part 3: Dehalogenation of 2-halo-2H-azirine-2-carboxylates

The dehalogenation of 2-halo-3-phenyl-2H-azirine-2-carboxylates is described. Using sodium borohydride and tributyltin hydride 3-phenyl-2H-azirine-2-carboxylates were obtained in moderate yields. The synthesis of a new 2-bromo-2H-azirines with a chiral auxiliary, 10-phenylsulfonylisobornyl 2-bromo-3-phenyl-2H-azirine-2-carboxylate, is reported. Its dehalogenation led to 10-phenylsulfonylisobornyl 2H-azirine-2-carboxylate as single stereoisomer together with the formation of 10-phenylsulfonylisobornyl acetate.     

Studies on the synthesis of orthogonally protected azalanthionines,and of routes towards β-methyl azalanthionines,by ring opening of N-activated aziridine-2-carboxylates

Orthogonally protected azalanthionines were successfully synthesised by the ring-opening of N-activated aziridine-2-carboxylates with protected diaminopropanoic acids (DAPs). The required DAPs were also prepared by ring-opening of N-activated aziridine-2-carboxylates with para-methoxybenzylamine, but it was found that the choice of aziridine protecting groups dictated both the success of the reaction as well as the regioselectivity of the isolated products. Attempts to extend the methodology to the preparation of the more sterically demanding β-methyl azalanthionines have, so far, been unsuccessful.     

Reaction of methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrrole-2-carboxylates with arylhydrazines. synthesis of isomeric 5-arylcarbamoyl-4-aroyl- and 5-aryl-4-aryloxamoyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazoles

Methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with arylhydrazines to give methyl 3-aroyl-1-aryl-2-(2-arylhydrazinyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates which underwent thermal recyclization into isomeric methyl 1-aryl-5-(arylcarbamoyl)-4-aroyl-1H-pyrazole- 3-carboxylates and methyl 1,5-diaryl-4-[2-oxo-2-(arylamino)acetyl]-1H-pyrazole-3-carboxylates.     

New approaches to polysubstituted pyrroles and pyrrolinones from α-cyanomethyl-β-ketoesters

In this present paper, we report the efficient, regioselective one-pot synthesis of 5-alkoxy and 5-alkylsulfanylpyrrole-3-carboxylates in high yields via the zinc perchlorate-catalyzed addition of alcohols and thiols to the nitrile carbon of α-cyanomethyl-β-ketoesters followed by annulation. The addition-annulation process is undertaken in aqueous solution to give 4,5-dihydro-5-oxo-1H-pyrrole-3-carboxylates (pyrrolinones) in good yields. These 4,5-dihydro-5-oxo-1H-pyrrole-3-carboxylates are also obtained by the hydrolysis of 5-alkoxypyrrole-3-carboxylates.     

Microwave assisted synthesis of some new thiazolopyrimidine, thiazolodipyrimidine and thiazolopyrimidothiazolopyrimidine derivatives with potential antioxidant and antimicrobial activity

Biginelli reaction of ethyl acetoacetate, thiourea and the appropriate aromatic aldehyde was used to produce ethyl 4-aryl-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylates, that reacted with bromomalononitrile to give ethyl 3-amino-5-aryl-2-cyano-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylates rather than the isomeric 7H-thiazolo[3,2-a]pyrimidines. Thiazolopyrimidine derivatives reacted with carbon disulphide to yield ethyl 9-aryl-7-methyl-2,4-dithioxo-2,3,4,9-tetrahydro-1H-thiazolo[3,2-a:4,5-d']dipyrimidine-8-carboxylates, that reacted with phenacyl bromide to produce ethyl 8-methyl-10-(4-methoxyphenyl)-3-substituted-5-thioxo-2(un)subatituted-10H-thiazolo[3',2':1',2']pyrimido[4',5':4,5]thiazolo[3,2-a]pyrimidine-9-carboxylates. The aforementioned reactions were carried out using both conventional chemical methods and with the assistance of microwave irradaition. Comparison between both methods showed that the microwave assisted method is preferable because of the time reduction and yield improvements achieved. The new compounds were tested for their biological activity as antioxidants, antibacterial or antifungal agents. Some of the new compounds were found to have moderate to good antioxidant and antimicrobial activities.     

HPLC-MS/MS identification of tryptophan-derived tetrahydro-β-carboline derivatives in food

Based on electrospray ionization – tandem mass spectrometry coupled to liquid chromatography (HPLC-ESI-MS/MS) a method for separation and selective detection of 1,2,3,4-tetrahydro-β-carboline derivatives (THC) was developed. Retro-Diels Alder (RDA) fragmentation of the tetrahydropyrido moiety resulted in the characteristic neutral loss of 73 amu for tryptophan-derived THC-3-carboxylates. Accordingly, Pictet-Spengler condensation products of tryptamin exhibited product ions formed by loss of 29 amu. However, THC-1-carboxylates as obtained by reaction of tryptamin with α-oxo acids also yielded product ions [M+H-73]⁺, apparently originating from the combination of RDA-cleavage plus subsequent decarboxylation. As result, one had to consider the possibility of false-positive identification of THC-3-carboxylates in presence of isomeric THC-1-carboxylates. In order to overcome these analytical pitfalls, the unequivocal identification of trace amounts of THC-3-carboxylates by HPLC-MS/MS required the chromatographic separation of isomeric THC prior to selected reaction monitoring (SRM). Utilizing SRM, limits of detection for various THC were established in the 10 ng mL^–1 range. Subsequent analysis of food samples like seasoning sauce and yeast extract by HPLC-ESI-MS/MS revealed the presence of tryptamin-derived 1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid, 1-methyl-tetrahydro-β-carboline-1-carboxylic acid, 1-carboxyethyl-tetrahydro-β-carboline and 1-carboxyethyl-tetrahydro-β-carboline-1-carboxylic acid beside established THC-3-carboxylates and -1,3-dicarboxylates. Received: 31 July 1997 / Revised: 23 October 1997 / Accepted: 30 October 1997     

Unexpected pathway of the reaction of N-[(β-halogeno-α-tosyl)alkyl]ureas with β-oxoester enolates. Synthesis of ethyl 5-ureido-4,5-dihydrofuran-3-carboxylates and N-carbamoylpyrrole-3-carboxylates

Reaction of β-halogeno-α-tosyl-substituted N-alkylureas with sodium enolates of β-oxoesters proceeds predominantly via nucleophilic substitution of the halogen rather than the tosyl group followed by spontaneous cyclization to give ethyl 5-ureido-4,5-dihydrofuran-3-carboxylates. The latter are transformed into ethyl N-carbamoylpyrrole-3-carboxylates under acidic conditions.     

Stereoselective synthesis of anti-2-oxazolidinones by Ph3P-CCl4-Et3N mediated SN2 cyclization of N-Boc-β-amino alcohols

Ethyl anti-4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates were synthesized stereoselectively in excellent yields using the Ph₃P-CCl₄-Et₃N system by S_N2 cyclization of N-Boc-β-amino alcohols. syn to anti conversion of ethyl 4-substituted phenyl-2-oxo-1,3-oxazolidine-5-carboxylates using DBU as base is also described.     

Cyclization of functionalized ketene-N,S-acetals to substituted pyrroles: applications in the synthesis of marine pyrrole alkaloids

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinates with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in the presence of the Vilsmeier reagent to afford alkyl 3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates in excellent yields. When the reaction was extended to β-oxodithiocarboxylates derived from deoxyanisoin, 3,4-diarylpyrrole-2-carboxylates, the key intermediates in the synthesis of lukianol A and lamellarin Q were formed.     

Regioselective Synthesis of 5- and 3-Hydroxy-N-Aryl-1H-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).     

Stereoselective synthesis of a new trihydroxyindolizidine lactone

A general approach to 1,6,7-trihydroxyindolizidin-8-carboxylates is illustrated through the synthesis of a γ-lactone in an enantiopure form in seven steps starting from (3S)-3-t-butyloxy-1-pyrroline N-oxide and the acetonide of (2E,4S)-4,5-dihydroxy-2-pentenoic acid derived from (S)-malic acid and mannitol, respectively. The process was completely stereoselective and allowed the total control of the relative and absolute configuration of the five contiguous stereocentres of the product.     

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, Part VI [1]. Synthesis and X-ray structure of model indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylic esters

Cyclocondensation reaction of ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate with 1-methylisatin produced a separable mixture of the corresponding indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates, of which the latter isomer predominates. On the other hand, interaction with 1H-isatin or 5-chloroisatin gave the respective indolo[2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates as the sole regiospecific products. The structures of these new pentacyclic derivatives are based on microanalytical, spectral (IR, MS, and NMR) and X-ray crystal structure data.     

Regioselective dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones mediated by ceric ammonium nitrate

Ceric ammonium nitrate (CAN) has been explored for the regioselective oxidation of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs). Interestingly, we obtained ethyl 2,4-dioxo-6-phenyl-tetrahydropyrimidin-5-carboxylates as the major products during the oxidation of DHPMs by CAN/AcOH at 80 °C. The reaction afforded a mixture of products while employing CAN in organic solvents without additives. However, the regioselective dehydrogenated product, ethyl 6-methyl-4-aryl(alkyl)-pyrimidin-2(1H)-one-5-carboxylate was obtained by performing the reaction with NaHCO₃. The single crystal X-ray crystallography of ethyl 6-methyl-4-(2-phenyl)-pyrimidin-2(1H)-one-5-carboxylate revealed that the oxidized product existed in amidic form rather than aromatized enol form of pyrimidines. The efficiency of the present protocol enabled the synthesis of structurally diverse pyrimidines in moderate to good yields under milder reaction conditions.     

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 and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by ¹H-, ¹³C-, and ¹⁵N-NMR spectroscopy and HRMS investigation.     

Thermal and acid-catalyzed transformations of 3<Emphasis Type="Italic">H</Emphasis>-pyrazoles obtained from diphenyldiazomethane and methyl phenylpropiolate

Reaction of diphenyldiazomethane with methyl phenylpropiolate in diethyl ether alongside the expected methyl triphenyl-3H-pyrazole-4-and-5-carboxylates (I and II) (38 and 24%) gave rise also to 8% of methyl 3,5-diphenyl-1-(1-ethoxyethyl)-1H-pyrazole-4-carboxylate. The main thermolysis product obtained from 4-methoxy-carbonyl derivative I was methyl 1,3,5-triphenyl-1H-pyrazole-4-carboxylate, whereas from regioisomer II formed predominantly methyl 4,4,5-triphenyl-4H-pyrazole-3-carboxylate and 1-methoxycarbonyl-2,3,3-triphenylcyclopropene that was a minor product of 3H-pyrazole I thermolysis. Addition of concn. H₂SO₄ to the solutions of methyl triphenyl-3H-pyrazole-4-and-5-carboxylates in AcOH resulted in fast regioselective isomerization of the 3H-pyrazole derivatives into the corresponding 4H-pyrazoles.     

A convenient synthesis of furo[3,2-c]pyran-3-carboxylates from 3-bromo-3-nitroacrylates

Novel 4-oxo-4H-furo[3,2-c]pyran-3-carboxylates and 4-oxo- 4H-furo[3,2-c]chromene-3-carboxylates were prepared from available alkyl 3-bromo-3-nitroacrylates and 4-hydroxy-6- methyl-2H-pyran-2-one or 4-hydroxycoumarin, respectively. Their structures were confirmed by NMR and X-ray data.     

Synthesis and properties of ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-3-carboxylates

Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates reacted with phenylhydrazine to give the corresponding hydrazones, ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates, which were converted to ethyl 1′-aryl-4-formyl-5′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazole-3′-carboxylates by treatment with the Vilsmeier–Haack reagent. No indole derivatives were formed from the same hydrazones under the Fischer reaction conditions, but cyclization to 2-aryl-3,4-dimethyl-6-phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-ones was observed.