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A silver trifluoromethanesulfonate catalyzed efficient access to the indolylpyranoquinoline scaffold is reported. Starting from 2-alkynylquinoline-3-carbaldehyde units with various substitution patterns on the quinoline and alkynyl parts, the use of silver trifluoromethanesulfonate (10 mol%) in 1,2-dichloroethane allowed a domino hydroarylation/cycloisomerization reaction, generating (hetero)aryl-functionalized pyranoquinolines. The heteroarenes that were used are N -methylindole (18 compounds, 67–100%), indole, and 2-methylindole (4 compounds, 36–89%), and the reaction was also compatible to a lesser extent with arenes such as pyrroles (5 compounds, 43–90%), 1,3,5-trimethoxybenzene, and 3-methylbenzofuran.

To synthesize unsubstituted pyrrolo[3′,4′:5,6] pyrido[2,3-d]pyrimidine-2,4,6,8-tetraone, we have developed new synthon 4-formyl-3-hydroxy-2,5-dioxo-2,5-dihydro-1H-pyrrole, which was then treated under mild conditions with 6-aminouracil. This new synthetic pathway could be extended to the preparation of N7-selectively substituted heterocycles by starting either from this new synthon or from its N-substituted analogues. Examples of N1,N7-disubstituted and N1,N3,N7-trisubstituted derivatives are also described. We have thus developed new synthons that lead to easy access to the unsubstituted pyrrolo[3′,4′:5,6]pyrido[2,3-d]pyrimidine-2,4,6,8-tetraone skeleton and to selectively N7-substituted analogues.

A broad variety of hetarylamines and anilines reacted with 2-trichloro-4-chloroquinazoline (II) to give corresponding 4-aminated compounds in varying yields.

3H-Phenanthro[9,10-d]oxazol-2-ones (III) are prepared either from 9,10-phenanthrenequinone monoimines (I) in the presence of PPh3 or 2,3-dihydro-2,2,2-triphenylphenanthro [9,10-d]-1,3,2-λ5-oxazaphospholes (IV) using CO2 as C1 building block.

A novel and practical two-step approach to an intriguing class of imidazo[1,5-a]pyrazines with exocyclic CX (X = CH2, O) bonds is described. The process utilizes a sequential three-component reaction of propargyl amine or aminoester, 1,2-diaza-1,3-dienes and isothiocyanates to furnish functionalized 2-thiohydantoins which are transformed into thiohydantoin-fused tetrahydropyrazines by subsequent regioselective base-promoted cyclization.

The peptido-mimetic reaction between 4-dialkylamino-carbonyl-l,2-diaza-l,3-butadienes and sarcosine ethyl ester gave α-aminohydrazones. These compounds, in ethanol under reflux with sodium hydride, furnished new and unexpected 7-oxo-8-oxa-2,3,6-triazabicyclo[3.2. l]oct-3-ene-2-carboxylates and 5-oxo-4,5-dihydro-2-pyrazines. By treatment with Amberlyst 15H in acetone-water (10:1), the same hydrazones were converted into the corresponding ethyl 2-[{1-[(diethylamino)carbonyl]-2-oxopropyl}(methyl)amino]acetates.

A variety of α,β-unsaturated aldehydes and ketones gave very high-yielding Michael addition reactions with α-nitrocycloalkanones in water, at room temperature without added catalyst. These can be considered as one of the very few “on-water” Michael reactions known in the literature, because they took place in suspension or emulsion and at increased speed relative to the same transformations performed in organic solvents. A related protocol that uses very dilute, aqueous solutions of potassium carbonate as the reaction media extended the scope of the method to cyclic enones and unsaturated esters, nitriles and sulfones and is likely to take place in the bulk of the aqueous phase, i.e., “in-water”. Both preparative methods constitute environmentally benign and efficient alternatives to previously known procedures.

An optimized procedure is elaborated for the preparation of the target compound (II) from the known aldehyde precursor (I).

Hydroxylamines, oximes and hydroxamic acids have been extensively studied by mass spectrometry. Different ionization techniques and mass spectrometry methods, such as high resolution, study of metastable ions, collision induced dissociations, together with chemical modifications and stable isotope labeling, have been used for investigating the gas phase properties and reactivity of radical cations, positively and negatively charged species produced by these classes of molecules. Keywords: mass spectrometry; gas phase ion chemistry; tandem mass spectrometry; electron ionization; chemical ionization; electrospray; hydroxylamines; oximes; hydroxamic acids

Nucleophilic addition of indole to nitroolefins gives the expected Michael-type adducts (III) and (VI) as well as the carbazoles (IX) and (X).

The method is highly efficient for the preparation of 2-thiohydantoins and 2-iminothiazolidinones.

This paper describes an efficient route leading to new thienylpyridyl garlands as non-peptidic alpha helix mimetics and potential protein–protein interactions disruptors. Firstly, we have studied the reactivity of boronic acids and halogenated pyridines and/or thiophenes towards the Suzuki–Miyaura cross-coupling reaction in order to obtain bis-thienylpyridines. Secondly, we have functionalized these compounds by a reaction of bromination and the resultant bis-bromothienylpyridines have been found to undergo iterative Pd-catalyzed coupling based on a pseudo-Garlanding approach with a range of pyridyl boronic acids to produce a new library of thienylpyridyl oligomers.

In the current bid for synthetic efficiency, multiple bond-forming transformations are becoming a key concept in organic synthesis. In this context, domino protocols have become increasingly common in the synthesis of bicyclic systems. This tutorial review aims at providing a short but authoritative overview of this topic, focusing on the preparation of bridged bicyclo[n.3.1]alkane systems, and is organized according to the number of rings created in the key domino process.

The zinc(II) triflate-catalyzed synthesis of highly functionalized pyrroles is described. The se- quence involves the preliminary preparation of a- aminohydrazones by Michael addition of primary amines to 1,2-diaza-1,3-dienes. The treatment of these intermediates with dialkyl acetylenedicarboxy- lates produces a-(N-enamino)-hydrazones that are converted into the corresponding pyrroles. The sub- stituents on the carbon in position four of 1,2-diaza- 1,3-dienes drive the regioselectivity of the ring clo- sure process. Starting from 4-aminocarbonyl-1,2- diaza-1,3-dienes only dialkyl 1-substituted 5-amino- carbonyl-1H-pyrrole-2,3-dicarboxylates are achieved by Lewis acid-catalyzed ring closure. A screening of several Lewis/Bronsted acid catalysts is performed. Zinc(II) triflate is the most efficient catalyst. Under similar reaction conditions, employing 4-alkoxycar- bonyl-1,2-diaza-1,3-dienes, only 4-hydroxy-1H-pyr- role-2,3-dicarboxylates are synthesized. These latter reactions can be accomplished regioselectively also in one pot. Using 4-aminocarbonyl-1,2-diaza-1,3- dienes, diamines and dialkyl acetylenedicarboxylates the sequence provides the corresponding a,w-di(N- pyrrolyl)alkanes.

DBU-promoted alkylation of cyclic α-nitroketones (I) with o-bromobenzyl halides, e.g. (II), (V) or (VIII), followed by Pd-catalyzed intramolecular C-arylation provides an efficient access towards benzo-fused bicyclo[n.3.1]alkane derivatives (III), (VI) and (IX), respectively.

The reaction must be carried out under nitrogen atmosphere in deoxygenated solvent to prevent the oxidation of the imidazole products.

The convenient one-pot sequence starts from 1,2-dialdehydes and α-nitroketones and proceeds via nitroaldol reaction, retro Dieckmann-type ring opening and a final intramolecular nitroaldol reaction.

Depending on the nature of the solvent, amidine (I) shows a different nucleophilic behavior in the presence of two equivalents of the diazadienes.

The thienopyrimidines synthesized, including five newly synthesized compounds, possess scaffolds which are very similar to those of known tyrosine kinase inhibitors approved for cancer treatment.

This paper reports the preparation of some (p-thiosubstituted)-benzyl (disulfides, thiols, and ethyl 2-mercaptopropionates) nitrogen heterocycles (1,2,3-triazole, imidazole, pyridine, tetrazole and 1,3,4-oxadiazole) and the evaluation of their inhibitory activity of in vitro prostaglandin synthesis. The mercaptopropionates, isosters of previously studied and very effective oxyderivatives, maintain high enzyme activity which is also present, although to a lower degree, in the corresponding disulfides.

The crystal and molecular structure of propane-1,2,3-triamine trihydrochloride monohydrate (1·3HCl·H2O) is reported. 1·3HCl·H2O crystallizes in the triclinic system, space group P(no. 2), a= 11.078(1), b= 11.935(2), c= 7.862(1)A, α= 102.88(2), β= 100.79(1), γ= 81.07(1)°, Z= 4. The structure refinement converged to R= 0.036 and Rw= 0.038. Two 1·H33+ cations, six Cl– anions and two water molecules are contained in the asymmetric unit. The two triammonium ions have almost the same conformation. The four C–C bond lengths average 1.521 (4)A while the six C–N bond lengths average 1.485(4)A. A network of strong hydrogen-bond interactions involve all of the chloride ions, the triprotonated nitrogen atoms as well as the water molecules. These forces are responsible for the non-equivalence in the two C–C–N(terminal) bond angles for the two 1·H33+ cations.The protonation equilibria of propane-1,2,3-triamine (1) in aqueous solution (0.15 mol dm–3 NaCl, 298 K) have been studied with potentiometric and calorimetric techniques. The logarithms of the protonation constants are 9.642 ± 0.002, 7.981 ± 0.001 and 3.715 ± 0.002 for 1, 1·H+ and 1·H22+, respectively. A comparison with the log K values previously determined for similar triamines containing three equivalent –CH2NH2 groups, such as 2-methyl-2-aminomethylpropane-1,3-diamine (2) and 2-ethyl-2-aminomethylpropane-1,3-diamine (3), shows that 1 is the least basic ligand. The decrease in the basicity is particularly evident for the third step. The enthalpy changes for 1 are – 10.97 ± 0.04, –11.07 ± 0.07 and –8.52 ± 0.08 kcal mol–1‡ in the first, second and third protonation step, respectively.A molecular-mechanics analysis was carried out on the 1·H33+ cation to obtain a proper force field for this kind of triamine. Atomic charges for all the atoms were calculated by means of the semiempirical MNDO method. The energy-minimized conformation for the folded 1·H33 + cation is in good agreement with the molecular structure found in the solid state for 1·3HCl·H2O. However, the two calculated C–C–N (terminal) bond angles are equal to each other showing that intermolecular interactions are responsible for the distortion found in the solid-state structure. In the most stable conformation of the 1·H22+ species, the protonated amino groups are the terminal ones. The cation shows an elongated chain similar to that previously found for the protonated linear polyamine spermine when co-crystallized with nucleic acid molecules.

Several 9-(2′,3′-O-isopropylidene)- and 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines were synthesized by a “one pot” method starting from the acetonide of racemic or (S)-1-azido-2,3-dihydroxypropane, obtained from D-mannitol. 9-(2′,3′-Dihydroxypropyl)-8-azapurines were tested as adenosine deaminase inhibitors.

A regio- and stereoselective didehydrodimerization procedure, whose key step involves the anodic oxidation, allows the conversion of β-anilinoacrylic alkaloids belonging to the Aspidosperma class, typified by tabersonine (1) and its 3-oxo derivative 2, into the hitherto unknown 16,10′-didehydro dimers 3 and 7, respectively.

Summary The synthesis of some N-[2-(1H-pyrrol-1-yl)benzyl]arylacetamides and new 4-arylmethyl-5,6-dihydro-4H-pyrrolo[1,2-a]-[1,4]benzodiazepines as their conformationally restricted analogues is reported. The reduction of arylacetamides and N-methylation of pyrrolobenzodiazepines led to the corresponding N-[2-(lH-pyrrol-1-yl)benzyl]arylethylamines and the 4-arylmethyl-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines, respectively. The new compounds were subjected to pharmacological tests for evaluation of antinociceptive effects. Neurobehavioural assays were also carried out on selected compounds to acquire data on neurotoxicity. Among the derivatives tested, arylacetamides 7b and 7e and 4-(4-methoxybenzyl)-5-methyl-5,6-dihydro-4H-pyrrolo[l,2-a][1,4]benzodiazepine 10d were the most active derivatives in antinociceptive assays, showing high significance in both hot-plate and acetic-acid-induced writhing tests in mice without sedative or myorelaxant effects.

Synthesis and pharmacological evaluation of a series of condensed quinoline derivatives bearing a basic nitrogen on piperazine or [(dimethylamino)ethyl]thio moieties attached at the 2-position of the quinoline nucleus are described. 5-HT receptor binding studies revealed, for most of the compounds studied, nanomolar affinity for the 5-HT3 receptor subtype. The most active compound, benzopyrano[3,4-c]quinoline derivative 5f, displayed a Ki value very similar to that reported for quipazine along with an improved selectivity. Functional and in vivo testing carried out on three selected compounds showed that 5f,j,n are potent 5-HT3 receptor antagonists with potencies in the same range as the best known 5-HT3 receptor antagonists ondansetron, tropisetron, and zacopride. The crystal and molecular structures of compounds 5f,j,n were determined by single-crystal X-ray diffraction and used as starting structures for molecular modeling studies. Comparative molecular field analysis (CoMFA) was applied to binding constants of compounds 5a-p and 6a-h. The cross-validated r2, derived from partial least-squares calculations, indicated a good predictive capacity for affinity values in the series of compounds investigated. Evidence for the prediction capacity is provided in the form of plots of actual vs predicted pKi values. The steric and electrostatic features of the CoMFA-derived model are presented as standard coefficient contour maps of steric and electrostatic fields.

This paper describes the preparation of title compounds starting from 3-benzyl-4-amino5-carboxyamidothiazole-2(3H)-thione, which, by heating with alkyl orthobenzoates, was converted into 3-benzyl-5-phenyl-7-alkoxy-thiazolo[4,5-d]pyrimidines. The treatment of these compounds with hydrobromic acid in acetic acid gave 3-benzyl-5-phenyl-7-oxo-thiazolo[4,5-d]pyrimidine-2(3H)-thione which, by reaction with phosphorus oxychloride and subsequent substitution of the halogen with amines, gave the corresponding title compounds

This paper reports the synthesis of 3-substituted-1,2,3-triazolo[1,5-a]quinazolin-5-ones prepared by 1,3-dipolar cycloaddition reaction of 2-azidobenzoic acid to methylenic compounds activated by a cyano group. The new derivatives were submitted to benzodiazepine receptor binding assays: the results indicated an interesting receptorial affinity of the 1,2,3-triazolo[1,5-a]quinazoline ring. On the basis of the biological results, theoretical calculations were performed, which suggested useful structural modifications.

Some new v-triazolo[1,2-a]benzotriazoles or 2,3-benzo-1,3a,6,6a-tetraazapentalenes were prepared according to previously employed synthetic routes concerning deoxycyclization reactions of appropriate nitrophenyl-1,2,3-triazole derivatives and/or thermal decompositions of appropriate azidophenyl-1,2,3-triazoles. The nitration of 9-phenyl-1,2,3-triazolo[1,2-a]benzotriazoles allowed the isolation of some mononitro- and trinitro-derivatives, whose structures were assigned by chemical and spectroscopic methods.