A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

An unexpected synthesis of 7-azidofurazano[3,4-b]tetrazolopyrazine

In the course of our program focused on the preparation of high-nitrogen content heterocyclic compounds, we wish to report an original synthesis of the tricyclic 7-azidofurazano[3,4-b]tetrazolopyrazine via an unprecedented reaction between 2,6-dimethoxy-3,5-dinitropyrazine and hydrazine hydrate. This compound was identified by an X-ray diffraction analysis. Further studies of its structure by ¹⁵N and ¹³C NMR spectroscopy were carried out in different solvents. This allowed us to observe a noteworthy equilibrium involving three forms resulting from the reversible opening of a tetrazole ring.     

Studies on mechanisms of the rearrangement of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines into thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines

Recyclization of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines was studied experimentally and theoretically by B3LYP/6-31G** calculations in the gas phase and in solution (EtOH). The experimentally observed characteristic features of the isomerization (the possibility of the Dimroth rearrangement occurring by the ANRORC mechanism and high energy barriers in acid-catalyzed reactions) were confirmed by quantum chemical calculations. Substituents in the triazole ring were found to play the principal role in the rearrangement. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2164–2171, December, 2006.     

Pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine: a new ring system through Dimroth rearrangement

Derivatives of the new ring system pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine were synthesized from the corresponding angular isomers, through a Dimroth rearrangement, in quantitative yields. Preliminary computational studies demonstrated that this class of compounds could be a good candidate as DNA intercalating agents.     

A new synthesis for 1,2,4-triazolo[1,5-a]-pyridines and 1,2,4-triazolo[1,5-a]isoquinolines

Summary Condensation of cyano acid hydrazide1 with cyclopentanone in refluxing ethanolic piperidine yields hydrazone2. With mixtures of aliphatic aldehydes and different active methylene reagents,2 reacts to 1,2,4-triazolo[1,5-a]pyridines (8a–f). Compound2 also reacts with arylidenes9a–g to give triazolopyridines10a–g. Reaction of2 with aromatic aldehydes affords compounds13a–c. Diazotation of2 with aryldiazonium chloride in ethanol at 0 °C leads to the azo adducts15a–d. The thieno-1,2,4-triazolopyridine16 is obtained by reaction of8a with elementary sulfur.16 undergoes cycloaddition with -nitrostyrene, maleic anhydride, N-arylmalemide, and acrylonitrile yielding the isoquinolines21–24. All new compounds have been characterized by their IR,¹H NMR, and mass spectra.

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Ein neuer Syntheseweg für 1,2,4-Triazolo[1,5-a]pyridine und 1,2,4-Triazolo[1,5-a]isochinoline

Zusammenfassung Kondensation des Cyanohydrazids1 mit Cyclopentanon in ethanolischem Piperidin bei Rückflußtemperatur ergibt das Hydrazon2. Mit Gemischen aus aliphatischen Aldehyden und verschiedenen Verbindungen mit aktiven Methylengruppen reagiert2 zu 1,2,4-Triazolo[1,5-a]pyridinen (8a–f). Verbindung2 reagiert außerdem mit den Arylidenen9a–g zu den Triazolopyridinen10a–g. Umsetzung von2 mit aromatischen Aldehyden führt zu den Verbindungen13a–c. Diazotierung von2 mit Aryldiazoniumchloriden in Ethanol bei 0°C ergibt die Azoaddukte15a–d. Das Thieno-1,2,4-triazolylpyridin16 erhält man durch Reaktion von8a mit elementarem Schwefel.16 geht it -Nitrostyrol, Maleinsäureanhydrid, N-Arylmaleimid und Acrylnitril eine Cycloaddition zu den Isochinolinen21–24 ein. Alle neuen Verbindungen wurden durch ihre IR-,¹H-NMR- und Massenspektren charakterisiert.

     

Synthesis and rearrangements of 7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]-and 7h-pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidines

7H-Pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines were synthesized by the reactions of 2-ethoxymethyleneamino-1H-pyrrole-3-carbonitriles with acid hydrazides and by the reactions of aminoiminopyrimidines (prepared based on the above-mentioned carbonitriles) with acid chlorides. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1438–1443, August, 2006.     

The Dimroth rearrangement as a probable cause for structural misassignments in imidazo[1,2-a]pyrimidines: A 15N-labelling study and an easy method for the determination of regiochemistry

Structural misassignments are often seen for complex natural products, but this can also be an issue with seemingly simpler structures. In this paper, we describe how, using a ¹⁵N-labelled analogue, we established that the Dimroth rearrangement can occur in imidazo[1,2-a]pyrimidines and result in an incorrect regiochemical assignment of such compounds. These studies supported a rearrangement mechanism involving addition of hydroxide ion followed by ring opening. It was also observed that C(2) and C(3) substituted regioisomers could be readily distinguished using ¹H NMR spectroscopy.     

Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent

A useful and rapid access to 4-anilino-6-nitroquinazolines was investigated in a multi-gram scale via microwave-accelerated condensation and Dimroth rearrangement of the starting anilines with imines obtained by reaction of anthranilonitriles with formamide dimethylacetal. A novel short and efficient route to Azixa™ (EPi28495, MPC-6827), a microtubule destabilizing agent and apoptosis inducer, was performed with success demonstrating that well controlled parameters offer comfortable using of microwave technology with safe and environmental benefits.     

Smiles rearrangement for the synthesis of 5-amino-substituted [1]benzothieno[2,3-b]pyridine

The Smiles rearrangement was successfully applied to 4-hydroxybenzo[b]thiophene furnishing a facile entry to the 4-amino derivative. The rearrangement was extended to 5-methoxy-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine obtained via aza-Wittig/electrocyclization reaction of novel N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenylphosphorane with methyl trans-4-oxo-2-pentenoate. The preparation of a novel 5-amino-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine, which is of interest as a potential secondary peptide structure mimic, was successfully achieved.     

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids has been developed for the preparation of vasicinone and deoxyvasicinone by two approaches. The derivative of polymer-supported p-nitrophenyl carbonate was attached to anthranilic acid and then coupled with various bromo-lactams. This resin-linked bromo intermediate upon acetylation, hydrolysis and resin cleavage gave the cyclized [2,1-b]quinazolinones (vasicinone). Alternatively, resin-linked azido-benzoic acids were coupled with bromo-substituted lactams followed by cyclization in an aza-Wittig reductive cyclization process giving the bromo-substituted quinazolinone intermediates, with subsequent acetylation, hydrolysis and resin cleavage affording the fused [2,1-b]quinazolinones.     

Dimroth rearrangement in the row of new pyrano[3,4-c][1,2,4]triazolo[4,3-a][1,5-a]pyridines and synthesis of new heterocyclic systems: Pyranopyrazolo[4,3-e][1,2,4]triazolopyridines

New and effective methods for the synthesis of derivatives of pyrano[3,4-c][1,2,4]triazolo[4,3-a][1,5-a]pyridines were developed. Synthesized new tetracyclic heterocyclic systems containing pyrano[3,4-c]pyridine ring unknown in the literature were obtained for the first time. The rearrangement of Dimroth in the triazolo[4,3-a]pyridine systems for the first time was studied. The possibility of rearrangement of Dimroth in the new heterocyclic system has been investigated.     

2-Benzyliden-2H-thieto[3,2-b]quinoline: a new heterocycle and its rearrangement to 2-phenylthieno[3,2-b]quinoline

Synthesis of the strained 2H-thieto[3,2-b]quinoline ring system is reported for the first time. Treatment of (Z)-2-benzyliden-2H-thieto[3,2-b]quinoline derivatives of this heterocycle with base, at reflux in ethanol, causes a novel rearrangement to 2-phenylthieno[3,2-b]quinolines. Indeed, the one-pot reaction of 2-aminobenzaldehydes and (Z)-2-benzylidenethietan-3-one in refluxing basic ethanol leads directly to 2-phenylthieno[3,2-b]quinolines in good yields.     

A mild synthesis of [1,2,4]triazolo[4,3-a]pyridines

The reaction between 2-hydrazinopyridines and ethyl imidates was examined as a one-pot method for rapidly preparing [1,2,4]triazolo[4,3-a]pyridines. A diverse set of 2-hydrazinopyridines were cyclized with a variety of alkyl- and aryl-substituted ethyl imidates in good yields. The reaction proceeds optimally under mild conditions (50−70 °C) using 1.5 equiv of acetic acid. The electronic and steric properties of the hydrazine and imidate strongly impact the rate of the reaction. When highly electron deficient 2-hydrazinopyridines were used, the products rearranged to [1,2,4]triazolo[1,5-a]pyridines.     

A new modular and flexible approach to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines

A new synthetic route for the access to [1,2,3]triazolo[1,5-a][1,4]benzodiazepines and other derivatives is described. This strategy is based on the cycloaddition of 2-oxoalkylidenephosphoranes to o-functionalized aryl azides followed by the reaction of the corresponding triazole intermediate with amines. This new approach presents unique properties such as regioselectivity, modularity, mild reaction conditions, and high yields.     

Parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives

The parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives is described. The key intermediate 2,6-bis-aminopyridine-4-carboxylic acid methyl ester was synthesised in a two step procedure in 64% overall yield and elaborated to a variety of triazolopyridine-5-carboxylic acid methyl ester by selective pyridine-N-amination, condensation of the adduct with a wide selection of aldehydes and subsequent cyclisation and oxidation. The desired esters were obtained in yields up to 70%. The final transformation to the amide derivatives was accomplished by application of carefully optimised reaction conditions thus giving access to a library of total 500 triazolopyridine amide derivatives. Iterative synthetic cycles (12-48 library members each) allowing for maximal flexibility in chemistry and maximal efficiency in in vitro biological activity optimisation guided by molecular modelling efforts constitute a synergistic procedure for rapid lead optimisation.     

A new synthetic method for the 2H-[1,2,3]thiadiazolo[5,4-b]indoles

The systematic study of oxidative cyclization of 3-hydrazono-1,3-dihydroindole-2-thiones has been carried out and a series of new 2H-[1,2,3]thiadiazolo[5,4-b]indoles has been prepared. The elaborated reaction represents an efficient method for the synthesis of fused 1,2,3-thiadiazoles.     

Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

Triazolopyridines. Part 25: Synthesis of new chiral ligands from [1,2,3]triazolo[1,5-a]pyridines

The synthesis of new chiral triazolopyridine ligands possessing fluorescent properties is described. The triazolo ring opening was studied in order to obtain new chiral 2,6-disubstituted pyridines. A preliminary coordination assay with Zn(II) is also presented.     

Highly regioselective synthesis of trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidines bearing fused cycloalkane rings using (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones

8-Trifluoromethyl-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and 9-trifluoromethyl-5,6,7,8-tetrahydropyrazolo[5,1-b]quinazolines were efficiently generated by condensation of 5(3)-aminopyrazoles with (2-ethoxycycloalkenyl)-2,2,2-trifluoroethanones and isolated in excellent yields. The regiochemistry of the prepared compounds was established by ¹H, ¹³C and ¹⁹F NMR spectroscopy and X-ray diffraction analysis.     

MAOS protocols for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.