A facile one-pot synthesis of 7-substituted pyrazolo[1,5-a]pyrimidines by base induced three-component reaction

The preparation of steroid/nonsteroid fused 7-substituted pyrazolo[1,5-a]pyrimidines is described by a one-pot reaction of steroidal/nonsteroidal ketones, aromatic aldehydes and 3-amino-1H-pyrazoles/5-amino-1H-pyrazoles in the presence of potassium tert-butoxide in good yield under reflux condition in ethanol.     

A facile synthesis of steroidal D-ring fused pyrazolo[1,5-a]pyrimidines

A facile method for the synthesis of steroidal D-ring fused pyrazolo[1,5-a]pyrimidines through a microwave mediated reaction between steroidal β-bromovinyl aldehydes and pyrazoloamines using palladium(II) catalyst has been described.     

Regioselective synthesis of novel substituted pyrazolo[1,5-a]pyrimidines under solvent-free conditions

A series of 6-(2-hydroxybenzoyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines 5 have been synthesized directly by the solvent-free reaction between 5-amino-1H-pyrazoles 1 and 3-benzoyl-2-methyl-4H-chromen-4-one 4. This solvent-free reaction proceeds in a regiospecific fashion by intramolecular opening of the γ-pyrone ring in a Michael-type reaction, that followed by cyclization via nucleophilic attack of endocyclic pyrazole nitrogen toward benzoyl group gives the pyrazolo[1,5-a]pyrimidines 5. The use of this method affords high yields in short reaction times.     

Novel one pot synthesis of polysubstituted pyrazolo[1,5-a]- and imidazo[1,2-a]pyrimidines

We have described a convenient regioselective one-pot approach to pyrazolo[1,5-a]- and imidazo[1,2-a]pyrimidine derivatives from α,β-unsaturated imines generated in situ and amino heterocycles. Reaction is general with respect to all three components, namely (i) nitrile, (ii) aldehyde, and (iii) amino heterocycle reagents. Good yields (52-77%), convenient isolation of the targeted molecules are the distinct characteristics of the developed protocol.     

Synthesis of trifluoromethyl-promoted functional pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones

Ethyl 5-amino-3-trifluoromethyl-1H-pyrazole-4-carboxylate (1) was efficiently synthesized via the condensation of ethyl cyanoacetate and trifluoroacetic anhydride, followed by chloridization and the condensation with aqueous hydrazine. Its unique reactivity was exploited for the synthesis of trifluoromethylated pyrazolo[1,5-a]pyrimidine (5) and pyrazolo[5,1-d][1,2,3,5]tetrazine-4(3H)-ones (8a-j). Among them, 5 was firstly found to be a novel fluorescent molecule that might be exploited as an attractive fluorophore for possessing many binding sites, and its fluorescence intensity was obviously stronger than its methyl analogue. 8 were found to be a new chemical class of potential monocotyledonous Echinochloa crus-galli L. Beauv inhibitors, and were more active than their methyl analogues.     

Copper-catalyzed tandem reactions of 2-bromobenzaldehydes/ketones with aminopyrazoles toward the synthesis of pyrazolo[1,5-a]quinazolines

An efficient and straightforward synthesis of pyrazolo[1,5-a]quinazolines through copper-catalyzed tandem reactions of 2-bromobenzaldehydes or 2-bromophenyl alkyl/aryl ketones with 5-aminopyrazoles is presented.     

Regioselective synthesis of novel 4-aryl-2-ethylthio-7-methyl pyrazolo[1,5-a]-[1,3,5]-triazines

Pyrazolo[1,5-a]-[1,3,5]-triazines 6a-d were obtained by an efficient one-step reaction from S,S-diethyl aroyliminodithiocarbonates 4a-d and 5-amino-3-methylpyrazole 5 or by an alternative two-step reaction from 5 and aroyl isothiocyanates 8a-d to give initially the thiourea derivatives 9a-d, which after S-ethylation and cyclization afforded compounds 6a-d. The intermediate 7a isolated from reaction between 4a and 5 permitted us to establish the orientation.     

A new, one-pot, three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines

A new, one-pot and three-component synthesis of 4H-pyrido[1,2-a]pyrimidines, 4H-pyrimido[1,2-a]pyrimidines, and 4H-pyrazino[1,2-a]pyrimidines is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by N-(2-heteroaryl)amides to yield a ketenimine intermediate, which was cyclized and then rearranged under the reaction conditions to afford the title compounds under mild reaction conditions in good yields. Single-crystal X-ray analysis conclusively confirms the structure of the obtained bridgehead bicyclic 6-6 heterocyclic compounds.     

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.     

Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives.     

Regioselective synthesis of novel polyfunctionally substituted pyrazolo[1,5-a]pyrimidines under solvent-free conditions

A series of 2-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoic acids 5 has been prepared by a novel protocol that uses the fusion method between 5-amino-1H-pyrazoles 4 and 3-(3-oxo-2-benzofuran-1(3H)-ylidene)pentane-2,4-dione 3. The use of this novel protocol renders good to excellent yields along with short reaction times. In addition, this solvent-free cyclocondensation proceeds in a regiospecific fashion by intramolecular ring opening of the furane ring in a Michael-type reaction.     

A facile synthesis of the novel thiazolo[3,2-a]pyrimidine derivatives

2-Bromomethyl- and 2-iodomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones are prepared via the reaction of 3-allyl-2-thiouracil derivatives with bromine or iodine chloride, respectively. The 6-bromo and 6-nitro derivatives are synthesized by an electrophilic substitution at C-6 of the thiazolopyrimidine system. As a result, novel 2,3-dihydrothiazolo[3,2-a]pyrimidin-5-one derivatives are obtained. Hydrogen halide elimination from the 2-halomethyl-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones is also reported.     

Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl₃ gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a–h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a–f furnished the 1-alkyl derivatives 17a–f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a–d and 16m,n, selectively.     

Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.     

A practical, multigram synthesis of the 2-(2-(4-alkoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (DPA) class of high affinity translocator protein (TSPO) ligands

A practical, multigram approach to the 2-(2-(4-alkoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide (DPA) class of ligands targeting the translocator protein (TSPO) is described. This synthetic route offers several improvements over all previously described sequences, including the isolation of intermediates without resort to chromatography. The common precursor to the DPA class of high affinity TSPO ligands, N,N-diethyl-2-(2-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide, was produced in 40% yield over six steps, and was cleanly alkylated to give multigram quantities of several DPA analogues in 90-96% yield after recrystallization.     

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.     

Pyrazolo[1,5-a]pyridines: synthetic approaches to a novel class of antiherpetics

Synthesis of a novel class of 7-amino-3-pyrimidinyl-pyrazolo[1,5-a]pyridine antiherpetic compounds is described. The synthetic methodology is designed to allow for rapid analog synthesis around the C-3 and C-7 positions of the pyrazolo[1,5-a]pyridine. The 7-chloropyrazolo[1,5-a]pyridine D, produced through an azirine rearrangement, served as a key building block. Two complementary methodologies for construction of the C-3 pyrimidine are described. These methods include the development of a novel cyclization utilizing alkynyl ketones or enones to give highly substituted pyrimidines. The outlined strategies facilitated late stage manipulation of either the C-3 or C-7 positions providing flexibility for rapid analog synthesis.     

One-step reaction leading to new pyrazolo[1,5-a]pyrimidines by condensation of 2-pyrone with 5(3)-amino-3(5)-arylpyrazoles

Condensation of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran-2-one leads to 5,7-dimethyl-2-arylpyrazolo[1,5-a]pyrimidines, 5-alkoxycarbonylmethyl-7-methyl-2-arylpyrazolo[1,5-a]pyrimidines and their isomeric 7-alkoxycarbonylmethyl-5-methyl-2-arylpyrazolo[1,5-a]pyrimidines. These compounds result from competitive reactions and from different cyclization pathways. Structure and mechanism of formation of these new products are reported.     

A general approach toward the synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines

An expedient synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines was developed by treating 8-amino-4-[N-(4-aminophenyl)-N-(methyl)amino]pyrazolo[1,5-a]-1,3,5-triazine with various acyl chlorides following by the displacement of the so-formed N-(methyl)-N-[4-(acylamido)phenyl]amino leaving group with various amines. Applications to high-throughput synthesis are suggested.     

Synthesis of bridgedhead azolo[3,2-a]pyrimidines and imidazo[2,1-b]thiazines through ring transformation of 2H-pyran-2-ones

Suitably functionalized 3-carbomethoxy/cyano-2H-pyran-2-ones are excellent synthons for the synthesis of arenes and heteroarenes of therapeutic importance. The compounds 6-aryl-3-cyano-4-methylsulfanyl-2H-pyran-2-ones have been transformed into bridgedhead azolopyrimidines and imidazothiazines through thermal and base-induced ring transformation reactions with aminoazoles and imidazolidin-2-thiones, respectively.