Efficient synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines by regioselective acylation

An efficient two-step synthesis of 8-acylated pyrazolo[1,5-a]-1,3,5-triazines has been accomplished. The key strategic elements of this novel synthetic approach involve the use of the N-methyl-N-phenylamino activating group, which was easily obtained in high yield by treatment of the pyrazolotriazin-4-one with phosphorus oxychloride and dimethylaniline through high pressure reaction coupled with a regioselective acylation at position 8 followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with various amines.     

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.     

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.     

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.     

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.     

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.     

Synthesis of 1,3-diarylated imidazo[1,5-a]pyridines with a combinatorial approach: metal-catalyzed cross-coupling reactions of 1-halo-3-arylimidazo[1,5-a]pyridines with arylmetal reagents

The halogenation of 3-arylimidazo[1,5-a]pyridines was carried out with iodine, bromine, N-chlorosuccinimide, and 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as halogenating agents to give selectively halogenated products 1-halo-3-arylimidazo[1,5-a]pyridines in good to excellent yields. Kumada-Tamao-Corriu cross-coupling of the obtained 1-iodo-3-arylimidazo[1,5-a]pyridines and aryl Grignard reagents led to 1,3-diarylated imidazo[1,5-a]pyridines in good to excellent yields. Suzuki-Miyaura cross-coupling of the 1-bromo-3-phenylimidazo[1,5-a]pyridine and p- or m-methoxycarbonylphenylboronic acids furnished the coupling product in respective yields of 91% and 61%. The obtained 1,3-diarylated imidazo[1,5-a]pyridines showed a wide variety of fluorescent emissions in a wavelength range of 449-533 nm with improved quantum yields compared to monoarylated ones.     

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.     

A simple approach for the regioselective synthesis of imidazo[1,2-a]pyrimidiones and pyrimido[1,2-a]pyrimidinones

Several imidazo and pyrimido[1,2-a]pyrimidinones of type 1 and 2 were synthesized through intramolecular cyclization of pyrimidines 9 or pyrimidinones 10 bearing a variety of β and γ-aminoalcohols at the 2-position. Ring closure of the pyrimidinones of type 10 under Mitsunobu conditions lead to mixtures of both bicyclic regioisomers 1 and 2. Treatment of pyrimidines of type 9 with H₂SO₄ provided an efficient and operationally simple one-pot hydrolysis-cyclization procedure for obtaining imidazo and pyrimido[1,2-a]pyrimidinones 1 in good yields as the sole regioisomeric bicyclic product.     

Novel synthesis of C-3-(hetero)aryl [1,2,3]triazolo[1,5-a]pyridines using the Stille reaction

Herein, we report a novel and high yielding approach for the preparation of the first C-3-organometallic substituted [1,2,3]triazolo[1,5-a]pyridine and its application to the Stille reaction using MAOS.     

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.     

One pot synthesis of imidazo[2,1-b]thiazoles and benzo[d]thiazolo[3,2-a]imidazoles

A series of imidazo[2,1-b]thiazole and benzo[d]thiazolo[3,2-a]imidazole analogues were synthesized by stirring an equimolar mixture of dibenzoylacetylene with imidazole/thiazole derivatives in toluene or acetonitrile at room temperature. The products were generated in good yields and characterized by standard analytical techniques such as IR, ¹H NMR, ¹³C NMR and mass spectrometry. The structure of products 19, 20, 22, 24 and 25 were also unambiguously confirmed by single crystal X-ray analysis.     

Expeditious synthesis of 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones

A convenient synthesis of new 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones from the Baylis-Hillman adducts of acrylonitrile and their derivatives is described. A common strategy employed to achieve the syntheses of title compounds involved generation of diamines from different Baylis-Hillman derivatives followed by treatment with cyanogen bromide at reflux temperature to trigger a double intramolecular cyclization.     

A convenient synthesis of linear pyridinoimidazo[1,2-a]pyridine and pyrroloimidazo[1,2-a]pyridine cores

Two new imidazo[1,2-a]pyridine derivatives, pyridinoimidazo[1,2-a]pyridine (10) and pyrroloimidazo[1,2-a]pyridine (16), were synthesised from 2-amino-4-methyl-5-nitropyridine (1) by linear cyclisation, making use of dimethylformamide dimethylacetal (DMFDMA) as an agent of vinylamine functionalisation. This report describes first the formation of pyridine and pyrroloimidazopyridine from (1), and then the formation of pyridine-fused and pyrrolo-fused pyridine by the Friedländer method and reductive cyclisation followed by treatment of the resulting adduct with chloroacetaldehyde.     

Abnormal aza-Wittig reaction on the solid-phase: chemoselectivity studies towards the parallel synthesis of 3-aryl-2,4-dioxo-1,3,5-triazino[1,2-a]benzimidazoles

An abnormal aza-Wittig reaction was observed when resin-bound iminophosporanes were treated with aryl isocyanates on the solid-phase. The mechanism of the reaction may involve the loss of triphenylphosphinimide instead of triphenylphosphinoxide, resulting in the formation of isocyanates instead of carbodiimides as intermediates. The selectivity of the abnormal aza-Wittig reaction versus the normal aza-Wittig reaction was shown to be strongly dependent on the reaction temperature and the nature of the aryl isocyanate employed. Optimization studies revealed that employing electron poor aryl isocyanates at high temperature leads to 95% of abnormal aza-Wittig product. The reaction was used for the parallel solid-phase synthesis of 3-aryl-2,4-dioxo-1,3,5-triazino[1,2-a]benzimidazoles.     

Synthesis of carbamoylpyridine and imidazo[1,5-a]pyridin-1,3-diones via ortho-acetalhydantoin intermediates

A new method for preparing carbamoylpyridine and imidazo[1,5-a]pyridin-1,3-dione rings from an ortho-acetalmethylideneimidazolidin-2,4-dione is described.     

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.     

Condensed Tetrazolo-1,3,5-triazines. 2. Alkylation and Nucleophilic Substitution of 5-Trinitromethyltetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]-1,3,5-triazin-7-ones

A new heterocyclic compound, 3-methyl-5-trinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one, was synthesized by the reaction of methyl iodide and the silver salt of 5-trinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one. An X-ray diffraction structural analysis of this product was carried out and feasibility was demonstrated for the nucleophilic substitution of the trinitromethyl group in this compound by the action of phenol, phenol derivatives, and thiophenol.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 582–588, April, 2005.     

Three practical approaches for the synthesis of novel 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines

Novel 4,7-dihetarylpyrazolo[1,5-a][1,3,5]triazines were synthesized from three different approaches. The first one, involved a one-step reaction between 5-amino-3-hetaryl-1H-pyrazoles and O,S-diethyl hetaroylimidothiocarbonates or S,S-diethyl hetaroylimidodithiocarbonates under solvent-free conditions employing microwave irradiation as the energy source. In the second approach, conventional heating under reflux in DMF as solvent was used instead of the microwave irradiation; and the third one was achieved from a two-step sequence through the treatment of 5-amino-3-hetaryl-1H-pyrazoles with hetaroyl isothiocyanates and the subsequent S-alkylation and cyclization process in DMF as solvent. Some intermediates were isolated and characterized to support the regiochemistry of the studied reactions. The structures of the new compounds were unambiguously established by spectroscopic and analytical techniques.