Efficient palladium-mediated or base-induced 5-endo-dig cyclisation of C5-alkynylated pyrimidine derivatives: conventional and microwave-assisted synthesis of novel furo[2,3-d]pyrimidines

A series of the novel 5-alkynyl- and furo[2,3-d]pyrimidine derivatives in which the sugar moiety is replaced by a methoxymethyl (MOM) group is synthesised using the Sonogashira cross-coupling reaction under both conventional and microwave conditions, in good to excellent yields. The 5-endo-dig cyclisation of 5-alkynylpyrimidine derivatives promoted by a Pd-catalyst or base gives the corresponding furo[2,3-d]pyrimidines in good yields.     

Spirooxindoles: reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins

A simple and efficient cyclocondensation reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5′-pyrrolo[2,3-d]pyrimidine] and spiro[indoline-pyrido[2,3-d:6,5-d′]dipyrimidine] derivatives is reported.     

Synthesis of 6-substituted 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones using the Vilsmeier reaction

The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50-80%. Functionalization of these dihydropyridopyrimidine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carboxaldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine derivatives.     

Studies on uracils: a facile one-pot synthesis of oxazino[4,5-d]-, pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines using microwave irradiation in the solid state

N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent yields. Under identical conditions, N,N-dimethyl-6-amino-5-formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.     

Studies on uracils: synthesis of novel pyrido[2,3-d]pyrimidine oxides via ring transformation of isoxazolo[3,4-d]pyrimidine

The reaction of isoxazolo[3,4-d]pyrimidine 1 and cyanoolefins 2 in the presence of triethylamine (Et₃N) as a catalyst afforded an unprecedented one-pot synthesis of biologically important pyrido[2,3-d]pyrimidine oxides 3 in excellent yields.     

Synthesis of novel oxindolylpyrrolo[2,3-d]pyrimidines via a three-component sequential tandem reaction

A novel one-pot three-component reaction of 6-amino-uracil, isatin, and acetophenone was accomplished through a programmed pH variation for the synthesis of 5-(2-oxoindolin-3-yl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione derivatives. The reaction was conducted in a sequential tandem manner to give the oxindole substituted pyrrolo[2,3-d]pyrimidine products in good to excellent yields. Despite of timing all the processes were carried out in one pot. Most of these novel compounds show narrow to good spectrum of antimicrobial activities in vitro.     

Synthesis of novel 5,6-substituted furo[2,3-d]pyrimidines via Pd-catalyzed cyclization of alkynylpyrimidinols with aryl iodides

A flexible method for the synthesis of 5,6-disubstituted furo[2,3-d]pyrimidine derivatives is described. The key step is a palladium-catalyzed arylative cyclization of alkynylpyrimidinols with various aryl iodides, which gave the title compounds in 36-75% yield.     

Synthesis and photophysical properties of oligoarylenes with a pyrrolo[2,3-d]pyrimidine core

The palladium-catalyzed Suzuki-Miyaura reaction of 2,4-dichloropyrrolo[2,3-d]pyrimidine with aryl boronic acids has been studied. Pd(OAc)₂/dicyclohexyl(2-biphenyl)phosphine/K₃PO₄ was found to be an efficient catalyst system to prepare 4-aryl-2-chloro- and 2,4-diarylpyrrolo[2,3-d]pyrimidines. Novel non-linear molecules consisting of a pyrrolo[2,3-d]pyrimidine core and aryl branches have been elucidated as blue light-emitters with fluorescence quantum yields ranging from 4% to 67% in THF solution. The impact of an electron-withdrawing t-BuOCO group attached to the pyrrole ring of pyrrolopyrimidine derivatives on optical properties is discussed.     

Synthesis of 1H-pyrazolo[3,4-d]pyrimidines via solid-phase Aza-Wittig/electrocyclic ring closure reaction

An elegant solid-phase synthetic route of pyrazolo[3,4-d]pyrimidine derivatives via Aza-Wittig/electrocyclic ring closure reaction was developed and validated. By manipulating the R group from the primary amine building block, one can easily prepare the library of pyrazolo[3,4-d]pyrimidine derivatives.     

Tandem reactions of 6-phenylethynylpyrimidine-5-carbaldehydes with alcohols: regioselective synthesis of 5-alkoxy-(7Z)-7-benzylidene-5,7-dihydrofuro[3,4-d]pyrimidines and 5-alkoxy-7-phenyl-5H-pyrano[4,3-d]pyrimidines

An efficient and versatile tandem processes of acetalisation and cycloisomerization reactions have been developed for the reactions of 6-phenylethynylpyrimidine-5-carbaldehydes. The influence of the catalyst and role of the substituent in the position 4 of the pyrimidine ring have been studied. Regioselective synthesis of 5,7-dihydrofuro[3,4-d]pyrimidine and pyrano[4,3-d]pyrimidine cores is described.     

Indium chloride catalyzed intramolecular cyclization of N-aryl imines: synthesis of pyrrolo[2,3-d]pyrimidine annulated tetrahydroquinoline derivatives

The intramolecular aza Diels-Alder cyclization reaction of aldimines derived from aromatic amines and N-prenyl/cinnamyl derivatives of pyrrolo[2,3-d]pyrimidine were efficiently catalyzed by InCl₃ to afford the corresponding tetrahydroquinoline derivatives in good yields.     

Synthesis of pyrido[2,3-d]pyridazines and pyrazino[2,3-d]-pyridazines—novel classes of GABAA receptor benzodiazepine binding site ligands

Novel syntheses of 2,3,8-trisubstituted pyrido[2,3-d]pyridazines and 2,3,5-trisubstituted pyrazino[2,3-d]pyridazines are described. Two complementary routes to pyrido[2,3-d]pyridazines were developed, the first of which began by constructing the pyridine ring, and the second of which started by constructing the pyridazine ring. Pyrazino[2,3-d]pyridazines were prepared in a route employing an aza-Wadsworth-Emmons cyclization as the key step. The resulting compounds were found to be high affinity ligands for the GABA_A receptor benzodiazepine binding site.     

A modular approach to 4,5-diaminopyrrolo[2,3-d]pyrimidines and 2,4,5-triaminopyrrolo[2,3-d]pyrimidines

A short and highly modular approach to various 4,5-diaminopyrrolo[2,3-d]pyrimidines and 2,4,5-triaminopyrrolo[2,3-d]pyrimidines was developed starting from 4-chloro-5-halopyrrolo[2,3-d]pyrimidines and 5-bromo-2,4-dichloropyrrolo[2,3-d]pyrimidine, respectively. Direct amination at the 5-position was achieved without the use of transition metals or other catalysts in 32-86% yield. Ten examples are given.     

Cascade assembly of N,N′-dialkylbarbituric acids and aldehydes: a simple and efficient one-pot approach to the substituted 1,5-dihydro-2H,2′H-spiro(furo[2,3-d]pyrimidine-6,5′-pyrimidine)-2,2′,4,4′,6′(1′H,3H,3′H)-pentone framework

Cascade assembly of N,N′-dialkylbarbituric acids and aldehydes in the presence of bromine leads to the selective and efficient formation of substituted 1,5-dihydro-2H,2′H-spiro(furo[2,3-d]pyrimidine-6,5′-pyrimidine)-2,2′,4,4′,6′-(1′H,3H,3′H)-pentones in 70-88% yields via a complex cascade process. Spirobarbiturates containing the furo[2,3-d]pyrimidine framework are a class of compounds with interesting pharmacological and physiological activity.     

A short, concise synthesis of queuine

A short, concise synthesis of queuine was accomplished in a 36% overall yield through a convergent scheme utilizing a reductive amination as the penultimate step. The synthesis demonstrates the utility of silylation to facilitate reactions of various pyrrolo[2,3-d]pyrimidine intermediates, and offers the possibility of easily accessing related pyrrolo[2,3-d]pyrimidines as well as making additional analogues of queuine.     

Application of cyclic-1,3-diketones in domino and multicomponent reactions: facile route to highly functionalized chromeno[2,3-d]pyrimidinones and diazabenzo[b]fluorenones under solvent-free conditions

A facile and efficient protocol for the synthesis of chromeno[2,3-d]pyrimidinones and diazabenzo[b]fluorenones has been developed by one-pot three-component cyclocondensation of aldehydes, cyclic-1,3-diketones and 1,3-dimethylbarbituric acid in the presence of InCl₃ or P₂O₅ under solvent-free conditions.     

A novel and efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4,7-trione and pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives

An efficient and direct procedure for the synthesis of pyrimido[4,5-d]pyrimidine-2,4,7-trione derivatives has been described under microwave-assisted conditions. Reaction of 6-amino-1,3-dimethyluracil with aromatic aldehydes resulted in the formation of pyrido[2,3-d:6,5-d] dipyrimidine-2,4,6,8-tetrone derivatives.     

Antimony trichloride catalyzed three-component reaction of urea, aldehydes and cyclic enol ethers: a novel route to 4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones

Antimony trichloride efficiently catalyses diastereoselective three-component reaction of urea, aromatic aldehydes and 2,3-dihydrofuran or 3,4-dihydro-2H-pyran leading to 4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones and 4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-ones, respectively in good yield.     

New HA 14-1 analogues: synthesis of 2-amino-4-cyano-4H-chromenes

The synthesis of 2-amino-4-cyano-4H-chromene derivatives as new HA 14-1 analogues by a simple and efficient method is reported. In addition, the reaction of 2-amino-2H-chromene-3-carbonitriles, salicylaldehydes and amines results in the formation of new chromeno[2,3-d]pyrimidine derivatives.     

Optical study of the formation of pyrrolo[2,3-d]pyrimidine-based fluorescent nanoaggregates

Pyrrolo[2,3-d]pyrimidine derivatives possessing different sterically-hindered end-groups at position 7 of the heterocycle were studied and compared with respect to nanoaggregate formation ability by the reprecipitation method in aqueous solutions. The emergence of nanoaggregates with an increasing water fraction in THF/water mixture was traced by observing sudden changes in spectral and transient fluorescence dynamics accompanied by fluorescence efficiency turn-on. The aggregation induced emission with a maximal 20-fold emission efficiency enhancement was obtained. Tuning of the nanoaggregates sizes from about 50 nm to 600 nm by increasing the THF/water ratio was revealed by electron microscopy. Almost perfect spherical shapes of the nanoaggregates and their structureless fluorescence bands similar to those of their neat amorphous films suggested an amorphous-like nature of the pyrrolo[2,3-d]pyrimidine-based nanoparticles.