A three-component synthesis of pyrido[2,3-d]pyrimidines

A new, high yield multicomponent reaction providing multifunctionalized pyrido[2,3-d]pyrimidines in a microwave-assisted one-pot cyclocondensation of α,β-unsaturated esters, amidine systems and malononitrile (or ethyl cyanoacetate) is described (the ‘Victory’ reaction).     

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.     

Tertiary amine effect: synthesis of some novel spirosubstituted pyrido[2,3-d]pyrimidines

5-Formyl-6-tertiaryamino uracils 3 prepared from 6-chloro-5-formyl uracil derivative 1 react with barbituric acids 4 in the presence of base catalyst to afford a novel class of spirosubstituted pyrido[2,3-d]pyrimidines 5 via 1,6-electro-cyclisation in excellent yields.     

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.     

Solid supported synthesis of structurally diverse dihydropyrido[2,3-d]pyrimidines using microwave irradiation

We have synthesized a library of 16 dihydropyrido[2,3-d]pyrimidines in high yields (82-92%) on solid support using microwave irradiation.     

One-pot synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives using Fischer carbene complex

A new route for the synthesis of furo[2,3-h]quinoline and furo[2,3-h]isoquinoline derivatives have been explored through the coupling of carbene complexes with pyridine-bridged enynes. This reaction process, involving the annulation of both furan and benzene ring on to a pre-existing pyridine ring is highly efficient in the presence of triphenylphosphine as ligand additive.     

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.     

Application of the intramolecular aza-Wittig reaction to the synthesis of pyrido[2,3-d]pyrimidines

Pyrido[2,3-d]pyrimidines are synthesized in a two-step procedure from amides and tetrazolo[1,5-a]pyridine-8-carbonyl chloride. Reaction of the crude imides with triphenylphosphine effects an intramolecular aza-Wittig reaction to afford a variety of substituted pyrido[2,3-d]pyrimidines in good to moderate yields (30-76%).     

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.     

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.     

Facile synthesis and biological activities of novel fluorine-containing pyrido[4,3-d]pyrimidines

Fourteen novel 3-substituted-5-methyl-4-methylene-7-alkylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitriles, compounds 4a-n, were designed and synthesized via a facile regioselective cyclization process. The intermediate 2 reacted with triethyl orthoformate (molar ratio is 1:4) in the presence of acetic anhydride to give formamidate 3, which was cycled to 4 regioselectively upon addition of different amines at mild condition. The structures of compounds 4a-n were confirmed by IR, ¹H NMR, MS and elemental analysis. The preliminary bioassay indicated that some compounds possess significant herbicidal activity against the roots of rape and barnyard grass, especially when the fluorine atom was introduced to the para position of the substitutents on pyrimidine ring; some compounds showed fungicidal activities against Rhizoctonia solani, Botrytis cinereapers, Gibberella zeae, Dothiorella gregaria, Colletotrichum gossypii as well, and the introduction of fluorine has negative effect on the antifungal activities.     

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.     

Synthesis of novel 2,3-substituted-2,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-diones

Novel 2,3-substituted-2,4-dihydro-pyrazolo[4,3-d]pyrimidine-5,7-diones were successfully synthesized with moderate to good yields using a new synthetic approach. The structures of the regio-isomers in this series were determined by single crystal X-ray analysis and NMR spectra.     

A novel multicomponent reaction to synthesize substituted furo[3,2-c]chromenes via a Pd-catalyzed cascade process

A novel one-pot three-component reaction for the synthesis of multisubstituted furo[3,2-c]chromenes using 3-(1-alkynyl)chromones, aryl iodides, and alcohols is developed via Pd-catalyzed cascade 1,4-addition and cyclization. This synthetic approach efficiently generates two C-O bonds and one C-C bond to construct diverse furo[3,2-c]chromenes structures.     

Synthesis and reactions of 2-substituted 1-phenyl-4-oxo-1,4-dihydropyrido-[2,3-d]pyrimidines

2-Methyl-4-oxo-1-phenyl-1,4-dihydropyrido[2,3-d]pyrimidine was acylated by succinic and trifluoroacetic anhydrides and also underwent the Claisen reaction with diethyl oxalate and ethyl oxanilate to give acyl derivatives at the methyl group, which, according to UV, IR, and¹H NMR spectra, exist as enaminocarbonyl and iminoenol tautomers with intramolecular hydrogen bonds.Perm State Pharmaceutical Academy, Perm 614600, Russia. e-mail: GIO@pharm.perm.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1119–1122, August, 2000.     

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.     

Synthesis of furo[2,3-c]-2,7-naphthyridine derivatives via domino heterocyclization reaction

2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles were found to react with substituted oxiranes yielding 5,6-diamino-8-dialkylamino-1,2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitriles. The oxirane ring was shown to be opened selectively from the unsubstituted side and further cyclization occurred with participation of 3-CN, but not 5-CN of the starting pyridines. The furonaphthyridines obtained were converted into 2-dialkylamino-5-methyl-9,10-dihydro-4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-5,6,9,10-tetrahydro-4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles by treatment with acetic anhydride and cyclohexanone, respectively. The structure of prepared compounds was confirmed unambiguously by X-ray crystallographic study.     

Synthesis of enantiopure furo[2,3-b]pyrroles

A simple method for the preparation of enantiopure furo[2,3-b]pyrroles, a rare class of concave bicyclic nitrogen and oxygen heterocycle, in promising yield has been developed. The 3-substituted pyrrolidinediones prepared from (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (Garcinia acid) have been cyclized diastereo as well as enantioselectively to furo[2,3-b]pyrroles. The cyclization follows Baldwin’s rule.     

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.     

Synthesis of 4-aza analog of ramelteon: a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative as melatonin receptor ligand

The 4-aza analog of ramelteon (−)-1, a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridine derivative, was synthesized via the intramolecular inverse electron demand Diels-Alder reaction followed by fluoride-induced desilylation-cyclization.