Highly efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4-dione derivatives catalyzed by iodine

A new and efficient synthesis of pyrimido[4,5-d]pyrimidine-2,4-dione derivatives through the reaction of 6-aminouracils and N,N′-bis(arylmethylidene) arylmethane in the presence of molecular iodine as a readily available and feasible catalyst.     

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.     

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.     

Studies on 6-[(dimethylamino)methylene]aminouracil: a facile one-pot synthesis of novel pyrimido[4,5-d]pyrimidine derivatives

The reactions of 6-[(dimethylamino)methylene]aminouracil 1, with various heterocumulenes such as aryl isocyanates and isothiocyanates give rise to novel pyrimido[4,5-d]pyrimidines in excellent yields, after elimination of dimethylamine from the (1:1) cycloadducts and tautomerisation. This procedure provides a convenient method for direct synthesis of pyrimido[4,5-d]pyrimidine derivatives under thermal conditions.     

Hetero Diels-Alder reaction: a novel strategy to regioselective synthesis of pyrimido[4,5-d]pyrimidine analogues from Biginelli derivative

A number of potent pyrimido[4,5-d]pyrimidine analogues have been efficiently synthesized by hetero Diels-Alder cycloaddition of 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester, a Biginelli compound with N-arylidine-N′-methylformamidines and N-arylidine guanidine in dry toluene. Structures of the newly obtained cycloadducts were established on the basis of elemental and spectral (IR, NMR and Mass) data. The molecular mechanism of the observed cycloaddition reaction has been investigated theoretically by means of PM3 semiempirical method. Transition state structure determinations and activation energy calculations have shown the preference for the endo approach over the exo approach of dienophile towards the diene fragments used, which is consistent with the experimental results. The studied cycloadditions proceed via an asynchronous concerted mechanism. It was demonstrated that FMO theory could reasonably predict the relative reactivities between dienes as well as indicating that these reactions belong to normal Diels-Alder type cycloadditions.     

A straightforward synthesis of pyrimido[4,5-b]quinoline derivatives assisted by microwave irradiation

Several pyrimido[4,5-b]quinolines, flavin analogues, have been prepared by assisted microwave intramolecular cyclization of N⁴-substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes. The reaction takes place with hydrolysis of amino-group and chlorine. Particularly valuable features of this method included the broader substrate scope and operational simplicity as well as increased safety for small-scale high-speed synthesis.     

An efficient synthesis of novel 1,3-oxazolo[4,5-d]pyridazinones

A convenient and versatile synthetic approach to substituted 1,3-oxazolo[4,5-d]pyridazinones is developed. The oxazole ring was formed upon reaction of 5-amino-4-hydroxy-3(2H)-pyridazinone with various carboxylic acid derivatives using a microwave-assisted procedure, which favors the reaction time and purity of the resulting products. The developed methodology is suitable for rapid, parallel, automated synthesis of oxazolopyridazinone libraries.     

An efficient one-pot synthesis of pyrimido[2,1-b][1,3]thiazine derivatives by reaction of activated acetylenes, thiouracils, and isocyanides

The reactive 1:1 zwitterionic intermediate, formed by the addition of isocyanides to dialkyl acetylenedicarboxylates, was trapped by thiouracils to yield a ketenimine intermediate, which cyclized and then rearranged to afford pyrimido[2,1-b][1,3]thiazines in good 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.     

One-pot synthesis and antiproliferative evaluation of pyrazolo[3,4-d]pyrimidine derivatives

An efficient one-pot methodology for the synthesis of pyrazolo[3,4-d]pyrimidines was developed by using 5-aminopyrazoles with formamide in presence of PBr₃ as the coupling agent. Among the examples presented in this work, compounds 41 and 54-56 with phenyl or 2-quinolinyl groups at N-1 and p-Me-Ph, p-Cl-Ph, or p-OMe-Ph group at C-3 position in the pyrazole ring possessed better potency against NCI-H226 and NPC-TW01 cancer cells with GI₅₀ values between 18 μM and 39 μM.     

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.     

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 fused pyrrolo[3,4-d]tetrahydropyrimidine derivatives by proline-catalyzed multicomponent reaction

Novel proline-catalyzed multicomponent reactions (MCRs) for the synthesis of fused pyrrolo[3,4-d]tetrahydropyrimidines 7 and 9 with different substituted patterns have been developed, which provide rapid access to a library of compounds 7 and 9 in medium to excellent yields, by using N-methyl-α-aryl(alkyl)aminomaleimides, amines, and aldehydes as reactants. The catalyst and the ratio of reactants were found to have significant impact on these reactions, and a reasonable mechanism was also proposed.     

Polyethylene glycol (PEG-400): an efficient green reaction medium for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones under catalyst-free conditions

A simple and an efficient eco-friendly methodology has been developed for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones in excellent yields under catalyst-free-conditions using inexpensive and non-toxic polyethylene glycol (PEG-400) medium. This new protocol offers an environmental acceptability, shorter reaction time, room temperature, low cost, high yields, and recyclability of the PEG-400 medium are the important features. This method provides a green and much improved protocol over the existing methods.     

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.     

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.     

Synthesis and spectroscopic characterization of novel 2-amino-4,5,6,7-tetrahydro-3H-cyclopenta[d]pyrimidine and pyrimido[1,2-a]pyrimidine derivatives

2-Aminocyclopenta[d]pyrimidines 3a-c were achieved via a one-pot, three-component reactions of cyclopentanone 1, aromatic aldehyde and guanidine hydrochloride (1:2:1 molar ratio). Also, cyclization of 2,5-bis-(arylmethylidene)cyclopentanones 2 with guanidine hydrochloride (1:1 molar ratio) in methanol in the presence of sodiummethoxide afforded cyclopenta-[d]pyrimidines 3. Compound 3a has been shown to be a useful building block for the synthesis of some novel pyrimido[1,2-a]pyrimidines 5, 7 and 12. The structures of the newly synthesized compounds were confirmed on the basis of analytical and spectral data.     

A facile synthesis and herbicidal activities of novel fluorine-containing thiazolo[4,5-d]pyrimidin-7(6H)-ones

Eighteen novel 5-alkylamino-6-aryl-3-phenyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-ones 5a-r were designed and easily synthesized via a tandem aza-Wittig reaction. Treatment of iminophosphorane 2 with aromatic isocyanate gave carbodiimide 3, which reacted with fluoro-substituted alkylamines to provide the title compounds in 65-87% isolated yields using sodium ethoxide as catalyst. All compounds 5 were confirmed by IR, ¹H NMR, MS and elemental analysis, and compound 5p was further analyzed by single-crystal X-ray diffraction. The preliminary bioassay indicated that some compounds showed significant inhibition activities against the root growth of rape and barnyard grass at a dosage of 100 mg/L.     

Rapid access to multi-substituted pyrimido[4,5-b][1,4]diazepine-2,4,6-trione and pyrimido[4,5-b][1,4]diazepine-2,4-dione as novel and versatile scaffolds for drug discovery

A novel pyrimido[4,5-b][1,4]diazepine-2,4,6-trione was synthesized with an efficient strategy. Especially, the key intermediate 2,4-dimethoxypyrimido[4,5-b][1,4]diazepin-6-one was promoted by one pot tandem reduction-cyclization with Na₂S₂O₄. Subsequently, reduction of lactams 6 with LiAlH₄ afforded a more flexible scaffold of pyrimidodiazepines. The synthetic strategy was versatile since it facilitated the sequential functionalization on the pyrimidodiazepine at three positions. Thus a convenient and effective method for the rapid preparing of multi-substituted pyrimido[4,5-b][1,4]diazepines was developed.     

Novel isocyanide-based three-component reaction: a facile synthesis of substituted 1H-chromeno[2,3-d]pyrimidine-5-carboxamides

A mild and efficient method for the synthesis of 1H-chromeno[2,3-d]pyrimidine-5-carboxamide derivatives via a one-pot, three-component reaction of an isocyanide, barbituric acid, and a salicylaldehyde in the presence of acetic acid in ethanol/water mixture at 75 °C is reported. This high atom economy reaction led to the construction of one benzopyran ring, and one amide group in a single synthetic step.