Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

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).     

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.     

Solid-phase synthesis of pyrido[2,3-d]pyrimidin-7-ones

A novel solid-phase method for the synthesis of 4-methyl-pyrido[2,3-d]pyrimidin-7-one compounds with two diversity points is described. The polymer supported methylsulfonyl derivatives A₃, achieved by coupling compound G with different resin-bound amines A₁ followed by oxidation with MCPBA, are substituted with several amines R₁R₂NH. Final cleavage affords 126 compounds having formula H in good yield and purity.     

Selective bifunctionalization of pyrido[2,3-d]pyrimidines in positions 2 and 4 by SNAr and palladium-catalyzed coupling reactions

Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with various nucleophiles was investigated. Suzuki and Stille cross-coupling reactions on monosubstituted compound 4-tert-butylamino-2-chloro-pyrido[2,3-d]pyrimidine were performed 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.     

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.     

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.     

Synthesis of novel pyrido[2,3-e][1,3]oxazines

The preparation of novel pyrido[2,3-e][1,3]oxazines starting from 3-hydroxy-pyridine-2-carbonitrile, N-aralkoxy-3-hydroxy-pyridine-2-carboxamides and 3-hydroxy-pyridine-2-carboxylic acid hydrazides is described.     

A novel three-component one-pot synthesis of pyrano[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines using microwave heating in the solid state

Microwave-assisted three-component cyclocondensation of barbituric acids 1, benzaldehyde 2 and alkyl nitriles 3 proceeds in the absence or presence of triethylamine to afford pyrano[2,3-d]pyrimidines 4 and 6-aminouracils 5 or 6-hydroxyaminouracils 6 react with 2 and 3 under identical conditions to yield pyrido[2,3-d]pyrimidines 7, all in high yields.     

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 of 2,6-disubstituted pyrido[2,3-b][1,4]oxazines

A new preparative method for pyrido[2,3-b][1,4]oxazines from 6-substituted 3-nitro-2-pyridones is demonstrated. This method consists of two steps: O-alkylation and reductive cyclization. In the former step, the bulkiness of both starting nitropyridones and C2 reagents is found to be essential for avoiding N-alkylation, which undergoes O-alkylation efficiently. The subsequent reductive cyclization affords pyridoxazines with carbon substituents at both the 2- and the 6-positions that have not been available.     

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.     

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%).     

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 2-aminothieno[3,2-d]thiazoles and selenolo[3,2-d]thiazoles

In this work, we described the synthesis of 3-isothiocyanatoselenophenes starting from 3-aminoselenophenes (using thiophosgene). Those compounds were then converted to the corresponding thioureas in the presence of ammonium hydroxide. Cyclization in 2-aminoselenolo[3,2-d]thiazoles was achieved using DDQ. 2-Aminothieno[3,2-d]thiazoles were obtained from 3-isothiocyanatothiophenes using the same pathway.     

Cyclisation of 3-alkenylpyrido[1,2-a]pyrimidines to furo[2,3-d]pyrido[1,2-a]pyrimidines

3-Alkenylpyrido[1,2-a]pyrimidines react under mild conditions to give novel tricyclic furo[2,3-d]pyrido[1,2-a]pyrimidines in high yields. The cyclisation takes place in the presence of an acid catalyst. The product yield is affected by the type and the strength of the acid used. Exceptionally high yields were obtained when an organic acid like trifluoromethanesulfonic acid and trifluoroacetic acid were used. On the other hand, sulfuric acid gave the best results of the inorganic acids examined.     

Synthesis of new compounds containing the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system as a substructure

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.     

Diastereoselective one-pot synthesis of novel ABCD-fused chromeno[2,3-d]pyrazolo[3,4-b]pyridines

A new aspect concerning chromone chemistry leading to the one-pot synthesis of functionalized novel ABCD-fused chromenopyrazolopyridines has been described. The synthesis involves a multicomponent reaction of chromone-3-benzoylhydrazones with isocyanides and acetylenedicarboxylates, whereupon novel complex tetracyclic benzopyrone derivatives containing three stereogenic centres were formed. The structure elucidation of the products was accomplished by 1D and 2D NMR experiments and confirmed by X-ray crystallographic analysis. Full assignment of all ¹H and ¹³C NMR chemical shifts has been unambiguously achieved. The reaction mechanism is also discussed. In addition, eight chromenopyrazolopyridine derivatives were tested for possible biological activity (antioxidant and lipid peroxidation inhibition).