Studies on the chemistry of 5-propynyloxy- and 5-propynylthiopyrimidines: New syntheses of furo- and thieno[3,2-d]pyrimidines

The utility of certain 5-alkynyloxy-, 5-alkynylthio, and 5-alkynylsulfinyl-pyrimidines as precursors of 7-substituted furo[3,2-d]- and thieno[3,2-d]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3-dimethyl-5-(2-propynyloxy)uracil ( 6 ) cyclizes to afford 1,3,7-tri-methylfuro[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 12 ) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5-(2-butynyloxy)pyrimidine ( 7 ), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8-methylpyrano[3,2-d]pyrimidine 8 in methyl sulfoxide and the 6,7-dimethylfuro[3,2-d]pyrimidme 11 in dimethylformamide. The 5-(2-propynylthio)pyrimidine 15 affords the allene 19 and the 1-propyne 22 when treated with various bases, but none of the 7-methylthieno[3,2-d]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio-Claisen rearrangement process to afford the 6-methylthieno[3,2-d]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7-thiomethoxymethyl substituent derived from the solvent. Heating the 5-(2-propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3-dimethyl-7-formylthieno[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 29 ) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′-proton of 23 . This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma-tropic rearrangements, and the intermediacy of a dihydrothieno[3,2-d]pyrimidine such as compound 30.     

Synthesis of 4-(trifluoromethyl)pyrido[4,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidine derivatives

Earlier unknown 4-alkoxy-and 4-hydroxy-5-methyl-4-trifluoromethyl-1,4-dihydropyri-do[4,3-d]pyrimidines were obtained by the reaction of 5-acetyl-4-dimethylaminovinyl-6-(trifluoromethyl)pyrimidine with alcoholic (aqueous) solutions of NH₃. The former eliminate alcohol (water) on sublimation in vacuo to be converted to 5-methyl-4-(trifluoromethyl)-pyrido[4,3-d]pyrimidine. The latter upon the action of alcohols (water) under mild conditions were reverted to the corresponding 4-alkoxy-and 4-hydroxydihydropyrido[4,3-d]pyrimidines.     

Synthesis of N-Alkylated Derivatives of Pyrazolo[1,5-a]pyrimidine and Their Reaction with Methylamine

With the object of studying the factors influencing the course of enamine rearrangements, we have carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the NOEDIF NMR spectroscopic method for the cases of 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidines it was found that addition of the alkyl group occurs at the N₍₄₎ atom of the pyrimidine fragment in the pyrazolo[1,5-a]pyrimidine. It was shown that, when reacting with an alcoholic solution of methylamine, the 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidine iodomethylates undergo decomposition to give 5-methylamino-3-phenylpyrazole and 5-(1,3-diphenyl-3-methylamino-2-propenylid-1-ene)amino-3-phenylpyrazole.     

Synthesis,in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents

New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4-d]pyrimidine scaffold. The docking analyzes have shown that 7-piperazine substituted oxazolo[4,5-d]pyrimidines 8a – 8c could be potential VEGFR2 inhibitors with high free energy of ligand–protein complex formation (ΔG: −10.1, −9.6, −9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5-d]pyrimidines 8a – 8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4-[5-(4-Chlorophenyl)-2-phenyl[1,3]oxazolo[4,5-d]pyrimidin-7-yl]piperazin-1-ium trifluoroacetate ( 8c ) exhibited a slightly higher antiproliferative effect (IC₅₀=0.21 μm ) than doxorubicin (IC₅₀=0.36 μm ) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC₅₀=1.7 μm ) and HCT-116 (IC₅₀=0.24 μm ) cells.     

Synthese von 2,4-Diamino-thieno[2,3-d]pyrimidin-Derivaten

Synthesis of 2,4-Diamino-thieno[2,3-d]pyrimidines Condensation of 2-aminothiophene-3-carbonitrile ( 4 ) with guanidine or sequential addition of CS₂ and NH₃ to 4 provides 2,4-diaminothieno[2,3-d]pyrimidine ( 7 ). This compound yields, after sequential addition of sec-BuLi and either [3-(trifluoromethyl)benzene]sulfenyl chloride ( 8 ) or the corresponding disulfide 9 , followed by acidic work up, 2,4-diamino-6-{[3-(trifluoromethyl)phenyl]thio}thieno[2,3-d]pyrimidine ( 10 ). In another approach, 2-amino-5-{[3-(trifluoromethyl)phenyl]thio}thiophene-3-carbonitrile ( 11 ) obtained from 4 and 8 is transformed to 10 by condensation with guanidine. Corresponding to the second route, 2,4-diamino-6-[(naphth-2-yl)thio]thieno-[2,3-d]pyrimidine ( 16 ) is synthesized. Oxidation of 10 with m-chloroperbenzoic acid gives 2,4-diamino-6-{[3-(tri-fluoromethyl)phenyl]sulfinyl}thieno[2,3-d]pyrimidine ( 13 ).     

A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.     

2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物的合成

以2-溴丙酸甲酯、α,α-二氯甲基甲醚和胍唑为原料, 经缩合以及环化反应制得2-氨基-6-甲基-5-氧代-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶. 为了提高其在有机溶剂中的溶解性, 该化合物再同1-溴丁烷发生亲核取代反应得到了2-氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶, 然后与芳基醛和叔丁基异氰发生Ugi多组分反应, 合成了一系列具有潜在催吐活性的2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物, 产品结构经质谱、核磁共振谱及元素分析确认.     

Synthesis and in vitro evaluation of some new pyrimidines and related condensed ring systems as potential anticancer agents

Several new pyrimidines 6–11, 18–20 , furo-, thieno-, and pyrrolo[2,3-d]pyrimidines 3, 8, 12 , triazolo-[4,3-a]pyrimidines 14, 15, 16 and tetrazolo[1,5-a]pyrimidine 17 were prepared from the known intermediate 5-(2-hydroxyethyl)-6-methyl-2-thiouracil ( 2 ). Compound 7 (4-chloro-5-(2-chloroethyl)-2-methylthio-6-methyl-pyrimidine) exhibited weak antitumor activity in vitro.     

Sur diverses possibilités de formation de pyrimidines à partir de formyl-3 chromone

Guanidine transforms the following: (a) 3-formylchromone into a mixture of 2-amino-5-(2-hydroxybenzoyl)pyrimidine and 2-amino-5H-[1]-benzopyrano[4,3-d]pyrimidine; (b) the diacetate of 3-methylidyne-chromone into 2-amino-5-hydroxy-5H-[1]benzopyrano[4,3-d]pyrimidine; and (c) the oxime of 3-formylchromone into 2-amino-5H-[1]benzopyrano-[4,3-d]pyrimidin-5-one. Thiourea, acetamidine and nitroguanidine can also generate pyrimidines of the same type with 3-formylchromone, the diacetate of 3-methylidynechromone or 3-(1,3-dioxolan)chromone.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

Folate antagonists. 6. Synthesis and antimalarial effects of fused 2,4-diaminothieno[2,3-d]pyrimidines

2,4-Diamino-5,7-dihydro-6H-thiopyrano[4′,3′:4,5]thieno[2,3-d]pyrirnidine, 2,4-diamino-9H-mdeno[1′,2′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-5H-indeno[2′,1′:4,5]thieno[2,3-d]pyrimidine, 9,11-diamino-5,6-dihydronaphtho[1′,2′:4,5]thieno[2,3-d]pyrimidine, 7,9-diamino-5,6-dihydronaphtho[2′,1′:4,5]thieno[2,3-d]pyrimidine, 2,4-diamino-7-benzy]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine, and various 2,4-diamino-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidines were synthesized by cyclization of the requisite fused 2-aminothio-phenene-3-carbonitriles utilizing chloroformamidine hydrochloride in diglyme. Several compounds exhibited strong inhibitory effects against Streptococcus faecalis (MGH-2), Staphylococcus aureus (UC-76), Streptococcus faecium (ATCC 8043), Lactobacillus casei (ATCC 7469), and Pediococcus cerevisiae (ATCC 8081) in vitro, and three compounds displayed antimalarial activity against Plasmodium berghei in mice and P. falciparum (Uganda I) in vitro.     

An efficient,multicomponent, green protocol to access 4, 7-dihydrotetrazolo [1, 5-a] pyrimidines and 5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-ones using PEG-400 under microwave irradiation

Abstract

A facile one-pot synthesis of ethyl 5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine, 5-tert-butyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine, 6,6-dimethyl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-one and 5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-one derivatives were described via a three-component reaction of aldehyde, 5-aminotetrazole and diketones in PEG-400 under microwave irradiation at 110?°C for 30?min. A wide range of diketones such as ethylacetoacetate, tert-butyl acetoacetate, 5,5-dimethylcyclohexane-1,3-dione and 1,3-cyclohexanedione were utilized to carry out the synthesis of different dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones. This method has the advantage of green protocol, operational simplicity, high yields, recyclability of the solvent and involves isolation of the final product without column purification. The scope of this reaction tolerates with aromatic, heteroaromatic and alicyclic aldehydes.     

Recent developments in the chemistry of bicyclic 6-6 systems: Chemistry of pyrido[1,2-c]pyrimidines

The present review provides a study on the structural features, reactions, and synthetic methodologies of pyrido[1,2-c]pyrimidines. The maximum deviation from the mean plane of the pyridopyrimidine skeleton of 4-(pyridin-2-yl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione indicated a reasonably planar system. The aim of this review is to give an overview of the diverse methodologies that have been reported on the chemistry of pyrido[1,2-c]pyrimidines. The different synthetic routes have been grouped according to the way the pyrido[1,2-c]pyrimidine moiety has been created. Thus, pyrido[1,2-c]pyrimidine compounds were obtained by the formation of one bond α to the bridgehead nitrogen atom [6+0(β)] and formation of two bonds from ([3+3], [4+2], and [5+1]) atom fragments. The mechanistic pathways of the reactions are discussed.     

Synthesis of an Isotopically Isomeric Mixture of 1,4,6,8-Tetramethyl[13C2]azulene and Its Thermal Reaction with Dimethyl Acetylenedicarboxylate

Sodium [1,3-¹³C₂]cyclopentadienide in tetrahydrofuran (THF) has been prepared from the corresponding labelled [¹³C₂]cyclopentadiene which was synthesized from ¹³CO₂ and (chloromethyl)trimethylsilane (cf. Scheme 10) according to an established procedure. It could be shown that the acetate pyrolysis of cis-cyclopentane-1,2-diyl diacetate (cis- 22 ) at 550 ± 5° under reduced pressure (60 Torr) gives five times as much cyclopentadiene as trans- 22 . The reaction of sodium [1,3-¹³C₂]cyclopentadienide with 2,4,6-trimethylpyrylium tetrafluoroborate in THF leads to the formation of the statistically expected 2:2:1 mixture of 4,6,8-trimethyl[1,3a-¹³C₂], -[2,3a-¹³C₂]-, and -[1,3-¹³C₂]azulene ( 20 ; cf. Scheme 7 and Fig. 1). Formylation and reduction of the 2:2:1 mixture [¹³C₂]- 20 results in the formation of a 1:1:1:1:1 mixture of 1,4,6,8-tetramethyl[1,3-¹³C₂]-, -[1,3a-¹³C₂]-, -[2,3a-¹³C₂]-, -[2,8a-¹³C₂]-, and -[3,8a-¹³C₂]azulene ( 5 ; cf. Scheme 8 and Fig. 2). The measured ²J(¹³C, ¹³C) values of [¹³C₂]- 20 and [¹³C₂]- 5 are listed in Tables 1 and 2. Thermal reaction of the 1:1:1:1:1 mixture [¹³C₂]- 5 with the four-fold amount of dimethyl acetylenedicarboxylate (ADM) at 200° in tetralin (cf. Scheme 2) gave 5,6,8,10-tetramethyl-[¹³C₂]heptalene-1,2-dicarboxylate ([¹³C₂]- 6a ; 22%), its double-bond-shifted (DBS) isomer [¹³C₂]- 6b (19%), and the corresponding azulene-1,2-dicarboxylate 7 (18%). The isotopically isomeric mixture of [¹³C₂]- 6a showed no ¹J(¹³C,¹³C) at C(5) (cf. Fig. 3). This finding is in agreement with the fact that the expected primary tricyclic intermediate [7,11-¹³C₂]- 8 exhibits at 200° in tetralin only cleavage of the C(1)? C(10) bond and formation of a C(7)? C(10) bond (cf. Schemes 6 and 9), but no cleavage of the C(1)? C(11) bond and formation of a C(7)? C(11) bond. The limits of detection of the applied method is ≥96% for the observed process, i.e., [1,3a-¹³C₂]- 5 + ADM→ [7,11-¹³C₂]- 8 →[1,6-¹³C₂]- 9 →[5,10a-¹³C₂]- 6a (cf. Scheme 6).     

Utility of [4-(3-methoxyphenyl)pyrimidin-2-yl]cyanamide in synthesis of some heterocyclic compounds

N-[4-(3-Methoxyphenyl)pyrimidin-2-yl]cyanamide ( 1 ) was reacted with morpholine and respective binuclephilic reagents namely: ethylenediamine, o-phenylenediamine, o-aminothiophenol, or o-aminophenol to give the corresponding carboximidamide 2 , imidazolidine 3 , and benzazoles 4–6 . While its reaction with hydrazides in DMF at 90°C, gave the corresponding 1,2,4-triazols 7–11 . Also, treatment of cyanamide 1 with heterocycles having both nucleophilic and electrophilic groups (─NH₂/─COOEt) in iso-propanol in presence of catalytic amount of Conc. HCl, gave the corresponding thieno[2,3-d]pyrimidinone 12 and unexpected thieno[3,2-d]pyrimidine 13 instead of bis-thieno[3,2-d]pyrimidine 14 , respectively. While, its reaction with ethyl 5-amino-1,3-thiazole-4-carboxylate yielded the unexpected N-(pyrimidin-2-yl)urea 15 rather than the corresponding thiazolo[5,4-d]pyrimidine 16 . Unexpected N-(pyrimidin-2-yl)thiourea 17 was obtained, when cyanamide 1 reacted with potassium thiolates in iso-propanol with catalytic amount of Conc. HCl.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 1

A series of 7-methylpyrazolo[1,5-a]pyrimidines were reacted with dimethylformamide dimethylacetal to give the corresponding dimethylaminovinyl derivatives. These were reacted with ammonium acetate affording, through a ring closure, a number of 6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidines bearing various substituents on the pyrazole ring. The 6-acetyl-2-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine was used as starting material for obtaining some O-alkyl derivatives. Catalytic transfer hydrogenation of 2-benzyloxy-6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine led to the 2-hydroxy derivative.     

Polycyclic N-Heterocyclic Compounds,Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and Evaluation of Their Antiplatelet Aggregation Activity

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[2′,3′:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro.

Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.     

Hoogsteen-Duplex DNA: Synthesis and base pairing of oligonucleotides containing 1-deaza-2′-deoxyadenosine

Oligodeoxyribonucleotides containing 1-deaza-2′-deoxyadenosine ( = 7-amino-3-(2-deoxy-β-D -erythro-pentofuranosyl)-3H-imidazo[4, 5-b]pyridine; 1b ) form Hoogsteen duplexes. Watson-Crick base pairs cannot be built up due to the absence of N(1). For these studies, oligonucleotide building blocks – the phosphonate 3a and the phosphoramidite 3b – were prepared from 1b via 4a and 5 , as well as the Fractosil-linked 6b , and used in solid-phase synthesis. The applicability of various N-protecting groups (see 4a – c ) was also studied. The Hoogsteen duplex d[(c¹A)₂₀] · d(T₂₀) ( 11 · 13 ; T_m 15°) is less stable than d(A₂₀) · d(T₂₀) ( 12 · 13 ; T_m 60°). The block oligomers d([c¹A)₁₀–;T₁₀] ( 14 ) and d[T₁₀–(c¹A)₁₀] ( 15 ) containing purine and pyrimidine bases in the same strand are also able to form duplexes with each other. The chain polarity was found to be parallel.     

Synthesis and xanthine oxidase inhibitory activity of 4,6-disubstituted 1-p-chlorophenylpyrazolo[3,4-d]pyrimidines

Several 4,6-disubstituted 1-p-chlorophenylpyrazolo[3,4-d]pyrimidines were prepared from 4,6-dichloro-1-p-chlorophenylpyrazolo[3,4-d]pyrimidine and their xanthine oxidase inhibitory activity were tested in vitro.     

Syntheses of 8-aminoimidazo[4′,5′:5,6]pyrido[2,3-d]pyrimiciines: Linear tricyclic analogs of adenine

The syntheses of 8-aminoimidazo[4′,5′:5,6]pyrido[2,3-d]pyrimidines (7), stretched-out versions of the naturally occuring nucleoside base adenine, are reported. Their preparation involves conversion of purine into 5-arninoimidazo[4,5-b]pyrimidine-6-carbonitrile ( 1 ) by reaction with malononitrile, followed by construction of the pyrimidine ring in two steps via the ethoxymethylene derivative 3 . 8-Azapurine can be converted to 8-amino-1,2,3-triazolo[4′,5′:5,6]pyrido[2,3-d]pyrimidines 8 in a similar fashion.