Synthesis of [1,2,3]Triazolo[4,5-d]pyrimidine 3-Oxides

[1,2,3]Triazolo[4,5-d]pyrimidine 3-oxides were synthesized by replacement of the amino group in 6-aminouracil by hydroxyamino, coupling of the resulting 6-hydroxyaminopyrimidine with benzenediazonium salts, and oxidation of 6-hydroxyamino-5-phenylazouracils with a solution of K₃[Fe(CN)₆] in water.     

新型[1,2,3]三唑-[4,5-d]嘧啶酮类衍生物的微波法合成

以卤代烃、邻甲基苯胺、氰基乙酸和乙酰氯为原料,经取代、成环、偶联和关环4步反应,用微波法合成了9个[1,2,3]三唑-[4,5-d]嘧啶酮类衍生物（5a~5i）,其中5a~5e, 5g和5i为新化合物,其结构经¹H NMR, ¹³C NMR和HR-MS(ESI)表征。     

New access to thiazolo[4,5‐d]pyrimidine derivativess

4‐Amino‐5‐bromo‐2‐substituted‐aminopyrimidines are readily obtained from the newly prepared 5‐bromo‐2,4‐dichloro‐6‐methylpyrimidine by sequential treatment with ethanolic ammonia and secondary amines. These compounds were successfully reacted with various isothiocyanates in the presence of sodamide in DMF to form the new thiazolo[4,5‐d] pyrimidine derivatives.     

Synthesis of 1‐substituted [1,2,3]triazolo[4,5‐d]pyridazines as precursors for novel tetraazapentalene derivatives

A series of 1‐substituted 4,5‐diformyl‐[1,2,3]triazole derivatives were prepared by 1,3‐dipolar cyclo‐addition of aryl azides with acetylene dicarboxaldehyde mono‐diethylacetal. The triazoles were readily converted into 1‐substituted [1,2,3]triazolo[4,5‐d]pyridazines in good yields. The 1‐(2‐nitrophenyl)‐[1,2,3]triazolo[4,5‐d]pyridazine was found to be a useful intermediate for the generation of the novel 5H‐benzo[1,2,3]triazolo[1′,2′:1,2]triazolo[4,5‐d]pyridazin‐6‐ium inner salt ring system.     

New 1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidine derivatives II

The 7‐chloro‐3‐(2‐chlorobenzyl)‐ and 7‐chloro‐3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐d]pyrimidines ( 1 and 4 ), by nucleophilic replacement with some hydrazides, gave the corresponding 7‐hydrazidoderivatives ( 2a‐e and 5a‐e ). These, by heating in Dowtherm, underwent an intramolecular cyclization to form the new tricyclic 7‐substituted‐3‐(2‐chlorobenzyl)‐ and 3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidines ( 3a‐d and 6a‐d ). The 7‐hydrazino‐3‐(2‐chlorobenzyl)‐ and 7‐hydrazino‐3‐(2‐fluorobenzyl)‐triazolo‐pyrimidines ( 9a and 9b ) were also prepared via the corresponding mercapto ( 7a and 7b ) and thiomethyl ( 8a and 8b ) derivatives.     

Pyrrolo[3,4‐e][1,2,3]triazolo[1,5‐a]pyrimidine and pyrrolo[3,4‐d] [1,2,3]triazolo[1,5‐a]pyrimidine. New tricyclic ring systems of biological interest

Derivatives of the new ring system pyrrolo[3,4‐e][1,2,3] triazolo[1,5‐a]pyrimidine 6 were prepared in high yields in one step by reaction of 3‐azidopyrrole 3 and substituted acetonitriles. Compound 6b rearranged, upon heating in dimethyl sulfoxide in the presence of water, to pyrrolo[3,4‐d][1,2,3]triazolo‐[1,5‐a]pyrimidine 7.     

Synthesis of [1,2,3]Triazolo[1,5-a]quinoline-3-carboxamides Promoted by Organocatalyst and Base

We described here a simple and metal-free protocol to synthesize [1,2,3]triazolo[1,5-a]quinoline 3-carboxamides through a two-step synthetic strategy, in which the first step uses organocatalysis (10 mol % of diethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, while the second step involves the use of inorganic base (1.2 or 0.1 equiv. of potassium hydroxide). These reactions were performed between β-keto amides and o-carbonyl phenylazides in dimethylsulfoxide as solvent at 70 °C for 2 h. The synthetic protocol is ample, which thirteen examples of secondary [1,2,3]triazolo[1,5-a]quinoline 3-carboxamides were synthesized ranging from good to excellent yields (63-96 %), and six different tertiary [1,2,3]triazolo[1,5-a]quinolines 3-carboxamides were obtained ranging from moderate to good yields (48–76 %).     

New 1,2,3‐triazolo[4,5‐d]1,2,4‐triazolo[3,4‐b]pyridazine derivatives II

New tricyclic 1,2,3‐triazolo‐1,2,4‐triazolo‐pyridazine derivatives, bearing a methyl substituent on the 1,2,3‐triazole ring, were prepared as potential biological agents. N‐Methylation of dimethyl 1,2,3‐triazole‐4,5‐dicarboxylate allowed synthesis of the isomeric 1‐methyl‐4,7‐dihydroxy and 2‐methyl‐4,7‐dihydroxy triazolo‐pyridazines 4a and 4b which, by a chlorination reaction, gave the corresponding 1‐methyl‐4‐chloro‐( 6a ), 1‐methyl‐7‐chloro‐ ( 6b ) and 2‐methyl‐4‐chloro‐ ( 9 ) substituted 1,2,3‐triazolo‐pyridazines. The nucle‐ophilic substitution with hydrazine hydrate and the suitable cyclization to form the 1,2,4‐triazole ring, provided the expected tricyclic isomeric derivatives 8a, 8b and 11 respectively. The p‐methoxybenzyl substituent, introduced as a leaving group to obtain either v‐triazolo‐pyridazine or v‐triazolo‐s‐triazolo‐pyri‐dazine derivatives unsubstituted on the 1,2,3‐triazole ring, appeared inadequate. Some compounds underwent binding assays toward the adenosine A₁and A_2A receptors.     

An expedient synthesis of novel,fused pyrimido[4,5‐d]pyrimidine and pyrimido [5,4‐e] [1,2,4]triazolo[4,3‐c]pyrimidine analogues from 4‐amino‐2,6‐dichloro‐pyrimidine

A number of potent pyrimido[4,5‐d]pyrimidine have efficiently been synthesized by the condensation of 4‐amino‐2,6‐dichloropyrimidine with various substituted benzaldehyde followed by cyclization with ammonium thiocyanate. Also, these newly synthesized derivatives were utilized for the construction of novel pyrimido[5,4‐e][1,2,4]triazolo[4,3‐c]pyrimidine analogues via oxidative cyclization involving 1,5‐hydrogen abstraction. Structure of all the newly constructed derivatives was corroborated by the elemental and spectral data. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:245–253, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20177     

Syntheses of [1,2,3]selenadiazolo[4,5‐e]benzofuran or benzothiophene, [1,2,3]thiadiazolo[4,5‐e]benzofuran or benzothiophene,and 2‐benzofuranyl‐1,3,4‐oxodiazole derivatives

Dehydrogenation of ethyl 3‐methyl‐4‐oxo‐4,5,6,7‐tetrahydrobenzofuran‐2‐carboxylate 1 with 2,2′‐azobi‐sisobutyronitrile and N‐bromosuccinimide gave ethyl 4‐hydroxy‐3‐methylbenzofuran‐2‐carboxylate 3 . Reaction of compounds 3–4 with hydrazine hydrate afforded the corresponding hydrazides 5a‐b . The reaction of 5a‐b with aldehydes yielded substituted hydrazones 6a‐l . Compounds 7a‐d were prepared from compounds 6a‐d and bromine in acetic acid. Lead tetraacetate oxidation of compounds 6e‐l afforded substituted oxadiazoles 8e‐l . Selenium dioxide oxidation of 4‐oxo‐4,5,6,7‐tetrahydrobenzofuran semicarbazones 9, 14a and 4‐oxo‐4,5,6,7‐tetrahydrobenzothiophene 14b gave the tricyclic 1,2,3‐selenadiazoles 10, 15a and 15b respectively. Reaction of semicarbazones 9, 14a and 14b with thionyl chloride afforded the corresponding 1,2,3‐thiadiazoles 12, 16a and 16b respectively.     

2‐Phenanthrenyl–DNA: Synthesis,Pairing, and Fluorescence Properties

Three 2′‐phenanthrenyl‐C‐deoxyribonucleosides with donor (phenNH₂), acceptor (phenNO₂), or no (phenH) substitution on the phenanthrenyl core were synthesized and incorporated into oligodeoxyribonucleotides. Duplexes containing either one or three consecutive phenR residues, which were located opposite each other, were formed. Within these residues, the phenR residues are expected to recognize each other through interstrand stacking interactions, in much the same way as described previously for biphenyl DNA. The thermal, thermodynamic, and fluorescence properties of such duplexes were determined by UV melting analysis and fluorescence spectroscopy. Depending on the nature of the substituent, the thermal stability of single‐modified duplexes can vary between ?2.7 to +11.3 °C in T_m and that of triple‐modified duplexes from +7.8 to +11.1 °C. Van′t Hoff analysis suggested that the observed higher thermodynamic stability in phenH‐ and phenNO₂‐containing duplexes is of enthalpic origin. A single phenH or phenNO₂ residue in a bulge position also stabilizes a corresponding duplex. If a phenNO₂ residue is placed in a bulge position next to a base mismatch this can lead, in a sequence‐dependent manner, to duplex destabilization. The phenNO₂ residue was found to be a highly efficient (10–100‐fold) quencher of phenH and phenNH₂ fluorescence if placed in the opposite position to the fluorophores. When phenH and phenNH₂ residues were placed opposite each other, efficient quenching of phenH and enhancement of phenNH₂ fluorescence was found, which is an indicator for electron‐ or energy‐transfer processes between the aromatic units.     

Synthesis and antifolate activity of new pyrrolo[2,3‐d]pyrimidine and thieno[2,3‐d]pyrimidine inhibitors of dihydrofolate reductase

Three previously undescribed dihydrofolate reductase (DHFR) inhibitors, N^α‐[4‐[N‐[(2,4‐diaminopyrrolo[2,3‐d]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐N^δ‐hemiphthaloyl‐L‐ornithine (7) , N^α‐ [4‐ [N‐[(2,4‐diaminothieno[2,3‐d]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐ N^δ‐hemiphthaloyl‐L‐ornithine (8) , and N‐[4‐[N‐[(2,4‐diaminothieno[2,3‐d]pyrimidin‐5‐yl)methyl]amino]benzoyl]‐L‐glutamic acid (12) , were synthesized and their antifolate activity was assessed. The ability of 7 and 8 to bind to DHFR and inhibit the growth of CCRF‐CEM human lymphoblastic leukemia cells in culture were dramatically reduced in comparison with the corresponding pteridine analogue, N^α‐(4‐amino‐4‐deoxypteroyl)‐N^δ‐hemiphmaloyl‐L‐ornithine ( 1 , PT523). In a similar manner, the antifolate activity of 12 was markedly reduced in comparison with that of the corresponding glutamate analogue, aminopterin ( 5 , AMT). In contrast, 7, 8 , and 12 all displayed excellent affinity for the reduced folate carrier (RFC) of CCRF‐CEM cells as measured by a standard competitive influx assay. Lack of a consistent correlation between the results of the growth inhibition assays and those of the DHFR and RFC binding assays results suggest that additional factors also play a role in the antifolate activity of these compounds.     

Synthesis of Novel Pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine Derivatives and Their Cytotoxic Activity

The 3‐amino‐6‐(trifluoromethyl)furo[2,3‐b]pyridine‐2‐carbohydrazide ( 5 ) was prepared from 3‐cyano‐6‐trifluoromethyl‐2(1H)pyridone ( 2 ) in series of steps via selective O‐alkylation, Thorpe–Ziegler cyclization followed by reaction with hydrazine hydrate. The 2‐carbohydrazide ( 5 ) was further reacted with aliphatic acids under different reaction temperatures to form a series of novel N‐acylfuro[2,3‐b]pyridine‐2‐carbohydrazide ( 6 ) and pyrido[3′,2′:4,5]furo[3,2‐d]pyrimidine derivatives ( 7 ). All the compounds 6 and 7 were screened for cytotoxic activity against breast carcinoma MD Anderson‐Metastatic Breast (MDA‐MB) 231 (aggressive) cell lines at 10 µM concentration. Compounds 6a , 6b , and 6c showed promising activity.     

Synthesis and Spectral Characteristics of Novel Fluorescent Dyes Based on Pyrimido[4,5‐d] [1,2,4]triazolo[4,3‐a]pyrimidine

Different derivatives of a novel heterocyclic system, i.e., pyrimido[4,5‐d] [1,2,4]triazolo[4,3‐a]pyrimidine, are synthesized in moderate‐to‐good yields. These compounds exhibit excellent photochromism upon photoirradiation. The photophysical characterizations of these new compounds were evaluated by UV/VIS absorption and fluorescence emission studies. The emission spectra in various solvents are also presented and discussed. The changes are due to the intramolecular H‐bonding of pyrimido‐triazolo‐pyrimidine with H₂O, and photoinduced electron and general solvent effect. These compounds display high fluorescence quantum yields and are reported as new fluorophores.     

Synthesis of New [1,2,4]Triazolo[1,5‐a]pyrimidine Derivatives: Reactivity of 3‐Amino[1,2,4]triazole towards Enaminonitriles and Enaminones

A diversity of new 7 ‐substituted[1,2,4]triazolo[1,5‐a]pyrimidine and 6‐substituted[1,2,4]triazolo[1,5‐a]pyrimidine‐7‐amine derivatives has been synthesized via reaction of 3‐amino‐[1,2,4]triazole with enaminonitriles and enaminones. The regio orientation and the structure of the products were confirmed by spectral and analytical data and synthesis via an alternative route. The procedure proved to be simple, efficient, and high yielding, and diversities of [1,2,4]triazolo[1,5‐a]pyrimidines were obtained.     

Three‐component,one‐pot synthesis of pyrimido[4,5‐b]‐quinoline and pyrido[2,3‐d]pyrimidine derivatives

Reaction of 6‐amino‐2‐methylthiouracil and 6‐amino‐1,3‐dimethyluracil with equimoler amounts of cyclic ketones or cyclic 1,3‐diketones and the appropriate aromatic aldehydes yielded regioselectivity a series of polycyclic pyrimido[4,5‐b]quinoline and pyrido[2,3‐d]pyrimidine derivatives in good yields.     

2′‐Deoxyimmunosine: a thiazolo[4,5‐d]pyrimidine nucleoside adopting the syn conformation

The title compound [systematic name: 5‐amino‐3‐(2‐deoxy‐β‐d ‐erythro‐pentofuranosyl)thiazolo[4,5‐d]pyrimidine‐2,7‐(3H,6H)‐dione], C₁₀H₁₂N₄O₅S, exhibits a syn glycosylic bond conformation, with a torsion angle χ of 61.0 (3)°. The furanose moiety adopts the N‐type sugar pucker (³T₄), with P = 33.0 (5)° and τ_m = 15.1 (1)°. The conformation at the exocyclic C4′—C5′ bond is +ap (trans), with the torsion angle γ = 176.71 (14)°. The extended structure is a three‐dimensional hydrogen‐bond network involving O—H...O and N—H...O hydrogen bonds.