Synthesis of 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones via copper-(I)-catalyzed alkyne-azide 'click chemistry' and their reactivity

In this paper we present the room temperature synthesis of a novel serie of 1,4-disubstituted-1,2,3-triazoles 4a-l by employing the (3+2) cycloaddition reaction of pyrimidinones containing alkyne functions with different model azides in the presence of copper sulphate and sodium ascorbate. To obtain the final triazoles, we also synthesized the major precursors 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 3a-r from ethyl 2,2-dicyanovinylcarbamate derivatives 2a-c and various primary aromatic amines containing an alkyne group. The triazoles were prepared in good to very good yields.     

Preparation of 1,2-disubstituted-3-hydroxy-4(1H)-quinolinones and the influence of substitution on the course of cyclization

Synthesis of 1,2-disubstituted-3-hydroxy-4(1H)-quinolinones by the cyclization of N-substituted phenacyl or acetonyl anthranilates is described. Two methods were employed for cyclization of anthranilates. Heating in polyphosphoric acid has a wide scope of applicability. The thermal cyclization in boiling N-methylpyrrolidone is limited by steric effect.     

Synthesis and activity of a metabolite of (S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione (CX-659S)

CX-659S (1) [(S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione], has been developed as a new type anti-inflammatory agent for the treatment of dermatitis. The structure of a major metabolite of CX-659S was determined as (S)-6-amino-5-[2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadienyl)butanamide]-3-methyl-1-phenyl-2,4-(1H,3H)-pyrimidinedione (2) by direct comparison with the synthesized authentic compound. The anti-inflammatory activity of 2 was equipotent with that of 1 on the contact hypersensitivity reaction (CHR) induced by picryl chloride (PC) in mice, suggesting that compound 2 contributes, at least in part, to the anti-inflammatory activity of CX-659S.     

2H-3,1-benzoxazine-2,4-(1H)-dione (isatoic anhydride). 15. Reactions with lactone enolates

The reaction of N-methylisatoic anhydride, 1 , with the lithium enolates derived from various butyrolactones or δ-valerolactone produces stable anthranoyl lactone derivatives 4 . Heating these products in toluene results in a cyclization to afford 4-hydroxy-3-(2-hydroxyalkyl)-1-methyl-2(1H)-quinolinones, 8 and 14 , in good yields.     

Two general routes to 1,4-disubstituted-2,3,4,5-tetrahydro- 1H-3-benzazepines

[structure] Two general routes to 1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepines are described. Both routes utilize an appropriately functionalized phenethylamino alcohol as the penultimate intermediate: the first route makes use of the reductive amination of a benzyl alkyl ketone with alpha-(aminomethyl)benzyl alcohol, while the second route utilizes the addition of a Grignard reagent to the oxazolidine derived from a substitued phenylacetaldehyde and alpha-(methylaminomethyl)benzyl alcohol. In all cases studied, the cis-1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepine was obtained as the major product.     

Redox chemistry of the acetato-bridged clusters [M3(mu3-O)n(mu-O2CCH3)6(H2O)3]2+ (M = Mo, W, n = 1, 2): reversible redox between mono-micro3-oxo d8 M(III)2M(IV) and d9 M(III)3 forms

A cyclic voltammogram of aqueous 0.1 mol dm(-3) triflic acid solutions of the d6 bioxo-capped M-M bonded cluster [Mo3(mu3-O)2(O2CCH3)6(H2O)3]2+ at a glassy carbon electrode at 25 degrees C gives rise to an irreversible 3e- cathodic wave to a d9 Mo(III)3 species at -0.8 V vs. SCE which on the return scan gives rise to two anodic waves at +0.05 V vs. SCE (E(1/2), 1e- reversible to d8 Mo(III)2Mo(IV)) and +0.48 V vs. SCE (2e- irreversible back to d6 Mo(IV)3). The number of electrons passed at each redox wave has been confirmed by redox titration and controlled potential electrolysis which resulted in 90% recovery of [Mo3(mu3-O)2(O2CCH3)6(H2O)3]2+ following electrochemical re-oxidation at +0.8 V. A corresponding CV study of the d8 monoxo-capped W(III)2W(IV) cluster [W3(mu3-O)(O2CCH3)6(H2O)3]2+ gives rise to a reversible 1e- cathodic process at -0.92 V vs. SCE to give the d9 W(III)3 species [W3(mu3-O)(O2CCH3)6(H2O)3]+; the first authentic example of a W(III) complex with coordinated water ligands. However the cluster is too unstable (O2/water sensitive) to allow isolation. Comparisons with the cv study on [Mo3(mu3-O)2(O2CCH3)6(H2O)3]2+ suggest irreversible reduction of this complex to monoxo-capped [Mo(III)3(mu3-O)(O2CCH3)6(H2O)3]+ followed by reversible oxidation to its d8 counterpart [Mo3(mu3-O)(O2CCH3)6(H2O)3]2+ (Mo(III)2Mo(IV)) and finally irreversible oxidation back to the starting bioxo-capped cluster. Exposing the d9 Mo(III)3 cluster to air (O2) however gives a different final product with evidence of break up of the acetate bridged framework. Corresponding redox processes on d6 [W3(mu3-O)2(O2CCH3)6(H2O)3]2+ are too cathodic to allow similar generation of the monoxo-capped W(III)3 and W(III)2W(IV) clusters at the electrode surface.     

Facile solid phase synthesis of 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines using a tetrafunctional scaffold

Solid phase synthesis of 1, 2-disubstituted-6-nitro-1,4-dihydroquinazolines is described. The new tetrafunctional scaffold N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was prepared by nitration of 3-amino-3-(2-fluorophenyl)propionic acid. The scaffold was anchored to Rink resin via its carboxylic group and treated with primary amines to displace the arylfluorine followed by cyclization with aryl isothiocyanates in the presence of DIC upon Alloc deprotection to afford 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines in high yield.     

Preparation and some spectral properties of benzo-fused 1,4-dimethyl-2(1H)-quinolinones

The preparation of the angular and linear isomers of benzo-fused 1,4-dimethyl-2(1H)-quinolinones 3a–5a and their spectral data including ¹³C-nmr data are reported. Structural difference among 3a–5a is confirmed from the proximity effect in ¹H- and ¹³C-nmr data and from the uv spectral pattern.     

亲电硫试剂参与的2-芳基-3-硫代-2,3-二氢喹啉-4(1H)-酮的合成研究

本文报道了以(E)-1-(2-对甲苯磺酰胺基)-3-芳基丙-2-烯-1-酮(1)为底物与N-硫代丁二酰亚胺(2)通过亲电环化反应合成2-芳基-3-硫代-2,3-二氢喹啉-4(1H)-酮类化合物。以三氟化硼乙醚为催化剂(20 mol %),1,2-二氯乙烷为溶剂,反应温度为60 _oC,可以60-92%的收率得到一系列2-芳基-3-硫代-4(1H)-喹啉酮衍生物,化合物3a-k均未见文献报道,其结构均经过₁H NMR, ₁₃C NMR以及高分辨质谱进行确定。     

Oxidation of 1,4-disubstituted-1,2,3-triazoles with H2O2–CF3CO2H: efficient synthesis of 1,2,3-triazole 3-oxides

A collection of 1,2,3-triazole-3-oxides was obtained from oxidation of the corresponding 1,4-disubstituted-1,2,3-triazoles mediated by a H₂O₂–CF₃CO₂H system through a simple protocol in good yields showing high efficiency.     

Efficient solid-phase synthesis of 2-substituted-3-hydroxy-4(1H)-quinolinone-7-carboxamides with two diversity positions

A highly efficient solid-phase synthesis of 2-substituted-3-hydroxy-4(1H)-quinolinone-7-carboxamides was developed using anthranilates and bromoketones as the key synthons. Primary amines immobilized to an acid-cleavable BAL linker were acylated with 1-methyl-2-aminoterephtalate. After cleavage of the methyl ester, bromoketones were used to form resin-bound phenacyl esters. Acid-mediated cleavage and subsequent cyclization in solution afforded 3-hydroxy-4(1H)-quinolinones in high purity and yield. Highly efficient solid-phase synthesis (purity>90%, yield>80%, synthetic time=2 days using commercially available synthons) is amenable to high-throughput/combinatorial synthesis to match the high-throughput screening capability.     

The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). 10. Reactions with ester enolates. Synthesis of 4-hydroxy-1-methyl-3-prenyl-2(1H)-quinolinones,Crucial intermediates in the synthesis of quinoline alkaloids

N-Methylisatoic anhydride reacts with the lithium enolates of esters to produce β-ketoesters 4 in nearly quantitative yield. Thermal cyclization of these relatively unstable intermediates afford the corresponding 3-substituted-4-hydroxy-1-methyl-2(1H)-quinolinones (5) in good yields. The reaction of the lithium enolate of 5-methyl-4-hexenoic acid ethyl ester ( 14 ) with various nuclear substituted isatoic anhydrides gives 4-hydroxyl-methyl-3-prenyl-2(1H)-quinolinones 8, 9 , and 18 which are highly desirable intermediates in the synthesis of a variety of quinoline alkaloids. Treatment of 18 with DDQ furnishes oricine in 73% yield.     

Synthesis and Crystal Structure of Ethyl 2-(6-(1,3-Dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) Butanoate

The title compound ethyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) butanoate 3 was synthesized by the reaction of ethyl 2-(6-amino-7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) butanoate with 4,5,6,7-tetraydrophthalic anhydride,and its structure was determined by X-ray single-crystal diffraction.The crystal belongs to the monoclinic system,space group P21/n with a = 9.3469(2),b = 16.7715(5),c = 13.7153(4) ,β = 104.9680(10)°,μ = 0.107 mm-1,Mr = 430.42,V = 2077.08(10) 3,Z = 4,Dc = 1.376 g/cm3,F(000) = 904,T = 296(2) K,R = 0.0508 and wR = 0.1478.     

2,3-二取代-1,4-萘醌的合成

常温下, 在丙酮与水的混合介质中(V∶V＝1∶1), 4-羟基香豆素类化合物与1,4-萘醌进行Michael加成反应, 生成6个未见文献报道的2,3-二取代-1,4-萘醌. 产物经MS, 1H NMR, 元素分析表征, 确定了其化学结构.     

Synthesis of 5-Aryl-1,4-naphthoquinone and 1-Aryl-9,10-anthraquinone Derivatives by Cycloaddition of 1-(Dimethoxyphenyl)-3-trimethylsiloxy-1,3-butadienes to 1,4-Benzoquinones and 1,4-Naphthoquinones

The Diels-Alder reaction of new 1-(3,4-dimethoxyphenyl)- or 1-(2,4-dimethoxyphenyl)-2-R-3-trimethylsiloxy-1,3-butadienes with 2,5- and 2,6-dibromo-, and 2-bromo-6-methyl-1,4-benzoquinones regioselectively yields substituted 7-hydroxy-5-(dimethoxyphenyl)-1,4-naphthoquinones. By cycloaddition of the siloxydienes to naphthoquinone, bromonaphthoquinone, and juglone the corresponding substituted 3-hydroxy-1-(dimethoxyphenyl)-9,10-anthraquinones or their 4,4a-dihydro or 1,1a,4,4a-tetrahydro derivatives were obtained.     

Estimating the limiting reducing power of SmI2/H2O/amine and YbI2/H2O/amine by efficient reduction of unsaturated hydrocarbons

The mixture of samarium diiodide, amine, and water (SmI2/H2O/Et3N) is known to be a particularly powerful reductant, but until now the limiting reducing power has not been determined. A series of unsaturated hydrocarbons with varying half-wave reduction potentials (E(1/2) = -1.6 to -3.4 V, vs SCE) have been treated with SmI2/H2O/Et3N and YbI2/H2O/Et3N, respectively. All hydrocarbons with potentials of -2.8 V or more positive were readily reduced with SmI2/H2O/Et3N, whereas all hydrocarbons with potentials of -2.3 V or more positive were readily reduced using YbI2/H2O/Et3N. This defines limiting values of the chemical reducing power of SmI2/H2O/Et3N to -2.8 V and of YbI2/H2O/Et3N to -2.3 V vs SCE.     

Traceless solid-phase synthesis of 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinoline-2-ones

A traceless solid-phase route to 1,4-disubstituted-6-nitro-3,4-dihydro-1H-quinazolin-2-ones is described. N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was tethered to Rink resin via its carboxylic group. The protected amine was coupled with an organic acid after Alloc-deprotection and the arylfluorine was displaced with a primary amine to generate a resin-bound aniline with two diversity points. The aniline was released via cleavage to produce the desired products in high yield and purity.     

Synthesis and molecular structure of 3-[5-(quinolin-2-yl)penta-1,4-dien-1-yl]-1,4-benzodioxin-2-one

Acid-catalyzed reaction of 6,10a-dihydroxy-3,4a,7,9-tetra(tert-butyl)-1,2,4a,10a-tetrahydrodibenzo-[b,e][1,4]dioxine-1,2-dione with 4-chloro-2,7,8-trimethylquinoline gave previously unknown 3,6,8-tri-tert-butyl-3-[2-tert-butyl-5-(4-chloro-7,8-dimethylquinolin-2-yl)-4-hydroxy-3-oxopenta-1,4-dien-1-yl]-5-hydroxy-1,4-benzodioxin-2-one whose structure was determined by X-ray analysis. The energy and structure parameters of possible isomers of the product in the gas phase and in solution were estimated by PBE0/6-31G** quantum-chemical calculations.     

4:2钼、钨过氧配合物的制备、结构及其氧化还原分解行为

本文作者曾在用过钨酸分解法制备钨酸的过程中发现, 溶液中W与O2^2^-之比始终为2:1, 这一事实说明溶液中有2:1金属过氧配合物形成, 2:1铂过氧络合物[Mo4O12(O2)2]^4^-文献上已有记载, 但类似的钨配合物尚未见报道。本文制备了这二种配合物, 对比它们的红外和Raman光谱, 并用循环伏安法, 恒电位电解法探讨它们的氧化还原分解体系。     

Selective synthesis of 2,3-disubstituted-2H-isoindol-1-ylphosphonate and 2,3-disubstituted-1,2-dihydroiso-quinolin-1-ylphosphonate via metal-tuned reaction of alpha-amino (2-alkynylphenyl)methylphosphonate

Palladium(II)-catalyzed reaction of alpha-amino (2-alkynylphenyl)methylphosphonate provides a novel and efficient route to 2,3-disubstituted-2H-isoindol-1-ylphosphonate via 5-exo-cyclization and [1,5]-H shift; while 2,3-disubstituted-1,2-dihydroisoquinolin-1-ylphosphonate is afforded through 6-endo-cyclization utilizing silver triflate as catalyst.