- Reactions of N,N-bis(siloxy)enamines with trimethylsilyl cyanide: Aliphatic nitro compounds as convenient precursors of 5-aminoisoxazoles
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A convenient procedure was developed for the synthesis of 5-aminoisoxazoles by the consecutive double silylation and cyanation of aliphatic nitro compounds.
- Lesiv, Aleksei V.,Ioffe, Sema L.,Strelenko, Yurii A.,Bliznets, Igor' V.,Tartakovsky, Vladimir A.
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- Bulk synthesis of thermally unstable 5-amino-3-methylisoxazole using silica coated magnetite nanoparticles (Fe3O4@SiO2)
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5-Amino-3-methylisoxazole is an important intermediate in medicinal chemistry. Bulk scale synthesis of it is reported and the reaction yields are typically around 40 %. The reaction of 3-aminocrotonitrile and hydroxylamine hydrochloride in aqueous environment in about 12 h at room temperature results in 5-amino-3-methylisoxazole. This simple one pot synthesis has an issue, which contributes to lower reaction yields. The melting point of 5-amino-3-methylisoxazole is 83-85 °C, but around 70 °C it can rapidly decompose causing an explosion. Hence, this molecule is synthesized by maintaining reaction temperature at 0-25 °C. Due to exothermic nature of the reaction, maintenance of lower temperature is mandatory. Due to lower reaction temperature, this reaction yields are usually low. Though these kind of lower yields are reported for synthesis of this class of compounds, attempts to improve the reaction yields are sparse. We report silica coated magnetic nanoparticle (Fe3O4@SiO2) as an inert surface for preparation of 5-amino-3-methylisoxazole. The yield of reaction is around 80 %, almost double the reported yield and it is enabled by the 40 nm Fe3O4@SiO2 particles. The 40 nm Fe3O4@SiO2 are synthesized by modification to the famous "Stober" protocol. The obtained 40 nm particles contain intermittent particles with about 200 nm as reported in literature. Though isolation of 40 nm size magnetic nanoparticles in reactions is difficult, presence of about 200 nm size Fe3O4@SiO2 is enabling for easy isolation. The work up of reaction is simple isolation of Fe3O4@SiO2 by magnet, basification of reaction mixture to pH 10, dissolving the precipitated solid in diethyl ether, removal of ether to obtain crude 5-amino-3-methylisoxazole, which was recrystallized using distilled water. This protocol paves way for simple synthesis of related isoxazoles, which are increasingly forming base structure for many drugs and medicinal chemistry leads.
- Reddy, G.V. Shiva,Chandrappa,Rahaman, Fazlur,Murthy, B. Narasimha,Pullela, Phani Kumar
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- An enantioselective aza-Friedel-Crafts reaction of 5-aminoisoxazoles with isatin-derived: N -Boc ketimines
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By employing a chiral phosphoric acid as a catalyst, an enantioselective aza-Friedel-Crafts reaction of 5-aminoisoxazoles with isatin-derived N-Boc ketimines was realized. The reaction provided a wide variety of novel 3-isoxazole 3-amino-oxindoles with good yields (up to 99%) and moderate to good enantioselectivities (up to 99%). The absolute configuration of one product was assigned by X-ray crystal structural analysis and a plausible reaction mechanism was proposed. In addition, a scale-up reaction was performed successfully. Finally, one product was subjected to Suzuki-Miyaura coupling with phenylboronic acid to afford the product in a moderate yield without erosion of the enantioselectivity. This journal is
- Liu, Hui,Yan, Yingkun,Li, Min,Zhang, Xiaomei
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supporting information
p. 3820 - 3824
(2021/05/14)
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- Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin
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To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4–7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 μM = 81.6%), 4w (CMA at 10 μM = 71.2%) and 6b (CMA at 10 μM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 μM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure–activity relationship (SAR) studies were conducted. Para substitution (-Cl, –OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 μM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.
- Boggu, Pulla Reddy,Venkateswararao, Eeda,Manickam, Manoj,Sharma, Niti,Kang, Jong Seong,Jung, Sang-Hun
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- Approach to the library of fused pyridine-4-carboxylic acids by combes-type reaction of acyl pyruvates and electron-rich amino heterocycles
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A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.
- Volochnyuk, Dmitriy M.,Ryabukhin, Sergey V.,Plaskon, Andrey S.,Dmytriv, Yuri V.,Grygorenko, Oleksandr O.,Mykhailiuk, Pavel K.,Krotko, Dmitriy G.,Pushechnikov, Alexei,Tolmachev, Andrey A.
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scheme or table
p. 510 - 517
(2010/09/05)
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- (2-imidazolin-2-yl) fused heteropyridine compounds, intermediates for the preparation of and use of said compounds as herbicidal agents
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There are provided novel (2-imidazolin-2-yl) fused heteropyridine compounds, and intermediate compounds for the preparation thereof, and a method for controlling a wide variety of annual and perennial plant species therewith.
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