Syntheses of Novel 4-Polfluoroalkyl-Substituted 5,6-Oligomethylene Pyrimidines

Sevenard, Dmitrii; Khomutov, O. G.; Koryakova, O. V.; Sattarova, V. V.; Кодесс, М. И.; Stelten, Johannes; Loop, Ildiko; Lork, Enno; Pashkevich, K. I.; Röschenthaler, Gerd‐Volker

doi:10.1055/s-2000-8200

Cited by 31 publications

(15 citation statements)

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“…General. The 2-(polyfluoroacyl)cycloalkanones 1a,f [13], 1b [24], 1c [21] [25], 1d [26], 1e,g [27], and 1h [25] were synthesized by a Claisen-type condensation of cyclopentanone or cyclohexanone and alkyl polyfluoroalkanoates. The 4-ene-1,3-diones 3 were prepared from the corresponding compounds 1 according to the procedure elaborated earlier by us [12].…”

Section: Experimental Partmentioning

confidence: 99%

“…These compounds, having several unequal electrophilic centers, proved to be valuable building blocks in the synthesis of various heterocycles [13] [14]. Now we have found that (E)-alk-4-ene-1,3-diones 3a ± c react with hydroxylamine in the presence of BF 3 ¥ OEt 2 at the 1,3-dione moiety exclusively, furnishing the corresponding 4,5-dihydro-5-R F -isoxazol-5-ol derivatives 4a ± c (Scheme 2).…”

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confidence: 99%

“…In 1 H-, 13 C-, and 19 F-NMR spectra (Tables 4 ± 7) of the reaction products of 2-(polyfluoroacyl)cycloalkanones with hydroxylamine, only one set of signals was (4) 101.95 (12) O(2)ÀC(6)ÀC (7) 104.30(11) C(3)ÀC(4)ÀC (5) 106.52 (12) O(1)ÀC(6)ÀC (7) 105.11(11) C(2a)ÀC(5a)ÀC (6) 99.92(11) C(5a)ÀC(6)ÀC (7) 115.74(11) C(2a)ÀC(5a)ÀC (5) 102.37(12) Tables 4 and 5) of 2a,b,d ± g and 4a ± c show signals corresponding to the methine proton HÀC(3a) (d(H) 3.1 ± 4.0) and the OH group (d(H) ca. 8).…”

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Reaction of 2-(Polyfluoroacyl)cycloalkanones with Hydroxylamine

Sevenard¹,

Khomutov²,

Pashkevich³

et al. 2002

HCA

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The 2-acylcycloalkanones 1a ± g and 3a ± c, possessing a polyfluoroalkyl group, react with hydroxylamine regio-and stereoselectively to yield 4,5-dihydroisoxazol-5-ols 2a ± g and 4a ± c, respectively, i.e., products of Naddition to the oxo group at the cycloalkane ring (Schemes 1 and 2). The products 2 and 4 can be dehydrated under drastic conditions only (Schemes 3 and 4). The structure of one of the 4,5-dihydroisoxazol-5-ols was confirmed by X-ray crystal-structure analysis.Introduction. ± The interaction of 1,3-dicarbonyl compounds with hydroxylamine is considered to be one of the basic synthetic routes to isoxazole derivatives [1], which possess significant chemical potential [1] [2], as well as various biological activities [3].For a nonsymmetrical 1,3-dicarbonyl substrate in this reaction, the formation of regioisomers is possible. Thus, in the case of 2-acetylcyclohexanone, a mixture of isomeric 3-methyl-and 5-methylisoxazoles was obtained [4] [5]. The introduction of a polyfluorinated substituent in the 1,3-dicarbonyl compound results in a significant change of the electron-density distribution and consequently in a change of relative reactivity of the two carbonyl groups. The reaction of linear polyfluoroalkyl 1,3-diketones with hydroxylamine occurs unambigously affording 4,5-dihydro-5-(polyfluoroalkyl)isoxazol-5-ols exclusively ± an intermediate step in the 5-(polyfluoroalkyl)isoxazole formation. The dihydroisoxazolols represent stable compounds that may be dehydrated to the corresponding isoxazoles under drastic conditions only [6 ± 8]. Moreover, 2-(trifluoroacetyl)-and 2-(polychloroacetyl)-substituted cyclohexanones [5], triterpen-3-ones [9], and homoadamantanone [10] are known to give 4,5-dihydro-5-R Hal -isoxazol-5-ols, 5-(trifluoromethyl)isoxazoles, or 3-(trifluoromethyl)isoxazoles in the reaction with hydroxylamine, depending on the size of the carbocyclic ring in the 1,3-diketone molecule and on the reaction conditions.Among the 2-acyl-substituted cycloalkanones, the cyclopentanone derivatives represent a special case, forming an alternative product ± 4,5-dihydro-3-R-isoxazol-5-ols ± in the reaction with hydroxylamine, independent of the presence of F-atoms in the RCO moiety [11]. In the case of 2-(trifluoroacetyl)cyclopentanone, the dioxime [11], which cyclizes in acidic medium only, was also isolated.The present work aimed at the investigation of the chemical behavior of a variety of 2-(polyfluoroacyl)cycloalkanones in the reaction with hydroxylamine, the former differing in ring size, (polyfluoroalkyl)-radical length, and the presence of substituents at the cycloalkane ring. The expected products of such reactions can possess a set of

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Section: Experimental Partmentioning

confidence: 99%

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Reaction of 2-(Polyfluoroacyl)cycloalkanones with Hydroxylamine

Sevenard¹,

Khomutov²,

Pashkevich³

et al. 2002

HCA

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“…Thiourea and their related analogs have become the focus of interest in recent past on account of their pharmacological activities such as anti-HIV [5], antinociceptive [6], antibacterial [7], antiviral [8], and anticancer [8]. It is convenient to synthesize substituted pyrimidines by reaction of amidines or guanidines with a,b-unsaturated ketones [9] [10], b-diketones [11] [12], b-alkoxy-and b-aminovinyl ketones [13 -16], and N-arylacetylenic imines [17] [18]. Natural isoflavones display a wide range of biological activities [19].…”

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One‐Step Synthesis of 1‐(4,5‐Diphenylpyrimidin‐2‐yl)thiourea

Han

Zhang

et al. 2010

Helvetica Chimica Acta

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A simple and straightforward methodology toward the synthesis of novel 1-(4,5-diphenylpyrimidin-2-yl)thiourea has been developed by a one-step reaction of isoflavones with amidinothiourea. A series of 16 new compounds was synthesized. All compounds were characterized by FT-IR, NMR, and elemental analysis. The structure of a typical compound was established by X-ray diffraction. A variety of substrates can participate in the process with good yields and high purities, making this methodology suitable for library synthesis in drug discovery. , and anticardio-cerebral vascular disease activities [22]. Ipriflavone (¼ 7-(1-methylethoxy)-3-phenyl-4H-benzopyran-4-one) has been reported to be efficient in preventing and treating osteoporosis [23]. It was reported that the chromone fragment present in isoflavones can generate a 1,3-diketone equivalent which readily react with amidines [24], guanidine [2], carbamide [25], and sulfocarbamides [26] to form the corresponding 2-substituted pyrimidines. The use of combinatorial approaches for the highthroughput synthesis of this drug-like scaffold would be a powerful advance in helping to speed up drug discovery. Recently, we have reported the high-throughput synthesis of 3,4-diarylpyrazoles and 4,5-diphenylpyrimidin-2-ylguanidine by a one-pot reaction of hydrazine [27] or bisguanidine [28] with isoflavones. To the best of our knowledge, using isoflavone as starting material to synthesize the pyrimidinylthioureas has not been reported so far. Herein, we report a new way for the preparation of the unknown class of 1-(4,5-diphenylpyrimidin-2-yl)thiourea by the cyclocondensation of isoflavones (1) with amidinothiourea (2; Table 1).

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“…For example, the cyclization of N-C-N blocks (urea, guanidines and amidines) with perfluoroalkyl containing 1,3-bielectrophiles (1,3-diketones, 1,3-ketoesters, 1,3-ketoamides, α,β-enones) is considered the main procedure for the synthesis of perfluoroalkyl substituted pyrimidine derivatives. [15][16][17][18] Derivatives 2-substituted of the 6-(2-furyl)-4-trifluoromethylpyrimidines and 6-(2-thienyl)-4-trifluoromethylpyrimidines were early synthesized by cyclocondensation respectively of 1-(2-furyl)-4,4,4-trifluorobutane-1,3-dione or 1-(2-thienyl)-4-trifluorobutane-1,3-dione with amidines NH 2 C(NH)X [ X = OR, NH 2 , SMe], however only few analytical data were reported. [19][20][21][22][23] The patent reports show only melting point as accessible analytical data for these compounds.…”

Section: Introductionmentioning

confidence: 99%