- Catalyst-free and visible light promoted trifluoromethylation and perfluoroalkylation of uracils and cytosines
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Fluoroalkylated enaminones, such as trifluridine and 5-trifluoromethyluracil, have widespread applications in pharmaceuticals and agrochemicals. Although these kinds of pharmaceutical agent often bear CF3 and perfluoroalkyl motifs in the core structure, access to such analogues typically requires multi-step synthesis. Here, we report a mild, metal-free and operationally simple strategy for the direct perfluoroalkylation of uracils, cytosines and pyridinones through a visible-light induced pathway from perfluoroalkyl iodides. This photochemical transformation features synthetic simplicity, mild reaction conditions without any photoredox catalyst, and high functional group tolerance, providing a facile route for applications in medicinal chemistry.
- Huang, Yang,Lei, Yun-Yun,Zhao, Liang,Gu, Jiwei,Yao, Qiuli,Wang, Ze,Li, Xiao-Fei,Zhang, Xingang,He, Chun-Yang
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Read Online
- Facile perfluoroalkylation of uracils and uridines at the C-5 position
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Perfluoroalkylation at the C-5 position of uracil has been achieved in yields of 38-56percent by the reaction of its bis(trimethylsilyl) derivative with bis(perfluoroalkanoyl) peroxides and the hydrolytic deprotection of the silylated products.A substituent or nitrogen replacement at C-6 does not interfere with perfluoroalkylation at C-5, but no significant reaction occurs at C-6 when C-5 is blocked.
- Nishida, Masakazu,Fujii, Shozo,Kimoto, Hiroshi,Hayakawa, Yoshio,Sawada, Hideo,Cohen, Louis A.
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Read Online
- Au@ZnO Core-Shell: Scalable Photocatalytic Trifluoromethylation Using CF3CO2Na as an Inexpensive Reagent under Visible Light Irradiation
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Trifluoromethylation is of significant importance for the synthesis of many small molecules vital for medicinal and agrochemical research. The importance of the CF3 group as well as the related synthetic challenges is so evident that many reagents have been reported for the synthesis of trifluoromethylated compounds, but these typical reagents are expensive and the methods for preparing them are difficult. Here, we report a new scalable and operationally simple trifluoromethylation reaction using sodium trifluoroacetate as a reagent and Au-modified ZnO as a photocatalyst under visible light irradiation. The reaction proceeds via trifluoromethylation of a broad range of aryl halides, arylboronic acids, and arene and heteroarene substrates. Some pharmaceutical and agrochemical compounds have been trifluoromethylated directly to demonstrate the applicability of the method.
- Bazyar, Zahra,Hosseini-Sarvari, Mona
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supporting information
p. 2345 - 2353
(2019/10/16)
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- Method for preparing 5-trifluoromethyl uracil
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The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing 5-trifluoromethyl uracil. The method comprises the following steps: firstly, carrying out chlorination reaction on 5-iodouracil and phosphorus oxychloride, thus obtaining 2,4-dichloro-5-iodopyrimidine; secondly, carrying out trifluoromethylation reaction on the 2,4-dichloro-5-iodopyrimidineand a trifluoromethylating reagent, thus obtaining 2,4-dichloro-5-trifluoromethylpyrimidine; finally, enabling the 2,4-dichloro-5-trifluoromethylpyrimidine to react with acetic acid, thus obtaining aproduct. According to the method disclosed by the invention, since chlorination reaction, trifluoromethylation reaction and hydrolysis reaction are adopted, a key intermediate-trifluoromethyl uracil of trifluorothymidine is synthesized in high yield, low cost and low pollution.
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Paragraph 0038-0039
(2019/06/05)
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- Organic semiconductor photocatalyst can bifunctionalize arenes and heteroarenes
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Photoexcited electron-hole pairs on a semiconductor surface can engage in redox reactions with two different substrates. Similar to conventional electrosynthesis, the primary redox intermediates afford only separate oxidized and reduced products or, more rarely, combine to one addition product. Here, we report that a stable organic semiconductor material, mesoporous graphitic carbon nitride (mpg-CN), can act as a visible-light photoredox catalyst to orchestrate oxidative and reductive interfacial electron transfers to two different substrates in a two- or three-component system for direct twofold carbon–hydrogen functionalization of arenes and heteroarenes. The mpg-CN catalyst tolerates reactive radicals and strong nucleophiles, is straightforwardly recoverable by simple centrifugation of reaction mixtures, and is reusable for at least four catalytic transformations with conserved activity.
- Ghosh, Indrajit,Khamrai, Jagadish,Savateev, Aleksandr,Shlapakov, Nikita,Antonietti, Markus,K?nig, Burkhard
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p. 360 - 366
(2019/08/15)
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- Synthetic method of 5-trifluoromethyl uracil
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The invention discloses a synthetic method of 5-trifluoromethyl uracil prepared under simple and convenient conditions. The synthetic method is characterized in that starting from uracil and trifluoroiodomethane, after alkali is added, the 5-trifluoromethyl uracil is efficiently obtained under the irradiation of visible light. Some of products obtained are listed drug molecules or important pharmaceutical intermediates. The synthetic method has the benefits that the uracil and the trifluoroiodomethane which are cheap and easy to obtain are used as raw materials; in the reaction process, only the illumination is required, and the cheap alkali is added without the use of a catalyst; during the mass production, a solvent can be recovered through a vacuum distillation method; the synthetic method is green, economic and efficient in the whole production process and has very significant advantages compared with an existing production process.
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Paragraph 0023; 0026; 0029; 0032; 0033; 0034; 0035; 0038
(2018/09/21)
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- Synthesis method of fluoropyrimidine-containing medical intermediate 2,4-dichloro-5-trifluoromethylpyrimidine
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The invention relates to a synthesis method of a fluoropyrimidine-containing medical intermediate 2,4-dichloro-5-trifluoromethylpyrimidine. The method comprises steps as follows: (1) uracil, sodium trifluoromethanesulfonate, persulfate and water are added to a reaction container, the reaction temperature is controlled, and 5-(trifluoromethyl)uracil is obtained after the reaction; (2) 5-(trifluoromethyl)uracil, phosphorus oxychloride and diisopropylethylamine are added to a pressure reaction container and react at the reaction temperature of 150-220 DEG C, and a product is obtained after the reaction. In the preparation process of 5-(trifluoromethyl)uracil, only water is taken as a solvent, no other organic solvents or organic free radical initiators are used, aftertreatment is simple, theproduct purity is high, the next reaction can be directly performed, operation is simple, pollution is low, and the cost is low; through the pressure reaction container, the reaction temperature is increased, the dosage of phosphorus oxychloride is greatly reduced, three wastes are reduced, and the atom economy is met.
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Page/Page column 3-6
(2018/09/28)
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- A 5-trifluoro methyl uracil method for the synthesis of
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The invention discloses a synthetic method of 5-trifluoromethyl uracil. According to the method, uracil and sodium trifluoromethanesulfonate are used as raw materials, a mixed solvent of dichloromethane and water is used as a reaction solvent, tert-butyl hydroperoxide is used as a catalyst, and the target product namely 5-trifluoromethyl uracil is obtained with a relatively high yield in a micro-reduction system. The synthetic method is simple in synthetic step, mild in reaction condition and high in product yield, and can be used for industrial production.
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Paragraph 0013-0019
(2017/06/08)
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- Condensed-phase, halogen-bonded CF3I and C2F5I adducts for perfluoroalkylation reactions
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A family of practical, liquid trifluoromethylation and pentafluoroethylation reagents is described. We show how halogen bonding can be used to obtain easily handled liquid reagents from gaseous CF3I and CF3CF2I. The synthetic utility of the new reagents is exemplified by a novel direct arene trifluoromethylation reaction as well as adaptations of other perfluoroalkylation reactions. Its (no longer) a gas! A family of practical, liquid trifluoromethylation and pentafluoroethylation reagents enabled by halogen bonding is described. The synthetic utility of these reagents is exemplified by a novel direct arene trifluoromethylation reaction as well as adaptations of other perfluoroalkylation reactions.
- Sladojevich, Filippo,McNeill, Eric,B?rgel, Jonas,Zheng, Shao-Liang,Ritter, Tobias
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supporting information
p. 3712 - 3716
(2015/03/18)
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- FLUOROALKYLATION REAGENTS AND USES THEREOF
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Provided herein are halogen-bonded complexes of Formula (I), wherein is a halogen bond; R1 is unsubstituted C1-3 fluoroalkyl; D is N(R2)3, ((R2)2N)2C=NR2, 0=S(R2)2, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, and wherein R2 and y are as defined herein. D----(I??R1)y (I) Further provided are methods of preparing compounds of Formula (I), compositions, reagents, and kits comprising a compound of Formula (I), and methods for fluoroalkylating an organic compound using a compound of Formula (I).
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Paragraph 00234; 00235
(2015/11/23)
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- Radical C-H functionalization of heteroarenes under electrochemical control
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Electrochemical reactions are shown to be effective for the C-H functionalization of a number of heterocyclic substrates that are recalcitrant to conventional peroxide radical initiation conditions. Monitoring reaction progress under electrochemical conditions provides mechanistic insight into the C-H functionalization of a series of heterocycles of interest in medicinal chemistry.
- O-Brien, Alexer G.,Maruyama, Akinobu,Inokuma, Yasuhide,Fujita, Makoto,Baran, Phil S.,Blackmond, Donna G.
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supporting information
p. 11868 - 11871
(2015/02/19)
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- SYNTHESIS OF 2,4-DICHLORO-5-TRIFLUOROMETHYL-PYRIMIDINE
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This invention relates to a novel method for the synthesis of 2,4-dichloro-5-trifluoromethyl-pyrimidine useful as intermediate in the manufacture of pharmaceutically active ingredients.
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Paragraph 0055; 0056; 0057; 0058; 0059
(2014/05/20)
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- NOVEL PROCESS FOR THE MANUFACTURE OF 2,4-DICHLORO-5-TRIFLUOROMETHYL-PYRIMIDINE
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This invention relates to a novel method for the synthesis of 2,4-dichloro-5-trifluoromethyl- pyrimidine useful as intermediate in the manufacture of pharmaceutically active ingredients.
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Page/Page column 8-9
(2014/06/11)
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- REACTION REAGENT FOR TRIFLUOROMETHYLATION
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Provided is a reaction reagent for trifluoromethylation with high general versatility and good efficiency. The reaction reagent for trifluoromethylation contains an iron compound, trifluoromethyl iodide, a sulfoxide and a peroxide, and may further contain an acid. The iron compound is, for example, iron(II) sulfate, ammonium iron(II) sulfate, iron(II) tetrafluoroborate, ferrocene, bis(η5-pentamethylcyclopentadienyl)iron or an iron powder; the sulfoxide is, for example, dimethyl sulfoxide; the peroxide is, for example, hydrogen peroxide or hydrogen peroxide-urea composite; and the acid is, for example, sulfuric acid, tetrafluoroboric acid or trifluoromethanesulfonic acid.
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Page/Page column 6
(2009/08/14)
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- NUCLEIC ACID BASE HAVING PERFLUOROALKYL GROUP AND METHOD FOR PRODUCING THE SAME
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Provided is a simple and efficient production process of a nucleobase having a perfluoroalkyl group. A nucleobase (for example, uracils, cytosines, adenines, guanines, hypoxanthines, xanthines, or the like) is reacted with a perfluoroalkyl halide in the presence of a sulfoxide, a peroxide and an iron compound to produce a perfluoroalkyl-substituted nucleobase, which is useful as an intermediate for medical drugs, economically.
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Page/Page column 36; 37
(2008/12/07)
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- Uracil reductase inactivators
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The present invention relates to a group of 5-substituted uracil derivatives which are inactivators of uracil reductase and which are particularily useful in cancer chemotherapy, especially in combination with antimetabolite antineoplastic agents such as 5-fluorouracil (5-FU).
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- 5-Fluorouracil derivatives
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Novel compounds comprising 5-fluorouracil or 5-fluorouridine covalently linked to 5-ethynyluracil, 5-ethynyluridine or 5-propynyluracil and pharmaceutical compositions comprising such compounds are disclosed.
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- A new synthesis of 5-trifluoromethyluracil
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5-Trifluoromethyluracil, an important intermediate for the preparation of the antiviral trifluridine, is obtained by chlorinating thymine to give the new 2,4-dichloro-5-trichloromethylpyrimidine. Reacting the latter with hydrogen fluoride yields the new 2,4-difluoro-5-trifluoromethylpyrimidine, and hydrolysis with water gives 5-trifluoromethyluracil in high purity and good yield.
- Andres, Peter,Marhold, Albrecht
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- Process for Producing 1-(2'-deoxy-beta-D-erythropentofuranosyl)-5-trifluoromethyluracil Derivatives
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A process for producing 1-(2'-deoxy-β-D-erythro-pentofuranosyl)-5-trifluoromethyluracil derivative of the formula (3) by which the desired compound can be produced easily at a low cost with high selectivity is disclosed. The process according to the present invention comprises (a) reacting 5-trifluoromethyl-5,6-dihydrouracil with alkylsulfoxide in the presence of a halogen and an acid catalyst to obtain 5-trifluoromethyluracil; (b) reacting the obtained 5-trifluoromethyluracil with a silylating agent to obtain 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine of the formula (1) and (c) reacting the obtained 5-trifluoromethyl-2,4-bis(trimethylsilyloxy)pyrimidine with 2-deoxy-α-D-erythro-pentofuranosyl halide derivative of the formula (2) in chloroform solvent in the presence of fluoride ion and in the presence of a copper compound as a catalyst.
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- Process for the preparation of 5-(trifluoromethyl)-uracil, and the novel compounds 2,4-dichloro-5-trichloromethyl-pyrimidine and 2,4-difluoro-5-trifluoromethyl-pyrimidine
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5-Trifluoromethyl-uracil is obtained by chlorinating thymine under mild conditions, further chlorinating the resulting 2,4-dichloro-5-methyl-pyrimidine under drastic conditions to give 2,4-dichloro-5-trichloromethylpyrimidine, reacting the latter with a fluorinating agent to give 2,4-fluorinated and/or -chlorinated 5- trifluoromethylpyrimidines and subjecting these to hydrolysis. The novel chemical compounds 2,4-dichloro- 5-trichloromethylpyrimidine and 2,4-difluoro-5-trifluoromethylpyrimidine are obtained in the course of this process.
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- 4'-substituted nucleosides
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Nucleosides compounds of Formula I: STR1 wherein B is a purine or a pyrimidine; X and X' are H; Y is H; Y' is OH, F or H; or Y' and X' together makes a bond; Z is STR2 where n is zero, one, two or three; or Y' and Z together form a cyclic phosphate ester; Z' is --CN, --CH3, CH2 N3 or --CH2 J, where J is a halogen atom; or Z' and Y' together are --CH2 O--; and pharmaceutically acceptable esters, ethers, amides, N-acyl moieties and salts thereof.
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- Photochemical Trifluoromethylation of Some Aromatic and Heteroaromatic Compounds with Trifluoromethyl Bromide
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The photochemical introduction of trifluoromethyl group with CF3Br in aromatic and heteroaromatic rings was investigated for 9 compounds.Naphthalene, anthracene, anisole, N,N-dimethylaniline, ferrocene, benzothiophene, isoquinoline, and N-methylpyrrole gave trifluoromethylated products in 6.5-100percent yields.In one step from uracil, a pharmacologically important 5-trifluoromethyluracil can be synthesized by this method in 11percent yield.Based on the mechanistic study carried out for the naphthalene-CF3Br-CH3CN system, the reaction is found to proceed via the electron transfer from an excited singlet state of naphthalene to CF3Br.
- Akiyama, Takeo,Kato, Kohji,Kajitani, Masatsugu,Sakaguchi, Yoshio,Nakamura, Junko,et al.
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p. 3531 - 3538
(2007/10/02)
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- A SELECTIVE AND EFFICIENT METHOD FOR THE DEPROTECTION OF N-BENZYLOXYMETHYL (BOM) PROTECTING GROUPS FROM PYRIMIDINE AND DIHYDROPYRIMIDINE RING SYSTEMS
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N1,N3-dibenzyloxymethyl derivatives of pyrimidines and dihydropyrimidines have been successfully deprotected by using trifluoroacetic acid (TFA).These N-BOM derivatives can be selectively removed from a variety of derivatives including nucleosides and compounds which are sensitive to base and reducing conditions.
- DeFrees, Shawn A.,Reddy, Kalakota S.,Cassady, John M.
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p. 213 - 220
(2007/10/02)
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- Production of 5-perfluoroalkyldihydrouracil derivatives
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A process for preparing a 5-perfluoroalkyl-dihydrouracil derivative of the general formula STR1 wherein Rf represents a perfluoroalkyl group, each of R1 and R2 represents a hydrogen atom, or an alkyl, cycloalkyl, aryl, aralkyl or heterocyclic group, and Y is an oxygen or sulfur atom, which comprises (a) reacting a compound of the general formula STR2 wherein X represents a halogen atom or hydroxyl group, with a urea derivative of the general formula STR3 provided that when X is a hydroxyl group and at least one of R1 and R2 is a hydrogen atom, said reaction is carried out in the presence of a condensing agent, or (b) cyclizing a compound of the general formula STR4 and a novel intermediate compound of the above formula (IV).
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- A FACILE CONVERSION OF 5-TRIFLUOROMETHYL-5,6-DIHYDROURACILS TO 5-TRIFLUOROMETHYLURACILS
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5-Trifliuoromethyl-5,6-dihydrouracils were directly converted to the corresponding 5-trifluoromethyluracils by the reaction with copper(II) bromide in dimethylformamide/water or dimethylformamide/acetic acid in good to excellent yields.
- Fuchikami, Takamasa,Yamanouchi, Akiko
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p. 1595 - 1598
(2007/10/02)
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- A New Method of the Introduction of CF3- and C2F5-Groups into Pyrimidine Derivatives and their Antiherpes Activity
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A new method of the perfluoroalkylation of uracil derivatives is described.The irradiation of aqueous solutions of uracil and uracilnucleosides with bis-(perfluoroalkyl)mercury (CnF2n+1)2Hg n = 1,2 under the exclusion of oxygen in the presence of catalytic amounts of azo-bis-isobutyronitril at 254 nm for several hours gave new 5-perfluoroalkylated compounds.In this way we obtained 5-trifluoromethyluracil (5a), 5-pentafluoroethyluracil (5b), 5-trifluoromethyl-2'-deoxyuridine (6a), 5-pentafluoroethyl-2'-deoxyuridine (6b) and 1-(β-D-arabinofuranosyl)-5-trifluoromethyluracil (7a) in different yields.The perfluoroalkylated compounds were tested against HSV-1 and HSV-2 viruses on human lungefibroblasts.The compounds are markedly less potent than other known nonfluorinated compounds.
- Schwarz, B.,Cech, D.,Reefschlaeger, J.
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p. 985 - 993
(2007/10/02)
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- NEW AND DIRECT ROUTE TO 5-TRIFLUOROMETHYL-5,6-DIHYDROURACILS BY MEANS OF PALLADIUM COMPLEX CATALYZED "UREIDOCARBONYLATION" OF 2-BROMO-3,3,3-TRIFLUOROPROPENE
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Palladium complex catalyzed carbonylation of 2-bromo-3,3,3-trifluoropropene (2-Br-TFP) with ureas afforded 5-trifluoromethyl-5,6-dihydrouracils in moderate to good yields, which were converted into 5-trifluoromethyluracils in nearly quantitative yields.
- Fuchikami, Takamasa,Ojima, Iwao
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p. 4099 - 4100
(2007/10/02)
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