- Pyrimidine derivatives. XI. Facile carbon-carbon bond-cleavage reaction of 6-bromomethylpyrimidinediones and (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)methyl nitrate via 6-formyl derivatives
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The reaction of 5-bromo-6-bromomethyl-1,3-dimethyl- (1a) and 5-bromo-6-bromomethyl-1-(3-bromopropyl)-3-methyl-2,4(1H,3H)-pyrimidined ione (4a) with 1.0 and 2.0 eq of the sodium salt of 2-nitropropane yielded a mixture of 6-formyl (2 and 5a) and carbon-carbon bond-cleavage products (3 and 6a). When a large excess of the sodium salt of 2-nitropropane was used, 3 and 6a were obtained as sole products, respectively. The nitrates [(5-bromo-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)methy l nitrate (1b) and the dinitrate of 5-bromo-6-hydroxymethyl-1-(3-hydroxypropyl)-3-methyl-2,4(1H,3H)-pyrimid inedione (4b)] were exclusively converted to 6-formylpyrimidines (2 and 5b) or 6-unsubstituted pyrimidinediones (3 and 6b) by reaction with 1.0 or 2.0 eq of sodium methoxide, respectively. The dinitrate of 5-bromo-1-(2-hydroxyethyl)-6-hydroxymethyl-3-methyl-2,4(1H,3H)-pyrimidi nediones (7) was treated with sodium methoxide to yield 2-(5-bromo-6-formyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl )ethyl nitrate (8), a 3,4-dihydropyrimido[6,1-c][1,4]oxazine derivative (9) and 2-(5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)ethyl nitrate (10). A plausible reaction mechanism is presented.
- Kinoshita,Ohishi,Tanimoto
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- Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes
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Fosu, Hambira, and colleagues describe the direct C–H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc)2. The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included. The discovery of new medicines is a time- and labor-intensive process that frequently requires over a decade to complete. A major bottleneck is the synthesis of drug candidates, wherein each complex molecule must be prepared individually via a multi-step synthesis, frequently requiring a week of effort per molecule for thousands of candidates. As an alternate strategy, direct, post-synthetic functionalization of a lead candidate could enable this diversification in a single operation. In this article, we describe a new method for direct manipulation of drug-like molecules by incorporation of motifs with either known pharmaceutical value (halides) or that permit subsequent conversion (pseudo-halides) to medicinally relevant analogs. This user-friendly strategy is enabled by combining commercial iodine reagents with salts and acids. We expect this simple method for selective, post-synthetic incorporation of molecular diversity will streamline the discovery of new medicines. A strategy for C–H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C–H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.
- Fosu, Stacy C.,Hambira, Chido M.,Chen, Andrew D.,Fuchs, James R.,Nagib, David A.
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supporting information
p. 417 - 428
(2019/02/14)
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- Room-Temperature Gold-Catalysed Arylation of Heteroarenes: Complementarity to Palladium Catalysis
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Tailoring of the pre-catalyst, the oxidant and the arylsilane enables the first room-temperature, gold-catalysed, innate C?H arylation of heteroarenes. Regioselectivity is consistently high and, in some cases, distinct from that reported with palladium ca
- Cresswell, Alexander J.,Lloyd-Jones, Guy C.
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supporting information
p. 12641 - 12645
(2016/08/30)
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- DERIVATIVES OF TRIAZINES AND URACILS, THEIR PREPARATION AND THEIR APPLICATION IN HUMAN THERAPEUTICS
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The present invention relates to derivatives of general formula I wherein : - W represents nitrogen, - R1 represents: ? a hydrogen or a linear or branched C1-C5 alkyl radical or, ? a C1-C3 alkyl radical substituted with groups such as trifluoromethyl, nitrile, hydroxy, C1-C3 alcoxy, C3-C6 alkoxyalkoxy, indolyl, thiophenyl, oxothiophenyl, C1-C3 N-alkylcarbamoyl groups or, ? a phenyl or pyridyl or naphthyl, or thiophenyl group optionally substituted with one or more groups such as halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear branched C1-C4 alkyl, linear or branched C1-C3 alkoxy groups, ? a C6 2-oxocycloalkyl radical - R2 represents a methyl or heptyl, - m, n are equal to 1, - V represents CH2, - X-Y represents -N- (C=O) -, -CH-O-, - Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms or linear C1-C4 alkyl groups.
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Page/Page column 18
(2010/04/03)
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- Pyrimidine derivatives XII. A convenient preparation of 6-formylpyrimidinedione and 2- and 3-formylpyridine derivatives from corresponding nitrooxymethyl derivatives
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The convenient preparation of 6-formylpyrimipinedione derivatives and 2- and 3-formylpyridine are described. Thus, 5-bromo-1,3-dimethyl- (1a), 5-bromo-3-methyl-1-(2-nitrooxyethyl)- (1b), and 5-bromo-3-methyl-1-(3-nitrooxypropyl)-2,4(1H,3H)-pyrimidine-dione (1c) were converted to the corresponding 6-formyl compounds 2a, 2b, and 2c, respectively, in excellent yields by the reaction with triethylamine and 1,4-diazabicyclo[2.2.2]octane. These 6-formylpyrimidinedione derivatives are key intermediates for the preparation of 6-carbon-carbon substituted compounds, which are expected to be potential antitumor and antiviral agents. Similarly, 2-(and 3-)formylpyridine (9a (and 9b)) were obtained by the reaction of 2-(and 3)nitrooxymethylpyridine (8a (and 8b)) with 1,4-diazabicyclo[2.2.2]octane.
- Kinoshita,Ohishi
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p. 1599 - 1603
(2007/10/02)
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- Selective Oxidative Halogenation of Uracils
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A variety of N-substituted uracils has been selectively brominated to the corresponding 5-bromouracils in high yield by CHBr3-O2.Both oxidative bromination and chlorination of N-substituted uracils can be performed by means of combination of haloalkane solvents with m-chloroperbenzoic acid, magnesium monoperoxyphthalate, tert-butyl hydroperoxide or iodosylbenzene.Intermediates along the reaction path leading to the 5-halouracils have been identified; the intermediates depend on the oxidant used.Mechanistic aspects of the halogenation reactions and the reactive intermediates are discussed.
- Moltke-Leth, Claus,Joergensen, Karl Anker
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p. 1117 - 1121
(2007/10/02)
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- Photochemistry of Uracils in Halogenated Solvents
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The photochemistry of uracil and 1-substituted and 1,3-disubstituted uracils in CHBr3-CH2Cl2 is investigated.Photolysis of uracil leads to the formation of 5,6-dibromo-5,6-dihydrouracil as the main product, with 5-bromouracil as the by-product.In contrast with this the 5-bromouracils are formed as the main products by the photolysis of 1-substituted and 1,3-disubstituted uracils, with the corresponding 5,6-dihydro- and 5-bromo-5,6-dihydrouracils as the by-products.The kinetics of the bromination reaction have also been investigated and based on these results a free radical mechanism is proposed.
- Moltke-Leth, Claus,Joergensen, Karl Anker
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p. 1487 - 1490
(2007/10/02)
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- In-cell Indirect Electrochemical Halogenation of Pyrimidine Bases and their Nucleosides to 5-Haloderivatives
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Reaction of anodically generated "halonium" species (LiX or Bu4NX, LiClO4, MeCN, Pt/Pt; I2, LiClO4, MeCN) with pyrimidine bases and their nucleosides leads to 5-halo compounds in good yields.
- Palmisano, G.,Danieli, B.,Santagostino, M.,Vodopivec, B.,Fiori, G.
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p. 7779 - 7782
(2007/10/02)
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- Cerium(IV)-Mediated Halogenation at C-5 of Uracil Derivatives
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Treatment of protected uracil nucleosides 1 or 2 with elemental iodine or metal halogenides and ceric ammonium nitrate (CAN) at 80 deg C gave the corresponding protected 5-halouracil nucleosides 3a-f in excellent yields.Treatment of the resulting crude 3a-f with 0.1 M NaOMe/MeOH at ambient temperature gave the corresponding 5-halouridines 4a-f in high overall yields from 1 or 2.Further, 5-halouraciles 9a-f were prepared in good yields by treatment of 1,3-dimethyluracil (7) or uracil (8) with elemental iodine, metal halogenides, or hydrochloric acid and CAN.Halouridines 4a-e also were obtained in good yields by treatment of unprotected uracil nucleosides 5 or 6 with halogen sources as above and CAN.
- Asakura, Jun-ichi,Robins, Morris J.
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p. 4928 - 4933
(2007/10/02)
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- Halo-demercuration Reactions of the 1,3-Dimethyluracil and 1-Methyluracil 5-Substituted Mercurials
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Detailed procedures are submitted for direct mercuration (with Hg(II) acetate or chloride) of 1,3-dimethyluracil (I) or 1-methyluracil (VIII) with formation, subsequently, of 5-acetoxymercuri-1,3-dimethyluracil (II), 5-chloromercuri-1,3-dimethyluracil (III) or 5-acetoxymercuri-1-methyluracil (IX) in 52percent, 64percent or 49percent yields, respectively; II with hot solution of NaCl gave III in 45percent yield, whereas from II in hot aq.KI solution 5,5'-mercuribis(1,3-dimethyluracil) (IV) was formed in 89percent yield.The mercurials II, IV or IX were effectively halo-demercurated forming thus: 5-iodo- (V), 5-bromo- (VI) and 5-chloro-1,3-dimethyluracil (VII) or (from IX) 5-bromo-1-methyluracil (X) in the respective yields: 83-88percent, 82-85percent, 74 or 78percent.The structures of I-X are supported chemically, in part analytically as well as by the 1H-NMR spectra (see the Figure).
- Skulski, Lech,Kujawa, Anna,Kujawa, Tadeusz M.
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p. 499 - 505
(2007/10/02)
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- Oxidation of Thymines and Uracils with Sodium Peroxodisulfate
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Reaction of thymines with Na2S2O8 in water resulted in selective oxidation of the methyl group at 5-position of thymines.Oxidation of thymines with Na2S2O8 in hydrochloric acid gave 5-chloro-6-hydroxy-5,6-dihydrothymines and in acetic acid containing NaCl gave 6-acetoxy-5-chloro-5,6-dihydrothymines which were converted to 6-alkoxy-5-chloro-5,6-dihydrothymines with alcohols.The reaction of uracils also gave similar products together with 5-chlorouracils.
- Itahara, Toshio,Ebihara, Reiko,Fujii, Yukiko,Tada, Miki
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p. 1319 - 1322
(2007/10/02)
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- THE SYNTHESIS OF 5-BROMO-1,3-DIMETHYLURACIL AND ITS 6-ALKYL DERIVATIVES
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Bromination of 1,3-dimethyluracil and 6-alkyl-1,3-dimethyluracils with N-bromosuccinimide leads to the corresponding 5-bromo substituted uracils in high yields.
- Celewich, Lech,Koroniak, Henryk
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p. 1001 - 1006
(2007/10/02)
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- The bromination and iodination of N1-substituted uracils
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Reaction of N1-substituted uracils with bromine in water at pH=7 leads to 5-bromo-6-hydroxy-5,6-hydrouracils.For different N1-substituents these products were isolated and the relatively stable derivatives were characterized by 1H NMR and mass spectroscopy.On electrophilic iodination with iodide and chloramine-T in water no indications were obtained for the formation of such dihydrouracils except for uridine and deoxyuridine.However, on reaction of N1-substituted uracils with N-iodosuccinimide in CHCl3 containing ethanol, or in ethanol, 5-iodo-6-ethoxy-5,6-dihydrouracils could be isolated as reaction products.
- Bakker, Cees N. M.,Kaspersen, Frans M.
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p. 267 - 271
(2007/10/02)
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- Mechanisms of Bromination of Uracil Derivatives. 5. Reaction of Uracil and 5-Bromouracil via Their Anions in Weakly Acidic Aqueous Solution
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The rates of reaction of bromine with uracil, 1-methyluracil, 3-methyluracil, 1,3-dimethyluracil, 5-bromouracil, and 5-bromo-1,3-dimethyluracil have been measured in acidic, aqueous solutions (pH 0-5).For those derivatives having a methyl group at N1 the observed second-order rate constants are invariant with acidity, whereas for those derivatives having hydrogen at N1 they increase with decreasing acidity.These results suggest that reaction upon the anions of uracil, 3-methyluracil, and 5-bromouracil predominates at higher pH.The mechanistic implications of these findings are discussed.
- Tee, Oswald S.,Berks, Charles G.
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p. 830 - 835
(2007/10/02)
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