Uracil derivatives, oxidation

Eosin Flavonoids Morin Flavonol, fisetin, robinetin Quercetin Rutin condensation products of urea, formaldehyde and methanol [126], pesticide derivatives [127] sweetening agents [128, 129] anion-active and nonionogenic surface-active agents [130] steroids, pesticides [29,132, 133] pesticides [134—137] vanadium in various oxidation states [138] uracil derivatives [139]... 

Scheme 18 Oxidation of an uracil derivative by the MTO/H2O2 system or the MTO/UHP combination...

Bianchini F, Hall J, Donato F, Cadet J (1996) Monitoring urinary excretion of 5-hydroxymethyluracil for assessment of oxidative DNA damage and repair. Biomarkers 1 178-184 Bienvenu C, Wagner JR, Cadet J (1996) Photosensitized oxidation of 5-methyl-2 -deoxycytidine by 2-methyl-1,4-naphthoquinone characterization of 5-(hydroperoxymethyl)-2 -deoxycytidine and stable methyl group oxidation products. J Am Chem Soc 118 11406-11411 Bothe E, Behrens G, Schulte-Frohlinde D (1977) Mechanism of the first order decay of 2-hydroxypro-pyl-2-peroxyl radicals and of O2 formation in aqueous solution. Z Naturforsch 32b 886-889 Bothe E, Deeble DJ, Lemaire DGE, Rashid R, Schuchmann MN, Schuchmann H-P, Schulte-Frohlinde D, Steenken S, von Sonntag C (1990) Pulse-radiolytic studies on the reactions of S04 with uracil derivatives. Radiat Phys Chem 36 149-154... 

In addition to the thermal decomposition the photochemical reaction of geminal diazide 62 was also studied. Irradiation of an acetone solution of 62 under an inert gas atmosphere afforded a complex mixture of products which could not be separated or identified. However, if the reaction was carried out in the presence of oxygen the uracil derivative 66 was obtained in 48 % yield. Surprisingly, in addition to the oxidation of the CH2 group, the 6-diazidomethyl function was completely lost during the reation [91JCS(P1)1342]. At the present time no mechanistic explanation for this unusual behavior can be presented. On the other hand, photooxidation of compound 63 leads straightforward to compound 67 [91 JCS(P1)1342],... 

The cycloreversion of the cyclobutane radical cation Pyr +oPyr could proceed in either a concerted or stepwise manner, and many attempts were made to determine the mechanism of this cleavage step. Because the radical cation is delocalized, it is not unreasonable that both the C(5)-C(5 ) and the C(6)-C(6 ) bonds are weakened by oxidation of PyroPyr. The observation of a substantial secondary deuterium isotope effect for the cleavage of the first bond [C(6)-C(6 )] and a small isotope effect for the cleavage of the second bond [C(5)-C(5 )] in various deu-terated uracil-derived cyclobutane dimers was, however, taken as an indication of a stepwise splitting mechanism via the distonic radical cation Pyr+-Pyr [9]. Theoretical studies performed by Rosch, Michel-Beyerle et al. also strongly support the assumption of a successive cycloreversion [10]. 

Nitrile oxides undergo dipolar [3 + 2] cycloadditions to carbon-carbon double bonds and triple bonds, for example, as in reactions 17-19 with an olefin a uracil derivative ... 

The oxidation of DNA is a known source of genomic instability, possibly caused by the oxidation of thymine and uracil. The oxidation of these compounds would change their pK values, which in turn would affect the base pairing and coding. In fact, some thymine derivatives, protected in the positions that undergo oxidation more easily, have demonstrated antitumor and antiviral properties [11]. Thus, studies directed at these processes could be extremely valuable for the understanding and prevention of mutations [12]. 

Oxidative Halogenation. Benzylic bromination and a-iodination of ketones and uracil derivatives can be achieved with CAN as in situ oxidant. 

Zinc Derivatives. Zincated and Al-protected 6-iodouracil 155 can be used under Negishi conditions for the preparation of 6-arylated uracil derivatives (Scheme 63). The conversion of the 6-iodouracil derivative is best performed using highly active zinc dust in DMAC.f The oxidative addition of active zinc has also been applied to a number of other iodo- and bromo-substituted 7r-deficient heteroarenes such as pyridine, pyrimidine, and quinoline, giving the corresponding heteroarylzinc halides 156, which are transformed to arylated derivatives by palladium catalysis. ... 

The palladium(II)-assisted alkenylation of aromatic compounds has also been applied to the synthesis of heterocycles. A novel synthesis of pyrido[3,4-d] pyrimidines, pyrido[2,3-d]pyrimidines and quinazolines was developed by Hirota et al. [18] employing the palladium(ll)-promoted oxidative coupling of uracil derivatives and alkenes. l,3-Dimethyluracil-6-carboxaldehyde dimethylhydrazone (22), 6-dimethylaminomethylenamino-l,3-dimethyluracil (24) and ( )-6-(2-dimethylaminovinyl) uracil (26) all reacted with methyl acrylate in the presence of stoichiometric Pd(OAc)2, producing pyrido[3,4-ii]pyrimidine 23, pyrido[2,3-if]pyrimidine 25 and quinazoline 27, each apparently arising from direct arylation, 6ti electrocycliza-tion, and elimination of dimethylamine, in 67%, 89% and 64% yields respectively (Scheme 9.3). 

The palladium(ll)-catalysed direct oxidative coupling reaction was also extended to other heterocycles, such as uracils. Hirota et al. [30] reported a simple method for the synthesis of 5-alkenylated uracil derivatives by treatment of 1,3-dimethyluracil (46) and 2, 3 -isopropylideneuridine (48) with methyl acrylate (4b) in the presence of 5 mol% Pd(OAc)2 and 2 equiv rcrt-butyl perbenzoate in refluxing acetonitrile (Scheme 9.7). The reaction successfully generated the corresponding alkenylated heterocycles 47 and 49 in 75% and 46% yields respectively. 

Hirota, K., Isobe, Y., Kitade, Y. and Maki, Y. (1987) A simple synthesis of 5-(l-alkenyl)uracil derivatives by palladium-catalyzed oxidative coupling of uracils with olefins. Synthesis, 495-6. 

Uracil derivatives also participate in catalytic intermolecular oxidative Mizo-roki-Heck-type reactions [123]. 

The conversion of norbornene into bicyclo[3,2,l]octan-3-one, achieved by standard procedures, has been used to effect a synthesis of the uracil derivative (462). Baeyer-V illiger oxidation of the above ketone followed by treatment of the product lactone with... 

A manganese(IV) species absorbing around 300 nm is formed in the permanganate oxidation of substituted uracil derivatives. " The rate-... 

Caffeine (a trimethylxanthine ) is metabolized in the human liver by cytochrome P450 oxidase enzymes, which rip methyl groups off the caffeine molecule, producing three dimethylxanthines called paraxanthine (84%), theobromine (12%) and theophylline (4%) -followed by further demethylation and oxidation, leading to urates and uracil derivatives. 

There are many synthetic routes to alloxan. Probably the best is direct oxidation of barbituric acid (1004 R = H) with chromium trioxide (5208(32)6) but it may be made from barbituric acid via its benzylidene derivative by direct or indirect oxidation of uric acid from 5-chlorobarbituric acid (1004 R = C1) by nitration or from 5-nitrobarbituric acid (1004 R = N02) by chlorination, both via the intermediate (1005) (64M1057) or by permanganate oxidation of uracil (1006) under carefully controlled conditions (73BSF1167). 

The 1,3-dimethyluracil derivative 109 with two reactive centers reacts with 1,2,4-tiiazine 4-oxide 58 only at the uracil fragment to afford compound 110 (96MC116). 

Electron-rich 6-[(dimethyl(amino)methylene)amino uracil 82 underwent [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides to afford novel pyrinhdo[4,5-J]pyrimicline derivatives 83-84 after elimination of dimethylamine from the (1 1) cycloadducts and oxidative aromatization. This one-pot procedure yielded excellent yields when carried out in the solid state and under microwave irradiation <06BMCL3537>. 

Phenylglyoxal and alkoxyphenylglyoxals react selectively with the guanine moiety of nucleosides and nucleotides in phosphate buffer (pH 7.0) at 37°C for 5-7 min to give the corresponding fluorescent derivatives [12-15], as shown in Figure 6. Other nucleic acid bases and nucleotides (e.g., adenine, cytosine, uracil, thymine, AMP, CMP) do not produce derivatives under such mild reaction conditions. The fluorescent derivative emits chemiluminescence on oxidation with di-methylformamide (DMF) and H202 at pH 8.0-12 [14, 15],... 

In addition to the protein and low-molecular-weight thiols that react with PAN, there are several other reactive biochemicals. Reduced nicotinamide derivatives are susceptible to oxidation by PAN (at 72 ppm for 1-5 min), whereas the oxidized forms are resistant. The capability of PAN to oxidize these compounds rapidly dissipates in aqueous solution, with a half-life of 4-10 min, depending on pH. The oxidation products appear to be the biologically active forms of the nicotinamide derivatives. Purines and pyrimidines react with PAN (at 1,000 ppm for 30-120 min). The order of sensitivity is thymine, guanine, uracil, cytosine, and adenine. Their reactions were studied at relatively low pH and at high PAN concentration and are probably not of biologic significance. 

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