1.3- Dimethyluracil formation

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

The hydrate formed by photolysis of this substance is one of the few such products (the others are uracil hydrate, 5-fluorouracil hydrate, and uridine hydrate) that have actually been isolated and compared with authentic material of known structure.7 It is nearly the only product formed in the photolysis, is definitely stable at room temperature and neutral pH, and the thermal reversal to dimethyluracil is nearly quantitative. These properties, as Moore observed, make the reaction ideal for mechanistic investigation. Burr and Park have investigated the reaction mechanism by measuring the photolysis rate of dimethyluracil in mixtures of water with several nonaqueous, nonreactive solvents as a function of water concentration.64 The photolysis rate for 10" iM DMU was found to be the same in water-saturated cyclohexane (about 5 x 10-3M in water) as in dry cyclohexane. The photolysis rate in dry, highly purified dioxane was quite insensitive to water, and it was observed that hydrate formation (measured by thin-layer chromatography and by thermal absorbance reversal) became appreciable only at water concentrations above 40%. 

It was found that the rate of hydrate formation jn the photolysis of dimethyluracil in acetonitrile was zero, and the rate in acetonitrile-water mixtures was a monotonic function of water concentration... 

Fig. 5. The rates of formation of dimethyluracil hydrate, uracil hydrate, and uracil dimer in mixtures of acetonitrile and water. Temperature about 24°C (Burr and Park64).

Fig. 7. The rate of dimethyluracil hydrate formation in acetonitrile-water mixtures as a function of the square of the water concentration (Burr and Park64).

Fig. 5). The fraction of hydrate formed at each water concentration was measured by the fraction of thermal reversal and reaches 100% at about 30% water (Fig. 6). The rate of hydrate formation is proportional to the square of the water concentration (Fig. 7). These results are to be compared with those observed for uracil in acetonitrile-water mixtures (Sect. V) the rate of uracil hydrate formation was proportional to the water concentration. A dimethyluracil dimer is formed in pure acetonitrile (indicated by photoreversal), but the structure of the dimer is not known. 

It is also possible to determine the nature of the excited molecule reaction leading to product formation by kinetic methods. For example, variation in the rate of formation of dimethyluracil hydrate with water concentration in acetonitrile-water mixtures is convex to the water concentration axis (Fig. 15).65 The rate of formation of uracil hydrate under similar conditions is linear with water concentration. The first of these is not the shape of curve to be expected if the function of the water molecules were simply to quench an excited state according to the common mechanism ... 

Another interesting reaction of diamines with isothiocyanates is the formation of l,3,5-triazepine-2-thione derivatives by the action of various classes of diamines on 2,3,4,5,6-penta-O-acetyl-D-gluconyl isothiocyanate (32). The reaction has been performed in acetonitrile or N,N-dimethyl-formamide solution with o-phenylenediamine, diaminomalononitrile, 5,6-diamino-l,3-dimethyluracil, 4,5-diamino-2,6-dithiopyrimidine, 4,5-diamino-2-thiopyrimidine, and 4,5-diaminopyrimidine, and afforded... 

Some oxidations of heterocyclcs with two heteroatoms proceed very readily. Thus, fluorinated quinazoline is oxidized to quinazol-4-one on fusing for only 2 minutes (Table 16).264 On the other hand, more vigorous oxidation of 5-fluoro-l,3-dimethyluracil by 3-chloroperoxybenzoic acid leads to the formation of unstable intermediate radicals that tend to rearrange to 4-hy-droxy-l,3-dimethylimidazoledione 3-chlorobenzoate (Table 16), similar177 to the chemical behavior of trifluoromethylated phenol.265... 

Synthesis of annelated diazepines based on unsaturated aromatic diazepines may involve the preliminary transformation of ketones into the corresponding l,3-diaryl-2,3-dibromopropane-3-ones (chalcone dibromides). The interaction between o-PDA or some of its substituted analogues with chalcone dibromides leads to the formation of aziridine derivatives [64] (see Chap. 1). However, in the case of 4-nitro-o-PDA, either azirenoquinoxalynes 53 or benzodiazepine derivatives 54 may be obtained depending on the reaction conditions [65] (Scheme 4.15). Diazepine derivatives 56 are obtained by the condensation of chalcone dibromides 51 with 5,6-diamino-1,3-dimethyluracil 55 [66], but aziridine derivatives are not isolated in this reaction. It should be noted that compounds 54 and 56 are formed owing to cyclization of the intermediate (3-enaminoketones [65, 66, 67] and are easily isolated from the reaction mixture. 

In the cyclocondensation, in the second diamine group of 1,2-diamine both the ortho and ipso heterocycle atoms may react. Such a nontrivial result was obtained while studying the interaction of chalcones 157 and cyclic unsaturated ketones 161 with 5,6-diamino- 1,3-dimethyluracil 55 [61, 62]. This refuted the data [57] on the oxazepine 158 structure of the products of this reaction the formation of the spiro systems 159 and 162 was unambiguously proven... 

An interesting pyrazine ring formation was detected between 5,6-diamino-1,3-dimethyluracil (309) and 6-hydroxy-6-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)-2//-pyran-3(6//)-one (310) leading to a mixture of l,3-dimethyl-7-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)lumazine (311), 1,3-dimethyl-6-[3-(2,3,5-tri-0-benzoyl-/ -D-ribofuranosyl)-3-oxopropyl]-lumazine (312), and 6,8-dimethyl-l-(2,3,5-tri-0-behzoyl-/ -D-ribofuranosyl)pyrrolo[l,2-/]pteridine-7,9-dione (313) (Equation (14)) <89JOC3927>. 

Under conditions of the Hilbert-Johnson reaction, the 2,4-dialkoxypyrimidines (29) can furnish the following by-products uracil,13 1-alkyluracil,3-7 1,3-dialkyluracil,19 4-alkoxy-2(lIZ)-pyri-midinone,7 and l-alkyl-4-alkoxy-2(lH)-pyrimidinone.7,20 Thus, for example, 5-chloro-, 5-bromo-, and 5-iodouracil were isolated32- 33 as by-products in the Hilbert-Johnson reaction (in acetonitrile at 20°) of the corresponding 5-halo-2,4-dimethoxypyrimidines and 3,5-di-O-p-toluyl-2-deoxy-D-ribofuranosyl chloride. The formation of 1,3-dimethyluracil and 1,3,5-trimethyluracil as by-products has been observed quite recently19 when the reaction of 2,3,5-tri-O-benzoyl-D-ribofuranosyl chloride with 2,4-dimethoxypyrimidine and 5-methyl-2,4-dimethoxypyrimidine, respectively, was performed in toluene at 70°. 

Azido-5-formyl-l,3-dimethyluracil is cyclized with hydrazines to afford pyrazolo[3,4-reaction with triphenylphosphine in benzene result in the formation of isoxazolo[3,4-c/]pyrimidine and pyrimido[4,5-[Pg.182]

Chloro-5-formyl-l,3-dimethyluracil reacts, furthermore, with 2-aminothiophenole in the presence of l,5-diazabicyclo-[4,3,0]non-5-ene (DBN) via a Smiles rearrangement to afford pyrimido[4,5-6][l, 4]benzothi-azine, while, without base, a simple condensation-substitution step leads to the formation of pyrimido[4,5- ]-[ 1,5]benzothiazepines (85UP1) (Scheme 104). 

Instead of the nucleophilic N-atoms, the attempted attack of appropriate carbanions (from acetamides substituted with an electron-withdrawing group) on the C-6 position of dimethyluracil leads to the cleavage of the uracil ring. This reaction splits off dimethylurea and leads finally to the formation of tautomeric pyridine-2,6-diones, such as 2,6-dihydroxynico-tinamide. Similarly, the reaction of 1,3-dimethyl-4-thiouracil with malo-namide proceeds smoothly to give 2-hydroxy-6-mercaptonicotinamide (791A4423 81JOC846) (Scheme 136). 

Imidazole ring formation of acyclo C-nucleoside 543 was made by reaction of 6-chloro-l,3-dimethyl-5-nitrouracil with o-glucopyranosylamine (541), followed by catalytic hydrogenation and concomitant cyclization of 542 (67CB492). The same C-nucleoside (543) was obtained by reacting 1-amino-l-deoxy-D-glucitol (544) with 6-chloro-l,3-dimethyluracil and subsequent nitrosation and cyclization (96S459) (Scheme 145). 

The essential step of this method is the electrocyclization of the azahexatriene system in 5-[(arylmethylene)amino]-6-[(./V,./V-dimethylamino)vinyl]-l, 3-dimethyluracils 5, which rearrange in situ following their formation from 5-(arylidene imino)-1,3,6-trimcthyluracils 4 and dimethylformamide dimethyl acetal. Aromatization then occurs by elimination of dimethyl-amine. The intermediate 6-[(W,Af-dimethylamino)vinyl] compounds 5 may be isolated in low yield.440 441... 

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