Pyrimidone formation

Extension of this work by studying the reaction of 3-methyl-5-nitro-pyrimidin-4(3//)-one with -X-arylketones in the presence of ammonium acetate surprisingly revealed the formation of a mixture of 4-arylpyrimidines and 6-arylpyridin-2(l//)-ones (00JCS(P1)27). The ratio between pyridine and pyrimidine formation is dependent on the substituent X. With electron-donating substituents the formation of the pyridin-2(l//)-ones is favored, with electron-attracting substituents the formation of the pyrimidine derivatives (Scheme 21) In the formation of the 6-arylpyridin-2(l//)-ones the C-4- C-5-C-6 part of the pyrimidone-4 is the building block in the construction of the pyridine ring. Therefore, the pyrimidone can be considered as an activated o -nitroformylacetic acid (Scheme 21). 

One such compound, bropirimine (112), is described as an agent which has both antineo-plastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. 

A similar approach via desulfurization of the thiosemicarbazide-substituted pyrimidone 290 using 4-nitrobenzyl bromide leads to efficient formation of the tricyclic system 291 in excellent yield (Equation 79) <2000RJ0430>. 

DNA strongly absorbs UV radiation, especially mid-range UVB (290 to 320 nm) radiation. Two major DNA lesions are induced following UV exposure, pyrimidine dimers and 6-4 pyrimidine-pyrimidone photoproducts. Because the action spectrum (induction of a biological activity as a function of wavelength) for erythema closely matches the action spectrum for pyrimidine dimer formation, DNA is believed to be the chromophore for sunburn.6 Pyrimidine dimer formation, or more properly, the failure to adequately repair dimers after solar irradiation is also the primary cause of sunlight-induced skin cancer formation.7-8... 

The diselenides [A -(6-Et-4-pyrimidone)(6-Et-SeU)J (31) and [7V-(6-n-Pr-4-pyrimidone)(6-n-Pr-SeU)j] (32) were produced upon re-ciystallization of [( -PrSeU)IJ (30) and [(n-EtSeU) ] (33) from acetone, as oxidation products. On the other hand deselenation with the formation of 6-n-propyl-2-uracil (n-Pr-U) (34) was observed when (30) was re-crystallized from methanol/acetonitrile solutions [7]. 

The reaction of 2-pyrimidone (PMOH " CT) (15) with di-iodine in a molar ratio of 1 1 resnlted to the formation of [LOHJ CTl (37) complex. 

A somewhat different route is used to prepare an analogue that bears additional oxygen. The sequence, in this case, starts by base-catalyzed formylation of the hydro-cinnamic acid derivative (40-1) with ethyl formate. Condensation of the product (40-2) with guanidine in this case leads to a pyrimidone (40-3), with the cyclization involving an ester-amide interchange between guanidine and the ester. Reaction of... 

Amino-l-methylimidazole (169) reacted with DMAD145 in dioxane to form 30% of imidazo[l,2-a]pyrimidone (170), identified by the low-field 3-proton, and 5% of the diazepine 171, which was presumably built up by cyclobutene formation across the 4,5-double bond of 169 and ring expansion.148 Both l-methyl-2-methylthioimidazoline and its... 

The most important feature of organocobalt cyclizations is that a variety of functionalized products can be obtained, depending on the nature of the substrate and the reaction conditions. The most common transformation has been formation of an alkene by cobalt hydride elimination. Alkenes are often formed in situ during the photolysis, and with activated alkene acceptors the formation of these products by cobalt hydride elimination is very facile. Scheme 31 provides a representative example from the work of Baldwin and Li.143 The alkene that is formed by cobalt hydride elimination maintains the correct oxidation state in the product (54) for formation of the pyrimidone ring of acromelic acid. Under acidic conditions, protonation of the cyclic organocobalt compound may compete 144 however, if protonated products are desired, the cyclization can probably be conducted by the reductive method with only catalytic quantities of cobalt (see Section 4.2.2.2.2). 

The H NMR spectra of the pyrano[3,2-< ]pteridine (341) and its enantiomer derived from the phenylhydrazone of D-arabinose (343) show a time-dependent change due to the formation of an equilibrium involving the isomeric furo[3,2- ]-pteridines. Analogous results were obtained with 5,6-diamino-3-methyl-2-methylthio- and 5,6-diamino-2-methylthio-4(3//)-pyrimidone (342), respectively, leading in the latter case even to a separation of the two enantiomers (344) and (345) with respect to the chiral centers at the 6- and 7-position of the pteridine moiety (Equation (15)). 

In an aqueous buffered medium, over the pH range 1-12, pyrimidone-2 exhibits a single one-electron wave. Preparative electrolysis, at a potential corresponding to the initial limiting current, led to formation of an insoluble product, isolated as a white amorphous powder, and shown by various physico-chemical criteria to correspond to a dimer consisting of two molecules of reduced pyrimidone-2. This was further confirmed by H NMR spectroscopy, which also established the structure of the product as 6,6 (or 4,4 )-bis-(3,6(4)-dihydropyrimidone-2), shown in Scheme 2, below. The structure of the dimer reduction product, and its solid state conformation, were subsequently further established by X-ray diffraction (see Sect. III.3.). 

In aqueous 0.1 M (CH3)4NBr, pyrimidone-2 was found to exhibit two reduction waves of equal height, with E1/2 values of —0.75 V and —1.55 V for waves I and II, respectively 1,2). (Fig. 1) Preparative electrolysis under these conditions at the potential of wave I resulted in formation of the same dimer reduction product as in aqueous buffered medium. By contrast, electrolysis on wave II led to formation of two products, one of which was identical with that formed on wave I. The other, readily soluble in aqueous medium, was identified as 3,6-dihydropyrimidone-2, identical with that synthesized chemically and described earlier by Skaric75). 

In acid medium (pH 4.5) electrochemical reduction led to formation of two products. One of these was characterized as the 6,6 -dimer of the riboside of pyrimidone-2. It was photochemically converted to the riboside of pyrimidone-2. The second, on the basis of its chromatographic behaviour, UV spectrum, and reaction with the Fink reagent, was identified as the riboside of 3,6-dihydropyrimidone-2. The mechanism of electrochemical reduction of cytidine in acid medium is consequently analogous to that for 1-methylcytosine. The products of reduction of cytidine at pH 7 were shown chromatographically to contain 5,6-dihydrocytidine 1 84). A comparison of the electrochemical and catalytic reduction products under analogous conditions at pH 7 demonstrated that both led to the same products, one of them 5,6-dihydrocytidine 84). 

In view of the earlier demonstration that pyrimidone-2 undergoes one-electron reduction, with formation of a dimer identified as 6,6 -6ij-3,6-dihydropyrimidine-2, which is suceptible to quantitative photodissociation to the parent pyrimidone-2, and bearing in mind that 2-oxopurine may be considered a formal analogue of a 5,6-disubstitut-ed pyrimidone-2, it appeared of interest to examine whether an analogous reaction sequence occurs with 2-oxopurine. 

Condensation with ethyl formate (HC02Et) and cyclization with guanidine gives the pyrimidine ring system but with an OH instead of the required amino group. Aromatic nucleophilic substitution in the pyrimidone style from Chapter 43 gives trimethoprim. 

There are two major types of DNA damage following UV radiation cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts that are often simply called (6-4) photoproducts. Formation of these UV lesions may be influenced by the DNA sequence. Nevertheless, in general, CPDs are more abundant than (6-4) photoproducts in UV irradiated DNA. For example, in UVC-irradiated DNA, the overall ratio of CPDs to (6-4) photoproducts is about 3 1. 

Cytosine (257) loses ammonia in a two-electron reduction298 with the formation of 2-pyrimidone (258), which, as other pyrimidones,200 is reduced in a one-electron reaction with dimerization. 

Pofy-l-vinyluradl (poly-VUr, 10) was also obtained by a free-radical polymerization6). In this case, it should be noted that the formation of substituted dihydrouradl rings occurred via a cydopolymerization mechanism11). y-Ray induced solid-state polymerization of the monomer (9) in high concentration and at low temperature excluded cydopolymerization completely12). Poly-VUr was also prepared by a free-radical polymerization of 2-ethoxy-4-l-vinyl-pyrimidone (ii)8) or 4-ethoxy-l-vinyl-2-pyrimidone (13)iy> followed by acid hydrolysis of the resulting polymers (12) or (14) (Scheme 2). 

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