Dihydropyrimidines oxidation

There are at least eight syntheses of orotic acid in the literature. The most practical in the laboratory is that involving the condensation of diethyl oxalacetate (972) with S-methylthiourea to give 2-methylthio-6-oxo-l,6-dihydropyrimidine-4-carboxylic acid (973) which undergoes either direct acidic hydrolysis or a less smelly oxidative hydrolysis, via the unisolated sulfone (974), to afford orotic acid (971) (B-68MI21303). 

The analog program on pyrimidines included some open-chain versions of this heterocycle as well. These last, the biguanides, were found to be quite active in their own right. (It was subsequently established that these compounds undergo oxidative cyclization to dihydropyrimidines in the body to give the actual antimalarial—see cycloguanyl). 

AO is also effective in metabolizing a wide range of nitrogen-containing heterocycles such as purines, pyrimidines, pteridines, quinolines, and diazanaphthalenes (95). For example, phthalazine is rapidly converted to 1-phthalazinone by AO and the prodrug, 5-ethynyl-2-(l//)-pyrimidone, is oxidized to the dihydropyrimidine dehydrogenase mechanism-based inhibitor, 5-ethynyluracil, by AO (Fig. 4.40) (96). 

A further example for oxidation by O2 are 5,6-dihydropyrimidine-6-yl radicals. These react with O2 to give the 6-peroxyl radicals shown [23, 24, 25, 37],... 

Oxo-4-amino-l,2,5,6-tetrahydro-lf/-pyrimidine. A dihydropyrimidine, not a tetrahydropyrimidine (two exo- and endoeyclic double bonds) 4-Amino-5,6-dihydro-2(l//)-pyr>midone (Chem. Abstr.) assigns the correct oxidation state, tautomeric form and location of the proton the danger is that the latter is not always known, however. 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

Dihydropyrimidines are normally readily oxidized to the corresponding pyrimidines by dehydrogenation, hydrogen transfer, or disproportionation reactions <1994HC(52)1, 1996CHEC-II(6)93>. For example, the oxidation of a series of trifluoromethyl ketones 522 with DDQ occurred readily at room temperature <1997H(44)349>. Facile room temperature oxidation with ceric ammonium nitrate (CAN) has also been achieved <2003ARK(xv)22>. 

From the yields of 5,6-dihydropyrimidine radicals, we predict reduction product yields of 0.04-0.06 pmol/J for 5,6-dihydrouracil and 0.03-0.05 pmol/J for 5,6-dihydro-thymine for B-form DNA hydrated to 9 waters per nucleotide. With respect to oxidation products, we predict strand-break yields —0.10 pmol/J. A very surprising prediction of this model is that the yield of damaged guanine is nil. Half the damage is oxidized sugar products and the other half is reduced pyrimidines. 

Nitropyrimidine, its 2- and 4-methoxy, and 2,4- and 4,6-dimethoxy derivatives react with acetone in the presence of potassium hydroxide to yield the potassium salts of the anionic adducts 74 and 75, with structures elucidated by spectral ( H-NMR, IR, and UV-visible) methods. The nucleophilic attachment was found to occur only at CH positions, and when there was a choice between 2- and 4(6)-positions, the latter was preferred.125,126 An adduct of the kind corresponding to structure 75 was also obtained by using the conjugate base of acetophenone. The adducts can be converted to the corresponding CH3COCH2- or PhCOCH2-substituted pyrimidines by oxidation, either directly or via the related dihydropyrimidine derivatives.127... 

No evidence has been found for the presence of the isomeric adduct 97 in spite of the presence of a small amount of 2-phenylpyrimidine (nearly 4%) in the reaction mixture as obtained after hydrolysis of the adduct to dihydropyrimidine and subsequent oxidation. The composition of the reaction mixture is not affected if TMEDA is added. 

Diazines also react more readily than pyridine. Thus, pyrimidine and phenylmagnesium bromide give adduct (276), which can be oxidized to 4-phenylpyrimidine. Aryl- and heteroaryl-lithium reagents at low temperature (79AG1, 80RTC234) add across the 3,4-double bond of pyrimidines to give dihydropyrimidines. 2,5-Dimethylpyrazine and lithium aryls afford the 3-aryl derivatives. 

Oxidation of 3,4-dihydropyrimidin-2(l //)-oncs (DHPMs) with ceric ammonium nitrate (CAN) in acetic acid resulted in ethyl 2,4-dioxo-6-phenyltetrahydropyrimidin-5-carboxylates as the major product. However, DHPMs undergo a regioselective oxidation with CAN in the presence of sodium hydrogencarbonate in neutral aqueous acetone solution to yield ethyl 6-meihyl-4-aryl(alkyl)pyrimidin-2(l //)-one-5-carboxylates. A mechanism involving a nitrolic acid intermediate has been suggested.72... 

Amidines and thioamidines can also be viewed as urea-like binucleophilic compounds. There are a series of publications about their treatment with unsaturated carbonyls [7, 86, 87, 88, 89, 90, 91, 92]. The most general reaction products in this case are 1,4-dihydropyrimidines or 1,6-dihydropyr-imidines. Interaction of acetamidine 88 with mesityl oxide 52 [86] and benzamidine 90 with arylidenetetraline 91 [91] led to the corresponding 1,6-dihydropyrimidines 89 and 92, while the reaction of bezamidine and benzylideneacetone 24 yielded 1,4-dihydropyrimidine 93 [87] (Scheme 3.27). 

O-tethered P-keto esters, through the intermediacy of aiylidene keto esters, have been efficiently utilized for the construction of immobilized dihydropyridines. Ceric ammonium nitrate (CAN) oxidation to pyridines followed by acidolytic cleavage provides a facile entry into nicotinic acid derivatives 57 [42], A three-component Biginelli cyclization of ureas on resin with a solution mixture of aldehydes and P-keto esters provides dihydropyrimidines 58 in high yield and purity [43], Heterocycles such as dihydropyridines and pyrimidines have historically proven to be a rich source of antimicrobial, antitumor, antiviral, and cardiovascular agents. 

Treatment of 4-ethoxy-6-methylpyrimidine-l-oxide (602) with acetic anhydride at 25-35 °C in chloroform followed by the addition of diketene at <20°C caused an exothermic reaction from which was isolated 7-acetyl-4-ethoxy-2-methyloxazolo[4,5-c]pyridine (603) (22%) and 7-acetyl-4-ethoxy-3-methylisoxazolo[4,5-c]pyridine (604) (8%) (88CPB168). A plausible mechanism for the formation of the isomers (603) and (604) is shown in Scheme 77. Acetylation with acetic anhydride furnishes an initial intermediate, l,2-diacetoxy-l,2-dihydropyrimidine (605). Electrophilic attack by diketene at C-5 then yields an acetoacetyl intermediate (606). Ring-opening and recyclization of (606) then gives via intermediates (607) and (608) the pyridine (609). Compound (609), which is not... 

Nanosized sulfated tin oxide (STO) particles dispersed in the micropores of Al-pillared clay (STO/Al-P), were used by Mishra and co-workers [91] as an environmentally benign, recyclable and efficient catalyst for the solvent-free synthesis of 3,4-dihydropyrimidin-2(l//)-ones 42 using a domestic microwave oven. The protocol offers advantages in terms of simple experimentation, reusable catalyst, excellent yields, short reaction times, and preclusion of toxic solvents (Scheme 31). 

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