Pyrimidines, 1,2-dihydro-2- -, formation

A similar degenerate ring transformation was observed when 4-amino-6-chloro-l-methylpyrazolo[3,4-(f]pyrimidine was treated with dilute alkali. In this reaction as well, the expected product, 4-amino-6,7-dihydro-6-oxo-l-methylpyrazolo[3,4-(f]pyrimidine, was not obtained, but rather a rearranged isomer, i.e., 6-amino-4,5-dihydro-4-oxo-l-methylpyrazolo-[3,4- f] pyrimidine. The formation of this compound takes place according to the same mechanism as that postulated for the formation of 86 (Scheme 11.39) (54JOC1570). 

Surprisingly, Kashima et al. (83TL209) reported the formation of individual 1,4-dihydro- and 1,6-dihydropyrimidines on desulfurization of the corresponding pyrimidine-2-thiones with Raney Ni and claimed that no tautomerization occurs under the reaction conditions (heating under reflux in MeOH). 

Other degradation products of the cytosine moiety were isolated and characterized. These include 5-hydroxy-2 -deoxycytidine (5-OHdCyd) (22) and 5-hydroxy-2 -deoxyuridine (5-OHdUrd) (23) that are produced from dehydration reactions of 5,6-dihydroxy-5,6-dihydro-2 -deoxycytidine (20) and 5,6-dihydroxy-5,6-dihydro-2 -deoxyuridine (21), respectively. MQ-photosen-sitized oxidation of dCyd also results in the formation of six minor nucleoside photoproducts, which include the two trans diastereomers of AT-(2-de-oxy-/j-D-eryf/iro-pentofuranosyl)-l-carbamoyl-4 5-dihydroxy-imidazolidin-2-one, h/1-(2-deoxy-J8-D-crythro-pentofuranosyl)-N4-ureidocarboxylic acid and the a and [5 anomers of N-(2-deoxy-D-eryfhro-pentosyl)-biuret [32, 53]. In contrast, formation of the latter compounds predominates in OH radical-mediated oxidation of the pyrimidine ring of dCyd, which involves preferential addition of OH radicals at C-5 followed by intramolecular cyclization of 6-hydroperoxy-5-hydroxy-5,6-dihydro-2 -deoxycytidine and subsequent generation of the 4,6-endoperoxides [53]. 

Partly saturated pyrazino[l,2-r-]pyrimidines were prepared by formation of the pyrazine ring. 2-Substituted-8-hydroxy-3,4-dihydro-177,277-pyrazino[l,2-r-]pyrimidin-l-ones were prepared by a [6+0] synthesis involving cyclization of 6-hydroxy-pyrimidine-4-(fV-hydroxyethyl)carboxamides <2005W02005/087766>. The 2/7-pyra-zino[l,2-c]pyrimidine-3-carboxamide 164 (Y = NH) was formed from [5+1] atom fragments via the uracil derivative 163 (Y = NH) and DMF-dimethyl acetal. Compounds 163 were prepared from 6-chloromethyluracil and glycine methyl ester 162 (Y = NH) (Scheme 20) <2004W02004/014354>. 

The reaction of potassium 3-amino-4-oxo-3,4-dihydroquinazoline-2-thiolate 62 with a-bromophenylacetic acid 63 resulted in the formation of (3-amino-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-phenyl-acetic acid methyl ester 64 which on alkali treatment and subsequent acidification resulted in the synthesis of 2-phenyl- 1-thia-4,4a,9-triaza-anthracene-3,10-dione 65 <1999JCR(S)86>. Similarly, the reaction of potassium 3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3- pyrimidine-2-thiolate 66 with a-bromo-ester 67 resulted in the formation of 2-(3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3- / pyrimidin-2-ylsulfanyl)-propionic acid ethyl ester 68. Subsequent treatment with alkali followed by acidification resulted in the formation of 2,3,7-trimethyl-3a,9a-dihydro-l,8-dithia-4a,5,9-triazacyclopenta[ ]naphthalene-4,6-dione 69 <2000JHC1161>... 

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... 

Thiamin (vitamin B-l, 177) when photolysed, gives preparations having a characteristic odour. Photolysis of an aqueous solution with a high-pressure mercury lamp is reported to give the pyrimidine (178) [ 113]. Other work used irradiation at 254 nm and concentrated on the approximately 0.1% yield of ether-soluble odoriferous products. As many as nine compounds have been identified (179), (180), (181), 2-methyl-3-formyl-4,5-dihydrofuran, 3-acetyl-4,5-dihydrofuran, 4-oxopentyl formate, 3-formyl-5-hydroxypentan-2-one, 3-mercapto-2-methyl-4,5-dihydrofuran and bis(4,5-dihydro-2-methylfuran-3-yl)disulphide [114, 115]. 

Uracils and related pyrimidines undergo oxidative addition to the 5,6-double bond, and the reaction with a number of oxidants to form 5,6-epoxides and 5,6-diols was discussed in CHEC-II(1996) <1996CHEC-II(6)93>. Oxidative halogenation can also occur <1996SC3583, 1998NN1125>, as shown by the formation of 5-bromo-5,6-dihydro-6-methoxyuracil 100 from uracil 99 by treatment with a mixture of potassium bromate and potassium bromide in the presence of Dowex ion-exchange resin in methanol <1996SC3583>. 

Oxidative cyclization of the 4-(2-aminobenzyl)-l,4-oxazine (576) with manganese dioxide gave the 1,4-oxazino[3,4-6]quinazoline (577) through the formation of its pyrimidine ring [68JCS(C)1722]. Cyclocondensation of anthranilic acids with the thioimidate ester (578) gave 3,4-dihydro-l,4-oxazino[3,4-6]quinazolin-6(l/f)-ones (579) [791JC(B) 107]. 

Hydrazinolysis of the imidate and carboxylic ester functions of 1-aryl-oxycarbonyl-l,6-dihydro-2-methoxypyrimidines (61) with 1 molar equivalent of hydrazine hydrate culminated in the formation of the 1,2,4-tria-zolo[4,3-a]pyrimidine-3-ones 63 [89GEP(0)3839711] (Scheme 25). 

When 2,4-dioxopyrido[l,2-a]pyrimidines 391 were treated dropwise in acetonitrile with tetrachlorosilane in 1,2-dichloroethane in the presence of sodium iodide at room temperature, 2-acetamido-3,4-dihydro-2//-pyridopyrimidin-4-ones 396 were obtained after work-up [92MJ24 93IJC(B)637]. In the first step iodotrichlorosilane was formed, and 1,2-addition of iodotrichlorosilane to a 2-carbonyl group of pyridopyrimidine 391 led to the formation of a-iodosilyl esters 392, which reacted with acetonitrile. After the rearrangement of adduct 393 and a further reaction with a second mole of iodotrichlorosilane, the hydrolysis of disylylated intermediates 395 yielded 2-acetamido-3,4-dihydro-2//-pyridopyrimidin-4-ones 396 (see Scheme 24). 

Vilsmeier-Haack formylation of 9-phenylhydrazonotetrahydropyr-ido[ 1,2-a]pyrimidin-4-ones 636 with a mixture of phosphoryl chloride and dimethylformamide at 60°C for 2 hours, then at 90°C for 0.5 hour, led to the formation of unsaturated dichlorinated 4//-pyrido[l,2-a]pyrimidin-4-ones 331 (91H1455). Because the analog 9-(phenylaminomethylene)tetra-hydropyrido[l,2-a]pyrimidin-4-one 558 (R = COOEt) did not give a similar product, it was assumed that the 6,7-dihydro form 637 was involved in the ring transformation. 

The formation of imidazo[l,2-c]pyrimidines (171) via a ring closure of 2-(2-sulfon-ylimino-1,2-dihydro-l-pyrimidinyl)acetamides (170) has been studied using DFT methods, which revealed the requirement for Brpnsted acid catalysis.220... 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

Antimetabolites that are used to prevent the formation of DNA may be classified as antifolates, purine antimetabolites and pyrimidine antimetabolites (Table 7.5). Antifolates are believed to inhibit dihydrofolate reductase (DHFR). This enzyme is responsible for catalysing the conversion of dihydro-folic acid (DHF or FH2) to tetrahydrofolic acid (THF or FH4), which occurs in... 

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