Pyrimidine-5-acetates, formation from

Pyrimidine bases can be less reactive than purines in these processes, but the tri-O-acetyl-D-galactal-derived compounds 51 have been obtained (a, 40% (3, 24%) by use of bis-0-(trimethylsilyl)uracil in ethyl acetate with antimony pentachloride as catalyst, the -anomer being required for the synthesis of an antibiotic [83]. Although trace proportions of 3-substituted glycals are present in the products of this reaction, their formation from the initial 2,3-unsaturated compounds is apparently less easy than is the case with the purine analogues. 

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>. 

Each base has a nitrogen atom capable of forming an acetal-like bond to the anomeric (or hemiacetal) carbon of deoxyribose. Recall that formation of an acetal from an alcohol and a hemiacetal involves elimination of water. We can envision that the water molecule is formed from the hydroxyl group of the hemiacetal and a hydrogen atom from the alcohol (or, in this case, the amine). Figure 12.57 illustrates this reaction for a purine base and for a pyrimidine base. 

Oxidation of 6-niethylpyrido[3.2-c/]pyrimidine-2,4(l //.3//)-di ne with 3-chloroperoxybenzoic acid in acetic acid affords the 5-oxide.448 Because of the lactam structure, in this example N5 is the only site available for oxidation. When activated by electron-donating substituents such as amino groups, oxidations are also observed in the pyrimidine part, as in the formation of the 1,5-dioxide from 6-(arylsulfonyl)pyrido[3,2-rf]pyrimidine-2,4-diamine.43 4 6-Chloropyri-do[3,2- /]pyrimidine-2,4-diamine, however, gives only the 5-oxide under the same conditions.435... 

A more versatile synthesis of the pteridine ring from pyrimidine-4,5-diamine involves the initial formation of a Schiff base by reaction with an aldehyde followed by cyclization with triethyl orthoformate or dimethylformamide diethyl acetal. The general reaction is shown below, and is exemplified by the synthesis of 6-phenylpteridine-2,4(1 //,3//)-dione (2)." 7... 

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of BFg-EtaO or of HC104, jS-phenylpropio-phenone (76) was obtained as by-product its formation is due to hydride transfer to the conjugate acid of chalcone (75), which is the acceptor (experimental data and theoretical calculations show that chalcones are protonated at the oxygen atom). Balaban obtained a 72% yield in the conversion 70 -> 37 using as acceptor chalcone and as catalysts perchloric or sulfuric acids (i.e., 75). The formation of j8-phenylpropiophenone (76) in the Chichibabin synthesis of pyridines from chalcones and ketones in the presence of ammonium acetate, and in the pyrimidine synthesis from chalcones and amidines is undoubtedly due to a similar hydride transfer. 

Oxidative desulfurization can be effected by ozonolysis (Scheme 74). 2-Thiol-4(3//)-quinazolinone on ozonolysis in dry dichloromethane yields the disulfide (448) which is resistant to further oxidation under the reaction conditions. In acetic acid, desulfurization results with hydrogen substitution (449). Rationalization of the reaction in acetic acid involves formation of an unstable sulfinic acid which loses SO2 with replacement by hydrogen. In dichloromethane containing ethanol, the 2-ethoxy product (450) formed, corresponding to nucleophilic substitution of the reactive sulfinic acid from the oxidation. Similarly, ozonolysis of pyrimidine-2-thione acid gave bis-2-pyrimidinyl disulfide in dry dichloromethane and 2-ethoxypyrimidine in the presence of ethanol <93TL1631>. 

Pyrrole-based anthranilic acid derivatives have been prepared utilizing a four step sequence starting from arylacetonitriles 4 <04T2267>. Condensation of the latter with ethyl formate followed by treatment with diethylaminomalonate hydrochloride (DEAM-HCl) led to enamine 6. Cyclization and transesterification then gave 3-aminopyrrole-2-carboxylate 7. The acid-mediated cyclocondensation of methylaminoacetaldehyde dimethyl acetal with malonitrile provided a novel synthesis of 2-amino-3-cyanopyrroles, useful building blocks for the preparation ofpyrrolo[2,3- f]pyrimidines <04OL2857>. 

Glycine can follow any one of a number of paths and during metabolism it may be transformed into a variety of substances formate, acetate, ethanolamine, serine, aspartic acid, fatty adds, purines, pyrimidines, ribose or protoporphyrin. Its complete degradation, like that of serine or ethanolamine into which it is readily transformed, may be brought about by conversion to pyruvic acid from whence it can enter the glycolysis chain or the tricarboxylic acid cycle. 

Vinamidinium salt 840 is a promising reagent for the synthesis of 5-trifluoromethylpyrimidines 841, unsubstituted at positions C-4 and C-6. Compound 840 was prepared from 2,2,2-trifluoropropanoic acid (839). Acid 839 was obtained via radical addition of nifluoromethyl iodide to TBS-enolate 838 of ferf-butyl acetate 837, followed by acidic hydrolysis (Scheme 168) [512], Reaction of 840 with amidines and their analogues led to formation of the corresponding pyrimidines 841 in 54-85 % yields. Additional examples of such transformations were described [347, 513], including also reaction with aminopyrazole 843 (Scheme 169) [514]... 

ABT-925 (229) was obtained starting from amidine 250 and ethyl triflnoroaceto-acetate to give pyrimidine 251 (Scheme 59) [221], Reaction of 251 with SOCI2 and then - piperazine led to the formation of amine 252. Selective alkylation of 252 with l-bromo-3-chloropropane gave chloride 253, which reacted with thionracil anion to form ABT-925 (229). 

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