Pyrimidines, 2-amino-, 1-oxides, formation

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Attempts to establish the structure of the initial adduct by NMR-spectroscopy failed because of the low solubility of 27. This makes it impossible to draw a clear conclusion as to whether the ammonia adds to C-6 (as occurs in the case of the A-methylpyrimidinium salts) or at C-2. Since NMR spectroscopy of a solution of 4,6-diphenylpyrimidine in potassium amide/liquid ammonia strongly supports the formation of an anionic C-2 adduct (75UP1], it is justified to assume that also in the deamination of 27 by liquid ammonia, a C-2 adduct 28 is involved (Scheme III. 16). It is evident that the major part of the deamination (73%) does not involve a ringopening reaction the main deamination reaction occurs by an Sn2 attack of ammonia on the A-amino group in 27. A similar mechanism has also been postulated in the deoxygenation of pyrimidine A-oxides, when they are heated with liquid ammonia (Scheme III.16) [77UP2]. 

A vigorous reaction occurs when 1,2,5-thia- and selena-diazole A -oxides annulated onto pyrimidine rings are treated with 10-30% hydrogen peroxide resulting in the formation of 6-amino-5-nitrouracils (Scheme 25) <2000CHE1359>. 

From a pulse radiolysis study on the S04 -induced reactions of Thd (Deeble et al. 1990), it has been concluded that the pKa of the Thd radical cation (deprotonation at N(3)) should be near 3.5, i.e. close to that at N( 1) in Thy. It is noted that also in the parent, Thy, the pKa values at N( ) and at N(3) are quite close. A Fourier-transform EPR study using photoexcited anthraquinone-2,5-disulfonic acid to oxidize Cyt and IMeCyt shows that the radical cation of the former de-protonates rapidly at N(l) while that of the latter deprotonates at the exocylic amino group (Geimer et al. 2000). The EPR evidence for the formation of heteroatom-centered radicals by S04 in its reactions with some other pyrimidines (Bansal and Fessenden 1978 Hildenbrand et al. 1989 Catterall et al. 1992) is in agreement with a marked acidity of such radical cations. It is re-emphasized that this conclusion does not require that radical cations are formed in the primary step. 

The reaction of 4,5-diphenylimidazole-1,2-diamine 152 with substituted chalcones 153 in dimethylformamide for 1 h proceeds with the elimination of the hydrazine amino group, oxidation and formation of the appropriate 2,3,5,7-tetraaryl-5,6-dihydroimidazo[l,2-a]pyrimidin-6-ol 154 in low or moderate yields [126] (Scheme 4.47). The treatment of the same diamine with dibromo derivatives 155 produced imidazo[l,2-a]pyrimidines 156 [126]. 

Azole approach. The substituted isothiazole (142) can be reacted with an ortho ester to form a methyleneamine which reacts with hydroxylamine to yield the 5-oxide (143). With amidines, (142) yields 4-amino derivatives (75JHC883). The reaction of 5-amino-4-ethoxycar-bonylisothiazole with iminoethers results in pyrimidine annulation, as in the formation of... 

Azine approach. The fused pyrimidines can be synthesized in the same way as the pyridines, e.g. by the cyclization of vicinal aminothiocyanates (70JCS(C)2478>. Another useful method for aminoazines is the reaction with chlorocarbonylsulfenyl chloride, e.g. with the aminopyrimidine (440) (73LA1018). The reaction can be rationalized by initial acylation of the amino group which is then cyclized with formation of the 2(3//)-one (441). Another case is the reaction of the 6-aminouracil (442) with thionyl chloride (69JOC3285). The reaction is rationalized as an initial electrophilic substitution at the 5-position of the activated pyrimidine. Subsequently the chlorosulfinyl derivative (443) is cyclized to a thiazoline S-oxide which loses water to yield the thiazole. 

Condensation of 6-amino-5-nitrosouracils with ethanethiol and phenyl-methanethiol leads to formation of 8-substituted xanthines and 1,2,5-thiadiazolo[3,4-t/]pyrimidines [75JCS(P1) 1857]. Oxidation with lead tetraacetate forms furazano[3,4-with sodium nitrite or potassium nitrate and subsequent heating in DMF [73JHC415, 73JHC993 76JCS(P 1) 1327] (Scheme 65). 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

Villalgordo et al. [22, 23] as well as Gayo and Suto [25] developed a strategy to cleave pyrimidines from the solid support. After oxidation of the thioether-linkage 17, aromatic substitution of the sulfonyl unit was performed with different N-nucleophiles as amines and azides to give free amino- or azido-pyrimidines 19 (Scheme 16.5). To demonstrate the stability of the linker, the resin-bound derivatives were subjected to different reactions such as saponification, ester reduction, acid chloride formation or Mitsunobu alkylation. A similar approach was presented later on by Hwang and Gong in the SPOS of 2-aminobenzoxazoles [26]. 

Examples for the alkaline hydrolysis of acylated 2-amino groups are the formation of 6-bromo-l-methylpyrido[2,3-i/]pyrimidine-2,4(l//,3//)-dione (35) from 6-bromo-l-methyl-2-(pivaloylamino)pyrido[2,3-[Pg.151]

Heating pyrido[2,3-r/]pyrimidin-4-amine 3-oxide in water for 7 hours leads to the formation of 4-(hydroxyamino)pyrido[2,3-c/]pyrimidine as the main product.14 This compound apparently results from ring opening followed by ring closure involving the former 4-amino group. 

Ar-[(Ar,Ar-Dimethylamino)methylene]pyrido[2,3-c/]pyrimidin-4-amine 3-oxide (6) plays a central role as an educt for 3-(3-pyridyl)-l,2,4-oxadiazoles. Thus, it has been treated with carbon nucleophiles such as the anions of diethyl malonate, ethyl cyanoacetate, or pentanc-2,4-dione.417 After addition across the 2,3-bond, ring opening of the pyrimidine moiety with simultaneous 1,2,4-oxadiazole ring formation occurs. Evidently, the five-membered ring is formed easily through participation of the [(dimethylamino)methylene]amino and TV-oxide functions. 

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