Nitrosation of pyrimidines

Diaminopyridine with nitrous acid forms the 3-nitroso derivatives. Nitrosation of pyrimidines occurs readily in the presence of three electron-releasing substituents pyrimidine-4,6-diamine is also nitrosated to the blue 5-nitroso derivative. 

Nitrosation. 2,6-Diaminopyridine with nitrous acid forms the 3-nitroso derivatives. Nitrosation has been much used in pyrimidine chemisty nitrosation of pyrimidines occurs readily in the presence of three electron-releasing substituents pyrimidine-4,6-diamine is also nitrosated to the blue 5-nitroso derivative treatment of 4-amino-2,6-dimethoxypyrimidine 137 with isoamyl nitrite in DMSO at room temperature gives the 5-nitroso derivative 138 in 75% yield <2002SL255>. 

In modern medicinal chemistry, the creation of diversity on a structural framework is important. In principle, diversity at positions 2, 4, 6, 7, and 8 of pteridines can be achieved using such solid-phase chemistry. This prototype solid-phase synthesis involved nitrosation of the resin-bound pyrimidine, reduction of nitroso group with sodium dithionite, and subsequent cyclization with biacetyl to afford pteridines 114 and 115. Cleavage from the resin by nucleophilic substitution of the oxidized sulfur linker using w-chloroperbenzoic acid or DMDO led to the pteridine products 116 and 117 (Scheme 23). 

Nitrosation of malonyl-a-aminopyridine (37) in 2 N hydrochloric acid at 0°C with a 1 N aqueous sodium nitrite afforded the 3-nitroso derivative 329 [91IJC(B)839]. 2-Amino-3-nitroso-4//-pyrido[l,2-a]pyrimidin-4-one was prepared from 2-amino-4//-pyrido[l, 2-a]pyrimidin-4-one by treatment of 1 N sodium nitrite in 2 N hydrochloric acid at 0°C for 30 minutes (92MI23). 

Methylating agents can be generated by chemical ni-trosation of endogenous metabolites. For example, methylamine produced by the decomposition of organic matter can condense with carbamyl phosphate, a precursor of pyrimidines, to form methylurea, which in turn can be nitrosated to yield methylnitrosourea (MNU). Such nitrosation reactions can be catalyzed by bacterial enzymes (35). 

The parent, 8-azapurine, has been made only by nitrosation of 4,5-di-aminopyrimidine, which is an item of commerce. - - The 7- and 8-alkyl derivatives of 8-azapurine, whether with or without further substituents, require 1,2,3-triazole starting materials (Section IV,B), of which the best source is Hoover and Day s historic condensation of benzyl azide with ethyl cyanoacetate or (better) cyanoacetamide. An 8-aralkyl group has been introduced similarly. In favorable cases, an 8-aryl group can be derived from the action of a benzenediazonium chloride on a pyrimidine that bears enough electron-releasing substituents to activate the 5 position (the Benson synthesis Section IV,A). 

Reactions of 2-nitrosoarylamines with carbon nucleophiles leading to quinoxalin-2(17f)-one A-oxides are mentioned in literature, but the reported examples are limited to a few intramolecular reactions of pyrimidine derivatives, easy to synthesize via the direct nitrosation of appropriate aminopyrimidines (Pachter et al. 1963 Steinlin et al. 2008 Steinlin and VaseUa 2009). Because carbocyclic o-nitrosoaniUnes were not so easily available, the common synthesis of... 

When the synthesis of a heterocyclic system containing a diazole fused onto l,2,3-triazin-4-one (e.g., imidazo[4,5-i [l,2,3]tnazin-4-one (Section 10.13.9.1.l(i)) and pyrazolo[3,4-rf [l,2,3]triazin-4-one (Section 10.13.9.1.1(ii))) or 1,2,3-triazole fused onto pyrimidin-4(7)-(di)one (e.g., [l,2,3]triazolo[4,5-rf pyrimidin-4(7)-(di)one (Section 10.13.9.1.l(iv))) is required, the synthesis of the six-membered ring is the most reliable method. There are several recent accounts of six-membered annulations onto 1,2,3-triazoles to give [l,2,3]triazolo[4,5-r/ pyrimidines (Section 10.13.9.1.l(iv)), which are valuable alternatives to 1,2,3-triazole annulation using nitrosation techniques <1996CHEC-II(7)489>. 

Chloro, 3-bromo, 3-iodo, and 3-nitro derivatives of 5,7-dimethyl-pyrazolo[l,5-a]pyrimidine derivatives were prepared by chlorination, bromination, iodination, and nitration of 3-unsubstituted 5,7-dimethyl-pyrazolo[l,5-a]pyrimidines. Reaction with bromine and potassium thiocyanate gave a 3-thiocyanato derivative, which was converted into the mercapto derivative upon saponification. Nitrosation gives the 3-nitroso derivative and acylation with trifluoroacetic anhydride affords the trifluoroacetyl derivative (74JMC645 77JMC386). 

The pyrimidine moiety of 31 was nitrosated and then reduced to give amino derivative 46, which was transformed into 25a as described in Section 14.05.2.6 (Scheme 4). Deprotection of the ribose moiety in acid medium led to 47. The same acidic deprotection conducted on intermediates 31 and 46 led to the pyrimido-l,3-diazocines 48 and 49, respectively (Scheme 8). Starting from xanthosine 42, through isopropylidene protection, the Mitsunobu reaction and deprotection sequence derivative 6 was also synthesized <2004W0013300, 2005TL2825>. 

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