Aminopyrimidines, tautomerism

It was already suggested in the early investigations that the differences between the chemical properties of aminopyrimidines and anilines might result from tautomerism see, for example, reference 319. The early infrared studies on the solid-state spectra of these... 

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention. Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the eyelized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31). ... 

While the search of new antimalarials was still on, Schoenhoefer [36] proposed that the antimalarial activity of aminoquinolines was due to their ability to exist in tautomeric forms. This observation and the fact that sulfapyrimidines possess antimalarial activity was exploited by Curd and Rose working at Imperial Chemical Industries in the UK. These workers selected 4-aminopyrimidines (25) for molecular modifications on two counts (a) such a skeleton is present in various antimalarial sulphonamides, and (b) they exist in the tautomeric structures similar to 4-aminoqui-nohne antimalarials [37-40]. 

UV, IR, and H NMR spectroscopic studies of 2-(phenylamino)pyrimidine showed that this compound exists as a tautomeric mixture containing only a small amount (ca. 0.2%) of the imino tautomer in an aqueous ethanolic solution (Kt=5. 5 x 102, amino/imino tautomer), but the Ky value is considerably smaller than that of 2-(phenylamino)pyridine (80BCJ717). The amino tautomer was also found to be highly predominant in solutions of 2-(phenylamino)-4,6-dimethylpy-rimidine (84H(22)2591) and 2-[/V-(2,4,6-trinitrophenyl)amino]pyrimidine in both polar and apolar solvents (92JHC1461). For cyclohexane-fused 2-aminopyrimidines 54 (X = NH2 R = CF3) and 55 (X = NH2 R = CF3 Ar = 4-Et2NC6H4), both amino and imino tautomers are present in the solid state however, only amino tautomers were observed in CHC13 solution (00S1738). 

Information about tautomeric systems relies on physical measurements which do not affect the tautomeric equilibria reactions of tautomeric systems give no reliable information about equilibria. In tautomeric studies of hydroxy-, thiol-, and aminopyrimidines, or heterocycles in general, methyl-ation has been used to isolate the various tautomeric forms which were to serve as models for comparison of spectroscopic data (UV, IR, NMR) or values. However, recent NMR techniques allow direct tautomeric determinations in solution. X-ray structure data gives full information in the solid, crystalline state. 

In the recent past, the author with collaborators established the presence of various tautomeric and ionization states of ThDP (Schemes 1 and 2). With the publication of the first high-resolution X-ray structures of ThDP enzymes,two issues were clarified for the first time (1) The conformation of the bound coenzyme (defining the dihedral angles formed by the thiazolium and 4 -aminopyrimidine rings with respect to the bridge methylene group was quite different (so-called V conformation) from that found and predicted for both free... 

The notion that the 4 -aminopyrimidine could exist in the l, 4 -iminopyrimidine tautomeric form was suggested earlier by models attempting to mimic the reactivity of such a tautomer. The N1 -methyl analog of both the... 

A detailed study of the scope of the amidine Diels-Alder reaction of 1,3,5-triazines has been carried out. The thermal reaction of amidines with symmetrical 1,3,5-triazines proceeds with in situ amidine to 1,1-diaminoethene tautomerism, [4+2] cycloaddition, loss of ammonia with imine generation, imine to enamine tautomerism, then retro-Diels-Alder loss of ethyl cyanoformate to yield substituted 4-aminopyrimidines. 

Many aminopyrimidines do not condense directly with sugars. The lack of reactivity may be due to tautomerism of the amidine type ... 

Three different substituted pyrimidines are found in the nucleic acids, namely cytosine (2-oxy-4-aminopyrimidine) which is present in both DNA and RNA, uracil (2,4-dioxypyrimidine) which is present in RNA but not in DNA and thymine (5-methyluracil) which is present in DNA but not in RNA. They all exhibit keto-enol tautomerism. 

These compounds exist in several tautomeric forms. As a rule, hydroxypyrimidines prefer the lactam form, aminopyrimidines, however, the enamine form. 

Metzler (273) the possibility that the enzyme might stabilize a minor tautomeric form of the aminopyrimidine ring is attractive. It would constitute a... 

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