Pyrimidines, amino-, tautomerism

Pyrazolo[3,4-d]pyrimidine, 4-amino-tautomerism, 5, 310 Pyrazolopyrimidinediones synthesis, 5, 324 Pyrazolopyrimidines acidity, 5, 309 anions... 

As is the case for pyrimidines, purines also exist in oxo, thio, and amino tautomeric forms. The lactam-amino and lactim-imino forms of the purine base hypoxanthine are shown in Fig. 3. 

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

Pyrazolopyrimidines, amino-acidity, 5, 309 alkylation, 5, 310 N-oxide synthesis, 5, 324 synthesis, 4, 525 5, 328 Pyrazolopyrimidines, dimethyl-synthesis, 5, 316 Pyrazolo[ 1,5-a]pyrimidines electrophilic attack, 5,311 synthesis, 5, 271, 320, 331 Pyrazolo[ 1,5-c]pyrimidines electrophilic attack, 5, 312 Pyrazolo[3,4- d]pyrimidines nucleophilic attack, 5, 313 synthesis, 5, 161, 272, 323, 334 tautomerism, 5, 309 Pyrazolo[4,3-d]pyrimidines alkylation, 5, 310 synthesis, 5, 272... 

In tautomeric equilibria of some functionalized pyrimidine derivatives, such as isocytosine 52 (R = H) [77ZN(C)894] or pseudocytidine 52 (R = furanosyl) (99MI1), the potentially tautomeric oxo and amino groups are practically not involved, and only annular tautomeric interconversions N(1)H N(3)H are ob-... 

Figure 33-2. Tautomerism of the oxo and amino functional groups of purines and pyrimidines.

Oxo-4-amino-l,2,5,6-tetrahydro-lf/-pyrimidine. A dihydropyrimidine, not a tetrahydropyrimidine (two exo- and endoeyclic double bonds) 4-Amino-5,6-dihydro-2(l//)-pyr>midone (Chem. Abstr.) assigns the correct oxidation state, tautomeric form and location of the proton the danger is that the latter is not always known, however. 

We should note particularly that uracil and thymine are dioxypyrimidines, whereas cytosine is an amino-oxypyrimidine. All three pyrimidines are thus capable of existing in several tautomeric forms (see Section 11.6.2). 

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

The bases are monocyclic pyrimidines (see Box 11.5) or bicyclic purines (see Section 11.9.1), and all are aromatic. The two purine bases are adenine (A) and guanine (G), and the three pyrimidines are cytosine (C), thymine (T) and uracil (U). Uracil is found only in RNA, and thymine is found only in DNA. The other three bases are common to both DNA and RNA. The heterocyclic bases are capable of existing in more than one tautomeric form (see Sections 11.6.2 and 11.9.1). The forms shown here are found to predominate in nucleic acids. Thus, the oxygen substituents are in keto form, and the nitrogen substituents exist as amino groups. 

Hydroxy, thiol, and amino groups in pyrimidine exist in tautomeric equilibria with their oxo, thioxo, and imino forms. An amino group in an electrophilic position exists predominantly as such, and the compound is named as an amine. Pyrimidines with a hydroxy or thiol group in an electrophilic position are dominated by the oxo or thioxo forms and are named as such, or with -one or -thione suffixes, if these are the principal groups. In the benzenoid 5-position, these derivatives are mainly present in the hydroxy, thiol, or amino forms and are named as such. Similar considerations apply to the nomenclature of quinazolines and perimidines <1996CHEC-II(6)93>. 

Neutral 4-aminopyrazolo[3,4-d]pyrimidines exists in water in two tautomeric forms 1//-4-amino (1H4APP) and 2//-4-amino (2H4APP) isomers (X = 2H4APP/1H4APP = O.I at lOO C and OH tautomerization = 9.0kcal mol ). Interconversion of the two forms is catalyzed by and OH through either an intermediate cation common to both tautomers or through an intermediate anion. 

The tautomeric equilibrium between IH- and 2//-formycin (7-amino-3)8-D-ribofuranosyl-l//-pyrazolo[4,3-d]pyrimidine) has a constant ratio N(2)H/N(1)H = 0.2 and an enthalpy difference estimated at 1 kcal mol". The tautomeric interconversion is catalyzed by (3 x 10 Msec" ) and by OH" (5 X 10 M" sec" ). No other catalytic pathway such as water catalysis or tautomerization via tautomeric cations contributes significantly to the interconversion. Protonation on the pyrazole ring of formycin does not occur significantly (80JA3897). 

Similarly, cyclization of 3-amino-l, 2,4-triazoles (65) with methyl propio-late or methyl phenylpropiolate gave a mixture of the l,2,4-triazolo[4,3-a]pyrimidin-7-ones 97 and the l,2,4-triazolo[l,5-a]pyrimidin-7-ones 98 (70CB3266 71CB2702). In addition, methyl tram-3-(3-amino-l,2,4-triazol-l-yl)acrylates (99) were also obtained. Production of the 1,2,4-triazolopy-rimidines 97 and 98 started by condensation of the ester function with the amino group of 65, followed by cycloaddition of the triazole N4 or N1 of the two tautomeric intermediates 96a and 96b, respectively, onto the carbon-carbon triple bond of the side chain. In contrast, formation of the triazolyl acrylates 99 took place through addition only of the triazole N1 onto the propiolate carbon-carbon triple bond. The relative amounts of products were found to depend on the reaction conditions (temperature, solvent, and time) (70CB3266) (Scheme 42). 

The 15N magnetic resonance studies of the pyrimidine bases or their derivatives are scarce. Roberts et al.BB have measured the 1H and 15N magnetic resonance spectra of a number of pyrimidines including uracil and 1-methylcytosine. The most important result of this study was the elucidation of the dominant tautomeric structures of uracil and proto-nated 1-methylcytosine as the diketo, 32, and keto-amine form, 7, respectively (cf. Sections II and IV and the spectrum of 1-methylcytosine hydrochloride labeled only in the amino group62). In the case of uracil,85 the two 15N-bonded protons gave two doublets centered at 10.78 and 10.96 ppm (measured downfield from internal tetramethyl-... 

These relationships are general. Hydroxyl-substituted purines and pyrimidines exist in their keto forms amino-substituted ones retain structures with an amino group on the ring. The pyrimidine and purine bases in DNA and RNA listed in Table 28.1 follow this general rule. Beginning in Section 28.7 we ll see how critical it is that we know the correct tautomeric forms of the nucleic acid bases. 

Dioxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-a]pyrimidines 35 exhibit an oxo-enol tautomerism, which was studied by UV, IR, and NMR methods (85JHC1253). In the solid phase enol tautomers are present, while in a polar solvent an electron withdrawing substituent at position 3 shifts the equilibrium toward the enol form. The analogous 9-amino derivatives exist exclusively as 9-amino-6,7-dihydropyrido[l,2-a]pyrimidin-4-ones. 

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