2.5- Dihydropyrimidines, tautomerism

No data on tautomerism of dihydropyiimidines were available at the time of the early summary (76AHCS1), but much has been done since then. The results of tautomeric studies carried out during the period between 1976 and 1984 were reviewed comprehensively in [85AHC(38)l,pp. 63-77]. Later, Weis and vanderPlas published an excellent review on the synthesis, structure, and tautomerism of dihydropyrimidines [86H(24)1433], where the tautomeric interconversions of these compounds were discussed in detail. In a more recent review on dihydropyrimidines (94MI1), the question of tautomerism in partially hydrogenated pyrimidines was also included. 

Van der Plas et al. (86JOC1147) demonstrated that the formation of identical tautomeric 1,2-dihydropyrimidines 46a and 46a on amination of 5-nitropyrimidine is favored at a low temperature, while ammonia addition at room temperature produces the thermodynamically more stable 1,4-dihydro adduct 46b (Scheme 15). 

X-Ray analyses and solid-state IR spectra were recorded for a number of 1,4-and 1,6-dihydropyrimidines, demonstrating the dependency of the tautomeric composition in the crystal on the substitution in the pyrimidine ring and on the ability of these compounds to form intermolecular hydrogen bonds. Thus,... 

Tautomerism of simple monosubstituted 1,4-dihydropyrimidines in solution has been studied on an example of 2-phenyldihydropyrimidine 48, prepared by condensation of benzamidine with acrolein [84H(22)657]. IR and H and NMR spectra at -60°C in specially purified solvents showed that this compound exists as a tautomeric mixture of 1,4- and 1,6-dihydro tautomers (Scheme 17), with the relative amount of 1,4-dihydro isomer 48a increasing with the polarity of the solvent. 

Surprisingly, Kashima et al. (83TL209) reported the formation of individual 1,4-dihydro- and 1,6-dihydropyrimidines on desulfurization of the corresponding pyrimidine-2-thiones with Raney Ni and claimed that no tautomerization occurs under the reaction conditions (heating under reflux in MeOH). 

In most of the papers discussing tautomerism in dihydropyrimidines, the possibility of the existence of 4,5-dihydro isomer 47c (Scheme 19) was not even considered or was ruled out on the basis of H NMR spectra. In 1985, however, Kashima et al. (85TL5057) reported that, although dihydropyrimidines 47 with r = H or Pr (R = R = R = Me, R = H) indeed exist only as mixtures of 47a and 47b tautomers, for analogs with r = Ph, OEt, or SMe, 4,5-dihydro tautomers 47c were also observed in CDCI3 solution in relative amounts of 10%, 20%, and 31%, respectively. The proportion of this tautomer rises to 45% in the case of the 2-dimethylamino-substituted derivative. The electronic effects of a heteroatom or an aromatic group in the 2 position were proposed as an explanation for this phenomenon. No 4,5-dihydropyrimidine has ever been found in the solid state. 

Interesting results were also obtained on treatment of 2-amino-4,6,6-trimethyl-dihydropyrimidine 50 and 2,4,6,6-tetramethyldihydropyrimidine 51 with CD3OD in the absence of a base (91TL2057). It was shown that, under these conditions, the 4-methyl protons of 50, the 2,4-dimethyl protons of 51, and H(5) in 50 and 51 undergo H-D exchange. The suggested mechanism involves annular (1,4-dihydro 4,5-dihydro) as well as substituent tautomeric equilibria, as shown in Scheme 20 for H-D exchange in 50. 

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. 

There are five possible dihydropyrimidine forms, although most of the known dihydropyrimidines have either the 1,2- 491 or the tautomeric 1,4- 492 or 1,6-dihydro structures 493 <1986H(24)1433>. Of the three possible tetra-hydropyrimidine forms, the most commonly found is the 1,4,5,6-tetrahydro- or cyclic amidine structure 498. 

There are five dihydropyrimidines (455)-(459). Most of those known have either the 1,2- or the tautomeric 1,4- or 1,6-dihydro structures. Gaussian 70 ab initio calculations of the energy of unsubstituted dihydropyrimidines yielded the following order of stability (457) > (456) > (455) > (458) > (459). The results agree with the experimentally observed behavior of these compounds... 

A high density of electrons associated with atoms C(3) and C(5) of 1,4-dihydropyridines and 1,4-dihydropyrimidines is also observed when these heterocycles undergo electrophilic substitutions such as Friedel-Crafts [315, 316, 317, 318, 319, 320] and Vilsmeier [297, 321] reactions (Scheme 3.99). In [315] it was shown that treatment of dihydropyridines 371 with aroyl or acyl chlorides 372 in the presence of SnCl4 leads to acylation of the heterocycle at position 3 (compounds 373). Dihydropyridines 374 and dihydroazolopyrimidines 376 undergo Vilsmeier reaction with the formation of the corresponding derivatives 375 and 377. It is interesting that imine heterocycle 376 after Vilsmeier reaction exists in the enamine tautomeric form. The tautomerism of dihydroazines and factors influencing it will be discussed in detail in Sect. 3.8. 

The most investigated type of tautomerism of dihydropyrimidines is the amidine equilibrium (Scheme 3.137). The energies of substituted dihydropyrimidines with these structures are usually similar and the existence of mixtures of tautomeric forms is typical [248]. 

It has been shown [248] that unsubstituted dihydropyrimidine 427 existed in tautomeric form D. But introduction of phenyl substituents at positions 2 and 4 leads to a convergence of energies of the tautomeric forms and 4,6-diphenyl-l,2(2,5)-dihydropyrimidine is observed in solutions of CDC13 as a mixture of D and E in a ratio of 2 1 [248]. Pyrimidines 427 containing electron-donors at positions 4 and 6 exist in the dihydro form E [424]. 

There are many possibilities for tautomerism in partially-saturated derivatives. Dihydropyridines can exist in several tautomeric forms, e.g., 37 and 38, of which the 1,4-dihydro isomers are usually the most stable. Similarly, dihydro-1,2,4,5-tetrazines have been formulated as the 1,2-, 1,4-, 1,6- and 3,6-dihydro structures but the 1,4-dihydro structure is probably the most stable. In contrast, 2/7-pyrans, e.g., 67, are more stable than 4/7-pyrans, e.g., 68. Of the five possible dihydropyrimidines most known derivatives have 1,2-, 1,4-, or 1,6-dihydro structures of which the 1,2-structure is calculated to be the most stable <1985AHC(38)1>. 

Barbituric acids, 5-ylidene derivatives of 83WCH479. Dihydropyrimidines, synthesis, structure, tautomerism of 86H(24)1433, Hydrazinopyrimidines, advances in chemistry of 82KGS579. 

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