Dihydropyrimidine, structure tautomerism

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

It has been shown that this compound in the solid state has the 1,4-dihydropyrimidine structure 20a,24 whereas in solution it exists in a tautomeric equilibrium of 20a and 20b23,24,153 (see Section V,C,1). Unpublished data on the preparation of 1,6-dihydropyrimidine by treatment of pyrimidine with terf-butyllithium was mentioned earlier.174 However, the action of... 

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. 

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... 

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]. 

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>. 

In 1975, Weis and Mamaev153 showed that the 6-methyl-2,4-diphenyl dihydropyrimidine (MDHP) (20), which was obtained by condensation of benzylidene, acetone, and benzamidine, exists in solution in a tautomeric equilibrium of 6-methyl-2,4-diphenyl-1,4-dihydropyrimidine (20a) and 6-methyl-2,4-diphenyl-3,4-dihydropyrimidine (20b) [although the systematic nomenclature for structure 20b would be 4-methyl-2,6-diphenyl-1,6-dihy-dropyrimidine (see Section 111,8), we have retained the original nomenclature to provide a convenient comparison of the two tautomers]. This tautomerism was detected by spectral studies (NMR, IR, and UV) of solutions of 20. Thus the NMR spectra of the two individual tautomeric structures can be observed in dipolar aprotic solvents such as dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA).153... 

The UV spectra of 1,6-dihydropyrimidines usually appear at a higher wavelength than their corresponding 1,4 isomers and display an n - n transition for the C=C—N=C—N chromophore, which appears as a medium intensity absorption (e 5000) in the 300-320 nm region.188,189 This absorption also depends on substituents and the solvents. This difference in UV absorption of tautomeric 1,4- and 1,6-dihydropyrimidines may be used for quantitative study of amidinic tautomerism of dihydropyrimidines, as well as for assigning structures. 

Tautomeric studies on dihydropyrimidines have usually been carried out on pyrimidines substituted by strongly conjugative groups or on geminally disubstituted derivatives to reduce the number of tautomeric forms. X-ray structure analysis is often used for information in the solid phase. NMR is most frequently used for tautomeric equilibrium studies in solution. A short summary is available B-94MI 602-01 >, p. 817). 

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