Tautomerism of 1,2-Dihydropyrimidines

Successful preparation of 4,6-diphenyl-1,2-dihydropyrimidine (21a) (Section V,B) stimulated comprehensive spectral studies of this compound.184 Of particular interest were NMR measurements to verify the presence of homoaromaticity as previously found for dihydrotetrazine.24,26 To facilitate observation of two signals for the protons on carbon 2, measurements were made at — 60°C. However, all attempts to detect homoaromaticity under 

Instead of homoaromaticity in the CDC13 spectra of 4,6-diphenyl-1,2-dihydropyrimidine, two new triplets were observed at 8 3.56 (J = 6.6 Hz) and 8 5.79 (J = 6.6 Hz). These were assigned to 4,6-diphenyl-2,5-dihydropyrimidine (21b) (Fig. 8), the second tautomeric form of the imine-enamine tautomeric equilibrium. The ratio of 21a to 21b is 2 1. In DMSO-d6 solution, the equilibrium shifts completely toward 1,2-dihydropyrimidine 21a because of strong intermolecular hydrogen bonding with the solvent. An analogous effect was observed in 1,6-dihydropyrazine.46 

Existence of this imine-enamine tautomerism is clearly indicated in the 13C-NMR spectrum of 21a in CDC13 (Fig. 9). A simple calculation using the concentrations of the two tautomers in CDC13 gives the value of AG° in this solvent as 0.41 kcal mol-1.184 Unsymetrically substituted 1,2-dihydropyrim-idines undergo tautomeric equilibration via [l,5]-hydrogen shift.49 

---

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. 

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]. 

The steric environment of substituents adjacent to the amidine fragment of dihydropyrimidines (particularly the bulkiness of substituents at the neighboring sp3-hybridized carbon atom) also affects tautomeric exchange. [An analogous situation was found in the dihydro-1,3,5-triazine series (Section VIII,C).] Further investigations are necessary to clarify the mechanisms, particularly 15N-NMR studies of the annular tautomerism of dihydropyrimidines, the chemical shift data of which enable calculation of the electron... 

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. 

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. 

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. 

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. 

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

This observation stimulated further investigations directed toward identifying the factors, enabling observation of annular tautomerism in dihydropyrimidine systems. The easily available and reasonably stable MDHP (20a) proved to be a convenient model for carrying out these measurements. 

Tautomeric 1,4- and 1,6-dihydropyrimidines easily undergo nucleophilic addition. For example, upon prolonged contact with moisture, the addition of water across the C=C bond, with quantitative formation of 6-hydroxy-1,4,5,6-tetrahydropyrimidines, was observed [Eq. (55)]. The products are identical to those obtained by interaction of a,/ -unsaturated carbonyl compounds with amidines and indicate the reversibility of the dehydration step in the course of dihydropyrimidine formation for 6-hydroxytetrahydro-pyrimidines (Section V,B,1). 

Dihydro-1,3,5-triazines are of fundamental interest because of their ability to undergo amidinic tautomerism. Furthermore, as these are nitrogen-containing analogues of dihydropyrimidines (methylene at position 5 replaced by N) it would certainly be interesting to compare the effects of nitrogen substitution on the structual stability and tautomeric behavior of these compounds. 

During our investigation on tautomerism in dihydropyrimidines, we measured the IR and H- and 13C-NMR spectra of several known dihydro-1,3,5-triazines,147 which exist in the solid state as the 1,2-dihydro isomers. The NMR measurements were carried out in two solvents, CDC13 and DMSO, and signals of the two tautomers A and B were always observed. The rate of tautomeric exchange was rather slow, very similar to that in 121, obviously owing to the presence of two phenyls at positions 2 and 4 (see Section V,C,l,d). 

All the factors affecting amidinic tautomerism in dihydropyrimidines (see Section V,C,l,b) apply equally to dihydro-1,3,5-triazine derivatives. In CDC13 the rate of tautomerism was clearly affected by the bulkiness of the... 

IR spectra of dihydro-1,3,5-triazines showed the absorptions similar to those of dihydropyrimidines. Thus two C=N absorption peaks were found for the 1,2- and 1,4-dihydro-l,3,5-triazines at 1610 and 1640 cm-1, respectively. In addition, a reanalysis of the IR data given by Kobayashi271 clearly reveals two signals for C=N absorption, at 1680and 1740cm-1, which indicates the presence of two tautomeric forms. 

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,... 

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). 

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... 

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>. 

The reaction of easily available a,/ -unsaturated carbonyl compounds and amidines is an attractive <3 + 3) combination for the preparation of tautomeric 1,4- (9b) and 1,6- (9c) dihydropyrimidines (Scheme 4). 

A similar type of tautomerism was found in a series of dihydropyridazines (see Section IV,C) and dihydropyrimidines (see Section V,C,2). For example, on the basis of NMR measurements in CDC13, it has been shown that 3,6-diphenyl-4,5-dihydropyridazine (28a) exists in tautomeric equilibrium with the corresponding 1,4-dihydro compound (28b) in the ratio 1 8. 

Furthermore, 1H- and 13C-NMR investigations of 1,2-dihydropyrimidine 21a in CDCI3 have demonstrated the existence of tautomeric equilibrium with the corresponding 2,5-dihydro isomer (21b) in the ratio 2 1 (See Section V,C,2). 

---