Dihydropyrimidine, structure

XVI), most of the aforementioned change does not appear to be caused by an electron density increase at C-5 but by the change to a dihydropyrimidine structure. This is conceivable if the adduct is not a free anion but is strongly associated with lithium. Further information about the structure of adduct 96 comes from a comparison between the anionic adduct 30 with the neutral adduct 33, formed from pyrimidine and 1-methylpyrimidinium cation, respectively, by reaction with NH2". Here the C-5 position of the anionic adduct is found to be 10.2 ppm upheld with respect to the neutral adduct. If it is assumed that in ammonia the anionic adduct is not associated with the positive counterion, the aforementioned phenyllithium adduct is more likely to possess a slightly delocalized electronic structure (104) resembling that of a dihydropyrimidine. This fact is not surprising, also in view of the low polarity of the solvent. 

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 Unpublished data on the preparation of 1,6-dihydropyrimidine by treatment of pyrimidine with terf-butyllithium was mentioned earlier.174 However, the action of...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. 

Fig. 3-15. Spatial structure of ( )-4-(9-phenanthryl)-dihydropyrimidine 22 determined by X-ray diffraction. The hydrogen atoms are not shown for clarity.

Two types of derivatives of 1,2-cyclohexadiene with two heteroatoms were proposed as reactive intermediates more than 20 years ago. Lloyd and McNab [168] observed the reaction of the 5-bromo-l,2-dihydropyrimidinium ions 411 with thiourea in refluxing ethanol to give the bromine-free cations 413. Suspected as intermediates, the 5d2-dihydropyrimidines 412 were initially considered as zwitterions of the type 414-Zj. However, quantum-chemical calculations on the parent systems suggested an unambiguous preference of the allene structure 414 over the zwitterion 414-Za [169]. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

The heterocyclic ring of hydantoins, like that of succinimides (see Sect. 4.4.2), is hydrolytically cleaved by dihydropyrimidine aminohydrolase (DHPase, EC 3.5.2.2). Since both hydantoins and succinimides are hydrolyzed by the same enzyme, it is not surprising that structural features, such as absolute configuration, ring-substitution, and TV-substitution, exhibit comparable influence on catalysis. 

The 5,6-dihydropyrimidine-6-yl radicals discussed above behave, in their reactions with nitrobenzenes, like the simpler radicals CH2OH and CH(al-kyl)Oalkyl do, i.e. they react exclusively by addition to give nitroxyl radicals and uncatalyzed heterolysis is not observed (khs < 10 s ). If, however, a methyl group is introduced at C(6) (= CJ of the pyrimidine-6-yl radical, the corresponding nitroxyl radicals heterolyze with rate constants at 20 °C of 10 to 5 X 10 s depending on the structure of the pyrimidine and of the nitrobenzene (Eq. 16). This SnI type reaction is characterized by activation enthalpies of 30-40 kJ mol and activation entropies of — 89 to — 7 Jmol K (entropy control) [27]. The rate-enhancing effect of the methyl group is, of course, due to... 

Additional heterocyclic ring systems, such as benzofurans [125], dihydropyrroles and dihydroazepines [41], piperidines and dihydropyrimidines 36 [126], and fused oxazole derivatives [127], have been described (Eq. 7). The formation of epoxides and aziri-dines, formally emanating from ylides, was recently reported by Doyle et al. [77]. Rho-dium(II)-catalyzed isomiinchnone cycioaddition followed by Lewis acid-mediated ring opening has been used as an entry into the protoberberine azapolycyclic ring structure [128]. 

The Gong group utilized 2a in the multicomponent Biginelli reaction to provide structurally diverse 3,4-dihydropyrimidin-2(lH)-ones in high yields and ee s (Scheme 5.19) [33]. Notably, the authors found that bulky 3,3 subshtuents on the catalyst had a deleterious effect with respect to yields and enantioselectivities. 

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. 

Kappe et al. (166) employed an isomilnchnone generation-trapping sequence to access conformationally restricted dihydropyrimidine derivatives as novel calcium channel modulators. For example, the conformationally restricted analogues 269 were prepared via intramolecular cycloadditions from the isomiinchnones generated from a-diazo imides 268. The structures of these cycloadducts were established by X-ray crystallography. 

Johnson MR, Wang K, Tillmanns S et al. Structural organization of the human dihydropyrimidine dehydrogenase gene. Cancer Res 1997 57 1660-1663. 

Nitropyrimidine, its 2- and 4-methoxy, and 2,4- and 4,6-dimethoxy derivatives react with acetone in the presence of potassium hydroxide to yield the potassium salts of the anionic adducts 74 and 75, with structures elucidated by spectral ( H-NMR, IR, and UV-visible) methods. The nucleophilic attachment was found to occur only at CH positions, and when there was a choice between 2- and 4(6)-positions, the latter was preferred.125,126 An adduct of the kind corresponding to structure 75 was also obtained by using the conjugate base of acetophenone. The adducts can be converted to the corresponding CH3COCH2- or PhCOCH2-substituted pyrimidines by oxidation, either directly or via the related dihydropyrimidine derivatives.127... 

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... 

Tetrodotoxin, an extremely poisonous heterocycle present in Japanese puffer fish (various species of Spheroides), exerts its action by blocking the sodium ion channels in the peripheral nervous system. Chemically it has an adamantane-like structure, namely octahydro-12 - (hydroxymethyl) - 2 - imino-5,7,9,1 Oa-dimethano- 10aH-[ 1,3] -dioxo-cino-[6,5-d]pyrimidine-4,7,10,11,12-pentol. When chemically dehydrated, it rehydrates in dilute acid.73 Methanol, and ammonia, can add similarly. Because 2-amino-1,6-dihydropyrimidine forms the central part... 

The photoaddition of water to a variety of naturally occurring pyrimidine derivatives has been reported. Photolysis in aqueous solution of uracil (224 R = H), uridine (224 R=ribosyl), and uridylic acid results in the formation of the corresponding 6-hydroxy-5,6-dihydropyrimidine (225)208-210 these structures have been established by independent synthesis.209 Analogous photoadditions have been observed in 1,3-dimethyluracil211 and 5-fluorouracil.212 These additions are reversible. 

The C(6)-yl radical is also formed upon the reaction of OH with dihydropyrimidines [reaction (144) Schuchmann et al. 1984b], as can be seen from the data compiled in Table 10.19. For a quantum-mechanical study of their structure and EPR coupling constants see Jolibois et al. (1998). 

Dihydro derivatives of pyridine and pyrimidine can exist as five isomeric structures A-F (Scheme 3.134) for dihydropyridenes B is the same as C for dihydropyrimidines B is the same as F. It is clear that dihydroforms A and B, D... 

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 reaction of ethyl acetoacetate, benzaldehyde, and urea leads to ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenyl-5-pyrimidinecarboxylate. This reaction (the so called Biginelli reaction) was discovered over 100 years ago [93T6937], Interest in these dihydropyrimidines has increased rapidly mainly due to their close structural relationship to the pharmacologically important dihydropyridine calcium channel blockers of the nifedipine-type [93T6937], The dibromo (51) and monobromo derivatives (55) of the most simple Biginelli compounds mentioned above are readily obtained by bromination [93T6937], and the reactions of these derivatives with sodium azide have been studied recently [90LA505] [91 JCS(P1)1342],... 

O.V. Shishkin, Molecular, electronic structure and conformational flexibility of the 1, 6-dihydropyrimidine, 4, 5-dihydrofuro[2, 3-d]pyrimidine and their oxo, imino and methylene derivatives. J. Mol. Struct. 385, 55-63 (1996)... 

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>. 

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