Dihydropyrimidines, formation

The reason for the lack of follow-up on this synthetic route may be attributed to literature reports of failures to isolate or even observe the expected dihydropyrimidines, particularly in the case of the simple a,/ -ethylenic aldehydes.143,146 Dihydropyrimidine formation from a,/ -unsat-urated carbonyl compounds and amidines occurs via nucleophilic attack by amidine at the activated double bond (Michael-type addition), followed by ring closure and dehydration (see Scheme 4). In the course of confirming this reaction scheme, the intermediacy of tetrahydropyrimidines and dihydropyrimidines was demonstrated. 

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). 

In addition to modification of the catalyst, several variants of the Biginelli reaction have emerged as viable alternatives however, each method requires pre-formation of intermediates that are normally formed in the one-pot Biginelli reaction. First, Atwal and coworkers reported the reaction between aldol adducts 39 with urea 40a or thiourea 40b in the presence of sodium bicarbonate in dimethylformamide at 70°C to give 1,4-dihydropyrimidines 41. DHPM 42 was then produced by deprotection of 41. 

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). 

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). 

After intravenous administration, about 80-90% of the dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) [38] (Figure 14.3). The formation of the inactive 5-fluoro-5,6-dihydrouracil (5-FUH2) by DPD is the rate-limiting step of 5-FU catabolism [39]. DPD is widely distributed among tissues, with the highest levels found in the liver. Once 5-FU entered tumor cells, its antitumor effect is mainly dependent on the extent of 5-FU anabolism. After two sequential anabolic steps involving thymidine phosphorylase (TP) and thymidine kinase... 

Using a similar format, dihydropyrimidines were obtained in a microwave-expedited version of the classical Biginelli three-component condensation (Scheme 12.24) [73]. Neat mixtures of /i-kctocstcrs, aryl aldehydes and (thio)ureas with polyphosphate ester (PPE) as reaction mediator were irradiated in a domestic microwave oven for 1.5 min. The desired dihydropyrimidines were obtained in 61-95% yield after aqu-... 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

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. 

A domino reaction of 1,1-diphenyl-3,3-dilithioallene (157) with benzonitrile yields both a yellow imidazole (158 R = Ph X = NH) (12%) and a colourless 5-imidazol-5-yl-l,4-dihydropyrimidine (159 R = Ph) (51%), the products, respectively, of the incorporation of three and four nitrile molecules. The proposed mechanism (Scheme 13) involves initial formation of an intermediate (160) that is the product of the interaction of three molecules of benzonitrile with l,l-diphenyl-3,3-dilithioallene (157), which cyclizes to (162 R = Ph) and then eliminates a molecule of benzonitrile to produce (161 R = Ph). Re-addition of benzonitrile at a different locus produces... 

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]. 

It was reported [59] that temperature in combination with the choice of catalyst is, indeed, the main factor in controlling the direction of this MCR. Under ambient and neutral conditions, the reaction between 5-amino-3-phenylpyrazole, cyclic diketones, and aromatic aldehydes yielded Biginelh-type dihydropyrimidines 54 (Scheme 24). Increase in the reaction temperature with simultaneous addition of triethylamine allowed the reaction to proceed along the thermodynamically controlled pathway with formation of dihydropyrazolopyridines 53. 

Along with the formation of dihydropyrimidine derivatives, an unusual directions of multicomponent treatment of 2,4-dioxobutanoates with aldehydes and several aminoazoles were described by Gein and co-authors [151]. Thus, fusion of carbonyl compounds with 3,5-diamino-l,2,4-triazole gave as usual for this type... 

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. 

Flayon E, Simic M (1973) Addition of hydroxyl radicals to pyrimidine bases and electron transfer reactions of intermediates to quinones. J Am Chem Soc 95 1029-1035 Flaysom FIR, Phillips JM, Scholes G (1972) Formation of carbonium ions from dihydropyrimidyl radicals in they-radiolysis of aqueous solutions of dihydropyrimidines. J Chem Soc Chem Commun 1082-1083... 

As mentioned already, a reaction of enamines with a, 3-unsaturated ketones may be one of the stages of Hantzch synthesis. But in the literature there are a lot of examples of independent applications of a broad set of enamines in dihydropyrimidine syntheses. For example, in [3, 4], a reaction of 3-aminocy-clohex-2-enones 1 with an unsaturated ketone 2 was described which results in a dehydrogenation leading to the formation of a quinoline 3 (Scheme 3.2). 

Another representative of urea-like binucleophiles is guanidine and its derivatives. There are dozens of publications devoted to their reactions with a,(3-unsaturated carbonyls, which are usually very simple processes. For example, routine magnetic stirring of guanidine 61 with chalcone 5 at room temperature in ethanol led to the formation of 1,6-dihydropyrimidin-2-ylamine 76 [78] with good yields (Scheme 3.24). But in several publications it was mentioned that such reactions may be complicated by side reactions and isolation of the target dihydropyrimidines is difficult. Very often among... 

Taking into account that self-condensation of two molecules of ketones cannot be the first step of the formation of dihydrotriazolopyrimidines 191 and 196 (treatment of unsaturated ketones 190 with aminoazoles leads exclusively to heterocycles 192) led to two alternative mechanisms (A and B) being suggested in [178, 179] (Scheme 3.56). In the eyes of Desenko et al. [178], the key intermediate in the formation of the dihydropyrimidine ring is azomethines (pathway A), while in the work reported in [179] enamines were formed (pathway B). 

When one of the components of such multicomponent reactions was a molecule of DMF, the formation of angular dihydropyrimidines was also observed. For example, amines 197,198 and 208 in boiling DMF reacted with dimedone 200, leading to azolopyrimidines 217-219 [184, 186, 187]. These treatments, in the opinion of Lipson et al. [184], resulted in the reaction passing through an enamine intermediate 216 formed at the endocyclic nitrogen atom (Scheme 3.60). 

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. 

Styryl substituted 1,4-dihydropyrimidine 352 treated with hydrogen chloride gas in chloroform leads to a complicated polyheterocyle 354 [379]. The mechanism of the reaction most likely involves formation of a benzyl cation 353 followed by a nucleophilic attack of the aminocrotonate moiety. 

Treatment of 4-ethoxy-6-methylpyrimidine-l-oxide (602) with acetic anhydride at 25-35 °C in chloroform followed by the addition of diketene at <20°C caused an exothermic reaction from which was isolated 7-acetyl-4-ethoxy-2-methyloxazolo[4,5-c]pyridine (603) (22%) and 7-acetyl-4-ethoxy-3-methylisoxazolo[4,5-c]pyridine (604) (8%) (88CPB168). A plausible mechanism for the formation of the isomers (603) and (604) is shown in Scheme 77. Acetylation with acetic anhydride furnishes an initial intermediate, l,2-diacetoxy-l,2-dihydropyrimidine (605). Electrophilic attack by diketene at C-5 then yields an acetoacetyl intermediate (606). Ring-opening and recyclization of (606) then gives via intermediates (607) and (608) the pyridine (609). Compound (609), which is not... 

Pyrimido[4,5-6][l, 4]thiazine can be obtained by a versatile and convenient method reported by Sako, Maki et al. <9iJCS(Pl)2675> treatment of 5-hydroxyuracil (253 X = 0) and 5-hydroxy-isocytosin (253 X = NH) with TV-bromosuccinimide in ethanol followed by the thermal condensation with (i- and y-aminothiols such as 2-aminothiophenol, cysteamine, L-cysteine, and d,l-homocysteine resulted in the formation of the pyrimido[4,5-6][l,4]thiazines (256). This new method for the construction of pyrimido[4,5-6][l, 4]thiazine ring systems was shown to involve the condensation of 5,6-diethoxy-5-hydroxy-5,6-dihydropyrimidin-4(3//)-one intermediates (255) with / -and y-aminothiols which is accelerated in the presence of an acid catalyst (Scheme 42). 

In aprotic medium, on the other hand, pyrimidine gives a reversible diffusion-controlled le wave at a very negative potential, with formation of a radical anion which is deactivated via two pathways rapid formation of the anionic, probably 4,4 -, dimer, with a rate constant of 8 x 105 L mol-1 sec-1, and proton abstraction from residual water in the medium at a much lower rate constant, 7 L mol-1 sec-1 98). This is rapidly followed by a further le reduction to produce, ultimately, 3,4-dihydropyrimidine 98). In the presence of acid there is also a le reduction wave corresponding to formation of a free radical which, as in aqueous medium, dimerizes, most likely to 4,4 -Z w-(3,4-dihydropyrimidine). Examination of the mechanism of reduction in acetonitrile in the presence of acids supported the conclusion that reduction of pyrimidine in aqueous medium is preceded by its protonation98). 

Following initial studies by Cavalieri Lowy 96), it was shown by Smith Elving74) that the polarographic behaviour of 2-aminopyrimidine in acid medium is similar to that for the parent pyrimidine, which exhibits three waves at the dropping mercury electrode 74). The initial le step involves formation of a free radical which dimerizes and, at the potential of the second le reduction step, 2-amino-3,4-dihydropyrimidine is formed. But, unlike pyrimidine, 2-aminopyrimidines do not undergo a second 2e reduction to tetrahydro derivatives. Wave III (pH 7-9) involves two electrons and two protons, and is due to the combined processes responsible for waves I and II at lower pH. Both Smith Elving 74), and Sugino 104>, found that reduction of 2-aminopyrimi-dine on a mercury electrode 74) and lead cathode 104) resulted in the formation of unstable products. 

In view of the earlier demonstration that pyrimidone-2 undergoes one-electron reduction, with formation of a dimer identified as 6,6 -6ij-3,6-dihydropyrimidine-2, which is suceptible to quantitative photodissociation to the parent pyrimidone-2, and bearing in mind that 2-oxopurine may be considered a formal analogue of a 5,6-disubstitut-ed pyrimidone-2, it appeared of interest to examine whether an analogous reaction sequence occurs with 2-oxopurine. 

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