2- dihydropyrimidine derivatives

Stereochemistry also plays an important role in the recently disclosed 3,4-dihydropyrimidinethione analogs [32]. Racemic dihydropyrimidine derivative (32) is reported to inhibit activation by the TRPA1 agonist HH-dibenzo[fc,e]azepine-10-carboxylic acid methyl ester (16) with an IC50 value of 128 nM for human TRPA1 in HEK293 cells. 

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... 

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. 

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... 

As already mentioned at the beginning of this chapter, one of the facile methods for the synthesis of dihydropyrimidine derivatives is the treatment of oc,(3-unsaturated carbonyls with urea and its analogues—thiourea, guanidine and amidines. However, the majority of the publications have dealt with syntheses involving thiourea. Most likely is the possibility of the modification of 3,4-dihydropyrimidine-2-thiones or their heteroaromatized analogues, which produces a diverse class of heterocycles. The reagent involved in this modification process can act like a,(3-unsaturated carbonyls [16] (Scheme 3.9). 

A tabular literature survey with about 650 entries listing all dihydropyrimidine derivatives of type 14 prepared via three-component Biginelli reactions up to the year 2001 has been published [7]. 

A conceptually different approach to dihydropyrimidine analogues was developed by Kishi and co-workers (Scheme 4.8) [137, 138], The trimolecular room-temperature condensation of an enamine, acetaldehyde, and isocyanic acid provides the bicyclic dihydropyrimidine derivative 21. With some modification, this strategy was initially employed toward a stereospecific [138, 139] and later an enan-tioselective [140] synthesis of the natural product saxitoxin. Recent investigations by Elliott and coworkers have shown that substituted isocyanates can also be employed in this method [141-146], but a more general modification of this trimolecular condensation towards monocyclic dihydropyrimidine derivatives of the Bigi-nelli type has not yet been reported. 

Reaction of 2,3-diphenylcyclopropenone with 2-aminothiazole and related compounds in tet-rahydrofuran produced acrylamide derivatives 2 and/or c -dihydropyrimidine derivatives 3. ... 

The reactions of 4,4-bis(trifluoromethyl)-substituted 1,3-diazabuta-1,3-diene with acetylene and its derivatives yield [4 + 2] cycloadducts, 4,4-bis-(trifluoro-methyl)-l,4-dihydropyrimidine derivatives (83CZ271) (Scheme 23). In the reaction... 

The Atwal modification of the Hantzsch synthesis consists of a condensation reaction between a thiouronium salt, an aldehyde and a P-oxoacid derivative to form dihydropyrimidine derivatives as shown in Scheme 1.8.5.9. 

S-Alkylated DHPM derivatives 34 (R = H) have been prepared by condensation of S-alkylthiourea derivatives with a,p-unsaturated ketoe-sters (87H1185, 87H1189, 89JOC5898). C-2 unsubstituted 1,4-dihydropyrimidines 35 were obtained by reductive desulfurization of 22 (86KGS1223) (X = S, = Me, Ph) or from S-methylated 1,4-dihydropyrimidine derivative 34 (R = H, Me alkyl = Me) with Raney-Ni (89KGS1076) (Scheme 15). 

DHPM 22 has been transformed to 2-(2-hydroxy-2-arylvinyl) dihydropyrimidine derivatives 90 via Eschenmoser sulfide contraction through the selective alkylation of 22 at C-2 with a-bromoketone 88 under basic conditions and subsequent elimination of the bridged sulfur by the thiophilic... 

Malonodinitrile derivative 807, as well as compounds with phosphonate (808) and trifluoromethylthio (809) groups were used in reactions with NCN binucleophiles, including Af-alkylamidines, 3-aminopyrazoles and 2-aminopyridines to form 707 (Table 39). Activated aUcenes 807-809, unlike the compound 777 containing COOMe group, gave amino or imino derivatives of pyrimidines, which arose from attack of the nucleophile at the nitrile group. Analogous reaction was observed in case of 810 as a result dihydropyrimidine derivatives 811 or 812 were formed (Scheme 161) [497-500]. 

Dihydropyrimidines are associated with broad spectrum of biological activities. Excellent results were obtained for the preparation of dihydropyrimidine derivatives by Biginelle reaction with microwave enhancement (Banks, 1999). An increase in yield was observed to 60-90%, while there was a drastic decrease in reaction time for 12-24 h to 5 min. 

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. 

Hydrolysis of 3-[(2,6-dimethoxy-4-pyrimidinyl)hydroxymethyl]perhydro-pyrido[l,2-c]pyrimidin-l-iminium salts 174-177 in boiling cone. HCl afforded the appropriate 3-[(2-hydroxy-6-oxo-l,6-dihydropyrimidin-4-yl) hydroxymethyl] derivative (98TL7021, 00JA5017). 

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