3.4- dihydropyrimidine-2- -ones

Joseph JK, Jain SL, Sain B (2006) Ion exchange resins as recyclable and heterogeneous solid acid catalysts for the Biginelli condensation an improved protocol for the synthesis of 3,4-dihydropyrimidin-2-ones. J Mol Catal A Chem 247 99-102... 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Photolysis in Ar matrixes at ca. 15 K affords the corresponding triplet nitrenes that are converted photochemically to the seven-membered ring carbodiimide and then to an open-chain carbodiimide, depending on the subtituents present. Yet different products are formed by flash vacuum thermolysis, such as A-cyanobenzimidazoles by ring contraction (see Scheme 10)." In a similar way, a photochemical and thermal cyclization of 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-one takes place and gives a l,2,3a,9b-tetrahydro-4-methylenepyrimidino[5,4-h]indol-2-one (see Scheme 11)." ... 

Sodium benzenesulfinate resin 43 can also be used to prepare a traceless solid-phase synthesis for 3,4-dihydropyrimidine-2-ones 54 and 55 (Scheme 12.13). This strategy highlighted the sulfinate acidification to yield resin-bound benzenesulfinic acid 52, followed by the condensation of urea or thiourea with aldehydes and sulfinic acid. A one-pot cyclization-dehydration process with 1,3-dicarbonyl compounds or )8-ketoesters (generated in situ by treating the latter reagents with KOH/EtOH) afforded 54, while cyclization with a mixture of pyrrolidine and /8-ketoacid in ethanol followed by the addition of TsOH HaO gave the ester form of 55. When THF was used as a solvent, the free carboxylic acid form of 55 was obtained in comparable yields. 

In a three-component process, a P-ketoester, a (preferentially aromatic) aldehyde, and urea undergo cyclocondensation catalyzed by acids, Lewis acids or metal ions to give 3,4-dihydropyrimidin-2-ones (33), whose dehydrogenation [260] leads to pyrimidin-2-ones (34) (Biginelli synthesis) [261-264] ... 

S. Das, P. Gogoi, D. Konwar, A highly efficient and green method for the synthesis of 3,4-dihydropyrimidin-2-ones and 1,5-benzodiazepines catalyzed by dodecyl sulfonic acid in water. Green Chem. 9 (2007) 153-157. 

Synthesis of both enanthiomers of a-amino-a-trifluoromethyl-y-oxobutylphosphonate derivatives (537) has been realised via proline-catalysed reactions between NH-iminotrifluoroethylphosphonate (536) and acetone. The synthetic utility of these chiral synthons has been illustrated by cyclocondensation reactions of (537a) with 4-chlorophenylisocyanate (538) and 2,5-dimethox)4 etrahydrofuran (540) to afford the first representatives of phosphorylated 3,4-dihydropyrimidin-2-ones (539) and 3/f-pyrrolizines (541) (Scheme 157). °... 

Scheme 20.3.4, Synthesis of 3,4-dihydropyrimidin-2-ones on the DES L-(+)-tartaric acid/DMU.

When the aromatic aldehyde is omitted from a Biginelli reaction mixture, a dihydropyrimidine is still formed. Thus, for example, phenylacetaldehyde (2 mol) and urea (1 mol) react to give 4-benzyl-5-phenyl-3,4-dihydropyrimidin-2(li/)-one (676) (33JA3361). 

If one replaces one of the two equivalents of P-dicarbonyl with urea, such that the reaction is now carried out with one equivalent of aldehyde 123, one equivalent of P-dicarbonyl 124 and an equivalent of urea 125 in acidic ethanol solution, then dihydropyrimidines 126 are formed. This class of reactions has been named Biginelli reactions and are reviewed in section 10.6... 

The Biginelli reaction involves an one-pot reaction between aldehyde 1, 1,3-dicarbonyl 2, and urea 3a or thiourea 3b in the presence of an acidic catalyst to afford 3,4-dihydropyrimidin-2(l//)-one (DHPM) 4. This reaction is also referred to as the Biginelli condensation and Biginelli dihydropyrimidine synthesis. It belongs to a class of transformations called multi-component reactions (MCRs). 

In 1893 Pietro Biginelli reported the first synthesis of 4-aryl-3,4-dihydropyrimidin-2(l//)-ones (DHPMs) via an one-pot process using three components. Thus, DHPM 7 was synthesized by mixing benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) in ethanol at reflux in the presence of a catalytic amount of HCl. 

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. 

Other examples of CN/CC replacement are observed in reactions of l-phenyl-pyrimidin-2(l//)-one with active methylene compounds, such as diethyl malonate and benzoylacetate, giving in good yield 2-oxo-l,2-dihydro-3-pyridinecarboxylate and 3-benzoylpyridin-2(l H)-one, respectively (84CPB2942, 87H2223) (Scheme 8). In a similar way 4,6-dimethyl-1-phenylpyrimidin-2( 1 //)-one, 4,6-dimethyl-1 -phenylpyrimidine-2( 1 //)-thione and 4,6-dimethyl-1 -phenyl-2-phenylimino-1,2-dihydropyrimidine yield with malonitrile 2-amino-4,6-dimethyl-3-pyridinecarbonitrile. In a similar way 2,3-diarylpyrimidin-4(3//)-thiones give with malonitrile CN/CC replacement (84H763) (Scheme 8). The reaction takes a similar course as described in Scheme 7. 

In a 100 mL round-bottomed flask coimected to a reflux condenser, 4.88 g (20 mmol) uridine 1 is suspended and stirred in 12.44 mL (60 mmol) HMDS 2, 4.15 mL (50 mmol) pyrrolidine, 0.1 mL Me3SiCl 14, and 15 mL abs. pyridine. After 4.5 h heating in an oil bath at 140-145 °C the reaction mixture turns yellowish and is complete according to TLC (acetone-methanol, 3 1). After evaporation of the solvents in vacuo, the yellowish, partly crystalline residue of crude 5 b is boiled for 3 h in 100 mL methanol and then kept at room temperature for 16 h. After evaporation of the solvent, 6.09 g crade 4-pyrrohdino-l-(79-D-ribofuranosyl)-l,2-dihydropyrimidine-2-one 6b is obtained. This is recrystallized from 90 mL boiling methanol and subsequently from 30 mL methanol to give, in two crops, 5.677 g (95.4%) pure 6b, m.p. 211-213°C [11]. 

The following syntheses all proceeded regioselectively 4,6-diaryl-3,4-dihydropyrimidine-2-thiones with 3-bromopropionic acid in a Ac20/AcOH system <2001MI407, 2000IJH49>, or with acrylonitrile in pyridine followed by hydrolysis <1996IJB915> resulted 6,8-diaryl-2,3-dihydro+//,6//-pyrirnido[2,l+][l,3]thiazin-4-ones in good yield 4-phenyl-5-carbethoxy-3,4-dihydropyrimidine-2-thiones with benzylidenemalonitrile in a NaOAc/AcOH system... 

Substantial MW rate enhancements have been reported in the Biginelli synthesis of dihydropyrimidines [50, 51] under homogeneous conditions. The synthesis involves a one-pot cyclocondensation of a /i-ketoester with an aryl aldehyde and urea or thiourea in the presence of a catalytic amount of HC1 in ethanol solution. An example of this synthesis is shown in Scheme 4.17. 

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... 

Dexrazoxane was also hydrolyzed enzymatically in the liver and kidney by dihydropyrimidine aminohydrolase. This enzyme could hydrolyze one but not a second ring of this molecule. Levrazoxane, the enantiomer of dexrazoxane, was also hydrolyzed enzymatically by DHPase in liver homogenates, but at a rate 4.5-fold slower [136], However, in vivo studies in rats dosed with razoxane (the racemic mixture of levrazoxane and dexrazoxane) revealed only a relatively small difference in elimination of the two enantiomers. This suggests that distribution and excretion reduced the impact of stereoselective biotransformation on the pharmacokinetics of these two enantiomers [137]. 

C-Acyclic nucleoside analogs of inosine and guanosine 8-[(/ 5)-2,3-dihydroxypropyl]imidazo[l,5-fl]-l,3,5-triazin-4(3//)-ones were synthesized. The route involved the cyclization and rearrangement of 5-acylamino-5-allyl-6-amino-4,5-dihydropyrimidin-4-ones (1122) to 8-allylimidazo[l,5-a]-l,3,5-triazin-4(3//)-ones (1123). Osmium tetroxide hydroxylation gave 1124. None of these analogs showed appreciable antiviral or antitumor cell activity (84NAR263 87MI6). 

Sabitha G, Reddy KB, Yadav JS, Shailaja D, Sivudu KS (2005) Ceria/vinylpyridine polymer nanocomposite an ecofriendly catalyst for the synthesis of 3,4-dihydropyrimidin-2(lH)-ones. Tetrahedron Lett 46 8221-8224... 

Dabiri M, Salehi P, Baghbanzadeh M, Shakouri M, Otokesh S, Ekrami T, Doosti R (2007) Efficient and eco-friendly synthesis of dihydropyrimidinones, bis(indolyl) methanes, and N-alkyl and N-arylimides in ionic liquids. J Iran Chem Soc 4 393 01 Legeay JC, Eynde JJV, Bazureau JP (2008) Ionic liquid phase organic synthesis (loLiPOS) methodology applied to the preparation of new 3,4-dihydropyrimidine-2(lH)-ones bearing bioisostere group in N-3 position. Tetrahedron 64 5328-5335... 

Gui JZ, Liu D, Wang C, Lu F, Lian JZ, Jiang H, Sun ZL (2009) One-Pot Synthesis of 3,4-Dihydropyrimidin-2(lH)-ones Catalyzed by Acidic Ionic Liquids Under Solvent-Free Conditions. Synth Commun 39 3436-3443... 

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