Dihydropyrimidinone

Forty years after the initial proposal, Sweet and Fissekis proposed a more detailed pathway involving a carbenium ion species. According to these authors the first step involved an aldol condensation between ethyl acetoacetate (6) and benzaldehyde (5) to deliver the aldol adduct 11. Subsequent dehydration of 11 furnished the key carbenium ion 12 which was in equilibrium with enone 13. Nucleophilic attack of 12 by urea then delivered ureide 14. Intramolecular cyclization produced a hemiaminal which underwent dehydration to afford dihydropyrimidinone 15. These authors demonstrated that the carbenium species was viable through synthesis. After enone 13 was synthesized, it was allowed to react with N-methyl urea to deliver the mono-N-methylated derivative of DHPM 15. 

Scheme 7.49 Preparation of bicyclic dihydropyrimidinones employing cyclative cleavage.

In recent decades, the Biginelli-type dihydropyrimidinones (DHPM) have received considerable attention, because of the interesting pharmacological properties of this heterocydic scaffold [30]. It was soon established that DHPM has a similar pharmacological profile to the well-known dihydropyridine (DHP) caldum-channel modulations of the Hantzsch type [31]. 

Scheme 1 Hantzsch s dihydropyridines and Biginelli s dihydropyrimidinones synthesis...

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... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

Sodium borohydride can be used to reduce pyrimidinones to their dihydro derivatives, and the reduction of the axially chiral pyrimidinone 379 occurred stereoselectivily to give the dihydropyrimidinone 380 in 94% yield and 85% enantiomeric excess <2003AGE4360>. 

Although much less common than with fully conjugated pyrimidines, cross-coupling reactions can still be performed with dihydropyrimidines, and thus the Heck reaction of the dihydropyrimidinone 518 with 4-iodoanisole 517 gave the product 519 where the double bond had migrated to the more stable 1,2-position <1996OS201>. 

However, dihydropyrimidinones 524 derived from the Biginelli reaction are less readily oxidized <1997H(45)1967>, and there have been several investigations of oxidation systems that can convert compounds of this class to the fully conjugated pyrimidine derivatives 525. 

Dihydropyrimidinones can be reduced by hydrogenation over palladium on charcoal, as demonstrated by the synthesis of the tetrahydropyrimidinone 534 from the chiral precursor 533 <1996TA2233, 1999JOC8668, 2004HCA1016>. 

Although sodium borohydride cannot reduce unactivated pyrimidines, it can reduce the polarized C=N bonds in dihydropyrimidines to their tetrahydro derivatives. For example, the reduction of the dihydropyrimidinone 537 can be performed enantioselectively with sodium borohydride to give the tetrahydropyrimidinone 538 in 85% yield <199608201 >. 

Rearrangement reactions involving 1,3-thiazines are often very facile. For example, reaction of 2-imino-4-phenyl-2/7-1,3-thiazinium perchlorate 957 with NaOH at room temperature gave 4-phenylpyrimidine-2(l//)-thione 958 <2004CHE1595>, while treatment of 6-amino-2,3-dihydro-l,3-thiazin-4(l// )-ones 959 with KOH readily gave the potassium salt of the dihydropyrimidinone 960 <2005HAC426>. 

Polymer-assisted methodology has been used several times for parallel-array synthesis of libraries involving three to five synthetic steps. Scheme 11 shows a three-step solution-phase synthesis of 2-thioxo-4-dihydro-pyrimid-inones wherein the key purification step involved amine resin 1 to sequester excess aldehydes and isot,hiocyanates from upstream transformations. Thermal cyclization of the purified intermediates gave the desired 2-thioxo-4-dihydropyrimidinones in excellent yields and purities.83... 

Keywords / -dicarbonyl compound, aldehyde, urea, Biginelli reaction, Yb(III)-resin, dihydropyrimidinone... 

Ambersep 900 OH (400 mg) were added to the combined filtrates. The suspension was shaken for 2 h and then the resins were filtered and washed thoroughly with methanol. The combined filtrates were concentrated to give dihydropyrimidinones. 

Aryl-vinyl coupling fi-aryl-fi-amino acids.2 A novel route to P-amino acids is based on the formal conjugate addition of an aryl iodide to an enantiomerically pure dihydropyrimidinone such as 1, prepared by pivaldehyde acetalization of (R)-aspara-gine (c/., 14, 69-70). Thus 4-iodoanisole couples with 1 under Heck conditions, Pd(OAc)2, Ar3P, triethylamine, and DMF to give 2 in 78% yield. Reduction of 2... 

An alternative solution to the workup issue relied on the attachment of CH-acidic compounds 64 to a soluble polymer support (PEG-4000). The approach improved the yields of the dihydropyrimidinones 66 by the use of a 2-fold excess of other components—urea and aldehyde in the microwave-assisted solvent-free cyclocondensation [118]. Another single-step approach towards 4,5-disubstituted pyrimidines was based on cyclocondensation of a variety of aromatic, heterocyclic and aliphatic ketones, formamide and HMDS as the ammonium source [119]. The high temperature (215 °C) required to effect the formation of pyrimidines was secured by microwave dielectric heating in sealed vessels (Scheme 45). 

Despite the numerous reports dealing with combinatorial diversification of the dihydropyrimidinone (DHPM) template, transition metal-catalyzed derivatizations have been poorly explored. In a collaborative effort between the groups of C.O. Kappe and M. Larhed, high-speed transition metal-catalyzed functionalizations of this important scaffold were investigated [34]. 

O.V. Shishkin, Conformational flexibility of dihydropyrimidinone and tetrahydopyrimidin-2,4-dione rings in DNA bases, J. Chem. Soc.Chem.Commun, 1538 (1995). 

Ma Y, Qian C, Wang L, Yang M, Lanthanide triflate catalyzed Biginelli reaction. One-pot synthesis of dihydropyrimidinones under solvent-free conditions, J. Org. Chem., 65 3864-3868, 2000. 

The dihydropyrimidinone 338 is produced from 1-pyrrolidinobutene and the silylated diazadiene 337 (equation 137)166. 

Diazoninones 64 were synthesized by reduction of hexahydro-l//-pyrazolo[l,2-tf]pyridazin-l-ones with sodium in liquid ammonia (Scheme 7, Section 14.10.5.2.1) <2000CL1104, 2002T7177>. One of the synthetic routes for the preparation of diazoninone 291 includes reduction of dihydropyrimidinone 292 (Scheme 53) <2002T7177>. 

Kappe CO, Stadler A (2004) The Biginelli dihydropyrimidinone synthesis. Org React 63 1-117... 

The classic Biginelli reaction features the cyclocondensation of an aldehyde, a urea and an active methylene compound to form dihydropyrimidinones (Fig. 4). The reaction has been extensively utilized and reviewed [20] and its applications to drug discovery have also been highlighted [21]. This chapter will focus on some of the most recent developments and applications of Biginelli reactions to the discovery of biologically active molecules. 

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