Synthesis of dihydropyrimidines

TheBiginelli dihydropyrimidine synthesis o is another relevant multicomponent condensation reaction that has been recently adapted to the solid phase by Wipf et to prepare a small library 

In this sequence, y-aminobutyric acid derived urea 241, prepared from GABA and KOCN in HjO/THF, was attached to Wang resin 84 to provide 242 in high yield. Subsequent 

The individual products 246 were obtained in high yields and excellent purity ( 95%). Since P-oxoesters 243 are readily obtained in one step and many aldehydes 244 are commercially available, this reaction is applicable to the parallel synthesis of large compound libraries. The GABA-derived acid linker increases the water solubility of the products and offers a convenient handle for additional functionalisation. 

Multigeneration assembly strategies with cyclisation-assisted cleavage 

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The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas. 

An important multicomponent transformation for the synthesis of dihydropyrimidines is the Biginelli reaction, which involves the acid-catalyzed condensation... 

Scheme 6.246 Biginelli three-component synthesis of dihydropyrimidines.

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. 

Desai, B. and Dallinger, D. and Kappe, C.O. (2006). Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron, 62, 4651-4664. 

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... 

Amini MM, Shaabani A, Bazgir A (2006) Tangstophosphoric acid (H3PW12040) an efficient and eco-friendly catalyst for the one-pot synthesis of dihydropyrimidin-2(lH)-... 

Huang YJ, Yang FY, Zhu CJ (2005) Highly enantioseletive biginelli reaction using a new chiral ytterbium catalyst Asymmetric synthesis of dihydropyrimidines. J Am Chem Soc 127 16386-16387... 

The Biginelli procedure is amenable to microwave technology, and several microwave-assisted procedures have now been published <2002SC147, 2004SL235>. An example is the microwave-assisted solution-phase synthesis of dihydropyrimidine C-5 amides and esters 723 using ytterbium triflate as the Lewis acid catalyst <2006T4651>. 

Yaddav, J.S., Reddy, B.V.S., Reddy, E.J. and Ramalingam, T., Microwave-assisted efficient synthesis of dihydropyrimidines improved high yielding protocol for the Biginelli reaction,/. Chem.Res. (S), 2000,354-355. 

The microwave-assisted Biginelli synthesis of dihydropyrimidine was investigated in open vessels as well as sealed reaction vessels. The reaction carried out at atmospheric pressure under microwave irradiation in a solution showed no rate increase compared to... 

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). 

Scheme 44 Microwave-promoted automated synthesis of dihydropyrimidine library...

Kappe, C. O., Falsone, S. F. Synthesis and reactions of Biginelli compounds. Part 12. Polyphosphate ester-mediated synthesis of dihydropyrimidines. Improved conditions for the Biginelli reaction. Synlett 1998, 718-720. 

R = Ph, R = Et) and arylaldehydes ArCHO has been reported to yield azadienes with general formula ArC=N-C(R)=CHC02R. These azadienes appear to be very useful as starting materials for the preparation of nitrogen heterocycles. An easy one-pot synthesis of dihydropyrimidines from NH=C(Ph)N=PPh3 and a,(3-unsaturated aldehydes has been described. The reaction is supposed to proceed via an aza-Wittig mechanism followed by ring closure. ... 

The development of a support/linker system for the microwave-assisted synthesis of dihydropyrimidine test libraries, and methods for solid-phase scale-up on cellulose were recently described [101]. 

An MS investigation of the three-component base-mediated Biginelli synthesis of dihydropyrimidines has found evidence for a hemiacetal intermediate (117), but no sign of a bis-ureide (118). ° A prolinamide gives up to 99% ee in Biginelli cyclocondensations of urea, aldehyde, and ethyl acetoacetate. ... 

Karami, B., Haghighijou, Z., Farahi, M. and Khodabakhshi, S. 2012d. One-pot synthesis of dihydropyrimidine-thione derivatives using tungstate sulfuric acid (TSA) as recyclable catalyst. Phosphorus Sulfur Silicon Relat. Elem. 187(6) 754—761. 

In 1893, Pietro Biginelli published his pioneering findings on a threereaction that has become known as the Biginelli reaction. This three-component one-pot reaction leads to the synthesis of dihydropyrimidines (130), typically via the reaction of a benzaldehyde (131), an acetoacetate (132), and a (thio)urea (133) under acid catalysis [73]. The Biginelli reaction is quite versatile since it can be performed with variations in all three components, leading therefore to a myriad of dihydropyrimidines (Scheme 3.33). 

Y. Huang, F. Yang, C. Zhu, J. Am. Chem. Soc. 2005, 127, 16386-16387. Highly enantioselective Biginelli reaction using a new chiral ytterbium catalyst asymmetric synthesis of dihydropyrimidines. 

Bigi F, Carloni S, Erullanti B, Maggi R, Sartori S (1999) A revision of the Biginelli reaction under solid acid catalysis. Solvent-free synthesis of dihydropyrimidines over montmorilion-ite KSF. Tetrahedron Lett 40 3465-3468... 

Liu Q, Pan N, Xu J, Zhang W, Kong F (2013) Microwave-assisted and iodine-catalyzed synthesis of dihydropyrimidin-2-thiones via biginelli reaction under solvent-fiee conditions. Synth Commun 43 139-146... 

A. Vasconcelos, P.S. Oliveira, M. Ritter, R.A. Freitag, R.L. Romano, F.H. Quina, L. Pizzuti, C.M.P. Pereira, F.M. Stefanello, A.G. Barschak, Antioxidant capacity and environmentally friendly synthesis of dihydropyrimidin-(2fl)-ones promoted by naturally occurring organic acids, J. Biochem. Mol. Toxicol. 26 (2012) 155-161. 

D.Z. Xu, H. Li, Y. Wang, Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst asymmetric synthesis of dihydropyrimidines. Tetrahedron 68 (2012) 7867-7872. 

Khabazzadeh, H. Saidi, K. Sheibani, H. Microwave-assisted synthesis of dihydropyrimidin-2(lH)-ones using graphite supported lanthanum chloride as a mild and efficient catalyst. Bioorg. Med. Chem. Lett. 2008,18,278-280. 

W. Y. Chen, S. D. Qin and J. R. Jin, HBF4-catalyzed Biginelly Reaction One-pot synthesis of dihydropyrimidin-2(lH)-ones under solvent-free conditions . Catalysis Communications, 8(2), 123 (2007). 

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