Biginelli heterocyclic synthesis

Limberakis, C. Biginelli Pyrimidone Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 509—520. (Review). 

Surprisingly, the synthetic potential of this heterocycle synthesis remained unexplored for quite some time. In the 1970s and 1980s interest for the original Biginelli cyclocondensation reaction slowly increased and... 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

It is very important that this preparative procedure allowed selective synthesis of Biginelli-like fused dihydropyrimidines of type 69 having angular stmcture. As everyone can see from the other publications cited above in other cases, these heterocycles were usually minor reaction by-products. The third direction discovered in [97-99] led to acridinediones 70 (Scheme 30). 

Nilsson BL, Overman LE (2006) Concise synthesis of guanidine-containing heterocycles using the Biginelli reaction. J Org Chem 71 7706-7714... 

Kidwai, M., Saxena, S., Mohan, R. and Venkataramanan, R., A novel one pot synthesis of nitrogen containing heterocycles an alternate methodology to the Biginelli and Hantzsch reactions, /. Chem. Soc., Perkin Trans. 1,2002, 1845-1846. 

The classical Biginelli synthesis of heterocycles from /3-diketones, urea, and aldehydes has been extended by the replacement of the dione with a cycloalkanone.343 The... 

Kappe, C. O., Falsone, S. F., Fabian, W. M. F., Belaj, F. Synthesis and reactions of Biginelli compounds. 13. Isolation, conformational analysis and x-ray structure determination of a trifluoromethyl-stabilized hexahydropyrimidine - an intermediate in the Biginelli reaction. Heterocycles 1999, 51, 77-84. 

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

P. Zhang, W. Li, G. Zhou, Y. Lai, S. Xu, Heterocycles 2011, 83, 2061-2011. One-pot synthesis of dihydropyrimidiones via environmentally Mendly enzyme-catalyzed Biginelli reaction. 

This was followed by the attachment of a suitable urea-bearing carboxylic acid to generate the handle for the synthesis of the heterocyclic moiety (Scheme 8.5). The dihydropyrimidine core was then assembled using a standard microwave-assisted Biginelli reaction at 140°C for 40 min using DMF/HCl (4 1), followed by a TFA-mediated cleavage of the target molecule from the resin. 

In the previous sections discussing synthesis of chain-fluorinated diazines by heterocyclizations, there were many examples of formation of di-, tetra- and hexahydropyrimidines - so-called hydrates (or other solvates) - instead of the corresponding aromatic products. This situation was quite common for the preparation of chain-fluorinated pyrimidinones or fused pyrimidines possessing an additional electron-withdrawing group, as well as Biginelli-type adducts (Fig. 30, see also Sect. 7 of this chapter). 

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