Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Aug 24:6:376.
doi: 10.3389/fchem.2018.00376. eCollection 2018.

A Five-Component Biginelli-Diels-Alder Cascade Reaction

Taber S Maskrey  1 , Madeline C Frischling  1 , Mikhaila L Rice  1 , Peter Wipf  1
Affiliations

A Five-Component Biginelli-Diels-Alder Cascade Reaction

Taber S Maskrey et al. Front Chem. .

Abstract

A new multi-component condensation was discovered during the reaction of a urea, β-keto ester, and formaldehyde. In the presence of catalytic indium bromide, a Biginelli dihydropyrimidinone intermediate was further converted to a five-component condensation product through a formal hetero Diels-Alder reaction. The product structure was confirmed by NMR and NOE analysis, and the proposed stepwise mechanism was supported by the reaction of the Biginelli intermediate with ethyl 2-methylene-3-oxobutanoate.

Keywords: 5-CC; Biginelli reaction; InBr3; dihydropyrimidinone; hetero Diels-Alder reaction; multi-component condensation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
DHPM structure and biologically active analogs.
Figure 2
Figure 2
Literature precedence and synthetic plans.
Figure 3
Figure 3
Five-component condensation reaction. For conditions, see Table 1.
Figure 4
Figure 4
Attempted five-component condensation reaction with a cyclic 1,3-diketone.
Figure 5
Figure 5
Stepwise conversions of intermediate DHPM (Biginelli) products in a hetero Diels-Alder reaction.
Figure 6
Figure 6
Retro Diels-Alder reaction under Krapcho dealkylation conditions.
Figure 7
Figure 7
Proposed mechanism of five-component condensation.
See this image and copyright information in PMC

References

    1. Dai C., Meschini F., Narayanam J. M., Stephenson C. R. (2012). Friedel–crafts amidoalkylation via thermolysis and oxidative photocatalysis. J. Organ. Chem. 77, 4425–4431. 10.1021/jo300162c - DOI - PMC - PubMed
    1. de Fátima Â., Braga T. C., da S. Neto L., Terra B. S., Oliveira B. G., da Silva D. L., et al. . (2015). A mini-review on biginelli adducts with notable pharmacological properties. J. Adv. Res. 6, 363–673. 10.1016/j.jare.2014.10.006 - DOI - PMC - PubMed
    1. Fu N. Y., Yuan Y. F., Cao Z., Wang S. W., Wang J. T., Peppe C. (2002). Indium(III) bromide-catalyzed preparation of dihydropyrimidinones: improved protocol conditions for the Biginelli reaction. Tetrahedron 58, 4801–4807. 10.1016/S0040-4020(02)00455-6 - DOI
    1. Hu E. H., Sidler D. R., Dolling U.-H. (1998). Unprecedented catalytic three component one-pot condensation reaction:an efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones. J. Organ. Chem. 63, 3454–3457. 10.1021/jo970846u - DOI
    1. Huryn D. M., Brodsky J. L., Brummond K. M., Chambers P. G., Eyer B., Ireland A. W., et al. . (2011). Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators. Proc. Natl. Acad. Sci. U.S.A. 108, 6757–6762. 10.1073/pnas.1015251108 - DOI - PMC - PubMed

LinkOut - more resources