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Multicomponent Heterocyclic Chemistry for Undergraduate Organic

Laboratory: Biginelli Reaction with Multiple Unknowns
Fehmi Damkaci* and Adam Szymaniak
Department of Chemistry, State University of New York at Oswego, Oswego, New York 13126, United States
S Supporting Information
*

ABSTRACT: Multicomponent reactions and heterocyclic chemistry are

important concepts of organic synthesis, especially in the pharmaceutical
industry. A one-pot, multicomponent Biginelli condensation reaction to
synthesize dihydropyrimidine derivatives from multiple unknowns is
investigated as a discovery-based experiment in a second semester, secondyear undergraduate organic chemistry laboratory course. Three 1,3-dicarbonyl
compounds, two aryl aldehydes, and urea are utilized to provide six dierent
unknown dihydropyrimidine derivatives with average yields ranging from 63
79%. Students identify their products using 1H NMR, 13C NMR, DEPT, and
IR spectroscopic data. The experiment provides an opportunity to discuss
multicomponent reactions, carbonyl condensations with amines, enol
chemistry, and interpretation of spectra, while being completed in a 3-h
laboratory period.
KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives,
Aldehydes, Amines, Heterocycles, IR Spectroscopy, NMR Spectroscopy, Synthesis

antiviral, and antibacterial activities, and are an eective scaold

for subsequent additions.5 The experiment and the approach
discussed herein have the pedagogical goals to develop
understanding of MCRs, combinatorial chemistry, acidcatalyzed condensations and the role of Lewis Acids, and to
develop the ability to determine an organic structure through
spectral analysis.
The most widely accepted mechanism for the Biginelli
reaction, which is supported by Kappes experimental
evidence, 4a involves an acid-catalyzed condensation of
benzaldehyde and urea aording a hemiaminal, which
dehydrates to a key N-acyliminium ion intermediate.
Subsequently, an enol form of ethyl acetoacetate attacks the
N-acyliminium ion to generate an open chain ureide, which
readily cyclizes to form the dihydropyrimidine product.
For student laboratory use, Holden and Crouch developed a
microscale Biginelli synthesis that takes 1.5 h in the presence of
ethanol and HCl with an average yield of 58%.2i Aktoudianakis
and co-workers developed a solvent-free Biginelli synthesis that
takes 15 min in the presence of ZnCl2 with an average yield of
65%.2f Both experiments utilized the condensation of
benzaldehyde, ethyl acetoacetate, and urea to give a single
product.
A discovery-based (the possible reactants are known, but the
specic reactants are unknown to students) Biginelli synthesis
with focus on MCRs is described where students synthesize
one of six dierent dihydropyrimidines (Table 1) when given
one of three known 1,3-dicarbonyl compounds and one of two

ue to its eciency in accessing complex heterocyclic

structures in one step, multicomponent reactions
(MCRs)1 have been widely adapted in organic research and
industry. Following the same trend, the number of undergraduate organic laboratory experiments using MCRs2 has also
increased in recent years. MCRs have the advantage of
conserving most of the atoms from the building blocks that
are present in the product to generate libraries of compounds in
an ecient manner. Therefore, MCRs can be used to introduce
the concept of combinatorial chemistry as a tool utilized in drug
discovery to the undergraduate laboratory curriculum.2e,3
The reaction of interest was the Biginelli reaction,4 a one-pot
condensation of a 1,3-dicarbonyl compound, aryl aldehyde, and
urea in the presence of a Lewis acid to form a dihydropyrimidine (Scheme 1). Dihydropyrimidine derivatives show many
medicinal properties, such as calcium channel blocking,
Scheme 1. Reaction Mechanism for the Biginelli
Condensation Reaction

Published: May 6, 2014

2014 American Chemical Society and
Division of Chemical Education, Inc.

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Journal of Chemical Education

Communication

Ytterbium(III) triuoromethanesulfonate hydrate causes eye

irritation and may be harmful if swallowed, inhaled, or absorbed
through skin. Glacial acetic acid is a ammable liquid and
causes severe eye irritation and skin burns; it may be harmful if
inhaled or swallowed. Dimethyl sulfoxide-d6 is slightly hazardous in case of inhalation, of skin contact, of eye contact, and of
ingestion. The hazards of the products are unknown, and all
should be handled as hazardous in case of inhalation, skin
contact, eye contact, and ingestion. Eye protection and gloves
must be used throughout the entire experiment.

Table 1. Starting Materials and Products for Biginelli

Synthesis

R1

R2

OEt
OMe
Me
OEt
OMe
Me

H
H
H
Me
Me
Me

Average Student Yields (Ranges)

63
75
73
66
74
79

(5776%)
(6977%)
(6891%)
(6469%)
(7176%)
(7584%)

RESULTS AND DISCUSSION

This experiment was run once by 15 students in a 3-h
laboratory period of a second-semester organic chemistry
laboratory course. The experiment setup and workup took 1.5
h, and the remaining time was used to obtain and analyze
spectral data. Students easily followed the procedure with all
reactions going to completion; student yields ranged from 57%
to 91%, with an average yield of 72% (Table 1). Products had a
purity of 90% or higher, with acetic acid and water as major
impurities, according to student 1H NMR spectra. The
pedagogical goals stated above were assessed by a postlaboratory report (accuracy of structural determination and postlab
questions) and a laboratory nal exam. Students were required
to use the spectra of their dihydropyrimidine to identify the
correct product and, thus, the unknown building blocks. Two of
the 15 students did not correctly identify both the product and
the unknown building blocks. All students correctly answered
one nal exam question describing MCRs and providing a
conceptual reaction example.
Overall, the feedback from students was extremely positive.
Comments included how they liked the straightforwardness of
the experimental section, as well as the intrigue and challenge of
the discovery-based approach. The Biginelli reaction products
were suciently complex to challenge students in identifying
the structures using spectral data, a good feature of the
experiment, which was a comment by most students. Also,
students commented how they thought it was exciting to read
about the medicinal activity of some dihydropyrimidines.

known benzaldehydes. The reaction is carried out in the

presence of ytterbium(III) triate using water and acetic acid as
solvent at 95 C for 15 min. From IR and 1H NMR
spectroscopic data a student obtains on the product of the
synthesis and 13C NMR and DEPT spectroscopic data of the
product provided (see Supporting Information), a student
identies the correct reactants from the product. This
experiment, designed for one 3-h laboratory period in the
second semester, second-year undergraduate organic curriculum, provides an opportunity to discuss and review various
concepts (enols, amines, aromatic compounds, heterocyclic
compounds, carbonyl chemistry, multicomponent reactions,
and spectral interpretation) taught in multiple chapters of a
typical second-year organic chemistry course.

EXPERIMENTAL SECTION
Students work individually. The reaction is carried out at the 4
mmol level for the aryl aldehyde. Urea (2 equiv), 1,3-dicarbonyl
compound (2 equiv), aryl aldehyde (1 equiv), and ytterbium(III) triate hydrate (0.1 equiv) are dissolved in acetic acid and
water solvent (3:1) in a reaction vial containing a magnetic stir
bar. An oil bath is heated to 95 C and the capped vial is kept in
the oil bath for 15 min. The reaction mixture is cooled to room
temperature; the contents are poured onto ice and the product
is precipitated with ice-cold water. The precipitate is collected
by vacuum ltration and washed with ice-cold water and
toluene under vacuum to remove residual acetic acid; the
dihydropyrimidines are white, yellow, or orange solids. Each
student obtains an IR spectrum and submits a sample for 1H
NMR analysis during the laboratory period. 13C NMR and
DEPT data are provided for analysis.

CONCLUSION
The Biginelli reaction provided a good opportunity to review
and reinforce numerous concepts from various organic
chemistry chapters in one laboratory period. The short reaction
time and workup procedure prevented students from having
extended idle times for heating and time to become
disinterested in the lab. Overall, this experiment was also
successful in employing essential skills, such as spectral
interpretation and percent yield calculations, while stimulating
students with a synthesis of medicinally active dihydropyrimidine products from unknown starting materials.

HAZARDS
Ethyl acetoacetate causes eye and skin irritation, gastrointestinal
and respiratory tract irritation with nausea, drowsiness, and
dizziness. Methyl acetoacetate causes eye irritation and may
cause skin, respiratory, and gastrointestinal tract irritation. 2,4Pentanedione is a ammable liquid and vapor (ash point 34
C), causes eye irritation and skin irritation, and is harmful if
ingested or inhaled. Benzaldehyde is a reducing agent,
potentially causing a re and explosion risk near oxidizing
agents; it will cause eye and skin irritation and is harmful if
swallowed or inhaled. p-Tolualdehyde may cause skin, eye,
respiratory, and gastrointestinal tract irritation. Urea may cause
skin, eye, respiratory, and gastrointestinal tract irritation.

ASSOCIATED CONTENT

S Supporting Information
*

Instructions for students and instructors, and 1H NMR, 13C

NMR, DEPT, and FT-IR spectra for all products. This material
is available via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*E-mail: fehmi.damkaci@oswego.edu.
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Notes

(5) (a) Debonis, S.; Simorre, J. P.; Crevel, I.; Lebeua, L.; Skoufias, D.
A.; Blangy, A.; Ebel, C.; Gans, P.; Cross, R.; Hackney, D. D.; Wade, R.
H.; Kozielski, F. Interaction of the mitotic inhibitor monastrol with
Human Kinesin Eg5. Biochemistry 2003, 42, 338349. (b) KristalKaan, H. Y.; Ulaganathan, V.; Rath, O.; Prokopcova, H.; Dallinger, D.;
Kappe, C. O.; Kozielski, F. Structural basis for inhibition of Eg5 by
dihydropyrimidines: Stereoselectivity of antimitotic inhibitors Enastron, Dimethylenastron and Fluorastrol. J. Med. Chem. 2010, 53,
56765683. (c) Kappe, C. O. Biologically active dihydropyrimidones
of the Biginelli-typea literature survey. Eur. J. Med. Chem. 2000, 35,
10431052. (d) Kappe, C. O. Recent advances in the Biginelli
dihydropyrimidine synthesis. New tricks from an old dog. Acc. Chem.
Res. 2000, 33, 879888.

The authors declare no competing nancial interest.

ACKNOWLEDGMENTS
We would like to especially thank Kristin Gublo of SUNY
Oswego for all the help setting up the laboratory equipment
necessary and Fred Scoles for the instrumental assistance. We
would also like to thank the Provost, Lorrie Clemo, and the
Chemistry Department for providing funds.

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