Multicomponent Heterocyclic Chemistry for Undergraduate Organic

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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 different 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

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antiviral, and antibacterial activities, and are an effective scaffold 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 Kappe’s experimental evidence, 4a involves an acid-catalyzed condensation of benzaldehyde and urea affording 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 specific reactants are unknown to students) Biginelli synthesis with focus on MCRs is described where students synthesize one of six different dihydropyrimidines (Table 1) when given one of three known 1,3-dicarbonyl compounds and one of two

ue to its efficiency 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 efficient 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

© XXXX American Chemical Society and Division of Chemical Education, Inc.

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Ytterbium(III) trifluoromethanesulfonate hydrate causes eye irritation and may be harmful if swallowed, inhaled, or absorbed through skin. Glacial acetic acid is a flammable 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

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Average Student Yields (Ranges) 63 75 73 66 74 79

(57−76%) (69−77%) (68−91%) (64−69%) (71−76%) (75−84%)

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 final 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 final 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 sufficiently 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) triflate 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 identifies 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.

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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) triflate 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 filtration 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.

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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.

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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 flammable liquid and vapor (flash point 34 °C), causes eye irritation and skin irritation, and is harmful if ingested or inhaled. Benzaldehyde is a reducing agent, potentially causing a fire 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.

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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.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. B

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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, 338−349. (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, 5676−5683. (c) Kappe, C. O. Biologically active dihydropyrimidones of the Biginelli-typea literature survey. Eur. J. Med. Chem. 2000, 35, 1043−1052. (d) Kappe, C. O. Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Acc. Chem. Res. 2000, 33, 879−888.

The authors declare no competing financial interest.

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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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REFERENCES

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