Communication pubs.acs.org/jchemeduc
Synthesis of trans-4,5-Bis-dibenzylaminocyclopent-2-enone from Furfural Catalyzed by ErCl3·6H2O Mónica S. Estevaõ , Ricardo J. V. Martins, and Carlos A. M. Afonso* Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-009 Lisboa, Portugal S Supporting Information *
ABSTRACT: An experiment exploring the chemistry of the carbonyl group for the one-step synthesis of trans-4,5dibenzylaminocyclopent-2-enone is described. The reaction of furfural and dibenzylamine in the environmentally friendly solvent ethanol and catalyzed by the Lewis acid ErCl3·6H2O afforded the product in high yield (79−97%) with high purity by simple filtration. This experiment can be performed during a 3 h class, and requires only basic glassware without an anhydrous or inert atmosphere. It is suitable for use in introductory organic chemistry laboratories, where the purity of the product can be determined, using simple techniques such as TLC analysis and melting point measurement, as well as for more advanced classes allowing the consolidation of important reactivity features of the carbonyl group and the interpretation of the 1H NMR spectrum. KEYWORDS: Organic Chemistry, Hands-On Learning/Manipulatives, Aldehydes/Ketones, Catalysis, Mechanisms of Reactions, Spectroscopy, Upper-Division Undergraduate
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this facile transformation of furfural (1) into cyclopentenones with Lewis acids, an undergraduate laboratory experiment, catalyzed by ErCl3·6H2O,9 was developed using the environmentally friendly solvent ethanol (Scheme 1). The use of this solvent allowed the isolation of product 2 by simple filtration, since crystallization can be induced while the product is formed.
unctionalized cyclopentenones are important compounds because this structural moiety is found in a large number of natural compounds, including biologically active molecules such as prostaglandins1 and pesticides,2 and are also important as very useful synthetic intermediates for the synthesis of bioactive carbocycles.3 Their importance arises mainly due to the rich chemistry of the enone functionality which allows 1,2- and/or 1,4-additions, cycloadditions, and allylic and α-carbonyl functionalization.4 Consequentially, a high number of reports concerning functionalized cyclopentenones (approximately 25,000 in SciFinder, with over 8000 chiral examples) are described in the literature. The trans-4,5-diamino functionality has mainly been explored as a synthetic intermediate for the synthesis of Agelastatin A,5 pactamycin,6 and 2,4-bifunctionalized cyclopentenones.7 Although a wide range of methodologies for the synthesis of functionalized cyclopentenones exist, the Lewis acid catalyzed transformation of furfural using Sc(OTf)3, Dy(OTf)3,8 AlCl3,7 ErCl3·6H2O,9 p-toluenesulfonamide,10 BF3·OEt2,11 or a heteronuclear 3d/Dy(III) cluster12 is especially efficient and practical. Moreover, the proposed mechanism for this transformation is very interesting for educational purposes.8,12 On the basis of © XXXX American Chemical Society and Division of Chemical Education, Inc.
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EXPERIMENTAL SECTION
Students work individually or in groups of two. Erbium(III) chloride hexahydrate (0.1 g, 5 mol %), ethanol (2.6 mL), dibenzylamine (2.0 mL, 10.4 mmol, 2.0 equiv), and furfural (0.43 mL, 5.2 mmol, 1.0 equiv) are added to a round-bottom flask. The reaction mixture is stirred for 30 min at 50 °C. After 10−15 min a yellow solid starts to form. After 30 min the reaction mixture is cooled down in an ice bath, and cold distilled water (10 mL) is added. The solid is filtered and ovendried. The purity of the product is confirmed by TLC and Received: June 27, 2016 Revised: August 3, 2017
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DOI: 10.1021/acs.jchemed.6b00470 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Communication
Scheme 1. Synthesis of trans-4,5-Bis-dibenzylaminocyclopent-2-enone (2) from Furfural (1)
Scheme 2. Reaction Mechanism8
melting point. Its structure is analyzed by spectroscopy.
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catalysts.7−11 On the basis of the recently reported method using the catalyst erbium(III) chloride hexahydrate, which is moderately expensive and has low toxicity,9 the procedure was adapted to the teaching laboratory environment to address the following needs: (1) use of a substrate that permits isolation of the product in high yield and without need of column chromatography, (2) completion of an experiment that is feasible during one laboratory session (3 h), and (3) use of a readily available and environmentally friendly solvent (published experiment uses ethyl lactate as a solvent). From this study, reproducible results were observed using dibenzylamine (2. 0 equiv), and ErCl3·6H2O (5 mol %) in ethanol for 30 min, at 50 °C, affording product 2 in 85% yield, and in high purity, with filtration of the precipitate formed during the reaction. This experiment was reproduced by 16 groups of students (one or two students/group) in the first year of a pharmaceutical science course in two semesters taking the organic chemistry laboratory unit (3 h/period). The students obtained the product 2 in yields above 82% and in high purity (see Supporting Information). The purity of the product was easily assessed by TLC and later confirmed by 1H NMR spectroscopy. The analysis of the 1H NMR spectra also allows consolidation of the chemical shift and multiplicity, namely, by observation of an AX system for the olefinic protons (dd, J = 6, 2 Hz). It was observed that the reaction occurred in the temperature range 45−55 °C. The order of addition is critical. When furfural was added before dibenzylamine, no precipitate was formed, even after 45 min. Considering the multistep reaction mechanism of the transformation of furfural to 2, this experiment is a good example for the students to consolidate the following functional group reactivity: (1) iminium formation, (2) 1,6-addition, (3) ring-opening with formation
H NMR
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HAZARDS Students should use protective clothing, gloves, and safety goggles, and perform all the manipulations in a fume-hood. Erbium(III) chloride hexahydrate is hazardous in the case of skin contact (irritant), eye contact (irritant), ingestion, and inhalation. Furfural is toxic if swallowed or if inhaled, harmful in the case of skin contact (irritant), or eye contact (irritant), and may cause respiratory irritation. Dibenzylamine is harmful if swallowed and causes severe skin burns and eye damage. Deuterated chloroform is irritating to the respiratory system, skin, and eyes, and toxic if swallowed. Exposure to its decomposition products may cause a health hazard, and may cause cancer depending on duration and level of exposure. Ethanol, ethyl acetate, and n-hexane are hazardous in the case of ingestion and inhalation and slightly hazardous in the case of skin contact (irritant) and eye contact (irritant); n-hexane is a neurotoxin. Toxicity of trans-4,5-dibenzylaminocyclopent-2enone is unknown. It could be an irritant in the case of skin and eye contact and may be hazard if swallowed or inhaled.
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RESULTS AND DISCUSSION This experiment is designed for undergraduate organic chemistry students and provides them an interactive laboratory exercise in carbonyl chemistry, electrochemical and domino cyclization reactions, Nazarov reaction, and use of lanthanide catalysts. Additionally, 1H NMR spectroscopy is used to identify the product. The direct transformation of furfural 1, to trans-4,5-bis-diaminocyclopent-2-enone, has been reported for several amines (mainly secondary) using different B
DOI: 10.1021/acs.jchemed.6b00470 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Communication
(4) (a) Ball, D. B.; Mollard, P.; Voigtritter, K. R.; Ball, J. L. Rearrangements of Allylic Sulfinates to Sulfones: A Mechanistic Study. J. Chem. Educ. 2010, 87 (7), 717−720. (b) Harrison, E. A. The Preparation of 4-Hydroxy-2,3,4,5-Tetraphenyl-2-Cyclopenten-1-One and Its Base-Catalyzed Conversion into 2,3,4,5-Tetraphenylcyclopentadienone - an Organic Laboratory Experiment. J. Chem. Educ. 1988, 65 (9), 828−828. (c) Jefford, C. W. Syntheses and Rearrangements of Cage Molecules Related to Cubane. J. Chem. Educ. 1976, 53 (8), 477− 482. (5) Duspara, P. A.; Batey, R. A. A Short Total Synthesis of the Marine Sponge Pyrrole-2-aminoimidazole Alkaloid (±)-Agelastatin A. Angew. Chem., Int. Ed. 2013, 52 (41), 10862−10866. (6) Yamaguchi, M.; Hayashi, M.; Hamada, Y.; Nemoto, T. Synthetic Study of Pactamycin: Enantioselective Construction of the Pactamycin Core with Five Contiguous Stereocenters. Org. Lett. 2016, 18 (10), 2347−2350. (7) Nunes, J. P. M.; Afonso, C. A. M.; Caddick, S. Synthesis of 2,4bifunctionalised cyclopentenones from 2-furaldehyde. RSC Adv. 2013, 3 (35), 14975−14978. (8) Li, S. W.; Batey, R. A. Mild lanthanide(III) catalyzed formation of 4,5-diaminocyclopent-2-enones from 2-furaldehyde and secondary amines: a domino condensation/ring-opening/electrocyclization process. Chem. Commun. 2007, 36, 3759−3761. (9) Procopio, A.; Costanzo, P.; Curini, M.; Nardi, M.; Oliverio, M.; Sindona, G. Erbium(III) Chloride in Ethyl Lactate as a Smart Ecofriendly System for Efficient and Rapid Stereoselective Synthesis of trans-4,5-Diaminocyclopent-2-enones. ACS Sustainable Chem. Eng. 2013, 1 (5), 541−544. (10) Liu, J. Q.; Yu, J. J.; Zhu, M. Y.; Li, J.; Zheng, X. Z.; Wang, L. M. Novel Role of p-Toluenesulfonamide in the Preparation of 4,5Diaminocyclopent-2-enones. Synthesis 2013, 45 (15), 2165−2170. (11) Caldarelli, A.; De Biasio, V.; Giovenzana, G. B.; Mastronardo, G.; Negri, R. N-Polybenzylated alicyclic 1,2-diamines: cytotoxicity and G1 phase arrest in cancer cell line. Mol. Diversity 2014, 18 (4), 879− 886. (12) Griffiths, K.; Gallop, C. W. D.; Abdul-Sada, A.; Vargas, A.; Navarro, O.; Kostakis, G. E. Heteronuclear 3d/Dy-III Coordination Clusters as Catalysts in a Domino Reaction. Chem. - Eur. J. 2015, 21 (17), 6358−6361.
of stable conjugated enamine-enolate-iminium salt (Stenhouse salt intermediate), (4) favorable 5-exo-trig ring-closure between an enamine and an iminium ion driven by the concerted enone formation, (5) favorable formation of the diasteriomer in trans orientation, and (6) the role of the Lewis acid catalyst in this multistep mechanism (Scheme 2).
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SUMMARY An experiment allowing the students to explore the rich chemistry of the carbonyl group by conducting a mechanistically rich synthesis of a highly functionalized cyclopentenone is described. The experiment is straightforward and can be completed in less than a 3 h laboratory session, requiring no special glassware or inert conditions, using readily available starting materials, including the biorenewable solvent ethanol.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00470. Students’ handout containing an introduction, detailed experimental procedure, hazards and safety, and guidelines and hints for student discussion; and additional notes for the instructors containing general remarks, student results, experimental photos, answer keys for students’ discussion, notes for the experiments and additional information (1H NMR and characterization data) (PDF, DOCX)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: carlosafonso@ff.ulisboa.pt. ORCID
Carlos A. M. Afonso: 0000-0002-7284-5948 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors acknowledge the help of the first-year students of Integrated Master Course on Pharmaceutical Science from Faculty of Pharmacy, University of Lisbon, Portugal, and Fundaçaõ para a Ciência e a Tecnologia (FCT) (ref UID/ DTP/04138/2013), and European Structural & Investment Funds through the COMPETE Programme and from National Funds through FCT (ref SAICTPAC/0019/2015) and European Research Area Network; ERANet LAC (ref ELAC2014/ BEE-0341) for financial support.
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REFERENCES
(1) Simeonov, S. P.; Nunes, J. P. M.; Guerra, K.; Kurteva, V. B.; Afonso, C. A. M. Synthesis of Chiral Cyclopentenones. Chem. Rev. 2016, 116 (10), 5744−5893. (2) Kelly, L. F. A Synthesis of Chrysanthemic Ester - an Undergraduate Experiment. J. Chem. Educ. 1987, 64 (12), 1061−1061. (3) (a) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Synthesis and conformational and biological aspects of carbasugars. Chem. Rev. 2007, 107 (5), 1919−2036. (b) Kurteva, V. B.; Afonso, C. A. M. Synthesis of Cyclopentitols by Ring-Closing Approaches. Chem. Rev. 2009, 109 (12), 6809−6857. (c) Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chemical Synthesis of Heterocyclic-Sugar Nucleoside Analogues. Chem. Rev. 2010, 110 (6), 3337−3370. C
DOI: 10.1021/acs.jchemed.6b00470 J. Chem. Educ. XXXX, XXX, XXX−XXX
