In the Laboratory edited by
Green Chemistry
Mary M. Kirchhoff ACS Green Chemistry Institute Washington, DC 20036
Asymmetric Aldol Reaction Induced by Chiral Auxiliary
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Jorge Pereira Escola Superior de Tecnologia de Setúbal, Campus do Instituto Politécnico de Setúbal, Estefanilha, 2910-761 Setúbal, Portugal Carlos A. M. Afonso* CQFM, Departmento de Engenharia Química, Instituto Superior Técnico, 1049-001 Lisboa, Portugal; *
[email protected] Asymmetric synthesis is an important topic in organic chemistry, including many applications in the pharmaceutical industry. The creation of asymmetric centers by stereoselective synthesis is a powerful methodology and this important topic needs more attention in the classroom. Among several general methodologies for the synthesis of chiral target molecules, the induction of chirality by asymmetric catalysis (1) and by using chiral auxiliaries (2) are two important approaches in modern organic chemistry. Each one presents some advantages and disadvantages. In the case of chiral auxiliaries the main advantage is the robustness for a considerable range of substrates, while the main disadvantage is the necessity to attach the chiral auxiliary to the substrate, which also causes an increase in the mass of the product and may be troublesome on a large scale during the purification process. The development of efficient systems to recover the chiral auxiliary is also an important issue so that the overall asymmetric process can be attractive. The asymmetric aldol reaction is a powerful methodology for the construction of chiral substrates “chirons” by making new C⫺C bonds and creating useful functional
Scheme I. Three-step asymmetric aldol reaction.
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groups (3). Among other established methodologies for the asymmetric aldol reaction, the Evans oxazolidin-2-one auxiliaries are very efficient and have been used in many asymmetric syntheses, including on an industrial scale (4, 5). The imidazolidinone (4R,5S )-1,5-dimethyl-4-phenylimidazolidin-2-one 1 is structurally very close to the Evans auxiliaries and has been a useful chiral auxiliary for numerous asymmetric transformations such as aldol, dynamic kinetic resolution, cycloaddition, alkylation, cross-coupling, cyclization, and protonation (6–13). This auxiliary is easily prepared in a one-step procedure from readily available materials, (−)ephedrine hydrochloride and urea (14–16). Here we present a simple optimized protocol based on reported literature (16) that allows the students to examine asymmetric methodology by performing one asymmetric aldol reaction in three steps (Scheme I): synthesis of the chiral auxiliary (step 1); attachment of the chiral auxiliary to the aldol substrate (step 2); and aldol reaction via in situ formation of the corresponding boron enolate (step 3). The optimization of the experimental protocol was done to make the experiment feasible in an undergraduate laboratory environment and also to minimize the use of organic solvents, silica gel for chromatography, and waste aqueous solutions for the normal workups, which is an important issue in the context of more sustainable chemistry. Additionally, the first step is also an example of one transformation performed in a solventless fashion. This three-step experiment is intended for upper-division undergraduate students currently learning advanced organic chemistry. We believe that this is a good experiment for small classes or assigned as a project for a single group of students to further explore the reaction. Each step of the experiment can be performed in a 3–4 hour period in a normal organic chemistry laboratory. Depending on the background of the students, the instructor can also use this experiment to (i) rationalize the reaction mechanism in each step; (ii) apply 1H, 13C, and 2D NMR techniques for structural analysis, and (iii) determine the diastereomeric ratio of the products by 1H NMR or by HPLC using a normal silica stationary-phase chromatographic column instead of the expensive chiral columns necessary for the analysis of the enantiomeric ratio for aldol products where no chiral auxiliary is used. Depending on the experimental conditions available in the laboratory, the diastereoselectivity can be determined either by 1H NMR or HPLC or using both methods.
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Overview of the Experiment We chose (4R,5S )-1,5-dimethyl-4-phenylimidazolidin2-one 1 as the chiral auxiliary because it is commercially available1 but can also be prepared by the students in a single reaction by fusion of urea and (−)-ephedrine hydrochloride using the reported procedure (14–16) (Scheme I). This step has also been reproduced in two research laboratories more than 20 times in different scales (2–20 g) and by different researchers giving the product 1 in yields in the range of 30 to 50%.2 The other minor side product, observed by TLC and crude 1H NMR, is the corresponding oxazolidin-2-one formed in less than 25% yield. This step is also interesting from the pedagogical point of view, since it is done in a solventless fashion. This is possible because urea melts at 133 ⬚C and works as both reagent and solvent. Typical student yields are 30–40%. The chiral auxiliary 1 was then coupled with isobutyryl chloride in the absence of base following the reported procedure (17) to yield 2. The literature (17) describes a laboratory procedure using an inert atmosphere; however, our laboratory does not have an inert gas line in the fume hood, so we had to adapt the protocol to our conditions. Our students successfully performed the reaction using a large excess of acid chloride (3 equiv) and by refluxing in acetonitrile for 3 hours (76% yield). The reaction is also possible in higher yield (95%) using smaller quantities of acid chloride (1.7 equiv) under reflux for longer periods (24 hours), but this can not be recommended owing to safety considerations. Finally, the aldol reaction was performed using benzaldehyde and dibutylborontriflate under experimental conditions adapted from the reported ones (16). This is certainly the most interesting and versatile step of the overall experiment since the instructor may choose to run this step at different temperatures to study the effect of the temperature in the selectivity. Additionally, other substrate combinations are possible, but benzaldehyde and the isobutyryl group have the added benefit that no elimination is possible and only one chiral center is generated, allowing an easier purification, identification, and diastereomeric ratio determination of the reaction products. Under the simplest conditions (ice bath and using benzaldehyde) students got 80% yield with a diastereomeric ratio of 86:14. Hazards (−)-Ephedrine hydrochloride is harmful if swallowed, inhaled, or absorbed through skin and it may cause irritation to eyes, skin, mucous membranes, and upper respiratory tract. Dichloromethane causes irritation to eyes and skin. Excessive inhalation of vapors can cause nasal and respiratory irritation. Dichloromethane can cause GI irritation if swallowed and is a probable human carcinogen. MgSO4 dust can cause eye and skin irritation. Acetonitrile and ethyl acetate are flammable and may cause CNS depression on inhalation. CaCl2 dust is an irritant by inhalation and on contact with the skin, it also causes transient corneal injury
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on contact with the eyes. Isobutyryl chloride is an irritant, corrosive, flammable, and water reactive. n-Hexane is flammable, an irritant to the respiratory tract, and causes CNS depression in high concentrations. Dibutylborontriflate is highly flammable, toxic by inhalation, in contact with skin or if swallowed, causes burns, and has shown mutagenic activity in laboratory tests. Triethylamine has an irritating odor, causes eye and skin burns, and possible respiratory system and GI tract burns. Benzaldehyde may cause allergic reactions in contact with skin. Hydrogen peroxide is a strong oxidizer, corrosive and causes burns. Conclusion The overall experiment allows the students to experience real-world asymmetric synthesis and also allows a better critical comparison of the advantage and disadvantage of this chiral auxiliary-based methodology with other asymmetric methods such as chiral catalysis. Students also have the opportunity to rationalize the observed stereoselectivity of the aldol reaction and the retention of configuration during the formation of the chiral auxiliary 1 as well to learn and validate their spectroscopic interpretation skills by fully characterizing all isolated compounds using IR, 1H, 13C, and 2D NMR. If HPLC is available in the laboratory, the students can also determine observed diastereomer ratio by HPLC using a routine silica solid-phase column and organic eluents. Additionally, one step is performed in a solventless fashion and the experimental procedures were developed to reduce the used chemical resources and to minimize the waste chemicals. Acknowledgments We would like to acknowledge the undergraduate students of the chemistry course at Department of Chemical Engineering, IST-UTL for testing this experiment, the Department of Chemistry of FCT-UNL for providing some of the laboratory and NMR facilities, and Fundação para a Ciência e Tecnologia and FEDER (Ref POCTI/QUI/42983/ 2001 and POCTI/EQU/35437/1999) for the financial support. WSupplemental
Material
Detailed procedures of each step, notes for the instructor, sample spectra, and sample HPLC chromatograms are available in this issue of JCE Online. Notes 1. The chiral auxiliary (4R,5S )-1,5-dimethyl-4-phenylimidazolidin-2-one is commercially available from Aldrich (reference 38,217-5) and Fluka (reference 41412). 2. For some additional experimental comments and details for the preparation of (4R,5S )-1,5-dimethyl-4-phenylimidazolidin-2-one, see: Mistry, M. SyntheticPage 2001, 67; http://www.syntheticpages.org (accessed Jun 2006).
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In the Laboratory
Literature Cited 1. Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; WileyVCH: New York, 2000. 2. Atkinson, R. S. Stereoselective Synthesis; John Wiley & Sons: Chichester, United Kingdom, 1995. 3. Smith, M. B. Organic Synthesis, 2nd ed.; McGraw-Hill: New York, 2002. 4. Evans, D. A.; Kim, A. S. Handbook of Reagents for Organic Synthesis: Reagents, Auxiliaries, and Catalysts for C-C Bond Formation; Coates, R. M., Denmark, S. E., Eds.; John Wiley & Sons: 1999; pp 91. 5. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3–12. 6. Roos, G. H. P. S. Afr. J. Chem. 1998, 51, 7–24. 7. Kim, T. H.; Lee, G.-J. Tetrahedron Lett. 2000, 41, 1505–1508 and references cited therein. 8. Candeias, S. X.; Jenkins, K.; Afonso, C. A. M.; Caddick, S. Synthetic Comm. 2001, 31, 3241–3254 and references cited therein.
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9. Caddick, S.; Parr, N. J.; Pritchard, M. C. Tetrahedron Lett. 2000, 41, 5963–5966. 10. Caddick, S.; Afonso, C. A. M.; Candeias, S. X.; Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.; Santos, A. G.; Treweeke N. R.; Weaving, R. Tetrahedron 2001, 57, 6589–6605. 11. Caddick, S.; Parr, N. J.; Pritchard, M. C. Tetrahedron 2001, 57, 6615–6626. 12. Powers, T. S.; Wulff, W. D.; Quinn, J.; Shi, Y.; Jiang, W.; Hsung, R.; Parisi, M.; Rahm, A.; Jiang, X. W.; Yap, G. P. A.; Rheingold, A. L. J. Organometallic Chem. 2001, 617–618, 182–208. 13. Pohmakotr, M.; Soorunkram, D.; Tuchinda, P.; Prabpai, S.; Kongsaeree, P.; Reutrakul, V. Tetrahedron Lett. 2004, 45, 4315– 4318. 14. Close, W. J. J. Org. Chem. 1950, 15, 1131–1134. 15. Roder, H.; Helmchen, G.; Peters, E.–M.; Peters, K.; Schnering, H.–G. Angew. Chem., Int. Ed. Eng. 1984, 23, 898–899. 16. Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. Chem. Ber. 1993, 126, 2663–2673. 17. Clark, W. M.; Bender, C. J. Org. Chem. 1998, 63, 6732–6734.
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