A New Philosophy for Teaching Advanced Organic Chemistry Representative Laboratory Experiment: Stereoselective Reduction of a Chiral lminium Ion Richard P. Polniaszek Duke University, Durham. NC 27706 Organic chemical research during the past three decades has resulted in the development of a vast array of reazents that are capable of effecting very selective functional Goup transformations. Concurrent with the intellectual advances associated with this research have been sienificant technical advances in performing chemical react& at the bench. Thus, introductory organic chemistry texts describe deprotonation reactions effected with lithium diisopropylamide (LDA) and conjugate addition reactions with Gilman reagents (lithium dialkylcuprates). Both of these reagents must be prepared and manipulated under dry, oxygen-free conditions. At the sophomore level, students get very little feel for the technical problems associated with using these reagents. Recognizing these facts, we recently developed a new third-semester organic chemistry class at Duke. The emphasis of our curriculum is to introduce undergraduates at the juniorlsenior level to the recent technical advances associated with manipulating moisture- and air-sensitive reagents. A secondary goal of our program is to acquaint the student with contemporary methods of product analysis: HPLC and capillarv GC methods with numerical chromatographic - . an&& provided by a Hewlett-l'arkard integrator. The chemistry chosen LO serve as a vehicle fur providing the necessary experimental framework is both intellectuall; and practically significant. The students are introduced to LDA. enolate chemistm. .. and the field of asvrnmetric svnthesid by prepnringand alkylating (4H,5S)-norephedrineoxazolidinone rooi ion ate. the Evanschiralenolate svnthon ( 1 ) . In the area of oiidatiod, the students prepare a racemic seidndary allylic alcohol and perform an asymmetric epoxidationl kinetic resolution by the Sharpless method (titanium tetraisopropoxide, t-butyl hydroperoxide, (+)-diisopropyltartrate) (2).Another series of experiments illustrates the use of metal hydride reagents and involves diastereoselective reduction of a chiral iminium ion (3). The emphasis of our course differs philosophically from the more traditional approach of qualitative organic analysislstructure determinationlanalysis of unknowns. We do, however, provide a solid introduction to spectroscopic methods of analysis, and the student is required to assign mass, infrared, high-field (300-MHz) and low-field (60-MHz) NMR spectra of each compound he or she prepares. Lectures on spectroscopy are presented after laboratory check-in (week 1)and during extended periods of reflux (cf. horane reduction) or reaction. We do recognize that our program is quite ambitious and requires a highly coordinated effort of teaching assistant and instructor. However, the course reflects con&mporary organic chemistry as it is practiced in 1989. The training that our course provides allows the student immediately to begin an independent study research project andlor feel at ease in any research-oriented graduate curriculum in the country. 970
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We maintain that our initiative fulfills the requirements of advanced undergraduate chemical education set forth in the Pimentel report (4). The experiments do require an environment including solvent stills and nitrogen lines. We have converted an undergraduate laboratory into such an environment at very low cost using Swagelock fittings and valves and 114-in. copper tubing. An ISCO HPLC unit and a Hewlet-Packard 5890 gas chromatograph were also acquired as quantitative analysis tools. This investment was richly rewarded by the overwhelming positive response of the 10 students who were enrolled. The following five-step reaction sequence represents experiments 9-12 in our Chemistry 154 course.
The chemistry involves incorporation of S-(-).a-phenethylamine into a cvclic iminium ion. The chiral. acvclic side chain creates different steric environments onkach diastereoface of the iminium ion (eq 1).The iminiumion is attacked by sodium borohydride on its least hindered face, affording a 91:9 mixture of diastereoisomers (eq 2). The ratio of diastereamers may be measured by HPLC on a silica HPLC column with UV detection, or the resulting mixture of diastereoisomers may be hydrogenolyzed to the natural product (-)-salsolidine. The original ratio of diastereoisomers (D1:Dd may be assayed by comparison of the specific rotation of the hydrogenolysis products to the value for (-)salsolidine (5) [ a ]= ~-59.5O (c = 4.39, EtOH). water
sidearm stopcock
Figure 1. Solvent still tor preparing dry solvents.
organ~clayer with 5% NaHCOx solution, separate, and dry over anhydrous sodium sulfate. Filter the mixture, and remove solvent on the rotary evaporator. Recrystallize the solid from hot ethyl acetatehexme. Yields range from 6&8090, mp 107-109 "C.
Borane Reduction. Preparation of (S)hC[2(3.4-DimethoxyphenylJethyl]1-(phenylJethylamine
-
The aim of this series of experiments is to stress state-ofthe-art techniaues a n d instrumentation for conductine svnthetic reactions. Thus, the s t u d e n t is introduced t o opeiatina routinely in dm elassware under an inert a t m o s ~ h e r e . pirificationbfinte;&ediates hy flash chromatograph;, and analysis of reaction products by HPLC and optical rotation.
Preparation of (S)+ acetamide
I-PhenylelhylJ-2,~3,edimethoxyphenylJ-
AU glassware must be oven dried and cooled in a desiccator. Weight out 4 g of 3,4-dimethoxyphenylaeeticacid, and pour it into a 50-mL single-necked, round-bottom flask, through a dust funnel. Add a stir har, stopper your flask with a rubber septum, add 3 mL of neat thianyl chloride to the solid 3,4-dimethoxyphenylacetic acid, and place a drying tube filled with Drierite atop the flask. Begin to stir the mixture. The solid eventually dissolves, with the formation of bubbles (HCI gas). Let stir for 2 h. During this time, charge a dry, 250-mL single-necked, round-bottom flask with (S)-(-1-a-phenethylamine (2.22 g), 4-dimethylaminopyridine (200 mg), and a stir bar. Attaeh a rubber septum, purge the flask with nitrogen for 5-7 min. and estahlish a oositive nressure of nitroeen. Add to this flask dry diehloromethan; (120 m i ) , and then add neat trietbylamine (2.6 mL) to the solution. Begin to stir the solution, and cool in an ice bath. Dry dichloromethane and triethylamine are freshly distilled prior to usefromthe appropriate drying agent in aspecially designed still. Dry solvent or reagent is removed from the stillhead by syringe. A typical solvent still which maintains freshly distilled solvent under an inert, dry atmosphere and allows solvent removal through a sidearm sto~cackin the receiver bulb is nresented in Fieure 1. After 2- h:the aietvl chloride isreadv. De~~, 3.4-dimethoxvnhenvl ~, tach ihedryinbrrube,andremovethertirh'rfrom the flaskwihthe plastic stir bar retriever. Attach the flask to the rotary evaporator. in the hood, and rotary evaporate the sample for 5-7 min. When finished, place a rubber septum on the flask. Establish a positive pressure of nitrogen in the flask, and dissolve the residue in 30 mL of dry dichloromethane. Pierce one end of a cannula into this flask, and the other end into the 250-mL singlenecked flask. Shut off the nitrogen supply to both flasks, and suhmerge the needle of the cannula below the level of the liquid in the 50-mL flask containing the acid chloride. An illustration of this cannulation technique is presented in Figure 2. Open the nitrogen valve leading to this flask, and slowly cannulate the acid chloride solution into the ice-cold a-phenethylamine solution (dropwise!). Upon completion of addition, remove the ice bath, and let the solution stir for 1h. Pour the solution onto aqueous 5% HCI, and pour the resultant mixture into a separatory funnel. Separate the layers, saving the lower dichloromethane layer. Discard the aqueous layer. Wash the ~~~~
..
.
Figwe 2. lllystratlon of me cannulation technique
Charge a dry 100-mL single-necked, round-bottom flask with a magnetic stir bar and the amide substrate(600 mg). Attach a reflm condenser, place a rubber septum atop the reflm condenser, and purge the flask with nitrogen. When finished purging, establish a positive pressure of nitrogen above the reaction vessel. An example of such a reaction vessel is presented in Figure 3. Carry the 10-mL syringe equipped with s 12-in. needle to the THF still, and remove 10 mL of THF. Transfer the THF to your reaction vessel by piercing the septum in the reflux condenser, carefully lowering the needle into the round-hottomed flask, and addine the THF solvent. Withdraw the needle. and rinse the svrinae . with Getone in the hood. Attach a water inlet and outlet to the reflux condenser, and begin cooling it with a slow stream of water. Using a 1-mI. syringe equipped with a 12-in. needle, withdraw 0.25 mL of BF3-Etz0 from the reagent bottle in the hood. Transfer the BF3-Et20 to your reaction vessel by piercing the septum in the reflux condenser, carefully lowering the needle into the round bottom flask and adding the reagent. Remove the needle, and carefully rinse with acetone in the hood. Sumund the flask with an oil bath, begin stimng, and heat to gentle reflux (bath temperature of 70 OC). Carry your 5-mL syringe equipped with a 12-in. needle over to the hood, and remove 5 mL of the borane-THF stock solution (1 M)from the reagent bottle. Carefully pierce the needle atop the reflux condenser of the reaction vessel, lower the needle to the area just below the neck of the 100-mL flask, and add the BHa-THF solution dropwise. Withdraw the needle, clean the syringe and needle in the hood with acetone. Reflux the reaction mixture for 2.5 h. Cool the solution to room temperature, and remove the septum and nitrogen inlet. Carefullyadd, in adropwise manner, 15mLof 4.5 N HC1, with stirring. The initial reaction is quite vigorous. Upon completion of this addition, stir for 30 min. Remove the stir bar with a stir-bar retriever, and place the flask on a rotary evaporator to remove the THF. Spin the tlask rapidly, to help avoid bumping. Add 30 mL dichloromethane, 20 mL of water, and pour into your 250-mL seoaratorv funnel. shake. and discard the lower dichloromethane layer. PO& the aqueous layer into your reaction flask, add a stir bar, and cool in an ice bath. After 5 min, begin adding solid
water out
water in
Figure 3. Apparatus employed faboane redunion of the chid amide
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KOH in portions. (Heat is generated, be careful.) From time to time, check the pH with litmus paper. When you reach pH = 13, add 40 mL dichloromethane, pow into your (clean) 250-mL separatory funnel. shake. and drain the Lower dichloromethane laver into a 250hl. ~ i e n m e y e rflask. Extract the aqueous phase wlth additional dichloromethane (2.5 mL), and dry the rombined organic extracts over anhydrous sodium rulfate. Spot some of thissulution on ananalyticalTLC plate, develop the silica gel plate with 298 Me0H:EtOAc. The product is UV active and h& anR,of 0.1. Your product should he "one spot by TLC". Filter the mixture into a sinde-neck, round-bottom flask, and remove solvent on the rotarv evskratar. Purifv the residue hv flash
.. . .
.
Bischler-Ne~ieralsklCycllzation, NaBHd Reduction. Preparation of l-~eth2-2((1s)-l-phenylethyd-6,7dimethoxytehahydroisquinoline
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Port 1: Bischler-Naoieralski Cvelizotion. Weieh out 1W me of the amide suhstrate in ;dry 10-mfsingle-neck,round-bottom fl&k. Add a Teflon stir condenser. ~ . -~~~har. ~ -, attach ~ a reflux . ~ ~. olace a ruhher septum atop the reflux condenser, and purge the vessel with nitrogen for 5-7 mi". Establish a positive pressure of nitrogen above the flask. Sequentially add 2 mL of dry benzene and 1 mL of POCl, to the flask. Surround the reaction flask with an oil hath, begin stirring, and reflux for 3 h. Use this "free time" to obtain any needed physical data (IR,NMR, mp) on your previously prepared reaction products. Remove the oil hath, cwl the flask to room temperature, and remove the stir bar with the plastic stir bar retriever. Remove the volatile solvent on a rotary evaporator i n the hood. Place the flask an the high vacuum rotary evaporator, and after 5 min heat the flask gently with a heat gun. (This is required to remove the Last traces of POC13 from the iminium ion.) After 10 min remove the flask from the high vacuum rotary evaporator. Port 2: Stereoseleetiue NoBHn Reduction. Add a magnetic stir bar to the flask, seal with a ruhher septum, and purge with nitrogen. Establish a positive pressure of nitrogen ahove the iminium ion, and add 2.5 mL of dry methanol by syringe. Surround the flask with a dry iceacetone hath. After 5 min add solid NaB& (25 mg). After 15 min add a second portion (25 mg) of NaBH4. Let the mixture stir at -78 OC for 30 min, remove the cold hath, and add 40 drops of 10% HCI. Remove the stir bar with the stir bar retriever, and place the flask on the rotary evaporator (to remove methanol). After removing the flask from the rotary evaporator, add water (3 mL) and surround the 10-mL flask with an ice hath, and while stirring, add solid KOH Figure 4. Apparatus required fw flash chromatogaphy. until pH = 13. Then add dichloromethane (5 mL), transfer the mixture to a small separatory funnel, wash the raund-bottom flask with an additional 10 mL dichloromethane, add to the separatory product in a round-bottomed flask, and remove solvent on the funnel, shake, and drain off the lower diehloromethane layer into an rotary evaporator. You should obtain a dear oil. Yields range heErlenmeyer flask. Reextract the aqueous layer with dichloromethtween 60 and 90%. [u]n= -38.9 'C (e = 1.7, CH&). ane (25 mL), combine the organic extracts and dry over NasS01. Filter the mixture into a tared, single-neck round-bottom flask, and remove solvent on the rotarv evaoorator. The vield of the Acetic Anhydride Acylation. Preparation o f (3-N[ l~Phenyl)ethyl]-N-[2~3,~'imethoxyphenyl)ethyl]acetamide ""purified resetitrn product should be 7695%. Preparean HPLC rampleof an aliquot ofyour product. Obtain an HPLC rhromatopaph of your unpurified sample using 40:40:20 ethyl acetate:hexsnr:iuuprupi(nvl as sulvrr~tsystem, urr a 6-ulu4.;mm X 25-cm silica column. The CV detector may be set at 254 nm. The selectivity uf the hydride reduction should be on the order of
~~
~
~~
eluant. Flash chromatography iscarricdout according 11, the general procedure of Still ( 6 ) .A typical column and reservoir required for flashchromatography appears in Figure 4. Combine frartionk of the
Charge a dry 25-mL single-neck round-bottom flask with the m i n e substrate (300 mg),4-dimethylaminopyridine (30 mg) and a stir har. Seal the flask with a rubber septum, and purge with nitrogen for 5 min. Establish a positive pressure of nitrogen ahove the reaction mixture. Add sequentially 10 mL of dry diehloromethane followed by 0.12 mL of freshly distilled triethylamine to the reaction vessel. Surround the reaction vessel with an ice-water hath, and begin stirring the solution. After 5 min, add 60 pL of acetic anhydride slowly and dropwise tothe reaction mixture. Upon completion of this operation get another 60 pL of acetic anhydride, and repeat the process. After 1.5 h, quench. Quenching in this case simply means rotary evaporating the sample to a small volume, placing the concentrated dichloromethane solution atop a flash column of Silica-Gel, and eluting. "Wet pack" a 2.5-cm flash chromatography mlumn with SilicaGel, using 298 methano1:ethyl acetate as eluant. Place your sample atop the column, and flash chromatograph the sample with 298 Me0H:EtOAc. Combine fractions containing product in a tared, single-neck, raund-bottom flask, and remove solvent on a rotary evaporator. Yields range from 55 to 90%.
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Journal of Chemical Education
~
~~~~~
~~~
~~
~
~
~
.
Charge a 10-mL round-bottomed flask with a Teflon stir bar, 1Wo palladium on carbon (35 mg), ethanol (2 mL), and 10% HC1 (30 drops). Stopper the flask with a rubber septum, begin stirring in the hwd, and briefly purge the flask with hydrogen (contained in a balloon and introduced to the flask through a needle connected to the balloon). Prereduce the catalyst for 1h by stirring the mixture under the balloon filled with hydrogen. Then add a solution of the m i n e (75 mg) in ethanol (2 mL) via syringe. The reaction is monitored by removing aliquots of the reaction mixture with a 50-pL syringe, spatting on an analytical TLC plate, and developing the Silica-Gel plate with 50:50 ethyl acetakhexane. A typical hydrogenolysis requires 2 h. When the reaction is complete, filter the
mixture through s small pad of Celire, runcenrrnte the solution, and add 2 mL of water and 2 mL of dichloromethane. The mixture is hasified with solid KOH t o pH 13 and extracted with dichluromethane, and the extracts are dried (NanSOa),filtered, and concentrated. This process affords an ail. The specific rotation of a sample prepared by this sequence should have a value near [& = -51.2' (c = 2.1. EtOH). This corresoonds to a ratio of DI:D* . .of 937. Acknowledgment
Support Of this work by the Duke University Research is gratefully We greatly appreciate
funds provided by t h e administration of Duke University for t h e purchase of equipment t h a t made Chemistry 154 possi. hl, Lllerature Clied Evans, D. A.
2. ~ s r t i nv. . s.: wmdard. s
IJ8Z,15, 2332.
8.: ~ a b u k iT.: . yamads: Y.: lkeda. M.: Shamless. K. B. J. Am. Chem. Soe. 1981; 103,62374240. 3. Pdniaszek, R. P.; McKee J. A. Tetmhedmn Left. 1981,%9,45114514. 4. Pimentel 0 ,Chairman. Opportunities in Chamisfry;National Academy: Washington, DC, 1985:pp 28S287. 5. Betternby, A. R.;Edwards, T. P. J. Chom. Soe. 1960,1214-12Z1. 6, Still. W. C.:Kahn, M.:Mibe, A. J. Or& Chern. 1S18.43.2923-2925.
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