Microscale Organic Laboratory IV. A Simple and Rapid Procedure for Carrying Out Wittig Reactions R. M. Pike1, D. W. Mayo, S. S. Butcher, D. J. Mcher, and R. J. Hinkle Bowdoin College. Brunswick, ME 04011 The Wittie reaction has been extensively em~lovedin synthetic organic chemistry following its di&oveiy ih 1953 (1,2). The transformation involves the conversion of certain carbonyl functions to olefins, generally without isomeric product formation. As an undergraduate laboratory preparation, the Wittig reaction, which employs an unstable ylid reagent, is relativelv The reaction reouires a time-consumine , so~histicated. . preparation of the ylid precursor, an alkyltriphenylphosuhunium halide (the Wittir Rcaecntl. .. followed hv treatment kith either phenyl lithium or a freshly sodium metal alkoxide in drv ether under an inert atmos~here.For~ base rpquires handling significant quanmation ol t h latter tities of yodium metal at the introductorv le\,el. Alternatively, the Horner-Emmons "phosphonate modification", a procedure limited to phosphonium halides derived from reactive halides (allyl, etc.) has been employed ( 3 , 4 ) .This latter approach has the advantage that the initial phosphonium halide formed, as the result of the reaction of a trialkylphosphite with the active halide (for example benzyl chloride). undereoes elimination of an alkvl chloride. to vield a dia~k~lbenz$~bos~honate. This 1atte;product is aiistable and will undereo a Wittie t w e condensation in strone base with carbonyl Gmpounds toiield olefins. T o our kno&edge all preparation of ylids from phosphonium salts even in the most favorable cases appear to involve minimum reaction times of an hour. Usually several hours are required to achieve optimum yields. Currently, the Wittig reaction, as described in five organic laboratory manuals, involves one of or both of two similar preparations employing the Horner-Emmons modification (5-9). In every case these procedures utilize benzyltriethylphospbonium chloride as the intermediate in route to diethylbenzylphosphonate. Thus, in all cases the starting material required for the ylid generation is benzyl chloride, a potent lachrvmator. This is a less-than-satisfactom choice for use in an undergraduate laboratory in the large quantities ouoted. Successful -vlid eeneration even em~lovinethe mod&ed route continues to require a freshly prepared sodium alkoxide (unless a phase-transfer system is employed (10)).
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Procedure Recently Schlosser and Schaub (11) have established that alkyltriphenylphosphonium bromides form stable dry mixtures with sodium amide, which may be stored indefinitely.% Addition of T H F or diethyl ether t o the mixture rapidly (15 min) generates the desired ylid. Condensation with aldehydes, ketones, or formates yields the expected olefinic ~ r o d u cusuallv t in excellent vield. Furthermore. the reaction system need n i t be purged with an inert gas. simple drying tubes will suffice to Drotect the reactine medium from moisture. We have explored the utility of the Schlosser-Schaub saltbase mixtures, the "instant ylid" reagents, for incorporation in the microscale organic laboratory program (12). This study has resulted in preparing an interesting variety of products which can be successfully obtained via these reagents a t the microscale level. Two examples that illustrate this new synthetic method
are given below. The first example utilizes an isopropyltriphenylphosphonium bromide-sodium amide reagent. The isolated compound, 4, is a substituted isomer of isosafrole, belonging to the class of compounds known as "essential oils". This isomer, 4, has the odor and color of the other members of this series. Safrole. the oarent member. is the chief constitutent of the "oil of sissaf;as7'. The second example utilizes a steroid derivative and illustrates the formation of an exocyclic methylene unit. This synthesis, to our knowledge, is the first feasible preparation of this particular group available for the introductory organic laboratory.
Experimental Preparation of 1,2-Methylenedioxy4(2-methylpropenyl)benzene, 4
An oven-dried 5.0-mL conical reaction vial containing a magnetic spin vane and equipped with an air condenser protected with a calcium chloride dryingtube was charged with 750 mg (-1.73 mmol) of the "instant ylid" mixture, 1. Freshly distilled dry tetrahydrofuran (1.0 mL) was added and the mixture stirred at room temperature for 15 min. During this time the reaction medium acquired an orange-brown appearance. After addition of 150 mg (1.00 mmol) of piperonal(3, mp 37 "C) to the ylid, the reaction mixture was stirred for an additional 15 min at room temperature. During this period the system becomes lighter in color. The reaction was quenched by the addition of 1.0 mL of 25% aqueous NaOH solution and the resulting mixture transferred to a 12-mL centrifuge tube hy means of a Pasteur pipet. The reaction vial was rinsed with two 1.0-mL portions of ether and the rinsings also transferred to the centrifuge tube. The ether layer was separated (Pasteurfilter pipet) and placed in a 25-mL Erlenmeyer flask. The remaining aqueous layer was extracted with three additional 5.0-mL portions of ether and the extracts combined with the original ether layer. The combined ether solution was dried by passage through a short microcolumn (constructed from aPasteur pipet and a prewashed cotton plug) containing 1.5 g of anhydrous sodium sulfate. The dried eluate was collected in a 25-mL Erlenmeyer flask containing a boiling stone. The crude product, obtained as a yellow oil on evaporation (caution: a hood should be used) of the solvent under a stream of dry Nz, was diluted
' Visiting Charles Weston Pickard Professor of Chemistry, Spring 1984.
A variety of Wittig Reagents prepared by this route may be obtained from Fluka Chemical Corp.. 255 Oser Avenue, Hauppauge, NY 11788.
Volume 63 Number 10 October 1986
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with ligroin 1:l and initially loaded on a basic A1203(1.0 g) microchromatographiccolumnpremoistened with 2.0mL of ligroin. (In this, and all subsequent manipulations, ligroin (60-80 O C ) was used.) Elution occurs directly with 4 mL of 8:2 IigroinlCHzClz. A second chromatogram of the partially purified residue obtained from the concentration of the initial eluate, is carried out on 0.5 g of (activated) basic alumina premoistened with 1.0 mL of ligroin. The residue was dissolved in 1 mL of ligroin and applied to the top of the second microcolumn. This application was followed by a 1.0 mL ligroin rinse of the residue vial. Elution then occurred directly with 5 mL of ligroin. Removal of the solvent (caution: a hood should be used) under reduced pressure gave the expected olefinic product, 4, without further purification. Auerage student yield: 72 mg, 43%,hp 255 O C ; noz0 1.5603; (lit. hp 252-254 OC). Preparation time: -4.5 h. Standard infrared spectre are availahle from Bowdoin College on request.
150 mg (0.49 mmol) of 3-keto-17@-hydroxy-l7ar-methyl-5n-androstane, 8, the reaction mixture was stirred for 90min at room temperat ~ r eDuring . ~ this latter period the reaction medium developed a tan color. The reaction was quenched with 1.0 mL of 25% NaOH solution and the resulting mixture transferred to a 12-mL centrifuge tuhe (Pasteur pipet). The reaction vial was rinsed with three 2.0-mL portions of diethyl ether. The washings are also transferred to the centrifuge tuhe. The resulting two-phase system was then partially neutrallized by the careful addition of 3.0 mL of 0.2 N HCI. Following extraction and drying of the ether layer as described in the previous experiment, removal of the solvent (caution: a hood should he used) produced a white solid product, 8, which was recrystallized from 95% ethanol. Aueroge student yield: 90 mg, 60% mp 175-177 ' C ; (lit. mp 179-181 OC (14)). Preparation time: -3.5 h. Infrared comparison peak values are given in ref 14 and standard spectra are availahle from Bowdoin College on request.
Discussion T h e Schlosser-Schaub "instant vlid" reaeent makes available for the first time a practical system-for demonstrating in the undergraduate laboratory the great utility of Wittig reagents. While the ease of handling these new reagents greatly enhances their practicality in the student laboratory, the rapid generation ,of the ylid is perhaps the most important property which they possess. Thus, i t now b e ~ o r n e ~ ~ o s stoi bcondense l~ these reagents with aldehydes and ketones and isolate and -purify most reaction products in a single four-hour laboratory period. Of particular interest to us has been the observation that the "instant ylid" approach is conveniently incorporated into microscale laboratory experiments. ~
Literature Clted (1) Maarksr,A. 0w.Reort.
Employ the same procedure as used above in thegeneration of the "instant ylid". The reaction vial was charged with 320 mg ( 4 . 7 2 mmol) of the "instant ylid" mixture, 5. The ylid, 6, was generated in 1mL of THF to give a bright yellow salt. Following the addition of A varlety of steroidal compounds suitable for Wittig reactions may be obtalned from Steraloids. Inc., P.O. Box 310. Wikon. NH 03086.
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Journal of Chemical Education
1965,14,270.
(2) Sehollkopf,U."Newer Methdod of PreparpartiiiO~ganiiChsmistry~F~t, W.,Ed.; Academic: New York, ISM: Vol3. pp 111-150. (3) Wadsworth, W. S.:Emmons, W. D. J.Am.Chem.Sac. IW1,83,1733. (4) Homer. L.;Hoffman, H.; Wippd. H. 0.Chem. Ber. l96491.61. (5) A u k A. "Techniques and Ex~erimentafor Chemiatrv". AUm and . . 4th d.; earon: B W ~ism; , p 444. (6) Durst, H. D.: Gokel, G. W. "Experimental Organic ChemisUy":McCrsw-Hik New York, 1981: p 473. (7) Fieser, L. F.;Williamsul, K. L. "Organic Experiment.", 5th ed.: Heath: Lexington, MA. 1983:p 226. (9) Jacob. T. I.:Truce, W. E.; Robemn, G. R. "Laboratory Practice of Organic C h c miam",5th ed.: Macmillan: New Yo*, 1971: p 331. (9) Wilcox, C. F.. JI."Experimental 0rganicch.miaVy-Th~h'y and Practice'';MaunilIan: New York, 1994 p 287. (10) Gilbis, J.; Guillsrm, G.;Sad-. M : Stephan, E.; Vo.Quang, L. J. Chem. Edu. ,as" s7
>&,
(11) Sehlosser, M.: Sehauh, B.Chimieo 1982.36.596. (12) Mayo.D.W.;Butche~,S.S.:Pilre,R.M.;Fwte.C.M.;Hotham.J.R.:Pape.D.S.J. Cham. Edu. 1985.62.149.
(13) Muxhimki.D. W. Chem.Zontro1.1302,11,119. (14) Evana, D. D.; Evaar, D. E.; k w h , G.S. J. Chom. Soe. 1963,4312.
