Heterocycles and Reactive Intermediates in the Undergraduate Organic Lab K. Dean Bowles, David Quincy, Brenda Mallet, John I. McKenna, and N.R. Natale' University of Idaho, Moscow, ID 83843 Although heterocyclic compounds comprise over half the compounds in Beilstein and make up the greater share of ~harmaceuticals.medicinals. and alkaloid natural ~ r o d u c t s ( I ) , they are scarcely touched upon in the average organic textbook. and are eenerallv- ienored in most undereraduate organic courses. In light of our research interest in heterocycles and an interest in bringing relevance to the undergraduate laboratory, we have found that the nitrile oxide cycloaddition (2) with enamines represents a reaction that can easily be incorporated into undergraduate organic laboratories and undergraduate research. This reaction is a widely used method for the synthesis of isoxazoles and isoxazolines (3). The reaction sequence is also useful in illustrating the concevts of reactive intermediates in svnthesis (both enaminesLandnitrile oxides) and frontier m~lecularorbital theory. An important factor in generating student interest in such advanced laboratory experiments is the potential that starting materials produced by their own hands may find use in the research going on in their very own university! We have had great success with this reaction sequence both as an extra credit second semester organic laboratory experiment and as an "ice breaker" and confidence builder for novice undergraduate research participants. Enamines (I) are carhauion equivalents, easily formed from ketones (11)
The resrriun pn~ceedsby nucleophilic artack of the amine (Ill) on the ketone rll~.'l'heresulting retrahedrnl intermediate rlV) is in equilil~riumwith the enamine (I).and watrr. The reaction is driven to complet~onI)? removing the water hv azeotnmic distillation with a Dean-Stark rrav. This is an excellent way to demonstrate the principle of shifting equilibrium bv removine one reaction product, made easy to visualize 6y the collection of water droplets. ~ n a m i n e a( 4 ) have found such wide use in organic synthesis that they are co\,ered in most undergraduate organic chemistry textlwoks. For underrraduare urzanic chem:stry laboratories, howe\,er. the sensit&ity of enamines to air often discourages their use. We have found that by a modification of the method of McMurry ( 5 ) ,enamines can be generated and utilized in the nitrile oxide cycloaddition reaction without direct isolation. Thus, no special equipment is necessary other than that normally available to the undergraduate lab. The nitrile oxide cycloaddition
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continues to find new applications in synthesis (3) and remains a lively source of mechanistic controversy (6). The reactive nitrile oxide (V) is generated insitu by the dehydration of nitro ethane. Reaction with the enamine (I)gives the isoxazole (VI) in good yields after isolation and purification. A type of 1,3-dipolar cycloaddition, this single reaction can be used to introduce heterocyclic chemistry, frontier Molecular orbital theory, dianion intermediate alternatives and healthy skepticism to the advanced undergraduate student all in one laboratory period! The camps in the mechanistic controversy can be divided in to the followers of Huisgen the concerted and Firestone the radical. If the nitrile oxide cycloaddition is considered a concerted process (7),the orbital symmetry of the process can be depicted as MeOCO R-CEN-4
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The bond forming takes place by overlap of the highest occupied molecular orbital (HOMO) of the nitrile oxide (which is approximated by the use of the allvl anion orbital symmetry) and the lowest unoccupied molecular orbital (LUMO) of the olefin reaction partner (which is a ~ o r o x i mated by ethylene). For a reaition to be concert& the reactants proceed to products without isolable or detectable intermediates. Huisym's arzument is based upon the exrellent stereochrmistry obtained from certain examples of the nitrile oxide c\,cloaddition. which he feels is not consistent with a two-step mechanism. If we cunsider [he reaction of nitriie o n d c I\'III with dimerhsl fumarate (\'I111. the conservation of orbital symmetry demands attack ofthe nitrile oxide (VII) in a suprafacial manner on the olefin (VIII). In the transition state, in other words, the p orbital's overlap end-on. Thus, the product (IX) must be obtained in a stereospecific manner. Firestone (8) has argued that certain data are explained more completely by a diradical mechanism, ~
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Author to whom correspondence should be addressed
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Thus side ~ r o d u c t sthat are sometimes produced in this reaction are consistent with radical intermediates. In Firestone's mechanistic scheme, radical coupling of nitrile (X) with acetylene (XI) can proceed to the &ra&cal intermediate (XII) referred to the "cyclo" intermediate. Pairing of the radicals of the "cyclo" intermediate (XII) proceeds to the usual product (XIII). However, the "extended" diradical (XIV) explains the possibility of obtaining the acetylenic oxime (XV), which is sometimes associated with the nitrile oxide cvcloaddition. presenting both sides of a mechanistic pathway allows students to appreciate that the science of organic chemistry is still wrestling with certain questions, and that everything is not already known. This clearly illustrates the fact that there is more to the study of areaction than whether i t works or not. This practice also encourages students to look a t experimental-facts in a discriminating manner, in other words, to think for themselves. A class discussion of mechanistic possibilities serves to reinforce the laboratory experience. T h e nroduct isoxazoles are useful and versatile heterocvcles (9). Many isoxazoles have important biological activity. Isoxazoles have been reported which have anabolic, antituberculosis, antibiotic, anthelmintic, and myolytic activity (10). Analogs of ibotemic acid (XVI) show CNS activity. Analogs of muscimol (XVII) show activity as GABA agouists. T h e antibacterial activity of 5-aryl-isoxazolium salts has been correlated to substituent effects in the aryl group (10). We recently have found that isoxazole dihydropyridines (XVIII) have useful biological activity as calcium entry antagonists (11).
Another common use of isoxazoles exploits their synthetic potential as protected 1.3-dicarhonyl equivalents. Once aeain. the work of Stork and McMurrv is an eleeant exampie. The 1,3-dicarbonyl character of ;he isoxazhe can be unveiled bvreductive cleavaee of thelahile 0 - N bond (2.12). .. . This dicarbonyl can then b e k e d for other reactions, such as intramolecular-aldol condensations.
The keto-isoxazole (XIX) was ring-opened to the tri-ketone (XX) using reductive conditions. T h e tri-ketone (XX) was then subjected to intramolecular-aldol condensation to give the enone (XXI). Thus, the isoxazole performed the role of a masked or protected carbonyl group. In summary, we have found that the nitrile oxide cycloaddition with enamines is feasible for use in advanced undergraduate organic lab be., second semester) or beginning undereraduate research. The reaction illustrates the use of reactive intermediates in synthesis, and represents a good example of hetereocyclic synthesis. The reaction sequence can also be used as a vehicle for the discussion of orbital symmetry, presenting to students alternative reaction mechanisms such as the diradical pathway. We have found this sequence most valuable as a method to reinforce advanced lecture topics with relevant examples and hands-on experience. Experlrnental Ethyl acetoacetate (150 mL) in toluene (250 mL) was placed in a round-bottomed flask (1 L), equipped with a magnetic stir har, Dean-Stark tube, and reflux condenser. This solution was cooled in an ice bath and pyrrolidine (100 mL) was added. The reaction was then heated to reflux until the theoretical amount of water had been collected (2.5 to 5 h). The reaction was allowed to cool (through a drying tube), and the toluene concentrated on a rotary evaporator. The resulting golden oil can he used as is, or further purification can he performed by flash distillation on a Kugelrohr apparatus (110120PC/0.5-0.7 mm Hg). The typical yield is 85-9790. Enamines are moisture sensitive and must be stared under an inert atmosphere or used quickly. The enamine was cooled to O'C, and a solution of nitroethane (100 mL) and toluene was added (this solution had been predried over anhydrous magnesium sulfate and filtered directly into the enamine flask). Triethyl amine catalyst was added (10 mL). An addition funnel was charged with phenyl isocyanate (260mL, 2.38 mol), and added dropwise to a vigorously stirred solution. The reaction mixture was allowed to warm to room temperature overnight, after which time voluminous amounts of yellow solid (diphenylurea)had deoosited. The solid was filtered. washed with ether. and the combined filtrates concentrated on'the rotary evaporator and flash distilled on the Kugelrohr apparatus (70-100DC/1.5 mm Hg). The isoxazole ester was obtained as a yellow oil in -70% yield. This material is of sufficient purity to be taken on to the next step. The isoxazole ester can he redistilled through a Vigereaux column, and the isoxazole ester collected aver a 64-70DCrange (1.5 mm Hg) with most of the product having h.p. 68-69'C. The isoxazole ester ohtained in this manner was a sliehtlv vellow ail. 112.5 e (58%).
Mass Spectrum mlz 169(33% rel. intensity); 141(52); 124(59); 82(72),43(100). We have found it convenient to store the isoxazole as the earboaylic acid. To a 1-L round-bottomed flask equipped with a reflux condenser was added the isoxazole ester (121.1 g, 0.66 mol) and sodium hydroxide (31.2 g, 0.78 mol) dissolved in water (300 mL). The two layers were heated to reflux for 4.5 h, then cooled to room temperature. The resulting solution was washed with chloroform (100 mL, which was discarded), filtered, and the basic aqueous solution rendered acidic by the addition af concentrated HCI at O°C (-55 mL). The white precipitate was washed with chloroform (3 X 250 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in uncuo gave an off-white solid (99.7 g, 99%),crude m.p. 133-139'C. Further purification was effected either by dissolution in a minimum amount of toluene followed by addition of hexane to induce crystallization, or alternatively by sublimation at reduced pressure on the Kugelrohr apparatus (1lO0C 10.45 mm Hg). The purified acid is a white solid with m.p. 141°C. Volume 62
Number I 2
December 1985
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Literature Cited (1) Meyero, A. I., "Hcteroeyele in Organic Synthesis." Wiiey-htersience, New York,
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(2) Stork, G., and McMurry,J. E., J. Amer Cham. Soe., 89,5462 (1967). (3) Grundmsn, C.. Brunsnger, P.. "The Nitrile Oxides." Springer-Vdag, New York, 1971. Recent applications of thin methodology are numerous; some recent highlighu: W8de.P. M.,Hinney, H.R. J . Amel. ChemSoc., I01,1319 (1979);Smith. A. B.. 111. Schow, S. R.. Bloom. J . D., Thompson, A. S., and Winzanburg. K. N., J. Amer. Chrm. Sac.. 104.40l5 (1982): Kozikowski. A. P.,and Stein,P. D., J. Amer. Cham. Soc., 104.4023 (1982): Cuman, D. P.. J. Arne,. Chem Soc., 104,4024 (1982); Kozikouski, A. P., and Adamczyk, M., Tetrahedron Lett., 3123, (1982): Kodkowkni, A. P., Hiraga, K., Springer, J. P., Wang. B. C., and Xu,2.-B., J. Amen Cham. Sac., 106,1645(1984); Houek.K.N.,Moses, S.R., Wu,Y.-D.,Rondon,N. G., Tager, V., Schohe, R., and Franczek, F. R., J . Amsr. Cham Soe., lO6.3880 (19841.
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181 Firertone, R. A,. Tetrahedron, 33,3W9 (1977). (9) For a review on isorazoles, see Wa*efleld, B. J., Wright, D.J.. Ado. Heterncycle Cham..25. 147 (19791. (10) The biological aetivityaf isorazolesiasummarized onpp. 203-204 ofrot (91. (11) Nats1e.N.R.. andQuincy.D.A.,Synth. Commlm., 13,617 (1983). (12) Stork,G.,andLoguseh,E. W., J.Amer. Chem.Soe., 102,1218 (1980);Scott,J. W.,and W.,Borcr,R.,andSaucy,G.. J. Saucy.G., J. Ow. Cham.,37,1652,(1972);Scott,J. Olg. Chem., 37, 1659, (1972): Scott, J . W., Banner, B. L.. and Saucy, G.. J. Org. Chem.,37,1664, (1972):Buchi,G..andVederes, J . C., J.Amar. Cham. Soc..92,91%9 119711;Nitta.M.andKobaveshi.T..J. Ckom.Soc..Chem. Commun.877.119821:
