Selective Oxidation in the Presence of a Heterocycle K. Dean Bowles, David A. Qulncy, John I. McKenna, and N. R. Nalale' University of Idaho, Moscow, ID 83843 We have previously commented upon the lack of heterocyclic examples in undergraduate organic chemistry ( I ) . Is there a special strategy for heterocycles? How does one weigh the possibilities when "R" is a heterocyclic ring? We required a synthetic method for oxidation of an alcohol in the presence of the isoxazole ring (2). We have critically surveyed several of the most common oxidation methods and herein report on a catalytic method that is effective and operationally simple. This method illustrates the concept of a catalytic oxidation cvcle and demonstrates the technioue of using a gaseous reagent. We have found that this experiment can be performed by advanced high school and undergraduate students. The process of weighing the advantages and disadvantages of various methods is presented in this paper. T o evaluate the possible complications of allowing "R" to be a heterocycle, the chemistrycharacteristic of the-heterocycle must be carefully considered. The isoxazole ring contains several potential problem areas. Electron deficient centers a t C-3 and C-5 are potentially vulnerable to nucleophiles. The nitrogen nonbonded pair will react with electrophiles and Lewis acids (Fig. 1). These problems should be somewhat lessened by the Huckel aromaticity of the isoxazole; therefore, with sufficiently mild reagents, selective oxidation should be possible. The transformation of an alcohol to a carbonyl derivative is a basic tool in the bag of tricks of a synthetic chemist (3).A prominent problem in oxidation of primary alcohols (1) to aldehydes (2) is the tendency for many oxidative conditions to overoxidize to the carhoxvlic acid oxidation state (3) . . or even further (Fig. 2). Isoxazoles are a case in point. We desired a convenient ~rocedureto convert isoxazole carhinols (4) t o the aldehydes (5)without overoxidation (Fig. 3). We were aware that isoxazoles with electron-withdrawing groups attached to the heterocyclic ring are subject to such overoxidation. For example, Nesi and coworkers have recently reported ( 4 ) that during the permanganate oxidation of the isoxazole (6), the isoxazole carboxylic acid (7) reacted further via a spiro lactone (8) to give decarhoxylation to the isoxazolone (9) (Fig. 4). This was verified by formation of the methoxv isoxazole (10) hv treatment with diazomethane.2 ~~~~~~~~ c i d i cdichromate solutions (active ingredient: CrV') are widely used for oxidation in organic chemistry (3).When this reaction is carried out in the presence of primary alcohols, however, overoxidation to the carhoxylic acid is a prominent side reaction. In fact, CrV' oxidation in aqueous media has been used successfully to oxidize a primary alcohol (11) to the ester (14) (6).as shown in Figure 5. In the acidic medium, the initially formed aldehyde (12) forms a hemi-acetal(13) from unreacted alcohol (111, and this hemiacetal (13) is then oxidized to the ester (14) in moderate yield! The reactivity of CrV' can be moderated by the formation of complexes, for example, with pyridine (7). The most ~
Recently, W. Kolimeyer of Shell Development has discovered that MnO, is successfulfor oxidations in the presence of isoxazoles a This type of "reality" often faces the lab worker of limited means (see also ref 9).
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Journal of Chemical Education
R-CHzOH I
Figure 2.
-
RXHO 2
-
R-COOH 3
Oxidation of a primary alcohol.
Figure 3. Oxidation of an isoxazoie to lhe isoxarolyl-aldehyde
Figure 4. ikoxaroles are subjed to overaxidation wilh permanganate.
~
' Author to whom correspondence should be addressed.
cn.
Figure 1. Characteristic chemistry and numbering d ikoxazole.
Figure 5. Chromium(V0 oxidation of primary alcohols in acldic soiulion may ~rcduceesters.
widely used reagent of this type is pyridinium chloro chromate (PCC) (8). Of the pyridinium-complex-type reagents we have found that PCC gives the highest yields. Another criterion that we have used for comparison is the relative expense of the reagent systems, and again PCC is the least expensive of the CrV' reagents. The cost is an estimate based on Aldrich prices of reagents and solvents necessary to perform the reaction on a 0.1-mol scale.3 Another approach to
A
Critical Cornparlaon of Oxldatlon Methods for the Conversion of 4 to 5 Cost Reagern
%
(dollars)
CfldfY Adogen-464/K2Cr20,
44 70 80 47 77
2.56 5.89 1.00 1.52 6.97 1.89 1.49 1.77 1.16 0.71
PCC PDC BPOC PYPDC Swern (DMSO/(COClM TEMPO (10 mol %) TEMPO (5 mol %) TEMPO (1 mol %)
29
84 78 64 41
Ref. 7
I0 6 17 18 19 14
16 16 16
oxidations in organic media is to render the inorganic salt soluble by the use of a phase-transfer catalyst. An earlier investination from our laboratom (26) has revealed that on a small scale we could successfull; use Crvl under mild conditions with the aid of n phase-transfer caralw. Ado~en-464 (10). However, scale-up of this method w ~ c o k p l i c ~ t by ed several factors. The expense of the phase-transfer reagent was one factor (see table). The major complication is the decomposition of the phase-transfer reagent (Adogen-464) to give by-products that are difficult to separate from the desired product. Thus, this method proved inconvenient to scale up. All of the Crvlreagent systems, however, must he handled with care as CrV1is a carcinogen (11). On larger scales the CrV1reagents also pose limitations due to expense, since a t best the oxidizing agent must he used in a stoichiometric amount. These concerns lead us to examine some other, alternative methods for oxidation. Recently much attention has been focused on the use of aqueous hypochlorite solutions (household bleach) for alcohol oxidation. This reagent is inexpensive and efficient (12). In the case of an "R" group containing a nitrogen heterocycle, however, there is a clear limitation. The nitrogen lone pair can N-chlorinate, and the resulting species is more vulnerable t o nucleonhiles. In fact. this reaeent svstem has been used for "deprot&tionn of oxaiolines (13)(F& 6). The reaction of oxazoline (15) with sodium hvnochlorite eave Nchlorination (16). This product is rapLdly attackei by nucleophiles, in this case water. t o give tetrahedral intermediate (17). Collapse of the tetriheiral intermediate produces the ester (18). The authors found that this reagent provided a facile way to "deprotect" the heterocyclic ring. If we wish to leave the heterocyclic ring intact, however, reagent systems other than hypochlorite would appear more appropriate. The Swern protocol (DMSO, oxalyl chloride) (14) is among the most inexpensive stoichiometric oxidation methods. This method is generally recognized as the method of choice for nitrogen-containing molecules. The Swern reaction has been widelv used for functionallv c o m ~ l e xmolecules. The reaction is efficient, selective, add without racemization of nearby chiral centers (15). The maior drawback of the Swern reaction is the overpowering stench
of the liberated dimethyl sulfide, which permeates the lah and usually the laboratory worker. For the isoxazole system, the Swern reaction gave the highest chemical yields (see table). Yet students often a ~ p r o a c hthe reaction with reluctance. During the work-up; coworkers often approach the library! Recently our attention has been drawn t o methods that use catalytic amounts of the more expensive oxidation reagents. We have examined one of the most recent developments in this area and happily report that the method of Semmelhack (16) . . fulfills all of our reouirements for a useful selective oxidation method. The reaction involves the catalvtic cvcle illustrated in Fieure 7. The reaction henins when a ;ataly"tic amount of cupricchloride oxidizes tetramethyl piperdinyl oxy free radical (TEMPO, 19) t o the corresponding nitrosonium ion (20). The alcohol (1) is then oxidized generating the aldehyde (2) and hydroxylamine (21). Rapid syn proportionation of (20) and (21) regenerates (19). Cupric chloride is regenerated by oxygen, completing the catalytic cycle. The net reaction is oxidation of alcohol (1) hy oxygen to give aldehyde (2) and water. We have examined this reagent svstem usine catalvtic amounts of the most exoensiveingredient, TEMPO. Tbe reaction proceeds a t a reasonable rate in good yield a t 5 mol % of TEMPO. In summary, this catalytic reagent system competes successfully with other oxidation systems in efficiency, convenience, and cost. On larger scales, the catalytic system offers additional advantaes in cost. This procedure can also he used as an introdu&ion to the technique of handling a reagent in the gas phase and provides a vehicle for the discussion of catalytic reaction cycles. Experimental A 50-mL, three-neck, round-bottom flask was charged with N, Ndimethylformamide(25 mL), TEMPO (131mg), CuCL (88mg), and isoxazole alcohol (152mg, 5.9 mmol) (I,26). Oxygen was introduced via a 10-mLgraduated pipet, usingarubber septum as adaptor, at a rate of -1 bubble per second. The oxygen was bubbled through the
solution overnight.The reaction mixture was poured into water (100 mL) and extracted with ether (3 X 50 mL). The combined ether extracts were washed with water (3 X 20 mL) and dried over anhydrous NanSO.. The residue was flash distilled on a Kueelrohr ama.. k u i 150'~/0.15m m H g ~to give 582 mg uf aldehyde ~ ? Y % Ias m oil that solid~fipson rtandrna tu n waxlike solid.'lH.NhlH-~CDCI:,~ 9.8 (s, llil): 2.6(5,3Ht: 2.4 (s,3H1.
20
21
19 (TEMPO1
4Cu++4Hi+O~-ICu2*+2Hz0 Overdl Reaction: 2 RCHsOH
I
Flgure 6. Nitrogen heterocycles react with hypochlorite
-
+ 0%
2 RCHO
+ 2 H20
2
Figure 7. Gatalyttc ox~damnof alcohols to aldehydes. Volume 63 Number 4
April 1966
359
Acknowledgment
The authors are grateful to the M. J. Murdock Charitable Trust Grant of Research Cor~orationand the Petroleum Research Fund ~dministered-bythe American Chemical Society for support of this work. K.D.B. is grateful to Project-SEED of the American Chemical Society. Literature Clted (11 Bowla, K. D.;Quincy, D.: Mallet. B.; McKenna. J. I.; Natal.. N . R J, Chem. Educ. 1985.62, 118. (2) (a1 Nstsle. N. R. TetrahedronLett. 1982.5W9 (b) Natale, N.R.,Quincy.D.A.Synlh. Commvn. 1983.13,817 (el Nata1e.N. R.;Niou,C.-S. TerrohedronLett. 1984,3943. (31 House, H. 0. "Modern Synthetic Readiona". 2nd ed.: W. A. Benjamin: Monlo Park, CA. 1972:Chap 11. (41 Neai. R.;Chimichi, S.; DeSio, F.;Pepino. R.; Tedeschi. P. Tmohedron Lett. 1982.
1984.1118. (131 Lsuin, J. I.; Weinreb,S. M. TetrohedmnLotL 1982,2347. A. J.: Swern. D. Synthesis 1981, 165. (b) (141 (a1 For a recent review. nee: Mane-, Mancuso,A.J.:Husng,S.-L.;Swern,D. J.Org.Chem. 1978,43,2480.(cllnsaurvey of oxidation of 3-hydmry-ketones to 1.3-dicarbonyla, Sluern oxidation also gave higher yields than the Crm reagents: Smith, A. B., III: Levenberg,P. A. Synthesis ,a*,
KC,
(161 Meyers,A. I.;etal. JAmsr. Chem.Sor. 1983.105.5015. (161 Semmolhack. M. F.; Sehmid, C. R.; Corks, D. A ; Chou, C. S. J. Amar. Chem Soc. 1984,106,3374. (171 (a) Coates. W. M.;Corrigan.J.R. C h m Ind. 1969.1594. (bl C0rey.E. J.;Sehmidf G. Tetrahedron Lett. 1919.399. (181 Guziec,F. S.,Jr.;Lunio, F.A.Synthesis 1980,691. (191 (a) Freehet, J. M.; Darling. P.; Farrall, M. J. J. Org. Chrm. 1981.46, 1128. (b) T h a e authors claim that their reseent can he used with 1- e x e s . than other oolnner auppmlad reapents: ~ a i n e l l i ; ~ Cardillo,G.:Orena. .: M.: Ssndri, S. J.Amer. Chem. Sac. 1976. 98. 6337. (cl Tho reagent d a d in ref 19b has been suggeatad for use: Wade.L.G..Jr.:Stoll, L. M. J . Chrm.Edue. 1980.57.438.
..
360
Journal of Chemical Education
