D. R. Paulson, A. 1. Hartwig, and 0. F. Moran California State Collese 10s Angeles, 90032
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The Ethylene Ketal Protecting Group in Organic Synthesis An undergraduate laboratory experiment
One of the most useful procedures in organic chemistry is t h a t of employing protecting groups in organic synthesis (1). This procedure is encountered when one wishes t o "protect" a functional group from a n undesirable reaction a t some point in a synthetic scheme. The protecting group may then be easily removed in a later step. Many organic laboratory texts illustrate this method by acylation of a n amine in a synthetic sequence (2). A common example of a protecting group is the use of a n ethylene ketal to mask a carbonyl group and protect it from reaction in basic media '(3). However, despite the widespread use of ethylene ketals, a perusal of the standard organic laboratory texts failed to produce a single example of this useful technique in a synthetic sequence. We have thus developed a series of reactions which amply demonstrate the use of the ethylene ketal protecting group. This sequence involves the preparation of the ethylene ketal of ethyl acetoacetate using the standard p-toluenesulfonic acid catalyzed procedure (4).
due to the much enhanced reactivity of a ketone over a n ester with nucleophilic reagents (7). This experiment employs a wide range of techniques used in purification. T h e ketal-ester is purified by vacuum distillation a t water aspirator pressure, the ketal-alcohol is purified by recrystallization, and the final product is purified by column chromatography monitored by tlc. Experimental In order t o maintain flexibility in this experiment we have not indicated how far a student should progress in a given amount of time. However, we have noted, with a n asterisk, places where a student may stop and continue during the next laboratory period without detrimental effects. Preparation of ethyl acetoacetate ethylene ketol (I):to a 250 ml round bottom flask equipped with a reflux condenser and a Dean-Stark water separator is added 30 g (0.231 mole) of ethyl acetoacetate, 15 g (0.240 mole) of ethylene glycol, 0.13 g of ptoluenesulfonic acid monohydrate, and 100 ml of reagent grade benzene. The resulting solution is refluxed until the theoretical amount of water is removed (4.2 ml, 1 hr). If the solution foams excessively one can add a drop of antifoaming agent. The reaction mixture is cooled to room temperature and washed with 35 ml of 10% sodium hydroxide, two 50-ml portions of water, and dried over anhydrous potassium carbonate.* After filtration the henzene is removed by flash evaporation* and the residue distilled to give 25.5 g (64%) of ketal (b.p. 135-138°C at 50 mm): ir 5.75, 7.3, 8.1, 8.4, 9.1, 9.7, 10.5 r ; nmr r (CCI.) 8.80(t,3), 8.61(s,3), 7.52(~,2), 6.13(s,4)and 5.97(q,2).
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Once the reactive ketone moiety has been masked, the less reactive ester group can be modified. The ester is reduced using phenyl magnesium bromide t o give the corresponding tertiary alcohol (5). T h e last step involves removal of the ketal protecting group to give the unisolated keto-alcohol. A subsequent dehydration of the labile tertiary alcohol produces 4,4-diphenyl-3-buten-2-one. The structure of this final product was verified by independent synthesis (6).
Preparation of keto-alcohol (11): to a 5W-ml round bottom flask equipped with a reflux condenser, addition funnel and mechanical stirrer is added 5.35 g (0.22 g-atom) of magnesium turnings. The flask is then flamed out and a calcium chloride drying tube placed an top of the condenser. After the flask has coaled, 30 ml of anhydrous ether and a crystal of iodine are added to the flask. A solution of 31.4 g (0.2 mole) of bromobenzene in 50 ml of anhydrous ether is added dropwise with stirring at such a rate as to maintain a steady reflux. After the addition is complete the mixture is refluxed on the steam hath for 25 min, caaled in an icehath, and 17.4 g (0.10 mole) of the ketal-ester in 50 ml of anhydrous ether is added dropwise with stirring. After addition is complete, the reaction mixture is stirred at room temperature for 30 mi", and then a mixture of 50 ml of water and 50 g of ice is added to the reaction flask.* When the ice has melted, 50 ml of ether is added and the mixture stirred until the gummy residue dissolves. The layers are separated and the water layer washed with 50 ml of ether, and the combined ether portions are washed with 50 ml of water and dried over anhydrous magnesium sulfate.* The ether is removed by flash evaporation to give sn orange liquid which crystallizes upon cooling to give 23.8 g (84%) of crude nraduct.* The crude ~roductis recrvstallized from oetroleurn ether r 2.9. .~~. ~ lfi0-9WC) ~ ~ ~ oure ketal-alcohol. m.o. 90-91": L ,~~ - , to- give 6.25, 6.65, 8.3, 11.8, 12.9, 13.3, 13.8 and 14.3 ; n k r r (CCl,) 8.99 (s,3), 7.30 (s,2),6.2-6.6 (m,4),5.11(s,l),and 2.5-3.0 (m,10). Anal. Calcd for ClsHzaOa: C, 76.03; H, 7.09. Found: C, 75.95; H, 6.92. ~~
If this procedure were t o he employed without the use of the ethylene ketal protecting group, the ketone moiety would have been reduced along with the ester function 21 6
/ Journal of Chemical Education
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Preparation of 4,4-diphenyl-3-buten-Z-one (111): to 10 g of the ketoalcahol in a 250-ml round bottom flask, is added 2.5 ml of concentrated HCI. 100 ml of acetone and 4.5 ml of water. The
mixture is refluxed one hour, diluted with 100 ml of water, and extracted with two 50-ml portions of ether. The comb~nedether extracts are washed with 50 ml of saturated sodium bicarbonate and 50 ml of water and dried over anhydrous magnesium sulfate.* After filtration the solvent is removed by flash evaporation to give 6.0 g (80%) of crude 4,4-diphenyl-3-huten-%one. A sample of the crude product (1.5 g) can be purified by column chromatography over silica gel (60 g) using benzene as eluent. The chromatography is conveniently followed using preeaated silica gel tle plates with uv indicator. Two minor impurities are eluted first (R,0.69 and 0.38) followed by the desired product lRr . , = 0.12). In this fashion 1.3 e of uure yellow Ill is obtained: ir 6.0, 6.3, 6.7, 6.9, 7.4, 7.9,8.5, 1
