Crown ether catalysis of decarboxylation and decarbalkoxylation of β-keto acids and malonates: a...

Crown ether catalysis of decarboxylation and decarbalkoxylation of p-keto acids and malonates: a synthetic application

DUNCAN H. HUNTER,' VIJAY PATEL, A N D RICHARD A. PERRY Department of Chemistry, University of Western Ontario, London, Ont., Canada N6A 5B7

Received May 20, 1980

DUNCAN H. HUNTER, VIJAY PATEL, and RICHARD A. PERRY. Can. J. Chem. 58,2271 (1980). The effect of 18-crown-6 ether on the decarboxylation rates of the sodium and potassium salts of 3-camphorcarboxylic acid 1 and

of 1-carbomethoxy-1-carboxycyclohexane 2 was studied. For2the K-18C6salt reacted ca. lo4 timesfasterthan the parent acid. This remarkable difference in reactivity was used in developing a one-pot, two-step procedure for decarbalkoxylation of malonic esters. This procedure was then applied to a range of malonates, $-keto esters, and an a-cyano ester. The effect of 15C5, other cations, and good nucleophiles was also studied.

DUNCAN H. HUNTER, VIJAY PATEL et RICHARD A. PERRY. Can. J. Chem. 58,2271 (1980).

On a etudie I'effet de I'ether 18-couronne-6 sur la vitesse de dkcarboxylation des sels de sodium et de potassium de I'acide carboxylique-3 camphre 1 et du carbomethoxy-1 carboxy-1 cyclohexane 2. Dans le cas du compost 2, le sel K-18C6 reagit environ lo4 fois plus vite que celui de I'acide apparent&. On a utilisk cette grande diffkrence de rkactivite pour developper une methode en deux etapes et dans le mime recipient permettant de decarboxyler des esters maloniques. On aappliquk cette methode sur un certain nombre de malonates de $-ceto esters et d'a-cyanoesters. On a kgalement etudik I'effet du 15C5, d'autres cations et de bons nuclkophiles.

[Traduit par le journal]

A prior study of the catalytic effect of crown ethers upon the rate of decarboxylation of carboxylate salts (1) revealed the importance of a number of governing factors among which was the stability of the resultant carbanion (R-). It was found that if the corresponding hydrocarbon (RH) had a pKa of ca. 30 or less, decarboxylation occurred under fairly mild conditions (1 100°C). Of the various acidifying groups which can provide a pKa of less than 30, the carbonyl group occurs in a large number of compounds. This

of half-lives from a first order analysis are presented in Table 1. While these data show trends similar to those obtained earlier with triphenylacetates, the most dramatic comparison is of the acid forms of 2 and its potassium-crown ether complex salt form. The rate of decarboxylation changed by about lo4 (250 000 min for 2-H and 16 min for 2-K,CE). This should be contrasted with the decarboxylation of 1 where the corresponding rate ratio is 20. Thus although the acid form of the malonate, 2-H, decar-

led us to look at the effect of crown ethers on the boxylates much more slowly than the P-ketoacid, decarboxylation of both P-ketoacids and malonic 1-H, the K,CE salts react at almost the same rate. It acids with a view to synthetic applications. is this dramatic rate enhancement that encouraged

Decarboxvlation Two c&boxylic acids with P-carbonyl groups were

chosen for the study of the effect of counterion on the rate of decarboxylation. Of these two the camphor-carboxylic acid 1 purchased was a mixture of exo and endo-isomers with the endo-CO'H pre- dominating. It was used as such without noticeably affecting our rate measurements. The l-carbomethoxy-1-carboxycyclohexane 2 was prepared as described in the Experimental. The salts of both were prepared by titration and by lyophilization.

The rates of decarboxylation were measured for 1 and 2 and for their sodium and potassium salts in refluxing dioxane both in the absence and presence of 18-crown-6 ether (18C6). Benzene and tetrahydrofuran were used also to determine the sensitivity of rate to solvent. These rate data, expressed in terms

'Author to whom correspondence may be addressed.

us to develop a crown ether assisted route for decarboxyalkylations applied, in particular, to the malonic ester synthesis as described in the following section.

The mechanism of decarboxylation of P-keto acids has received much attention and is thought to pro- ceed through a cyclic state (for a recent critique see ref. 2). The reduced reactivity of 2 versus 1 is attribut- able in part to the reduced basicity of an ester carbonyl relative to a ketonic carbonyl(3) and to the relative stability of the two enolic intermediates.' It is tempting to attribute the similar rates of decarboxylation of the K+,CE salts to similar stabilities of the resultant enolates; however, it is difficult to substantiate this suggestion. While the pKa values of numerous ketones are available, esters have not proven amenable to measurement. What little data

2The % en01 for acetone is (4) and is estimated to be N 10-l3 for ethyl acetate (J. P. Guthrie, unpublished results).

0008-4042/80/2 1227 1 -07$01 .OO/O 01980 National Research Council of Canada/Conseil national de recherches du Canada

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CAN. J. CHEM. VOL. 58, 1980

TABLE 1. Effect of counterion on the rate of decarboxylation of 1 and 2 at reflux

Concentration, Concentration, Solvent Cation M t l I2 , mina M t l I2 , mina

Decarbalkoxylation The greatly enhanced rate of decarboxylation of

the potassium-crown ether salt of 2 relative to the acid form of the malonic half ester made us turn our attention to malonic esters. As part.of a traditional malonic ester synthesis, the diester 3 is first hydrolyzed to the diacid 4, which is then heated to effect decarboxylation and the acid 5 is then often re- esterified for further conversions (Scheme 1). As an alternative to this procedure we decided to explore the route via the salt of the half-ester 6 which in the

Dioxane H 0.060 160 0.015 250,000b Dioxane Na 0.054 2,200 Dioxane Na-18C6 0.038 340 THF Na-l8C6 0.050 1,040 Dioxane K 0.023 1,040 0.044 2,100 Dioxane K-18C6 0.040 8' 0.059 16 Benzene K-18C6 0.076 120

OObtained from four points showing first order behaviour. bBoth a sealed tube and reflux experiment. =Calculated from 75% reaction at 14 min and 87% reaction at 20 min.

there are suggest that acetone should be more acidic presence of crown ether should decarboxylate under than ethyl acetate (5). But of the ketones, camphor conditions much milder than those required for the is one of the less acidic (pKaDMSO = 30.40; cf. phenyl- diacid 4. We were further encouraged in this regard cyclohexyl ketone = 26.7).3 Thus it may be that by the realization that crown ethers also greatly camphor and methyl cyclohexylcarboxylate do have accelerate the saponification of esters (6). If a similar acidities. selective saponification could be realized then both

Interpretation of the effect of added 18C6 is com- steps could be telescoped into a one-pot conversion plicated by the fact that the reactions run in the of malonate 3 to acetate 7. absence of crown ether were heterogeneous. But /Co2Et

~ 3 0 ~ /C02H

certainly one role of the crown ether is to dissolve the salts and in the case of 1 this has led to a rate R2C

Hz0 + R2C

enhancement of 7 for the sodium salt and of 130 for \ C O ~ E ~ \CO~H

4 the potassium salt. The potassium salt of 2 showed a

3F. G . Bordwell, personal communication.

similar rate enhancement. The replacement of dioxane by benzene in this case led to an eight-fold decrease in rate but of course the reaction tempera- - +

/C02 K. CE ture has been reduced by about 20" (100 to 80°C). In the case of the sodium salt of 1 the change from \C02Et dioxane to THF led to only a 3-fold drop in rate in

Diethyl Butylmalonate In this regard we studied the conversion of diethyl

butylmalonate 8 under a variety of conditions to optimize yields and then looked at a number of other malonates. Initial attempts were directed at preparing and utilizing a 1: 1 complex of KOH-18C6 in an aprotic solvent; protic solvents reduce the rate of decarboxylation. Attempts using solid KOH and equimolar 18C6 resulted in a largely insoluble reagent in a wide range of aprotic solvents (iso- octane, benzene, dioxane, THF, pyridine, aceto-

spite of a temperature drop of 35". This seems con- v

sistent with the earlier observations (1) of the effect of solvent on decarboxvlation rates. R2CH-C02Et R2CH-C02H

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HUNTER ET AL. 2273

nitrile). Nonetheless these reaction mixtures were stirred for 0.5 h at 25OC and then refluxed for 20-24 h and gave quite similar product distribution; -40% recovered 8, -40% ethyl caproate 9, and - 20% of

1 other products amongst which both butylmalonic acid and caproic acid were identified. The insoluble reagent seemed to favour complete saponification of the malonate rather than selective hydrolysis to the half-ester which is needed for a successful malonate to acetate conversion.

Attempts were made to enhance the solubility of the potassium hydroxide in benzene by preforming the crown ether complex initially in water followed by lyophilization and also directly in benzene by removing the water as an azeotrope. These attempts led to no improvement in the product distribution and again a largely insoluble reagent resulted.

A homogeneous reaction mixture was obtained in ethanol with KOH-18C6 and while this led to quite selective monohydrolysis there was incomplete decarboxylation after 24 h at reflux (10% recovered 8, 40% 9, 45% ethyl hydrogen butylmalonate CH3CH2CH2CH2CH(C0,H)C02Et). In an attempt ' to maintain homogeneity but to enhance the rate of decarboxylation, a benzene-ethanol mixture (5 vo1.z

I ethanol) was employed for the ambient temperature hydrolysis. For the decarboxylation step, the ethanol was removed by distillation from the refluxing reaction mixture with the concurrent addition of benzene to keep the volume approximately constant. This led to 97% conversion (vpc) after 24 h and yields (after distillation) of 9 of 72% at 5 h, 81% at 16 h, and 84% at 24 h.

At this stage the use of benzene was somewhat arbitrary but did present some practical advantages. Its boiling point was high enough to effect efficient decarboxylation and removal of the ethanol. The 18C6 could be removed and subsequently recovered by washing with KC1 solution (7).

Comparison of Malonates The near optimum yield of ethyl valerate from

diethyl butylmalonate led us to apply this same two step one-pot procedure to other malonates (Table 2). These reactions, run on a 3 mmol scale, gave high yields (76-87%) of crude product sufficiently pure for further use. In some cases (runs 2, 4, 7, 9, 11) the reaction was run also on a 30 mmol scale and the product was distilled (> 99% pure). As is evident in runs 2 and 4, the yields are affected by the volatility of the liquid products and a glc analysis of the crude reaction mixture showed better than 90% yields. Both monoalkyl and dialkylmalonates (runs 1-8) reacted under similar conditions to give comparable yields.

For most cases the hydrolysis step was complete

in 1-3 h but the acidifying influence of a phenyl or nitro group led to competitive deprotonation of the malonic diester with consequent reduction in the rate of ester hydrolysis. The phenylmalonate (runs 10 and 11) proved to be borderline and an extended hydrolysis period sufficed to complete the reaction. How- ever, in the case of the nitro-malonate the conversion to enolate was so complete that only starting material was recovered upon acidification. Thus, the presence of strong acidifying groups represents a limitation to this method of decarboxylation.

For most of the malonates in Table 2, a reflux period, after ethanol removal, of about 12-20 h was appropriate to complete decarboxylation. However there were two exceptions worth noting. The phenylmalonate (runs 10 and 11) proved very reactive once the ester hydrolysis was complete. In contrast, the decarboxylation of the cyclobutyl compound (run 6) was quite slow even in the higher boiling dioxane. Estimated half-lives for decarboxylation were 2 60 h in refluxing benzene and 12 h in refluxing dioxane compared with the cyclohexyl compound (run 7) with t3 -2 h (benzene). This reduced reactivity does not seem to reflect the stability of the derived anion (cyclobutylphenylketone pKaDMSO = 26.1 ; cyclo- hexylphenylketone pKaDMSO = 26.7,) and the source of this reduced reactivity remains a puzzle.

In one other case (run 9), dioxane was substituted for benzene but this was to enhance the solubility of the hydrolysis product to facilitate decarboxylation. It was also in this run that the usual precipitate of KHCO, was characterized and isolated in yields comparable to the product. Thus the CO, acts to trap the hydroxide generated during the final protonation producing an insoluble and unreactive precipitate.

R2CH-C02Et + KHCO, 4

This one-pot, two-step procedure for the decarbalkoxylation of malonate diesters to acetate esters gives good yields at moderate temperatures (80 or 100°C) under mildly basic conditions and acts to comple- ment the other procedures for decarbalkoxylation. Thus the traditional three-step procedure (hydrolysis to the diacid, thermal decarboxylation, and re- esterification) gives comparable yields (73% ethyl caproate versus 75% of caproic acid (8); 59% ethyl valerate versus 60% (9); and 45% 2-heptanone versus 52-61% (10)). However, the present procedure employs basic rather than acidic conditions; the de-

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CAN. J. CHEM. VOL. 58, 1980

TABLE 2. Conditions and yields for one-pot decarbalkoxylation of malonates using equimolar KOH-18C6 in ethanol and benzene or dioxane

Substrate Reaction time, h % Product

Run Nature Amount, g Solventa 5 250Cb Reflux % SM Crudec Purifiedb

'B = benzene, D = dioxane. The large scale reactions were run using ca. 200 mL of solvent and the small scale in 50 mL. T h e reactants were mixed at -10°C and allowed to warm to ambient temperature. CNeat liquid analyzed for purity by nmr after solvent removal. 'Analyzed by glc. 'Distilled in runs 2, 4, 7, and l l (> 99% pure by glc) and recrystallized in run 9. JIsolated as the ethyl ester.

TABLE 3. Conditions and yields for decarbalkoxylation of keto and cyanoesters using equimolar KOH- 18C6 in ethanol and benzene or dioxane

Substrate Reaction time, h % Product

Run Nature Amount, g Solventa s 250Cb Reflux Crudec Purifiedc % Other

'B = benzene, D = dioxane. Runs 13.15, and 16 were in 50 mL of solvent and run 14 used 200 mL. In run 14 a 5 M KOH/ H 2 0 solution was used rather than ethanol.

bThe 18C6 was added after the hvdrolvsis oeriod. =The camphor was sublimed and-the <apr6nitrile was distilled. 'Ethyl hydrogen adipate. *a-Cyanocaproic acid.

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HUNTER ET AL.

TABLE 4. Comparison of cations and crown ethers upon the reaction of diethyl butylmalonate with equimolar KOHIethanol - benzenea

Run Reagentb Reflux period, h % SM % Product % EHBMc

2 KOH, 18C6 24 3 84 17 KOH, 15C5 50 12 5 1 14 18 NaOH, 18C6 44 14 33 17 19 NaOH, 15C5 43 7 50 15 20 Ba(OH),, 18C6 40 6 61 8 21 KOH, 0.2 18C6 42 10 72 22 KOH, DB18C6 24 4 70 4 23 KOH, N ( ~ B u ) ~ B ~ 22 8 73 24 KOH, N(r~pr)~Br 21 6 57 25 KOH, 0.5 N ( ~ B u ) ~ B ~ 22 13 55 15

'The reagent solution was added to the substrate in benzene at -lO°C over 0.5 h and then warmed to 2S°C for 1 h. The ethanol was removed by distillation during the first part of the reflux period.

b15C5 = 15-crown-5 ether; DB18C6 = dibenzo-18-crown-6 ether. <Ethyl hydrogen butylmalonate.

carboxylation step is run at a lower temperature; and fewer steps are required.

Decarboxylation has also been effected with refluxing dimethylsulfoxide (11) containing water, sometimes with added salts, with yields comparable to the present study (76% CH,CONHCH,CO,Et in this study versus 70%; 78% ethyl phenylacetate in this study versus 90%; and 76% (CH,),CHCO,Et in this study versus 80-90%). However, the present procedure employs a significantly lower temperature, 80-100°C versus 160°C; and uses slightly basic rather than neutral conditions.

There are some limitations to the present procedure : particularly acidic substrates can deprotonate rather than hydrolyze (e.g. diethyl nitromalonate); substrates containing base sensitive groups may not be satisfactory; and large amounts of 18C6 may be needed since equimolar quantities give optimum results. The importance of this latter factor is reduced since 18C6 is recoverable by the simple expedient of a KC1 wash (7). There are a number of other procedures (12) for decarbalkoxylation but most have been developed for P-ketoesters.

15) gave the usual (13) ring opening reaction even in the presence of 18C6 and only traces of the desired product were observed. The ethyl a-cyanocaproate hydrolyzed readily (before adding the crown ether) but the decarboxylation was quite slow even in refluxing dioxane. Thus even after 48 h at reflux (run 16), there was isolated 21% of a-cyanocaproic acid. This reduced reactivity presumably reflects the reduced acidifying effect of a nitrile grouping (pKaDMSO: CH3CN 31.3; CH3COCH3 26.5)3 relative to a carbonyl.

a-Cyano and P-Keto Esters Although the potassium-crown ether salt of

camphor-3-carboxylic acid decarboxylated only 20 times faster than the acid (Table I), the present procedure would allow a mildly basic alternative to the usual route. Consequently three P-ketoesters were investigated (Table 3; runs 13, 14, and 15) as well as an a-cyanoester (run 16).

The reactions of 3-carbethoxy-2-heptanone (run 13) and camphor-3-methylcarboxylate (run 14) proceeded in good yield, although in both these cases it was found the hydrolysis step proceeded more rapidly without 18C6, which was added after the initial step. The 2-carbethoxy cyclopentanone (run

Other Cations and Crown Ethers A series of experiments was run using diethyl

butylmalonate 8 under the standard conditions for decarbalkoxylation (1-2 h at 125", 20-50 h at reflux) except that the reagent was altered by varying both the cation and the crown ether. Although no attempt was made beyond this to optimize either yields or conditions, some effects are apparent. The replacement of 18C6 (run 2) with 15C5 (run 17) led to reduced amounts of both hydrolysis and decarboxylation. The replacement of potassium by sodium led to reduced yields although in this case 15C5 (run 17) was better-than 18C6 (run 18). These changes are consistent with the cation selectivity shown by crown ethers (14) and with the effect of cation on the rate of decarboxylation (Table 1).

Barium (run 20) was also chosen for its com- patibility with 18C6 and gave moderate yields although long reflux periods were needed. Long reflux periods were needed when less than equimolar 18C6 was used (run 21). With less than equimolar 18C6, the reaction mixture remained gelatinous but nonetheless yields were quite good. However since the 18C6 can be recovered by KC1 extraction, use of equimolar crown ether seems advisable. Dibenzo- 18C6 (run 22) also gave reasonable yields but pre-

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2276 CAN. J . CHEM. VOL. 58, 1980

sented practical problems due to its reduced solubility. Of the cations and crown ethers surveyed, equimolar 18C6 and potassium hydroxide gave optimum yields in minimum time.

The effectiveness of quaternary ammonium cations was also explored albeit in a brief manner (runs 23, 24, and 25). While tetrapropylammonium bromide was effective, the longer chain tetrabutylammonium bromide, in equimolar amounts, behaved very similarly to K-18C6. A reduction in the amount of tetrabutylammonium bromide led to a reduction in yield both at the hydrolysis stage and at the decarboxylation stage. Although no attempt was made to optimize conditions it is fairly clear that tetrabutyl, or perhaps longer chain (1 5), quarternary ammonium salts can be very effective particularly on the large scale. This point deserves further study.

An SN2 Route to Decarbalkoxylation The feasibility of using 18C6 in combination with

the salts of good nucleophiles to effect decarbalkoxylation was studied. The study with diethyl butylmalonate was limited to potassium iodide and

0 0 I 1 K+Nu- 11 -

R'-C-0-R R'-C-0 K+.CE + Nu-R C.E.

potassium cyanide with equimolar 18C6 in a number of solvents at reflux. The following combinations were attempted with no detectable reaction of the malonate: KI in benzene, 5% ethanol-benzene, dioxane, 5% ethanol-dioxane, acetonitrile, dimethylsulfoxide (< 120°C); KCN in dioxane. The reluctance of diethyl butylmalonate to undergo even the first step made us look at the reactions of methyl oleate. Again there was no reaction with KI in tetrahydrofuran and in dioxane, and with KF in dioxane. There was reaction with potassium 2-propanethiolate in both tetrahydrofuran and dioxane but water may have been responsible for this result and the matter was not explored further.

It has been clearly demonstrated that both water and salts (KCN, NaC1, or LiC1) in refluxing dimethylsulfoxide (160°C) provide good yields in decarbalkoxylation without the use of crown ethers (11). If there is a catalytic effect of 18C6, it is not of sufficient magnitude to lower the reaction temperature to that of the solvents employed here (< 100°C).

Experimental The d,l-3-camphorcarboxylic acid, diethyl n-butylmalonate,

diethyl acetamidomalonate, and diethyl phenylmalonate were

purchased. Diethyl propylmalonate, diethyl allylmalonate, and diethyl nitromalonate were provided by F. H. Pattison and 2-carbethoxycyclopentanone was provided by P. de Mayo. A sample of 3-rarbethoxy 2-heptanone was prepared in 70% yield by the procedure of Marvel and Hager (16). The d,l-methyl-3- camphorcarboxylate was prepared from commercial, d,l-3- camphorcarboxylic acid using the esterification procedure of Clinton and Laskowski (17). The ester was obtained as a mixture of 80% endo-C02CH3 and 20% exo-CO2CH3 and was used as such. The I-carbomethoxy cyclohexanecarboxylic acid was prepared in 50% yield by the procedure of Reiffers, Wynberg, and Strating (18). Diethyl-I,]-cyclobutanedicarboxylate was prepared by al-

kylation of diethylmalonate with 1.3-dibromopropane. The c~clobutyl compound was 0btained.h about 50% yield but contaminated with about 25% diethyl allylmalonate. The allylmalonate was removed by treatment with KMnO, and the net overall yield of purified cyclobutyl compound was 40%. The procedure follows.

A mixture of 1,3-dibromopropane (27.5 g, 0.136 mol) and diethyl malonate (21.5 g, 0.134 mol) in dry EtOH (125 mL) was added dropwise from one addition funnel into refluxing EtOH (100 mL) while simultaneously adding 150 mL of 1.7 M from another addition funnel, over a period of 2.5 h. After an additional half hour reflux, the solution was filtered, evaporated, and the residue extracted with CH2C12. The CH2CI2 extracts were evaporated to give a liquid mixture (26.3 g) which was dissolved in glacial acetic acid (60 mL) and cooled to < 10°C. Solid KMnO, (15.0 g) was added in portions over 10 min and the exothermic reaction was maintained at < 50°C by external cooling for 314 hour. Dilute NaOH (100 mL) was added, and the mixture extracted with ether. The dried ether extracts were evaporated to yield a liquid which was distilled. After a forerun, the diethyl cyclobutanedicarboxylate was collected (10.83 g, bp 108-110°C (18 Torr)).

Diethyl 1,l-cyclohexanedicarboxylate was prepared by the reaction of diethyl malonate and 1,5-dibromopentane by the following procedure.

To 150 mL of 1.9 M sodium ethoxide in ethanol was added a solution of diethyl malonate (23.0 g, 0.144 mol) and 1,5- dibromopentane (34.5 g, 0.15 mol) in ethanol (150 mL) at reflux over 2.5 h. After an additional hour reflux the solution was cooled, pentane (100 mL) was added, and the solution filtered. The residue after evaporation of the filtrate was distilled and after a forerun of dibromopentane, the diethyl ester was collected (17.08 g, 52%, bp 83-92°C at 0.2-0.3 Torr; lit. (19) bp 100°C at 2 Torr).

Ethyl a-cyanocaproate was prepared by alkylation of ethyl cyanoacetate with butylbromide according to the following procedure. To 150 mL of 2.8 M sodium ethoxide in ethanol was added ethyl cyanoacetate (49.0 g, 0.43 mol) in EtOH (876 mL) followed by butyl bromide (60.5 g, 0.44 mol) in EtOH (75 mL). The solution was refluxed 8.5 h, cooled, filtered, and evaporated. The residue was extracted with pentane (200 mL), evaporated, and the resulting liquid distilled to give a forerun (25.1 g) followed by ethyl a-cyanohexanoate (30.53 g, 43%, bp. 140-144°C (134 Torr)).

The sodium and potassium salts of d,l-3-camphorcarboxylic acid and 1-carbomethoxy cyclohexanecarboxylic acid were prepared by lyophilization of an aqueous solution from titration of the corresponding acids (to the equivalence point). The 18C6 was prepared by the usual procedure (20).

Procedure for Decarboxylation The decarboxylation reactions were run on doubly degassed

solutions under an argon atmosphere. Typically 25 mL of solvent were used and sufficient substrate, 18C6, and glc

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HUNTER E T AL. 2277

standard (mesitylene) to provide concentrations in the range of 0.02 M to 0.08 M were used. Aliquots of these solutions were removed to determine the progress of the reaction and for the heterogeneous reactions an attempt was made to remove representative samples. The aliquot was treated by extraction with water-pentane to remove the unreacted salt. After three water extractions and drying with sodium sulfate, the pentane layer was concentrated and analyzed by glc (5 ft x ) in. column of 5% SE-30 on 45-60 Chromosorb P).

Procedure for Decarbalkoxylations The procedures described here for removal of a COzR grpup

involve two distinct steps; first, low temperature hydrolysis of one of the ester groupings with an equimolar amount of potassium hydroxide in ethanol, and second, heating to reflux in benzene or dioxane to induce decarboxylation of the potassium carboxylate. The decarboxylation is facilitated by removal of the ethanol by distillation as the temperature is raised to reflux. In most reactions benzene was used as the solvent (Procedure A) while in some cases dioxane was used (Procedure B). In two cases KOH in water (Procedure C) replaced KOH in ethanol.

(A) Benzene and Ethanol A mixture of benzene (20 mL) and potassium hydroxide in

ethanol (2.8 mL (3.1 mmol) of 1.1 M ) was added dropwise over about 25 min to a stirred solution of substrate (3.0 mmol) and 18C6 (3.0 mmol) in 30 mL of benzene at 5-10°C. After stirring several hours at room temperature to effect hydrolysis of the esters, the solution was heated to reflux. To facilitate the decarboxylation reaction about 10-15 mL of distillate was collected, resulting in removal of most of the ethanol. After the reflux period was over the reaction mixture was cooled and then acidified with 3 M hydrochloric acid. The benzene layer was washed three times with ca. 15 mL of saturated potassium chloride solution to remove the crown ether and then dried with sodium sulfate. The benzene was removed by distillation and the residual oil analyzed by glc and nmr.

For those reactions run on a 30 mmol scale, the residual oil was distilled and checked for purity by glc.

(B) Dioxane and Ethanol Following procedure A, the dioxane-ethanol-hydroxide

solution was added at < 15°C and the ethanol was removed by distillation until the temperature rose to 100°C. After the reflux period, the reaction mixture was cooled and 50 mL of pentane was added. (See below for acetamidoester isolation procedure.) Then 3 N hydrochloric acid and saturated potassium chloride solution were added and the above washing procedure followed. After evaporation of the solvent, if the crude material was contaminated with crown ether (20-50 mg), this was removed by filtration of a pentane solution through neutral alumina (1-2 g) and reevaporation. Since the acetamidoester was sparingly soluble in pentane and soluble in water, after the reaction was completed, the solution was filtered and evaporated. The residue was taken up in dichloromethane (50 mL), washed four times with saturated potassium chloride solution, dried, and evaporated to yield 54% ester and 10% diester. The combined washes were continuously extracted with ether, which was dried and evaporated to yield 24x ester product.

(C) Benzene and Water To the compound (3.0 mmol) in benzene (50 mL) at 25OC

was added 5 N aqueous potassium hydroxide solution (3.5 mmol, 0.7 mL). (If crown was also present then 6 mmol of potassium hydroxide were added.) After 3.5 h reflux, 18C6 (3.0 mmol) was added, the water distilled off as an azeotrope, and the solution refluxed for an additional 7.5 h. The isolation procedure of A was then followed.

Acknowledgments The authors wish to acknowledge financial support

from the Natural Sciences and Engineering Research Council of Canada.

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