[CONTBIBUTION FROM TEE NOYE8 CHEMICAL LABORATORY, UNIVERSITY
OF
ILLINOIS]
ALKYLATION OF ETHYL MALONATE WITH DIETHOXYMETHYL ACETATE' REYNOLD C. FUSON, WrLLIAM E. PARHAM,
AND
LESTER J. REED
Received December $6, lQ@
In an attempt to improve the yield of ethyl ethoxymethylenemalonate(I) by the Claisen method (l),a study has been made of the mechanism of the reaction. The original procedure involved treatment of ethyl malonate with ethyl orthoformate in the presence of acetic anhydride and zinc chloride. It was believed that the two esters underwent condensation with the elimination of ethanol, and that the function of the anhydride was to remove the ethanol. G H K O C H ( O C ~ H ~HaC(CCGaH& )~
CaH,OCH=C(COzCzHa)z 4- 2CzHaOH I
An entirely different mechanism was suggested by the discovery of Post and Erickson (2) that ethyl orthoformate reacts with acetic anhydride to form diethoxymethyl acetate (11) and that the latter can be condensed with ethyl acetoacetate to give ethyl w(ethoxymethy1ene)acetoacetate (111).
+ + (CsH60)tCHOCOCHa 4- CHJ202CzHs I1 C&COCHzC02C2H6 + (CrH60)2CHOCOCHa (C~HKO)&HOC~H~ (CH&O)zO
-
I1
CHaCOCC 0 2 C a
n
CHOCtH6
I11 These observations indicate that in the Claisen process the ethyl malonate might undergo alkylation with diethoxymethyl acetate to yield ethyl diethoxymethylmalonate (IV), which by loss of a molecule of ethanol would yield ethyl ethoxymethylenemalonate (I). (C~H~O)~CHOCOCHI 4- CHz(CO2CzHa)a I1 + ( C B H ~ O ) ~ C H C H ( C O ~4C ~CHsCOOH H~)~ IV In the present work it has been shown that this alkylation does occur. When diethoxymethyl acetate (11) was heated with ethyl malonate in the absence of a catalyst, a new ester, ethyl cliethoxymethylmalonate (IV) was obtained in a 1 The work described in this paper was done under a contract, recommended by the National Defense Research Committee and the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Illinois.
194
195
ALKYLATION OF ETHYL MALONATE
yield of 17%. The presence of a small amount of zinc chloride increased the yield considerably. In this case, however, the product was a mixture of ethyl diethoxymethylmalonate (IV) and ethyl ethoxymethylenemalonate (I). If it is assumed that the latter is formed by way of the diethoxymethylmalonate, the extent of diethoxymethylation corresponds to 53% of the theoretical amount. The alkylation of an active methylene compound by an ester of a carboxylic acid rarely has been observed. Ethyl acetoacetate was found by Hauser and Breslow (4)to undergo isopropylation when treated with isopropyl acetate in the presence of boron trifluoride. Metal derivatives of monoalkylated malonic esters were found by Wallingford and Jones ( 5 ) to undergo alkylation when treated with alkyl carbonates. It appears that esters of alcohols of the allyl type are able to alkylate ethyl acetoacetate in a similar way. This hypothesis affords a satisfactory explanation of the formation of the esters of @-phenylpropionic and allylacetic acids when the sodium derivative of ethyl acetoacetate is treated with benzyl or allyl acetate, respectively, in the presence of sodium ethoxidie (6). It would appear that the new example of alkylation is closely related to that which occurs with allyl and benzyl esters, in which the release of the alkyl radicals occurs with unusual readiness. In diethoxymethyl acetate the release of the diethoxymethyl group as a carbonium ion is facilitated by the presence of the ethoxy groups on the carbon atom which is the electron-accepting component in the alkylation. The new ester (IV) also was isolated by careful fractionation of ethyl ethoxymethylenemalonate prepared by the Claisen method,2a fact which is in harmony with the belief that it is formed as an intermediate in that process. It was prepared a k o in 90% yield by the addition of a molecule of ethanol to ethyl ethoxymethylenemalonate in the presence of sodium ethoxide. CaHbOCH=C(COzC2Hs), I
+ C2H60H * (CzHsO)&KCH(COd22Hs)z Iv
The reaction was found to be reversed by heating in the presence of zincchloride; however, the main product under these conditions was not ethyl ethoxymethylenemalonate (I) but 3,5-dicarbethoxy-6-ethoxy-a-pyrone(V), a compound the structure of which was established by Guthzeit and Dressel (3). Since ethyl orthoformate was identified as a product of this decomposition, it seems likely that the formation of V may have occurred in the following way.
+
(C~H~O)ZCHCH(CO~C,H ZnCltk ,)~ CZH~OCH=C(CO~C~H&CzHaOH heat
IV I ( C ~ ” S O ) Z C H C H ( C O ~ C ~ HC2”aOH ~)Z + (C2H6O)&H CH~(CO~CZH~)Z C2HsOCH=C(COzC2Hs)i CHz(COzC2Hs)z +
+
+
+
The authors are indebted to Dr. Wesley Minnis of the National Aniline Division of the Allied Chemical and Dye Corporation for carrying out this fractionation.
196
FUSON, PARHAM, AND REED
0
II CzHsOC I CzHs02CCH
oczcs I c=o e I CCOZCzHs
OH
I CzH60C I
C2Hs02CC
\ /
OCtHs
I c=o I
Ft
CCOzCtHs
\ /
CH
CH
C!2H602C H 6O RC02CzHs F 0
V When ethyl diethoxymethylrnalonate (IV) was heated with zinc chloride in the presence of acetic anhydride the main product was ethyl ethoxymethylenemalonate (I). It is probable that under these conditions the acetic anhydride removes the ethyl alcohol which is formed, thus preventing the liberation of ethyl malonate and in turn formation of the pyrone. On the basis of this observation it seemed likely that the yield of ethyl ethoxymethylenemalonate from the Claisen procedure might be improved simply by heating the reaction product, without removal of the zinc chloride, in order to decompose the ethyl diethoxymethylmalonate. Experiment has verified this expectation. The heating converts the diethoxymethyl compound to the ethoxymethylene derivative, thus at once destroying a troublesome contaminant and increasing the yield of the desired product. EXPERIMENTAL
Condensation of diethoxymethgl acetate with ethyl malonate. Diethoxymethyl acetate, prepared by the method of Post and Erickson (2), was condensed with ethyl malonate by the following procedure. An equimolecular mixture of the two esters (80 g. of each) was heated until the temperature reached 116" (forty-five minutes). After four hours a t this temperature the mixture was distilled under reduced pressure; fraction 1, b.p. 69-92' (14-18 mm.), n t 1.3810-1.4150 (124 g.), consisted of a mixture of diethoxymethyl acetate and ethyl malonate; fraction 2, collected up to 125' (7.5 mm.), n: 1.4150 (3 g.), was mainly ethyl diethoxymethylmalonate; fraction 3, b.p. 126-129' (7 mm.), ng 1.4220 (22 g. or 17% of the theoretical amount), wae pure ethyl diethoxymethylrnalonate. When the foregoing experiment was carried out with 0.2 g. of anhydrous zinc chloride in the reaction mixture the yield of alkylation product was much greater. The product was separated by fractional distillation into three fractions. Fraction 1, b.p. 70-100' (15 mm.), n g 1.3980-1.4180 (54 g.), consisted mainly of unchanged reactants; fraction 2, b.p. 126-131' (8 mm.), n: 1.4180-1.4225 (17 g.), was ethyl diethoxymethylmalonate; fraction 3, b.p. 107-115' (0.5 mm.), n: 1.4275-1.4550 (53 g.), was a mixture of ethyl diethoxymethylmalonate and ethyl ethoicymethylenemalonate. Ethyl diethozymethylmalonate. To a mixture of 108 g. (0.5 mole) of ethyl ethoxymethylenemalonate and 5 ml. of a 10% solution of sodium ethoxide was added 41.4 g. (0.9 mole) of anhydrous ethanol during the course of ten minutes. The temperature was maintained at 30-40" during the addition of ethyl alcohol and for one hour afterward. The reaction mixture was neutralized with acetic acid and distilled under reduced pressure. The yield of ethyl diethoxymethylrnalonate. b.p. 88-89' (0.18 mm.), was 118 g. (90% of the theoretical amount). A redistilled sample, 55; 1.4209, was submitted for analysis.
ALKYL4TION OF ETHYL MALONATE
197
Anal. Calc'd for C12Ht206:C, 54.95;€I, 8.45. Found: C,54.75; H, 8.36. The compound isolated by fractional distillation of ethyl ethoxymethylenemalonate, prepared according to the Claisen method, had the boiling point 133-134" (7-9 mm.); ng 1.4209, ng 1.4220. A n d . Calc'd for C12H120c:C, 54.95;H, 8.45. Found: C, 54.97;H. 8.15. Pyrolysis of ethyl diethoxymethylmalonate. A . I n the presence of zinc chloride. A mixture of 30 g. of ethyl diethoxymethylmalonate and 0.1 g. of anhydrous zinc chloride was heated at 95-125" for two and one-half hours and then at 125-130" for two hours, while a slow stream of nitrogen gas was bubbled through it, During the heating process 12 ml. of distillate was collected. The reaction mixture was distilled under reduced pressure; fraction 1, b.p. 100-104" (0.19mm.), n: 1.4530,weighed 1.7 g. and consisted mainly of ethyl ethoxymethylenernalonate; fraction 2, b.p. 104" (0.19mm.), n: 1.4605 (6.5 g.), was pure ethyl iethoxymethylenemalonate; the residue (10.0 g.), solidified on cooling. After recrystallization from toluene and then from petroleum ether (90-110"), i t melted at 94-96" and did not depress the melting point of a n authentic sample of 3,5-dicarbethoxy-6-ethoxya-pyrone (V). During the vacuum distillation 4 g. of volatile material was collected in the dry-ice trap. This material and that colIected during the pyrolysis were combined and redistilled to give 5.4 g. of ethyl alcohol, b.p. 77", n t 1.3610 and 1 g. of ethyl orthoformate, b.p. 140-145", n t 1.3!)50. The latter compound was characterized by conversion to trianilinomethane, m.p. 107-138" (2). A mixed melting point with a n authentic sample was not depressed. B . I n the presence of zinc chloride and acetic anhydride. A mixture of 75 g. (0.286mole) of ethyl diethoxymethylmalonate, 35 g. (0.343mole) of acetic anhydride, and 0.1 g. of anhydrous zinc chloride was heated at 150-160° for two hours in a 200-ml. distilling flask equipped with a 6-in. column, still-head, and condenser. During the heating process 19 g. (0.21 mole) of ethyl acetate distilled and was collected. The reaction mixture was cooled, filtered, and distilled under reduced pressure; fraction 1, b.p. 85-109" (0.5mm.), n t 1.4300-1.4585 (18 g.), consisted of ethyl ethoxymethylenernalonate contaminated with unchanged ethyl diethoxymethylmalonate; fraction 2, b.p. 109' (0.5mm.), ng 1.4602 (37 g. or 627,), consisted of pure ethyl ethoxymethylenernalonate. Ethyl ethoxyrnethylenemalonate. This ester was made by a modification of the procedure of Claisen (1). A mixture of 1000 g. (6.75moles) of ethyl orthoformate, 1260 g. (12.3 moles) of acetic anhydride, 960 g. (6.0 moles) of ethyl malonate, and 0.5 g. of zinc chloride was placed in a 5-1. three-necked flask equipped with a thermometer and a 12-in. column packed with Berl saddles. The column was attached to a still-head and condenser. The mixture was well agitated and then heated as follows. Reaction Temp., "C.
Time ( H r s . )
102-115 2.5 115-127 7 127-145 2 145-155 2 After e[ght hours of heating, 250 g. (2.45 moles) of acetic anhydride and 200 g. (1.35moles) of ethyl orthoformate were added. The eleventh hour of heating was carried out at slightly reduced pressure (735 mm.) to aid in the removal of the last traces of volatile materials. The mixture was cooled to room temperature, filtered, and distilled under reduced pressure. A forerun, collected up to 70" (17 mm.), contained very little malonic ester. A second fraction was collected from 70-100" (17 mm.); when redistilled i t yielded 148 g. (15.3%) of malonic ester, n: 1.4142. The residue then was distilled in vucuo. In addition to a small forerun (15g,), 818 g. of ethyl ethoxymethylenemalonate was collected; b.p. 10&llOo (0.25 mm.); n: 1.4600-1.4620. The weight of residue was 35 g. The yield of ethyl ethoxymethylenernalonate was 63%, based upon the amount of malonic ester employed, or 75%, based upon the malonic ester which was consumed in the reaction.
198
FUSON, PARHAM, AND REED SUMMARY
It has been shown that ethyl malonate is alkylated when heated with diethoxymethyl acetate. The yield of' diethoxymethylation product is increased by the presence of a small amount of zinc chloride. The alkylation product, ethyl diethoxymethylmalonate, is a new compound; it has been prepared also by the addition of ethanol to ethyl ethoxymethylenemalonate in the presence of sodium ethoxide. URBANA, ILL. REFERENCES (I) CLAISEN, Ber., 26, 2729 (1893);Ann., 297, 16 (1897). (2) POSTAND ERICKSON, J . Org. Chem., 2, 260 (1937). (3) GUTHZEITAND DRESSEL, Ber., 22, 1413 (1889). (4) HAUSER AND BRESLOW, J . Ani. Chem. SOC.,62,2611 (1940). (5) WALLINGFORD AND JONES, J . Am. Chem. Soc., 84,578 (1942). (6) TSEOUAND WANO,J . Chinese Chem. Soe., 5 , 224 (1937); BACON, Am. Chem. J . , 33, 08 (1905).
