Phase-Transfer-Catalyzed Alkylation of Ethyl Acetoacetate and Diethyl Malonate Douglas L. Thompson and Peny C. Reeves1 Abilene Christian University. Abilene, TX 79699 Carbon alkylation of the esters of acetoacetic acid and malonic acid is an important topic in the introductorv orcanic chemistry course. it is also i&uded in most of thelabbratory manuals; however, several experimental difficulties make the reaction unattractive. w i t h sodium ethoxide in ethanol as a base system, the reaction is rather slow and the operation takes more than one lab period. There is also the hazard of working with sodium metal. Use of strong bases in nolar aurotic solvents increases the rate of the reaction but iields considerable quantities of 0-alkylation product ( I ) . The technique of phase-transfer catalysis has been shown to he useful for carbon alkylatious (2).Unfortunately phasetransfer-catalvzed alkvlations of diethvl malonate or ethvl acetoacetate "sing aqueous sodium hydroxide have not he& successful because of rapid hydrolysis of the ester groups. This prohlem has been offset by the use of tert-butyl esters (3) or by the use of stoichiometric amounts of quaternary ammonium hydroxides in a process called "extractive alkylation" ( 4 ) ;however, these techniques offer little advantage over the usual procedure. Recently it has been found that many reactions proceeding via carbanions can be carried out efficientlv usine- anhvdrous sodium or ootassium carbonate . as the h s e a n d crown ethersor t~~traalkylarnmonium salts as the catalvsrs i n a liaui(l-solid,two-vhnse svstetn (51. The aikylation of ethyl ac&oac&ate h i this method was studied in detail. In a typical experiment, the ester is mixed with powdered anhyd&us pot&sium carbonate, the catalyst, and a slight excess of an alkyl halide. The suspension is stirred and heated a t 100° for 1.5 h. I n the absence of a solvent the suspension becomes so thick that i t cannot be stirred magnetically. Suitable solvents are toluene and acetonitrile with the latter being preferred because of its ease of removal. The crude uroduct was analvzed bv- eas chromatography and shown to contain compounds arising from C- and from 0-alkylation (6).The C/O alkylation ratio was found to vary depending on the halide used (Table 1). Furthermore, the reaction temDerature has an effect on the C/O ratio with increases in temperature leading to an increase in the amount of 0-alkvlation. The results reveal that alkyl chlorides react slowest nnd that alkyl iodides produce the greatest amount of C-alkylation. In a related study ( 7 ) it was ubsewed that vary active halides ibenzyllic, allyliu) give prcdmninant amounts of Calkylation products. The oreoarative asuects of the reaction were then examined. series of alkyiiodides was reacted with ethyl acetoacetate and the results are uresented in Table 2. Secondarv hahdes may be used, but the rutes are diminished greatly. The produ~.tsareisolated I~vsimoledistillatiunand found to he 92-95% pure by gas chiomaiographic analysis with the impurities being 0-alkylated and dialkylated products. Similarly, reaction of diethyl malonate with alkyl bromides produces good yields of C-alkvlated products (Tahle 2). The impurities (-5%) are unreacted malonic ester and dialkylated product. The complete "acetoacetic ester synthesis" or "malonic ester synthesis2,can he demonstrated by cunver-
' Author to whom correspondence should be addressed.
Table 1. Alkylation of Ethyl Acetoacetate
n
I
I1
R-X
Reaction Completion ( % )
IIII Ratio
ffi,H&I ffi4H@r +CIHgl
10
2.711
97 97
10.511 42.411
Table 2. Products from Alkylation of Ethyl Acetoacetate and Diethyl Malonate
R
Compound l Yield ( % )
Compound I l l Bp ("C)
Bp (OC)
Yield (%)
sion of these products to the corresponding substituted acetone or acetic acid by the usual procedures (8). Conclusion There areseveral featurrsof this work that make it attfactive for the undergraduate organic lnboratory. These include (1)shorter reaction and workup times than the traditional method, (2) the use of a mild base t o form the carbanion, (3) the use of a phase-transfer catalyst, (4) a variety of reactants from which to choose, and (5) the ability to demonstrate and examine factors governing C/O alkylation ratios. Furthermore, this method provides a good illustration of the liquidsolid, two-phase system employed in some variations of phase-transfer catalysis. Experlrnental Procedure excent that The same ~raeedurewas followed for all alkvlations , alkyl hromider sere wpd in the nlkylationl of dirthyl malanntt.. and alkyl iodide5 were wed in thp alk>latiunsot ethyl acetoacetnrc. The prepnration c ~ fdirtllvl n-penryhnolunaters deacrilwd m detail aa a typical example. Into a dry 50-ml round-bottomed flask equipped with a mag~
~~
~
Volume 62 Nwnhar I n
~
Octnhar l Q R 5
~~~~~
F~
~~
~ n 7
netic stirring bar and
condenser were placed 8.00 g (0.050 mol) diethyl malonate, 8.30 g (0.055 moll 1-hromopentane, 0.50 g (0.002 mol) of 18-crown-6 (caution: toxic) and 5 ml of acetonitrile. Anhydrous potassium carbonate (8.29 g, 0.060 mol) was pulverized finely and added immediately. The mixture was heated at 1 0 0 T for 1.5 h with vigorous stirring. Following this time the mixture was poured into water and extracted with 25 of dichloromethane. T h e organic layer was collected, the solvent removed, and the residue distilled rapidly to minimize thermal decomposition (short path distillation with burner or heating mantle). Unreacted diethy1 m a h a t e and excess l-hromopentane were collected below 215°C and the product (8.22 g, 72%) was collected from 248-253°C. T h e identity of the compound was confirmed by comparisonwith IR and NMR spectra of the authentic compound. Gas chromatographic analysis (6) of the product indicated a purity of 95%.
908
Journal of Chemical Education
Acknowledgment
The authors thank the Robert A. Welch Foundation, Houston, Texas*for "pport Of this work. ~
l
t cited ~
~
a
~
~
~
G.. and Pelletier. W..Tetrahedron L d t . 3555 (19651. 12) Weber. W., and Goke1.G.. J. CmM. Eouc., 55,350,429 (1978):Starha,C.,andLiotta, c., "~hasp~ransrer catalysis," ~cademic press. N ~ W ~ork. 1978. I31 Jonnyk. A,. Ludwikow, M. and Makoeza, M., Rocz. Chem.,47.89 (19731. 14) Brandstr6m. A., and Junggren, U.,Aefo Chem. Seond.. 23.2203 (1969):Singh. R..and Danishefsky. S., J . Org. Chem.. 40,2969 (19751. i5) ~ . d ~ ~ ~ M., i,~ ~ k~i , j ~ i ~ K., ~~ h~ ~ tz~ ..aand ~ ~M k .i~ ,~ W M., UJ., olg. cham..43. 4682 (19781. (61 Le Noble, W..and Morris, H.,J Org. Cham. 34,1969 l1969l. (71 Dur~t.H.,sndLiekkind,L.,J . 0 % Chm,39,3271(1974). (8) Gilman, H. (Editor),Wrg. Synth., Coll. Vol. I." 2nd ed., John Wiley and Som, Inc, ~ew ~ o r k1941.p. , 351:~ l s t t ,i~ditor), ~. "erg. synth..coll. vol. 11." 2nd ed.,hhn wo r k1943.p. , 116. wiley8r.d sons, I ~ C~, e ~ (1) B"eg-.
