Efficient transesterification of ethyl acetoacetate with higher alcohols without catalysts

Article abstract of DOI:10.1016/j.tetlet.2008.01.018

The transesterification of ethyl acetoacetate (EtOAcac) without the use of catalysts is shown for primary, secondary and tertiary alcohols. The use of molecular sieves, which are used to shift the equilibrium, allows the synthesis of products in high yields and acceptable reaction times, which are on a par with those for transesterification processes using catalysts. The kinetics of the transesterification of EtOAcac with tert-amyl alcohol is studied.

Full text of DOI:10.1016/j.tetlet.2008.01.018

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Tetrahedron Letters 49 (2008) 1645–1647
Efficient transesterification of ethyl acetoacetate with higher
alcohols without catalysts
L. I. Koval *, V. I. Dzyuba, O. L. Ilnitska, V. I. Pekhnyo
V.I. Vernadskii Institute of General and Inorganic Chemistry, Ukrainian National Academy of Sciences, Prospect Palladina 32-34, 03680 Kyiv 142, Ukraine
Received 16 October 2007; revised 20 December 2007; accepted 3 January 2008
Available online 8 January 2008
Abstract
The transesterification of ethyl acetoacetate (EtOAcac) without the use of catalysts is shown for primary, secondary and tertiary alco-
hols. The use of molecular sieves, which are used to shift the equilibrium, allows the synthesis of products in high yields and acceptable
reaction times, which are on a par with those for transesterification processes using catalysts. The kinetics of the transesterification of
EtOAcac with tert-amyl alcohol is studied.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Transesterification; b-Ketoesters; Alcohols; Molecular sieves
The sphere of our scientific interests is in coordination
chemistry of biometals1 with organic compounds as
ligands, which contain functional coordinating groups typ-
ical of biochemical systems. The use of such coordination
compounds in various fields of science and engineering
has promise in the development of modern environmen-
tally acceptable technologies.
structural analogs of b-diketones, also have antiviral activ-
ity. In view of this, compounds, which contain bulky
alicyclic fragments of alcohols such as menthol, borneol
and adamantanol in addition to a b-dicarbonyl group,
are of interest. These compounds are bioactive substances
that occur in Nature, and efficient antiviral drugs have been
developed based on adamantane.6
Among the above organic compounds, b-ketoesters are
of interest since their chelate complexes with metals can
find application as multifunctional additives in various
lubricating compositions, including those based on oils of
biological origin,2 as potential antiviral drugs3 and cata-
lysts for various stereoselective reactions.4 Moreover,
b-ketoesters are of practical importance in preparative
organic synthesis and can be used in lubricants as efficient
friction modifiers.5
The aim of our work was to obtain a number of b-keto-
esters by the simple and commonly used method of trans-
esterification from readily available ethyl acetoacetate. The
latter can be synthesized by Claisen condensation from ethyl
acetate, which can be produced commercially from renew-
able raw materials of vegetable origin, viz. by esterification
of acetic acid with ethanol. In addition to menthol, borneol
and 1-adamantanol, we also used 1-hexanol, 1-dodecanol,
cyclohexanol and 2-methyl-2-butanol as substrates. The
presence of bulky alkyl substituents will impart high solubil-
ity in organic media of the coordination compounds.
For the transesterification of b-ketoesters, a large num-
ber of catalysts have been proposed and investigated,7 many
of which are expensive (e.g., Nb2O5)8 and rather dangerous
to the environment and health (tin derivatives).9 Different
catalysts give different results: the transesterification time,
reactant ratio and end product yields differ greatly for the
It is known3 that metal chelates of b-diketones suppress
the activity of some pathogenic viruses through the forma-
tion of a coordinate bond to metal ions at the active site of
the virus enzyme responsible for virus replication. It may
be assumed that b-ketoester derivatives, as the closest
*
Corresponding author. Tel.: +380 44 424 3461; fax: +380 44 424 3070.
E-mail address: l_koval@ionc.kiev.ua (L. I. Koval).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.018

1646
L. I. Koval et al. / Tetrahedron Letters 49 (2008) 1645–1647
[molecular sieves]
toluene, reflux
O
O
O
O
Molecular
sieves
CH2CH3
+ ROH
C2H5OH
+
R
O
H3C
O
H3C
same starting compounds. According to Le Chatelier’s prin-
ciple, effective removal of one of the products from the reac-
tion is required to shift the equilibrium of reversible
processes, for example, transesterification. Bader et al.10
synthesized a number of b-ketoesters of higher alcohols,
including 1-dodecanol, cyclohexanol and menthol, in high
yields without the use of catalysts, by continuously distilling
the lower alcohol formed from the reaction mixtures. A sim-
ple and more convenient method for the removal of the
lower alcohol is azeotropic distillation, which allows the
use of stoichiometric reactants.11 An alternative method,
involving adsorption of the alcohol formed with molecular
sieves,12 is more efficient. The use of molecular sieves has
been reported for the transesterification of carboxylic
esters,13 sugar orthoesters,14 and methyl or ethyl b-ketoest-
ers with allyl alcohol derivatives.15 At the same time, all the
above reactions were carried out in the presence of catalysts.
Studying the transesterification of dimethyl terephthalate
with tert-butanol, which is catalyzed by potassium tert-
butylate in the presence of molecular sieves, Roelofsen
et al.16 showed that the time for almost complete transeste-
rification of the original ester into the end product was
much shorter in cases where molecular sieves form part of
the reaction medium. However, the interpretation of this
result was not correct since molecular sieves themselves
can be transesterification reaction catalysts.17
In our experiments, we used molecular sieves with a pore
˚
size of 0.4 nm (4 A) (ethyl alcohol molecules penetrate easily
into pores of this size and are selectively bound by the active
adsorbent), placed in a Sohxlet apparatus, to obtain pri-
mary, secondary and tertiary b-ketoesters from ethyl aceto-
acetate using equimolar reactant ratios (with the exception
of reaction with 2-methyl-2-butanol) in the absence of cata-
lysts.18 Under such conditions, the transesterification pro-
cess was carried out successfully with special preparation
of the molecular sieves (which increased greatly their
adsorption capacity) and exclusion of atmospheric mois-
ture. The molecular sieves were first activated at 300 °C at
atmospheric pressure for 8 h and then further dried for
3 h at the same temperature under 12 Pa vacuum using a
trap placed in liquid nitrogen to freeze out water vapor.19
The results of our investigations are listed in Table 1.
Analysis of the tabulated data shows that the reaction
time increases as expected, in going from primary to
Table 1
Transesterification of ethyl acetoacetate using various alcohols and molecular sieves
Entry
Alcohol
Time (h)
B
Product
Boiling point of product, (°C)
Yield (%)
B
A
4
A
O
O
O
1
2
1-Hexanol
—
127–128 (25 hPa)
115–116 (12 Pa)
95
—
CH2(CH2)4CH3
CH2(CH2)10CH3
O
O
O
O
1-Dodecanol
5
817
93
87
8617
O
O
3
4
Cyclohexanol
Menthol
9.5
249a
132–134 (25 hPa)
92–93 (12 Pa)
919a
O
O
O
O
12
16
817, 249a
92
78
9517, 939a
O
5
Borneol
429a
90–91 (12 Pa)
959a
O
O
O
O
O
6
7
1-Adamantanol
24
9
—
—
94–95 (12 Pa)
25
90
—
—
O
O
2-Methyl-2-butanol
99–101 (25 hPa)
(A) Experimental data; (B) literature data.

L. I. Koval et al. / Tetrahedron Letters 49 (2008) 1645–1647
1647
secondary alcohols and on complication of the hydrocar-
bon skeleton of secondary alcohols. The yields of the
desired b-ketoester decreased in the same order. Both the
reaction time and the end product yield were on a par with
the literature data for transesterifications carried out in the
presence of a catalyst.
possibility of regeneration of molecular sieves, and the
use of raw materials of vegetable origin make the proposed
method acceptable for the development of environmentally
friendly industrial technology.
References and notes
The rate of transesterification is greatly affected by steric
factors, thus tertiary alcohols are less active. However, we
obtained 1-adamantanyl acetoacetate; the yield of the puri-
fied product (a colorless labile liquid, which crystallizes
with time) was 25% after boiling the reaction mixture for
24 h. The identity of the product was confirmed by liquid
chromatography (TLC and HPLC); 1H, 13C NMR and
IR spectroscopic data agreed with the literature data.20
Thermodynamic and kinetic investigations of b-ketoester
transesterification reactions in the absence of catalysts have
been reported. Witzeman has asserted that it is impossible to
obtain tertiary b-ketoesters from methyl acetoacetate or
ethyl acetoacetate because of the high thermodynamic
stability of the latter and high rate of product decomposition
in the reverse reaction.21 We decided to verify this assertion
by studying the kinetics of the reaction of ethyl acetoacetate
with tert-amyl alcohol. Taking into account that displace-
ment of the equilibrium of reversible reactions is easily
attained by using an excess of one of the reactants, the syn-
thesis was carried out in tert-amyl alcohol pre-dried over
molecular sieves; the bp of this alcohol (102 °C) is much
higher than that of ethanol, which makes it possible to
remove effectively the latter from the reaction medium.
The rate of the reaction was checked by following the
increase in concentration of tert-amyl acetoacetate and by
the consumption of the starting b-ketoester using GC. The
results showed that the original b-ketoester was almost con-
verted completely to the desired product within 9 h (Fig. 1).
Thus the use of specially prepared molecular sieves for
the removal of ethanol formed during the transesterifi-
cation of ethyl acetoacetate with various alcohols makes
is possible to obtain b-ketoesters of primary, secondary
and tertiary alcohols in high yields, including those with
bulky alicyclic fragments. The simple experimental set-up,
1. Williams, D. R. In The Metals of Life; Russian Ed.; Mir: Moscow,
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3. (a) Hutchinson, D. W. Antiviral Res. 1985, 5, 193–205; (b) Tramon-
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Antiviral Res. 2005, 65, 117–124.
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Chem. Rev. 1995, 95, 1065–1114.
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¨
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van Bekkum, H. Rec. Trav. Chim. 1970, 89, 193–210.
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18. General procedure for the transesterification: freshly distilled (or
sublimated) dry alcohol (1 equiv) and ethyl acetoacetate (1 equiv) were
refluxed (Table 1) in dry toluene under an inert-gas atmosphere in a
system provided with Soxhlet extractor body (filled with molecular
sieves) to remove the ethanol formed. Toluene was chosen as a solvent
since it forms an azeotropic mixture with an ethanol content of 70%,
owing to which the effectiveness of ethanol removal increases (unlike
benzene, in which the reaction does not go to completion under the
same conditions). The inert atmosphere was produced by passing
argon through a capillary; gas bubbles created boiling centers on the
one hand and prevented superfluous resinification of the reaction
medium on the other hand. The extent of the reaction was checked by
TLC. The solvent was removed using a rotary evaporator. The
residues were distilled in vacuo to yield the products. All products were
analyzed by bp, NMR, IR, GC and HPLC, and the spectra were
consistent with the structures of the desired products.
19. Baudler, M.; Brauer, G.; Feher, F.; Huber, F.; Klement, R.; Kwasnik,
W.; Schenk, P. W.; Schmeiser, M.; Steudel, R. Handbuch der
Pra¨parativen Anorganischen Chemie in drei Ba¨nden; Herausgegeben
von Brauer G. Dritte umgearbeitete Auflage; Ferdinand Enke Verlag:
Stuttgart, 1975. Russian Ed.; Mir: Moscow, 1985; Vol. 1, pp 43–44.
20. Fukushima, K.; Lu, Y.-Q.; Ibata, T. Bull. Chem. Soc. Jpn. 1996, 69,
3289–3295.
100
80
60
40
20
0
PRODUCT
tert-amyl acetoacetate
Ethyl acetoacetate
0
2
4
6
8
10
TIME, h
Fig. 1. Kinetic curves for the transesterification of ethyl acetoacetate with
21. Witzeman, J. S. Tetrahedron Lett. 1990, 31, 1401–1404.
tert-amyl alcohol at 102 °C.