Convenient synthesis and characterization of molecules containing multiple β-keto ester units

Article abstract of DOI:10.1016/j.tetlet.2012.07.025

Three compounds containing two β-keto ester units and one containing three were obtained in good yields from sebacyl, terepthaloyl, isophthaloyl, and trimesoyl chlorides. In this one pot procedure the acid chlorides were first treated with ethyl acetoacetate and barium oxide and then with ethyl alcohol. The aliphatic ester exists mainly as keto ester with a very small amount of the enol tautomer. In the case of aromatic esters, all possible tautomers were found in considerable concentrations in deuterochloroform solution. Theoretical chemical shifts were estimated from GIAO/WP04/aug - cc-pVDZ/SCRF calculations, for a probable signal assignation for the corresponding tautomeric species. Our theoretical results are in agreement with experimental findings and account for negligible stability differences between the tautomers of each aromatic compound.

Full text of DOI:10.1016/j.tetlet.2012.07.025

Tetrahedron Letters 53 (2012) 4984–4988
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient synthesis and characterization of molecules containing multiple
b-keto ester units
⇑
Julio Belmar , Leandro Ortiz, Denis Ramírez, Fabiola Fuentes, María Parra, Verónica A. Jiménez,
Claudio A. Jiménez
Department of Organic Chemistry, Faculty of Chemical Sciences, University of Concepcion, Casilla 160-C, Concepción, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
Three compounds containing two b-keto ester units and one containing three were obtained in good
yields from sebacyl, terepthaloyl, isophthaloyl, and trimesoyl chlorides. In this one pot procedure the acid
chlorides were first treated with ethyl acetoacetate and barium oxide and then with ethyl alcohol. The
aliphatic ester exists mainly as keto ester with a very small amount of the enol tautomer. In the case
of aromatic esters, all possible tautomers were found in considerable concentrations in deuterochloro-
form solution. Theoretical chemical shifts were estimated from GIAO/WP04/aug—cc-pVDZ/SCRF calcula-
tions, for a probable signal assignation for the corresponding tautomeric species. Our theoretical results
are in agreement with experimental findings and account for negligible stability differences between the
tautomers of each aromatic compound.
Received 8 June 2012
Revised 4 July 2012
Accepted 6 July 2012
Available online 16 July 2012
Keywords:
b-Diketodiesters
b-Triketotriester
Prototropic tautomerism
Keto–enol
Ó 2012 Elsevier Ltd. All rights reserved.
b-Keto esters represent very valuable precursors in organic
synthesis,1–4 being widely used to prepare heterocycles,4–6
ketones,3 and b-hydroxyesters.3 These chemicals are important for
agrochemical, pharmaceutical, and dye industries.2 They have been
used in the syntheses of complex natural products too.2,7 b-Keto es-
ters can also be valuable in condensation reactions as stabilized
enolates or active methylene equivalents.8 This wide variety of
applications and the fact that a rather small number of them are
commercially available,4 have probably provided the driving force
to develop a significant number of procedures to obtain them,1,9
ever since the first reports by Claisen.10,11 Molecules containing
multiple b-keto ester moieties have been used in polymerization
reactions by poly-Michael condensation, yielding analogues to car-
bon monoxide copolymers.12 They also represent attractive syn-
thetic building blocks, for instance in asymmetric reductions to
polyols.13 Since b-keto esters are able to chelate metal ions they
could be used to obtain metal-organic supramolecular assemblies
in a similar way it has been reported for molecules with several
b-diketone units.14 However, molecules containing more than one
b-keto ester unit are seldom reported.15–17 Their syntheses repre-
sent an extra challenge because procedures that are suitable to ob-
tain mono b-keto esters will not necessarily furnish the same results
trying to obtain molecules with a superior number of this moiety.
Our interest in molecules containing several b-keto ester units
stems from the idea of using them in condensation reactions with
hydrazines in order to obtain molecules that incorporate several
5-pyrazolone rings in its structure. To date, condensation of hydra-
zines with b-keto esters is still the most general and practical reac-
tion to obtain pyrazolones. The models in this objective are some
related structures containing heterocyclic moieties already re-
ported in the literature.18,19,15c
There are some previous reports regarding aromatic homo-
logues. Compound 1 (Scheme 1) was easily obtained in a one pot
procedure and with good yield from therephtalaldehyde and ethyl
diazoacetate, using montmonirrollite K-10 as catalyst.15b However,
the diazo reagent raises some safety concerns for large scale syn-
theses. Besides, the procedure was used to synthesize small
amounts of the product. Compound 2 (Scheme 1) was obtained
by a several step route.15c Dimethyl m-phenylenediacrylate acid
was brominated and then transformed into dimethyl m-phenylen-
edipropiolate acid which by sulfuric acid catalyzed hydration affor-
ded the target product. The main drawback of the synthesis is the
number of steps, which is especially important if the diester is pre-
pared to be used as a starting material in a subsequent reaction or
synthesis. The availability and the price of the starting material is a
second problem with this synthesis. In these two cases, spectro-
scopic data were not reported and therefore no information
regarding tautomerism is known. For compound 2 the situation
is absolutely understandable considering the date it was reported.
In this Letter the successful application of one procedure to prepare
some di-b-keto esters and one tri-b-keto ester from readily avail-
able and not expensive reagents is reported. The tautomerism ob-
served is also discussed.
The fact that a reaction between two functional groups can be
carried out successfully with high yields does not necessarily imply
⇑
Corresponding author. Tel.: +56 41 2204258; fax: +56 41 2245974.
E-mail address: jbelmar@udec.cl (J. Belmar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.025

J. Belmar et al. / Tetrahedron Letters 53 (2012) 4984–4988
4985
Scheme 1. Reagents and conditions: (a) BaO, H2O, ethyl acetoacetate, toluene, rt, (b) EtOH, H2SO4 5%, toluene, rt, yields: 1 (78%), 2 (73%), 3 (73%), and 4 (78%).
that the same result will be observed for the same reaction taking
place simultaneously at several points in one substrate. This situa-
tion makes relevant the search for new procedures or to study
which ones among those already known are suitable to obtain
multifunctional counterparts. In the case of obtaining molecules
with several b-keto ester units, reports are not as general as they
could be expected. Random results have been reported in some
cases.15a,20 In order to obtain the target compounds, our attention
was focused on procedures characterized by fairly good yields and
at a convenient scale, considering that the products would be used
as starting materials in other reactions. Thus, in the first experi-
ments the procedure described by Yonemitsu21 that gives b-keto
esters in good yields starting from an acid chloride and Meldrum’s
acid followed by solvolysis with an alcohol was tried. The proce-
dure was useless in trying to obtain aromatic di- or tri-b-keto es-
ters. It is interesting to mention that Mahulikar and Mane20
serendipitously isolated di-b-keto esters from glutaroyl or adipoyl
dichlorides and Meldrum’s acid. Kosower15a has also reported good
results following the same procedure in the synthesis of diethyl
3,8-dioxodecanedioate, but he also failed with other aliphatic dia-
cid dichlorides. After the bad results obtained with Meldrum’s acid,
the procedure reported by Yuasa and Tsuruta22 was tried (Scheme
1). It was this procedure that finally furnished the desired prod-
ucts. As it can be seen, it worked for aromatic and aliphatic acyl ha-
lides. The reaction was repeated increasing up to four times the
amounts of reagents described in the Supplementary data without
noticeable effect in the yields. The limit was the size of the flask to
carry out the reaction and the stirring system.
signals are observed at 8.04 and 7.82 ppm. However, with the
available information it is not possible to unequivocally assign
each signal to the corresponding tautomer. Signals corresponding
to the aromatic hydrogens of tautomer 1b can be identified with-
out any doubt, because they constitute an AA’BB’ spin system that
gives rise to a doublet of doublets centered at 7.94 ppm. The spec-
trum of compound 2 also supports the presence of three tautomers
in the aromatic region; however, establishing which hydrogen is
responsible for each signal is again not straightforward with the
present information.
The small variations in the structure on going from one tauto-
mer to the other, makes it difficult to assign the signals with their
corresponding protons. In order to provide complementary infor-
mation to help in NMR signal assignments, DFT computational
chemistry calculations were carried out with the method GIAO/
WP04/aug—cc-pVDZ/SCRF,28 which has been described in the liter-
ature as a reliable method to obtain theoretical chemical shifts
comparable with experimental values.29 Tables SI1, SI2 and SI3
summarize these results for compounds 1, 2, and 3, respectively.
As it can be concluded the hydrogen atoms in the aromatic rings
of the di- or tri-keto structures are less shielded than the di- or
tri-enol. Calculations also indicated that the vinylic protons are
more shielded as the number of enolized groups in a molecule in-
crease. Although in some cases theoretical calculations clearly dif-
fer from experimental shifts and in other cases, the differences in
calculated values for related hydrogen atoms are too small to be
reliable, the fact that enolization produces a shielding was used
as a guide for the assignation. But, it is important to consider that
with the information available an unequivocal assignation based
on the calculated data is not possible in all the cases and the
assignments are only likely ones. Additional experiments are re-
quired to get fully reliable assignments. Thus, the chemical shift
for the vinyl proton is smaller for the dienol 1c, than for the
monoenol 1b, 5.72 and 5.74 ppm, respectively (seeFig. 1) and it fol-
lows that the concentration of dienol is lower than that of the
monoenol. On the other side, methylenic hydrogens of tautomers
1a and 1b, 4.02 and 4.01 ppm, respectively. As previously stated,
assigning the signals corresponding to the aromatic part is easier
owing to symmetry. Besides, due to the better resolution of these
signals, it is possible to ingrate their areas in order to estimate
the relative abundances of the tautomers.
Organic chemists are quite familiar with keto–enol tautomer-
ism.23–26 Particularly in the case of di-b-keto esters, Langer et al.
studied the synthesis and tautomerism of 3,5-dioxopimelates.17
In the present case several tautomers can be envisaged for com-
pounds 1 to 4 (Scheme 2).
According to the solubility of the compounds the 1H NMR spec-
tra were recorded in CDCl3.27 Since our goal was the synthesis and
the rapid characterization of the products, trials in other solvents
were not attempted. For the di-esters 1 and 2, two singlets around
4 ppm are observed, corresponding to the methylenic hydrogens
between the carbonyls. This result indicates that compounds 1
and 2 exist in two different tautomeric forms (1a/1b and 2a/2b),
which share a common connectivity in the methylenic hydrogen
region. Additionally, two signals are observed near 6 ppm corre-
sponding to the vinylic hydrogens of enolized tautomers, which
indicate the coexistence of tautomers 1b/1c for compound 1, and
tautomers 2b/2c for compound 2 (Fig. 1).
Chemical shift of the aromatic protons in tautomer 1a is
8.04 ppm, while in tautomer 1c the value is 7.82 ppm. For tauto-
mer 1b the values are 7.99 ppm and 7.87 ppm. The abundances
as obtained from the areas are 54% of 1b, 36% of 1a, and 10% for
1c. Chemical shifts for the OH protons are in agreement with the
assignment based on the relative abundance for tautomer 1b and
1c.
Regarding compound 2 (Fig. 1) the signals at 5.73 and 5.72 ppm
can be assigned to 2b and 2c, respectively. The methylenes be-
tween the carbonyls in tautomers 2a and 2b are observed at 4.03
Other important signals that account for the presence of enol
tautomers appear over 12 ppm. These signals correspond to OH
groups that are strongly shifted downfield by intramolecular
hydrogen bonding. Compound 1 is the easiest to analyze, consider-
ing the symmetry of structures 1a and 1c, which should be de-
tected as two singlets in the aromatic region, respectively. Those

4986
J. Belmar et al. / Tetrahedron Letters 53 (2012) 4984–4988
Scheme 2. Tautomeric forms for di-b-ketodiesters and tri-b-ketotriesters.
Figure 1. Selected areas of 1H NMR of compounds 1 and 2. Each signal shows the corresponding experimental and (calculated) chemical shifts.
and 4.02 ppm, correspondingly. As concluded from the previous re-
sult for 2b and 2c, the methylene in 2b must have a smaller chem-
ical shift than in 2a. The protons in the aromatic ring are not well
resolved, rendering integration not accurate; this in turn makes
unreliable any calculation of the tautomers concentration. Regard-
ing the OH protons, calculations predict that they are more
shielded in 2c than in 2b. The corresponding experimental values
are 12.61 and 12.59 ppm. Thus, for this compound it is possible

J. Belmar et al. / Tetrahedron Letters 53 (2012) 4984–4988
4987
Table 1
Selected 13C NMR chemical shifts (ppm) of 1, 2, 3, and 4
Compound
C@O (keto)
C@O (ester)
@C–OH
@C–H (vinyl)
1
192.0
173.1
172.9
170.1
169.5
167.3
167.1
89.4(8)
89.4(9)
2
3
191.9
191.7
172.9
172.8
170.9
169.6
167.2
167.1
88.2
87.9
191.3
191.2
191.0
174.7
166.8(4)
166.7(7)
166.7(3)
89.1(7)a
88.9(7)
88.8(4)a
172.7(2)
172.6(9)
172.6(5)
168.7
168.4
168.2
4
202.9
167.3
n.o.b
89.0
a
More intense.
Not observed.
b
Regarding the aliphatic ester, the proton spectrum shows that
compound 4 exists mainly as the di-keto compound (4a). However
it is still possible to observe a tiny signal for the OH at 12.08 ppm
and two signals at 4.95 and 5.57 ppm for vinylic hydrogens. The
area of the signal corresponding to the OH group duplicates the
one of the vinylic protons. Comparing with the area of the CH2 be-
tween the carbonyls at 3.41 ppm, the signal of the OH represents
almost 1%. Another clue for enolization is that all the other impor-
tant signals in the spectrum are accompanied by a small replica-
tion of them. For instance, the quartet that corresponds to OCH2
that appears at 4.18 ppm and is accompanied by a small quartet
slightly shifted downfield and appears at 4.25 ppm. The singlet
for the methylene between the carbonyls appears at 3.41 ppm
and it is also accompanied by a small singlet at 3.43 ppm. The trip-
let for the C-4 and C-11 methylene groups appears at 2.51 ppm and
his partner at 2.63 ppm. The bigger difference in chemical shift in
this case can be due to the nearness respect to the changing part
of the molecule. There is a multiplet at 1.57 ppm corresponding
to the methylene group of C-5 and C-10. In this case the partner
signal is only a small shoulder. The last signal, at 1.26, corresponds
to the two CH3 and the rest of the CH2 at the center of the molecule
(C-6, C-7, C-8, and C-9). This signal is a distorted triplet and it is
accompanied by a small triplet at 1.35. The coupling constant is
7.25 Hz, and this signal cannot be integrated because the small sig-
nal lies at the base of the bigger one. Other authors have also de-
scribed that the di-keto tautomer is the most abundant for
homologous di-esters.12,14,26 The 13C NMR for compound 4 is also
consistent with the presence of the di-keto tautomer as the main
species in the solution.
The FTIR spectra of compounds 1 and 2 show a characteristic
band between 1740–1745 cmÀ1 for C@O of the ester. The ketone
C@O appears between 1685 and 1690 cmÀ1. In the case of com-
pound 3 the values are 1736 and 1690 cmÀ1, correspondingly. There
is also another very intense signal around 1633 and 1640 cmÀ1 that
may correspond to C@C stretching of the enol moiety.
As a consequence of enolization, C@O bands appear to be broad-
ened, C@C–OH bands are more intense and broad than conven-
tional C@C bands, which are of moderate intensity. In these
spectra a wide signal from around 3500 cmÀ1 until 2400 cmÀ1 that
corresponds to the O-H involved in hydrogen bonding. This signal
is overlapped with those corresponding the different C–H
stretching.
Figure 2. Selected 1H NMR signals of compound 3 (calculated values between
parentheses). Insert: patterns of the aromatic region in 1H NMR spectrum for the
tautomers of compound 3.
to affirm that 2b is the most abundant species followed by 2a and
finally 2c; but, again, the percentages cannot be obtained owing to
the low resolution.
Compound 3 exhibits three singlets around 4 ppm, correspond-
ing to the methylenic hydrogen,
a to the carbonyl groups. This re-
sult agrees with the presence of tautomers 3a, 3b, and 3c. Three
signals near 6 ppm corresponding to three vinylic hydrogens are
also observed. This result shows that there are three tautomers
with different enolic groups as is the case of structures 3b, 3c,
and 3d. Three signals between 12 and 13 ppm corresponding to
the three OH are also observed and support the coexistence of
the different tautomeric species (Fig. 2).
Figure 2 shows that for compound 3 the vinylic hydrogen in tau-
tomer 3d is the most shielded, then in tautomer 3c and finally in
tautomer 3b. Following the tendency of the calculated values, the
experimental chemical shifts at 5.82, 5.79, and 5.77 ppm were as-
signed to the vinylic protons of tautomers 3b, 3c, and 3d, corre-
spondingly. In a similar way the signals at 4.08, 4.07, and
4.05 ppm were assigned to the methylenic hydrogens between
the carbonyls in tautomers 3a, 3b, and 3c, correspondingly. The
signals at 8.24 and 8.71 ppm were assigned to the aromatic hydro-
gen of tautomers 3d and 3a, the tri-enol, and the tri-keto, respec-
tively (Fig. 2, insert). The other signals in the aromatic region
were assigned following the guide provided by the calculated
chemical shifts.
The abundances of the tautomers, as calculated from the aro-
matic signal areas, are 48% of 3b, 27% of 3a, 21% of 3c, and 4% of
3d. Finally the signals corresponding to the hydroxyl protons
(Fig. 2) can be assigned considering the relative abundances of
the tautomers provided by the aromatic signals, beside the infor-
mation provided by the calculated chemical shifts. Additionally,
this assignation agrees with that of the vinylic protons.
13C NMR data are in well agreement with the mixture of tau-
tomers. A first inspection of the spectra indicates that there are
some missing signals. However, the relative intensities of some
of them show that this may be due to overlapping. Table 1 summa-
rizes the 13C signal for compound 1, 2, 3, and 4.
Further results including more detailed NMR experiments with
a more powerful spectrometer in order to obtain unambiguous
assignations of the chemical shifts will be reported in due time.

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J. Belmar et al. / Tetrahedron Letters 53 (2012) 4984–4988
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The acylation of ethyl acetoacetate using BaO as base has been
successfully extended to obtain compounds with more than one
b-keto ester units. The synthesized products were conveniently
isolated from the reacting mixture and purified by crystallization
or column chromatography. The large volumes of solvent and ethyl
acetoacetate are recovered and can be reused. This alternative
allows overcoming the difficulties that appeared following the con-
ventional pathway with Meldrum’s acid which turned out to be
unsuitable with several aromatic diacyl or triacyl chlorides that
were included in the study; despite the good yields that have been
reported in the syntheses of compounds with one b-keto ester
functionality. Thus, the presented results widen the scope of proce-
dures so far reported in the synthesis molecules containing multi-
ple b-keto ester moieties and open possibilities to prepare novel
derivatives.
Results obtained show that the condensation of Meldrum’s acid
di or tri acyl chlorides is not as general as the condensation with
mono acyl halides.
Computational calculations were employed as an auxiliary tool
to guide the assignment of probable chemical shifts in the experi-
mental 1H NMR spectra.
NMR data support the existence of several tautomers in solu-
tion. The main tautomer in CDCl3 solution in the case of aromatic
keto esters is the monoenol, in the case of the non-aromatic homo-
logue the main tautomer is largely the diketo.
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Acknowledgment
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Financial support was provided by the Chilean National Re-
search Council, Fondecyt (Grant 1080262). Authors are also fully
indebted to Prof. K. Raymond who provided a place in his labora-
tory to graduate student L. Ortiz.
25. Long, J. A.; Harris, N. J.; Lamertsma, K. J. Org. Chem. 2001, 66, 6762.
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27. Compounds were characterized by FTIR (Nicolet, Magna 550), 1H and 13C NMR
(Bruker AC 250P; 250 MHz for 1H and 62.9, operating temperature was 28 °C)
and using TMS as internal standard. CDCl3 from Merck Chemicals was used
without further treatment. Concentrations roughly 10 to 15 mg per ml for 1H
and 40–50 mg per ml for 13C were used.
28. Geometry optimization of each tautomeric species was carried out at B3LYP/6-
311++G(d,p) level of theory without imposing any symmetry restriction.
Conformational analysis was performed in order to identify the most stable
conformation of the b-keto ester units related to the aromatic ring. Theoretical
chemical shifts were obtained from the standard GIAO/WP04/aug—cc-pVDZ/
SCRF method, using TMS as reference compound. More specifications see in
Supplementary data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
025.
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