Accepted Manuscript
An efficient synthesis of β-ketoesters via transesterification and its applicationin Biginelli reaction under solvent-free, catalyst-free conditions
G.B. Dharma Rao, B.N. Acharya, M.P. Kaushik
PII: S0040-4039(13)01705-XDOI: http://dx.doi.org/10.1016/j.tetlet.2013.09.130Reference: TETL 43630
To appear in: Tetrahedron Letters
Please cite this article as: Dharma Rao, G.B., Acharya, B.N., Kaushik, M.P., An efficient synthesis of β-ketoestersvia transesterification and its application in Biginelli reaction under solvent-free, catalyst-free conditions,Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.130
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Graphical Abstract
An efficient synthesis of β-ketoesters via transesterification and
its application in Biginelli reaction under solvent-free,
catalyst-free conditions
G. B. Dharma Rao, B. N. Acharya, M.P. Kaushik*
A simple and efficient transesterification process for the synthesis of β-ketoester derivatives has been achieved by the
reaction of methyl β-ketoester with higher alcohols at 110 °C under solvent-free, catalyst-free conditions and its
application in synthesis of 3,4-dihydropyrimidin-2(1H)-ones C-5 ester derivatives via Biginelli reaction has been described.
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An efficient synthesis of β-ketoesters via transesterification and its application in
Biginelli reaction under solvent-free, catalyst-free conditions
G. B. Dharma Rao, B. N. Acharya, M .P. Kaushik*
Discovery Centre, Process Technology Development Division, Defence R. & D. Establishment, Jhansi Road, Gwalior-474002, M. P.,
India.
Abstract— A simple and efficient transesterification process for the synthesis of β-ketoester derivatives has been achieved by the reaction of methyl β-
ketoester with higher alcohols at 110 °C under solvent-free, catalyst-free conditions and its application in synthesis of 3,4-dihydropyrimidin-2(1H)-ones C-5
ester derivatives via Biginelli reaction has been described. © 2013 Elsevier Science. All rights reserved.
The recent focus on the development of sustainable
chemical process has provided an emerging task to those
who applied chemistry in industry and academic research.
The construction of chemical compounds or protocols by
avoiding relatively volatile toxic solvents and hazardous
catalysts is the need in the present scenario for green
synthesis.1,2
Besides, it has been observed that the catalyst
employed protocols are not always environmentally benign,
and because of this several environmental solid mass
pollutants often results during the process of waste disposal.
These limitations prompted us to investigate the efficient,
viable and feasibility of solvent and catalyst-free reactions
under modified experimental conditions towards the
development of greener protocol for the synthesis of
diversified and functionalized cascade molecules.
In the current existence, transesterification
transformation have received considerable attention and
emerged as a most significant protocol in organic synthesis
(Scheme 1).3
Transesterification was one of the easiest
procedures for the synthesis of β-ketoesters, which are not
available commercially. β-Ketoesters serves as an
authoritative synthon which were used in synthesis of
polymers, drugs, biologically active compounds.4 Besides
this they are also used as building blocks in the synthesis of
complex natural products.5 β-Ketoesters have also proved to
be a superior synthon essentially because of the presence of
both electrophilic as well as nucleophilic centers.
______________________________________________
∗Corresponding author. Tel.:+91-751-2343972; fax: +91-751-
2340042. E-mail address: [email protected]. (M. P.
Kaushik)
Keywords:- Transesterification; β-Ketoester; Alcohol; Biginelli reaction;
Dihydropyrimidinone; Green chemistry.
Transesterification reaction is also more advantageous than
the Claisen condensation or the reaction of diketene with
alcohols for the synthesis of β-ketoesters. Diketenes were
very difficult to handle due to corrosive and very reactive in
nature.
Scheme 1: General transesterification transformation
tert-Butyl β-ketoester readily underwent
transesterification transformation with alcohol to form the
corresponding β-ketoester in presence of toluene/xylene as
solvent under catalyst-free condition6 due to presence of
better leaving group and this protocol was only restricted to
tert-butyl β-ketoester. Toluene was found to be the best
solvent in comparison to other solvents. However, it was not
found to be environmental friendly. Transesterification is an
equilibrium driven process and it can be controlled by acidic
and basic catalysts7 in hydrocarbon solvents or usage of
excess of one of the precursor to get quantitative yield.
Literature survey revealed that, most of the reported
methods were developed either by the use of catalyst8 or
solvents.9
However, in spite of their potential utility, most of
these reported methods experienced from various
disadvantages such as drastic reaction conditions, modest
yields, requires special experimental apparatus and the use
of catalysts which are expensive, toxic, and air sensitive. To
the best of our knowledge, there are no reports for
transesterification of alcohol under solvent-free and catalyst-
free conditions using methyl β-ketoester as the
acetoacetylating agent.
Pergamon
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In continuation of our work on new synthetic
methodologies for the synthesis of various bioactive
compounds10
there was a need to synthesize various
functionalized β-ketoesters. Recently, we have developed a
protocol for transesterification of alcohols by using
ytterbium(III)triflate as catalyst under solvent-free
conditions.11
With an objective to develop greener protocol
of transesterification, the reaction (Scheme 1) was carried
out under solvent-free and catalyst-free conditions to obtain
a number of β-ketoesters by the simple and commonly used
method of transesterification from readily available methyl
β-ketoester. Herein, we report a realistic method for the
synthesis of β-ketoester using methyl β-ketoester with
different functionalized alcohols under solvent-free and
catalyst-free conditions at 110 Co.
With the intention of optimize the reaction conditions, we
initiated our investigation on transesterification of methyl β-
ketoester with cyclohexanol as a model substrate. The
cyclohexanol β-ketoester was obtained in moderate yield,
when methyl β-ketoester was reacted with an equilmolar
amount of cyclohexanol (1:1) in the absence of solvent and
catalyst after 3h at 110 °C. The methyl β-ketoester was
completely converted into cyclohexanol analogue, which
was obtained in 85% yield (Table 1, Entry 6). It also
revealed that the reaction proceeds under solvent-free and
catalyst-free conditions, when methyl β-ketoester and
cyclohexanol were used in a mole ratio of 1:1.5 (Figure 1).
Figure 1: Comparison of various mole ratio of cyclohexanol with methly β-ketoester in transesterification (GC yields).
The applicability of optimized reaction conditions were
further extended to the synthesis of more complex β-
ketoester with a wide range of structurally diverse and
functionalized alcohols. As expected, the rate of this
transformation also depends on steric hindrance and all the
results were appended in Table 1. The salient features of this
methodology are as follows, (i) methyl β-ketoester is
successfully transformed into synthetically useful higher
homologue of esters; even bulkier alcohols could be used for
transesterification (Table 1, Entry 7), (ii) the synthesis of
long chain esters which can be used as a precursors in the
polymer industry ( Table 1, Entry 4), (iii) the special features
of this protocol is that unsaturated alcohols (Table 1, Entries
13-15) smoothly underwent transesterification affording
unsaturated esters in high yields.
Table 1. Transesterification of methyl β-ketoester using various alcohols.
a,16
Entry ROH Time (h) Product %yieldb
1 3 9211
2 3
9011
3 3
85
4 3
8511
5 3 9011
6
3
8511
7
5.5
6011
8 3.5
8811
9 3
90
10
4
85
11 3
8311
12 4
80
13 3
8011
14 4 7611
15 3 7512
aReaction conditions: methyl β-ketoester (1.0 equiv.), and
alcohol (1.5 equiv.) at 110 ˚C under solvent- and catalyst-free conditions.
bIsolated yields.
β-Ketoester is one of the precursors, out of the three
building blocks in the Biginelli reaction13
to synthesize the
3,4-dihydropyrimidin-2(1H)-ones (DHPMs) which occupied
a prestigious position in medicinal chemistry due to their
pharmacological and biological activities such as calcium
channel blockers, mitotic kinesine inhibitor, adrenergic
receptor antagonist, antibacterial and antiviral activities.14,15
100
90
80
70
60
50
% c
on
ver
tio
n
1.51.41.31.21.11.0
mole ratio of cyclohexanol
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The β-ketoester can be varied to the largest extent by the
synthesis of non-commercial β-ketoester via
transesterification as mentioned above to achieve diversity at
C-5 position of DHPMs.
Recently, we have reported a Biginelli reaction10a
for
the construction of dihydropyrimidinones/thiones. The same
procedure was employed to Biginelli reaction under solvent-
free and catalyst-free conditions by using various types of β-
ketoesters which were synthesized via transesterification
transformation with constant arylaldehyde. From these
experiments, we found that tolerance of various β-ketoester
bearing diverse functionality underwent reaction smoothly
with p-methoxy benzaldehyde and urea to afford the
corresponding dihydropyrimidinone C-5 ester derivatives in
excellent yields and all the results are appended in Table 2.
Table 2: Synthesis of dihydropyrimidinones using non-
commercial β-ketoester under thermal conditionsa,17
Entry β-Ketoester Product M.P (°C) (%)Yield
1
196-198 9210a
2
172-174 90
3
190-192 92
4
178-180 92
5
200-202 90
6
140-142 89
7
152-154 90
8
128-130 87
9
194-196 85
10
158-160 82
aReaction conditions: β-ketoester (1.0 equiv.), arylaldehyde
(1.0 equiv.) and urea (1.2 equiv.) at 110 ˚C under solvent and catalyst free conditions.
bIsolated yields.
On the basis of above observations and the literature
reports, a plausible reaction pathway for the formation of
dihydropyrimidinone C-5 ester derivatives is depicted in
Scheme 2. Methyl β-ketoester is easily converted into
reactive acetylketene intermediate6 by the loss of relatively
volatile methyl alcohol at 110 °C followed by the
nucleophilic attack of the alcohol to form new β-ketoester
with corresponding alcohol. The resulting imine
intermediate10a
by the condensation of arylaldehyde and urea
undergo a cyclization with new β-ketoester furnish the
corresponding dihydropyrimidinone C-5 ester derivative
followed by the elimination of water molecule.
Scheme 2: Proposed mechanism for the synthesis of
dihydropyrimidinone C-5 ester derivatives.
In summary, we have developed and demonstrated a new
and highly efficient viable procedure for the synthesis of
non-commercial β-ketoester via transesterification
transformation and its function in synthesis of
dihydropyrimidinone C-5 ester derivatives through straight
forward Biginelli reaction under solvent-free, catalyst-free
conditions. The noteworthy merits of this protocol is the
simple operation, mild reaction conditions, easy work-up
procedure, no hazardous catalysts or corrosive, toxic
solvents. We believe that, this will be a better and more
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viable green methodology for solvent- and catalyst-free
reactions. Further research to widen the scope of this
enhanced protocol is in progress.
Acknowledgements:
We express special gratitude to the Director, DRDE,
Gwalior, for his keen interest and encouragement.
Supplementary data:
Supplementary data (Details experimental procedure and
characterization data of selected compounds and copies of 1H NMR and
13C NMR spectras are given in supplementary
material) associated with this article can be found.
References and note:
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Tetrahedron Lett., 2002, 43, 8583.
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16. Typical experimental procedure (transesterification
transfomation): A homogeneous mixture of an alcohol
(1.5 equiv.) and methylacetoacetate (1.0 equiv.) was
charged in a round bottomed flask and gently heated at
110 ˚C under solvent-free, catalyst-free conditions, for a
certain period of time as required. The progress of the
reaction was monitored by TLC. After completion, the
resulting desired product was distilled out directly or
separated by short column chromatography over silica
gel using light petroleum ether and ethylacetate (80:20)
to afford the pure product in 60-92% yield.
17. Typical Experimental Procedure (Biginelli reaction): A
25ml round bottom flask equipped with a reflux
condenser was charged with arylaldehyde (1.0 equiv.)
and urea (1.2 equiv.). Both precursors were finely
powdered and mixed together and allowed to stir for 30
min at room temperature. The β-ketoester (1.0 equiv.)
was subsequently added to above mixture. The resulting
reaction mixture was heated at 110 ˚C (oil bath) under
solvent- and catalyst-free conditions with constant
mechanical stirring for 3h. The progress of the reaction
was monitored by TLC (6 : 4, hexane : ethylacetate ).
After completion of the reaction as indicated on TLC, the
contents were cooled to room temperature and the crude
reaction mixture was crushed and washed with chilled
water (15ml x 3), filtered and dried under vacuum. For
analytically pure products, the final solid mass was
washed with diethyl ether (10ml x 2) to remove the un-
reacted reagents to afford the pure product in 82-92%
yield.
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