Manganese(II) salts as efficient catalysts for chemo selective transesterification of β-keto esters under non-conventional conditions

Article abstract of DOI:10.1016/j.tetlet.2012.12.030

Transesterification of β-ketoesters with various alcohols has been studied under conventional and non-conventional conditions using desktop chemicals such as Mn(II) salts as catalysts. These methods offered transesterification of β-ketoesters in good yields with dramatic rate accelerations and reduced reaction times. The developed protocols under nonconventional methods such as sonication and microwave irradiation are highly promising compared with the existing procedures.

Full text of DOI:10.1016/j.tetlet.2012.12.030

Tetrahedron Letters 54 (2013) 703–706
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Manganese(II) salts as efficient catalysts for chemo selective
transesterification of b-keto esters under non-conventional conditions
G. Krishnaiah a, B. Sandeep b, D. Kondhare d, K. C. Rajanna a, , J. Narendar Reddy b, Y. Rajeshwar Rao c,
⇑
P. K. Zhubaidha d
a Department of Chemistry, Osmania University, Hyderabad 500 007, AP, India
b Department of Chemistry, Govt. City College, Hyderabad 500 001, AP, India
c Department of Chemistry, Rajiv Gandhi University of Knowledge Technologies, IIIT Basara, AP, India
d School of Chemical Sciences, SRTM University, Nanded 431 606, MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Transesterification of b-ketoesters with various alcohols has been studied under conventional and non-
conventional conditions using desktop chemicals such as Mn(II) salts as catalysts. These methods offered
transesterification of b-ketoesters in good yields with dramatic rate accelerations and reduced reaction
times. The developed protocols under nonconventional methods such as sonication and microwave irra-
diation are highly promising compared with the existing procedures.
Received 31 October 2012
Revised 7 December 2012
Accepted 8 December 2012
Available online 19 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Transesterification
b-Ketoesters
Sonication
Microwave irradiation
Manganese carbonate
Manganese sulfate
Transesterification of b-ketoesters is an important class of syn-
thetic procedures.1 Transesterification is more advantageous than
the ester synthesis from carboxylic acid and alcohol, due to poor
solubility of some of the acids in organic solvents, whereas the es-
ters are commonly soluble in most of the solvents.2 Some esters,
especially methyl and ethyl esters are commercially available
and thus serve conveniently as starting materials in transesterifica-
tion. A survey of literature shows that b-ketoesters are versatile
organic intermediates that are extensively used in agrochemical,
pharmaceutical, and dyestuff industries.3 Apart from these
b-ketoesters are also useful organic building blocks for the synthe-
sis of complex natural products like thiolactomycin,4 polyoxomim-
ic acid,5 prostaglandin,6 and syncarpic acid.7 In general,
transesterification of b-ketoesters is a sluggish reaction,8,9 which
requires large excess of b-ketoester and high boiling alcohols. Over
a period of time quite some attention is paid to effectively catalyze
this reaction by using Bronsted acids, Lewis acids,10 and basic cat-
alysts.11–14 But protic acid catalysts such as sulfuric acid and phos-
phoric acid are known to cause several environmental problems.1
Therefore, lot of attention has been diverted to overcome this prob-
lem. Several heterogeneous catalysts such as sulfated tin oxide,15
borated zirconia,16 zeolites,17 kaolinitic clay,18 Mo–ZrO2,19 FeSO4,
and CuSO4,20 yettria-based strong Lewis acid,21 DMAP,22 Zinc,23
montmorillonite K-10,24 Mg–Al–O–t-Bu hydrotalcite,25 and ionic
liquid-regulated sulfamic acid26 have been employed to minimize
the problems associated with the homogeneous catalysts.
Although there are many reagents to catalyze the transesterifi-
cation, they are either expensive, less selective, and require long
reaction times. Therefore, practical and environmentally benign
protocols are needed for laboratory and industrial scale prepara-
tions. Manganese (Mn) is a versatile element27 with the electronic
configuration [Ar] 4s2 3d5. It is a required trace mineral for all
known living organisms and essential for aerobic life because its
compounds are not highly toxic. The most common oxidation
states of manganese are +2, +3, +4, +6, and +7, though oxidation
states from À3 to +7 are observed. Mn(II) often competes with
Mg(II) in biological systems. Manganese(II) ions are known to
function as cofactors for a large variety of enzymes with many
O
O
O
O
Catalyst
R
+
+
R
OH
OH
O
(i)Conventional
(ii)Sonication
(iii)MW
O
⇑
Where Catalyst = MnSO4, MnCO3
Corresponding author.
E-mail addresses: kcrajannaou@yahoo.com, kcrajannaou@rediffmail.com (K.C.
Rajanna).
Scheme 1. Transesterification of b-ketoesters.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.030

704
G. Krishnaiah et al. / Tetrahedron Letters 54 (2013) 703–706
functions. Manganese enzymes are particularly essential in the
detoxification of superoxide free radicals in organisms that must
deal with elemental oxygen. Manganese also functions in the
oxygen-evolving complex of photosynthetic plants. Manganese
carbonate is widely used as an additive to plant fertilizers to cure
Mn deficient crops. Above all, Mn(II) is a well known readily avail-
able, easy to use, inexpensive compound. Probably because of
these reasons Mn(II) has been used as a catalyst for rate enhance-
ments in several chemical reactions performed under homoge-
neous and heterogeneous conditions.28 Compounds such as
b-ketoesters are multicoupling reagents having electrophilic car-
bonyl and nucleophilic carbon which make them a valuable tool
for the synthesis of complex molecules. Toluene was chosen as a
solvent since it forms an azeotropic mixture with ethanol content
Table 1
Ultrasonic and microwave assisted chemoselective transesterification of ethyl acetoacetate by certain hydroxy compounds in the presence of inexpensive Mn(II) carbonate and
Mn(II) sulfate
Entry
Hydroxy compound
Product
Mn(II) catalyst
Conventional synthesis
USAS
MWAS
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (h)
Yield (%)
OH
O
O
O
O
MnSO4
MnCO3
18.0
18.0
72
75
2.00
2.15
73
74
0.75
0.75
72
74
O
1
2
OH
O
MnSO4
MnCO3
24.0
24.0
76
73
3.50
3.50
74
75
0.83
0.83
73
75
O
O
OH
MnSO4
MnCO3
24.0
24.0
76
72
3.15
3.15
73
71
0.83
0.83
72
75
3
4
O
OH
O
O
O
O
MnSO4
MnCO3
24.0
24.0
68
69
3.50
3.15
67
71
0.75
0.75
70
69
O
OH
MnSO4
MnCO3
24.0
24.0
62
60
3.50
3.40
60
63
0.75
0.75
65
65
5
6
O
OH
O
O
MnSO4
MnCO3
24.0
24.0
58
63
3.30
3.30
61
64
0.91
0.91
64
67
O
OH
O
O
O
O
MnSO4
MnCO3
24.0
24.0
57
52
2.50
2.50
59
55
0.66
0.66
65
69
7
O
O
O
O
O
MnSO4
MnCO3
24.0
24.0
58
53
2.30
2.40
59
61
0.58
0.58
68
65
8
9
O
O
O
O
O
HO
O
O
OH
MnSO4
MnCO3
18.0
18.0
60
60
2.15
2.15
69
65
0.63
0.66
68
65
O
O
O
O
O
MnSO4
MnCO3
15.0
15.5
68
69
3.00
3.15
73
72
0.75
0.70
72
70
OH
10
O
OH
O
O
O
O
MnSO4
MnCO3
16.0
16.0
71
71
3.00
3.00
75
79
0.91
0.90
75
75
11
12
O
OH
MnSO4
MnCO3
16.0
16.0
63
64
3.15
3.00
67
66
0.83
0.83
70
70
O
O
O
MnSO4
MnCO3
19.0
19.0
58
60
2.15
2.15
60
60
0.66
0.66
57
58
13
14
OH
O
OH
O
O
MnSO4
MnCO3
16.0
16.0
67
65
2.15
2.30
72
75
0.70
0.70
68
70
O
O
O
MnSO4
MnCO3
18.0
18.0
57
54
2.15
2.15
69
70
0.66
0.66
70
75
15
O
HO

G. Krishnaiah et al. / Tetrahedron Letters 54 (2013) 703–706
705
of 70%, owing to which the effectiveness of ethanol removal in-
creases. In this present work, we report that Mn(II) serves as an
efficient catalyst for the selective transesterification of b-ketoesters
with a variety of alcohols and ethyl acetoacetate (Scheme 1).
Preliminary studies with Mn(II) sulfate and Mn(II) carbonate as
catalysts for transesterification of ethylacetoacetate (EAA) with hy-
droxy compounds indicated that the reactions are too sluggish
even at reflux temperatures. These observations necessitated us
to carry out the reactions under non-conventional conditions such
as sonication and microwave irradiation because in recent past
ultrasonically assisted (USA)29–32 and microwave assisted
(MWA)33,34 protocols provided important tools to accelerate chem-
ical reactions by providing eco-friendly and green environment.35
Control experiments36 were performed with a mixture of ethyl
acetoacetate (5 mmol), phenol (5 mmol), and varied amounts of
catalyst in the range of 0.2–3.0 mmol (separately Mn(II) sulfate
and Mn(II) carbonate) in toluene (20 mL) stirred at 100–110 °C in
a round bottom flask provided with a distillation condenser to re-
move ethanol and the progress of the reaction monitored by thin
layer chromatography (TLC). Reactions afforded very good yield
of product only when 1.0 mmol catalyst was used. Below 1.0 mmol
reactions were too slow even after 24 h and under reflux condi-
tions, and above 1.0 mmol reaction times and yield of the product
did not differ much. In view of this we have performed the reaction
under ultrasonic and microwave assisted (USA and MWA) condi-
tions.37 Experimental results obtained for the transesterification
reaction with a variety of alcohols under different conditions are
summarized in Table 1, which indicated that even though the reac-
tion times in Mn(II) sulfate and Mn(II) carbonate mediated reac-
tions are too long, very good yields of products are obtained. The
+2 oxidation state of Mn is the most used state in living organisms
for essential functions while other states are toxic for the human
body. The +2 oxidation state of Mn results from the removal of
two 4s electrons, leaving a ‘high spin’ ion in which all five of the
3d orbitals contain a single electron. Mn(II) is a hard acid with suf-
ficient number of vacant orbitals that can easily form adducts with
ethyl acetoacetate and hydroxy compounds. According to Pearson’s
HSAB theory,38 ‘Hard acids (HA) prefer to bind to hard bases (HB)
and soft acids (SA) prefer to bind to soft bases (SB)’. Ethyl acetoac-
etate being a harder base than hydroxy compound interaction be-
tween hard acid Mn(II) and hard base ethyl acetoacetate through
two carbonyl oxygen atoms to form a cyclic intermediate is more
likely. Further support for the formation of cyclic intermediate dur-
ing the complexation of Lewis acid with 1,3 dicarbonyl systems can
be obtained from the recent work of Dario Pasini et al. on supramo-
lecular systems.39 The cyclic intermediate thus formed then prob-
ably reacts with hydroxy compound and affords the product with
the elimination of ethyl alcohol and Mn(II) catalyst. Reaction se-
quence of the proposed mechanism is shown in Scheme 2. Further,
it is interesting to note that the catalyst could be recycled without
any problem.
Comparison of the results obtained under three procedures
made it possible to draw some general conclusions regarding the
effect of sonication and MW irradiation on the transesterification.
Data presented in Table 1 clearly indicate that even though the
yields of end products are by and large similar with very good per-
centage, there is a remarkable change in the rates/reaction times
from the conventional method to sonication and/or microwave
irradiation. Reaction times reduced by almost ten times from con-
ventional to USA conditions. This remarkable rate acceleration
could be attributed to the ‘Cavitation phenomenon’, which is gen-
erated during ultra-sonication. A large amount of energy and pres-
sure are released from the collapse of cavitation bubbles during
sonication of the reaction,29–32 which may cause an increase in
O
O
O
O
L
Mn(II)
L
Mn(II)
O
O
ROH
R
O
R
O
O
O
O
O
L
Mn(II)
OH
H
L
Mn(II)
O
2-
L= SO42-;CO3
R= Alkyl, Aryl, Heteroaryl...etc
SCHEME-2
Scheme 2. Mn(II) catalyzed transesterification mechanism (proposed).

706
G. Krishnaiah et al. / Tetrahedron Letters 54 (2013) 703–706
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All chemicals used in the experiments were purchased either
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36. General procedure for transesterification under conventional method: A mixture of
b-ketoesters (5 mmol), alcohol (5 mmol), and catalyst (1 mmol) in toluene
(20 mL) was stirred at 100–110 °C in a round bottom flask provided with a
distillation condenser to remove ethanol and the progress of the reaction was
monitored by thin layer chromatography (TLC). Then the reaction mixture was
filtered and the filtrate was concentrated to get crude product, which was
purified by column chromatography on silica gel (ethyl acetate/petroleum
ether, 1:9) to afford the ester as a viscous colorless liquid in good to excellent
yields.
Acknowledgements
The authors thank the authorities of Osmania University,
Hyderabad, Govt. City College, Hyderabad, Rajiv Gandhi University
of Knowledge Technologies, IIIT Basara, and SRTM University, Nan-
ded for constant encouragement. One of the authors (G. Krishna-
iah) thanks CSIR, New Delhi, for support in the form of the CSIR,
JRF fellowship.
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assisted transesterification,
a flask containing a mixture of b-ketoesters
(5 mmol), alcohol (5 mmol), and catalyst (1 mmol) in toluene (20 mL) was
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column chromatography on silica gel (ethyl acetate/petroleum ether, ratio?) to
afford the ester as a viscous colorless liquid in excellent yields.
(b) General procedure for microwave assisted transesterification: The synthesis in
the MW oven was performed with a radiation source consisting of a magnetron
tube operating at 2.45 GHz with power output ranging from 0 to 300 W. The
flask containing a mixture of b-ketoesters (5 mmol), alcohol (5 mmol), and
catalyst (1 mmol) in toluene (20 mL) was placed in MW oven. The solutions
were stirred by a magnetic stir bar to ensure high homogeneity. To prevent
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progress of the reaction was monitored by TLC. Final product was obtained by
using the above mentioned work up.
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