AgOTf-catalyzed transesterification of β-keto esters

Article abstract of DOI:10.1002/aoc.2826

AgOTf proved to be an effective catalyst for the transesterification of β-keto esters with primary, secondary and tertiary alcohols. The products were obtained in high yield within a reasonable reaction time period. The kinetics of the transesterification reaction were also studied and the reaction was found to follow second-order kinetics. Copyright

Full text of DOI:10.1002/aoc.2826

Full Paper
Received: 19 October 2011
Accepted: 11 January 2012
Published online in Wiley Online Library: 8 February 2012
(wileyonlinelibrary.com) DOI 10.1002/aoc.2826
AgOTf-catalyzed transesterification of
b-keto esters
Rima Das and Debashis Chakraborty*
AgOTf proved to be an effective catalyst for the transesterification of b-keto esters with primary, secondary and tertiary alcohols.
The products were obtained in high yield within a reasonable reaction time period. The kinetics of the transesterification reac-
tion were also studied and the reaction was found to follow second-order kinetics. Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: transesterification; b-keto esters; AgOTf; Lewis acid; kinetics
BF3.OEt2,[4] BiCl3
and Bi(NO3)5 have also been reported for
[26]
[3]
Introduction
the transesterification of b-keto esters with alcohol.
Among the various classical organic reactions, transesterification
has enormous use in the laboratory and in industry. Transesterifi-
cation of b-keto esters is a routinely utilized transformation in
organic chemistry. The classical method for the synthesis of
b-keto esters is by Claisen condensation between two esters or
one ester and another carbonyl compound.[1,2] Esters can also
be synthesized from carboxylic acids and alcohols, but some-
times carboxylic acids are less soluble and difficult to subject to
esterification. When the parent carboxylic acids are labile and dif-
ficult to isolate then transesterification becomes more advanta-
geous.[3] Among the esters, b-keto esters are of special interest
because of their electrophilic and nucleophlic centers, making
them a valuable synthon for the synthesis of natural products
such as karrikinolide (KAR1), tetrahydrozerumbone, serricornine
and trichodiene.[4]
Recently, we have used AgOTf as a mild Lewis acid catalyst in
acylation reactions.[27] Our continued success with a silver-based
catalytic process[28,29] prompted us to study the AgOTf-catalyzed
transesterification of b-keto esters.
Results and Discussion
Transesterification of b-Keto Esters
Since transesterification is an equilibrium process, the reaction
was performed with the aid of Dean–Stark apparatus to drive
the reaction in the forward direction. As a model reaction, we
used readily available ethyl acetoacetate and benzyl alcohol in
the presence of a catalytic amount of Ag(I) salt.
It is reported that the chelate complex of b-keto esters sup-
presses the activity of some pathogenic viruses through the
formation of a coordinate bond to metal ions at the active site
of the virus enzyme responsible for virus replication.[5,6] Besides
this, metal chelates of b-diketones find application in oils of
biological origin, lubricating compositions and potential anti-
viral drugs.[7]
Our next aim was to optimize the reaction conditions with var-
ious readily available Ag(I) salts in different solvents (Table 1).
With AgOTf as catalyst, the reaction proceeds smoothly in boiling
toluene to give the product in 90% isolated yield in 7 h. Highly
polar solvents such as DMF, DMSO and 1,4-dioxane (Table 1,
entries 3–5) give only 40%, 30% and 10% yield of product,
respectively, with long reaction time. Under similar conditions, a
low boiling solvent such as THF (Table 1, entry 1) at 80 ꢀC gives
20% yield in 15 h and CH3NO2 (Table 1, entry 6) at 110 ꢀC gave
70% yield in 10 h. Among the various Ag(I) salts, AgCl, AgBr and
AgNO3 (Table 1, entries 7–9) gave 5–30% yield in 24 h, whereas
AgI and AgOAc (Table 1, entries 10 and 11) gave 50–70% yield
in 15–20 h in boiling toluene. The reaction performed in toluene
with AgOTf under ambient conditions took much longer and
without AgOTf no product formation was observed (Table 1,
Recently, transesterification has been affected by various transi-
tion metal catalysts such as NiCl2, CuCl2 and CoCl2.[3] Iron-based
[9]
catalysts such as [Bu4N][Fe(CO)3(NO)][8] and Fe(acac)3 are also
reported. Solid acid catalysts such as S-SnO2,[10] CuSO4,[11]
montorillonite K-10,[12] B2O3/ZrO2,[13] Nb2O5,[14] zeolites[15–18] and
Amberlyst-15[19] have also been used. Recent literature shows the
application of ionic liquids[20,21] and enzymes.[22] Use of molecular
sieves alone is also effective in transesterification of b-keto esters
with higher alcohols.[5,6] Recently, molecular iodine had been
explored as a powerful catalyst for esterification and transesterifica-
tion reactions, with good yields.[23] Recently, Singh and Nolan have
reported the synthesis of phosphorous esters by transesterification
with NHC catalyst.[24] Again, NaBH4 is a common reducing reagent
and alcoholic solutions of sodium borohydride are neither strongly
acidic nor basic, which makes it suitable for transesterification of
acid- and base-labile esters.[25] Several Lewis acid catalysts such as
*
Correspondence to: D. Chakraborty, Department of Chemistry, Indian
Institute of Technology Madras, Chennai-600 036, Tamil Nadu, India. E-mail:
dchakraborty@iitm.ac.in
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600
036, Tamil Nadu, India
Appl. Organometal. Chem. 2012, 26, 140–144
Copyright © 2012 John Wiley & Sons, Ltd.

AgOTf-catalyzed transesterification of b-keto esters
Table 1. Transesterification of ethyl acetoacetate with benzyl alcohol in different solvents and Ag(I) salts
Entry
Solvent
Ag(I) salt
Time (h)a
Yield (%)b
1
THF (80 ꢀC)
Toluene
1,4-Dioxane
DMSO
AgOTf
AgOTf
15
7
20
90
10
30
40
70
5
2
3
AgOTf
24
12
15
10
24
24
24
20
15
24
24
10
6.5
4
AgOTf
5
DMF
AgOTf
6
CH3NO2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
AgOTf
7
AgNO3
8
AgCl
5
9
AgBr
30
50
70
5
10
11
12
13
14
15
AgI
AgOAc
—
AgOTf (RT)
AgOTf (5 mol%)
AgOTf (20 mol%)
30
80
89
aMonitored using thin-layer chromatography.
bIsolated yield after column chromatography of the crude product.
entries 12 and 13). A large amount of catalyst decreased the
reaction time slightly but yield did not improve (Table 1, entry 15).
Having realized the optimized conditions, we investigated the
transesterification of ethyl acetoacetate with various alcohols
using AgOTf as catalyst. Several aromatic and aliphatic alcohols
were subjected to the transesterification reaction (Table 2). The
expected products were obtained in high yield. Aromatic
alcohols containing electron-donating substituents (Table 2,
entries 2–4) gave the corresponding acetoacetates in 6–8 h
with around 90% yield, whereas alcohols containing electron-
withdrawing substituent (Table 3, entry 5 ) took a much longer
time.
faster, so the reaction becomes faster as compared to when R′
is the electron-donating group such as in normal esters.
Next, we decided to explore the kinetic studies of transesterifi-
cation. Thus the transesterification of benzyl alcohol and i-butyl
alcohol with ethyl acetoacetate (Table 2) and t-butyl acetoacetate
with benzyl alcohol (Table 3) have been subjected to high-
performance liquid chromatographic analysis to determine
the starting materials and product present as a function of
time. Kinetics were studied by monitoring the disappearance
of ester and appearance of the corresponding product (Fig. 1).
Using Van’t Hoff differential method, the order (n) and rate
constant (k) have been determined. The rates of the reaction at
different concentrations have been estimated by evaluating the
slope of the tangent at each point on the curve (Fig. 1). With
these data log10 (rate) vs. log10 (concentration) were plotted
(Fig. 2). The order (n) and rate constant (k) were obtained from the
slope of the line and its intercept on the log10 (rate) axis. From Fig. 2,
the rate of the reaction was found to be second order (n=2.05) and
the rate constant was k=9.18Â 10À4 LmolÀ1 sÀ1. Similarly, for the
transesterification of i-butyl alcohol and ethyl acetoacetate; t-butyl
acetoacetate and benzyl alcohol showed second-order kinetics
(n ꢁ 2) with rate constant 3.9 Â 10À4 L molÀ1 sÀ1 and
9.09 Â 10À4 L molÀ1 sÀ1 respectively (see supporting informa-
tion for details).
In the case of allylic alcohols (Table 2, entries 7 and 8), it is
known that allylic acetoacetates are difficult to prepare because
there is a chance of their undergoing Carroll rearrangement,[30,31]
but here expected b-keto esters are obtained with good yield. In
the case of aliphatic alcohols, going from primary to secondary
to tertiary the bulkiness of carbon skeleton increases, reaction
time increases and the yield of desired keto esters decreases
in the same order (Table 2, entries 9–13). Thus tertiary alcohols
are less active as the rate of reaction is greatly affected by steric
effects.
Besides this, we have performed transesterification by varying
the substituent on b-keto esters (Table 3).
The transesterification reaction is highly effected by the steric
factor; thus t-butyl acetoacetates (Table 3, entry 4) become more
active than the secondary and primary (Table 3, entries 1–3) in
order to relieve the strain by transesterification. The proposed
mechanism is shown in Scheme 1.
Coordination of Ag(I) to the oxygen increases the electrophilic-
ity of the carbonyl carbon. When R′ is CH2COCH3, due to the
electron-withdrawing effect of this group electrophilicity of the
carbonyl carbon increases and attack by the alcohol becomes
Conclusions
We have found that AgOTf is a versatile and mild Lewis acid
catalyst for the transesterification of various b-keto esters. Various
functionalized alcohols as well as b-keto esters undergo
transesterification smoothly. Further studies to extend the scope
of the Ag(I)-based catalytic system are in progress in our laboratory.
Appl. Organometal. Chem. 2012, 26, 140–144
Copyright © 2012 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

R. Das and D. Chakraborty
Table 2. Transesterification of ethyl acetoacetate with various alcoholsa
Entry
1
Alcohol
Product
Time (h)b
7
Yield (%)c
90
2
6.5
92
3
4
6
8
90
84
5
6
7
19
10
9
70
80
85
8
9
8
6
87
81
10
11
12
13
9
79
78
77
78
15
10
12
aReactions performed in toluene with 10 mol% AgOTf under reflux conditions.
bMonitored using thin-layer chromatography.
cIsolated yield after column chromatography of the crude product.
extracted in dichloromethane. The residue was concentrated
and purified by column chromatography using hexane and ethyl
acetate as eluents. The spectroscopic characterization of all the
compounds matches well with the literature.[32–38] (see support-
ing information).
Experimental
Typical procedure for Transesterification of b-Keto Esters
A mixture of b-keto ester (for ethyl acetoacetate, 1.26 ml,
10 mmol), alcohol (for benzyl alcohol, 2.16 ml, 20 mmol) and the
catalyst AgOTf (10 mol%, 0.256 g) in toluene (10 ml) was heated
to reflux. The reaction mixture was connected to a Dean–Stark
apparatus to remove the newly formed alcohol. After consump-
tion of ester, the reaction mixture was concentrated and
Acknowledgments
This work was supported by the Department of Science and
Technology and the Council of Scientific and Industrial Research,
wileyonlinelibrary.com/journal/aoc
Copyright © 2012 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2012, 26, 140–144

AgOTf-catalyzed transesterification of b-keto esters
Table 3. Transesterification of benzyl alcohol with b-keto esters
Entry
1
b-Keto ester
Product
Time (h)b
10
Yield (%)c
79
2
3
7
8
83
82
4
6
85
aReactions performed in toluene with 10 mol% AgOTf under reflux conditions.
bMonitored using thin-layer chromatography.
cIsolated yield after column chromatography of the crude product.
-4.0
-4.2
-4.4
-4.6
-4.8
-5.0
-5.2
-5.4
-5.6
Y = - 3.037 + 2.057 X
R = 0.98608
R'
OEt
Ag
R"
O
H
O
R'
OEt
O
"R
H
O
R'
Ag
OEt
O
Ag
R'
OR"
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
+
EtOH
O
log 10
C
"RO
R'
H
O
Et
Figure 2. Van’t Hoff differential plot for the conversion of ethylacetoacetate
O
to benzylacetoacetate by AgOTf at 110 ꢀC.
Ag
Scheme 1. Proposed mechanism of transesterification.
the Council of Scientific and Industrial Research, New Delhi, for a
research fellowship.
C6H10O3
C11H12O3
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
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