Boric acid: an efficient and environmentally benign catalyst for transesterification of ethyl acetoacetate

Article abstract of DOI:10.1016/j.tetlet.2007.11.008

An efficient and environmentally benign boric acid catalyzed protocol for the transesterification of ethyl acetoacetate with a variety of primary and secondary alcohols in good to excellent yields is described. The versatility of this transformation is demonstrated with problematic substrates such as propargyl alcohol and allyl alcohol, which are known to undergo Carroll rearrangement during transesterification.

Full text of DOI:10.1016/j.tetlet.2007.11.008

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Tetrahedron Letters 49 (2008) 106–109
Boric acid: an efficient and environmentally benign catalyst
for transesterification of ethyl acetoacetateI
G. C. M. Kondaiah,a L. Amarnath Reddy,a K. Srihari Babu,a V. M. Gurav,b K. G. Huge,b
R. Bandichhor,a P. Pratap Reddy,a A. Bhattacharyaa and R. Vijaya Ananda,*
aCenter of Excellence, IPDO-Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur,
R. R. District, 500 072 Andhra Pradesh, India
bDepartment of Chemistry, Yeshwant Mahavidhyalaya, Nanded 431 602, Maharashtra, India
Received 21 September 2007; revised 24 October 2007; accepted 1 November 2007
Available online 6 November 2007
Abstract—An efficient and environmentally benign boric acid catalyzed protocol for the transesterification of ethyl acetoacetate with
a variety of primary and secondary alcohols in good to excellent yields is described. The versatility of this transformation is
demonstrated with problematic substrates such as propargyl alcohol and allyl alcohol, which are known to undergo Carroll
rearrangement during transesterification.
Ó 2007 Elsevier Ltd. All rights reserved.
b-Keto esters are valuable synthons in organic synthesis
since their electrophilic and nucleophilic sites allow their
derivatization to complex natural products.1 Typically,
b-keto esters are prepared by decomposing highly reac-
tive and unstable diketene with various alcohols.2,3
Although this methodology is atom economic, the
corrosiveness and handling difficulties of diketene make
it practically less attractive. A few alternative methods
have been developed,4–8 in particular, transesterifica-
tion9 of b-keto esters to other b-keto ester analogs
(Scheme 1). Since transesterification is an equilibrium
process, an acidic or basic catalyst is required to
promote the reaction. In this regard, several protic
acid10–13 and basic catalysts14–20 have been reported in
the literature to effect this transformation. The limita-
tion of using protic acids or basic catalysts is that acid
or base sensitive substrates are not compatible under
these reaction conditions. To overcome this problem,
Lewis acid catalyzed transesterifications have been
developed, using Lewis acids such as distannoxanes,21
indium triiodide,22 yttria–zirconia,23 Mo–ZrO2,24
LiClO4,25 Zn dust,26 titanium(IV) alkoxides,27 zinc–
I2,28 sodium perborate29 and niobium(V) oxide.30
A
few other homogeneous31,32 and heterogeneous33–37
catalysts are also known to be effective for this trans-
formation. However, some of these catalysts are toxic,
difficult to prepare and are expensive.
In recent years, there has been considerable interest in
developing Green Chemistry38 for organic synthesis
due to environmental demands and sustainability. The
development of catalytic processes to replace stoichio-
metric reactions, which produce large amounts of waste
by-products, has made a significant contribution to the
reduction of environmental pollution. With this in mind,
we have developed the transesterification of ethyl aceto-
acetate using boric acid as a catalyst. Boric acid is an
environmentally benign catalyst, which has been suc-
cessfully utilized in numerous reactions.39–41 Though
boric acid catalyzed esterification of a-hydroxy acids42
and phenols43 is known, transesterification of b-keto
esters using this catalyst, to the best of our knowledge,
has not been reported in the literature.
O
O
O
O
Catalyst
R2OH, solvent, Δ
R1OH
OR1
OR2
Scheme 1. General transesterification process.
Keywords: Transesterification; b-Keto esters; Boric acid; Green
catalysis.
q DRL-IPD Communication number: IPDO-IPM-00086.
*
To prove the catalytic activity of boric acid in trans-
esterification reactions, we initially conducted a blank
Corresponding author. Tel.: +91 40 44346430; fax: +91 40
44346164; e-mail: vijayaanandr@drreddys.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.008

G. C. M. Kondaiah et al. / Tetrahedron Letters 49 (2008) 106–109
107
reaction, in which ethyl acetoacetate 1 was reacted with
2 equiv of benzyl alcohol in xylene at reflux without
boric acid. The desired benzyl ester was obtained in only
trace amounts even after 24 h. When the same reaction
was conducted using 1.5 equiv of benzyl alcohol and
10 mol % of boric acid at reflux, b-keto ester 2 was
obtained in 75% yield within 5 h (Scheme 2).
these experiments ethanol was continuously removed
from the reaction mixture using
condenser.
a
Dean–Stark
O
O
O
O
B(OH)3 (10 mol%)
BnOH, o-xylene, Δ
OEt
OBn
5 h, 75%
To demonstrate the scope of this methodology, a wide
variety of aliphatic alcohols were reacted with ethyl ace-
toacetate using 10 mol % of boric acid in refluxing tolu-
ene44 and the results are summarized in Table 1. In all
1
2
Scheme 2. Boric acid catalyzed transesterification of ethyl aceto-
acetate.
Table 1. B(OH)3 catalyzed transesterification of ethyl acetoacetate with alcoholsa
S. No.
Alcohol (equiv)
Product
Yieldb (%)
92
O
O
1
(2)
OH
OH
O
O
O
O
O
OH
(1.5)
2
3
95
82
F3C
CF3
O
(2)
O
O
O
4
5
80
72
OH
(2)
O
O
O
O
O
O
O
O
O
OH
(2)
O
O
O
O
OH
O
6
7
72
71
O
(2)
OH (2)
OH
(2)
8
9
69
77
OH
(1.5)
O
O
O
O
O
O
10
92
(1.5)
OH
OH
O
O
O
O
11
12
95
92
(2)
O
O
OH
N
(1.5)
N
a All reactions were carried out with 10 mol % of B(OH)3 in refluxing toluene for 5 h.
b All compounds showed satisfactory 1H NMR and mass spectral data.

108
G. C. M. Kondaiah et al. / Tetrahedron Letters 49 (2008) 106–109
3. Tezuka, Y.; Ogura, T.; Kawaguchi, S. Bull. Chem. Soc.
O
O
(HO)3B
-R1OH
Jpn. 1969, 42, 443.
B(OH)3
O
O
H
4. Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266.
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OR1
3
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1203.
HO
O
OH
B
O
O
R2OH
O
H
B(OH)3
OR2
O
4
5
Scheme 3. Possible mechanism for the boric acid catalyzed
11. Rehberg, C. E.; Faucette, W. A.; Fisher, C. H. J. Am.
Chem. Soc. 1944, 66, 1723.
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Under optimized reaction conditions, transesterification
of ethyl acetoacetate proceeded very cleanly. It is appar-
ent from Table 1 that a variety of primary (entries 1–9)
and secondary (entries 10–12) alcohols could be con-
verted to their corresponding b-keto esters in good
yields. In most cases 2 equiv of alcohol was used, in
some cases 1.5 equiv of alcohol was found to be suffi-
cient. A remarkable feature of this protocol is that
substituted benzyl, propargyl and allyl alcohols (entries
2, 7, and 8) underwent transesterification efficiently with
ethyl acetoacetate to provide the corresponding b-keto
esters. Allyl and propargyl esters are known to be very
difficult to prepare as they readily undergo the Carroll
rearrangement.45,46 Secondary alcohols such as (À)-
menthol, cyclohexanol and quinuclidinol47 (entries
10–12) were also transesterified smoothly under these
conditions. Tertiary alcohols did not undergo the trans-
esterification reaction even under drastic conditions.
A plausible mechanism is shown in Scheme 3. Probably,
boric acid catalyzes the enolization of the b-keto ester to
form intermediate 3, which could then be converted to
the cyclic intermediate 4. Nucleophilic ring opening of
the cyclic intermediate 4 by the alcohol gives the product
along with the elimination of boric acid.
29. Bandgar, B. P.; Sadavarte, V. S.; Uppalla, L. S. Chem.
Lett. 2001, 9, 894.
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3086.
32. Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y.
Tetrahedron Lett. 2000, 41, 5249.
In conclusion, we have developed an efficient and cost
effective protocol for the transesterification of ethyl aceto-
acetate using boric acid as an environmentally benign
catalyst. We have also shown the versatility of this trans-
formation by applying this method to a wide variety of
alcohols.
33. Chavan, S. P.; Pasupathy, K.; Shengule, S.; Shinde, V.;
Anand, R. ARKIVOC 2005, 162.
Acknowledgments
34. Chavan, S. P.; Zubaidha, P. K.; Dantale, S. W.; Keshav-
araja, A.; Ramaswamy, A. V.; Ravindranathan, T. Tet-
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Chem. Commun. 1996, 707.
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Gajare, A. S. J. Org. Chem. 1998, 63, 1058.
38. Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2169.
39. Chaudhuri, M. K.; Hussain, S. J. Mol. Catal. A 2007, 269,
214.
We greatly appreciate the supportive environment
encouraged at Dr. Reddy’s Laboratories Ltd. We are
thankful to IPM of IPDO and NMR group of DRF
for their generous support. We also thank Dr. N.V.
Kalyankar of Yeshwant Mahavidhyalaya, Nanded for
helpful discussions.
References and notes
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G. C. M. Kondaiah et al. / Tetrahedron Letters 49 (2008) 106–109
109
43. Lowrance, W. W., Jr. Tetrahedron Lett. 1971, 37, 3453.
44. Except for benzyl alcohol, all the other primary and
secondary alcohols examined underwent transesterifica-
tion smoothly with ethyl acetoacetate in refluxing toluene.
Since, in the case of benzyl alcohol, the transesterification
reaction in toluene took a very long time, it was replaced
with o-xylene (Scheme 2).
15.0 mmol) and boric acid (60 mg, 10 mol %) in toluene
(50 mL) was refluxed for 5 h with continuous removal of
ethanol using a Dean–Stark condenser. The solvent was
removed under reduced pressure and the crude material
was subjected to column chromatography on silica gel to
give pure product. Data for quinuclidinyl acetoacetate
1
(Table 1, entry 12) (92% yield, 1.94 g). H NMR (CDCl3,
45. Carrol, F. M. J. Am. Chem. Soc. 1940, 62, 704.
46. Kimel, W.; Cope, A. C. J. Am. Chem. Soc. 1943, 65, 1992.
47. In a typical experimental procedure, a mixture of ethyl
acetoacetate (1.30 g, 10.0 mmol), quinuclidinol (1.90 g,
400 MHz) d 1.21–1.38 (m, 1H), 1.49–1.55 (m, 1H), 1.61–
1.68 (m, 1H), 1.74–1.79 (m, 1H), 2.24 (s, 3H), 2.64–2.83
(m, 6H), 3.19 (ddd, J = 14.8, 8.4, 1.6 Hz, 1H), 3.44 (s, 2H),
4.79–4.83 (m, 1H); MS (ESI): 212 (M+1).