Synthesis of β-Keto Esters Promoted by Yttria-Zirconia Based Lewis Acid Catalyst

Article abstract of DOI:10.1081/SCC-120028644

A variety of aldehydes react with methyl/ethyl diazoacetate in the presence of yttria-zirconia based catalyst to afford the corresponding β-keto esters in excellent yields.

Full text of DOI:10.1081/SCC-120028644

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 6, pp. 1117–1123, 2004
Synthesis of b-Keto Esters Promoted
by Yttria-Zirconia Based Lewis
Acid Catalyst
*
Rajesh K. Pandey, Anis N. Deshmukh, and Pradeep Kumar
Division of Organic Chemistry: Technology, National Chemical
Laboratory, Pune, India
ABSTRACT
A variety of aldehydes react with methyl/ethyl diazoacetate in the
presence of yttria-zirconia based catalyst to afford the corresponding b-
keto esters in excellent yields.
Key Words: Yttria-zirconia based Lewis acid; Heterogeneous catalysis;
Aldehyde; Diazoacetate; b-keto esters.
b-Keto esters are multicoupling reagents having electrophilic carbonyl
and nucleophilic carbon. They are basic building blocks[1] in the total
synthesis of sex pheromones,[2] natural products[3] and are extensively used in
*
Correspondence: Pradeep Kumar, Division of Organic Chemistry: Technology,
National Chemical Laboratory, Pune-411008, India; Fax: 0091-20-25893614; E-mail:
tripathi@dalton.ncl.res.in.
1117
DOI: 10.1081/SCC-120028644
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Pandey, Deshmukh, and Kumar
Scheme 1.
the agrochemical, pharmaceutical and dyestuff industries. Numerous methods
have been reported for their preparations.[4] The method involving the
condensation of aldehyde with ethyl diazoacetate is short and direct. Apart
from the classical Claisen condensation[5] and related reactions,[6] the diazo-
mediated protocol is effected either thermally[7] or in the presence of Lewis
acids.[8] Solid catalysts have also been used in b-keto esters synthesis.[9]
As a part of our research program aimed at developing new catalyst and
subsequent applications to various organic transformations, the yttria-zirconia
based Lewis acid was found to be extremely efficient for various
transformations.[10] In this report we have explored the efficacy of yttria-
zirconia based Lewis acid catalyst in the synthesis of b-keto esters (Sch. 1).
RESULTS AND DISCUSSION
The condensation of aldehydes with methyl/ethyl diazoacetate in the
presence of catalytic amount of yttria-zirconia based Lewis acid afforded the
corresponding ß-keto esters in good to excellent yields (Table 1). The aliphatic
aldehyde reacted faster than aromatic (Table 1, entry 1). The substitution
pattern in the aromatic ring has distinctive influence on the rate of reaction.
For example, the aromatic aldehyde with electron donating substituents
accelerated the reaction (Table 1, entries 4, 9) whereas an electron with-
drawing substituent retarded the rate of reaction (Table 1, entries 3, 6),
although yields were comparable. The reactions of benzaldehyde with ethyl
diazoacetate with varying amounts of yttria-zirconia catalyst were studied
which indicated that the optimised amount of catalyst needed for high
efficiency was 20 wt%. In the absence of the catalyst there was no reaction up
to 48 hr (Table 1, entry 11). The formation of b-keto esters could be visualized
through a a-diazo-b-keto ester type of intermediate generated by electrophilic
attack on diazoacetate of species formed upon complexation of aldehyde with
the acid sites of the catalyst. Loss of nitrogen followed by 1,2-hydride shift is
expected to lead to the observed b-keto ester.

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1119
Table 1. Synthesis of b-keto esters via condensation of aldehydes and diazoacetates
catalyzed by yttria-zirconia based Lewis acid catalyst.
Aldehyde
1
Diazoacetate Reaction
2
Producta
Yieldb
(%)
Entry
1
time (h)
3
Methyl
10
85
83
85
2
3
Methyl
Methyl
12
20
4
5
6
Methyl
Methyl
Methyl
12
20
18
86
83
80
7
8
Ethyl
Ethyl
13
12
80
85
9
10
11
Ethyl
Ethyl
Ethyl
12
22
75
80
48c
No reaction
aProducts were characterized by spectroscopic data and comparison with authentic
samples.
bYields refer to isolated pure products.
cReaction was performed without catalyst.

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Pandey, Deshmukh, and Kumar
The method described herein is simple and high yielding but more
importantly offers easy work-up procedure. The advantages of the present
method can be attributed to the preparation of the catalyst and reactivation at
5008C.
EXPERIMENTAL
Solvents were purified and dried by standard procedures before use
according to reported procedure; petroleum ether of boiling range 60–808C
was used. The aldehydes were obtained from commercial sources and were
purified by distillation/recrystallization before the experiment. Infrared
spectra were recorded with ATI MATT-SON RS-1 FT-IR spectrometer.
Proton NMR spectra were recorded on Bruker AC-200 machine in CDCl3
with TMS as internal standard. Mass spectra were obtained with Finningen
MAT mass spectrometer. The diffractogram of X-ray powder diffraction
pattern was recorded on a Rigaku diffractometer model D/Max. IIIVC
with Ni-filtered Cu-Ka radiation. FTIR spectrum of pyridine adsorbed on
the yttrium-based catalyst was recorded on a Nicolet 60 SXB FTIR
spectrometer. TPD profile (ammonia) of the yttrium-based catalyst was
recorded on a Sorbstar apparatus. Determination of specific surface area was
carried out by BET (Brunner–Emmett–Teller) N2 adsorption using an
Omnisorp 100CX apparatus.
Procedure for the Preparation of Catalyst
The catalyst was prepared by mixing aq. solution of yttrium nitrate and
zirconyl nitrate in the mole ratio 16 : 84, followed by addition of aqueous
ammonia (28%) with vigorous stirring until a pH of 8.5 reached. The
precipitate was washed with deionized water, dried at 1108C for 24 hr. Then
the solid was treated with sulfuric acid (4M), dried at 1208C and calcined at
5008C for 3 hr with a heating rate of 28C min21. The chemical composition
of the final catalyst (determined by XRF technique) was found to be
82.6 mol% Zr, 15.6 mol% Y and 1.8 mol% S. The physicochemical char-
acterization of the catalyst was carried out by titrations, temperature
programmed desorption (TPD), scanning electron microscopy (SEM) and N2
adsorption techniques.

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1121
Typical Experimental Procedure for the Condensation of
Diazoacetates with Aldehydes
A solution of aldehyde (5.0 mmol) and diazoacetate (7.5 mmol) in
dichloroethane (10 mL) containing yttria-zirconia based Lewis acid catalyst
(50 mg; 10% w/w) was refluxed for the indicated length of time (Table 1)
under N2 atmosphere. The catalyst was recovered by filtration and solvent was
evaporated under reduced pressure to furnish the crude material. Purification
by silica gel column chromatography using pet ether: ethylacetate (9.8 : 0.2)
afforded the pure product.
4-Methyl-3-oxopentanoic acid methyl ester (3a): Colorless liquid.
IRnmax/cm21 (Neat): 1732, 1695, 1456. 1H NMR (CDCl3) d: 1.3
(d, J ¼ 6.25 Hz, 6H), 2.1–2.28 (m, 1H), 3.5 (s, 2H), 3.9 (s, 3H). 13C NMR
(CDCl3) d: 16.2, 33.5, 42.1, 50.0, 171.3, 196.0. Anal. calcd. for C7H12O3: C
58.32, H 8.39%; found: C 58.05, H 8.10%.
3-Oxo-3-phenylpropionic acid methyl ester (3b):[11] Colorless liquid.
1
IRnmax/cm21 (Neat): 1735, 1695,1450. H NMR (CDCl3) d: [4.0,5.7,12.3]
(s, 2H), 4.1 (s, 3H), 7.8–7.4 (m, 3H), 8.1–7.9 (m, 2H).
3-(3-Nitrophenyl)-3-oxopropionic acid methyl ester (3c): White solid:
1
M.P. 708C. IRnmax/cm21 (Neat): 3310, 1740, 1700, 1595, 1540. H NMR
(CDCl3) d: [3.9,5.8,12.6] (s, 2H), 4.1(s, 3H), 7.6–7.3 (m, 2H), 8.1–7.9
(m, 2H). 13C NMR (CDCl3) d: 42.2, 50.0, 89.0 (enolic), 123.5, 128.0, 129.5,
134.5, 138.3, 148.3, 171.0, 196.5. Anal. calcd. for C10H9NO5: C 53.82, H 4.06,
N 6.28%; found: C 53.50, H 3.80, N 5.91%.
3-(4-Methoxyphenyl)-3-oxopropionic acid methyl ester (3d): Color-
less liquid. IRnmax/cm21 (Neat): 3300, 1725, 1695,1590. 1H NMR (CDCl3) d:
3.7 (s, 3H) 3.8 (s, 3H), [4.1,5.5,12.6] (s, 2H), 7.8–6.9 (m, 4H). 13C NMR
(CDCl3) d: 42.1, 50.1, 56.2, 114.0, 129.7, 166.5, 171.5, 196.5. Anal. calcd. for
C11H12O4: C 63.45, H 5.81%; found: C 63.01, H 5.51%.
3-(3,4-Methylenedioxyphenyl)-3-oxopropionic acid methyl ester (3e):
1
Colorless liquid. IRnmax/cm21 (Neat): 3300, 1727, 1698, 1593. H NMR
(CDCl3) d: [4.0, 5.6, 12.6] (s, 2H), 4.1(s, 3H), 6.05 (s, 2H), 6.95 (d, J ¼ 7 Hz,
1H), 7.45 (d, J ¼ 7 Hz, 1H), 7.6–7.55 (m, 1H). 13C NMR (CDCl3) d: 42.1,
50.1, 91.3, 115.2, 121.5, 131.0, 147.5, 152.0, 171.0, 196.5. Anal. calcd. for
C11H10O5: C 59.46, H 4.54%; found: C 59.21, H 4.24%.
3-(2-Nitro-4-methylphenyl)-3-oxopropionic acid methyl ester (3f):
White solid: M.P. 1108C. IRnmax/cm21 (Neat): 3300, 1746, 1698, 1557, 1447.
1H NMR (CDCl3) d: 2.6 (s, 3H), [3.9, 5.7, 12.3] (s, 2H), 4.1 (s, 3H), 7.2 (s, 1H),
8.0 (d, J ¼ 7 Hz, 1H), 8.4 (d, J ¼ 7 Hz, 1H). 13C NMR (CDCl3) d: 19.9, 41.2,
50.1, 124.2, 129.3, 129.5, 135.5, 143.0, 171.0, 196.5. Anal. calcd. for
C11H11NO5: C 55.70, H 4.67, N 5.90% found: C 55.25, H 4.35, N 5.55%.

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Pandey, Deshmukh, and Kumar
3-Phenyl-3-oxopropionic acid ethyl ester (3g):[9a] Colorless liquid.
1
IRnmax/cm21 (Neat): 3345, 1738, 1695, 1592, 1447. H NMR (CDCl3) d:
1.18–1.3 (m, 3H), [3.9, 5.7, 12.3] (s, 2H), 4.1–4.2 (m, 2H), 7.4–7.8 (m, 3H),
8.0–8.1 (m, 2H).
3-(4-Methylphenyl)-3-oxopropionic acid ethyl ester (3h):[9a] Colorless
liquid. IRnmax/cm21 (Neat): 3300, 1740, 1700, 1560, 1450. 1H NMR (CDCl3)
d: 1.15–1.28 (m, 3H), 2.4 (s, 3H), [4.0, 5.7, 12.5] (s, 2H), 4.1–4.2 (m, 2H),
7.2–7.8 (m, 4H).
3-(4-Methoxyphenyl)-3-oxopropionic acid ethyl ester (3i):[9a] Color-
1
less liquid. IRnmax/cm21 (Neat): 3300, 1725, 1698, 1557, 1447. H NMR
(CDCl3) d: 1.1–1.22 (m, 3H), 3.8 (s, 3H), [4.0, 5.7, 12.6] (s, 2H), 4.1–4.2
(m, 2H), 7.0–7.5 (m, 4H).
3-(3,4-Methylenedioxyphenyl)-3-oxopropionic acid ethyl ester
(3j):[9a] Solid: M.P. 408C (lit. 418C).[9a] IRnmax/cm21 (Neat): 1740, 1685,
1
1640, 1447. H NMR (CDCl3) d: 1.22 (t, J ¼ 7.4 Hz, 3H), [4.0, 5.65, 12.6]
(s, 2H), 4.2 (q, J ¼ 7.4 Hz, 2H), 6.1 (s, 2H), 6.95 (d, J ¼ 7 Hz, 1H), 7.4
(d, J ¼ 7 Hz, 1H), 7.5–7.6 (m, 1H).
ACKNOWLEDGEMENTS
RKP thanks CSIR, New Delhi for award of senior research fellowship.
We are grateful to Dr. M. K. Gurjar, Head, Organic Chemistry: Technology
Division for his constant encouragement and support. This is NCL
communication No. 6653.
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Received in India September 30, 2003

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