Efficient and chemoselective alkyl bromoacetate-Zn mediated transesterification method

Article abstract of DOI:10.1016/S0040-4020(03)00472-1

Alkyl bromoacetates were shown to be versatile transesterification reagents. Isoxazoles underwent chemoselective transesterification when treated with alkyl bromoacetate-Zn in THF at reflux. A suggested mechanism of the new reaction was discussed.

Full text of DOI:10.1016/S0040-4020(03)00472-1

Tetrahedron 59 (2003) 3481–3485
Efficient and chemoselective alkyl bromoacetate–Zn mediated
transesterification method
*
Necdet Co s¸ kun and Mustafa Er
Department of Chemistry, Uluda g˘ University, Gorukle, 16059 Bursa, Turkey
Received 6 January 2003; revised 27 February 2003; accepted 21 March 2003
Abstract—Alkyl bromoacetates were shown to be versatile transesterification reagents. Isoxazoles underwent chemoselective
transesterification when treated with alkyl bromoacetate–Zn in THF at reflux. A suggested mechanism of the new reaction was
discussed. q 2003 Elsevier Science Ltd. All rights reserved.
Transesterification of esters is a widely used process in
academia and industry. A number of transesterifications
the benzoyl (benzoate and p-bromobenzoate) groups present
f
in the molecule.
3
1
,2
have been reported in the literature and investigations on
the chemoselectivity of transesterifications have appeared
Recently, we have reported results on the 1,3-dipolar
cycloaddition reaction of imidazoline 3-oxides with
3
recently. The chemoselective capabilities of porcine
4
a
pancreatic lipase and Candida rugosalipase have been
reported for selective acetylation and deacetylation of
hydroxymethylated phenols and hydroxyaryl alkyl ketones
DMAD and the reactions of the obtained adducts 1.
4
b
Selective Michael addition of methoxide ion prompted us
to investigate the reaction of organozinc compounds
obtained from a-bromoacetic acid esters and Zn with
isoxazoles 1. This would be an important step in the
synthesis of tricarboxylic acids such as citric and isocitric
acids. However, the conjugate addition of the ethoxycarbo-
nylmethyl anion to C-2 of compounds 1 attempted under
Reformatsky reaction conditions led to the formation of
compounds 2 instead of any conjugate addition reaction
(Scheme 1 and Table 1).
3
a
and their peracetylated derivatives. Organotin-mediated
3
b
monoacylation of diols, transesterification and trans-
thioesterification of b-keto esters with a variety of alcohols
and thiols catalyzed by natural kaolinitic clay are des-
3
c
cribed. An efficient method for the chemoselective one-
step conversion of tetrahydropyranyl ethers of primary
alcohols into the corresponding acetates through an indium
triiodide catalyzed transesterification process in ethyl
Scheme 1.
3
d
acetate has been reported. Facile and selective transesteri-
fication of b-keto esters using N-bromosuccinimide as an
Table 1. Chemoselective transesterification of 3a,4,5,6-tetrahydro-
imidazo[1,5-b]isoxazoles
3
e
efficient and neutral catalyst is also described. The acetyl
group was chemoselectively cleaved in the presence of
p-toluenesulfonic acid in CH Cl /MeOH without affecting
1
R
2
R
a
Yield of 2 (%)
Entry
R
2
2
a
b
c
d
e
Et
Et
Et
Et
Et
4-MeC H
6
H
H
H
Ph
Ph
90
89
91
94
95
4
4-MeOC
4-ClC
4-MeC
4-MeOC
6
H
4
4
6
H
4
6
H
4
Keywords: chemoselective transesterification; Reformatsky reagent.
*
6
H
Corresponding author. Tel.: þ90-44292561308; fax: þ90-4428022;
a
e-mail: coskun@uludag.edu.tr
Yields of isolated pure compounds.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00472-1

3482
N. Co s¸ kun, M. Er / Tetrahedron 59 (2003) 3481–3485
Here we report a new high yield transesterification reaction
of alkyl esters with Reformatsky reagents at neutral
conditions. The chemoselectivity of this transesterification
is also discussed.
The structure of 2 was unequivocally proved to be the
corresponding isoxazole-2,3-dicarboxylic acid 3-methyl
ester 2-ethyl ester. The IR spectra of the products are nearly
indistinguishable from those of the starting isoxazoles, they
have the same carbonyl patterns in their IR spectra as the
Figure 1. Selected NOESY correlations for 2a,c.
1
starting isoxazoles. The H NMR spectra are different from
those of the starting compounds only with the triplet and
quartet instead of the singlet at 3.85 ppm corresponding to
the methoxy group at C-2 linked carbonyl.
Scheme 2.
The NOESY spectra of the compounds 2a,c show a clear
Table 2. Transesterifications of esters with Reformatsky reagents
Entry
1
Starting ester
PhCO Me
Product
Et
Reagent (equiv.)
Reaction time (h)
Yield (%)
13
2
PhCO
2
BrCH
2
CO
2
Et/Zn (5)
2
3
19
31
31
15
54
80
28
38
43
55
86
8
1
1
0
6
BrCH
2
CO
2
Et/Zn (10)
2
4
20
2.5
4
5
4
20
2.5
4
4
20
2
BrCH
BrCH
2
CO
CO
2
Et/Zn (20)
Et/Zn (5)
2
6
2-ClC H
4
CO
2
Me
6 4 2
2-ClC H CO Et
2
2
BrCH
BrCH
2
CO
CO
2
Et/Zn (20)
Et/Zn (5)
3
4
6
4-MeOC H
4
CO Me
2
6 4 2
4-MeOC H CO Et
2
2
13
20
70
75
BrCH
BrCH
2
CO
CO
2
Et/Zn (20)
Et/Zn (5)
2
2
4
8
2.5
4
8
2
4
8
2
4
80
95
44
62
91
46
70
93
29
31
32
50
56
62
60
69
90
0
5
6
7
PhCH
2
2
CO
2
2
Me
CO
PhCH
2
CO
CH
2
Et
BrCH
BrCH
BrCH
BrCH
BrCH
2
2
2
2
2
CO
CO
CO
CO
CO
2
2
2
2
2
Et/Zn (5)
i-Pr/Zn (5)
Et/Zn (1)
Et/Zn (2.5)
PhCH
CH
2
Et
PhCH
2
2
CO
2
i-Pr
PhCHvCHCO Me
2
PhCHvCHCO
2
Et
1
0
2
4
1
0
Et/Zn (5)
2
8
1
2
a
EtOH/I
2
(5)
25
25
25
8
a
EtOH as a solvent/I
EtOH/H SO (5)
EtOH as a solvent/H
2
11
9
50
2
4
2
SO
4
b
8
RvMe
RvEt
BrCH
2
CO
2
Et/Zn (5)
16
No reaction
a
The amounts of iodine as in Ref. 1.
The starting adduct was obtained from the 1,3-dipolar cycloaddition of corresponding imidazoline 3-oxide and methylphenylpropinoate and characterized by
spectral means.
b

N. Co s¸ kun, M. Er / Tetrahedron 59 (2003) 3481–3485
3483
Scheme 3.
correlation between the ethyl group’s methylene signal at
presented in Table 2 clearly confirm that electron-donating
groups decrease the reactivity of aromatic esters while
electron-withdrawing groups increase it. Aliphatic esters are
much more reactive than the corresponding benzoic acid
esters. 2-Furoate is much more reactive than the corre-
sponding benzoates, entry 4. On the other hand, the presence
of an electron-donating group b to the conjugated ester
carboxyl decreases its reactivity (entry 8 Table 2). All these
are a reliable basis for the assessment of the reactivity and
chemoselectivity of the developed transesterification
method.
4
4
.25 ppm and the part of the methylene AB system at
.36 ppm. On the other hand, the methyl protons of the ester
group give cross peaks with the methylene protons at C-4
(
[
Fig. 1). 2-Phenyl-5-p-tolyl-3a,4,5,6-tetrahydro-imidazo-
1,5-b]isoxazole-3-carboxylic acid methyl ester remains
unchanged in the same reaction conditions thus confirming
the position of the transesterification (Scheme 2 and
Table 2).
To our knowledge these are the first examples of
chemoselective transesterifications using organozinc com-
pounds. To determine the scope and limitations of the
reaction a series of selected carboxylic acid esters were
subjected to transesterification (Table 2) in the presence of
the Reformatsky reagents. The transesterification of methyl
cinnamate with ethanol in the presence of catalytic amounts
of I or conc. H SO proceeds with low yields when a five
We propose that the mechanism of the transesterification of
adducts 1a–e and esters 3 in the conditions of the
Reformatsky reaction involves the coordination of the
5
ester through the acyl oxygen as shown in transition state A
in Scheme 3. For aliphatic, conjugated and aromatic esters,
the transition state may involve the solvent molecule, while
the presence of an a oxygen in the ester may serve as a
readily coordinating atom instead of the solvent molecule.
Intramolecular cyclization of intermediate A could give B
which in turn undergo ring opening to give acylium species
C. Rotation around the Zn coordinated oxygen–carbon
bond and recyclization of C will give D the ring opening and
decomposition of which afford the transesterified ester and
the new Reformatsky reagent. To prove the formation of the
proposed new Reformatsky reagent in the reaction con-
ditions we have treated the mixture of methyl 2-chloro-
benzoate and ethyl 2-furoate with ethyl bromoacetate/Zn
and the reaction was monitored by HPLC. The formation of
methyl 2-furoate was evidence in support of the assumed
mechanism. The observed substituent effects on the
reactivity of esters are in good agreement with the
cyclization recyclization mechanism discussed.
2
2
4
fold excess of ethanol was used. The yields are low even
when it was used as a solvent (Table 2 entry 7).
The low reactivity of the aromatic esters 1–3, (the reactions
requires large excess of the organozinc species to get a good
yield) encouraged us to explore the chemoselectivity limits
of the reaction in the series of esters 1–8. Thus we have
subjected pairs of esters, with different reactivities, as
models for compounds having two ester groups to
transesterification with a five fold excess of ethyl bromo-
acetate/Zn and the yields of the product esters were
determined by HPLC. In the case of methyl benzoate and
methyl furoate the ratio of the ethyl esters was 1:9 after 2.5 h
reflux. In the case of methyl phenylacetate and methyl
p-methoxybenzoate the ratio of the ethyl esters was 1:10
under the same reaction conditions. These and the results

3484
N. Co s¸ kun, M. Er / Tetrahedron 59 (2003) 3481–3485
Thus a new high yield chemoselective transesterification
reaction of alkyl esters with Reformatsky reagent at neutral
conditions was developed. Electron-rich esters were shown
to be less reactive than electron poor ones and this was the
basis for the chemoselectivity of the reaction.
(3H, s), 3.88 (3H, s) 4.18 (1H, d, J¼10.8 Hz), 4.36 (2H, q,
7.1), 4.62 (1H, d, J¼9.7 Hz), 5.09 (1H, d, J¼10.8 Hz), 6.72
(2H, d, J¼8.9 Hz), 6.85 (2H, d, J¼8.9 Hz), 7.28–7.39 (3H,
1
3
m), 7.60 (2H, d, J¼7.3 Hz); C NMR CDCl d 14.4; 52.1;
3
56.1; 58.2; 63.2; 76.5; 83.1; 110.9; 115.2; 117.1; 127.4;
128.4; 128.7; 140.7; 141.4; 152.6; 154.0; 159.1; 163.0.
Anal. calcd for C H N O (424.46) C, 65.08; H, 5.70; N,
2
3 24 2 6
þ
1. Experimental
6.60. Found C, 65.05; H, 5.71; N, 6.65. MS m/z 424 (M ).
Melting points were taken on a Electrothermal Digital
melting point apparatus. Infrared spectra were recorded on a
Mattson 1000 FTIR. Proton magnetic resonance spectra
were recorded on a Bruker Dpx 400 MHz spectrometer. All
1.1.3. 5-(4-Chloro-phenyl)-3a-phenyl-3a,4,5,6-tetra-
hydro-imidazo[1,5-b]isoxazole-2,3-dicarboxylic acid
2-ethyl ester 3-methyl ester (2c). Yield, 0.390 g, 91%.
The melting point of the colorless crystals after recrystal-
spectra were taken inCDCl . Mass spectra were routinely
3
recorded at 70 eV by electron impact. Visualization was
effected with UV light. Freshly prepared imidazoline
lization from ether–petroleum ether is 130.1–131.28C. IR
(KBr) nCvO 1750, 1716; nCvC 1665 cm2 ; H NMR CDCl
1 1
3
d 1.36 (3H, t, J¼7.1 Hz), 3.50 (1H, d, J¼9.7 Hz), 3.68 (3H,
s), 4.29 (1H, d, J¼10.8 Hz), 4.36 (2H, q, 7.1), 4.7 (1H, d,
J¼9.7 Hz), 5.03 (1H, d, J¼10.8 Hz), 6.70 (2H, d,
J¼8.9 Hz), 7.24 (2H, d, J¼8.9 Hz), 7.28–7.42 (3H, m),
d 14.4; 52.3; 57.4;
3
3
-oxide adducts with DMAD were used after recrystalliza-
tion from ethanol. Commercially available esters or
prepared by routine methods were used as starting materials
as well as for comparison.
1
3
7.63 (2H, d, J¼7.3 Hz); C NMR CDCl
6
3.2; 76.0; 83.0; 111.4; 116.7; 125.1; 127.3; 128.6; 128.8;
129.6; 141.0; 145.1; 152.4; 158.9; 162.9. Anal. calcd for
21ClN (428.88) C, 61.61; H, 4.94; N, 6.53. Found
1.1. General procedure for transesterification of
isoxazoles (1) and esters (3)
C
H
O
2 5
22
C, 61.76; H, 5.13; N, 6.54.
Zinc powder (0.328 g, 5 mmol) was placed in a flask with
THF (2 mL) and refluxed for 15 min. Ethyl bromoacetate
1.1.4. 3a,6-Diphenyl-5-p-tolyl-3a,4,5,6-tetrahydro-imi-
dazo[1,5-b]isoxazole-2,3-dicarboxylic acid 2-ethyl ester
3-methyl ester (2d). Yield, 0.455 g, 94%. Oily product IR
(
0.835 g, 5 mmol) dissolved in THF (10 mL) was added and
the mixture stirred at 50–558C for 20 min. After the green
colored solution is formed compound 1 or 3 (1 mmol)
dissolved in THF (2 mL) was added and the mixture was
refluxed for the specified time. The reaction was monitored
by TLC or by HPLC for the reactions of esters 3. The
solvent was evaporated and the residue dissolved in diethyl
ether (30 mL) at heating. The compound was recrystallised
from ethanol in the cases of 2a–c,e or purified by flash
column chromatography using silica gel as adsorbent and
ethyl acetate and hexane as eluent in the cases of 2d and
esters 4.
(neat) nCvO 1750, 1716; nCvC 1665 cm2 ; H NMR CDCl
1 1
3
d 1.36 (3H, t, J¼7.1 Hz), 2.23 (3H, s), 3.62 (3H, s), 4.13
(1H, d, J¼10.5 Hz), 4.36 (2H, q, 7.1), 4.76 (1H, d,
J¼10.5 Hz), 5.97 (1H, s), 6.64 (2H, d, J¼8.9 Hz), 7.01
(2H, d, J¼8.9 Hz), 7.21–7.39 (8H, m), 7.57 (2H, d,
H N O (484.56) C,
28 2 5
J¼7.3 Hz). Anal. calcd for C29
71.88; H, 5.82; N, 5.78. Found: C, 72.00; H, 5.75; N, 5.90.
1.1.5. 5-(4-Methoxy-phenyl)-3a,6-diphenyl-3a,4,5,6-
tetrahydro-imidazo[1,5-b]isoxazole-2,3-dicarboxylic
acid 2-ethyl ester 3-methyl ester (2e). Yield, 95%. The
melting point of the colorless crystals after recrystallization
1
.1.1. 3a-Phenyl-5-p-tolyl-3a,4,5,6-tetrahydro-imi-
dazo[1,5-b]isoxazole-2,3-dicarboxylic acid 2-ethyl ester
-methyl ester (2a). The compound was obtained according
from ether–petroleum ether is 104–105.38C. IR (KBr)
n d 1.36
1 1
CvO 1750, 1716; nCvC 1665 cm2 ; H NMR CDCl
3
3
to the general procedure. Yield 0.367 g, 90%. The melting
point of the colorless crystals after recrystallization from
(3H, t, J¼7.1 Hz), 3.70 (3H, s), 3.75 (3H, s), 4.18 (1H, d,
J¼10.5 Hz), 4.36 (2H, q, 7.1), 4.68 (1H, d, J¼10.5 Hz), 5.87
13
ethanol is 126.7–127.28C. IR (KBr) n
1750, 1716;
(1H, s), 6.73–6.77 (4H, m), 7.29–7.40 (8H, m), 7.59 (2H, d,
CvO
1 1
nCvC 1665 cm2 ; H NMR CDCl d 1.36 (3H, t, J¼7.1 Hz),
J¼7.4 Hz); C NMR CDCl
d 14.4; 52.3; 56.00; 59.2; 63.2;
3
3
2
.30 (3H, s), 3.46 (1H, d, J¼9.8 Hz), 3.68 (3H, s), 4.26 (1H,
80.5; 88.8; 111.6; 115.0; 117.3; 127.0; 127.3; 128.1; 128.2;
128.7; 128.9; 137.8; 140.5; 141.8; 152.1; 153.7; 159.2; 163.2.
d, J¼10.9 Hz), 4.37 (2H, q, 7.1), 4.65 (1H, d, J¼9.8 Hz),
5
.07 (1H, d, J¼10.9 Hz), 6.73 (2H, d, J¼8.0 Hz), 7.08 (2H,
Anal. calcd for C29
5.60. Found C, 69.65; H, 5.69; N, 5.62. MS m/z 500 (M ).
H
28
N
2
O
6
(500.56) C, 69.59; H, 5.64; N,
þ
d, J¼8.0 Hz), 7.28–7.39 (3H, m), 7.63 (2H, d, J¼8.0 Hz);
1
3
C NMR CDCl d 14.4; 20.9; 52.1; 57.6; 63.2; 76.5; 83.4;
3
1
1
10.9; 115.8; 127.3; 128.5; 128.8; 129.6; 130.3; 141.2;
44.2; 152.2; 159.4; 162.9. Anal. calcd for C H N O
3 24 2 5
2
Acknowledgements
(
6
408.46) C, 67.63; H, 5.92; N, 6.86. Found C, 67.29; H,
þ
.04; N, 6.81. MS m/z 408 (M ).
Uluda g˘ University Research Fund is gratefully acknowl-
edged for the financial support (Project No. 2000/38).
1
.1.2. 5-(4-Methoxy-phenyl)-3a-phenyl-3a,4,5,6-tetra-
hydro-imidazo[1,5-b]isoxazole-2,3-dicarboxylic acid
-ethyl ester 3-methyl ester (2b). Yield, 0.382 g, 89%.
The melting point of the colorless crystals after recrystal-
2
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