Novel and effective synthesis of 2-acyloxy-3-keto esters

Article abstract of DOI:10.1055/s-2006-926468

A one-pot effective synthesis of 2-acyloxy-3-keto ester is reported. Treatment of 2-chloroglycidic esters with carboxylate salts in acetonitrile provided 2-acyloxy-3-keto esters in excellent to reasonable yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926468

PAPER
1767
Novel and Effective Synthesis of 2-Acyloxy-3-keto Esters
S
ynthesis of 2-A
a
cyloxy-3-
k
keto
E
sters uzo Komiyama, Yutaka Takaguchi, Sadao Tsuboi*
Department of Material and Energy Science, The Graduate School of Environmental Science, Okayama University, Okayama 700-8530,
Japan
Fax +81(86)2518898; E-mail: stsuboi6@cc.okayama-u.ac.jp
Received 21 November 2005; revised 4 January 2006
In connection with our study of 2-chloroglycidic esters,8
Abstract: A one-pot effective synthesis of 2-acyloxy-3-keto ester
we investigated the application of carboxylate salts for the
is reported. Treatment of 2-chloroglycidic esters with carboxylate
conversion of 2-chloroglycidic esters into polyfunctional-
salts in acetonitrile provided 2-acyloxy-3-keto esters in excellent to
ized esters. We found that the treatment of 2-chlorogly-
cidic ester 1a with potassium acetate gave 2-acetoxy-3-
keto esters 2a smoothly in good yields (Scheme 1). A
plausible mechanism of formation of 2a is shown in
Scheme 1. A substitution reaction of 1a with acetoxy an-
ion and rearrangement of epoxide furnished 3-acetoxy-2-
keto ester 3a directly (path A). Otherwise, chlorine–ep-
oxide rearrangement took place first and further substitu-
tion reaction with acetoxy anion also could give 3a (path
B). Then migration of the acetyl group occurred via keto-
enol tautomerism of 3a and further protonation furnished
2a.
reasonable yields.
Key words: epoxides, ring-opening, rearrangements, ketones, tan-
dem reactions
The title compounds, 2-acyloxy-3-keto esters, are very at-
tractive and useful intermediates in the field of organic
chemistry and are used as important precursors for the
synthesis of various natural products.1 As for the prepara-
tion of 2-acyloxy-3-keto esters, they are usually synthe-
sized from 2-halo-3-keto esters by reaction with the
respective carboxylate anion.2 However, this procedure
requires halogenation of the 3-keto esters in the prepara-
tion of 2-halo-3-keto esters. Iodobenzene-catalyzed acet-
oxylation of ketones also provided 2-acyloxy-3-keto
esters by the use of excess amount of m-chloroperbenzoic
acid.3
This reaction is a very useful and effective method for the
preparation of 2-acyloxy-3-keto esters, because rear-
rangement reaction of the epoxide ring and substitution
reaction of the carboxylate anion occur in one pot. Fur-
thermore, the reaction conditions are mild and the yield is
also good. Here, we wish to report a novel and effective
one-pot method for the preparation of 2-acyloxy-3-keto
esters by the reaction of 2-chloroglycidic esters with car-
boxylate salts.
On the other hand, 2-chloroglycidic esters have been
known as particularly useful compounds for the precur-
sors of polyfunctionalized esters, such as 2-hydroxy
esters,4 3-chloro-2-keto esters,5 2,3-unsaturated 2-phos-
phoryloxy esters,6 and 3-amino-2-keto esters.7 So far,
there is no report about application of the carboxylate salt
for the conversion of 2-chloroglycidic esters into the poly-
functionalized esters.
First, we investigated the difference in the reactivity of
potassium and sodium carboxylate for the synthesis of
2-acyloxy-3-keto esters (2a and 5a) from 2-chloroglycid-
ic ester 1a (Scheme 2, Table 1). The starting material, 2-
chloroglycidic esters 1 can be prepared easily from vari-
O
AcO–
OAc
O
CO2Me
keto-enol
tautomerism
O
Pr
Cl
AcOK
O
Pr
H
AcO–
O
Pr
O
3a
– KCl
(path A)
CO2Me
CO2Me
1a
AcOK
– KCl
Cl
O
O
rearrangement
(path B)
protonation
Cl
CO2Me
CO2Me
CO2Me
–
OAc
Pr
Pr
Pr
AcO–
Pr
CO2Me
OAc
2a
O
1a
4a
Scheme 1
SYNTHESIS 2006, No. 11, pp 1767–1770
x
x.
x
x
.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-926468; Art ID: F20105SS
© Georg Thieme Verlag Stuttgart · New York

1768
T. Komiyama et al.
PAPER
O
ous aldehydes via the Darzens condensation with dichlo-
roacetates (Scheme 3).8 When 1a was treated with
potassium acetate in MeCN under refluxing condition, the
reaction was complete smoothly in one hour and methyl
2-acetoxy-3-oxohexanoate (2a) was obtained after purifi-
cation by silica gel flash chromatography in 93% yield
(entry 1). When we used potassium benzoate for the re-
agent, methyl 2-benzoyloxy-3-oxohexanoate (5a) also
could be obtained in good yield (entry 2). Next, we inves-
tigated the application of sodium carboxylates in this re-
action. By the treatment of sodium acetate, 1a was
converted into 2a in good yield although it showed low re-
activity and it took 36 hours to complete the reaction (en-
try 3). We found that the reaction of sodium acetate or
sodium benzoate with 1a proceeded smoothly by the use
of 15-crown-5-ether. In these cases, the reaction was com-
plete in one hour.
O
Cl
CO2Et
AcOK (1.2 equiv)
MeCN, reflux
R
R
CO2Et
OAc
2b–h
1b–h
Scheme 4
Table 2 Synthesis of Various 2-Acetoxy-3-keto Esters 2
Entry
Substrate
R
Time (h)
Product,
yield (%)
2b, 94
2c, 96
2d, 96
2e, 92
2f, 94
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
C3H7
C4H9
C5H11
C6H13
i-Bu
i-Pr
2
2
2
2
2
O
R''CO2K
O
CO2Me
OCOR''
or R''CO2Na
Cl
1g
1h
48
3
2g, 79
2h, 75
Pr
Pr
MeCN
reflux
CO2Me
Bn
1a
2a: R'' = Me
5a: R'' = Ph
Scheme 2
O
Cl
CO2Et
CO2Et
AcOK (1.2 equiv)
O
Pr
Pr
Cl
base, Et2O
R
MeCN, reflux
2 h, 95 %
OAc
O
4b
RCHO
+
CHCl2CO2R'
CO2R'
2b
1
Scheme 5
Scheme 3
In conclusion, we have developed an efficient and novel
one-pot method for the synthesis of 2-acyloxy-3-keto es-
ters by the treatment of 2-chloroglycidic esters with either
potassium or sodium carboxylate. This one-pot reaction
proceeds very smoothly under mild conditions. Various
2-acyloxy-3-keto esters can be prepared by applying this
reaction to different 2-chloroglycidic esters. Further ex-
ploitation of this strategy towards the synthesis of a natu-
ral compound is in progress and will be reported in the
near future.
Table 1 Reaction of Glycidic Ester 1a with Potassium or Sodium
Carboxylate
Entry
Reagent, additivea R¢¢
Time (h) Product,
yield (%)
1
2
3
4
5
AcOK
Ac
Bz
Ac
Ac
Bz
1
5
2a, 93
5a, 85
2a, 82
2a, 87
5a, 94
BzOK
AcONa
36
1
AcONa, 15-c-5
BzONa, 15-c-5
1
NMR spectra were recorded on JEOL JNM-AL300 instrument and
calibrated using residual undeuterated solvent as an internal refer-
ence. IR spectra were recorded on a Thermo Nicolet Avatar 360T2
IR spectrophotometer. Elemental analyses were performed on Per-
kin-Elmer 2400 series II CHNS/O analyzer. For TLC, aluminum
sheets (Merck silica gel coated 60 F254) were used and the plates
were visualized with UV light and phosphomolybdic acid (5% in
EtOH). Merck silica gel 60 N (spherical, neutral) (40–50 mm) was
used for the flash chromatography. All chemicals were used as re-
ceived.
a In each case, 1.2 equiv of carboxylate salt were used. In entries 4 and
5, 1.2 equiv of 15-crown-5 were added.
Next, we applied this reaction to various 2-chloroglycidic
esters 1b–h for the synthesis of 2-acetoxy-3-keto esters
2b–h (Scheme 4). Through treatment with 1.2 equivalents
of potassium acetate, 2-chloroglycidic esters 1b–h were
also converted into 2b–h in excellent to reasonable yields
(Table 2).
2-Keto Esters 2a–h and 5a; Methyl 2-Acetoxy-3-oxohexanoate
(2a); Typical Procedure
Then we investigated the reaction of 3-chloro-2-keto ester
4b,5a which is the rearrangement product of 2-chlorogly-
cidic ester 1b, with potassium acetate (Scheme 5). Treat-
ment of 4b with potassium acetate also gave 2b in good
yield (cf. Scheme 1, 4a → 2a).
To a stirred solution of the glycidic ester 1a (100 mg, 0.56 mmol) in
MeCN (5 mL) was added AcOK (66 mg, 0.67 mmol) and the mix-
ture was refluxed for 1 h. Then the mixture was allowed to cool to
r.t. Distilled H2O was added and the organic layer was extracted
with EtOAc (3 × 5 mL). The combined organic layers were dried
Synthesis 2006, No. 11, 1767–1770 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Acyloxy-3-keto Esters
IR (neat): 2961, 1751, 1730 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (d, J = 6.6 Hz, 3 H), 0.94 (d,
J = 6.6 Hz, 3 H), 1.31 (t, J = 7.2 Hz, 3 H), 2.11–2.27 (m, 1 H), 2.23
(s, 3 H), 2.53 (d, J = 6.9 Hz, 2 H), 4.28 (q, J = 7.2 Hz, 2 H), 5.48 (s,
1 H).
1769
(MgSO4) and concentrated. The crude product was purified by col-
umn chromatography on silica gel (eluent: hexane–EtOAc, 10:1) to
give 2a; yield: 105 mg (93%); colorless oil.
IR (neat): 2965, 1750, 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.5 Hz, 3 H), 1.56–
1.71 (m, 2 H), 2.23 (s, 3 H), 2.64 (t, J = 7.2 Hz, 2 H), 3.82 (s, 3 H),
5.52 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.0, 20.4, 22.3, 22.4, 24.0, 48.5,
62.4, 77.8, 164.6, 169.5, 199.4.
13C NMR (75 MHz, CDCl3): d = 13.4, 16.5, 20.4, 41.6, 53.1, 77.2,
165.2, 169.5, 199.8.
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.26; H,
7.77.
Anal. Calcd for C9H14O5: C, 53.46; H, 6.98. Found: C, 53.53; H,
6.95.
Ethyl 2-Acetoxy-4-methyl-3-oxopentanoate (2g)
Yield: 89 mg (79%); colorless oil.
Ethyl 2-Acetoxy-3-oxohexanoate (2b)
IR (neat): 2978, 1752, 1728 cm–1.
Yield: 106 mg (94%); colorless oil.
IR (neat): 2966, 1749, 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7.2 Hz, 3 H), 1.31 (t,
J = 7.2 Hz, 3 H), 1.59–1.71 (m, 2 H), 2.23 (s, 3 H), 2.64 (t, J = 7.2
Hz, 2 H), 4.28 (q, J = 7.2 Hz, 2 H), 5.50 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.13 (d, J = 6.9 Hz, 3 H), 1.18 (d,
J = 6.9 Hz, 3 H), 1.31 (t, J = 7.2 Hz, 3 H), 2.23 (s, 3 H), 3.05 (m, 1
H), 4.28 (q, J = 7.2 Hz, 2 H), 5.66 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 17.6, 18.3, 20.4, 38.1, 62.4,
76.1, 164.8, 169.4, 203.7.
13C NMR (75 MHz, CDCl3): d = 13.5, 14.0, 16.5, 20.4, 41.6, 62.4,
77.6, 164.7, 169.5, 199.9.
Anal. Calcd for C10H16O5: C, 55.55; H, 7.46. Found: C, 55.45; H,
7.29.
Anal. Calcd for C10H16O5: C, 55.55; H, 7.46. Found: C, 55.59; H,
7.40.
Ethyl 2-Acetoxy-3-oxo-4-phenylbutanoate (2h)
Yield: 82 mg (75%); pale-yellow oil.
Ethyl 2-Acetoxy-3-oxoheptanoate (2c)
IR (neat): 1748, 1733 cm–1.
Yield: 107 mg (96%); colorless oil.
IR (neat): 2961, 1750, 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.2 Hz, 3 H), 1.29–
1.39 (m, 5 H), 1.56–1.65 (m, 2 H), 2.23 (s, 3 H), 2.66 (t, J = 7.2 Hz,
2 H), 4.28 (q, J = 7.2 Hz, 2 H), 5.50 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 3 H), 2.22 (s,
3 H), 3.97 (s, 2 H), 4.23 (q, J = 7.2 Hz, 2 H), 5.58 (s, 1 H), 7.20–7.36
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 20.4, 46.7, 62.5, 76.9, 127.4,
128.7, 129.6, 132.3, 164.5, 169.4, 197.4
13C NMR (75 MHz, CDCl3): d = 13.7, 14.0, 20.4, 22.0, 25.1, 39.5,
62.4, 77.6, 164.7, 169.5, 200.0.
Anal. Calcd for C14H16O5: C, 63.63; H, 6.10. Found: C, 63.69; H,
5.92.
Anal. Calcd for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.53; H,
7.81.
Methyl 2-Benzoyloxy-3-oxohexanoate (5a)
Yield: 125 mg (85%); colorless oil.
Ethyl 2-Acetoxy-3-oxooctanoate (2d)
IR (neat): 2963, 1763, 1725 cm–1.
Yield: 107 mg (96%); colorless oil.
IR (neat): 2958, 1750, 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.6 Hz, 3 H), 1.29–
1.40 (m, 6 H), 1.57–1.67 (m, 3 H), 2.23 (s, 3 H), 2.65 (t, J = 7.2 Hz,
2 H), 4.28 (q, J = 7.2 Hz, 2 H), 5.50 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 0.96 (t, J = 7.2 Hz, 3 H), 1.64–
1.76 (m, 2 H), 2.74 (t, J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 5.75 (s, 1 H),
7.46–7.52 (m, 2 H), 7.60–7.65 (m, 1 H), 8.12–8.15 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.5, 16.6, 41.6, 53.1, 77.7, 128.4,
128.6, 130.1, 133.9, 165.1, 165.2, 200.0.
13C NMR (75 MHz, CDCl3): d = 13.8, 14.0, 20.4, 22.3, 22.7, 31.1,
39.7, 62.4, 77.6, 164.7, 169.5, 200.0.
Anal. Calcd for C14H16O5: C, 63.63; H, 6.10. Found: C, 63.45; H,
5.97.
Anal. Calcd for C12H20O5: C, 59.00; H, 8.25. Found: C, 59.11; H,
8.09.
References
Ethyl 2-Acetoxy-3-oxononanoate (2e)
Yield: 101 mg (92%); colorless oil.
IR (neat): 2932, 1750, 1731 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.9 Hz, 3 H), 1.28–
1.40 (m, 9 H), 1.53–1.65 (m, 2 H), 2.23 (s, 3 H), 2.65 (t, J = 7.2 Hz,
2 H), 4.28 (q, J = 7.2 Hz, 2 H), 5.50 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.9, 14.0, 20.4, 22.4, 23.0, 28.6,
31.4, 39.8, 62.4, 77.6, 164.7, 169.5, 200.0.
(1) (a) Takeda, A.; Amano, E.; Tsuboi, S. Bull. Chem. Soc. Jpn.
1977, 50, 2191. (b) Hecker, S. J.; Werner, K. M. J. Org.
Chem. 1993, 58, 1762. (c) Chen, D.; Sprules, T. J.; Lavallee,
J.-F. Bioorg. Med. Chem. Lett. 1995, 5, 759. (d) Wood, J.
L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.; Petsch, D. T.
J. Am. Chem. Soc. 1997, 119, 9641.
(2) (a) Henecka, H. Chem. Ber. 1948, 81, 179. (b)Zhao, M.-X.;
Wang, M.-X.; Yu, C.-Y.; Huang, Z.-T.; Fleet, G. W. J. J.
Org. Chem. 2004, 69, 997. (c) Scheid, G.; Kuit, W.; Ruijter,
E.; Orru, R. V. A.; Henke, E.; Bornscheuer, U.; Wessjohann,
L. A. Eur. J. Org. Chem. 2004, 1063.
Anal. Calcd for C13H22O5: C, 60.45; H, 8.58. Found: C, 60.68; H,
8.40.
(3) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.;
Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244.
(4) Grison, C.; Coutrot, F.; Comoy, C.; Lemilbeau, C.; Coutrot,
P. Tetrahedron Lett. 2000, 41, 6571.
Ethyl 2-Acetoxy-5-methyl-3-oxohexanoate (2f)
Yield: 105 mg (94%); colorless oil.
Synthesis 2006, No. 11, 1767–1770 © Thieme Stuttgart · New York

1770
T. Komiyama et al.
PAPER
(5) (a) Tsuboi, S.; Furutani, H.; Takeda, A. Synthesis 1987, 292.
(b) Coutrot, P.; Grison, C.; Tabyaoui, M.; Czernecki, S.;
Valery, J. M. J. Chem. Soc., Chem. Commun. 1988, 1515.
(6) Janecki, T.; Bodalski, R. Heteroat. Chem. 2000, 11, 115.
(7) Amos, J.; Castro, B.; Selve, C. Bull. Soc. Chim. Fr. 1993,
130, 683.
(8) (a) Takeda, A.; Wada, S.; Fujii, M.; Tanaka, H. Bull. Chem.
Soc. Jpn. 1970, 43, 2997. (b) Tsuboi, S.; Furutani, H.;
Takeda, A.; Kawazoe, K.; Sato, S. Bull. Chem. Soc. Jpn.
1987, 60, 2475.
Synthesis 2006, No. 11, 1767–1770 © Thieme Stuttgart · New York