Synthesis of δ-hydroxy-β-oxo esters using sonochemical Blaise reaction

Article abstract of DOI:10.1055/s-1998-2213

A simple and convenient synthesis of δ-hydroxy-β-oxo esters starting from β-hydroxynitriles and ethyl bromoacetate using zinc under sonication is reported.

Full text of DOI:10.1055/s-1998-2213

SYNTHESIS
December 1998
1713
Synthesis of δ-Hydroxy-â-oxo Esters Using Sonochemical Blaise Reaction
Kesavaram Narkunan, Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300, Republic of China
Fax +886(3)5711082; E-mail: bjuang@chem.nthu.edu.tw
Received 14 May 1998
Abstract: A simple and convenient synthesis of δ-hydroxy-β-oxo
esters starting from β-hydroxynitriles and ethyl bromoacetate
using zinc under sonication is reported.
above modification were not fruitful due to low yields and
side products. During our efforts on the above study, we
realized that β-hydroxynitriles 1a–f when treated with ex-
cess of zinc and ethyl bromoacetate under sonication for 2
hours at room temperature followed by acidic workup led
to the required δ-hydroxy-β-oxo esters 2a–f in good
yields (Table). The advantages of this method are (a) the
starting materials are readily available either by opening
an epoxide7 or by reaction of a cyclic 1,2-sulfite8 with cy-
anides, (b) the reaction is general, works with primary and
secondary hydroxy groups, also aromatic and aliphatic
substrates yield the respective products in good yields, (c)
very importantly this method does not require tiresome
protection and deprotection of the hydroxy group and can
be applied to prepare chiral δ-hydroxy-β-oxo esters, start-
ing from chiral epoxides.
Key words: δ-hydroxy-β-oxo esters, Blaise reaction, β-hydroxy-
nitriles, sonication, zinc.
The Blaise reaction has earned very little significance in
synthetic organic chemistry since its discovery in 1901,1
due to the problems of low yields, narrow scope and com-
peting side reactions.2 δ-Hydroxy-β-oxo esters, on the
other hand, are used in many natural product syntheses.3
The presence of the δ-hydroxy group has been used as an
anchor to control the stereochemistry of β-oxo reduction
to yield either 1,3-syn or 1,3-anti dihydroxy products.1c,4
Further studies on stereoselective alkylation at the α-posi-
tion are also well known.5 In spite of the versatility of
δ-hydroxy-β-oxo esters in synthetic organic chemistry, a
general and convenient approach for their synthesis has
not yet been realized.6 The existing methods either suffer
from low yields6a or many iterative steps6b or else are not
useful for the preparation of chiral analogs.
THF was freshly distilled from Na/benzophenone. Ethyl bromoace-
tate was obtained from Aldrich Company and used without further
purification. Zn was activated before use as described in the litera-
ture.1a Column chromatography was performed with Merck silica gel
(70–230 mesh). Derivatives 2a,6a 2b6c and 2c9 have previously been
reported. 1H and 13C NMR spectra were recorded on Brucker 300 and
Varian Unity 400 spectrometer in CDCl3 using TMS as an internal
standard. MS were obtained by EI mode using Jeol JMS-HX 110
mass spectrometer.
δ-Hydroxy-â-oxo Esters 2a–f; General Procedure:
To a mixture containing β-hydroxynitrile (1.0 mmol) and activated
Zn1a (15.0 mmol) in anhyd THF (4 mL) was added dropwise ethyl
bromoacetate (10.0 mmol) and the mixture sonicated at 30°C for 2 h
under argon. The resultant mixture was left at 30 ˚C for another 2 h
and the THF layer was decanted. The unreacted Zn was washed with
THF (2 × 2 mL), centrifuged and the THF layers were combined to-
gether. The combined THF solution was concentrated to about 1 mL
under reduced pressure and stirred vigorously for 30 min with a mix-
ture of EtOAc (8 mL) and 1.0 M HCl (12 mL). The organic layer was
separated and the aqueous layer was washed with EtOAc (2 × 15 mL).
The combined organic layers were washed with sat. NaHCO3
(10 mL) and brine (10 mL) and dried (Na2SO4). Concentration of the
dried organic extract under reduced pressure followed by purification
by column chromatography (silica gel, 30–40% EtOAc/hexane) af-
forded the required products in good yields.
Table. Synthesis of δ-Hydroxy-β-oxo Esters 2
Entry
Product
R
Yield (%)a
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
Et
Ph
70
74
76
67
71
76
PhOCH2
BnOCH2
α-NpOCH2
b
a The yields were determined after chromatographic purification.
b Np = naphthyl.
2d:
IR (neat): ν = 3489, 1732, 1713 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.4 Hz, 3H), 2.89 (d, J
= 6.0 Hz, 2H), 3.50 (s, 2H), 3.95 (d, J = 5.2 Hz, 2H), 4.18 (q, J =
7.5 Hz, 2H), 4.46 (m, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.95 (t, J = 7.2
Hz, 1H), 7.27 (t, J = 7.6 Hz, 2H).
Recently, Kishi1a has introduced an improved procedure
for the Blaise reaction by slow addition of excess bromo-
acetate to a refluxing mixture of aromatic or aliphatic ni-
triles and zinc in THF. However, our attempts to prepare
δ-hydroxy-β-oxo esters from β-hydroxynitriles using the
13C NMR (100 MHz): δ = 14.04, 46.15, 49.94, 61.58, 66.27, 70.64,
114.58, 121.30, 129.70, 158.41, 167.02, 202.59.
HRMS: Calcd for C14H18O5: 266.1154. Found: 266.1150.

SYNTHESIS
Short Papers
1714
2e:
(2) (a) Blaise, E. E. C. R. Acad. Sci. 1901, 132, 978.
IR (neat): ν = 3464, 1737, 1713 cm–1.
(b) Kagan, H. B.; Suen, Y.-H. Bull. Soc. Chim. Fr. 1966, 1819.
(3) (a) Tabuchi, H.; Hamamoto, T.; Miki, S.; Tejima, T.; Ichihara, A.
J. Org. Chem. 1994, 59, 4749.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 7.6 Hz, 3H), 2.73–2.75
(m, 2H), 3.45 (s, 2H), 3.42–3.46 (m, 2H), 4.17 (q, J = 7.6 Hz, 2H),
4.28 (m, 1H), 4.52 (s, 2H), 7.29–7.33 (m, 5H).
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125.
(c) Tanabe, Y.; Miyakado, M.; Ohno, N.; Yoshioka, H. Chem.
Lett. 1982, 1543.
13C NMR (100 MHz): δ = 14.04, 46.27, 49.94, 61.49, 66.69, 73.14,
73.41, 127.86, 127.93, 128.56, 137.87, 167.12, 202.69.
HRMS: Calcd for C15H20O5: 280.1311. Found: 280.1309.
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1993, 49, 1997.
(e) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
12360.
2f:
IR (neat): ν = 3469, 1737, 1713 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 3H), 2.97–2.98
(m, 2H), 3.52 (s, 2H), 4.11–4.19 (m, 4H), 4.62 (m, 1H), 6.78 (d, J =
8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 4 Hz, 1H), 7.46–7.50
(m, 3H), 7.78–7.80 (m, 1H), 8.20–8.22 (m, 1H).
13C NMR (100 MHz): δ = 14.02, 46.30, 49.97, 61.60, 66.36, 70.88,
105.01, 120.89, 121.78, 125.41, 125.48, 125.89, 126.58, 127.65,
134.57, 154.07, 167.08, 202.77.
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Pharm. Bull. 1990, 38, 2890.
HRMS: Calcd for C18H20O5: 316.1311. Found: 316.1313.
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Financial support from the National Science Council, Republic of
China is gratefully acknowledged.
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