A simple method for the synthesis of esters of 2-hydroxy-3-oxo-2,3- dihydrofuran-2-ylacetic acid [1]

Full text of DOI:10.1007/s10593-007-0103-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
LETTERS TO THE EDITOR
A SIMPLE METHOD FOR THE SYNTHESIS OF ESTERS OF 2-HYDROXY-
3-OXO-2,3-DIHYDROFURAN-2-YLACETIC ACID
E. N. Kozminykh1, V. I. Goncharov2, D. B. Oborin3, and V. O. Kozminykh3
Keywords: acetophenone, dibenzoylmethane, diethyl oxalate, ethyl acetate, ethyl esters of 2-hydroxy-
3-oxo-2,3-dihydrofuran-2-ylacetic acids.
2-Hydroxy-2,3-dihydrofuran-3-ones are successfully used in organic synthesis, especially for the
preparation of biologically active compounds [1-5]. The known methods for the synthesis of 5-aryl-
2-hydroxyfuran-3(2H)-ones generally include several stages and are not suitable for preparation [4, 5]. We have
developed a very simple and suitable one-step method for the synthesis of 2-hydroxy-3-oxo-2,3-dihydrofuran-
2-ylacetate esters 1,2 by the reaction of ethyl acetate with diethyl oxalate and methyl ketones (for example,
acetophenone or dibenzoylmethane) in the presence of sodium hydride with subsequent treatment of the mixture
with hydrochloric acid:
R
O
1) NaH
2) HCl
EtO
Me
O
EtO
OEt
+
+
– EtOH
O
O
R
O
O
H
O
O
1, 2
OEt
1 R = H, 2 R = PhCO
Apart from compound 1, a secondary product – Z-2-hydroxy-4-oxo-4-phenyl-2-butenoic acid
(benzoyltartaric acid) was isolated in 27% yield from the reaction mixture of ethyl acetate, diethyl oxalate, and
acetophenone, which was identified by comparison with a known sample [6].
__________________________________________________________________________________________
1Moscow State University of Technologies and Management. Perm Branch, Perm 614065, Russia;
2
3
e-mail: kvoncstu@yahoo.com. Stavropol State Medicinal Academy. Stavropol 355023, Russia. Perm State
Pedagogical University, Perm 614990, Russia; e-mail: kvo@perm.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, 782-784. May, 2007. Original article submitted November 19, 2006.
658
0009-3122/07/4305-658©2007 Springer Science+Business Media, Inc.

1
In the H NMR spectra of the hydroxyfuranones 1 and 2 there are two doublets of two interacting CH2
groups at δ 2.94 and 2.98, and 3.16 and 3.28 respectively, corresponding to AB spin systems, and also the signal of
the hydroxy group C(2)OH at δ7.58 and 8.36 ppm. The possible open chain forms of compounds 1 and 2 , suggested
for analogs in [5], were not observed in the spectra.
Compounds 1 and 2 posses bacteriostatic activity against lines of Staphylococcus aureus and the intestinal
bacteria Eschericia coli, effective on bacterial cultures with a minimum effective concentration of 250 µg/ml.
1H NMR spectra of DMSO-d6 solutions of compounds 1 and 2 with TMS as internal standard were
recorded on a Bruker DRX-500 (500 MHz) machine and the 13C NMR spectrum of a CDCl3 solution with TMS
as internal standard was recorded with a Gemini -300BB (75 MHz). IR spectra of nujol mulls were recorded with
a Specord M-80 spectrometer.
Cyclocondensation of ethyl acetate with diethyl oxalate and methyl ketones. To a mixture of AcOEt
(5.0 ml, 0.05 mol, diethyl oxalate (6.8 ml, 0.05 mol), and dioxin (40-50 ml), sodium hydride (60% suspension in
mineral oil ) (2.0 g, 0.05 ml) was added with stirring and cooling, then, after 10 min, acetophenone (6.0 ml,
0.05 mol) or 1,3-diphenylpropane-1,3-dione (dibenzoylmethane) (11.2 g, 0.05 mol) and NaH (2.0 g, 0.05 mol)
were added with cooling. Cold water (100 ml) and 15% hydrochloric acid (20 ml) were added over 3-5 h and the
mixture was extracted with ethyl acetate (150-200 ml). The solvent was evaporated, the residue was triturated
with diethyl ether (20 ml) and recrystallized from MeCN or AcOEt to give compound 1 or 2. Benzoylpyruvic
acid was additionally isolated by fractional crystallization from AcOEt. Yield 2.60 g (27%); mp 156-157°C (dec.
AcOEt) [6].
Ethyl 2-hydroxy-3-oxo-5-phenyl-2,3-dihydrofuran-2-ylacetate (1). Yield 5.68 (43%); mp 117-118°C
(from MeCN) (112-114°C [5]). Spectra are not reported in [5], so we list them here. IR spectrum, ν, cm-1: 3128
(C(2)OH), 1742 (COester), 1690 (C(3)O), 1660, 1637, 1588 (C(4)=C(5), C=Carom). 1H NMR spectrum, δ, ppm (J, Hz):
1.02 (3H, t, J = 6.9, gemJ = 11.5, CH3 in COOEt), 2.94, 2.98 (2H, 2 d, gemJ = 16.2, CH2 in CH2COOEt), 3.93 (2H,
q, J =6.9 , gemJ = 10.7, CH2 in COOEt); 6.38 (1H, s, C(4)H); 7.56-8.08 (5H, m, C6H5); 7.58 (1H, s, C(2)OH).
Found, %: C 64.38, H 5.21. C14H14O5. Calculated, %: C 64.12, H 5.38.
Ethyl 4-benzoyl-2-hydroxy-3-oxo-5-phenyl-2,3-dihydrofuran-2-ylacetate (2). Yield 11.50 g (63%);
mp 124-125°C (from AcOEt). IR spectrum, ν, cm-1: 3120 (C(2)OH), 1736 (COester), 1708 (C(3)O), 1665 (PhCO),
1655, 1630, 1575 (C(4)=C(5), C=Carom). 1H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t, J = 6.9, gemJ = 11.5, CH3
in COOEt); 3.16, 3.28 (2H, 2 d, gemJ = 17.4, CH2 in CH2COOEt); 3.91 (2H, q, J =6.9, gemJ = 10.7, CH2 in
COOEt); 7.25-7.90 (10H, m, 2C6H5); 8.36 (1H, s, C(2)OH). 13C NMR spectrum, δ, ppm: 13.5 (COOCH2CH3);
40.7 (CH2COOEt); 59.6 (COOCH2CH3); 102.4 (C(3)); 114.3 (C(4)); 128.7, 128.8, 129.6, 133.9 (C6H5); 130.4,
132.4, 133.6, 137.6 (C6H5); 168.8 (COOEt); 184.3 (C(5)), 190.2 (C6H5CO); 195.8 (C(3)O). Found, %: C 68.49,
H 4.73. C21H18O6. Calculated, %: C 68.85; H. 4.95.
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