Facile synthesis of β-keto esters from methyl acetoacetate and acid chloride: The barium oxide/methanol system

Article abstract of DOI:10.1021/op980044g

The synthesis of β-keto esters has been performed in good yield by reacting excess methyl acetoacetate with barium oxide, acylating the resulting barium complex with acid chloride, and then cleaving the α-acyl β-keto ester with methanol at a mild temperature. Using this new procedure, various β-keto esters were prepared. Thus, methyl 4-phenyl-3-oxobutanoate, methyl 3-phenyl-3-oxopropionate, methyl 4-cyclohexyl-3-oxobutanoate, and methyl 3-oxooctadecanoate were prepared from methyl acetoacetate and the corresponding acid chloride in 69%, 84%, 67%, and 74% yields, respectively.

Full text of DOI:10.1021/op980044g

Organic Process Research & Development 1998, 2, 412−414
Technical Notes
Facile Synthesis of â-Keto Esters from Methyl Acetoacetate and Acid
Chloride: The Barium Oxide/Methanol System1
Yoshifumi Yuasa* and Haruki Tsuruta
Technical Engineering Department, Fine Chemical DiVision, Takasago International Corporation,
1-5-1 Nishiyawata, Hiratsuka, Kanagawa, 254-0073, Japan
Yoko Yuasa
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji,
Tokyo, 192-0355, Japan
Abstract:
an acetoacetic ester with acid chloride, further, the use of
The synthesis of â-keto esters has been performed in good yield
by reacting excess methyl acetoacetate with barium oxide,
acylating the resulting barium complex with acid chloride, and
then cleaving the r-acyl â-keto ester with methanol at a mild
temperature. Using this new procedure, various â-keto esters
were prepared. Thus, methyl 4-phenyl-3-oxobutanoate, methyl
3-phenyl-3-oxopropionate, methyl 4-cyclohexyl-3-oxobutanoate,
and methyl 3-oxooctadecanoate were prepared from methyl
acetoacetate and the corresponding acid chloride in 69%, 84%,
67%, and 74% yields, respectively.
magnesium alcoholates is suggested.5 In practice, however,
this method also has its difficulties because the commercially
available magnesium alcholate is inadequate, so the mag-
nesium alcoholate needed for the reaction always has to be
freshly prepared. In addition, ammonolysis, which is used
for the deacetylation of R-acyl â-keto esters to â-keto esters,
produced acetamide as the byproduct in this cleavage process.
Thus, the yield is reduced, and the posttreatment becomes
troublesome. We have been studying a process for the
acylation of acetoacetate and cleavage of the R-acylacetoace-
tic ester, particularly investigating the base component. We
have found that the condensation of acetoacetic ester and
acid chloride using barium oxide as a base component and
then cleavage with an alcohol (MeOH) led to the â-keto ester
in good yield, and we now report a process for the
preparation of â-keto esters which is economically advanta-
geous and applicable to industrial production.
â-Keto esters are known to be useful as intermediates in
the synthesis of drugs, ceramides, biodegradable polymers,
etc., and there have been reported a number of syntheses
for â-keto esters.2 For example, recently, Benetti et al.2d
reviewed the synthesis of â-keto esters. In this review,
numerous procedures were reported; in particular, the acyl-
ation of an acetoacetic ester at the C2 carbon, a well-known
process, was discussed in detail. As the base component to
be employed in this acylation process, NaH, NaNH2, or alkali
metal alcoholates are usually used.3,4 However, the achieved
yields are only of the order of 30-40%, because the â-keto
ester formed during the condensation reaction has a higher
reactivity than the starting compounds to be converted, which
can lead to numerous secondary reactions. As an improve-
ment in the base component in the reaction for condensing
We first tried the synthesis of methyl 4-phenyl-3-
oxobutanoate (3a), which is a useful intermediate of allophen-
ylnorstatine.6 To prepare the barium chelate complex 1,
excess methyl acetoacetate in toluene was reacted with
barium oxide, which was activated by the addition of a small
amount of water, at 25-30 °C, and then the resulting barium
chelate 1 was acylated to give an acylated complex (2a) with
phenylacetyl chloride for 2 h at the same temperature. To
deacetylate the complex 2a, the suspension was then treated
with 2 mol of methanol (based on phenylacetyl chloride) at
25-30 °C for 16 h. The deacylation of 2a easily proceeded
with addition of 2 equiv of methanol at a mild temperature.
No methanol addition produced a very low yield. An
increase in the reaction temperature (50 °C) did not contribute
to increased yield. The resulting barium compound was
treated with 5% H2SO4 solution to remove any insoluble
BaSO4. Subsequently, the excess methyl acetoacetate was
recovered, and the â-keto ester 3a could be purified by
* To whom correspondence should be addressed. Phone: 81-(0)463-21-7150.
Fax: 81-(0)463-23-1655. E-mail: TIC00488@niftyserve.or.jp.
(1) This work has appeared in preliminary form: Sotoguchi, T.; Yuasa, Y.;
Tachikawa, A.; Harada, S. JP Patent 10053561, 1998; Chem. Abstr. 1998,
128, 167178n.
(2) (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; W. A. Benjamin:
Menlo Park, CA, 1972. (b) Caine, D. In Carbon-Carbon Bond Formation;
Augustine, R. L., Ed.; Marcel Dekker: New York, 1979; Vol. 1, pp 250-
258. (c) Barton, D.; Ollis, W. D. ComprehensiVe Organic Chemistry, 1st
ed.; Pergamon Press: Oxford, 1979; Vol. 2, pp 707-708 and 785-787.
(d) Benetti, S.; Romagnoli, R.; Risi, C. D. R.; Spalluto, G.; Zanirato, V.
Chem. ReV. 1995, 95, 1065 and references therein.
(3) Shriner, R. L.; Schmidt, A. G.; Roll, L. J. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, p 266.
(4) Miller, W. H.; Roblin, R. O., Jr.; Astwood, E. B. J. Am. Chem. Soc. 1945,
67, 2197.
(5) Viscontimi, M.; Merckling, N. HelV. Chim. Acta 1952, 35, 2280.
(6) Sayo, N.; Yamasaki, T.; Kumobayashi, H.; Yuasa, Y.; Sotoguchi, T. US
Patent 5581007, 1996; Chem. Abstr. 1996, 125, 276572v.
412
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Vol. 2, No. 6, 1998 / Organic Process Research & Development
10.1021/op980044g CCC: $15.00 © 1998 American Chemical Society and Royal Society of Chemistry
Published on Web 09/03/1998

Scheme 1
which involved refluxing several times, were needed.
In summary, it has been found that â-keto esters are
obtained in good yields, 67-84%, by the acylation of methyl
acetoacetate using barium oxide, acylating the resulting
barium complex with acid chloride, and then cleaving the
product with methanol at a mild temperature to form the
â-keto ester. This method is suitable for the large-scale
preparation of â-keto esters.
Experimental Section
All reagents and solvents were obtained from commercial
sources and used without further purification. For determin-
ing the melting points, a Yanagimoto micromelting apparatus
was used, and the values are uncorrected. Boiling points
are given as uncorrected values. NMR spectra were obtained
with a Bruker AM-400. 1H and 13C NMR were measured
at 400 and 100 MHz, respectively. The NMR spectra were
recorded in CDCl3 with TMS as the internal standard. The
chemical shifts were given in δ (ppm). IR spectra were
obtained with a Jasco IR-810. MS data were obtained with
a Hitachi M-80A mass spectrometer at 70 eV. GC was done
using a Hewlett Packard HP5890 II (column, silicon NB-1,
30 m × 0.25 mm, 0.25 µm; He gas, 1 kg/cm2; oven
temperature, 100-220 °C programmed at 5 °C/min; injection
temperature, 250 °C; detector temperature, 250 °C). HPLC
was done using a Hitachi L-6200 [column, Inertsil ODS-2;
solvent, CH3CN/MeOH/H2O ) 47.5/47.5/5; flow rate, 1.0
mL/min; detector, Hitachi L-4000 (210 nm)].
Table 1. Yield of 3a upon varying the molar ratio of methyl
acetoacetate
methyl acetoacetate
(molar equiv)
yield of
runa
3a (%)b
1
2
3
4
2.0
4.0
6.0
8.0
58
69
65
64
a 1.2 equiv of BaO and 2.0 equiv of MeOH based on phenylacetyl chloride
were used in all cases. b Isolated yield after purification by distillation.
Methyl 4-Phenyl-3-oxobutanoate (3a). Typical Pro-
cedure. To toluene (200 mL) was added BaO (37.8 g, 0.24
mol). After addition of H2O (0.5 mL) and activation with
vigorous stirring, methyl acetoacetate (92.9 g, 0.8 mol) was
added dropwise at 25-30 °C over a period of 1 h. Into the
solution was added dropwise phenylacetyl chloride (30.9 g,
0.2 mol) at the same temperature over a period of 1 h, and
then stirring was continued for an additional 1 h. Next,
MeOH (15 g, 0.47 mol) was added to the reaction mixture,
which was then stirred for 16 h. After the pH value of the
reaction mixture was adjusted to 1 using 5% H2SO4 solution,
the insoluble barium salt was filtered off, and the organic
layer was washed with 5% NaHCO3 solution and brine. After
the solvent was recovered, the oily residue (86.6 g) was
distilled at reduced pressure to recover the methyl acetoac-
etate (45.7 g) and gave methyl 4-phenyl-3-oxobutanoate (29.5
g, 69%) as a colorless oil. The purity was 96% by GC: bp
Table 2. Yield of 3a upon varying the molar ratio of BaO
runa
BaO (molar equiv)
yield of 3a (%)b
1
2
3
4
1.2
1.0
0.8
0.5
69
65
63
57
a 4.0 equiv of methyl acetoacetate and 2.0 equiv of MeOH based on
phenylacetyl chloride were used in all cases. b Isolated yield after purification
by distillation.
Table 3. Yields of â-keto esters 3a-da
3
R
yield (%)b
a
b
c
C6H5CH2
C6H5
c-C6H11CH2
n-C15H31
69
84
67
74
d
1
122-123 °C/1 Torr (lit.5 bp 125 °C/3 Torr); H NMR 3.45
a 1.2 equiv of BaO, 4.0 equiv of methyl acetoacetate, and 2.0 equiv of MeOH
based on acid chloride were used in all cases. b Isolated yield after purification
by distillation or recrystallization.
(2H, s, COCH2CO2), 3.70 (3H, s, CO2CH3), 3.82 (2H, s,
PhCH2CO), 7.19-7.36 (5H, s, aromH); 13C NMR 48.5
(CH2), 50.6 (CH2), 52.9 (CH3), 127.9 (CH), 129.4 (2×CH),
130.1 (2×CH), 133.8 (C), 168.1 (CO), 200.9 (CO); IR (neat)
1750, 1720, 1655, 1625, 1600, 1500 cm-1; EI-MS (m/e,
relative intensity) 192 (M+, 42), 160 (8), 118 (55), 101 (43),
91 (100), 59 (26).
Methyl 3-Phenyl-3-oxopropanoate (3b). The product
was recovered as a colorless oil (84%). The purity was 95%
by GC: bp 118-120 °C/1 Torr (lit.7 bp 90-92 °C/0.05
Torr); 1H NMR 3.74 (3H, s, CO2CH3), 4.01 (2H, s,
distillation at reduced pressure (Scheme 1). The optimized
amounts of methyl acetoacetate and barium oxide were
investigated and found to be 4 equiv and 1.2 equiv per mole
of the acid chloride, respectively (see Tables 1 and 2). The
utility of this new synthetic method was demonstrated for
various â-keto ester compounds (see Table 3). This new
reaction was also accomplised by using CaO or SrO.
However, as the basicity of these alkaline earth metal oxides
is weaker than that of BaO, more drastic reaction conditions,
(7) McElvain, S. M.; McKay, G. R., Jr. J. Am. Chem. Soc. 1956, 78, 6086.
Vol. 2, No. 6, 1998 / Organic Process Research & Development
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413

PhCOCH2CO2), 7.41-7.79 (3H, m, aromH), 7.93-7.96 (2H,
m, aromH); 13C NMR 46.1 (CH2), 52.9 (CH3), 129.2
(2×CH), 129.3 (2×CH), 134.3 (CH), 136.5 (C), 168.4 (CO),
192.9 (CO); IR (neat) 1745, 1690, 1650, 1620, 1600, 1580
cm-1; EI-MS (m/e, relative intensity) 178 (M+, 9), 146 (26),
117 (70), 106 (9), 105 (100), 77 (38), 69 (3), 64 (1), 59 (2),
51 (9).
Methyl 3-Oxooctadecanoate (3d). This procedure was
similar to that described above. After workup, the solvent
was recovered in vacuo, and the residue was dissolved in
MeOH and allowed to stand at -20 °C overnight. The
precipitated crystals were filtered and dried and gave methyl
3-oxooctadecanoate as white crystals (74%). The purity was
1
95% by HPLC: mp 40-41 °C (lit.5 mp 46 °C); H NMR
Methyl 4-Cyclohexyl-3-oxobutanoate (3c). The product
was recovered as a colorless oil (67%). The purity was 96%
by GC: bp 95-98 °C/1.5 Torr (lit.8 bp 80-81 °C/0.35 Torr);
1H NMR 0.92-0.97 (2H, m), 1.13-129 (3H, m), 1.64-1.85
(6H, m), 2.40 (2H, d, J ) 6.8 Hz, CH2CO), 3.43 (2H, s,
COCH2CO2), 3.74 (3H, s, CO2CH3); 13C NMR 26.6 (CH2),
26.7 (CH2), 26.8 (2×CH2), 33.7 (CH2), 34.3 (CH), 50.2
(CH2), 51.3 (CH2), 52.9 (CH3), 168.3 (CO), 203.0 (CO); IR
(neat) 1750, 1715, 1650, 1625 cm-1; EI-MS (m/e, relative
intensity) 198 (M+, 3), 125 (26), 117 (70), 116 (100), 97
(32), 85 (30), 74 (23), 64 (21), 55 (53), 43 (25).
0.81 (3H, t, J ) 7 Hz, CH3(CH2)-), 1.18 (24H, m, 12×CH2),
1.50-1.54 (2H, m, CH2), 2.46 (2H, t, J ) 7 Hz, CH2CO),
3.37 (2H, s, COCH2CO2), 3.66 (3H, s, CO2CH3); 13C NMR
14.8 (CH3), 23.4 (CH2), 24.2 (CH2), 29.7 (CH2), 30.0
(2×CH2), 30.1 (CH2), 30.3 (3×CH2), 30.4 (2×CH2), 32.6
(CH2), 43.8 (CH2), 49.7 (CH2), 52.9 (CH3), 168.4 (CO), 203.5
(CO); IR (CHCl3) 1750, 1715 cm-1; EI-MS (m/e, relative
intensity) 312 (M+, 2), 294 (2), 239 (13), 158 (4), 143 (6),
129 (24), 117 (33), 116 (100), 97 (11), 85 (11), 74 (11), 57
(20), 43 (32).
Received for review May 26, 1998.
OP980044G
(8) Kugatova-Schemyakina, G. P.; Andreev, V. M.; Anarkulova, L. S. Zh. Org.
Khim. 1967, 3, 1213; Chem. Abstr. 1967, 67, 90429 g.
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