A simple method for the preparation of new α-oxoacetic acid esters with a plug flow reactor

Article abstract of DOI:10.1055/s-1998-6091

The formation of ethyl 2-(2-substituted-4,5-dimethoxyphenyl)-2-oxoacetates in high yield, with negligible byproducts, by reaction of 2-substituted 4,5-dimethoxyphenyl bromides with diethyl oxalate using a plug flow reactor is reported.

Full text of DOI:10.1055/s-1998-6091

SYNTHESIS
September 1998
1241
A Simple Method for the Preparation of New α-Oxoacetic Acid Esters
with a Plug Flow Reactor
Fred Hollwedel, Gerhard Koßmehl*
Institut für Organische Chemie, Freie Universität Berlin, Takustraße 3, D-14195 Berlin, Germany
Fax +49(30)8385310
Received 31 October 1997
This double addition is well known3 and many workers
have tried to suppress it by the use of ethyl oxalyl
chloride4 or ethyl cyanoformate5 with organocadmium
compounds or different solvent mixtures and low temper-
atures.6 No reaction of 2b with magnesium was observed,
even if it was activated with iodine, dibromoethane or ul-
trasound. So we had to use butyllithium for generating the
anion. Axiotis7 described the addition of organolithium
compounds to triethoxyacetonitrile to give α-oxoacetic
acid esters in high yields. The main drawback is, however,
the expense and the low yield of the nitrile from tetraethyl
orthocarbonate and acetonitrile.8
Abstract: The formation of ethyl 2-(2-substituted-4,5-dimethoxy-
phenyl)-2-oxoacetates in high yield, with negligible byproducts,
by reaction of 2-substituted 4,5-dimethoxyphenyl bromides with
diethyl oxalate using a plug flow reactor is reported.
Key words: α-oxoacetic acid esters, plug flow reactor, diethyl
oxalate
For the preparation of 4-hydroxy-6,7-dimethoxyisochro-
man-3-ones1 we needed some α-oxoacetic acid esters 1a–
d of the type shown in the Scheme.
In order to avoid formation of 3 when using the low-cost
diethyl oxalate we constructed a small plug flow reactor
out of a 1-mL syringe, a T-junction as mixing chamber
and some Teflon tubes as shown in the Figure. The low
pressure in the 2-L flask leads to a flow velocity of about
7 mL/s. This prevents the direct contact between anion
and 1 and therefore no double addition can take place.
With this procedure we obtained the new α-oxoacetic acid
esters 1a–d in high yields with negligible yields of the
side reaction products 3a–d, as shown in the Table.
This method should also be suitable for generating other
oxo esters.
Preparation of the Aryl Bromides:
2-(2-Bromo-4,5-dimethoxyphenyl)-5,5-dimethyl-1,3-dioxane (2a):
Out of a solution of 2-bromo-4,5-dimethoxybenzaldehyde (12.2 g,
0.05 mol), 2,2-dimethylpropane-1,3-diol (6.3 g, 0.06 mol) and TsOH
(60 mg) in toluene (150 mL), was distilled azeotropically ca. 100 mL
of water/toluene over ca. 1 h. The residue was cooled down, diluted
with hexane (50 mL) and filtered over a column (5 × 3 cm) fitted with
alox ”super active”. The solvents were evaporated and the oil crystal-
lized from Et2O/hexane (2:1, 30 mL); yield: 14.0 g (85%); colorless
crystals.
Scheme
Benzyl [(2-Bromo-4,5-dimethoxyphenyl)phenylmethyl] Ether (2b):
(2-Bromo-4,5-dimethoxyphenyl)phenylmethanol9 was protected
with benzyl bromide/NaH by conventional methods.10
For the synthesis of α-oxoacetic acid esters many meth-
ods have been published,2 most of which, however,
proved to be unsatisfactory for the preparation of 1.
[(2-Bromo-4,5-dimethoxyphenyl)phenylmethyl] 1-Ethoxyethyl Ether
(2c):
The reaction of 2b with butyllithium and trapping the
formed anion with diethyl oxalate gave only a 23% yield
of the desired ester 1b besides 50% of the alcohol 3b as a
double addition product, even if the solution of the anion
was injected in diethyl oxalate dissolved in THF. In our
system, 2a–d, we found similar product distribution, if we
used dimethyl oxalate, ethyl oxalyl chloride or 2,3-dioxo-
1,4-dioxane instead of diethyl oxalate.
(2-Bromo-4,5-dimethoxyphenyl)phenylmethanol was protected with
ethyl vinyl ether/TsOH by conventional methods.10
(2-Bromo-4,5-dimethoxyphenylmethyl) 1-Ethoxyethyl Ether (2d):
2-Bromo-4,5-dimethoxyphenylmethanol11 was protected with ethyl
vinyl ether/TsOH by conventional methods.

SYNTHESIS
Short Papers
Table. Preparation of α-Oxoacetic Acid Esters via Lithioarenes and Diethyl Oxalate with a Plug Flow Reactor
1242
Product
Yield
(%)
mp
(°C)
1H NMR (DMSO-d6 250 MHz)
δ, J (Hz)
IR (KBr)
MS (EI)
m/z (%)
υ (cm–1)
1a
83
142a
0.74 (s, 3 H, CH3 ax); 1.03 (s, 3 H, CH3 eq); 1.28 (t, 3 H, J = 6, 1698, 1726
OCH2CH3); 3.58 (q, 4 H, CH2); 3.76 (s, 3 H, OCH3); 3.82 (s, 3 H,
OCH3); 4.34 (q, 2 H, J = 6, OCH2CH3); 5.50 (s, 1H, CH); 7.08 (s,
1H, arom); 7.10 (s, 1H, arom)
352 (M+ 8.78), 279;
250; 193 (100)
1b
1c
71
82
92a
oil
1.25 (t, 3 H, J = 5, OCH2CH3); 3.78 (s, 6 H, OCH3); 3.82 (s, 6 H, 1669, 1735
OCH3), 4.33 (q, 2 H, J = 5, OCH2CH3); 4.44 (m, 2 H, CH2); 6.22 (s,
1 H, CH); 7.16 (s, 1 H, arom); 7.30 (m, 11 H, arom)
434 (M+ 0.58); 361;
343; 269; 91 (100)
1.00 (dt, 3 H, J = 6, OCH2CH3); 1.22 (m, 6 H, CHCH3
+
1674, 1736
1669, 1734
416 (M+ 0.77);
327; 326; 271 (100);
255; 73
COOCH2CH3); 3.38 (m, 2 H, OCH2CH3); 3.78 (d, 3 H, OCH3), 3.88
(d, 3 H, OCH3); 4.34 (q, 2 H, J = 6, COOCH2CH3); 4.65 (dq, 1 H,
CHCH3); 6.52 (ds, 1 H, CH); 7.09 (s, 1 H, arom); 7.16 (s, 1 H, arom);
7.24 (m, 5 H, arom)
1d
64
oil
1.08 (t, 3 H, J = 6, OCH2CH3), 1.30 (m, 6H, CHCH3
+
340 (M+ 2.09);
268; 251; 195; 73
(100)
COOCH2CH3); 3.50 (m, 2 H, OCH2CH3); 3.8 (s, 3H, OCH3); 3.90
(s, 3 H; OCH3); 4.36 (q, 2 H, J = 6, COOCH2CH3); 4.78 (m, 3 H,
CHCH3 + CH2); 7.18 (s, 1H, arom); 7.24 (s, 1 H, arom)
a Satisfactory microanalyses were obtained: C ± 0.41; H ± 0.08.
Figure
Preparation of α-Oxoacetic Acid Esters 1a–d with the Plug Flow
Reactor; General Procedure:
The diethyl oxalate contained about 3–4% THF as major impurity and
was used a second time without further purification.
A 2-L round-bottomed flask was filled with ice (ca. 300 g), closed
with the head of a gas washing bottle and then connected with the
plug flow reactor, as shown in the Figure. In a 250-mL two-necked,
round-bottomed flask equipped with an argon balloon and a septum
was the aryl bromide 2 (0.05 mol) dissolved in abs THF (50 mL) and
cooled to –80°C. 1.6 M BuLi in hexane (38 mL, 0.06 mol) was add-
ed via a syringe and stirred for 5 min keeping the temperature of the
solution below 60°C. Then one of the Teflon tubes with a cannula
was put into the bottle containing diethyl oxalate (50 mL, 0.32 mol)
and the other was stuck through the septum of the flask. Evacuation
was started. The two-necked flask should be empty after ca. 1 min.
Just before the flask was empty, abs THF (20 mL) was added
through the septum to remove the solution of the aryllithium com-
pletely. The two cannulae were pulled out and put into a flask with
CH2Cl2 (200 mL) for the purpose of cleaning the tubes and the re-
actor. Then evacuation was stopped, the head of the gas washing
bottle removed and the 2-L flask was shaken vigorously. The organ-
ic layer was separated and the aqueous layer was extracted once
with CH2Cl2. The combined organic layers were washed with brine,
dried (MgSO4 or CaCl2), (a small amount of Na2CO3 was added in
the cases of 1c and 1d) and then the solvent was evaporated. From
the residue, the diethyl oxalate was distilled off on a rotary evapo-
rator at 5 mbar and 60–70°C water bath temperature. 1a and 1b
were crystallized from Et2O; 1c and 1d were isolated by column
chromatography (hexane/EtOAc 7:3).
We thank the DIC Berlin GmbH for the financial support.
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