SHORT PAPER
1311
Simple Synthesis of Arylsuccinic Acids
S
M
ynthesis of
A
rylsucci
i
A
ci
e
ds czy saw M kosza,* Agnieszka Marcinowicz
Institute of Organic Chemistry, Polish Academy of Science, ul. Kasprzaka 44/52, 01–224 Warszawa, Poland
Fax +48(22)6326681; E-mail: icho-s@icho.edu.pl
Received 15 March 2001; revised 27 March 2001
Abstract: Alkylation of arylacetonitriles with potassium chloroac-
etate proceeds selectively leading to 3-cyano-3-arylpropionic acids,
which are directly hydrolyzed to arylsuccinic acids.
Key words: alkylations, hydrolysis, nitriles, propionic acid, suc-
cinic acid
Scheme Ar = C H , 4-ClC H , 2,4-Cl C H , 2-CH C H , 4-BrC H
4
6
5
6
4
2
6
3
3
6
4
6
To a stirred suspension of anhyd K CO (8 g, 0.06 mol) in DMF (20
mL), chloroacetic acid (4.7 g, 0.05 mol) was added. From the result-
synthesis particularly in medicinal chemistry. The most ed suspension, DMF (approx. 10 mL) was distilled off under re-
2
3
Aryl succinic acids are important intermediates in organic
1
important method of synthesis of these acids consists in duced pressure at approx. 54°C /30 mm Hg. The suspension was
cooled to r.t. and DMF (30 mL) followed by phenylacetonitrile
the condensation of aromatic aldehydes with ethyl mal-
(5.86 g, 0.05 mol) were added. Powdered KOH (5.8 g, 0.1 mol) was
onate and addition of cyanide anion to produce arylidene-
malonates. Hydrolysis and decarboxylation of the
intermediate 3-cyano-3-arylpropionates gave arylsuccinic
added in portions at 20–25°C. The reaction mixture was stirred fur-
ther for 2 h at 20–25°C, and the solvent was completely distilled off
under reduced pressure at approx. 54°C /30 mm Hg. The solid res-
2
acids. Other reported methods, such as addition of
idue was dissolved in H O (approx. 20 mL) and the solution was ex-
2
BrZnCH COOEt to nitrostyrenes and subsequent oxida- tracted with hexane (2 10 mL). The aqueous layer containing
2
3
tive Nef reaction, alkylation of arylacetonitriles with bro- potassium 3-cyano-3-phenylpropionate was further elaborated in
moacetal followed by hydrolysis and oxidation,4 or
two ways giving 3-cyano-3-phenylpropionic acid and phenylsuc-
cinic acid.
alkylation of the dianion of phenylacetic acid with lithium
5
6
iodoacetate, etc. are without practical value. An attrac- 3-Cyano-3-phenylpropionic Acid
tive possibility of synthesis of arylsuccinic acids appears The aqueous layer was acidified with HCl and extracted with
to be phase-transfer catalyzed (PTC) alkylation of arylac- EtOAc (2 10 mL). Evaporation of the solvent gave an oily residue
(
slowly solidified) which was recrystallized from benzene to give 3-
etonitriles with isopropyl chloroacetate and hydrolysis of
the produced 3-aryl-3-cyanopropionates. Unfortunately,
cyano-3-phenylpropionic acid (4.75 g, 81%).
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this process is not selective and produces, in addition to Mp 82°C (Lit. mp 74–76°C).
the monoalkylation product, the product of dialkylation –
1H NMR (200 MHz, DMSO-d6): = 2.5 (m, 1H, Ja a = 16.6 Hz,
diisopropyl 3-phenyl-3-cyano-glutarate in substantial Ja b = 5.1 Hz, H , CH ), 2.9 (m, 1H, J = 16.6 Hz, J = 9.5 Hz, H ,
a
2
aa
ab
a
7
quantity, even when the nitrile is used in excess.
CH
2
), 3.8–3.9 (m, 1H, Jba = 9.5 Hz, Jba = 5.1 Hz, CH), 7.5 (m, 5H,
C H ), 12.2 (s, 1H, COOH).
13C NMR (DMSO-d6): = 37.2, 40.7, 46.8, 126.7, 127.5, 128.3,
40.2, 172.7, 173.7.
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5
We have expected that alkylation of phenylacetonitrile
with salts of chloroacetic acid should proceed with high
selectivity because of the negatively charged substituent,
which would decrease substantially the CH acidity of the
1
Phenylsuccinic Acid
product and so avoid the dialkylation. Indeed treatment of To the aqueous layer, NaOH (20%, 15 mL) was added and the mix-
ture was refluxed for approx. 16 h. Upon cooling, the reaction mix-
phenylacetonitrile in DMF with potassium chloroacetate
ture was acidified with HCl (38 %), the precipitated acid was
and solid powdered KOH resulted in a mild exothermic
filtered with suction, and dried to give phenylsuccinic acid (5.14 g,
reaction giving the expected salt of 3-cyano-3-phenyl-
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5%).
propionic acid which can be easily isolated upon acidifi-
cation. Direct hydrolysis of the reaction mixture gave phe-
nylsuccinic acid in excellent yield (Scheme). The reaction
also proceeded with other arylacetonitriles to give the cor-
responding arylsuccinic acids.
2
Mp 162–163°C (Lit. mp 163–164°C).
1
H NMR (CD COCD ): = 2.6 (m, 1H, Ja a = 17.1 Hz, Ja b = 5.1 Hz,
3
3
H , CH ), 3.1 (m, 1H, J = 17.1 Hz, J = 10.1 Hz, H , CH ), 4.0–
4
a
2
aa
ab
a
2
.1 (m, 1H, J = 10.1 Hz, J = 5.1 Hz, CH), 7.3 (m, 5H, C H ), 12.4
ba ba 6 5
(
s, 2H, COOH).
1
3
C NMR (CD COCD ): = 37.8, 46.8, 127.0, 127.6, 128.5, 138.5,
3
3
3
1
72.5, 173.8.
Other arylsuccinic acids were prepared in this way from the corre-
sponding arylacetonitriles: 2-chlorophenyl-succinic acid 82.5%,
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mp 159–160°C (Lit. mp 161–162°C; 2,4-dichloro phenyl-succinic
Synthesis 2001, No. 9, 29 06 2001. Article Identifier:
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acid 84%, mp 175°C (Lit. 175°C); 2-methylphenyl-succinic acid
1
437-210X,E;2001,0,09,1311,1312,ftx,en;Z03201SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
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8
3.2%, mp 183–184°C (Lit. mp 184–185°C); 4-bromophenyl-
©
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succinic acid 84.6%, mp 211–212°C (Lit. 211–212°C).