Short synthesis of ethyl 3-(3-aminophenyl)propanoate

Article abstract of DOI:10.1002/ardp.200900164

A short and effective synthesis of ethyl 3-(3-aminophenyl)propanoate is presented, employing a tandem Knoevenagel condensation/alkylidene reduction of 3-nitrobenzaldehyde with Meldrum's acid in TEAF (triethylammonium formate) followed by reduction of the

Full text of DOI:10.1002/ardp.200900164

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Arch. Pharm. Chem. Life Sci. 2011, 344, 840–842
Short Communication
Short Synthesis of Ethyl 3-(3-aminophenyl)propanoate
Ulrike Nagel, Gregor Radau, and Andreas Link
Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
A short and effective synthesis of ethyl 3-(3-aminophenyl)propanoate is presented, employing a
tandem Knoevenagel condensation/alkylidene reduction of 3-nitrobenzaldehyde with Meldrum’s
acid in TEAF (triethylammonium formate) followed by reduction of the intermediate 3-(3-
nitrophenyl)propanoic acid by stannous chloride in ethanol. The use of stannous chloride as the
reducing agent in ethanol enabled the simultaneous esterification of the carboxylic acid. Thus,
stannous chloride was acting simultaneously as a Lewis acid, which activates the carboxylic acid
towards a nucleophilic attack by ethanol.
Keywords: Aryl propanoic acids / Condensation / Lewis acid catalysis / Tandem reaction
Received: July 15, 2009; Accepted: September 11, 2009
DOI 10.1002/ardp.200900164
Introduction
5% palladium on charcoal to yield ethyl 3-(3-aminophenyl)-
propanoate 1 [6].
Chemical equivalents for synthons for the incorporation of
the 3-(3-aminophenyl)propionyl moiety represent important
building blocks in the synthesis of biologically active
compounds, e.g., GPR40 receptor agonists [1], focal adhesion
kinase inhibitors [2], agonists of the EP2 receptor [3], and
inhibitors of protein-tyrosine phosphatase [4].
In an alternative strategy reported recently, the title com-
pound was synthesized in a four-step procedure, starting
with benzylation of diethyl malonate and subsequent sapo-
nification (Scheme 1, route C) [7, 8]. The resulting 2-(3-nitro-
benzyl)malonic acid 8 was decarboxylated to the appropriate
propanoic acid 6, transformed into the ethyl ester 9, and
As part of our program directed towards analogues of
contrast agents for oral cholangiography, we were looking
for a short and effective synthetic approach to ethyl 3-(3-
aminophenyl)propanoate (1, Fig. 1).
hydrogenated by means of PtO to 1. The shortcoming of this
2
approach is the extremely low overall yield of 6%, mainly
originating from the sluggish alkylation/saponification of
diethyl malonate as well as the failed hydrogenation as
the final step.
Results
In order to shorten the routes described above, we envis-
aged the condensation of 2 with Meldrum’s acid (2,2-
dimethyl-1,3-dioxane-4,6-dione 5 [9, 10]), which has been
widely used in organic syntheses for more than a hundred
years [11]. In our approach, the reactants were subjected to a
tandem Knoevenagel condensation/alkylidene reduction
In a formal synthesis of two published partial syntheses, 3-
nitrobenzaldehyde 2 was initially condensed with malonic
acid in
a
Knoevenagel–Doebner type aldole reaction
(Scheme 1, route B) [5]. The resulting 3-nitrocinnamic acid
3
was transformed into the ethyl ester 4 in order to achieve a
employing triethylammonium formate ([Et
3
N]
2
2 5
ꢀ [HCO H] ,
more lipophilic intermediate with an improved reactivity
towards nucleophilic reagents. The double bond and the
nitro group were finally reduced by hydrogenation with
O
O
Correspondence: Prof. Dr. Andreas Link, Institute of Pharmacy, Ernst-
Moritz-Arndt-University Greifswald, F.-L.-Jahn-Str. 17, 17487 Greifswald,
Germany.
1
NH2
E-mail: link@uni-greifswald.de
Fax: þ49-3834-864895
Figure 1. Ethyl 3-(3-aminophenyl)propanoate 1.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 840–842
Ethyl 3-(3-aminophenyl)propanoate
841
Route C:
Overall yields:
Route A: 42%
Route B: 51%
Route C: 5.5%
Cl
NO2
7
diethyl
malonate
1. NaOEt
2. KOH
Route B:
4
2%
2
O
OH
OH
malonic
acid
Piperidine
Pyridine
O
8
5%
NO
2
Route A:
8
O
O
D
H
OH
-
CO2
9%
8
NO2
NO2
2
3
6
O
O
TEAF
00 °C
EtOH
1
. SOCl
2
O
O
1
H SO
2. NaOEt
67%
2
4
6
8%
7
4%
5
O
O
O
O
OH
O
NO2
NO2
NO2
6
4
9
EtOH
2%
H
PtO2
2
EtOH
22%
SnCl2
H2
EtOH
6
Pd/C 81%
Scheme 1. Synthesis routes to ethyl 3-(3-
aminophenyl)propanoate 1.
1
TEAF [12, 13]) as reducing agent in a slightly modified, pre-
viously reported manner (Scheme 1, route A). In the second
step, the nitro group of the intermediate 3-(3-nitrophenyl)-
propanoic acid 6 was reduced by stannous chloride in etha-
nol according to the previously described reduction of 4-
nitrobenzoic acid to 4-aminobenzoic acid [14]. The occur-
rence of an esterification at this reaction step obviously
depends on the capability of stannous chloride to act as a
Lewis acid, which diminishes the mesomeric stability of
the carboxylic group in 6 through formation of a complex
between carbonyl oxygen atoms and tin. This complexation
is associated with an enhanced reactivity of the carboxyl
group towards nucleophilic agents, such as the solvent
ethanol.
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U. Nagel et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 840–842
anhydrous sodium sulfate and the solvent was removed by
rotary evaporation. The residue was purified by column chroma-
tography (4:1, ethyl acetate/petroleum ether (40–608C)).
Conclusion
The use of Meldrum’s acid as outlined above is a short and
efficient route to target compound 1. The simultaneous
reduction and esterification of nitro propanoic acid 6 is
the key for the convenient two-step synthesis. Further efforts
will be invested to optimize the route reported here.
Yield: 1.20 g (62.2%); colorless oil; R
petroleum ether (40–608C)).
IR (KBr) n (cm ): 3369 (–NH
f
¼ 0.34 (2:1, ethyl acetate/
ꢂ1
), 2979 (aliph. C–H), 1720 (–C–O),
603, 1461, 1346, 1259, 1265, 1036, 860, 780, 695, 446;
2
1
1
H-NMR (DMSO-d
6
, 200 MHz) d [ppm]: 1.16 (t, J ¼ 7.0 Hz, 3H,
–
O–CH –CH ), 2.50 (t, 2H, H-C2), 2.68 (t, 2H, H-C3), 4.04
2
3
(
q, J ¼ 7.0 Hz, 2H, –O–CH
2
–CH
3
), 4.95 (s, 2H, –NH
0
2
), 6.35
0
0
0
Experimental
(m, 3H, H-C2 , H-C4 , H-C6 ), 6.89 (t, 1H, H-C5 ).
The authors have declared no conflict of interest.
Materials and methods
3-Nitrobenzaldehyde and Meldrum’s acid were purchased from
Sigma-Aldrich, Germany, and were used as received. TLC was
performed on silica gel plates (Merck 60, F254, 0.2 mm; Merck,
Germany). Melting points were determined on a MEL-TEMP II,
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(
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www.archpharm.com