An expeditious synthesis of 3-nitropropionic acid and its ethyl and methyl esters

Article abstract of DOI:10.1081/SCC-100000587

The synthesis to 3-nitropropionic acid 1 was easily accomplished, in two steps, from commercially available acrolein in 60% yield. The ethyl and methyl esters of 1 were also obtained.

Full text of DOI:10.1081/SCC-100000587

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AN EXPEDITIOUS SYNTHESIS OF 3-NITROPROPIONIC
ACID AND ITS ETHYL AND METHYL ESTERS
a
a
b
Paulo C. Silva , Jeronimo S. Costa & Vera L. P. Pereira
a
Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Núcleo de
Pesquisas de Produtos Naturais, Laboratório de Síntese Estereosseletiva de Substâncias
Bioativas, Bloco H, Ilha da Cidade Universitária, Rio de Janeiro, RJ, 21941-590, Brazil
b
Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Núcleo de
Pesquisas de Produtos Naturais, Laboratório de Síntese Estereosseletiva de Substâncias
Bioativas, Bloco H, Ilha da Cidade Universitária, Rio de Janeiro, RJ, 21941-590, Brazil
Version of record first published: 16 Aug 2006.
To cite this article: Paulo C. Silva, Jeronimo S. Costa & Vera L. P. Pereira (2001): AN EXPEDITIOUS SYNTHESIS OF 3-
NITROPROPIONIC ACID AND ITS ETHYL AND METHYL ESTERS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:4, 595-600
To link to this article: http://dx.doi.org/10.1081/SCC-100000587
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SYNTHETIC COMMUNICATIONS, 31(4), 595–600 (2001)
AN EXPEDITIOUS SYNTHESIS OF
3
-NITROPROPIONIC ACID AND ITS
ETHYL AND METHYL ESTERS
Paulo C. Silva, Jeronimo S. Costa,
∗
and Vera L. P. Pereira
N u´ cleo de Pesquisas de Produtos Naturais, Laborat o´ rio de
S ´ı ntese Estereosseletiva de Subst aˆ ncias Bioativas,
Universidade Federal do Rio de Janeiro, Centro de Ci eˆ ncias
da Sa u´ de, Bloco H, Ilha da Cidade Universit a´ ria,
21941-590, Rio de Janeiro, RJ, Brazil
ABSTRACT
The synthesis to 3-nitropropionic acid 1 was easily accom-
plished, in two steps, from commercially available acrolein in 60%
yield. The ethyl and methyl esters of 1 were also obtained.
The 3-nitropropionic acid 1, also known as hiptagenic acid, is a widely
distributed plant and fungal neurotoxin. In the vegetal kingdom it is produced
by plants of the family Fabeaceae, in which it occurs both in the free form and
as a component of the glycoside hiptagin (1–3). In fungi it is produced from
Pennicillium and Aspergillus genera (4,5). The biosynthesis of 1 seems to occur by
quite different routes in fungi and higher plants (6,7). This toxic metabolic presents
diverse biological activities. Owing to irreversible inhibitor action of succinate
∗
Corresponding author. E-mail: Patrocinio@nppn.ufrj.br
595
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

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5
96
SILVA, COSTA, AND PEREIRA
dehydrogenase, 1 has been widely used as an animal model for Huntington’s
disease (8–12). Antihypertensive (13) and carcinogenic (14) properties, among
several others, are also observed. Chemically, 1 and its methyl and ethyl esters
have been used in the preparation of synthetic products (15–19), natural products
(
20,21), and in kinetic studies (22).
In an ample program aiming at the synthesis of biological active β-aminoac-
ids by diastereoselective Michael reaction (24,25), we need to prepare multi-
grams of 3-nitropropionic acid 1 and its methyl and ethyl esters. Although 1 is
commercially available (Fluka or Aldrich), the high cost makes the use of this
material to direct esterification to the methyl and ethyl esters prohibitive. A de-
tailed inspection of the literature showed us three synthetic routes for obtaining
1
(26–30). Lewkowitsch, in 1879, synthesized 1 for the first time by treatment
of β-iodo propionic acid with sodium nitrite (26,27). The yield was not fur-
nished. A second route consists in the slow addition of the expensive and toxic β-
propiolactone on aqueous solution of sodium nitrite (28,29). The 3-nitropropionic
acid was obtained in 35% yield after successive recrystallizations. Finally, 1 was
also produced (30) by nitration in gas phase through complex operating condi-
tions, which led to poor (< 5%) yield. On the other hand, the methyl ester of
1
was produced in 50% yield (31) by treatment of methyl 3-bromopropionate
with anhydrous silver nitrite, both expensive reagents, in the absence of solvent
◦
◦
to 60 –65 C. However, if the acid 1 is required, for example for biological final-
ities, hydrolysis will be necessary. Owing to the difficulty of obtaining 1 via the
routes described of we have developed an easy and inexpensive route to 1 and
its methyl and ethyl esters 3a and 3b from commercially available acrolein (see
Scheme).
Acrolein was treated with sodium nitrite and acetic acid in THF to furnish
3
-nitropropanal 2 in 63% yield according to conditions described in the literature
Jones reagent
(70–80%)
O
O
O
NaNO2, THF
O N
2
O2N
OH
AcOH, −10 °C, 4h
(
63%)
2
NaClO2/30%H2O2
CH3CN
1
Acrolein
(
96%)
O
MeOH, H2SO4 cat.
73%)
(
O N
2
OR
1
EtOH, PhH, TsOH
75%)
3a-R = Methyl
3b-R = Ethyl
(
Scheme.

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3
-NITROPROPIONIC ACID
597
(
16). Oxidation of 2 to desired 3-nitropropionic acid could be accomplished either
by Jones reagent (32) (70–80% yield) or by the use of sodium chlorite and 30%
hydrogen peroxide in 96% yield by Dalcanale-Montanary’s method (33). The
oxidation performed by NaClO2/30% H2O2 was found to be more convenient
than the first oxidation method, as it presents an easier work-up and low toxicity of
the reagents involved, and affordsa higher yield. Esterification to the desired ethyl
ester derived 3b was effected in 75% yield by treatment of 1 with ethanol, catalytic
p-toluenesulfonic acid, and benzene in a Dean-Stark apparatus. The corresponding
methyl ester was obtained from esterification of 1 using the described procedure
(
15).
In summary, a simple, rapid, and high-yielding method for preparation of
the biologically and synthetically useful 3-nitropropionic acid and its methyl and
ethyl esters has been developed that avoids the use of expensive and toxic reagents
employed in earlier methods.
EXPERIMENTAL
Acrolein, THF, NaNO2, AcOH, 30% H2O2, CrO3, NaClO2, CH3CN, MeOH,
EtOH, Benzene, TsOH, NaH2PO3, Acetone, and H2SO4 were commercially avail-
able (Aldrich, Merck, or Vetec) and were used as purchased. IR spectra were
recorded on a Nicolet Magna-IR-760 spectrometer and only the principal bands
1
13
are reported. H NMR and C NMR spectra were recorded on a Gemini-200
Varian spectrometer (200 and 50.4 MHz, respectively) in CDCl3 or CD3OD with
TMS as internal reference. Melting point was determined on a Kofler apparatus
and is uncorrected.
3-Nitropropionic Acid 1
Oxidation by NaClO2/H2O2
A solution of 8.0 g (70 mmol) of 80% NaClO2 (purchased from the Aldrich
Company, technical grade) in 70 mL of water was added dropwise over 2 h to a
stirred mixture of 6.6 g (64 mmol) of 3-nitropropanal (16) in 50 mL of acetonitrile
and 1.6 g of NaH2PO4 in 20 mL of water and 5.0 mL (52 mmol) of 30% H2O2,
◦
keeping the temperature at 25 C. Oxygen evolved from the solution was monitored
until the end of the reaction (about 1 h) with a bubbler connected to the apparatus.
Addition of about 0.5 g of Na2SO3 and stirring for 10 min destroy the unreacted
HOCl and H2O2. The reaction mixture is acidified with 10% aqueous HCl, water
is added (about 30 mL), and extraction with AcOEt (3 × 50 mL) is accomplished.
Solid NaCl is added to the remaining aqueous phase and an additional extraction

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5
98
SILVA, COSTA, AND PEREIRA
with AcOEt (3 × 50 mL) is effected. The combined organic extracts were dried
over Na2SO4 and evaporated under reduced pressure to furnish a light yellow
viscous oil. Purification by column chromatography on silica gel (Hexane/AcOEt
1
1
7
(
1
:1) provided 1 as a white solid in high purity; (measured by H NMR) yield:
◦
.3 g (96%). Recrystallization can be effected from CHCl3, mp 65 C; Literature
26–29) 66 C and 65.6 C IR (KBr): ν 3019, 2994, 2935, 1704, 1690, 1558, 1425,
◦ ◦
−
1 1
404, 1377, 1266, 1243, 1212, 956, 874 cm . H NMR(CD3OD): δ 4.66 (t, 2H),
3
.06 (t, 2H); 13C NMR (50.4 Mz, CD3OD): 174.31(C), 69.24 (CH2) 30.65 (CH2).
Oxidation by Jones Reagent
To a mixture, vigorously stirred, of 3-nitropropanal 3.38 g (32.8 mmol) in
◦
acetone (90 mL) at −12 C is added dropwise 19.5 mL of Jones reagent (prepared
from 10 g CrO3, 8.6 mL of 96% H2SO4, 14 mL of H2O, and brought up to 40 mL).
◦
The reaction mixture is stirred for 2 h and 45 min at 0 C. After this time isopropanol
in excess (about 90 mL) is added and the suspension is stirred for about 90 min
until the green coloration persists. Neutralization of the reaction mixture with
solid NaHCO3 until pH neutral and evaporation of the volatile liquids furnished
a green slurry, which was resuspended in Hexane/EtOAc (9:1) and filtered twice
through a column of celite. The reunited organic phases were evaporated under
reduced pressure and the remaining viscous pale green oil was purified by column
chromatography on silica gel (Hexane/EtOAc, 1:1) to give 2.85 g of 1 as a white
1
solid of satisfactory purity by H NMR analysis. Recrystallization was effected
from CHCl3.
Methyl 3-Nitropropionate 3a
To a solution of 3-nitropropionic acid 7.0 g (58.8 mmol) in anhydrous
methanol (100 mL) was added concentrated sulfuric acid (1.5 mL). The reaction
❛
mixture was heated at reflux in a Soxhlet apparatus charged with 4Amolecular
sieves for a period of 6 h. After this time, methanol was removed under vacuum
and the remaining residue diluted with CH2Cl2 (80 mL) and washed with water
(
3 × 40 mL). The combined organic phase was dried in Na2SO4 and evaporated
under reduced pressure. The remaining oil was distilled in a Kugelhor apparatus,
yielding 5.7 g (73%) of 3a as a light yellow oil, b.p. 85 C/2.5 Torr; (Literature
(
1
◦
◦ ◦
15,31) 68 C/1Torr and 63 C/0.5Torr). IR (film): ν 3008, 2959, 2926, 1740, 1560,
380, 1021, 872, 850 cm . H NMR (CDCl3): 3.00 (t, J = 6.0 Hz), 3.78 (s), 4.64
−1 1
13
(
3
t, J = 6 Hz); C NMR (50.4 Mz, CDCl3): 169.81(C), 69.34 (CH3), 51.75 (CH3),
0.27(CH2).

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3
-NITROPROPIONIC ACID
599
Ethyl 3-Nitropropionate 3b
A mixture of 3-nitropropionic acid (8.92 g 75 mmol), p-toluenesulfonic acid
monohydrate (0.25 g 1.31 mmol), ethyl alcohol (15 mL), and benzene
◦
(
75 mL) under stir was refluxed at 90 C for a period of 6 h in a Dean-Stark
apparatus. The resultant solution was cooled to room temperature and the volatile
liquids evaporated to furnish a drak yellow viscous oil, which was diluted in
80 mL of dichloromethane and washed with water (30 mL). The organic phase
was dried under anhydrous Na2SO4, filtered, and concentrated in a rotatory evap-
orator to give 8.48 g of 1 crude. Distillation in a Kugelhor apparatus yieldes 8.26
◦
g (75%) of 1 as a colorless oil. (b.p 92 C/2.5 Torr) IR (film): ν 2986, 2942, 2878,
−
1 1
1
6
2
736, 1560, 1381, 1194, 1024, 872, 856 cm . H NMR (CDCl3): δ 4.66 (t, J =
.0 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 2.97 (t, J = 6.0 Hz, 2H), 1.28 (t, J = 7.0 Hz,
H); 13C NMR (50.4 Mz, CDCl3): 169.28 (C) 69.49 (CH2), 61.13 (CH2), 30.72
(
CH2),13.70 (CH3).
ACKNOWLEDGMENTS
We thank CAPES-Brazil for a fellowship for Paulo C. Silva, and the Jose´
Bonif a´ cio Foundation (FUJB) and Research Foundation of the Rio de Janeiro
(
FAPERJ) for financial support.
REFERENCES
Carter, C.L.; McChesney, W.J. Nature 1949, 164, 575.
Williams, M.C. Can. J. Bot. 1982, 60, 1956.
Williams, M.C. Agron. J. 1983, 75, 520.
Turner, W.B. Fungal Metabolite, Academic Press: London, 1971; 303.
Cole, R.J.; Cox, R.H. Handbook of Toxic Fungal Metabolites; Academic
Press: New York, 1981; 755.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Baxter, R.L.; Smith, S.L.; Martin, J.R.; Hanley, B. J. Chem. Soc. Perkin Trans
1
1994, 2297.
Baxter, R.L.; Hanley, B.; Chan, H.W.S.; Greenwood, S.L.; Abbot, E.M.;
McFarlane, I.J.; Milne. K. J. Chem. Soc. Perkin Trans 1 1992, 2495.
Brouillet, E.; Conde, F.; Beal, M.F.; Hantraye, P. Prog Neurobiol. 1999, 59,
427.
Brouillet, E.; Guyot, M.C.; Mittoux, V.; Altairac, S.; Conde. F.; Palfi, S.;
Hantraye, P. Journal of Neurochemistry 1998, 70, 794.
10. Matthews, R.T.; Yang. L.; Jenkins, B.G.; Ferrante, R.J.; Rosen, B.R.;
Kaddurah-Daouk, R,; Beal, M.F. Journal of Neuroscience 1998, 18, 156.

ORDER
REPRINTS
6
1
1
00
SILVA, COSTA, AND PEREIRA
1. Reynolds, N.C.; Jr. Lin, W.; Cameron, C.M.; Roering, D.L. Brain Research
997, 778, 140.
2. Brouillet, E.; Jenkins, B.G.; Hyman, B.T.; Ferrante. R.J.; Kowall, N.W.;
Srivastava, R.; Roy, D.S.; Rosen, B.R.; Beal, M.F. Journal of Neurochemistry
1
1
993, 60, 356.
3. Castillo, C.; Valencia, L.; Reyes, G.; Hong, E. Drug Development Research
993, 28, 183.
4. Ludolph, A.C.; He, F.; Spencer, P.S.; Hammesrstad, I.; Sabril, M. Can. J.
Neurol. Sci. 1991, 18, 492.
1
1
1
1
1
1
5. Seebach, D.; Henning, R.; Mukhopadhyay, T. Chem Ber. 1982, 115, 1705.
6. Ohrlein, R.; Schwab, W.; Ehrler, R.; J a¨ ger, V. Synthesis 1986, 535.
7. Lawrance, G.A.; Maeder, M.; O’Leary, M.; Woon, F. Polyhedron 1990, 9,
¨
2
227.
8. Schwan, T.J.; Honkomp, L.; Snyder, H.R., Jr.; Watson, E.J. J. Pharm. Sci.
978, 67, 421.
9. Ioffe, S.L.; Lyapkalo, I.M.; Tishkov, A.A.; Danilenko, V.M.; Strelenko, Y.A.;
Tartakovsky, V.A. Tetrahedron 1997, 53, 13085.
1
1
1
2
2
0. Hanessian, S.; Kloss, J. Tetrahedron Lett. 1985, 26, 1261.
1. Bakuzis, P.; Bakuzis, M.L.F.; Weingartner, F. Tetrahedron Lett. 1978, 19,
2371.
22. Wilson, H.; Lewis, E.S. J. Am. Chem. Soc. 1972, 94, 2283.
23. Gupta, S.L. Raghavan, P.S. Indian J. Chem. 1971, 9, 233.
24. Patrocinio, V.L.; Correia, C.R.D.; Costa, P.R.R. Synthesis 1994, 474.
25. Costa, J.S.; Dias, A.G.; Anholeto, A.L.; Patrocinio, V.L.; Costa, P.R.R.
J. Org. Chem. 1997, 62, 4002.
2
2
2
2
3
3
6. Lewkowitsch, J. J. Prakt. Chem. 1879, 20, 169.
7. Lewkowitsch. G.; Beil. 2, 262.
8. Hass, H.B.; Feuer, H.; Pier, S.M. J. Am Chem. Soc. 1951, 73, 1858.
9. Gresham, T.L., U.S. Patent 2,449,987, 1948.
0. Hass, H.B.; Hudgin, D.E. J. Am. Chem. Soc. 1954, 76, 2692.
1. Belikov, V.M., Izv. Akad. Nauk, S.S.S.R.; Otdel. Khim. Nauk 1956, 855.
[
Chem. Abstr. 51, 1837j (1957)].
2. Bower, A.; Halsall, T.G.; Jones, E.R.H.; Lemin, A.J. J. Chem. Soc. 1953,
548.
3. Dalcanale, E.; Montanari, F. J. Org. Chem. 1986, 51, 567.
3
3
2
Received in the USA May 10, 2000

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