Synthesis of methyl 5-amino-3-arylaminoisoxazole-4-carboxylates

Article abstract of DOI:10.1515/HC.2011.014

The reaction of arylisothiocyanate derivatives with sodium methyl cyanoacetate in tetrahydrofuran gave the corresponding thioxo-propanoates, the reaction of which with hydrox-ylamine in ethanol and ammonium acetate under reflux conditions provided a synth

Full text of DOI:10.1515/HC.2011.014

Heterocycl. Commun., Vol. 17(1-2), pp. 65–68, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.014
Synthesis of methyl 5-amino-3-arylaminoisoxazole-4-
carboxylates
methyl 5-amino-3-arylaminoisoxazole-4-carboxylates were
synthesized in high yield, which are suitable intermediates
for synthesis of a series of new heterocycles.
Jabbar Khalafy*, Ahmad Poursattar Marjani and
Ali Rostamzadeh
Department of Chemistry, Faculty of Science, Urmia
University, Urmia 57154, Iran
*Corresponding author
e-mail: j.khalafi@mail.urmia.ac.ir; jkhalafi@yahoo.com
Results and discussion
The reaction of arylisothiocyanates 1a–g with sodium methyl
cyanoacetate in tetrahydrofuran under reflux gave the cor-
responding arylaminothioxopropanoates 2a–g in high yield
(Scheme 1).
Compounds 2a–g were allowed to react with hydroxyl-
amine hydrochloride in aqueous ethanol in the presence
of ammonium acetate under reflux conditions to afford the
corresponding methyl 5-amino-3-arylaminoisoxazole-4-
carboxylates 3a–g in 68–90% yield. The suggested reaction
mechanism is shown in Scheme 2 along with the target com-
pounds 3a–g.
Abstract
The reaction of arylisothiocyanate derivatives with sodium
methyl cyanoacetate in tetrahydrofuran gave the correspond-
ing thioxo-propanoates, the reaction of which with hydrox-
ylamine in ethanol and ammonium acetate under reflux
conditions provided a synthetically useful method for the
synthesis of methyl 5-amino-3-arylaminoisoxazole-4-carbox-
ylates in good yields.
Previously, we have reported (Khalafy et al., 2005, 2006,
2008; Baradarani et al., 2008) that the reaction of arylisothio-
cyanates with sodium diethyl malonate gave the arylthiocar-
bamoylmalonates 4. Subsequent reaction with hydroxylamine
under reflux conditions gave 3-arylaminoisoxazol-5(2H)-ones
5asasourceofimidazopyrimidineandaminoindolederivatives
(Poursattar Marjani and Khalafy, 2010) or ethyl 2,9-dioxo-4,
9-dihydro-2H-isoxazolo[3,2-b]quinazoline-3-carboxylate (6)
when X=2-CO2Et by intramolecular condensation (Scheme
3). In the case of arylaminothioxopropanoates 2a–g, forma-
tion of isoxazoles instead of isoxazolones in Scheme 2 might
be due to the higher electrophilicity of the cyano group over
the ester functionality in malonate 4. Ultimately the reaction
of the nucleophilic oximino group with the cyano functional-
ity of 2a–g produced the corresponding methyl 5-amino-3-
arylaminoisoxazole-4-carboxylates 3a–g.
Keywords: isothiocyanates; isoxazoles; methylcyano-
acetate; thioxopropanoates.
Introduction
Synthesis of highly substituted isoxazoles is important due
to their biological activity (Giomi et al., 2008; Lee et al.,
2009). The chemical properties of isoxazole derivatives have
been studied and these compounds have served as a versatile
building block in organic synthesis. Thus, synthesis of these
molecules with high efficiency is highly desirable (Ghosh and
Bandyopadhyay, 2004; Ahmed et al., 2005; Dang et al., 2006;
Wang et al., 2008; Gaywood and McNab, 2009; Girardin et
al., 2009; Li et al., 2009; Tang et al., 2009). Although a typi-
cal strategy for the synthesis of these molecules is the [3+2]
cycloaddition reaction between alkynes and nitrile oxides, a
cycloaddition reaction with internal alkynes for the direct con-
struction of trisubstituted isoxazole has been less frequently
reported (Pevarello et al., 1993; Denmark and Kallemeyn,
2005; Hansen et al., 2005; Moore et al., 2005; Bourbeau and
Rider, 2006; Grecian and Fokin, 2008; Willy et al., 2008;
Bhosale et al., 2009; Conti et al., 2009; McClendon et al.,
2009). These methods require harsh conditions and provide
poor chemo- and regioselectivities. As an alternative strat-
egy for efficient construction of isoxazoles, Larock and co-
workers recently reported stepwise synthesis of trisubstituted
isoxazoles by electrophilic cyclization of O-methyl alkynyl
oxime ethers and a subsequent palladium-catalyzed coupling
reaction of the resulting 4-haloisoxazole (Waldo and Larock,
2005, 2007; Waldo et al., 2008). In this paper, a series of new
Experimental
General
Freshly distilled solvents were dried according to Perrin and
Armarego (1988). Melting points were determined on an
Electrothermal. IA 9000 SERIES digital melting point apparatus
(Electrothennal, Essex, UK) and are uncorrected. Elemental micro-
analyses of the compounds studied were performed using a Carlo-
Erba 1104 instrument (Milan, Italy). 1H and 13C NMR spectra were
recorded on a Bruker AM-400 spectrometer (Ettlingen, Germany) at
300 MHz and 75.5 MHz, respectively. The spectra were measured
in CDCl3 or DMSO-d6 using TMS as the internal standard. Infrared
spectra were determined on a Thermo-Nicolet 670 Nexus FT-IR
spectrometer (Waltham, MA, USA) using KBr disks.
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66 J. Khalafy et al.
13C NMR (CDCl3): δ 52.1, 73.4, 118.7, 121.6, 128.4, 128.5, 130.2,
133.8, 135.98, 167.8, 169.3; FT-IR: ν 3150 (NH), 3060, 3020, 2952,
2198 (CN), 1663 (C=O), 1554, 1435, 1273, 1022, 767/cm. Analysis
calcd for C11H9BrN2O2S: C, 42.19; H, 2.90; N, 8.95%. Found: C,
42.36; H, 2.78; N, 9.01%.
S
CN
Tetrahydrofuran
71-88%
C
CN
NaCH
+
N C S
Ar
ArHN CH
CO2Me
CO2Me
2a-g
1a-g
a, Ar=ph
b, Ar=2-BrC6H4 c, Ar=2-MeC6H4 d, Ar=3-BrC6H4
Methyl 3-(2-methylanilino)-2-cyano-3-thioxopropanoate (2c)
Pale yellow solid; yield 77%; mp 119–121oC; 1H NMR (CDCl3):
δ 2.28 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 4.58 (s, 1H, CH), 7.20
(d, J=7.2 Hz, 1H, ArH), 7.22–7.33 (m, 3H, ArH), 11.45 (s, 1H, ex-
changeable with D2O, NH) ppm; 13C NMR (CDCl3): δ 17.7, 51.9,
71.9, 119.0, 127.2, 127.4, 129.4, 131.5, 135.4, 135.8, 168.2, 170.2;
FT-IR: ν 3122 (NH), 2955, 2201 (CN), 1666 (C=O), 1541, 1443,
1368, 1270, 1196, 1025, 785/cm. Analysis calcd for C12H12N2O2S:
C, 58.05; H, 4.87; N, 11.28%. Found: C, 58.21; H, 4.69; N, 11.33%.
e, Ar=3-MeC6H4 f, Ar=4-BrC6H4 g, Ar=4-MeC6H4
Scheme 1 Synthesis of arylaminothioxopropanoates 2a–g.
Methyl 2-cyano-3-anilino-3-thioxopropanoate (2a)
Methyl cyanoacetate (0.618 g, 6.24 mmol) in anhydrous
tetrahydrofuran (8 ml) was treated with sodium (0.140 g,
6.24 mmol) and the mixture was heated under reflux under an
atmosphere of nitrogen for 2 h. The solution was cooled to
room temperature, treated dropwise with phenylisothiocyanate
(0.977 g, 7.24 mmol), and the resulting yellow solution was
stirred at room temperature for 2 h before being quenched
with ice cold water. The mixture was extracted with
diethylether (4×25 ml) and the aqueous phase was added
dropwise to vigorously stirred, ice cold 1 m HCl, yielding a
yellow precipitate. The precipitate was washed with water
and crystallized from ethanol to give the thioxopropanoate
2a as yellow crystals in 71% yield; mp 115–116°C; 1H NMR
(CDCl3): δ 3.82 (s, 3H, OCH3), 4.71 (s, 1H, CH), 7.25–7.28 (m,
2H, ArH), 7.31–7.49 (m, 3H, ArH), 11.68 (s, 1H, exchangeable
with D2O, NH); 13C NMR (CDCl3): δ 51.9, 72.8, 118.9, 126.1,
128.7, 129.8, 137.0, 168.1, 169.2;FT-IR: ν 3134 (NH), 3063,
2959, 2201 (CN), 1680 (C=O), 1544, 1438, 1377, 1263, 1194,
1028, 772/cm. Analysis calculated (calcd) for C11H10N2O2S:
C, 56.39; H, 4.30; N, 11.96%. Found: C, 56.44; H, 4.39; N,
11.81%.
Methyl 3-(3-bromoanilino)-2-cyano-3-thioxopropanoate (2d)
Yellow solid; yield 74%; mp 118–120°C; 1H NMR (CDCl3): δ
3.83 (s, 3H, OCH3), 4.77 (s, 1H, CH), 7.16 (d, J=8.1 Hz, 1H, ArH),
7.22–7.46 (m, 2H, ArH), 7.53 (d, J=7.5 Hz, 1H, ArH), 11.70 (s, 1H,
exchangeable with D2O, NH); 13C NMR (CDCl3): δ 52.1, 73.4,
118.7, 123.1, 124.7, 129.1, 131.0, 131.7, 138.1, 168.0, 168.9; FT-
IR: ν 3147 (NH), 3065, 2951, 2202 (CN), 1660 (C=O), 1547, 1433,
1271, 1021, 774/cm. Analysis calcd for C11H9BrN2O2S: C, 42.19; H,
2.90; N, 8.95%. Found: C, 42.41; H, 2.82; N, 9.14%.
Methyl 3-(3-methylanilino)-2-cyano-3-thioxopropanoate (2e)
Orange solid; yield 77%; mp 121–123oC; 1H NMR (CDCl3): δ 2.36
(s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.68 (s, 1H, CH), 7.04 (s, 1H,
ArH), 7.18 (d, J=7.2 Hz, 1H, ArH), 7.27–7.32 (m, 2H, ArH), 11.62
(s, NH, 1H, exchangeable with D2O); 13C NMR (CDCl3): δ 21.3,
51.9, 71.8, 119.0, 123.1, 126.6, 127.7, 129.5, 136.8, 140.0, 168.1,
169.3; FT-IR: ν 3158 (NH), 3062, 2953, 2594, 2199 (CN), 1658,
1547, 1435, 1370, 1276, 1193, 1027, 771/cm. Analysis calcd for
C12H12N2O2S: C, 58.05; H, 4.87; N, 11.28%. Found: C, 58.32; H,
4.79; N, 11.48%.
The following thioxopropanoates 2b–g were made by the same
procedure.
Methyl 3-(2-bromoanilino)-2-cyano-3-thioxopropanoate (2b)
Yellow solid; yield 76%; mp 116–117°C; 1H NMR (CDCl3): δ 3.80
(s, 3H, OCH3), 4.68 (s, 1H, CH), 7.25–7.45 (m, 3H, ArH), 7.70 (d,
J=7.5 Hz, 1H, ArH), 11.61 (s, 1H, exchangeable with D2O, NH) ppm;
Methyl 3-(4-bromoanilino)-2-cyano-3-thioxopropanoate (2f)
Yellow solid; yield 84%; mp 117–119oC; 1H NMR (CDCl3): δ 3.79 (s,
3H, OCH3), 4.74 (s, 1H, CH), 7.14 (d, J=7.2 Hz, 2H, ArH), 7.56 (d,
SH
SH
H
H
S
ArHN
HN
ArHN
CN
O
CO2Me
EtOH/NH2OH
Amm. acetate
reflux
C
CN
ArHN CH
HN
HO
or
CO2Me
HO
N
MeO
2a-g
SHH
CN
O
ArHN
ArHN
SH
O
CO2Me
NH2
HN
H
ArHN
-
O
H
H2S
CO2Me
OMe
N
HN
68-90%
NH
O
- MeOH
- H2S
3a-g
ArHN
HN
CN
O
O
a, Ar=ph
b, Ar=2-BrC6H4
f, Ar=4-BrC6H4
c, Ar=2-MeC6H4
g, Ar=4-MeC6H4
d, Ar=3-BrC6H4
e, Ar=3-MeC6H4
Scheme 2 Synthesis of methyl 5-amino-3-arylaminoisoxazole-4-carboxylates 3a–g.
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5-Amino-3-arylaminoisoxazole-4-carboxylates 67
X
S
O
CO2Et
NH2OH
EtOH
NH C CH
H
N
O
N
HN
EtO2C
CO2Et
O
or
O
X
N
H
CO2Et
O
4
5
6
X=H, Br, CH3, NO2
X=2-CO2Et
Scheme 3 Synthesis of 3-arylaminoisoxazol-5(2H)-ones or ethyl 2,9-dioxo-4,9-dihydro-2H-isoxazolo[3,2-b]quinazoline-3-carboxylate.
J=7.2 Hz, 2H, ArH), 11.62 (s, 1H, exchangeable with D2O, NH); 13
C
2H, exchangeable with D2O, NH2), 8.17 (s, 1H, exchangeable with
D2O, NH); 13C NMR (DMSO-d6): δ 17.6, 51.4, 77.1, 117.6, 121.4,
124.3, 127.3, 130.6, 138.6, 159.5, 164.3, 169.5 (C=O); FT-IR: ν
3422 (NH2), 3322 (NH), 3030, 2950, 1691 (C=O), 1637, 1602, 1562,
1465, 780/cm. Analysis calcd for C12H13N3O3: C, 58.29; H, 5.30; N,
16.99%. Found: C, 58.01; H, 5.45; N, 16.88%.
NMR (CDCl3): δ 52.1, 73.2, 118.8, 122.4, 127.7, 132.9, 135.9, 168.0,
169.0; FT-IR: ν 3142 (NH), 3062, 3001, 2952, 2197 (CN), 1662 (C=O),
1551, 1440, 1269, 1016, 776/cm. Analysis calcd for C11H9BrN2O2S:
C, 42.19; H, 2.90; N, 8.95%. Found: C, 42.01; H, 3.19; N, 8.72%.
Methyl 3-(4-methylanilino)-2-cyano-3-thioxopropanoate (2g)
Brown solid; yield 88%; mp 117–118oC; 1H NMR (CDCl3): δ 2.40 (s,
3H, CH3), 3.84 (s, 3H, OCH3), 4.68 (s, 1H, CH), 7.15 (d, J=8.1 Hz,
2H, ArH), 7.26 (d, J=8.1 Hz, 2H, ArH), 11.59 (s, 1H, exchangeable
with D2O, NH); 13C NMR (CDCl3): δ 21.1, 51.9, 72.2, 119.1, 126.1,
130.4, 134.4, 138.9, 168.1, 169.5; FT-IR: ν 3154 (NH), 3069, 3004,
2955, 2197 (CN), 1667 (C=O), 1549, 1439, 1372, 1269, 1192, 1024,
778/cm. Analysis calcd for C12H12N2O2S: C, 58.05; H, 4.87; N,
11.28%. Found: C, 58.32; H, 4.65; N, 11.48%.
Methyl
5-amino-3-(3-bromoanilino)isoxazole-4-carboxylate
(3d) White needles; yield 68%; mp 141–142oC; 1H NMR (DMSO-
d6 ): δ 3.80 (s, 3H, OCH3), 7.07 (d, J=7.8 Hz, 1H, ArH), 7.21 (t,
J=7.2 Hz, 1H, ArH), 7.43 (d, J=7.5 Hz, 1H, ArH), 7.80 (s, 1H, ArH),
7.90 (s, 2H, exchangeable with D2O, NH2), 8.19 (s, 1H, exchange-
able with D2O, NH); 13C NMR (DMSO-d6): δ 51.3, 77.1, 117.1,
120.3, 122.3, 124.0, 131.2, 141.9, 159.1, 163.6, 169.9 (C=O); FT-IR:
ν 3448, 3354 (NH2), 3315 (NH), 2957, 1674 (C=O), 1610, 1562,
1431, 771/cm. Analysis calcd for C11H10BrN3O3: C, 42.33; H, 3.23;
N, 13.46%. Found: C, 42.21; H, 3.44; N, 13.59%.
Methyl 5-amino-3-anilinoisoxazole-4-carboxylate (3a) T o a
solution of 5a (0.230 g, 1 mmol), in ethanol (20 ml), were added
hydroxylamine hydrochloride (0.070 g, 1 mmol) and ammonium ac-
etate (0.250 g). The mixture was heated under reflux for 12 h, and
then poured onto ice cold water. The resulting solid was filtered off,
washed with cold water, dried and crystallized from ethanol to give
the desired product as white needles in 75% yield; mp 136–137°C;
1H NMR (DMSO-d6): δ 3.72 (s, 3H, OCH3), 6.89–7.40 (m, 5H,
ArH), 7.80 (s, 2H, exchangeable with D2O, NH2), 8.03 (s, 1H, ex-
changeable with D2O, NH); 13C NMR (DMSO-d6): δ 51.3, 77.0,
118.0, 121.6, 129.4, 140.2, 159.4, 163.9, 169.8 (C=O); FT-IR: ν
3484, 3300 (NH2), 3273 (NH), 3056, 2948, 1672 (C=O), 1648, 1605,
1587, 1556, 1479, 779/cm. Analysis calcd for C11H11N3O3: C, 56.65;
H, 4.75; N, 18.02%. Found: C, 56.41; H, 4.89; N, 18.27%.
Methyl 5-amino-3-(3-methylanilino)isoxazole-4-carboxylate
(3e) Pale brown needles; yield 83%; mp 136–138oC; 1H NMR
(DMSO-d6): δ 2.47 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 6.72 (d,
J=7.0 Hz, 1H, ArH), 7.15 (t, J=7.2 Hz, 1H, ArH), 7.17–7.25 (m,
2H, ArH), 7.83 (s, 2H, exchangeable with D2O, NH2), 8.02 (s, 1H,
exchangeable with D2O, NH); 13C NMR (DMSO-d6): δ 21.6, 51.3,
77.0, 115.1, 118.4, 122.3, 129.2, 138.6, 140.3, 159.4, 163.9, 169.8
(C=O); FT-IR: ν 3484, 3305 (NH2), 3276 (NH), 2921, 1678 (C=O),
1648, 1601, 1560, 1470, 776/cm. Analysis calcd for C12H13N3O3: C,
58.29; H, 5.30; N, 16.99%. Found: C, 58.39; H, 5.22; N, 16.75%.
Methyl
5-amino-3-(4-bromoanilino)isoxazole-4-carboxylate
(3f) White needles; yield 80%; mp 150-151oC; 1H NMR (DMSO-
d6): δ 3.74 (s, 3H, OCH3), 7.09 (d, J=7.2 Hz, 2H, ArH), 7.44 (d,
J=7.2 Hz, 2H, ArH), 7.89 (s, 2H, exchangeable with D2O, NH2), 8.16
(s, 1H, exchangeable with D2O, NH); 13C NMR (DMSO-d6): δ 51.3,
77.0, 112.9, 120.1, 132.0, 139.8, 159.2, 163.7, 169.9 (C=O); FT-IR:
ν 3466 (NH2), 3316 (NH), 2938, 1673 (C=O), 1650, 1598, 1552,
1474, 780/cm. Analysis calcd for C11H10BrN3O3: C, 42.33; H, 3.23;
N, 13.46%. Found: C, 42.14; H, 3.37; N, 13.69%.
The methyl 5-amino-3-arylaminoisoxazole-4-carboxylates 3b–g
were made by the same method.
Methyl
5-amino-3-(2-bromoanilino)isoxazole-4-carboxylate
(3b) White needles; yield 90%; mp 155–157°C; 1H NMR (DMSO-
d6): δ 3.78 (s, 3H, OCH3), 6.88 (t, J=7.2 Hz, 1H, ArH), 7.37 (t,
J=7.5 Hz, 1H, ArH), 7.62 (d, J=7.5 Hz, 1H, ArH), 7.97 (s, 2H, ex-
changeable with D2O, NH2), 8.04 (d, J=8.0 Hz, 1H, ArH), 8.75 (s,
1H, exchangeable with D2O, NH); 13C NMR (DMSO-d6): δ 51.5,
77.1, 118.9, 122.8, 128.6, 129.3, 132.9, 137.8, 159.2, 163.5, 169.6
(C=O); FT-IR: ν 3446, 3358 (NH2), 3321 (NH), 2956, 1678 (C=O),
1602, 1550, 1435, 778/cm. Analysis calcd for C11H10BrN3O3: C,
42.33; H, 3.23; N, 13.46%. Found: C, 42.41; H, 3.03; N, 13.57%.
Methyl
5-amino-3-(4-methylanilino)isoxazole-4-carboxylate
(3g) White needles; yield 69%; mp 172oC (dec); 1H NMR (DMSO-
d6): δ 2.48 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 7.08 (d, J=7.8 Hz, 2H,
ArH), 7.34 (d, J=7.8 Hz, 2H,ArH), 7.84 (s, 2H, exchangeable with D2O,
NH2), 7.98 (s, 1H, exchangeable with D2O, NH); 13C NMR (DMSO-
d6): δ 20.7, 51.2, 76.9, 117.7, 129.7, 130.2, 137.9, 159.4, 163.9, 169.8
(C=O). FT-IR: ν 3483, 3344 (NH2), 3224 (NH), 2949, 1672 (C=O),
1649, 1601, 1586, 1555, 1473, 778/cm. Analysis calcd for C12H13N3O3:
C, 58.29; H, 5.30; N, 16.99%. Found: C, 58.38; H, 5.12; N, 17.08%.
Methyl 5-amino-3-(2-methylanilino)isoxazole-4-carboxylate
(3c) White needles; yield 77%; mp 137–138oC; 1H NMR (DMSO-
d6): δ 2.48 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.85 (t, J=7.2 Hz, 1H,
ArH), 7.07–7.18 (m, 2H, ArH), 7.82 (d, J=8.4 Hz, 1H, ArH), 7.89 (s,
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68 J. Khalafy et al.
2-pyridyl-3-arylaminoisoxazol-5-(2H)-ones. Arkivoc. 2005, xiv,
59–70.
Acknowledgements
Khalafy, J.; Poursattar Marjani, A.; Molla Ebrahimlo, A. R. Synthesis
of new N-benzoxazole and N-benzothiazole derivatives of 3-(4-
substitutedphenyl)aminoisoxazol-5(2H)-ones and comparison of
their base induced rearrangement. J. Brazil. Chem. Soc. 2006,
17, 570–576.
Khalafy, J.; Akbari Dilmaghani, K.; Soltani, L.; Poursattar Marjani,
A. The synthesis of new 5-aminoisoxazoles by reaction of thio-
carbamoyl cyanoacetates with hydroxylamine. Chem. Heterocycl.
Comp. 2008, 44, 729–734.
The authors are grateful to the Urmia University for support of this
work.
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Received May 3, 2011; accepted May 23, 2011
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