Base-induced rearrangements of N-substituted 3-arylamino-isoxazol-5(2H)- ones to 2-aryl-aminoimidazo[1,2-a]pyridines

Article abstract of DOI:10.1007/s10593-008-0079-4

New N-substituted derivatives of 2-substituted 3-phenylamino- and 3-(1-naphthyl)aminoisoxazol-5(2H)-ones were synthesized. The reaction of isoxazolones with 2-chloro-5-nitropyridine gave the corresponding isoxazolones with a nitropyridyl group substituted

Full text of DOI:10.1007/s10593-008-0079-4

Chemistry of Heterocyclic Compounds, Vol. 44, No. 5, 2008
BASE-INDUCED REARRANGEMENTS
OF N-SUBSTITUTED 3-ARYLAMINO-
ISOXAZOL-5(2H)-ONES TO 2-ARYL-
AMINOIMIDAZO[1,2-a]PYRIDINES
M. M. Baradarani, J. Khalafy, S. Khadivi, A. Poursattar Marjani
New N-substituted derivatives of 2-substituted 3-phenylamino- and 3-(1-naphthyl)aminoisoxazol-5(2H)-
ones were synthesized. The reaction of isoxazolones with 2-chloro-5-nitropyridine gave the corresponding
isoxazolones with a nitropyridyl group substituted on N-2. Their rearrangements produced ethyl
2-arylaminoimidazo[1,2-a]pyridine-3-carboxylates in the presence of triethylamine.
Keywords: 2-chloro-5-nitropyridine, imidazopyridines, isoxazolones, triethylamine, base-induced
rearrangement.
Isoxazol-5(2H)-ones undergo a photochemically or thermally induced loss of CO2 to form an
iminocarbene [1, 2] or isomerize to a nitronoketene [3], the preferred pathway being greatly influenced by the
substituents in positions 2, 3, or 4.
We have previously reported that the reaction of isoxazol-5(2H)-ones 1, substituted on nitrogen with
isoquinoline and quinazoline groups with triethylamine gave imidazoannulated compounds 2 and 3,
respectively. When the N-substituent was 5-nitro-2-pyridyl the 2-aminoindole structure 4 was assigned to the
product [4].
The products were formally the same as those obtained in our study of the photochemical and thermal
reactions of N-substituted isoxazolones [5]. The reactions of 3-substituted isoxazolones with a base are not so well
known, and there are only a few reported reactions [6, 7].
Ar
N
Ph
N
ArHN
EtO2C
O
N
N
CO2Et
CO2Et
O
N
N
2
3
1
NHAr
NHAr
O2N
N
H
N
N
H
EtO2C
4
__________________________________________________________________________________________
Department of Chemistry, Faculty of Science, Urmia University, Urmia 57154, Iran; e-mail:
jkhalafi@yahoo.com, e-mail: j.khalafi@mail.urmia.ac.ir Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 5, pp. 751-757, May, 2008. Original article submitted April 24, 2007.
594
0009-3122/08/4405-0594©2008 Springer Science+Business Media, Inc.

3-Amino-2-arylisoxazol-5(2H)-ones undergo solvolysis to form 1,3-dipoles that give either
imidazopyridines or indoles via intramolecular cyclization in the presence of potassium carbonate [8]. It was
suggested that the cyclization mode is controlled by the electronegativity of the aryl substituent.
We have recently reported [9] the synthesis and single crystal X-ray structure of ethyl 2-(1,3-
benzoxazol-2-yl)-5-oxo-3-(4-toluidino)-2,5-dihydro-4-isoxazolecarboxylate by the reaction of ethyl 5-oxo-3-(4-
toluidino)-2,5-dihydro-4-isoxazolecarboxylate with benzoxazole.
In this paper we report the synthesis of three new 3-arylamino-2-hetarylisoxazol-5(2H)-ones and their
base-catalyzed decomposition to the corresponding 2-arylaminoimidazopyridines. The 2-hetaryl group was fixed
as the electron deficient 5-nitro-2-pyridyl group, and the 3-aryl groups (2-MeC6H4, 2-MeOC6H4, 1-naphthyl) were
all electron rich, but somewhat sterically congested.
The reaction of aryl isothiocyanates ArNCS 5 with sodium diethyl malonate in ethanol gave the
corresponding diethyl N-arylthiocarbamoylmalonates 6a–c in high yield.
The presence of two different ethoxy and carbonyl groups in the carbamates 6a–c was inferred from
their 1H NMR and FT-IR spectra, respectively, due to one ester carbonyl group being H-bonded to the NH, and
the other one free.
The reaction of thiocarbamoylmalonates 6a–c with hydroxylamine by the general method [10] afforded
the isoxazolones 7a–c in good yield (Scheme 1).
Scheme 1
H
S
H
N
N
Ar
NH2OH/EtOH
50–68%
O
HN
Ar
CH(CO2Et)2
EtO2C
O
6a-c
7a-c
a Ar = 2-MeC6H4, b 2-MeOC6H4, c 1-naphthyl
The reaction of isoxazolones 7a–c with 2-chloro-5-nitropyridine at 130–140°C for 2 h afforded the
corresponding 2-(5-nitropyrid-2-yl) derivatives 8a-c in 55-74% yield as shown in Scheme 2.
Scheme 2
NO2
NO2
N
N
H
N
N
N
H
Et3N
Ar
Cl
N
O
7a–c
N
45–76%
Ar
55–74%
NO2
EtO2C
O
EtO2C
9a–c
8a–c
a Ar = 2-MeC6H4, b 2-MeOC6H4, c 1-naphthyl
The reaction of compounds 8a–c with triethylamine in ethanol under reflux conditions gave the ethyl
2-arylamino-6-nitroimidazo[1,2-a]pyridine-3-carboxylates 9a–c (Scheme 2).
The mechanisms of rearrangements are consistent with our earlier suggestions [4, 11] for the formation
of imidazopyridine (Scheme 3). The present results, when considered with those obtained previously [4, 8],
595

suggest that the 2-hetaryl group of the 3-arylamino-2-hetarylisoxazol-5(2H)-ones is most likely to intercept the
ylide intermediate formed by the reaction with a base, unless the 3-aryl group is both electron rich and sterically
unhindered.
Scheme 3
NO2
N
H
H
Et N
3 ··
N
N
+
N
N
–CO2
Ar
Ar
O
N
EtO2C
NO2
NEt3
EtO2C
–
O
CO2
H
H
N
N
N
N
Ar
Ar
EtO2C
N
·
N
·
NO2
EtO2C
NEt3
+
NO2
a Ar = 2-MeC6H4, b 2-MeOC6H4, c 1-naphthyl
The decomposition of 3-arylaminoisoxazolones 8a–c substituted on nitrogen with a nitropyridyl group
in the presence of triethylamine provides imidazopyridines 9a–c, which are suitable for the synthesis of
intermediates of a series of polycyclic heterocycles that could be expected to have pharmaceutical applications [12,
13].
EXPERIMENTAL
Freshly distilled solvents were used throughout, and anhydrous solvents were dried according to Perrin
and Armarego [14]. IR spectra were recorded on a Thermonicolet (Nexus 670) FT-IR spectrometer, using
1
sodium chloride cells and measured as a film or KBr disks. H (400 MHz) and 13C (100 MHz) NMR
measurements were recorded on a Bruker 400 spectrometer in CDCl3 or DMSO-d6 using TMS as an internal
standard. Melting points were determined on a Philip Harris C4954718 apparatus and are uncorrected.
Microanalyses were performed on a Carlo-Erba Analyzer 1104. High resolution mass spectra were recorded on a
Varian Matt 311 spectrometer. Mass spectra were determined on a HP 5973 MSD instrument, and relative
abundances of fragments are quoted in parentheses after the m/z values.
Diethyl N-(2-methylphenyl)thiocarbamoylmalonate (6a). Dry ethanol (40 ml) reacted with sodium
(2.3 g, 0.10 mol) and after cooling to room temperature diethyl malonate (16.2 g, 15.25 ml, 0.10 mol) was
added. The reaction mixture was stirred at room temperature for 30 min and 2-methylphenyl isothiocyanate
(14.92 g, 0.10 mol) was added; after 4 h, the yellowish white precipitate of sodium diethyl (2-methyl-
phenyl)thiocarbamoylmalonate was formed and collected. The pure salt was dissolved in water (20 ml) and
neutralized by dropwise addition of 10% hydrochloric acid to pH 7. The precipitate was collected and washed
with light petroleum (5×20 ml) to give diethyl thiocarbamoylmalonate 6a as yellow oil. Yield 27.8 g (90%).
1
FT-IR spectrum (film), ν, cm–1: 3296, 2983, 1732, 1614, 1588, 1517, 1462, 1369, 1310, 1150, 1027. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.27 (6H, t, J = 7.1, CH2CH3); 2.27 (3H, s, CH3); 4.24 (2H, q, J = 7.1,
CH2CH3); 4.25 (2H, q, J = 7.1, CH2CH3); 5.10 (1H, s, CH); 7.16–7.24 (3H, m, Ar); 7.55–7.57 (1H, m, Ar);
596

10.48 (1H, br. s, exchanged by D2O addition, NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.07, 17.82, 47.10,
61.51, 126.07, 126.48, 127.85, 130.90, 133.39, 137.17, 170.28, 193.72. Found, %: C 58.38; H 6.27; N 4.65.
C15H19NO4S. Calculated, %: C 58.23; H 6.19; N 4.53.
Diethyl N-(2-methoxyphenyl)thiocarbamoylmalonate (6b). This compound was prepared as described
above, using 2-methoxyphenyl isothiocyanate (13.87 g, 0.08 mmol) and stirring for a further 6 h after addition of
isothiocyanate, to give thiocarbamoylmalonate 6b as a pale yellow solid. Yield 25.69 g (95%); mp 49-51°C.
FT-IR spectrum, ν, cm–1: 3241, 1749, 1717, 1607, 1423, 1368, 1310, 1248, 1117, 1019, 746. 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.27 (6H, t, J = 7.1, 2CH2CH3 ); 3.88 (3H, s, CH3); 4.25 (2H, q, J = 7.1, CH2CH3);
4.26 (2H, q, J = 7.1, CH2CH3); 5.07 (1H, s, CH); 6.92 (1H, dd, J= 8.0, J= 1.2, Ar); 6.95 (1H, t, J = 8.0, Ar); 7.16
(1H, td, J = 8.0, J = 1.2, Ar); 9.03 (1H, dd, J = 8.0, J = 1.2, Ar); 11.22 (1H, br. s, exchanged by D2O addition,
NH). 13C NMR spectrum (CDCl3), δ, ppm: 13.92, 56.20, 62.89, 68.65, 110.66, 120.22, 121.67, 126.94, 128.30,
150.42, 165.58, 185.56. Found, %: C 55.55; H 5.86; N 4.54. C15H19NO5S. Calculated, %: C 55.37; H 5.89;
N 4.30.
Diethyl (1-naphthyl)thiocarbamoylmalonate (6c). This compound was prepared as described above,
using 1-naphthyl isothiocyanate (9.25 g, 0.05 mmol) and stirring for a further 6 h after addition of
isothiocyanate, to give thiocarbamoylmalonate 6c as a pale yellow solid. Yield 14.84 g (86%); mp 56-57°C.
FT-IR spectrum, ν, cm–1: 3224, 1736, 1597, 1503, 1410, 1298, 1172, 1148, 1016, 775. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 1.35 (6H, t, J = 7.1, 2CH2CH3); 4.32 (2H, q, J = 7.1, CH2CH3); 4.34 (2H, q, J = 7.1, CH2CH3);
5.25 (1H, s, CH), 7.48–7.57 (3H, m, Ar); 7.82 (1H, d, J = 8.4, Ar); 7.89 (2H, t, J = 8.4, Ar); 8.03 (1H, d, J = 8.4,
Ar); 10.94 (1H, br. s, exchanged by D2O addition, NH). Found, %: C 62.35; H 5.34; N 3.92. C18H19NO4S.
Calculated, %: C 62.59; H 5.54; N 4.06.
Ethyl 3-(2-methylphenyl)amino-5-oxo-2,5-dihydroisoxazole-4-carboxylate (7a). To a solution of
hydroxylamine hydrochloride (17.37 g, 250 mmol) in water (74 ml), potassium bicarbonate (25.03 g, 250 mmol) was
slowly added. Ethanol (295 ml) was added and the resulting potassium chloride was filtered off. Diethyl N-(2-
methylphenyl)thiocarbamoylmalonate (15.75 g, 83 mmol) was added to the filtrate and the mixture refluxed for 24 h.
The reaction mixture was acidified with diluted hydrochloric acid and the white precipitate was collected by vacuum
filtration and recrystallized from ethanol to give the desired product as colorless needles. Yield 11.57 g (53%); mp
173-174°C. FT-IR spectrum, ν, cm–1: 2989, 1733, 1707, 1663, 1467, 1325, 1220, 1045, 804, 761. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.25 (3H, t, J = 7.1, CH2CH3); 2.26 (3H, s, CH3), 4.22 (2H, q, J = 7.1, CH2CH3); 6.23
(1H, br. s, exchanged by D2O addition, NH); 7.21 (1H, t, J = 7.2, Ar); 7.27 (1H, t, J = 7.2, Ar); 7.33 (1H, d, J = 7.2,
Ar); 7.37 (1H, d, J = 7.2, Ar); 9.25 (1H, s, exchanged by D2O addition, NH). 13C NMR spectrum (DMSO-d6), δ,
ppm: 14.45, 17.67, 60.48, 75.64, 122.69, 127.14, 127.41, 131.46, 133.71, 164.61, 165.43, 167.31. Found, %:
C 55.23; H 5.01; N 9.86. C13H14N2O4.H2S. Calculated, %: C 55.90; H 5.41; N 10.03.
Ethyl 3-(2-methoxyphenyl)amino-5-oxo-2,5-dihydroisoxazole-4-carboxylate (7b). The compound was
prepared as described above using diethyl N-(2-methoxyphenyl)thiocarbamoylmalonate (9.75 g, 30 mmol) and
refluxing for 12 h to give the desired product as white crystals. Yield 5.67 g (68%); mp 178-179°C. FT-IR spectrum,
1
ν, cm–1: 3202, 3044, 1736, 1713, 1676, 1627, 1588, 1492, 1325, 1228, 1041, 752. H NMR spectrum (CDCl3 +
DMSO-d6), δ, ppm (J, Hz): 1.27 (3H, t, J = 7.1, CH2CH3); 3.85 (3H, s, CH3), 4.15 (2H, q, J = 7.1, CH2CH3); 6.81
(1H, td, J = 7.6, J = 1.2, Ar); 6.88 (1H, td, J = 7.6, J = 1.2, Ar); 6.94 (1H, td, J= 7.6, J = 1.2, Ar); 7.99 (1H, dd,
J = 7.6, J = 1.2, Ar); 8.73 (1H, br. s, exchanged by D2O addition, NH); 10.35 (1H, br. s, exchanged by D2O addition,
NH). 13C NMR spectrum (CDCl3 + DMSO-d6), δ, ppm: 13.91, 56.27, 61.80, 112.25, 121.61, 121.94, 128.18, 150.67,
159.11, 159.70, 164.10, 170.31. Found, %: C 52.84; H 5.46; N 9.43. C13H14N2O5 ⋅ H2S. Calculated, %: C 52.88;
H 5.12; N 9.49.
Ethyl 3-(1-naphthyl)amino-5-oxo-2,5-dihydroisoxazole-4-carboxylate (7c). The compound was
prepared as described above using diethyl (1-naphthyl)thiocarbamoyl- malonate (10.35 g, 30 mmol) and
refluxing for 10 h to give the desired product as a white solid. Yield 4.47 g (50%); mp 127°C (decomposed at
178–180°C). FT-IR spectrum, ν, cm–1: 3438, 3299, 1716, 1676, 1606, 1397, 1313, 1213, 1123, 1027, 782.
1H NMR spectrum (CDCl3 + DMSO-d6), δ, ppm (J, Hz): 1.29 (3H, t, J = 7.1, CH2CH3); 4.26 (2H, q, J = 7.1,
H2CH3); 7.55 (1H, t, J = 7.6, Ar); 7.62 (2H, t, J = 8.3, Ar); 7.66 (1H, d, J = 7.6, Ar); 7.87 (1H, d, J = 8.3, Ar);
597

7.93 (1H, d, J = 8.3, Ar); 8.01 (1H, d, J = 7.6, Ar); 9.74 (1H, br. s, exchanged by D2O addition, NH). Found, %:
C 64.32; H 4.92; N 9.29. C16H14N2O4. Calculated, %: C 64.42; H 4.73; N 9.39.
Ethyl 3-(2-methylphenyl)amino-2-(5-nitropyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8a).
A mixture of 2-chloro-5-nitropyridine (317 mg, 2 mmol) and ethyl 3-(2-methylphenyl)amino-5-oxo-2,5-dihydro-
isoxazole-4-carboxylate (524 mg, 2 mmol) was heated neat under an atmosphere of nitrogen in an oil bath at 140°C
for 2 h. The residue was recrystallized from ethanol to give the desired isoxazolone as yellow crystals. Yield 499 mg
1
(65%); mp 168-170°C. FT-IR spectrum, ν, cm–1: 3060, 1776, 1701, 1610, 1521, 1336, 1200, 1118, 1021, 754. H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.28 (3H, t, J = 7.1, CH2CH3); 2.43 (3H, s, CH3); 4.24 (2H, q, J = 7.1,
CH2CH3); 6.98 (1H, t, J = 7.4, Ar); 7.06 (1H, d, J = 7.4, Ar); 7.07 (1H, t, J = 7.4, Ar); 7.24 (1H, d, J = 7.4, Ar); 7.49
(1H, d, J = 9.1, Ar); 8.50 (1H, dd, J= 9.1, J= 2.5, Ar); 8.82 (1H, d, J = 2.5, Ar); 10.16 (1H, br. s, exchanged by D2O
addition, NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.48, 17.67, 60.44, 78.54, 115.04, 122.78, 131.39, 133.66,
136.38, 141.76, 143.26, 145.42, 153.65, 157.12, 160.95, 163.39, 163.89. Found: m/z 384.10698 [M]+. C18H16N4O6.
Calculated : M = 384.10699. Mass spectrum (EI, 70 eV), m/z (Irel, %): 384 [M]+ (1), 340 [(M–CO2)]+ (100), 294
(13), 267 (55), 248 (27), 220 (23), 144 (7), 118 (6), 91 (9), 65 (5). Found, %: C 56.10; H 3.86; N 14.28. C18H16N4O6.
Calculated, %: C 56.25; H 4.16; N 14.58.
Ethyl 3-(2-methoxyphenyl)amino-2-(5-nitropyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8b).
This compound was prepared as described above, using the corresponding isoxazolone (139 mg, 5 mmol) and
2-chloro-5-nitropyridine (79 mg, 5 mmol), as yellow needles after recrystalization from ethanol. Yield 148 mg
(74%); mp 132-136°C. FT-IR spectrum, ν, cm–1: 3448, 1774, 1702, 1600, 1577, 1558, 1523, 1335, 1119, 1021, 752.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.27 (3H, t, J = 7.1, CH2CH3); 3.93 (3H, s, CH3); 4.25 (2H, q, J = 7.1,
CH2CH3); 6.75 (1H, td, J = 7.8, J = 1.2, Ar); 6.92 (1H, dd, J = 7.8, J = 1.2, Ar); 7.06 (1H, dd, J = 7.8, J = 1.2, Ar);
7.11 (1H, td, J= 7.8, J= 1.2, Ar); 7.55 (1H, dd, J= 9.1, J= 0.5, Ar); 8.54 (1H, dd, J= 9.1, J= 2.6, Ar); 8.87 (1H, d,
J = 2.6, Ar); 10.40 (1H, br. s, exchanged by D2O addition, NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.18, 55.93,
61.35, 79.24, 111.37, 112.32, 120.48, 121.68, 122.11, 124.26, 127.65, 127.87, 134.55, 141.55, 143.53, 151.39. Mass
spectrum (EI, 70 eV), m/z (Irel, %): 400 [M]+ (3), 356 [(M–CO2)]+ (1), 207 (9), 149 (100), 134 (54), 123 (32), 120
(45), 108 (45), 106 (50), 80 (30), 77 (28), 51 (20), 28 (71). Found, %: C 54.00; H 4.01; N 14.00. C18H16N4O7.
Calculated, %: C 54.10; H 3.78; N 14.11.
Ethyl 3-(1-naphthyl)amino-2-(5-nitropyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8c). This
compound was prepared as described above, using the corresponding isoxazolone (596 mg, 2 mmol) and 2-chloro-
5-nitropyridine (317 mg, 2 mmol) as yellow needles after recrystalization from ethanol. Yield 462 mg (55%);
mp 186–188°C. FT-IR spectrum, ν, cm–1: 3319, 1762, 1669, 1541, 1448, 1310, 1201, 1102, 752. 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.60 (3H, t, J = 7.1, CH2CH3); 4.58 (2H, q, J = 7.1, CH2CH3); 7.26 (2H, t, J = 7.6, Ar);
7.28 (1H, d, J = 7.6, Ar); 7.42 (1H, d, J = 9.0, Ar); 7.58 (1H, td, J = 8.3, J = 1.2, Ar); 7.64 (1H, td, J= 8.3, J= 1.2,
Ar); 7.70 (1H, d, J = 8.3, Ar); 8.10 (1H, d, J = 8.3, Ar); 8.41 (1H, dd, J= 9.0, J= 2.6, Ar); 9.21 (1H, d, J = 2.6, Ar);
10.65 (1H, br. s, exchanged by D2O addition, NH). Found, %: C 60.23; H 3.80; N 13.51. C21H16N4O6. Calculated, %:
C 60.00; H 3.84; N 13.33.
Ethyl 2-(2-methylphenyl)amino-6-nitroimidazo[1,2-a]pyridine-3-carboxylate (9a). Isoxazolone 8a
(384 mg, 1 mmol) and triethylamine (0.4 ml) were refluxed in ethanol (10 ml) for 8 h. The reaction mixture was
cooled to room temperature and the resulting precipitate was collected to give ethyl 2-(2-methylphenyl)amino-
6-nitroimidazo[1,2-a]pyridine-3-carboxylate (9a) as pale red needles. Yield 284 mg (76%); mp 178-179°C. FT-IR
1
spectrum, ν, cm–1: 3321, 3109, 2980, 1664, 1624, 1602, 1493, 1474, 1342, 1306, 1214, 1081, 757. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.54 (3H, t, J = 7.1, CH2CH3); 2.39 (3H, s, CH3); 4.57 (2H, q, J = 7.1, CH2CH3);
7.02 (1H, t, J = 7.6, Ar); 7.23 (1H, d, J = 7.6, Ar); 7.30 (1H, t, J = 7.6, Ar); 7.52 (1H, d, J = 9.7, Ar); 8.14 (1H, dd,
J= 9.7, J= 2.0, Ar); 8.40 (1H, d, J = 7.6, Ar); 8.94 (1H, br. s, Ar); 9.25 (1H, br. s, exchanged by D2O addition, NH).
13C NMR spectrum (CDCl3), δ, ppm: 14.59, 17.72, 61.59, 98.12, 112.86, 123.81, 124.88, 126.85, 127.31, 131.23,
131.81, 135.23, 138.61, 143.89, 153.55, 160.34. Found: 340.11715 [M]+. C17H16N4O4. Calculated: M = 340.11716.
Mass spectrum (EI, 70 eV), m/z (Irel, %): 340 [M]+ (1), 281 (65), 264 (73), 253 (90), 207 (45), 146(100), 90 (39), 28
(100). Found, %: C 59.58; H 4.32; N 16.00. C17H16N4O4. Calculated, %: C 60.00; H 4.70; N 16.47.
598

Ethyl 2-(2-methoxyphenyl)amino-6-nitroimidazo[1,2-a]pyridine-3-carboxylate (9b). Isoxazolone 8b
(100 mg, 25 mmol) and triethylamine (0.4 ml) were refluxed in ethanol (10 ml) for 2 h. The reaction mixture was
cooled to room temperature and the resulting precipitate was collected to give ethyl 2-(2-methoxyphenyl)amino-
6-nitroimidazo[1,2-a]pyridine-3-carboxylate (9b) as yellow needles. Yield 50 mg (56%); mp 218–220°C. FT-IR
spectrum, ν, cm–1: 3378, 1674, 1609, 1575, 1467, 1345, 1315, 1300, 1227, 1097, 1025, 751. 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.56 (3H, t, J = 7.0, CH2CH3); 3.96 (3H, s, CH3); 4.54 (2H, q, J = 7.0, CH2CH3); 6.93 (1H,
dd, J = 7.5, J = 1.9, Ar); 7.00 (1H, td, J = 7.5, J = 1.9, Ar); 7.04 (1H, td, J = 7.5, J = 1.9, Ar); 7.51 (1H, d, J = 9.7,
Ar); 8.12 (1H, dd, J= 9.7, J= 2.3, Ar); 8.64 (1H, d, J = 7.5, Ar); 8.76 (1H, br. s, Ar); 10.29 (1H, br. s, exchanged by
D2O addition, NH). 13C NMR spectrum (CDCl3), δ, ppm: 14.49, 55.79, 61.78, 84.69, 96.38, 99.24, 110.03, 114.12,
117.62, 121.21, 122.04, 122.56, 126.67, 129.34, 137.08, 147.12, 154.92. Mass spectrum (EI, 70 eV), m/z (Irel, %):
356 [M]+ (1), 296 (38), 267 (100), 207 (9), 190 (14), 158 (13), 130 (22), 107 (20), 77 (11), 28 (23). Found, %:
C 57.88; H 4.50; N 16.12. C17H17N4O5. Calculated, %: C 57.30; H 4.49; N 15.73.
Ethyl 2-(1-naphthyl)amino-6-nitroimidazo[1,2-a]pyridine-3-carboxylate (9c). Isoxazolone 8c (210 mg,
0.5 mmol) and triethylamine (0.4 ml) were refluxed in ethanol (10 ml) for 3 h. The reaction mixture was cooled to
room temperature and the resulting precipitate was collected to give ethyl 2-(1-naphthyl)amino-6-nitroimidazo-
[1,2-a]pyridine-3-carboxylate (9c) as brown needles. Yield 85 mg (45%); mp 174-175°C. FT-IR spectrum, ν, cm-1:
3421, 1656, 1605, 1591, 1484, 1342, 1311, 1218, 1107, 771. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.59 (3H, t,
J = 7.1, CH2CH3); 4.62 (2H, q, J = 7.1, CH2CH3); 7.51-7.64 (5H, m, Ar); 7.88 (1H, d, J = 9.6, Ar); 8.02-8.12 (1H,
m, Ar); 8.13 (1H, dd, J = 9.6, J = 2.0, Ar); 8.46 (1H, d, J = 7.3, Ar); 9.24 (1H, br. s, exchanged by D2O
addition, NH); 9.92 (1H, br. d, J = 0.9, Ar). Mass spectrrum (EI, 70 eV), m/z (Irel, %): 376 [M]+ (1), 356 (100), 325
(41), 305 (23), 297 (7), 279 (20), 235 (9), 193 (7), 155 (5), 77 (7). Found, %: C 64.20; H 4.62; N 15.01. C20H16N4O4.
Calculated, %: C 63.82; H 4.28; N 14.89.
The authors are grateful to Urmia University for financial support, to Professor R. H. Prager (Flinders
University, Australia) for his valuable comments and to Professor H. A. Oskooei (Azzahra University, Iran) for
determining the mass spectra.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
D. S. Millan, R. H. Prager, J. Chem. Soc., Perkin Trans 1, 3245 (1998).
K. H. Ang, R. H. Prager, Tetrahedron, 48, 9073 (1992).
R. H. Prager, J. A. Smith, J. Chem. Soc. Chem. Commun., 1805 (1994).
J. Khalafy, R. H. Prager, J. Sci. I. R. Iran., 11, 32 (2000).
J. Khalafy, R. H. Prager, J. A. Smith, J. Chem. Res. (M), 518 (1999).
G. Doleschall, Tetrahedron Lett., 29, 6339 (1988).
M. Cox, R. H. Prager, D. M. Riessen, ARKIVOC, 7, 88 (2001).
D. Jeffery, R. H. Prager, D. Turner, M. Dreimanis, Tetrahedron, 58, 9965 (2002).
A. Souldozi, J. Khalafy, A. Poursattar Marjani, K. Slepokura, T. Lis, A. Ramazani, Z. Naturforsch., 62b,
705 (2007).
10.
11.
12.
D. E. Worrall, J. Am. Chem. Soc., 45, 3092 (1923).
J. Khalafy, A. R. Molla Ebrahimlo, K. Akbari Dilmaghani, J. Chin. Chem. Soc., 51, 1347 (2004).
N. Tuteja, T.-N. Phan, R. Tuteja, A. Ochem, A. Falaschi, Biochem. Biophys. Res. Commun., 236, 636
(1997).
13.
14.
M. Stiborova, C. A. Bieler, M. Wiessler, E. Frei, Biochem. Pharmacol., 62, 1675 (2001).
D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals, Pergamon Press: Oxford
(U.K.), 1988, p. 20.
599