Net rearrangements of 4-acetyl-3-(4-substituted phenylamino)-2-(5- nitropyridin-2-yl)isoxazol-5(2H)-ones to imidazo [1,2-a]pyridines by Flash-Vacuum-Pyrolysis (F.V.P)

Article abstract of DOI:10.13005/ojc/290421

4-acetyl-3-(4-substituted phenylamino)-2-(5-nitropyridin-2-yl) isoxazol-5(2H)-ones, rearranged under Flash-Vacuum-Pyrolysis (F.V.P) conditions accompanied by elimination of carbon dioxide to give imidazo[1, 2-a]pyridines in high to excellent yields (90-95%).

Full text of DOI:10.13005/ojc/290421

ISSN: 0970-020 X
CODEN: OJCHEG
2013, Vol. 29, No. (4):
Pg. 1443-1448
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Net Rearrangements of 4-acetyl-3-(4-substituted
phenylamino)-2-(5-nitropyridin-2-yl)isoxazol-5(2H)-ones to
Imidazo [1, 2-a]pyridines by Flash-Vacuum-Pyrolysis (F.V.P)
CHALAk AzIMI*, FARHAD SEPEHRADDIN and HELAL TAHAzADEH
Department of Chemistry Management, College of Chemistry, Mahabad Branch,
Islamic Azad University, Mahabad, Iran.
*Corresponding author E-mail: chalakazimi@yahoo.com
http://dx.doi.org/10.13005/ojc/290421
(Received: November 11, 2013; Accepted: November 25, 2013)
AbSTRACT
4-acetyl-3-(4-substituted phenylamino)-2-(5-nitropyridin-2-yl) isoxazol-5(2H)-ones, rearranged
under Flash-Vacuum-Pyrolysis (F.V.P) conditions accompanied by elimination of carbon dioxide to
give imidazo[1, 2-a]pyridines in high to excellent yields (90-95%).
key words: Isoxazolones, Imidazopyridines, Flash-Vacuum-Pyrolysis.
INTRODUCTION
We have reported that the reaction of 4-acetyl-3-
(4-substituted phenylamino)-2-(5-nitropyridin-2-yl)
isoxazol-5(2H)-ones (1,X:Br, Me)2 with triethylamine
in ethanol, give imidazo annulated compounds (2,
X: Br (84%), Me (75%) as net products, Scheme 1.
The thermal or photochemical loss of
nitrogen and carbon dioxide from triazoles and
isoxazole-5-ones, respectively, have been reported.1
NO2
N
X
N
X
HN
N
NH
Et3N/EtOH
Reflux
N
O
O2N
H3COC
COCH3
O
1, X: Br, Me
2, X: Br, Me
Scheme 1

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AzIMI et al., Orient. J. Chem., Vol. 29(4), 1443-1448 (2013)
However, the reaction of 4-acetyl-3-(4- gives imidazo (2, X:OMe, 59%) and indole (3, 20%)2
substituted phenylamino)-2-(5-nitropyridin-2-yl) annulated compounds respectively, Scheme 2.
isoxazol-5(2H)-ones (1, X: OMe) with triethylamine
NO2
X
NO2
H
N
N
N
N
NH
NH
X
HN
Et3N/EtOH
Reflux
N
N
+
O2N
X
O
COCH3
COCH3
H3COC
O
1, X: OMe
2, X: OMe
3, X: OMe
Scheme 2
Here we describe the net rearrangement by modification of the procedure of Worrall.3, 4 Thus,
of 4-acetyl-3-(4-substituted phenylamino)-2-(5- the reaction of the sodium salt of ethylacetoacetate
nitropyridin-2-yl) isoxazol-5(2H)-ones (1, X: Br, Me in ethanol with arylisothiocyanates (4) gave the
and 3) to Imidazo[1, 2-a]pyridines (2, X:Br, Me, OMe) thiocarbamates (5) in high yield (70-90%) and this
under Flash-Vacuum-Pyrolysis (F.V.P) conditions.
converted to corresponding isoxazolone (6) by
reaction with 2 equiv of hydroxylamine. N-arylation
of isoxazolone (6) with 2-chloro-5-nitropyridine
in solid phase condition gave the corresponding
RESULTS AND DISCUSSION
The required isoxazolones (1) were N-substituted isoxazolones (1) in fair yield (70-85%),
synthesized by reaction of 2-chloro-5-nitropyridine Scheme 3.
with 2H-isoxazolones (6) which in turn were made
X
NO2
S
S
NO2
C
CO2Et
N
X
CH
HN
CO2Et
N
COCH3
NaHC
H
HN
COCH3
N
N
Cl
X
HN
O
EtOH
N
NH2OH
O
H3COC
X
5
O
H3COC
O
4
6
1
X: Br, Me, OMe
X: Br, Me, OMe
X:Br, Me, OMe
X: Br, Me, OMe
Scheme 3
The rearrangement of (1) as shown in to net Imidazo[1,2-a]pyridines which is consist the
Scheme 4, proceeded in 90-95% yield under F.V.P electronic requirement of the reaction as shown in
conditions accompanied by elimination of carbon Scheme 5 or with the alternative pathway suggested
dioxide for 60 min. The reaction pathway leading by Prager and Co-workers.5
NO2
X
N
N
NH
X
HN
N
F.V.P
N
O2N
O
COCH3
H3COC
O
1, X: Br, Me, OMe
2, X: Br (90%), Me (93%), OMe (95%)
Scheme 4

AzIMI et al., Orient. J. Chem., Vol. 29(4), 1443-1448 (2013)
1445
NO2
N
X
X
HN
X
NH
H3COC
N
N
N
-CO2
NH
O
N
F.V.P
N
O2N
H3COC
NO2
COCH3
O
X: Br, Me, OMe
Scheme 5
Withanumberofimidazopyridinestructures
under F.V.P conditions.The exact mechanism of this
synthetic method has been unclear so far. However,
we think that the zwitterionoic (7) plays a role under
refluxing ethanol with triethylamine, (scheme 6).
This is consistent with electronic requirements of
the reaction. The zwitterionoic (7) probably can be
stabilised by ethanol as protic solvent, however
under F.V.P conditions it can not be produced.
in hand, the structures of all imidazopyridines were
1
confirmed by H-NMR, 13C-NMR, FT-IR, MASS
spectra or microanalyses. 4-methoxy derivative
(1, Ar: MeOC6H4) reacts in refluxing ethanol with
triethylamine to form a mixture of imidazopyridine
(2, Ar: MeOC6H4) and indole (3) in a 2:1 ratio,
respectively, but it only rearranges to imidazopyridine
NO2
NO2
NO2
N
N
N
H
Et3N/EtOH
MeO
MeO
N
N
MeO
N
N
N
N
O
O
H3COC
H3COC
H3COC
CO2
O
OH
-CO2
N
NO2
NH
OMe
(2)
N
O2N
COCH3
N
N
N
H3COC
H
OMe
H
O2N
N
N
H
(3)
(7)
OMe
H3COC
Scheme 6
ExPERIMENTAL
internal standard and all signals due to amino
protons were removed by exchange with D2O.
Infrared spectra were recorded on a Unicam Matsson
1000 Fourier-Transform Spectrometer.Mass spectra
were recorded on a Varian Matt 311 spectrometer
and relative abundance of fragments are quoted in
parentheses after the m/z values.Melting points were
determined on a Philip Harris C4954718 apparatus
and are uncorrected. Micronalyses were preformed
on a Carlo–Erba Analyzer 1104.
General
Freshly distilled solvents were used
throughout, and anhydrous solvents were dried
according to Perrin and Amarego.6 1H-NMR and 13C-
NMR spectra were recorded, in deuteriochloroform,
unless otherwise stated, at 500 and 125 MHz
respectively, with a Bruker DRX-500 Avance
spectrometer. Tetramethylsilane was used as an

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AzIMI et al., Orient. J. Chem., Vol. 29(4), 1443-1448 (2013)
4-acetyl-3-(4-bromo phenylamino) isoxazol- for 24 hours gave the desired product (80%) which
5(2H)-ones (6, x: br)
was recrystallized from ethanol/acetone (1:1) as
1
Toasolutionofhydroxylaminehydrochloride a white solid, m.p: 206-207 ºC (dec.); H-NMR
(7.06 g, 102 mmol) in water (30 mL), sodium (D6-DMSO+CDCl3)δ(ppm) 2.3 (s, J= 7.0Hz, 3H,
bicarbonate (10.17 g, 102 mmol) was added slowly. CH3), 3.35 (s, 3H, OMe), 6.38 (d, J=8.5Hz, 2H,
Ethanol (80 mL) was added and the resulting Ar), 6.94 (d, J= 8.5Hz, 2H, Ar), 6.96 (bs,1H, NH),
potassium chloride was filtered off. Ethyl-2-(4- 7.70(bs,1H,NH).
bromophenyl) carbamothioyl)-3-oxobutanoate (5, X:
Br) 12.71g, 34 mmol) was added to the filtrate and the
13C-NMR(D6-DMSO+CDCl3)δ(ppm) 15.64,
mixture was stirred at room temperature for 24 hours. 55.55, 73.5 ,114.6, 118.6, 135.73, 153.7, 165.73,
The reaction mixture was acidified with dilute HCl and 168.14, 174.81.
the white precipitate was collected and recrystallized
from acetone to give the title product (8.78 g, 79%)
FT-IR νmax 3407, 1708, 1615, 1554, 1248,
1
as colourless needles, m.p: 200-202 ºC (dec.); H- 1077, 792 cm-1.
NMR (D6-DMSO)δ (ppm) 2.25(s, J=7.1Hz, 3H, CH3),
7.37(d, J=8.4Hz, 2H, Ar),
7.57(d, J=8.4Hz, 2H, 4-acetyl-3-(4-bromo phenylamino) -2-(5-
Ar), 8.30 (bs, 1H, NH), 9.39 (bs, 1H, NH).
nitropyridin-2-yl) isoxazol-5(2H)-ones(1, x: br)
A mixture of 2-chloro-5-nitropyridine
13C-NMR (D6-DMSO)δ(ppm) 15.31, 74.69, (48.5 mg, 0.30 mmol) and 4-acetyl-3-(4-bromo
118.02, 125.08, 132.94, 137.10, 163.53, 164.74, phenylamino) isoxazol-5(2H)-ones (6, X: Br), 100
167.39.
mg, 0.30 mmol) was heated neat under nitrogen
FT-IR νmax 3250, 2950, 2740, 1723, 1696, in an oil bath at 130 ºC for 2 hours. The residue
1666, 1607, 1563, 1456, 1398, 1316, 1183, 1018, was recrystallized from ethanol to give the desired
818 cm-1.
isoxazolone as yellow crystals (112 mg, 82%), m.p:
218 ºC.
4-acetyl-3-(4-methyl phenylamino) isoxazol-
5(2H)-ones (6, x: Me).
1H-NMR(D6-DMSO+CDCl3) δ(ppm) 2.25 (s,
This compound was prepared as described J=7.0Hz, 3H, CH3), 6.87 (d, J=8.5Hz, 2H,Ar), 7.18
above using Ethyl-2-(4-methylphenyl) carbamothioyl)- (d, J=8.5Hz, 2H, Ar), 7.73 (d, J=9.1Hz,1H, Ar), 8.40
3-oxobutanoate (5, X:Me) and Refluxing for 24 hours (dd, J1=9.1Hz, J2=2.3Hz, 1H, Ar), 8.75 (d, J=2.3Hz,
gave colourless crystals (85%), m.p: 164-166 ºC 1H, Ar), 10.29 (bs, 1H, NH).
(dec.).
13C-NMR (D6-DMSO+CDCl3)δ (ppm) 14.41,
1H-NMR (D6-DMSO+CDCl3)δ(ppm) 2.30 79.05, 114.63, 119.46, 124.11, 132.46, 135.08,
(s, J=7.0Hz, 3H, CH3), 2.35 (s, 3H, Me), 6.78 (d, 137.21, 141.66, 143.79, 153.92, 158.31, 161.38,
J=9.2Hz, 2H, Ar), 6.79 (bs, 1H, NH), 6.80(d, J=9.2Hz, 165.88.
2H, Ar), 8.85 (bs, 1H, NH).
FT-IR νmax 3140, 2965, 1773, 1683, 1591,
13C-NMR (D6-DMSO+CDCl3,400 MHz) δ 1531, 1324, 1188, 1114, 1010, 961, 832 cm-1.
(ppm) 14.52, 20.85, 74.69, 121.53, 130.13, 133.29,
135.64, 163.59, 165.51, 166.74.
MS m/z 419(M+, 27%), 417(M+, 30%),
406(74), 404(77), 279(100), 251(20), 184(35),
FT-IR νmax 3669, 2979, 2746, 1705, 1669, 182(36), 157(29), 155(29), 102(22), 72(23), 44(59).
1615, 1331, 1208, 1115, 1023, 800 cm-1.
4-acetyl-3-(4-methyl phenylamino)-2-(5-
4-acetyl-3-(4-methoxy phenylamino) isoxazol- nitropyridin-2-yl) isoxazol-5(2H)-ones(1, x:
5(2H)-ones (6, x: OMe)
Me)
This compound was prepared
This compound was prepared as as described for above using the corresponding
described above using Ethyl-2-(4-methoxyphenyl) isoxazolone (6, X: Me) and 2-chloro-5-nitropyridine
carbamothioyl)-3-oxobutanoate (5, X:OMe) Refluxing to give the desired product after recrystalization from

AzIMI et al., Orient. J. Chem., Vol. 29(4), 1443-1448 (2013)
1447
ethanol yellow needles (85%), m.p:156-158 ºC, after
recrystalization from ethanol.
1-(2-(4-bromophenylamino)-6-nitroimidazo[1,2-a]
pyridine-3-yl) ethanone (2, x: br)
Pyrolysis (580°C, 0.01 mm Hg, sublimation
flask 110°C, 60 min) of isoxazolone (1, X: Br) (100
mg, 0.23 mmol) gave pale cream needles (81.17
mg, 90%), m.p: 195-196 ºC.
1H-NMR (CDCl3)δ(ppm) 2.29 (s,J=7.05Hz,
3H, CH3), 2.35 (s, 3H, Me), 7.04 (d, J=8.5Hz, 2H,
Ar), 7.07 (d, J=8.5Hz, 2H, Ar), 7.54 (d, J= 9.0Hz, 1H,
Ar), 8.55 (dd, J1=9.0Hz, J2=2.5Hz, 1H, Ar), 8.91 (d,
J=2.5Hz, 1H, Ar), 10.33 (s, 1H, NH).
1H-NMR(D6-DMSO)δ(ppm)2.55(s, J=7.0Hz,
3H, CH3), 7.49 (d, J=8.5Hz, Ar), 7.68 (d, J=9.7Hz,
1H, Ar), 7.74 (d, J=8.5Hz , 2H, Ar), 8.19 (dd,
J1=9.7Hz, J2=1.6Hz, 1H, Ar), 8.87 (bd, J=1.6Hz, 1H,
Ar), 9.88 (s,1H,NH).
13C-NMR (CDCl3)δ(ppm) 14.66, 21.35,
79.05, 115.42, 122.40, 130.29, 134.74, 135.36,
136.83, 141.89, 143.92, 154.28, 160.88, 163.62,
164.19.
13C-NMR (D6-DMSO)δ(ppm)15.25, 99.72,
114.62, 114.97, 121.76, 123.93, 127.61, 132.38,
137.66, 140.01, 147.17, 155.28, 160.87.
FT-IR νmax 3177, 1762, 1700, 1600, 1515,
1338, 1208, 1123, 976, 838 cm-1.
MS m/z 355(M+, 13%), 354(100), 294(57),
269(16), 248(40), 230(16), 220(16), 158(39),
144(13), 118(21), 117(20), 107(16), 91(67), 78(16),
65(20), 44(33).
FT-IR νmax 3285, 2955, 1643, 1611, 1555,
1475, 1331, 1294, 1201, 1102, 1079, 1002, 820
cm-1.
MS m/z 375(M+, 62%), 374(M+,64%),
360(5), 358(6), 279(100), 251(16), 233(14), 205(12),
184(11), 182(12), 157(12), 155(12), 102(14), 78(13),
77(11).
4-acetyl-3-(4-methoxy phenylamino) -2-(5-
nitropyridin-2-yl) isoxazol-5(2H)-ones (1, x:
OMe).
This compound was prepared as described
for above using the corresponding isoxazolone (6, X:
OMe) and 2-chloro-5-nitropyridine to give the desired
product Yellow needles (80%), m.p: 186-188 ºC.
1 - ( 2 - ( 4 - m e t h y l
-6-nitroimidazo[1,2-a] pyridine-3-yl) ethanone
(2, x:Me)
p h e n y l a m i n o )
Pyrolysis (580°C, 0.01 mm Hg, sublimation
1H-NMR (CDCl3)δ(ppm) 2.30 (s, J=7.0Hz,
3H, CH3), 3.77 (s, 3H, OMe), 6.79 (d, J=8.7Hz,
2H,Ar), 7.10 (d, J=8.7Hz, 2H, Ar), 7.52 ( d, J=9.0Hz,
1H, Ar), 8.54 (dd, J1=9Hz, J2=2.1Hz, 1H, Ar), 8.93
(bd, J=2.1Hz, 1H, Ar), 10.26 (s,1H,NH).
flask 110°C, 60 min) of isoxazolone
(1, X: Me)
(100 mg, 0.26 mmol) gave the desired imidazole as
pale cream needles (82.34 mg, 93%), m.p: 187-188
ºC.
1H-NMR (D6-DMSO)δ(ppm) 2.35 (s,
J=6.9Hz, 3H, CH3), 2.55 (s, 3H, Me), 7.19 (d,
J=8.2Hz, 2H, Ar), 7.51 (d, J=9.7Hz, 1H, Ar), 7.59
(bd, J=8.2Hz, 2H, Ar), 8.15 (bd, J=6.7Hz, 1H, Ar),
8.85 (bs, 1H, NH), 9.84 (bs, 1H, Ar).
13C-NMR (CDCl3)δ(ppm) 14.72, 55.89,
78.87, 114.85, 115.59, 124.34, 130.74, 134.68,
141.93, 143.95, 154.33, 158.40, 161.38, 163.69,
164.32.
FT-IR νmax 3823, 1785, 1700, 1592, 1345,
13C-NMR (CDCl3)δ(ppm): 15.03, 61.44,
98.99, 114.30, 119.33, 122.80, 127.26, 130.07,
132.93, 137.11, 147.34, 157.76, 161,15 .
1207, 1115, 1030, 838 cm-1.
MS m/z 370 (M+, 10%), 356(100), 310(49),
295(43), 264(21), 249(13), 221(14), 193(12),
194(10), 174(21), 146(10), 134(34), 133(22),
123(17), 92(16), 77(29), 44(37).
FT-IR νmax 3455, 1662, 1608, 1555, 1308,
1208, 1015, 822 cm-1.
MS m/z 310 (M+, 100%), 294(48), 248(27),
220(9), 144(10), 118(13), 91(20), 78(6), 65(6).

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AzIMI et al., Orient. J. Chem., Vol. 29(4), 1443-1448 (2013)
1-(2-(4-methoxy phenyl amino) -6-nitroimidazo
MS m/z 326(M+, 70%), 310(100), 295(27),
[1,2-a] pyridine-3-yl) ethanone(2, x: OMe)
264(32), 249(13), 221(29), 193(12), 194(10),
Pyrolysis (580°C, 0.01 mm Hg, sublimation 150(13), 78(6), 77(5).
flask 110°C, 60 min) of isoxazolone (1, X:OMe) (100
mg, 0.25 mmol) gave the title compound as a red
solid (84.55 mg, 95%), m.p: 160-161 ºC;
CONCLUSION
In conclusion we have shown that a variety
1H-NMR (CDCl3)δ(ppm) 2.52 (s, J=7.1Hz, of 4-acetyl-3-(4-substituted phenylamino)-2-(5-
3H, CH3), 3.73 (s, 3H, OMe), 6.86 (dd, J1=8.7Hz, nitropyridin-2-yl) isoxazol-5(2H)-ones, rearranged
J2= 2.5Hz, 1H, Ar), 6.92 (d, J=9.1Hz, 1H, Ar), 7.32 under Flash-Vacuum-Pyrolysis (F.V.P) conditions to
(d, J=8.7Hz, 1H, Ar), 7.45 (bs, 1H, Ar), 8.42 (dd, give imidazo [1,2-a] pyridines.These rearrangements,
J1=9.1Hz, J2=2.6Hz, 1H, Ar), 9.26 (d, J=2.6Hz, 1H, therefore, appear to be generally applicable to
Ar), 10.72 (bs, 1H, NH).
the synthesis of imidazoheterocycles which are
suitable synthetic intermediates for a series of
13C-NMR (CDCl3)δ(ppm) 15.02, 50.43, polycyclic heterocycles with possible pharmaceutical
89.99, 103.86, 111.00, 111.69, 112.14, 125.67, applications.
126.89, 133.76, 138.65, 145.26, 145.59, 156.41,
156.58.
ACkNOwLEDGEMENTS
FT-IR νmax 3345, 1642, 1615, 1500, 1331,
1215, 1117, 1035, 838 cm-1.
The authors gratefully appreciated the
financial support of this, work by the research council
of Islamic Azad University branch of Mahabad.
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