Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates as sources of imidazopyrimidine and aminoindole derivatives

Article abstract of DOI:10.3906/kim-1002-73

The reaction of ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates with 2-chloropyrimidine and 2-chlorobenzoxazole gave the corresponding isoxazolones with pyrimidine and benzoxazole rings substituted on N-2. Their rearrangements with triethylamine in ethanol produced the corresponding imidazopyrimidine and aminoindole derivatives, respectively, through intramolecular cyclisation. TUeBITAK.

Full text of DOI:10.3906/kim-1002-73

Turk J Chem
34 (2010) , 847 – 858.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1002-73
Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-
carboxylates as sources of imidazopyrimidine and
aminoindole derivatives
Ahmad POURSATTAR MARJANI, Jabbar KHALAFY∗
Department of Chemistry, Faculty of Science, Urmia University,
P. O. Box 57154, Urmia, IRAN
e-mail: j.khalafi@mail.urmia.ac.ir, jkhalafi@yahoo.com
Received 20.02.2010
The reaction of ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4- carboxylates with 2-chloropyrimidine and
2-chlorobenzoxazole gave the corresponding isoxazolones with pyrimidine and benzoxazole rings substituted
on N -2. Their rearrangements with triethylamine in ethanol produced the corresponding imidazopyrimidine
and aminoindole derivatives, respectively, through intramolecular cyclisation.
Key Words: Isoxazolones, 2-chloropyrimidine, 2-chlorobenzoxazole, rearrangements, imidazopyrimidines,
aminoindoles
Introduction
The synthesis of some mono- and bis-isoxazolinyl derivatives of pyrimidine 1 and benzothiazole 2 as central
nervous system-active compounds and their base-catalysed rearrangements to the corresponding annelated
heterocycles have been reported.1,2
∗Corresponding author
847

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
X
H
N
S
N
Ar
N
N
NHAr
O
NH
Me
N
N
O
N
H
O
O
CO2Et
H
EtO2C
CO2Et
O
EtO2C
O
2
1
3
4
O
O
N
X= Cl ,
CO2Et
H
We have recently reported3 that the reaction of 2-pyridyl-3-arylaminoisoxazolones 3 with triethylamine
leads to the formation of indoles 4 and carbon dioxide, an outcome that is formally the same as that achieved
by photolysis.4 The evidence for the indole structure, rather than that of an isomer, rested on the number of
aryl proton signals visible in the 1 H-NMR spectrum.
We have recently reported5 that the treatment of quinoxaline 5 with base afforded 2 different rearranged
products depending on the kind of base. Its reaction with potassium carbonate in THF under reflux conditions
produced tetracyclic compound 6 via intramolecular nucleophilic substitution, but with triethylamine under
similar conditions the tricyclic compound 7 was formed (Scheme 1).
O
O
N
N
N
N
THF/ K2CO3
THF/ Et3N
Scheme 1
CO2Et
CO2Et
O
HN
N
N
O
6
N
Cl
HN
N
EtO2C
5
N
N
Cl
7
In the present study a number of ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates substituted
with nitrogen heterocycles on N -2 were synthesised. Annelated imidazopyrimidine and aminoindole derivatives
848

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
were obtained in excellent yields on their treatment with triethylamine in ethanol, which were presumed to arise
by intramolecular cyclisation of an imino carbene intermediate.
Experimental section
General procedures. Melting points were determined on a digital melting point apparatus (electrothermal)
and remain uncorrected. Infrared spectra were recorded on a Thermonicolet (Nexus 670) FT-infrared spectrom-
eter, using sodium chloride cells and measured as film or KBr disks. 1 H (300 MHz) and 13 C (75.5 MHz) NMR
measurements were recorded on a Bruker 300 spectrometer in CDCl3 using TMS as the internal reference.
Microanalyses were performed on a Carlo-Erba Analyser 1104.
Ethyl 2-(benzo[d]oxazol-2-yl)-5-oxo-3-(2-bromophenylamino)-2,5-dihydroisoxazole-4-carboxylate
(10a)
Ethyl 5-oxo-2-bromophenylamino-2,5-dihydroisoxazole-4-carboxylate (9a) (100 mg, 0.3 mmol) and 2-chloroben-
zoxazole (47 mg, 0.3 mmol) were refluxed in chloroform (10 mL) for 48 h. The solvent was removed under reduced
pressure to give colourless oil; the residue was recrystallised from ethanol to afford ethyl 2-(benzo[d]oxazol-2-yl)-
5-oxo-3-(2-bromophenyl amino)-2,5-dihydroisoxazole-4-carboxylate as white needles (82 mg, 60%), mp 130-132
◦ C. Anal calcd for C19 H14 BrN3 O5 : C, 51.37; H, 3.18; N, 9.46%. Found: C, 51.22; H, 3.28; N, 9.61%.1 H-NMR
(CDCl3): δ 1.40 (t, J = 7.2 Hz, 3H, CH3), 4.41 (q, J = 7.2 Hz, 2H, CH2), 6.82 (t, J = 7.8 Hz, 1H, Ar),
6.99 (t, J = 7.8 Hz, 1H, Ar), 7.25 (t, J = 8.4 Hz, 1H, Ar), 7.29 (d, J = 7.2 Hz, 1H, Ar), 7.34 (d, J = 7.2 Hz,
1H, Ar), 7.41 (d, J = 7.8 Hz, 1H, Ar), 7.46 (t, J = 7.8 Hz, 1H, Ar), 7.48 (d, J = 8.7 Hz, 1H, Ar), 10.05 (s,
1H, NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.38, 61.27, 79.48, 110.84, 118.06, 120.65,
123.13, 125.47, 126.78, 127.96, 128.21, 133.29, 134.16, 139.31, 149.62, 150.93, 163.27, 163.62, 164.46 ppm; FT-IR
(KBr): ν 3189, 3097, 2992, 1784, 1671, 1624, 1570, 1499, 1449, 1237, 1023, 983, 791, 753 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-yl)-5-oxo-3-(3-bromophenylamino)-2,5-dihydroisoxazole-4-carboxylate
(10b)
This compound was prepared as described for 10a using the corresponding isoxazolone (9b)6 (100 mg, 0.3 mmol)
and 2-chlorobenzoxazole (47 mg, 0.3 mmol) and recrystallising from ethanol to afford the desired product as
cream needles (87 mg, 64%), mp 149-151 ◦ C. Anal calcd for C19 H14 BrN3 O5 : C, 51.37; H, 3.18; N, 9.46%.
Found: C, 51.41; H, 3.01; N, 9.69%. 1 H-NMR (CDCl3): δ 1.42 (t, J = 7.2 Hz, 3H, CH3), 4.42 (q, J = 7.2
Hz, 2H, CH2), 7.05 (d, J = 7.5 Hz, 1H, Ar), 7.08-7.12 (m, 2H, Ar), 7.32 (dd, J1 = 8.7 Hz, J2 = 1.2 Hz, 1H,
Ar), 7.35 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H, Ar), 7.39 (td, J1 = 7.5 Hz, J2 = 1.5 Hz, 1H, Ar), 7.48 (t, J =
8.7 Hz, 1H, Ar), 7.51 (t, J = 7.8 Hz, 1H, Ar), 9.98 (s, 1H, NH, removed by D2 O addition) ppm; 13 C-NMR
(CDCl3): δ 14.37, 61.34, 79.28, 110.98, 120.62, 122.82, 125.55, 125.58, 126.97, 129.79, 130.56, 132.31, 136.56,
139.23, 149.71, 150.95, 163.21, 163.76, 164.75 ppm; FT-IR (KBr): ν 3282, 3074, 2981, 1786, 1668, 1628, 1582,
1488, 1450, 1288, 1198, 1031, 767, 792 cm−1
.
849

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
Ethyl 2-(benzo[d]oxazol-2-yl)-5-oxo-3-(o-tolylamino)-2,5-dihydroisoxazole-4-carboxylate (10c)
This compound was prepared as described for 10a using the corresponding isoxazolone (9c)7 (100 mg, 0.38
mmol) and 2-chlorobenzoxazole (58 mg, 0.38 mmol) and recrystallising from ethanol to afford the desired
◦
product as white needles (78 mg, 54%), mp 130-132 C. Anal calcd for C20 H17 N3 O5 : C, 63.32; H, 4.52; N,
11.08%. Found: C, 63.43; H, 4.44; N, 11.01%.1 H-NMR (CDCl3): δ 1.41 (t, J = 7.2 Hz, 3H, CH3), 2.37 (s,
3H, CH3), 4.40 (q, J = 7.2 Hz, 2H, CH2), 6.84 (d, J = 8.4 Hz, 1H, Ar), 6.87 (t, J = 8.4 Hz, 1H, Ar), 7.01
(t, J = 8.7 Hz, 1H, Ar), 7.12 (dd, J1 = 6.9 Hz, J2 = 1.5 Hz, 1H, Ar), 7.26-7.35 (m, 2H, Ar), 7.37 (dd, J1
=
7.4 Hz, J2 = 1.5 Hz, 1H, Ar), 7.46 (dd,J1 = 6.9 Hz, J2 = 1.5 Hz, 1H, Ar), 9.71 (s, 1H, NH, removed by D2 O
addition) ppm;13 C-NMR (CDCl3): δ 14.42, 17.81, 61.04, 78.26, 110.79, 120.55, 123.73, 125.35, 126.55, 126.79,
127.67, 130.93, 133.07, 133.55, 139.37, 149.64, 151.16, 163.66, 165.04, 165.10 ppm; FT-IR (KBr): ν 3266, 3078,
2983, 1782, 1632, 1487, 1388, 1351, 1287, 1231, 1028, 796, 754 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-yl)-5-oxo-3-(m-tolylamino)-2,5-dihydroisoxazole-4-carboxylate (10d)
This compound was prepared as described for 10a using the corresponding isoxazolone (9d)6 (100 mg, 0.38
mmol) and 2-chlorobenzoxazole (58 mg, 0.38 mmol) and recrystallising from ethanol to afford the desired
◦
product as cream prisms (84 mg, 58%), mp 121-123 C. Anal calcd for C20 H17 N3 O5 : C, 63.32; H, 4.52; N,
11.08%. Found: C, 63.50; H, 4.44; N, 11.15%. 1 H-NMR (CDCl3): δ 1.43 (t, J = 7.2 Hz, 3H, CH3), 2.11 (s,
3H, CH3), 4.42 (q, J = 7.2 Hz, 2H, CH2), 6.74 (d, J = 6.9 Hz, 1H, Ar), 6.75-7.2 (m, 3H, Ar), 7.31 (d, J =
9 Hz, 1H, Ar), 7.39 (d, J = 8.7 Hz, 1H, Ar), 7.46 (d, J = 9 Hz, 1H, Ar), 7.51 (d, J = 7.5 Hz, 1H, Ar), 9.90
(s, 1H, NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.41, 20.91, 61.13, 78.53, 110.82, 119.43,
120.64, 123.03, 125.4, 126.83, 127.60, 129.17, 135.01, 139.41, 139.57, 149.7, 151.24, 163.6, 164.23, 164.93 ppm;
FT-IR (KBr): ν 3281, 3069, 1785, 1670, 1630, 1607, 1583, 1489, 1288, 1216, 1030, 986, 792 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-yl)-3-(3-methoxyphenylamino)-5-oxo-2,5-dihydroisoxazole-4-carboxy-
late (10e)
This compound was prepared as described for 10a using the corresponding isoxazolone (9e) (100 mg, 0.36 mmol)
and 2-chlorobenzoxazole (55 mg, 0.36 mmol) and recrystallising from ethanol to afford the desired product as
brown needles (85 mg, 60%), mp 133-135 ◦ C. Anal calcd for C20 H17 N3 O6 : C, 60.76; H, 4.33; N, 10.63%.
Found: C, 60.45; H, 4.62; N, 10.50%. 1 H-NMR (CDCl3): δ 1.43 (t, J = 7.2 Hz, 3H, CH3), 3.65 (s, 3H, CH3),
4.43 (q, J = 7.2 Hz, 2H, CH2), 6.49 (d, J = 8.4 Hz, 1H, Ar), 6.71 (bs, 1H, Ar), 6.76 (d, J = 8.1 Hz, 1H, Ar),
7.01 (t, J = 8.1 Hz, 1H, Ar), 7.32 (d, J = 7.5 Hz, 1H, Ar), 7.38 (t, J = 7.8 Hz, 1H, Ar), 7.46 (d, J = 7.8 Hz,
1H, Ar), 7.51 (t, J = 8.7 Hz, 1H, Ar), 9.95 (s, 1H, NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3):
δ 14.41, 55.33, 61.21, 78.81, 107.63, 110.88, 112.9, 114.23, 120.68, 125.44, 126.83, 130.18, 136.26, 139.39, 149.73,
151.34, 160.28, 163.51, 164.06, 164.91 ppm; FT-IR (KBr): ν 3182, 2972, 1783, 1682, 1640, 1608, 1589, 1493,
1296, 1155, 1029, 796, 795, 765, 752 cm−1
.
850

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
Ethyl 2-(benzo[d]oxazol-2-yl)-5-oxo-3-(4-nitrophenylamino)-2,5-dihydroisoxazole-4-carboxylate
(10f)
This compound was prepared as described for 10a using the corresponding isoxazolone (9f)6 (100 mg, 0.34
mmol) and 2-chlorobenzoxazole (52 mg, 0.34 mmol) and recrystallising from ethanol to afford the desired
product as yellow needles (95 mg, 68%), mp 157-159 ◦ C. Anal calcd for C19 H14 N4 O7 : C, 55.61; H, 3.44; N,
13.65%. Found: C, 55.74; H, 3.21; N, 13.52%. 1 H-NMR (CDCl3): δ 1.43 (t, J = 7.2 Hz, 3H, CH3), 4.44 (q,
J = 7.2 Hz, 2H, CH2), 7.31 (d, J = 8.4 Hz, 2H, Ar), 7.33 (d, J = 8.7 Hz, 1H, Ar), 7.38 (d, J = 8.1 Hz, 1H,
Ar), 7.46 (t, J = 8.1 Hz, 1H, Ar), 7.52 (t, J = 8.1 Hz, 1H, Ar), 8.07 (d, J = 8.4 Hz, 2H, Ar), 10.33 (s, 1H, NH,
removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.41, 61.74, 81.30, 111.08, 119.41, 120.57, 121.14,
125.21, 125.68, 127.12, 138.93, 141.43, 144.94, 149.68, 151.01, 162.98, 164.54 ppm; FT-IR (KBr): ν 3230, 3086,
2981, 1783, 1666, 1626, 1590, 1506, 1344, 1208, 1027, 788, 748 cm−1
.
Ethyl 3-(3-bromophenylamino)-5-oxo-2-(pyrimidin-2-yl)-2,5-dihydroisoxazole-4-carboxylate (11b)
A mixture of 2-chloropyrimidine (34 mg, 0.3 mmol) and ethyl 3-(3-bromophenyl) amino-5-oxo-2,5-dihydroisoxazole-
4-carboxylate6 (100 mg, 0.3 mmol) was heated neat under the atmosphere of nitrogen in oil bath at 130 ◦ C
for 20 min. The residue was recrystallised from ethanol to give the desired isoxazolone as white needles (100
mg, 81%), mp 181-183 ◦ C. Anal calcd for C16 H13 BrN4 O4 : C, 47.43; H, 3.23; N, 13.83%. Found: C, 47.22; H,
3.10; N, 14.02%. 1 H-NMR (CDCl3): δ 1.34 (t, J = 7.2 Hz, 3H, CH3), 4.31 (q, J = 7.2 Hz, 2H, CH2), 7.07
(t, J = 7.5 Hz, 1H, Ar), 7.09 (dt, J1 = 6.6 Hz, J2 = 1.8 Hz, 1H, Ar), 7.15 (t, J = 4.8 Hz, 1H, Ar), 7.21 (dt,
J1 = 6.6 Hz, J2 = 2.0 Hz, 1H, Ar), 7.32 (bt, J = 1.8 Hz, 1H, Ar), 8.58 (d, J = 4.8 Hz, 2H, Ar), 10.26 (s,
1H, NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.32, 60.97, 79.35, 119.27, 120.19, 122.69,
124.89, 128.86, 130.40, 138.65, 156.01, 158.57, 160.62, 163.36, 164.33 ppm; FT-IR (KBr): ν 3207, 3075, 2981,
1759, 1695, 1575, 1550, 1395, 1069, 780 cm−1
.
The following compounds were prepared by the same method.
Ethyl 5-oxo-2-(pyrimidin-2-yl)-3-(m-tolylamino)-2,5-dihydroisoxazole-4-carboxylate (11d)
Isoxazolone 9d6 (100 mg, 0.38 mmol) and 2-chloropyrimidine (43 mg, 0.38 mmol) gave 11d (98 mg, 75%) as
yellow prisms after recrystallisation from ethanol, mp 168-170 ◦ C. Anal calcd for C17 H16 N4 O4 : C, 59.99; H,
4.74; N, 16.46%. Found: C, 60.21; H, 4.55; N, 16.52%.1H-NMR (CDCl3): δ 1.33 (t, J = 7.2 Hz, 3H, CH3),
2.22 (s, 3H, CH3), 4.31 (q, J = 7.2 Hz, 2H, CH2), 6.85 (d, J = 7.5 Hz, 1H, Ar), 6.93 (bt, J = 7.5 Hz, 1H, Ar),
6.96 (bs, 1H, Ar), 7.04 (d, J = 7.8 Hz, 1H, Ar), 7.10 (t, J = 4.8 Hz, 1H, Ar), 8.54 (d, J = 4.8 Hz, 2H, Ar),
10.13 (s, 1H, NH, removed by D2 O addition) ppm;13 C-NMR (CDCl3) δ 14.34, 21.13, 60.78, 78.73, 118.71,
119.26, 122.27, 126.63, 128.99, 137.08, 139.32, 156.28, 158.47, 161.23, 163.82, 164.62 ppm; FT-IR (KBr): ν
3203, 3078, 2979, 1758, 1698, 1578, 1394, 1070, 834, 781, 691 cm−1
.
Ethyl 5-oxo-2-(pyrimidin-2-yl)-3-(p-tolylamino)-2,5-dihydroisoxazole-4-carboxylate (11j)
Isoxazolone 9j8 (100 mg, 0.38 mmol) and 2-chloropyrimidine (43 mg, 0.38 mmol) gave 11j (94 mg, 74%) as pale
yellow prisms after recrystallisation from ethanol, mp 187-189 ◦ C. Anal calcd for C17 H16 N4 O4 : C, 59.99; H,
851

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
4.74; N, 16.46%. Found: C, 60.11; H, 4.61; N, 16.46%.1H-NMR (CDCl3): δ 1.35 (t, J = 7.2 Hz, 3H, CH3),
2.23 (s, 3H, CH3), 4.32 (q, J = 7.1 Hz, 2H, CH2), 6.98 (d, J = 8.7 Hz, 2H, Ar), 7.03 (d, J = 8.7 Hz, 2H,
Ar), 7.09 (t, J = 4.8 Hz, 1H, Ar), 8.53 (d, J = 4.8 Hz, 2H, Ar), 10.10 (s, 1H, NH, removed by D2 O addition)
ppm;13 C-NMR (CDCl3): δ 14.36, 20.85, 60.78, 78.62, 119.24, 121.71, 129.73, 134.64, 135.83, 156.35, 158.48,
161.61, 163.87, 164.74 ppm; FT-IR (KBr) ν 3207, 3083, 2985, 1761, 1699, 1579, 1558, 1393, 1371, 1069, 781
cm−1
.
Ethyl 5-oxo-3-(4-bromophenylamino)-2-(pyrimidin-2-yl)-2,5-dihydroisoxazole-4-carboxylate (11h)
Isoxazolone 9h8 (100 mg, 0.3 mmol) and 2-chloropyrimidine (34 mg, 0.3 mmol) gave 11h (110 mg, 85%) as
white prism after recrystallisation from ethanol, mp 202-204 ◦ C. Anal calcd for C16 H13 BrN4 O4 : C, 47.43; H,
3.23; N, 13.83%. Found: C, 47.29; H, 3.32; N, 14.09%. 1 H-NMR (CDCl3): δ 1.36 (t, J = 7.2 Hz, 3H, CH3),
4.33 (q, J = 7.2 Hz, 2H, CH2), 7.05 (d, J = 8.7 Hz, 2H, Ar), 7.14 (t, J = 4.8 Hz, 1H, Ar), 7.32 (d, J =
8.7 Hz, 2H, Ar), 8.57 (d, J = 4.8 Hz, 2H, Ar), 10.19 (s, 1H, NH, removed by D2 O addition) ppm;13 C-NMR
(CDCl3): δ 14.33, 60.96, 79.27, 118.96, 119.37, 123.24, 132.29, 136.56, 156.16, 158.59, 161.13, 163.44, 164.58
ppm; FT-IR (KBr): ν 3310, 3208, 3083, 1759, 1698, 1601, 1578, 1556, 1392, 1069, 835, 781 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-ylamino)-7-bromo-1H-indole-3-carboxylate (12a)
N -aryl isoxazolone (10a) (100 mg, 0.22 mmol) and triethylamine (0.4 mL) were refluxed in ethanol (10 mL)
for 48 h. The reaction mixture was left to cool to room temperature and the resulting precipitate was collected
to afford ethyl 2-(benzoxazol-2-ylamino)-7-bromo-1H-indole-3-carboxylate as white prisms (62 mg, 69%), mp
128-130 ◦ C. Anal calcd for C18 H14 BrN3 O3 : C, 54.02; H, 3.53; N, 10.50%. Found: C, 53.99; H, 3.45; N,
10.65%.1 H-NMR (CDCl3): δ 1.55 (t, J = 7.2 Hz, 3H, CH3), 4.55 (q, J = 7.2 Hz, 2H, CH2), 6.85 (t, J = 7.5
Hz, 1H, Ar), 7.30-7.40 (m, 3H, Ar), 7.55 (t, J = 6.9 Hz, 2H, Ar), 8.21 (bs, 1H, NH, removed by D2 O addition),
8.58 (d, J = 8.1 Hz, 1H, Ar), 9.35 (bs, 1H, NH, removed by D2 O addition) ppm;13 C-NMR (CDCl3): δ 15.02,
60.57, 112.07, 113.89, 114.19, 118.55, 122.23, 124.08, 124.14, 124.81, 127.37, 128.35, 132.41, 134.19, 138.12,
149.89, 153.39, 156.64 ppm; FT-IR (KBr): ν 3289, 2998, 1668, 1628, 1613, 1596, 1569, 1557, 1272, 1199, 1076,
1021, 756, 742 cm−1
.
The following aminoindoles were made by the same procedure.
Ethyl 2-(benzo[d]oxazol-2-ylamino)-6-bromo-1H-indole-3-carboxylate (12b)
N -aryl isoxazolone 10b (100 mg, 0.22 mmol) gave 12b as cream prisms (61 mg, 68%), mp 155-157 ◦ C. Anal
calcd for C18 H14 BrN3 O3 : C, 54.02; H, 3.53; N, 10.50%. Found: C, 53.91; H, 3.36; N, 10.71%. 1 H-NMR
(CDCl3): δ 1.58 (t, J = 7.2 Hz, 3H, CH3), 4.52 (q, J = 7.2 Hz, 2H, CH2), 7.19-7.39 (m, 4H, Ar), 7.52 (dd,
J1 = 8.4 Hz, J2 = 1.2 Hz, 2H, Ar), 7.54 (d, J = 7.5 Hz, 1H, Ar), 7.93 (bs, 1H, NH, removed by D2 O addition),
8.75 (bs, 1H, NH, removed by D2 O addition) ppm;13 C-NMR (CDCl3): δ 14.84, 60.46, 112.20, 113.40, 116.43,
120.61, 122.85, 124.15, 124.61, 124.81, 127.34, 130.32, 132.41, 133.65, 141.38, 145.31, 149.86, 158.32 ppm; FT-IR
(KBr): ν 3423, 3305, 2979, 1660, 1628, 1617, 1593, 1568, 1552, 1477, 1444, 1197, 741 cm−1
.
852

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
Ethyl 2-(benzo[d]oxazol-2-ylamino)-7-methyl-1H-indole-3-carboxylate (12c)
N -aryl isoxazolone 10c (100 mg, 0.25 mmol) gave 12c as cream prisms (53 mg, 60%), mp 168-170 ◦ C. Anal
calcd for C19 H17 N3 O3 : C, 68.05; H, 5.11; N, 12.53%. Found: C, 67.95; H, 5.22; N, 12.63%.1 H-NMR (CDCl3):
δ 1.54 (t, J = 6.9 Hz, 3H, CH3), 2.41 (s, 3H, CH3), 4.52 (q, J = 6.9 Hz, 2H, CH2), 6.96 (t, J = 7.2 Hz,
1H, Ar), 7.20 (d,J = 7.2 Hz, 1H, Ar), 7.25-7.38 (m, 3H, Ar), 7.51 (d, J = 7.8 Hz, 1H, Ar), 7.94 (bs, 1H,
NH, removed by D2 O addition), 8.33 (d, J = 8.4 Hz, 1H, Ar), 8.78 (bs, 1H, NH, removed by D2 O addition)
ppm; 13 C-NMR (CDCl3): δ 14.92, 17.92, 60.28, 112.05, 113.30, 114.35, 118.07, 121.86, 123.86, 124.70, 125.48,
126.99, 127.47, 130.29, 137.31, 138.48, 149.83, 151.83, 155.09 ppm; FT-IR (KBr): ν 3326, 2979, 1652, 1625,
1592, 1477, 1441, 1267, 1193, 1077, 749 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-ylamino)-6-methyl-1H-indole-3-carboxylate (12d)
N -aryl isoxazolone 10d (100 mg, 0.25 mmol) gave 12d as pale yellow needles (56 mg, 64%), mp 125-127 ◦ C.
Anal calcd for C19 H17 N3 O3 : C, 68.05; H, 5.11; N, 12.53%. Found: C, 67.89; H, 5.28; N, 12.59%.1H-NMR
(CDCl3): δ 1.57 (t, J = 6.9 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 4.51 (q, J = 6.9 Hz, 2H, CH2), 6.84 (d,
J = 7.2 Hz, 1H, Ar), 7.22 (d, J = 7.2 Hz, 1H, Ar), 7.27-7.40 (m, 3H, Ar), 7.45 (bs, 1H, Ar), 7.54 (d, J =
8.1 Hz, 1H, Ar), 7.96 (bs, 1H, NH, removed by D2 O addition), 8.73 (bs, 1H, NH, removed by D2 O addition)
ppm;13 C-NMR (CDCl3): δ 14.87, 21.65, 60.25, 112.10, 113.30, 114.51, 115.27, 117.64, 118.75, 122.82, 123.90,
124.74, 127.50, 128.97, 133.34, 138.96, 139.95, 149.83, 155.09 ppm; FT-IR (KBr): ν 3310, 3072, 2986, 1696,
1652, 1601, 1561, 1487, 1276,1160, 1071, 840, 745, 720 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-ylamino)-6-methoxy-1H-indole-3-carboxylate (12e)
N -aryl isoxazolone 10e (100 mg, 0.24 mmol) gave 12e as pale yellow prisms (58 mg, 66%), mp 134-136 ◦ C.
Anal calcd for C19 H17 N3 O4 : C, 64.95; H, 4.88; N, 11.96%. Found: C, 64.85; H, 5.02; N, 12.10%. 1 H-NMR
(CDCl3): δ 1.58 (t, J = 7.2 Hz, 3H, CH3), 3.86 (s, 3H, OCH3), 4.52 (q, J = 7.2 Hz, 2H, CH2), 6.58 (dd,
J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, Ar), 7.12 (bs, 1H, Ar), 7.18-7.41 (m, 4H, Ar), 7.54 (d, J = 8.4 Hz, 1H, Ar),
7.96 (bs, 1H, NH, removed by D2 O addition), 8.79 (bs, 1H, NH, removed by D2 O addition) ppm;13 C-NMR
(CDCl3): δ 14.85, 55.29, 60.30, 103.83, 107.64, 110.60, 112.12, 113.39, 115.81, 121.41, 123.96, 124.75, 127.48,
129.79, 141.79, 144.27, 149.86, 155.03, 160.44 ppm; FT-IR (KBr): ν 3315, 2979, 1663, 1628, 1598, 1561, 1422,
1155, 1074, 865, 752, 684 cm−1
.
Ethyl 2-(benzo[d]oxazol-2-ylamino)-5-nitro-1H-indole-3-carboxylate (12f)
N -aryl isoxazolone 10f (100 mg, 0.24 mmol) gave 12f as yellow prisms (54 mg, 61%), mp 198-200 ◦ C. Anal
calcd for C18 H14 N4 O5 : C, 59.02; H, 3.85; N, 15.29%. Found: C, 58.95; H, 4.00; N, 15.32%.1 H-NMR (CDCl3):
δ 1.58 (t, J = 7.2 Hz, 3H, CH3), 4.55 (q, J = 7.2 Hz, 2H, CH2), 7.36-7.61 (m, 4H, Ar), 7.76 (d,J = 9 Hz, 2H,
Ar), 8.23 (d, J = 8.4 Hz, 1H, Ar), 8.51 (bs, 1H, NH, removed by D2 O addition), 9.19 (bs, 1H, NH, removed by
D2 O addition) ppm;13 C-NMR (CDCl3): δ 14.79, 60.88, 112.38, 112.74, 113.77, 114.95, 115.77, 116.69, 124.66,
125.01, 125.56, 126.15, 127.12, 131.40, 141.42, 145.89, 149.95, 155.61 ppm; FT-IR (KBr): ν 3304, 1662, 1590,
1566, 1509, 1477, 1458, 1331, 1317, 1282, 1200, 1078, 748 cm−1
.
853

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
Ethyl 2-(3-bromophenylamino)imidazo[1,2-a]pyrimidine-3-carboxylate (13b)
N -aryl isoxazolone 11b (100 mg, 0.24 mmol) and triethylamine (0.4 mL) were refluxed in ethanol (10 mL) for
48 h. The reaction mixture was left to cool to room temperature and the resulting precipitate was collected
to give ethyl 2-(3-bromophenylamino)imidazo[1,2-a]pyrimidine-3-carboxylate (13b) as white prisms (64 mg,
72%), mp 174-176 ◦ C. Anal calcd for C15 H13 BrN4 O2 : C, 49.88; H, 3.63; N, 15.51%. Found: C, 50.01; H,
3.55; N, 15.41%.1H-NMR (CDCl3): δ 1.50 (t, J = 7.2 Hz, 3H), 4.50 (q, J = 7.2 Hz, 2H, CH2), 7.02 (dt,
J1 = 6.9 Hz, J2 = 4.8 Hz, 1H, Ar), 7.12-7.22 (m, 2H, Ar), 7.73 (d, J = 7.8 Hz, 1H, Ar), 8.03 (bs, 1H, Ar),
8.54-8.57 (m, 2H, Ar), 9.21 (s, 1H, NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.68, 60.79,
96.52, 109.58, 116.99, 121.03, 122.76, 125.16, 130.32, 134.89, 141.02, 149.01, 151.21, 154.32, 160.92 ppm; FT-IR
(KBr): ν 3395, 2986, 2925, 1673, 1613, 1592, 1571, 1461, 1094, 793 cm−1
.
The following imidazopyrimidines were made by the same procedure.
Ethyl 2-(m-tolylamino)imidazo[1,2-a]pyrimidine-3-carboxylate (13d)
N -aryl isoxazolone 11d (100 mg, 0.26 mmol) gave 13d as green prisms (56 mg, 64%), mp 138-140 ◦ C. Anal calcd
for C16 H16 N4 O2 : C, 64.85; H, 5.44; N, 18.91%. Found: C, 64.65; H, 5.61; N, 19.01%.1H-NMR (CDCl3)
δ
1.26 (t, J = 7.2 Hz, 3H, CH3), 2.40 (s, 3H, CH3), 4.52 (q, J = 7.1 Hz, 2H, CH2), 6.86 (d, J = 7.5 Hz, 1H,
Ar), 6.99 (dd, J1 = 6.6 Hz, J2 = 4.5 Hz, 1H, Ar), 7.25 (t, J = 7.8 Hz, 1H, Ar), 7.64 (t, J = 9 Hz, 2H, Ar),
8.53-8.56 (m, 2H, Ar), 9.23 (s, 1H, NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.69, 21.64,
60.60, 96.22, 109.34, 115.81, 119.15, 123.35, 128.94, 134.81, 138.10, 139.56, 149.25, 150.10, 158.23, 161.01 ppm;
FT-IR (KBr): ν 3398, 2986, 1665, 1616, 1584, 1548, 1465, 1098, 808, 753 cm−1
.
Ethyl 2-(p-tolylamino)imidazo[1,2-a]pyrimidine-3-carboxylate (13j)
N -aryl isoxazolone 11j (100 mg, 0.26 mmol) gave 13j as yellow needles (52 mg, 61%), mp 147-149 ◦ C. Anal
calcd for C16 H16 N4 O2 : C, 64.85; H, 5.44; N, 18.91%. Found: C, 64.71; H, 5.65; N, 19.11%.1 H-NMR (CDCl3):
δ 1.51 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 4.52 (q, J = 7.2 Hz, 2H, CH2), 7.01 (t, J = 6.6 Hz,
1H, Ar), 7.18 (d, J = 8.4 Hz, 2H, Ar), 7.71 (d, J = 8.4 Hz, 2H, Ar), 8.48-8.70 (m, 2H, Ar), 9.24 (s, 1H,
NH, removed by D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.66, 20.79, 60.70, 96.42, 109.55, 119.07, 121.73,
129.66, 131.92, 134.96, 137.73, 150.98, 158.46, 161.23 ppm; FT-IR (KBr): ν 3225, 2984, 2923, 1699, 1653, 1611,
1568, 1264, 1180, 1094, 760 cm−1
.
Ethyl 2-(4-bromophenylamino)imidazo[1,2-a]pyrimidine-3-carboxylate (13h)
N -aryl isoxazolone 11h (100 mg, 0.24 mmol) gave 13h as yellow prisms (68 mg, 76%), mp 148-150 ◦ C. Anal
calcd for C15 H13 BrN4 O2 : C, 49.88; H, 3.63; N, 15.51%. Found: C, 50.18; H, 3.47; N, 15.66%.1H-NMR
(CDCl3): δ 1.52 (t, J = 7.0 Hz, 3H, CH3), 4.52 (q, J = 7.0 Hz, 2H, CH2), 7.02 (t, J = 6.9 Hz, 1H, Ar),
7.45 (d, J = 9 Hz, 2H, Ar), 7.75 (d, J = 9 Hz, 2H, Ar), 8.54-8.58 (m, 2H, Ar), 9.20 (s, 1H, NH, removed by
D2 O addition) ppm; 13 C-NMR (CDCl3): δ 14.68, 60.74, 96.43, 109.52, 114.57, 119.94, 120.02, 131.92, 134.85,
138.84, 149.17, 151.20, 162.48 ppm; FT-IR (KBr): ν 3319, 2975, 1667, 1618, 1566, 1448, 1186, 1092, 920, 757
cm−1
.
854

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
Results and discussion
The required isoxazolones (10a-f) were synthesised by N -arylation of the corresponding 2H -isoxazolones (9a-
f), which in turn were made by a modification of the procedure of Worrall.9,10 Thus, the reaction of the sodium
salt of diethyl malonate in ethanol with aryl isothiocyanates gave the thiocarbamates (8a-h) in high yield, and
these were converted to the corresponding isoxazolone (9a-h) by reaction with hydroxylamine.
N -arylation of 9a-f with 2-chlorobenzoxazole in chloroform under reflux afforded the correspondingN -
benzoxazole derivatives (10a-f) in good yield (Scheme 2).
O
N
H
S
NHAr
ArHN
ArHN
NH2OH
N
N
2-chlorobenzoxazole
CHCl3
O
O
EtO2C
CO2Et
EtO2C
EtO2C
O
O
10a-f
8a-f
9a-f
a, Ar =2-BrC6H4
b, Ar = 3-BrC6H4
c, Ar = 2-MeC6H4
d, Ar = 3-MeC6H4 e, Ar = 3-OMeC6H4 f, Ar = 4-NO2C6H4
Scheme 2
The reaction of the isoxazolones 9b-h with 2-chloropyrimidine gave the desired N -pyrimidine derivatives
11b-h (Scheme 3). While the formation of 11b-h appears trivial, the reaction generally proceeded best in the
absence of solvent, by heating the required reagents under nitrogen atmosphere at 130 ◦ C.
N
N
H
ArHN
ArHN
N
N
2-chloropyrimidine
N2
O
O
EtO2C
EtO2C
O
O
9b-h
11b-h
b, Ar = 3-BrC6H4
d, Ar = 3-MeC6H4 j, Ar = 4-MeC6H4 h, Ar = 4-BrC6H4
Scheme 3
The reaction of the corresponding isoxazolones, substituted on nitrogen with a benzoxazole group 10a-f
with triethylamine, afforded the rearranged aminoindoles 12a-f in 60%-69% yield (Scheme 4).
855

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
EtO2C
O
N
O
TEA
X
ArHN
N
N
H
N
H
N
O
EtO2C
O
10a-f
12a-f
a, Ar =2-BrC6H4
b, Ar = 3-BrC6H4
c, Ar = 2-MeC6H4
d, Ar = 3-MeC6H4 e, Ar = 3-OMeC6H4 f, Ar = 4-NO2C6H4
Scheme 4
The rearrangement of 2-arylisoxazolones 11b-h in the presence of triethylamine in ethanol under reflux
afforded the rearranged imidazopyrimidines 13b-h (Scheme 5).
N
N
EtO2C
ArHN
ArHN
TEA
61-76%
N
N
O
N
N
EtO2C
O
13b-h
11b-h
b, Ar = 3-BrC6H4
d, Ar = 3-MeC6H4 j, Ar = 4-MeC6H4 h, Ar = 4-BrC6H4
Scheme 5
The structures of all new compounds were confirmed by 1 H-NMR, 13 C-NMR, FT-IR spectral data, and
microanalyses.
The mechanisms of rearrangements are consistent with our earlier suggestions3,11 for the formation of
aminoindoles and imidazopyrimidine (Scheme 6). The present results, when considered with those obtained
previously,3,12 suggest that in the case of imidazopyrimidine formation the heteroaryl group of the heteroaryl
isoxazolones is most likely to intercept the ylide intermediate formed by reaction with a base, unless the 3-aryl
group is both electron rich and sterically unhindered.
It is interesting that in the case of pyrimidine derivative the rearrangement gave only imidazopyrimidine,
as shown in Scheme 5, but in the case of benzoxazole derivatives, aminoindoles are formed with no sign of any
imidazobenzoxazole derivative formation as shown in Scheme 4, which may be due to the fact that oxygen in
the benzoxazole ring is more electronegative than nitrogen in the pyrimidine ring and, therefore, the lone pair
on nitrogen of the pyrimidine ring is more available than that in the benzoxazole ring.
856

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
O
N
Et3N
H
N
-CO2
O
N
O
H
N
H
N
N
X
O
N
N
N
EtO2C
O2C
NEt3
O
O2C
NEt3
X
X
CO2Et
CO2Et
N
O
H H
N
N
EtO2C
EtO2C
-TEA
O
O
H
X
X
NEt3
X
N
N
EtO2C
N
H
N
H
N
N
a, X = 2-BrC6H4
b, X = 3-BrC6H4
c, X = 2-MeC6H4
d, X = 3-MeC6H4
e, X = 3-OMeC6H4 f, X = 4-NO2C6H4
N
N
O
EtO2C
ArHN
EtO2C
O2C
Et3N
NEt3
NEt3
-TEA
EtO2C
ArHN
ArHN
- CO2
N
N
N
N
ArHN
N
N
N
N
N
N
EtO2C
O
b, Ar = 3-BrC6H4 d, Ar = 3-MeC6H4 j, Ar = 4-MeC6H4 h, Ar = 4-BrC6H4
Scheme 6
Conclusion
These rearrangements of 2-heterocyclyl isoxazolones appear to be generally applicable to the synthesis of
heterocycles, which are suitable synthetic intermediates for a series of new polycyclic heterocycles with possible
pharmaceutical applications and could be expected to intercalate with DNA.13−15
Acknowledgements
The authors are grateful to Urmia University for its support of this work.
857

Ethyl 5-oxo-3-arylamino-2,5-dihydroisoxazole-4-carboxylates..., A. POURSATTAR MARJANI, J. KHALAFY
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