The synthesis of potential DNA intercalators. 2. Tri- and tetra-cyclic heterocycles

Article abstract of DOI:10.1071/CH08370

The reaction of 1,4-dichlorophthalazine and 2,3-dichloroquinoxaline with some isoxazolones gave their mono- and bis-isoxazolinyl derivatives. The base-catalyzed rearrangement of these derivatives afforded the corresponding tri- and tetracyclic heterocycle

Full text of DOI:10.1071/CH08370

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 126–132
www.publish.csiro.au/journals/ajc
The Synthesis of Potential DNA Intercalators.
2. Tri- and Tetra-Cyclic Heterocycles∗
Ali Reza Molla Ebrahimlo,A Jabbar Khalafy,A,C and Rolf H. PragerB
AChemistry Department, Urmia University, Urmia 57159, Iran.
BChemistry Department, Flinders University of South Australia, GPO Box 2100,
Adelaide, SA 5001, Australia.
CCorresponding author. Email: j.khalafi@mail.urmia.ac.ir
The reaction of 1,4-dichlorophthalazine and 2,3-dichloroquinoxaline with some isoxazolones gave their mono- and
bis-isoxazolinyl derivatives. The base-catalyzed rearrangement of these derivatives afforded the corresponding tri- and
tetracyclic heterocycles.
Manuscript received: 1 September 2008.
Final version: 19 December 2008.
Introduction
We have extended this work by reporting[7] that 1,3-
bis(isoxazol-3-ylamino)benzenes 9, substituted on the isoxazole
nitrogen with a pyrimidine group, react with triethylamine
in ethanol under reflux to afford the corresponding 2-
indolylaminoimidazopyrimidine derivatives 10 (Scheme 3).
Structures 6, 8, and 10 are clearly well set up as precursors
for polycyclic structures, which are of considerable interest
as pharmacophores for therapeutic drugs. Such compounds
have been used to reduce neurotoxin injury associated with
anoxia or ischaemia,[8] or as antiviral agents.[9] Tricyclic
Prager and coworkers have reported[1,2] the synthesis of some
mono- and bis-isoxazolinyl derivatives of pyrimidine 1 and pyri-
dazine 2 as central nervous system-active compounds and their
base-catalyzed rearrangements to the corresponding annelated
heterocycles. They also reported[1] the based-catalyzed re-
arrangement of several isoxazolones substituted on N with
different heterocycles (Scheme 1).
Khalafy and coworker have reported[3–5] that the arylamino-
isoxazol-5(2H)-ones, substituted on nitrogen with nitropyridine
3, benzoxazole 5, or benzothiazole 7 groups react with
triethylamine in ethanol under reflux conditions to form the cor-
responding imidazopyridines 4, indoles 6, and imidazobenzo-
thiazoles 8, respectively, an outcome that is similar to that
achieved by pyrolysis or photolysis[6] (Scheme 2).
NO2
N
ArHN
N
N
Et3N
ArHN
N
EtO2C
O
X
EtO2C
NO2
O
O
N
N
N
O
X
N
O
3
4
Me
N
N
O
CO2Et
H
H
CO2Et
EtO2C
N
1
2
O
N
H
O
O
N
H
N
X ꢀ Cl ,
6
CO2Et
X
Et3N
N
H
ArHN
N
O
ArHN
N
N
EtO2C
O
N
S
(1) OHꢁ
(2) Hꢂ
N
O
EtO2C
N
H
N
O
5 X ꢀ O
7 X ꢀ S
CO2Et
OH
EtO2C
O
8
Scheme 1.
∗Part 1. A. R. Molla Ebrahimlo, J. Khalafy, Arkivoc 2008, xiii, 65.
Scheme 2.
© CSIRO 2009
10.1071/CH08370
0004-9425/09/020126

The Synthesis of Potential DNA Intercalators
127
aza-heterocycles also display platelet-derived growth factor
inhibitory activity.[10]
Here we report the synthesis of new mono- and bis-
isoxazolinyl derivatives of phthalazine and quinoxaline and
their base-catalyzed rearrangement to the corresponding tri- and
tetracyclic heterocycles (Schemes 4–8).
and 13a–c (Scheme 5), respectively. Although the formation of
12a–c and 13a–c appears to be straightforward extensions of
our previous work,[3–5] the reaction generally proceeded best in
the absence of solvent, by heating the required reactants under
nitrogen at 130◦C for 30 min.
It is interesting that treatment of 2,3-dichloroquinoxaline
with two equivalent of the isoxazolones 11b,c gave only mono-
adducts 12b,c, which may reflect the lower susceptibility of
the quinoxaline ring to nucleophilic substitution. Treatment of
1,4-dichlorophthalazine with two equivalents of isoxazolones
11a–c gave the corresponding bis-adducts 13a–c, as shown in
Scheme 5.
Results and Discussion
The synthesis of starting materials has generally involved
displacement of an activated halide in a heterocyclic sys-
tem by a suitable 2H-isoxazolone. Thus, reaction of 2,3-
dichloroquinoxaline and 1,4-dichlorophthalazine with two
equivalents of the isoxazolones 11a–c gave the correspond-
ing quinoxaline and phthalazine bis-adducts 12a (Scheme 4)
The reaction of bis-adduct 12a with triethylamine in chloro-
form under reflux, conditions we had previously found most con-
ducive for the desired rearrangement,[3–5] afforded a rearranged
CO2Et
NH
O
O
O
O
CO2Et EtO2C
Et3N/EtOH
N
H
HN
N
N
N
N
N
H
N
H
N
R
Reflux
N
R
N
N
CO2Et
N
N
N
9
10
R ꢀ H, Me
Scheme 3.
CO2Et
O
H
H
N
N
N
O
O
N
O
N
Cl
Cl
H
N
R
CO2Et
N
O
12a
Solid phase
EtO2C
O
N
N
Cl
11a–c
O
N
O
HN
H
N
a R ꢀ H
b R ꢀ
c R ꢀ
R
CO2Et
12b,c
Scheme 4.
EtO2C
O
O
Cl
Cl
N
R
N
N
H
N
R
N
N
O
Solid phase
EtO2C
N
O
R
O
11a–c
EtO2C
O
HN
H
N
a R ꢀ H
b R ꢀ
c R ꢀ
13a–c
Scheme 5.

128
A. R. Molla Ebrahimlo, J. Khalafy, and R. H. Prager
product. According to the work cited above,[1] the rearranged
compound was expected to have structure 14, but interestingly,
only compound 15 was formed (Scheme 6).
We suggest the pathway in Scheme 7 for the rearrangement
of 12a.
Owing to the extreme insolubility of compound 15, we could
not measure its 13C NMR even in [D6]DMSO, and therefore
decided to synthesize its acetyl derivative 16 in order to confirm
its structure by spectral data (Scheme 7).
Treatment of compound 12b with base afforded two dif-
ferent rearranged products depending on the kind of base
used. Its reaction with potassium carbonate in THF under
reflux conditions produced the tetracyclic compound 17 via
intramolecular nucleophilic substitution, but with triethylamine
under similar conditions, the tricyclic compound 18 was formed
(Scheme 8).
Compound 12c did not undergo base-catalyzed rearrange-
ment under either of the above conditions, and only starting
material was recovered.
CO2Et
It is interesting to note that when isoxazolone 19 was reacted
with 2,3-dichloroquinoxaline in ethanol under reflux in the
absence of base, the rearranged product 20 was precipitated out
in 20% yield (Scheme 9).
The reaction of the phthalazine bis-adduct 13a with tri-
ethylamine in chloroform under reflux conditions gave the
rearranged tetracyclic product 21, without the loss of CO2, the
pathway shown in Scheme 10 being suggested.
O
OH
N
N
N
N
CO2Et
O
H
H
O
OH
N
N
N
N
CO2Et
14
Et3N
O
O
O
Finally, the reaction of bis-adducts 13b,c with triethylamine
in refluxing chloroform produced the different tetracyclic re-
arranged product 22b,c by loss of two moles of CO2 via the
mechanism shown in Scheme 11.
CO2Et
OH
CO2Et
HO
N
N
12a
CO2Et
N
N
Conclusions
15
The above base-catalyzed rearrangements again illustrate that
the synthesis of several tri- and tetracyclic heterocycles that
Scheme 6.
O
CO2Et
O
EtO2C
EtO2C
H
N
CO2Et
O
O
ꢁ
C
N
N
ꢁ2Hꢂ
N
N
CO2
N
N
N
N
N
CO2Et
N
O
O
O
ꢁ
CO2
N
N
N
N
H
N
C
O
ꢁ
ꢁ
C
CO2Et
CO2Et
CO2Et
CO2
O2C
ꢁ
ꢁ
12a
H3C
O
CO2Et
CO2Et
OH
HO
HO
O
CO2Et
O
AC2O
N
N
N
N
ꢁCO2
N
N
CO2ꢁ
CO2Et
N
OH
N
N
CO2Et
N
CO2Et
N
N
16
15
Scheme 7.
O
O
O
O
N
N
N
N
CO2Et
N
N
N
THF/K2CO3
CO2Et
N
ꢁ
Cl
CO2Et
O
HN
N
N
N
O
17
Cl
THF/Et3N
HN
N
EtO2C
12b
ꢁCO2
N
N
Cl
18
Scheme 8.

The Synthesis of Potential DNA Intercalators
129
Br
CO2Et
Br
Br
HN
N
N
N
Cl
Cl
EtO2C
N
H
N
H
H
N
Br
N
O
O
N
O
O
N
O
N
H
N
EtO2C
N
O
N
N
CO2Et
Br
EtO2C
HN
19
20
Scheme 9.
2,3-Bis(4-ethoxycarbonyl-5-oxo-2,5-dihydroisoxazolin-
EtO2C
H
O
OH
2-yl)quinoxaline 12a
CO2Et
O
O
N
11a[15]
N
N
Ethyl
5-oxo-2,5-dihydro-isoxazole-4-carboxylate
Et3N
N
N
(100 mg, 0.63 mmol) and 2,3-dichloroquinoxaline (63 mg,
0.3 mmol) were heated neat under nitrogen in 130◦C for 15 min.
The resulting product was recrystallized from ethanol to give the
bis-isoxazolinyl derivative 12a (110 mg, 80%) as yellow crys-
tals, mp 183–184◦C. δH (CDCl3) 1.42 (t, J 7.2, 6H), 4.42 (q,
J 7.2, 4H), 7.94 (dd, J1 6.6, J2 3.6, 2H), 8.09 (dd, J1 6.6, J2
3.6, 2H), 9.34 (s, 2H). δC (CDCl3) 14.34, 61.50, 99.12, 128.16,
132.82, 134.71, 139.52, 150.16, 160.3, 163.41. νmax(KBr)/cm−1
1794, 1718, 1599, 1500, 1452, 1372, 1205, 1023, 777. m/z (%)
440 (M+, 20), 395 (30), 278 (81), 210 (59), 209 (80), 113 (84),
101 (66), 45 (100).
N
N
CHCl3/reflux
NH
O
H
O
OH
EtO2C
EtO2C
O
13a
21
EtO2C
N
O
O
O
ꢁ
2-Chloro-3-(4-ethoxycarbonyl-3-phenylamino-5-oxo-
2,5-dihydroisoxazolin-2-yl)quinoxaline 12b
O
N
EtO2C
N
N
N
N
The corresponding isoxazolone 11b[16] (100 mg, 0.4 mmol)
using the same procedure as above gave 12b (60 mg, 70%) as
pale yellow solid, mp 169–170◦C. δH (CDCl3) 1.47 (t, J 7.1, 3H),
4.47 (q, J 7.1, 2H), 6.78 (t, J 7.8, 1H), 6.97 (t, J 7.9, 2H), 7.1
(d, J 7.8, 2H), 7.74–7.85 (m, 3H), 7.93 (d, J 7.8, 1H), 9.86 (bs,
1H). δC (CDCl3) 14.52, 61.02, 122.78, 126.71, 128.14, 128.71,
129.27, 130.12, 131.25, 132.60, 135.61, 138.87, 141.52, 142.56,
144.33, 164.38, 165.38, 165,93. νmax(KBr)/cm−1 3429, 3281,
1777, 1665, 1620, 1497, 1297, 959, 793. m/z (%) 412 ([M+ + 2],
8), 410 (M+, 20), 366 (27), 320 (61), 245 (23), 216 (100), 144
(36), 77 (29).
H
O
NH
N
O
ꢁ
OH
EtO2C
O
CO2Et
Scheme 10.
have not been previously prepared appears possible, and because
of their multiple H-bonding and H-acceptor sites, these com-
pounds could be expected to intercalate with DNA.[11–13] They
could also serve as intermediates for new planar polycyclic
heterocycles.
2-Chloro-3-(4-ethoxycarbonyl-3-(1-naphthylamino)-
5-oxo-2,5-dihydroisoxazolin-2-yl)quinoxaline 12c
The corresponding isoxazolone 11c[17] (100 mg, 0.34 mmol)
using the same procedure as above gave 12c (110 mg, 71%)
as pale yellow solid, mp 165–167◦C. δH (CDCl3) 1.51 (t, J 7.2,
3H), 4.53 (q, J 7.2, 2H), 7.1 (t, J 7.8, 1H), 7.24 (d, J 8.4, 1H),
7.32 (d, J 8.4, 1H), 7.38 (t, J 7.2, 2H), 7.44–7.5 (m, 2H), 7.56 (td,
J1 8.4, J2 1.5, 1H), 7.62 (td, J1 8.4, J2 1.5, 1H), 7.74 (d, J 8.4,
1H), 8.1 (d, J 8.4,1H), 10.11 (s, 1H). δC (CDCl3) 14.57, 61.05,
121.92, 122.1, 124.72, 126.89, 127.17, 127.74, 128, 128.02,
128.22, 128.53, 130.76, 131.53, 132.2, 133.61, 138.52, 141.32,
141.92, 144.13, 164.45, 165.69, 167.07. νmax(KBr)/cm−1 3423,
3268, 1782, 1661, 1617, 1482, 1292, 1110, 966, 778. m/z (%)
462 ([M+ + 2], 8), 460 (M+, 22), 417 (75), 371 (100), 307 (48),
180 (23), 153 (32), 128 (25).
Experimental
General Procedures
Freshly distilled solvents were used throughout, and anhy-
drous solvents were dried according to Perrin and Armarego.[14]
Melting points were determined on a Philip Harris C4954718
apparatus and are uncorrected. Infrared spectra were recorded on
a Thermonicolet (Nexus 670) Fourier-transform (FT)-infrared
spectrometer, using sodium chloride cells and measured as
film or KBr discs. H (300 MHz) and 13C (75.5 MHz) NMR
1
measurements were recorded on a Bruker 300 spectrometer
in [D6]DMSO, CD2Cl2, or CDCl3 using TMS as the internal
reference. Mass spectra were recorded on a Varian Matt 311
spectrometer and relative abundances of fragments are quoted in
parentheses after the m/z values. Microanalyses were performed
on a Leco Analyzer 932.
1,4-Bis(4-ethoxycarbonyl-5-oxo-2,5-dihydroisoxazolin-
2-yl)phthalazine 13a
The corresponding isoxazolone 11a (100 mg, 0.63 mmol) and
1,4-dichlorophthalazine (63 mg, 0.3 mmol) were heated neat

130
A. R. Molla Ebrahimlo, J. Khalafy, and R. H. Prager
EtO2C
R
O
O
R
N
N
N
N
N
CO2Et
N
Et3N
NH
CHCl3/reflux
R
O
N
EtO2C
EtO2C
O
R
13b,c
22b,c
R
ꢁ
R
CO2
N
N
N
CO2Et
NEt3
CO2Et
N
N
N
ꢂ
N
ꢁ
H
EtO2C
ꢂ
ꢁ2CO2
N
EtO2C
ꢂ
Et3N
Et3N
R
O2C
R
ꢁ
b R ꢀ PhꢁNHꢁ
c R ꢀ NaphꢁNHꢁ
Scheme 11.
under nitrogen in 130◦C for 15 min. The resulting product was
recrystallized from ethanol to give the isoxazolone 13a (110 mg,
80%) as a yellow solid, mp 185–187◦C. δH (CDCl3) 1.42 (t,
J 7.2, 6H), 4.42 (q, J 7.2, 4H), 8.2 (dd, J1 5.4, J2 2.4, 2H),
8.79 (dd, J1 5.4, J2 2.4, 2H), 9.55 (s, 2H). δC (CDCl3) 14.32,
61.53, 98.27, 122.05, 125.33, 134.98, 148.6, 150.54, 160.22,
164.05. νmax(KBr)/cm−1 1790, 1708, 1568, 1447, 1317, 1218,
1025, 779, 578. m/z (%) 440 (M+, 8), 439 (8), 325 (4), 271
(8), 195 (17), 169 (17), 129 (63), 127 (100), 101 (62), 54 (50),
52 (88).
1,4-Bis(4-ethoxycarbonyl-3-(1-naphthylamino)-5-oxo-
2,5-dihydroisoxazolin-2-yl)phthalazine 13c
The corresponding isoxazolone 11c (100 mg, 0.34 mmol) using
the same procedure as above gave 13c (90 mg, 74%) as a cream
solid, mp 177–179◦C. δH (CDCl3) 1.51 (t, J 7.2, 6H), 4.52 (q, J
7.2, 4H), 6.72 (t, J 7.8, 2H), 6.94 (d, J 7.8, 2H), 7.17 (d, J 8.4, 2H),
7.37 (t, J 7.8, 2H), 7.45–7.51 (m, 8H), 7.85 (d, J 8.1, 2H), 9.84 (s,
2H). δC (CDCl3) 14.57, 61.03, 79.22, 121.94, 122.83, 123.91,
124.33, 124.59, 126.84, 127.39, 127.92, 128.18, 128.29, 130.68,
133.47, 152.44, 164.79, 165.23, 168.75. νmax(KBr)/cm−1 3436,
3273, 1782, 1665, 1630, 1616, 1478, 1208, 798, 776. m/z (%)
722 (M+, 6), 711 (29), 526 (21), 463 (41), 384 (39), 365 (41),
307 (30), 268 (35), 255 (38), 208 (86), 180 (50), 131 (100),
57 (48).
1,4-Bis(4-ethoxycarbonyl-3-phenylamino-5-oxo-
2,5-dihydroisoxazolin-2-yl)phthalazine 13b
The corresponding isoxazolone 11b (100 mg, 0.4 mmol) using
the same procedure as above gave 13b (100 mg, 80%) as a pale
yellow solid, mp 207–208◦C. δH (CDCl3) 1.45 (t, J 7.2, 6H),
4.46 (q, J 7.2, 4H), 6.8–6.86 (m, 6H), 6.9–6.94 (m, 4H), 8.06
(dd, J1 6.3, J2 3.3, 2H), 8.29 (dd, J1 6.3, J2 3.3, 2H), 9.83 (s,
2H). δC (CDCl3) 14.49, 61.05, 79.37, 122.91, 124.07, 125.02,
127.02, 129.22, 134.63, 135.26, 152.55, 164.46, 165.03, 166.79.
νmax(KBr)/cm−1 3438, 3232, 1783, 1695, 1610, 1485, 1198,
1037, 793, 730. m/z (%) 623 ([M+ + 1], 8), 579 (18), 537 (48),
390 (23), 362 (40), 316 (41), 287 (55), 144 (63), 131 (100), 120
(72), 45 (74).
3,5-Bisethoxycarbonyl-4,6-dihydroxyimidazo
[1,2-a]pyrido[4,5-b]quinoxaline 15 and Its
Acetylated Derivative 16
The isoxazolone 12a (100 mg, 0.23 mmol) was refluxed in
chloroform with triethylamine (0.5 mL) for 12 h. The solvent
was removed:
(i)The residue was dissolved in water (2 mL), and the solution
acidified to pH 2 with concentrated HCl. The yellow precipitate

The Synthesis of Potential DNA Intercalators
131
was filtered to give the compound 15 (80 mg, 89%), mp 220–
222◦C. δH ([D6]DMSO) 1.3 (t, J 7.2, 3H), 1.35 (t, J 6.9, 3H),
4.29 (q, J 7.2, 2H), 4.45 (q, J 6.9, 2H), 7.79 (t, J 7.8, 1H), 7.85 (t,
J 7.8, 1H), 8.04 (d, J 7.8, 1H), 8.13 (d, J 7.8, 1H), 13.5 (bs, 1H).
νmax(KBr)/cm−1 3314, 2982, 1725, 1663, 1637, 1600, 1529,
1392, 1329, 1140, 1023, 804. m/z (%) 396 (M+, 25), 350 (25),
304 (100), 236 (12), 208 (25), 143 (16), 102 (12), 45 (10).
(ii) The residue was heated in acetic anhydride (2 mL) for
2 h. The mixture was left to cool to room temperature and the
desired compound 16 was collected as yellow needles (66 mg,
60%), mp 148–149◦C. δH (CDCl3) 1.42 (t, J 7.2, 3H), 1.49 (t,
J 7.2, 3H), 2.37 (s, 3H), 4.42 (q, J 7.2, 2H), 4.49 (q, J 7.2, 2H),
7.82 (t, J 8.1, 1H), 7.88 (t, J 8.1, 1H), 8.11 (d, J 8.1, 1H), 8.4
(d, J 8.2, 1H), 11.56 (bs, 1H). δC (CDCl3) 14.24, 14.32, 20.81,
61.77, 62.02, 86.91, 127.82, 129.06, 130.08, 130.67, 136.65,
137.22, 137.82, 139.13, 140.12, 148.88, 155.1, 159.5, 162.66,
164.38, 167.48. νmax(KBr)/cm−1 3536, 2985, 1781, 1733, 1704,
1675, 1541, 1195, 1016, 768. m/z (%) 438 (M+, 10), 437 (12),
395 (24), 349 (45), 302 (100), 277 (19), 209 (22), 142 (13),
101 (10).
8.1, 2H), 7.59 (dd, J1 6.6, J2 3.3, 2H), 7.68 (d, J 8.2, 2H), 8.22
(dd, J1 6.6, J2 3.3, 2H), 8.34 (t, J 2.1, 2H), 8.93 (bs, 2H). δC
(CDCl3) 14.52, 61.31, 116.94, 118.88, 121.02, 121.17, 122.95,
125.02, 125.22, 125.63, 130.44, 141.3. νmax(KBr)/cm−1 3401,
2975, 1691, 1645, 1610, 1598, 1563, 1447, 1380, 1080, 761. m/z
(%) 692 (M+, 100), 645 (11), 574 (16), 519 (30), 440 (30), 346
(15), 260 (25), 221 (64), 192 (49), 129 (40), 102 (62).
Diethyl 6,12-Dihydroxy-4,10-dioxo-7,10-dihydro-
4H-azepino[2,3,4-de]pyrimido[2,1-a]phthalazine-
5,11-dicarboxylate 21
This compound was prepared by the same procedure as described
for compound 15; using the corresponding isoxazolone 13a
gave 21 as a cream solid (80 mg, 80%), mp 114◦C (dec.) δH
([D6]DMSO) 1.22 (t, J 6.9, 3H), 1.29 (t, J 7.2, 3H), 4.21 (q, J
7.2, 2H), 4.3 (q, J 6.9, 2H), 5.15 (bs, 1H), 8.11–8.13 (m, 2H),
8.79 (d, J 7.2, 1H), 11.48 (bs, 1H). δC (CDCl3) 14.36, 14.56,
61.74, 62.44, 93.69, 124.24, 126.24, 126.73, 127.07, 128.64,
133.32, 134.45, 134.98, 146.21, 149.14, 152.24, 155.95, 165.1,
167.5, 168.61. νmax(KBr)/cm−1 3277, 2984, 1734, 1701, 1644,
1529, 1489, 1302, 1127. m/z (%) 439 ([M+ − 1], 2), 368 (10),
243 (17), 213 (9), 187 (8), 142 (12), 115 (12), 100 (32), 83 (31),
58 (100), 43 (78).
Ethyl 2-Oxo-4-phenyl-2,4-dihydroquinoxalino[d]
isoxazolo[2,3-a]imidazole-3-carboxylate 17
The isoxazolone 12b (100 mg, 0.24 mmol) was refluxed in THF
with potassium carbonate (33 mg, 0.24 mmol) for 1.5 h. The sol-
vent was removed under reduced pressure, water was added to
the residue and the resulting precipitate was collected by filtra-
tion. The yellow solid was recrystallized from ethanol to afford
17 (70 mg, 77%) as pale yellow crystals, mp 186–188◦C. δH
(CDCl3) 0.98 (t, J 7.2, 3H), 3.96 (q, J 7.2, 2H), 7.58–7.81 (m,
7H), 7.99 (dd, J1 8.1, J2 1.5, 1H), 8.14 (dd, J1 8.1, J2 1.8, 1H).
δC (CDCl3) 13.93, 60.5, 127.62, 128.24, 128.58, 128.98, 129.38,
129.7, 130.13, 131.55, 132.65, 138.47, 138.78, 139.42, 153.46,
159.91, 164.82. νmax(KBr)/cm−1 3052, 2983, 1708, 1692, 1594,
1575, 1182, 1119, 1069, 774, 579. m/z (%) 375 ([M+ + 1], 100),
374 (M+, 44), 287 (9), 285 (39), 256 (57), 219 (23), 166 (6),
78 (10).
Diethyl 5,10-Bis(phenylamino)-7H-imidazo[2,1-a]
pyrido[2,3,4-de]phthalazine-4,9-dicarboxylate 22b
The isoxazolone 13b (100 mg, 0.16 mmol) was refluxed in
chloroform with triethylamine (0.5 mL) for 3 h. The solvent was
removed under reduced pressure. On addition of acetone (5 mL)
to the residue, a fine solid was formed. The precipitate was fil-
tered to afford 22b as a pale yellow solid (50 mg, 58%), mp
205–207◦C. δH (CD2Cl2) 1.5 (t, J 7.2, 3H), 1.51 (t, J 7.2, 3H),
4.41 (q, J 7.2, 2H), 4.5 (q, J 7.2, 2H), 7.04 (t, J 7.2, 1H), 7.13
(td, J1 7.2, J2 1.2, 1H), 7.2 (td, J1 7.2, J2 1.2, 1H), 7.38 (d, J
8.4, 2H), 7.41 (d, J 7.2, 1H), 7.7 (t, J 7.5, 1H), 7.79 (d, J 7.5,
1H), 7.8 (t, J 8.3, 3H), 7.84 (d, J 7.2, 1H), 7.8 (bs, 1H), 8.45 (d,
J 7.5, 1H), 11.15 (bs, 1H), 12.23 (bs, 1H). δC (CD2Cl2) 14.41,
14.51, 59.81, 60.39, 101.35, 111.24, 116.39, 117.43, 119.56,
121.11, 121.24, 121.8, 121.93, 123.9, 124.55, 128.92, 130.06,
132.38, 132.73, 134.92, 140.87, 144.93. νmax(KBr)/cm−1 3403,
3266, 2975, 1686, 1629, 1602, 1568, 1102, 1076. m/z (%) 535
([M+ + 1], 4), 534 (M+, 4), 489 (12), 415 (27), 390 (75), 287
(85), 270 (13), 150 (29), 129 (100), 77 (36).
4-Chloro-1-ethoxycarbonyl-2-phenylaminoimidazo
[1,2-a]quinoxaline 18
The isoxazolone 12b (100 mg, 0.24 mmol) was refluxed in THF
with triethylamine (0.5 mL) for 1.5 h. The solvent was removed
under reduced pressure to give yellow oil; the residue was
crystallized from ethanol to afford 18 (60 mg, 67%) as yellow
needles, mp 142◦C. δH (CDCl3) 1.57 (t, J 7.2, 3H), 4.58 (q, J 7.2,
2H), 7.08 (t, J 7.8, 1H), 7.4 (t, J 7.8, 2H), 7.62 (td, J1 7.5, J2 1.5,
1H), 7.66 (td, J1 8.1, J2 1.8, 1H), 7.81 (d, J 7.8, 2H), 8.06 (dd, J1
7.5, J2 2.1, 1H), 8.62 (bs, 1H), 8.65 (dd, J1 8.3, J2 1.5, 1H). δC
(CDCl3) 14.46, 61.63, 103.85, 118.21, 119.29, 122.35, 126.91,
127.57, 128.56, 129.23, 129.81, 136.12, 136.87, 139.91, 141.57,
154.71, 160.72. νmax(KBr)/cm−1 3409, 1708, 1602, 1570, 1488,
1459, 1249, 1182, 1071, 743. m/z (%) 368 ([M+ + 2], 4), 366
(M+, 15), 320 (52), 258 (21), 128 (11), 102 (66), 77 (100).
Diethyl 5,10-Bis(naphthalen-1-ylamino)-7H-imidazo
[2,1-a]pyrido[2,3,4-de]phthalazine-4,9-dicarboxylate 22c
This compound was prepared by the same procedure as described
for compound 22b; using the corresponding isoxazolone 13c
(100 mg, 0.14 mmol) gave 22c as a pale yellow solid (62 mg,
71%), mp 260◦C (dec.) δH (CDCl3 + CD2Cl2 + CF3CO2H) 1.5
(t, J 7.2, 3H), 1.65 (t, J 7.2, 3H), 4.4 (q, J 7.2, 2H), 4.67 (q,
J 7.2, 2H), 7.34 (d, J 8.4, 1H), 7.41 (t, J 7.5, 1H), 7.53 (t, J
8.4, 1H), 7.6 (d, J 8.4, 1H), 7.67–7.75 (m, 4H), 7.79 (t, J 7.2,
1H), 7.85 (bs, 1H), 8.07–8.11 (m, 6H), 8.24 (d, J 8.4, 1H), 8.89
(d, J 8.4, 1H), 11.37 (bs, 1H), 12.3 (bs, 1H). νmax(KBr)/cm−1
3424, 3243, 1683, 1630, 1605, 1575, 1439, 1302. m/z (%)
635 ([M+ + 1], 7), 587 (25), 515 (26), 337 (45), 336 (66),
323 (21), 209 (54), 180 (100), 155 (34), 45 (52). Owing to
extreme insolubility, its 13C NMR could not be measured in any
solvent.
Diethyl 2,11-Bis(3-bromophenylamino)diimidazo
[1,2-a:2ꢀ,1ꢀ-c]quinoxaline-3,10-dicarboxylate 20
The corresponding isoxazolone 19[5] (100 mg, 0.3 mmol) and
2,3-dichloroquinoxaline (30 mg, 0.15 mmol) were refluxed in
ethanol for 48 h. On refluxing, 20 was precipitated out as yellow
crystals (21 mg, 20%), mp 236–237◦C. δH ([D6]DMSO) 1.38
(t, J 7.2, 6H), 4.47 (q, J 7.2, 4H), 7.18 (d, J 8.2, 2H), 7.29 (t, J

132
A. R. Molla Ebrahimlo, J. Khalafy, and R. H. Prager
Acknowledgements
[9] A. Gueiffier, S. Marvel, M. Lahssani, A. Elhakmaoui, R. Snoeck,
G. Andrei, O. Chavignon, J. C. Teulade, M. Witvrouw, J. Balzarini,
E. De Clercq, J.-P. Chapat, J. Med. Chem. 1998, 41, 5108.
doi:10.1021/JM981051Y
We are grateful to the University of Urmia for support of the present work.
We also thank the Chemistry Department of Flinders University for the gift
of chemicals.
[10] T. Ikemoto, T. Kawamoto, K. Tomimatsu, M. Takatani, M. Wakimasu,
Tetrahedron 2000, 56, 7915. doi:10.1016/S0040-4020(00)00709-2
[11] N. Tuteja, T.-N. Phan, R. Tuteja, A. Ochem, A. Falaschi, Biochem.
Biophys. Res. Commun. 1997, 236, 636. doi:10.1006/BBRC.
1997.7021
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