Synthesis of oxadiazoloquinoxaline, oxathiadiazoloquinoxaline and oxadiazolobenzothiazine derivatives

Article abstract of DOI:10.1002/jhet.5570430309

Bis-amidoxime 1 reacts with phosgene, thiophosgene and thionylchloride to give the corresponding bis-fused oxadiazolo- and oxathiadiazoloquinoxalines 2, 4, 5 along with the unexpected furazano-derivative 3, while monoamidoximes 9, 13 by treatment with ethyl chloroformate affords the oxadiazoloquinoxaline and the oxadiazolobenzothiazine derivatives 14, 15 along with the dicarboxylated product 16.

Full text of DOI:10.1002/jhet.5570430309

May-Jun 2006
579
Synthesis of Oxadiazoloquinoxaline, Oxathiadiazoloquinoxaline and
Oxadiazolobenzothiazine Derivatives#
Konstantina C. Fylaktakidoua, Konstantinos E. Litinasb, Athanasios Saragliadisb, Spyros
G. Adamopoulosb and Demetrios N. Nicolaides*b
aMolecular Biology and Genetics Department, Democritus University of Thrace, Alexandroupolis 68100, Greece
bLaboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki
54124, Greece
Received July 8, 2005
O
O
S
S
O
O
O
O
S
H
N
N
N
NOH
NOH
N
N
N
N
N
COCl2 or CSCl2
or SOCl2
N
or
or
N
N
N
N
H
N
O
O
S
O
O
O
O
H
NH2
XH
NOH
O
N
N
EtO
Cl
Et3N, Et2O
N
X
O
ClCO2Et
+
NOH
Et3N, Me2CO
X=NH,S
X
O
X=NH,O,S
Bis-amidoxime 1 reacts with phosgene, thiophosgene and thionylchloride to give the corresponding bis-
fused oxadiazolo- and oxathiadiazoloquinoxalines 2, 4, 5 along with the unexpected furazano-derivative 3,
while monoamidoximes 9, 13 by treatment with ethyl chloroformate affords the oxadiazoloquinoxaline and
the oxadiazolobenzothiazine derivatives 14, 15 along with the dicarboxylated product 16.
J. Heterocyclic Chem., 43, 579 (2006).
dihydro[1,2,4]oxadiazolo[4,3-a]quinoxaline (III) in
high yield [8].
Introduction.
Numerous quinoxaline derivatives such as triazolo-
quinoxalines [1,2], ditriazoloquinoxalinediones [3],
imidazoloquinoxalin-4-ones [4] have been synthesized
and still attract the attention of many research groups, due
to their biological importance [1-4]. 1H-[1,2,4]Oxadia-
zolo[4,3-a]quinoxalin-1-one (ODQ, I) [5,6] and 4H-8-
bromo-[1,2,4]oxadiazolo[3,4-d]benzo[b][1,4]oxazin-1-one
(NS2028, II) [6] appear to be potent and specific
inhibitors of NO-stimulated soluble guanylyl cyclase
activity in various cell types.
[1,2,4]Oxadiazolones are easily prepared, treating
the appropriate amidoxime with ethyl chloroformate or
phosgene [7]. Treatment of 2-oximino-1,2,3,4-tetra-
hydroquinoxaline (easily prepared from the reaction of
N-cyanomethyl-o-phenylenediamine with hydroxyl-
amine) with ethyl chloroformate gave 1-oxo-4,5-
In a previous paper [9] we reported the synthesis of
some 2,3-bishydroxyimino-1,2,3,4-tetrahydroquinoxalines
IVa and 2,3-bishydroxyimino-2,3-dihydro-4H-[1,4]benz-
oxazines IVb from the corresponding o-diamines or o-
aminophenols and dicyan di-N-oxide. Also later it was
studied [10] their reactions with ethyl chloroformate, in
order to prepare the corresponding fused-oxadiazolones.
Reflux of IVa in dry benzene with an excess of ethyl
chloroformate led solely to the known [11,12] furazano-
[3,4-b]quinoxalines in 17-28 % yield, while from IVb
afforded the corresponding 4-hydroxyimino-1H,4H-[1,2,4]-
oxadiazolo[3,4-c][1,4]benzoxazin-1-ones Va, the 4-ethoxy-
carbonyloxyimino- derivatives Vb, as well as the
bis(ethoxycarbonyloxyimino)-derivatives of the starting
bis-oximes IV [10]. In continuation here we report the
syntheses of the title compounds depicted in Schemes 1,4.
O
O
O
O
O
O
O
O
H
N
N
NOH
NOH
N
N
N
N
N
Br
N
O
N
N
O
R
R
N
H
X
N-A
V a: A=OH
b: A=OCO2Et
I
II
III
IV a: X=NH
b: X=O

580
K. C. Fylaktakidou, K. E. Litinas, A. Saragliadis, S. G. Adamopoulos and D. N. Nicolaides
Vol 43
Results and Discussion.
oxadiazole ring followed by ring opening and elimination
of COX can lead to the formation of product 3 obtained,
as it is depicted in the mechanism proposed in Scheme 2.
We also studied similar reactions of 1,4-dihydro-2,3-
quinoxalinedione 2-oxime 9, as well as of 2H-[1,4]benz-
oxazine-2,3(4H)-dione 3-oxime 11 and 2H-[1,4]benzo-
thiazine-2,3-(4H)-dione 3-oxime 13 in order to transform
Treatment of bis-amidoxime 1 [9] with excess of
phosgene and triethylamine in dry dioxane at room
temperature afforded the expected di[1,2,4]oxadiazolo-
[4,3-a:3,4-c]quinoxaline-3,10-dione 2 in 33% yield and
the known [13] 4,9-dihydrofurazano[3,4-b]quinoxaline 3
in 18% yield (Scheme 1).
Scheme 1
O
O
H
N
N
N
N
COCl2
N
N
+
O
Et3N, r.t.
N
H
N
O
O
S
3
2
O
H
NOH
N
N
CSCl2
N
N
+
3
Et3N, r.t.
N
H
NOH
N
O
1
S
4
O
O
S
N
SOCl2
N
Pyridine, r.t.
N
N
S
O
O
5
Following a similar procedure di[1,2,4]oxadiazolo[4,3-
a:3,4-c]quinoxaline-3,10-dithione 4 was obtained in 31%
yield along with compound 3 (18%) by treating
compound 1 with two equivalents of thiophosgene [14].
Similarly, by treating compound 1 with thionyl chloride
and pyridine [15] in dry THF, 1ꢀ4,6ꢀ4-di[1,2,3,5]oxathia-
diazolo[3,4-a:4,3-c]quinoxaline-1,6-dione 5 was obtained
in 34% yield. Obviously products 2, 4, 5 were formed by
a double lactamization of a bis(ethoxycarbonyloxyimino)-
intermediate derivative of 1, while compound 3 can be
formed from the monolactamized intermediates 6. Further
intramolecular attack of the –OH group of 6 to its
their amidoxime moiety to the corresponding mono-fused
systems. Several 4,4-dihydro-[1,2,4]triazoloquinoxaline-4-
ones [16], 2,4-dihydro[1,2,4]triazolo[3,4-c][1,4]benzoxazines
and –benzothiazines [17] show interesting biological and
useful pharmacological properties. (Z)-Chloro-(hydroxyi-
mino)acetic acid ethyl ester [18] reacted in the presence of
triethylamine with o-phenylenediamine 8, or with o-amino-
phenol 10 or with o-aminothiophenol 12 to give compounds
9, 11, 13 respectively in 87%, 83%, and 84% yield (Scheme
3). During the time that this work was in progress Csikos et
al. [19] reported the syntheses, of 5,7-dichloro-, 6,8-dichloro-,
6-chloro-7-(trifluoromethyl)- and 7-chloro-6-(trifluoromethyl)-
Scheme 2
X
O
H
H
N
NOH
N
N
C(=X)Cl2
X=O,S
N
N
N
O
-2HCl
N
H
-COX
N
H
NOH
N
H
N-OH
1
3
6

May-Jun 2006 Oxadiazoloquinoxaline, Oxathiadiazoloquinoxaline and Oxadiazolobenzothiazine Derivatives
581
Perkin-Elmer 1310 spectrophotometer as nujol mulls. Nmr
spectra were recorded on a Bruker AM 300 (300 MHz, and
75 MHz), for 1H and 13C respectively, using deuterio-
chloroform as solvent and tetramethylsilane as an internal
standard; J values are reported in Hz. Mass spectra were
determined on a VG-250 spectrometer at 70 eV under
Electron Impact (EI) conditions. High resolution mass spectra
(hrms) were recorded on an Bruker Daltonics ICR-MS-APEX
II mass spectrometer under Electronspray Ionization (ESI)
conditions. MicroAnalyses were performed on a Perkin-
Elmer 2400-II Element Analyzer. Analyses indicated by the
symbols of the elements were within ±0.4% of the theoretical
values. Silica gel No 60, Merck A.G. has been used for
column chromatographies.
derivatives of 9, following a similar treatment of the
corresponding substituted 1,2-phenylenediamines with 7.
Scheme 3
NH2
H
N
NOH
8
NH2
Et3N, CHCl3
N
H
O
9
NH2
OH
H
N
EtO
Cl
O
NOH
O
10
Di[1,2,4]oxadiazolo[4,3-a:3,4-c]quinoxaline-3,10-dione (2).
Et3N, Et2O
NOH
O
A 20% solution of phosgene in toluene (1.5 ml, 0.297 g, 3
mmoles) was added dropwise during an hour, through a
dropping funnel, to a solution of compound 1 (0.192 g, 1
mmole) and dry triethylamine (0.8 ml) in dry dioxane (20 ml) at
rt, under stirring. The reaction mixture was stirred for 24 h. The
precipitated triethylamine hydrochloride was removed by
filtration, the solvent was evaporated in a rotary evaporator and
the residue was subjected to a column chromatography (silica
gel, hexane/ethyl acetate 6:1 up to 0:1) to give brown crystals of
compound 2 (80 mg, 33%), m.p. 246-248°C (from ether); ir:
7
11
NH2
SH
H
N
NOH
O
12
Et3N, Et2O
S
13
When mono-amidoximes 9 and 13 were treated with
ethyl chloroformate and triethylamine in acetone, the
desired [1,2,4]oxadiazolo[4,3-a]quinoxaline-1,4(5H)-dione
14 and 4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzothiazine-
1,4-dione 15 were obtained in 70% and 6% yield
respectively. In the second reaction ethyl 3-{[(ethoxy-
carbonyl)oxy]imino}-2-oxo-2H-1,4-benzothiazine-4-car-
boxylate 16 was derived also in 93 % yield.
1
3060, 1810, 1790, 1640, 1585 cm-1; H-nmr: ꢁ 7.55-7.62 (m,
1H), 8.61-8.70 (m, 1H); 13C-nmr: ꢁ 116.1, 128.6, 148.1, 154.3,
162.9; ms (EI): m/z 244 (M+., 92%), 200 (78), 170 (48), 156
(72), 143 (52), 128 (32), 120 (56), 104 (100).
Anal. Calcd for C10H4N4O4: C, 49.12; H, 1.77; N, 22.93.
Found: C, 48.84; H, 1.98; N, 23.20.
4,4a,8a,9-Tetrahydro[1,2,5]oxadiazolo[3,4-b]quinoxaline (3).
This compound was obtained from the above described
reaction between 1 and phosgene and eluted after compound 2
(32 mg, 18%), m.p. 244-246°C (lit. [13] m.p. 244-246°C).
Treatment of compound 11 with ethyl chloroformate, as
well as with phosgene under the same experimental
conditions failed to give the expected [1,4]benzoxazine
derivatives. Unsuccessful were also our efforts for the
synthesis of the corresponding fused ring systems of
compounds 9, 11 with 1,2ꢀ4,3,5-oxathiadiazol-2(3H)-one
ring, via the reaction of 9, 11 with thionylchloride.
The analytical and spectral data of new compounds
resemble well with the structures suggested for them (see
Experimental).
Di[1,2,4]oxadiazolo[4,3-a:3,4-c]quinoxaline-3,10-dithione (4).
A solution of thiophosgene (0.206 g, 1.79 mmoles) in benzene
(1.65 ml) was added dropwise during an 1.5 h period to a
solution of compound 1 (0.172 g, 0.89 mmole) and dry
triethylamine (0.5 ml) in dioxane (20 ml) under stirring at rt. The
reaction mixture was stirred for further 16 h. The precipitated
triethylamine hydrochloride was filtered, the solvent was
removed in a rotary evaporator and the residue was
chromatographed (silica gel, hexane/ethyl acetate 9:1) to give
EXPERIMENTAL
light yellow crystals of compound 4 (75 mg, 31%), m.p. 223-
1
225°C (d); ir: 3040, 1605, 1580 cm-1; H-nmr: ꢁ 7.58-7.63 (m);
Melting points are uncorrected and were measured on a
Kofler hot-stage apparatus. IR spectra were obtained with a
13C-nmr: ꢁ 116.3, 117.1, 152.1, 156.6, 161.3; ms (EI): m/z 276
(M+., 100%), 216 (8), 188 (90), 156 (8), 136 (16), 104 (62).
Scheme 4
O
O
CO2Et
H
NOH
N
N
NOCO2Et
N
X
N
ClCO2Et
+
Et3N, Acetone
X
S
O
O
O
14: X=NH
15: X=S
9,13
16

582
K. C. Fylaktakidou, K. E. Litinas, A. Saragliadis, S. G. Adamopoulos and D. N. Nicolaides
Vol 43
Anal. Calcd for C10H4N4O2S2: C, 43.44; H, 1.56; N, 20.28.
Found: C, 43.78; H, 1.70; N, 20.30.
Compound 3 (28 mg, 18%) was eluted next.
ml) was added dropwise, during 20 min, at rt under stirring.
After storage at rt the precipitate was collected by filtration and
washed with water to give white crystals of compound 13 (0.84
g, 84%), m.p. 264-266°C (d); ir: 3230, 3150, 3030, 1680, 1625,
1ꢀ4,6ꢀ4-Di[1,2,3,5]oxathiadiazolo[3,4-a:4,3-c]quinoxaline-1,6-
dione (5).
1
1580 cm-1; H-nmr (CDCl3-DMSO-d6): ꢁ 7.02 (t, J=8.2, 1H),
7.11-7.21 (m, 2H), 7.26 (d, J=8.2, 1H), 10.48 (s, 1H), 12.92 (s,
1H); 13C-nmr(CDCl3-DMSO-d6): ꢁ 114.7, 117.0, 122.6, 125.1,
126.3, 132.8, 139.1, 152.9; ms (EI): m/z 194 (M+., 50%), 177
(17), 165 (56), 164 (56), 151 (83), 150 (42), 136 (88), 124 (100),
109 (99).
A solution of thionylchloride (0.264 g, 2.21 mmoles) in dry
THF (15 ml) was added dropwise during 3 h at rt under stirring
to a solution of compound 1 (0.192 g, 1 mmole) and dry
pyridine (0.312 g, 3.95 mmoles) in dry THF (20 ml). The
reaction mixture was stirred for further 24 h and then was
filtered. The solvent was evaporated in a rotary evaporator and
the residue was subjected to column chromatography to give
orange crystals of compound 5 (96 mg, 34%), m.p. 186-188°C
Anal. Calcd for C8H6N2O2S: C, 49.37; H, 3.33; N, 14.40.
Found: C, 49.65; H, 3.58; N, 14.16.
[1,2,4]Oxadiazolo[4,3-a]quinoxaline-1,4(5H)-dione (14).
1
(d); ir: 3060, 1635, 1605, 1500 cm-1; H-nmr: ꢁ 7.74-7.85 (m,
Ethyl chloroformate (0.216 g, 2 mmoles) was added dropwise
to a mixture of compound 9 (0.117 g, 1 mmole) and
triethylamine (0.1 ml) in acetone (2.5 ml), at rt under stirring.
The reaction mixture was left under stirring for further 12 h. The
precipitated triethylamine hydrochloride was filtered off and the
filtrate was concentrated in a rotary evaporator. The oily residue
was treated with dichloromethane to give brown crystals of
compound 14 (0.124 g, 70%), m.p. 268-270°C(d); ir: 3370,
1H), 7.95-8.04 (m, 1H); 13C-nmr: ꢁ 116.6, 130.8, 135.0, 156.1 ;
ms (EI): m/z 284 (M+., 100%), 258 (6), 232 (50), 174 (14), 173
(92), 172 (74), 143 (80), 142 (83), 115 (25).
Anal. Calcd for C8H4N4O4S2: C, 33.77; H, 1.52; N, 19.71.
Found: C, 33.87; H, 1.53; N, 19.83.
1,4-Dihydro-2,3-quinoxalinedione 2-oxime (9).
1
3090, 1775, 1660, 1605, 1500 cm-1; H-nmr (CDCl3-DMSO-d6):
A solution of triethylamine (1.335 g, 13.2 mmoles) in
chloroform (20 ml) was added to a solution of imidochloride 7
(2 g, 13.2 mmoles) and o-phenylenediamine 8 (1.427 g, 13.2
mmoles) in chloroform (120 ml) dropwise during 30 min under
stirring at rt. After storage at room temperature, the precipitate
was collected by filtration and washed with water to give yellow
crystals of compound 9 (1.74 g, 87%), m.p. >300°C (from
methanol/THF); ir: 3380, 3125, 3070, 1680, 1640, 1600, 1520
ꢁ 7.24-7.41 (m, 3H), 8.39 (d, J=7.9, 1H), 12.25 (s, 1H,
exchanged by D2O); 13C-nmr(CDCl3-DMSO-d6): ꢁ 114.3, 116.5,
123.7, 126.9, 132.8, 132.9, 149.2, 156.5, 160.1; ms (EI): m/z
203 (M+., 34%), 160 (31), 159 (28), 132 (32), 131 (30), 105 (86),
90 (32), 44 (100).
Anal. Calcd. for C9H5N3O3: C, 53.19; H, 2.48; N, 20.69.
Found: C, 53.07; H, 2.29; N, 20.84.
1
cm-1; H-nmr (CDCl3-DMSO-d6): ꢁ 6.81 (t, J=7.3, 1H), 6.90 (t,
4H-[1,2,4]Oxadiazolo[3,4-c][1,4]benzothiazine-1,4-dione 15 and
Ethyl 3-{[(ethoxycarbonyl)oxy]imino}-2-oxo-2H-1,4-benzo-
thiazine-4-carboxylate 16.
J=7.3, 1H), 6.94 (d, J=7.3 Hz, 1H), 7.26 (d, J=7.3, 1H), 9.87 (s,
1H), 10.75 (s, 1H), 11.18 (s, 1H); 13C-nmr(CDCl3-DMSO-d6): ꢁ
113.9, 114.7, 120.2, 122.7, 124.3, 126.8, 140.1, 154.4; ms (EI):
m/z 177 (M+., 53%), 161 (100), 147 (59), 133 (52), 119 (47),
105 (56), 104 (37), 90 (32).
To a solution of compound 13 (0.194 g, 1.0 mmole) and
triethylamine (0.1 ml) in acetone (2.5 ml) ethyl chloroformate
(0.216 g, 2 mmoles) was added dropwise, at r.t. under stirring.
The reaction mixture was stirred at r.t. for further 12 h and the
precipitated triethylamine hydrochloride was then filtered off.
The filtrate was concentrated in a rotary evaporator and the oily
residue was triturated with methylene chloride to give at first
compound 15 (11 mg, 6%), m.p. 233-235°C (dec.); ir: 1767,
Anal. Calcd for C8H7N3O2: C, 54.22; H, 3.98; N, 23.73.
Found: C, 54.16; H, 4.27; N, 23.58.
2H-[1,4]Benzoxazine-2,3(4H)-dione 3-oxime (11).
To a solution of compound 7 (2 g, 13.2 mmoles) and o-
aminophenol 10 (1.44 g, 13.2 mmoles) in dry ether (110 ml) a
solution of dry triethylamine (1.335 g, 1.32 mmoles) in ether (20
ml) was added dropwise, during 30 min, at rt, under stirring.
After storage at rt the precipitate was collected by filtration and
was washed with water to give light brown crystals of
compound 11 (1.66 g, 83%), m.p. 288-290°C (d)
(ether/methanol); ir: 3330, 3160, 3050, 1740, 1620, 1585, 1490
1
1672, 1585, 1515 cm-1; H-nmr (CDCl3): ꢁ 7.11-7.36(m, 4H);
13C-nmr(CDCl3): ꢁ 118.0, 120.4, 124.3, 125.4, 128.0, 131.8,
137.2, 151.6, 158.2; ms (EI): m/z 220 (M+., 14%), 176 (100),
150 (52), 148 (38), 121 (29), 90 (30).
Anal. Calcd for C9H4N2O3S: C, 49.03; H, 1.96; N, 12.71.
Found: C, 48.74; H, 2.29; N, 12.44.
Compound 16 was crystalised next (314 mg, 93%), m.p. 101-
1
cm-1; H-nmr (CDCl3-DMSO-d6): ꢁ 6.89 (t, J=6.9, 1H), 7.0-7.1
(m, 2H), 7.29 (d, J=6.9, 1H), 10.02 (s, 1H, exchanged by D2O),
11.39 (s, 1H, exchanged by D2O); 13C-nmr(CDCl3-DMSO-d6): ꢁ
114.5, 115.6, 120.4, 124.6, 125.6, 136.3, 138.7, 153.2; ms (EI):
m/z 178 (M+., 42%), 161 (67), 147 (14), 134 (100), 119 (15),
105 (96), 104 (99), 91 (30).
1
103°C; ir: 1755, 1725, 1670, 1620, 1515 cm-1; H-nmr (CDCl3):
ꢁ 1.40 (t, 3H, J=6.9 Hz), 1.41 (t, 3H, J=6.9 Hz), 4.38 (q, 4H,
J=6.9 Hz), 7.35-7.45 (m, 3H), 7.61-7.68 (m, 1H); 13C-nmr
(CDCl3): ꢁ 14.0, 14.2, 65.7, 65.9, 122.9, 124.9, 128.0, 129.3,
131.6, 135.8, 143.7, 151.1, 174.8, 183.3. HRMS (ESI): m/z for
[M+Na]+ C14H14N2NaO6S: 361.04666. Calcd: 361.04648.
Anal. Calcd for C8H6N2O3: C, 53.79; H, 3.62; N, 15.69.
Found: C, 54.05; H, 3.49; N, 15.76.
2H-[1,4]Benzothiazine-2,3(4H)-dione 3-oxime (13).
REFERENCES AND NOTES
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aminothiophenol 12 (0.826 g, 6.59 mmoles) in dry ether (50 ml)
a solution of triethylamine (0.667 g, 6.5 mmoles) in ether (10
#
Preliminary communication presented at 16th Panhellenic
Chemical Conference, Athens, Greece, December 1995, Abstrs. Vol. A, p. 87.

May-Jun 2006 Oxadiazoloquinoxaline, Oxathiadiazoloquinoxaline and Oxadiazolobenzothiazine Derivatives
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