Cyclocondensation reaction of heterocyclic carbonyl compounds [1]. The direction of competitive cyclocondensation between carbonyl groups of 6-azauracile and 1,2-dihydro-quinoxalin-2-one cycles

Article abstract of DOI:10.1002/jhet.5570410419

In the article the study of cyclocondensation of 3-[2-arnino-3-(3,5-dioxo- 2,3,4,5-tetrahydro[1,2,4]-triazine-6-yl)phenyl]-2,3-dihydro-quinoxalin-2-one 5 is described and it was found, that the reaction does not proceed by both possible directions, but only cyclization with the carbonyl group of 6-azauracile cycle proceeds. The 6-(3-oxo-3,4-dihydro-quinoxaline-2-yl)-4H-2,3- dihydro[1,2,4]triazino[5,6-b]indol-3-one 6 was formed in this way. This course of cyclocondensation was confirmed by the fact, that the product 6, mentioned above, is quite different from isomeric compound 7, prepared unambiguously by condensation of 7-(6-azauracile-5-yl)isatine 8 with o-phenylenediamine.

Full text of DOI:10.1002/jhet.5570410419

Jul-Aug 2004
597
Cyclocondensation Reaction of Heterocyclic Carbonyl Compounds
[1]. The Direction of Competitive Cyclocondensation
Between Carbonyl Groups of 6-Azauracile and
1,2-Dihydro-quinoxalin-2-one Cycles.
Roman Buchtíka, Jan Hlavácˇ *a, Jan Sloukaa and Petr Frycˇákb
a
Department of Organic Chemistry, Palacky University, Trˇ. Svobody 8, 771 46 Olomouc, Czech Republic,
Fax: ++420-58-5634405, E-mail: hlavac@prfnw.upol.cz
b
Department of Analytical Chemistry, Palacky University, Trˇ. Svobody 8, 771 46 Olomouc, Czech Republic
Received December 29, 2003
In the article the study of cyclocondensation of 3-[2-amino-3-(3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]-
triazine-6-yl)phenyl]-2,3-dihydro-quinoxalin-2-one 5 is described and it was found, that the reaction does
not proceed by both possible directions, but only cyclization with the carbonyl group of 6-azauracile cycle
proceeds. The 6-(3-oxo-3,4-dihydro-quinoxaline-2-yl)-4H-2,3-dihydro[1,2,4]triazino[5,6-b]indol-3-one 6
was formed in this way. This course of cyclocondensation was confirmed by the fact, that the product 6,
mentioned above, is quite different from isomeric compound 7, prepared unambiguously by condensation of
7-(6-azauracile-5-yl)isatine 8 with o-phenylenediamine.
J. Heterocyclic Chem., 41, 597 (2004).
Introduction.
thio-6-azauracile-cycle than with that of the carbonyl
group of 6-azauracile-cycle has been described earlier [2].
During our study of heterocyclic carbonyl group reactivity,
we became very interested in comparison of the carbonyl
group reactivity in the 6-azauracile-cycle with that of the
heterocyclic carbonyl group in ring systems other than
[1,2,4] triazine compounds.
Thus we focused on the study of cyclocondensation of
3-[2-amino-3-(3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-
6-yl)phenyl]-2,3-dihydro-quinoxalin-2-one 5, in which the
amino group is between 6-azauracile and 1,2-dihydro-
quinoxalin-2-one cycle.
Cyclocondensation reactions of amino group with hete-
rocyclic carbonyl are the subject of our study because of
the possibility of their use for preparation of various hete-
rocycles. When only one heterocyclic carbonyl group is
able to undergo to cyclocondensation, the product of this
reaction can be easily predicted, but there is an interesting
question of the direction of the cyclocondensation, if the
amino group is able to condense with carbonyl groups
belonging to two different heterocycles. For example an
amino group affinity of about three times greater for the
cyclocondensation reaction with the carbonyl group of 2-
Figure 1.

598
R. Buchtík, J. Hlavácˇ, J. Slouka and P. Frycˇák
Vol. 41
Results and Discussions.
condensation of intermediate 5 (Figure 3), we subjected
the derivative 5 to cyclization under the same reaction con-
ditions and no reaction was found. It means that reaction
of isatine 8 with o-phenylendiamine in solution of DMF
unambiguously afforded product 7. The different product
of cyclocondensation of compound 5 in acetic acid then
possesses the structure 6 (Figure 3).
The starting material for preparation of this compound
was 3-(2-aminophenyl)-1,2-dihydro-quinoxalin-2-one 1 [3],
which was converted to the corresponding isonitrosoac-
etanilide 2 by Sandmeyer method. A cyclization of the com-
pound 2 in sulfuric acid afforded 3-(isatine-7-yl)-1,2-dihy-
dro-quinoxalin-2-one 3. The reaction of the isatine 3 with
semicarbazide in acetic acid afforded the corresponding
semicarbazone 4. Compound 4 was recyclized to the 2,6-
disubstituted aniline 5 by boiling in alkaline medium.
The cyclocondensation was carried out in boiling acetic
acid. Surprisingly we isolated only one product of this
reaction, purity of which was declared by NMR and HPLC
methods, which means that the cyclization proceeds only
one way. Because of theoretically higher sensitivity of car-
bonyl group in position 5 of the triazine ring in comparison
with the carbonyl in the quinoxaline skeleton, it was possi-
ble to assume formation of product 6 (Figure 2).
Figure 3
Figure 2
All the prepared compounds are practically insoluble in
water and only partially soluble in most organic solvents.
They are soluble in hot acetic acid and N,N-dimethylfor-
mamide. These properties aggravated their characteriza-
tion and study in solution with use of IR and NMR
spectroscopy.
Due to low solubility of the product it was very difficult
to recognize, with use of spectral methods, if the product
of cyclocondensation is really 6-(3-oxo-3,4-dihydro-
quinoxalin-2-yl)-4H-2, 3-dihydro[1, 2, 4]triazino[5. 6-b]-
indol-3-one 6 or an isomeric 4-(3,5-dioxo-2,3,4,5-tetrahy-
dro[1, 2, 4]triazin-6-yl)-5 H-indolo[2.3-b]quinoxaline 7
(Figure 3).
Therefore we decided to determine its structure by com-
parison with product of the condensation of 7-(6-azau-
racil-5-yl)isatine 8 [4] with o-phenylenediamine. The
product obtained from this reaction is an isomer with the
same elemental analyses and molecular weight but differ-
ent MS fragmentation, retention time in HPLC analyses,
NMR and IR spectra. Because the product could have been
6 or 7 derivative as well, if the reaction had occurred
through the opening of the pyrrole ring (known from reac-
tion of isatines and amines [5,6]) with following cyclo-
EXPERIMENTAL
Melting points were determined on a Boetius stage. Infrared
spectra (KBr disks) were taken with an ATI Unicam Genesis
FTIR instrument. NMR spectra of solutions in DMSO-d (TMS
6
as internal standard) were measured on a Bruker Avance 300
spectrometer (300 MHz). Mass spectrometric experiments were
performed using an LCQ ion trap mass spectrometer (Finnigan
MAT, San Jose, CA, USA). Elemental analyses were obtained
with an EA 1108 Elemental Analyzer (Fison Instrument). The
purity of compounds was confirmed by HPLC analyzer
Beckmann System Gold (USA) with Merck Lichrospher RP-
select B 250x3 mm, 5µm column on reversed phase C-18, gradi-
ent H O/methanol.
2

Jul-Aug 2004
Cyclocondensation Reaction of Heterocyclic Carbonyl Compounds
599
3-[2-(2-Oximinoacetylamino)phenyl]-1,2-dihydro-quinoxalin-2-
one (2).
11.96 (s, 1H, NH), 12.35 (s, 1H, NH), 12.50 (s, 1H, NH); ms: m/z
+
349 [M+H] .
Anal. Calcd. for C H N O (348.32): C, 58.62; H, 3.47; N,
17 12
6 3
24.13. Found: C, 59.01; H, 3.42; N, 24.22.
To the solution of 3-(2-aminophenyl)-1,2-dihydro-quinoxalin-
2-one (1) [3] (15.00 g, 63 mmoles) in a boiling mixture of water
(2400 ml) and 37% HCl (45 ml) was added chloralhydrate (12.00
g, 72,6 mmoles) in water (20 ml). After 1 minute a solution of
hydroxylamine hydrochloride (16.20 g, 234.8 mmoles) in water
(20 ml) was added and the reaction mixture was refluxed for 25
minutes. The next day the solid was collected by filtration,
washed with water and dried to yield 13.40 g (69%), mp 260-
6 - ( 3 - O x o - 3 , 4 - d i h y d r o - q u i n o x a l i n - 2 - y l ) - 4 H- 2 , 3 - d i h y d r o -
[1,2,4]triazino[5,6-b]indol-3-one (6).
Compound (5) (100.0 mg, 0.29 mmoles) was refluxed in acetic
acid (15 ml) for 5 hours. Then the solvent was evaporated with
heating to one third of volume and cooled. The yellow crystalline
solid was collected by filtration, washed with water and dried to
yield 80.0 mg (95%), mp >360°; ir: NH 3285, Ar-H 3007, CO
-1 1
262°; ir: NH 3282, Ar-H 3003, CO 1669 cm ; H nmr: δ 7.26 (t,
1H, Ar-H, J= 7.5 Hz), 7.38 (m, 2H, Ar-H), 7.55 (m, 3H, Ar-H, C-
H), 7.91 (d, 1H, Ar-H, J= 7 Hz), 8.14 (m, 2H, Ar-H), 11.29 (s,
1H, NH), 12.29 (s, 1H, NH), 12.68 (b, 1H, =NOH); ms: m/z 309
-1 1
1686, 1658 cm ; H nmr: δ 7.37 (m, 3H, Ar-H), 7.60 (t, 1H, Ar-
H, J= 7 Hz), 8.00 (m, 2H, Ar-H), 8.18 (d, 1H, Ar-H, J= 7 Hz),
11.85 (b, 1H, NH), 12.70 (b, 1H, NH), 13.05 (b, 1H, NH); ms:
+
[M+H] .
+
m/z 331 [M+H] . Fragments obtained by collision-induced dis-
Anal. Calcd. for C H N O (308.30): C, 62.34; H, 3.92; N,
16 12 4 3
18.17. Found: C, 61.94; H, 3.88; N, 17.77.
sociation of the quasimolecular ions had massed: 313 (11), 303
(100), 286 (25), 275 (56), 260 (12), 248 (51), 245(26).
Anal. Calcd. for C H N O (330.31): C, 61.82; H, 3.05; N,
3-(2,3-Dioxo-2,3-dihydro-indole-7-yl)-2,3-dihydro-quinoxalin-
2-one (3).
17 10 6 2
25.44. Found: C, 61.65; H, 3.01; N, 24.98.
Compound (2) (13.39 g, 43.4 mmoles) was added to 89% sul-
furic acid (145 ml). The mixture was stirred at 55-60° for 7 hours.
Then the mixture was poured onto crushed ice. The next day, the
resulting solid was collected by filtration, properly washed with
water and dried at 150° to yield 7.00 g (55%). Recrystallization
from N,N-dimethylformamide afforded orange crystals, mp
>360°; ir: NH 3320, CO 1743, 1656 cm ; H nmr: δ 7.20 (t, 1H,
Ar-H, J= 7.5 Hz), 7.38 (m, 2H, Ar-H), 7.63 (m, 2H, Ar-H), 7.93
(d, 1H, Ar-H, J= 7.5 Hz), 8.18 (d, 1H, Ar-H, J= 7.5 Hz), 10.89 (b,
4 - ( 3 , 5 - D i o x o - 2 , 3 , 4 , 5 - t e t r a h y d r o [ 1 , 2 , 4 ] t r i a z i n - 6 - y l ) - 5 H-
indolo[2,3-b]quinoxaline (7).
To the mixture of compound (8) (200.0 mg, 0.78 mmoles) [4]
in N,N-dimethylformamide (10 ml) o-phenylendiamine (84.0 mg,
0.78 mmoles) was added and the reaction mixture was refluxed
for 30 minutes. After cooling, the yellow crystalline solid was
collected by filtration, washed with ethanol, water and dried to
yield 150.0 mg (58.5%), mp >360°; ir: NH 3296, 2982, CO 1716,
-1 1
-1
1684 cm ; 1H nmr: δ 7.45 (t, 1H, Ar-H, J= 8 Hz), 7.79 (m, 2H,
+
1H, NH), 12.58 (b, 1H, NH); ms: m/z 292 [M+H] .
Anal. Calcd. for C H N O (291.27): C, 65.98; H, 3.11; N,
Ar-H), 7.94 (d, 1H, Ar-H, J= 7 Hz), 8.10 (d, 1H, Ar-H, J= 7 Hz),
8.29 (d, 1H, Ar-H, J= 8 Hz), 8.45 (d, 1H, Ar-H, J= 7 Hz), 11.85
(s, 1H, NH), 12.27 (b, 1H, NH), 12,49 (b, 1H, NH); ms: m/z
16
14.43. Found: C, 65.70; H, 2.98; N, 13.97.
9 3 3
+
3-(2-Oxo-3-carbamoylhydrazono-2,3-dihydro-indol-7-yl)-2,3-
dihydro-quinoxaline-2-one (4).
331[M+H] . Fragments obtained by collision-induced dissocia-
tion of the quasimolecular ions had masses: 303 (2), 292 (3), 260
(100), 245 (3), 232(10).
Anal. Calcd. for C H N O (330.31): C, 61.82; H, 3.05; N,
To the boiling solution of compound (3) (500.0 mg, 1.7
mmoles) in acetic acid
17 10
6 2
25.44. Found: C, 61.75; H, 3.04; N, 25.05.
(300 ml) semicarbazide hydrochloride (300.0 mg, 2.7 mmoles)
was added. The reaction mixture was refluxed for 5 hours. Then
the solvent was evaporated to dryness, the solid was then mixed
with water (100 ml), collected by filtration and dried to yield
320.0 mg (53.5%), mp >360°; ir: NH 3497, 3230, Ar-H 3009, CO
Acknowledgements.
Financial support for this work by the Ministry of Education,
Youth and Sport of Czech Republic, grant No 15 31 0008 and 15
31 00013, is gratefully acknowledged.
-1 1
1740, 1698, 1664 cm ; H nmr: δ 7.20 (m, 3H, Ar-H, NH ), 7.35
2
(m, 2H, Ar-H), 7.57 (t, 1H, Ar-H, J= 7.7 Hz), 7.76 (d, 1H, Ar-H,
J= 7.5), 7.95 (m, 2H, Ar-H), 10.91 (b, 1H, NH), 11.75 (b, 1H,
REFERENCES AND NOTES
+
NH), 12.54 (b, 1H, NH). ms: m/z 349 [M+H] .
Anal. Calcd. for C H N O (348.32): C, 58.62; H, 3.47; N,
17 12
24.13. Found: C, 57.98; H, 3.40; N, 23.89.
6 3
[1] Part 10 in this series. For the previous paper see: P. Bílek
and J. Slouka, Heterocycl. Commun. 10, 67 (2004)
[2] J. Hlavácˇ, J. Slouka, P. Hradil and K. Lemr, J. Heterocyclic
Chem. 37, 115 (2000).
3-[2-Amino-3-(3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-
yl)phenyl]-2,3-dihydro-quinoxalin-2-one (5).
[3] E. Schunck and L. Marchlewski, Ber. Dtsch. Chem. Ges.
29, 194 (1896); I. Wiedermannová, J. Slouka and J. Hlavácˇ, Acta
Univ. Palacki. Olomouc., Fac. Rerum Nat., Chemica 39, 69 (2000);
Chem. Abstr. 136, 134 733b (2002).
[4] J. Hlavácˇ and J. Slouka, J. Heterocyclic Chem. 3 4, 917
(1997).
[5] J. Bergman, C. Staalhandske and H. Vallberg, Acta
Chemica Scandinavica 51(6/7), 753 (1997).
[6] A. A. Samarkandy, S. Al-Thabaiti, E. A. Hamed and I. M.
Sidahmed, Alexandria Journal of Pharmaceutical Sciences, 10, 161
(1996).
Compound (4) (100.0 mg, 0.29 mmoles) was refluxed in 10%
solution of sodium bicarbonate (20 ml) for 4.5 hours. After cool-
ing, the mixture was filtered then acidified with acetic acid. The
resulting powder was collected by filtration after several hours,
washed with water and dried at 100° to yield 83.0 mg (83%).
Recrystallization from cellosolve afforded yellow crystals, mp
-
>360°; ir: NH 3382, 3251, Ar-H 3041, CO 1730, 1705, 1648 cm
1 1
; H nmr: δ 6.32 (s, 2H, NH ), 6.65 (t, 1H, Ar-H, J= 8 Hz), 7.23
2
(d, 1H, Ar-H, J= 6 Hz), 7.32 (m, 2H, Ar-H), 7.53 (t, 1H, Ar-H, J=
8 Hz), 7.78 (d, 1H, Ar-H, J= 8 Hz), 7.95 (d, 1H, Ar-H, J= 6 Hz),