Synthesis of spirohydantoins and schiff bases of indenoquinoxalinones and indenopyridopyrazinones

Article abstract of DOI:10.14233/ajchem.2020.22679

The main structure of many compounds containing spirohydantoin and Schiff bases of indenoquinoxalines and indenopyridopyrazinones expose valuable pharmacological properties. Herein, an effective synthesis and stereochemistry of indenoquinoxalinones (2a, 2

Full text of DOI:10.14233/ajchem.2020.22679

Asian Journal of Chemistry; Vol. 32, No. 8 (2020), 1925-1930
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22679
Synthesis of Spirohydantoins and Schiff Bases of
Indenoquinoxalinones and Indenopyridopyrazinones
1,*,
1,
1,
1,
2,*
J.H. SONG
, S.M. BAE , H.Y. SHIN , D.I. JUNG and J.H. CHO
1Department of Chemistry, Dong-A University, Busan 604-714, Republic of Korea
2Department of Medical Biotechnology, Dong-A University, Busan 604-714, Republic of Korea
*Corresponding authors: E-mail: jhsong@dau.ac.kr, jhcho@dau.ac.kr
Received: 16 February 2020;
Accepted: 28 April 2020;
Published online: 27 July 2020;
AJC-19969
The main structure of many compounds containing spirohydantoin and Schiff bases of indenoquinoxalines and indenopyridopyrazinones
expose valuable pharmacological properties. Herein, an effective synthesis and stereochemistry of indenoquinoxalinones (2a, 2b+bi~2d+di)
and indenopyridopyrazinones (2e+ei~g+gi) via the reaction of ninhydrin with desirable diamines is reported. We synthesized the corres-
ponding spirohydantoins (3a, 3b~d and 3bi~di) from synthesized indeno[1,2-b]quinoxalinones and indeno[1,2-b]pyrido[3,2-e]pyrazinones
with the standard Bucherer-Bergs conditions (KCN, ammonium carbonate, acetonitrile, refluxing, without NaHSO3).And also synthesized
the azomethine analogs (4~8+8i) of tetracyclic indeno[1,2-b]quinoxalinones as a Schiff base.
Keywords: Spirohydantoin, Indenoquinoxalinones, Indenopyridopyrazinones, Ninhydrin, Diamine.
group of spiroindenoquinoxalines with bicyclic group spiro-
attachted to hydantoin ring, herein the synthesis, stereochemistry
and biological evaluation of new spiroindenoquinoxalines
derivatives as potential pharmacological agents. Pharmacol-
ogically hydantoin and spirohydantoin derivatives possess a
range of biochemical and pharmacological properties and subse-
quently are used to treat many human diseases as anticonvulsants
in the treatment of seizure disorders, a muscle relaxant to treat
neuroleptic malignant syndrome, malignant hyperthermia,
ecstasy intoxication and spasticity [18,19]. But, there are only
few studies concentrating on their potential as cancer thera-
peutic agents. In present work, develop a special and resource-
ful process for the combinatorial synthesis of a spiro-substituted
indenoquinoxalines library for biological screening.
INTRODUCTION
Much attention during the past few years has been focused
to a large range of nitrogen-containing heterocyclics and hetero-
cyclic indenoquinoxalines because of their pharmacological
properties and clinical applications [1-7]. Indenoquinoxalines
as a significant group of aza-polycyclics are important classes
of N-heterocycles since are useful intermediates for spiro-
indeno synthesis. The main structure of many spiro compounds
containing spiroindenoquinoxalines expose valuable pharma-
cological properties such as anticancer, antitumor agents and
antibacterial treatments, antimicrobial action of particular
interest [8,9]. Especially spiro-N-heterocycles are also of notice-
able interest because of the presence of a spirocarbon supplies
a fortifying of the structural frame and together with a varity of
hydantoins and spirohydantoins are the main significant core
of many pharmacological agents [10,11].
EXPERIMENTAL
Except where explicitly stated, all chemicals were purchased
from Aldrich, Fisher and TCI, and used as received. Melting
points were established using an electrothermal capillary melting
point equipment and are uncorrected. 1H & 13C NMR spectra
were analyzed with Bruker AC 2000 (200 MHz) and Varian
Gemini (200 or 300 MHz) spectrometers. Mass spectra were
calculated with HP 5890 GC/Mass (70 eV, EI).
Existing spirohydantoin and indenoquinoxaline moieties
in structure of one spiro compound can be attractive to organic
and bioorganic scientists due to the integration of more than
one N-heterocyclic scaffold in structure of molecule causes
interesting bioorganic and biological properties [12-18]. As
away of our efforts to discover and develop novel studies on a
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1926 Song et al.
Asian J. Chem.
Indeno[1,2-b]pyrido[3,2-e]pyrazine-6-one: Ninhydrin
400 MHz): δ 8.60 (d, 1H), 8.33 (d, 1H), 8.26 (m, 1H), 8.17 (dd,
2H), 7.96 (m, 1H), 7.88 (m, 2H), 7.83 (m, 1H), 7.68 (m, 1H),
7.54 (m, 1H), 7.26 (m, 1H); 13C-NMR (DMSO-d6, 100 MHz):
δ195.01, 189.21, 159.46, 151.58, 144.52, 141.45, 141.11, 138.31,
137.55, 136.88, 133.83, 133.68, 133.26, 132.20, 130.28, 129.23,
124.81, 123.19. Elemental analysis calcd. (found) %: C, 78.55
(78.54); H, 3.66 (3.69); N, 8.33 (8.31); O, 9.51 (9.51).
8-Benzoyl-11H-indeno[1,2-b]quinoxalin-11-one (2di):
Yield: 95.7%; m.p.: 96-97 ºC; Rf: 0.81 (TLC eluent; n-hexane
:ethyl acetate = 1:1, v/v). Mass (70 eV), m/z (rel. int. %): 338.10
(2.7), 337.09 (23.8), 336.09 (100); 1H-NMR (DMSO-d6, 400
MHz): δ 8.61 (d, 1H), 8.33 (d, 1H), 8.26 (m, 1H), 8.17 (dd, 2H),
7.96 (m, 1H), 7.88 (m, 2H), 7.83 (m, 1H), 7.66 (m, 1H), 7.54
(m, 1H), 7.26 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): δ 195.01,
189.22, 158.48, 151.59, 144.52, 141.45, 141.11, 138.31, 137.55,
136.88, 133.83, 133.68, 133.26, 132.20, 130.28, 129.22, 124.81,
123.19. Elemental analysis calcd. (found) %: C, 78.56 (78.54);
H, 3.66 (3.69); N, 8.33 (8.31); O, 9.51 (9.51).
6H-Indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one (2e):
Yield: 97.7%; m.p.: 96-97 ºC; Rf: 0.81 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
234.06 (1.1), 234.06 (15.1), 233.06 (100); 1H NMR (DMSO-
d6, 400 MHz): δ 9.15 (d, 1H), 8.62 (d, 1H), 8.17 (m, 1H), 7.91
(dd, 2H), 7.76 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): δ
189.91, 159.97, 155.68, 151.48, 151.33, 141.11, 140.24, 137.57,
133.85, 126.11, 124.77, 123.36. Elemental analysis calcd.
(found) %: C, 72.10 (72.14); H, 3.03 (3.01); N, 18.02 (18.02);
O, 6.86 (6.87).
(0.06 mol) and phenylenediamine (0.06 mol) were dissolved
in MeOH (15 mL). The reaction mixture was allowed to mix
at room temperature and observed by TLC to the point of comp-
letion. After mixing for 24 h, the reaction was poured into 15
mL of ice-water and the solid material was gathered. This
material was then dissolved in CH2Cl2. The remaining residual
water in the organic layer was separated from and dried over
MgSO4. Products were purified by column chromatography
to afford the following compounds 2a-2gi.
11H-Indeno[1,2-b]quinoxalin-11-one (2a):Yield: 93.2%;
m.p.: 151-153 ºC; Rf: 0.82 (TLC eluent; ethyl acetate:n-hexane
= 1:1, v/v). Mass (70 eV), m/z (rel. int. %): 234.07 (1.2), 233.07
(16.2), 232.06 (100); 1H-NMR (CDCl3, 400 MHz): δ 8.22 (d,
1H), 8.08 (dd, 2H), 7.91 (d, 1H), 7.76 (dd, 3H), 7.59 (d, 1H);
13C NMR (CDCl3, 100 MHz): δ 189.41, 156.58, 149.94, 142.26,
141.96, 141.08, 137.06, 136.76, 132.88, 132.55, 131.07, 130.47,
129.49, 124.33, 122.39. Elemental analysis calcd. (found) %:
C, 77.58 (77.58); H, 3.47 (3.47); N, 12.06 (12.06); O, 6.89 (6.89).
7-Methyl-11H-indeno[1,2-b]quinoxalin-11-one (2b):
Yield: 90.4%; m.p.: 113-115 ºC; Rf: 0.79 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
248.09 (1.4), 247.08 (17.3), 246.08 (100); 1H-NMR (CDCl3,
400 MHz): δ 8.05 (d, 2H), 7.94 (d, 1H), 7.86 (m, 2H), 7.70
(dd, 2H), 2.58 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 189.39,
156.59, 148.87, 143.25, 142.22, 140.27, 136.83, 132.64,
132.34, 130.52, 129.87, 126.90, 126.45, 124.14, 122.15, 21.41.
Elemental analysis calcd. (found) %: C, 78.02 (78.03); H, 4.05
(4.09); N, 11.39 (11.38); O, 6.51 (6.50).
10H-Indeno[1,2-b]pyrido[2,3-e]pyrazin-10-one (2ei):
Yield: 97.7%; m.p.: 96-97 ºC; Rf: 0.81 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
236.07 (1.1), 236.08 (15.1), 235.07 (100); 1H NMR (DMSO-
d6, 400 MHz): δ 9.15 (d, 1H), 8.62 (d, 1H), 8.17 (m, 1H), 7.92
(dd, 2H), 7.76 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): δ189.91,
159.97, 155.68, 151.48, 151.33, 141.11, 140.24, 137.57, 133.85,
126.11, 124.77, 123.36. Elemental analysis calcd. (found) %:
C, 72.10 (72.14); H, 3.03 (3.01); N, 18.02 (18.02); O, 6.86 (6.87).
6H-Indeno[1,2-b]pyrido[4,3-e]pyrazin-6-one (2f):
Yield: 91.35%; m.p.: 246-247ºC; Rf: 0.77 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. Int. %):
234.06 (1.1), 234.06 (15.1), 233.06 (100); 1H NMR (DMSO-
d6, 400 MHz): δ 8.60 (d, 1H), 8.33 (d, 2H), 8.26 (m, 1H), 8.17
(dd, 2H), 7.88 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): δ189.33,
157.80, 150.74, 143.05, 141.03, 140.98, 137.46, 133.61, 132.98,
131.18, 128.18, 124.74, 122.98. Elemental analysis calcd.
(found) %: C, 72.10 (72.10); H, 3.03 (3.06); N, 18.02 (18.04);
O, 6.86 (6.87).
10H-Indeno[1,2-b]pyrido[3,4-e]pyrazin-10-one (2fi):
Yield: 91.35%; m.p.: 246-247 ºC; Rf: 0.77 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. Int. %):
234.06 (1.1), 234.06 (15.1), 233.06 (100); 1H NMR (DMSO-
d6, 400 MHz): δ 8.60 (d, 1H), 8.33 (d, 2H), 8.26 (m, 1H), 8.17
(dd, 2H), 7.88 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): δ
189.33, 157.80, 150.74, 143.05, 141.03, 140.98, 137.46, 133.61,
132.98, 131.18, 128.18, 124.74, 122.98. Elemental analysis
calcd. (found) %: C, 72.10 (72.10); H, 3.03 (3.06); N, 18.02
(18.04); O, 6.86 (6.87).
8-Methyl-11H-indeno[1,2-b]quinoxalin-11-one (2bi):
Yield: 90.4%; m.p.: 106-107 ºC; Rf: 0.79 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
248.09 (1.4), 247.08 (17.3), 246.08 (100); 1H-NMR (CDCl3,
400 MHz): δ 8.05 (d, 2H), 7.94 (d, 1H), 7.86 (m, 2H), 7.70
(dd, 2H), 2.58 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 190.42,
156.60, 143.24, 141.92, 140.95, 140.73, 136.90, 136.84, 134.42,
129.87, 128.20, 124.19, 124.22, 122.15, 21.40. Elemental
analysis calcd. (found) %: C, 78.02 (78.03); H, 4.05 (4.09);
N, 11.39 (11.38); O, 6.51 (6.50).
7-Chloro-11H-indeno[1,2-b]quinoxalin-11-one (2c):
Yield: 90.4%; m.p.: 149-150 ºC; Rf: 0.78 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
267.03 (16.2), 268.02 (32), 266.02 (100); 1H-NMR (DMSO-
d6, 400 MHz): δ 7.57 (m, 3H), 7.36 (m, 4H). Elemental analysis
calcd. (found) %: C, 67.56 (67.57); H, 2.65 (2.69); Cl, 13.29
(13.30); N, 10.50 (10.52); O, 6.00 (6.01).
8-Chloro-11H-indeno[1,2-b]quinoxalin-11-one (2ci):
Yield: 90.4%; m.p.: 391-394 ºC; Rf: 0.78 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
267.03 (16.2), 268.02 (32), 266.02 (100); 1H-NMR (DMSO-
d6, 400 MHz): δ 7.57 (m, 3H), 7.36 (m, 4H) Elemental analysis
calcd. (found) %: C, 67.56 (67.57); H, 2.65 (2.69); Cl, 13.29
(13.30); N, 10.50 (10.52); O, 6.00 (6.01).
7-Benzoyl-11H-indeno[1,2-b]quinoxalin-11-one (2d):
Yield: 95.7%; m.p.: 88-90 ºC; Rf: 0.81 (TLC eluent; ethyl
acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. int. %):
338.10 (2.7), 337.09 (23.8), 331.09 (100). 1H-NMR (CDCl3,

Vol. 32, No. 8 (2020)
Synthesis of Spirohydantoins and Schiff Bases of Indenoquinoxalinones and Indenopyridopyrazinones 1927
3-Bromo-10H-indeno[1,2-b]pyrido[2,3-e]pyrazin-10-
one (2g):Yield: 96.0%; m.p.: 140-142 ºC; Rf: 0.25 (TLC eluent;
ethyl acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. Int.
to mix at room temperature for 30 min. The precipitated solids
were gathered by filteration, air dried and recrystallized from
CH2Cl2-MeOH to give products, which were purified by column
chromatography to afford the corresponding compounds 4-8i.
Schiff base 4: Yield: 75.2% ; Rf: 0.72 (TLC eluent; n-
1
%): 311.97 (15.1), 312.97 (97.3), 310.97 (100); H NMR
(DMSO-d6, 400 MHz): δ 9.22 (d, 1H), 8.98 (d, 1H), 8.17 (m,
1H), 7.94 (dd, 2H); 13C NMR (DMSO-d6, 100 MHz): δ189.01,
158.35, 156.08, 154.49, 153.53, 150.18, 141.53, 140.17, 138.96,
137.66, 133.96, 124.91, 123.16, 120.79. Elemental analysis
calcd. (found) %: C, 53.87 (53.88); H, 1.94 (1.94); Br, 25.60
(25.61); N, 13.46 (13.46); O, 5.13 (5.13).
1
hexane:ethyl acetate = 2:1, v/v); H NMR (DMSO-d6, 400
MHz): δ 8.324 (d, 1H), 8.202 (d, 1H), 7.773 (m, 1H), 7.605
(dd, 2H), 7.273 (m, 1H), 7.191 (d, 2H), 7.089 (dd, 2H), 6.922
(m, 2H); 13C NMR (DMSO-d6, 100 MHz): δ161.571, 159.150,
154.518, 151.573, 147.118, 147.089, 143.395, 142.595, 140.275,
133.547, 131.143, 131.265, 131.046, 129.907, 129.470, 126.800,
122.870, 119.584, 116.497, 116.272.
Schiff base 5:Yield: 78.5 %; Rf: 0.69 (TLC eluent; n-hexane:
ethyl acetate = 2:1, v/v); 1H NMR (DMSO-d6, 400 MHz): δ
8.078 (d, 2H), 8.057 (m, 6H), 7.705 (m, 4H), 2.587 (s, 3H),
1.987 (s, 3H).
Schiff base 6: Yield: 76.5% ; Rf: 0.72 (TLC eluent; n-
hexane:ethyl acetate = 2:1, v/v); 1H NMR (DMSO-d6, 400 MHz):
δ 9.196 (d, 1H), 8.993 (d, 1H), 8.987 (m, 6H), 8.093 (dd, 1H),
7.933 (m, 2H), 7.785 (m, 1H), 7.777 (m, 1H), 2.449 (s, 3H);
13C NMR (DMSO-d6, 100 MHz): δ 161.526, 159.707, 157.435,
155.843, 154.882, 153.573, 151.536, 142.885, 142.285, 141.986,
141.523, 140.317, 139.046, 135.436, 135.318, 126.264, 124.855,
124.509, 124.301, 122.145.
Schiff base 7:Yield: 75.2%; Rf: 0.72 (TLC eluent; n-hexane:
ethyl acetate = 2:1, v/v); 1H NMR (DMSO-d6, 400 MHz): δ
8.302 (d, 3H), 7.774 (m, 2H), 7.418 (dd, 2H), 7.368 (m, 2H),
7.282 (m, 1H), 7.095 (m, 1H).
3-Bromo-6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one
(2gi): Yield: 96.0%; m.p.: 140-142ºC; Rf: 0.25 (TLC eluent;
ethyl acetate:n-hexane = 1:1, v/v). Mass (70 eV), m/z (rel. Int.
1
%): 311.97 (15.1), 312.97 (97.3), 310.97 (100); H NMR
(DMSO-d6, 400 MHz): δ 9.22 (d, 1H), 8.98 (d, 1H), 8.17 (m,
1H), 7.94 (dd, 2H); 13C NMR (DMSO-d6, 100 MHz): δ 182.91,
158.35, 156.08, 154.49, 153.53, 150.18, 141.53, 140.17, 138.96,
137.66, 133.96, 124.91, 123.15, 120.79. Elemental analysis
calcd. (found) %: C, 53.87 (53.88); H, 1.94 (1.95); Br, 25.60
(25.61); N, 13.46 (13.46); O, 5.13 (5.13).
Spirohydantoins : Indeno[1,2-b]quinoxalin-11-one (0.03
mol), KCN (0.045 mol) and ammonium carbonate (0.06 mol)
were dissolved in acetonitrile (75 mL). The reaction mixture
was heated under stirring to 80 ºC for 72 h. After cooling to
room temperature, the mixture was water down with 35 mL
of water and filtered. The filtrate was acidified with diluted
HCl to pH 7 and permited to mix at room temperature for 30
min. The precipitated solids were gathered by filteration, air
dried and recrystallized from CH2Cl2-CH3OH to give 3a-3di.
Spirohydantoin 3a:Yield: 50.7%; Rf: 0.81 (TLC eluent ;
n-hexane:ethyl acetate = 1:1, v/v); 1H NMR (DMSO-d6, 400
MHz): δ 8.708 (d, 1H), 8.196 (d, 1H), 7.907 (m, 1H), 7.796
(dd, 2H), 7.719 (m, 1H); 13C NMR (DMSO-d6, 100 MHz): δ
172.860, 158.247, 153.622, 142.406, 140.827, 137.245, 132.991,
131.213, 130.316, 129.346, 129.146, 124.902, 122.479, 70.064.
Spirohydantoin 3b:Yield: 43.3% ; Rf: 0.81 (TLC eluent
; n-hexane:ethyl acetate = 1:1, v/v); 1H NMR (DMSO-d6, 400
MHz): δ 8.708 (d, 1H), 8.196 (d, 1H), 7.907 (m, 1H), 7.796
(dd, 2H), 7.719 (m, 1H), 2.674 (s, 3H); 13C NMR (DMSO-d6,
100 MHz): δ 172.860, 158.247, 153.622, 142.406, 140.827,
137.245, 132.991, 131.213, 130.316, 129.346, 129.146, 124.902,
122.479, 70.064, 23.233.
Spirohydantoin 3c:Yield: 60.2%; Rf : 0.35 (TLC eluent
; n-hexane:ethyl acetate = 2:1, v/v); 1H NMR (DMSO-d6, 400
MHz): δ 10.742 (d, 1H), 8.165 (d, 1H), 7.696 (m, 1H), 6.912
(dd, 2H); 13C NMR (DMSO-d6, 100 MHz): δ167.518, 154.614,
142.807, 139.496, 135.295, 133.304, 131.040, 127.903, 124.623,
122.627, 120.259, 109.644, 108.484, 67.414.
Spirohydantoin 3d:Yield: 46.3%; Rf : 0.35 (TLC eluent
; n-hexane:ethyl acetate = 2:1, v/v); 1H NMR (DMSO-d6, 400
MHz): δ 8.504 (s, 1H), 8.364 (d, 1H), 8.238 (m, 2H), 7.881
(m, 3H), 7.746 (m, 3H), 7.625 (m, 3H), 4.796 (s, 1H).
Schiff bases: Indeno[1,2-b]quinoxalin-11-one (0.03 mol)
and 4-fluoroaniline (0.03 mol) were dissolved in CH3Cl (30
mL). The reaction mixture was allowed to stir at 40 ºC. After
stirring for 48 h, cool to room temperature, the mixture was
poured with 30 mL of water and filtered.The filtrate was permited
Schiff base 8:Yield: 60.2% ; Rf: 0.72 (TLC eluent; n-hexane
:ethyl acetate = 2 : 1, v/v); 1H NMR (DMSO-d6, 400 MHz): δ
8.223 (d, 1H), 8.088 (d, 1H), 7.765 (m, 1H), 7.597 (dd, 3H),
7.260 (m, 4H), 1.679 (s, 3H).
RESULTS AND DISCUSSION
We report here in an effective synthesis and stereochem-
istry of indenoquinoxalinones and indenopyridopyrazinones
via the reaction of ninhydrin with a variety of reagents as phenyl-
enediamines, diaminopyridines, and diaminobenzophenone.
A multi-component reaction between indenoquinoxalinones,
potassium cyanide and ammonium carbonate, which result in
the formation of spirohydantoins derived indenoquinoxalinones.
Indenoquinoxalinones reacted quantitatively with highly funt-
ionalized amines by refluxing to give Schiff bases derived indeno-
quinoxalinones with high yield. First of all the adjacent access
of a hydroxyl group of ninhydrin to the presence of carbonyl
groups makes this extremely reactive compound an attractive
starting point for cascade reactions with diamino starting
materials. The reaction of ninhydrin with o-phenylenediamine
in MeOH is fully regiospecific and afforded the corresponding
indeno[1,2-b]quinoxalin-11-one in 93.2% yield without the
aid of any catalysts.A reasonable reaction mechanism is addition
to C=O and substitution of two OH resulting from elimination
of two water. IR spectrum of indeno[1,2-b]quinoxalin-11-one
confirmed the existence of –C=N and C=O absorption bands
1
at 1605 and 1728 cm-1. The H NMR spectrum revealed the
ArH at δ7.25-8.20 ppm.The mass spectrum indicated a molecular
ion peak (M+) at m/z = 232.34 according to the molecular weight

1928 Song et al.
Asian J. Chem.
TABLE-1
of the molecular formula C15H8N2O = 232.23. As illustrated,
indenoquinoxalinones and indenopyridopyrazinones are signi-
ficant classes of nitrogen containing heterocycles and they
consist useful intermediates in organic synthesis. In view of
the biochemical and biological importance of indenoquino-
xalinones and indenopyridopyrazinones, we report synthesis
of indeno[1,2-b]quinoxalinones (2a, 2b+bi~2d+di) and indeno-
[1,2-b]pyrido[3,2-e]pyrazin-6-ones (2e+ei~g+gi) from the
reactions of ninhydrin with various phenylenediamines (o-
phenylenediamine (1a), 3,4-diaminotoluene (1b), 4-chloro-
1,2-phenylenediamine (1c), 3,4-diaminobenzophenone (1d),
2,3-diaminopyridine (1e), 3,4-diaminopyridine (1f), 2,3-diamino-
5-bromopyridine (1g), indeno[1,2-b]quinoxalin-11-one (2a),
7-methyl-11H-indeno[1,2-b]quinoxalin-11-one (2b), 8-methyl-
11H-indeno[1,2-b]quinoxalin-11-one (2bi), 7-chloro-11H-
indeno[1,2-b]quinoxalin-11-one (2c), 8-chloro-11H-indeno-
[1,2-b]quinoxalin-11-one (2ci), 7-benzoyl-11H-indeno[1,2-b]-
quinoxalin-11-one (2d), 8-benzoyl-11H-indeno[1,2-b]quino-
xalin-11-one (2di), 6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-
one (2e), 10H-indeno[1,2-b]pyrido[2,3-e]pyrazin-10-one (2ei),
6H-indeno[1,2-b]pyrido[4,3-e]pyrazin-6-one (2f), 10H-indeno-
[1,2-b]pyrido[3,4-e]pyrazin-10-one (2fi), 3-bromo-10H-indeno-
[1,2-b]pyrido[2,3-e]pyrazin-10-one (2g), 3-bromo-6H-indeno-
[1,2-b]pyrido[3,2-e]pyrazin-6-one (2gi). From here, we have
a lot of concern for the stereochemistry of synthesized 11H-
indeno[1,2-b]quinoxalin-11-ones and indeno[1,2-b]pyrido-
[3,2-e]pyrazin-6-ones.As illustrated in Table-1, 7-methyl-11H-
indeno[1,2-b]quinoxalin-11-one (2b) and 8-methyl-11H-indeno-
[1,2-b]quinoxalin-11-one (2bi) as a stereoisomer were obtained
with 90.4% yield by the reaction of ninhydrin with 3,4-diamino-
toluene. The 1H NMR spectrum of 2b-CH3 and 2bi-CH3 showed
band at δ 2.60 ppm and 2.62 ppm, respectively. We couldn’t
separate 2b and 2bi as a single product. Compounds 2c~g and
2c′~g′ as structural isomers like 2b and 2bi to form spirohydan-
toins and imines were used without separation. Spirohydantoin
derivatives possess a range of biochemical and pharmacological
characteristic and subse-quently are used to treat many human
diseases. Synthesis of spirohydantoin from synthesized indeno-
[1,2-b]quinoxalinones and indeno[1,2-b]pyrido[3,2-e]pyrazi-
nones of a series of substituted spirohydantoins are described
herein. When indeno[1,2-b]quinoxalinones were subjected to
the standard Bucherer-Bergs conditions (KCN, (NH4)2CO3,
acetonitrile, refluxing, without NaHSO3), spirohydantoins were
isolated with high yield. Initially, we prepared spiro[imidazoli-
dine-4,11′-indeno[1,2-b]quinoxaline]-2,5-dione (3a) from
indeno[1,2-b]-quinoxalin-11-one (2a) with high yield as shown
in Table-2 and Scheme-I.
PHYSICAL DATA AND YIELDS OF INDENO
QUINOXALINONES AND INDENO PYRIDOPYRAZINONES
Reaction
time (h)
Diamine
Product
m.p. (°C)
Yielda (%)
12
12
12
24
12
12
12
151-153
156-160
131-132
160-162
126-129
154-155
128-133
93.2
90.4
97.7
91.3
90.4
96.0
95.7
1a
1b
1e
1f
1c
1g
1d
2a
2b+2bi
2e+2ei
2f+2fi
2c+2ci
2g+2gi
2d+2di
aAll products were characterized using GC/MS and compared with
authentic samples
TABLE-2
PHYSICAL DATA AND YIELDS OF
SPIROHYDANTOIN DERIVATIVES
Starting
material
Reaction
time (h)
Product
m.p. (°C)
Yielda (%)
72
72
72
72
185-187
184-190
177-180
189-190
50.7
43.3
60.2
46.3
2a
3a
2b+2bi
2c+2ci
2d+2di
3b+3bi
3c+3ci
3d+3di
aAll products were characterized using GC/MS and compared with
authentic samples.
[imidazolidine-4,11′-indeno[1,2-b]quinoxaline]-2,5-dione
(3c) and 8′-chlorospiro[imidazolidine-4,11′-indeno[1,2-b]-
quinoxaline]-2,5-dione (3ci) from cmpounds 2c and 2ci, and
7′-(2,5-dioxo-4-phenylimidazolidin-4-yl)spiro[imidazolidine-
4,9′-indeno[1,2-b]pyrazine]-2,5-dione (3d) and 8′-(2,5-dioxo-
4-phenylimidazolidin-4-yl)spiro[imidazolidine-4,9′-indeno-
[1,2-b]pyrazine]-2,5-dione (3di) from compounds 2d and 2di
were synthesized with high yield. Like synthesized 11H-indeno-
[1,2-b]quinoxalin-11-ones and indeno[1,2-b]pyrido[3,2-e]-
pyrazin-6-ones, we couldn’t isolate spiroisomers 3b~d and
3bi~di synthesized from 2b~d and 2bi~di. Separation of synthe-
sized isomers as a single product was the most difficult problem.
In continuation of our research for potential anticancer agents,
the present Schiff base synthesis describes azomethine analogs
of tetracyclic indeno[1,2-b]quinoxalinones.A mixture of indeno-
[1,2-b]quinoxalin-11-one (2a) and 4-fluoroaniline in CHCl3
and HCl was refluxed for 48 h. Progress of reaction was confirmed
byTLC. The mixture was cooled and concentrated, then dissolved
in water, neutralized by K2CO3 and extracted with CH2Cl2 thrice.
The organic layer evaporated in vacuo and purified by column
chromatography (n-hexane:ethyle acetate = 10:1, v/v). The residue
was dried to give (Z)-N-(4-fluorophenyl)-11H-indeno[1,2-b]-
quinoxalin-11-imine (4) as a yellow solid with 75.2% yield.
The evidence of formation for (Z)-N-(4-fluorophenyl)-11H-
indeno[1,2-b]quinoxalin-11-imine (4) using 1H NMR spectrum
revealed peaks of eleven hydrogens for three ArHs at δ 6.9~
8.4 ppm. The mass spectrum showed a molecular ion peak (M+)
at m/z = 326. 326.21 (M+ + 1), corresponding to the molecular
weight of the molecular formula C17H10N4O2 = 325.23. In a
similar way, (Z)-N-(4-fluorophenethyl)-11H-indeno[1,2-b]-
quinoxalin-11-imine (5), (Z)-N-(3-fluoro-4-methylphenyl)-
11H-indeno[1,2-b]quinoxalin-11-imine (6), (Z)-N-(4-fluoro-
The chemical structure of compound 3a synthesized from
compound 2a was constituted on the base of spectral data.
1
The H NMR spectrum of compound 3a revealed peaks of
eight hydrogens for twoArH at δ7.7-8.7 ppm. The mass spectrum
indicated a molecular ion peak(M+) at m/z = 303.15 (M+ + 1),
according to the molecular weight of the molecular formula
C17H10N4O2 = 302.36. In a similar way, 7′-methylspiro[imidazo-
lidine-4,11′-indeno[1,2-b]quinoxaline]-2,5-dione (3b) and 8′-
methylspiro[imidazolidine-4,11′-indeno[1,2-b]quinoxaline]-
2,5-dione (3bi) from compounds 2b and 2bi, 7′-chlorospiro-

Vol. 32, No. 8 (2020)
Synthesis of Spirohydantoins and Schiff Bases of Indenoquinoxalinones and Indenopyridopyrazinones 1929
Ketone
SpirOohydantoin
Diamine
O
NH
HN
NH2
O
N
N
N
NH2
N
3a
2a
1a
O
O
O
O
NH
NH
NH2
HN
HN
N
N
O
O
N
NH2
N
N
N
2bi
2b
1b
3b
3bi
N
N
O
O
O
O
NH
NH
HN
HN
NH2
N
N
O
O
N
N
N
N
Cl
NH2
Cl
2c
2ci
N
1c
N
3c
3ci
Cl
Cl
Cl
O
O
O
O
O
NH
NH
HN
HN
NH2
NH2
N
N
O
O
N
N
O
N
N
2d
2di
1d
N
N
NH
3d
3di
O
O
O
O
N
H
HN
NH
O
O
N
NH2
NH2
O
N
N
N
N
N
2e
2ei
1e
N
O
O
NH2
NH2
N
N
N
N
N
2f
N
2fi
1f
N
N
O
O
N
NH2
N
N
N
Br
NH2
N
2g
Br
2gi
1g
N
Br
Scheme-I: Structure of indenoquinoxalines, indeno pyridopyrazinones and spirohydantoins
3-nitrophenyl)-11H-indeno[1,2-b]quinoxalin-11-imine (7),
(Z)-N-(4-fluorophenyl)-7-methyl-11H-indeno[1,2-b]quino-
xalin-11-imine (8) and (Z)-N-(4-fluorophenyl)-8-methyl-11H-
indeno[1,2-b]quinoxalin-11-imine (8i) as Schiff bases from
the corresponding amine (4-fluorophenethylamine, 3-fluoro-
4-methylaniline, 4-fluoro-3-nitroaniline or 4-fluoroaniline)
were synthesized with high yield (Table-3 and Scheme-II).
Conclusion
An effective synthesis and stereochemistry of indeno-
quinoxalinones and indenopyridopyrazinones via the reaction
of ninhydrin with a variety of reagents as phenylenediamines,
diaminopyridines and diaminobenzophenone are reported. A
multi-component reaction between indenoquinoxalinones, KCN
and (NH4)2CO3, which contribute to the formation of spirohyd-

1930 Song et al.
Asian J. Chem.
TABLE-3
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CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
https://doi.org/10.1111/j.1365-2044.2004.03658.x