Synthesis of substituted indolo[1,2-a]quinoxalines

Article abstract of DOI:10.1081/SCC-120016331

1-(2-Nitrophenyl)indole-2-carboxylates 5, obtained by the N-arylation of indole-2-carboxylates 4, on catalytic reductive cyclization afford indolo[1,2-a]quinoxalino-6(5H)-ones 6. These compounds on reduction with LAH in ether/THF yielded indolo[1,2-a]quin

Full text of DOI:10.1081/SCC-120016331

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Synthesis of Substituted Indolo[1,2- a ]quinoxalines
Maddirala Shambabu Joseph a & L. D. Basanagoudar a
a P. G. Department of Studies in Chemistry , Karnatak University , Dharwad, India
Published online: 17 Aug 2006.
To cite this article: Maddirala Shambabu Joseph & L. D. Basanagoudar (2003) Synthesis of Substituted Indolo[1,2- a
]quinoxalines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:5, 851-862, DOI: 10.1081/SCC-120016331
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 5, pp. 851–862, 2003
Synthesis of Substituted
Indolo[1,2-a]quinoxalines
*
Maddirala Shambabu Joseph and L. D. Basanagoudar
P. G. Department of Studies in Chemistry,
Karnatak University, Dharwad, India
ABSTRACT
1-(2-Nitrophenyl)indole-2-carboxylates 5, obtained by the N-aryl-
ation of indole-2-carboxylates 4, on catalytic reductive cyclization
afford indolo[1,2-a]quinoxalino-6(5H )-ones 6. These compounds on
reduction with LAH in ether/THF yielded indolo[1,2-a]quinoxalines 7.
Key Words: N-Arylation; LAH; Reduction; Ethyl indole-2-carbox-
ylates; Indolo[1,2-a]quinoxalines.
*Correspondence: L. D. Basanagoudar, P. G. Department of Studies in
Chemistry, Karnatak University, Dharwad 580 003, India; E-mail:
ldbasanagoudar @rediffmail.com.
851
DOI: 10.1081/SCC-120016331
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852
Shambabu Joseph and Basanagoudar
The tetracyclic ring system of indolo[1,2-a]quinoxalin-6(5H )-one is
an interesting skeleton and has attracted the interests of many organic
chemists. Synthesis of indolo[1,2-a]quinoxalin-6(5H )-ones and 5,6-
dihydroindolo[1,2-a]quinoxalines with either methyl or phenyl group at
7-position were reported earlier from this laboratory.[1–4] A literature
survey revealed only one report[5,6] on the synthesis of fully aromatic
system which involved boiling sodio derivative of 2-aroylindole with
ketal of a-bromocyclohexanone, cyclisation of resulting N-cyclohexyl
derivative 1 by the action of ammonium acetate in boiling acetic acid to
indolo[1,2-a]quinoxaline 2, dehydrogenation of 2 over Raney nickel
yielded the fully aromatic indolo[1,2-a]quinoxaline 3.
The difficulty in obtaining substituted 2-chlorocyclohexanones
restricts the generality of this procedure. Herein, we report the synthesis
of fully aromatic 7-benzylquinoxalino[1,2-a]indoles 7 which makes use of
easily available substituted orthonitrobenzenes.
DISCUSSION
Various ethyl 5-substituted indole-2-carboxylates 4 were prepared in
40–63% yields via Fischer indolization of appropriate phenylhydrazones
using ethanolic HCl as the cyclising agent (Table 1). The phenylhydra-
zones were, in turn, obtained by Japp-Klingemann condensation between
appropriate diazonium salt and a-phenethylacetoacetate. N-Arylation of
carboxylates 4 was achieved via Ullmann chemistry[7,8] by refluxing
appropriate indole-2-carboxylate with substituted 2-bromo/chloronitro-
benzene in pyridine in presence of cupric oxide and potassium carbonate
to obtain 5. The occurrence of N-arylation was confirmed by the absence
of stretching vibrations due to N–H in the IR spectra (Table 2).
Russell et al.[9] used similar principles for the synthesis of 7-unsubsti-
tuted indolo[1,2-a]quinoxalin-6(5H )-one which takes the advantage
of nucleophilic displacement of the fluorine atom in substituted

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Substituted Indolo[1,2-a]quinoxalines
853

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854
Shambabu Joseph and Basanagoudar
Table 2. Physical and IR spectral data of 5-substituted ethyl 1-(2-nitrophenyl)-3-
benzylindole-2-carboxylates.
Yielda
(%)
Product
R
X
M.p.b (ꢀC)
125–126
IR (KBr)c,d ꢀ (cmꢁ1
)
5a
H
H
65
1702, 1523, 1338,
1270, 1171
5b
5c
5d
5e
5f
CH3
H
H
52
47
48
52
50
55
66
58
63
105–106
108–109
118–119
130–131
92–93
1709, 1524, 1345,
1283, 1171
Cl
Cl
Cl
Cl
1696, 1535, 1350, 1279,
1232, 1181
CH3
OCH3
OC2H5
H
1708, 1536, 1338, 1276,
1202, 1171
1696, 1530, 1350, 1280,
1214, 1177
1696, 1540, 1352,
1214, 1176
5g
5h
5i
OCH3
OCH3
OCH3
OCH3
102–103
140–141
135–136
98–99
1709, 1542, 1340,1276,
1227, 1172
CH3
OCH3
OC2H5
1714, 1540, 1340,
1270, 1171
1700, 1542, 1340,
1214, 1171
5j
1702, 1524, 1348,
1172, 1122
aThe yields are not optimized.
bMelting points were taken in open capillaries and are uncorrected.
cThe IR spectrawere recorded on Nicolet Impact-410 FT-IR spectrophotometer.
dSatisfactory microanalyses were obtained: C, Æ0.30; H, Æ0.32; N, Æ0.17.
2-fluoronitrobenzenes. The N-arylated products 5 were subjected to cat-
alytic reductive cyclisation in DMF, instead of methanol and THF,[1–4]
because of the poorer solubility of the formed quinoxalin-6-ones 6. These
were recrystallised from DMF and are described in Table 3.
The quinoxalin-6-ones when subjected to reduction with LAH
in ether/THF did not give the expected reduction products 8, instead
fluorescent solids 7, were obtained in 60–85% yields. The structures of
compounds 7 were assigned by IR and 1H-NMR data (Table 4).
Confirmation for the structures assigned was obtained from the
2D-NMR techniques-HETCOR, 1H–1H-COSY, HSQC, and HMBC.
The correlations thus obtained for 7d (Table 5) are shown in Fig. 1.
Usually, reaction of lactams with LAH result in the reduction of
amide (–CON<) group to amine (–CH2–N<).[10,11] However, to our
surprise, reduction of 6 with LAH in THF yielded the fully aromatic

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Substituted Indolo[1,2-a]quinoxalines
855
Table 3. Physical and IR spectral data of 9-substituted 7-benzylindolo[1,2-a]-
quinoxalin-6(5H)-ones.
Yielda
(%)
Product
R
X
M.p.b (ꢀC)
295–296
IR (KBr)c,d ꢀ (cmꢁ1
)
6a
H
H
80
3181, 1665, 1617, 1502,
1451, 1409
6b
6c
6d
6e
CH3
H
H
82
65
75
70
>300
>300
3178, 1659, 1498, 1455,
1400
Cl
Cl
Cl
3172, 1677, 1597, 1504,
1407
CH3
OCH3
>300
3179, 1678, 1600, 1561,
1504, 1409
310–311
3168, 1657, 1602, 1493,
1450, 1403, 1377
3184, 1666, 1616
3165, 1665, 1528, 1505,
1453, 1413
6f
6g
OC2H5
H
Cl
OCH3
64
78
>300
289–290
6h
6i
6j
CH3
OCH3
OCH3
OCH3
75
65
80
>300
3172, 1665, 1530, 1501,
1449, 1406
OCH3
OC2H5
290–291
285–286
3162, 1658,1604, 1526,
1498, 1452
3166, 1677, 1535
aThe yields are not optimized.
bMelting points were taken in open capillaries and are uncorrected.
cThe IR spectrawere recorded on Nicolet Impact-410 FT-IR spectrophotometer.
dSatisfactory microanalyses were obtained: C, Æ0.30; H, Æ0.32; N, Æ0.17.
indolo[1,2-a]quinoxaline in contrast to our earlier observations.[1–4] Such
an unusual reaction has been reported by de Mayo and Rigby[12] who
obtained phenanthridenes by the LAH reduction of phenanthridones.
Even when the lactams 6 were reduced with excess of LAH[13] (1:4),
then also compounds with fully aromatic systems 7 were obtained but
not the compounds 8 (Sch. 1).
The results of the studies on the fluorescent properties of the
indolo[1,2-a]quinoxalines 7 will be published elsewhere.
EXPERIMENTAL
Preparation of Compounds 5a–j: General Procedure
A mixture of appropriate ethyl 3-benzylindole-2-carboxylate
(50 mmol), appropriate 2-bromo/chloronitrobenzene (50 mmol),
4

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856
Shambabu Joseph and Basanagoudar

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Substituted Indolo[1,2-a]quinoxalines
857

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858
Shambabu Joseph and Basanagoudar
Table 5. 1H-NMR (500 MHz), 13C-NMR (125 MHz), 1H–1H COSY, and
HMBC spectral data of 3-chloro-9-methyl-7-benzylindolo[1,2-a]quinoxaline.a
ꢁ (ppm), mult,
intgr., J (Hz)
ꢁC
(HSQC)
1H-1H
COSY
HMBC
(C. No.)
Position
1
8.17, d, 1H, 8.5
115.30
129.12
128.10
128.44
129.48
136.83
147.18
126.75
112.60
129.42
120.33
132.23
126.87
113.78
130.41
140.04
128.56
128.10
126.30
29.31
H-2
—
4a, 3
—
4, 12a
12a—
2
7.47, dd, 1H, 9,2.5
—
7.91, d, 1H, 2.5
H-1
—
3
—
2, 12a
4
H-2
—
H-70
—
4a—
6
—
6a, 4a
6, 70
8.88, s, 1H
—
6a—
7
—
—
8
7a—
8
11, 70
7.63, s, 1H
—
H-10
—
7, 10, 11a, 90
—
9
10
7.35, d, 1H, 9
8.11, d, 1H, 8.5
H-8, H-11
H-10
—
11a, 8
9, 7a
—
11
11a—
10
20, 60
30, 50
40
70
90
—
—
—
—
—
7.35, m, 2H
7.35, m, 2H
7.25, m, 1H
4.45, s, 1H
2.55, s, 1H
—
—
—
—
0
—
–
7, 6a, 20, 60, 7a , 1
21.50
8, 9, 10
aThe NMR spectrawere recorded at 500 MHz on Bruker DRX-500 Instrument.
anhydrous potassium carbonate (7 g) and cupric oxide (0.25 g) in dry pyr-
idine (20 mL) was heated under reflux for 30–35 h. The mixture was cooled
and filtered. The residue was washed thoroughly with hot pyridine. The
combined filtrate was poured into ice-cold dilute hydrochloric acid.
The brownish solid that separated was collected by filtration and dried.
The solid was crystallized from ethanol to get the corresponding ethyl 1-(2-
nitrophenyl)-3-benzylindole-2-carboxylates 5a–j as yellow shining needles.
Preparation of Compounds 6a–j: General Procedure
Appropriate nitro compound 5 (5 g) was subjected to reductive cycli-
zation in dimethylformamide (80 mL) with freshly prepared Raney nickel

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Substituted Indolo[1,2-a]quinoxalines
859
Figure 1. 2D-NMR correlations.
(2.5 g) and hydrogen (60 lb/in2) in Paar low-pressure hydrogenator for
8 h. The catalyst was removed by filtration and repeatedly washed with
dimethylformamide. The solvent was removed under reduced pressure
when quinoxaline amides were obtained as very light yellow solids. All
these quinoxaline amides were crystallized from dimethylformamide-
ethanol mixture to get corresponding 7-benzylindolo[1,2-a]quinoxalin-
6(5H)-ones 6a–j as pale yellow crystals.
Reduction of 6a–j: General Procedure
A suspension of appropriate 6 (10 mmol) in dry tetrahydrofuran
(80 mL) was added to a well stirred slurry of LAH (20 mmol) in dry
ether (50 mL). The mixture was heated under reflux for 10 h and
cooled. The excess of lithium aluminium hydride was decomposed by
drop wise addition of water (1 mL), sodium hydroxide (15%, 1.5 mL)

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860
Shambabu Joseph and Basanagoudar
Scheme 1.

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Substituted Indolo[1,2-a]quinoxalines
861
and water (2 mL). The white precipitate formed was filtered off and the
precipitate was washed several times with boiling benzene. The combined
filtrate, after washing with water was dried over anhydrous sodium
sulfate. Removal of the solvent by distillation under reduced pressure
furnished yellow solid, which was crystallized from ethanol to get the
corresponding 7-benzylindolo[1,2-a]quinoxalines 7a–j as yellow shining
needles.
ACKNOWLEDGMENTS
We thank the Director, and Dr. G. A. Naganagowda of SIF, Indian
Institute of Science, Bangalore, India, for providing NMR facility to
carry out the 2D-NMR studies.
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862
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Received in the UK February 17, 2002