A green synthesis of indolo[2,3-b]quinoxaline derivatives

Article abstract of DOI:10.3184/174751914X14146737095013

A simple, efficient and eco-friendly synthesis of a series of structurally new indolo[2,3-b]quinoxaline derivatives has been developed. The synthesis mainly relies on the condensation reaction of various isatins with o-phenylenediamine in water with the u

Full text of DOI:10.3184/174751914X14146737095013

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 DECEMBER, 705–709
RESEARCH PAPER 705
A green synthesis of indolo[2,3-b]quinoxaline derivatives
Hong Zhang*
College of Chemistry, Chemical Engineering and Food Safety, Bohai University, Keji Street, Jinzhou 121000, P.R. China
A simple, efficient and eco-friendly synthesis of a series of structurally new indolo[2,3-b]quinoxaline derivatives has been
developed. The synthesis mainly relies on the condensation reaction of various isatins with o-phenylenediamine in water with
the use of benzyltriethylammonium chloride as catalyst. The protocol is very simple, avoids toxic solvents and catalysts, is easy
to work-up and is thus especially ‘green’.
Keywords: indolo[2,3-b]quinoxaline, condensation reaction, benzyltriethylammonium chloride, isatin, o-phenylenediamine
Indolo[2,3-b]quinoxalines are pharmacologically important
components of numerous biologically and medicinally
significant compounds.1–3 They represent an important series of
DNA intercalating agents and are endowed with potent antiviral
and cytotoxic activities.4–6 For example, compound B-220
(2,3-dimethyl-6-(2-dimethylaminoethyl)-6H-indolo[2,3-b]
quinoxaline) has been reported to show remarkable activity
against herpes virus.7 A recent review describes the DNA
intercalating properties and associated pharmacological
activities of indolo[2,3-b]quinoxaline derivatives.8
The most common approach to access this class of molecules
has involved the condensation reaction of o-phenylenediamine
with isatins in acetic acid,9–11 which is still widely used and is
appealing to synthetic chemists because the transformation
is generally a high-yielding process.12–14 Although some
achievements have been made in this area, the methods
developed suffer from the use of toxic, corrosive and
environmentally hazardous organic solvents, which may be
a limitation for its broad application. Considering current
environmental and safety standards, it is therefore apparent that
significant challenges exist for the development of sustainable
and environmentally acceptable synthetic procedures to replace
these efficient but somewhat outdated methods.
catalyst for the synthesis of the structurally new indolo[2,3-b]
quinoxaline derivatives 7-methyl-6H-indolo[2,3-b]quinoxaline
3a and 7-ethyl-6H-indolo[2,3-b]quinoxaline 3b.
In our first attempts to carry out the transformation of isatins
1a and 1b with o-phenylenediamine 2 in water in the absence
of any catalyst, the reaction scarcely proceeded and the desired
product was detected in negligible amount that did not warrant
isolation. Recently, Mahesh et al.17 described the application of
citric acid as an efficient and green catalyst in the condensation
of o-phenylenediamines with 1,2-dicarbonyl compounds for
the synthesis of quinoxaline derivatives in high yields at room
temperature.17 We envisioned that that citric acid might also be
used for the synthesis of indolo[2,3-b]quinoxalines. However,
contrary to expectation, under the same conditions, the reaction
mixture showed a combination of starting materials and
1
numerous products (according to TLC and H NMR analyses
of the crude product), and the yield of the expected products
was very poor. We also tried the reaction under solvent-free,
co-grinding conditions, which has recently been published for
this type of transformation.18 Although the procedure is very
easy, eco-friendly and impressive, this purported approach
was ineffective in our hands and the reaction did not proceed
satisfactorily, giving poor yields of highly impure product. In
addition we used β‑cyclodextrin as a catalyst in water,19 which
has been reported to yield better results for this type of reaction
but this was also ineffective.
In recent years, BTEAC has found many applications as an
effective and inexpensive phase-transfer catalyst for various
synthetic transformations because of its high catalytic activity
and benign character in the context of green chemistry.20–22
We felt that this approach could be judiciously extended for
the synthesis of indolo[2,3-b]quinoxalines. Thus, we first
investigated the condensation reactions of isatins 1a and 1b
with o-phenylenediamine 2 under BTEAC catalysis in water
at reflux temperature. We found that under these conditions
BTEAC catalysis did afford a significant amelioration in the
preparation of the desired indolo[2,3-b]quinoxalines 3a and 3b.
Thus, taking these facts into account and in continuation
of our ongoing efforts to develop new and efficient protocols
for heterocyclic systems,15,16 we now report a facile and green
protocol for the synthesis of a series of structurally new
6H-indolo[2,3-b]quinoxaline derivatives by the reactions
of indole-2,3-diones with o-phenylenediamine using
benzyltriethylammonium chloride (BTEAC) as catalyst in
aqueous media.
Results and discussion
Scheme 1 outlines the condensation reaction of commercially
available 7-methylindoline-2,3-dione 1a or 7-ethylindoline-2,3-
dione 1b with o-phenylenediamine 2 in water using BTEAC as
O
N
H2N
BTEAC
O
+
N
N
H
H2O, reflux
N
H2N
R1
H
R1
1a,b
2
3a,b
1a, 3a: R1= Me; 1b, 3b: R1= Et
Scheme 1
* Correspondent. E-mail: isfcli@bhu.edu.cn

706 JOURNAL OF CHEMICAL RESEARCH 2014
Synthesis of 1‑alkyl‑7‑methyl‑ and 1‑alkyl‑7‑ethyl‑ indoline‑2,3‑diones
(1c–l); general procedure
We found that the mole ratio of BTEAC influenced the yield
of the product. Accordingly, we evaluated the catalyst loading.
With the use of 5 mol%, 10 mol% and 15 mol% of BTEAC,
the yields of 3a and 3b increased steadily with loading until
they reached a maximum of 86% and 88%, respectively, at
15 mol% catalyst. No additional increase in yield was observed
upon further increasing the loading of BTEAC. In addition,
the reaction could also be promoted according the method
described in literature using tetrabutylammonium bromide
(TBAB) as catalyst,23 although under these conditions the
products 3a and 3b were obtained in slightly lower yields of
68% and 71%, respectively.
To further investigate the viability of the transformation, the
reaction was tested with other N-alkylisatins 1c–l, which were
obtained in good yields by the N-alkylation of 1a and 1b using
dry DMF as solvent in the presence of NaH as base, as shown
in Scheme 2.
A solution of 7-methyl- (1a) or 7-ethyl-indoline-2,3-dione (1b)
(10.0 mmol) in DMF (25 mL) was cooled to 0 °C. At this temperature,
NaH (0.264 g, 11.0 mmol) was added slowly to the solution, which
changed to a deep purple colour. After stirring at room temperature
for 10 min, the appropriate haloalkane (12.0 mmol) (MeI for 1c and
1h, EtBr for 1d and 1i, n-BuBr for 1e and 1j, BnCl for 1f and 1k and
4-ClC6H4CH2Cl for 1g and 1l) was added slowly to the solution. The
resulting mixture was stirred at room temperature for 3 h. After the
reaction was complete (monitored by TLC), the reaction mixture was
poured into ice-water and acidified with 1 M HCl, and filtered to give
the crude product, which was recrystallised from ethanol to give the
corresponding pure product 1c–l.
1,7‑Dimethylindoline‑2,3‑dione (1c): Red solid; yield 94%; m.p.
176–177 °C (lit.25 162–163 °C); IR (KBr) νmax/cm–1: 1731 (C=O), 1695
1
(C=O); H NMR (CDCl3, 400 MHz): δ 2.48 (s, 3H, CH3), 3.42 (s, 3H,
CH3), 6.91 (t, J=7.5 Hz, 1H, ArH), 7.25 (d, J=7.7 Hz, 1H, ArH), 7.34
(d, J=7.3 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 18.76, 29.63,
118.35, 121.93, 123.20, 123.81, 142.26, 148.88, 159.11, 183.68; ESI-MS
m/z: 176.1 [M+H]+. Anal. calcd. for C10H9NO2: C, 68.56; H, 5.18; N,
8.00; found: C, 68.68; H, 5.07; N, 8.19%.
1‑Ethyl‑7‑methylindoline‑2,3‑dione (1d): Red solid; yield 93%;
m.p. 164–166 °C (lit.26 167–168 °C); IR (KBr) νmax/cm–1: 1732 (C=O),
1699 (C=O); 1H NMR (DMSO-d6, 400 MHz): δ 1.22 (t, J=7.0 Hz, 3H,
CH2CH3), 2.49 (s, 3H, CH3), 3.87 (q, J=6.8 Hz, 2H, CH2CH3), 7.03 (t,
J=7.4 Hz, 1H, ArH), 7.38 (d, J=7.1 Hz, 1H, ArH), 7.45 (d, J=7.5 Hz,
1H, ArH); 13C NMR (DMSO-d6, 100 MHz): δ 13.14, 16.85, 35.03,
117.36, 120.20, 121.35, 122.04, 140.81, 146.80, 157.56, 182.63; ESI-MS
m/z: 189.9 [M+H]+. Anal. calcd for C11H11NO2: C, 69.83; H, 5.86; N,
7.40; found: C, 69.96; H, 6.04; N, 7.26%.
In
a
similar fashion the reaction of 1c–l with
o-phenylenediamine led to the formation of the corresponding
indolo[2,3-b]quinoxalines 3c–l in good yields. The results of
this series of experiments are compiled in Table 1. This shows
that the condensation reaction using BTEAC catalysis in water
appears to be generally applicable, as most of the substrates
were consumed within 4 h to give the corresponding products
3a–l in good yields of 75–88%. These products have, apart
from 3a and 3b,24 not been previously reported in the literature,
and their structures were characterised from spectral analyses.
All data were fully consistent with the assigned structures (see
Experimental).
In summary, a facile synthesis of a series of structurally
new indolo[2,3-b]quinoxaline derivatives has been achieved in
water using BTEAC as a catalyst with yields ranging from 75
to 88%. The merits of this protocol are the simple operation,
mild reaction conditions, easy work-up procedure, and
environmentally benign milder reaction conditions. Further
investigations are in progress in our laboratory to evaluate the
process with a broader range of substrates, and to synthesise
more complex products.
1‑Butyl‑7‑methylindoline‑2,3‑dione (1e): Red solid; yield 89%; m.p.
1
63–64 °C; IR (KBr) νmax/cm–1: 1735 (C=O), 1694 (C=O); H NMR
(DMSO-d6, 400 MHz): δ 1.88 (t, J=7.4 Hz, 3H, CH3), 2.31 (sext,
J=7.4 Hz, 2H, CH2), 2.55 (quint., J=7.3 Hz, 2H, CH2), 3.43 (s, 3H,
CH3), 4.77 (t, J=7.5 Hz, 2H, CH2), 7.98 (t, J=7.5 Hz, 1H, ArH), 8.34
(d, J=7.4 Hz, 1H, ArH), 8.40 (d, J=7.6 Hz, 1H, ArH); 13C NMR
(DMSO-d6, 100 MHz): δ 14.01, 18.55, 19.87, 31.43, 41.41, 119.00,
121.87, 123.04, 123.73, 142.55, 148.55, 159.39, 184.19; ESI-MS m/z:
218.1 [M+H]+. Anal. calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45;
found: C, 72.09; H, 6.78; N, 6.28%.
Experimental
1‑Benzyl‑7‑methylindoline‑2,3‑dione (1f): Red crystals; yield
85%; m.p. 174–175 °C; IR (KBr), νmax/cm–1: 1733 (C=O), 1697 (C=O);
1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H, CH3), 5.12 (s, 2H, NCH2),
6.94 (t, J=7.5 Hz, 1H, ArH), 7.13 (d, J=7.3 Hz, 2H, ArH), 7.17–7.22
(m, 3H, ArH), 7.27 (t, J=7.2 Hz, 1H, ArH), 7.45 (d, J=7.2 Hz, 1H,
ArH); 13C NMR (CDCl3, 100 MHz): δ 18.61, 45.28, 118.75, 122.06,
123.59, 124.08, 125.61, 127.65, 129.06, 136.19, 142.56, 148.52, 159.56,
183.65; ESI-MS m/z: 252.1 [M+H]+. Anal. calcd for C16H13NO2: C,
76.48; H, 5.21; N, 5.57; found: C, 76.57; H, 5.06; N, 5.43%.
The chemicals used in this work were obtained from Fluka and were
used without purification. The melting points were determined
by using a WRS-1B melting point apparatus and are uncorrected.
The IR spectra were obtained in the range of 400–4000 cm–1 on a
1
Shimadzu FTIR-8400S spectrophotometer. The H (400 MHz) and
13C (100 MHz) NMR spectra were recorded on a Bruker BRX 400
spectrometer. The reported chemical shifts were relative to TMS. The
mass spectra were determined using a MSD VL ESI1 spectrometer.
The elemental analyses were performed for C, H, N using an
Elementar Vario EL III element analyser. The progress of reactions
was monitored by TLC on silica gel GF254 using hexane/ethyl acetate
mixture as eluent (4:1, v/v) as the eluent.
1‑(4‑Chlorobenzyl)‑7‑methylindoline‑2,3‑dione (1g): Red solid;
yield 86%; m.p. 238–239 °C; IR (KBr), νmax/cm–1: 1734 (C=O), 1693
1
(C=O); H NMR (DMSO-d6, 400 MHz): δ 2.15 (s, 3H, CH3), 5.11 (s,
N
O
O
H2N
BTEAC
NaH, DMF
+
O
O
N
N
N
H2O, reflux
R2 KI
H2N
N
X,
R1
H
R2
R1
R2
3c-l
R1
1a,b
2
1c-l
R1= Me, Et; R2= Me, X = I; R2= Et, X = Br; R2= n-Bu, X = Br;
R2= Bn, X = Cl; R2= 4-ClC6H4CH2, X = Cl
Scheme 2

707 JOURNAL OF CHEMICAL RESEARCH 2014
JOURNAL OF CHEMICAL RESEARCH 2014 707
2H, CH2), 7.05 (t, J=7.5 Hz, 1H, ArH), 7.21–7.26 (m, 1H, ArH),
7.34 (d, J=7.6 Hz, 2H, ArH), 7.41 (d, J=7.6 Hz, 2H, ArH), 7.55 (d,
J=7.5 Hz, 1H, ArH); 13C NMR (DMSO-d6, 100 MHz): δ 18.18, 44.35,
119.41, 121.89, 123.04, 123.96, 128.24, 129.13, 132.19, 136.91, 142.08,
148.34, 160.06, 183.63; ESI-MS m/z: 286.9 [M+H]+. Anal. calcd for
C16H12ClNO2: C, 67.26; H, 4.23; N, 4.90; found: C, 67.06; H, 4.10; N,
4.74%.
Table 1 Yields and physical properties of the compounds 3a–l
Entry
Compd.
R
Yield/%a
M.p./oC
N
1
3a
86
291–293 (>320)b
N
N
H
N
7‑Ethyl‑1‑methylindoline‑2,3‑dione (1h): Red crystals; yield 91%;
m.p. 109–110 °C; IR (KBr) νmax/cm–1: 1735 (C=O), 1697 (C=O);
1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=7.5 Hz, 3H, CH2CH3), 2.84
(q, J=7.5 Hz, 2H, CH2CH3), 3.47 (s, 3H, NCH3), 7.00 (t, J=7.6 Hz,
1H, ArH), 7.34 (d, J=7.7 Hz, 1H, ArH), 7.42 (d, J=7.6 Hz, 1H, ArH);
13C NMR (CDCl3, 100 MHz): δ 14.83, 22.96, 27.83, 117.02, 121.66,
122.41, 126.89, 139.26, 146.55, 157.69, 182.03; ESI-MS m/z: 190.1
[M+H]+. Anal. calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40; found:
C, 69.52; H, 5.88; N, 7.34%.
2
3
3b
3c
85
88
271–272 (>320)b
167–168
N
N
H
N
N
N
N
1,7‑Diethylindoline‑2,3‑dione (1i): Red solid; yield 89%;
m.p. 80–81 °C; IR (KBr) νmax/cm–1: 1732 (C=O), 1695 (C=O);
1H NMR (CDCl3, 400 MHz): δ 1.25 (t, J=7.5 Hz, 3H, CH2CH3), 1.34
(t, J=7.5 Hz, 3H, CH2CH3), 2.76 (q, J=7.5 Hz, 2H, CH2CH3), 3.92
(q, J=7.1 Hz, 2H, CH2CH3), 7.01 (t, J=7.5 Hz, 1H, ArH), 7.35 (d,
J=7.8 Hz, 1H, ArH), 7.42 (d, J=7.3 Hz, 1H, ArH); 13C NMR (CDCl3,
100 MHz): δ 12.68, 14.43, 23.03, 35.37, 117.41, 121.88, 122.31, 126.40,
139.21, 145.79, 157.67, 182.44; ESI-MS m/z: 204.0 [M+H]+. Anal. calcd
for C12H13NO2: C, 70.92; H, 6.45; N, 6.89; found: C, 70.66; H, 6.71; N,
6.68%.
4
5
N
3d
3e
84
79
138–139
87–88
N
N
N
N
N
N
N
1‑Butyl‑7‑ethylindoline‑2,3‑dione (1j): Red solid; yield 91%; m.p.
1
75–76 °C; IR (KBr) νmax/cm–1: 1734 (C=O), 1697 (C=O); H NMR
N
6
7
3f
85
81
176–177
194–195
(CDCl3, 400 MHz): δ 0.81 (t, J=7.2 Hz, 3H, CH3), 1.21 (t, J=7.4 Hz,
3H, CH2CH3), 1.39 (sext., J=7.4 Hz, 2H, CH2), 1.85 (quint., J=7.4 Hz,
2H, CH2), 2.64 (q, J=7.5 Hz, 2H, CH2CH3), 3.79 (t, J=7.3 Hz, 2H,
CH2), 6.86–6.92 (m, 1H, ArH), 7.26 (d, J=7.6 Hz, 1H, ArH), 7.47 (d,
J=7.2 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 13.51, 15.86,
19.77, 24.49, 30.96, 41.75, 118.93, 123.18, 123.81, 128.03, 140.76,
147.49, 159.28, 183.80; ESI-MS m/z: 232.1 [M+H]+. Anal. calcd for
C14H17NO2: C, 72.70; H, 7.41; N, 6.06; found: C, 72.57; H, 7.16; N,
5.88%.
N
N
3g
Cl
1‑Benzyl‑7‑ethylindoline‑2,3‑dione (1k): Red crystals; yield 80%;
m.p. 121–122°C; IR (KBr) νmax/cm–1: 1735 (C=O), 1696 (C=O);
1H NMR (CDCl3, 400 MHz): δ 1.21 (t, J=7.4 Hz, 3H, CH2CH3), 2.58
(q, J=7.5 Hz, 2H, CH2CH3), 5.14 (s, 2H, CH2), 7.04 (t, J=7.5 Hz, 1H,
ArH), 7.17 (d, J=7.4 Hz, 2H, ArH), 7.25 (d, J=7.3 Hz, 1H, ArH),
7.27 (t, J=7.2 Hz, 1H, ArH), 7.38 (d, J=7.4 Hz, 2H, ArH), 7.50 (d,
J=7.2 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 181.96, 158.11,
146.00, 139.47, 134.30, 127.41, 126.98, 126.03, 123.97, 122.66, 121.96,
117.40, 43.91, 22.59, 14.39. ESI-MS m/z: 266.2 [M+H]+; Anal. calcd
for C17H15NO2: C, 76.96; H, 5.70; N, 5.28; found: C, 76.73; H, 5.88; N,
5.12%.
N
8
9
3h
3i
87
82
108–109
87–88
N
N
N
N
N
N
1‑(4‑Chlorobenzyl)‑7‑ethylindoline‑2,3‑dione (1l): Red crystals;
N
reaction time 3 h; yield 88%; m.p. 133–135°C; IR (KBr) νmax/cm–1:
N
10
11
3j
76
82
115–116
156–157
1
1733 (C=O), 1695 (C=O); H NMR (CDCl3, 400 MHz): δ 1.24 (t,
J=7.5 Hz, 3H, CH2CH3), 2.47 (q, J=7.5 Hz, 2H, CH2CH3), 5.06 (s,
2H, CH2), 7.02 (t, J=7.6 Hz, 1H, ArH), 7.08 (d, J=8.2 Hz, 2H, ArH),
7.24 (d, J=7.4 Hz, 1H, ArH), 7.31 (d, J=8.0 Hz, 2H, ArH), 7.47 (d,
J=7.3 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 14.41, 22.59,
43.44, 117.43, 122.12, 122.82, 125.45, 126.77, 127.60, 131.90, 132.91,
139.42, 145.72, 158.08, 181.67; ESI-MS m/z: 300.1 [M+H]+. Anal.
calcd for C17H14ClNO2: C, 68.12; H, 4.71; N, 4.67; found: C, 67.98; H,
4.93; N, 4.49%.
N
N
N
3k
N
Synthesis of 6‑alkyl‑7‑methyl‑ and 6‑alkyl‑7‑ethyl‑6H‑indolo[2,3‑b]
quinoxalines (3a–l); general procedure
N
N
A
suspension of the selected 1-alkyl-7-methyl or 1-alkyl-7-
12
3l
75
207–208
ethyl-isatin (1 mmol), o-phenylenediamine (0.11 g, 1 mmol) and
benzyltriethylammonium chloride (BTEAC) (0.035 g, 0.15 mmol)
was stirred in water (6 mL) at reflux temperature for 4 h. After the
completion of the reaction (monitored by TLC), the reaction mixture
was cooled, and the precipitated crude product was collected by
Cl
aIsolated yields.
bMelting points of 3a and 3b in ref. 24.

708 JOURNAL OF CHEMICAL RESEARCH 2014
filtration, washed with water and recrystallised from 95% EtOH to
give the corresponding pure indolo[2,3-b]quinoxaline derivative. The
melting points and yields of all the compounds are summarised in
Table 1, and the spectral and analytical data are given below.
6‑(4‑Chlorobenzyl)‑7‑methyl‑6H‑indolo[2,3‑b]quinoxaline
(3g):
Yellow solid; IR (KBr) νmax/cm–1: 1616 (C=N), 1586 (C=N); H NMR
(CDCl3, 400 MHz): δ 2.57 (s, 3H, Me), 5.89 (s, 2H, PhCH2), 6.92 (d,
J=8.1 Hz, 2H, ArH), 7.16 (d, J=8.1 Hz, 2H, ArH), 7.22–7.29 (m, 3H,
ArH), 7.64 (t, J=7.5 Hz, 1H, ArH), 8.00 (d, J=8.2 Hz, 1H, ArH),
8.26 (d, J=8.1 Hz, 1H, ArH), 8.34 (d, J=7.5 Hz, 1H, ArH); 13C NMR
(CDCl3, 100 MHz): δ 19.56, 45.77, 120.81, 121.30, 121.83, 126.14,
126.54, 126.90, 125.47, 125.85, 126.29, 127.15, 127.91, 128.65, 129.00,
129.27, 134.76, 136.97, 140.79, 146.27; ESI-MS m/z: 358.7 (M+H)+.
Anal. calcd for C22H16ClN3: C, 73.84; H, 4.51; N, 11.74; found: C, 73.92;
H, 4.35; N, 11.44%.
1
7‑Methyl‑6H‑indolo[2,3‑b]quinoxaline (3a): Yellow solid; IR (KBr)
ν
max/cm–1: 1613 (C=N), 1589 (C=N); 1H NMR (DMSO-d6, 400 MHz): δ
2.60 (s, 3H, CH3), 7.29 (t, J=7.4 Hz, 1H, ArH), 7.53 (d, J=7.4 Hz, 1H,
ArH), 7.76–7.81 (m, 2H, ArH), 8.09 (d, J=7.8 Hz, 1H, ArH), 8.19 (d,
J=7.5 Hz, 1H, ArH), 8.26 (d, J=7.8 Hz, 1H, ArH), 12.08 (s, 1H, NH);
13C NMR (DMSO-d6, 100 MHz): δ 19.12, 99.87, 101.80, 102.69, 107.17,
108.75, 109.87, 110.25, 113.09, 119.86, 122.38, 127.38, 137.38, 143.45,
147.51; ESI-MS m/z: 234.3 (M+H)+. Anal. calcd for C15H11N3: C, 77.23;
H, 4.75; N, 18.01; found: C, 77.47; H, 4.95; N, 17.79%.
7‑Ethyl‑6H‑indolo[2,3‑b]quinoxaline (3b): Yellow crystals; IR
(KBr) νmax/cm–1: 1613 (C=N), 1588 (C=N); 1H NMR (DMSO-d6,
400 MHz): δ 1.34 (t, J=7.5 Hz, 3H, CH2CH3), 3.00 (q, J=7.5 Hz, 2H,
CH2CH3), 7.33 (t, J=7.6 Hz, 1H, ArH), 7.55 (d, J=7.6 Hz, 1H, ArH),
7.74–7.80 (m, 2H, ArH), 8.09 (d, J=8.4 Hz, 1H, ArH), 8.22–8.27 (m,
2H, ArH), 12.10 (s, 1H, NH); 13C NMR (DMSO-d6, 100 MHz): δ 13.93,
22.81, 118.23, 119.02, 120.05, 120.70, 125.16, 126.14, 126.97, 127.91,
128.37, 129.34, 138.06, 139.61, 141.90, 145.61; ESI-MS m/z: 248.1
(M+H)+. Anal. calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99; found:
C, 78.06; H, 5.07; N, 16.75%.
6,7‑Dimethyl‑6H‑indolo[2,3‑b]quinoxaline (3c): Yellow solid;
IR (KBr) νmax/cm–1: 1610 (C=N), 1596 (C=N); 1H NMR (CDCl3,
400 MHz): δ 2.79 (s, 3H, Me), 4.16 (s, 3H, NMe), 7.16 (d, J=7.5 Hz, 1H,
ArH), 7.31 (d, J=7.3 Hz, 1H, ArH), 7.56–7.60 (m, 1H, ArH), 7.64–7.70
(m, 1H, ArH), 8.04 (t, J=7.4 Hz, 1H, ArH), 8.19 (d, J=8.2 Hz, 1H,
ArH), 8.27 (d, J=8.2 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz):
δ 19.56, 29.57, 102.34, 102.87, 103.06, 107.75, 109.45, 110.94, 116.02,
122.50, 125.28, 128.10, 134.80, 141.63, 143.45, 146.68; ESI-MS m/z:
248.1 (M+H)+. Anal. calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99;
found: C, 77.58; H, 5.28; N, 16.75%.
6‑Ethyl‑7‑methyl‑6H‑indolo[2,3‑b]quinoxaline (3d): Yellow solid;
IR (KBr) νmax/cm–1: 1614 (C=N), 1580 (C=N); 1H NMR (CDCl3,
400 MHz): δ 1.60 (t, J=7.1 Hz, 3H, NCH2CH3), 2.95 (s, 3H, Me), 4.90
(q, J=7.0 Hz, 2H, CH2CH3), 7.38 (t, J=7.5 Hz, 1H), 7.53 (d, J=7.3 Hz,
1H, ArH), 7.79 (d, J=8.2 Hz, 1H, ArH), 7.87 (t, J=7.5 Hz, 1H, ArH),
8.25 (t, J=8.2 Hz, 1H, ArH), 8.42 (d, J=8.2 Hz, 1H, ArH), 8.48 (d,
J=7.6 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 15.70, 19.64,
38.00, 118.60, 120.81, 121.91, 124.52, 125.91, 126.40, 127.00, 127.78,
128.57, 129.10, 134.35, 140.80, 142.62, 145.86; ESI-MS m/z: 262.2
(M+H)+. Anal. calcd for C17H15N3: C, 78.13; H, 5.79; N, 16.08; found:
C, 78.11; H, 5.77; N, 16.28%.
7‑Ethyl‑6‑methyl‑6H‑indolo[2,3‑b]quinoxaline (3h): Yellow solid; IR
(KBr) νmax/cm–1: 1608 (C=N), 1579 (C=N); 1H NMR (CDCl3, 400 MHz):
δ 1.28 (t, J=7.4 Hz, 3H, CH2CH3), 3.05 (q, J=7.4 Hz, 2H, CH2CH3),
4.17 (s, 3H, Me), 7.23 (t, J=7.6 Hz, 1H, ArH), 7.38 (t, J=7.5 Hz, 1H,
ArH), 7.61–7.68 (m, 2H, ArH), 8.05 (d, J=8.3 Hz, 1H, ArH), 8.22 (d,
J=8.2 Hz, 1H, ArH), 8.28 (d, J=7.5 Hz, 1H, ArH); 13C NMR (CDCl3,
100 MHz): δ 15.69, 24.42, 29.59, 119.43, 120.19, 121.35, 124.89, 126.61,
126.81, 127.62, 128.10, 128.97, 131.70, 132.01, 139.67, 141.77, 145.42;
ESI-MS m/z: 262.1 (M+H)+. Anal. calcd for C17H15N3: C, 78.13; H, 5.79;
N, 16.08; found: C, 78.29; H, 5.89; N, 15.79%.
6,7‑Diethyl‑6H‑indolo[2,3‑b]quinoxaline (3i): Yellow crystals;
IR (KBr) νmax/cm–1: 1613 (C=N), 1584 (C=N); 1H NMR (CDCl3,
400 MHz): δ 1.21 (t, J=7.5 Hz, 3H, CH2CH3), 1.38 (t, J=7.4 Hz, 3H,
CH2CH3), 3.09 (q, J=7.5 Hz, 2H, CH2CH3), 4.70 (q, J=7.4 Hz, 2H,
CH2CH3), 7.25 (t, J=8.3 Hz, 1H, ArH), 7.43–7.48 (m, 1H, ArH),
7.62–7.67 (m, 2H, ArH), 8.07 (d, J=8.4 Hz, 1H, ArH), 8.23 (t,
J=8.4 Hz, 1H, ArH), 8.31 (d, J=8.2 Hz, 1H, ArH); 13C NMR (CDCl3,
100 MHz): δ 15.28, 16.11, 25.52, 38.10, 120.52, 121.02, 121.22, 125.80,
125.99, 127.45, 127.81, 128.64, 129.17, 132.43, 132.63, 140.83, 141.79,
146.07; ESI-MS m/z: 276.2 (M+H)+. Anal. calcd for C18H17N3: C,
78.52; H, 6.22; N, 15.26; found: C, 78.78; H, 6.43; N, 15.04%.
6‑Butyl‑7‑ethyl‑6H‑indolo[2,3‑b]quinoxaline (3j): Yellow crystals;
IR (KBr) νmax/cm–1: 1620 (C=N), 1591 (C=N); 1H NMR (CDCl3,
400 MHz): δ 0.90 (t, J=7.5 Hz, 3H, CH3), 1.24 (t, J=7.5 Hz, 3H,
CH2CH3), 1.46 (sext., J=7.5 Hz, 2H, CH2), 1.85 (quint., J=7.6 Hz, 2H,
CH2), 3.07 (q, J=7.5 Hz, 2H, CH2CH3), 4.62 (t, J=7.6 Hz, 2H, CH2),
7.25 (t, J=7.5 Hz, 1H, ArH), 7.43 (d, J=8.2 Hz, 1H, ArH), 7.61–7.67
(m, 2H, ArH), 8.07 (t, J=8.3 Hz, 1H, ArH), 8.23 (d, J=8.2 Hz, 1H,
ArH), 8.32 (d, J=7.5 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz): δ
13.96, 16.09, 20.08, 25.54, 32.29, 43.02, 120.67, 121.42, 125.70, 126.11,
127.83, 128.35, 128.71, 129.12, 132.37, 132.88, 132.90, 140.83, 146.45;
ESI-MS m/z: 304.2 (M+H)+. Anal. calcd for C20H21N3: C, 79.17; H,
6.98; N, 13.85; found: C, 78.92; H, 6.81; N, 13.70%.
6‑Benzyl‑7‑ethyl‑6H‑indolo[2,3‑b]quinoxaline (3k): Yellow solid;
IR (KBr) νmax/cm–1: 1618 (C=N), 1589 (C=N); 1H NMR (CDCl3,
400 MHz): δ 1.18 (t, J=7.5 Hz, 3H, CH2CH3), 2.85 (q, J=7.5 Hz, 2H,
CH2CH3), 5.92 (s, 2H, PhCH2), 6.96 (d, J=7.4 Hz, 1H, ArH), 7.11 (t,
J=8.1 Hz, 1H, ArH), 7.16–7.21 (m, 2H, ArH), 7.28 (t, J=7.5 Hz, 1H,
ArH), 7.37 (d, J=7.4 Hz, 1H, ArH), 7.61–7.65 (m, 3H, ArH), 8.02 (d,
J=8.1 Hz, 1H, ArH), 8.26 (d, J=8.0 Hz, 1H, ArH), 8.37 (d, J=7.5 Hz,
1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 16.17, 24.97, 46.49, 120.69,
121.32, 121.87, 125.40, 125.72, 125.77, 125.77, 126.01, 126.42, 127.51,
127.95, 128.52, 129.09, 132.50, 133.02, 138.15, 140.89, 146.60; ESI-MS
m/z: 338.1 (M+H)+. Anal. calcd for C23H19N3: C, 81.87; H, 5.68; N,
12.45; found: C, 81.66; H, 5.59; N, 12.32%.
6‑Butyl‑7‑methyl‑6H‑indolo[2,3‑b]quinoxaline (3e): Yellow solid;
IR (KBr) νmax/cm–1: 1610 (C=N), 1586 (C=N); 1H NMR (CDCl3,
400 MHz): δ 0.89 (t, J=7.4 Hz, 3H, CH3), 1.36 (sext, J=7.4 Hz, 2H,
CH2), 1.85 (quint., J=7.4 Hz, 2H, CH2), 2.73 (s, 3H, Me), 4.64 (t,
J=7.4 Hz, 2H, CH2), 7.16 (d, J=7.5 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H,
ArH), 7.58 (t, J=7.5 Hz, 1H, ArH), 7.66 (t, J=7.4 Hz, 1H, ArH), 8.05 (t,
J=8.3 Hz, 1H, ArH), 8.21 (d, J=8.3 Hz, 1H, ArH), 8.27 (d, J=7.6 Hz,
1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 13.78, 14.00, 20.08, 32.75,
42.93, 120.61, 121.13, 125.63, 126.06, 127.84, 128.31, 128.93, 129.22,
134.07, 134.60, 139.29, 140.01, 140.82, 146.22; ESI-MS m/z: 290.3
(M+H)+. Anal. calcd for C19H19N3: C, 78.86; H, 6.62; N, 14.52; found:
C, 78.54; H, 6.54; N, 14.43%.
6‑(4‑Chlorobenzyl)‑7‑ethyl‑6H‑indolo[2,3‑b]quinoxaline
(3l):
Yellow crystals; IR (KBr) νmax/cm–1: 1604 (C=N), 1576 (C=N);
1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=7.5 Hz, 3H, CH2CH3), 2.90
(q, J=7.5 Hz, 2H, CH2CH3), 5.93 (s, 2H, PhCH2), 6.97 (d, J=8.4 Hz,
2H, Ph‑H), 7.24 (d, J=8.4 Hz, 2H, Ph‑H), 7.35 (t, J=7.6 Hz, 1H,
ArH), 7.44 (d, J=7.4 Hz, 1H, ArH), 7.68–7.72 (m, 2H, ArH), 8.07 (t,
J=8.2 Hz, 1H, ArH), 8.32 (d, J=8.3 Hz, 1H, ArH), 8.42 (d, J=7.6 Hz,
1H, ArH); 13C NMR (CDCl3, 100 MHz): δ 16.13, 24.96, 46.00, 120.52,
122.01, 126.13, 126.52, 126.92, 127.15, 128.78, 128.99, 129.26, 129.35,
130.10, 131.57, 132.49, 132.99, 136.72, 140.82, 146.45; ESI-MS m/z:
373.1 (M+H)+. Anal. calcd for C23H18ClN3: C, 74.29; H, 4.88; N, 11.30;
found: C, 74.17; H, 4.75; N, 11.41%.
6‑Benzyl‑7‑methyl‑6H‑indolo[2,3‑b]quinoxaline
(3f):
Yellow
crystals; IR (KBr) νmax/cm–1: 1604 (C=N), 1576 (C=N); 1H NMR
(CDCl3, 400 MHz): δ 2.53 (s, 3H, Me), 5.93 (s, 2H, PhCH2), 6.97 (d,
J=7.4 Hz, 1H, ArH), 7.15–7.22 (m, 3H, ArH), 7.27 (d, J=7.3 Hz, 1H,
ArH), 7.31–7.34 (m, 2H, ArH), 7.37 (t, J=7.3 Hz, 1H, ArH), 7.63 (t,
J=8.0 Hz, 1H, ArH), 7.96 (d, J=8.0 Hz, 1H, ArH), 8.19 (d, J=8.0 Hz,
1H, ArH), 8.31 (d, J=7.4 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz):
δ 19.58, 46.28, 120.74, 121.13, 121.66, 125.02, 125.55, 126.01, 126.41,
126.99, 127.49, 128.12, 128.82, 129.19, 134.72, 138.45, 136.83, 140.87,
141.36, 146.41; ESI-MS m/z: 324.3 (M+H)+. Anal. calcd for C22H17N3:
C, 81.71; H, 5.30; N, 12.99; found: C, 81.68; H, 5.25; N, 12.76%.

709 JOURNAL OF CHEMICAL RESEARCH 2014
JOURNAL OF CHEMICAL RESEARCH 2014 709
9
A.V. Ivashchenko, A.G. Drushlyak and V.V. Titov, Chem. Heterocycl.
Compd,1984, 20, 537.
The author would like to thank the Scientific Research
Foundation of the National Natural Science Foundation of
China (grant no. 21402011) and Education Department of
Liaoning Province (grant no. L2013428) for financial support.
10 F.D. Popp, J. Heterocycl. Chem., 1969, 6, 125.
11 P.B. Arimondo, B. Baldeyrou, W. Laine, C. Bal, F.A. Alphonse, S. Routier,
G. Coudert, J.Y. Mérour, P. Colson, C. Houssier and C. Bailly, Chem. Biol.
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12 K. Manna and Y.K. Agrawal, Bioorg. Med. Chem. Lett., 2009, 19, 2688.
13 M.O. Shibinskaya, A.S. Karpenko, S.A. Lyakhov, S.A. Andronati, N.M.
Zholobak, N.Y. Spivak, N.A. Samochina, L.M. Shafran, M.J. Zubritsky
and V.F. Galat, Eur. J. Med. Chem., 2011, 46, 794.
Received 9 September 2014; accepted 29 October 2014
Paper 1402873 doi: 10.3184/174751914X14146737095013
Published online: 19 December 2014
14 M.O. Shibinskaya, N.A. Kutuzova, A.V. Mazepa1, S.A. Lyakhov, S.A.
Andronati, M.J. Zubritsky, V.F. Galat, J. Lipkowski and V.C. Kravtsov, J.
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