First synthesis of tert-butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols and indolo[2,3-b]quinoxalines

Article abstract of DOI:10.1007/s11164-014-1788-1

In this investigation, the first introduction of a tert-butyl group into [1,2,4]triazino[5,6-b]indole and indolo[2,3-b]quinoxaline systems, leading to a series of structurally novel 8-(t-butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiol and 9-(t-butyl)-6H-indolo[2,3-b]quinoxaline derivatives, has been achieved by condensation of tert-butyl-substituted isatins with benzene-1,2-diamine or thiosemicarbazide. The molecular structures of these newly synthesized compounds were elucidated on the basis of elemental analysis and spectral data.

Full text of DOI:10.1007/s11164-014-1788-1

Res Chem Intermed
DOI 10.1007/s11164-014-1788-1
First synthesis of tert-butyl-substituted
[
[
1,2,4]triazino[5,6-b]indole-3-thiols and indolo
2,3-b]quinoxalines
Mingyue Lv
Wentao Gao
•
Hongmei Zheng
•
Yang Li
•
Received: 18 May 2014 / Accepted: 11 August 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract In this investigation, the first introduction of a tert-butyl group into
[
1,2,4]triazino[5,6-b]indole and indolo[2,3-b]quinoxaline systems, leading to a
series of structurally novel 8-(t-butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiol and
-(t-butyl)-6H-indolo[2,3-b]quinoxaline derivatives, has been achieved by con-
9
densation of tert-butyl-substituted isatins with benzene-1,2-diamine or thiosemi-
carbazide. The molecular structures of these newly synthesized compounds were
elucidated on the basis of elemental analysis and spectral data.
Keywords tert-Butyl group Á [1,2,4]Triazino[5,6-b]indole Á Indolo
[
2,3-b]quinoxaline Á Isatin Á Benzene-1,2-diamine Á Thiosemicarbazide
Introduction
N-Heterocycle-fused indole skeletons, for example [1,2,4]triazino[5,6-b]indoles and
indolo[2,3-b]quinoxalines, are gaining importance in medicinal and organic
chemistry because of their wide range of biological activity and medicinal
applications. Compounds containing the 1H-[1,2,4]triazino[5,6-b]indole group have
been reported to have potent antimalarial [1], antidepressant [2], and antileishmanial
[
3] activity. Indolo[2,3-b]quinoxalines are important DNA intercalating agents with
antiviral and cytotoxic activity [4]. Accordingly, much synthetic effort has been
devoted to synthesis of novel and interesting [1,2,4]triazino[5,6-b]indole [5–7] and
indolo[2,3-b]quinoxaline [8–11] derivatives.
Introduction of a tert-butyl group into some heterocycles substantially enhances
their biological activity [12–14]. For example, it has recently been reported that
attachment of a metabolically stable tert-butyl group at the C-2 position of the
M. Lv Á H. Zheng Á Y. Li (&) Á W. Gao
Institute of Superfine Chemicals, Bohai University, Jinzhou 121000, China
e-mail: bhuzh@163.com
123

M. Lv et al.
quinolone system in primaquine resulted in a substantial improvement in blood
schizontocidal antimalarial activity [13]. Introduction of tert-butyl group into
organic molecules increases their lipophilicity, which is very important for passage
through the extraordinary thick and light cell wall [15]. It is, therefore, not
surprising that in recent years the synthesis of new tert-butyl-substituted hetero-
aromatic compounds has been frequently reported in the literature [16–18]. In this
regard, we have recently reported the synthesis of tert-butyl-substituted 3-carboxy
coumarins [19] and 2,6-bis(5-t-butylbenzo[b]furan-2-ylcarbonyl) pyridines [20].
In connection with these findings, and because structural diversity is important in
medicinal and combinatorial chemistry as a faster and more efficient route toward
new drug discovery [21], we conceived that incorporation of tert-butyl group into
indoloquinoxaline and [1,2,4]triazino[5,6-b]indole systems, leading to a series of
structurally novel compounds as possible drug candidates, would be of synthetic
importance for current medicinal chemistry needs. Thus, in continuation of our
efforts to synthesize highly interesting types of heterocycle [22, 23], we report
herein a simple and efficient procedure for synthesis of tert-butyl-substituted
indoloquinoxalines and [1,2,4]triazino[5,6-b]indoles by condensation of 5-tert-
butylisatins with benzene-1,2-diamine and thiosemicarbazide, respectively.
Results and discussion
The synthesis commenced with preparation of 5-tert-butylisatin (3a), by the
Sandmeyer process, from commercially available tert-butylaniline, by use of a
method reported in the literature (Scheme 1) [24]. The –NH group of 3a was then
alkylated in dry DMF as solvent with NaH as base to furnish the corresponding N-
alkyl-5-t-butylisatins 3b–f in 86–92 % yields.
Compounds 3a–f subsequently underwent condensation with thiosemicarbazide
to afford the desired tert-butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols (5a–
f), as outlined in Scheme 2.
Cl
O
Cl
CHO
N
O
OH
H2SO4
Cl
O
NH2
NH2OH HCl, Na2SO4
N
H
0 o
N
H
9
C
H2O, 90 o
C
1
3
a
2
O
RX
DMF, NaH
O
N
R
3
b-f
3
3
b: R=Me; 3c: R=Et; 3d: R=n-Bu
e: R= Bn, 3f: R=4-Cl-Bn
Scheme 1 Preparation of N-alkyl-5-t-butylisatins (3a–f)
1
23

tert-Butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols
O
S
N
N
K2CO3, 30% aq. 1,4-dioxane
refluxing
O
+
H2N
SH
N
NH2
N
R
N
H
N
R
3
a-f
4
5
a-f
Scheme 2 Synthesis of 8-(t-butyl)-N-alkyl-5H-[1,2,4]triazino[5,6-b]indole-3-thiols (5a–f)
We initially performed the condensation reaction in water as solvent, under
reflux, in accordance with a literature method [3]. Although the procedure was very
easy and eco-friendly, it was ineffective in our hands and the reaction always
proceeded heterogeneously, probably because of the presence of the highly
hydrophobic tert-butyl group. We have recently reported the one-pot reaction of
tert-butyl-substituted salicylaldehydes with Meldrum’s acid in water and use of
triethylbenzyl ammonium chloride (TEBAC) as catalyst [19]. Unfortunately, no
product was obtained by use of this method, the starting materials being recovered
unchanged. We investigated use of b-cyclodextrin as catalyst in water, because this
has been reported to yield better results in this type of reaction [6], but this, also,
was to no avail. After many attempts, we found that in 1,4-dioxane and H O as
2
mixed solvent (30 % aq. 1,4-dioxane), with K CO as base, reaction of 5-tert-
2
3
butylisatins (3a–f) with thiosemicarbazide (4) proceeded smoothly and cleanly, and
the target products were obtained in high yield (85–92 %) after recrystallization
from acetic acid. To keep the procedure simple, no further changes in reaction
conditions were tested. The results from this series of experiments are listed in
Table 1.
Thomas et al. [10] recently reported the synthesis of n-butyl-substituted 6H-
indolo[2,3-b]quinoxalines. To the best of our knowledge, synthesis of tert-butyl-
substituted indolo[2,3-b]quinoxaline derivatives was unprecedented. Thus, we
became interested in the synthesis of 6-tert-butyl-6H-indolo[2,3-b]quinoxalines to
increase molecular diversity for current medicinal chemistry needs. In a typical
experiment, 5-tert-butylisatin (3a) was reacted with phenylenediamine (6), in the
mole ratio 1:1, in acetic acid under reflux, by use of a method reported in the
literature [10]. The reaction proceeded well, and thin-layer chromatography (TLC)
did not indicate the formation of any distinct byproduct (Scheme 3). After the usual
workup then purification of crude product by column chromatography over silica
gel, the desired product 7a was obtained in high yield (90 %). Thus, no further
optimization was necessary for substrate 3a. It is worth mentioning that use of the
conditions reported by Kenning et al. [25] (use of ethanol as solvent at room
temperature) resulted in a modest yield (31 %) of 7a.
Encouraged by the successful synthesis of compound 7a, we further extended the
reaction to other substituted isatins 3b–f in a similar fashion. The reaction invariably
led to formation of the corresponding 9-(t-butyl)-N-alkyl-6H-indolo[2,3-b]quinox-
alines (7b–f) in high yields. The results from this series of experiments are listed in
Table 2.
123

M. Lv et al.
Table 1 Yields and melting points of compounds 5a–f
a
Entry
1
Product
5a–f
Yield (%)
m.p. (°C)
5a
85
287–288
N
N
SH
N
N
H
2
3
5b
5c
89
87
293–295
271–272
N
N
N
SH
SH
N
N
N
N
N
4
5
6
5d
5e
5f
91
85
92
261–263
269–270
277–279
N
N
N
SH
SH
SH
N
N
N
N
N
N
N
N
N
Cl
a
Isolated yields
The structures of all the newly synthesized compounds were characterized by use
of spectral data and elemental analysis, and the results were in good agreement with
the compounds expected. For instance, the IR spectra of compounds 5a–f clearly
-
1
contained absorption bands characteristic of the –SH group at 3,431–3,441 cm
.
1
23

tert-Butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols
O
NH2
CH COOH
3
N
O
+
refluxing
N
NH2
N
H
H
N
3
a
6
7a
Scheme 3 Synthesis of 9-(t-butyl)-6H-indolo[2,3-b]quinoxaline (7a)
Table 2 Yields and melting points of compounds 7a–f
a
Entry
1
Product
7a–f
Yield (%)
m.p. (°C)
7a
90
195–196
N
N
N
H
2
3
7b
7c
88
85
178–180
116–117
N
N
N
N
N
N
4
7d
84
94–95
N
N
N
5
7e
82
212–213
N
N
N
123

M. Lv et al.
Table 2 continued
a
Entry
6
Product
7a–f
Yield (%)
m.p. (°C)
7f
81
177–178
N
N
N
Cl
Isolated yields
a
1
The main features of their H NMR spectra were the presence of signals
corresponding to the tert-butyl protons and the –SH proton at 1.33–1.36 and
4.55–14.67 ppm, respectively, and the signals for the aromatic protons exactly
1
1
3
matched the compound structures. The C NMR spectra, which were also in good
agreement with the assigned structures, revealed the presence of the tert-butyl
carbon atoms at approximately 31.7 and 35.0 ppm. Further, the structures assigned
to 5a–f were fully supported by their HRMS and elemental analysis, which
established their molecular formulae in accordance with the suggested molecular
structures.
Conclusions
In conclusion, we have described a facile synthesis of a series of tert-butyl-
substituted [1,2,4]triazino[5,6-b]indole-3-thiols and indolo[2,3-b]quinoxalines.
Because of the synergism of the tert-butyl group, the newly synthesized compounds
are likely to be biologically active and could be used for development of lead
compounds. The biological activity of the compounds are under investigation.
Experimental
The chemicals used in this work were obtained from Fluka and were used without
purification. Melting points were determined by use of a WRS-1B melting-point
-
apparatus and were uncorrected. IR spectra in the range 400–4,000 cm were
1
1
obtained as KBr pellets on a Shimadzu (Japan) FTIR-8400S spectrophotometer. H
1
NMR and C NMR spectra were recorded on a Bruker Avance NMR spectrometer
3
with CDCl or DMSO-d as solvent. Reported chemical shifts (d values) are given
3
6
in parts per million downfield from tetramethylsilane (TMS) as internal standard.
Mass spectra were determined by use of a MSD VL ESI1 spectrometer. Elemental
analysis was performed for C, H, and N by use of an Elementar Vario EL III
elemental analyzer. The progress of reactions was monitored by TLC on silica gel
GF254 with 5:1 (v/v) hexane–ethyl acetate as mobile phase.
1
23

tert-Butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols
Procedure for synthesis of 5-(t-butyl)indoline-2,3-dione (3a)
Sodium sulfate (300 g), 4-tert-butylaniline (59.6 g, 0.4 mol), concentrated hydro-
chloric acid (40 mL), and a solution of hydroxylamine hydrochloride (83.4 g,
0
.12 mol) in water (400 mL) were successively added to a solution of chloral
hydrate (71.1 g, 0.43 mol) in water (1,000 mL). The resulting solution was heated
under reflux for approximately 1 min. The precipitate obtained was filtered,
collected, then added in small portions to 200 mL sulfuric acid at 50 °C. The
mixture was heated at 80 °C for approximately 10 min, cooled to room temperature,
added slowly to crushed ice, and left to stand for 30 min. The precipitate formed
was collected by filtration, washed with water, and dried under vacuum. The crude
product was purified by column chromatography over silica gel. This compound
-
1
was obtained as red crystals. Yield 65 %, m.p. 142.3–143.0 °C. IR (KBr) m/cm
:
,458, 3,303, 2,963, 2,904, 1,749, 1,718, 1,625, 1,486, 1,366, 1,131, 833, 661, 494;
3
1
H NMR (400 MHz, CDCl ) d (ppm): 9.18 (s, 1H, NH), 7.64–7.56 (m, 2H, ArH),
3
1
3
.93 (d, J = 8.0 Hz, 1H, ArH), 1.27 (s, 9H, tert-butyl); C NMR (100 MHz,
6
CDCl ) d (ppm): 31.12, 34.59, 112.38, 117.71, 122.59, 136.05, 147.29, 147.44,
3
?
60.36, 183.92; MS (ESI, m/z): 203.9 [M ? H] ; HRMS (ESI, m/z): Calcd. for
1
C H NNaO [M ? Na] 226.0845, found 226.0850. Anal. Calcd for C H NO :
C, 70.92; H, 6.45; N, 6.89. Found: C, 70.82; H, 6.40; N, 6.80.
?
1
2
13
2
12 13
2
General procedure for synthesis of N-alkyl-5-(t-butyl)indoline-2,3- diones
3b–f)
(
An orange solution of 5-(tert-butyl)indoline-2,3-dione 3a (1.02 g, 5 mmol) in
DMF (10 mL) was cooled to 0 °C. At this temperature, NaH (0.13 g, 5.5 mmol)
was added slowly to the solution. The resulting mixture was stirred at room
temperature for 10 min, during which its color turned from orange to deep purple.
The respective halogenated compound (6 mmol) was slowly added to the solution,
which was then stirred for 3 h. When the reaction was complete (monitored by
TLC), the mixture was poured into ice–water, acidified with 1 M HCl, and the
crude product was isolated by filtration then recrystallized from ethanol to give
the pure product 3b–f.
5
-(t-Butyl)-1-methylindoline-2,3-dione (3b)
-
1
Red crystals, m.p. 144.7–144.8 °C, Yield 86 %. IR (KBr) m/cm : 3,446, 3,096,
1
,959, 1,744, 1,618, 1,491, 1,368, 1,327, 1,189, 1,113, 837, 618, 535; H NMR
2
(
400 MHz, CDCl ) d (ppm): 7.64 (d, J = 9.2 Hz, 2H, ArH), 6.83 (d, J = 8.0 Hz,
H, ArH), 3.24 (s, 3H, CH ), 1.31 (s, 9H, tert-butyl); C NMR (101 MHz, CDCl3)
3
3
1
3
1
d (ppm): 26.21, 31.15, 34.61, 109.53, 117.23, 122.40, 135.36, 147.34, 149.20,
?
58.55, 183.85; MS (ESI, m/z): 218.0 [M ? H] ; HRMS (ESI, m/z): Calcd. for
1
C H NNaO [M ? Na] 240.1001, found 240.0994. Anal. Calcd for C H NO :
C, 71.87; H, 6.96; N, 6.45. Found: C, 72.01; H, 6.95; N, 6.33.
?
1
3
15
2
13 15
2
123

M. Lv et al.
5
-(t-Butyl)-1-ethylindoline-2,3-dione (3c)
-
1
Red solid, m.p. 134.8–135.3 °C, Yield 88 %. IR (KBr) m/cm : 3,446, 2,967, 1,729,
1
,622, 1,491, 1,367, 1,339, 1,261, 1,121, 1,041, 990, 845, 617, 550; H NMR
1
(
ArH), 3.70 (q, J = 7.2 Hz, 2H, CH ), 1.29 (s, 9H, tert-butyl), 1.24 (t, J = 7.2 Hz,
400 MHz, CDCl ) d (ppm): 7.62–7.51 (m, 2H, ArH), 6.77 (d, J = 8.2 Hz, 1H,
3
2
1
3
3
1
2
2
6
H, CH3); C NMR (100 MHz, CDCl ) d (ppm): 12.58, 31.14, 34.57, 34.90,
3
09.65, 117.40, 122.59, 135.30, 147.10, 148.38, 158.15, 184.20; MS (ESI, m/z):
?
?
32.1 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H NNaO [M ? Na]
1
4
17
2
54.1158, found 254.1154. Anal. Calcd for C H NO : C, 72.70; H, 7.41; N,
2
1
4
17
.06. Found: C, 72.82; H, 7.58; N, 5.95.
5
-(t-Butyl)-1-butylindoline-2,3-dione (3d)
-
1
Red crystals, m.p. 52.7–53.2 °C, Yield 89 %. IR (KBr) m/cm : 3,444, 3,071, 2,964,
1
,930, 2,871, 1,729, 1,621, 1,490, 1,464, 1,340, 1,125, 845, 715, 593; H NMR
2
(
ArH), 3.64 (t, J = 7.3 Hz, 2H, CH ), 1.61 (p, J = 7.4 Hz, 2H, CH ), 1.34 (dd,
400 MHz, CDCl ) d (ppm): 7.63–7.48 (m, 2H, ArH), 6.76 (d, J = 8.2 Hz, 1H,
3
2
2
J = 15.1, 7.5 Hz, 2H, CH ), 1.26 (s, 9H, tert-butyl), 1.02 (t, J = 7.3 Hz, 3H, CH );
2
3
1
3
C NMR (101 MHz, CDCl ) d (ppm): 13.68, 20.11, 29.33, 31.14, 34.56, 39.96,
3
1
2
2
5
09.80, 117.35, 122.50, 135.28, 147.03, 148.79, 158.42, 184.16; MS (ESI, m/z):
?
?
60.0 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H NNaO [M ? Na]
1
6
21
2
82.1471, found 282.1467. Anal. Calcd for C H NO : C, 74.10; H, 8.16; N,
1
6
21
2
.40. Found: C, 74.28; H, 8.05; N, 5.52.
1
-Benzyl-5-(t-butyl)indoline-2,3-dione (3e)
-
1
Red solid, m.p. 123.9–124.5 °C, Yield 92 %. IR (KBr) m/cm : 3,452, 2,963, 2,868,
1
,739, 1,620, 1,488, 1,367, 1,190, 1,081, 912, 827, 750, 700, 548; H NMR
1
(
400 MHz, CDCl ) d (ppm): 7.63 (s, 1H, ArH), 7.49 (d, J = 8.3 Hz, 1H, ArH),
3
7
9
1
1
.40–7.31 (m, 5H, ArH), 6.69 (d, J = 8.3 Hz, 1H, ArH), 4.88 (s, 2H, CH ), 1.24 (s,
2
1
3
H, tert-butyl); C NMR (100 MHz, CDCl ) d (ppm): 31.11, 34.56, 44.01, 110.61,
3
17.43, 122.47, 127.47, 128.08, 128.98, 134.67, 135.38, 147.30, 148.44, 158.56,
?
83.73; MS (ESI, m/z): 294.06 [M ? H] ; HRMS (ESI, m/z): Calcd. for
?
C H NNaO [M ? Na] 316.1314, found 316.1321. Anal. Calcd for
C H NO : C, 77.79; H, 6.53; N, 4.77. Found: C,77.68; H, 6.47; N,4.89.
1
9
19
2
1
9
19
2
5
-(t-Butyl)-1-(4-chlorobenzyl)indoline-2,3-dione (3f)
-
1
Red solid, m.p. 106.3–107.8 °C, Yield 90 %. IR (KBr) m/cm : 3,735, 3,447, 2,958,
1
,905, 2,867, 1,738, 1,623, 1,490, 1,368, 1,343, 1,131, 828, 624; H NMR
2
(
400 MHz, CDCl ) d (ppm): 7.59 (s, 1H, ArH), 7.45 (d, J = 8.3 Hz, 1H, ArH), 7.22
3
(
dd, J = 14.6, 8.2 Hz, 4H, ArH), 6.61 (d, J = 8.2 Hz, 1H, ArH), 4.80 (s, 2H, CH ),
2
1
3
1
1
1
.20 (s, 9H, tert-butyl); C NMR (100 MHz, CDCl ) d (ppm): 31.09, 34.59, 43.37,
3
10.43, 117.44, 122.62, 128.86, 129.29, 133.19, 133.99, 135.40, 147.53, 148.09,
?
58.52, 183.45; MS (ESI, m/z): 328.0 [M ? H] ; HRMS (ESI, m/z): Calcd. for
1
23

tert-Butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols
3
18
5
?
C H ClNNaO [M ? Na] 350.0925, found 350.0933. Anal. Calcd for C H
19 18-
1
9
2
ClNO : C, 69.62; H, 5.53; N, 4.27. Found: C, 69.82; H, 5.55; N, 4.09.
2
General procedure for synthesis of 8-(t-butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-
thiols (5a–f)
A mixture of the appropriate 5-(t-butyl)indoline-2,3-dione 3 (1 mmol), thiosemi-
carbazide 4 (0.1 g, 1.1 mmol), and K CO (0.21 g, 1.5 mmol) in 30 % aqueous 1,4-
2
3
dioxane (25 mL) was heated under reflux for 10 h. On completion of the reaction
the mixture was cooled to room temperature, quenched by addition of ice–water
(
10 mL), and acidified with acetic acid. The resulting crude product was washed
with water, dried, and recrystallized from acetic acid to give the corresponding pure
product 5a–f. The yields and physical properties of 5a–f are summarized in Table 1;
their spectral and analytical data are given below.
8
-(t-Butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (5a)
-
1
Brown crystals. IR (KBr) m/cm : 3,436, 2,965, 2,848, 1,605, 1,566, 1,460, 1,318,
1
1
1
1
3
,148, 816; H NMR (400 MHz, DMSO-d ) d (ppm): 14.57 (s, 1H, SH), 12.34 (s,
6
H, NH), 7.97 (s, 1H, ArH), 7.71 (d, J = 8.4 Hz, 1H, ArH), 7.38 (d, J = 8.5 Hz,
1
H, ArH), 1.35 (s, 9H, tert-butyl); C NMR (101 MHz, DMSO-d ) d (ppm): 31.72,
4.99, 112.96, 117.83, 118.46, 129.83, 136.18, 141.41, 146.23, 149.72, 179.24; MS
?
ESI, m/z): 259.0 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H N NaS
3
6
(
1
3 14 4
?
[
M ? Na] 281.0837, found 281.0835. Anal. Calcd for C H N S: C, 60.44; H,
13 14 4
5
.46; N, 21.69. Found: C, 60.53; H, 5.39; N, 21.81.
8
-(t-Butyl)-5-methyl-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (5b)
-
1
Yellow crystals. IR (KBr) m/cm : 3,435, 2,965, 2,849, 2,350, 1,606, 1,567, 1,462,
1
1
,319, 1,147, 816; H NMR (400 MHz, DMSO-d ) d (ppm): 14.55 (s, 1H, SH), 8.00
6
(
s, 1H, ArH), 7.79 (d, J = 7.5 Hz, 1H, ArH), 7.58 (d, J = 6.1 Hz, 1H, ArH), 3.64
1
3
(
s, 3H, CH ), 1.36 (s, 9H, tert-butyl); C NMR (100 MHz, DMSO-d ) d (ppm):
3
6
2
7.88, 31.73, 35.05, 111.61, 117.46, 118.38, 129.71, 135.91, 142.60, 146.80,
?
48.69, 179.17; MS (ESI, m/z): 273.2 [M ? H] ; HRMS (ESI, m/z): Calcd. for
1
C H N NaS [M ? Na] 295.0994, found 295.0983. Anal. Calcd for C H N S:
C, 61.74; H, 5.92; N, 20.57. Found: C, 61.88; H, 5.95; N, 20.43.
?
1
4
16
4
14 16 4
8
-(t-Butyl)-5-ethyl-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (5c)
-
1
Yellow crystals. IR (KBr) m/cm : 3,438, 2,965, 2,850, 1,605, 1,565, 1,464, 1,318,
1
1
ArH), 7.77 (d, J = 10.2 Hz, 1H, ArH), 7.64 (d, J = 8.6 Hz, 1H, ArH), 4.23 (q,
,148, 815; H NMR (400 MHz, DMSO-d ) d (ppm): 14.57 (s, 1H, SH), 8.01 (s, 1H,
6
1
3
J = 7.1 Hz, 2H, CH ), 1.36 (s, 9H, tert-butyl), 1.33 (t, J = 7.2 Hz, 3H, CH );
2
C
3
NMR (100 MHz, DMSO-d ) d (ppm): 13.46, 31.71, 35.03, 36.30, 111.68, 117.65,
6
1
18.57, 129.74, 135.94, 141.61, 146.72, 148.11, 179.16; MS (ESI, m/z): 287.2
?
?
[
M ? H] ; HRMS (ESI, m/z): Calcd. for C H N NaS [M ? Na] 309.1151,
15 18 4
123

M. Lv et al.
found 309.1157. Anal. Calcd for C H N S: C, 62.91; H, 6.33; N, 19.56. Found: C,
1
5 18 4
6
2.75; H, 6.39; N, 19.70.
8
-(t-Butyl)-5-butyl-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (5d)
-
1
Yellow crystals. IR (KBr) m/cm : 3,436, 2,968, 2,850, 2,350, 1,605, 1,566, 1,464,
1
1
,318, 1,148, 1,117, 1,018, 818, 539; H NMR (400 MHz, DMSO-d ) d (ppm):
6
1
ArH), 4.18 (t, J = 7.1 Hz, 2H, CH ), 1.73 (dd, J = 14.9, 7.4 Hz, 2H, CH ),
4.58 (s, 1H, SH), 8.00 (s, 1H, ArH), 7.75 (s, 1H, ArH), 7.63 (d, J = 8.6 Hz, 1H,
2
2
1
3
1
.37–1.31 (m, 11H, CH and tert-butyl), 0.91 (t, J = 7.3 Hz, 3H, CH ); C NMR
2 3
(
100 MHz, DMSO-d ) d (ppm): 14.08, 20.00, 30.05, 31.70, 35.02, 41.16, 111.80,
6
1
3
3
1
17.57, 118.50, 129.73, 135.81, 141.99, 146.69, 148.47, 179.19; MS (ESI, m/z):
?
?
15.2 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H N NaS [M ? Na]
1
7 22 4
37.1464, found 337.1459. Anal. Calcd for C H N S: C, 64.93; H, 7.05; N,
7 22 4
1
7.82. Found: C, 65.09; H, 6.98; N, 17.71.
5
-Benzyl-8-(t-butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (5e)
-
1
Yellow crystals. IR (KBr) m/cm : 3,431, 2,960, 2,838, 1,605, 1,566, 1,318, 1,148,
1
1
,057, 810, 700; H NMR (400 MHz, DMSO-d ) d (ppm): 14.67 (s, 1H, SH), 8.02
6
(
s, 1H, ArH), 7.70 (d, J = 8.3 Hz, 1H, ArH), 7.43 (d, J = 8.6 Hz, 1H, ArH),
1
3
7
.39–7.23 (m, 5H, ArH), 5.43 (s, 2H, CH ), 1.33 (s, 9H, tert-butyl); C NMR
2
(
100 MHz, DMSO-d ) d (ppm): 31.67, 35.03, 44.43, 112.01, 117.75, 118.58,
6
1
MS (ESI, m/z): 349.3 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H N NaS
27.70, 128.18, 129.16, 129.73, 135.89, 135.94, 141.72, 146.94, 148.85, 179.43;
?
2
0 20 4
?
[
M ? Na] 371.1307, found 371.1300. Anal. Calcd for C H N S: C, 68.93; H,
20 20 4
5
.79; N, 16.08. Found: C, 69.05; H, 5.70; N,16.19.
8
-(t-Butyl)-5-(4-chlorobenzyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiol (5f)
-
1
Yellow solid. IR (KBr) m/cm : 3,441, 2,959, 2,838, 1,606, 1,566, 1,318, 1,148,
1
8
7
1
4
1
21; H NMR (400 MHz, DMSO-d ) d (ppm): 14.68 (s, 1H, SH), 8.02 (s, 1H, ArH),
6
.69 (d, J = 8.2 Hz, 1H, ArH), 7.42 (d, J = 12.0 Hz, 5H, ArH), 5.43 (s, 2H, CH ),
3
.34 (s, 9H, tert-butyl); C NMR (100 MHz, DMSO-d ) d (ppm): 31.66, 35.03,
3.77, 109.99, 111.92, 117.81, 118.61, 129.10, 129.67, 132.80, 134.94, 136.00,
?
41.57, 146.98, 148.90, 179.44; MS (ESI, m/z): 383.7 [M ? H] ; HRMS (ESI, m/
2
1
6
3
19
5
?
z): Calcd. for C H ClN NaS [M ? Na] 405.0917, found 405.0909. Anal. Calcd
4
2
0
for C H ClN S: C, 62.73; H, 5.00; N, 14.63. Found: C, 62.87; H, 5.09; N, 14.52.
2
0
19
4
General procedure for the synthesis of 9-(t-butyl)-6H-indolo[2,3-b]quinoxaline
7a–f)
(
o-Phenylenediamine (0.11 g, 1 mmol) was added to a stirred solution of the
respective 5-(t-butyl)indoline-2,3-dione 3 (1 mmol) in acetic acid (3 mL). The
resulting reaction mixture was heated under reflux for 16 h. When the reaction was
complete (TLC), the reaction mixture was quenched by addition of 8 mL H O. The
2
1
23

tert-Butyl-substituted [1,2,4]triazino[5,6-b]indole-3-thiols
resulting precipitate was isolated by filtration to give the crude product, which was
purified by silica gel column chromatography with ethyl acetate–petroleum ether
(1:6) as eluent to afford the products, 7a–f. The yields of 7a–f are summarized in
Table 2; their spectral and analytical data are given below.
9
-(t-Butyl)-6H-indolo[2,3-b]quinoxaline (7a)
-
1
1
Yellow solid. IR (KBr) m/cm : 3,066, 2,953, 1,614, 1,579, 1,481, 763; H NMR
(
400 MHz, DMSO-d ) d (ppm): 11.94 (s, 1H, NH), 8.40–8.23 (m, 2H, ArH), 8.07
6
(
d, J = 8.2 Hz, 1H, ArH), 7.97–7.85 (m, 1H, ArH), 7.81 (d, J = 8.5 Hz, 1H, ArH),
1
.76–7.70 (m, 1H, ArH), 7.55–7.44 (m, 1H, ArH), 1.43 (s, 9H, tert-butyl); C NMR
3
7
(
100 MHz, DMSO-d ) d (ppm): 30.26, 36.13, 109.87, 119.42, 120.69, 126.96,
6
1
MS (ESI, m/z): 276.1 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H N Na
27.32, 127.86, 128.96, 130.40, 131.03, 131.98, 141.63, 143.45, 144.68, 153.62;
?
1
8 17 3
?
[
M ? Na] 298.1321, found 298.1312. Anal. Calcd for C H N : C, 78.52; H,
18 17 3
6
.22; N, 15.26. Found: C, 78.72; H, 6.11; N, 15.12.
9
-(t-Butyl)-6-methyl-6H-indolo[2,3-b]quinoxaline (7b)
-
1
1
Yellow solid. IR (KBr) m/cm : 3,060, 2,953, 1,614, 1,577, 1,476, 749; H NMR
400 MHz, DMSO-d ) d (ppm): 8.33 (d, J = 1.6 Hz, 1H, ArH), 8.26 (d,
J = 8.3 Hz, 1H, ArH), 8.11 (d, J = 8.2 Hz, 1H, ArH), 7.84 (m, 2H, ArH),
(
6
7
9
1
1
.76–7.72 (m, 1H, ArH), 7.67 (d, J = 8.6 Hz, 1H, ArH), 3.90 (s, 3H, CH ), 1.44 (s,
3
1
3
H, tert-butyl); C NMR (100 MHz, DMSO-d ) d (ppm): 25.87, 29.89, 32.87,
6
08.25, 116.30, 116.38, 124.17, 125.72, 127.15, 127.36, 136.76, 138.09, 138.21,
?
41.38, 141.98, 143.84, 150.55; MS (ESI, m/z): 290.1 [M ? H] ; HRMS (ESI, m/
?
z): Calcd. for C H N Na [M ? Na] 312.1478, found 312.1470. Anal. Calcd for
1
9 19 3
C H N : C, 78.86; H, 6.62; N, 14.52. Found: C, 79.01; H, 6.50; N, 14.61.
19 19 3
9
-(t-Butyl)-6-ethyl-6H-indolo[2,3-b]quinoxaline (7c)
-
1
1
Pale yellow powder. IR (KBr) m/cm : 3,068, 2,953, 1,634, 1,576, 1,476, 751; H
NMR (400 MHz, DMSO-d ) d (ppm): 8.35 (s, 1H, ArH), 8.27 (d, J = 8.2 Hz, 1H,
6
ArH), 8.13 (d, J = 8.2 Hz, 1H, ArH), 7.84–7.78 (m, 2H, ArH), 7.73 (t, J = 8.6 Hz,
2
9
3
1
H, ArH), 4.50 (q, J = 7.2 Hz, 2H, CH ), 1.45 (t, J = 7.2 Hz, 3H, CH ), 1.38 (s,
2 3
1
3
H, tert-butyl); C NMR (100 MHz, DMSO-d ) d (ppm): 13.88, 31.96, 34.94,
6
6.22, 109.99, 110.38, 118.58, 118.63, 126.29, 127.87, 129.44, 129.61, 138.92,
?
40.23, 140.29, 142.39, 144.01, 145.26; MS (ESI, m/z): 304.1 [M ? H] ; HRMS
?
ESI, m/z): Calcd. for C H N Na [M ? Na] 326.1634, found 326.1638. Anal.
(
Calcd for C H N : C, 79.17; H, 6.98; N, 13.85. Found: C, 79.35; H, 6.92; N,
2
0 21 3
2
0 21 3
1
3.69.
9
-(t-Butyl)-6-butyl-6H-indolo[2,3-b]quinoxaline (7d)
-
1
Pale yellow crystals. IR (KBr) m/cm : 3,030, 2,953, 1,614, 1,580, 1,476, 1,403,
1
7
51; H NMR (400 MHz, DMSO-d ) d (ppm): 8.34 (s, 1H, ArH), 8.27 (d,
6
123

M. Lv et al.
J = 8.3 Hz, 1H, ArH), 8.11 (d, J = 8.4 Hz, 1H, ArH), 7.82 (dd, J = 12.4, 4.7 Hz,
2H, ArH), 7.73 (t, J = 7.5 Hz, 1H, ArH), 7.66 (d, J = 8.5 Hz, 1H, ArH), 4.45 (t,
J = 6.8 Hz, 2H, CH ), 1.89–1.79 (m, 2H, CH ), 1.44 (s, 9H, tert-butyl), 1.33–1.36
2
2
1
3
(
m, 2H, CH ), 0.91 (t, J = 7.3 Hz, 3H, CH ); C NMR (100 MHz, DMSO-d ) d
2
3
6
(
ppm): 11.96, 18.02, 28.43, 29.84, 32.81, 40.61, 108.33, 116.41, 116.43, 124.15,
1
MS (ESI, m/z): 332.2 [M ? H] ; HRMS (ESI, m/z): Calcd. for C H N Na
25.80, 127.32, 127.43, 136.81, 137.94, 138.20, 140.63, 141.81, 143.55, 149.81;
?
2
2 25 3
?
[
M ? Na] 354.1947, found 354.1956. Anal. Calcd for C H N : C, 79.72; H,
22 25 3
7
.60; N, 12.68. Found: C, 79.87; H, 7.51; N, 12.56.
6
-Benzyl-9-(t-butyl)-6H-indolo[2,3-b]quinoxaline (7e)
-
1
Yellow flocculent solid. IR (KBr) m/cm : 3,068, 2,961, 1,615, 1,581, 1,475, 757;
1
H NMR (400 MHz, DMSO-d ) d (ppm): 8.36 (s, 1H, ArH), 8.30 (d, J = 8.1 Hz,
6
1
H, ArH), 8.13 (d, J = 7.9 Hz, 1H, ArH), 7.87–7.72 (m, 3H, ArH), 7.60 (d,
J = 8.2 Hz, 1H, ArH), 7.38–7.23 (m, 5H, ArH), 5.72 (s, 2H, CH ), 1.41 (s, 9H, tert-
2
1
3
butyl); C NMR (100 MHz, DMSO-d ) d (ppm): 29.83, 32.87, 42.49, 108.74,
6
1
16.51, 124.45, 124.48, 125.47, 125.78, 125.85, 127.02, 127.30, 128.70, 129.12,
34.28, 136.83, 142.46, 143.78, 144.86, 145.51, 149.20; MS (ESI, m/z): 366.3
1
?
?
[
M ? H] ; HRMS (ESI, m/z): Calcd. for C H N Na [M ? Na] 388.1791, found
25 23 3
388.1795. Anal. Calcd for C H N : C, 82.16; H, 6.34; N, 11.50. Found: C, 82.25;
25 23 3
H, 6.41; N, 11.36.
9
-(t-Butyl)-6-(4-chlorobenzyl)-6H-indolo[2,3-b]quinoxaline (7f)
-
1
1
Yellow solid. IR (KBr) m/cm : 3,121, 2,956, 1,660, 1,534, 1,443, 1,421, 736; H
NMR (400 MHz, DMSO-d ) d (ppm): 8.36 (s, 1H, ArH), 8.30 (d, J = 8.2 Hz, 1H,
6
ArH), 8.12 (d, J = 8.2 Hz, 1H, ArH), 7.86–7.73 (m, 3H, ArH), 7.61 (d, J = 8.6 Hz,
1
3
1
H, ArH), 7.40–7.33 (m, 4H, ArH), 5.72 (s, 2H, CH ), 1.41 (s, 9H, tert-butyl);
2
C
NMR (100 MHz, DMSO-d ) d (ppm): 29.83, 32.88, 41.84, 108.68, 116.55, 116.75,
6
1
24.52, 125.85, 127.00, 127.35, 127.41, 127.62, 130.39, 134.34, 137.15, 138.10,
?
38.21, 140.32, 142.40, 143.66, 149.20; MS (ESI, m/z): 400.5 [M ? H] ; HRMS
1
3
5
?
(ESI, m/z): Calcd. for C H ClN Na [M ? Na] 422.1401, found 422.1395. Anal.
25 22 3
Calcd for C H ClN : C, 75.08; H, 5.54; N, 10.51. Found: C, 75.26; H, 5.62; N,
2
5
22
3
1
0.29.
Acknowledgments The authors are grateful for financial support from the Scientific Research
Foundation of the Education Department of Liaoning Province (grant no. L2013428).
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