Synthesis of New tert-Butyl- and Bromo-functionalized [1,2,4]Triazino [5,6-b]indole-3-thiols and Indolo[2,3-b]quinoxalines

Article abstract of DOI:10.1002/jhet.2895

In the present investigation, the synthesis of a series of structurally new and interesting tert-butyl- and bromo-functionalized [1,2,4]triazino[5,6-b]indoles (6a–f) and indolo[2,3-b]quinoxalines (8a–f) has been achieved, involving the condensation reacti

Full text of DOI:10.1002/jhet.2895

Month 2017
Synthesis of New tert-Butyl- and Bromo-functionalized [1,2,4]Triazino
[5,6-b]indole-3-thiols and Indolo[2,3-b]quinoxalines
*
Yang Li,
Yang Wang, and Hong Zhang
Institute of Superfine Chemicals, Bohai University, Jinzhou, 121000, China
*
E-mail: bhuzh@163.com
Additional Supporting Information may be found in the online version of this article.
Received December 22, 2016
DOI 10.1002/jhet.2895
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
In the present investigation, the synthesis of a series of structurally new and interesting tert-butyl- and
bromo-functionalized [1,2,4]triazino[5,6-b]indoles (6a–f) and indolo[2,3-b]quinoxalines (8a–f) has been
achieved, involving the condensation reaction of 7-bromo-5-tert-butylisatins (4a–f) with thiosemicarbazide
(5) and benzene-1,2-diamine (7). The substrates 4a–f were prepared through bromination reaction of 5-tert-
butylisatin (3) with NBS in PEG-400 followed by alkylation reaction. The molecular structures of these
newly synthesized compounds were elucidated on the basis of their elemental analyses and spectral data.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
introduction of tert-butyl group into organic molecules
could increase their lipophilicity, which is very important
for passing through the extraordinary thick and light cell
wall [19,20], thereby leading to significant enhancement
of their biological activity.
Functionalized indole-fused heterocyclic ring systems
such as [1,2,4]triazino[5,6-b]indoles and indolo[2,3-b]
quinoxalines represent an important class of organic
molecules that have attracted a great deal of attention
because of their potent biological activities and medicinal
applications [1–4]. Compounds containing [1,2,4]
triazino[5,6-b]indole moiety exhibited potent antifungal
[5], anti-hypertensive [6], and antileishmanial activities
[7] and were frequently used as privileged structural
motifs in drug discovery [8,9]. Indolo[2,3-b]quinoxalines
could intercalate into base pairs of DNA as an
intercalator to induce topoisomerase II dependent DNA
cleavage, thereby exhibiting potent antiviral and
Taking the above-mentioned observations into account,
and in view of structural diversity playing a prominent
role in medicinal and combinatorial chemistry for a faster
and more efficient route toward new drug discovery [21],
we conceived that the construction of tert-butyl- and
bromo-functionalized [1,2,4]triazino[5,6-b]indole and
indolo[2,3-b]quinoxaline derivatives as possible drug-like
candidates or useful synthetic building blocks would be
of synthetic importance for current medicinal chemistry
needs. Accordingly, in the context of our ongoing efforts
to the interesting types of hybrid N-heterocycles [22–25],
herein, we would like to report a simple and facile
synthesis of such compounds through the condensation
antitumor activities [10,11]. As
a
consequence,
considerable synthetic efforts have been devoted to the
use of such ring-fused framework for further modification
and functionalization by organic and medicinal chemists
aiming to enhance the potency of this class of ring
systems [12–14].
As well known, indole nucleus upon bearing a
derivatizable bromo functional group would make them
particularly appealing, because the group could provide
ample opportunities for further synthetic manipulation
reaction
between
7-bromo-5-tert-butylisatins
and
thiosemicarbazide or benzene-1,2-diamine. To the best of
our knowledge, the synthesis of such meaningful
indole-fused heterocyclic compounds has not been
achieved so far.
such
as
transition-metal-catalyzed
cross-coupling
RESULTS AND DISCUSSION
reactions [15,16] and thus play an important role as
valuable building blocks in molecular assemblies and
new drug design. Furthermore, the bromo-functionalized
indole motifs are also significant structure fragment in
many pharmaceuticals and natural products [17,18]. On
the other hand, it has been well established that the
Our synthesis commenced with the preparation of the
required 7-bromo-5-tert-butylisatin (4a) as shown in
Scheme 1 via a facile two-step procedure, involving the
Sandmeyer synthesis of 5-tert-butylisatin (3) from the
commercially available 4-(tert-butyl)aniline (1) [26] and
© 2017 Wiley Periodicals, Inc.

Y. Li, Y. Wang, and H. Zhang
Vol 000
Scheme 1. Route for the preparation of N-alkyl-7-bromo-5-t-butylisatins (4a–f).
subsequent bromination reaction by using NBS/PEG-400
system. It is worthy to mention that the direct
bromination of 3 using bromine has great drawbacks
arising out of its toxic, corrosive, and environmentally
hazardous nature. Moreover, the reaction is also generally
unselective forming mixtures of monobrominated and
polybrominated products. Thus, in our search for a
simpler procedure, we found that 4a could be efficiently
synthesized by employing NBS as the brominating agent
in eco-friendly PEG-400 medium at room temperature
[27]. The approach is very simple, convenient, and easy
to work up. After usual workup and recrystallization from
ethanol, the product 4a was obtained in a good yield of
81%. Subsequently, the resulting 4a was further
underwent N-alkylation reaction using NaH as the base in
dry DMF as the solvent to furnish the corresponding
N-alkyl-7-bromo-5-tert-butylisatins 4b–f in 89–93%
yields.
Having the required substrates 4a–f in hand, our
attention was transferred to their condensation reaction
with thiosemicarbazide (5) with the aim of building the
desired 6-bromo- and 8-tert-butyl-functionalized [1,2,4]
triazino[5,6-b]indole-3-thiols (6a–f) according to the
conditions described in Scheme 2.
In fact, at the initial stage of this study, we conducted the
transformation between isatin 4a and 5 using water as the
solvent at refluxing temperature, which had recently been
published for this type of transformation [7]. Although
the procedure was very easy, eco-friendly, and
impressive, this purported approach was ineffective in our
hands, and the reaction proceeded in heterogeneous phase
all time, probably because of the presence of highly
hydrophobic tert-butyl group. In our earlier publications,
we described the application of triethylbenzyl ammonium
chloride (TEBAC) as an efficient phase transfer catalyst
in the one-pot aqueous reaction of tert-butyl-substituted
salicylaldehydes with Meldrum’s acid for the synthesis of
tert-butyl-substituted 3-carboxycoumarins [28]. On this
basis, we envisioned that TEBAC might also be used for
the present synthesis. Unfortunately, contrary to
expectation, no formation of the desired product was
observed under the reaction conditions, and the starting
materials were recovered unchanged. In an effort, we
further investigated the aqueous reaction by employing
β-cyclodextrin as the catalyst, which was reported to
yield better results in this type of reaction [29]. However,
this attempt was also to no avail in our case.
After these unsuccessful trials, we were delighted to find
that upon employing H2O/1,4-dioxane system as the mixed
solvent the condensation reaction of 4a with 5 proceeded
smoothly, and 30% aq. 1,4-dioxane was found to be
optimal to complete the reaction, providing the maximum
yield of 6a in 82% (Scheme 2). When using other
organic solvents such as EtOH, DMF, and MeCN instead
of 1,4-dioxane, no further improvement in the product
yield was observed. Because of the satisfactory yield
obtained and in order to retain the simplicity of the
procedure, no further optimization in reaction conditions
was necessary, and the mentioned condition was chosen
for the following work. Thereafter, we tested this
protocol for the condensation reaction of N-alkyl
substituted 4b–f under the same reaction conditions. As
Scheme 2. Synthesis of 6-bromo-8-(tert-butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiols (6a–f).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New tert-Butyl- and Bromo-functionalized [1,2,4]Triazino [5,6-b]
indole-3-thiols and Indolo[2,3-b]quinoxalines
expected, these substrates were equally amenable to the
reaction process without any experimental difficulties,
successfully furnishing the corresponding targeted
products 6b–f in good yields of 74–86%.
In summary, the synthesis of a series of hitherto
unreported tert-butyl- and bromo-functionalized[1,2,4]
triazino[5,6-b]indole-3-thiols and indolo[2,3-b] quinoxalines
has been achieved with good yields. These molecules we
have synthesized should allow us, in the future, to
investigate the structure–activity relationships over
various biotests. In addition, it is important to mention
that these newly synthesized compounds contain a
derivatizable bromo group on the indole ring, which
makes them particularly appealing, because the bromo
functional group provides ample opportunities for further
synthetic manipulation, for example, by cross-coupling
reactions to obtain more complex compounds. Further
elaboration of these compounds to a variety of other
functional groups is ongoing and will be covered in
further publications.
Recently, Reddy et al. reported the synthesis of
chloro/fluoro-substituted
6-N-butyl-6H-indolo[2,3-b]
quinoxalines, which exhibited significant in vitro
cytotoxic activity against HeLa cells [30]. To the best of
our knowledge, the synthesis of bromo- and tert-butyl-
functionalized indolo[2,3-b]quinoxaline derivatives is still
unprecedented. Thus, we became interested in the
condensation reaction of 4a–f with benzene-1,2-diamine
(7) for the synthesis of the structurally new 7-bromo-
9-(tert-butyl)-6-alkyl-6H-indolo[2,3-b]quinoxalines (8a–f)
as possible drug-like candidates.
Our investigation toward the reaction was conducted as
shown in Scheme 3 with a mole ratio of 1:1 in refluxing
acetic acid. Gratifyingly, the reaction proceeded well, and
the TLC analysis did not indicate the formation of any
distinct byproduct. After usual workup followed by
purification of the crude product by recrystallization from
ethyl acetate, the desired products 8a–f were obtained in
good yields of 79–94%. Worthy to mention that
additional experiments employing the reaction conditions
reported by Kenning et al. [31] (using ethanol as the
solvent at room temperature) resulted in modest product
yields.
EXPERIMENTAL
General.
All chemicals (AR graded) were
commercially available and used without further
purification. The melting points were determined by
using WRS-1B melting points apparatus and were
uncorrected. The IR spectra were obtained as KBr pellets
in the range of 400–4000 cmÀ1 on a Shimadzu FTIR-
8400S spectrophotometer (Shimadzu, Japan). 1H NMR
and 13C NMR spectra were recorded on a Bruker Avance
NMR spectrometer using CDCl3, DMSO-d6, or CF3COOD
as the solvent. The reported chemical shifts (δ values) are
given in parts per million downfield from TMS as the
internal standard. The mass spectra were determined using
an MSD VL ESI1 spectrometer. The elemental analyses
were performed for C, H, N using an Elementar Vario EL
III element analyzer. The progress of reactions was
monitored by TLC on silica gel GF254 using
hexane/ethyl acetate mixture as eluent (5:1, v/v) as the
The structures of the newly synthesized products 6a–f and
8a–f were well characterized by their spectral data and
elemental analyses with the results being in good agreement
with the expected compounds (See Supporting
Information). For instance, the IR spectra of 6a–f clearly
exhibited the absorption bands characteristic of the ─SH
1
group at 3435–3438 cmÀ1. The main features of their H
NMR spectra were the presence of the signal corresponding
to the tert-butyl protons and ─SH proton at 1.25–1.35 ppm
and 14.71–15.11 ppm, respectively, along with the signals
for aromatic protons exactly matching their structures in the
aromatic range. Further, their 13C NMR spectra were also in
good agreement with the assigned structure, which revealed
the presence of the tert-butyl carbons at 30.85–32.82 ppm
and 34.50–35.19 ppm. Finally, the structures assigned for
6a–f were fully supported by their elemental analyses,
which established their molecular formulas in accordance
with the suggested molecular structures.
eluent.
Procedure for the synthesis of 5-(t-butyl)indoline-2,3-dione
(3). To a 1000-mL aqueous solution of 71.1-g chloral
hydrate (0.43 mol) were added 300-g sodium sulfate,
59.6-g 4-tert-butylaniline (0.4 mol), 40-mL concentrated
hydrochloric acid, and a 400-mL aqueous solution of
83.4-g hydroxylamine hydrochloride (0.12 mol),
successively. This solution was then heated at refluxing
Scheme 3. Synthesis of 7-bromo-9-(tert-butyl)-6H-indolo[2,3-b]quinoxalines (8a–f).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Li, Y. Wang, and H. Zhang
Vol 000
temperature for about 1 min. The precipitate was filtered,
collected, and then added to 200-mL sulfuric acid at
50°C in small portions. The resulting mixture was further
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 is collected by
filtration, washed with water, and dried under vacuum.
The crude product was purified by column
chromatography over silica gel to give 5-(t-butyl)
indoline-2,3-dione (3) as red crystals. Yield 65%, mp
142–143°C; IR (KBr) ν/cmÀ1: 3458, 3303, 2963, 2904,
3734, 3461, 2953, 2360, 1743, 1614, 1567, 1463, 1368,
1166, 1095, 887, 711, 620; H NMR (400 MHz, CDCl3)
1
δ (ppm): 7.61 (s, 1H, Ar H), 7.55 (s, 1H, Ar H), 3.56 (s,
3H, Me), 1.23 (s, 9H, tert-butyl); 13C NMR (100 MHz,
CDCl3) δ (ppm): 27.73, 29.11, 32.80, 102.17, 118.41,
120.13, 138.74, 144.01, 147.28, 157.06, 181.18.
Anal. Calcd for C13H14BrNO2: C, 52.72; H, 4.76; N,
4.73. Found: C, 52.60; H, 4.70; N, 4.75.
7-Bromo-5-(t-butyl)-1-ethylindoline-2,3-dione (4c).
Red
crystals, yield 92%, mp 102–103°C; IR (KBr) ν/cmÀ1
:
3734, 3455, 2959, 2869, 2360, 1753, 1625, 1563, 1460,
1
1
1332, 1238, 1108, 1037, 842, 783, 624, 560; H NMR
1749, 1718, 1625, 1486, 1366, 1131, 833, 661, 494; H
(400 MHz, CDCl3) δ (ppm): 7.61 (s, 1H, Ar H), 7.55 (s,
1H, Ar H), 4.14 (q, J = 7.2 Hz, 2H, CH2CH3), 1.29 (t,
J = 5.8 Hz, 3H, CH2CH3), 1.23 (s, 9H, tert-butyl); 13C
NMR (100 MHz, CDCl3) δ (ppm): 12.86, 29.10, 32.75,
34.51, 101.78, 118.78, 120.30, 138.92, 143.52, 147.07,
156.96, 181.53. Anal. Calcd for C14H16BrNO2: C, 54.21;
H, 5.20; N, 4.52. Found: C, 54.00; H, 5.12; N, 4.39.
7-Bromo-5-(t-butyl)-1-butylindoline-2,3-dione (4d). Orange
solid, yield 89%, mp 96–97°C; IR (KBr) ν/cmÀ1: 3734,
3458, 2949, 2860, 2360, 1748, 1621, 1567, 1478, 1365,
NMR (400 MHz, CDCl3) δ (ppm): 9.18 (s, 1H, NH),
7.64–7.56 (m, 2H, Ar H), 6.93 (d, J = 8.0 Hz, 1H, Ar H),
1.27 (s, 9H, tert-butyl); 13C NMR (100 MHz, CDCl3) δ
(ppm): 31.12, 34.59, 112.38, 117.71, 122.59, 136.05,
147.29, 147.44, 160.36, 183.92; Anal. Calcd for
C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.82;
H, 6.40; N, 6.80.
Procedure for the synthesis of 7-bromo-5-(t-butyl)indoline-
2,3-dione (4a).
5-(tert-Butyl)indoline-2,3-dione
3
(0.203 g, 1 mmol) and NBS (0.196 g, 1.1 mmol) were
dissolved in PEG-400 (1 mL) and then stirred at room
temperature for 24 h. After completion of the reaction
monitored by TLC, the reaction mixture was poured into
icy water. The crude products were obtained after
filtration and washing with water. The pure product 4a
was obtained as red solid by recrystallization from
1
1335, 1161, 1101, 1033, 839, 715; H NMR (400 MHz,
CDCl3) δ (ppm): 7.60 (s, 1H, Ar H), 7.55 (s, 1H, Ar H),
4.04 (t, J = 7.6 Hz, 2H, CH2), 1.67 (q, J = 7.4 Hz, 2H,
CH2), 1.35 (dd, J = 15.0, 7.5 Hz, 2H, CH2), 1.23 (s, 9H,
tert-butyl), 0.90 (t, J = 7.4 Hz, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ (ppm): 13.77, 19.87, 30.92, 31.38,
34.56, 41.09, 103.69, 120.60, 122.11, 140.74, 145.50,
148.86, 158.88, 183.33. Anal. Calcd for C16H20BrNO2:
C, 56.82; H, 5.96; N, 4.14. Found: C, 56.57; H, 5.79; N,
3.99.
ethanol. Yield 81%; mp 222–223°C; IR (KBr) ν/cmÀ1
:
3465, 3185, 3114, 2360, 1746, 1624, 1482, 1300, 1204,
1
1166, 889, 703, 676, 600; H NMR (400 MHz, CDCl3) δ
(ppm): 8.48 (s, 1H, NH), 7.69 (s, 1H, Ar H), 7.59 (s, 1H,
Ar H), 1.29 (s, 9H, tert-butyl); 13C NMR (100 MHz,
CDCl3) δ (ppm): 31.08, 34.88, 105.41, 119.29, 121.70,
138.00, 145.66, 149.20, 158.90, 182.97. Anal. Calcd for
C12H12BrNO2: C, 51.09; H, 4.29; N, 4.96. Found: C,
50.97; H, 4.16; N, 5.05.
1-Benzyl-7-bromo-5-(t-butyl)indoline-2,3-dione (4e). Red
crystals, yield 93%, mp 130–130°C; IR (KBr) ν/cmÀ1
:
3734, 3455, 3033, 2959, 2868, 2360, 1740, 1615, 1566,
1478, 1333, 1150, 1110, 976, 882, 746, 719, 556; 1H
NMR (400 MHz, CDCl3) δ (ppm): 7.59 (s, 1H, Ar H),
7.56 (s, 1H, Ar H), 7.18–7.29 (m, 5H, Ar H), 5.33 (s,
2H, CH2), 1.22 (s, 9H, tert-butyl); 13C NMR (100 MHz,
CDCl3) δ (ppm): 30.90, 34.60, 44.44, 104.05, 120.63,
122.22, 126.48, 127.54, 128.72, 136.09, 140.95, 145.27,
149.20, 159.27, 182.83. Anal. Calcd for C19H18BrNO2:
C, 61.30; H, 4.87; N, 3.76. Found: C, 61.66; H, 5.08; N,
General procedure for the synthesis of N-alkyl-7-bromo-5-
(tert-butyl)indoline-2,3-diones (4b–f). A solution of 7-bromo-
5-(tert-butyl)indoline-2,3-dione 4a (1.41 g, 5.0 mmol) in
DMF (12 mL) was cooled to 0°C. At this temperature,
NaH (0.13 g, 5.5 mmol) was added slowly to the
solution, which was changed to deep purple. After
stirring at room temperature for 10 min, the respective
halogenated agent (6 mmol) was added slowly to the
solution. The resulting mixture was stirred at room
temperature for 3 h. After the reaction was completed
(monitored by TLC), the reaction mixture was poured
into iced water and acidified with 1-M HCl and filtered to
give the respective crude product, which was
recrystallized from ethanol to give the corresponding
3.54.
7-Bromo-5-(t-butyl)-1-(4-chlorobenzyl)indoline-2,3-dione
(4f). Red crystals, yield 92%, mp 127–128°C; IR (KBr)
ν/cmÀ1: 3734, 3466, 2956, 2360, 1741, 1620, 1566, 1475,
1409, 1321, 1152, 1104, 1014, 884, 799, 716, 621, 515;
1H NMR (400 MHz, CDCl3) δ (ppm): 7.60 (s, 1H, Ar
H), 7.57 (s, 1H, Ar H), 7.23 (d, J = 8.1 Hz, 2H, Ar H),
7.15 (d, J = 8.0 Hz, 2H, Ar H), 5.29 (s, 2H, CH2), 1.22
(s, 9H, tert-butyl); 13C NMR (100 MHz, CDCl3) δ
(ppm): 29.07, 32.82, 42.08, 102.12, 118.83, 120.60,
126.17, 127.09, 131.61, 132.83, 139.11, 143.13, 147.61,
pure products 4b–f.
7-Bromo-5-(t-butyl)-1-methylindoline-2,3-dione (4b). Red
solid, yield 93%, mp 132–133°C; IR (KBr) ν/cmÀ1
:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New tert-Butyl- and Bromo-functionalized [1,2,4]Triazino [5,6-b]
indole-3-thiols and Indolo[2,3-b]quinoxalines
157.42, 180.75. Anal. Calcd for C19H17BrClNO2: C,
56.11; H, 4.21; N, 3.44. Found: C, 56.27; H, 4.31; N, 3.15.
General procedure for the synthesis of 6-bromo-8-(t-butyl)-
19.73, 31.40, 31.99, 35.02, 42.31, 104.07, 118.20,
121.41, 134.43, 135.18, 138.48, 148.54, 149.65, 179.81.
Anal. Calcd for C17H21BrN4S: C, 51.91; H, 5.38; N,
5H-[1,2,4]triazino[5,6-b]indole-3-thiols (6a–f).
A mixture
14.24. Found: C, 51.59; H, 5.30; N, 14.15.
5-Benzyl-6-bromo-8-(t-butyl)-5H-[1,2,4]triazino[5,6-b]indole-
3-thiol (6e). Yellow crystals, yield 77%, mp 263–265°C;
of appropriate 7-bromo-5-(t-butyl)indoline-2,3-dione 4
(1 mmol), thiosemicarbazide (5) (0.1 g, 1.1 mmol), and
K2CO3 (0.21 g, 1.5 mmol) in 30% aqueous 1,4-dioxane
(25 ml) was heated at reflux within 15 h. After the
completion of the reaction (TLC), the reaction mixture
was cooled, filtered, and precipitated by acidification with
acetic acid. The resulting solid was washed with water,
dried, and recrystallized from DMF to give the
IR (KBr) ν/cmÀ1: 3437, 2966, 2870, 2350, 1566, 1464,
1
1318, 1148, 1047, 877; H NMR (400 MHz, DMSO-d6)
δ (ppm): 14.84 (s, 1H, SH), 8.09 (s, 1H, Ar H), 7.78 (s,
1H, Ar H), 7.35–7.25 (m, 3H, Ar H), 7.19 (d,
J = 7.3 Hz, 2H, Ar H), 5.75 (s, 2H, CH2), 1.35 (s, 9H,
tert-butyl); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
30.85, 34.50, 45.07, 103.66, 117.72, 120.93, 125.79,
127.09, 128.46, 133.81, 134.79, 136.56, 137.98, 148.25,
149.74, 179.46. Anal. Calcd for C20H19BrN4S: C, 56.21;
corresponding products 6a–f.
6-Bromo-8-(t-butyl)-5H-[1,2,4]triazino[5,6-b]indole-3-thiol
(6a).
Brown crystals, yield 82%, mp 291–292°C; IR
(KBr) ν/cmÀ1: 3436, 2960, 2869, 2350, 1574, 1476,
H, 4.48; N, 13.11. Found: C, 56.19; H, 4.46; N, 13.28.
6-Bromo-8-(t-butyl)-5-(4-chlorobenzyl)-5H-[1,2,4]triazino[5,6-
b]indole-3-thiol (6f). Yellow solid, yield 74%, mp 273–
1
1318, 1168, 1038, 539; H NMR (400 MHz, DMSO-d6)
δ (ppm): 14.71 (s, 1H, SH), 12.65 (s, 1H, NH), 7.98 (s,
1H, Ar H), 7.84 (s, 1H, Ar H), 1.35 (s, 9H, tert-butyl);
13C NMR (100 MHz, DMSO-d6) δ (ppm): 31.56, 35.19,
105.26, 117.84, 120.06, 131.98, 136.27, 140.37, 148.15,
150.45, 179.65. Anal. Calcd for C13H13BrN4S: C, 46.30;
H, 3.89; N, 16.61. Found: C, 46.65; H, 3.66; N, 16.37.
6-Bromo-8-(t-butyl)-5-methyl-5H-[1,2,4]triazino[5,6-b]indole-
3-thiol (6b). Yellow solid, yield 86%, mp 302–303°C; IR
275°C; IR (KBr) ν/cmÀ1: 3436, 2967, 2869, 2354, 1570,
1466, 1321, 1153, 1050, 880; 1H NMR (400 MHz,
DMSO-d6) δ (ppm): 14.84 (s, 1H, SH), 8.08 (s, 1H, Ar
H), 7.78 (s, 1H, Ar H), 7.39 (d, J = 8.4 Hz, 2H, Ar H),
7.25 (d, J = 8.4 Hz, 2H, Ar H), 5.72 (s, 2H, CH2), 1.35
(s, 9H, tert-butyl); 13C NMR (100 MHz, DMSO-d6) δ
(ppm): 31.39, 35.06, 45.14, 104.11, 118.28, 121.55,
128.40, 128.94, 132.25, 134.26, 135.45, 136.28, 138.41,
148.85, 150.34, 180.01. Anal. Calcd for C20H18BrClN4S:
C, 52.02; H, 3.93; N, 12.13. Found: C, 51.89; H, 3.91;
N, 11.89.
(KBr) ν/cmÀ1: 3438, 2963, 2869, 2355, 1570, 1470, 1319,
1160, 1040, 541; 1H NMR (400 MHz, CF3COOD) δ
(ppm): 15.11 (s, 1H, SH), 8.22 (s, 1H, Ar H), 7.99 (s,
1H, Ar H), 4.15 (s, 3H, Me), 1.25 (s, 9H, tert-butyl); 13C
NMR (100 MHz, CF3COOD) δ (ppm): 32.82, 34.65,
37.90, 108.97, 113.33, 116.15, 118.96, 121.78, 122.97,
141.90, 156.42, 182.01. Anal. Calcd for C14H15BrN4S:
C, 47.87; H, 4.30; N, 15.95. Found: C, 47.95; H, 4.14;
General procedure for the synthesis of 7-bromo-9-(t-butyl)-
6H-indolo[2,3-b] quinoxaline (8a–f). To a stirred solution
of the respective 7-bromo-5-t-butylindoline-2,3-dione 4
(1 mmol) in acetic acid (5 mL) was added benzene-1,2-
diamine (7) (0.11 g, 1 mmol). The resulting reaction
mixture was heated under reflux within 12 h. After the
reaction was completed (TLC), the reaction mixture was
quenched by addition of 8-mL H2O. The resulting
precipitate was filtered to give the crude product, which
was then purified by silica gel column chromatography
with ethyl acetate/petroleum ether (1:5) as eluent to
N, 15.65.
6-Bromo-8-(t-butyl)-5-ethyl-5H-[1,2,4]triazino[5,6-b]indole-
3-thiol (6c). Yellow crystals, yield 80%, mp 283–285°C;
IR (KBr) ν/cmÀ1: 3435, 2964, 2869, 2350, 1572, 1471,
1
1318, 1165, 1039, 538; H NMR (400 MHz, DMSO-d6)
δ (ppm): 14.74 (s, 1H, SH), 8.03 (s, 1H, Ar H), 7.85 (s,
1H, Ar H), 4.52 (q, J = 7.2 Hz, 2H, CH2), 1.38 (t,
J = 7.2 Hz, 3H, CH3), 1.31 (s, 9H, tert-butyl); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 14.83, 30.86, 34.47,
37.20, 103.50, 117.65, 120.88, 133.77, 134.78, 137.88,
147.98, 148.91, 179.26. Anal. Calcd for C15H17BrN4S:
C, 49.32; H, 4.69; N, 15.34. Found: C, 49.29; H, 4.64;
afford the corresponding products 8a–f.
7-Bromo-9-(t-butyl)-6H-indolo[2,3-b]quinoxaline (8a). Yellow
solid, yield 81%, mp 273–274°C; IR (KBr) ν/cmÀ1
:
3445, 2960, 2858, 2351, 1584, 1475, 1370, 1250,
1188, 1130, 1035, 830, 788; 1H NMR (400 MHz,
DMSO-d6) δ (ppm): 12.28 (s, 1H, NH), 8.33 (s, 1H, Ar
H), 8.28 (d, J = 8.3 Hz, 1H, Ar H), 8.11 (d,
J = 8.3 Hz, 1H, Ar H), 7.96 (s, 1H, Ar H), 7.85 (t,
J = 7.3 Hz, 1H, Ar H), 7.77 (t, J = 7.5 Hz, 1H, Ar H),
1.43 (s, 9H, tert-butyl); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 31.81, 35.13, 104.74, 117.88,
121.14, 126.86, 128.06, 129.49, 129.58, 131.74, 139.19,
140.15, 140.77, 141.02, 145.70, 146.86. Anal. Calcd for
C18H16BrN3: C, 61.03; H, 4.55; N, 11.86. Found: C,
61.27; H, 4.75; N, 11.64.
N, 15.11.
6-Bromo-8-(t-butyl)-5-butyl-5H-[1,2,4]triazino[5,6-b]indole-
3-thiol (6d). Yellow crystals, yield 75%, mp 253–254°C;
IR (KBr) ν/cmÀ1: 3436, 2968, 2873, 2346, 1578, 1476,
1
1319, 1162, 1040, 565; H NMR (400 MHz, DMSO-d6)
δ (ppm): 14.75 (s, 1H, SH), 8.03 (s, 1H, Ar H), 7.85 (s,
1H, Ar H), 4.46 (t, J = 7.2 Hz, 2H, CH2), 1.76 (dd,
J = 14.9, 7.2 Hz, 2H, CH2), 1.39 (q, J = 7.4 Hz, 2H,
CH2), 1.32 (s, 9H, tert-butyl), 0.94 (t, J = 7.4 Hz, 3H,
CH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm): 14.14,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. Li, Y. Wang, and H. Zhang
Vol 000
7-Bromo-9-(t-butyl)-6-methyl-6H-indolo[2,3-b]quinoxaline
135.38, 141.45, 142.02, 146.87, 150.26. Anal. Calcd
(8b).
Yellow crystals, yield 89%, mp 233–234°C; IR
(KBr) ν/cmÀ1: 3445, 2960, 2858, 2350, 1585, 1476,
1375, 1250, 1188, 1130, 748; 1H NMR (400 MHz,
CF3COOD) δ (ppm): 8.57 (s, 1H, Ar H), 8.49 (d,
J = 8.4 Hz, 1H, Ar H), 8.44 (d, J = 8.4 Hz, 1H, Ar H),
8.33 (s, 1H, Ar H), 8.13–8.16 (m, 2H, Ar H), 4.59 (s,
3H, Me), 1.49 (s, 9H, tert-butyl); 13C NMR (100 MHz,
CF3COOD) δ (ppm): 29.55, 31.14, 34.45, 104.90,
110.03, 112.85, 115.66, 118.48, 119.98, 121.51, 126.27,
131.49, 132.43, 140.75, 142.14, 145.69, 150.22.
Anal. Calcd for C19H18BrN3: C, 61.97; H, 4.93; N,
for C25H22BrN3: C, 67.57; H, 4.99; N, 9.46. Found: C,
67.31; H, 5.25; N, 9.25.
7-Bromo-9-(t-butyl)-6-(4-chlorobenzyl)-6H-indolo[2,3-b]
quinoxaline (8f).
Yellow solid, yield 94%, mp 166–
167°C; IR (KBr) ν/cmÀ1: 3445, 2960, 2858, 2350, 1586,
1
1477, 1375, 1251, 1188, 1128, 748; H NMR (400 MHz,
CDCl3) δ (ppm): 8.46 (s, 1H, Ar H), 8.26 (d, J = 8.2 Hz,
1H, Ar H), 8.03 (d, J = 8.2 Hz, 1H, Ar H), 7.74 (s, 1H,
Ar H), 7.65–7.69 (m, 2H, Ar H), 7.14 (d, J = 8.3 Hz,
2H, Ar H), 7.04 (d, J = 8.3 Hz, 2H, Ar H), 6.08 (s, 2H,
CH2), 1.38 (s, 9H, tert-butyl); 13C NMR (100 MHz,
CDCl3) δ (ppm): 31.38, 34.86, 45.00, 103.25, 118.90,
122.58, 126.27, 127.17, 128.00, 128.20, 128.55, 128.83,
129.33, 129.73, 130.15, 133.18, 133.95, 136.63, 139.58,
140.96, 146.36. Anal. Calcd for C25H21BrClN3: C,
62.71; H, 4.42; N, 8.78. Found: C, 62.40; H, 4.44; N, 8.72.
11.41. Found: C, 61.83; H, 5.15; N, 11.23.
7-Bromo-9-(t-butyl)-6-ethyl-6H-indolo[2,3-b]quinoxaline
(8c).
Yellow crystals, yield 85%, mp 149–150°C; IR
(KBr) ν/cmÀ1: 3444, 2960, 2858, 2350, 1585, 1476,
1377, 1247, 1188, 1125, 1057, 869, 748; 1H NMR
(400 MHz, CDCl3) δ (ppm): 8.42 (s, 1H, Ar H), 8.23 (d,
J = 8.4 Hz, 1H, Ar H), 8.08 (d, J = 8.4 Hz, 1H, Ar H),
7.79 (s, 1H, Ar H), 7.70 (t, J = 7.6 Hz, 1H, Ar H), 7.62
(t, J = 7.6 Hz, 1H, Ar H), 4.92 (q, J = 7.1 Hz, 2H, CH2),
1.45 (t, J = 7.0 Hz, 3H, CH3), 1.38 (s, 9H, tert-butyl);
13C NMR (100 MHz, CDCl3) δ (ppm): 15.71, 31.63,
34.82, 37.47, 103.03, 115.61, 118.54, 122.52, 124.82,
126.35, 127.93, 129.04, 134.11, 138.98, 139.32, 141.00,
145.71, 146.24. Anal. Calcd for C20H20BrN3: C, 62.83;
Acknowledgments. The project was financially supported by the
National Natural Science Foundation of China (Nos. 21402011
and 21476028) and the Natural Science Foundation of Liaoning
Province (No. 201602006).
REFERENCES AND NOTES
H, 5.27; N, 10.99. Found: C, 62.60; H, 5.45; N, 10.83.
7-Bromo-9-(t-butyl)-6-butyl-6H-indolo[2,3-b]quinoxaline
[1] Ram, V. J Arch Pharm 1980, 313, 108.
[2] Jan, M. Z.; Gladych, R. H.; Hunt, J. H.; Jack, D. J Med Chem
1972, 15, 277.
(8d).
Yellow crystals, yield 79%, mp 155–156°C; IR
(KBr) ν/cmÀ1: 3445, 2960, 2858, 2350, 1585, 1476,
1376, 1248, 1188, 1128, 748; 1H NMR (400 MHz,
CF3COOD) δ (ppm): 8.36 (s, 1H, Ar H), 8.27 (d,
J = 8.4 Hz, 1H, Ar H), 8.20 (d, J = 8.3 Hz, 1H, Ar H),
8.12 (s, 1H, Ar H), 7.90–7.95 (m, 2H, Ar H), 4.94 (t,
J = 7.7 Hz, 2H, CH2), 1.87 (dd, J = 14.6, 7.4 Hz, 2H,
CH2), 1.34 (q, J = 7.2 Hz, 2H, CH2), 1.26 (s, 9H, tert-
butyl), 0.84 (t, J = 7.2 Hz, 3H, CH3); 13C NMR
(100 MHz, CF3COOD) δ (ppm): 15.15, 22.43, 32.84,
35.15, 37.71, 47.21, 107.95, 116.14, 118.96, 121.77,
123.41, 124.56, 129.83, 131.37, 134.84, 135.62, 141.35,
144.33, 144.96, 153.30. Anal. Calcd for C22H24BrN3: C,
64.39; H, 5.90; N, 10.24. Found: C, 64.26; H, 5.65; N,
[3] Zegar, I.; Gräslund, A.; Bergman, J.; Eriksson, M.; Nordén, B.
Chem Biol Interact 1989, 72, 277.
[4] Harmenberg, J.; Åkesson-Johansson, A.; Gräslund, A.;
Malmfors, T.; Bergman, J.; Wahren, B.; Åkerfeldt, S.; Lundblad, L.;
Cox, S. Antiviral Res 1991, 15, 193.
[5] Kinsman, O. S.; Livermore, D. G.; Smith, C. Antimicrob
Agents Chemother 1993, 37, 1243.
[6] Monge, A.; Palop, J.; Ramirez, C.; Font, M.; Fernandez-
Alvarez, E. Eur J Med Chem 1991, 26, 179.
[7] Gupta, L.; Sunduru, N.; Verma, A.; Srivastava, S.; Gupta, S.;
Goyal, N.; Chauhan, P. M. S. Eur J Med Chem 2010, 45, 2359.
[8] Youssef, A. S. A. Chem Pap 2002, 56, 132.
[9] Hamid, H. M. A. J Chem Res 2004, 183.
[10] Wilhelmsson, L. M.; Kingi, N.; Bergman, J. J Med Chem
2008, 51, 7744.
[11] Narayana, M. N. S. H.; Manivannan, E.; Karthikeyan, C.;
Trivedi, P. Mini-Rev Med Chem 2013, 13, 1415.
[12] Przyjazna, B.; Kucybała, Z.; Pączkowski, J. Polymer 2004, 45,
2559.
[13] Driller, K. M.; Libnow, S.; Hein, M.; Harms, M.; Wende, K.;
Lalk, M.; Michalik, D.; Reinke, H.; Langer, P. Org Biomol Chem 2008,
6, 4218.
[14] Thomas, K. R. J.; Tyagi, P. J Org Chem 2010, 75, 8100.
[15] Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J Org Chem 1986,
51, 5106.
10.06.
6-Benzyl-7-bromo-9-(t-butyl)-6H-indolo[2,3-b]quinoxaline
(8e). Yellow crystals, yield 86%, mp 246–247°C; IR
(KBr) ν/cmÀ1: 3445, 2960, 2858, 2350, 1585, 1476,
1
1366, 1256, 1188, 1137, 1007, 810, 748, 598, 432; H
NMR (400 MHz, CF3COOD) δ (ppm): 8.40 (s, 1H, Ar
H), 8.19–8.24 (m, 2H, Ar H), 8.11 (s, 1H, Ar H),
7.85–7.94 (m, 2H, Ar H), 7.03–7.08 (m, 5H, Ar H),
6.22 (s, 2H, CH2), 1.27 (s, 9H, tert-butyl); 13C NMR
(100 MHz, CF3COOD) δ (ppm): 29.63, 34.53, 46.83,
105.01, 110.13, 112.94, 115.76, 118.58, 120.31, 120.72,
125.82, 127.42, 127.88, 128.62, 132.06, 132.37,
[16] Feldman, K. S.; Gonzalez, I. Y.; Brown, J. E. Tetrahedron Lett
2015, 56, 3564.
[17] Ochi, M.; Kataoka, K.; Ariki, S.; Iwatsuki, C.; Kodama, M.;
Fukuyama, Y. J Nat Prod 1998, 61, 1043.
[18] Suárez-Castillo, O. R.; Beiza-Granados, L.; Meléndez-
Rodríguez, M.; Álvarez-Hernández, A.; Morales-Ríos, M. S.; Joseph-
Nathan, P. J Nat Prod 2006, 69, 1596.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of New tert-Butyl- and Bromo-functionalized [1,2,4]Triazino [5,6-b]
indole-3-thiols and Indolo[2,3-b]quinoxalines
[19] Vinsova, J.; Cermakova, K.; Tomeckova, A.; Ceckova, M.;
Jampilek, J.; Cermak, P.; Kunes, J.; Dolezal, M.; Staud, F. Bioorg Med
Chem 2006, 14, 5850.
[20] Huy, N. T.; Mizunuma, K.; Kaur, K.; Nhien, N. T. T.; Jain, M.;
Uyen, D. T.; Harada, S.; Jain, R.; Kamei, K. Antimicrob Agents
Chemother 2007, 51, 2842.
[21] Dolle, R. E.; Nelson, K. H. Jr. J Comb Chem 1999, 1, 235.
[22] Gao, W.; Fu, X.; Zhang, X.; Wang, D.; Li, Y. Tetrahedron Lett
2016, 57, 4145.
[25] Gao, W. T.; Xing, X. D.; Li, Y.; Lan, S. Tetrahedron 2014, 70,
2180.
[26] Sandmeyer, T. Helv Chim Acta 1919, 2, 234.
[27] Venkateswarlu, K.; Suneel, K.; Das, B.; Reddy, K. N.; Reddy,
T. S. Syn Commun 2008, 39, 215.
[28] Li, Y.; Gao, W. T. Syn Commun 2012, 42, 2067.
[29] Ramesh, K.; Murthy, S. N.; Karnakar, K.; Nageswar, Y. V. D.
Tetrahedron Lett 2011, 52, 4734.
[30] Reddy, S. S.; Pallela, R.; Kim, D. M.; Won, M. S.; Shim, Y. B.
Chem Pharm Bull 2013, 61, 1105.
[23] Li, Y.; Li, K.; Gao, W. Chem Heterocycl Compd 2016,
52, 200.
[31] Kenning, D. D.; Mitchell, K. A.; Calhoun, T. R.; Funfar, M. R.;
Sattler, D. J.; Rasmussen, S. C. J Org Chem 2002, 67, 9073.
[24] Lv, M.; Zheng, H.; Li, Y. Res Chem Intermed 2015, 41, 6927.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet