Synthesis of selenium-containing biindolyls and their Diels–Alder reaction toward the synthesis of heteroannulated [a]- and [c]-carbazoles

Article abstract of DOI:10.1002/jccs.201900278

We reported the first syntheses of 2- and 3-(2-(benzo[b]selenophen-2-yl)-indoles and their Diels–Alder reactions to furnish six unique annulated benzoselenphene carbazoles. This facile route can be used to synthesize selenium-containing biindolyl derivati

Full text of DOI:10.1002/jccs.201900278

Received: 11 July 2019
Revised: 5 October 2019
Accepted: 13 October 2019
DOI: 10.1002/jccs.201900278
A R T I C L E
Synthesis of selenium-containing biindolyls and their
Diels–Alder reaction toward the synthesis of
heteroannulated [a]- and [c]-carbazoles
Ruei-Yu Wang | Wei-Ting Kao | Tzenge-Lien Shih
Department of Chemistry, Tamkang
Abstract
University, New Taipei City, Taiwan,
Republic of China
We reported the first syntheses of 2- and 3-(2-(benzo[b]selenophen-2-yl)-indoles
and their Diels–Alder reactions to furnish six unique annulated benzoselenphene
carbazoles. This facile route can be used to synthesize selenium-containing
biindolyl derivatives that possessed potential pharmaceutical activities.
Correspondence
Tzenge-Lien Shih, Department of
Chemistry, Tamkang University, 25137
Tamsui District, New Taipei City, Taiwan,
Republic of China.
K E Y W O R D S
Email: tlshih@mail.tku.edu.tw;
biindolyl, carbazole, Castro–Stephens indole synthesis, Diels–Alder reaction, Glaser coupling,
selenium
Funding information
the Ministry of Science of Taiwan, Grant/
Award Number: MOST 105-2113-M-
032-001
1
| INTRODUCTION
selenium-containing molecules were not only used as
anticancer agents but also applied in material chemistry.
K252a, staurosporine, and arcyriaflavin are classified as
the indolocarbazole family of natural products (Figure 1).
They all exhibited inhibitors of protein kinase C, as well as
Due to the importance of selenium, we tried to replace one
of the nitrogen atoms of biindolyl with a selenium element to
synthesize 2- and 3-(2-(benzo[b]selenophen-2-yl)-indoles
(Figure 2) and applied them in the synthesis of indolocarbazole
[1]
[
1,2]
cytotoxicity of cancer cell lines.
tive molecules all possessed a biindolyl skeleton.
Therefore, biindolyl was used as a key intermediate in
These three representa-
[
3]
[6,10]
derivatives through the Diels–Alder reaction.
[4]
the synthesis of indolocarbazole derivatives. On the other
hand, the synthesis of 2,3 -indolo[3,2,-b]indole3a to obtain
arcyriaflavin derivatives also attracted attention.
0
[5]
2 | RESULTS AND DISCUSSION
[6]
Elemental selenium is a trace nutrient in the prevention
of human diseases and is associated with the similar role of
In order to synthesize 2- and 3-(benzo[b]seleophen-2-yl)-
indoles (via infra), we needed to prepare two compounds,
5 and 6 (Scheme 1). Although compounds 5 and 6 were com-
mercially available, their list prices were costly. The facile
route was to use compounds 1 and 2, respectively, coupled
[7]
vitamin E. Selenium is very essential to our daily life;
however, lower or the higher levels of selenium content in
foods are correlated to humans' health. There are some
selenium-containing enzymes in humans; therefore, people
with a selenium deficiency have Keshan and Kashin–Beck
diseases.7b The development of selenium-containing agents
to mimic selenoenzymes properties has attracted consider-
[11]
with tirmethylsilylacetylene (TMSA),
followed by the
removal of silane by tetrabutylammonium fluoride (TBAF)
to furnish compounds 5 and 6 with high yields in two steps.
It is worth noting that compound 6 should be handled with
care owing to its volatility.
Compounds 5 and 6 underwent 4-(dimethylamino)
pyridine (DMAP)-catalyzed Glaser heterocoupling of
[8]
able concern. Besides, benzo[b]selenophene derivatives, as
well as its analogues benzo[b]thiophenes, were widely
[9]
applied in optoelectronic devices. As a consequence,
©
2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–9.
http://www.jccs.wiley-vch.de
1

2
WANG ET AL.
FIGURE 1 Bioactive molecules
0
with symmetrical biindolyl (2,2 -
biindole) framework (marked in blue
color)
FIGURE 2 Frameworks of
biindolyl and its 2- and 3-(2-benzo[b]
selenophen-2-yl)-indole derivatives
SCHEME 1 Synthesis of 5 and 6
[12]
terminal alkynes
to furnish 7. However, it required the
Boc O to furnish 12, which was not stable, and was
2
slow addition of five equivalents of compound 5 into a solu-
tion to obtain the optimized yield (Scheme 2 and in
supporting information). Fortunately, the side product of the
above-mentioned reaction was mainly the homo coupling of
immediately coupled with 6 to afford 13 (Scheme 3). The
selenium was introduced, followed by intramolecular
cyclization, and deprotected the Boc group in one step to
provide 14, which was methylated to afford 15.
5
, which can be used for further synthesis of biindolyl. Com-
Compound 9 was conducted using the Diels–Alder
reaction with different dienophiles, diphenylacetylene
(16), and diethyl acetylenedicarboxylate (17) in different
reaction conditions10a (Scheme 4). The expected cyclic
adduct 18 was not obtained, but 19 was obtained in a
low yield. On the contrary, compound 10 underwent
Diels–Alder reaction with both dienophiles to afford 20
and 21 but suffered low yields.
[13]
pound 7 was conducted by Glaser method
indole derivative 8. In this course of cyclization to synthesize
-benzo[b]selenophene-indole 9, the key step is to replace
to afford C-2
2
the C-Br bond of 8 with a C-Se bond. There are some stan-
dard preparations to achieve this goal, such as metal–halogen
exchange (tert-BuLi/Se), Cu cat, and Cu cat/additive.
We selected the in situ reduction of selenium powder by
NaBH in EtOH
cyclization to afford 9, which was methylated to furnish 10.
Both steps gave satisfactory yields.
On the other hand, the synthesis of 3-(benzo[b]
selenophen-2-yl)-indoles used a strategy similar to
Scheme 2. Indole (11) was iodinated and protected by
[11]
[14]
[15]
[16]
mixing with 8, followed by subsequent
Condition a: Pd(OAc) , TBAB, PivOH,K CO , DMF,
4
2
2
3
ꢀ
ꢀ
O , 150 C for reacting with 16; condition b: xylene, 185 C
2
for. reacting with 17. *Yield given in parenthesis is
reported as yield of recovery of starting material.
Compound 14 underwent the same process as com-
pound 9 in reactions with 16 and 17 (Scheme 5). Again,

WANG ET AL.
3
SCHEME 2 Synthesis of 2-(benzo[b]selenophen-2-yl)-indole derivatives 9 and 10
SCHEME 3 Synthesis of
3
-(benzo[b]selenophen-2-yl)-indole
derivatives 14 and 15
compound 14 was inactive with 16 but was active 17 to
afford the expected 23 with a satisfactory yield. Com-
pound 15 in reaction with 16 and 17 afforded 24 and 25
in low to moderate yields.
chemical shifts were reported in part per million (ppm)
and referenced the residual of solvents: CDCl (7.26 ppm
3
1
13
for H; 77.0 ppm for C) and (CD ) CO (2.04 ppm for
H; 206.5 ppm for C). The melting points were deter-
3
2
1
13
Condition a: Pd(OAc) , TBAB, PivOH, K CO , DMF,
O , 150 C for reacting with 16; condition b: xylene, 185 C
mined on a Fargo MP-2D apparatus and not corrected. High
resolution mass (HRMS) were measured on TMS-700.
2
2
3
ꢀ
ꢀ
2
for reacting with 17.
It has been reported that the electron-donating,
electron-withdrawing, or bulky substituents of alkynes
did not have much influence on the yields of the synthe-
sis of carbazoles by Diels–Alder reaction;10a however,
3.1 | 2-Ethynylaniline (5)
A mixture of PdCl (PPh ) (0.064 g, 0.091 mmol) and CuI
2
3 2
the ester group (CO Et) rather than phenyl group
(0.034 g, 0.182 mmol) in a flask was vacuumed and then
introduced to a nitrogen atmosphere. This procedure was
repeated thrice. To this flask was sequentially added tetrahy-
2
furnished better results in both Schemes 4 and 5.
drofuran (THF) (10 ml), Et N (10 ml), and 2-iodoaniline
3
3
| EXPERIMENTAL
(1.0 g, 4.56 mmol). This mixture was stirred for 10 min,
followed by addition of TMSA (0.67 g, 6.84 mmol), and then
stirred for 12 hr. The resulting mixture was filtrated, and
the solvents were removed under reduced pressure and
All chemicals were commercially available and used
without further purification. The H and C NMR spec-
tra were recorded on a Bruker 600 MHz instrument. The
1
13
diluted with EtOAc and H O. The organic layer was dried
2

4
WANG ET AL.
SCHEME 4 The Diels–Alder reaction of 2-benzoselenophen-2-yl-indoles (9 and 10) with dienophiles 16 and 17
SCHEME 5 The Diels–Alder reaction of 3-benzoselenophen-2-yl-indoles (14 and 15) with dienophiles 16 and 17
(
MgSO ), filtrated, and concentrated to afford 3. Com-
3.2 | 1-Bromo-2-ethynylbenzene (6)
4
pound 3 was dissolved in THF (20 ml) and TBAF (4.5 ml,
.5 mmol) was added and then stirred for 30 min at room
4
A mixture of PdCl (PPh ) (0.027 g, 0.038 mmol) and CuI
2 3 2
temperature. The resulting mixture was concentrated and
diluted with CH Cl and H O. The organic layer was
(0.015 g, 0.077 mmol) in a flask was vacuumed and then
introduced to a nitrogen atmosphere. This procedure was
repeated thrice. To this flask was sequentially added THF
2
2
2
dried (MgSO ) and concentrated. The crude product was
4
purified by flash column chromatography (230–400 mesh
(10 ml), Et N (10 ml), and 2-iodoaniline (0.55 g,
3
SiO , EtOAc:Hexane = 1:10) to afford 5 (0.480 g,
1.944 mmol). This mixture was stirred for 10 min,
followed by addition of TMSA (0.286 g, 2.916 mmol), and
then stirred for 12 hr. The resulting mixture was filtrated,
and the solvents were removed under reduced pressure
2
4
.104 mmol) as a red-brown liquid in 91% yield (two
1
step). H NMR (600 MHz, CDCl ) δ 7.32 (d, J = 6.0 Hz,
3
1
H), 7.14 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.67
13
(d, J = 7.8 Hz, 1H), 3.38 (s, 1H). C NMR (150 MHz,
and diluted with EtOAc and H O. The organic layer was
2
CDCl ) δ 148.5, 132.6, 130.1, 117.8, 114.3, 106.6, 82.4,
dried (MgSO ), filtrated, and concentrated to afford 4.
Compound 4 was dissolved in THF (10 ml) and TBAF
3
4
+
8
0.6. HRMS (EI) calculated for C H N [M + H]
8
8
1
18.0657. Found: 118.0659.
(2.0 ml, 2.0 mmol) was added and then stirred for 30 min

WANG ET AL.
5
+
at room temperature. The resulting mixture was concen-
trated and diluted with CH Cl and H O. The organic
calculated for C H BrN [M + H] 296.0069. Found:
16 11
296.0075.
2
2
2
layer was dried (MgSO ) and concentrated. The crude
4
product was purified by flash column chromatography
(
230–400 mesh SiO , pentane) to afford 6 as a clear liquid
3.5 | 2-(Benzo[b]selenophen-2-yl)-1H-
indole (9)
2
1
in 90% (two step). H NMR (600 MHz, CDCl ) δ 7.59 (dd,
J = 8.1, 1.2 Hz, 1H), 7.53 (dd, J = 7.7, 1.7 Hz, 1H), 7.26
3
(
3
td, J = 7.7, 1.1 Hz, 1H), 7.19 (td, J = 7.7, 1.7 Hz, 1H),
A mixture of selenium powder (0.053 g, 0.675 mmol) and
13
.39 (s, 1H). C NMR (150 MHz, CDCl ) δ 134.0, 132.4,
NaBH (0.025 g, 0.675 mmol) in a flask was equipped
3
4
1
29.9, 130.0, 125.5, 124.2, 81.8, 81.7. LRMS (EI) for
with a Dean-Stark trap. The system was vacuumed and
introduced to a nitrogen atmosphere. This procedure was
repeated thrice. To this system was added EtOH (4 ml),
and the mixture was stirred for 1 hr in an ice bath. Com-
pound 8 (0.10 g, 0.337 mmol) in NMP (8 ml) was added
+
C H Br [M] 181.03. Found: 181.0.
8
5
3
1
.3 | 2-([2-Bromophenyl]Buta-1,3-diyn-
-yl)aniline (7)
ꢀ
and heated at 190 C for 12 hr, and EtOH was distilled dur-
ing the reaction course. The resulting black mixture was
Compound 6 (0.10 g, 0.55 mmol) and CuI (0.010 g,
.055 mmol) were dissolved in MeCN (3.0 ml), followed
diluted with saturated NH Cl (100 ml), filtrated by suction,
and washed with small amount of toluene. The filtrate
was extracted with toluene and washed with brine thrice.
4
0
by slow addition of compound 5 (0.32 g, 2.76 mmol) in
MeCN (5 ml) over 15 min. under air. The mixture was
stirred for 12 hr at ambient temperature. The solvent was
concentrated, and the resulting mixture was purified by
flash column chromatography (230–400 mesh SiO2,
The organic layer was dried (MgSO ), filtrated, and con-
4
centrated. The resulting mixture was purified by flash col-
umn chromatography (230–400 mesh SiO , EtOAc:
2
Hexane = 1:20–1:4) to afford 9 (0.060 g, 0.202 mmol) as a
ꢀ
1
EtOAc:Hexane
=
1:30–1:4) to afford
7
(0.117 g,
light-brown solid with a 60% yield. Mp = 275–277 C. H
NMR (600 MHz, (CD ) CO) δ 7.97 (d, J = 8.0 Hz, 1H),
ꢀ
1
0
.396 mmol) in a yield of 72%. Mp = 88–90 C. H NMR
3
2
(
(
(
(
(
600 MHz, CDCl ) δ 7.60 (d, J = 8.1 Hz, 1H), 7.55
7.90 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.9 Hz,
1H), 7.42 (d, J = 8.1 Hz), 7.36 (t, J = 7.5 Hz, 1H), 7.26
(t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.6 Hz,
3
d, J = 7.7, 1.1 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.28
t, J = 7.6 Hz, 1H), 7.21 (td, J = 7.9, 1.4 Hz, 1H), 7.17
1
3
13
td, J = 7.9, 1.4 Hz, 1H), 6.71–6.67 (m, 2H). C NMR
1H), 6.77 (s, 1H). C NMR (150 MHz, (CD ) CO) δ 144.1,
3
2
150 MHz, CDCl ) δ 149.5, 134.4, 133.2, 132.6, 130.9,
144.1, 138.8, 138.7, 138.6, 138.5, 135.0, 134.8, 129.8, 129.8,
126.3, 126.1, 125.9, 125.5, 123.4, 123.3, 121.2, 120.7, 112.1,
3
1
7
2
30.1, 127.1, 126.1, 124.3, 118.1, 114.5, 106.0, 80.8, 80.2, 78.9,
+
8.1. HRMS (FAB) calculated for C H BrN [M + H]
112.1, 102.9, 102.9. HRMS (EI) calculated for C H NSe
16
11
16 11
+
96.0069. Found: 296.0076.
[M] 297.0057. Found: 297.0058.
3
.4 | 2-([2-Bromophenyl]ethynyl)-1H-
3.6 | 2-(Benzo[b]selenophen-2-yl)-
1-methyl-1H-indole (10)
indole (8)
To a sure-sealed tube, 7 (0.62 g, 2.09 mmol) and CuI
A solution of 9 (0.050 g, 0.16 mmol) and KOH (0.047 g,
0.84 mmol) in DMF was stirred for 10 min., followed by
addition of MeI (0.47 g, 0.33 mmol). This mixture was
stirred for 3 hr at room temperature. The resulting mixture
was diluted with H O and extracted with CH Cl . The
(
0.80 g, 4.19 mmol) were added in DMF (18 ml). This
ꢀ
mixture was heated at 150 C for 3 hr. The solvent was
concentrated and diluted with EtOAc/H O. The organic
2
layer was dried (MgSO ), concentrated, and purified with
4
2
2
2
flash column chromatography (230–400 mesh, EtOAc:
Hexane = 1:30–1:10) to afford 8 (0.495 g, 1.672 mmol) as
organic layer was dried (MgSO ), concentrated, and puri-
4
fied with flash column chromatography (230–400 mesh
ꢀ
1
a yellow solid in 80% yield. Mp = 115–118 C. H NMR
600 MHz, CDCl ) δ 8.31 (s, 1H), 7.63 (t, J = 7.1, 0.7 Hz,
SiO , EtOAc:Hexane = 1:10) to afford 10 (0.033 g,
2
(
0.1072 mmol) as a yellow solid in 67% yield. Mp = 170–173-
3
ꢀ
C. H NMR (600 MHz, CDCl ) δ 7.90 (d, J = 7.8 Hz, 1H),
3
1
2
1
1
0
1
1
H), 7.57 (dd, J = 7.6, 1.3 Hz, 1H), 7.36 (d, J = 8.2 Hz,
H), 7.31 (td, J = 7.6, 1.0 Hz, 1H), 7.26 (td, J = 7.6,
.0 Hz, 1H), 7.20 (td, J = 8.0, 1.6 Hz, 1H), 7.14 (td, J = 7.9,
7.82 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.56
(s, 1H), 7.41–7.38 (m, 2H), 7.36–7.27 (m, 2H), 7.15
13
13
.7 Hz, 1H), 6.90 (s, 1H). C NMR (150 MHz, CDCl ) δ
(t, J = 7.3 Hz, 1H), 6.76 (s, 1H), 3.92 (s, 3H). C NMR
3
36.3, 133.1, 132.5, 129.6, 127.8, 127.1, 125.3, 124.9, 123.8,
21.0, 120.6, 118.3, 110.8, 109.4, 91.1, 86.3. HRMS (FAB)
(150 MHz, CDCl ) δ 142.6, 141.8, 138.8, 136.8, 135.5, 127.7,
3
126.5, 125.2, 125.0, 124.8, 122.5, 120.7, 120.2, 119.1, 109.6,

6
WANG ET AL.
+
+
1
3
04.2, 31.3. HRMS (EI) calculated for C H NSe [M]
11.0213. Found: 311.0211.
HRMS (EI) calculated for C H BrNO [M] 395.0521.
21 18 2
Found: 395.0521.
17
13
3
1
.7 | tert-butyl 3-iodo-1H-indole-
-carboxylate (12)
3.9 | 3-(Benzo[b]selenophen-2-yl)-1H-
indole (14)
A solution of indole (1.0 g, 8.53 mmol) in DMF (30 ml)
was added to KOH (1.20 g, 21.34 mmol) and stirred for
To a round-bottomed flask was added selenium powder
(0.20 g, 2.52 mmol) and NaBH (0.10 g, 2.52 mmol) and
4
1
0 min. at room temperature. To this solution was added
set up with a Dean-Stark trap. The system was vacuumed
and introduced to a nitrogen atmosphere. This procedure
was repeated thrice. To this system was added EtOH
(5 ml), and the mixture was stirred for 1 hr in an ice bath.
Compound 13 (0.50 g, 1.26 mmol) in NMP (10 ml) was
I2 (2.16 g, 8.53 mmol) and stirred for 1 hr at room tem-
perature. The mixture was diluted with Na SO (satu-
rated) (80 ml) and extracted with EtOAc. The organic
layer was dried (MgSO ) and concentrated. The crude
product was dissolved in CH Cl (40 ml), followed by the
2
3
4
ꢀ
added and heated at 190 C for 12 hr, and EtOH was dis-
2
2
addition of Et N (3.6 ml, 25.60 mmol), DMAP (0.104 g,
tilled during the reaction course. The resulting black mix-
3
0
.85 mmol), and Boc O (2.235 g, 10.24 mmol). This mix-
ture was diluted with saturated NH Cl (100 ml), filtrated by
2
4
ture was stirred for 1 hr and diluted with CH Cl and
suction, and washed with a small amount of toluene. The
filtrate was extracted with toluene and washed with brine
2
2
H O. The organic layer was dried (MgSO ) and purified
2
4
by flash column chromatography (230–400 mesh SiO2,
thrice. The organic layer was dried (MgSO ), filtrated, and
concentrated. Purification by flash column chromatography
4
EtOAc:Hexane = 1:10) to afford 12 as a clear liquid
1
(
2.692 g, 7.847 mmol) with a 92% yield. H NMR
(230–400 mesh SiO , EtOAc:Hexane = 1:20–1:10) afforded
2
(
600 MHz, CDCl ) δ 8.14 (d, J = 6.6 Hz, 1H), 7.74 (s, 1H),
14 (0.246 g, 0.8316 mmol) as a light yellow solid with a 66%
3
ꢀ
1
7
.41 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.32
yield. Mp = 178–180 C. H NMR (600 MHz, CDCl ) δ 8.26
3
13
(t, J = 7.6 Hz, 1H), 1.68 (s, 9H). C NMR (150 MHz,
(s, 1H), 8.08 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H),
CDCl ) δ 148.7, 134.8, 132.1, 130.1, 125.3, 123.3, 121.5,
7.78 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.43
3
1
15.0, 84.3, 65.4, 28.1 (3×). LRMS calculated for
(d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.1 Hz, 1H), 7.31–7.27 (m,
+
13
C H INO [M] 343.16. Found: 343.0.
2H), 7.23 (t, J = 7.1 Hz, 1H). C NMR (150 MHz, CDCl ) δ
13
14
2
3
143.3, 140.3, 139.8, 136.6, 125.3, 125.2, 124.7, 124.6, 123.8,
1
23.3, 123.0, 122.1, 120.9, 120.0, 114.2, 111.5. HRMS (ESI)
+
3
.8 | tert-butyl 3-([2-bromophenyl]
calculated for C H NSe [M + H] 298.0129. Found:
16 12
ethynyl)-1H-indole-1-carboxylate (13)
298.0135.
A mixture of PdCl (Ph P) (0.015 g, 0.022 mmol)and CuI
2
3
2
(
0.008 g, 0.044 mmol) in a flask was vacuumed and then
3.10 | 3-(Benzo[b]selenophen-2-yl)-
1-methyl-1H-indole (15)
introduced to a nitrogen atmosphere. This procedure was
repeated thrice. To this flask was sequentially added THF
(
4 ml), Et N (4 ml), and 12 and was stirred for 10 min at
A solution of 14 (0.050 g, 0.16 mmol) and KOH (0.047 g,
0.84 mmol) in DMF was stirred for 10 min, followed by
addition of MeI (0.47 g, 0.33 mmol). This mixture was
stirred for 3 hr at room temperature. The resulting mixture
was diluted with H O and extracted with CH Cl . The
3
room temperature. To this mixture was added 6 (0.13 ml,
.10 mmol) portion wise and stirred for 12 hr. The
1
resulting mixture was filtrated by suction, concentrated,
and diluted with EtOAC and H O. The organic layer was
2
2
2
2
dried (MgSO ) and purified by flash column chromatog-
organic layer was dried (MgSO ), concentrated, and purified
4
4
raphy (230–400 mesh SiO , EtOAc:Hexane = 1:30–1:10)
by flash column chromatography (230–400 mesh SiO2,
EtOAc:Hexane = 1:10) to afford 15 (0.0446 g, 0.144 mmol) as
2
to afford 13 (0.309 g, mmol) as an orange-yellow liquid
1
ꢀ
1
with a 71% yield. H NMR (600 MHz, CDCl ) δ 8.18
a red solid with a 90% yield. Mp = 132–134 C. H NMR
3
(d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H),
(600 MHz, CDCl )δ 8.06 (d, J= 7.8 Hz, 1H), 7.85 (d, J=7.8Hz,
3
7
1
.64 (dd, J = 8.0, 1.0 Hz, 1H), 7.60 (dd, J = 7.7, 1.6 Hz
H), 7.40 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.31
1H), 7.73 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.37–7.31 (m, 4H),
7.27 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 3.84 (s, 3H).
C NMR (150 MHz, CDCl ) δ 143.5, 140.4, 137.5, 128.0,
3
13
(td, J = 7.6, 1.0 Hz, 1H), 7.18 (td, J = 7.8, 1.7 Hz, 1H),
13
1
1
1
.70 (s, 9H). C NMR (150 MHz, CDCl ) δ 149.0, 134.7,
33.1, 132.4, 130.5, 129.2, 129.0, 127.0, 125.6, 125.3, 125.2,
23.4, 120.4, 115.2, 103.2, 91.4, 86.2, 84.4, 28.1 (3x).
125.8, 125.2, 124.7, 124.5, 123.6, 122.5, 121.4, 120.5, 120.1,
3
+
112.5, 109.7, 33.0. HRMS (EI) calculated for C H NSe [M]
1
7 13
311.0213. Found: 311.0213.

WANG ET AL.
7
3
.11 | Diethyl 12H-benzo[4,5]
selenopheno[2,3-a]carbazole-
,6-dicarboxylate (19)
3.13 | Diethyl 12-methyl-12H-benzo[4,5]
selenopheno[2,3-a]carbazole-
5,6-dicarboxylate (21)
5
Compounds 9 (0.030 g, 0.1013 mmol) and 17 (0.069 g,
Compounds 10 (0.0140 g, 0.045 mmol) and 17 (0.030 g,
0
.4054 mmol) were dissolved in xylene (2 ml) and
0.18 mmol) were dissolved in xylene (3 ml) and heated at
185 C for 24 hr in a sealed tube. At the end of reaction
time, the mixture was concentrated and purified by flash
ꢀ
ꢀ
heated at 185 C for 24 hr in a sealed tube. At the end
of reaction time, the mixture was concentrated and
purified by flash column chromatography (230–400
mesh SiO , Hexane:CH Cl = 1:2–0:1) to afford 19
column chromatography (230–400 mesh SiO , EtOAc:
2
Hexane =1:10–1:4) to afford 21 as a white solid (0.007 g,
2
2
2
ꢀ
1
(
0.0061 g, 0.0131 mmol) as a brown solid with a 13%
0.014 mmol) with a 31% yield. Mp = 198–200 C. H NMR
yield (16% based on recovery of 0.0060 g of 9).
Mp = 207–210 C. H NMR (600 MHz, CDCl ) δ 8.37 (s,
1
(600 MHz, CDCl ) δ 8.17 (d, J = 7.8 Hz, 1H), 8.07
3
ꢀ
1
(d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.54
(t, J = 7.8 Hz, 1H), 7.49–7.41 (m, 3H), 7.28 (t, J = 7.8 Hz,
1H), 4.60 (q, J = 7.2 Hz, 2H), 4.56 (q, J = 7.2 Hz, 2H),
4.25 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz,
3
H), 8.07 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H),
.07 (t, J = 8.2 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.53
8
(
(
dd, J = 7.4, 0.6 Hz, 1H), 7.49 (d, J = 6.2 Hz, 1H), 7.46
td, J = 8.2, 1.3 Hz, 1H), 7.41 (td, J = 7.9, 1.3 Hz, 1H),
13
3H). C NMR (150 MHz, CDCl ) δ 169.4, 168.3, 142.1,
3
7
4
3
.28 (dd, J = 8.2, 1.0 Hz, 1H), 4.61 (q, J = 7.2 Hz, 2H),
.58 (q, J = 7.2 Hz, 2H), 4.25 (s, 3H), 1.51 (t, J = 7.2 Hz,
H), 1.46 (t, J = 7.2 Hz, 3H). C NMR (150 MHz,
139.2, 139.0, 136.7, 132.5, 126.7 (2×), 125.5, 125.4, 125.1,
124.5, 123.4, 122.8, 122.1, 121.3, 120.3, 116.4, 109.1, 62.0,
61.9, 30.8, 14.1, 14.0. HRMS (EI) calculated for
1
3
+
CDCl ) δ 169.3, 168.1, 140.3, 139.0, 137.4, 137.3, 132.1,
C H NO Se [M] 479.0636. Found: 479.0635.
3
25 21
4
1
1
26.9, 126.8, 125.5, 125.4, 125.3, 124.7, 124.0, 123.3,
23.1, 122.4, 120.8, 117.1, 11.2, 62.0 (2x), 14.2, 14.0.
+
HRMS (ESI) calculated for C H NO Se [M-H]
3.14 | Diethyl 5H-benzo[4,5]selenopheno
[3,2-c]carbazole-6,7-dicarboxylate (23)
2
4
18
4
4
64.0401. Found: 464.0402.
Compounds 14 (0.050 g, 0.168 mmol) and 17 (0.0860 g,
3
.12 | 12-Methyl-5,6-diphenyl-12H-benzo
0.507 mmol) were dissolved in xylene (3 ml) and heated at
185 C for 12 hr in a sealed tube. At the end of reaction
time, the mixture was concentrated and purified by flash col-
ꢀ
[4,5]selenopheno[2,3-a]carbazole (20)
Compound 10 (0.030 g, 0.096 mmol), compound 16
0.0260 g, 0.145 mmol), Pd(OAc) (0.0020 g, 0.009 mmol),
umn chromatography (230–400 mesh SiO , EtOAc:Hexane
2
(
=1:10–1:4) to afford 23 as an orange-red solid (0.050 g,
2
ꢀ
1
TBAB
(0.016 g,
0.048 mmol),
PivOH
(0.010 g,
0.109 mmol) with a 65% yield. Mp = 179–181 C. H NMR
0
.096 mmol), and K CO (0.0040 g, 0.029 mmol) were
(600 MHz, CDCl ) δ 10.19 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H),
2
3
3
added to a Schlenk flask and vacuumed and then intro-
duced to a nitrogen atmosphere. This procedure was
repeated thrice. To this mixture was added DMF (3 ml)
8.04 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.58
(d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.1 Hz, 1H), 7.47 (t, J = 7.1 Hz,
1H), 7.41 (t, J = 7.5 Hz, 2H), 4.67 (q, J = 7.2 Hz, 2H), 4.56 (q,
J = 7.1 Hz, 2H), 1.53 (t, J = 7.2 Hz, 3H), 1.48 (t, J = 7.1 Hz,
ꢀ
and heated at 100 C for 12 hr under an oxygen atmo-
13
sphere. The mixture was concentrated and diluted with
EtOAc and H O. The organic layer was dried (MgSO ) and
3H). C NMR (150 MHz, CDCl ) δ 169.6, 166.5, 139.8, 139.7,
3
138.7, 137.1, 136.3, 129.9, 126.7, 126.6, 126.2, 126.1, 125.4,
124.1, 121.9, 121.3, 121.1, 120.7, 111.3, 107.5, 62.1, 61.9, 14.4,
14.0. HRMS (FAB) calculated For C H NO NaSe [M
2
4
purified by flash column chromatography (230–400 mesh
SiO , EtOAc:Hexane = 1:20–1:10) to afford 20 (0.0079 g,
2
24 19
4
+
0
.0163 mmol) as a white solid with a 17% yield.
+ Na] 488.0377. Found: 488.0377.
ꢀ
1
Mp = 251–253 C. H NMR (600 MHz, CDCl ) δ 7.92
3
(d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.40
(
1
t, J = 7.8 Hz, 1H), 7.30–7.21 (m, 11H), 7.00 (t, J = 7.8 Hz,
3.15 | 5-Methyl-6,7-diphenyl-5H-benzo
[4,5]selenopheno[3,2-c]carbazole (24)
H), 6.91 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.61
13
(d, J = 7.8 Hz, 1H), 4.32 (s, 3H). C NMR (150 MHz,
CDCl ) δ 141.8, 140.2, 139.6, 139.2, 139.1, 137.5, 134.9,
Compound 15 (0.030 g, 0.096 mmol), compound 16
3
1
1
3
34.7, 131.4, 131.1, 130.3, 128.1, 127.9, 127.0, 126.8, 126.7,
25.5, 125.4, 125.2, 124.3, 123.0, 122.4, 119.4, 119.3, 108.5,
(0.0260 g, 0.145 mmol), Pd(OAc) (0.0020 g, 0.009 mmol),
2
TBAB (0.0160 g, 0.048 mmol), PivOH (0.010 g, 0.096 mmol),
and K CO (0.0040 g, 0.029 mmol) were added to a Schlenk
+
0.7. HRMS (EI) calculated for C H NSe [M] 487.0839.
31
21
2
3
Found: 487.0838.
flask and vacuumed and then introduced to a nitrogen

8
WANG ET AL.
atmosphere. This procedure was repeated thrice. To this
mixture was added DMF (3 ml) and heated at 100 C for
ACKNOWLEDGMENTS
ꢀ
We gratefully acknowledge the Ministry of Science
(MOST 105-2113-M-032-001) for supporting this work.
We thank the National Taiwan Normal University for
LRMS and HRMS measurements.
12 hr under an oxygen atmosphere. The mixture was con-
centrated and diluted with EtOAc and H O. The organic
2
layer was dried (MgSO ) and purified by flash column chro-
4
matography (230–400 mesh SiO , EtOAc:Hexane = 1:10–1:4)
2
to afford 24 (0.0098 g, 0.02016 mmol) as a white solid with a
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
ꢀ
1
2
1% yield. Mp = 253–255 C. H NMR (600 MHz, CDCl ) δ
3
8.21 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.54
(
t, J = 7.9 Hz, 1H), 7.42 (dd, J = 17.3, 8.8 Hz, 2H), 7.28–7.17
ORCID
(m, 11H), 6.98 (t, J = 8.1 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H),
Tzenge-Lien Shih https://orcid.org/0000-0001-5378-
0782
13
3
1
1
1
.22 (s, 3H). C NMR (150 MHz, CDCl ) δ 142.3, 140.1,
3
39.1, 139.0, 138.0, 137.9, 137.1, 132.5, 132.0 (2×), 130.6 (2×),
28.6, 128.1 (2×), 127.3, 126.9, 126.8, 125.9, 125.8, 125.7,
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2
2
2
:1–1:2) to afford 25 (0.0236 g, 0.0492 mmol) as an orange
ꢀ
1
solid with a 51% yield. Mp = 196–198 C. H NMR (600 MHz,
CDCl ) δ 8.14 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H),
3
7.63 (td, J = 8.1, 0.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H),
7
.47–7.44 (m, 2H), 7.40 (td, J = 7.3, 1.1 Hz, 1H), 4.60 (q,
J = 7.2 Hz, 2H), 4.53 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz,
[
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13
3
1
1
6
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3
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4
| CONCLUSIONS
2
[
Due to the importance of elemental selenium in pharma-
cological activity and material chemistry, this is the first
synthesis of selenium-containing benzo[b]selenophenyl-
indoles (9, 10, 14 and 15), which was used to evaluate their
Diels–Alder reactions. In comparison with the results in
Schemes 4 and 5, we concluded that 3-benzoselenophen-
4
[11] H. Sashida, K. Sadamori, T. Tsuchiya, Synth. Commun. 1998,
28, 713.
[
[
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Y. Kitamura, Y. Murata, N. Kakusawa, K. Yamaguchi,
S. Yasuike, Tetrahedron Lett. 2016, 57, 5484.
2
-yl-indoles (14 and 15) were more suitable dienes in
Diels–Alder reactions. We believe that the resulting target
molecules (19–21 and 23–25) are valuable, and their bio-
logical activities will be evaluated in the near future.
[15] P. Sun, M. Jiang, W. Wei, Y. Min, W. Zhang, W. Li, D. Yang,
H. Wang, J. Org. Chem. 2017, 82, 2906.

WANG ET AL.
9
[
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K. Takimiya, M. Ikeda, H. Kuwabara, Org. Lett. 2009, 11, 2473.
How to cite this article: Wang R-Y, Kao W-T,
Shih T-L. Synthesis of selenium-containing
biindolyls and their Diels–Alder reaction toward
the synthesis of heteroannulated [a]- and [c]-
carbazoles. J Chin Chem Soc. 2019;1–9. https://doi.
org/10.1002/jccs.201900278
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.