One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts alkylation/oxidative coupling reaction of indoles and salicylaldehydes

Article abstract of DOI:10.1016/j.tet.2018.03.065

An I₂-mediated Friedel-Crafts alkylation/oxidative coupling reaction of indoles and salicylaldehydes was developed. With the developed protocol, a series of indolylchromeno[2,3-b]indoles were obtained in good yields (up to 88%) under mild reaction conditions. Two possible reaction mechanisms were tentatively brought forward to account for the formation of the products in light of some control experiments.

Full text of DOI:10.1016/j.tet.2018.03.065

Tetrahedron xxx (2018) 1e8
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated
Friedel-Crafts alkylation/oxidative coupling reaction of indoles and
salicylaldehydes
,
Guang-Qing Rong a c, Jian-Qiang Zhao b, Xiao-Mei Zhang a, Xiao-Ying Xu a,
,
, **
Wei-Cheng Yuan a *, Ming-Qiang Zhou a
a National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Institute for Advanced Study, Chengdu University, Chengdu 610106, China
c University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An I2-mediated Friedel-Crafts alkylation/oxidative coupling reaction of indoles and salicylaldehydes was
developed. With the developed protocol, a series of indolylchromeno[2,3-b]indoles were obtained in
good yields (up to 88%) under mild reaction conditions. Two possible reaction mechanisms were
tentatively brought forward to account for the formation of the products in light of some control
experiments.
Received 2 February 2018
Received in revised form
26 March 2018
Accepted 28 March 2018
Available online xxx
© 2018 Elsevier Ltd. All rights reserved.
Keywords:
Indolylchromeno[2,3-b]indoles
Friedel-Crafts alkylation
Salicylaldehydes
Indoles
Iodine
1. Introduction
new type of compounds, which probably have some potential
biological activities and fuel ongoing investigations on the new
Chromeno[2,3-b]indoles are ubiquitous structural motifs in
numerous natural or synthetic biologically active molecules.1 For
examples, Hyrtimomine A and B were isolated from a sponge
Hyrtios sp. in 2013, and Hyrtimomine A exhibited cytotoxicity
against KB and L1210 cells.1d Chromeno[2,3-b]indole derivative C
also possesses biological activity, as shown by antimalarial agents
(Fig. 1).1a It is noteworthy that these biologically active compounds
not only contain a chromeno[2,3-b]indole framework core but also
incorporate different groups on the C-11 position. Therefore, many
efforts have been made to the development of efficient synthetic
methods to access various chromeno[2,3-b]indole compounds,
which are particularly characterized by a substitution installed at
the C-11 position.2 Certainly, installing different subsets at the C-11
position of the chromeno[2,3-b]indole scaffold should generate a
drug discovery. On the other hand, the indole moiety is a privileged
heterocyclic ring system featured in a large number of biologically
interesting natural and unnatural compounds.3 However,
a
comprehensive literature study reveals that the strategy for the
synthesis of indolylchromeno[2,3-b]indoles, bearing a indole group
at the C-11 position of chromeno[2,3-b]indole framework core,
remains underdeveloped.4 In particular, Lankalapalli and co-
workers recently reported
a
2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ)-mediated intramolecular CꢀO bond forma-
tion method for the synthesis of indolylchromeno[2,3-b]indole
compounds by 3,30-diindolylmethanes as starting materials, and
further evaluate their antibiotic activity.4 Therefore, taking account
of the potentially biological significance of indolylchromeno[2,3-b]
indoles in medicinal chemistry research, the development of sim-
ple and efficient approaches for the synthesis of the structurally
diverse indolylchromeno[2,3-b]indoles from readily available
starting materials is highly in demand.
* Corresponding author.
In recent years, iodine-catalyzed or iodine-mediated cascade
reactions have attracted great attentions from organic chemists due
** Corresponding author.
E-mail addresses: yuanwc@cioc.ac.cn (W.-C. Yuan), screenfilm@foxmail.com
(M.-Q. Zhou).
https://doi.org/10.1016/j.tet.2018.03.065
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065

2
G.-Q. Rong et al. / Tetrahedron xxx (2018) 1e8
Table 1
Optimization of reaction conditions.a
Fig. 1. Examples of biologically active compounds containing chromeno[2,3-b]indole
scaffold.
Entry
x
Solvent
Temp. (ꢁC) Time (h) 3a/yield (%)b 4a/yield (%)b
1
2
3
4
5
6
7
8
1.0 MeOH
0.5 MeOH
2.0 MeOH
3.0 MeOH
2.0 EtOH
2.0 H2O
2.0 DMSO
2.0 DMF
2.0 CH3CN
2.0 EtOAc
reflux
reflux
reflux
reflux
reflux
80
80
80
80
reflux
2
2
2
2
2
2
2
2
2
2
2
2
2
2
0.5
0.5
41
13
51
50
54
11
e
18
e
to the inexpensive and eco-friendly of molecular iodine.5 It is well
known that iodine could be applied in oxidative coupling reaction
based on its oxidizing ability.6 Meanwhile, iodine also could serve
as a mild Lewis acid for some transformations.7 As part of our
ongoing investigation aiming at developing new methodologies for
the synthesis of diverse heterocycles,8 recently, we have found that
the reaction between indoles and salicylaldehydes could be real-
ized via a Friedel-Crafts alkylation/oxidative coupling process in the
presence of molecular iodine, affording a series of structurally
diverse indolylchromeno[2,3-b]indole compounds (Scheme 1).
Herein, we wish to report our research findings in this subject.
28
44
27
12
e
e
e
9
e
e
10
11
12
13
14c
15d
16d,e
e
e
2.0 Toluene 80
e
e
2.0 DCE
2.0 EtOH
2.0 EtOH
2.0 EtOH
2.0 EtOH
80
rt
reflux
reflux
reflux
e
e
42
62
89
88
43
23
e
e
2. Results and discussion
a
Unless otherwise noted, all reactions were carried out with 1a (0.5 mmol), 2a
(0.5 mmol) and I2 in 5.0 mL of solvent at specified temperature for the specified
reaction time under Ar.
We initiated our investigation with the reaction of indole 1a and
salicylaldehyde 2a in the presence of an equivalent of molecular
iodine in methanol at reflux temperature. The reaction could pro-
ceed to completion within 2 h and furnish the desired 11-(1H-
indol-3-yl)chromeno[2,3-b]indole 3a in 41% yield and co-product
4a in 18% yield (Table 1, entry 1). Lowering the amount of iodine
to 0.5 equivalent, product 3a was obtained only in 13% yield
(Table 1, entry 2). To our delight, increasing the amount of iodine to
2.0 equivalents, an improved yield was achieved (Table 1, entry 3).
Further enhancing the amount of iodine to 3.0 equivalents, no
further improvement in the yield was obtained (Table 1, entry 4).
Afterwards, the screening of various solvents was performed in the
presence of 2.0 equivalent of molecular iodine (Table 1, entries
5e12). It was observed that the reaction only occurred in protonic
solvents and ethanol turned out to be the best choice for the re-
action in light of the yield (Table 1, entry 5 vs entries 6e12). When
the reaction was carried out at room temperature, product 3a and
co-product 4a were obtained in 42% and 43% yield, respectively
(Table 1, entry 13). Ultimately, the ratio of 1a to 2a was investigated.
Excellent yield (89%) could be achieved when the ratio of 1a to 2a
was elevated from 2:1 to 3:1 (Table 1, entry 14 vs entry 15). It's
worth noting that the reaction could conduct in air and it has
almost no influence on the reactivity and yield (Table 1, entry 16).
With the optimized reaction conditions in hand, the substrate
scope of the Friedel-Crafts alkylation/oxidative coupling reaction
was explored. Firstly, various indoles were tested by reacting with
salicylaldehyde 2a. As summarized in Scheme 2, the position and
electronic nature of the substituents on the indoles generally had
slight effect on the reactivities. As to the substrates with either
electron-withdrawing or electron-donating substituents at the C5-
position of indoles, their reactions with 2a could proceed smoothly,
b
Isolated yield.
1.0 mmol of 1a was used.
1.5 mmol of 1a was used.
The reaction was run in air.
c
d
e
Scheme 2. Scope of I2-mediated reaction of various indoles with salicylaldehyde.
and furnished the corresponding products 3b-f in 62e83% yields.
Moreover, the substrates with different substituent in the C4-, C6-,
and C7-position also could react with 2a and delivered the desired
products in good results (products 3h-j). However, 4-Cl substituted
indole 1f reacting with 2a furnished the product 3g only in 45%
Scheme 1. The strategies for the synthesis of indolylchromeno[2,3-b]indole
compounds.
Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065

G.-Q. Rong et al. / Tetrahedron xxx (2018) 1e8
3
yield possibly due to the steric hinderance effect. It should be noted
that 1H-pyrrolo[2,3-b]pyridine also could smoothly react with 2a,
giving the coresponding product 3k in acceptable result (62% yield).
The scope of the reaction was further investigated by using the
reactions of indole 1a with various salicylaldehydes 2 (Scheme 3).
The salicylaldehydes containing various electron-donating sub-
stituents at different positions on the phenyl ring were well-
tolerated to the reaction conditions and delivered the corre-
sponding products 3l-p in good yields. Nevertheless, the sterically
hindered tert-butyl group incorporated into the C5-position of
salicylaldehyde, had little effect on the reactivity, providing the
expected product 3q in 78% yield. Next, various electron-
withdrawing groups including -F, -Br and -NO2 at the different
positions on the phenyl ring of salicylaldehyde were investigated.
The reactions furnished their respective product 3r-u in yields
ranging from 79% to 84%. Meanwhile, it was found that the reaction
of 2,5-dihydroxybenzaldehyde with indole (1a) proceeded
smoothly and provided the desired product 3v in 64% yield. Finally,
this protocol also could be broadened to 1-(2-hydroxyphenyl)
ethanone, and 11-methylchromeno[2,3-b]indole 3w could be ob-
tained in 77% yield under the standard reaction conditions. Notably,
product 3w was obviously different from products 3a-v which are
11-indolylchromeno[2,3-b]indole derivatives.
Scheme 4. Iodine-mediated Friedel-Crafts alkylation/oxidative coupling reaction of
indole and other substrates.
control experiments were conducted (Scheme 5). Firstly, the reac-
tion of indole 1a and 2-methoxybenzaldehyde 11 did not generate
the desired product 3a, but afforded the Friedel-Crafts alkylation
product 12 in 88% yield. This result indicated that hydroxyl group is
necessary in the oxidative coupling process (Scheme 5, (a)).
Furthermore, 2-hydroxybenzaldehyde 2a respectively reacted with
2-methylindole 13 and 1-methylindole 15, only Friedel-Crafts
alkylation products 14 and 16 were detected (Scheme 5, (b) and
(c)). These results suggested that no substituent at N1-and C2-
position of indole is vital important for the following oxidative
coupling process. Next, the control experiment of 1a and 2a using
5 mol % I2 was carried out, giving product 17 in 91% yield. And then
compound 17 could be transformed into product 3a under the
standard conditions (Scheme 5, (d)). This reaction demonstrated
that iodine not only acted as a catalyst for Friedel-Crafts alkylation,
Encouraged by the above-obtained results, we attempted to
explore the possibility of I2-mediated Friedel-Crafts alkylation/
oxidative coupling process for the reactions between indole and
some other substrates. As shown in Scheme 4, 1a reacted smoothly
with 2-mercaptobenzaldehyde 5 under the established standard
reaction
conditions,
giving
the
corresponding
11-
indolylthiochromeno[2,3-b]indole 8 in 81% yield. It is noteworthy
that the reaction of indole with 2-aminobenzaldehyde 6 delivered
not 11-indolyl-5H-indolo[2,3-b]quinoline but 6H-indolo[2,3-b]
quinoline 9 in 61% yield. Similarly, it was also observed that the
reaction of indole 1a with 1-(2-aminophenyl)ethanone 7 afforded
11-methyl-6H-indolo[2,3-b]quinoline 10 in 42% yield.
To investigate the possible reaction mechanism of the I2-medi-
ated Friedel-Crafts alkylation/oxidative coupling reaction, some
Scheme 3. Scope of I2-mediated reaction of indole with various salicylaldehydes.
Scheme 5. Control experiments.
Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
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4
G.-Q. Rong et al. / Tetrahedron xxx (2018) 1e8
but also an oxidizing reagent for the oxidative coupling process in
the reaction. Finally, the reaction of 4a and 1a was conducted, and
the expected product 3a also could be obtained in 93% yield
(Scheme 5, (e)). This reaction suggested that the final product 3a
could be generated through the addition reaction of 1a to 4a, and
subsequent oxidative dehydrogenation.
77.20 ppm, DMSO‑d6 at 39.51 ppm). Melting points were recorded
on a melting point apparatus.
4.2. General procedure for the synthesis of 3
In an ordinary vial equipped with a magnetic stirring bar, indole
1 (1.5 mmol), salicylaldehyde 2 (0.5 mmol) and I2 (1 mmol) were
dissolved in ethanol (5 mL), and then the mixture was stirred at
80 ꢁC for the indicated time. After the completion of reaction, 5%
Na2S2O3 solution (10 mL) and saturated sodium carbonate solution
(10 mL) were added to the mixture. The mixture was extracted with
EtOAc (3 ꢂ 15 mL) and the organic layer was dried (Na2SO4) and
evaporated. The resulting residue was subjected to column chro-
matography on silica gel using petroleum ether/ethyl acetate as
eluent to afford the product 3.
Based on these experiments and relevant reports,9 a plausible
mechanism for this Friedel-Crafts alkylation/oxidative coupling
reaction is proposed in Scheme 6. Firstly, salicylaldehyde reacts
with indole in the presence of I2 to afford compound A. Then,
dehydration of A gives key intermediate B. And then, there are two
different possible pathways to generate product 3a from interme-
diate B. The addition of indole into intermediate B furnishes the
corresponding bis(indolyl)methane 17, which undergoes intra-
molecular cyclization reaction to afford D. Subsequent elimination
of HI yields E. Finally, oxidative dehydrogenation of E by iodine
gives chromeno[2,3-b]indole 3a (path a). Alternatively, oxidative
dehydrogenation of B might occur in the presence I2 to yield 4a. The
addition reaction of 4a with indole furnishes compound E, which
undergoes oxidative dehydrogenation to give 3a (path b).
4.2.1. 11-(1H-indol-3-yl)chromeno[2,3-b]indole (3a)
Yellow solid; 88% yield; m.p. 310e311 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
12.15 (s, 1H), 8.02 (d, J ¼ 2.5 Hz, 1H), 7.88e7.85 (m, 2H),
7.79 (t, J ¼ 5.1 Hz, 1H), 7.67 (d, J ¼ 8.0 Hz, 1H), 7.56 (d, J ¼ 7.8 Hz, 1H),
7.45 (d, J ¼ 7.6 Hz, 1H), 7.38 (t, J ¼ 7.8 Hz, 1H), 7.27 (t, J ¼ 7.4 Hz, 1H),
7.17 (d, J ¼ 7.9 Hz,1H), 7.04 (d, J ¼ 7.5 Hz,1H), 6.95e6.92 (m, 2H); 13
C
3. Conclusion
NMR (75 MHz, DMSO‑d6)
d 163.8, 152.2, 151.2, 139.8, 136.5, 132.0,
In conclusion, we have developed an I2-mediated Friedel-Crafts
alkylation/oxidative coupling reaction for the construction of
chromeno[2,3-b]indole derivatives from readily available indoles
and salicylaldehydes. Utilizing the developed protocol, a series of
indolylchromeno[2,3-b]indoles were smoothly obtained in good
yield (up to 88% yield) under mild conditions. Additionally, in order
to illustrate the reaction mechanism, some control experiments
were conducted and two different possible reaction mechanisms
were tentatively brought forward.
128.8, 128.3, 127.8, 125.8, 124.5, 123.9, 122.9, 122.3, 121.6, 121.4,
120.4, 120.2, 119.8, 118.7, 117.7, 112.6, 106.7; HRMS (ESI-TOF) Calcd.
for C23H15N2O [M þ H]þ 335.1179, found: 335.1176.
4.2.2. 9-Methoxy-11-(5-methoxy-1H-indol-3-yl)chromeno[2,3-b]
indole (3b)
Yellow solid; 62% yield; m.p. 264e266 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
11.97 (br s, 1H), 7.99 (s, 1H), 7.95 (d, J ¼ 7.8 Hz, 1H),
7.85e7.77 (m, 2H), 7.57 (d, J ¼ 8.7 Hz, 1H), 7.45 (t, J ¼ 8.5 Hz, 2H),
6.99e6.91 (m, 2H), 6.60 (s,1H), 6.51 (s,1H), 3.49 (s, 3H), 3.41 (s, 3H);
4. Experimental section
13C NMR (75 MHz, DMSO‑d6)
d 162.8, 154.5, 154.2, 151.3, 145.8,
139.7, 132.0,131.5, 128.4,126.0,124.4, 124.3, 121.2, 120.2,118.7, 117.6,
115.0, 113.4, 112.6, 108.8, 106.4, 101.8, 55.3, 55.0; HRMS (ESI-TOF)
Calcd for C25H19N2O3 [M þ H]þ 395.1390, found: 395.1385.
4.1. General
Reagents were purchased from commercial sources and were
used as received unless mentioned otherwise. Reactions were
monitored by TLC. 1H NMR and 13C NMR spectra were recorded in
CDCl3 and DMSO‑d6. 1H NMR chemical shifts are reported in ppm
relative to tetramethylsilane (TMS) with the solvent resonance
employed as the internal standard (CDCl3 at 7.26 ppm, DMSO‑d6 at
2.50 ppm). Data are reported as follows: chemical shift, multiplicity
(s ¼ singlet, br s ¼ broad singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet), coupling constants (Hz) and integration. 13C NMR
chemical shifts are reported in ppm from tetramethylsilane (TMS)
with the solvent resonance as the internal standard (CDCl3 at
4.2.3. 9-Methyl-11-(5-methyl-1H-indol-3-yl)chromeno[2,3-b]
indole (3c)
Yellow solid; 71% yield; m.p. 295e296 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
11.91 (s, 1H), 7.95 (d, J ¼ 2.3 Hz, 1H), 7.88e7.70 (m, 3H),
7.54 (d, J ¼ 8.4 Hz, 1H), 7.43 (dd, J ¼ 7.5, 4.5 Hz, 2H), 7.18 (d,
J ¼ 8.0 Hz, 1H), 7.09 (d, J ¼ 8.2 Hz, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 2.25
(s, 3H), 2.12 (s, 3H); 13C NMR (75 MHz, DMSO‑d6)
d 163.3, 151.0,
149.9, 139.8, 134.8, 131.8, 130.2, 129.6, 128.9, 128.2, 127.6, 126.1,
124.2, 124.0,123.8, 123.2, 121.4, 120.4, 119.2, 118.1, 117.5, 112.2, 106.3,
21.12, 21.08; HRMS (ESI-TOF) Calcd for C25H19N2O3 [M þ H]þ
363.1492, found: 363.1485.
4.2.4. 9-Fluoro-11-(5-fluoro-1H-indol-3-yl)chromeno[2,3-b]indole
(3d)
Yellow solid; 78% yield; m.p. 338e339 ꢁC; 1H NMR (300 MHz,
DMSO‑d6) d 12.31 (br s, 1H), 8.10 (s, 1H), 7.85e7.79 (m, 3H), 7.64 (dd,
J ¼ 8.2, 2.8 Hz, 1H), 7.53 (dd, J ¼ 8.6, 3.8 Hz, 1H), 7.45 (t, J ¼ 7.5 Hz,
1H), 7.11 (t, J ¼ 7.7 Hz, 1H), 7.10 (t, J ¼ 7.4 Hz, 1H), 6.90 (dd, J ¼ 9.8,
2.4 Hz, 1H), 6.56 (dd, J ¼ 9.2, 2.6 Hz, 1H); 13C NMR (75 MHz,
DMSO‑d6)
d
163.7, 157.7 (d, J ¼ 234.2 Hz, 1C), 157.6 (d, J ¼ 232.4 Hz,
1C), 151.4148.3, 140.7, 133.2, 132.5, 129.8, 128.4, 125.9 (d, J ¼ 10.4 Hz,
1C), 124.6, 124.4, 121.0, 120.0, 119.4 (d, J ¼ 8.6 Hz, 1C), 117.7, 115.5 (d,
J ¼ 23.5 Hz, 1C), 113.9 (d, J ¼ 9.8 Hz, 1C), 110.8 (d, J ¼ 26.0 Hz, 1C),
109.0 (d, J ¼ 25.7 Hz, 1C), 106.5 (d, J ¼ 4.6 Hz, 1C), 104.5 (d,
J ¼ 24.1 Hz, 1C); HRMS (ESI-TOF) Calcd for C23H13F2N2O [M þ H]þ
371.0990, found: 371.0988.
Scheme 6. Proposed mechanism.
Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065

G.-Q. Rong et al. / Tetrahedron xxx (2018) 1e8
5
4.2.5. 9-Bromo-11-(5-bromo-1H-indol-3-yl)chromeno[2,3-b]indole
(3e)
Yellow solid; 83% yield; m.p. 339e340 ꢁC; 1H NMR (300 MHz,
DMSO‑d6) 12.31(s, 1H), 8.10 (s, 1H), 7.87e7.78 (m, 3H), 7.64 (d,
J ¼ 8.4 Hz, 1H), 7.48e7.43 (m, 3H), 7.38e7.32 (m, 2H), 6.96 (s, 1H);
13C NMR (75 MHz, DMSO‑d6)
163.9,151.4,151.0,140.9,135.4,132.5,
4.2.11. 5-(1H-pyrrolo[2,3-b]pyridin-3-yl)chromeno[30,20:4,5]
pyrrolo[2,3-b]pyridine (3k)
Yellow solid; 62% yield; m.p. >400 ꢁC; 1H NMR (300 MHz,
d
DMSO‑d6)
d
12.74 (s, 1H), 8.42 (d, J ¼ 4.6 Hz, 2H), 8.27 (s, 1H), 7.96 (t,
J ¼ 8.8 Hz, 2H), 7.87 (t, J ¼ 7.4 Hz, 1H), 7.87 (t, J ¼ 7.8 Hz, 1H), 7.64 (d,
J ¼ 7.4 Hz, 1H), 7.53 (t, J ¼ 7.2 Hz, 1H), 7.21 (d, J ¼ 6.7 Hz, 1H), 7.15
(dd, J ¼ 8.0, 4.6 Hz, 1H), 7.00 (t, J ¼ 5.3 Hz, 1H); 13C NMR (150 MHz,
d
131.0, 129.7, 128.3, 127.4, 125.7, 125.0, 124.6, 121.9, 120.4, 120.3,
120.1, 117.7, 114.8, 113.5, 112.9, 106.5; HRMS (ESI-TOF) Calcd for
DMSO‑d6)
d 167.0, 165.5, 152.0, 149.5, 148.9, 141.2, 133.0, 130.4,
C
23H13Br2N2O [M þ H]þ 490.9389, found: 490.9378.
128.9, 128.7, 128.6, 125.3, 120.9, 120.3, 118.7, 118.4, 117.8, 117.7, 117.2,
106.0, 100.0; HRMS (ESI-TOF) Calcd for C21H13N4O [M þ H]þ
337.1084, found: 337.1086.
4.2.6. 11-(5-cyano-1H-indol-3-yl)chromeno[2,3-b]indole-9-
carbonitrile (3f)
Yellow solid; 77% yield; m.p. 396e397 ꢁC; 1H NMR (300 MHz,
4.2.12. 11-(1H-indol-3-yl)-4-methylchromeno[2,3-b]indole (3l)
Yellow solid; 75% yield; m.p. 311e312 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d 12.69 (s, 1H), 8.36 (s, 1H), 7.95e7.78 (m, 6H), 7.71 (t,
J ¼ 9.2 Hz, 2H), 7.55 (t, J ¼ 6.9 Hz, 1H), 7.10 (s, 1H); 13C NMR
DMSO‑d6)
d
12.05 (s, 1H), 8.00 (d, J ¼ 2.4 Hz, 1H), 7.73e7.64 (m, 3H),
(140 MHz, DMSO‑d6)
d
165.8, 155.5, 151.4, 141.5, 138.3, 132.7, 132.2,
7.54 (d, J ¼ 7.7 Hz, 1H), 7.34 (t, J ¼ 7.8 Hz, 1H), 7.28e7.25 (m, 2H), 7.14
130.1, 128.1, 125.8, 125.4, 125.1, 125.0, 124.8, 124.1, 120.2, 119.6, 119.4,
119.1, 117.6, 113.9, 107.1, 103.4, 102.8, 99.3; HRMS (ESI-TOF) Calcd for
(d, J ¼ 7.9 Hz, 1H), 7.05 (d, J ¼ 7.3 Hz, 1H), 6.96e6.91 (m, 2H), 2.48 (s,
3H); 13C NMR (75 MHz, DMSO‑d6)
d 163.8, 151.9, 151.2, 142.9, 140.0,
C
25H13N4O [M þ H]þ 385.1084, found: 385.1092.
136.4, 128.5, 127.9, 127.7, 125.7, 125.5, 123.9, 122.6, 122.3, 121.4,
120.3, 120.2, 119.7, 118.4, 118.0, 117.5, 112.5, 106.8, 21.1; HRMS (ESI-
TOF) Calcd for C24H17N2O [M þ H]þ 349.1335, found: 349.1324.
4.2.7. 10-Chloro-11-(4-chloro-1H-indol-3-yl)chromeno[2,3-b]
indole (3g)
Yellow solid; 45% yield; m.p. 310e311 ꢁC; 1H NMR (300 MHz,
4.2.13. 11-(1H-indol-3-yl)-3-methylchromeno[2,3-b]indole (3m)
Yellow solid; 77% yield; m.p. 286e289 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
12.01 (s, 1H), 7.86 (d, J ¼ 7.9 Hz, 1H), 7.77 (t, J ¼ 7.6 Hz,
1H), 7.72 (s,1H), 7.54 (dd, J ¼ 14.4, 7.3 Hz, 3H), 7.40 (t, J ¼ 7.8 Hz, 2H),
DMSO‑d6)
d
12.04 (s, 1H), 8.00 (d, J ¼ 2.6 Hz, 1H), 7.72e7.64 (m, 2H),
7.20 (t, J ¼ 7.9 Hz, 1H), 7.11e7.00 (m, 2H); 13C NMR (75 MHz,
7.67 (d, J ¼ 8.2 Hz, 1H), 7.54 (d, J ¼ 7.8 Hz, 1H), 7.28 (t, J ¼ 7.0 Hz, 1H),
7.12e7.09 (m, 2H), 7.03 (d, J ¼ 7.7 Hz, 1H), 6.96 (t, J ¼ 7.1 Hz, 1H),
6.95e6.92 (m, 2H), 2.51 (s, 3H); 13C NMR (75 MHz, DMSO‑d6)
DMSO‑d6) d 163.6,154.3,149.8,144.0,137.2,132.4,130.1,129.1,128.9,
128.1, 126.4, 124.6, 124.4, 123.0, 122.8, 122.7, 122.1, 120.2, 117.6, 117.1,
111.4, 109.0; HRMS (ESI-TOF) Calcd for C23H13Cl2N2O [M þ H]þ
403.0399, found: 403.0405.
d
163.8, 151.9, 151.2, 142.9, 140.0, 136.4, 128.5, 127.9, 127.7, 125.7,
125.6,123.9,122.6,122.3,121.4, 120.3,120.2,119.7, 118.4, 118.0, 117.6,
112.5, 106.8, 21.1; HRMS (ESI-TOF) Calcd for C24H17N2O [M þ H]þ
349.1335, found: 349.1321.
4.2.8. 8-Chloro-11-(6-chloro-1H-indol-3-yl)chromeno[2,3-b]indole
(3h)
Yellow solid; 81% yield; m.p. 265e266 ꢁC; 1H NMR (300 MHz,
4.2.14. 11-(1H-indol-3-yl)-3-methoxychromeno[2,3-b]indole (3n)
Yellow solid; 74% yield; m.p. 257e258 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d 12.23 (s, 1H), 8.09 (s, 1H), 7.94e7.75 (m, 3H), 7.70 (d,
J ¼ 1.4 Hz, 1H), 7.58 (d, J ¼ 1.8 Hz, 1H), 7.47 (t, J ¼ 7.5 Hz, 1H), 7.13 (d,
DMSO‑d6)
d
12.08 (s, 1H), 8.09 (s, 1H), 7.82 (d, J ¼ 9.1 Hz,1H), 7.68 (d,
J ¼ 8.5 Hz, 1H), 7.08e6.97 (m, 2H), 6.84 (d, J ¼ 8.3 Hz, 1H); 13C NMR
J ¼ 7.9 Hz, 1H), 7.54 (d, J ¼ 7.7 Hz, 1H), 7.39e7.31 (m, 4H), 7.18 (d,
J ¼ 7.7 Hz, 1H), 7.04 (d, J ¼ 7.9 Hz, 1H), 6.93e6.88 (m, 2H), 3.67 (s,
(75 MHz, DMSO‑d6)
d 164.6, 153.3, 151.2, 140.0, 136.8, 133.1, 132.3,
128.9, 128.2, 127.1, 124.7, 124.4, 123.7, 122.4, 121.5, 121.1, 120.7, 120.5,
120.2, 118.4, 117.7, 112.2, 106.6; HRMS (ESI-TOF) Calcd for
3H); 13C NMR (75 MHz, DMSO‑d6)
d 163.9, 155.4, 152.3, 145.5, 139.5,
128.8, 127.8, 125.5, 123.7, 122.8, 122.3, 121.4, 121.3, 120.9, 120.1,
119.9, 119.1, 118.6, 118.7, 112.6, 110.6, 106.7, 55.5; HRMS (ESI-TOF)
Calcd for C24H17N2O2 [M þ H]þ 365.1285, found: 365.1270.
C
23H13Cl2N2O [M þ H]þ 403.0399, found: 403.0403.
4.2.9. 7-Methyl-11-(7-methyl-1H-indol-3-yl)chromeno[2,3-b]
indole (3i)
4.2.15. 11-(1H-indol-3-yl)-4-methoxychromeno[2,3-b]indole (3o)
Yellow solid; 72% yield; m.p. 229e230 ꢁC; 1H NMR (300 MHz,
Yellow solid; 75% yield; m.p. 270e271 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
12.30 (s, 1H), 7.99 (d, J ¼ 2.5 Hz, 1H), 7.86 (d, J ¼ 8.43 Hz,
DMSO‑d6)
d
12.07 (s, 1H), 8.00 (s,1H), 7.67 (d, J ¼ 8.2 Hz,1H), 7.56 (d,
2H), 7.78 (t, J ¼ 7.1 Hz, 1H), 7.43 (t, J ¼ 7.3 Hz, 1H), 7.21 (t, J ¼ 5.7 Hz,
1H), 7.05 (d, J ¼ 5.2 Hz, 1H), 6.95e6.93 (m, 2H), 6.83e6.79 (m, 2H),
J ¼ 7.8 Hz, 1H), 7.45 (d, J ¼ 1.6 Hz, 1H), 7.38e7.34 (m, 3H), 7.25 (t,
J ¼ 7.7 Hz, 1H), 7.12 (d, J ¼ 7.9 Hz, 1H), 7.02 (d, J ¼ 7.4 Hz 1H),
6.95e6.92 (m, 2H), 4.04 (s, 3H); 13C NMR (75 MHz, DMSO‑d6)
2.63 (s, 3H), 5.51(s, 3H); 13C NMR (75 MHz, DMSO‑d6)
d 164.0, 151.1,
150.6, 139.7, 136.0, 131.8, 129.7, 128.2, 127.3, 125.5, 124.3, 123.3,
122.7, 121.9, 121.8, 121.4, 120.4, 120.3, 117.5, 117.3, 107.1, 16.9, 16.6;
HRMS (ESI-TOF) Calcd for C25H19N2O [M þ H]þ 363.1492, found:
363.1469.
d 163.5, 152.2, 147.9, 140.7, 140.1, 136.4, 128.9, 127.7, 125.8, 123.9,
123.8, 122.8, 122.3,121.5, 121.5, 121.0, 120.2, 119.8, 119.4, 118.5, 114.0,
112.6, 107.0, 56.4; HRMS (ESI-TOF) Calcd for C24H17N2O2 [M þ H]þ
365.1285, found: 365.1278.
4.2.10. 7-Bromo-11-(7-bromo-1H-indol-3-yl)chromeno[2,3-b]
indole (3j)
4.2.16. 11-(1H-indol-3-yl)-2-methoxychromeno[2,3-b]indole (3p)
Yellow solid; 71% yield; m.p. 285e286 ꢁC; 1H NMR (300 MHz,
Yellow solid; 84% yield; m.p. 338e339 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
12.05 (s, 1H), 8.00 (d, J ¼ 2.5 Hz, 1H), 7.75 (d, J ¼ 9.0 Hz,
DMSO‑d6)
d
12.31 (s, 1H), 8.10 (s, 1H), 7.89e7.84 (m, 3H), 7.58 (dd,
1H), 7.65 (d, J ¼ 8.0 Hz, 1H), 7.53 (d, J ¼ 8.0 Hz, 1H), 7.48 (d,
J ¼ 2.4 Hz, 1H), 7.34 (t, J ¼ 6.3 Hz, 1H), 7.26 (t, J ¼ 7.7 Hz, 1H), 7.15 (d,
J ¼ 7.8 Hz, 1H), 7.09e7.02 (m, 2H), 6.93 (q, J ¼ 7.8 Hz, 2H), 3.95 (s,
J ¼ 7.3, 1.6 Hz, 1H), 7.49 (d, J ¼ 7.7 Hz, 2H), 7.17 (d, J ¼ 8.0 Hz, 1H),
6.99 (d, J ¼ 7.7 Hz, 1H), 6.89e6.86 (m, 2H); 13C NMR (75 MHz,
DMSO‑d6)
d
163.9, 151.3, 149.9, 141.3, 135.0, 132.6, 131.5, 129.1, 128.3,
3H); 13C NMR (150 MHz, DMSO‑d6)
d 163.6, 162.1, 152.7, 151.3, 139.7,
127.3, 125.2, 125.1, 124.8, 123.1, 121.9, 121.7, 121.7, 120.2, 119.3, 117.7,
111.8, 107.6, 105.1; HRMS (ESI-TOF) Calcd for C23H13Br2N2O [M þ
H]þ 490.9389, found: 490.9378.
136.1, 128.8, 127.5, 126.6, 125.5, 123.7, 121.8, 120.8, 119.6, 119.1, 118.8,
117.9,113.8,112.0,112.0,106.8,101.4, 55.7; HRMS (ESI-TOF) Calcd for
C
24H17N2O2 [M þ H]þ 365.1285, found: 365.1278.
Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065

6
G.-Q. Rong et al. / Tetrahedron xxx (2018) 1e8
4.2.17. 2-(tert-butyl)-11-(1H-indol-3-yl)chromeno[2,3-b]indole
(3q)
Calcd for C23H15N2O2 [M þ H]þ 351.1128, found: 351.1116.
Yellow solid; 78% yield; m.p. 264e265 ꢁC; 1H NMR (300 MHz,
4.2.23. 11-methylchromeno[2,3-b]indole (3w)
DMSO‑d6)
d
12.06 (s, 1H), 8.09 (d, J ¼ 2.5 Hz, 1H), 7.90 (s, 1H),
Yellow solid; 77% yield; m.p. 167e168 ꢁC; 1H NMR (300 MHz,
7.89e7.81 (m, 2H), 7.67 (d, J ¼ 8.2 Hz, 1H), 7.55 (d, J ¼ 7.8 Hz, 1H),
7.36 (t, J ¼ 7.6 Hz, 1H), 7.27 (t, J ¼ 7.8 Hz, 1H), 7.19 (d, J ¼ 7.9 Hz, 1H),
7.07e7.04 (m, 2H), 7.04 (t, J ¼ 7.5 Hz, 1H), 1.20 (s, 9H); 13C NMR
DMSO‑d6)
d
8.20 (d, J ¼ 8.0 Hz, 1H), 8.16 (d, J ¼ 7.3 Hz, 1H), 7.80 (d,
J ¼ 3.9 Hz, 2H), 7.58 (d, J ¼ 8.0 Hz, 2H), 7.51 (t, J ¼ 7.3 Hz, 1H), 7.32 (t,
J ¼ 7.4 Hz, 1H); 13C NMR (75 MHz, DMSO‑d6)
d 163.0, 152.0, 150.6,
(75 MHz, DMSO‑d6)
d
163.9, 152.1, 149.3, 146.5, 140.2, 136.5, 129.6,
143.9, 132.0, 128.7, 126.1, 124.5,124.1, 123.4,122.1, 121.6, 120.2,118.6,
117.4, 14.9; HRMS (ESI-TOF) Calcd for C16H12NO [M þ H]þ 234.0913,
found: 234.0913.
128.7, 128.0, 125.7, 124.2, 123.9, 122.7, 122.3, 121.4, 120.9, 120.1,
112.0, 119.4, 118.5, 117.2, 112.6, 106.8, 34.5, 31.0; HRMS (ESI-TOF)
Calcd for C27H23N2O [M þ H]þ 391.1805, found: 391.1792.
4.3. General procedure for the synthesis of 4a
4.2.18. 2-Fluoro-11-(1H-indol-3-yl)chromeno[2,3-b]indole (3r)
Yellow solid; 82% yield; m.p. 310e312 ꢁC; 1H NMR (300 MHz,
In an ordinary vial equipped with a magnetic stirring bar, indole
1a (0.5 mmol), salicylaldehyde 2a (0.5 mmol) and I2 (1 mmol) were
dissolved in ethanol (5 mL), and then the mixture was stirred at
room temperature for 2 h. After the completion of reaction, 5%
Na2S2O3 solution (10 mL) and saturated sodium carbonate solution
(10 mL) were added to the mixture. The mixture was extracted with
EtOAc (3 ꢂ 15 mL) and the organic layer was dried (Na2SO4) and
evaporated. The resulting residue was subjected to column chro-
matography on silica gel using petroleum ether/ethyl acetate as
eluent to afford the product 4a.
DMSO‑d6)
d 12.10 (s, 1H), 8.07 (s, 1H), 7.94e7.90 (m, 1H), 7.68 (d,
J ¼ 8.0 Hz, 2H), 7.55 (d, J ¼ 8.3 Hz, 2H), 7.38 (d, J ¼ 4.2 Hz,1H), 7.29 (t,
J ¼ 7.1 Hz, 1H), 7.17 (d, J ¼ 7.7 Hz, 1H), 7.07 (t, J ¼ 7.1 Hz, 1H),
6.93e6.92 (m, 2H); 13C NMR (75 MHz, DMSO‑d6)
d 163.7, 158.0 (d,
J ¼ 239.3 Hz, 1C), 152.3, 147.4, 138.6 (d, J ¼ 2.6 Hz, 1C), 136.5, 129.2,
127.9, 125.4,123.5,123.1, 122.4,121.8 (d, J ¼ 34.1 Hz, 1C),121.7, 120.3,
119.7, 119.6 (d, J ¼ 8.7 Hz, 1C), 119.2 (d, J ¼ 24.6 Hz, 1C), 118.6, 113.1
(d, J ¼ 25.3 Hz, 1C), 112.7, 106.2; HRMS (ESI-TOF) Calcd for
C
23H14FN2O [M þ H]þ 353.1085, found: 353.1083.
4.2.19. 3-Bromo-11-(1H-indol-3-yl)chromeno[2,3-b]indole (3s)
Yellow solid; 79% yield; m.p. 281e282 ꢁC; 1H NMR (300 MHz,
4.3.1. Chromeno[2,3-b]indole (4a)
Yellow solid; 54% yield; m.p. 216e217 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
12.08 (s, 1H), 8.16 (d, J ¼ 1.8 Hz, 1H), 8.01 (s, 1H), 7.76 (d,
DMSO‑d6)
d
8.82 (s, 1H), 8.08 (d, J ¼ 7.5 Hz, 1H), 8.04 (d, J ¼ 7.7 Hz,
J ¼ 8.6 Hz, 1H), 7.63e7.62 (m, 2H), 7.55 (d, J ¼ 7.8 Hz, 1H), 7.37 (t,
J ¼ 7.5 Hz, 1H), 7.26 (t, J ¼ 8.1 Hz, 1H), 7.14 (d, J ¼ 7.4 Hz, 1H), 7.06 (d,
J ¼ 7.1 Hz, 1H), 6.97e6.94 (m, 2H); 13C NMR (75 MHz, DMSO‑d6)
1H), 7.81 (m, 2H), 7.54 (m, 3H), 7.31 (t, J ¼ 7.5 Hz, 1H); 13C NMR
(75 MHz, DMSO‑d6)
d 164.0, 152.4, 151.1, 132.0, 131.4, 129.8, 129.7,
124.8, 124.8, 123.5, 122.3, 122.0, 119.3, 118.7, 117.3; HRMS (ESI-TOF)
d
163.4, 152.0, 151.4. 139.1, 136.5, 129.7, 129.0, 127.9, 127.5, 125.6,
Calcd. for C15H10NO [M þ H]þ 220.0757, found: 220.0750.
124.5, 123.8, 122.9, 122.4, 121.9, 121.5, 120.4, 120.3, 119.8, 119.8,
118.7, 112.6, 106.3; HRMS (ESI-TOF) Calcd for C23H14BrN2O [M þ H]þ
413.0284, found: 413.0283.
4.4. General procedure for the synthesis of 8e10
In an ordinary vial equipped with a magnetic stirring bar, indole
1 (1.5 mmol), 5 or 6 or 7 (0.5 mmol) and I2 (1 mmol) were dissolved
in ethanol (5 mL), and then the mixture was stirred at 80 ꢁC for the
indicated time. After the completion of reaction, 5% Na2S2O3 solu-
tion (10 mL) and saturated sodium carbonate solution (10 mL) were
added to the mixture. The mixture was extracted with EtOAc
(3 ꢂ 15 mL) and the organic layer was dried (Na2SO4) and evapo-
rated. The resulting residue was subjected to column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate as eluent to
afford the product 8 or 9 or 10.
4.2.20. 2-Bromo-11-(1H-indol-3-yl)chromeno[2,3-b]indole (3t)
Yellow solid; 84% yield; m.p. 255e256 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
12.07 (s, 1H), 8.03 (d, J ¼ 1.9 Hz, 1H), 7.88e7.85 (m, 2H),
7.80 (t, J ¼ 9.1 Hz, 1H), 7.65 (d, J ¼ 8.1 Hz, 1H), 7.51 (d, J ¼ 7.8 Hz, 1H),
7.33e7.32 (m, 1H), 7.24 (t, J ¼ 7.3 Hz, 1H), 7.14 (d, J ¼ 7.9 Hz, 1H), 7.04
(d, J ¼ 7.2 Hz, 1H), 6.91e6.90 (m, 2H); 13C NMR (75 MHz, DMSO‑d6)
d
163.5, 152.2, 150.1, 138.2, 136.5, 134.1, 129.9, 129.3, 127.9, 125.5,
123.7, 123.0, 122.5, 122.3, 122.2, 121.9, 120.3, 119.9, 119.6, 118.7, 116.1,
112.7, 106.1; HRMS (ESI-TOF) Calcd for C23H14BrN2O [M þ H]þ
413.0284, found: 413.0285.
4.4.1. 11-(1H-indol-3-yl)thiochromeno[2,3-b]indole (8)
4.2.21. 11-(1H-indol-3-yl)-2-nitrochromeno[2,3-b]indole (3u)
Yellow solid; 82% yield; m.p. >400 ꢁC; 1H NMR (300 MHz,
Red solid; 81% yield; m.p. 278e279 ꢁC; 1H NMR (300 MHz,
DMSO‑d6)
d
11.91 (s, 1H), 8.14 (d, J ¼ 7.8 Hz, 1H), 7.85 (d, J ¼ 8.1 Hz,
DMSO‑d6)
d
12.18 (s, 1H), 8.67 (d, J ¼ 2.6 Hz, 1H), 8.59 (d, J ¼ 9.1 Hz,
1H), 7.78 (s,1H), 7.72 (t, J ¼ 7.8 Hz,1H), 7.63 (dd, J ¼ 16.4, 8.0 Hz, 2H),
7.50 (t, J ¼ 7.7 Hz, 1H), 7.38 (t, J ¼ 7.5 Hz, 1H), 7.24 (t, J ¼ 7.5 Hz, 1H),
7.04 (d, J ¼ 7.6 Hz, 1H), 6.97 (d, J ¼ 7.1 Hz, 1H), 6.90 (dd, J ¼ 13.9,
6.5 Hz, 1H), 6.54 (d, J ¼ 7.6 Hz, 1H); 13C NMR (75 MHz, DMSO‑d6)
1H), 8.13e8.12 (m, 2H), 7.71 (d, J ¼ 8.1 Hz, 1H), 7.61 (d, J ¼ 7.6 Hz,
1H), 7.44 (t, J ¼ 7.2 Hz, 1H), 7.31 (t, J ¼ 7.8 Hz, 1H), 7.22 (d, J ¼ 8.2 Hz,
1H) 7.01e6.99 (m, 2H); 13C NMR (75 MHz, DMSO‑d6)
d 163.4, 154.7,
152.1, 143.4, 138.1, 136.5, 129.6, 128.3, 126.2, 125.4, 123.8, 123.5,
123.3, 122.7, 122.4, 120.9, 120.5, 119.8, 119.3, 119.0, 112.8, 105.9;
HRMS (ESI-TOF) Calcd for C23H14N3O2 [M þ H]þ 380.1030, found:
380.1026.
d 160.1, 154.5, 141.7, 136.3, 132.0, 131.1, 129.9, 129.6, 128.7, 128.6,
127.1, 126.5, 126.2, 126.1, 125.6, 123.0, 122.1, 121.8, 120.0, 118.8, 117.9,
112.3, 109.1; HRMS (ESI-TOF) Calcd for C23H15N2S [M þ H]þ
351.0950, found: 351.0941.
4.2.22. 11-(1H-indol-3-yl)chromeno[2,3-b]indol-2-ol (3v)
4.4.2. 6H-indolo[2,3-b]quinoline (9)
Yellow solid; 64% yield; m.p. 306e307 ꢁC; 1H NMR (300 MHz,
Pale yellow solid; 61% yield; m.p. 341e342 ꢁC; 1H NMR
DMSO‑d6)
d
12.00 (s, 1H), 10.80 (br s, 1H), 7.97 (d, J ¼ 2.3 Hz, 1H),
(300 MHz, DMSO‑d6)
d
11.68 (s,1H), 9.04 (s, 1H), 8.27 (d, J ¼ 7.7 Hz,
7.70 (d, J ¼ 8.9 Hz, 1H), 7.65 (d, J ¼ 8.1 Hz,1H), 7.52 (d, J ¼ 7.9 Hz, 1H),
7.28e7.25 (m, 2H), 7.18e7.13(m, 2H), 7.04 (t, J ¼ 6.8 Hz, 1H), 6.92 (m,
1H), 8.12 (d, J ¼ 7.0 Hz, 1H), 7.99 (d, J ¼ 8.5 Hz, 1H), 7.44 (dd, J ¼ 6.8,
1.5 Hz, 1H), 7.53e7.48 (m, 3H), 7.28 (t, J ¼ 5.2 Hz, 1H); 13C NMR
3H); 13C NMR (75 MHz, DMSO‑d6)
d
164.0, 161.4, 153.2, 151.3, 140.7,
(75 MHz, DMSO‑d6) d 152.91, 146.34, 141.78, 128.67, 128.21, 127.55,
136.4, 129.7, 127.7, 127.5, 125.7, 124.1, 122.23, 122.16, 121.2, 120.1,
119.7, 118.3, 117.6, 113.5, 112.9, 112.5, 107.0, 103.1; HRMS (ESI-TOF)
127.00, 123.69, 122.74, 121.84, 120.31, 119.68, 117.92, 110.94; HRMS
(ESI-TOF) Calcd for C15H11N2 [M þ H]þ219.0917, found: 219.0919.
Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065

G.-Q. Rong et al. / Tetrahedron xxx (2018) 1e8
7
4.4.3. 11-Dimethyl-6H-indolo[2,3-b]quinoline (10)
J ¼ 15.5, 7.7 Hz, 3H), 6.74 (s, 2H), 6.66 (t, J ¼ 7.3 Hz, 1H), 6.20 (s, 1H),
3.67 (s, 6H); HRMS (ESI-TOF) Calcd for C25H22N2NaO2 [MþNa]þ
389.1624; found: 389.1625.
Yield 42%; light-yellow solid; m.p. 269e270 ꢁC; 1H NMR
(300 MHz, CDCl3)
J ¼ 8.7 Hz, 1H), 7.77 (dd, J ¼ 7.2, 1.2 Hz, 1H), 7.56e7.51 (m, 3H),
d
10.33 (1H, s), 8.29 (d, J ¼ 8.2 Hz, 2H), 8.14 (d,
7.35e7.31 (m, 1H), 3.24 (s, 3H); 13C NMR (75 MHz, DMSO‑d6)
4.8. General procedure for the synthesis of 17
d
151.46, 145.93, 142.21, 138.90, 128.64, 127.58, 127.53, 124.48,
123.55, 122.55, 120.40, 119.95, 115.53, 109.04, 14.81; HRMS (ESI-
In an ordinary vial equipped with a magnetic stirring bar, indole
1a (1.5 mmol), salicylaldehyde 2a (0.5 mmol) and 5 mol % I2 were
dissolved in ethanol (5 mL), and then the mixture was stirred at
room temperature for 1 h. After the completion of reaction, 5%
Na2S2O3 solution (10 mL) and saturated sodium carbonate solution
(10 mL) were added to the mixture. The mixture was extracted with
EtOAc (3 ꢂ 15 mL) and the organic layer was dried (Na2SO4) and
evaporated. The resulting residue was subjected to column chro-
matography on silica gel using petroleum ether/ethyl acetate as
eluent to afford the product 17.
TOF) Calcd for C16H13N2 [M þ H]þ 233.1073, found: 233.1076.
4.5. General procedure for the synthesis of 12
In an ordinary vial equipped with a magnetic stirring bar, indole
1a (1.5 mmol), 11 (0.5 mmol) and I2 (1 mmol) were dissolved in
ethanol (5 mL), and then the mixture was stirred at 80 ꢁC for
10 min. After the completion of reaction, 5% Na2S2O3 solution
(10 mL) and saturated sodium carbonate solution (10 mL) were
added to the mixture. The mixture was extracted with EtOAc
(3 ꢂ 15 mL) and the organic layer was dried (Na2SO4) and evapo-
rated. The resulting residue was subjected to column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate as eluent to
afford the product 12.
4.8.1. 2-[di(1H-indol-3-yl)methyl]phenol (17)
Red solid, 91% yield; m.p.104e105 ꢁC; 1H NMR (300 MHz, CDCl3)
d
7.97 (brs, 2H), 7.42e7.36 (m, 4H), 7.22e7.17 (m, 4H), 7.06 (t, J ¼ 6.1,
2H), 6.87e6.77 (m, 4H), 6.00 (s, 1H); 5.37 (s, 1H); HRMS (ESI-TOF)
Calcd for C23H18N2NaO [MþNa]þ 361.1311; found: 361.1307.
4.5.1. 3,30-[(2-methoxyphenyl)methylene]bis(1H-indole) (12)
Pink solid; 88% yield; m.p. 135e136 ꢁC; 1H NMR (300 MHz,
Acknowledgements
DMSO‑d6)
d
10.78 (s, 2H), 7.37 (d, J ¼ 8.0 Hz, 2H), 7.26 (d, J ¼ 7.8 Hz,
2H), 7.19 (d, J ¼ 9.1 Hz, 2H), 7.14e6.75 (m, 8H), 6.25 (s, 1H), 3.80 (s,
3H); HRMS (ESI-TOF) Calcd for C24H20N2NaO [MþNa]þ 375.1468;
found: 375.1465.
We are grateful for financial support from the National Natural
Science Foundation of China (No. 21572223, 21572224 and
21602217), the Chinese Academy of Sciences western light pro-
gram, and Sichuan Youth Science and Technology Foundation
(2015JQ0041 and 2016JQ0024).
4.6. General procedure for the synthesis of 14
In an ordinary vial equipped with a magnetic stirring bar, 2-
methyl-1H-indole 13 (1.5 mmol), salicylaldehyde 2a (0.5 mmol)
and I2 (1 mmol) were dissolved in ethanol (5 mL), and then the
mixture was stirred at 80 ꢁC for 2 min. After the completion of re-
action, 5% Na2S2O3 solution (10 mL) and saturated sodium car-
bonate solution (10 mL) were added to the mixture. The mixture
was extracted with EtOAc (3 ꢂ 15 mL) and the organic layer was
dried (Na2SO4) and evaporated. The resulting residue was subjected
to column chromatography on silica gel using petroleum ether/
ethyl acetate as eluent to afford the product 14.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.03.065.
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Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065

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Please cite this article in press as: Rong G-Q, et al., One-pot access to indolylchromeno[2,3-b]indoles via iodine-mediated Friedel-Crafts
alkylation/oxidative coupling reaction of indoles and salicylaldehydes, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.03.065