Convenient Synthesis of 6,7,12,13-Tetrahydro-5H-Cyclohepta[2,1-b:3,4-b’]diindole Derivatives Mediated by Hypervalent Iodine (III) Reagent

Article abstract of DOI:10.3390/molecules24050960

Bisindolyl alkaloids represent a large family of natural and synthetic products that display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles have received little attention. Only two methods have been developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindole scaffold thus far, including the classical Fischer indole synthesis conducted by reacting indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles through intramolecular oxidative coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to excellent yields.

Full text of DOI:10.3390/molecules24050960

molecules
Article
Convenient Synthesis of
,7,12,13-Tetrahydro-5H-Cyclohepta[2,1-b:3,4-b’]diindole
Derivatives Mediated by Hypervalent Iodine
III) Reagent
6
(
Lei Peng 1,2, Xiaofei Zhang 1,* and Chunhao Yang 1,2,
*
1
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China;
leipeng@simm.ac.cn
School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road,
Beijing 100049, China
2
*
Correspondence: xiaofeizhang@simm.ac.cn (X.Z.); chyang@simm.ac.cn (C.Y.); Tel.: +86-21-5080-6770 (X.Z.);
+
86-21-5080-6770 (C.Y.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Richard A. Bunce, Philippe Belmont, Wim Dehaen and Eugene Babaev
Received: 16 February 2019; Accepted: 6 March 2019; Published: 8 March 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Bisindolyl alkaloids represent a large family of natural and synthetic products that
display various biological activities. Among the bisindole compounds, 6,7,12,13-tetrahydro-
5H-cyclohepta[2,1-b:3,4-b’]diindoles have received little attention. Only two methods have been
developed for the construction of the 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindole
scaffold thus far, including the classical Fischer indole synthesis conducted by reacting
indole-fused cycloheptanone and hydrazines, and the condensation reaction to build the
seven-membered ring. Here, we report for the first time a new route to synthesize 6,7,12,13-
tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles through intramolecular oxidative coupling of
1,3-di(1H-indol-3-yl)propanes in the presence of PIFA, DDQ and TMSCl with moderate to
excellent yields.
Keywords: phenyliodine(III)bis(trifluoroacetate); cyclohepta[2,1-b:3,4-b’]diindole; intramolecular
oxidative coupling
1
. Introduction
The bisindole core constitutes a valuable class of biologically active molecules that are prevalent
in nature [
antitumor, antimicrobial and antidiabetic. For example, Iheyamine A (Figure 1A), an alkaloid isolated
from a colonial ascidian Polycitorella sp., shows interesting moderate cytotoxicity [ ], and Rebeccamycin
Figure 1B), an antitumor antibiotic isolated from cultures of Saccharotrix aerocolonigenes, is well-known
for its inhibitory potency toward topoisomerase I [ 10]. In addition, natural product derivative
1–6]. These natural and synthetic compounds display various biological activities such as
7
(
8–
Midostaurin (Figure 1C) has been approved by the US FDA for the treatment of FLT3-mutated
acute myelogenous leukemia (AML) [11], and synthetic indolocarbazole derivative D (Figure 1D)
shows excellent antibacterial activity and good antifungal activity [12]. Furthermore, Caulersin
(
Figure 1E) from the alga Caulerpa serrulate [13–15] and Racemosin C (Figure 1F) isolated from the green
alga Caulerpa racemose [16] exhibit significant PTP1B inhibitory activity. It is worth noting that both
compounds E and F contain a medium ring besides the bisindole structure. The bisindole core also has
applications in material science. For example, the synthetic cyclopenta[2,1-b:3,4-b’]diindole derivatives
(Figure 1G) show excellent luminous efficiency as organic electroluminescent compounds [17].
Molecules 2019, 24, 960; doi:10.3390/molecules24050960
www.mdpi.com/journal/molecules

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Figure 1. Some bioactive bisindolyl alkaloids and synthetic compounds.
Among the bisindole compounds, the rarely explored 6,7,12,13-tetrahydro-5H-cyclohepta
2,1-b:3,4-b’]diindoles attracted our interest. To the best of our knowledge, only two methods have
[
been reported to construct 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles. One was the
establishment of the second indole by classic Fischer indole synthesis, which usually suffered from
an excess of acids, hazardous hydrazines, and a limited number of indole-fused cycloheptanones
(
Scheme 1a) [18–20]. The other approach was the construction of seven-membered ring by condensation
reaction, and this process strictly required specific functional groups on the substrates (Scheme 1b) [21].
Scheme 1. Methods for the synthesis of 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles.
Our group has been focused on the synthesis of natural product analogues for bioactive
screening for many years [22
–26]. Thus we hoped to develop a convenient and practical method
for the synthesis of 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles. Inspired by previous

Molecules 2019, 24, 960
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work, the hypervalent iodine reagents, such as phenyliodine(III)bis(trifluoroacetate) (PIFA) and
phenyliodine(III)diacetate (PIDA), have been widely applied to organic synthesis due to its mild
oxidation capacity, low toxicity and environmentally benign properties [27,28]. Intermolecular
oxidative coupling reactions of aromatic rings mediated by hypervalent iodine reagents have
been studied by many researchers and many excellent examples have been reported, including
heteroaromatic couplings [29
aromatic couplings [38 41]. In the meantime, some progress have been achieved in intramolecular
oxidative coupling reactions mediated by hypervalent iodine reagents, including the establishment
of spiro structures [42 44] and fused rings [45 48]. Constructing a seven-membered ring through
–34], cross-couplings of heteroaromatic and aromatic rings [35–37] and
–
–
–
intramolecular oxidation is still highly desirable. Herein, we report for the first time a new route
to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles by intramolecular oxidative
coupling of 1,3-di(1H-indol-3-yl)propanes in the presence of phenyliodine(III)bis(trifluoroacetate)
(PIFA), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and trimethylsilyl chloride (TMSCl).
This convenient and practical protocol shows good functional-group tolerance with moderate to
excellent yields.
2
. Results and Discussion
2
.1. Preparation of 1,3-di(1H-indol-3-yl)propanes
First, we managed to prepare 1,3-di(1H-indol-3-yl)propanes
substitution reaction between the indole trimethyl quaternary ammonium salts and esters
1
by two steps with high yielded
49].
5 [
The synthetic route is shown in Scheme 2. The experimental characterization data are given in the
Supplementary Materials.
Scheme 2. Synthetic route to 1,3-di(1H-indol-3-yl)propanes 1.
2
.2. Intramolecular Oxidative Coupling of 1,3-di(1H-indol-3-yl)propanes
Our studies initiated with the reaction of diethyl 2,2-bis((1H-indol-3-yl)methyl)malonate (1a
)
in the presence of PIFA and TMSBr in dichloromethane (DCM), the reaction mixture was stirred at
◦
0
C for 4 h, and then warmed to room temperature to stir for 12 h (Table 1, entry 1). To our delight,
the desired product 2a was isolated with 55% yield, and a trace of nonaromatic intermediate 3a was
detected. Interestingly, reducing the usage of PIFA did not affect the total yield of 2a and 3a, but the
yield of 3a was slightly increased (Table 1, entries 2–3). When 0.3 equiv. of PIFA was used and the
reaction was performed under argon atmosphere, the total yield was decreased, but the yield of 3a
was improved (Table 1, entry 4 vs. 3). To suppress the formation of intermediate 3a and decrease the
loading of PIFA, the additional oxidant DDQ was employed (Table 1, entries 5–7). When 0.3 equiv.
of PIFA and 0.5 equiv. of DDQ were added, the reaction yield of 2a was improved to 60% (Table 1,
entry 7). By replacing DDQ with BQ (1,4-benzoquinone) or CAN (ceric ammonium nitrate), the yield
of desired product was decreased (Table 1, entries 8–9). Moreover, increasing the DDQ loading resulted
in a reduced yield (Table 1, entries 5–6). Notably, when only DDQ was added as oxidant, the reaction
also generated 2a with 48% yield (Table 1, entry 10). In general, we found that 0.3 equiv. of PIFA and
0
.5 equiv. of DDQ was the most favorable combination.

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Table 1. Optimization of PIFA mediated oxidative cyclization/ aromatization.
Entry
Hypervalent Iodine Reagent
Additive
Yield/% (2a/3a) b
1
2
3
PIFA (1 eq)
PIFA (0.5 eq)
PIFA (0.3 eq)
PIFA (0.3 eq)
PIFA (0.3 eq)
PIFA (0.3 eq)
PIFA (0.3 eq)
PIFA (0.3 eq)
PIFA (0.3 eq)
None
None
None
None
55/trace
38/19
36/22
a
4
None
21/25
5
6
7
8
9
DDQ (1 eq)
DDQ (0.7 eq)
DDQ (0.5 eq)
BQ (0.5 eq)
CAN (0.5 eq)
DDQ (1 eq)
43/trace
56/trace
60/trace
53/trace
50/trace
48/trace
◦
1
0
Reagents and reaction conditions: 1a (0.3 mmol, 1 eq), TMSBr (0.3 mmol, 1 eq), solvent (DCM, 2 mL), 0 C for 4 h
and then room temperature for 12 h. The reaction was performed under Ar. b Isolated yields.
a
◦
Next, a set of Lewis acids were examined at 0 C. The yield was slightly increased when
TMSBr was replaced by TMSCl (Table 2, entry 2 vs 1), while TMSOTf and BF OEt reduced the
3
2
yield down to 23% and 49% (Table 2, entries 3–4). Moreover, lower temperatures turned out to
◦
◦
be better for the reaction with a yield of 88% at
−
40 C and 70% at
−
78 C, respectively (Table 2,
entries 5–6). Subsequently, an investigation of different hypervalent iodine reagents was performed
◦
at
−
40 C. It revealed that the use of PIDA decreased the reaction yield slightly (85%, Table 2,
entry 7), and the yield was reduced when IBX (2-iodoxybenzoic acid) and DMP (Dess-Martin
periodinane) were used (Table 2, entries 8, 9). Finally, the optimized condition for the synthesis
of 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles from 1,3- di(1H-indol-3-yl)propanes was
obtained: ethyl 2-((1H-indol-3-yl)methyl)-3-(1H-indol-3-yl)propanoate 1a (1 equiv.), PIFA (0.3 equiv.),
◦
DDQ (0.5 equiv.), and TMSCl (1 equiv.), the reaction mixture was stirred at
for 4 h, and then warmed to room temperature and stirred for 12 h.
−
40 C under air atmosphere
Table 2. Optimization of reaction conditions.
Entry
Hypervalent Iodine Reagent
Lewis Acid
Temperature
Yield/% a
◦
1
2
3
4
5
6
7
8
9
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIDA
IBX
TMSBr
TMSCl
TMSOTf
0 C
60
61
23
49
88
70
85
58
75
◦
0 C
◦
0 C
◦
BF OEt
0 C
3
2
◦
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
−40 C
◦
−78 C
◦
−40 C
◦
−40 C
◦
DMP
−40 C
Reagents and reaction conditions: 1a (0.3 mmol, 1 eq), hypervalent iodine reagent (0.1 mmol, 0.3 eq), DDQ (0.15
mmol, 0.5 eq), Lewis acid (0.3 mmol, 1 eq), solvent (DCM, 2 mL), Low temperature for 4 h and then room temperature
a
for 12 h. Isolated yields.

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With the optimized reaction conditions in hand, we further examined the substrate scope of the
1,3-di(1H-indol-3-yl)propane derivatives as shown in Scheme 3. The 1,3-di(1H-indol-3-yl)propanes
substituted by both electron-donating groups (-Me and -OMe) and electron-withdrawing groups
-F, -Cl, -Br and -CF ) on the indole ring were investigated. Both the electron-donating (-Me) and
(
3
electron-withdrawing groups (-F, -Cl, and -Br) at the C5/C6 positions of the indole substrates reacted
smoothly to provide the target products with good to excellent yields. The substitution position
had significant influence on the reaction yield: C6-substituted indoles generated the corresponding
products (2c
It is worth noting that, as an interesting exception, a -OMe group on the C5, C6 and C7 positions
gave similar yields under the optimized conditions (2n 2o and 2p). Moreover, for substituents
Me, -F, -Cl, -Br and -OMe, reactions conducted on symmetrical substrates (2d 2g 2j 2m and 2q
showed moderate to excellent yields similar to asymmetrical ones (2c 2f 2i 2l and 2o). As for strong
, 2f, 2i, and 2l) in higher yields than the C5 substituted substrates (2b, 2e, 2h, and 2k).
,
-
,
,
,
)
,
,
,
electron-withdrawing groups, the indole bearing a C5 CF group showed a moderate yield (2r, 55%).
3
These results may be determined by the stability of cationic radical intermediate involved in the
reaction (Scheme 4). To further explore the scope of the substrates, the starting materials bearing
3
-
SO CH or -CN in place of -COOEt for R were also employed and were found to afford good yields,
2
3
respectively (2s, 65% and 2t, 63%).
Scheme 3. The substrate scope for the synthesis of 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles.
a
Conversion yield.

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Scheme 4. Plausible reaction mechanism.
Inspired by the mature mechanism research of oxidative coupling reaction mediated
by hypervalent iodine reagents [29 30], a possible mechanism for the synthesis of
,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindoles from 1,3-di(1H-indol-3-yl)propanes
in the presence of PIFA, DDQ and TMSCl was proposed in Scheme 4. Initially, the radical cation
was formed from 1a with PIFA/DDQ/TMSCl. Intermediate was then produced by intramolecular
,
6
9
single electron transfer (SET), and deprotonated intermediate 10 was formed subsequently. Finally,
product 2a was generated via a further one-electron oxidation and deprotonation process (Scheme 4,
Path a). Additionally, a small amount of intermediate 3a was formed during the reaction (confirmed
by LC-MS) [30,50], which may have resulted from the protonation and Friedel-Crafts type reaction
of substrate 1a in the presence of Lewis acid. This intermediate was subsequently oxidized to give
product 2a (Scheme 4, path b).
3
. Materials and Methods
3
.1. General Information
All the chemical reagents were commercial products and were used without purification in all
cases. TLC was performed on silica gel plates (0.15–0.2 mm thickness, Yantai Huiyou Company, Yantai,
China) and detected with UV light at 254 nM, Column chromatography was carried out on silica
1
13
gel (200–300 mesh). Proton and carbon magnetic resonance spectra ( H-NMR and C-NMR) were
recorded on Varian Mercury-300, Varian Mercury-400, Varian Mercury-500 and/or Varian Mercury-600
spectrometers (Palo Alto, CA, United States). NMR experiments were conducted in CDCl , CD OD
3
3
and DMSO-d . Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts (
δ) are
6
reported in parts per million (ppm). Data are reported as follows: chemical shift, multiplicity (br
s = broad singlet, d = doublet, dd = doublet of doublet, dt = doublet of triplet, m = multiple, s = singlet
and t = triplet), coupling constants (Hz). Low-resolution mass spectra (ESI) were obtained using
Agilent HPLC-MS (Palo Alto, CA, United States) (1200-6110). High resolution mass spectra (HRMS)
were obtained using Agilent 1290-6545 UHPLC-QTOF. Melting points (mp) were measured by Büchi
5
10 melting point apparatus without further correction.
3
.2. General Procedure for the Synthesis of 6,7,12,13-Tetrahydro-5H-Cyclohepta[2,1-b:3,4-b’]diindoles (2a–t)
PIFA (0.1 mmol, 43 mg), DDQ (0.15 mmol, 34 mg) and TMSCl (0.3 mmol, 38
stirred solution of 1,3-di(1H-indol-3-yl)propane
sequence. The mixture was stirred under air at the same temperature for 4 h and then warmed to room
µ
L) were added to the
◦
1
(0.3 mmol) in dichloromethane (2 mL) at
−
40 C in

Molecules 2019, 24, 960
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◦
temperature (25 C) and stirred for an additional 12 h. After completion of the reaction, the mixture
was diluted with aqueous NaHCO solution and extracted with dichloromethane. After drying with
3
anhydrous Na SO , dichloromethane was removed under reduced pressure. The residue was purified
2
4
by column chromatography on silica gel using petroleum ether/ethyl acetate (10:1 to 5:1, v/v) as the
eluent to provide the product 2.
Diethyl 5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2a). Yellow solid, 110 mg
◦
1
(
yield 88%). mp 187–189 C. H-NMR (400 MHz, DMSO-d )
δ
10.93 (s, 2H, NH), 7.54 (d, J = 7.9 Hz, 2H,
6
Ar-H), 7.41 (d, J = 8.0 Hz, 2H, Ar-H), 7.12 (ddd, J = 8.1, 6.9, 1.2 Hz, 2H, Ar-H), 7.04 (ddd, J = 7.9, 6.9,
1
6
2 2 3 2
q
.1 Hz, 2H, Ar-H), 3.94 (q, J = 7.1 Hz, 4H, -CO CH CH ), 3.54 (s, 4H, C -CH Ar), 0.88 (t, J = 7.1 Hz,
13
H, -CO CH CH ). C-NMR (125 MHz, DMSO-d6)
δ
170.40 (C=O), 135.67 (C), 128.75 (C), 127.22 (C),
2
2
3
1
1
21.75 (CH), 119.11 (CH), 117.76 (CH), 110.95 (CH), 108.62 (C), 60.79 (OCH ), 54.36 (C), 30.72 (CH ),
2
2
+
3.54 (CH ). HRMS (ESI): m/z calcd for C H N O [M + H] : 417.1809, found: 417.1820.
3
25 25
2
4
Diethyl 3-methyl-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2b). Yellow
◦
1
solid, 101 mg (yield 78%). mp 203–205 C. H-NMR (400 MHz, Methanol-d )
δ
7.52 (d, J = 7.8 Hz, 1H,
Ar-H), 7.33 (d, J = 8.0 Hz, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.23 (d, J = 8.2 Hz, 1H, Ar-H), 7.12 (t, J = 7.5 Hz,
H, Ar-H), 7.05 (t, J = 7.4 Hz, 1H, Ar-H), 6.97 (d, J = 8.0 Hz, 1H, Ar-H), 4.00 (q, J = 7.1 Hz, 4H,
CO CH CH ), 3.61 (s, 2H, C -CH Ar), 3.59 (s, 2H, C -CH Ar), 2.44 (s, 3H, Ar-CH ), 0.98 (t, J = 7.1 Hz,
4
1
-
6
q
q
2
2
3
2
2
3
13
H, -CO CH CH ). C-NMR (150 MHz, Methanol-d4)
δ
172.83 (C=O), 137.67 (C), 136.06 (C), 130.76
C), 130.54 (C), 129.57 (C), 128.85 (C), 128.78 (C), 124.69 (CH), 123.00 (CH), 120.39 (CH), 118.75 (CH),
18.49 (CH), 111.67 (CH), 111.44 (CH), 110.04 (C), 109.86 (C), 62.45 (OCH ), 56.56 (C), 32.31 (CH ), 32.25
2
2
3
(
1
2
2
+
(
CH ), 21.70 (ArCH ), 14.10 (CH ). HRMS (ESI): m/z calcd for C H N O [M + H] : 431.1965, found:
2
3
3
26 27
2
4
4
31.1976.
Diethyl 2-methyl-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2c). Yellow solid,
◦
1
1
7
1
07 mg (yield 83%). mp 174–176 C. H-NMR (400 MHz, Methanol-d )
δ
7.51 (d, J = 7.7 Hz, 1H, Ar-H),
.39 (d, J = 8.1 Hz, 1H, Ar-H), 7.33 (d, J = 7.9 Hz, 1H, Ar-H), 7.15 – 7.09 (m, 2H, Ar-H), 7.05 (t, J = 7.5 Hz,
H, Ar-H), 6.90 (dd, J = 8.0, 1.1 Hz, 1H, Ar-H), 3.99 (q, J = 7.1 Hz, 4H, -CO CH CH ), 3.60 (s, 2H,
4
2
2
3
C
2 2 3 2 2 3
q q
-CH Ar), 3.58 (s, 2H, C -CH Ar), 2.44 (s, 3H, Ar-CH ), 0.97 (t, J = 7.1 Hz, 6H, -CO CH CH ).
13
C-NMR (125 MHz, Methanol-d4)
C), 128.53 (C), 128.06 (C), 122.91 (CH), 122.16 (CH), 120.38 (CH), 118.70 (CH), 118.56 (CH), 111.65
2CH), 110.27 (C), 109.81 (C), 62.44 (OCH ), 56.54 (C), 32.38 (CH ), 32.26 (CH ), 21.88 (ArCH ), 14.09
δ 172.83 (C=O), 138.14 (C), 137.65 (C), 132.95 (C), 130.57 (C), 128.92
(
(
(
2
2
2
3
+
CH ). HRMS (ESI): m/z calcd for C H N O [M + H] : 431.1965, found: 431.1971.
3
26 27
2
4
Diethyl 2,10-dimethyl-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-di carboxylate (2d), 112
◦
1
mg (yield 84%). Yellow solid. mp 212–214 C. H-NMR (400 MHz, DMSO-d )
7
δ
10.72 (s, 2H, NH),
.39 (d, J = 8.0 Hz, 2H, Ar-H), 7.19 (s, 2H, Ar-H), 6.87 (d, J = 8.1 Hz, 2H, Ar-H), 3.94 (q, J = 7.1 Hz, 4H,
CO CH CH ), 3.50 (s, 4H, C -CH Ar), 2.42 (s, 6H, Ar-CH ), 0.89 (t, J = 7.1 Hz, 6H, -CO CH CH ).
6
-
q
2
2
3
2
3
2
2
3
1
3
C-NMR (125 MHz, DMSO-d6)
δ 170.43 (C=O), 136.04 (C), 130.76 (C), 126.83 (C), 126.76 (C), 120.81
(
(
CH), 117.40 (CH), 110.71 (CH), 108.11 (C), 60.75 (OCH ), 54.31 (C), 30.79 (CH ), 21.44 (ArCH ), 13.57
2
+
2
3
CH ). HRMS (ESI): m/z calcd for C H N O [M + H] : 445.2122, found: 445.2131.
3
27 29
2
4
Diethyl 3-fluoro-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2e). Yellow solid,
◦
7 mg (yield 67%). mp 202–204 C. H-NMR (400 MHz, Methanol-d ) δ 7.53 (d, J = 7.8 Hz, 1H, Ar-H),
4
.35 (d, J = 8.0 Hz, 1H, Ar-H), 7.30 (dd, J = 8.8, 4.4 Hz, 1H, Ar-H), 7.18 (dd, J = 9.8, 2.5 Hz, 1H, Ar-H),
.16–7.12 (m, 1H, Ar-H), 7.07 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H, Ar-H), 6.89 (td, J = 9.1, 2.5 Hz, 1H, Ar-H),
1
8
7
7
4
6
2
2
3
2 2
q q
.00 (q, J = 7.1 Hz, 4H, -CO CH CH ), 3.62 (s, 2H, C -CH Ar), 3.56 (s, 2H, C -CH Ar), 0.98 (t, J = 7.1 Hz,
13
H, -CO CH CH ). C-NMR (125 MHz, Methanol-d4)
δ
172.68 (C=O), 159.38 (d, J = 233.3 Hz, CF),
2
2
3
137.80 (C), 134.23 (C), 130.96 (d, J = 9.6 Hz, C), 130.77 (C), 130.46 (C), 128.28 (C), 123.35 (CH), 120.51
(
(
(
CH), 118.94 (CH), 112.51 (d, J = 9.8 Hz, CH), 111.80 (CH), 110.90 (d, J = 26.5 Hz, CH), 110.90 (C), 110.35
d, J = 5.0 Hz, C), 103.49 (d, J = 23.9 Hz, CH), 62.50 (OCH ), 56.56 (C), 32.26 (CH ), 32.20 (CH ), 14.09
2
2
2
+
CH ). HRMS (ESI): m/z calcd for C H FN O [M + H] : 435.1715, found: 435.1715.
3
25 24
2
4

Molecules 2019, 24, 960
8 of 13
Diethyl 2-fluoro-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2f). Yellow solid,
◦
1
1
7
1
04 mg (yield 80%). mp 219–221 C. H-NMR (400 MHz, Methanol-d )
δ
7.52 (d, J = 7.9 Hz, 1H, Ar-H),
.48 (dd, J = 8.7, 5.2 Hz, 1H, Ar-H), 7.34 (d, J = 8.0 Hz, 1H, Ar-H), 7.13 (ddd, J = 8.1, 7.0, 1.2 Hz,
H, Ar-H), 7.09–7.03 (m, 2H, Ar-H), 6.85 (ddd, J = 9.7, 8.7, 2.3 Hz, 1H, Ar-H), 4.00 (q, J = 7.1 Hz, 4H,
CO CH CH ), 3.61 (s, 2H, Cq-CH Ar), 3.59 (s, 2H, Cq-CH Ar), 0.98 (t, J = 7.1 Hz, 6H, -CO CH CH ).
4
-
2
2
3
2
2
2
2
3
1
3
C-NMR (125 MHz, Methanol-d4)
J = 14.0 Hz, C), 130.49 (C), 129.27 (d, J = 3.5 Hz, C), 128.48 (C), 127.30 (C), 123.13 (CH), 120.48 (CH),
19.72 (d, J = 10.3 Hz, CH), 118.82 (CH), 111.76 (CH), 110.34 (C), 110.14 (C), 108.75 (d, J = 24.9 Hz, CH),
7.88 (d, J = 26.2 Hz, CH), 62.49 (OCH ), 56.51 (C), 32.26 (CH ), 32.17 (CH ), 14.09 (CH ). HRMS (ESI):
δ 172.70 (C=O), 161.54 (d, J = 236.2 Hz, CF), 137.74 (C), 137.68 (d,
1
9
2
2
2
3
+
m/z calcd for C H FN O [M + H] : 435.1715, found: 435.1723.
25
24
2
4
Diethyl 2,10-difluoro-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2g). Yellow
◦
1
solid, 107 mg (yield 79%). mp 254–256 C. H-NMR (400 MHz, DMSO-d )
δ
11.05 (s, 2H, NH), 7.53 (dd,
6
J = 8.7, 5.4 Hz, 2H, Ar-H), 7.25 (dd, J = 9.9, 2.4 Hz, 2H, Ar-H), 6.89 (ddd, J = 9.9, 8.7, 2.4 Hz, 2H, Ar-H),
3
2 2 3 2 2 2 3
q
.94 (q, J = 7.1 Hz, 4H, -CO CH CH ), 3.52 (s, 4H, C -CH Ar), 0.88 (t, J = 7.1 Hz, 6H, -CO CH CH ).
13
C-NMR (125 MHz, DMSO-d6)
27.58 (d, J = 3.5 Hz, C), 125.63 (C), 118.89 (d, J = 10.4 Hz, CH), 108.61 (C), 107.56 (d, J = 24.5 Hz, CH),
7.27 (d, J = 25.9 Hz, CH), 60.86 (OCH ), 54.24 (C), 30.64 (CH ), 13.56 (CH ). HRMS (ESI): m/z calcd for
δ 170.30 (C=O), 159.28 (d, J = 235.2 Hz, CF), 135.60 (d, J = 12.8 Hz, C),
1
9
2
2
3
+
C H F N O [M + H] : 453.1620, found: 453.1629.
25
23
2
2
4
Diethyl 3-chloro-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2h). Yellow solid,
◦
1
8
4 mg (yield 62%). mp 229–231 C. H-NMR (400 MHz, Methanol-d )
δ
7.54 (d, J = 7.8 Hz, 1H, Ar-H),
4
7.49 (d, J = 2.0 Hz, 1H, Ar-H), 7.35 (d, J = 8.0 Hz, 1H, Ar-H), 7.31 (d, J = 8.5 Hz, 1H, Ar-H), 7.15
(
2
t, J = 7.5 Hz, 1H, Ar-H), 7.10–7.04 (m, 2H, Ar-H), 4.00 (q, J = 7.1 Hz, 4H, -CO CH CH ), 3.62 (s,
H, C -CH Ar), 3.56 (s, 2H, C -CH Ar), 0.98 (t, J = 7.1 Hz, 6H, -CO CH CH ). C-NMR (150 MHz,
q q
2 2 2 2 3
2 2 3
13
Methanol-d4)
δ
172.61 (C=O), 137.82 (C), 136.05 (C), 131.64 (C), 130.47 (C), 130.42 (C), 128.07 (C), 126.19
(
(
C), 123.43 (CH), 123.00 (CH), 120.54 (CH), 118.98 (CH), 118.18 (CH), 112.93 (CH), 111.83 (CH), 111.10
C), 109.83 (C), 62.52 (OCH ), 56.48 (C), 32.21 (CH ), 32.05 (CH ), 14.10 (CH ). HRMS (ESI): m/z calcd
2
+
2
2
3
for C H ClN O [M + H] : 451.1419, found: 451.1426.
25
24
2
4
Diethyl 2-chloro-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2i). Yellow solid,
◦
1
1
03 mg (yield 76%). mp 231–233 C. H-NMR (400 MHz, DMSO-d )
δ
11.08 (s, 1H, NH), 10.99 (s, 1H,
NH), 7.55 (d, J = 8.4 Hz, 1H, Ar-H), 7.54 (d, J = 7.7 Hz, 1H, Ar-H), 7.50 (d, J = 1.9 Hz, 1H, Ar-H), 7.41
d, J = 8.0 Hz, 1H, Ar-H), 7.14 (ddd, J = 8.0, 6.9, 1.2 Hz, 1H, Ar-H), 7.08–7.01 (m, 2H, Ar-H), 3.94 (q,
J = 7.0 Hz, 4H, -CO CH CH ), 3.54 (s, 2H, C -CH Ar), 3.53 (s, 2H, C -CH Ar), 0.88 (t, J = 7.1 Hz,
6
(
2
2
3
q
2
q
2
1
3
6
1
(
1
H, -CO CH CH ). C-NMR (125 MHz, DMSO-d6)
δ
170.32 (C=O), 136.06 (C), 135.77 (C), 128.69 (C),
28.32 (C), 127.60 (C), 126.70 (C), 126.27 (C), 122.02 (CH), 119.49 (CH), 119.22 (CH), 119.14 (CH), 117.91
CH), 111.06 (CH), 110.66 (CH), 109.20 (C), 108.77 (C), 60.86 (OCH ), 54.28 (C), 30.73 (CH ), 30.56 (CH ),
2
2
3
2
2
2
+
3.57 (CH ). HRMS (ESI): m/z calcd for C H ClN O [M + H] : 451.1419, found: 451.1422.
3 25 24 2 4
Diethyl 2,10-dichloro-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-di carboxylate (2j). Yellow
◦
1
solid, 111 mg (yield 76%). mp 273–275 C. H-NMR (300 MHz, DMSO-d )
δ
11.16 (s, 2H, NH), 7.56
6
(
d, J = 8.5 Hz, 2H, Ar-H), 7.50 (d, J = 1.9 Hz, 2H, Ar-H), 7.05 (dd, J = 8.5, 1.9 Hz, 2H, Ar-H), 3.94 (q,
13
J = 7.1 Hz, 4H, -CO CH CH ), 3.52 (s, 4H, C
q
-CH Ar), 0.88 (t, J = 7.1 Hz, 6H, -CO CH CH ). C-NMR
2
2
3
2
2
2
3
(
(
150 MHz, DMSO-d6) δ 170.21 (C=O), 136.13 (C), 127.77 (C), 127.52 (C), 126.52 (C), 119.59 (CH), 119.28
CH), 110.73 (CH), 109.33 (C), 60.91 (OCH ), 54.18 (C), 30.56 (CH ), 13.58 (CH ). HRMS (ESI): m/z calcd
2
2
3
−
for C H Cl N O [M − H] : 483.0884, found: 483.0880.
25
21
2
2
4
Diethyl 3-bromo-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2k). Yellow solid,
◦
1
9
2 mg (yield 62%). mp 253–255 C. H-NMR (400 MHz, DMSO-d )
δ
11.14 (s, 1H, NH), 10.96 (s, 1H,
NH), 7.73 (s, 1H, Ar-H), 7.55 (d, J = 7.9 Hz, 1H, Ar-H), 7.42 (d, J = 7.5 Hz, 1H, Ar-H), 7.39 (d, J = 8.6 Hz,
H, Ar-H), 7.22 (d, J = 8.5 Hz, 1H, Ar-H), 7.14 (t, J = 7.7 Hz, 1H, Ar-H), 7.05 (t, J = 7.5 Hz, 1H, Ar-H), 3.94
q, J = 7.1 Hz, 4H, -CO CH CH ), 3.55 (s, 2H, C -CH Ar), 3.51 (s, 2H, C -CH Ar), 0.89 (t, J = 7.1 Hz,
6
1
(
2
2
3
q
2
q
2

Molecules 2019, 24, 960
9 of 13
H, -CO CH CH ). 3C-NMR (125 MHz, DMSO-d6)
1
δ
170.30 (C=O), 135.80 (C), 134.38 (C), 130.60 (C),
6
2
2
3
1
1
28.79 (C), 128.65 (C), 126.59 (C), 124.02 (CH), 122.10 (CH), 120.11 (CH), 119.23 (CH), 117.95 (CH),
12.96 (CH), 111.74 (C), 111.08 (CH), 109.50 (C), 108.30 (C), 60.85 (OCH ), 54.33 (C), 30.69 (CH ), 30.54
2
+
2
(CH ), 13.54 (CH ). HRMS (ESI): m/z calcd for C H BrN O [M + H] : 495.0914, found: 495.0918.
2
3
25 24
2
4
Diethyl 2-bromo-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2l). Yellow solid,
◦
07 mg (yield 72%). mp 230–232 C. H-NMR (400 MHz, DMSO-d ) δ 11.08 (s, 1H, NH), 11.00 (s, 1H,
6
1
1
NH), 7.63 (d, J = 1.8 Hz, 1H, Ar-H), 7.54 (d, J = 7.9 Hz, 1H, Ar-H), 7.50 (d, J = 8.5 Hz, 1H, Ar-H), 7.41 (d,
J = 8.1 Hz, 1H, Ar-H), 7.19–7.11 (m, 2H, Ar-H), 7.05 (t, J = 7.3 Hz, 1H, Ar-H), 3.94 (q, J = 7.1 Hz, 4H,
-
CO CH CH ), 3.54 (s, 2H, Cq-CH Ar), 3.52 (s, 2H, Cq-CH Ar), 0.88 (t, J = 7.1 Hz, 6H, -CO CH CH ).
2 2 3 2 2 2 2 3
1
3
C-NMR (125 MHz, DMSO-d6)
δ 170.31 (C=O), 136.52 (C), 135.78 (C), 128.70 (C), 128.23 (C), 127.83 (C),
1
1
26.64 (C), 122.05 (2CH), 119.53 (CH), 119.23 (CH), 117.92 (CH), 114.31 (C), 113.55 (CH), 111.07 (CH),
09.31 (C), 108.80 (C), 60.87 (OCH ), 54.27 (C), 30.73 (CH ), 30.52 (CH ), 13.57 (CH ). HRMS (ESI): m/z
2
+
2
2
3
calcd for C H BrN O [M + H] : 495.0914, found: 495.0915.
25
24
2
4
Diethyl 2,10-dibromo-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-di carboxylate (2m). Yellow
◦
1
solid, 136 mg (yield 79%). mp 269–271 C. H-NMR (400 MHz, DMSO-d )
δ
11.15 (s, 2H, NH), 7.64
6
(
d, J = 1.8 Hz, 2H, Ar-H), 7.52 (d, J = 8.4 Hz, 2H, Ar-H), 7.17 (dd, J = 8.4, 1.8 Hz, 2H, Ar-H), 3.94 (q,
13
J = 7.1 Hz, 4H, -CO CH CH ), 3.52 (s, 4H, C
q
-CH Ar), 0.88 (t, J = 7.1 Hz, 6H, -CO CH CH ). C-NMR
2
2
3
2
2
2
3
(
150 MHz, DMSO-d6) δ 170.19 (C=O), 136.59 (C), 127.76 (C), 127.62 (C), 122.16 (CH), 119.66 (CH), 114.59
(
C), 113.62 (CH), 109.47 (C), 60.90 (OCH ), 54.19 (C), 30.52 (CH ), 13.57 (CH ). HRMS (ESI): m/z calcd
2
2
3
−
for C H Br N O [M − H] : 570.9874, found: 570.9867.
25
21
2
2
4
Diethyl 3-methoxy-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2n). Yellow
◦
1
solid, 90 mg (yield 67%). mp 192–194 C. H-NMR (400 MHz, DMSO-d )
δ
10.89 (s, 1H, NH), 10.76 (s,
6
1
7
H, NH), 7.52 (d, J = 7.8 Hz, 1H, Ar-H), 7.40 (d, J = 8.0 Hz, 1H, Ar-H), 7.30 (d, J = 8.7 Hz, 1H, Ar-H),
.12 (t, J = 7.1 Hz, 1H, Ar-H), 7.06–6.99 (m, 2H, Ar-H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H, Ar-H), 3.95 (q,
-CH Ar), 3.51 (s, 2H, C -CH Ar),
J = 7.0 Hz, 4H, -CO CH CH ), 3.80 (s, 3H, -OCH ), 3.53 (s, 2H, C
0
q
q
2
2
3
3
2
2
13
.90 (t, J = 7.1 Hz, 6H, -CO CH CH ). C-NMR (125 MHz, DMSO-d6)
δ
170.48 (C=O), 153.61 (C),
2
2
3
135.67 (C), 130.76 (C), 129.15 (C), 128.77 (C), 127.86 (C), 127.36 (C), 121.71 (CH), 119.09 (CH), 117.74
(
5
CH), 112.03 (CH), 111.74 (CH), 110.93 (CH), 108.52 (C), 108.45 (C), 99.43 (CH), 60.81 (OCH ), 55.39 (C),
2
+
4.47 (OCH ), 30.84 (CH ), 30.75 (CH ), 13.58 (CH ). HRMS (ESI): m/z calcd for C H N O [M + H] :
3
2
2
3
26 27
2
5
4
47.1914, found: 447.1920.
Diethyl 2-methoxy-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2o). Yellow
◦
1
solid, 76 mg (yield 57%). mp 118–120 C. H-NMR (400 MHz, Methanol-d )
δ
7.50 (d, J = 7.8 Hz, 1H,
Ar-H), 7.39 (d, J = 8.7 Hz, 1H, Ar-H), 7.32 (d, J = 7.9 Hz, 1H, Ar-H), 7.10 (t, J = 7.5 Hz, 1H, Ar-H), 7.04
t, J = 7.4 Hz, 1H, Ar-H), 6.87 (d, J = 2.2 Hz, 1H, Ar-H), 6.73 (dd, J = 8.7, 2.2 Hz, 1H, Ar-H), 3.99 (q,
J = 7.1 Hz, 4H, -CO CH CH ), 3.84 (s, 3H, -OCH ), 3.58 (s, 2H, C -CH Ar), 3.57 (s, 2H, C -CH Ar),
4
(
2
2
3
3
q
2
q
2
1
3
0
.97 (t, J = 7.2 Hz, 6H, -CO CH CH ). C-NMR (150 MHz, Methanol-d4)
δ
172.82 (C=O), 158.23 (C),
2
2
3
138.47 (C), 137.61 (C), 130.60 (C), 129.01 (C), 127.52 (C), 125.07 (C), 122.76 (CH), 120.35 (CH), 119.48
(
(
CH), 118.61 (CH), 111.59 (CH), 110.44 (CH, C), 109.22 (C), 95.14 (CH), 62.44 (OCH ), 56.51 (C), 55.99
2
+
OCH ), 32.38 (CH ), 32.20 (CH ), 14.10 (CH ). HRMS (ESI): m/z calcd for C H N O [M + H] :
3
2
2
3
26 27
2
5
4
47.1914, found: 447.1924.
Diethyl 1-methoxy-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-dicarboxylate (2p). Yellow
◦
1
solid, 83 mg (yield 62%). mp 224–226 C. H-NMR (400 MHz, DMSO-d )
δ
11.09 (s, 1H, NH), 10.97
6
(s, 1H, NH), 7.53 (d, J = 7.8 Hz, 1H, Ar-H), 7.39 (d, J = 8.1 Hz, 1H, Ar-H), 7.16–7.09 (m, 2H, Ar-H),
7
.03 (t, J = 7.4 Hz, 1H, Ar-H), 6.97 (t, J = 7.8 Hz, 1H, Ar-H), 6.71 (d, J = 7.7 Hz, 1H, Ar-H), 3.97 (s, 3H,
-CH Ar), 3.53 (s, 2H, C -CH Ar), 0.89
-OCH ), 3.95 (q, J = 7.1 Hz, 4H, -CO CH CH ), 3.54 (s, 2H, C
q
q
3
2
2
3
2
2
13
(
(
1
t, J = 7.1 Hz, 6H, -CO CH CH ). C-NMR (125 MHz, DMSO-d6)
δ
170.38 (C=O), 145.63 (C), 135.46
C), 130.05 (C), 128.67 (C), 127.11 (C), 126.81 (C), 125.66 (C), 121.69 (CH), 119.73 (CH), 119.04 (CH),
17.73 (CH), 110.82 (CH), 110.68 (CH), 109.09 (C), 108.31 (C), 102.40 (CH), 60.79 (OCH ), 55.14 (C),
2
2
3
2

Molecules 2019, 24, 960
10 of 13
+
5
3.99 (OCH ), 31.00 (CH ), 30.82 (CH ), 13.55 (CH ). HRMS (ESI): m/z calcd for C H N O [M + H] :
3
2
2
3
26 27
2
5
4
47.1914, found: 447.1927.
Diethyl 2,10-dimethoxy-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-di carboxylate (2q).
◦
1
Yellow solid, 84 mg (yield 59%). mp 199–201 C. H-NMR (400 MHz, Methanol-d )
2
δ
7.37 (d, J = 8.6 Hz,
H, Ar-H), 6.86 (d, J = 2.2 Hz, 2H, Ar-H), 6.72 (dd, J = 8.6, 2.3 Hz, 2H, Ar-H), 3.99 (q, J = 7.1 Hz, 4H,
CO CH CH ), 3.83 (s, 6H, -OCH ), 3.54 (s, 4H, C -CH Ar), 0.98 (t, J = 7.1 Hz, 6H, -CO CH CH ).
4
-
q
2
2
3
3
2
2
2
3
1
3
C-NMR (150 MHz, Methanol-d4)
δ 172.85 (C=O), 158.01 (C), 138.37 (C), 127.86 (C), 125.16 (C), 119.28
(
(
CH), 110.26 (CH), 109.37 (C), 95.19 (CH), 62.42 (OCH ), 56.52 (C), 56.01 (OCH ), 32.31 (CH ), 14.12
2
+
3
2
CH ). HRMS (ESI): m/z calcd for C H N O [M + H] : 477.2020, found: 477.2025.
3
27 29
2
6
Diethyl 3-(trifluoromethyl)-5,7,12,13-tetrahydro-6H-cyclohepta[2,1-b:3,4-b’]diindole-6,6-di carboxylate (2r).
◦
1
Yellow solid, 80 mg (yield 55%). mp 263–265 C. H-NMR (300 MHz, DMSO-d )
1
–
δ
11.41 (s, 1H, NH),
1.00 (s, 1H, NH), 7.94 (s, 1H, Ar-H), 7.61 (d, J = 8.4 Hz, 1H, Ar-H), 7.57 (d, J = 8.3 Hz, 1H, Ar-H), 7.47
7.37 (m, 2H, Ar-H), 7.16 (t, J = 7.0 Hz, 1H, Ar-H), 7.06 (t, J = 7.5 Hz, 1H, Ar-H), 3.94 (q, J = 7.1 Hz, 4H,
CO CH CH ), 3.59 (s, 2H, Cq-CH Ar), 3.57 (s, 2H, Cq-CH Ar), 0.88 (t, J = 7.1 Hz, 6H, -CO CH CH ).
6
-
2
2
3
2
2
2
2
3
1
3
C-NMR (125 MHz, DMSO-d6)
δ 170.29 (C=O), 137.22 (C), 135.86 (C), 129.50 (C), 128.64 (C), 128.14
(
C), 126.38 (C), 125.58 (q, J = 271.4 Hz, CF ), 122.26 (CH), 120.09 (q, J = 31.1 Hz, CCF ), 119.30 (CH),
3
3
1
1
18.04 (CH), 117.93 (d, J = 3.1 Hz, CH), 115.40 (d, J = 3.9 Hz, CH), 111.68 (CH), 111.16 (CH), 109.87 (C),
09.49 (C), 60.87 (OCH ), 54.34 (C), 30.75 (CH ), 30.43 (CH ), 13.51 (CH ). HRMS (ESI): m/z calcd for
2
+
2
2
3
C H F N O [M + H] : 485.1683, found: 485.1682.
26
24
3
2
4
Ethyl 6-(methylsulfonyl)-6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindole-6-carboxylate (2s). Yellow
◦
1
solid, 82 mg (yield 65%). mp 227–229 C. H-NMR (400 MHz, Methanol-d )
δ
7.61 (d, J = 7.8 Hz, 2H,
4
Ar-H), 7.36 (d, J = 8.1 Hz, 2H, Ar-H), 7.16 (t, J = 7.5 Hz, 2H, Ar-H), 7.09 (t, J = 7.4 Hz, 2H, Ar-H),
4
2
.17 (d, J = 14.7 Hz, 2H, C
q
2 2 3
-CHHAr), 3.76 (q, J = 7.1 Hz, 2H, -CO CH CH ), 3.48 (d, J = 14.7 Hz,
13
H, C -CHHAr), 3.33 (s, 3H, -SO CH ), 0.53 (t, J = 7.1 Hz, 3H, -CO CH CH ). C-NMR (125 MHz,
q
2
3
2
2
3
DMSO-d6)
δ 165.95 (C=O), 135.73 (C), 128.73 (C), 126.88 (C), 122.03 (CH), 119.27 (CH), 118.04 (CH),
1
11.03 (CH), 107.36 (C), 71.30 (C), 61.26 (OCH ), 37.23 (SO CH ), 27.31 (CH ), 12.84 (CH ). HRMS
2
2
3
2
3
+
(ESI): m/z calcd for C H N O S [M + H] : 423.1373, found: 423.1373.
23 23 2 4
Ethyl 6-cyano-6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’]diindole-6-carboxylate (2t). Yellow solid, 45
◦
1
mg (recycled raw material 39 mg, conversion yield 63%). mp 252–254 C. H-NMR (300 MHz,
DMSO-d6) 11.19 (s, 2H, NH), 7.60 (d, J = 7.9 Hz, 2H, Ar-H), 7.47 (d, J = 8.0 Hz, 2H, Ar-H), 7.17
ddd, J = 8.1, 7.0, 1.2 Hz, 2H, Ar-H), 7.07 (ddd, J = 8.0, 7.0, 1.1 Hz, 2H, Ar-H), 4.32 (q, J = 7.1 Hz,
δ
(
2
(
H, -CO CH CH ), 3.87 (d, J = 15.9 Hz, 2H, C
q
-CHHAr), 3.54 (d, J = 16.0 Hz, 2H, C
q
-CHHAr), 1.28
2
2
3
t, J = 7.1 Hz, 3H, -CO CH CH ). 3C-NMR (150 MHz, DMSO-d6)
1
δ
169.11 (C=O), 135.63 (C), 128.47 (C),
2
2
3
1
4
27.52 (C), 122.25 (CH), 119.50 (CH), 118.49 (CN), 117.98 (CH), 111.18 (CH), 106.70 (C), 62.79 (OCH ),
2
+
2.75 (C), 32.97 (CH ), 13.81 (CH ). HRMS (ESI): m/z calcd for C H N O [M + H] : 370.1550, found:
2
3
23 20
3
2
3
70.1553.
4
. Conclusions
In summary, we have developed a novel oxidative cyclization/ aromatization of
,3-di(1H-indol-3-yl)propanes to synthesize 6,7,12,13-tetrahydro-5H-cyclohepta[2,1-b:3,4-b’] diindoles.
1
By employing PIFA/DDQ as coordinative oxidants in the presence of TMSCl as Lewis acid, the efficient
intramolecular cyclization/aromatization generated the corresponding products with moderate to
excellent yields. This protocol tolerated a broad range of functional-groups and the reaction could
be carried out in air. Notably, no expensive transition metal catalysts/reagents were used for this
transformation and this provided a new approach for these valuable compounds. Most importantly,
the existing ester/CN groups in the target compounds could be transformed into other functional
groups. Further biological evaluation of these compounds is in progress in our lab and the results will
be reported soon.

Molecules 2019, 24, 960
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Supplementary Materials: The NMR spectra of the obtained compounds and some additional experimental
details are available online.
Author Contributions: Conceptualization, C.Y.; methodology, L.P. and X.Z.; chemical experiments, L.P.;
inspiration and discussions, L.P., X.Z. and C.Y.; writing—original draft preparation, L.P.; writing—review and
editing, X.Z. and C.Y.
Funding: This study was supported by Shanghai Sailing Program (17YF1423400) and China Postdoctoral Science
Foundation Grant (2017M621572).
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Praveen, P.; Parameswaran, P.; Majik, M. Bis(indolyl)methane Alkaloids: Isolation, Bioactivity, and Syntheses.
Synthesis 2015, 47, 1827–1837. [CrossRef]
2
.
Damodiran, M.; Muralidharan, D.; Perumal, P.T. Regioselective synthesis and biological evaluation of
bis(indolyl)methane derivatized 1,4-disubstituted 1,2,3-bistriazoles as anti-infective agents. Bioorg. Med.
Chem. Lett. 2009, 19, 3611–3614. [CrossRef] [PubMed]
3
.
.
Ma, S.; Mei, W.; Guo, Z.; Liu, S.; Zhao, Y.; Yang, D.; Zeng, Y.; Jiang, B.; Dai, H. Two New Types of Bisindole
Alkaloid from Trigonostemon lutescens. Org. Lett. 2013, 15, 1492–1495. [CrossRef] [PubMed]
4
Ling, F.; Xiao, L.; Fang, L.; Feng, C.; Xie, Z.; Lv, Y.; Zhong, W. B(C F ) -catalyzed Markovnikov addition of
6
5 3
indoles to aryl alkynes: An approach toward bis(indolyl)alkanes. Org. Biomol. Chem. 2018, 16, 9274–9278.
CrossRef] [PubMed]
[
5
6
.
.
Ma, C.; Jiang, F.; Sheng, F.T.; Jiao, Y.; Mei, G.J.; Shi, F. Design and Catalytic Asymmetric Construction of
Axially Chiral 3,3’-Bisindole Skeletons. Angew. Chem. Int. Ed. 2018, 57, 1–7. [CrossRef]
Liu, Y.; Hu, X.; Wu, Y.; Zhang, W.; Chen, X.; You, X.; Hu, L. Synthesis and structure-activity relationship of
novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria. Eur. J. Med. Chem.
2
018, 150, 771–782. [CrossRef] [PubMed]
7
8
9
1
.
.
.
Sasaki, T.; Ohtani, I.I.; Tanaka, J.; Higa, T. Iheyamines, new cytotoxic bisindole pigments from a colonial
ascidian, Polycitorella sp. Tetrahedron Lett. 1999, 40, 303–306. [CrossRef]
Nettleton, D.E.; Doyle, T.W.; Krishnan, B. Isolation and structure of rebeccamycin—A new antitumor
antibiotic from nocardia aerocoligenes. Tetrahedron Lett. 1985, 26, 4011–4014. [CrossRef]
Bush, J.A.; Long, B.H.; Catino, J.J.; Bradner, W.T. Production and biological activity of rebeccamycin, a novel
antitumor agent. J. Antibiot. 1987, 40, 668–678. [CrossRef]
0. Yamashita, Y.; Fujii, N.; Murakata, C.; Ashizawa, T.; Okabe, M.; Nakano, H. Induction of Mammalian DNA
Topoisomerase I Mediated DNA Cleavage by Antitumor Indolocarbazole Derivatives. Biochemistry 1992, 31,
1
2069–12075. [CrossRef]
1. Wu, M.; Li, C.; Zhu, X. FLT3 inhibitors in acute myeloid leukemia. J. Hematol. Oncol. 2018, 11, 133. [CrossRef]
PubMed]
2. Balamurali, R.; Prasad, K.J.R. Synthesis, characterization and pharmacological activities of
,6,11,12-tetrahydroindolo[2,3-a]carbazole derivatives. II Farmaco 2001, 56, 229–232. [CrossRef]
3. Su, J.; Zhu, Y.; Zeng, L.; Xu, X. A New Bisindole from Alga Caulerpa serrulata. J. Nat. Prod. 1997, 60, 1043–1044.
CrossRef]
4. Wahlström, N.; Stensland, B.; Bergman, J. Synthesis of the marine alkaloid caulersin. Tetrahedron 2004, 60, 2147–2153.
CrossRef]
1
1
1
1
1
[
5
[
[
5. Miki, Y.; Aoki, Y.; Miyatake, H.; Minematsu, T.; Hibino, H. Synthesis of caulersin and its isomers by reaction
of indole-2,3-dicarboxylic anhydrides with methyl indoleacetates. Tetrahedron Lett. 2006, 47, 5215–5218.
[CrossRef]
1
6. Yang, H.; Liu, D.Q.; Liang, T.J.; Li, J.; Liu, A.H.; Yang, P.; Lin, K.; Yu, X.Q.; Guo, Y.W.; Mao, S.C.; et al.
Racemosin C, a novel minor bisindole alkaloid with protein tyrosine phosphatase-1B inhibitory activity from
the green alga Caulerpa racemosa. J. Asian Nat. Prod. Res. 2014, 16, 1158–1165. [CrossRef] [PubMed]

Molecules 2019, 24, 960
12 of 13
1
7. Park, S.M.; Lee, D.H.; Park, S.H.; Ham, J.S.; Nam, H.G.; Jang, S.H.; Baek, Y.G.; Cho, G.O. Novel Organic
Electroluminescent Compound and Organic Electroluminescent Element Including the Same; KR
016126150; 2 November 2016. Available online: https://worldwide.espacenet.com/publicationDetails/
2
originalDocument?CC=KR&NR=20160126150A&KC=A&FT=D&ND=3&date=20161102&DB=EPODOC&
locale=en_EP# (accessed on 8 March 2019).
1
1
2
2
8. Kuckländer, U.; Töberich, H. Eine neue Synthese von 7,8,9,10-Tetrahydrocyclohept[b]indol-6(5H)-onen.
Chem. Ber. 1981, 114, 2238–2244. [CrossRef]
9. Thummel, R.P.; Hegde, V. Polyaza-Cavity Shaped Molecules. 14. Annelated 2-(2’-Pyridyl)indoles,
2
,2’-Biindoles, and Related Systems. J. Org. Chem. 1989, 54, 1720–1725. [CrossRef]
0
0
0. Kavitha, C.; Prasad, K.J.R. Synthesis, Characterization and Biological Activity of Some Indolo[2 ,3 :7,6]
0
0
cyclohept[b]indoles and 1,2,3-Selenadiazolo[4 ,5 :6,7]cyclohept[b]indoles. Asian J. Chem. 2004, 16, 40–48.
1. Wahlström, N.; Slätt, J.; Stensland, B.; Ertan, A.; Bergman, J.; Janosik, T. Synthetic Applications of
Cyanoacetylated Bisindoles: Synthesis of Novel Cycloheptadiindoles, Indolocarbazoles, and Related Aza
Analogues. J. Org. Chem. 2007, 72, 5886–5889. [CrossRef]
2
2
2
2. Yang, X.; Sun, G.; Yang, C.; Wang, B. Novel Rhein Analogues as Potential Anticancer Agents. ChemMedChem
2
011, 6, 2294–2301. [CrossRef] [PubMed]
3. Jiang, M.; Xiong, B.; Shen, Y.; Yang, C. Design, synthesis, and preliminary biological evaluation of novel
ketone derivatives of shikimic acid. RSC Adv. 2013, 3, 20599. [CrossRef]
4. Zhang, X.; He, Q.; Xiang, H.; Song, S.; Miao, Z.; Yang, C. Rapid access to
reaction of -unsaturated ketones with 2-nitrophenylacetonitrile and the anti-proliferative activities of the
products. Org. Biomol. Chem. 2014, 12, 355–361. [CrossRef] [PubMed]
α-carbolines via a one-pot tandem
α,β
2
2
5. Hou, C.; Chen, H.; Xu, X.; Zhu, F.; Guo, L.; Jiang, M.; Yang, C.; Deng, L. Synthesis of Rigid Analogues of
Flavone by Intramolecular Heck Reaction. Eur. J. Org. Chem. 2015, 2015, 3040–3043. [CrossRef]
6. Xu, X.; Qi, X.; Yan, Y.; Qi, J.; Qian, N.; Guo, L.; Li, C.; Wang, F.; Huang, P.; Zhou, H.; et al. Synthesis and
biological evaluation of rhein amides as inhibitors of osteoclast differentiation and bone resorption. Eur. J.
Med. Chem. 2016, 123, 769–776. [CrossRef] [PubMed]
2
2
2
7. Yoshimura, A.; Zhdankin, V.V. Advances in Synthetic Applications of Hypervalent Iodine Compounds.
Chem. Rev. 2016, 116, 3328–3435. [CrossRef] [PubMed]
8. Morimoto, K.; Dohi, T.; Kita, Y. Metal-free Oxidative Cross-Coupling Reaction of Aromatic Compounds
Containing Heteroatoms. Synlett 2017, 28, 1680–1694. [CrossRef]
9. Tohma, H.; Iwata, M.; Maegawa, T.; Kiyono, Y.; Maruyama, A.; Kita, Y. A novel and direct synthesis of
0
alkylated 2,2 -bithiophene derivatives using a combination of hypervalent iodine(III) reagent and BF3
·
Et O.
2
Org. Biomol. Chem. 2003, 1, 1647–1649. [CrossRef]
3
0. Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Direct Synthesis of Bipyrroles Using Phenyliodine
Bis(trifluoroacetate) with Bromotrimethylsilane. Org. Lett. 2006, 8, 2007–2010. [CrossRef]
3
1. Morimoto, K.; Yamaoka, N.; Ogawa, C.; Nakae, T.; Fujioka, H.; Dohi, T.; Kita, Y. Metal-Free Regioselective
Oxidative Biaryl Coupling Leading to Head-to-Tail Bithiophenes: Reactivity Switching, a Concept Based on
the Iodonium(III) Intermediate. Org. Lett. 2010, 12, 3804–3807. [CrossRef]
3
2. Rana, A.; Panda, P.K. β-Octamethoxyporphycenes. Org. Lett. 2014, 16, 78–81. [CrossRef] [PubMed]
3
3. Rana, A.; Lee, S.; Kim, D.; Panda, P.K. β-Octakis(methylthio)porphycenes: Synthesis, characterisation and
third order nonlinear optical studies. Chem. Commun. 2015, 51, 7705–7708. [CrossRef] [PubMed]
4. Yang, P.S.; Tsai, M.T.; Tsai, M.H.; Ong, C.W. The regioselective homocoupling of meta-hydroxypyridines with
hypervalent iodine(III). Chem. Asian. J. 2015, 10, 849–852. [CrossRef]
5. Jean, A.; Cantat, J.; Bérard, D.; Bouchu, D.; Canesi, S. Novel Method of Aromatic Coupling between N-Aryl
Methanesulfonamide and Thiophene Derivatives. Org. Lett. 2007, 9, 2553–2556. [CrossRef] [PubMed]
6. Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. Unusual ipso substitution of diaryliodonium
bromides initiated by a single-electron-transfer oxidizing process. Angew. Chem. Int. Ed. Engl. 2010, 49, 3334–3337.
3
3
3
[CrossRef] [PubMed]
3
3
7. Morimoto, K.; Ohnishi, Y.; Koseki, D.; Nakamura, A.; Dohi, T.; Kita, Y. Stabilized pyrrolyl iodonium salts
and metal-free oxidative cross-coupling. Org. Biomol. Chem. 2016, 14, 8947–8951. [CrossRef]
8. Kantak, A.A.; Potavathri, S.; Barham, R.A.; Romano, K.M.; DeBoef, B. Metal-free intermolecular oxidative C-N bond
formation via tandem C-H and N-H bond functionalization. J. Am. Chem. Soc. 2011, 133, 19960–19965. [CrossRef]

Molecules 2019, 24, 960
13 of 13
3
9. Parumala, S.K.R.; Peddinti, R.K. Reversal of Polarity in Masked o-Benzoquinones: Rapid Access to
Unsymmetrical Oxygenated Biaryls. Org. Lett. 2013, 15, 3546–3549. [CrossRef]
4
0. Morimoto, K.; Sakamoto, K.; Ohshika, T.; Dohi, T.; Kita, Y. Organo-Iodine(III)-Catalyzed Oxidative
Phenol-Arene and Phenol-Phenol Cross-Coupling Reaction. Angew. Chem. Int. Ed. 2016, 55, 3652–3656.
[CrossRef]
4
4
1. Sharma, S.; Parumala, S.K.R.; Peddinti, R.K. Lewis Acid-Mediated Site-Selective Synthesis of Oxygenated
Biaryls from Methoxyphenols and Electron-Rich Arenes. J. Org. Chem. 2017, 82, 9367–9383. [CrossRef]
2. Arisawa, M.; Ramesh, N.G.; Nakajima, M.; Tohma, H.; Kita, Y. Hypervalent Iodine(III)-Induced
Intramolecular Cyclization of
α-(Aryl)alkyl-β-dicarbonyl Compounds: A Convenient Synthesis of
Benzannulated and Spirobenzannulated Compounds. J. Org. Chem. 2001, 66, 59–65. [CrossRef] [PubMed]
3. Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. A Novel and Useful Oxidative Intramolecular Coupling
Reaction of Phenol Ether Derivatives on Treatment with a Combination of Hypervalent Iodine(III) Reagent
and Heteropoly Acid. Chem. Eur. J. 2002, 8, 5377–5383. [CrossRef]
4. Hamamoto, H.; Shiozaki, Y.; Hata, K.; Tohma, H.; Kita, Y. A Novel and Concise Synthesis of Spirodienone
Alkaloids Using Hypervalent Iodine(III) Reagents. Chem. Pharm. Bull. 2004, 52, 1231–1234. [CrossRef]
4
4
[PubMed]
4
4
5. Moreno, I.; Tellitu, I.; Domínguez, E.; SanMartín, R.l. A Simple Route to New Phenanthro- and Phenanthroid-Fused
Thiazoles by a PIFA-Mediated (Hetero)biaryl Coupling Reaction. Eur. J. Org. Chem. 2002, 2126–2135. [CrossRef]
6. Barrett, T.N.; Braddock, D.C.; Monta, A.; Webb, M.R.; White, A.J. Total synthesis of the marine metabolite
(
±
)-polysiphenol via highly regioselective intramolecular oxidative coupling. J. Nat. Prod. 2011, 74, 1980–1984.
[CrossRef] [PubMed]
4
4
7. Desjardins, S.; Andrez, J.C.; Canesi, S. A Stereoselective Oxidative Polycyclization Process Mediated by a
Hypervalent Iodine Reagent. Org. Lett. 2011, 13, 3406–3409. [CrossRef] [PubMed]
8. Zhou, Y.; Zhang, X.; Zhang, Y.; Ruan, L.; Zhang, J.; Zhang-Negrerie, D.; Du, Y. Iodocyclization of
N-Arylpropynamides Mediated by Hypervalent Iodine Reagent: Divergent Synthesis of Iodinated
Quinolin-2-ones and Spiro[4,5]trienones. Org. Lett. 2017, 19, 150–153. [CrossRef]
4
5
9. Suvorov, N.N.; Velezheva, V.S.; Vampilova, V.V. Indole derivatives. LXXXVII. Improved methods for the
synthesis of skatyl- and substituted skatylmalonic esters. Chem. Heterocycl. Compd. 1973, 9, 1367–1369.
[
CrossRef]
0. Pelcman, B.; Gribble, G.W. Total Synthesis of The Marine Sponge Pigment Fascaplysin. Tetrahedron Lett. 1990
1, 2381–2384. [CrossRef]
,
3
Sample Availability: Samples of the compounds 1a–t and 2a–t are available from the authors.
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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(