Facile synthesis of 3,4-fused tricyclic indoles with a seven-membered ring through a three-component reaction of 4-hydroxyindole, aldehyde, and malonodinitrile or ethyl cyanoacetate

Article abstract of DOI:10.1016/j.tet.2016.03.014

Three-component reactions of 4-hydroxyindole, aldehydes, and malonodinitrile or ethyl cyanoacetate were developed for the first time by using either potassium fluoride or diethylamine as a catalyst, which provided an easy access to 3,4-fused tricyclic indoles in good to excellent yield. The merits of this synthesis route are attributed to its simplicity, practicality, efficiency, and eco-friendliness, as well as the easy availability of the catalyst.

Full text of DOI:10.1016/j.tet.2016.03.014

Accepted Manuscript
Facile synthesis of 3,4-fused tricyclic indoles with a seven-membered ring through a
three-component reaction of 4-hydroxyindole, aldehyde, and malonodinitrile or ethyl
cyanoacetate
Rongxian Bai, Jian Yang, Lijun Min, Changhui Liu, Fengtian Wu, Yanlong Gu
PII:
S0040-4020(16)30146-6
10.1016/j.tet.2016.03.014
TET 27554
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 January 2016
Revised Date: 29 February 2016
Accepted Date: 2 March 2016
Please cite this article as: Bai R, Yang J, Min L, Liu C, Wu F, Gu Y, Facile synthesis of 3,4-fused tricyclic
indoles with a seven-membered ring through a three-component reaction of 4-hydroxyindole, aldehyde,
and malonodinitrile or ethyl cyanoacetate, Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.014.
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ACCEPTED MANUSCRIPT
Graphic Abstract
Facile synthesis of 3,4-fused tricyclic indoles with a seven-membered ring
through a three-component reaction of 4-hydroxyindole, aldehyde, and
malonodinitrile or ethyl cyanoacetate
Rongxian Bai, Jian Yang, Lijun Min, Changhui Liu, Fengtian Wu and Yanlong Gu
H N
2
X
OH
O
R
X
R
KF or Et NH
2
+
+
CN
O
H
ethanol, 80 C
o
N
N
H
H
X = CN, CO Et, C(O)Ph
29 examples, 49~98% yields
2
R = aryl and alkyl
Salient features: (i) High efficiency and wide scope of substrate.
ii) Simple operation.
iii) Mild and environmentally benign conditions.
(
(

ACCEPTED MANUSCRIPT
Facile synthesis of 3,4-fused tricyclic indoles with a seven-membered
ring through a three-component reaction of 4-hydroxyindole,
aldehyde, and malonodinitrile or ethyl cyanoacetate
a
a
a
a
a
a,b
Rongxian Bai, Jian Yang, Lijun Min, Changhui Liu, Fengtian Wu, and Yanlong Gu*
a
Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, School of
Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 430074,
Wuhan, PR China
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical
Physics, Lanzhou, 730000, PR China
○
S
Supporting Information
*
corresponding author
1

ACCEPTED MANUSCRIPT
ABSTRACT: Three-component reactions of 4-hydroxyindole, aldehydes, and
malonodinitrile or ethyl cyanoacetate were developed for the first time by using
either potassium fluoride or diethylamine as a catalyst, which provided an easy
access to 3,4-fused tricyclic indoles in good to excellent yield. The merits of this
synthesis route are attributed to its simplicity, practicality, efficiency, and
eco-friendliness, as well as the easy availability of the catalyst.
KEYWORDS: three-component reaction; 4-hydroxyindole; 3,4-fused tricyclic indole;
seven-membered heterocycle
2

ACCEPTED MANUSCRIPT
■
INTRODUCTION
The synthesis of complex organic compounds exhibiting particular properties and
chemical structures is always a central research target for organic chemists.
Multicomponent reactions (MCRs) comprise an efficacious method to construct
valuable and complex organic compounds owing to atomic economy, convergence,
1
-4
and high bond-forming index. At present, MCRs play a very important role in
synthetic methodology. In this context, many sequential multistep synthesis reactions
can be replaced by MCRs, especially for pharmaceutical and heterocyclic molecular
1
, 2
synthesis.
Therefore, considering the advantages of MCRs, the search and
development of novel MCRs remain a central topic in organic synthetic chemistry.
The molecule-containing indole nucleus is one of the most important heterocyclic
5
, 6
compounds extensively existing in nature, agrochemicals, and pharmaceuticals.
Furthermore, indole and its derivatives can be widely applied in optic-electronic
materials, intercellular signal molecules, scavengers of free radicals, plant growth
7
-9
regulators, medicine, and so forth.
Therefore, the synthesis and framework
embellishment of indoles have attracted broad and continuous attention. The 3,4-fused
indole is particularly noteworthy because it presents a key structural motif of
1
0
11
numerous bioactive natural products, such as lysergic acid, dehydrobufotenine,
1
2
13
14
15
hapalindole U,
chuangxinmycin,
aurantioclavine,
N-methylwelwistatin,
1
6
17
communesin F, and dragmacidin E. Thus, continued interest is present in the
18
development of new methods to access this scaffold. Although many methods have
1
9-26
been developed for the synthesis of 3,4-fused indoles,
these methods heavily rely
3

ACCEPTED MANUSCRIPT
on the usage of noble metal catalysts. Such methods also suffered from limitations of
substrate generality, availability of starting materials, multistep synthesis, low product
yields, and harsh reaction conditions. Hence, the design of improved and
environmentally benign approaches allowing for rapid and cost-effective synthesis of
3
,4-fused indoles from readily available precursors would be highly desired.
27-29
Bisnucleophiles are often used to establish MCRs.
C,O- and C,N-based
30
31
1
,3-bisnucleophiles, such as 1,3-dicarbonyl compounds, activated phenols, and
3
2
anilines, have been extensively used in conjunction with aldehydes to synthesize
heterocycles through MCRs. However, 1,4-bisnucleophiles have been rarely adopted
to develop MCRs, probably because the common 1,4-bisnucleophiles, such as
2
-aminothiophenol, o-phenylenediamine, and glycinamide, tended to react with
aldehyde alone to form a two-component adduct, thus precluding the possibility of
33-38
establishing MCRs with them.
We have recently been engaged in developing
3
9-43
MCRs of aldehyde and two different nucleophiles,
and some of our works were
4
4-46
also associated with the use of bisnucleophiles.
On the basis of our previous
results, we envisioned that 4-hydroxyindole, an easily available and inexpensive
indole derivative, may act as a C,O-based 1,4-bisnucleophile because the C3 position
of indole and the OH group are both reactive. However, given that the two reactive
sides exist in the two fused aromatic rings, these 1,4-bisnucleophiles, if they work,
may not behave like the conventional one because of their rigid structure. Therefore,
the possibility of using 4-hydroxyinole as a 1,4-bisnucleophile is of particular interest.
Consequently, a research program has started to explore new MCRs by using
4

ACCEPTED MANUSCRIPT
4
-hydroxyindoles as building blocks. This paper reports the preliminary results on the
use of 4-hydroxyindole as a 1,4-bisnucleophile, which reacted readily with an
aromatic aldehyde and malonodinitrile or ethyl cyanoacetate, providing a 3,4-fused
indole with a seven-membered ring by using a base catalyst (Scheme 1). This
three-component reaction did not only provide an easy access to a class of highly
useful indole derivatives but also displayed a good scope of substrates under
environmentally benign conditions.
H2N
O
X
OH
R
X
R
base catalyst
ethanol, 80 o
C
+
+
O
H
N
CN
H
N
H
X = CN, CO2Et and C(O)Ph
Scheme 1. Three-component reaction of 4-hydroxyindole, aldehyde, and
α-electron-withdrawing group-substituted acetonitrile.
■
RESULTS AND DISCUSSION
A mixture of 4-hydroxyindole 1a, 4-chlorobenzaldehyde 2a, and malonodinitrile 3a
was initially treated with different organic and inorganic bases, and the results are
listed in Table 1. The reaction was performed in ethanol at 60 °C for 6 h. In the
absence of any catalyst, no reaction occurred (entry 1). An addition of 20 mol% of
piperidine significantly changed the result of the model reaction, and a 3,4-fused
indole with a seven-membered ring 4a was obtained in 83% yield (entry 2).
Diethylamine showed a better catalytic activity than piperidine under the same
conditions, and the yield of 4a reached 91% (entry 3). Triethylamine and morphoine
were also examined, but their yields were slightly inferior compared with the two
5

ACCEPTED MANUSCRIPT
former systems (entries 4 and 5).
for this reaction (entries 6 and 7).
L-Proline and pyridine were proven inappropriate
a
Table1. Effect of basic catalysts on the three-component reaction of 1a, 2a, and 3a.
H
2
N
CN
OH
Cl
CHO
O
catalyst (20 mol%)
solvent, 60 oC, 6 h
CN
+
+
N
Cl
CN
H
1
a
2a
3a
N
4a
H
b
Entry
Catalyst
―
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Yield (%)
1
2
3
4
5
6
7
8
9
0
piperidine
83
diethylamine
triethylamine
morpholine
L-proline
91
76
70
12
pyridine
14
K CO3
2
66
KOH
51
1
0
Cs CO3
24
2
11
KF
KF
KF
KF
KF
KF
KF
98
12
13
14
15
16
17
CH NO
84
3
2
CH CN
79
3
DCE
83
1,4-dioxane
Toluene
28
< 5
81
EtOH (aqu. 95%)
a
Reaction conditions: 1a, 0.4 mmol; 1a/2a/3a: = 1:1:1; catalyst: 0.08 mmol; 60 °C,
b
anhydrous ethanol, 2.0 mL, 6 h. Isolated yield.
Inorganic bases, such as K CO , KOH, and Cs CO , were then examined, and the
2
3
2
3
6

ACCEPTED MANUSCRIPT
maximum yield of 4a only reached 66% (entries 8-10). When KF was used, the
reaction proceeded very well, and 4a can be obtained at 98% (entry 11). As such, the
effect of solvent on the synthesis of 4a was investigated using KF as a catalyst.
Among the various solvents that were screened, anhydrous ethanol was recognized to
be the most feasible medium for this reaction (entries 11-16). An aqueous solution of
ethanol (95%) was also examined, but the yield declined to 81% (entry 17). Therefore,
anhydrous ethanol was used as the solvent of choice.
Figure 1 shows the effect of the amount of KF on the model three-component
reaction. As shown in the figure, the performance of the model reaction was
influenced quite notably by the dosage of KF catalyst. The increase of the catalyst
amount significantly improved the reaction yield when it is lower than 20 mol%. The
yield reached the maximum level when 20 mol% KF was used.
100
80
60
40
20
0
5
10
15
20
25
30
Catalyst amount / mol %
Figure 1. Effect of KF amount on the model reaction.(1a, 0.4 mmol; 2a, 0.4 mmol; 3a,
0
.4 mmol; anhydrous ethanol 2.0 mL; 60 °C, 12 h).
Figure 2 presents the effects of reaction time on the model reaction. The yield
7

ACCEPTED MANUSCRIPT
increased quickly with the escalation of the reaction time from 2 h to 6 h. Thereafter,
the yield remained at an almost constant level. The maximum yield of 4a was
achieved after 6 h of reaction.
100
80
60
40
20
0
0
2
4
6
8
10
12
Time / h
Figure 2. Effect of reaction time on the synthesis (1a, 0.4 mmol; 2a, 0.4 mmol; 3a,
0
.4 mmol, anhydrous ethanol 2.0 mL; 60 °C).
Considering the optimized conditions, the scope and generality of this
three-component reaction were then investigated. First, the scope with respect to the
benzaldehyde component was studied, and the results are listed in Table 2. A set of
benzaldehydes spanning a convenient spectrum of lipophilicity and reactivity was
selected to react with 1a and 3a. In all cases, excellent yields were obtained with the
aid of a KF catalyst, regardless of the nature of the substituent present on the aldehyde
(electron-donating or electron-withdrawing). Benzaldehydes containing sterically
demanding
substituents,
such
as
2-methoxybenzaldehyde,
4
-methyl-2-bromobenzaldehyde,
4-fluoro-2-bromobenzaldehyde,
8

ACCEPTED MANUSCRIPT
2
-chlorobenzaldehyde, 2-chloro-6-fluorobenzaldehyde, and 2-nitrobenzaldehyde, also
participated in this reaction readily (entries 4, 6–9, and 15). However, in some cases,
the obtained yields were slightly inferior compared with those of the para-substituted
congener aldehydes. Nevertheless, moderate product yield can be achieved when
2
-chloro-6-fluorobenzaldehyde, in which the reactive formyl group blocked by two
substituents in this molecule, was used as a substrate (4j). This result implied that the
existence of an ortho-substituent group in benzaldehyde only demonstrated a slight
detrimental effect on the synthetic efficiency of the desired indole. In some cases, the
generated 3,4-fused indoles, such as 4l and 4m, precipitated out from the reaction
solution, thus facilitating the isolation of the product. These reactions can also be
effectively scaled up with similar efficiency. For example, a 10 mmol scale reaction of
1
a, 3,4,5-trimethoxybenzaldehyde, and 3a gave the corresponding indole derivative 4l
in a 96% yield (3.6 g).
a
Table 2. KF-catalyzed three-component reaction of 1a, 3a, and different aldehydes.
H
2
N
CN
R
OH
CHO
KF (20 mol%)
O
CN
+
R
+
N
ethanol, 60 oC, 6 h
CN
3a
H
1a
N
4b-4r
H
b
Entry
R
H
Product
4b
Yield (%)
1
2
3
4
5
6
71
95
84
78
96
85
4-Me
4c
4-OMe
2-OMe
4-Br
4d
4e
4f
4-Me-2-Br
4g
9

ACCEPTED MANUSCRIPT
7
8
9
1
4-F-2-Br
2-Cl
4h
4i
87
67
2-Cl-6-F
4j
67
0
3,4-(OMe)2
3,4,5-(OMe)3
4-OMe-3-Bn
4-SCF3
4k
4l
77
c
11
94 (96)
1
1
1
1
1
2
3
4
5
6
7
4m
4n
4o
4p
4q
4r
92
81
4-NO2
86
2-NO2
80
4-CN
90
1
4-CF3
79
a
Reaction conditions: 1a, 0.4 mmol; 3a, 0.4 mmol; aldehyde, 0.4 mmol, KF, 0.08
b
c
mmol, anhydrous ethanol, 2.0 mL, 60 °C, 6 h. Isolated yield. 10 mmol scale
reaction.
Aldehydes with heterocyclic substituent, such as furfural 2b and
1
-benzothiophene-3-carbaldehyde 2c, can also be used to synthesize the 3,4-fused
indole derivatives in the KF/ethanol system. In these cases, the desired products, 4s
and 4t, were obtained in 88% and 97% yields, respectively (Scheme 2). In the
presence of KF, cyclopropanecarboxaldehyde 2d, which is an aliphatic aldehyde, also
reacted smoothly with 1a and 3a, producing a 3,4-fused indole 4u in ethanol in an 84%
yield (Scheme 3).
1
0

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O
CHO
H N
2
CN
2
b (1.0 equiv.)
O
O
KF (20 mol%)
ethanol, 60 oC, 6 h
N
H
4
s 88%
OH
CN
CHO
S
+
N
CN
3a
H
1a
H N
2
CN
S
2c (1.0 equiv.)
O
KF (20 mol%)
ethanol, 60 oC, 6 h
N
H
4t 97%
Scheme 2. KF-catalyzed three-component reaction of 1a, 3a, and 2b or 2c.
2
H N
CN
OH
O
CN
KF (20 mol%)
+
CHO +
2d
N
CN
ethanol, 60 oC, 6 h
H
N
H
1a
3a
4
u 84%
Scheme 3. KF-catalyzed three-component reaction of 1a, 3a, and 2d.
We found that as well as being able to use malonodinitrile 3a, it was also possible
to use ethyl cyanoacetate 3b. But, KF catalyst had to be replaced by diethylamine;
otherwise, a low yield would be obtained. In ethanol solvent, the similar 3,4-fused
indole products were obtained in moderation to acquire a good yield with this reaction
(Table 3). In this reaction, benzaldehydes contain sterically demanding substituents,
such as 4-chloro-2-bromobenzaldehyde, also worked well.
a
Table 3. Et NH-catalyzed three-component reaction of 1a, 3b and aldehyde.
2
EtO
H N
2
O
R
OH
CHO
O
O
Et NH (20 mol%)
2
R
NC
+
+
OEt
N
ethanol, 60 oC, 6 h
H
3b
N
1
a
4
v-4ab
H
1
1

ACCEPTED MANUSCRIPT
b
Entry
R
Product
Yield (%)
1
2
3
4
5
6
4-OMe
3,4,5-(OMe)3
4-Cl
4v
70
49
4w
4x
c
86 (20)
4-Cl-2-Br
4-NO2
4y
60
72
84
71
4z
4-CN
4aa
4ab
7
4-CH3
a
Reaction conditions: 1a, 0.4 mmol; 3b, 0.4 mmol; aldehyde, 0.4 mmol, diethylamine,
b
c
0
.08 mmol, anhydrous ethanol, 2.0 mL, 60 °C, 6 h. Isolated yield. KF was used as
catalyst.
The KF/ethanol system was also discovered to be able to promote the reaction of
benzoylacetonitrile 3c, 1a, and 2a. With the established three-component reaction, a
,4-fused indole 4ac was obtained in 61% yield (Scheme 4), thereby introducing the
3
substrate scope of the reaction.
OH
CHO
+
Cl
2
H N
N
O
H
KF (20 mol%)
2
a
Cl
1
a
O
+
ethanol, 60 oC, 6 h
O
NC
N
3c
H
4
ac 61%
Scheme 4. Three-component reaction of 3c, 1a, and 2a.
In the reaction of 3,4,5-trimethoxybenzaldehyde, 1a, and 3a, an interesting
phenomenon was observed. Before starting the reaction, all substrates dissolved very
well in ethanol solvent (Figure 3, photo a). Once the stirring was triggered, a large
amount of yellow solid appeared immediately (photo b). However, the reaction
1
2

ACCEPTED MANUSCRIPT
mixture became gradually transparent with the progress of the reaction (photo c).
Finally, some insoluble species appeared again in the vial at the end of the reaction
(photo d). To obtain the inside information, the stepwise reaction of 1a, 3a, and
3
,4,5-trimethoxybenzaldehyde was selected to scale up. The reaction was performed
under identical conditions, and the yellow solid was isolated. Spectroscopic analysis
revealed that the compound was 2-(3,4,5-trimethoxybenzylidene)malononitrile 5a.
Literature survey indicated that malonodinitrile can react easily with aromatic
4
7
aldehyde even in the absence of any catalyst. 5a was also found to react with 1a in
the presence of a catalytic amount of KF in ethanol at 60 °C, providing 4l in an almost
quantitative yield after 6 h (Scheme 5).
Figure 3.
A
progressive view of the three-component reaction of
3
,4,5-trimethoxybenzaldehyde, 1a, and 3a: (a) before starting the reaction; (b) after
starting the stirring; (c) after 3 h of reaction; (d) at the end of the reaction.
OMe
H N
2
CN
OMe
OMe
OH
MeO
MeO
CN
KF (20 mol%)
O
(
a)
N
H
+
(b)
(c)
(d)
CN
ethanol, 60 oC, 6 h
N
OMe
5a
H
1
a
4l 98%
1
3

ACCEPTED MANUSCRIPT
Scheme 5. Reaction of 5a and 1a.
On the basis of the above results, a plausible mechanism for the model reaction is
proposed in Figure 4. The initial event of the reaction should be the formation of
arylidenenitrile (I) through a Knoevenagel reaction between the aldehyde and
malonodinitrile in the presence of a basic catalyst; A Michael-type addition reaction of
1
a to this intermediate led to the formation of intermediates (II); Then, 4a was formed
through a tandem reaction involving an intramolecular nucleophilic addition of the
phenolic OH group to one of the cyano groups, which provided intermediates (III);
And finally, tautomerization of (III) to form the final product 4a.
CN
CHO
KF
CN
+
CN
Knoevenagel
Cl
Cl
CN
(I)
2
a
3a
OH
4
a
Michael
N
H
isomerization
Cl
1a
HN
CN
HN
O
intramolecular addition
OH
CN
N
CN
H
Cl
(
III)
(II)
Figure 4. Plausible mechanism of the model reaction.
■
CONCLUSION
In summary, a three-component reaction of 4-hydroxyindole, aldehyde, and
malonodinitrile or ethyl cyanoacetate was developed for the first time, providing an
expedient way to access 3,4-fused indoles with a seven-membered ring. All reactions
were conducted under mild and environment-friendly conditions by using either KF
1
4

ACCEPTED MANUSCRIPT
or diethylamine as catalyst. The three-component reaction displayed a good scope of
substrates. In some cases, the products can be easily isolated by simple filtration. This
experiment is the first to demonstrate that 4-hydroxyindole can be used as a
C,O-based 1,4-bisnucleophile for organic synthesis. This observation inspires
synthetic chemists to use this easily available indole in many other reactions, which
can be adopted to synthesize other valuable indole-containing compounds.
■
EXPERIMENTAL SECTION
Chemicals. Reagents and starting materials were directly purchased from commercial
resources and used as received without further purification. All chemicals were of
reagent grade.
Typical procedure for the three-component reaction of 4-hydroxyindole,
aldehydes, and malonodinitrile. The reaction was performed in a 20 mL V-type tube
equipment with a triangle magnetic stirring bar. In a typical reaction, 4-hydroxyindole
(0.4 mmol) was mixed with malonodinitrile (0.4 mmol) and aldehydes (0.4 mmol) in
2
.0 mL of ethanol. KF (0.08 mmol) was then added. The mixture was subsequently
heated to 60 °C under stirring for 6 h. After the reaction, the mixture was cooled to
room temperature, and the target product was isolated using a preparative thin-layer
chromatograph (TLC) with eluting solution [petroleum ether/ethyl acetate = 3/1 (v/v)].
Test for substrate scope expansion was the same as the abovementioned analogous
procedure.
Stepwise three-component reaction of 4-hydroxyindole, malonodinitrile, and
3
,4,5-trimethoxybenzaldehyde. The reaction was performed similar to the
1
5

ACCEPTED MANUSCRIPT
abovementioned typical procedure. Malonodinitrile (4 mmol) was mixed with
3
,4,5-trimethoxybenzaldehyde (4 mmol) and KF (0. 4 mmol) in 20 mL of ethanol.
The mixture was then heated to 60 °C under stirring for 0.5 h. After the reaction, the
mixture was cooled to room temperature, and the precipitated solid was separated by
filtration. The acquired solid was washed with cold ethanol (4×4.0 mL) and dried at
1
00 °C for 1 h. Thereafter, 4-hydroxyindole (2 mmol) was mixed with the
aforementioned acquired solid (2 mmol) and KF (0. 4 mmol) in 10 mL of ethanol. The
mixture was then stirred at 60 °C for 6 h. After the reaction, the mixture was cooled to
room temperature, and the target product was isolated by filtration.
Product analysis. Melting points were determined on an electrothermal type (Yuhua
1
13
X-4) melting point apparatus and were uncorrected. H and C NMR spectra were
recorded on a Bruker Advance instrument by using TMS as an internal reference, and
chemical shifts were expressed in ppm. Infrared spectra were recorded (KBr pellets)
−
1
on a Bruker Equinox 55 spectrometer with a resolution of 0.4 cm . HRMS was
recorded on a Bruker MicrOTOF-Q II instrument.
Spectral data for the products
2
-Amino-4-(4-chlorophenyl)-4,
6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carbonitrile (4a): Yellow solid; m.p. 196–198 C; H NMR (400 MHz,
o
DMSO, 25 C, TMS): δ = 4.84 (s, 1H), 6.51 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.98 (s,
2
1
1
2
H), 7.13 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.35–7.38 (m, 3H), 11.33 (s,
1
3
H); C NMR (100 Mz, DMSO): δ = 160.9, 146.3, 141.2, 136.8, 131.6, 129.8, 129.0,
26.1, 122.1, 121.3, 116.9, 111.7, 109.1, 98.0, 56.8, 28.7 ppm; IR: ν = 3451, 3354,
-1
179, 1659, 1602, 1490, 1398, 1349, 1223, 1088, 887, 793, 770, 737, 490 cm ;
+
HRMS (TOF, ESI): m/z calcd for C H ClN O, [M + H] 322.0747, found 322.0741.
1
8
13
3
1
6

ACCEPTED MANUSCRIPT
2
-Amino-4-phenyl-4, 6-dihydrooxepino [4, 3, 2-cd] indole-3-carbonitrile (4b):
o
1
o
Yellow solid; m.p. 188–190 C; H NMR (400 MHz, DMSO, 25 C, TMS): δ = 4.69
(s, 1H), 6.41 (s, 1H), 6.60 (d, J = 12.0 Hz, 1H), 6.84 (s, 2H), 7.02 (d, J = 8.0 Hz, 1H),
1
3
7
.06–7.12 (m, 3H), 7.19 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 11.21 (s, 1H); C NMR
(100 Mz, DMSO): δ = 160.9, 147.4, 141.2, 136.8, 129.0, 128.0, 127.0, 126.1, 122.2,
1
1
21.4, 116.9, 112.3, 109.0, 98.0, 57.2, 41.3 ppm; IR: ν = 3394, 3310, 2201, 1656,
-1
487, 1453, 1390, 1349, 1221, 1089, 882, 771, 741, 699, 587, 526, 482 cm . HRMS
+
(
TOF, ESI): m/z calcd for C H N O, [M + H] 288.1137, found 288.1132.
1
8
14
3
2
-Amino-4-(p-tolyl)-4, 6-dihydrooxepino [4, 3, 2-cd] indole-3-carbonitrile (4c):
o
1
o
Yellow solid; m.p. 187–189 C; H NMR (400 MHz, DMSO, 22 C, TMS): δ = 2.26 (s,
3
5
1
2
1
H), 4.74 (s, 1H), 6.59 (s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.89 (s, 2H), 7.09–7.16 (m,
1
3
H), 7.38 (s, 1H), 11.27 (s, 1H); C NMR (100 Mz, DMSO): δ = 160.8, 144.3, 141.0,
36.6, 136.3, 129.6, 127.8, 126.0, 122.2, 121.6, 112.3, 109.0, 98.1, 79.3, 57.4, 40.8,
1.0 ppm; IR: ν = 3339, 2189, 1654, 1607, 1509, 1401, 1350, 1254, 1220, 1174, 1089,
-1
029, 798, 756, 733, 567 cm . HRMS (TOF, ESI): m/z calcd for C H N O, [M +
1
9
16
3
+
H] 302.1293, found 302.1289.
-Amino-4-(4-methoxyphenyl)-4,
2
6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carbonitrile (4d): Yellow solid; m.p. 132–134 C; H NMR (400 MHz,
o
DMSO, 21 C, TMS): δ = 3.60 (s, 3H), 4.63 (s, 1H), 6.40 (s, 1H), 6.57 (d, J = 8.0 Hz,
1
1
1
H), 6.75 (d, J = 8.0 Hz, 2H), 6.79 (s, 2H), 7.00–7.03 (m, 3H), 7.26 (t, J = 2.8 Hz,
1
3
H), 11.20 (s, 1H); C NMR (100 Mz, DMSO): δ = 160.7, 158.4, 141.1, 139.6, 136.7,
29.0, 126.0, 122.3, 121.5, 116.9, 114.3, 112.5, 108.9, 97.9, 57.6, 55.5, 28.7 ppm; IR:
ν = 3338, 2186, 1654, 1606, 1509, 1401, 1350, 1254, 1220, 1174,1089, 1029, 798,
-
1
+
7
3
2
56, 733, 678, 523 cm . HRMS (TOF, ESI): m/z calcd for C H N O , [M + H]
19 16 3 2
18.1243, found 318.1242.
-Amino-4-(2-methoxyphenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbonitrile
o
1
o
(
4e): Yellow solid; m.p. 134–136 C; H NMR (400 MHz, DMSO, 25 C, TMS): δ =
3
.83 (s, 3H), 5.25 (s, 1H), 6.52 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 6.87 (s,
H), 6.98–7.03 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.10–7.18 (m, 1H), 7.36 (s, 1H),
2
1
7

ACCEPTED MANUSCRIPT
1
3
1
1
3
8
1.28 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.6, 156.6, 141.5, 136.7, 135.2,
29.3, 128.2, 125.9, 121.7, 121.3, 116.9, 112.6, 111.9, 108.9, 97.9, 79.6, 56.4, 56.1,
4.1 ppm; IR: ν = 3452, 3325, 2192, 1696, 1652, 1492, 1407, 1352, 1224, 1098, 1026,
-1
84, 761, 734, 585, 535 cm . HRMS (TOF, ESI): m/z calcd for C H N O , [M +
19
16
3
2
+
H] 318.1243, found 318.1249.
-Amino-4-(4-bromophenyl)-4,
2
6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carbonitrile (4f): Yellow solid; m.p. 213–215 C; H NMR (400 MHz,
o
DMSO, 25 C, TMS): δ = 4.82 (s, 1H), 6.50 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.97 (s,
2
H), 7.12 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.38 (s, 1H), 7.49 (d, J = 8.0
1
3
Hz, 2H) 11.32 (s, 1H); C NMR (100 Mz, DMSO): δ = 160.9, 146.8, 141.2, 136.8,
31.9, 130.2, 126.1, 122.1, 121.3, 120.1, 116. 9, 111.6, 109.1, 98.0, 56.7, 40.6 ppm;
IR: ν = 3444, 3354, 2180, 1658, 1602, 1488, 1401, 1349, 1222, 1088, 1009, 887, 791,
1
-
1
+
7
3
2
69, 736, 487 cm . HRMS (TOF, ESI): m/z calcd for C H BrN O, [M + H]
18 13 3
66.0242, found 366.0233.
-Amino-4-(2-bromo-4-methylphenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carb
o
1
o
onitrile (4g): Yellow solid; m.p. 197–199 C; H NMR (400 MHz, DMSO, 25 C,
TMS): δ = 2.12 (s, 3H), 5.23 (s, 1H), 6.43 (s, 1H), 6.56 (d, J = 12.0 Hz, 1H), 6.89 (s,
2
H), 6.95 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 2H), 7.28 (s, 1H), 7.31 (s, 1H) 11.24
1
3
(
s, 1H); C NMR (100 Mz, DMSO): δ = 161.0, 142.8, 141.2, 138.9, 136.9, 133.2,
31.3, 129.7, 126.1, 122.5, 121.4, 121.1, 116.9, 111.4, 109.1, 98.1, 56.3, 28.7, 20.5
ppm; IR: ν = 3435, 3336, 2188, 1653, 1628, 1490, 1403, 1350, 1221, 1090, 1039, 886,
1
-
1
+
8
3
2
01, 760, 734, 492 cm . HRMS (TOF, ESI): m/z calcd for C H BrN O, [M + H]
19 15 3
80.0398, found 380.0385.
-Amino-4-(2-bromo-4-fluorophenyl)-4,
6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carbonitrile (4h): Yellow solid; m.p. 203–205 C; H NMR (400 MHz,
o
DMSO, 25 C, TMS): δ = 5.35 (s, 1H), 6.51 (s, 1H), 6.62 (d, J = 8.0 Hz, 1H), 7.02 (s,
2
H), 7.13 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 2.4 Hz, 1H), 7.56
1
3
(
d, J = 8.0 Hz, 1H), 11.34 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.0, 160.8 (d, J
=
246.0 Hz), 141.2, 136.9, 132.9 (d, J = 8 Hz), 128.7. 128.2, 126.2, 122.6 (d, J = 10.0
1
8

ACCEPTED MANUSCRIPT
Hz), 121.2, 120.9, 119.8 (d, J = 25.0 Hz), 116.9, 116.2 (d, J = 21.0 Hz), 111.0, 109.2,
1
9
9
8.0, 55.9, 28.6 ppm; F NMR (400 Mz, DMSO): δ = - 113.68 ppm; IR: ν = 3441,
3
334, 2189, 1653, 1631, 1601, 1486, 1352, 1218, 1088, 884, 856, 763, 733, 514, 452
-1
+
cm . HRMS (TOF, ESI): m/z calcd for C H BrFN O, [M + H] 384.0148, found
18
12
3
3
84.0137.
2
-Amino-4-(2-chlorophenyl)-4,
6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carbonitrile (4i): Yellow solid; m.p. 200–202 C; H NMR (400 MHz,
o
DMSO, 25 C, TMS): δ = 5.37 (s, 1H), 6.53 (s, 1H), 6.67 (d, J = 8.0 Hz, 1H), 7.02 (s,
2
1
1
H), 7.14 (d, J = 8.0 Hz, 1H), 7.26–7.32 (m, 3H), 7.41 (s, 1H), 7.46 (d, J = 8.0 Hz,
1
3
H), 11.36 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.2, 144.0, 141.3, 136.9, 132.1,
31.4, 130.0, 128.9, 126.2, 121.4, 121.0, 116.9, 111.1, 109.1, 98.0, 55.8, 38.1 ppm; IR:
ν = 3450, 3353, 2270, 1658, 1612, 1489, 1399, 1348, 1225, 1086, 887, 795, 767, 737,
-
1
+
4
3
2
91 cm ; HRMS (TOF, ESI): m/z calcd for C H ClN O, [M + H] 322.0747, found
18 13 3
22.0752.
-Amino-4-(2-chloro-6-fluorophenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbo
o
1
o
nitrile (4j): Yellow solid; m.p. 254–256 C; H NMR (400 MHz, DMSO, 21 C,
TMS): δ = 5.55 (s, 1H), 6.50 (s, 1H), 6.60 (s, 1H), 7.02 (s, 2H), 7.12 (d, J = 8.0 Hz,
1
3
2
1
5
1
6
3
2
H), 7.32–7.38 (m, 3H), 11.32 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.5, 141.6,
37.0, 130.0 (d, J = 10.0 Hz), 126.2, 120.9 (d, J = 10.0 Hz), 116.8, 115.9, 109.0, 97.9,
1
9
3.3, 32.5 ppm; F NMR (400 Mz, DMSO): δ = - 112.71 ppm; IR: ν = 3303, 2198,
657, 1577, 1494, 1453, 1397, 1349, 1263, 1222, 1170, 1096, 1061, 896, 787, 730,
-1
+
79, 582, 528, 461 cm . HRMS (TOF, ESI): m/z calcd for C H ClFN O, [M + H]
1
8
12
3
40.0653, found 340.0644.
-Amino-4-(3,4-dimethoxyphenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbonit
o
1
o
rile (4k): Yellow solid; m.p. 215–217 C; H NMR (400 MHz, DMSO, 25 C, TMS):
δ = 3.60 (d, J = 2.8 Hz, 6H ), 4.64 (s, 1H), 6.39 (s, 1H), 6.62 (d, J = 8.0 Hz, 2H),
6
.73–6.76 (m, 2H), 6.79 (s, 2H), 7.01 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 11.19 (s, 1H);
C NMR (100 Mz, DMSO): 160.8, 149.1, 148.0, 141.0, 140.0, 136.7, 128.7, 128.2,
26.0, 122.2, 121.5, 120.1, 116.9, 112.4, 111.9, 108.8, 98.0, 57.4, 55.9, 40.8 ppm; IR:
1
3
1
1
9

ACCEPTED MANUSCRIPT
ν = 3449, 3386, 3329, 2195, 1666, 1603, 1513,1493, 1464, 1401, 1351, 1261, 1225,
-1
1
141, 1089, 1022, 889, 791, 738, 570, 527 cm . HRMS (TOF, ESI): m/z calcd for
+
C H N O , [M + H] 348.1348, found 348.1339
20
18
3
3
2
-Amino-4-(3, 4, 5-trimethoxyphenyl)-4, 6-dihydrooxepino [4, 3, 2-cd]
o
1
indole-3-carbonitrile (4l): Yellow solid; m.p. 235–237 C; H NMR (400 MHz,
o
DMSO, 25 C, TMS): δ = 3.64 (s, 3H), 3.72 (s, 6H), 4.79 (s, 1H), 6.51 (s, 1H), 6.56 (s,
2
H), 6.80 (d, J = 8.0 Hz, 1H), 6.94 (s, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 2.4
13
Hz, 1H), 11.32 (s, 1H); C NMR (100 Mz, DMSO): δ = 160.9, 153.4, 143.0, 141.0,
1
4
1
36.8, 136.6, 126.0, 122.2, 121.5, 116.9, 112.0,108.9, 106.2, 98.0, 60.4, 56.9, 56.3,
1.4 ppm; IR: ν = 3453, 3383, 3334, 2193, 1659, 1667, 1595, 1505, 1463, 1425, 1401,
-1
352, 1326, 1231, 1124, 1093, 1004, 891, 802, 746, 689, 574, 530 cm . HRMS (TOF,
+
ESI): m/z calcd for C H N O4, [M + H] 378.1454, found 378.1455.
2
1
20
3
2
-Amino-4-(3-benzyl-4-methoxyphenyl)-4, 6-dihydrooxepino [4, 3, 2-cd]
o
1
indole-3-carbonitrile (4m): Yellow solid; m.p. 236–238 C; H NMR (400 MHz,
o
DMSO, 21 C, TMS): δ = 3.72 (s, 3H), 4.71 (s, 1H), 4.99 (q, J = 12.0 Hz, 2H), 6.48 (s,
1
H), 6.65 (d, J = 4.0 Hz, 1H), 6.75 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H), 6.89 (s, 2H),
a b
1
3
6
.91–6.93 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.30–7.41 (m, 6H), 11.29 (s, 1H); C
NMR (100 Mz, DMSO): δ = 160.8, 148.4, 148.1, 141.0, 139.9, 137.4, 136.7, 128.8,
1
5
1
28.6, 128.3, 125.9, 122.2, 121.5, 120.4, 116.9, 113.9, 112.7, 112.4, 108.8, 97.9, 70.5,
7.2, 56.1, 40.7 ppm; IR: ν = 3395, 3335, 2183, 1654, 1601, 1513, 1402, 1350, 1225,
-1
086, 889, 794, 772, 741, 699, 478 cm . HRMS (TOF, ESI): m/z calcd for
+
C H N O , [M + H] 408.1712, found 408.1704.
26
22
3
2
2
-Amino-4-(4-((trifluoromethyl) thio) phenyl)-4, 6-dihydrooxepino [4, 3, 2-cd]
o
1
indole-3-carbonitrile (4n): Yellow solid; m.p. 174–176 C; H NMR (400 MHz,
o
DMSO, 21 C, TMS): δ = 4.91 (s, 1H), 6.52 (s, 1H), 6.71 (d, J = 8.0 Hz, 1H), 7.05 (s,
2
H), 7.14 (d, J = 8.0 Hz, 1H),7.38 (d, J = 8.0 Hz, 3H), 7.66 (d, J = 8.0 Hz, 2H), 11.36
1
3
(
s, 1H); C NMR (100 Mz, DMSO): δ = 161.0, 150.9, 141.3, 137.0, 136. 9, 131.6,
29.5, 128.6, 126.2, 122.0, 121.3 (d, J = 7.0 Hz), 116.9, 111.4, 109.2, 97.9, 56.5, 40.9
1
19
ppm; F NMR (400 Mz, DMSO): δ = - 42.16 ppm; IR: ν = 3388, 3305, 3192, 2201,
2
0

ACCEPTED MANUSCRIPT
1
5
3
2
655, 1627, 1488, 1393, 1350, 1222, 1166, 1117, 1083, 1015, 884, 794, 773, 740, 654,
-1
+
96, 519, 493 cm . HRMS (TOF, ESI): m/z calcd for C H F N OS, [M + H]
1
9
13
3
3
88.0731, found 388.0718.
-Amino-4-(4-nitrophenyl)-4, 6-dihydrooxepino [4, 3, 2-cd] indole-3-carbonitrile
o
1
o
(
4o): Yellow solid; m.p. 202–204 C; H NMR (400 MHz, DMSO, 25 C, TMS): δ =
5
.04 (s, 1H), 6.54 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 7.12 (s, 2H), 7.15 (d, J = 12.0 Hz,
1
3
1
H), 7.41 (s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8.0 Hz, 2H), 11.38 (s, 1H); C
NMR (100 Mz, DMSO): δ = 161.0, 154.8, 146.7, 141.3, 137.0, 129.2, 126.3, 124.4,
1
22.0, 121.1, 117.0, 110.9, 109.2, 98.0, 56.1, 40.9 ppm; IR: ν = 3441, 3395, 3335,
-1
2
184, 1655, 1513, 1402, 1350, 1225, 1087, 889, 772, 741, 700, 479 cm . HRMS
+
(
TOF, ESI): m/z calcd for C H N O , [M + H] 333.0988, found 333.0980.
1
8
13
4
3
2
-Amino-4-(2-nitrophenyl)-4, 6-dihydrooxepino [4, 3, 2-cd] indole-3-carbonitrile
o
1
o
(
4p): Yellow solid; m.p. 224–226 C; H NMR (400 MHz, DMSO, 25 C, TMS): δ =
5
.37 (s, 1H), 6.54 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 7.11 (s, 2H), 7.16 (d, J = 8.0 Hz,
H), 7.31 (d, J = 8.0 Hz, 1H), 7.41–7.47 (m, 2H), 7.60–7.64 (m, 1H), 7.87 (d, J = 8.0
1
13
Hz, 1H), 11.38 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.1, 149.1, 141.5, 140.5,
1
3
7
3
2
37.0, 133.9, 132.0, 128.5, 126.4, 124.0, 121.6, 120.8, 116.9, 110.6, 109.4, 98.1, 56.2,
6.0 ppm; IR: ν = 3443, 3342, 2189, 1656, 1521, 1408, 1350, 1224, 1091, 860, 773,
-1
+
44, 682, 635, 483 cm . HRMS (TOF, ESI): m/z calcd for C H N O , [M + H]
1
8
13
4
3
33.0988, found 333.0983.
-Amino-4-(4-cyanophenyl)-4, 6-dihydrooxepino [4, 3, 2-cd] indole-3-carbonitrile
o
1
o
(
4q): Yellow solid; m.p. 210–212 C; H NMR (400 MHz, DMSO, 25 C, TMS): δ =
4
.85 (s, 1H), 6.43 (s, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.99 (s, 2H), 7.05 (d, J = 8.0 Hz,
H), 7.29 (d, J = 4.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 11.27
1
1
3
(
s, 1H); C NMR (100 Mz, DMSO): δ = 161.1, 152.8, 141.3, 137.0, 133.1, 129.0,
1
3
8
3
26.3, 122.0, 121.1, 119.3, 117.0, 111.1, 109.9, 109.2, 98.0, 56.2, 41.2 ppm; IR: ν =
334, 2231, 2185, 1654, 1627, 1488, 1401, 1350, 1222, 1164, 1089, 1061, 888, 741,
-1
+
64, 798, 749, 659, 493 cm . HRMS (TOF, ESI): m/z calcd for C H N O, [M + H]
19
13
4
13.1089, found 313.1094.
2
1

ACCEPTED MANUSCRIPT
2
-Amino-4-(4-(trifluoromethyl) phenyl)-4, 6-dihydrooxepino [4, 3, 2-cd]
o
1
indole-3-carbonitrile (4r): Yellow solid; m.p. 169–171 C; H NMR (400 MHz,
o
DMSO, 21 C, TMS): δ = 4.96 (s, 1H), 6.53 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 7.06 (s,
2
2
8
1
3
H), 7.15 (d, J = 8.0 Hz, 1H),7.40 (s, 1H), 7.45 (d, J = 8.0 Hz, 2H),7.69 (d, J = 8.0 Hz,
13
H), 11.36 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.0, 151.9, 141.3, 136.9, 128.
, 127.7 (q, J = 31 Hz), 126.2, 126.0 (d, J = 3.0 Hz), 123.4, 122.0, 121.2, 116.9, 111.3,
19
09.2, 98.0, 56.4, 41.0 ppm; F NMR (400 Mz, DMSO): δ = - 60.81 ppm; IR: ν =
448, 3423, 3354, 3199, 2189, 1658, 1579, 1491, 1402, 1352, 1328, 1254, 1224, 1162,
-1
1
111, 1066, 1018, 888, 864, 848, 799, 754, 732, 668, 608, 488 cm . HRMS (TOF,
+
ESI): m/z calcd for C H F N O, [M + H] 356.1011, found 356.1005.
1
9
13
3
3
2
-Amino-4-(furan-2-yl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carbonitrile (4s):
o
1
o
Yellow solid; m.p. 177–179 C; H NMR (400 MHz, DMSO, 21 C, TMS): δ = 4.83
s, 1H), 6.08 (d, J = 4.0 Hz, 1H), 6.24–6.25 (m, 1H), 6.38 (s, 1H), 6.75 (d, J = 8.0 Hz,
H), 6.91 (s, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 2.8 Hz, 1H), 7.39 (d, J = 4.0
(
1
13
Hz, 1H), 11.24 (s, 1H); C NMR (100 Mz, DMSO): δ = 161.6, 158.0, 142.7, 141.5,
37.0, 126.1, 121.8, 121.2, 117.0, 110.8, 109.6, 108.8, 105.9, 97.9, 54.1, 34.9 ppm; IR:
ν = 3431, 3369, 3328, 2193, 1655, 1627, 1492, 1404, 1349, 1216, 1150, 1084, 1007,
1
-
1
+
7
2
2
50, 598, 479 cm . HRMS (TOF, ESI): m/z calcd for C H N O , [M + H]
1
6
12
3
2
78.0930, found 278.0927.
-Amino-4-(benzo[b]thiophen-3-yl)-4,
6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carbonitrile (4t): Yellow solid; m.p. 217–219 C; H NMR (400 MHz,
o
DMSO, 22 C, TMS): δ = 5.33 (s, 1H), 6.55 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.99 (s,
2
8
H), 7.09 (d, J = 8.0 Hz, 1H), 7.21–7.30 (m, 2H), 7.39 (t, J = 2.4 Hz, 1H), 7.61 (d, J =
1
3
.0 Hz, 1H), 7.65 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 11.32 (s, 1H); C NMR (100 Mz,
DMSO): δ = 160.9, 141.2, 140.2, 137.5, 137.0, 126.1, 124.8, 124.6, 124.4, 123.7,
1
2
22.4, 121.7, 110.5, 108.9, 100.1, 98.0, 55.8, 36.1 ppm; IR: ν = 3467, 3416, 3327,
-1
194, 1659, 1657, 1489, 1399, 1349, 1218, 1092, 1060, 1015, 760, 737, 505 cm .
+
HRMS (TOF, ESI): m/z calcd for C H N OS, [M + H] 344.0858, found 344.0855.
2
0
14
3
2
-Amino-4-cyclopropyl-4, 6-dihydrooxepino [4, 3, 2-cd] indole-3-carbonitrile (4u):
2
2

ACCEPTED MANUSCRIPT
o
1
o
Yellow solid; m.p. 147–149 C; H NMR (400 MHz, DMSO, 21 C, TMS): δ = 0.26–
0
.38 (m, 4H), 0.78–0.83 (m, 1H), 2.88 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 6.65 (s, 2H),
1
3
6
.92 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 11.15 (s, 1H); C
NMR (100 Mz, DMSO): δ = 161.7, 141.6, 136.8, 125.8, 122.1, 121.4, 117.0, 113.1,
1
1
08.5, 97.8, 55.3, 38.4, 21.6, 3.34 ppm; IR: ν = 3460, 3346, 2186, 1665, 1607, 1490,
-1
400, 1352, 1224, 1090, 797, 763, 721, 497 cm . HRMS (TOF, ESI): m/z calcd for
+
C H N O, [M + H] 252.1137, found 252.1121.
15
14
3
Ethyl
-amino-4-(4-methoxyphenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carboxylate
2
o
1
o
(
4v): Yellow solid; m.p. 207–209 C; H NMR (400 MHz, DMSO, 22 C, TMS): δ =
1
1
7
1
9
1
.06 (t, J = 8.0 Hz, 3H), 3.62 (s, 3H), 3.95 (q, J = 8.0 Hz, 2H), 4.85 (s, 1H), 6.46 (s,
H), 6.72 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 12.0 Hz, 3H),
1
3
.30 (s, 1H), 7.58 (s, 2H), 11.19 (s, 1H); C NMR (100 Mz, DMSO): δ = 169.1,
61.5, 157.7, 141.8, 141.2, 136.5, 128.5, 125.8, 122.3, 116.9, 115.6, 113.8, 108.6,
7.8, 77.8, 59.0, 55.4, 39.3, 14.8 ppm; IR: ν = 3417, 3315, 1672, 1609, 1509, 1487,
-1
351, 1254, 1212, 1169, 1092, 1061, 1030, 797, 751, 726, 541 cm . HRMS (TOF,
+
ESI): m/z calcd for C H N O , [M + H] 365.1501, found 365.1492.
2
1
21
2
4
Ethyl 2-amino-4-(3, 4, 5-trimethoxyphenyl)-4, 6-dihydrooxepino [4, 3, 2-cd]
o
1
indole-3- carboxylate (4w): Yellow solid; m.p. 231–233 C; H NMR (400 MHz,
o
DMSO, 22 C, TMS): δ = 1.07 (t, J = 8.0 Hz, 3H), 3.54 (s, 3H), 3.64 (s, 6H), 3.96 (q,
J = 4.0 Hz, 2H), 4.87 (s, 1H), 6.45 (s, 2H), 6.47(s, 1H), 6.90 (d, J = 12.0 Hz, 1H),
1
3
7
.07 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.61 (s, 2H), 11.21 (s, 1H); C NMR (100 Mz,
DMSO): δ = 169.1, 161.7, 153.0, 145.4, 141.2, 136.6, 136.1, 125.8, 122.3, 116.9,
15.1, 108.7, 104.9, 97.9, 77.3, 60.4, 59.0, 56.2, 40.4, 14.8 ppm; IR: ν = 3433, 3365,
1
1
1
4
680, 1615, 1506, 1486, 1461, 1422, 1352, 1326, 1289, 1235, 1212, 1125, 1094, 1064,
+
002, 726, 693, 661, 598. HRMS (TOF, ESI): m/z calcd for C H N O , [M + H]
2
3
25
2
6
25.1713, found 425.1706.
Ethyl
2-amino-4-(4-chlorophenyl)-4,6-dihydrooxepino
[4,
3,
2-cd]
o
1
indole-3-carboxylate (4x): Yellow solid; m.p. 181–183 C; H NMR (400 MHz,
2
3

ACCEPTED MANUSCRIPT
o
CDCl , 22 C, TMS): δ = 1.17 (t, J = 8.0 Hz, 3H), 4.07 (q, J = 4.0 Hz, 2H), 5.00 (s,
3
1
5
1
3
1
H), 6.64 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.13–7.19 (m,
1
3
H), 7.25 (s, 2H), 8.37 (s, 1H); C NMR (100 Mz, CDCl ): δ = 169.0, 160.4, 147.4,
3
41.4, 136.2, 131.4, 129.2, 128.1, 124.2, 123.0, 116.9, 115.1, 108.0, 99.0, 79.1, 59.5,
0.3, 14.4 ppm; IR: ν = 3438, 3369, 2978, 2904, 1669, 1605, 1528, 1504, 1404, 1365,
351, 1313, 1290, 1247, 1211, 1159, 1086, 1059, 1018, 891, 790, 761, 733, 484, 454.
+
HRMS (TOF, ESI): m/z calcd for C H ClN O , [M + H] 369.1006, found
2
0
18
2
3
3
69.1002.
Ethyl 2-amino-4-(2-bromo-4-chlorophenyl)-4,6-dihydrooxepino [4, 3, 2-cd]
o
1
indole-3- carboxylate (4y): Yellow solid; m.p. 157–159 C; H NMR (400 MHz,
o
DMSO, 22 C, TMS): δ = 0.98 (t, J = 8.0 Hz, 3H), 3.89 (q, J = 4.0 Hz, 2H), 5.48 (s,
1
H), 6.48 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 7.06–7.09 (m, 2H), 7.33 (s,
1
3
1
H), 7.54 (d, J = 8.0 Hz, 1H), 7.78 (s, 2H), 11.28 (s, 1H); C NMR (100 Mz, DMSO):
δ = 168.8, 161.7, 151.1, 140.7, 136.9, 134.5, 132.9, 129.9, 128.1, 126.1, 120.9, 116.9,
1
09.1, 103.3, 98.0, 76.0, 59.1, 39.1, 14.6 ppm; IR: ν = 3425, 3314, 1671, 1606, 1488,
1
302, 1213, 1165, 1097, 1063, 1024, 736. HRMS (TOF, ESI): m/z calcd for
+
C H BrClN O , [M + H] 447.0111, found 447.0101.
20
17
2
3
Ethyl
-amino-4-(4-nitrophenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carboxylate (4z):
2
o
1
o
Yellow solid; m.p. 141–143 C; H NMR (400 MHz, DMSO, 22 C, TMS): δ = 1.07 (t,
J = 7.2 Hz, 3H), 3.97 (q, J = 6.8 Hz, 2H), 5.13 (s, 1H), 6.54 (s, 1H), 6.84 (d, J = 8.0
Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 2.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H),
1
3
7
1
1
1
.80 (s, 2H), 8.11 (d, J = 8.0 Hz, 2H), 11.32 (s, 1H); C NMR (100 Mz, DMSO): δ =
68.7, 161.6, 157.3, 146.0, 141.2, 136.9, 128.9, 126.1, 124.0, 122.2, 117.0, 113.5,
09.0, 97.9, 76.3, 59.1, 30.6, 14.7 ppm; IR: ν = 3443, 3311, 2981, 1737, 1675, 1604,
510, 1406, 1346, 1294, 1243, 1213, 1163, 1105, 894, 827, 741, 583, 531, 481;
+
HRMS (TOF, ESI): m/z calcd for C H N O , [M + H] 380.1246, found 380.1239.
2
0
18
3
5
Ethyl
-amino-4-(4-cyanophenyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carboxylate
2
2
4

ACCEPTED MANUSCRIPT
o
1
o
(
4aa): Yellow solid; m.p. 165–167 C; H NMR (400 MHz, DMSO, 22 C, TMS): δ =
.02 (t, J = 4.0 Hz, 3H), 3.92 (q, J = 4.0 Hz, 2H), 5.02 (s, 1H), 6.48 (s, 1H), 6. 79 (d, J
8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz,1H), 7.32–7.36 (m, 3H), 7.64 (d, J = 8.0 Hz, 2H),
1
=
1
3
7
1
5
1
.72 (s, 2H), 11.25 (s, 1H); C NMR (100 Mz, DMSO): δ = 168.7, 161.6, 155.2,
41.2, 136.8, 132.6, 128.7, 126.1, 122.2, 119.5, 116.9, 113.8, 108.9, 108.9, 97. 9, 76.4,
9.1, 30.5, 14.7 ppm; IR: ν = 3503, 3305, 2983, 2916, 2225, 1675, 1605, 1526, 1486,
405, 1350, 1300, 1257, 1209, 1160, 1104, 1060, 1025, 891, 787, 746, 673, 582, 454.
+
HRMS (TOF, ESI): m/z calcd for C H N O , [M + H] 360.1348, found 360.1332.
2
1
18
3
5
Ethyl
2-amino-4-(p-tolyl)-4,6-dihydrooxepino[4,3,2-cd]indole-3-carboxylate
o
1
o
(
4ab): Yellow solid; m.p. 220–222 C; H NMR (400 MHz, DMSO, 22 C, TMS): δ =
1
1
.10 (t, J = 8.0 Hz, 3H), 2.18 (s, 3H), 3.98 (q, J = 4.0 Hz, 2H), 4.92 (s, 1H), 6.53 (s,
H), 6. 83 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.11
1
3
(
s, 1H), 7.36 (s, 1H), 7.66 (s, 2H), 11.26 (s, 1H); C NMR (100 Mz, DMSO): δ =
1
1
1
8
69.1, 161.6, 146.7, 141.3, 136.6, 134.9, 129.0, 127.5, 125.8, 122.4, 116.9, 115.5,
08.6, 103.4, 97.8, 77.6, 59.0, 21.0, 14.8 ppm; IR: ν = 3413, 3313, 2984, 2904, 1664,
638, 1599, 1504, 1482, 1402, 1351, 1315, 1294, 1247, 1210, 1158, 1099, 1060, 1018,
92, 751, 727, 580, 505, 456; HRMS (TOF, ESI): m/z calcd for C H N O , [M +
21
21
2
3
+
H] 349.1552, found 349.1539.
-Amino-4-(4-chlorophenyl)-4, 6-dihydrooxepino [4, 3, 2-cd] indol-3-yl)
2
o
1
(
phenyl)methanone (4ac): Yellow solid; m.p. 132–134 C; H NMR (400 MHz,
o
DMSO, 22 C, TMS): δ = 5.00 (s, 1H), 6.55 (s, 1H), 6.76 (d, J = 8.0 Hz, 2H), 6.82 (d,
J = 8.0 Hz, 1H), 7.08–7.13 (m, 5H), 7.32–7.39 (m, 4H), 9.26 (s, 2H), 11.31 (s, 1H);
1
3
C NMR (100 Mz, DMSO): δ = 193.9, 163.7, 147.9, 142.5, 140.7, 136.8, 130.7,
1
29.1, 128.9, 128.5, 128.5, 126.5, 126.2, 122.0, 117.0, 115.3, 109.0, 97.8, 88.1, 31.1
ppm; IR: ν = 3421, 1692,1596, 1491, 1448, 1352, 1261, 1092, 1015, 789, 699, 508.
+
HRMS (TOF, ESI): m/z calcd for C H ClN O , [M + H] 401.1057, found
2
4
18
2
2
4
01.1056.
AUTHOR INFORMATION
Corresponding Author
■
2
5

ACCEPTED MANUSCRIPT
*
Y. Gu. Phone: +86 27 87543032. Fax: +86 27 87543632. E-mail: klgyl@hust.edu.cn.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENT
This work was supported by National Natural Science Foundation of China (21373093) and the
Fundamental Research Funds for the Central Universities of China (2014ZZGH019). The authors
thank for Analytical and Testing Center of HUST, Chutian Scholar Program of the Hubei
Provincial Government and the Cooperative Innovation Center of Hubei Province.
■
REFERENCES
1
2
3
4
. Ganem, B. Acc. Chem. Res. 2009, 42, 463−472.
. Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300−1308.
. Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083–3135.
. (a) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16, 2958−2975; (b) Liu, C.;
Zhou, L.; Jiang, D.; Gu, Y. Asian J.Org. Chem. 2016, DOI: 10.1002/ajoc.201500497; (c) Min,
L.; Pan, P.; Gu, Y. Org. Lett., 2016, 18, 364–367.
5
6
7
8
. Karl-Heinz, V.; Jutta, L. Curr. Top. Phytochem. 2002, 5, 1–21.
. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
. Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920.
. (a) Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.; Verma, A.; Choi, E. Molecules,
2
013, 18, 6620–6662; (b) Liu, C.; Zhou, L.; Huang, W.; Wang, M.; Gu, Y. Adv. Synth. Catal.
016, DOI: 10.1002/adsc.201500993.
2
9
. (a) Marcos, I. S.; Moro, R. F.; Costales, I.; Basabe, P.; Diez, D. Nat. Prod. Rep. 2013, 30, 1509–
526; (b) Taheri, A.; Lai, B.; Cheng, C.; Gu, Y. Green Chem. 2015, 17, 812–816.
1
1
0. Umezaki, S.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2013, 15, 4230–4233, and the
references therein.
11. Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028–1030.
1
2. Rafferty, R. J.; Williams, R. M. J. Org. Chem. 2012, 77, 519–524.
2
6

ACCEPTED MANUSCRIPT
1
1
1
1
3. Xu, X. –B.; Liu, J.; Zhang, J. –J.; Wang, Y. –W.; Peng, Y. Org. Lett. 2013, 15, 550–553 and the
references therein.
4. Suetsugu, S.; Nishiguchi, H.; Tsukano, C.; Takemoto, Y. Org. Lett. 2014, 16, 996–999 and the
references therein.
5. Komine, K.; Nomura, Y.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2015, 17, 3918–3921 and the
references therein.
6. Han, S. –J.; Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. J. Org.
Chem. 2015, 80, 528–547 and the references therein.
1
7. Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2011, 13, 5704–5707 and the references therein.
8. (a) Samet, A. V.; Yamskov, A. N.; Strelenko, Y. A.; Semenov, V. V. Tetrahedron, 2009, 65,
1
6
868–6872; (b) See also a review, Shan, D.; Jia, Y. Youji Huaxue 2013, 33, 1144–1156.
9. Zhou, B.; Yang, Y.; Tang, H.; Du, J.; Feng, H.; Li, Y. Org. Lett. 2014, 16, 3900−3903.
0. Zhang, Y.; Hubbard, J. W.; Akhmedov, N. G.; Petersen, J. L.; Soderberg, B. C. G. J. Org.
1
2
̈
Chem. 2015, 80, 4783−4790.
2
1. Zhang, X.; Li, Y.; Shi, H.; Zhang, L.; Zhang, S.; Xu, X.; Liu, Q. Chem. Commun., 2014, 50,
7
306–7309.
2
2
2
2
2
2
2
2
3
2. Tao, P.; Jia, Y. Chem. Commun. 2014, 50, 7367–7370.
3. Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15, 4528–4531.
4. Zhang, Y. –A.; Qiang, L.; Wang, C.; Jia, Y. Org. Lett. 2013, 15, 3662–3665.
5. Nakano, S. –i.; Inoue, N.; Hamada, Y.; Nemoto, T. Org. Lett. 2015, 17, 2622–2625.
6. Han, D.; He, Q.; Fan, R. Angew. Chem. Int. Ed. 2015, 54, 14013-14016.
7. Cheng, Y.; Huang, Z. –T.; Wang, M. –X. Curr. Org. Chem. 2004, 8, 325–351
8. Dandia, A.; Singh, R.; Maheshwari, S. Curr. Org. Chem. 2014, 18, 2513–2529.
9. Gu, Y. Green Chem. 2012, 14, 2091–2128.
0. Bugaut, X.; Bonne, D.; Coquerel, Y.; Rodriguez, J.; Constantieux, T. Curr. Org. Chem.
2
013, 17, 1920–1928.
3
3
3
1. Sunderhaus, J. D.; Martin, S. F. Chem. –Eur. J. 2009, 15, 1300–1308.
2. Estevez, V.; Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2014, 43, 4633–4657.
3. Azuaje, J.; El Maatougui, A.; Garcia-Mera, X.; Sotelo, E. ACS Comb. Sci. 2014, 16, 403–411.
2
7

ACCEPTED MANUSCRIPT
3
4. Wang W.; Cao, H.; Wolf, S.; Camacho-Horvitz, M. S.; Holak, T. A.; Domling, A. Bioorg. Med.
Chem. 2013, 21, 3982–3989.
3
3
3
5. Shaabani, A.; Maleki, A.; Mofakham, H. J. Comb. Chem. 2008, 10, 595–598.
6. Maleki, A. Tetrahedron 2012, 68, 7827–7833.
7. Wang, S. –L.; Wu, F. –Y.; Cheng, C.; Zhang, G.; Liu, Y. –P.; Jiang, B.; Shi, F.; Tu, S. –J. ACS
Comb. Sci. 2011, 13, 135–139.
3
3
4
4
4
8. Crich, D.; Bowers, A. A. Org. Lett. 2007, 9, 5323–5325.
9. Li, M.; Zhang, B.; Gu, Y. Green Chem., 2012, 14, 2421–2428.
0. Pan, X.; Li, M.; Gu, Y. Chem. –Asian J. 2014, 9, 268–274.
1. Liu, C.; Shen, M.; Lai, B.; Taheri, A.; Gu, Y. ACS Comb. Sci. 2014, 16, 652–660.
2. Bai, R.; Zhang, H.; Mei, F.; Wang, S.; Li, T.; Gu, Y.; Li, G. Green Chem. 2013, 15,
2
929−2934.
4
3. Bai, R.; Liu, P.; Yang, J.; Liu, C.; Gu, Y. ACS Sustainable Chem. Eng. 2015, 3, 1292–1297.
4. Sun, S.; Cheng, C.; Yang, J.; Taheri, A.; Jiang, D.; Zhang, B.; Gu, Y. Org. Lett. 2014, 16,
4
4
520–4523.
4
4
4
5. Yang, J.; Sun, S.; Zhang, B.; Zhang, J.; Gu, Y. Tetrahedron, 2014, 70, 9214–9223.
6. Sun, S.; Bai, R.; Gu, Y. Chem. Eur. J. 2014, 20, 549−558.
7. Kaupp, G.; Naimi-Jamal, M.; Schmeyers, J. Tetrahedron 2003, 59, 3753–3760.
2
8