Synthesis of Seven-Membered Azepino[3,2,1- hi]indoles via Rhodium-Catalyzed Regioselective C-H Activation/1,8-Diazabicyclo[5.4.0]undec-7-ene-Catalyzed Intramolecular Amidation of 7-Phenylindoles in One Pot

Article abstract of DOI:10.1021/acs.joc.9b02289

An unprecedented rhodium-catalyzed regioselective C-H activation/1,8-diazabicyclo[5.4.0]undec-7-ene-catalyzed intramolecular amidation of 7-arylindoles with diazomalonates is described that provides a straightforward route to seven-membered azepino[3,2,1-hi]indoles in good to excellent yields in one pot. A wide range of functional groups, including F, OMe, NPh₂, SiMe₃, Cl, CN, CHO, COMe, CO₂Me, CF₃, and NO₂, were all well-tolerated.

Full text of DOI:10.1021/acs.joc.9b02289

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Article
Synthesis of seven-membered azepino[3,2,1-hi]indoles via
rhodium-catalyzed regioselectively C-H activation/DBU-
catalyzed intramolecualr amidation of 7-phenylindoles in one pot
Yumeng Yuan, Guoshuai Pan, Xiaofeng Zhang, Buhong Li, Shengchang Xiang, and Qiufeng Huang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02289 • Publication Date (Web): 24 Oct 2019
Downloaded from pubs.acs.org on October 25, 2019
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Synthesis of Seven-membered Azepino[3,2,1-hi]indoles via
Rhodium-Catalyzed Regioselectively C-H Activation/DBU-Catalyzed
Intramolecualr Amidation of 7-Phenylindoles in One Pot
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Yumeng Yuan†, Guoshuai Pan†, Xiaofeng Zhang†, Buhong Li‡, Shengchang Xiang†,
Qiufeng Huang*†
†Fujian Key Laboratory of Polymer Materials, College of Chemistry & Materials
Science, Fujian Normal University, Fuzhou, Fujian 350007, P. R. China
‡MOE Key Laboratory of Optoelectronic Science and Technology for Medicine,
Fujian Key Laboratory for Photonics Technology, Fujian Normal University, Fuzhou,
Fujian 350007, P. R. China
E-mail: qiufenghuang@fjnu.edu.cn
Abstract
An
unprecedented
rhodium-catalyzed
regioselectively
C-H
activation/DBU-catalyzed intramolecular amidation of 7-arylindoles with
diazomalonates is described that provides a straightforward route to seven-membered
azepino[3,2,1-hi]indoles in good to excellent yields in one pot. A wide range of
functional groups, including F, OMe, NPh2, SiMe3, Cl, CN, CHO, COMe, CO2Me,
CF3, NO2 were all well tolerated.
[Cp*RhCl2]2 (2.5 mol%)
AgOAc (15 mol%)
DBU (30 mol%)
EtOAc, Ar, 60 oC,
R1
R2
R1
R2
N2
N
H
N
+
O
R4OOC
COOR3
H
COOR3
R3 = less bulky group
R4 = more bulky group
Tandem C-H activation/amidation in one-pot
Mild conditions, excellent yields, gram scale
Selectively (ortho-C-H activation, mono-C-H activation)
High functional group tolerance
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INTRODUCTION
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Transition-metal-catalyzed C-H bond activation is a versatile synthetic tool for
the construction of carbon-carbon bonds and carbon-heteroatom bonds.1 In particular,
transition-metal-catalyzed C-H activation/cyclization is a powerful and distinct
method for the synthesis of cyclic and heterocyclic compounds.2 In this context,
recent years have witnessed a lot of efficient methods for the synthesis of
five-membered or six-membered cyclic compounds.3 However, one pot C-H
activation/cyclization strategies leading to seven-membered rings have rarely been
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developed
due
to
entropic
factors
and
transannular
interactions.4
Azepino[3,2,1-hi]indoles and their derivatives are important classes of fused tricyclic
compounds containing a seven-membered ring that are found in a wide range of
natural products and biological active compounds (Figure 1). For example,
erythrivarine B was isolated from the flower of Erythrina Variegata,5 and extracts
from the roots of stemonaceae plants were found to contain a class of polycyclic
alkaloids which are structurally characterized by the presence of
a
azepino[3,2,1-hi]indole nucleus as show in stenine,6 stemona-lactam,7
tuberostemonol,8 dehydrostenine9 and tridehydrotuberostemonine.10 These alkaloids
exhibit a wide variety of biological activities, such as antitussive activity, insecticidal
activity, anti-inflammatory and so on.11 The structural diversity associated with
biological activities of azepino[3,2,1-hi]indoles have attracted the attention of the
synthetic community.12 However, the synthesis of azepino[3,2,1-hi]indoles usually
requires multistep approaches, and the development of novel strategies for efficient
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and straightforward construction of azepino[3,2,1-hi]indoles still remains a great
challenge. Indole nuclei are ubiquitous structural motifs. Recently, our group and
other laboratories have demonstrated that NH-indole was explored as an intrinsic
directing group which is present in the final product.13 Herein, we report a
regioselective Cp*Rh(III)-catalyzed C-H activation/base-catalyzed intramolecular
amidation of 7-phenylindoles with diazomalonates to give the corresponding
azepino[3,2,1-hi]indoles in good to excellent yields (Scheme 1). This catalytic method
offers opportunities for the synthesis of azepino[3,2,1-hi]indoles derivatives’
synthesis.
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HO
O
O
N
H
H
H
N
H
N
O
O
O
OCH3
H
H
O
O
HO
H3CO
N
OH
H
H
O
O
erythrivarine B
stenine
H
stemona-lactam
O
O
O
H
H
O
H
O
O
H
H
H
N
OH
N
N
H
O
H
O
O
H
O
tuberostemonol
dehydrostenine
tridehydrotuberostemonine
Figure 1.Natural products bearing azepino[3,2,1-hi]indole core
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[Cp*RhCl2]2 (2.5 mol%)
AgOAc (15 mol%)
DBU (30 mol%)
EtOAc, Ar, 60 oC,
R1
R2
R1
R2
N2
N
H
N
+
O
R4OOC
COOR3
R1
H
COOR3
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N
R3 = less bulky group
R4 = more bulky group
H
COOR3
C-H activation
amidation
COOR4
R2
Tandem C-H activation/amidation cyclization in one-pot
Selectively (ortho-C-H activation, mono-C-H activation)
Mild conditions, excellent yields (up to 98%)
High functional group tolerance
Gram scale
Scheme 1 Synthesis of Azepino[3,2,1-hi]indoles via Tandem C-H
Activation/Amidation in One Pot
RESULT AND DISCUSSION
To begin, the experiments were performed with 7-phenyl-1H-indole (1a, 1
equiv) and dimethyl diazomalonate (2a, 1.5 equiv) in the presence of [Cp*RhCl2]2
o
(2.5 mol %) and AgOAc (15 mol %) at 60 C for 24 h, and the desired
mono-substituted product 3a was obtained selectively in 91% yield (Scheme 2, eq. 1).
No disubstituted product13b-c or C3-substititued product14 was found in the reaction
mixture. The structure of 3a was confirmed by X-ray crystallography (see the
Supporting Information). Treating 3a with 30 mol % KOH in EtOAc resulted in
intramolecular amidation to provide 7-membered ring 4a in 69% yield. Changing the
base to DBU afforded 4a in quantitative yield (Scheme 2, eq. 2). The structure of 4a
was also confirmed by X-ray crystallography (see the Supporting Information).
Encourage by the above results, the tandem C-H activation/amidation of
7-phenyl-1H-indole
with
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[Cp*RhCl2]2 (2.5 mol%)
AgOAc (15 mol%)
EtOAc, Ar, 60 oC,
COOMe
N2
N
N
H
+
H
eq. 1
COOMe
COOMe
MeOOC
8
9
1a
2a
3a
CCDC 1939322
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91% yield
N
H
N
eq. 2
Base (30 mol%)
COOMe
COOMe
O
EtOAc, Air, R.T.
5 h
COOMe
4a
3a
CCDC 1939305
KOH: 69% yield
DBU: 100% yield
Scheme 2 Rhodium-Catalyzed ortho C-H Coupling of 7-Arylindoles with Diazo
Compounds (eq. 1); Base-Catalyzed Intramolecular Amidation Cyclization (eq. 2).
dimethyl diazomalonate leading to azepino[3,2,1-hi]indole 4a in one pot was
surveyed (Table 1). It is found that KOH was incompatible with the
[Cp*RhCl2]2/AgOAc catalyst system; almost no annulated product was formed, and
the starting material 1a was recovered totally (Table 1, entry 1). We reasoned that
strong base KOH had an adverse impact on Rhodium-catalyzed NH-indole directed
C-H activation cycle. To our delight, by changing the base from KOH to DBU, the
yield of the desired product was significantly improved to 94% (Table 1, entry 2).
Other bases such as Et3N, KOtBu, DMAP, LiOH, piperidine, Me4NOAc and
nBu4NOAc gave unsatisfactory results (Table 1, entries 3-9). The effect of the solvent
on the formation of 4a was also briefly investigated. In xylene, the reaction proceeded
as smoothly as in EtOAc (Table 1, entry 10). However, the use of other solvents such
as CH3CN, 1,4-dioxane, DCM and MeOH resulted in significant decreases of the
yields (Table 1, entries 11-15).
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Table 1. Optimization of the Reaction Conditionsa
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9
[Cp*RhCl2]2 (2.5 mol%)
AgOAc (15 mol%)
Base (30 mol%)
Solvent, Ar, 60 oC, 24h
N2
N
H
N
+
O
MeOOC
COOMe
H
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COOMe
1a
entry
2a
base
4a
yield (%)b
solvent
1
2
3
KOH
DBU
Et3N
KOtBu
DMAP
LiOH
EtOAc
EtOAc
EtOAc
trace
94
0
4
EtOAc
trace
5
6
7
8
EtOAc
EtOAc
EtOAc
EtOAc
trace
0
piperidine
trace
22
Me4NOAc
nBu4NOAc
9
EtOAc
30
10
11
DBU
DBU
xylene
91
CH3CN
trace
12
13
14
15
DBU
DBU
DBU
DBU
1,4-dioxane
DCM
47
79
DCE
trace
0
MeOH
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), [Cp*RhCl2]2 (2.5 mol%), AgOAc (15
mol%), base (30 mol%), solvent (2 mL), argon atmosphere, 60oC, 24 h. bisolated yield on the basis
of the amount of 1a used.
Under the optimal catalytic reaction conditions, the generality of the Rh(III)-catalyzed
tandem C-H activation/cyclization was examined (Table 2). The reaction is found to
be very sensitive with respect to the positions of substituents. Substituents at the 4 or
5-positions of the indole ring or the 3 or 4-positions of the benzene ring favored the
reaction, affording the desired products in good to excellent yields (Table 2. 4b-e),
while substituents on other positions led to complete reaction shutdown (4f-i).
Notably, a wide range of functional groups, including F, OMe, NPh2, SiMe3, Cl, CN,
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CHO, COMe, CO2Me, CF3, NO2 were all well tolerated (4e, 4j, 4l-t), providing the
corresponding products in 56-95% yields. The diverse groups in the products can
serve as a handle for further transformation. Only 18% yield of the desired product
was detected when an OH group was present, which is probably a result of the
chelating ability of the OH group with Rh metal (see 4w). It is worth mentioned that
7-naphthylindole and 1,4-diindolylbenzene both coupled smoothly with 2a to afford
the annulated products. The resulting structures 4u and 4v may be useful as valuable
intermediate for preparing optoelectronic materials. In order to determine if the
electronic nature of the substituent affected the reaction, an intermolecular
competition experiment was conducted with an equimolar mixture of
7-(4-methoxyphenyl)-1H-indole and 7-(4-nitrophenyl)-1H-indole. A ratio of 3:1 was
obtained between 4j and 4t after 12 h, which suggests that electron-rich substrates are
favorable to the reaction (Scheme 3, eq. 1). An intermolecular competition reaction
between 7-phenyl-1H-indole 1a and its deuterated derivative 1a-D5 gave a KIE value
of 2.5, indicating that the C-H bond cleavage might be involved in the
rate-determining step (Scheme 3, eq. 2). Next, various diazo compounds were
examined under the standard conditions. It is found that the steric effects of the
substituents on the diazomaonates play an important role in the cyclization step.
Changing the methyl group to ethyl group afforded a lower yield (4x, 55%).
Diisopropyl 2-diazomalonate was found to couple with 1a to afford the
mono-substituted product 3y in quantitative yield; and the amidation cyclization of 3y
can not happen in one pot. However, treating 3y with 30 mol% KOH in DCM
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Table 2. Substrate Scopea
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6
7
8
[Cp*RhCl2]2 (2.5 mol %)
AgOAc (15 mol %)
DBU (30 mol %)
EtOAc, Ar, 60 oC,
R1
R2
R1
N2
N
H
N
+
O
R4OOC
COOR3
H
R2
COOR3
1
2
4
9
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N
N
N
O
O
O
CO2Me
CO2Me
CO2Me
4b
CCDC 1939302
4c
CCDC 1939299
4d
76%
77%
67%
F
N
N
N
N
O
O
O
O
CO2Me
CO2Me
4h
0%
CO2Me
69%
CO2Me
4e
CCDC 1939303
4f
4g
0%
0%
N
N
O
N
O
O
N
O
CO2Me
CO2Me
CO2Me
OMe
CO2Me
N
CCDC 1940810
4i
4j
4k
4l
0%
95%
89%
84%
N
N
N
O
O
O
CO2Me
CO2Me
CO2Me
Si
Cl
CHO
4o
CCDC 1939304
93%
N
4m
CCDC 1940811
4n
85%
75%
N
N
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
4r
CN
COMe
4q
4p
CCDC 1940812
CCDC 1939300
75%
71%
90%
N
N
N
O
O
O
CO2Me
CO2Me
CO2Me
F
F
NO2
4t
F
4s
CCDC 1940814
4u
CCDC 1940815
77%
N
56%
98%
O
N
O
N
O
CO2Me
CO2Me
H
CO2Et
N
OH
4w
18%
4x
CCDC 1939301
55%
4v
50%
KOH (30 mol %)
DCM, rt. 5 h
N
N
iPrO2C
iPrO2C
N
H
O
O
MeO2C
CO2n-Bu
CO2iPr
N2
CO2Me
4a
56%
3y
4y
50%
100%
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aReaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), [Cp*RhCl2]2 (2.5 mol%), AgOAc (15
5
6
7
mol%), DBU (30 mol%), EtOAc (2 mL), argon atmosphere, 60 oC, 24 h; isolated yield.
8
9
[Cp*RhCl2]2 (2.5 mol%)
AgOAc (15 mol%)
DBU (30 mol%)
EtOAc, Ar, 60 oC, 12 h
N
N
10
11
12
13
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H
H
N
N
+
O
+
O
eq (1)
MeO2C
CO2Me
CO2Me
CO2Me
NO2
OMe
N2
OMe
NO2
4t
1j
1t
4j
, 75.8%
, 0.1 mmol
, 0.1 mmol
, 24.2%
[Cp*RhCl2]2 (2.5 mol%)
AgOAc (15 mol%)
DBU (30 mol%)
EtOAc, Ar, 60 oC, 2 h
N
H
N
H
D
N
N
D
O
O
1b
+
eq (2)
D
D
D
D
+
+
CO2Me
CO2Me
28% yield
D
D
D
1a
1a-D5
, 0.1 mmol
4a
4a-D4
, 0.1 mmol
KH/KD = 2.5 : 1
Scheme 3. Competition Experiment
delivered cyclization product 4y in 50% yield. Interestingly, when the unsymmetrical
diazomalonate n-butyl methyl 2-diazomalonate was employed, the amidation
occurred at the more bulky group and reserved the less bulky group in the final
product 4a.
In order to demonstrate the practical application of the methodology, the reaction
of 1a and 2a was carried out on a gram scale, which provided an 89% yield of 4a
(1.55 g, Scheme 4, eq. 1). Demethoxycarbonylation of 4a through a saponification
and decarboxylation sequence gave benzo[4,5]azepino[3,2,1-hi]indol-4(5H)-one 5a in
60% yield (Scheme 4, eq. 2).15 Finally, 4a can be efficiently alkenylated at the
3-position with acrylate affording 6a in 80% yield by
a Pd(OAc)2-catalyzed
Fujiwara-Moritani reaction (Scheme 4, eq. 3).16
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7
[Cp*RhCl2]2 (2.5 mol %)
AgOAc (15 mol %)
DBU (30 mol %)
EtOAc, Ar, 60 oC.
MeO2C
CO2Me
N
H
N
+
O
N2
eq (1)
8
CO2Me
9
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1a
2a
4a
, 89%, 1.55g
, 6 mmol
, 9 mmol
N
N
(i) 5% KOH/MeOH, R.T., 2 h
O
O
(ii) (a)10 % HCl
(b) 70 oC, 2 h
pH 4-5, 0 oC
eq (2)
CO2Me
4a
, 1 mmol
5a
60%
CO2Et
Pd(OAc)2 (5 mol%)
N
AgOAc (2 equiv)
Acetone (2 mL)
Ar, 80 oC, 24 h
+
eq (3)
N
CO2Et
O
O
CO2Me
CO2Me
4a
, 0.3 mmol
0.75 mmol
6a
, 80%
Scheme 4. Synthetic Transformations
In fact, several attempts to recrystallize or in situ characterize the key
intermediates from the reaction of 7-phenyl-1H-indole with equimolar [Cp*RhCl2]2
were problematic. However, based on our group’s previous research of
NH-indole-directed C-H bond functionalization,13a-b a possible mechanism for the
present reaction is depicted briefly in Scheme 5. First, the active Rh(III) species A is
generated with the assistance of AgOAc, which undergoes N-H bond cleavage and
C-H bond cleavage to give six-membered rhodacycle B. Then rhodacycle B
decomposes the diazo compound 2a to generate metal carbene species D; D
undergoes migratory insertion to produce seven-membered rhodacycle E. At this
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point, E is protonated to afford the coupling product 3a and regenerate the active
Rh(III) catalyst A. Finally, 3a can be converted into the seven-membered product 4a
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via intramolecualr amidation in the presence of DBU catalyst.
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3a
DBU
[Cp*Rh(III)Cl2]2
N
OMe
O
N
H
HN
OMe
O
H
N
AgCl
COOMe AgOAc
COOMe
1a
H
COOMe
COOMe
Cp*Rh(III)(OAc)2
A
2 HOAc
2 HOAc
MeOH
N
Cp*
Rh
CO2Me
CO2Me
N
O
E
N
B
COOMe
Rh
Cp*
N2
4a
MeO2C
CO2Me
2a
C
D
N
N
Cp*
CO2Me
Cp*
CO2Me
Rh
Rh
N
N
MeO2C
MeO2C
N2
Scheme 5. Proposed Reaction Mechanism
In conclusion, we have developed a significant advancement to catalytic C-H
activation/cyclization. This protocol enables unprecedented general access to the
seven-membered azepino[3,2,1-hi]indoles. The tandem rhodium-catalyzed C-H
coupling of 7-phenylindoles with diazo compounds and DBU-catalyzed
intramolecular amidation proceeds in one pot under mild reaction conditions. The
reactions have a broad range of substrates giving a variety of functionalized products
in high yields. A wide range of functional groups, including F, OMe, NPh2, SiMe3,
Cl, CN, CHO, COMe, CO2Me, CF3, NO2 were all well tolerated. Further applications
of this C-H activation/cyclization in the synthesis of related targets are in progress.
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Experimental Section
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General Method
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7-Phenyl-1H-indoles (1) were synthesized from 7-bromo-1H-indoles and
Phenylboronic acid via Suzuki coupling.17 1a, 1c, 1f, 1h-j, 1p, 1s-u are known
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compounds, H NMR data of the isolated products were in agreement with the
literature reports.18 1b, 1d-e, 1g, 1k-o, 1q, 1v-w are new compounds. They were
characterized by 1H NMR, 13C NMR and HRMS. Diazo compounds (2) were prepared
according to the reported procedures, and the compounds’ spectra data are in
agreement with the reports.19 1H NMR spectra were recorded at 400 MHz and 13C
1
NMR spectra at 100 MHz, respectively. H chemical shifts (δ) were referenced to
TMS, and 13C NMR chemical shifts (δ) were referenced to internal solvent resonance.
ESI-HRMS spectra were recorded by using a Q-TOF mass spectrometer. Data
collection and structural analysis of the crystal was collected on a Single Crystal
Diffractometer equipped with graphite monochromatic Cu/Mo Kα radiation
(λ=1.54184Å).
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7-Phenyl-1H-indole (1a): H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.69 –
7.64 (m, 3H), 7.55 – 7.50 (m, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.26 – 7.20 (m, 3H), 6.64
(dd, J = 3.2, 2.1 Hz, 1H).
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4-Methyl-7-phenyl-1H-indole (1b): H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H),
7.64 (dt, J = 7.7, 1.5 Hz, 2H), 7.54 – 7.49 (m, 2H), 7.42 – 7.38 (m, 1H), 7.23 (dd, J =
3.2, 2.5 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.03 (dd, J = 7.5, 1.0 Hz, 1H), 6.66 (dd, J =
13
3.2, 2.1 Hz, 1H), 2.63 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 139.4, 133.3,
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129.6, 129.1, 128.2, 128.0, 127.1, 123.7, 123.3, 122.0, 120.5, 101.6, 18.7. HRMS
(ESI) m/z: [M+H]+ Calcd for C15H14N, 208.1121; found, 208.1117.
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7-(p-Tolyl)-1H-indole (1c): H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.71 –
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7.57 (m, 3H), 7.44 – 7.20 (m, 5H), 6.68 (s, 1H), 2.49 (s, 3H).
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7-(m-Tolyl)-1H-indole (1d): H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.68 –
7.63 (m, 1H), 7.48 – 7.44 (m, 2H), 7.41 (td, J = 7.2, 1.4 Hz, 1H), 7.25 – 7.19 (m, 4H),
6.64 (dd, J = 3.2, 2.1 Hz, 1H), 2.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.2,
138.8, 133.7, 129.0, 128.9, 128.2, 128.1, 125.7, 125.2, 124.2, 121.8, 120.2, 119.9,
103.0, 21.6. HRMS (ESI) m/z: [M+H]+ Calcd for C15H14N, 208.1121; found,
208.1119.
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5-Fluoro-7-phenyl-1H-indole (1e): H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H),
7.65 – 7.61 (m, 2H), 7.56 – 7.51 (m, 2H), 7.47 – 7.42 (m, 1H), 7.31 (dd, J = 9.3, 2.3
Hz, 1H), 7.25 (t, J = 2.9 Hz, 1H), 7.02 (dd, J = 10.0, 2.4 Hz, 1H), 6.60 (dd, J = 3.1,
2.1 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.2 (d, J = 234.5 Hz), 138.1,
130.2, 129.2, 128.5 (d, J = 10.5 Hz), 128.1, 127.9, 126.3 (d, J = 9.4 Hz), 125.9, 110.1
(d, J = 26.6 Hz), 104.6 (d, J = 23.4 Hz), 103.2 (d, J = 4.8 Hz). 19 F NMR (376 MHz,
CDCl3)δ -124.7 (t, J = 9.3 Hz). HRMS (ESI) m/z: [M+H]+ Calcd for C14H11FN,
212.0870; found, 212.0865.
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2-Methyl-7-phenyl-1H-indole (1f): H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H),
7.67 – 7.63 (m, 2H), 7.55 – 7.50 (m, 3H), 7.43 – 7.38 (m, 1H), 7.19 – 7.13 (m, 2H),
6.33 – 6.27 (m, 1H), 2.45 (s, 3H).
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3-Methyl-7-phenyl-1H-indole (1g): H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H),
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7.73 – 7.64 (m, 2H), 7.64 – 7.59 (m, 1H), 7.57 – 7.49 (m, 2H), 7.44 – 7.39 (m, 1H),
7.27 – 7.24 (m, 2H), 7.00 (dd, J = 2.3, 1.2 Hz, 1H), 2.40 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 139.3, 134.0, 129.1, 128.6, 128.2, 127.3, 125.4, 121.8, 119.6, 118.1,
112.1, 9.8. HRMS (ESI) m/z: [M+H]+ Calcd for C15H14N, 208.1121; found, 208.1116.
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6-Methyl-7-phenyl-1H-indole (1h): H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H),
7.56 – 7.49 (m, 3H), 7.45 – 7.40 (m, 3H), 7.12 – 7.05 (m, 2H), 6.55 (dd, J = 3.2, 2.1
Hz, 1H), 2.31 (s, 3H).
7-(o-Tolyl)-1H-indole (1i): 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.68 (dt,
J = 8.0, 0.9 Hz, 1H), 7.40 – 7.30 (m, 4H), 7.24 – 7.18 (m, 2H), 7.10 (dd, J = 7.2, 1.1
Hz, 1H), 6.64 (dd, J = 3.2, 2.1 Hz, 1H), 2.21 (s, 3H).
7-(4-Methoxyphenyl)-1H-indole (1j): 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H),
7.65 – 7.55 (m, 3H), 7.23 – 7.18 (m, 3H), 7.08 – 7.02 (m, 2H), 6.66 – 6.59 (m, 1H),
3.89 (s, 3H).
1
7-(4-(Tert-butyl)phenyl)-1H-indole (1k): H NMR (400 MHz, CDCl3) δ 8.45 (s,
1H), 7.65 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.62 – 7.58 (m, 2H), 7.57 – 7.53 (m, 2H),
7.25 – 7.20 (m, 3H), 6.64 (dd, J = 3.2, 2.1 Hz, 1H), 1.42 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3) δ 150.3, 136.3, 133.8, 128.2, 127.9, 126.0, 125.5, 124.2, 121.8, 120.3,
119.8, 103.0, 34.6, 31.4. HRMS (ESI) m/z: [M+H]+ Calcd for C18H20N, 250.1590;
found, 250.1584.
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4-(1H-Indol-7-yl)-N,N-diphenylaniline (1l): H NMR (400 MHz, CDCl3) δ 8.47
(s, 1H), 7.63 (dd, J = 6.4, 2.2 Hz, 1H), 7.55 – 7.48 (m, 2H), 7.33 – 7.27 (m, 4H), 7.24
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– 7.16 (m, 8H), 7.13 (dt, J = 8.7, 1.8 Hz, 1H), 7.09 – 7.04 (m, 2H), 6.63 (dd, J = 3.2,
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2.1 Hz, 1H). C{1H} NMR (100 MHz, CDCl3) δ 147.6, 147.2, 133.7, 133.1, 129.3,
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129.2, 128.9, 128.2, 127.3, 125.2, 124.5, 124.3, 124.2, 124.0, 123.1, 122.8, 121.6,
120.3, 119.7, 103.1. HRMS (ESI) m/z: [M+H]+ Calcd for C26H21N2, 361.1699; found,
361.1689.
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7-(4-(Trimethylsilyl)phenyl)-1H-indole (1m): H NMR (400 MHz, CDCl3) δ
8.45 (s, 1H), 7.71 – 7.63 (m, 5H), 7.26 – 7.20 (m, 3H), 6.64 (dd, J = 3.2, 2.1 Hz, 1H),
0.35 (t, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.6, 139.5, 134.1, 133.7, 128.2,
127.5, 125.5, 124.3, 121.8, 120.3, 120.1, 103.0, -1.1. HRMS (ESI) m/z: [M+H]+ Calcd
for C17H20NSi, 266.1360; found, 266.1352.
7-(4-Chlorophenyl)-1H-indole (1n): 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H),
7.67 (ddd, J = 7.3, 1.9, 0.7 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.51 – 7.47 (m, 2H), 7.24 –
13
7.18 (m, 3H), 6.64 (dd, J = 3.2, 2.0 Hz, 1H). C{1H} NMR (100 MHz, CDCl3) δ
137.7, 133.5, 133.3, 129.5, 129.3, 128.4, 124.5, 124.3, 121.9, 120.4, 120.3, 103.2.
HRMS (ESI) m/z: [M+H]+ Calcd for C14H11ClN, 228.0575; found, 228.0569.
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4-(1H-Indol-7-yl)benzaldehyde (1o): H NMR (400 MHz, CDCl3) δ 10.06 (s,
1H), 8.51 (s, 1H), 8.03 – 8.00 (m, 2H), 7.84 – 7.81 (m, 2H), 7.71 (ddd, J = 7.2, 1.8,
0.7 Hz, 1H), 7.29 – 7.21 (m, 3H), 6.66 (dd, J = 3.2, 2.0 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 191.8, 145.7, 135.2, 133.4, 130.6, 128.7, 128.6, 124.7, 124.1, 122.2,
121.2, 120.4, 103.3. HRMS (ESI) m/z: [M+H]+ Calcd for C15H12NO, 222.0913; found,
222.0908.
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4-(1H-Indol-7-yl)benzonitrile (1p): H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H),
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7
7.81 – 7.75 (m, 4H), 7.73 – 7.68 (m, 1H), 7.28 – 7.19 (m, 4H), 6.66 (dd, J = 3.2, 2.0
8
9
Hz, 1H).
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1-(4-(1H-Indol-7-yl)phenyl)ethan-1-one (1q): H NMR (400 MHz, CDCl3) δ
8.56 (s, 1H), 8.11 – 8.06 (m, 2H), 7.77 – 7.73 (m, 2H), 7.70 (dd, J = 7.0, 1.7 Hz, 1H),
7.28 – 7.21 (m, 3H), 6.66 (dd, J = 3.1, 2.1 Hz, 1H), 2.65 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 197.8, 144.3, 135.8, 129.2, 128.5, 128.3, 124.7, 124.3, 122.0, 121.0,
120.3, 104.9, 103.2, 26.6. HRMS (ESI) m/z: [M+H]+ Calcd for C16H14NO, 236.1070;
found, 236.1064.
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Methyl 4-(1H-indol-7-yl)benzoate (1r): H NMR (400 MHz, CDCl3) δ 8.50 (s,
1H), 8.17 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.69 (dd, J = 7.0, 2.0 Hz, 1H),
7.27 – 7.21 (m, 3H), 6.65 (dd, J = 3.2, 2.1 Hz, 1H), 3.96 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 166.9, 144.0, 133.4, 130.4, 128.9, 128.5, 128.1, 124.6, 124.4, 122.0,
120.9, 120.3, 103.2, 52.2. HRMS (ESI) m/z: [M+H]+ Calcd for C16H14NO2, 252.1019;
found, 252.1012.
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7-(4-(Trifluoromethyl)phenyl)-1H-indole (1s): H NMR (400 MHz, CDCl3) δ
8.37 (s, 1H), 7.80 – 7.75 (m, 4H), 7.72 – 7.68 (m, 1H), 7.26 – 7.22 (m, 3H), 6.66 (dd,
J = 3.2, 2.0 Hz, 1H).
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7-(4-Nitrophenyl)-1H-indole (1t): H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H),
8.39 – 8.35 (m, 2H), 7.85 – 7.80 (m, 2H), 7.75 – 7.71 (m, 1H), 7.32 – 7.20 (m, 3H),
6.67 (dd, J = 3.2, 2.0 Hz, 1H).
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7-(Naphthalen-2-yl)-1H-indole (1u): 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H),
8.11 (s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.95 – 7.90 (m, 2H), 7.78 (dd, J = 8.4, 1.7 Hz,
1H), 7.70 (d, J = 7.8 Hz, 1H), 7.59 – 7.51 (m, 2H), 7.35 (d, J = 7.1 Hz, 1H), 7.30 –
7.23 (m, 2H), 6.67 (m, 1H).
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1,4-Di(1H-indol-7-yl)benzene (1v): H NMR (400 MHz, CDCl3) δ 8.51 (s, 2H),
7.80 (s, 4H), 7.69 (d, J = 7.2 Hz, 2H), 7.31 – 7.23 (m, 6H), 6.67– 6.65 (m, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 138.4, 133.7, 128.9, 128.4, 127.7, 125.1, 124.4,
121.9, 120.4, 120.3, 103.2. HRMS (ESI) m/z: [M+H]+ Calcd for C22H17N2, 309.1386;
found, 309.1379.
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4-(1H-Indol-7-yl)phenol (1w): H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.64
(d, J = 7.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.27 – 7.17 (m, 3H), 6.97 (d, J = 8.4 Hz,
2H), 6.67 – 6.59 (m, 1H), 5.09 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.9,
133.8, 131.8, 129.5, 128.2, 125.2, 124.3, 121.7, 120.3, 119.6, 116.0, 103.0. HRMS
(ESI) m/z: [M+H]+ Calcd for C14H12NO, 210.0913; found, 210.0908.
General Procedure for the Synthesis of Azepino[3,2,1-hi]indoles 4a-4x:
Under argon atmosphere, 7-aryl-1H-indoles 1(0.3 mmol), diazo compounds 2 (0.45
mmol, 1.5 equiv.), [Cp*RhCl2]2 (4.7 mg, 0.0075 mmol, 2.5mol%), AgOAc (7.5 mg,
0.045 mmol, 15 mol%), DBU (13.5 μL, 0.09 mmol, 30 mmol%) and EtOAc (2 mL)
were placed in a 25 mL seal tube. The mixture was heated in oil bath at 60 oC for 24 h
and then cooled to room temperature. The crude reaction mixture was diluted with
EtOAc to 5 mL, filtered through a celite pad, and then washed with 10 mL EtOAc.
The volatiles were removed under reduced pressure, and the residue was subjected to
silica gel column chromatography [eluting with petroleum ether/ethyl acetate] to
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afford the corresponding product.
Dimethyl 2-(2-(1H-indol-7-yl)phenyl)malonate (3a): 88 mg (91%); white solid,
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o
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mp 151-152 C; Purification (Petroleum ether/ethyl acetate = 10/1). H NMR (400
MHz, CDCl3) δ 8.22 (s, 1H), 7.68 (dt, J = 8.0, 1.0 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.51
– 7.38 (m, 3H), 7.20 (dd, J = 8.0, 7.2 Hz, 1H), 7.14 (dd, J = 3.2, 2.4 Hz, 1H), 7.06
(dd, J = 7.2, 1.2 Hz, 1H), 6.60 (dd, J = 3.2, 2.1 Hz, 1H), 4.72 (s, 1H), 3.68 (s, 3H),
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3.63 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 169.7, 168.9, 138.9, 134.6, 131.7,
130.6, 129.4, 128.5, 128.3, 127.8, 124.6, 123.3, 122.8, 120.4, 119.9, 102.8, 53.8, 52.8.
HRMS (ESI) m/z: [M+Na]+ Calcd for C19H17NO4Na, 346.1050; found, 346.1051. It
was crystallized from cyclohexane/dichloromethane.
Methyl 4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4a):
82 mg (94%); white solid, mp 128-129 oC; Purification (Petroleum ether/ethyl acetate
1
= 10/1). H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 3.7 Hz, 1H), 7.75 – 7.72 (m, 2H),
7.66 (dd, J = 7.7, 1.0 Hz, 1H), 7.56 – 7.47 (m, 3H), 7.41 (t, J = 7.7 Hz, 1H), 6.77 (d, J
= 3.7 Hz, 1H), 5.07 (s, 1H), 3.26 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.3,
165.1, 135.6, 131.8, 131.6, 131.5, 129.6, 129.5, 129.0, 128.6, 127.1, 125.6, 124.2,
123.5, 121.6, 109.8, 62.1, 52.6. HRMS (ESI) m/z: [M+Na]+ Calcd for C18H13NO3Na,
314.0788; found, 314.0788. It was crystallized from cyclohexane/dichloromethane.
Methyl
12-methyl-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate
o
(4b):70 mg (76%); white solid, mp 172-173 C; Purification (Petroleum ether/ethyl
1
acetate = 10/1). H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.8 Hz, 1H), 7.71 (d, J =
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7.6 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.53 – 7.43 (m, 3H), 7.21 (dd, J = 7.8, 0.9 Hz,
1H), 6.81 (d, J = 3.8 Hz, 1H), 5.07 (s, 1H), 3.27 (s, 3H), 2.60 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 167.5, 165.0, 135.7, 131.6, 131.5, 131.44, 131.41, 131.1, 129.2,
128.9, 128.3, 126.4, 125.0, 123.5, 123.2, 108.1, 62.1, 52.6, 18.4. HRMS (ESI) m/z:
[M+Na]+ Calcd for C19H15NO3Na, 328.0944; found, 328.0944. It was crystallized
from cyclohexane/dichloromethane.
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Methyl
7-methyl-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4c): 71
o
mg (77%); white solid, mp 164-165 C; Purification (Petroleum ether/ethyl acetate =
1
10/1). H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 3.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H),
7.63 (d, J = 7.7 Hz,2H), 7.41 – 7.28 (m, 3H), 6.76 (d, J = 3.7 Hz, 1H), 5.01 (s, 1H),
3.25 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 165.1, 138.7,
132.8, 132.1, 131.7, 131.5, 129.9, 129.4, 127.1, 125.6, 124.2, 123.3, 121.2, 109.7,
62.1, 52.6, 21.0. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H15NO3Na, 328.0944;
found, 328.0944. It was crystallized from cyclohexane/dichloromethane.
Methyl
8-methyl-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4d): 61
o
mg (67%); white solid, mp 127-128 C; Purification (Petroleum ether/ethyl acetate =
1
10/1). H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.7 Hz, 1H), 7.72 (dd, J = 7.7, 1.0 Hz,
1H), 7.64 (dd, J = 7.7, 1.0 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.39 (dd, J = 15.7, 7.8 Hz,
2H), 7.29 (d, J = 7.7 Hz,1H), 6.76 (d, J = 3.7 Hz, 1H), 5.03 (s, 1H), 3.25 (s, 3H), 2.46
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 165.3, 139.0, 135.4, 131.8, 131.7,
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131.4, 130.2, 129.5, 127.1, 126.9, 125.7, 124.2, 123.4, 121.5, 109.7, 61.7, 52.6, 21.3.
HRMS (ESI) m/z: [M+Na]+ Calcd for C19H15NO3Na, 328.0944; found, 328.0943.
Methyl
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11-fluoro-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4e): 64
o
mg (69%); white solid, mp 140-141 C; Purification (Petroleum ether/ethyl acetate =
1
10/1). H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 3.7 Hz, 1H), 7.70 (dd, J = 7.3, 1.7
Hz, 1H), 7.57 – 7.43 (m, 4H), 7.33 (dd, J = 8.1, 2.4 Hz, 1H), 6.73 (d, J = 3.7 Hz, 1H),
5.07 (s, 1H), 3.30 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.1, 164.6, 159.8 (d,
2
3
1JC-F = 240.8 Hz), 134.6, 132.9 (d, JC-F = 10.5 Hz), 131.7, 129.5 (d, JC-F = 4.6 Hz),
3
2
129.2 (d, JC-F = 4.3 Hz), 128.8, 128.1, 126.8 (d, JC-F = 9.2 Hz), 110.7, 110.5, 109.6
(d, 3JC-F = 4.0 Hz), 107.6, 107.4, 62.0, 52.8. 19F NMR (376 MHz, CDCl3)δ-118.9 (t, J
= 9.0 Hz, 1F).HRMS (ESI) m/z: [M+Na]+ Calcd for C18H12FNO3Na, 332.0693; found,
332.0693. It was crystallized from cyclohexane/dichloromethane.
Methyl
7-methoxy-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4j):
92 mg (95%); white solid, mp 125-126 oC; Purification (Petroleum ether/ethyl acetate
1
= 4/1). H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 3.7 Hz, 1H), 7.67 – 7.63 (m, 2H),
7.60 (dd, J = 7.7, 1.0 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.07 (dd, J = 8.7, 2.7 Hz, 1H),
7.01 (d, J = 2.7 Hz, 1H), 6.76 (d, J = 3.7 Hz, 1H), 5.00 (s, 1H), 3.89 (s, 3H), 3.26 (s,
13
3H). C{1H} NMR (100 MHz, CDCl3) δ 167.2, 164.8, 159.9, 131.7, 131.3, 130.8,
130.7, 128.2, 127.0, 125.4, 124.2, 123.0, 120.8, 116.2, 115.1, 109.8, 62.1, 55.5, 52.6.
HRMS (ESI) m/z: [M+Na]+ Calcd for C19H15NO4Na, 344.0893; found, 344.0893.
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7-(tert-butyl)-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4k):
8
9
93 mg (89%); white solid, mp 167-168 oC; Purification (Petroleum ether/ethyl acetate
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= 10/1). H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.7 Hz, 1H), 7.71 (dd, J = 7.7, 1.0
Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 7.7, 1.0 Hz, 1H), 7.55 (dd, J = 8.2, 2.0
Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 6.76 (d, J = 3.7 Hz, 1H),
5.07 (s, 1H), 3.26 (s, 3H), 1.39 (s, 9H). C{1H} NMR (100 MHz, CDCl3) δ 167.5,
13
165.2, 151.9, 132.8, 131.7, 131.6, 129.2, 129.2, 128.4, 127.0, 126.3, 125.6, 124.2,
123.2, 121.2, 109.7, 62.5, 52.6, 34.7, 31.3. HRMS (ESI) m/z: [M+H]+ Calcd
forC22H22NO3, 348.1594; found, 348.1589.
Methyl
7-(diphenylamino)-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylat
e (4l): 116 mg (84%); white solid, mp 198-199 oC; Purification (Petroleum ether/ethyl
1
acetate = 10/1). H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 3.7 Hz, 1H), 7.65 (d, J =
7.7 Hz, 1H), 7.60 (dd, J = 7.7, 1.0 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.37 (t, J = 7.7
Hz, 1H), 7.31 (td, J = 8.5, 7.2 Hz, 4H), 7.21 – 7.15 (m, 5H), 7.13 – 7.07 (m, 3H), 6.75
(d, J = 3.7 Hz, 1H), 4.84 (s, 1H), 3.26 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ
13
167.3, 164.9, 148.4, 147.1, 131.7, 131.3, 130.4, 130.3, 129.5, 128.7, 127.0, 125.5,
125.2, 124.3, 124.2, 123.8, 123.0, 122.6, 120.8, 109.8, 62.1, 52.6. HRMS (ESI) m/z:
[M+H]+ Calcd for C30H23N2O3, 459.1698; found, 459.1698. It was crystallized from
cyclohexane/dichloromethane.
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Methyl
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4-oxo-7-(trimethylsilyl)-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate
8
9
o
(4m): 82 mg (75%); white solid, mp 153-154 C; Purification (Petroleum ether/ethyl
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acetate = 8/1). H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 3.7 Hz, 1H), 7.76 – 7.71 (m,
2H), 7.69 – 7.64 (m, 2H), 7.59 (d, J = 0.8 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 6.77 (d, J
= 3.7 Hz, 1H), 5.12 (s, 1H), 3.26 (s, 3H), 0.35 (t, 9H). C{1H} NMR (100 MHz,
13
CDCl3) δ 167.4, 165.2, 141.4, 136.5, 135.9, 133.9, 131.8, 131.6, 128.8, 128.6, 127.1,
125.7, 124.2, 123.4, 121.6, 109.7, 62.3, 52.6, -1.2. HRMS (ESI) m/z: [M+Na]+ Calcd
for C21H21NO3SiNa, 386.1183; found, 386.1183. It was crystallized from
cyclohexane/dichloromethane.
Methyl
7-chloro-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4n): 83
o
mg (85%); white solid, mp 165-166 C; Purification (Petroleum ether/ethyl acetate =
1
10/1). H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.7 Hz, 1H), 7.70– 7.64 (m, 3H),
7.54 – 7.46 (m, 2H), 7.40 (t, J = 7.7 Hz, 1H), 6.77 (d, J = 3.7 Hz, 1H), 5.00 (s, 1H),
13
3.27 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 166.7, 164.4, 134.5, 134.2, 131.9,
131.4, 131.2, 130.9, 130.7, 129.1, 127.2, 124.5, 124.3, 123.4, 121.9, 109.9, 61.5, 52.8.
HRMS (ESI) m/z: [M+Na]+ Calcd for C18H12ClNO3Na, 348.0398; found, 348.0398.
Methyl
7-formyl-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4o): 89
o
mg (93%); white solid, mp 222-223 C; Purification (Petroleum ether/ethyl acetate =
1
3/1). H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.04 – 7.99 (m, 2H), 7.92 – 7.88 (m,
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2H), 7.77 (dt, J = 7.8, 0.6 Hz, 1H), 7.73 (dd, J = 7.7, 1.0 Hz, 1H), 7.45 (t, J = 7.7 Hz,
1H), 6.80 (d, J = 3.7 Hz, 1H), 5.19 (s, 1H), 3.27 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 191.1, 166.7, 164.3, 141.5, 135.9, 133.1, 132.1, 131.7, 130.4, 130.3, 129.6,
127.4, 124.4, 124.1, 122.9, 109.9, 61.8, 52.9. HRMS (ESI) m/z: [M+Na]+ Calcd for
C19H13NO4Na, 342.0737; found, 342.0731. It was crystallized from
cyclohexane/dichloromethane.
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Methyl
7-cyano-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4p): 71
o
mg (75%); white solid, mp 160-161 C; Purification (Petroleum ether/ethyl acetate =
1
4/1). H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 3.7 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H),
7.82 – 7.78 (m, 2H), 7.76 – 7.71 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 6.80 (d, J = 3.7 Hz,
1H), 5.09 (s, 1H), 3.28 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 164.0,
140.3, 135.0, 132.2, 132.2, 131.7, 130.6, 130.3, 127.4, 124.54, 124.51, 124.0, 123.2,
118.0, 112.3, 110.0, 61.4, 53.0. HRMS (ESI) m/z: [M+Na]+ Calcd for C19H12N2O3Na,
339.0740; found, 339.0740.
Methyl
7-acetyl-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4q): 71
o
mg (71%); white solid, mp 149-150 C; Purification (Petroleum ether/ethyl acetate =
1
3/1). H NMR (400 MHz, CDCl3) δ 8.11 – 8.06 (m, 2H), 7.88 (d, J = 3.7 Hz, 1H),
7.84 – 7.81 (m, 1H), 7.75 (dd, J = 7.7, 0.9 Hz, 1H), 7.71 (dd, J = 7.7, 0.9 Hz, 1H),
7.43 (tt, J = 7.7, 0.6 Hz, 1H), 6.78 (dd, J = 3.7 Hz, 1H), 5.17 (s, 1H), 3.26 (s, 3H),
2.68 (t, J = 0.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 197.0, 166.9, 164.6,
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140.2, 136.7, 132.0, 131.7, 131.7, 129.9, 129.9, 128.7, 127.3, 124.6, 124.4, 124.0,
122.7, 109.9, 77.1, 62.0, 52.8, 26.8. HRMS (ESI) m/z: [M+Na]+ Calcd for
C20H15NO4Na, 356.0893; found, 356.0888. It was crystallized from
cyclohexane/dichloromethane.
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Dimethyl 4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5,7-dicarboxylate
o
(4r): 94 mg (90%); white solid, mp 170-171 C; Purification (Petroleum ether/ethyl
1
acetate = 4/1). H NMR (400 MHz, CDCl3) δ 8.18 – 8.13 (m, 2H), 7.88 (d, J = 3.7 Hz,
1H), 7.79 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 7.7, 0.9 Hz, 1H), 7.68 (dd, J = 7.7, 0.9 Hz,
1H), 7.41 (td, J = 7.7, 0.7 Hz, 1H), 6.77 (dd, J = 3.7, 0.7 Hz, 1H), 5.16 (s, 1H), 3.96 (d,
J = 0.7 Hz, 3H), 3.24 (s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 166.2, 164.5,
139.9, 132.8, 131.9, 131.6, 129.9, 129.8, 129.6, 129.6, 127.2, 124.5, 124.3, 123.9,
122.5, 109.7, 61.8, 52.7, 52.3. HRMS (ESI) m/z: [M+Na]+ Calcd for C20H15NO5Na,
372.0842; found, 372.0842. It was crystallized from cyclohexane/dichloromethane.
Methyl
4-oxo-7-(trifluoromethyl)-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylat
e (4s): 83 mg (77%); white solid, mp 149-151 oC; Purification (Petroleum ether/ethyl
1
acetate = 10/1). H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 3.7 Hz, 1H), 7.86 (d, J =
8.1 Hz, 1H), 7.79 – 7.70 (m, 4H), 7.44 (t, J = 7.7 Hz, 1H), 6.79 (d, J = 3.7 Hz, 1H),
13
5.13 (s, 1H), 3.27 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 166.6, 164.3, 139.2,
132.0, 131.7, 130.5 (q, J = 33.0 Hz), 130.3, 130.0, 128.4 (q, J = 3.0 Hz), 127.3, 126.5
(q, J = 271 Hz), 125.7 (q, J = 4.0 Hz), 124.4, 124.3, 123.9, 122.6, 109.9, 61.8, 52.8.
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19F NMR (376 MHz, CDCl3) δ-62.4 (s, 3F). HRMS (ESI) m/z: [M+Na]+ Calcd for
C19H12F3NO3Na, 382.0661; found, 382.0661. It was crystallized from
cyclohexane/dichloromethane.
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Methyl
7-nitro-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4t): 57
o
mg (56%); white solid, mp 177-178 C; Purification (Petroleum ether/ethyl acetate =
1
5/1). H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 2.4 Hz, 1H), 8.35 (dd, J = 8.6, 2.4 Hz,
1H), 7.92 – 7.87 (m, 2H), 7.76 (d, J = 7.7 Hz, 2H), 7.46 (dd, J = 8.0, 7.5 Hz, 1H), 6.81
(d, J = 3.7 Hz, 1H), 5.20 (s, 1H), 3.28 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ
13
166.2, 163.8, 147.3, 142.1, 132.2, 131.6, 130.6, 130.5, 127.5, 126.6, 124.6, 124.3,
123.7, 123.6, 123.4, 110.0, 61.5, 53.0. HRMS (ESI) m/z: [M+Na]+ Calcd for
C18H12N2O5Na, 359.0638; found, 359.0637.
Methyl
4-oxo-4,5-dihydronaphtho[2',3':4,5]azepino[3,2,1-hi]indole-5-carboxylate (4u): 101
o
mg (98%); white solid, mp 169-170 C; Purification (Petroleum ether/ethyl acetate =
1
10/1). H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.01 – 7.85 (m, 5H), 7.67 (dd, J =
7.7, 1.0 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.44 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 3.7 Hz,
1H), 5.25 (s, 1H), 3.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 165.2,
133.3, 133.2, 132.8, 132.1, 131.9, 130.7, 129.2, 128.14, 128.07, 127.5, 127.14, 127.12,
126.9, 126.0, 124.4, 123.5, 121.5, 109.8, 62.4, 52.7. HRMS (ESI) m/z: [M+Na]+
Calcd for C22H15NO3Na, 364.0944; found, 364.0944. It was crystallized from
cyclohexane/dichloromethane.
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Methyl7-(1H-indol-7-yl)-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-
6
7
o
carboxylate (4v): 61mg (50%); white solid, mp 208-209 C; Purification (Petroleum
8
9
1
ether/ethyl acetate = 4/1). H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.90 (d, J = 3.8
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Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.81 – 7.75 (m, 3H), 7.69 (dq, J = 7.7, 1.3 Hz, 2H),
7.45 (t, J = 7.7 Hz, 1H), 7.31 – 7.22 (m, 3H), 6.80 (d, J = 3.7 Hz, 1H), 6.66 (dd, J =
3.2, 2.0 Hz, 1H), 5.14 (s, 1H), 3.29 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.2,
164.9, 139.8, 134.6, 133.6, 131.9, 131.6, 131.1, 130.3, 130.3, 128.8, 128.5, 127.2,
125.3, 124.6, 124.4, 124.0, 123.5, 122.0, 121.7, 120.6, 120.4, 109.9, 103.2, 62.1, 52.8.
HRMS (ESI) m/z: [M+Na]+ Calcd for C26H18N2O3Na, 429.1210; found, 429.1202.
Methyl
7-hydroxy-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate
o
(4w):17 mg (18%); white solid, mp 124-125 C; Purification (Petroleum ether/ethyl
1
acetate = 2/1). H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 3.7 Hz, 1H), 7.65 (dd, J =
7.8, 1.0 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.38 (t, J = 7.7 Hz, 1H), 6.99 (dd, J = 8.5, 2.6
Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 6.76 (d, J = 3.7 Hz, 1H), 5.84 (s, 1H), 4.96 (s, 1H),
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3.28 (s, 3H). C{1H} NMR (100 MHz, CDCl3) δ 167.3, 165.0, 156.4, 131.7, 131.3,
131.1, 130.8, 128.2, 127.0, 125.5, 124.3, 123.1, 120.9, 118.0, 116.6, 110.0, 61.8, 52.8.
HRMS (ESI) m/z: [M+Na]+ Calcd for C18H13NO4Na, 330.0737; found, 330.0731.
Ethyl 4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate (4x):
51 mg (55%); white solid, mp 119-120 oC; Purification (Petroleum ether/ethyl acetate
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= 10/1). H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 3.7 Hz, 1H), 7.75 – 7.71 (m, 2H),
7.65 (dd, J = 7.7, 1.1 Hz, 1H), 7.55 – 7.46 (m, 3H), 7.40 (t, J = 7.7 Hz, 1H), 6.77 (d, J
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= 3.7 Hz, 1H), 5.05 (s, 1H), 3.82 – 3.74 (m, 1H), 3.72 – 3.64 (m, 1H), 0.60 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.7, 165.3, 135.6, 131.9, 131.7, 131.6,
129.9, 129.5, 129.0, 128.6, 127.2, 125.9, 124.2, 123.6, 121.5, 109.6, 62.3, 61.7, 13.4.
HRMS (ESI) m/z: [M+Na]+ Calcd for C19H15NO3Na, 328.0944; found, 328.0944. It
was crystallized from cyclohexane/dichloromethane.
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Diisopropyl 2-(2-(1H-indol-7-yl)phenyl)malonate (3y): 114 mg (100%); white
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solid, mp 84-85 oC; Purification (Petroleum ether/ethyl acetate = 10/1). H NMR (400
MHz, CDCl3) δ 8.37 (s, 1H), 7.72 – 7.65 (m, 2H), 7.50 (td, J = 7.5, 1.8 Hz, 1H), 7.45
(td, J = 7.4, 1.5 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.21 (dd, J = 8.0, 7.2 Hz, 1H), 7.17 (dd,
J = 3.2, 2.5 Hz, 1H), 7.08 (dd, J = 7.2, 1.1 Hz, 1H), 6.62 (dd, J = 3.2, 2.0 Hz, 1H),
5.07 – 4.94 (m, 2H), 4.62 (s, 1H), 1.24 (dd, J = 6.3, 4.3 Hz, 6H), 1.18 (d, J = 6.3 Hz,
3H), 1.11 (d, J = 6.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.0, 167.8,
139.0, 134.6, 132.2, 130.7, 129.4, 128.3, 127.8, 124.5, 123.7, 123.0, 120.2, 119.9,
102.7, 69.6, 69.2, 54.7, 21.5. HRMS (ESI) m/z: [M+Na]+Calcd for C23H25NO4Na,
402.1676; found, 402.1676.
Procedure
for
Synthesis
of
Isopropyl
(4y):
4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate
Compound 3y (0.3 mmol) and KOH (0.09 mmol, 30 mol%) were added in an
oven-dried sealing tube, then CH2Cl2 was added. The reaction mixture was stirred at
room temperature for 2 h and then filtered through a plug of silica and washed with
EtOAc. The filtrate was concentrated under vacuum and purified by flash column
chromatography (petroleum ether/EtOAc = 2/1) to give product 4y as a white solid.
Isopropyl
4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]indole-5-carboxylate
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(4y): 48 mg (50%); white solid, mp 135-136 C; Purification (Petroleum ether/ethyl
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acetate = 10/1). H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 3.2 Hz, 1H), 7.76 – 7.69
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(m, 2H), 7.64 (d, J = 7.4 Hz, 1H), 7.55 – 7.45 (m, 3H), 7.39 (td, J = 7.7, 2.2 Hz, 1H),
6.76 (t, J = 3.1 Hz, 1H), 5.02 (s, 1H), 4.59 – 4.49 (m, 1H), 0.87 (dd, J = 6.1, 2.2 Hz,
3H), 0.43 (dd, J = 6.1, 2.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 165.5,
135.6, 132.0, 131.7, 131.7, 130.2, 129.5, 128.9, 128.6, 127.3, 126.0, 124.2, 123.6,
121.4, 109.5, 105.0, 69.6, 62.5, 21.1, 20.6. HRMS (ESI) m/z: [M+Na]+ Calcd for
C20H17NO3Na, 342.1101; found, 342.1110.
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Competition Experiments Between 1j and 1t: The reaction of
7-(4-methoxyphenyl)-1H-indole 1j (22.3 mg, 0.1 mmol), 7-(nitrophenyl)-1H-indole
1t (23.8 mg, 0.1 mmol) was run following the general procedure. After 12 h, the
reaction mixture was subjected to silica gel column chromatography [eluting with
petroleum ether/ethyl acetate=10:1] to provide the product including 4j (24.3 mg,
75.8% yield) and 4t (8.1 mg, 24.2% yield).
Experiments for intermolecular kinetic isotope effects: The reaction of
7-phenyl-1H-indole 1a (19.3 mg, 0.1 mmol), D5-7-phenyl-1H-indole 1a-D5 (19.8
mg, 0.1 mmol) was run for 2 h following the general procedure. After the reaction the
crude reaction mixture was subjected to silica gel column chromatography [eluting
with petroleum ether/ethyl acetate=10:1] to provide the product including 4a and
1
4a-D4 (16.8 mg, ~28% yield). This mixture was analyzed by H NMR to give the
relative ration of two isomers.
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4a-D4: H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 3.7 Hz, 1H), 7.73 (d, J = 7.8
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Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.41 (td, J = 7.8, 0.5 Hz, 1H), 6.77 (d, J = 3.7 Hz,
1H), 5.08 (s, 1H), 3.26 (s, 3H).
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Procedure for Synthesis of Benzo[4,5]azepino[3,2,1-hi]indol-4(5H)-one (5a):
Compound 4a (291.4 mg, 1 mmol) was dissolved in aqueous KOH (5%, 10 mL),and
the mixture was stirred at 20 °C for 2 h. HCl (10%) was then added dropwise at 0 °C
until pH 2.5 was reached. The resulting mixture was heated at 70 °C for 2 h, basified
with NH4OH (1 mL) and extracted with CH2Cl2 (30 mL). The combined organic
layers were filtered, and the solvents were evaporated in vacuum to yield an oily
residue that was purified by flash-chromatograph on silica gel [PE/EA (10:1-20:1)].
This afforded benzo[4,5]azepino[3,2,1-hi]indol-4(5H)-one 5a 140 mg, 0.61 mmol,
60% yield.
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Benzo[4,5]azepino[3,2,1-hi]indol-4(5H)-one (5a): 140 mg (60%); white oil;
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Purification (Petroleum ether/ethyl acetate = 15/1). H NMR (400 MHz, CDCl3) δ
7.83 (d, J = 3.7 Hz, 1H), 7.76 (dd, 1H), 7.70 – 7.66 (m, 2H), 7.47 – 7.41 (m, 4H), 6.73
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(d, J = 3.8 Hz, 1H), 3.93 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 168.0, 135.9,
132.7, 132.1, 130.3, 130.1, 128.9, 128.5, 128.0, 126.3, 126.2, 123.9, 123.5, 121.3,
109.0, 45.5. HRMS (ESI) m/z: [M+H]+ Calcd for C16H12NO, 234.0913; found,
234.0926.
Procedure
for
Synthesis
of
(E)-Methyl
1-(3-ethoxy-3-oxoprop-1-en-1-yl)-4-oxo-4,5-dihydrobenzo[4,5]azepino[3,2,1-hi]in
dole-5-carboxylate (6a): Under argon atmosphere, 4a (0.3 mmol), ethyl acrylate
(0.36 mmol, 1.2 equiv.), Pd(OAc)2 (3.4 mg, 0.015 mmol, 5 mol%), AgOAc (100 mg,
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