Construction of Benzo[c]carbazoles and Their Antitumor Derivatives through the Diels-Alder Reaction of 2-Alkenylindoles and Arynes

Article abstract of DOI:10.1021/acs.joc.5b01223

The direct assembly of benzo[c]carbazole derivatives via the Diels-Alder reaction of arynes and easily accessible 2-alkenylidoles was reported. By employing different aryne precursor loads, 6,7-dihydrobenzo[c]carbazoles or aryl-substituted 7,11b-dihydrobenzo[c]carbazoles could be controllably generated in good to excellent yields under a nitrogen atmosphere. On the other hand, when the reaction was conducted under oxygen, oxidated/aromatized product benzo[c]carbazoles could be generated directly with high selectivity and efficiency in a one-step manner. Interestingly, the benzo[c]carbazole-5-carboxamide amidation derivatives of the above products showed good antitumor activities. The inhibitory effect of these molecules against cancer cells was also described.

Full text of DOI:10.1021/acs.joc.5b01223

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Construction of Benzo[c]carbazoles and Their Anti-tumor
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Derivatives through the Diels-Alder Reaction of
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2-Alkenylindoles and Arynes
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Feng Sha,* Yuan Tao, ChenꢀYu Tang, Fei Zhang, and XinꢀYan Wu*
Key Lab for Advanced Materials and Institute of Fine Chemicals, East China University of
Science and Technology, Meilong Road 130, Shanghai, China
shaf@ecust.edu.cn;
xinyanwu@ecust.edu.cn
TOC Graphic
Abstract: The direct assembly of benzo[c]carbazole derivatives via the DielsꢀAlder
reaction of arynes and easily accessible 2ꢀalkenylidoles was reported. By employing
different aryne precursor load, 6,7ꢀdihydroꢀbenzo[c]carbazoles or aryl substituted
7,11bꢀdihydroꢀbenzo[c]carbazoles could be controllably generated in good to
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excellent yields under nitrogen atmosphere. On the other hand, when the reaction was
conducted under oxygen, oxidated/aromatized product benzo[c]carbazoles could be
generated directly with high selectivity and efficiency in one step manner.
Interestingly, the amidation derivatives benzo[c]carbazoleꢀ5ꢀcarboxamides of the
above products showed good antiꢀtumor activities. The inhibitory effect of these
molecules against cancer cells was also described.
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INTRODUCTION
The benzo[c]carbazole skeleton is a kind of privileged molecular scaffold of
pharmaceuticals and natural products, and also a pivotal building block in material
science.1,2 Therefore, much effort has been devoted to develop the synthetic methods
for the construction of benzo[c]carbazoles. However, most of the literature
approaches involve harsh reaction conditions and lengthy procedures or low yields.3
Thus, it is still of importance to develop direct and efficient routes to produce
benzo[c]carbazole derivatives under mild and efficient conditions.
Arynes are highly reactive intermediates in organic synthesis and have received
much attention during the past decades.4 Due to their highly electrophilic character,
arynes, in situ generated from 2ꢀ(trimethylsilyl)aryl triflates, have been widely applied
in various procedures to afford aromatic compounds.5 Especially, DielsꢀAlder
reactions involving aryne6 can lead to a variety of promising natural products and
useful material skeletons. Recently, Jia and coꢀworkers reported the DielsꢀAlder
reaction of aryne with 3ꢀmethyleneindolinꢀ2ꢀone as the diene to
furnishnaphtho[3,2,1ꢀcd]indolꢀ5(4H)ꢀone (eq. 1, Scheme 1).7 Very recently, our group
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introduced vinyl indoles as dienes to react with arynes, and the reaction was
successfully disclosed to generate useful benzo[a]carbazole derivatives in
goodꢀtoꢀexcellent yields (eq. 2).8 On the basis of our previous study on arynes,9 herein
we wish to describe the direct and concise synthesis of benzo[c]carbazoles through
the DielsꢀAlder reaction of 2ꢀalkenylindoles and arynes as the ongoing research (eq.
3).
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Scheme 1. Diels-Alder Reactions Involving Aryne
RESULTS AND DISCUSSION
Initially, the reaction of ethyl (E)ꢀ3ꢀ(1ꢀmethylꢀ1Hꢀindolꢀ2ꢀyl)acrylate (1a) with
2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) was carried out in the
presence of TBAF in THF at room temperature under nitrogen atmosphere. However,
neither desired [4+2] adduct 7,11bꢀdihydroꢀ5Hꢀbenzo[c]carbazoleꢀ5ꢀcarboxylate A
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nor its rearrangement product 4a was observed (Table 1, entry 1). Instead, product 3a,
the adduct of intermediate A and another molecular of aryne, was isolated in 37%
yield. When the reaction was conducted in the presence of KF/18ꢀcrownꢀ6, the yield
of 3a was greatly increased to 64%, accompanied by a trace amount of 4a isolated
(entry 2). With the utilization of 3.0 equiv of 2a, up to 95% of 3a could be obtained
(entry 3). By changing the fluoride source to CsF, the yield of 4a was enhanced to 20%
(entry 4). To our pleasure, with MeCN as solvent, the yield of 4a was dramatically
increased to 73% (entry 5). Enhancement of the reaction temperature to 60 oC led to a
higher yield of 4a (76% vs 73%, compare entry 6 with 5). Furthermore, toluene was
added to slow down the generation rate of benzyne (Table 1, entries 7ꢀ12).10 It is
demonstrated that when the reaction was conducted in MeCN and toluene (v/v 1:4) at
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o
80 C, the yield of 4a could be further improved to 92% (entry 9). Moreover, trials
were conducted with the enhancement or reduction of the benzyne precursor (entries
11ꢀ13). It appeared that employment of 1.5 equiv of benzyne precursor resulted in 4a
in a higher yield. Thus, the optimal reaction conditions for the synthesis of 3a and 4a
are settled as that described in entries 3 and 9, respectively.
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Table 1. Optimization of the Reaction Conditionsa
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Solvent
Yield
of 3a
(%)b
37
Yield
of 4a
(%)b
ꢀꢀ
1a/2a
Temp
Entry
Fꢀ source
(MeCN/toluene)
(v/v)
THF
THF
THF
THF
MeCN
MeCN
1/2
(mol)
(oC)
1
2
TABF
KF/18ꢀCꢀ6
KF/18-C-6
CsF
1:1.5
1:1.5
1:3
rt
rt
64
trace
--
3
rt
95
4
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.3
1:1.7
1:2
rt
5
20
5
CsF
rt
12
73
6
CsF
60
60
80
80
80
80
80
80
14
76
7
CsF
trace
ꢀꢀ
84
8
CsF
1/2
86
9
CsF
1/4
--
92
10
11
12
13
CsF
1/6
ꢀꢀ
53
CsF
1/4
ꢀꢀ
88
CsF
1/4
19
73
CsF
1/4
31
55
Reaction conditions: 1.0 equiv of 1a (0.3 mmol), 1.2ꢀ1.7 equiv of 2a, 2.0 equiv of Fꢀ source
a
based on 2a and 3.0 mL of solvent. b Isolated yield based on 1a.
With the optimized conditions in hand, we then focused on the application scope
of the reaction furnishing product 3. As shown in Table 2, with the utilization of 5ꢀ, 6ꢀ
or 7ꢀsubstituted 1, reactions all proceeded smoothly and generated corresponding
substituted 7,11bꢀdihydroꢀ5Hꢀbenzo[c]carbazoles 3aꢀf in goodꢀtoꢀexcellent yields.
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When substrate 1 with chloroꢀsubstituted 1 was applied, the yields of 3d and 3e were
slightly decreased. Moreover, 1 with acryl substituent as electronꢀwithdrawing group
furnished corresponding product 3g in good yield. Benzyl group could also be applied
as the Nꢀprotecting group, and 89% yield of product 3h was obtained. In addition, the
NOESY study of compound 3g has been investigated, which demonstrated the cisꢀ
configuration of product 3g (Table 2).
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Table 2. Reaction of Substrates 1 with Benzyne Precursor 2a to Afford 3a,b
R2
R2
TMS
KF, 18-C-6
THF, rt
R1
R1
+
N
R3
N
R3
OTf
2a
1
3
CO2Et
CO2Et
CO2Et
Me
MeO
N
Me
N
Me
N
Me
3a (95%)
3b (94%)
3c (91%)
CO2Et
Cl
CO2Et
CO2Et
Cl
N
Me
N
Me
N
Me
Me
3d (75%)
3e (76%)
3f (92%)
NOE
O
H
H
CO2Et
Me
N
N
Me
Bn
3g (71%)
3h (89%)
a
Reaction conditions: 1.0 equiv of 1 (0.3 mmol), 3.0 equiv of 2a, 6.0 equiv of KF, 5.0 equiv of
18ꢀcrownꢀ6 in 3.0 mL of THF at room temperature. b Isolated yield of 3 based on 1.
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In addtion, we explored the substrate scope of this reaction with a series of
substituted indoleꢀ2ꢀacrylates 1 and aryne precursors 2 to afford product 4. As shown
in Table 3, various indoleꢀ2ꢀacrylates 1 bearing both electronꢀwithdrawing and
ꢀdonating substituents on C5ꢀC7 position were successfully applied to react with
2ꢀ(trimethylsilyl)phenyl triflate 2a, dihydrobenzo[c]carbazoles 4cꢀf were generated in
goodꢀtoꢀexcellent yields (80ꢀ93%, entries 3ꢀ6). It’s worth noting that the reaction of
ethyl (E)ꢀ3ꢀ(1,4ꢀdimethylꢀ1Hꢀindolꢀ2ꢀyl)acrylate (1b) with 2a led to product 4b in a
relatively lower yield (55%, entry 2), which may lie in the steric hindrance between
the C1ꢀH and the C11ꢀMe (Fig. 1). With the employment of different Nꢀprotecting
groups on 1, excellent yields were also observed (entries 7ꢀ8). Moreover, the
annulation reaction could also be successfully realized by introducing acetyl group
instead of ester moiety of 1i, and led to the corresponding product 4i in 71% yield
(entry 9). Other than ester or acryl substituents, a phenyl group could also be
introduced into (E)ꢀ1ꢀmethylꢀ2ꢀstyrylꢀ1Hꢀindole (1j). To our delight, the reaction was
conducted successfully and afforded the desired product 4j in 87% yield (entry 10). In
addition, other substituted symmetric arynes (derived from precursors 2b and 2c)
were also examined, with 4k and 4l furnished in good yields (entries 11ꢀ12).
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Table 3. Reaction of Substrates 1 with Aryne Precursors 2 to Afford 4a
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1
2
Product
(4)
4a
Entry
Yield (%)b
R1
R2
R3
R4
1
H
CO2Et
CO2Et
Me
Me
Me
Me
Me
Me
Ph
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
H
(2a)
2a
92
55
80
93
84
90
93
94
71c
87d
77e
73
2
4ꢀMe
4b
4c
3
5ꢀMeO CO2Et
2a
4
5ꢀCl
6ꢀCl
7ꢀMe
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
Ph
2a
4d
4e
5
2a
6
2a
4f
7
(1g)
2a
4g
8
H
Boc (1h)
2a
4h
4i
9
H
Me
Me
Me
Me
(1i)
(1j)
(1a)
(1a)
2a
10
11
H
2a
4j
H
CO2Et
CO2Et
Me
F
(2b)
(2c)
4k
4l
12
H
a
Reaction conditions: 1.0 equiv of 1 (0.3 mmol), 1.5 equiv of 2, 3.0 equiv of CsF in 0.6 mL of
MeCN and 2.4 mL of toluene at 80 oC under nitrogen atomosphere. b Isolated yields of 4 based on
1. c The reaction was conducted at 100 oC. d The reaction was conducted at 100 oC using 2.5 equiv
of 2 and 5.0 equiv of CsF. e The reaction was conducted with 2.0 equiv of 2, 4.0 equiv of CsF.
Moreover, regioselectivity of this DielsꢀAlder reaction was examined by
applying nonꢀsymmetric arynes. Reaction of 1a and orthoꢀmethylꢀsubstituted aryne
precursor 2d was carried out (eq. 4). As expected, a mixture of regioisomers 4ma11
and 4mb in a ratio of 79:21 was obtained (determined by 1H NMR analysis). Similar
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with the reaction of 1b with 2a (Fig. 1), steric hindrance among the C11ꢀH atom and
the methyl group of 4mb may affect the selectivity, with 4ma favored as the major
isomer. When the reaction was carried out by using bulkier tꢀbutyl benzyne (derived
from precursor 2e) and 1a, only the sole regioisomer 4n was isolated in 69% yield (eq.
5). Furthermore, introduction of orthoꢀmethoxy aryne (derived from precursor 2f)
afforded regioisomer 4o as the sole product in 83% yield (eq. 6). The structure of 4o
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was further confirmed by the Xꢀray diffraction analysis.
TMS
Me
Me
OTf
CO2Et
CO2Et
2d
Me
(4)
+
N
N
91%
Me
4mb
21
Me
4ma
79
:
TMS
OTf
2e
t-Bu
CO2Et
t-Bu
69%
CO2Et
N
(5)
Me
1a
N
Me
OMe
83%
4n
TMS
OMe
CO2Et
OTf
2f
(6)
N
Me
4o
Figure 1. Effect of Steric Hindrance
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Considering that benzo[c]carbazoles are an important structural motif in
medicinal and material science but rare in nature,12 we tried to approach the
benzo[c]carbazole skeleton via the oxidationꢀaromatization of 4. As shown in eq. 7,
benzo[c]carbazole 5a could be smoothly afforded in 98% yield from 4a in the
presence of Cs2CO3 under oxygen atmosphere.
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Inspired by the above result, we proposed to combine the DielsꢀAlder reaction
and oxidative transformation in one step to explore a direct strategy for the synthesis
of the useful benzo[c]carbazole skeleton. Therefore, the reaction of 1a and 2a was
o
carried out in the presence of CsF and Cs2CO3 in MeCN and toluene at 100 C under
oxygen for 36 h. To our great pleasure, benzo[c]carbazole 5a was furnished directly in
up to 95% yield (Table 4). Further examination demonstrated that substituents such as
halide, alkyl and alkoxyl group could be smoothly introduced, generating
corresponding products 5b-h in goodꢀtoꢀexcellent yields (72ꢀ92%). Notably, when the
reaction was conducted with difluorobenzyne (generated from 2c), desired product 5i
was obtained in a slightly lower yield (81%), which may attribute to the higher
reactivity of difluorobenzyne in side reactions.
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Table 4. Reaction of Indole-2-acrylates 1 with Aryne Precursors 2 to Afford 5a,b
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a Reaction conditions: 1.0 equiv of 1 (0.3 mmol), 1.5 equiv of 2, 3.0 equiv of CsF in 0.6 mL of
MeCN and 2.4 mL of toluene at 100 oC under O2 atmosphere. b Isolated yields of 5 based on 1.
7Hꢀbenzo[c]carbazole skeleton is of potential utility due to the facile further
transformation of the free NꢀH bond. Therefore, an acyl group was employed as the
Nꢀprotecting group instead of methyl or phenyl group for easier deacylation.
Interestingly, employment of 1h with the Nꢀtꢀbutoxycarbonyl group (NꢀBoc) 1h led to
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76% of 5ja in 36 h accompanied with 21% of deprotected product 6a, indicating a
high overall conversion rate (Scheme 2). When the reaction mixture of 1h and 2a was
treated with trifluoroacetic acid after 36 h, up to 96% yield of the product 6a could be
isolated. In addition, 5ꢀCl and 5ꢀBr substituents were also tolerated, affording 6b and
6c in high yields.
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Scheme 2. Synthesis of N-H Benzo[c]carbazoles 6
Notably, Nꢀ(2ꢀ(dimethylamino)ethyl)ꢀ11Hꢀbenzo[a]carbazoleꢀ5ꢀcarboxamide 8 can
serve as the antiꢀtumor agent, which inspired us to synthesize its isomer 7a starting
from 6a.13 As demonstrated in Scheme 3, a series of benzo[c]carbazole amides 7a-e
were obtained with the previous product 6. Pleasingly, benzo[c]carbazole amide 7
also revealed antiꢀtumor activity as demonstrated in Table 5.
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Scheme 3. Synthesis of Benzo[c]carbazole Amides 7
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The compounds 7a-e were evaluated against human lung cancer A549 cells and
human
colon
cancer
HCTꢀ116
cells
using
the
MTT
(3ꢀ(4,5)ꢀdimethylthiahiazo(ꢀzꢀy1)ꢀ3,5ꢀdiꢀphenytetrazoliumromide)
assay.14
Fortunately, most of the compounds exhibited comparable potency against HCTꢀ116
cell lines. First, we evaluated the effect on the inhibitory activity of substituent on the
8ꢀposition of the core structure among 7aꢀc. Compounds 7b and 7c with halogen atom
substituted were found to be more potent than 7a in both A549 and HCTꢀ116 cell lines
(Table 5, entries 1ꢀ3). Furthermore, basic side chain (BSC) at 5ꢀposition was replaced
with other amines (7d and 7e). Increasing the length of the BSC (7d) improved the
inhibitory activity of A549 slightly. The BSC with a piperidinꢀcycle (7e) is more
preferable than the ones bearing N,Nꢀdimethyl substituent in A549.
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Table 5. Structures and Growth Inhibitory Activity (IC50) of Compounds 7a-e
5
6
7
8
IC50 (ꢁM) a, b
7
Entry
R1
R2
A549
HCTꢀ116
36.4±1.7
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H (7a)
41.3±1.2
Cl (7b)
Br (7c)
H (7d)
H (7e)
32.2±1.1
30.1±0.8
34.3±1.7
27.3±1.5
34.3±1.5
36.1±1.3
39.2±2.1
35.7±1.8
a Exposure time: 72 h. b The average IC50 values were determined by MTT assay.
CONCLUSION
In summary, a novel and direct methodology for the construction of
benzo[c]carbazole skeleton has been realized via the DielsꢀAlder reaction of arynes
and 2ꢀalkenylindoles. With high selectivity, desired benzo[c]carbazole derivatives
were obtained in goodꢀtoꢀexcellent yields. By controlling the reaction conditions,
dihydrobenzo[c]carbazoles and benzo[c]carbazoles could be obtained effectively in a
oneꢀpot manner. On the other hand, benzo[c]carbazole amide derivative 7 was
synthesized, and exhibited comparable IC50 potency against both A549 and HCTꢀ116
cell lines. Due to the high formation efficiency of the carbazole skeletons and the
promising utilization of the benzo[c]carbazole derivative products, this methodology
may be of high interest to organic and pharmaceutical chemistry.
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General Information. Anhydrous solvents were distilled prior to use: THF, Et2O,
and toluene were distilled from sodiumꢀbenzophenone; MeCN was distilled from
P2O5; CH2Cl2 was distilled from CaH2. Petroleum ether refers to the fraction with
boiling point in the range of 60ꢀ90 °C. 1H NMR and 13C NMR spectra were measured
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on a 400 MHz spectrometer (1H 400 MHz, C 100 MHz), using CDCl3 or d6ꢀDMSO
as the solvent at room temperature. Chemical shifts are expressed in ppm and J values
are given in Hz. Melting points are uncorrected. High Resolution Mass Spectra
(HRMS) were recorded on an electron spray ionization timeꢀofꢀflight (ESIꢀTOF) mass
spectrometer. IR spectra were measured on
a
FTꢀIR spectrometer.
2ꢀ(Trimethylsilyl)aryl triflates 2 were prepared according to the known methods.15
General Procedure for the Preparation of 2-Alkenylindoles (1a-c, 1f, 1i, 1j).
To a solution of indole (1.76 g, 15 mmol) and potassium hydroxide (4.20 g, 75
mmol) in anhydrous DMF (50 mL) was added iodomethane (1.9 mL, 30 mmol). The
reaction mixture was stirred at room temperature for 20 min. The mixture was then
filtered through a plug of silica gel and H2O (200 mL) was added into the filtrate. The
water layer was extracted by CH2Cl2 (50 mL × 2). The organic layer was combined
and dried over Na2SO4. After filtration and evaporation, the residue was purified by
silica gel chromatography (petroleum ether/ethyl acetate 10:1) to afford
1ꢀmethylꢀ1Hꢀindole (1.93 g, 98%).
Under nitrogen atmosphere, to a solution of 1ꢀmethylꢀ1Hꢀindole (1.31 g, 10
mmol) in anhydrous ether (15 mL) was added nꢀBuLi (1.2 M, 10.1 mL, 12 mmol)
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dropwisely at room temperature. The mixture was heated to reflux for 3 h followed by
the addition of DMF (3.0 mL, 15 mmol) dropwise. The mixture was then reflux for 5
h monitored by TLC and quenched by saturated solution of NH4Cl at room
temperature. The water layer was then extracted by ethyl acetate (30 mL × 3). The
organic layer was combined and dried over Na2SO4. After filtration and evaporation,
the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate
20:1) to afford 1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde (1.24 g, 78%).
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To a solution of 1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde (0.80 g, 5.0 mmol) in
anhydrous EtOH (40 mL) was added phosphorus ylide (1.92 g, 5.5 mmol) in one
portion and the reaction mixture was stirred at room temperature monitored by TLC.
The mixture was then concentrated under reduced pressure, and the residue was
purified by silica gel chromatography (petroleum ether/ethyl acetate 15:1) to give
compound 1a (0.75 g, 65%).
(E)-Ethyl 3-(1-methyl-1H-indol-2-yl)acrylate (1a). Yellow solid, mp 89ꢀ90 oC;
1H NMR(CDCl3, 400MHz): δ 7.80 (d, J = 15.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.32
(d, J = 8.4 Hz, 1H), 7.29ꢀ7.25 (m, 1H), 7.14ꢀ7.10 (m, 1H), 6.96 (s, 1H), 6.49 (d, J =
15.6 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 3.83 (s, 3H), 1.36 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 167.0, 138.9, 134.8, 132.6, 127.3, 123.5, 121.3, 120.4,
118.1, 109.6, 103.6, 60.5, 29.9, 14.3; IR (neat): 2992, 2938, 1709, 1462, 1402, 1178,
960, 771, 751 cmꢀ1; HRMS (EI) calcd for C14H15NO2 229.1103, found 229.1106.
(E)-Ethyl 3-(1,4-dimethyl-1H-indol-2-yl)acrylate (1b). 64% yield (0.70 g),
yellow solid, mp 105ꢀ106 oC; 1H NMR(CDCl3, 400MHz): δ 7.78 (d, J = 15.6 Hz, 1H),
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7.18ꢀ7.11 (m, 2H), 6.97 (s, 1H), 6.90 (d, J = 6.4 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H),
4.30ꢀ4.25 (m, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 1.35 (td, J1 = 2.0 Hz, J2 = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 167.1, 138.8, 134.3, 132.6, 130.9, 127.4, 123.7, 120.4,
117.7, 107.2, 102.3, 60.5, 30.1, 18.5, 14.3; IR (neat): 2988, 2938, 1709, 1635, 1354,
1304, 1167, 968, 759 cmꢀ1; HRMS (EI) calcd for C15H17NO2 243.1259, found
243.1260.
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(E)-Ethyl 3-(5-methoxy-1-methyl-1H-indol-2-yl)acrylate (1c). 68% yield
(0.70 g), yellow solid, mp 121ꢀ122 oC; 1H NMR(CDCl3, 400MHz): δ 7.75 (d, J = 16.0
Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.92 (dd, J1 = 2.4 Hz, J2 =
9.2 Hz, 1H), 6.86 (s, 1H), 6.44 (d, J = 15.2 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.83 (s,
3H), 3.77 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 167.1,
154.5, 135.1, 134.5, 132.5, 127.6, 117.6, 114.7, 110.4, 103.0, 101.6, 60.5, 55.6, 30.1,
14.3; IR (neat): 3005, 2951, 1699, 1634, 1300, 1166, 1026, 839, 798 cmꢀ1; HRMS (EI)
calcd for C15H17NO3 259.1208, found 259.1201.
(E)-Ethyl 3-(1,7-dimethyl-1H-indol-2-yl)acrylate (1f). 67% yield (0.74 g),
o
1
yellow solid, mp 72ꢀ73 C; H NMR(CDCl3, 400MHz): δ 7.74 (d, J = 15.6 Hz, 1H),
7.40 (d, J = 7.6 Hz, 1H), 6.97ꢀ6.90 (m ,2H), 6.88 (s, 1H), 6.42 (d, J = 15.6 Hz, 1H),
4.27 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 2.71 (s, 3H), 1.34 (td, J1 = 1.6 Hz, J2 = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 167.0, 138.0, 135.4, 132.7, 128.2, 126.5, 121.2,
120.4, 119.4, 118.2, 104.1, 60.4, 32.8, 20.4, 14.3; IR (neat): 2976, 2926, 1705, 1627,
1445, 1279, 1178, 1156, 1037, 743 cmꢀ1; HRMS (EI) calcd for C15H17NO2 243.1259,
found 243.1262.
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(E)-4-(1-Methyl-1H-indol-2-yl)but-3-en-2-one (1i). 50% yield (0.50 g), yellow
solid, mp 109ꢀ110 oC; 1H NMR(CDCl3, 400MHz): δ 7.66ꢀ7.60 (m, 2H), 7.32ꢀ7.25 (m,
2H), 7.12 (t, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.80 (d, J = 16.0 Hz, 1H), 3.82 (s, 3H),
2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.4, 139.4, 134.9, 130.9, 127.4, 126.3,
123.9, 121.5, 120.5, 109.6, 104.2, 30.0, 28.3; IR (neat): 3054, 2926, 1661, 1594, 1348,
1250, 967, 747, 729 cmꢀ1; HRMS (EI) calcd for C13H13NO 199.0997, found 199.0999.
NaH in mineral oil (200.0 mg, 60%, 5.0 mmol) was added to the suspension of
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BnPh3PCl (1.94 g, 5.0 mmol) in toluene (10 mL) at 0 C. The mixture was stirred at
room
temperature
for
30
min
followed
by
the
addition
of
1ꢀmethylꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde (0.67 g, 4.2 mmol) in toluene (3 mL). Then the
o
mixture was heated to 80 C for 2 h monitored by TLC and quenched by saturated
solution of NH4Cl at room temperature. The water layer was then extracted by ethyl
acetate (30 mL × 3). The organic layer was combined and dried over Na2SO4. After
filtration and evaporation, the residue was purified by silica gel chromatography
(petroleum ether/ethyl acetate 10:1) to afford (E)ꢀ1ꢀmethylꢀ2ꢀstyrylꢀ1Hꢀindole (1j,
o
0.55 g, 56% yield). Yellow solid, mp 112ꢀ113 C; 1H NMR(CDCl3, 400MHz): δ 7.59
(d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.31ꢀ7.28
(m ,2H), 7.21 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 2.8 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H),
6.81 (s, 1H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 138.4, 138.1, 137.2, 130.9,
128.8, 128.0, 127.8, 126.4, 121.8, 120.4, 119.9, 117.1, 109.1, 99.0, 29.9; IR (neat):
2921, 2847, 1594, 1463, 1396, 1346, 1319, 957, 748,690 cmꢀ1; HRMS (EI) calcd for
C17H15N 233.1204, found 233.1209.
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General Procedure for the Preparation of 2-Alkenylindoles (1g, 1h, 1d, 1e,
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1k).
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To a solution of ethyl 1Hꢀindoleꢀ2ꢀcarboxylate (3.78 g, 20 mmol) in THF (20 mL)
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was added dropwise to a suspension of LiAlH4 (2.27 g, 60 mmol) in THF (20 mL) at
o
0 °C under nitrogen atmosphere. The solution was stirred for 30 min at 0 C and
quenched by H2O carefully. The solution was then diluted with dichloromethane (40
mL) and the layers were separated. The water layer was extracted with
dichloromethane (2 × 20 mL). The organic layer was combined and dried over
Na2SO4. After filtration and evaporation, the residue was purified by silica gel
chromatography (petroleum ether/ethyl acetate 2:1) to afford (1Hꢀindolꢀ2ꢀyl)methanol
(2.10 g, 71% yield).
To a solution of (1Hꢀindolꢀ2ꢀyl)methanol (1.47 g, 10 mmol) in MeCN (20 mL)
was added acetic acid (0.69 mL, 12 mmol) and IBX (3.38 g, 12 mmol). The reaction
mixture was stirred at room temperature monitored by TLC. After filtration and
evaporation, the residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate 20:1) to afford 1Hꢀindoleꢀ2ꢀcarbaldehyde (1.23 g, 85% yield).
To a solution of 1Hꢀindoleꢀ2ꢀcarbaldehyde (0.73 g, 5.0 mmol) in anhydrous
EtOH (40 mL) was added phosphorus ylide (1.92 g, 5.5 mmol) in one portion and the
reaction mixture was stirred at room temperature monitored by TLC. The mixture was
then concentrated under reduced pressure, and the residue was purified by silica gel
chromatography (petroleum ether/ethyl acetate 15:1) to give compound (E)ꢀethyl
3ꢀ(1Hꢀindolꢀ2ꢀyl)acrylate (0.65 g, 60% yield).
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Under nitrogen atmosphere, compound (E)ꢀethyl 3ꢀ(1Hꢀindolꢀ2ꢀyl)acrylate (1.08
g, 5.0 mmol), Iodobenzene (1.22 g, 6.0 mmol), CuI (47.6 mg, 0.25 mmol), K3PO4
(2.20 g, 10 mmol) and cyclohexaneꢀ1,2ꢀdiamine (121 ꢁL, 1.0 mmol) were added to a
Schlenk tube equipped with a stir bar. Then 10 mL toluene was added. The reaction
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mixture was stirred at 90 C for 24 h. The mixture was then cooled to ambient
temperature, diluted with CH2Cl2 (10 mL), filtered through a plug of silica gel, eluting
with additional CH2Cl2 (50 mL). The filtrate was concentrated and the resulting
residue was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate 20:1) to provide (E)ꢀethyl 3ꢀ(1ꢀphenylꢀ1Hꢀindolꢀ2ꢀyl)acrylate (1g, 1.06 g, 73%
yield). Yellow solid, mp 69ꢀ70 C; 1H NMR(CDCl3, 400MHz): δ 7.66 (d, J = 7.2 Hz,
o
1H), 7.57ꢀ7.46 (m, 4H), 7.34 (d, J = 7.2 Hz, 2H), 7.21ꢀ7.13 (m, 3H), 7.09 (s, 1H),
6.27 (d, J = 16.0 Hz, 1H), 4.19 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 166.9, 139.7, 136.9, 135.3, 133.4, 129.7, 128.4, 128.2, 127.5,
124.0, 121.3, 121.1, 118.1, 110.7, 105.1, 60.4, 14.2; IR (neat): 3054, 2980, 1707, 1629,
1500, 1341, 1269, 1166, 1037, 977, 749 cmꢀ1; HRMS (EI) calcd for C19H17NO2
291.1259, found 291.1257.
To a solution of (E)ꢀethyl 3ꢀ(1Hꢀindolꢀ2ꢀyl)acrylate (1.08 g, 5.0 mmol) in DCM
(50 mL) was added DMAP (60.9 mg, 0.5 mmol) and triethylamine (0.9 mL, 6.5
mmol). Then (Boc)2O (1.41 g, 6.5 mmol) was added. The reaction mixture was stirred
at room temperature monitored by TLC and quenched by saturated solution of NH4Cl.
The water layer was then extracted by ethyl acetate (30 mL × 3). The organic layer
was combined and dried over Na2SO4. After filtration and evaporation, the residue
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was purified by silica gel chromatography (petroleum ether/ethyl acetate 10:1) to
afford (E)ꢀtertꢀbutyl 2ꢀ(3ꢀethoxyꢀ3ꢀoxopropꢀ1ꢀenꢀ1ꢀyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (1h,
1.40 g, 89% yield). White solid, mp 85ꢀ86 oC; 1H NMR(CDCl3, 400MHz): δ 8.26 (d,
J = 16.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 8.0
Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 6.94 (s, 1H), 6.36 (d, J = 15.6 Hz, 1H), 4.27 (q, J =
7.2 Hz, 2H), 1.70 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
166.6, 150.0, 137.6, 136.4, 136.0, 128.6, 125.6, 123.3, 121.1, 119.2, 115.8, 110.1,
84.8, 60.5, 28.2, 14.3; IR (neat): 2980, 2938, 1735, 1712, 1626, 1371, 1328, 1161,
1093, 747 cmꢀ1; HRMS (EI) calcd for C18H21NO4 315.1471, found 315.1478.
According to the above reported methylation procedure to furnish
1ꢀmethylꢀ1Hꢀindole, 2ꢀvinylindoles 1d, 1e and 1k could be prepared from substituted
(E)ꢀethyl 3ꢀ(1Hꢀindolꢀ2ꢀyl)acrylate.
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(E)-Ethyl 3-(5-chloro-1-methyl-1H-indol-2-yl)acrylate (1d). 99% yield (0.65
o
1
g), yellow solid, mp 71ꢀ72 C; H NMR(CDCl3, 400MHz): δ 7.73 (d, J = 16.0 Hz,
1H), 7.55 (s, 1H), 7.22ꢀ7.17 (m, 2H), 6.85 (s, 1H), 4.48 (d, J = 16.0 Hz, 1H), 4.28 (q,
J = 7.2 Hz, 2H), 3.78 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 166.8, 137.2, 136.1, 132.0, 128.2, 126.0, 123.8, 120.4, 119.2, 110.6, 102.7, 60.7,
30.2, 14.3; IR (neat): 2976, 2930, 1706, 1632, 1467, 1306, 1285, 1180, 968, 789 cmꢀ1;
HRMS (EI) calcd for C14H1435ClNO2 263.0713, found 263.0710.
(E)-Ethyl 3-(6-chloro-1-methyl-1H-indol-2-yl)acrylate (1e). 99% yield (0.73
o
g), yellow solid, mp 109ꢀ110 C; 1H NMR(CDCl3, 400MHz): δ 7.71 (d, J = 15.6 Hz,
1H), 7.47 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 2.0
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Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.73ꢀ3.72 (m, 3H), 1.35
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.8, 139.2, 135.6, 132.0, 129.4,
125.8, 122.1, 121.2, 118.7, 109.5, 103.5, 60.6, 30.1, 14.3; IR (neat): 2976, 2930, 1704,
1632, 1461, 1348, 1305, 1280, 1179, 970, 808 cmꢀ1; HRMS (EI) calcd for
C14H1435ClNO2 263.0713, found 263.0708.
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(E)-Ethyl 3-(5-bromo-1-methyl-1H-indol-2-yl)acrylate (1k). 99% yield (0.69
o
g), yellow solid, mp 82ꢀ83 C; 1H NMR(CDCl3, 400MHz): δ 7.78ꢀ7.72 (m, 2H), 7.33
(dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 6.87 (s, 1H), 6.49 (d, J =
16.0 Hz, 1H), 4.29 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 166.8, 137.5, 136.0, 132.1, 128.9, 126.3, 123.6, 119.4,
113.6, 111.1, 102.6, 60.7, 30.2, 14.3; IR (neat): 2976, 2930, 1706, 1632, 1465, 1284,
1180, 1050, 966, 788 cmꢀ1; HRMS calcd for C14H1579BrNO2 [M+H]+ : 308.0286,
found 308.0291.
General Procedure for the Synthesis of Products (3). Under the nitrogen
atmosphere, 2ꢀalkenylindole 1 (0.3 mmol), KF (104.6 mg, 1.8 mmol) and 18ꢀcrownꢀ6
(396.5 mg, 1.5 mmol) were added to a 25 mL Schlenk tube equipped with a stir bar.
Then 3.0 mL of THF and aryne precursor 2a (268.6 mg, 0.9 mmol) were added. The
reaction mixture was stirred at room temperature. When the reaction was complete as
monitored by TLC, the mixture was poured into water (10 mL), and the water layer
was extracted by CH2Cl2 (10 mL × 3). The organic layer was combined and dried over
Na2SO4. After evaporation, the residue was purified by silica gel chromatography
(petroleum ether/ethyl acetate 20:1) to afford 3a-h.
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Ethyl 7-methyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate
(3a). 95% yield (108.7 mg), white solid, mp 176ꢀ177 oC; 1H NMR (400 MHz, CDCl3):
δ 8.13ꢀ8.10 (m, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.38ꢀ7.32 (m, 2H), 7.26ꢀ7.23 (m, 2H),
7.19ꢀ7.13 (m, 4H), 7.07ꢀ6.99 (m, 3H), 4.97 (d, J =0.8 Hz, 1H), 4.11ꢀ4.04 (m, 1H),
4.00ꢀ3.93 (m, 2H), 3.60 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 172.5, 139.6, 138.7, 138.1, 133.4, 131.0, 128.8, 128.2, 127.9, 127.6, 127.1,
124.3, 124.3, 122.3, 121.4, 120.3, 120.0, 110.0, 109.5, 61.3, 54.4, 39.8, 29.4, 14.0; IR
(neat): ν 1724, 1602, 1471, 1377, 1241, 1198, 1080, 749, 702 cmꢀ1; HRMS calcd for
C26H24NO2 [M+H]+: 382.1807, found: 382.1810.
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7,10-dimethyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate (3b). 94%
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yield (111.2 mg), pale yellow solid, mp 210ꢀ211 C; H NMR (400 MHz, CDCl3): δ
7.95 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.37ꢀ7.32 (m, 1H), 7.22ꢀ7.10 (m, 5H),
7.09ꢀ6.97 (m, 4H), 4.95 (s, 1H), 4.09ꢀ4.02 (m, 1H), 3.99ꢀ3.92 (m, 2H), 3.49 (s, 3H),
2.53 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.6, 139.7,
138.7, 136.5, 133.6, 131.0, 129.6, 128.7, 128.1, 127.8, 127.6, 127.1, 124.4, 124.1,
122.8, 122.2, 119.9, 109.5, 109.2, 61.2, 54.4, 39.8, 29.4, 21.7, 14.0; IR (neat): ν 2980,
2922, 1724, 1594, 1545, 1481, 1242, 1162, 748 cmꢀ1; HRMS calcd for C27H26NO2
[M+H]+: 396.1964, found: 396.1964.
Ethyl
10-methoxy-7-methyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate
(3c). 91% yield (112.5 mg), white solid, mp 162ꢀ163 oC; 1H NMR (400 MHz, CDCl3):
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δ 7.90 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.38ꢀ7.33 (m, 1H), 7.22ꢀ7.12 (m, 5H),
7.05ꢀ6.98 (m, 3H), 6.92ꢀ6.88 (m, 1H), 4.94 (s, 1H), 4.12ꢀ4.03 (m, 1H), 4.00ꢀ3.93 (m,
5H), 3.55 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.5,
154.7, 139.6, 139.3, 133.5, 133.4, 131.1, 128.7, 128.1, 127.8, 127.6, 127.1, 124.5,
124.1, 121.9, 110.9, 110.1, 109.6, 102.8, 61.2, 56.1, 54.4, 39.8, 29.5, 13.9; IR (neat): ν
2934, 1724, 1602, 1480, 1233, 1159, 1030, 742 cmꢀ1; HRMS calcd for C27H25NO3Na
[M+Na]+: 434.1732, found: 434.1736.
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Ethyl
10-chloro-7-methyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate
(3d). 75% yield (93.6 mg), yellow solid, mp 230ꢀ231 oC; 1H NMR (400 MHz, CDCl3):
δ 8.06 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.38ꢀ7.33 (m, 1H), 7.23ꢀ7.13 (m,
6H), 7.07ꢀ7.03 (m, 1H), 7.00ꢀ6.97 (m, 2H), 4.93 (d, J = 0.8 Hz, 1H), 4.08ꢀ4.04 (m,
1H), 3.99ꢀ3.95 (m, 2H), 3.57 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 172.4, 140.0, 139.3, 136.5, 132.7, 131.1, 128.8, 128.3, 127.9, 127.5, 127.3,
126.1, 125.0, 124.7, 122.2, 121.5, 119.5, 110.4, 109.6, 61.3, 54.2, 39.8, 29.6, 13.9; IR
(neat): ν 2922, 1731, 1601, 1471, 1286, 1245, 1155, 1022, 805, 706 cmꢀ1; HRMS
calcd for C26H2235ClNO2Na [M+Na]+: 438.1237, found: 438.1241.
Ethyl
9-chloro-7-methyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate (3e).
76% yield (94.4 mg), pale yellow solid, mp 159ꢀ160 oC; 1H NMR (400 MHz, CDCl3):
δ 8.02ꢀ7.98 (m, 1H), 7.91ꢀ7.87 (m, 1H), 7.38ꢀ7.31 (m, 2H), 7.22ꢀ7.15 (m, 5H),
7.09ꢀ7.04 (m, 1H), 7.00ꢀ6.97 (m, 2H), 4.94 (d, J = 6.0 Hz, 1H), 4.12ꢀ4.05 (m, 1H),
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4.00ꢀ3.94 (m, 2H), 3.56 (d, J = 2.0 Hz, 3H), 1.13ꢀ1.07 (m, 3H); 13C NMR (100 MHz,
CDCl3): δ 172.4, 139.3, 139.3, 138.6, 132.8, 131.1, 128.9, 128.2, 127.9, 127.5, 127.4,
127.3, 124.7, 122.7, 122.3, 120.8, 110.1, 109.6, 61.3, 54.3, 39.7, 29.5, 14.0; IR (neat):
ν 1725, 1602, 1494, 1472, 1240, 1198, 1060, 948, 742 cmꢀ1; HRMS calcd for
C26H2235ClNO2Na [M+Na]+: 438.1237, found: 438.1234.
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Ethyl
7,8-dimethyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate (3f). 92%
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yield (109.0 mg), pale yellow solid, mp 197ꢀ198 C; H NMR (400 MHz, CDCl3): δ
8.00ꢀ7.94 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.20ꢀ7.07 (m, 5H), 7.05ꢀ6.98 (m, 3H),
6.93 (d, J = 6.8 Hz, 1H), 4.95 (s, 1H), 4.10ꢀ4.03 (m, 1H), 3.99ꢀ3.90 (m, 2H), 3.85 (s,
3H), 2.75 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.5,
139.5, 139.1, 137.0, 133.4, 131.0, 128.7, 128.1, 128.0, 127.7, 127.1, 125.1, 124.6,
124.2, 122.3, 121.4, 120.3, 118.1, 110.2, 61.2, 54.5, 39.8, 32.6, 20.5, 14.0; IR (neat): ν
2930, 1709, 1598, 1459, 1405, 1241, 1029, 742 cmꢀ1; HRMS calcd for C27H26NO2
[M+H]+: 396.1964, found: 396.1968.
1-(7-Methyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazol-5-yl)ethanone (3g).
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71% yield (74.9 mg), white solid, mp 204ꢀ205 C; H NMR (400 MHz, CDCl3): δ
8.12ꢀ8.08 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.34ꢀ7.31 (m,
1H), 7.27ꢀ7.23 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.14ꢀ7.05 (m, 4H), 6.97ꢀ6.94 (m,
2H), 5.03 (s, 1H), 3.79 (s, 1H), 3.59 (d, J = 0.8 Hz, 3H), 1.95 (d, J = 1.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 207.9, 139.7, 139.6, 138.1, 133.8, 131.0, 128.7, 128.4,
127.6, 127.0, 124.5, 124.1, 122.6, 121.5, 120.4, 119.9, 109.8, 109.6, 62.8, 38.8, 29.4,
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28.5; IR (neat): ν 3050, 2918, 1705, 1599, 1541, 1472, 1377, 750 cmꢀ1; HRMS calcd
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for C25H21NONa [M+Na]+: 374.1521, found: 374.1518.
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7-benzyl-6-phenyl-7,11b-dihydro-5H-benzo[c]carbazole-5-carboxylate
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(3h). 89% yield (122.4 mg), white solid, mp 132ꢀ133 oC; 1H NMR (400 MHz, CDCl3):
δ 8.16 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H), 7.40ꢀ7.35 (m, 1H), 7.26ꢀ7.18 (m,
7H), 7.12ꢀ7.00 (m, 6H),6.97ꢀ6.95 (m, 2H), 5.17 (dd, J1 = 16.8 Hz, J2 = 36.0 Hz, 2H),
4.87 (s, 1H), 3.99ꢀ3.93 (m, 3H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 172.2, 139.7, 138.5, 137.8, 136.9, 133.4, 130.9, 128.8, 128.6, 128.2, 128.0,
127.6, 127.3, 127.2, 126.3, 124.5, 124.5, 122.5, 121.7, 120.5, 120.2, 110.6, 110.2,
61.2, 54.5, 46.9, 40.2, 13.9; IR (neat): ν 3059, 2976, 2926, 1726, 1599, 1495, 1463,
1195, 1026, 749 cmꢀ1; HRMS calcd for C32H27NO2Na [M+Na]+: 480.1939, found:
480.1938.
General Procedure for the Synthesis of Products 4. Under the nitrogen
atmosphere, 2ꢀalkenylindole 1 (0.3 mmol) and CsF (136.7 mg, 0.9 mmol) were added
to a 25 mL Schlenk tube equipped with a stir bar. Then 0.6 mL of MeCN, 2.4 mL of
toluene and aryne precursor 2 (0.45 mmol) were added. The reaction mixture was
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stirred at 80 C. When the reaction was complete as monitored by TLC, the reaction
mixture was filtered through a short column of silica gel and eluted with CH2Cl2. The
filtrate was concentrated under reduced pressure to afford the residue, which was
purified by silica gel chromatography (petroleum ether/ethyl acetate 20:1) to afford
4a-n.
Ethyl 7-methyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate (4a). 92%
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yield (84.3 mg), white solid, mp 88ꢀ90 C; H NMR (CDCl3, 400 MHz): δ 8.01ꢀ7.99
(m, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.36ꢀ7.29 (m, 3H), 7.21ꢀ7.18 (m, 2H), 7.10 (td, J1 =
1.6 Hz, J2 = 7.6 Hz, 1H), 4.12ꢀ4.00 (m, 2H), 3.96 (t, J = 6.0 Hz, 1H), 3.71 (s, 3H),
3.47 (dd, J1 = 5.2 Hz, J2 = 16.0 Hz, 1H), 3.08 (dd, J1 = 6.4 Hz, J2 = 16.4 Hz, 1H), 1.14
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 173.1, 137.9, 137.1, 133.7, 129.8,
128.9, 128.0, 124.3, 124.1, 122.4, 121.0, 120.2, 119.4, 109.4, 109.2, 61.0, 45.3, 29.4,
23.3, 14.0; IR (neat): 3046, 2980, 2926, 1753, 1603, 1541, 1499, 1472, 1201, 1154,
766, 748 cmꢀ1; HRMS (EI) calcd for C20H19NO2 305.1416, found 305.1418.
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Ethyl 7,11-dimethyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate (4b). 55%
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yield (52.8 mg), oil; H NMR (CDCl3, 400 MHz): δ 7.66 (d, J = 7.6 Hz, 1H),
7.33ꢀ7.26 (m, 2H), 7.18ꢀ7.08 (m, 3H), 6.97 (d, J = 6.8 Hz, 1H), 4.11ꢀ4.07 (m, 2H),
3.90 (t, J = 5.6 Hz, 1H), 3.72 (s, 3H), 3.41 (dd, J1 = 6.0 Hz, J2 = 16.0 Hz, 1H), 2.97
(dd, = 6.0 Hz, J2 = 15.6 Hz, 1H), 2.76 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR
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(100 MHz, CDCl3): δ 173.1, 138.5, 138.3, 133.8, 131.5, 129.9, 128.1, 127.3, 126.3,
124.0, 123.8, 122.6, 121.2, 111.0, 106.8, 61.0, 46.0, 29.7, 23.9, 23.2, 14.1; IR (neat):
3038, 2919, 2851, 1730, 1494, 1416, 1186, 1150, 1021, 758 cmꢀ1; HRMS (EI) calcd
for C21H21NO2 319.1572, found 319.1573.
Ethyl 10-methoxy-7-methyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate
(4c). 80% yield (80.7 mg), white solid, mp 120ꢀ121 C; 1H NMR (CDCl3, 400 MHz):
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= 7.6 Hz, 1H), 7.19 (d, J = 9.2 Hz, 1H), 7.09 (td, J1 = 0.8 Hz, J2 = 7.2 Hz, 1H), 6.86
(dd, J1 = 2.4 Hz, J2 = 9.2 Hz, 1H), 4.13ꢀ4.00 (m, 2H), 3.94 (t, J = 5.8 Hz, 1H), 3.90 (s,
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3H), 3.67 (s, 3H), 3.44 (dd, J1 = 5.6 Hz, J2 = 16.0 Hz, 1H), 3.05 (dd, J1 = 6.4 Hz, J2 =
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16.0 Hz, 1H), 1.14 (t, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl3): δ 173.2, 137.6,
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109.2, 61.1, 45.3, 32.7, 23.5, 20.5, 14.0; IR (neat): 2976, 2926, 2826, 1728, 1505,
1479, 1234, 1168, 1031, 757 cmꢀ1; HRMS (EI) calcd for C21H21NO3 335.1521, found
335.1516.
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Ethyl
10-chloro-7-methyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate
(4d). 93% yield (94.8 mg), white solid, mp 146ꢀ148 oC; 1H NMR (CDCl3, 400 MHz):
δ 7.94 (d, J = 1.6 Hz, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.35 (td, J1 = 1.2 Hz, J2 = 7.6 Hz,
1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.15ꢀ7.10 (m, 2H), 4.12ꢀ4.00
(m, 2H), 3.96 (t, J = 5.8 Hz, 1H), 3.70 (s, 3H), 3.45 (dd, J1 = 5.2 Hz, J2 = 16.0 Hz,
1H), 3.07 (dd, J1 = 6.4 Hz, J2 = 16.0 Hz, 1H), 1.14 (t, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 172.9, 138.4, 136.2, 132.9, 129.7, 129.1, 128.0, 125.9, 125.0, 124.4,
122.2, 121.0, 118.8, 110.2, 108.8, 61.1, 45.0, 29.5, 23.2, 14.0; IR (neat): 2976, 2918,
2847, 1729, 1503, 1471, 1288, 1181, 1084, 1035, 757 cmꢀ1; HRMS (EI) calcd for
C20H1835ClNO2 339.1026, found 339.1029.
Ethyl 9-chloro-7-methyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate (4e).
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84% yield (85.8 mg), white solid, mp 155ꢀ156 C; H NMR (CDCl3, 400 MHz): δ
7.84 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.34ꢀ7.27 (m, 3H), 7.14ꢀ7.08 (m,
2H), 4.12ꢀ4.00 (m, 2H), 3.94 (t, J = 5.6 Hz, 1H), 3.65 (s, 3H), 3.43 (dd, J1 = 5.2 Hz, J2
= 16.0 Hz, 1H), 3.04 (dd, J1 = 6.4 Hz, J2 = 16.0 Hz, 1H), 1.13 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 172.9, 138.4, 137.7, 133.0, 129.9, 129.1, 128.0, 126.9,
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124.5, 122.8, 122.3, 120.7, 120.1, 109.5, 109.3, 61.1, 45.1, 29.5, 23.2, 14.0; IR (neat):
2976, 2918, 2847, 1728, 1498, 1471, 1202, 951, 798, 740 cmꢀ1; HRMS (EI) calcd for
C20H1835ClNO2 339.1026, found 339.1023.
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Ethyl 7,8-dimethyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate (4f). 90%
yield (86.2 mg), white solid, mp 137ꢀ139 oC; 1H NMR (CDCl3, 400 MHz): δ 7.85 (dd,
J1 = 4.0 Hz, J2 = 8.0 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.09 (t,
J = 7.4 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 6.8 Hz, 1H), 4.12ꢀ4.00 (m, 2H),
3.94 (s, 3H), 3.92 (t, J = 6.0 Hz, 1H), 3.42 (dd, J1 = 5.6 Hz, J2 = 16.0 Hz, 1H), 2.99
(dd, J1 = 6.4 Hz, J2 = 15.6 Hz, 1H), 2.75 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 173.2, 154.7, 137.7, 133.7, 133.2, 129.8, 129.0, 128.0, 124.6,
123.9, 122.0, 110.4, 109.9, 108.8, 102.3, 61.1, 56.0, 45.3, 29.5, 23.4, 14.1; IR (neat):
3042, 2976, 2922, 2851, 1729, 1600, 1504, 1459, 1181, 1032, 779, 741 cmꢀ1; HRMS
(EI) calcd for C21H21NO2 319.1572, found 319.1573.
Ethyl 7-phenyl-6,7-dihydro-5H-benzo[c]carbazole-5-carboxylate (4g). 93%
yield (102.5 mg), oil; 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 8.0 Hz, 1H), 7.93 (d,
J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.45ꢀ7.36 (m, 4H), 7.32 (d, J = 7.6 Hz, 1H),
7.28ꢀ7.12 (m, 4H), 4.11ꢀ3.99 (m, 2H), 3.90 (t, J = 5.2 Hz, 1H), 3.38 (dd, J1 = 5.2 Hz,
J2 = 16.0 Hz, 1H), 3.00 (dd, J1 = 6.4 Hz, J2 = 16.4 Hz, 1H), 1.12 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 173.0, 138.3, 136.9, 133.4, 130.6, 129.6, 129.1, 128.0,
127.8, 127.4, 127.4, 124.6, 124.5, 122.7, 121.7, 121.0, 119.4, 110.6, 110.5, 61.0, 45.4,
23.9, 14.0; IR (neat): 3054, 2976, 2926, 2847, 1728, 1596, 1498, 1454, 1197, 1026,
765, 748 cmꢀ1; HRMS (EI) calcd for C25H21NO2 367.1572, found 367.1575.
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7-tert-Butyl 5-ethyl 5H-benzo[c]carbazole-5,7(6H)-dicarboxylate (4h). 94%
yield (110.4 mg), oil; 1H NMR (CDCl3, 400 MHz): δ 8.22 (t, J = 3.8 Hz, 1H), 7.99 (d,
J = 3.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.39ꢀ7.30 (m, 4H), 7.21 (t, J = 7.2 Hz, 1H),
4.08 (q, J = 6.8 Hz, 2H), 4.03ꢀ3.97 (m, 2H), 3.40 (dd, J1 = 8.4 Hz, J2 = 20.0 Hz, 1H),
1.70 (s, 9H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 172.9, 150.2,
136.7, 136.1, 131.8, 131.3, 128.7, 127.8, 126.4, 125.9, 123.6, 123.3, 123.1, 119.4,
115.7, 115.5, 84.2, 61.0, 45.3, 28.2, 25.9, 14.0; IR (neat): 3052, 2976, 2930, 1753,
1454, 1359, 1301, 1152, 1121, 769, 744 cmꢀ1; HRMS (EI) calcd for C24H25NO4
391.1784, found 391.1782.
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1-(7-Methyl-6,7-dihydro-5H-benzo[c]carbazol-5-yl)ethan-1-one (4i). 71% yield
(58.7 mg), white solid, mp 118ꢀ120 oC; 1H NMR (CDCl3, 400 MHz): δ 7.99ꢀ7.97 (m,
1H), 7.87 (d, J = 7.2 Hz, 1H), 7.40ꢀ7.32 (m, 3H), 7.23ꢀ7.19 (m, 2H), 7.14 (t, J = 7.2
Hz, 1H), 3.75ꢀ3.73 (m, 4H), 3.60 (dd, J1 = 2.0 Hz, J2 = 15.6 Hz, 1H), 3.01 (dd, J1 =
6.8 Hz, J2 = 16.0 Hz, 1H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 208.7, 138.1,
137.8, 134.0, 130.6, 129.8, 128.3, 124.2, 124.2, 122.6, 121.0, 120.3, 119.3, 109.4,
108.8, 53.1, 29.5, 28.4, 22.2; IR (neat): 3042, 2918, 2847, 1705, 1599, 1498, 1471,
1163, 766, 748 cmꢀ1; HRMS (EI) calcd for C19H17NO 275.1310, found 275.1309.
7-Methyl-5-phenyl-6,7-dihydro-5H-benzo[c]carbazole (4j). 87% yield (80.5
o
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mg), white solid, mp 209ꢀ210 C; H NMR (C6D6, 400 MHz): δ 8.20 (d, J = 7.6 Hz,
1H), 8.10 (d, J = 7.6 Hz, 1H), 7.34ꢀ7.25 (m, 3H), 7.14ꢀ6.98 (m, 8H), 4.12 (t, J = 8.0
Hz, 1H), 2.73 (d, J = 2.4 Hz, 1H), 2.71 (d, J = 1.2 Hz, 1H), 2.69 (s, 3H); 13C NMR
(100 MHz, C6D6): δ 144.8, 138.4, 137.4, 135.9, 134.8, 128.9, 128.8, 127.9, 127.7,
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