Copper-Catalyzed Three-Component Formal [3 + 1 + 2] Benzannulation for Carbazole and Indole Synthesis

Article abstract of DOI:10.1021/acs.joc.0c01056

Three-component formal [3 + 1 + 2] benzannulation reactions of indole-3-carbaldehydes or 1-methyl-pyrrole-2-carbaldehydes with two different molecules of saturated ketones have been successfully developed under Cu-catalyzed and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated conditions. Various unsymmetrically substituted carbazoles and indoles were obtained up to 95% yield. Furthermore, the resulting products exhibit unusual aggregation-induced emission (AIE) properties in the solid state. This method features high atom-economy, cheap catalysts and oxidants, wide substrate scope, and saturated ketones as one-carbon and two-carbon sources, thus providing an efficient approach to polycyclic carbazole and indole compounds.

Full text of DOI:10.1021/acs.joc.0c01056

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Article
Copper-Catalyzed Three-Component Formal [3+1+2]
Benzannulation for Carbazoles and Indoles Synthesis
Tenglong Guo, Li Han, Tingpeng Wang, Lan Lei, Jian Zhang, and Dezhu Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01056 • Publication Date (Web): 17 Jun 2020
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Copper-Catalyzed Three-Component Formal [3+1+2] Benzannulation for
Carbazoles and Indoles Synthesis
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Tenglong Guo,†,§ Li Han,‡,§ Tingpeng Wang,† Lan Lei,‡ Jian Zhang*,† and Dezhu Xu*,†
† Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023,
People’s Republic of China
‡Dalian University of Technology, Dalian 116024 (China)
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
_____________________________________________________________________
R3
O
O
CHO
or
R2
or
C
NaOH
O
cat. Cu/TEMPO
O
R2
C
CHO
N
N
R1
N
R1
R3
N
O
R2
R3
C
H3
O
• Novel formal [3+1+2] benzannulation
• Saturated ketones as one-carbon and two-carbon sourcce
• Cheap Cu catalyst and organic oxidants
• Unsymmetrically substituted carbazole and indole products
ABSTRACT: Three-component formal [3+1+2] benzannulation reactions of
indole-3-carbaldehydes or 1-methyl-pyrrole-2-carbaldehydes with two different
molecules of saturated ketones have been successfully developed under Cu-catalyzed
and TEMPO-mediated conditions. Various unsymmetrically substituted carbazoles
and indoles were obtained up to 95% yield. Furthermore, the resulting products
exhibit unusual AIE properties in the solid state. This method features high
atom-economy, cheap catalyst and oxidants, wide substrate scope and saturated
ketones as one-carbon and two-carbon source, thus providing an efficient approach to
polycyclic carbazole and indole compounds.
____________________________________________________________________
INTRODUCTION
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Carbazoles and indoles are important nitrogen containing heterocycles because
their structural core is omnipresent in natural products and biologically active
compounds.1 The recently known carbazole and indole syntheses are predominantly
directed towards construction of a heterocyclic ring onto a prefunctionalized benzene
precursor.2 On the other hand, the alternative method which uses a heterocyclic ring
as the “template”-like structure to establish a benzene ring onto it may provide a
complementary and valuable strategy. In this aspect, indoles or pyrroles reacted with
highly reactive coupling partners such as 1,4-dicarbonyl compounds3 and their
derivatives,4 α-diazocarbonyl compounds,5 biaryl compounds6 through [2+4]
annulation to afford the carbazole or indole products; [2+2′+2′] annulations of indoles
or pyrroles with two molecules of alkene7 or alkyne8 in the presence of a
transition-metal catalyst were also well established, allowing efficient synthesis of
highly symmetric carbazoles and indoles; Meanwhile, [2+2′+2″] annulation, in which
indoles coupled with two different molecules provide a concise method for the
preparation of unsymmetrically substituted carbazoles derivatives (Scheme 1a).9
Among these strategies, the [2+2′+2″] annulation was the most attractive method for
carbazole synthesis since different substituents can be introduced in one-pot. However,
to date, the productivity for creating molecular diversity has not yet to be fully
displayed, very limited annulation reactions of pyrroles have been reported to
synthesize unsymmetrically substituted indoles due to the poor regioselectivity and
significant polymerization of the pyrrole substrates. Therefore, the development of
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novel three-component synthetic methods for the unsymmetrically substituted
carbazoles and indoles synthesis in green and efficient fashion is highly desirable.
_____________________________________________________________________
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Scheme 1. Indole-to-Carbazole and Pyrrole-to-Indole Transformation
a) Previous benzannulation reactions
R'
4C coupling partners
[2+4]
2
or2
R'
R'
R'
R'
N
R
[2+2'+2']
N
R
[2+2'+2'']
O
+
EWG
R'
b) Our previous work
R4
O
O
R4
O
cat.Pd/Cu
R4
+
or
2
R4
R3
or
R2
Cl
N
N
R2
R3
N
R1
R1
N
R1
R1
O
R4
O
c) This work
R3
O
O
CHO
or
R2
or
C
NaOH
O
cat. Cu/TEMPO
O
R2
C
CHO
N
R1
N
R1
N
R1
R3
N
R1
O
R2
CH3
R3
O
 Novel formal [3+1+2] benzannulation
 Saturated ketones as one-carbon and two-carbon sourcce
 Cheap Cu catalyst and organic oxidants
 Unsymmetrically substituted carbazole and indole products
_____________________________________________________________________
α,β-Unsaturated ketones are ubiquitous in bioactive compounds and regarded as
versatile synthetic intermediates in the syntheses of fine chemicals, pharmaceuticals
and materials.10 Traditionally, approaches to access α,β-unsaturated ketones required
multiple steps11 or use of stoichiometric oxidants12 and some substrates such as aryl
vinyl ketones (enones) are hardly to prepare and isolate due to their poor stability and
high reactivity. To overcome these problem, the one-pot reactions of in situ generated
enones through catalytic dehydrogenation13 or transition-metal-free α-Csp3-H
methylenation14 of saturated ketones have been well developed in the recent years and
provided efficient methods for the application of unstable enones. As an alternative
route, our group utilized β-chloroalkyl aryl ketones as the precursors of enones to
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realize the one-shot synthesis of carbazoles and indoles through [2+2′+2′]
benzannulation of simple indoles15a and pyrroles15b (Scheme 1b). However, these
reactions suffer from several shortcomings: 1) the requirements of expensive metal
catalyst and excess metal oxidants; 2) the limited product structures, only highly
symmetric carbazoles and 2-substituted indoles were obtained; 3) the poor
atom-economy due to the dehydrochlorination of β-chloroalkyl aryl ketones. Intrigued
by the advantages of utilizing in situ generated enones as olefin sources for the
heterocycles synthesis, herein, we report a three-component formal [3+1+2]
benzannulation reaction16 for the synthesis of unsymmetrically substituted carbazoles
and 1,2-unsubstituted indoles by using saturated ketones as one-carbon and
two-carbon source (Scheme 1c).
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RESULTS AND DISCUSSION
Initially, the adol reaction of 1-methyl-1H-indole-3-carbaldehyde (1a) with
4-methylacetophenone (2b) was conducted in EtOH at ambient temperature in the
presence of NaOH (4.0 equiv), then the further one-pot, two-step reaction with
propiophenone (3a) in chlorobenzene at 120 oC was chosen as a model system for the
optimization studies by using 20 mol% Cu(OAc)2 as catalyst, 30 mol% Bipy as ligand,
TEMPO (3.0 equiv) as oxidant and HOAc as additives (Table 1, entry 1). The desired
carbazole product 4e was isolated in 87% yield. Encouraged by this exciting result we
investigated several solvents i.e., DMF, DMSO, Toluene, EtOH (Table 1, entries 1-5).
Chlorobenzene proved to facilitate the reaction. The reaction hardly occurred without
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Table 1. Screening of Conditionsa
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2) 20 mol% cat.
30 mol% Bipy
HOAc (4.0 equiv)
TEMPO (x equiv)
O
CHO
O
Me
1) NaOH (4.0 equiv)
EtOH, 25 o
+
solvent, 120 o
C
C
N
N
O
Me
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Ph
3a
O
Ph
2b
1a
4e
entry
1
cat.
solvent
TEMPO
(x equiv)
yieldb (%)
87
Cu(OAc)2·H2O
chlorobenzene
3.0
2
3
4
5
6
7
8
9
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
-
DMF
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
80
62
DMSO
Toluene
57
EtOH
trace
NR
93
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
CuCl2·2H2O
CuCl
85
CuI
77
10
11
FeCl3
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
3.0
3.0
3.0
-
NR
NR
80
CoCl2
12c
13
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
NR
77
14
2.0
3.0
3.0
3.0
15d
16e
17f
67
10
95
a Conditions: 1) 1a (0.2 mmol), 2b (0.4 mmol), NaOH (0.8 mmol), EtOH (2.0
mL), 24 h. 2) catalyst (0.04 mmol), Bipy (0.06 mmol), HOAc (0.8 mmol),
TEMPO (0.6 mmol), 3a (0.6 mmol), solvent (2.5 mL), air, 16 h, in oil bath. b
Isolated yields. c CuCl2·2H2O (0.02 mmol). d Without Bipy. e Without HOAc. f
3a (0.4 mmol).
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a catalyst (Table 1, entry 6). Among the screened copper catalysts, i.e., Cu(OAc)2,
CuCl, CuI, CuCl2•2H2O was found to be the most efficientive and 93% yield of the
desired product was obtained (Table 1, entries 7-9). Other transition metals i.e., FeCl3,
CoCl2 did not exhibited any catalytic activity (Table 1, entries 10 and 11). Decreasing
the amount of catalyst to 0.1 equiv. led to 80% yield (Table 1, entry 12). No reaction
occurred in the absence of TEMPO and the yield of 4e decreased to 77% when
TEMPO amount was reduced (Table 1, entries 13 and 14). Low yield (67%) was
obtained without ligand (Table 1, entry 15). HOAc was acquired to neutralized NaOH
to ensure the high yield of 4e (Table 1, entry 16). To our delight, reducing the amount
of 3a had little impact on the reaction, the target product 4e was achieved up to 95%
yield (Table 1, entry 17).
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Next, the protocol generality was investigated by reacting indole-3-carbaldehydes
with various saturated ketones 2 and 3 (Table 2). The highly symmetric carbazole 4a
was obtained in 95% yield through the reaction of 1a with acetophenone 2a and
propiophenone 3a, which was more effective than our previous work (82% yield).15a
Changing the N-R moiety in indoles from methyl to benzyl had a slight influence on
the yield of 4b (89%). The electron-donating methyl substituent on the aryl ring of the
indole did not obviously affect the reaction efficiency as 4c was obtained in 90% yield,
whereas the electron-withdrawing chloro group lessened the formation of the desired
products 4d (80%). Aryl methyl ketones 2 bearing electron-donating methyl or
methoxy substituent reacted with 1a and 3a to form the desired products 4e-g in
73-93% yields, and the steric hindrance from a 2-methyl group on the aryl ring of 2c
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lessened the reaction efficiency, producing 4f in 73% yield. The reaction of naphthyl
or electron-withdrawing group substituted aryl methyl ketones also efficiently gave
the desired products 4h-k (85-95%). Heteroaryl methyl ketones underwent the same
reactions to generate carbazoles 4l (85%) and 4m (90%), respectively. However,
cyclopropyl methyl ketone exhibited a low reactivity, and its reaction with 1a and 3a
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_____________________________________________________________________
Table 2. One-pot three-component synthesis of carbazoles (4) a,b
2) 20 mol% CuCl2•2H2O
O
30 mol% Bipy
HOAc (4.0 equiv)
TEMPO (3.0 equiv)
chlorobenzene, 120 o
CHO
R2
O
R
1) NaOH (4.0 equiv)
EtOH, 25 o
R2
R
+
C
C
N
R1
N
O
R3
3
R1
O
R3
2
1
4
O
O
O
O
Me
Me
Me
Cl
N
N
N
Bn
N
O
O
O
O
4c
, 90%
4d
, 80%
4b
, 89%
4a
, 95%
OMe
OMe
Me
O
O
O
Me
N
N
N
O
O
O
4f
, 73%
4e
, 95%
4g
, 93%
O
O
O
Cl
F
N
N
N
O
O
O
4i
, 91%
4j
, 92%
4h
, 95%
Br
S
O
O
O
O
O
N
N
N
N
O
O
O
O
4n
, 78%
4k
, 85%
4m
, 90%
4l
, 85%
O
O
O
O
Cl
Br
OMe
Me
N
N
N
N
O
O
O
O
4r
, 93%
4q
, 95%
4p
, 68%
4o
, 89%
a Conditions: 1) 1 (0.2 mmol), 2 (0.4 mmol), NaOH (0.8 mmol), EtOH
(2.0 mL), 25 oC. 2) CuCl2·2H2O (0.04 mmol), Bipy (0.06 mmol), HOAc
(0.8 mmol), TEMPO (0.6 mmol), 3 (0.4 mmol), chlorobenzene (2.5 mL),
120 oC, air, 16 h, in oil bath. b Yields refer to the isolated products.
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gave 4n in 78% yield. Then different substituted aryl ethyl ketones 3 were also
investigated. 1a and 2a reacted with aryl ethyl ketones bearing a substituent on the
aryl moiety proceeded to form the target products 4o-r in 68-95% yields. Strong
electron-donating methoxy was detrimental to the reaction efficiency, giving the
product 4p only in 68% yield.
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The substrate scope was further investigated by reacting 1-methyl-1H-pyrrole-
2-carbaldehydes 5 with a variety of saturated ketone substrates 2 and 3 to synthesize
1,2-unsubstituted indoles (Table 3). Treatment of 5a with acetophenone 2a and
propiophenone 3a gave the desired highly symmetric indole 6a in 55% yield which
_____________________________________________________________________
Table 3. One-pot three-component synthesis of indoles (6) a,b
2) 20 mol% CuCl2•2H2O
R3
O
30 mol% Bipy
HOAc (4.0 equiv)
TEMPO (3.0 equiv)
O
1) NaOH (4.0 equiv)
EtOH, 25 o
R2
+
CHO
R
chlorobenzene, 120 o
C
N
R2
C
N
O
3
O
R3
5
2
6
Cl
Cl
O
O
O
O
Me
Me
N
N
N
N
O
O
Me
O
O
6b
, 43%
6a
, 55%
6c
, 70%
6d
, 58%
Cl
Cl
Cl
Cl
O
O
O
O
MeO
MeO
F
N
N
N
N
O
O
O
O
6h
O
6e
, 62%
6f
, 84%
6g
, 68%
, 65%
Cl
Cl
Cl
Br
MeO
O
O
O
O
O
N
N
N
N
S
N
O
6j
O
6l
O
O
6m
O
6k
, 50%
6i
, 73%
, 66%
, 74%
, 80%
a Conditions: 1) 5 (0.2 mmol), 2 (0.4 mmol), NaOH (0.8 mmol), EtOH (2.0 mL), 25
oC. 2) CuCl2·2H2O (0.04 mmol), Bipy (0.06 mmol), HOAc (0.8 mmol), TEMPO
o
b
(0.6 mmol), 3 (0.4 mmol), chlorobenzene (2.5 mL), 120 C, air, 16 h, in oil bath.
Yields refer to the isolated products.
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was much higher than that in our previous work (17% yield).15b The reaction of
1,5-dimethyl-1H-pyrrole-2-carbaldehyde (5b) only formed 6b in 43% yield,
exhibiting a negative electronic effect from the 2-substituent of the pyrrole backbone.
The electron-donating substituents i.e., methyl and methoxy or electron-withdrawing
substituents i.e., naphthyl, -F, -Br on the aryl rings of the aryl methyl ketone
substrates 2 did not obviously affect the reaction efficiency and target products 6c,
6e-g were obtained in 62-84% yields. Increasing the steric hindrance of the aryl
moiety in 2 by introducing methyl led to 58% yield of the corresponding products 6d,
which is attributed to the steric effect of the aryl moiety of 2. The reaction also
tolerated furyl and thienyl, yielding indole products 6h (65%) and 6i (73%),
respectively. To our delight, cyclopropyl methyl ketone exhibited a high reactivity,
giving 6j in 80% yield. Methoxy, -Cl, -Br substituted propiophenones also smoothly
reacted with 1a and 2a to afford products 6k (50%), 6l (74%) and 6m (66%),
respectively.
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Me
O
CHO
O
NaOH (4.0 equiv)
EtOH, 25 o
+
(1)
C
N
N
Me
7,
96%
2b
1a
20 mol% CuCl2•2H2O
30 mol% Bipy
TEMPO 3.0 equiv
NaOAc 4.0 equiv
O
O
(2)
Ph
Ph
chlorobenzene
120 oC, 16 h, air
8
, 46%
3a
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To investigate the mechanism of this reaction, adol reaction of 1a and 2b was
conducted and suspended prior to the next step (eq 1). 3-Alkenylated indole 7 was
isolated and characterized. Propiophenone 3a was treated under the standard reaction
conditions of the second step without other substrates, enone 8 was obtained in 46%
yield (eq 2). To probe further into the reaction pathway of 7 with the in situ generated
enone 8, the controlled reaction of 7 with 8 was investigated (Scheme 2). Under the
standard conditions as shown in Scheme 2, 4e was formed in 65% yield lower than
one-pot two-steps reaction, revealing that enone 8 was a key reaction intermediate and
in situ generated enone was more efficient for carbazole synthesis. Without
CuCl2·2H2O or TEMPO, the yield of 4e slightly decreased to 57% and 58%,
respectively. In the absence of CuCl2·2H2O and TEMPO, 4e was still obtained in 45%
yield. These results suggested that CuCl2·2H2O and TEMPO as added oxidants could
promote the reaction.
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_____________________________________________________________________
Scheme 2. Controlled reactions of 7 with 8
Me
O
20 mol% CuCl2•2H2O
30 mol% Bipy
O
TEMPO (3.0 equiv)
NaOAc (4.0 equiv)
Me
O
+
Ph
chlorobenzene
120 oC, 16 h, air
N
N
Ph
O
"standard condition"
7
8
4e,
65%
(0.2 mmol)
(0.4 mmol)
without CuCl2•2H O
57%
58%
2
without TEMPO
without CuCl2•2H O and TEMPO
45%
2
_____________________________________________________________________
Based on the experimental results and aforementioned control experiments, a
proposed mechanism for this transformation is illustrated in Scheme 3.13b Initially,
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CuCl2·2H2O enolizes saturated ketone 3 to give complex A which undergoes
homolytic bond cleavage to generate Cu(I) species and intermediate B which upon
reaction with TEMPO produced α-TEMPO-substituted ketone, another molecule of
TEMPO then abstracted β-hydrogen of α-TEMPO-substituted ketone to generate
intermediate C, resulting in elimination of TEMPOH from C to form the desired
enone 8. Cu(I) species gets oxidized by TEMPO or TEMPOH to regenerate Cu(II)
species. 3-Alkenylated indoles 7 or 2-alkenylated pyrroles 7’ are generated through
the adol reactions of 1 or 5 with saturated ketones 2. A Diels-Alder cycloaddition of
enone 8 to 7 or 7’ forms tetrahydrocarbazole 9 or tetrahydroindole 9’, which is
subsequently oxidized to carbazoles 4 or indoles 6 by the Cu(II), TEMPO and air. In
the reaction sequence, CuCl2·2H2O acts as a disfunctional agent: catalyst of in situ
generated enone reaction and oxidant of benzannulation reaction.
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_____________________________________________________________________
Scheme 3. Proposed Mechanism
O
H O
2
+
N
O
R3
H
H
LnCuX2
3
O
O
H
- HX
or
+
R2
N
R1
N
2
O
+
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1
N
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N
LnCu(I)X
NaOH
R3
Ln
OH
Cu
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or
X
R2
O
A
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R3
+
N
8
N
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N
O
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O
R1
7'
R3
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O
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N
R3
O
R2
O
R2
or
O
R3
N
N
R3
O
R1
9
O
9'
R2
O
R2
O
or
O
H2
2
•
l2
O
C
P
R3
u
M
C
E
N
R1
N
r
i
T
a
O
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With the carbazoles 4 and indoles 6 in hand, a preliminary survey of their optical
properties was carried out. To our delight, both products 4 and 6 displayed unusual
aggregation-induced emission (AIE)17 phenomenon in solid state, which were very
different from the reported solvent fluorescence emission.18,6c The fluorescence
spectra of 4g and 6e in solid state (as the representative examples) were outlined in
Figure 1. The emission maximum of carbazoles 4 range from 425 to 440 nm.
Otherwise indoles 6 displayed broader emissions with emission maximum from 425
to 535 nm, depending on the electronic properties of the substituent groups (see the
Supporting Information for details). Owing to the unique AIE property, products 4
and 6 could be applied as promising materials in various fields such as fluorescence
sensing and one- and two-photon bioimaging.19
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_____________________________________________________________________
Figure 1. Fluorescence spectra of 4g and 6e in solid state.
In conclusion, a copper-catalyzed, TEMPO-mediated three-component formal
[3+1+2] benzannulation reaction has been successfully developed for the synthesis of
unsymmetrically substituted carbazoles and indoles by using saturated ketones as
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one-carbon and two-carbon source. A one-pot two-step adol reaction/
dehydrogenation/Diels-Alder cycloaddition/aromatization sequence was established
as the reaction pathway. Considering the wide availability of the starting materials,
broad substrate scopes and high atom economy, the present method provides an
attractive and novel route to unsymmetrically substituted carbazoles and indoles
which are regarded as promising solid fluorescence materials for optoelectronics.
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EXPERIMENTAL SECTION
1
General Considerations. H and 13C{1H} NMR spectra were recorded on a
Bruker DRX-400 spectrometer and all chemical shift values refer to TMS = 0.00 ppm
or CDCl3 ((1H), 7.26 ppm; (13C), 77.16 ppm). The HRMS analysis was obtained on
a Waters GC-TOF CA156 mass spectrometer. Fluorescence emission spectra were
measured on Agilent Cary Eclipse Fluorescence Spectrophotometer (MY16500004)
in solid state at room temperature with excitation at 370 nm for all of the products. All
the melting points were uncorrected. Analytical TLC plates, Sigma-Aldrich silica gel
60F200 were viewed by UV light (254 nm). Column chromatographic purifications
were performed on SDZF silica gel 160. The starting substrates 1b,20a 1c,20b 1d20b and
5b20c were known compounds and prepared by the literature procedures. Products
4a,15a 4b,15a 4o,15a 4q,15a 6a,15b 6b,15b 721a and 821b were also known compounds and
their spectroscopic features are in good agreement with those reported in the
literatures. All of the other chemical reagents were purchased from commercial
sources and used as received unless otherwise indicated.
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Synthesis of 1-benzyl-1H-indole-3-carbaldehyde 1b:
A
mixture of
6
7
8
9
1H-indole-3-carbaldehyde (145 mg, 1.0 mmol) and KOH (168 mg, 3.0 mmol) in 5.0
mL DMSO was stirred at ambient temperature under an air atmosphere. Then
(bromomethyl)benzene (340 mg, 2.0 mmol) was added. The reaction mixture was
further stirred at room temperature and monitored by TLC. When
1H-indole-3-carbaldehyde was consumed completely, the reaction mixture was
quenched with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The
combined organic layer was dried over anhydrous sodium sulfate (Na2SO4) and
concentrated under reduced pressure. The resulting residue was purified by silica gel
column chromatography (eluent: petroleum ether (60-90 oC) /EtOAc/CH2Cl2 = 10:1:2,
v/v/v) to afford 1b as a white solid (211 mg, 90%).
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1
1-Benzyl-1H-indole-3-carbaldehyde (1b): 211 mg, 90% yield; white solid. H
NMR (400 MHz, CDCl3) δ 10.01 (s, 1 H), 8.37-8.28 (m, 1 H), 7.72 (s, 1 H), 7.38 –
7.29 (m, 6 H), 7.19 (m, 2 H), 5.37 (s, 2 H). 13C NMR (101 MHz, CDCl3) δ 184.8 (Cq,
C=O), 137.6, 135.4, 125.64 and 118.64 (Cq each), 138.6, 129.3, 128.5, 127.4, 124.3,
123.2, 122.3, 110.5, 51.1.
A typical procedure for N-methylation of indoles and pyrrole Synthesis of 1c:
A mixture of 5-methyl-1H-indole-3-carbaldehyde (159 mg, 1.0 mmol) and KOH (168
mg, 3.0 mmol) in 4.0 mL DMF was stirred at ambient temperature under an air
atmosphere. Then MeI (282 mg, 2.0 mmol) was added. The reaction mixture was
further stirred at room temperature and monitored by TLC. When
5-methyl-1H-indole-3-carbaldehyde was consumed completely, the reaction mixture
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was quenched with water (20 mL) and extracted with ethyl acetate (3 × 30 mL). The
combined organic layer was dried over anhydrous sodium sulfate (Na2SO4) and
concentrated under reduced pressure. The resulting residue was purified by silica gel
column chromatography (eluent: petroleum ether (60-90 oC) /EtOAc/CH2Cl2 = 10:3:2,
v/v/v) to afford 1c as a yellow solid (147 mg, 85%).
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1,5-Dimethyl-1H-indole-3-carbaldehyde (1c): 147 mg, 85% yield; yellow solid.
1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1 H), 8.22 (s, 1 H), 7.68 (s, 1 H), 7.30 (m, 2
H), 3.90 (s, 3 H), 2.59 (s, 3 H). 13C{1H}NMR (100 MHz, CDCl3) δ 184.50 (Cq, C=O),
139.5, 136.4, 132.8 and 117.7 (Cq each), 125.6, 125.5, 121.8, 109.6, 33.7, 21.5.
5-Chloro-1-methyl-1H-indole-3-carbaldehyde (1d): Following the general
procedure, compound 1d was obtained by column chromatography on silica gel
(eluent: petroleum ether (60−90 °C)/EtOAc/CH2Cl2 = 10:3:2, v/v/v). 158 mg, 82%
yield; white solid. 1H NMR (400 MHz, CDCl3) δ 9.91 (d, J = 1.2 Hz, 1 H), 8.27 (s, 1
H), 7.65 (s, 1 H), 7.25 (m, 2 H), 3.85 (s, 3 H). 13C{1H}NMR (100 MHz, CDCl3) δ
184.3 (Cq, C=O), 136.3, 129.0, 126.2 and 117.5 (Cq each), 140.0, 124.5, 121.6, 111.0,
34.0.
1,5-Dimethyl-1H-pyrrole-2-carbaldehyde (5b): Following the general procedure,
compound 5b was obtained by column chromatography on silica gel (eluent:
petroleum ether (60−90 °C)/EtOAc/CH2Cl2 = 10:3:2, v/v/v). 111 mg, 90% yield;
yellow liquid. 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J = 3.0 Hz, 1 H), 6.78 (m, 1 H),
5.98 (d, J = 3.5 Hz, 1 H), 3.82 (s, 3 H), 2.22 (s, 3 H). 13C{1H}NMR (100 MHz, CDCl3)
δ 178.5 (Cq, C=O), 140.6 and 131.8 (Cq each), 124.6, 109.6, 32.3, 12.1.
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A typical procedure for the synthesis of carbazoles 4  Synthesis of 4e: A
mixture of 1-methyl-1H-indole-3-carbaldehyde (1a) (32 mg, 0.2 mmol),
4-methylacetophenone (2b) (54 mg, 0.4 mmol), and NaOH (32 mg, 0.8 mmol) in 2.0
mL EtOH was stirred at ambient temperature under an air atmosphere. When 1a was
consumed completely, HOAc (48 mg, 0.8 mmol) was added and EtOH was
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o
evaporated at 120 C. CuCl2·2H2O (6.8 mg, 0.04 mmol), Bipy (9.4 mg, 0.06 mmol),
TEMPO (94 mg, 0.6 mmol), propiophenone (3a) (54 mg, 0.4 mmol), and
o
chlorobenzene (2.5 ml) was added to the mixture and stirred at 120 C under an air
atmosphere for 16 h. After cooled to ambient temperature, 10 mL CH2Cl2 was added
and the resultant mixture was filtered through a short pad of celite, followed by
rinsing with 20 mL CH2Cl2. The combined filtrate was concentrated under reduced
pressure. The resulting residue was purified by silica gel column chromatography
o
(eluent: petroleum ether (60-90 C) /EtOAc/CH2Cl2 = 20:1:2, v/v/v) to afford 4e as a
white solid (76 mg, 95%).
(9-Methyl-9H-carbazole-1,3-diyl)bis(phenylmethanone) (4a): Following the
general procedure, compound 4a was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc/CH2Cl2 = 20:1:2, v/v/v). 74 mg, 95%
1
yield; pale yellow solid. H NMR (400 MHz, CDCl3),. δ 8.76 (d, J = 1.6 Hz, 1 H),
8.16 (d, J = 7.8 Hz, 1 H), 8.04 (d, J = 1.6 Hz, 1 H), 7.98 (m, 2 H), 7.84 (m, 2 H), 7.64
(t, J = 7.4 Hz, 1 H), 7.58 (m, 2 H), 7.50 (m, 5 H), 7.35 (t, J = 7.4 Hz, 1 H), 3.69 (s, 3
H). 13C {1H} NMR (100 MHz, CDCl3) δ 195.83 and 195.79 (Cq each, C=O), 142.6,
141.1, 138.4, 137.7, 127.5, 124.8, 122.7 and 122.4 (Cq each), 133.8, 132.1, 130.7,
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129.9, 129.8, 128.8, 128.4, 127.3, 125.6, 120.8, 120.6, 109.6, 33.2.
6
7
8
9
(9-Benzyl-9H-carbazole-1,3-diyl)bis(phenylmethanone) (4b): Following the
general procedure, compound 4b was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc/CH2Cl2 = 20:1:2, v/v/v). 81 mg, 89%
yield; yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 0.9 Hz, 1 H), 8.22 (d, J
= 7.8 Hz, 1 H), 7.86 (s, 1 H), 7.82 (d, J = 7.4 Hz, 2 H), 7.56 (m, 3 H), 7.48 (m, 5 H),
7.40 (m, 1 H), 7.29 (d, J = 7.7 Hz, 2 H), 6.91 (d, J = 7.1 Hz, 1 H), 6.86 (t, J = 7.3 Hz,
2 H), 6.65 (d, J = 7.4 Hz, 2 H), 5.61 (s, 2 H). 13C {1H} NMR (100 MHz, CDCl3) δ
195.8 and 195.4 (Cq each, C=O), 143.0, 139.8, 138.2, 137.1, 135.7, 127.5, 125.4,
123.4 and 122.8 (Cq each), 133.0, 132.1, 130.4, 130.0, 129.8, 128.4, 128.3, 128.1,
127.5, 127.3, 126.9, 125.6, 121.1, 120.7, 109.9, 48.2.
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(1-benzoyl-6,9-dimethyl-9H-carbazol-3-yl)(p-tolyl)methanone (4c): Following the
general procedure, compound 4c was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc/CH2Cl2 = 20:1:2, v/v/v). 75 mg, 90%
yield; white solid, m.p.: 168-170 oC. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1 H), 8.02
(s, 1 H), 7.97 (m, 3 H), 7.76 (d, J = 7.8 Hz, 2 H), 7.63 (d, J = 7.4 Hz, 1 H), 7.51 (t, J =
7.6 Hz, 2 H), 7.36 (m, 2 H), 7.30 (d, J = 7.8 Hz, 2 H), 3.66 (s, 3 H), 2.55 (s, 3 H), 2.45
(s, 3 H). 13C {1H} NMR (100 MHz, CDCl3) δ 196.0 and 195.7 (Cq each, C=O), 142.8,
141.3, 141.1, 137.9, 130.4, 135.8, 127.6, 124.6, 123.0 and 122.3 (Cq each), 133.8,
130.8, 130.3, 129.7, 129.1, 128.8, 128.7, 125.6, 120.6, 109.4, 33.3, 21.8, 21.5. HRMS
Calcd for C29H24NO2 [M+H]+: 418.1807; Found: 418.1805.
(9-Benzyl-9H-carbazole-1,3-diyl)bis(phenylmethanone) (4d): Following the
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general procedure, compound 4d was obtained by column chromatography on silica
gel (eluent: petroleum ether (60−90 °C)/EtOAc/CH2Cl2 = 20:1:10, v/v/v). 70 mg, 80%
8
9
o
1
yield; white solid, m.p.: 256-259 C. H NMR (400 MHz, CDCl3) δ 8.66 (s, 1 H),
8.13-8.04 (m, 2 H), 7.98 (d, J = 7.6 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.65 (t, J = 7.3
Hz, 1 H), 7.55-7.48 (m, 3 H), 7.38 (d, J = 8.7 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 2 H), 3.68
(s, 3 H), 2.46 (s, 3 H). 13C {1H} NMR (100 MHz, CDCl3) δ 195.7 and 195.4 (Cq each,
C=O), 143.1, 141.4, 141.0, 137.6, 135.5, 128.2, 126.5, 123.9, 123.7 and 122.8 (Cq
each), 134.0, 130.8, 130.2, 130.2, 129.2, 128.9, 127.4, 125.8, 120.4, 110.7, 33.4, 21.8.
HRMS Calcd for C28H21ClNO2 [M+H]+: 438.1261; Found: 438.1265.
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(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(p-tolyl)methanone (4e): Following the
general procedure, compound 4e was obtained by column chromatography on silica
gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:1:2, v/v/v). 76 mg, 95%
yield; white solid, m.p.: 167-170 oC. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1 H), 8.16
(d, J = 7.8 Hz, 1 H), 8.04 (s, 1 H), 7.99 (d, J = 7.7 Hz, 2 H), 7.77 (d, J = 7.9 Hz, 2 H),
7.64 (t, J = 7.4 Hz, 1 H), 7.54 (m, 3 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1
13
H), 7.30 (d, J = 7.9 Hz, 2 H), 3.68 (s, 3 H), 2.45 (s, 3 H). C{1H} NMR (100 MHz,
CDCl3) δ 195.9 and 195.6 (Cq each, C=O), 142.9, 142.7, 141.1, 137.8, 135.7, 127.9,
124.8, 122.8 and 122.4 (Cq each), 133.8, 130.8, 130.3, 129.8, 129.1, 128.8, 127.3,
125.5, 120.8, 120.6, 109.6, 33.2, 21.7. HRMS Calcd for C28H22NO2 [M+H]+:
404.1651; Found: 404.1653.
(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(o-tolyl)methanone (4f): Following the
general procedure, compound 4f was obtained by column chromatography on silica
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gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:1:2, v/v/v). 59 mg, 73%
yield; white solid, m.p.: 139-141 oC. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1 H), 8.12
(d, J = 7.8 Hz, 1 H), 8.07 (m, 1 H), 7.97 (d, J = 7.4 Hz, 2 H), 7.65 (t, J = 7.4 Hz, 1 H),
7.54 (m, 3 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.40 (m, 2 H), 7.35 (d, J = 7.4 Hz, 1 H), 7.30
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(m, 2 H), 3.67 (s, 3 H), 2.37 (s, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 197.5 and
195.8 (Cq each, C=O), 142.6, 141.4, 139.1, 137.7, 136.5, 128.0, 124.9, 122.8 and
122.6 (Cq each), 133.8, 131.1, 130.7, 130.1, 129.4, 128.8, 128.3, 127.3, 125.6, 125.3,
120.9, 120.6, 109.6, 33.2, 20.0. HRMS Calcd for C28H22NO2 [M+H]+: 404.1651;
Found: 404.1651.
(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(3,4-dimethoxyphenyl)methanone
(4g):
Following the general procedure, compound 4g was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 =
20:5:2, v/v/v). 83 mg, 93% yield; white solid, m.p.: 132-134 oC. 1H NMR (400 MHz,
CDCl3) δ 8.74 (d, J = 1.6 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.98 (m, 3 H), 7.63 (m,
1 H), 7.56 (m, 1 H), 7.52 (m, 1 H), 7.49 (m, 2 H), 7.44 (m, 2 H), 7.33 (m, 1 H), 6.91
(d, J = 8.3 Hz, 1 H), 3.95 and 3.93 (s each, 3:3 H), 3.67 (s, 3 H). 13C{1H} NMR (100
MHz, CDCl3) δ 195.9 and 194.7 (Cq each, C=O), 152.7, 149.0, 142.6, 140.9, 137.8,
130.9, 128.1, 124.7, 122.7 and 122.3 (Cq each), 133.8, 130.7, 129.6, 128.8, 127.2,
125.3, 125.1, 120.8, 120.6, 112.4, 109.9, 109.6, 56.2, 56.1, 33.2. HRMS Calcd for
C29H24NO4 [M+H]+: 450.1705; Found: 450.1702.
(3-(2-Naphthoyl)-9-methyl-9H-carbazol-1-yl)(phenyl)methanone (4h): Following
the general procedure, compound 4h was obtained by column chromatography on
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silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:1:5, v/v/v). 83 mg,
95% yield; white solid, m.p.: 161-163 oC. 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J =
1.4 Hz, 1 H), 8.34 (s, 1 H), 8.14 (d, J = 7.4 Hz, 2 H), 8.00 (m, 4 H), 7.92 (m, 2 H),
7.63 (d, J = 7.5 Hz, 1 H), 7.57 (m, 3 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.46 (d, J = 8.3 Hz,
1 H), 7.34 (t, J = 7.4 Hz, 1 H), 3.70 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ
195.75 and 195.73 (Cq each, C=O), 142.7, 141.2, 137.7, 135.7, 135.1, 132.3, 127.7,
124.9, 122.7 and 122.4 (Cq each), 133.8, 131.4, 130.7, 129.9, 129.4, 128.8, 128.3,
128.2, 127.9, 127.3, 126.8, 126.0, 125.6, 120.8, 120.6, 109.6, 33.2. HRMS Calcd for
C31H22NO2 [M+H]+: 440.1651; Found: 440.1651.
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(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(4-fluorophenyl)methanone (4i): Following
the general procedure, compound 4i was obtained by column chromatography on
silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:1:5, v/v/v). 74 mg,
91% yield; white solid, m.p.: 189-192 oC. 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J =
1.3 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.99 (m, 3 H), 7.87 (m, 2 H), 7.64 (t, J = 7.4
Hz, 1 H), 7.54 (m, 3 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 1 H), 7.17 (t, J
= 8.6 Hz, 2 H), 3.68 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.7 and 194.3
(Cq each, C=O), 165.2 (Cq, d, J = 252.0 Hz, i-C of C6H4F), 142.7, 141.1, 137.7 and
134.6 (Cq, d, J = 3.0 Hz, p-C of C6H4F) (Cq), 127.3, 124.8, 122.7, 122.5, 132.5 (CH,
d, J = 8.9 Hz, m-C of C6H4F), 133.9, 130.7, 129.6, 128.8, 127.4, 125.4, 120.9, 120.6,
115.5 (CH, d, J = 21.7 Hz, o-C of C6H4F), 109.7, 33.2. 19F NMR (100 MHz, CDCl3) δ
106.6. HRMS Calcd for C27H19FNO2 [M+H]+: 408.1400; Found: 408.1398.
(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(4-chlorophenyl)methanone
(4j):
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Following the general procedure, compound 4j was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 =
20:1:5, v/v/v). 78 mg, 92% yield; white solid, m.p.: 190-193 oC. 1H NMR (400 MHz,
CDCl3) δ 8.72 (d, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.97 (m, 3 H), 7.78 (d, J = 8.5 Hz, 2
H), 7.65 (t, J = 7.4 Hz, 1 H), 7.57 (m, 1 H), 7.52 (t, J = 7.7 Hz, 2 H), 7.47 (m, 3 H),
7.36 (m, 1 H), 3.68 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3) δ 195.8 and 194.6 (Cq
each, C=O), 142.7, 141.2, 138.5, 137.7, 136.8, 127.2, 124.9, 122.7 and 122.6 (Cq
each), 134.0, 131.4, 130.8, 129.6, 128.9, 128.8, 127.5, 125.5, 121.0, 120.7, 109.7,
33.3. HRMS Calcd for C27H19ClNO2 [M+H]+: 424.1104; Found: 424.1107.
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(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(3-bromophenyl)methanone
(4k):
Following the general procedure, compound 4k was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 =
20:1:5, v/v/v). 79 mg, 85% yield; white solid, m.p.: 172-174 oC. 1H NMR (400 MHz,
CDCl3) δ 8.74 (d, J = 1.5 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.98 (m, 4 H), 7.74 (d, J
= 7.7 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.55 (m, 3 H), 7.47
(d, J = 8.2 Hz, 1 H), 7.36 (t, J = 7.7 Hz, 2 H), 3.69 (s, 3 H). 13C{1H} NMR (100 MHz,
CDCl3) δ 195.6 and 194.2 (Cq each, C=O), 142.8, 141.4, 140.4, 137.7, 126.8, 125.1,
122.7, 122.7 and 122.5 (Cq each), 135.0, 133.9, 132.7, 130.8, 130.0, 129.8, 128.9,
128.4, 127.5, 125.6, 121.1, 120.7, 109.8, 33.3. HRMS Calcd for C27H19BrNO2
[M+H]+: 468.0599; Found: 468.0595.
(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(furan-2-yl)methanone (4l): Following the
general procedure, compound 4l was obtained by column chromatography on silica
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gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:5:2, v/v/v). 79 mg, 85%
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yield; yellow solid, m.p.: 168-170 oC. H NMR (400 MHz, CDCl3) δ 8.99 (m, 1 H),
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8.24 (d, J = 1.5 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.99 (d, J = 7.5 Hz, 2 H), 7.68 (s,
1 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.53 (m, 3 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.34 (t, J = 7.4
Hz, 1 H), 7.29 (d, J = 3.5 Hz, 1 H), 6.58 (d, J = 1.8 Hz, 1 H), 3.65 (s, 3 H). 13C{1H}
NMR (100 MHz, CDCl3) δ 195.7 and 181.2 (Cq each, C=O), 152.8, 142.6, 141.2,
137.8, 127.0, 124.9, 122.7 and 122.4 (Cq each), 146.7, 133.8, 130.7, 129.2, 128.8,
127.3, 124.8, 120.8, 120.5, 119.9, 112.2, 109.6, 33.2. HRMS Calcd for C25H18NO3
[M+H]+: 380.1287; Found: 380.1286.
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(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(thiophen-2-yl)methanone (4m): Following
the general procedure, compound 4m was obtained by column chromatography on
silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:5:2, v/v/v). 71 mg,
90% yield; white solid, m.p.: 110-113 oC. 1H NMR (400 MHz, CDCl3) δ 8.86 (d, J =
1.6 Hz, 1 H), 8.19 (d, J = 7.7 Hz, 1 H), 8.11 (d, J = 1.5 Hz, 1 H), 8.00 (d, J = 7.4 Hz, 2
H), 7.72 (m, 2 H), 7.65 (t, J = 7.4 Hz, 1 H), 7.55 (m, 3 H), 7.46 (d, J = 8.2 Hz, 1 H),
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7.36 (t, J = 7.4 Hz, 1 H), 7.18 (m, 1 H), 3.69 (s, 3 H). C{1H} NMR (100 MHz,
CDCl3) δ 195.7 and 186.9 (Cq each, C=O), 143.8, 142.5, 140.9, 137.6, 127.9, 124.8,
122.6 and 122.4 (Cq each), 134.2, 133.7, 133.5, 130.6, 128.9, 128.7, 127.9, 127.2,
124.5, 120.7, 120.5, 109.5, 33.1. HRMS Calcd for C25H17SNO2 [M+H]+: 396.1058;
Found: 396.1061.
(1-Benzoyl-9-methyl-9H-carbazol-3-yl)(cyclopropyl)methanone (4n): Following
the general procedure, compound 4n was obtained by column chromatography on
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silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:2:3, v/v/v). 55 mg,
78% yield; white solid, m.p.: 170-173 oC. 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J =
1.5 Hz, 1 H), 8.20 (t, 2 H), 7.98 (m, 2 H), 7.64 (t, 1 H), 7.58-7.48 (m, 3 H), 7.43 (d, J
= 8.2 Hz, 1 H), 7.35 (t, 1 H), 3.64 (s, 3 H), 2.84-2.74 (m, 1 H), 1.30 (m, 2 H), 1.06 (m,
2 H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.2 and 196.0 (Cq each, C=O), 142.7,
141.2, 137.9, 128.5, 124.9, 122.9 and 122.5 (Cq each), 133.8, 130.7, 128.9, 127.8,
127.2, 123.3, 120.8, 120.5, 109.6, 33.2, 17.1, 11.6. HRMS Calcd for C24H19NO2
[M+H]+: 354.1494; Found: 354.1492.
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(3-Benzoyl-9-methyl-9H-carbazol-1-yl)(p-tolyl)methanone (4o): Following the
general procedure, compound 4o was obtained by column chromatography on silica
gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 = 20:1:2, v/v/v). 72 mg, 89%
yield; yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 1.6 Hz, 1 H), 8.15 (d, J
= 7.8 Hz, 1 H), 8.03 (d, J = 1.6 Hz, 1 H), 7.86 (m, 4 H), 7.57 (m, 2 H), 7.49 (t, J = 7.5
Hz, 2 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.33 (m, 3 H), 3.68 (s, 3 H), 2.45 (s, 3 H). 13C{1H}
(100 MHz, CDCl3) δ 195.9 and 195.7 (Cq each, C=O), 145.0, 142.7, 141.1, 138.6,
135.4, 127.7, 124.8, 122.9 and 122.8 (Cq each), 132.1, 130.9, 130.0, 129.6, 128.4,
127.3, 125.4, 120.8, 120.6, 109.6, 33.1, 21.9.
(3-Benzoyl-9-methyl-9H-carbazol-1-yl)(4-methoxyphenyl)methanone
(4p):
Following the general procedure, compound 4p was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 =
20:5:2, v/v/v). 57 mg, 68% yield; yellow solid, m.p.: 209-210 oC. 1H NMR (400 MHz,
CDCl3) δ 8.74 (d, J = 1.1 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 1.1 Hz, 1 H),
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7.95 (d, J = 8.8 Hz, 2 H), 7.85 (d, J = 7.3 Hz, 2 H), 7.57 (m, 2 H), 7.50 (t, J = 7.5 Hz,
2 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2 H),
3.89 (s, 3 H), 3.68 (s, 3 H). 13C{1H} (100 MHz, CDCl3) δ 196.0 and 194.7 (Cq each,
C=O), 164.3, 142.6, 141.0, 138.6, 130.7, 129.3, 127.6, 124.7 and 122.8 (Cq each),
133.2, 132.1, 130.0, 128.4, 127.2, 125.3, 120.8, 120.6, 114.1, 109.6, 55.7, 33.0.
HRMS Calcd for C28H22NO3 [M+H]+: 420.1600; Found: 420.1602.
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(3-Benzoyl-9-methyl-9H-carbazol-1-yl)(4-chlorophenyl)methanone
(4q):
Following the general procedure, compound 4q was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/EtOAc/CH2Cl2 =
20:1:5, v/v/v). 80 mg, 95% yield; yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.75 (d,
J = 1.6 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 1.6 Hz, 1 H), 7.92 (m, 2 H),
7.83 (m, 2 H), 7.63-7.54 (m, 2 H), 7.53-7.45 (m, 5 H), 7.35 (t, J = 7.4 Hz, 1 H), 3.68
(s, 3 H). 13C {1H} NMR (100 MHz, CDCl3) δ 195.7 and 194.5 (Cq each, C=O), 142.7,
141.1, 140.5, 138.4, 136.1, 127.6, 125.0, 122.8 and 122.0 (Cq each), 132.2, 132.1,
130.0, 129.7, 129.2, 128.5, 127.5, 125.9, 121.0, 120.7, 109.7, 33.3.
(3-Benzoyl-9-methyl-9H-carbazol-1-yl)(4-bromophenyl)methanone
(4r):
Following the general procedure, compound 4r was obtained by column
chromatography on silica gel (eluent: petroleum ether (60−90 °C)/EtOAc/CH2Cl2 =
20:1:5, v/v/v). 87 mg, 93% yield; yellow solid, m.p.: 174-176 oC. 1H NMR (400 MHz,
CDCl3) δ 8.75 (s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 8.02 (s, 1 H), 7.84 (m, 4 H), 7.65 (m,
2 H), 7.58 (m, 2 H), 7.49 (dd, J = 3 H), 7.35 (t, J = 7.4 Hz, 1 H), 3.68 (s, 3 H). 13C{1H}
(100 MHz, CDCl3) δ 195.7 and 194.7 (Cq each, C=O), 142.7, 141.1, 138.4, 136.5,
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129.3, 127.6, 124.9, 122.7 and 121.9 (Cq each), 132.2, 132.2, 130.0, 129.7, 128.4,
127.4, 125.9, 121.0, 120.7, 109.7, 33.3. HRMS Calcd for C27H19BrNO2 [M+H]+:
468.0599; Found: 468.0595.
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Gram-scale
experiment
Synthesis
of
4e:
A
mixture
of
1-methyl-1H-indole-3-carbaldehyde (1a) (480 mg, 3.0 mmol), 4-methylacetophenone
(2b) (675 mg, 5.0 mmol), and NaOH (480 mg, 12.0 mmol) in 30.0 mL EtOH was
stirred at ambient temperature under an air atmosphere. When 1a was consumed
completely, HOAc (720 mg, 12.0 mmol) was added and EtOH was evaporated at 120
oC. CuCl2·2H2O (102 mg, 0.6 mmol), Bipy (141 mg, 0.9 mmol), TEMPO (1410 mg,
9.0 mmol), propiophenone (3a) (810 mg, 6.0 mmol), and chlorobenzene (50 ml) was
o
added to the mixture and stirred at 120 C under an air atmosphere for 24 h. After
cooled to ambient temperature, 30 mL CH2Cl2 was added and the resultant mixture
was filtered through a short pad of celite, followed by rinsing with 50 mL CH2Cl2.
The combined filtrate was concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (eluent: petroleum ether (60-90 oC)
/EtOAc/CH2Cl2 = 20:1:2, v/v/v) to afford 4e as a white solid (1.01 g, 84%).
A typical procedure for the synthesis of indoles 6  Synthesis of 6a: A mixture
of 1-methyl-1H-pyrrole-2-carbaldehyde (5a) (22 mg, 0.2 mmol), acetophenone (2a)
(48 mg, 0.4 mmol), and NaOH (32 mg, 0.8 mmol) in 2.0 mL EtOH was stirred at
ambient temperature under an air atmosphere. When 5 was consumed completely,
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HOAc (48 mg, 0.8 mmol) was added and EtOH was evaporated at 120 C.
CuCl2·2H2O (6.8 mg, 0.04 mmol), Bipy (9.4 mg, 0.06 mmol), TEMPO (94 mg, 0.6
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mmol), propiophenone (3a) (54 mg, 0.4 mmol), and chlorobenzene (2.5 ml) was
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added to the mixture and stirred at 120 C under an air atmosphere for 16 h. After
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cooled to ambient temperature, 10 mL CH2Cl2 was added and the resultant mixture
was filtered through a short pad of celite, followed by rinsing with 20 mL CH2Cl2.
The combined filtrate was concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (eluent: petroleum ether (60-90
oC)/Et2O/CH2Cl2 = 20:5:2, v/v/v) to afford 6a as a yellow liquid (37 mg, 55%).
(1-Methyl-1H-indole-4,6-diyl)bis(phenylmethanone) (6a): Following the general
procedure, compound 6a was obtained by column chromatography on silica gel
(eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 = 20:5:2, v/v/v). 37 mg, 55% yield;
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yellow oil liquid. H NMR (400 MHz, CDCl3) δ 8.12 and 7.91 (s each, 1:1 H), 7.83
(m, 4 H), 7.56 (m, 2 H), 7.47 (m, 4 H), 7.38 (d, J = 3.0 Hz, 1 H), 6.93 (d, J = 2.6 Hz, 1
13
H), 3.92 (s, 3 H). C{1H}NMR (100 MHz, CDCl3) δ 196.9 and 196.5 (Cq, C=O),
138.6, 138.4, 137.2, 131.2, 130.1 and 129.0 (Cq), 134.8, 132.5, 132.2, 130.2, 130.1,
128.4, 126.1, 115.9, 102.9, 33.4.
(1,2-dimethyl-1H-indole-4,6-diyl)bis(phenylmethanone) (6b): Following the
general procedure, compound 6b was obtained by column chromatography on silica
gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 = 20:5:2, v/v/v). 30 mg, 43%
1
yield; yellow oil liquid. H NMR (400 MHz, CDCl3) δ 8.06 (s, 1 H), 7.87 (s, 1 H),
7.81 (m, 4 H), 7.55 (t, J = 7.4 Hz, 2 H), 7.46 (m, 4 H), 6.76 (s, 1 H), 3.78 (s, 3 H),
2.50 (s, 3 H). 13C{1H}NMR (100 MHz, CDCl3) δ 197.0 and 196.5 (Cq, C=O), 144.2,
138.8, 138.6, 138.0, 131.1, 128.8 and 127.4 (Cq each), 132.3, 132.0, 130.1, 130.0,
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(4-(4-Chlorobenzoyl)-1-methyl-1H-indol-6-yl)(p-tolyl)methanone (6c): Following
the general procedure, compound 6c was obtained by column chromatography on
silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 = 20:5:2, v/v/v). 54 mg,
70% yield; yellow oil liquid. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1 H), 7.86 (d, J =
1.3 Hz, 1 H), 7.78 (m, 2 H), 7.73 (d, J = 8.1 Hz, 2 H), 7.43 (m, 2 H), 7.37 (d, J = 3.0
Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 6.89 (m, 1 H), 3.91 (s, 3 H), 2.44 (s, 3 H). 13C{1H}
(100 MHz, CDCl3) δ 196.2 and 195.6 (Cq, C=O), 143.1, 138.9, 137.1, 136.9, 135.5,
130.8, 130.5 and 128.5 (Cq), 134.7, 131.6, 130.3, 129.1, 128.7, 125.7, 116.1, 102.7,
33.4, 21.8. HRMS Calcd for C24H19ClNO2 [M+H]+: 388.1104; Found: 388.1101.
(4-(4-Chlorobenzoyl)-1-methyl-1H-indol-6-yl)(o-tolyl)methanone (6d): Following
the general procedure, compound 6d was obtained by column chromatography on
silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 = 20:5:2, v/v/v). 45 mg,
58% yield; yellow oil liquid. 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1 H), 7.86 (d, J =
1.1 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 2 H), 7.43 (s, 1 H), 7.41 (s, 1 H), 7.36 (m, 3 H), 7.29
(d, J = 7.6 Hz, 1 H), 7.24 (m, 1 H), 6.88 (d, J = 2.9 Hz, 1 H), 3.89 (s, 3 H), 2.35 (s, 3
H). 13C {1H} NMR (100 MHz, CDCl3) δ 198.2 and 195.5 (Cq, C=O), 139.1, 138.9,
137.2, 136.8, 136.7, 131.4, 130.5 and 128.8 (Cq), 135.2, 131.5, 131.2, 130.3, 128.7,
128.3, 125.7, 125.3, 116.0, 102.9, 33.5, 20.1. HRMS Calcd for C24H19ClNO2 [M+H]+:
388.1104; Found: 388.1110.
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(4-(4-Chlorobenzoyl)-1-methyl-1H-indol-6-yl)(3,4-dimethoxyphenyl)methanone
(6e): Following the general procedure, compound 6e was obtained by column
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chromatography on silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 =
20:10:2, v/v/v). 54 mg, 62% yield; yellow solid, m.p.: 68-70 oC. 1H NMR (400 MHz,
CDCl3) δ 8.07 (s, 1 H), 7.83 (s, 1 H), 7.78 (d, J = 8.2 Hz, 2 H), 7.47 (s, 1 H), 7.42 (d,
J = 8.3 Hz, 2 H), 7.37 (m, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 3.95 and 3.93 (s each, 3:3
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H), 3.91 (s, 3 H). C{1H} NMR (100 MHz, CDCl3) δ 195.6 and 195.2 (Cq each,
C=O), 152.9, 149.1, 138.9, 137.1, 136.9, 134.5, 130.6 and 128.5 (Cq each), 131.5,
130.8, 128.7, 125.6, 125.2, 115.9, 112.4, 109.9, 102.6, 56.20, 56.18, 33.4. HRMS
Calcd for C25H21ClNO4 [M+H]+: 434.1159; Found: 434.1158.
(6-(2-Naphthoyl)-1-methyl-1H-indol-4-yl)(4-chlorophenyl)methanone
(6f):
Following the general procedure, compound 6f was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 =
20:5:5, v/v/v).71 mg, 84% yield; yellow solid, m.p.: 159-162 oC. 1H NMR (400 MHz,
CDCl3) δ 8.29 (s, 1 H), 8.17 (s, 1 H), 7.93 (m, 5 H), 7.80 (m, 2 H), 7.60 (m, 2 H), 7.40
(m, 3 H), 6.95 (m, 1 H), 3.92 (s, 3 H). 13C {1H} NMR (100 MHz, CDCl3) δ 196.5 and
195.6 (Cq, C=O), 138.9, 137.2, 136.9, 135.6, 135.3, 132.4, 131.1, 130.5 and 128.6
(Cq), 134.9, 131.6, 131.6, 129.4, 128.8, 128.4, 128.4, 128.0, 127.0, 126.0, 125.8,
116.2, 102.8, 33.5. HRMS Calcd for C27H19ClNO2 [M+H]+: 424.1104; Found:
424.1101.
(4-(4-Chlorobenzoyl)-1-methyl-1H-indol-6-yl)(4-fluorophenyl)methanone
(6g):
Following the general procedure, compound 6g was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 =
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20:5:2, v/v/v). 53 mg, 68% yield; yellow solid, m.p.: 56-58 oC. H NMR (400 MHz,
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CDCl3) δ 8.08 (s, 1 H), 7.85 (m, 3 H), 7.78 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2
H), 7.39 (d, J = 3.0 Hz, 1 H), 7.16 (t, J = 8.5 Hz, 2 H), 6.87 (d, J = 3.0 Hz, 1 H), 3.92
(s, 3 H).13C {1H} NMR (100 MHz, CDCl3) δ 195.5 and 195.0 (Cq each, C=O), 165.4
(Cq, d, J = 252.3 Hz, i-C of C6H4F), 139.1, 137.1, 136.8, 134.5 (Cq, d, J = 3.1 Hz,
p-C of C6H4F), 131.1, 130.1 and 100.1 (Cq), 134.9, 132.6 (CH, d, J = 9.0 Hz, m-C of
C6H4F), 131.6, 128.8, 125.4, 115.8 (CH, d, J = 22.7 Hz, o-C of C6H4F), 115.5, 102.8,
33.5. 19F NMR (100 MHz, CDCl3) δ 106.2. HRMS Calcd for C23H16ClFNO2 [M+H]+:
392.0854; Found: 392.0855.
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(4-(4-Chlorobenzoyl)-1-methyl-1H-indol-6-yl)(furan-2-yl)methanone
(6h):
Following the general procedure, compound 6h was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 =
o
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20:10:2, v/v/v). 47 mg, 65% yield; yellow solid, m.p.: 170-173 C. H NMR (400
MHz, CDCl3) δ 8.31 (s, 1 H), 8.14 (d, J = 1.3 Hz, 1 H), 7.80 (m, 2 H), 7.68 (d, J = 1.5
Hz, 1 H), 7.46 (m, 2 H), 7.38 (d, J = 3.0 Hz, 1 H), 7.27 (d, J = 3.5 Hz, 1 H), 6.89 (d, J
= 3.0 Hz, 1 H), 6.60 (m, 1 H, furyl CH), 3.95 (s, 3 H). 13C {1H} NMR (100 MHz,
CDCl3) δ 195.6 and 181.8 (Cq, C=O), 152.9, 138.9, 137.2, 137.0, 131.1, 129.7 and
128.7 (Cq), 146.9, 134.9, 131.6, 128.7, 125.2, 120.2, 115.6, 112.4, 102.8, 33.5.
HRMS Calcd for C21H15ClNO3 [M+H]+: 364.0740; Found: 364.0743.
(4-(4-Chlorobenzoyl)-1-methyl-1H-indol-6-yl)(thiophen-2-yl)methanone
(6i):
Following the general procedure, compound 6i was obtained by column
chromatography on silica gel (eluent: petroleum ether (60-90 °C)/Et2O/CH2Cl2 =
o
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20:10:2, v/v/v). 55 mg, 73% yield; yellow solid, m.p.: 184-187 C. H NMR (400
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