Gold-catalyzed Michael addition/intramolecular annulation cascade: An effective pathway for the chemoselective- and regioselective synthesis of tetracyclic indole derivatives in water

Article abstract of DOI:10.1039/c2gc36301a

The report describes a gold(i) complex and trifluoroacetic acid (TFA) cocatalyzed one-pot, Michael addition/intramolecular cyclization cascade reaction for the synthesis of unusual tetracyclic indoles containing a seven-membered ring in water with microwa

Full text of DOI:10.1039/c2gc36301a

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Gold-catalyzed Michael addition/intramolecular
annulation cascade: an effective pathway for the
chemoselective- and regioselective synthesis of
tetracyclic indole derivatives in water†
Cite this: Green Chem., 2013, 15, 718
Shengtao Xu,‡a,b Yu Zhou,‡b Jinyi Xu,*a Hualiang Jiangb and Hong Liu*a,b
The report describes a gold(I) complex and trifluoroacetic acid (TFA) cocatalyzed one-pot, Michael
addition/intramolecular cyclization cascade reaction for the synthesis of unusual tetracyclic indoles con-
taining a seven-membered ring in water with microwave irradiation (MW). This protocol presents an
operationally simple, rapid and environmentally friendly strategy for preparing potential biologically
interesting fused-indole molecular architectures from some simple starting materials.
Received 17th August 2012,
Accepted 16th December 2012
DOI: 10.1039/c2gc36301a
www.rsc.org/greenchem
has been well documented that the C2- and C3-positions of an
indole are the active positions for the reactivity,5 which can
Introduction
Fused-indoles have received much attention because of the serve as a double nucleophile in the proposed sequence and,
broad scope of their biological activities, and they are found in therefore, provide many opportunities to construct diversified
a large number of natural products and bioactive molecules.1 fused-indole derivatives. Commonly, indole 3-derivatization
In particular, tetracyclic indoles that contain a seven-mem- could be performed by the Michael addition6 of indoles with
bered ring represent a common structural motif present in a α,β-unsaturated compounds in the presence of a protic or
variety of bioactive compounds, such as anticancer com- Lewis acid, such as SmI3, ScCO2, CeCl3·7H2O–NaI/SiO2, Yb-
pounds a and b,2 and antimicrobial compound c3 (Scheme 1). (OTf)3, InCl3, InBr3, and I2. However, long reaction times are
Therefore, developing efficient methods for the construction often required in these transformations,7 and most of these
of these tetracyclic indoles is a priority. However, the available reactions must be carried out in organic solvents.
strategies for the synthesis of these compounds are limited,4
Within the framework of green chemistry,8 microwaves and
and these synthetic challenges inspired us to explore various water have emerged as attractive tools for the rapid and
efficient strategies for achieving these intriguing molecules. It environmental friendly construction of these unusual com-
pounds.9 Water is one of the most benign solvents, and often
has an unprecedented effect on the rate and selectivity of
organic reactions through hydrophobic interactions and the
enrichment of organic substrates in the local hydrophobic
environment.10 However, water is rarely used in transition
metal catalysis because many catalysts are highly sensitive
towards moisture.11 In our previous research, we have
Scheme 1 The active molecules of tetracyclic indoles.
successfully developed an efficient and regioselective method
for the synthesis of indole derivatives via gold-catalyzed
aDepartment of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia
intramolecular hydroamination in water under microwave
Xiang, Nanjing 210009, P. R. China. E-mail: jinyixu@china.com;
irradiation.12 In the light of our ongoing efforts to develop new
Tel: +86-25-83271445; Fax: +86-25-83302827
methods for synthesizing potential bioactive fused-polycyclic
compounds using green reaction conditions, we here report
our recent findings of the chemoselective- and regioselective
synthesis of tetracyclic indole derivatives containing a seven-
bThe Center for Drug Discovery and Design, State Key Laboratory of Drug Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai
201203, P. R. China. E-mail: hliu@mail.shcnc.ac.cn; Tel: (+86) 21-50807042;
Fax: (+86) 21-50807042
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
membered ring by means of
a gold-catalyzed Michael
NMR spectra for target compounds. CCDC 894928 (3Ba). For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c2gc36301a
‡These authors contributed equally to this work.
addition/intramolecular annulation cascade in water using
microwave irradiation.
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Results and discussion
We initiated our studies by examining catalyst and reaction
conditions using the ortho-phenylethynyl substituted nitrosty-
rene 1A and indole (2a) as a model substrate. As shown in
Table 1, we firstly explored the reaction of the starting material
1A with unsubstituted indole (2a) under the condition of using
10 mol% of Au catalyst I that is (acetonitrile)[(2-biphenyl)di-
tert-butylphosphine]gold(I)hexafluoroantimonate (Scheme 2)
as a catalyst at 100 °C for 20 min in water using microwave
irradiation, but the desirable product 3Aa was not detected
(Table 1, entry 1). However, we were surprised to observe the
expected fused-tetracyclic indole product with 27% yield when
a catalytic amount of TFA (20 mol%) was used as an additive
(Table 1, entry 2). The yield could be improved to 86%
by increasing the reaction temperature to 120 °C (Table 1,
entry 3).
Scheme 2 The structure of the Au catalysts.
However, a further elevation of the temperature to 140 °C
did not improve the yield of this transformation (Table 1, entry
4). It was apparent that the reaction time had a significant
Table 1 Optimization of the reaction conditionsa
Scheme 3 The 6-exo and 7-endo cyclization pathways.
influence on the yield of this reaction. Only 53% yield was
obtained when the reaction time was shortened to 10 min
(Table 1, entry 5). It was reported that the C3-position of an
indole is the most reactive among three reactive positions
(N1, C2, C3) of indole.5 Therefore, in principle, as shown in
Scheme 3, there are two possible reaction pathways to con-
struct four products for this tandem cyclization from the start-
ing material 1 and indole: (a) the formation of intermediates 4
and/or 5 via gold-catalyzed hydroarylation, which are sub-
sequently cyclized to give products 6 and/or 7 via a further
Michael addition; (b) the first formation of the key intermedi-
ate 8 via a Lewis acid mediated Michael addition, and further
cyclizing to the compounds 3 and/or 9 via gold-catalyzed intra-
Entry
Catalyst system
Additive
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
AuCl(PPh3)
NaAuCl4·2H2O
Au catalyst II
Au catalyst III
—
AgOTf
Yb(OTf)3
AgSbF6
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
Au catalyst I
—
TFA
TFA
TFA
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
0b
27c
86
83d
53e
0
TFA
PhCOOH
ClCH2COOH
CH3COOH
TsOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
0
0
9
52
25
5
10
11
12
13
14
15
16
17
18
19
20
21
22
70f
71g
0
0
0
0
74
30
23
0h
59i
1
molecular hydroarylation. However, H NMR, 13C NMR, mass
spectroscopy and X-ray crystallography (as shown in Fig. 1)
demonstrated that the final product is the expected structure
3, and no other products were detected. Subsequently, other
protic acids, such as PhCOOH, ClCH2COOH and CH3COOH,
were screened as the additive for this transformation, and did
not catalyze the cascade cyclization (Table 1, entries 6–8).
H2O
Toluene
DMF
THF
Toluene–H2O
H2O
a Reaction conditions: 1A (0.2 mmol), 2a (0.3 mmol), catalyst
(0.02 mmol), additive (0.04 mmol), water (3 mL) under 120 °C for However, it seems that TsOH was slightly effective for this reac-
20 min. b Au catalyst
butylphosphine]gold(I)hexafluoroantimonate.
I
=
(acetonitrile)[(2-biphenyl)di-tert-
c Reaction
was
tion (Table 1, entry 9). Different gold catalysts such as AuCl-
(PPh3), NaAuCl4, Au catalyst II and Au catalyst III were also
performed at 100 °C. d Reaction was performed at 140 °C. e The
reaction time was shortened to 10 min. f Au catalyst II = 1,3-bis(2,6- tested in this system (Table 1, entries 10–13), but Au catalyst I
diisopropylphenyl imidazol-2-ylidene)gold(I) chloride. g Au catalyst III =
was proved to be the most effective catalyst for the transfor-
mation. In the absence of Au catalyst I, the product 3Aa was
not detected when only TFA was used as the catalyst (Table 1,
chloro[(1,1′-biphenyl-2-yl)di-tert-butylphosphine]gold(I). h Toluene–H2O
(v/v) = 1 : 1. i Reaction was performed at 120 °C in water using an oil
bath for 14 h.
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high yields (Table 2, entries 13–16). Subsequently, we prepared
substrates 1J–1M by introducing fluoro and methyl groups into
the different positions of ortho-phenylethynyl substituted
nitrostyrene (1A). Results of further investigations demon-
strated that all the substrates tested were tolerated in this
cascade transformation with good to excellent yields (Table 2,
entries 17–28). However, treatment of substituted nitrostyrenes
with 5-fluoro and 4-methyl indoles resulted in a slight
reduction in the yield of the target compounds (Table 2,
entries 18, 20 and 25). We speculate that it is due to electronic
effects and/or steric effects of these substituents. In the light
of these findings, this cascade transformation would be an
effective and rapid strategy for the synthesis of intriguing
fused tetracyclic indole molecular scaffolds.
Fig. 1 X-ray crystal structure of 3Ba.
Based on our previous knowledge and the results of our
present study, we propose a plausible mechanism for construc-
tion of the tetracyclic indole frameworks. As shown in
Scheme 4, TFA is a strong Lewis acid and it catalyzes the
addition of indoles to nitroolefins first. The intermediate 8
which has been isolated by stopping the reaction at 5 min con-
firmed our conjecture. The results clearly showed that the
Michael reaction selectively occurred at the C3-position of the
indole ring. The intramolecular cyclization of 8 catalyzed by
AuL/TFA proceeded smoothly to provide the desired product 3.
The results strongly supported our assumption that 3 was
formed through Au(I)-catalyzed cyclization of enyne 8 in the
one-pot procedure. We propose that the initial Au(I)-assisted
electrophilic activation of the triple bond triggers a Friedel–
Crafts-type alkylation at the C3-position of the indole ring,
with the formation of spirocyclic derivative 11.14 The inter-
mediate 11 can rearrange through a 1,2-shift to form the
seven-membered-ring compound 12, which would lose a
proton, and then form compound 3 by protodemetalation.15
entry 14). Some other Lewis acids, such as AgSbF6, AgOTf and
Yb(OTf)3, were also considered, and the results demonstrated
that they could not also catalyze this cascade cyclization to
form the desired products either (Table 1, entries 15–17). It
was also found that the reaction solvent has a significant
action on the yield of this domino transformation. When
toluene, DMF and THF were used as the solvent instead of
H2O, the yields of the desired product 3Aa were decreased to
74%, 30% and 23%, respectively (Table 1, entries 18–20). This
was most probably because the water facilitates the organic
reaction by significant factors such as a hydrophobic effect,
enhanced hydrogen bonding in the transition state and cohe-
sive energy density.13 When the reaction was performed in the
mixed solvent of toluene–water (1 : 1, v/v), no product was
detected (Table 1, entry 21), which was most likely due to the
mixed solvent reducing the chemical interactions between
reactants and catalysts. When we performed this transfor-
mation under the traditional heating condition, a long reaction
time (14 h) was needed to finish this reaction, and only 59% of
the target product was isolated (Table 1, entry 22).
After determining the optimized conditions (10 mol% Au
catalyst I, 20 mol% TFA, H2O, MW, 120 °C for 20 min), we
examined the cascade process, as shown in Table 2. Firstly, a
variety of ortho-alkyne substituted nitrostyrenes including aryl-
alkyne substituted, heterocycle-alkyne substituted and alkyl-
alkyne substituted nitrostyrenes were tolerant and could
provide the desired products (3Aa–3Ha) in moderate to good
yields (53–87%) (Table 2, entries 1–9). It seems that aryl-alkyne
substituted nitrostyrenes are more suitable for the cyclization
transformation (Table 2, entries 1–6). Moderate yields could be
observed for heterocyclic and aliphatic alkyne substituted
nitrostyrenes (Table 2, entries 7–9).
We further examined the extent of the action of the sub-
strate using a variety of different indoles (Table 2, entries
10–16). These investigations revealed that the yield of the
cascade cyclization was slightly affected by the electronic prop-
erties of the R3 substituents of the indole ring. Relatively low
yields were observed for the indoles bearing halogens (Table 2,
entries 10–12).
Conclusion
In summary, we have developed a new and environmentally
friendly Au(I)/TFA-catalyzed regioselective one-pot cascade for
the synthesis of tetracyclic indoles containing a seven-mem-
bered ring. The reaction can be performed in aqueous media
using microwave irradiation, which reveals excellent tolerance
to various substrates, and the target compounds can be
obtained with good to excellent yields. In view of a large
number of bioactivities involving fused-indole scaffolds, we
expect that these potential special structures will have wide
applicability in medicinal chemistry. Further studies are being
undertaken, and the corresponding results will be reported in
due course.
Experimental section
General experimental procedures
When methoxy, methyl and cyano groups were introduced
into the indole ring, the desired products were obtained with
The reagents were purchased from commercial sources and
used without further purification. Analytical thin layer
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Table 2 Gold-mediated one-pot domino synthesis of target compoundsa
Entry
1
Product
Yield (%)
86
Entry
15
Product
Yield (%)
90
3Aa
3Ah
2
3
4
3Ba
3Fa
3Ca
84
87
71
16
17
18
3Af
3Ja
3Jb
85
94
71
5
6
3Da
3Ea
64
74
19
20
3Ka
3Kb
79
59
7
8
3Ia
63
76
21
22
3Ke
85
95
3Ga
3Me
9
3Ha
3Ab
53
65
23
24
3Le
86
86
10
3Md
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Table 2 (Contd.)
Entry
11
Product
Yield (%)
62
Entry
25
Product
Yield (%)
66
3Ac
3Ad
3Mh
3Mi
12
78
26
91
13
14
3Ae
3Ag
87
78
27
28
3Mj
84
87
3Mk
a Reagents and conditions: 1A (0.2 mmol), 2a (0.3 mmol), Au catalyst I (10 mol%), TFA (20 mol%), H2O (3–4 mL), M.W. irradiation (120 °C,
20 min).
Low- and high-resolution mass spectra (LRMS and HRMS)
were measured on a Finnigan MAT 95 spectrometer.
Typical procedure for synthesis of the 12-(nitromethyl)-
6-phenyl-5,12-dihydrobenzo[4,5]cyclohepta[1,2-b]indoles (3Aa
as an example) in water. To a mixture of (E)-1-(2-nitrovinyl)-2-
(phenylethynyl)benzene (1A, 0.2 mmol) and indole (2a,
0.3 mmol) in 3 mL of H2O was added Au catalyst I (0.02 mmol)
and trifluoroethanoic acid (0.04 mmol). The reaction vial was
sealed and the mixture was then irradiated at 120 °C for
20 min. After cooling to ambient temperature, the mixture
was concentrated in vacuum, and the resulting residue was
purified by flash chromatography (petroleum ether–ethyl
acetate = 10 : 1, v/v) to afford the expected product 3Aa
(64 mg, 87%) as a white solid. 1H NMR (400 MHz, CDCl3) δ
Scheme 4 A proposed mechanism.
7.98 (s, 1H), 7.86 (d, J = 3.2 Hz, 1H), 7.64–7.59 (m, 2H),
7.53–7.34 (m, 7H), 7.24–7.12 (m, 4H), 5.39 (t, J = 8.0 Hz, 1H),
chromatography (TLC) was performed on HSGF 254 4.64 (d, J = 8.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 145.0,
(0.15–0.2 mm thickness). All the microwave-assisted reactions 139.7, 136.8, 135.1, 134.3, 133.8, 131.8, 131.4, 129.9, 129.9,
were performed in an Initiator™ EXP microwave system 129.6, 129.1, 128.9, 128.8, 127.3, 126.3, 123.5, 120.3, 118.2,
(Biotage, Inc.) at the specified temperature using the standard 112.9, 111.0, 75.0, 41.4; LRMS (ESI) m/z 367 [M + H]+; HRMS
mode of operation. Column chromatography was performed (ESI) calcd for C24H18N2O2Na [M + Na]+ 389.1266, found
with a CombiFlash® Companion system (Teledyne Isco, Inc.). 389.1264.
Proton and carbon magnetic resonance spectra (1H NMR and
12-(Nitromethyl)-6-(p-tolyl)-5,12-dihydrobenzo[4,5]cyclo-
13C NMR) were recorded using tetramethylsilane (TMS) in the hepta[1,2-b]indole (3Ba). 1H NMR (400 MHz, CDCl3) δ
solvent of CDCl3 as the internal standard (1H NMR: TMS at 7.95–7.88 (m, 2H), 7.52–7.45 (m, 4H), 7.40–7.26 (m, 4H),
0.00 ppm; CHCl3 at 7.24 ppm; 13C NMR: CDCl3 at 77.0 ppm). 7.24–7.21 (m, 3H), 7.17 (s, 1H), 5.41 (t, J = 8.0 Hz, 1H), 4.64
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(d, J = 8.0 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3) δ LRMS (ESI) m/z 385 [M
+
H]+; HRMS (ESI) calcd for
138.7, 136.7, 136.6, 135.0, 134.4, 133.6, 131.9, 131.2, 129.8, C24H17N2O2NaF [M + Na]+ 407.1172, found 407.1164.
129.6, 129.4, 129.3, 128.7, 127.2, 126.2, 123.4, 120.2, 118.1,
2-Chloro-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]-
112.6, 110.9, 74.9, 41.4, 21.2; LRMS (ESI) m/z 381 [M + H]+; cyclohepta[1,2-b]indole (3Ac). 1H NMR (400 MHz, CDCl3) δ
HRMS (ESI) calcd for C25H20N2O2Na [M + Na]+ 403.1422, 7.95 (s, 1H), 7.82 (s, 1H), 7.60–7.58 (m, 2H), 7.54–7.49 (m, 4H),
found 403.1435.
7.46–7.40 (m, 3H), 7.18 (s, 1H), 7.14 (t, J = 1.2 Hz, 2H), 5.31 (t,
12-(Nitromethyl)-6-(4-fluorophenyl)-5,12-dihydrobenzo[4,5]- J = 8.4 Hz, 1H), 4.68–4.56 (m, 2H); 13C NMR (125 MHz, CDCl3)
cyclohepta[1,2-b]indole (3Ca). 1H NMR (400 MHz, CDCl3) δ δ 139.4, 135.0, 134.9, 134.2, 133.5, 133.2, 131.5, 130.6, 129.9,
7.88–7.86 (m, 2H), 7.58–7.56 (m, 2H), 7.51–7.45 (m, 2H), 129.8, 129.1, 128.9, 128.8, 127.5, 127.4, 126.1, 123.8, 117.7,
7.42–7.39 (m, 2H) 7.26–7.21 (m, 5H), 7.13 (s, 1H), 5.41 (t, J = 112.3, 112.1, 74.9, 41.4; LRMS (ESI) m/z 401 [M + H]+; HRMS
8.4 Hz, 1H), 4.68–4.58 (m, 2H); 13C NMR (125 MHz, CDCl3) δ (ESI) calcd for C24H17N2O2NaCl [M + Na]+ 423.0876, found
163.1 (d, J = 251 Hz), 136.8, 135.8 (d, J = 2.5 Hz), 135.1, 134.2, 423.0896.
132.7, 131.7, 131.3, 130.6 (d, J = 7.5 Hz), 129.9 (d, J = 12.5 Hz),
2-Bromo-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]-
127.3, 126.3, 123.7, 120.5, 118.2, 116.2, 116.0, 113.0, 111.1, cyclohepta[1,2-b]indole (3Ad). 1H NMR (400 MHz, CDCl3) δ
74.9, 41.4; 19F NMR (471 MHz, CDCl3) δ = −112.65 ppm; LRMS 7.99–7.97 (m, 2H), 7.60–7.58 (m, 2H), 7.54–7.42 (m, 4H),
(ESI) m/z 385 [M + H]+; HRMS (ESI) calcd for C24H17N2O2NaF 7.40–7.35 (m, 3H), 7.27–7.25 (m, 1H), 7.19 (s, 1H), 7.07 (d, J =
[M + Na]+ 407.1172, found 407.1183.
8.4 Hz, 1H), 5.31 (t, J = 8.4 Hz, 1H), 4.68–4.56 (m, 2H); 13C
12-(Nitromethyl)-6-(4-chlorophenyl)-5,12-dihydrobenzo[4,5]- NMR (125 MHz, CDCl3) δ 139.4, 135.3, 134.9, 134.2, 133.4,
cyclohepta[1,2-b]indole (3Da). 1H NMR (300 MHz, CDCl3) δ 133.0, 131.5, 130.6, 129.9, 129.8, 129.2, 128.9, 128.8, 128.1,
7.88–7.85 (m, 2H), 7.56–7.43 (m, 6H), 7.41–7.34 (m, 2H), 127.5, 126.3, 120.8, 113.6, 112.5, 112.2, 74.8, 41.3; LRMS (ESI)
7.26–7.20 (m, 3H), 7.15 (s, 1H), 5.41 (t, J = 8.4 Hz, 1H), 4.62 m/z 445 [M + H]+; HRMS (ESI) calcd for C24H17N2O2NaBr
(dd, J = 8.4, 3.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 138.1, [M + Na]+ 467.0371, found 467.0371.
136.9, 135.2, 134.8, 134.1, 132.6, 131.4, 131.4, 130.2, 130.0,
2-Methoxy-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]-
129.9, 129.9, 129.3, 127.3, 126.3, 123.7, 120.5, 118.2, 113.2, cyclohepta[1,2-b]indole (3Ae). 1H NMR (400 MHz, CDCl3) δ
111.0, 75.0, 41.4; LRMS (ESI) m/z 401 [M + H]+; HRMS 7.83 (s, 1H), 7.61–7.60 (m, 2H), 7.53–7.47 (m, 5H), 7.40–7.34
(ESI) calcd for C24H17N2O2NaCl [M + Na]+ 423.0876, found (m, 2H), 7.27–7.26 (m, 1H), 7.14–7.11 (m, 2H), 6.89 (dd, J = 8.8,
423.0896.
2.4 Hz, 1H), 5.35 (t, J = 8.0 Hz, 1H), 4.64 (d, J = 8.0 Hz, 2H),
12-(Nitromethyl)-6-(4-bromophenyl)-5,12-dihydrobenzo[4,5]- 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 154.6, 139.8, 135.1,
cyclohepta[1,2-b]indole (3Ea). 1H NMR (300 MHz, CDCl3) 134.4, 133.9, 132.6, 132.1, 131.4, 129.9, 129.6, 129.6, 129.0,
δ 7.88–7.86 (m, 2H), 7.66–7.63 (m, 2H), 7.51–7.34 (m, 6H), 128.9, 128.7, 127.3, 126.7, 114.3, 112.6, 111.9, 99.4, 75.2, 56.0,
7.26–7.20 (m, 3H), 7.15 (s, 1H), 5.41 (t, J = 8.4 Hz, 1H), 41.6; LRMS (ESI) m/z 397 [M + H]+; HRMS (ESI) calcd for
4.62 (dd, J = 8.4, 3.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) C25H20N2O3Na [M + Na]+ 419.1372, found 419.1368.
δ 138.6, 136.9, 135.2, 134.1, 132.6, 132.2, 131.4, 131.3, 130.5,
2-Carbonitrile-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo-
130.0, 129.9, 127.3, 126.3, 123.8, 122.9, 120.5, 118.2, 113.3, [4,5]cyclohepta[1,2-b]indole (3Af). 1H NMR (500 MHz, CDCl3)
111.1, 75.0, 41.4; LRMS (ESI) m/z 445 [M + H]+; HRMS (ESI) δ 8.26 (s, 1H), 8.21 (s, 1H), 7.60–7.57 (m, 2H), 7.56–7.38 (m,
calcd for C24H17N2O2NaBr [M
467.0353.
+
Na]+ 467.0371, found 8H), 7.30–7.25 (m, 2H), 5.35 (t, J = 8.0 Hz, 1H), 4.74–4.55 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 139.0, 138.1, 134.6, 134.1,
12-(Nitromethyl)-6-(m-tolyl)-5,12-dihydrobenzo[4,5]cyclo- 134.0, 133.1, 131.6, 131.5, 130.3, 129.8, 129.3, 129.1, 128.8,
hepta[1,2-b]indole (3Fa). 1H NMR (300 MHz, CDCl3)
127.7, 126.4, 126.1, 123.9, 120.4, 113.0, 111.9, 103.6, 74.6, 41.1;
7.94–7.87 (m, 2H), 7.53–7.40 (m, 2H), 7.39–7.30 (m, 6H), LRMS (ESI) m/z 392 [M
H]+; HRMS (ESI) calcd for
7.26–7.21 (m, 3H), 7.17 (s, 1H), 5.42 (t, J = 8.1 Hz, 1H), 4.65 (d, C25H17N3O2Na [M + Na]+ 414.1218, found 414.1216.
J = 8.1 Hz, 2H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
2,3-Dimethoxy-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo-
δ
+
139.7, 138.8, 136.8, 135.1, 134.4, 133.9, 132.0, 131.4, 129.9, [4,5]cyclohepta[1,2-b]indole (3Ag). 1H NMR (400 MHz, CDCl3)
129.8, 129.6, 129.5, 129.5, 129.0, 127.3, 126.3, 126.0, 123.5, δ 7.77 (s, 1H), 7.61–7.59 (m, 2H), 7.52–7.48 (m, 5H), 7.39–7.33
120.3, 118.2, 112.7, 111.1, 75.0, 41.4, 21.6; LRMS (ESI) m/z 381 (m, 2H), 7.26–7.22 (m, 1H), 7.06 (s, 1H), 6.74 (s, 1H), 5.31
[M + H]+; HRMS (ESI) calcd for C25H20N2O2Na [M + Na]+ (t, J = 8.0 Hz, 1H), 4.63 (dd, J = 8.4, 3.2 Hz, 2H), 4.04 (s, 3H),
403.1422, found 403.1425.
3.86 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 148.3, 145.7, 140.0,
2-Fluoro-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]- 134.7, 134.6, 133.8, 131.6, 131.3, 130.6, 129.8, 129.3, 128.9,
cyclohepta[1,2-b]indole (3Ab). 1H NMR (400 MHz, CDCl3) δ 128.9, 128.6, 128.1, 127.2, 119.1, 112.8, 99.4, 94.0, 75.1, 56.5,
7.91 (s, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.56–7.30 (m, 8H), 56.1, 41.7, 30.9, 30.9; LRMS (ESI) m/z 427 [M + H]+; HRMS
7.26–7.17 (m, 2H), 6.93 (dd, J = 9.2, 2.4 Hz, 1H), 5.30 (t, J = 8.0 (ESI) calcd for C26H22N2O4Na [M + Na]+ 449.1477, found
Hz, 1H), 4.67–4.56 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 158.2 449.1456.
(d, J = 235 Hz), 139.5, 135.0, 134.3, 133.6 (d, J = 8 Hz), 133.3,
4-Methyl-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]-
131.5, 130.4, 129.8 (d, J = 2.5 Hz), 129.1, 128.9, 127.4, 126.8 (d, cyclohepta[1,2-b]indole (3Ah). 1H NMR (400 MHz, CDCl3) δ
J = 10 Hz), 112.8 (d, J = 5 Hz), 112.2, 112.0, 111.8, 111.8, 103.2, 7.79–7.73 (m, 2H), 7.66–7.64 (m, 2H), 7.57–7.50 (m, 5H),
103.0, 75.0, 41.5; 19F NMR (471 MHz, CDCl3) δ = −122.99 ppm; 7.47–7.26 (m, 2H), 7.20–7.14 (m, 2H), 7.04–7.02 (m, 1H), 5.40
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(t, J = 8.0 Hz, 1H), 4.65 (d, J = 8.4 Hz, 2H), 2.35 (s, 3H); 13C m/z 381 [M + H]+; HRMS (ESI) calcd for C25H20N2O2Na
NMR (100 MHz, CDCl3) δ 139.7, 136.4, 135.2, 134.3, 133.8, [M + Na]+ 403.1422, found 403.1407.
131.4, 131.2, 129.8, 129.7, 129.5, 129.0, 128.7, 127.2, 125.8,
2,10-Difluoro-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo-
124.1, 120.5, 120.2, 115.8, 113.6, 74.9, 41.5, 16.5; LRMS (ESI) [4,5]cyclohepta[1,2-b]indole (3Jb). 1H NMR (400 MHz, CDCl3) δ
m/z 381 [M + H]+; HRMS (ESI) calcd for C25H20N2O2Na 7.93 (s, 1H), 7.59–7.46 (m, 7H), 7.26–7.13 (m, 3H), 7.07–7.03 (m,
[M + Na]+ 403.1422, found 403.1439.
1H), 6.99–6.94 (m, 1H), 5.23 (t, J = 8.0 Hz, 1H), 4.65–4.61 (m,
12-(Nitromethyl)-6-(thiophen-3-yl)-5,12-dihydrobenzo[4,5]- 2H); 13C NMR (100 MHz, CDCl3) δ 163.3 (d, J = 249 Hz), 158.4
cyclohepta[1,2-b]indole (3Ia). 1H NMR (500 MHz, CDCl3) (d, J = 235 Hz), 139.3, 136.9 (d, J = 7 Hz), 133.5, 133.3, 133.2 (d,
δ 8.13 (s, 1H), 7.88–7.86 (m, 1H), 7.58 (dd, J = 3.0, 1.5 Hz, 1H), J = 18 Hz), 130.5 (d, J = 3 Hz), 129.1, 129.0 (d, J = 24 Hz), 128.8,
7.51–7.39 (m, 5H), 7.38–7.22 (m, 5H), 5.39 (t, J = 8.0 Hz, 1H), 126.6 (d, J = 10 Hz), 116.5 (d, J = 22 Hz), 114.6 (d, J = 22 Hz),
4.63–4.60 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 140.8, 112.3, 112.1, 111.9 (d, J = 4 Hz), 111.9 (d, J = 8 Hz), 103.1, 102.9,
136.6, 135.2, 134.2, 131.7, 131.3, 129.9, 129.6, 128.9, 128.2, 74.5, 41.2; 19F NMR (471 MHz, CDCl3)
δ = −111.83,
127.8, 127.2, 126.8, 126.3, 124.0, 123.6, 120.4, 118.2, 112.6, −122.69 ppm; LRMS (ESI) m/z 403 [M + H]+; HRMS (ESI) calcd
111.0, 74.9, 41.3; LRMS (ESI) m/z 373 [M + H]+; HRMS for C24H16N2O2NaF2 [M + Na]+ 425.1078, found 425.1096.
(ESI) calcd for C22H16N2O2NaS [M + Na]+ 395.0830, found
395.0841.
2-Bromo-10-methyl-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Md). 1H NMR (300 MHz,
12-(Nitromethyl)-6-cyclopentyl-5,12-dihydrobenzo[4,5]cyclo- CDCl3) δ 7.97–7.94 (m, 2H), 7.48–7.46 (d, J = 7.8 Hz, 2H),
hepta[1,2-b]indole (3Ga). 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 7.33–7.12 (m, 6H), 7.12–7.06 (m, 2H), 5.26 (t, J = 8.1 Hz, 1H),
1H), 7.86–7.83 (m, 1H), 7.43–7.19 (m, 7H), 6.95 (s, 1H), 5.30 (t, 4.63–4.58 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H); 13C NMR
J = 8.1 Hz, 1H), 4.58–4.45 (m, 2H), 3.18–3.13 (m, 1H), 2.15 (t, (125 MHz, CDCl3) δ 138.9, 137.1, 136.6, 135.2, 134.1, 133.3,
J = 6.2 Hz, 2H), 1.99–1.77 (br, 5H), 1.58–1.55 (m, 1H); 13C NMR 133.1, 132.4, 131.9, 130.6, 130.3, 129.8, 129.8, 128.7, 128.1,
(125 MHz, CDCl3) δ 136.7, 135.9, 134.8, 134.4, 133.3, 131.0, 126.2, 120.8, 113.5, 112.4, 112.2, 75.1, 40.9, 21.3, 20.9; LRMS
129.6, 128.9, 127.0, 126.3, 125.5, 123.2, 120.3, 118.1, 112.1, (ESI) m/z 473 [M + H]+; HRMS (ESI) calcd for C26H21N2O2NaBr
110.9, 74.6, 44.3, 41.2, 33.3, 31.6, 25.1, 24.8; LRMS (ESI) m/z [M + Na]+ 495.0684, found 495.0710.
359 [M + H]+; HRMS (ESI) calcd for C23H22N2O2Na [M + Na]+
381.1579, found 381.1574.
2-Fluoro-9-methyl-12-(nitromethyl)-6-phenyl-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Kb). 1H NMR (400 MHz,
12-(Nitromethyl)-6-propyl-5,12-dihydrobenzo[4,5]cyclohepta- CDCl3) δ 7.87 (s, 1H), 7.60–7.58 (m, 2H), 7.54–7.46 (m, 4H),
[1,2-b]indole (3Ha). 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 7.35–7.31 (m, 2H), 7.26–7.21 (m, 1H), 7.15–7.13 (m, 2H),
7.86–7.83 (m, 1H), 7.41–7.21 (m, 7H), 6.92 (s, 1H), 5.30 6.97–6.94 (m, 1H), 5.25 (t, J = 8.4 Hz, 1H), 4.68–4.55 (m, 2H),
(t, J = 8.1 Hz, 1H), 4.60–4.45 (m, 2H), 2.83 (br, 1H), 2.64–2.54 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.1 (d, J = 235 Hz),
(m, 1H), 1.70 (br, 2H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR 139.6, 137.0, 134.0, 133.5, 133.4 (d, J = 9 Hz), 132.3, 131.9,
(125 MHz, CDCl3) δ 136.8, 134.6, 134.3, 132.7, 132.4, 130.9, 130.5 (d, J = 19 Hz), 129.7, 129.1, 128.8 (d, J = 4 Hz), 126.8 (d,
129.8, 129.1, 128.8, 127.2, 126.5, 123.3, 120.3, 118.1, 112.1, J = 9 Hz), 113.0 (d, J = 6 Hz), 112.0, 111.8, 111.7, 111.6, 103.2
111.0, 74.8, 41.4, 38.1, 22.7, 14.1; LRMS (ESI) m/z 333 [M + H]+; (d, J = 23 Hz), 75.1, 41.1, 20.9; 19F NMR (471 MHz, CDCl3) δ =
HRMS (ESI) calcd for C21H20N2O2Na [M + Na]+ 355.1422, −123.09 ppm; LRMS (ESI) m/z 399 [M + H]+; HRMS (ESI) calcd
found 355.1419.
for C25H19N2O2NaF [M + Na]+ 421.1325, found 421.1328.
10-Fluoro-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]-
2-Methoxy-9-methyl-12-(nitromethyl)-6-phenyl-5,12-dihydro-
cyclohepta[1,2-b]indole (3Ja). 1H NMR (400 MHz, CDCl3) δ benzo[4,5]cyclohepta[1,2-b]indole (3Ke). 1H NMR (400 MHz,
7.93 (s, 1H), 7.86–7.84 (m, 1H), 7.60–7.58 (m, 2H), 7.50–7.46 CDCl3) δ 7.79 (s, 1H), 7.60–7.58 (m, 2H), 7.53–7.46 (m, 3H),
(m, 4H), 7.26–7.16 (m, 4H), 7.13 (s, 1H), 7.05–7.04 (m, 1H), 7.36–7.21 (m, 4H), 7.13–7.09 (m, 2H), 6.86 (dd, J = 8.8, 2.4 Hz,
5.34 (t, J = 8.0 Hz, 1H), 4.66–4.63 (m, 2H); 13C NMR (100 MHz, 1H), 5.31 (t, J = 8.4 Hz, 1H), 4.63 (d, J = 8.4 Hz, 2H), 4.95 (s,
CDCl3) δ 163.2 (d, J = 257 Hz), 162.3, 139.5, 137.1, 137.0, 136.7, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.5, 139.8,
133.3, 133.2, 133.1, 131.8, 130.6 (d, J = 3 Hz), 129.1, 128.8 (d, 136.8, 134.2, 133.7, 132.5, 132.4, 132.0, 131.8, 130.3, 129.8,
J = 9 Hz), 128.7, 126.1, 123.6, 120.4, 118.0, 116.5 (d, J = 22 Hz), 129.7, 128.9, 128.8, 128.6, 126.6, 114.1, 112.7, 111.8, 99.3, 75.3,
114.5 (d, J = 21 Hz), 111.9, 111.0, 74.6, 41.1; 19F NMR 55.9, 41.1, 20.9; LRMS (ESI) m/z 411 [M + H]+; HRMS (ESI)
(471 MHz, CDCl3) δ = −112.25 ppm; LRMS (ESI) m/z 385 calcd for C26H22N2O3Na [M + Na]+ 433.1528, found 433.1507.
[M + H]+; HRMS (ESI) calcd for C24H17N2O2FNa [M + Na]+
407.1172, found 407.1187.
2-Methoxy-10-fluoro-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Le). 1H NMR (400 MHz,
9-Methyl-12-(nitromethyl)-6-phenyl-5,12-dihydrobenzo[4,5]- CDCl3) δ 7.85 (s, 1H), 7.48–7.44 (m, 3H), 7.32–7.30 (d, J =
cyclohepta[1,2-b]indole (3Ka). 1H NMR (400 MHz, CDCl3) δ 7.6 Hz, 2H), 7.26–7.00 (m, 5H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H),
7.89–7.86 (m, 2H), 7.61–7.59 (m, 2H), 7.54–7.47 (m, 3H), 5.27 (t, J = 8.4 Hz, 1H), 4.69–4.60 (m, 2H), 3.95 (s, 3H), 2.46 (s,
7.34–7.31 (m, 2H), 7.26–7.19 (m, 4H), 7.13 (s, 1H), 5.37 (t, J = 3H); 13C NMR (125 MHz, CDCl3) δ 163.4 (d, J = 249 Hz), 154.7,
8.0 Hz, 1H), 4.61 (dd, J = 8.4, 1.2 Hz, 2H), 2.37 (s, 3H); 13C 138.8, 137.0 (d, J = 7 Hz), 136.7, 133.3, 133.1 (d, J = 8 Hz),
NMR (100 MHz, CDCl3) δ 139.8, 136.8, 136.7, 134.1, 133.6, 132.7, 132.0, 130.8 (d, J = 3 Hz), 129.7, 128.8, 127.9, 126.5,
132.4, 131.8, 130.5, 130.0, 129.8, 129.0, 128.8, 128.6, 126.3, 116.6 (d, J = 22 Hz), 114.5 (d, J = 23 Hz), 112.0, 111.6 (d, J =
123.4, 120.2, 118.1, 113.0, 110.9, 75.2, 41.0, 20.9; LRMS (ESI) 5 Hz), 99.2, 74.7, 56.0, 41.2, 21.3; 19F NMR (471 MHz, CDCl3)
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δ = −112.64 ppm; LRMS (ESI) m/z 429 [M + H]+; HRMS (ESI)
Acknowledgements
calcd for C26H21N2O3NaF [M + Na]+ 451.1434, found 451.1439.
2-Methoxy-9-methyl-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro- We gratefully acknowledge financial support from the National
benzo[4,5]cyclohepta[1,2-b]indole (3Me). 1H NMR (400 MHz, Basic Research Program of China (Grants 2009CB940903 and
CDCl3) δ 7.80 (s, 1H), 7.50–7.48 (m, 2H), 7.36–7.30 (m, 4H), 2012CB518005), the National Natural Science Foundation of
7.26–7.18 (m, 2H), 7.12–7.07 (m, 2H), 6.88–7.85 (dd, J = 8.8, China (Grants 81102307 and 81025017), National S&T Major
2.4 Hz, 1H), 5.30 (t, J = 8.4 Hz, 1H), 4.62 (d, J = 8.4 Hz, 2H), Projects (2012ZX09103-101-072), China-EU Science and Tech-
3.95 (s, 3H), 2.46 (s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, nology Cooperation Project (1109) and Silver Project (260644).
CDCl3) δ 154.6, 138.7, 137.0, 136.8, 134.3, 133.7, 132.8, 132.4,
132.0, 131.8, 130.3, 129.8, 129.7, 129.2, 128.8, 126.7, 114.0,
112.6, 111.8, 99.4, 75.3, 56.0, 41.2, 27.0, 21.3, 20.9; LRMS (ESI)
References
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[M + Na]+ 447.1685, found 447.1669.
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1-Methyl-9-methyl-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Mh). 1H NMR (400 MHz,
CDCl3) δ 7.90 (s, 1H), 7.52–7.50 (m, 2H), 7.38–7.32 (m, 4H),
7.21–7.19 (m, 1H), 7.13 (s, 1H), 7.06–7.05 (m, 2H), 6.89 (m, 1H),
5.84 (t, J = 8.0 Hz, 1H), 4.76–4.59 (m, 2H), 3.00 (s, 3H), 2.47 (s,
3H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.7, 137.1,
137.0, 136.8, 134.2, 133.9, 133.2, 132.1, 131.5, 130.6, 130.2,
129.7, 129.6, 129.1, 128.8, 124.5, 123.2, 122.4, 113.8, 109.1,
75.1, 42.3, 21.3, 21.0; LRMS (ESI) m/z 409 [M + H]+; HRMS (ESI)
calcd for C27H24N2O2Na [M + Na]+ 431.1735, found 431.1723.
2-Methyl-9-methyl-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Mi). 1H NMR (400 MHz,
CDCl3) δ 7.82 (s, 1H), 7.64 (s, 1H), 7.50–7.48 (m, 2H), 7.34–7.31
(m, 4H), 7.18 (dd, J = 7.2, 2.0 Hz, 1H), 7.13–7.02 (m, 3H), 5.33
(t, J = 8.0 Hz, 1H), 4.61 (dd, J = 8.0, 2.0 Hz, 2H), 2.52 (s, 3H),
2.47 (s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.6,
137.0, 136.8, 135.1, 134.3, 133.7, 132.5, 132.2, 131.8, 130.3,
129.8, 129.7, 129.5, 129.3, 128.8, 126.5, 125.1, 117.7, 112.4,
110.6, 75.3, 41.1, 21.6, 21.3, 21.0; LRMS (ESI) m/z 409 [M + H]+;
HRMS (ESI) calcd for C27H24N2O2Na [M + Na]+ 431.1735,
found 431.1717.
3-Methyl-9-methyl-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Mj). 1H NMR (400 MHz,
CDCl3) δ 7.79 (s, 1H), 7.74–7.73 (m, 1H), 7.51–7.49 (m, 2H),
7.34–7.32 (m, 4H), 7.20–7.18 (m, 1H), 7.07–7.02 (m, 3H), 5.33
(t, J = 8.0 Hz, 1H), 4.61 (d, J = 8.0 Hz, 2H), 2.48 (s, 3H), 2.45 (s,
3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.6, 137.2,
137.1, 136.8, 134.4, 133.7, 133.4, 132.4, 131.8, 131.5, 130.3,
129.8, 129.7, 129.0, 128.8, 124.3, 122.1, 117.9, 112.9, 110.8,
75.2, 41.2, 21.9, 21.3, 21.0; LRMS (ESI) m/z 409 [M + H]+;
HRMS (ESI) calcd for C27H25N2O2 [M + H]+ 409.1916, found
409.1930.
4-Methyl-9-methyl-12-(nitromethyl)-6-(p-tolyl)-5,12-dihydro-
benzo[4,5]cyclohepta[1,2-b]indole (3Mk). 1H NMR (400 MHz,
CDCl3) δ 7.79 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.55–7.53 (m,
2H), 7.35–7.32 (m, 4H), 7.21–7.12 (m, 3H), 7.04–7.02 (m, 1H),
5.35 (t, J = 8.4 Hz, 1H), 4.63 (d, J = 8.4 Hz, 2H), 2.49 (s, 3H),
2.38 (s, 3H), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.7,
137.0, 136.8, 136.4, 134.3, 133.6, 132.6, 131.8, 131.7, 130.2,
129.8, 129.5, 128.7, 125.9, 124.0, 120.5, 120.2, 115.9, 113.7,
75.2, 41.2, 21.3, 21.0, 16.6; LRMS (ESI) m/z 409 [M + H]+;
HRMS (ESI) calcd for C27H24N2O2Na [M + Na]+ 431.1735,
found 431.1720.
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