Synthesis of indoline-fused eight-membered azaheterocycles through Zn-catalyzed dearomatization of indoles and subsequent base-promoted C-C activation

Article abstract of DOI:10.1039/d0ob01626h

A cascade reaction involving the Zn-catalyzed dearomatization of indoles, base-promoted ring-expansion and intramolecular SNAr reaction has been developed. This process realized a novel, atom economical and efficient synthesis of indoline-fused eight-membered azaheterocycles in a one pot manner.

Full text of DOI:10.1039/d0ob01626h

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Synthesis of indoline-fused eight-membered azaheterocycles
through Zn-catalyzed dearomatization of indoles and subsequent
base-promoted C–C activation
Received 00th January 20xx,
Accepted 00th January 20xx
Yuanyang Mu,a Yang Yuan,a Ye Wang,a Murong Xu,a Ye Feng,a Yulei Zhao*b and Yanzhong Li*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A cascade procedure of Zn-catalyzed dearomatization of indoles, base-promoted ring-expansion and intramolecular SNAr
reaction has been developed. This process realized a novel, atom economic and efficient synthesis of indoline-fused eight-
membered azaheterocycles in a one-pot manner.
Feringa's work: Cu-catalyzed allylic substitution / Ru-catalyzed ring-closing metathesis
Introduction
Tos
cat. CuBr/Taniaphos
N
cat. Hoveyda-Grubbs 2
CH2Cl2, reflux
MeMgBr
(a)
(b)
N
CH2Cl2, -80 o
C
Tos
Br
N
Tos
Dearomatization of indoles has been well developed as an
efficient and powerful strategy to construct a variety of
compounds containing indoline alkaloid skeletons.1 And these
compounds attracted great interest from chemists due to their
biological activities such as anti-cancer and anti-inflammation.2
In recent years, cleavage reactions of carbon-carbon σ-bonds
have received much attention as well since these
transformations can reorganize molecular framework and
afford versatile scaffolds with high efficiency.3 On the other
hand, eight-membered nitrogen heterocycle fused indoline
skeletons are commonly found in indoline alkaloids, such as
Lundurine B,4 Lapidilectine B,5 and Grandilodine A6 (Figure 1).
Rovis's work: Rh-catalyzed [4+2+2] cycloaddition
O
O
cat. [Rh(C2H4)2Cl]2
phosphoramidite L
O
C
n-Hex
N
N
+
+
n-Hex
PhMe, 110 o
C
n-Hex
Louie's work: Ni-catalyzed cycloaddition
O
Me
Me
CO2Me
MeO2C
cat. [Ni(cod)2]
IPr
O
CO2Me
CO2Me
+
(c)
N
PhMe, 0 o
C
Boc
N
Boc
Me Me
our idea: Zn-catalyzed dearomative alkylation / base-promoted C-C bond activation
R4
R4
X
O
O
N
O
R2
X
R4
-O
N
O
R3
(d)
O
O
O
2
Cat. Zn
SNAr
R3
O
R3
Base
N
O
R1
O
O
1
O
N
H O
H O
ring expansion
R2
R2
R2
3
R1
R1
N
N
N
O
O
dearomative
alkylation
MeO2C
MeO
R1
4
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
Lundurine B
Lapidilectine B
Scheme 1 Synthesis of eight-membered nitrogen heterocycles.
Grandilodine A
Figure
1 Selective natural products with indoline-fused eight-membered
azaheterocycles.
Feringa et al. reported a combination of Cu-catalyzed allylic
substitution and Ru-catalyzed ring-closing metathesis to chiral
eight-membered unsaturated azocane (Scheme 1, a).8a Rh-
catalyzed [4+2+2] cycloaddition of dienyl isocyanates to
bicyclic azocine rings was achieved by the Rovis group
(Scheme1, b).8b Louie and co-workers realized the synthesis of
nitrogen-containing eight-membered ring through Ni/IPr-
catalyzed coupling of 3-azetidinone and diynes (Scheme1, c).8f
Although these methods are effective, precious or air-sensitive
catalysts are usually required. So, a simple, robust and
economical strategy for the synthesis of eight-membered
nitrogen heterocycles is very appealing in synthetic organic
chemistry. Recently, we developed a novel methodology for
the synthesis of medium-sized ring compounds via C-C σ-
However, the synthesis of this ring system has always been a
challenging task, especially for the construction of an eight-
membered nitrogen heterocycle.7 There are several reports on
the synthesis of eight-membered nitrogen heterocycles, and
most of the reactions are catalyzed by transition metals.8
a. School of Chemistry and Molecular Engineering, East China Normal University,
500 Dongchuan Road, Shanghai 200241, China. E-mail: yzli@chem.ecnu.edu.cn
b. School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu,
273165, Shandong, China. E-mail: zhaoyulei86@126.com
†Electronic Supplementary Information (ESI) available. CCDC 2006635 (3a) and
2006638 (5a). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Journal Name
bonds cleavage reactions.9a-d We reason that the merging of spectral data.10 Increasing the amount of ZnI2 Vtieow A1rt0iclemOonllin%e
dearomatization of indoles and carbon-carbon σ-bond resulted in the same yield as that of 5DmOoI:l1%0.1(0e3n9t/rDy0O4B).01N6e26xHt,
cleavage reaction may be of great value to the synthesis of other catalysts were tested. CuI failed to give the desired
complex indoline alkaloid skeletons which are difficult to product and ZnCl2 gave a lower yield (69%) of 4a (entries 5 and
achieve by conventional methods. In this context, we designed 6). Then, we investigated the effect of temperature. Increasing
the substrate of benzoates tethered with ortho-indole moiety or decreasing the reaction temperature all gave lower yields of
1 (Scheme 1, d). We assume that this substrate may first the desired product (entries 7 and 8). A higher yield of 97%
undergo
transition
metal-catalyzed
intramolecular was obtained under N2 atmosphere (entry 9).
dearomative cyclization of indole to form a six-membered ring
4. Next, an insertion of alkyne into the C(O)-C bond of 4 and
further intramolecular SNAr reaction may give rise to polycyclic
ring expansion product 3. Herein, we report a one-pot Table 2 Optimization of reaction conditions for the formation of 3aa
synthesis of indoline-fused eight-membered nitrogen
O
heterocycles initiated by zinc-catalyzed dearomatization of
O
O
O
O
N
O
H
indoles. This is the first example of the synthesis of polycyclic
compounds fused with six rings involving eight-membered
heterocycles via successive C-H/C-C activation reactions, to the
best of our knowledge.
H
O
Br
O
O
2a
ZnI2 (5 mol%)
N
N
O
Solvent 1, 80 o
N2, 0.5 h
C
Base, Additive
Temp, Solvent 2
O
3a
Solvent 2 Temp Time Yieldb
1a
4a
Entry
Solvent 1
Base
Additive
(equiv)
(oC)
80
80
80
80
80
80
80
60
(h)
(%)
Results and discussion
Cs2CO3
Cs2CO3
1
2
Toluene (2.0 mL)
Toluene (2.0 mL)
-
-
-
13 Trace
DMAc
4
29
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
3
4
5
6d
7e
Toluene (0.2 mL)
Toluene (0.2 mL)
Toluene (0.2 mL)
Toluene (0.2 mL)
Toluene (0.2 mL)
Toluene (0.2 mL)
Toluene (0.2 mL)
-
-
-
-
-
-
-
-
-
-
DMAc
DMSO
1,4-Dioxane
DMAc
4
8
62
58
NPc
47
43
62
53
50
38
13
4
Table 1 Optimization of reaction conditions for the formation of 4aa
DMAc
3
8
DMAc
11
3
9
DMAc
100
80
80
80
80
80
O
N
O
O
N
O
H
H
10 Toluene (0.2 mL)
11 Toluene (0.2 mL)
12 Toluene (0.2 mL)
13 Toluene (0.2 mL)
14 Toluene (0.2 mL)
DMAc
13
13
O
O
Na2CO3
DMAc
Catalyst
Solvent
DBU
DMAc
13 Trace
Cs2CO3
Cs2CO3
18-Crown-6 (0.5 ) DMAc
3
3
65
71
DMAc
PhenH2O (0.5 )
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
15 Toluene (0.2 mL)
16 Toluene (0.2 mL)
DMAc
DMAc
DMAc
DMAc
80
80
80
80
4
3
3
3
62
70
73
77
PhenH2O (0.2)
Phen (1.0)
Phen (0.5 )
Phen (0.5)
1a
4a
17f
Toluene (0.2 mL)
Entry Catalyst Solvent Temp (oC) Time (h) Yieldb (%)
18f,g
Toluene (0.2 mL)
a
Reaction conditions: 1a (0.2 mmol), ZnI2 (5 mol%), N2, 0.5 h; 2a (0.3 mmol),
1
2
3
4c
5
ZnI2
ZnI2
ZnI2
ZnI2
CuI
DMSO
DMAc
Toluene
Toluene
Toluene
80
80
80
80
80
7.0
7.0
0.5
0.5
7.0
NR
Trace
96
96
NR
b
additive (0.5 equiv), solvent 2 (2.0 mL), air. Isolated yield after column
chromatography. c NP=no product. d Cs2CO3 (1.0 equiv). e Cs2CO3 (3.0 equiv). f 2a
(0.4 mmol), g N2. Phen.H2O=1,10-phenanthroline hydrate.
6
7
ZnCl2
ZnI2
ZnI2
ZnI2
Toluene
Toluene
Toluene
Toluene
80
110
50
7.0
0.5
7.0
0.5
69
94
8
78
97
With the best conditions for the zinc-catalyzed
intramolecular cyclization in hand (Table 1, entry 9). We next
attempted to realize the base-promoted ring expansion
reaction (Table 2). When the first step reaction was finished
(Table 1, entry 9), we added Cs2CO3 (2.0 equiv) and 1-(2-
bromophenyl)-3-(p-tolyl)prop-2-yn-1-one (2a) (1.5 equiv) to
9d
80
a Reaction conditions: 1a (0.2 mmol), catalyst (5 mol%), solvent (2.0 mL), air.
b Isolated yields after column chromatography. c ZnI2 (10 mol%). d N2.
o
the reaction system, and kept the reaction at 80 C for 13 h
under air. However, only a trace amount of 3a was detected
(Table 2, entry 1). Next, we tried to add other polar solvents to
the reaction mixture. When DMAc (2.0 mL) was added, the
expected eight-membered nitrogen heterocycle 3a could be
formed in 29% yield within 4 h (Table 2, entry 2). Structural
identification of 3a was carried out by X-ray crystallography.11
It was worth noting that too much toluene in the first step
would lead to a low yield of the tandem reaction. Therefore,
the amount of toluene used in the first step was reduced to
0.2 mL, and the yield of 3a was increased to 62% (Table 2,
To test our assumption, we started the investigation by
using methyl 3-(2-(1H-indol-1-yl)phenyl)-3-oxopropanoate (1a)
as the model substrate (Table 1). When 1a was treated with 5
mol% ZnI2 in DMSO at 80 oC under air, no reaction was
observed after 7 hours (entry 1). We then examined the effect
of solvents on the reaction. DMAc as the solvent gave trace
product (entry 2). To our delight, when toluene was used, the
desired product 4a was obtained in a high yield of 96% (entry
3). The stereochemistry of 4a was assigned on the basis of its
2 | J. Name., 2012, 00, 1-3
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entry 3). Other solvents such as DMSO and 1,4-Dioxane were
COMMUNICATION
The substrate scope of alkynones 2 was also examined
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DOI: 10.1039/D0OB01626H
also examined for the second step. It was found that DMAc (Figure 3). Different ortho-halide-substituted ynones were
was the most effective for this reaction (Table 2, entry 3 vs. investigated firstly. It was found that ynones bearing a bromo
entries 4 and 5). Then the amount of Cs2CO3 was tested. leaving group gave a higher yield of the corresponding product
Decreasing or increasing the amount of Cs2CO3 gave lower than fluoro- or iodo-substituted ynones (3l). However, a
yields of the 3a (Table 2, entries 6 and 7). A lower temperature complex mixture was observed when the ynone without the
of 60 oC or a higher temperature of 100 oC resulted in reduced leaving group (LG=H) was used. For R3 substituent on the triple
yields (Table 2, entries 8 and 9). Other bases such as K2CO3, bond, substrates with both electron-donating (3- Me, 4-OMe,
Na2CO3 and DBU, afforded 3a in lower yields (Table 2, entries 3,4,5-(OMe)3) and electron-withdrawing groups (2- F, 4-F, 4-Cl)
10-12). Addition of 18-crown-6 (0.5 equiv) to the system gave on the aryl ring were suitable for the reaction, offering the
a slightly higher yield of 65% (Table 2, entry 13). When desired products (3m−3r) in yields of 53-82%. When alkyl
phen.H2O (1,10-phenanthroline hydrate) was used, the yield of substituents such as methyl or n-butyl was used under the
3a was increased to 71%. When the amount of phen.H2O was standard conditions, a complex mixture was observed. When
o
reduced to 0.2 equiv or raised to 1.0 equiv, the yield of 3a was the temperature was lowered to 50 C in the second step, the
decreased to 62% and 70%, respectively (Table 2, entries 15 desired products 3s and 3t were obtained in 30% and 38%
and 16). Increasing 2a to 2.0 equiv gave rise to a higher yield of yields, respectively. For R4 substituents, such as 5-F and 5-Cl
3a (Table 2, entry 17). When the reaction was proceeded were all compatible in the reaction to produce the
under the N2 atmosphere for the second step, a better yield of corresponding products (3u−3x) in yields of 56-73%. However,
the desired product was observed (Table 2, entry 18).
the nitro substituent (5-NO2) of R4 gave no desired compound
(3y).
O
O
N
O
O
R4
R2
O
O
O
Br
ZnI2
2a
R4
O
N
O
N
O
O
R3
Toluene, 80oC, N2 Cs2CO3, Phen
O
LG
O
O
DMAc, 80 oC, N2
R3
R2
2
ZnI2
R1
R1
1
3
Toluene, 80 oC, N2
N
O
Cs2CO3, PhenH2O
DMAc, 80 oC, N2
O
O
O
O
O
O
3
1a
O
O
O
O
O
R
H
N
O
N
O
N
O
N
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H
O
R = CH3, 3d, 74%c
R = H, 3e, 64%c
3b, 85%b
Cl
3c, 72%c
3f,
66%
O
3a, 77%
O
3l, LG=Br, 74%
LG=F, 68%
LG=I, 64%
N
O
N
O
N
O
N
O
O
O
O
O
O
O
O
O
3n, 78%
O
3m, 72%
3o, 82%
O
O
O
O
R
O
O
N
O
N
O
N
O
O
F
O
N
O
O
N
O
O
O
O
O
O
O
O
O
F
Cl
Br
N
O
O
N
O
N
O
N
O
Cl
CN
3i, 51%d
O
3j, 64%c
O
O
R = CH3, 3g, 68%
R = H, 3h, 60%
3k, 73%
O
O
3s, 30%b
3t, 38%b
3p, 53%
3r, 80%
3q, 77%
a
Figure 2 Substrate scope of 1. Reaction conditions: 1a (0.2 mmol), ZnI2 (5 mol%) in
toluene (0.2 mL) under N2 atmosphere at 80 oC for 0.5 h; 2a (0.4 mmol), Cs2CO3 (2.0
equiv), Phen.H2O (0.5 equiv) in DMAc (2.0 mL) under N2 atmosphere at 80 oC for 3.0 h.
b step1 at 110 oC for 1.0 h. c step1 at 80 oC for 1.0 h. d step1 at 120 oC for 2.0 h.
NO2
F
Cl
Cl
Cl
O
O
O
O
O
O
O
O
O
O
O
N
O
N
O
N
O
N
O
N
O
O
O
O
O
O
3y,-
3u, 71%
3w, 67%
3x, 73%
3v, 56%
a
Figure 3 Substrate scope of alkynones 2. Reaction conditions: 1a (0.2 mmol),
ZnI2 (5 mol%) in toluene (0.2 mL) under N2 atmosphere at 80 oC for 0.5 h; 2a (0.4
mmol), Cs2CO3 (2.0 equiv), Phen.H2O (0.5 equiv) in DMAc (2.0 mL) under N2
atmosphere at 80 oC for 3.0 h. b step2 at 50 oC for 6.0 h.
With the optimal conditions established (Table 2, entry 18),
we next examined the substrate scope. Firstly, a variety of
benzoates 1 was examined (Figure 2). For substituents R1 on
the indole ring, both electron-donating (3-Me, 4-OMe, 5-OMe)
and electron-withdrawing groups (4-Cl, 5-Cl, 5-CN, 6-Br) were
well tolerated under the reaction conditions, leading to
moderate to good yields of the desired products (3a–3j). It was
noteworthy that substrate bearing a methyl group at indole C3
position worked smoothly, and gave only one diastereoisomer
in 85% yield (3b). The stereochemistry of 3b was determined
by 1D NOESY spectra. For substituents R2, the ethyl-
substituted substrate afforded the corresponding product 3k in
73% yield.
To clarify the reaction mechanism, we carried out the
following control experiments (Scheme 2). First, treatment of
4a with 2a (2.0 equiv) under the general reaction condition for
the second step produced 3a and 5a in 77% and 21% yields,
respectively (Scheme 2, a). The structure of 5a was confirmed
by X-ray crystallography.11 These results implicated that 4a
may be the reaction intermediate for the formation of 3a in
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the one-pot reaction, and ZnI2 was not necessary for the ring
Journal Name
On the basis of our experimental results andVtiehweArptircelevOionluines
9
DOI: 10.1039/D0OB01626H
expansion reaction. In a one-pot process, when the reaction reports, a plausible reaction mechanism is depicted in Scheme
was carried out in the absence of phen.H2O under air for the 3. First, 1a might coordinate with ZnI2 to afford A, then the
second step, three products of 3a, 4a and 5a were obtained in attack of the indolyl moiety to ZnI2 generate the iminium
55%, 17% and 27% yields, respectively (Scheme 2, b). It intermediate B. A nucleophilic attack of enol carbon to the
indicated that phen.H2O could improve the yield of 3a. And, air iminium ion from the less hindered face of the azaheterocyclic
was conducive to the formation of the by-product 5a. When ring and subsequent protonation to give the intermediate 4a.
this one-pot process was conducted without the addition of In the presence of a base, 2a is attacked by 4a to produce C,
alkynone 2a, not only intermediate 4a was formed, but also its which undergoes an intramolecular nucleophilic addition/ring
oxidation product 6a (Scheme 2, c). The reaction of 6a with 2a opening to offer a formal alkyne insertion product E.
(1.0 equiv) in DMAc (2.0 mL) in the presence of Cs2CO3 (2.0 Tautomerization of E leads to intermediate F, which undergoes
equiv) under air for 2 h, afforded compound 5a in quantitative intramolecular SNAr reaction to afford 3a.
yield (Scheme 2, d). These results suggested that 4a could be
easily oxidized to 6a under air, and 6a readily reacts with Conclusions
alkynone 2a to give the by-product 5a, hence resulting in lower
yield of the desired product. Therefore, N2 atmosphere and In summary, we have developed a one-pot procedure for the
phen.H2O are necessary in the one-pot reaction to improve the atom-economical synthesis of polycyclic compounds fused
yield of desired product 3a.
with six rings including indoline and eight-membered nitrogen
heterocycle. This reaction proceeds through cascade reactions
of Zn-catalyzed dearomatization of indoles, base-promoted
ring expansion and intramolecular nucleophilic aromatic
substitution reactions. The combination of dearomatization
and C-C bond activation is the key for the construction of such
complex ring systems that are usually difficult to achieve.
O
OH
N
O
O
N
O
H
O
H
O
O
Br
O
2a, 2.0 equiv
(a)
(b)
N
O
+
O
Br
Cs2CO3 (2.0 equiv), Phen·H2O (0.5 equiv)
DMAc (2.0 mL), 80 oC, N2, 3.0 h
O
4a
5a, 21%
3a, 77%
2a, (2.0 equiv)
ZnI2 (5 mol%),Tol (0.2 mL) Cs2CO3 (2,0 equiv), DMAc (2.0 mL)
3a, 55% + 4a, 17% + 5a, 27%
1a
1a
80 oC, N2, 0.5 h
air, 80 oC, 3.0 h
Experimental
OH O
O
ZnI2 (5 mol%),Tol (0.2 mL) Cs2CO3 (2.0 equiv), DMAc (2.0 mL)
4a, 68%
+
(c)
(d)
80 oC, N2, 0.5 h
(1.0 equiv)
air, 80 oC, 3.0 h
Cs2CO3 (2.0 equiv)
General experimental method
N
6a, 22%
+ 2a
6a
5a, 99%
DMAc (2.0 mL), 80 oC,air, 2.0 h
All reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen, unless otherwise noted.
Column chromatographic purification of products was carried
out using silica gel (300~400 mesh). The reagents were used
Scheme 2 Control Experiments.
1
without further purification. H NMR spectra was recorded at
400 MHz or 500 MHz; 13C NMR spectra was recorded at 100
MHz or 125 MHz, and in CDCl3 (containing 0.03% TMS)
solutions. 1H NMR spectra was recorded with
O
N
O
O
N
O
OH
N+
O
O
N
O
H
H
ZnI2
O
O
O
H
O
Zn
I
tetramethylsilane (δ = 0.00 ppm) as the internal reference; 13
C
I
ZnI
ZnI2
NMR spectra was recorded with CDCl3 (δ = 77.00 ppm) as the
internal reference. High-resolution mass spectra were
recorded on a mass spectrometer with a TOF (ESI) analyzer.
Single crystal X-raydiffraction data was collected in Bruker
SMARTAPEX diffractiometers with molybdenum cathodes.
Compounds 2 were prepared using the literature methods.9
1a
B
A
4a
O
Br
O
-O
Br
Br
CO2Me
N
-O
CO2Me
2a
base, -H+
O
N
C
D
Typical procedure for the synthesis of benzoates tethered
with ortho-indole moiety 1a.
O
Br
O
O
Br
O
CO2Me
CO2Me
-
SNAr
-O
To a DMF solution containing 1-(2-iodophenyl)ethanone (10.0
mmol, 2.46 g), indoles (12.0 mmol, 1.41 g) and CuI (3.0 mmol,
571.3 mg) was added K2CO3 (30.0 mmol, 4.15 g) under
N
O
N
CO2Me
N
E
F
3a
o
nitrogen. The reaction mixture was stirred for 24 h at 120 C.
Scheme 3 A plausible reaction mechanism.
After completion of the reaction, the reaction mixture was
cooled to room temperature, diluted with H2O (10 mL), and
extracted with EA (40 mL ×3). The organic layer was washed
4 | J. Name., 2012, 00, 1-3
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7.66-7.63 (m, 1H), 7.54-7.50 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H),
DOI: 10.1039/D0OB01626H
7.15-7.11 (m, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.86-6.77 (m, 2H),
with brine, dried with anhydrous Na2SO4, and concentrated
under vacuum to give the crude product. The residue was
purified by silica gel column with petroleum ether/EA as the
eluent to give the analytical pure 1-(2-(1H-indol-1-
yl)phenyl)ethenone.
View Article Online
6.60-6.55 (m, 1H), 3.97 (s, 3H), 3.50 (s, 3H), 2.89 (s, 2H); enol
tautomer: 1H NMR (400 MHz, CDCl3): δ 12.25 (s, 1H), 7.54-7.50
(m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 6.86-
6.77 (m, 2H), 4.76 (s, 1H), 3.60 (s, 3H), other peaks are
overlapped with the signals of the first isomer; 13C NMR (100
MHz, CDCl3): δ 196.09, 173.30, 170.30, 167.78, 153.75, 153.53,
138.53, 138.26, 137.80, 137.43, 136.56, 133.23, 132.03, 131.42,
130.53, 130.04, 128.81, 128.38, 128.08, 127.26, 127.18, 124.30,
123.37, 119.51, 119.30, 103.44, 102.24, 100.91, 100.75, 100.19,
91.11, 55.18, 51.85, 51.12, 46.46. HRMS (ESI) calcd for
C19H18NO4 [M+H]+ 324.1230, found 324.1228.
To a dried 25-mL RBF was added NaH (28 mmol, 60%
dispersion in mineral oil, 1.12 g), dimethyl carbonate (20
mmol, 1.7 mL) and toluene (10 mL) under nitrogen. After the
mixture was heated to reflux, a solution of 1-(2-(1H-indol-1-yl)
phenyl)ethanone (10 mmol, 2.35 g) in toluene (5 mL) was
added dropwise over 0.5 h. After the evolution of hydrogen
ceased (15-20 min), the reaction was cooled down to room
temperature. After cooling, the reaction mixture was poured
into ice-water (10 mL), acidified with aqueous HCl (3 M) to PH
2~3 and extracted with EA (40 mL × 3). The combined organic
layer was washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure.
Purification by chromatography on silica gel with petroleum
ether/EA as the eluent to give the yellow oil methyl-3-(2-(1H-
indol-1-yl)phenyl)-3-oxopropanoate 1a.
Methyl 3-(2-(5-methoxy-1H-indol-1-yl)phenyl)-3-oxopropa-
noate (1d). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (10:1); yield 63%;
mixture of enol and keto forms (keto 75% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 7.81-7.77 (m, 1H), 7.67-
7.63 (m, 1H), 7.55-7.43 (m, 2H), 7.13-7.08 (m, 3H), 6.88-6.82
(m, 1H), 6.67 (d, J = 2.8 Hz, 1H), 3.86 (s, 3H), 3.50 (s, 3H), 2.91
1
(s, 2H); enol tautomer: H NMR (400 MHz, CDCl3): δ 12.25 (s,
1H), 7.55-7.43 (m, 2H), 7.13-7.08 (m, 2H), 6.88-6.82 (m, 1H),
6.59 (d, J = 3.2 Hz, 1H), 4.75 (s, 1H), 3.62 (s, 3H), other peaks
are overlapped with the signals of the first isomer; 13C NMR
(100 MHz, CDCl3): δ 196.26, 173.35, 170.43, 167.79, 155.25,
154.78, 137.85, 137.50, 136.50, 133.22, 132.38, 132.09, 131.89,
131.48, 130.55, 130.13, 129.58, 129.37, 129.19, 128.64, 128.22,
127.93, 127.86, 113.46, 112.61, 111.12, 111.08, 104.70, 103.41,
102.80, 102.58, 91.03, 55.60, 51.91, 51.18, 46.50. HRMS (ESI)
calcd for C19H18NO4 [M+H]+ 324.1230, found 324.1235.
Methyl 3-(2-(1H-indol-1-yl)phenyl)-3-oxopropanoate (1a).
Yellow oil after chromatography on silica gel using petroleum
ether/ethyl acetate as eluant (20:1); yield 70%; mixture of enol
1
and keto forms (keto 81% in CDCl3). Keto tautomer: H NMR
(400 MHz, CDCl3): δ 7.83-7.79 (m, 1H), 7.71-7.64 (m, 2H), 7.56-
7.44 (m, 2H), 7.24-7.15 (m, 4H), 6.75 (d, J = 2.8 Hz, 1H), 3.48 (s,
1
3H), 2.90 (s, 2H); enol tautomer: H NMR (400 MHz, CDCl3): δ
12.23 (s, 1H), 7.56-7.44 (m, 3H), 7.24-7.15 (m, 3H), 6.67 (d, J =
2.8 Hz, 1H), 4.73 (s, 1H), 3.60 (s, 3H), other peaks are
overlapped with the signals of the first isomer; 13C NMR (100
MHz, CDCl3): δ 196.15, 173.33, 170.38, 167.74, 137.73, 137.40,
137.19, 136.89, 136.63, 133.26, 132.09, 131.49, 130.58,
130.14, 128.98, 128.84, 128.80, 128.71, 128.38, 128.09,
123.34, 122.56, 121.50, 121.16, 121.08, 120.42, 110.29,
105.01, 103.75, 91.09, 51.90, 51.17, 46.55. HRMS (ESI) calcd
for C18H16NO3 [M+H]+ 294.1125, found 294.1124.
Methyl 3-(2-(4-chloro-1H-indol-1-yl)phenyl)-3-oxopropano-
ate (1f). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (15:1); yield 50%;
mixture of enol and keto forms (keto 73% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 7.6 Hz, 1H),
7.69-7.66 (m, 1H); 7.58-7.52 (m, 1H), 7.45-7.41 (m, 1H), 7.22-
7.18 (m, 2H), 7.15-7.11 (m, 1H), 7.09-7.07 (m, 1H), 6.86 (d, J =
1
2.8 Hz, 1H), 3.50 (s, 3H), 2.95 (s, 2H); enol tautomer : H NMR
(400 MHz, CDCl3): δ 12.19 (s, 1H), 7.58-7.52 (m, 1H), 7.45-7.41
(m, 1H), 7.15-7.11 (m, 1H), 7.09-7.07 (m, 2H), 6.77 (d, J = 3.2
Hz, 1H), 4.79 (s, 1H), 3.62 (s, 3H), other peaks are overlapped
with the signals of the first isomer; 13C NMR (100 MHz, CDCl3):
δ 195.68, 173.18, 170.30, 167.55, 137.86, 137.64, 137.17,
136.88, 136.53, 133.37, 132.19, 131.58, 130.60, 130.20, 129.42,
129.32, 128.82, 128.77, 128.51, 128.21, 127.76, 127.56, 126.69,
126.25, 123.91, 123.15, 120.90, 120.21, 109.00, 103.39, 102.21,
91.24, 51.98, 51.25, 46.62. HRMS (ESI) calcd for C18H15ClNO3
[M+H]+ 328.0735, found 328.0738.
Methyl 3-(2-(5-chloro-1H-indol-1-yl)phenyl)-3-oxopropano-
ate (1g). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (15:1); yield 61%;
mixture of enol and keto forms (keto 69% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 7.82-7.79 (m, 1H), 7.69-
7.62 (m, 2H), 7.57-7.51 (m, 1H), 7.46-7.41 (m, 1H), 7.19-7.15
(m, 2H), 7.12-7.09 (m, 1H), 6.69 (d, J = 2.8 Hz, 1H), 3.51 (s, 3H),
2.93 (s, 2H); enol tautomer : 1H NMR (400 MHz, CDCl3): δ 12.20
(s, 1H), 7.82-7.79 (m, 1H), 7.69-7.62 (m, 1H), 7.57-7.51 (m, 1H),
7.46-7.41 (m, 1H), 7.12-7.09 (m, 1H), 6.60 (d, J = 2.8 Hz, 1H),
4.73 (s, 1H), 3.62 (s, 3H), other peaks are overlapped with the
signals of the first isomer; 13C NMR (100 MHz, CDCl3): δ 195.78,
173.22, 170.23, 167.58, 137.20, 136.91, 136.55, 135.62, 135.33,
Methyl 3-(2-(3-methyl-1H-indol-1-yl)phenyl)-3-oxopropa-
noate (1b). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (20:1); yield 71%;
mixture of enol and keto forms (keto 77% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 7.81-7.77 (m, 1H), 7.66-
7.62 (m, 2H), 7.54-7.40 (m, 2H), 7.21-7.16 (m, 3H), 6.94 (s, 1H),
1
3.50 (s, 3H), 2.93 (s, 2H), 2.39 (s, 3H); enol tautomer : H NMR
(400 MHz, CDCl3): δ 12.23 (s, 1H), 7.66-7.62 (m, 2H), 7.54-7.40
(m, 3H), 7.21-7.16 (m, 1H), 4.80 (s, 1H), 3.61 (s, 3H), 2.37 (s,
3H), other peaks are overlapped with the signals of the first
isomer; 13C NMR (100 MHz, CDCl3): δ 196.50, 173.42, 170.67,
167.86, 138.01, 137.66, 137.34, 137.09, 136.43, 133.21, 131.81,
131.45, 130.53, 130.11, 129.58, 129.40, 128.71, 127.93, 127.84,
127.66, 126.36, 126.18, 123.32, 122.50, 120.58, 119.78, 119.59,
119.14, 114.52, 113.07, 110.22, 110.17, 91.06, 51.91, 51.16,
46.59, 9.31, 9.24. HRMS (ESI) calcd for C19H18NO3 [M+H]+
308.1281, found 308.1284.
Methyl 3-(2-(4-methoxy-1H-indol-1-yl)phenyl)-3-oxopropa-
noate (1c). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (10:1); yield 67%;
mixture of enol and keto forms (keto 81% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 6.8 Hz, 1H),
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J. Name., 2013, 00, 1-3 | 5
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COMMUNICATION
Journal Name
133.35, 132.14, 131.62, 130.60, 130.22, 130.04, 129.99, 129.82, General procedure for the synthesis of six-membVeirewedArtricinlegO4nlain.e
DOI: 10.1039/D0OB01626H
128.73, 128.45, 128.08, 126.85, 126.09, 123.61, 122.86, 120.88,
120.48, 111.42, 111.35, 104.44, 103.28, 91.11, 51.99, 51.26,
46.61. HRMS (ESI) calcd for C18H15ClNO3 [M+H]+ 328.0735,
found 328.0737.
In
a schlenk tube methyl 3-(2-(1H-indol-1-yl)phenyl)-3-
oxopropanoate 1a (0.20 mmol, 58.6 mg), ZnI2 (0.01 mmol, 3.2
mg) and toluene (2.0 mL) were stirred at 80 oC for 0.5 h under
N2. After the reaction was completed as monitored by thin-
layer chromatography, water was then added to the reaction
mixture, and the water layer was extracted with ethyl acetate
(10 mL × 3). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. Purification by chromatography on
silica gel (petroleum ether/ethyl acetate = 20:1) afforded
desired compound 4a.
Methyl 3-(2-(5-cyano-1H-indol-1-yl)phenyl)-3-oxopropano-
ate (1i). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (5:1); yield 52%;
mixture of enol and keto forms (keto 66% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 8.06-8.02 (m, 1H), 7.84-
7.80 (m, 1H), 7.74-7.71 (m, 1H), 7.64-7.55 (m, 1H), 7.47-7.39
(m, 2H), 7.33-7.30 (m, 1H), 7.24-7.20 (m, 1H), 6.83 (d, J = 2.8
Hz, 1H), 3.53 (s, 3H), 3.07 (s, 2H); enol tautomer: 1H NMR (400
MHz, CDCl3): δ 12.13 (s, 1H), 8.06-8.02 (m, 1H), 7.84-7.80 (m,
1H), 7.64-7.55 (m, 1H), 7.47-7.39 (m, 1H), 7.33-7.30 (m, 1H),
7.24-7.20 (m, 1H), 6.75 (d, J = 3.2 Hz, 1H), 4.79 (s, 1H), 3.64 (s,
3H), other peaks are overlapped with the signals of the first
isomer; 13C NMR (100 MHz, CDCl3): δ 195.01, 173.04, 170.19,
167.38, 138.71, 138.52, 136.45, 136.36, 136.17, 133.54, 132.36,
131.79, 131.36, 131.16, 130.63, 130.35, 129.32, 129.05, 128.73,
128.64, 128.46, 127.05, 126.75, 126.04, 125.54, 120.76, 120.39,
111.34, 111.22, 105.20, 104.29, 104.24, 103.51, 91.27, 52.12,
51.34, 46.78. HRMS (ESI) calcd for C19H15N2O3 [M+H]+ 319.1077,
found 319.1084.
(6S,6aS)-methyl 5-oxo-5,6,6a,7-tetrahydroindolo[1,2-a]qui-
noli-ne-6-carboxylate (4a). Yellow solid; obtained in 0.5 h and
purified by chromatography on silica gel (petroleum
ether/ethyl acetate = 20:1); 56.9 mg (97% yield); mp 146-148
oC; H NMR (600 MHz, CDCl3): δ 8.03 (dd, J = 7.8, 1.2 Hz, 1H),
1
7.61-7.56 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.23-7.19 (m, 2H),
7.02-6.99 (m, 1H), 6.91-6.89 (m, 1H), 4.89 (ddd, J = 13.2, 9.4,
6.6 Hz, 1H, 1-H), 3.87 (s, 3H), 3.87 (d, J = 13.2 Hz, 1H, 2-H), 3.53
(dd, J = 16.2, 9.6 Hz, 1H), 2.90 (dd, J = 16.2, 6.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 189.01, 169.14, 145.72, 144.43,
135.80, 129.55, 129.21, 128.00, 125.93, 121.64, 121.02, 120.91,
117.56, 109.02, 61.36, 58.98, 52.39, 33.22. HRMS (ESI) calcd
for C18H16NO3 [M+H]+ 294.1125, found 294.1129.
Methyl 3-(2-(6-bromo-1H-indol-1-yl)phenyl)-3-oxopropa-
noate (1j). Yellow oil after chromatography on silica gel using
petroleum ether/ethyl acetate as eluant (15:1); yield 54%;
mixture of enol and keto forms (keto 69% in CDCl3). Keto
tautomer: 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 6.4 Hz, 1H),
7.69-7.67 (m, 1H), 7.57-7.55 (m, 2H), 7.47-7.43 (m, 1H), 7.37-
7.35 (m, 1H), 7.31-7.24 (m, 1H), 7.12 (s, 1H), 6.72 (s, 1H), 3.52
Typical procedure for the synthesis of indoline-fused eight-
membered nitrogen heterocycles 3a.
In
a schlenk tube methyl 3-(2-(1H-indol-1-yl)phenyl)-3-
1
(s, 3H), 2.99 (s, 2H); enol tautomer: H NMR (400 MHz, CDCl3):
oxopropanoate 1a (0.20 mmol, 58.7 mg), ZnI2 (0.01 mmol, 3.2
mg) and toluene (0.2 mL) were stirred at 80 oC under N2. After
0.5 h, 1-(2-bromophenyl)-3-(p-tolyl)prop-2-yn-1-one 2a (0.4
mmol, 119.7 mg), Cs2CO3 (0.4 mmol, 130.3 mg), phen.H2O (0.1
mmol, 19.8 mg) and DMAc (2.0 mL) were added. After the
completion of the addition, the reaction mixture was allowed
to react at 80 °C for 3 h in N2. Then, the reaction mixture was
quenched by water, extracted with EA, dried over anhydrous
Na2SO4 and filtered. After removal of the EA, the residue was
purified by chromatography on basic silica gel (PE/EA = 10:1)
to afford the desired product 3a.
δ 12.20 (s, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.57-7.55 (m, 2H), 7.47-
7.43 (m, 1H), 7.37-7.35 (m, 1H), 7.31-7.24 (m, 1H), 7.12 (s, 1H),
6.63 (s, 1H), 4.76 (s, 1H), 3.64 (s, 3H), other peaks are
overlapped with the signals of the first isomer; 13C NMR (100
MHz, CDCl3): δ 195.62, 173.24, 170.29, 167.63, 137.89, 137.71,
137.01, 136.73, 136.55, 133.38, 132.18, 131.65, 130.69, 130.30,
129.69, 129.48, 128.86, 128.72, 128.54, 128.23, 127.75, 127.63,
124.49, 123.77, 122.77, 122.35, 116.83, 116.15, 113.33, 113.28,
104.91, 103.78, 91.26, 52.06, 51.28, 46.70. HRMS (ESI) calcd
for C18H15BrNO3 [M+H]+ 372.0230, found 372.0233.
Ethyl 3-(2-(1H-indol-1-yl)phenyl)-3-oxopropanoate (1k).
Yellow oil after chromatography on silica gel using petroleum
ether/ethyl acetate as eluant (20:1); yield 33%; mixture of enol
(E)-methyl
13-oxo-12-(p-tolyl)-10a,13-dihydro-10H-
benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-carbo-
xylate(3a). Yellow solid; obtained in 3.5 h and purified by
chromatography on silica gel (petroleum ether/ethyl acetate =
10:1); 78.9 mg (77% yield); mp 198-200 oC. 1H NMR (400 MHz,
CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.55 (d, J =
8.4 Hz, 1H), 7.48-7.34 (m, 4H), 7.20-7.10 (m, 4H), 7.04-7.00 (m,
3H), 6.92 (d, J = 8.0 Hz, 1H), 6.74-6.70 (m, 1H), 5.56 (dd, J =
11.2, 9.6 Hz, 1H), 3.42 (s, 3H), 3.30-3.24 (m, 1H), 3.14 (dd, J =
15.6, 9.2 Hz, 1H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
175.77, 168.04, 163.65, 157.00, 147.02, 145.22, 141.55,
138.33, 135.04, 134.14, 133.77, 131.45, 130.46, 129.69,
128.89, 127.92, 127.54, 127.32, 126.13, 125.56, 125.09,
124.23, 123.98, 123.76, 122.75, 119.64, 118.31, 108.82, 65.44,
51.52, 33.84, 20.91. HRMS (ESI) calcd for C34H26NO4 [M+H]+:
512.1856, found: 512.1868.
1
and keto forms (keto 75% in CDCl3). Keto tautomer: H NMR
(400 MHz, CDCl3): δ 7.80 (d, J = 7.6 Hz, 1H), 7.71-7.64 (m, 2H),
7.56-7.45 (m, 2H), 7.21-7.16 (m, 4H), 6.75 (d, J = 3.2 Hz, 1H),
3.95 (q, J = 7.2 Hz, 2H), 2.88 (s, 2H), 1.08 (t, J = 7.2 Hz, 3H); enol
tautomer: 1H NMR (400 MHz, CDCl3): δ 12.30 (s, 1H), 7.71-7.64
(m, 1H), 7.56-7.45 (m, 3H), 7.21-7.16 (m, 2H), 6.67 (d, J = 2.8
Hz, 1H), 4.78 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz,
3H), other peaks are overlapped with the signals of the first
isomer; 13C NMR (100 MHz, CDCl3): δ 196.44, 173.01, 170.55,
167.31, 137.70, 137.42, 137.17, 136.91, 136.74, 133.16, 132.17,
131.42, 130.57, 130.18, 129.00, 128.90, 128.81, 128.69, 128.33,
128.01, 123.32, 122.50, 121.49, 121.15, 121.06, 121.01, 120.39,
110.33, 104.99, 103.72, 91.54, 61.00, 60.17, 46.93, 13.78,
13.54. HRMS (ESI) calcd for C19H18NO3 [M+H]+ 308.1281, found
308.1284.
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
COMMUNICATION
(10S,10aS,E)-methyl 10-methyl-13-oxo-12-(p-tolyl)-10a,13- 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J = 8.3 Hz,
View Article Online
dihydro-10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]in-
1H), 5.56 (dd, J1 = J2 = 10.2 Hz, 1H), 3.7D4O(Is: ,103.1H0)3,93/D.400OB(0s,1632H6H),
dole-11-carboxylate (3b). Yellow solid; obtained in 4.0 h and 3.31-3.24 (m, 1H), 3.13 (dd, J = 15.8, 9.6 Hz, 1H); 13C NMR (125
purified by chromatography on silica gel (petroleum MHz, CDCl3): δ 175.33, 167.53, 163.59, 156.74, 153.72, 145.18,
ether/ethyl acetate = 8:1); 89.3 mg (85% yield); mp 227-229 142.19, 140.62, 137.90, 134.26, 133.93, 131.34, 130.97,
1
oC. H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 8.0 Hz, 1H), 7.68- 130.23, 128.21, 127.94, 127.89, 127.10, 125.95, 125.41,
7.64 (m, 1H), 7.54-7.36 (m, 5H), 7.23-7.15 (m, 3H), 7.10-7.03 124.20, 123.64, 123.32, 122.05, 118.23, 111.98, 111.71,
(m, 4H), 6.91 (d, J = 8.0 Hz, 1H), 6.79-6.76 (m, 1H), 5.03 (d, J = 109.35, 65.44, 55.92, 51.62, 34.37. HRMS (ESI) calcd for
11.6 Hz, 1H), 3.50 (qd, J = 12.0, 6.4 Hz, 1H), 3.44 (s, 3H), 2.26 (s, C34H26NO5 [M+H]+ 528.1805, found 528.1808.
3H), 1.41 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
(E)-methyl
9-chloro-13-oxo-12-(p-tolyl)-10a,13-dihydro-
175.78, 168.31, 163.41, 157.06, 146.91, 145.79, 141.25, 10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-
138.42, 135.07, 134.40, 134.15, 133.36, 131.53, 130.61, carboxylate (3f). Yellow solid; obtained in 3.5 h and purified by
128.98, 127.93, 127.60, 127.55, 126.22, 125.55, 124.49, chromatography on silica gel (petroleum ether/ethyl acetate =
o
1
124.05, 123.77, 123.39, 122.95, 119.70, 118.36, 108.33, 73.75, 8:1); 72.1 mg (66% yield); mp 163-165 C. H NMR (400 MHz,
51.61, 40.50, 20.96, 15.89. HRMS (ESI) calcd for C35H28NO4 CDCl3): δ 8.16 (d, J = 7.6 Hz, 1H), 7.70-7.66 (m, 1H), 7.53-7.38
[M+H]+ 526.2013, found 526.2018.
(m, 5H), 7.21-7.14 (m, 3H), 7.03 (d, J = 7.6 Hz, 2H), 6.98-6.94
(E)-methyl 9-methoxy-13-oxo-12-(p-tolyl)-10a,13-dihydro- (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.60 (J1
10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-
= J2 = 10.4 Hz, 1H), 3.45 (s, 3H), 3.25-3.21 (m, 2H), 2.26 (s, 3H);
carboxylate (3c). Yellow solid; obtained in 4.0 h and purified by 13C NMR (100 MHz, CDCl3): δ 175.77, 167.86, 163.40, 157.06,
chromatography on silica gel (petroleum ether/ethyl acetate = 148.41, 146.00, 141.26, 138.51, 134.98, 134.26, 133.28,
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5:1); 78.1 mg (72% yield); mp 168-170 C. H NMR (400 MHz, 131.64, 131.19, 130.53, 128.94, 128.83, 128.13, 128.01,
CDCl3): δ 8.15 (d, J = 8.0 Hz, 1H), 7.69-7.65 (m, 1H), 7.55 (d, J = 127.75, 126.28, 125.71, 124.42, 123.93, 123.87, 123.31,
8.0 Hz, 1H), 7.49-7.37 (m, 4H), 7.18-7.13 (m, 3H), 7.04-7.00 (m, 119.69, 118.38, 107.26, 65.34, 51.66, 33.04, 20.99. HRMS(ESI)
3H), 6.59 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 5.56 (dd, J1 calcd for C34H25ClNO4 [M+H]+ 546.1467, found 546.1486.
= J2 = 10.4 Hz, 1H), 3.80 (s, 3H), 3.44 (s, 3H), 3.19 (dd, J = 15.8,
(E)-methyl
8-chloro-13-oxo-12-(p-tolyl)-10a,13-dihydro-
9.6 Hz, 1H), 3.09 (dd, J = 16.2, 11.2 Hz, 1H), 2.26 (s, 3H); 13C 10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-
NMR (100 MHz, CDCl3): δ 175.85, 167.98, 163.76, 157.06, carboxylate (3g). Yellow solid; obtained in 3.5 h and purified
156.74, 148.51, 145.18, 141.88, 138.33, 135.10, 134.16, by chromatography on silica gel (petroleum ether/ethyl
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134.01, 131.46, 130.33, 128.89, 128.68, 128.07, 127.60, acetate = 8:1); 73.9 mg (68% yield); mp 163-165 C. H NMR
126.24, 125.60, 124.47, 124.14, 123.86, 122.70, 118.36, (400 MHz, CDCl3): δ 8.15 (d, J = 7.6 Hz, 1H), 7.70-7.66 (m, 1H),
116.30, 102.87, 102.58, 65.89, 55.16, 51.53, 30.81, 20.97. 7.50-7.38 (m, 5H), 7.19-7.14 (m, 3H), 7.06- 6.96 (m, 4H), 6.82
HRMS (ESI) calcd for C35H28NO5 [M+H]+ 542.1962, found (d, J = 8.4 Hz, 1H), 5.60 (dd, J = 10.8, 9.6 Hz, 1H), 3.43 (s, 3H),
542.1982.
(E)-methyl 8-methoxy-13-oxo-12-(p-tolyl)-10a,13-dihydro- 13C NMR (125 MHz, CDCl3): δ 175.32, 167.48, 163.09, 156.70,
10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11- 145.57, 145.45, 141.11, 138.20, 134.72, 133.97, 133.13,
3.29-3.22 (m, 1H), 3.13 (dd, J = 15.8, 9.4 Hz, 1H), 2.26 (s, 3H);
carboxylate (3d). Yellow solid; obtained in 4.0 h and purified 131.46, 131.39, 130.33, 128.69, 127.74, 127.46, 126.89,
by chromatography on silica gel (petroleum ether/ethyl 126.02, 125.46, 125.02, 124.17, 123.79, 123.65, 123.48,
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acetate = 5:1); 80.2 mg (74% yield); mp 167-169 C. H NMR 122.89, 118.21, 109.63, 65.74, 51.71, 33.82, 21.22. HRMS (ESI)
(400 MHz, CDCl3): δ 8.15 (d, J = 7.6 Hz, 1H), 7.68-7.65 (m, 1H), calcd for C34H25ClNO4 [M+H]+ 546.1467, found 546.1485.
7.54-7.36 (m, 5H), 7.19-7.10 (m, 3H), 7.03 (d, J = 7.6 Hz, 2H),
(E)-methyl 8-chloro-13-oxo-12-phenyl-10a,13-dihydro-10H-
6.86 (d, J = 8.4 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J = 6.8 Hz, 1H), benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-carbo-
5.56 (dd, J1 = J2 = 10.2 Hz, 1H), 3.74 (s, 3H), 3.43 (s, 3H), 3.30- xylate (3h). Yellow solid; obtained in 3.5 h and purified by
3.24 (m, 1H), 3.12 (dd, J = 16.0, 9.2 Hz, 1H), 2.26 (s, 3H); 13C chromatography on silica gel (petroleum ether/ethyl acetate =
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NMR (100 MHz, CDCl3): δ 175.83, 168.13, 163.97, 157.09, 8:1); 63.7 mg (60% yield); mp 159-161 C. H NMR (400 MHz,
153.99, 145.33, 142.46, 140.92, 138.37, 135.13, 134.15, CDCl3): δ 8.15 (d, J = 6.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.51-7.38
133.89, 131.51, 131.24, 130.45, 128.92, 128.01, 127.33, (m, 5H), 7.24-7.18 (m, 6H), 7.07 (s, 1H), 6.97 (d, J = 7.2 Hz, 1H),
126.21, 125.59, 124.48, 123.85, 123.46, 122.21, 118.39, 6.83 (d, J = 8.0 Hz, 1H), 5.60-5.55 (m, 1H), 3.40 (s, 3H), 3.29-
112.07, 111.83, 109.40, 65.49, 55.80, 51.56, 34.19, 20.96. 3.23 (m, 1H), 3.17-3.11 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
HRMS (ESI) calcd for C35H28NO5 [M+H]+ 542.1962, found 175.76, 167.74, 163.51, 157.07, 146.02, 145.76, 141.38,
542.1966.
137.99, 134.29, 134.01, 131.74, 131.68, 130.60, 128.55,
(E)-methyl 8-methoxy-13-oxo-12-phenyl-10a,13-dihydro-10 128.14, 128.11, 127.64, 127.15, 126.20, 125.74, 125.27,
H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-car-
124.29, 124.05, 123.83, 123.74, 123.15, 118.42, 109.84, 65.55,
boxylate (3e). Yellow solid; obtained in 4.0 h and purified by 51.58, 33.57. HRMS (ESI) calcd for C33H23ClNO4 [M+H]+
chromatography on silica gel (petroleum ether/ethyl acetate = 532.1310, found 532.1315.
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5:1); 67.5 mg (64% yield); mp 158-160 C. H NMR (400 MHz,
(E)-methyl
8-cyano-13-oxo-12-(p-tolyl)-10a,13-dihydro-
CDCl3): δ 8.15 (d, J = 8.0 Hz, 1H), 7.69-7.65 (m, 1H), 7.53-7.48 10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-
(m, 2H), 7.44-7.37 (m, 3H), 7.26-7.22 (m, 5H), 7.15-7.11 (m, carboxylate (3i). Yellow solid; obtained in 4.0 h and purified by
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Organic & Biomolecular Chemistry
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chromatography on silica gel (petroleum ether/ethyl acetate = 9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 175.36, 167.51,
View Article Online
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DOI: 10.1039/D0OB01626H
3:1); 54.5 mg (51% yield); mp 192-194 C. H NMR (400 MHz, 163.33, 156.71, 146.77, 145.14, 141.33, 137.83, 134.20,
CDCl3): δ 8.16 (d, J = 7.6 Hz, 1H), 7.72-7.68 (m, 1H), 7.52-7.48 133.96, 131.34, 130.28, 129.50, 128.24, 127.91, 127.91,
(m, 4H), 7.43-7.40 (m, 1H), 7.34-7.26 (m, 3H), 7.12 (d, J = 8.0 127.36, 127.17, 125.96, 125.44, 124.95, 124.02, 123.91,
Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H), 5.60 123.61, 122.63, 119.56, 118.20, 108.82, 65.45, 51.66, 34.08.
(dd, J = 11.6, 9.6 Hz, 1H), 3.45 (s, 3H), 3.32-3.25 (m, 1H), 3.19 HRMS (ESI) calcd for C33H24NO4 [M+H]+ 498.1700, found
(dd, J = 15.8, 9.4 Hz, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, 498.1712.
CDCl3): δ 175.75, 167.67, 162.80, 157.02, 150.86, 146.64,
(E)-methyl 13-oxo-12-(m-tolyl)-10a,13-dihydro-10H-benzo
139.75, 138.73, 134.74, 134.41, 133.19, 132.58, 131.87, [7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-carboxylate
130.80, 130.73, 128.99, 128.43, 128.09, 127.90, 126.28, (3m). Yellow solid; obtained in 3.5 h and purified by
125.85, 124.44, 124.24, 124.12, 123.82, 120.28, 118.40, chromatography on silica gel (petroleum ether/ethyl acetate =
108.90, 101.35, 66.08, 51.72, 32.98, 20.98. HRMS (ESI) calcd 10:1); 73.8 mg (72% yield); mp 145-147 oC. 1H NMR (500 MHz,
for C35H25N2O4 [M+H]+ 537.1809, found 537.1827.
(E)-methyl 7-bromo-13-oxo-12-(p-tolyl)-10a,13-dihydro-10
H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-car-
CDCl3): δ 8.15 (d, J = 8.0 Hz, 1H), 7.68-7.64 (m, 1H), 7.57-7.55
(m, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.45-7.42 (m, 2H), 7.39-7.36
(m, 1H), 7.19-7.16 (m, 1H), 7.12-7.09 (m, 3H), 7.06-7.01 (m,
boxylate (3j). Yellow solid; obtained in 4.0 h and purified by 3H), 6.92 (d, J = 8.0 Hz, 1H), 6.75-6.72 (m, 1H), 5.57-5.53(m,
chromatography on silica gel (petroleum ether/ethyl acetate = 1H), 3.42 (s, 3H), 3.31-3.25 (m, 1H), 3.15 (dd, J = 15.5, 9.0 Hz,
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8:1); 76.1 mg (64% yield); mp 181-183 C. H NMR (500 MHz, 1H), 2.26 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 175.34, 167.62,
CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.52-7.42 163.28, 156.71, 146.79, 145.10, 141.30, 137.70, 137.40,
(m, 4H), 7.40-7.37 (m, 7.5 Hz, 1H), 7.22-7.19 (m, 1H), 7.14 (d, J 133.91, 133.87, 131.29, 130.27, 129.52, 129.13, 128.40,
= 8.5 Hz, 2H), 7.04-7.02 (m, 3H), 6.97-6.94 (m, 1H), 6.84-6.82 127.80, 127.37, 127.15, 125.99, 125.39, 124.96, 124.92,
(m, 1H), 5.55 (dd, J = 11.7, 9.2 Hz, 1H), 3.43 (s, 3H), 3. 3.19 (dd, 124.01, 123.92, 123.63, 122.60, 119.52, 118.19, 108.75, 65.53,
J = 15.5, 12.0 Hz, 1H), 3.09 (dd, J = 16.0, 9.0 Hz, 1H), 2.26 (s, 51.62, 34.09, 21.42. HRMS (ESI) calcd for C34H26NO4 [M+H]+
3H); 13C NMR (125 MHz, CDCl3): δ 175.34, 167.48, 162.94, 512.1856, found 512.1878.
156.69, 148.31, 145.54, 140.51, 138.23, 134.69, 134.00,
(E)-methyl 12-(4-methoxyphenyl)-13-oxo-10a,13-dihydro-
133.01, 131.57, 130.40, 128.71, 128.64, 127.72, 127.54, 10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-
126.00, 125.96, 125.47, 124.04, 123.75, 123.62, 123.25, carboxylate (3n). Yellow solid; obtained in 3.5 h and purified
122.10, 120.75, 118.22, 111.78, 66.12, 51.73, 33.54, 21.23. by chromatography on silica gel (petroleum ether/ethyl
HRMS (ESI) calcd for C34H25BrNO4 [M+H]+ 590.0961, found acetate = 5:1); 82.0 mg (78% yield); mp 150-152 C. H NMR
590.0974. (500 MHz, CDCl3): δ 8.14 (d, J = 7.5 Hz, 1H), 7.67-7.64 (m, 1H),
(E)-ethyl 13-oxo-12-(p-tolyl)-10a,13-dihydro-10H-benzo[7, 7.55 (d, J = 10.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.44-7.36 (m,
8]chromeno[3',2':5,6]azocino[1,2-a]indole-11- 3H), 7.22 (d, J = 9.0 Hz, 2H), 7.17-7.14 (m, 1H), 7.11 (d, J = 7.5
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carboxylate(3k). Yellow solid; obtained in 3.5 h and purified by Hz, 1H), 7.03-7.00 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.77-6.71
chromatography on silica gel (petroleum ether/ethyl acetate = (m, 3H), 5.55 (dd, J = 11.8, 9.2 Hz, 1H), 3.72 (s, 3H), 3.44 (s, 3H),
10:1); 76.3 mg (73% yield); mp 138-140 oC. 1H NMR (400 MHz, 3.26 (dd, J = 15.2, 12.2 Hz, 1H), 3.14 (dd, J = 15.7, 9.2 Hz, 1H);
CDCl3): δ 8.15 (d, J = 7.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.57 (d, J = 13C NMR (125 MHz, CDCl3): δ 175.40, 167.75, 163.28, 159.48,
8.4 Hz, 1H), 7.49-7.36 (m, 4H), 7.19-7.11 (m, 4H), 7.04-6.93 (m, 156.69, 146.74, 144.57, 141.36, 133.91, 133.25, 131.24,
4H), 6.75-6.71 (m, 1H), 5.56 (J1 = J2 = 10.4 Hz, 1H), 3.90 (q, J 130.19, 130.07, 129.51, 129.23, 127.35, 127.12, 125.95,
=7.6 Hz, 2H), 3.32-3.26 (m, 1H), 3.15 (dd, J = 15.6, 9.6 Hz, 1H), 125.39, 124.91, 124.08, 123.80, 123.61, 122.56, 119.49,
2.26 (s, 3H), 0.87 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): 118.18, 113.38, 108.74, 65.58, 55.05, 51.69, 34.11. HRMS (ESI)
δ 175.87, 167.35, 163.73, 157.06, 147.04, 145.31, 141.82, calcd for C34H26NO5 [M+H]+ 528.1805, found 528.1817.
138.25, 135.12, 134.18, 134.15, 131.41, 130.44, 129.85,
(E)-methyl 13-oxo-12-(3,4,5-trimethoxyphenyl)-10a,13-di-
128.76, 128.76, 128.23, 127.60, 127.31, 126.20, 125.59, hydro-10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indo-
125.13, 124.51, 123.82, 122.65, 119.67, 118.36, 109.09, 65.41, le-11-carboxylate (3o). Yellow solid; obtained in 3.5 h and
60.45, 33.81, 20.94, 13.33. HRMS (ESI) calcd for C35H28NO4 purified by chromatography on silica gel (petroleum
[M+H]+ 526.2013, found 526.2028.
(E)-methyl 13-oxo-12-phenyl-10a,13-dihydro-10H-benzo[7,
8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-carboxylate
ether/ethyl acetate = 2:1); 96.2 mg (82% yield); mp 222-224
1
oC. H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.0 Hz, 1H), 7.71-
7.67 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.52-7.39 (m, 4H), 7.19-
(3l). Yellow solid; obtained in 3.5
h and purified by 7.12 (m, 2H), 7.05-7.02 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.76-
chromatography on silica gel (petroleum ether/ethyl acetate = 6.73 (m, 1H), 6.52 (s, 2H), 5.54 (dd, J1 = J2 = 10.4 Hz, 1H), 3.78
10:1); 73.6 mg (74% yield); mp 140-142 oC. 1H NMR (500 MHz, (s, 3H), 3.75 (s, 6H), 3.47 (s, 3H), 3.27-3.21 (m, 1H), 3.15 (dd, J
CDCl3): δ 8.15 (d, J = 8.0 Hz, 1H), 7.68-7.65 (m, 1H), 7.57 (d, J = = 15.6, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 175.78,
8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.45-7.42 (m, 2H), 7.40- 168.06, 163.70, 157.01, 152.90, 146.94, 144.68, 141.73,
7.37 (m, 1H), 7.28-7.26 (m, 2H), 7.24-7.21 (m, 3H), 7.19-7.16 138.02, 134.54, 134.27, 133.55, 131.53, 130.14, 129.57,
(m, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.04-7.01 (m, 1H), 6.93 (d, J = 127.59, 127.39, 126.12, 125.70, 125.13, 124.33, 124.01,
8.0 Hz, 1H), 6.75-6.72 (m, 1H), 5.56 (dd, J = 11.7, 9.2 Hz, 1H), 123.73, 122.65, 119.77, 118.41, 109.01, 105.11, 65.25, 60.54,
3.40 (s, 3H), 3.27 (dd, J = 15.5, 12.0 Hz, 1H), 3.15 (dd, J = 15.5,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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55.73, 51.68, 33.73. HRMS (ESI) calcd for C36H30NO7 [M+H]+ 7.03-7.00 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.73-6.70 (m 1H),
View Article Online
DOI: 10.1039/D0OB01626H
588.2017, found 588.2029.
5.46 (dd, J = 11.2, 9.5 Hz, 1H),3.71 (s, 3H), 3.14 (dd, J = 15.5,
(Z)-methyl 12-(2-fluorophenyl)-13-oxo-10a,13-dihydro-10H- 11.0 Hz, 1H), 3.02 (dd, J = 15.2, 9.5 Hz, 1H), 2.18 (s, 3H); 13C
benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11- NMR (125 MHz, CDCl3): δ 175.47, 167.43, 162.45, 156.68,
carboxylate (3p). Yellow solid; obtained in 3.5 h and purified 146.63, 144.84, 141.42, 133.95, 131.38, 131.20, 130.12,
by chromatography on silica gel (petroleum ether/ethyl 129.50, 127.07, 126.98, 125.90, 125.45, 125.18, 124.98,
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acetate = 8:1); 55.2 mg (53% yield); mp 102-104 C. H NMR 123.43, 122.98, 122.07, 119.42, 118.25, 108.89, 64.77, 51.54,
(400 MHz, CDCl3): δ 8.13 (d, J = 7.6 Hz, 1H), 7.69-7.65 (m, 1H), 33.83, 19.06. HRMS (ESI) calcd for C28H21NNaO4 [M+H]+
7.58-7.54 (m, 2H), 7.50-7.37 (m, 4H), 7.22-7.02 (m, 5H), 6.96- 458.1363, found 458.1366.
6.88 (m, 2H), 6.76-7.73 (m, 1H), 5.54 (dd, J1 = J2 = 10.2 Hz, 1H),
(E)-methyl 12-butyl-13-oxo-10a,13-dihydro-10H-benzo[7,8]
3.42 (s, 3H), 3.36-3.29 (m, 1H), 3.16 (dd, J = 15.2, 9.2 Hz, 1H); chromeno[3',2':5,6]azocino[1,2-a]indole-11-carboxylate (3t).
13C NMR (100 MHz, CDCl3): δ 175.97, 167.10, 164.28, 160.04 (J Yellow oil; obtained in 6.5 h and purified by chromatography
= 249.0 Hz), 157.09, 147.15, 141.21, 136.46, 134.23, 132.00 (J on silica gel (petroleum ether/ethyl acetate = 15:1); 36.7 mg
= 3.0 Hz), 131.50, 131.35, 130.34, 130.26, 129.69, 127.55, (38% yield). 1H NMR (500 MHz, CDCl3): δ 8.24 (dd, J = 8.0, 1.5
127.40, 126.11, 125.71, 125.18, 123.70, 123.63, 123.54 (J = 3.0 Hz, 1H), 7.71-7.68 (m, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.49-7.38
Hz), 123.24, 122.55, 119.71, 118.41, 115.40, 115.18, 108.74, (m, 3H), 7.27-7.25 (m, 1H), 7.09-6.99 (m, 3H), 6.92 (d, J = 8.0
64.93, 51.61, 33.98. HRMS (ESI) calcd for C33H23FNO4 [M+H]+ Hz, 1H), 6.72-6.69 (m, 1H), 5.43 (dd, J = 11.0, 9.5 Hz, 1H), 3.71
516.1606, found 516.1619.
(E)-methyl 12-(4-fluorophenyl)-13-oxo-10a,13-dihydro-10H- 0.95-0.80 (m, 3H), 0.66 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11- CDCl3): δ 175.59, 167.78, 163.37, 156.72, 147.93, 146.74,
(s, 3H), 3.10-3.00 (m, 2H), 2.79-2.67 (m, 2H), 1.19-1.14 (m, 1H),
carboxylate (3q). Yellow solid; obtained in 3.5 h and purified 141.21, 133.93, 131.75, 131.11, 130.49, 129.38, 127.32,
by chromatography on silica gel (petroleum ether/ethyl 127.10, 125.97, 125.43, 124.96, 123.37, 123.16, 121.98,
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acetate = 8:1); 79.6 mg (77% yield); mp 158-160 C. H NMR 119.34, 118.25, 108.67, 64.59, 51.55, 33.82, 31.80, 30.35,
(400 MHz, CDCl3): δ 8.15 (d, J = 7.6 Hz, 1H), 7.70-7.67 (m, 1H), 22.10, 13.77. HRMS (ESI) calcd for C31H27NNaO4 [M+H]+
7.58 (d, J = 8.0 Hz, 1H), 7.51-7.39 (m, 4H), 7.28-7.12 (m, 5H), 500.1832, found 500.1824.
7.04-7.02 (m, 1H), 6.94-6.90 (m, 3H), 6.76-6.73 (m, 1H), 5.55
(E)-methyl
15-fluoro-13-oxo-12-phenyl-10a,13-dihydro-
(dd, J1 = J2 = 10.4 Hz, 1H), 3.43 (s, 3H), 3.28-3.21 (m, 1H), 3.15 10H-benzo[7,8]chromen[3',2':5,6]azocino[1,2-a]indole-11-
(dd, J = 15.6, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 175.83, carboxylate (3u). Yellow solid; obtained in 3.5 h and purified
167.79, 163.84, 162.93 (J = 248.0 Hz), 157.09, 147.02, 144.43, by chromatography on silica gel (petroleum ether/ethyl
o
1
141.62, 134.89, 134.34, 134.01 (J = 3.0 Hz), 131.69, 130.44, acetate = 8:1); 73.3 mg (71% yield); mp 154-156 C. H NMR
130.17, 130.09, 129.66, 127.44, 126.14, 125.78, 125.20, (400 MHz, CDCl3): δ 7.79-7.76 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H),
124.11, 123.77, 122.87, 119.84, 118.44, 115.21, 114.99, 7.52-7.40 (m, 5H), 7.25-7.13 (m, 6H), 7.06-7.02 (m, 1H), 6.93
109.00, 65.30, 51.64, 33.88. HRMS (ESI) calcd for C33H23FNO4 (d, J = 8.0 Hz, 1H), 6.77-6.73 (m, 1H), 5.54 (dd, J = 11.4, 9.4 Hz,
[M+H]+ 516.1606, found 516.1622.
(E)-methyl 12-(4-chlorophenyl)-13-oxo-10a,13-dihydro-10H 1H); 13C NMR (100 MHz, CDCl3): δ 175.09, 167.85, 164.03,
-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-car- 159.99 (J = 247.0 Hz), 153.29, 147.04, 145.08, 141.64, 137.92,
1H), 3.41 (s, 3H), 3.30-3.24 (m, 1H), 3.16 (dd, J = 15.6, 9.2 Hz,
boxylate (3r). Yelllow solid; obtained in 3.5 h and purified by 134.68, 131.76, 130.49, 129.73, 128.59, 128.21, 128.12, 127.39
chromatography on silica gel (petroleum ether/ethyl acetate = (J = 11.0 Hz), 125.22, 124.17, 123.62, 122.88, 122.59, 122.33,
o
8:1); 84.6 mg (80% yield); mp 168-170 C. 1H NMR (400 MHz, 120.61 (J = 8.0 Hz), 119.86, 111.07, 110.84, 108.98, 65.36,
CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.70-7.66 (m, 1H), 7.57 (d, J = 51.60, 33.88. HRMS (ESI) calcd for C33H23FNO4 [M+H]+
8.0 Hz, 1H), 7.50-7.38 (m, 4H), 7.21-7.11 (m, 6H), 7.05-7.01 (m, 516.1606, found 516.1622.
1H), 6.93 (d, J = 7.6 Hz, 1H), 6.76-6.72 (m, 1H), 5.55 (dd, J1 = J2
(E)-methyl 15-chloro-13-oxo-12-phenyl-10a,13-dihydro-10
= 10.4 Hz, 1H), 3.44 (s, 3H), 3.28-3.22 (m, 1H), 3.15 (dd, J = H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-car-
15.6, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 175.78, 167.66, boxylate (3v). Yellow solid; obtained in 3.5 h and purified by
163.96, 157.05, 146.96, 144.25, 141.55, 136.47, 135.05, chromatography on silica gel (petroleum ether/ethyl acetate =
o
1
134.45, 134.36, 131.70, 130.43, 129.62, 129.61, 128.38, 8:1); 59.4 mg (56% yield); mp 152-154 C. H NMR (500 MHz,
127.43, 127.36, 126.10, 125.79, 125.18, 124.08, 123.89, CDCl3): δ 8.13 (d, J = 2.5 Hz, 1H), 7.65-7.59 (m, 2H), 7.50-7.46
123.70, 122.87, 119.84, 118.42, 108.98, 65.26, 51.69, 33.84. (m, 2H), 7.44-7.42 (m, 1H), 7.28-7.25 (m, 5H), 7.22-7.19 (m,
HRMS (ESI) calcd for C33H23ClNO4 [M+H]+ 532.1310,found 1H), 7.16 (d, J = 7.0 Hz, 1H), 7.08-7.05 (m, 1H), 6.96 (d, J = 8.0
532.1324.
Hz, 1H), 6.80-6.77 (m, 1H), 5.57 (dd, J = 11.8, 9.3 Hz, 1H), 3.44
(E)-methyl
12-methyl-13-oxo-10a,13-dihydro-10H- (s, 3H), 3.30 (dd, J = 14.8, 11.3 Hz, 1H), 3.19 (dd, J = 15.5, 9.0
benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-carbo- Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 174.20, 167.38, 163.59,
xylate (3s). Yellow oil; obtained in 6.5 h and purified by 155.04, 146.70, 144.75, 141.41, 137.60, 134.48, 134.17,
chromatography on silica gel (petroleum ether/ethyl acetate = 131.54, 131.40, 130.23, 129.48, 128.35, 127.96, 127.89,
1
15:1); 26.3 mg (30% yield). H NMR (500 MHz, CDCl3): δ 8.25 127.20, 127.04, 125.36, 125.00, 124.57, 124.11, 123.98,
(dd, J = 8.0, 1.5 Hz, 1H), 7.71-7.67 (m , 1H), 7.56 (d, J = 8.0 Hz, 122.66, 119.97, 119.69, 108.88, 65.44, 51.69, 34.09. HRMS
1H), 7.48-7.38 (m, 3H), 7.27-7.26 (m, 1H), 7.10-7.07 (m, 2H), (ESI) calcd for C33H23ClNO4 [M+H]+ 532.1310, found 532.1326.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 11
COMMUNICATION
Journal Name
(E)-methyl 15-chloro-13-oxo-12-(p-tolyl)-10a,13-dihydro-10
H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]indole-11-car-
boxylate (3w). Yellow solid; obtained in 3.5 h and purified by
chromatography on silica gel (petroleum ether/ethyl acetate =
View Article Online
DOI: 10.1039/D0OB01626H
Conflicts of interest
There are no conflicts to declare.
o
1
7:1); 73.9 mg (67% yield); mp 153-155 C. H NMR (400 MHz,
CDCl3): δ 8.09 (d, J = 2.0 Hz, 1H), 7.63-7.55 (m, 2H), 7.46-7.39
(m, 3H), 7.19-7.13 (m, 4H), 7.04 (d, J = 7.6 Hz, 3H), 6.93 (d, J =
8.0 Hz, 1H), 6.77-6.73 (m, 1H), 5.53 (dd, J = 11.2, 9.6 Hz, 1H),
3.44 (s, 3H), 3.30-3.23 (m, 1H), 3.16 (dd, J = 15.6, 9.2 Hz, 1H),
2.27 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 174.69, 167.99,
163.97, 155.39, 147.02, 144.90, 141.68, 138.55, 134.84,
134.41, 134.10, 131.72, 131.59, 130.46, 129.74, 129.00,
127.95, 127.42, 127.27, 125.60, 125.21, 124.78, 124.39,
124.13, 122.83, 120.15, 119.82, 108.94 , 65.49, 51.64, 33.91,
20.98. HRMS (ESI) calcd for C34H25ClNO4 [M+H]+ 546.1467,
found 546.1480.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant No. 21871087) and the Natural Science Foundation of
Shandong Province (Grant no. ZR2018BB026) for financial
support.
Notes and references
1
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(E)-methyl 15-chloro-12-(4-methoxyphenyl)-13-oxo-10a,13-
dihydro-10H-benzo[7,8]chromeno[3',2':5,6]azocino[1,2-a]in-
dole-11-carboylate (3x). Yellow solid; obtained in 3.5 h and
purified by chromatography on silica gel (petroleum
ether/ethyl acetate = 5:1); 81.5 mg (73% yield); mp 160-162
1
oC. H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 2.0 Hz, 1H), 7.62-
7.55 (m, 2H), 7.45-7.39 (m, 3H), 7.24-7.12 (m, 5H), 7.05-7.01
(m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.77-6.73 (m, 3H), 5.52 (dd, J =
11.2, 9.6 Hz, 1H), 3.73 (s, 3H), 3.45 (s, 3H), 3.29-3.25 (m, 1H),
3.15 (dd, J = 15.6, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
174.69, 168.05, 163.93, 159.92, 155.37, 146.98, 144.46,
141.71, 134.40, 133.77, 131.70, 131.57, 130.39, 130.03,
129.72, 129.44, 127.39, 127.23, 125.54, 125.18, 124.75,
124.36, 124.07, 122.80, 120.16, 119.80, 113.58, 108.91, 65.49,
54.96, 51.63, 33.90. HRMS (ESI) calcd for C34H25ClNO5 [M+H]+
562.1416, found 562.1420.
(Z)-methyl 7-(3-(2-bromophenyl)-3-oxo-1-(p-tolyl)prop-1-
en-1-yl)-5-hydroxyindolo[1,2-a]quinoline-6-carboxylate (5a).
Yellow solid; purified by chromatography on silica gel
(petroleum ether/ethyl acetate = 15:1); mp 182-184 oC. 1H
NMR (400 MHz, CDCl3): δ 12.54 (s, 1H), 8.28 (dd, J = 14.0, 8.0
Hz, 2H), 8.01 (d, J = 8.0 Hz, 1H), 7.74-7.70 (m, 1H), 7.62-7.60
(m, 2H), 7.40-7.36 (m, 1H), 7.25-7.14 (m, 5H), 7.00 (s, 1H), 6.71
(d, J = 8.0 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.47-6.43 (m, 1H),
6.24-6.20 (m, 1H), 3.43 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 196.19, 170.43, 161.72, 150.69, 140.94, 140.43,
138.61, 136.77, 133.06, 132.93, 132.42, 131.88, 130.71,
129.59, 128.71, 128.71, 128.01, 126.10, 125.40, 124.80,
123.23, 122.40, 122.00, 120.91, 118.53, 117.88, 115.53,
113.27, 107.46, 97.06, 50.84, 21.12. HRMS (ESI) calcd for
C34H25BrNO4 [M+H]+ 590.0961, found 590.0972.
2
3
Methyl
5-hydroxyindolo[1,2-a]quinoline-6-carboxylate
(6a). Yellow solid; purified by chromatography on silica gel
(petroleum ether/ethyl acetate = 30:1); mp 134-136 oC. 1H
NMR (400 MHz, CDCl3): δ 13.21 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H),
8.26-8.23 (m, 2H), 7.75-7.67 (m, 2H), 7.33-7.31 (m, 3H), 7.08 (s,
1H), 4.08 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 172.19, 162.08,
139.22, 133.01, 132.63, 132.37, 131.44, 126.11, 122.79,
122.24, 121.30, 120.65, 117.92, 115.47, 113.96, 97.75, 96.48,
52.39. HRMS (ESI) calcd for C18H14NO3 [M+H]+ 292.0968, found
292.0972.
4
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11 CCDC 2006635 (3a) and CCDC 2006638 (5a) contain the
supplementary crystallographic data for this paper†.
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