Palladium-Catalyzed Amination/Dearomatization Reaction of Indoles and Benzofurans

Article abstract of DOI:10.1021/acs.joc.0c00475

This report describes a palladium-catalyzed dearomatization and amination tandem reaction of 2,3-disubstituted indoles and benzofurans via the Catellani strategy. This reaction provides a new method for the construction of amino-substituted indoline-fused cyclic and benzofuran spiro compounds in good yields. The reaction has broad functional group compatibility and substrate scope.

Full text of DOI:10.1021/acs.joc.0c00475

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Article
Palladium-Catalyzed Amination/Dearomatization
Reaction of Indoles and Benzofurans
Zhe Zhang, Bo-Sheng Zhang, Kai-Li Li, Yang An, Ce Liu, Xue-Ya Gou, and Yong-Min Liang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00475 • Publication Date (Web): 22 May 2020
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Page 1 of 24
The Journal of Organic Chemistry
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Palladium-Catalyzed Amination/Dearomatization Reaction of
Indoles and Benzofurans
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Zhe Zhang,a Bo-Sheng Zhang,a Kai-Li Li,b Yang An,a Ce Liu,a Xue-Ya Gou,a Yong-Min Liang*,a
a State key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b Lanzhou University Second Clinical Medical College, Lanzhou 730000, China
R2
ABSTRACT: This report describes
a
palladium-catalyzed
O
R1
N
N
Ar'
dearomatization and amination tandem reaction of 2,3-
disubstituted indoles and benzofurans via a Catellani strategy.
This reaction provides a new method for the construction of
amino-substituted indoline fused cyclic and benzofuran spiro
compounds in good yields. The reaction has broad functional
group compatibility and substrate scope.
ArI
Ar
Pd/NBE
N
O
Ar'
X
L
Ar
R2
N
Ar'
N
X=N/O
R1
O
38 example
up to 88% yield
12 example
up to 74% yield
After Catellani discovered the Pd/NBE cooperative catalytic
reaction system in 1997, Lautens introduced phosphine ligands
to make the reaction system more compatible and established
the palladium/norbornene cooperative catalysis reaction
system.10 In past studies, ortho-alkylation, ortho-arylation,
ortho-carbonylation and ortho-amination reactions have been
developed by Catellani, Lautens, Dong, Bach, Gu and others.11
Among them, ortho-amination was first realized by the Dong
group in 2013.12 Although the reaction system has ma de some
gratifying achievements, its application in the rapid
construction of complex structures, especially in the
construction of natural products and drug skeletons, still faces
great challenges.
1. INTRODUCTION
Indoline derivatives and benzofuran derivatives are important
heterocyclic aromatic compounds that exist widely in natural
products and have important applications in medicine and
materials science.1 Isatisine A acetonide is separated from
Folium isatidis and exhibits anti-HIV-1 activity. The screw-
shaped alkaloid (+)-hinckdentine A was isolated from the
marine bryozoan Hincksinoflustra denticulata in 1987. These
two natural products offer great potential for drug development
and attract the interest of many synthetic researchers.2 In
addition, (+)-aspidospermidine,
a
natureproduct with
significant respiratory stimulation and antibiotic activity, is an
alkaloid extracted from Aspidosperma.3 Spiropyran dye can be
used to make photochromic functional materials.4 (+)-
Griseofulvin is a selective antifungal agent used to treat skin
infections in animals and humans. Recently, it has been reported
that griseofulvin exhibits both antitumor and antiviral activities
in mammals.5 Due to the low natural abundance, the synthesis
of these skeletons has attracted much attention.
Scheme
1.
Palladium-Catalyzed
Amination/Dearomatization Reaction of Indoles and
Benzofurans
Aromatics can now be rapidly transformed into spiro or fused
cyclic compounds with complex structures by dearomatization
reactions.6 The dearomatization reactions of indole, benzofuran,
pyrrole and furan derivatives and other compounds were carried
out by Yao, Jia and Luan.7 Pyrrole has an electrophilic property
after the dearomatization occurs. The selective C-H
functionalizations of the cyanation, arylation and alkynylation
of indole at the C3 position have been successfully achieved at
the same time as dearomatization. These works were
implemented by Lautens, Jia, our group and other research
groups.8 Some achievements in the dearomatization reactions
of benzofuran derivatives have also been obtained by Yin,
Yamaguchi and others.9 In these studies, the tandem reactions
are usually completed by nucleophilic reagents combined with
specific sites, while the tandem reactions with electrophilic
reagents are less common.
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Some molecules with indole and benzofuran skeletons
these compounds has always been a primary focus of organic
synthesis research. However, the domino reaction of selective
NO2
H
N
N
1
2
3
4
5
6
7
8
Br
Cl
O
O
O
N
N
O
O
O
amination of benzene ring and heterocyclic dearomatization has
not been realized. We attempt to use the electrophilic N-
(benzoyloxy)amine reagents as the amine source and introduce
amines into the construction of fused cyclic compounds
containing indole framework or spiro compounds containing
benzofuran framework at the same time via Pd/NBE
cooperative catalysis. (Scheme 1)
O
Br
OH
N
H
R
N
NH
O
Br
O
N
O
H
O
O
H
O
(+)-Aspidospermidine
Isatisine A acetonide
(+)-hinckdentine A
Spiropyran dye
(+)-Griseofulvin
Some bioactive molecules with morpholine and piperazine structures
O
F
Cl
O
HN
O
N
O
O
N
O
N
N
N
HN
F
O
F
OH
OH
F
O
N
N
2. RESULTS AND DISCUSSION
N
N
9
N
N
NH
O
N
O
O
O
10
11
12
13
14
15
16
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18
19
20
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Enrofloxacin
1-AR
Linezolid
Previous work
Gefitinib
Levofloxacin
β
For the tandem reaction conditions of dearomatization and
amination of indole derivatives, we used morpholine benzoate
as the amino source with Pd(OAc)2/PPh3/Cs2CO3 as the starting
condition. Fortunately, we detected the presence of the product
by GC-MS and successfully separated it to determine the
structure. Interestingly, toluene was not the best solvent in the
initial solvent selection, and the yield was only 51%. With the
decrease of reaction temperature, the advantage of toluene as
reaction solvent gradually emerged. When the temperature was
reduced to 80 ℃, the yield reached 67% (Entries 1-7). However,
the reaction was not complete, and there was a surplus of
starting substrate 1a. Therefore, the reaction time was
prolonged, and the conversion rate of the reaction was
significantly improved. We finally found that 48 h was the
optimal reaction time (Entry 8). After that, we found that
phosphine ligands crucially influenced the reaction direction.
When trialkylphosphine ligands (such as PCy3 and PtBu3-HBF4)
were used, the dearomatization reaction was more likely to
occur without amination. When electron-poor aromatic
phosphine ligands were used, the reaction was promoted.
Finally, TFP exerted the best effect on the reaction, and the
yield reached 84% (Entries 9-12). At last, we screened the base
and palladium. We found that when we used another base to
replace Cs2CO3, the yield decreased or the reaction direction
moved towards the product of the dearomatization reaction
without amination. Finally, we found that Pd(OAc)2 was the
best palladium catalyst. (Entries 13-17) (Table 1)
a)Intramolecular Dearomatization Reaction via Palladium-Catalyzed.
R'
The functionalization of
C3 position is widely
known.
R
Ar'
Ar
N
N
N
O
Ar
Ar
O
O
ArX
Pd/[L]
Ar'
R'
Z
L
R'
12
R
3
11
Ar' 10
9
4
Z=NR/O
N
Ar
2
5
O
Ar
Ar'
Ar'
z
Ar
6
1N
N
8
z
RN
7
R
N
R
O
Ar
O
O
b) Dearomatization Tandem reaction of Cyanation, Arylation and Alkynylation.
R'
CN
R
Ph
R
R
Ar
Functional groups could
not be introduced directly
into C12 position.
Ar
Ar
Ar
N
Pd/[L]
[Nu]
R
N
N
N
Ar'
O
Ar'
Ar'
Ar'
O
O
Br
X
O
This work
R2
Ar'
O
N
R1
N
Ar'
R2
R1
Ar
O
ArI
Pd/NBE
N
OBz
Ar
R2
N
Ar'
N
R1
X=N/O
O
A large number of biologically active molecules in nature have
amino functional groups,13 such as piperidine, piperazine,
morpholine and other functional groups.14 In addition, in
pharmaceutical chemistry, antibacterial linezolid15 and anti-
tumor targeted therapy drug gefitinib16 has morpholine group,
hypertension drug β1-AR,17 antibacterial levofloxacin18 and
wide-spectrum veterinary antibacterial enrofloxacin19 has
piperazine group, etc. These show that the site-selective
introduction of amino functional groups is very valuable for
drug screening. Due to the limitations of natural extraction,
artificial synthesis is particularly important, and the synthesis of
Table 1. Optimization of the Tandem Reaction Conditions of Dearomatization and Amination of Indole Derivatives
a
O
O
N
Pd, P, NBE
N
N
Base, solvent, T, time
N
O
OBz
I
O
1a
2a
3a
Temperatu
re (℃)
Time
(h)
Yield
(%)
Entry
Solvent
Pd
Ligand
Base
1
2
toluene
120
120
120
120
80
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
TFP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
18
18
18
18
18
18
18
48
18
18
18
51
66
1,4-dioxane
THF
3
70
4
DCE
62
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
67
6
100
140
80
68
7
46
8
78
9
80
74
10
11
80
X-Phos
PCy3
60
80
trace
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12
13
14
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toluene
toluene
toluene
toluene
toluene
toluene
80
80
80
80
80
80
Pd(OAc)2
Pd(OAc)2
TFP
TFP
TFP
TFP
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
48
24
24
24
24
24
84
81
33
76
79
55
1
2
3
4
5
Pd(PPh3)4
Pd(PPh3)Cl2
Pd(PPh3)Cl2
Pd(OAc)2
TFP
6
7
8
9
a Reaction conditions: substrate 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol %), TFP (0.04 mmol, 20
mol %), norbornene (0.8 mmol, 4.0 equiv.), Cs2CO3 (0.8 mmol, 4.0 equiv.), toluene (3.0 mL), 80 °C, 48 h. TFP = Trifurylphosphine,
PCy3 = Tricyclohexylphosphine.
Amination reagents derived from cyclic amines, such as
morpholine, thiomorpholine, pyrrolidine, hexamethyleneimine,
piperidine and piperazine, provided the required products (3a-
3o, 3r) with good yields. Among them, morpholine (3a), ketal-
protected (3k) and piperazinyl products (3l-3o) can be found in
reaction system (4q-4r). In addition, the reaction still proceeded
smoothly when there was a large steric hindrance group at the
C2 position of indole (4s-4t). (Table 2)
10
11
12
13
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For the tandem reaction conditions of dearomatization and
amination of benzofuran derivatives, we found that both
Pd(OAc)2/X-Phos/DCE/120 ℃ and Pd(OAc)2/TFP/toluene/80
℃ are suitable for this reaction. On the basis of the optimum
conditions, the scope of the amination reagents was investigated
again:25 the ketal-protected skeleton (6c) and piperazinyl
skeleton products (6d-6f) were successfully obtained, but
piperidine was not ideal. We then investigated the scope of
substrate 5 and found that the desired products (6g-6l) could be
obtained successfully with either an electron-withdrawing
group or electron-donating group. (Table 3)
20
a large number of natural products or drug molecules.13e,
Noncyclic amination reagents also afforded the target products
in good yields (3p, 3q). The structures of representative
products 3a, 3b and 3c were confirmed by single-crystal X-ray
diffraction technique.25 In particular, the corresponding product
(3r) of the antidepressant drug paroxetine was also derived by
this method. (Table 2)
We next used piperidin-1-yl benzoate as an amination reagent
to expand the substrate scope. The results showed that the target
product (4a-4m) can be obtained in good yields when including
halogenated substrates (-F, -Cl, -Br or -CF3), electron-rich
groups (-CH3, -OCH3) or the strong electron-withdrawing
group -NO2.25 It is noteworthy that higher temperature (100 ℃)
was required to make the reaction proceed smoothly (4m, 4q-
4t). When the C3 position of indole was substituted with the
benzyl group or there were electron donor groups in the C5
position, the reaction could proceed smoothly (4n-4p). The C3-
hexyl/isopropyl substituted indoles were also suitable for this
Table 2. Investigation of Substrate Scope a
To study the feasibility of an asymmetric version of this domino
reaction, we utilized 1a and 2b as the reactants, and preliminary
studies with chiral phosphine ligand demonstrated that product
7 could be formed in 32% yield and with 66: 34 er by chiral
phosphine ligand L3. We realized the asymmetric conversion
of the amination/dearomatization reaction; unfortunately, we
did not obtain better results after screening various ligands.
(Scheme 2)
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R5
R2
R5
R1
N
1
2
Pd(OAc)2, TFP, NBE
R3
R6
R6
R2
R1
N
R4
N
Cs2CO3, toluene, 80 ℃, 48 h
OBz
R4
N
R3
O
3
O
3, 4
I
1
2
4
5
6
7
O
O
O
S
N
N
N
N
N
N
N
N
8
N
N
N
N
N
N
N
N
9
O
O
O
O
O
O
O
O
3c 84%
3d 84%
3e 87%
3g 76%
3h 80%
3a 84%
3b 73%
3f 71%
10
11
12
13
14
15
16
17
18
19
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
O
O
O
O
N
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
3m 72%
3p 79%
3j 79%
3k 80%
3l 69%
3o 70%
3i 80%
3n 60%
F
O
O
F
O
O
O
N
N
N
N
N
N
O
Br
Cl
F
N
N
N
O
N
O
N
H
N
F
O
O
O
Paroxetine
O
4c 86%
4d 75%
4b 76%
4a 88%
3r 75%
3q 71%
N
N
N
N
N
N
N
N
F3
C
Cl
F
O
O
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
4k 86%
O
4f 86%
4g 81%
4e 81%
4l 80%
4i 89%
4j 83%
4h 83%
N
N
N
N
N
N
N
N
O2
N
O
N
N
N
N
N
O
N
N
N
O
O
O
O
O
O
O
4qb 53 %
4rb 79%
4tb 63%
4sb 43%
4mb 79%
4o 71%
4p 78%
4n 81%
a Reaction conditions: substrate 1a (0.2 mmol), 2 (0.4 mmol, 2.0 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol %), TFP (0.04 mmol, 20 mol
%), norbornene (0.8 mmol, 4.0 equiv.), Cs2CO3 (0.8 mmol, 4.0 equiv.), toluene (3.0 mL), 80 °C, 48 h. b at 100 °C.
To further expand the application of electrophilic reagents, we
used n-butane bromide as an electrophilic reagent to explore the
tandem reaction of dearomatization and alkylation. After
selecting the reaction conditions, it was found that the target
product 8 could be obtained in 23% yield after 24 h reaction at
℃ with DMF instead of toluene as the solvent.
Unfortunately, this method cannot produce the products of the
dearomatization/arylation reaction. (Scheme 3)
solvent under 1 atm H2, and product 10 could be obtained in
66% yield.7c (Scheme 6)
In particular, we attempted to use substrate 11 with H in the C2
position of indole and found that norbornene could not be
removed. Therefore, we speculate that the 2-substituent groups
of indole are very important for the dearomatization reaction
and ortho-amination. (Scheme 7)
60
Table 3. Reaction Scopea a
To demonstrate the scalability of this method, we expanded the
scale of 1a to 2.7 mmol (1.01 g) and finally obtained the target
product 3e with 79% yield (0.71g). (Scheme 4) To explore the
versatility of product skeletons and the potential application of
this new method, we also conducted some derivative
experiments. Considering that many bioactive compounds and
natural products often contain unprotected N-H bonds,13e we
previously attempted to use TFA and SiO2, respectively, to
remove the Boc-protecting group of 3m, and we could obtain
the target product 9 with yields of 63% and 73%, respectively.
Product 9 can be further modified according to specific needs.
(Scheme 5) In addition, the hydrogenation reaction could be
carried out for 3d by using Pd/C as catalyst and ethyl acetate as
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O
N
R7
Pd(OAc)2, X-Phos, NBE
R2
R1
R7
N
N
O
1
2
N
O
O
Cs2CO3, DCE, 120 ℃,18 h
OBz
R2
N
I
H2, Pd/C (10 mol%)
R8
N
R1
R8
N
N
EA (3 mL), 1 atm, r.t., 72 h
3
5
2
6
O
O
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
3d 0.2mmol
10 66%
O
N
O
O
O
N
N
N
O
N
O
O
O
N
Scheme 7. Amination/Dearomatization Reaction of
Substrate 11
N
O
N
O
O
N
O
O
O
6b 57% (63%b
6c 55% (60%b
)
6a 58% (66%b
O
)
6d 48% (31%b
)
)
O
Pd(OAc)2 (10 mol%)
O
N
O
N
N
TFP (20 mol%)
N
N
N
N
O
N
O
N
Cs2CO3 (4.0 equiv.)
O
O
N
O
OBz
O
toluene (3 mL)
O
O
N
O
O
N
N
I
N
N
F
Cl
80 ℃, 48 h
O
O
12 25%
2.0 equitv.
4.0 equitv.
11 0.2mmol
O
O
6e 65% (68%b
)
6f 57% (55%b
)
6h 74% (65%b
)
6g 64% (60%b
)
Based on the mechanism proposed by Catellani, Lautens, Dong
and others, we propose the following reaction mechanism:
O
O
O
O
N
N
N
N
O
N
O
First, Pd(0) is bound to iodobenzene by oxidative addition
reaction, and then, under the action of norbornene and
palladium, intermediate I is formed through carbopalladation of
norbornene and subsequent ortho-C-H activation. Then, N-
(benzoyloxy)amine is added to intermediate I by oxidative
addition, and aminated aromatic II is obtained by reductive
elimination. Alternatively, N-(benzoyloxy)amine can undergo
electrophilic amination directly with intermediate I to produce
aminated aromatic II. Next, after intramolecular coordination
of the indole to Pd and carbopalladation, the beta-hydride
elimination reaction of intermediate III takes place under the
action of cesium carbonate, and the desired target product Ⅳ is
finally obtained. Pd then participates in the reaction cycle again.
(Scheme 8)
O
N
O
N
O
O
N
O
N
N
O
N
CF3
Br
N
O
O
O
O
O
O
6j 47% (38%b
)
6i 51% (55%b
)
6l 64%
6k 58% (61%b
)
a Reaction conditions: substrate 5 (0.2 mmol), 2 (0.4 mmol, 2.0
equiv.), Pd(OAc)2 (0.02 mmol, 10 mol %), X-Phos (0.04 mmol,
20 mol %), norbornene (0.8 mmol, 4.0 equiv.), Cs2CO3 (0.8
mmol, 4.0 equiv.), DCE (3.0 mL), 120 °C, 18 h.b TFP (0.04 mmol,
20 mol %), toluene (3.0 mL), 80 °C, 48 h.
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Asymmetric Tandem Reaction of 1a
Pd(OAc)2 (10 mol%)
N
O
N
P
L3
(20 mol%), NBE (4.0 equitv.)
N
O
N
Cs2CO3 (4.0 equiv.), toluene (3 mL)
Scheme 8. Possible Catalytic Cycle
N
O
OBz
80 ℃, 48 h
O
I
R1
1a 0.2mmol
2b 0.4mmol
7
32% 66:34 er
L3
R2
Pd(OAc)2+TFP
N
N
Scheme 3. Alkylation/Dearomatization Reaction of 1a
N
Pd0Ln
O
I
O
Ⅳ
CsHCO3
Cs2CO3
Pd(OAc)2 (10 mol%)
N
TFP (20 mol%), NBE (4.0 equitv.)
N
BzO
R1
H
R2
Br
N
N
Pd
L Pd
O
n
Cs2CO3 (4.0 equiv.), DMF (3 mL)
Ln
O
I
60 ℃, 24 h
O
I
N
0.4mmol
8
23%
1a 0.2mmol
Ⅲ
O
Scheme 4. Gram-scale Synthesis
O
N
N
N
Pd(OAc)2 (10 mol%)
PdLn
R2
N
O
N
n R1
TFP (20 mol%), NBE (4.0 equitv.)
P
d
L
BzO
Ⅱ
N
N
Cs2CO3 (4.0 equiv.), toluene (3 mL)
Ⅰ
O
OBz
80 ℃, 48 h
I
O
1a 1 g
2.0 equitv.
3e 79% (0.71g)
R2
R1
N
O
N
N
O
OBz
Scheme 5. Deprotection of Production 3m
or
Ln
Pd
OBz
PdLn
R2
R1
N
N
O
R1
O
73%
H
N
O
R2
Bz
SiO2 (1 g), toluene (5 mL)
N
110 ℃, 48 h
N
N
3. CONCLUSIONS
or
N
N
①
②
TFA (30 equiv.)
DCM (2 mL), r.t., 2 h
NaOH
O
In summary, we have demonstrated a new method for the direct
construction of bicyclic compounds of indoles or spiro
compounds of benzofurans with C2-quaternary center, C3-exo
double bond and amino group by Pd/NBE cooperative catalysis.
The synthesis method is efficient and convenient, and it exhibits
O
9
63%
3m 0.2mmol
Scheme 6. Hydrogenation Reaction of 3d
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The Journal of Organic Chemistry
Page 6 of 24
good functional group tolerance. It may be useful in industrial addition of a solution of (R)-[1,1'-binaphthalene]-2,2'-diol (1.3
1
2
3
4
5
6
7
8
production, complex natural product synthesis and asymmetric
synthesis. The extension to additional aromatic hydrocarbon
substrates and enhancement of enantioselectivity of synthesis
are currently being studied in the laboratory.
mmol) and Et3N (7.8 mmol) in dry THF (5 mL) over 2 min. The
mixture was warmed to room temperature and stirred 24 h. It
was then filtered and the solid was washed with THF. After
evaporation, the residue was purified by chromatography on
silica gel, eluting with petroleum ethyl/acetate ether to afford
the ligands.
4. EXPERIMENTAL SECTION
Ph
Ph
O
General Procedures. Unless otherwise noted, reactions were
performed under an argon atmosphere. Plastic syringes were
used to transfer air-and moisture-sensitive reagents. Solvent
was freshly distilled/degassed prior to use unless otherwise
noted. Analytical TLC was performed with silica gel GF254
plates. For column chromatography, a 200-300 mesh silica gel
was employed. Organic solutions were concentrated under
reduced pressure using a rotary evaporator. Room temperature
(r.t.) is 23-25 °C. Commercial reagents were used as received
without further purification unless otherwise noticed. Other
commercially available reagents and solvents were used
without further purification. Ligands L1-L6 were purchased or
prepared according to the literature procedures and used
directly as received. Deuterated solvents were purchased from
Cambridge Isotope Laboratories. 1H NMR spectra were
recorded on Bruker AVANCE III 400 with 400 MHz
frequencies, and 13C NMR spectra were recorded on Bruker
AVANCE III 400 with 101 MHz frequencies. 19F NMR spectra
were recorded on a Bruker AVANCE III 400 spectrometer with
a 19F operating frequency of 376 MHz. Chemical shifts (δ) were
reported in ppm relative to the residual solvent signal (CDCl3 δ
P
P
Ph
Ph
O
Ph
Ph
Ph
Ph
P
O
P
O
9
L5
L6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ligands L5-L6 are purchased from reagent manufacturers and
used without further purification.
O
R2
N
O
K2CO3, DCM, r.t.
R2
R1
O
N
O
R1
O
H
O
2
Typical procedure for the synthesis of O-benzoyl
hydroxylamine 2: O-Benzoyl hydroxylamines was synthesized
using a modified procedure.11e, 12 To a 100 mL flask equipped
with stir bar and benzoyl peroxide (3.46 g, 70% purity 10 mmol,
1 equiv.), K2CO3 (2.76g, 20 mmol, 2 equiv.), and CH2Cl2 (50
mL) was added sequentially. Then a solution of amine (15
mmol, 1.5 equiv.) was added dropwise at 0 ℃. Upon
completion, the reaction was further stirred at room temperature
overnight. After monitored by TLC to see the full conversion of
benzoyl peroxide, water (100 mL) was added, and the products
were extracted with CH2Cl2 (3 × 50 mL). The combined organic
extract was dried over Na2SO4, filtered and concentrated under
vacuum. The residue was purified by column chromatography
on silica gel to give O-benzoyl hydroxylamine 2.
1
= 7.26 for H NMR and δ = 77.00 for 13C NMR). Chemical
shifts (ppm) were recorded with tetramethylsilane (TMS) as the
internal reference standard. Multiplicities are given as s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublets) or td (triplet of doublets). HRMS was
obtained using a Q-TOF instrument equipped with an ESI
source. Data collection for crystal structure was performed at
room temperature using Mo Kα radiation on a Bruker APEXII
diffractometer. HPLC analyses were performed using Agilent
1260 chromatography. Chiralpak AD-H columns were
purchased from Daicel Corporation.
R5
O
NHNH2HCl
AcOH
℃, 3 h
R3
R6
R5
Ⅰ
R3
R6
100
N
H
OH
KOH
Ⅱ
R3
150 ℃, 18 h
N
H
R3
N
H
Typical procedure for the synthesis of 1: Methods Ⅰ:
Phenylhydrazine hydrochloride (12 mmol), AcOH (5 mL) and
ketone (10.0 mmol) were added into a 20 mL tube, the mixture
was stirred at 100 ℃ for 3 h. After the reaction was completed,
water (10 mL) was added, and the mixture was extracted with
ethyl acetate. The combined organic phase was washed with
brine, dried over Na2SO4 and concentrated in vacuo to give
crude product, which was purified by flash chromatography on
silica gel to afford the fused indole products.7d Methods Ⅱ: 2-
methyl-1H-indole (6 mmol), KOH (7.8 mmol) and
phenylmethanol (18 mmol) were added into a 20 mL tube, the
mixture was stirred at 150 ℃ for 18 h. After the reaction was
completed, water (10 mL) was added, and the mixture was
extracted with ethyl acetate. The combined organic phase was
washed with brine, dried over Na2SO4 and concentrated in
vacuo to give crude product which was purified by flash
chromatography on silica gel to afford the fused indole
products.22
General Methods of Product Preparation and Product
Derivatization.
R
O
R
R
Et3
N
OH
OH
N
P
N
R
O
PCl2
THF
O
O
O
O
N
N
N
N
P
P
P
P
O
O
O
O
L3
L2
L4
L1
Synthesis of chiral phosphoramidite ligands: The ligands L1-
L4 were prepared according to the literature method with some
21
modification.7c,
To a solution of 10,11-dihydro-5H-
dibenzo[b,f]azepine (2.6 mmol) in dry THF (5 mL) at 0 ℃ was
added n-BuLi (2.4 M in hexanes, 3.9 mmol) dropwise over 3
min under argon atmosphere. After stirring at 0 ℃ for 30 min,
PCl3 (7.8 mmol) was added to the reaction mixture in one
portion. The resulting mixture was warmed to room
temperature, stirred for 1 h, and then concentrated at room
temperature. The remaining PCl3 was removed under vacuum.
Dry THF (5 mL) was then added to the resulting residue. After
stirring for 10 min, the mixture was cooled to 0 ℃, followed by
R5
R5
R3
R6
O
I
O
I
R3
R6
N
(SOCl)2, r.t.
H
H2
O
N
OH
Cl
R4
R4
DCM, overnight
R4
NaH, DMF, 70 ℃, 18 h
K2CO3
O
I
1
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The Journal of Organic Chemistry
Substrates 1 were prepared according to the known procedure sealed with tipping plug). Toluene (3 mL) and norbornadiene
1
2
3
4
5
6
7
8
by the condensation of 2-iodobenzoic acid with indole
accordingly. The corresponding indoles was synthesis by
known methods Ⅰ (Fisher indole synthesis) or methods Ⅱ.
Unless otherwise indicated, all other reagents and solvents were
obtained from commercial suppliers and used as received. To a
solution of substituted indole (6 mmol) in 25 mL DMF was
added NaH (60%, 9 mmol) in portion at 0 ℃, after which the
mixture was stirred at room temperature for 1 h. A solution of
substituted 2-iodobenzoyl chloride (12 mmol) in 5 mL DMF
was then introduced to the above mixture and the resulting
mixture was reacted at 70 ℃ for 18 h. After quenched by water,
the mixture was extracted with ethyl acetate and washed by
saturated potassium carbonate solution. The collected organic
phase was then dried over Na2SO4 followed by filtration and
concentration under vacuum to afford the crude product, which
was then purified by flash chromatography on slica gel, eluting
with petroleum ether/ethyl acetate 100:1 (v/v) to afford the
(0.6 mmol, 3.0 equiv.) was injected into the tube via plastic
syringes. Then the white medical adhesive tape was used to
reinforce the tipping plug. The resulting light yellow suspension
was stirred vigorously at room temperature for 10 minutes
before being placed in a preheated oil bath at 80 °C stirring at
700~900 rpm for 48 h. After the reaction was completed, the
residue was purified with chromatography column on silica gel,
eluting with petroleum ethyl/acetate ether to afford the product
3 or 4.
9
O
R7
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd(OAc)2, X-Phos, NBE
R7
R2
R1
O
N
O
O
Cs2CO3, DCE, 120 ℃,18 h
R2
OBz
N
I
R8
N
R8
R1
5
2
6
In a 20 mL tube, 5 (0.2 mmol), 2 (0.4 mmol, 2.0 equiv.),
Pd(OAc)2 (0.02 mmol, 10 mol%), X-Phos (0.04 mmol, 20
mol%), Cs2CO3 (0.8 mmol, 4.0 equiv.) were added and charged
with argon more than five times (The tube was sealed with
tipping plug). DCE (3 mL) and norbornadiene (0.6 mmol, 3.0
equiv.) was injected into the tube via plastic syringes. Then the
white medical adhesive tape was used to reinforce the tipping
plug. The resulting light yellow suspension was stirred
vigorously at room temperature for 10 minutes before being
placed in a preheated oil bath at 120 °C stirring at 700~900 rpm
for 18 h. After the reaction was completed, the residue was
purified with chromatography column on silica gel, eluting
with petroleum ethyl/acetate ether to afford the product 6.
substrates 1.7d, 8d
I
H2N
O
O
(COCl)2
R8
R7
R7
DMF, DCM, 4 h
Et3N, DCM, r.t., 24 h
O
O
OH
Cl
O
O
CH3I, r.t.
R8
R8
R7
R7
O
N
O
HN
NaH, THF
I
5
A
I
Typical procedure for the synthesis of 5: To a stirred solution
of substituted 2-iodobenzoic acid (10 mmol) in CH2Cl2 (15 mL)
were added a catalytic amount of DMF (18 μL) and (COCl)2
(20 mmol, 0.7 mL), and the mixture was stirred for 4 h at room
temperature. The mixture was then concentrated under reduced
pressure. To a stirred solution of this residue in DCM (5.0 mL)
was added a mixture of Substituted 2-iodoaniline (12 mmol)
and Et3N (3 mL) in DCM (25 mL). The mixture was stirred at
room temperature for 24 h. After the reaction was completed,
water (10 mL) was added, and the mixture was extracted with
ethyl acetate. The combined organic phase was washed with
brine, dried over Na2SO4. After filtration, the solvent was
concentrated under vacuum and the residue was purified by
flash chromatography on silica gel, eluting with petroleum
ether/ethyl acetate 100:1 (v/v) to afford the substrates A. A 60%
dispersion of NaH in mineral oil (20 mmol) was added to a
stirred solution of the substrates A in THF at 0 ℃, after which
the mixture was stirred at room temperature for 15 min, CH3I
(20 mmol) was then introduced to the above mixture and the
resulting mixture was reacted at room temperature. At this time
the extent of completion of the reaction was determined by TLC
analysis. After the reaction was completed, water (10 mL) was
added, and the mixture was extracted with ethyl acetate. The
combined organic phase was washed with brine, dried over
Na2SO4 and concentrated in vacuo to give crude product, which
was purified by flash chromatography on silica gel, eluting with
petroleum ether/ethyl acetate 100:1-20:1 (v/v) to afford the
substrates 5.7c
Pd(OAc)2, TFP, NBE
N
Br
Cs2CO3, DMF, 60 ℃, 24 h
N
O
I
O
1a
8
Product Derivatization: In a 20 mL tube, 1a (0.2 mmol),
Pd(OAc)2 (0.02 mmol, 10 mol%), TFP (0.04 mmol, 20 mol%),
Cs2CO3 (0.8 mmol, 4.0 equiv.) were added and charged with
argon more than five times (The tube was sealed with tipping
plug). DMF (3 mL), norbornadiene (0.6 mmol, 3.0 equiv.) and
1-bromobutane (0.4 mmol, 2.0 equiv.) was injected into the tube
via plastic syringes. Then the white medical adhesive tape was
used to reinforce the tipping plug. The resulting light yellow
suspension was stirred vigorously at room temperature for 10
minutes before being placed in a preheated oil bath at 60 °C
stirring at 700~900 rpm for 24 h. After the reaction was
completed, water (10 mL) was added, and the products were
extracted with acetate ether (3 × 5 mL). The combined organic
extract was dried over Na2SO4, filtered and concentrated under
vacuum. The residue was purified by column chromatography
on silica gel to afford the product 8.
N
N
H2, Pd/C
EA, 1atm, r.t., 72 h
N
N
O
O
R5
R2
R1
R6
3d
N
10
R5
R3
R6
Pd(OAc)2, TFP, NBE
R2
R1
R4
N
N
Pd/C (47.3 mg, palladium on activated carbon, 5% Pd basis, 0.1
equiv.) was added to a solution of 3d (33.1 mg, 0.1 mmol) in
EtOAc (3.0 mL). The reaction mixture was stirred under H2
atmosphere (1 atm) at r.t. for 72 h. After the reaction was
complete (monitored by TLC), the crude reaction mixture was
filtered with celite and washed with EtOAc. The solvent was
removed under reduced pressure. Then the residue was purified
Cs2CO3, toluene, 80 ℃, 48 h
N
OBz
R4
R3
O
O
I
1
2
3 or 4
Product Preparation: In a 20 mL tube, 1 (0.2 mmol), 2 (0.4
mmol, 2.0 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%), TFP (0.04
mmol, 20 mol%), Cs2CO3 (0.8 mmol, 4.0 equiv.) were added
and charged with argon more than five times (The tube was
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The Journal of Organic Chemistry
(2,3-dimethyl-1H-indol-1-yl)(5-fluoro-2-
Page 8 of 24
by silica gel column chromatography (PE/EA = 14:1) to afford
1
the desired product 10.23
iodophenyl)methanone (1b) 1.25 g, yield: 53%, yellow oil. H
NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 8.7, 5.1 Hz, 1H), 7.30
(d, J = 7.7 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.12 (t, J = 7.4 Hz,
1H), 7.07 – 6.98 (m, 2H), 6.84 (td, J = 8.4, 3.0 Hz, 1H), 2.08 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.3 (d, J = 2.2 Hz),
162.7 (d, J = 251.3 Hz), 144.0 (d, J = 6.7 Hz), 141.3 (d, J = 7.6
Hz), 135.7, 132.0, 131.4, 124.0, 123.5, 119.2 (d, J = 21.7 Hz),
118.1, 116.9, 116.5 (d, J = 23.7 Hz), 114.6, 86.3 (d, J = 3.7 Hz),
13.5, 8.7. 19F NMR (376 MHz, CDCl3) δ -116.96. HRMS (ESI)
m/z: [M+H]+ Calcd for C17H14FINO 394.0099; found 394.0105.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 90:1 then petroleum ethyl/acetone
3:1 (v/v);
1
2
3
4
5
6
7
8
O
73%
H
N
O
SiO2 (1 g), toluene (5 mL)
N
N
110 ℃, 48 h
N
or
N
N
①
②
TFA (30 equiv.)
DCM (2 mL), r.t., 2 h
NaOH
O
O
9
63%
3m 0.2mmol
Methods 1: In a 20 mL tube, 3m (86.4 mg, 0.2 mmol) and silica
gel (1.0 g) and toluene (5 mL) were added. The mixture was
stirred at 110 ℃ reflux for 24 h. After the reaction was complete
(monitored by TLC), the residue was purified with
chromatography column on silica gel (CH2Cl2/MeOH = 15:1)
to afford the desired product 9.13d Methods 2: Product 3m (86.4
mg, 0.2 mmol) was dissolved in CH2Cl2 (2 mL) and then TFA
(0.46 mL, 30 equiv.) was added. The reaction was stirred for 2
h at room temperature. Then the reaction was quenched with 6
M NaOH and rapidly stirred for 30 min at room temperature.
The crude was extracted with dichloromethane (3 x 5 mL), then
dried over Na2SO4 and filtered. The crude product was purified
by flash column chromatography (CH2Cl2/MeOH = 15:1) to
afford the desired product 9.24
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
N
I
O
(2,3-dimethyl-1H-indol-1-yl)(2-fluoro-6-
iodophenyl)methanone (1c) 0.90 g, yield: 38%, white soild. 1H
NMR (400 MHz, CDCl3) δ 9.14 – 5.54 (m, 7H), 2.17 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 164.1, 158.7 (d, J = 253.8
Hz), 135.2, 132.6, 132. 6, 131.9, 131.6, 131.6, 124.4, 123.8,
118.1, 117.2, 116.1, 115.9, 93.5, 13.3, 8.8.19F NMR (376 MHz,
CDCl3) δ -110.90. HRMS (ESI) m/z: [M+H]+ Calcd for
C17H14FINO 394.0099; found 394.0105. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 70:1 (v/v);
Pd(OAc)2, TFP
Cs2CO3, toluene, 80 ℃, 48 h
N
N
N
O
OBz
O
I
11
12
In a 20 mL tube, 11 (0.2 mmol), piperidin-1-yl benzoate (0.4
mmol, 2.0 equiv.), Pd(OAc)2 (0.02 mmol, 10 mol%), TFP (0.04
mmol, 20 mol%), Cs2CO3 (0.8 mmol, 4.0 equiv.) were added
and charged with argon more than five times (The tube was
sealed with tipping plug). Toluene (3 mL) and norbornadiene
(0.6 mmol, 3.0 equiv.) was injected into the tube via plastic
syringes. Then the white medical adhesive tape was used to
reinforce the tipping plug. The resulting light yellow suspension
was stirred vigorously at room temperature for 10 minutes
before being placed in a preheated oil bath at 80 °C stirring at
700~900 rpm for 48 h. After the reaction was completed, the
residue was purified with chromatography column on silica gel,
eluting with petroleum ethyl/acetate ether, eluting with
petroleum ethyl/acetate ether 100:1 (v/v) to afford the product
12.
Cl
N
O
I
(5-chloro-2-iodophenyl)(2,3-dimethyl-1H-indol-1-
yl)methanone (1d) 1.28 g, yield: 52%, white soild. H NMR
1
(400 MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 7.7
Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.24
(t, J = 7.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 7.13 (t, J =
7.8 Hz, 1H), 2.20 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
167.4, 143.9, 141.0, 135.8, 135.1, 132.1, 131.9, 131.5, 129.0,
124.1, 123.6, 118.1, 117.1, 114.7, 90.3, 13.6, 8.8. HRMS (ESI)
m/z: [M+H]+ Calcd for C17H14ClINO 409.9803; found
409.9811. Purified by chromatography on silica gel, eluting
with petroleum ethyl/acetate ether 100:1 (v/v);
Characterization Data of Substrate.
N
O
I
Br
N
(2,3-dimethyl-1H-indol-1-yl)(2-iodophenyl)methanone
(1a)
O
1.58 g, yield: 70%, white soild. 1H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 7.9 Hz, 1H), 7.49 – 7.36 (m, 3H), 7.32 – 7.16 (m,
3H), 7.15 – 7.06 (m, 1H), 2.25 – 2.15 (m, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 168.8, 142.5, 139.9, 136.0, 132.4, 131.7,
131.4, 129.0, 128.5, 123.8, 123.3, 118.0, 116.5, 114.8, 93.2,
13.6, 8.8. HRMS (ESI) m/z: [M+H]+ Calcd for C17H15INO
376.0193; found 376.0200. Purified by chromatography on
silica gel, eluting with petroleum ethyl/acetate ether 100:1
(v/v);
I
(5-bromo-2-iodophenyl)(2,3-dimethyl-1H-indol-1-
1
yl)methanone (1e) 1.31 g, yield: 48%, white soild. H NMR
(400 MHz, CDCl3) δ 7.75 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.1
Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.36 – 7.29 (m, 2H), 7.25 (t,
J = 7.5 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 2.20 (s, 6H). 13C{1H}
NMR (101 MHz, CDCl3) δ 167.2, 144.2, 141.2, 135.8, 134.8,
132.0, 131.7, 131.5, 124.1, 123.6, 122.8, 118.1, 117.1, 114.7,
91.2, 13.7, 8.8. HRMS (ESI) m/z: [M+H]+ Calcd for
C17H14BrINO 453.9298; found 453.9307. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 100:1 (v/v);
F
N
I
O
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The Journal of Organic Chemistry
J = 7.6 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.19 (t, J = 7.4 Hz,
F
1
2
3
4
5
6
7
8
9
1H), 7.08 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 3.0 Hz, 1H), 6.74 (dd,
J = 8.7, 3.0 Hz, 1H), 3.73 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 159.9, 143.1, 140.4,
135.7, 132.2, 131.3, 123.7, 123.2, 118.2, 117.8, 116.4, 114.6,
114.4, 81.4, 55.5, 13.4, 8.7. HRMS (ESI) m/z: [M+H]+ Calcd
for C18H17INO2 406.0298; found 406.0305. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 21:1 (v/v);
I
N
O
(5-fluoro-2,3-dimethyl-1H-indol-1-yl)(2-
iodophenyl)methanone (1f) 1.23 g, yield: 52%, white soild. 1H
NMR (400 MHz, CDCl3) δ 7.95 – 7.85 (m, 1H), 7.47 (td, J =
7.5, 0.9 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.32 (dd, J = 9.0, 4.5 Hz,
1H), 7.21 (td, J = 7.7, 1.9 Hz, 1H), 7.06 (dd, J = 8.7, 2.7 Hz,
1H), 6.82 (td, J = 9.1, 2.7 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 159.7 (d, J = 240.5
Hz), 142.3, 139.8, 134.0, 132.7 (d, J = 9.4 Hz), 132.2, 131.8,
128.9, 128.5, 116.3 (d, J = 3.7 Hz), 115.9 (d, J = 8.8 Hz), 111.1
(d, J = 24.4 Hz), 103.8 (d, J = 23.5 Hz), 93.1, 13.6, 8.8. 19F
NMR (376 MHz, CDCl3) δ -119.48. HRMS (ESI) m/z: [M+H]+
Calcd for C17H14FINO 394.0099; found 394.0104. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 70:1 (v/v);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
I
(2-iodophenyl)(2,3,5-trimethyl-1H-indol-1-yl)methanone (1j)
1.28 g, yield: 55%, yellow soild. 1H NMR (400 MHz, CDCl3) δ
7.92 – 7.87 (m, 1H), 7.48 – 7.42 (m, 1H), 7.41 – 7.36 (m, 1H),
7.22 – 7.16 (m, 2H), 7.13 – 7.05 (m, 1H), 6.93 – 6.88 (m, 1H),
2.43 – 2.38 (m, 3H), 2.21 – 2.15 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 168.7, 142.6, 139.8, 134.1, 132.9, 132.5, 131.7,
131.6, 128.9, 128.4, 125.0, 118.1, 116.4, 114.5, 93.2, 21.3, 13.6,
8.8. HRMS (ESI) m/z: [M+H]+ Calcd for C18H17INO 390.0349;
found 390.0343. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 100:1 (v/v);
Cl
N
O
I
(5-chloro-2,3-dimethyl-1H-indol-1-yl)(2-
iodophenyl)methanone (1g) 1.40 g, yield: 57%, white soild. 1H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.49 (t, J
= 7.5 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.26 – 7.20 (m, 2H), 7.06
(dd, J = 8.8, 2.2 Hz, 1H), 2.16 (s, 3H), 2.15 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.7, 142.1, 139.9, 134.3, 133.9,
132.8, 132.0, 129.0, 129.0, 128.6, 123.8, 117.8, 115.9, 115.8,
93.1, 13.6, 8.7. HRMS (ESI) m/z: [M+H]+ Calcd for
C17H14ClINO 409.9803; found 409.9802. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 100:1 (v/v);
N
O
O
I
(2-iodophenyl)(5-methoxy-2,3-dimethyl-1H-indol-1-
yl)methanone (1k) 1.29 g, yield: 53%, yellow soild. H NMR
1
(400 MHz, CDCl3) δ 7.91 – 7.84 (m, 1H), 7.48 – 7.42 (m, 1H),
7.41 – 7.35 (m, 1H), 7.25 – 7.15 (m, 2H), 6.90 – 6.84 (m, 1H),
6.74 – 6.66 (m, 1H), 3.83 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.4, 156.4, 142.6, 139.7,
133.1, 132.5, 131.6, 130.4, 128.8, 128.4, 116.5, 115.7, 111.4,
101.5, 93.1, 55.6, 13.6, 8.8. HRMS (ESI) m/z: [M+H]+ Calcd
for C18H17INO2 406.0298; found 406.0293. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 50:1 (v/v);
F3C
N
O
I
(2,3-dimethyl-5-(trifluoromethyl)-1H-indol-1-yl)(2-
iodophenyl)methanone (1h) 1.22 g, yield: 46%, white soild. 1H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.69 (s,
1H), 7.51 (t, J = 7.5 Hz, 1H), 7.46 – 7.40 (m, 1H), 7.39 – 7.30
(m, 2H), 7.28 – 7.23 (m, 1H), 2.23 (s, 3H), 2.20 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.9, 141.9, 140.0, 137.6, 134.4,
132.2, 131.2, 129.2, 128.6, 125.5 (q, J = 32.1 Hz), 124.7 (q, J =
271.9 Hz), 120.6 (q, J = 3.6 Hz), 116.3, 115.4 (q, J = 4.0 Hz),
114.8, 93.06, 13.5, 8.7. 19F NMR (282 MHz, CDCl3) δ -61.76.
HRMS (ESI) m/z: [M+H]+ Calcd for C18H14F3INO 444.0067;
found 444.0065. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 100:1 (v/v);
I
N
O
(2,3-dimethyl-1H-indol-1-yl)(2-iodo-5-
methylphenyl)methanone (1l) 1.01 g, yield: 43%, white soild.
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 1H), 7.41 (d,
J = 7.6 Hz, 1H), 7.26 – 7.19 (m, 3H), 7.12 – 7.06 (m, 1H), 7.02
(dd, J = 8.1, 2.2 Hz, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 142.3, 139.6, 138.8,
135.9, 132.7, 132.5, 131.4, 129.6, 123.7, 123.2, 117.9, 116.4,
114.7, 89.1, 20.9, 13.5, 8.8. HRMS (ESI) m/z: [M+H]+ Calcd
for C18H17INO 390.0349; found 390.0356. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 70:1 (v/v);
O
N
O
I
N
(2,3-dimethyl-1H-indol-1-yl)(2-iodo-5-
O
I
methoxyphenyl)methanone (1i) 1.12 g, yield: 46%, colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.8 Hz, 1H), 7.38 (d,
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(3-benzyl-5-methoxy-2-methyl-1H-indol-1-yl)(2-
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(1,2-dimethyl-3H-benzo[e]indol-3-yl)(2-
1
1
2
3
4
5
6
7
8
iodophenyl)methanone (1m) 1.22 g, yield: 48%, yellow soild.
1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.4 Hz, 1H), 7.87 –
7.79 (m, 2H), 7.52 – 7.36 (m, 6H), 7.18 – 7.10 (m, 1H), 2.57 (s,
3H), 2.20 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.3,
142.0, 140.1, 132.9, 132.1, 131.1, 131.0, 129.7, 128.5, 128.4,
128.0, 125.8, 124.6, 124.1, 124.0, 123.6, 117.6, 114.5, 93.4,
13.0. HRMS (ESI) m/z: [M+H]+ Calcd for C21H17INO
426.0349; found 426.0342. Purified by chromatography on
silica gel, eluting with petroleum ethyl/acetate ether 25:1 (v/v);
iodophenyl)methanone (1q) 1.21 g, yield: 42%, yellow oil. H
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 1H), 7.37 (d, J
= 4.6 Hz, 2H), 7.26 – 7.17 (m, 5H), 7.15 – 7.06 (m, 2H), 6.78
(d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.9, 2.6 Hz, 1H), 3.95 (s, 2H),
3.66 (s, 3H), 2.17 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.4, 156.2, 142.2, 139.6, 139.4, 134.1, 131.7, 131.6, 130.5,
128.8, 128.4, 128.3, 128.0, 126.0, 119.3, 115.5, 111.2, 101.9,
93.0, 55.3, 29.7, 13.7. HRMS (ESI) m/z: [M+H]+ Calcd for
C24H21INO2 [M+H]+ 482.0611; found 482.0609. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 25:1 (v/v);
9
O2N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
I
O
I
N
O
(2,3-dimethyl-5-nitro-1H-indol-1-yl)(2-iodophenyl)methanone
(1n) 1.11 g, yield: 44%, yellow soild. H NMR (400 MHz,
1
CDCl3) δ 8.24 – 8.18 (m, 1H), 7.94 – 7.85 (m, 2H), 7.58 – 7.47
(m, 2H), 7.36 (d, J = 9.1 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 2.21
(s, 3H), 2.14 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.4,
143.4, 140.9, 139.7, 138.7, 135.4, 132.3, 131.0, 129.2, 128.5,
118.5, 116.2, 114.2, 113.7, 92.7, 13.2, 8.4. HRMS (ESI) m/z:
[M+H]+ Calcd for C17H14IN2O3 421.0044; found 421.0051.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 25:1 (v/v);
(2-iodophenyl)(3-isopropyl-2-methyl-1H-indol-1-
yl)methanone (1r) 1.33 g, yield: 55%, yellow oil. 1H NMR (400
MHz, CDCl3) δ 7.89 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.8 Hz,
1H), 7.46 – 7.38 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.22 – 7.14
(m, 2H), 7.06 (t, J = 7.8 Hz, 1H), 3.24 – 3.10 (m, 1H), 2.18 (s,
3H), 1.42 (s, 3H), 1.40 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 169.0, 142.3, 140.0, 136.4, 131.8, 130.9, 129.3, 129.2,
128.4, 126.2, 123.3, 122.8, 119.6, 114.8, 93.3, 25.7, 22.0, 13.5.
HRMS (ESI) m/z: [M+H]+ Calcd for C19H19INO 404.0504;
found 404.0506. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 100:1 (v/v);
N
I
O
N
O
(3-benzyl-2-methyl-1H-indol-1-yl)(2-iodophenyl)methanone
(1o) 1.35 g, yield: 50%, yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.86 (d, J = 8.0 Hz, 1H), 7.43 – 7.39 (m, 2H), 7.31 (d, J = 7.3
Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.22 – 7.09 (m, 7H), 7.07 –
7.03 (m, 1H), 4.01 (s, 2H), 2.23 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 168.9, 142.2, 139.8, 139.6, 136.1, 133.5, 131.8,
130.6, 129.1, 128.5, 128.4, 128.1, 126.0, 123.8, 123.3, 119.3,
118.5, 114.7, 93.1, 29.8, 13.6. HRMS (ESI) m/z: [M+H]+ Calcd
for C23H19INO 452.0506; found 452.0516. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 25:1 (v/v);
I
(3-hexyl-2-methyl-1H-indol-1-yl)(2-iodophenyl)methanone
(1s) 1.15 g, yield: 43%, yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.90 (d, J = 8.0 Hz, 1H), 7.49 – 7.40 (m, 3H), 7.27 (d, J = 8.0
Hz, 1H), 7.24 – 7.17 (m, 2H), 7.08 (t, J = 7.7 Hz, 1H), 2.64 (t,
J = 7.6 Hz, 2H), 2.18 (s, 3H), 1.64 – 1.53 (m, 2H), 1.39 – 1.26
(m, 6H), 0.92 – 0.82 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 168.9, 142.4, 139.9, 136.1, 132.3, 131.7, 130.8, 129.1, 128.4,
123.6, 123.2, 121.4, 118.1, 114.8, 93.2, 31.7, 29.8, 29.2, 23.9,
22.6, 14.1, 13.5. HRMS (ESI) m/z: [M+H]+ Calcd for
C22H25INO 446.0975; found 446.0969. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 100:1 (v/v);
N
I
O
(3-benzyl-2,5-dimethyl-1H-indol-1-yl)(2-
iodophenyl)methanone (1p) 1.12 g, yield: 40%, yellow soild. 1H
NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.9 Hz, 1H), 7.48 – 7.40
(m, 2H), 7.24 – 7.08 (m, 8H), 6.88 (d, J = 8.4 Hz, 1H), 4.00 (s,
2H), 2.32 (s, 3H), 2.22 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.8, 142.4, 139.8, 139.7, 134.3, 133.7, 132.9, 131.7,
130.9, 129.1, 128.5, 128.4, 128.1, 126.0, 125.1, 119.2, 118.5,
114.4, 93.1, 29.7, 21.3, 13.7. HRMS (ESI) m/z: [M+H]+ Calcd
for C24H21INO 466.0662; found 466.0658. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 25:1 (v/v);
N
O
I
(2-iodophenyl)(3-methyl-2-(p-tolyl)-1H-indol-1-yl)methanone
(1t) 1.57 g, yield: 58%, white soild. 1H NMR (400 MHz, CDCl3)
δ 8.13 – 8.06 (m, 1H), 7.57 – 7.53 (m, 2H), 7.38 – 7.32 (m, 2H),
7.09 – 7.02 (m, 4H), 6.96 – 6.91 (m, 2H), 6.86 – 6.79 (m, 1H),
2.23 (s, 3H), 2.15 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
169.3, 141.4, 139.3, 137.2, 136.9, 135.5, 130.9, 130.3, 130.0,
129.2, 128.3, 127.3, 125.1, 123.7, 118.7, 118.3, 115.4, 94.3,
21.1, 9.3. HRMS (ESI) m/z: [M+H]+ Calcd for C23H19INO
452.0506; found 452.0500. Purified by chromatography on
N
I
O
O
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The Journal of Organic Chemistry
silica gel, eluting with petroleum ethyl/acetate ether 100:1
(v/v);
124.3, 122.8, 120.6, 111.3, 96.4, 37.2, 9.5. HRMS (ESI) m/z:
[M+H]+ Calcd for C17H14ClINO2 425.9752; found 425.9748.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 100:1-20:1 (v/v);
1
2
3
4
5
N
I
O
O
N
I
Br
6
7
8
9
O
(3,4-dihydro-1H-carbazol-9(2H)-yl)(2-iodophenyl)methanone
(1u) 0.91 g, yield: 38%, yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.77 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.36 – 7.28
(m, 3H), 7.17 (t, J = 7.4 Hz, 1H), 7.13 – 7.04 (m, 2H), 2.58 (s,
2H), 2.33 (d, J = 20.9 Hz, 2H), 1.77 – 1.61 (m, 4H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.1, 142.2, 139.3, 135.9, 134.7,
131.3, 130.2, 128.4, 128.1, 123.8, 123.3, 119.0, 117.4, 115.1,
92.9, 25.3, 23.3, 21.6, 20.8. HRMS (ESI) m/z: [M+H]+ Calcd
for C19H17INO 402.0349; found 402.0354. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 70:1 (v/v);
N-(5-bromo-2-iodophenyl)-N,3-dimethylbenzofuran-2-
carboxamide (5d) 1.79 g, yield: 38%, white soild. 1H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 1H), 7.57 – 7.49 (m, 2H),
7.30 – 7.23 (m, 1H), 7.23 – 7.11 (m, 2H), 6.98 (d, J = 7.8 Hz,
1H), 3.35 (s, 3H), 2.59 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.8, 153.2, 147.8, 143.3, 140.3, 132.2, 132.2, 128.7,
126.6, 124.3, 122.7, 122.2, 120.6, 111.3, 97.3, 37.2, 9.5. HRMS
(ESI) m/z: [M+H]+ Calcd for C17H14BrINO2 469.9247; found
469.9243. Purified by chromatography on silica gel, eluting
with petroleum ethyl/acetate ether 100:1-20:1 (v/v);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
O
N
I
CF3
O
I
O
N-(2-iodophenyl)-N,3-dimethylbenzofuran-2-carboxamide (5a)
2.82 g, yield: 72%, white soild. 1H NMR (400 MHz, CDCl3) δ
7.82 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.35 – 7.28
(m, 2H), 7.24 – 7.13 (m, 2H), 7.03 – 6.96 (m, 1H), 6.92 (d, J =
8.0 Hz, 1H), 3.37 (s, 3H), 2.58 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 161.2, 153.2, 146.5, 143.7, 139.5, 129.1, 129.0,
128.8, 126.4, 123.5, 122.6, 120.5, 111.2, 98.9, 37.3, 9.5. HRMS
(ESI) m/z: [M+H]+ Calcd for C17H15INO2 392.0142; found
392.0140. Purified by chromatography on silica gel, eluting
with petroleum ethyl/acetate ether 100:1-20:1 (v/v);
N-(2-iodo-5-(trifluoromethyl)phenyl)-N,3-dimethylbenzofuran-
2-carboxamide (5e) 1.88 g, yield: 41%, white soild. H NMR
1
(400 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 1H), 7.67 (s, 1H), 7.53
(d, J = 7.6 Hz, 1H), 7.28 – 7.15 (m, 3H), 6.88 (d, J = 8.1 Hz,
1H), 3.39 (s, 3H), 2.59 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.8, 153.1, 147.3, 143.2, 140.2, 132.3, 131.9, 131.6,
131.3, 128.6, 127.4, 126.7, 126.3, 126.2, 125.5, 125.5, 125.4,
125.4, 124.7, 124.4, 122.8, 122.0, 120.6, 119.3, 111.1, 103.5,
37.1, 9.5. 19F NMR (376 MHz, CDCl3) δ -62.81. HRMS (ESI)
m/z: [M+H]+ Calcd for C18H14F3INO2 460.0016; found
460.0012. Purified by chromatography on silica gel, eluting
with petroleum ethyl/acetate ether 100:1-20:1 (v/v);
O
N
I
F
O
O
O
N
I
N-(5-fluoro-2-iodophenyl)-N,3-dimethylbenzofuran-2-
O
carboxamide (5b) 2.01 g, yield: 49%, white soild. 1H NMR (400
MHz, CDCl3) δ 7.80 – 7.72 (m, 1H), 7.54 (d, J = 7.7 Hz, 1H),
7.29 – 7.17 (m, 2H), 7.11 (dd, J = 8.9, 2.9 Hz, 1H), 6.97 (d, J =
8.1 Hz, 1H), 6.82 (td, J = 8.3, 2.9 Hz, 1H), 3.36 (s, 3H), 2.59 (s,
3H).13C{1H} NMR (101 MHz, CDCl3) δ 164.2, 161.8, 160.9,
153.2, 148.0, 147.9, 143.4, 140.1, 140.1, 128.7, 126.6, 124.2,
122.8, 120.6, 116.8, 116.8, 116.6, 116.5, 111.3, 92.3, 37.2, 9.5.
19F NMR (376 MHz, CDCl3) δ -112.37. HRMS (ESI) m/z:
[M+H]+ Calcd for C17H14FINO2 410.0048; found 410.0045.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 100:1-20:1 (v/v);
O
methyl
3-(N,3-dimethylbenzofuran-2-carboxamido)-4-
iodobenzoate (5f) 2.02 g, yield: 45%, white soild. 1H NMR (400
MHz, CDCl3) δ 8.00 – 7.88 (m, 2H), 7.66 (d, J = 7.7 Hz, 1H),
7.52 (d, J = 7.4 Hz, 1H), 7.25 – 7.13 (m, 2H), 6.89 (d, J = 7.9
Hz, 1H), 3.90 (s, 3H), 3.38 (s, 3H), 2.60 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 165.7, 160.8, 153.1, 147.0, 143.3, 139.7,
131.4, 129.6, 129.6, 128.7, 126.6, 124.3, 122.7, 120.5, 111.2,
105.6, 52.4, 37.2, 9.5. HRMS (ESI) m/z: [M+H]+ Calcd for
C19H17INO4 450.0197; found 450.0190. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 8:1 (v/v);
O
N
I
Cl
O
O
N
O
I
N-(5-chloro-2-iodophenyl)-N,3-dimethylbenzofuran-2-
carboxamide (5c) 2.72 g, yield: 64%, white soild. 1H NMR (400
MHz, CDCl3) δ 7.77 – 7.68 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H),
7.36 (d, J = 2.3 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.23 – 7.17 (m,
1H), 7.03 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 3.36 (s,
3H), 2.60 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.8,
153.2, 147.7, 143.3, 140.1, 134.7, 129.4, 129.3, 128.7, 126.7,
N-(2-iodo-5-methylphenyl)-N,3-dimethylbenzofuran-2-
carboxamide(5g) 2.03 g, yield: 50%, white soild. 1H NMR (400
MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 7.4 Hz,
1H), 7.26 – 7.12 (m, 3H), 6.95 (d, J = 8.1 Hz, 1H), 6.82 (d, J =
8.0 Hz, 1H), 3.36 (s, 3H), 2.58 (s, 3H), 2.28 (s, 3H). 13C{1H}
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NMR (101 MHz, CDCl3) δ 161.1, 153.2, 146.2, 143.8, 139.3,
Page 12 of 24
N
1
2
3
4
5
6
7
8
139.0, 130.0, 129.7, 128.8, 126.3, 123.4, 122.5, 120.4, 111.2,
94.6, 37.3, 20.7, 9.4. HRMS (ESI) m/z: [M+H]+ Calcd for
C18H17INO2 406.0298; found 406.0294. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 100:1-20:1 (v/v);
N
O
10b-methyl-11-methylene-10-(pyrrolidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (3c) 53.3 mg, yield:
84%, white soild, mp 150℃. 1H NMR (400 MHz, CDCl3) δ 7.75
(d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.63 (d, J = 7.9 Hz,
1H), 7.49 – 7.42 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.12 (t, J =
7.6 Hz, 1H), 6.02 (s, 1H), 5.66 (s, 1H), 3.25 – 3.15 (m, 2H),
3.07 – 2.98 (m, 2H), 2.06 – 1.97 (m, 4H), 1.86 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.9, 148.2, 147.7, 147.6, 140.8,
133.9, 133.4, 130.1, 130.0, 129.7, 124.5, 122.3, 121.2, 117.3,
106.1, 106.1, 75.6, 56.1, 30.2, 24.6. HRMS (ESI) m/z: [M+H]+
Calcd for C21H21N2O 317.1648; found 317.1646. IR (cm-1):
2969.37, 2823.15, 1710.26, 1465.73, 1348.47, 1299.67, 900.47,
760.36. Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 15:1 (v/v);
N
I
O
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
37
38
39
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41
42
43
44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2-iodophenyl)(3-methyl-1H-indol-1-yl)methanone (11) 1.19 g,
yield: 55%, white soild. 1H NMR (400 MHz, CDCl3) δ 8.50 (s,
1H), 7.90 (d, J = 7.8 Hz, 1H), 7.54 – 7.41 (m, 2H), 7.41 – 7.27
(m, 3H), 7.22 – 7.14 (m, 1H), 6.68 (s, 1H), 2.20 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 167.5, 141.3, 139.4, 135.6, 132.1,
131.3, 128.1, 125.2, 124.1, 123.3, 119.0, 119.0, 118.9, 116.5,
92.4, 9.6. HRMS (ESI) m/z: [M+H]+ Calcd for C16H13INO
362.0036; found 362.0032. Purified by chromatography on
silica gel, eluting with petroleum ethyl/acetate ether 25:1 (v/v);
N
N
Characterization Data of Product.
O
O
10-(azepan-1-yl)-10b-methyl-11-methylene-10b,11-dihydro-
6H-isoindolo[2,1-a]indol-6-one (3d) 58.0 mg, yield: 84%,
white soild, mp 134℃. 1H NMR (400 MHz, CDCl3) δ 7.74 (d,
J = 7.8 Hz, 1H), 7.67 (dd, J = 7.4, 0.9 Hz, 1H), 7.61 – 7.55 (m,
1H), 7.49 – 7.40 (m, 2H), 7.35 (td, J = 7.8, 1.0 Hz, 1H), 7.12
(td, J = 7.6, 1.0 Hz, 1H), 6.28 (s, 1H), 5.68 (s, 1H), 3.18 – 3.02
(m, 4H), 1.91 – 1.78 (m, 11H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.8, 153.6, 147.7, 145.0, 140.8, 133.9, 133.4, 130.6,
130.1, 129.7, 124.6, 122.2, 121.2, 117.4, 106.6, 75.7, 59.8, 29.9,
28.5, 26.6. HRMS (ESI) m/z: [M+H]+ Calcd for C23H25N2O
345.1961; found 345.1965. IR (cm-1): 2929.21, 2857.88,
1710.52, 1465.54, 1349.19, 1301.70, 1134.84, 899.27, 759.85.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 15:1 (v/v);
N
N
O
10b-methyl-11-methylene-10-morpholino-10b,11-dihydro-6H-
isoindolo[2,1-a]indol-6-one (3a) 56.0 mg, yield: 84%, white
soild, mp 146℃. 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.72 (m,
2H), 7.68 – 7.64 (m, 1H), 7.53 – 7.46 (m, 2H), 7.37 (td, J = 7.7,
1.0 Hz, 1H), 7.14 (td, J = 7.6, 0.8 Hz, 1H), 6.15 (s, 1H), 5.67 (s,
1H), 3.94 (t, J = 4.6 Hz, 4H), 3.16 – 3.07 (m, 2H), 2.99 – 2.89
(m, 2H), 1.88 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.6, 149.4, 147.9, 146.5, 140.8, 134.2, 133.2, 130.2, 129.9,
129.7, 124.7, 123.2, 121.3, 117.5, 106.0, 75.6, 67.1, 54.5, 30.0.
HRMS (ESI) m/z: [M+H]+ Calcd for C21H21N2O2 333.1598;
found 333.1601. IR (cm-1): 2962.66, 2853.84, 1712.00,
1483.97, 1369.28, 1300.26, 1114.70, 761.86, 735.27. Purified
by chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 6:1 (v/v);
N
N
O
S
10b-methyl-11-methylene-10-(piperidin-1-yl)-10b,11-dihydro-
6H-isoindolo[2,1-a]indol-6-one (3e) 57.7 mg, yield: 87%,
yellow soild, mp 130℃. 1H NMR (400 MHz, CDCl3) δ 7.74 (d,
J = 7.9 Hz, 1H), 7.69 (dd, J = 7.3, 0.8 Hz, 1H), 7.62 (dd, J =
7.8, 0.8 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.35 (td, J = 7.8, 1.0 Hz,
1H), 7.12 (td, J = 7.7, 1.0 Hz, 1H), 6.21 (s, 1H), 5.66 (s, 1H),
3.06 – 2.98 (m, 2H), 2.91 – 2.76 (m, 2H), 1.88 (s, 3H), 1.82 –
1.74 (m, 4H), 1.65 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.9, 151.2, 147.8, 146.3, 140.8, 134.0, 133.5, 129.9, 129.8,
129.6, 124.6, 122.6, 121.2, 117.5, 106.3, 75.7, 55.6, 29.6, 26.1,
24.0. HRMS (ESI) m/z: [M+H]+ Calcd for C22H23N2O
331.1805; found 331.1807. IR (cm-1): 2935.97, 2853.94,
1710.68, 1465.87, 1349.94, 1301.96, 898.95, 761.19. Purified
by chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 20:1 (v/v);
N
N
O
10b-methyl-11-methylene-10-thiomorpholino-10b,11-dihydro-
6H-isoindolo[2,1-a]indol-6-one (3b) 51.0 mg, yield: 73%,
white soild, mp 186℃. 1H NMR (400 MHz, CDCl3) δ 7.73 (d,
J = 7.7 Hz, 2H), 7.65 – 7.61 (m, 1H), 7.52 – 7.46 (m, 2H), 7.40
– 7.34 (m, 1H), 7.17 – 7.12 (m, 1H), 6.09 (s, 1H), 5.66 (s, 1H),
3.36 – 3.29 (m, 2H), 3.20 – 3.12 (m, 2H), 2.90 (s, 4H), 1.86 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 150.4, 147.9,
145.8, 140.7, 134.3, 133.2, 130.2, 130.0, 129.8, 124.7, 123.2,
121.3, 117.5, 106.0, 75.6, 56.1, 29.7, 28.0. HRMS (ESI) m/z:
[M+H]+ Calcd for C21H21N2OS 349.1369; found 349.1365. IR
(cm-1): 2923.74, 2828.49, 1708.06, 1481.85, 1352.78, 1301.82,
946.83, 762.13, 734.96. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 10:1 (v/v);
N
N
O
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The Journal of Organic Chemistry
O
10b-methyl-11-methylene-10-(3-methylpiperidin-1-yl)-10b,11-
O
1
2
dihydro-6H-isoindolo[2,1-a]indol-6-one (3f) 49.1 mg, yield:
71%, yellow soild, mp 108℃. H NMR (400 MHz, CDCl3) δ
1
N
N
7.74 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.64 – 7.58
(m, 1H), 7.48 – 7.42 (m, 2H), 7.35 (td, J = 7.7, 1.2 Hz, 1H), 7.12
(td, J = 7.6, 1.1 Hz, 1H), 6.18 (d, J = 5.5 Hz, 1H), 5.65 (d, J =
2.6 Hz, 1H), 3.09 – 2.93 (m, 2H), 2.91 – 2.25 (m, 2H), 1.99 –
1.73 (m, 7H), 1.17 – 1.02 (m, 1H), 0.94 (dd, J = 27.7, 6.4 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 168.9, 151.0,
151.0, 147.9, 147.9, 146.3, 140.9, 140.9, 134.0, 133.4, 129.9,
129.8, 129.6, 129.5, 124.6, 122.6, 121.2, 117.5, 106.2, 75.7,
64.5, 61.5, 56.6, 53.6, 32.8, 32.7, 31.8, 31.2, 29.6, 29.6, 25.9,
25.7, 19.7, 19.6. HRMS (ESI) m/z: [M+H]+ Calcd for
C23H25N2O 345.1961; found 345.1966. IR (cm-1): 2928.17,
2851.58, 1711.67, 1464.79, 1350.40, 1301.72, 1133.32, 760.71,
735.92. Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 25:1 (v/v);
3
4
5
6
7
8
9
O
ethyl 1-(10b-methyl-11-methylene-6-oxo-10b,11-dihydro-6H-
isoindolo[2,1-a]indol-10-yl)piperidine-4-carboxylate (3i) 64.6
mg, yield: 80%, white soild, mp 160℃. H NMR (400 MHz,
1
CDCl3) δ 7.76 – 7.67 (m, 2H), 7.61 (d, J = 7.9 Hz, 1H), 7.49 –
7.43 (m, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H),
6.11 (s, 1H), 5.66 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.20 – 3.12
(m, 1H), 3.12 – 3.05 (m, 1H), 3.00 (td, J = 11.2, 2.9 Hz, 1H),
2.74 (td, J = 11.4, 2.8 Hz, 1H), 2.57 – 2.47 (m, 1H), 2.15 – 1.95
(m, 4H), 1.87 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 174.8, 168.7, 150.3, 147.7, 146.2, 140.7,
134.1, 133.3, 130.0, 129.8, 129.3, 124.6, 122.9, 121.3, 117 .4,
106.2, 75.6, 60.5, 55.3, 52.9, 40.6, 29.5, 28.6, 28.3, 14.2. HRMS
(ESI) m/z: [M+H]+ Calcd for C25H27N2O3 403.2016; found
403.2020. IR (cm-1): 2952.80, 2814.09, 1716.22, 1466.17,
1348.62, 1302.06, 1135.37, 1045.08, 762.21. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 8:1 (v/v);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
O
N
O
methyl
1-(10b-methyl-11-methylene-6-oxo-10b,11-dihydro-
O
N
6H-isoindolo[2,1-a]indol-10-yl)piperidine-3-carboxylate (3g)
1
59.2 mg, yield: 76%, yellow soild, mp 102℃. H NMR (400
MHz, CDCl3) δ 7.76 – 7.70 (m, 2H), 7.63 (d, J = 7.9 Hz, 1H),
7.50 – 7.45 (m, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.6 Hz,
1H), 6.06 (s, 1H), 5.68 – 5.63 (m, 1H), 3.72 – 3.67 (m, 3H), 3.35
– 3.22 (m, 1H), 3.18 – 2.90 (m, 2H), 2.88 – 2.65 (m, 2H), 2.25
– 2.07 (m, 1H), 1.97 – 1.90 (m, 1H), 1.88 – 1.84 (m, 3H), 1.82
– 1.56 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 174.1,
173.9, 168.7, 150.1, 150.1, 147.9, 147.8, 146.1, 146.1, 140.8,
134.2, 133.3, 133.3, 130.1, 130.0, 129.9, 129.9, 129.5, 129.5,
124.7, 123.1, 123.0, 121.3, 117.5, 117.4, 106.0, 106.0, 75.6,
75.6, 57.7, 56.4, 55.3, 53.6, 51.8, 51.7, 42.4, 41.7, 29.7, 29.6,
26.8, 26.5, 24.9. HRMS (ESI) m/z: [M+H]+ Calcd for
C24H25N2O3 389.1860; found 389.1865. IR (cm-1): 2949.83,
2854.11, 1713.27, 1465.14, 1352.06, 1302.82, 761.93. Purified
by chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 8:1 (v/v);
N
N
O
10b-methyl-11-methylene-10-(4-morpholinopiperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (3j) 65.8 mg,
yield: 79%, white soild, mp 218℃. 1H NMR (400 MHz, CDCl3)
δ 7.75 – 7.69 (m, 2H), 7.62 (d, J = 7.9 Hz, 1H), 7.50 – 7.43 (m,
2H), 7.39 – 7.33 (m, 1H), 7.17 – 7.10 (m, 1H), 6.12 (s, 1H), 5.64
(s, 1H), 3.87 – 3.71 (m, 4H), 3.21 – 3.08 (m, 2H), 3.07 – 2.98
(m, 1H), 2.78 – 2.70 (m, 1H), 2.68 – 2.58 (m, 4H), 2.43 – 2.33
(m, 1H), 2.11 – 1.98 (m, 2H), 1.87 (s, 3H), 1.83 – 1.68 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.8, 150.2, 147.7, 146.2,
140.8, 134.1, 133.4, 129.9, 129.8, 129.2, 124.6, 122.9, 121.2,
117.5, 106.2, 75.6, 67.2, 61.7, 55.6, 52.7, 50.1, 29.5, 29.1, 28.7.
HRMS (ESI) m/z: [M+H]+ Calcd for C26H30N3O2 416.2333;
found 416.2333. IR (cm-1): 2952.12, 2853.18, 1710.06,
1465.81, 1348.83, 1301.90, 1119.64, 898.58, 762.10. Purified
by chromatography on silica gel, eluting with
dichloromethane/methanol 25:1 (v/v);
N
N
O
O
O
10b-methyl-11-methylene-10-(4-phenylpiperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (3h) 65.2 mg, yield:
N
N
1
80%, yellow soild, mp 216℃. H NMR (400 MHz, CDCl3) δ
O
7.77 – 7.70 (m, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.50 – 7.45 (m,
2H), 7.38 – 7.30 (m, 5H), 7.27 – 7.21 (m, 1H), 7.16 – 7.10 (m,
1H), 6.24 (s, 1H), 5.69 (s, 1H), 3.27 – 3.18 (m, 1H), 3.18 – 3.10
(m, 2H), 2.92 – 2.81 (m, 1H), 2.81 – 2.69 (m, 1H), 2.09 – 1.96
(m, 4H), 1.91 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
169.0, 150.9, 148.1, 146.5, 146.0, 141.0, 134.3, 133.6, 130.2,
130.0, 129.6, 128.7, 126.9, 126.5, 124.8, 123.0, 121.5, 117.7,
106.4, 75.8, 57.1, 54.1, 42.2, 33.9, 33.7, 29.8. HRMS (ESI) m/z:
[M+H]+ Calcd for C28H27N2O 407.2118; found 407.2122. IR
(cm-1): 2934.53, 2811.47, 1709.52, 1466.00, 1348.95, 1301.09,
759.66, 700.63. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 14:1 (v/v);
10b-methyl-11-methylene-10-(1,4-dioxa-8-
azaspiro[4.5]decan-8-yl)-10b,11-dihydro-6H-isoindolo[2,1-
a]indol-6-one (3k) 62.3 mg, yield: 80%, yellow soild, mp
150℃. 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.66 (m, 3H), 7.49
– 7.42 (m, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H),
6.15 (s, 1H), 5.65 (s, 1H), 4.04 (s, 4H), 3.23 – 3.12 (m, 2H),
3.05 – 2.95 (m, 2H), 2.00 – 1.92 (m, 4H), 1.88 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.7, 150.1, 147.8, 146.1, 140.8,
134.0, 133.3, 130.0, 129.8, 129.5, 124.6, 122.9, 121.3, 117.4,
106.5, 106.0, 75.6, 64.3, 52.6, 35.3, 29.5. HRMS (ESI) m/z:
[M+H]+ Calcd for C24H25N2O3 389.1860; found 389.1864. IR
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The Journal of Organic Chemistry
(cm-1): 2959.45, 2835.30, 1710.22, 1482.87, 1366.15, 1306.27,
1140.81, 1112.64, 1042.59, 762.46, 735.29. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 5:1 (v/v);
Page 14 of 24
(ESI) m/z: [M+H]+ Calcd for C28H26N3O2 436.2020; found
436.2025. IR (cm-1): 3058.18, 2923.08, 2826.84, 1712.41,
1633.50, 1485.57, 1369.77, 1014.79, 762.44, 733.80, 709.23.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 2:1 (v/v);
1
2
3
4
O
O
N
5
6
7
8
O
O
N
N
N
N
O
N
9
O
ethyl 4-(10b-methyl-11-methylene-6-oxo-10b,11-dihydro-6H-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
isoindolo[2,1-a]indol-10-yl)piperazine-1-carboxylate (3l) 64.7
mg, yield: 69%, yellow soild, mp 130℃. H NMR (400 MHz,
benzyl 4-(10b-methyl-11-methylene-6-oxo-10b,11-dihydro-6H-
1
isoindolo[2,1-a]indol-10-yl)piperazine-1-carboxylate
(3o)
CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.48
(t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz,
1H), 6.12 (s, 1H), 5.66 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.73 (s,
4H), 3.14 – 3.03 (m, 2H), 2.97 – 2.86 (m, 2H), 1.88 (s, 3H), 1.31
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.5,
155.5, 149.3, 147.8, 146.1, 140.7, 134.2, 133.1, 130.1, 129.9,
129.3, 124.7, 123.2, 121.3, 117.4, 105.9, 75.5, 61.5, 53.9, 45.7,
43.8, 29.9, 14.6, 8.5. HRMS (ESI) m/z: [M+H]+ Calcd for
C24H26N3O3 404.1969; found 404.1974. IR (cm-1): 2981.38,
2859.74, 1704.42, 1466.21, 1353.31, 1304.12, 1245.73,
1130.82, 989.21, 762.65. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 4:1 (v/v);
1
65.3 mg, yield: 70%, yellow soild, mp 76℃. H NMR (400
MHz, CDCl3) δ 7.77 – 7.68 (m, 2H), 7.59 – 7.54 (m, 1H), 7.49
– 7.44 (m, 2H), 7.40 – 7.32 (m, 6H), 7.12 (t, J = 7.5 Hz, 1H),
6.09 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.74 (s, 4H), 3.06 (s,
2H), 2.91 (s, 2H), 1.86 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.4, 155.2, 149.2, 147.9, 146.1, 140.7, 136.5, 134.2,
133.1, 130.1, 129.9, 129.3, 128.4, 128.0, 127.9, 124.7, 123.3,
121.2, 117.4, 105.8, 75.5, 67.3, 55.6, 53.9, 44.0, 42.1, 29.9.
HRMS (ESI) m/z: [M+H]+ Calcd for C29H28N3O3 466.2125;
found 466.2132. IR (cm-1): 3061.03, 2949.06, 2859.71,
1704.51, 1464.70, 1431.11, 1359.05, 1244.27, 976.08, 761.73,
735.19, 700.58. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 4:1 (v/v);
O
O
N
N
N
N
N
O
O
tert-butyl 4-(10b-methyl-11-methylene-6-oxo-10b,11-dihydro-
10-(dimethylamino)-10b-methyl-11-methylene-10b,11-
6H-isoindolo[2,1-a]indol-10-yl)piperazine-1-carboxylate (3m)
dihydro-6H-isoindolo[2,1-a]indol-6-one (3p) 46.1 mg, yield:
79%, white soild, mp 136℃. 1H NMR (400 MHz, CDCl3) δ 7.75
(d, J = 7.9 Hz, 1H), 7.70 (dd, J = 7.4, 1.1 Hz, 1H), 7.65 (dd, J =
8.0, 1.1 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.35 (td, J = 7.7, 1.2 Hz,
1H), 7.12 (td, J = 7.5, 1.1 Hz, 1H), 6.14 (s, 1H), 5.69 (s, 1H),
2.75 (s, 6H), 1.88 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.8, 151.5, 147.4, 146.4, 140.8, 133.9, 133.3, 130.0, 129.7,
129.1, 124.5, 122.6, 121.2, 117.3, 106.3, 75.5, 47.1, 30.1.
HRMS (ESI) m/z: [M+H]+ Calcd for C19H19N2O 291.1492;
found 291.1495. IR (cm-1): 3051.46, 2975.75, 2938.96,
2861.56, 2827.31, 2786.70, 1711.52, 1465.85, 1350.13,
1300.34, 761.14. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 15:1 (v/v);
1
62.3 mg, yield: 72%, yellow soild, mp 120℃. H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 7.4 Hz, 2H), 7.60 (d, J = 7.8 Hz,
1H), 7.48 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.14 (t, J
= 7.5 Hz, 1H), 6.13 (s, 1H), 5.65 (s, 1H), 3.67 (s, 4H), 3.12 –
3.02 (m, 2H), 2.94 – 2.86 (m, 2H), 1.88 (s, 3H), 1.52 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.5, 154.8, 149.5, 147.9,
146.2, 140.7, 134.2, 133.2, 130.2, 129.9, 129.4, 124.7, 123.3,
121.3, 117.5, 105.9, 80.0, 75.5, 54.1, 29.9, 28.4. HRMS (ESI)
m/z: [M+H]+ Calcd for C26H30N3O3 432.2282; found 432.2285.
IR (cm-1): 2977.73, 2861.06, 1696.21, 1484.78, 1368.24,
1248.15, 1168.54, 762.22, 735.90. Purified by chromatography
on silica gel, eluting with petroleum ethyl/acetate ether 7:1
(v/v);
O
N
N
N
N
O
N
O
10-(benzyl(methyl)amino)-10b-methyl-11-methylene-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (3q) 52.0 mg, yield:
71%, light yellow soild, mp 124℃. 1H NMR (400 MHz, CDCl3)
δ 7.79 – 7.73 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.54 – 7.46 (m,
4H), 7.42 – 7.30 (m, 4H), 7.17 – 7.11 (m, 1H), 6.20 (s, 1H), 5.71
(s, 1H), 4.26 (d, J = 13.5 Hz, 1H), 3.99 (d, J = 13.5 Hz, 1H),
2.63 (s, 3H), 1.94 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
168.6, 151.0, 147.6, 146.0, 140.7, 137.7, 134.4, 133.4, 130.0,
130.0, 129.9, 128.8, 128.6, 127.5, 124.6, 123.0, 121.3, 117.3,
106.7, 75.8, 63.6, 43.6, 29.7. HRMS (ESI) m/z: [M+H]+ Calcd
for C25H23N2O 366.1805; found 366.1810. IR (cm-1): 3030.32,
10-(4-benzoylpiperazin-1-yl)-10b-methyl-11-methylene-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (3n) 52.4 mg,
yield: 60%, yellow soild, mp 90℃. 1H NMR (400 MHz, CDCl3)
δ 7.74 (dd, J = 7.5, 3.1 Hz, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.52
– 7.46 (m, 4H), 7.46 – 7.43 (m, 3H), 7.37 (t, J = 7.6 Hz, 1H),
7.14 (t, J = 7.5 Hz, 1H), 6.10 (s, 1H), 5.66 (s, 1H), 4.25 – 3.51
(m, 4H), 3.25 – 2.79 (m, 4H), 1.88 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 170.8, 168.6, 149.0, 148.1, 146.3, 140.9, 135.6,
134.5, 133.2, 130.4, 130.2, 130.1, 129.5, 128.7, 127.2, 124.9,
123.6, 121.5, 117.6, 105.9, 75.6, 54.5, 48.1, 42.4, 30.1. HRMS
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The Journal of Organic Chemistry
2924.20, 2847.46, 2797.33, 1709.90, 1464.77, 1353.30,
1300.08, 760.28. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 20:1 (v/v);
N
F
1
2
3
N
O
F
4
5
6
7
8
7-fluoro-10b-methyl-11-methylene-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4b) 53.1 mg, yield:
1
N
O
76%, yellow soild, mp 109℃. H NMR (400 MHz, CDCl3) δ
N
O
7.72 (d, J = 7.9 Hz, 1H), 7.62 – 7.53 (m, 1H), 7.47 (d, J = 7.4
Hz, 1H), 7.35 (td, J = 7.8, 1.0 Hz, 1H), 7.13 (td, J = 7.6, 0.8 Hz,
1H), 7.08 (t, J = 8.6 Hz, 1H), 6.19 (s, 1H), 5.67 (s, 1H), 3.00 –
2.92 (m, 2H), 2.80 (s, 2H), 1.86 (s, 3H), 1.80 – 1.73 (m, 4H),
1.64 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.7, 157.2
(d, J = 260.9 Hz), 148.2, 147.5, 147.0 (d, J = 4.2 Hz), 140.7,
133.2, 131.4 (d, J = 7.9 Hz), 129.8, 124.8, 121.2, 120.3 (d, J =
12.9 Hz), 117.6, 117.1 (d, J = 20.2 Hz), 106.5, 75.3, 55.8, 29.5,
26.0, 23.9. 19F NMR (376 MHz, CDCl3) δ -119.41. HRMS
(ESI) m/z: [M+H]+ Calcd for C22H22FN2O 349.1711; found
349.1716. IR (cm-1): 2936.37, 2854.16, 2810.54, 1715.76,
1495.07, 1465.22, 1342.94, 1300.11, 1261.42, 752.76. Purified
by chromatography on silica gel, eluting with
dichloromethane/petroleum ethyl 3:2 (v/v);
O
O
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10-((3S,4R)-3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-
fluorophenyl)piperidin-1-yl)-10b-methyl-11-methylene-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (3r) 86.3 mg,
yield: 75%, yellow soild, mp 94℃. 1H NMR (400 MHz, CDCl3)
δ 7.77 – 7.66 (m, 3H), 7.51 – 7.45 (m, 2H), 7.37 (td, J = 7.7, 1.2
Hz, 1H), 7.28 – 7.23 (m, 2H), 7.17 – 7.11 (m, 1H), 7.03 (t, J =
8.6 Hz, 2H), 6.60 (dd, J = 15.0, 8.5 Hz, 1H), 6.31 (dd, J = 20.5,
2.5 Hz, 1H), 6.22 (d, J = 16.0 Hz, 1H), 6.16 – 6.06 (m, 1H),
5.86 (s, 1H), 5.84 (s, 1H), 5.69 (d, J = 12.3 Hz, 1H), 3.70 – 3.40
(m, 3H), 3.26 – 3.05 (m, 2H), 2.91 – 2.66 (m, 2H), 2.50 – 2.38
(m, 1H), 2.12 – 1.96 (m, 2H), 1.95 – 1.90 (m, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.7 (d, J = 2.4 Hz), 161.6 (d, J =
244.8 Hz), 154.0 (d, J = 4.4 Hz), 150.3 (d, J = 3.4 Hz), 148.1,
148.1 (d, J = 9.1 Hz), 146.1 (d, J = 2.7 Hz), 141.6 (d, J = 2.7
Hz), 140.8, 139.2 (d, J = 3.0 Hz), 134.2 (d, J = 5.5 Hz), 133.4
(d, J = 1.5 Hz), 130.0, 129.9, 129.3 (d, J = 21.1 Hz), 128.8 (d, J
= 7.9 Hz), 124.7 (d, J = 1.6 Hz), 123.0 (d, J = 6.2 Hz), 121.3,
117.5, 115.6, 115.4, 107.8 (d, J = 3.3 Hz), 106.0 (d, J = 11.7
Hz), 105.6 (d, J = 7.5 Hz), 101.0 (d, J = 2.3 Hz), 97.9 (d, J =
10.1 Hz), 75.7 (d, J = 2.3 Hz), 69.2 (d, J = 13.0 Hz), 60.2, 57.0
(d, J = 40.2 Hz), 53.6, 43.8 (d, J = 2.3 Hz), 42.5 (d, J = 38.2
Hz), 34.7 (d, J = 30.0 Hz), 29.6 (d, J = 2.8 Hz). 19F NMR (376
MHz, CDCl3) δ -115.92. HRMS (ESI) m/z: [M+H]+ Calcd for
C36H32FN2O4 575.2341; found 575.2344. IR (cm-1): 2918.58,
1709.99, 1507.17, 1486.09, 1350.49, 1222.63, 1185.99,
1037.08, 761.61. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 7:1 (v/v);
N
N
O
Cl
8-chloro-10b-methyl-11-methylene-10-(piperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (4c) 62.9 mg,
yield: 86%, white soild, mp 129℃. 1H NMR (400 MHz, CDCl3)
δ 7.71 (d, J = 7.9 Hz, 1H), 7.68 – 7.62 (m, 1H), 7.55 (s, 1H),
7.46 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.13 (t, J =
7.5 Hz, 1H), 6.16 (s, 1H), 5.65 (s, 1H), 3.04 – 2.94 (m, 2H),
2.87 – 2.75 (m, 2H), 1.85 (s, 3H), 1.82 – 1.75 (m, 4H), 1.65 (s,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.4, 152.3, 147.5,
144.7, 140.5, 135.6, 135.5, 133.3, 130.0, 129.8, 124.9, 122.7,
121.3, 117.5, 106.4, 75.5, 55.7, 29.5, 26.0, 23.8. HRMS (ESI)
m/z: [M+H]+ Calcd for C22H22ClN2O 365.1415; found
365.1422. IR (cm-1): 3075.04, 2919.16, 2850.56, 1707.99,
1461.05, 1263.16, 740.26. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 50:1 (v/v);
N
N
F
O
8-fluoro-10b-methyl-11-methylene-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4a) 61.5 mg, yield:
88%, white soild, mp 129℃. 1H NMR (400 MHz, CDCl3) δ 7.72
(d, J = 7.8 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.39 – 7.29 (m, 3H),
7.13 (td, J = 7.6, 1.1 Hz, 1H), 6.16 (s, 1H), 5.65 (s, 1H), 3.03 –
2.92 (m, 2H), 2.89 – 2.70 (m, 2H), 1.86 (s, 3H), 1.82 – 1.75 (m,
4H), 1.64 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 167.7 (d,
J = 3.8 Hz), 163.6 (d, J = 251.1 Hz), 152.9 (d, J = 6.7 Hz), 147.6,
142.1 (d, J = 2.8 Hz), 140.5, 135.6 (d, J = 9.2 Hz), 133.4, 129.8,
124.8, 121.3, 117.5, 116.8 (d, J = 21.2 Hz), 109.3 (d, J = 23.6
Hz), 106.3, 75.4, 55.7, 29.5, 26.0, 23.8. 19F NMR (376 MHz,
CDCl3) δ -110.51. HRMS (ESI) m/z: [M+H]+ Calcd for
C22H22FN2O 349.1711; found 349.1715. IR (cm-1): 3052.35,
2937.33, 2855.19, 2810.55, 1714.24, 1606.55, 1472.35,
1345.51, 1307.40, 1119.41, 868.56, 745.28. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 45:1 (v/v);
N
N
O
Br
8-bromo-10b-methyl-11-methylene-10-(piperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (4d) 61.4 mg,
1
yield: 75%, yellow soild, mp 200℃. H NMR (400 MHz,
CDCl3) δ 7.86 – 7.79 (m, 1H), 7.73 – 7.68 (m, 2H), 7.46 (d, J =
7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H),
6.15 (s, 1H), 5.65 (s, 1H), 3.03 – 2.96 (m, 2H), 2.87 – 2.77 (m,
2H), 1.85 (s, 3H), 1.81 – 1.74 (m, 4H), 1.65 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 167.3, 152.4, 147.4, 145.2, 140.5,
135.8, 133.4, 132.9, 129.9, 125.7, 124.9, 123.3, 121.3, 117.5,
106.4, 75.5, 55.7, 29.5, 26.0, 23.8. HRMS (ESI) m/z: [M+H]+
Calcd for C22H22BrN2O 409.0910; found 409.0919. IR (cm-1):
3072.02, 2936.63, 2853.79, 1713.11, 1464.39, 1348.04,
1302.77, 760.25, 737.17. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 50:1 (v/v);
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
832.05, 759.49. Purified by chromatography on silica gel,
eluting with petroleum ethyl/acetate ether 25:1 (v/v);
N
F
1
2
3
N
O
N
4
5
6
7
8
9
2-fluoro-10b-methyl-11-methylene-10-(piperidin-1-yl)-10b,11-
N
O
O
dihydro-6H-isoindolo[2,1-a]indol-6-one (4e) 56.6 mg, yield:
1
81%, yellow soild, mp 128℃. H NMR (400 MHz, CDCl3) δ
7.71 – 7.65 (m, 2H), 7.65 – 7.60 (m, 1H), 7.46 (t, J = 7.7 Hz,
1H), 7.14 (dd, J = 8.3, 2.5 Hz, 1H), 7.04 (td, J = 8.8, 2.6 Hz,
1H), 6.26 (s, 1H), 5.64 (s, 1H), 3.05 – 2.97 (m, 2H), 2.89 – 2.73
(m, 2H), 1.87 (s, 3H), 1.82 – 1.74 (m, 4H), 1.65 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 169.0, 160.4 (d, J = 242.6 Hz),
151.2, 147.4 (d, J = 2.9 Hz), 146.1, 137.0, 135.1 (d, J = 8.6 Hz),
133.7, 130.0, 129.7, 122.6, 118.4 (d, J = 8.6 Hz), 116.4 (d, J =
24.0 Hz), 108.2 (d, J = 24.2 Hz), 107.7, 76.1, 55.6, 29.5, 26.1,
23.9. 19F NMR (376 MHz, CDCl3) δ -118.04. HRMS (ESI) m/z:
[M+H]+ Calcd for C22H22FN2O 349.1711; found 349.1715. IR
(cm-1): 2936.79, 2854.58, 2807.84, 1712.10, 1479.26, 1349.03,
1270.38, 904.50, 817.44, 737.91. Purified by chromatography
on silica gel, eluting with petroleum ethyl/acetate ether 20:1
(v/v);
8-methoxy-10b-methyl-11-methylene-10-(piperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (4h) 60.0 mg,
yield: 83%,, yellow soild, mp 238℃. H NMR (400 MHz,
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3) δ 7.72 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.36
(t, J = 7.5 Hz, 1H), 7.20 – 7.16 (m, 2H), 7.13 (t, J = 7.5 Hz, 1H),
6.16 (s, 1H), 5.63 (s, 1H), 3.85 (s, 3H), 3.05 – 2.94 (m, 2H),
2.88 – 2.74 (m, 2H), 1.85 (s, 3H), 1.82 – 1.73 (m, 4H), 1.64 (s,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.0, 161.2, 152.2,
148.0, 140.8, 139.2, 134.9, 133.6, 129.7, 124.6, 121.3, 117.7,
117.5, 106.0, 105.1, 75.4, 55.8, 29.6, 26.2, 24.0. HRMS (ESI)
m/z: [M+H]+ Calcd for C23H25N2O2 361.1911; found 361.1917.
IR (cm-1): 2935.15, 2852.45, 1710.38, 1611.34, 1464.95,
1347.50, 1131.75, 745.14. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 15:1 (v/v);
N
Cl
N
N
O
N
O
2-chloro-10b-methyl-11-methylene-10-(piperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (4f) 62.8 mg,
yield: 86%, white soild, mp 129℃. 1H NMR (400 MHz, CDCl3)
δ 7.72 – 7.58 (m, 3H), 7.46 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 1.7
Hz, 1H), 7.30 (dd, J = 8.3, 1.8 Hz, 1H), 6.26 (s, 1H), 5.65 (s,
1H), 3.06 – 2.96 (m, 2H), 2.90 – 2.71 (m, 2H), 1.86 (s, 3H), 1.81
– 1.74 (m, 4H), 1.65 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 168.8, 151.2, 146.9, 146.0, 139.4, 135.1, 133.6, 130.1, 130.1,
129.8, 129.6, 122.7, 121.4, 118.4, 107.7, 76.0, 55.6, 29.6, 26.1,
23.9. HRMS (ESI) m/z: [M+H]+ Calcd for C22H22ClN2O
365.1415; found 365.1412. IR (cm-1): 2932.90, 1714.08,
1468.47, 1342.55, 1265.91, 880.28, 817.63, 757.05. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 24:1 (v/v);
2,10b-dimethyl-11-methylene-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4i) 61.5 mg, yield:
89%, yellow soild, mp 122℃. H NMR (400 MHz, CDCl3) δ
1
7.68 (d, J = 7.3 Hz, 1H), 7.64 – 7.58 (m, 2H), 7.44 (t, J = 7.6
Hz, 1H), 7.27 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H),
5.62 (s, 1H), 3.05 – 2.95 (m, 2H), 2.89 – 2.74 (m, 2H), 2.35 (s,
3H), 1.86 (s, 3H), 1.81 – 1.73 (m, 4H), 1.64 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.8, 151.2, 147.9, 146.2, 138.6,
134.2, 134.1, 133.5, 130.5, 129.8, 129.4, 122.5, 121.6, 117.1,
105.9, 75.9, 55.6, 29.5, 26.1, 24.0, 21.2. HRMS (ESI) m/z:
[M+H]+ Calcd for C23H25N2O 345.1961; found 345.1960. IR
(cm-1): 2935.56, 2854.66, 2806.91, 1709.75, 1482.67, 1344.29,
1286.06, 1234.64, 967.12, 899.64, 815.21, 737.02. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 15:1 (v/v);
N
F3C
N
O
N
O
N
O
10b-methyl-11-methylene-10-(piperidin-1-yl)-2-
(trifluoromethyl)-10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-
one (4g) 64.7 mg, yield: 81%, yellow soild, mp 180℃. 1H NMR
(400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 1H), 7.73 – 7.63 (m,
2H), 7.66 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.48 (t,
J = 7.6 Hz, 1H), 6.34 (s, 1H), 5.76 (s, 1H), 3.06 – 2.98 (m, 2H),
2.90 – 2.76 (m, 2H), 1.88 (s, 3H), 1.83 – 1.76 (m, 4H), 1.67 (s,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.8, 151.3, 146.7,
146.2, 143.4, 133.9, 133.4, 130.2, 130.1, 127.0 (q, J = 3.8 Hz),
126.9 (q, J = 32.5 Hz), 125.6, 122.9, 118.4 (q, J = 3.8 Hz),
117.4, 108.3, 76.0, 55.7, 29.7, 26.1, 23.9. 19F NMR (376 MHz,
CDCl3) δ -61.80. HRMS (ESI) m/z: [M+H]+ Calcd for
C23H22F3N2O 399.1679; found 399.1676. IR (cm-1): 2937.60,
1719.37, 1346.40, 1324.95, 1270.91, 1161.99, 1122.18, 888.96,
2-methoxy-10b-methyl-11-methylene-10-(piperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (4j) 60.0 mg,
yield: 83%, yellow oil. H NMR (400 MHz, CDCl3) δ 7.70 –
1
7.59 (m, 3H), 7.45 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H),
6.92 (dd, J = 8.6, 2.5 Hz, 1H), 6.20 (s, 1H), 5.63 (s, 1H), 3.82
(s, 3H), 3.07 – 2.95 (m, 2H), 2.91 – 2.71 (m, 2H), 1.87 (s, 3H),
1.81 – 1.74 (m, 4H), 1.65 (s, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.9, 157.3, 151.1, 148.0, 146.1, 134.7, 134.6, 134.0,
129.9, 129.4, 122.5, 118.1, 115.6, 106.4, 76.1, 55.7, 29.4, 26.1,
24.0. HRMS (ESI) m/z: [M+H]+ Calcd for C23H25N2O2
361.1911; found 361.1907. IR (cm-1): 2935.94, 1707.00,
1592.13, 1483.07, 1351.48, 1279.28, 1230.82, 1067.34,
1032.37, 900.41, 759.66, 659.79. Purified by chromatography
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on silica gel, eluting with petroleum ethyl/acetate ether 14:1
(v/v);
1720.93, 1592.04, 1521.32, 1469.50, 1320.36, 1268.94,
1130.14, 903.97, 740.86. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 20:1 (v/v);
1
2
3
4
N
N
5
N
6
7
8
9
O
N
O
8,10b-dimethyl-11-methylene-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4k) 59.4 mg, yield:
86%, white soild, mp 136℃. 1H NMR (400 MHz, CDCl3) δ 7.72
(d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.41
(s, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.18
(s, 1H), 5.63 (s, 1H), 3.04 – 2.95 (m, 2H), 2.88 – 2.74 (m, 2H),
2.39 (s, 3H), 1.85 (s, 3H), 1.80 – 1.73 (m, 4H), 1.63 (s, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 169.0, 150.9, 148.0, 143.5,
140.9, 140.1, 133.9, 133.4, 130.3, 129.6, 124.5, 122.8, 121.2,
117.4, 106.0, 75.4, 55.6, 29.5, 26.1, 24.0, 21.0. HRMS (ESI)
m/z: [M+H]+ Calcd for C23H25N2O 345.1961; found 345.1965.
IR (cm-1): 3049.64, 2935.26, 2853.91, 2807.87, 1711.01,
1602.61, 1465.16, 1341.33, 1302.79, 896.32, 744.28. Purified
by chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 25:1 (v/v);
11-benzylidene-10b-methyl-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4n) 66.0 mg, yield:
81%, white soild, mp 152℃. 1H NMR (400 MHz, CDCl3) δ 8.05
– 7.94 (m, 1H), 7.78 – 6.50 (m, 12H), 3.61 – 2.33 (m, 4H), 2.04
– 1.90 (m, 3H), 1.80 – 1.33 (m, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.4, 167.9, 153.6, 151.1, 146.4, 142.8, 141.9, 141.5,
140.8, 138.8, 138.6, 137.1, 136.3, 134.3, 132.8, 132.1, 130.3,
129.9, 129.7, 129.5, 129.3, 129.1, 128.9, 128.5, 128.3, 128.1,
127.9, 127.8, 127.2, 126.8, 125.7, 125.0, 124.7, 124.0, 124.0,
122.7, 121.2, 120.6, 118.9, 117.8, 76.6, 75.5, 57.4, 55.6, 29.4,
26.7, 26.2, 26.1, 24.9, 24.2, 23.9, 23.2. HRMS (ESI) m/z:
[M+H]+ Calcd for C28H27N2O 407.2118; found 407.2124. IR
(cm-1): 3054.44, 2935.50, 2854.17, 2805.67, 1709.33, 1599.96,
1464.40, 1333.12, 759.33, 735.57, 702.36. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 15:1 (v/v);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
O
N
12b-methyl-13-methylene-12-(piperidin-1-yl)-12b,13-dihydro-
8H-benzo[e]isoindolo[2,1-a]indol-8-one (4l) 61.0 mg, yield:
80%, yellow soild, mp 198℃. H NMR (400 MHz, CDCl3) δ
N
O
1
8.36 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.87 (d, J =
8.5 Hz, 2H), 7.73 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H),
7.53 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.5
Hz, 1H), 6.46 (s, 1H), 6.09 (s, 1H), 3.07 – 2.99 (m, 2H), 2.84 (s,
2H), 1.96 (s, 3H), 1.83 – 1.76 (m, 4H), 1.65 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.4, 151.2, 149.0, 146.3, 140.3,
134.4, 131.8, 131.1, 130.0, 130.0, 129.7, 129.5, 127.5, 125.4,
124.5, 122.8, 122.7, 117.3, 110.1, 76.8, 55.7, 29.2, 26.1, 24.0.
HRMS (ESI) m/z: [M+H]+ Calcd for C26H25N2O 381.1961;
found 381.1959. IR (cm-1): 3055.01, 2935.56, 2853.57,
2806.94, 1708.84, 1588.22, 1480.07, 1330.61, 819.32, 739.75.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 16:1 (v/v);
11-benzylidene-2,10b-dimethyl-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4o) 59.8 mg, yield:
71%, white soild, mp 160℃. 1H NMR (400 MHz, CDCl3) δ 8.04
– 7.91 (m, 1H), 7.79 – 7.67 (m, 1H), 7.66 – 7.50 (m, 2H), 7.49
– 7.41 (m, 1H), 7.41 – 7.15 (m, 5H), 7.11 – 6.94 (m, 2H), 3.10
– 2.44 (m, 4H), 2.41 – 2.12 (m, 3H), 2.03 – 1.92 (m, 3H), 1.89
– 1.54 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.3,
151.1, 146.4, 140.9, 139.3, 137.2, 134.4, 133.5, 132.2, 130.2,
129.9, 129.5, 128.4, 128.2, 127.2, 125.4, 125.2, 122.6, 117.5,
76.8, 55.7, 29.3, 26.2, 24.0, 21.2. HRMS (ESI) m/z: [M+H]+
Calcd for C29H29N2O 421.2274; found 421.2273. IR (cm-1):
3054.45, 3027.32, 2934.97, 2854.61, 2806.63, 1709.05,
1602.03, 1480.01, 1444.77, 1339.27, 814.71, 737.26, 702.66.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 16:1 (v/v);
N
O2N
N
O
N
O
10b-methyl-11-methylene-2-nitro-10-(piperidin-1-yl)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4m) 59.5 mg, yield:
79%, white soild, mp 192℃. 1H NMR (400 MHz, CDCl3) δ 8.33
(d, J = 2.2 Hz, 1H), 8.26 (dd, J = 8.7, 2.3 Hz, 1H), 7.83 (d, J =
8.7 Hz, 1H), 7.75 – 7.66 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 6.44
(s, 1H), 5.86 (s, 1H), 3.06 – 2.99 (m, 2H), 2.91 – 2.77 (m, 2H),
1.89 (s, 3H), 1.84 – 1.77 (m, 4H), 1.68 (s, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 168.5, 151.3, 146.1, 145.9, 145.7, 144.9,
134.4, 132.9, 130.5, 130.4, 125.8, 123.0, 117.0, 116.9, 109.6,
76.3, 55.7, 30.0, 26.1, 23.9. HRMS (ESI) m/z: [M+H]+ Calcd
for C22H22N3O3 376.1656; found 376.1663. IR (cm-1): 2935.29,
N
O
11-benzylidene-2-methoxy-10b-methyl-10-(piperidin-1-yl)-
10b,11-dihydro-6H-isoindolo[2,1-a]indol-6-one (4p) 68.2 mg,
yield: 78%, white soild, mp 144℃. 1H NMR (400 MHz, CDCl3)
δ 7.97 (s, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H),
7.47 (t, J = 7.6 Hz, 1H), 7.41 – 7.33 (m, 4H), 7.31 – 7.26 (m,
1H), 6.84 (dd, J = 8.7, 2.6 Hz, 1H), 6.80 – 6.69 (m, 1H), 3.53
(s, 3H), 3.12 – 2.98 (m, 2H), 2.84 (s, 2H), 1.96 (s, 3H), 1.86 –
1.73 (m, 4H), 1.65 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
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168.5, 156.3, 151.0, 146.3, 141.0, 137.0, 135.3, 134.4, 133.2, 7.75 (dd, J = 6.1, 2.5 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.50 (d,
1
2
3
4
5
6
7
8
129.9, 129.5, 128.4, 128.3, 127.4, 125.9, 122.6, 118.3, 115.7,
109.8, 55.5, 55.2, 29.3, 26.2, 23.9. HRMS (ESI) m/z: [M+H]+
Calcd for C29H29N2O2 437.2224; found 437.2218. IR (cm-1):
3054.80, 3025.98, 2935.93, 2852.97, 2832.65, 2807.00,
1706.84, 1590.18, 1481.11, 1442.00, 1359.19, 1329.81,
J = 7.6 Hz, 1H), 7.47 – 7.42 (m, 4H), 7.29 – 7.24 (m, 1H), 7.10
– 7.02 (m, 3H), 6.44 (s, 1H), 6.00 (s, 1H), 2.55 – 2.35 (m, 2H),
2.27 – 2.13 (m, 5H), 1.56 – 1.37 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 168.8, 150.6, 146.5, 144.1, 140.3, 137.4, 137.0,
134.8, 134.1, 130.3, 129.8, 129.2, 128.6, 127.1, 124.8, 122.1,
121.1, 117.5, 110.5, 80.3, 54.5, 26.1, 23.9, 20.9. HRMS (ESI)
m/z: [M+H]+ Calcd for C28H27N2O 407.2118; found 407.2116.
IR (cm-1): 2935.40, 2853.57, 2805.70, 1709.31, 1465.63,
1350.18, 1304.49, 758.94. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 20:1 (v/v);
1272.70,
1226.29,
1032.66,
736.94.
Purified
by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 10:1 (v/v);
9
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
N
N
O
10b-methyl-10-(piperidin-1-yl)-11-(propan-2-ylidene)-10b,11-
dihydro-6H-isoindolo[2,1-a]indol-6-one (4q) 38.1 mg, yield:
1
53%, yellow soild, mp 192℃. H NMR (400 MHz, CDCl3) δ
5-(piperidin-1-yl)-3,4-dihydroisoindolo[1,2-k]carbazol-9(2H)-
one (4t) 45.1 mg, yield: 63%, white soild, mp 196℃. 1H NMR
(400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 6.1,
2.4 Hz, 1H), 7.40 – 7.35 (m, 3H), 7.19 (t, J = 7.7 Hz, 1H), 7.00
(t, J = 7.5 Hz, 1H), 6.21 – 6.17 (m, 1H), 3.26 – 2.77 (m, 4H),
2.56 – 2.42 (m, 1H), 2.32 – 2.18 (m, 1H), 2.09 – 1.98 (m, 1H),
1.88 – 1.37 (m, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.6,
151.8, 150.9, 143.6, 136.0, 133.6, 131.1, 129.7, 128.4, 126.0,
123.6, 123.3, 121.7, 119.6, 114.0, 74.1, 40.0, 26.1, 25.7, 23.8,
16.6. HRMS (ESI) m/z: [M+H]+ Calcd for C24H25N2O
357.1961; found 357.1969. IR (cm-1): 2930.18, 2856.74,
2812.14, 1716.86, 1598.70, 1461.34, 1358.50, 1324.75,
7.76 – 7.72 (m, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.60 – 7.56 (m,
1H), 7.53 – 7.45 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.15 (t, J =
7.9 Hz, 1H), 3.11 – 2.99 (m, 2H), 2.79 – 2.61 (m, 2H), 2.19 (s,
3H), 1.99 (s, 3H), 1.89 (s, 3H), 1.81 – 1.66 (m, 6H). 13C{1H}
NMR (101 MHz, CDCl3) δ 168.1, 153.3, 142.4, 139.3, 137.1,
136.3, 135.5, 130.8, 130.3, 128.2, 126.1, 124.4, 121.9,
119.0, 78.2, 26.2, 25.6, 24.1, 23.1, 21.9. HRMS (ESI) m/z:
[M+H]+ Calcd for C24H27N2O 359.2118; found 359.2118. IR
(cm-1): 2934.26, 1707.23, 1476.64, 1361.56, 1321.18, 965.99,
758.00. Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 14:1 (v/v);
1294.50,
1133.29,
1099.34,
765.31.
Purified
by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 50:1 (v/v);
N
O
N
N
O
O
N
O
11-hexylidene-10b-methyl-10-(piperidin-1-yl)-10b,11-dihydro-
6H-isoindolo[2,1-a]indol-6-one (4r) 63.4 mg, yield: 79%,
yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.11 – 7.37 (m, 5H),
7.36 – 7.27 (m, 1H), 7.18 – 7.08 (m, 1H), 6.78 – 5.89 (m, 1H),
4.27 – 2.98 (m, 2H), 2.94 – 2.29 (m, 4H), 1.94 – 1.83 (m, 3H),
1.82 – 1.60 (m, 6H), 1.59 – 1.39 (m, 2H), 1.39 – 1.28 (m, 4H),
0.91 – 0.77 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.0,
168.4, 153.0, 151.1, 146.6, 141.6, 140.9, 140.0, 138.9, 138.7,
137.2, 135.0, 134.3, 133.7, 130.8, 130.3, 129.7, 129.4, 128.7,
128.5, 128.2, 128.0, 128.0, 125.3, 124.9, 124.4, 122.5, 121.9,
120.3, 118.7, 117.7, 76.4, 76.2, 55.6, 31.8, 30.8, 29.4, 29.3,
29.2, 28.6, 26.2, 26.1, 24.0, 24.0, 22.7, 22.5, 14.0, 14.0. HRMS
(ESI) m/z: [M+H]+ Calcd for C27H33N2O 401.2587; found
401.2582. IR (cm-1): 3055.28, 2930.71, 2857.03, 2808.85,
1710.87, 1602.92, 1479.75, 1463.18, 1347.60, 759.93, 736.92.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 20:1 (v/v);
1'-methyl-3-methylene-4'-morpholino-3H-spiro[benzofuran-
2,3'-indolin]-2'-one (6a) 40.6 mg, yield: 58%, white soild, mp
234℃. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 1H),
7.37 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 7.5
Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.67
(d, J = 7.7 Hz, 1H), 5.41 (s, 1H), 4.56 (s, 1H), 3.26 – 3.20 (m,
5H), 3.11 – 3.03 (m, 2H), 3.03 – 2.97 (m, 2H), 2.71 – 2.64 (m,
2H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 161.9, 151.4,
145.6, 131.7, 130.9, 126.4, 122.9, 121.6, 121.0, 116.3, 110.6,
104.6, 101.3, 88.7, 66.8, 52.8, 26.6. HRMS (ESI) m/z: [M+H]+
Calcd for C21H21N2O3 349.1547; found 349.1543. IR (cm-1):
2858.46, 1725.21, 1601.35, 1464.93, 1340.34, 1354.95,
1229.99, 1108.70, 854.33, 739.70. Purified by chromatography
on silica gel, eluting with petroleum ethyl/acetate ether 5:1
(v/v);
O
N
O
N
N
O
N
O
O
ethyl 1-(1'-methyl-3-methylene-2'-oxo-3H-spiro[benzofuran-
2,3'-indolin]-4'-yl)piperidine-4-carboxylate (6b) 47.8 mg,
yield: 57%, yellow soild, mp 118℃. H NMR (400 MHz,
CDCl3) δ 7.47 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.26
11-methylene-10-(piperidin-1-yl)-10b-(p-tolyl)-10b,11-
1
dihydro-6H-isoindolo[2,1-a]indol-6-one (4s) 35.1 mg, yield:
1
43%, yellow soild, mp 170℃. H NMR (400 MHz, CDCl3) δ
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(t, J = 7.6 Hz, 1H), 7.02 – 6.91 (m, 2H), 6.82 (d, J = 8.3 Hz, tert-butyl
4-(1'-methyl-3-methylene-2'-oxo-3H-
1
2
3
4
5
6
7
8
1H), 6.64 (d, J = 7.7 Hz, 1H), 5.40 (s, 1H), 4.55 (s, 1H), 4.05
(q, J = 7.1 Hz, 2H), 3.29 – 3.15 (m, 4H), 2.97 – 2.86 (m, 1H),
2.76 – 2.64 (m, 1H), 2.54 – 2.42 (m, 1H), 2.17 – 2.07 (m, 1H),
1.58 (d, J = 12.4 Hz, 1H), 1.46 (d, J = 12.7 Hz, 1H), 1.30 – 1.18
(m, 4H), 0.89 – 0.77 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3)
δ 174.7, 173.4, 162.1, 152.2, 145.6, 145.5, 131.5, 130.7, 126.3,
122.6, 121.4, 121.0, 116.5, 110.7, 104.2, 101.1, 88.7, 60.0, 53.4,
51.0, 40.5, 28.1, 28.0, 26.6, 14.2. HRMS (ESI) m/z: [M+H]+
Calcd for C25H27N2O4 419.1965; found 419.1963. IR (cm-1):
2950.99, 2806.97, 1732.73, 1603.82, 1463.13, 1340.73,
1303.70, 1253.82, 1169.87, 1046.00, 1013.19, 865.07, 749.08.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 7:1 (v/v);
spiro[benzofuran-2,3'-indolin]-4'-yl)piperazine-1-carboxylate
(6e) 58.3 mg, yield: 65%, light yellow soild, mp 240℃. H
1
NMR (400 MHz, CDCl3) δ 7.48 – 7.44 (m, 1H), 7.36 (t, J = 8.0
Hz, 1H), 7.30 – 7.25 (m, 1H), 7.02 – 6.97 (m, 1H), 6.94 (d, J =
8.1 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H),
5.40 (d, J = 1.2 Hz, 1H), 4.56 (d, J = 1.2 Hz, 1H), 3.22 (s, 3H),
3.00 – 2.88 (m, 4H), 2.88 – 2.74 (m, 2H), 2.65 – 2.57 (m, 2H),
1.41 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 162.0,
154.4, 151.5, 145.7, 145.6, 131.7, 131.0, 126.3, 123.0, 121.6,
120.9, 116.5, 110.6, 104.8, 101.3, 88.7, 79.5, 52.4, 44.0, 43.0,
28.3, 26.6. HRMS (ESI) m/z: [M+H]+ Calcd for C26H30N3O4
448.2231; found 448.2227. IR (cm-1): 2975.79, 2818.02,
1733.77, 1691.66, 1605.01, 1462.59, 1422.60, 1365.35,
1252.62, 1170.48, 1126.78, 1014.36, 738.04. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 5:1 (v/v);
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
O
N
O
O
N
O
O
O
N
N
1'-methyl-3-methylene-4'-(1,4-dioxa-8-azaspiro[4.5]decan-8-
O
yl)-3H-spiro[benzofuran-2,3'-indolin]-2'-one (6c) 44.6 mg,
1
yield: 55%, yellow soild, mp 202℃. H NMR (400 MHz,
benzyl 4-(1'-methyl-3-methylene-2'-oxo-3H-spiro[benzofuran-
CDCl3) δ 7.46 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.27
(t, J = 7.8 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.1 Hz,
1H), 6.87 (d, J = 8.2 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 5.41 (s,
1H), 4.56 (s, 1H), 3.86 – 3.82 (m, 4H), 3.21 (s, 3H), 3.11 – 3.03
(m, 2H), 2.83 – 2.75 (m, 2H), 1.32 – 1.25 (m, 2H), 1.18 – 1.10
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 162.1,
151.9, 145.6, 145.3, 131.5, 130.8, 126.3, 122.2, 121.4, 120.9,
116.6, 110.5, 106.6, 104.2, 101.2, 88.7, 64.0, 50.7, 34.7, 26.6.
HRMS (ESI) m/z: [M+H]+ Calcd for C24H25N2O4 405.1809;
found 405.1806. IR (cm-1): 2957.43, 1731.77, 1604.59,
1462.47, 1340.27, 1254.55, 1110.09, 749.17. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 5:1 (v/v);
2,3'-indolin]-4'-yl)piperazine-1-carboxylate (6f) 55.0 mg,
yield: 57%, yellow soild, mp 196℃. H NMR (400 MHz,
1
CDCl3) δ 7.46 (d, J = 7.6 Hz, 1H), 7.37 – 7.29 (m, 6H), 7.27 –
7.24 (m, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H),
6.80 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 5.40 (s, 1H),
5.11 – 5.02 (m, 2H), 4.56 (s, 1H), 3.22 (s, 3H), 3.10 – 3.00 (m,
2H), 2.98 – 2.83 (m, 4H), 2.64 (s, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 173.2, 161.9, 154.9, 151.3, 145.7, 145.6, 136.6,
131.8, 131.0, 128.4, 127.9, 127.8, 126.3, 123.1, 121.6, 120.9,
116.5, 110.6, 104.9, 101.3, 88.6, 67.0, 52.3, 43.7, 26.6. HRMS
(ESI) m/z: [M+H]+ Calcd for C29H28N3O4 482.2074; found
482.2071. IR (cm-1): 2936.07, 1732.99, 1700.27, 1604.71,
1463.31, 1430.30, 1246.84, 1123.84, 1013.85, 749.95, 699.21.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 4:1 (v/v);
O
O
N
O
N
N
O
N
O
O
N
N
4'-(4-benzoylpiperazin-1-yl)-1'-methyl-3-methylene-3H-
O
F
spiro[benzofuran-2,3'-indolin]-2'-one (6d) 43.5 mg, yield:
1
48%, yellow soild, mp 187℃. H NMR (400 MHz, CDCl3) δ
7.48 (d, J = 7.5 Hz, 1H), 7.46 – 7.33 (m, 5H), 7.31 – 7.28 (m,
2H), 7.03 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.83 (d,
J = 8.2 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 5.42 (s, 1H), 4.58 (s,
1H), 3.29 – 3.22 (m, 4H), 3.10 – 2.88 (m, 3H), 2.82 – 2.57 (m,
3H), 1.74 – 1.57 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
173.3, 170.0, 162.0, 151.0, 145.8, 145.7, 135.7, 131.9, 131.1,
129.6, 128.4, 127.0, 126.4, 123.4, 121.7, 121.0, 116.6, 110.7,
105.2, 101.5, 88.7, 26.8. HRMS (ESI) m/z: [M+H]+ Calcd for
C28H26N3O3 452.1969; found 452.1966. IR (cm-1): 1731.80,
1633.81, 1605.33, 1461.92, 1256.61, 1011.51, 750.08, 710.09.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 2:1 (v/v);
tert-butyl
4-(6'-fluoro-1'-methyl-3-methylene-2'-oxo-3H-
spiro[benzofuran-2,3'-indolin]-4'-yl)piperazine-1-carboxylate
(6g) 59.7 mg, yield: 64%, white soild, mp 80℃. 1H NMR (400
MHz, CDCl3) δ 7.46 (d, J = 7.6 Hz, 1H), 7.32 – 7.25 (m, 1H),
7.00 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.50 – 6.44
(m, 1H), 6.41 (dd, J = 8.1, 2.2 Hz, 1H), 5.41 (s, 1H), 4.56 (s,
1H), 3.20 (s, 3H), 3.02 – 2.90 (m, 4H), 2.88 – 2.79 (m, 2H), 2.68
– 2.59 (m, 2H), 1.41 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3)
δ 173.3, 165.3 (d, J = 249.5 Hz), 161.7, 154.3, 153.0 (d, J = 9.5
Hz), 147.2 (d, J = 13.8 Hz), 145.0, 131.1, 126.1, 121.8, 121.0,
117.1 (d, J = 3.2 Hz), 110.7, 102.6 (d, J = 22.5 Hz), 101.6, 93.3
(d, J = 28.0 Hz), 88.3, 79.6, 55.8, 52.2, 28.3, 26.7. 19F NMR
(376 MHz, CDCl3) δ -106.27. HRMS (ESI) m/z: [M+H]+ Calcd
for C26H29FN3O4 466.2137; found 466.2134. IR (cm-1):
2976.49, 1740.33, 1693.03, 1608.51, 1454.66, 1420.51,
1252.16, 1170.89, 1130.03, 1017.39, 749.89. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 11:2 (v/v);
O
O
O
N
O
N
N
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O
516.2105; found 516.2101. IR (cm-1): 2977.05, 1740.84,
N
1
2
3
1693.46, 1616.90, 1454.73, 1420.71, 1286.83, 1251.74,
1167.82, 1128.31, 1016.96, 860.20, 749.19. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 6:1 (v/v);
O
O
O
N
N
Cl
4
5
6
7
8
O
N
tert-butyl
4-(6'-chloro-1'-methyl-3-methylene-2'-oxo-3H-
spiro[benzofuran-2,3'-indolin]-4'-yl)piperazine-1-carboxylate
(6h) 71.4 mg, yield: 74%, yellow soild, mp 74℃. 1H NMR (400
MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 1H), 7.31 – 7.25 (m, 1H),
7.00 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.76 (d, J =
1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 5.41 (s, 1H), 4.56 (s, 1H),
3.21 (s, 3H), 3.02 – 2.89 (m, 4H), 2.87 – 2.77 (m, 2H), 2.67 –
2.58 (m, 2H), 1.41 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
173.1, 161.7, 154.3, 152.1, 146.7, 145.0, 137.4, 131.2, 126.1,
121.8, 121.0, 120.4, 116.5, 110.7, 105.3, 101.6, 88.2, 79.6, 52.2,
43.1, 28.3, 26.8. HRMS (ESI) m/z: [M+H]+ Calcd for
C26H29ClN3O4 482.1841; found 482.1837. IR (cm-1): 2975.25,
1739.79, 1692.77, 1597.92, 1460.81, 1422.51, 1251.12,
1170.49, 1015.81, 976.03, 748.22. Purified by chromatography
on silica gel, eluting with petroleum ethyl/acetate ether 6:1
(v/v);
O
O
N
N
O
O
9
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methyl 4'-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1'-methyl-3-
methylene-2'-oxo-3H-spiro[benzofuran-2,3'-indoline]-6'-
carboxylate (6k) 58.8 mg, yield: 58%, yellow soild, mp 64℃.
1H NMR (400 MHz, CDCl3) δ 7.55 – 7.52 (m, 1H), 7.47 (d, J =
7.5 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.02 (t, J = 7.5 Hz, 1H), 6.96
(d, J = 8.1 Hz, 1H), 5.41 (s, 1H), 4.54 (s, 1H), 3.95 (s, 3H), 3.28
(s, 3H), 3.02 – 2.92 (m, 4H), 2.88 – 2.79 (m, 2H), 2.69 – 2.60
(m, 2H), 1.41 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
173.0, 166.2, 161.9, 154.3, 151.3, 145.9, 145.2, 133.6, 131.2,
127.5, 126.1, 121.9, 121.1, 118.4, 110.8, 105.4, 101.6, 88.3,
79.6, 52.4, 28.4, 26.9. HRMS (ESI) m/z: [M+H]+ Calcd for
C28H32N3O6 506.2286; found 506.2282. IR (cm-1): 2925.50,
1726.41, 1693.27, 1447.02, 1251.86, 1171.47, 1016.60, 750.59.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 4:1 (v/v);
O
N
O
O
N
N
O
Br
O
N
tert-butyl
4-(6'-bromo-1'-methyl-3-methylene-2'-oxo-3H-
O
spiro[benzofuran-2,3'-indolin]-4'-yl)piperazine-1-carboxylate
(6i) 53.7 mg, yield: 51%, yellow soild, mp 94℃. 1H NMR (400
MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 1H), 7.32 – 7.25 (m, 2H),
7.01 (t, J = 7.5 Hz, 1H), 6.96 – 6.90 (m, 2H), 6.84 – 6.81 (m,
1H), 5.41 (s, 1H), 4.56 (s, 1H), 3.21 (s, 3H), 3.00 – 2.89 (m,
4H), 2.87 – 2.76 (m, 2H), 2.67 – 2.57 (m, 2H), 1.41 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 173.0, 161.7, 154.3, 152.3,
146.8, 145.0, 131.2, 126.1, 125.3, 121.8, 121.1, 119.6, 110.7,
108.2, 101.7, 88.3, 79.7, 52.3, 43.7, 28.4, 26.8. HRMS (ESI)
m/z: [M+H]+ Calcd for C26H29BrN3O4 526.1336; found
526.1335. IR (cm-1): 2975.48, 1739.96, 1692.78, 1592, 28,
1460.68, 1422.78, 1250.94, 1170.387, 1014.91, 973.10, 749.50.
Purified by chromatography on silica gel, eluting with
petroleum ethyl/acetate ether 6:1 (v/v);
O
N
N
O
tert-butyl
4-(1',6'-dimethyl-3-methylene-2'-oxo-3H-
spiro[benzofuran-2,3'-indolin]-4'-yl)piperazine-1-carboxylate
(6l) 59.2 mg, yield: 64%, yellow oil. H NMR (400 MHz,
1
CDCl3) δ 7.45 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 6.98
(t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.60 (s, 1H), 6.50
(s, 1H), 5.39 (s, 1H), 4.56 (s, 1H), 3.20 (s, 3H), 3.00 – 2.88 (m,
4H), 2.87 – 2.76 (m, 2H), 2.65 – 2.56 (m, 2H), 2.37 (s, 3H), 1.41
(s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 173.5, 161.9,
154.3, 151.2, 145.7, 145.6, 142.3, 130.9, 126.3, 121.5, 120.9,
119.7, 116.8, 110.6, 105.6, 101.2, 88.7, 79.4, 52.3, 43.9, 43.1,
28.3, 26.6, 22.1. HRMS (ESI) m/z: [M+H]+ Calcd for
C27H32N3O4 462.2387; found 462.2382. IR (cm-1): 2975.35,
2816.56, 1734.09, 1692.74, 1614.38, 1460.03, 1365.82,
1252.21, 1170.72, 1127.32, 1016.09, 862.53, 749.81. Purified
by chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 5:1 (v/v);
O
N
O
O
N
N
O
CF3
tert-butyl
4-(1'-methyl-3-methylene-2'-oxo-6'-
(trifluoromethyl)-3H-spiro[benzofuran-2,3'-indolin]-4'-
yl)piperazine-1-carboxylate (6j) 48.6 mg, yield: 47%, yellow
oil. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 1H), 7.33
– 7.28 (m, 1H), 7.06 (s, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.96 (d, J
= 8.1 Hz, 1H), 6.88 (s, 1H), 5.44 – 5.42 (m, 1H), 4.58 – 4.55
(m, 1H), 3.26 (s, 3H), 3.03 – 2.93 (m, 4H), 2.88 – 2.79 (m, 2H),
2.70 – 2.63 (m, 2H), 1.41 (s, 9H). 13C{1H} NMR (101 MHz,
CDCl3) δ 172.9, 161.8, 154.2, 151.6, 146.5, 144.9, 134.0 (q, J
= 32.5 Hz), 131.3, 126.0, 123.5 (q, J = 272.8 Hz), 122.0, 121.1,
113.6 (q, J = 3.5 Hz), 110.8, 101.7, 101.3 (q, J = 3.6 Hz), 88.0,
79.7, 52.2, 43.6, 43.0, 28.3, 26.8. 19F NMR (376 MHz, CDCl3)
δ -62.84. HRMS (ESI) m/z: [M+H]+ Calcd for C27H29F3N3O4
N
O
10-butyl-10b-methyl-11-methylene-10b,11-dihydro-6H-
isoindolo[2,1-a]indol-6-one (8) 14.0 mg, yield: 23%, yellow
oil. 1H NMR (400 MHz, CDCl3) δ 7.73 (t, J = 8.0 Hz, 2H), 7.54
– 7.49 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz,
1H), 7.38 (t, J = 7.7 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 5.59 (s,
1H), 5.40 (s, 1H), 3.09 – 2.92 (m, 2H), 1.84 (s, 3H), 1.77 – 1.71
(m, 2H), 1.58 – 1.46 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H). 13C{1H}
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NMR (101 MHz, CDCl3) δ 168.3, 148.4, 146.2, 140.3, 138.2,
2H), 1.03 – 0.84 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
1
2
3
4
5
6
7
8
134.5, 134.0, 133.1, 130.1, 129.0, 124.7, 122.8, 121.4, 117.8,
105.6, 75.8, 34.3, 33.3, 28.6, 23.0, 14.0. HRMS (ESI) m/z:
[M+H]+ Calcd for C21H22NO 304.1692; found 304.1696. IR
(cm-1): 2958.48, 2928.22, 2869.18, 1712.81, 1603.45, 1465.03,
1310.00, 1139.21, 760.03. Purified by chromatography on silica
gel, eluting with petroleum ethyl/acetate ether 25:1 then
petroleum ethyl/dichloromethane 1:1 (v/v);
166.9, 147.3, 146.0, 136.1, 131.9, 129.2, 127.7, 127.3, 125.0,
124.9, 124.4, 123.6, 118.8, 117.7, 116.5, 50.9, 50.6, 36.6, 36.5,
32.1, 27.6, 27.6, 9.6. HRMS (ESI) m/z: [M+H]+ Calcd for
C23H22NO 437.2224; found 437.2218. IR (cm-1): 3053.08,
2955.97, 2870.19, 1682.46, 1605.13, 1451.00, 1349.21,
1263.49, 1188.50, 1065.59, 769.44, 750.33. Purified by
chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 100:1 (v/v);
H
N
9
ASSOCIATED CONTENT
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
SUPPORTING INFORMATION
Crystallographic data for compound 3a (CIF)
Crystallographic data for compound 3b (CIF)
Crystallographic data for compound 3c (CIF)
Crystallographic data for compound 4c (CIF)
Crystallographic data for compound 6a (CIF)
Experimental procedures, compound characterization, and
NMR spectra (PDF)
10b-methyl-11-methylene-10-(piperazin-1-yl)-10b,11-dihydro-
6H-isoindolo[2,1-a]indol-6-one (9) 48.5 mg, yield: 73%, white
soild, mp 232℃. 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.71 (m,
2H), 7.70 – 7.66 (m, 1H), 7.54 – 7.46 (m, 2H), 7.37 (td, J = 7.7,
1.2 Hz, 1H), 7.14 (td, J = 7.6, 1.1 Hz, 1H), 6.09 (s, 1H), 5.66 (s,
1H), 3.30 – 3.13 (m, 6H), 3.07 – 2.99 (m, 2H), 1.87 (s, 3H), 1.29
– 1.22 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.6,
149.4, 147.9, 146.2, 140.7, 134.2, 133.2, 130.2, 130.0, 129.7,
124.7, 123.3, 121.3, 117.5, 105.9, 75.5, 54.0, 45.4, 29.8. HRMS
(ESI) m/z: [M+H]+ Calcd for C21H22N3O 332.1755; found
332.1757. IR (cm-1): 2925.32, 2851.85, 1709.67, 1601.36,
1464.84, 1352.72, 1301.03, 1132.96, 761.83, 734.39. Purified
by chromatography on silica gel, eluting with
dichloromethane/methanol 15:1 (v/v);
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*liangym@lzu.edu.cn
ORCID
Yong-Min Liang: 0000-0001-8280-8211
N
Notes
N
O
The authors declare no competing financial interest.
ACKNOWLEDGMENT
10b,11-dimethyl-10-(piperidin-1-yl)-10b,11-dihydro-6H-
isoindolo[2,1-a]indol-6-one (10) 44.0 mg, yield: 66%, white
soild, mp 208℃. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.3
Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.47
(t, J = 7.6 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.19 – 7.15 (m, 1H),
7.11 (t, J = 7.4 Hz, 1H), 3.36 (q, J = 7.1 Hz, 1H), 2.96 – 2.87
(m, 2H), 2.87 – 2.78 (m, 2H), 1.87 – 1.73 (m, 7H), 1.71 – 1.59
(m, 2H), 1.57 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
167.1, 151.0, 148.0, 141.7, 138.4, 134.6, 129.7, 128.5, 127.7,
124.6, 123.8, 122.3, 116.8, 76.5, 55.6, 43.8, 26.2, 24.0, 20.6,
12.6. HRMS (ESI) m/z: [M+H]+ Calcd for C22H25N2O
333.1959; found 333.1961. IR (cm-1): 2932.66, 2851.99,
2800.38, 1702.99, 1480.00, 1367.12, 1309.73, 762.32. Purified
by chromatography on silica gel, eluting with petroleum
ethyl/acetate ether 14:1 (v/v);
We thank the National Natural Science Foundation of China
(NSF 21532001 and 21772075) for their financial support. We
thank ACS Chem Worx Authoring Services for providing
linguistic assistance during the preparation of this
manuscript.
REFERENCES
(1) (a) Chen, C.-C.; Hsin, W.-C.; Ko, F.-N.; Huang, Y.-L.; Ou, J.-C.;
Teng, C.-M. Antiplatelet Arylnaphthalide Lignans from Justicia
procumbens. J. Nat. Prod. 1996, 59, 1149-1150; (b) Kuehne, M. E.;
Seaton, P. J. Studies in biomimetic alkaloid syntheses. 13. Total
syntheses of racemic aspidofractine, pleiocarpine, pleiocarpinine,
kopsinine, N-methylkopsanone, and kopsanone. J. Org. Chem.
1985, 50, 4790-4796; (c) Magnus, P.; Brown, P. Total synthesis of
(–)-kopsinilam, (–)-kopsinine, and the bis-indole alkaloids (–)-
norpleiomutine and (–)-pleiomutine. J. Chem. Soc., Chem.
Commun. 1985, 184-186; (d) Magnus, P.; Gallagher, T.; Brown, P.;
Huffman, J. C. Synthesis of (.+-.)-10,22-dioxokopsane and (.+-.)-
kopsanone, heptacyclic indole alkaloids. Synthetic and
mechanistic studies. J. Am. Chem. Soc. 1984, 106, 2105-2114; (e)
Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Pérez, C. General
Behavior, Toxicity, and Cytotoxic Activity of Elenoside, a Lignan
from Justicia hyssopifolia. J. Nat. Prod. 2001, 64, 134-135; (f) Ono,
M.; Kung, M.-P.; Hou, C.; Kung, H. F. Benzofuran derivatives as
Aβ-aggregate-specific imaging agents for Alzheimer’s disease.
Nucl. Med. Biol. 2002, 29, 633-642; (g) Ruiz-Sanchis, P.; Savina, S.
N
O
((1R,4S,4aS,8bR)-1,2,3,4,4a,8b-hexahydro-1,4-
methanobiphenylen-5-yl)(3-methyl-1H-indol-1-yl)methanone
(12) 21.9 mg, yield: 25%, white soild, mp 128℃. 1H NMR (400
MHz, CDCl3) δ 8.41 (d, J = 8.2 Hz, 1H), 7.55 – 7.51 (m, 1H),
7.47 (d, J = 7.9 Hz, 1H), 7.41 – 7.30 (m, 3H), 7.19 (d, J = 7.3
Hz, 1H), 7.09 (d, J = 1.4 Hz, 1H), 3.27 (s, 2H), 2.35 – 2.29 (m,
1H), 2.27 – 2.23 (m, 4H), 1.63 – 1.47 (m, 2H), 1.22 – 1.05 (m,
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(25) CCDC 1966190, 1966189, 1966188, 1966191 and 1966187
(3a, 3b, 3c, 4c and 6a) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from the cambridge crystallographic data centre.
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