Palladium-Catalyzed [2 + 2 + 1] Annulation of Alkyne-Tethered Aryl Iodides with Diaziridinone: Synthesis of 3,4-Fused Tricyclic Indoles

Article abstract of DOI:10.1021/acs.joc.0c01365

A novel palladium-catalyzed [2 + 2 + 1] annulation of alkyne-tethered aryl iodides with diaziridinone was developed, leading to the formation of 3,4-fused tricyclic indoles. From a mechanistic standpoint, the formation of fused tricyclic indole scaffolds involved C,C-palladacycles, which were synthesized through the intramolecular reaction of aryl halides and alkynes. The cascade reaction described herein could be carried out with a broad range of substrates and provided various 3,4-fused tricyclic indoles with yields up to 98%.

Full text of DOI:10.1021/acs.joc.0c01365

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Article
Palladium-Catalyzed [2+2+1] Annulation of Alkyne-tethered Aryl
iodides with Diaziridinone: Synthesis of 3,4-Fused Tricyclic Indoles
Lei Zhang, Junyu Chen, Tianshuo Zhong, Xiangyun Zheng, Jian Zhou, Xinpeng Jiang, and Chuanming Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01365 • Publication Date (Web): 30 Jul 2020
Downloaded from pubs.acs.org on July 31, 2020
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Palladium-Catalyzed [2+2+1] Annulation of Alkyne-tethered Aryl iodides with
Diaziridinone：Synthesis of 3,4-Fused Tricyclic Indoles
Lei Zhang , Junyu Chen , Tianshuo Zhong , Xiangyun Zheng , Jian Zhou , Xinpeng Jiang* and
a
a
a
a
a
a
Chuanming Yu*a
a
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR
China
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E-mail: Xjiang@zjut.edu.cn; ycm@zjut.edu.cn
O
Y
Y
N
N
I
+
Pd
R
R
N
solvent (0.1 M)
diaziridinone
up to 98% yield
 diaziridinone as amine source
 3,4-fused tricyclic indoles
C,C-palladacycle
 [2+2+1] annulation
Abstract: A novel palladium-catalyzed [2+2+1] annulation of alkyne-tethered aryl iodides with
diaziridinone was developed, leading to the formation of 3,4-fused tricyclic indoles. From a
mechanistic standpoint, the formation of fused tricyclic indole scaffolds involved
C,C-palladacycles, which were synthesized through intramolecular reaction of aryl halides and
alkynes. The cascade reaction described herein could be carried out with a broad range of
substrate and provided various 3,4-fused tricyclic indoles with yields up to 98%.
Introduction
Indole derivatives represent one of the most widely distributed class of compounds that may be
1
found in various natural products and pharmaceuticals. In particular, 3,4-fused tricyclic indoles
2
have attracted significant interest in the scientific community with wide ranging applications. As
3
shown in Figure 1, lysergic acid, produced in the fungus species Claviceps purpurea, features
4
5
broad biological and pharmacological activities. (-)-Indolactam V and dragmacidin E, isolated
from Streptoverticillium blastmyceticum NA39-17 and Spongosortes, possessing tumor promoting
6
and
serine-threonine protein phosphatase inhibitory activities. Rucaparib, a novel PARP
inhibitor, may be used to treat breast and ovarian cancers. Therefore, the development of both
practical and efficient synthetic methods to produce 3,4-fused tricyclic indoles remains a critical
goal in organic synthetic chemistry.
NH2
Me
H
Me
Me
HN
HO2C
OH
N
H
NH
Me
N
NH
H
N
N
O
N
O
Br
N
O
H
N
H
N
N
H
F
HO
N
H
H
N
H
lysergic acid
indolactam V
dragmacidin E
rucaparib
Figure 1. Selected natural products and drug compounds containing 3,4-fused tricyclic indoles.
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Scheme 1. Application of diaziridinone and synthesis of 3,4-fused indoles.
Previous work
-
Application of diaziridinone
I
t-Bu
N
t-Bu
ref. 12
ref. 13
O
N
ref. 9
N
t-Bu
N
t-Bu
0
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N
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I
I
N
+
O
ref. 11
R1
R2
R1
I
N
N
N
[Pd]
[
Pd]
+
R2
t-Bu
N
O
,
,
ref. 14
Shi s work (a)
Zhang s work (b)
t-Bu
O
I
ref. 11
N
I
N
t-Bu
ref. 15
Ph
t-Bu
I
Bn
N
Bn
O
N
I
ref. 11
O
ref. 16
N
Ph
N
t-Bu
t-Bu
- Synthesis of 3,4-fused indoles
,
Jia s work (2013 and 2014) (c)
Y
Y
Y
[Pd] or [Rh]
I
R2
R2
R2
or
solvent (0.01 M)
N
R1
NHR1
NHR1
ref. 19 and ref. 20
3,4-fused indoles
R1 = H or Ac
,
Luan s work (2020) (d)
O
H
Y
Y
N
Pd(PPh3)2Cl2
+
Ts
O
I
R
R
N
Ts
CO2Me
solvent (0.025 M)
ref. 21
3,4-fused indoles
This work (e)
Y
O
Y
Pd(OAc)2
I
+
N
N
R
R
N
solvent (0.1 M)
diaziridinone
3,4-fused indoles
Over the past few decades, transition-metal-catalyzed C−H bond activation and
functionalization have been utilized for the efficient synthesis of diverse complex compounds
7
through synchronous C−C, C−N, or C−O bond formation. Specifically, C,C-palladacycles, an
2
important class of metallacycles, may be prepared from aryl halides via Pd-enabled C(sp )−H
8
activation exhibiting unique characteristics resulting in the discovery of novel reactions. In 2013,
Shi et al. first reported diaziridinones could be used as a new amine source to react with
9
10
C,C-palladacycles to form indolines via various amination reactions. Moreover, Shi et al.
also demonstrated the preparation of various indoline and indole derivatives by using important
intramolecular design motifs (Scheme 1a).11 Subsequently, the synthetic use of diaziridinone was
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further expanded by Zhang and co-workers using C−H amination reactions to synthesize
1
2
13
heterocycles, such as carbazoles, benzimidazoles, and indole derivatives, including substituted
1
4
15
16
indoles, indolines, and 3,4-fused tricyclic indoles (Scheme 1b).
Various synthetic methods have been developed thereafter for the construction of indoles
through transition-metal-catalysis.17 However, efficient synthetic methods for the production of
the 3,4-fused indole scaffold are still limited.18 In 2013, Jia and co-workers reported a
palladium-catalyzed protocol for the construction of 3,4-fused tricyclic indoles via intramolecular
Larock indolization.19 Subsequently, in 2014 Jia et al. reported the rhodium-catalyzed
intramolecular annulation of alkyne-tethered acetanilides for the construction of such scaffolds
(Scheme 1c).20 In 2020, Luan et al. developed a palladium-catalyzed synthesis of 3,4-fused
tricyclic indoles with alkyne-tethered aryl iodides and a secondary hydroxylamine (Scheme 1d).21
Based on Luan’s work22 and our preliminary research on metal catalyzed functionalization23 and
1
1
1
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0
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0
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indole chemistry, in this paper we report a highly efficient palladium-catalyzed one-pot [2+2+1]
annulation reaction of alkyne-tethered aryl iodides with diaziridinone to generate 3,4-fused
tricyclic indoles (Scheme 1e).
Results and Discussion
Initially, we commenced our study with 1-iodo-2-(5-phenylpent-4-yn-1-yl)benzene 1a and
1,2-di-tert-butyldiaziridin-3-one 2a in an effort to achieve optimized reaction conditions (Table 1).
The substrates were treated with Pd(OAc) (10 mol %), Cs CO (1 equiv.), and KOAc (1 equiv.)
2
2
3
o
in DMF (2 mL) at 130 C under Ar for 4 h. The desired product 3a was obtained in 61% yield
(entry 1). Among the various screened catalysts (entries 1-3), Pd(OAc) proved to be the most
2
suitable. Different bases such as CsOAc and KOPiv were then investigated, however, no outcome
benefits could be observed (entries 4-5). The reaction proceeded with reasonable efficiency when
Cs CO was used as a base (entry 6). The total yield of 3a could be improved to 83% when a
2
3
series of phosphine ligands were added, with PPh demonstrating to be the most effective ligand
3
(entries 7-13). After screening the different solvents such as toluene, N,N-dimethylacetamide
(DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and MeCN, DMF was found to be
still the most efficient solvent, providing compound 3a in 83% yield (entries 14−18). When the
amount of Cs CO was increased to 2 equiv., the yield of 3a did not change (entry 19). Control
2
3
experiments confirmed that the yield of 3a could be decreased upon lowering the reaction
temperature (entry 20) and reducing amount of PPh (entries 21 and 22). Finally, the optimized
3
reaction conditions were determined as follows: 1a (0.2 mmol), 2a (2 equiv.), Pd(OAc) (10
2
mol %), Cs CO (1 equiv.), and PPh (1 equiv.) in DMF (2.0 mL) at 130 °C for 4 h under Ar
2
3
3
atmosphere.
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Table 1. Optimization of reaction conditionsa.
O
[Pd] (10 mol %)
base, ligand
I
N
N
+
N
solvent (2 mL), 130 oC, 4 h, Ar
1a
2a
3
a
b
0
1
2
3
4
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0
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1
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0
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0
Entry
Catalyst
Base (equiv.)
Ligand
Solvent
Yield (%)
1
2
Pd(OAc)2
Pd(PPh3)4
Pd(dba)3
KOAc (1)/Cs CO (1)
-
-
-
-
-
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMA
DMSO
THF
61
53
2
3
KOAc (1)/Cs CO (1)
2
3
3
KOAc (1)/Cs CO (1)
46
2
3
4
5
6
7
8
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
CsOAc (1)/Cs
KOPiv (1)/Cs
2
CO
3
(1)
(1)
55
60
63
69
83
0
20
15
0
0
trace
43
45
trace
trace
83%
80%
53%
70%
CO
2
3
Cs
Cs
CO
CO
(1)
(1)
2
2
3
PCy
PPh3
DPPBz
BINAP
DPPF
DPPP
DPPE
PPh3
3
3
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
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cs CO (1)
2
3
9
Cs CO (1)
2
3
10
Cs CO (1)
2
3
1
1
2
Cs CO (1)
2
3
1
Cs CO (1)
2
3
13
Cs CO (1)
2
3
1
1
1
4
5
6
Cs CO (1)
2
3
Cs CO (1)
PPh3
2
3
Cs CO (1)
PPh3
2
3
17
Cs CO (1)
PPh3
2
3
1
8
Cs CO (1)
PPh3
MeCN
DMF
DMF
DMF
DMF
2
3
1
9c
20d
1e
2f
Cs CO (2)
PPh3
2
3
Cs CO (1)
PPh3
2
3
2
Cs CO (1)
PPh3
2
3
2
Cs CO (1)
PPh3
2
3
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10 mol %), base, ligand (1 equiv.),
o
b
c
d
DMF (2 mL), 130 C, for 4 h, under Ar. Isolated yield. Cs CO (2 equiv.). The reaction
2
3
e
f
temperature was 100 °C. PPh (20 mol % ). PPh (50 mol % ). DMF = N,N-dimethylformamide,
3
3
DMA = N,N-dimethylacetamide, DMSO = dimethyl sulfoxide, THF = tetrahydrofuran.
P
PPh2
PPh2
P
Ph2P
PPh2
PPh2
PPh2
PPh2
PPh2
DPPP
Fe
PPh2
Ph2P
DPPE
PCy3
PPh3
DPPBz
DPPF
BINAP
With these optimized reaction conditions in hand, the scope and limitations of
alkyne-tethered aryl iodides 1 were examined as shown in Scheme 2. First, the electronic
effects of phenyl substituents on the alkynes were examined, including Me-, Cl-, and CF3-
functional groups (3a–3g). Substrates containing both electron-donating and
electron-withdrawing groups in para (3b−3d), meta (3e−3f) and ortho (3g) positions of the
aryl groups on the internal alkyne all displayed high reactivity, providing the desired products in
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1-96% yields. Moreover, disubstituted alkynes were found to be well tolerated in this
transformation, providing the corresponding products 3h and 3i in 93% and 70% yields,
respectively. Furthermore, this reaction was not limited to phenyl substrates, giving athiophene
ring containing product 3j in 53% yield. Alkenyl substituents, however, did not provide the
desired product 3k under optimized conditions.
O
Pd(OAc)2 (10 mol %)
Cs2CO3 (1 equiv.)
PPh3 (1 equiv.)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Y
Y
+
N
N
I
R1
R1
DMF, 130 oC, Ar, 4 h
N
1
2a
3
Cl
N
N
N
3a, 83%
3b, 84%
3c, 77%
CF3
N
N
N
Cl
3d, 71%
3e, 86%
3f, 93%
Cl
O
O
F
N
N
N
F
3g, 96%
3h, 93%
3i, 70%
S
N
N
3j, 53%
3k, N.R
Scheme 2. Substrate scope of phenyl substituents on the alkyne species a,b. a Reaction conditions: 1 (0.2
mmol), 2a (0.4 mmol), Pd(OAc)
2
2 3 3
(10 mol %), Cs CO (1 equiv.) and PPh (1 equiv.) in DMF (2.0 mL)
o
b
at 130 C for 4 h under Ar atmosphere. Isolated yield.
Next, the electronic effects of the aryl iodide moiety were examined (Scheme 3, 3l–3o).
Surprisingly, substrates bearing electron-rich (Me and OMe) and electron-deficient (F and Cl)
functional groups provided the desired products in good to excellent yields (78-98%).
Subsequently, substrates containing a carbon- and oxygen-tether were studied, and the desired
3,4-fused indoles 3p-3u could be obtained in 69-96% yields. However, alkyl-substituted and
unsubstituted alkyne 1v-1z failed to form the desired product. To demonstrate the synthetic utility
of this protocol, a scaled-up reaction of 1-iodo-2-(5-phenylpent-4-yn-1-yl)benzene 1a and
diaziridinone ylide 2a was carried out under optimized reaction conditions, providing the
corresponding product 3a in 85% yield (Scheme 4).
Furthermore, the tert-butyl group could be easily removed to form the unprotected 3,4- fused
,
25
tricyclic indole product 3a in 75% yield under acidic conditions (Scheme 5). Various indole
derivatives could then be formed thereafter. Moreover, a competitive experiment was carried out
between two alkyne-tethered aryl iodides with differing electronic effects. The ratio of two
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
corresponding products (3c/3b = 1.3 and 3o/3l = 1.3) suggested that the
electron-withdrawing alkyne-tethered aryl iodides exhibited a slightly higher reactivity
(Scheme 6).
O
Pd(OAc)2 (10 mol %)
Cs2CO3 (1 equiv.)
PPh3 (1 equiv.)
Y
Y
+
N
N
I
R2
Ph
Ph
R2
DMF, 130 oC, Ar, 4 h
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2a
3
N
N
N
O
F
3l, 87%
3m, 78%
3n, 96%
CO2Et
O
EtO2C
N
N
Cl
N
3o, 98%
3p, 75%
3q, 91%
EtO2C CO2Et
EtO2C CO2Et
EtO2C CO2Et
N
N
N
Cl
O
3r, 95%
3s, 96%
3t, 75%
EtO2C CO2Et
I
I
1w
1v
N
O
O
Cl
I
I
I
3u, 69%
Cl
1x
1y
1z
Unsuccessful substrates
Scheme 3. Substrate scope of alkyne-tethered aryl iodidesa,b. a Reaction conditions: 1 (0.2 mmol), 2a
o
(
0.4 mmol), Pd(OAc)
2
(10 mol %), Cs
2
CO
3
(1 equiv.) and PPh
3
(1 equiv.) in DMF (2.0 mL) at 130 C
b
for 4 h under Ar atmosphere. Isolated yield.
O
Pd(OAc)2 (10 mol %)
Cs2CO3 (1 equiv.)
PPh3 (1 equiv.)
Ph
+
I
N N
DMF, 130 oC, Ar, 4 h
N
1
a
2a
2 eq
3
a
1
.500 g
1
.067 g, 85%
Scheme 4. Gram-scale reaction.
1
M HCl
N
MeCN
rt, 12 h
N
H
,
3a, 0.2 mmol
3a , 75% yield
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Scheme 5. Removal of the tert-butyl group from compound 3a.
Cl
2a
Cl
I
I
+
(
a)
+
standard conditions
N
N
1b (0.2 mmol)
1c (0.2 mmol)
3b
c/3b = 1.3:1 determined by 1H NMR analysis
3c
3
1
1
1
1
1
1
1
1
1
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2
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5
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5
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0
1
2
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4
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7
8
9
0
1
2
3
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8
9
0
1
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8
9
0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
a
+
(b)
I
I
N
N
+
Cl
standard conditions
Cl
3o
o/3l = 1.3:1
3l
determined by 1H NMR analysis
1l (0.2 mmol)
1o (0.2 mmol)
3
Scheme 6. Competition experiments.
On the basis of various reports found in the literature,11, 21-22, 26 a plausible reaction mechanism
could be proposed (Scheme 7). Initially, via oxidative addition of the carbon-halogen bond in
1
-iodo-2-(5-phenylpent-4-yn-1-yl)benzene 1a to Pd(0) forms intermediate A, which undergoes an
intramolecular migratoy insertion, generating a primary vinylpalladium complex species B. Then,
intermediate B undergoes intramolecular C−H activation to generate C,C-pallada-cycle C. Next,
the pallada(IV)cycle D is obtained due to B insertion into the N-N bond of diaziridinone 2a via
oxidative addition. Subsequently, intermediate D to G may undergo two possible pathways, one is
the reductive elimination of D to afford intermediate E. Species G may be formed by β-N
elimination (pathway a) or via a Pd(IV)-nitrene pathway (pathway b). The final product 3a is
formed by reductive elimination and regeneration of the Pd(0)-catalytic species, completing this
catalytic cycle.
Conclusions
In conclusion, we have developed a cascade reaction to generate various functionalized
3,4-fused tricyclic indoles via palladium-catalyzed [2+2+1] annulation between alkyne-tethered
aryl iodides and diaziridinone, in which C,C-palladacycles may act as key intermediates. The
protocol proved to be useful for the preparation of diverse 3,4-fused tricyclic indole species due to
high atom economy, good to excellent yields, and suitable functional group tolerance. Moreover,
further chemical transformations of the desired products enhance the overall synthetic value.
Further studies on the applicability of 3,4-fused tricyclic indoles for the synthesis of natural
products are currently ongoing in our laboratory.
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I
Pd(OAc)2
N
1
a
3
a
n L
oxidative
addition
Pd(0)Ln
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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0
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8
9
0
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2
3
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5
6
7
8
9
0
reductive
elimination
PdII
PdIL2
N
G
t-Bu
t-BuNCO
reductive
elimination
A

-N
elimination
intramolecular
migratory insertion
N
PdII
PdIV
t-Bu
N
O
E
N
t-Bu
t-Bu
F
reductive
elimination
t-BuNCO
pathway a
L
Pd
pathway b
L
I
B
C-H
activation
PdIV
N
t-Bu
N
t-Bu
PdII
O
D
Cl
L
oxidative
addition
C
O
N
N
2a
Scheme 7. Plausible reaction mechanism.
Experimental Section
General methods. All commercials obtained from commercial sources were used as received unless
otherwise noted. The progress of the reactions was monitored by TLC with silica gel plates, and the
visualization was carried out under UV light (254 nm). Melting points were determined using a Büchi
B-540 capillary melting point apparatus. NMR spectra were recorded on 400 MHz and 600 MHz
1
spectrometers in the solvent indicated. Chemical shifts are reported downfield from TMS (= 0) for H
NMR. For 13C NMR, chemical shifts are reported in the scale relative to CDCl
3
6
(= 77.0), DMSO-d (=
4
0.0) and Benzene-d (= 128.0). Mass spectra were measured with a low-resolution MS instrument
6
using ESI ionization. HRMS spectra were recorded on an electrospray ionization quadrupole
time-of-flight (ESI-Q-TOF) mass spectrometer.
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Preparation of Substrates.The substrates (1a−1o, 1v-1w),26d, 27 1p,26d, 28 (1q-1u),26d, 29 1x,27a
y-1z,30 2a31 were prepared using the literature procedures, and the NMR data of all these compounds
1
were compared with the corresponding reported data.
1
-iodo-2-(5-phenylpent-4-yn-1-yl)benzene (1a). Eluent in chromatography: petroleum ether, 1a was
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
isolated as a colorless oil (1.30 g, 75%); H NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 7.6 Hz, 1H), 7.44 –
7
1
1
.39 (m, 2H), 7.33 – 7.22 (m, 5H), 6.94 – 6.84 (m, 1H), 2.98 – 2.83 (m, 2H), 2.48 (t, J = 6.8 Hz, 2H),
.95 – 1.86 (m, 2H). 13C{ H} NMR (100 MHz, CDCl
1
) δ 144.2, 139.5, 131.6, 129.6, 128.3, 128.2,
3
27.8, 127.6, 123.9, 100.5, 89.6, 81.3, 39.8, 29.0, 19.0. HRMS (EI) m/z calcd for C17
H
15I [M]+
346.0218, found 346.0197.
1
-iodo-2-(5-(p-tolyl)pent-4-yn-1-yl)benzene (1b). Eluent in chromatography: petroleum ether, 1b
1
was isolated as a light yellow liquid (1.40 g, 78%); H NMR (400 MHz, CDCl
3
) δ 7.81 (d, J = 8.0 Hz,
1
2
H), 7.31 (d, J = 8.2 Hz, 2H), 7.29 – 7.19 (m, 2H), 7.09 (d, J = 7.8 Hz, 2H), 6.90 – 6.84 (m, 1H), 2.93 –
.83 (m, 2H), 2.46 (t, J = 6.8 Hz, 2H), 2.33 (s, 3H), 1.94 – 1.85 (m, 2H). 13C{ H} NMR (100 MHz,
1
CDCl
3
) δ 144.2, 139.5, 137.5, 131.4, 129.6, 128.9, 128.3, 127.8, 120.8, 100.5, 88.8, 81.3, 39.8, 29.1,
+
2
1.4, 19.0. HRMS (EI) m/z calcd for C18H17I [M] 360.0375, found 360.0388.
1
-(5-(4-chlorophenyl)pent-4-yn-1-yl)-2-iodobenzene (1c). Eluent in chromatography: petroleum
1
ether, 1c was isolated as a yellow liquid (1.52 g, 80%); H NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 7.8
Hz, 1H), 7.38 – 7.32 (m, 2H), 7.30 – 7.20 (m, 4H), 6.92 – 6.85 (m, 1H), 2.94 – 2.82 (m, 2H), 2.46 (t, J
1
=
7.0 Hz, 2H), 1.94 – 1.85 (m, 2H). 13C{ H} NMR (100 MHz, CDCl
3
) δ 144.1, 139.6, 133.5, 132.8,
129.5, 128.5, 128.3, 127.9, 122.4, 100.5, 90.7, 80.3, 39.8, 28.9, 19.0. HRMS (EI) m/z calcd for
+
C
17
H
14ClI [M] 379.9829, found 379.9820.
1-iodo-2-(5-(4-(trifluoromethyl)phenyl)pent-4-yn-1-yl)benzene (1d). Eluent in chromatography:
1
petroleum ether, 1d was isolated as a yellow liquid (1.45 g, 70%); H NMR (400 MHz, DMSO-d
6
) δ
7
2
.85 (d, J = 7.6 Hz, 1H), 7.75 – 7.60 (m, 4H), 7.39 – 7.33 (m, 2H), 7.01 – 6.95 (m, 1H), 2.86 – 2.82 (m,
H), 2.57 – 2.50 (m, , 2H), 1.90 – 1.77 (m, 2H). 13C{ H} NMR (100 MHz, CDCl
1
) δ 144.0, 139.6,
3
131.8, 129.5, 129.2, 128.3, 127.9, 127.8, 125.1 (q, JC-F = 3.8 Hz), 122.6, 100.5, 92.5, 80.2, 39.8, 28.9,
1
9
+
1
9.0. F NMR (376 MHz, CDCl
14.0088.
3 14 3
) δ -62.72. HRMS (EI) m/z calcd for C18H F I [M] 414.0092, found
4
1
-iodo-2-(5-(m-tolyl)pent-4-yn-1-yl)benzene (1e). Eluent in chromatography: petroleum ether, 1e
1
was isolated as a yellow liquid (1.48 g, 82%); H NMR (400 MHz, CDCl
3
) δ 7.81 (d, J = 7.6 Hz, 1H),
7.31 – 7.21 (m, 4H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.92 – 6.82 (m, 1H), 2.94 – 2.83
13
1
(
m, 2H), 2.47 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H), 1.95 –1.85 (m, 2H). C{ H} NMR (100 MHz, CDCl
3
) δ
1
2
44.2, 139.5, 137.8, 132.2, 129.6, 128.6, 128.5, 128.3, 128.1, 127.8, 123.7, 100.5, 89.2, 81.4, 39.8, 29.0,
+
1.2, 18.9. HRMS (EI) m/z calcd for C18H17I [M] 360.0375, found 360.0364.
1
-(5-(3-chlorophenyl)pent-4-yn-1-yl)-2-iodobenzene (1f). Eluent in chromatography: petroleum ether,
1
1
f was isolated as a colorless oil (1.44 g, 76%); H NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 8.8 Hz, 1H),
7.41 – 7.38 (m, 1H), 7.32 – 7.23 (m, 4H), 7.23 – 7.17 (m, 1H), 6.97 – 6.79 (m, 1H), 2.98 – 2.82 (m,
13
1
2
3
H), 2.47 (t, J = 8.0 Hz, 2H), 1.96 – 1.82 (m, 2H). C{ H} NMR (100 MHz, CDCl ) δ 144.0, 139.6,
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34.0, 131.5, 129.7, 129.6, 129.4, 128.3, 127.9, 127.9, 125.6, 100.5, 91.1, 80.1, 39.8, 28.9, 18.9.
+
HRMS (EI) m/z calcd for C17
H
14ClI [M] 379.9829, found 379.9809.
1
-chloro-2-(5-(2-iodophenyl)pent-1-yn-1-yl)benzene (1g). Eluent in chromatography: petroleum
1
ether, 1g was isolated as a light yellow liquid (1.37 g, 72%); H NMR (400 MHz, CDCl
3
) δ 7.8 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8.6 Hz, 1H), 7.5 – 7.4 (m, 1H), 7.4 – 7.3 (m, 1H), 7.31 – 7.25 (m, 2H), 7.2 – 7.1 (m, 2H), 6.91 – 6.85
13
1
(m, 1H), 3.0 – 2.9 (m, 2H), 2.5 (t, J = 6.8 Hz, 2H), 1.98 – 1.88 (m, 2H). C{ H} NMR (100 MHz,
CDCl
3
) δ 144.1, 139.5, 135.8, 133.3, 129.7, 129.1, 128.6, 128.3, 127.8, 126.3, 123.7, 100.5, 95.3, 78.3,
+
3
9.6, 28.8, 19.1. HRMS (EI) m/z calcd for C17
H
14ClI [M] 379.9829, found 379.9849.
1
-(5-(2-iodophenyl)pent-1-yn-1-yl)-3,5-dimethoxybenzene (1h). Eluent in chromatography:
1
petroleum ether, 1h was isolated as a light yellow liquid (1.14 g, 56%); H NMR (400 MHz, CDCl
3
) δ
7.82 (d, J = 8.2 Hz, 1H), 7.32 – 7.18 (m, 2H), 6.94 – 6.82 (m, 1H), 6.60 – 6.53 (d, J = 2.2 Hz, 2H), 6.41
(t, J = 2.4 Hz, 1H), 3.77 (s, 6H), 2.96 – 2.82 (m, 2H), 2.47 (t, J = 6.8 Hz, 2H), 1.92 – 1.86 (m, 2H).
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 160.5, 144.2, 139.5, 129.6, 128.3, 127.8, 125.2, 109.4, 101.1,
+
100.5, 89.3, 81.3, 55.4, 39.8, 29.0, 18.9. HRMS (EI) m/z calcd for C19
06.0412.
H
19IO
2
[M] 406.0430, found
4
1
,3-difluoro-5-(5-(2-iodophenyl)pent-1-yn-1-yl)benzene (1i). Eluent in chromatography: petroleum
1
ether, 1i was isolated as a colorless oil (0.96 g, 50%); H NMR (400 MHz, CDCl
3
) δ 7.82 (d, J = 7.6
Hz, 1H), 7.32 – 7.25 (m, 1H), 7.24 – 7.17 (m, 1H), 6.95 – 6.83 (m, 3H), 6.79 – 6.67 (m, 1H), 2.91 –
1
3
1
2
3
.83 (m, 2H), 2.46 (t, J = 6.8 Hz, 2H), 1.96 – 1.85 (m, 2H). C{ H} NMR (100 MHz, CDCl ) δ 162.6
(dd, J = 248.2, 13.6 Hz), 143.9, 139.6, 129.5, 128.3, 127.9, 114.6 (d, JC-F = 7.4 Hz), 114.4 (d, JC-F = 7.4
19
Hz), 103.8 (t, JC-F = 25.4 Hz), 100.5, 92.1, 79.4, 39.8, 28.7, 18.9. F NMR (376 MHz, CDCl
3
) δ -105.5
+
–
-113.3 (m). HRMS (EI) m/z calcd for C17
H
13
F
2
I [M] 382.0030, found 382.0048.
2
-(5-(2-iodophenyl)pent-1-yn-1-yl)thiophene (1j). Eluent in chromatography: petroleum ether, 1j
1
was isolated as a light yellow liquid (1.14 g, 65%); H NMR (400 MHz, CDCl
3
) δ 7.81 (d, J = 8.2 Hz,
1
H), 7.30 – 7.21 (m, 2H), 7.19 – 7.11 (m, 2H), 6.96 – 6.92 (m, 1H), 6.91 – 6.85 (m, 1H), 2.94 – 2.81
(m, 2H), 2.49 (t, J = 7.0 Hz, 2H), 1.94 – 1.85 (m, 2H). 13C{ H} NMR (100 MHz, CDCl
1
) δ 144.1,
3
1
39.5, 131.0, 129.6, 128.3, 127.9, 126.8, 126.0, 124.0, 100.5, 93.7, 74.4, 39.8, 28.9, 19.2. HRMS (ESI)
+
m/z calcd for C15H14IS [M + H] 352.9855, found 352.9851.
1
-iodo-2-(6-methylhept-6-en-4-yn-1-yl)benzene (1k). Eluent in chromatography: petroleum ether, 1k
1
was isolated as a light yellow liquid (1.05 g, 68%); H NMR (400 MHz, CDCl
3
) δ 7.81 (d, J = 7.8 Hz,
1H), 7.30 – 7.26 (m, 1H), 7.24 – 7.21 (m, 1H), 6.91 – 6.85 (m, 1H), 5.24 (s, 1H), 5.16 (s, 1H), 2.89 –
13
1
2
.77 (m, 2H), 2.37 (t, J = 7.0 Hz, 2H), 1.90 (s, 3H), 1.88 – 1.79 (m, 2H). C{ H} NMR (100 MHz,
CDCl
3
) δ 144.2, 139.5, 129.5, 128.3, 127.8, 127.2, 120.5, 100.5, 88.6, 82.6, 39.7, 29.0, 23.9, 18.8.
+
HRMS (EI) m/z calcd for C14
H
15I [M] 310.0218, found 310.0209.
1
-iodo-4-methyl-2-(5-phenylpent-4-yn-1-yl)benzene (1l). Eluent in chromatography: petroleum ether,
1
1
l was isolated as a yellow liquid (1.53 g, 85%); H NMR (400 MHz, CDCl
3
) δ 7.67 (d, J = 8.0 Hz,
1H), 7.45 –7.40 (m, 2H), 7.33 – 7.27 (m, 3H), 7.07 (s, 1H), 6.73 – 6.69 (m, 1H), 2.90 – 2.77 (m, 2H),
13
1
2
3
.47 (t, J = 6.8 Hz, 2H), 2.27 (s, 3H), 1.93 – 1.83 (m, 2H). C{ H} NMR (100 MHz, CDCl ) δ 143.9,
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39.2, 138.2, 131.6, 130.5, 128.8, 128.2, 127.5, 124.0, 96.4, 89.7, 81.3, 39.7, 29.2, 20.9, 19.0. HRMS
+
(EI) m/z calcd for C18
H
17I [M] 360.0375, found 360.0366.
1
-iodo-4-methoxy-2-(5-phenylpent-4-yn-1-yl)benzene (1m). Eluent in chromatography: petroleum
1
ether/ethyl acetate 100:1, 1m was isolated as a yellow liquid (1.65 g, 88%); H NMR (400 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
) δ 7.67 (d, J = 8.6 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.32 – 7.25 (m, 3H), 6.84 (d, J = 3.0 Hz, 1H),
6
.50 (dd, J = 8.6, 3.06 Hz, 1H), 3.76 (s, 3H), 2.90 – 2.79 (m, 2H), 2.48 (t, J = 6.8 Hz, 2H), 1.95 – 1.85
13
1
(
m, 2H). C{ H} NMR (100 MHz, CDCl
13.8, 89.6, 89.0, 81.3, 55.3, 39.8, 28.9, 18.9. HRMS (ESI) m/z calcd for C18
399.0216, found 399.0193.
3
) δ 159.9, 145.2, 139.9, 131.5, 128.2, 127.6, 123.9, 115.7,
1
H
17INaO[M + Na]+
4
-fluoro-1-iodo-2-(5-phenylpent-4-yn-1-yl)benzene (1n). Eluent in chromatography: petroleum ether,
1
1n was isolated as a yellow liquid (1.46 g, 80%); H NMR (400 MHz, CDCl
3
) δ 7.74 (dd, J = 8.6, 5.6
Hz, 1H), 7.44 – 7.40 (m, 2H), 7.33 – 7.25 (m, 3H), 7.00 (dd, J = 9.6, 2.98 Hz, 1H), 6.66 (td, J = 8.4, 2.8
1
3
1
Hz, 1H), 2.91 – 2.84 (m, 2H), 2.48 (t, J = 6.8 Hz, 2H), 1.94 – 1.83 (m, 2H). C{ H} NMR (100 MHz,
CDCl ) δ 163.0 (d, JC-F = 247.2 Hz), 146.4 (d, JC-F = 7.2 Hz), 140.5 (d, JC-F = 7.8 Hz), 131.5, 128.2,
27.6, 123.8, 116.6 (d, JC-F = 21.8 Hz), 115.2 (d, JC-F = 21.6 Hz), 93.2, 89.2, 81.5, 39.8, 28.7, 18.9. 19F
3
1
+
3
NMR (376 MHz, CDCl ) δ -114.35. HRMS (EI) m/z calcd for C17H14FI [M] 364.0124, found
3
64.0107.
4
-chloro-1-iodo-2-(5-phenylpent-4-yn-1-yl)benzene (1o). Eluent in chromatography: petroleum ether,
1
1
o was isolated as a yellow liquid (1.42 g, 75%); H NMR (400 MHz, CDCl
3
) δ 7.71 (d, J = 8.4 Hz,
1H), 7.45 – 7.40 (dd, J = 6.4, 3.2 Hz, 2H), 7.33 – 7.21 (m, 4H), 6.89 (dd, J = 8.4, 2.6 Hz, 1H), 2.98 –
13
1
2
3
.74 (m, 2H), 2.48 (t, J = 6.8 Hz, 2H), 1.94 –1.84 (m, 2H). C{ H} NMR (100 MHz, CDCl ) δ 146.1,
1
40.4, 134.5, 131.6, 129.5, 128.2, 128.0, 127.6, 123.8, 97.5, 89.2, 81.5, 39.7, 28.7, 19.0. HRMS (EI)
+
m/z calcd for C17
H
14ClI [M] 379.9829, found 379.9833.
1
-iodo-2-((5-phenylpent-4-yn-1-yl)oxy)benzene (1p). Eluent in chromatography: petroleum
1
ether/ethyl acetate 100:1, 1p was isolated as a light yellow liquid (1.23 g, 70%); H NMR (400 MHz,
CDCl ) δ 7.76 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 – 7.35 (m, 2H), 7.31 – 7.18 (m, 4H), 6.83 (dd, J = 8.2, 1.2
Hz, 1H), 6.70 (td, J = 7.6, 1.2 Hz, 1H), 4.15 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H), 2.17 – 2.08 (m,
3
1
3
1
2
H). C{ H} NMR (100 MHz, CDCl
3
) δ 157.3, 139.4, 131.5, 129.4, 128.2, 127.6, 123.7, 122.5, 112.1,
+
89.1, 86.7, 81.2, 67.5, 28.5, 16.3. HRMS (ESI) m/z calcd for C17
H
15INaO [M + Na] 385.0060, found
3
85.0061.
diethyl 2-(2-iodobenzyl)-2-(4-phenylbut-3-yn-1-yl)malonate (1q). Eluent in chromatography:
1
petroleum ether/ethyl acetate 20:1, 1q was isolated as a colorless oil (1.69 g, 67%); H NMR (400 MHz,
Benzene-d ) δ 7.64 (dd, J = 7.6, 1.2 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.34 (dd, J = 7.8, 1.6 Hz, 1H), 7.08 –
.80 (m, 4H), 6.46 (td, J = 7.6, 1.60 Hz, 1H), 3.94 (q, J = 7.0 Hz, 4H), 3.73 (s, 2H), 2.71 – 2.62 (m, 2H),
6
6
2.62 – 2.51 (m, 2H), 0.85 (t, J = 7.2 Hz, 6H). 13C{ H} NMR (100 MHz, Benzene-d
1
) δ 170.6, 140.3,
6
1
40.2, 131.9, 130.5, 128.7, 128.4, 124.5, 103.4, 89.5, 81.8, 61.4, 58.8, 43.3, 33.4, 16.2, 13.8. HRMS
+
(ESI) m/z calcd for C24
H
26IO
4
[M + H] 505.0870, found 505.0866.
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2
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diethyl 2-(2-iodobenzyl)-2-(3-phenylprop-2-yn-1-yl)malonate (1r). Eluent in chromatography:
1
petroleum ether/ethyl acetate 20:1, 1r was isolated as a colorless oil (2.08 g, 85%); H NMR (400 MHz,
Benzene-d
6
) δ 7.68 (dd, J = 7.8, 1.22 Hz, 1H), 7.54 (dd, J = 7.6, 1.6 Hz, 1H), 7.47 – 7.44 (m, 2H), 7.04
–
3
6.96 (m, 3H), 6.91 (td, J = 7.6, 1.2 Hz, 1H), 6.48 (td, J = 7.6, 1.6 Hz, 1H), 4.09 – 4.01 (m, 4H), 4.00 –
1
3
1
6
.92 (m, 2H), 3.31 (s, 2H), 0.92 (t, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, Benzene-d ) δ 169.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
140.4, 140.1, 132.0, 131.1, 128.8, 128.5, 128.2, 123.9, 102.8, 85.9, 85.0, 61.7, 58.7, 42.1, 25.0, 13.9.
+
4
HRMS (ESI) m/z calcd for C23H23INaO [M + Na] 513.0533, found 513.0514.
diethyl
2-(2-iodo-5-methoxybenzyl)-2-(3-phenylprop-2-yn-1-yl)malonate
(1s).
Eluent
in
chromatography: petroleum ether/ethyl acetate 30:1, 1s was isolated as a light yellow liquid (1.98 g,
1
7
7
6%); H NMR (400 MHz, CDCl
3
) δ 7.68 (d, J = 8.6 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.31 – 7.26 (m, 3H),
.06 (d, J = 3.0 Hz, 1H), 6.53 (dd, J = 7.8, 1.6 Hz, 1H), 4.32 – 4.13 (m, 4H), 3.74 (s, 3H), 3.64 (s, 2H),
1
3
1
3.03 (s, 2H), 1.3 (t, J = 7.2 Hz, 1H). C{ H} NMR (100 MHz, CDCl
3
) δ 169.7, 159.6, 140.3, 140.3,
1
31.6, 128.2, 128.0, 123.2, 116.6, 115.2, 90.6, 85.1, 84.4, 61.8, 58.1, 55.2, 41.4, 24.3, 13.9. HRMS
+
(
5
ESI) m/z calcd for C24H25INaO [M + Na] 543.0639, found 543.0631.
diethyl
chromatography: petroleum ether/ethyl acetate 20:1, 1t was isolated as a yellow liquid (2.02 g, 77%);
1H NMR (400 MHz, CDCl
) δ 7.74 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.42 – 7.38 (m, 2H),
2-(5-chloro-2-iodobenzyl)-2-(3-phenylprop-2-yn-1-yl)malonate
(1t).
Eluent
in
3
7.32 – 7.28 (m, 3H), 6.91 (dd, J = 8.4, 2.54 Hz, 1H), 4.37 – 4.09 (m, 4H), 3.64 (s, 2H), 3.03 (s, 2H),
1
1
1
.28 – 1.22 (m, 6H). 13C{ H} NMR (100 MHz, CDCl
3
) δ 169.5, 141.4, 140.8, 134.3, 131.6, 130.8,
28.9, 128.2, 128.1, 123.1, 99.3, 84.7, 84.6, 62.0, 58.2, 41.4, 24.5, 13.9. HRMS (ESI) m/z calcd for
+
C
23
H
22ClINaO
4
[M + Na] 547.0144, found 547.0131.
diethyl
2-(4-chloro-2-iodobenzyl)-2-(3-phenylprop-2-yn-1-yl)malonate
(1u).
Eluent
in
chromatography: petroleum ether/ethyl acetate 20:1, 1u was isolated as a light yellow liquid (2.17 g,
1
8
8
3%); H NMR (400 MHz, Benzene-d
6
) δ 7.70 (d, J = 2.2 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.31 (d, J =
.4 Hz, 1H), 7.02 – 6.91 (m, 3H), 6.84 (dd, J = 8.2, 2.2 Hz, 1H), 4.04 – 3.89 (m, 4H), 3.87 (s, 2H), 3.24
1
3
1
(
6
s, 2H), 0.95 – 0.86 (m, 6H). C{ H} NMR (100 MHz, Benzene-d ) δ 169.3, 139.0, 138.4, 133.2, 131.7,
131.3, 128.3, 127.7, 127.5, 123.4, 102.3, 85.3, 84.8, 61.5, 58.3, 41.1, 24.7, 13.6. HRMS (ESI) m/z calcd
+
for C23
H
22ClINaO
4
[M + Na] 547.0144, found 547.0138.
1-iodo-2-(oct-4-yn-1-yl)benzene (1v). Eluent in chromatography: petroleum ether, 1v was isolated as
1
a colorless oil (1.09 g, 70%); H NMR (400 MHz, CDCl
3
) δ 7.80 (d, J = 7.6 Hz, 1H), 7.30 – 7.17 (m,
2
H), 6.90 – 6.82 (m, 1H), 2.87 – 2.72 (m, 2H), 2.27 – 2.19 (m, 2H), 2.19 – 2.09 (m, 2H), 1.82 – 1.73
(m, 2H), 1.58 – 1.46 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C{ H} NMR (100 MHz, CDCl
1
) δ 144.4,
3
1
39.5, 129.5, 128.2, 127.7, 100.5, 80.9, 79.6, 39.7, 29.4, 22.5, 20.8, 18.3, 13.6. HRMS (EI) m/z calcd
+
for C14H17I [M] 312.0375, found 312.0381.
1-iodo-2-(tridec-4-yn-1-yl)benzene (1w). Eluent in chromatography: petroleum ether, 1w was
1
isolated as a colorless oil (1.18 g, 62%); H NMR (400 MHz, CDCl
3
) δ 7.82 –7.78 (m, 1H), 7.30 – 7.17
(
m, 2H), 6.90 – 6.84 (m, 1H), 2.92 – 2.74 (m, 2H), 2.31 – 2.11 (m, 4H), 1.88 – 1.70 (m, 2H), 1.55 –
1.46 (m, 2H), 1.42 – 1.35 (m, , 2H), 1.27 (s, 8H), 0.90 – 0.84 (m, 3H). 13C{ H} NMR (100 MHz,
1
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CDCl
3
) δ 144.4, 139.5, 129.5, 128.2, 127.7, 100.5, 81.1, 79.4, 39.7, 31.9, 30.3, 29.4, 29.2, 29.2, 28.9,
+
2
2.7, 18.8, 18.3, 14.1. HRMS (EI) m/z calcd for C19
H
27I [M] 382.1157, found 382.1165.
4
-chloro-1-iodo-2-(pent-4-yn-1-yl)benzene (1x). Eluent in chromatography: petroleum ether/ethyl
1
acetate 100:1, 1x was isolated as a yellow liquid (1.67 g, 55%); H NMR (400 MHz, CDCl
3
) δ 7.71 (dd,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 8.4, 2.2 Hz, 1H), 7.23 – 7.15 (m, 1H), 6.92 – 6.86 (m, 1H), 2.90 – 2.69 (m, 2H), 2.26 (td, J = 6.8,
.6 Hz, 2H), 2.05 – 2.00 (m, 1H), 1.86 – 1.76 (m, 2H). 13C{ H} NMR (100 MHz, CDCl
1
) δ 145.9,
2
1
3
3
40.4, 134.5, 129.4, 128.0, 97.5, 83.6, 69.2, 39.4, 28.4, 18.0. HRMS (EI) m/z calcd for C11
H
10ClI [M]+
03.9516, found 303.9525.
1
-(but-3-yn-1-yloxy)-2-iodobenzene (1y). Eluent in chromatography: petroleum ether/ethyl acetate
1
1
00:1, 1y was isolated as a colorless oil (1.77 g, 65%); H NMR (400 MHz, CDCl
3
) δ 7.77 (dd, J = 7.8,
1.6 Hz, 1H), 7.31 – 7.26 (m, 1H), 6.82 (dd, J = 8.2, 1.2 Hz, 1H), 6.72 (td, J = 7.6, 1.2 Hz, 1H), 4.14 (t,
13
1
3
J = 7.2 Hz, 2H), 2.75 (td, J = 7.2, 2.6 Hz, 2H), 2.08 – 2.04 (m, 1H). C{ H} NMR (100 MHz, CDCl )
9
δ 157.0, 139.6, 129.4, 123.0, 112.6, 86.8, 80.1, 70.1, 67.3, 19.5. HRMS (EI) m/z calcd for C H10IO
+
[M] 271.9698, found 271.9707.
1
-iodo-2-(pent-4-yn-1-yloxy)benzene (1z). Eluent in chromatography: petroleum ether/ethyl acetate
1
1
00:1, 1z was isolated as a colorless oil (1.94 g, 68%); H NMR (400 MHz, CDCl
3
) δ 7.76 (dd, J = 7.8,
1.6 Hz, 1H), 7.31 – 7.26 (m, 1H), 6.82 (dd, J = 8.2, 1.2 Hz, 1H), 6.70 (td, J = 7.6, 1.2 Hz, 1H), 4.11 (t,
1
3
1
J = 5.8 Hz, 2H), 2.51 (td, J = 6.8, 2.6 Hz, 2H), 2.12 – 2.01 (m, 2H), 2.00 – 1.95 (m, 1H). C{ H} NMR
(100 MHz, CDCl
3
) δ 157.3, 139.4, 129.4, 122.5, 112.1, 86.7, 83.5, 68.9, 67.2, 28.1, 15.3. HRMS (ESI)
+
m/z calcd for C11
H
11INaO [M + Na] 308.9747, found 308.9735.
1
,2-di-tert-butyldiaziridin-3-one (2a). Distilled under reduced pressure (56 ºC/ 4 mmHg) to give 2a
1
13
1
as a colorless liquid (4.40 g, 75% yield). H NMR (400 MHz, CDCl
3
) δ 1.22 (s, 18H). C{ H} NMR
(100 MHz, CDCl ) δ 159.3, 59.2, 26.9.
3
General procedure for the synthesis of compounds 3,4-Fused tricyclic indoles. Synthesis of 3a is
representative. 1-iodo-2-(5-phenylpent-4-yn-1-yl)benzene 1a (0.2 mmol), diaziridinone 2a (0.4 mmol),
Pd(OAc) (0.02 mmol), Cs CO (0.2 mmol) and PPh (0.2 mmol) were dissolved in DMF (2.0 mL). The
2
2
3
3
mixture was placed in a preheated metal block and stirred at 130 °C (temperature of the metal block)
under argon atmosphere for 4 hours. Then the resulting mixture was cooled to room temperature and
then diluted with ethyl acetate. The combined organic layer was washed with brine, dried over
2 4
anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was purified by flash
chromatography (petroleum ether/ethyl acetate = 100 : 1) to give 3a (48 mg, 83% yield) as a white
solid.
Gram-scale
-iodo-2-(5-phenylpent-4-yn-1-yl)benzene 1a (1.500 g，4.34 mmol), diaziridinone 2a (1.480 g，8.68
mmol), Pd(OAc) (0.098 g，10 mol %), Cs CO (1.415 g，1 equiv.), PPh (1.142 g，1 equiv.) and
synthesis
of
3a.
To
a
three-neck
flask
was
added
1
2
2
3
3
DMF (40.0 mL). After stirring at 130 °C (temperature of the oil bath) under argon atmosphere for 4
hours, the resulting mixture was cooled to room temperature and then diluted with ethyl acetate. The
2 4
combined organic layer was washed with brine, dried over anhydrous Na SO , filtered, and
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concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum
ether/ ethyl acetate = 100 : 1) to give 3a as a white solid (1.067 g，85% yield).
1-(tert-butyl)-2-phenyl-1,3,4,5-tetrahydrobenzo[cd]indole (3a). Following the general procedure
(eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3a was isolated as a white solid (48
1
mg, 83%); m.p. 157 – 159 °C; H NMR (400 MHz, CDCl
3
) δ 7.46 (d, J = 8.4 Hz, 1H), 7.38 – 7.31 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
H), 7.12 – 7.04 (m, 1H), 6.82 (d, J = 7.0 Hz, 1H), 2.95 – 2.87 (m, 2H), 2.51 – 2.43 (m, 2H), 1.98 –
1.92 (m, 2H), 1.57 (s, 9H). 13C{ H} NMR (100 MHz, CDCl
1
) δ 137.2, 135.2, 134.6, 132.2, 130.6,
3
1
27.7, 127.6, 127.2, 121.4, 115.7, 114.4, 112.2, 58.6, 32.0, 28.0, 24.2, 21.7. HRMS (ESI) m/z calcd for
+
C
21
H24N [M + H] 290.1903, found 290.1889.
1
-(tert-butyl)-2-(p-tolyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3b). Following the general procedure
(eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3b was isolated as a white solid (51
1
mg, 84%); m.p. 144 – 146 °C; H NMR (400 MHz, CDCl
3
) δ 7.46 (d, J = 8.4 Hz, 1H), 7.24 – 7.19 (m,
2
H), 7.19 – 7.14 (m, 2H), 7.11 – 7.04 (m, 1H), 6.82 (d, J = 7.0 Hz, 1H), 2.95 – 2.86 (m, 2H), 2.51 –
1
3
1
2
3
.43 (m, 2H), 2.41 (s, 3H), 1.99 – 1.89 (m, 2H), 1.59 –1.56 (m, 9H). C{ H} NMR (100 MHz, CDCl )
δ 136.8, 135.1, 134.7, 134.1, 132.1, 130.5, 128.3, 127.7, 121.2, 115.6, 114.1, 112.2, 58.5, 32.0, 28.0,
+
24.2, 21.8, 21.3. HRMS (ESI) m/z calcd for C22
H
26N [M + H] 304.2060, found 304.2065.
1
-(tert-butyl)-2-(4-chlorophenyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3c). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3c was isolated as a white
1
solid (50 mg, 77%); m.p. 205 – 207 °C; H NMR (400 MHz, CDCl
3
) δ 7.45 (d, J = 8.4 Hz, 1H), 7.38 –
7
.32 (m, 2H), 7.30 – 7.25 (m, 2H), 7.10 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 2.95 – 2.88 (m,
1
3
1
2H), 2.52 – 2.43 (m, 2H), 2.00 – 1.89 (m, 2H), 1.57 (s, 9H). C{ H} NMR (100 MHz, CDCl
3
) δ 135.7,
1
35.4, 133.2, 133.1, 132.3, 131.8, 127.9, 127.6, 121.7, 115.9, 114.9, 112.3, 58.6, 32.1, 27.9, 24.2, 21.7.
+
HRMS (ESI) m/z calcd for C21H23ClN [M + H] 324.1514, found 324.1496.
1-(tert-butyl)-2-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3d). Following the
general procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3d was isolated as
1
a white solid (51 mg, 71%); m.p. 160 – 162 °C; H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 8.0 Hz, 2H),
7.51 – 7.43 (m, 3H), 7.15 – 7.08 (m, 1H), 6.85 (d, J = 6.8 Hz, 1H), 2.95 – 2.86 (m, 2H), 2.53 – 2.38 (m,
13
1
2
1
H), 2.00 – 1.88 (m, 2H), 1.57 (s, 9H). C{ H} NMR (100 MHz, CDCl
3
) δ 141.0, 135.8, 132.9, 132.5,
30.6, 129.1 (q, JC-F = 32.6 Hz), 127.7, 125.6, 124.6 (q, JC-F = 3.8 Hz), 122.0, 116.0, 115.5, 112.4, 58.7,
1
9
3 23 3
32.1, 27.9, 24.2, 21.7. F NMR (376 MHz, CDCl ) δ -62.34. HRMS (ESI) m/z calcd for C22H F N [M
+
+
H] 358.1777, found 358.1774.
1
-(tert-butyl)-2-(m-tolyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3e). Following the general procedure
(eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3e was isolated as a white solid (52
1
mg, 86%); m.p. 118 – 120 °C; H NMR (400 MHz, Benzene-d
6
) δ 7.45 (d, J = 8.4 Hz, 1H), 7.27 – 7.20
(m, 1H), 7.19 – 7.16 (m, 2H), 7.14 – 7.07 (m, 1H), 7.01 – 6.93 (m, 2H), 2.90 – 2.80 (m, 2H), 2.58 –
1
3
1
2.50 (m, 2H), 2.15 (s, 3H), 1.90 – 1.79 (m, 2H), 1.44 (s, 9H). C{ H} NMR (100 MHz, Benzene-d
6
) δ
1
3
37.9, 137.2, 136.2, 134.8, 132.5, 131.6, 128.7, 128.1, 128.2, 127.8, 122.0, 116.3, 114.8, 112.8, 58.4,
+
2.1, 28.5, 24.8, 22.4, 21.3. HRMS (ESI) m/z calcd for C22H26N [M + H] 304.2060, found 304.2049.
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-(tert-butyl)-2-(3-chlorophenyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3f). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3f was isolated as a white
1
solid (60 mg, 93%); m.p. 139 – 141 °C; H NMR (400 MHz, Benzene-d
6
) δ 7.40 – 7.35 (m, 2H), 7.25 –
7
.18 (m, 1H), 7.11 – 7.05 (m, 1H), 7.04 – 6.97 (m, 1H), 6.95 (d, J = 6.8 Hz, 1H), 6.82 (t, J = 7.8 Hz,
1
3
1
1
H), 2.84 – 2.76 (m, 2H), 2.46 – 2.33 (m, 2H), 1.83 – 1.73 (m, 2H), 1.33 (s, 9H). C{ H} NMR (100
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
8
9
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, Benzene-d
15.7, 112.8, 58.4, 32.0, 28.3, 24.7, 22.2. HRMS (ESI) m/z calcd for C21
found 324.1495.
6
) δ 139.8, 136.5, 133.9, 132.8, 132.7, 130.8, 129.0, 129.0, 128.5, 127.4, 122.5, 116.5,
+
1
H23ClN [M + H] 324.1514,
1-(tert-butyl)-2-(2-chlorophenyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3g). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3g was isolated as a white
1
solid (62 mg, 96%); m.p. 168 – 170 °C; H NMR (400 MHz, CDCl
3
) δ 7.45 (t, J = 8.6 Hz, 2H), 7.36 –
7.25 (m, 3H), 7.15 – 7.07 (m, 1H), 6.83 (d, J = 7.0 Hz, 1H), 2.98 – 2.88 (m, 2H), 2.49 – 2.29 (m, 2H),
.06 – 1.88 (m, 2H), 1.57 (s, 9H). 13C{ H} NMR (100 MHz, CDCl
1
2
1
3
) δ 136.4, 135.2, 134.6, 132.8,
32.4, 130.8, 129.1, 129.1, 127.6, 126.0, 121.6, 115.5, 114.3, 112.1, 58.5, 31.0, 27.9, 24.2, 21.3.
+
HRMS (ESI) m/z calcd for C21
H
23ClN [M + H] 324.1514, found 324.1511.
1
-(tert-butyl)-2-(3,5-dimethoxyphenyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3h). Following the
general procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3h was isolated as
1
a white solid (65 mg, 93%); m.p. 104 – 106 °C; H NMR (400 MHz, CDCl
3
) δ 7.45 (d, J = 8.4 Hz, 1H),
7
.08 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.0 Hz, 1H), 6.55 – 6.49 (m, 2H), 6.48 – 6.40 (m, 1H), 3.81 (s, 6H),
1
3
1
2
.95 – 2.87 (m, 2H), 2.58 – 2.48 (m, 2H), 2.00 – 1.90 (m, 2H), 1.62 (s, 9H). C{ H} NMR (100 MHz,
CDCl
3
) δ 160.0, 139.0, 135.3, 134.5, 132.3, 127.6, 121.5, 115.7, 114.2, 112.3, 109.1, 99.2, 58.6, 55.4,
+
3
1.8, 28.0, 24.2, 21.8. HRMS (ESI) m/z calcd for C23
H
28NO
2
[M + H] 350.2115, found 350.2099.
1-(tert-butyl)-2-(3,5-difluorophenyl)-1,3,4,5-tetrahydrobenzo[cd]indole (3i). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3i was isolated as a white
1
solid (46 mg, 70%); m.p. 113 – 115 °C; H NMR (400 MHz, Benzene-d
6
) δ 7.35 (d, J = 8.2 Hz, 1H),
7
.25 – 7.17 (m, 1H), 6.94 (d, J = 7.0 Hz, 1H), 6.79 – 6.67 (m, 2H), 6.54 – 6.43 (m, 1H), 2.85 – 2.75 (m,
1
3
1
2H), 2.38 – 2.30 (m, 2H), 1.82 – 1.70 (m, 2H), 1.29 (s, 9H). C{ H} NMR (100 MHz, Benzene-d
6
) δ
62.7 (dd, J = 248.8, 13.2 Hz), 141.1 (t, J = 10.0 Hz), 136.8, 132.8, 131.8 (t, J = 2.2 Hz), 122.8, 116.7,
16.0, 113.8 (d, J = 6.8 Hz), 113.6 (d, J = 6.8 Hz), 112.9, 102.6 (t, J = 25.2 Hz), 58.4, 31.8, 28.3, 24.7,
) δ -110.45. HRMS (ESI) m/z calcd for C21
N [M + H]+
1
1
22.1. 19F NMR (376 MHz, Benzene-d
6
22 2
H F
3
26.1715, found 326.1712.
1-(tert-butyl)-2-(thiophen-2-yl)-1,3,4,5-tetrahydrobenzo[cd]indole (3j). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3j was isolated as a white
1
solid (31 mg, 53%); m.p. 140 – 142 °C; H NMR (400 MHz, CDCl
3
) δ 7.50 (d, J = 8.6 Hz, 1H), 7.43 (d,
J = 5.2 Hz, 1H), 7.17 – 7.07 (m, 2H), 7.06 – 7.02 (m, 1H), 6.86 (d, J = 7.0 Hz, 1H), 3.00 – 2.90 (m,
1
3
1
2H), 2.63 – 2.55 (m, 2H), 2.07 – 1.95 (m, 2H), 1.70 (s, 9H). C{ H} NMR (100 MHz, CDCl
3
) δ 137.4,
1
35.4, 132.5, 129.2, 127.1, 126.4, 126.4, 125.7, 122.1, 117.4, 115.6, 112.2, 58.9, 31.5, 27.9, 24.1, 21.8.
+
HRMS (ESI) m/z calcd for C19
H
22NS [M + H] 296.1467, found 296.1454.
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-(tert-butyl)-7-methyl-2-phenyl-1,3,4,5-tetrahydrobenzo[cd]indole (3l). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3l was isolated as a yellow
1
solid (53 mg, 87%); m.p. 124 – 126 °C; H NMR (400 MHz, CDCl
3
) δ 7.38 – 7.30 (m, 5H), 7.29 – 7.25
(
m, 1H), 6.85 – 6.50 (m, 1H), 3.06 – 2.75 (m, 2H), 2.65 – 2.34 (m, 5H), 2.12 – 1.80 (m, 2H), 1.57 (s,
1
3
1
9
H). C{ H} NMR (100 MHz, CDCl
3
) δ 137.4, 135.7, 134.0, 131.9, 131.1, 130.6, 127.5, 127.0, 125.7,
26N [M + H]+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
117.4, 114.3, 112.3, 58.4, 32.0, 27.9, 24.4, 22.6, 21.8. HRMS (ESI) m/z calcd for C22
04.2060, found 304.2048.
H
3
1
-(tert-butyl)-7-methoxy-2-phenyl-1,3,4,5-tetrahydrobenzo[cd]indole (3m). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3m was isolated as a light
1
yellow solid (50 mg, 78%); m.p. 130 – 132 °C; H NMR (400 MHz, CDCl
3
) δ 7.48 – 7.32 (m, 5H),
7
.05 – 7.03 (m, 1H), 6.61 – 6.59 (m, 1H), 3.92 (s, 3H), 2.95 – 2.87 (m, 2H), 2.63 – 2.40 (m, 2H), 2.07 –
1.82 (m, 2H), 1.60 (s, 9H). 13C{ H} NMR (100 MHz, CDCl
1
3
) δ 156.1, 137.3, 135.6, 133.6, 132.6,
1
30.6, 127.5, 127.0, 122.5, 114.2, 105.1, 97.7, 58.4, 56.3, 31.8, 28.0, 24.3, 21.6. HRMS (ESI) m/z calcd
+
for C22H26NO [M + H] 320.2009, found 320.2005.
1
-(tert-butyl)-7-fluoro-2-phenyl-1,3,4,5-tetrahydrobenzo[cd]indole (3n). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3n was isolated as a white
1
solid (59 mg, 96%); m.p. 137 – 139 °C; H NMR (400 MHz, CDCl
3
) δ 7.53 – 7.32 (m, 5H), 7.20 (dd, J
= 12.2, 1.8 Hz, 1H), 6.67 (d, J = 11.4 Hz, 1H), 2.95 – 2.87 (m, 2H), 2.58 – 2.40 (m, 2H), 2.02 – 1.90
1
3
1
(
m, 2H), 1.59 (s, 9H). C{ H} NMR (100 MHz, CDCl
3
) δ 159.7 (d, JC-F = 234.6 Hz), 136.8, 134.7 (d,
J
J
C-F = 3.8 Hz), 134.5 (d, JC-F = 12.8 Hz), 133.0 (d, JC-F = 10.2 Hz), 130.6, 127.6, 127.3, 123.9, 114.2 (d,
1
9
C-F = 1.4 Hz), 104.7 (d, JC-F = 25.0 Hz), 98.8 (d, JC-F = 28.8 Hz), 58.7, 31.9, 27.9, 24.1, 21.5. F NMR
+
(
376 MHz, CDCl
3
) δ -120.71. HRMS (ESI) m/z calcd for C21
H
23FN [M + H] 308.1809, found
3
08.1801.
1
-(tert-butyl)-7-chloro-2-phenyl-1,3,4,5-tetrahydrobenzo[cd]indole (3o). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 100:1), 3o was isolated as a white
1
solid (63 mg, 98%); m.p. 142 – 144 °C; H NMR (400 MHz, CDCl
3
) δ 7.49 – 7.44 (m, 1H), 7.41 – 7.29
(m, 5H), 6.86 – 6.80 (m, 1H), 2.90 – 2.83 (m, 2H), 2.48 – 2.40 (m, 2H), 1.97 – 1.87 (m, 2H), 1.55 (s,
1
3
1
9
1
H). C{ H} NMR (100 MHz, CDCl
3
) δ 136.6, 135.2, 135.2, 133.1, 130.5, 127.7, 127.4, 127.1, 126.1,
23ClN [M + H]+
16.5, 114.3, 112.1, 58.8, 32.0, 27.8, 24.1, 21.5. HRMS (ESI) m/z calcd for C21
H
324.1514, found 324.1503.
6
-(tert-butyl)-5-phenyl-2,3,4,6-tetrahydrooxepino[4,3,2-cd]indole (3p). Following the general
procedure (eluent in chromatography: petroleum ether/ethyl acetate 30:1), 3p was isolated as a white
1
solid (46 mg, 75%); m.p. 170 – 172 °C; H NMR (400 MHz, CDCl
3
) δ 7.43 – 7.35 (m, 3H), 7.35 – 7.28
(
m, 3H), 7.07 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 4.34 – 4.24 (m, 2H), 2.53 – 2.41 (m, 2H),
.11 – 2.01 (m, 2H), 1.57 (s, 9H). 13C{ H} NMR (100 MHz, CDCl
1
2
3
) δ 153.0, 138.6, 137.6, 136.0,
130.9, 127.9, 127.6, 121.2, 118.1, 113.2, 107.7, 106.1, 72.5, 58.8, 31.9, 30.3, 27.3. HRMS (ESI) m/z
+
calcd for C21
H
24NO [M + H] 306.1852, found 306.1843.
diethyl 2-(tert-butyl)-1-phenyl-2,6,8,9-tetrahydro-7H-cyclohepta[cd]indole-7,7-dicarboxylate (3q).
Following the general procedure (eluent in chromatography: petroleum ether/ethyl acetate 50:1), 3q
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was isolated as a white solid (81 mg, 91%); m.p. 135 – 137 °C; H NMR (400 MHz, CDCl
3
) δ 7.54 (d,
J = 8.6 Hz, 1H), 7.43 – 7.36 (m, 3H), 7.35 – 7.30 (m, 2H), 7.10 – 7.02 (m, 1H), 6.89 (d, J = 7.2 Hz,
1H), 4.23 – 4.11 (m, 4H), 3.67 (s, 2H), 2.64 – 2.54 (m, 2H), 2.41 – 2.27 (m, 2H), 1.56 (s, 9H), 1.24 (t, J
1
=
7.2 Hz, 6H). 13C{ H} NMR (100 MHz, CDCl
3
) δ 172.1, 136.8, 136.5, 136.2, 131.1, 130.3, 128.9,
1
27.6, 127.5, 120.9, 119.6, 117.8, 113.4, 61.2, 58.9, 58.5, 37.2, 34.2, 31.9, 21.3, 14.0. HRMS (ESI) m/z
+
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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4
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5
5
5
5
5
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0
1
2
3
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7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
calcd for C28
H
34NO
4
[M + H] 448.2482, found 448.2479.
diethyl 1-(tert-butyl)-2-phenyl-1,5-dihydrobenzo[cd]indole-4,4(3H)-dicarboxylate (3r). Following
the general procedure (eluent in chromatography: petroleum ether/ethyl acetate 50:1), 3r was isolated
1
as a white solid (82 mg, 95%); m.p. 85 – 87 °C; H NMR (400 MHz, CDCl
3
) δ 7.45 (d, J = 8.4 Hz, 1H),
7
2
.42 – 7.30 (m, 5H), 7.12 – 7.05 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.06 (q, J = 7.2 Hz, 4H), 3.49 (s,
1
3
1
3
H), 3.06 (s, 2H), 1.55 (s, 9H), 1.10 (t, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, CDCl ) δ 171.2,
136.5, 135.5, 134.8, 130.6, 128.0, 127.7, 127.4, 126.2, 121.8, 116.1, 112.7, 110.7, 61.3, 58.8, 56.0, 34.3,
+
3
2.0, 28.4, 13.9. HRMS (ESI) m/z calcd for C27
H
32NO
4
[M + H] 434.2326, found 434.2325.
diethyl 1-(tert-butyl)-7-methoxy-2-phenyl-1,5-dihydrobenzo[cd]indole-4,4(3H)-dicarboxylate (3s).
Following the general procedure (eluent in chromatography: petroleum ether/ethyl acetate 50:1), 3s
1
was isolated as a light yellow liquid (89 mg, 96%); H NMR (400 MHz, CDCl
3
) δ 7.40 – 7.30 (m, 5H),
6
.97 (s, 1H), 6.61 (s, 1H), 4.07 (q, J = 7.2 Hz, 4H), 3.87 (s, 3H), 3.44 (s, 2H), 3.04 (s, 2H), 1.53 (s, 9H),
1
3
1
1.11 (t, J = 7.2 Hz, 6H). C{ H} NMR (100 MHz, CDCl
3
) δ 171.1, 156.4, 136.7, 135.4, 134.5, 130.6,
1
28.4, 127.7, 127.3, 121.2, 110.6, 105.4, 98.3, 61.3, 58.6, 56.2, 56.2, 34.4, 31.9, 28.4, 13.9. HRMS
+
(
5
ESI) m/z calcd for C28H34NO [M + H] 464.2431, found 464.2417.
diethyl 1-(tert-butyl)-7-chloro-2-phenyl-1,5-dihydrobenzo[cd]indole-4,4(3H)-dicarboxylate (3t).
Following the general procedure (eluent in chromatography: petroleum ether/ethyl acetate 50:1), 3t was
1
isolated as a light yellow solid (70 mg, 75%); m.p. 80 – 82 °C; H NMR (400 MHz, CDCl
3
) δ 7.45 (s,
1
1
1
H), 7.41 – 7.29 (m, 5H), 6.89 (s, 1H), 4.07 (q, J = 7.2 Hz, 4H), 3.44 (s, 2H), 3.03 (s, 2H), 1.53 (s, 9H),
1
3
1
3
.10 (t, J = 6.8 Hz, 6H). C{ H} NMR (100 MHz, CDCl ) δ 170.9, 136.2, 136.0, 134.9, 130.5, 129.0,
27.8, 127.7, 127.5, 124.8, 116.9, 112.7, 110.8, 61.4, 59.1, 55.9, 34.0, 32.0, 28.2, 13.9. HRMS (ESI)
+
m/z calcd for C27
H
31ClNO
4
[M + H] 468.1936, found 468.1939.
diethyl 1-(tert-butyl)-8-chloro-2-phenyl-1,5-dihydrobenzo[cd]indole-4,4(3H)-dicarboxylate (3u).
Following the general procedure (eluent in chromatography: petroleum ether/ethyl acetate 50:1), 3u
1
was isolated as a light yellow liquid (64 mg, 69%); H NMR (400 MHz, DMSO-d
6
) δ 7.54 – 7.33 (m,
5
H), 7.13 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.99 – 3.93 (m, 4H), 3.36 (s, 2H), 3.04 (s, 2H),
1
3
1
1.54 (s, 9H), 1.02 – 0.94 (m, 6H). C{ H} NMR (100 MHz, DMSO-d
6
) δ 170.4, 140.3, 136.4, 135.4,
1
30.4, 129.4, 128.8, 127.9, 127.6, 125.7, 119.8, 116.1, 112.8, 61.6, 59.5, 55.3, 33.9, 33.9, 28.7, 14.2.
+
4
HRMS (ESI) m/z calcd for C27H31ClNO [M + H] 468.1936, found 468.1926.
Removal of the tert-butyl group of product 3a. To an oven-dried 10 mL pressure tube was added
-(tert-butyl)-2-phenyl-1,3,4,5-tetrahydrobenzo[cd]indole 1a (0.2 mmol) , 1 M HCl (0.3 mL) and
1
MeCN (0.7 mL). After stirring at room temperature for overnight, the resulting mixture was diluted
4
with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na SO ,
2
filtered and concentrated under reduced pressure. The residue was purified by flash chromatography
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6
,
(
petroleum ether/ethyl acetate = 10 : 1) to give 3a (35 mg, 75% yield) as a white solid, m.p. 117 –
1
1
19 °C; H NMR (400 MHz, DMSO-d
6
) δ 11.00 (s, 1H), 7.72 – 7.70 (m, 2H), 7.47 (t, J = 7.8 Hz, 2H),
7.28 (t, J = 7.4 Hz, 1H), 7.13 – 7.11 (m, 1H), 7.04 – 6.94 (m, 1H), 6.71 (d, J = 6.8 Hz, 1H), 3.01 (t, J =
13
1
6
1
6
.0 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 2.00 (p, J = 6.4 Hz, 2H). C{ H} NMR (100 MHz, DMSO-d ) δ
34.7, 133.7, 131.9, 130.5, 129.3, 128.6, 126.8, 126.3, 122.8, 115.7, 110.5, 108.6, 27.4, 24.9, 23.5.
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HRMS (ESI) m/z calcd for C17
H
16N [M + H] 234.1277, found 234.1274.
Competition experiments. (a) To an oven-dried 10 mL pressure tube was added substrate 1b (36
mg, 0.1 mmol), substrate 1c (38 mg, 0.1 mmol), Pd(OAc) (5 mg, 10 mol %), PPh (0.2 mmol), Cs CO
(0.2 mmol), diaziridinone 2a (68 mg, 0.4 mmol) and DMF (2.0 mL) under Ar. After stirring at 130 °C
temperature of the metal block) under argon atmosphere for 4 hours, the resulting mixture was diluted
4
with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na SO ,
2
3
2
3
(
2
filtered and concentrated under reduced pressure. The residue was purified by flash chromatography
1
(
petroleum ether/ethyl acetate = 100 : 1). The ratio of product 3c/3b was analyzed by H NMR.
(
b) To an oven-dried 10 mL pressure tube was added substrate 1l (36 mg, 0.1 mmol), substrate 1o
(38 mg, 0.1 mmol), Pd(OAc) (5 mg, 10 mol %), PPh (0.2 mmol), Cs CO (0.2 mmol), diaziridinone
a (68 mg, 0.4 mmol) and DMF (2.0 mL) under Ar. After stirring at 130 °C (temperature of the metal
block) under argon atmosphere for 4 hours, the resulting mixture was diluted with ethyl acetate. The
combined organic layer was washed with brine, dried over anhydrous Na SO , filtered and
2
3
2
3
2
2
4
concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum
1
ether/ethyl acetate = 100 : 1). The ratio of product 3o/3l was analyzed by H NMR.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
1
0.1021/acs.joc.xxxxxxx
Copies of NMR spectra of products.
AUTHOR INFORMATION
Corresponding Author
Chuanming Yu − College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, P. R. China; Email: ycm@zjut.edu.cn
Xinpeng Jiang− College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
3
10014, P. R. China; Email: xjiang@zjut.edu.cn
Authors
Lei Zhang − College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
3
10014, P. R. China
Junyu Chen − College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
10014, P. R. China
3
Tianshuo Zhong − College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, P. R. China
Xiangyun Zheng − College of Pharmaceutical Sciences, Zhejiang University of Technology,
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Hangzhou 310014, P. R. China
Jian Zhou − College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
310014, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/
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Notes
The authors declare no competing financial interest.
Acknowledgements
We thank the National Natural Science Foundation of China (NSFC) (Grant No. 21676252 and
2
1506191) for financial support.
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