Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles via Michael Addition–Condensation of 3-Substituted Indoles with α,β-Unsaturated Ketimines

Article abstract of DOI:10.1002/jhet.2661

By employing copper dibromide as a catalyst, Michael addition–condensation of 3-substituted indoles with α,β-unsaturated ketimines was realized. The reactions afforded a large variety of 9H-pyrrolo[1,2-α]indoles with good yields (up to 99 %). In addition, a plausible reaction mechanism was proposed.

Full text of DOI:10.1002/jhet.2661

Month 2016
Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles via Michael Addition–
Condensation of 3-Substituted Indoles with α,β-Unsaturated Ketimines
Minmin Zhang,a,b Lihua Liao,a,b Shuowen Yu,a,b Yijun Liao,a,b Xiaoying Xu,a
a
a
*
Weicheng Yuan, and Xiaomei Zhang
aKey Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
bUniversity of Chinese Academy of Sciences, Beijing 100049, China
*
E-mail: xmzhang@cioc.ac.cn
Received January 13, 2016
DOI 10.1002/jhet.2661
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
By employing copper dibromide as a catalyst, Michael addition–condensation of 3-substituted indoles
with α,β-unsaturated ketimines was realized. The reactions afforded a large variety of 9H-pyrrolo[1,2-α]in-
doles with good yields (up to 99 %). In addition, a plausible reaction mechanism was proposed.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
can be seen in Table 1, no reaction was observed with zinc
triflate (Table 1, entry 1). Inseparable mixture was obtained
with copper(II) triflate (Table 1, entry 2). Several other cop-
per salts were found to be inactive in the reaction (Table 1,
entries 3–5). To our delight, when copper dibromide was
employed, the reaction was completed in only 1 h to afford
the product in good yield (Table 1, entry 6). SnCl4.5H2O
delivered obviously lower yield in 2 h (Table 1, entry 7).
When FeCl3 was employed, the reaction was completed in
2 h (Table 1, entry 8). In addition, some Brønsted acids
were also tested in the reaction. Trifluoromethanesulfonic
acid and p-toluenesulfonic acid provided moderate yields
of the product (Table 1, entries 9 and 10). Meanwhile, reac-
tion could not proceed with acetic acid as catalyst (Table 1,
entry 11). Therefore, copper dibromide was determined as
the optimal catalyst and was employed in further investiga-
tions. Subsequently, various solvents were evaluated. 1,2-
Dichloroethaneprovidedthesameresultasdichloromethane
(Table 1, entry 9). Reaction in chloroform produced almost
quantitative of the product in only 0.5h (Table 1, entry 10).
No product was detected in polar solvent THF (Table 1, entry
11). It took longer time for reactions in acetonitrile and
toluene to give lower yields of the product (Table 1, entries
12 and 13). Thus, chloroform was identified as the most
favorable solvent in the reaction. Afterwards, the catalyst
loading was reduced to 5mol% and no adverse effect was
observed (Table 1, entry 14).
9H-Pyrrolo[1,2-α]indoles are key intermediates for the
synthesis of cytostatic mytomycine derivatives [1]. There-
fore, preparation of 9H-pyrrolo[1,2-α]indoles has attracted
much attention. Recently, several efficient approaches has
been established to prepare these compounds [2]. For ex-
amples, Kumar et. al. reported a method for the synthesis
of 9H-pyrrolo[1,2-α]indoles by reaction of 3-substituted-
4,6- dimethoxyindoles with chalcones in the presence of
hydrochloric acid [2h]. However, the scope of the reaction
was limited to 3-substituted-4,6-dimethoxyindoles. Re-
cently, Zu et. al. demonstrated a highly efficient and widely
applicable approach of 9H-pyrrolo[1,2-α]indoles by [3 +2]
annulation of 3-substituted indoles with α,β-unsaturated
ketones catalyzed by TsOH [2].
In this article, we demonstrated that α,β-unsaturated
ketimines could undergo Michael addition–condensation
with 3-substituted indoles in the presence of 5 mol% of
copper dibromide. This transformation enables easy access
to a wide variety of 9H-pyrrolo[1,2-α]indoles in moderate
to good yields (up to 99%).
RESULTS AND DISCUSSION
We initiated the investigation with the reaction of 3-
methylindole 1a with (E)-N-(1,3-diphenylallylidene)-4-
methylbenzenesulfonamide 2a in dichloromethane at room
temperature. First, various Lewis acids were screened. As
Having established the optimal conditions, the scope of
the reaction was investigated. The results were summarized
in Table 2. First, various 3-substituted indoles were
© 2016 Wiley Periodicals, Inc.

M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
Table 1
Michael addition–condensation of 3-methyl indole 1a with (E)-N-(1,3-diphenylallylidene)-4-methylbenzenesulfonamide 2a.
Entrya
Catalyst
Solvent
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Zn(OTf)2
Cu(OTf)2
Cu(OAc)2 · 4H2O
CuSO4.5H2O
CuBr
CuBr2
SnCl4.5H2O
FeCl3
TfOH
TsOH
HOAc
CuBr2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CHCl3
24
24
24
24
24
1
2
2
0.5
3
24
1
0.5
24
2
3
0.5
NR
ND
NR
NR
NR
91
77
91
82
75
NR
92
98
NR
85
91
9
10
11
12
13
14
15
16
17c
CuBr2
CuBr2
CuBr2
CuBr2
THF
CH3CN
Toluene
CHCl3
CuBr2
97
aUnless specified otherwise, reactions were carried out with 1a (0.3 mmol), 2a (0.2 mmol) and Lewis acid (0.02 mmol) in the solvent (3 mL) at room
temperature.
bIsolated yield based on 2a.
c5 mol% of CuBr2 was used.
subjected
to
the
reaction
with
(E)-N-(1,3-
ketimines were also tested in the reaction with 3-methyl in-
dole 1a. Most of the α,β-unsaturated ketimines bearing
many sorts of substituents on different positions of the
arenes underwent the reaction smoothly to afford the corre-
sponding product in good yields (Table 2, entries 14–18
and 20–28), in which 2l needed 10mol% of copper bro-
mide (Table 2, entry 24). However, 2g bearing a strong
electron-withdrawing 4-nitrophenyl group was totally inac-
tive in the reaction and no corresponding product was de-
tected (Table 2, entry 19).
Based on the reaction results, a plausible reaction mech-
anism was proposed. As can be seen in Scheme 1, first,
Michael addition of 3-substituted indole 1 with α,β-
unsaturated ketimine 2 generated adduct A. Following in-
tramolecular nucleophilic attack of N to C¼N double bond
gave rise to B. Elimination of TsNH2 produced C. Finally,
C isomerized to structurally stable 9H-pyrrolo[1,2-α]in-
dole 3.
diphenylallylidene)-4-methyl-benzenesulfonamide 2a. It
is noteworthy that the yield dropped remarkably when
chalcone was employed instead of α,β-unsaturated
ketimine 2a (Table 2, entry 1 vs. entry 2), demonstrating
that α,β-unsaturated ketimine is much more active than
chalcone. Generally, most of the 3-methylindoles bearing
various substituents on 4, 5, and 6-position underwent the
reaction smoothly to provide corresponding products in
moderate to good yields (Table 2, entries 1 and 3–9). How-
ever, 3,7-dimethylindole 1i resulted in complex mixture in
the reaction and no desired product was detected (Table 2,
entry 10). When 3-cyclohexyl indole 1j and ethyl 2-(1H-
indol-3-yl)acetate 1k were used, obviously lower yields
were observed, perhaps because of the steric hindrance of
the 3-substituents (Table 2, entries 11 and 12). Meanwhile,
3-phenyl indole gave rise to excellent yield of the product
(Table 2, entry 13). Afterwards, various α,β-unsaturated
Journal of Heterocyclic Chemistry
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Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles
Month 2016
Table 2
Michael addition-condensation of 3-substituted indoles 1 with α,β-unsaturated ketimines 2.
Entrya
1
3
t (h)
0.5
Yieldb (%)
97 (60)c
3aa
2
3ba
0.5
96
3d
3ca
3
92
4
3da
0.5
95
(Continued)
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M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
Table 2
(Continued)
Entrya
5
3
t (h)
1
Yieldb (%)
3ea
92
74
50
99
6
7
8
3fa
1
1
1
3ga
3ha
(Continued)
Journal of Heterocyclic Chemistry
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Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles
Month 2016
Table 2
(Continued)
Entrya
9
3
t (h)
24
Yieldb (%)
ND
3ia
10
3ja
1
60
11
3ka
2
67
12
3la
0.5
99
(Continued)
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M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
Table 2
(Continued)
Entrya
13
3
t (h)
0.5
Yieldb (%)
91
3ab
14
15
16
3ac
0.5
0.5
0.5
97
3ad
94
3ae
91
(Continued)
Journal of Heterocyclic Chemistry
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Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles
Month 2016
Table 2
(Continued)
Entrya
17
3
t (h)
0.5
Yieldb (%)
92
3af
18
3ag
24
NR
19
3ah
0.5
91
20
3ai
0.5
90
(Continued)
Journal of Heterocyclic Chemistry
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M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
Table 2
(Continued)
Entrya
21
3
t (h)
0.5
Yieldb (%)
3aj
99
22
3ak
1
3
1
99
91
89
23e
3al
24
3am
(Continued)
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Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles
Month 2016
Table 2
(Continued)
Entrya
25
3
t (h)
Yieldb (%)
99
3an
0.5
26
3ao
1
88
27
3ap
1
99
aUnless specified otherwise, reactions were carried out with 1 (0.3 mmol), 2 (0.2 mmol) and copper dibromide (0.01 mmol) in chloroform (3 mL) at room
temperature.
bIsolated yield based on 2.
cChalcone was used instead of α,β-unsaturated ketimine 2a.
dThe catalyst loading was 10 mol%.
eThe reaction was carried out with 1a (0.2 mmol), 2 l (0.3 mmol) and copper dibromide (0.02 mmol).
Journal of Heterocyclic Chemistry
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M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
Scheme 1. Proposed reaction mechanism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
CONCLUSION
chemical shifts are reported in ppm (δ) relative to
tetramethylsilane with the solvent resonance employed as
the internal standard (CDCl3, δ 7.26ppm). Data are re-
ported as follows: chemical shift, multiplicity (s, singlet;
brs, broad singlet; d, doublet; t, triplet; td, triplet of dou-
blets; q, quartet; m, multiplet), coupling constants (Hz),
and integration. 13C NMR chemical shifts are reported in
ppm from tetramethylsilane with the solvent resonance
as the internal standard (CDCl3, δ 77.0ppm). HRMS data
were obtained on a Bruker Daltonics Inc. mass instrument
(USA Buluke Spectrograph Co., Beijing, China) (ESI).
Synthesis of 3-substituted indoles 1. 3-Methylindole 1a
is commercially available. 3-Substituted indoles 1b–1i
[3], 1j [3], 1k [3], and 1l [3] were prepared
according to known procedures, and all of the 1H
NMR data are identical with corresponding data in
the literatures.
In conclusion, we have developed a mild and efficient
methodology to construct 9H-pyrrolo[1,2-α]indoles via
copper dibromide promoted Michael addition–con-
densation of 3-substituted indoles with α,β-unsaturated
ketimines. The reaction is tolerable to a wide variety of
substrates, which allows for easy access to structurally di-
verse 9H-pyrrolo[1,2-α]indoles in moderate to good
yields.
EXPERIMENTAL
Chemicals were purchased from commercial suppliers
and used without further purification unless otherwise
stated. Solvents were dried and purified according to the
standard procedures before use. Reactions were monitored
by TLC. Flash chromatography was performed on silica
Synthesis of N-Tosyl-1-aza-1,3-butadienes 2. N-Tosyl-1-
aza-1,3-butadienes 2a–2k and 2m–2p [4], 2l [4] were
prepared according to known procedures. The H NMR
1
1
gels (200–300mesh). H NMR and 13C NMR (300 and
75MHz, respectively) spectra were recorded on a Bruker
data of 2a, 2c, 2d–2g, 2l, 2m, and 2n are identical with
corresponding data in the literatures.
300MHz NMR spectrometer in CDCl3. 1H NMR
Journal of Heterocyclic Chemistry
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Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles
Month 2016
4-Methyl-N-[(E)-1-phenyl-3-(p-tolyl)allylidene]benzenesulfo
namide (2b).
J= 7.4Hz, 2H), 7.58 (s, 2H), 7.44–7.42 (m, 3H), 7.39–
7.31 (m, 3H), 7.27–7.11 (m, 2H), 7.10–7.09 (m, 2H),
3.83 (s, 3H), 2.43 (s, 3H)
4-Methyl-N-[(E)-1-(naphthalen-2-yl)-3-phenylallylidene]ben
zenesulfonamide (2p). Yellow solid, 56% yield, 1H NMR
(300 MHz, CDCl3) δ 8.17 (s, 2H), 7.96 (d, J = 7.4 Hz, 2H),
7.90–7.88 (m, 3H), 7.60 (d, J = 1.2 Hz, 1H), 7.60–7.54 (m,
4H), 7.43–7.42 (m, 3H), 7.32 (d, J = 7.9 Hz, 2H), 7.11 (d,
J = 16.1 Hz, 1H), 2.43 (s, 3H).
Yellow solid, 80% yield, 1H NMR
(300 MHz, CDCl3) δ 7.94–8.10 (m, 1H), 7.92 (d,
J = 7.6 Hz, 2H), 7.63 (d, J = 6.6 Hz, 2H), 7.56–7.40 (m,
5H), 7.31 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H),
7.05 (d, J = 16.0 Hz, 1H), 2.42 (s, 3H), 2.39 (s, 3H).
4-Methyl-N-[(E)-1-phenyl-3-(m-tolyl)allylidene]benzenesulfo
namide (2h).
Yellow solid, 40% yield, 1H NMR
(300 MHz, CDCl3) δ 7.95–8.24 (m, 1H), 7.93 (d,
J =7.7 Hz, 2H), 7.64 (d, J =6.5 Hz, 2H), 7.54–7.52 (m,
1H), 7.45–7.40 (m, 3H), 7.35-7.30 (m, 3H), 7.27–7.25
(m, 2H), 7.04 (d, J= 16.0 Hz, 1H), 2.42 (s, 3H), 2.38 (s,
3H).
N-[(E)-3-(3-bromophenyl)-1-phenylallylidene]-4-methylben
zenesulfonamide (2i). Yellow solid, 60% yield, 1H NMR
(300 MHz, CDCl3) δ 7.94–8.09 (m, 1H), 7.92 (d,
J = 7.8 Hz, 2H), 7.67–7.63 (m, 3H), 7.58–7.50 (m, 3H),
7.46–7.42 (m, 2H), 7.33–7.29 (m, 3H), 6.96 (d,
J = 16.1 Hz, 1H), 2.43 (s, 3H).
General procedure of 3-substituted indoles
N-Tosyl-1 -aza-1,3-butadienes 2.
1 with
3-Substituted indole 1
(0.30 mmol); N-Tosyl-1-aza-1,3-butadienes 2 (0.2 mmol);
and CuBr2 (0.01 mmol, 5 mol %) were placed in a flame-
dried vial equipped with a magnetic stirring bar. Then
2 mL of CHCl3 was added to dissolve the mixture. The
reaction mixture was stirred at room temperature until no
starting material was detected by TLC. The solvent was
evaporated, and the residue was subjected to
chromatography (silica gel, Petroleum ether/EtOAc:
300/1 to 200/1) to afford the desired product 3.
N-[(E)-3-(2,6-dichlorophenyl)-1-phenylallylidene]-4-methyl
1
benzenesulfonamide (2j).
Yellow solid, 70% yield, H
9-Methyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole (3aa). Yellow
1
NMR (300 MHz, CDCl3) δ 8.15 (d, J = 15.1 Hz, 1H),
7.93 (d, J = 7.0 Hz, 2H), 7.78 (s, 2H), 7.56–7.53 (m,
1H), 7.48–7.42 (m, 2H), 7.38–7.30 (m, 4H), 7.26–7.21
(m, 1H), 7.18–7.10 (m, 1H), 2.42 (s, 3H).
4-Methyl-N-[(E)-3-(naphthalen-1-yl)-1-phenylallylidene]ben
zenesulfonamide (2 k). Yellow solid, 75% yield, 1H NMR
(300 MHz, CDCl3) δ 7.99–8.20 (m, 1H), 7.99–7.87 (m,
7H), 7.76 (m, 2H), 7.60–7.50 (m, 6H), 7.32 (d,
J = 8.1 Hz, 2H), 2.43 (s, 3H).
solid; 97% yield; H NMR (300 MHz, DMSO) δ 7.66 (d,
J = 7.4 Hz, 2H), 7.62 (d, J = 6.9 Hz, 2H), 7.57–7.49 (m,
3H),7 7.45–7.38 (m, 3H), 7.20–7.12 (m, 3H), 7.0 (d,
J = 7.3 Hz, 1H), 6.66 (s, 1H), 4.60 (q, J = 6.9 Hz, 1H), 1.44
1
(d, J = 7.1 Hz, 3H). The H NMR spectrum is identical
with that on literature [2] e.
8,9-Dimethyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole (3ba). Yellow
1
solid; 96% yield; H NMR (300 MHz, CDCl3) δ 7.68 (d,
J = 7.4 Hz, 2H), 7.62 (d, J = 6.9 Hz, 2H), 7.53–7.39 (m,
5H), 7.24 (d, J = 2.8 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.96
(d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.62 (s, 1H),
4.50 (q, J = 7.0 Hz, 1H), 2.47 (s, 3H), 1.57 (d, J = 7.0 Hz,
N-[(E)-1-(3-methoxyphenyl)-3-phenylallylidene]-4-methylben
1
enesulfonamide (2o). Yellow solid, 62% yield, H NMR
(300MHz, CDCl3) δ 7.96–8.25 (m, 1H), 7.94 (d,
Journal of Heterocyclic Chemistry
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M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
3H). 13C NMR (75 MHz, CDCl3) δ 140.3, 138.8, 138.7,
135.4, 135.0, 132.9, 129.1, 128.6, 128.4, 128.3, 127.4,
127.2, 125.7, 125.4, 125.2, 117.6, 112.6, 109.5, 35.7,
18.6, 16.0. ESI HRMS exact mass calcd. For (C25H21N
+ H)+ requires m/z 336.1747, found m/z 336.1708.
132.9, 129.0, 128.6, 128.5, 128.3, 127.5, 126.0, 125.4,
124.2, 124.0, 118.1, 112.7, 112.6, 35.75, 21.7, 17.3. ESI
HRMS exact mass calcd. For (C25H21N + H)+ requires m/
z 336.1747, found m/z 336.1734.
6-Fluoro-9-methyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole
1
(3 ha).
Yellow solid; 99% yield; H NMR (300MHz,
8-Bromo-9-methyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole
White solid; 92% yield; 1H NMR (300 MHz,
CDCl3) δ 7.71–7.55 (m, 4H), 7.57–7.38 (m, 5H), 7.36-
7.20 (m, 2H), 6.88–6.74 (m, 2H), 6.62 (s, 1H), 4.45 (q,
J=7.0Hz, 1H), 1.56 (d, J=7.1Hz, 3H). 13C NMR
(3ca).
CDCl3) δ 7.70–7.62 (m, 2H), 7.62–7.56 (m, 2H), 7.54–
7.39 (m, 5H), 7.29–7.19 (m, 2H), 7.06–6.95 (m, 2H),
6.62 (s, 1H), 4.52 (q, J = 7.0 Hz, 1H), 1.67 (d, J = 7.0 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 142.0, 140.1, 138.4,
135.2, 132.8, 129.4, 1292, 129.0, 128.7, 128.0, 127.2,
126.1, 126.0, 119.9, 118.5, 113.5, 111.0, 38.1, 15.8. ESI
HRMS exact mass calcd. For (C24H18BrN + H)+ requires
m/z 400.0695, found m/z 400.0678.
(75MHz, CDCl3) δ 162.1 (d, J C-F =241.5Hz), 141.2 (J
C-
F =6.6Hz), 139.3, 136.46, 136.4, 135.1, 132.3, 129.0,
128.6, 128.5, 127.8, 126.0, 125.6, 125.2, 125.0, 118.6,
113.2, 109.6 (d, J C-F =22.6Hz), 100.3 (d, J C-F =28.2),
35.6, 17.2. ESI HRMS exact mass calcd. For (C24H18FN
+H )+ requires m/z 340.1496, found m/z 340.1485.
9-Cyclohexyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole (3ja). White
solid; 60% yield; 1H NMR (300 MHz, CDCl3) δ 7.63–7.54
(m, 4H), 7.50–7.35 (m, 6H), 7.22 (t, J = 7.3 Hz, 1H), 7.15–
6.98 (m, 3H), 6.57 (s, 1H), 4.36 (d, J = 3.0 Hz, 1H), 2.14 (td,
J = 12.0, 2.9 Hz, 1H), 1.83 (d, J = 12.5 Hz, 1H), 1.72 (d,
J = 13.1 Hz, 1H), 1.53–1.34 (m, 3H), 1.21 (t, J = 14.3 Hz,
2H), 1.04–0.91 (m, 2H), 0.58 (dt, J = 12.4, 8.9 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ 141.5, 138.0, 137.2, 135.8,
132.9, 129.0, 128.5, 128.3, 127.4, 127.1, 126.2, 126.0,
125.4, 122.7, 118.6, 113.1, 111.6, 47.4, 41.5, 31.3, 28.4,
26.8, 26.3, 26.2. ESI HRMS exact mass calcd. For
(C29H27N + H)+ requires m/z 390.2216, found m/z
390.2204.
7-Methoxy-9-methyl-1,3-diphenyl-9H-pyrrolo[1,2-α] indole
1
(3da).
Yellow solid; 95% yield; H NMR (300MHz,
CDCl3) δ 7.64 (ddd, J = 6.6, 4.0, 1.2 Hz, 4H), 7.54–7.39
(m, 5H), 7.25 (dd, J = 5.5, 3.0 Hz, 1H), 7.04 (d,
J =8.7 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.66 (dd, J = 8.7,
2.5Hz, 1H), 6.58 (s, 1H), 4.46 (q, J= 7.1 Hz, 1H), 3.82
(s, 3H), 1.57 (d, J= 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 156.4, 142.8, 138.4, 135.5, 134.3, 132.8,
128.9, 128.6, 128.3, 128.2, 127.4, 125.9, 125.3, 118.2,
112.1, 112.0, 111.5, 111.4, 55.7, 36.3, 17.3. ESI HRMS
exact mass calcd. For (C25H21NO + H)+ requires m/z
352.1696, found m/z 352.1687.
7-Chloro-9-methyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole
Ethyl 2-[1,3-diphenyl-9H-pyrrolo(1,2-α)indol-9-yl] acetate
1
(3ea).
Yellow solid; 92% yield; H NMR (300MHz,
(3ka).
White solid; 67% yield; 1H NMR (300MHz,
CDCl3) δ 7.67–7.57 (m, 4H), 7.54–7.35 (m, 6H), 7.29–
7.21 (m, 1H), 7.14–7.07 (m, 1H), 7.01 (d, J=8.5Hz, 1H),
6.61 (s, 1H), 4.47 (q, J=7.1Hz, 1H), 1.56 (d, J=7.2Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 142.9, 138.9, 138.2,
135.0, 132.4, 128.9, 128.6, 128.6, 128.4, 127.7, 127.1,
126.0, 125.6, 125.0, 118.6, 113.1, 112.5, 36.1, 17.1. ESI
HRMS exact mass calcd. For (C24H18ClN+H)+ requires
m/z 356. 1201, found m/z 356.1188.
CDCl3) δ 7.62 (ddd, J = 12.3, 5.4, 3.5 Hz, 4H), 7.56–7.36
(m, 6H), 7.32–7.20 (m, 1H), 7.18–7.01 (m, 3H), 6.59 (s,
1H), 4.96 (dd, J= 3.1, 9.9 Hz, 1H), 4.37–3.94 (m, 2H),
3.20 (dd, J = 16.4, 3.4 Hz, 1H), 2.48 (dd, J = 16.3,
10.1 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 172.1, 140.6, 138.7, 135.4, 135.0,
132.8, 132.6, 129.0, 129.0, 128.8, 128.6, 128.5, 128.4,
127.7, 127.6, 125.9, 125.7, 125.4, 123.5, 118.5, 113.0,
111.8, 60.7, 37.2, 36.5, 14.1. ESI HRMS exact mass
calcd. For (C27H23NO2 +H)+ requires m/z 394.1802,
found m/z 394.1798. ESI HRMS exact mass calcd. For
(C27H23NO2 + Na)+ requires m/z 416.1621, found m/z
416.1619.
7-Bromo-9-methyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole
(3fa).
Yellow solid; 74% yield; 1H NMR (300MHz,
CDCl3) δ 7.66–7.54 (m, 4H), 7.45 (ddd, J=19.4, 11.1,
4.6Hz, 6H), 7.24 (dt, J=5.9, 2.2Hz, 2H), 6.94 (d,
J=8.5Hz, 1H), 6.59 (s, 1H), 4.46 (q, J=7.1Hz, 1H), 1.54
(d, J=7.1Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 143.3,
139.4, 138.1, 135.0, 132.4, 130.1, 129.0, 128.7, 128.4,
127.9, 127.7, 126.0, 125.7, 118.6, 116.1, 113.2, 113.0,
36.0, 17.1 ESI HRMS exact mass calcd. For (C24H18BrN
+H)+ requires m/z 400.0695, found m/z 400.0668.
1,3,9-Triphenyl-9H-pyrrolo[1,2-α]indole (3la).
Yellow
1
solid; 99% yield; H NMR (300 MHz, CDCl3) δ 7.73 (dd,
J = 8.1, 1.2 Hz, 2H), 7.66–7.46 (m, 3H), 7.44 (dd, J= 6.8,
5.5 Hz, 2H), 7.38–7.28 (m, 4H), 7.28–7.19 (m, 4H), 7.19–
7.08 (m, 3H), 7.04 (td, J= 7.3, 1.3 Hz, 1H), 6.78 (s, 1H),
5.39 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 140.5, 140.3,
139.7, 136.5, 134.6, 132.7, 129.2, 129.1, 128.9, 128.4,
128.2, 127.8, 127.6, 127.4, 127.1, 125.9, 125.7, 125.3,
123.6, 119.3, 112.8, 111.8, 47.7. ESI HRMS exact mass
calcd. For (C29H21N +H)+ requires m/z 384.1747, found
m/z 384.1749.
6,9-Dimethyl-1,3-diphenyl-9H-pyrrolo[1,2-α]indole (3ga). White
soild; 50% yield; 1H NMR (300 MHz, CDCl3) δ 7.67–7.58
(m, 4H), 7.45 (dt, J = 15.2, 7.4 Hz, 5H), 7.30–7.17 (m, 2H),
6.92 (d, J = 8.3 Hz, 2H), 6.58 (s, 1H), 4.43 (q, J = 7.1 Hz,
1H), 2.27 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 140.5, 139.1, 138.2, 137.1, 135.4,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Efficient Synthesis of 9H-Pyrrolo[1,2-α]Indoles
Month 2016
9-Methyl-3-phenyl-1-(p-tolyl)-9H-pyrrolo[1,2-α]indole
9-Methyl-3-phenyl-1-(m-tolyl)-9H-pyrrolo[1,2-α]
indole (3ah).
Yellow solid; 91% yield; 1H NMR
1
(3ab).
Yellow solid; 91% yield; H NMR (300MHz,
CDCl3) δ 7.65 (d, J=7.7Hz, 2H), 7.58 (d, J=8.0Hz, 2H),
7.51 (t, J= 7.4 Hz, 2H), 7.43 (dd, J= 7.7, 5.0 Hz, 2H), 7.26
(d, J=7.9Hz, 2H), 7.20-7.07 (m, 3H), 6.61 (s, 1H), 4.49 (q,
J=7.1Hz, 1H), 2.43 (s, 3H), 1.59 (d, J=7.1Hz, 3H). 13C
NMR (75MHz, CDCl3) δ 141.1, 140.4, 138.3, 135.0,
132.9, 132.5, 129.3, 129.0, 128.4, 128.3, 127.4, 127.1,
125.9, 124.6, 123.2, 118.2, 112.8, 111.7, 36.0, 21.1, 17.2.
ESI HRMS exact mass calcd. For (C25H21N+H)+ requires
m/z 336.1747, found m/z 336.1740.
(300MHz, CDCl3) δ 7.70–7.58 (m, 2H), 7.54–7.37 (m,
6H), 7.33 (t, J=7.9Hz, 1H), 7.17–7.04 (m, 4H), 6.61 (s,
1H), 4.49 (q, J=7.1Hz, 1H), 2.45 (s, 3H), 1.59 (d,
J=7.1Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 141.1,
140.4, 138.6, 138.1, 135.3, 132.9, 129.0, 128.5, 128.3,
127.4, 127.1, 126.8, 126.2, 124.6, 123.3, 123.1, 118.3,
112.9, 111.8, 36.1, 21.6, 17.2. ESI HRMS exact mass
calcd. For (C25H21N+H)+ requires m/z 336.1747, found
m/z 336.1743.
1-(4-Methoxyphenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-α]in
dole (3ac). Yellow solid; 97% yield; 1H NMR (300MHz,
CDCl3) δ 7.61 (ddd, J = 4.9, 3.6, 1.5 Hz, 2H), 7.59–7.53
(m, 2H), 7.52–7.44 (m, 2H), 7.44–7.37 (m, 2H), 7.14–
7.04 (m, 3H), 7.03–6.92 (m, 2H), 6.54 (s, 1H), 4.44 (q,
J =7.1 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 157.6, 141.1, 140.4, 137.8,
132.9, 129.0, 128.3, 128.1, 127.4, 127.1, 124.6, 123.2,
118.0, 114.1, 112.7, 111.7, 55.3, 35.9, 17.2. ESI HRMS
exact mass calcd. For (C25H21NO + H)+ requires m/z
352.1696, found m/z 352.1682.
1-(4-Fluorophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-α]in
dole (3ad). Yellow solid; 94% yield; 1H NMR (300MHz,
CDCl3) δ 7.73–7.54 (m, 4H), 7.55–7.34 (m, 4H), 7.20–7.02
(m, 5H), 6.55 (s, 1H), 4.44 (q, J=7.1Hz, 1H), 1.56 (d,
J=7.1Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 161.0 (d, J
C-F =242.8Hz), 159.4, 140.9, 140.3, 138.2, 132.7, 131.6
(d, J C-F =3.2Hz), 129.0, 128.6, 128.4, 127.6, 127.4,
1-(3-Bromophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-α] in
dole (3ai). White solid; 90% yield; H NMR (300MHz,
1
CDCl3) δ 7.77 (t, J = 1.7 Hz, 1H), 7.60 (dt, J = 8.1, 1.9 Hz,
2H), 7.58–7.52 (m, 1H), 7.52–7.38 (m, 4H), 7.38–7.32
(m, 1H), 7.27 (dd, J= 8.7, 6.8 Hz, 1H), 7.18-7.03 (m,
3H), 6.55 (s, 1H), 4.46 (q, J= 7.1 Hz, 1H), 1.56 (d,
J = 7.2 Hz, 4H). 13C NMR (75 MHz, CDCl3) δ 140.9,
140.2, 139.0, 137.7, 132.6, 130.1, 129.0, 128.8, 128.4,
128.2, 127.6, 127.2, 124.7, 124.4, 123.6, 122.8, 116.8,
112.5, 111.9, 36.0, 17.1. ESI HRMS exact mass calcd.
For (C24H18BrN +H)+ requires m/z 400.0695, found m/z
400.0679.
1-(2,6-Dichlorophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-α]
indole (3aj).
Yellow solid; 99% yield; 1H NMR
(300 MHz, CDCl3) δ 7.68 (dd, J = 5.2, 3.3 Hz, 2H), 7.55–
7.32 (m, 6H), 7.24–7.04 (m, 4H), 6.41 (s, 1H), 4.20 (q,
J = 7.2 Hz, 1H), 1.30 (d, J = 7.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 141.1, 141.0, 140.9, 136.3, 135.6,
133.9, 132.8, 129.0, 128.3, 128.2, 128.0, 127.8, 127.6,
127.3, 127.1, 124.5, 123.2, 115.6, 112.8, 111.8, 36.2,
17.0. ESI HRMS exact mass calcd. For (C24H17Cl2N
+ H)+ requires m/z 390.0811, found m/z 390.0790.
127.3, 127.2, 124.6, 123.4, 117.4, 115.4 (d, J
C-
F =21.2Hz), 115.3, 112.7, 111.8, 35.9, 17.1. ESI HRMS
exact mass calcd. For (C24H18FN+H)+ requires m/z
340.1496, found m/z 340.1482.
1-(4-Chlorophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-α]in
Yellow solid; 91% yield; 1H NMR
9-Methyl-1-(naphthalen-1-yl)-3-phenyl-9H-pyrrolo
dole (3ae).
1
[1,2-α] indole (3ak). Yellow oil; 99% yield; H NMR
(300 MHz, CDCl3) δ 7.66–7.59 (m, 2H), 7.57 (d,
J = 8.5 Hz, 2H), 7.50 (dd, J = 11.3, 4.5 Hz,/ 2H), 7.46–
7.35 (m, 4H), 7.18–7.06 (m, 3H), 6.55 (s, 1H), 4.44 (q,
J = 7.1 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 140.9, 140.2, 138.7, 134.0, 132.6,
130.9, 129.0, 128.7, 128.4, 127.6, 127.2, 127.1, 124.6,
123.5, 117.1, 112.5, 111.8, 36.0, 17.1. ESI HRMS exact
mass calcd. For (C24H18ClN + H)+ requires m/z 356.
1201, found m/z 356. 1188.
(300MHz, CDCl3) δ 8.39–8.23 (m, 1H), 7.95 (dd, J=5.4,
3.9Hz, 1H), 7.86 (d, J=8.2Hz, 1H), 7.70 (ddd, J=8.2,
7.8, 1.2Hz, 3H), 7.55 (ddd, J=14.7, 9.9, 5.8Hz, 5H), 7.44
(dd, J= 10.4, 4.2Hz, 1H), 7.37 (d, J=6.6Hz, 1H), 7.23 (s,
1H), 7.21-7.07 (m, 2H), 6.60 (s, 1H), 4.31 (q, J=7.2Hz,
1H), 1.22 (d, J=7.2Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 141.1, 140.8, 140.3, 133.9, 133.8, 132.9, 132.0, 129.0,
128.4, 128.3, 128.0, 127.3, 127.1, 126.8, 126.6, 126.4,
125.7, 125.6, 125.5, 124.6, 123.2, 117.1, 116.1, 111.8,
35.9, 17.6. ESI HRMS exact mass calcd. For (C28H21N
+H)+ requires m/z 372.1747, found m/z 372.1706.
1-(4-Bromophenyl)-9-methyl-3-phenyl-9H-pyrrolo[1,2-α] in
dole (3af).
Yellow solid; 92% yield; 1H NMR
(300 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 1.3 Hz, 2H), 7.56–
7.37 (m, 8H), 7.19–7.03 (m, 3H), 6.55 (s, 1H), 4.43 (q,
J =7.1 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 140.9, 140.2, 138.7, 134.4, 132.6,
131.7, 129.0, 128.8, 128.4, 127.6, 127.5, 127.2, 124.6,
123.5, 118.9, 117.1, 112.5, 111.9, 36.0, 17.0. ESI HRMS
exact mass calcd. For (C24H18BrN + H)+ requires m/z
400.0695, found m/z 400.0677.
Methyl
boxylate (3al).
9-methyl-3-phenyl-9H-pyrrolo[1,2-α]indole-1-car
White solid; 91% yield; 1H NMR
(300 MHz, CDCl3) δ 7.55 (dt, J = 8.2, 2.1 Hz, 2H), 7.51–
7.38 (m, 4H), 7.19–7.02 (m, 3H), 6.71 (s, 1H), 4.29 (q,
J = 7.2 Hz, 1H), 3.89 (s, 3H), 1.71 (d, J= 7.3 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 165.1, 147.7, 141.1, 139.9,
132.0, 129.2, 128.5, 128.4, 128.0, 127.2, 124.8, 124.2,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Zhang, L. Liao, S. Yu, Y. Liao, X. Xu, W. Yuan, and X. Zhang
Vol 000
114.2, 112.3, 109.4, 51.0, 36.9, 17.3 ESI HRMS exact
mass calcd. For (C20H17NO2 + H)+ requires m/z 304.1330,
found m/z 304.1329.
(m, 2H), 7.46 (dd, J = 13.4, 5.8 Hz, 3H), 7.29 (d,
J = 7.4 Hz, 1H), 7.21–7.06 (m, 3H), 6.75 (s, 1H), 4.54 (q,
J = 7.1 Hz, 1H), 1.63 (d, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 141.1, 140.4, 135.4, 133.3, 132.6,
130.2, 128.6, 128.0, 127.9, 127.8, 127.5, 127.2, 127.2,
126.4, 126.1, 126.0, 125.5, 124.6, 123.4, 118.4, 113.2,
111.9, 36.1, 17.2. ESI HRMS exact mass calcd. For
(C28H21N + H)+ requires m/z 372.1747, found m/z
372.1735.
3-(4-Methoxyphenyl)-9-methyl-1-phenyl-9H-pyrrolo[1,2-α]
indole (3am). White solid; 89% yield; 1H NMR (300MHz,
CDCl3) δ 7.67 (dd, J=8.2, 1.1Hz, 2H), 7.48–7.37 (m, 4H),
7.31–7.21 (m, 2H), 7.21–7.08 (m, 4H), 6.99 (ddd, J=8.3,
2.6, 0.9Hz, 1H), 6.64 (s, 1H), 4.49 (q, J=7.1Hz, 1H), 3.89
(s, 3H), 1.59 (d, J=7.2Hz, 3H). 13C NMR (75MHz,
CDCl3) δ 159.5, 141.0, 140.3, 138.6, 135.4, 134.1, 129.3,
128.6, 128.4, 127.2, 126.0, 125.5, 124.6, 123.3, 121.5,
118.2, 114.2, 113.5, 112.8, 111.9, 55.3, 36.0, 17.2. ESI
HRMS exact mass calcd. For (C25H21NO+H)+ requires m/z
352.1696, found m/z 352.1688.
Acknowledgments. We are grateful for financial support from
the National Natural Science Foundation of China (21372218).
3-(4-Chlorophenyl)-9-methyl-1-phenyl-9H-pyrrolo[1,2-α]in
dole (3an). White solid; 99% yield; 1H NMR (300 MHz,
CDCl3) δ 7.67–7.59 (m, 2H), 7.59–7.51 (m, 2H), 7.51–
7.37 (m, 5H), 7.24 (t, J = 7.4 Hz, 1H), 7.19–7.02 (m,
3H), 6.58 (s, 1H), 4.47 (q, J = 7.1 Hz, 1H), 1.56 (d,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 141.1,
140.2, 139.0, 135.2, 133.4, 131.3, 130.2, 128.6, 128.6,
127.2, 126.0, 125.6, 124.8, 123.5, 118.4, 113.1, 111.6,
36.1, 17.2. ESI HRMS exact mass calcd. For (C24H18N
+ H)+ requires m/z 356.1201, found m/z 356.1210.
3-(3-Methoxyphenyl)-9-methyl-1-phenyl-9H-pyrrolo[1,2-α]
REFERENCES AND NOTES
[1] (a) Mazzola, V. J.; Bernady, K. F.; Franck, R. W. J Org Chem
1967, 32, 486; (b) Verboom, W.; Lammerink, B. H. M.; Egberink, R.
J. M.; Reinhoudt, D. N.; Harkema, S. J Org Chem 1985, 50, 3797; (c)
Fogassy, K.; Kovacs, K.; Keseru, G. M.; Toke, L.; Faigl, F. J Chem Soc
Perk T 2001, 1, 1039.
[2] For some recent references about synthesis of 9H-pyrrolo[1,2-
α]indoles, see:(a) Li, H.; Wang, Z.; Zu, L. RSC Adv 2015, 5, 60962;
(b) Liu, H. Q.; El-Salfiti, M.; Lautens, M. Angew Chem Int Edit
2012, 51, 9846; (c) Kobayashi, K.; Hashimoto, K.; Hashimoto, H.;
Kondo, H.; Konishi, H. Helv Chim Acta 2011, 94, 1277; (d)
Kobayashi, K.; Himei, Y.; Fukamachi, S.; Tanmatsu, M.; Morikawa,
O.; Konishi, H. Tetrahedron 2007, 63, 4356; (e) Hao, L.; Pan, Y. M.;
Wang, T.; Lin, M.; Chen, L.; Zhan, Z. P. Adv Synth Catal 2010, 352,
3215; (f) Aiello, F.; Garofalo, A.; Grande, F. Tetrahedron Lett 2010,
51, 6635; (g) Aiello, F.; Garofalo, A.; Grande, F. Tetrahedron 2010,
66, 274; (h) Wood, K.; Black, D. S.; Kumar, N. Tetrahedron Lett
2009, 50, 574; (i) Hwang, S. J.; Cho, S. H.; Chang, S. J Am Chem
Soc 2008, 130, 16158; (j) Ren, H. J.; Knochel, P. Angew Chem Int
Ed 2006, 45, 3462; (k) Feldman, K. S.; Iyer, M. R.; Hester, D. K.
Org Lett 2006, 8, 3113.
[3] (a) Cheng, H. G.; Lu, L. Q.; Wang, T.; Yang, Q. Q.; Liu, X.
P.; Li, Y.; Deng, Q. H.; Chen, J. R.; Xiao, W. J. Angew Chem Int Ed
2013, 52, 3250; (b) Angelovski, G.; Keranen, M. D.; Linnepe, P.;
Grudzielanek, S.; Eilbrachta, P. Adv Synth Catal 2006, 348, 1193; (c)
Du, Y.; Huang, H. Y.; Liu, H.; Ruan, Y. P.; Huang, P. Q. Synlett
2011 565; (d) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.; Romo,
D. J Org Chem 2011, 76, 2.
indole (3ao).
White solid; 88% yield; 1H NMR
(300 MHz, CDCl3) δ 7.67 (dd, J = 8.2, 1.1 Hz, 2H),
7.59–7.50 (m, 2H), 7.49–7.37 (m, 3H), 7.30–7.21 (m,
1H), 7.19–7.08 (m, 3H), 7.08–7.02 (m, 2H), 6.57 (s,
1H), 4.49 (q, J = 7.1 Hz, 1H), 3.92 (s, 3H), 1.59 (d,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 159.2,
141.0, 140.4, 137.9, 135.5, 130.4, 128.6, 128.2, 127.1,
125.9, 125.4, 125.3, 124.6, 123.2, 118.0, 113.8, 112.1,
111.6, 55.3, 36.0, 17.2. ESI HRMS exact mass calcd.
For (C25H21NO + H)+ requires m/z 352.1696, found m/z
352.1698.
9-Methyl-3-(naphthalen-2-yl)-1-phenyl-9H-pyrrolo[1,2-α] in
1
[4] (a) Espinosa, M.; Blay, G.; Cardona, L.; Pedro, J. R. Chem Eur J
2013, 19, 14861; (b) Stark, D. G.; Morrill, L. C.; Yeh, P. P.; Slawin, A.
M. Z.; Riordan, T. J. C. O.; Smith, A. D. Angew Chem Int Ed 2013, 52,
11642.
dole (3ap). Yellow oil; 99% yield; H NMR (300MHz,
CDCl3) δ 8.12 (s, 1H), 8.03–7.89 (m, 3H), 7.79 (dd,
J =8.4, 1.5Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.63–7.53
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet