An efficient iron-promoted synthesis of 6H-indolo[2,3- b] quinolines and neocryptolepine derivatives

Article abstract of DOI:10.1039/c6ob00469e

A facile and practical method for the preparation of 6H-indolo[2,3-b]quinolines and neocryptolepines was developed under the promotion of the easily available ferric trichloride, affording the desired products with moderate to good yields.

Full text of DOI:10.1039/c6ob00469e

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DOI: 10.1039/C6OB00469E
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An efficient iron-promoted synthesis of 6H-indolo[2,3-
b]quinolines and neocryptolepine derivatives
Zicong Yan,a Changfeng Wan*,b Jianyong Wanb and Zhiyong Wang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A facile and practical method for the preparation of 6H-indolo[2,3- emerging and active.13 In our group, great effort has been devoted
b]quinolines and neocryptolepines was developed under the to the Friedel-Crafts reaction,14 iron catalysis,15 and the synthesis of
promotion of the easily available ferric trichloride, affording the N-heterocyclic compounds.16 Herein, we report a simple and
desired products with moderate to good yields.
efficient iron-mediated synthesis of indolo[2,3-b]quinolines and
neocryptolepine derivatives.
Indoloquinolines alkaloids are receiving considerable interest due to
their striking biological activities.1 For example, 6H-indolo[2,3-
b]quinoline (norcryptotackieine) is a natural product isolated from
the leaves of Justicia betonica2 and shares many biological
properties with 5-methyl-5H-indolo[2,3-b]quinoline.3 The latter is
isolated from Cryptolepis sanguinolenta4-5 and usually used in
traditional medicine against a variety of disorders.6 5H-indolo[2,3-
b]quinolines and their analogues act as DNA topoisomerase II
inhibitors.7 Furthermore, these scaffolds witnessed the
development of the design and synthesis for modern drugs.8 Over
the past decades, several synthetic methods were developed to
prepare these polycyclic aromatic rings.3 In 2011, for instance,
Seidel group reported an extremely facile method for the synthesis
of neocryptolepine derivatives.9 Besides, other syntheses for the
similar scaffolds were also developed and the neocryptolepines
could be obtained easily by virtue of these scaffolds.10 Subsequently,
Parvatkar et al. also developed a microwave-assisted reductive
cyclization to prepare 6H-indolo[2,3-b]quinoline alkaloids and the
other two heterocyclic alkaloids in one step.11 However, some of
the synthetic routes were tedious, eco-unfriendly, or low atom
efficiency. Therefore, developing more efficient and practical
protocols for the preparation of indolo-fused quinolines is still
highly desirable.
Table 1. Optimization of reaction conditions a
Ph
N
Ph
OH
NH2
metal salt
+
solvent
temperature
2h
N
N
1a
2a
3a
Entry
1c
Metal Salt
FeCl3
Solvent
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
Temp. (oC)
80
yieldb (%)
16
2d
3e
4
FeCl3
FeCl3
FeCl3
80
37
80
47
80
53
5
-
80
0
6
FeCl2
80
0
7
FeCl3•6H2O
80
32
8
9
Fe(ClO4)3•6H2O
Cu(OAc)2•H2O
Fe2(SO4)3
FeCl3
80
80
Trace
0
DMA
DMA
10
11
12
13
14
15
16
17
18
80
80
Trace
23
CH3CN
ClCH2CH2Cl
DMF
Toluene
MeOH
MeOH
MeOH
MeOH
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
80
45
80
49
80
80
Trace
83
As an abundant, economical and environmentally benign
element, iron has shown increasing promise in many organic
syntheses.12 Recently, iron catalyzed or mediated processes are still
65
58
r. t.
90
Trace
82
a Reaction conditions: 1a (1.5 equiv, 0.3 mmol), 2a (1.0 equiv, 0.2 mmol), metal
salt (2.5 equiv) in solvent (0.5 mL). b Isolated yield. c 0.25 equiv of FeCl3. d 1 equiv
of FeCl3. e 2.0 equiv of FeCl3.
a.Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory
of Soft Matter Chemistry and Department of Chemistry & Collaborative
Innovation Center of Suzhou Nano Science and Technology, University of Science
and Technology of China, Hefei, 230026, P. R. China. Fax: (+86) 551-6360-3185; E-
mail: zwang3@ustc.edu.cn
b.College of Chemistry and Chemical Engineering, Jiangxi Normal University,
330022,Nanchang, P. R. China. E-mail: wanfeng@jxnu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 2 The reaction of 2-amino-α-phenylbenzenemethanol with different indoles
entry 18). Therefore, the optimal reaction condition was selected as
listed in entry 15.
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DOI: 10.1039/C6OB00469E
With the optimized conditions in hand, we explored the scope of
different substrates. Firstly, several substituted indoles were
examined, and the results were listed in Table 2. Generally, both N-
substituted and N-unsubstituted indoles could be converted to the
corresponding products in moderate to good yields (Table 2, 3a-3h).
The electron-withdrawing groups seemed to less efficient than the
electron-donating groups in this reaction (Table 2, 3g-3h). For
example, 5-bromo-1H-indole could only afford the product with
34% yield (Table 2, 3g) while 4-methyl-1H-indole could be a good
substrate to give the product with a high yield of 81% (Table 2, 3d).
Moreover, no reaction was observed in the case of the 1-tosyl
indole (Table 2, 3i), perhaps due to the strong electron-withdrawing
effect. Subsequently, the reactions of 1-methylindole with different
(2-aminophenyl)methanol derivatives were also investigated (Table
3, 3j-3r). Regardless of that R3 was alkyl or aryl groups, the
corresponding products could be obtained in moderate to good
yields (Table 3, 3j-3q). It was noticed that allyl group was tolerated
in the reaction (Table 3, 3o). As for the 2-aminobenzyl alcohol,
which had no any substitution on the benzyl position of the 2-
aminobenzyl alcohol, the corresponding reaction yield was
decreased to 40%. It was possibly due to the lack of electron-rich
substituent R3 (Table 3, 3j). And these different R4 substituent
groups implied that electron-rich substituent favored the reaction.
No reaction occurred when the R4 was nitro-group (Table 3, 3r).
OH
R2
R2
FeCl3
+
N
R1
MeOH, 80oC
2h
NH2
N
R1
N
1a
2a - 2i
3a - 3i
N
H
N
N
N
N
N
Bn
3a 83%
3b 52%
3c 75%
O
F
N
N
H
N
N
N
H
N
H
3d 81%
3e 60%
3f 72%
Br
COOMe
N
N
N
N
H
N
H
N
Tos
3g 34%
3h 63%
3i 0
Table 3 The reaction of various (2-aminophenyl)methanol derivatives with 1-
a Reaction conditions: 1a (1.5 equiv, 0.3 mmol), 2 (1.0 equiv, 0.2 mmol), FeCl3 (2.5
equiv) in methanol (0.5 mL).b Isolated yield.
methylindole a
R3
OH
R3
FeCl3
At
the
outset
of
our
investigations,
2-amino-α-
R4
R4
+
MeOH, 80oC
N
N
phenylbenzenemethanol (1a) and 1-methylindole (2a) were chosen
as model substrates to investigate the reaction. The results were
summarized in Table 1. Firstly, the reaction of 1.5 equiv of 1a and 1
equiv of 2a offered 16% yield of the expected product 6-Methyl-11-
phenyl-6H-indolo[2,3-b]quinoline (3a) in the presence of 0.25 equiv
NH2
1b - 1j
N
2h
2a
3j - 3r
F
o
FeCl3 in DMA at 80 C for 2 h (Table 1, entry 1). It was found that
N
N
the loading of metal salt had an important influence on the reaction
(Table 1, entries 2-4). When 2.5 equiv of FeCl3 was added in the
reaction, 53% yield of the product was obtained (Table 1, entry 4).
When the metal salt was raplaced with FeCl2 or absent, we could
not get the desired products (Table 1, entry 5 and 6). It indicated
that FeCl3 played a role of oxidant in the process of reaction other
than the function of catalysis. Then the different Lewis acids were
screened, and we found that FeCl3 was the best (Table 1, entries 7-
10). Subsequently, different solvents were optimized. The result
illustrated that methanol offered the product in 83% yield, while
CH3CN, DMF and ClCH2CH2Cl provided relatively low yields (Table 1,
entries 11-15). Thus methanol was the best solvent. On the other
hand, the reaction temperature had a great influence on the
reaction. With the decrease of the temperature, the reaction yield
was reduced (Table 1, entry 16). When the reaction was carried out
at room temperature, only trace amount of product was isolated
(Table 1, entry 17). Nevertheless, when the reaction temperature
was beyond 80°C, the reaction yield was slightly decreased (Table 1,
N
N
N
N
3j 40%
3k 74%
3l 58%
5
)
1
H2C
(
N
N
N
N
N
N
3m 61%
3n 33%
3o 80%
Cl
O2N
N
N
N
N
N
N
3p 65%
3q 92%
3r 0
a Reaction conditions: 1 (1.5 equiv, 0.3 mmol), 2a (1.0 equiv, 0.2 mmol), FeCl3 (2.5
equiv) in methanol (0.5 mL). b Isolated yield.
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Ph
N
Table 4 The synthesis of neocryptolepine derivatives a
Ph
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DOI: 10.1039/C6OB00469E
OH
R2
N
OH
NH2
H
FeCl3
R2
+
the desired product 3a
1a
FeCl3
N
MeOH, 80oC
R5
H
N
N
+
N
H
-
2h
oxidation of FeCl3
Ph
H
R5
1k - 1l
2c - 2g, 2j
4a - 4h
Ph
N
H
NH2
O
A
N
N
H2
Ph
+
H
C
N
N
N
N
N
NH+
N
NH2
B
4a 58%
4b 25%
4c 77%
Scheme 2 Postulated reaction pathway for the construction of indolo[2,3-b]quinolines.
Br
CN
F
To get an insight into the mechanism of this process, several
controlled experiments were conducted. First, only 2-amino-α-
phenylbenzenemethanol (1a) was employed under the standard
conditions, and no 2-aminobenzophenone (1aa) was detected
(Scheme 1a). Subsequently, using 2-aminobenzophenone (1aa) and
1-methylindole (2a) as the reagent under the standard conditions
had no reaction, suggesting that 1aa might not be an intermediate
in this reaction (Scheme 1b). Furthermore, 3-(1,1-Diphenylmethyl)-
1-methyl-1H-indole (3ab) could be isolated from the reaction of
diphenylmethanol (1ab) with 2a in a 90% yield (Scheme 1c). This
indicates that there may be a Friedel-Crafts progress during this
reaction.
N
N
N
N
N
N
4d 67%
4e 48%
4f trace
N
N
4g 45%
a Reaction conditions: 1 (1.5 equiv, 0.3 mmol), 2 (1.0 equiv, 0.2 mmol), FeCl3 (2.5
equiv) in methanol (0.5 mL). b Isolated yield.
Based on the experimental results and previous literature9, 15(a), a
possible reaction pathway is proposed as shown in Scheme 2. Firstly,
Knowing the importance of the neocryptolepines as biologically
active molecules, α-methyl-2-(methylamino)-benzenemethanol was
employed as the substrate to access the relevant product. To our
FeCl3 as
a
strong Lewis acid may activate 2-amino-α-
phenylbenzenemethanol (1a) to generate intermediate A, which
undergoes the Friedel-Crafts reaction to generate intermediate B.
Then intramolecular cyclization is proceeded to yield intermediate C,
C subsequently undergoes a deprotonation and oxidation by FeCl3
to give the desired product 3a17.
delight,
5,11-dimethyl-5H-indolo[2,3-b]quinoline
(11-methyl
neocryptolepine, 4a) and its derivatives can be obtained in one-step
with moderate yields (Table 4, 4a - 4e). The yield was decreased a
lot while there was a strong electron-withdrawing group (Table 4,
4f). α-Phenyl-2-(methylamino)-benzenemethanol was also chosen
as the substrates to access the relevant product in 45% yield (Table
4, 4g). Although the yields needed to be optimized further, this
provided a viable and facile access to neocryptolepine derivatives.
In summary, an efficient and simple protocol for the synthesis of
indolo[2,3-b]quinolines and neocryptolepines by reactions of
aminophenyl alcohols and indoles was described under the
promotion of iron trichloride. This procedure features mild reaction
conditions, operational simplicity, and environmentally friendly
reagent. Moreover, 11-methyl neocryptolepine and its derivatives
were synthesized through this procedure. Further applications and
detailed mechannism of this reaction are in progress in our
laboratory.
OH
O
standard conditions
(a)
NH2
NH2
1a
1aa, 0 %
O
standard conditions
+
(b)
N
We are grateful to the National Natural Science Foundation of
China (21272222, 91213303, 21172205, J1030412, 21402068).
NH2
N
N
1aa
2a
3a, 0 %
OH
Notes and references
standard conditions
+
(c)
N
1
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N
,
1ab
2a
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Scheme 1 Controlled experiments for mechanistic investigations
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