Practical Synthesis of Chromeno[2,3-b]indole Skeleton via an Aldehyde Group Insertion/Aromatization Strategy

Article abstract of DOI:10.1002/asia.201601681

The synthesis of chromeno[2,3-b]indole from simple starting materials remains a demanding process. Herein, 2-bromoindole undergoes nucleophilic attack from salicylaldehyde, followed by intramolecular insertion of an aldehyde group and aromatization to generate the desired chromeno[2,3-b]indoles. Moreover, various functional groups were tolerated and a gram-scale synthesis of the product could be achieved under the optimized condition.

Full text of DOI:10.1002/asia.201601681

DOI: 10.1002/asia.201601681
Communication
Indole Synthesis
Practical Synthesis of Chromeno[2,3-b]indole Skeleton via an
Aldehyde Group Insertion/Aromatization Strategy
Jianming Liu,* Na Liu, Yuanyuan Yue, Yanyan Wang, Kaige Chen, Jia Zhang, Shufang Zhao,
and Kelei Zhuo*[a]
Abstract: The synthesis of chromeno[2,3-b]indole from
simple starting materials remains a demanding process.
Herein, 2-bromoindole undergoes nucleophilic attack from
salicylaldehyde, followed by intramolecular insertion of an
aldehyde group and aromatization to generate the de-
sired chromeno[2,3-b]indoles. Moreover, various functional
groups were tolerated and a gram-scale synthesis of the
product could be achieved under the optimized condi-
tion.
Chromeno[2,3-b]indoles are privileged motifs of both natural
products and drug molecules.[1] Moreover, chromeno[2,3-
b]indole derivatives can also have biological activity, as shown
by antimalarial and anticancer agents (Figure 1).[2,3] Despite the
Scheme 1. Classical and present approaches for the synthesis of chrome-
no[2,3-b]indoles.
great importance of chromeno[2,3-b]indole compounds, their
synthesis lacked simple, mild and direct approaches. So far, the
traditional route for the synthesis of chromeno[2,3-b]indoles
was based on multistep processes (Scheme 1).[4] Several steps
tion) to afford the desired products. This process could be ach-
were required (cyclization, Claisen condensation and chlorina-
ieved by using stoichiometric reagents under harsh conditions.
These features restricted the development of chromeno[2,3-
b]indole derivatives bearing various substituent groups. The
construction of chromeno[2,3-b]indoles remains relatively un-
exploited through cascade reactions from available starting
materials.
Aiming for general and straightforward methods, we identi-
fied a plausible and efficient route to synthesize chromeno[2,3-
b]indoles (Scheme 1). In this envisioned route, 2-bromoin-
dole[5–7] undergoes nucleophilic attack from salicylaldehyde[8–12]
to form a CÀO bond.[13–16] Subsequently, the resulting inter-
mediate was transformed into the desired product by an intra-
molecular insertion of the aldehyde group, bromide elimina-
tion and aromatization. In this process, we aimed to solve the
limitation of inserting an aldehyde group through an intramo-
lecular nucleophilic attack. This work not only represented
a new strategy to provide a conceptually alternative route, but
could also be practically favored both in terms of reagent ac-
cessibility and substrate scope. Herein, we described a cascade
reaction of salicylaldehyde and 2-bromoindole for a direct
preparation of chromeno[2,3-b]indoles.
Figure 1. Biologically active chromeno[2,3-b]indoles.
[a] Dr. J. Liu, N. Liu, Dr. Y. Yue, Y. Wang, K. Chen, J. Zhang, S. Zhao, Dr. K. Zhuo
Collaborative Innovation Center of Henan Province for Green Manufactur-
ing of Fine Chemicals
Key Laboratory of Green Chemical Media and Reactions, Ministry of Educa-
tion
Henan Key Laboratory of Boron Chemistry and Advanced Energy Materials
School of Chemistry and Chemical Engineering
Henan Normal University
Xinxiang, Henan 453007 (P. R. China)
E-mail: jmliu@htu.cn
Screening was performed using commercially available sali-
cylaldehyde (1a) and 2-bromoindole (2a) in the presence of
10 mol% Pd2dba3 and 30 mol% Xantphos, providing the de-
sired chromeno[2,3-b]indole (3a) in 61% yield (Table 1,
klzhuo@263.net
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/asia.201601681.
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Table 1. Optimization of the reaction conditions.[a]
Entry Cat. [mol%] Ligand [mol%] Base
Solvent
Yield [%][b]
1
Pd2dba3(10)
Pd2dba3(10)
Pd2dba3(10)
Pd2dba3 (5.0) Xantphos(15)
Pd2dba3 (5.0) Xantphos(15)
Pd2dba3 (5.0) Xantphos(15)
Pd2dba3 (5.0) Xantphos(15)
Pd2dba3 (5.0) PPh3(15)
Xantphos(30)
Xantphos(30)
Xantphos(30)
K2CO3 1,4-dioxane 61
2c
3d
4
K2CO3 1,4-dioxane 56
K2CO3 1,4-dioxane trace
K2CO3 1,4-dioxane 90
5
6
7
8
K2CO3 Toluene
K2CO3 DMSO
48
40
Cs2CO3 1,4-dioxane 54
K2CO3 1,4-dioxane 55
K2CO3 1,4-dioxane 80
K2CO3 1,4-dioxane 52
K2CO3 1,4-dioxane 62
K2CO3 1,4-dioxane 81
9
Pd2dba3 (5.0) dppf(15)
Pd2dba3 (5.0) dppb(15)
Pd(OAc)2(10) Xantphos(15)
10
11
12
PdCl2(10)
Xantphos(15)
Reaction conditions: [a] 1a (0.30 mmol), 2a (0.45 mmol), base (3.0 equiv),
and ligand in solvent (2.0 mL) at 1008C for 24 h under N2. [b] Isolated
yield. [c] At 808C for 24 h under N2. [d] At 1208C for 24 h under N2.
entry 1). The structure of 3a was unambiguously confirmed by
single-crystal XRD analysis (Figure 2).[17] To improve the yield of
the desired product, we further screened different reaction
conditions. No positive results were obtained by changing re-
action temperature (Table 1, entries 2 and 3). To our delight,
the target product 3a was obtained in 90% yield with a de-
Scheme 2. Substrate scope of the methodology. [a] 1 (0.30 mmol), 2
(0.45 mmol), Pd2dba3 (5.0 mol%), Xantphos (15 mol%), and K2CO3
(0.90 mmol) in 1,4-dioxane (2.0 mL) at 1008C for 24 h under N2. [b] Isolated
yield.
Figure 2. X-ray crystal structure of 3a.
product in 48% and 54% yields, respectively (Scheme 2, 3g
and 3h). Disubstituted substrates gave the desired product in
good yield (Scheme 2, 3i). To further exemplify and challenge
the catalytic potential of Pd catalyst, a series of 2-bromoindole
derivatives were chosen as reaction partners. Different elec-
tron-donating (OMe) and electron-withdrawing (Cl, F) groups
on 2-bromoindoles were compatible with the reaction condi-
tion to provide the chromeno[2,3-b]indole derivatives in mod-
erate to good yields (Scheme 2, 3j–3n). Considering that most
bioactive chromeno[2,3-b]indoles contain the fluoride group,
a variety of salicylaldehydes and 2-bromo-5-fluoro-1H-indole
were investigated. The reactions generated the target products
in 40%–89% yields (Scheme 2, 3o–3v). When 2-hydroxyaceto-
phenone was tested instead of salicylaldehyde, no desired
product was detected. The reaction suggested that the ketone
group did not undergo an intramolecular insertion.
creased amount of Pd2dba3 and Xantphos (Table 1, entry 4).
Different solvents and bases were also examined, and the best
results showed were obtained in 1, 4-dioxane using K2CO3 as
a base (Table 1, entries 4–7). To improve the properties and sta-
bility of the palladium catalyst, different P ligands were also
evaluated for this transformation. The results demonstrated
that Xantphos provided the best reactivity (Table 1, entries 8–
10). In addition, Pd(OAc)2 and PdCl2 exhibited lower catalytic
activities than Pd2dba3 to form the desired products (Table 1,
entries 11 and 12).
With the optimized reaction conditions in hand, we subse-
quently turned our attention to explore the substrate scope.
Salicylaldehyde derivatives bearing electron-donating and elec-
tron-withdrawing groups at the 4-position of the aromatic ring
were examined, affording the corresponding products in 48–
90% yields (Scheme 2, 3a–3 f). Substituents in the 5- and 6-po-
sitions of salicylaldehydes were also tolerated, generating the
Notably, this transformation could be smoothly achieved on
gram scale, and the desired product 3a was isolated in 63%
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coupling. Meanwhile, the desired chromeno[2,3-b]indole was
obtained in 80% yield in the presence of Fe(OTf)3 (Scheme 4 f).
This result suggested that PdIILn would act as a Lewis acid and
coordinate with the aldehyde group to form the desired inter-
mediate. Finally, deuterated salicylaldehyde (62% D content)
was examined, and the same deuterium distribution was ob-
served in the final product (Scheme 4g). The result demon-
strated that the hydrogen atom from the aldehyde was not
eliminated in the reaction and the hydrogen atom from the 3-
position of 2-bromoindole underwent elimination.
Scheme 3. Gram-scale experiment.
yield by using 5.0 mol% Pd2dba3 (Scheme 3). This result dem-
onstrated that the domino reaction was scalable.
To investigate the mechanism of these transformations, con-
trol experiments were conducted (Scheme 4). First, the domino
reaction of salicylaldehyde and indole did not generate the de-
sired product. This result indicated that the insertion of alde-
hyde did not occur in the absence of 2-bromoindole
(Scheme 4a). Furthermore, benzaldehyde and phenol reacted
with 2-bromoindole and no desired products were obtained
(Scheme 4b and 4c). This suggested that the aldehyde and
the hydroxyl group were not only coupled with 2-bromoin-
dole, but also possessed a directing role. Next, we carried out
control experiments of salicyladehyde with 2-bromo-3-methyl-
1H-indole and bromobenzene under the optimized conditions
and no products were obtained (Scheme 4d and 4e). These re-
sults showed that the first step did not undergo CÀO cross
Based on these experiments and previous reports,[18] a plausi-
ble mechanism for this cascade sequence is proposed in
Figure 3. First, salicylaldehyde reacts with the base to generate
Figure 3. Possible mechanism.
intermediate I, which attacks the 2-position of 2-bromoindole
to form intermediate II. The carbonyl group of intermediate II
was activated by PdIILn to form intermediate III, which under-
goes cyclization to form intermediate IV and to release PdIILn.
Elimination of HBr would form intermediate V, which can re-
lease the product 3a upon dehydration and aromatization.
In summary, we designed a simple and efficient route to
synthesize chromeno[2,3-b]indoles from 2-bromoindole and
salicylaldehyde via a cascade reaction. 2-Bromoindole plays
a decisive role to control the chemoselectivity, and a cascade
reaction comprising of a nucleophilic attack and an intramolec-
ular insertion of an aldehyde group leads to the desired highly
functionalized chromeno[2,3-b]indole derivatives. This ap-
proach could open the pathway for other bromoindoles and
salicylaldehydes in the synthesis of heterocyclic compounds.
Experimental Section
A mixture of 2-bromoindole derivative (0.45 mmol), salicylaldehyde
(0.30 mmol), Pd2dba3 (5.0 mol%), Xantphos (15 mol%), K2CO3
(0.90 mmol), 1,4-dioxane (2.0 mL) was stirred at 1008C under N2 for
24 h. After cooling to room temperature, the residues were con-
centrated in vacuo. Then, the residues were subjected to chroma-
tography on silica gel with petroleum ether/ethyl acetate (10:1) as
an eluent to afford the desired product.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21573057, 21205029), China
Scheme 4. Control experiments.
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Rodrꢁguez-Solla, A. M. S. Silva, R. Llavona, F. A. A. Paz, J. Org. Chem.
2013, 78, 12831–12836.
Postdoctoral Science Foundation (2014M552005 and
2015T80770), and the Program for Innovative Research Team in
University of Henan Province (17IRTSTHN001). The Education
Department of Henan Province (14B150020) is also gratefully
acknowledged.
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Keywords: aldehydes · cyclization · heterocycles · indoles ·
palladium
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Revised: January 2, 2017
Final Article published: && &&, 0000
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COMMUNICATION
Indole Synthesis
Jianming Liu,* Na Liu, Yuanyuan Yue,
Yanyan Wang, Kaige Chen, Jia Zhang,
Shufang Zhao, Kelei Zhuo*
&& – &&
Practical Synthesis of Chromeno[2,3-
b]indole Skeleton via an Aldehyde
Group Insertion/Aromatization
Strategy
One, [2,3-b]indoles: The synthesis of
chromeno[2,3-b]indoles from simple
starting materials is a demanding pro-
cess. Herein, 2-bromoindole undergoes
nucleophilic attack from salicylaldehyde,
followed by intramolecular insertion of
an aldehyde group and aromatization
to generate the desired chromeno[2,3-
b]indoles. Moreover, various functional
groups were tolerated and a gram-scale
synthesis was possible.
Chem. Asian J. 2017, 00, 0 – 0
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These are not the final page numbers! ÞÞ