Efficient synthesis of pyrano[4,3-b]indol-1(5H)-ones from CO2 and alkynyl indoles promoted by a protic ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2020.152449

An efficient method was developed for the synthesis of pyrano[4,3-b]indol-1(5H)-ones, which uses a protic ionic liquid [HTBD⁺][TFE^–] as both the solvent and reaction promoter. The reactions could be efficiently carried out at atmosph

Full text of DOI:10.1016/j.tetlet.2020.152449

Tetrahedron Letters 61 (2020) 152449
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of pyrano[4,3-b]indol-1(5H)-ones from CO2
and alkynyl indoles promoted by a protic ionic liquid
1
1
⇑
Chun Li , Jian Jiang , Linlin Li, Ling Zhang, Qian Chen, Mengna Wang, Changli Fu, Lin Zhang
School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 550004, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method was developed for the synthesis of pyrano[4,3-b]indol-1(5H)-ones, which uses a pro-
tic ionic liquid [HTBD+][TFE–] as both the solvent and reaction promoter. The reactions could be effi-
ciently carried out at atmospheric pressures of CO2, and various pyrano[4,3-b]indol-1(5H)-ones bearing
versatile functionalities were obtained in moderate to high yields (71–99%).
Received 7 August 2020
Revised 4 September 2020
Accepted 9 September 2020
Available online 12 September 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Carbon dioxide
Protic ionic liquid
Pyrano[4,3-b]indol-1(5H)-ones
Green chemistry
Introduction
media for the synthesis of quinazoline-2,4(1H,3H)-diones utilising
CO2 under mild reaction conditions [12]. In addition, in our previ-
Functionalized indoles are useful structural motifs in hetero-
cyclic chemistry [1] which have drawn significant attention due
to their various biological and pharmaceutical activities [2]. In par-
ticular, pyranoindolones have gained increased interest due to the
importance of the pyranone core which is widely present in phar-
maceutical intermediates and natural products [3]. For example,
pyrano[4,3-b]indol-1(5H)-ones were reported as tumor cell growth
inhibitors against human cervix adenocarcinoma (HeLa) [4]. Pyr-
ano[4,3-b]indol-1(5H)-ones have also been utilized for the synthe-
Table 1
Reaction of 1a with CO2 using different PIL systems.a
O
O
O
CF3
Ph
N
ionic liquid
+
Ph
CO2
N
H
N
N
H
N
H
2a
H
[HTBD ][TFE ]
1a
sis of
c-carbolinone alkaloids with serotonin 5-HT3 receptor
b
Entry
PIL/Solvent
Time [h]
Yield 2a [%]
antagonist properties [5]. Typically, pyrano[4,3-b]indol-1(5H)-ones
are synthesized via metal-catalyzed methods, using AuCl3 [6],
[(Cp*RhCl2)2]/Cu(OAc)2 [7], Pd(OAc)2/Ag2O [8], and CuI [9]. How-
ever, these synthetic routes possess a negative environmental
impact. Recently, the organocatalyzed CO2 trapping of alkynyl
indoles was reported as an atom-economical and green route to
synthesise pyrano[4,3-b]indol-1(5H)-ones [10], since CO2 is an
abundant, non-toxic, inexpensive and renewable C1 resource
[11]. Therefore, it is of interest to develop highly-efficient routes
to transform CO2 into pyrano[4,3-b]indol-1(5H)-ones using simple
systems.
1
2
3
4
5
6
7
8
9
10
11
12
–
–
–
[HDBU+][TFAÀ]
[HDBU+][AcÀ]
[HDBU+][TFEÀ]
[HDBN+][TFEÀ]
[HTBD+][TFEÀ]
[HTBD+][TFEÀ]
[HTBD+][TFEÀ]
[HTBD+][TFEÀ]
[HTBD+][TFEÀ]
[HTBD+][TFEÀ]
[HTBD+][TFEÀ]
18
18
18
18
18
7
6
7
7
7
15
28
64
68
96
95
83
99
58
50
–
c
d
e
f
7
a
b
c
d
e
f
Protic ionic liquids (PILs) formed by an equimolar combination
of a Brønsted base and Brønsted acid can be employed as reaction
Reagents and conditions: 1a (1 mmol), PIL (6 mmol), CO2 (balloon), 80 °C.
Isolated yield.
100 °C.
[HTBD+][TFEÀ] (4 mmol).
[HTBD+][TFEÀ] (2 mmol).
Room temperature.
⇑
Corresponding author.
E-mail address: gmulinzhang@163.com (L. Zhang).
These authors contributed equally to this work.
1
https://doi.org/10.1016/j.tetlet.2020.152449
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

C. Li et al.
Tetrahedron Letters 61 (2020) 152449
Table 2
Scope of the aromatic 2-alkynyl indoles.a
O
O
R1
[HTBD ][TFE ]
100 °C, 7 h
R1
R2
CO2
R2
+
N
H
N
H
b
b
Entry
1
Substrate
Product
Yield [%]
99
Entry
2
Substrate
Product
Yield [%]
84
O
O
O
O
Ph
N
H
N
H
1b
1d
1f
1a
1c
N
N
2b
2a
H
H
3
5
96
91
4
6
90
72
O
O
O
O
O
CN
O
F
CN
Cl
N
H
N
H
N
H
N
H
O
2d
2c
O
F
O
Cl
O
N
H
N
H
1e
1g
N
H
N
H
2e
2f
7
86
87
97
8
72
86
83
O
F
F
O
O
Br
Br
O
N
H
N
H
1h
N
H
2g
N
H
2h
9
10
12
Cl
F
Cl
F
O
O
O
O
N
H
N
H
1j
1l
1i
N
H
N
H
O
2i
2j
11
O
O
O
O
O
N
H
N
N
N
H
N
H
1k
N
H
2l
2k
13
15
17
19
21
93
94
71
89
71
14
16
18
20
93
91
75
71
O
O
O
O
N
H
S
N
H
1n
S
1m
N
H
N
H
O
2n
2m
F
O
O
O
F
N
H
N
H
1o
1p
N
N
H
2p
2o
H
O
Cl
O
Br
O
O
Br
Cl
N
H
N
H
1q
1r
1t
N
N
H
O
2r
2q
H
O
HO
O
O
O
O
O
HO
N
N
1s
H
H
N
H
O
N
2t
2s
H
O
O
O
O
O
O
N
1u
H
N
2u
H
a
Reagents and conditions: substrate 1 (1 mmol), [HTBD+][TFEÀ] (6 mmol), CO2 (balloon), 100 °C, 7 h.
Isolated yield.
b
ous research regarding the preparation of various heterocycle-
fused pyrimidine-2,4(1H,3H)-diones, PILs displayed superior
performance for CO2 capture and conversion under solvent-free
conditions [13]. Thus, we postulated that pyrano[4,3-b]indol-1
(5H)-ones could be obtained using CO2 as a C1 resource under
PILs-promoted conditions.
Results and discussion
Initially, five PILs were synthesized according to literature pro-
cedures: [12] [HDBU+][TFEÀ], [HDBN+][TFEÀ], [HTBD+][TFEÀ],
[HDBU+][TFAÀ], and [HDBU+][AcÀ]. 2-Phenylethynyl-1H-indole 1a
was selected as a model substrate, and the reaction with CO2
2

C. Li et al.
Tetrahedron Letters 61 (2020) 152449
but only trace amounts of the product was obtained due to poor
solubility (Entry 12).
With the optimal conditions in hand, we set out to explore the
scope and limitations of the reaction using various alkynyl indoles
derivatives (Table 2). Gratifyingly, substrates possessing either
electron-donating or electron-withdrawing substituents on the
phenyl ring readily reacted with CO2 to give the corresponding pyr-
ano[4,3-b]indol-1(5H)-ones 2a-g (Entries 1–7). Moreover, sub-
strates bearing ortho- and meta-positioned substituents on the
phenyl ring were likewise tolerated, giving 2h-k in good yields
(Entries 8–11). Additionally, alkynyl indoles with heterocyclic sub-
stituents, such as pyridyl and thienyl, afforded 2l and 2m in 83%
and 93% yield, respectively (Entries 12, 13). It was worth noting
that aliphatic 2-alkynyl indoles were well tolerated, affording 2n
and 2o in 93% and 94% yield, respectively (Entries 14, 15). The reac-
tion was then extended to substrates containing substituted indole
rings, and a range of pyrano[4,3-b]indol-1(5H)-ones 2p-u were
obtained in high yields (Entries 16–21). Notably, the incorporation
of electron-withdrawing groups on the indole rings of these sub-
strates improved the yields, while electron-donating groups gave
reduced yields.
Scheme 1. Reaction of 1v or 1w with CO2.
In previous studies, CO2 was reported as being initially acti-
vated by TBD to form a zwitterionic adduct X (Scheme 2) [12,14].
Nevertheless, in this study, the peak at 183.1 m/z corresponding
to X was not found by MS analysis of the mixture of [HTBD+][TFEÀ]
with CO2 at 100 °C for 7 h, which indicated that X was not the key
intermediate of the reaction. However, a new 13C NMR signal peak
at d = 164.36 ppm appeared, which may belong to the carbonyl car-
bon atom of the carbonate, suggesting CO2 was activated by the
anion [TFEÀ] (Fig. 1). In the FTIR spectrum a new band appeared
at 1637 cmÀ1, which was assigned to the stretching vibration of
the C@O bond of the carbonate, thus confirming its formation
and the 13C NMR data (ESI, Fig. S2).
Scheme 2. Plausible reaction pathway.
On the other hand, when the reaction of 1v or 1w with CO2 was
carried out under the optimized reaction conditions, the desired
product was not obtained. It can therefore be speculated that there
was an interaction between the indole NAH and TBD (Scheme 1).
On the basis of these experimental results, a plausible mecha-
nism is presented in Scheme 2. In [HTBD+][TFEÀ], CO2 was acti-
vated by the anion [TFEÀ] to form carbonate intermediate A.
Then, the CAC bond is formed by nucleophilic attack of the indole
C3-position onto the carbon atom of A to afford intermediate C.
Finally, re-aromatization via deprotonation and cyclization pro-
duces the desired pyrano[4,3-b]indol-1(5H)-ones D and regener-
ates [HTBD+][TFEÀ].
Fig. 1. 13C NMR spectrum of [HTBD+][TFEÀ] and the intermediate derived from
exposure of [HTBD+][TFEÀ] to CO2.
Conclusion
In summary, a new and highly efficient, solvent-free system
was developed for the preparation of various pyrano[4,3-b]indol-
1(5H)-ones using [HTBD+][TFEÀ] as a promoter and CO2 as a C1
resource. The advantages of the present protocol are moderate to
excellent yields, broad substrate scope and easy workup.
was carried out in the absence and presence of the PILs, which
acted as both the solvent and reaction promoter (Table 1). The
reaction did not proceed in the absence of PILs (Entry 1). The PILs
[HDBU+][TFAÀ] and [HDBU+][AcÀ] afforded low yields of 3-phenyl-
5H-pyrano[4,3-b]indol-1-one 2a after 18 h (Entries 2, 3). However,
when [HDBU+][TFEÀ] was used, 2a was obtained in 64% yield
(Entry 4), thus suggesting that the anion of the PILs affected the
reactivity. Encouraged by these results, [HDBN+][TFEÀ] and
[HTBD+][TFEÀ] which have the same anion as [HDBU+][TFEÀ] were
tested, affording 2a in 68% and 96% yield, respectively (Entries 5,
6). Furthermore, we found that 2a was obtained in 95% yield after
7 h (Entry 7), but the yield decreased when the reaction time was
reduced to 6 h (Entry 8). When the reaction was conducted at
100 °C for 7 h, the isolated yield was improved to 99% (Entry 9).
However, the yield decreased significantly upon decreasing the
amount of [HTBD+][TFEÀ] (Entries 10, 11). Finally, the [HTBD+]
[TFEÀ] promoted reaction was examined at room temperature,
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21601039, 21562010) for financial support.
3

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Tetrahedron Letters 61 (2020) 152449
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Appendix A. Supplementary data
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