Photo-induced tandem cyclization of 3-iodoflavones with electron rich five-membered heteroarenes

Article abstract of DOI:10.1039/c7ra07793a

Vinyl radicals were generated from 3-iodoflavones under a mercury lamp and tandem cyclization reactions occurred with five-membered heteroarenes entailing two consecutive C-C bond formations to synthesize benzo[e]chromeno[2,3-g]indol-13(1H)-one derivatives. The tandem cyclization reactions worked in acetonitrile without any additives such as transition metals, ligands and oxidants, giving rise to a broad variety of novel polycyclic xanthone frameworks in good yield under mild and environmentally friendly reaction conditions.

Full text of DOI:10.1039/c7ra07793a

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Photo-induced tandem cyclization of 3-
iodoflavones with electron rich five-membered
Cite this: RSC Adv., 2017, 7, 43206
heteroarenes†
a
Qian Yang,ab Rui Wang,a Jie Han,a Chenchen Li,a Tao Wang,
Yong Liangc
a
*
and Zunting Zhang
Vinyl radicals were generated from 3-iodoflavones under a mercury lamp and tandem cyclization reactions
occurred with five-membered heteroarenes entailing two consecutive C–C bond formations to synthesize
benzo[e]chromeno[2,3-g]indol-13(1H)-one derivatives. The tandem cyclization reactions worked in
acetonitrile without any additives such as transition metals, ligands and oxidants, giving rise to a broad
variety of novel polycyclic xanthone frameworks in good yield under mild and environmentally friendly
reaction conditions.
Received 15th July 2017
Accepted 21st August 2017
DOI: 10.1039/c7ra07793a
rsc.li/rsc-advances
of fac-Ir(ppy)3 at room temperature (Scheme 1, middle).16 In
2017, another transition-metal catalyzed tandem cyclization of
Introduction
vinyl radicals used for the synthesis of substituted indolines was
developed via a photoredox-mediated reductive quenching cycle
(Scheme 1, bottom).17
Following our interest in the photo-reactions of chromone
analogues18–21 as well as nucleoside substrates,22 we herein
report a new photo-induced tandem cyclization of 3-iodo-
avones with p-excessive ve-membered heteroaromatics at
ambient temperature without the requirement of any
transition-metal-catalyst and/or oxidant additives.
Flavones are a class of natural products and can be found in
numerous plants. They display various biological activities,
including antioxidant, anti-tumor, anti-proliferative and anti-
inammatory activities, and have been used in the treatment
of cancer, cardiovascular diseases, neurodegenerative disor-
ders, etc. Flavones are also an important scaffold for medicinal
chemistry and versatile building blocks for the construction of
various heteroaromatics.1–3
Tandem cyclizations, as a powerful method for the synthesis
of polycyclic compounds, have been successfully applied to the
Diels–Alder reactions,4–7 Michael addition,8 rearrangements9–11
and radical cyclizations.12–14 During the last decade, extensive
investigations have been made on the photo-induced tandem
vinyl radical cyclization, which could build multiple C–C bonds
in a single step under mild conditions.15–17 In 2014, O. Reiser
Results and discussion
Initially, a stirred solution of 3-iodoavone 1a (0.2 mmol) and
N-methylpyrrole 2a (6 mmol) in DMF (40 mL) was irradiated
using a high-pressure mercury lamp (500 W) at room
temperature under an argon atmosphere for 5 h. The cycliza-
tion product 3a was isolated (13%) and characterized by NMR
and HRMS (Table 1, entry 1). Inspired by this promising result,
various solvents, such as THF, t-BuOH, Me2CO and MeCN,
were screened. However, only a trace amount of the cyclization
product 3a was observed in THF, while the yields of 3a were
slightly increased in other solvents (entries 2–5). In order to
avoid the coupling of 1a with benzene and toluene, such
aromatic solvents were not used. As expected, the cyclization
yields increased upon increasing the loading of 2a
(entries 6–8). In addition, it was noteworthy that the yield of 3a
dropped to 35% when 0.35 M of 2a was employed (entry 9),
which clearly indicated that solvent free conditions will not
work very well. Finally, the irradiation time was optimized and
the yield of 3a was increased to 47% when the reaction time
was extended to 7 h (entries 10–14).
reported
a radical tandem addition–cyclization of a-bro-
mochalcones or a-bromocinnamates with heteroarenes using
an iridium complex as the catalyst and irradiating with visible
light (Scheme 1, top).15 Similarly, O. Reiser reported a visible
light-mediated coupling of a-bromochalcones with alkenes
under the visible-light photo-redox conditions in the presence
aKey Laboratory of the Ministry of Education for Medicinal Resources and Natural
Pharmaceutical Chemistry, National Engineering Laboratory for Resource
Development of Endangered Crude Drugs in Northwest of China, School of
Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an 710062,
People's Republic of China. E-mail: zhangzunting@sina.com; Fax: +86-29-81530727;
Tel: +86-29-85303940
bSchool of Sciences, Xi'an University of Technology, Xi'an 710054, China
cDepartment of Molecular Medicine, Beckman Research Institute, Hope Duarte, CA
91010, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra07793a
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Scheme 1 The reported photo-induced tandem radical cyclization.
Table 1 Optimization of the tandem reaction of 3-iodoflavone 1a with
N-methylpyrrole 2aa
ve-membered heteroarenes 2 were screened, and the cycliza-
tion yields are listed in Table 2. Thus, irradiation of 1a and N-
methylpyrrole 2a in MeCN using a high-pressure mercury lamp
(500 W) at room temperature for 7 h gave 3a in 47% yield (entry
1). Analogously, treatment of 1b, bearing an additional methyl
group at the R2 position, gave the cyclization product 3b in
a lower yield (entry 2). However, treatment of 1c, bearing an
additional uoro group at the R2 position, gave the cyclization
product 3c in a higher yield (entry 3). Various combinations of
hydrogen, electron-withdrawing and electron-donating groups
were explored for the 3-iodoavone 1 substrates (entries 4–16).
As shown in the table, the yields of 3 were signicantly affected
by the functional groups attached. The presence of electron-
donating groups on both R1 and R2 gave the cyclization prod-
ucts 3 in much lower yields (entries 2, 4, 6 and 7) when compared
to the substrate bearing only one electron-donating group at
either R1 or R2 (entries 1, 5 and 10–11). For example, the yield of
3d was decreased to 38% when –OCH3 was present at both R1
and R2 (entry 4). On the other hand, the yield of 3 could be easily
increased to over 68% with the introduction of an electron-
withdrawing group to either R1 or R2 (entries 3, 8 and 13–15).
Various p-excessive ve-membered heteroarenes 2 were also
explored to examine their compatibility and reactivity (entries
17–19). Thus, irradiation of 1i with pyrrole 2b in MeCN at room
temperature for 10 h gave the cyclization product 3q (entry 17).
Due to the ring closure for the formation of an aromatic system
(vide infra), the stability issue22 was not observed with the
current protocol. The cyclization of 3-iodoavone 1a also pro-
ceeded smoothly with furan 2c and thiophene 2d to give the
corresponding products in fair yields (entries 18–19). It is
noteworthy that no cyclization products were observed for
benzene or other six-membered aromatics under the optimal
conditions. Generally, the cyclization efficiency follows the
electrophilic reactivity N-methylpyrrole > pyrrole > furan >
Concentration
Entry
Solvent
of 2a [mol Lꢀ1
]
Time [h]
Yieldb [%]
1
2
3
4
5
6
7
8
DMF
THF
0.15
0.15
0.15
0.15
0.15
0.05
0.2
0.25
0.35
0.25
0.25
0.25
0.25
0.25
5
5
5
5
5
5
5
5
5
1
3
6
7
10
13
Trace
16
20
24
15
31
40
35
18
30
43
47
43
t-BuOH
Me2CO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
10
11
12
13
14
a
A mixture of 1a (0.2 mmol, 0.005 M) and 2a (2–14 mmol, 0.05–0.35 M)
in anhydrous MeCN (40 mL) was irradiated using a high-pressure
mercury lamp (500 W) at ambient temperature under an Ar
atmosphere. b Isolated yield.
Cyclization of 3-iodoavones with various ve membered
heteroarenes
In order to screen the scope of the substrates and compatibility
of functional groups, various 3-iodoavones 1 and p-excessive
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Table 2 Cyclization of different 3-iodoflavones 1 and heteroarenes 2a
intermediate D,21,23 followed by a thermal suprafacial [1,5]-H
shi to form intermediate E. Furthermore, keto–enol tautome-
rization of E led to the formation of the enol intermediate F,
which generated a more stable syn-isomer G via another keto–
enol tautomerization.21–24 Finally, the cyclization product 3 was
formed via the syn-elimination of a hydrogen molecule from
intermediate G along with the restoration of the aromaticity of
the conjugated system.
In order to study the importance of keto–enol tautomeri-
zation and gure out the rate limiting step, coupling product
1aa was isolated and subjected to the cyclization conditions
separately (Scheme 4). Thus, irradiation of 1a and 2a under
a high-pressure mercury lamp at ambient temperature for 1 h
yielded the coupling product 1aa with 25% along with a trace
amount of the cyclization product 3a. A solution of 1aa (5 mM)
in MeCN was irradiated under a high-pressure mercury lamp
at ambient temperature in parallel with a solution of 1a
(5 mM) and 2a (0.25 M) in MeCN. Aer 7 h, substrate 1aa gave
the cyclization product 3a in 95% yield, while only 47% of 3a
was obtained for 3-iodoavone 1a. Thus, we could easily
conclude that coupling of 3-iodoavone with heteroarenes was
the rate-limiting step.
To obtain further insight into reaction mechanism
pathway and validate the rationality of the proposed mecha-
nism, a substrate without the presence of C4]O was synthe-
sized and subjected to the cyclization conditions. Initially,
1aa was reduced to 1ab using LiAlH4–AlCl3 according to the
procedure reported in literature26,27 (Scheme 5). Then, the 4,4-
dihydro substrate 1ab was subjected to the optimal condi-
tions. As expected, no cyclization product 1ac was detected,
which could be explained by the lack of keto–enol
tautomerization.
Entry
R1
R2
1
2
3
Yieldsb [%]
1
2
3
4
5
6
7
8
OCH3
OCH3
OCH3
OCH3
CH3
CH3
CH3
CH3
H
H
H
H
F
H
6-CH3
6-F
7-OCH3
H
6-CH3
OCH3
6-F
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
47
40
49
38
50
46
42
56
61
51
45
66
68
54
49
64
40c
25
18
9
H
10
11
12
13
14
15
16
17
18
19
6-CH3
7-OCH3
6-F
H
F
F
6-CH3
7-OCH3
H
H
H
COOC2H5
H
OCH3
OCH3
1a
1a
H
3s
a
A mixture of 1 (0.2 mmol, 0.005 M) and 2 (10 mmol, 0.25 M) in
high-pressure
anhydrous MeCN (40 mL) was irradiated using
a
mercury lamp (500 W) at ambient temperature for 7 h under an Ar
atmosphere. b Isolated yield. c Irradiation for 10 h.
In order to expand the photo-induced tandem cyclization
of 3-iodoavones with p-excessive ve-membered hetero-
arenes methodology to other systems bearing a similar func-
thiophene, which can easily explain why no cyclization product
was observed for the six-membered aromatics.
tional
moiety,
we
subjected
the
(Z)-a-bromo-b-
Electrophilic aromatic substitution (EAS)
phenylvinylketone analogues 4 to our cyclization protocol
(Scheme 6). Thus, irradiation of a-bromochalcones 4a and the
pyrrole analogues 2 under the optimal conditions for 10 h
yielded 5a and 5b in 57% and 42% yield, respectively. Simi-
larly, irradiation of 4b with pyrrole analogues 2 gave 5c and 5d
in 47% and 38% yield, respectively. Due to the stabilization of
the additional phenyl ring through the larger conjugation
system, a-bromochalcone 4a gave the cyclization product
in an improved yield compared to the methyl substrate 4b.
Even though a similar cyclization has been reported,15 it is
important to mention that the current protocol avoids the
On the basis of the experimental results and literature,19,20,24,25
a two-step mechanism for the cyclization of 3-iodoavones 1
with p-excessive ve-membered heteroarenes 2 has been
proposed. Initially, the photo-induced hemolytic cleavage of the
C–I bond of 1 under UV light irradiation gave the radical
intermediate A. Coupling of A with heteroarenes 2 afforded the
reactive intermediate B, followed by the abstraction of hydrogen
with an iodine radical to give the coupling product C with the
release of HI (Scheme 2).19,20
The cyclization step (second step, Scheme 3) started with the
UV irradiation of C via the formation of the ring closed
Scheme 2 Proposed mechanism for the preparation of coupling product C.
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Scheme 3 Proposed mechanism for the preparation of the photocyclization product.
Scheme 4 The stepwise reaction of the tandem cyclization reaction.
Scheme 5 Reductive carbonyl experiments.
heteroarenes. The described methodology provides rapid access
to polycyclic xanthones with excellent regioselectivity under
mild and environment friendly conditions without the
requirement of any catalyst or additives.
Experimental section
Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without purication. MeCN
was distilled from CaH2 just prior to use. Thin-layer chro-
matography (TLC) was performed using silica gel 60 GF254
plates. The silica gel (size 200–300 mesh) used for the
column chromatography was purchased from Qingdao
Haiyang Chemistry Plant (China). 1H NMR and 13C NMR
spectra were recorded on 400 (1H) and 100 (13C) MHz
spectrometers. The spectra were referenced internally to
CDCl3 or DMSO-d6. High-resolution mass spectrometry
Scheme 6 Cyclization of a-bromo-b-phenylvinylketone analogues 4
with pyrrole 2.
use of transition-metal complexes and high boiling
solvent, which could be problematic during the purication
stage.
Conclusion
In conclusion, we have demonstrated a new tandem cyclization (HRMS) was recorded using the electron-spray ionization
protocol for the synthesis of fused heterocyclic aromatic (ESI) technique. The melting points were measured using
systems via the coupling of both 3-iodoavone and a-bro- X-5 micro-melting point apparatus and were uncorrected. IR
mochalcone derivatives with various p-excessive ve-membered spectra were recorded on
a
Nicolet 170SX FT-IR
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spectrophotometer using KBr pellets. All the irradiation removed under reduced pressure and the residue was puried
experiments were performed on
BL-GHX-V photo- using column chromatography (hexane : EtOAc ¼ 20 : 1) to give
chemical reactor equipped with a 500 W high-pressure Hg the corresponding product 3a (47%) as a white solid.
a
lamp.
Analogously, 3b–3s, 5a–5d were prepared using the same
method described for 3a.
General procedure for the preparation of 3-iodoavones 128
Conflicts of interest
A
solution
of
2-(4-methoxyphenyl)-4H-chromen-4-one
(1.0 mmol), I2 (1.2 mmol) and CAN (1.1 mmol) in anhydrous
MeCN (100 mL) was stirred at 65 ꢁC (oil/water bath) under
an Ar atmosphere until the disappearance of the substrate.
Aer being cooled to ambient temperature, the reaction
mixture was poured into a cold solution of Na2S2O3 (50 mL,
0.1 M) and extracted with CH2Cl2 (20 mL, ꢂ3). The organic
layers were combined, washed (H2O), dried (MgSO4)
and concentrated. The residue was puried by column
chromatography (hexane : EtOAc ¼ 9 : 1) to afford the desired
product 1a (70%) as a white solid.
There are no conicts to declare.
Acknowledgements
We are grateful for the nancial support from the National
Natural Science Foundation of China (No. 21672132 and
21502110).
Notes and references
Analogously, compounds 1b–1p were prepared using the
same method as described for 1a.
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