One-pot synthesis of 3-haloflavones from flavones using Oxone and potassium halide as a halogenation reagent

Article abstract of DOI:10.1016/j.tetlet.2019.151511

A two-step, one-pot method has been developed for the synthesis of 3-haloflavones from the corresponding flavones. The method uses Oxone and potassium halide to produce the active molecular halogen in situ. The solvent (methanol) then participates in the reaction to afford the 2-methoxy-3-haloflavanone derivative. After adding sodium hydroxide, the corresponding 3-haloflavone product is obtained in good to excellent yields. This method provides a convenient synthesis of 3-chloro, 3-bromo and 3-iodo flavones from the same flavone starting material.

Full text of DOI:10.1016/j.tetlet.2019.151511

Journal Pre-proofs
One-pot synthesis of 3-haloflavones from flavones using Oxone® and potassi-
um halide as a halogenation reagent
Tao Peng, Gang Wang, Shouguo Zhang, Yunbo Sun, Shuchen Liu, Lin Wang
PII:
S0040-4039(19)31310-3
DOI:
https://doi.org/10.1016/j.tetlet.2019.151511
TETL 151511
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 November 2019
5 December 2019
6 December 2019
Please cite this article as: Peng, T., Wang, G., Zhang, S., Sun, Y., Liu, S., Wang, L., One-pot synthesis of 3-
haloflavones from flavones using Oxone® and potassium halide as a halogenation reagent, Tetrahedron Letters
(2019), doi: https://doi.org/10.1016/j.tetlet.2019.151511
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One-pot synthesis of 3-haloflavones from
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Tao Peng, Gang Wang, Shouguo Zhang, Yunbo Sun, Shuchen Liu,* and Lin Wang*

1
Tetrahedron Letters
One-pot synthesis of 3-haloflavones from flavones using Oxone® and potassium
halide as a halogenation reagent
Tao Peng, Gang Wang, Shouguo Zhang, Yunbo Sun, Shuchen Liu,* and Lin Wang
Department of Medicinal Chemistry, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A two-step, one-pot method has been developed for the synthesis of 3-haloflavones from the
corresponding flavones. The method uses Oxone® and potassium halide to produce the active
molecular halogen in situ. The solvent (methanol) then participates in the reaction to afford the
2-methoxy-3-haloflavanone derivative. After adding sodium hydroxide, the corresponding 3-
haloflavone product is obtained in good to excellent yields. This method provides a convenient
synthesis of 3-chloro, 3-bromo and 3-iodo flavones from the same flavone starting material.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
3-Haloflavones
One-pot synthesis
Halogenation
Flavones
Introduction
yields. An interesting study on the preparation of 3-
bromoflavones and 3-chloroflavones via the reaction of the
Flavones, as micronutrients in our diet, can be found in many
vegetables and fruits.1 The bioactivities displayed by flavones are
wide ranging and include anti-inflammatory,2 antioxidant,3
anticancer,4 and other activities.5 The flavone structure is also an
important building block for the synthesis of bioactive
compounds.6 In order to alter and improve the bioactivity of
flavones, significant research effort has been devoted towards
modifying their structures.7 Among these modifications, 3-
haloflavones are useful intermediates for the synthesis of C3-
substituted flavones and C3-linked bioflavonoids.8
corresponding
flavones
with
PhI(OAc)2/TMSBr
or
PhI(OAc)2/TMSCl has been reported.17 This method is very
attractive to medicinal chemists because it allows the synthesis of
3-bromoflavones and 3-chloroflavones from the same starting
materials under similar reaction conditions. However, this
method is of limited use because only four compounds were
synthesized and 3-iodoflavones were not obtained when using
PhI(OAc)2/TMSI as the iodinating reagent. Furthermore, the
quantity of TMSBr or TMSCl (3.0 equiv.) and PhI(OAc)2 (1.5
equiv.) used in the method, render it economically unattractive.
3-Haloflavones can be synthesized using indirect or direct
methods. Indirect methods prepare 3-haloflavones via cyclization
of their precursors, which are halogenated before or at the same
time as formation of the target flavone.9 Direct methods prepare
3-haloflavones from their corresponding flavones via
halogenation. Considering that flavones can be acquired
conveniently using organic synthesis or from natural sources, the
use of direct methods to prepare 3-haloflavones has been
extensively studied. Among the direct methods reported to date,
most of the reported research work has focused on the synthesis
of 3-iodoflavones, which are prepared via iodinating flavones
using I2/CAN,10 LDA/I2,11 or I2/DMSO.12 There are some reports
on the synthesis of 3-bromoflavones and 3-chloroflavones from
Oxone® is a widely used reagent in organic synthesis and
exhibits many useful properties such as being easy to handle,
water soluble, non-toxic, stable, and inexpensive.18 There are
numerous reports on the efficient halogenation of aromatic
compounds using binary systems consisting of Oxone®/KX (X =
Cl, Br, and I). In continuation of our interest in the halogenation
of organic compounds using Oxone®/KX, we report a two-step,
one-pot method for transforming flavones into 3-haloflavones
using Oxone®/KX as the halogenation reagent.
Results and Discussion
Initially, 4'-methoxyflavone (1a) was chosen as the model
substrate to explore the synthesis of 3-iodoflavones from
flavones using Oxone®/KI as an iodinating reagent (Scheme 1).
The reaction conditions were as follows: flavone 1a (0.5 mmol),
KI (0.5 mmol) and Oxone® (0.5 mmol) were stirred in methanol
(12 mL) at room temperature for 16 h. Unfortunately, the desired
product 3a was not obtained. The structure of the product was
flavones
using
2,4,4,6-tetrabromo-2,5-cyclohexadienone,13
Bu4NBr/PhI(OAc)2,14 pyridinium bromide perbromide,15 and
NCS16 as bromination and chlorination reagents. However, most
of these methods are of limited use due to the requirement of
t—ox—ic o—r unstable reagents, tedious synthetic procedures, and low
 Corresponding author. Tel.: +86-10-66932239; fax: +86-10-66931209; E-mail: liusc118@163.com; wanglin@bmi.ac.cn

2
Tetrahedron Letters
determined to be 2-methoxy-3-iodo-4'-methoxyflavanone (2a)
using 1H-NMR, 13C-NMR, HMQC, and HMBC (see ESI for
spectra). We found that 2a could be almost quantitatively
converted into 3-iodo-4'-methoxyflavone (3a) within a short time
when treated with a catalytic amount of NaOH in methanol.
Subsequently, we developed a two-step method for the synthesis
of 3a from 1a (Scheme 1).
The results of the optimization experiments are summarized in
Table 1. The yield of 2a was 53% using 1.0 equiv. of Oxone®
and KI in CH3OH (Entry 1). However, no reaction took place
when using CH3CN or THF as the solvent under the same
reaction conditions (Entries 2 and 3). We assumed the methoxy
group in 2a originates from the reaction solvent (CH3OH). An
isotope labelling experiment was conducted using CD3OD as the
reaction solvent and the results confirmed our assumption (see
ESI for experimental details). In order to increase the solubility
of the inorganic salts used in the reaction, an aqueous solution of
methanol was used and we were pleased to find the yield of 2a
increased (Entry 4). The yield of 2a changed when the quantity
of oxone and KI was increased from 1.0 to 2.0 equiv. (Entries 4–
7). This optimization indicated that 1.2 equiv. of Oxone® and KI
gave the best results (Entry 5). Increasing the proportion of water
in the solvent increases the solubility of the inorganic salts, but
also decreases the solubility of the reaction substrates. The
optimal ratio of methanol to water was determined as 12:0.2 (v/v),
which gave 2a in 92% yield (Entry 8). Under the optimal reaction
conditions, the yield of 2a decreased slightly when using other
iodides, such as NH4I and n-Bu4I (Entries 9 and 10). We decided
to use KI as the optimal iodide salt due to its low cost.
Scheme 1. Two-step synthesis of 3-iodo-4'-methoxyflavone (2a).
The synthesis of 3-iodoflavones from flavones can be
accomplished in one-pot because the two reactions steps use the
same solvent (CH3OH). To develop our methodology, the
reaction conditions used to prepare 2a were initially optimized.
Table 1.
Optimization of the reaction conditions used to prepare 2a.a
Entry
Oxone®
Iodide salt
Solvent
Yield 2a
(%) b
53
1
1.0 equiv.
1.0 equiv.
1.0 equiv.
1.0 equiv.
1.2 equiv.
1.5 equiv.
2.0 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.0 equiv. KI
1.0 equiv. KI
1.0 equiv. KI
1.0 equiv. KI
1.2 equiv. KI
1.5 equiv. KI
2.0 equiv. KI
1.2 equiv. KI
1.2 equiv. NH4I
1.2 equiv. n-Bu4I
CH3OH (12 mL)
2
CH3CN (12 mL)
–
3
THF (12 mL)
–
4
CH3OH/H2O (12 mL/0.5 mL)
CH3OH/H2O (12 mL/0.5 mL)
CH3OH/H2O (12 mL/0.5 mL)
CH3OH/H2O (12 mL/0.5 mL)
CH3OH/H2O (12 mL/0.2 mL)
CH3OH/H2O (12 mL/0.2 mL)
CH3OH/H2O (12 mL/0.2 mL)
74
5
81
6
76
7
69
8
92
9
88
10
89
a Reagents and conditions: flavone 1a (0.5 mmol), iodide salt and Oxone® were suspended in the reaction solvent and the resulting
mixture was stirred at room temperature. After reaction completion, the reaction mixture was quenched with water. The product was
purified by SiO2 column chromatography.
b Isolated yield based on 1a.
With the optimized reaction conditions in hand, we explored
the synthesis of 3a from 1a in one-pot. When 1a was not detected
in the reaction mixture by TLC, NaOH was added to the reaction.
desired product in low yields, which may be attributed to steric
hindrance (Entries 2 and 8). Among the substrates bearing a
para-substituent on ring B, electron-donating groups afforded the
desired product in high yields (Entries 1, 4, and 7), while
electron-withdrawing groups gave relatively low yields (Entries
5, 6, and 10). Flavones containing a phenolic hydroxyl group
gave a complex mixture of products under these reaction
conditions, but the reaction was improved when the hydroxyl
group was protected using a benzyl group (Entry 4). Substitution
on ring A did not significantly affect the yield. Surprisingly, 1k
and 1l, in which ring B contains three electron-donating groups,
did not give the aromatic iodination product. The halogenation of
aromatic rings is an aromatic electrophilic substitution reaction
and the higher the electron density in the aromatic ring, the easier
Considering that Oxone® is
a
triple acid salt
(2KHSO5∙KHSO4∙K2SO4), 5.0 equiv. of NaOH was added to the
reaction mixture to counteract the acid salts. As expected, 3a was
obtained in 87% yield (Table 2, entry 1). To extend our study, the
optimized conditions were applied to other flavones and the
results are summarized in Table 2. A wide range of substituted
flavones were transformed into their corresponding 3-
iodoflavones in moderate to high yields. Flavones containing a
para-methoxy substituent on ring B performed better than the
meta- and ortho-substituted substrates (Entries 1–3 and 7–9).
Substrates bearing an ortho-substituent on ring B gave the

3
the reaction will take place. The electron density in the aromatic
ring can be reflected by the chemical shifts of the aromatic
signals of benzene are observed at δ = 7.27, the electron density
in ring B of 1k and 1l is not much higher than that of benzene.
This may explain why 1k and 1l did not give the aromatic
iodination products.
1
protons observed in the H-NMR spectrum. From the reported
1H-NMR data, the aromatic proton signals in ring B of 1k and 1l
are observed at δ = 7.15 and 7.12, respectively.19 As the proton
Table 2.
One-pot synthesis of 3-iodoflavone derivatives.a
Entry
Substrate 1
Time Product 3
Yield
(%) b
Entry
Substrate 1
Time Product 3
Yield
(%) b
1
2
3
4
5
6
14 h
15 h
10 h
16 h
18 h
9 h
87
79
82
91
85
84
7
14 h
22 h
14 h
14 h
10 h
17 h
83
77
81
73
77
74
1g
3g
1a
3
8
1b
3b
1h
3h
9
1i
1j
3i
3j
1c
3c
10
11
12
1d
3d
1e
3e
1k
3k
1f
3f
1l
3l
a Reagents and conditions: flavone 1 (0.5 mmol), KI (0.6 mmol) and Oxone® (0.6 mmol) were suspended in CH3OH (12 mL) and H2O (0.2 mL). The
resulting mixture was stirred at room temperature until the substrate disappeared by TLC. NaOH (2.5 mmol) was added to the reaction mixture and after 10
min, the reaction was quenched with water. The product was purified by SiO2 column chromatography. b Isolated yield based on 1.
Encouraged by the synthesis of 3-iodoflavones, we decided to
use this method to prepare a variety of 3-chloroflavone and 3-
bromoflavone derivatives by replacing KI with KCl and KBr,
respectively, and the results summarized in Table 3. Gratifyingly,
the 3-chloroflavone or 3-bromoflavone derivatives were obtained
in improved yields with shorter reaction times.
Table 3.
One-pot synthesis of 3-chloroflavone and 3-bromoflavone derivatives. a
Entry
Substrate 1
Time Product 4
Yield
(%) b
Entry
Substrate 1
Time Product 4
Yield
(%) b
1
2
12 h
3 h
89
86
5
6
14 h
7 h
89
86
1a
1a
1e
1e
4e
4f
4a
4b

4
Tetrahedron
3
4
9 h
8 h
82
7
11 h
3 h
88
93
1g
1g
4g
1d
1d
4c
84
8
4h
4d
a Reagents and conditions: flavone 1 (0.5 mmol), KX (0.6 mmol, KCl=45 mg, KBr=71 mg) and Oxone® (0.6 mmol) were suspended in CH3OH (12 mL) and
H2O (0.2 mL). The resulting mixture was stirred at room temperature until the substrate disappeared by TLC. NaOH (2.5 mmol) was added to the reaction
mixture and after 10 min, the reaction was quenched with water. The product was purified by SiO2 column chromatography. b Isolated yield based on 1.
Scheme 3. Proposed reaction mechanism.
Finally, a reaction mechanism for the synthesis of 3-
haloflavones has been proposed based on our results, as shown in
Scheme 2. Halogenation of 3',5'-dimethoxyflavone.
Oxone® and halogenated salts are reagents commonly used in
aryl halogenation reactions.20 Although no aromatic halogenation
compounds were observed in the above examples (Table 2 and
Table 3), there is likely to be a competitive halogenation reaction
between the C3-position and the aromatic ring when the aromatic
ring contains an appropriate activating group. We chose 3',5'-
dimethoxyflavone (1m) to demonstrate this competitive reaction,
as shown in Scheme 2. When using Oxone® and KI as the
iodinating reagent, the yield of 3-iodoflavone 3m was only 11%
and the aromatic iodination compound 3n became the main
product. In the chlorination reaction, 4'-chloroflavone 4i was
isolated in 76% yield. Two aromatic bromination products, 4j
and 4k, were obtained in the bromination reaction in 66% and
25% yield, respectively. No 3-chloroflavone or 3-bromoflavone
products were formed in these two reactions. The presence of the
3',5'- dimethoxy groups in 1m allow the halogenation reaction to
take place at the 4'-position, instead of the C3-position. The
differences in the halogenation products of 1m can be attributed
to the atomic radius of chlorine, bromine and iodine. The iodine
atom faces greater steric hindrance at the 4'-position because it
has the largest atomic radius among the three halogens studied.
This results in the formation of a small amount of 3-iodoflavone
3m. Therefore, we can conclude that the aromatic halogenation
compound may become the main product under these reaction
conditions when there is more than one activating group
(electron-donating group) at appropriate positions in the flavone
starting material.
Scheme 3. Oxone® reacts with the potassium halide to generate
the active molecular halogen. The halonium intermediate is
formed via addition of the active molecular halogen to the C=C
bond in the flavone starting material. Then, nucleophilic attack
by methanol on the halonium intermediate gives 2-methoxy-3-
haloflavanone as an isolable intermediate. Deprotonation occurs
at the C3-position after adding NaOH to the reaction mixture.
Consequently, the 3-haloflavone product is generated via
elimination of the methoxy group.
Conclusion
In conclusion, we have developed a mild and convenient one-
pot method for the synthesis of 3-haloflavones from the
corresponding flavones. The protocol uses readily available and
inexpensive Oxone® and potassium halide to produce the active
molecular halogen in situ. The solvent (methanol) then
participates in the reaction to afford the 2-methoxy-3-
haloflavanone derivative. After adding NaOH to the reaction
mixture, the 3-haloflavone product is obtained in good to
excellent yields. The method provides a convenient and facile
synthesis of 3-chloro, 3-bromo and 3-iodo flavones from the
same flavone starting material.
Acknowledgments
This work was supported financially by the National Natural
Science Foundation of China (21272273 and 81273431), which
is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/
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6
Tetrahedron
Highlights
 3-Haloflavones were synthesized from the
corresponding flavones.
 This method use Oxone® and potassium halide
as a halogenation reagent.
 3-Chloro, 3-bromo and 3-iodo flavones can be
conveniently synthesized.

7