Synthesis of 8-aryl-3,5,7,3′,4′-penta-O-methylcyanidins from the corresponding quercetin derivatives by reduction with LiAlH4

Article abstract of DOI:10.1016/j.tetlet.2017.01.065

Synthesis of 8-aryl-3,5,7,3′,4′-penta-O-methylcyanidins from the corresponding quercetin derivatives by reduction with LiAlH₄is reported. Regioselective iodination at the 8-position of penta-O-methylquercetin followed by a Suzuki-Miyaura reaction gave the 8-arylated quercetin derivatives. By the reduction of 8-arylated quercetins using 4 equiv. of LiAlH₄at room temperature for 30 min, the corresponding anthocyanidins were obtained with a good yield.

Full text of DOI:10.1016/j.tetlet.2017.01.065

Accepted Manuscript
Synthesis of 8-aryl-3,5,7,3',4'-penta-O-methylcyanidins from the corresponding
quercetin derivatives by reduction with LiAlH4
Yuki Kimura, Kin-ichi Oyama, Tadao Kondo, Kumi Yoshida
PII:
S0040-4039(17)30093-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.065
TETL 48568
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
2 December 2016
13 January 2017
20 January 2017
Please cite this article as: Kimura, Y., Oyama, K-i., Kondo, T., Yoshida, K., Synthesis of 8-aryl-3,5,7,3',4'-penta-
O-methylcyanidins from the corresponding quercetin derivatives by reduction with LiAlH4, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.065
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Synthesis of 8-aryl-3,5,7,3',4'-penta-O-
methylcyanidins from the corresponding
quercetin derivatives by reduction with
LiAlH4
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Yuki Kimura, Kin-ichi Oyama, Tadao Kondo, Kumi Yoshida*

1
Tetrahedron Letters
Synthesis of 8-aryl-3,5,7,3',4'-penta-O-methylcyanidins from the corresponding
quercetin derivatives by reduction with LiAlH4
Yuki Kimuraa, Kin-ichi Oyamab, Tadao Kondoa and Kumi Yoshida*a
a Graduate School of Information Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
b Chemical Instrumentation Facility, Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Corresponding author Tel./fax: +81-052-789-5638; e-mail: yoshidak@is.nagoya-u.ac.jp
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of 8-aryl-3,5,7,3',4'-penta-O-methylcyanidins from the corresponding quercetin
derivatives by reduction with LiAlH4 is reported. Regioselective iodination at the 8-position of
penta-O-methylquercetin followed by a Suzuki-Miyaura reaction gave the 8-arylated quercetin
derivatives. By the reduction of 8-arylated quercetins using 4 equiv. of LiAlH4 at room
temperature for 30 min, the corresponding anthocyanidins were obtained with a good yield.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
8-aryl-anthocyanidin
8-aryl-flavonol
LiAlH4
flavenol
Suzuki-Miyaura coupling
Anthocyanidins, which are polyphenol pigments responsible
for the colors of flowers, leaves, and fruits,1 have attracted
attention as functional food colorants2 with various
pharmacological properties.3 Recently, their material utility in
applications such as sensitizers for dye-sensitized solar cells
(DSSCs)4 and molecular switching system5 have also been
explored. We have been studying the mechanisms of flower
coloration1b,c and the usage of anthocyanins for DSSCs. To
advance these studies, the synthesis of anthocyanins and
anthocyanidins are essential. In DSSC research, we focused
especially on the introduction of an aryl group at the 8-position
of the A-ring to elevate the HOMO level of the dye to match the
conducting band of TiO2. However, until now, the efficient
synthesis of 8-substituted anthocyanidin has not been reported.
Here, we report an efficient synthetic route of 8-
arylanthocyanidins from flavonols.
and Jurd reported the transformation from penta-O-
methylquercetin (1) to penta-O-methylcyanidin (2) by a two-step
reaction using LiAlH4 reduction followed by quinone oxidation
(Scheme 1, A).11 Recently, Sundeep et al. reported that the
reduction of penta-O-benzylquercetin by LiAlH4 afforded penta-
O-benzylflavenols.12 From these experimental results, it has been
believed that the LiAlH4 reduction of per-O-alkylflavonol gives
From the other point of view, structural transformation
of anthocyanin from flavonols is also one of important subjects
for study. In 1910’s it was already reported that the reduction of
flavonol gives anthocyanidin.6 This transformation reaction has
been paid much attention to both chemical and biological
community due to developing the synthetic method as well as
understanding of anthocyanin biosynthetic pathway.7 Because the
reduction of flavonols may give flav-2-en-3,4-diol, which has the
same oxidation level as with anthocyanindin and this compound
is proposed to be an intermediate in biosynthetic pathway of
anthocyanin.8,9 However, the involvement of the flav-2-en-3,4-
diol in biosynthetic pathway is not clear even today.8
Concerning with reduction reaction Zn or Mg was used
as a reagent at the early of 20th century. In 1950, the usage of
LiAlH4 was reported by Mirza and Robinson.10 Afterward, Waiss
Scheme 1. Synthesis of anthocyanidin by LiAlH4.

2
Tetrahedron
Scheme 2. Retrosynthetic strategy to 8-aryl-3,5,7,3',4'-penta-O-methyl-cyanidin.
Scheme 3. Synthesis of 8-iodo-3,5,7,3',4'-penta-O-methylquercetin (3).
Table 1. Suzuki-Miyaura coupling of 8-iodo-3,5,7,3',4'-penta-O-methylquercetin (3) with boronic acid 4 and 5
Entry
1
Boronic acid
Product
PPh3 (mol%)
3
Solvent
CPME
Time (h)
12
Yield(%)a
61
6
4
4
4
2
3
6
6
0
0
CPME
toluene
6
7
79
90
4
7
3
CPME
18
69
5
5
5
5
5
6
7
7
7
7
0
0
3
CPME
toluene
toluene
24
10
10
36
57
66
2 equiv. of boronic acid was used in all reactions.
a Isolated yield.
per-O-alkylflavenol, and to obtain anthocyanidins, further
oxidation should be necessary.11,13 In contrast to previous reports,
we found that when the amount of LiAlH4 and reaction
temperature were controlled, penta-O-methylquercetin (1)
directly gave penta-O-methylcyanidin (2) in a good yield
(Scheme 1, B). It is note that this new findings afforded not only
a concise synthetic pathway without an oxidation step but also a
clue of the understanding of biotransformation reaction to
anthocyanidin. Using this synthetic method, we synthesized
various 8-aryl-3,5,7,3',4'-penta-O-methyl-cyanidins.
Our retrosynthesis is shown in Scheme 2. 8-aryl-3,5,7,3',4'-penta-
O-methylcyanidins was obtained by LiAlH4 reduction of the
corresponding 8-arylated quercetin derivatives. The introduction
of the 8-aryl group could be realized by a Suzuki-Miyaura
Scheme 4. Synthesis of 3,5,7,3',4'-penta-O-methyl-8-[4-(diphenylamino)-
phenyl]quercetin (9)

3
reaction of 8-iodo-penta-O-methylquercetin (3) with various
boronic acids. 3 was prepared by regioselective iodination of
penta-O-methylquercetin (1).
methylcyanidins (Table 2). At first, 3,5,7,3',4'-penta-O-
methylquercetin (1) was reduced by 1 equiv. of LiAlH4 in THF at
room temperature. Previous reports claimed that the reduction of
1 by LiAlH4 should afford mixtures of flavenols (flav-2-enol 10
and flav-3-enol 11), which could be oxidized easily to 3,5,7,3',4'-
penta-O-methylcyanidin (2) by quinone oxidants (Scheme 1,
A).9,11 However, in our experiment, 1 equiv. of LiAlH4 gave
3,5,7,3',4'- penta-O-methylcyanidin (2) as a major product.
We have already established the preparation of penta-O-
methylquercetin (1);14 therefore, our synthesis was commenced
with regioselective iodination of 1. Since the C-atom at the 8-
position of 1 has the highest electron density, the treatment of 1
with NIS (N-iodosuccinimide) in DMF gave the 8-iodinated
compound 3 as a sole regioisomer in 90% yield (Scheme 3).15
Then, a Suzuki-Miyaura coupling reaction of 3 with boronic
acids (4 and 5) was carried out in the presence of Pd(OAc)2 and
K3PO4 at 100 °C (Table 1). Since a phosphine ligand was usually
added,16 we tried the standard condition with phenylboronic acid
(4) in the presence of PPh3 in CPME (cyclopentyl methyl ether)
for 12 h and obtained the desired 8-phenylflavonol (6) in 61%
yield (Table 1, entry 1). Unexpectedly, without PPh3, the yield
increased to as high as 79% (Table 1, entry 2).17 As a further
optimization, the use of toluene gave 6 in 90% yield (Table 1,
entry 3). Based on these results, the reaction of 1-
naphthylboronic acid (5) without PPh3 in toluene was examined.
However, the yield of 7 was moderate (57%). Therefore, we
resurveyed the combinations of ligand and solvent and found that
with PPh3 in CPME the yield was the highest (69%) (Table
Table 2. Synthesis of 8-aryl-3,5,7,3',4'-penta-O-methylcyanidins (2, 12-14)
from the corresponding flavonols (1, 6, 7, 9) by using LiAlH4
Entry
Flavonol
Product
Yield(%)a
entries 4-7). The coupling reaction of
3
with 4-
1
2
3
4
1
6
7
9
2
70
41
57
66
(diphenylamino)phenylboronic acid (8) was examined according
to Liu’s ligand-free condition (Scheme 4).18 The reaction of 3
with 8 in the presence of Pd(OAc)2 and K2CO3 in EtOH/H2O at
80 °C under Ar gave the desired coupling product 9in 80% yield.
12
13
14
a Isolated yield.
With further examination, we could detect the generation of flav-
3-enol 10 and flav-2-enol 11 when a large excess of LiAlH4 (10
equiv.) was used (Figure 1).19 In this reaction for 30 min, 1 was
disappeared and 2, 10, and 11 was generated. When the reaction
time was 20 h, 2 was deceased and both 10 and 11 was increased.
Thus, the generation of flavenols might be due to the over-
reduction of 2.12,20 Thus, we concluded that 2 could be obtained
by LiAlH4 reduction at room temperature when the amount of the
reagent was controlled. Finally, we established the reaction
condition as 4 equiv. of LiAlH4 in THF at room temperature to
obtain 2 in 70% yield.21 Using this direct transformation protocol,
LiAlH4 reduction of 8-aryl-3,5,7,3',4'-penta-O-methylquercetins
(6, 7, and 9) afforded the corresponding 8-aryl-3,5,7,3',4'-penta-
O-methylcyanidins (12, 13, and 14) in 41, 57, and 66% yield,
respectively (Table, 2).
In conclusion, we developed a synthetic route for 8-aryl-
3,5,7,3',4'-penta-O-methylcyanidins from the corresponding
quercetin derivatives through LiAlH4 reduction. Our re-visiting
experiments revealed that the reduction of penta-O-
methylcyanidins from the corresponding quercetin derivatives by
4 equiv. of LiAlH4 at room temperature transformed directly to
penta-O-methylcyanidins.
Acknowledgments
We acknowledge doctoral student financial support to (Y.K.) by
the Graduate School of Information Science, Nagoya University.
References and Notes
Figure 1. HPLC chromatogram of the reduction of 1 with LAH.
1.
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Since the requisite penta-O-methylquercetins (1, 6, 7, and 9)
were in hand, we examined the transformation reaction to

4
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2014/115174 A2; in this patent, the reduction of penta-O-benzylquercetin
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21. Reduction of 1 with LiAlH4: To a solution of 3,5,7,3',4'-penta-O-
methylquercetin (1) (50 mg, 0.13 mmol) in anhydrous THF (2.5 mL)
was added LiAlH4 (0.52 mL, 0.52 mmol, 1.0 M solution in THF) slowly
at room temperature. After stirring for 30 min at room temperature, the
reaction mixture was added distilled water (2.5 mL) and 15% TFA aq.
(2.5 mL) at 0 ºC. After THF was removed under reduced pressure, the
residue was added with 0.5% TFA aq. (15 mL). After the crude products
were extracted with CH2Cl2 (15 mL x 3), the combined organic phases
were dried over anhydrous Na2SO4. The solvent was concentrated under
reduced pressure and the residue was purified by flash silica gel
chromatography (33% AcOEt/Hexane with 0.5% TFA  AcOEt with
0.5% TFA  1% MeOH/AcOEt with 0.5% TFA  3% MeOH/AcOEt
with 0.5% TFA) to give 2 (44 mg, 70%) as a dark red solid.
Supplementary Material
Supplementary data including the detailed experimental
procedures and spectral data related to this article can be found at
the journal’s homepage.

5
Highlights
Synthesis
of
8-aryl-3,5,7,3',4'-penta-O-
methylcyanidins from the corresponding quercetin
by using LiAlH4.
LiAlH4 reduction directly gave penta-O-
methylcyanidins from the corresponding flavonols.
Chemical transformation to anthocyanidin is very
important for understanding of anthocyanin
biosynthetic pathway.