Regioselective synthesis of C-prenylated flavonoids via intramolecular [1,3] or [1,5] shift reaction catalyzed by acidic clays

Article abstract of DOI:10.1016/j.tetlet.2019.151138

Prenyl side chain and dihydropyrano skeleton exists in many natural and synthetic biologically active flavonoids. A highly efficient and regioselective method for the synthesis of C-prenylated flavonoids via intramolecular [1,3] or [1,5] shift reaction of

Full text of DOI:10.1016/j.tetlet.2019.151138

Tetrahedron Letters 60 (2019) 151138
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective synthesis of C-prenylated flavonoids via intramolecular
[1,3] or [1,5] shift reaction catalyzed by acidic clays
⇑
Wei Li, Liang Shu, Kexiong Liu, Qiuan Wang
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2019
Revised 9 September 2019
Accepted 10 September 2019
Available online 11 September 2019
Prenyl side chain and dihydropyrano skeleton exists in many natural and synthetic biologically active fla-
vonoids. A highly efficient and regioselective method for the synthesis of C-prenylated flavonoids via
intramolecular [1,3] or [1,5] shift reaction of 5-O-prenylflavonoids catalyzed by Florisil or
Montmorillonite clays is described. Florisil catalyzes intramolecular [1,5] shift reaction of 5-O-prenylfla-
vonoids to obtain 8-C-prenylated flavonoids exclusively, Montmorillonite K10 exhibits the superior selec-
tivity to promote intramolecular [1,3] shift reaction to obtain 6-C-prenylated flavonoids compared with
Florisil and Montmorillonite KSF. This method provides a practical process to regioselective synthesize
biologically important C-prenylated flavonoids in good yields using commercially available and inexpen-
sive catalyst under mild conditions.
Keywords:
C-Prenylated flavonoids
Acidic clays
Intramolecular [1,3] or [1,5] shift reaction
Regioselective synthesis
Ó 2019 Elsevier Ltd. All rights reserved.
Introduction
complex catalyst [Eu(fod)3], the yield of para-position (C-8 for fla-
vonoid) has greatly improved, but rare earth metals are expensive
C-Prenylated flavonoids are a unique class of naturally occur-
ring flavonoids characterised by the presence of a prenylated
side-chain on the flavonoid skeleton. Over the past few decades,
an impressive number of bioactivities and their potential use in
medicinal applications have been demonstrated for C-prenylated
flavonoids [1,2]. C-Prenylflavonoids are also useful as precursors
for the synthesis of naturally occurring bioactive flavonoids con-
taining, for example, pyrano substituents [3]. C-prenylated flavo-
noids are interesting synthetic targets.
and unstable [9,10]. There are certain limitations in the method of
introducing prenyl group in 8-position.
In order to study the biological activities of C-prenylated flavo-
noids, a facile and efficient synthetic approach was required. The
development of a straightforward and tunable entry into C-6 and
C-8 prenylflavones from a common precursor would there for rep-
resent a significant addition to the field, paving the way to system-
atic structure-activity studies for this class of compounds.
The use of eco-friendly approaches for the synthesis of a diver-
sity of bioactive small molecules has been increasing during recent
years. Acid catalysis of organic transformations by clay aluminosil-
icates is an area of considerable potential and interest due to ease
of handling and workup, naturally abundant, inexpensive, nontox-
ic, chemically versatile and recyclable [11,12]. Florisil and Mont-
morillonite clays, including K10 and KSF, are generally employed
as effective and environmentally benign heterogeneous catalysts
for several reactions, which was used to obtain dihydropyranoxan-
thones [13], para-allyl phenols, and ortho-allyl phenols [14,15].
Therefore, these solid catalysts seem to be an interesting green
alternative to conventional chemistry practices.
In general, the direct prenylation of flavonoids is difficult to
control in terms of chemoselectivity (C- vs O-alkylation), regiose-
lectivity, and number of prenyl introduced [4]. The [3,3]-Sigmat-
ropic
rearrangement
(Claisen
rearrangement)
of
O-
prenylflavonoids provides convenient access to para-allyl phenols
(C-8 for flavonoids) precursors to a variety of natural products,
including flavonoids and coumarins [5,6]. The difficulty in prepar-
ing 2,2-disubstituted ethers often renders the Claisen rearrange-
ment inconvenient for the preparation of terminally substituted
ortho-allyl phenols [7]. For Claisen rearrangement of O-prenylfla-
vonoids at 5-position, the chances of prenyl being rearrangement
to flavonoids C-6 and C-8 are close, there is a problem of poor
selectivity [8]. Catalytic use of b-diketone and rare earth metals
In the present paper, we describe the regioselective syntheses of
8-C-prenylflavonoids and 6-C-prenylflavonoids via intramolecular
[1,3] or [1,5] shift reaction of 5-O-prenylflavonoids catalyzed by
acidic clay. A series of 8-C-prenylflavonoids 1–4 were synthesized
under the catalysis of Florisil clay and 6-C-prenylflavonoids 5–8
⇑
Corresponding author.
E-mail address: wangqa@hnu.edu.cn (Q. Wang).
https://doi.org/10.1016/j.tetlet.2019.151138
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
W. Li et al. / Tetrahedron Letters 60 (2019) 151138
were synthesized under the catalysis of Montmorillonite K10 clay
starting from commercially available diosmetin and quercetin.
Four dihydropyranoflavonoids 9–12 were synthesized by cycliza-
tion reaction of the prenyl group with the neighboring OH-group
under acidic conditions.
diosmentin according to literature procedures [23]. Then chloro-
methyl methyl ether (MOMCl), which was stable in basic condi-
tions and easily removed by acidic treatment, was added to
protect the hydroxy group of diosmetin and quercetin to obtain
selectively methoxymethyl (MOM) group protected products 13
and 21. Luteolin was successively treated with MOMCl and (Me)2-
SO4 to obtain 30,7-bis-O-methoxymethylchrysoeriol (17). O-Preny-
lation of the free 5-hydroxy group of 13, 17 and 21 was
respectively prenylated with prenyl bromide affording target pre-
nyl ethers 14, 18 and 22.
Reagents and conditions: (a) CH3OCH2Cl, K2CO3, acetone, r.t.,
84%; (b) prenyl bromide, K2CO3, acetone, 45 °C, 70%; (c) Florisil,
toluene, reflux, 92%; (d) Montmorillonite K10, toluene, reflux,
54%; (e) dilute HCl (aq.), CH3OH, r.t., 80%; (f) H2SO4, CH3OH, reflux,
85%;
Reagents and conditions: (a) CH3OCH2Cl, K2CO3, acetone, r.t.;
(b) (Me)2SO4, K2CO3, acetone, r.t, 65%; (c) prenyl bromide, K2CO3,
acetone, 45 °C, 72%; (d) Florisil, toluene, reflux, 88%; (e) Montmo-
rillonite K10, toluene, reflux, 54%; (f) dilute HCl (aq.), CH3OH, r.t.,
84%; (g) H2SO4, CH3OH, reflux, 90%;
Reagents and conditions: (a) CH3OCH2Cl, K2CO3, acetone, r.t.,
80%; (b) prenyl bromide, K2CO3, acetone, 45 °C, 85%; (c) Florisil,
toluene, reflux, 86%; (d) Montmorillonite K10, toluene, reflux,
8-C-Prenyldiosmetin (1) was isolated from Peanut Hull, which
has been previously described as vasorelaxant agent [16]. Isocann-
flavin B (2) and Cannflavin B (6) were isolated from Cannabis sativa
L, which has demonstrated ability to inhibit the BMP2K kinase and
implied in the development of myopia [17,18]. 8-Prenyl quercetin
(3) was found in Desmodium caudatum [19] with strong suppressed
LPS-induced inflammation activity [2]. 6-C-Prenyldiosmetin (5)
was obtained from cultured cells of Morus alba or Cudrania tricus-
pidate [20] and 3,30,40,7-Tetramethoxy-8-C-Prenylquercetin (4)
was isolated from Phebalium dentatum Smith (Rutaceae) [21]. 6-
C-Prenyl quercetin (7) was isolated from the sheaths of Vellozia kol-
bekii Alves, which was found to be active as 1,1-diphenyl-2-picryl-
hydrazyl (DPPH) radical scavengers [22].
Results and discussion
As is shown in Schemes 1–3, staring materials diosmetin and
quercetin was commercial available, luteolin was prepared from
Scheme 1. Synthetic routes of C-prenylated flavonoids from diosmetin.
Scheme 2. Synthetic routes of C-prenylated flavonoids from luteolin.

W. Li et al. / Tetrahedron Letters 60 (2019) 151138
3
Scheme 3. Synthetic routes of C-prenylated flavonoids from quercetin.
45%; (e) dilute HCl (aq.), CH3OH, r.t., 80%; (f) (Me)2SO4, K2CO3, ace-
tone, r.t, 82%;
MOM-protected 6-C-prenylflavonoid 16 (yield 34%) and MOM-pro-
tected 8-C-prenylflavonoid 15 (yield 38%). The result showed that
Florisil has high selective catalysis on intramolecular [1,5] shift
reaction of 5-O-prenylflavonoids, Montmorillonite K10 clay has
superior catalysis on intramolecular [1,3] shift reaction than Flori-
sil and Montmorillonite KSF (Table 1). The possible mechanism for
the synthesis of 15 and 16 showed that intramolecular [1,3] and
[1,5] shift reaction were formed through an aromatic electrophilic
substitution at nucleophilic aromatic position (C-6 or C-8) under
the catalyzation of acidic clays (in Fig. 2).
Removing the MOM protecting group of MOM-protected 6-C
and 8-C prenylflavonoids 15, 16, 19, 20, 23 and 24 were achieved
by stirring these compounds in 1 mL HCl (3 mol Lꢀ1) and 20 mL
CH3OH for 4 h in reflux. After purification by column chromatogra-
phy methods, we could obtain 8-C-prenylflavonoids 8-C-prenyl-
diosmetin (1), isocannflavin B (2) and 8-C-prenylquercetin (3),
and 6-C prenylflavonoids 6-C-prenyldiosmetin (5), cannflavin B
(6) and Gancaonin P (7). The cyclization reaction of compounds
1, 2, 5 and 6 under acidic conditions in reflux, we could obtain
dihydropyranflavonoids 9–12 [characteristic signals for the 100–
CH2- group at d = 2.64–2.88 (t, J = 6.7 Hz, 2H), 200–CH2- group at
d = 1.85–1.89 (t, J = 6.7 Hz, 2H), and 300–2CH3 group at d = 1.36–
1.32 (s, 6H)]. Introduction of desired methyl functionality on 8-C-
prenylquercetin (3) and Gancaonin P (7) was accomplished by
Once 5-O-prenylflavonoids 14, 18 and 22 were available, our
attention was focused on the formation of 6-and 8-C-prenylated
flavonoid. In our previous research, the key route of synthetic strat-
egy of 8-C-prenylated flavonoid was a regioselective microwave-
assisted Claisen rearrangement from 5-O-prenylflavonoid [5].
Although we were readily able to obtain 8-C-prenylated flavonoid
in good yields under microwave-assisted Claisen rearrangement
reaction, 6-C-prenylated flavonoids were unreachable. In conjunc-
tion with ongoing efforts in our laboratories, we tried to use a con-
venient acidic clay catalyzed intramolecular [1,3] or [1,5] shift
reaction, which was originally reported by Dauben [6], to trans-
form 5-O-prenylflavonoids into 6-or 8-C-prenylated flavonoids. In
Dauben’s work, Montmorillonite KSF clay was used to catalyze
[1,3] shift reaction and obtained a 34% yield of ortho-prenyl phenol
along with small amounts of para-prenyl phenol. Herein we pre-
sent a more detailed investigation of this reaction for the conver-
sion of 5-O-prenylflavonoids to 6-or 8-C-prenylflavonoids.
For compound 14, Florisil (60–100 mesh), Montmorillonite K10
clay (240 m2/g), or Montmorillonite KSF clay (20–40 m2/g) was
used to catalyze this reaction respectively (in Fig. 1). The starting
material 14 was completely consumed after 4 h in the catalysis
of Florisil, with a complete transformation of MOM-protected 8-
C-prenylflavonoid 15 (yield 92%), which was confirmed by the
characteristic NMR signals at d = 3.42 [d, J = 7.0 Hz, 2H, –CH2–
CH = C(CH3)2], 6.47 (s, 1H, 6-H) and loss of H-8 (C-8 position). In
the catalysis of Montmorillonite K10 clay, we could obtain desired
MOM-protected 6-C-prenylflavonoid 16 as major products (yield
Table 1
Intramolecular [1,3] or [1,5] shift reaction of 14 catalyzed by acidic clays respectively.
Acidic clay
Product yield (%)
13
15
16
54%) [characteristic signals for the –CH2–CH@C(CH3)2 group at
d = 3.32 (d, J = 5.9 Hz, 2H), d = 6.65 (s, 1H, 8-H) and loss of H-6]
and MOM-protected 8-C-prenylflavonoid 15 (yield 25%). The treat-
ment of 14 with Montmorillonite KSF clay also give us desired
Florisil
Montmorillonite K10
Montmorillonite KSF
0
18
21
92
25
38
0
54
34
Fig. 1. Intramolecular [1,3] or [1,5] shift reaction of 14 catalyzed by acidic clays respectively.

4
W. Li et al. / Tetrahedron Letters 60 (2019) 151138
Fig. 2. Possible mechanism of intramolecular [1,3] and [1,5] shift reaction for the synthesis of 6-and 8-C-prenylated flavonoids.
using dimethyl sulfate in the presence of potassium carbonate to
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Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151138. These data include
MOL files and InChiKeys of the most important compounds
described in this article.