A simple and effective preparation of quercetin pentamethyl ether from quercetin

Article abstract of DOI:10.3762/bjoc.14.291

Among the five hydroxy (OH) groups of quercetin (3,5,7,3',4'-pentahydroxyflavone), the OH group at 5 position is the most resistant to methylation due to its strong intramolecular hydrogen bonding with the carbonyl group at 4 position. Thus, it is generally difficult to synthesize the pentamethyl ether efficiently by conventional methylation. Here, we describe a simple and effective perO-methylation of quercetin with dimethyl sulfate in potassium (or sodium) hydroxide/dimethyl sulfoxide at room temperature for about 2 hours, affording quercetin pentamethyl ether (QPE) quantitatively as a single product. When methyl iodide was used in place of dimethyl sulfate, the C-methylation product 6-methylquercetin pentamethyl ether was also formed. A computational study provided a rationale for the experimental results.

Full text of DOI:10.3762/bjoc.14.291

A simple and effective preparation of quercetin
pentamethyl ether from quercetin
Jin Tatsuzaki1,2, Tomohiko Ohwada2, Yuko Otani2, Reiko Inagi3 and Tsutomu Ishikawa*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 3112–3121.
1Tokiwa Phytochemical Co. Ltd., 158 Kinoko, Sakura, Chiba
285-0801, Japan, 2Graduate School of Pharmaceutical Sciences, The
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0013, Japan
and 3Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-0013, Japan
doi:10.3762/bjoc.14.291
Received: 25 October 2018
Accepted: 12 December 2018
Published: 28 December 2018
Email:
Associate Editor: B. Stoltz
Tsutomu Ishikawa* - t-ishikawa@tokiwaph.co.jp
© 2018 Tatsuzaki et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
computational calculation; per-O-methylation; quercetin; quercetin
pentamethyl ether; reactivity
Abstract
Among the five hydroxy (OH) groups of quercetin (3,5,7,3',4'-pentahydroxyflavone), the OH group at 5 position is the most resis-
tant to methylation due to its strong intramolecular hydrogen bonding with the carbonyl group at 4 position. Thus, it is generally
difficult to synthesize the pentamethyl ether efficiently by conventional methylation. Here, we describe a simple and effective per-
O-methylation of quercetin with dimethyl sulfate in potassium (or sodium) hydroxide/dimethyl sulfoxide at room temperature for
about 2 hours, affording quercetin pentamethyl ether (QPE) quantitatively as a single product. When methyl iodide was used in
place of dimethyl sulfate, the C-methylation product 6-methylquercetin pentamethyl ether was also formed. A computational study
provided a rationale for the experimental results.
Introduction
Flavonoids are distributed widely in plants, and exhibit various [9-19]. Various PMFs have been isolated from this plant
biological activities [1]. Polymethoxyflavones (PMFs) in partic- [13,19]. Recently our group reported that K. parviflora exhib-
ular have attracted much attention due to their broad spectrum ited sirtuin-activating and antiglycation activities, and we
of activities [2-8]. Kaempferia parviflora Wall. ex. Baker showed that the active principles were PMFs, among which
(Zingiberaceae), called “black turmeric” or “black ginger” in quercetin pentamethyl ether (QPE, 3,5,7,3',4'-pentamethyl-
southern Asia, has been used as a folk medicine for vitality, as a quercetin; 3,5,7,3',4'-pentamethoxyflavone, 1, Figure 1) was the
nutritional supplement, and to reduce blood glucose levels; it most potent [20]. Previous reports have shown that QPE (1) ex-
has been reported to exhibit multiple biological activities hibits anticardiac hypertrophy [21], antidiabetic [22,23],
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to re-examine the per-O-methylation of 2 in detail. In this paper,
we describe a simple, practical and effective preparation of 1
from quercetin (2). A computational study of the methylation
reactions of 2 is also presented.
Results and Discussion
Reported per-O-methylation reactions and
our re-examination
Conventional methylation of phenolic compounds is generally
performed with methyl iodide (MeI) or dimethyl sulfate
(Me2SO4) in an aprotic polar solvent in the presence of a base.
Although acetone and potassium carbonate (K2CO3) are gener-
ally selected as the solvent and base, acetone can be replaced
with dimethylformamide (DMF) if the starting phenol is poorly
soluble in acetone.
Figure 1: Structures of quercetin pentamethyl ether (QPE, 1) and
quercetin (2).
antimetabolic disorder [13,24,25], antithrombotic [26] and
α-glycosidase inhibition activities [14]. However, purification
of large amounts of PMFs from natural sources for further
studies of their bioactivities is difficult because of the presence To our knowledge four reactions [37-40] were found in the lit-
of many structurally related compounds [2]. Therefore, simple erature as successful per-O-methylations of quercetin (2),
and efficient syntheses are required.
among which the three carried out methylations under the
conventional conditions (Table 1). Using MeI and K2CO3 in
PMFs can be synthesized from o-hydroxyacetophenone deriva- DMF QPE (1) was isolated in 86% yield [37] (run 1 in Table 1).
tives in several steps [27,28] or, more easily, from the corre- Per-O-methylations using acetone as a solvent have also been
sponding phenolic flavones by conventional methylation, if the reported. Reactions under reflux with MeI and K2CO3 in 0.2 M
starting phenolic substrate is available [29-33]. Direct prepara- solution [38] (run 2 in Table 1) and with Me2SO4 and K2CO3 in
tion of QPE (1) from quercetin (2) by per-O-methylation is 0.023 M solution [39] (run 3 in Table 1) afforded 1 in 86% and
difficult because the OH group at 5 position is resistant to alkyl- 72% yields, respectively. In the remaining reaction the use of
ation due to its strong intramolecular hydrogen bonding with sodium hydride (NaH) as a base produced 1 in 84% yield [40]
the carbonyl group at 4 position. Indeed, inconsistent experi- (run 4 in Table 1).
mental results have been reported in the literature; incomplete
methylation occurred in some cases [24,34-36], though 1 was We at first re-examined these reactions under the reported
smoothly obtained in other cases [37-40]. Therefore, we set out conditions (Table 1, see Suporting Information, File1). In the
Table 1: Previous per-O-methylations of quercetin (2) and our trials using the reported conditions.
run
methylating agent
(equiv)
base
(equiv)
solvent
(mol/L)a
temp
(°C)
time
(h)
1
(%)
reference
our results
products (%)b
1
2
3
4
MeI (7)
MeI (7)
K2CO3 (6)
K2CO3 (3)
DMF (0.4)
35
reflux
reflux
rtc
12
24
23
12
86
86
72
84
[37]
[38]
[39]
[40]
1 (21), 3 (22), 4 (49)
2 (86)
acetone (0.2)
Me2SO4 (13)
MeI (16)
K2CO3 (33) acetone (0.023)
NaH (4) DMF (0.05)
1 (89)
3 (39)d
a2/solvent. bAlthough commercially available 2 contains water, the yields of products were calculated based on the anhydrous form. The isolated
yields are given. cRoom temperature. dTri-O-methyl derivative 3 was isolated as the main product, though multiple products including 1 and 4 were
observed on TLC.
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first and last reactions, the desired QPE (1) was contaminated mixture of dichloromethane (CH2Cl2) and 10% sodium hydrox-
with 3,7,4'-trimethyl- (3) and 3,7,3',4'-tetramethylquercetin (4), ide (NaOH) aqueous solution in the presence of 0.1 equiv of
albeit the main product was dependent upon the reaction condi- benzyl(triethyl)ammonium chloride [Bn(Et)3NCl] as PTC at
tions (runs 1 and 4 in Table 1). The reaction using a limited room temperature (rt) afforded a mixture of 4 and 1, in which
amount of acetone resulted in the recovery of the staring materi- the desired 1 was a minor component (run 1 in Table 2, see
al due to its practical insolubility (run 2 in Table 1). On the Supporting Information File 1).
other hand QPE (1) was obtained cleanly in good yield at high
dilution, such that 2 was completely dissolved in the latter case The tetramethyl ether 4 showed a lower-field-shifted signal at
(run 3 in Table 1). Thus, we found that an acceptable result was 12.64 ppm in the 1H NMR spectrum (see Supporting Informa-
obtained only under the high dilution conditions using acetone tion File 2), due to strong intramolecular hydrogen-bonding of
as a solvent [39] among our re-examination trials. It is note- the OH group at 5 position with the carbonyl group at 4 posi-
worthy that the per-O-methylated product 1 can be easily tion. This indicates the difficult methylation of the OH group at
detected as a characteristic blue-fluorescent spot on a thin-layer 5 position. Therefore, we consider to apply the more strongly
chromatography (TLC) plate under irradiation with long wave- basic system of potassium hydroxide (KOH) and dimethyl sulf-
length UV light (360 nm).
oxide (DMSO). To a suspension of powdered KOH (9 equiv) in
DMSO were successively added quercetin (2) and Me2SO4
(8 equiv), and the resulting reaction mixture was stirred at rt
Optimization of methylation conditions with Me2SO4
Based on our re-examination of the reported methods, we (CAUTION: careful addition with control of temperature is
selected Me2SO4 as a methylating agent and performed the necessary, because the reaction is exothermic). During the reac-
reaction with only a slight excess of reagents and a limited tion the dark brownish mixture turned a lighter brown, and QPE
volume of solvent, to minimize the cost. The results are summa- (1) was precipitated. Complete methylation was confirmed by
rized in Table 2.
means of TLC (2 h), and 1 was easily isolated in pure form in
85% yield simply by partition with ethyl acetate (EtOAc, run 2
Phase transfer catalysts (PTCs), such as quaternary ammonium in Table 2). QPE (1) was also obtained when NaOH was used in
salt, are effective catalysts for the alkylation of less reactive OH place of KOH (run 3 in Table 2); in this case the product was
functions, such as a hydrogen-bonded phenolic group [41,42]. isolated by filtration after quenching the reaction mixture with a
However, treatment of 2 with 6 equiv of Me2SO4 in a biphasic large amount of water (ca. 9 volumes vs DMSO, see Support-
Table 2: Our studies on the per-O-methylation of quercetin (2) using Me2SO4.
run
Me2SO4 (equiv)
base (equiv)
catalyst (equiv)
solvent (mol/L)a
temp time (h)
products (%)b
1c
2
6
8
10% NaOH aq (6)
KOH (9)
Bn(Et)3NCl (0.1 )
none
CH2Cl2 (0.33)
DMSO (0.42)
DMSO (0.67)
DMF (0.84)
rtd
rtd
rtd
rtd
rtd
rtd
4
2
1 (31), 4 (46)
1 (85)
3e
4
9
NaOH (8)
none
2
1 (66)
9
KOH (9)
none
24
24
24
1 (9), 3 (29), 4 (25)
a mixture (95%)f
a mixture (91%)g
5
9
K2CO3 (9)
K2CO3 (8)
none
DMSO (0.41)
DMF (0.5)
6
5.5
none
a2/solvent. bAlthough commercially available 2 contains water, product yields were calculated based on the anhydrous form. Work-up was done by
partition with EtOAc after quenching with H2O. The isolated yields are given. cThe use of larger amounts of reagents [Me2SO4 (8 equiv) and
Bn(Et)3NCl (0.35 equiv)] decreased the combined yields of 1 and 4 (77%→68%); individual yields of 1 and 4 were 39% and 29% yields, respectively.
dRoom temperature. eFiltration was used for work-up. fTLC revealed a mixture of 3, 4 and an undefined product. The yield was calculated based on
the weight balance of a crude product to 2. gTLC revealed a mixture of 1, 3, 4 and an undefined product. The yield was calculated based on the
weight balance of a crude product to 2.
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ing Information File 1). On the other hand, per-O-methylation Computational insights
was incomplete in the KOH/DMF, K2CO3/DMSO Kim et al. [35] reported that the order of reactivity of the OH
and K2CO3/DMF systems (runs 4, 5 and 6 in Table 2), groups for alkylation of 2 was 7 > 4' > 3 > 3' > 5. Rao et
suggesting that strongly basic potassium (or sodium) methyl- al. [48] showed that methylation occurred in the order of
sulfinylmethylide (KCH2SOMe or NaCH2SOMe) [43-45] 4' > 7 > 3 > 3' > 5, while Bouktaib et al. [49] assigned a reactiv-
might be formed in the KOH (or NaOH)/DMSO system. ity order of 7 > 3 ≈ 4' for monomethylation with a limited
However, almost no reaction was observed upon amount of MeI. On the other hand, Shi et al. [34] obtained a
treatment of 2 with NaCH2SOMe prepared from DMSO mixture of 7,4'-dimethyl and 3,7,4'-trimethyl ethers 3 when 2
and NaH (data not shown). This result suggests that was treated with 3.5 equiv of MeI and a mixture of 3,7,4'-
the hydroxide anion may serve as an effective base in the per- trimethyl 3, 3,7,3',4'-tetramethyl 4 and pentamethyl ethers 1
O-methylation reaction of 2 using the KOH (or NaOH)/DMSO with 5 equiv of MeI. The latter three-component mixture was
system.
also obtained in our re-examination of the reported methyla-
tions as mentioned above. Furthermore, they [34] had indepen-
dently reported the preparation of 3'-methylquercetin from 2 by
Per-O-methylation trial with MeI
We next attempted per-O-methylation of 2 by use of MeI in the following successive reactions: tribenzylation, selective
place of Me2SO4 in the KOH/DMSO system (see Supporting methylation of the OH group at 3' position in the resulting
Information File 1). Although smooth conversion of 2 to 1 3,7,4'-tribenzylquercetin, and deprotection of the benzyl groups.
(67%) occurred, a less polar component 5, showing similar blue These results allowed us to deduce the reactivity order of the
fluorescence to that of 1 under long-wavelength UV-light, was five OH functions on 2 to be 7 ≈ 4' > 3 > 3' > 5, and the ratio-
unexpectedly co-produced in a trace amount. The byproduct 5 nale was accessed by computational studies.
was suggested to be a nuclear-methylated QPE derivative based
on the appearance of a peak at m/z: 387 (MH+) in the MS and Conformation of quercetin and stability of its
an additional 3H signal at 2.18 ppm due to a C-methyl group in oxyanions
the 1H NMR spectrum (see Supporting Information File 2). Computational studies were carried out by using the Gaussian
C-Methylation apparently occurred at the 6- or 8-position, since 09 suite of programs [50]. The geometries of all compounds
the meta-coupled aromatic signals of 1 at 6.33 and 6.49 ppm were fully optimized by using the B3LYP/6-311++G(2d,p)
were replaced by a singlet signal at 6.69 ppm. Inspection of level. Harmonic vibrational frequency calculations character-
2D NMR spectra data (COSY, NOESY, HSQC and HMBC, see ized the optimized structures as ground minima. Bulk solvation
Supporting Information File 2) confirmed that the byproduct 5 effects (self-consistent reaction field, SCRF) were simulated by
was 6-methyl-3,5,7,3',4'-pentamethylquercetin. Selected HMBC using the CPCM method in DMSO as a solvent. The zero-point
correlations between the C-methyl protons (2.18 ppm) and the vibrational energy corrections were done without scaling.
root carbons (157.5 and 162.2 ppm) of 5- and 7-methoxyl
groups are shown in Figure 2. This C-methylation product 5 had Three typical conformers of quercetin (2) were considered
been yielded by the further methylation of 6-methyl-3,7,3',4'- (Figure 3). These are the regioisomers with respect to the direc-
tetra-O-methylquercetin, which was obtained in addition to tion of the OH groups at 3- and 5-positions. The most stable
QPE (1) and the tetramethyl ether 4 in the methylation of 2 conformer 2A contains a hydrogen bond between the OH group
using a large excess of MeI (29 equiv) and KOH (11 equiv) in at 5 position and the carbonyl group at 4 position. The overall
methanol (MeOH) [46,47].
conformation is sensitive to the direction of the OH group at
3 position. The OH isomer at 3 position (2B) was significantly
destabilized as compared with 2A, by 11.7 kcal/mol (in the gas
phase) and 7.9 kcal/mol (in DMSO). This is probably due to
rotation of the 2-phenyl group with respect to the chromenone
plane (by 44°). Furthermore, loss of hydrogen bonding of the
OH group at 5 position with the carbonyl group at 4 position
due to rotation of the OH group at 5 position destabilizes the
system dramatically, as in 2C, by 9.7 kcal/mol (in the gas
phase) and 5.4 kcal/mol (in DMSO); however, the hydrogen
bond is not crucial for the overall planar structure.
Figure 2: Selected HMBC correlations of 6-methyl-3,5,7,3',4'-penta-O-
methylquercetin (5).
The structures and energies of all possible isomeric mono-
anions derived by deprotonation of a single OH group of
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Figure 3: Three representative conformers of neutral quercetin (2). Top and side views are shown. The relative energy is shown in parentheses (gas
phase) and in brackets (in DMSO, in kcal/mol). The dihedral angle around the biaryl structure (3–2–1'–2') is also shown.
quercetin (2) were calculated. The deprotonation is an Change of proton affinity during the methylation
endothermic process in this calculation model. The most stable reaction
anion was derived from the OH group at 7 position (7-anion Although we focused on the deprotonation energy of quercetin
2A), which is stabilized by the conjugation with the carbonyl (2), the deprotonation energy of each OH group may change
group at 4 position. The relative energies of all isomeric oxy- with the progress of methylation. Figure 5 compares the depro-
anions are shown in Figure 4. All the monoanions (anions 2A) tonation energies during generation of 5-anion 2A from neutral
derived from the stable neutral conformer 2A were more stable quercetin 2A, and 5-anion 4A from neutral 3,7,3',4'-tetra-
than those (anions 2B) from the conformer 2B. Among the oxy- methylquercetin (4, conformation 4A). Conformation 4A has a
anions at the OH group at 3 position (3-anions), we calculated structure in which the phenyl group is rotated due to the OMe
the species (3-anion 2C) derived from the neutral conforma- group at the 3 position (the biaryl dihedral angle is +28.2°), and
tion 2C. The 3-anion 2C was significantly more unstable than upon ionization of the OH at 5 position to the oxyanion, the
3-anion 2A, the geometrical difference being only the flip of planarity was not significantly restored. This may increase the
the OH group at 5 position. This is consistent with a large stabi- deprotonation energy in the case of neutral 3,7,3',4'-tetramethyl-
lizing contribution of the hydrogen bond. The 5-anion 2A was quercetin (4). This result is consistent with the experimental ob-
the most unstable species among the anions 2A, and the nega- servation of the difficulty of methylation of the OH group at
tive charge of the anionic oxygen is small (−0.679). While the 5 position, as exemplified by the formation of 4 in some of the
thermodynamic stability (instability) and kinetic reactivity in per-O-methylation trials (see Table 2).
methylation reaction do not always coincide, these features are
consistent with the experimental finding that the OH group at On C-methylation
5 position shows the lowest reactivity, while the OH group at In the methylation reaction using MeI, the C-methylation prod-
7 position shows the highest reactivity. In the cases of anions uct was isolated as a minor product. On the basis of spectros-
2B, all the corresponding anions 3'-anion 2B, 4'-anion 2B, copic analysis, we identified this as the 6-methyl product rather
5-anion 2B, 7-anion 2B tended to take planar overall struc- than the 8-methyl product. The energy difference between the
tures, that is, the biaryl dihedral angles (3–2–1'–2') were two isomeric C-methylation products of the tetramethyl ether
reduced from that of the neural species (2B: −43.8°). In particu- 6-Me-4 and 8-Me-4 was 0.5 kcal/mol (in DMSO, Figure 6); the
lar, 4'-anion 2B and 5-anion 2B are affected by conjugation 6-methyl derivative 6-Me-4 was more stable than the 8-methyl
between the chromenone moiety and the phenyl group one 8-Me-4. The energy difference between the C-methylation
(biaryl dihedral angle: −29.6° in 4'-anion 2B; −29.6° in isomers of per-O-methylated derivative 6-Me-1 and 8-Me-1
5-anion 2B).
was of similar magnitude, 0.6 kcal/mol (in DMSO); again the
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Beilstein J. Org. Chem. 2018, 14, 3112–3121.
Figure 4: Structures of oxyanions derived from quercetin (2) by deprotonation of a single OH group. Top and side views are shown. The relative
energy (in blue) is shown (gas phase) and in brackets (in red, in DMSO, in kcal/mol). The positions of the anions are based on the relative energies in
DMSO. The dihedral angle around the biaryl structure (3–2–1'–2') is also shown. The natural bond orbital (NBO) charge of the anionic oxygen atom is
shown in magenta.
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Beilstein J. Org. Chem. 2018, 14, 3112–3121.
Figure 5: Deprotonation energy of the OH group at 5 position in neutral 2A and tetra-O-methylated quercetin 4A.
6-methylated product 6-Me-1 was more stable than the spectra (HRMS). Quercetin (2) was purchased from Tokyo
8-methylated one 8-Me-1 (Figure 6). These calculation results Chemical Industry Co. Ltd., Japan.
are consistent with the structure 5 (= 6-Me-1) obtained experi-
mentally.
Methylation of quercetin (2) with the Me2SO4/KOH/DMSO
system (run 2 in Table 2): QPE [2-(3,4-Dimethoxyphenyl)-
3,5,7-trimethoxy-4H-1-benzopyran-4-one] (1). To a suspen-
Conclusion
In conclusion, a detailed re-examination of reported methods sion of powdered KOH (1.66 g, 29.7×10−3 mol) in DMSO
enabled us to develop a simple and effective per-O-methylation (8 mL) was slowly added quercetin (2, 1 g, 3.3 × 10−3 mol), fol-
method of quercetin using an Me2SO4/KOH(or NaOH)/DMSO lowed by Me2SO4 (2.5 mL, 26.4 × 10−3 mol), with control of
system as a cost–performance-optimized reaction. In addition, a the temperature to less than 10 °C (CAUTION: The reaction is
computational study could provide a rationale for the experi- exothermic). The resulting dark brown solution was stirred at rt
mental observations.
for 2 h, during which time the color changed to light brown.
The reaction was quenched with H2O (80 mL), and the result-
ing suspension was extracted with EtOAc (50/20/20 mL) The
Experimental
General procedures. Melting points were determined with a EtOAc solution was successively washed with 5% NaOH aq
melting point hot-stage instrument without correction. (10 mL × 4), H2O (10 mL × 3), and brine (10 mL), dried over
1H (400 MHz) and 13C NMR spectra (100 MHz) were recorded sodium sulfate, and evaporated under reduced pressure to give
in CDCl3 on a Bruker Avance 400. Chemical shifts were shown QPE (1) as a light brown solid (1.05 g), which was homoge-
in ppm (δ) values, and coupling constants are shown in hertz neous on TLC and showed a single peak at the same retention
(Hz). Chemical shifts were calibrated with internal tetramethyl- time as that of an authentic sample. Recrystallization
silane or with the solvent peak for the 1H and 13C NMR spectra. from MeOH gave colorless prisms, mp 147–149 °C
The following abbreviations are used: s = singlet, d = doublet, (lit. mp 136–137 °C [34]; mp 151 °C [39]; mp 151.2 °C [51]:
t = triplet, q = quartet, dd = double doublet. Electron spray 1H NMR δ 3.88 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.95 (s, 9H,
ionization time-of-flight mass spectra (ESI–TOF MS) were re- OMe × 3), 6.34 (d, J = 2.2 Hz, 1H, 6- or 8-H), 6.49 (d,
corded on a Bruker micrOTOF-05 to give high-resolution mass J = 2.2 Hz, 1H, 6- or 8-H), 6.97 (d, J = 8.4 Hz, 1H, 5'-H), 7.71
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Figure 6: Structures and energies of C-methylated products of the tetra- 4 and the penta-O-methyl quercetins 1.
(dd, J = 8.4, 2.0 Hz, 1H, 6'-H), 7.72 (s-like, 1H, 2'-H); Acknowledgements
13C NMR δ 55.9, 56.1, 56.3, 56.6, 60.1, 92.7, 96.0, 109.8, The computations were performed at the Research Center for
111.2, 111.8, 121.8, 123.8, 141.4, 149.0, 151.2, 152.6, 159.0, Computational Science, Okazaki, Japan.
161.3, 164.1, 174.1.
ORCID® iDs
Tomohiko Ohwada - https://orcid.org/0000-0001-5390-0203
Supporting Information
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