Synthesis of oriented anti-virus 7-O-substituted apigenins

Article abstract of DOI:10.3987/COM-08-S(N)79

7-O-Substituted apigenins were synthesized for searching anti-virus active compound. Using a commercially available naringenin as a starting material, 7-O-methylapigenin (1) and seven unnatural 7-0-substituted apigenin derivatives (13-19) were prepared via 4'-O-methoxymethylapigenin (5) as an intermediate.

Full text of DOI:10.3987/COM-08-S(N)79

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1607 - 1615. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2008, Accepted, 12th June, 2008, Published online, 16th June, 2008. COM-08-S(N)79
SYNTHESIS OF ORIENTED ANTI-VIRUS
7-O-SUBSTITUTED APIGENINS†
Kin-ichi Oyama,a Tadao Kondo, and Kumi Yoshidab,*
a Chemical Instrument Room, Research Center for Materials Science, bGraduate
School of Inforamtion Science, Nagoya University, Chikusa, Nagoya 464-8601,
Japan; *E-mail address: yoshidak@is.nagoya-u.ac.jp
Abstract – 7-O-Substituted apigenins were synthesized for searching anti-virus
active compound. Using a commercially available naringenin as a starting
material, 7-O-methylapigenin (1) and seven unnatural 7-O-substituted apigenin
derivatives (13-19) were prepared via 4’-O-methoxymethylapigenin (5) as an
intermediate.
INTRODUCTION
Flavonoids are plant second metabolites possessing various biological functions and have a long history
as Chinese medicine, herbal medicines and folk medicines. Among them flavone is one of important class
of compounds that displays a broad range of medicinal properties.1-3 Recently anti-virus activity of
flavones attracts interests and some natural products such as 7-O-methylapigenin (1) was reported to
posess a anti-influenza activity.3 Therefore, we studied on anti-virus oriented synthesis of flavone
derivatives. For this purpose divergent synthesis of 7-O-substituted flavones is necessary, but synthetic
study of alkylated flavones by direct alkylation reaction is rare,4 because regioselective reaction for
polyphenolic OHs in flavone skelton is difficult. We have been studied on synthesis of flavonoids and
reported the difference in reactivity of phenolic hydroxyl groups.5-7 In the case of naringenin 7-OH
showed the highest reactivity in nucleophilic alkylation and 4’-OH showed the next and 5-OH exhibited
the lowest reactivity.5,6 In benzylation of (+)-catechin 7-OH was less reactive than 5 and 4’-OH.7
Furthermore, we have reported that DDQ oxidation of naringenin to apigenin proceed easily.5 Therefore,
† Dedicated to Prof. Ryoji Noyori on the occasion of his 70th birthday.

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we planed to the synthesis of 7-O-subustituted apigenin derivatives from corresponding naringenin
derivatives. Here, we report synthesis of a natural occurring 7-O-methylapigenin (1)8 and seven unnatural
7-O-substituted apigenin analogues by a systematical synthesis via 4’-O-methoxymethylapigenin (5) as a
key intermediate.
RESULTS AND DISCUSSION
At first 7-O-methylapigenin (1) was synthesized. Commercially available naringenin was methylated with
MeI to give 7-O-methyl compound 2 as a major compound (76%).6 2 was, then, oxidized with DDQ to
give flavone 1 in 45% yield.
OH
OH
OH
MeO
O
O
HO
O
O
MeO
O
O
DDQ
45%
MeI
76%
OH
OH
OH
naringenin
2
1
Scheme 1. Synthesis of 7-O-methylapigenin (1).
Scheme 2. Synthesis of 4’-O-methoxymethylapigenin (5).
Since the separation of 1 from DDQ was difficult because of the high polarity of 1, this reaction sequence
seemed to be improper for a large scale preparation and structural diversity oriented synthesis. Therefore,

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we change the strategy; naringenin having bulky protecting group was oxidaized with DDQ, then
replacing of protecting group and 7-O-alkylation reaction was carried out. We designed a precursor 5 for
a key intermediate. 7-OH of naringenin was protected with TBS group, then the 2,3-bond was oxidized
with DDQ to give 3.5 Then, 4’-OH was eterified by MOMCl (69%) followed by desilylation by TBAF to
give 5 in 81%. Fortunately, 5 was purified by recrystallization.
Table 1. Synthesis of 7-O-substituted apigenin anlogues (13-19).
7-OH of 5 was substituted with various alkyl- and sulfonyl-reagents (Table 1). The alkylation reaction of
5 was carried out with NaH and each alkylhalide in DMF to give 7-O-ethyl-, n-propyl-, i-propyl-, n-butyl-
and benzyl-apigenin 6-10 (entries 1-5). Mesylation and tosylation of 5 were carried out with
corresponding sulfonyl chloride with Et3N in CH2Cl2 to give 11 and 12 (Table 1, entries 6 and 7).
Deprotection of 4’-O-MOM residue of 6-12 was carried out in AcCl/MeOH to be obtained
7-O-substituted apigenin derivatives 13-19 in high yield, repectively.
A naturally occurring 7-O-methylapigenin (1) with seven unnatural 7-O-substituted apigenins were
synthesized from naringenin. The studies on anti-virus activities are in progress. Furthermore,
7-O-TBS-apigenin (3) and 4’-O-methoxymethylapigenin (5) should be a usuful and powerful
intermediate for synthesis of a variety of apigenin derivatives, therefore, further synthesis of substituted
apigenins are going on.

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EXPERIMENTAL
General
Melting points were recorded on a Yanagimoto MP-S3 apparatus and uncorrected. IR spectra were
obtained with a JASCO FT/IR-6100 spectrometer. NMR spectra were obtained with a JEOL A-600 (13C:
13
13
150 MHz ), ECA-500 (1H: 500 MHz, C: 125 MHz), and a JNM-A400 (1H: 400 MHz, C: 100 MHz)
instrument in a 5-mm φ tube at variable temperature using CDCl3 and DMSO-d6 as a solvent. Chemical
shifts were reported as δ (ppm) with the CD2HCl resonance as a standard and the coupling constant was
expressed in Hz. FABMS (m-nitrobenzyl alcohol as a matrix) were recorded on a JEOL JMS-700
spectrometer. Elemental analyses were perpormed on YANACO MT-6 elemental analyser. Silica gel
column chromatography was performed with Fuji Silysia FL60D. Thin layer chromatography was
performed on Merck Kieselgel 60 F254.
7-O-Methylapigenin (1)
A solution of 2 (543 mg, 1.9 mmol) and DDQ (863 mg, 1.9 mmol) in 1,4-dioxane (15 mL) was refluxed
for 15 h at 110 ˚C. The reaction mixture was purified by flash column chromatography (hexane-AcOEt
1:1) to afford 1 (241 mg, 45%) as a pale yellow powder: mp 293-294 ºC; IR (KBr) 3277, 1668, 1605,
1500, 1294 cm-1; (DMSO-d6, 500 MHz) δ 3.83 (3H, s), 6.34 (1H, d, J = 2.0 Hz), 6.73 (1H, d, J = 2.0 Hz),
13
6.81 (1H, s), 6.89 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5), 10.39 (1H, s), 12.92 (1H, s); C NMR
(DMSO-d6, 125 MHz) δ 56.6, 93.2, 98.5, 103.5, 105.2, 116.5, 121.6, 129.1, 157.7, 161.7, 161.8, 164.6,
165.7, 182.5; HRMS (FAB) Calcd. for C16H13O5 (M+H+) 285.0763, found 285.0775; Anal. Calcd for
C16H12O5: C, 67.60; H, 4.25. Found: C, 67.24; H, 4.25
7-O-tert-Butyldimethylsilyl-4’-O-methoxymethylapigenin (4)
To a solution of 3 (581 mg, 1.51 mmol) and i-PrNEt2 (0.39 mL, 2.26 mmol) in CH2Cl2 (10 mL) was
added MOMCl (0.18 mL, 2.26 mmol) at rt. After stirring for 2 h, the reaction mixture was quenched by
addition of saturated aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were dried over
anhydrous MgSO4 and evaporated in vacuo. The crude product was purified by flash column
chromatography (hexane-AcOEt 3:1) to give 4 (450 mg, 69%) as a pale yellow powder: mp 113-114 ºC;
IR (KBr) 2928, 1651, 1606, 1499, 1235, 847 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.28 (6H, s), 1.00 (9H,
s), 3.50 (3H, s), 5.25 (2H, s), 6.30 (1H, d, J = 2.0 Hz), 6.43 (1H, d, J = 2.0 Hz), 6.58 (1H, s), 7.15 (2H, d,
13
J = 9.0 Hz), 7.83 (2H, d, J = 9.0 Hz); C NMR (CDCl3, 150 MHz) δ -4.4, 18.2, 25.5, 56.3, 94.2, 98.7,
103.8, 104.6, 106.1, 116.5, 124.7, 128.0, 157.6, 160.2, 162.1, 162.2, 163.9, 182.5; HRMS (FAB) Calcd.
for C23H29O6Si (M+H+) 429.1733, found 429.1726.

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4’-O-Methoxymethylapigenin (5)
To a solution of 4 (118 mg, 0.275 mmol) in THF (2 mL) was added TBAF (1 M solutin in THF) (275 µL,
0.275 mmol) at rt. After 10 min, the reaction mixture was poured into saturated aqueous NH4Cl and
extracted with AcOEt. The combined extracts were dried over anhydrous MgSO4 and evaporated in vacuo.
The crude product was purified by recrystallization (AcOEt-CHCl3-hexane) to afford 5 (70 mg, 81%) as a
1
pale yellow solid: mp 209-210 ºC; IR (KBr) 3162, 1650, 1620, 1506, 1237, 830 cm-1; H NMR (CDCl3,
400 MHz) δ 3.39 (3H, s), 5.29 (2H, s), 6.19 (1H, d, J = 2.0 Hz), 6.49 (1H, d, J = 2.0 Hz), 6.87 (1H, s),
7.17 (2H, d, J = 9.0 Hz), 8.02 (2H, d, J = 9.0 Hz), 12.89 (1H, s);13C NMR (DMSO-d6, 100 MHz) δ 55.9,
93.8, 94.1, 99.0, 103.8, 103.9, 116.5, 123.9, 128.3, 157.4, 159.8, 161.5, 163.3, 164.3, 181.8; HRMS
(FAB) Calcd. for C17H15O6 (M+H+) 315.0869, found 315.0869.
Typical procedure for alkylation
To a solution of 5 (15.7 mg, 50 µmol), and NaH (6 mg, 150 µmol) in DMF (0.5 mL) was added n-PrBr
(14 µL, 150 µmol) at rt. After stirring for 2 h, the reaction mixture was quenched by addition of saturated
aqueous NH4Cl and extracted with AcOEt. The combined extracts were dried over anhydrous MgSO4 and
evaporated in vacuo. The crude product was purified by thin layer chromatography (hexane-AcOEt 3:1)
to give 7 (10.9 mg, 61%) as a pale yellow powder.
7-O-Ethyl-4’-O-methoxymethyl apigenin (6)
Pale yellow powder: mp 131-132 ºC; IR (KBr) 2928, 1666, 1603, 1503, 1243, 828 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.45 (3H, t, J = 7.0 Hz), 3.50 (3H, s), 4.10 (2H, q, J = 7.0 Hz), 5.23 (2H, s), 6.35 (1H, d, J =
2.0 Hz), 6.47 (1H, d, J = 2.0 Hz), 6.58 (1H, s), 7.18 (2H, d, J = 9.0 Hz), 7.82 (2H, d, J = 9.0 Hz), 12.75
13
(1H, s); C NMR (CDCl3, 100 MHz) δ 14.6, 56.3, 64.2, 93.0, 94.2, 98.4, 104.6, 105.5, 116.5, 124.7,
128.0, 157.7, 160.1, 162.1, 163.8, 164.9, 182.4; HRMS (FAB) Calcd. for C19H19O6 (M+H+) 343.1182,
found 343.1177.
4’-O-Methoxymethyl-7-O-n-propylapigenin (7)
Pale yellow powder: mp 115-116 ºC; IR (KBr) 2925, 1663, 1603, 1503, 1242, 829 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.05 (3H, t, J = 7.0 Hz), 1.84 (2H, sec, J = 7.0 Hz), 3.99 (2H, t, J = 7.0 Hz), 5.25 (2H, s),
6.35 (1H, d, J = 2.0 Hz), 6.47 (1H, d, J = 2.0 Hz), 6.57 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.82 (2H, d, J =
13
9.0 Hz), 12.75 (1H, s); C NMR (CDCl3, 100 MHz) δ 10.4, 22.3, 56.3, 70.1, 93.0, 94.2, 98.5, 104.6,
105.4, 116.5, 124.7, 127.9, 157.7, 160.1, 162.1, 163.8, 165.1, 182.4; HRMS (FAB) Calcd. for C20H21O6
(M+H+) 357.1338, found 357.1338.

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4’-O-Methoxymethyl-7-O-i-Propylapigenin (8)
Pale yellow powder: mp 144-145 ºC; IR (KBr) 2925, 1663, 1609, 1499 1237, 840 cm-1;1H NMR (CDCl3,
400 MHz) δ 1.39 (6H, d, J = 6.0 Hz), 3.50 (3H, s), 4.63 (1H, sep, J = 6.0 Hz), 5.25 (2H, s), 6.33 (1H, d, J
= 2.0 Hz), 6.45 (1H, d, J = 2.0 Hz), 6.57 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.82 (2H, d, J = 9.0 Hz), 12.69
(1H, s); 13C NMR (CDCl3, 100 MHz) δ 21.9, 56.3, 70.7, 93.9, 94.2, 99.1, 104.6, 105.3, 116.5, 124.7,
128.0, 157.8, 160.1, 162.2, 163.8, 164.0, 182.4; HRMS (FAB) Calcd. for C20H21O6 (M+H+) 357.1338,
found 357.1338.
7-O-n-Butyl-4’-O-methoxymethylapigenin (9)
Pale yellow powder: mp 120-121 ºC; IR (KBr) 2956, 1662, 1606, 1504, 1240, 836 cm-1; 1H NMR (CDCl3,
400 MHz) δ 0.99 (3H, t, J = 7.0 Hz), 1.51 (2H, sec, J = 7.0 Hz), 1.80 (2H, quint, J = 7.0 Hz), 3.50 (3H, s),
4.04 (2H, t, J = 6.5 Hz), 5.25 (2H, s), 6.35 (1H, d, J = 2.0 Hz), 6.47 (1H, d, J = 2.0 Hz), 6.57 (1H, s), 7.15
(2H, d, J = 9.0 Hz), 7.83 (2H, d, J = 9.0 Hz), 12.64 (1H, s);13C NMR (CDCl3, 100 MHz) δ 13.8, 19.1,
31.0, 56.3, 68.3, 93.0, 94.2, 98.5, 104.6, 105.4, 116.5, 124.7, 127.9, 157.7, 160.1, 162.1, 163.8, 165.1,
182.4; HRMS (FAB) Calcd. for C21H23O6 (M+H+) 371.1495, found 371.1505.
7-O-Benzyl-4’-O-methoxymethylapigenin (10)
Pale yellow powder: mp 101-102 ºC; IR (KBr) 2903, 1663, 1605, 1502, 1243, 834 cm-1; 1H NMR (CDCl3,
400 MHz) δ 3.50 (3H, s), 5.14 (2H, s), 5.25 (2H, s), 6.45 (1H, d, J = 2.0 Hz), 6.56 (1H, d, J = 2.0 Hz),
6.58 (1H, s), 7.15 (2H, d, J = 9.0 Hz), 7.4-7.3 (5H, m), 7.82 (2H, d, J = 9.0 Hz), 12.79 (1H, s);13C NMR
(CDCl3, 150 MHz) δ 56.3, 70.4, 93.5, 94.2, 98.8, 104.7, 116.6, 124.6, 127.5, 128.0, 128.3, 128.7, 135.8,
157.7, 160.2, 162.2, 163.9, 164.5, 182.4; HRMS (FAB) Calcd. for C24H21O6 (M+H+) 405.1338, found
405.1331.
Typical procedure for Mesylation and tosylation
To a solution of 5 (15.7 mg, 50 µmol), and NEt3 (21 µL, 150 µmol) in CH2Cl2 (1 mL) was added MsCl (5
µL, 60 µmol) at 0 ºC. After stirring for 40 min, the reaction mixture was quenched by addition of
saturated aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were dried over anhydrous
MgSO4 and evaporated in vacuo. The crude product was purified by recrystallization
(AcOEt-CHCl3-hexane) to give 11 (17.0 mg, 87%) as a colorless powder.
7-O-Mesyl-4’-O-methoxymethylapigenin (11)
1
Colorless solid: mp 170-171 ºC; IR (KBr) 1651, 1605, 1364, 1239, 1001, 838 cm-1; H NMR (CDCl3, 400
MHz) δ 3.24 (3H, s), 3.51 (3H, s), 5.26 (2H, s), 6.70 (1H, d, J = 2.0 Hz), 7.02 (1H, d, J = 2.0 Hz), 6.68

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(1H, s), 7.18 (1H, d, J = 9.0 Hz), 7.85 (2H, d, J = 9.0 Hz), 12.93 (1H, s);13C NMR (CDCl3, 150 MHz) δ
38.1, 56.3, 94.2, 101.1, 105.0, 105.2, 109.6, 116.7, 123.9, 128.3, 153.6, 156.8, 160.7, 162.4, 165.0, 182.6;
HRMS (FAB) Calcd. for C18H17O8S (M+H+) 393.0644, found 393.0640.
4’-O-Methoxymethyl-7-O-tosylapigenin (12)
1
Colorless solid: mp 164-165 ºC; IR (KBr) 1650, 1605, 1352, 1242, 998, 826 cm-1; H NMR (CDCl3, 400
MHz) δ 2.47 (3H, s), 3.51 (3H, s), 5.26 (2H, s), 6.32 (1H, d, J = 2.0 Hz), 6.65 (1H, s), 6.91 (1H, d, J = 2.0
Hz), 7.17 (2H, d, J = 9.0 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 9.0 Hz),
13
12.82 (1H, s); C NMR (CDCl3, 150 MHz) δ 21.8, 56.3, 94.2, 101.6, 104.9, 105.5, 109.5, 116.7, 124.0,
128.2, 128.5, 130.0, 146.0, 154.3, 156.6, 160.6, 161.9, 164.9, 182.7; HRMS (FAB) Calcd. for C24H21O8S
(M+H+) 469.0957, found 469.0952.
Typical procedure for deprotection of 6-12
To a solution of 8 (9.3 mg, 26 µmol) in a mixture of MeOH (1 mL) and CH3Cl (1 mL) was added AcCl
(0.3 mL) at rt. After 10 min, the reaction mixture was poured into saturated aqueous NaHCO3 and
extracted with AcOEt. The combined extracts were dried over anhydrous MgSO4 and evaporated in vacuo.
The crude product was purified by thin layer chromatography (hexane-AcOEt 2:1) to give 14 (6.8 mg,
84%) as a pale yellow powder.
7-O-Ethylapigenin (13)
Pale yellow powder: mp 247-248 ºC: IR (KBr) 3146, 2925, 1663, 1598, 1256, 836 cm-1; (DMSO-d6, 500
MHz) δ 1.31 (3H, t, J = 6.0 Hz), 4.11 (2H, q, J = 7.0 Hz), 6.31 (1H, d, J = 2.0 Hz), 6.72 (1H, d, J = 2.0
Hz), 6.80 (1H, s), 6.89 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5), 10.45 (1H, s), 12.90 (1H, s); 13C NMR
(DMSO-d6, 125 MHz) δ 14.9, 64.7, 93.5, 98.8, 103.5, 105.0, 116.5, 121.6, 129.1, 157.7, 161.7, 161.8,
164.6, 164.9, 182.4; HRMS (FAB) Calcd. for C17H15O5 (M+H+) 299.0919, found 299.0929; Anal. Calcd
for C17H14O5: C, 68.45; H, 4.73. Found: C, 68.22 ; H, 4.73.
7-O-n-Propylapigenin (14)
1
Pale yellow powder: mp 209-210 ºC: IR (KBr) 3157, 2963, 1664, 1612, 1240, 833 cm-1; H NMR
(DMSO-d6, 500 MHz) δ 0.94 (3H, t, J = 7.5 Hz), 1.72 (2H, sec, J = 7.5 Hz), 4.01 (2H, t, J = 7.5 Hz), 6.31
(1H, d, J = 2.0 Hz), 6.73 (1H, d, J = 2.0 Hz), 6.80 (1H, s), 6.89 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5),
10.44 (1H, s), 12.90 (1H, s); 13C NMR (DMSO-d6, 125 MHz) δ 10.8, 22.3, 70.4, 93.6, 98.8, 103.5, 105.1,
116.5, 121.6, 129.1, 157.8, 161.7, 161.8, 164.6, 165.1, 182.4; HRMS (FAB) Calcd. for C18H17O5 (M+H+)
313.1076, found 313.1061; Anal. Calcd for C18H16O5: C, 69.22; H, 5.16. Found: C, 69.16; H, 5.39.

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7-O-i-Propylapigenin (15)
1
Pale yellow powder: mp 255-256 ºC: IR (KBr) 3162, 2980, 1661, 1607, 1244, 834 cm-1; H NMR
(DMSO-d6, 500 MHz) δ 1.26 (6H, d, J = 6.0 Hz), 4.74 (1H, sep, J = 6.0 Hz), 6.28 (1H, d, J = 2.0 Hz),
6.72 (1H, d, J = 2.0 Hz), 6.78 (1H, s), 6.89 (2H, d, J = 8.5 Hz), 7.92 (2H, d, J = 8.5), 10.45 (1H, s), 12.87
(1H, s); 13C NMR (DMSO-d6, 125 MHz) δ 22.2, 71.0, 94.2, 99.5, 103.5, 104.9, 116.5, 121.6, 129.1, 157.9,
161.7, 161.8, 164.0, 164.6, 182.4; HRMS (FAB) Calcd. for C18H17O5 (M+H+) 313.1076, found 313.1061;
Anal. Calcd for C18H16O5: C, 69.22; H, 5.16. Found: C, 68.68 ; H, 5.26.
7-O-n-Butylapigenin (16)
1
Pale yellow powder: mp 183-184 ºC; IR (KBr) 3142, 2926, 1665, 1606, 1173, 819 cm-1; H NMR
(DMSO-d6, 500 MHz) δ 0.90 (3H, t, J = 7.5 Hz), 1.41 (2H, sec, J = 7.5 Hz), 1.68 (2H, sep, J = 7.5 Hz),
4.06 (1H, t, J = 7.5 Hz), 6.31 (1H, d, J = 2.0 Hz), 6.74 (1H, d, J = 2.0 Hz), 6.80 (1H, s), 6.89 (2H, d, J =
8.5 Hz), 7.91 (2H, d, J = 8.5), 10.42 (1H, s), 12.90 (1H, s); 13C NMR (DMSO-d6, 125 MHz) δ 14.2, 19.2,
31.0, 68.7, 93.6, 98.8, 103.5, 105.1, 116.5, 121.6, 129.8, 157.7, 161.7, 161.8, 164.6, 165.1, 167.9, 182.4;
HRMS (FAB) Calcd. for C19H19O5 (M+H+) 327.1232, found 327.1240; Anal. Calcd for C19H18O5: C,
69.93; H, 5.56. Found: C, 69.37 ; H, 5.64.
7-O-Benzylapigenin (17)
1
Pale yellow powder: mp 217-218 ºC: IR (KBr) 3142, 2924, 1660, 1596, 1174, 834 cm-1; H NMR
(DMSO-d6, 500 MHz) δ 5.21 (2H, s), 6.43 (1H, d, J = 2.0 Hz), 6.82 (1H, s), 6.83 (1H, d, J = 2.0 Hz), 6.89
(2H, d, J = 8.5 Hz), 7.32 (1H, m), 7.38 (2H, m), 7.44 (2H, m), 7.92 (2H, d, J = 8.5), 10.41 (1H, s), 12.92
13
(1H, s); C NMR (DMSO-d6, 500 MHz) δ 70.5, 94.1, 99.1, 103.6, 105.3, 116.5, 121.6, 128.4, 128.7,
129.1, 136.7, 157.7, 161.7, 161.8, 164.7, 182.5; HRMS (FAB) Calcd. for C22H17O5 (M+H+) 361.1076,
found 361.1069. ; Anal. Calcd for C22H16O5: C, 73.33; H, 4.48. Found: C, 73.30 ; H, 4.79.
7-O-Mesylapigenin (18)
1
Pale yellow solid: mp 228-229 ºC; IR (KBr) 3248, 1652, 1606, 1357, 1177, 836 cm-1; H NMR
(DMSO-d6, 400 MHz) δ 3.50 (3H, s), 6.81 (1H, d, J = 2.0), 6.94 (2H, d, J = 9.0 Hz), 7.00 (1H, s), 7.25
(1H, d, J = 2.0 Hz), 8.01 (2H, d, J = 9.0), 10.46 (1H, s), 13.12 (1H, s); 13C NMR (DMSO-d6, 125 MHz) δ
38.3, 102.3, 104.1, 105.8, 109.5, 116.6, 121.2, 129.5, 154.1, 154.8, 161.7, 162.2, 165.6, 182.9; HRMS
(FAB) Calcd. for C16H13O7S (M+H+) 349.0382, found 349.0391; Anal. Calcd for C16H12O7S: C, 55.17; H,
3.47. Found: C, 55.12 ; H, 3.54.
7-O-Tosylapigenin (19)

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1
Pale yellow solid: mp 224-225 ºC; IR (KBr) 3220, 1651, 1604, 1338, 1180, 836 cm-1; H NMR
(DMSO-d6, 500 MHz) δ 2.39 (3H, s), 6.38 (1H, d, J = 2.5 Hz), 6.91 (2H, d, J = 8.5 Hz), 6.93 (1H, s), 7.02
(1H, d, J = 2.5), 7.48 (2H, d, J = 8.0 Hz), 7.81 (2H, d, J = 8.0), 7.95 (2H, d, J = 8.5), 10.51 (1H, s), 13.01
13
(1H, s); C NMR (DMSO-d6, 125 MHz) δ 21.7, 102.1, 104.1, 105.3, 109.4, 116.6, 121.1, 128.9, 129.5,
131.0, 131.5, 146.9, 153.9, 156.6, 161.4, 162.2, 165.6, 182.7; HRMS (FAB) Calcd. for C22H17O7S
(M+H+) 425.695, found 425.0708; Anal. Calcd for C22H16O7S: C, 62.26; H, 3.80. Found: C, 62.35 ; H,
3.95.
ACKNOWLEDGEMENTS
This work was financially supported by The Ministry of Education, Culture, Sports, Science and
Technology, Japan (The 21st Century COE Program No. 14COEB01-00, Creative Scientific Research
No.16GS0206, Global COE in Chemistry, Nagoya University and Research on Priority Area No.
18032037 and Young Scientist (B) No. 18780086).
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