Synthesis of fluorine-containing 3-hydroxyflavanones and isoflavones

Article abstract of DOI:10.1007/s10600-011-9824-5

Fluorine-containing 3-hydroxyflavanones and isoflavones were synthesized by epoxidation of F-containing chalcones by hydrogen peroxide under basic conditions and subsequent intramolecular cyclization of the resulting epoxides using BF₃·Et₂O. The ratio of products depended on the presence and position of the F atom.

Full text of DOI:10.1007/s10600-011-9824-5

Chemistry of Natural Compounds, Vol. 47, No. 1, March, 2011 [Russian original No. 1, January–February, 2011]
SYNTHESIS OF FLUORINE-CONTAINING
3-HYDROXYFLAVANONES AND ISOFLAVONES
*
T. S. Khlebnikova, Yu. A. Pivenꢀ,
UDC 547.814.5:547.539.1
N. B. Khripach, and F. A. Lakhvich
Fluorine-containing 3-hydroxyflavanones and isoflavones were synthesized by epoxidation of F-containing
chalcones by hydrogen peroxide under basic conditions and subsequent intramolecular cyclization of the
resulting epoxides using BF ·Et O. The ratio of products depended on the presence and position of the F
3
2
atom.
Keywords: F-containing 3-hydroxyflavanones, isoflavones, chalcone epoxides.
Flavonoids include a large group of polyphenolic natural compounds that are widely distributed in higher plants and
exhibit various types of biological activity [1]. Notable among them is 3-hydroxyflavanone, taxifolin (dihydroquercetin),
which exhibits strong hepatoprotective activity [2] and is a powerful antioxidant [3] that is used to treat is chemic
stroke, angina pectoris, and other cardiovascular diseases [3]. Genistein (5,7,4ꢀ-trihydroxyisoflavone) and diadzein
(7,4ꢀ-dihydroxyisoflavone) are some of the most common and most studied isoflavonoids with broad spectra of biological
activity (antioxidant, antitumor, estrogenic, and other types of physiological activity) [3, 4–8].
Selective introduction of F atoms or fluoroalkyl groups is a well-known technique for modifying the biological
activity of various classes of natural compounds including steroids, nucleosides, antibiotics, prostaglandins, and others [9].
Herein the synthesis of novel 3-hydroxyflavanones and isoflavones containing an F atom is investigated. For this, we
studied a synthetic approach that included transformation of F-containing chalcone epoxides using BF ·Et O as a Lewis acid
3
2
[10]. This approach enabled both 3-hydroxyflavanones 1 and isoflavones 2 (mono- and di-F-substituted depending on the
structures of the starting materials) to be obtained. The chalcones were prepared via condensation of the corresponding
acetophenones and benzaldehydes under basic conditions. The starting material for constructing the F-substituted flavonoid
ring A was 2-hydroxy-4-fluoroacetophenone; F-substituted ring B, 4-fluorobenzaldehyde.
Y
OCH C H
2
6
5
OH
F
X
OR
OR
X
X
2'
Y
4'
2
B
4a,b
O
TsOH
H O
2 2
4
H
A
6'
A
B
6
ꢁ
NaOH
H
ꢀ
O
OH
O
O
O
3a,b, 7a,b
3a, b: R = H
7a, b: R = CH C H
9a - c
5
6, 8a - c
6: R = H
8a - c: R = CH C H
8a - c
9a - c
2
6
5
2
6
5
3'
6'
CHO
Y
2'
4'
5'
1
1
8
8
X
7
8a
4a
O
X
7
8a
4a
O
2
2
BF - Et O
3
2
+
2'
1'
6
6
4
4
3'
4'
3
3
OH
5
5
Y
O
2a,b
O
1a - c
6'
Y
5'
4a,b
1a, 2a, 6, 8a, 9a: X = H, Y = F; 1b, 2b, 6, 8b, 9b: X = Y = F; 1c, 8c, 9c: X = F, Y = NO ; 3a, 7a: X = H; 3b, 7b: X = F; 4a: Y = F; 4b: Y = NO
2
2
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141, Minsk, ul. Akad. Kuprevicha,
5/2, e-mail: khlebnicova@iboch.bas-net.by. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 31–35, January–
February, 2011. Original article submitted May 18, 2010.
©
0009-3130/11/4701-0033 2011 Springer Science+Business Media, Inc.
33

13
TABLE 1. PMR and C NMR Spectra of 1a–c and 2a, 2b
1à 1b
1c
2à
2b
C atom
Ñ, ppm, 2JCF/Hz
ꢃ
C-2
83.12
73.66
83.46
73.36
192.68
82.95
73.40
191.97
152.91
124.55
176.21
124.49
126.42
125.36
133.75
118.09
156.24
152.93
124.84
175.33
C-3
C-4
C-4a
C-5
C-6
C-7
C-8
C-8a
C-1ꢀ
194.05
118.44
127.39
122.27
137.05
118.11
161.58
115.40 (d, 4J = 3)
129.93 (d, 3J = 11)
110.88 (d, 2J = 23)
168.12 (d, 1J = 256)
105.12 (d, 2J = 23)
163.29 (d, 3J = 12)
131.81 (d, 4J = 3)
129.37 (d, 3J = 8)
115.74 (d, 2J = 23)
163.25 (d, 1J = 247)
115.44 (d, 4J = 3)
130.18 (d, 3J = 12)
111.35 (d, 2J = 23)
168.33 (d, 1J = 257)
105.35 (d, 2J = 23)
163.01 (d, 3J = 13)
143.06
121.41 (d, 4J = 3)
129.83 (d, 3J = 11)
114.26 (d, 2J = 23)
164.72 (d, 1J = 256)
104.70 (d, 2J = 25)
157.26 (d, 3J = 13)
127.59 (d, 4J = 4)
130.74 (d, 3J = 8)
115.60 (d, 2J =22)
162.94 (d, 1J = 247)
132.21 (d, 4J = 3)
129.35 (d, 3J = 8)
115.70 (d, 2J = 21)
163.20 (d, 1J = 248)
127.78 (d, 4J = 3)
130.70 (d, 3J = 8)
115.51 (d, 2J = 22)
162.78 (d, 1J = 248)
128.36
123.89
148.54
ꢀ
ꢀ
C-2 , C-6
C-3ꢀ, C-5ꢀ
C-4ꢀ
H atom
ꢃ
Í, ppm, J/Hz
Í-2
Í-3
Í-5
Í-6
Í-7
Í-8
Í-2 , Í-6
Í-3ꢀ, Í-5ꢀ
Î-Í
5.13 (d, J = 12.5)
4.59 (dd, J = 12.5, 1.6)
7.93 (dd, J = 7.7, 1.6)
7.13 m
7.57 m
7.05 (dd, J = 8.3, 1.6)
7.56 m
5.14 (d, J = 12.8)
4.56 (dd, J = 12.8, 1.6)
7.95 (dd, J = 8.6, 6.4)
6.85 (td, J = 8.3, 2.2)
–
6.74 (dd, J = 9.6, 2.2)
7.55 m
5.27 (d, J = 12.2)
4.50 (dd, J = 12.2, 1.3)
7.98 (dd, J = 8.6, 6.4)
6.98 (td, J = 8.4, 2.2)
–
6.79 (dd, J = 9.3, 2.2)
8.32 m
8.01 s
–
7.98 s
–
8.33 m
8.32 (dd, J = 8.3, 1.9)
7.45 (ddd, J = 8.0, 7.0, 0.9) 7.17 m
7.70 (ddd,J = 1.6, 7.0, 8.7)
7.50 (d, J = 8.7)
7.56 m
7.14 m
–
–
7.18 m
7.54 m
7.14 m
–
ꢀ
ꢀ
7.17 m
3.70 (d, J = 1.6)
7.16 m
–
7.78 m
3.75 (d, J = 1.3)
The reaction of equivalent amounts of 2-hydroxyacetophenone (3a) and 4-fluorobenzaldehyde (4a) in the presence
of KOH at 0°C for 72 h formed only ꢁ-hydroxy-4-fluorodihydrochalcone 5, dehydration of which in refluxing benzene in the
presence of p-toluenesulfonic acid produced trans-chalcone 6. However, subsequent epoxidation of 6 formed a complicated
product mixture. Therefore, the hydroxyl of 2-hydroxyacetophenones 3a and 3b was protected by refluxing with benzylchloride
in EtOH in the presence of K CO to produce 2-benzyloxyacetophenones 7a and 7b in good yields. Alkaline aldol condensation
2
3
of benzylated 2-hydroxyacetophenones 7a and 7b and benzaldehydes 4a and 4b at 0°C produced trans-chalcones 8a-c in 70–
90% yields. Epoxidation of F-containing chalcones 8a–c by H O in the presence of NaOH (10%) gave the F-containing
2
2
trans-epoxides of chalcones 9a–c (52–90% yields). Then, these underwent cyclization by BF ·Et O to form 2,3-trans-3-
3
2
hydroxyflavanones 1a–c and rearrangement with subsequent cyclization to form isoflavones 2a and 2b, the ratio of which
depended on the positions of the substituents. Thus, the yield of 1a was 40% with an F atom in the 4-position of 9a; of
isoflavone 2a, 6%. Introduction of an F atom in the 4ꢀ-position of 9b gave 1b (42%) and also increased the yield of 2b (to
28%). Apparently the formation of only 1c in 60% yield can be explained by the influence of the nitro group in the 4-position
of epoxide 9c ring B.
13
19
The structures of the synthesized 1, 2, and 5–9 were confirmed by IR, PMR, C NMR, and F NMR spectral data.
2
Thus, the PMR spectrum of 5 showed resonances for two nonequivalent ꢂ-methylene protons at ꢃ 3.43 ppm (dd, J = 17.7 Hz,
3
2
3
3
J = 9.0 Hz) and 3.36 (dd, J = 17.7 Hz, J = 3.2 Hz), for a proton as a doublet at 5.36 ( J = 9.0 Hz), and for a hydroxyl proton
as a broad singlet at 3.32. According to the literature [11, 12], this confirmed that 5 was a ꢁ-hydroxychalcone. The presence
of resonances for vinyl protons at 7.59 and 7.89 with SSCC 15.6 Hz and at 7.38–7.45 and 7.40–7.62 with SSCC 15.7–15.8 was
indicative of the trans-configuration of 6 and benzylated chalcones 8a–c, respectively. PMR spectra of trans-epoxides 9a–c
typically showed resonances for the epoxide ring at 3.96–4.03 and 4.23-4.39 with SSCC 1.7 [13] in addition to methylene
resonances of the benzyl at 4.91–4.98 and 4.98–5.01 with geminal SSCC 10.9–12.0 because of the nonequivalent protons.
34

H
H
O
O
H
X
H
H
H
Y
H
H
Fig. 1. Characteristic C—H correlations in HMBC spectra of 2a and 2b.
3
The orientations of the C-2 and C-3 substituents of 1a–c were established based on the SSCC J = 12.1–12.8 Hz,
2,3
19
which were characteristic of trans-diaxial coupled protons. The F NMR spectra of 1a, 1c, 2a, 5, 6, 8a, 8c, and 9a gave an F
resonance in the range from –97.3 to –113.6 ppm; for 1b, 2b, 8b, and 9b, for two F atoms in the range from –98.4 to –104.1
and –110.1 to –113.6.
Table 1 presents the NMR spectral data for 1a–c and 2a, 2b. It can be seen that the positions and shapes of the
resonances for C-1ꢀ–C-6ꢀ of 4ꢀ-fluoro 3-hydroxyflavanones 1 and isoflavones 2 are practically independent of the structure of
2
the other parts of the molecules. The location of the F atom in the 4ꢀ-position was confirmed by the J
SSCC of 247–
C4ꢀ,F
3
4
5
248 Hz. The SSCC J , J , and J were 20–23, 8, and 3-4, respectively, and agreed with the expected values. Resonances
CF
CF
CF
13
in the PMR and C NMR spectra were fully assigned using two-dimensional spectroscopy (COSY, HSQC, HMBC, NOESY,
J-resolved, TOCSY) included in the standard programs of the spectrometer. Quaternary C atoms were assigned by analyzing
their through-space C–H couplings. Thus, a cross-peak for the C-4a resonance with those for H-6 and H-8; for C-8a with
H-5, H-8, and H-2; and for C-7 with H-5, H-6, and H-8 appeared in the HMBC spectra of all studied compounds (Fig. 1).
Splitting of the C-1ꢀ resonance as the result of through-space coupling with F also argued in favor of the selected assignments
for C-3 (cross peaks with H-2, H-2ꢀ, and H-6ꢀ) and C-1ꢀ (cross peaks with H-2, H-3ꢀ, and H-5ꢀ).
Thus, F-containing 3-hydroxyflavanones and isoflavones were synthesized from the corresponding chalcone epoxides.
Transformation by BF ·Et O of chalcone epoxides containing an F atom in the 4ꢀ -position gave primarily 3-hydroxyflavanones
3
2
whereas introduction of an F atom in the 4-position favored isomerization of the epoxide and increased the yield of the
isoflavone. The presence of a nitro group in the 4-position formed only the 3-hydroxyflavanone.
EXPERIMENTAL
NMR spectra were taken in CDCl on a Bruker Avance-500 spectrometer (if not indicated otherwise) using TMS as
3
13
19
an internal standard for PMR (500 MHz) and C NMR (125 MHz) spectra and CCl F for F NMR (470 MHz). IR spectra
3
were recorded in KBr disks on a Bomem Michelson 100 instrument. Melting points were determined on a Boetius block. The
course of reactions and the purity of products were monitored by TLC on Silufol UV-254 plates using Et O. Elemental
2
analyses of all compounds agreed with those calculated.
Benzylation of Acetophenones 3a and 3b. A solution of acetophenone (3a, 3b, 0.001 mol) and benzylchloride
(0.006 mol) in Et O (30 mL) was treated with K CO (0.006 mol) and refluxed for 6 h. The solvent was removed in a rotary
2
2
3
evaporator. The solid was dissolved in CHCl (30 mL), washed with H O (3 ꢄ 10 mL), and dried over MgSO . The solvent
3
2
4
was removed in a rotary evaporator. The solid was purified by column chromatography (EtOAc:hexane) to afford 7a and 7b.
2-Benzyloxyacetophenone (7a): yield 92%, mp 38–40°C (EtOH), in agreement with the literature [14].
2-Benzyloxy-4-fluoroacetophenone (7b): yield 83%, mp 58–59°C (EtOH), C H FO .
15 13
2
–1
IR spectrum (KBr, ꢅ, cm ): 1664 (C=O), 1606, 1265. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 2.57 (3H, s, Me), 5.14
3
13
(2H, s, CH ), 6.73 (2H, m, H
), 7.36–7.45 (5H, m, H
), 7.83 (1H, m, H
).
C NMR spectrum (CDCl , ꢃ, ppm,
2
arom
arom
arom
3
2
2
3
J
/Hz): 32.21, 71.20, 100.86 (d, J = 26), 108.06 (d, J = 21), 124.87, 127.8, 128.79, 128.65, 132.92 (d, J = 11), 135.55,
159.97 (d, J = 11), 166.26 (d, J = 253), 198.11. F NMR spectrum (CDCl , ꢃ, ppm): –103.91.
CF
3
1
19
3
Condensation of Acetophenones 3a, 7a, 7b and Benzaldehydes 4a and 4b. A solution of acetophenone (3a, 7a,
7b, 2 mmol) and benzaldehyde (4a, 4b, 2 mmol) in EtOH (10 mL) was stirred at room temperature and treated dropwise with
KOH (3 mL, 3%). For 4a, the mixture was held at 0°C for 72 h. The resulting precipitate was filtered off, washed with H O
2
(3 mL), and dried in vacuo to afford ꢁ-hydroxydihydrochalcone 5 or chalcones 8a and 8b, respectively. For 4b, the mixture
35

was stirred at room temperature under an Ar atmosphere for 18 h and treated with H O (10 mL). The resulting precipitate was
2
filtered off and dried in vacuo to afford 8c. Compounds 5 and 8a–c were isolated as colorless crystalline compounds.
ꢁ-Hydroxy-4-fluorodihydrochalcone 5: yield 63%, mp 107–109°C (EtOH), C H FO .
15 13
3
–1
IR spectrum (KBr, ꢅ, cm ): 1639 (C=O), 1604, 1512. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 3.32 (1H, br.s, OH),
3.34 (1H, dd, J = 17.7, J = 3.2), 3.42 (1H, dd, J = 17.7, J = 9.0), 5.36 (1H, d, J = 9.0), 6.89 (1H, m, H
3
2
3
2
3
3
), 7.00 (1H, m,
arom
13
H
), 7.07 (2H, m, H
), 7.42 (2H, m, H
), 7.50 (1H, m, H
), 7.69 (1H, m, H
), 12.04 (1H, m, OH). C NMR
arom
arom
arom
arom
arom
2
3
spectrum (CDCl , ꢃ, ppm, J /Hz): 47.27, 69.39, 115.64 (d, J = 21), 118.86, 119.33, 128.59 (d, J = 8), 130.14, 137.37,
138.58, 162.46 (d, J = 246), 162.73, 205.45. F NMR spectrum (CDCl , ꢃ, ppm): –114.78.
3
CF
1
19
3
2ꢀ-Benzyloxy-4-fluorochalcone (8a): yield 90%, mp 108–110°C (EtOH), C H FO .
22 17
2
–1
IR spectrum (KBr, ꢅ, cm ): 1654 (C=O), 1599, 1583. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 5.16 (2H, s, CH ),
3
2
3
6.98 (2H, t, J = 8.6, H
), 7.07 (2H, m, H
), 7.58 (1H, d, J = 15.7, H
), 7.32 (5H, m, H
), 7.42 (3H, m, H
), 7.42 (3H, m, H ), 7.43 (1H,
arom
arom
arom
arom
arom
3
3
13
d, J = 15.7, H
), 7.76 (1H, m, H
). C NMR spectrum (CDCl , ꢃ, ppm, J /Hz): 70.74,
112.87, 115.84 (d, J = 22), 121.23, 127.07, 127.74, 128.16, 128.67, 129.12, 130.19 (d, J = 9), 131.02, 131.40, 133.35,
136.18, 141.34, 157.64, 163.74 (d, J = 251), 191.77. F NMR spectrum (CDCl , ꢃ, ppm): –110.23.
vinyl
vinyl
arom
3
CF
2
3
1
19
3
2ꢀ-Benzyloxy-4,4ꢀ-difluorochalcone (8b): yield 89%, mp 101–104°C (EtOH), C H F O .
22 16 2
2
–1
IR spectrum (KBr, ꢅ, cm ): 1649 (C=O), 1600, 1587. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 5.14 (2H, s, CH ), 6.79
3
2
3
(2H, m, H
), 6.97 (2H, m, H
), 7.28 (2H, m, H
), 7.35 (3H, m, H
), 7.45 (3H, m, H
), 7.45 (1H, d, J = 15.8,
arom
arom
arom
arom
arom
3
13
H
), 7.62 (1H, d, J = 15.8, H
), 7.85 (1H, m, H
). C NMR spectrum (CDCl , ꢃ, ppm, J /Hz): 71.16, 100.78 (d,
arom
vinyl
arom
3
CF
2
2
2
3
J = 26), 108.28 (d, J = 22), 115.86 (d, J = 22), 125.15, 126.72, 127.25, 127.86, 128.48, 128.82, 130.21 (d, J = 9), 133.30 (d,
3
3
1
1
19
J = 11), 135.42, 141.44, 159.44 (d, J = 11), 163.77 (d, J = 251), 166.07 (d, J = 253), 189.85. F NMR spectrum (CDCl ,
3
ꢃ, ppm): –104.11, –110.12.
2ꢀ-Benzyloxy-4-nitro-4ꢀ-fluorochalcone (8c): yield 71%, mp 178–180°C (EtOH), C H FNO .
22 16
4
–1
IR spectrum (KBr, ꢅ, cm ): 1653 (C=O), 1606, 1587. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 5.14 (2H, s, CH ), 6.83
3
2
3
3
(2H, m, H
(2H, m, H
), 7.31 (2H, m, H
), 7.63 (2H, m, H
), 7.31 (1H, m, H
), 7.38 (1H, d, J = 15.6, H
), 7.40 (1H, d, J = 15.6, H
). C NMR spectrum (CDCl , ꢃ, ppm, J /Hz):
71.41, 100.76 (d, J = 26), 108.57 (d, J = 22), 123.95, 124.40, 128.24, 128.69, 128.80, 128.95, 130.71, 133.73 (d, J = 11),
135.15, 139.00, 141.50, 148.15, 159.88 (d, J = 11), 166.55 (d, J = 254), 188.87. F NMR spectrum (CDCl , ꢃ, ppm):
), 7.46
arom
arom
arom
arom
vinyl
vinyl
13
), 7.92 (1H, m, H
), 8.08 (2H, m, H
arom
arom
arom
3
CF
2
2
3
3
1
19
3
–102.75.
Dehydration of ꢁ-Hydroxy-4-fluorodihydrochalcone (5). A solution of 5 (0.52 g, 2 mmol) in benzene (30 mL)
was refluxed with a Dean—Stark trap in the presence of a catalytic amount of p-toluenesulfonic acid for 7 h, washed with
H O, and dried over MgSO . The solvent was removed in a rotary evaporator. The solid was purified by column chromatography
2
4
(EtOAc:hexane) to afford 6 (0.48 g, 88%) as a yellow crystalline compound, mp 115–117°C (Et O:hexane), C H FO .
2
15 11
2
–1
IR spectrum (KBr, ꢅ, cm ): 1639 (C=O), 1581, 1508. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 6.95 (1H, m, H
),
3
arom
3
7.04 (1H, m, H
), 7.14 (2H, m, H
), 7.51 (2H, m, H
), 7.59 (1H, d, J = 15.6, H
), 7.67 (2H, m, H
), 7.89 (1H,
arom
arom
arom
13
vinyl
arom
3
2
d, J = 15.6, H
), 7.91 (1H, m, H
), 12.79 (1H, s, OH). C NMR spectrum (CDCl , ꢃ, ppm, J /Hz): 116.40 (d, J = 22),
118.63, 119.02, 119.96, 120.09, 129.74, 130.76 (d, J = 8), 131.03, 136.62, 144.28, 163.75, 164.42 (d, J = 252), 193.08.
vinyl
arom
3
CF
3
1
19
F
NMR spectrum (CDCl , ꢃ, ppm): –108.53.
3
Epoxidation of F-Containing Chalcones 8a-c. A solution of 8a-c (1 mmol) in acetone (10 mL) and MeOH (2 mL)
was stirred at room temperature, treated with NaOH solution (0.3 mL, 10%), treated dropwise with H O solution (1 mL,
2
2
30%), and refluxed for 1.5–6 h (TLC monitoring). The organic solvents were removed in a rotary evaporator. The residue was
dissolved in CHCl (30 mL), washed with H O (2 ꢄ 10 mL), and dried over MgSO . The CHCl was removed in a rotary
3
2
4
3
evaporator to afford chalcone epoxides 9a-c as colorless crystalline compounds.
2ꢀ-Benzyloxy-4-fluorochalcone epoxide (9a): yield 90%, mp 112–115°C (Et O), C H FO .
2
22 17
3
–1
3
IR spectrum (KBr, ꢅ, cm ): 1660 (C=O), 1597, 1514. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 3.98 (1H, d, J = 1.6,
3
3
2
2
H
), 4.23 (1H, d, J = 1.6, H
), 4.98 (1H, d, J = 12.0, CH ), 5.01 (1H, d, J = 12.0, CH ), 6.93 (2H, m, H
), 7.04
epoxide
epoxide
2
2
arom
13
(2H, m, H
), 7.13 (4H, m, H
), 7.24 (3H, m, H
), 7.50 (1H, m, H
), 7.84 (1H, m, H
). C NMR spectrum
arom
arom
arom
arom
arom
2
(CDCl , ꢃ, ppm, J /Hz): 59.37, 63.23, 70.83, 112.89, 115.58 (d, J = 22), 121.32, 126.39, 127.44, 127.52, 128.33, 128.68,
3
CF
1
19
131.02, 131.77, 134.86, 135.38, 158.61, 162.90 (d, J = 247), 194.97. F NMR spectrum (CDCl , ꢃ, ppm): –113.35.
3
2ꢀ-Benzyloxy-4,4ꢀ-difluorochalcone epoxide (9b): yield 52%, mp 114–117°C (Et O), C H F O .
2
22 16 2 3
–1
3
IR spectrum (KBr, ꢅ, cm ): 1668 (C=O), 1600, 1514. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 3.96 (1H, d, J = 1.6,
3
3
2
2
H
), 4.39 (1H, d, J = 1.6, H
), 4.94 (1H, d, J = 11.5, CH ), 4.98 (1H, d, J = 11.5, CH ), 6.75 (2H, m, H
), 6.93
epoxide
epoxide
2
2
arom
36

13
(2H, m, H
), 7.12 (4H, m, H
), 7.26 (3H, m, H
), 7.90 (1H, m, H
). C NMR spectrum (CDCl , ꢃ, ppm, J /Hz):
arom 3 CF
arom
arom
arom
2
2
2
71.16, 100.78 (d, J = 26), 108.28 (d, J = 22), 115.86 (d, J = 22), 125.15, 126.72, 127.25, 127.86, 128.48, 128.82, 130.21 (d,
J = 9), 133.30 (d, J = 11), 135.42, 141.44, 159.44 (d, J = 11), 163.77 (d, J = 251), 166.07 (d, J = 253), 189.85. F NMR
3
3
3
1
1
19
spectrum (CDCl , ꢃ, ppm): –104.11, –110.12.
3
2ꢀ-Benzyloxy-4-nitro-4ꢀ-fluorochalcone epoxide (9c): yield 67%, mp 170–173°C (Et O), C H FNO .
2
22 16
5
–1
3
IR spectrum (KBr, ꢅ, cm ): 1674 (C=O), 1605, 1523. PMR spectrum (CDCl , ꢃ, ppm, J/Hz): 4.03 (1H, d, J = 1.6,
3
3
2
2
H
m, H
), 4.39 (1H, d, J = 1.6, H
), 4.91 (1H, d, J = 10.8, CH ), 4.97 (1H, d, J = 10.8, CH ), (2H, m, H
), 7.17 (7H,
epoxide
epoxide
2
2
arom
13
), 7.95 (1H, m, H
), 8.03 (2H, m, H
). C NMR spectrum (CDCl , ꢃ, ppm, J /Hz): 58.54, 63.02, 71.57,
arom
arom
arom 3 CF
2
2
3
100.86 (d, J = 26), 108.91 (d, J = 22), 123.82, 126.32, 127.98, 128.77, 133.60 (d, J = 11), 134.23, 143.15, 147.93, 151.90,
160.60 (d, J = 11), 167.15 (d, J = 256). F NMR spectrum (CDCl , ꢃ, ppm): –100.67.
3
1
19
3
Transformation of Chalcone Epoxides 9a-c by BF ·Et O. A solution of F-containing epoxide 9a-c (1 mmol) in
3
2
benzene (15 mL) was stirred, treated with BF ·Et O (0.5 mL) at room temperature, stirred for 30 min, treated with Et O
3
2
2
(50 mL), washed with H O (3 ꢄ 15 mL), and extracted with NaOH solution (5%, 3 ꢄ 15 mL). The organic layer was dried over
2
MgSO . The solvent was removed in a rotary evaporator. The solid was chromatographed over a column (EtOAc:hexane) to
4
afford 1a-c in 40, 42, and 60% yields, respectively. The alkaline solution was acidified with dilute HCl (1:10) and extracted
with Et O. The extract was dried over MgSO . The solvent was removed. The solid was chromatographed over a column
2
4
(EtOAc:hexane) to afford 2a and 2b in 6 and 28% yields, respectively. Isoflavone 2c was not isolated.
3-Hydroxy-4ꢀ-fluoroflavanone (1a): yield 40%, mp 149–133°C (Et O:hexane), C H FO . IR spectrum (KBr,
2
15 11
3
–1
19
ꢅ, cm ): 1697 (C=O), 1606, 1577. F NMR spectrum (CDCl , ꢃ, ppm): –112.52.
3
3-Hydroxy-7,4ꢀ-difluoroflavanone (1b): yield 42%, mp 97–100°C (Et O:hexane), C H F O . IR spectrum (KBr,
2
15 10 2 3
–1
19
ꢅ, cm ): 1695 (C=O), 1615, 1591. F NMR spectrum (CDCl , ꢃ, ppm): –98.46, –112.20.
3
3-Hydroxy-4ꢀ-nitro-7-fluoroflavanone (1c): yield 60%, mp 153–156°C (Et O:hexane), C H FNO . IR spectrum
2
15 10
5
–1
19
(KBr, ꢅ, cm ): 1695 (C=O), 1612, 1591. F NMR spectrum (CDCl , ꢃ, ppm): –97.83.
3
4ꢀ-Fluoroisoflavone (2a): yield 6%, mp 188–190°C (Et O:hexane), which agreed with the literature [15], C H FO .
2
15
9
2
–1
19
IR spectrum (KBr, ꢅ, cm ): 1639 (C=O), 1604, 1573. F NMR spectrum (CDCl , ꢃ, ppm): –113.92.
7,4ꢀ-Difluoroisoflavone (2b): yield 28%, mp 225–227°C (Et O:hexane), C H F O . IR spectrum (KBr, ꢅ, cm ):
1643 (C=O), 1620, 1604. F NMR spectrum (CDCl , ꢃ, ppm): –102.96, –113.59.
3
–1
2
15 8 2 2
19
3
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