Synthesis of 6- or 8-bromo flavonoids by regioselective mono-bromination and deprotection protocol from flavonoid alkyl ethers

Article abstract of DOI:10.1002/bkcs.10286

C-6 and C-8 monobromo flavonoids are important building blocks for the synthesis of flavonoid natural products and their derivatives. Bromination of suitably alkylated flavonoids with N-bromosuccinimide in dichloromethane (DCM), followed by deprotection with BCl₃, gives either a C-6 or a C-8 monobromo flavonoid in high yield and with high regioselectivity, depending on the protection pattern of the C-5 and C-7 OH groups. The mild and neutral conditions are particularly useful for the regioselective bromination of acid-labile substrates.

Full text of DOI:10.1002/bkcs.10286

Article
DOI: 10.1002/bkcs.10286
BULLETIN OF THE
G. Pan et al.
KOREAN CHEMICAL SOCIETY
Synthesis of 6- or 8-Bromo Flavonoids by Regioselective Mono-
Bromination and Deprotection Protocol from Flavonoid Alkyl Ethers
†,
Guojun Pan,† Ke Yang,† Yantao Ma,† Xia Zhao,‡ Kui Lu,†, and Peng Yu
*
*
†Key Laboratory of Industrial Fermentation Microbiology (Tianjin University of Science and Technology),
Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology,
Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, Tianjin University of
Science & Technology, Tianjin 300457, China. *E-mail: lukui@tust.edu.cn; yupeng@tust.edu.cn
‡College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules,
Tianjin Normal University, Tianjin 300387, China
Received November 19, 2014, Accepted January 28, 2015, Published online April 28, 2015
C-6 and C-8 monobromo flavonoids are important building blocks for the synthesis of flavonoid natural
products and their derivatives. Bromination of suitably alkylated flavonoids with N-bromosuccinimide in
dichloromethane (DCM), followed by deprotection with BCl3, gives either a C-6 or a C-8 monobromo flavo-
noid in high yield and with high regioselectivity, depending on the protection pattern of the C-5 and C-7 OH
groups. The mild and neutral conditions are particularly useful for the regioselective bromination of acid-labile
substrates.
Keywords: Flavonoids, Regioselective, Bromination
Introduction
susceptible to dehalogenation in the aforementioned coupling
reactions, especially when a bulky substituent is located ortho
to the halogen group, compared to the corresponding bromide.
In 1985, Ichikawa achieved the transformations of quercetin
and kaempferol to their 6-bromo and 6,8-dibromo derivatives
by a mixture of HBr and H2O2 in methanol.6 However, the
strong acidic conditions limited their applications. In 2010
and 2014, Lewin7 and Rocco8 reported the bromination of
quercetin and its derivatives with N-bromosuccinimide
(NBS), respectively. However, a mixture of 6-bromo, 8-
bromo, and 6,8-dibromo products was obtained under these
conditions. This encouraged us to develop an efficient regio-
selective method to prepare bromo-substituted flavonoids.
Herein we report a mild and regioselective monobromination
of O-alkylated flavonoid derivatives using NBS as
Flavonoids are polyphenolic secondary metabolites found in
plants and various common food.1 Many of them possess a
broad range of pharmacological properties including antican-
cer, antiviral, antioxidant, and anti-inflammatory properties.2
Among those, C-6 and C-8 alkyl or aryl substituted flavonoids
are most common; they can be prepared from the correspond-
ing halogen-substituted flavonoids by Suzuki coupling3 or
Ullmann coupling.4 Recently, we developed a regioselective
iodination method for flavonoids by N-iodosuccinimide
(NIS) under neutral conditions (Scheme 1).5 Although the
O-alkylated mono-iodo flavonoids can be obtained in high
yield, the subsequent dealkylation is always accompanied
bydeiodination. Moreover, itiswellknown that iodideismore
Scheme 1. Regioselective iodination of flavonoids by NIS.
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Regioselective Bromination of Flavonoids
KOREAN CHEMICAL SOCIETY
bromination reagent in DCM. By using this protocol, mono-
bromo flavonoids can be prepared easily by regioselective
bromination and subsequent dealkylation.
25 ꢀC. After the addition, the mixture was stirred for 2 h and
thenconcentratedtodryness under reducedpressure, thecrude
product was purified by column chromatography on silica
(petroleum ether/ethyl acetate 3:1) to afford compound 15
(433 mg, 96%) as a white solid. Data for 15: 1H NMR (400
MHz, CDCl3, δ): 7.98 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.00
(d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 4.04 (s, 6H), 3.98 (s, 3H),
3.97 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3, δ):
56.0, 56.1, 56.8, 60.2, 90.6, 93.9, 106.4, 110.9, 111.3,
122.3, 122.6, 139.1, 148.9, 151.6, 155.7, 156.2, 158.2,
161.3, 178.2; LRMS (ESI) m/z 453 [M + H]+; HRMS (ESI)
m/z: Calcd for C20H20O7Br [M + H]+ 451.0387; found,
451.0380; m.p.: 185.9–186.0 ꢀC.
Experimental
Synthesis of Bromo-Flavonoid Alkyl Ethers. 6-Bromo-2-
(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chro-
men-4-one
(2);
8-bromo-2-(3,4-dimethoxyphenyl)-5-
hydroxy-3,7-dimethoxy-4H-chromen-4-one (3); and 6,8-
dibromo-2-(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-
4H-chromen-4-one (4). NBS (196 mg, 1.1 mmol) was
added in portions to 1 (358 mg, 1.0 mmol) in DCM (10 mL)
at −40 ꢀC over 5 min. The mixture was stirred for 6 h at
−40 ꢀC. After completion of the reaction, the mixture was con-
centrated to dryness under reduced pressure. The crude product
was purified by column chromatography on silica (petroleum
ether/ethyl acetate/dichloromethane 30:1:1) to afford com-
pound 2 (223 mg, 51%)and compound 3 (109 mg, 25%)asyel-
6-Bromo-2-(3,4-diethoxyphenyl)-3,7-diethoxy-5-hydroxy-
4H-chromen-4-one (9) and 8-bromo-2-(3,4-diethoxyphe-
nyl)-3,7-diethoxy-5-hydroxy-4H-chromen-4-one
(10).
NBS (196 mg, 1.1 mmol) was added in portions to 8 (414
mg, 1.0 mmol) in DCM (10 mL) at −40 ꢀC over 5 min. The
mixture was stirred for 6 h at −40 ꢀC. After completion of
the reaction, the mixture was concentrated to dryness under
reduced pressure, the crude product was purified by column
chromatography on silica (petroleum ether/ethyl acetate/
dichloromethane 30:1:1) to afford compound 9 (281 mg,
57%) and compound 10 (59 mg, 12%) as yellow solids. Data
for 9: 1H NMR (400 MHz, CDCl3, δ): 13.45 (s, 1H), 7.74 (s,
1H), 7.71 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.49 (s,
1H), 4.16–4.21 (m, 6H), 4.08 (q, J = 7.2 Hz, 2H), 1.51 (m,
9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
δ): 14.4, 14.7, 14.9, 15.6, 64.5, 64.9, 65.5, 68.7, 91.2, 94.2,
106.2, 112.2, 113.7, 122.2, 122.7, 137.9, 148.2, 151.4,
155.7, 156.6, 158.2, 160.7, 178.34; LRMS (ESI) m/z 493
[M + H]+; HRMS (ESI) m/z: Calcd for C23H26O7Br [M +
H]+ 493.0856; found, 493.0851; m.p.: 169.3–171.9 ꢀC. Data
1
low solids. Data for 2: H NMR (400 MHz, DMSO-d6, δ):
13.42 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.17 (d,
J = 8.8 Hz,1H), 7.06 (s, 1H), 3.99 (s, 3H), 3.87 (s, 6H), 3.84
(s, 3H); 13C NMR (100 MHz, CDCl3, δ): 56.0, 56.1, 56.8,
60.3, 90.6, 94.0, 106.4, 110.9, 111.3, 122.3, 122.6, 139.1,
148.9, 151.6, 155.7, 156.2, 158.2, 161.3, 178.2; LRMS (ESI)
m/z 439 [M + H]+; HRMS (ESI) m/z: Calcd for C19H17O7Br
[M + H]+ 437.0230; found, 437.0226; m.p.: 180.9–182.0 ꢀC.
Data for 3: 1H NMR (400 MHz, CDCl3, δ): 12.79 (s, 1H),
8.00 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.02 (d, J = 8.8 Hz, 1H),
6.46 (s, 1H), 3.99 (s, 9H), 3.92 (s, 3H); 13C NMR (100 MHz,
CDCl3, δ): 55.9, 56.0, 56.9, 60.1, 87.7, 95.6, 106.2, 111.0,
111.2, 122.8, 122.8, 138.9, 148.9, 151.7, 152.4, 155.8,
161.6, 178.6; LRMS (ESI) m/z 439 [M + H]+; HRMS (ESI)
m/z: Calcd for C19H17O7Br [M + H]+ 437.0230; found,
437.0228; m.p.: 218.8–219.0 ꢀC.
1
for 10: H NMR (400 MHz, CDCl3, δ): 7.95–7.97 (m, 2H),
7.00 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 4.18–4.23 (m, 6H),
4.13 (q, J = 6.8 Hz, 2H), 1.50–1.54 (m, 9H), 1.39 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3, δ): 14.5, 14.7, 14.8,
15.7, 64.5, 64.6, 65.5, 68.6, 87.9, 96.3, 106.1, 112.4, 113.3,
122.6, 122.9, 137.8, 148.2, 151.3, 152.5, 156.2, 161.0,
161.4, 178.8; LRMS (ESI) m/z 493 [M + H]+; HRMS (ESI)
m/z: Calcd for C23H26O7Br [M + H]+ 493.0856; found,
493.0849; m.p.: 172.4–173.2 ꢀC.
NBS (196 mg, 1.1 mmol) was added in portions to 1
(358 mg, 1 mmol) in DMF (10 mL) at 0 ꢀC over 5 min. The
mixture was stirred for 6 h at 0 ꢀC. After completion of the
reaction, the mixture was diluted with DCM (50 mL) and
washed with water (100 mL × 3). The organic phase was con-
centrated to dryness under reduced pressure, the crude product
was purified by column chromatography on silica (petroleum
ether/ethyl acetate/dichloromethane 30:1:1) to afford com-
pound 2 (101 mg, 23%) and compound 4 (160 mg, 31%)
8-Bromo-2-(3,4-diethoxyphenyl)-3,5,7-triethoxy-4H-
chromen-4-one (17). NBS (178 mg, 1.0 mmol) was added to
a stirred solution of 16 (442 mg, 1.0 mmol) in DCM (10 mL)
at 25 ꢀC. After completion of the reaction, the mixture was
concentrated to dryness under reduced pressure, the crude
product was purified by recrystallization in ethyl acetate to
get a yellow solid 17 (505 mg, 97%). Data for 17: 1H NMR
(400 MHz, CDCl3, δ): 7.97 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H),
6.99 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 4.12–4.23 (m, 10H),
1.50–1.58 (m, 12H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3, δ): 14.6, 14.7, 14.8, 15.7, 64.4, 64.5,
65.3, 65.6, 67.9, 76.8, 77.1, 77.4, 90.8, 94.1, 110.1, 112.4,
113.2, 122.1, 123.4, 139.8, 148.1, 150.6, 152.8, 154.1,
159.4, 159.7, 173.8; LRMS (ESI) m/z 521 [M + H]+; HRMS
1
as yellow solids. Data for 4: H NMR (400 MHz, CDCl3,
δ): 12.49 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.01
(d, J = 8.8 Hz, 1H) 4.00 (s, 3H), 3.98 (s, 6H), 3.92 (s, 3H);
13C NMR (100 MHz, CDCl3, δ): 55.9, 56.1, 60.1, 61.2,
95.1, 100.5, 108.9, 111.1, 111.1, 122.3, 122.9, 139.1,
148.9, 151.2, 152.0, 156.5, 157.8, 159.8, 178.2; LRMS
(ESI) m/z 514 [M + H]+; HRMS (ESI) m/z: Calcd for
C19H17O7Br2: [M + H]+ 514.9336; found, 514.9320; m.p.:
199.0–200.6 ꢀC.
8-Bromo-2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H-
chromen-4-one (15). NBS (178 mg, 1.0 mmol) was added to a
stirred solution of 14 (372 mg, 1 mmol) in DCM (10 mL) at
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(ESI) m/z: Calcd for C25H30O7Br [M + H]+ 521.1169; found,
521.1174; m.p.: 174.9–176.8 ꢀC.
1H), 1.46 (d, J = 6.0 Hz, 12H); 13C NMR (100 MHz, CDCl3,
δ): 21.9, 22.0, 72.6, 73.7, 93.4, 99.8. 108.2, 111.3, 126.3,
129.0, 131.3, 131.4, 155.6, 158.5, 158.9, 160.8, 177.1; LRMS
(ESI) m/z 417 [M + H]+; HRMS (ESI) m/z: Calcd for
C21H22O4Br [M + H]+ 417.0690; found, 417.0684; m.p.:
115.5–115.7 ꢀC.
6-Bromo-2-(3,4-diisopropoxyphenyl)-5-hydroxy-3,7-dii-
sopropoxy-4H-chromen-4-one (12). NBS (196 mg, 1.1
mmol) was added in portions to 11 (470 mg, 1.0 mmol) in
DCM (10 mL) at −40 ꢀC over 5 min. The mixture was stirred
for 6 h at −40 ꢀC. After completion of the reaction, the mixture
was concentrated to dryness under reduced pressure, the crude
product was purified by column chromatography on silica
(petroleum ether/ethyl acetate 30:1) to afford compound 12
6-Bromo-5-hydroxy-7-isopropoxy-3-(4-isopropoxyphe-
nyl)-4H-chromen-4-one (29). This compound was synthe-
sized by following the same procedure for the synthesis of
compound 12 by using 28 (354 mg, 1.0 mmol) as substrate.
Purification of the crude product by column chromatography
on silica (petroleum ether/ethyl acetate 20:1) gave compound
1
(411 mg, 75%) as a yellow solid. Data for 12: H NMR
(400 MHz, CDCl3, δ): 13.53 (s, 1H), 7.78 (s, 1H), 7.72 (d,
J = 8.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H),
4.48–4.74 (m, 4H), 1.46 (d, J = 6.0 Hz, 6H), 1.38–1.41 (m,
12H), 1.21 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3,
δ): 21.9, 22.1, 22.3, 71.7, 72.5, 72.9, 75.1, 92.2, 95.0, 105.9,
115.6, 119.7, 123.3, 123.5, 136.6, 148.0, 151.9, 155.6, 156.9,
158.3, 159.8, 178.6; LRMS (ESI) m/z 549 [M + H]+; HRMS
(ESI) m/z: Calcd for C27H33O7Br [M + H]+ 549.1482; found,
549.1489; m.p.: 110.8–111.0 ꢀC.
8-Bromo-2-(3,4-diisopropoxyphenyl)-3,5,7-triisopro-
poxy-4H-chromen-4-one (19). This compound was synthe-
sized by following the same procedure for the synthesis of
compound 17 by using 18 (512 mg, 1.0 mmol) as substrate
to afford compound 19 (573 mg, 97%) as a yellow solid. Data
for 19: 1H NMR (400 MHz, CDCl3, δ): 7.99 (s, 1H), 7.95 (d, J
= 8.8 Hz, 1H), 6.99(d, J = 8.8 Hz, 1H), 6.42(s, 1H), 4.50–4.83
(m, 5H), 1.38–1.47 (m, 24H), 1.21 (d, J = 6.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3, δ): 21.9, 22.1, 22.2, 22.3, 22.4,
71.8, 72.4, 72.6, 73.8, 74.0, 93.1, 99.7, 111.5, 116.0, 118.4,
123.1, 124.3, 138.4, 148.2, 151.0, 153.5, 154.4, 158.4,
158.6, 173.9; LRMS (ESI) m/z 591 [M + H]+; HRMS (ESI)
m/z: Calcd for C30H40O7Br [M + H]+ 591.1952; found,
591.1926; m.p.: 124.4–124.6 ꢀC.
1
29 (307 mg, 71%) as a yellow solid. Data for 29: H NMR
(400 MHz, CDCl3, δ): 13.62 (s, 1H), 7.89 (s, 1H), 7.43 (d,
J = 8.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 4.68
(m, 1H), 4.58 (m, 1H), 1.45 (d, J = 6.0 Hz, 6H), 1.35 (d, J =
6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3, δ): 21.8, 22.0,
69.9, 72.6, 92.2, 95.7, 106.3, 115.9, 122.3, 123.8, 130.1,
152.7, 156.8, 158.3, 158.9, 160.2, 180.3; LRMS (ESI) m/z
433 [M + H]+; HRMS (ESI) m/z: Calcd for C21H21O5BrNa
[M + Na]+ 455.0465; found, 455.0478; m.p.: 148.8–149.0 ꢀC.
8-Bromo-5,7-diisopropoxy-3-(4-isopropoxyphenyl)-4H-
chromen-4-one (32). This compound was synthesized by fol-
lowing the same procedure for the synthesis of compound 17
by using 31 (396 mg, 1.0 mmol) as substrate to afford com-
1
pound 32 (394 mg, 83%) as a white solid. Data for 32: H
NMR (400 MHz, CDCl3, δ): 7.84 (s, 1H), 7.43 (d, J = 8.8
Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.49 (s, 1H), 4.52–4.73
(m, 3H), 1.43–1.46 (m, 12H), 1.34 (d, J = 6.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3, δ): 21.9, 22.0, 22.1, 69.9, 72.6,
73.1, 92.6, 99.2, 111.9, 115.8, 123.8, 125.9, 130.5, 150.1,
155.8, 157.9, 158.7, 159.0, 175.1; LRMS (ESI) m/z 475 [M
+ H]+; HRMS (ESI) m/z: Calcd for C24H28BrO5 [M + H]+
475.1115; found, 475.1107; m.p.: 95.5–96.6 ꢀC.
6-Bromo-5-hydroxy-7-isopropoxy-2-phenyl-4H-chro-
men-4-one (23). This compound was synthesized by follow-
ing the same procedure for the synthesis of compound 12 by
using 22 (296 mg, 1.0 mmol) as substrate. Purification of the
crude product by column chromatography on silica (petro-
leum ether/ethyl acetate/dichloromethane 30:1:1) gave com-
200,2000,300,3000,400,4000-Hexa-O-acetyl-8-bromo-30,40,5,7-tetra-
O-methylrutin (35). This compound was synthesized by fol-
lowing the same procedure for the synthesis of compound 17
by using 34 (918 mg, 1.0 mmol) as substrate to afford com-
1
pound 35 (918 mg, 92%) as a white solid. Data for 35: H
NMR (400 MHz, CDCl3, δ): 7.97 (d, J = 8.4 Hz, 1H), 7.88
(s, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 5.91 (d, J =
8.0 Hz, 1H), 5.22–5.33 (m, 2H), 5.03–5.11 (m, 3H), 4.92 (t,
J = 10.0 Hz, 1H), 4.51 (s, 1H), 4.05 (s, 6H), 4.02 (s, 3H),
3.97 (s, 3H), 3.71–3.75 (m, 1H), 3.59–3.66 (m, 2H), 3.44
(dd, J = 11.6 Hz, 4.8 Hz, 1H), 2.09 (s, 3H), 2.05 (s, 3H),
2.03 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.93 (s, 3H), 1.03
(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, δ): 17.2,
20.7, 20.8, 20.9, 55.9, 56.1, 56.6, 56.7, 60.4, 66.6, 66.6,
68.8, 69.4, 69.5, 70.8, 71.6, 72.7, 73.0, 90.6, 91.8, 97.8,
98.6, 109.7, 110.9, 111.7, 122.7, 122.9, 135.5, 148.5,
151.2, 154.1, 154.1, 160.2, 160.6, 169.7, 169.7, 169.9,
170.0, 170.1, 172.8; LRMS (ESI) m/z 997 [M + H]+; HRMS
(ESI) m/z: Calcd for C43H50O22Br [M + H]+ 997.1972; found,
997.1944; m.p.: 103.1–103.3 ꢀC.
1
pound 23 (318 mg, 85%) as a yellow solid. Data for 23: H
NMR (400 MHz, CDCl3, δ): 13.48 (s, 1H), 7.90 (d, J = 6.4
Hz, 2H), 7.53–7.55 (m, 3H), 6.72 (s, 1H), 6.57 (s, 1H),
4.69–4.75 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H); 13C NMR (100
MHz, CDCl3, δ): 21.9, 72.6, 92.5, 95.9, 105.8, 105.9,
126.4, 129.2, 131.2, 132.0, 156.8, 158.6, 160.3, 164.2,
181.9; LRMS (ESI) m/z 375 [M + H]+; HRMS (ESI) m/z:
Calcd for C18H16O4Br [M + H]+ 375.0226; found,
375.0227; m.p.: 170.2–170.8 ꢀC.
8-Bromo-5,7-diisopropoxy-2-phenyl-4H-chromen-4-one
(26). This compound was synthesized by following the same
procedure for the synthesis of compound 17 by using 25
(338 mg, 1.0 mmol) as substrate to afford compound 26 (380
1
mg, 91%) as a yellow solid. Data for 26: H NMR (400
MHz, CDCl3, δ): 8.00–8.02 (m, 2H), 7.51–7.53 (m, 3H),
6.71 (s, 1H), 6.50 (s, 1H), 4.66–4.75 (m, 1H), 4.55–4.64 (m,
Synthesis of Bromo-Flavonoids. 6-Bromo-2-(3,4-dihy-
droxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (20).
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Regioselective Bromination of Flavonoids
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Boron tri-chloride (10 mL, 10 mmol, 1 M solution in hexane)
was added to a stirred solution of 12 (550 mg, 1.0 mmol) in
anhydrous DCM (20 mL) at −20 ꢀC for 30 min. After addition,
thereactionmixturewasheatedtorefluxfor2 h. Thenthereac-
tion was cooled to room temperature, excess methanol was
added drop wise at −10 ꢀC with stirring for 10 min and then
concentrated under reduced pressure. The crude product
was purified by recrystallization in DCM to get compound
8-Bromo-5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chro-
men-4-one (33). This compound was synthesized by follow-
ing the same procedure for the synthesis of compound 20
by using 32 (476 mg, 1.0 mmol) as substrate to afford com-
1
pound 33 (345 mg, 99%) as a white solid. Data for 33: H
NMR (400 MHz, DMSO-d6, δ): 13.01 (s, 1H), 11.72 (s,
1H), 9.62 (s, 1H), 8.49 (s, 1H), 7.40 (d, J = 8.8 Hz, 2H),
6.84 (d, J = 8.8 Hz, 2H), 6.45 (s, 1H); 13C NMR (100 MHz,
DMSO-d6, δ): 86.5, 99.5, 105.8, 115.6, 121.3, 123.0, 130.7,
154.4, 154.6, 158.1, 161.2, 161.5, 180.7; LRMS (ESI) m/z
371 [M + Na]+; HRMS (ESI) m/z: Calcd for C15H9O5BrNa
[M + Na]+ 370.9526; found, 370.9512; m.p.: 227.6–227.8 ꢀC.
1
20 (377 mg, 99%) as a yellow solid. Data for 20: H NMR
(400 MHz, DMSO-d6, δ): 13.39 (s, 1H), 11.65 (s, 1H), 9.62
(s, 1H), 9.53 (s, 1H), 9.32 (s, 1H), 7.68(s, 1H), 7.56 (d, J =
8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H); 13C
NMR (100 MHz, DMSO-d6, δ): 92.5, 94.0, 103.8, 115.6,
116.1, 120.6, 122.2, 136.2, 145.6, 147.9, 148.4, 154.9,
157.8, 160.5, 175.9.
Results and Discussion
8-Bromo-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-
chromen-4-one (21). This compound was synthesized by
following the same procedure for the synthesis of compound
20 by using 19 (590 mg, 1.0 mmol) as substrate to afford
compound 21 (377 mg, 99%) as an orange solid. Data
Initially, wetriedthebrominationonthetetramethyl-protected
quercetin 1 substrate by using NBS as bromination reagent
in DMF at 0 ꢀC. Unlike the iodination by NIS,5 we got
the 6-bromo product 2 and 6,8-dibromo product 4 (Table 1,
entry 1). We envisioned that the strong electrophilicity
of NBS compared to NIS diminished the selectivity. Carrying
out the reaction at − 20 ꢀC in CH2Cl2 (DCM), proved
effective in blocking the formation of the dibromide by-prod-
uct. However, the 8-bromo derivative 3 was afforded in
26 % yield (Table 1, entry 2). Other bromination reagents such
1
for 21: H NMR (400 MHz, DMSO-d6, δ): 12.45 (s, 1H),
11.61 (s, 1H), 9.62 (s, 2H), 7.83 (s, 1H), 7.68 (d, J = 8.4 Hz,
1H), 6.92 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H); 13C NMR
(100 MHz, DMSO-d6, δ): 86.4, 98.7, 104.2, 115.7, 116.2,
120.5, 122.4, 136.4, 145.6, 147.5, 148.5, 152.6, 159.9,
161.0, 176.1.
as
2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-die-
6-Bromo-5,7-dihydroxy-2-phenyl-4H-chromen-4-one
(24). Boron tri-chloride (5.0 mL, 5.0 mmol, 1 M solution in
hexane) was added to a stirred solution of 23 (375 mg, 1.0
mmol) inanhydrousDCM(20 mL)at−20 ꢀCfor30 min. After
addition, the reaction mixture was heated to reflux for 2 h.
Then the reaction was cooled to room temperature, excess
methanol was added dropwise at −10 ꢀC with stirring for 10
min and then concentrated under reduced pressure. The crude
product was purified by recrystallization in DCM to get com-
none, which is reported as a mild nitration9 or bromination
agent,10 5,5-dibromobarbituric acid,11 and 1,3-dibromo-5,5-
dimethylhydantoin12 were tested (Table 1, entries 3–5). All
of them afforded the mono-bromo products 2 and 3. When
the reaction was carried out at −40 ꢀC by using NBS, the yield
of compound 2 improved slightly (Table 1, entry 6). Further
decreasing the reaction temperature to − 78 ꢀC did not affect
the yield and regioselectivity of the reaction (Table 1, entry
7). It is worth mentioning that compounds 2–4 are not easy
to separate and the solubilities of these three compounds are
not good which leads to the loss of the compounds during col-
umn separation.
To improve regioselectivity, bulkier substituents such as
ethyl and isopropyl were employed to protect the correspond-
ing phenolic –OH groups. As expected, the regioselectivity
and the yield of the 6-bromo product improved under the opti-
mized conditions (Scheme 2). It is noteworthy that the solubi-
lities of the products were greatly increased when isopropyl
was used, which makes it much easier to separate the regioi-
somers on a column.
1
pound 24 (330 mg, 99%) as a white solid. Data for 24: H
NMR (400 MHz, DMSO-d6, δ): 13.73 (s, 1H), 11.84 (s,
1H), 8.10–8.11 (m, 2H), 7.57–7.64 (m, 3H), 7.08 (s, 1H),
6.75 (s, 1H).
8-Bromo-5,7-dihydroxy-2-phenyl-4H-chromen-4-one
(27). This compound was synthesized by following the same
procedure for the synthesis of compound 24 by using 26 (417
mg, 1.0 mmol) as substrate to afford compound 27 (330 mg,
1
99%) as a yellow solid. Data for 27: H NMR (400 MHz,
DMSO-d6, δ): 12.84 (s, 1H), 11.75 (s, 1H), 8.14 (m, 2H),
7.60–7.65 (m, 3H), 7.12 (s, 1H), 6.45 (s, 1H).
6-Bromo-5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chro-
men-4-one (30). This compound was synthesized by follow-
ing the same procedure for the synthesis of compound 20
by using 29 (433 mg, 1.0 mmol) as substrate to afford com-
Based on our previous work on regioselective iodination by
NIS,5 thepentamethyl-protected quercetin 14is expectedtobe
less reactive compared with the corresponding tetramethyl-
protected substrate 1 because of its steric effect and the
absence of H-bonding between the halogenating reagent and
phenolic –OH group of the substrate. Therefore, the bromina-
tion of compound 14 was initially carried out at 25 ꢀC with
NBS in DCM. To our delight, only the 8-bromo derivative
15 was obtained with 96% yield (Table 2, entry 1). When
the reaction was carried out at 0 ꢀC, conversion was
1
pound 30 (345 mg, 99%) as a white solid. Data for 30: H
NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1H), 11.77 (s,
1H), 9.61 (s, 1H), 8.40 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H),
6.83 (d, J = 8.0 Hz, 2H), 6.62 (s, 1H); 13C NMR (100 MHz,
DMSO-d6, δ): 93.4, 94.2, 105.2, 115.6, 121.4, 122.7, 130.7,
154.8, 156.5, 158.0, 159.1, 161.1, 180.4.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1460–1466
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Regioselective Bromination of Flavonoids
KOREAN CHEMICAL SOCIETY
Table 1. Bromination of compound 1 under different conditions.a
OMe
OMe
OMe
OMe
Br
Bromination
reagent
MeO
O
O
MeO
Br
O
O
MeO
O
OMe
OMe
OMe
OMe
OMe
+
OH
O
OH
OH
Br
O
1
2
3
OMe
OMe
Br Br
O
O
O
O
Br
Br
Br
Br
MeO
Br
O
O
Br
N
N
Br
HN
NH
+
OMe
NO2
O
OH
5
6
7
4
Yieldb (%)
Entry
Reagent
Solvent
Temperature (ꢀC)
2
3
4
1
2
3
4
5
6
7
NBS
NBS
5
6
7c
DMF
DCM
DCM
DCM
DCM
DCM
DCM
0
−20
−20
−20
−20
−40
−78
23
47
41
33
36
51
49
0
26
25
31
41
25
26
31
0
0
0
0
NBS
NBS
0
0
a Reaction conditions: 1 (1.0 mmol), bromination reagent (1.1 mmol), in DMF (10 mL) or DCM (10 mL).
b Isolated yield after purification by silica gel chromatography.
c 1 (1.0 mmol) and 7 (0.5 mmol) were used.
OR
OR
OR
OR
OR
OR
Br
RO
RO
Br
RO
O
O
O
O
O
O
NBS
+
DCM
–40 °C
OR
OR
OR
OH
OH
OH
8
11
9, 57%,
12, 75%
10 R = Ethyl
12%
13 R = Isopropy l0%
Scheme 2. Regioselective bromination of compounds 8 and 11.
incomplete, which led to a drop in yield (Table 2, entry 2). For
this substrate, other reagents such as 5–7 effected smooth bro-
mination togive desired productingood yield(Table2, entries
3–5). When ethyl or isopropyl groups were used as protecting
groups, the mono-bromination yield was increased to 97 %
(Table 2, entries 6 and 7).
With the bromo-quercetin derivatives 12 and 19 in hand,
we tried the deprotection of the phenolic –OH groups with
BCl3 in DCM. Unlike the demethylation of 2 and 15 with
BBr3, the reaction was quite clean and the desired products
20 and 21 were obtained in nearly quantitative yields
(Scheme 3).
regioselective brominations were achieved by alternating the
pattern of phenolic –OH protection and good to high yields
were obtained for the desired mono-bromo products, which
were de-isopropylated with BCl3 in nearly quantitative yields
(Table 3).
Finally, this bromination protocol was applied to a rutin
derivative containing an acid-labile glycosidic bond 34. Due
to its almost neutral conditions, the corresponding monobro-
mide 35 was obtained as a single product in 92% yield
(Scheme 4).
Conclusion
To further explore the scope and generality of this reaction,
other flavonoids such as chrysin (Table 3, entries 1 and 2) and
genistein (Table 3, entries 3 and 4) were converted into their
isopropyl ethers and subjected to bromination with NBS/
DCM under the optimized conditions. In all cases, completely
Insummary, anefficientmethodwasdevelopedtoprepareC-6
or C-8 mono-bromo flavonoids regioselectively, by bromina-
tion and subsequent dealkylation. The bromination can be
conveniently directed to either the C-6 or C-8 position by
Bull. Korean Chem. Soc. 2015, Vol. 36, 1460–1466
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BULLETIN OF THE
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Regioselective Bromination of Flavonoids
KOREAN CHEMICAL SOCIETY
Table 2. Bromination of compounds 14–18 under different conditions.a
OR
OR
Br
Bromination
reagent
RO
O
O
RO
O
O
OR
OR
DCM
OR
OR
OR
OR
14
16
18
15 R = Methyl
17 R = Ethyl
19 R = Isopropyl
Entry
Reagent
Substrate
Temperature (ꢀC)
Product
Yield (%)b
1
2
3
4
5
6
7
NBS
NBS
5
6
7c
14
14
14
14
14
16
18
25
0
15
15
15
15
15
17
19
96
85
78
82
93
97
97
25
25
25
25
25
NBS
NBS
a Reaction conditions: 1 (1.0 mmol), bromination reagent (1.0 mmol), in DCM (10 mL).
b Isolated yield after purification by silica gel chromatography.
c 7 (0.5 mmol) was used.
OMe
Y
BBr3
O
O
MeO
X
OMe
messy
DCM
-78 °C-rt
OMe
OR
2 R = H, X = Br,Y = H
15 R = Me, X = H,Y = Br
Oi-Pr
OH
OH
Y
Y
HO
X
O
O
O
i-PrO
Oi-Pr
BCl3
DCM
-20 °C-reflux
X
Oi-Pr
OH
OR
O
OH
12 R = H, X = Br,Y = H
19 R = Me, X = H,Y = Br
20 X = Br,Y = H 99%
21 X = H,Y = Br 99%
Scheme 3. Dealkylation of mono-bromo flavonoids.
alternating the protection pattern on the C-5 and C-7 OH
Acknowledgments.
The authors sincerely thank the
groups with high regioselectivity. Thus, 5,7-O-
diisopropylated flavonoids can be brominated with NBS/
DCM to give the 8-bromo derivatives exclusively, whereas
isopropyl ethers of flavonoids bearing a free OH group at
C-5 yield 6-bromo regioisomers as the major products. The
mild and neutral conditions of this protocol were found to
be applicable tosubstrates containing an acid-labile glycosidic
bond.
financial support from National Science Foundation of
China (Grants 21202118 and 21202119) and China Interna-
tional Science and Technology Cooperation Projects
(2013DFA31160).
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
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Regioselective Bromination of Flavonoids
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Table 3. Bromination of protected flavonoid derivatives.
Entry
1
Substrates
Methoda
A
Iodinated products
Yieldb (%)
85
Deprotected productc
Yieldb (%)
99
i-PrO
O
HO
Br
O
O
i-PrO
O
O
Br
OH
23
O
OH
24
OH
22
Br
Br
i-PrO
O
i-PrO
O
HO
O
O
2
3
4
B
A
B
91
61
83
99
99
99
Oi-Pr O
OH
Oi-Pr O
25
O
26
O
27
O
i-PrO
i-PrO
HO
Br
Br
OH
30
O
OH
28
O
OH
29
O
OH
OH
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
i-PrO
O
Br
Br
i-PrO
O
HO
O
O
Oi-Pr O
Oi-Pr O
OH
31
33
32
a Method A: reactions were performed with substrate (1.0 mmol) and NBS (1.1 mmol) in DCM at −40 ꢀC; method B: reactions were performed with
substrate (1.0 mmol) and NBS (1.0 mmol) in DCM at room temperature.
b Isolated yield after chromatography.
c Deprotection: reactions were performed with substrate (1.0 mmol) and BCl3 (10 mmol) in anhydrous DCM at −20 ꢀC.
OMe
OMe
Br
MeO
O
O
MeO
OMe
OMe
O
O
OMe O
O
OAc
OMe O
O
OAc
NBS (1.2 eq)
O
O
O
DCM, 25 °C
92%
O
OAc
OAc
OAc
OAc
AcO
OAc
AcO
OAc
OAc
OAc
34
35
Scheme 4. Regioselective bromination of rutin derivative 34.
6. M. Ichikawa, S. Hibino, M. Onishi, J. F. Hatcher,
A. M. Pamukcu, G. T. Bryan, Org. Prep. Proced. Int. 1985,
17, 56.
7. G. Lewin, A. Maciuk, S. Thoret, G. Aubert, J. Dubois, T. Cres-
teil, J. Nat. Prod. 2010, 73, 702.
8. M. C. Foto, C. Rocco, Tetrahedron Lett. 2014, 55, 1602.
9. C. K. Arnatt, Y. Zhang, Tetrahedron Lett. 2012, 53, 1592.
10. R. G. Coombes, J. Chem. Soc. Perkin Tran 2 1992, 7, 1007.
11. G. Grundke, W. Keese, M. Rimpler, Chem. Ber. 1985,
118, 4288.
References
1. J. B. Harborne, H. Baxter, The Handbook of Natural Flavonoids,
Vol. 1, John Wiley & Sons, Chichester, 1999.
2. J. B. Harborne, C. A. Williams, Phytochemistry 2000, 55, 481.
3. (a) K. Yoshihito, H. Yukio, M. Haruo, M. Hiroto, Heterocycles
2010, 81, 1871; (b) D. E. Zembower, H. Zhang, J. Org. Chem.
1998, 63, 9300.
4. (a) I.-H. Lee, F.-L. Chen, J. Chin. Chem. Soc. 1982, 29, 143; (b)
M. Rahman, M. Riaz, U. R. Desai, Chem. Biodivers. 2007,
4, 2495.
5. K. Lu, J. Chu, H. Wang, X. Fu, D. Quan, H. Ding, Q. Yao, P. Yu,
Tetrahedron Lett. 2013, 54, 6345.
12. A. Alam, Y. Takaguchi, H. Ito, T. Yoshida, S. Tsuboi, Tetrahe-
dron 2005, 61, 1909.
Bull. Korean Chem. Soc. 2015, Vol. 36, 1460–1466
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