Article BULLETIN OF THE

DOI: 10.1002/bkcs.10286 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@[Link]; yupeng@[Link]
‡
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
Flavonoids are polyphenolic secondary metabolites found in to the halogen group, compared to the corresponding bromide.
plants and various common food.1 Many of them possess a In 1985, Ichikawa achieved the transformations of quercetin
broad range of pharmacological properties including antican- and kaempferol to their 6-bromo and 6,8-dibromo derivatives
cer, antiviral, antioxidant, and anti-inflammatory properties.2 by a mixture of HBr and H2O2 in methanol.6 However, the
Among those, C-6 and C-8 alkyl or aryl substituted flavonoids strong acidic conditions limited their applications. In 2010
are most common; they can be prepared from the correspond- and 2014, Lewin7 and Rocco8 reported the bromination of
ing halogen-substituted flavonoids by Suzuki coupling3 or quercetin and its derivatives with N-bromosuccinimide
Ullmann coupling.4 Recently, we developed a regioselective (NBS), respectively. However, a mixture of 6-bromo, 8-
iodination method for flavonoids by N-iodosuccinimide bromo, and 6,8-dibromo products was obtained under these
(NIS) under neutral conditions (Scheme 1).5 Although the conditions. This encouraged us to develop an efficient regio-
O-alkylated mono-iodo flavonoids can be obtained in high selective method to prepare bromo-substituted flavonoids.
yield, the subsequent dealkylation is always accompanied Herein we report a mild and regioselective monobromination
by deiodination. Moreover, it is well known that iodide is more of O-alkylated flavonoid derivatives using NBS as

Scheme 1. Regioselective iodination of flavonoids by NIS.

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Article Regioselective Bromination of Flavonoids KOREAN CHEMICAL SOCIETY

bromination reagent in DCM. By using this protocol, mono- 25
C. After the addition, the mixture was stirred for 2 h and
bromo flavonoids can be prepared easily by regioselective then concentrated to dryness under reduced pressure, the crude
bromination and subsequent dealkylation. product was purified by column chromatography on silica
(petroleum ether/ethyl acetate 3:1) to afford compound 15
Experimental (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
Synthesis of Bromo-Flavonoid Alkyl Ethers. 6-Bromo-2- (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 4.04 (s, 6H), 3.98 (s, 3H),
(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy-4H-chro- 3.97 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3, δ):
men-4-one (2); 8-bromo-2-(3,4-dimethoxyphenyl)-5- 56.0, 56.1, 56.8, 60.2, 90.6, 93.9, 106.4, 110.9, 111.3,
hydroxy-3,7-dimethoxy-4H-chromen-4-one (3); and 6,8- 122.3, 122.6, 139.1, 148.9, 151.6, 155.7, 156.2, 158.2,
dibromo-2-(3,4-dimethoxyphenyl)-5-hydroxy-3,7-dimethoxy- 161.3, 178.2; LRMS (ESI) m/z 453 [M + H]+; HRMS (ESI)
4H-chromen-4-one (4). NBS (196 mg, 1.1 mmol) was m/z: Calcd for C20H20O7Br [M + H]+ 451.0387; found,
added in portions to 1 (358 mg, 1.0 mmol) in DCM (10 mL) 451.0380; m.p.: 185.9–186.0
C.
at −40
C over 5 min. The mixture was stirred for 6 h at 6-Bromo-2-(3,4-diethoxyphenyl)-3,7-diethoxy-5-hydroxy-
−40
C. After completion of the reaction, the mixture was con- 4H-chromen-4-one (9) and 8-bromo-2-(3,4-diethoxyphe-
centrated to dryness under reduced pressure. The crude product nyl)-3,7-diethoxy-5-hydroxy-4H-chromen-4-one (10).
was purified by column chromatography on silica (petroleum NBS (196 mg, 1.1 mmol) was added in portions to 8 (414
ether/ethyl acetate/dichloromethane 30:1:1) to afford com- mg, 1.0 mmol) in DCM (10 mL) at −40
C over 5 min. The
pound 2 (223 mg, 51%) and compound 3 (109 mg, 25%) as yel- mixture was stirred for 6 h at −40
C. After completion of
low solids. Data for 2: 1H NMR (400 MHz, DMSO-d6, δ): the reaction, the mixture was concentrated to dryness under
13.42 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.17 (d, reduced pressure, the crude product was purified by column
J = 8.8 Hz,1H), 7.06 (s, 1H), 3.99 (s, 3H), 3.87 (s, 6H), 3.84 chromatography on silica (petroleum ether/ethyl acetate/
(s, 3H); 13C NMR (100 MHz, CDCl3, δ): 56.0, 56.1, 56.8, dichloromethane 30:1:1) to afford compound 9 (281 mg,
60.3, 90.6, 94.0, 106.4, 110.9, 111.3, 122.3, 122.6, 139.1, 57%) and compound 10 (59 mg, 12%) as yellow solids. Data
148.9, 151.6, 155.7, 156.2, 158.2, 161.3, 178.2; LRMS (ESI) for 9: 1H NMR (400 MHz, CDCl3, δ): 13.45 (s, 1H), 7.74 (s,
m/z 439 [M + H]+; HRMS (ESI) m/z: Calcd for C19H17O7Br 1H), 7.71 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.49 (s,
[M + H]+ 437.0230; found, 437.0226; m.p.: 180.9–182.0
C. 1H), 4.16–4.21 (m, 6H), 4.08 (q, J = 7.2 Hz, 2H), 1.51 (m,
Data for 3: 1H NMR (400 MHz, CDCl3, δ): 12.79 (s, 1H), 9H), 1.34 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
8.00 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.02 (d, J = 8.8 Hz, 1H), δ): 14.4, 14.7, 14.9, 15.6, 64.5, 64.9, 65.5, 68.7, 91.2, 94.2,
6.46 (s, 1H), 3.99 (s, 9H), 3.92 (s, 3H); 13C NMR (100 MHz, 106.2, 112.2, 113.7, 122.2, 122.7, 137.9, 148.2, 151.4,
CDCl3, δ): 55.9, 56.0, 56.9, 60.1, 87.7, 95.6, 106.2, 111.0, 155.7, 156.6, 158.2, 160.7, 178.34; LRMS (ESI) m/z 493
111.2, 122.8, 122.8, 138.9, 148.9, 151.7, 152.4, 155.8, [M + H]+; HRMS (ESI) m/z: Calcd for C23H26O7Br [M +
161.6, 178.6; LRMS (ESI) m/z 439 [M + H]+; HRMS (ESI) H]+ 493.0856; found, 493.0851; m.p.: 169.3–171.9
C. Data
m/z: Calcd for C19H17O7Br [M + H]+ 437.0230; found, for 10: 1H NMR (400 MHz, CDCl3, δ): 7.95–7.97 (m, 2H),
437.0228; m.p.: 218.8–219.0
C. 7.00 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 4.18–4.23 (m, 6H),
NBS (196 mg, 1.1 mmol) was added in portions to 1 4.13 (q, J = 6.8 Hz, 2H), 1.50–1.54 (m, 9H), 1.39 (t, J = 7.2
(358 mg, 1 mmol) in DMF (10 mL) at 0
C over 5 min. The Hz, 3H); 13C NMR (100 MHz, CDCl3, δ): 14.5, 14.7, 14.8,
mixture was stirred for 6 h at 0
C. After completion of the 15.7, 64.5, 64.6, 65.5, 68.6, 87.9, 96.3, 106.1, 112.4, 113.3,
reaction, the mixture was diluted with DCM (50 mL) and 122.6, 122.9, 137.8, 148.2, 151.3, 152.5, 156.2, 161.0,
washed with water (100 mL × 3). The organic phase was con- 161.4, 178.8; LRMS (ESI) m/z 493 [M + H]+; HRMS (ESI)
centrated to dryness under reduced pressure, the crude product m/z: Calcd for C23H26O7Br [M + H]+ 493.0856; found,
was purified by column chromatography on silica (petroleum 493.0849; m.p.: 172.4–173.2
C.
ether/ethyl acetate/dichloromethane 30:1:1) to afford com- 8-Bromo-2-(3,4-diethoxyphenyl)-3,5,7-triethoxy-4H-
pound 2 (101 mg, 23%) and compound 4 (160 mg, 31%) chromen-4-one (17). NBS (178 mg, 1.0 mmol) was added to
as yellow solids. Data for 4: 1H NMR (400 MHz, CDCl3, a stirred solution of 16 (442 mg, 1.0 mmol) in DCM (10 mL)
δ): 12.49 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.01 at 25
C. After completion of the reaction, the mixture was
(d, J = 8.8 Hz, 1H) 4.00 (s, 3H), 3.98 (s, 6H), 3.92 (s, 3H); concentrated to dryness under reduced pressure, the crude
13
C NMR (100 MHz, CDCl3, δ): 55.9, 56.1, 60.1, 61.2, product was purified by recrystallization in ethyl acetate to
95.1, 100.5, 108.9, 111.1, 111.1, 122.3, 122.9, 139.1, get a yellow solid 17 (505 mg, 97%). Data for 17: 1H NMR
148.9, 151.2, 152.0, 156.5, 157.8, 159.8, 178.2; LRMS (400 MHz, CDCl3, δ): 7.97 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H),
(ESI) m/z 514 [M + H]+; HRMS (ESI) m/z: Calcd for 6.99 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 4.12–4.23 (m, 10H),
C19H17O7Br2: [M + H]+ 514.9336; found, 514.9320; m.p.: 1.50–1.58 (m, 12H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR
199.0–200.6
C. (100 MHz, CDCl3, δ): 14.6, 14.7, 14.8, 15.7, 64.4, 64.5,
8-Bromo-2-(3,4-dimethoxyphenyl)-3,5,7-trimethoxy-4H- 65.3, 65.6, 67.9, 76.8, 77.1, 77.4, 90.8, 94.1, 110.1, 112.4,
chromen-4-one (15). NBS (178 mg, 1.0 mmol) was added to a 113.2, 122.1, 123.4, 139.8, 148.1, 150.6, 152.8, 154.1,
stirred solution of 14 (372 mg, 1 mmol) in DCM (10 mL) at 159.4, 159.7, 173.8; LRMS (ESI) m/z 521 [M + H]+; HRMS

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(ESI) m/z: Calcd for C25H30O7Br [M + H]+ 521.1169; found, 1H), 1.46 (d, J = 6.0 Hz, 12H); 13C NMR (100 MHz, CDCl3,
521.1174; m.p.: 174.9–176.8
C. δ): 21.9, 22.0, 72.6, 73.7, 93.4, 99.8. 108.2, 111.3, 126.3,
6-Bromo-2-(3,4-diisopropoxyphenyl)-5-hydroxy-3,7-dii- 129.0, 131.3, 131.4, 155.6, 158.5, 158.9, 160.8, 177.1; LRMS
sopropoxy-4H-chromen-4-one (12). NBS (196 mg, 1.1 (ESI) m/z 417 [M + H]+; HRMS (ESI) m/z: Calcd for
mmol) was added in portions to 11 (470 mg, 1.0 mmol) in C21H22O4Br [M + H]+ 417.0690; found, 417.0684; m.p.:
DCM (10 mL) at −40
C over 5 min. The mixture was stirred 115.5–115.7
C.
for 6 h at −40
C. After completion of the reaction, the mixture 6-Bromo-5-hydroxy-7-isopropoxy-3-(4-isopropoxyphe-
was concentrated to dryness under reduced pressure, the crude nyl)-4H-chromen-4-one (29). This compound was synthe-
product was purified by column chromatography on silica sized by following the same procedure for the synthesis of
(petroleum ether/ethyl acetate 30:1) to afford compound 12 compound 12 by using 28 (354 mg, 1.0 mmol) as substrate.
(411 mg, 75%) as a yellow solid. Data for 12: 1H NMR Purification of the crude product by column chromatography
(400 MHz, CDCl3, δ): 13.53 (s, 1H), 7.78 (s, 1H), 7.72 (d, on silica (petroleum ether/ethyl acetate 20:1) gave compound
J = 8.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 29 (307 mg, 71%) as a yellow solid. Data for 29: 1H NMR
4.48–4.74 (m, 4H), 1.46 (d, J = 6.0 Hz, 6H), 1.38–1.41 (m, (400 MHz, CDCl3, δ): 13.62 (s, 1H), 7.89 (s, 1H), 7.43 (d,
12H), 1.21 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3, J = 8.0 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 4.68
δ): 21.9, 22.1, 22.3, 71.7, 72.5, 72.9, 75.1, 92.2, 95.0, 105.9, (m, 1H), 4.58 (m, 1H), 1.45 (d, J = 6.0 Hz, 6H), 1.35 (d, J =
115.6, 119.7, 123.3, 123.5, 136.6, 148.0, 151.9, 155.6, 156.9, 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3, δ): 21.8, 22.0,
158.3, 159.8, 178.6; LRMS (ESI) m/z 549 [M + H]+; HRMS 69.9, 72.6, 92.2, 95.7, 106.3, 115.9, 122.3, 123.8, 130.1,
(ESI) m/z: Calcd for C27H33O7Br [M + H]+ 549.1482; found, 152.7, 156.8, 158.3, 158.9, 160.2, 180.3; LRMS (ESI) m/z
549.1489; m.p.: 110.8–111.0
C. 433 [M + H]+; HRMS (ESI) m/z: Calcd for C21H21O5BrNa
8-Bromo-2-(3,4-diisopropoxyphenyl)-3,5,7-triisopro- [M + Na]+ 455.0465; found, 455.0478; m.p.: 148.8–149.0
C.
poxy-4H-chromen-4-one (19). This compound was synthe- 8-Bromo-5,7-diisopropoxy-3-(4-isopropoxyphenyl)-4H-
sized by following the same procedure for the synthesis of chromen-4-one (32). This compound was synthesized by fol-
compound 17 by using 18 (512 mg, 1.0 mmol) as substrate lowing the same procedure for the synthesis of compound 17
to afford compound 19 (573 mg, 97%) as a yellow solid. Data by using 31 (396 mg, 1.0 mmol) as substrate to afford com-
for 19: 1H NMR (400 MHz, CDCl3, δ): 7.99 (s, 1H), 7.95 (d, J pound 32 (394 mg, 83%) as a white solid. Data for 32: 1H
= 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 4.50–4.83 NMR (400 MHz, CDCl3, δ): 7.84 (s, 1H), 7.43 (d, J = 8.8
(m, 5H), 1.38–1.47 (m, 24H), 1.21 (d, J = 6.0 Hz, 6H); 13C Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.49 (s, 1H), 4.52–4.73
NMR (100 MHz, CDCl3, δ): 21.9, 22.1, 22.2, 22.3, 22.4, (m, 3H), 1.43–1.46 (m, 12H), 1.34 (d, J = 6.0 Hz, 6H); 13C
71.8, 72.4, 72.6, 73.8, 74.0, 93.1, 99.7, 111.5, 116.0, 118.4, NMR (100 MHz, CDCl3, δ): 21.9, 22.0, 22.1, 69.9, 72.6,
123.1, 124.3, 138.4, 148.2, 151.0, 153.5, 154.4, 158.4, 73.1, 92.6, 99.2, 111.9, 115.8, 123.8, 125.9, 130.5, 150.1,
158.6, 173.9; LRMS (ESI) m/z 591 [M + H]+; HRMS (ESI) 155.8, 157.9, 158.7, 159.0, 175.1; LRMS (ESI) m/z 475 [M
m/z: Calcd for C30H40O7Br [M + H]+ 591.1952; found, + H]+; HRMS (ESI) m/z: Calcd for C24H28BrO5 [M + H]+
591.1926; m.p.: 124.4–124.6
C. 475.1115; found, 475.1107; m.p.: 95.5–96.6
C.
6-Bromo-5-hydroxy-7-isopropoxy-2-phenyl-4H-chro- 200 ,2000 ,300 ,3000 ,400 ,4000 -Hexa-O-acetyl-8-bromo-30 ,40 ,5,7-tetra-
men-4-one (23). This compound was synthesized by follow- O-methylrutin (35). This compound was synthesized by fol-
ing the same procedure for the synthesis of compound 12 by lowing the same procedure for the synthesis of compound 17
using 22 (296 mg, 1.0 mmol) as substrate. Purification of the by using 34 (918 mg, 1.0 mmol) as substrate to afford com-
crude product by column chromatography on silica (petro- pound 35 (918 mg, 92%) as a white solid. Data for 35: 1H
leum ether/ethyl acetate/dichloromethane 30:1:1) gave com- NMR (400 MHz, CDCl3, δ): 7.97 (d, J = 8.4 Hz, 1H), 7.88
pound 23 (318 mg, 85%) as a yellow solid. Data for 23: 1H (s, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 5.91 (d, J =
NMR (400 MHz, CDCl3, δ): 13.48 (s, 1H), 7.90 (d, J = 6.4 8.0 Hz, 1H), 5.22–5.33 (m, 2H), 5.03–5.11 (m, 3H), 4.92 (t,
Hz, 2H), 7.53–7.55 (m, 3H), 6.72 (s, 1H), 6.57 (s, 1H), J = 10.0 Hz, 1H), 4.51 (s, 1H), 4.05 (s, 6H), 4.02 (s, 3H),
4.69–4.75 (m, 1H), 1.48 (d, J = 6.0 Hz, 6H); 13C NMR (100 3.97 (s, 3H), 3.71–3.75 (m, 1H), 3.59–3.66 (m, 2H), 3.44
MHz, CDCl3, δ): 21.9, 72.6, 92.5, 95.9, 105.8, 105.9, (dd, J = 11.6 Hz, 4.8 Hz, 1H), 2.09 (s, 3H), 2.05 (s, 3H),
126.4, 129.2, 131.2, 132.0, 156.8, 158.6, 160.3, 164.2, 2.03 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.93 (s, 3H), 1.03
181.9; LRMS (ESI) m/z 375 [M + H]+; HRMS (ESI) m/z: (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3, δ): 17.2,
Calcd for C18H16O4Br [M + H]+ 375.0226; found, 20.7, 20.8, 20.9, 55.9, 56.1, 56.6, 56.7, 60.4, 66.6, 66.6,
375.0227; m.p.: 170.2–170.8
C. 68.8, 69.4, 69.5, 70.8, 71.6, 72.7, 73.0, 90.6, 91.8, 97.8,
8-Bromo-5,7-diisopropoxy-2-phenyl-4H-chromen-4-one 98.6, 109.7, 110.9, 111.7, 122.7, 122.9, 135.5, 148.5,
(26). This compound was synthesized by following the same 151.2, 154.1, 154.1, 160.2, 160.6, 169.7, 169.7, 169.9,
procedure for the synthesis of compound 17 by using 25 170.0, 170.1, 172.8; LRMS (ESI) m/z 997 [M + H]+; HRMS
(338 mg, 1.0 mmol) as substrate to afford compound 26 (380 (ESI) m/z: Calcd for C43H50O22Br [M + H]+ 997.1972; found,
mg, 91%) as a yellow solid. Data for 26: 1H NMR (400 997.1944; m.p.: 103.1–103.3
C.
MHz, CDCl3, δ): 8.00–8.02 (m, 2H), 7.51–7.53 (m, 3H), Synthesis of Bromo-Flavonoids. 6-Bromo-2-(3,4-dihy-
6.71 (s, 1H), 6.50 (s, 1H), 4.66–4.75 (m, 1H), 4.55–4.64 (m, droxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one (20).

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Article Regioselective Bromination of Flavonoids KOREAN CHEMICAL SOCIETY

Boron tri-chloride (10 mL, 10 mmol, 1 M solution in hexane) 8-Bromo-5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chro-

was added to a stirred solution of 12 (550 mg, 1.0 mmol) in men-4-one (33). This compound was synthesized by follow-
anhydrous DCM (20 mL) at −20
C for 30 min. After addition, ing the same procedure for the synthesis of compound 20
the reaction mixture was heated to reflux for 2 h. Then the reac- by using 32 (476 mg, 1.0 mmol) as substrate to afford com-
tion was cooled to room temperature, excess methanol was pound 33 (345 mg, 99%) as a white solid. Data for 33: 1H
added drop wise at −10
C with stirring for 10 min and then NMR (400 MHz, DMSO-d6, δ): 13.01 (s, 1H), 11.72 (s,
concentrated under reduced pressure. The crude product 1H), 9.62 (s, 1H), 8.49 (s, 1H), 7.40 (d, J = 8.8 Hz, 2H),
was purified by recrystallization in DCM to get compound 6.84 (d, J = 8.8 Hz, 2H), 6.45 (s, 1H); 13C NMR (100 MHz,
20 (377 mg, 99%) as a yellow solid. Data for 20: 1H NMR DMSO-d6, δ): 86.5, 99.5, 105.8, 115.6, 121.3, 123.0, 130.7,
(400 MHz, DMSO-d6, δ): 13.39 (s, 1H), 11.65 (s, 1H), 9.62 154.4, 154.6, 158.1, 161.2, 161.5, 180.7; LRMS (ESI) m/z
(s, 1H), 9.53 (s, 1H), 9.32 (s, 1H), 7.68(s, 1H), 7.56 (d, J = 371 [M + Na]+; HRMS (ESI) m/z: Calcd for C15H9O5BrNa
8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H); 13C [M + Na]+ 370.9526; found, 370.9512; m.p.: 227.6–227.8
C.
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, Results and Discussion
157.8, 160.5, 175.9.
8-Bromo-2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H- Initially, we tried the bromination on the tetramethyl-protected
chromen-4-one (21). This compound was synthesized by quercetin 1 substrate by using NBS as bromination reagent
following the same procedure for the synthesis of compound in DMF at 0
C. Unlike the iodination by NIS,5 we got
20 by using 19 (590 mg, 1.0 mmol) as substrate to afford the 6-bromo product 2 and 6,8-dibromo product 4 (Table 1,
compound 21 (377 mg, 99%) as an orange solid. Data entry 1). We envisioned that the strong electrophilicity
for 21: 1H NMR (400 MHz, DMSO-d6, δ): 12.45 (s, 1H), of NBS compared to NIS diminished the selectivity. Carrying
11.61 (s, 1H), 9.62 (s, 2H), 7.83 (s, 1H), 7.68 (d, J = 8.4 Hz, out the reaction at − 20
C in CH2Cl2 (DCM), proved
1H), 6.92 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H); 13C NMR effective in blocking the formation of the dibromide by-prod-
(100 MHz, DMSO-d6, δ): 86.4, 98.7, 104.2, 115.7, 116.2, uct. However, the 8-bromo derivative 3 was afforded in
120.5, 122.4, 136.4, 145.6, 147.5, 148.5, 152.6, 159.9, 26 % yield (Table 1, entry 2). Other bromination reagents such
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 none, which is reported as a mild nitration9 or bromination
(24). Boron tri-chloride (5.0 mL, 5.0 mmol, 1 M solution in agent,10 5,5-dibromobarbituric acid,11 and 1,3-dibromo-5,5-
hexane) was added to a stirred solution of 23 (375 mg, 1.0 dimethylhydantoin12 were tested (Table 1, entries 3–5). All
mmol) in anhydrous DCM (20 mL) at −20
C for 30 min. After of them afforded the mono-bromo products 2 and 3. When
addition, the reaction mixture was heated to reflux for 2 h. the reaction was carried out at −40
C by using NBS, the yield
Then the reaction was cooled to room temperature, excess of compound 2 improved slightly (Table 1, entry 6). Further
methanol was added dropwise at −10
C with stirring for 10 decreasing the reaction temperature to − 78
C did not affect
min and then concentrated under reduced pressure. The crude the yield and regioselectivity of the reaction (Table 1, entry
product was purified by recrystallization in DCM to get com- 7). It is worth mentioning that compounds 2–4 are not easy
pound 24 (330 mg, 99%) as a white solid. Data for 24: 1H to separate and the solubilities of these three compounds are
NMR (400 MHz, DMSO-d6, δ): 13.73 (s, 1H), 11.84 (s, not good which leads to the loss of the compounds during col-
1H), 8.10–8.11 (m, 2H), 7.57–7.64 (m, 3H), 7.08 (s, 1H), umn separation.
6.75 (s, 1H). To improve regioselectivity, bulkier substituents such as
8-Bromo-5,7-dihydroxy-2-phenyl-4H-chromen-4-one ethyl and isopropyl were employed to protect the correspond-
(27). This compound was synthesized by following the same ing phenolic –OH groups. As expected, the regioselectivity
procedure for the synthesis of compound 24 by using 26 (417 and the yield of the 6-bromo product improved under the opti-
mg, 1.0 mmol) as substrate to afford compound 27 (330 mg, mized conditions (Scheme 2). It is noteworthy that the solubi-
99%) as a yellow solid. Data for 27: 1H NMR (400 MHz, lities of the products were greatly increased when isopropyl
DMSO-d6, δ): 12.84 (s, 1H), 11.75 (s, 1H), 8.14 (m, 2H), was used, which makes it much easier to separate the regioi-
7.60–7.65 (m, 3H), 7.12 (s, 1H), 6.45 (s, 1H). somers on a column.
6-Bromo-5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chro- Based on our previous work on regioselective iodination by
men-4-one (30). This compound was synthesized by follow- NIS,5 the pentamethyl-protected quercetin 14 is expected to be
ing the same procedure for the synthesis of compound 20 less reactive compared with the corresponding tetramethyl-
by using 29 (433 mg, 1.0 mmol) as substrate to afford com- protected substrate 1 because of its steric effect and the
pound 30 (345 mg, 99%) as a white solid. Data for 30: 1H absence of H-bonding between the halogenating reagent and
NMR (400 MHz, DMSO-d6, δ): 13.84 (s, 1H), 11.77 (s, phenolic –OH group of the substrate. Therefore, the bromina-
1H), 9.61 (s, 1H), 8.40 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), tion of compound 14 was initially carried out at 25
C with
6.83 (d, J = 8.0 Hz, 2H), 6.62 (s, 1H); 13C NMR (100 MHz, NBS in DCM. To our delight, only the 8-bromo derivative
DMSO-d6, δ): 93.4, 94.2, 105.2, 115.6, 121.4, 122.7, 130.7, 15 was obtained with 96% yield (Table 2, entry 1). When
154.8, 156.5, 158.0, 159.1, 161.1, 180.4. the reaction was carried out at 0
C, conversion was

Bull. Korean Chem. Soc. 2015, Vol. 36, 1460–1466 © 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 1463
 BULLETIN OF THE
Article Regioselective Bromination of Flavonoids KOREAN CHEMICAL SOCIETY

Table 1. Bromination of compound 1 under different conditions.a

OMe OMe OMe
Br
MeO O Bromination MeO O MeO O
OMe reagent OMe OMe

OMe Br OMe OMe

OH O OH O + OH O
1 2 3

OMe
O Br Br Br
O
Br Br O O Br MeO O
N OMe
HN NH N Br +
Br Br Br OMe
NO2 O O OH O
5 6 7 4

Yieldb (%)
Entry Reagent Solvent Temperature (
C) 2 3 4
1 NBS DMF 0 23 0 31
2 NBS DCM −20 47 26 0
3 5 DCM −20 41 25 0
4 6 DCM −20 33 31 0
5 7c DCM −20 36 41 0
6 NBS DCM −40 51 25 0
7 NBS DCM −78 49 26 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
Br
RO O RO O RO O
OR NBS OR OR
+
OR DCM Br OR OR
OH O –40 °C OH O OH O
8 9, 57%, 10 R = Ethyl 12%
11 12, 75% 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 regioselective brominations were achieved by alternating the
this substrate, other reagents such as 5–7 effected smooth bro- pattern of phenolic –OH protection and good to high yields
mination to give desired product in good yield (Table 2, entries were obtained for the desired mono-bromo products, which
3–5). When ethyl or isopropyl groups were used as protecting were de-isopropylated with BCl3 in nearly quantitative yields
groups, the mono-bromination yield was increased to 97 % (Table 3).
(Table 2, entries 6 and 7). Finally, this bromination protocol was applied to a rutin
With the bromo-quercetin derivatives 12 and 19 in hand, derivative containing an acid-labile glycosidic bond 34. Due
we tried the deprotection of the phenolic –OH groups with to its almost neutral conditions, the corresponding monobro-
BCl3 in DCM. Unlike the demethylation of 2 and 15 with mide 35 was obtained as a single product in 92% yield
BBr3, the reaction was quite clean and the desired products (Scheme 4).
20 and 21 were obtained in nearly quantitative yields
(Scheme 3). Conclusion
To further explore the scope and generality of this reaction,
other flavonoids such as chrysin (Table 3, entries 1 and 2) and In summary, an efficient method was developed to prepare C-6
genistein (Table 3, entries 3 and 4) were converted into their or C-8 mono-bromo flavonoids regioselectively, by bromina-
isopropyl ethers and subjected to bromination with NBS/ tion and subsequent dealkylation. The bromination can be
DCM under the optimized conditions. In all cases, completely conveniently directed to either the C-6 or C-8 position by

Bull. Korean Chem. Soc. 2015, Vol. 36, 1460–1466 © 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [Link] 1464
 BULLETIN OF THE
Article Regioselective Bromination of Flavonoids KOREAN CHEMICAL SOCIETY

Table 2. Bromination of compounds 14–18 under different conditions.a

OR
OR
Br
RO O Bromination
OR reagent RO O
OR
OR DCM
OR
OR O
OR O
14 15 R = Methyl
16 17 R = Ethyl
18 19 R = Isopropyl

Entry Reagent Substrate Temperature (
C) Product Yield (%)b

1 NBS 14 25 15 96
2 NBS 14 0 15 85
3 5 14 25 15 78
4 6 14 25 15 82
5 7c 14 25 15 93
6 NBS 16 25 17 97
7 NBS 18 25 19 97
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
MeO O BBr3
OMe messy
DCM
X OMe -78 °C-rt

OR O
2 R = H, X = Br, Y = H
15 R = Me, X = H, Y = Br

Oi-Pr OH
Y Y
i-PrO O HO O
Oi-Pr BCl3 OH

X Oi-Pr DCM X OH
-20 °C-reflux
OR O OH O

12 R = H, X = Br, Y = H 20 X = Br, Y = H 99%

19 R = Me, X = H, Y = Br 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- financial support from National Science Foundation of
diisopropylated flavonoids can be brominated with NBS/ China (Grants 21202118 and 21202119) and China Interna-
DCM to give the 8-bromo derivatives exclusively, whereas tional Science and Technology Cooperation Projects
isopropyl ethers of flavonoids bearing a free OH group at (2013DFA31160).
C-5 yield 6-bromo regioisomers as the major products. The
mild and neutral conditions of this protocol were found to
be applicable to substrates containing an acid-labile glycosidic Supporting Information. Additional supporting information
bond. is available in the online version of this article.

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 BULLETIN OF THE
Article Regioselective Bromination of Flavonoids KOREAN CHEMICAL SOCIETY

Table 3. Bromination of protected flavonoid derivatives.

Entry Substrates Methoda Iodinated products Yieldb (%) Deprotected productc Yieldb (%)

i-PrO O i-PrO O HO O

1 A Br 85 Br 99
OH O OH O OH O
22 23 24
Br Br
i-PrO O i-PrO O HO O

2 B 91 99
Oi-Pr O Oi-Pr O OH O
25 26 27
i-PrO O i-PrO O HO O

Br Br
3 OH O
Oi-Pr
A OH O
Oi-Pr
61 OH O
OH
99
28 29 30
i-PrO O Br Br
i-PrO O HO O

Oi-Pr O
4 Oi-Pr B Oi-Pr O
83 OH O
99
31 Oi-Pr OH
32 33

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 MeO O
OMe OMe

O O
OMe O OAc OMe O OAc
O NBS (1.2 eq)
O
O O DCM, 25 °C O O
OAc 92% OAc
OAc OAc
AcO OAc AcO OAc
OAc OAc
34 35
Scheme 4. Regioselective bromination of rutin derivative 34.

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