Copper-mediated trimethylsilyl azide in amination of bromoflavonoids to synthesize unique aminoflavonoids

Article abstract of DOI:10.1016/j.tet.2014.04.022

Aminoflavonoids are unique antioxidants comparing to other abundant flavonoids in nature. Their syntheses and biological activities were scarcely reported. An effectively copper-mediated amination of the corresponding bromoflavonoids to synthesize a serie

Full text of DOI:10.1016/j.tet.2014.04.022

Tetrahedron 70 (2014) 3657e3664
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-mediated trimethylsilyl azide in amination of
bromoflavonoids to synthesize unique aminoflavonoids
*
Tzenge-Lien Shih , Chi-En Chou, Wen-Yu Liao, Chih-Ang Hsiao
Department of Chemistry, Tamkang University, Tamsui Dist., 25137 New Taipei City, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Aminoflavonoids are unique antioxidants comparing to other abundant flavonoids in nature. Their
syntheses and biological activities were scarcely reported. An effectively copper-mediated amination of
the corresponding bromoflavonoids to synthesize a series of new aminoflavonoids is described.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 24 January 2014
Received in revised form 25 March 2014
Accepted 8 April 2014
Available online 13 April 2014
Keywords:
Aminoflavonoids
BakereVenkataraman rearrangement
ClaiseneSchmidt reaction
Copper-mediated amination
Trimethylsilyl azide
1. Introduction
aminoflavones as potent agents against HIV-2 virus.8g Therefore, it
prompted our interests in aminoflavones’ properties and their
Flavonoids are an important class of natural products that
exhibited a variety of biological activities.1 They are mainly ob-
tained from the plants2 and widely used, for example, as health care
agents,3 antioxidants,1b,4 antiinflamatory,5 and anticancer
drugs,1,4,6 etc. The hydroxyl groups are the most common func-
tional groups on flavonoids’ scaffolds and play as chelating roles as
well as radical inhibitors (Fig. 1).1a,4c Even though the amino groups
were considered showing the same behaviors7 as the hydroxyl
groups in flavonoids, however, the aminoflavonoids were less re-
ported in the syntheses and biological data to date.8 Early, the
synthetic aminoflavones were used to evaluate their inhibitory
activities against protein tyrosine kinase.8c A recent report showed
syntheses.9 In this regard, one of aminoflavones synthesized by
us9,10 exhibited the potent inhibition against cell proliferation in
Her2 cancer cells based on the preliminary data.11
Conventionally, the amino groups in synthetic aminoflavonoids
are generally derived from the reduction of the existing nitro
groups,8a,c deprotection of amides8c,g or amino derivatives8d on
flavones’ skeletons. The reported methods in syntheses of amino-
flavonoids sometimes required few steps for preparing the desig-
nated material.8c In our previous report, we have synthesized
a reported aminoflavone in three steps rather than six steps by
literature.9 The only drawback suffered was the lower yields owing
to the various substituent groups on the A or B rings of flavones. In
order to overcome this obstacle, we highlight a modified strategy in
this article. Unlike our reported method,9 we utilized the corre-
sponding bromoflavonoid’s framework then replaced the bromo
group(s) with the amino group(s) via efficiently copper-mediated
amination to synthesize a series of unique aminoflavonoids. Our
synthetic routes were shorter or equivalent steps to the established
methods8 but more versatile, especially, the starting materials are
cheap.
2. Results and discussion
Fig. 1. The frameworks of flavonoids.
Preparations of bromoflavones 4aeh (Tables 1 and 2) are
required for syntheses of aminoflavones 5 (Table 3). The strategy
for our target molecules employed the BakereVenkataraman
* Corresponding author. Tel./fax: þ886 2 86315024; e-mail address: tlshih@mail.
tku.edu.tw (T.-L. Shih).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.022

3658
T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
Table 1
Table 2
Synthesis of esters 3
Synthesis of bromoflavones 4
rearrangement,12 acid-catalyzed cyclization, and copper-catalyzed
amination on either the A or B rings of bromoflavones at the final
stage. The cheap and commercially available starting materials 1
and 2 were used. Coupling between 1 and 2 mediated by 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI)
afforded high yields of ester adducts 3 (Table 1). The base mediated
rearrangement by KOH in pyridine at 60 ꢀC followed by the acid-
catalyzed cyclization (H2SO4) in AcOH affords 4aef in two steps,
respectively (Table 2). In order to receive the higher yields of cyclic
adducts 4aef, it is noteworthy that the complete removal of pyri-
dine by washing with hexanes before acid treatment is necessary
(see Experimental). The amination of 4a was first applied Cu2O/
NH4OH/H2O/NMP at 80 ꢀC.13 However, the desired 5a was obtained
in only 15%. It is probably owing to the high volatility of NH4OH at
Flavonols are with an external hydroxy group at C3 position of
flavones’ scaffolds. We can apply the similar strategy of the above-
mentioned method for aminoflavanol’s synthesis. We tried to in-
troduced two amino groups on the A ring of dibromoflavols 8 to
synthesize diaminoflavonols. The condensations of 1 and 6 were
conducted by ClaiseneSchmidt reaction16 to give high yields of 7
(Table 4). Different ether protections (OMe and OMOM) of 6 were
used. It was found that the choice of protecting groups dramatically
influenced the yields of final deprotecting step (vide infra). Oxi-
dation of compounds 7 were carried out hydrogen peroxide and
sodium hydroxide (AlgareFlynneOyamada reaction)17 to provide
dibromoflavonols 8 (Table 5). We are also intended on the synthesis
of diaminoflavonols from compounds 8aec applying condition of
TMSN3/Cu/2-aminoethanol/DMA/120 ꢀC. However, not only the
mono amino substitution 9aec were isolated as the major com-
ponents but also obtained in lower yields (Table 6). None of the
expected 6,8-diaminoflavonols were detected or isolated from
column chromatography. Therefore, compound 8b was selected for
study in improvement of copper-mediated amination conditions
and an array of catalysts was screened in order to optimize the
yields. We applied the same condition as in Table 6 except with
80 ꢀC. Another method, CuI/ -proline/NH4Cl/K2CO3/80 ꢀC,14 was
L
also tried but gave a complex mixture. The most efficient condition
was using TMSN3/Cu/2-aminoethanol/N,N-dimethylacetamide
(DMA)/120 ꢀC15 (Table 3). This method was originally applied in
amination of simple haloaromatic compounds.15a It is noticed that
the fluoride group of 4a was also aminated during the reaction
course to give diamino compound 5a8c (41%). Applying the same
condition on 4b and 4f gives the corresponding aminoflavones 5b
(80%) and 5f (51%), respectively. On the other hand, we intended
the preparation of 6,8-diaminoflavone 5d from the corresponding
dibromide 4d. The expected 5d was received in 37% yield along
with the unexpected mono aminoflavone 5b (35%). Obviously, the
bromide at C8 position of 4d is more readily to be cleaved than its
C6 bromide before amino groups are incorporated. Unlike the
amination of 4a, compound 4e was completely decomposed during
the reaction condition and no desired product was received.

T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
3659
Table 3
Table 5
Synthesis of aminoflavones 5 via copper-mediated amination of bromoflavones 4
Synthesis of bromoflavonols 8
various copper catalysts. The yields were low by Cu2O and CuI with
11% and 7%, respectively. Other catalysts, such as CuCl, CuBr, CuO,
CuCl2, CuBr2, and Cu(OAc)2, were used but all failed to obtain the
desired product 9b and a complicated mixture was observed by
TLC. On the other hand, conditions with different ligands were
tried, such as, Cu2O/NaN3/
bic acid/NH4OH/100 ꢀC,19 CuI/
90 ꢀC,20 CuI/4-hydroxy- -proline/NH4OH/DMSO/50 ꢀC,21 again, to
L
-proline/DMSO/100 ꢀC,13,18 CuI/
-proline/K2CO3/NH4OH/DMSO/
L-ascor-
L
L
fail receiving the desired compound 9b. Therefore, the best catalyst
is copper for synthesis of aminoflavonols under this condition. We
suspect that the C3eOH is labile under this harsh condition and
require further protection before amination.22
Table 4
Synthesis of 7 via ClaiseneSchmidt reaction
We found the final deprotecting step of 9aec by either 48% HBr
or 3 N HCl was critical. Demethylation of 9a by 48% HBr under
reflux was not practical and low yield of 9e (21%) was received. On
the other hand, the MOM protection in 9b and 9c could be easily
removed to afford higher yields of 9d (85%) and 9e8a (66%), re-
spectively, under 3 N HCl condition.
3. Conclusion
The condition of TMSN3/Cu/2-aminoethanol/DMA/120 ꢀC is ef-
fective in copper-mediated amination of the corresponding bro-
moflavonoids to synthesize unique aminoflavone 5a and
derivatives 5b,d,f in moderate to good yields. Deprotection of the
compounds 5b,d,f affords 5c,e,g, respectively. It is worthwhile no-
tice that aminoflavones 5c and 5e can not be synthesized from the
corresponding nitro starting materials 1, which are not commer-
cially available. We provide an alternative and a more flexible
method in construction of amino group(s) on flavonoids’ motifs
comparing with the conventional methods. The strategy in

3660
T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
Table 6
saturated NaHCO3 solution, diluted with CH2Cl2 and stirred for
10 min. The organic layer was separated, dried over MgSO4, filtered,
and purified with flash column chromatography (230e400 mesh
SiO2) to provide 3b.
Copper-mediated amination of bromoflavonols 8 in synthesis of aminoflavonols 9
4.1.2. General procedure of BakereVenkataraman rearrangement and
cyclization. A mixture of 3 (2.050 g, 4.48 mmol), for example, and
KOH (0.380 g, 6.72 mmol) in pyridine (15 mL) was heated at 60 ꢀ
C
for 2 h. The reaction was neutralized by 2 N HCl and diluted with
EtOAc. The organic layer was dried over MgSO4, filtered, and con-
centrated to give a yellow-brown solid. The solid was used for the
next step without further purification. The solid was dissolved in
acetic acid (15 mL) and catalytic amount of H2SO4 (0.3 mL) to heat
under reflux for 1 h. The mixture was cooled to ambient temper-
ature and diluted with H2O and EtOAc. The organic layer was sep-
arated and washed with saturated NaHCO3 solution. The organic
layer was dried over MgSO4, filtered, concentrated, and purified by
flash column chromatography (230e400 mesh SiO2) to provide 4d.
4.1.3. General procedure of ClaiseneSchmidt reaction. Compound 7a
(1.060 g, 2.40 mmol) in 1,4-dioxane (10.6 mL) was sequentially added
ethanol (30 mL), 5.4% NaOH (10.6 mL, 0.015 mmol), and 35% H2O2
(1.2 mL, 0.12 mmol) at 0 ꢀC. The mixture was stirred at that tem-
perature for 12 h before neutralized by 2 N HCl. The precipitate was
filtered and washed with ice water. The solid was dissolved in CH2Cl2,
dried with MgSO4, and concentrated. Purification by flash column
chromatography (230e400 mesh SiO2) afforded a yellow solid.
4.1.4. General procedure of copper-catalyzed amination. All of re-
actions were conducted under a sure-sealed bottle. Compound 4d
(0.440 g, 1.00 mmol), for example, and copper powder (0.450 g,
6.00 mmol) was dissolved in DMA (5 mL). To this mixture was
added 2-aminoethanol (0.42 mL, 7.00 mmol) and TMSN3 (0.79 mL,
6.00 mmol) and heated at 120 ꢀC for 4 h (note: the equivalents of
TMSN3 were three times of the number(s) of bromide atom(s) to
the corresponding flavone). The solution was cooled to ambient
temperature, diluted with EtOAc, and filtered. The solid was
washed sequentially with EtOAc, H2O, and NH4OH. The organic
layer was extracted with EtOAc, dried with MgSO4, and purified by
flash column chromatography (230e400 mesh SiO2) to provide 5d.
synthesis of 6-aminoflavonol’s derivatives 9aec from amination of
bromoflavonols 8 needs improvement owing to the fragile struc-
tures under reaction conditions. The new aminoflavonoids 5c and
5e may show potentials biological activities than other natural
flavonoids and require further studies.
4.1.5. General procedure of ether bond cleavage
4.1.5.1. Cleavage of methyl ether. Compound 5b (21 mg,
0.067 mmol), for example, was dissolved in 48% HBr (3 mL) and
heated under reflux for 12 h. The solution was cooled to ambient
temperature, diluted with H2O, saturated Na2SO3, and extracted
with 1-butanol. The solvent was removed and the resulting syrup
was purified by flash column chromatography (230e400 mesh
SiO2) to afford 5c.
4. Experimental section
4.1. General
All chemicals and solvents were purchased from the commercial
providers and used without further purification except otherwise
stated. 1H NMR (600 MHz) and 13C NMR (150 MHz) spectra were
recorded on a Bruker 600 MHz instrument.
Purification by flash column chromatography was performed on
silica gel 230e400 mesh except otherwise mentioned. All samples
were dissolved in designated d-solvents with the internal reference
as the following: CDCl3 (1H: 7.26 ppm; 13C: 77.0 ppm); DMSO-d6
(1H: 2.50 ppm; 13C: 39.51 ppm). Melting points were measured on
a MPe2D apparatus and uncorrected. LRMS and HRMS were de-
termined by Finnigan Mat 95s mass spectrometer.
4.1.5.2. Cleavage of methoxymethyl ether. Compound 9c (30 mg,
0.08 mmol) in MeOH (2.5 mL) was added 3 N HCl (1.5 mL) and
heated under reflux for 7 h. The solution was cooled to ambient
temperature and diluted with H2O. The solvent was removed under
reduced pressure and diluted with EtOAc and H2O. The organic
layer was separated and the aqueous layer was neutralized with
saturated NaHCO3 solution and extracted with EtOAc. The organic
layers were combined and dried over MgSO4. The residue was
purified by flash column chromatography (230e400 mesh SiO2) to
afford 9e.
4.1.1. General procedure of esterification. Compound 1 (1.200 g,
4.08 mmol) and 2 (1.490 g, 8.16 mmol), for example, were dissolved
in CH2Cl2 (20 mL). To this mixture was added EDCI (1.960 g,
10.21 mmol) and DMA (0.250 g, 2.04 mmol) at 0 ꢀC and stirred to
ambient temperature for 12 h. The reaction was quenched with
4.2. 2-Acetyl-4-bromophenyl-4-fluorobenzoate (3a)
1 (1.6040 g, 7.46 mmol), 2 (1.5290 g,10.91 mmol). Purification by
flash column chromatography (Hex:EtOAc¼40:1e10:1; Rf 0.5,

T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
3661
Hex:EtOAc¼20:1) afforded a white solid. Yield¼2.2820 g (91%). Mp
112e114 ꢀC. 1H NMR (CDCl3)
8.21 (dd, J¼9.0, 5.4 Hz, 2H), 7.96 (d,
121.2, 117.9, 116.3, 116.1, 106.8. HRMS (EI) calcd for C15H8BrFO2
([M]þ) 317.9692. Found: 317.9698.
d
J¼2.4 Hz, 1H), 7.69 (dd, J¼8.4, 2.4 Hz, 1H), 7.20 (t, J¼8.4 Hz, 2H), 7.13
(d, J¼8.4 Hz, 1H), 2.53 (s, 3H). 13C NMR (CDCl3)
d 196.0, 166.5
4.8. 2-(30,40-Dimethoxyphenyl)-6-bromo-4H-chromen-4-one
(4b)
(JCeF¼255.0 Hz), 163.9, 148.2, 136.2, 133.0, 132.9, 132.7, 125.7, 125.2,
119.4, 116.1, 116.0, 29.5. HRMS (EI) calcd for C15H10BrFO3 ([Mþ])
335.9797. Found: 335.9796.
3b (1.000 g, 2.637 mmol). Purification by flash column chro-
matography (CH2Cl2; Rf 0.25, CH2Cl2) afforded a pale purple solid.
Yield¼0.7820 g (82%) (two steps). Mp 207e209 ꢀC. 1H NMR (DMSO-
4.3. 50-Bromo-20-(3,4-dimethoxybenzoyloxy)acetophenone
(3b)
d6)
d
8.09 (d, J¼2.5 Hz, 1H), 7.97 (dd, J¼8.9, 2.5 Hz, 1H), 7.80 (d,
J¼8.9 Hz, 1H), 7.72 (dd, J¼8.5, 2.1 Hz, 1H), 7.60 (d, J¼1.8 Hz, 1H), 7.13
(d, J¼8.6 Hz, 1H), 7.10 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H). 13C NMR
1 (1.4470 g, 6.728 mmol), 2 (1.5930 g, 8.746 mmol). Purification
by flash column chromatography (Hex:EtOAc¼5:1e2:1; Rf 0.3,
Hex:EtOAc¼4:1) afforded a white solid. Yield¼2.1880 g (86%). Mp
(DMSO-d6)
d 175.7, 163.0, 154.6, 152.1, 149.0, 136.6, 126.8, 124.8,
123.0, 121.3, 120.1, 117.7, 111.7, 109.5, 105.7, 55.9, 55.7. HRMS (EI)
144e146 ꢀC. 1H NMR (CDCl3)
d
7.94 (d, J¼2.5 Hz,1H), 7.85 (dd, J¼8.4,
calcd for C17H13BrO4 ([M]þ) 359.9997. Found: 359.9995.
2.0 Hz, 1H), 7.67 (dd, J¼8.6, 2.5 Hz, 1H), 7.64 (d, J¼2.0 Hz, 1H), 7.12
(d, J¼8.6 Hz, 1H), 6.96 (d, J¼8.5 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H). 13
C
4.9. 6-Bromo-2-(30,40-dihyoxyphenyl)-4H-chromen-4-one (4c)
NMR (CDCl3)
d 196.2, 164.5, 154.0, 149.0, 148.5, 136.0, 133.0, 132.8,
125.7, 124.7, 121.1, 119.2, 112.5, 110.6, 56.1 (ꢁ2), 29.8. HRMS (EI)
3b (0.300 g, 0.791 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼1:1e0:1; Rf 0.18, Hex:EtOAc¼1:1) affor-
calcd for C17H15BrNaO5 ([MþNa]þ) 401.0001. Found: 400.9995.
ded
a
yellow solid. Yield¼0.0820
g (31%) (two steps). Mp
4.4. 2-Acetyl-4,6-dibromophenyl-3,4-dimethoxybenzoate (3c)
236e238 ꢀC. 1H NMR (DMSO-d6)
d
8.07 (d, J¼2.5 Hz, 1H), 7.94 (dd,
J¼8.9, 2.5 Hz, 1H), 7.71 (d, J¼8.8 Hz, 1H), 7.44 (dd, J¼8.3, 2.3 Hz, 1H),
1 (1.200 g, 4.08 mmol), 2 (1.490 g, 8.16 mmol). Purification by
flash column chromatography (Hex:EtOAc¼10:1e4:1; Rf 0.5,
Hex:EtOAc¼5:1) afforded a white solid. Yield¼1.6740 g (90%). Mp
7.41 (d, J¼1.9 Hz, 1H), 6.86 (d, J¼8.2 Hz, 1H), 6.78 (s, 1H). 13C NMR
(DMSO-d6)
d 175.5, 163.7, 154.5, 150.6, 146.0, 136.6, 126.9, 124.9,
121.0 (ꢁ2), 119.2, 117.6, 115.9, 113.1, 104.5. HRMS (EI) calcd for
141e142 ꢀC. 1H NMR (CDCl3)
d
7.94 (d, J¼2.3 Hz, 1H), 7.91 (dd, J¼8.5,
C
15H8BrO4 ([MꢂH]þ) 330.9606. Found: 330.9600.
2.0 Hz, 1H), 7.87 (d, J¼2.3 Hz, 1H), 7.67 (d, J¼2.0 Hz, 1H), 6.98 (d,
J¼8.5 Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 2.51 (s, 3H). 13C NMR (CDCl3)
4.10. 6,8-Dibromo-2-(30,40-dimethoxyphenyl)-4H-chromen-4-
one (4d)
d
195.4, 163.4, 154.2, 149.0, 146.2, 138.9, 134.8, 131.9, 125.0, 120.6,
119.7, 119.6, 112.6, 110.6, 56.2, 56.1, 29.6. HRMS (EI) calcd for
C
17H14Br2NaO5 ([MþNa]þ) 478.9106. Found: 478.9100.
3c (2.050 g, 4.48 mmol). Purification by flash column chroma-
tography (CH2Cl2; Rf 0.3, CH2Cl2) afforded a pale white solid.
Yield¼1.5350 g (73%) (two steps). Mp 249e251 ꢀC. 1H NMR (DMSO-
4.5. 2-Acetyl-4,6-dibromophenyl-4-fluorobenzoate (3d)
d6)
d
8.28 (d, J¼2.3 Hz, 1H), 8.01 (d, J¼2.3 Hz, 1H), 7.62 (dd, J¼8.5,
1 (1.000 g, 3.40 mmol), 2 (0.950 g, 6.80 mmol). Purification by
flash column chromatography (Hex:EtOAc¼20:1e10:1; Rf 0.7,
Hex:EtOAc¼10:1) afforded a pale white solid. Yield¼1.3090 g (93%).
2.1 Hz, 1H), 7.50 (d, J¼2.1 Hz, 1H), 7.00 (d, J¼8.5 Hz, 1H), 6.78 (s, 1H),
3.98 (s, 3H), 3.97 (s, 3H). 13C NMR (DMSO-d6)
d
176.2, 163.5, 152.6,
151.6, 149.4, 139.1, 127.8, 126.0, 123.2, 120.3, 118.4, 112.8, 111.3, 108.9,
105.8, 56.1, 56.0. HRMS (EI) calcd for C17H12Br2O4 ([M]þ) 437.9102.
Found: 437.9103.
Mp 113e114 ꢀC. 1H NMR (CDCl3)
d 8.26e8.22 (m, 2H), 7.95 (d,
J¼2.3 Hz, 1H), 7.89 (d, J¼2.3 Hz, 1H), 7.22 (t, J¼11.4 Hz, 2H), 2.51 (s,
3H). 13C NMR (CDCl3)
139.0, 134.3, 133.2 (ꢁ2), 132.8, 132.5, 132.1, 130.9, 124.6, 119.8, 116.2,
116.0, 29.4. LRMS (ESI) m/z ([MþNa]þ) 437 (100%), 413 (10%), 381
(60%).
d
195.1, 166.6 (JCeF¼254 Hz), 162.8, 145.9,
4.11. 6,8-Dibromo-2-(40-fluorophenyl)-4H-chromen-4-one
(4e)
3d (0.970 g, 2.35 mmol). Purification by flash column chroma-
tography (Hex:CH2Cl2¼2:1e0:1; Rf 0.7, CH2Cl2) afforded a pale
yellow solid. Yield¼0.6870 g (74%) (two steps). Mp 251e252 ꢀC. 1H
4.6. 2-Acetyl-3,5-dimethoxyphenyl-4-bromobenzoate (3e)
1 (0.500 g, 2.55 mmol), 2 (1.020 g, 5.1 mmol). Purification by
flash column chromatography (Hex:EtOAc¼10:1e3:1; Rf 0.3,
Hex:EtOAc¼10:1) afforded a white solid. Yield¼0.8680 g (90%). Mp
NMR (CDCl3)
d
8.29 (d, J¼2.1 Hz,1H), 8.04 (d, J¼2.1 Hz,1H), 8.00 (dd,
J¼8.5, 5.2 Hz, 2H), 7.25 (d, J¼8.5 Hz, 2H), 6.81 (s, 1H). 13C NMR
123e124 ꢀC. 1H NMR (DMSO-d6)
d
7.99 (d, J¼1.7 Hz, 1H), 7.98 (s, 1H),
(CDCl3)
d 176.5, 166.0, 164.3, 162.7, 151.8, 139.4, 128.8, 127.9, 126.9
(J1 ¼223.0 Hz), 118.7, 116.6 (J2 ¼23.0 Hz), 113.0, 107.0. HRMS
CeF
CeF
7.63 (d, J¼1.7 Hz, 1H), 7.62 (s, 1H), 6.41 (d, J¼2.1 Hz, 1H), 6.35 (d,
(EI) calcd for C15H7Br79Br81FO2 ([M]þ) 397.8776. Found: 397.8775.
J¼2.1 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.47 (s, 3H). 13C NMR
(DMSO-d6)
d
199.1, 164.4, 162.3, 159.4, 149.8, 131.9 (ꢁ2), 131.7 (ꢁ2),
128.9, 128.2, 117.0, 100.1, 96.8, 55.9, 55.7, 31.9. HRMS (EI) calcd for
4.12. 2-(40-Bromophenyl)-5,7-dimethoxy-4H-chromen-4-one
(4f)
C
17H15BrO5 ([M]þ) 378.0103. Found: 378.0101.
4.7. 2-(40-Fluorophenyl)-6-brmomo-4H-chromen-4-one (4a)
3e (0.840 g, 2.21 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼2:1e1:2; Rf 0.45, Hex:EtOAc¼1:2) afforded
3a (2.1450 g, 6.363 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼40:1e0:1; Rf 0.53, Hex:EtOAc¼4:1)
afforded a pale white solid. Yield¼1.5220 g (75%) (two steps). Mp
a
pale yellow solid. Yield¼0.5170
g (65%) (two steps). Mp
197e198 ꢀC. 1H NMR (DMSO-d6)
J¼8.6 Hz, 2H), 6.84 (d, J¼1.9 Hz, 1H), 6.80 (s, 1H), 6.50 (d, J¼1.9 Hz,
1H), 3.89 (s, 3H), 3.83 (s, 3H). 13C NMR (DMSO-d6)
175.8, 164.1,
d
7.97 (d, J¼8.6 Hz, 2H), 7.74 (d,
177e179 ꢀC. 1H NMR (DMSO-d6)
d
8.13 (dd, J¼8.8, 5.4 Hz, 2H), 8.04
d
(d, J¼2.3 Hz, 1H), 7.94 (dd, J¼8.8, 2.5 Hz, 2H), 7.73 (d, J¼8.9 Hz, 1H),
160.6, 159.4, 158.8, 132.3 (ꢁ2), 130.4, 128.2 (ꢁ2), 125.3, 108.8, 108.6,
96.6, 93.6, 56.4, 56.3. HRMS (EI) calcd for C17H13BrO4 ([M]þ)
359.9997. Found: 359.9991.
7.39 (t, J¼8.8 Hz, 2H), 7.03 (s, 1H). 13C NMR (DMSO-d6)
d 175.8, 164.3
(JCeF¼249 Hz), 161.9, 154.5, 136.8, 129.2, 129.1, 127.3, 126.9, 124.7,

3662
T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
4.13. 6,8-Dibromo-2-(30,40-dihydroxyphenyl)-4H-chromen-4-
one (4g)
solid. Yield¼0.1160 g (37%). Mp 240e242 ꢀC. 1H NMR (DMSO-d6)
d
7.78 (dd, J¼8.6, 2.1 Hz, 1H), 7.56 (d, J¼2.1 Hz, 1H), 7.07 (d, J¼8.6 Hz,
1H), 6.77 (s, 1H), 6.36 (d, J¼2.6 Hz, 1H), 6.34 (d, J¼2.6 Hz, 1H), 5.44
4d (0.290 g, 0.64 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼1:1e0:1; Rf 0.15, Hex:EtOAc¼1:1) afforded
a yellow solid. Yield¼0.1260 g (48%). Mp 297e298 ꢀC. 1H NMR
(s, 2H), 5.11 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H). 13C NMR (DMSO-d6)
d
177.4, 161.0, 151.4, 148.9, 146.4, 138.8, 137.6, 124.7, 124.1, 119.9,
111.6, 109.5, 104.7, 104.5, 93.6, 55.7 (ꢁ2). HRMS (EI) calcd for
C
17H16N2O4 ([M]þ) 312.1110. Found: 312.1112.
(DMSO-d6)
d
8.34 (d, J¼2.3 Hz, 1H), 8.05 (d, J¼2.3 Hz, 1H), 7.50 (d,
J¼1.9 Hz,1H), 7.49 (dd, J¼8.3, 2.3 Hz,1H), 6.91 (d, J¼8.2 Hz,1H), 6.87
(s, 1H). 13C NMR (DMSO-d6)
d
175.1, 163.5, 151.3, 150.2, 145.9, 138.7,
4.19. 6,8-Diamino-2-(30,40-dihydroxyphenyl)-4H-chromen-4-
126.7, 125.7, 121.2, 119.2, 117.7, 116.1, 113.6, 113.0, 104.7. HRMS (EI)
calcd for C15H8Br2O4 ([M]þ) 409.8789. Found: 409.8795.
one (5e)
5d (0.160 g, 0.44 mmol). Purification by flash column chroma-
tography (CH2Cl2:MeOH¼12:1e2:1; Rf 0.5, EtOAc) afforded a brown
solid. Yield¼0.0510 g (41%). Mp 201e202 ꢀC. 1H NMR (DMSO-d6)
4.14. 2-(40-Bromophenyl)-5,7-dihydroxy-4H-chromen-4-one
(4h)
d
7.47 (dd, J¼8.4, 2.3 Hz,1H), 7.40 (d, J¼2.2 Hz,1H), 6.85 (d, J¼8.4 Hz,
4f (0.100 g, 0.26 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼10:1e2:1; Rf 0.4, Hex:EtOAc¼3:1) afforded
a yellow solid. Yield¼0.0460 g (52%). Mp 282e283 ꢀC. 1H NMR
1H), 6.49 (s, 1H), 6.34 (d, J¼2.5 Hz, 1H), 6.32 (d, J¼2.5 Hz, 1H), 5.32
(s, 2H), 5.06 (s, 2H). 13C NMR (DMSO-d6)
d
171.5, 161.6, 149.0, 146.4,
145.7, 138.7, 137.6, 124.7, 122.7, 118.7, 115.9, 113.4, 104.9, 103.6, 93.9.
HRMS (ESI) calcd for C15H13N2O4 ([MþH]þ) 285.0875. Found:
285.0870.
(DMSO-d6)
d
7.99 (d, J¼8.6 Hz, 2H), 7.76 (d, J¼8.6 Hz, 2H), 6.97 (s,
1H), 6.50 (d, J¼2.0 Hz, 1H), 6.21 (d, J¼2.0 Hz, 1H). 13C NMR (DMSO-
d6)
d
181.8, 164.6, 162.1, 161.5, 157.4, 132.2 (ꢁ2), 130.0, 128.4 (ꢁ2),
125.8, 105.6, 104.0, 99.2, 94.2. HRMS (EI) calcd for C15H9BrO4 ([M]þ)
331.9684. Found: 331.9693.
4.20. 2-(40-Aminophenyl)-5,7-dimethoxy-4H-chromen-4-one
(5f)
4.15. 6-Amino-2-(40-aminophenyl)-4H-chromen-4-one (5a)8a
4f (0.100 g, 0.276 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼2:1e0:1; Rf 0.5, EtOAc) afforded a yellow
solid. Yield¼0.0420 g (51%). Mp 201e202 ꢀC. 1H NMR (DMSO-d6)
4a (0.1570 g, 0.4918 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼1:2e0:1; Rf 0.58, EtOAc) afforded an orange-
yellow solid. Yield¼0.0520 g (41%). Mp 265e275 ꢀC. 1H NMR
d
7.69 (d, J¼8.8 Hz, 2H), 6.78 (d, J¼2.3 Hz, 1H), 6.63 (d, J¼8.8 Hz, 2H),
6.45 (d, J¼2.3 Hz, 1H), 6.42 (s, 1H), 5.87 (s, eNH2, 2H), 3.87 (s, 3H),
(DMSO-d6)
d
7.70 (d, J¼8.8 Hz, 2H), 7.39 (d, J¼8.9 Hz, 1H), 7.06 (d,
3.80 (s, 3H). 13C NMR (DMSO-d6)
d
175.8, 163.5, 161.0, 160.2, 159.1,
J¼2.8Hz,1H), 6.99 (dd, J¼8.8,2.9 Hz,1H), 6.65(d,J¼8.7 Hz,2H), 6.55 (s,
152.2, 127.5, 116.9, 113.6, 108.3, 104.3, 96.0, 93.3, 56.1, 56.0. HRMS
(EI) calcd for C17H15NO4 ([M]þ) 297.1001. Found: 297.1006.
1H), 5.90 (s, 2H), 5.38 (s, 2H). 13C NMR (DMSO-d6)
d
176.8,163.0,152.3,
147.7, 146.3, 127.7 (ꢁ2),124.2,121.1,118.6,117.6,113.5 (ꢁ2),105.3,102.1.
HRMS (EI) calcd for C15H12N2O2 ([M]þ) 252.0899. Found: 252.0904.
4.21. 2-(40-Aminophenyl)-5,7-dihydroxy-4H-chromen-4-one
(5g)
4.16. 6-Amino-2-(30,40-dimethoxyphenyl)-4H-chromen-4-one
(5b)
5f (0.080 g, 0.2401 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼1:1e0:1; Rf 0.5, EtOAc) afforded a yellow
solid. Yield¼0.020 g (30%). Mp 316e318 ꢀC. 1H NMR (DMSO-d6)
4b (0.500 g, 1.38 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼3:2e0:1; Rf 0.83, EtOAc) afforded a yellow-
green solid. Yield¼0.3280 g (80%). Mp 210e212 ꢀC. 1H NMR
d
7.74 (d, J¼8.7 Hz, 2H), 6.66 (d, J¼8.7 Hz, 2H), 6.60 (s, 1H), 6.43 (d,
J¼2.0 Hz, 1H), 6.15 (d, J¼2.0 Hz, 1H), 6.06 (s, 2H). 13C NMR (DMSO-
(DMSO-d6)
d
7.63 (dd, J¼8.5, 2.2 Hz, 1H), 7.53 (d, J¼2.1 Hz, 1H), 7.48
d6)
d
181.6, 164.7, 164.1, 161.5, 157.3, 153.0, 128.2 (ꢁ2), 116.6, 113.6
(d, J¼8.9 Hz, 1H), 7.11 (d, J¼8.6 Hz, 1H), 7.08 (d, J¼2.8 Hz, 1H), 7.04
(ꢁ2), 103.6, 100.8, 98.8, 93.9. HRMS (ESI) calcd for C15H12NO4
(dd, J¼8.8, 2.8 Hz, 1H), 6.84 (s, 1H), 5.46 (s, 2H), 3.87 (s, 3H), 3.83 (s,
([MþH]þ) 270.0766. Found: 270.0755.
3H). 13C NMR (DMSO-d6)
d 177.1, 161.8, 151.6, 149.0, 147.9, 146.5,
124.2, 123.9, 121.5, 119.6, 118.9, 109.3, 105.0, 104.7, 55.8, 55.7. HRMS
4.22. (E)-1-(3,5-Dibromo-2-hydroxyphenyl)-3-(3,4-
dimethoxyphenyl)prop-2-en-1-one (7a)
(EI) calcd for C17H15NO4 ([M]þ) 297.1001. Found: 297.1003.
4.17. 6-Amino-2-(30,40-dihydroxyphenyl)-4H-chromen-4-one
(5c)
1 (3.120 g, 10.62 mmol), 6 (1.470 g, 8.85 mmol). Purification by
flash column chromatography (Hex:EtOAc¼15:1e1:1; Rf 0.65,
Hex:EtOAc¼2:1) afforded an orange solid. Yield¼3.760 g (96%). Mp
5b (0.0210 g, 0.0672 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼1:0e2:1; Rf 0.55, EtOAc) afforded a yel-
low solid. Yield¼0.0082 g (43%). Mp 250 ꢀC (decomposed). 1H NMR
152e153 ꢀC. 1H NMR (CDCl3)
d
8.00 (d, J¼2.0 Hz, 1H), 7.96 (d,
J¼15.2 Hz, 1H), 7.87 (d, J¼2.0 Hz, 1H), 7.39 (d, J¼15.2 Hz, 1H), 7.30
(dd, J¼8.3, 1.7 Hz, 1H), 7.18 (d, J¼1.7 Hz, 1H), 6.93 (d, J¼8.3 Hz, 1H),
(DMSO-d6)
d
7.40 (d, J¼8.8 Hz, 1H), 7.36 (s, 1H), 7.35 (dd, J¼8.0,
3.99 (s, 3H), 3.96 (s, 3H). 13C NMR (CDCl3)
d 192.2, 159.2, 152.5,
2.1 Hz, 1H), 7.07 (d, J¼2.8 Hz, 1H), 7.02 (dd, J¼8.9, 2.8 Hz, 1H), 6.86
149.5, 148.0, 141.0, 131.0, 127.1, 124.3, 121.7, 116.4, 113.4, 111.2, 110.6,
110.2, 56.2, 56.2. HRMS (EI) calcd for C17H14Br2O4 ([M]þ) 439.9259.
Found: 439.9252.
(d, J¼8.0 Hz, 1H), 6.56 (s, 1H), 3.70e3.10 (br s, 2H). 13C NMR (DMSO-
d6)
d 176.9, 162.4, 149.1, 147.7, 146.4, 145.7, 124.2, 122.4, 121.3, 118.6,
118.4,115.9,113.1,105.1,103.8. HRMS (EI) calcd for C15H11NO4 ([M]þ)
269.0688. Found: 269.0680.
4.23. (E)-1-(3,5-Dibromo-2-hydroxyphenyl)-3-(3-methoxy-4-
(methoxymethoxy)phenyl)prop-2-en-1-one (7b)
4.18. 6,8-Diamino-2-(30,40-dimethoxyphenyl)-4H-chromen-4-
one (5d)
1 (2.090 g, 7.12 mmol), 6 (1.270 g, 6.47 mmol). Purification by
flash column chromatography (Hex:EtOAc¼8:1e1:1; Rf 0.4,
Hex:EtOAc¼1:1) afforded an orange solid. Yield¼2.8130 g (92%).
4d (0.440 g, 1.0 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼1:1e0:1; Rf 0.3, EtOAc) afforded a brown
Mp 150e151 ꢀC. 1H NMR (CDCl3)
d
7.99 (d, J¼2.2 Hz, 1H), 7.95 (d,

T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
3663
J¼15.2 Hz, 1H), 7.87 (d, J¼2.2 Hz, 1H), 7.40 (d, J¼15.2 Hz, 1H), 7.28
(dd, J¼8.4, 1.8 Hz, 1H), 7.21 (d, J¼8.4 Hz, 1H), 7.18 (d, J¼1.8 Hz, 1H),
1H), 7.86e7.82 (m, 2H), 6.96 (d, J¼8.4 Hz, 1H), 3.85 (s, 3H). 13C NMR
(DMSO-d6)
d 171.0, 149.8, 149.2, 147.6, 146.5, 138.4, 138.0, 126.6,
5.31 (s, 2H), 3.99 (s, 3H), 3.53 (s, 3H). 13C NMR (CDCl3)
d
192.2,159.2,
123.6, 122.2, 122.0, 116.7, 115.8, 113.0, 111.4, 55.7. HRMS (EI) calcd for
150.0, 149.9, 147.8, 141.1, 131.0, 128.4, 123.7, 121.7, 116.9, 115.8, 113.4,
111.3, 110.2, 95.1, 56.5, 56.2. HRMS (ESI) calcd for C18H17Br2O5
([MþH]þ) 470.9443. Found: 470.9454.
C
16H10Br2O5 ([M]þ) 439.8895. Found: 439.8884.
4.29. 6,8-Dibromo-3-hydroxy-2-(30,40-dihydroxyphenyl)-4H-
chromen-4-one (8e)
4.24. (E)-3-(3,4-Bis(methoxymethoxy)phenyl)-1-(3,5-
dibromo-2-hydroxyphenyl)prop-2-en-1-one (7c)
8c (0.080 g, 0.154 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼1:1e0:1; Rf 0.4, Hex:EtOAc¼1:1) afforded
a yellow solid. Yield¼0.0620 g (94%). Mp 287 ꢀC (decomposed). 1H
1 (0.1090 g, 0.37 mmol), 6 (0.070 g, 0.31 mmol). Purification by
flash column chromatography (Hex:EtOAc¼6:1e3:1; Rf 0.65,
Hex:EtOAc¼2:1) afforded an orange solid. Yield¼0.135 g (87%). Mp
NMR (DMSO-d6)
d 9.73 (s, 1H), 9.40 (s, 1H), 8.29 (s, 1H), 8.13 (d,
J¼2.3 Hz, 1H), 7.82 (s, 1H), 7.67 (dd, J¼8.5, 2.1 Hz, 1H), 6.92 (d,
129e131 ꢀC. 1H NMR (CDCl3)
J¼15.2 Hz, 1H), 7.87 (d, J¼2.3 Hz, 1H), 7.48 (d, J¼2.1 Hz, 1H), 7.40 (d,
J¼15.2 Hz, 1H), 7.33 (dd, J¼8.5, 2.1 Hz, 1H), 7.22 (d, J¼8.5 Hz, 1H),
5.32 (s, 2H), 5.31 (s, 2H), 3.57 (s, 3H), 3.53 (s, 3H). 13C NMR (CDCl3)
d
7.99 (d, J¼2.3 Hz, 1H), 7.93 (d,
J¼8.5 Hz, 1H). 13C NMR (DMSO-d6)
d 170.9, 149.8, 148.2, 146.9, 145.3,
138.2, 137.9, 126.6, 123.7, 121.9, 120.3, 116.6, 115.8, 115.4, 112.9.
HRMS (EI) calcd for C15H8Br2O5 ([M]þ) 425.8738. Found: 425.8752.
d
192.3, 159.2, 150.5, 147.5, 147.4, 141.1, 131.1, 128.5, 124.8, 121.6,
4.30. 6-Amino-3-hydroxy-2-(30,40-dimethoxyphenyl)-4H-
117.2, 116.6, 116.2, 113.4, 110.2, 95.6, 95.1, 56.4 (ꢁ2). HRMS (ESI)
chromen-4-one (9a)
calcd for C19H19Br2O6 ([MþH]þ) 500.9548. Found: 500.9565.
8a (0.100 g, 0.22 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼3:1e0:1; Rf 0.7, EtOAc) afforded a dark yel-
low solid. Yield¼0.0210 g (30%). Mp 223e224 ꢀC. 1H NMR (DMSO-
4.25. 6,8-Dibromo-3-hydroxy-2-(3,4-dimethoxyphenyl)-4H-
chromen-4-one (8a)
d6)
d
9.09 (s, 1H), 7.82 (dd, J¼8.8, 2.0 Hz, 1H), 7.76 (d, J¼1.6 Hz, 1H),
7 (1.060 g, 2.398 mmol). Purification by flash column chroma-
7.48 (d, J¼8.9 Hz, 1H), 7.14e7.12 (m, 2H), 7.06 (dd, J¼8.9, 2.7 Hz, 1H),
tography (CH2Cl2; Rf 0.4, CH2Cl2) afforded
a
yellow solid.
5.43 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H). 13C NMR (DMSO-d6)
d
172.3,
Yield¼0.6130 g (56%). Mp 258e259 ꢀC. 1H NMR (DMSO-d6)
d
8.31
150.1, 148.4, 147.1, 145.8, 144.7, 137.5, 124.1, 122.0, 121.2, 118.8, 111.5,
110.9, 104.1, 55.6, 55.5. HRMS (ESI) calcd for C17H16NO5 ([MþH]þ)
314.1028. Found: 314.1020.
(d, J¼2.0 Hz, 1H), 8.04e8.02 (m, 2H), 7.95 (s, 1H), 7.09 (br s, 1H), 7.03
(d, J¼8.6 Hz, 1H), 3.99 (s, 3H), 3.97 (s, 3H). 13C NMR (DMSO-d6)
d
171.4, 151.2, 150.4, 148.9, 145.9, 138.8, 137.9, 127.3, 123.1, 122.7,
122.1, 117.4, 113.0, 111.1, 110.5, 56.0, 55.9. HRMS (EI) calcd for
4.31. 6-Amino-3-hydroxy-2-(30-methoxy-40-(methox-
ymethoxy)phenyl)-4H-chromen-4-one (9b)
C
17H12Br2O5 ([M]þ) 453.9051. Found: 453.9036.
4.26. 6,8-Dibromo-3-hydroxy-2-(30-methoxy-40-(methox-
ymethoxy)phenyl)-4H-chromen-4-one (8b)
8b (0.200 g, 0.411 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼3:1e1:1; Rf 0.2, Hex:EtOAc¼1:1) afforded
a dark yellow solid. Yield¼0.0380 g (28%). Mp 216e217 ꢀC. 1H NMR
7 (0.1150 g, 0.244 mmol). Purification by flash column chro-
matography (CH2Cl2; Rf 0.5, CH2Cl2) afforded a yellow solid.
Yield¼0.0660 g (56%). Mp 251 ꢀC (decomposed).1H NMR (CDCl3)
(DMSO-d6)
d
9.13 (s,1H), 7.80 (s,1H), 7.76 (dd, J¼8.8,1.4 Hz,1H), 7.48
(d, J¼8.9 Hz, 1H), 7.22 (d, J¼8.6 Hz, 1H), 7.14e7.13 (m, 1H), 7.07 (dd,
J¼9.1, 2.6 Hz, 1H), 5.44 (s, 2H), 5.24 (s, 2H), 3.86 (s, 3H), 3.41 (s, 3H).
d
8.32 (d, J¼1.5 Hz, 1H), 8.03 (d, J¼1.5 Hz, 1H), 7.98 (d, J¼8.3 Hz, 1H),
13C NMR (DMSO-d6)
d 172.4, 149.3, 147.1, 145.8, 144.5, 137.6, 125.7,
7.97 (s, 1H), 7.31 (d, J¼8.3 Hz, 1H), 7.02 (s, 1H), 5.33 (s, 2H), 3.99 (s,
122.8, 122.1, 120.9, 118.8, 115.9, 112.6, 111.6, 104.1, 94.6, 55.9, 55.7.
3H), 3.54 (s, 3H). 13C NMR (CDCl3)
d
171.5, 150.5, 149.6, 148.7, 145.8,
HRMS (EI) calcd for C18H17NO6 ([M]þ) 343.1056. Found: 343.1050.
138.9, 138.1, 127.4, 124.5, 122.7, 121.9, 117.5, 115.7, 113.1, 111.2, 95.2,
56.4, 56.0. HRMS (EI) calcd for C18H14Br2O6 ([M]þ) 483.9157. Found:
483.9167.
4.32. 2-(30,40-Bis(methoxymethoxy)phenyl)-6-amino-3-
hydroxy-4H-chromen-4-one (9c)
4.27. 2-(30,40-Bis(methoxymethoxy)phenyl)-6,8-dibromo-3-
hydroxy-4H-chromen-4-one (8c)
8c (0.100 g, 0.194 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼3:1e0:1; Rf 0.6, EtOAc) afforded a yellow
solid. Yield¼0.0190 g (26%). Mp 138e140 ꢀC. 1H NMR (DMSO-d6)
7 (0.160 g, 0.319 mmol). Purification by flash column chroma-
d
9.13 (s, 1H), 7.92 (d, J¼2.0 Hz, 1H), 7.83 (dd, J¼8.8, 2.0 Hz, 1H), 7.45
tography (CH2Cl2; Rf 0.5, CH2Cl2) afforded
a
yellow solid.
(d, J¼8.9 Hz, 1H), 7.26 (d, J¼8.7 Hz, 1H), 7.13 (d, J¼2.7 Hz, 1H), 7.07
(dd, J¼9.0, 2.9 Hz, 1H), 5.44 (s, 2H), 5.28 (s, 2H), 5.24 (s, 2H), 3.45 (s,
Yield¼0.0850 g (51%). Mp 197e198 ꢀC. 1H NMR (DMSO-d6)
d 8.30
(d, J¼2.3 Hz, 1H), 8.21 (d, J¼2.0 Hz, 1H), 8.02 (dd, J¼8.1, 2.0 Hz, 2H),
3H), 3.43 (s, 3H). 13C NMR (DMSO-d6)
d 172.4, 148.3, 147.1, 146.4,
7.32 (d, J¼8.7 Hz, 1H), 6.98 (s, 1H), 5.33 (s, 4H), 3.57 (s, 3H), 3.55 (s,
145.8, 144.3, 137.7, 125.6, 122.5, 122.1, 122.0, 118.8, 116.7, 116.2, 104.1,
95.2, 94.5, 55.9 (ꢁ2). HRMS (EI) calcd for C19H19NO7 ([M]þ)
373.1162. Found: 373.1172.
3H). 13C NMR (DMSO-d6)
d 171.5, 150.5, 149.5, 147.0, 145.5, 138.9,
138.1, 127.3, 124.5, 123.4, 122.6, 117.5, 116.5, 116.1, 113.2, 95.7, 95.1,
56.4, 56.3. HRMS (ESI) calcd for C19H17Br2O7 ([MþH]þ) 514.9341.
Found: 514.9357.
4.33. 6-Amino-3-hydroxy-2-(40-hydroxy-30-methoxyphenyl)-
4H-chromen-4-one (9d)
4.28. 6,8-Dibromo-3-hydroxy-2-(40-hydroxy-30-methox-
yphenyl)-4H-chromen-4-one (8d)
9b (0.0220 g, 0.064 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼1:1e1:2; Rf 0.25, Hex:EtOAc¼1:2) affor-
ded a yellow solid. Yield¼0.0160 g (85%). Mp 197e198 ꢀC. 1H NMR
8b (0.050 g, 0.103 mmol). Purification by flash column chro-
matography (Hex:EtOAc¼1:1e0:1, Rf 0.25, Hex:EtOAc¼1:1) affor-
ded a yellow solid. Yield¼0.0440 g (96%). Mp 275e276 ꢀC. 1H NMR
(DMSO-d6)
d
9.64 (s, 1H), 8.99 (s, 1H), 7.77 (s, 1H), 7.70 (d, J¼8.3 Hz,
1H), 7.46 (d, J¼8.9 Hz,1H), 7.13 (s,1H), 7.05 (d, J¼8.8 Hz,1H), 6.93 (d,
(DMSO-d6)
d
9.90 (s, 1H), 9.81 (s, 1H), 8.28 (s, 1H), 8.11 (d, J¼1.9 Hz,
J¼8.5 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H). 13C NMR (DMSO-d6)
d 172.2,

3664
T.-L. Shih et al. / Tetrahedron 70 (2014) 3657e3664
6. (a) Dixon, R. A.; Steele, C. L. Trends Plant Sci. 1999, 4, 394e400; (b) Pietta, P.-G. J.
Nat. Prod. 2000, 63, 1035e1042; (c) Hernandez-Abreu, O.; Castillo-Espana, P.;
148.4, 147.4, 147.1, 145.7, 145.2, 137.2, 122.8, 122.1, 121.9, 121.6, 118.8,
115.5, 111.7, 104.2, 55.8. HRMS (ESI) calcd for C16H14NO5 ([MþH]þ)
300.0872. Found: 300.0852.
ꢀ
~
ꢀ
ꢀ
ILeon-Rivera, I.; Ibarra-Barajas, M.; Villalobos-Molina, R.; Gonzales-Christen, J.;
Vergara-Galicia, J.; Estrada-Soto, S. Biochem. Pharmacol. 2009, 78, 54e61; (d)
Torres-Piedra, M.; Ortiz-Andrade, R.; Villalobos-Molina, R.; Singh, N.; Medina-
ꢀ
Franco, J. L.; Webster, S. P.; Binnie, M.; Navarrete-Vazquez, G.; Estrada-Soto, S.
4.34. 6-Amino-3-hydroxy-2-(30,40-dihydroxyphenyl)-4H-chro-
Eur. J. Med. Chem. 2010, 45, 2606e2612.
men-4-one (9e)8c
7. (a) Deeb, O.; Clare, B. W. Chem. Biol. Drug Des. 2007, 70, 437e449; (b) Y
i
lmaz, H.;
€
€
Guzel, Y.; Onal, Z.; Altiparmak, G.; Kocakaya, S. O. Bull. Korean Chem. Soc. 2011,
32, 4352e4360.
9c (0.030 g, 0.08 mmol). Purification by flash column chroma-
tography (Hex:EtOAc¼1:1e1:4; Rf 0.7, EtOAc) afforded a dark yel-
low solid. Yield¼0.0150 g (66%). Mp 231 ꢀC (decomposed). 1H NMR
8. The reported synthetic aminoflavonoids and biological data, see: (a) Cushman,
M.; Nagarathnam, D.; Burg, D. L.; Geahlen, R. L. J. Med. Chem. 1991, 34, 798e806;
(b) Cushman, M.; Nagarathnam, D. J. Nat. Prod. 1991, 54, 1656e1660; (c)
Cushman, M.; Zhu, H.; Geahlen, R. L.; Kraker, A. J. J. Med. Chem. 1994, 37,
3353e3362; (d) Akama, T.; Shida, Y.; Sugaya, T.; Ishida, H.; Gomi, K.; Kasai, M. J.
Med. Chem. 1996, 39, 3461e3469; (e) Thakur, A.; Vishwakarma, S.; Thakur, M.
Bioorg. Med. Chem. 2004, 12, 1209e1214; (f) Yap, S.; Loft, K. J.; Woodman, O. L.;
Williams, S. J. ChemMedChem 2008, 3, 1572e1579; (g) Casano, G.; Dumetre, A.;
Pannecouque, C.; Hutter, S.; Azas, N.; Robin, M. Bioorg. Med. Chem. 2010, 18,
6012e6023; (h) Sousa, R. M. S.; Pinto, D. C. G. A.; Silva, A. M. S.; Serra, V. V.;
Barros, A. I. R. N. A.; Maria, A. F.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Cav-
aleiro, J. A. S. Eur. J. Org. Chem. 2012, 132e143; (i) Jin, F.; Gao, D.; Zhang, C.; Liu,
F.; Chu, B.; Chen, Y.; Chen, Y. Z.; Tan, C.; Jiang, Y. Bioorg. Med. Chem. 2013, 21,
824e831.
(DMSO-d6)
d
7.65 (s, 1H), 7.53 (d, J¼8.3 Hz, 1H), 7.40 (d, J¼8.9 Hz,
1H), 7.11 (d, J¼2.3 Hz, 1H), 7.04 (dd, J¼9.1, 2.8 Hz, 1H), 6.82 (d,
J¼8.4 Hz, 1H), 5.39 (s, 2H). 13C NMR (DMSO-d6)
d 172.1, 147.2, 147.0,
145.7, 145.3, 145.0, 137.1, 122.7, 122.0, 121.9, 119.7, 118.6, 115.5, 115.1,
104.2. HRMS (EI) calcd for C15H11NO5 ([M]þ) 285.0637. Found:
285.0645.
Acknowledgements
9. Shih, T.-L.; Hsiao, C.-A.; Lin, Z.-Y.; Chen, Y.-H. Molecules 2012, 17, 8206e8216.
10. It is 2-(30,40-diaminophenyl)-5,7-dihydroxy-4H-chromen-4-one.
11. Unpublished results.
12. (a) Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V.
Tetrahedron Lett. 1998, 39, 4995e4998; (b) Barros, A. I. R. N. A.; Silva, A. M. S.
Monatsh. Chem. 2006, 137, 1505e1528.
The authors are gratefully acknowledged the National Science
Council Taiwan (NSC-102-2113-M-032-003) and Tamkang Univer-
sity for financial supports. We thank the National Taiwan University
and the National Chung Hsing University for LRMS/HRMS
experiments.
13. Xu, H.; Wolf, C. Chem. Commun. 2009, 3035e3037.
14. Guo, Z.; Guo, J.; Song, Y.; Wang, L.; Zou, G. Appl. Organomet. Chem. 2009, 23,
150e153.
Supplementary data
15. (a) Monguchi, Y.; Meajima, T.; Mori, S.; Sajiki, H. Chem.dEur. J. 2010, 16,
7372e7375; (b) Maejima, T.; Shimoda, Y.; Nozaki, K.; Mori, S.; Sawama, Y.;
Monguchi, Y.; Sajiki, H. Tetrahedron 2012, 68, 1712e1722; (c) Maejima, T.; Ueda,
M.; Nakano, J.; Sawama, Y.; Monguchi, Y.; Sajiki, H. J. Org. Chem. 2013, 78,
8980e8985.
16. (a) Yap, S.; Woodman, O. L.; Crack, P. J.; Williams, S. J. Bioorg. Med. Chem. Lett.
2011, 21, 5102e5106; (b) Verma, A. K.; Pratap, R. Tetrahedron 2012, 68,
8523e8538.
17. (a) van Acker, F. A. A.; Hageman, J. A.; Haenen, G. R. M. M.; van der Vijgh, W. J. F.;
Bast, A.; Menge, W. M. P. B. J. Med. Chem. 2000, 43, 3752e3760; (b) Smith, J. A.;
Maloney, D. J.; Hecht, S. M.; Lannigana, D. A. Bioorg. Med. Chem. 2007, 15,
5018e5034 and references cited therein.
18. (a) Markiewicz, J. T.; Wiest, O.; Helquist, P. J. Org. Chem. 2010, 75, 4887e4890.
19. Ji, P.; Atherton, J. H.; Page, M. I. J. Org. Chem. 2012, 77, 7471e7478.
20. Aoyama, H.; Sugita, K.; Nakamura, M.; Aoyama, A.; Salim, M. T. A.; Okamoto, M.;
Baba, M.; Hashimoto, Y. Bioorg. Med. Chem. 2011, 19, 2675e2687.
21. Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 4542e4546.
22. (a) Tanaka, H.; Stohlmeyer, M. M.; Wandless, T. J.; Taylor, L. P. Tetrahedron Lett.
2000, 41, 9735e9739; (b) Lee, H. S.; Park, K.-S.; Lee, C.; Lee, B.; Kim, D.-E. Bioorg.
Med. Chem. Lett. 2010, 20, 5709e5712.
Copies of 1H NMR and 13C NMR data for all new products.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.04.022.
References and notes
1. (a) Nijveldt, R. J.; van Nood, E.; van Hoorn, D. E.; Boelens, P. G.; van Norren, K.;
van Leeuwen, P. A. Am. J. Clin. Nutr. 2001, 74, 418e425; (b) Verma, A. K.; Pratap,
€
R. Nat. Prod. Rep. 2010, 27, 1571e1593; (c) Jager, A. K.; Saaby, L. Molecules 2011,
16, 1471e1485 and references cited therein.
2. Koes, R. E.; Quattrocchio, F.; Mol, J. N. M. Bioessays 1994, 16, 123e132.
3. Middleton, E., Jr.; Kandaswami, C.; Theoharides, T. C. Pharmacol. Rev. 2000, 52,
673e751.
4. (a) Havsteen, B. Biochem. Pharmacol. 1983, 32, 1141e1148; (b) Veitch, N. C.;
Grayer, R. J. Nat. Prod. Rep. 2011, 28, 1626e1695; (c) Valko, M.; Rhodes, C. J.;
Moncol, J.; Izakovic, M.; Mazur, M. Chem. Biol. Interact. 2006, 160, 1e40.
5. Manthey, J. A.; Grohmann, K.; Montanari, A.; Ash, K.; Manthey, C. L. J. Nat. Prod.
1999, 62, 441e444.