A convenient microwave-assisted 5-amination of flavones

Article abstract of DOI:10.1016/j.tet.2008.09.043

A few examples of 5-aminoflavones' syntheses exist in the literature and for those, which are described, the amino group is introduced before the formation of the flavone skeleton. We describe here an efficient method, which permits the access to 5-aminoflavones by a simple procedure using an SNAr amination under microwaves irradiation.

Full text of DOI:10.1016/j.tet.2008.09.043

Tetrahedron 64 (2008) 11243–11248
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A convenient microwave-assisted 5-amination of flavones
a
a
b
b
a,
*
´
´ ´
Cedric Lecoutey , Christine Fossey , Luc Demuynck , François Lefoulon , Frederic Fabis
,
Sylvain Rault a
a
´
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie UPRES-EA 4258, U.F.R. des Sciences Pharmaceutiques, Universite de Caen Basse-Normandie,
5 rue Vaube´nard, 14032 Caen cedex, France
b Technologie Servier, 27 rue Euge`ne Vignat, 45000 Orle´ans, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A few examples of 5-aminoflavones’ syntheses exist in the literature and for those, which are described,
the amino group is introduced before the formation of the flavone skeleton. We describe here an efficient
method, which permits the access to 5-aminoflavones by a simple procedure using an SNAr amination
under microwaves irradiation.
Received 28 April 2008
Received in revised form
12 September 2008
Accepted 15 September 2008
Available online 24 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
benzophenoneimine as the amino-precursor.12 Despite the sub-
strate scope for the metal-catalyzed arylamination has been largely
Flavones belong to the very important class of natural com-
pounds of the flavonoid group and are widely represented in na-
ture. A great number of biological activities were reported for
flavones,1 such as antiestrogenic,2 antitumor,3 antiallergic4 or anti-
inflammatory.5 These promising properties led to numerous
chemical works focusing on the synthesis and the structural
modifications of flavones.6 It is noteworthy that many of the bi-
ologically active flavones possess at least one free hydroxyl group
on their skeleton.7 The hydroxyl group is able to bind with various
targets acting either as a hydrogen bond acceptor (HBA) or a hy-
drogen bond donor (HBD). Considering that an amino group is also
able to act either as an HBA or an HBD, it has often successfully been
employed as a bioisostere of the hydroxyl group in the design of
biologically active flavones.7a,8
However, very few studies are reported concerning the syn-
thesis of aminoflavones. The amino group is generally introduced
before the construction of the chromone moiety limiting thus the
diversity and the possibilities of SAR’s studies.7a,8,9 The introduction
of an amino group directly on the flavone nucleus is more scarcely
reported. Sasaki et al. report the synthesis of 3-aminoflavones from
3-tosyl and 3-mesyloxyflavones, which is supposed to proceed via
an aziridine intermediate.10 Caddick et al. describe Buchwald’s
aminations from flavone triflates and halides.11 Amination of the
7-triflyloxyflavone gave only low yields, whereas the 5-isomer was
not reactive.
extended recently,13 this reaction always suffers from limitations
due to the use of expensive and sensitive catalysts and/or ligands
and has not been yet largely applied yet in the synthesis of
aminoflavones.
SNAr reaction is another way for the amination of aromatic rings,
which most often requires activating substituents, high tempera-
tures, hard bases and/or long reaction times.14 Recently, aryltriflates
were described as good partners for metal-free amination reactions
under microwave heating conditions, even in the absence of any
activating substituent, to afford regioselectively arylamines with
good yields and short reaction times.15
We wish to report here our efforts directed to the synthesis of
various 5-aminoflavones starting from diosmetin (30,5,7-tri-
hydroxy-40-methoxy-2-phenylchromone) by a simple method us-
ing a microwave-assisted SNAr reaction.
2. Results and discussion
Diosmetin was first protected with benzyl bromide at room
temperature to afford the 30,7-dibenzylated flavone 1 in 60% yield.16
Under these conditions, the 5-OH group was not benzylated. The
latter was then triflated in 88% yield using the smooth triflating
agent N-phenylbistriflimide (Scheme 1).
We chose benzylamine to explore the best conditions for the
amination of 2. We investigated the effects of the amine quantity (2,
3 and 4 equiv) and temperature (150 and 200 ꢀC). The reaction was
monitored by LC–MS analysis at 5, 10 and 20 min. The results are
summarized in Table 1. At 150 ꢀC, the reaction did not go to com-
pletion even in increasing the quantity of amine or the reaction
time. The best result was obtained with 4 equiv of benzylamine
after 20 min. When the temperature was raised to 200 ꢀC, the use of
Lemiere et al. report the palladium-catalyzed synthesis of
a
7-aminoflavone from a 7-triflyloxyflavone by using the
* Corresponding author. Tel.: þ33 231936458; fax: þ33 231931188.
E-mail address: frederic.fabis@unicaen.fr (F. Fabis).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.043

11244
C. Lecoutey et al. / Tetrahedron 64 (2008) 11243–11248
OMe
OBn
and 36% yield. As expected, the more nucleophilic 4-methoxyani-
line gave the best result (Table 3).
OMe
OH
BnO
O
O
HO
O
O
(i)
Finally, we decided to remove the protective benzyl groups by
catalytic hydrogenation. Starting from 3a, the three benzyl groups
were easily removed, giving the 5-amino flavone 4a, whereas the
5-(4-methoxybenzylamino)flavone 3b only led to the double
O-debenzylation to give 4b (Scheme 2).
OH
OH
1
diosmetin
OMe
BnO
O
(ii)
OBn
3. Conclusion
We have developed a convenient 5-amination of flavones
starting from the corresponding triflates by using an SNAr reaction
under microwave heating conditions. The reaction gave good yields
with primary and secondary non aromatic amines and has been
even successful with anilines in moderate yields. The procedure is
very easy and the use of palladium catalysts or ligands and hard
bases is not necessary. This methodology allows the synthesis of
various 5-aminoflavones and could be used to design new bi-
ologically interesting compounds in the flavone series.
OTf
O
2
Scheme 1. Reagents and conditions: (i) benzyl bromide, K2CO3, DMF, 12 h, rt, 60%; (ii)
PhNTf2, NaHMDS, anhydrous THF, 1 h, rt, 88%.
4 equiv of benzylamine permitted the total conversion of 2 after
10 min. The 5-benzylaminoflavone 3a was isolated in 82% yield.
Under classical heating conditions, 1 h was requested for the total
conversion of 2, and 3a was isolated with a lower 65% yield.
These results prompted us to apply these reaction conditions to
other amines (amine: 4 equiv, temperature: 200 ꢀC). In all cases, the
reaction was monitored by LC–MS analysis and carried on until all
the starting material has disappeared. The results are summarized
in Table 2. Using benzylamines (entry a–h), the reaction was
completed within 10–15 min with good isolated yields of 5-ben-
zylaminoflavones (61–92%) except with the bulky trifluoromethoxy
group (entry i) for which 30 min were necessary for the reaction to
be completed. Primary alkylamines (entry j–l) and cycloalkyl-
amines (entry m–o) reacted more slowly to afford the corre-
sponding aminoflavones in moderate to good yields.
The reaction appeared to be general with nucleophilic amines
and we then tried to apply these conditions to aniline, which is
known to be less or non reactive under SNAr conditions. The first
attempts did not permit to detect traces of the expected 5-anili-
noflavone even after 2 h of microwave heating. So, in order to im-
prove the reactivity of the flavone moiety, we decided to add
triethylamine (1 equiv) in the reaction mixture. After 60 min at
200 ꢀC the 5-anilinoflavone 3p was isolated in a 37% yield. The
reaction was repeated with 4-methoxyaniline and 4-fluoroaniline
and gave the corresponding derivatives 3q–r, respectively, in 54
4. Experimental
4.1. General
All commercial solvents and reagents were used as-received
except THF, which was distilled over Na/benzophenone under Ar-
gon. Sodium bis(trimethylsilyl)amide (NaHMDS) was purchased as
a 2 M solution in THF.
Reactions were monitored by LC/MS and stopped when all the
starting material has disappeared. Flash chromatography was re-
alized on silica gel (SDS AAC 60, 70–200) or on neutral alumina gel
(Merck 90, 63–200). IR spectra were recorded on KBr disks with
a Perkin–Elmer BX FTIR apparatus. 1H and 13C NMR spectra were
recorded, respectively, at 400 and 100 MHz with a Jeol Lambda 400
NMR spectrometer. Chemical shifts
d are reported in parts per mil-
lion with the solvent resonance as the internal standard; coupling
constants J are given in hertz. Multiplicity is given as follows:
s (singlet), d (doublet), t (triplet), q (quartet), quint. (quintet), sept.
(septet), m (multiplet). The microwave reactions were performed
using a Biotage Initiator Microwave oven using 2-5 mL sealed vials.
Temperaturewasmeasured with an IR-sensorand reaction times are
given as hold times. LC/MS (ESI) analyses were realized with a Wa-
ters alliance 2695 as separating module using the following gradi-
ent: A (95%)/B (5%) to A (5%)/B(95%) in 10 min. This ratio was hold
during 3 min before return to initial conditions in 1 min. Initial
conditions were then maintained for 5 min (A: H2O, B: CH3CN; each
containing HCOOH: 0.1%; Column: C18 Xterra MSC 118/2.1ꢁ50 mm).
MS detection was performed with a Micromass ZMD 2000 by pos-
itive ESI. EIMS and HRMS (EI) were performed at 70 eV with a JEOL
JMS GCMate. Melting points were determined on Kofler melting
point apparatus. Elemental analyses were performed at the ‘Institut
de Recherche en Chimie Organique Fine’ (IRCOF, Rouen-France).
Table 1
Results of SNAr reaction between 2 and benzylamine to give 3a
OMe
OMe
OBn
BnO
O
O
BnO
O
O
OBn
(i)
OTf
NH
2
3a
4.2. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
hydroxy-4H-chromen-4-one (1)
Benzylamine
(equiv)
Time (min)
150 ꢀ
C
200 ꢀ
C
2 (%)
3a(%)
2 (%)
3a (%)
5,7-Dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-
4-one (diosmetin) (9 g, 30 mmol), benzyl bromide (7.83 mL,
66 mmol), and potassium carbonate (20.7 g, 150 mmol) were dis-
solved in DMF (150 mL). The mixture was stirred at room temper-
ature for 4 h and diluted with water (500 mL). The solid was
filtrated, washed with water and diethyl ether, dried, and purified
by silica gel chromatography with methylene chloride as eluent to
give 1 as a yellow solid (8.6 g, 60%); mp: 174 ꢀC, Lit:16 176–177 ꢀC; 1H
2
2
2
3
3
3
4
4
4
5
10
20
5
10
20
5
71
57
45
55
54
31
45
32
14
29
43
55
45
46
69
55
68
86
25
15
11
19
12
8
75
85
89
81
88
92
4
96
10
20
100a
100
NMR (400 MHz, CDCl3)
2H, CH2), 6.40 (d, J¼2.2 Hz,1H, H6), 6.50 (s,1H, H3), 6.53 (d, J¼2.2 Hz,
d: 3.97 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 5.23 (s,
(i) Reagents and conditions: benzylamine, NMP, microwave irradiation.
a
1 h at 200 ꢀC under classical heating conditions.

C. Lecoutey et al. / Tetrahedron 64 (2008) 11243–11248
11245
Table 2
Table 2 (continued)
Synthesis of 5-aminoflavones 3a–o from 2
Entry
Amine
Time (min)
45
Yielda (%)
48
OMe
OMe
NH2
l
N
BnO
O
O
BnO
R1R2NH (4 equiv.)
NMP, µw, 200 °C
O
OBn
OBn
H
N
OTf
N
O
3a-o
R2
R1
2
m
60
90
83
67
Entry
Amine
Time (min)
Yielda (%)
Me
NH2
H
N
10
82
65
a
n
o
60b
O
NH2
H
N
b
c
15
15
92
71
30
39
N
Me
OMe
NH2
a
Isolated yields.
Classical heating conditions.
b
0
1H, H8), 6.99 (d, J¼8.5 Hz, 1H, H5 ), 7.34–7.52 (m, 12H), 12.80 (s, 1H,
OH). 13C NMR (100 MHz, CDCl3)
d
: 56.3, 70.6, 71.6, 93.6, 98.9, 104.7,
Me
105.9, 111.7, 111.9, 120.7, 123.8, 127.6, 127.7, 128.4, 128.6, 128.9, 136.0,
136.6, 148.5, 153.1, 157.8, 162.4, 164.1, 164.7, 182.5. IR (KBr, cmꢂ1):
NH2
ꢃ
1665 (C]O). EIMS m/z: 480.0 (Mþ , 100). Elemental analysis: calcd
d
e
F
F
15
10
68
63
(%) for C30H24O6: C 47.99, H 5.03; found: C 47.85, H 4.81.
NH2
4.3. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
trifluoromethanesulfonyloxy-4H-chromen-4-one (2)
Compound 2 (2 g, 4.17 mmol) was dissolved in dry THF (30 mL).
Under N2, NaHMDS (2 M) in THF (2.5 mL, 5 mmol) was added at
room temperature and the mixture was stirred for 15 min. PhNTf2
(1.93 g, 5.42 mmol) was added and the mixture was stirred at room
temperature for 1 hour. The solvent was evaporated under reduced
pressure. CH2Cl2 (50 mL) was added and the resulting solution was
washed with water (3ꢁ50 mL), dried over MgSO4 and evaporated
under reduced pressure. The residue was purified by flash chro-
matography (SiO2, CH2Cl2) to give 2 as a beige solid (2.24 g, 88%);
NH2
f
15
15
65
61
F
NH2
mp: 174 ꢀC; 1H NMR (400 MHz, CDCl3)
d: 3.95 (s, 3H, OCH3), 5.18 (s,
g
2H, CH2), 5.22 (s, 2H, CH2), 6.59 (s,1H, H3), 6.84 (d, J¼2.2 Hz,1H, H8),
0
6.98 (d, J¼8.5 Hz, 1H, H5 ), 7.03 (d, J¼2.2 Hz, 1H, H6), 7.33–7.59 (m,
12H). 13C NMR (100 MHz, CDCl3)
d: 56.1, 71.2, 71.5, 102.1, 107.3,
CF3
108.9, 111.7, 111.8, 111.9, 118.2 (q, J¼347 Hz), 120.5, 123.2, 127.4,
NH2
127.6, 128.2, 128.7, 128.8, 128.9, 134.7, 136.5, 147.9, 148.4, 153.0,
h
15
30
67
67
Table 3
Synthesis of 5-anilinoflavones 3p–r
F3C
OMe
OBn
OMe
OBn
R
NH2
BnO
O
BnO
O
NH2
TEA (1 eq.)
i
CF3O
NMP, µw, 200 °C, 60 min.
OTf
O
NH
O
R
2
3p-r
NH2
j
30
60
77
71
Compound
R
Yielda
3p
3q
3r
H
37
54
36
4-MeO
4-F
NH2
k
a
Isolated yield.

11246
C. Lecoutey et al. / Tetrahedron 64 (2008) 11243–11248
OMe
OBn
OMe
OH
70.0, 71.3, 89.1, 92.1,104.5,106.3,111.5,120.0,124.1,127.0,127.5,127.6,
128.1,128.2,128.6,128.7,129.3,135.3,136.2,136.6,136.7,148.2,151.6,
152.3, 159.7, 161.1, 163.9, 180.9. IR (KBr, cmꢂ1): 3269 (N–H), 1654
(C]O). LC–MS (ESI): tR¼14.08 min; m/z [MþH]þ: 583.79. Elemental
analysis: calcd (%) for C38H33NO5: C 78.20, H 5.70, N 2.40; found: C
77.94, H 5.43, N 2.36.
BnO
HO
H2, Pd/C
MeOH, room temp.
NH
O
NH O
R1
3a R=H
3b R=OCH3
4a, R1=H, 68%
4b, R1=4-methoxybenzyl, 60%
4.4.4. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(2-fluorobenzylamino)-4H-chromen-4-one (3d)
R
Obtained as a yellow solid (130 mg, 68%); mp: 194 ꢀC; 1H NMR
Scheme 2. Benzyl deprotection of 3a and 3b.
(400 MHz, CDCl3)
d
: 3.95 (s, 3H, OCH3), 4.49 (d, J¼5.8 Hz, 2H, CH2–
NH), 5.06 (s, 2H, CH2), 5.23 (s, 2H, CH2), 5.97 (d, J¼2.2 Hz, 1H, H6),
0
6.25 (d, J¼2.2 Hz, 1H, H8), 6.43 (s, 1H, H3), 6.97 (t, J¼8.6 Hz, 1H, H5 ),
158.3, 161.9, 162.2, 175.4. IR (KBr, cmꢂ1): 1651 (C]O). EIMS m/z:
7.03–7.09 (m, 2H,), 7.22–7.50 (m, 14H), 9.75 (t, J¼5.8 Hz,1H, NH). 13C
ꢃ
612.2 (Mþ ). Elemental analysis: calcd (%) for C31H23F3O8S: C 60.78,
NMR (100 MHz, CDCl3)
d: 40.3 (d, J¼4.9 Hz), 56.1, 70.1, 71.3, 89.5,
H 3.78; found: C 60.55, H 3.52.
92.0,104.6,106.3,111.5,111.6,115.3 (d, J¼21.4 Hz),120.0,124.0,124.3
(d, J¼3.3 Hz), 125.3 (d, J¼14.1 Hz), 127.4, 127.5, 128.1, 128.2, 128.7 (d,
J¼8.0 Hz), 128.7, 128.8, 128.8 (d, J¼4.1 Hz), 136.2, 136.6, 148.2, 151.5,
152.4, 159.7, 160.7 (d, J¼245.3 Hz), 161.2, 164.0, 180.9. IR (KBr,
cmꢂ1): 3240 (N–H), 1644 (C]O). LC–MS (ESI): tR¼13.80 min; m/z
[MþH]þ: 587.73. Elemental analysis: calcd (%) for C37H30FNO5: C
75.62, H 5.15, N 2.38; found: C 75.29, H 4.84, N 2.19.
4.4. General procedure for compounds 3a–o
In a 2–5 mL microwave vial, triflate 2 (200 mg, 0.33 mmol) and
the amine (1.32 mmol, 4 equiv) were dissolved in N-methyl-
pyrrolidin-2-one (2.8 mL). The solution was warmed under mi-
crowave heating conditions at 200 ꢀC until all the starting material
has disappeared (Controlled by LC–MS analysis, see Table 2 for
reaction times). After cooling, the resulting solution was diluted
with CH2Cl2 (20 mL), washed with water (5ꢁ20 mL), dried over
MgSO4, and evaporated under reduced pressure. The residue was
then purified by flash chromatography (SiO2, CH2Cl2 unless stated
otherwise) to afford the corresponding 5-aminoflavones 3a–o.
4.4.5. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(3-fluorobenzylamino)-4H-chromen-4-one (3e)
Obtained as a yellow solid (120 mg, 63%); mp: 157 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
: 3.95 (s, 3H, OCH3), 4.42 (d, J¼5.6 Hz, 2H, CH2–
NH), 5.03 (s, 2H, CH2), 5.22 (s, 2H, CH2), 5.88 (d, J¼2.2 Hz, 1H, H6),
6.25 (d, J¼2.2 Hz, 1H, H8), 6.43 (s, 1H, H3), 6.94–7.06 (m, 3H), 7.13 (d,
J¼7.6 Hz, 1H), 7.28–7.49 (m, 13H), 9.79 (t, J¼5.6 Hz, 1H, NH). 13C
4.4.1. 5-Benzylamino-7-benzyloxy-2-(3-benzyloxy-4-
methoxyphenyl)-4H-chromen-4-one (3a)
NMR (100 MHz, CDCl3)
d: 46.5 (d, J¼2.5 Hz), 56.1, 70.1, 71.3, 89.4,
92.4, 104.6, 106.3, 111.5, 111.6, 113.9 (d, J¼19.8 Hz), 114.0 (d,
J¼19.8 Hz), 120.1, 122.4 (d, J¼2.5 Hz), 124.0, 127.5, 127.6, 128.1, 128.2,
128.7, 128.8, 130.2 (d, J¼8.2 Hz), 136.1, 136.6, 141.2 (d, J¼6.6 Hz),
148.3, 151.4, 152.4, 159.7, 161.3, 163.1 (d, J¼245.2 Hz), 163.9, 181.0. IR
(KBr, cmꢂ1): 3241 (N–H), 1645 (C]O). LC–MS (ESI): tR¼13.70 min;
m/z [MþH]þ: 587.83. Elemental analysis: calcd (%) for C37H30FNO5:
C 75.62, H 5.15, N 2.38; found: C 75.38, H 4.80, N 2.31.
Obtained as a yellow solid (152 mg, 82%); mp: 182 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
: 3.95 (s, 3H, OCH3), 4.42 (d, J¼5.6 Hz, 2H, CH2–
NH), 5.04 (s, 2H, CH2), 5.22 (s, 2H, CH2), 5.95 (d, J¼2.2 Hz, 1H, H6),
0
6.23 (d, J¼2.2 Hz, 1H, H8), 6.42 (s, 1H, H3), 6.97 (d, J¼8.5 Hz, 1H, H5 ),
7.31–7.50 (m,17H).13C NMR (100 MHz, CDCl3)
d: 47.0, 56.1, 70.0, 71.3,
89.2, 92.2, 104.5, 106.3, 111.5, 120.0, 124.1, 127.0, 127.1, 127.5, 128.1,
128.2,128.7,136.2,136.6,138.4,148.2,151.6,152.3,159.7,161.1,163.9,
180.9. IR (KBr, cmꢂ1): 3234 (N–H), 1644 (C]O). LC–MS (ESI):
tR¼13.70 min; m/z [MþH]þ: 569.81. Elemental analysis: calcd (%) for
C37H31NO5: C 78.01, H 5.49, N 2.46; found: C 77.73, H 5.18, N 2.26.
4.4.6. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-fluorobenzylamino)-4H-chromen-4-one (3f)
Obtained as a yellow solid (125 mg, 65%); mp: 179 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
: 3.95 (s, 3H, OCH3), 4.38 (d, J¼5.6 Hz, 2H, CH2–
4.4.2. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-(4-
methoxylbenzylamino)-4H-chromen-4-one (3b)
NH), 5.05 (s, 2H, CH2), 5.23 (s, 2H, CH2), 5.90 (d, J¼2.2 Hz, 1H, H6),
6.25 (d, J¼2.2 Hz, 1H, H8), 6.42 (s, 1H, H3), 6.96–7.03 (m, 3H,), 7.26–
7.50 (m, 14H), 9.74 (t, J¼5.6 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3)
Obtained as a yellow solid (180 mg, 92%); mp: 170 ꢀC; 1H NMR
(400 MHz, CDCl3)
d: 3.80 (s, 3H, OCH3), 3.96 (s, 3H, CH3O), 4.35 (d,
d: 46.8, 56.1, 70.0, 71.3, 89.3, 92.3, 104.5, 106.3, 111.4, 111.6, 115.5 (d,
J¼5.4 Hz, 2H, CH2–NH), 5.06 (s, 2H, CH2), 5.23 (s, 2H, CH2), 5.96
J¼20.7 Hz),120.0, 124.1,127.4, 127.5, 128.1,128.2,128.5 (d, J¼8.2 Hz),
128.7, 128.8, 134.0 (d, J¼3.3 Hz), 136.1, 136.6, 148.2, 151.4, 152.4,
159.7, 161.2, 162.0 (d, J¼244.5 Hz), 163.9, 180.9. IR (KBr, cmꢂ1): 3257
(N–H), 1652 (C]O). LC–MS (ESI): tR¼13.73 min; m/z [MþH]þ:
587.87. Elemental analysis: calcd (%) for C37H30FNO5: C 75.62, H
5.15, N 2.38; found: C 75.47, H 4.95, N 2.29.
(d, J¼2.2 Hz, 1H, H6), 6.23 (d, J¼2.2 Hz, 1H, H8), 6.41 (s, 1H, H3), 6.87 (d,
0
J¼8.8 Hz, 2H), 6.97 (d, J¼8.6 Hz, 1H, H5 ), 7.28 (d, J¼8.8 Hz, 2H), 7.33–
7.50 (m, 12H), 9.68 (t, J¼5.4 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3)
d:
46.5, 55.3, 56.1, 70.0, 71.4, 89.2, 92.1, 102.3, 106.3, 111.6, 111.7, 114.1,
120.0, 124.1, 127.4, 127.5, 128.1, 128.2, 128.3, 128.4, 128.7, 130.4, 136.3,
136.6, 148.3,151.6, 152.4, 158.8, 159.7, 161.1,163.9,180.9. IR (KBr, cmꢂ1):
3240 (N–H),1649 (C]O). LC–MS (ESI): tR¼13.55 min; EIMS m/z: 599.5
4.4.7. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-trifluoromethylbenzylamino)-4H-chromen-4-one (3g)
Obtained as a yellow solid (127 mg, 61%); mp: 174 ꢀC; 1H NMR
ꢃ
ꢃ
(Mþ , 100), 508.3 (Mþ ꢂPhCH2, 82.5). Elemental analysis: calcd (%) for
C38H33NO6: C 76.11, H 5.55, N 2.34; found: C 75.77, H 5.51, N 2.25.
(400 MHz, CDCl3)
d
: 3.95 (s, 3H, OCH3), 4.48 (d, J¼5.8 Hz, 2H, CH2–
4.4.3. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-methylbenzylamino)-4H-chromen-4-one (3c)
NH), 5.04 (s, 2H, CH2), 5.23 (s, 2H, CH2), 5.84 (d, J¼2.2 Hz, 1H, H6),
0
6.26 (d, J¼2.2 Hz, 1H, H8), 6.44 (s, 1H, H3), 6.97 (d, J¼8.5 Hz, 1H, H5 ),
Obtained as a yellow solid (140 mg, 71%); mp: 177 ꢀC; 1H NMR
7.33–7.58 (m, 16H), 9.84 (t, J¼5.8 Hz, 1H, NH). 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
: 2.34 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 4.37 (d,
CDCl3) d: 46.5, 56.1, 70.1, 71.3, 89.6, 92.4, 104.7, 111.6, 111.7, 120.1,
J¼5.6 Hz, 2H, CH2–NH), 5.04 (s, 2H, CH2), 5.21 (s, 2H, CH2), 5.96
124.0, 106.3, 125.6 (q, J¼3.3 Hz), 126.9 (q, J¼271.8 Hz, CF3), 127.1,
127.4, 127.5, 128.2, 128.3, 128.7, 128.8, 129.4 (q, J¼32.2 Hz), 136.1,
136.6, 142.7, 148.3, 151.3, 152.5, 159.8, 161.4, 163.9, 181.0. IR (KBr,
cmꢂ1): 3259 (N–H), 1651 (C]O). LC–MS (ESI): tR¼14.08 min. EIMS
(d, J¼2.2 Hz, 1H, H6), 6.22 (d, J¼2.2 Hz, 1H, H8), 6.41 (s, 1H, H3), 6.96
0
(d, J¼8.6 Hz, 1H, H5 ), 7.13 (d, J¼8.0 Hz, 2H), 7.24–7.49 (m, 14H), 9.72
(t, J¼5.6 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3)
d: 21.1, 46.8, 56.1,

C. Lecoutey et al. / Tetrahedron 64 (2008) 11243–11248
11247
ꢃ
ꢃ
m/z: 637.0 (Mþ , 100), 546.0 (Mþ ꢂPhCH2, 5.6). Elemental analysis:
calcd (%) for C38H30F3NO5: C 71.58, H 4.74, N 2.20; found: C 71.87, H
4.39, N 2.53.
4.4.12. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-(2-N,N-
dimethylaminoethylamino)-4H-chromen-4-one (3l)
Obtained as a yellow solid after flash chromatography on alu-
mina gel with CH2Cl2/MeOH 99:1 (87 mg, 48%); mp: 130 ꢀC; 1H
4.4.8. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(3-trifluoromethylbenzylamino)-4H-chromen-4-one (3h)
Obtained as a yellow solid (140 mg, 67%); mp: 171 ꢀC; 1H NMR
NMR (400 MHz, CDCl3)
d
: 2.34 (s, 6H, 2 CH3), 2.65 (t, J¼6.6 Hz, 2H,
CH2–N(CH3)2), 3.29 (dd, J¼6.6 Hz and 5.1 Hz, 2H, CH2–NH), 3.95 (s,
3H, OCH3), 5.14 (s, 2H, CH2), 5.22 (s, 2H, CH2), 6.01 (d, J¼2.2 Hz, 1H,
H6), 6.22 (d, J¼2.2 Hz, 1H, H8), 6.39 (s, 1H, H3), 6.96 (d, J¼8.6 Hz, 1H,
(400 MHz, CDCl3)
d
: 3.95 (s, 3H, OCH3), 4.47 (d, J¼5.6 Hz, 2H, CH2–
H5 ), 7.32–7.49 (m, 12H), 9.37 (t, J¼5.1 Hz, 1H, NH). 13C NMR
0
NH), 5.04 (s, 2H, CH2), 5.23 (s, 2H, CH2), 5.87 (d, J¼2.2 Hz, 1H, H6),
0
6.26 (d, J¼2.2 Hz, 1H, H8), 6.44 (s, 1H, H3), 6.97 (d, J¼8.6 Hz, 1H, H5 ),
(100 MHz, CDCl3) d: 40.9, 45.4, 56.1, 57.7, 70.0, 71.3, 88.7, 91.4, 104.4,
7.33–7.60 (m, 16H), 9.83 (t, J¼5.6 Hz, 1H, NH). 13C NMR (100 MHz,
106.3, 111.4, 111.5, 119.9, 124.1, 127.4, 127.5, 128.1, 128.2, 128.6, 128.7,
136.3, 136.6, 148.2, 151.5, 152.3, 159.8, 161.0, 164.0, 180.7. IR (KBr,
cmꢂ1): 3248 (N–H), 1648 (C]O). LC–MS (ESI): tR¼9.30 min; m/z
[MþH]þ: 550.82. Elemental analysis: calcd (%) for C34H34N2O5: C
74.16, H 6.22, N 5.09; found: C 73.87, H 6.08, N 4.71.
CDCl3) d: 46.5, 56.1, 70.1, 71.4, 89.6, 92.4, 104.7, 106.3, 111.6, 111.7,
120.1, 123.8 (q, J¼4.1 Hz), 124.0, 124.1 (q, J¼272.6 Hz), 124.2 (q,
J¼4.1 Hz), 127.4, 127.5, 128.2, 128.3, 128.7, 128.8, 129.2, 130.2, 130.9
(q, J¼31.3 Hz), 136.1, 136.6, 139.6, 148.3, 151.3, 152.5, 159.8, 161.3,
163.9, 181.0. IR (KBr, cmꢂ1): 3234 (N–H), 1644 (C]O). LC–MS (ESI):
ꢃ
ꢃ
tR¼14.02. EIMS m/z: 637.3 (Mþ , 100), 546.2 (Mþ ꢂPhCH2, 9.0). El-
emental analysis: calcd (%) for C38H30F3NO5: C 71.58, H 4.74, N 2.20;
found: C 71.88, H 4.38, N 2.51.
4.4.13. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-methylpiperidin-1-yl)-4H-chromen-4-one (3m)
Obtained as a yellow solid after chromatography with CH2Cl2/
MeOH 94:6 (152 mg, 83%); mp: 164 ꢀC; 1H NMR (400 MHz, CDCl3)
4.4.9. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(2-trifluoromethoxybenzylamino)-4H-chromen-4-one (3i)
Obtained as a yellow solid (144 mg, 67%); mp: 153 ꢀC; 1H NMR
d
: 1.01 (d, J¼6.4 Hz, 3H, CH3–CH), 1.69–1.72 (m, 1H, CH–CH3), 2.63–
2.66 (m, 4H, 2CH2), 3.43–3.46 (m, 4H, 2CH2), 3.95 (s, 3H, OCH3), 5.14
(s, 2H, CH2), 5.22 (s, 2H, CH2), 6.45 (s, 1H, H3), 6.48 (d, J¼2.2 Hz, 1H,
0
(400 MHz, CDCl3)
d
: 3.96 (s, 3H, OCH3), 4.52 (d, J¼5.6 Hz, 2H, CH2–
H6), 6.87 (d, J¼8.6 Hz, 1H, H8), 6.97 (d,¼8.6 Hz, 1H, H5 ), 7.32–7.49
NH), 5.04 (s, 2H, CH2), 5.22 (s, 2H, CH2), 5.89 (d, J¼2.2 Hz, 1H, H6),
(m, 12H). 13C NMR (100 MHz, CDCl3)
d: 21.9, 30.7, 34.2, 53.6, 56.0,
0
6.26 (d, J¼2.2 Hz, 1H, H8), 6.44 (s, 1H, H3), 6.97 (d, J¼8.6 Hz, 1H, H5 ),
70.3, 71.3, 94.3, 102.5, 107.6, 111.4, 111.5, 111.6, 120.0, 124.0, 127.4,
127.6, 128.1, 128.3, 128.7, 128.8, 136.0, 136.6, 148.2, 152.2, 154.8,
159.7, 160.7, 162.5, 177.3. IR (KBr, cmꢂ1): 1641 (C]O). LC–MS (ESI):
tR¼9.72 min; m/z [MþH]þ: 561.78. Elemental analysis: calcd (%) for
C36H35NO5: C 76.98, H 6.28, N 2.49; found: C 76.72, H 6.41, N 2.20.
7.26–7.50 (m, 16H), 9.80 (t, J¼5.6 Hz, 1H, NH). 13C NMR (100 MHz,
CDCl3) d: 41.2, 56.1, 70.1, 71.3, 89.7, 92.0, 100.5, 104.6, 106.3, 111.4,
111.6, 120.1, 120.7, 122.3 (q, J¼225.5 Hz), 124.0, 127.2, 127.4, 128.1,
128.2, 128.3, 128.5, 128.7, 128.8, 130.9, 136.1, 136.6, 148.3, 151.5,
152.4, 159.7, 161.0, 161.3, 164.0, 181.0. IR (KBr, cmꢂ1): 3236 (N–H),
ꢃ
1644 (C]O). LC–MS (ESI): tR¼14.17. EIMS m/z: 562.1 (Mþ ꢂPhCH2,
4.4.14. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(morpholin-4-yl)-4H-chromen-4-one (3n)
100). Elemental analysis: calcd (%) for C38H30F3NO6: C 69.83, H 4.63,
N 2.14; found: C 69.63, H 4.32, N 1.81.
Obtained as a yellow solid after elution with CH2Cl2/triethyl-
amine 98:2 (120 mg, 67%); mp: 202 ꢀC. 1H NMR (400 MHz, CDCl3)
d:
4.4.10. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
isobutylamino-4H-chromen-4-one (3j)
3.08–3.12 (m, 4H), 3.96 (s, 3H, OCH3), 3.97–3.99 (m, 4H), 5.15 (s, 2H,
CH2), 5.23 (s, 2H, CH2), 6.46 (s, 1H, H3), 6.47 (d, J¼2.2 Hz, 1H, H6),
0
Obtained as a yellow solid after chromatography with CH2Cl2/
6.63 (d, J¼8.5 Hz, 1H, H8), 6.98 (d, J¼8.6 Hz, 1H, H5 ), 7.32–7.53 (m,
MeOH 98:2 (135 mg, 77%); mp: 160 ꢀC; 1H NMR (400 MHz, CDCl3)
d:
12H). 13C NMR (100 MHz, CDCl3)
d: 53.2, 56.1, 67.1, 70.4, 71.3, 95.1,
1.02 (d, J¼6.7 Hz, 6H, 2CH3), 1.99 (m, 1H, CH–(CH3)2), 2.96 (dd,
J¼6.7 Hz and 5.2 Hz, 2H, CH2–NH), 3.95 (s, 3H, OCH3), 5.13 (s, 2H,
CH2), 5.22 (s, 2H, CH2), 5.97 (d, J¼2.2 Hz, 1H, H6), 6.20 (d, J¼2.2 Hz,
102.5, 107.7, 111.4, 111.5, 111.6, 119.9, 123.8, 127.4, 127.6, 128.1, 128.4,
128.7, 128.8, 135.7, 136.6, 148.2, 152.3, 153.9, 160.1, 160.7, 162.6,
177.2. IR (KBr, cmꢂ1): 1642 (C]O). LC–MS (ESI): tR¼11.67 min; m/z
[MþH]þ: 549.75. Elemental analysis: calcd (%) for C34H31NO6: C
74.30, H 5.69, N 2.55; found: C 73.95, H 5.36, N 2.38.
0
1H, H8), 6.38(s,1H, H3), 6.96(d, J¼8.6 Hz,1H, H5 ), 7.29–7.49 (m,12H),
9.38 (t, J¼5.2 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3)
d: 20.6, 27.6,
50.8, 56.1, 70.1, 71.3, 88.3, 91.3, 104.3, 106.3, 111.5, 111.6, 120.0, 124.2,
127.5,127.6,128.1,128.2,128.7,128.8,136.4,136.6,148.2,152.0,152.3,
159.9, 161.0, 164.0, 180.9. IR (KBr, cmꢂ1): 3259 (N–H), 1649 (C]O).
LC–MS: tR¼14.22 min; m/z [MþH]þ: 535.78. Elemental analysis:
calcd (%) for C34H33NO5: C 76.24, H 6.21, N 2.61; found: C 75.88, H
5.88, N 2.36.
4.4.15. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-methylpiperazin-1-yl)-4H-chromen-4-one (3o)
Obtained as a yellow solid after flash chromatography on alumina gel
with CH2Cl2/MeOH 99:1 (72 mg, 39%); mp: 181 ꢀC. 1H NMR (400 MHz,
CDCl3) d: 2.39 (s, 3H, CH3), 2.78–2.84 (m, 4H), 3.16–3.23 (m, 4H), 3.96 (s,
3H, OCH3), 5.15 (s, 2H, CH2), 5.23 (s, 2H, CH2), 6.45 (s, 1H, H3), 6.48 (d,
0
4.4.11. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
butylamino-4H-chromen-4-one (3k)
J¼2.2 Hz, 1H, H6), 6.62 (d, J¼8.6 Hz, 1H, H8), 6.98 (d, J¼8.6 Hz, 1H, H5 ),
7.33–7.50 (m, 12H). 13C NMR (100 MHz, CDCl3)
d: 45.8, 52.2, 55.0, 56.1,
Obtained as a yellow solid (124 mg, 71%); mp: 147 ꢀC. 1H NMR
70.3, 71.3, 95.1, 102.7, 107.7, 111.4, 111.5, 111.6, 120.0, 123.9, 127.4, 127.6,
128.1, 128.4, 128.7, 128.8, 135.8, 136.6, 148.2, 152.4, 153.5, 160.0, 160.7,
162.6,177.2. IR (KBr, cmꢂ1): 1643 (C]O). LC–MS (ESI): tR¼8.98 min; m/z
[MþH]þ: 562.81. Elemental analysis: calcd (%) for C35H34N2O5:C74.71, H
6.09, N 4.98; found: C 74.57, H 5.91, N 4.58.
(400 MHz, CDCl3)
d
: 0.96 (t, J¼7.3 Hz, 3H, CH3), 1.48 (sept., J¼7.3 Hz,
2H, CH2–CH3), 1.66 (quint., J¼7.3 Hz, 2H, CH2–CH2NH), 3.14 (dd,
J¼7.3 Hz and 5.2 Hz, 2H, CH2NH), 3.95 (s, 3H, OCH3), 5.13 (s, 2H,
CH2), 5.22 (s, 2H, CH2), 5.98 (d, J¼2.2 Hz, 1H, H6), 6.20 (d, J¼2.2 Hz,
0
1H, H8), 6.38 (s, 1H, H3), 6.97 (d, J¼8.6 Hz, 1H, H5 ), 7.26–7.50 (m,
12H), 9.25 (t, J¼5.2 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3)
d: 13.9,
4.5. General procedure for compounds 3p–r
20.4, 30.8, 42.7, 56.1, 70.1, 71.3, 88.4, 91.3, 104.3, 106.3, 111.5, 111.6,
119.9, 124.2, 127.4, 127.5, 128.1, 128.2, 128.6, 128.7, 136.3, 136.6,
148.2, 151.9, 152.3, 159.8, 160.9, 164.0, 180.8. IR (KBr, cmꢂ1): 3258
(N–H), 1645 (C]O). LC–MS: tR¼14.08 min; m/z [MþH]þ: 535.84.
Elemental analysis: calcd (%) for C34H33NO5: C 76.24, H 6.21, N 2.61;
found: C 75.88, H 5.95, N 2.45.
In a 2–5 mL microwave vial, triflate 2 (200 mg, 0.33 mmol),
aniline (1.32 mmol), and triethylamine (0.12 mL, 0.33 mmol) were
dissolved in N-methylpyrrolidin-2-one (2.5 mL). The solution was
warmed under microwave heating conditions at 200 ꢀC for 1 hour.
After cooling, the resulting solution was diluted with CH2Cl2

11248
C. Lecoutey et al. / Tetrahedron 64 (2008) 11243–11248
(20 mL), washed with water (5ꢁ20 mL), dried over MgSO4, and
evaporated under reduced pressure. The residue was then purified
by flash chromatography (Al2O3, CH2Cl2/MeOH 98:2) to afford the
corresponding 5-anilinoflavones 3p–r.
4.7. 7-Hydroxy-2-(3-hydroxy-4-methoxyphenyl)-5-
(4-methoxybenzylamino)-4H-chromen-4-one (4b)
Compound 3b (0.75 g, 1.25 mmol) was dissolved in MeOH
(50 mL) and the solution was degassed. Pd/C (50 mg) was added
and the solution was stirred under H2 in a Paar apparatus for 5 h.
After filtration on Celite, the solvent was removed under reduced
pressure and the residue purified by flash chromatography (SiO2,
CH2Cl2/MeOH 98/2) to afford 4b as a yellow solid (0.313 g, 60%);
4.5.1. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(phenylamino)-4H-chromen-4-one (3p)
Obtained as a yellow solid (67 mg, 37%); mp: 172 ꢀC; 1H NMR
(400 MHz, CDCl3) d: 3.96 (s, 3H, OCH3), 5.08 (s, 2H, CH2), 5.24 (s, 2H,
CH2), 6.36 (d, J¼2.2 Hz,1H, H6), 6.46 (s,1H, H3), 6.61 (d, J¼2.2 Hz,1H,
mp: 245 ꢀC; 1H NMR (400 MHz, DMSO-d6)
d: 3.73 (s, 3H, OCH3),
0
H8), 6.99 (d, J¼8.5 Hz, 1H, H5 ), 7.09–7.52 (m, 17H), 11.16 (s, 1H, NH).
3.83 (s, 3H, OCH3), 4.29 (d, 2H, J¼5.1 Hz, CH2–NH), 5.82 (d, 1H,
13C NMR (100 MHz, CDCl3)
d: 56.1, 70.1, 71.3, 91.1, 93.7, 104.9, 106.1,
J¼1.7 Hz, H6), 6.07 (d, 1H, J¼1.7 Hz, H8), 6.45 (s, 1H, H3), 6.91 (d,
0
111.5, 111.6, 120.1, 122.9, 123.0, 123.9, 124.0, 127.4, 127.5, 128.1, 128.2,
128.7, 129.4, 136.1, 136.6, 140.2, 148.3, 148.8, 152.5, 159.6, 161.5,
163.6, 180.9. IR (KBr, cmꢂ1): 1644 (C]O). LC–MS (ESI):
tR¼14.03 min; m/z [MþH]þ: 555.77. Elemental analysis: calcd (%) for
C36H29NO5: C 77.82, H 5.26, N 2.52; found: C 77.56, H 4.93, N 2.54.
2H, J¼8.3 Hz), 7.04 (d, 1H, J¼8.5 Hz, H5 ), 7.27 (d, 2H, J¼8.3 Hz),
0
0
7.32 (d, 1H, J¼2.2 Hz, H2 ), 7.44 (dd, 1H, J¼8.5 and 2.2 Hz, H6 ), 9.54
(t, 1H, J¼5.1 Hz, NH). 13C NMR (100 MHz, DMSO-d6)
d: 45.5, 55.0,
55.7, 90.0, 92.4, 102.4, 105.1, 112.2, 112.5, 114.0, 117.9, 123.4, 128.4,
146.7, 150.5, 151.2, 158.4, 159.1, 160.4, 179.5. IR (KBr, cmꢂ1): 3189
(NH), 1637 (C]O). LC–MS (ESI): tR¼9.58 min; m/z [MþH]þ:
419.93. HRMS (EI): calcd (Mþ.) for C24H21NO6: 419.1369, found:
419.1375.
4.5.2. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-methoxyphenylamino)-4H-chromen-4-one (3q)
Obtained as a yellow solid (104 mg, 54%); mp: 175 ꢀC; 1H NMR
(400 MHz, CDCl3) d: 3.83 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 5.05 (s,
2H, CH2), 5.24 (s, 2H, CH2), 6.30 (d, J¼2.2 Hz, 1H, H6), 6.34 (d,
J¼2.2 Hz, 1H, H8), 6.46 (s, 1H, H3), 6.85 (d, J¼8.8 Hz, 2H), 6.98 (d,
J¼8.6 Hz, 1H), 7.17 (d, J¼8.8 Hz, 2H), 7.33–7.51 (m, 12H), 10.88 (s, 1H,
Acknowledgements
The authors would like to thank the ‘Reseau PunchOrga’ for CL
PhD financial support.
NH). 13C NMR (100 MHz, CDCl3)
d: 55.6, 56.1, 70.0, 71.3, 90.4, 93.1,
104.6, 106.1, 111.5, 111.6, 114.7, 120.1, 124.0, 126.0, 127.5, 127.6, 128.1,
128.2, 128.7, 128.8, 132.9, 136.2, 136.6, 148.3, 150.3, 152.4, 156.8,
159.7, 161.3, 163.6, 180.9. IR (KBr, cmꢂ1): 1650 (C]O). LC–MS (ESI):
tR¼13.85 min; m/z [MþH]þ: 585.74. Elemental analysis: calcd (%) for
C37H31NO6: C 75.88, H 5.34, N 2.39; found: C 75.52, H 5.08, N 2.41.
References and notes
1. For reviews see: (a) Graf, B. A.; Milbury, P. E.; Blumberg, J. B. J. Med. Food 2005, 8,
281; (b) Ross, J. A.; Kasum, C. M. Annu. Rev. Nutr. 2002, 22, 19.
4.5.3. 7-Benzyloxy-2-(3-benzyloxy-4-methoxyphenyl)-5-
(4-fluorophenylamino)-4H-chromen-4-one (3r)
2. Gobbi, S.; Cavalli, A.; Rampa, A.; Belluti, F.; Piazzi, L.; Paluszcak, A.; Hartmann,
R. W.; Recanatini, M.; Bisi, A. J. Med. Chem. 2006, 49, 4777.
3. Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M. L.; Piro, O. E.; Castellano, E. E.;
Vidal, A.; Azqueta, A.; Monge, A.; de Cerain, A. L.; Sagrera, G.; Seoane, G.;
Cerecetto, H.; Gonzalez, M. Bioorg. Med. Chem. 2007, 15, 3356.
Obtained as a yellow solid (67 mg, 36%); mp: 196 ꢀC; 1H NMR
(400 MHz, CDCl3) d: 3.96 (s, 3H, OCH3), 5.07 (s, 2H, CH2), 5.24 (s, 2H,
4. Kawai, M.; Hirano, T.; Higa, S.; Arimitsu, J.; Maruta, M.; Kuwahara, Y.; Ohka-
wara, T.; Hagihara, K.; Yamadori, T.; Shima, Y.; Ogata, A.; Kawase, I.; Tanaka, T.
Allergol. Int. 2007, 56, 113.
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CH2), 6.34 (d, J¼2.2 Hz, 1H, H6), 6.40 (d, J¼2.2 Hz, 1H, H8), 6.47 (s,
0
1H, H3), 6.98 (d, J¼8.5 Hz, 1H, H5 ), 7.02 (d, J¼8.6 Hz, 1H), 7.04 (d,
J¼8.6 Hz, 1H), 7.17 (d, J¼8.6 Hz, 1H), 7.19 (d, J¼8.6 Hz, 1H), 7.34–7.52
(m, 12H), 11.01 (s, 1H, NH). 13C NMR (100 MHz, CDCl3)
d: 56.1, 70.1,
71.4, 91.0, 93.1, 104.8, 106.1, 111.5, 116.7 (d, J¼22.3 Hz), 120.1, 123.9,
125.0 (d, J¼8.2 Hz), 127.5, 128.1, 128.2, 128.7, 136.1, 136.6, 147.6,
148.3,149.5, 152.5, 159.6, 161.2 (d, J¼245.2 Hz), 161.5, 163.6, 181.0. IR
(KBr, cmꢂ1): 1645 (C]O). LC–MS (ESI): tR¼13.97 min; m/z [MþH]þ:
573.81. Elemental analysis: calcd (%) for C36H28FNO5: C 75.38, H
4.92, N 2.44; found: C 75.01, H 4.57, N 2.34.
4.6. 5-Amino-7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-
4H-chromen-4-one (4a)
9. (a) Mahboobi, S.; Pongratz, H. Synth. Commun. 1999, 29, 1645; (b) Dauzonne, D.;
Folleas, B.; Martinez, L.; Chabot, G. G. Eur. J. Med. Chem. 1997, 32, 71; (c) Deka,
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16. Ferte, J.; Ku¨ hnel, J. M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M. A. J. Med.
Chem. 1999, 42, 478.
Compound 3a (0.37 g, 0.65 mmol) was dissolved in MeOH
(50 mL) and the solution was degassed. Pd/C (50 mg) was added
and the solution was stirred under H2 in a Paar apparatus for 5 h.
After filtration on Celite, the solvent was removed under reduced
pressure and the residue was crystallized in diethyl ether to give 4a
as a yellow solid (0.132 g, 68%); mp: 182 ꢀC; 1H NMR (400 MHz,
DMSO-d6)
1H, J¼1.9 Hz, H8), 6.40 (s, 1H, H3), 7.02 (d, 1H, J¼8.8 Hz), 7.31–7.40
(m, 4H, 2Har and 2 OH). 13C NMR (100 MHz, DMSO-d6)
: 55.7, 90.6,
d
: 3.82 (s, 3H, OCH3), 5.90 (d, 1H, J¼1.9 Hz, H6), 6.00 (d,
d
96.6, 102.2, 105.0, 112.1, 112.5, 117.8, 123.6, 146.9, 150.5, 152.0, 158.9,
160.3, 163.7, 179.5. IR (KBr, cmꢂ1): 3449, 3330, 1642 (C]O). HRMS
(EI): calcd (Mþ.) for C16H13NO5: 299.0793, found: 299.0800.