Synthesis of 7-vinylflavone and 7-aminoflavone by palladium-catalyzed coupling reactions

Article abstract of DOI:10.1002/(SICI)1099-0690(199910)1999:10<2683::AID-EJOC2683>3.0.CO;2-8

Palladium-catalyzed cross-coupling reactions of flavone triflates 2a-c, 4a with tetravinyltin give the corresponding vinylflavones 5a-d, whereas reactions with benzophenone imine, followed by cleavage, afford the corresponding aminoflavone.

Full text of DOI:10.1002/(SICI)1099-0690(199910)1999:10<2683::AID-EJOC2683>3.0.CO;2-8

FULL PAPER
Synthesis of 7-Vinylflavone and 7-Aminoflavone by Palladium-Catalyzed
Coupling Reactions
[a]
[a]
[a]
`
`
Bo-Liang Deng, Jozef Arsene Lepoivre, and Guy Lemiere*
Keywords: Flavone / Palladium / Cross coupling / Triflate / Aminations
Palladium-catalyzed cross-coupling reactions of flavone
triflates 2a–c, 4a with tetravinyltin give the corresponding
vinylflavones 5a–d, whereas reactions with benzophenone
imine, followed by cleavage, afford the corresponding
aminoflavone.
Stille et al.[27] have reported the synthesis of 5-hydroxy-
7-triflyloxyflavone (2a) in good yield from 5,7-dihydroxy-
flavone (1a) using triflic anhydride in pyridine. However,
when we carried out this reaction as originally described,
we found that some starting material invariably remained
in the reaction mixture. On the other hand, the separation
of the mono- and ditriflates of flavone by regular column
chromatography proved very tedious (see the TLC Rf val-
ues). Several modifications aimed at reducing the formation
of ditriflates were tested. On reducing the amount of triflic
anhydride and on decreasing the reaction time, only the
amount of recovered starting material increased. We found
that by treating the reaction mixture with Ac2O/pyridine, to
convert compounds 2a and 2c into acetylated compounds
4a and 4c, respectively, the separations of 3a, 4a and 3c, 4c
became much easier (cf. the relevant Rf values).
The palladium-catalyzed cross coupling of organotin re-
agents with organic electrophiles is known as the Stille reac-
tion.[28][29] Since tetravinyltin is cheaper than tributylvinyl-
tin, and use of the former avoids the introduction of a butyl
group, we used tetravinyltin as our organotin reagent rather
than the tributylvinyltin employed by Stille and other au-
thors.
The palladium-catalyzed cross-coupling reaction for the
conversion of 5-hydroxy-7-triflyloxyflavone (2a) to 5a was
studied under various conditions (Table 1). When the reac-
tion was carried out under StilleЈs conditions[30] (Entry 1),
some black material appeared in the reaction mixture after
about 2.5 h, possibly due to decomposition of the catalyst.
Even when the reaction was allowed to proceed for 24 h,
18% of the starting material was recovered. When 10 mol-
% of the ligand PPh3 was added to the mixture, the reaction
afforded a yield of 52% within a few hours (Entry 2), al-
though some black material was also observed in the reac-
tion mixture after about 3 h. The yield of the coupling reac-
tion was further improved when the amounts of catalyst
and ligand were increased (Entry 4), and in this case no
black material was seen. When triphenylarsane or tris(2-
furyl)phosphane was used as the ligand,[31] the yield was
fairly good (Entries 5 and 6). Nevertheless, after 1 h and
1.5 h, respectively, some black material was again found.
Some unsuccessful attempts to promote the coupling in-
cluded the addition of CuII[32] (Entry 3) and the use of
Introduction
Flavonoids are natural products with many biological
and pharmacological activities.[1] Antiviral,[2][3] antitu-
mour,[4Ϫ6] antioxidant,[7][8] and antiinflammatory[9] proper-
ties, as well as inhibition of HIV proteinase,[10] HIV inte-
grase,[11][12] reverse transcriptase,[13][14] xanthine oxidase,[15]
and protein tyrosine kinase[16] have been demonstrated. In
most cases, pronounced structureϪactivity relationships
have been defected. For example, some studies have indi-
cated that the presence of a 3-methoxy group in the flavone
skeleton is essential for antipicornavirus activity.[17Ϫ19]
In the last ten years, the scope of the application of aryl
triflates in highly regioselective cross-coupling reactions
with various organometallic compounds under mild con-
ditions has broadened enormously.[20][21] We have at-
tempted to introduce triflyloxy and vinyl groups on ring A
of flavone in order to obtain useful synthons. The vinyl
group can be transformed into numerous other
groups.[22][23]
A few aminoflavones have been synthesized and, as far
as their biological activities have been examined, analogous
activities have been found as for the corresponding
hydroxyflavones.[24Ϫ26] Aminoflavones are normally synthe-
sized by reduction of the corresponding nitroflavones. Obvi-
ously, this method has limited applicability since the nitro-
flavones are difficult to obtain. We attempted to synthesize
flavones aminated at ring A by palladium-catalyzed amin-
ation, which would be a practical complementary method
for synthesizing aminoflavone. In this paper, the synthesis
of 7-vinylflavones and 7-aminoflavone from 7-triflyloxyfla-
vones is described and their antiviral activities are reported.
Results and Discussion
The triflate of flavone 1a was synthesized by treating 1a
with triflic anhydride in the presence of pyridine, as out-
lined in Scheme 1.
[a]
Department of Chemistry (Natural Products), University of
Antwerp (RUCA),
Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Fax: (internat.) ϩ 32-3/2180233
E-mail: lemiere@ruca.ua.ac.be
Eur. J. Org. Chem. 1999, 2683Ϫ2688
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1010Ϫ2683 $ 17.50ϩ.50/0
2683

´
B.-L. Deng, J. A. Lepoivre, G. Lemiere
FULL PAPER
Scheme 1. Synthesis of 7-triflyloxyflavones
Echavarren et al.[33] The synthesis of 7-amino-5-hydroxy-
flavone 7 was attempted as illustrated in Scheme 3.[34] 5-
Acetoxy-7-triflyloxyflavone (4a) was coupled with benzo-
phenone imine in the presence of palladium acetate, BI-
NAP, and cesium carbonate to give the diphenyl ketimine
adduct 6 with a free hydroxy group in the 5-position, which
was recrystallized from MeOH/acetone (5:2). The diphenyl
ketimine adduct 6 was then hydrogenolyzed using Pd(OH)2
on carbon in the presence of cyclohexene to give 7-amino-
5-hydroxyflavone 7 in good yield. The utility of this method
in the synthesis of aminoflavones will be investigated
further.
The antiviral potencies of compounds 2Ϫ5 against
Coxsakie B2 (COXB2) and Poliomyelitis virus type 1 (PO-
LIO I) as well as human rhinovirus type 30 (HRV 30) or
human rhinovirus type 81 (HRV 81) were determined by
the end-point titration technique (EPTT) as described else-
where.[18] The inhibitory effects of the compounds on virus
replication were monitored by the virus strength reduction
factor (RF) in the presence of the maximum nontoxic dose
of the compound. The results of the tests are presented in
Table 2. A reduction factor of 103 to 104 or more indicates
a pronounced antiviral activity, constituting a selection cri-
terion for further investigation. However, analysis of the re-
sults for compounds 2؊5 indicates that these compounds
show insufficient activity.
Scheme 2. Synthesis of 7-vinylflavones
Pd2(dba)3 (Entry 7). These results indicate that PPh3 (40%)
and Pd(PPh3)4 (10%) (Entry 4) are likely to provide the op-
timum catalyst for the synthesis of 7-vinylflavones.
The 3-methoxy-7-vinylflavones 5b, c (Scheme 2) were also
synthesized in good yields under these reaction conditions.
5-Acetoxy-7-triflyloxyflavone (4a) was chosen for use in a
coupling reaction with tetravinyltin under the same con-
ditions, which led to the isolation of 5-acetoxy-7-vinylflav-
one (5d) (47%) and some free 5-hydroxy-7-vinylflavone (5a)
(3.3%). Partially deacetylated products of both the starting
material and the coupling product were also observed by
Table 1. Effects of various reaction conditions on the coupling reaction of compound 2a; catalyst A, Pd(PPh3)4; catalyst B, Pd2(dba)3 ϭ
tris(dibenzylideneacetone)dipalladium(0); NMP ϭ 1-methylpyrrolidinone; BHT ϭ 2,6-di-tert-butyl-4-methylphenol; P(o-Fu)3 ϭ tri(2-fu-
ryl)phosphane
Entry
1
2
3
4
5
6
7
(CH2CH)4Sn (equiv.)
Catalyst (mol-%)
LiCl (equiv.)
1.15
1.25
1.25
5.0 A
3
1.45
1.15
1.20
1.30
5.0 A
5.0 A
10 A
10 A
10 A
5.0 B
3
3
0
3
0
3
0
3
0
3
0
CuII (mol-%)
0
10
Ligand (mol-%)
Solvent
0
10 PPh3
10 PPh3
dioxane
reflux
24
9.5
53
40 PPh3
40 AsPh3
40 P(o-Fu)3
20 AsPh3
NMP
dioxane
reflux
24
dioxane
dioxane
dioxane
dioxane
reflux
4
Reaction temp.
Reaction time [h]
Yield (%)
reflux
reflux
reflux
room temp.
7
4
5
4
38
18
52
5
55
0
45
6
45.5
6
no reaction
Recovered material%
2684
Eur. J. Org. Chem. 1999, 2683Ϫ2688

Synthesis of 7-Vinylflavone and 7-Aminoflavone by Palladium-Catalyzed Coupling Reactions
FULL PAPER
Scheme 3. Synthesis of 7-aminoflavones
Table 2. Antiviral activities; N ϭ precipitation of the sample; T ϭ toxicity; T/2 ϭ less toxic; T/4 ϭ very low toxicity; the product
concentrations (e.g. 100Ϫ5) are given in µg/mL; test concentration: (for viruses) starting from 100 µg/mL, dilutions of 50 µg/mL, 25 µg/
mL, 10 µg/mL, and 1 µg/mL were used
No.
COXB2
conc. [µg/mL]
POLIO I
conc. [µg/mL]
HRV30
conc. [µg/mL]
HRV81
conc. [µg/mL]
2a
2b
100Ϫ10
T
100Ϫ25
10
T
100Ϫ50
25
T
1
RF 1
T/2
RF 1
N
T/2
RF 1
N
1
10Ϫ1
100Ϫ50
100
100Ϫ50
100Ϫ1
N
RF1
100Ϫ25
100Ϫ50
T
RF 1
T/2
T/4
RF 1
50
50Ϫ1
2c
3a
3b
100Ϫ25
100Ϫ50
25
N
T
100Ϫ25
10Ϫ1
N, T
RF 1
100Ϫ50
100Ϫ1
N
RF 1
T/4
RF 1
N
25Ϫ1
100Ϫ25
100Ϫ50
25Ϫ1
100Ϫ25
100
N
100Ϫ50
100Ϫ1
N
RF 1
T
RF 1
T/2
50
T/4
100Ϫ1
100
RF 1
T/2
100Ϫ50
100
N
100Ϫ1
RF 1
T/4
RF 1
N
100Ϫ1
RF 1
100Ϫ1
100Ϫ50
100Ϫ1
100Ϫ50
100Ϫ25
10Ϫ1
4a
4c
100Ϫ1
RF 1
100Ϫ50
25Ϫ1
N, RF 10
RF 1
RF 1
N
100
100Ϫ1
N
RF 1
100Ϫ50
100Ϫ1
N
RF 1
T
RF 1
N
5a
5b
5c
100Ϫ50
100Ϫ1
100
100Ϫ1
N
RF 1
100Ϫ25
50
N
RF 1
RF 102
RF 10
RF 1
N
25
10Ϫ1
100Ϫ50
50Ϫ1
100Ϫ25
100
N
100Ϫ50
100
100Ϫ1
N
T/2
RF 1
T/4
RF 1
100Ϫ25
25Ϫ1
RF 102
RF 1
RF 1
100Ϫ1
100
100Ϫ1
N
RF 1
100
100Ϫ1
N
RF 1
trometer equipped with a cesium ion gun (Micromass, Manchester,
U.K.) and were performed on protonated molecules generated by
LSI-MA. Samples were analyzed at 5,000 resolution by linear-acce-
lerating voltage scanning. The data were acquired in the multichan-
nel analyzer mode by measuring the mass of the unknown peak
against two mass references originating from the calibrant and av-
eraging 25 scans. As calibrant, a mixture of glycerol and polyethyl-
ene glycol 300 or 600 was used. Ϫ Column chromatography was
Experimental Section
General Remarks: Melting points were determined in glass capillar-
ies with a Tottoli apparatus and are uncorrected. Ϫ H- and 13C-
1
NMR spectra were recorded with a Varian Unity 400 spectrometer
and DCI mass spectra with a Ribermag R10Ϫ10B quadrupole
mass spectrometer; ammonia was used as reagent gas; accurate
mass measurements were made using a VG-SEQ hybrid mass spec-
Eur. J. Org. Chem. 1999, 2683Ϫ2688
2685

´
B.-L. Deng, J. A. Lepoivre, G. Lemiere
FULL PAPER
performed on Kieselgel 60 (Merck), 0.040Ϫ0.063 mm (230Ϫ400
mesh ASTM). Ϫ TLC analyses were performed on Alugram Sil G/
1Ј), 129.2 (C-3Ј,5Ј), 126.3 (C-2Ј,6Ј), 118.7 (7-SO2CF3), 117.1 (C-
10), 113.3 (C-6), 109.4 (C-8), 109.0 (C-3), 21.0 (CH3CO). Ϫ DCI
UV254 (MachereyϪNagel) with CH2Cl2/MeOH (50:1) (Rf denoted MS; m/z: 429 [M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ: found 429.028;
as Rf1) and heptane/EtOAc (8:1) (Rf denoted as Rf2) as eluents. Ϫ calcd. 429.026. Ϫ C18H11F3O7S (428.34): calcd. C 50.47, H 2.59, S
Dichloromethane, dimethylformamide, and N-methylpyrrolidinone
7.48; found C 50.35, H 2.72, S 7.13.
(NMP)[35] were distilled from CaH2 and stored over activated mo-
5-Hydroxy-3-methoxy-7-triflyloxyflavone (2b): To a solution of 5,7-
dihydroxy-3-methoxyflavone (1b) (0.70 g, 2.5 mmol) in 20 mL of
dichloromethane and 8 mL of pyridine at 0°C was slowly added
trifluoromethanesulfonic anhydride (0.5 mL, ca. 3.0 mmol). The re-
sulting mixture was stirred at 0°C for 10 min., allowed to warm to
room temperature, and then stirred for 23 h. It was then concen-
trated and the residue was chromatographed (heptane/EtOAc, 8:1)
to give 5-hydroxy-3-methoxy-7-triflyloxyflavone (2b) (recrystallized
˚
lecular sieves (4 A). Lithium chloride was dried for about 12 h in
a vacuum oven at 120°C. Dioxane was treated with solid potassium
hydroxide, refluxed in the presence of Na, and distilled under N2.
5,7-Dihydroxy-3-methoxyflavone (1b) and 3Ј,4Ј-bis(benzyloxy)-5,7-
dihydroxy-3-methoxyflavone (1c) were synthesized according to a
published method.[36]
5-Hydroxy-7-triflyloxyflavone (2a): To a solution of 5,7-dihydroxy-
flavone (1a) (1.02 g, 4.0 mmol) in 30 mL of dichloromethane and from heptane, 0.59 g, 56%; m.p. 124.5°C; Rf1 ϭ 0.76, Rf2 ϭ 0.20)
10 mL of pyridine at 0°C was slowly added trifluoromethanesul- and 3-methoxy-5,7-bis(triflyloxy)flavone (3b) (recrystallized from
fonic anhydride (0.75 mL, ca. 4.5 mmol) in 1 mL of dichlorometh- heptane/EtOAc, 8:1, 56 mg, 4%; m.p. 171.5Ϫ172.5°C; Rf1 ϭ 0.80,
ane. The mixture was allowed to warm to room temperature and
then stirred for 22.5 h. Thereafter, it was concentrated and the resi-
due was chromatographed (heptane/EtOAc, 8:1) to give 5-hydroxy-
7-triflyloxyflavone (2a) as pale-yellow needles (1.13 g, 73%; m.p.
133.5Ϫ134°C, ref.[27] 129Ϫ130°C; Rf1 ϭ 0.82, Rf2 ϭ 0.16), 5,7-
bis(triflyloxy)flavone (3a) as white crystals (98 mg, 5%; m.p.
206.5Ϫ207.5°C, ref.[27] 206Ϫ207°C; Rf1 ϭ 0.76, Rf2 ϭ 0.06), and
starting material (20 mg, 2%).
2a: 1H NMR (CDCl3, TMS): δ ϭ 12.92 (s, 1 H, 5-OH), 7.90 (m, 2 [M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ: found 417.028; calcd. 417.026.
H, 2Ј,6Ј-H), 7.57 (m, 3 H, 3Ј,4Ј,5Ј-H), 6.98 (d, 1 H, J6,8 ϭ 2.28 Hz, Ϫ C17H11F3O7S (416.32): calcd. C 49.05, H 2.66, S 7.70; found C
8-H), 6.87 (s, 1 H, 3-H), 6.74 (d, 1 H, J6,8 ϭ 2.28 Hz, 6-H). Ϫ 13C 49.01, H 2.47, S 7.76.
Rf2 ϭ 0.13).
2b: 1H NMR (CDCl3, TMS): δ ϭ 12.80 (s, 1 H, 5-OH), 8.07 (m, 2
H, 2Ј,6Ј-H), 7.54 (m, 3 H, 3Ј,4Ј,5Ј-H), 6.95 (d, 1 H, J6,8 ϭ 2.10 Hz,
8-H), 6.72 (d, 1 H, J6,8 ϭ 2.10 Hz, 6-H), 3.90 (s, 3 H, OCH3). Ϫ
13C NMR (CDCl3, TMS): δ ϭ 179.3 (C-4), 162.5 (C-5), 157.5 (C-
2), 155.7 (C-9), 153.3 (C-7), 140.4 (C-3), 131.7 (C-4Ј), 129.8 (C-
1Ј), 128.8 (C-3Ј,5Ј), 128.6 (C-2Ј,6Ј), 118.7 (7-SO2CF3), 110.9 (C-
10), 104.4 (C-6), 100.7 (C-8), 60.5 (OCH3). Ϫ DCI MS; m/z: 417
NMR (CDCl3, TMS): δ ϭ 182.6 (C-4), 165.4 (C-2), 162.7 (C-5),
1
3b: H NMR (CDCl3, TMS): δ ϭ 8.07 (m, 2 H, 2Ј,6Ј-H), 7.60 (d,
156.8 (C-9), 153.4 (C-7), 132.6 (C-4Ј), 130.6 (C-1Ј), 129.3 (C-3Ј,5Ј),
1 H, J6,8 ϭ 2.38 Hz, 8-H), 7.55 (m, 3 H, 3Ј,4Ј,5Ј-H), 7.14 (d, 1 H,
126.6 (C-2Ј,6Ј), 118.7 (7-SO2CF3), 110.5 (C-10), 106.5 (C-3), 105.2
J6,8 ϭ 2.38 Hz, 6-H), 3.92 (s, 3 H, OCH3). Ϫ 13C NMR (CDCl3,
(C-6), 100.8 (C-8). Ϫ DCI MS; m/z: 387 [M ϩ H]ϩ. Ϫ HR MS;
TMS): δ ϭ 171.9 (C-4), 156.3 (C-2), 155.7 (C-9), 150.6 (C-7), 147.9
[M ϩ H]ϩ: found 387.017; calcd. 387.015.
(C-5), 142.4 (C-3), 131.6 (C-4Ј), 129.5 (C-1Ј), 128.8 (C-3Ј,5Ј), 128.5
(C-2Ј,6Ј), 118.9, 118.7 (5-SO2CF3, 7-SO2CF3), 117.9 (C-10), 112.7
1
3a: H NMR (CDCl3, TMS): δ ϭ 7.89 (m, 2 H, 2Ј,6Ј-H), 7.63 (d,
1 H, J6,8 ϭ 2.28 Hz, 8-H), 7.57 (m, 3 H, 3Ј,4Ј,5Ј-H), 7.15 (d, 1 H, (C-6), 112.1 (C-8), 60.3 (OCH3). Ϫ DCI MS; m/z: 548 [M ϩ H]ϩ.
J6,8 ϭ 2.28 Hz, 6-H), 6.83 (s, 1 H, 3-H). Ϫ 13C NMR (CDCl3,
TMS): δ ϭ 174.6 (C-4), 163.4 (C-2), 157.5 (C-9), 150.9 (C-7), 147.9
(C-5), 132.6 (C-4Ј), 130.2 (C-1Ј), 129.4 (C-3Ј,5Ј), 126.4 (C-2Ј,6Ј),
118.8, 118.7 (5-SO2CF3, 7-SO2CF3), 117.8 (C-10), 113.2 (C-6),
112.3 (C-8), 109.1 (C-3). Ϫ DCI MS; m/z: 519 [M ϩ H]ϩ. Ϫ HR
MS; [MϩH]ϩ: found 518.967; calcd. 518.964.
Ϫ HR MS; [M ϩ H]ϩ: found 548.978; calcd. 548.975.
3Ј,4Ј-Bis(benzyloxy)-5-hydroxy-3-methoxy-7-triflyloxyflavone
(2c): To a solution of 3Ј,4Ј-bis(benzyloxy)-5,7-dihydroxy-3-meth-
oxyflavone (1c) (0.50 g, 1.0 mmol) in 15 mL of dichloromethane
and 3 mL of pyridine at 0°C was slowly added trifluoromethanes-
ulfonic anhydride (0.16 mL, ca. 0.95 mmol). The resulting mixture
was stirred at 0°C for 3.5 h, allowed to warm to room temperature,
stirred for a further 2.5 h, and then mixed with 20 mL of water.
The dichloromethane phase was separated, washed twice with di-
5-Acetoxy-7-triflyloxyflavone (4a): To a solution of 5,7-dihydroxy-
flavone (1a) (2.54 g, 10 mmol) in 100 mL of dichloromethane and
25 mL of pyridine at 0°C was slowly added trifluoromethanesul-
fonic anhydride (1.73 mL, 10.3 mmol). The mixture was stirred at lute HCl solution, and concentrated to afford a yellow residue.
0°C for 3 h and at room temperature for 0.5 h, then mixed with Chromatography (CH2Cl2/MeOH, 50:1) of this residue gave 3Ј,4Ј-
200 mL of 5% aqueous hydrochloric acid and the resulting mixture bis(benzyloxy)-5-hydroxy-3-methoxy-7-triflyloxyflavone (2c)
(0.27 g, 44%; m.p. 132Ϫ133°C; Rf1 ϭ 0.85, Rf2 ϭ 0.09) and the
starting material 3Ј,4Ј-bis(benzyloxy)-5,7-dihydroxy-3-meth-
was stirred for a few minutes. The dichloromethane phase was sepa-
rated and the aqueous phase was extracted with dichloromethane
(2 ϫ 50 mL). The combined dichloromethane phases were then
dried (MgSO4) and concentrated. The residue was chromato-
graphed (hexane/EtOAc, 8:1) to give a mixture of 5-hydroxy-7-tri-
flyloxyflavone and 5,7-bis(triflyloxy)flavone. This mixture was ace-
tylated with acetic anhydride/pyridine (5:1), worked up, and sepa-
rated by column chromatography (CH2Cl2/MeOH, 50:1) to furnish
5-acetoxy-7-triflyloxyflavone (4a) (2.76 g, 68%; m.p. 178.5Ϫ179°C;
Rf1 ϭ 0.30, Rf2 ϭ 0.03) and 5,7-bis(triflyloxy)flavone (3a) (0.31 g,
3%).
oxyflavone (0.22 g, 44%).
1
2c: H NMR (CDCl3, TMS): δ ϭ 12.84 (s, 1 H, 5-OH), 7.73 (d, 1
H, J2Ј,6Ј ϭ 2.10 Hz, 2Ј-H), 7.69 (dd, 1 H, J2Ј,6Ј ϭ 2.10 Hz, J5Ј,6Ј
8.60 Hz, 6Ј-H), 7.47 (m, 4 H, 2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ-H), 7.39 (m, 4 H,
3ЈЈ,3ЈЈЈ,5ЈЈ,5ЈЈЈ-H), 7.33 (m, 2 H, 4ЈЈ,4ЈЈЈ-H), 7.04 (d, 1 H, J5Ј,6Ј
8.60 Hz, 5Ј-H), 6.85 (d, 1 H, J6,8 ϭ 2.19 Hz, 8-H), 6.68 (d, 1 H,
6,8 ϭ 2.19 Hz, 6-H), 5.28, 5.26 (s, 4 H, 2CH2), 3.73 (s, 3 H, OCH3).
13C NMR (CDCl3, TMS): δ ϭ 178.9 (C-4), 162.5 (C-5), 157.1
ϭ
ϭ
J
Ϫ
(C-2), 155.4 (C-9), 153.1 (C-7), 152.1 (C-4Ј), 148.5 (C-3Ј), 139.6 (C-
3), 136.9, 136.5 (C-1ЈЈ,1ЈЈЈ), 128.7 (C-3ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ), 128.1, 128.0
1
4a: H NMR (CDCl3, TMS): δ ϭ 7.87 (m, 2 H, 2Ј,6Ј-H), 7.54 (m,
3 H, 3Ј,4Ј,5Ј-H), 7.45 (d, 1 H, J6,8 ϭ 2.38 Hz, 8-H), 6.70 (s, 1 H, (C-4ЈЈ,4ЈЈЈ), 127.2 (C-2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ), 123.0 (C-6Ј), 122.4 (C-1Ј),
3-H), 6.99 (d, 1 H, J6,8 ϭ 2.38 Hz, 6-H), 2.46 (s, 3 H, CH3CO). Ϫ 118.7 (7-SO2CF3), 115.4 (C-2Ј), 113.9 (C-5Ј), 110.7 (C-10), 104.2
13C NMR (CDCl3, TMS): δ ϭ 175.7 (C-4), 169.0 (COCH3), 163.0 (C-6), 100.6 (C-8), 71.6, 71.0 (2CH2), 60.1 (3-OCH3). Ϫ DCI MS;
(C-2), 151.4, 151.2 (C-7, C-5), 157.7 (C-9), 132.2 (C-4Ј), 130.6 (C-
m/z: 629 [M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ: found 629.111; calcd.
2686
Eur. J. Org. Chem. 1999, 2683Ϫ2688

Synthesis of 7-Vinylflavone and 7-Aminoflavone by Palladium-Catalyzed Coupling Reactions
FULL PAPER
629.109. Ϫ C31H23F3O9S (628.57): calcd. C 59.24, H 3.69, S 5.10;
found 59.01, H 3.57, S 4.84.
160.8 (C-5), 156.7 (C-9), 144.9 (C-7), 135.8 (CHCH2), 132.0 (C-4Ј),
131.3 (C-1Ј), 129.1 (C-3Ј,5Ј), 126.4 (C-2Ј,6Ј), 118.2 (CHCH2), 110.3
(C-10), 109.0 (C-6), 106.2 (C-8), 104.9 (C-3). Ϫ DCI MS; m/z: 265
[M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ: found 265.086; calcd. 265.086.
5-Acetoxy-3Ј,4Ј-bis(benzyloxy)-3-methoxy-7-triflyloxyflavone
(4c): To a solution of 3Ј,4Ј-bis(benzyloxy)-5,7-dihydroxy-3-meth-
oxyflavone (1c) (0.50 g, 1.0 mmol) in 10 mL of dichloromethane
and 3 mL of pyridine at 0°C was slowly added trifluoromethanes-
ulfonic anhydride (0.2 mL, ca. 1.19 mmol). The resulting mixture
was stirred at 0°C for 3 h, then mixed with 20 mL of water. The
dichloromethane phase was separated, washed with 6% HCl
(45 mL), and concentrated to leave a yellow residue. Chromatogra-
phy (CH2Cl2/MeOH, 50:1) of this residue afforded a yellow mix-
ture, which was treated with Ac2O/pyridine (5:1) and worked-up to
give 5-acetoxy-3Ј,4Ј-bis(benzyloxy)-3-methoxy-7-triflyloxyflavone
(4c) (0.21 g, 31%; m.p. 140.5Ϫ141.5°C; Rf1 ϭ 0.50, Rf2 ϭ 0.01) and
5-Hydroxy-3-methoxy-7-vinylflavone (5b): A three-necked flask was
charged with a mixture of tetravinyltin (0.20 g, 0.9 mmol), 5-
hydroxy-3-methoxy-7-triflyloxyflavone (2b) (0.25 g, 0.6 mmol), tri-
phenylphosphane (0.06 g, 0.24 mmol), tetrakis(triphenylphos-
phane)palladium (0.07 g, 0.06 mmol), lithium chloride (0.08 g,
1.8 mmol), and dioxane (15 mL) under argon. A few crystals of
2,6-di-tert-butyl-4-methylphenol were also added to the mixture,
which was stirred at reflux under argon for 4 h. After workup as
described in the case of compound 5a, 5-hydroxy-3-methoxy-7-vi-
nylflavone (5b) (0.11 g, 62%; m.p. 105Ϫ106°C; Rf1 ϭ 0.81, Rf2
ϭ
3Ј,4Ј-bis(benzyloxy)-3-methoxy-5,7-bis(triflyloxy)flavone
(3c)
0.32) was obtained.
(0.27 g, 35%).
5b: 1H NMR (CDCl3, TMS): δ ϭ 12.36 (s, 1 H, 5-OH), 8.09 (m, 2
H, 2Ј,6Ј-H), 7.53 (m, 3 H, 3Ј,4Ј,5Ј-H), 6.99 (d, 1 H, J6,8 ϭ 1.28 Hz,
4c: 1H NMR (CDCl3, TMS): δ ϭ 7.68 (d, 1 H, J2Ј,6Ј ϭ 2.02 Hz,
2Ј-H), 7.62 (dd, 1 H, J2Ј,6Ј ϭ 2.02 Hz, J5Ј,6Ј ϭ 8.61 Hz, 6Ј-H), 7.44
(m, 4 H, 2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ-H), 7.34 (m, 4 H, 3ЈЈ,3ЈЈЈ,5ЈЈ,5ЈЈЈ-H), 7.28
(m, 2 H, 4ЈЈ,4ЈЈЈ-H), 6.99 (d, 1 H, J5Ј,6Ј ϭ 8.61 Hz, 5Ј-H), 7.28 (d,
1 H, J6,8 ϭ 2.47 Hz, 8-H), 6.90 (d, 1 H, J6,8 ϭ 2.47 Hz, 6-H), 5.20,
5.19 (s, 4 H, 2CH2), 3.65 (s, 3 H, OCH3), 2.44 (s, 3 H, COCH3). Ϫ
13C NMR (CDCl3, TMS): δ ϭ 172.3 (C-4), 168.7 (COCH3), 156.1
(C-2), 154.7 (C-9), 151.5 (C-4Ј), 150.9, 150.8 (C-5, C-7), 148.3 (C-
3Ј), 141.3 (C-3), 136.8, 136.4 (C-1ЈЈ,1ЈЈЈ), 128.4 (C-3ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ),
127.9, 127.8 (C-4ЈЈ,4ЈЈЈ), 127.0 (C-2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ), 122.4 (C-6Ј,1Ј),
118.5 (7-SO2CF3), 117.0 (C-10), 115.0 (C-2Ј), 113.6 (C-5Ј), 112.3
(C-6), 109.0 (C-8), 71.2, 70.7 (2CH2), 59.6 (3-OCH3), 20.8
(COCH3). Ϫ DCI MS; m/z: 671 [M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ:
found 671.125; calcd. 671.120. Ϫ C33H25F3O10S (670.61): calcd. C
59.10, H 3.76, S 4.78; found C 58.93, H 3.62, S 4.36.
3c: 1H NMR (CDCl3, TMS): δ ϭ 7.71 (d, 1 H, J2Ј,6Ј ϭ 2.20 Hz,
2Ј-H), 7.67 (dd, 1 H, J2Ј,6Ј ϭ 2.2 Hz, J5Ј,6Ј ϭ 8.60 Hz, 6Ј-H), 7.48
(d, 1 H, J6,8 ϭ 2.20 Hz, 8-H), 7.47 (m, 4 H, 2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ-H), 7.39
(m, 4 H, 3ЈЈ,3ЈЈЈ,5ЈЈ,5ЈЈЈ-H), 7.33 (m, 2 H, 4ЈЈ,4ЈЈЈ-H), 7.09 (d, 1 H,
J6,8 ϭ 2.20 Hz, 6-H), 7.04 (d, 1 H, J5Ј,6Ј ϭ 8.60 Hz, 5Ј-H), 5.26,
5.25 (s, 4 H, 2CH2), 3.75 (s, 3 H, OCH3). Ϫ 13C NMR (CDCl3,
TMS): δ ϭ 171.6 (C-4), 156.1 (C-2), 155.3 (C-9), 152.0 (C-4Ј), 150.4
(C-7), 148.5 (C-3Ј), 147.8 (C-5), 141.7 (C-3), 136.9, 136.5 (C-
1ЈЈ,1ЈЈЈ), 128.7 (C-3ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ), 128.1, 128.0 (C-4ЈЈ,4ЈЈЈ), 127.3,
127.2 (C-2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ), 122.9 (C-6Ј), 122.2 (C-1Ј), 118.8, 118.2
(7-SO2CF3, 5-SO2CF3), 115.4 (C-2Ј), 113.9 (C-5Ј), 117.8 (C-10),
112.5 (C-6), 112.0 (C-8), 71.6, 71.0 (2CH2), 60.0 (3-OCH3). Ϫ DCI
MS; m/z: 761 [M ϩ H]ϩ.
8-H), 6.86 (d, 1 H, J6,8 ϭ 1.28 Hz, 6-H), 6.71 (q, 1 H, Jac
ϭ
17.40 Hz, Jab ϭ 10.80 Hz, Ha), 5.92 (d, 1 H, Jac ϭ 17.40 Hz, Hc),
5.47 (d, 1 H, Jab ϭ 10.80 Hz, Hb), 3.89 (s, 3 H, 3-OCH3). Ϫ 13C
NMR (CDCl3, TMS): δ ϭ 179.5 (C-4), 160.8 (C-5), 156.6, 155.8
(C-2, C-9), 144.8 (C-7), 140.1 (C-3), 135.8 (CHCH2), 131.1 (C-4Ј),
130.5 (C-1Ј), 128.7 (C-3Ј,5Ј), 128.5 (C-2Ј,6Ј), 118.2 (CHCH2), 110.8
(C-10), 108.1 (C-6), 105.0 (C-8), 60.3 (3-OCH3). Ϫ DCI MS; m/z:
295 [M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ: found 295.097; calcd.
295.097.
3Ј,4Ј-Bis(benzyloxy)-5-hydroxy-3-methoxy-7-vinylflavone (5c): This
compound was synthesized from 3Ј,4Ј-bis(benzyloxy)-5-hydroxy-3-
methoxy-7-triflyloxyflavone (2c) according to the procedure used
for 5b. 5c (0.094 g, 61%; m.p. 89.5Ϫ90.5°C; Rf1 ϭ 0.84, Rf2 ϭ 0.12).
1
5c: H NMR (CDCl3, TMS): δ ϭ 12.39 (s, 1 H, 5-OH), 7.77 (d, 1
H, J2Ј,6Ј ϭ 2.10 Hz, 2Ј-H), 7.69 (dd, 1 H, J2Ј,6Ј ϭ 2.10 Hz, J5Ј,6Ј
8.60 Hz, 6Ј-H), 7.47 (m, 4 H, 2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ-H), 7.38 (m, 4 H,
3ЈЈ,3ЈЈЈ,5ЈЈ,5ЈЈЈ-H), 7.32 (m, 2 H, 4ЈЈ,4ЈЈЈ-H), 7.03 (d, 1 H, J5Ј,6Ј
8.60 Hz, 5Ј-H), 6.90 (d, 1 H, J6,8 ϭ 1.46 Hz, 8-H), 6.81 (d, 1 H,
6,8 ϭ 1.46 Hz, 6-H), 6.67 (q, 1 H, Jac ϭ 17.58 Hz, Jab ϭ 10.81 Hz,
ϭ
ϭ
J
Ha), 5.89 (d, 1 H, Jac ϭ 17.58 Hz, Hc), 5.44 (d, 1 H, Jab ϭ 10.81 Hz,
Hb), 5.26, 5.25 (s, 4 H, 2CH2), 3.72 (s, 3 H, OCH3). Ϫ 13C NMR
(CDCl3, TMS): δ ϭ 178.2 (C-4), 159.7 (C-5), 155.2, 154.5 (C-2, C-
9), 150.6 (C-4Ј), 147.4 (C-3Ј), 143.5 (C-7), 138.5 (C-3), 136.0, 135.6,
134.8 (C-1ЈЈ, CHCH2, C-1ЈЈЈ), 127.6 (C-3ЈЈ,5ЈЈ,3ЈЈЈ,5ЈЈЈ), 127.0 (C-
4ЈЈ,4ЈЈЈ), 126.2 (C-2ЈЈ,2ЈЈЈ,6ЈЈ,6ЈЈЈ), 122.3 (C-6Ј), 121.8 (C-1Ј), 116.9
(C-2Ј), 114.4 (CHCH2), 112.8 (C-5Ј), 109.6 (C-10), 107.0 (C-6),
103.9 (C-8), 70.5, 70.0 (2CH2), 59.1 (3-OCH3). Ϫ DCI MS; m/z:
507 [M ϩ H]ϩ. Ϫ HR MS; [M ϩ H]ϩ: found 507.183; calcd.
507.181.
5-Hydroxy-7-vinylflavone (5a): An oven-dried three-necked flask
was charged with a mixture of 5-hydroxy-7-triflyloxyflavone (2a),
the chosen palladium catalyst and ligand, and anhydrous lithium
chloride or copper(I) iodide in NMP or dioxane under argon (Table
1). A few crystals of 2,6-di-tert-butyl-4-methylphenol were also ad-
ded to the mixture. After stirring for a few minutes, tetravinyltin
was added. The mixture was either stirred at room temperature or
refluxed for several hours and cooled, then treated with 5% aque-
ous potassium fluoride solution and extracted with diethyl ether.
The combined ethereal extracts were washed with water, dried
(MgSO4), concentrated, and separated by column chromatogra-
phy (CH2Cl2).
5-Acetoxy-7-vinylflavone (5d): A 100-mL flask, equipped with a
magnetic stirring bar, a septum inlet and a condenser, was charged
with 5-acetoxy-7-triflyloxyflavone (4a) (2.14 g, 5 mmol), tri-
phenylphosphane (0.52 g, 2 mmol), tetrakis(triphenylphosphane)-
palladium (0.58 g, 0.5 mmol), lithium chloride (0.64 g, 15 mmol),
and a few crystals of 2,6-di-tert-butyl-4-methylphenol in dioxane
(40 mL), and flushed with argon. A solution of tetravinyltin (1.71 g,
75 mmol) in 10 mL of dioxane was then added. The resulting mix-
ture was stirred at reflux under argon for 5 h. After workup, 5-
acetoxy-7-vinylflavone (5d) (0.72 g, 47%) and 5-hydroxy-7-vinyl-
flavone (5a) (0.04 g, 3.3%) were obtained.
5a: M.p. 141.5Ϫ142.5°C. Ϫ 1H NMR (CDCl3, TMS): δ ϭ 12.48
(s, 1 H, 5-OH), 7.90 (m, 2 H, 2Ј,6Ј-H), 7.54 (m, 3 H, 3Ј,4Ј,5Ј-H),
7.02 (d, 1 H, J6,8 ϭ 1.38 Hz, 8-H), 6.86 (d, 1 H, J6,8 ϭ 1.38 Hz, 6- 5d: H NMR (CDCl3, TMS): δ ϭ 7.87 (m, 2 H, 2Ј,6Ј-H), 7.52 (m,
1
H), 6.71 (s, 1 H, 3-H), 6.70 (q, 1 H, Jac ϭ 17.58 Hz, Jab ϭ 10.80 Hz,
Ha), 5.71 (d, 1 H, Jac ϭ 17.58 Hz, Hc), 5.47 (d, 1 H, Jab ϭ 10.80 Hz, J6,8 ϭ 1.46 Hz, 6-H), 6.65 (s, 1 H, 3-H), 6.75 (q, 1 H, Jac
Hb). Ϫ 13C NMR (CDCl3, TMS): δ ϭ 183.1 (C-4), 164.6 (C-2), 17.58 Hz, Jab ϭ 10.99 Hz, Ha), 5.94 (d, 1 H, Jac ϭ 17.58 Hz, Hc),
3 H, 3Ј,4Ј,5Ј-H), 7.44 (d, 1 H, J6,8 ϭ 1.46 Hz, 8-H), 7.08 (d, 1 H,
ϭ
Eur. J. Org. Chem. 1999, 2683Ϫ2688
2687

´
B.-L. Deng, J. A. Lepoivre, G. Lemiere
FULL PAPER
[3]
5.51 (d, 1 H, Jab ϭ 10.99 Hz, Hb), 2.45 (s, 3 H, COCH3). Ϫ 13C
NMR (CDCl3, TMS): δ ϭ 176.8 (C-4), 169.8 (COCH3), 162.5 (C-
2), 157.7 (C-9), 149.5 (C-5), 143.2 (C-7), 134.8 (CHCH2), 131.7 (C-
4Ј), 131.4 (C-1Ј), 129.1 (C-3Ј,5Ј), 126.3 (C-2Ј,6Ј), 118.7 (CHCH2),
116.7 (C-6), 116.3 (C-10), 113.7 (C-8), 108.8 (C-3), 21.2 (COCH3).
Ϫ DCI MS; m/z: 307 [M ϩ H]ϩ.
N. Desideri, C. Conti, I. Sestilli, P. Tomao, M. L. Stein, N. Orsi,
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0.2 mmol), 5-acetoxy-7-triflyloxyflavone (4a) (86 mg, 0.2 mmol)
and cesium carbonate (164 mg, 0.50 mmol) and then purged with
argon. A solution of benzophenone imine (46 mg, 0.025 mmol) in
5 mL of THF was added and the mixture was stirred at reflux un-
der argon for 3.5 h. After this period, DCI MS showed that the
starting material had been consumed. The mixture was cooled to
room temperature, diluted with diethyl ether (100 mL), filtered, and
concentrated. The brown residue was purified by column chroma-
tography (CH2Cl2/MeOH, 50:1) to give 6 (53 mg, 63%). The di-
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6: 1H NMR ([D6]acetone): δ ϭ 12.71 (s, 1 H, 5-OH), 8.02 (m, 2 H,
2Ј,6Ј-H), 7.70Ϫ7.33 (m, 10 H, 2C6H5), 7.58 (m, 3 H, 3Ј,4Ј,5Ј-H),
6.77 (s, 1 H, 3-H), 6.52 (d, 1 H, J6,8 ϭ 1.75 Hz, 8-H), 6.18 (d, 1 H,
J6,8 ϭ 1.75 Hz, 6-H). Ϫ DCI MS; m/z: 418 [M ϩ H]ϩ. Ϫ HR
MS; [M ϩ H]ϩ: found 418.145; calcd. 418.144. Ϫ A mixture of
the diphenyl ketimine adduct 6 (42.7 mg, 0.10 mmol), palladium
hydroxide on carbon (57 mg), cyclohexene (2 mL), and ethanol
(5 mL) was heated under reflux for 2 h. After cooling to room tem-
perature, the solution was passed through a short column of silica
gel, which was eluted with dichloromethane. The eluate was col-
lected, concentrated, and chromatographed (CH2Cl2/MeOH, 50:1)
to yield 7-amino-5-hydroxyflavone (7) (23 mg, 79%).
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2Ј,6Ј-H), 7.55 (m, 3 H, 3Ј,4Ј,5Ј-H), 6.79 (s, 1 H, 3-H), 6.44 (m, 2
H, NH2), 6.19 (d, 1 H, J6,8 ϭ 1.84 Hz, 8-H), 5.96 (d, 1 H, J6,8
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1.84 Hz, 6-H). Ϫ 13C NMR ([D6]DMSO): δ ϭ 180.5 (C-4), 162.0
(C-2), 161.1 (C-5), 157.7 (C-9), 156.0 (C-7), 131.5 (C-4Ј), 131.0 (C-
1Ј), 128.9 (C-3Ј,5Ј), 126.0 (C-2Ј,6Ј), 104.8 (C-3), 101.3 (C-10), 95.9
(C-6), 90.4 (C-8). Ϫ DCI MS; m/z: 254 [M ϩ H]ϩ. Ϫ HR MS; [M
ϩ H]ϩ: found 254.085; calcd. 254.082.
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We thank Prof. M. Claeys for carrying out high-resolution mass
measurements, Ir. J. Verreydt for recording the DCI mass spectra,
and Ir. J. Aerts and Dr. A. De Groot for recording the NMR spec-
tra. We are also grateful to Prof. D. A. Vanden Berghe for per-
forming the biological tests. This work was supported by the Flem-
ish government (Belgium) in a concerted action 92/94Ϫ9.
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