One-pot synthesis of 3-methylflavones and their transformation into (E)-3-styrylflavones via Wittig reactions

Article abstract of DOI:10.1055/s-0033-1340013

An efficient one-pot synthesis of 3-methylflavone derivatives is established. Furthermore, their transformation into phosphorus ylides, which are then used in the diastereoselective synthesis of (E)-styrylflavones through Wittig reactions, is also studied

Full text of DOI:10.1055/s-0033-1340013

LETTER
▌2683
letter
One-Pot Synthesis of 3-Methylflavones and Their Transformation into
(E)-3-Styrylflavones via Wittig Reactions
Synthesis of 3-Methylflavones and (E)-3-Styrylflavones
Djenisa H. A. Rocha, Diana C. G. A. Pinto,* Artur M. S. Silva*
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: diana@ua.pt; E-mail: artur.silva@ua.pt
Received: 27.08.2013; Accepted after revision: 18.09.2013
salts, which were further used in Wittig reactions with
various benzaldehydes to afford 3-styrylflavones
(Scheme 2).
Abstract: An efficient one-pot synthesis of 3-methylflavone deriv-
atives is established. Furthermore, their transformation into phos-
phorus ylides, which are then used in the diastereoselective
synthesis of (E)-styrylflavones through Wittig reactions, is also
studied.
5'
R
6'
O
Key words: 3-methylflavones, lithium bis(trimethylsilyl)amide,
phosphonium salts, Wittig reaction, 3-styrylflavones
8
O
2
3
3'
7
6
Cl
(i)
+
2'
R
5
OH
O
O
Flavone derivatives constitute one of the major classes of
naturally occurring oxygen-containing heterocycles, and
their abundance in plants, fruits and vegetables make
them important human dietary constituents.1,2 Their asso-
ciation with biological activities,3 such as anticancer,4
anti-inflammatory5 and anti-oxidant6 has important poten-
tial consequences. 3-Methylflavones are scarce in Nature,
with only four derivatives having been isolated from the
aerial parts of Eugenia kurzii: 3-methylapigenin, 3-
methylluteolin and their 5-O-rhamnoside derivatives.7
Synthetic derivatives are also uncommon; the methyl
ethers of 3-methylapigenin and 3-methylluteolin were
synthesized to confirm the structures of the natural agly-
cones,7 and a few years ago we disclosed the synthesis of
3-methylluteolin8 and reported on its potential to prevent
low-density lipoproteins (LDL) oxidation.9 In both cases
the 3-methylflavones were obtained by modified Baker–
Venkataraman transformations. As far as we are aware,
only a single total synthesis of 3-methylluteolin has been
published and the overall yield was very low (less than
20%).8 The synthesis, anti-oxidant and antibacterial activ-
ities were reported for twenty 3-methylflavones,10 these
flavones having been obtained by cyclodehydrogenation
of the corresponding 2′-hydroxy-α-methylchalcones in
overall yields of below 50%.
1
2a R = H
2b R = OMe
2c R = Cl
3a–d
2d R = NO2
O
2''
5''
5'
3''
6''
3'
6'
OMe
3''
2''
6'
O
O
4'
3'
4'
5'
1
2
6''
3
5''
OMe
2
3
O
O
O
O
4
OMe
6'''
5'''
2'''
3'''
6
OH
O
O
OMe
R
5
MeO
O
O
MeO
OMe
O
2a,b
(i)
OMe
OH
7
8a,b
Scheme 1 Synthesis of 3-methylflavones 3a–d and 8a,b. Reagents
and conditions: (i) (1) LiHMDS, anhydrous toluene, r.t.; (2) HCl
(37%), r.t.
The synthetic approach to the 3-methylflavones started
with the reaction of 2′-hydroxypropiophenone (1) with
p-methoxybenzoyl chloride (2b) in the presence of an
excess amount of lithium bis(trimethylsilyl)amide
(LiHMDS),12 followed by treatment with hydrochloric
acid (Table 1, entry 1). Under these conditions the desired
product, 3-methyl-4′-methoxyflavone (3b), was obtained
in a low yield, whilst compounds 4, 5 and 6 were obtained
as the major products (Scheme 1).13 Based on our previ-
ously established conditions for analogous transforma-
tions,11 we decided to increase the amount of base and to
use longer reaction times in both steps (Table 1, entry 2),
particularly for the second step (after the addition of HCl),
since the isolation of products 5 and 6 indicates that a lon-
ger reaction time is needed to allow the β-diketone inter-
mediate to cyclize in the acidic medium. As can be seen in
We previously developed a new and efficient synthetic
route toward 3-aroylflavones involving reactions of 2′-hy-
droxyacetophenones with aroyl chlorides in the presence
of lithium bis(trimethylsilyl)amide.11 The good yields and
the experimental simplicity prompted us to use this meth-
od for the synthesis of 3-methylflavones (Scheme 1), not
only because these derivatives can have potentially im-
portant biological activities, but also because they can be
used to generate new chromone derivatives. In addition,
we also studied their transformation into phosphonium
SYNLETT 2013, 24, 2683–2686
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340013; Art ID: ST-2013-D0823-L
© Georg Thieme Verlag Stuttgart · New York

2684
D. H. A. Rocha et al.
LETTER
Table 1, it was necessary to optimize the reaction condi-
tions (reaction time and/or amount of base) in each case,
but eventually the flavone derivatives 3a–d were obtained
in good yields (Table 1, entries 2, 3, 5 and 6).14 The results
indicated that β-diketone formation was favored by the
presence of strong electron-withdrawing or electron-do-
nating groups (e.g., p-methoxybenzoyl and p-nitrobenzo-
yl chlorides, Table 1, entries 2 and 3), while the
cyclization step was less affected by these substituents.
R
R
O
O
(i)
O
3a–d
O
9a–d
Br
O
(ii)
R
R
H
O
O
O
R1
Taking into consideration that the available methodolo-
gies for synthesis of natural 5,7-dihydroxy-3-methylfla-
vones involve several steps, and consequently reduced
yields, we applied our procedure to the synthesis of new
3-methyl-5,7-dimethoxyflavones 8a,b (Scheme 1). These
flavones were obtained in moderate yields (Table 1, en-
tries 7 and 8), but in view of the fewer steps and purifica-
tions required, this process represents a significant
synthetic development for these materials.
(iii)
α
O
10a–d
PPh3Br
β
R1
11a R1 = H, R2 = H
11b R1 = OMe, R2 = H
11c R1 = Cl, R2 = H
11d R1 = NO2, R2 = H
11e R1 = H, R2 = NO2
11f R1 = H, R2 = OMe
Table 1 Optimization Studies on the Synthesis of 3-Methylflavones
3a–d and 8a,b
Scheme 2 Synthesis of (E)-3-styrylflavones 11a–f. Reagents and
conditions: (i) NBS, benzoyl peroxide, CCl4, reflux; (ii) Ph3P, anhy-
drous toluene, reflux; (iii) NaH, anhydrous THF, r.t.
Entry Product Equiv
Time
Time
Yield
of base before HCl (h) after HCl (h) (%)
1
2
3
4
5
6
7
8
3b
3b
3d
3a
3a
3c
8a
8b
4.5
4.7
4.7
5
3
2
45
41
44
72
44
25
25
13
80
74
40
70
90
40
31
The next step in our strategy was the synthesis of the 3-
(bromotriphenylphosphoranyl)methylflavones
10a–d
5
(Scheme 2), by the reaction of 3-bromomethylflavones
9a–d with triphenylphosphine in anhydrous toluene.19,20
In addition to the characteristic signals of the flavone moi-
ety, significant features of the 1H and 13C NMR spectra of
compounds 10a–d21 were the proton and carbon reso-
nances of the methylene group, both appearing as dou-
blets due to coupling with phosphorus (δΗ 5.19–5.48, J ~
14 Hz; δC 23.3–23.8, J ~ 50 Hz).
4.5
19
5
27
19
12
12
5
4.7
4.7
Following our earlier work on the synthesis of 3-styryl-
chromones using the Wittig reaction,22,23 3-(bromotriphe-
nylphosphoranyl)methylflavones 10a–d were used as the
sources of ylides for the synthesis of 3-styrylflavones
11a–f (Scheme 2).24,25 Products 11a–f were obtained in
moderate to good yields (45–80%) (Table 2), although all
attempts to improve the yields of this transformation were
not successful. However, careful analysis of the reaction
mixture allowed the isolation of the corresponding 3-
methylflavones 3a–d in yields from 19–40%.24 It was ob-
served that an electron-withdrawing group on the benz-
aldehyde improved the yield (80%, Table 2, entry 10)
compared with the unsubstituted case (70%, Table 2, en-
try 2); when an electron-donating group was present, it
was necessary to heat the reaction and the yield was lower
(65%, Table 2, entry 13).
The main feature of the 1H NMR spectra of the 3-methyl-
flavones was the singlet at δ 2.09–2.19 due to the 3-CH3
proton resonance.15 The aliphatic regions of the 1H NMR
spectra of 3-methyl-5,7-dimethoxyflavones 8a,b also
present singlets due to the 5- and 7-OCH3 groups at δ
3.87–3.96. Other important signals of these new 3-meth-
ylflavones are the aromatic proton resonances of H-6 and
H-8 at δ 6.34–6.36 and δ 6.44–6.45, respectively, with
typical meta-coupling constants (4J = 2.3 Hz).
Having established an efficient synthetic route for 3-
methylflavones, we next sought to use them in Wittig re-
actions toward the synthesis of 3-styrylflavones. The reac-
tions of 3-methylflavones with N-bromosuccinimide
(NBS) in the presence of benzoyl peroxide16 afforded the
desired 3-bromomethylflavones 9a–d in good yields (50–
It should be noted that all the 3-styrylflavones were ob-
tained with a trans-configured vinylic system (J ~ 16 Hz),
and this result is in accord with those previously reported
for the Heck reaction.26 The observed trans stereochemis-
try is in keeping with Wittig reactions involving stabilized
ylides.27,28 This indicates that the chromone nucleus acts
87%) (Scheme 2).17 Both the H and 13C NMR spectra
1
confirmed the structures of flavones 9a–d, the most im-
portant resonances being those due to the 3-CH2Br group
(δH 4.43–4.67; δC 24.4–33.7).18
Synlett 2013, 24, 2683–2686
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Methylflavones and (E)-3-Styrylflavones
2685
Phytochemistry 2007, 68, 1189. (d) Zhu, J. T. T.; Choi, R. C.
Y.; Chu, G. K. Y.; Cheung, A. W. H.; Gao, Q. T.; Li, J.;
Jiang, Z. Y.; Dong, T. T. X.; Tsim, K. W. K. J. Agric. Food
Chem. 2007, 55, 2438.
Table 2 Optimization of the Wittig Reactions in the Synthesis of
(E)-3-Styrylflavones 11a–f
Entry Product Equiv Time to ylide Time after
Yield
of base formation
(min)
aldehyde addition (%)
(h)
(5) (a) Park, K. Y.; Lee, S.-H.; Min, B.-K.; Lee, K.-S.; Choi, J.-
S.; Chung, S. R.; Min, K. R.; Kim, Y. Planta Med. 1999, 65,
457. (b) Nagaoka, T.; Banskota, A. H.; Tezuka, Y.;
Midorikawa, K.; Matsushige, K.; Kadota, S. Biol. Pharm.
Bull. 2003, 26, 487. (c) Moscatelli, V.; Hnatyszyn, O.;
Acevedo, C.; Megias, J.; Alcaraz, M. J.; Ferrana, G. Planta
Med. 2006, 72, 72.
(6) (a) Beyer, G.; Melzig, M. F. Planta Med. 2003, 69, 1125.
(b) Vaya, J.; Mahmood, S.; Goldblum, A.; Aviram, M.;
Volkova, N.; Shaalan, A.; Musa, R.; Tamir, S.
1
2
11a
11a
11b
11b
11b
11c
11c
11d
11d
11e
11e
11f
1
50
30
60
10
5
48
6
55
70
23
38
45
55
45
60
67
80
75
45
65
1.2
1
3
4
4
1
3
5
1.2
1.2
1
3 h 50 min
Phytochemistry 2003, 62, 89.
(7) Painuly, P.; Tandon, J. S. Phytochemistry 1983, 22, 243.
(8) Seixas, R. S. G. R.; Pinto, D. C. G. A.; Silva, A. M. S.;
Cavaleiro, J. A. S. Aust. J. Chem. 2008, 61, 718.
(9) Filipe, P.; Silva, A. M. S.; Seixas, R. S. G. R.; Pinto, D. C.
G. A.; Santos, A.; Patterson, L. K.; Silva, J. N.; Cavaleiro, J.
A. S.; Freitas, J. P.; Mazière, J.-C.; Santus, R.; Morlière, P.
Biochem. Pharmacol. 2009, 77, 957.
6
30
15
30
20
10
30
30
30
2 h 30 min
3 h 50 min
3
7
8
1.2
1.2
1.2
1.2
1.2
1.2
9
2 h 40 min
1
(10) Jayashree, B. S.; Alam, A.; Nayak, Y.; Kumar, D. V. Med.
Chem. Res. 2012, 21, 1991.
10
11
12
13
(11) Vaz, P. A. A. M.; Pinto, D. C. G. A.; Rocha, D. H. A.; Silva,
A. M. S.; Cavaleiro, J. A. S. Synlett 2012, 23, 2353.
(12) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675.
(13) 2-Propionylphenyl 4-Methoxybenzoate (4)
Yield: 46 mg (15%). 1H NMR (300.13 MHz, CDCl3):
δ = 1.11 (t, J = 7.2 Hz, 3 H, H-3), 2.92 (q, J = 7.2 Hz, 2 H,
H-2), 3.90 (s, 3 H, 4′′-OCH3), 7.00 (d, J = 9.0 Hz, 2 H, H-
3′′,5′′), 7.22 (dd, J = 1.3, 8.1 Hz, 1 H, H-3′), 7.34 (ddd,
J = 1.3, 7.0, 8.1 Hz, 1 H, H-5′), 7.55 (ddd, J = 1.3, 7.0, 8.1
Hz, 1 H, H-4′), 7.81 (dd, J = 1.3, 8.1 Hz, 1 H, H-6′), 8.16 (d,
J = 9.0 Hz, 2 H, H-2′′,6′′).
1 h 20 min
6
11f
2 (60 °C)
as an electron-withdrawing group and not as an electron-
donating group, as might be anticipated on considering
the conjugation present between the heterocyclic oxygen
atom and the ylide.
1-(2-Hydroxyphenyl)-3-(4-methoxyphenyl)-2-methyl-
propane-1,3-dione (5)
In conclusion, we have established a very efficient route
for the synthesis of 3-methylflavones, which can be suc-
cessfully applied in the synthesis of natural derivatives.
These compounds can also be transformed into phospho-
nium salts and used as the source of phosphorus ylides,
which can be further used in diastereoselective syntheses
of (E)-styrylflavones via a Wittig reaction.
Yield: 137 mg (30%). 1H NMR (300.13 MHz, CDCl3):
δ = 1.60 (d, J = 7.0 Hz, 3 H, 2-CH3), 3.87 (s, 3 H, 4′′-OCH3),
5.23 (q, J = 7.0 Hz, 1 H, H-2), 6.86 (ddd, J = 1.2, 7.2, 8.1 Hz,
1 H, H-5′), 6.95 (d, J = 8.1 Hz, 2 H, H-3′′,5′′), 7.00 (dd,
J = 1.2, 8.1 Hz, 1 H, H-3′), 7.46 (ddd, J = 1.2, 7.2, 8.1 Hz, 1
H, H-4′), 7.69 (dd, J = 1.2, 8.1 Hz, 1 H, H-6′), 7.95 (d,
J = 8.1 Hz, 2 H, H-2′′,6′′), 12.09 (s, 1 H, 2-OH).
2-[3-(4-Methoxyphenyl)-2-methyl-3-oxo-propanoyl]-
phenyl 4-Methoxybenzoate (6)
Acknowledgment
Yield: 77 mg (25%). 1H NMR (300.13 MHz, CDCl3):
δ = 1.48 (d, J = 7.0 Hz, 3 H, 2-CH3), 3.83 (s, 3 H, 4′′-OCH3),
3.88 (s, 3 H, 4′′′-OCH3), 5.07 (q, J = 7.0 Hz, 1 H, H-2), 6.80
(d, J = 9.0 Hz, 2 H, H-3′′,5′′), 6.93 (d, J = 9.0 Hz, 2 H, H-
3′′′,5′′′), 7.20 (dd, J = 1.1, 8.1 Hz, 1 H, H-6′), 7.32 (ddd,
J = 1.1, 7.0, 8.1 Hz, 1 H, H-5′), 7.53 (ddd, J = 1.1, 7.0, 8.1
Hz, 1 H, H-4′), 7.77 (dd, J = 1.1, 8.1 Hz, 1 H, H-3′), 7.81 (d,
J = 9.0 Hz, 2 H, H-2′′,6′′), 8.04 (d, J = 9.0 Hz, 2 H, H-
2′′′,6′′′).
Thanks are due to the University of Aveiro, ‘Fundação para a
Ciência e a Tecnologia’, European Union, QREN, FEDER and
COMPETE for funding the Organic Chemistry Research Unit (pro-
ject PEst-C/QUI/UI0062/2013) and the Portuguese National NMR
network. D.H.A. Rocha also thanks FCT for her PhD grant
(SFRH/BD/68991/2010).
References and Notes
(14) 3-Methylflavones 3a–d, 8a,b; General Procedure
2′-Hydroxypropiophenone (1) (0.15 mL, 1.09 mmol) was
dissolved in anhydrous toluene (5 mL) in a screw-cap vial,
equipped with a magnetic stir bar and sealed with a septum.
The solution was cooled to 0 °C under N2 and LiHMDS
(5.14 mL in THF, 5.13 mmol) was added quickly via a
syringe. The solution was stirred for approximately 30 min
before the addition of aroyl chloride 2a–d (1.42 mmol) in
one portion. The mixture was removed from the ice-bath and
stirred at r.t. for the appropriate period of time (Table 1). HCl
(4 mL, 37%) was added and the resulting solution stirred at
r.t. for the requisite amount of time (Table 1). H2O (50 mL)
(1) Andersen, Ø. M.; Markham, K. R. Flavonoids: Chemistry,
Biochemistry and Applications; Taylor & Francis: Boca
Raton, 2006.
(2) Birt, D. F.; Hendrich, S.; Wang, W. Pharmacol. Ther. 2001,
90, 157.
(3) Verma, A. K.; Pratap, R. Nat. Prod. Rep. 2010, 27, 1571.
(4) (a) Cummings, J.; Double, J. A.; Bibby, M. C.; Farmer, P.;
Evans, S.; Kerr, D. J.; Kaye, S. B.; Smyth, J. F. Cancer Res.
1989, 49, 3587. (b) Cárdenas, M.; Marder, M.; Blank, V. C.;
Roguin, L. P. Bioorg. Med. Chem. 2006, 14, 2966. (c) Lin,
Y.-P.; Hsu, F.-L.; Chen, C.-S.; Chern, J.-W.; Lee, M.-H.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2683–2686

2686
D. H. A. Rocha et al.
LETTER
(21) 3-(Bromotriphenylphosphoranyl)methyl-4′-chloro-
and ice (30 g) were added and the mixture was extracted with
EtOAc (3 × 30 mL). The organic layer was dried over
Na2SO4, filtered and evaporated under reduced pressure. The
residue was purified by column chromatography (gradient:
PE→PE–EtOAc, 4:1). After solvent evaporation, the
expected 3-methylflavones 3a–d and 8a,b were obtained in
very good yields (see Table 1).
flavone (10c)
Yield: 21 mg (64%); white powder; mp 282–284 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 5.33 (d, J = 13.8 Hz, 2 H,
3-CH2), 7.34 (ddd, J = 1.3, 7.0, 8.0 Hz, 1 H, H-6), 7.43 (br d,
J = 8.0 Hz, 1 H, H-8), 7.46–7.52 (m, 8 H, PPh3), 7.61–7.71
(m, 10 H, H-2′,6′, H-7 and 7 H of PPh3), 7.77 (dd, J = 1.3,
(15) 3-Methyl-5,7,4′-trimethoxyflavone (8b)
8.0 Hz, 1 H, H-5), 7.87 (d, J = 9.0 Hz, 2 H, H-3′,5′). 13
C
Yield: 110 mg (31%); white powder; mp 188–190 °C. 1H
NMR (500.13 MHz, CDCl3): δ = 2.10 (s, 3 H, 3-CH3), 3.87
(s, 3 H, 4′-OCH3), 3.88 (s, 3 H, 5-OCH3), 3.95 (s, 3 H, 7-
OCH3), 6.34 (d, J = 2.3 Hz, 1 H, H-6), 6.44 (d, J = 2.3 Hz, 1
H, H-8), 7.01 (d, J = 6.9 Hz, 2 H, H-3′,5′), 7.58 (d, J = 6.9
Hz, 2 H, H-2′,6′). 13C NMR (75.47 MHz, CDCl3): δ = 11.6
(3-CH3), 55.4 (5-OCH3), 55.6 (4′-OCH3), 56.2 (7-OCH3),
92.2 (C-8), 95.7 (C-6), 108.0 (C-4a), 113.7 (C-3′,5′), 118.5
(C-3), 125.7 (C-1′), 130.4 (C-2′,6′), 158.1 (C-2), 159.6 (C-
8a), 160.7 (C-7), 160.8 (C-4′), 163.6 (C-5), 177.8 (C-4). MS
(ESI): m/z (%) = 327 (100) [M + H]+, 349 (8) [M + Na]+.
HRMS (EI): m/z calcd for C19H18O5: 326.1154; found:
326.1153.
NMR (75.47 MHz, CDCl3): δ = 23.6 (d, J = 50.0 Hz, 3-
CH2), 111.8 (C-3), 118.0 (C-8), 119.1 (C-4a), 121.3 (C-1′),
125.4 (C-5), 125.7 (C-6), 129.5 (C-1 of PPh3), 129.7 (C-3,5
of PPh3), 129.9 (C-4 of PPh3), 130.6 (C-3′,5′), 133.9 (C-2,6
of PPh3), 134.5 (C-7), 134.6 (C-2′,6′), 137.8 (C-4′), 155.6
(C-8a), 163.7 (C-2), 176.4 (C-4). MS (ESI): m/z (%) = 531
(100) [35Cl, M]+, 532 (56) [35Cl, M + H]+, 533 (40) [37Cl,
M]+. HRMS (ESI): m/z calcd for C34H25ClO2P: 531.1264;
found: 531.1275.
(22) Sandulache, A.; Silva, A. M. S.; Pinto, D. C. G. A.; Almeida,
L. M. P. M.; Cavaleiro, J. A. S. New J. Chem. 2003, 27,
1592.
(23) Silva, V. L. M.; Silva, A. M. S.; Pinto, C. D. G. A.;
Cavaleiro, J. A. S.; Vasas, A.; Patonay, T. Monatsh. Chem.
2008, 139, 1307.
(24) (E)-3-Styrylflavones 11a–f; General Procedure
To a suspension of the appropriate 3-(bromotriphenyl-
phosphoranyl)methylflavone 10a–d (0.022 mmol) in THF
(20 mL) was added NaH (0.5 mg, 0.022 mmol) and the
mixture was stirred for the appropriate amount of time
(Table 2). The appearance of coloration and the
(16) Aoki, S.; Matsuo, Y.; Ogura, S.; Ohwada, H.; Hisamatsu, Y.;
Moromizato, S.; Shiro, M.; Kitamura, M. Inorg. Chem.
2011, 50, 806.
(17) 3-Bromomethylflavones 9a–d; General Procedure
To a solution of the appropriate 3-methylflavone 3a–d (0.17
mmol) in CCl4 (40 mL) was added benzoyl peroxide (8.2
mg, 0.033 mmol) and NBS (39 mg, 0.22 mmol). The mixture
was heated at reflux temperature under an N2 atm for 6–24 h
(depending on the substituent). The solvent was evaporated
and the residue was taken in CHCl3 (40 mL) and the obtained
solution washed with H2O (3 × 20 mL). The organic layer
was concentrated and purified by thin-layer chromatography
(CH2Cl2–hexane, 8:2) affording 3-bromomethylflavones
9a–d (9a, 87%; 9b, 50%; 9c, 50%; 9d, 60%).
disappearance of the suspension due to the phosphonium salt
was indicative of ylide formation. The appropriate
benzaldehyde (2.3 μL, 0.022 mmol) was added and the
mixture was stirred for the time given in Table 2. The solvent
was evaporated and the residue was taken in CH2Cl2 (20 mL)
and then washed with H2O (3 × 20 mL). The organic layer
was dried over anhydrous Na2SO4, filtered, concentrated and
purified by thin-layer chromatography (CH2Cl2) to give the
desired (E)-3-styrylflavones 11a–f (see yields in Table 2)
and 3-methylflavones 3a–d (3a, 19%; 3b, 40%; 3c, 28%; 3d,
20%).
(18) 3-Bromomethyl-4′-methoxyflavone (9b)
Yield: 30 mg (50%); yellow powder; mp 161–163 °C. 1H
NMR (500.13 MHz, CDCl3): δ = 3.90 (s, 3 H, 4′-OCH3),
4.67 (s, 2 H, 3-CH2), 7.05 (d, J = 8.9 Hz, 2 H, H-3′,5′), 7.42
(br dd, J = 7.0, 8.0 Hz, 1 H, H-6), 7.49 (br d, J = 8.0 Hz, 1 H,
H-8), 7.68 (ddd, J = 1.6, 7.0, 8.0 Hz, 1 H, H-7), 7.74 (d,
J = 8.9 Hz, 2 H, H-2′,6′), 8.24 (dd, J = 1.6, 8.0 Hz, 1 H, H-
5). 13C NMR (75.47 MHz, CDCl3): δ = 30.9 (3-CH2), 55.5
(4′-OCH3), 114.2 (C-3′,5′), 117.9 (C-8), 118.1 (C-3), 122.7
(C-4a), 125.3 (C-6), 126.1 (C-5), 130.0 (C-2′,6′), 130.3 (C-
1′), 133.9 (C-7), 156.0 (C-8a), 161.8 (C-4′), 163.8 (C-2),
176.6 (C-4). MS (ESI): m/z (%) = 345 (47) [79Br, M]+, 347
(40) [81Br, M]+, 367 (100) [79Br, M + Na]+, 369 (90) [81Br, M
+ Na]+. HRMS (ESI): m/z calcd for C17H13BrO3: 345.0133;
found: 345.0142.
(25) (E)-3-(4-Nitrostyryl)flavone (11d)
Yield: 6 mg (67%); orange powder; mp 174–176 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 6.72 (d, J = 16.2 Hz, 1 H,
H-α), 7.26–7.30 (m, 1 H, H-4′′), 7.33 (t, J = 7.9 Hz, 2 H, H-
3′′,5′′), 7.38 (br d, J = 7.9 Hz, 2 H, H-2′′,6′′), 7.48 (ddd,
J = 1.7, 7.2, 8.3 Hz, 1 H, H-6), 7.52 (dd, J = 1.7, 7.2 Hz, 1
H, H-8), 7.73 (ddd, J = 1.7, 7.2, 8.3 Hz, 1 H, H-7), 7.95 (d,
J = 16.2 Hz, 1 H, H-β), 7.97 (d, J = 9.1 Hz, 2 H, H-2′,6′),
8.33 (dd, J = 1.7, 7.2 Hz, 1 H, H-5), 8.40 (d, J = 9.1 Hz, 2 H,
H-3′,5′). 13C NMR (75.47 MHz, CDCl3): δ = 117.8 (C-8),
118.6 (C-α), 118.9 (C-3), 123.4 (C-4a), 123.7 (C-3′,5′),
125.5 (C-6), 126.4 (C-5), 126.6 (C-2′′,6′′), 128.1 (C-4′′),
128.7 (C-3′′,5′′), 130.9 (C-2′,6′), 133.9 (C-7), 136.3 (C-β),
137.5 (C-1′′), 139.2 (C-1′), 148.7 (C-4′), 155.4 (C-8a), 159.6
(C-2), 177.1 (C-4). MS (ESI): m/z (%) = 370 (60) [M + H]+,
392 (99) [M + Na]+. HRMS (ESI): m/z calcd for C23H15NO4:
369.1001; found: 369.1003.
(19) Das, J.; Ghosh, S. Tetrahedron Lett. 2011, 52, 7189.
(20) 3-(Bromotriphenylphosphoranyl)methylflavones 10a–d;
General Procedure
To a solution of the appropriate 3-bromomethylflavone 9a–
d (0.06 mmol) in anhydrous toluene (10 mL) was added
PPh3 (16 mg, 0.06 mmol). The mixture was heated at reflux
temperature under an N2 atm for 24 h, after which the solvent
was evaporated to give the corresponding 3-(bromotriphenyl-
phosphoranyl)methylflavone 10a–d (10a, 67%; 10b, 58%;
10c, 64%; 10d, 60%).
(26) Rocha, D. H. A.; Pinto, D. C. G. A.; Silva, A. M. S.; Patonay,
T.; Cavaleiro, J. A. S. Synlett 2012, 23, 559.
(27) Vedejs, E. J. Org. Chem. 2004, 69, 5159.
(28) Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey, J. N.
J. Am. Chem. Soc. 2005, 127, 13468.
Synlett 2013, 24, 2683–2686
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