A new synthesis of 5-arylbenzo[c]xanthones from photoinduced electrocyclisation and oxidation of (E)-3-styrylflavones

Article abstract of DOI:10.1055/s-0031-1290355

A new synthetic route to 5-arylbenzo[c]xanthones is -established. This was accomplished by use the Heck reaction of 3-bromoflavones with styrene derivatives, leading to (E)-3-styrylflavones with total diastereoselectivity. This transformation was greatly improved under microwave irradiation. The one-pot, photoinduced electrocyclisation of (E)-3-styrylflavones and further in situ oxidation of the cycloadduct leads to 5-arylbenzo[c]xan-thones. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290355

LETTER
559
A New Synthesis of 5-Arylbenzo[c]xanthones from Photoinduced
Electrocyclisation and Oxidation of (E)-3-Styrylflavones
S
ynthesis of 5-Ary
j
lbenzo
e
[
c
]xanthone
n
s
isa H. A. Rocha,a Diana C. G. A. Pinto,*a Artur M. S. Silva,*a Tamás Patonay,b José A. S. Cavaleiroa
a
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt; E-mail: diana@ua.pt
b
Department of Organic Chemistry, University of Debrecen, 4010 Debrecen, Hungary
Received 17 November 2011
styrylflavones 4a–g plays a key role in the new synthetic
procedure.
Abstract: A new synthetic route to 5-arylbenzo[c]xanthones is
established. This was accomplished by use the Heck reaction of 3-
bromoflavones with styrene derivatives, leading to (E)-3-styrylfla-
vones with total diastereoselectivity. This transformation was great-
ly improved under microwave irradiation. The one-pot,
photoinduced electrocyclisation of (E)-3-styrylflavones and further
in situ oxidation of the cycloadduct leads to 5-arylbenzo[c]xan-
thones.
Initially, we studied the synthesis of 3-bromoflavones 2a–
f
by treating 3-aryl-1-(2-hydroxyphenyl)propan-1,3-
diones 1a–f with phenyltrimethylammonium tribromide
(PTT),12 in a one-pot method in which bromination and
cyclisation occurred leading to the formation of 3-bromo-
chromones in moderate yields.14 However, in this work,
the expected bromo-derivatives were obtained in only
modest yields, with the highest being obtained with 3-bro-
mo-4-methylflavone15 (2b; 45%) and the lowest with 3-
bromo-3,4-dimethoxyflavone (2f; 32%). Since our results
were not satisfactory, mostly because the corresponding
non-brominated flavones were obtained as by-products,
we investigated other methodologies. The direct bromina-
tion of flavones using pyridinium bromide perbromide16
or N-bromosuccinimide,17 and also microwave irradia-
tion,18 were attempted, but in all cases the results were un-
satisfactory, with the desired 3-bromo-flavones being
obtained in poor yields (up to 20%).19
Key words: microwave irradiation, Heck reaction, photocyclisa-
tion, oxidation
The xanthone ring system is a structural motif present in
natural products and prevalent in higher plant families
such as Guttiferae and Gentianaceae.1 Both natural and
synthetic derivatives are often endowed with interesting
pharmacological properties, such as anti-inflammatory,2
antitumour3 and antioxidant activity.4 To the best of our
knowledge, benzo[c]xanthones and 3-styrylflavones are
not found in natural sources and their syntheses are
scarce.5 On the other hand, related compounds, such as
benzo[a] and benzo[b]xanthones exhibit appealing phar-
macological properties. For instance, antibacterial and
fungicidal activities,6 a-glucosidase inhibition7 and cyto-
toxicity against L1210 cells8 have been described.
These results, together with the fact that the first method
involves fewer reaction steps and can be applied to deriv-
atives bearing either electron-donating or electron-with-
drawing groups, meant that the initial approach was used
to obtain 3-bromoflavones 2a–f. The most important fea-
tures in the NMR spectra of 3-bromoflavones 2a–f are: (i)
the resonances of the deshielded aromatic protons H-5 and
H-7 at d = 8.29–8.31 and 7.72–7.78 ppm, due to the me-
someric (both protons) and anisotropic (H-5) deshielding
effect of the carbonyl group; (ii) the absence of the typical
H-3 signal of flavones, which generally appears as a sin-
glet at d = 6–7 ppm; and (iii) the resonances of C-3 and C-
4 carbon atoms appearing at, respectively, d = 108.6–
110.8 and 172.6–173.3 ppm.
The next step in our strategy was the Heck reaction9b,12,20
of 3-bromoflavones 2a–f with styrene 3a. A study to find
the optimal reaction conditions (palladium catalysts, sol-
vent, reaction time and heating conditions) was carried
out (Table 1). Attempts were made to take advantage of
the beneficial effects of microwave (MW) irradiation in
synthesis,21 and using the Jeffery reaction conditions,22
since they are reported to improve the yields of the Heck
reaction; however, (E)-3-styrylflavone 4a was only ob-
tained in poor yields (Table 1, entries 1–4). Lowering the
MW irradiation power allowed 4a to be obtained in good
yields (Table 1, entry 5). Changing the palladium source
Following our research interests in the synthesis of 3-
styrylchromone9 and benzoxanthone derivatives,5d,10
along with the fact that new synthetic routes towards these
compounds are of significance in both synthetic and me-
dicinal chemistry, a program aimed at the synthesis of (E)-
3-styrylflavones 4a–g and their photoinduced electrocy-
clisation and oxidation into 5-arylbenzo[c]xanthones 5a–
h was set up (Scheme 1). One important transformation in
this synthetic route is the Heck reaction of 3-bromofla-
vones 2a–f with styrene derivatives 3a and 3b. The Heck
reaction is widely used in synthetic chemistry as it is one
of the most noteworthy methodologies for carbon–carbon
bond formation,11 however, it has rarely been used in the
field of oxygen heterocycles.9b,12 Photoinduced reactions
have played important roles in building diverse organic
frameworks that are otherwise difficult to make.13 In our
case, the photoinduced electrocyclisation of (E)-3-
SYNLETT 2012, 23, 559–564
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 13.02.2012
DOI: 10.1055/s-0031-1290355; Art ID: D68311ST
© Georg Thieme Verlag Stuttgart · New York

560
D. H. A. Rocha et al.
LETTER
R2'
2
5'
R1
R2
R1
R2
3
R1
R2
6'
1
B
11
8
8
4
R1
(i)
O
O
2
3
O
10
7
6
(ii)
(iii)
2'
A
5
R3
R4
7
α
9
R2
5
Br
OH
O
HO
6
6''
3''
R3
R4
O
O
β
O
2
R4
1
4
5
R3
3
2''
1a,2a R1, R2 = H
3a R3, R4 = H
4a R1, R2, R3, R4 = H
4b R2, R3, R4 = H, R1 = Me
5a R1, R2, R2', R3, R4 = H
1b,2b R2 = H, R1 = Me
1c,2c R2 = H, R1 = OMe
1d,2d R2 = H, R1 = Cl
1e,2e R2 = H, R1 = NO2
1f,2f R2, R1 = OMe
diketone
form
3b R3, R4 = OMe
5b R2, R2', R3, R4 = H, R1 = Me
5c R2, R2', R3, R4 = H, R1 = OMe
5d R2, R2', R3, R4 = H, R1 = Cl
5e R2, R2', R3, R4 = H, R1 = NO2
5f R2, R1 = OMe, R2', R3, R4 = H
5g R2', R1 = OMe, R2, R3, R4 = H
5h R3, R4 = OMe, R1, R2, R2' = H
4c R2 , R3, R4 = H, R1 = OMe
4d R2, R3, R4 = H, R1 = Cl
4e R2, R3, R4 = H, R1 = NO2
4f R2, R1 = OMe, R3, R4 = H
4g R3, R4 = OMe, R1, R2 = H
(i) PTT, THF, r.t., 24–48 h
(ii) Pd(OAc)2, K2CO3, (Bu)4NBr, DMF, 300 W, 5–10 min
(iii) 1,2,4-trichlorobenzene, I2, hν
Scheme 1
did not improve our results (Table 1, entries 6 and 7), nor NMR spectroscopic assignments were possible due to
did using classical heating conditions (Table 1, entry 8). HSQC and HMBC experiments, and the most noticeable
In the latter case, the reaction time was clearly too long carbon resonances appeared at d = 177.1–177.6 ppm (C-
(3 h) compared with the reaction time under MW irradia- 4), and at d = 118.3–120.4 and 133.9–136.3 ppm, due to
tion (10 min).
the vinylic C-a and C-b, respectively.
The Heck/Jeffery reaction conditions were extended to Following our interest in thermal electrocyclisations,12,25
the reaction of 3-bromoflavones 2b–f with styrene 3a,23 (E)-3-styrylflavones 4a–g were heated at reflux in 1,2,4-
and the corresponding (E)-3-styrylflavone derivatives trichlorobenzene, however, all attempts to cyclise the
4b–f were obtained in moderate to good yields (46%). The compounds failed, even when iodine26 was used as cata-
reaction of 3-bromoflavone (2a) with 3,4-dimethoxysty- lyst or microwave radiation as heating source (Table 2,
rene (3b) also yielded the expected (E)-3-styrylflavone entries 1–4). Knowing that photoinduced electrocyclisa-
4g24 in good yield (63%).
tions can be a successful methodology,5c a chloroform so-
lution of (E)-3-styrylflavone 4a was irradiated with a
halogen white-light projector; under these conditions, the
desired 5-phenyl-7H-benzo[c]xanthen-7-one (5a)27 was
obtained, albeit in poor yield (Table 2, entry 5). Some
starting material 4a was recovered (50%) and the by-prod-
uct, 5-phenyl-5H-benzo[c]xanthen-7(6H)-one (6a)28 was
also obtained (8%; Scheme 2). The most important fea-
tures in the 1H NMR spectrum of 6a are the double dou-
blets at d = 3.24, 3.33 and 4.32 ppm, assigned respectively
to the resonances of H-6cis, H-6trans, and H-5. In the 13C
The main features in the 1H NMR spectra of (E)-3-styryl-
flavones are the resonances of H-a and H-b, which appear
as two doublets at d = 6.72–6.88 and 7.95–8.04 ppm, re-
spectively. The coupling constant for these protons (J ~17
Hz) indicates a trans configuration for this vinylic system.
The higher frequency values of H-b resonances are due to
the anisotropic deshielding effect of the carbonyl group.
The depicted 3-styryl group conformation was also con-
firmed by NOESY experiments in which NOE correla-
tions between H-a and H-2¢,6¢ were observed. The 13C
Table 1 Synthesis of (E)-3-Styrylflavone 4a
Entry
Reagents
Solvent
NMP
DMF
DMF
NMP
DMF
DMF
DMF
DMF
Heating
Time (min)
Yield 4a (%)a
1
2
3
4
5
6
7
8
Pd(OAc)2, K2CO3, KCl, TBAB, DABCO
Pd(OAc)2, K2CO3, TBAB
Pd(OAc)2, K2CO3, NBu4HSO4
Pd(OAc)2, K2CO3, TBAB
Pd(OAc)2, K2CO3, TBAB
PdCl2(PPh3)2, K2CO3, TBAB
Pd(Ph3)4, K2CO3, TBAB
Pd(OAc)2, K2CO3, TBAB
400 W (MW)
400 W (MW)
400 W (MW)
400 W (MW)
300 W (MW)
300 W (MW)
300 W (MW)
150 °C
15
35
40
–
10
10
10
25
72
40
37
45
10
10
10
1–3 h
a Maximum yield obtained.
Synlett 2012, 23, 559–564
© Thieme Stuttgart · New York

LETTER
Synthesis of 5-Arylbenzo[c]xanthones
561
Table 2 Synthesis of 5-Arylbenzo[c]xanthone 5a
NMR spectrum, the aliphatic resonances of C-6 and C-5
at d = 27.2 and 43.1 ppm, respectively, and the carbonyl
carbon at d = 177.2 ppm should be highlighted. The most
Entry Conditionsa
Heating
Time (d) Yield 6a Yield 5a
(%)b
(%)
1
noticeable signal from the H NMR spectrum of ben-
1
2
3
4
5
6
7
8
TCB
230 °C
230 °C
230 °C
400 W
500 Wc
r.t.
3
–
–
zo[c]xanthen-7-one (5a) is the singlet at d = 8.24 ppm as-
signed to H-6, which resonates at high frequency values
due to the carbonyl anisotropic deshielding effect.
TCB, I2
TCB, I2
TCB, I2
CHCl3
3
–
–
7
–
–
Since the previous procedures in the synthesis of ben-
zo[c]xanthen-7-one 5a did not give satisfactory results, an
attempt using daylight in the presence or absence of io-
dine was carried out, but, once again, the desired product
was obtained in only poor yield (Table 2, entries 6 and 7).
These results, together with the fact that the use of a mer-
cury lamp seems to be a good method for a photocycliza-
tion process to give a dihydrobenzo[c]xanthone,5a led us
to use a high pressure mercury UV lamp. This procedure
led us to develop a new synthetic route for 5-phenyl-7H-
benzo[c]xanthen-7-one (5a)29 (Table 2, entry 8). We then
successfully extended this method to the other derivatives,
except for 3-nitro-5-phenyl-7H-benzo[c]xanthen-7-one
(5e), which was obtained in low yield.29 This low yield
can be explained by the formation of 6-hydroxy-3-nitro-
45 min
–
–
7
7
5
8
15b
14b
17b
70d
CHCl3
15
10
–
TCB, I2
r.t.
TCB, I2, hu
400 W
a TCB = 1,2,4-trichlorobenzene.
b Maximum yield obtained.
c Halogen white light projector;
d Average yield.
The appearance of this 6-hydroxyl group can be envisaged
from the reaction mechanism (Scheme 3). After electro-
cyclisation and rearomatisation of I, the intermediate 6
can be directly oxidised to compounds 5; this is the main
pathway for derivatives having electron-donating R sub-
stituents (e.g., 4b). In the case of strong electron-with-
drawing groups (R = NO2; 4e), the loss of the acidic
methylenic H-6 proton generates diene II, which may re-
act with singlet oxygen leading to the formation of cy-
cloadduct III (Scheme 3). The latter can rearrange to
hydroperoxide IV, which can dehydrate, as reported by
others authors in similar circumstances,31 to give a ketone
that undergoes a keto-enol tautomerism to afford a com-
pletely aromatised 3-nitro-5-phenyl-7H-benzo[c]xan-
then-7-one (7e). To confirm this idea, reactions of 4b and
4e were repeated in the presence of methylene blue, which
is a known singlet oxygen sensitiser.31 Under these condi-
tions, 4e was only transformed into 5e and the yield of
xanthone 7e improved to 86%, confirming the involve-
ment of singlet oxygen in the unexpected formation of 7e.
5-phenyl-7H-benzo[c]xanthen-7-one30
(7e;
54%,
Scheme 2). The 1H NMR spectrum of 7e shows, in addi-
tion to the benzo[c]xanthone protons, a singlet at d =
12.71 ppm due to a hydroxyl group proton involved in a
hydrogen bond with a carbonyl group. This data, the dis-
appearance of the typical H-6 singlet of 5-aryl-ben-
zo[c]xanthone 5a, and the HMBC connectivities
unequivocally prove the structure of 7e (Scheme 2).
NO2
O
O
O
HO
O
7e
6a
OMe
OMe
OMe
OMe
O
O
O
O
6'
2'
Photoinduced electrocyclisation and oxidation processes
of (E)-3,4-dimethoxy-3-styrylflavone (4f) yielded two
isomers, 3,4-dimethoxy-5-phenyl-7H-benzo[c]xanthen-
7-one (5f) and 2,3-dimethoxy-5-phenyl-7H-benzo[c]xan-
then-7-one (5g), with the latter being formed as the major
product. The free rotation of the (E)-3,4-dimethoxy-3-
styrylflavone B ring allowed two possible sites for elec-
trocyclisation, C-2¢ or C-6¢. Probably due to some steric
hindrance between the 3¢-OMe group and the styryl
group, the cyclisation at C-6¢ is favourable (Scheme 2).
Unequivocal proof for the proposed structures was mainly
based on the 1H and 13C NMR spectra. The 1H NMR spec-
trum of compound 5f32 shows, in addition to the phenyl-
xanthone moiety protons, two doublets at d = 7.49 and
8.60 ppm (J = 9.2 Hz), due to the resonance of H-2 and H-
1, respectively. In the case of 5g,33 the 1H NMR spectrum
shows, in addition to the phenylxanthone moiety protons,
OMe
2
OMe
OMe
OMe
1
1
O
O
4
O
O
5g
5f
Scheme 2 Structures of 5-phenyl-5H-benzo[c]xanthen-7(6H)-one
(6a), 6-hydroxy-3-nitro-5-phenyl-7H-benzo[c]xanthen-7-one (7e)
and formation of 3,4-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-
one (5f) and 2,3-dimethoxy-5-phenyl-7H-benzo[c]xanthen-7-one
(5g)
© Thieme Stuttgart · New York
Synlett 2012, 23, 559–564

562
D. H. A. Rocha et al.
LETTER
R
R
R
O
O
O
O
O
H
H
H
6
H
H
O
I
6
4e
O
N
O
N
R
O
O
O
O
O
O
O
O
O
H
H
H
O
5
III
II
NO2
NO2
NO2
O
O
O
O
H
– H2O
OH
O
O2H
O
O
IV
V
7e
Scheme 3
(3) (a) Shadid, K. A.; Shaari, K.; Abas, F.; Israf, D. A.; Hamzah,
A. S.; Syakroni, N.; Saha, K.; Lajis, N. H. j. Phytochemistry
2007, 68, 2537. (b) Ee, G. C. L.; Daud, S.; Izzaddin, S. A.;
Rahmani, M. J. Asian Nat. Prod. Res. 2008, 10, 475.
(4) Suvarnakuta, P.; Chaweerungrat, C.; Devahastin, S. Food
Chem. 2011, 125, 240.
two singlets at d = 7.34 and 8.01 ppm, due to the reso-
nance of protons H-4 and H-1, respectively. The higher
frequency values of the H-1 resonances in both cases can
be attributed to the through-space deshielding effect of the
heterocyclic oxygen atom.
(5) (a) Goyal, S.; Parthasarathy, M. R. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1992, 31, 391. (b) Lokshin,
V.; Heynderickx, A.; Samat, A.; Pèpe, G.; Guglielmetti, R.
Tetrahedron Lett. 1999, 40, 6761. (c) Clarke, D. S.;
Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M. Tetrahedron
Lett. 2005, 46, 5515. (d) Brito, C. M.; Pinto, D. C. G. A.;
Silva, A. M. S.; Silva, A. M. G.; Tomé, A. C.; Cavaleiro, J.
A. S. Eur. J. Org. Chem. 2006, 2558. (e) Xu, W.-Z.; Huang,
Z.-T.; Zheng, Q.-T. J. Org. Chem. 2008, 73, 5606.
(6) Sonawane, S. A.; Chavan, V. P.; Shingare, M. S.; Karale,
B. K. Indian J. Heterocycl. Chem. 2002, 12, 65.
In conclusion, a successful methodology for the synthesis
of (E)-3-styrylflavones using microwave irradiation to
perform the Heck reaction of 3-bromoflavones with sty-
rene has been developed. The beneficial effects of micro-
wave irradiation were a reduction in reaction time (from
more than 1 h to 10 min or less), and an improvement in
product yield (from 45 to 73%). Photoinduced electro-
cyclisation and oxidation processes undergone by (E)-3-
styrylflavones with a high-pressure mercury lamp led to a
new synthetic route to 5-arylbenzo[c]xanthones in moder-
ate yields.
(7) Liu, Y.; Ma, L.; Chen, W.-H.; Wang, B.; Xu, Z.-L. Bioorg.
Med. Chem. 2007, 15, 2810.
(8) Sittisombut, C.; Boutefnouchet, S.; Van-Dufat, H. T.; Tian,
W.; Michel, S.; Koch, M.; Tillequin, F.; Pfeiffer, B.; Pierré,
A. Chem. Pharm. Bull. 2006, 54, 1113.
Acknowledgment
(9) (a) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.;
Cavaleiro, J. A. S.; Vasas, A.; Patonay, T. Monatsh. Chem.
2008, 139, 1307. (b) Patonay, T.; Vasas, A.; Kiss-Szikszai,
A.; Silva, A. M. S.; Cavaleiro, J. A. S. Austr. J. Chem. 2010,
63, 1592; and references cited therein.
(10) Sandulache, A.; Silva, A. M. S.; Cavaleiro, J. A. S.
Tetrahedron 2002, 58, 105.
Thanks are due to the University of Aveiro, Fundação para a Ciên-
cia e a Tecnologia (FCT) and FEDER for funding the Organic
Chemistry Research Unit (project PEst-C/QUI/UI0062/2011) and
the grants to D.H.A.R. (BI/UI51/4889/2010 and SFRH/BD/68991/
2010). We are also grateful to the Portuguese National NMR Net-
work (RNRMN) supported with funds from FCT.
(11) (a) Heck, R. F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37,
2330. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009.
(12) (a) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S.
Synlett 2007, 3113. (b) Santos, C. M. M.; Silva, A. M. S.;
Cavaleiro, J. A. S. Eur. J. Org. Chem. 2009, 2642.
(13) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
(14) Optimised procedure for the synthesis of 3-bromo-
flavones 2a–f: Phenyltrimethylammonium tribromide (0.94
g, 2.45 mmol) was added to an anhydrous THF (30 mL)
References and Notes
(1) (a) Roberts, J. C. Chem. Rev. 1961, 38, 591. (b) Gales, L.;
Damas, A. M. Curr. Med. Chem. 2005, 12, 2499.
(2) Park, H. H.; Park, Y.-D.; Han, J.-M.; Im, K.-R.; Lee, B. W.;
Jeong, I. Y.; Jeong, T.-S.; Lee, W. S. Bioorg. Med. Chem.
Lett. 2006, 16, 5580.
Synlett 2012, 23, 559–564
© Thieme Stuttgart · New York

LETTER
solution of the appropriate 3-aryl-1-(2-hydroxyphenyl)-
Synthesis of 5-Arylbenzo[c]xanthones
563
73 mg (70%); 4d: 66 mg (62%); 4e: 55 mg (50%); 4f: 51 mg
(45%)]. The reaction of 3-bromoflavone 2a (0.296 mmol)
with styrene 3b (1.48 mmol), under the same reaction
conditions, yielded 3-(3,4-dimethoxystyryl)flavone 4g (72
mg, 63%)
propan-1,3-dione 1a–f (1.63 mmol). The reaction mixture
was stirred at room temperature for 24–48 h. After that
period, the reaction mixture was poured into a mixture of ice
(10 g) and water (30 mL), stirred for 30 min, and extracted
with chloroform (3 × 20 mL). The combined extracts were
dried over sodium sulfate and evaporated to dryness. The
obtained residue was purified by TLC (CH2Cl2–light
petroleum, 9:1). After solvent evaporation, the obtained
residue was recrystallised from ethanol giving 3-
bromoflavones 2a–f [2a: 196 mg (40%); 2b: 226 mg (44%);
2c: 343 mg (45%); 2d: 230 mg (42%); 2e: 237 mg (42%); 2f:
188 mg (32%)]
(24) (E)-3-(3,4-Dimethoxystyryl)flavone (4g): Yellow solid;
mp 158–160 °C. 1H NMR (300.13 MHz, CDCl3): d = 3.86
(s, 3 H, 4¢¢-OCH3), 3.88 (s, 3 H, 3¢¢-OCH3), 6.72 (d,
J = 16.2 Hz, 1 H, H-a), 6.82 (d, J = 8.1 Hz, 1 H, H-5¢¢), 6.93
(d, J = 1.6 Hz, 1 H, H-2¢¢), 6.95 (d, J = 9.2 Hz, 1 H, H-6¢¢),
7.44 (ddd, J = 1.7, 7.1, 8.3 Hz, 1 H, H-6), 7.51 (dd, J = 1.7,
8.3 Hz, 1 H, H-8), 7.53–7.58 (m, 3 H, H-3¢,4¢,5¢), 7.69 (ddd,
J = 1.7, 7.1, 8.3 Hz, 1 H, H-7), 7.76–7.79 (m, 2 H, H-2¢,6¢),
7.95 (d, J = 16.2 Hz, 1 H, H-b), 8.33 (dd, J = 1.7, 8.3 Hz,
1 H, H-5). 13C NMR (75.47 MHz, CDCl3): d = 55.8 (4¢¢-
OCH3), 55.9 (3¢¢-OCH3), 109.3 (C-2¢¢), 111.2 (C-5¢¢), 117.8
(C-3), 117.9 (C-8), 118.3 (C-a), 119.3 (C-6¢¢), 123.5 (C-10),
125.1 (C-6), 126.3 (C-5), 128.4 (C-3¢,5¢), 129.9 (C-2¢,6¢),
130.6 (C-4¢), 131.3 (C-1¢¢), 133.3 (C-1¢), 133.4 (C-7), 134.1
(C-b), 148.8 (C-3¢¢), 148.9 (C-4¢¢), 155.4 (C-9), 162.5 (C-2),
177.6 (C-4). MS (ESI+): m/z (%) = 385 (100) [M + H]+, 407
(20) [M + Na]+. Anal. Calcd for C25H20O4 (384.42): C,
78.11; H, 5.24. Found: C, 78.15; H, 5.31
(15) 3-Bromo-4-methylflavone (2b): Yellow solid; mp 146–
148 °C. 1H NMR (300.13 MHz, CDCl3): d = 2.47 (s, 3 H, 4¢-
CH3), 7.34 (d, J = 8.2 Hz, 2 H, H-3¢,5¢), 7.44 (br dd, J = 7.1,
8.3 Hz, 1 H, H-6), 7.51 (br d, J = 8.3 Hz, 1 H, H-8), 7.72
(ddd, J = 1.7, 7.1, 8.1 Hz, 1 H, H-7), 7.78 (d, J = 8.2 Hz,
2 H, H-2¢,6¢), 8.31 (dd, J = 1.7, 8.3 Hz, 1 H, H-5). 13C NMR
(75.47 MHz, CDCl3): d = 21.6 (4¢-CH3), 108.9 (C-3), 117.8
(C-8), 121.8 (C-10), 125.6 (C-6), 126.5 (C-5), 129.0 (C-
3¢,5¢), 129.3 (C-2¢,6¢), 133.7 (C-1¢), 134.1 (C-7), 141.7 (C-
4¢), 155.6 (C-9), 162.1 (C-2), 173.2 (C-4). MS (ESI+): m/z
(%) = 315 (100) ([M + H]+, 79Br), 317 (90) ([M + H]+, 81Br),
337 (87) ([M + Na]+, 79Br), 339 (83) ([M + Na]+, 81Br). Anal.
Calcd for C16H11O2Br (315.16): C, 60.98; H, 3.52. Found: C,
60.88; H, 3.52
(16) Joo, Y. H.; Kim, J. K. Synth. Commun. 1998, 28, 4287.
(17) Miyake, H.; Nishino, S.; Nishimura, A.; Sasaki, M. Chem.
Lett. 2007, 36, 522.
(18) Rinker, B.; Schnakenburg, G.; Nieger, M.; Waldvogel, S. R.
Synthesis 2011, 0593.
(19) Rocha D. H. A., Pinto D. C. G. A., Silva A. M. S., Patonay
T., Cavaleiro J. A. S.; unpublished results
(20) (a) Fitzmaurice, R. J.; Etheridge, Z. C.; Jumel, E.; Woolfson,
D. N.; Caddick, S. Chem. Commun. 2006, 4814.
(25) Silva, V. L. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett
2010, 2565.
(26) Yamashita, S. Bull. Chem. Soc. Jpn. 1961, 34, 487.
(27) 5-Phenyl-7H-benzo[c]xanthen-7-one (5a): Mp 197–
198 °C. 1H NMR (300.13 MHz, CDCl3): d = 7.47 (br dd,
J = 7.0, 8.0 Hz, 1 H, H-9), 7.47–7.50 (m, 1 H, H-4¢), 7.52–
7.54 (m, 4 H, H-2¢,3¢,5¢,6¢), 7.67 (ddd, J = 1.5, 6.2, 8.0 Hz,
1 H, H-3), 7.74 (ddd, J = 1.5, 6.2, 8.0 Hz, 1 H, H-2), 7.75 (br
d, J = 8.0 Hz, 1 H, H-11), 7.81 (ddd, J = 1.3, 7.0, 8.0 Hz,
1 H, H-10), 8.02 (dd, J = 1.5, 8.0 Hz, 1 H, H-4), 8.24 (s, 1 H,
H-6), 8.44 (dd, J = 1.3, 8.0 Hz, 1 H, H-8), 8.81 (dd, J = 1.5,
8.0 Hz, 1 H, H-1). 13C NMR (75.47 MHz, CDCl3): d = 117.1
(C-6a), 118.1 (C-11), 121.9 (C-6), 122.5 (C-7a), 123.1 (C-1),
124.4 (C-12b), 124.5 (C-9), 126.6 (C-2), 126.7 (C-4), 126.8
(C-8), 127.6 (C-4¢), 128.4 (C-2¢,6¢), 129.6 (C-3), 130.1 (C-
3¢,5¢), 132.1 (C-10), 133.7 (C-4a), 134.4 (C-5), 136.6 (C-1¢),
155.8 (C-12a), 168.4 (C-11a), 177.2 (C-7). MS (ESI+): m/z
(%) = 323 (100) [M + H]+, 345 (22) [M + Na]+. MS (EI+):
m/z calcd for C23H14O2: 322.0994; found: 322.0995
(b) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41,
629.
(21) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Kappe, C. O.; Dallinger, D. Nat. Drug Discovery 2006,
5, 51.
(22) (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667. (b)Jeffery,
T. Synthesis 1987, 70. (c) Woodcock, S.; Branchaud, B. P.
Tetrahedron Lett. 2005, 46, 7213. (d) Pan, K.; Noël, S.;
Pinel, C.; Djakovitch, L. J. Organomet. Chem. 2008, 693,
2863.
(28) 5-Phenyl-5H-benzo[c]xanthen-7(6H)-one (6a): 1H NMR
(300.13 MHz, CDCl3): d = 3.24 (dd, J = 9.0, 16.5 Hz, 1 H,
H-6cis), 3.33 (dd, J = 7.3, 16.5 Hz, 1 H, H-6trans), 4.32 (dd,
J = 7.3, 9.0 Hz, 1 H, H-5), 7.06 (dd, J = 7.6 Hz, 1 H, H-2),
7.18–7.23 (m, 2 H, H- 3¢,5¢), 7.23–7.26 (m, 1 H, H-4), 7.27–
7.32 (m, 2 H, H-2¢,6¢), 7.38- 7.49 (m, 3 H, H-9,3,4¢), 7.59
(dd, J = 1.4, 8.3 Hz, 1 H, H-11), 7.69 (ddd, J = 1.4, 7.0,
8.3 Hz, 1 H, H-10), 8.09 (dd, J = 1.8, 7.6 Hz, 1 H, H-1), 8.24
(dd, J = 1.4, 8.3 Hz, 1 H, H-8). 13C NMR (75.47 MHz,
CDCl3): d = 27.2 (C-6), 43.1 (C-5), 115.4 (C-6a), 117.9 (C-
11), 123.6 (C-7a), 124.0 (C-1), 125.9 (C-8), 126.8 (C-4),
127.3 (C-4¢), 128.2 (C-3¢,5¢), 128.47 (C-12b), 128.5 (C-
2¢,6¢), 128.7 (C-2), 131.4 (C-3), 133.3 (C-10), 141.7 (C-1¢),
142.7 (C-4a), 155.6 (C-11a), 157.4 (C-12a), 177.2 (C-7). MS
(EI+): m/z calcd for C23H16O2: 324.1150; found: 324.1147
(29) Optimised procedure for the synthesis of 5-phenyl-7H-
benzo[c]xanthen-7-ones 5a–h: A mixture of the
(23) Optimised procedure for the synthesis of 3-styryl-
flavones 4a–g: A mixture of the appropriate 3-bromo-
flavone 2a–f (0.296 mmol), anhydrous K2CO3 (123 mg,
0.888 mmol), tetrabutylammonium bromide (TBAB; 238
mg, 0.740 mmol), palladium acetate (9.97 mg, 0.044 mmol)
and styrene 3a (0.170 mL, 1.48 mmol) in DMF (6 mL), was
poured into a two-necked flask equipped with a magnetic
stirring bar, fibre-optic temperature control, and reflux
condenser and placed under a nitrogen atmosphere. The
mixture was then irradiated in an Ethos SYNTH microwave
(Milestone Inc.) at constant power of 300 W from 5–10 min.
After that period, the reaction mixture was poured into a
mixture of ice (1 g) and water (10 mL) and extracted with
diethyl ether (3 × 10 mL). The organic layer was evaporated
to dryness and the obtained residue was taken in ethyl
acetate (10 mL) and washed with water (2 × 10 mL). The
organic layer was dried with anhydrous sodium sulfate,
evaporated and purified by column chromatography
(CHCl3–acetone, 9.6:0.4). After solvent evaporation, the
obtained residue was recrystallised from ethanol to give 3-
styrylflavones 4a–g [4a: 67 mg (70%); 4b: 68 mg (68%); 4c:
appropriate 3-styrylflavone 4a–g (0.15 mmol) and a
catalytic amount of I2 (10% mol) in 1,2,4-trichlorobenzene
(20 mL), was poured into a three-necked flask equipped with
a magnetic stirring bar, reflux condenser and a high-pressure
mercury UV lamp with 400 W power. The mixture was then
irradiated from 2 to 6 days. After that period, the reaction
mixture was poured into a silica gel column and eluted with
light petroleum to remove the excess of iodine and 1,2,4-
© Thieme Stuttgart · New York
Synlett 2012, 23, 559–564

564
D. H. A. Rocha et al.
LETTER
trichlorobenzene. Upon changing the eluent to ethyl acetate–
light petroleum (1:9 or 3:7), 5-phenyl-7H-benzo[c]xanthen-
7-ones were obtained, which were recrystallised from
ethanol 5a–h [5a: 50 mg (70%); 5b: 22 mg (45%); 5c: 50 mg
(73%); 5d: 35 mg (74%); 5e: 15 mg (30%); 5f: 11 mg (20%);
5g: 23 mg (40%); 5h: 35 mg (60%)]
7.34–7.46 (m, 6 H, H-9,2¢,3¢,4¢,5¢,6¢), 7.49 (d, J = 9.2 Hz,
1 H, H-2), 7.72 (d, J = 8.3 Hz, 1 H, H-11), 7.79 (ddd,
J = 1.5, 7.0, 8.3 Hz, 1 H, H-10), 8.04 (s, 1 H, H-6), 8.41 (dd,
J = 1.5, 8.3 Hz, 1 H, H-8), 8.60 (d, J = 9.2 Hz, 1 H, H-1). 13
NMR (75.47 MHz, CDCl3): d = 56.4 (4-OCH3), 60.6 (3-
C
OCH3), 110.1 (C-6a), 114.0 (C-2), 118.0 (C-11), 120.1 (C-
1), 122.6 (C-7a), 124.4 (C-9), 124.8 (C-6), 126.3 (C-4¢),
126.6 (C-8), 126.9 (C-2¢,6¢), 129.2 (C-3¢,5¢), 130.4 (C-4a),
130.8 (C-5), 134.2 (C-10), 141.4 (C-12a), 144.6 (C-4), 155.1
(C-3), 156.7 (C-11a), 178.9 (C-7). MS (EI+): m/z calcd for
C25H18O4: 382.1205; found: 382.1207
(30) Physical data of 6-hydroxy-3-nitro-5-phenyl-7H-
benzo[c]xanthen-7-one (7e): 1H NMR (300.13 MHz,
CDCl3): d = 7.46 (br d, J = 8.4 Hz, 2 H, H-3¢,5¢), 7.52–7.56
(m, 1 H, H-4¢), 7.53–7.59 (m, 1 H, H-9), 7.56–7.62 (m, 2 H,
H-2¢,6¢), 7.79 (br d, J = 8.3 Hz, 1 H, H-11), 7.93 (ddd,
J = 1.4, 7.0, 8.3 Hz, 1 H, H-10), 8.20 (dd, J = 2.2, 9.2 Hz,
1 H, H-2), 8.41 (dd, J = 1.4, 8.3 Hz, 1 H, H-8), 8.51 (d,
J = 2.2 Hz, 1 H, H-4), 8.77 (d, J = 9.2 Hz, 1 H, H-1), 12.71
(s, 1 H, 6-OH). 13C NMR (75.47 MHz, CDCl3): d = 109.5
(C-6a), 116.9 (C-2), 118.2 (C-11), 119.5 (C-5), 120.3 (C-
12b), 121.3 (C-7a), 121.4 (C-4), 125.0 (C-1), 125.5 (C-9),
126.2 (C-8), 128.3 (C-4¢), 128.9 (C-2¢,6¢), 131.0 (C-3¢,5¢),
133.3 (C-1¢), 136.1 (C-10), 136.6 (C-4a), 148.7 (C-3), 153.0
(C-12a), 154.3 (C-6), 155.7 (C-11a), 182.0 (C-7) ppm. MS
(EI+): m/z calcd for C23H13O5N 383.0794; found: 383.0791
(31) Xu, W. Z.; Huang, Z. T.; Zheng, Q. Y. J. Org. Chem. 2008,
73, 5607.
(33) Physical data of 2,3-dimethoxy-5-phenyl-7H-
benzo[c]xanthen-7-one (5g): 1H NMR (300.13 MHz,
CDCl3): d = 3.88 (s, 3 H, 3-OCH3), 4.18 (s, 3 H, 2-OCH3),
7.34 (s, 1 H, H-4), 7.45 (br dd, J = 7.0, 8.2 Hz, 1 H, H-9),
7.46–7.49 (m, 1 H, H-4¢), 7.50–7.58 (m, 4 H, H-2¢,3¢,5¢,6¢),
7.75 (dd, J = 1.7, 8.2 Hz, 1 H, H-11), 7.79 (ddd, J = 1.7, 7.0,
8.2 Hz, 1 H, H-10), 8.01 (s, 1 H, H-1), 8.13 (s, 1 H, H-6),
8.45 (dd, J = 1.7, 8.2 Hz, 1 H, H-8). 13C NMR (75.47 MHz,
CDCl3): d = 55.9 (3-OCH3), 56.2 (2-OCH3), 102.0 (C-4),
105.9 (C-1), 116.4 (C-6a), 118.0 (C-11), 119.2 (C-12b),
120.7 (C-6), 122.4 (C-1¢), 124.2 (C-9), 126.5 (C-7a), 126.7
(C-8), 127.6 (C-4¢), 128.5 (C-2¢,6¢), 129.9 (C-3¢,5¢), 131.4
(C-4a), 134.1 (C-5), 135.3 (C-10), 139.9 (C-12a), 149.8 (C-
2), 151.9 (C-3), 155.8 (C-11a), 176.9 (C-7). MS (EI+):
m/z calcd for C25H18O4: 382.1205; found: 382.1207
(32) Physical data of 3,4-dimethoxy-5-phenyl-7H-
benzo[c]xanthen-7-one (5f): 1H NMR (300.13 MHz,
CDCl3): d = 3.18 (s, 3 H, 4-OCH3), 4.03 (s, 3 H, 3-OCH3),
Synlett 2012, 23, 559–564
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.