XXVth European Colloquium o
Heterocyclic Chemistry
organised by the
Department of Chemistry
University of Reading
Poster Presentations
P0-39
NEWSYNTHESESOFNOVELARYLXANTHONES
Djenisa H. A. Rocha,a Catia I. C. Esteves,a Diana C. G. A. Pinto, a
Clementina M. M. Santos,b Cristela M. Brito,a Artur M. S. Silva,a Jose A. S. Cavaleiroa
aDepartment of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
~epartment of Vegetal Production and Technology, Scholl of Agriculture,
Campus de Santa Apol6nia, 5301-855 Braganc;a, Portugal
Xanthones represent an outstanding class of oxyg~1_1ated heterocycles widespread in
nature, commonly distributed in several higher plant families, such as Gentianaceae,
Guttiferae and Polygalaceae and in a few families of fungi and lichens [1]. Both natural
and synthetic derivatives often endowed with interesting pharmacological properties
(e.g. anti-inflammatory, antitumour and antioxidant activities [1,2]. Naturally-occurring
xanthones present different types .of substituents (e.g. hydroxyl, methoxyl and prenyl
groups, among others) in different positions of their scaffold leading to a large variety
of analogues [2]. The presence of an aryl ring attached to the xanthone core has only
been reported in some synthetic derivatives [3 ,4].
We have dedicated our previous work to the development of novel methodologies for
the synthesis of xanthones bearing a 2,3-diaryl substitution pattern [4]. Herein, we
report the latest advances in the synthesis of novel 5-arylbenzo[c]xanthones 2 and 1aryl-9H-xanthen-9-ones 4 [5]. 5-Arylbenzo[c]xanthones 2 are obtained by the Heck
reaction of 3-bromoflavones 1 with styrene derivatives, leading to (E)-3-styrylflavones,
followed by an one-pot photoinduced electrocyclisation and in situ oxidation of
cycloadducts. The condensation of 2-methylchromone 3 with cinammaldehydes leaded
to (E,E)-2-(4-arylbuta-1,3-dien-1-yl)-4H-chromen-4-ones, which after an one-pot
electrocyclization and in situ oxidation of cycloadducts gave the desired 1-aryl-9Hxanthen-9-ones 4.
UYOuCH3
~
1
-......:;,r8 .....__.
2
3
~
~
Acknowledgment: Thanks are due to the University of Aveiro, Funda<;ao para a Ciencia e a Tecnologia
and FEDER for funding the Organic Chemistry Research Unit (project PEst-C/QUI!UI0062/20 11 ), the
Portuguese National NMR Network (RNRMN) and the grants to D.H.A. Rocha (BIIUI51/4889/2010 and
SFRH/BD/68991/2010) and C.I.C. Esteves (SFRH/BI/51098/2010).
[1]
a) Gales, L.; Damas, A.M. Curr. Med. Chem. 2005, 12, 2499. b) Vieira, L.M.M.; K.ijjoa, A. Curr.
Med. Chem. 2005, 12,2413.
[2] a) Pinto, M.M.M.; Sousa, M.E.; Nascimento M.S.J. Curr. Med. Chem. 2005, 12, 2517. b) Riscoe,
M.; K.elly, J.X.; Winter, R Curr. Med. Chem. 2005, 12, 2539. c) El-Seedi, H.R.; El-Barbary, M.A.;
El-Ghorab, D.M.; Bohlin, L.; Borg-K.arlson, A. K..; Goransson, U.; Verpoorte, R. Curr. Med. Chem.
2010, 17, 854.
(3] a) Fukawa, I.; Yoneda, H.; Asahi, K..K..K..K. Eur. Patent EP0237004, Sep, 1987. b) K.elkar, A.S.;
Letcher. R.M.; Cheung, K..-K..; Chiu, K..-F.; Brown, G.D. J. Chem. Soc. Perkin Trans /2000,3732.
[4] Santos, C.M.M.; Silva, A.M.S.; Cavaleiro, J.A.S. Synlett 2005, 3095; Synlett 2007, 3113; Eur. J.
Org. Chem. 2009,2642.
[5]. a) Esteves, C.I.C.; Santos, C.M.M.; Brito, C.M.; Silva, A.M.S.; Cavaleiro, J.A.S. Synlett, 2011,
1403. b) Rocha, D.H.A.; Pinto, D.C.G.A.; Silva, A.M.S.; Patonay, T.; Cavaleiro, J.A.S. Synlett,
2012,23,559.
'
a
Rocha,
a
Esteves,
a
Pinto,
Djenisa H. A.
Cátia I. C.
Diana C. G. A.
a
a
b
a
Clementina M. M. Santos, Cristela M. Brito, Artur M. S. Silva, José A. S. Cavaleiro
Reading / UK
August 13th-17th, 2012
aDepartment of Chemistry & QOPNA,
University of Aveiro, 3810-193 Aveiro, Portugal
bDepartment of Vegetal Production and Technology, Scholl of Agriculture, Campus de Santa Apolónia, 5301-855 Bragança,
Portugal
INTRODUCTION



Xanthones represent an outstanding class of oxygenated heterocycles widespread in nature, commonly distributed in several higher plant families, such as Gentianaceae, Guttiferae and Polygalaceae and in a few families of fungi and lichens [1]. Both natural and synthetic
derivatives often endowed with interesting pharmacological properties (e.g. anti-inflammatory, antitumour and antioxidant activities) [1,2].
Naturally-occurring xanthones present different types of substituents (e.g. hydroxyl, methoxyl and prenyl groups, among others) in different positions of their scaffold leading to a large variety of analogues [2]. The presence of an aryl ring attached to the xanthone
scaffold has only been reported in some synthetic derivatives [3,4].
We have dedicated our previous work to the development of novel methodologies for the synthesis of xanthones bearing a 2,3-diaryl substitution pattern [4]. Herein, we report the latest advances in the synthesis of novel 5-arylbenzo[c]xanthones 5 and 1-aryl-9Hxanthen-9-ones 9 [5].
SYNTHESIS OF 5-ARYLBENZO[C]XANTHONES 5
SYNTHESIS OF 1-ARYL-9H-XANTHEN-9-ONES 9
5-Arylbenzo[c]xanthones 5 are obtained by the Heck reaction of 3-bromoflavones 2 with styrene derivatives 3,
leading to (E)-3-styrylflavones 4, followed by an one-pot photoinduced electrocyclisation and in situ oxidation of
the formed cycloadducts.
OH O
OH
R
1
R
2
O
(i)
R
2
O
3
R (ii)
Br
O
1
R
1
R
OH O
R3
4
R4
R
O
R1
R2
R
R4
40 R1, R2 = H
R3, R4 = H
72 R1, R2 = H
R3, R4 = H
70
b R1 = Me, R2 = H
48 R1 = Me, R2 = H
R3, R4 = H
70 R1 = Me, R2 , R2’ = H
R3, R4 = H
45
c R1 = OMe, R2 = H
45 R1 = OMe, R2 = H R3, R4 = H
69 R1 = OMe, R2 , R2’ = H R3, R4 = H
73
d R1 = Cl, R2 = H
42 R1 = Cl, R2 = H
62 R1 = Cl, R2 , R2’ = H
R3, R4 = H
74
e R1 = NO2 , R2 = H
30 R1 = NO2 , R2 = H R3, R4 = H
50 R1 = NO2 , R2 , R2’ = H
R3, R4 = H
30
f
= OMe
32
R1 , R2
---
-
R1 , R2 = OMe
g
h
---
-
= OMe
---
R3, R4
=H
50
43 R1 , R2’ = OMe
R2 , R3, R4 = H
15
45
R3, R4 = OMe
---
= OMe
R2’, R3, R4 = H
-
R1 , R2
R1 , R2 , R2’ = H
R3, R4 = OMe
8
O
7
2
5
O
4c
1''

6''
3'
H-2’,6’
H-8
g
H-6
H-g
3
H-a
H-3
a
O
H-
2''
3''
H-d
H-a
H-7
H-5
8d
H-8
H-7
H-5
8.0
7.8
7.6
7.4
7.2
7.0
6.8
5
6
H-3’,5’
5''
H-2’,6’
H-6
H-2,4
2
3-OCH3
1
10
9
H-1
H-8
3
O
OCH3
4
O
3
2
O 6'
2'
5'
3'
H-2
H-7
H-5
H-8
9d
Br
4
2'
8
O
5c
3'
6
8.2
8.1
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
7.2
4'
6'
5'
H
H
H
10
11
11a
H
HMBC connectivities
O
2
3
1
4
11b
4a
1
R
H
6
H
H
7
2'
9
REFERENCES
H-4
H-3
11
ppm
7.1
ppm
6
H-10 H-11
H-4’,9
6.4
7
8
H-2’,3’,5’,6’
6.6
H-4’’
4''
H-6
Xanthones 9
(%)
30
26
70
56
50
H-3’,5’
8.2
a
3
Br
R1
9
H-6,2’’,6’’
6'
6
O
6
H-3’’,5’’
5'
5'
R1 = H
R1 = Me
R1 = OMe
R1 = Br
R1 = NO2
a
b
c
d
e
8
Cinnamaldehydes 7 Chromones 8
(%)
(%)
80
63
77
68
83
33
70
69
68
2'

5
O
O
7
60
H-3’,5’
OCH3
O
R
d
8
(vi)
3
2'
O
CHO (v)
6'
H-2’,6’
4'
R1
(i) Dry Py, room temp., 12h
(ii) Dry THF, NaH, reflux, 1 h
(iii) DMSO, TsOH ac., 100 ºC, 2 h
(iv) Dry DMF, Pd(OAc)2 , K2 CO3, (Bu)4NOAc, KCl, 90 ºC
(v) EtOH, NaOEt, room temp.
(vi) 1,2,4-Trichlorobenzene, I2 , reflux, 48h
7
3'
CH3
6
3
a R1, R2 = H
R1 , R2
O
X = Br or I
(iv)
O
Benzoxanthones 5
(%)
R3, R4 = H
O
1
O 5
3-Styrylflavones 4
(%)
R
(i)
(ii)
(iii)
2'
O
X
CH3COCl
O
(iii)
(i) THF, PTT, room temp., 24-48h
(ii) DMF, Pd(OAc)2 , K2 CO3, (Bu)4NBr, 300 W, 5-10 min.
(iii) 1,2,4-Trichlorobenzene, I2 , h
3-Bromoflavones 2
(%)
R
2
4
3
a R3, R4 = H
b R3, R4 = OMe
2
R
1
The condensation of 2-methylchromone 6 with cinnamaldehydes 7 leaded to (E,E)-2-(4-arylbuta-1,3-dien-1-yl)-4H-chromen-4ones 8, which after an one-pot electrocyclization and in situ oxidation of the formed cycloadducts gave the desired 1-aryl-9Hxanthen-9-ones 9.
8
H
7a
7
6a
6
O
H
1'
5
3'
H
H
5
8
H
4b
8a
O
9
4a
9a
OH 6'
H4
3
2
1
1'
2'
5'
4'
6'
5'
H
[1] a) Gales, L.; Damas, A.M. Curr. Med. Chem. 2005, 12 , 2499. b) Vieira, L.M.M.; Kijjoa, A. Curr. Med. Chem. 2005, 12 , 2413.
[2] a) Pinto, M.M.M.; Sousa, M.E.; Nascimento M.S.J. Curr. Med. Chem. 2005, 12 , 2517. b) Riscoe, M.; Kelly, J.X.; Winter, R. Curr. Med. Chem. 2005, 12 , 2539. c) El-Seedi, H.R.; El-Barbary, M.A.; ElGhorab, D.M.; Bohlin, L.; Borg-Karlson, A.K.; Göransson, U.; Verpoorte, R. Curr. Med. Chem. 2010, 17, 854.
[3] a) Fukawa, I.; Yoneda, H.; Asahi, K.K.K.K. Eur. Patent EP0237004, Sep, 1987. b) Kelkar, A.S.; Letcher. R.M.; Cheung, K.-K.; Chiu, K.-F.; Brown, G.D. J. Chem. Soc. Perkin Trans I 2000, 3732.
[4] Santos, C.M.M.; Silva, A.M.S.; Cavaleiro, J.A.S. Synlett 2005, 3095; Synlett 2007, 3113; Eur. J. Org. Chem. 2009, 2642.
[5] a)Esteves, C.I.C.; Santos, C.M.M.; Brito, C.M.; Silva, A.M.S.; Cavaleiro, J.A.S. Synlett, 2011, 1403. b) Rocha, D.H.A.; Pinto, D.C.G.A.; Silva, A.M.S.; Patonay, T.; Cavaleiro, J.A.S. Synlett, 2012, 559.
H
4'
3'
1
H
HMBC connectivities
H
H
H
R
ACKNOWLEDGMENTS
Thanks are due to the University of Aveiro, Fundação para a Ciência e a Tecnologia and FEDER for
funding the Organic Chemistry Research Unit (project PEst-C/QUI/UI0062/2011), the Portuguese
National NMR Network (RNRMN) and the grants to D.H.A. Rocha (BI/UI51/4889/2010 and
SFRH/BD/68991/2010) and C.I.C. Esteves (SFRH/BI/51098/2010).