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 1-aryl-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 FED ER 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. '

Djenisa H. A. Rocha,a Cátia I. C. Esteves,a Diana C. G. A. Pinto,a Clementina M. M. Santos,b Cristela M. Brito,a Artur M. S. Silva,a José A. S. Cavaleiroa

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

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).

[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.; El-Ghorab, 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.

REFERENCES ACKNOWLEDGMENTS

INTRODUCTION

(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, K2CO3, (Bu)4NOAc, KCl, 90 ºC (v) EtOH, NaOEt, room temp. (vi) 1,2,4-Trichlorobenzene, I2, reflux, 48h

Reading / UK

August 13th-17th, 2012

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-9H-

xanthen-9-ones 9 [5].

SYNTHESIS OF 5-ARYLBENZO[C]XANTHONES 5 SYNTHESIS OF 1-ARYL-9H-XANTHEN-9-ONES 9

Cinnamaldehydes 7 さ (%)

Chromones 8 さ (%)

Xanthones 9 さ (%)

a R1 = H - 80 30

b R1 = Me 63 77 26

c R1 = OMe 68 83 70

d R1 = Br 33 70 56

e R1 = NO2 69 68 50

O

O

R1

CHO

R1

O

R1

O

O CH3

O

(v) (vi)

R

X

X = Br or I

O

OOH O

CH3COCl

(i)

(ii)

(iii)(iv)

(i) THF, PTT, room temp., 24-48h (ii) DMF, Pd(OAc)2, K2CO3, (Bu)4NBr, 300 W, 5-10 min. (iii) 1,2,4-Trichlorobenzene, I2, hに

3-Bromoflavones 2 さ (%)

3-Styrylflavones 4 さ (%)

Benzoxanthones 5 さ (%)

a R1, R2 = H 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 R3, R4 = 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 R1 , R2 = OMe 32 R1 , R2 = OMe R3, R4 = H 45 R1 , R2 = OMe R2’, R3, R4 = H 50

g --- - R1 , R2 = OMe R3, R4 = OMe 43 R1 , R2’ = OMe R2, R3, R4 = H 15

h --- - --- --- - R1 , R2, R2’ = H R3, R4 = OMe 60

1 2 3 4

5

a R3, R4 = H b R3, R4 = OMe

6 7 8 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.

The condensation of 2-methylchromone 6 with cinnamaldehydes 7 leaded to (E,E)-2-(4-arylbuta-1,3-dien-1-yl)-4H-chromen-4-ones 8, which after an one-pot electrocyclization and in situ oxidation of the formed cycloadducts gave the desired 1-aryl-9H-xanthen-9-ones 9.

6.46.66.87.07.27.47.67.88.08.2 ppm

3

H-5 H-7

H-8 H-2’,6’

H-g H-d

H-a

H-3

H-6

H-3’,5’

HMBC connectivities

7.17.27.37.47.57.67.77.87.98.08.18.2 ppm

6

H-8

H-6

H-3

H-3’,5’

H-4

H-5 H-7

H-2’,6’

H-2

O

O

Br

35

6

78

a

g

d2'

3'

5'6'

O

Br

O

2

345

6

78

2'

3'5'

6'

O

O

2

35

6

78

2'

3'

5'6'

a

2''

3''

4''

5''6''

OCH34'

1''

4c

5c

8d

9d

O

R1

O1

2

34a4b5

6

78

8a9 9a

1'2'

3'4'

5'

6'

H

H

H

HH

HHH

HH

4H

O

O

R1H

H

HH

H

H

HH

H

23

4a

6a 56

78

11a

9

11b

2'3'

4'

5'

6'

410

11

1

7a 1'

HMBC connectivities

O

O8

9

10

11

12

4

2'3'

4'

5'6'

6

OCH33

OH O OH

R1

R2

O

OBr

R1

R2 O

O

R1

R2

R3

R4

O

O

R1

R2

R3

R4

R2'

(i) (ii)

(iii)

R3

R4

H-5

H-2’,6’

H- H-7

H-8

H-6,2’’,6’’

H-3’’,5’’

H-4’’

H-3’,5’

H-a

H-1 H-8

H-6

H-10 H-11

H-2’,3’,5’,6’

H-4’,9

H-2,4 3-OCH3