R1 R2 R3 R4 R5 Yield 6 (%)

Yield 9 (%)

Yield 10 (%)

a H H H H H 47 12 12

b H OCH3 OCH3 H H 21 12 7

c H OCH3 OCH3 OCH3 OCH3 31 13 5

d H H H OCH3 H 24 35 5

e H H H OCH3 OCH3 22 5 2

f OCH3 H H H H 21 47 1

g OCH3 OCH3 OCH3 H H 29 19 0

h OCH OCH3 OCH3 OCH3 OCH3 24 3 2

i OCH3 H H OCH3 H 31 40 2

j OCH3 H H OCH3 OCH3 24 15 10

[1] K. Hostettman, M. Hostettman, in Methods in Plant Biochemistry, Vol. 1 – PlantPhenolics, Ed. P. M. Dey, J. B. Harbone, Academic Press, 1989, pp. 493.

[2] (e.g.) G. J. Bennett, H.-H. Lee, Phytochemistry, 1989, 28, 967-998; H. Minami,M. Kinoshita, Y. Fukuyama, M. Komoda, T. Yoshizawa, M. Sugiura, K. Nakagawa,H. Tago, Phytochemistry, 1994, 36, 501-506; A. Abdel-Lateff, C. Klemke, G. M.König, A. D. Wright, J. Nat. Prod., 2003, 66, 706-708; Y.-M. Chiang, Y.-H. Kuo,S. Oota, Y. Fukuyama, J. Nat. Prod., 2003, 66, 1070-1073.

[3] C.M. M. Santos, A. M. S. Silva, J. A. S. Cavaleiro, Synlett, 2005, 3095-3098.

Thanks are due to the University of Aveiro, FCT and FEDER forfunding the Organic Chemistry Research Unit and the projectPOCI/QUI/59284/2004. One of us (C.M.M. Santos) is also gratefulto PRODEP 5.3 for financial support.

1H NMR

SYNTHESIS OF 2,3-DIARYLXANTHONES USING PALLADIUM CATALYSTS

aDepartment of Agro-Industries, Escola Superior Agrária de Bragança, 5301-855 Bragança, PortugalbDepartment of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal

CLEMENTINA M. M. SANTOS,a,b Artur M. S. Silva,b José A. S. Cavaleirob

Xanthones constitute an important class of heterocyclic compounds with a broad range of biological

properties [1]. Antimicrobial, antitumour, anti-inflammatory as well as antioxidant activities are someexamples of the applications presented for several derivatives of this type of compounds [2].

ACKNOWLEDGEMENTS

Scheme 1

Xanthones bearing aryl substituents are scarce and no natural derivatives have been reported with the

2,3-diaryl substitution pattern. In this communication we will describe the synthesis of 2,3-arylxanthones (6), in which Scheme 1 presents the synthesis of the unsubstituted derivative, by two different routes, involving the use of palladium catalysts [PdOAc2, PdCl2, Pd(PPh3)2Cl2, Pd(PPh3)4],

The first method involves the Heck reaction of 3-bromo-2-styrylchromone (5) as aryl halides andstyrene as alkene [3]. In the second one there is a Heck reaction of 3-bromo-2-methylchromone (4B)with styrene followed by an Aldol condensation of the obtained compound (7B) with benzaldehyde to give2,3-distyrylchromone (8B), which gives the desired 2,3-diarylxanthone (6) after electrocyclisation andoxidation processes.

O

O

Br

(5)

XII

OCH3

R1

R2

R3

R5

R45

XII. 1 eq. Et3N, 0,05 eq. Pd(PPh3)4, 0.1 eq. PPh3, NMP, reflux, 3h

O

(6)O

R1

OCH3

R2

R3

R5

R4

O

(9)O

R1

OCH3

R2

R3

R5

R4

H H

H

O

(10)O

R1

OH

R2

R3

R5

R4

When 3-bromo-2-styrylchromones (5) were substituted with a 5-methoxyl

group, interesting results were obtained...

...the Heck reaction of (5) with styrenes leads to the formation of the desired 2,3-diarylxanthones (6) and also two other compounds:

2,3-diaryl-3,4-dihydroxanthones (9), a semi-oxidized intermediate of the final xanthones (6) and 8-hydroxyl derivatives (10), as result of the cleavage of the protecting group in the 2,3-diarylxanthones (6).

6.46.56.66.76.86.97.07.17.27.3 ppm

4.55.05.56.06.57.07.58.0 ppm

3.259

3.163

3.115

1.011

1.046

2.113

2.228

2.232

3.887

1.078

1.000

H-1

6-OCH3

H-7H-5

H-4

H-3’,5’H-3’’,4’’,5’’ 4’-OCH3

H-2’’,6’’8-OCH3

H-2’,6’

1H NMR

H-1

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm

16

92

39

70

34

97

20

79

61

59

00

6.326.34 ppm

6.317

6.325

6.333

2.020

3.03.54.0 ppm

16

.9

H-2’’,6’’

8-OCH3

H-5 and H-7

H-3’,5’H-3’’,4’’,5’’H-2’,6’

H-4cisH-3H-4trans

6-OCH3

4’-OCH3

1H NMR

13 12 11 10 9 8 7 6 5 4 3 2 1 ppm

6.46.56.66.76.86.97.07.17.27.3 ppm

H-4

4’-OCH3

H-7H-5

H-3’,5’H-3’’,4’’,5’’

H-2’’,6’’H-2’,6’

8-OHH-1

6-OCH3

(10i)

O

OOCH3

1 2

34

4a4b5

6

7

88a 9a

9 1'2'

3'

4'5'

6'

1''

2'' 3''4''

5''

6''

OH

H3CO

H

HH

H

H

H

H

H

HMBC connectivities

O

OOCH3(9i)

12

344a

4b5

6

7

88a 9a

91'

2'

3'

4'5'

6'

1''

2''

3''

4''

5''

6''

OCH3

H H

HH3CO

H

HMBC connectivities

HMBC connectivities

60708090100110120130140150160170 ppm

56

13C NMR

C-9

8-OCH3

C-5C-7

C-3’,5’

C-4

6-OCH3

C-1 and C-3’’,5’’

C-8aC-9a

4’-OCH3

130135140145150155160165 ppm

C-2’’,6’’

C-4’ C-3 C-1’’ C-2 C-1’C-4’’’

C-2’,6’C-8C-6 C-4b C-4a

(6i)

HSQC

Scheme 2

H-2’,6’C-3’’,4’’,5’’

ppm

3.03.54.04.55.05.56.06.57.07.5 ppm

40

50

60

70

80

90

100

110

120

130

H-4cisH-3

8-OCH3 4’-OCH3H-4trans

H-5 and H-7H-3’,5’H-16-OCH3

C-3’,5’

C-4

C-3

8-OCH3

4’-OCH3

C-7C-5

6-OCH3

C-2’,6’C-1

C-2’’,6’’

O

OOCH3

(9i)

12

34

4a4b5

6

7

88a 9a

9 1'2'

3'

4'5'

6'

1''

2''

3''

4''

5''

6''

OCH3

H H

H

H3CO

INTRODUCTION

REFERENCES

MORE RESULTS…

STRUCTURAL ELUCIDATION

O

OOCH3(6i)

12

34

4a4b56

78

8a 9a9 1'

2'

3'

4'5'

6'

1''

2''3''

4''

5''

6''

OCH3

H3CO

H

HH

H

IV and IX present the best conditions obtained in the Heck reaction, using several Pd catalysts

OOH

O

O

O

ClOC II

O OHOHO

O

Br

(5)(1)

OOH

O

O

OOH OH

O

O

CH3

Br

CH3COCl

O

O

CH3

O

O

(3A)(2A)

(2B) (3B)(4B)

(7B)

(8B)

III

I

IVV

VI VII

VIII

IX

O

O (6)

X

XI

I. dry Py, r.t., 2h

II. KOH, DMSO, r.t., 2h

III. PTT, THF, r.t., 12h

IV. Styrene, Pd(PPh3)4,

PPh3, Et3N, 160ºC, 6h

V. dry Py, r.t., 12h

VI. KOtBu, THF, reflux, 2h

94 % 94 % 90 %

97 %

82 %

56 %

VII. 1. Br2, ethanol, r.t., 2h 2. HCl, reflux, 2hVIII. Benzaldehyde, NaOMe, MeOH, r.t., 48hIX. Styrene, PdCl2, PPh3, Et3N, 160ºC, 9hX. Benzaldehyde, NaOMe, MeOH, r.t., 48hXI. 1,2,4-Trichlorobenzene, reflux

87 %

48 %

53 %

66 %

67 %