Synthesis of novel 1-aryl-9 H -xanthen-9-ones

Article abstract of DOI:10.1055/s-0030-1260567

A novel route for the synthesis of 1-aryl-9H-xanthen-9-ones is reported. This methodology involves the condensation of 2-methylchromone with cinnamaldehydes leading to (E,E)-2-(4-arylbuta-1,3-dien-1-yl)-4H-chromen-4-ones. The final steps involved electrocyclization and oxidation of the latter compounds, in an one-pot synthesis, giving the desired 1-aryl-9H-xanthen-9-ones. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260567

LETTER
1403
Synthesis of Novel 1-Aryl-9H-xanthen-9-ones
S
ynthesisof
Nov
á
el1-Aryl-9
t
H
-xanth
i
en-9-o
a
ne
s
I. C. Esteves,a Clementina M. M. Santos,b Cristela M. Brito,a Artur M. S. Silva,*a José A. S. Cavaleiroa
a
Department of Chemistry & QOPNA, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: artur.silva@ua.pt
Department of Vegetal Production and Technology, School of Agriculture, Campus de Santa Apolónia, 5301-855 Bragança, Portugal
b
Received 28 February 2011
molecular Ullmann condensation of phenolates with
ortho-halobenzoic acids or by Smiles rearrangement of
diaryl esters. To build more complex structures, several
modifications on the traditional methods have been made
Abstract: A novel route for the synthesis of 1-aryl-9H-xanthen-9-
ones is reported. This methodology involves the condensation of 2-
methylchromone with cinnamaldehydes leading to (E,E)-2-(4-
arylbuta-1,3-dien-1-yl)-4H-chromen-4-ones. The final steps in-
volved electrocyclization and oxidation of the latter compounds, in and a great number of nonconventional approaches have
emerged.13
an one-pot synthesis, giving the desired 1-aryl-9H-xanthen-9-ones.
Key words: 1-arylxanthones, 2-methylchromone, aldol condensa-
tion, electrocyclization, oxidation
In the present communication we report a new strategy for
the synthesis of novel 1-aryl-9H-xanthen-9-ones 6a–e
(Scheme 1).
Xanthone or 9H-xanthen-9-one is the parent compound of
an important class of oxygenated heterocycles with a
OH
X
X = Br or I
dibenzo-g-pyrone framework. This heterocyclic system is
a R1 = H
R1
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
O
1
b R1 = Br
c R1 = OMe
d R1 = Me
e R1 = NO2
3
1 step
B
3 steps
A
OHC
O
Naturally occurring xanthones present different types of
substituents (e.g., hydroxy, methoxy, and prenyl groups)
in different positions of their scaffold leading to a large
variety of analogues.2 The presence of an aryl ring at-
tached to the xanthone core has only been reported in
some synthetic derivatives.3–5 In our previous studies we
have developed methodologies for the synthesis of xan-
thones bearing a 2,3-diaryl substitution pattern but, as far
as we are aware, the introduction of a 1-aryl substituent in
the xanthone nucleus has never been reported.5
+
R1
R1
4
O
2
C
O
H4trans
H4cis
O
O
D
O
H
O
5
O
R1
In recent years, several studies have emphasized the bio-
logical and pharmacological properties of both natural
and synthetic xanthones,6 including anti-inflammatory,7
cancer chemopreventive,8 antimalarial,9 and radical
scavenging10 activities, but also inhibition of cyclooxyge-
nase, cholinesterase, and other enzymes.6,11 Some xan-
thones even surpass the antimicrobial activity of
traditional antibiotics.12 These promising applications and
the restricted chemical xanthone scaffolds have motivated
the search for novel synthetic derivatives and the develop-
ment of new synthetic routes for 9H-xanthen-9-one-type
compounds.
6
7
R1
Scheme 1 Reagents and conditions: A. (i) MeCOCl, pyridine, r.t.,
15 h; (ii) NaH, THF, reflux, 2 h; (iii) DMSO, I2 (4 h) or p-toluenesul-
fonic acid (2 h), 100 °C; B. (i) dry DMF, Pd(OAc)2, NBu4OAc,
K2CO3, KCl, 90 °C, 2–8 h; (ii) HCl, r.t., 10 min; C. Na, EtOH, r.t.
D. 1,2,4-trichlorobenzene, I2, reflux, 48 h.
The required starting material 2-methylchromone (2) was
prepared by three-step Baker–Venkataraman sequence,14
in good overall yields (Scheme 1) involving acetylation of
2¢-hydroxyacetophenone (1) followed by the base-cataly-
sed Baker–Venkataraman rearrangement14 of the formed
ester, leading to the formation of a 1,3-diketone deriva-
tive, which, after cyclodehydration afforded the desired 2-
methylchromone (2). The last step was carried out with a
catalytic amount of p-toluenesulfonic acid or iodine in
DMSO. The results obtained seem to indicate that the cy-
clodehydration is favorable in the acidic medium, as pre-
viously reported for the synthesis of other chromone-type
The classical methods for the synthesis of xanthones are
based on the formation of key intermediates, such as ben-
zophenones, obtained by a Friedel–Crafts acylation or a
Fries rearrangement, or diaryl ethers, prepared by inter-
SYNLETT 2011, No. 10, pp 1403–1406
x
x
.x
x
.2
0
1
1
Advanced online publication: 16.05.2011
DOI: 10.1055/s-0030-1260567; Art ID: D06911ST
© Georg Thieme Verlag Stuttgart · New York

1404
C. I. C. Esteves et al.
LETTER
compounds.15 The reaction of aryl bromides or iodides 3 tions to compounds 5b–e led to preparation of 6b–e in
with acrolein diethyl acetal in a palladium-catalyzed cou- good yields (50–70%). An extensive study on the referred
pling reaction provided the required cinnamaldehydes electrocyclization and oxidation reactions, involving oth-
4b–e (Scheme 1).16
er solvents, temperature, and reaction time and even with
irradiation with a high-pressure UV lamp, did not lead to
better yields of 6a–e.
The chemical reactivity of 2-methylchromones and fur-
ther transformation into other biologically active ana-
logues have been the subject of several works.17 Among The initial stereochemistry of the a,b,g,d,e,z-unsaturated
them is a number of condensation reactions with carbonyl system (vide infra) of 5a–e was clearly not appropriate for
compounds to afford new heterocyclic systems. For ex- the ring closure in the attempted thermal electrocycliza-
ample, 2-styrylchromone derivatives have been synthe- tion, even at higher temperature. However, since it is well
sized from 2-methylchromones and these even find use as known that iodine is an efficient catalyst in the trans–cis
substrates in the preparation of new and remarkably bio- isomerisation of alkenes,23 a catalytic amount was enough
active xanthones.10
to initiate reaction. A plausible mechanism for the de-
scribed transformations invokes a thermal electrocycliza-
tion of the a,b,g,d,e,z-unsaturated system of 5a–e
followed by a [1,3]-sigmatropic shift to give 1,4-dihy-
droxanthen-9-ones 7a–e, which, after in situ oxidation,
yield 1-aryl-9H-xanthen-9-ones 6a–e.
Focussing on this concept, optimization studies were car-
ried out for the synthesis of the novel (E,E)-2-(4-arylbuta-
1,3-dien-1-yl)-4H-chromen-4-ones 5a–e. The condensa-
tion of 2-methylchromone (2) with cinnamaldehydes 4a–
e using sodium methoxide, formed in situ from sodium
and methanol, as base was ineffective. After several at- All novel compounds synthesized have been character-
tempts we concluded that the base, its stoichiometry and ized by NMR, MS, and elemental analysis. The most im-
the reaction time were very important to provide 5a–e in portant feature in the 1H NMR spectra of chromones 5a–
good yields (Scheme 1, Table 1). (E,E)-2-(4-Arylbuta- e are the singlets corresponding to the resonance of pro-
1,3-dien-1-yl)-4H-chromen-4-ones 5a–e were thus ob- tons H-3, at dH = 6.24–6.31 ppm. Other important charac-
3
3
tained using four equivalents of base, sodium ethoxide, teristics are the JHa–Hb and JHg–Hd values of 15–16 Hz
with the exception of the nitro derivative, which was pre- indicating a trans-trans configuration for the two vinylic
pared using only one equivalent of base but with longer systems. The assignments of vinylic protons and of their
reaction time (Table 1).18,19
stereochemistry were confirmed by HMBC and NOESY
spectra. Thus, in the HMBC spectrum of chromones 5a–e
it was possible to observe the connectivity of H-a with C-
2 and C-3 and of H-g and H-3¢,5¢ with C-1¢. In the NOESY
spectra it was possible to observe the close proximity of
H-a with H-3 and H-g and of H-b with H-d (Figure 1).
Table 1 Conditions and Yields Obtained in the Formation of 5a–e
and Yields in the Synthesis of 6a–e
Entry
Base (equiv) Time (h) Yield of 5 (%) Yield of 6 (%)
1
2
3
4
5
4
4
4
4
1
4
8
5a 80
5b 70
5c 80
5d 77
5e 68
6a 55
6b 56
6c 70
6d 67
6e 50
R1
H
5´
HMBC
NOESY
H
R1
6'
H
δ
4'
4
1'
δ
H
3'
β
H
H
2'
4
γ
H
β
H
H
γ
O
O
H
H
55
α
H
8
9
H
H
O
α
H
7
3
H
Subsequently, extensive studies into the electrocycliza-
tion and oxidation reactions of (E,E)-2-(4-arylbuta-1,3-
dien-1-yl)-4H-chromen-4-ones 5a–e were performed. In
the first attempt, chromone 5a was refluxed in 1,2,4-
trichlorobenzene but, even after one week, no product was
observed. However, when a catalytic amount of iodine
was added to the reaction mixture, TLC analysis after 18
hours revealed the presence of three spots; the one with
the lowest Rf value corresponding to the unreacted starting
material 5a (44%).The NMR spectra of the other two
spots proved that the one with the highest Rf value was the
expected 1-phenyl-9H-xanthen-9-one 6a (15%) and the
other one as the semioxidized intermediate of the final
xanthone, 1,4-dihydro-1-phenyl-9H-xanthen-9-one (7a,
20%).20 On extending the reaction time to 48 hours only
the desired xanthone 6a was isolated and the best yields
were accomplished with these reaction conditions
(Scheme 1, Table 1).21,22 The extension of these condi-
6
5
10
3
H
5
H
O
5
H
H
4
5
4b
4a
3
H
H
H
O
9
6
2
7
H
8
1
1'
H
O
HMBC
R1
6
Figure 1 Main results obtained in the HMBC (connectivities) and
NOESY (close proximity) spectra of compounds 5 and 6
1
The main features in the H NMR spectra of 1-aryl-9H-
xanthen-9-ones 6a–e are the double doublets correspond-
ing to the protons H-8, resonating at higher frequency val-
ues (dH = 8.15–8.19 ppm) due to the anisotropic and
Synlett 2011, No. 10, 1403–1406 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel 1-Aryl-9H-xanthen-9-one
1405
(12) Franklin, G.; Conceição, L. F. R.; Kombrink, E.; Dias, A. C.
P. Phytochemistry 2009, 70, 60.
(13) Sousa, M. E.; Pinto, M. M. M. Curr. Med. Chem. 2005, 12,
2447.
(14) (a) Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934,
1767. (b) Baker, W. J. Chem. Soc. 1933, 1381.
(15) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J.
Org. Chem. 2003, 4575.
mesomeric deshielding effects of the carbonyl group, and
the lowest frequency aromatic signals corresponding to
the resonance of protons H-2, at dH = 7.13–7.18 ppm. The
structure of xanthones 6a–e was also supported by the
main connectivities found in their HMBC spectra
(Figure 1).
In conclusion, we have established a simple synthetic
methodology for preparing 1-aryl-9H-xanthen-9-ones
6a–e, by the electrocyclization and oxidation reactions of
the new (E,E)-2-(4-arylbuta-1,3-dien-1-yl)-4H-chromen-
4-ones 5a–e. The latter compounds were obtained by con-
densation of 2-methylchromone (2) with cinnamalde-
hydes 4a–e.
(16) Battistuzzi, G.; Cachi, S.; Fabrizi, G. Org. Lett. 2003, 5, 777.
(17) Ibrahim, M. A.; Ali, T. E.; Alnamer, Y. A.; Gabr, Y. A.
ARKIVOC 2010, (i), 98.
(18) Typical Experimental Procedure
Sodium (0.11 g, 4.8 mmol) was gradually added to dry EtOH
(5 mL), and the mixture was stirred until it reached r.t. 2-
Methylchromone (2, 0.2 g, 1.2 mmol) and the appropriate
cinammaldehyde 4a–e (1.5 mmol) were added and the
reaction mixture allowed to stand at r.t. until complete
disappearance of chromone 2 (TLC). The solution was then
poured into ice (20 g) and H2O (30 mL) and adjusted to pH
4 with dilute HCl. The solid was removed by filtration,
dissolved in CH2Cl2, and purified by silica gel column
chromatography using CH2Cl2 as eluent. The solvent was
evaporated the residue were recrystallized from EtOH to
give the (E,E)-2-(4-arylbuta-1,3-dien-1-yl)-4H-chromen-4-
ones 5a–e in good yields (Table 1).
Acknowledgment
Thanks are due to the University of Aveiro, ‘Fundação para a
Ciência e a Tecnologia’, and FEDER for funding the Organic Che-
mistry Research Unit and the Portuguese National NMR Network
(RNRMN). One of us (C. I. C. Esteves) is also grateful to FCT for
her fellowship (SFRH/BI/51098/2010).
(19) Physical Data of (E,E)-2-[-4-(4-methoxyphenyl)buta-1,3-
dien-1-yl]-4H-chromen-4-one (5c)
References and Notes
Mp 137–139 °C. 1H NMR (300,13 MHz, CDCl3): d = 3.84
(s, 3 H, OCH3), 6.24 (s, 1 H, H-3), 6.32 (d, 1 H, J = 15.3 Hz,
H-a), 6.84–6.87 (m, 1 H, H-d), 6.90 (d, 2 H, J = 8.8 Hz, H-
3¢,5¢), 6.90–6.96 (m, 1 H, H-g), 7.38 (ddd, 1 H, J = 8.2, 7.1,
0.9 Hz, H-6), 7.41–7.44 (m, 1 H, H-b), 7.43 (d, 2 H, J = 8.8
Hz, H-2¢,6¢), 7.49 (d, 1 H, J = 8.1 Hz, H-8), 7.67 (ddd, 1 H,
J = 8.1, 7.1, 1.7 Hz, H-7), 8.18 (dd, 1 H, J = 8.2, 1.7 Hz, H-
5). 13C NMR (75.47 MHz, CDCl3): d = 55.3 (OCH3), 109.9
(C-3), 114.3 (C-3¢-5¢), 117.7 (C-8), 122.3 (C-a), 124.1 (C-
10), 124.8 (C-6), 125.0 (C-g), 125.5 (C-5), 128.5 (C-2¢,6¢),
128.6 (C-1¢), 133.6 (C-7), 137.8 (C-b), 138.9 (C-d), 140.4
(C-9), 160.3 (C-4¢), 162.0 (C-2), 178.4 (C-4). ESI-MS: m/z
(rel. int.) = 305 (100) [M + H]+, 327 (110) [M + Na]+, 343
(20) [M + K]+, 631 (11) [2 M + Na]+. Anal. Calcd for
C20H16O3: C, 78.93; H, 5.30. Found: C, 78.86; H, 5.30.
(20) Physical Data of 1,4-Dihydro-1-phenyl-9H-xanthen-9-
one (7a)
(1) (a) Hostettman, K.; Hostettman, M. Plant Phenolics, In
Methods in Plant Biochemistry, Vol. 1; Dey, P. M.; Harbone,
J. B., Eds.; Academic Press: San Diego, 1989, 493.
(b) Gales, L.; Damas, A. M. Curr. Med. Chem. 2005, 12,
2499.
(2) Vieira, L. M. M.; Kijjoa, A. Curr. Med. Chem. 2005, 12,
2413.
(3) Fukawa, I.; Yoneda, H.; Asahi, K. K. K. K. EP 0237004,
1987.
(4) Kelkar, A. S.; Letcher, R. M.; Cheung, K.-K.; Chiu, K.-F.;
Brown, G. D. J. Chem. Soc., Perkin Trans. 1 2000, 3732.
(5) (a) Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur.
J. Org. Chem. 2009, 2642. (b) Santos, C. M. M.; Silva, A.
M. S.; Cavaleiro, J. A. S. Synlett 2007, 3113. (c) Santos,
C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Synlett 2005,
3095.
(6) (a) 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. (b) Pinto, M. M. M.;
Sousa, M. E.; Nascimento, M. S. J. Curr. Med. Chem. 2005,
12, 2517.
(7) (a) 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. (b) Jiang, D.-J.; Dai, Z.; Li,
Y.-J. Cardiovasc. Drug Rev. 2004, 22, 91.
(8) (a) Na, Y. J. Pharm. Pharmacol. 2009, 61, 707. (b) Ee, G.
C. L.; Daud, S.; Izzaddin, S. A.; Rahmani, M. J. Asian Nat.
Prod. Res. 2008, 10, 475.
Yellow oil. 1H NMR (300.13 MHz, CDCl3): d = 2.76 (ddd,
1 H, J = 18.6, 5.8, 1.3 Hz, H-4trans), 3.01 (ddd, 1 H, J = 18.6,
9.7, 2.8 Hz, H-4cis), 4.56 (d, 1 H, J = 9.7 Hz, H-1), 6.39 (dd,
1 H, J = 9.7, 2.8 Hz, H-2), 6.44–6.51 (m, 1 H, H-3), 7.14–
7.26 (m, 3 H, H-3¢,4¢,5¢), 7.33–7.35 (m, 2 H, H-2¢,6¢), 7.33–
7.37 (m, 1 H, H-7), 7.45 (d, 1 H, J = 7.9 Hz, H-5), 7.62 (ddd,
1 H, J = 7.9, 7.7, 1.6 Hz, H-6), 8.17 (dd, 1 H, J = 7.9, 1.6 Hz,
H-8). 13C NMR (75.47 MHz, CDCl3): d = 31.5 (C-4), 33.4
(C-1), 116.6 (C-9b), 117.9 (C-5), 121.9 (C-2), 124.3 (C-8a),
124.8 (C-7), 125.9 (C-8), 125.9 (C-4¢), 127.1 (C-2¢,6¢), 128.4
(C-3¢,5¢), 133.1 (C-6), 138.4 (C-3), 143.3 (C-1¢), 155.4 (C-
4b), 159.3 (C-4a), 176.4 (C-9).
(9) (a) Riscoe, M.; Kelly, J. X.; Winter, R. Curr. Med. Chem.
2005, 12, 2539. (b) Portela, C.; Afonso, C. M. M.; Pinto, M.
M. M.; Ramos, M. J. Bioorg. Med. Chem. 2004, 12, 3313.
(10) (a) Santos, C. M. M.; Freitas, M.; Ribeiro, D.; Gomes, A.;
Silva, A. M. S.; Cavaleiro, J. A. S.; Fernandes, E. Bioorg.
Med. Chem. 2010, 18, 6776. (b) Pothitirat, W.;
Chomnawang, M. T.; Supabphol, R.; Gritsanapan, W.
Fitoterapia 2009, 80, 442.
(21) Typical Experimental Procedure
Iodine (18 mg, 0.07 mmol) was added to a solution of the
appropriated chomone 5a–e (0.35 mmol) in 1,2-4-
trichlorobenzene (5 mL), and the mixture was refluxed for
48 h. After this period the solution was directly purified by
silica gel column chromatography using light PE as eluent to
remove 1,2,4-trichlorobenzene and then CH2Cl2 to recover
the product. The solvent was evaporated to dryness and the
residue were recrystallized from EtOH to give the 1-aryl-
9H-xanthen-9-ones 6a–e in moderated yields (Table 1).
(11) Khan, M. T. H.; Orhan, I.; Şenol, F. S.; Kartal, M.; Sener, B.;
Dvorská, M.; Šmejkal, K.; Šlapetová, T. Chem. Biol.
Interact. 2009, 181, 383.
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1406
C. I. C. Esteves et al.
LETTER
(22) Physical Data of 1-Phenyl-9H-xanthen-9-one (6a)
Mp 177–179 °C. 1H NMR (300.13 MHz, CDCl3): d = 7.18
(dd, 1 H, J = 7.2, 1.2 Hz, H-2), 7.31 (ddd, 1 H, J = 7.8, 7.5,
1.1 Hz, H-7), 7.33–7.36 (m, 2 H, H-2¢,6¢), 7.41–7.45 (m, 3
H, H-3¢,4¢,5¢), 7.48 (d, 1 H, J = 8.6 Hz, H-5), 7.53 (dd, 1 H,
J = 8.4, 1.2 Hz, H-4), 7.67–7.80 (m, 2 H, H-3 and H-6), 8.18
(dd, 1 H, J = 7.8, 1.7 Hz, H-8). 13C NMR (75.47 MHz,
CDCl3): d = 117.4 (C-5), 117.7 (C-4), 119.3 (C-9b), 122.7
(C-8a), 123.8 (C-7), 127.0 (C-8), 127.1 (C-4¢), 127.2 (C-2),
127.5 (C-3¢,5¢), 128.4 (C-2¢,6¢), 133.4 (C-3), 134.5 (C-6),
141.8 (C-1¢), 144.2 (C-1), 155.4 (C-4b), 157.3 (C-4a), 176.9
(C-9). ESI-MS: m/z (rel. int.) = 273 (100) [M + H]+, 295 (76)
[M + Na]+, 311 (12) [[M + K]+, 567 (4) [2 M + Na]+. Anal.
Calcd for C19H12O2: C, 83.81; H, 4.44. Found: C, 83.57; H,
4.13.
(23) Hepperle, S. S.; Li, Q.; East, A. L. L. J. Phys. Chem. A 2005,
109, 10975.
Synlett 2011, No. 10, 1403–1406 © Thieme Stuttgart · New York