Synthesis of benzo[c]xanthones from 2-benzylidene-1-tetralones by the ultraviolet radiation-mediated tandem reaction

Article abstract of DOI:10.1021/jo8008929

(Chemical Equation Presented) A facile one-pot method to prepare benzo[c]xanthones from readily accessible benzylidene-1-tetralones by the ultraviolet radiation-mediated tandem reaction is reported. The overall transformation presumably involves cis-trans

Full text of DOI:10.1021/jo8008929

pylamide or with acetyl chloride to yield xanthones.4 Recently,
Zhao and Larock reported a facile one-pot coupling method to
synthesize xanthones and thioxanthones from arynes and
substituted benzoates with good yields.5 The key intermediate
of this method is a diaryl (thio)ether. Other less used methods
of synthesis of xanthones include thermal condensation of phenols
and ꢀ-keto-esters (to prepare dihydrobenzo[a]xanthones),6 Diels-
Alder reaction of chromone-3-carboxaldehydes with o-benzoquin-
odimethane (to prepare benzo[b]xanthones),7 benzannulation of 1,2-
adducts derived from 3-(o-anisoyl)-4-substituted cyclobutenedi-
ones,8 and cycloaddition of 2-styrylchromones with appropriate
dienophiles.9 In particular, photooxidative cyclization of 2-styryl-
chromones,10 2-benzyl-3-benzoylchromones,11 and 2-styryl-4H-
chromen-4-ones12 can also afford benzoxanthones. But most
reported methods are multistep, with harsh reaction conditions, or
are not atom-economic. Here, we reported a new one-pot method
to prepare benzo[c]xanthones from readily accessible benzylidene-
1-tetralones by the ultraviolet radiation-mediated tandem reaction.
The overall transformation presumably involves cis-trans isomer-
ization, oxa-6π electrocyclization, singlet oxygen ene reaction,
dehydration, and aromatization. Moreover, in contrast to the
methods described above, the oxygen atom of the carbonyl group
of xanthone comes from the oxygen dissolved in the solvent.
Synthesis of Benzo[c]xanthones from
2-Benzylidene-1-tetralones by the Ultraviolet
Radiation-Mediated Tandem Reaction
Wen-Zhi Xu, Zhi-Tang Huang, and Qi-Yu Zheng*
Beijing National Laboratory for Molecular Sciences,
Research Center for Chemical Biology, Institute of
Chemistry, Chinese Academy of Sciences,
Beijing 100080, China
zhengqy@iccas.ac.cn
ReceiVed April 24, 2008
A facile one-pot method to prepare benzo[c]xanthones from
readily accessible benzylidene-1-tetralones by the ultraviolet
radiation-mediated tandem reaction is reported. The overall
transformation presumably involves cis-trans isomerization,
oxa-6π electrocyclization, singlet oxygen ene reaction,
dehydration, and aromatization.
SCHEME 1. Synthesis of Benzo[c]xanthones from
Benzylidene-1-tetralones
Xanthones have engendered a great deal of interest due to
their wide range of biological and pharmacological activities,
e.g., antibacterial, anti-inflammatory, antioxidant, antiulcer, and
antitumor.1 Mangostins, a kind of xanthones isolated from the
pericarps of mangosteen, can induce caspase-3-dependent apo-
ptosis in human leukemia HL60 cells or cell-cycle arrest and
apoptosis in human colon cancer DLD-1 cells. They would be
candidates for preventive and therapeutic application for cancer
treatment.2
Two main methods have been applied for the synthesis of
xanthones. One is through the intermediates of benzophenones.
2,2′-Dioxygenated benzophenones, which can be prepared by
acylation or Fries arrangement, are cyclized through the
dehydrative or oxidative process to form xanthones.3 Another
is through the intermediates of diary ethers. 2-Carboxy biphenyl
ethers, which are obtained by the Ullmann method or Smiles
rearrangement, are cyclized in one step with lithium diisopro-
Irradiating the solution of 2-benzylidene-1-tetralone (1e) in
acetonitrile with ultraviolet light (a 500 W middle-pressure Hg
(3) (a) Grover, P. K.; Shah, G. D.; Shah, R. C. J. Chem. Soc. 1955, 3982.
(b) Quillinan, A. J.; Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1973, 1329.
(c) Lown, J. W.; Sondhi, S. M. J. Org. Chem. 1984, 49, 2844. (d) Casillas,
L. K.; Townsend, C. A. J. Org. Chem. 1999, 64, 4050. (e) Piettre, A.; Chevenier,
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Synlett 2004, 2693.
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Snieckus, V. Synlett 1997, 1081.
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R. C. J. Org. Chem. 2007, 72, 583.
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L. M. V. J. Chem. Soc., Perkin Trans. 1 1998, 1547. (d) Kelkar, A. S.; Letcher,
R. M.; Cheung, K.-K.; Chiu, K.-F.; Brown, G. D. J. Chem. Soc., Perkin Trans.
1 2000, 3732.
(1) For some reviews on xanthones and related compounds, see: (a) Roberts,
J. C. Chem. ReV. 1961, 61, 591. (b) Afzal, M.; Al-Hassan, J. M. Heterocycles
1980, 14, 1173. (c) Lown, J. W. Chem. Soc. ReV. 1993, 22, 165. (d) Peres, V.;
Nagem, T. J.; Faustino de Oliveria, F. Phytochemistry 2000, 55, 683. (e) Sousa,
M. E.; Pinto, M. M. M. Curr. Med. Chem. 2005, 12, 2447. (f) Pinto, M. M. M.;
Sousa, M. E.; Nascimento, M. S. J. Curr. Med. Chem. 2005, 12, 2517.
(2) (a) Matsumoto, K.; Akao, Y.; Kobayashi, E.; Ohguchi, K.; Ito, T.; Tanaka,
T.; Iinuma, M.; Nozawa, Y. J. Nat. Prod. 2003, 66, 1124. (b) Matsumoto, K.;
Akao, Y.; Yi, H.; Ohguchi, K.; Ito, T.; Tanaka, T.; Kobayashi, E.; Iinuma, M.;
Nozawa, Y. Bioorg. Med. Chem. 2004, 12, 5799. (c) Matsumoto, K.; Akao, Y.;
Ohguchi, K.; Ito, T.; Tanaka, T.; Iinuma, M.; Nozawa, Y. Bioorg. Med. Chem.
2005, 13, 6064.
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Jimeno, M. L.; Elguero, J. Eur. J. Org. Chem. 1998, 2031.
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5606 J. Org. Chem. 2008, 73, 5606–5608
10.1021/jo8008929 CCC: $40.75 2008 American Chemical Society
Published on Web 06/14/2008

TABLE 2. Ultraviolet Radiation-Mediated Oxidative Cyclization
of Benzylidene-1-tetralones to Benzo[c]xanthonesa
FIGURE 1. Crystal structure of compound 2i. The 50% thermal
ellipsoid is shown for the non-hydrogen atoms.
TABLE 1. Optimization of the Photooxidative Cyclization of
2-Benzyliene-7-bromo-1-tetralone (1b)
entry
filter
sensitizer
yield (%)a
1
2
3
4
5
6
7
8
9
no
8
7
6
10
19
26
trace
11
35
27
glass filter
toluene/hexane
1,4-dimethylbenzene/EtOH
1,3,5-trimethylbenzene/EtOH
b
1,3,5-trimethylbenzene/EtOH fullerene C60
1,3,5-trimethylbenzene/EtOH methylene blueb
1,3,5-trimethylbenzene/EtOH rhodamine Bb
1,3,5-trimethylbenzene/EtOH rose bengalb
10 1,3,5-trimethylbenzene/EtOH 9,10-dicyanoan-thraceneb
a All the reactions were carried out for 24 h except entry 2 (42 h).
b With 0.027 equiv of singlet oxygen sensitizer.
a No oxidative cyclization product was isolated.
lamp) for several days, we obtained a new compound from the
reaction mixture (Scheme 1). Compared with the original
tetralone structure, this product displays no methylene hydrogen
dissolved in the solution. We have also carried out the reaction
with a continuous stream of oxygen, but the yield could not be
increased. However, the yield of this ultraviolet radiation-
mediated reaction could be improved upon addition of a singlet
oxygen sensitizer. A number of typical singlet oxygen sensitizers
have been screened, and rose bengal is the best one for this
reaction. These results also indicate that it is the singlet oxygen
that participates in the oxidative cyclization.
1
signals in its H NMR spectrum. The high-resolution mass
spectrum indicates that its chemical formula is C17H10O2. The
final structure of the product has been deduced to be 7H-
benzo[c]xanthen-7-one (2e), whose NMR spectra coincide with
the reported data.5a The crystal structure of 2i (Figure 1), which
was synthesized by our method from 2-benzylidene-6-methoxy-
1-tetralone, has confirmed the core structure of 7H-benzo[c]-
xanthen-7-one.13
The scope and limitation of the photoinduced oxidative
cyclization were examined under optimized conditions (Table
2). The results show that the substituents on the phenyl group
of tetralone have no apparent effect on the reaction. The
irradiation of 2-benzyliene-1-tetralones containing less electron-
poor aromatic rings (1a-d), neutral aromatic rings (1e-g), or
electron-rich aromatic rings (1h-j) affords the expected xan-
thones with moderate yields. But the tetralone skeleton is
essential here. Under the same condition, we only isolated the
[2 + 2] cyclization dimer starting from 2-benzylidenecyclo-
hexanone. On the other hand, the nature of the substituents
present at para or meta positions of the benzylidene unit greatly
influences the reaction. Neither a strong electron-withdrawing
group (NO2) nor a strong electron-donating group (OCH3) atthe
para position of the benzylidene (1k, 1l) is tolerated. For the
2-benzyliene-1-tetralones with these groups, the cleaved benzoic
acids were occasionally isolated. The substituent located at the
meta position of benzylidene is also disadvantageous, and the
transformation of 1m did not occur. However, it is not easy to
find a clear rule for the substitutent effect, which may be due
to the nature of the photochemical reactions.
The conditions of this ultraviolet radiation-mediated reaction
have been optimized carefully. We first studied the effect of
different solvents and found that acetonitrile could give the best
yield. This reaction did not occur in other solvents such as
acetone, THF, dioxane, ethyl acetate, CCl4, and DMF. Due to
the complicated side reactions found in most ultraviolet radia-
tion-mediated reactions, it is necessary to control the irradiation
wavelength. We have used a 360 nm glass filter, but the yield
was as low as without it (Table 1). Many solution filters have
also been investigated. Irradiating 2-benzylidene-1-tetralones
through the solution filters of chlorobenzene/ethanol, aniline/
water, acetone/hexane, acetophone/ethanol, and pyridine/hexane
did not afford the xanthones. The solution filter of 1,4-
dimethylbenzene/EtOH and toluene/hexane did not affect reac-
tion. Only the solution filter of 1,3,5-trimethylbenzene/EtOH
improved the yield of the reaction. Finally, the role of oxygen
was investigated. When the reaction solution was degassed with
an argon stream for 30 min prior to irradiation, the cis isomer
of benzylidene-1-tetralone was isolated, but it slowly converted
into starting material on standing. Therefore, the additional
oxygen atom of the final product should come from the oxygen
The mechanism shown in Scheme 2 is proposed for this
process. The benzylidene-1-tetralone undergoes cis-trans isomer-
ization first. We noticed that this oxidative cyclization could
not take place upon irradiating the crystalline powder of
benzylidene-1-tetralone. It may be interpreted that the cis-trans
isomerization is not easy in the solid state. By TLC, GC-MS,
and NMR (see the Supporting Information), we have also
observed the cis-isomer of benzylidene-1-tetralone (I) as an
(13) Crystal data for 2i: C18H12O3, M ) 276.28, orthorhombic, space group
Pna21, a ) 10.5803(14) Å, b ) 23.761(3) Å, c ) 4.9298(7) Å, V ) 1239.3(3)
Å3, Z ) 4, µ(Mo KR) ) 0.101 mm-1, T ) 113(2) K, final residuals (191
parameters) R1 ) 0.0439 for 1570 reflections with I > 2σ(I), and R1 ) 0.0467,
wR2 ) 0.1114, GoF ) 1.076 for all 1644 data.
J. Org. Chem. Vol. 73, No. 14, 2008 5607

SCHEME 2. Proposed Mechanism for Benzo[c]xanthones
Formation
SCHEME 3. Formation of
5H-Dibenzo[c,h]xanthen-7(6H)-ones
In conclusion, we report herein a facile one-pot approach to
synthesize biologically interesting benzo[c]xanthones from
readily accessible 2-benzylidene-1-tetralones by an ultraviolet
radiation-mediated tandem reaction.
intermediate in the reaction, which emerged upon ultraviolet
irradiation and disappeared at the end. The cis-benzylidene-1-
tetralone is easily cyclized to generate the (2H)-pyran ring
through a thermoneutral oxa-6π electrocyclization, which cy-
clizes with low activation energies.14 Then the intermediate
6,11a-dihydro-5H-benzo[c]xanthene (II), which could not be
isolated in the absence of oxygen due to highly reversible
electrocyclization,14b is oxidized to afford an allylic hydroper-
oxide in a typical singlet oxygen ene reaction.15 This process
is strongly supported by the fact that the reaction yield was
improved significantly upon adding the singlet oxygen sensitiz-
ers (Table 1).
Experimental Section
Experimental Procedure of Photooxidation Cyclization. A
quartz tube was charged with a solution of benzylidene-1-tetralone
(0.2 mmol) and rose Bengal (0.027 equiv) in acetonitrile (10 mL).
The solution was saturated with oxygen for 30 min and then
irradiated through a filter solution (1,3,5-trimethylbenzene/EtOH
1:1) with a high-pressure mercury lamp (500 W) for the time
indicated in Table 2. The reaction mixture was then concentrated
under vacuum and the residue was purified by silica gel column
chromatography with petroleum ether/EtOAc as eluent.
2-Bromo-10-tert-butyl-7H-benzo[c]xanthen-7-one (2a). Mp
214-216 °C; yield 48%. IR (KBr) ν 2956, 1649, 1632, 1618, 1446,
847 cm-1. 1H NMR (CDCl3) δ 1.46 (s, 9H), 7.52 (dd, J ) 8.4, 1.8
Hz, 1H), 7.68-7.71 (m, 2H), 7.79 (m, 2H), 8.30 (t, J ) 8.1 Hz,
2H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 31.1, 35.6, 114.5, 118.3,
120.1, 121.0, 122.2, 122.6, 123.5, 125.4, 126.2, 129.7, 132.6, 134.8,
152.6, 155.8, 159.4, 176.4. MS (EI) m/z (%) 382 (73), 380 (73),
367 (96), 365 (100). HRMS (EI) m/z calcd for C21H17O281Br
382.0391, found 382.0395; calcd for C21H17O279Br 380.0412, found
382.0408.
The next step is the dehydration16 of the hydroperoxide (III)
to afford 5H-benzo[c]xanthen-7(6H)-one (IV). In all cases
shown in Table 2, compound IV was easily aromatized to yield
the final product benzo[c]xanthone.17 However, for the 2-(naph-
thalen-2-ylmethylene)-1-tetralones (1n,o), there is no further
dehydrogenation (Scheme 3). Only the 5H-dibenzo[c,h]xanthen-
7(6H)-ones (2n,o) have been isolated with low yields (16% and
19%, respectively). This outcome also supports the mechanism
of the overall transformation.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China and the Chinese Academy of
Sciences for financial support. Dr. Q.-Y. Zheng thanks Prof.
Y. Shi and Prof. M.-X. Wang for discussion of this work.
(14) For recent reviews of 6π-oxa-electrocyclization, see: (a) Beaudry, C. M.;
Malerich, J. P.; Trauner, D. Chem. ReV. 2005, 105, 4757. (b) Hsung, R. P.;
Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(15) For some reviews of singlet oxygen ene reactions, see: (a) Stratakis,
M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595. (b) Clennan, E. L.
Tetrahedron 2000, 56, 9151. (c) Clennan, E. L.; Pace, A. Tetrahedron 2005,
61, 6665.
Supporting Information Available: Full experimental details
for the syntheses reported together with spectroscopic and X-ray
crystallographic information file. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) Pagni, R.; Burnett, M. N.; Hassaneen, H. M. Tetrahedron 1982, 38,
843.
(17) (a) Uemura, M.; Take, K.; Hayashi, Y. J. Chem. Soc., Chem. Commun.
1983, 858. (b) Harvey, R.; Pataki, J.; Lee, H. J. Org. Chem. 1986, 51, 1407. (c)
Fang, X.; Liu, Y.; Li, C. J. Org. Chem. 2007, 72, 8608.
JO8008929
5608 J. Org. Chem. Vol. 73, No. 14, 2008