An efficient three-component synthesis of benzoxanthenes in water

Article abstract of DOI:10.1002/jhet.420

(Chemical Equation Presented) A clean, one-pot and three-component synthesis of new dibenzo[a,i]xanthene-diones derivatives by cyclo-condensation reaction of 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and dimedone or 2-naphthol in aqueous media is reported.

Full text of DOI:10.1002/jhet.420

1062
An Efficient Three-Component Synthesis of Benzoxanthenes
in Water
Vol 47
Minoo Dabiri, Zeinab Noroozi Tisseh, and Ayoob Bazgir*
Department of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran
*E-mail: a_bazgir@sbu.ac.ir
Received November 23, 2009
DOI 10.1002/jhet.420
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A clean, one-pot and three-component synthesis of new dibenzo[a,i]xanthene-diones derivatives by
cyclo-condensation reaction of 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and dimedone or 2-
naphthol in aqueous media is reported.
J. Heterocyclic Chem., 47, 1062 (2010).
INTRODUCTION
reported for the preparation of xanthene derivatives
[4,5f–h, 14–17].
ortho-Quinone methides (o-QMs) are highly reactive
intermediates that have been extensively harnessed by
nature. Despite the general knowledge of o-QMs for
over a century these intermediates still lie outside the
synthetic mainstream [1,2]. Very recently, Pettus
described the methods by which o-QMs are prepared,
the benefits and limitations associated with each method
as well as current applications in total synthesis [3]. The
pseudo three-component condensation reaction of 2-
naphthol with aldehydes in the presence of various cata-
lysts to form xanthenes has been studied widely. The
reaction proceeds through the in situ formation of ortho-
quinone methides with 2-naphthol acting as a nucleo-
phile [4]. However, the three-component condensation
reactions of 2-naphthol and aldehydes with other nucleo-
philes is rarely reported in literature [5].
Molecules with the naphthoquinone structure consti-
tute one of the most interesting classes of compounds in
organic chemistry, because of their biological properties,
their industrial applications, and their potential as inter-
mediates in the synthesis of heterocycles [18]. Naphtho-
quinone moiety occurs in different natural products,
including b-lapachone A, a-xiloidone B, lambertellin C,
WS-5995A D, and pyranokunthone B E [19]. Com-
pounds F and G were extracted from marine actinomy-
cete strain CNQ-525 bacteria; these bacteria were iso-
lated from ocean sediments, which were collected at a
depth of 152 m near La Jolla, California (Fig. 1). Com-
pounds F and G possess significant antibiotic properties
and cancer cell cytotoxicities activities [20].
In continuation of our previous works on synthesis of
heterocycles containing naphthoquinone or xanthene
moiety [21–25], herein we report a simple and efficient
method for the preparation of benzo[b]xanthene-triones
and dibenzo[a,i]xanthene-diones in aqueous media.
Xanthenes and benzoxanthenes have been reported to
posses diverse biological and therapeutic properties,
such as antibacterial [6], antiviral [7], and anti-inflam-
matory activities [8], as well as photodynamic therapy
[9] and for antagonism of the paralyzing action of zoxa-
zolamine [10]. The other useful applications of this het-
erocycles are as dyes [11], fluorescent materials for vis-
ualization of biomolecules [12], and in laser technolo-
gies [13]. Therefore, a number of methods have been
RESULTS AND DISCUSSION
We found that a mixture of 2-hydroxynaphthalene-
1,4-dione 1, 2-naphthol 2 and aromatic aldehydes 3a–i,
C
V
2010 HeteroCorporation

September 2010
An Efficient Three-Component Synthesis of Benzoxanthenes in Water
1063
Figure 1. Examples of biologically active naphthoquinone derivatives.
in the presence of a catalytic amount of p-toluenesul-
fonic acid (p-TSA) as an inexpensive and readily avail-
able catalyst at refluxing water for 8–10 h, afforded 14-
aryl-8H-dibenzo[a,i]xanthene-8,13(14H)-diones 4a–i in
83–91% yields (Scheme 1). The optimized results are
summarized in Table 1. In all cases, aromatic aldehydes
substituted with either electron-donating or electron-
withdrawing groups underwent the reaction smoothly
and gave the products in good yields.
The nature of the compounds 4 and 7 as 1:1:1 adducts
was apparent from their mass spectra, which displayed,
in each case, the molecular ion peak at appropriate m/z
values. Compounds 4 and 7 are stable solids whose
structures are fully supported by IR, NMR spectroscopy,
and elemental analysis.
In summary, a novel, simple, convenient, and practi-
cal method for the synthesis of substituted benzo[b]xan-
thene-triones and dibenzo[a,i]xanthene-diones has been
reported by one-pot and three component reaction using
p-TSA as an inexpensive and readily available catalyst.
This protocol includes some important aspects like the
use of water as a ‘‘green’’ reaction medium, high atom
economy, mild reaction conditions, and excellent yields.
The results were good in terms of yields and product
purity in the presence of p-TSA, while without p-TSA
and over long period of time (24 h) the yields of prod-
ucts were low (<30%).
When this reaction was carried out with aliphatic
aldehyde, such as butanal or pentanal, TLC and 1H
NMR spectra of the reaction mixture showed a combi-
nation of starting materials and numerous products, the
yield of the expected product was very poor.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. Mass spectra were recorded on
a FINNIGAN-MAT 8430 mass spectrometer operating at an
ionization potential of 70 eV. IR spectra were recorded on a
By referring to the literature [4], the formation of prod-
ucts 4 can be rationalized by initial formation of ortho-
quinone methides intermediate 5. Subsequent addition of
1 to the intermediate 5, followed by elimination of water
afforded the corresponding products 4 (Scheme 2).
To further explore the potential of this protocol for
xanthene synthesis, we investigated reaction of 1,3-
cyclohexadione 6 instead of 2-naphthol 2 and obtained
3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,12H)-trione
7a–i, in good yields for 14–16 h (Scheme 3). The opti-
mized results are summarized in Table 2.
1
Shimadzu IR-470 spectrometer. H and 13C NMR spectra were
recorded on a BRUKER DRX-300 AVANCE spectrometer at
Table 1
Synthesis of dibenzo[a,i]xanthene-diones 4.
Product 4
Ar
Time (h)
Yield (%)
a
b
c
d
e
f
C6H5
10
9
88
83
89
85
84
87
78
91
87
4-ClAC6H4
4-BrAC6H4
4-FAC6H4
4-MeOAC6H4
4-MeAC6H4
4-HOAC6H4
3-NO2AC6H4
2-ClAC6H4
10
8
Scheme 1
10
10
10
8
g
h
i
9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1064
M. Dabiri, Z. N. Tisseh, and A. Bazgir
Vol 47
Scheme 2
Table 2
Synthesis of dibenzo[a,i]xanthene-diones 7.
Product 7
Ar
Time (h)
Yield (%)
a
b
c
d
e
f
g
h
I
C6H5
16
15
16
14
14
16
16
15
16
82
90
86
82
84
83
87
81
80
4-ClAC6H4
4-BrAC6H4
4-FAC6H4
4-NO2AC6H4
4-MeAC6H4
2-ClAC6H4
3-NO2AC6H4
3-BrAC6H4
300.13 and 75.47 MHz, respectively. Elemental analyses were
performed using a Heracus CHN-O-Rapid analyzer.
8.07 (1H, m, H-Ar). 13C NMR (75 MHz, DMSO-d6): dc 26.9,
28.9, 32.4, 32.7, 40.1, 113.6, 124.2, 126.2, 126.5, 127.2, 128.7,
128.8, 129.0, 130.9, 131.4, 134.6, 135.0, 143.2, 149.5, 163.4,
177.5, 183.2, 196.3. MS (m/z) 384 (Mþ). Anal. Calcd for
C25H20O4: C, 78.11; H, 5.24;%. Found: C, 78.21; H, 5.29%.
12-(4-Chlorophenyl)-3,3-dimethyl-3,4-dihydro-1H-ben-
zo[b]xanthene-1,6,11(2H,12H)-trione (7b). Yellow powder
(90%); mp: 282–284ꢀC. IR (KBr) (mmax/cmꢁ1): 2932, 1663,
Typical procedure for preparation of 14-phenyl-8H-
dibenzo[a,i]xanthene-8,13(14H)-dione (4a). A mixture of
benzaldehyde (0.11 g, 1 mmol), 2-naphtol (0.140 g, 1 mmol),
2-hydroxynaphthalene-1,4-dione (0.17 g, 1 mmol), p-TSA (0.1
g) was refluxed in water (5 mL) for 10 h (TLC). At the end of
the reaction, the precipitate formed was collected by filtration
and washed with ethanol to afford the pure product 4a. Orange
powder (88%); m.p. 294–297ꢀC; IR (KBr) (mmax/cmꢁ1): 3054,
1
1
1618, 1594. H NMR (300 MHz, DMSO-d6): dH 0.94 (3H, s,
1703, 1656; H NMR (DMSO-d6): dH 5.09 (1H, s, CH), 7.16–
8.08 (15H, m, H-Ar). MS (m/z) 388 (Mþ). Anal. Calcd (%) for
C27H16O3: C, 83.49; H, 4.15. Found C, 83.55; H, 4.10.
Selected Characterization Data.
CH3), 1.06 (3H, s, CH3), 2.15 and 2.31 (2H, AB system, J ¼
16.2 Hz, CH2), 2.67 (2H, s, CH2), 4.89 (1H, s, CH), 7.28–7.37
(4H, m, H-Ar), 7.83–7.90 (3H, m, H-Ar), 8.03–8.06 (1H, m,
H-Ar). 13C NMR (75 MHz, DMSO-d6): dc 26.9, 29.0, 32.5,
33.7, 33.5, 50.5, 113.7, 124.2, 126.2, 126.5, 127.2, 128.6,
129.1, 130.9, 131.4, 134.6, 135.0, 143.2, 149.5, 163.4, 183.3,
196.4. MS (m/z) 418 (Mþ). Anal. Calcd for C25H19ClO4: C,
71.69; H, 4.57%. Found: C, 71.78; H, 4.50%.
14-(4-Chlorophenyl)-8H-dibenzo[a,i]xanthene-8,13(14H)-
dione(4b). Yellow powder (83%); m.p. 281–284ꢀC; IR (KBr)
1
(mmax/cmꢁ1): 3044, 1699, 1663; H NMR (DMSO-d6): dH 5.77
(1H, s, CH), 7.24 (2H, d, J ¼ 7.4 Hz, H-Ar), 7.39 (2H, d, J ¼
7.4 Hz, H-Ar), 7.46–7.51 (2H, m, H-Ar). 7.67–7.74 (2H, m,
H-Ar). 7.86 (1H, d, J¼7.1 Hz, H-Ar), 7.90–8.02 (4H, m, H-
Ar), 8.20 (1H, d, J¼7.1 Hz, H-Ar). MS (m/z, %) 422 (Mþ).
Anal. Calcd (%) for C27H15ClO3: C, 76.69; H, 3.58. Found C,
76.61; H, 3.52.
12-(4-Bromophenyl)-3,3-dimethyl-3,4-dihydro-1H-ben-
zo[b]xanthene-1,6,11(2H,12H)-trione (7c). Yellow powder
(86%); mp: 268–270ꢀC. IR (KBr) (mmax/cmꢁ1): 2957, 1660,
1
1616, 1579. H NMR (300 MHz, DMSO-d6): dH 0.94 (3H, s,
CH3), 1.07 (3H, s, CH3), 2.15 and 2.31 (2H, AB system, J ¼
15.9 Hz, CH2), 2.67 (2H, s, CH2), 4.88 (1H, s, CH), 7.10–7.12
(2H, d, J ¼ 8.4 Hz, H-Ar), 7.42–7.45 (2H, m, H-Ar), 7.83–
7.90 (3H, m, H-Ar), 8.03–8.06 (1H, m, H-Ar). 13C NMR (75
MHz, DMSO-d6): dc 27.3, 29.0, 32.4, 33.7, 40.7, 50.5, 113.3,
123.8, 123.9, 126.6, 126.8, 129.7, 130.4, 131.4, 134.1, 134.7,
146.9, 149.3, 149.6, 163.4, 177.5, 196.0. MS (m/z) 464 (Mþ),
462 (Mþ). Anal. Calcd for C25H19BrO4: C, 64.81; H, 4.13%.
Found: C, 64.73; H, 4.20%.
14-(4-Bromophenyl)-8H-dibenzo[a,i]xanthene-8,13(14H)-
dione (4c). Yellow powder (89%); m.p. 294–298ꢀC; IR (KBr)
1
(mmax/cmꢁ1): 3075, 1704, 1663; H NMR (DMSO-d6): dH 5.89
(1H, s, CH), 7.27–7.34 (4H, m, H-Ar), 7.45 (2H, t, J ¼ 6.8
Hz, H-Ar). 7.50–7.62 (2H, m, H-Ar), 7.79 (1H, t, J ¼ 7.6 Hz,
H-Ar). 7.85–7.92 (3H, m, H-Ar), 8.11–8.18 (2H, m, H-Ar).
MS (m/z, %) 468 (Mþ þ 2), 466 (Mþ). Anal. Calcd (%) for
C27H15BrO3: C, 69.39; H, 3.24. Found C, 69.30; H, 3.33.
Due to very low solubility of the product 4a–c, we cannot
report the 13C NMR data for this product.
12-phenyl-3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,12H)-
trione (7a). Orange powder (82%); mp: 263–265ꢀC. IR (KBr)
(mmax/cmꢁ1): 2926, 1678, 1606. 1H NMR (300 MHz, DMSO-
d6): dH 0.94 (3H, s, CH3), 1.07 (3H, s, CH3), 2.15 and 2.31
(2H, AB system, J ¼ 16.2 Hz, CH2), 2.67 (2H, s, CH2), 4.88
(1H, s, CH), 7.10–7.15 (1H, m, H-Ar), 7.21–7.32 (2H, m, H-
Ar), 7.43–7.46 (2H, m, H-Ar). 7.80–7.91 (3H, m, H-Ar) 7.99–
REFERENCES AND NOTES
¨
[1] Domling, Wan, P.; Backer, B.; Diao, L.; Fischer, M.; Shi,
Y.; Yang, C. Cancer J. Chem. 1996, 74, 465.
[2] Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651.
[3] Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58,
5367.
[4] (a) Rajitha, B.; Kumar, B. S.; Reddy, Y. T.; Reddy, P. N.;
Sreenivasulu, N. Tetrahedron Lett. 2005, 46, 8691; (b) Khosropour,
A. R.; Khodaei, M. M.; Moghannian, H. Synlett 2005, 955; (c) Ko, S.;
Yao, C.-F. Tetrahedron Lett. 2006, 47, 8827.
Scheme 3
[5] (a) Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron:
Asymmetry 2002, 13, 2417; (b) Lu, J.; Xu, X.; Wang, C.; He, J.; Hu,
´ ´ ´
Y.; Hu, H. Tetrahedron Lett 2002, 43, 8367; (c) Szatmari, I.; Lazar,
¨
L.; Fu¨lop, F. Tetrahedron Lett. 2006, 47, 3881; (d) Saidi, M. R.; Azizi,
N. Tetrahedron: Asymmetry 2003, 14, 389; (e) Khosropour, A. R.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
An Efficient Three-Component Synthesis of Benzoxanthenes in Water
1065
Khodaei, M. M.; Moghannian, H. Synlett 2005, 916. (f) Khurana, J.
M.; Magoo, D. Tetrahedron Lett. 2009, 50, 4777; (g) Li, J.; Tang, W.;
Lu, L.; Su, W. Tetrahedron Lett. 2008, 49, 7117; (h) Das, B.; Laxmi-
narayana, K.; Krishnaiah, M.; Srinivas, Y. Synlett 2007, 3107.
[6] Hideu, T.; Teruomi, J. Jpn. Pat. 56,005,480, 1981.
[7] Lamberk, R. W.; Martin, J. A.; Merrett, J. H.; Parkes, K. E.
B.; Thomas, G. J. PCT Int. Appl. WO 9706178, 1997.
[8] Poupelin, J. P.; Saint-Rut, G.; Fussard-Blanpin, O.;
Narcisse, G.; Uchida-Ernouf, G.; Lakroix, R. Eur J Med Chem 1978,
13, 67.
[15] Bekaert, A.; Andrieux, J.; Plat, M. Tetrahedron Lett 1992,
33, 2805.
[16] Jha, A.; Beal, J. Tetrahedron Lett 2004, 45, 8999.
[17] Knight, D. W.; Little, P. B. J Chem Soc Perkin Trans 1
2001, 1771.
[18] Thomson R H. Naturally Occurring Quinones, 4th ed.;
Chapman & Hall: London, 1997.
[19] Noroozi Tisseh, Z.; Azimi, S. C.; Mirzaei, P.; Bazgir, A.
Dyes Pigments 2008, 79, 273.
[20] Bazgir, A.; Noroozi Tisseh, Z. Dyes Pigments 2009,
83, 258.
[9] Ion, R.-M.; Frackowiak, D.; Planner, A.; Wiktorowicz, K.
Acta Biochim Pol 1998, 45, 833.
[21] Bazgir, A.; Noroozi Tisseh, Z.; Mirzaei, P. Tetrahedron Lett
2008, 49, 5165.
[10] Saint-Ruf, G.; De, A.; Hieu, H. T. Bull Chim Ther 1972,
7, 83.
[22] Seyyedhamzeh, M.; Mirzaei, P.; Bazgir, A. Dyes Pigments
2008, 76, 836.
[11] Banerjee, A.; Mukherjee, A. K. Stain Technol. 1981,
56, 83.
[23] Imani Shakibaei, G.; Mirzaei, P.; Bazgir, A. Appl Catal A:
Gen 2007, 325, 188.
[12] Knight, C. G.; Stephenes, T. Biochem. J. 1989, 258, 683.
[13] Sirkecioglu, O.; Tulinli, N.; Akar, A. J Chem Res (S)
1995, 502.
[24] Amini, M. M.; Seyyedhamzeh, M.; Bazgir, A. Appl Catal
A: Gen 2007, 323, 242.
[14] Van Allan, J. A.; Giannini, D. D.; Whitesides, T. H. J Org
Chem 1982, 47, 820.
[25] Imani Shakibaei, G.; Mirzaei, P.; Bazgir, A. Appl Catal A:
Gen 2007, 325, 188.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet