One-pot synthesis of tetrahydrobenzo[a]xanthen-11-one derivatives catalyzed by ruthenium chloride hydrate as a homogeneous catalyst

Article abstract of DOI:10.1139/v11-042

Three-component cyclocondensation of β-naphthol, aldehydes, and 5,5-dimethylcyclohexane-1,3-dione (dimedone) was catalyzed efficiently by ruthenium chloride hydrate under mild reaction conditions to afford 12-aryl or alkyl-8,9,10,12-tetrahydrobenzo[a]xant

Full text of DOI:10.1139/v11-042

623
One-pot synthesis of tetrahydrobenzo[a]xanthen-
11-one derivatives catalyzed by ruthenium
chloride hydrate as a homogeneous catalyst
Khalil Tabatabaeian, Alireza Khorshidi, Manouchehr Mamaghani, Ali Dadashi, and
Milad Khoshnood Jalali
Abstract: Three-component cyclocondensation of b-naphthol, aldehydes, and 5,5-dimethylcyclohexane-1,3-dione (dimedone)
was catalyzed efficiently by ruthenium chloride hydrate under mild reaction conditions to afford 12-aryl or alkyl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one derivatives in good to excellent yields.
Key words: ruthenium, one-pot synthesis, tetrahydrobenzo[a]xanthen-11-one.
Résumé : La cyclocondensation à trois composants du b-naphtol, d’aldéhydes et de 5,5-diméthylcyclohexane-1,3-dione (di-
médone) est catalysée d’une façon efficace par l’hydrate du chlorure de ruthénium, dans des conditions douces, pour
conduire à la formation de dérivés 12-aryl- ou 12-alkyl- de la 8,9,10,12-tétrahydrobenzo[a]xanthén-11-one, avec des rende-
ments allant de bons à excellents.
Mots‐clés : ruthénium, synthèse monotope, tétrahydrobenzo[a]xanthén-11-one.
[Traduit par la Rédaction]
of these methodologies, however, suffer from severe draw-
backs including long reaction times and toxic solvents,16–18,22
the use of expensive reagents,19 drastic conditions for catalyst
preparation,27 the use of a toxic catalyst,21 and the require-
ment of a large or stoichiometric amount of catalysts.20
Therefore, to avoid these limitations, the discovery of a new
and efficient catalyst for preparation of these important mole-
cules is of prime interest.
Introduction
In recent years, multicomponent reactions (MCRs) have at-
tracted great attention from research groups working in me-
dicinal chemistry, drug discovery, and materials science as
they furnish the desired products in a single operation with-
out isolating the intermediates. Simple procedures, facile exe-
cution, atom economy, and high selectivity are among the
described advantages of multicomponent reactions.1–5
Recently, we have been involved in the study of the cata-
lytic activity of ruthenium towards organic reactions such as
the condensation of indoles and aldehydes,28 oxidation of ar-
omatic and heteroaromatic compounds,29 double-conjugate
1,4-addition to enones,30 nucleophilic addition to epoxides,31
oxidative trimerization of indoles,32 and Michael addition of
indoles to hormone steroids.33 As a matter of fact, many or-
ganic transformations that involve ruthenium species as cata-
lyst are known and well-documented.34–36 In continuation of
our investigation in this context, hereby, we introduce a sim-
ple and efficient method for the synthesis of tetrahydrobenzo
[a]xanthen-11-ones from one-pot condensation of b-naphthol,
aldehydes, and dimedone in the presence of ruthenium chlor-
ide hydrate under mild reaction conditions.
Developing ways to synthesize xanthenes and benzoxan-
thenes has been of considerable interest because these com-
pounds possess antiviral,6 antibacterial,7 and anti-inflammatory
properties.8 Such compounds are also utilized for antagonism
of the paralyzing action of zoxazolamine,9 and can also be
employed as dyes,10 as pH-sensitive fluorescent materials for
the visualization of biomolecules,11 and in cancer therapy.12
In addition, these heterocyclic compounds are structural key
units in several natural products.13 Xanthone derivatives are
also found abundantly in a variety of natural products and
exhibit various biological properties.14,15 Synthetic tetrahy-
drobenzo[a]xanthen-11-ones have been prepared through
three-component reaction of b-naphthol, aldehydes, and 1,3-
dicarbonyl compounds in the presence of catalysts such as
BF3·Et2O,16 NaHSO4·SiO2,17 strontium triflate (Sr(OTf)2),18
p-toluenesulfonic acid (pTSA),19 indium trichloride (InCl3),20
phosphorous pentoxide (P2O5),20 I2,21 tetrabutylammonium
fluoride (TBAF),22 HBF4-SiO2,23 dodecatungstophosphoric
acid (H3PW12O40),24 ceric ammonium nitrate (CAN),25 2,4,6-
trichloro-1,3,5-triazine (TCT),26 and HClO4-SiO2.27 Several
Results and discussion
Typical results of the ruthenium-catalyzed cyclocondensa-
tion of b-naphthol, aldehydes, and 5,5-dimethylcyclohexane-
1,3-dione are shown in Table 1. In an optimized procedure,
with respect to the catalyst concentration, choice of solvent,
Received 6 November 2010. Accepted 15 February 2011. Published at www.nrcresearchpress.com/cjc on 5 May 2011.
K. Tabatabaeian, A. Khorshidi, M. Mamaghani, A. Dadashi, and M.K. Jalali. Department of Chemistry, Faculty of Sciences,
University of Guilan, P. O. Box 41335-1914, Iran.
Corresponding author: K. Tabatabaeian (e-mail: Taba@guilan.ac.ir).
Can. J. Chem. 89: 623–627 (2011)
doi:10.1139/V11-042
Published by NRC Research Press

624
Can. J. Chem. Vol. 89, 2011
Table 1. RuCl3·nH2O catalyzed synthesis of 12-aryl or alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones.
Mp (°C)
Time
(min)
Yield
(%)a
Entry
1
2
3
4
5
6
7
8
R
C6H5
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Found
Reported
149–150
178–180
168–170
188–189
179–180
178–180
176–177
151–152
206–207
213–215
—
30
30
35
30
45
35
50
55
55
45
50
50
70
88b
92b
86b
92b
86b
85b
88b
85b
86b
84b
82
148–151
177–180
169–171
187–189
177–180
178–181
175–177
151–153
206–208
214–216
201–204
209–211
116–119
2-ClC6H4
2,4-Cl2C6H3
4-CH3C6H4
4-OHC6H4
4-OCH3C6H4
2-OH-3-OCH3C6H3
3,4-(CH3O)2C6H3
4-SCH3-C6H4
(CH3)2CH
9
10
11
12
13
86
—
4m
75b
116–117
Note: All products were characterized by H NMR, 13C NMR, and IR data.
1
aIsolated yields.
bIdentified by comparison with authentic samples.21, 20, 17, 27
temperature, and time, the treatment of benzaldehyde
(1 mmol), b-naphthol (1 mmol), and dimedone (1.2 mmol)
in the presence of RuCl3·nH2O catalyst (5 mol%) in ethanol
(2.5 mL) at 80 °C for 30 min gave the corresponding tetrahy-
drobenzo[a]xanthen-11-one as a precipitate, which was easily
purified (see Experimental) (product 4a, 88% yield).
of our protocol covers the expensive cost of ruthenium chlor-
ide hydrate. Moreover, reusability of the catalyst was also
studied to minimize costs and inorganic waste. As it is shown
in Table 3, after four times, the reused catalyst showed only a
4% decrease in the yield of desired product.
To improve efficiency, we carried out this reaction under
microwave irradiation. As it is shown in Table 4, this method
affords the desired products in excellent yields in rather short
times.
To evaluate the generality of the process, we also exam-
ined the reaction of b-naphthol and 5,5-dimethylcyclohex-
ane-1,3-dione with a variety of aromatic aldehydes (Table 1,
entries 2–12). Both aromatic aldehydes bearing electron-
withdrawing and electron-donating groups afforded corre-
sponding tetrahydrobenzo[a]xanthen-11-one derivatives in
high yields (82%–92%). It is also noteworthy that the elec-
tronic properties of the aromatic ring have an effect on the
time of this nucleophilic addition reaction. Aromatic alde-
hydes with electron-withdrawing groups reacted, somehow,
faster than the aromatic aldehydes with electron-donating
groups. An aliphatic aldehyde (Table 1, entry 13), however,
showed a longer reaction time and lower yield. Although the
precise mechanism of the reaction awaits further studies, a
plausible mechanism for this transformation, which rational-
izes the formation of products, is outlined in Scheme 1. By
referring to the literature,16,17 we proposed that after prior ac-
tivation of the carbonyl group of aldehyde by RuIII (inter-
mediate 1), nucleophilic attack from C1 of b-naphthol
provides an ortho-quinone methide intermediate (o-QM, in-
termediate 2). After subsequent attack of dimedone to the o-
QM and loss of water, intermediate 3 undergoes dehydration
to afford the desired product 4.
Conclusion
In brief, we have reported a convenient synthesis of tetra-
hydrobenzo[a]xanthen-11-ones by using RuCl3·nH2O as a
homogeneous catalyst. The unique feature of the reaction is
that the corresponding tetrahydrobenzo[a]xanthen-11-ones
are insoluble in the reaction solvent and this leads to an easy
workup along with high yields (75%–92%). In all cases, sim-
ple filtration of the reaction mixture and rinsing with cold
ethanol provided spectroscopically pure products. Several
merits, such as efficiency, mild reaction conditions, short re-
action times, high yields of products, easy workup procedure,
low catalyst loading, reusability of the catalyst, and use of
ethanol as an eco-friendly solvent, make this protocol a use-
ful and attractive process for the synthesis of tetrahydrobenzo
[a]xanthen-11-ones.
Experimental
General
A comparison between the present results and other re-
ported methods in this context is shown in Table 2.
As it is shown, operational simplicity and higher efficiency
All products were characterized by spectroscopic data (IR,
1H NMR, 13C NMR). IR spectra were recorded on a Shimadzu
Published by NRC Research Press

Tabatabaeian et al.
625
Scheme 1. Proposed mechanistic pathway for the formation of tetrahydrobenzo[a]xanthen-11-one derivatives under ruthenium catalysis.
1
Materials
FTIR-8400S spectrophotometer. H NMR spectra were meas-
ured on a Bruker DRX-400 Avance spectrometer. 13C NMR
spectra were obtained on a Bruker DRX-100 Avance spec-
All the reagents were purchased from Merck and used
without further purification.
trometer. Chemical shifts of H and 13C NMR spectra were
1
expressed in parts per million downfield from trimethylsi-
lane (TMS) as the internal standard. Melting points were
measured on a BÜCHI Melting Point B-540 and are uncor-
rected.
Elemental analyses were made by a Carlo-Erba EA1110
CNNO-S analyzer and agreed with the calculated values. Mi-
crowave irradiation was performed in a LBP125 microwave
oven.
Typical experimental procedure
To a mixture of b-naphthol (144.17 mg, 1 mmol), benzal-
dehyde (106.13 mg, 1 mmol), and dimedone (168.22 mg,
1.2 mmol) in ethanol (2.5 mL), RuCl3·nH2O (10.71 mg,
0.05 mmol) was added and the mixture was refluxed in an
oil bath at 80 °C for 30 min, which yielded a precipitate.
The progress of the reaction was monitored by thin-layer
chromatography (TLC). After completion of the reaction, as
Published by NRC Research Press

626
Can. J. Chem. Vol. 89, 2011
Table 2. Comparison of our results with those obtained by other groups in the reaction of b-naphthol, benzaldehyde, and dimedone.
Entry
Catalyst
Concentration of
catalyst (mol %)
Solvent
Temperature (°C)
Time
(min)
Yield
(%)
References
1
2
3
4
5
6
7
8
NaHSO4·SiO2
Sr(OTf)2
pTSA
InCl3
P2O5
56
10
10
30
20
10
10
5
ClCH2CH2Cl
ClCH2CH2Cl
[bmim]BF4
80
80
80
120
120
60
80
60
80
80
80
240
300
180
30
40
75
65
70
50
72
87
85
90
84
76
90
91
86
90
89
88
17
18
19
20
20
21
23
24
26
27
—
—
—
I2
—
HBF4-SiO2
H3PW12O40
TCT
HClO4-SiO2
RuCl3·nH2O
—
—
9
10
11
5
5
5
—
—
C2H5OH
30
Table 3. Reusability of the catalyst in
the reaction of b-naphthol, benzalde-
hyde, and dimedone in the presence of
RuCl3·nH2O (5 mol%).
1H, J = 7.2 Hz), 7.36 (t, 1H, J = 7.2 Hz), 7.18 (d, 1H, J =
8.8 Hz), 6.69 (d, 1H, J = 7.6 Hz), 6.59 (d, 1H, J = 7.6 Hz),
6.50 (s, 1H), 5.64 (s, 1H), 3.68 (s, 3H), 3.57 (s, 3H), 2.54 (s,
2H), 2.42 (d, 1H, J = 16.4 Hz), 2.27 (d, 1H, J = 16.4 Hz),
1.09 (s, 3H), 0.98 (s, 3H). 13C NMR (100 MHz, CDCl3, 25 °C,
ppm) d: 196.2, 162.8, 153.6, 142.1, 136.0, 133.5, 130.2,
129.0, 128.2, 127.1, 126.8, 125.4, 124.3, 123.5, 116.9,
116.4, 115.8, 113.2, 112.4, 53.7, 53.4, 49.6, 40.2, 32.7,
31.2, 27.8, 26.0. Anal. calcd. for C27H26O4: C 78.24, H
6.32; found: C 78.25, H 6.34.
Run No.
Yield (%)
1
2
3
4
88
88
86
84
Table 4. RuIII-catalyzed synthesis of tetrahydrobenzo[a]xanthen-
11-one derivatives under microwave irradiation.
9,9-Dimethyl-12-(4-methylthiophenyl)-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one (4l)
Solid; mp 209–211 °C. IR (KBr, cm–1) n : 3050, 2960,
1642, 1593, 1372, 1220, 1180, 1020, 800. 1H NMR
(400 MHz, CDCl3, 25 °C, ppm) d: 7.93 (d, 1H, J = 8.4 Hz),
7.78 (d, 1H, J = 8.0 Hz), 7.62 (d, 1H, J = 8.8 Hz), 7.52 (t,
1H, J = 7.2 Hz), 7.41 (t, 1H, J = 7.2 Hz), 7.19 (d, 1H, J =
8.4 Hz), 7.08 (d, 2H, J = 7.6 Hz), 6.98 (d, 2H, J = 7.6 Hz),
5.66 (s, 1H), 2.56 (s, 2H), 2.50 (s, 3H), 2.38 (d, 1H, J =
16.4 Hz), 2.28 (d, 1H, J = 16.4 Hz), 1.12 (s, 3H), 0.98 (s,
3H). 13C NMR (100 MHz, CDCl3, 25 °C, ppm) d: 196.7,
163.2, 154.1, 147.2, 136.2, 133.7, 132.1, 131.8, 130.1,
129.4, 127.9, 126.3, 124.3, 123.5, 117.8, 116.2, 113.7, 50.6,
40.8, 33.9, 31.9, 28.3, 26.6, 25.4. Anal. calcd. for
C26H24O2S: C 77.97, H 6.04; found: C 77.98, H 6.05.
Time
(min)
Yield
(%)
Entry
R
C6H5
4-NO2C6H4
4-ClC6H4
4-CH3C6H4
(CH3)2CH
Product
4a
4b
4d
4g
1
2
3
4
5
4
2
3
5
7
88
90
93
87
78
4m
indicated by TLC, the precipitate was filtered off and rinsed
with cold ethanol. The solid was dried under vacuum to af-
ford the desired compound in pure form (311.78 mg, 88%).
The same procedure was also used for the other products
listed in Table 1. To reuse the catalyst, after filtration, sub-
strates were added into solution and the same procedure was
repeated. For microwave reactions, irradiation was conducted
in an open vessel at 50 °C in a 500 W microwave oven (Ta-
ble 4).
Acknowledgement
Partial support of this work by the Research Council of the
University of Guilan is gratefully acknowledged.
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