Ultrasound assisted synthesis of tetrahydrobenzo[c]xanthene-11-ones using CAN as catalyst

Article abstract of DOI:10.1016/j.ultsonch.2012.02.002

Tetrahydrobenzo[c]xanthenes-11-ones was synthesized by a three component reaction of α-naphthol, aromatic aldehyde and dimedone. Ceric ammonium nitrate acts as a suitable eco-friendly catalyst for this method. Shorter reaction duration, mild reaction cond

Full text of DOI:10.1016/j.ultsonch.2012.02.002

Ultrasonics Sonochemistry 19 (2012) 994–998
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Short Communication
Ultrasound assisted synthesis of tetrahydrobenzo[c]xanthene-11-ones using CAN
as catalyst
⇑
S. Sudha, M.A. Pasha
Department of Studies in Chemistry, Bangalore University, Central College Campus, Palace Road, Bengaluru 560001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Tetrahydrobenzo[c]xanthenes-11-ones was synthesized by a three component reaction of
a-naphthol,
Received 22 November 2011
Received in revised form 25 January 2012
Accepted 2 February 2012
Available online 9 February 2012
aromatic aldehyde and dimedone. Ceric ammonium nitrate acts as a suitable eco-friendly catalyst for this
method. Shorter reaction duration, mild reaction condition and low cost make this protocol more
effective.
Ó 2012 Elsevier B.V. All rights reserved.
Keywords:
a-Naphthol
Aromatic aldehydes
Dimedone
Ceric ammonium nitrate (CAN)
1. Introduction
a
-naphthol in the literature [17]. The search for new methods for
the synthesis of tetrahydro[c]xanthene-11-ones from -naphthol
is therefore, exceedingly demanding. We herein, propose to use
ultrasound for their synthesis, which we feel can activate -naph-
a
Xanthenes and benzoxanthenes are important structures which
have been investigated extensively in recent years. Xanthene skel-
eton is present in a number of natural products [1], and these mo-
tifs are found to bear diverse biological applications such as
bactericidal [2], anti-inflammatory [3], antiviral [4] activities. They
act as antagonists for paralyzing the action of zoxazolamine, [5]
and are useful in the photodynamic therapy [6]. Their applications
are also found in laser technology [7], are used as pH sensitive fluo-
rescent materials for visualization of bimolecular assemblies [8]
and as dyes [9]. In recent years there is a growing demand for
the synthesis of such biologically and industrially significant
molecules.
Literature survey indicates that, a few methods have been re-
ported for the synthesis of tetrahydrobenzo[a]xanthene-11-ones
from b-naphthol. Different catalysts such as sulfamic acid [10], p-
TSA [11], selectfluor TM [12], iodine [13], silica sulfuric acid [14],
Yb(OTf)3 [15] and ionic liquids [16] find application in the synthe-
sis of benzo[a]xanthenes. The existing methods have not been con-
ceded for the synthesis of tetrahydrobenzo[c]xanthene-11-ones
a
thol and act as a very good energy source in the synthesis of tetra-
hydrobenzo[c]xanthenes-11-ones.
Use of ultrasound in the field of organic chemistry has received
considerable attention in the last two decades. The technique re-
duces the reaction duration, improves the yields and involves easier
work-up procedures than conventional methods [18a]. Ultrasound
works by the phenomenon of cavitation; which involves the growth,
oscillation, and collapse of bubbles under the action of an acoustic
field. There are three different theories about cavitation: the hot-
spot, the electrical and the plasma theory; and the most popular
one is the hot spot theory. It has been experimentally shown that,
the cavitational collapse creates drastic conditions inside the med-
ium for an extremely short time and temperatures of 2000–5000 K,
pressures up to 1800 atm inside the collapsing cavity have been
produced under sonic condition [18a,b]. The collapse causes a cou-
ple of strong physical effects outside the bubble such as-shear
forces, jets and shock waves. These cavitation-induced effects can
cause physical, chemical, and biological transformations more
effectively. Thus, ultrasound has found applications in chemistry,
in materials, in life sciences as well as in medicine [18c].
from
a-naphthol (Scheme 1), this is because, the electron density
at the b-position of the
a
-naphthol is not sufficient for the forma-
tion of the corresponding ortho-Quinone Methides (o-QMs,
Scheme 2) under these conditions. As per our knowledge, there is
only one article which involves use of proline triflate as a catalyst
for the synthesis of tetrahydrobenzo[c]xanthenes-11-ones from
It is noted that, ceric ammonium nitrate (CAN) as a catalyst
shows superior properties like eco-friendliness and is commer-
cially available. It is inexpensive and can be easily handled. Its
wider usability in the reactions like carbon–carbon and carbon–
heteroatom bond formation, single-electron oxidation reactions
has recently attracted much attention [19a–e]. The use of CAN
⇑
Corresponding author.
E-mail address: m_af_pasha@ymail.com (M.A. Pasha).
1350-4177/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2012.02.002

S. Sudha, M.A. Pasha / Ultrasonics Sonochemistry 19 (2012) 994–998
995
physical and spectral data (1H NMR) and are compared with those
of authentic samples [17].
H
R
R
O
O
+
O
OH
2
))))) / CAN
2.3. 1H NMR spectral data
O
4
DCM-EtOH, 120min
O
4a: 1H NMR (400 MHz, CDCl3): 6.8–7.3 (m, 11H, ArH); 5.6
(s, 1H); 2.2 (s, 2H); 1.9 (d, J = 17.2 Hz, 2H); 0.95 (s, 3H, CH3); 0.92
(s, 3H, CH3).
3
1
Scheme 1. Synthesis of tetrahydrobenzo[c]xanthene-11-ones.
4d: 1H NMR (400 MHz, CDCl3): 7.5 (m, 4H, ArH); 7.3 (m, 3H,
ArH); 7.1 (m, 3H, ArH); 5.1 (s, 1H); 3.74 (s, 3H, OCH3); 2.5–2.15
(m, 2H); 2.14–1.9 (m, 2H); 0.84 (s, 6H, 2Â CH3).
4e: 1H NMR (400 MHz, CDCl3): 7.5 (m, 4H, ArH); 7.3 (m, 3H,
ArH); 7.1 (m, 3H, ArH); 5.1 (s, 1H); 2.25–2.23 (m, 2H); 2.20–2.19
(m, 2H); 0.87 (s, 6H, 2Â CH3).
OH
O
H
R
R
)))),
CAN
O
4i: 1H NMR (400 MHz, CDCl3): 7.39–7.37 (m, 1H, ArH); 7.28–
7.20 (m, 4H, ArH); 7.18–7.15 (m, 1H, ArH); 7.05–6.99 (m, 2H,
ArH); 6.85–6.83 (m, 1H, ArH); 5.3 (s, 1H); 2.25–2.03 (m, 2H);
1.83–1.78 (m, 2H); 0.99 (s, 3H, CH3); 0.95 (s, 3H, CH3).
5a: 1H NMR (400 MHz, CDCl3): 7.7–7.3 (m, 2H, ArH); 6.9–6.6
(m, 3H, ArH); 5.9 (s, 1H); 2.5–2.4 (m, 4H, 2Â CH2); 0.94–0.89 (m,
12H, 4Â CH3).
DCM-EtOH
Scheme 2. Formation of ortho-Quinone Methides.
1
2
for the synthesis of tetrahydrobenzo[c]xanthene-11-ones (Scheme
1) will therefore be of greater advantage.
3. Results and discussion
2. Methods
In search of simple energy efficient methods and eco-friendly
catalysts for the synthesis of tetrahydrobenzo[c]xanthene-11-ones,
2.1. Materials and instruments
we studied the model reaction of
a-naphthol, benzaldehyde and
dimedone by a solvent-free ultrasonic reaction (Scheme 1). The
reaction was initially carried out without catalyst, and it did not
yield any product. It was found that, CAN showed better catalytic
activity under sonic conditions among other catalysts that were
tested (Table 1) under solvent-free condition. The above reaction
was also carried out under silent condition to study the effect of
ultrasound; the results of which are given in Table 1, under silent
condition, in some cases (Table 1, entries 3 and 5) a minimum per-
iod of 10 h is required to form the ortho-Quinone Methides (o-QM,
TLC), and in most of the cases the reaction did not proceed at all.
All chemicals were commercial and used without further puri-
fication; ultrsonication was performed using SIDILU, Indian make
sonic bath working at a constant frequency of 35 kHz and an out-
put power of 70 W at 26 °C (maintained by circulating water). The
reactions were performed in open vessels without any mechanical
stirring. Melting points were recorded on a RAAGA melting point
apparatus (Indian make). 1H NMR spectra were recorded in CDCl3
using a Bruker 400 MHz instrument with TMS as an internal
standard.
Since dimedone is more reactive compared to
a-naphthol, 1,8-di-
2.2. General procedure for the synthesis of tetrahydrobenzo[c]xan
thene-11-ones
oxo-dodecahydroxanthene (5a) was formed as major product un-
der silent condition as shown in Scheme 3. This clearly indicates
that, formation of the intermediate o-QM and cyclization to xanth-
enes are the two important steps governing the formation of tetra-
a-Naphthol (2 mmol), aromatic aldehydes (2 mmol) and dime-
done (2 mmol) were taken in a test tube to which CAN (5 mol%)
and a 1:1 mixture of DCM–ethanol (2 mL) was added. The test tube
was placed in a sonic bath and sonicated at 26 °C until the reaction
was complete (about 120 min, monitored on TLC; eluent: n-hex-
ane:EtOAc:: 2:1). The mixture was filtered to remove the catalyst,
the catalyst was washed with minimum quantity of ethyl acetate,
the organic layer (filtrate) was then evaporated and the crude
product was purified by silica gel column chromatography (EtOAc:
light petrol:: 2:8). All the products were characterized by their
hydrobenzo[c]xanthene-11-ones.
condition, 5 mol% of CAN was sufficient to give the product 4a
but only in moderate yield. This could be because of the non-reac-
Under
solvent-free
sonic
tive nature of
a-naphthol with the solid aromatic aldehydes or
may be due to non-participation of dimedone with the thick reac-
tion mass which was formed when liquid aromatic aldehydes were
treated with a-naphthol in the absence of any solvent.
The model reaction, with 5 mol% of CAN, was then reinvestigated
in different solvent systems under sonic condition, the results of the
Table 1
Optimization of catalysts for the one-pot condensation: a comparative study under ultrasonic and silent conditions.
Sl. No.
Catalyst
Silent conditiona (120 °C)
Ultrasonic conditionb (26 °C)
1
2
3
4
5
6
MgCl2
CuCl
p-TSA
Lithium perchlorate
CAN
No product
No product
Trace
No product
By productd
No product
No product
No product
30%c with by-productd
No product
65%c
Anhyd. AlCl3
25%c
a
b
c
Reaction condition: a-naphthol (2 mmol), benzaldehyde (2 mmol), dimedone (2 mmol), catalyst (2 mmol) solvent-free condition, 14 h.
a-Naphthol (2 mmol), benzaldehyde (2 mmol), dimedone (2 mmol), catalyst (5 mol%), solvent-free, 2 h.
Tetrahydrobenzo[c]xanthene-11-one; isolated yield by column chromatography.
1,8-Dioxo-dodecahydroxanthene.
d

996
S. Sudha, M.A. Pasha / Ultrasonics Sonochemistry 19 (2012) 994–998
mediated reaction is more faster and high yielding than the reaction
R
O
H
carried out under reflux condition in DCM–ethanol (1:1) system.
It is clear from the above studies that, best results were achieved
with the use of 5 mol% of the CAN, and a mixture of DCM/ethanol
(1:1) as solvent under sonic condition (35 kHz). Various aromatic
aldehydes containing electron-withdrawing and electron-donating
substituents at ortho, meta and para-positions showed equal ease
towards the product formation in good to high yields. The results
of this outcome are given in Table 3. The by-product 1,8-dioxo-
dodecahydroxanthene (5a) formed by the condensation of one alde-
hyde molecule and two dimedone molecules was either formed to a
very little extent or did not form at all under the sonic condition.
The formation of tetrahydrobenzo[c]xanthene-11-one from
O
R
O
O
O
O
O
120o
CAN
C
2
+
O
3
3
5a
1,8-dioxo-dodecahydroxanthene
R = Ph
Scheme 3. Formation of 1,8-dioxo-dodecahydroxanthene under solvent-free silent
condition at 120 °C.
Table 2
Effect of solvent on the rate of CAN catalyzed reaction.a
a
-naphthol, benzaldehyde and dimedone in the presence of CAN
Sl. No. Solvent
Silent conditionb
Ultrasonic conditiond (4a) (%)
can be explained by a tentative mechanism presented in Scheme
4. The ultrasonic cavitation induced shear forces and the jets
produced near the surface of the vessel and the catalyst may acti-
vate the passive
The reaction between the activated
aldehyde (activated by CAN) may facilitate the formation of the
corresponding o-QM under sonic condition, and this o-QM inter-
mediate may then react with the active methylene of dimedone,
followed by cyclization to give tetrahydrobenzo[c]xanthene-11-
one with the removal of a molecule of water as shown in Scheme
4. As mentioned earlier, the formation of o-QM and the formation
of tetrahydrobenzo[c]xanthene-11-one in the last step by a cycliza-
tion reaction are crucial and both the steps are accelerated by
ultrasound.
1
2
3
4
5
Ether
THF
Acetonitrile
DCM
DCM:ethanol
(1:1)
No product
No product
30
30
20% byproduct (5a)c 50
a
-naphthol through sonolysis of the O–H bond.
-naphthol and the aromatic
No product
60
85% byproduct (5a) c 85
a
a
a-Naphthol (2 mmol), benzaldehyde (2 mmol), dimedone (2 mmol), CAN
(5 mol%).
b
Reflux, 14 h.
1,8-Dioxododecahydroxanthene.
26 °C, 2 h; isolated yield of the product tetrahydrobenzo[c]xanthene-11-one.
c
d
effect of solvents on the rate of the reaction and yield of the products
is given in Table 2, and it is clear from Table 2 that, ultrasound
Ce4+
Ce4+
Ce4+
OH
H
O
H
O
OH
R
H
O
)))))
O
R
R
H
Ce4+
Ce4+
O
O
OH
O
H
O
H
R
O
R
o-QM
4+ H
Ce
O
O
O
OH
)))))
O
R
R
Scheme 4. A probable mechanism of formation of tetrahydrobenzo[c]xanthene-11-ones.
Table 3
Synthesis of tetrahydrobenzo[c]xanthene-11-ones by the condensation of
a-naphthol, aromatic aldehydes and dimedone using DCM:ethanol (1:1) as solvent and CAN as
catalyst.a
Product
Aldehyde
Yield (%)
Time (min)
Melting point (°C)/Lit [17]
4a
4b
4c
4d
4e
4f
Benzaldehyde
85
85
83
86
82
87
85
87
120
120
135
120
144
135
144
120
149–152/151–152
222–224/223–225
207–209/206–207
235–237
167–170/170–180
179–181/180–181
185–187/185–186
155–158
4-Hydroxybenzaldehyde
4-Methoxybenzaldehyde
4-Hydroxy-3-methoxybenzaldehyde
3-Nitrobenzaldehyde
2-Chlorobenzaldehyde
4-Chlorobenzaldehyde
Furaldehyde
4g
4i
a
Reaction condition: a-naphthol (2 mmol), aromatic aldehyde (2 mmol), dimedone (2 mmol), CAN (5 mol%), solvent DCM:ethanol (1:1, 2 mL) was taken in test tube and
subjected to sonication.

S. Sudha, M.A. Pasha / Ultrasonics Sonochemistry 19 (2012) 994–998
997
Table 4
Study of the effect of ultrasound on the formation of tetrahydrobenzo [c]xanthene-11-one (4a).a
Quantity of starting materials
Silent (14 h)
Ultrasoundc (2 h)
Product
a
a
a
-Naphthol (2 mmol) benzaldehyde (2 mmol) and dimedone No reactionb
(2 mmol)
-Naphthol (4 mmol) benzaldehyde (4 mmol) and dimedone No reactionb
(2 mmol)
Product
-Naphthol (4 mmol) benzaldehyde (4 mmol) and dimedone 1,8-Dioxo-dodecahydroxanthene (5a, Product (4a, 85%) with trace amount of 1,8-dioxo-
(2 mmol) dodecahydroxanthene
85%)d
a
b
c
All the reaction were carried out using, CAN (5 mol%), solvent: DCM:ethanol (1:1, 2 mL).
Silent condition: 26 °C; stirring.
Ultrasonic condition: 26 °C; 2 h.
d
Silent condition: CAN (5 mol%), solvent: DCM:ethanol (1:1, 2 mL) reflux for 14 h.
R
H
R
O
O
O
R
O
O
O
CAN/Reflux
2
CAN/ )))))
+
O
14 h / DCM: EtOH
120 min/ DCM- EtOH
O
O
O
OH
4a
3
3
5a
1
Scheme 5. Sonochemical switching.
The energy and temperature parameters of the solvents influ-
encing the sonochemical reactivity depend on the intensity–Imax
(maximum cavitation intensity) and TI (the temperature at
[c]xanthene-11-ones by this new and energy efficient method has
proved to be useful both from economical and environmental point
of view. This methodology also overcomes the formation of un-
wanted by-products, low yields and external high temperatures.
max
which Imax is reached), and in the present reaction, the solvents
DCM and ethanol have a better Imax values at ambient conditions
[18c]. The effect of ultrasound on the present reaction which uses
DCM:ethanol as the solvent system can be viewed as follows: The
transmission of the sound waves induces vibrational motion to the
solvent; the solvent molecules then alternatively compress, stretch
and oscillate around their mean position due to time-varying pres-
sure, at a point when the intensity of ultrasound is higher enough
to break the intermolecular forces existing between the solvent
molecules it breaks down and a cavity is formed [18]. This cavity
is called cavitation bubble, the process is called acoustic cavitation
and the point where it starts is the cavitation threshold [18]. It is
worthy to note that, ultrasound with frequencies less than
50 kHz and presence of solid CAN in the reaction mixture has re-
sulted in increase in the reaction rate when compared with the si-
lent reaction because of the local raise in the temperature and
pressure due to the cavitation of some bubbles next to the surface
of the catalyst/reactants [18c].
From the optimized set of conditions we have made a compara-
tive study to highlight the effect of ultrasound on the present reac-
tion. The amount of product and by product formed under silent and
sonic condition are compared, these studies are presented in Table
4, surprisingly the reaction under silent condition predominantly
gave 1,8-dioxo-dodecahydroxanthene (characterized by 1H NMR
spectral analysis), whereas under sonic condition tetrahydrobenzo
[c]xanthene-11-one is formed exclusively. We feel that, sonication
has modified the reactivity’s of the substrates, hence we can
consider this reaction to be an example of ‘‘sonochemical switching’’
[20] as shown in Scheme 5.
Acknowledgement
The authors are grateful to the University Grants Commission
(UGC), New Delhi, for the financial aid and a research fellowship
[UGC No. F. No. 37-71/2009 (SR)].
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ultsonch.2012.02.002.
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