Methanesulfonic acid-catalyzed one-pot synthesis of 12-aryl or 12-alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives

Article abstract of DOI:10.1002/jhet.882

An efficient synthesis of 12-aryl or 12-alkyl-8,9,10,12-tetrahydrobenzo[a] xanthen-11-one derivatives has been developed under solvent-free conditions by one-pot condensation of aldehydes, 2-naphthol, and cyclic 1,3-dicarbonyl compounds in the presence of

Full text of DOI:10.1002/jhet.882

July 2012
Methanesulfonic Acid‐Catalyzed One‐Pot Synthesis of 12‐Aryl or
12‐Alkyl‐8,9,10,12‐tetrahydrobenzo[a]xanthen‐11‐one
Derivatives
861
a
b
*
Yu‐Heng Liu and Lei Li
aCollege of Preclinical Medicine, Hebei Medical University, Shijiazhuang 050017, China
bChina National Petroleum Corporation Occupational Health Center, Langfang 06500, China
*
E-mail: yu2795478@163.com
Received December 28, 2010
DOI 10.1002/jhet.882
View this article online at wileyonlinelibrary.com.
An efficient synthesis of 12‐aryl or 12‐alkyl‐8,9,10,12‐tetrahydrobenzo[a]xanthen‐11‐one derivatives
has been developed under solvent‐free conditions by one‐pot condensation of aldehydes, 2‐naphthol,
and cyclic 1,3‐dicarbonyl compounds in the presence of a catalytic amount of methanesulfonic acid.
The protocol has advantages of mild condition, short reaction time, high yield, and operational
simplicity.
J. Heterocyclic Chem., 49, 861 (2012).
INTRODUCTION
eco‐friendliness [25–27]. Therefore, if a one‐pot MCR
could be carried out under solvent‐free conditions, it may
be most efficient and eco‐friendly.
Xanthene derivatives are important heterocyclic
compounds that possess diverse biological and therapeutic
properties such as antibacterial, antiviral, antifungal,
antiproliferative, anticancer, and anti‐inflammatory activi-
ties [1–5]. Among this class of molecules, xanthone is a
prominent structural motif found in numerous natural pro-
ducts and synthetic compounds with important biological
activities [6,7]. Several elegant strategies for the synthesis
of tetrahydrobenzo[a]xanthen‐11‐ones involving different
types of catalysts have been reported [8–19]. The above
methods show varying degrees of successes as well as
limitations such as prolonged reaction times, low yields,
use of toxic organic solvents, special apparatus, harsh reac-
tion conditions, and complex work‐up procedures. Keeping
in view the disadvantages associated with reported protocols
as well as increasing importance of tetrahydrobenzo[a]
xanthen‐11‐ones in pharmaceutical and industrial chemistry,
there still remains a high demand for the development of an
efficient, low‐cost, and eco‐friendly protocol to construct
this type of heterocyclic compounds.
During the past decade, methanesulfonic acid (GMA)
has been reported as an inexpensive, readily biodegradable,
nontoxic, commercially available, and environmentally be-
nign catalyst for various organic transformations [28–32].
In the lights of our success in developing several catalytic
system for organic reactions [33–38], herein, we wish to
report a novel and high yielding solvent‐free method for
the preparation of 12‐aryl or 12‐alkyl‐8,9,10,12‐tetra-
hydrobenzo[a]xanthen‐11‐one derivatives in the presence
of GMA (Scheme 1).
RESULTS AND DISCUSSION
In a preliminary study, 4‐chlorobenzaldehyde (1q) was
treated with 2‐naphthol (2) and 5,5‐dimethyl‐1,3‐cyclo‐
hexanedione in the presence of 10 mol % of GMA. The
reaction went to completion in 30 min at 60°C under
solvent‐free conditions, and the product 12‐(4‐chloro‐phenyl)‐
9,9‐dimethyl‐8,9,10,12‐tetrahydrobenzo [a]xanth‐en‐11‐one
(4q) was obtained in 97% yield. In the absence of catalyst,
the desired product could not be obtained under similar re-
action conditions, even after a long time (2 h).
To explore the scope and limitations of this protocol,
a range of aldehydes were reacted with 2‐naphthol and
5,5‐dimethyl‐1,3‐cyclo‐hexanedione under the above‐
mentioned conditions. The results are displayed in Table 1.
Multicomponent reactions (MCRs) have attracted
considerable interest in combinatorial and medicinal
chemistry because they offer rapid and convergent con-
struction of complex molecular skeletons from common
staring materials in one‐pot synthesis [20–24]. In addition,
organic reactions that were performed under solvent‐free
conditions may lead to high efficiency and selectivity,
reduction of cost, easy separation and purification, and
© 2012 HeteroCorporation

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Y.-H. Liu and L. Li
Vol 49
Scheme 1. Synthesis of tetrahydrobenzo[a]xanthen‐11‐ones catalyzed by GMA.
As it can be seen from Table 1, when aromatic aldehydes
were applied, all reactions proceed efficiently and the
corresponding products were obtained in high to excellent
yields. The electronic effects and the nature of the substitu-
ents on the aldehydes show some effects in terms of yields
and reaction times. With aromatic aldehydes with electron‐
withdrawing groups as substrates, the reaction time was
shorter and the reaction proceeded well at faster rate com-
pared with aromatic aldehydes with electron‐donating
groups. Aliphatic aldehydes also afforded the desired pro-
ducts in slightly lower yields and required longer reaction
times. Also, the same reaction when carried out by replacing
5,5‐dimethyl‐1,3‐cyclo‐hexanedione with cyclohexane‐1,3‐
dione the similar results were obtained.
for the synthesis of 12‐aryl or 12‐alkyl‐8,9,10,12‐tetra-
hydrobenzo[a]xanthen‐11‐one derivatives catalyzed by GMA.
This new strategy has some advantages, such as high yields
of products, short reaction time, solvent‐free conditions, and
inexpensive and the use of readily available catalyst.
EXPERIMENTAL
Infrared (IR) spectra were obtained with a Shimadzu FTIR‐
8900 spectrometer with KBr plates. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on a Varian 400
spectrometer in CDCl3 using tetramethylsilane (TMS) as an inter-
nal standard. Elemental analyses were performed on Vario EL III
CHNOS elemental analyzer.
Representative procedure for the synthesis of 12‐aryl
Finally, to ascertain the effectiveness of this catalyst rel-
ative to those previously used, the synthesis of 4q was
considered as a representative example (Table 2). As dem-
onstrated in Table 2, GMA is an equally or more efficient
catalyst for this three‐component reaction in terms of the
reaction temperature, rate, and yields of product.
or 12‐alkyl‐8,9,10,12‐tetrahydrobenzo[a]xanthen‐11‐one.
A
mixture of 4‐chlorobenzaldehyde (2 mmol), 2‐naphthol
(2mmol), 5,5‐dimethyl‐1,3‐cyclohexanedione (2.5 mmol), and
GMA (19 mg, 0.2 mmol) was heated at 60°C. The completion
of reaction was monitored by thin‐layer chromatography, and
then the mixture was cooled to room temperature. Water (10
mL) was added and the mixture was extracted with ethyl acetate
(3× 5 mL). The combined organic layer was dried over
anhydrous Na2SO4, concentrated in vacuo, and the resulting
In conclusion, we have provided an efficient three‐
component route using readily available starting materials
Table 1
Scope for the synthesis of 12‐aryl or 12‐alkyl‐8,9,10,12‐tetrahydro‐benzo[a]xanthen‐11‐ones catalyzed by GMA.
m.p. (°C)
Entry
R
R1
Time (min)
Yield (%)a
Found
Reported
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
Ph
H
H
H
H
H
H
H
H
35
35
30
35
40
30
30
30
30
50
50
30
35
35
40
35
30
30
50
50
88
90
86
89
87
92
93
94
92
74
72
91
90
89
88
91
97
92
78
75
190–191
205–206
175–176
180–181
244–246
211–212
208–210
235–236
236–237
Oil
185–186
150–151
175–176
205–206
209–211
181–182
185–187
175–176
Oil
192–193 [8]
206–207 [8]
174–175 [14]
181–182 [8]
243–245 [8]
210–211 [8]
208–209 [8]
234–235 [8]
236–237 [8]
Oil [13]
186–187 [13]
151–152 [8]
176–177 [8]
206–207 [8]
210 [14]
4‐MeC6H4
3,4‐Me2C6H3
4‐MeOC6H4
2‐ClC6H4
3‐ClC6H4
4‐ClC6H4
3‐NO2C6H4
4‐NO2C6H4
CH3CH2
H
H
H
C6H11
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
4‐MeC6H4
4‐MeOC6H4
4‐OHC6H4
3,4‐Cl2C6H3
4‐ClC6H4
4‐NO2C6H4
CH3CH2
185–186 [8]
176–177 [8]
Oil [14]
t
(CH3)2CH
115–116
116–117 [8]
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2012
Methanesulfonic Acid‐Catalyzed one‐Pot Synthesis of 12‐Aryl or
12‐Alkyl‐8,9,10,12‐tetrahydrobenzo[a]xanthen‐11‐one Derivatives
863
Table 2
Comparison of the efficiency of GMA with other catalysts for the synthesis of 4q.
Entry
Catalyst
Reaction condition
Time (min)
Yield (%)
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1
2
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4
5
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8
9
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InCl3
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30
300
60
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120
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210
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88
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Solvent free, 120°C
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Solvent free, 80°C
Solvent free, 60°C
P2O5
HClO4/SiO2
GMA
60
30
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Natural Science Foundation of China (210720425) and Nature
Science Foundation of Hebei Province (B2011205031) is gratefully
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