pTSA-catalyzed one-pot synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones in ionic liquid and neat conditions

Article abstract of DOI:10.1016/j.tetlet.2009.06.029

Multi-component condensation of β-naphthol, aromatic aldehydes, and cyclic 1,3-dicarbonyl compounds catalyzed by p-toluenesulfonic acid has been accomplished for the synthesis of a series of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones in ionic liq

Full text of DOI:10.1016/j.tetlet.2009.06.029

Tetrahedron Letters 50 (2009) 4777–4780
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Tetrahedron Letters
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pTSA-catalyzed one-pot synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]
xanthen-11-ones in ionic liquid and neat conditions
*
Jitender M. Khurana , Devanshi Magoo
Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Multi-component condensation of b-naphthol, aromatic aldehydes, and cyclic 1,3-dicarbonyl compounds
catalyzed by p-toluenesulfonic acid has been accomplished for the synthesis of a series of 12-aryl-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones in ionic liquid([bmim]BF4) and in solvent-free media.
High yields, ease of recovery, and reusable reaction medium (ionic liquid) with consistent activity makes
this protocol efficient and environmentally benign.
Received 16 March 2009
Revised 3 June 2009
Accepted 8 June 2009
Available online 11 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Xanthene
b-Naphthol
Dimedone
Cyclohexane-1,3-dione
pTSA
Ionic liquid
1. Introduction
Thus ionic liquids are well suited as reaction media for MCRs
(multi-component reactions) in which the entropy of the reaction
Xanthenes and benzoxanthenes are important heterocycles that
are known to possess multiple biological activities. Although not
widely found in nature, xanthenes and compounds based on these
core templates exhibit a broad spectrum of pharmaceutical activi-
ties such as anti-bacterial,1 anti-inflammatory,2 and anti-viral.3
These structural motifs have also found a niche as antagonists for
paralyzing the action of zoxazolamine4 and demonstrate efficacy
in photodynamic therapy.5 In addition, these compounds have
been employed as dyes,6and pH-sensitive fluorescent materials
for visualization of biomolecular assemblies7 and utilized in laser
technologies.8 Thus a broad utility range has made xanthenes
prime synthetic candidates thereby accentuating the need to de-
velop newer synthetic routes for scaffold manipulation of xanthene
derivatives. The synthesis of tetrahydrobenzo[a]xanthen-11-ones
has been reported in the presence of strontium triflate9 and NaH-
SO4ÁSiO2 under reflux in halogenated solvents for long hours.10 In
this context it can undoubtedly be stated that solvent-free neat
reactions and the use of ionic liquids as ‘green’ recyclable substi-
tutes to the traditional volatile organic solvents11 have experi-
enced an impetus in recent years. Their negligible vapor pressure
makes them easily confinable and also enables an easy recyclabil-
ity. Moreover, the solvophobic properties of ionic liquids are able
to generate an internal pressure and promote the association of
reactants in the solvent cavity during the activation process.
is decreased in the transition state.
In view of our ongoing efforts to explore newer reactions for
synthesis of heterocyclic compounds,12 we decided to investigate
the possibility of synthesizing tetrahydrobenzo[a]xanthen-11-one
derivatives by one-pot three-component condensation reaction
strategy of b-naphthol with aldehydes and cyclic 1,3-dicarbonyl
compounds in ionic liquids as well as under neat conditions.
2. Results and discussion
In this Letter, we report an efficient and environmentally benign
protocol
for
the
synthesis
of
12-aryl-8,9,10,12-tetra-
hydrobenzo[a]xanthen-11-one derivatives by multi-component
condensation of b-naphthol, aromatic aldehydes, and cyclic 1,3-
dicarbonyl compounds catalyzed by pTSA in ionic liquid
([bmim]BF4) and also under solvent-free neat conditions. The prod-
ucts were obtained in high yields by a simple work-up. The con-
densation of benzaldehyde (1.0 mmol), b-naphthol (1.0 mmol),
and 5,5-dimethylcyclohexane-1,3-dione (1.2 mmol) was at-
tempted in different ionic liquids at room temperature and also
under heating. Only 28% of the desired 12-phenyl-8,9,10,12-tetra-
hydrobenzo[a]xanthen-11-one (1a) was obtained after heating the
reaction mixture for 14 h at 80 °C in [bmim]BF4 in the absence of a
catalyst. The reaction was then attempted under similar conditions
in the presence of different acids. The reactions carried out in the
presence of H2SO4, HCl, and CH3COOH were sluggish and incom-
* Corresponding author. Tel.: +91 11 27667725/1384; fax: +91 11 27666605.
E-mail address: jmkhurana@chemistry.du.ac.in (J.M. Khurana).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.029

4778
J. M. Khurana, D. Magoo / Tetrahedron Letters 50 (2009) 4777–4780
Table 1
plete even after 10 h. The yield of the product improved remark-
ably to 90% after heating the components at 80 °C for 3 h in the
presence of catalytic amount of pTSA. Subsequently, the condensa-
tion was attempted in different ionic liquids but the efficiency and
the yield of the reaction in [bmim]BF4 were higher than those in
other ionic liquids thereby making [bmim]BF4 the most suitable
reaction medium for successive reactions.
The application of this protocol was extended to a variety of
aromatic aldehydes. The reactions proceeded smoothly with differ-
ent aldehydes substituted with electron-donating/electron-with-
drawing groups giving excellent yields (Scheme 1). Interestingly
halo-substituted aromatic aldehydes required shorter reaction
times than their electron-rich counterparts. These results are com-
piled in Table 1 (entries 1–12, method A).
In order to broaden the scope of this protocol further, we
decided to explore the cyclocondensation reaction of cyclohex-
ane-1,3-dione with aldehydes and b-naphthol. The reaction of
benzaldehyde (1.0 mmol), b-naphthol (1.0 mmol), and cyclohex-
ane-1,3-dione (1.2 mmol) in [bmim]BF4 using pTSA as the catalyst
under similar conditions yielded 88% of tetrahydrobenzo[a]xan-
thene-11-one derivative (1 m) after 3.5 h. Other substituted benz-
aldehydes also underwent successful condensation with b-
naphthol and cyclohexane-1,3-dione (Table 1, entries 13–17).
It is obvious from the above observations that pTSA in
[bmim]BF4 is an efficient system for the synthesis of tetra-
hydrobenzo[a]xanthen-11-ones. However, we decided to investi-
gate the reaction further under solvent-free neat conditions and
thereby optimize the reaction conditions, if successful. Therefore,
4-chlorobenzaldehde, b-naphthol, and dimedone were mixed thor-
oughly and heated in a round-bottomed flask using varying
amounts of pTSA at different temperatures. It was observed that
the reaction was complete in 35 min by heating the mixture in
an oil bath maintained at 120 °C in the presence of only 2 mol %
of pTSA yielding 86% of pure 1b by a simple work-up. The reaction
did not proceed successfully in the absence of the catalyst. The
reaction procedure is remarkably simple and requires no solvent
media. Other substituted aromatic aldehydes also underwent con-
densation under these conditions and the corresponding xanthene
derivatives were obtained in high yields (method B, entries 1–12).
Also, on replacing dimedone with cyclohexane-1,3-dione, the reac-
tion reached successful completion under neat conditions. A com-
parison of the results obtained is drawn (Table 1, method B, entries
13–17). Though comparative yields were obtained by both meth-
ods, the reactions carried out under neat conditions required much
shorter times for completion. A plausible mechanism for the for-
mation of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one
derivatives (1a–q) in the presence of pTSA is proposed in Scheme 2.
Synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives by
condensation of aldehydes, b-naphthol, and 5,5-dimethylcyclohexane-1,3-dione/
cyclohexane-1,3-dione using pTSA as the catalyst
Entry
R
Product
Method A
Time (h) Yield (%)
Method B
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
3.0
2.0
2.0
3.0
2.0
2.5
3.5
3.0
3.5
2.5
2.5
2.0
3.5
2.5
3.0
2.5
2.5
90
85
86
90
95
91
83
90
88
85
84
91
88
84
90
89
92
45
35
35
40
35
40
45
45
45
40
40
40
40
40
40
40
40
88
86
82
88
90
92
85
90
86
82
84
89
89
80
86
90
90
4-ClC6H4
4-BrC6H4
4-CH3C6H4
2,4-Cl2C6H3
2-BrC6H4
4-CH3OC6H4
2-Naphthyl
4-HOC6H4
4-FC6H4
3-CF3C6H4
3-BrC6H4
C6H5
4-ClC6H4
2-BrC6H4
3-ClC6H4
4-NO2C6H4
tetrahydrobenzo[a]xanthen-11-ones. This multi-component cyclo-
condensation reaction is efficiently catalyzed by pTSA in ionic li-
quid at 80 °C and under neat conditions at 120 °C. Operational
simplicity, mild reaction conditions, enhanced rates, and high iso-
lated yields of the pure products are significant advantages of the
protocol presented here.
4. Experimental
4.1. General
The products were characterized by IR spectra, 1H NMR, 13C
NMR, and FAB mass analyses. IR spectra were recorded on Per-
kin–Elmer FT-IR-1710 instrument. 1H and 13C NMR spectra were
recorded on Bruker Advance Spectrospin 300 MHz and 400 MHz
using TMS as the internal standard. FAB mass spectra were re-
corded on Jeol SX 102/Da-600 mass spectrometer using Argon/ Xe-
non as the FAB gas.
4.2. General procedure for the synthesis of 12-aryl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one derivative (1a–q)
4.2.1. Method A
Aldehyde (1.0 mmol), b-naphthol (1.0 mmol), 5,5-dimethyl-
1,3-cyclohexanedione/1,3-cyclohexanedione
(1.2 mmol),
and
3. Conclusion
pTSA (0.1 mmol) were taken in a 10-mL round-bottomed flask
containing 0.5 mL of [bmim]BF4. The mixture was stirred at
80 °C for an appropriate time as mentioned in Table 1. After
completion of the reaction as monitored by TLC, the mixture
In conclusion, we have described an efficient and environmen-
tally benign method for the preparation of 12-aryl-8,9,10,12-
R'
O
R'
O
R
[bmim]BF4 / Neat
pTSA
OH
CHO
R
R'
O
O
R'
R' = CH3, H
1a-l (R' = CH3)
1m-q (R' = H)
Scheme 1.

J. M. Khurana, D. Magoo / Tetrahedron Letters 50 (2009) 4777–4780
4779
R1
R1
O
OH
O
OH
R
R1
H
R
R1
O
H+
O
H
OH
pTSA
H
R
CHR
O
OH
OH
H
R1
R1
O
R
R1
O
R
R1
- H2O
O
O
Scheme 2.
was allowed to cool to room temperature and quenched with
water (ꢀ5 mL). The precipitate formed was collected by filtra-
tion at pump, washed with water, and dried. The filtrate was
concentrated under reduced pressure and dried at 100 °C to re-
cover the ionic liquid for subsequent use. The crude product
was recrystallized from ethanol to yield pure xanthen-11-one
derivative.
Compound 1o: 1H NMR (300 MHz, CDCl3): d = 8.28 (d, J = 8.4 Hz,
1H), 7.72–7.76 (m, 2H), 7.34–7.50 (m, 3H), 7.17–7.30 (m, 2H), 7.0–
7.1 (m, 1H), 6.89–7.0 (m, 1H), 5.97 (s, 1H), 2.53–2.83 (m, 2H), 2.23–
2.46 (m, 2H), 1.93–2.16 (m, 2H). 13C NMR (300 MHz, CDCl3):
d = 196.8, 165.7, 147.5, 144.1, 133.3, 131.8, 131.7, 131.3, 129.1,
128.3, 127.8, 127.6, 127.0, 124.9, 123.4, 117.8, 115.0, 37.1, 35.3,
27.8, 20.3. IR mmax (KBr): 2957, 1652, 1595, 1371, 1227, 1189. MS
(FAB): m/z = 405, 407 [M+2].
4.2.2. Method B
Compound 1p: 1H NMR (300 MHz, CDCl3): d = 7.89 (d, J = 8.1 Hz,
1H), 7.76–7.79 (m, 2H), 7.23–7.46 (m, 5H), 6.90–7.17 (m, 2H), 5.71
(s, 1H), 2.60–2.77 (m, 2H), 2.22–2.52 (m, 2H), 1.90–2.12 (m, 2H).
13C NMR (300 MHz, CDCl3): d = 196.9, 165.8, 147.8, 146.9, 134.1,
131.5, 131.2, 129.4, 129.1, 128.5, 128.4, 127.1, 126.8, 125.0,
123.4, 117.0, 116.8, 114.9, 36.9, 34.4, 27.7, 20.2. IR mmax (KBr):
2952, 1649, 1594, 1375, 1225, 1189. MS (FAB): m/z = 361, 363
[M+2].
Aldehyde (1.0 mmol), b-naphthol (1.0 mmol), and 5,5-di-
methyl-1,3-cyclohexanedione/1,3-cyclohexanedione (1.2 mmol)
were mixed thoroughly and placed in a 10-mL round-bottomed
flask. pTSA (0.02 mmol) was added to the mixture and the mixture
was heated in an oil bath maintained at 120 °C for appropriate time
as given in Table 1. The reaction mixture was then cooled to room
temperature and quenched with water (ꢀ5 mL). The solid mass ob-
tained was washed with EtOH–H2O (1:1). The solid product ob-
tained was filtered and recrystallized from ethanol to yield pure
xanthen-11-one derivative.
Acknowledgment
D.M. thanks CSIR, New Delhi, India for the grant of junior and
senior research Fellowships.
4.3. Spectral data of some representative products are given
below
References and notes
Compound 1c: 1H NMR (400 MHz, CDCl3): d = 7.89 (d, J = 8.3 Hz,
1H), 7.76–7.80 (m, 2H), 7.38–7.45 (m, 2H), 7.26–7.33 (m,3H), 7.20–
7.23 (m, 2H), 5.66 (s, 1H), 2.56 (s, 2H), 2.31 (d, J = 16.3 Hz, 1H), 2.24
(d, J = 16.3 Hz, 1H), 1.12 (s, 3H), 0.96 (s, 3H). 13C NMR (300 MHz,
CDCl3): d = 196.8, 164.0, 147.7, 143.7, 131.5, 131.3, 131.2, 130.1,
129.1, 128.5, 127.1, 125.0, 123.4, 120.1, 117.0, 116.9, 113.7, 50.8,
41.4, 34.2, 32.2, 29.3, 27.1. IR mmax (KBr): 2955, 1652, 1596, 1373,
1228, 1185. MS (FAB): m/z = 433, 435[M+2].
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