Green approaches for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a] xanthen-11-ones in aqueous media and under microwave irradiation in solventless conditions

Article abstract of DOI:10.1080/00397911.2010.544832

Convenient and environmentally benign procedures have been reported for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives by multi component condensation reactions of aromatic aldehydes with β-naphthol and cyclic 1,3-dicarbon

Full text of DOI:10.1080/00397911.2010.544832

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Green Approaches for the
Synthesis of 12-Aryl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-ones in
Aqueous Media and Under Microwave
Irradiation in Solventless Conditions
Jitender M. Khurana a , Anshika Lumb a , Archana Pandey a
Devanshi Magoo a
&
a Department of Chemistry, University of Delhi, Delhi, India
Accepted author version posted online: 17 Nov 2011.Version of
record first published: 27 Feb 2012.
To cite this article: Jitender M. Khurana , Anshika Lumb , Archana Pandey & Devanshi Magoo (2012):
Green Approaches for the Synthesis of 12-Aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-ones in
Aqueous Media and Under Microwave Irradiation in Solventless Conditions, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:12, 1796-1803
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Synthetic Communications1, 42: 1796–1803, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.544832
GREEN APPROACHES FOR THE SYNTHESIS OF
12-ARYL-8,9,10,12-TETRAHYDROBENZO[a]XANTHEN-
11-ONES IN AQUEOUS MEDIA AND UNDER
MICROWAVE IRRADIATION IN SOLVENTLESS
CONDITIONS
Jitender M. Khurana, Anshika Lumb, Archana Pandey, and
Devanshi Magoo
Department of Chemistry, University of Delhi, Delhi, India
GRAPHICAL ABSTRACT
Abstract Convenient and environmentally benign procedures have been reported for the
synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives by multi
component condensation reactions of aromatic aldehydes with b-naphthol and cyclic
1,3-dicarbonyl compounds, namely, dimedone and cyclohexane-1,3-dione. The three-
component condensation has been successfully achieved in one pot by refluxing the compo-
nents in water and is efficiently catalyzed by sulfuric acid. The condensation has also been
achieved by irradiating the components in the presence of a catalytic amount of para-
toluene sulfonic acid under neat conditions with microwaves. The green methodologies
defined herein avoid the severe conditions posed by the older existing methods and prove
to be efficient in terms of good yields, operational simplicity, easy workup, and short
reaction time.
Keywords Cyclohexane-1,3-dione; dimedone; microwave; water; xanthene
INTRODUCTION
Among diverse families of dyes, xanthene and benzoxanthene derivatives hold a
prominent position because of their useful photochemical and photophysical proper-
ties.[1] Xanthenes and the related condensed ring system variants have been used as
dyes,[2] food colorants,[3] and fluorescent materials for visualization of biomolecular
assemblies.[4] Particularly, carboxy-functionalized fluorescein[5] and rhodamine[6]
Received October 12, 2010.
Address correspondence to Jitender M. Khurana, Department of Chemistry, University of Delhi,
Delhi 110007, India. E-mail: jmkhurana@chemistry.du.ac.in
1796

TETRAHYDROBENZO[a]XANTHEN-11-ONES
1797
dyes, which share a common xanthene-based skeleton, have become increasingly
important as conjugated fluorescent markers of biologically active compounds.
The xanthene- and benzoxanthene-based derivatives are also being used to
develop polymer photoimaging systems, which have numerous applications pri-
marily in the print and electronic industry.[7] Xanthene dyes are also utilized in fab-
ricating dye-doped materials with interesting applications in holography, optical
computing, and holographic interferometry.[8] Furthermore, benzoxanthene deriva-
tives are important components of biologically active heterocycles. They are known
to display pharmacological properties such as antibacterial,[9] anti-inflammatory,[10]
and antiviral activities.[11] Because of a wide utility range of xanthene derivatives,
there has been a significant impetus in developing newer synthetic routes for scaffold
manipulation of these structural motifs. Recent reports on the synthesis of
tetrahydrobenzo[a]xanthen-11-ones describe the reaction of aldehydes and b-naph-
thol with cyclic 1,3-dicarbonyl compounds in the presence of catalysts such as stron-
[13]
tium triflate[12] and NaHSO4 ꢀ SiO2 under reflux in halogenated solvents for long
hours. InCl3, P2O5,[14] and TBAF[15] have also been employed to bring about the
cyclocondensation reaction. These synthetic methods afforded good yields but have
limitations of long reaction times, harsh reaction conditions, and use of toxic sol-
vents and often expensive catalysts. Consequently, there is scope for developing
improved and environmentally benign methodologies for the synthesis of these
benzoxanthene derivatives.
Because of the ubiquitous use of toxic reagents, chemicals, and volatile, flam-
mable organic solvents, the concept of ‘‘green chemistry’’ has gained phenomenal
impetus. It emphasizes the development of environmentally clean synthesis, eliminat-
ing the use of hazardous reagents, chemicals, and solvents. In this regard, organic
synthesis in aqueous media is rapidly gaining importance. Because of its green cre-
dentials, safety, and economy, water has emerged as a promising alternative solvent
in the arena of organic synthesis.[16] Also, considerable attention has been drawn to
reactions carried out under solvent-free conditions. This solventless synthesis with
exposure to microwaves[17] has the associated benefits of shorter reaction time,
simple experimental setup, and efficient workup procedures.
In conjunction with our continuing efforts to explore new reactions for syn-
thesis of heterocyclic compounds,[18] we embarked upon environmentally benign
strategies to explore the possibility of synthesizing tetrahydrobenzo[a]xanthene-
11-one derivatives by one-pot condensation of aromatic aldehydes, b-naphthol,
and cyclic 1,3-dicarbonyl compounds in aqueous media using H2SO4 as catalyst
and under microwave irradiation in neat conditions using catalytic para-toluenesul-
fonic acid (p-TSA).
RESULTS AND DISCUSSION
We report herein efficient and green approaches for the synthesis of
12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-ones derivatives by one-pot,
three-component condensation of aromatic aldehydes, b-naphthol, and cyclic
1,3-dicarbonyl compounds catalyzed by H2SO4 in water as the solvent under reflux
conditions and also under microwave irradiation using p-TSA as catalyst in
solventless conditions (Scheme 1).

1798
J. M. KHURANA ET AL.
Scheme 1. Synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-ones.
To achieve optimum reaction conditions, we initially investigated the reaction
of 4-chlorobenzaldehyde (1.0 mmol), b-naphthol (1.0 mmol), and 5,5-dimethylcyclo-
hexane-1,3-dione (dimedone) (1.2 mmol) in different media in the presence of acid
catalysts such as HCl, HNO3, CH3COOH, and H2SO4. The best result was obtained
when the reaction was carried out in water in the presence of a catalytic amount of
sulfuric acid (0.1 mmol) under reflux conditions. The reaction underwent completion
in 3 h, yielding 88% of 12-(4-chlorophenyl)-9,9-dimethyl-8,9,10,12-tetrahydroben-
zo[a] xanthene-11-one (1) after a simple workup. Repeating the reaction under simi-
lar conditions using HNO3 as the catalyst resulted in a mixture of products while
reactions with HCl and CH3COOH resulted in sluggish and incomplete reactions
with only a trace amount of the product. In the absence of any catalyst, we did
not observe any product formation even after 10 h of reflux. Reactions using a
catalytic amount of H2SO4 in CH3CN under reflux resulted in a mixture of products
while the reaction in tetrahydrofuran (THF) resulted in an incomplete reaction with
an inferior yield (41%) of 1. Thus catalytic H2SO4 in water under reflux was chosen
as the optimum system to extend the protocol. Subsequent reactions of variously
substituted aromatic aldehydes with b-naphthol and dimedone were carried out
under these conditions. The reactions proceeded smoothly for different aldehydes
to afford the corresponding xanthene derivatives in excellent yields. The results have
been summarized in Table 1 (method A, entries 1–12).
The protocol was further extended by exploring the cyclocondensation of vari-
ous aldehydes and b-naphthol with another cyclic 1,3-dicarbonyl compound (i.e.,
cyclohexane-1,3-dione). The reaction of 4-chlorobenzaldehyde (1.0 mmol), b-naph-
thol (1.0 mmol), and cyclohexane-1,3-dione (1.2 mmol) in water using 10 mol% of
H2SO4 as catalyst under similar conditions yielded 89% of 12-(4-chlorophenyl)-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (1 m) after 3 h. Other substituted ben-
zaldehydes also underwent successful condensation with b-naphthol and
cyclohexane-1,3-dione, giving good yields of corresponding xanthene derivatives
(Table 1, method A, entries 13–17).
We decided to further explore these reactions under neat conditions with
exposure to microwave irradiation. The control reactions of 4-chlorobenzaldehyde,
b-naphthol, and dimedone mixed with a catalytic amount of H2SO4 under neat con-
ditions led to charring of the components. Therefore, we attempted the reaction
using solid acid catalyst p-TSA. A neat reaction mixture of 4-chlorobenzaldehyde,
b-naphthol, and dimedone with varying amounts of p-TSA was exposed to

TETRAHYDROBENZO[a]XANTHEN-11-ONES
1799
Table 1. Synthesis of tetrahydrobenzo[a]xanthene-11-ones by condensation of aldehydes, b-naphthol,
and dimedone=cyclohexane-1,3-dione
Method Aa
Method Bb
Time
(h)
Yield
(%)
Time
(min)
Yield
(%)
Mp
(ꢁC)
Lit. mp
(ꢁC)
Entry
Ar
R
Product
1
2
4-ClC6H4
4-BrC6H4
4-FC6H4
CH3
CH3
CH3
1a
1b
1c
1d
1e
1f
3
3
88
89
91
86
87
88
88
91
84
89
90
85
89
88
89
90
89
5.0
4.5
5.5
4.0
4.5
6.0
4.5
5.0
4.0
4.5
4.0
5.0
5.0
5.5
5.0
4.5
5.0
83
84
83
82
80
84
83
84
81
82
85
85
84
81
80
81
84
184–186 180–182[14]
180–182 183–184[18g]
180–182 185–186[14]
202–204 204–205[14]
174–176 176–178[14]
150–152 151–153[14]
176–178 178–180[14]
230–232 231–233[15]
166–168 169–170[15]
170–172 169–171[18g]
178–180 178–180[14]
210–212 213–214[12]
206–208 208–209[12]
204–206 202–203[18g]
234–236 235–237[15]
240–242 246–247[18g]
204–206 204–206[18g]
3
3
4
4-CH3OC6H4 CH3
3.5
3.5
3
5
4-CH3C6H4
C6H5
CH3
CH3
6
7
2,4-Cl2C6H3 CH3
1g
1h
1i
3
8
2-Naphthyl
2-BrC6H4
3-BrC6H4
CH3
CH3
CH3
3
9
3
10
11
12
13
14
15
16
17
1j
3
4-NO2C6H4 CH3
1k
1l
2.5
3.5
3
4-OH C6H4
4-ClC6H4
C6H5
CH3
H
1m
1n
1o
1p
1q
H
3
2-BrC6H4
4-NO2C6H4
3-ClC6H4
H
3
H
3
H
3
aMethod A: reaction in water under reflux, H2SO4 (0.1 mmol).
microwaves (120 ꢁC, 100 W). The best result was obtained using 2 mol% of the cata-
lyst after exposure for 5 min, yielding 83% of the desired xanthene derivative
12-(4-chlorophenyl)-9,9-dimethyl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one (1a).
Greater amount of the catalyst (2.5 mol%) did not aid the reaction significantly, and
Scheme 2. Proposed pathway for the synthesis of 1.

1800
J. M. KHURANA ET AL.
no reaction was observed in the absence of the catalyst. Also, the reaction of 4-chlor-
obenzaldehyde and b-naphthol with cyclohexane-1,3-dione under similar conditions
yielded 84% of the corresponding xanthene derivative 12-(4-chlorophenyl)-
8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (1 m) in 4.5 min. The generality of the
optimized protocol (i.e., catalytic p-TSA) under neat conditions with microwave
irradiation (method B) was checked by carrying out the reactions of different substi-
tuted aromatic aldehydes with b-naphthol and dimedone or cyclohexane-1,3-dione,
which yielded the corresponding products in good to excellent yields under these
conditions. These results have been compiled in Table 1.
A
plausible mechanism for the formation of 12-aryl-8,9,10,12-
tetrahydrobenzo[a]xanthen-11-one derivatives (1a–q) in the presence of acid catalysts
is proposed in Scheme 2. Our aim was to strategize the in situ trapping of the o-QM
intermediate with the carbon nucleophile, a facile synthesis of the desired xanthene
derivatives, which was successful under the conditions described.
CONCLUSION
In conclusion, we have reported efficient and environmentally benign meth-
odologies for the synthesis of tetrahydrobenzo[a]xanthene-11-ones by using catalytic
sulfuric acid in water under reflux and by microwave irradiation under neat con-
ditions in the presence of catalytic p-TSA. The methods offer several advantages
in terms of operational simplicity, easy workup, short reaction time, and good yields
of pure product, thus circumventing the problems posed by previous protocols.
EXPERIMENTAL
The reactions in microwave were carried out on the CEM Discover system
(Model No. 908010, manufactured by CEM Company in USA, with vertically
focused infrared [IR] temperature control system, maximum microwave power of
300 W, frequency @ 2.455 GHz) in vials (10 mL) sealed with a septum with a stirring
option. Melting points were recorded on a Tropical Labequip apparatus and Khera
digital melting-point apparatus and are uncorrected. IR spectra were recorded on
Perkin-Elmer FTIR-1710 instrument. NMR spectra were recorded on Bruker
Avance Spectrospin at 300 MHz and 400 MHz using tetramethylsilane (TMS) as
the internal standard. Fast atom bombardment (FAB) mass spectra were recorded
on a Jeol SX 102=Da-600 mass spectrometer using argon=xenon as the FAB gas
and a KC-455-TOF mass spectrometer (Micromass, Manchester, UK).
Preparation of Compounds 1a–q Under Conventional Heating
Conditions (Method A)
A mixture of aldehyde (1.0 mmol), b-naphthol (1.0 mmol), 5,5-dimethyl-1,3-
cyclohexanedione (dimedone) or 1,3-cyclohexanedione (1.2 mmol), H2SO4(0.1 m-
mol), and 10 mL of water was stirred magnetically under reflux for appropriate time
as mentioned in Table 1. The progress of the reaction was monitored by thin-layer
chromatography (TLC) using petroleum ether=ethyl acetate (85:15; v=v) as eluent.
After completion of the reaction, the reaction mixture was allowed to cool to room

TETRAHYDROBENZO[a]XANTHEN-11-ONES
1801
temperature. The precipitate formed was collected by filtration at pump, washed well
with water–ethanol (1:1, v=v), and dried. The crude product was recrystallized from
ethanol to yield pure 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-one deriva-
tives. The product was identified by mp, IR, NMR, and mass spectra.
Preparation of Compounds 1a–q Under MW Conditions (Method B)
In a 10-mL vial, aldehyde (1.0 mmol), b-naphthol (1.0 mmol), and dimedone or
1,3-cyclohexanedione (1.2 mmol) were mixed thoroughly and p-TSA (2 mol%) was
added. The vial was sealed with a cap containing a septum. The loaded vial was then
placed into the cavity of the microwave reactor and heated at 100 W and 100 ꢁC for
4–6 min (as indicated by thin-layer chromatography, TLC) (Table 1). The mixture
was cooled to room temperature and quenched with 5 mL of water. The precipitate
formed was collected by filtration at pump, washed with water–ethanol (1:1 v=v),
and dried. The crude product was recrystallized from ethanol to yield pure
xanthen-11-one derivative.
Representative Analytical Data
12-(4-Chlorophenyl)-9,9-dimethyl-8,9,10,12-tetrahydrobenzo[a]xanthene-
11-one (1a). White solid, mp 178–180 ꢁC; 1H NMR (400 MHz, CDCl3): d ¼ 7.90 (d,
J ¼ 8.3 Hz, 1H, Ar), 7.76–7.80 (m, 2H, Ar), 7.36–7.46 (m, 2H, Ar), 7.32 (d,
J ¼ 8.9 Hz, 1H, Ar), 7.26–7.28 (m, 2H, Ar), 7.12–7.15 (m, 2H, Ar), 5.67 (s, 1H,
CH), 2.56 (s, 2H, CH2), 2.31 (d, J ¼ 16.3 Hz, 1H, CH), 2.24 (d, J ¼ 16.3 Hz, 1H,
CH), 1.12 (s, 3H, CMe), 0.96 (s, 3H, CMe); IR (nmax cmꢂ1) (KBr): 2956, 1648,
1596, 1374, 1224, 1185; MS (ESI): m=z calc. for C25H21ClO2, 388; found (%) ¼ 388
[(M)þ, 90], 390 [32].
12-(4-Bromophenyl)-9,9-dimethyl-8,9,10,12-tetrahydrobenzo[a]xanthene-
11-one (1b). White solid, mp 183–184 ꢁC; 1H NMR (400 MHz, CDCl3): d ¼ 7.89 (d,
J ¼ 8.3 Hz, 1H, Ar), 7.76–7.80 (m, 2H, Ar), 7.38–7.45 (m, 2H, Ar), 7.26–7.33 (m, 3H,
Ar), 7.20–7.23 (m, 2H, Ar), 5.66 (s, 1H, CH), 2.56 (s, 2H, CH2), 2.31 (d, J ¼ 16.3 Hz,
1H, CH), 2.24 (d, J ¼ 16.3 Hz, 1H, CH), 1.12 (s, 3H, CMe), 0.96 (s, 3H, CMe); 13C
NMR (300 MHz, CDCl3): d ¼ 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 (nmax cmꢂ1) (KBr): 2955, 1652, 1596, 1373, 1228, 1185; MS
(FAB): m=z calc. for C25H21BrO2, 432; found (%) ¼ 433 [(M þ H)þ, 88], 435
[(M þ 2 þ H)þ, 90].
9,9-Dimethyl-12-(4-methylphenyl)-8,9,10,12-tetrahydrobenzo[a]xanthene-
1
11-one (1e). White solid, mp 176–178 ꢁC; H NMR (400 MHz, CDCl3): d ¼ 8.0 (d,
J ¼ 8.4 Hz, 1H, Ar), 7.33–7.77 (m, 2H, Ar), 7.40–7.44 (m, 1H, Ar), 7.32–7.37 (m, 2H,
Ar), 7.20–7.30 (m, 2H, Ar), 6.96 (d, J ¼ 8.0 Hz, 2H, Ar), 5.66 (s, 1H, CH), 2.54 (s,
2H, CH2), 2.30 (d, J ¼ 16.2 Hz, 1H, CH), 2.23 (d, J ¼ 16.2 Hz, 1H, CH), 2.19 (s,
3H, CH3), 1.10 (s, 3H, CMe), 0.98 (s, 3H, CMe); 13C NMR (300 MHz, CDCl3):
d ¼ 196.8, 163.7, 147.7, 141.8, 135.6, 131.5, 131.4, 128.9, 128.6, 128.3, 128.2, 126.9,
124.8, 123.6, 117.9, 117.0,114.4, 50.9, 41.4, 34.2, 32.2, 29.2, 27.2, 20.9; IR

1802
J. M. KHURANA ET AL.
(nmax cmꢂ1) (KBr): 2950, 1649, 1597, 1372, 1228, 1185; MS (FAB): m=z calc. for
C26H24O2 368; found (%) ¼ 369 [M þ Hþ, 90].
12-(4-Chlorophenyl)-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (1m).
1
White solid, mp 206–208 ꢁC; H NMR (300 MHz, CDCl3): d ¼ 7.87 (d, J ¼ 7.8 Hz,
1H, Ar), 7.76–7.79 (m, 2H, Ar), 7.24–7.45 (m, 5H, Ar), 7.13 (d, J ¼ 8.4 Hz, 2H,
Ar), 5.71 (s, 1H, CH), 2.60–2.79 (m, 2H, CH2), 2.32–2.51 (m, 2H, CH2), 1.91–2.12
(m, 2H, CH2); IR (nmax cmꢂ1) (KBr): 2962, 1647, 1593, 1374, 1231, 1189; MS
(ESI): m=z calc. for C23H17ClO2 360; found (%) ¼ 361 [M þ H]þ.
12-Phenyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one
1
(1n). White
solid, mp 204–206 ꢁC; H NMR (300 MHz, CDCl3): d ¼ 7.95 (d, J ¼ 8.1 Hz, 1H,
Ar), 7.74–7.78 (m, 2H, Ar), 7.03–7.44 (m, 8H, Ar), 5.73 (s, 1H, CH), 2.59–2.79
(m, 2H, CH2), 2.31–2.50 (m, 2H, CH2), 1.91–2.08 (m, 2H, CH2); IR (nmax cmꢂ1
)
(KBr): 2955, 1647, 1593, 1372, 1229, 1188; MS (ESI): m=z calc. for C23H18O2 326;
found (%) ¼ 326 [Mþ, 92].
12-(2-Bromophenyl)-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one (1o).
1
White solid, mp 235–237 ꢁC; H NMR (300 MHz, CDCl3): d ¼ 8.28 (d, J ¼ 8.4 Hz,
1H, Ar), 7.72–7.76 (m, 2H, Ar), 7.34–7.50 (m, 3H, Ar), 7.17–7.30 (m, 2H, Ar),
7.0–7.1 (m, 1H, Ar), 6.89–7.0 (m, 1H, Ar), 5.97 (s, 1H, CH), 2.53–2.83 (m, 2H,
CH2), 2.23–2.46 (m, 2H, CH2), 1.93–2.16 (m, 2H, CH2); 13C NMR (300 MHz,
CDCl3): d ¼ 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 (nmax cmꢂ1
)
(KBr): 2957, 1652, 1595, 1371, 1227, 1189; MS (FAB): m=z calc. for C23H17BrO2
404; found (%) ¼ 405 [(M þ H)þ, 99], 407 [(M þ 2 þ H)þ, 99].
ACKNOWLEDGMENTS
A. L. thanks the University of Delhi for the award of UTA and D. M. thanks
the Council for Scientific and Industrial Research, New Delhi, India, for the grant of
junior and senior research fellowships.
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