Eco-friendly synthesis of tetrahydrobenzo[c]xanthenes catalyzed by functional ionic liquid in water

Article abstract of DOI:10.1007/s00706-013-1057-9

A clean procedure for the synthesis of tetrahydrobenzo[ c]xanthenes was established in the presence of a functional ionic liquid, 1-butyl-(4- dimethylamino)pyridinium hydroxide [BDMAP][OH]. The reaction was carried out via the one-pot multi-component cond

Full text of DOI:10.1007/s00706-013-1057-9

Monatsh Chem (2013) 144:1705–1710
DOI 10.1007/s00706-013-1057-9
ORIGINAL PAPER
Eco-friendly synthesis of tetrahydrobenzo[c]xanthenes catalyzed
by functional ionic liquid in water
•
Jiaojiao Yang Jinming Yang Ting Zhu
•
•
•
Pingping Wang Dong Fang
Received: 3 January 2013 / Accepted: 8 July 2013 / Published online: 14 August 2013
Ó Springer-Verlag Wien 2013
Abstract A clean procedure for the synthesis of tetra-
hydrobenzo[c]xanthenes was established in the presence of
a functional ionic liquid, 1-butyl-(4-dimethylamino)pyrid-
inium hydroxide [BDMAP][OH]. The reaction was carried
out via the one-pot multi-component condensation of aro-
matic aldehydes, cyclic 1,3-dicarbonyl compounds, and a-
naphthol in aqueous media, to afford good to excellent
yields ranging from 80 to 85 % within 60–90 min. After
the reaction, the catalyst could be recycled and reused
several times without a noticeable reduction in catalytic
activity.
these compounds have been used as dyes [3], pH-sensitive
fluorescent materials for the visualization of bimolecules
[4], and in laser technology [5]. Thus, their versatility has
made xanthenes prime synthetic candidates for intensive
research in recent years.
Multi-component reactions (MCRs) play an important
role in organic synthesis, since they generally occur in a
single pot and exhibit high atom economy and selectivity,
the products are formed in a single step, and diversity can
be achieved simply by varying the reacting components.
Since they are performed without isolating any intermedi-
ate, the process reduces reaction time and saves both
energy and raw materials. Therefore, the design of novel
MCRs has attracted a great deal of attention from research
groups working in the fields of medicinal chemistry, drug
discovery, and materials science [6–10].
Keywords Tetrahydrobenzo[c]xanthene Á
Clean synthesis Á Basic ionic liquid Á Catalyst Á
Aqueous medium
Benzoxanthene derivatives have also been synthesized
via MCRs. However, existing methods have always focused
on tetrahydrobenzo[a]xanthenes [11–14]. To the best of our
knowledge, only three articles have reported syntheses of
tetrahydrobenzo[c]xanthene derivatives from a-naphthol,
using either proline triflate [15], ceric ammonium nitrate/
ultrasonic irradiation [16], or HY zeolite [17] as the acidic
catalyst. It may be that the low electron density at the b
position of the a-naphthol does not permit the formation of
the corresponding ortho-quinone methides under these
conditions when employing acidic catalysis. Hence, it is
more difficult to synthesize tetrahydrobenzo[c]xanthenes,
but they are urgently required, so the search is on for new
readily available and green catalysts in this context.
In our previous work, novel, efficient, and eco-friendly
SO3H-functional acidic ionic liquids were designed and
successfully prepared. Their catalytic performances in
MCRs were also investigated [18, 19]. As a continuation of
our work studying ionic-liquid-catalyzed MCRs with clean
Introduction
Xanthenes and benzoxanthenes comprise one of the most
widely distributed classes of natural compounds, as these
heterocyclic compounds exhibit a wide range of biological
and pharmaceutical properties, such as antiviral and anti-
inflammatory activities. These compounds can also be used
in photodynamic therapy [1, 2]. Additionally, some of
Jiaojiao Yang Á Jinming Yang Á P. Wang Á D. Fang (&)
Department of Pharmaceutical Engineering, School
of Chemistry and Chemical Engineering, Yancheng Teachers
University, Yancheng 224002, People’s Republic of China
e-mail: fang-njust@hotmail.com
T. Zhu
Jiangsu Provincial Key Laboratory of Coast Wetland
Bioresources and Environment Protection,
Yancheng 224002, People’s Republic of China
123

1706
J. Yang et al.
procedures, we prepared a basic ionic liquid, 1-butyl-4-
(dimethylamino)pyridinium hydroxide ([BDMAP][OH]),
and used it as a novel catalyst for the synthesis of tetra-
hydrobenzo[c]xanthenes via an MCR in aqueous media
(Scheme 1). This work is described below.
amino group on the pyridinium moiety should be taken into
account. [BDMAP][OH] and [BPy][OH] have the same
anion (OH-), but in terms of a cation, [BDMAP] is better
than [BPy]. The catalysts (C4H9)4NOH and (CH3)4NOH,
which have different cations, (C4H9)4N? and (CH3)4N?,
respectively, also showed relatively low activities (entries
10, 11), although they do have the same anion (OH-) as
[BDMAP][OH]. These results indicate that the cation sig-
nificantly influences this reaction. On the other hand, the
catalysts [BDMAP]Br and [BDMAP][BF4], which have
other anions, Br- and BF4-, respectively, gave very low
yields of no more than 5 % (entries 12, 13), even though
they have the same cation (BDMAP) as [BDMAP][OH].
This therefore indicates that OH- plays an important role.
These facts indicate that the amphipathic properties of the
cation (pyridinium ring and amino group) and the
hydroxide anion (naked and strongly basic) may affect the
catalytic performance. The action of the anion may be
more important than that of the cation for this procedure.
The ionic liquid [BDMAP][OH] was found to be the best
catalyst for this condensation. The optimized reaction
conditions are listed in Table 1 (entry 5).
Results and discussion
Initially in this study, a-naphthol, benzaldehyde, and
dimedone were selected as model reactants for comparing
the catalytic performances of the functional ionic liquids,
including N-butylpyridinium hydroxide [BPy][OH],
1-butyl-3-methylimidazolium hydroxide [BMIM][OH],
1-butyl-4-(dimethylamino)pyridinium bromide [BDMAP]
Br, and 1-butyl-4-(dimethylamino)pyridinium tetrafluoro-
borate [BDMAP][BF4]. Two basic quaternary ammonium
salts, tetrabutylammonium hydroxide (C4H9)4NOH and
tetramethylammonium hydroxide (CH3)4NOH, were also
explored for comparison.
As shown in Table 1, no xanthenes could be detected in
the absence of ionic liquids (entry 1), which indicated that
the catalyst was necessary for this MCR. All of the pre-
pared ionic liquids provided tetrahydrobenzo[c]xanthenes
in yields of 65–90 % (entries 2–8). According to the results
for entries 5 and 8 in Table 1, the effect of the tertiary
Subsequently, the reusability of [BDMAP][OH] in the
same model condensation reaction was investigated for
economic and environmental reasons. After the reaction,
the product was separated by filtration, and then the
Scheme 1
4a: R1=H, R2=Me; 4b: R1=2-Cl, R2=Me; 4c: R1=4-Cl, R2=Me; 4d: R1=4-Br, R2=Me;
4e: R1=4-HO, R2=Me; 4f: R1=3-NO2, R2=Me; 4g: R1=4-NO2, R2=Me; 4h: R1=CH3O,
R2=Me; 4i: 1= furaldehyde, R2=Me; 4j: R1=H, R2=H; 4k: R1=3-HO, R2=H; 4l:
1=propanal, R2=Me; 4m: 1= cyclohexanone, R2=Me
123

Eco-friendly synthesis of tetrahydrobenzo[c]xanthenes
1707
Table 1 Effects of different
Entry
Catalyst/mol%
Time/min
Isolated yield/%
catalysts on the reaction of a-
naphthol, benzaldehyde, and
dimedone
1
–
180
90
90
90
90
90
90
90
90
90
90
90
90
0
2
[BDMAP][OH] (3)
[BDMAP][OH] (5)
[BDMAP][OH] (8)
[BDMAP][OH] (10)
[BDMAP][OH] (12)
[BDMAP][OH] (15)
[BPy][OH] (10)
52
67
73
85
85
85
65
55
31
40
B5
B5
3
4
5
6
7
8
9
[BMIM][OH] (10)
(C4H9)4NOH (10)
(CH3)4NOH (10)
[BDMAP]Br (10)
[BDMAP][BF4] (10)
10
11
Reaction conditions: 10 mmol
12
13
benzaldehyde, 10 mmol a-
naphthol, 10 mmol dimedone,
5 cm3 H2O, 90 °C
catalyst-containing filtrate was reused in the next run
without further purification. The same amounts of reactants
were charged into the filtrate and then stirred under the
above optimal conditions. After the reaction, the same
post-procedure was used to obtain the same compounds.
The results showed that the catalyst could be reused at least
six times with only a small decrease in yield, which ranged
from 81 to 85 %. The loss of ionic liquid in aqueous media
was about 5 % after six cycles. This may be due to catalyst
loss in each post- and recycle procedure. Its ease of recy-
cling is another attractive property of this catalyst, for
environmental protection and economic reasons.
catalysts for this reaction. The data listed in Table 3 show
that the basic ionic liquid [BDMAP][OH] is a relatively good
catalyst for the synthesis of tetrahydrobenzo[c]xanthenes,
based on a comparison of reaction conditions, including
reaction medium, reaction temperature, reaction time, and
yields. Additionally, this represents the first example of a
tetrahydrobenzo[c]xanthene synthesis catalyzed by a basic
catalyst.
Lastly, with the above conditions in hand, a plausible
mechanism for this condensation reaction was proposed (see
Scheme 2). Since the substrates of this reaction, aromatic
aldehyde, 1,3-dimedone, and a-naphthol, are not soluble in
water, this reaction probably proceeds under heterogeneous
conditions. The amphipathic catalyst [BDMAP][OH] may
act mainly as a phase transfer catalyst; on the other hand, the
OH anion of the pyridinium salt is naked and strongly basic,
this reaction is not promoted by a basic ionic solution but by a
phase transfer catalyst that is strongly basic.
We then applied this MCR to other substituted benzal-
dehydes, a-naphthol, and cyclic 1,3-dicarbonyl compounds
under solvent-free conditions in the presence of [BDMA-
P][OH] under the above optimized reaction conditions
(Table 2). The procedure enabled effective preparation of
the required products, tetrahydrobenzo[c]xanthenes 4. All
aromatic aldehydes with either electron-withdrawing or
electron-donating groups, for example nitro or methoxy
groups, gave reasonable to good yields ranging from 80 to
85 % in 60–90 min. Both dimedone and 1,3-cyclohex-
anedione gave similarly good results. However, aromatic
aldehydes with electron-withdrawing groups were slightly
less active than those with electron-donating groups.
Unfortunately, for aliphatic aldehydes and ketones such as
propanal and cyclohexanone, no more than 5 % of the
target product could be obtained (4l–4m). The electron-
donating effect of aliphatic group is more that that of
aromatic group, hence, aliphatic aldehydes were inert to
this reaction. The tetrahydrobenzo[c]xanthenes were char-
In summary, it was demonstrated that a readily available
combined phase transfer/strongly basic bifunctional ionic
liquid [BDMAP][OH] can be used as a novel catalyst for
the synthesis of benzo[c]xanthenes. The merit of this cat-
alytic methodology is that it is simple, highly efficient, and
environmentally benign.
Experimental
Melting points were determined on an X-6 (Beijing Tech
Instrument Co., Beijing, China) melting point apparatus
1
with a microscope. H NMR spectra were recorded on a
1
acterized using H NMR spectral data and by comparing
Bruker (Rheinstetten, Germany) DRX300 (300 MHz)
spectrometer, and 13C NMR spectra on the same instrument
at 75 MHz. Mass spectra were obtained with an automated
Finnigan TSQ Quantum Ultra AM (Thermo Fisher Scien-
tific, Waltham, MA, USA) LC/MS spectrometer. Elemental
their physical properties with literature values.
The results obtained with a-naphthol, benzaldehyde, and
dimedone under optimized conditions were compared with
those obtained in three other recent works [15–17 using other
123

1708
J. Yang et al.
Table 2 Synthesis of
benzo[c]xanthene derivatives
Entry
R1
R2
Time/min
Isolated yield/%
M.p./lit. m.p.; °C
4a
4b
4c
4d
4e
4f
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
90
90
90
90
60
90
90
60
90
90
90
90
90
85
82
83
82
85
81
80
84
85
83
80
B5
B5
150–152 (149–152 [16])
178–180 (179–181 [16])
183–185 (185–187 [16])
213–215 (–)
2-ClC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
3-NO2C6H4
4-NO2C6H4
4-CH3OC6H4
Furaldehyde
C6H5
220–222 (222–224 [16])
166–168 (167–170 [16])
210–212 (–)
4g
4h
4i
147–148 (148–150 [17])
155–157 (155–158 [16])
173–175 (174–176 [15])
248–250 ([250 [15])
4j
4k
4l
3-HOC6H4
Propanal
H
Reaction conditions: 10 mmol
aldehyde, 10 mmol a-naphthol,
10 mmol diketone, 1 mmol
catalyst, 5 cm3 H2O, 90 °C
H
4m
Cyclohexanone
H
Table 3 Comparison of our
results with all other reported
methods
Entry
Reaction conditions
Time/h
Yield/%
1
2
3
4
Proline triflates (10 mol%)/H2O/reflux
CAN (5 mol%)/U.S./DCM:EtOH (1:1)/r.t.
HY zeolite (20 mg/mmol)/neat/80 °C
[BDMAP][OH] (10 mol%)/H2O/90 °C
5
79 [15]
2
85 [16]
1
87 [17]
1.5
85 (this work)
Scheme 2
123

Eco-friendly synthesis of tetrahydrobenzo[c]xanthenes
1709
analyses were recorded on a PerkinElmer (Waltham, MA,
USA) C spectrometer. All chemicals (AR grade) were
commercially available and used directly without further
purification.
NMR, and their physical data (m.p.) were compared with
those reported in the literature.
7-(4-Bromophenyl)-10,10-dimethyl-10,11-dihydro-7H-
benzo[c]xanthen-8(9H)-one (4d, C25H21BrO2)
1-Butyl-4-(dimethylamino)pyridinium hydroxide
White solid, m.p.: 213–215 °C; IR (KBr): vꢀ = 2,958,
([BDMAP][OH])
2,935, 1,646, 1,628, 1,370, 1,223, 807 cm-1 1H NMR
;
1-Butyl-4-(dimethylamino)pyridinium hydroxide [BDMA-
P][OH] was synthesized in accordance with previous
methods [20], albeit with some changes. 4-Dimethylami-
nopyridine (0.05 mol) and 1-bromobutane (0.05 mol) were
stirred in a three-necked flask with a reflux condenser at
90 °C for 2 h under solvent-free conditions. The resulting
mixture was cooled, filtrated, washed with ethyl acetate,
and then dried under vacuum to give the intermediate
1-butyl-4-(dimethylamino)pyridinium bromide ([BDMAP]Br)
in a yield of 95 %. Then, this intermediate was reacted with
equimolar potassium hydroxide to afford the ionic liquid
1-butyl-4-(dimethylamino)pyridine hydroxide [BDMA-
P][OH]; this step was performed in accordance with the
reported method. The catalyst was a light yellow oil,
obtained in a yield of 97 %. It dissolves in polar solvents
such as water, CH3OH, C2H5OH, CH3CN, and acetone,
and partly dissolves in nonpolar solvents such as CH2Cl2,
(300 MHz, CDCl3): d = 7.79–7.73 (m, 3H), 7.46–7.12 (m,
7H), 5.68 (s, 1H), 2.57 (s, 2H), 2.35–2.21 (dd, J = 16.2,
16.2 Hz, 2H), 1.12 (s, 3H), 0.96 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d = 198.0, 162.2, 143.5, 139.4, 132.7,
132.2 (CH 9 2), 130.5 (CH 9 2), 127.4, 126.4, 126.1,
125.7 (CH 9 2), 124.6, 123.7, 121.1, 119.9, 109.8, 51.5,
43.8, 41.3, 32.3, 29.2, 27.5 ppm; MS (ESI): m/z = 434
([M?1]?).
10,10-Dimethyl-7-(4-nitrophenyl)-10,11-dihydro-7H-
benzo[c]xanthen-8(9H)-one (4g, C25H21NO4)
Yellow solid, m.p.: 210–212 °C; IR (KBr): vꢀ = 2,958,
2,924, 1,648, 1,629, 1,371, 1,347, 764, 684 cm-1; 1H NMR
(300 MHz, CDCl3): d = 8.43–8.41 (d, J = 8.4 Hz, 1H),
8.20–8.17 (d, J = 8.7 Hz, 1H), 7.79–7.19 (m, 7H),
6.99–6.91 (m, 1H), 5.85 (s, 1H), 2.63 (s, 2H), 2.37–2.21
(dd, J = 16.2, 16.2 Hz, 2H), 1.14 (s, 3H), 1.00 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3): d = 199.0, 162.9,
146.5, 145.9, 143.5, 132.7, 129.2 (CH 9 2), 127.4, 126.4,
126.1, 125.7 (CH 9 2), 121.6 (CH 9 2), 121.1, 120.9,
120.2, 109.8, 51.5, 43.8, 41.3, 30.5, 29.1, 27.5 ppm; MS
(ESI): m/z = 400 ([M?1]?).
1
ether, cyclohexane, and benzene, etc. H NMR (300 MHz,
D2O): d = 0.73 (t, 3H, J = 6.3 Hz, –CH3), 1.09–1.16 (m,
2H, –CH2–), 1.62–1.68 (m, 2H, –CH2–), 2.77 (s, 6H,
N–CH3), 3.14 (t, 2H, J = 6.0 Hz, –CH2–), 6.70 (d, 2H,
J = 7.5 Hz, Py–H), 7.80 (d, 2H, J = 7.5 Hz, Py–H) ppm.
The basic ionic liquids used for comparison purposes, such
as N-butylpyridinium hydroxide [BPy][OH] and 1-butyl-3-
methylimidazolium hydroxide [BMIM][OH], were obtained
according to reported methods [21]; 1-butyl-4-dimethylami-
nopyridinium tetrafluoroborate [BDMAP][BF4], tetrabutyl-
ammonium hydroxide (C4H9)4NOH, and tetramethylammo-
nium hydroxide (CH3)4NOH were commercially available
and used directly without further purification.
Acknowledgments We express our sincere thanks to the Ministry
of Science and Technology of the People’s Republic of China
(11C26213201395), the Key Laboratory of Organic Synthesis of Ji-
angsu Province (KJS1112) for financial assistance, and the
Professional Talent Foundation of Yancheng Normal University
(10YSYJB0203).
References
General procedure for the synthesis
of benzo[c]xanthenes
1. Jamison JM, Krabill K, Hatwalkar A (1990) Cell Biol Int Rep
14:1075
2. Chibale K, Visser M, Schalkwyk DV, Smith PJ, Saravanamuthu
A, Fairlamb AH (2003) Tetrahedron 59:2289
3. Bhowmik BB, Ganguly P (2005) Spectrochim Acta A 61:1997
4. Liu J, Diwu Z, Leung WY (2001) Bioorg Med Chem Lett
11:2903
5. Ahmad MT, King A, Cha BH, Lee J (2002) J Phys D Appl Phys
35:1473
6. Domling A, Ugi I (2000) Angew Chem Int Ed 39:3168
7. Heck S, Domling A (2000) Synlett 3:424
8. Dallinger D, Gorobets NY, Kappe CO (2003) Org Lett 5:1205
9. Kumar RS, Perumal S (2007) Tetrahedron Lett 48:7164
10. Singh MS, Chowdhury S (2012) RSC Adv 2:4547
11. Zhang Q, Su H, Luo J, Wei Y (2012) Green Chem 14:201
12. Khazaei A, Zolfigol MA, Moosavi-Zare AR, Zare A, Khojasteh
M, Asgari Z, Khakyzadeh V, Khalafi-Nezhad A (2012) Catal
Commun 20:54
In a typical experiment, [BDMAP][OH] (1.0 mmol) dilu-
ted with 5 cm3 H2O was added to a mixture of a-naphthol
(10 mmol), aldehyde (10 mmol), and cyclic 1,3-dicarbonyl
compounds (10 mmol) in a round-bottomed flask. The
mixture was then stirred for a certain period of time at
90 °C (Scheme 1). On completion (as monitored by TLC),
the mixture was cooled to room temperature, and the pre-
cipitated solid was collected by filtration and then
recrystallized from ethanol (95 %) to afford pure
benzo[c]xanthenes 4. The catalyst [BDMAP][OH] present
in the filtrate could be used for subsequent cycles without
1
any treatment. The products were identified by IR and H
123

1710
J. Yang et al.
13. Karimi N, Oskooie HA, Heravi MM, Tahershamsi L (2011)
Synth Commun 41:307
14. Reddy NB, Rao KUM, Sundar CS, Nayak SK, Reddy CS (2012)
Heterocycl Commun 18:53
18. Fang D, Zhang DZ, Liu ZL (2010) Monatsh Chem 141:419
19. Fang D, Yang JM, Jiao CM (2011) Catal Sci Technol 1:243
20. Yi FP, Zhang X, Sun HY, Chen SH (2012) Acta Chim Sinica
70:741
15. Li JJ, Lu LM, Su WK (2010) Tetrahedron Lett 51:2434
16. Sudha S, Pasha MA (2012) Ultrason Sonochem 19:994
17. Rama V, Kanagaraj K, Pitchumani K (2012) Tetrahedron Lett
53:1018
21. Ranu BC, Banerjee S (2005) Org Lett 7:3049
123