Highly efficient synthesis of dicoumarols and xanthene derivatives in presence of Br?nsted–Lewis acidic ionic liquids catalyst

Article abstract of DOI:10.1007/s13738-017-1146-5

A series of metal chloride-based acidic ionic liquids have been prepared and used as an efficient catalyst in one-pot multicomponent synthesis of biscoumarins and substituted xanthenes derivatives under solvent-free conditions. Among the acidic ionic liqu

Full text of DOI:10.1007/s13738-017-1146-5

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1146-5
ORIGINAL PAPER
Highly effcient synthesis of dicoumarols and xanthene derivatives
in presence of Brønsted–Lewis acidic ionic liquids catalyst
Faezeh Abbasi1 · Najmedin Azizi2 · Masumeh Abdoli‑Senejani1
Received: 19 December 2016 / Accepted: 25 May 2017
© Iranian Chemical Society 2017
Abstract A series of metal chloride-based acidic ionic liq-
uids have been prepared and used as an effcient catalyst
in one-pot multicomponent synthesis of biscoumarins and
substituted xanthenes derivatives under solvent-free condi-
tions. Among the acidic ionic liquids, N-methylpyrrolido-
nium zinc chloride (Hnmp/ZnCl3)-based Brønsted–Lewis
acidic ionic liquids were found to be an effective and recy-
clable catalyst for a one-pot synthesis of biscoumarins
through the domino Knoevenagel–Michael reaction of a
variety of aldehydes with 4-hydroxycoumarin in short reac-
tion times. The reactions which occur under relatively mild
conditions afforded the biscoumarin derivatives employing
a very low loading of catalyst in satisfactory isolated yields
and high purity after simple work-up. The Brønsted–Lewis
acidic ionic liquid catalyst was reused four times without
any variation in yield.
derivatives have been extensively investigated with regard
to their biological activities, pharmaceutical and therapeu-
tic properties, and in therapeutic application besides their
employment as anticoagulant (antivitamin K activity) [2].
Undeniably, they are traditional blue-fuorescent labels,
nonlinear optical chromophores and sustaining agents.
α,α-(Benzylidene)-bis-(4-hydroxycoumarin), commonly
known as biscoumarin, is one of the important coumarin
derivatives have shown a remarkably broad spectrum of
pharmacological and physiological activities as well as
additives in food and cosmetics [3, 4]. Many synthetic
approaches to biscoumarins using Pechmann, Perkin,
Knoevenagel, Reformatsky, and Wittig reactions have
been reported [5]. Among the various approaches, domino
Knoevenagel–Michael reactions between carbonyl com-
pound and 4-hydroxycoumarin in the presence of catalyst
or promoter are a general strategy and many articles deal-
ing with their synthesis, and reactivity has been published
[6–17].
Keywords Brønsted–Lewis acidic ionic liquids ·
Dicoumarols · 4-Hydroxycoumarin
Acidic ionic liquids (ILs) have attracted a lot of attention
due to their low vapor pressure, ease of separation from
reaction products, excellent thermal stability and high ionic
conductivity with broad application such as catalysts, reac-
tion media, gas adsorbents and chromatography stationary
phases [18–21]. The introductions of functionalized ionic
liquids that are “task specifc” [22–24] containing metal
chlorides are designed to replace some expensive metal
halide catalysts and opened many new possibilities for the
application these halides in chemical reactions [25]. Fur-
thermore, acidic ILs possess the advantages of both liquid
and solid acid catalysts such as water solubilities, recycla-
ble, high acid density, easy separation and reusability. In
this context, acidic ILs are now widely acknowledged as a
new class of advanced acidic catalyst for applications in the
felds of chemistry and industry [18, 26–29].
Introduction
Coumarin and its derivatives are widely distributed
throughout nature, notably in high concentration in the
Tonka bean, woodruff and bison grass [1]. Coumarin
* Najmedin Azizi
azizi@ccerci.ac.ir
1
Department of Chemistry, Islamic Azad University-Arak
Branch, P.O. Box 38135-567, Ara¯k, Iran
2
Department of Green Chemistry, Chemistry and Chemical
Engineering Research Center of Iran, P.O. Box 14335-186,
Tehran, Iran
1 3

J IRAN CHEM SOC
Scheme 1 Preparation of acidic ionic liquids
Fig. 1 Structures of eight kinds of acidic ionic liquids
Table 1 Optimization of acidic ionic liquids for the synthesis of bis-
coumarin
Experimental
General
All starting materials and Brønsted–Lewis acidic ionic liq-
uids components such as aldehydes, dimedone, 4-hydroxy-
coumarin, ZnCl2, SnCl2, AlCl3 and FeCl3 were commer-
cially available. Melting point was determined on Buchi
535 melting point apparatus. 1H and 13C NMR spectra were
recorded on 500 MHz NMR spectrometer using DMSO-d6
as solvent. Chemical shifts were expressed in (ppm) down-
feld from TMS. All the reactions were monitored by thin-
layer chromatography (TLC) with UV light as detecting
agents.
Entry
IL
Temp. (°C)
Yields (%)a
1
IL1
IL2
IL3
IL4
IL5
IL6
IL7
IL8
IL1
IL1
IL1
IL1
100
100
100
100
100
100
100
100
25
97
80
90
92
78
65
72
78
18
25
65
86
2
3
4
5
6
7
8
Acidic ionic liquid preparations
9
10
11
12
40
IL5–IL8 was prepared according to our previous paper
[30].
60
80
a
Isolated yields. Reaction condition: 4-hydroxycoumarin (1 mmol),
benzaldehyde (0.5 mmol), catalyst (20 mg), stirred for 40 min
IL1–IL4
FTIR spectrum; the results were compared with the liter-
ature data. A 250-mL three-necked fask with a magnetic
stirrer under argon was vacuum-dried and cooled by an
Acidic ionic liquids (IL1–IL4) were prepared by known
methods reported on the literature [31, 32] (Scheme 1). The
obtained acidic ILs were characterized by H NMR and
1
1 3

J IRAN CHEM SOC
Table 2 Condensation reaction
of various aldehydes and
4-hydroxycoumarin
Entry Ar
Products (3)
Time (min) Yield (%)
m.p. (°C)
Found
Reported [refs.]
1
40
30
97
86
208–211 208–209 [40]
2
236–238 232–233 [12]
3
4
30
35
81
90
236–238 231–233 [12]
257–259 248–250 [12]
5
6
35
40
86
93
229–231 225–227 [16]
269–271 248–250 [12]
7
8
45
45
90
88
254–257 232–234 [12]
269–271 266–268 [41]
1 3

J IRAN CHEM SOC
Table 2 continued
Entry Ar
Products (3)
Time (min) Yield (%)
m.p. (°C)
Found
Reported [refs.]
9
50
81
215–216 222–225 [12]
10
11
50
78
193–194 199–200 [41]
50
90
266–268 263–265 [12]
ice-water bath and charged with 1-methyl-2-pyrrolidinone
NMP (7.43 g, 75 mmol), and HCl (75 mmol, aqueous solu-
tion, 32 wt%) was added dropwise for 45 min under stir-
ring. The crude reaction mixture was allowed to warm to
45 °C and continued for 24 h at this temperature. The water
was removed by rotary evaporation under reduced pressure
at 60 °C, and the crude solid was washed with ethyl acetate
to remove any unreacted starting materials. After vacuum
drying, [Hnmp]Cl as white solid was obtained. In the next
step, [Hnmp] Cl and MCl (ZnCl2, FeCl3, AlCl3 and SnCl2)
in the ratio 1:1 were mixed and stirred under heating at
100 °C for 24 h in N2 atmosphere to form the pure honey
like viscous ionic liquid (Scheme 1).
compounds were characterized as the basis of their spectro-
scopic data (NMR) and melting point by comparison with
those reported on the literature.
Results and discussion
As part of our continued work about the application of
green chemistry for organic transformation [33–35] herein,
we report the synthesis of a N-methylpyrrolidonium metal
chloride-based Brønsted–Lewis acidic ionic liquids, which
was applied as the highly effcient catalyst for one-pot syn-
thesis of biscoumarins through the domino Knoevenagel–
Michael reaction of a variety of aldehydes with 4-hydroxy-
coumarin under solvent-free conditions.
Typical experimental procedure
First, a series of N-methylpyrrolidonium and choline
metal chloride-based Brønsted–Lewis acidic ionic liquids
were synthesized following the procedure outlined in the
literature (Fig. 1).
After preparation of acidic ionic liquids, in order to opti-
mize the reaction condition, benzaldehyde and 4-hydroxy-
coumarin, as a model reaction under solvent-free condi-
tions to investigate the catalytic performance of acidic ionic
liquids. The results are summarized in Table 1. At room
temperature, in the presence of acidic ionic liquid, the con-
densation reaction was negligible. Attempts to improve the
With a mixture of aldehyde (0.5 mmol) and 4-hydroxycou-
marin (1 mmol) or dimedone (1 mmol) was added acidic
ionic liquid (20 mg), and the reaction mixture were heated
at the 100 °C with vigorously stirring for 30–50 min.
After completion of the reaction, the reaction mixture was
allowed to cool to room temperature and was extracted
with hot ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and evaporated to dryness. The
crude product was recrystallized from ethanol to afford the
pure product which required no further purifcation. All
1 3

J IRAN CHEM SOC
Table 3 Synthesis of various
xanthenes derivatives in
Brønsted–Lewis acidic ionic
liquids
Entry
1
ArCHO
Product
Yield (%)a
95
m.p (°C)
Found
Reported
204–205
202–203 [37]
2
3
80
82
240–242
242–243 [37]
226–228 [37]
230–232
4
90
80
214–215
230–232
215–216 [37]
238–239 [37]
5
a
Isolated yield
Fig. 2 Mechanistic assumption for the acidic ionic liquid catalyzed reaction
1 3

J IRAN CHEM SOC
100
80
60
40
20
0
A mechanism is proposed based on experimental
data, which suggests that in the initial step, acidic ionic
liquids behave as a Brønsted–Lewis acid catalyst and
activate carbonyl group of aldehyde (Fig. 2). The nucle-
ophilic addition of 4-hydroxycoumarin to activated alde-
hydes (I), after H2O removal to give Michael acceptor
II. Michael addition of another molecule of 4-hydroxy-
coumarin to activate intermediate II to give biscoumarin
products.
1
2
3
4
5
Number of Cycles
The recovery and reuse of the reaction system were
highly preferable in terms of industrial application
and green chemistry. To test the catalyst reusability,
4-hydroxycoumarin (6 mmol), benzaldehyde (3 mmol)
and IL1 (60 mg) were heated at 100 °C under solvent-
free condition for 40 min. After completion of the reac-
tion, the crude product was extracted with ethyl acetate
and was fltered to separate the IL1. The IL1 was washed
with ethyl acetate (10 mL) and dried in vacuum and used
for the next run over fve cycles without any variation in
product yield and reaction rate (Fig. 3). The spent cata-
lyst was characterized by EDAX and ICP. The catalyst
leaching was investigated for the model reaction, and the
zinc amount was determined by EDAX and ICP-AES in
the ethyl acetate solution. The amount of leached Zn in
the recovered samples is negligible.
Fig. 3 Recyclability of acidic ionic liquid
yields by raising the reaction temperature led to improve
the yields at 100 °C and reduced the time of reaction to
40 min. Screening different acidic ionic liquids revealed
that IL1 emerged as the best catalyst for the synthesis of
biscoumarins in quantitative yields (Table 1, entry 1).
With these optimistic results in hand, a variety of het-
eroaryl as well as aryl and alkyl aldehyde were evaluated
in terms of both scope and reaction effciency, and the
results are summarized in Table 2. Aldehyde substrates
with electron neutral and electron donating as well as elec-
tron withdrawing at the ortho-, meta-, and para-substituents
were converted to the biscoumarin derivatives with good
to excellent yields. Functional groups such as carboxyl,
halogen, methoxy, alkyl and hydroxyl groups were also
tolerated.
We next applied this fast reaction rate procedure to
another active methylene compound such as dimedone (4)
which gives highly functionalized biologically important
heterocyclic compounds [36–39] (Table 3). Interestingly,
the three-component reaction of a series of aromatic alde-
hydes with dimedone 4 when carried out under solvent-
free condition using IL1 furnished the corresponding
substituted xanthenes derivatives 5 in good to excellent
yields. The reaction proceeded well with no remarkable
difference in yields and reaction time between aromatic
aldehydes with neither electron-donating groups and nor
electron-withdrawing groups.
Finally, comparison of the acidic ionic liquid catalyzed
preparation of biscoumarins under solvent-free condi-
tions with a range of other methodologies demonstrated
the high yields, short reaction times, low loading of cata-
lyst and eco-friendly nature of the protocol (Table 4).
Conclusion
In summary, different metal chloride-based acidic ionic liq-
uids were synthesized and used as operationally simple and
clean catalyst for the preparation of a wide variety of bis-
coumarin and xanthene derivatives. The proposed method
is reliable, effective and greener and can replace maybe
Table 4 Comparison of acidic
ionic liquid with previous
Entry Solvent
Catalyst
Temp. Time (min) Yield (%) References
procedure
1
2
3
4
5
6
7
8
–
ChOH (40 mol%)
50
70
80
60
120
25
99
95
90
93
90
97
90
97
[6]
–
[[PSebim][OTf] (10 mol%))
BiVO4-NPs (30 mg)
[8]
Water
Water
Water
[12]
Phosphotungstic acid (15 mol%) 80
P4VPy–CuO-NPs (20 mg) Refux
20
[15]
20
[16]
Ethanol/water SBA-Pr-SO3H (40 mg)
Refux
80
25
[41]
Water
–
SBA-Pr-SO3H (40 mg)
IL1 (20 mg)
15
[42]
100
40
This work
1 3

J IRAN CHEM SOC
20. N. Azizi, M. Abdoli-Senejani, F. Abbasi, Tetrahedron Lett. 57,
5009 (2016)
21. A.W. Bhutto, R. Abro, S. Gao, T. Abbas, X. Chen, G. Yu, J. Tai-
wan Inst. Chem. 62, 84 (2016)
22. O. Goli-Jolodar, F. Shirini, M. Seddighi, J. Mol. Liq. 224, 1092
(2016)
23. Z.-H. Zhang, X.-N. Zhang, L.-P. Mo, Y.-X. Li, F.-P. Ma, Green
more promising candidates as recyclable ionic catalysts for
organic transformation.
Acknowledgements Financial support of this work by the Chemis-
try and Chemical Engineering Research Center of Iran is gratefully
appreciated.
Chem. 14, 1502 (2012)
24. D. Chaturvedi, Curr. Org. Chem. 15, 1236 (2011)
25. D. Chaturvedi, Curr. Org. Synth. 8, 438 (2011)
26. G. Nie, X. Tong, Y. Zhang, M. Liang, X. Zhuang, S. Xue, Res.
Chem. Intermed. 42, 8305 (2016)
27. K. Mohammadi, F. Shirini, A. Yahyazadeh, RSC Adv. 5, 23586
(2015)
28. Z. Ullah, M.A. Bustam, Z. Man, S. Nasir Shah, A. Sada Khan,
N. Muhammad, J. Mol. Liq. 223, 81 (2016)
29. X. Chen, Y. Guan, A.A. Abdeltawab, C. Wang, G. Yu, Fuel 146, 6
(2015)
30. N. Azizi, E. Batebi, Catal. Sci. Technol. 2, 2445 (2012)
31. X. Chen, H. Guo, A.A. Abdeltaw, Y. Guan, S.S. Al-Deyab, G. Yu,
L. Yu, Energy Fuel 29, 2998 (2015)
References
1. S. Kenmoku, Y. Urano, H. Kojima, T. Nagano, J. Am. Chem.
Soc. 129, 7313 (2007)
2. R.D.H. Murray, J. Mendez, S.A. Brown, The Natural Coumarins
(Wiley, Chichester, 1982)
3. J. Gordo, J. Avó, A.J. Parola, J.C. Lima, A. Pereira, P.S. Branco,
Org. Lett. 13, 5112 (2011)
4. M.M. Abdou, R.A. El-Saeed, S. Bondock, Arab. J. Chem (2015).
doi:10.1016/j.arabjc.2015.06.012
5. J.S. Yadav, V.S. Reddy, A.K. Basak, B. Visali, A.V. Narsaiah, K.
Nagaiah, Eur. J. Org. Chem. 2004, 546 (2004)
6. A. Zhu, S. Bai, L. Li, M. Wang, J. Wang, Catal. Lett. 145, 1089
(2014)
7. M. Kidwai, V. Bansal, P. Mothsra, S. Saxena, R.K. Somvanshi,
S. Dey, T.P. Singh, J. Mol. Catal. A Chem. 268, 76 (2007)
8. W. Li, Y. Wang, Z. Wang, L. Dai, Y. Wang, Catal. Lett. 141, 1651
(2011)
9. K.P. Boroujeni, P. Ghasemi, Catal. Commun. 37, 50 (2013)
10. Z.N. Siddiqui, F. Farooq, Catal. Sci. Technol. 1, 810 (2011)
11. G.-X. Gong, J.-F. Zhou, L.-T. An, X.-L. Duan, S.-J. Ji, Synth.
Commun. 39, 497 (2009)
12. F. Shirini, M.P. Lati, J. Iran. Chem. Soc. 14, 75 (2017)
13. A. Kumar, M.K. Gupta, M. Kumar, Tetrahedron Lett. 52, 4521
(2011)
14. B. Karmakar, A. Nayak, J. Banerji, Tetrahedron Lett. 53, 4343
(2012)
15. P. Singh, P. Kumar, A. Katyal, R. Kalra, S.K. Dass, S. Prakash,
R. Chandra, Catal. Lett. 134, 303 (2010)
16. F. Shirini, A. Fallah-Shojaei, L. Samavi, M. Abedini, RSC Adv.
6, 48469 (2016)
32. Y. Wei, C. Keke, Z. Xiaofang, K. Yingying, T. Xiujuan, H.
Xiaoxiang, J. Ind. Eng. Chem. 29, 185 (2015)
33. N. Azizi, B. Mirmashhori, M.R. Saidi, Catal. Commun. 8, 2198
(2007)
34. N. Azizi, M.R. Saidi, Phosphorus Sulfur Silicon Relat. Elem.
178, 1255 (2003)
35. N. Azizi, S. Dezfooli, M. Mahmoudi Hashemi, J. Mol. Liq. 194,
62 (2014)
36. H.R. Shaterian, M. Ghashang, A. Hassankhani, Dyes Pigm. 76,
564 (2008)
37. H.-Y. Lu, J.-J. Li, Z.-H. Zhang, Appl. Organomet. Chem. 23, 165
(2009)
38. M.A. Bigdeli, M.M. Heravi, G.H. Mahdavini, Catal. Commun.
8, 1595 (2007)
39. A.R. Khosropour, M.M. Khodaei, H. Moghannian, Synlett 6,
955 (2005)
40. J.J. Xin, J. Li, Z.D. Zhang, X. Bin Hu, M.K. Li, J. Mol. Struct.
1084, 200 (2015)
41. G.M. Ziarani, A. Badiei, M. Azizi, N. Lashgari, J. Chin. Chem.
Soc. 60, 499 (2013)
42. M. Seddighi, F. Shirini, M. Mamaghani, RSC Adv. 3, 24046
(2013)
17. A.S. Amarasekara, Chem. Rev. 116, 6133 (2016)
18. B. Wiredu, A.S. Amarasekara, Catal. Commun. 70, 82 (2015)
19. P. Liu, J.-W. Hao, L.-P. Mo, Z.-H. Zhang, RSC Adv. 6, 48675
(2015)
1 3