Protic guanidinium ionic liquid as a green and highly efficient catalyst for the synthesis of functionalized spirochromenes under solvent-free conditions

Article abstract of DOI:10.1016/j.crci.2013.12.005

A simple and efficient method for the synthesis of functionalized spirochromenes is explained using protic guanidinium ionic liquid as a catalyst under solvent-free conditions at room temperature. This procedure is simple, clean, and excellent yields are

Full text of DOI:10.1016/j.crci.2013.12.005

C. R. Chimie 17 (2014) 1160–1164
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Preliminary communication/Communication
Protic guanidinium ionic liquid as a green and highly efficient
catalyst for the synthesis of functionalized spirochromenes
under solvent-free conditions
b
b
Seyed Meysam Baghbanian a, , Mahmood Tajbakhsh , Maryam Farhang
*
a Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, 698 Amol, Iran
b Faculty of Chemistry, Mazandaran University, 47415 Babolsar, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple and efficient method for the synthesis of functionalized spirochromenes is
explained using protic guanidinium ionic liquid as a catalyst under solvent-free conditions
at room temperature. This procedure is simple, clean, and excellent yields are obtained in
short reaction times.
Received 5 November 2013
Accepted after revision 10 December 2013
Available online 23 July 2014
´
ß 2014 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Spirochromenes
Heterogeneous catalyst
Protic ionic liquid
Solvent-free conditions
1. Introduction
SiO2 [4], triethylbenzyl ammonium chloride (TEBA) [5],
NH4Cl [6], NEt3 [7], ethylenediamine diacetate [8],
b-
The spirooxindole system is the core structure of many
pharmacological agents and natural products [1], for
example, cytostatic alkaloids such as spirotryprostatins
A, B, pteropodine, strychnofoline, (–)-horsfiline and iso-
pteropodine have been shown to modulate the function of
muscarinic serotonin receptors [2].
Among the heterocyclic spirooxindole ring system,
these ones, together with substituted fused 4H-chromenes,
have gained great importance due to their spasmolitic,
anticoagulant, diuretic, anticancer, and antinaphylactic
activities [3]. There have been several reports available in
the literature on the synthesis of spirooxindoles with fused
4H-chromenes via multicomponent condensation reac-
tions. The general procedure for the synthesis of these
compounds involves the condensation of isatin, active
methylene component, and 1,3-dicarbonyl compound in
the presence of different catalysts, such as InCl3 or InCl3/
cyclodextrin [9],
L
-proline [10], HAuCl4ꢀ3H2O [11], MgO
[12], [BMIm]BF4 [13], and sodium stearate [14]. Although
all of these methods are effective, some of them have
drawbacks such as long reaction times [5,9], high cost of
the catalyst [6], harsh reaction conditions [4] and
unreusability of the catalyst [5–8]. Therefore, there is still
a demand for simple and facile methodologies for the
preparation of spirochromene compounds with more
efficiency and shorter reaction times.
Ionic liquids (ILs), considered as being a relatively
recent magical chemical due their unique properties, have
a large variety of applications in all areas of chemical
synthesis. The unique properties of ILs, such as a negligible
vapor pressure, good thermal stability, tunable viscosity,
miscibility with water and with organic solvents, as well as
good extractability for various organic compounds and
metal ions, mainly depend on their special structures [15].
Protic ionic liquids (PILs) are a subclass of ILs family formed
by an equimolar combination of a Brønsted acid and a
Brønsted base and have an additional tunable feature as a
result of proton transfer, proton activity. Environmentally
*
Corresponding author.
E-mail address: s.m.baghbanian@iauamol.ac.ir (S.M. Baghbanian).
1631-0748/$ – see front matter ß 2014 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.12.005

S.M. Baghbanian et al. / C. R. Chimie 17 (2014) 1160–1164
1161
N
H2N
X
O
O
X
R
N
N
O
O
X
H
H
R
O
O
N
O
R2
CN
N
IL I: X= CF3CO2
H
3 a-g
1
2
4
IL II:
X= BPh4
R= H (1a), Cl (1b)
Br (1c), NO2 (1d)
2a X= CN
2b X= CO2Et
O
O
O
O
O
IL III:
X= Cl
3a.
3e.
3b.
NH
3c.
3d.
3g.
O
N
H
S
O
O
O
O
O
O
O
CH3
3f.
N
OMe
OEt
O
N O
CH3
Scheme 1. Synthesis of spirochromenes catalyzed by [TBD]-based ionic liquids.
considerable properties of PILs motivated chemists to
investigate their application to other fields such as
catalysis [16–21]. However, there are some limitations
associated with the use of ILs as catalysts, such as a lack of
potential activation sites on the substrates and their
sensitivity to air and moisture, leading to the inactivation
of the reaction. Therefore, the design of more active PILs
that can also be employed as catalysts has been an
important topic in this research field.
In continuation of our studies on the development of
new catalysts and methods for organic synthesis [22],
herein we report the highly efficient and simple methods
for the synthesis of some spirochromene derivatives from
isatin derivatives, alkyl-malonates and 1,3-dicarbonyl
compounds in the presence of [TBD][TFA] ionic liquid
as a catalyst at room temperature under solvent-free
conditions (Scheme 1).
tetrahydrofuran, toluene, and dichloromethane. In all
solvents, the reaction procedure afforded the product with
a moderate yield in longer reaction times (Table 1, entries
5–9). Although ionic liquids II and III are effective in this
reaction, they give lower yields than IL I (Table 1, entries 10
and 11). When the model reaction was carried out in the
presence of TBD and CF3CO2H, only a moderate yield of
spirochromene was obtained in longer reaction times
(Table 1, entries 12 and 14). This clearly evidences the
significant role of IL I in this reaction. From the above
observations, the best yields were obtained under solvent-
free reaction conditions at room temperature (Table 1,
entry 4).
In order to evaluate the generality and applicability of
this methodology, the reaction of isatin with 1,3-dicarbo-
nyl and active methylene compounds were concentrated
using [TBD][TFA] (5 mol%) at room temperature under
solvent-free conditions for the synthesis of a series of
tetrahydrospiro [chromene-4,30-indoline] 4a–4t deriva-
tives, as shown in Table 2.
2. Results and discussion
Several types of isatins, including either electron-
withdrawing or electron-donating groups, malononitrile
or cyanoacetic ester and cyclic 1,3-diketones were used
in this reaction. It was observed that all these cyclic 1,
3-diketones as well as active methylene compounds were
Initially, three triazabicyclodecene-based ionic liquids
(Fig. 1, I–III) were synthesized and used as catalysts for the
synthesis of spirochromene compounds.
In order to determine optimum reaction conditions, the
reaction of isatin 1 (1 mmol) as a model compound with
malononitrile 2 (1 mmol) and dimedone (1 mmol) was
examined under different reaction conditions and shown
in Table 1. Different catalyst loadings were examined and,
as it is clear from Table 1, when an amount of 20 mol% of IL
I was used as a catalyst under solvent-free conditions at
room temperature after 20 min, the expected spirochro-
mene was obtained at a yield of 85% (Table 1, entry 1).
Lowering the catalyst loading to 5 mol%, an excellent yield
of the product was obtained in shorter reaction times
(Table 1, entries 2–4). The model reaction was also studied
in different organic solvent such as ethanol, acetonitrile,
Table 1
Optimization of reaction conditions for the synthesis of spirochromene
4a.
Entry
Catalyst
Solvent
Time
Yield
(%)a
(min)
1
IL I, 20 mol%
IL I, 15 mol%
IL I, 10 mol%
IL I, 5 mol%
IL I, 5 mol%
IL I, 5 mol%
IL I, 5 mol%
IL I, 5 mol%
IL I, 5 mol%
IL II, 5 mol%
IL III, 5 mol%
TBD, 5 mol%
TBD, 10 mol%
CF3CO2H, 5 mol%
–
20
15
10
5
85
90
95
98
65
70
85
72
65
95
88
65
75
60
2
–
3
–
4
–
5
EtOH
5
6
CH3CN
30
25
40
35
35
5
7
THF
8
Ph–CH3
9
CH2Cl2
N
N
N
10
11
12
13
14
–
–
–
–
–
CF3CO2
BPh4
Cl
N
N
N
N
N
N
25
30
35
H
H
H
H
H
H
I
II
III
a
Isolated yield.
Fig. 1. Structurally related TBD based protic ionic liquids.

1162
S.M. Baghbanian et al. / C. R. Chimie 17 (2014) 1160–1164
tolerated for this reaction, which affords satisfactory yield
of desired products (Table 2). The possibility of recycling
the catalyst was also examined. For this reason, the
reaction of isatin with malononitrile and dimedone in the
presence of [TBD][TFA] was studied. After completion of
the reaction (monitored by TLC), EtOAc was added to the
reaction mixture, and [TBD][TFA] was removed by filtra-
tion and washed with EtOAc (2 ꢁ 5 ml). The recovered
catalyst was reused in six subsequent runs, affording
yields from 90 to 98% of the product, without significant
loss of activity.
A plausible mechanism is shown in Fig. 2. Two
pathways are proposed for the synthesis of spiroox-
indole derivatives (A and B). In path A, the guanidinium
core of salts could form doubly H-bonded motifs
with the carbonyl group of isatin, thus enhancing
their electrophilicity; then the nucleophilic attack of
malononitrile on the carbonyl carbon produces the
isatylidene malononitrile I. The electron-deficient
Knoevenagel adduct I could be subsequently attacked
via Michael addition of dimedone II to give intermediate
III. In path B, isatin could form doubly H-bonded
O
CF3CO2
N
O
N
N
N
H
H
H
CF3CO2
N
CF3CO2
N
N
H
N
H
OH
N
H
O
O
N
H
O
C
N
O
CN
H
N
O
H
Path B
Path A
CF3CO2
N
N
H
CN
H
NH
CF3CO2
N
N
CF3CO2
N
HO
H
HO
CN
NH
O
HO
N
H
N
H
O
N
H
O
C
N
N
O
CN
H
H
IV
NC
[TBD][TFA]
HO
O
CN
O
O
N
H
[TBD][TFA]
II
I
O
HO
N
N
C
C
NC
NC
O
O
O
O
N
N
H
H
III
H2N
NC
HN
NC
O
O
O
O
O
O
N
N
H
H
4a
Fig. 2. Proposed mechanism for the synthesis of spirooxindole 4a via paths A and B.

S.M. Baghbanian et al. / C. R. Chimie 17 (2014) 1160–1164
1163
Table 2
Synthesis of spirochromene derivatives catalyzed by [TBD][TFA] ionic liquids.
Entry
R1
R2
X
1,3-dicarbonyl
compounds
Product
Time
Yielda
(%)
References
(min)
1
H
H
CN
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
5
6
98
96
92
95
90
96
94
92
90
95
98
95
92
90
90
95
92
96
92
[6]
2
H
H
CN
[6]
3
H
H
CN
8
[23]
[17]
[10b]
[12]
[10a]
[10a]
[13]
[10a]
[9]
4
H
H
CN
8
5
H
H
CN
12
18
20
3
6
H
H
CN
7
H
H
CN
3g
3a
3g
3a
3a
3a
3b
3c
3d
3a
3b
3b
3g
4g
4h
4i
8
Br
Br
Cl
NO2
H
H
CN
9
H
CN
15
5
10
11
12
13
14
15
16
17
18
19
H
CN
4j
H
CN
4k
4l
2
CH3
CH3
CH3
Et
CN
5
[11]
[11]
[11]
–
H
CN
4m
4n
4o
4p
4q
4r
4s
8
H
CN
10
10
8
H
CN
H
Benzyl
CH2CO2Et
H
CN
[13]
–
H
CN
8
H
CO2Et
CO2Et
7
[13]
[11]
H
H
8
a
Isolated yield.
motifs with the catalyst and react with dimedone to
afford the aldol adduct IV followed by dehydration
and nucleophilic attack of malononitrile to afford
intermediate III. In both paths, intermediate III affords,
through an intermolecular cyclization by nucleophilic
attack of the hydroxyl group on the cyano one, the final
product 4a.
3.2. General procedure for the synthesis of spirooxindole
derivatives
To a magnetically stirred mixture of isatins (1 mmol)
and IL I (12.6 mg, 0.05 mmol) were added alkyl-malonates
(1 mmol) or 1,3-dicarbonyl compounds (1 mmol) and then
the reaction mixture was stirred at room temperature.
After completion of the reaction (monitored by TLC), EtOAc
was added to the reaction mixture, and [TBD][TFA] was
removed by filtration and washed with EtOAc (2 ꢁ 5 ml).
The filtrate was evaporated under reduced pressure to give
the solid product as a residue in almost pure form. If
necessary, the product could further be purified by
recrystallization from ethanol. The physical data (mp, IR,
NMR) of known compounds were found to be identical
with those reported in the literature. Spectroscopic data for
selected examples are shown below.
3. Experimental
All reagents were obtained from Fluka (Germany) and
were used without further purification. Melting points
were measured on an Electrothermal 9100 apparatus.
Elemental analyses for C, H and N were performed using a
Heraeus CHN-O-Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MATT 8430 mass spectrometer
operating at an ionization potential of 20 eV. 1H-, 13C NMR
spectra were recorded on a Bruker DRX-400 AVANCE
spectrometer. IR spectra were recorded as KBr pellets on a
Shimadzu IR-460 spectrometer.
3.2.1. 7’-Amino-1-ethyl-2,4’-dioxo-2’-thioxo-1’,2’,3’,4’-
tetrahydrospiro[indoline-3,5’ pyrano[2,3-d]pyrimidine]-6’-
carbonitrile (4o)
3.1. General procedure for the synthesis of 1,2,3,4,6,7,8,9-
octahydropyrimido[1,2-a]pyrimidin-5-ium 2,2,2-
trifluoroacetate IL (I)
White powder; mp 257–259 8C; yield: 0.329 g (90%); IR
(KBr): 3452, 3327, 3169, 2212, 1689, 1626, 1588, 1468,
; d = 1.13 (t,
1389 cmꢂ1 1H NMR (400 MHz, DMSO-d6):
J = 6.9 Hz, 3 H, CH3), 3.72 (q, J = 7.8 Hz, 2 H,CH2), 6.98 (t,
J = 7.3 Hz, 1 Harom), 7.05 (d, J = 7.5 Hz, 1 Harom), 7.25–7.29
(m, 2 Harom), 7.45 (s, 2 H, NH2), 12.35 (s, 1 H, NH), 13.86 (br
Trifluoroacetic acid (92 mg, 0.81 mmol) was added
dropwise to a suspension of triazabicyclo[4.4.0]dec-5-ene
(70 mg, 0.50 mmol) in dry Et2O (5 mL) and the resulting
mixture was vigorously stirred for 30 min. The solid
formed was filtered off under reduced pressure and it
was washed with several portions of dry Et2O to give IL I
(119 mg, 94%) as a white solid. Spectral data: M.p. 161–
s, 1 H, NH); 13C NMR (100 MHz, DMSO-d6):
d = 12.6, 34.9,
46.6, 57.6, 91.9, 108.7, 117.1, 122.8, 123.4, 128.3, 133.9,
143.1, 154.5, 159.1, 159.6, 174.6, 175.7; MS (EI): m/z: 367
(M+); anal. calcd. (%) for C17H13N5O3S: C, 55.58; H, 3.57; N,
19.06. Found: C, 55.57; H, 3.58; N, 19.10.
163 8C; 1H NMR (DMSO-d6, 400 MHz)
dH = 3.27 (4H, t,
J = 6.0 Hz, 2 ꢁ CH2), 3.18 (4H, t, J = 5.6 Hz, 2 ꢁ CH2), 1.87
3.2.2. Ethyl-2-(2-amino-3-cyano-2’,5-dioxo-5,6,7,8-
tetrahydrospiro[chromene-4,3’-indoline]-1’-yl)acetate (4q)
White powder; mp 236–238 8C; yield: 0.367 g (92%);
IR (KBr): 3369, 3296, 3177, 2984, 2192, 1750, 1710,
(4H, quintet., J = 6.0 Hz, 2 ꢁ CH2). 13C NMR (DMSO-d6,
2
100 MHz)
d
C = 159.2 (q, JC–F = 35.9 Hz, CF3CO2), 151.1
1
(CN3), 116.2 (q, JC–F = 291.7 Hz, CF3CO2), 46.6 (CH2),
37.9 (CH2), 20.7 (CH2).
1673, 1605, 1457, 1419, 1381 cmꢂ1 1H NMR (400 MHz,
;

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S.M. Baghbanian et al. / C. R. Chimie 17 (2014) 1160–1164
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(2000) 6993–6996.
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2057–2063.
H, CH2), 2.18–2.22 (m, 2 H, CH2), 2.66–2.70 (m, 2 H, CH2),
4.12 (q, J = 7.2 Hz, 2 H, CH2), 4.40 and 4.54 (ABq, J = 16.4 Hz,
2 H, CH2), 6.96 (d, J = 7.2 Hz, 1 Harom), 7.2 (d, J = 7.2 Hz, 1
[5] S.L. Zhu, S.I. Ji, Y. Zhang, Tetrahedron 63 (2007) 9365–9372.
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741–745.
H
H
arom), 7.10 (d, J = 7.2 Hz, 1 Harom), 7.25 (t, J = 7.4 Hz, 1
arom), 7.24 (s, 2 H, NH2); 13C NMR (100 MHz, DMSO-d6)
d
:
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178.0, 195.3; MS (EI): m/z: 393 (M+); anal. calcd. (%) for
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4. Conclusion
In conclusion, a simple, efficient, and eco-friendly
procedure is described for the synthesis of spirochromene
derivatives at room temperature using [TBD][TFA] as a
reusable catalyst. The present approach offers the follow-
ing advantages: simple methodology, clean and mild
reaction conditions, high atom economy, short reaction
times, low loading of catalyst, high yield, and excellent
purity of the product.
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This research is supported by the Islamic Azad
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