Br?nsted acidic ionic liquids: Green, efficient and reusable catalyst for synthesis of fluorinated spiro [indole-thiazinones/thiazolidinones] as antihistamic agents

Article abstract of DOI:10.1016/j.jfluchem.2012.03.003

Br?nsted acidic ionic liquid containing nitrogen-based organic cations 1-methylimidazolium and 1-butyl-3-methylimidazolium and inorganic anions such as BF₄^-, PF₆^- and PTSA ^- used as catalysts and reaction medium for synthesis of fluorinated spiro[3H-indole-3,2′-tetrahydro-1,3-thiazine]-2,4′(1H)-diones (4a-f), fluorinated spiro[3H-indole-3,2′-thiazolidine]-2,4′ (1H)-diones (5a-f) in 90-97% yield by one-pot environmentally benign microwave induced technique. Synthesized compounds have been evaluated for their ability to inhibit the contractions induced by histamine on guinea pig ileum. The measurement of pA₂ values suggested that the reported compounds showed H1-antagonism.

Full text of DOI:10.1016/j.jfluchem.2012.03.003

Journal of Fluorine Chemistry 137 (2012) 117–122
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
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Short communication
Brønsted acidic ionic liquids: Green, efficient and reusable catalyst for synthesis of
fluorinated spiro [indole-thiazinones/thiazolidinones] as antihistamic agents
a
b
c
Kapil Arya a, , Diwan Singh Rawat , Anshu Dandia , Hiroaki Sasai
*
a Department of Chemistry, University of Delhi, Delhi 110007, India
b Department of Chemistry, University of Rajasthan, Jaipur 302055, India
c Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Brønsted acidic ionic liquid containing nitrogen-based organic catꢀions 1-methylimidazolium and 1-
butyl-3-methylimidazolium and inorganic anions such as BF4ꢀ, PF6 and PTSAꢀ used as catalysts and
reaction medium for synthesis of fluorinated spiro[3H-indole-3,20-tetrahydro-1,3-thiazine]-2,40(1H)-
diones (4a-f), fluorinated spiro[3H-indole-3,20-thiazolidine]-2,40 (1H)-diones (5a-f) in 90–97% yield by
one-pot environmentally benign microwave induced technique. Synthesized compounds have been
evaluated for their ability to inhibit the contractions induced by histamine on guinea pig ileum. The
measurement of pA2 values suggested that the reported compounds showed H1-antagonism.
ß 2012 Elsevier B.V. All rights reserved.
Received 9 January 2012
Received in revised form 2 March 2012
Accepted 5 March 2012
Available online 13 March 2012
Keywords:
Brønsted acidic ionic liquid
Fluorinated thiazine
Fluorinated thiazolidinone
Microwaves
Antihistamic agents
1. Introduction
Thiazolidinone, an important ‘‘privileged scaffold,’’ is a very
attractive target for combinatorial library synthesis because of
Room temperature ionic liquids (RTILs) have attracted exten-
sive research interest as environmentally benign solvents due to
their favorable properties such as non-inflammability, negligible
vapour pressure, reusability and high thermal stability [1,2]. They
have also been referred to as ‘designer solvents’ as their physical
and chemical properties could be adjusted by a careful choice of
cation and anion. Apart from this, they exhibit acidic properties.
Combining these unique properties of ionic liquids they are
emerging as a ‘green reaction media’ (catalyst + solvent). The use of
ionic liquids as reaction medium may offer a convenient solution to
both the solvent emission and catalytic recycling problem [3–5].
Multi-component reactions (MCRs) have been frequently used by
synthetic chemists as a facile means to generate molecular
diversity from bifunctional substrates that react sequentially in
an intramolecular fashion and the process inherently more
environmentally benign and atom-economic [6].
their structure activity relationship [9] and is an important class of
N and S containing heterocycles, which are widely used as key
building blocks in the field of drugs and pharmaceutical agents
[10]. Further, the presence of the N–C–S linkage in the thiazolidines
is also responsible for nematocidal, fungicidal, antibacterial and
antiviral activities [11–13].
In addition, the spiro[indole-thiazolidine] system is a structural
motif found or presented in many pharmacologically important
synthetic and naturally occurring compounds e.g. spirobrassinin.
The diversity of their biological functions such as anti-inflamma-
tory, antimicrobial, antileukemic and anticonvulsant activities has
stimulated efforts in the expedient development of their synthesis
[14,15]. Incorporation of fluorine to different heterocycles is
known to affect the course of the reaction besides influencing the
biological/pharmacological activity [16]. Further, incorporation of
trifluoromethyl substituents has been shown to increase the
phytoxicity along with selectivity and arenes bearing trifluor-
omethyl substituents that comprises the largest subgroup of
commercially promising pesticides and herbicides.
Devising such types of MCRs that achieve the formation of
multiple bonds in a single operation is one of the major challenges
in modern organic synthesis [7]. They provide a powerful tool
toward the one-pot synthesis of diverse and complex compounds
as well as small and drug-like heterocycles [8].
A literature survey shows that most of the reported methods for
the synthesis of thiazolidinone involves the use of high boiling
carcinogenic hydrocarbons with continuous azeotropic removal of
water [17a], or requiring desiccants like anhydrous ZnCl2, [17b],
sodium sulphate [17c], molecular sieves [18], or use of stoichio-
metric amount of DCC [19a], Hu¨nig base [19b] in solution phase
* Corresponding author. Tel.: +91 93108 26916; fax: +91 93108 26916.
E-mail address: aryakapil2001@yahoo.com (K. Arya).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.03.003

118
K. Arya et al. / Journal of Fluorine Chemistry 137 (2012) 117–122
Hb
Ha
Hb
O
Hc
O
S
N
O
Y
OH
HS
3a
X
X
N
H
O
N
H
1
O
4a-f
O
Hb
-
[MIM]+BF4
Mw, 2-4 min., 90-97%
+
O
Ha
Y
S
N
O
SH
H2N
OH
Y
3 b
X
2
N
H
X= 5-F, 7-F, 5-CF3, 7-CF3, 5-CH3
5a-f
Y= 4-COOH , 3-Cl , 2-Cl , 4-F, 4-CH3
Scheme 1. Synthesis of fluorinated spiro-[indole-thiazinones] and spiro[indole-thiazolidinones].
reactions and thermally unstable ionic liquids [20]. The yield of
products drastically decreased with increasing of reaction times in
recycling of ionic liquids. This would make the whole procedure
unsuitable for industrial applications.
reaction medium as well as promoters without any additional
catalyst at ambient temperature (Scheme 1). Synthesized com-
pounds are screened as antihistamic and antidiabetic agents.
In line with our interest on spiro indoles, extensive work has
been carried out in our lab on the spiro[indole-thiazolidinone] [21]
system. Recently we have reported [21a] a nonconventional three-
component, regioselective one-pot cyclocondensation method for
the synthesis of a series of novel spiro[indole-thiazolidinones]
using montmorillonite KSF as an inorganic solid support in an open
vessel using a modified domestic microwave. Although this
method has its own merits in comparison to a conventional
two-step procedure but these microwave assisted reactions still
require use of solvent for adsorption and desorption and also are
not suitable for large scale preparation with reproducibility. Hence
there is a scope for further development of an efficient, high
yielding green protocol without the use of any solvent.
As part of our program aimed at developing new selective
greener methodologies for the preparation of pharmaceutically
important scaffolds [22], we undertook improvement toward an
efficient and ecofriendly process for the preparation of fluorinated
spiro-[indole-thiazinones] (4a-f) and spiro[indole-thiazolidi-
nones] (5a-f) in the presence of Brønsted acidic ionic liquid as
2. Result and discussion
The cyclocondensation of thioacids (3a/b) with substituted
isatin (1) and heterocyclic amines (2) yielding exclusively
fluorinated spiro compounds (4, 5) was studied using different
types of Brønsted acidic ionic liquid with different inorganic anions
such as BF4ꢀ, PF6–and PTꢀSAꢀ. Since 1-methylimidazolium tetra-
) efficiently catalyzed the reaction,
fluoroborate ([MIM]+BF4
giving maximum yield (90–97%) with shortest period (2–4 min)
and easier work up. All compounds listed in Table 1 have been
synthesized in one pot using methylimidazolium tetrafluoroborate
([MIM]+BF4ꢀ) as Brønsted acidic ionic liquid (Table 1).
The Lewis and Brønsted acidity of the ionic liquids has been
determined using pyridine as a probe molecule by monitoring the
bands in the range of 1350–1600 cmꢀ1 arising from its ring
vibration modes [23,24].
The FTIR spectrum of neat pyridine shows a band at 1425 cmꢀ1
(Fig. 1a). On mixing pyridine with ionic liquid, the spectrum of
ionic liquid shows
a
band near 1450 cmꢀ1 indicating the
Table 1
Physical and structural characteristics of fluorinated spiro compounds.
Compoundsa
X
Y
Time (min)
M.P. (8C)
Yieldb (%)
Molecular formula
Found (Calcd.)
C
H
N
4a
4b
4c
4d
4e
4f
5-F
4-COOH
3-Cl
2
4
3
3
3
4
4
2
3
3
4
3
215–217
199–201
185–187
192–194
225–227
195–197 [16a]
212–214
175–177
230–232
205–207
278–281
>360 [21b]
93
96
90
92
91
95
97
96
90
93
95
96
C18H13FN2O4S
C17H12ClFN2O2S
C19H13F3N2O4S
C18H12ClF3N2O2S
C18H15FN2O2S
C19H18N2O2S
58.12 (58.06)
56.20 (56.28)
53.94 (54.03)
52.45 (52.37)
63.05 (63.14)
67.32 (67.43)
56.89 (56.98)
55.18 (55.10)
52.87 (52.94)
51.14 (51.20)
62.10 (62.18)
66.50 (66.64)
3.50 (3.52)
3.31 (3.33)
3.08 (3.10)
2.91 (2.93)
4.43 (4.42)
5.42 (5.36)
3.07 (3.09)
2.87 (2.89)
2.74 (2.72
2.54 (2.53)
3.97 (3.99)
4.90 (4.97)
7.48 (7.52)
7.75 (7.72)
6.67 (6.63)
6.76 (6.79)
8.15 (8.18)
8.35 (8.28)
7.85 (7.82)
8.05 (8.03)
6.88 (6.86)
7.04 (7.02)
8.56 (8.53)
6.61 (8.64)
7-F
5-CF3
7-CF3
5-CH3
5-CH3
5-F
4-COOH
2-Cl
4-F
4-CH3
4-COOH
3-Cl
5a
5b
5c
5d
5e
5f
C17H11FN2O4S
C16H10ClN2O2S
C18H11F3N2O4S
C17H10ClF3N2O2S
C17H13FN2O2S
C18H16N2O2S
7-F
5-CF3
7-CF3
5-CH3
5-CH3
4-COOH
2-Cl
4-F
4-CH3
a
All products were characterized by 1H NMR, mass and IR data.
Isolated yields.
b

K. Arya et al. / Journal of Fluorine Chemistry 137 (2012) 117–122
119
Table 3
ꢀ
Catalyst recycling of synthesis of spiro indole [thiazine] (4a) using [MIM]+BF4
.
Cycle
Time (min)
Yield (%)
Fresh
3
96
95
95
94
94
1st recycle
2nd recycle
3rd recycle
4th recycle
3
3.5
4
4
Reaction condition: ionic liquid = 1 g; temperature = 110 8C.
The results showed that the efficiency and the yield of the
reaction in shorter chain length on the ionic liquid cation
([MIM]+BF4ꢀ) were higher than those obtained in other ionic
liquids and the production of side products was also lowered [25].
[BMIM]+ [PF6]ꢀ ionic liquid gave higher yield compared to its anion
BF4ꢀ, PTSAꢀ, due to its hydrophobic nature. Also to illustrate the
need for ionic liquids, the reaction was studied in the absence of
ionic liquids. As a result, products were produced after a long time
irradiation. One of the main aims of the study was to investigate
the reuse and recycling of ([MIM]+BF4ꢀ). After filtration of the cold
reaction mixture to separate the product (4a), the filtrate was
charged with the same substrates and was reused for four cycles,
which gave yields similar to those obtained in the first run,
although slightly increase in reaction time was observed (Table 3,
Fig. 2).
100
90
80
70
60
50
40
30
20
10
0
Fig. 1. FTIR spectra: (a) neat pyridine, (b) pyridine with [BMIM]+ PF6ꢀ, (c) pyridine
with[BMIM]+BF4ꢀ, (d) pyridine with [BMIM]+PTSAꢀ, (e) pyridine with [MIM]+BF4
.
ꢀ
coordination of pyridine to the Lewis acid sites, with an additional
band near 1540 cmꢀ1 indicating the presence of Brønsted acid sites
due to the formation of pyridinium ions (Fig. 1b–e).
The purity of [MIM]+BF4 ionic liquid was determined by 1H
ꢀ
NMR spectra using the intensity of the C-13 satellites of the
imidazolium N-methyl group as internal standard. 1H NMR
spectrum shows that the protons resonate in the range
3H), 7.1(m, 2H), 9.4(s,1H). From the 1H spectral data, it is revealed
that the proton at C2 in the imidazole ring ( 9.4) might be acidic.
d1.18(s,
d
Such a chemical shift may be due to ring-current effect of the
imidazole ring. Further ionic liquids purity was also accessed by
HPLC.
In order to optimize the reaction conditions, we conducted the
one pot cyclocondensation of isatin, amines with thioacids
(5 mmol) under microwaves with different types of Brønsted
acidic ionic liquids (1 mmol or 0.05 mmol) (Table 2) or without
ionic liquids.
1
2
3
4
5
Number of cycles
Fig. 2. Recyclability of ionic liquid [MIM]+BF4 (Compound 4a, Table 1).
ꢀ
3. Experimental
Table 2
Optimization study of one pot cyclocondensation reaction of isatins, amines with
thioacids in different ionic liquids.
3.1. Materials
All the anilines, thioacids and [BMIM]+ ionic liquids with
inorganic anions such as BF4ꢀ, PF6–and PTSAꢀ were Aldrich
products and were used as received. Tetrafluoroboric acid (40%)
solution in water was obtained from Loba Chemie India. 1-
Methylimidazole (99%) received from Lancaster (UK).
Compounds
Ionic liquid
Ratioa
Time (min)
Yield (%)
[MIM]+BF4ꢀ
1:1
1:0.5
1:1
1:1
1:1
–
3
5
96
93
89
91
92
78
ꢀ
4b
[MIM]+BF4
[BMIM]+BF4ꢀ
[BMIM]+PF6
[BMIM]+PTSAꢀ
Neat
5
ꢀ
7
6
15
3.2. Characterization techniques
[MIM]+BF4ꢀ
1:1
1:0.5
1:1
1:1
1:1
–
4
6
97
92
87
84
85
69
ꢀ
5a
[MIM]+BF4
IR spectra (KBr) were recorded on a Shimadzu FT IR-8400S
spectrophotometer and 1H NMR was recorded on a Bruker DRX-
300, at 300.15 MHz, using CDCl3 as solvent. Direct insertion probe
mass spectrum (DIPMS) values are reported in m/z. The micro-
wave-assisted reactions were carried out in a monomode system,
ꢀ
[BMIM]+BF4ꢀ
8
[BMIM]+PF6
[BMIM]+PTSAꢀ
Neat
6
8
18
a
Reactant (isatins, amines and thioacids) to ionic liquids molar ratio.

Table 4
Spectral analysis of synthesized compounds (4a–e and 5a–e).
Compound
IR (cmꢀ1
)
1H NMR (
d
, ppm)
13C NMR (
d
, ppm)
19F NMR (
d
, ppm)
Mass [M]+
4a
3480 (OH), 3290 (NH),
1725, 1705, 1690 (3 ꢁ C5O),
740 (C–F)
2.69 (dt, 1H, Ha), 3.26 (dd, 2H, 2 ꢁ Hb),
4.15 (dt, 1H, Hc), 6.75–7.38 (m, 7H, Ar H),
8.97 (br, 1H, NH*),
10.03 (br, 1H, OH*)
26.2 (S-CH2), 31.3 (CH2C5O), 72.04 (spiro carbon),
117.01–139.65 (aromatic carbons), 151.8 (C–F),
168.93, 172.11, 174.8 (three C5O)
ꢀ118.54 (s, F)
372(M+, 100)
4b
4c
3270 (NH), 1715, 1695 (2 ꢁ C5O),
2.72 (dt, 1H, Ha), 3.20 (dd, 2H, 2 ꢁ Hb),
4.05 (dt, 1H, Hc), 6.85–7.45 (m, 7H, Ar H),
8.62 (br, 1H, NH*)
25.4 (S-CH2), 32.4 (CH2C5O), 70.2 (spiro carbon),
115.08–142.72 (aromatic carbons), 154.2 (C–F),
166.8, 171.3 (two C5O)
ꢀ119.56 (s, F)
ꢀ63.47 (s, CF3)
362(M+, 100), 364
(M++ 2, 45)
750 (C–F), 770 (C–Cl)
3490 (OH), 3280 (NH), 1720,
2.65(dt, 1H, Ha), 3.22 (dd, 2H, 2 ꢁ Hb),
4.13 (dt, 1H, Hc), 6.81–7.52 (m, 7H, Ar H),
8.89 (br, 1H, NH*),
10.13 (br, 1H, OH*)
25.8 (S-CH2), 30.9 (CH2C5O), 71.5 (spiro carbon),
119.08–138.62 (aromatic carbons), 121.8 (CF3),
135.3 (C–CF3), 169.58, 172.4, 175.2 (three C5O)
422(M+, 100)
1710, 1685 (3 ꢁ C5O), 750 (C–F)
4d
4e
3290 (NH), 1720, 1690 (2 ꢁ C5O),
2.70 (dt, 1H, Ha), 3.23 (dd, 2H, 2 ꢁ Hb), 4.08
(dt, 1H, Hc), 6.83–7.42 (m, 7H, Ar H), 8.73
(br, 1H, NH*)
25.4 (S-CH2), 32.4 (CH2C5O), 70.2 (spiro carbon),
115.08–142.72 (aromatic carbons), 122.5 (CF3)
138.7 (C–CF3), 166.8, 171.3 (two C5O)
ꢀ63.28 (s,CF3)
ꢀ118.02 (s, F)
412(M+, 100),414(M+, 75)
342(M+, 100)
745 (C–F), 765 (C–Cl)
3260 (NH), 1715, 1680 (2 ꢁ C5O),
1.68 (s, 3H, CH3), 2.68 (dt,1H, Ha), 3.20
(dd, 2H, 2 ꢁ Hb), 4.10 (dt, 1H, Hc), 6.71–7.28
(m, 7H, Ar H),
8.68 (br, 1H, NH*)
20.91 (C–CH3), 24.6 (S-CH2), 32.6 (CH2C5O), 73.1
(spiro carbon), 116.08–140.34 (aromatic carbons),
150.8 (C–F), 167.2, 170.5 (two C5O)
750 (C–F)
5a
3480 (OH), 3300 (NH), 1735, 1710,
4.05 (dd, 2H, Ha & Hb, J = 13.6 Hz), 6.73–7.45
(m, 7H, Ar H), 9.05 (br,1H, NH*), 9.55
(br, 1H, OH*)
33.98 (S-CH2), 74.01 (spiro carbon), 121.22–142.94
(aromatic carbons), 150.8 (C–F), 172.02, 176.32, 180.21
(three C5O)
ꢀ118.48 (s, F)
358(M+, 100)
1690 (3 ꢁ C5O), 745 (C–F)
5b
5c
3310 (NH), 1720, 1695 (2 ꢁ C5O),
740 (C–F), 780 (C–Cl)
4.02 (dd, 2H, Ha & Hb, J = 13.5 Hz), 6.81–7.42
(m, 7H, Ar H), 9.01 (br, 1H, NH*)
4.06 (dd, 2H, Ha & Hb, J = 13.7 Hz), 6.75–7.47
(m, 7H, Ar H), 9.02 (br, 1H, NH*), 9.58
(br, 1H, OH*)
33.33 (S-CH2), 73.12 (spiro carbon), 120.08–140.86
(aromatic carbons), 154.3 (C–F), 170.96, 177.12 (two C5O)
33.98 (S-CH2), 74.01 (spiro carbon), 121.22–142.94
(aromatic carbons), 123.2 (CF3) 134.4 (C–CF3) 172.02,
176.32, 180.21 (three C5O)
ꢀ119.42 (s, F)
ꢀ63.57 (s, CF3)
348 (M+, 100), 350
(M++ 2, 40)
408 (M+, 100)
3490 (OH), 3290 (NH), 1730, 1710,
1695 (3 ꢁ C5O), 750(C–F)
5d
5e
3320 (NH), 1715, 1690 (2 ꢁ C = O),
4.08 (dd, 2H, Ha & Hb, J = 13.5 Hz), 6.75–7.36
(m, 7H, Ar H), 9.15 (br, 1H, NH*)
34.68 (S-CH2), 74.30 (spiro carbon), 120.18–140.02
(aromatic carbons), 127.3 (CF3) 133.2 (C–CF3) 171.8, 173.9,
(two C5O)
ꢀ63.33(s,CF3)
ꢀ117.90(s, F)
398(M+, 100), 400
(M+, 80)
745 (C–F), 770(C–Cl)
3320 (NH), 1720, 1690 (2 ꢁ C5O),
2.13 (s, 3H, CH3), 3.99 (dd, 2H, Ha & Hb, J = 13.6 Hz),
6.70–7.51 (m, 7H, Ar H), 9.04 (br, 1H, NH*)
13.01, (CH3), 33.33 (S-CH2), 73.12 (spiro carbon),
120.08–140.86 (aromatic carbons), 153.2 (C–F) 170.96,
177.12 (two C5O)
328 (M+, 100)
725 (C–F)

K. Arya et al. / Journal of Fluorine Chemistry 137 (2012) 117–122
121
Table 6
purchased from CEM DISCOVER (m = 2450 MHz, 300 W) and
coupled with a microcomputer. C and N analyses were carried
out on a Perkin–Elmer model 240 analyzers.
Intraday effect of different aryl substituted thiazolidinone derivatives on serum
glucose at 1st day.
Compounds
Average serum glucose level (mg/dL) at (1st day)
3.3. Catalyst preparation and its applications
0 h
1 h
4 h
7 h
Control
277.30 ꢂ 1.46
272.41 ꢂ 2.56
282.29 ꢂ 2.75
270.13 ꢂ 3.89
289.46 ꢂ 4.79
292.14 ꢂ 5.78
288.27 ꢂ 2.46
278.19 ꢂ 2.34
249.75 ꢂ 2.88
283.27 ꢂ 5.07
289.22 ꢂ 2.90
294.74 ꢂ 3.70
284.55 ꢂ 1.78
278.24 ꢂ 1.45
277.35 ꢂ 3.02
238.36 ꢂ 2.42
239.56 ꢂ 1.25
269.35 ꢂ 3.98
283.25 ꢂ 1.02
285.49 ꢂ 1.75
265.89 ꢂ 4.02
233.34 ꢂ 2.76
272.21 ꢂ 2.98
275.43 ꢂ 2.05
273.22 ꢂ 2.90
268.46 ꢂ 3.08
268.02 ꢂ 2.13
298.12 ꢂ 1.78
155.23 ꢂ 1.89
165.78 ꢂ 2.89
187.79 ꢂ 1.53
214.27 ꢂ 4.76
242.36 ꢂ 4.56
172.65 ꢂ 0.58
134.37 ꢂ 1.78
179.67 ꢂ 2.98
222.65 ꢂ 5.09
234.98 ꢂ 4.07
165.43 ꢂ 3.09
265.12 ꢂ 3.09
306.66 ꢂ 1.78
118.24 ꢂ 3.98
122.45 ꢂ 4.49
132.33 ꢂ 2.05
178.67 ꢂ 1.39
241.44 ꢂ 0.79
135.24 ꢂ 1.22
119.22 ꢂ 0.77
131.95 ꢂ 1.09
170.55 ꢂ 3.87
232.67 ꢂ 2.30
127.11 ꢂ 0.87
Preparation
of
1-methylimidazolium
tetrafluoroborate
Alloxan
([MIM]+BF4
)
ꢀ
Standard
4a
Tetrafluoroboric acid (8.06 g, 0.03 mol, 40% solution in water)
was slowly added to a precooled solution (0 8C) of 1-methylimi-
dazole (3 g, 0.03 mol) placed in a two-necked flask with a magnetic
stirrer. The mixture was maintained at that temperature and
stirred for 2 h. The resulting colorless ionic liquid was dried in a
rotavapor for 2 h at 60 8C to remove water and used for synthesis of
spiro compounds.
4b
4c
4d
4e
5a
5b
5c
5d
Fluorinated
spiro[3H-indole-3,20-tetrahydro-1,3-thiazine]-2,40
5e
(1H)-diones (4a-f) and Spiro[indole-3,20-thiazolidine]-2,40 (1H)-
The values are presented as mean ꢂ S.E.M. of six determinations p < 0.01.
diones (5a-f)
Fluorinated spiro compounds 4/5 have been synthesized in one-
step without isolating the intermediate using 1-methylimidazo-
lium tetrafluoroborate ([MIM]+BF4ꢀ) under microwave irradiation.
Pyrex glass vial containing an equimolar mixture (5 mmol) of
appropriate indole-2,3-dione (1) and substituted aniline (2) and
thioacids (3a/b) adsorbed on 1-methylimidazolium tetrafluoro-
borate ([MIM]+BF4ꢀ) (1 gm) was placed in a screw capped Teflon
vessel. Microwave was applied for 5 min at 140 8C. After the
completion of reaction (TLC analysis), recyclable ionic liquid was
separated by filtration after eluting the product with ethanol under
reduced pressure and the residue washed with methanol gave a
pure product in high yield (Table 1). All synthesized compounds
were characterized by spectral analysis and data summarized in
Table 4.
capable of hydrogen bonding. In regard to the substituent effect on
the N(2)-phenyl group, it is noteworthy that the activity seems to
be affected by the nature (electron-donating or electron-with-
drawing) of the substituents in the phenyl group position. Apart
from this, presence of electron-withdrawing or donating group on
indole moieties in spiro [indole-thiazolidinone] system also
affected the biological activities [28]. In Table 5, compounds 4a,
4c–d, 4e and 5a, 5c–d, 5e, all carry electron-withdrawing groups
on ortho and para position of phenyl ring, but in compounds 4a, 4e
and 5a, 5e fluorine atom on indole moiety would show weak
electron-withdrawing power compared to CF3 group on indole
moiety in compounds 4c, d and 5c, d. Therefore compounds 4a, 4c–
d, 4e and 5a, 5c–d, 5e were less active towards histaminic
activities. However, electron-withdrawing groups achieved best
results on both, either phenyl ring or indole moieties, compared to
electron donating group (compounds 4f and 5f, Table 5).
Guinea pig ileum in vitro assay for Hl-receptor histamine
antagonism
4. Pharmacological evaluation
Synthesized fluorinated spiro compounds (4a–f, 5a–f) were
tested for new antidiabetic agents and in vitro for histamine HI-
antagonist activity of the inhibition of the histamine-induced
contractions on the isolated guinea pig ileum [26]. The activities
have been reported in Tables 5–7.
The assay was performed on ileum of either sex (weighing
ꢀ250 g) percentage inhibition for guinea pig [26] was calculated
on the response caused by 0.5
mM histamine in the absence of
drugs. Six observations were carried out for each drug concentra-
tion. The results, IC50 listed in Table 5, are reported as
5. Antihistamic activity
,
concentration of drug causing 50% inhibition of the submaximal
contractions induced by histamine.
The dissociation constant (KB), for pA2 value calculations
(pA2 = ꢀlog KB), was evaluated according to the method of Schild
[29], from the equation KB = B/(xꢀ1), where x is the respective ratio
The competitive HI-receptor antagonism was evaluated by pA2
data summarized in Table 5 and the potency of antagonistic effect
of the tested compounds was compared to the activity of
mepyramine. According to current research on antihistamine
drugs, four elements are required for the histamine HI-receptor
pharmacophore: two
heteroatom [27].
On the basis of the reported results, it seems that the
pharmacophore proposed by Naruto [27b] are present in spiro
indole [thiazine/thiazolidinone] moieties. The carbonyl and the
p sites, basic nitrogen, and a site for a
Table 7
Effect of different aryl substituted thiazolidinone derivatives on serum glucose at
1st, 3rd, 7th day.
Compounds
Average serum glucose level (mg/dL)
1st day
3rd day
7th day
N(2)-phenyl group could mimic the two
p sites, and the nitrogen
Control
245.74 ꢂ 2.88
272.41 ꢂ 2.56
122.24 ꢂ 2.03
167.89 ꢂ 0.97
188.34 ꢂ 2.09
245.89 ꢂ 2.36
222.37 ꢂ 1.62
205.86 ꢂ 2.74
145.73 ꢂ 1.57
198.22 ꢂ 3.09
225.75 ꢂ 4.55
209.56 ꢂ 3.76
199.87 ꢂ 1.11
222.67 ꢂ 2.83
324.67 ꢂ 0.63
115.67 ꢂ 1.37
137.54 ꢂ 4.09
160.25 ꢂ 1.56
234.72 ꢂ 2.88
204.73 ꢂ 1.55
180.22 ꢂ 3.22
127.89 ꢂ 2.90
172.86 ꢂ 2.49
199.67 ꢂ 1.23
181.32 ꢂ 2.22
178.90 ꢂ 4.37
183.79 ꢂ 5.90
298.75 ꢂ 1.78
108.98 ꢂ 4.88
116.76 ꢂ 2.33
122.78 ꢂ 0.33
218.90 ꢂ 1.97
178.30 ꢂ 3.99
127.57 ꢂ 0.46
110.99 ꢂ 3.89
127.39 ꢂ 1.99
167.57 ꢂ 2.02
145.32 ꢂ 1.57
119.90 ꢂ 2.17
atom of thiazolidine ring could correspond to the heteroatom
Alloxan
Standard
4a
Table 5
Histamine antagonist activity in vitro on guinea pig ileum.
4b
4c
Compounds
IC50
mM
pA2 ꢂ 0.2
Compounds
IC50
m
M
pA2 ꢂ 0.2
4d
4a
4b
4c
4d
4e
4f
60
5.8
6.4
8.6
7.9
5.6
2.7
5.3
5b
24
7.1
8.7
8.2
4.3
1.9
9.0
4e
60
10
5c
20
21
5a
5d
5b
20
5e
5f
>100
>100
5c
60
5d
>100
>100
Mepyramin
1.0
5e
5a
The values are presented as mean ꢂ S.E.M. of six determinations p < 0.01.

122
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(B) of antagonists. pA2 values, reported in Table 5, are the average
of five observations.
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7. Conclusion
Improved synthesis of biologically active scaffold fluorinated
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ionic liquids gave high substrate conversion and product
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reaction medium proceeded smoothly towards completion and
products were conveniently decanted out from the ionic liquid. Use
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Authors are thankful to UGC, New Delhi for financial support.
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