Synthesis of biologically important novel fluorinated spiro heterocycles under microwaves catalyzed by montmorillonite KSF

Article abstract of DOI:10.1016/j.jfluchem.2006.12.003

The arylidienes of fluorinated spiro thiazolidines (5) containing α,β-unsaturated function have been used as component of Micheal addition with equimolar amount of 2-aminopyridine (6a) to give novel fluorinated spiro [indole-3,2′-pyrido[1,2-a]thiazolo[5,4

Full text of DOI:10.1016/j.jfluchem.2006.12.003

Journal of Fluorine Chemistry 128 (2007) 224–231
www.elsevier.com/locate/fluor
Short communication
Synthesis of biologically important novel fluorinated spiro heterocycles
under microwaves catalyzed by montmorillonite KSF
a,
Kapil Arya , Anshu Dandia
b
*
a
Indian Oil Corporation Limited, Catalyst Division, R&D center, Sector-13, Faridabad 121007, Haryana, India
b
Chemistry Department, University of Rajasthan, Jaipur 302004, India
Received 5 November 2006; received in revised form 23 November 2006; accepted 3 December 2006
Available online 6 December 2006
Abstract
The arylidienes of fluorinated spiro thiazolidines (5) containing a,b-unsaturated function have been used as component of Micheal addition
0
with equimolar amount of 2-aminopyridine (6a) to give novel fluorinated spiro [indole-3,2 -pyrido[1,2-a]thiazolo[5,4-e]pyrimidines] (7) in a single
0
step under microwaves in presence of montmorillonite KSF as solid support. The new improved synthetic method for fluorinated spiro [indole-3,2 -
thiazolo[4,5-d]pyrimidines] (8) has also been developed involving the reaction of (5) with thiourea under monomode microwave reactor.
Comparison with conventional synthesis and multimode microwave oven indicated the enhanced yield with faster reactions under monomode
microwave reactor. Structure–activity relationships between the chemical structures and the antimycobacterial, antifungal activity of the evaluated
compounds are also discussed.
#
2006 Elsevier B.V. All rights reserved.
Keywords: Fluorinated spiro thiazolidines; MW irradiation; Arylidenes derivatives; Thiazolopyrimidines; Monomode microwave reactor
1
. Introduction
biological/pharmacological activity [12]. Further, incorpora-
tion of a trifluoromethyl substituents have been shown to
increase the phytoxicity along with selectivity and arenes
bearing a trifluoromethyl substituents comprise the largest sub-
group of commercially promising pesticides and herbicides.
For the preparation of the complex molecules, large efforts have
been directed towards the synthetic manipulation of triazolo-
pyrimidines. As a result, scanty reports have appeared which
usually require drastic conditions, prolonged reaction times,
complex synthetic pathways and often react in organic solvents
[13,14]. Thus, new route for the synthesis of these molecules
have attracted considerable attention in search for a rapid entry
to these heterocycles.
The chemistry of spiro indoles in which an indole ring is
joined to sulfur and nitrogen containing heterocycles at the C-3
position through a spiro carbon atom is of great interest due to
their physiological and biological activities [1,2]. Spiro
[
indole-thiazolidines] are known to possess various biological
activity, e.g. anti-inflammatory [3], antimicrobial [4], bacter-
iostatic [5] and anticonvulsant activities [6] and antifungal
agents [7]. The significance of these compounds can be judged
from the fact that most of the references of spiro-indoles in the
literature are patents [8]. Arylidene derivatives of condensed
4
-thiazolidinones have been found to be better medicinal
agents than the parent 4-thiazolidinones. Besides, condensed
-thiazolidinones are better anti-HIV, anti-anticonvulsant [9],
Microwave accelerated synthesis is also emerging as a
powerful tool for high-throughput organic synthesis [15,16].
It has been demonstrated that the use of microwave heating
can dramatically shorten reaction times, increase product
purities and yields, and allow precise control of reaction
parameters.
4
anti-inflammatory [10] and Hypnotic agents [11] than their
thiazole counterparts.
Incorporation of fluorine to different heterocycles is known
to affect the course of the reaction besides, influencing the
Microwaves also have shown an advantage where processes
involve sensitive reagents or when products may decompose
under prolonged reaction conditions. In view of this, more
interest has now been focused on dry media synthesis,
*
Corresponding author.
E-mail address: aryakapil2001@yahoo.com (K. Arya).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.12.003

K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
225
involving the coupling of MWI with solid supported reagents.
2. Results and discussion
The method provides unique chemical process with special
attribute to greater selectivity and ease of manipulation.
Literature survey reveals that there is no report on the
synthesis of titled novel nucleus yet so far. Therefore, it was
thought that it would be desirable to develop a facile, efficient,
environeconomic, microwave induced method for preparation
Fluorinated spiro [indole-thiazolidines] (4) were prepared by
the multicomponent condensation between indole-2,3-dione,a-
mines and mercaptoacetic acid [19] using montmorillonite KSF
as solid support. These on reaction with arylaldehydes ‘‘in situ’’
0
0
0
by Knoevengal condensation yielded 3 aryl-5 -benzylidene-4 H-
0
0
0
of novel fluorinated spiro [indole-3,2 -pyrido[1,2-a]thia-
0
spiro-[indole-3,2 -thiazolidine]-2,4 (1H)-dione (5a–d) in 92–
96% yield in 3–5 min under same reaction conditions in one pot.
These arylidenes with an a, b-unsaturated ketonic function
(–CH CH–CO–) in their structure have been used as a
component of Micheal addition with 2-aminopyridine and
zolo[5,4-e] pyrimidines] (7) and fluorinated 5 -thioxo-
0
0
4
,5,6,7-tetrahydro-2H,3 H-spiro [indole-3,2 -thiazolo[4,5-d]
pyrimidines] by the reaction of arylidiens derivative (5) with
-aminopyridine (6a) and thiourea (6b) using montmorillonte
2
0
KSF as solid support under microwaves.
yielded the novel compound fluorinated spiro [indole-3,2 -
As part of our ongoing program to develop efficient and
robust methods for the preparation of biologically relevant
compounds [17] from readily available building blocks, which
are novel yet resemble known biologically active molecules by
virtue of the presence of some critical structural features, we
sought to develop a convenient preparation of a novel
fluorinated spiro indolines 7 and 8 (Scheme 1) by combining
two to three steps as a one-pot reaction to reduce the pollution at
source as important green chemical theme [18] under
microwaves.
pyrido[1,2-a]thiazolo[5,4-e] pyrimidines]-2 (1H)-one (7) in a
single step in presence of montmorillonite KSF as solid
support in 85–91% yield in 5–6 min. A non-isolated intermedi-
ate has been presumed during such type of condensation
(Scheme 2).
Further
0
fluorinated
5 -thioxo-4,5,6,7-tetrahydro-spiro
0
[indole-3,2 -thiazolo[4,5-d]pyrimidine]-2(1H)-one (8a–d) were
also synthesized by improved enviroeconomic green chemical
procedure by the reaction of arylidenes derivatives (5) with
thiourea in 85–90% yield in 3–5 min.
Scheme 1.

226
K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
Scheme 2.
Conventional synthesis of 5, 7 and 8 requires long reflux
From the results shown in Table 1, it can be seen than for the
same time at the same temperature, the reactions performed
under microwave irradiation, using both the multimode reactor
at 1000 W and the monomode reactor, were faster than the
reaction performed by classical heating. Same yields were
obtained using both reactors but for different time intervals.
The structure assigned to arylidiene derivatives (5) was
period in volatile solvents such as dioxane, dry toluene, glacial
AcOH and fused sodium acetate and using Dean Strak
apparatus make whole procedure very tedious and yielding
the desired product in very low quantity.
The irradiation was performed in parallel using two kinds of
reactors: a usual microwave multimode reactor (National
panasonic oven) having 1000 W power, in this case the
microwaves are not focused, and a monomode reactor having
1
confirmed by spectral studies. H NMR spectrum of 5a showed
characteristicsignalsatd 2.49(s, 3H, CH ), 2.79(s, 3H, CH ), 5.1
(s, 1H, CH) and 7.13–7.64 (m, 12H, Ar–H) and 9.23 (s, 1H, NH).
3
3
5
0 W power (Maxidigest MY-350 Prolabo) with focused rays
1
Absence of CH signal (dd) in H NMR at d 3.80–4.22 ppm
and a much more homogenous electromagnetic field. In
comparison, the reactions realized under microwave irradiation
and interphase catalysis had higher yields than those performed
under classical conditions for the same time and temperature.
2
1
3
further confirmed the formation of 5. In C NMR spectrum of 5
signals were observed at d 81.6 (spiro carbon), 113.2–147.3
(olefiniccarbonandaromaticcarbons), 162.8, 169.2(bothC O).
Table 1
Comparative study of Micheal addition reaction on solid support mont. KSF
Compound no.
X
Y
Z
Rxn temp. (8C)
Reaction time (min)/yield (%)
D
MW
Multimode
Monomode
5
5
5
5
7
7
7
7
8
8
8
8
a
b
c
d
a
b
c
d
a
b
c
5-F
H
4-N(CH
3
)
)
)
2
2
2
120
120
120
120
100
100
100
100
100
100
100
100
300/58
320/54
280/60
340/61
480/54
500/55
480/52
520/58
540/62
480/59
620/60
560/53
6/92
5/94
8/96
6/95
9/89
8/91
11/90
9/85
8/86
9/90
8/88
9/85
5/92
4/94
5/96
3/95
5/89
5/91
6/90
5/85
4/86
5/90
4/89
3/85
7-F
H
4-OCH
3-OCH
3
3
5-CF
7-CF
5-F
3
H
3
4-OCH
3
3
3
CH
4-N(CH
3
H
3
7-F
H
4-OCH
3-OCH
3
3
5-CF
7-CF
5-F
3
H
3
4-OCH
CH
4-N(CH
3
H
3
7-F
H
4-OCH
3-OCH
3
3
5-CF
7-CF
3
H
d
3
4-OCH
CH
3

K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
227
Table 2
The formation of 7and 8 from arylidene derivatives (5) was
1
Calculated antimycobaterial evaluation (% of inhibition) and antifungal sus-
ceptibility (MIC) comparison with standards: pyrazinamide (PZA) and fluco-
nazole
confirmed by IR and H NMR data. In IR spectrum of 7a and 8a
ꢀ1
disappearance of C O absorption band at 1680–1695 cm
which was present in 5 confirmed the cyclization or
ꢀ1
1
involvement of a,b-unsaturated carbonyl system. H NMR
Compound
X
% Inhibition at
ꢀ
MIC (mmol ml )
1
6
.25 mg ml
spectrum of 7a showed characteristic signals at d 3.71 (s, 1H,
0
0
0
7a
5-F
7-F
5-CF
7-CF
5-F
7-F
5-CF
7-CF
–
50
54
71
68
58
56
72
31.24/63.85
31.23/31.23
125/250
C–10 H), 5.91 (m, 1H, C–8 H), 7.02 (m, 1H, C–6 H), 7.23–8.02
m, 16H, Ar–H) and 9.01 (s, 1H, NH). Formation of 7a was
7
7
7
b
c
d
(
further confirmed by C NMR and Mass spectra. C NMR
1
3
13
3
3
>500/>500
30.23/61.2
>500/>500
>500/>500
>500/>500
–
0
spectrum of 7a showed signals at d 58.9 (C-10 ), 84.9 (spiro
carbon), 107.6–142.6 (aromatic carbons), 165.2 (C N) and
8a
8b
8
c
3
3
1
peak m/z at 505 ([M] , 14.6%) corresponding to its molecular
68.5 (NH–C O). Mass spectrum of 7a showed molecular ion
+
8d
69
a
PZA
Fluconazole
100
–
+
weight along with base peak at 385 ([M ꢀC H N], 100%) and
8
10
–
1.95/3.91
other peaks at 281 (12.3), 188 (13), 160 (20.8), 121 (58.2), 78
(
a
ꢀ1
MIC = 12.5 mg ML , data from ref. [20].
19.3).
1
H NMR spectrum of 8a showed characteristic signals at d
0
4
.82 (s, 1H, C–7 H), 6.98–7.62 (m, 12H, Ar–H), 9.13 (s, 1H,
1
3. Conclusion
3
NH) and 10.25 (bs, 2H, pyridine NH). C NMR spectrum of 8a
0
showed signals at d 52.6 (C-7 ), 92.8 (spiro carbon), 112.9–
1
After studying the reaction of arylidienes of spiro
thiazolidines (5) containing a,b-unsaturated function and 2-
aminopyridine (6a) and thiourea (6b) in the solid phase and
with an interphase transfer catalyst, by classical heating or
under microwave irradiation, it can be concluded that reaction
performed much more efficient on the solid support compare
than those taking place in an organic solvent because: mont.
KSF is averystrong acid causing Micheal addition, which, in this
case, determines the ‘‘in situ’’ formation of the ylides; the solid
support allows the reaction temperature to be raised over the
boiling temperature of the solvent; the yields of the reactions
which are performed under the influence of microwaves, both in
the solidphaseandwithinterphasecatalysis, aresuperiortothose
reactions performed under classical conditions, due to the
temperature being more homogeneous and changes in the
activation enthalpy and entropy; the monomode reactor is more
efficient than the multimode reactor due to the better yield
of energy obtained by microwave fascicle focalization and the
more homogeneous electromagnetic field.
39.6 (aromatic carbons), 169.4 (C O) and 176.5 (C S). Mass
+
spectrum of 8a showed molecular ion peak m/z at 487 ([M] ,
7.4%) corresponding to its molecular weight along with base
1
+
peak at 443 ([M ꢀCS], 100) and other peaks at 367
+
(
(
[M ꢀC H ], 25.5), 281 (42), 185 (25), 165 (28.5), 131
8
10
1
9
63.7), 78 (50.4). The presence of fluorine was confirmed by
F
NMR spectra, where the C–F signal was observed at d 118.05–
1
20.42 (compound 5a,b, 7a,b, 8a,b) and CF signal at d 63.25–
3
6
4.07 ppm in case of compound 5c,d, 7c,d, 8c,d.
2
.1. Evaluation of antimicrobial and antifungal activity
All compounds prepared were evaluated for their in vitro
antimycobacterial activity. The highest activity (72% inhibi-
tion) against Mycobacterium tuberculosis was found for 5-
0
trifluoromethyl-spiro [indole-3,2 -pyrido[1,2-a]thiazolo[5,4-e]
0
pyrimidines] (7c) and 5-trifluoromethyl-5 -thioxo-4,5,6,7-tet-
0
rahydro-spiro [indole-3,2 -thiazolo[4,5-d]pyrimidine] (8c).
Two other compounds (7d, 8d) with the identical substitution
on the aromatic part of the molecule, exert a comparable
activity. The majority of compounds exhibited only modest
antimycobacterial activity (see Table 2).
On the basis of the biological evaluation, compounds 7c, 8c
seems to be very attractive as a antimicrobial agents, while,
among the compounds bearing trifluoromethyl (7c–d, 8c–d)
have shown the highest antituberculosis activity, i.e. against M.
tuberculosis H37Rv.
The evaluation of in vitro antifungal activity of the
synthesized compounds was performed against eight fungal
strains. The results revealed no interesting activity against the
majority of strains tested.
4. Experimental
0
Only the 5-fluoro-spiro [indole-3,2 -pyrido[1,2-a]thia-
0
Melting points were determined in open glass capillaries and
were uncorrected. Thin layer chromatography on silica gel ‘G’
coated glass plates using benzene, ethanol (8:2) as eluent was
used for monitoring the progress of the reactions. IR spectra
(KBr) were recorded on a Magna FT IR–550 spectro-
zolo[5,4-e] pyrimidines] (7a) and 5-fluoro-5 -thioxo-4,5,6,7-
0
tetrahydro-spiro [indole-3,2 -thiazolo[4,5-d]pyrimidine] (8a)
showed some promising in vitro antifungal activity against
Trichophyton mentagrophytes, the most susceptible fungal
ꢀ1
1
19
13
strain evaluated (MIC = 31.24/63.85 mmol ml ), although this
activity is only modest in comparison with fluconazole, the
photometer, H, F and C NMR spectra [CDCl ] were
3
taken on a Bruker-300DX spectrometer at 300 and 200 MHz,
respectively, using TMS as an internal standard for PMR and
ꢀ1
standard (MIC = 3.91 mmol ml after 120 h, see Table 2). The
negative antifungal screening results do not allow us to draw
detailed conclusions on potential structure–activity relation-
ships.
1
9
hexafluorobenzene as external standard for F NMR and mass
spectra were recorded on Jeol D-300 spectrometer at an
ionisation potential of 70 eV. Microwave assisted reactions

228
K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
0
0
0
0
were carried out on a BPL BMO model, operating at 700 W,
generating 2450 MHz frequency. All anilines were purchased
from Aldrich Chemical Co. and were used as received.
Microwave assisted reactions were carried out on a National
panasonic oven with inverter technology operating at fixed
frequency 2450 MHz with power out put range 1000 W. For the
monomode reactor, Maxidigest MX 350 Prolabo (50 W) were
used. Perkin-Elmer 2400 automatic CHNS analyzer used for
elemental analyses.
4.3. 5 -(4-Methoxybenzylidene)-3 -phenyl-7-fluoro-2 H-
0
spiro[indole-3,2 -thiazolidine]-2,4 (1H)-dione (5b) [22]
Yield: 94%; mp 205–207 8C; Rf 0.7 petroleum ether, EtOAc,
80:20).
IR (KBr): 3370–3250 (bs, NH), 1715, 1690 (both C O),
ꢀ
1 1
1150 (C–O–C), 760 (C–Cl) cm ; H NMR (CDCl ): d = 3.62
3
(s, 3H, OCH ), 5.21 (s, 1H, CH), 7.05–7.68 (m, 12H, Ar–H),
3
1
9
9.28 (s, 1H, NH); F NMR (CDCl ): d = ꢀ119.23 (s, F); Anal.
3
Calcd for C H ClN O S: C, 64.21; H, 3.82; N, 6.24. Found:
2 3
2
4
17
0
0
4.1. Fluorinated spiro [indole-3,2 -thiazolidine]-2,4 (1H)-
dione (4)
C, 64.15; H, 3.92; N, 6.35.
0
0
4.4. 5 -(3-Methoxybenzylidene)-3 -phenyl-5-
trifluoromethyl-2 H-spiro[indole-3,2 -thiazolidine]-
0
0
These compounds were synthesized in one pot by
0
multicomponent cyclocondensation reaction of Fluorinated
indole-2,3-dione, amines and mercaptoacetic acid using
montmorillonite KSF as solid support as reported by us
2,4 (1H)-dione 5c
Yield: 96%; mp 215–218 8C; Rf 0.6 petroleum ether, EtOAc,
80:20).
IR (KBr): 3360–3290 (bs, NH), 1720, 1695 (both C O),
[
19]. Since TLC studies showed 100% conversion with
formation of single product hence it is used as such for further
conversion without isolating them. For structure confirmation
some products are isolated by desorption with methanol and
compared with authentic samples prepared by literature
methods [21].
ꢀ1
1
1150 (C–O–C) cm ; H NMR (CDCl ): d = 3.57 (s, 3H,
3
OCH ), 5.4 (s, 1H, CH), 7.10–7.85 (m, 12H, Ar–H), 9.36 (s, 1H,
3
1
9
NH); F NMR (CDCl ): d = ꢀ63.89 (s, CF ); Anal. Calcd for
3
3
C H N O S: C, 70.07; H, 4.70; N, 6.54. Found: C, 70.15; H,
2
5 20 2 3
4
.62; N, 6.45.
0 0
.2. 5 -(4-N,N-dimethylbenzylidene)-3 -phenyl-5-fluoro-
4
2
0
0
0
0
0
H-spiro[indole-3,2 -thiazolidine]-2,4 (1H)-dione (5a)
4.5. 5 -(4-Methylbenzylidene)-3 -(4-methoxyphenyl)-7-
0
0
trifluoromethyl-2 H-spiro[indole-3,2 -thiazoli-dine]-
0
It was synthesized by following different ways.
2,4 (1H)-dione 5d
4
.2.1. Conventional method
An equimolar mixture of 4a (2.75 g, 0.01 mol), N,N-
Yield: 95%; mp 192–195; Rf 0.9 petroleum ether, EtOAc,
80:20).
IR (KBr): 3390–3280 (bs, NH), 1710, 1690 (both C O),
dimethylbenzaldehyde (1.75 g, 0.01 mol) and anhydrous
sodium acetate in glacial acetic acid (40 ml) was refluxed
for 5 h. On cooling, the reaction mixture was poured into ice-
cold water. The solid thus obtained was filtered, washed with
water, dried and crystallized from benzene.
ꢀ
1 1
1140 (C–O–C) cm ; H NMR (CDCl ): d = 2.28 (s, 3H, CH ),
3
3
3.58 (s, 3H, OCH ), 5.18 (s, 1H, CH), 7.15–7.89 (m, 11ssssH,
3
1
9
Ar–H), 9.23 (s, 1H, NH); F NMR (CDCl ): d = ꢀ64.23 (s,
3
CF ); Anal. Calcd for C H N O S: C, 70.18; H, 4.70; N, 6.54.
3
25 20 2 3
Found: C, 70.18; H, 4.62; N, 6.48.
4
.2.2. Microwave mediated synthesis
The N,N-dimethylbenzaldehyde (1.75 g, 0.01 mol) and
0
0
4.6. 10 -(4-N,N-dimethylphenyl)-3 phenyl-5-fluoro-
0
fluorinated spiro thiazolidinone (4a) (synthesized ‘‘in situ’’)
were dissolved in 50 ml anhydrous benzene. To this solution,
spiro[indole-3,2 -pyrido[1,2-a]thiazolo[5,4-e] pyrimi-
dines] (7a)
1
0 g of mineral support (mont KSF) was added under stirring.
After solvent evaporation under low pressure, the obtained solid
was exposed to microwaves. The activated solid was cooled and
washed several times with 10 ml of benzene. Then, the solvent
was evaporated and the product purified by methanol
recrystallization.
It was synthesized by following methods.
4.6.1. Conventional method
(i) An equimolar mixture of 5a (4.27 g, 0.01 mol), 2-amino
pyridine (6a) (0.94 g, 0.01 mol) and fused anhydrous
sodium acetate (2 g) in dioxane (40 ml) was refluxed for
8 h. The solvent was removed by distillation in vacuo and
residue poured into cold water. The solid thus obtained was
washed with water and crystallized from ethanol to give 7a.
mp = 132 8C, yield = 54%.
(ii) A equimolar mixture of 5a (4.27 g, 0.01 mol), 2-amino
pyridine (6a) (0.94 g, 0.01 mol) in ethanol (30 ml)
containing six to eight drops of glacial acetic acid was
refluxed for 7 h. A crude product appeared on cooling the
reaction mixture, which was filtered, washed with water
Yield: 92%; mp 240–242 8C; Rf 0.6 (petroleum ether,
EtOAc, 80:20).
IR (KBr): 3380–3290 (bs, NH), 1720, 1680 (both C O)
ꢀ
1 1
cm ; H NMR (CDCl ): d = 2.49 (s, 3H, CH ), 2.79 (s, 3H,
3
3
CH ), 5.10 (s, 1H, CH), 7.13–7.64 (m, 12H, Ar–H), 9.23 (s, 1H,
3
1
9
13
NH); F NMR (CDCl ): d = ꢀ118.09 (s, F); C NMR
3
(
CDCl ): d = 81.6 (spiro carbon), 113.2–147.3 (olefinic carbon
3
and Ar carbons), 162.8, 169.2 (both C O); Anal. Calcd for
C H N O S: C, 70.23; H, 4.95; N, 9.83. Found: C, 70.39; H,
2
5 21 3 2
4
.89; N, 9.78.

K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
229
and recrystallized form ethanol to give desired product 7a.
mp = 132 8C, yield = 57%.
IR (KBr): 3360–3250 (bs, NH), 1710 (C O), 1610 (C N),
ꢀ1 1
1145 (C–O–C) cm ; H NMR (CDCl ): d = 2.28 (s, 3H, CH ),
3
3
0
0
3.58 (s, 3H, OCH ), 3.79 (s, 1H, C–10 H), 5.95 (m, 1H, C–8 H),
6.95 (m, 1H, C–6 H), 7.10–8.02 (m, 15H, Ar–H), 9.26 (s, 1H,
3
0
4
.6.2. Microwave mediated synthesis
An equimolar mixture (0.01 mol) of 5a and 6a was adsorbed
1
9
13
NH); F NMR (CDCl ): d = ꢀ63.25 (s, CF ); C NMR
3
3
0
on montmorillonite KSF (70% weight of reactants). The
reaction mixture was irradiated for appropriate time (Table 1).
The recyclable montmorillonite KSF separated by eluting the
product with methanol and excess solvent was evaporated on
rotaevaporator to give pure product (TLC), with no need of
further purification.
(DMSO-d ): d = 57.9 (C-10 ), 83.9 (spiro carbon), 106.3–145.6
6
(aromatic carbons), 165.2 (C N), 168.5 (NH–C O); Anal.
Calcd for C H N O S: C, 71.12; H, 5.17; N, 11.06. Found: C,
71.02; H, 5.07; N, 11.11.
3
0 26 4 2
0
0
0
4.10. 7 -(4-N,N-dimethylphenyl)-3 -phenyl-5-fluoro-5 -
thioxo-4,5,6,7-tetrahydro-spiro[indole-3,2 -thiazo-lo[4,5-
d]pyrimidine] (8a)
7a: Yield: 89%; mp 132–135 8C; Rf 0.6 (petroleum ether,
EtOAc, 80:20).
0
IR (KBr): 3380–3270 (bs, NH), 1710 (C O), 1620 (C N)
ꢀ
1
cm
;
H NMR (CDCl ): d = 2.45 (s, 3H, CH ), 2.73 (s, 3H, CH ),
It was synthesized by following different way.
1
3
3
3
0
0
3
6
.71 (s, 1H, C–10 H), 5.91 (m, 1H, C–8 H), 7.02 (m, 1H, C–
0
19
H), 7.23–8.02 (m, 16H, Ar–H), 9.01 (s, 1H, NH); F NMR
4.10.1. Conventional method
1
3
(
CDCl ): d = ꢀ118.54 (s, F); C NMR (DMSO-d ): d = 58.9
An equimolar mixture of 5a (2.75 g, 0.01 mol), thiourea (6b)
(0.78 g, 0.01 mol) in absolute ethanol (25 ml)/anhyd pyridine
(25 ml) was refluxed for 9 h. On cooling, the crude solid
appeared which was filtered, washed with ice-cold water
containing dilute HCl with constant stirring. The solid mass
thus obtained was filtered and crystallized from ethanol.
mp = 212 8C, yield = 62%.
3
6
0
(
C-10 ), 84.9 (spiro carbon), 107.6–142.6 (aromatic carbons),
65.2 (C N), 168.5 (NH–C O); GC–MS (EI): m/z (%) = 505
1
+
+
[
M ], 385 (100) [M ꢀC H N], 281 (12.3), 188 (13), 160
30 27 5 5
8
10
(
20.8), 121 (58.2), 78 (19.3); Anal. Calcd for C H N O : C,
1.26; H, 5.38; N, 13.85. Found: C, 71.19; H, 5.31; N, 13.92.
7
0 0 0
.7. 10 -(4-methoxy)-3 phenyl-7-fluoro-spiro[indole-3,2 -
pyrido[1,2-a]thiazolo[5,4-e] pyrimidines] 7b
4
4
.10.2. Microwave mediated synthesis
It was synthesized by reaction of 5a and 6b using
montmorillonite KSF as solid support under microwaves as
similar manner as preparation of 7a.
Yield: 86%; mp 212–215 8C; Rf 0.5 (petroleum ether,
EtOAc, 80:20).
IR (KBr): 3380–3280 (bs, NH), 1710 (C O), 1220 (C S)
Yield: 91%; mp 137–139 8C; Rf 0.6 (petroleum ether,
EtOAc, 80:20).
IR (KBr): 3360–3290 (bs, NH), 1720 (C O), 1610 (C N),
ꢀ
150 (C–O–C) cm ; H NMR (CDCl ): d = 3.62 (s, 3H,
3
1
1
1
0
0
OCH ), 3.81 (s, 1H, C–10 H), 5.87 (m, 1H, C–8 H), 7.05 (m,
3
0
19
1
H, C–6 H), 7.18–8.09 (m, 16H, Ar–H), 9.15 (s, 1H, NH);
F
ꢀ
1 1
cm ; H NMR (CDCl ): d = 2.43 (s, 3H, CH ), 2.85 (s, 3H,
3
3
NMR (CDCl ): d = ꢀ119.56 (s, F); Anal. Calcd for
3
0
CH ), 4.82 (s, 1H, C–7 H), 6.98–7.62 (m, 12H, Ar–H), 9.13 (s,
3
19
H, NH), 10.25 (bs, 2H, pyridine NH); F NMR (CDCl3):
C H ClN O S: C, 66.09; H, 4.40; N, 10.63. Found: C,
2
2
9
23
4
1
6
6.21; H, 4.51; N, 10.71.
1
3
0
d = ꢀ120.36 (s, F); C NMR (DMSO-d ): d = 52.6 (C-7 ),
6
9
2.8 (spiro carbon), 112.9–139.6 (aromatic carbons), 169.4
0
0
4
spiro[indole-3,2 -pyrido[1,2-a]thiazolo[5,4-e] pyrimidi-
.8. 10 -(3-methoxy)-3 phenyl-5-trifluoromethyl-
0
+
C O), 176.5 (C S); GC–MS (EI): m/z (%) = 487 [M ], 443
(
+
+
(
100) [M ꢀCS], 367 (25.5) [M ꢀC H ], 281 (42), 185 (25),
8
10
nes] 7c
1
C H N OS : C, 64.04; H, 5.17; N, 14.36. Found: C,
65 (28.5), 131 (63.7), 78 (50.4); Anal. Calcd for
2
6
25
5
2
Yield: 90%; mp 148–150 8C; Rf 0.8 (petroleum ether,
EtOAc, 80:20).
IR (KBr): 3375–3290 (bs, NH), 1715 (C O), 1620 (C N),
6
4.15; H, 5.29; N, 14.42.
ꢀ
1 1
0
0
0
1
3
7
160 (C–O–C) cm ; H NMR (CDCl ): d = 3.56 (s, 3H, OCH ),
3
4.11. 7 -(4-methoxy)-3 -phenyl-7-fluoro-5 -thioxo-4,5,6,7-
0
3
0
0
0
.79 (s, 1H, C–10 H), 5.86 (m, 1H, C–8 H), 7.01 (m, 1H, C–6 H),
1
.15–8.12 (m, 16H, Ar–H), 9.28 (s, 1H, NH); F NMR (CDCl ):
tetrahydro-spiro[indole-3,2 -thiazolo[4,5-d]pyrimidine] 8b
9
3
d = ꢀ63.47 (s, CF ); Anal. Calcd for C H N O S: C, 71.12; H,
Yield: 90%; mp 170–172 8C; Rf 0.6 (petroleum ether,
EtOAc, 80:20).
IR (KBr): 3380–3250 (bs, NH), 1720 (C O), 1230 (C S),
3
30 26 4 2
5
.17; N, 11.06. Found: C, 71.26; H, 5.02; N, 11.23.
0
0
ꢀ1
1
4
trifluoromethyl spiro[indole-3,2 -pyrido[1,2-a]thiazolo[5,4-
.9. 10 -(4-methyl)-3 -(4-methoxyphenyl)- 7-
0
1145 (C–O–C) cm ; H NMR (CDCl ): d = 3.58 (s, 3H,
3
0
OCH ), 4.87 (s, 1H, C–7 H), 7.01–7.85 (m, 12H, Ar–H), 9.19
3
1
(s, 1H, NH), 10.32 (bs, 2H, pyridine NH); F NMR (CDCl3):
9
e]pyrimidines] 7d
d = ꢀ119.08 (s, F); Anal. Calcd for C H ClN O S :
2
5
21
4 2 2
Yield: 85%; mp 118–120 8C; Rf 0.7 (petroleum ether,
EtOAc, 80:20).
C, 58.99; H, 4.16; N, 11.01. Found: C, 58.78; H, 4.08; N,
11.09.

2
30
K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
ꢀ1
against M. tuberculosis strain H37Rv in
0
0
0
4
4
.12. 7 -(3-methoxy)-3 -phenyl-5-trifluoromethyl-5 -thioxo-
6.25 mg ml
0
,5,6,7-tetrahydro-spiro[indole-3,2 -thiazo-lo[4,5-
BACTEC 12B medium using the BACTEC 460 radiometric
system [24,25]. The results are presented in Table 2.
d]pyrimidine] 8c
Yield: 89%; mp 134–136 8C; Rf 0.7 (petroleum ether–
EtOAc, 80:20).
IR (KBr): 3390–3260 (bs, NH), 1720 (C O), 1225 (C S),
Acknowledgements
Author is highly thankful to IOCL, R&D Center, Faridabad,
Haryana, India for financial and technical support.
ꢀ
1
1
1
OCH ), 4.76 (s, 1H, C–7 H), 7.05–7.89 (m, 12H, Ar–H), 9.25
145 (C–O–C) cm . H NMR (CDCl ): d = 3.65 (s, 3H,
0
3
3
1
s, 1H, NH), 10.18 (bs, 2H, pyridine NH); F NMR (CDCl3):
9
(
References
d = ꢀ64.36 (s, CF ); Anal. Calcd for C H N O S : C, 63.91;
3
26 24 4 2 2
H, 4.95; N, 11.47. Found: C, 63.75; H, 4.89; N, 11.56.
[1] M. Ona, K. Aoki, Jpn. Kokai 116 (1989) 762;
M. Ona, K. Aoki, Chem. Abstr. 111 (1989) 778489.
[2] J.W. Skiles, D. Menil, Tetrahedron Lett. 31 (1990) 7277–7280.
0 0
.13. 7 -(4-methyl)-3 -(4-methoxyphenyl)-7-trifluoromethyl
4
5
[
3] G.C. Rovnyak, V.L. Narayanan, R.D. Haugwitz, U.S. Patent 4053613
1977).
G.C. Rovnyak, V.L. Narayanan, R.D. Haugwitz, Chem. Abstr. 88 (1978)
2889r.
0
0
-thioxo-4,5,6,7-tetrahydro-spiro[indole-3,2 -thiazolo[4,5-
(
d]pyrimidine] 8d
2
[
[
4] E. Piscopo, M.V. Diurno, O. Mazzoni, A.M. Ciaccio, Boll Soc. Ital. Biol.
Sper. 66 (12) (1990) 1181–1186.
Yield: 85%; mp 185–187 8C; Rf 0.7 (petroleum ether,
EtOAc, 80:20).
IR (KBr): 3395–3260 (bs, NH), 1715 (C O), 1235 (C S),
5] V. Sehgal, P. Singh, A. Dandia, R. Bohra, Acta Cryst. C50 (1994) 1156–
1
159.
ꢀ1 1
1
145 (C–O–C) cm . H NMR (CDCl ): d = 2.35 (s, 3H, CH ),
3
3
[6] M. Rajopadhye, F.D. Popp, J. Heterocycl. Chem. 24 (1987) 1637–1642.
[7] A. Dandia, R. Singh, S. Khaturia, C. M e´ rienne, G. Morgant, A. Loupy,
Bioorg. Med. Chem. 14 (2006) 2409–2417.
0
3
Ar–H), 9.26 (s, 1H, NH), 10.23 (bs, 2H, pyridine NH);
.54 (s, 3H, OCH ), 4.81 (s, 1H, C–7 H), 6.96–7.89 (m, 11H
1
3
9
F
1
3
[8] K.C. Joshi, R. Jain, P. Chand, Heterocycles 23 (1985) 957–996.
NMR (CDCl ): d = ꢀ63.94 (s, CF ); C NMR (DMSO-d6):
3
3
[
9] (a) R.K. Rawal, V.R. Solomon, Y.S. Prabhakar, S.B. Katti, E. De Clercq,
0
d = 58.2 (C-10 ), 85.3 (spiro carbon), 108.9–142.3 (aromatic
carbons), 163.2 (C N), 166.3 (NH–C O); Anal. Calcd for
C H N O S : C, 63.91; H, 4.95; N, 11.47. Found: C, 63.84;
Comb. Chem. High Throughput Screening 8 (2005) 439–443;
¨
b) N. Ulusoy, N. Ergen c¸ , A.C. Ekinci, H. Ozer, Monatsh Chem. 127
(
(1996) 1197–1202.
2
6 24 4 2 2
[
[
[
10] P.D. Mehta, N.P.S. Sengar, E.V.S. Subrahmanyam, D.D. Satyanarayana,
H, 4.86; N, 11.41.
Indian J. Pharm. Sci. 68 (2006) 103–106.
¨
¨
11] N. Ergen c¸ , G. C¸ apan, N.S. G u¨ nay, S. Ozkirimli, M. G u¨ ng o¨ r, S. Ozbey, E.
Kendi, Archiv der Pharmazie 332 (1999) 343–347.
4
.14. In vitro antifungal susceptibility testing
12] (a) A. Dandia, S. Khanna, K.C. Joshi, J. Indian Chem. 30B (1991) 469–
472 (and reference there in);
The broth microdilution test [23] was used for the
(
b) R. Filler, Chem. Tech. 4 (1974) 752–756.
13] (a) H.M. Hassneen, T.A. Abdallah, Molecules 8 (2003) 333–341;
b) B.C. Bishop, H. Marley, P.N. Preston, S.H.B. Wright, J. Chem. Soc.,
assessment of in vitro antifungal activity of the synthesized
compounds against Candida albicans ATCC 44859 (CA),
Candida tropicalis 156 (CT), Candida krusei E28 (CK),
Candida glabrata 20/I (CG), Trichosporon beigelii 1188 (TB),
Aspergillus fumigatus 231 (AF), Absidia corymbifera 272 (AC)
and T. mentagrophytes 445 (TM). Fluconazole was used as a
reference drug. The procedure was performed with two-fold
dilution of the compounds in RPMI 1640 medium (Seva-
pharma) buffered to pH 7.0 with 0.165 mol of 3-morpholino-
propane-1-sulfonic acid. The final concentrations of the
[
[
(
Perkin Trans. 1 (1999) 1527–1532.
14] (a) J.B. Medwid, R. Paul, J.S. Baker, J.A. Brockman, M.T. Du, W.A.
Hallett, J.W. Hanifin, R.A. Hardy, J. Med. Chem. 33 (1990) 1230–1241;
(
(
b) S.P. Singh, S.S. Parmar, K. Raman, V.I. Stenberg, Chem. Rev. 81
1981) 175–203.
[
15] (a) A. Loupy, Microwaves in Organic synthesis, Wiley-VCH, Weinheim,
006;
b) C.O. Kappe, A. Stadler, Microwaves in Organic and Medicinal
Chemistry, Wiley-VCH, Weinheim, 2005;
c) A. De La Hoz, A. Diaz-Ortiz, A. Moreno, Chem. Soc. Rev. 34 (2005)
64–178;
d) A.K. Bose, M.S. Manhas, S.N. Ganguly, A.H. Sharma, B.K. Banik,
Synthesis 11 (2002) 1578–1591;
e) M. Jeselnik, R.S. Varma, S. Polanc, M. Kocevar, Green Chem. 4
(2002) 35–38;
2
(
ꢀ
1
(
compounds ranged from 500 to 0.975 mmol l . Drug-free
controls were included. The minimal inhibitory concentrations
1
(
(
MICs) were determined after 24 and 48 h of static incubation
at 35 8C. With T. mentagrophytes, the final MICs were
determined after 72 and 120 h of incubation. The results of
all compounds in vitro tested against T. mentagrophytes, the
most susceptible fungal strain, are summarized in Table 2.
(
¨
(
f) P. LidstrOm, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57 (2001)
225–9283.
16] (a) S.A. Galema, Chem. Soc. Rev. 26 (1997) 233–238;
b) M. Larhed, C. Moberg, A. Hallberg, Acc. Chem. Res. 35 (2002) 717–
27;
c) A. Lew, P.O. Krutzik, M.E. Hart, J. Comb, Chemistry 4 (2002) 95–
05.
9
[
[
(
4
.15. Antimycobacterial assay
7
(
1
Antimycobacterial evaluation was carried out at the
17] (a) K. Arya, M. Agarwal, Bioorg. Med. Chem. Lett. (2006), doi:10.1016/
j.bmcl.2006.09.082;
Tuberculosis Antimicrobial Acquisition and Coordinating
Facility (TAACF), Southern Research Institute, Birmingham,
AL, USA, which is a part of the National Institutes of Health
(
(
b) K. Arya, A. Dandia, N. Dhaka, N. J. Chem. Res. (2006) 192–198;
c) A. Dandia, K. Arya, M. Sati, P. Sarawgi, A. Loupy, Arkivoc (2005)
(
NIH). Primary screening of all compounds was conducted at
105–113;

K. Arya, A. Dandia / Journal of Fluorine Chemistry 128 (2007) 224–231
231
(
d) A. Dandia, K. Arya, M. Sati, S. Gautum, Tetrahedron 60 (2004) 5253–
258;
e) A. Dandia, K. Arya, M. Sati, P. Sarawgi, J. Fluorine Chem. (2004)
273–1277;
f) A. Dandia, M. Sati, K. Arya, R. Sharma, A. Loupy, Chem. Pharm.
Bull. 50 (2003) 1137–1141;
g) A.Dandia,M.Sati,K.Arya,A.Loupy,Heterocycles60(2003)563–569.
[21] (a) G.B. Grippa, S. Pietra, Collect. Czech. Chem. Commun. 81 (1951)
195–198;
5
(
(b) M.J. Kallmeyar, Arch. Pharm. 308 (1975) 742;
(c) F.D. Popp, J. Heterocycl. Chem. 11 (1974) 79–82.
[22] G.P. Kondratenko, N.I. Geonya, S.N. Baranov, B.E. Zhitar, V.E. Kono-
nenko, Khim. Farm. Zh. 9 (1995) 26;
1
(
(
G.P. Kondratenko, N.I. Geonya, S.N. Baranov, B.E. Zhitar, V.E. Kono-
nenko, Chem. Abstr. 112 (1996) 74526e.
[
[
18] A.K. Bose, B.K. Banik, M.S. Manhas, M. Jayaram, N. Lavlinskaiai,
Chem. Tech. (1997) 18–23.
19] (a) A. Dandia, R. Singh, C. M e´ rienne, G. Morgant, A. Loupy, Sulfur Lett.
[23] National Committee for Clinical Laboratory Standards: Reference
Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts:
Proposed Standard M 27-P, National Committee for Clinical Laboratory
Standards, Villanova, PA, 1992.
2
6 (2003) 201–206;
b) A. Dandia, R. Singh, K. Arya, Phosphorus Sulfur Silicon 179 (2004)
51–563.
(
5
[24] http://www.taacf.org/about-TAACF.htm, 19 July, 2005.
[25] L. Collins, S.G. Franzblau, Antimicrob. Agents Chemother. 41 (1997)
1004–1008.
[
20] M. Dolezal, J. Hartl, A. Lycka, V. Buchta, Z. Odlerova, Collect. Czech.
Chem. Commun. 61 (1996) 1102–1108.