Solvent-free regioselective synthesis of novel isoxazoline and pyrazoline N-substituted saccharin derivatives under microwave irradiation

Article abstract of DOI:10.1007/s10593-016-1828-4

Novel isoxazoline and pyrazoline derivatives of N-substituted saccharin were synthesized in good yields by 1,3-dipolar cycloaddition of N-crotonoyl- or N-cinnamoylsaccharin as dipolarophile to arylnitrile oxides or nitrile imines using p-HAP300 as catalyst under solvent-free microwave conditions. In this process, the yields were significantly improved compared to classical conditions without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed.

Full text of DOI:10.1007/s10593-016-1828-4

DOI 10.1007/s10593-016-1828-4
Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
Solvent-free regioselective synthesis of novel isoxazoline
and pyrazoline N-substituted saccharin derivatives
under microwave irradiation
Aziza Saber1, Mohsine Driowya1, Soukaina Alaoui1, Hamid Marzag1,
Luc Demange2,3,4, Eleuterio Álvarez5, Rachid Benhida2, Khalid Bougrin1*
1 Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique,
URAC23, Université Mohammed V,
B. P. 1014 Rabat, Morocco; e-mail: kbougrin@yahoo.fr
2 Institut de Chimie de Nice, ICN, UMR 7272, Université Nice-Sophia Antipolis,
28 avenue de Valrose, 06108 Nice Cedex 2, France; e-mail: Benhida@unice.fr
3 Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Pharmaceutiques,
4 avenue de l’Observatoire, Paris 75006, France; e-mail: lucdemange@yahoo.ca
4 Université Paris Descartes, Sorbonne Paris Cité, UFR Biomédicale des Saints Pères,
45 rue des Saints Pères, Paris 75006, France
5 Instituto de Investigaciones Químicas, CSIC-Universidad de Sevilla,
Avda. Américo Vespucio, 49, Isla de La Cartuja, 41092 Sevilla, Spain
e-mail: ealvarez@iiq.csic.es
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(1), 31–40
Submitted October 8, 2015
Accepted after revision January 12, 2016
Novel isoxazoline and pyrazoline derivatives of N-substituted saccharin were synthesized in good yields by 1,3-dipolar cycloaddition of
N-crotonoyl- or N-cinnamoylsaccharin as dipolarophile to arylnitrile oxides or nitrile imines using p-HAP300 as catalyst under solvent-
free microwave conditions. In this process, the yields were significantly improved compared to classical conditions without alteration of
the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed.
Keywords: arylnitrile oxide, nitrile imine, catalysis, 1,3-dipolar cycloaddition, microwave irradiation, solvent-free.
Compounds containing five-membered heterocyclic ring
systems, such as isoxazoline and pyrazoline, continue to
attract considerable interest due to the wide range of their
biological activity. Isoxazoline derivatives have been
reported to possess antimicrobial,1,2 antituberculosis,3 anti-
inflammatory,4 antiviral,5 analgesic,6 antitumor,7 and anti-
thrombotic activities.8 Moreover, isoxazoline derivatives
have played an important role in the theoretical develop-
ment of heterocyclic chemistry and are also extensively
used as intermediates in organic synthesis.9 In similar way,
pyrazolines have been reported to exhibit a variety of
biological activities including anti-inflammatory,10 anti-
depressant,11 anticancer,12 analgesic,13 antioxidant,14 anti-
infective,15 antifungal,16 antihepatotoxic,17 antinocicep-
tive,18 and pesticidal properties.19 Furthermore, isoxazoline
and pyrazoline are commonly used as advanced inter-
mediates in organic synthesis or as basic scaffolds for
modular synthesis of bioactive compounds because of their
high chemical stability and their hydrogen-bonding
ability.5,10–12
Several procedures were reported for the synthesis of
such heterocycles. For example, isoxazolines are com-
monly prepared using 1,3-dipolar cycloaddition (1,3-DC)
of alkenes to nitrile oxides, generated in situ by dehydro-
halogenation of hydroxymoyl chlorides, or other cyclo-
condensation reactions.20 In a similar way, various methods
were reported for the synthesis of pyrazolines, such as the
reaction of α,β-unsaturated carbonyl compounds with
0009-3122/16/5201-0031©2016 Springer Science+Business Media New York
31

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
demonstrate the advantages obtained by the use of MW
irradiation compared to the conventional heating in the
synthesis of isoxazoline and pyrazoline adducts.
Synthesis of N-crotonoyl- and N-cinnamoylsaccha-
rins as dipolarophiles. Several methods of the N-acylation
of saccharin (1) have been described using either conven-
tional heating or microwave irradiation in dry media and
dimethylformamide as polar solvent. However, most of
them have resulted in poor yields and a long reaction time,
which could be ascribed in part to an inadequate solvent.29
In our work, we have carried out the synthesis of two
N-acylsaccharins containing an α,β-unsaturated acyl group
that could be used as dipolarophiles. The first reaction step
consisted in treatment of crotonic acid (2a) and cinnamic
acid (2b) with an excess of thionyl chloride without solvent
(Scheme 1).30 The corresponding acyl chlorides 3 and 4
were isolated in good yield after removal of the excess of
thionyl chloride at moderate temperature (35–40°C) under
reduced pressure (20 mmHg) to avoid the evaporation of
the product. The products 3 and 4 were used in the
subsequent step without additional purification. In the
second reaction step, the acylation of saccharin (1) with
acid chlorides 3 and 4 produced the desired dipolarophiles
5 and 6, respectively (Scheme 1).
Figure 1. Chemical structures of biologically active compounds
featuring N-substituted saccharin motif.
hydrazine or monosubstituted hydrazines.21 Other examples
based on 1,3-DC involving nitrile imines and alkenes have
been reported to access the functionalized pyrazolines.20a
However, all these reported procedures have their own
limitations. For example, the conventional heating of a
nitrile oxide or nitrile imine with an alkene in cycloaddition
reactions generally provide poor yields, side reactions, such
as the dimerization or polymerization of 1,3-dipole and
formation of by-products, poor regioselectivity, and a need
of costly catalysts to improve the reaction.22
Scheme 1
In continuation of our studies directed at the develop-
ment of new procedures for the synthesis of functionalized
heterocycles,23 we report here an efficient regioselective
synthesis of N-substituted saccharins, containing isoxazoline
and pyrazoline moieties, using cycloaddition reaction
between crotonamide dipolarophiles and nitrile oxide or
nitrile imine under solvent-free microwave conditions. We
chose to introduce saccharin moiety into the dipolarophile
structures because of its unique chemical and biological
properties.24 Indeed, as a key structural element, N-sub-
stituted saccharin fragment is present in several biolo-
gically active compounds, such as ipsapirone, WIN-63294,
supidimide, and repinotan (Fig. 1).25
The use of microwave activation in this case is moti-
vated by the fact that 1,3-DC involves a polar transition
state, which could make such reaction susceptible to MW
activation.26 Indeed, we recently reported several examples
of dipolar cycloadditions in which MW irradiation was
found to be extremely efficient in terms of yield, reaction
time, and regioselectivity.23e,g,27 The application of MW has
become a powerful technique to accelerate organic reac-
tions, the high heating efficiency giving significant rate
enhancement, remarkable reduction in reaction times, and
milder conditions.28 The aim of this work is also to
In our previous work,23d DMF has been found to be an
excellent solvent for the reaction of alkyl halides with
saccharin (1) in basic media. Recently, several reported
works have described the reaction of alkyl halides and
sodium alkoxide using DMF as a good solvent.31
However, in our study, phase-transfer catalysis (PTC)
combined with microwave irradiation was found to be an
excellent methodology for preparing N-crotonoyl- and
N-cinnamoylsaccharin derivatives 5 and 6 (method B,
Scheme 1). Indeed, the results were compared with those
obtained by conventional conditions (stirring at room
temperature, method A). Moreover, PTC under classical
condition has been successfully applied to the acylation of
NH groups of amides, sultams, and lactams.32 However,
this method provided the products in moderate yields and,
generally, an adequate control of both time and temperature
of the reaction.
32

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
Table 1. Effect of catalyst in the MW solvent-free synthesis
of isoxazoline 7a*
Oxidant–Catalyst
Time, min
T
MW**, °C
Yield, %
Figure 2. Molecular structure of N-cinnamoylsaccharin 6 with
–
4
4
3
3
4
122
118
115
113
120
–***
72
atoms represented as thermal vibration ellipsoids of 50% probability.
NCS–Al2O3
NCS–p-HAP300
p-HAP300
NCS–NP
80
The preparation of N-acylsaccharin derivatives 5 and 6
proved to be more efficient under microwave irradiation
(method B). It is worth noting that the reaction time was
remarkably shortened from 24 h (DMF–K2CO3 or THF–Et3N
at room temperature) to 90 s (K2CO3–Aliquat 336) under
PTC and microwave irradiation, and the yields were
improved from 78–87 to 95–97%. In addition, under
conventional heating at 95°C, the products 5 and 6 were
obtained in low yield (40%) after 1 h with a significant
degradation of the catalyst (Aliquat 336).
–***
56 (40)*4
* The reactions were performed under MW irradiation without solvent
using compound 5 (1.0 mmol) and benzaldoxime (1.2 mmol), NCS
(1.2 mmol, if applicable), and catalyst (1.0 g).
** Temperature at the end of the reaction (infrared detection and a digital
thermometric probe).
*** Incomplete reaction with unidentified products of degradation.
4
*
Yield of furoxan or 3,4-diphenyl-1,2,5-oxadiazole N-oxide (white
crystalline solid, mp 114–116°C (mp 114–117°C)36d).
The structures of products 3–6 were elucidated by
means of NMR spectroscopic techniques, IR spectra, and
mass spectrometry, in the case of product 6, also by single-
crystal X-ray diffraction analysis. Compound 6 crystallizes
from THF–H2O as colorless needles in the orthorhombic
Pbca space group. The asymmetric unit of this crystal
reveals a structure (Fig. 2) that differs from the one
described earlier33 for crystals of compound 6 obtained as
colorless prisms by crystallization from pure THF and that
crystallized in the monoclinic C2/c space group.
derivatives, products of dimerization of nitrile oxides, were
isolated, which is consistent with literature reports.36
Once the most suitable conditions have been found, we
extended the 1,3-DC reaction of dipolarophile 5 to other
arylnitrile oxides (Scheme 2). The reactions were carried
out in a single-mode cavity with focused MW irradiation
and were monitored by TLC (method D). For the purpose
of comparison, the reactions were carried out also under the
conventional conditions (method C). The results are
summarized in Table 2.
Synthesis of isoxazoline derivatives of saccharin via
1,3-dipolar cycloaddition. The dipolarophiles 5 and 6
were then treated with different arylnitrile oxides (gene-
rated in situ by the action of an oxidant34) under classical
conditions using aqueous sodium hypochlorite in biphasic
medium (method C) or under microwave activation using
NCS–Al2O3, NCS–p-HAP300 or NCS–natural phosphate
(NP) in dry media (Table 1). Under these conditions, the
best result for isoxazoline 7a was obtained with NCS–
p-HAP300 catalyst (method D). Recently we have reported
that hydroxyapatite p-HAP300 (Ca10(PO4)6(OH)2) is a
basic and efficient catalyst for the Knoevenagel
condensation.35b This catalyst was prepared according to
our previous reported procedure.35 Furthermore, the use of
p-HAP300 is particularly convenient for the 1,3-DC
reaction compared to alumina and NP, since the former is
efficiently recycled by simple heating at 300°C under
reduced pressure for 20 min. Excellent preservation of
basic capacity of the p-HAP300 catalyst was observed. The
catalyst was reused after seven cycles and the reactivity
was clearly conserved. We also performed the reactions
without oxidant or without both catalyst and oxidant under
both microwave and classical methods, and no reaction
products were observed even after a long reaction time.
With both methods C and D, dipolarophile 6 did not
undergo the cycloaddition reactions; instead, the furoxan
The isoxazoline products 7a–i were obtained in mode-
rate yields (37–48%) under classical conditions (two-phase
system, 18–24 h at 0–5°C), while rather high yields (80–
98%) were achieved with the use of the microwave
irradiation in a solvent-free system (3 min at 103–118°C).
No products 7a–i were isolated with classical heating under
same reaction conditions (3 min, final temperature, and
atmospheric pressure) determined under microwave irra-
diation.
In general, according to literature reports, the regio-
chemistry of 1,3-DC is governed by both steric and electro-
nic factors that often led to a mixture of two regioisomers.
It is noteworthy that in our case all cycloadditions with
various nitrile oxides and dipolarophile 5 afforded one
regioisomer (Scheme 2, Table 2), which was confirmed by
NMR spectra. For example, the 1H NMR spectrum of regio-
isomer 7a showed a doublet centered at 4.64 ppm for the
stereogenic center 5-CH and a multiplet at 2.44–2.51 ppm
for the 4-CH proton. The aromatic proton exhibited a
multiplet at 7.72–8.67 ppm. The 13C NMR spectrum of
compound 7a exhibited a signal at 12.2 ppm corresponding
to the CH3 carbon and two peaks at 46.1 and 71.3 ppm
assigned to the isoxazoline carbons C-5 and C-4. The C=N
and two carbonyl carbons resonated at 156.0, 166.7, and
173.2 ppm, respectively. This regiocontrolled process can
33

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
X
Scheme 2
X
N
O
O
N
Method
C or D
OH
N
H
X
X
O
N
O
O
N
N
S
O
S
O
5
O2
O2
X
Method C: NaOCl aq,
CH2Cl2, 0–5°C,
18–24 h
N
3
O
N
O
N
O
O
4
5
Me
N
Method D: NCS,
p-HAP300, MW,
103–118°C, 3 min
S
O
S
O
S
O
O2
O
O2
X
O
7a–i
O
N
O
N
X
Table 2. Synthesis conditions and yields of compounds 7a–i
Figure 4. Disfavored approach in the 1,3-DC of compound 6 to
nitrile oxides.
Microwave
Classical conditions
irradiation
Com-
pound
X
TMW**, °
Time, h Yield, %
Yield, %
C
It is important to note that the use of MW in this
cycloaddition reaction highly disfavored the dimerization
process of arylnitrile oxides, and this observation has been
rarely mentioned.23a,39 Finally, the structures of all cyclo-
H
4-Cl
4-NO2
3-NO2
4-MeO
4-Me
2,4,6-Me3
4-F
4-Me2N
2
2
1
1.5
1
1.5
1.5
1.5
2
38 (54)*
41
45
38
45
40
38
48
37
115
110
105
103
113
110
110
118
109
80
87
90
84
92
85
82
98
89
7a
7b
7c
7d
7e
7f
7g
7h
7i
adducts 7a–i were confirmed through H and 13C NMR,
1
MS, and IR analyses.
Synthesis of pyrazoline derivatives of saccharin via
1,3-dipolar cycloaddition. We have developed the synthe-
sis of novel N-substituted saccharin derivatives 8–11
containing pyrazoline moiety via 1,3-DC of some nitrile
imines (generated in situ by the action of base on the
hydrazonoyl halides40) with dipolarophiles 5 and 6 under
both microwave irradiation and conventional methods. The
reaction was carried out either by reflux in anhydrous THF
in the presence of triethylamine as base or under
microwave activation using p-HAP300 as solid support in
dry media. The reaction afforded, in each case, only one
isolated product as evidenced by TLC analysis (Scheme 3).
The end of the reaction was indicated by the appearance of
the pyrazolines 8–11 identified by their intense fluorescence
(λmax 365 nm). The obtained results are shown in Table 3.
Under solvent-free MW conditions, the four pyrazolines
8–11 were obtained as single regioisomers with good
yields (80–90%) within short reaction times (6–10 min).
They were also obtained under conventional reflux condi-
tions (8–24 h) in almost as good yields (70–88%). Similar
results were previously reported by our group when using
KF–Al2O3 or basic alumina as promoters under solvent-
free microwave conditions, for the in situ generation of
nitrile imines from hydrazonoyl halide.41 The structures of
all the pyrazolines 8–11 were established from their NMR,
MS, and IR data. For instance, the identity of the isomer of
compound 8 obtained was confirmed by its 1H NMR
spectrum, the one doublet of the proton 5-CH was observed
downfield at 5.28 ppm, trans-coupled to the proton 4-CH.
The observed deshielding of the proton 5-CH can be
explained by the electronegative substituent effects of the
pyrazoline nitrogen atom and the carbonyl group.
* Yield of the isolated furoxan.
** Temperature at the end of the reaction (infrared detection).
be explained by the highly disfavored steric hindrance
between the nitrile oxide and dipolarophile 5 as outlined in
Figure 3.37 Interestingly, no post-isomerization was observed
in contrast to the previously reported works.36c,38
Surprisingly, all reactions carried out under the same
conditions with dipolarophile 6 (X = H) did not work at all,
even at prolonged reaction times and forced conditions.
This result may be also explained by both unfavorable
steric (proximity of aryl and phenyl groups of nitrile oxide
and dipolarophile, respectively) and electronic factors
(repulsive interaction between the carbonyl of saccharin
and oxygen anion of nitrile oxide) as given in Figure 4. In
addition, we noticed during this work that the dipolarophile
6 has no reactivity in the cycloaddition reaction with nitrile
oxides, which could be ascribed to the highly disfavored
steric effects and the poor reactivity of compound 6 due to
the hyperconjugation.
Finally, to highlight the specific microwave effects, the
reactions for the synthesis of products 7a–i and 8–11 were
Figure 3. The control of regioselectivity by steric effects of the
1,3-DC of compound 5 to nitrile oxides.
34

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
Table 3. Synthesis conditions and yields of compounds 8–11
Scheme 3
Microwave irradiation Classical conditions
Compound
Time, TMW*, Yield**, Time, Yield, Yield**,
min
6
°C
%
h
%
%
140
90
11
88
10
Ph
Ph
O
N
O
N
Me
N
S
O
O
8
6
142
115
120
89
87
80
8
75
76
70
10
8
10
10
24
24
Ph
Ph
Ph
O
N
O
N
N
S
O
O
10
5
carried out using a preheated oil-bath applied to the same
respective reaction mixtures for the similar time, pressure,
vial size, and temperature (as measured at the end of MW
irradiation) as those during the microwave experiments.
The products 8–11 were obtained with 5–10% isolated
yield under conventional heating conditions, which could
suggest that the effect of microwave irradiation is not
purely thermal. Indeed, the nonthermal MW effects can be
explained by considering the development of polarities
ground state and transition state. Indeed, as the polarity is
enhanced with the reaction progress, the dipole–dipole
stabilization by the electric field is increased and,
consequently, a positive MW effect is expected.23d,26a
In conclusion, we have reported an efficient and green
method for the synthesis of novel isoxazoline- and
pyrazoline-containing N-substituted saccharins using a
cooperative effect of solvent-free MW activation and
p-HAP300 catalysis. The process involves a regiospecific
[3+2] cycloaddition between N-crotonoyl or N-cinnamoyl-
saccharin as dipolarophile, obtained by the N-acylation of
saccharin under both classical heating and MW irradiation
conditions, to arylnitrile oxides and nitrile imines. The best
results were observed under MW irradiation and assigned
to the rapid heating and the specific MW effects. The total
regiocontrol of the 1,3-dipolar cycloaddition of nitrile
oxides and nitrile imines with dipolarophiles was not
altered by using MW irradiation as the source of energy,
compared to the classical conditions. Also we noticed that
the N-cinnamoyl saccharin did not take part in the
cycloaddition reaction with nitrile oxides, which could be
ascribed to the highly disfavored steric effects and the poor
reactivity of this dipolarophile due to the hyperconjugation.
* Temperature at the end of the reaction (infrared detection).
** Yield of isolated product obtained with classical heating under same
reaction conditions (10 min, final temperature, and atmospheric pressure)
as used under microwave irradiation for the synthesis of the same
product.
Experimental
IR spectra were recorded on a Bruker Vertex 70 instru-
ment in KBr pellets or neat between two NaCl plates.
1H and 13C NMR spectra were recorded on a Bruker
Avance 300 spectrometer (300 and 75 MHz, respectively)
using TMS as internal standard. Mass spectra were
recorded on a Brucker Daltonics Esquire 3000+ instrument
equipped with an atmospheric pressure ionization ion
source. High-resolution mass spectra were recorded on a
ThermoFisher
Q Exactive Plus Hybrid Quadrupole-
Orbitrap Mass Spectrometer using positive ion electrospray
ionization mode. The spectral data for compounds have
been performed at the 'UATRS (Unites d'Appui Technique
à la Recherche Scientifique)-CNRST, Rabat, Morocco.
Melting points were determined on a Kofler block and are
uncorrected. The reactions were monitored by TLC
performed on silica gel plates GF254. Spots on chromato-
grams were detected under UV light (254 nm and 365 nm)
and also by iodine vapors. Column chromatography was
carried out on Merck silica gel 60 (70–230 mesh). The
microwave-assisted reactions were carried out in a CEM
Discover, single-mode cavity with focused MW heating
(MW power supply 0–300 W in 1 W increments, IR
temperature sensor, open or closed vessel mode, pressure
range 0–20 bar, 10-ml or 80-ml vials). Starting materials,
reagents, and solvents were obtained from commercial
35

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
sources and used as received unless otherwise indicated.
7.98 (2H, d, J = 7.5, H Ar); 8.07 (1H, d, J= 16.0, 3-CH);
8.17 (1H, d, J = 7.6, H Ar). 13C NMR spectrum (CDCl3),
δ, ppm: 117.0; 121.0; 122.4 (C-2); 125.5; 126.7; 128.5
(2C); 129.0 (2C); 131.8; 134.0; 135.1; 137.0; 155.8 (C-3);
158.1; 161.5. Mass spectrum, m/z (Irel, %): 336 [M+Na]+
(100), 352 [M+K]+ (40), 649 [2M+Na]+ (12). Found, m/z:
314.0488 [M+H]+. C16H12NO4S. Calculated, m/z: 314.0480.
p-HAP300 catalyst was prepared by following the pro-
cedure reported in previous studies.35 The porous calcium
hydroxyapatite particles (p-HAP300) were prepared by a
modified chemical wet method reported elsewhere.35a
Ca(OH)2 (0.5 M) was dissolved in deionized water at 25°C
and mixed with a NH4H2PO4 (0.6 M) solution at room
temperature in a mixture of EtOH–H2O, 1:1. The reagents
were introduced at molar ratio Ca/P 1.67. The suspension
was aged for 12 h, filtered, and dried at 100°C overnight
and then heated under the flow of air for 3 h at 300°C in a
muffle furnace.
Synthesis of isoxazolines 7a–i (General method). C.
Conventional method. A mixture of N-crotonoylsaccharin 5
(0.25 g, 1.0 mmol) and arylaldoxime (1.2 mmol) was
dissolved in CH2Cl2 (15 ml). The solution was then cooled
to 0–5°C, and excess of 3.6% aqueous sodium hypochlorite
solution (15 ml) was added dropwise under vigorous
stirring for 18–24 h. The reaction was monitored by TLC.
After completion of the reaction, the organic phase was
separated and washed many times with water, then dried
over anhydrous sodium sulfate, filtered, and the solvent
was evaporated under reduced pressure. The residue was
purified by recrystallization from ethanol (products 7a,f,h)
or by column chromatography (products 7b–e,g,i) using
hexane–AcOEt, 8:2 or 6:4, as eluent.
D. Microwave synthesis. A mixture of N-crotonoyl-
saccharin 5 (0.25 g, 1.0 mmol) and arylaldoxime (1.2 mmol)
was dissolved in CH2Cl2 (20 ml) and added with stirring to
a mixture of NCS (0.16 g, 1.2 mmol) and p-HAP300 (1.0 g) at
room temperature. The mixture was first stirred at room
temperature for 2 min, and then the solvent was evaporated
under reduced pressure. The resulting solid residue was
irradiated by microwaves for 3 min to complete the
reaction (TLC). The progress of the reaction was monitored
by TLC. After completion of the reaction, the mixture was
cooled and the product was extracted by CH2Cl2 or
acetonitrile (2×10 ml). The catalyst was removed by
filtration and washed with CH2Cl2 or acetonitrile (10 ml),
and the solvent was evaporated under reduced pressure to
obtain the solid product. The crude product was purified by
recrystallization from EtOH or by column chromatography
using hexane–AcOEt, 8:2 or 6:4, as eluent. Isoxazoline
product 7a was obtained also by using various hetero-
geneous catalysts (NCS–Al2O3, NCS–p-HAP300 or NCS–NP)
and also in neat conditions (without catalyst) under micro-
wave irradiation.
Transfer of anhydrous solvents or mixtures was accomp-
lished with oven-dried syringes/septum techniques. THF
was distilled from sodium/benzophenone just prior to use
and stored under Ar. Other solvents were purified
by standard procedures. NP used in this work was
obtained in the Khouribga region (Morocco), and the
structure of the material is similar to that of fluoroapatite
(Ca10(PO4)6F2).42
N-Acylation of saccharin (1) (General method). A.
Conventional method. Freshly prepared acyl chloride 3 or 4
(1.1 mmol) and triethylamine (0.13 ml, 0.10 g, 1.0 mmol)
or potassium carbonate (0.14 g, 1.0 mmol) were added to
saccharin (1) (0.18 g, 1.0 mmol) in anhydrous THF or
DMF (8 ml), respectively. The mixture was stirred at room
temperature for 24 h. In the case of K2CO3–DMF, the
mixture was processed by ice water (5 times the volume),
and the formed solid precipitate was isolated by filtration
under vacuum. In the case of Et3N–THF, the solvent was
removed under vacuum, and the residue was dissolved in
CH2C12 (20 ml) and washed with water (2×20 ml), the
organic phase was dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The solid residue in all
cases was recrystallized from THF–H2O, 4:1.
B. Microwave synthesis. Saccharin (1) (0.18 g,
1.0 mmol) and acyl chloride 3 or 4 (1.0 mmol) were placed
in a pyrex tube (length 6 cm, diameter 2 cm). Then K2CO3
(0.14 g, 1 mmol) and Aliquat 336 (0.05 mmol) were added,
and the obtained mixture was activated by MW irradiation
for 90 s at 95°C. The residue was dissolved in CH2C12
(5 ml) and then filtered through a pad of Celite 545 to remove
Aliquat 336. The solvent was evaporated under reduced
pressure, and the residue was recrystallized from THF–
H2O, 4:1.
2-(But-2-enoyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(5). Yield 78% (method A, DMF–K2CO3), 78% (method A,
THF–Et3N), 95% (method B). White crystals. Mp 182–
184°C (THF). Rf 0.38 (hexane–AcOEt, 6:4). IR spectrum
(KBr), ν, cm–1: 3038 (CH3 ν), 1697 (C=C trans ν), 1626
(C=O σ), 1458 (CH3 σ as); 1362 (CH3 σ sy), 1357 (SO2 ν sy),
1325 (=C–H trans σ), 1056 (SO2 νas), 972 (=C–H trans δ).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.03 (3H, d,
J = 7.1, CH3); 7.07 (1H, d, J =15.2, 2-CH); 7.41–7.46 (1H,
m, 3-CH); 7.15–7.90 (4H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 18.9 (C-4); 122.4 (C-2); 126.3; 134.9;
135.8; 143.3; 151.0 (C-3); 157.7; 162.9 (C-1,3'). Mass
spectrum, m/z (Irel, %): 274 [M+Na]+ (100), 290 [M+K]+
(35), 541 [2M+K]+ (18). Found, m/z: 252.0331 [M+H]+.
C11H10NO4S. Calculated, m/z: 252.0326.
2-Cinnamoyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(6). Yield 87% (method A, DMF–K2CO3), 87% (method A,
THF–Et3N), 97% (method B). White crystals. Mp 234–
236°C (THF–H2O, 4:1) (mp 232–234°C, THF33a). Rf 0.30
(hexane–AcOEt, 6:4). IR spectrum (KBr), ν, cm–1: 1695
(C=C trans ν), 1694 (C=O σ), 1347 (SO2 ν sy), 1319 (=C–H
trans σ), 1036 (SO2 ν as), 997 (=C–H trans δ), 764–680
2-[(4-Methyl-3-phenyl-4,5-dihydroisoxazol-5-yl)-
carbonyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (7a).
Yellow crystals. Mp 115–117°C (hexane–Et2O, 4:1).
Rf 0.25 (hexane–AcOEt, 4:1). IR spectrum (KBr), ν, cm–1:
3063 (CH3 ν), 1769 (C=N σ), 1593 (C=O σ), 1328 (SO2 ν sy),
1
(=C–H 5H adj δ). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.43–7.58 (3H, m, H Ar); 7.70 (1H, d, J= 16.0,
1
2-CH); 7.65–7.78 (2H, m, H Ar); 7.92–7.95 (1H, m, H Ar);
1074 (ν SO2 as), 783–693 (=C–H 5H adj δ). H NMR
36

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.58 (3H, d, J = 7.1,
(28), 853 [2M+Na]+ (19). Found, m/z: 416.0560 [M+H]+.
C18H14N3O7S. Calculated, m/z: 416.0547.
CH3); 2.44–2.51 (1H, m, 4-CH); 4.64 (1H, d, J = 7.7,
5-CH); 7.72–7.81 (3H, m, H Ar); 7.95–8.02 (1H, m, H Ar);
8.13–8.34 (4H, m, H Ar); 8.59–8.67 (1H, m, H Ar).
13C NMR spectrum (CDCl3), δ, ppm: 12.2 (CH3); 46.1
(C-4); 71.3 (C-5); 126.1; 126.3; 126.5; 127.6 (2C); 127.9
(2C); 130.8; 131.0; 131.2; 132.7; 138.8; 156.0 (C=N
isoxazoline); 166.7 (C=O saccharin); 173.2 (C=O). Mass
spectrum, m/z (Irel, %): 393 [M+Na]+ (100), 763 [2M+Na]+
(10). Found, m/z: 371.0699 [M+H]+. C18H15N2O5S. Calcu-
lated, m/z: 371.0696.
2-{[3-(4-Methoxyphenyl)-4-methyl-4,5-dihydroisoxazol-
5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(7e). Viscous product. Rf 0.63 (hexane–AcOEt, 4:1).
IR spectrum (neat), ν, cm–1: 2959–2929 (CH3 ν), 1720
(C=N σ), 1607 (C=O σ), 1337 (SO2 ν sy), 1104 (SO2 ν as),
836 (=C–H 2H adj δ). 1H NMR spectrum (CD2Cl2), δ, ppm
(J, Hz): 1.14 (3H, d, J = 7.4, CH3); 2.00–2.08 (1H, m,
4-CH); 3.69 (3H, s, OCH3), 4.25 (1H, d, J = 7.7, 5-CH);
6.85–6.98 (2H, m, H Ar); 7.75–7.93 (5H, m, H Ar); 8.15–
8.20 (1H, m, H Ar). 13C NMR spectrum (CD2Cl2), δ, ppm:
13.5 (CH3); 45.5 (C-4); 60.0 (OCH3); 73.3 (C-5); 115.1;
126.4; 127.3; 127.5; 128.8 (2C); 128.9 (2C); 130.7;
132.2; 139.8; 140.5; 157.0 (C=N isoxazoline); 167.7 (C=O
saccharin); 174.2 (C=O). Mass spectrum, m/z (Irel, %): 423
[M+Na]+ (100). Found, m/z: 401.0815 [M+H]+. C19H17N2O6S.
Calculated, m/z: 401.0802.
2-{[3-(4-Chlorophenyl)-4-methyl-4,5-dihydroisoxazol-
5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(7b). Yellow crystals. Mp 165–167°C (hexane–CH2Cl2,
4:1). Rf 0.62 (hexane–AcOEt, 6:4). IR spectrum (KBr),
ν, cm–1: 2925 (CH3 ν), 1650 (C=N σ), 1590 (C=O σ), 1400
(SO2 ν sy), 1092 (SO2 ν as), 837 (=C–H 2H adj δ), 756
(C–Cl ν). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.59
(3H, d, J = 7.2, CH3); 2.48–2.55 (1H, m, 4-CH); 4.65 (1H,
d, J = 7.6, 5-CH); 7.80–7.89 (2H, m, H Ar); 7.97–8.14 (5H,
m, H Ar); 8.20–8.23 (1H, m, H Ar). 13C NMR spectrum
(CDCl3), δ, ppm: 11.0 (CH3); 45.2 (C-4); 71.0 (C-5); 125.2;
125.3; 125.6; 125.8; 126.7; 128.5 (2C); 129.9 (2C); 130.4;
134.4; 137.9; 156.0 (C=N); 166.7 (C=O saccharin); 173.2
(C=O). Mass spectrum, m/z (Irel, %): 427 [M+Na]+ (100),
831 [2M+Na]+ (15). Found, m/z: 405.0309 [M+H]+.
C18H14ClN2O5S. Calculated, m/z: 405.0305.
2-{[4-Methyl-3-(4-nitrophenyl)-4,5-dihydroisoxazol-
5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (7c).
Yellow solid. Mp 215–217°C (EtOH). Rf 0.79 (hexane–
AcOEt, 3:2). IR spectrum (KBr), ν, cm–1: 2875 (CH3 ν),
1700 (C=N σ), 1582 (C=O σ), 1526–1350 (C–NO2 ν), 1351
(SO2 ν sy), 1100 (SO2 ν as), 856 (=C–H 2H adj δ). 1H NMR
spectrum (CD2Cl2), δ, ppm (J, Hz): 1.50 (3H, d, J = 7.2,
CH3); 2.39–2.47 (1H, m, 4-CH); 4.56 (1H, d, J = 7.8,
5-CH); 7.40–7.51 (3H, m, H Ar); 7.62–7.73 (2H, m, H Ar);
7.96–8.19 (3H, m, H Ar). 13C NMR spectrum (CD2Cl2),
δ, ppm: 10.6 (CH3); 44.5 (C-4); 70.3 (C-5); 118.3; 125.4;
125.5; 125.7; 126.8; 128.6 (2C); 129.7 (2C); 130.5; 134.3;
137.2; 156.0 (C=N isoxazoline); 166.7 (C=O saccharin);
173.2 (C=O). Mass spectrum, m/z (Irel, %): 438 [M+Na]+
(100), 853 [2M+Na]+ (10). Found, m/z: 416.0557 [M+H]+.
C18H14N3O7S. Calculated, m/z: 416.0547.
2-{[4-Methyl-3-(4-methylphenyl)-4,5-dihydroisoxazol-
5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(7f). White crystals. Mp 142–144°C (hexane–MeOH, 4:1).
Rf 0.63 (hexane–AcOEt, 4:1). IR spectrum (KBr), ν, cm–1:
2994–2980 (CH3 ν), 1700 (C=N σ), 1591 (C=O σ), 1351
(SO2 ν sy), 1100 (SO2 ν as), 812 (=C–H 2H adj δ). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.15 (3H, d, J = 7.2,
CH3); 2.10–2.17 (1H, m, 4-CH); 2.45 (3H, m, CH3 Ar);
4.35 (1H, d, J =7.7, 5-CH); 7.10–7.22 (2H, m, H Ar); 7.69–
7.80 (2H, m, H Ar); 7.94–8.06 (3H, m, H Ar); 8.15–8.20
(1H, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 13.2
(CH3); 24.0 (CH3 Ar); 47.1 (C-4); 72.9 (C-5); 126.4; 127.1;
127.4; 127.6; 128.8 (2C); 129.0 (2C); 130.5; 132.2; 139.8;
140.5; 157.0 (C=N isoxazoline); 167.7 (C=O saccharin);
174.25 (C=O). Mass spectrum, m/z (Irel, %): 407 [M+Na]+
(100). Found, m/z: 385.0862 [M+H]+. C19H17N2O5S. Calcu-
lated, m/z: 385.0853.
2-[4-Methyl-3-(2,4,6-trimethylphenyl)-4,5-dihydro-
isoxazol-5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one
1,1-dioxide (7g). White crystals. Mp 135–137°C (hexane–
CH2Cl2, 9:1). Rf 0.61 (hexane–AcOEt, 4:1). IR spectrum
(KBr), ν, cm–1: 2994–2980 (CH3 ν), 1668 (C=N σ), 1589
(C=O σ), 1350 (SO2 ν sy), 1098 (SO2 ν as), 825 (=C–H δ).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.09 (3H, d,
J = 6.8, 4-CH3); 2.30 (3H, s, CH3); 2.45–2.52 (1H, m,
4-CH); 2.48 (6H, s, 2CH3); 4.44 (1H, d, J =7.5, 5-CH);
7.00 (2H, s, H Ar); 7.81–7.95 (3H, m, H Ar); 8.16–8.22
(1H, m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 16.8
(isoxazoline CH3); 21.1 (2CH3); 22.1 (CH3); 48.1 (C-4);
75.2 (C-5); 122.9; 123.0; 126.2; 127.5 (2C); 128.1 (2C);
134.5; 136.3; 136.6; 140.2; 140.5; 157.2 (C=N isoxazo-
line); 170.0 (C=O saccharin); 174.5 (C=O). Mass spectrum,
m/z (Irel, %): 435 [M+Na]+ (100). Found, m/z: 413.1170
[M+H]+. C21H21N2O5S. Calculated, m/z: 413.1167.
2-{[4-Methyl-3-(3-nitrophenyl)-4,5-dihydroisoxazol-
5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(7d). Yellowish solid. Mp 125–127°C (hexane–MeOH,
4:1). Rf 0.75 (hexane–AcOEt, 3:2). IR spectrum (KBr), ν, cm–1:
2994 (CH3 ν), 1700 (C=N σ), 1591 (C=O σ), 1534–1351
(C–NO2 ν), 1351 (SO2 ν sy), 1100 (SO2 ν as), 740, 835
1
(=C–H 3H adj δ). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 1.40 (3H, d, J = 7.3, CH3); 2.27–2.35 (1H, m,
4-CH); 4.45 (1H, d, J = 7.9, 5-CH); 7.40–7.45 (1H, m,
H Ar); 7.68–7.76 (2H, m, H Ar); 7.83–7.90 (2H, m, H Ar);
7.99–8.11 (2H, m, H Ar); 8.16–8.20 (1H, m, H Ar).
13C NMR spectrum (DMSO-d6), δ, ppm: 10.2 (CH3); 44.1
(C-4); 69.9 (C-5); 117.9; 124.9; 125.3; 125.5; 126.4; 128.2
(2C); 129.6 (2C); 130.0; 134.1; 137.6; 155.6 (C=N
isoxazoline); 166.3 (C=O saccharin); 172.8 (C=O). Mass
spectrum, m/z (Irel, %): 438 [M+Na]+(100), 454 [M+K]+
2-{[3-(4-Fluorophenyl)-4-methyl-4,5-dihydroisoxazol-
5-yl]carbonyl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(7h). Yellow crystals. Mp 110–112°C (hexane–CH2Cl2,
4:1). Rf 0.62 (hexane–AcOEt, 3:2). IR spectrum (KBr), ν, cm–1:
2930 (CH3 ν), 1680 (C=N σ), 1598 (C=O σ), 1402 (SO2 ν sy),
1
1096 (SO2 ν as), 838 (=C–H 2H adj δ). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.10 (3H, d, J = 7.8, CH3); 2.47–
37

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
2.55 (1H, m, 4-CH), 4.62 (1H, d, J = 8.1, 5-CH); 7.40–7.55
129.1; 129.3; 129.5; 131.5; 132.1; 132.3; 133.1; 141.5;
143.8; 154.0 (C=N pyrazoline); 169.8 (C=O saccharin);
176.3 (C=O). Mass spectrum, m/z (Irel, %): 468
[M+Na]+ (100), 484 [M+K]+ (24), 929 [2M+K]+ (5).
Found, m/z: 446.1174 [M+H]+. C24H20N3O4S. Calculated,
m/z: 446.1167.
(2H, m, H Ar); 7.78–7.96 (5H, m, H Ar); 8.17–8.23 (1H,
m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 11.5 (CH3);
46.2 (C-4); 73.2 (C-5); 120.2; 123.3; 125.0; 126.7; 128.0;
128.8 (2C); 129.5 (2C); 130.8; 135.6; 140.3; 160.7 (C=N);
165.2 (C–F); 170.0 (C=O saccharin); 174.5 (C=O
isoxazoline). Mass spectrum, m/z (Irel, %): 411 [M+Na]+
(100), 799 [2M+Na]+ (20). Found, m/z: 389.0609 [M+H]+.
C18H14FN2O5S. Calculated, m/z: 389.0603.
Methyl 5-[(1,1-dioxido-3-oxo-1,2-benzothiazol-2(3H)-
yl)carbonyl]-4-methyl-1-phenyl-4,5-dihydro-1H-pyrazole-
3-carboxylate (9). Viscous oil. Rf 0.65 (hexane–AcOEt,
4:1). IR spectrum (neat), ν, cm–1: 1635 (C=N σ), 1580
(C=O σ), 1456 (CH3 σas), 1364 (CH3 σ sy), 1331 (SO2 ν sy),
2-({3-[4-(Dimethylamino)phenyl]-4-methyl-4,5-dihydro-
isoxazol-5-yl}carbonyl)-1,2-benzisothiazol-3(2H)-one
1,1-dioxide (7i). Yellowish solid. Mp 212–214°C (EtOH).
Rf 0.73 (hexane–AcOEt, 3:2). IR spectrum (KBr), ν, cm–1:
2993–2981 (CH3 ν), 1670 (C=N σ), 1600 (C=O σ), 1349
(SO2 ν sy), 1097 (SO2 ν as), 830 (=C–H 2H adj δ). 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.11 (3H, d, J = 6.8,
CH3); 2.50–2.56 (1H, m, 4-CH); 3.03 (6H, s, N(CH3)2); 4.50
(1H, d, J = 7.7, 5-CH); 6.88–7.01 (2H, m, H Ar); 7.78–7.89
(2H, m, H Ar); 7.96–8.11 (3H, m, H Ar); 8.20–8.26 (1H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 17.9 (CH3);
40.1 (N(CH3)2); 47.4 (C-4); 75.2 (C-5); 112.9; 120.3; 122.5;
123.2; 127.5 (2C); 128.4 (2C); 136.3; 140.0; 140.2; 152.2;
160.2 (C=N); 169.5 (C=O saccharin); 173.8 (C=O). Mass
spectrum, m/z (Irel, %): 436 [M+Na]+ (100). Found, m/z:
414.1134 [M+H]+. C20H20N3O5S. Calculated, m/z: 414.1120.
Synthesis of pyrazolines 8–11 (General method). E.
Conventional method. Triethylamine (0.28 ml, 2.0 mmol)
was added to a solution of hydrazonoyl halide (2.0 mmol)
and dipolarophile 5 or 6 (2.0 mmol) in THF (10 ml) at
room temperature. The mixture was refluxed for 8–24 h
and then filtered. The mixture was dried over anhydrous
sodium sulfate and then filtered. The solvent was then
evaporated under vacuum to give dark-brown oil. The
crude product was purified by column chromatography
using hexane–AcOEt, 8:2 or 6:4, as eluent.
F. Microwave synthesis. A mixture of hydrazonoyl
halide (2.0 mmol) and dipolarophile 5 or 6 (2.0 mmol) was
dissolved in CH2Cl2 (20 ml), and the solution was added
with stirring to p-HAP300 (2 g) at room temperature. The
mixture was first stirred at room temperature for 2 min, and
the solvent was evaporated under vacuum, then the resulting
solid was exposed to microwave irradiation with a power
of 80 W to complete the reaction (as monitored by TLC).
The reaction mixture was cooled, removed from vial, and
washed with CH2Cl2 (2×20 ml). The organic solvent was
dried over anhydrous sodium sulfate and then filtered. The
solvent was then evaporated under vacuum to give a dark-
brown crude oil which was purified by column chromato-
graphy using hexane–AcOEt, 8:2 or 6:4, as eluent.
1
1073 (SO2 ν as), 705–638 (=C–H 5H adj δ). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.55 (3H, d, J = 7.5,
CH3); 3.18–3.24 (1H, m, 4-CH); 3.75 (3H, s, OCH3); 5.58
(1H, d, J = 7.3, 5-CH); 7.07–7.15 (1H, m, H Ar); 7.32–7.46
(3H, m, H Ar); 7.70–7.88 (4H, m, H Ar); 7.96–8.01 (1H,
m, H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 9.0 (CH3);
31.5 (C-4); 51.0 (OCH3); 58.6 (C-5); 118.1; 120.8; 122.9;
123.8; 127.6; 129.1; 134.2; 136.5; 141.5; 142.2; 153.6
(C=N pyrazoline); 164.7 (C=O ester); 169.7 (C=O
saccharin); 176.3 (C=O). Mass spectrum, m/z (Irel, %): 450.
[M+Na]+ (100), 466 [M+K]+ (31). Found, m/z: 428.0925
[M+H]+. C20H18N3O6S. Calculated, m/z: 428.0913.
2-[(1,3,4-Triphenyl-4,5-dihydro-1H-pyrazol-5-yl)-
carbonyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (10).
Viscous oil. Rf 0.65 (hexane–AcOEt, 6:4). IR spectrum (neat),
ν, cm–1: 1634 (C=N σ), 1581 (C=O σ), 1332 (SO2 ν sy), 1072
1
(SO2 ν as), 700–658 (=C–H 5H adj δ). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 3.10 (1H, d, J= 7.4, 4-CH); 5.27
(1H, d, J = 14.7, 5-CH); 7.26–7.75 (19H, m, H Ar). 13C NMR
spectrum (CDCl3), δ, ppm: 45.8 (C-4); 53.4 (C-5); 120.1;
123.4; 126.0; 127.9; 128.0; 128.2; 128.4; 128.5, 128.6;
128.7; 129.0; 130.0; 131.0; 131.9; 132.2; 133.0; 154.1
(C=N pyrazoline); 170.6 (C=O saccharin); 172.9 (C=O).
Mass spectrum, m/z (Irel, %): 530 [M+Na]+ (100), 546 [M+K]+
(15). Found, m/z: 508.1330 [M+H]+. C29H22N3O4S.
Calculated, m/z: 508.1324.
Methyl 5-(1,1-dioxido-3-oxo-2,3-dihydrobenzo[d]iso-
thiazole-2-carbonyl)-1,4-diphenyl-4,5-dihydro-1H-pyrazole-
3-carboxylate (11). Viscous oil. Rf 0.68 (hexane–AcOEt,
3:2). IR spectrum (neat), ν, cm–1: 1633 (C=N σ), 1580
(C=O σ), 1330 (SO2 ν sy), 1075 (SO2 ν as), 689–648 (=C–H
1
5H adj δ). H NMR spectrum ( CDCl3), δ, ppm (J, Hz):
3.68 (3H, s, OCH3); 4.27 (1H, d, J = 15.0, 4-CH); 5.24 (1H,
d, J = 7.0, 5-CH); 7.00–7.19 (3H, m, H Ar); 7.31–7.64 (7H,
m, H Ar); 7.82–7.97 (3H, m, H Ar); 8.16–8.22 (1H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 47.7 (C-4);
52.3 (CH3); 53.7 (C-5); 119.1; 120.3; 122.4; 124.0; 126.0;
127.8; 128.0; 128.4; 129.2; 134.5; 136.0; 140.2; 140.6;
143.8; 152.1 (C=N pyrazoline); 163.9 (C=O ester);
170.6 (C=O saccharin); 175.1 (C=O). Mass spectrum, m/z
(Irel, %): 512 [M+Na]+ (100), 528 [M+K]+ (23). Found,
m/z: 490.1081 [M+H]+. C25H20N3O6S. Calculated, m/z:
490.1070.
2-[(4-Methyl-1,3-diphenyl-4,5-dihydro-1H-pyrazol-
5-yl)carbonyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide
(8). Viscous oil. Rf 0.74 (hexane–AcOEt, 4:1). IR spectrum
(neat), ν, cm–1: 1635 (C=N σ), 1582 (C=O σ), 1456 (CH3 σ as),
1364 (CH3 σ sy), 1331 (SO2 ν sy), 1073 (SO2 ν as), 700–
1
634 (=C–H 5H adj δ). H NMR spectrum (CDCl3), δ, ppm
X-Ray structural analysis of compound 6. The
crystals were obtained by by slow evaporation of solution
of compound 6 in THF–H2O, 4:1, at room temperature in
open air. A crystal of suitable size for X-ray diffraction
analysis was coated with dry perfluoropolyether, mounted
(J, Hz): 1.30 (3H, d, J = 7.2, CH3); 3.12–3.18 (1H, m,
4-CH); 5.28 (1H, d, J = 7.1, 5-CH); 7.27–7.78 (14H, m,
H Ar). 13C NMR spectrum (CDCl3), δ, ppm: 8.9 (CH3);
30.8 (C-4); 53.4 (C-5); 20.1; 121.5; 123.5; 127.6; 128.5;
38

Chemistry of Heterocyclic Compounds 2016, 52(1), 31–40
14. Martins, D. M.; Torres, B. G.; Spohr, P. R.; Machado, P.;
on glass fiber, and fixed in a cold nitrogen stream (100 K)
to the goniometer head. Data collection was performed on a
Bruker-Nonius X8Apex-II CCD diffractometer, using
monochromatic radiation λ(MoKα) 0.71073 Å, by means
of ω- and φ-scans with a width of 0.50 deg. The data were
reduced (SAINT)43 and corrected for absorption effects by
the multiscan method (SADABS).44 The structures were
solved by direct methods (SIR-2002)45 and refined against
all F2 data by full-matrix least-squares techniques
Bonacorso, H. G.; Zanatta, N.; Martins, M. A.; Emanuelli, T.
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2
(SHELXTL-6.12)46 minimizing w(Fo –Fc2)2. All the non-
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hydrogen atoms were refined anisotropically, while C–H
hydrogen atoms were placed in geometrically calculated
positions using a riding model and refined with isotropic
temperature factors (Uiso values fixed at 1.2 times the Ueq
values of the corresponding attached carbon atoms). X-ray
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This work was funded by grants from the CNRST-
Morocco ''Centre National de la Recherche Scientifique et
Technique'' and the University Mohammed V of Rabat. It
was also supported by Egide PHC Toubkal (30330ZF,
MA/14/304), CNRS-France ''Centre National de la
Recherche Scientifique'' and UNSA ''University Nice-
Sophia Antipolis''. The authors would like to thank UATRS
''Unités d'Appui Technique à la Recherche Scientifique'' –
CNRST for spectral analysis.
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