Regioselective Synthesis of Mono- and Dispiropyrazoline Derivatives via 1,3-dipolar Cycloaddition with Nitrilimines

Article abstract of DOI:10.1002/jhet.2684

The 1,3-dipolar cycloaddition reaction of (E,E)-1,3-bis(arylidene)indan-2-one 1a, 1b, 1c, 1d, 1e with diarylnitrilimines, generated in situ via dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a, 2b, 2c, affords predominantly monospiropyraz

Full text of DOI:10.1002/jhet.2684

Month 2016 Regioselective Synthesis of Mono- and Dispiropyrazoline Derivatives via
1,3-dipolar Cycloaddition with Nitrilimines
a
a
a
b
c
c
*
Fadwa Rouatbi, Chourouk Mhiri, Moheddine Askri, Michael Knorr, Yoann Rousselin, and Marek M. Kubicki
aDepartment of Chemistry, Faculty of Science, Laboratory of Heterocyclic Chemistry Natural Products and
Reactivity/LCHPNR-LR11ES39, 5000 Monastir, Tunisia
bInstitut UTINAM - UMR CNRS 6213, Université de Franche-Comté, 16 Route de Gray 25030 Besançon, France
cInstitut de Chimie Moléculaire-UMR CNRS 6302, Université de Bourgogne, 9 Avenue A. Savary 21078 Dijon, France
*
E-mail: moheddine.askri@fsm.rnu.tn
Received January 29, 2016
DOI 10.1002/jhet.2684
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
The 1,3-dipolar cycloaddition reaction of (E,E)-1,3-bis(arylidene)indan-2-one 1a–e with diarylnitrilimines,
generated in situ via dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a–c, affords predom-
inantly monospiropyrazolines 3 and 4 as a mixture of diastereoisomers. Also dispiropyrazolines 5 are formed
in moderate yields. The structure and stereochemistry of cycloadducts 3–5 were confirmed by 1H and
13C-NMR spectroscopy, elemental analyses data, and single-crystal X-ray diffraction studies of 3ba and 5ca.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
known, we tried to improve the yield were by synthesizing
them for the first time by condensation of the appropriate
aryl aldehydes and 2-indanone in using gaseous HCl as
catalyst (Scheme 1). In order to optimize the reaction
conditions, various aryl aldehydes with different substitu-
ent were explored (Table 1). Whereas no reaction occurred
with o-substituted aryl aldehydes, very satisfying results
were obtained using p-aryl aldehydes in Et2O, providing
the (E,E)-1,3-bis(arylidene)indan-2-ones 1a–e in excellent
yields up to 92% (Table 1). The (E,E) configuration of
Considerable attention has been focused on the synthesis
of functionalized pyrazolines because of their interesting
biological activities such as antiepileptic [1], antidepres-
sant [2–4], anti-inflammatory [5], antimicrobial [6], antitu-
bercular [7], and anticancer properties [8] (Fig. 1).
As fluorescent compounds, pyrazoline derivatives may
also show interesting photophysical properties [9,10]. On
the other hand, several indan-2-ones derivatives have been
recently screened for anticancer activities [11]. It therefore
appeared interesting to combine the potential biological
activity of a pyrazoline core with those of an indan-2-one
in a common scaffold.
In the continuation of our work on 1,3-dipolar cycload-
dition reactions [12–14], we therefore investigated the
possibility to construct this targeted scaffold via 1,3-
dipolar cycloaddition using (E,E)-1,3-bis(arylidene)indan-
2-ones across diarylnitrilimines. Note that the use of
diarylnitrilimines in cycloaddition across alkenes and other
dipolarophiles allowing the construction of N-heterocyclic
systems is well documented in the literature [15–18].
We were particularly interested in the regio-selective
and stereo-selective aspects of the cycloaddition process
and the potential microbiological activity of the resulting
pyrazoline derivatives [19–24].
1
1a–e were assigned based on their H-NMR spectra, in
accordance with previous literature data [11].
First, we tried to find for our study on the 1,3- dipolar
cycloaddition reaction of dipolarophiles 1c and 1d with
diarylnitrilimines, generated in situ via dehydrohalogenation
of the corresponding hydrazonoyl chloride 2a and 2c, the
suitable solvent and reaction temperature in different
solvents. As shown in Table 2, dichloromethane in the
presence of Et3N was the most appropriate solvent.
Thus, performing the reaction of an equimolar
mixture of (E,E)-1,3-bis(arylidene)indan-2-ones 1a–e with
diarylnitrilimines at room temperature for 12h afforded
diastereoisomeric mixtures of monocycloadducts 3 and 4
according to Scheme 2 and Table 3. Upon workup and
chromatographic separation, the pure compound were
isolated as orange solids by crystallization from ethanol.
The structure and composition of cycloadducts 3 and 4
has been elucidated using different spectroscopic techniques
as well as by elemental analyses. The respective regiochemistry
of the isomers 3 and 4 was deduced by 1H-NMR spectros-
copy. Compounds 3 and 4 display a singlet because of
hydrogen H4 at δ 4.93 ppm and δ 4.76ppm, respectively.
RESULTS AND DISCUSSION
Although some of the required dipolarophiles (E,E)-
1,3-bis(arylidene)indan-2-ones 1a–e are already literature-
© 2016 Wiley Periodicals, Inc.

F. Rouatbi, C. Mhiri, M. Askri, M. Knorr, Y. Rousselin, and M. M. Kubicki
Vol 000
Figure 1. Selected bioactive compounds containing the spiropyrazoline motif. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Scheme 1
Scheme 2 [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
Table 1
Effect of the substituent on acid-catalyzed condensation reactions of
indan-2-ones with aryl aldehydes.
signals of the suggested structures. Thus, the signal for C4
appears at δ 65.7ppm and δ 63.1ppm, respectively; the qua-
ternary spirocarbons C3 /5 resonate at δ 82.8ppm and δ
80.0ppm. These chemical shifts are in agreement with our
earlier studies and the literature data [25,26].
Entry
Solvent
Ar1
Yield (%)
1
2
3
4
5
6
7
8
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
p-O2NC6H4
p-FC6H5
p-FC6H5
m-CH3OC6H4
p-CH3OC6H4
o-FC6H4
5-Br-2-HOC6H3
o-NCC6H4
92
64
75
trace
84
NR
NR
NR
The appearance of this signal at the mentioned chemical
shift value region is consistent with many similar previously
reported structures, supporting the assigned regioisomeric
form [27–30]. The IR spectra of compounds 3 contain absorp-
tion bands at around 1690 cmꢀ1 and 1325cmꢀ1 which are
assigned to the C¼O and C¼N ring stretching vibrations.
NR, no reaction.
This hydrogen is shielded by the magnetic anisotropy effect
of the carbonyl group of the indan-2-one cycle in 4 (Fig. 2).
The 13C-NMR spectra of 3 and 4 display the characteristic
Final proof concerning the relative stereochemistry of one
of the products, namely 3ba, stems from the data of a single-
crystal X-ray diffraction study. The relative configuration of
Table 2
Optimization of the reaction conditiona.
Entry
Products
Solvent
Time (h)
Base
T (°C)
Yield (%)
1
2
3
4
5
6
7
3ca/4ca
3ca/4ca
3ca/4ca
3dc/4dc
3dc/4dc
3dc/4dc
3dc/4dc
Toluene
Dichloromethane
Dichloromethane
Acetonitrile
Toluene
Ethanol
Dichloromethane
78
12
48
48
48
48
48
Et3N
Et3N
–
Et3N
–
25
25
reflux
25
reflux
25
reflux
64
73
63
45
50
52
Et3N
Et3N
b
–
aAll reactions were carried of equimolar (E,E)-1,3-bis(arylidene)indan-2-ones with hydrazonoyl chlorides in the presence of 1 mmol of Et3N.
bReaction failed to occur.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Regioselective Synthesis of Mono- and Dispiropyrazoline Derivatives via 1,3-
dipolar Cycloaddition with Nitrilimines
Table 3
Synthesis of mono-cycloadducts 3 and 4.
Entry
Products
Ar1
Ar2
Time (h)
Yieldsa (%)
Isomer ratiob (%)
1
2
3
4
5
6
7
8
3aa/4aa
3ab/4ab
3ac/4ac
3ba/4ba
3bb/4bb
3bc/4bc
3ca/4ca
3cb/4cb
3cc/4cc
3da/4da
3db/4db
3dc/4dc
3ea/4ea
3eb/4eb
3ec/4ec
C6H4
C6H4
C6H4
C6H4
12
10
24
12
20
24
12
14
24
15
24
12
24
24
20
74
80
62
51
58
51
73
57
55
54
58
54
65
58
65
61/38
80/8
p-CH3C6H4
p-CH3OC6H4
C6H4
p-CH3C6H4
p-CH3OC6H4
C6H4
p-CH3C6H4
p-CH3OC6H4
C6H4
p-CH3C6H4
p-CH3OC6H4
C6H4
62/10
75/24
63/47
62/37
54/26
64/35
54/29
66/33
58/41
47/33
52/47
58/41
62/37
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-O2NC6H4
p-O2NC6H4
p-O2NC6H4
9
10
11
12
13
14
15
p-CH3C6H4
p-CH3OC6H4
aCondition: equimolar mixture of hydrazonoyl chloride (1 eq), 1a–e (1 eq) and Et3N (1 eq) in CH2Cl2 at 25°C.
1
bThe relative isomer ratio was determined by analysis of the H-NMR spectrum of the crude reaction mixture.
Figure 3. Molecular structure of one enantiomer of 3ba present in the
asymmetric unit. Only the non-aromatic H atoms are shown. Selected
bond lengths (Å) and angles (°):C8–C9 1.348(3), N1–N2 1.397(2),
C16–N1 1.477(3), C24–N2 1.286(3), C16–C31 1.572(3)C17–O1 1.208
(2); N1–C16–C17 112.23(16), N2–C24–C31 114.27(18), N2–C24–C25
121.81(18), N1–C16–C31 101.88(16), N2–N1–C16 109.63(16),N2–
N1–C18 115.30(16),C24–N2–N1109.23(16). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
To prove whether the presence of the remaining C¼C
bond in 3 and 4 could be exploited for a second cycloaddition
reaction, we then explored the reaction between 1mmol of
dipolarophile 1a–e with 1.5 mmol hydrazonoyl chlorides
2a–c at ambient temperature in the presence of Et3N. Indeed,
the reaction afforded isomeric mixtures of the corresponding
monospiropyrazolines 3 and 4 along with smaller amounts of
dispiropyrazolines 5 (Scheme 3). The latter could be obtained
pure as yellow solid after chromatographic separation. The
results were summarized in Table 4. In order to improve
the percentage of 5, we increased also the ratio of dipole 2,
Figure 2. H4 hydrogen shielded by anisotropic effect of the carbonyl ring
of indan-2-one. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
the cycloadduct 3ba depicted in Figure 3 was determined to
be R for atoms C31 and C16. Because the space group (P21/
c), in which 3ba crystallizes bears the symmetry center, the
crystals are racemic.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. Rouatbi, C. Mhiri, M. Askri, M. Knorr, Y. Rousselin, and M. M. Kubicki
Vol 000
Scheme 3 [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 4
Synthesis of mono cycloadducts 3, 4, and 5.
Entry
Products
Ar1
Ar2
Time (h)
Yieldsa (%)
Product ratiob (%)
1
2
3
4
3ca/4ca/5ca
3cc/4cc/5cc
3dc/4dc/5dc
3ba/4ba/5ba
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
C6H4
12
24
12
12
50
55
54
51
54/26/19
54/29/16
47/33/18
62/24/12
p-CH3OC6H4
p-CH3OC6H4
C6H4
p-CH3C6H4
aCondition: hydrazonoyl chloride (1.5 eq), 1a–e (1 eq), Et3N (3 eq) in CH2Cl2 at 25°C.
bThe relative product ratios were determined by analysis of the 1H-NMR spectra of the crude reaction.
but unfortunately, no optimized yields were obtained because
of separation problems during workup.
The 1H-NMR spectra of dicycloadduct 5ca clearly
supports the proposed structures of these compounds.
The identical pyrazolines protons at H4 and H4 appear
as a singlet at δ 3.61ppm. This chemical shift value
region is consistent with many similar reported structures,
where the dipole molecules attack the olefinic linkages of
diene system in a regioselective manner from two
opposite faces [31,32]. The 13C-NMR of 5ca reveals
the pyrazoline methane carbons C4/4 as one signal at δ
58.9ppm and the spiro-carbons (C3 /5) and (C1 /5 ) at δ
81.5ppm. These observed values are quite close to
those reported previously for similar heterocyclic
structures [31,32]. As exemplified in the IR spectrum of
5ca, the presence of absorption bands at 1700 cmꢀ1 and
1325 cmꢀ1 is due to the C¼O and C¼N ring stretching
vibrations. The stereochemistry of the cycloadduct 5ca
was also corroborated by X-ray crystallography (Fig. 4).
The molecule of 5ca contains four asymmetric carbon
atoms (C14, C22, C29, and C31), but like in the case of
3ba, the crystals of 5ca are racemic, belonging to space
group P21/c (Table 5).
Based on the afore mentioned spectroscopic data, we
can conclude that the dipole approach to the correspond-
ing enones system of dipolarophile occurs from the
slightest crowded face with retention of initial configura-
tion E,E. Because of the stereospecificity of the reaction
[33], the 1,3-dipolar cycloaddition reaction of (E,E)-
1,3-bis(arylidene)indan-2-one with diarylnitrilimines
generates two new stereogenic centers through the
pathways illustrated in Scheme 4. The cycloadduct 3
resulting from endo-approach of the dipole toward the
Figure 4. Molecular structure of one enantiomer of 5ca. The CH2Cl2
molecules and aromatic hydrogen atoms are not shown. Selected bond
lengths (Å) and angles (°):N1–N2 1.397(2), N3–N4 1.401(2), C22–N1
1.495(2), C7–N2 1.288(2), C29–N3 1.494(2), C39–N4 1.281(2),
C30–O2 1.206(2); N1–C22–C14 101.02(13), N2–N1–C22 108.42(13),
N1–N2–C7109.28(15), N2–C7–C14 113.75(16), N2–N11–C1 115.03
(14), N4–N3–C29 107.85(14), N4–N3–C46 113.53(15), C39–N4–
N3–109.13(15), N3–C29–C31 100.71(13). [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
indanone carbonyl group is more favorable. The
examination of this structure reveals a cis-relationship
between the N-phenyl and the C¼O group of the
indanone ring. Conversely, the stereoisomer formed via
the exo approach is less favorable because of steric
repulsion between the phenyl groups of the indan-2-one
and the N-phenyl (Scheme 4).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Regioselective Synthesis of Mono- and Dispiropyrazoline Derivatives via 1,3-
dipolar Cycloaddition with Nitrilimines
Table 5
Crystal data, data collection, and structure refinement of 3ba and 5ca.
Compound/Formula
3ba/C38H30N2O.(2C2H5OH)
5ca/C51.5H41ClN4O3
Formula weight
Temperature/K
530.64
115(2)
799.33
115(2)
Wavelength/Å
0.71073
0.71073
Crystal system
Space group
Monoclinic
P21/c
Monoclinic
P21/c
a/Å
10.8886(4)
12.6591(4)
b/Å
c/Å
25.0852(12)
14.9067(6)
19.4349(6)
19.0356(6)
β/°
127.303(2)
3238.8(2)
120.767(2)
4024.1(2)
Volume/ Å3
Z
4
4
Density (calculated) g/cm3
Absorp. coefficient/mmꢀ1
F(000)
1.088
0.065
1120
1.319
0.146
1676
Crystal size/mm3
Theta range for data collection/°
Index ranges
0.25 × 0.20 × 0.10
2.06–27.52
ꢀ14 < = h < = 14,
ꢀ32 < = k < = 32,
ꢀ19 < = l < = 19
59,518
0.40 × 0.40 × 0.30
1.941–27.524
ꢀ16 < = h < = 16,
ꢀ25 < = k < = 25,
ꢀ24 < = l < = 24
170,115
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ (I)]
7431 [R(int) = 0.0740]
Full-matrix least-squares on F2
7431/0/372
1.041
9244 [R(int) = 0.0362]
Full-matrix least-squares on F2
9244/0/537
1.050
R1 = 0.0714,
wR2 = 0.1631
R1 = 0.1271,
wR2 = 0.1810
0.263 and ꢀ0.235
R1 = 0.0610,
wR2 = 0.1679
R1 = 0.0757,
wR2 = 0.1852
0.544 and ꢀ1.390
R indices (all data)
Largest diff. peak and hole/e. Åꢀ3
aeruginosa). The determination of the minimum inhibitory
concentration was performed as recommended by the
Comité de l’Antibiogramme from the French Society for Mi-
crobiology, the European Committee for Antimicrobial Sus-
ceptibility Testing, and Clinical and Laboratory Standards
Institute. The minimum inhibitory concentration corre-
sponds to the lowest concentration of “drug” inhibiting bac-
terial growth. To make these determinations, a technique
called “liquid-based micro method” (96-well U-fund) was
used. Unfortunately, it was noticed that all the tested com-
pounds seem completely inactive.
Scheme 4 Proposed transition states for the approach of enones (E,E) 1
across a nitrilimine. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
CONCLUSION
In conclusion, we have successfully developed the 1,3-
dipolar cycloaddition of diarylnitrilimines to enones 1a–f
affording novel spiropyrazolines. The [3 +2] cycloaddition
in a 1:1 ratio led to formation of monocycloadducts 3 and 4
in the form of two diastereoisomers. Raising the dipole ratio
allowed to activate the second C¼C bond of the dipolarophile,
yielding dicycloadducts 5 in moderate yields. Despite the dis-
appointing microbiological activity of these N-heterocycles,
further research is in progress to extend the scope of these re-
actions and to analyze/understand theoretically the approach
ANTIMICROBIAL ACTIVITY
Antimicrobial activity screening of the synthesized
compounds 3–5 was determined by the agar dilution
technique [34] utilizing a variety of Gram-positive bacteria
(Staphylococcus aureus, Enterococcus faecalis) and
Gram-negative bacteria (Escherichia coli and Pseudomonas
Journal of Heterocyclic Chemistry
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F. Rouatbi, C. Mhiri, M. Askri, M. Knorr, Y. Rousselin, and M. M. Kubicki
Vol 000
between dipole and dipolarophile by means of DFT comput-
ing. Notably the possibility to construct novel heterocyclic
systems by cycloaddition of other dipoles such as organic
azides RN3 on the remaining reactive C¼C bond of 3 and 4
appears as an interesting objective for future investigations.
model of the structure of 3ba is based on the “solvent re-
moved” data. Squeeze located two voids, centered at coor-
dinates ꢀ0.015, ꢀ0.000, ꢀ0.015 and ꢀ0.109, 0.500,
0.391, both with a volume of 297Å3, each of which large
enough to accommodate approximately 2 molecules of eth-
anol per asymmetric unit (assuming a non-hydrogen atom
volume of 18Å3). From each void, the program removed
the contribution of 99 electrons, corresponding to 99% of
the electrons of two ethanol molecules per asymmetric
unit. Consequently, the correct chemical formula of crys-
tallized 3ba contains two solvent (ethanol) molecules per
one cycloadduct organic molecule (Table 5).
Crystallographic data (CIF files) have been deposited
with the Cambridge Crystallographic Data Center:
deposition numbers CCDC 1447438 for 3ba and
1447439 for 5ca.These data may be obtained free of charge
from the Cambridge Crystallographic Data Center through
www.ccdc.cam.ac.uk/data_request/cif.
EXPERIMENTAL
Melting points were determined on a Kofler bank
(Herlev, Denmark). The IR spectra were recorded as KBr
pellets on a Perkin-Elmer 197 spectrometer (Waltham,
MA); only structurally significant bands are reported,1H-
NMR and 13C-NMR spectra were recorded on a Bruker
300MHz instrument (Billerica, MA) in CDCl3 using
TMS as an internal standard. Chemical shifts are given in
parts per million (d-scale). Materials: thin-layer chroma-
tography (TLC): TLC plates (Merck, silica gel 60F254
0.2mm 200 ×200 nm; Darmstadt, Germany).
The enones 1a–e were prepared by the following general
method [35], hydrogen chloride gas was passed into a
solution of indan-2-one and the appropriate aryl aldehyde
in Et2O. The most important method for the preparation
of aromatic hydrazonoyl halides is the triphenylphosphine-
carbon tetrachloride system transforms N-aryl-N-phenyl-
N -benzoyl hydrazines into the corresponding hydrazonoyl
chloride 2a–c [36].
SPECTRAL DATA
1,3-Bis(benzylidene)-indan-2-one (1a). Yellow powder,
mp 180–182°C; IR (KBr) 1694 cmꢀ1 (s, C¼O), 75%
1
Yield; H-NMR: δ 7.05–7.84 (m, 16H, Harom + Holefinic);
13C-NMR: δ 119.7, 123.0, 128.4, 128.5, 128.7, 129.1,
130.4, 131.3, 132.1, 132.5, 132.9, 133.4, 134.2, 134.5,
134.8, 136.4, 140.1, 192.4; Anal. Calcd. for C23H16O: C,
89.58; H, 5.23; Found: C, 89.60; H, 5.20.
X-RAY CRYSTALLOGRAPHY
1,3-Bis(Tolulylidene)-indan-2-one (1b). Yellow powder,
mp 184–186°C; IR (KBr) 1698 cmꢀ1 (s, C¼O), 60%
Yield; 1H-NMR: δ 2.45 (6H, s, CH3), 7.12–7.83 (m,
14H, Harom + Holefinic); 13C-NMR: δ 21.5, 122.8, 128.1,
128.5, 128.8, 131.9, 132.8, 136.7, 139.0, 194.0; Anal.
Calcd. for C25H20O: C, 89.25; H, 5.99; Found: C, 89.20;
H, 5.96.
The crystals of 3ba (orange) and of 5ca (yellow) have
been mounted on a Nonius Kappa Apex II diffractometer
(Madison, WI), and the intensity data have been collected
at 115 K with MoKα radiation of λ = 0.71073 Å (Table 5).
These data were further treated with the suite of SAINT
V8.27B (Bruker AXS Inc., Madison, WI, 2012) programs
and within the OLEX2 frame (Durham University, UK)
[37]. Models of both structures have been solved by direct
methods with SHELXS-97 [38] and refined with SHELXL-97
(Göttingen, Germany) [38]. All non-hydrogen atoms were
refined with anisotropic temperature factors. All H atoms
were placed in calculated positions and refined as riding
on the heavy atoms bearing them. The crystal structure of
3ba contains two solvent accessible voids in the unit cell,
one per asymmetric unit. In spite of numerous attempts,
no sensible solvent model could be established, and the
solvent (ethanol, solvent of crystallization) is assumed to
be chaotically disordered within the voids. The program
Squeeze [39] as implemented in Platon (Utrecht, The Neth-
erlands) [40] allows to mathematically subtract the contri-
bution of disordered solvent contained in voids within the
crystal lattice from the diffraction intensities. This proce-
dure was applied to the data file, and the actually submitted
1,3-Bis(anisylidene)-indan-2-one (1c).
Yellow powder,
mp 156–158°C; IR (KBr) 1698 cmꢀ1 (s, C¼O), 84%
Yield;1H-NMR: δ 3.90 (6H, s, OCH3), 6.96–8.13 (m,
14H, Harom + Holefinic); 13C-NMR: δ 55.4, 113.5, 113.9,
119.4, 123.0, 127.7, 128.5, 128.9, 128.7, 129.9, 130.9,
131.0, 132.9, 133.2, 133.9, 134.7, 137.2, 140.7, 160.5,
161.3, 192.6; Anal. Calcd. for C25H20O3: C, 81.50; H,
5.47; Found: C, 81.52; H, 5.52.
1,3-Bis(4-chlorobenzylidene)-indan-2-one (1d).
Yellow
powder, mp 182–184°C; IR (KBr) 1698 cmꢀ1 (s, C¼O),
83% Yield; 1H-NMR: δ 6.87–8.06 (m, 14H, Harom
+ Holefinic); 13C-NMR: δ 120.0, 123.4, 123.5, 128.4,
128.5, 128.9, 129.0, 129.7, 130.2, 131.5, 131.7, 132.0,
132.8, 133.1, 133.8, 134.2, 134.9, 136.0, 140.3, 192.3;
Anal. Calcd. for C23H14Cl2O: C, 73.22; H, 3.74; Found:
C, 73.27; H, 3.77.
1,3-Bis(4-nitrobenzylidene)-indan-2-one (1e).
Yellow
powder, mp 190–192°C; IR (KBr) 1697 cmꢀ1 (s, C¼O),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Regioselective Synthesis of Mono- and Dispiropyrazoline Derivatives via 1,3-
dipolar Cycloaddition with Nitrilimines
92% Yield; 1H-NMR: δ 6.81–8.06 (m, 14H, Harom
+ Holefinic); 13C-NMR: δ 119.9, 123.3, 123.5, 128.3,
128.5, 128.8, 129.3, 129.6, 130.0, 131.0, 131.7, 132.0,
134.0, 134.7, 136.0, 140.6, 192.3; Anal. Calcd. for
C23H14N2O5: C, 69.35; H, 3.54; N, 7.03; Found: C,
69.30; H, 3.50; N, 7.01.
131.7, 131.8, 131.9, 134.9, 136.1, 137.3, 138.3, 140.2,
143.5, 146.8, 204.5. Anal. Calcd. for C38H30N2O: C,
86.01; H, 5.70; N, 5.28; Found: C, 86.14; H, 5.73; N, 5.16.
Spiro[(1,3-diphenyl,4-(p-Tolyl)-4-hydro-Δ2-pyrazoline-5:3′)-
1′-(-Tolulylidene)-2′-indanone](3bb). Orange crystals, mp
140–142°C; IR (KBr): 1325cmꢀ1 (m, C¼N), 1688cmꢀ1
1
General procedure for the cycloaddition reaction of enones
(1a–e) with hydrazonoyl chloride 2a–d. A equimolar mixture
of dipolarophiles 1a–e (1 mmol) and the appropriate
hydrazonoyl chloride precursor 2a–d (1mmol) in dry
CH2Cl2 (10 mL), containing triethylamine (2 mL) was
stirred for the appropriate time. After completion of the
reaction as determined by TLC (Merck, Silica gel
60 F2540.2mm 200× 200mm); substances were detected
using UV light at 254 nm. The reaction mixture was
extracted with CH2Cl2, then the organic layer was dried
over MgSO4 and was washed with brine and concentrated
in vacuo. Spiroadducts were separated by column
chromatography on silica gel eluted with hexane/ethyl
acetate (20:80) to afford the corresponding 3, 4, and 5.
Spiro[(1,3,4-triphenyl-4-hydro-Δ2-pyrazoline-5:3′)-1′-(-
benzylidene)-2′-indanone](3aa). Orange crystals, mp 206–
208°C; IR (KBr): 1325 cmꢀ1 (m, C¼N), 1690cmꢀ1 (s,
(s, C¼O); H-NMR: δ 2.18 (s, 3H, CH3), 2.32 (s, 3H,
CH3), 2.44 (s, 3H, CH3), 5.05 (s, 1H, H-4), 6.73–7.80 (m,
22H, Harom +H olefinic); 13C-NMR: δ 20.5, 20.8, 21.1,
62.8, 79.4, 114.9, 120.2, 122.4, 126.7, 126.8, 128.4,
128.7, 128.9, 129.0, 129.4, 131.7, 131.8, 131.9, 134.9,
136.1, 137.3, 138.3, 140.2, 143.5, 146.8, 204.3. Anal.
Calcd. for C39H32N2O: C, 86.00; H, 5.92; N, 5.14; Found:
C, 86.04; H, 5.89; N, 5.16.
Spiro[(1-phenyl,3-(p-anisyl)-4-(p-tolyl)-4-hydro-Δ2-pyrazoline-
5:3′)-1′-(Tolulylidene)-2′-indanone](3bc). Orange crystals,
mp 120–122°C; IR (KBr): 1324cmꢀ1 (m, C¼N),
1
1689 cmꢀ1 (s, C¼O); H-NMR: δ 2.35 (s, 3H, CH3), 2.37
(s, 3H, CH3), 3.85 (s, 3H, OCH3), 5.05 (s, 1H, H-4),
6.67–7.82 (m, 22H, Harom + H olefinic); 13C-NMR: δ 20.8,
54.5, 54.9, 67.0, 79.3, 113.5, 114.0, 119.3, 123.1, 126.1,
126.6, 128.0, 128.3, 128.5, 129.7, 130.4, 132.8, 135.3,
142.5, 146.0, 158.7, 160.2, 201.6. Anal. Calcd. for
C39H32N2O3: C, 83.54; H, 5.75; N, 5.00; Found: C,
83.26; H, 5.58; N, 4.97.
1
C¼O), H-NMR: δ 5.07 (s, 1H, H-4), 6.82–7.68 (m, 25H,
H
arom +Holefinic); 13C-NMR: δ 63.4, 79.9, 115.1, 122.5,
126.7, 127.7, 128.4, 128.7, 129.1, 129.7, 131.5, 134.8,
138.3, 146.5, 203.1. Anal. Calcd. for C36H26N2O: C, 86.03;
H, 5.21; N, 5.57; Found: C, 86.00; H, 5.23; N, 5.55.
Spiro[(1,3-diphenyl,
4-(p-anisyl)-4-hydro-Δ2-pyrazoline-
5:3′)-1′-(anisylidene)-2′-indanone](3ca).
Orange crystals,
mp 155–157°C; IR (KBr): 1325cmꢀ1 (m, C¼N),
Spiro[(1,4-diphenyl,3-(p-tolyl)-4-hydro-Δ2-pyrazoline-5:3′)-
1′-(-benzylidene)-2′-indanone](3ab). Orange crystals, mp
182–184°C; IR (KBr): 1327 cmꢀ1 (m, C¼N), 1688 cmꢀ1
1688 cmꢀ1 (s, C¼O); H-NMR: δ 3.53 (s, 3H, OCH3),
1
3.76 (s, 3H, OCH3), 5.06 (s, 1H, H-4), 6.61–7.66 (m,
23H, Harom +Holefinic); 13C-NMR: δ 55.0, 55.4, 67.3,
80.1, 113.7, 113.9, 114.6, 115.0, 122.1, 126.7, 127.0,
128.5, 128.7, 130.4, 131.1, 133.8, 134.7, 158.9, 161.2,
203.5. Anal. Calcd. for C38H30N2O3: C, 81.12; H, 5.37;
N, 4.98; Found: C, 80.32; H, 5.34; N, 4.94.
1
(s, C¼O); H-NMR: δ 2.30 (s, 3H, CH3), 5.04 (s, 1H,
H-4), 6.71–7.68 (m, 24H, Harom + Holefinic); 13C-NMR: δ
20.8, 63.0, 79.4, 114.4, 119.7, 122.0, 126.2, 127.8, 128.4,
128.6, 128.8, 129.2, 130.9, 134.2, 134.5, 135.3, 137.9,
138.0, 143.1, 146.2, 203.9. Anal. Calcd. for C37H28N2O :
C, 86.02; H, 5.46; N, 5.42; Found: C, 86.03; H, 5.35; N, 5.43.
Spiro[(1,4-diphenyl,3-(p-anisyl)-4-hydro-Δ2-pyrazoline-5:3′)-
Spiro[(1-phenyl,4-(p-anisyl)-3-(p-tolyl)-4-hydro-Δ2-pyrazoline-
5:3′)-1′-(anisylidene)-2′-indanone](3cb).
Orange crystals,
mp 160–162°C; IR (KBr): 1325cmꢀ1 (m, C¼N),
1
1′-(-benzylidene)-2′-indanone](3ac).
Orange crystals, mp
1688 cmꢀ1 (s, C¼O); H-NMR: δ 2.33 (s, 3H, CH3), 3.65
185–186°C; IR (KBr): 1325 cmꢀ1 (m, C¼N), 1690 cmꢀ1
(s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.07 (s, 1H, H-4),
6.69–7.85 (m, 22H, Harom + Holefinic); 13C-NMR: δ 20.8,
54.5, 54.9, 67.0, 79.3, 113.5, 114.0, 119.3, 123.1, 126.1,
126.6, 128.0, 128.3, 128.5, 129.7, 130.4, 132.8, 135.3,
142.5, 146.0, 158.7, 160.2, 201.6. Anal. Calcd. for
C39H32N2O3: C, 81.23; H, 5.59; N, 4.86; Found: C,
80.92; H, 5.44; N, 4.64.
1
(s, C¼O); H-NMR: δ 3.74 (s, 3H, OCH3), 4.99 (s, 1H,
H-4), 6.68–7.61 (m, 24H, Harom + H olefinic); 13C-NMR: δ
55.2, 63.6, 79.8, 114.8, 120.1, 122.5, 124.5, 126.8, 127.6,
128.2, 128.4, 128.7, 128.9, 129.3, 129.7, 131.4, 134.5,
134.8, 135.0, 135.8, 138.8, 143.7, 146.5, 159.9, 204.5.
Anal. Calcd. for C37H28N2O2: C, 83.43; H, 5.30; N, 5.26;
Found: C, 83.46; H, 5.42; N, 5.28.
Spiro[(1-phenyl,3,4-(p-anisyl)-4-hydro-Δ2-pyrazoline-5:3′)-
Spiro[(1,3-diphenyl,4-(p-Tolyl)-4-hydro-Δ2-pyrazoline-5:3′)-
1′-(-Tolulylidene)-2′-indanone](3ba). Orange crystals, mp
178–180°C; IR (KBr): 1325 cmꢀ1 (m, C¼N), 1690 cmꢀ1
1′-(anisylidene)-2′-indanone](3cc).
Orange crystals, mp
162–164°C; IR (KBr): 1324cmꢀ1 (m, C¼N), 1689cmꢀ1
1
(s, C¼O); H-NMR: δ 3.68 (s, 3H, OCH3), 3.80 (s, 3H,
1
(s, C¼O); H-NMR: δ 2.21 (s, 3H, CH3), 2.43 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 4.99 (s, 1H, H-4), 6.69–7.58
(m, 21H, Harom + Holefinic); 13C-NMR: δ 54.5, 54.7, 54.8,
67.3, 79.7, 112.8, 112.9, 113.4, 121.9, 123.4, 123.5,
126.6, 127.8, 129.6, 130.1, 130.8, 132.8, 135.0, 159.7,
CH3), 5.00 (s, 1H, H-4), 6.71–7.72 (m, 23H, Harom + H
olefinic); 13C-NMR: δ 21.0, 21.6, 63.1, 80.0, 114.9, 120.2,
122.4, 126.7, 126.8, 128.4, 128.7, 128.9, 129.0, 129.4,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

F. Rouatbi, C. Mhiri, M. Askri, M. Knorr, Y. Rousselin, and M. M. Kubicki
Vol 000
201.6. Anal. Calcd. for C39H32N2O4: C, 79.03; H, 5.44; N,
4.73; Found: C, 79.55; H, 5.32; N, 4.45.
Spiro[(1-phenyl,4-(p-nitrobenzyl)-3-(p-anisyl)-4-hydro-
Δ2-pyrazoline-5:3′)-1′-(p-nitrobenzylidene)-2′-indanone]
Spiro[(1,3-phenyl,4-(p-chlorobenzyl)-4-hydro-Δ2-pyrazoline-
(3ec).
Orange crystals, mp 180–182°C; IR (KBr):
1327 cmꢀ1 (m, C¼N), 1687cmꢀ1 (s, C¼O); H-NMR: δ
3.74 (s, 3H, OCH3), 4.98 (s, 1H, H-4), 6.23–8.45 (m,
21H, Harom +Holefinic); 13C-NMR: δ 53.1, 61.1, 80.1,
114.6, 120.6, 123.2, 123.8, 126.4, 126.5, 127.8, 128.0,
129.0, 129.4, 129.8, 130.5, 131.4, 131.7, 139.3, 141.1,
142.3, 145.3, 147.9, 148.1, 203.2. Anal. Calcd. for
C37H26N4O6: C, 71.58; H, 4.58; N, 8.79; Found: C,
71.36; H, 4.21; N, 8.82.
1
5:3′)-1′-(p-chlorobenzylidene)-2′-indanone](3da).
Orange
crystals, mp 158–160°C; IR (KBr): 1325 cmꢀ1 (m, C¼N),
1688 cmꢀ1 (s, C¼O); 1H-NMR: δ 4.59 (s, 1H, H-4),
6.27–8.06 (m, 22H, Harom + H olefinic); 13C-NMR: δ 65.5,
81.0, 119.9, 123.5, 126.3, 127.0, 128.6, 128.8, 129.3,
129.6, 130.0, 130.6, 131.0, 141.7, 145.4, 147.3, 148.2,
203.1. Anal. Calcd. for C36H24Cl2N2O: C, 75.66; H, 4.23;
N, 4.90; Found: C, 74.54; H, 4.23; N, 4.85.
Spiro[(1,3,1′′,3′′-tetraphenyl-4,4′′-hydro-Δ2-pyrazoline-3′:5,
Spiro[(1-phenyl,4-(p-chlorobenzyl)-3-(p-tolyl)-4-hydro-
Δ2-pyrazoline-5:3′)-1′-(p-chlorobenzylidene)-2′-indanone]
1′:5′′)-4,4′′-(p-anisyl)-2′-indanone](5ca).
Yellow crystals,
mp 280–282°C; IR (KBr): 1325cmꢀ1 (m, C¼N),
(3db).
Orange crystals, mp 166–168°C; IR (KBr):
1
1700 cmꢀ1 (s, C¼O); H-NMR: δ 3.62 (s, 3H, OCH3),
1327 cmꢀ1 (m, C¼N), 1688 cmꢀ1 (s, C¼O); H-NMR: δ
2.24 (s, 3H, CH3), 4.96 (s, 1H, H-4), 6.66–7.38 (m, 21H,
Harom + Holefinic); 13C-NMR: δ 21.3, 67.4, 80.4, 114.6,
115.1, 120.3, 122.6, 123.9, 124.8, 126.5, 128.5, 128.7,
128.8, 129.0, 129.3, 129.5, 130.4, 130.9, 131.2, 131.6,
132.0, 132.9, 133.2, 134.0, 135.5, 136.1, 138.6, 141.2,
143.2, 145.4, 146.3, 203.9. Anal. Calcd. for C37H26Cl2N2O:
C, 75.90; H, 4.48; N, 4.78; Found: C, 75.68; H, 4.96; N,
4.31.
1
3.49 (s, 1H, H-4/4 ), 6.13–7.44 (m, 17H, Harom);
13C-NMR: δ 54.7, 58.9, 81.5, 122.4, 123.8, 125.0, 126.1,
126.4, 127.8, 128.0, 128.3, 128.5, 131.0, 137.2, 145.5,
151.9, 158.8, 205.1. Anal. Calcd. for C51H40N4O3 : C,
80.93; H, 5.33; N 7.40; Found: C, 80.36; H, 5.33; N 7.67.
Spiro[(1,1′′-diphenyl-4,4′′-hydro-Δ2-pyrazoline-3′:5,1′:5′′)-3,
4, 3′′, 4′′-(p-anisyl)-2′-indanone](5cc). Yellow crystals, mp
284–286°C; IR (KBr): 1325cmꢀ1 (m, C¼N), 1710cmꢀ1
1
(s, C¼O); H-NMR: δ 3.66 (s, 1H, H-4/4 ), 3.90 (s, 3H,
Spiro[(1 phenyl,4-(p-chlorobenzyl)-3-(p-anisyl)-4-hydro-
Δ2-pyrazoline-5:3′)-1′-(p-chlorobenzylidene)-2′-indanone]
OCH3), 6.43–8.31 (m, 15H, Harom); 13C-NMR: δ 54.5,
54.8, 56.4, 81.5, 112.6, 113.5, 118.9, 122.5, 127.1,
127.3, 128.4, 128.5, 129.5, 130.7, 132.5, 133.0, 134.3,
140.2, 159.8, 160.8, 203.1. Anal. Calcd. for C53H44N4O5
: C, 77.92; H, 5.43; N, 6.86; Found: C, 77.90; H, 5.23;
N, 6.84.
(3 dc).
Orange crystals, mp 168–170°C; IR (KBr):
1325 cmꢀ1 (m, C¼N), 1687 cmꢀ1 (s, C¼O); H-NMR: δ
3.24 (s, 3H, CH3), 4.52 (s, 1H, H-4), 6.86–7.83 (m, 21H,
Harom + Holefinic); 13C-NMR: δ 53.3, 67.5, 80.4, 114.3,
115.1, 120.3, 122.6, 123.9, 124.5, 126.5, 128.5, 128.7,
128.8, 129.0, 129.3, 130.0, 130.4, 130.9, 131.2, 131.6,
132.2, 132.9, 133.2, 134.0, 135.1, 135.6, 136.1, 138.6,
141.2, 143.2, 145.4, 146.6, 203.1. Anal. Calcd. for
C37H26Cl2N2O2: C, 73.88, H, 4.36, N, 4.66, Found: C,
73.79, H, 4.45, N, 4.26.
1
REFERENCES AND NOTES
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Spiro[(1,3-phenyl,4-(p-nitrobenzyl)-4-hydro-Δ2-pyrazoline-
5:3′)-1′-(p-nitrobenzylidene)-2′-indanone](3ea).
Orange
crystals, mp 170–172°C; IR (KBr): 1325 cmꢀ1 (m, C¼N),
1689 cmꢀ1 (s, C¼O); 1H-NMR: δ 4.58 (s, 1H, H-4),
6.29–8.03 (m, 22H, Harom + Holefinic); 13C-NMR: δ 65.5,
81.1, 119.9, 123.3, 123.5, 126.3, 127.0, 128.6, 128.8,
129.3, 129.6, 130.0, 130.6, 131.0, 141.7, 145.4, 147.3,
148.2, 203.1. Anal. Calcd. for C36H24N4O5: C, 73.14; H,
4.48; N, 9.22; Found: C, 73.19; H, 4.67; N, 9.45.
Spiro[(1-phenyl,4-(p-nitrobenzyl)-3-(p-tolyl)-4-hydro-
Δ2-pyrazoline-5:3′)-1′-(p-nitrobenzylidene)-2′-indanone]
(3eb).
Orange crystals, mp 186–188°C; IR (KBr):
1325 cmꢀ1 (m, C¼N), 1688 cmꢀ1 (s, C¼O); H-NMR: δ
2.24 (s, 3H, CH3), 4.96 (s, 1H, H-4), 6.70–8.38 (m, 21H,
Harom + Holefinic); 13C-NMR: δ 62.6, 80.4, 114.9, 120.7,
123.4, 126.4, 126.6, 127.8, 128.9, 129.2, 129.5, 129.9,
130.6, 130.4, 131.0, 131.8, 139.3, 141.1, 142.8, 145.3,
147.4, 148.1, 202.8. Anal. Calcd. for C37H26N4O5: C,
73.42; H, 4.70; N, 9.01; Found: C, 73.40; H, 4.43; N, 9.24.
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Regioselective Synthesis of Mono- and Dispiropyrazoline Derivatives via 1,3-
dipolar Cycloaddition with Nitrilimines
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet