Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3 + 2] cycloaddition

Article abstract of DOI:10.1007/s00706-018-2227-6

Abstract: 5-(Nitromethyl)-3-phenyl-4,5-dihydroisoxazole was obtained as a product of a high-yielding [3 + 2] cycloaddition reaction of in situ-generated benzonitrile N-oxide and 3-nitroprop-1-ene. For the first time, the regiochemistry of this reaction wa

Full text of DOI:10.1007/s00706-018-2227-6

Monatshefte für Chemie - Chemical Monthly (2018) 149:1877–1884
https://doi.org/10.1007/s00706-018-2227-6(0123456789(). -, vo Vl
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ORIGINAL PAPER
Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-
dihydroisoxazole via [3 + 2] cycloaddition
Barbara Mirosław1 Dmytro Babyuk2
•
•
Agnieszka Łapczuk-Krygier3 Agnieszka Ka˛cka-Zych3
•
•
Oleg M. Demchuk4 Radomir Jasinski
3
•
´
Received: 1 February 2018 / Accepted: 13 May 2018 / Published online: 20 August 2018
Ó The Author(s) 2018
Abstract
5-(Nitromethyl)-3-phenyl-4,5-dihydroisoxazole was obtained as a product of a high-yielding [3 ? 2] cycloaddition
reaction of in situ-generated benzonitrile N-oxide and 3-nitroprop-1-ene. For the first time, the regiochemistry of this
reaction was unambiguously proven by X-ray structural analysis. The quantum-chemical calculation performed at the
M06-2X/6-31G(d) (PCM) theoretical level affords a basis for explaining the course of reaction as well as the nature of
transition states. Next, further DFT calculations together with spectral data shed light on structural aspects of the product.
Graphical abstract
Keywords Isoxazole Á Nitrocompounds Á 3-Nitroprop-1-ene Á DFT calculations Á [3 ? 2] Cycloaddition
Introduction
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00706-018-2227-6) contains supplementary
material, which is available to authorized users.
4,5-Dihydroisoxazoles (D2-isoxazolines) are heterocycles
with many important practical applications. They are used
as parasiticidal agents in veterinary medicine [1] and b-
´
& Radomir Jasinski
radomir@chemia.pk.edu.pl
adrenergic agonists [2]. Some of D2-isoxazolines exhibit
inhibitory activity in tubulin polymerization [3] and anti-
1
Department of Crystallography, Maria Curie-Sklodowska
cancer activity against human prostate cancer cell lines [4].
University, Maria Curie-Sklodowska St 3, 20-031 Lublin,
The liquid crystalline properties of D2-isoxazolines are also
Poland
known [5]. The synthetic potential of the use of D2-isox-
2
Institute of Biology, Chemistry and Bioresources, Chernivtsi
National University, 2 Kotsyubynski Str., Chernivtsi 58012,
Ukraine
azolines was explored in syntheses of b-hydroxyketones, c-
aminoalcohols, a,b-unsaturated oximes, and b-hydroxyni-
triles [6]. Applications of nitrosubstituted isoxazole
3
Institute of Organic Chemistry and Technology, Cracow
University of Technology, Warszawska St. 24,
´
31-155 Krakow, Poland
derivatives in the field the chemistry and biochemistry are
additionally also a logical consequence of (a) the wide
range of theoretically possible channels of transformation
4
Department of Organic Chemistry, Maria Curie-Sklodowska
University, Gliniana St 33, 20-031 Lublin, Poland
123

1878
B. Miros½aw et al.
of nitro group into other functional groups [7, 8] and (b) the
influence of the nitro group on the biological activity
[9, 10].
Results and discussion
In the first stage, we prepared 3-nitroprop-1-ene (3) in a
reaction between 3-bromoprop-1-ene and silver nitrite. The
second component for the 32CA reaction, benzonitrile N-
oxide (2), was generated in situ from phenylhydraxamoyl
chloride. Next, we performed cycloaddition between 2 and
3. The reaction was monitored by HPLC. It was found that
the reaction was completed after 20 h. HPLC analysis of
the crude reaction product confirmed the presence of
unreacted residual nitroalkene and a single adduct formed.
The product was isolated with sufficient purity for a full set
of structural analyses using LC–MS IT-TOF, IR, and NMR
techniques (please see for experimental section and Sup-
plementary Materials for details).
There are many efficient methods for preparation of
nitrosubstituted 4,5-dihydroisoxazoles; the most universal
one is [3 ? 2] cycloaddition (32CA) between nitrile N-
oxides as three atom components (TACs) [11, 12] and
conjugated nitroalkenes (CNA) [13–15]. At the same time,
nitromethyl-substituted 4,5-dihydroisoxazole is very poorly
studied. Only one incidental synthesis of a compound from
this group (nitromethyl-3-phenyl-4,5-dihydroisoxazole)
has been briefly reported [16] to date. Unfortunately, the
regiochemistry of that reaction was not reliably supported
by structural analysis of the product formed: only low-
1
resolution H and partial description of IR spectra have
been presented. The proposed structure of the product was
based rather on intuitive considerations than experimental
data analysis.
The recorded NMR spectra of nitromethyl-substituted
3-phenyl-4,5-dihydroisoxazole (please see for experimen-
tal section and Supplementary Materials for details) could
be compared with spectra of it known analogues for which
both C5 and C4 substituted isomers were reported. In
contrast to the substituted at C5 position isomers in the
literature there are only a few relevant examples of C4
substituted compounds, which NMR spectra were reported.
The spin system read from the 1H NMR spectrum of
studied nitromethyl-substituted 3-phenyl-4,5-dihydroisox-
azole corresponds some better to that, reported for 5-(hy-
droxymethyl)-3-phenyl-4,5-dihydroisoxazole [18], then for
Herein, we present the results of structural analysis of
nitromethyl-3-phenyl-4,5-dihydroisoxazole, which was
obtained in a 32CA reaction between in situ-generated
benzonitrile N-oxide (2) and 3-nitroprop-1-ene (3)
(Scheme 1).
The results obtained provide a valuable background for
understanding of the chemistry of nitromethyl-4,5-dihy-
droisoxazoles; they are also useful for better understanding
of other 32CA processes involving nitroallylic systems,
which are still only rarely used in cycloaddition reactions
[17].
4-(hydroxymethyl)-3-phenyl-4,5-dihydroisoxazole
[19],
but the signals corresponded to the both CH2 and H5
protons of nitromethyl-substituted compounds are shifted
into the low field significantly compare to the hydrox-
ymethyl-substituted analogues. Surprisingly, in the 13C
NMR spectrum of 5-(hydroxymethyl)-3-phenyl-4,5-dihy-
droisoxazole, chemical shift of C5 carbon is situated in
Scheme 1
123

Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3 ? 2…
1879
significantly lower field then corresponding signal of
nitromethyl-substituted compound (81.2 vs. 76.9 ppm), in
the same tome 13C NMR spectrum of C4 substituted isomer
had not been reported. The comparison of 1H and 13C NMR
of 5- [20] and 4- [21] hydroxymethyl-substituted 3-(p-
methoxyphenyl)-4,5-dihydroisoxazoles was even less
informative due to the signals overlapping and complicated
structure of multiplets they formed. Any other pair of
isomeric C4 and C5 substituted analogues with known
spectral data were found in the literature.
Table 1 Selected bond lengths of molecule 4
˚
Length/A
˚
Length/A
Bond
Bond
O1–N2
1.380(6)
1.452(7)
1.274(6)
1.446(8)
1.508(7)
1.425(7)
1.433(8)
1.358(7)
C5Ar–C6Ar
C3Ar–C4Ar
C4Ar–C5Ar
C5–C4
1.366(8)
1.376(8)
1.353(8)
1.532(8)
1.434(8)
1.504(10)
1.186(9)
1.117(9)
O1–C5
N2–C3
C3–ClAr
C3–C4
C1a–C5
C1Ar–C2Ar
C1Ar–C6Ar
C2Ar–C3Ar
C1a–N1a
N1a–O2a
N1a–O1a
The mentioned difficulties in comparison of the NMR
spectra left some doubts that the collected data are suffi-
cient to elucidate the structure of nitromethyl-substituted
3-phenyl-4,5-dihydroisoxazole surely. Therefore, to
resolve this issue, we performed X-ray diffraction struc-
tural analysis.
The conjugation of both rings results in shortening of the
˚
linkage bond C3–C1Ar (1.45(1) A) and lengthening of the
C1Ar–C2Ar and C1Ar–C6Ar bonds in the aromatic ring of
˚
up to 0.08 A in regard to the shortest bond length within
In the X-ray diffraction experiment, we have confirmed
unambiguously the molecular structure of 3-phenyl-5-(ni-
tromethyl)-4,5-dihydroisoxazole corresponding to the
structure of 4 in Scheme 1 (Fig. 1, Table 1). Although the
geometry of isoxazole ring shows high diversity in bond
length and valence angle values depending on the kind and
the localization of substituents, the data for isoxazole ring
in molecule 4 are within the ranges of values found in 751
structures deposited in the Cambridge Structural Database
(CSD ver. 5.39 with update Feb. 2018) [22] (see Supple-
mentary Materials). The isoxazole and phenyl rings in 4 are
nearly coplanar (twisted by 5.2(2)°). The mean plane of the
nitromethyl group (defined through atoms C1A, N1A,
O1A, and O2A) is rotated by 63.7(5)° in relation with the
isoxazole ring. In the CSD, there are no examples of
nitromethyl-4,5-dihydroisoxazoles, but to show the free-
dom of rotation for the nitromethyl substituent in regard to
the single bond (C5–C1) linking these two molecular
fragments, we have made a search for compounds having
5-membered ring substituted by nitromethyl group. The
values found for torsions between 5-membered ring and the
nitromethyl group (–CNO2) were in the ranges of 12°–90°
for 73 found crystal structures.
this ring. The HOMA index calculated for the benzene ring
is only 0.74, showing a high degree of dearomatization and
confirming the changes in the electronic structure of the
molecule [24].
In the crystal, the molecules lie parallel along the c-axis
in a ‘‘head-to-tail’’ manner (Fig. 2). They form zig-zag
layers of molecules oriented in the same direction inter-
acting only through a weak C4–H40…N2 hydrogen bond
within the layer (Table 2). In the neighbour layers, the
molecules are facing in the opposite direction. Between the
layers, the molecules contact through one cyclic C5–
H5…O2a and two linear C3Ar–H3Ar…N2 and C1a–
H1a…O1a hydrogen bonds. Although the molecule has a
planar structure, there are no p…p interactions. This
crystal arrangement favours the twin formation.
Next, we analyzed the mechanistic aspects of both the-
oretically possible competitive channels of the reaction
between 3-nitroprop-1-ene and benzonitrile N-oxide. For
this purpose, the results from DFT calculations were
used (Tables 3, 4).
Fig. 1 Molecular structure of 4
123

1880
B. Miros½aw et al.
Fig. 2 Crystal packing (view along the c-axis) and selected intermolecular interactions in 4. Two directions of columns of molecules oriented in
a head-to-tail manner are marked in grey and black
Table 2 Selected geometric
parameters of intermolecular
contacts in crystal 4
D–H…A#
d(H…A)/A
d(D…A)/A
\DHA/°
Symmetry code#
˚
˚
C5–H5…O2a#
2.71
2.72
2.67
2.73
3.424(2)
3.504(2)
3.626(2)
3.437(2)
130
143
169
130
- x, - y, - z
C3Ar–H3Ar…N2#
C4–H40…N12#
C1a–H1a…O1a#
- x, y ? 1/2, - z? 1/2
- x ? 1/2 ? 1, ? y? 1/2, ?z
x - 1/2, - y ? 1/2, - z
It was found that (regardless of the polarity of solvent)
both reactions proceeded according to a one-step mecha-
nism. In particular, only one transition state (TS) was
localized between the valleys of individual substrates and
products. However, the first reaction stage is always the
formation of a pre-reaction complex (MC). This is
accompanied by reduction of the enthalpy of the reaction
system by about a 27 kJ/mol. In the MC, new r-bonds are
not formed. Distances between reaction centers exist
beyond the area which is typical for new bonds in transi-
tions states.
Table 3 Energetic parameters for [3 ? 2] cycloadditions leading to
5-(nitromethyl)-3-phenyl-4,5-dihydroisoxazole (4) and regioisomeric
4-(nitromethyl)-3-phenyl-4,5-dihydroisoxazole (5) in diethyl ether
according to M06-2X/6-31G(d) (PCM) calculations (respective
parameters for reactions in more polar solvents are available in the
Supplementary Materials)
Transition
DH/kJ mol-1
DG/kJ mol-1
DS/J mol-1 K-1
2 ? 3 ? MC
MC ? TSA
2 ? 3 ? 4
MC ? TSB
2 ? 3 ? 5
- 27.2
76.2
19.3
87.1
- 156.2
- 192.8
- 208.0
- 194.7
- 208.6
- 213.0
84.6
- 151.0
96.1
Further transformation of the reaction system proceeds
into the transition state. In a weakly polar ethereal solution,
this is accompanied by an increase in the enthalpy of the
reaction system by 87.1 kJ/mol on path A and by
96.1 kJ/mol on path B (Table 3). In a strongly polar
aqueous solution, these parameters of activation are equal
to 85.6 and 97.0 kJ/mol, respectively. In general, polar
solvents increase slightly the activation energy and
decrease the exothermic character of 32CA reactions as a
consequence of a better solvation of the TACs than the low
- 201.3
- 139.0
polar TSs and cycloadducts [25]. However, irrespective of
the polarity of solvents, the reaction channel leading to a
4-nitromethyl adduct should be considered as evidently
unfavoured from the kinetic point of view. This conclusion
correlates well with the results from the experimental
123

Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3 ? 2…
1881
Fig. 3 Views of transition states
of cycloaddition between
3-nitroprop-1-ene and
benzonitrile N-oxide in a diethyl
ether solution according to
M06-2X/6-31G(d) (PCM)
calculations
study, which shows clearly that 5-nitromethyladducts is the
only reaction product.
It should also be noted at this point that the optimized
structure of 5-(nitromethyl)-3-phenyl-4,5-dihydroisoxazole
(4) is close to that obtained from the X-ray diffraction
structural analysis.
Structurally, all transition states are very similar. In TSs,
two new single bonds are formed (Fig. 3). These are bonds
C3–C4 and C5–O1. Their degree of development is very
similar, contrary to analogous transition states in cycload-
dition reactions involving conjugated nitroalkenes [26–30].
Subsequently, the low values of GEDT [31] indices clearly
confirm the non-polar nature of all considered reactions,
even in the aqueous solution (see Supplementary Materi-
als). In general, polar solvents increase slightly the acti-
vation energy and decrease the exothermic character of
32CA reactions as a consequence of a better solvation of
the TACs than the low polar TSs and cycloadducts (see
[28]).This conclusion is full agreement with fundamental
rules of molecular electron density theory. In particular,
Domingo has recently established a powerful classified of
the [3 ? 2] cycloaddition (32CA) reactions in base the
structure of the TACs [32]. In this approach, nitrile N-
oxides are classified as zwitterionic TACs, participating in
zw-type 32CA reactions [33, 34]. This type of 32CA
reaction demands the nucleophilic activation of the TAC
and the electrophilic activation of the ethylene, or vice
versa, to favour the 32CA reaction through a polar process
[35]. Analysis of the conceptual DFT (CDFT, [36]) indices
at the ground state of the reagents allows anticipate the
reactivity of the species involved in a zw-type 32CA
reaction. Thus, the low electrophilic (x = 1.46 eV [26])
and nucleophilic character (N = 2.78 eV [26]) of ben-
zonitrile N-oxide disable its participation in polar process,
in spite of the high electrophilic character of 3-nitroprop-1-
ene (x = 1.92 [17]). These behaviours make the non-par-
ticipation of nitrile N-oxides in polar zw-type 32CA
reactions.
The molecular overlay of the experimental and calcu-
lated structures shows that the main geometric difference
lies in the orientation of the nitromethyl substituent
(Fig. 4). Both the rings are nearly coplanar. The isoxa-
zoline ring is less planar in the calculated structures than
in the crystal. The root mean square deviations (RMSD)
for the bond lengths between the experimental and cal-
˚
culated geometry were 0.0915 A for all solvents. The
RMSD values were 2.198°, 2.181°, 2.172°, 2.170°, and
2.177° for valence angles and 11. 33°, 11.42°, 11.46°,
11.49°, and 11.50° for dihedral angles for diethyl ether,
dichloromethane, acetone, nitromethane, and water,
respectively. This geometric discrepancy may be regarded
as a consequence of the existence of a crystal field along
with the intermolecular interactions, which influence the
molecular geometry.
Conclusion
Our comprehensive structural analysis shed light on the
regiochemistry of formation of 5-(nitromethyl)-3-phenyl-
4,5-dihydroisoxazole in the [3 ? 2] cycloaddition between
benzonitrile N-oxide and 3-nitroprop-1-ene. It was found
that the structure of 5-(nitromethyl)-3-phenyl-4,5-dihy-
droisoxazole should be assigned to the product. This con-
clusion is in full agreement with the results from DFT
calculations, which also suggest relatively higher stability
of the 5-nitromethyl isomer in the relation to the 4-ni-
tromethyl one. It should be underlined that, for the first
time, we report the crystal structure of a nitromethyl-
123

1882
B. Miros½aw et al.
Table 4 Most important parameters for the key structures of [3 ? 2] cycloadditions leading to 5-(nitromethyl)-3-phenyl-4,5-dihydroisoxazole
(4) and regioisomeric 4-(nitromethyl)-3-phenyl-4,5-dihydroisoxazole (5) according to M06-2X/6-31G(d) (PCM) calculations (respective
parameters for reactions in more polar solvents are available in the Supplementary Materials)
Structure
C3–C4
C5–O1
GEDT/e
Imaginary frequencies/cm-1
la
la
˚
r/A
˚
r/A
TSA
4
2.192
1.511
2.213
1.516
0.549
2.281
1.440
2.221
1.439
0.416
0.002
0.005
- 462.63
- 475.79
TSB
5
0.540
0.457
TS
r
ÀrP
alXÀY ¼ 1 À
the corresponding product
XÀY , where rXTSÀY is the distance between the reaction centers X and Y in the transition structure and rXPÀY is the same distance in
XÀY
rXPÀY
Fig. 4 Two views of the best
fitting of the experimental
(colour) and theoretical (black,
data for the diethyl ether
environment) molecular
structures
substituted isoxazole compound. The rod-like shape of the
molecule in combination with the layer type of the crystal
packing implies the twin formation. Noteworthy, the con-
jugation of the aromatic and isoxazole rings results in
dearomatization of the benzene ring and in some changes
in the geometry and bond orders of the heterocyclic ring
and the linking single bond.
equipped with a UV–Vis detector. For monitoring of the
reaction progress and postreaction mixtures, a LiChrospher
18-RP 10 lm column (4 9 240 mm) and 70% methanol as
the eluent at a flow rate of 1.3 cm3 min-1 were used. MS
spectra were recorded on a Shimadzu LCMS IT-TOF
Ò
˚
spectrometer equipped with a Kinetex 2.6 lm C18 100 A,
LC column 100 9 2.1 mm, eluted with 50% aqueous
The results obtained provide a valuable background for
understanding of the chemistry of nitromethyl-4,5-dihy-
droisoxazoles. They are also useful for better understand-
ing of other 32CA processes involving nitroallylic systems.
acetonitrile at a flow rate of 0.3 cm3 min-1.
3-Nitroprop-1-ene (3) The powdered silver nitrite (50 g)
was suspended in 100 cm3 of anhydrous diethyl ether at
- 5 °C. Next, 35 g of 3-bromoprop-1-ene was slowly
added dropwise, while the temperature was maintained at
- 5 °C. The mixture was then left at 0–5 °C for 24 h, and
next for 48 h at room temperature. The reaction mixture
was filtered and the residue was washed with the diethyl
ether. The filtrate and the ethereal extract were combined
and the solvent was evaporated on a rotary evaporator. The
liquid residue was distilled under reduced pressure. 7.2 g
(29%) of 3-nitroprop-1-ene were obtained as a yellow
liquid with a characteristic odor (bp. 35 °C/10 Torr; Ref.:
44 °C/27 Torr [37]).
Experimental
Melting points were determined on a Boetius apparatus.
Elemental analysis was performed on a Perkin-Elmer PE-
2400 CHN apparatus. The IR spectrum was recorded on an
FTS Nicolet IS 10 apparatus. 1H NMR (500 MHz) and 13
C
NMR (125 MHz) spectra were taken on a Bruker Avance
500 MHz spectrometer calibrated to residual solvent peaks
at 7.27 and 77.00 ppm for 1H and 13C in CDCl3. The
chemical shifts are reported in ppm, and the following
abbreviations are used in reporting the NMR data: d
(doublet), dd (doublet of doublets), and m (multiplet).
Coupling constants (J) are given in Hz. Spectra are
reported as follows: chemical shift (d, ppm), multiplicity,
integration, and coupling constants (Hz). Liquid chro-
matography (HPLC) was done using a Knauer apparatus
5-(Nitromethyl)-3-phenyl-4,5-dihydroisoxazole (4, C10H10-
N2O3) A mixture of 40 mmol of 3-nitroprop-1-ene and
20 mmol of phenylhydraxamoyl chloride (which was
obtained via a typical procedure from benzaldoxime [38])
in 100 cm3 of dry Et2O was stirred and cooled down to
0 °C. 20 mmol of Et3N in 10 cm3 of Et2O was added
dropwise and the mixture was stirred at r.t. for 20 h. The
123

Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3 ? 2…
1883
organic layer was separated from the postreaction mixture,
dissolved in DCM, washed with water, and dried over
MgSO4. The solvent was evaporated to dryness and resi-
dues were crystallized from EtOH. Yield 80%; white
crystals; m.p.: 94–95 °C; 1H NMR (500 MHz, CDCl3):
d = 7.59 (m, 2H, Ar), 7.37 (m, 3H, Ar), 5.33 (dddd, 2H,
J =10.6, 6.6, 6.3, 6.2 Hz, H5), 4.62 (dd, 1H, J = 13.2,
6.6 Hz, H6a), 4.43 (dd, 1H, J = 13.2, 6.3 Hz, H6b), 3.58
(dd, J = 17.0, 10.6 Hz, 1H, H4a), 3.20 (dd, J = 17.0,
6.2 Hz, 1H, H4b) ppm; 13C NMR (125 MHz, CDCl3):
model of the crystal (Table 5). The diffraction data were
collected at room temperature on an XtaLAB AFC11
(RCD3): quarter-chi single diffractometer using CuKa
˚
radiation (k = 1.54184 A). Using Olex2 [37], the structure
was solved with the ShelXT [39] structure solution pro-
gram using intrinsic phasing and refined with the
Olex2.refine refinement package using Gauss–Newton
minimisation.
CCDC 1576601 contains supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.
html (or from the Cambridge Crystallographic Data Center,
12, Union Road, Cambridge CB2 1EZ, UK; fax: ?44 1223
336033).
0
0
0
d = 156.9 (C3), 130.8 (ArC4 ), 128.9 (ArC3 ?C5 ), 128.4
0
(ArC1 ), 126.9 (ArC2 ?C6 ), 76.8(C5) 76.1 (–CH2–), 38.7
0
0
ꢀ
(C4) ppm; IR (KBr): m = 3438, 2927, 2359, 1601, 1545,
1497, 1446, 1412, 1387, 1360, 1224, 1177, 1077, 1012,
912, 893, 822, 769, 712, 692, 546, 483, 438 cm-1; HRMS
(ESI): m/z = 207.0758, calc. for [C10H10N2O3 ? H]?
207.0764, diff. = 2.90 ppm.
DFT calculations
The quantum-chemical calculations reported in this paper
were performed on ‘‘Zeus’’ and ‘‘Prometheus’’ supercom-
puters in the ‘‘Cyfronet’’ regional computer center in
Cracow. The M06-2X [40] and B3LYP functionals with
6-31G(d) basis set implemented in the GAUSSIAN 09
package [41] was used. It should be underlined that M06-
2X functional is dedicated for precise energetic consider-
ations [40, 42] and has recently been [26, 43–45] applied
for analysis of several structural and energetic properties of
compounds with similar structural moieties.
X-ray crystallography
Crystals of 4 were obtained by recrystallization from
ethanol. The crystals were twinned; however, the diffrac-
tion data produced good quality electron density maps that
allowed us to unambiguously determine the structural
Table 5 Crystal data and structure refinement parameters for 5-(ni-
tromethyl)-3-phenyl-4,5-dihydroisoxazole (4)
Formula
C10H10N2O3
206.20
Acknowledgements The research was carried out with the equipment
purchased thanks to the financial support of the European Regional
Development Fund in the framework of the Operational Program
Development of Eastern Poland 2007–2013 (Contract no. UDA-
POIG.02.01.00-06-212/09-03, ECOTECH Complex—Man, Environ-
ment, Production). The authors also thank the Polish Ministry of
Science and High Education for financial support (Grant no. C-2/171/
2017/DS).
Formula weight
Temperature/K
Crystal system
Space group
295
Orthorhombic
Pbca
˚
a/A
8.5754(11)
9.8973(9)
23.684(3)
2010.2(4)
8
˚
b/A
˚
c/A
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://creative
commons.org/licenses/by/4.0/), which permits unrestricted use, dis-
tribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
3
˚
V/A
Z
q
calc/g cm-3
1.3626
l/mm-1
0.861
F(000)
Crystal size/mm3
867.1
0.01 9 0.2 9 0.2
Cu Ka (k = 1.54184)
Radiation
References
2h range for data collection/° 7.46 to 145.58
Reflections collected
Independent reflections
Data/parameters
28,948
1. Shoop WL, Hartline EJ, Gould BR, Waddell ME, McDowell RG,
Kinney JB, Lahm GP, Long JK, Xu M, Wagerle T, Jones GS,
Dietrich RF, Cordova D, Schroeder ME, Rhoades DF, Benner
EA, Confalone PN (2014) Vet Parasitol 201:179
2. Conti P, Dallanoce C, Amici MD, Micheli CD, Klotz K (1998)
Bioorg Med Chem 6:401
3. Song MY, Cao CY, He QR, Dong QM, Li D, Tang JJ, Gao JM
(2017) Bioorg Med Chem 25:5290
4. Banday AH, Giri AK, Parveen R, Bashir N (2014) Steroids 87:93
1853 [Rint = 0.3519, Rsigma = 0.0552]
1853/135
0.817
Goodness-of-fit on F2
Final R indexes [I C 2r (I)] R1 = 0.0935, wR2 = 0.2952
-3
˚
Largest diff. peak/hole/e A
CCDC no.
0.36/- 0.24
1576601
123

1884
5. Kotian SY, Kudva NU, Byrappa K, Lokanatha Rai KM (2016)
Mater Today Proc 3:4082
B. Miros½aw et al.
´
29. Jasinski R (2015) Tetrahedron Lett 56:532
30. Domingo LR (2014) RSC Adv 4:32415
6. Kara YS (2015) Spectrochim Acta. Part A Mol Biomol Spectrosc
151:723
7. Ono N (2001) The nitro group in organic synthesis. Wiley-VCH,
Weinheim
31. Domingo LR, Rios-Gutierrez M (2017) Molecules 22:750
32. Domingo LR, Rios-Gutierrez M, Perez P (2018) J Org Chem
83:2182
33. Ndassa IM, Adjieufack AI, Ketcha JM, Berski S, Rios-Gutierrez
M, Domingo LR (2017) Int J Quantum Chem 117:e25451
34. Domingo LR, Aurell MJ, Perez P (2014) Tetrahedron 70:4519
35. Domingo LR, Rios-Gutierrez M, Perez P (2016) Molecules
21:748
´
8. Jasinski R, Kubik M, Łapczuk-Krygier A, Ka˛cka A, Dresler E,
Boguszewska-Czubara A (2014) React Kinet Mech Cat 113:333
9. Boguszewska-Czubara A, Łapczuk-Krygier A, Rykała K, Bier-
nasiuk A, Wnorowski A, Popiołek Ł, Maziarka A, Hordyjewska
´
A, Jasinski R (2016) J Enzyme Inhib Med Chem 31:900
´
36. Bordwell FG, Bartmess JE, Hautala JA (1978) J Org Chem
43:3107
37. Singh UC, Kollman PA (1984) J Comp Chem 5:129
38. Lemercier BC, Pierce JG (2014) J Org Chem 79:2321
39. Dolomanov OV, Bourhis LJ, Gildea RJ, Howard JAK, Pusch-
mann H (2009) J Appl Crystallogr 42:339
10. Jasinski R, Dresler E, Mikulska M, Polewski D (2016) Curr
Chem Lett 5:123
11. Domingo LR, Emamian SR (2014) Tetrahedron 70:1267
´
72:1524
´ ´
12. Domingo LR, Rıos-Gutierrez M, Perez P (2016) Tetrahedron
13. Diamantini G, Duranti E, Tontini A (1993) Synthesis 11:1104
14. Koroleva EV, Nondar NF, Katok YM, Chekanov NA, Cherni-
khova TV (2007) Chem Heterocycl Comp 43:362
40. Sheldrick GM (2008) Acta Crystallogr A 64:112
41. Zhao Y, Truhlar DG (2008) Theor Chem Acc 120:215
42. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Montgomery JA, Vreven TJ, Kudin KN, Burant
JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B,
Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada
M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M,
Nakajima Y, Honda O, Kitao O, Nakai H, Klene M, Li X, Knox
JE, Hratchian HP, Cross JB, Adamo C, Jaramillo J, Gomperts R,
Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli P,
Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P,
Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain
MC, Farkas MC, Malick DK, Rabuck AD, Raghavachari K,
Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cio-
slowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P,
Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng
CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B,
Chen W, Wong MW, Gonzalez C, Pople JA (2009) Gaussian 09
rev A.1. Gaussian, Inc, Wallingford, CT
´
15. Jasinski R (2015) 1,3-Dipolar cycloaddition reactions: mecha-
nistic aspects and applications in organic synthesis. RTN, Radom
16. Baranski A (1985) Polish J Chem 59:605
´
17. Jasinski R (2015) J Heterocycl Chem 52:185
18. Triandafillidi I, Kokotos CG (2017) Org Lett 19:106
19. Toma L, Quadrelli P, Perrini G, Gandolfi R, Di Valentin C,
Corsaro A, Caramella P (2000) Tetrahedron 56:4299
20. Suga H, Adachi Y, Fujimoto K, Furihata Y, Tsuchida T, Kakehi
A, Baba T (2009) J Org Chem 74:1099
21. Dong L, Geng C, Jiao P (2015) J Org Chem 80:10992
22. Groom CR, Bruno IJ, Lightfoot MP, Ward SC (2016) Acta
Crystallogr B 72:171
23. Krygowski TM, Cyranski MK (2001) Chem Rev 101:1385
24. Benchouk W, Mekelleche SM, Silvi B, Aurell MJ (2011) Dom-
ingo LR 24:611
´
´
25. Jasinski R, Jasinska E, Dresler E (2017) J Mol Model 23:13
26. Jasinski R, Kula K, Ka˛cka A, Mirosław B (2017) Monatsh Chem
´
43. Zhao Y, Truhlar DG (2008) Acc Chem Res 41:157
´
44. Jasinski R (2014) J Fluorine Chem 160:29
´
45. Jasinski R (2014) Comp Theor Chem 1046:93
148:909
´
´
27. Jasinski R, Mroz K, Ka˛cka A (2016) J Heterocycl Chem 53:1424
28. Jasinski R (2015) RSC Adv 5:101045
´
123