Synthesis and structural characterization of three phenylsulfonyl derivatives: Influence of halogen substituents on the intermolecular interactions

Article abstract of DOI:10.1007/s10870-007-9256-z

Synthesis and X-ray structural determination of three halogenated nitroimidazo[1,2-a]pyridine phenylsulfonyl derivatives are reported. (2) is monoclinic P2₁/c with a = 9.6679(1), b = 11.3642(2), c = 15.2189(2)A, β = 105.9053(7)°; (3) is triclin

Full text of DOI:10.1007/s10870-007-9256-z

J Chem Crystallogr (2007) 37:831–836
DOI 10.1007/s10870-007-9256-z
ORIGINAL PAPER
Synthesis and Structural Characterization of Three
Phenylsulfonyl Derivatives: Influence of Halogen Substituents
on the Intermolecular Interactions
C. Castera Æ M. D. Crozet Æ M. Giorgi Æ
P. Vanelle
Received: 10 November 2005 / Accepted: 26 September 2007 / Published online: 11 October 2007
Ó Springer Science+Business Media, LLC 2007
Abstract Synthesis and X-ray structural determination
of three halogenated nitroimidazo[1,2-a]pyridine phen-
ylsulfonyl derivatives are reported. (2) is monoclinic P21/c
The phenylsulfonyl derivatives can be used on the one hand
in Suzuki reaction [2] and on the other hand, they can be
used in alternative syntheses to the Knoevenagel reaction to
prepare nitroheterocycles that bear the diethyl methylene-
malonate group in ortho-like of the nitro group [3].
˚
with a = 9.6679(1), b = 11.3642(2), c = 15.2189(2)A,
b = 105.9053(7)°; (3) is triclinic P –1 with a = 8.5556(2),
˚
b = 13.1191(3), c = 15.5132(4)A, a = 76.0110(8), b =
As part of an ongoing research program focused on the
synthesis by SRN1 reactions of new imidazo[1,2-a]pyridines
which can be used in different coupling reactions for the
preparation of more complex structures of pharmacological
interest, we have prepared new 2-(arylsulfonylmethyl)-
6-halo-3-nitroimidazo[1,2-a]pyridines.
89.1768(8), c = 78.953(2)°; (4) is monoclinic P21/c
˚
with a = 15.3353(2), b = 8.8621(2), c = 11.4189(3)A,
b = 90.9704(7)°. In the title compounds that differ by the
nature and number of halogen substituents, the arylsulfonyl
moieties are oriented differently relatively to the nitroim-
idazopyridine. Moreover non-classical intermolecular
interactions are revealed by the X-ray analysis.
In this work we present the synthesis and structural
X-ray analysis of three phenylsulfonyl derivatives inserting
a halogen atom in 6-position of the nitroimidazopyridine.
The influence of the nature and position of the chloride and
bromide atoms in terms of intermolecular interactions
between the molecules within the crystals is discussed.
Keywords Imidazo[1,2-a]pyridine Á Phenylsulfonyl
derivatives Á Crystal structure Á Intermolecular contacts
Introduction
Experimental
The use of sulfones, acting as an auxiliary group, is still an
important synthetic strategy, especially for making carbon–
carbon double bonds. This functional group can modify the
polarity of the molecule by acting as an electron-withdraw-
ing group to stabilise carbanions or as a leaving group [1].
Synthesis
Derivatives (2), (3) and (4) were prepared in excellent
yieldsbyreacting2-chloromethyl-6-halo-3-nitroimidazo[1,2-
a]pyridine and appropriate sulfinate anion according to a
known procedure, as shown in Scheme 1 [4].
C. Castera Á M. D. Crozet Á P. Vanelle (&)
The new compounds (2), (3) and (4) were identified by
1H NMR, 13C NMR and elemental analysis.
Laboratoire de Chimie Organique Pharmaceutique, UMR CNRS
´
´
´
´
6517, Faculte de Pharmacie, Universite de la Mediterranee, 27
Boulevard Jean Moulin, Marseille Cedex 5 13385, France
e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
General Procedure
M. Giorgi
ˆ
Spectropole-RX, Faculte des Sciences et Techniques, Universite
Paul Cezanne Aix-Marseille III, Avenue Escadrille Normandie-
Niemen, Marseille Cedex 20 13397, France
´
´
To a solution of sodium arylsulfinate (20.6 mmol) in
DMSO (45 mL) under inert atmosphere (N2) and irradiation
´
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J Chem Crystallogr (2007) 37:831–836
Na+
-
Scheme 1 Preparation of 2-
(arylsulfonylmethyl)-6-halo-3-
nitroimidazo[1,2-a]pyridines
SO2
O
Cl
O S R1
N
hν, N2
N
+
N
N
DMSO
X
X
NO2
NO2
R
R = CH3, Cl
2 X = Br, R1 = p-Cl-C6H5
3 X = Br, R1 = p-CH3-C6H5
4 X = Cl, R1 = p-CH3-C6H5
1a X = Br
1b X = Cl
with a tungsten 150 W lamp was added (10.3 mmol)
of 2-chloromethyl-6-halo-3-nitroimidazo[1,2-a]pyridine. The
mixture was stirred at room temperature for 3 h. After
disappearance of 2-chloromethyl-6-halo-3-nitroimidazo[1,2-
a]pyridine (monitored by TLC), the mixture was poured into an
ice-water mixture. After filtration, the solid was dried in the air
and purified byrecrystallizationwith appropriate solventto give
2-(arylsulfonylmethyl)-6-halo-3-nitroimidazo[1,2-a]pyridine.
general procedure gave after recrystallisation from benzene
3.24 g (86%) of (4) as white solid, mp 217 °C.
1H-NMR (200 MHz, CDCl3) d: 2.44 (s, 3H, CH3); 5.09 (s,
2H, CH2); 7.29–7.34 (m, 2H, CH); 7.60–7.82 (m, 4H, CH);
9.43 (m, 1H, H5). 13C-NMR (50 MHz, CDCl3) d: 21.7; 56.7;
118.9; 125.6; 125.8; 128.3; 129.9; 132.3; 136.1; 139.8; 143.1;
145.3. Anal. Calcd for: C15H12ClN3O4S: C, 49.25; H, 3.31;
N, 11.49. Found: C, 49.43; H, 3.36; N, 11.12.
6-Bromo-2-[(4-chlorophenylsulfony)methyl]-3-
Crystal Data
nitroimidazo[1,2-a]pyridine (2)
Compounds (2), (3) and (4) were measured at room
temperature on a Bruker-Nonius KappaCCD diffractome-
Reaction of sodium 4-chlorobenzenesulfinate hydrate
(4.09 g, 20.6 mmol) with (1a) (3.00 g, 10.3 mmol) accord-
ing to the general procedure gave after recrystallisation from
toluene 3.55 g (80%) of (2) as white solid, mp 220 °C.
1H-NMR (200 MHz, CDCl3) d: 5.12 (s, 2H, CH2); 7.25–
7.94 (m, 6H, CH); 9.55 (m, 1H, H5). 13C-NMR (50 MHz,
CDCl3) d: 56.7; 112.6; 119.1; 127.7; 129.6; 129.8; 134.7;
137.5;139.2;141.1;143.3.Anal. CalcdforC14H9BrClN3O4S:
C, 39.04; H, 2.11; N, 9.76. Found: C, 39.37; H, 2.24; N, 10.00.
˚
ter with monochromated MoKa (k = 0.71073 A) radiation.
For each measurement / and x scans with rotation steps
of 1° were performed in order to complete the Ewald
sphere and collect redundant data. Cell determinations and
data integrations were performed with Denzo and Scale-
pack [5]. Lorentz and polarization were applied to the raw
data for each compound and a multi-scan absorption
correction was applied to compounds (2) and (3) using
Sortav [6]. The structures were solved by direct methods
with SIR92 [7] and non-hydrogen atoms were refined
anisotropically using Shelxl97 [8]. H-atoms were intro-
duced in theoretical position, included in the calculations
but not refined.
6-Bromo-3-nitro-2-(tosylmethyl)imidazo[1,2-
a]pyridine (3)
Reaction of sodium toluene-4-sulfinate (3.62 g,
20.3 mmol) with (1a) (3.00 g, 10.3 mmol) according to the
general procedure gave after recrystallisation from propan-
2-ol 3.80 g (90%) of (3) as yellow solid, mp 201 °C.
1H-NMR (200 MHz, CDCl3) d: 2.44 (s, 3H, CH3); 5.09
(s, 2H, CH2); 7.31 (d, J = 7.9 Hz, 2H, CH); 7.72 (s, 2H,
CH); 7.73 (d, J = 7.9 Hz, 2H, CH); 9.52–9.53 (m, 1H, H5).
13C-NMR (50 MHz, CDCl3) d: 21.7; 56.7; 112.4; 119.1;
127.7; 128.3; 129.9; 134.5; 136.2; 139.7; 143.3; 145.3.
Anal. Calcd for: C15H12BrN3O4S: C, 43.92; H, 2.95; N,
10.24. Found: C, 43.97; H, 2.67; N, 10.45.
Full details for the crystals, data collections and refine-
ment parameters are reported in Table 1.
Results and Discussion
X-ray Analysis
Suitable crystals of (2), (3) and (4) were grown by slow
evaporation from chloroform at room temperature. Com-
pound (3) crystallized with two molecules in the
asymmetric unit. The molecular structures of (2), (3) and
(4) are represented in Figs. 1–3 respectively.
6-Chloro-3-nitro-2-(tosylmethyl)imidazo[1,2-
Each compound is constituted of two distinct parts, with
the flexible arylsulfonylmethyl moiety (A) branched to the
rigid substituted nitroimidazopyridine (B). In this latter the
two heterocyclic rings and the halogen atom are perfectly
a]pyridine (4)
Reaction of sodium toluene-4-sulfinate (3.62 g,
20.3 mmol) with (1b) (2.54 g, 10.3 mmol) according to the
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J Chem Crystallogr (2007) 37:831–836
833
Table 1 Data collection and processing parameters
Compounds
(2)
(3)
(4)
Formula
C14H9Br1Cl1N3O4S1
430.66
C30H24Br2N6O8S2
820.49
C15H12Cl1N3O4S1
365.79
Mw
Crystal system
Space group
Unit cell parameters
Monoclinic
P21/c
Triclinic
P–1
Monoclinic
P21/c
˚
a, A
9.6679(1)
11.3642(2)
15.2189(2)
8.5556(2)
13.1191(3)
15.5132(4)
76.0110(8)
89.1768(8)
78.953(2)
1657.35(7)
2
15.3353(2)
8.8621(2)
11.4189(3)
˚
b, A
˚
c, A
a, °
b, °
c, °
105.9053(7)
90.9704(7)
3
˚
V, A
1608.06(4)
4
1551.61(6)
4
Z
Density calc., g cm–1
1.779
856
1.645
1.566
752
F(000)
l(MoKa), cm–1
824
28.77
26.33
4.07
Transmission factor (min, max) 0.839, 0.894
0.686, 0.883
x and /
1°
Scan type
x and /
x and /
Scan steps
1°
–12/12, –15/15, –20/20
1°
–20/20, –11/11, –14/14
h, k, l range
Scan range h, °
Number of reflections
Measured
–11/11, –16/17, –20/20
2.19–28.26
1.35–28.32
1.33–28.25
19,264
19,068
14,110
Unique
3,896
7,948
3,666
Used in refinement ([2r(I))
Number of variables
R (Rw)
3,079
4,668
3,173
217
434
218
0.0355 (0.1043)
0.0888 (0.2348)
0.0417 (0.1336)
1/[\r2(Fo2) + (0.0966P)2 + 0.3326P]
W
1/[\r2(Fo2) + (0.0644P)2 + 0.0955P] 1/[\r2(Fo2) + (0.1626P)2]
where P = (Fo2 + 2Fc2)/3
0.412; –0.688
where P = (Fo2 + 2Fc2)/3
1.719; –0.663
where P = (Fo2 + 2Fc2)/3
3
˚
Max; min De/A
0.542; –0.444
1.16
Goodness of fit
1.098
0.966
planar while the nitro group accommodates itself out of
that plane by a slight rotation around its bonding to the
imidazole: the dihedrals between the plane defined by the
nitro and that of the imidazopyridine are equal to 11.37(4)°,
7.88(2)° or 7.19(4)° and 9.14(4)° for (2), (3) and (4)
respectively.
side of the molecule: the torsion angle C8–C7–S1–C1 is
equal to –164.1(2)°.
Beside the conformational differences between these
compounds, their X-ray structures revealed interesting
features at the level of the non-covalent interactions.
Thanks to their implications in numerous chemical and
biological processes [10–12] the studies of weak non-
classical intermolecular interactions, e.g. cation–p, CH–p,
arene–arene or halogen–halogen have recently been
the subject of intensive works [13–19]. Careful analyzes of
the structural characteristics of our compounds revealed the
presence of such contacts (i.e. the distance between the
interacting atoms is shorter than the sum of their Van der
Waal radii) within the crystals that might be of interest for
the understanding of their reactivity.
From a geometrical point of view, the main difference
between these compounds is characterized by the orienta-
tion of the arylsulfonylmethyl relatively to the
nitroimidazopyridine; in (2) and (3) the molecules adopt a
folded conformation characterized by a rather closed tor-
sion angle between moieties (A) and (B): C8–C7–S1–C1 is
equal to –71.8(2)° and 71.8(4)° or 75.7(4)° for (2) and (3)
respectively. In (4) the molecule adopts an extended con-
formation with moieties (A) and (B) positioned on both
123

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J Chem Crystallogr (2007) 37:831–836
Fig. 1 An ORTEPII [9] view of
compound (2), showing the
atom-labelling scheme and the
displacement ellipsoids at the
50% probability level
O2
O3
O1
S1
N3
O4
C7
C9
N2
C1
C6
C8
C5
C2
C10
C11
N1
C3
C14
C4
C13
Br1
Cl1
C12
Fig. 2 An ORTEPII [9] view of
compound (3), showing the
atom-labelling scheme and the
displacement ellipsoids at the
50% probability level. Only one
of the two molecules of the
asymmetric unit is represented
O3
C7
N3
O4
C9
C8
O2
S1
N2
O1
C6
C10
C1
N1
C14
C11
C2
C5
Br1
C13
C12
C3
C4
C15
Fig. 3 An ORTEPII [9] view of
compound (4), showing the
atom-labelling scheme and the
displacement ellipsoids at the
50% probability level
O4
O3
N3
C13
C3
O1
C2
Cl1
C14
C12
C11
C7
C4
C5
C15
C1
S1
C8
C9
C10
C6
N1
O2
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J Chem Crystallogr (2007) 37:831–836
835
In (2) two kinds of halogen–halogen (Hal–Hal) inter-
actions can be observed; the first one can be described as a
type II motif (which means that the h1 angle has a value
close to 90° and the h2 has a value close to 180°, contrary
to a type I interaction where the h1 and h2 angles are equal)
[17] that involves the chloride and the bromide atom of a
symmetry-related molecule (symmetry code: (i) –x, 1 – y,
interactions, the bromonitroimidazopyridine moiety of
molecule (3-1) forms infinite sheets parallel to the (14 18
10) plane within the crystal of (3).
In the second molecule of the asymmetric unit (3-2), only
the two C–HÁÁÁN bonds are present thus involving the for-
mation of a weakly bound dimer between (3-2) and a
symmetry-related molecule (symmetry code: (iii) 2 – x, –y,
1 – z): N4-H28iii = 2.719(5) A. Furthermore two other
˚
i
˚
1 – z): the distance C1l–Br1 is equal to 3.4613(8) A
˚
(shorter than the sum of their van der Waals radii: 3.6 A)
S–OÁÁÁH contacts can be observed between the sulfonates of
(3-2) and the methyl of two symmetry-related molecules
[20], the angle C4–Cl1ÁÁÁBr1i (h1) is equal to 103.69(1)°
and the angle C11i–Br1iÁÁÁCl1 (h2) is equal to 148.51(8)°.
A head to head Hal–Hal interaction is also present between
the chloride and that of a symmetry-related molecule
(symmetry code: (ii) 1 – x, –y, 1 – z): the distance Cl1–
(symmetry codes: (iv) 1 – x, 1 – y, –z; (v) 1 – x, –y, 1 – z):
O5–H12iv = 2.576(5) A and O7–H17 = 2.511(4) A. Fin-
ally, a CH/p interaction between the methyl of (3-2) and the
pyridine of a symmetry-related molecule (symmetry code:
2 – x, –y, 1 – z) achieves that description of the weak con-
tacts within the crystal of (3): the distance between C30 and
v
˚
˚
ii
˚
Cl1 is equal to 3.369(1) A (sum of their van der Waals
ii
˚
radii: 3.5 A) and the angle C4–Cl1ÁÁÁCl1 is equal to
˚
the centroid of the pyridine is equal to 3.93(1) A and the
179.89(8)°. Weak bonds of S–OÁÁÁH type do also occur in
the crystal structure of (2) and provide three more inter-
actions that are localized between the sulphur oxygen
atoms and the hydrogens of the aryl of three symmetry-
related molecules (symmetry codes: (iii) –x, –1/2 + y, 3/
2 – z; (iv) –x, 1/2 + y, 3/2 – z; (v) x, 1/2 – y, 1/2 + z): the
distances O1–H2iii, O2–H6iv and O2–H13v are equal to
C30–H30ÁÁÁcentroid angle is equal to 145.94°.
In compound (4) the intermolecular interactions are less
numerous than in (2) or (3) as only two weak contacts can be
reported: the chloride and one oxygen atom of the sulfonyl
are respectively hydrogen-bonded to two pyridines of two
symmetry-related molecules (symmetry codes: (i) x, –1/2 –
i
˚
˚
˚
˚
y, –1/2 + z; (ii) –x, –1 – y, 3 – z): Cl1–H10 = 2.7924(5) A
2.539(2) A, 2.581(2) A and 2.404(2) A. All these interac-
tions within the crystal of (2) are summarized in Scheme 2.
Complexes intermolecular contacts also occur in the
crystal of (3) (Scheme 3). Interestingly, no halogen–halo-
gen interactions are observed in neither of the two
molecules of the asymmetric unit which moreover present
different interactions. In one case (molecule (3-1)) the
bromide is involved into a halogen bonding [21] with the
nitro substituent of a symmetry-related molecule (symme-
try code: (i) –x, 3 – y, –z): the distance Br1–O4i is equal to
ii
and O2–H11 = 2.709(2) A. Nevertheless the extended
˚
shape of (4) allows the formation of intermolecular p-
stacking interactions between the chloronitroimidazopyri-
dine of the asymmetric unit and that of a symmetry-related
molecule (symmetry code: (iii) –x, –y, 3 – z) in one hand,
and the phenylsulfonylmethyl of the asymmetric unit and
that of another symmetry-related molecule (symmetry code:
(iv) –1 – x, –1 – y, 3 – z) on the other hand. The molecules
are then organized as two perpendicular sheets respectively
parallel to planes (4 5 7) and (10 –18 12) within the crystal of
(4) (Fig. 4): the dihedral between the pyridine rings and the
distance between their centroids are equal to 0.04° and
˚
˚
3.083(5) A (sum of their van der Waals: 3.37 A) and the
angle C11–Br1ÁÁÁO4i is equal to 161.2(2)°. Molecule 3-1
also interacts with another symmetry-related molecule
(symmetry code: (ii) 1 – x, 2 – y, –z) through two sym-
˚
3.922(1) A respectively while the dihedral between the
ii
˚
metrical C–HÁÁÁN bonds: H13ÁÁÁN1 = 2.574(5) A and
phenyl rings and the distance between their centroids are
C13–H13ÁÁÁN1ii = 170.32°. As a consequence of all these
equal to 0.02° and 4.066(1) A respectively.
˚
Further studies are now under way to transform these
phenylsulfonyl derivatives into the corresponding pyridi-
iv
(aryl)
v
none
precursors.
Moreover,
structure–reactivity
H
H
(aryl)
iii
(aryl)
relationship study is under investigation to rule on the
reactivity of these molecules which exert non-classsical
intermolecular interactions.
i
H
O
Br
Cl
O
ii
N
S
Cl
N
Br
Supplementary material
NO
2
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 288830, CCDC
Scheme 2 Summary of the intermolecular interactions within the
crystal of (2). Symmetry codes: (i) –x, 1 – y, 1 – z; (ii) 1 – x, –y, 1 – z;
(iii) –x, –1/2 + y, 3/2 – z; (iv) –x, 1/2 + y, 3/2 – z; (v) x, 1/2 – y, 1/
2 + z
123

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J Chem Crystallogr (2007) 37:831–836
v
iv
H(Met)
H(Met)
ii
iii
N(imid)
N(imid)
ii
iii
H(pyr)
H(pyr)
O
O
O
O
N
N
CH3
Pyrvi
S
CH3
S
N
N
Br
Br
i
NO2
NO2
NO2
Scheme 3 Summary of the intermolecular interactions within the crystal of (3). Left view: molecule 3-1, right view: molecule 3-2. Symmetry
codes: (i) –x, 3 – y, –z; (ii) 1 – x, 2 – y, –z; (iii) 2 – x, –y, 1 – z; (iv) 1 – x, 1 – y, –z; (v) 1 – x, –y, 1 – z
C
A
O
B
Fig. 4 Crystal packing of (4)
8. Sheldrick GM (1997) Shelxl97, Program for Crystal Refinement
288832 and CCDC 288833. Copies of available material
¨
Structures. University of Gottingen, Germany
can be obtained free of charge, on application to the
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk).
9. Farrugia, LJ (1997) J Appl Cryst, 30:565; Johnson, CK (1976)
OrtepII. Oak Ridge National Laboratory, Tenessee
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