Syntheses and Crystal Structures of 2-Chloromethyl-3,5-dimethyl-4-methoxy/ethoxy-pyridines and Their Methylsulphinyl Derivatives

Article abstract of DOI:10.1007/s10870-018-0713-7

Abstract: Treatment of 2-(chloromethyl)-pyridine derivatives 3,5-dimethyl-4-(alkoxy)-2-(chloromethyl)-pyridine hydrochloride (alkoxy = methoxy, 1; ethoxy, 2) with 1-(4-chloro-phenyl)imidazole-2-thione in the presence of sodium methoxide afforded the corresponding methylsulphinyl derivatives 3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-methylthio-1-(4-chloro-phenyl)-imidazole (alkoxy = methoxy, 3; ethoxy, 4). Similarly, reaction of 1 or 2 with 4,6-dimethyl-pyrimidine-2-thiol gave the methylsulphinyl derivatives 3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine (alkoxy = methoxy, 5; ethoxy, 6). While reaction of 5 with CuCl₂·2H₂O in methanol produced a square-planar copper(II) complex, trans-bis{3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine}-dichloro-copper(II) (7). The crystal structures of 1, 2, 4?HCl?2H₂O, and 7, along with their spectroscopic properties are reported. The weak hydrogen-bonding interactions exist in compounds 1, 2, and 4?HCl?2H₂O. Compound 1 crystallizes in the monoclinic space group P2₁/c with a = 6.074(11), b = 19.88(4), c = 9.230(16)??, β = 99.67(4)°, and Z = 4. Compound 2 crystallizes in the monoclinic space group P2₁/n with a = 10.0103(15), b = 7.9905(12), c = 15.120(2) ?, β = 93.924(2), and Z = 4. The unit cells of both 4?HCl?2H₂O and 7 have triclinic P-1 symmetry with the cell parameters a = 7.492(8), b = 10.170(12), c = 15.723(18) ?, α = 77.159(15)°, β = 91.113(13)°, γ = 81.194(16)°, and V = 1152(2)??³ for 4?HCl?2H₂O and a = 10.526(2), b = 12.936(2), c = 14.455(3)??, α = 107.929(2)°, β = 93.686(2)°, γ = 104.095(3)°, and V = 1734.3(6) ?³ for 7. Graphical Abstract: Interaction of 3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine and CuCl₂·2H₂O in methanol resulted in the formation of a square-planar copper(II) complex, trans-bis{3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine}-dichloro-copper(II), which was structurally characterized.

Full text of DOI:10.1007/s10870-018-0713-7

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-018-0713-7
ORIGINAL PAPER
Syntheses and Crystal Structures of 2-Chloromethyl-3,5-dimethyl-4-
methoxy/ethoxy-pyridines and Their Methylsulphinyl Derivatives
1
1
1
1
1
Sen Ma · Min Chen · Fang‑Fang Fan · Ai‑Quan Jia · Qian‑Feng Zhang
Received: 18 January 2016 / Accepted: 18 April 2018
©
Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Treatment of 2-(chloromethyl)-pyridine derivatives 3,5-dimethyl-4-(alkoxy)-2-(chloromethyl)-pyridine hydrochloride
(
alkoxy=methoxy, 1; ethoxy, 2) with 1-(4-chloro-phenyl)imidazole-2-thione in the presence of sodium methoxide afforded
the corresponding methylsulphinyl derivatives 3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-methylthio-1-(4-chloro-phenyl)-
imidazole (alkoxy = methoxy, 3; ethoxy, 4). Similarly, reaction of 1 or 2 with 4,6-dimethyl-pyrimidine-2-thiol gave the
methylsulphinyl derivatives 3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine (alkoxy=methoxy,
5
; ethoxy, 6). While reaction of 5 with CuCl ·2H O in methanol produced a square-planar copper(II) complex, trans-
2
2
bis{3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine}-dichloro-copper(II) (7). The crystal
structures of 1, 2, 4⋅HCl⋅2H O, and 7, along with their spectroscopic properties are reported. The weak hydrogen-bonding
2
interactions exist in compounds 1, 2, and 4⋅HCl⋅2H O. Compound 1 crystallizes in the monoclinic space group P2 /c with
2
1
a=6.074(11), b=19.88(4), c=9.230(16) Å, β=99.67(4)°, and Z=4. Compound 2 crystallizes in the monoclinic space group
P2 /n with a=10.0103(15), b=7.9905(12), c=15.120(2) Å, β=93.924(2), and Z=4. The unit cells of both 4⋅HCl⋅2H O
1
2
and 7 have triclinic P-1 symmetry with the cell parameters a=7.492(8), b=10.170(12), c=15.723(18) Å, α=77.159(15)°,
3
β=91.113(13)°, γ=81.194(16)°, and V=1152(2) Å for 4⋅HCl⋅2H O and a=10.526(2), b=12.936(2), c=14.455(3) Å,
2
3
α=107.929(2)°, β=93.686(2)°, γ=104.095(3)°, and V=1734.3(6) Å for 7.
Graphical Abstract
Interaction of 3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-pyrimidine and CuCl ·2H O in methanol
2
2
resulted in the formation of a square-planar copper(II) complex, trans-bis{3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methyl-
thio-4,6-dimethyl-pyrimidine}-dichloro-copper(II), which was structurally characterized.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10870-018-0713-7) contains
supplementary material, which is available to authorized users.
Extended author information available on the last page of the article
Vol.:(0
1
123456789)
3

Journal of Chemical Crystallography
Keywords 2-(Chloromethyl)-pyridine · Methylsulphinyl derivatives · Imidazole · Pyrimidine · X-ray structure · Copper(II)
complex
1
Introduction
SiMe4 ( H). Infrared spectra (KBr) were recorded on a
Perkin-Elmer 16 PC FT-IR spectrophotometer with the
use of pressed KBr pellets. Positive FAB mass spectra
were recorded on a Finnigan TSQ 7000 spectrometer.
Elemental analyses were carried out using a Perkin-Elmer
2400 CHN analyzer.
Secondary bonding interactions in halides of the simple
halogenated nitrogen bases, such as anilines and pyri-
dines have attracted much attention due to their interest-
ing structures and condensing reaction of chloromethyl
group, for example, the new thioether compound with
benzimidazole moiety is the critical reaction intermedi-
ate of the anti-ulcer drug lansoprazole [1–3]. A series
of 2-(chloromethyl)-pyridine derivatives were fully syn-
thesized from 2-picoline as a starting material accord-
ing to the literature method [4]. The condensing reaction
of 2-(chloromethyl)-pyridine and imidazole-2-thione or
pyrimidine-2-thiol in the presence of sodium methox-
ide as a strong base was performed, which results in the
formation of the methylsulphinyl derivatives [5]. In our
approach to the synthesis of the lansoprazole-like precur-
sor with the typical methylthio moiety, we tried to devise
a process that could use 2-(chloromethyl)-pyridine hydro-
chloride derivatives to react with 1-(4-chloro-phenyl)-
imidazole-2-thione or 4,6-dimethyl-pyrimidine-2-thiol, as
shown in Scheme 1. A mononuclear copper(II) complex
formed from the coordination of the chlorine atoms and
nitrogen atoms of pyridines was also isolated and struc-
turally characterized in this paper. Copper is the most
extensively used transition metal for the development of
anticancer drugs due to its oxidative nature and biocom-
patible properties [6]. For example, the DNA binding
and cleavage properties of numerous copper(II) com-
plexes with various amino acids and heterocyclic bases
have shown most of the complexes bound to DNA though
groove binding mode and cleaved DNA in the presence of
a reducing agent, 3-mercatopropionic acid [7].
Crystallization of 3,5‑Dime‑
thyl‑4‑(methoxy)‑2‑(chloromethyl)‑pyridine hydro‑
chlo‑ride (1)
Hydrochloride acid (1.0 mL, 1.0 M in water) was added
to 3,5-dimethyl-4-(methoxy)-2-(chloromethyl)-pyridine
(185.65 mg, 1.0 mmol) in ethanol (10 mL). The mixture was
stirred for 1 h at room temperature and further filtered to give
a clear solution. After the solution was kept in air for a week
at room temperature, colorless crystals were obtained and
−
1
1
indentified as 1. Yield: 92.6%. IR (cm ): 726.5 ν (C–Cl). H
NMR (DMSO-d6) δ (ppm): 2.32 (s, 3H, m-CH3), 2.36 (s, 3H,
m-CH3), 3.99 (s, 3H, p-OCH3), 5.09 (s, 2H, o-CH2-), 8.62
+
(s, 1H, o-H). MS (FAB): m/z 186 [M –Cl]. Anal. Calc. for
C9H13NOCl2: C, 48.67; H, 5.90; N, 6.31. Found: C, 48.63;
H, 5.88; N, 6.32%.
Crystallization of 3,5‑Dime‑
thyl‑4‑(ethoxy)‑2‑(chloromethyl)‑pyridine hydro‑
chloride (2)
The method was similar to that used for 1, employ-
ing 3,5-dimethyl-4-(ethoxy)-2-(chloromethyl)-pyridine
(199.6 mg, 1.0 mmol) instead of 3,5-dimethyl-4-(methoxy)-
−
1
2-(chloromethyl)-pyridine. Yield: 90.2%. IR (cm ): 715.6
1
ν (C–Cl). H NMR (DMSO-d6) δ (ppm): 1.39 (t, J=6.8 Hz,
3
4
8
H, p-OCH CH ), 2.36 (s, 3H, m-CH ), 2.38 (s, 3H, m-CH ),
2 3 3
.25 (q, J=10.4 Hz, 2H, p-OCH -), 5.13 (s, 2H, o-CH -),
3
2
2
+
.66 (s, 1H, o-H). MS (FAB): m/z 200 [M –Cl]. Anal. Calc.
Experimental
for C10H15NOCl2: C, 50.86; H, 6.40; N, 5.93. Found: C,
5
0.83; H, 6.37; N, 5.95%.
General
Synthesis of 3,5‑Dime‑
thyl‑[4‑(methoxy)‑2‑pyridinyl]‑methyl‑
thio‑1‑(4‑chloro‑phen‑yl)‑imidazole (3)
All syntheses were carried out under a nitrogen atmos-
phere. 3,5-Dimethyl-4-(methoxy)-2-(chloromethyl)-pyr-
idine [8], 3,5-dimethyl-4-(ethoxy)-2-(chloromethyl)-pyr-
idine [8], 1-(4-chloro-phenyl)imidazole-2-thione [9, 10],
and 4,6-dimethyl-pyrimidine-2-thiol [11] were prepared
according to the literature methods. Other chemicals
employed for syntheses were purchased from commer-
cial sources and used without further purification. NMR
spectra were recorded on a Bruker AM 400 spectrometer.
Chemical shifts (δ, ppm) were reported with reference to
To a slurry of 1-(4-chloro-phenyl)imidazole-2-thione
(212 mg, 1.0 mmol) and sodium methoxide (119 mg,
2.2 mmol) in methanol (20 mL) was added a solution of 1
(222 mg, 1.0 mmol) in methanol (10 mL). After the mixture
was refluxed with stirring for 4 h, the solvent was removed
in vacuo and the residue was washed with water to remove
the salt, and then extracted with dichloromethane (3×5 mL)
1
3

Journal of Chemical Crystallography
Scheme 1 The approach to the
syntheses of the lansoprazole-
like precursors and the mononu-
clear copper(II) complex
OR
N
N
N
H C
CH3
C
3
N
N
HS
S
MeONa, MeOH
reflux
H
R = CH
C H
3
3
4
2
2
5
OR
H C
CH
3
3
Cl
Cl
Cl
C
N
HCl
H
2
CH3
OR
N
N
CH
3
H C
3
CH
3
R = CH3
C H
1
MeONa, MeOH
reflux
N
HS
2
5
2
S
R = CH
C H 6
5
5
C
H
3
N
CH3
N
2
2
CH3
CuCl , MeOH, reflux
2
OCH3
CH
CH3
H C
3
3
N
N
S
N
C
H
2
CH3
Cl Cu Cl
N
H C
3
H
C
N
N
2
S
7
H C
CH3
H C
3
3
OCH3
at room temperature. The yellow solid product was directly
obtained by removal of the solvent, further dried at 40 °C
The methanol solution (pH = 4.5) of 4 was allowed to
stand in air for crystallization for 5 days. Yellow block-
shaped crystals, which were suitable for single-crystal
X-ray structural determination, were found and indentified
−
1
overnight and indentified as 3. Yield: 82.3%. IR (cm ):
1
8
34.4 ν (–CH –S–). H NMR (CDCl ) δ (ppm): 2.41 (s, 3H,
2
3
m-CH ), 2.43 (s, 3H, m-CH ), 4.12 (s, 3H, –OCH ), 4.57
as 4·HCl·2H O. The crystals were kept in their mother liquor
3
3
3
2
(
s, 2H, –CH S–), 6.68 (s, 1H, H in imidazole), 6.74 (s, 1H,
to avoid potential solvent loss before data collection.
2
H in imidazole), 7.53 (d, J=5.2 Hz, 2H, H in Ph), 7.75 (d,
J=8.5 Hz, 2H, H in Ph), 8.12 (s, 1H, H in py). MS (FAB):
+
m/z 349 [M ]. Anal. Calc. for C H N OSCl: C, 58.36; H,
Synthesis of 3,5‑Dime‑
thyl‑[4‑(methoxy)‑2‑pyridinyl]‑methylthio‑4,6‑di‑
methyl‑pyri‑midine (5)
1
7
20
3
5
.76; N, 12.01. Found: C, 58.14; H, 5.72; N, 12.05%.
Synthesis of 3,5‑Dime‑
thyl‑[4‑(ethoxy)‑2‑pyridinyl]‑methyl‑
thio‑1‑(4‑chloro‑phenyl)‑imidazole (4)
The method was similar to that used for 3, employing
4,6-dimethyl-pyrimidine-2-thiol (140 mg, 1.0 mmol) and
two instead of 1-(4-chloro-phenyl)imidazole-2-thione.
−
1
1
The method was similar to that used for 3, employing 2
Yield: 85.6%. IR (cm ): 830.2 ν (–CH –S–). H NMR
2
−
1
(
236 mg, 1.0 mmol) instead of 1. Yield: 80.5%. IR (cm ):
(CDCl ) δ (ppm): 2.32 (s, 3H, –CH in py), 2.35 (s, 6H,
3
3
1
8
34.7 ν (–CH –S–). H NMR (CDCl ) δ (ppm): 1.52 (t,
–CH in pyrimidine), 2.38 (s, 3H, –CH in py), 3.77 (s, 3H,
2
3
3
3
J=7.0 Hz, 3H, –OCH CH ), 2.39 (s, 3H, m-CH ), 2.44 (s,
–OCH ), 4.55 (s, 2H, –CH S–), 6.98 (s, H in pyrimidine),
3 2
2
3
3
+
3
2
H, m-CH ), 4.29 (q, J=3.9 Hz, 2H, –OCH CH ), 4.58 (s,
8.26 (s, 1H, H in py). MS (FAB): m/z 276 [M ]. Anal. Calc.
3
2
3
H, –CH S–), 6.72 (s, 1H, H in imidazole), 6.81 (s, 1H, H
for C H N OS: C, 60.62; H, 6.90; N, 15.15. Found: C,
2
14 19
3
in imidazole), 7.57 (d, J = 8.8 Hz, 2H, H in Ph), 7.70 (d,
60.54; H, 6.85; N, 15.12%.
J=8.8 Hz, 2H, H in Ph), 8.16 (s, 1H, H in py). MS (FAB):
+
m/z 363 [M ]. Anal. Calc. for C H N OSCl: C, 59.41; H,
1
8
22
3
6
.09; N, 11.55. Found: C, 59.25; H, 6.02; N, 11.63%.
1
3

Journal of Chemical Crystallography
Table 1 Crystallographic data
and experimental details for 1,
Compound
1
2
4·HCl·2H O
7
2
2
, 4·HCl·2H O, and 7
2
CCDC number
Empirical formula
Formula weight
Crystal system
a (Å)
b (Å)
c (Å)
1443777
C H NOCl
222.10
Monoclinic
6.074(11)
19.88(4)
9.230(16)
1443778
C H NOCl
236.13
Monoclinic
10.0103(15)
7.9905(12)
15.120(2)
1443779
1443780
C H N O S Cl Cu
1426.45
C H N O SCl
9
13
2
10 15
2
18 25
3
3
3
60 76 12
4
4
4
2
469.82
Triclinic
7.492(8)
10.170(12)
15.723(18)
77.159(15)
85.038(13)
81.194(16)
1152(2)
P-1
Triclinic
10.526(2)
12.936(2)
14.455(3)
107.929(2)
101.493(2)
104.095(3)
1734.3(6)
P-1
α (°)
β (°)
99.67(4)
1098(3)
93.924(2)
1206.6(3)
γ (°)
V (Å )
3
Space group
P2 /c
P2 /n
1
1
Z
4
4
2
1
Dcalc (g cm−3
)
1.343
296(2)
464
0.553
3109
1683
0.1204
0.0478, 0.1019
0.0553, 0.1190
0.988
1.300
296(2)
496
0.508
7105
2715
0.0248
0.0528, 0.1446
0.0704, 0.1588
1.085
1.354
296(2)
490
0.511
6932
4983
0.0361
0.0729, 0.1409
0.0927, 0.1763
1.010
1.366
296(2)
742
0.940
11,027
7732
0.0343
0.0508, 0.1013
0.0708, 0.1456
0.832
Temperature (K)
F(000)
µ (Mo-Kα) (mm−1)
Total refln
Independent refln
Rint
R1 , wR2 [I>2σ(I)]
R1, wR2 (all data)
a
b
c
GoF
∑
∑
a
��
�
�
− F
�
��
�
�
�
F ;
0�
R1 =
F
∕
�
�
0�
c��
�
ꢅ
ꢀ
ꢂ
1∕2
2
ꢃ
ꢄ
∑
ꢁ
ꢁ
ꢁ
ꢁ
∑
2
b
2
2
2
wR2 =
GoF =
w ꢁF ꢁ − −ꢁF ꢁ
∕
w F
0
c
0
ꢁ
ꢁ
ꢁ
ꢁ
�
ꢃ
ꢀ
ꢂ2 ꢀ
ꢂ
1∕2
∑
c
ꢁ
w F − F
ꢁ
ꢁ
ꢁ
∕ N − −Nparam
obs
ꢁ
0ꢁ
ꢁ
cꢁ
Synthesis of 3,5‑Dime‑
thyl‑[4‑(ethoxy)‑2‑pyridinyl]‑methylthio‑4,6‑dime‑
thyl‑pyrimi‑dine (6)
Synthesis of trans‑bis{3,5‑Dimethyl‑[4‑(methoxy)
‑2‑pyridinyl]‑methylthio‑4,6‑dimethyl‑pyrimidin
e}‑dichloro‑copper(II) (7)
The method was similar to that used for 3, employing
A solution of CuCl ·2H O (102 mg, 0.60 mmol) in methanol
2
2
4
,6-dimethyl-pyrimidine-2-thiol (140 mg, 1.0 mmol) and 2
(6 mL) was added with stirring to a solution of 5 (166 mg,
0.60 mmol) in methanol (8 mL). After the resulting solution
was heated under reflux for 1 h, the solvent was removed
(
236 mg, 1.0 mmol) instead of 1-(4-chloro-phenyl)-imida-
−
1
zole-2-thione and 1, respectively. Yield: 86.1%. IR (cm ):
1
8
29.8 ν (–CH –S–). H NMR (CDCl ) δ (ppm): 1.51 (t,
in vacuo and the residue was washed with Et O and fur-
2
3
2
J=7.8 Hz, 3H, –OCH CH ), 2.39 (s, 3H, –CH in py), 2.40
ther recrystallized from CH Cl /Et O (1:3) at room tem-
2
3
3
2
2
2
(
(
(
s, 3H, –CH in py), 2.48 (s, 6H, –CH in pyrimidine), 4.16
perature. Green needle-shaped crystals of 7 suitable for
3
3
q, J=4.0 Hz, 2H, –OCH CH ), 4.54 (s, 2H, –CH S–), 6.89
X-ray diffraction were obtained in 3 days. Yield: 68.3%. IR
2
3
2
−
1
s, H in pyrimidine), 8.37 (s, 1H, H in py). MS (FAB): m/z
(cm ): 826.5 ν (–CH –S–), 299.3 ν (Cu–Cl). MS (FAB):
2
+
+
+
+
2
91 [M ]. Anal. Calc. for C H N OS: C, 61.82; H, 7.26;
m/z 713 [M ], 678 [M –Cl], 643 [M –2Cl]. Anal. Calc. for
1
5
21
3
N, 14.42. Found: C, 61.76; H, 7.23; N, 14.50%.
C H N O S Cl Cu: C, 50.52; H, 5.37; N, 11.78. Found:
3
0
38
6
2
2
2
C, 50.44; H, 5.26; N, 11.72%.
X‑ray Crystallography
A summary of crystallographic data and experimental details
for 1, 2, 4·HCl·2H O, and 7 are summarized in Table 1.
2
1
3

Journal of Chemical Crystallography
Fig. 1 a The content of asymmetric unit in 1, showing the atom-
labelling scheme. Displacement ellipsoids are drawn at the 40%
probability level. b A view of the dimeric unit of the 2-isomer in the
crystal. Ellipsoids represent 40% probability levels and H-atom radii
are arbitrary. Hydrogen bonds C–H⋯Cl and N–H⋯Cl are shown as
dashed lines
Intensity data were collected on a Bruker SMART APEX 2
CCD diffractometer using graphite-monochromated Mo-Kα
radiation (λ=0.71073 Å) at 296(2) K. The collected frames
were processed with the software SAINT [12]. The data was
corrected for absorption using the program SADABS [13].
Structures were solved by direct methods and refined with
Fig. 2 a The content of asymmetric unit in 2, showing the atom-
labelling scheme. Displacement ellipsoids are drawn at the 40% prob-
ability level. b A packing diagram of 2, projected along the ac plane.
Hydrogen bonds are shown as dashed lines
3,5-dimethyl-4-(alkoxy)-2-(chloromethyl)-pyridine hydro-
chloride 1 and2 in high yields. As shown in Scheme 1, treat-
ment of 1 or 2 with the aryl substituted imidazole-2-thione
in refluxing methanol for 4 h in the presence of sodium
methoxide afforded the corresponding methylsulphinyl
derivatives 3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-methyl-
thio-1-(4-chloro-phenyl)-imidazole (alkoxy = methoxy, 3;
ethoxy, 4) in good yields. Similar reactions of compound
2
full-matrix least-squares on F using the SHELXTL soft-
ware package [14]. All non-hydrogen atoms were refined
anisotropically. The positions of all hydrogen atoms were
generated geometrically (C –H=0.96 Å, C –H=0.93 Å,
sp3
sp2
and N–H=0.86−0.93 Å), assigned isotropic thermal param-
eters, and allowed to ride on their respective parent carbon
atoms for the final cycle of least-squares refinement.
1
or 2 with 4,6-dimethyl-pyrimidine-2-thiol gave 3,5-dime-
thyl-[4-(alkoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-
pyrimidine (alkoxy=methoxy, 5; ethoxy, 6), respectively.
Moreover, the reaction of 5 with CuCl ·2H O in methanol
Results and Discussion
2
2
Hydrochloride acid was added to 3,5-dimethyl-
resulted in formation of a copper(II) complex trans-bis{3,5-
dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dime-
thyl-pyrimidine}-dichloro-copper(II) (7) as green crystals.
4
-(methoxy)-2-(chloromethyl)-pyridine or 3,5-dime-
thyl-4-(ethoxy)-2-(chloromethyl)-pyridine in eth-
anol to obtain the according crystalline solid
1
3

Journal of Chemical Crystallography
Fig. 4 Molecular structure of 7, showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 40% probability level (sym-
metry code: −x+1, −y+1, −z)
Table 2 Selected bond lengths (Å) and angles (°) for 1
Cl(1)–C(6)
O(1)–C(4)
O(1)–C(9)
N(1)–C(5)
C(3)–O(1)–C(9)
N(1)–C(1)–C(2)
O(1)–C(3)–C(2)
N(1)–C(5)–C(6)
1.795(5)
1.364(3)
1.393(4)
1.350(4)
127.5(4)
123.6(4)
124.2(4)
115.5(4)
O(1)–C(3)
O(1)–C(8)
N(1)–C(1)
1.338(4)
1.398(4)
1.332(5)
C(1)–N(1)–C(5)
O(1)–C(3)–C(4)
N(1)–C(5)–C(4)
C(5)–C(6)–Cl(1)
121.1(3)
113.8(4)
119.5(3)
111.4(3)
Fig. 3 a The content of asymmetric unit in 4·HCl·2H O, showing
2
the atom-labelling scheme. Displacement ellipsoids are drawn at the
4
0% probability level. b A packing diagram of 4·HCl·2H O, projected
2
along the ab plane. Hydrogen bonds are shown as dashed lines
Table 3 Selected bond lengths (Å) and angles (°) for 2
The infrared spectra of imidazole derivatives 3 and 4
−
1
showed –CH –S– peaks at about 834 cm , and for pyrimi-
Cl(2)–C(1)
O(1)–C(9)
N(1)–C(2)
C(4)–O(1)–C(9)
C(2)–C(1)–Cl(2)
N(1)–C(2)–C(1)
O(1)–C(4)–C(5)
1.798(3)
1.387(6)
1.346(3)
118.9(3)
109.88(18)
115.8(2)
117.9(2)
O(1)–C(4)
N(1)–C(6)
1.359(3)
1.334(3)
2
−
1
dine derivatives 5 and 6 showed peaks at around 830 cm .
−
1
The copper complex 7 showed –CH –S– peak at 826 cm
2
−
1
1
and Cu–Cl peak at 299.3 cm . The H NMR spectra of
C(6)–N(1)–C(2)
N(1)–C(2)–C(3)
O(1)–C(4)–C(3)
N(1)–C(6)–C(5)
123.1(2)
119.8(2)
120.0(2)
121.0(2)
compounds 3–6 all showed –CH –S– protons as a single
2
peak ranging from 4.54 to 4.58 ppm. The signals of imi-
dazole and pyrimidine heterocycles could easily be found
1
in the H NMR spectra of 3–4 (6.68–6.81 ppm) and 5–6
(
6.98, 6.89 ppm), respectively, indicating their stable struc-
tures during the reactions. The positive-ion ESI mass spectra
of compounds 3–7 all clearly displayed their molecular ion
peaks.
diffraction analysis, as shown in Figs. 1, 2, 3 and 4, respec-
tively. Crystallographic data and experimental details for
the four compounds are shown in Table 1, selected bond
lengths and angles are given in Tables 2, 3, 4 and 5, while
the hydrogen-bond characteristics and geometric parameters
Molecular structures of compounds 1, 2, 4·HCl·2H O,
2
and 7 were further confirmed by single-crystal X-ray
1
3

Journal of Chemical Crystallography
Table 4 Selected bond lengths (Å) and angles (°) for 4·HCl·2H O
special position on a crystallographic inversion center. The
Cu(1) atom in symmetrical structure 7 has a typical square-
planar coordination with two chlorides in a trans-geometry
and two nitrogen atoms of pyridine moieties in 3,5-dime-
thyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-
pyrimidine ligands. The Cu–Cl and Cu–N bond lengths are
2
S(1)–C(10)
1.753(3)
1.355(6)
1.342(6)
1.320(5)
1.367(5)
1.437(5)
99.86(18)
122.4(4)
106.9(4)
124.4(3)
115.9(4)
119.5(4)
S(1)–C(9)
O(1)–C(8)
1.840(4)
1.388(9)
1.367(4)
1.375(5)
1.393(5)
1.747(5)
118.6(4)
109.5(4)
128.7(3)
118.8(4)
119.0(3)
122.1(3)
O(1)–C(3)
N(1)–C(5)
N(1)–C(1)
N(2)–C(10)
N(3)–C(10)
N(2)–C(11)
N(3)–C(12)
2
.287(3) and 2.029(8) Å, respectively, which are comparable
N(3)–C(13)
Cl(1)–C(16)
to those in a similar copper complex trans-bis{2-chlorome-
thyl-pyridine}-dichloro-copper(II) (2.272 and 2.008 Å) [17].
A view of the dimeric unit of the 1-isomer in the crys-
tal is displayed in Fig. 1b. In the 1-isomer, the classi-
cal N–H⋯Cl hydrogen bond combines with the shortest
H⋯Cl interaction, N1–H1N⋯Cl2 [H1N⋯Cl2=2.15(1) Å,
N1–H1N⋯Cl2=174.9(2)°], to form a centrosymmtric dimer
C(10)–S(1)–C(9)
C(5)–N(1)–C(1)
C(10)–N(3)–C(12)
C(12)–N(3)–C(13)
N(1)–C(1)–C(9)
O(1)–C(3)–C(4)
C(3)–O(1)–C(8)
C(10)–N(2)–C(11)
C(10)–N(3)–C(13)
N(1)–C(1)–C(2)
O(1)–C(3)–C(2)
N(1)–C(5)–C(4)
[
18]. The packing view of compound 2 along the ac plane
is shown in Fig. 2b. The crystal packing in 2 molecules is
governed by weak intermolecular C–H⋯Cl and N–H⋯Cl
hydrogen-bonding interactions. In the crystal structure of 2,
the molecules are thus arranged in discrete two-dimensional
layers that lie parallel to the crystallographic ac plane. The
chloride ions act as the hydrogen-bond bridges, provid-
ing further stability to the crystal lattice. The separation of
H1N⋯Cl1 is 2.075(11) Å and the angle of N1–H1N⋯Cl1
is 174(3)°, which are compared with those in the molecule
Table 5 Selected bond lengths (Å) and angles (°) for 7
Cu(1)–N(1)
S(1)–C(9)
O(1)–C(3)
N(1)–C(1)
N(2)–C(11)
N(3)–C(10)
N(1)–Cu(1)–Cl(1)
C(3)–O(1)–C(8)
C(1)–N(1)–Cu(1)
2.029(8)
1.789(12)
1.376(11)
1.348(12)
1.332(15)
1.320(14)
88.4(2)
Cu(1)–Cl(1)
S(1)–C(10)
O(1)–C(8)
N(1)–C(5)
N(2)–C(10)
2.287(3)
1.787(12)
1.415(13)
1.351(11)
1.339(13)
1.351(13)
103.0(6)
118.6(9)
124.8(7)
N(3)–C(13)
C(9)–S(1)–C(10)
C(1)–N(1)–C(5)
C(5)–N(1)–Cu(1)
of 1-isomer. The packing view of compound 4·HCl·2H O
2
113.9(9)
116.7(7)
along the ab plane is shown in Fig. 3b. The crystal structure
of 4·HCl·2H O contains one independent molecular cation,
2
one chloride ion, one free hydrogen chloride molecule and
two water solvato molecules which are involved in the for-
mation of hydrogen-bonded three-dimensional framework
via N–H⋯Cl, N–H⋯O, O–H⋯Cl, O–H⋯O, and Cl–H⋯N
hydrogen bonds, as seen in Table 6 and Fig. 3b. Obviously,
the chloride ion, the free hydrogen chloride molecule and
the water molecules act as hydrogen-bond bridges which
may provide further stability to the crystal lattice. The crys-
tal packing exhibits that there is no obvious π–π interaction
between the imidazole and pyridine rings from the neigh-
bouring molecules.
for 1, 2, and 4·HCl·2H O are summarized in Table 6. The
2
C–Cl bond lengths are 1.795(5) Å in 1 and 1.798(3) Å in
2
, which are near to those in 1,6-bis(chloromethyl)pyri-
dine [1.8074(10), 1.8068(9) Å] [15]. The –CH –S– bond
2
distances are 1.840(4) Å in 4·HCl·2H O and 1.789(12) Å
2
in 7, which are compared to that in a known compound
2
-{[3-methyl-4-(2,2,2-trifluoroethoxy)-pyridin-2-yl]methyl-
sulfanyl}-1H-benzimidazole propan-2-ol mono-solvate
[
[
1.809(2) Å] [16]. The C–S–C bond angle of 4·HCl·2H O
2
99.86(18)°] is a little smaller than that in 7 [103.0(6)°].
In summary, a series of methylsulphinyl derivatives
3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-methylthio-1-(4-chloro-
In the crystal structure of 7, the copper atom occupies a
Table 6 Hydrogen-bonding
Compound
D–H⋯A
d (D–H) (Å)
d (H⋯A) (Å)
d (D⋯A) (Å)
∠ (DHA) (deg)
system for 1, 2, and 4·HCl·2H O
2
1
2
N1–H1N⋯Cl2
N1–H1N⋯Cl1
0.86
0.928(10)
0.86
2.15
2.075(11)
1.82
3.009(5)
3.000(2)
2.676(6)
3.015(5)
2.719(5)
3.218(6)
3.057(4)
3.151(5)
3.015(5)
174.9
174(3)
174.1
4
·HCl·2H O
N1–H1N⋯O1W
N2–H2N⋯Cl2
O1W–H2W⋯O2W
O2W–H3W⋯Cl3
O1W–H1W⋯Cl3
O2W–H4W⋯Cl3
Cl2–H2L⋯N2
2
0.86
2.19
161.5
0.916(10)
0.917(10)
0.913(10)
0.917(10)
1.294(10)
1.806(13)
2.316(13)
2.173(17)
2.34(3)
1.90(3)
174(6)
168(3)
163(4)
148(5)
141(3)
1
3

Journal of Chemical Crystallography
phenyl)-imidazole and 3,5-dimethyl-[4-(alkoxy)-2-pyridinyl]-
methylthio-4,6-dimethyl-pyrimidine (alkoxy = methoxy
and ethoxy) were synthesized and characterized by single-
crystal X-ray diffraction along with spectroscopic methods,
of which a square-planar copper(II) complex, trans-bis{3,5-
dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-dimethyl-
pyrimidine}-dichloro-copper(II) was obtained from reaction
of 3,5-dimethyl-[4-(methoxy)-2-pyridinyl]-methylthio-4,6-di-
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Acknowledgements This project was supported by the Natural Science
Foundation of China (21372007).
Affiliations
1
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Sen Ma · Min Chen · Fang‑Fang Fan · Ai‑Quan Jia · Qian‑Feng Zhang
1
*
Qian-Feng Zhang
Institute of Molecular Engineering and Applied Chemistry,
Anhui University of Technology, Ma’anshan 243002, Anhui,
People’s Republic of China
zhangqf@ahut.edu.cn
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