Synthesis of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)benzimidazoles

Article abstract of DOI:10.1002/jhet.5570400104

A useful approach for the synthesis of pharmacologically active tetrahydropyridinylbenzimidazoles is described. 2-Pyridin-3-ylbenzimidazoles 3a-d have been synthesized by condensation of 3-pyridinecarboxaldehyde 1 with substituted 1,2-phenylenediamines 2a-d following oxidative cyclization with iodobenzene diacetate. Methylation of 3a-d with iodomethane and potassium hydroxide, subsequent formation of methylpyridinium salts 4a-d and 7a-d and reduction thereafter afforded tetrahydropyridinylbenzimidazoles 5a-d and 8a-d.

Full text of DOI:10.1002/jhet.5570400104

Jan-Feb 2003
Synthesis of 2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)benzimidazoles
37
Myung Hee Jung*, Jung Mee Park, Ihl-Young Choi Lee, and Mija Ahn
Korea Research Institute of Chemical Technology, P.O. Box 107, Yusong, Taejon 305-600, Korea
Received March 28, 2002
A useful approach for the synthesis of pharmacologically active tetrahydropyridinylbenzimidazoles is
described. 2-Pyridin-3-ylbenzimidazoles 3a-d have been synthesized by condensation of 3-pyridinecarbox-
aldehyde 1 with substituted 1,2-phenylenediamines 2a-d following oxidative cyclization with iodobenzene
diacetate. Methylation of 3a-d with iodomethane and potassium hydroxide, subsequent formation of
methylpyridinium salts 4a-d and 7a-d and reduction thereafter afforded tetrahydropyridinylbenzimidazoles
5a-d and 8a-d.
J. Heterocyclic Chem., 40, 37 (2003).
The development of M -selective receptor agonists,
The general procedure for the synthesis of pyridinylbenz-
imidazoles has been to treat nicotinic acid with the appropri-
ate 1,2-phenylenediamine [8]. However, in a previous study,
we have succeeded in preparing pyridinylbenzimidazoles 3
in good yields from 3-pyridinecarboxaldehyde 1 and 1,2-
phenylenediamines 2 with iodobenzene diacetate via hyper-
valent iodine oxidative intramolecular cyclization. The
1
which play an important role in cognition function, has
been the focus of recent research efforts for Alzheimer's
disease (AD) treatment [1]. Arecoline (I, Figure 1), a natu-
rally occurring alkaloid, is one of the first clinical drugs
used for AD [2]. Despite being an M -agonist, its lack of
1
subtype selectivity and poor metabolic stability caused by
the ester moiety, has hindered its use as a therapeutic agent.
However, continuing efforts to synthesize derivatives of
this lead compound have brought about xanomeline (II) [3]
and milameline (III) [4] showing improved pharmacologi-
5
-substituted compounds 3b-3d were similarly prepared
using compounds 2b-2d. The structural assignment of these
5
-substituted benzimidazoles was based on results of X-ray
1
crystallography, H NMR muster of aromatic protons and
our previous experiments [6]. The spectral data for
compounds 3a-d are summarized in Table 1.
cal and pharmacokinetic properties. Both of these M selec-
1
tive muscarinic receptor agonists are in clinical trials.
Chemically, they possess a 1,2,5,6-tetrahydropyridine ring
and the unstable ester moiety of arecoline has been replaced
with its bioisosteres alkoxythiadiazole and alkoxyimino
groups. The structure of xanomeline (II) shows a resem-
blance to that of tetrahydropyridinylbenzoxazoles (IV) [6]
and tetrahydropyrimidinylbenzoxazoles (V) [7] previously
prepared in our laboratory (Figure 2). These compounds,
which possess a benzoxazole ring, exhibited interesting
biological activity as potential agrochemicals as well as
clinical drugs. Herein, we report the synthesis of tetrahy-
dropyridinyl-benzimidazoles that are bioisosteric con-
Table 1
1H NMR Data and 13C NMR Data of Compounds 3a-d
Proton
Carbon
δ [ppm]
'-H 4'-H 5'-H 6'-H C-2 C-2' C-3' C-4' C-5' C-6'
Compd
δ [ppm]
2
geners of the M selective muscarinic receptor agonists
1
shown in Figure 1 (Scheme 1 and Scheme 2).
3a
9.36 8.58 7.72 8.75 149.0 147.7 126.3 134.0 124.3 150.8
9.21 8.42 7.58 8.61 151.6 148.2 128.2 135.8 125.8 151.3
9.14 8.38 7.53 8.58 151.7 148.6 127.7 136.2 125.1 151.8
9.37 8.52 7.66 8.75 154.2 148.1 125.7 134.5 124.3 151.5
3
3
3
b
c
d
Subsequent treatment of compounds 3a-d with a large
excess of methyl iodide in acetone for 20 hours afforded the
quaternized compounds 4a-d. The quaternization occurred
only at the pyridine nitrogen due to its higher basicity. The
spectral data for compounds 4a-d are summarized in Table
Figure 1
2
. What is notable here is that unlike compounds 3a-d,
compounds 4a-d did not show the signals corresponding to
C-8 and C-9 (numbering based on arbitrary numbering of
13
X-ray Crystallography data – see Figure 3) in the C NMR
spectra [9]. Moreover, only one of the carbons of the benz-
imidazoles is observed and appears at 123.8 ppm in 4a,
113.4 ppm in 4b, 124.1 ppm in 4c, and 119.2 ppm in 4d.
Figure 2
Upon acquisition of HMQC and HMBC spectra of 4c, this

3
8
M. H. Jung, J. M. Park, I.-Y. Choi-Lee, and M. Ahn
Vol. 40
Scheme 1
carbon is determined to correspond to C-5. In the HMQC
hydropyridinylbenzimidazoles 5a-d. Again the 13C NMR
1
13
spectrum of 4c H/ C correlations corresponding to H-
/C-4 and H-7/C-7 are observed showing that C-4 and C-7
spectral data shown in Table 3 show that only aromatic
carbon is observed for compounds 5a-d, and as for 4c this
likely corresponds to C-6. The corresponding chemical
shifts were 123.1 ppm for 5a, 113.7 ppm for 5b, 124.5 ppm
for 5c, and 119.8 ppm for 5d. The coupling constants were
observed to be similar to those of compounds 4a-d.
4
resonate at ~119 and 114 ppm respectively. Interestingly,
protons corresponding to C-4 and C-7 also correlate with
carbons resonating at 112 and 124 ppm, respectively as
well. This indicates that the two tautomeric forms of com-
pound 4c, corresponding to 6-chloro- and 5-chloro-2-
pyridin-3-yl-1H-benzimidazole, exist and both are repre-
sented in the proton and carbon spectra of 4c.
Table 3
1H NMR Data and 13C NMR Data of Compounds 5a-d
Table 2
1H NMR Data and 13C NMR Data of Compounds 4a-d
Proton
δ [ppm]
'-H 4'-H 5'-H 6'-H C-2 C-2' C-3' C-4'
Carbon
Compd
δ [ppm]
2
C-5' C-6'
Proton
Carbon
C-2'
5
5
5
5
a
b
c
3.59 6.59 2.36 2.60 151.6 54.7 128.0 127.8 26.7 51.6
3.32 6.52 2.31 2.47 152.0 54.9 128.5 128.1 27.2 52.3
3.38 6.62 2.37 2.56 153.7 54.8 130.2 127.6 27.1 52.2
3.60 6.89 2.58 2.78 156.6 54.6 134.2 127.4 27.1 52.1
Compd
δ [ppm]
δ [ppm]
C-3'
+
2
'-H 5'-H, N CH3 C-2
C-4' C-5' C-6'
d
4
4
4
4
a
b
c
9.74 8.32 4.49 145.5 144.0 128.3 140.9 130.0 145.4
9.65 8.29 4.45 145.0 143.6 128.2 140.3 130.1 144.1
9.65 8.40 4.47 146.9 144.2 128.0 141.1 128.2 145.8
9.79 8.42 4.54 150.0 143.7 128.3 141.7 129.0 146.5
A commonly used literature method [10] for methylation
d
of benzimidazole is to add compounds 3a-d to a suspension
of 5 equivalents KOH in acetone, and then adding 3~5
equivalents of methyl iodide. This causes methylation at
either nitrogen of the benzimidazole yielding a 1:1 mixture
Treatment of methylpyridinium salts 4a-d with sodium
borohydride in cold (-20 °C) methanol yielded tetra-

Jan-Feb 2003
Synthesis of 2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)benzimidazoles
39
Scheme 2
Table 5
1H NMR Data and 13C NMR Data of Compounds 8a-c
Proton
Carbon
δ [ppm]
C-2' C-3' C-4'
Compd
δ [ppm]
'-H 4'-H 5'-H 6'-H C-2
2
C-5' C-6'
8
8
8
8
8
a
3.46 6.38 2.53 2.75 153.5 56.2 127.5 133.0 27.0 52.2
3.43 6.34 2.51 2.72 153.6 56.6 127.7 132.6 27.1 52.2
3.47 6.36 2.55 2.77 152.2 56.2 127.0 131.7 26.6 51.8
3.51 6.45 2.56 2.80 154.8 56.3 129.6 133.6 26.0 52.0
3.41 6.41 2.52 2.70 154.5 56.3 129.9 133.2 26.9 52.0
Figure 3. X-Ray Crystallography of 6Ab (arbitrary numbering system).
Ab
Bb
Ac
Bc
Table 4
1H NMR Data and 13C NMR Data of Compounds 6a-c
Compound 6d, however, remained as a mixture and thus
subsequent reaction proceeded without further purifica-
1
13
tion. The H and C NMR data of compounds 6a-d are
shown in Table 4. Compounds 7a-d were prepared using
the method used for compounds 4a-d followed by reduc-
tion with sodium borohydride in methanol to yield com-
pounds 8a-d. The spectral data of 8Aa-d and 8Ba-d are
summarized in Table 5.
Proton
Carbon
δ [ppm]
'-H 4'-H 5'-H 6'-H C-2 C-2' C-3' C-4' C-5' C-6'
Compd
δ [ppm]
2
EXPERIMENTAL
6
6
6
6
6
a
9.05 8.11 7.46 8.73 150.6 149.8 126.5 136.8 123.6 150.5
Ab 9.01 8.12 7.48 8.74 150.7 149.7 126.6 136.7 123.5 150.4
Bb 9.00 8.12 7.47 8.73 149.8 149.6 126.6 136.6 123.5 150.3
Ac
Bc
Melting points were determined on a Thomas-Hoover appara-
tus and are uncorrected. Infrared spectra were recorded on a
Mattson Genesis II FTIR. Nuclear magnetic resonance spectra
were measured on a Brucker AM-300 spectrometer. Mass spectra
were determined on JEOL JMS-DX 303 Mass Spectrometer
JEOL JMA-DA 5000 mass data system focusing high resolution
mass spectrometers. Single crystal X-ray diffractometry: The
intensity data were collected at room temperature on a Siemens P4
four-circle X-ray diffractometer with graphite-monochromated
9.00 8.12 7.49 8.77 151.8 149.7 126.1 136.9 123.6 150.9
9.01 8.12 7.49 8.76 151.4 149.7 126.0 136.8 123.6 150.8
of the 5-/6-substituted isomer of compounds 6a-d. Isomers
b and 6c were successfully separated by column chro-
6
matography and were distinguishable based on the results
of X-ray crystallography of compound 6Ab (Figure 3).

40
M. H. Jung, J. M. Park, I.-Y. Choi-Lee, and M. Ahn
Vol. 40
Mo Kα radiation (λ = 0.71073 Å). All calculation in the structural
solution and refinement was performed using the Siemens
SHELXTL crystallographic software package on a Silicon
Graphics system. All the non-hydrogen atoms were refined
anisotropically; all the hydrogen atoms fixed at the calculated
positions with the isotropic thermal parameters were included in
the final structure factor calculations.
C6'-H), 8.52 (m, 2H, C4-H, C4'-H), 8.16 (d, 1H, C6-H), 7.81 (d,
1
3
1H, C7-H), 7.66 (dd, 1H, C5'-H); C nmr (DMSO-d ): δ 154.2
6
(C-2), 151.5 (C-6'), 148.1 (C-2'), 143.7, 140.1 (C-8, C-9), 142.8
(C-5), 134.5 (C-4'), 125.7 (C-3'), 124.3 (C-5'), 118.1, 115.0,
112.6 (arom. C); C H N O (240.0647), MS: m/z = 240.0645.
1
2 8 4 2
Anal. Calcd. For C H N O : C, 60.00; H, 3.36; N, 23.32.
1
2 8 4 2
Found: C, 59.88; H, 3.36; N, 23.15.
General Procedure for Preparation of 2-Pyridin-3-ylbenzimida-
zoles (3a-d).
General Procedure for Preparation of Pyridium Salts (4a-d).
To a stirred solution of (3a-d) (5.0 mmol) in acetone (30 ml)
was added a solution of iodomethane (50.0 mmol) in acetone (10
ml). The mixture was stirred at room temperature for 20 hours.
The precipitate was collected by filtration, the filter cake washed
with acetone, then dried under reduced pressure to give 4a-d.
A mixture of 3-pyridinecarboxaldehyde (1) (5.0 mmol) and 1,2-
phenylenediamine (2) (5.0 mmol) in absolute ethanol (100 ml) was
stirred at room temperature for 2 hours. To the reaction mixture
was added iodobenzene diacetate (7.0 mmol). After 1 hour stirring,
the solvent was removed under reduced pressure, the residue
diluted with ethyl acetate and then washed with aqueous NaHCO3
solution. The organic layer was separated, washed with brine, dried
2-(1-Methyl)pyridinium-3-yl-1H-benzimidazole Iodide (4a).
This compound was obtained as yellow powder, yield 87 %,
over anhydrous MgSO , and then evaporated in vacuo. The residue
mp 221-223°; ir (potassium bromide): 3140 (CH), 1480, 1310
4
was purified by column chromatography on silica gel
cm-1; 1H nmr (DMSO-d ): δ 9.74 (s, 1H, C2'-H), 9.12, 9.06 (2 x
6
(n-hexane:ethyl acetate) to give the title compounds 3a-d.
d, 2H, C6'-H, C4'-H), 8.32 (dd, 1H, C5'-H), 7.74 (m, C4-H, C7-
+
13
H), 7.34 (m, C5-H, C6-H), 4.49 (s, 3H, N CH ); C nmr
3
2-Pyridin-3-yl-1H-benzimidazole (3a).
(
4
DMSO-d ): δ 145.5 (C-2), 145.4 (C-6'), 144.0 (C-2'), 140.9 (C-
'), 130.0 (C-5'), 128.3 (C-3'), 123.8 (arom. C), 48.7 (N CH );
6
This compound was obtained as yellow powder, yield 52 %,
+
3
mp 247-248°; ir (potassium bromide): 3040 (CH), 1490, 1450
C H N I(-CH I)(195.0796), MS: m/z = 195.0790.
1
3
12
3
3
-1 1
cm ; H nmr (CD OD): δ 9.36 (d, 1H, C2'-H), 8.75 (dd, 1H, C6'-
3
Anal. Calcd. For C H N I•1/2H O: C, 45.11; H, 3.79; N,
13 12 3 2
H), 8.58 (m, 1H, C4'-H), 7.72 (m, 3H, C4-H, C7-H, C5'-H), 7.40
1
5
2.14. Found: C, 45.51; H, 3.55; N, 12.02.
1
3
(
(
(
m, 2H, C5-H, C6-H); C nmr (CD OD): δ 150.8 (C-6'), 149.0
3
-Methoxy-2-(1-methyl)pyridinium-3-yl-1H-benzimidazole
C-2), 147.7 (C-2'), 143.9, 135.0 (C-8, C-9), 134.0 (C-4'), 126.3
C-3'), 124.3 (C-5'), 123.3, 122.3, 119.3, 111.7 (arom. C).
Iodide (4b).
Anal. Calcd. For C H N : C, 73.83; H, 4.65; N, 21.52. Found:
C, 73.84; H, 4.62; N, 21.53.
1
2
9
3
This compound was obtained as yellow powder, yield 75 %,
mp 183-186°; ir (potassium bromide): 3110 (CH), 1630, 1270
-1 1
cm ; H nmr (DMSO-d ): δ 9.65 (s, 1H, C2'-H), 9.03 (2xd, 2H,
6
5
-Methoxy-2-pyridin-3-yl-1H-benzimidazole (3b).
C6'-H, C4'-H), 8.29 (dd, 1H, C5'-H), 7.65-6.93 (m, 3H, C4-H,
This compound was obtained as yellow brown powder, yield
5 %, mp 174-176°; ir (potassium bromide): 3050 (CH), 1650,
+
13
C6-H, C7-H), 4.45 (s, 3H, N CH ), 3.83 (s, 3H, OCH ); C nmr
3
3
7
1
1
7
(
DMSO-d ): δ 158.9 (C-5), 145.0 (C-2), 144.1 (C-6'), 143.6 (C-
6
-1 1
435 cm ; H nmr (CD OD): δ 9.21 (d, 1H, C2'-H), 8.61 (dd,
3
2'), 140.3 (C-4'), 130.1 (C-5'), 128.2 (C-3'), 113.4 (arom. C), 55.8
H, C6'-H), 8.42 (m, 1H, C4'-H), 7.58 (m, 2H, C5'-H, C7-H),
.08 (d, 1H, C4-H), 6.91 (dd, 1H, C6-H), 3.84 (s, 3H, OCH3);
+
(
OCH ), 48.7 (N CH ); C H N OI(-CH I) (225.0902), MS:
3 3 14 14 3 3
m/z = 225.0902.
Anal. Calcd. For C14H14N OI•H O: C, 43.65; H, 4.19; N,
1
3
C nmr (CD OD): δ 158.9 (C-5), 151.5 (C-2), 151.2 (C-6'),
3
3
2
1
1
48.8, 136.5 (C-8, C-9), 148.2 (C-2'), 135.8 (C-4'), 128.2 (C-3'),
25.8 (C-5'), 127.8, 125.8, 114,6 (arom. C), 56.4 (OCH3);
1
0.91. Found: C, 44.03; H, 4.15; N, 10.89.
5-Chloro-2-(1-methyl)pyridinium-3-yl-1H-benzimidazole Iodide
C H N O(225.0902), MS: m/z = 225.0904.
13 11 3
(
4c).
This compound was obtained as yellow powder, yield 74 %,
mp 236-238°; ir (potassium bromide): 3090(CH), 1660, 1490,
Anal. Calcd. For C H N O•1/2H O: C, 66.65; H, 5.16; N,
1
3
11
3
2
1
5
7.94. Found: C, 66.96; H, 5.09; N, 17.52.
-Chloro-2-pyridin-3-yl-1H-benzimidazole (3c).
This compound was obtained as yellow crystal, yield 78 %, mp
-1 1
1
320 cm ; H nmr (DMSO-d ): δ 9.65 (s, 1H, C2'-H), 9.08 (br
6
d, 2H, C6'-H, C4'-H), 8.40 (dd, 1H, C5'-H), 7.84 (d, 1H, C4-H, J
= 1.6 Hz), 7.79 (d, 1H, C7-H, J = 8.6 Hz), 7.40 (dd, 1H, C6-H, J
-1
1
1
47-148°; ir (potassium bromide): 3100 (CH), 1440, 1420 cm ;
H nmr (CD OD): δ 9.14 (d, 1H, C2'-H), 8.58 (dd, 1H, C6'-H),
= 1.6 Hz, 8.6 Hz), 4.47 (s, 3H, N CH ); C nmr (DMSO-d ): δ
+
13
3
3 6
8
.38 (m, 1H, C4'-H), 7.53 (m, 3H, C5'-H, C4-H, C7-H), 7.18 (dd,
146.9 (C-2), 145.8 (C-6'), 144.2 (C-2'), 141.1 (C-4'), 129.6 (C-5),
1
1
1
H, C6-H); 13C nmr (CD OD): δ 151.8 (C-6'), 151.7 (C-2),
128.2 (C-5'), 128.0 (C-3’), 124.1 (arom. C), 48.7 (N CH ).
+
3
3
48.6 (C-2'), 136.2 (C-4'), 130.1, 129.5 (C-8, C-9), 127.7 (C-3'),
25.9 (C-5), 125.1 (C-5'), 118.9, 117.3, 116.4 (arom. C);
Anal. Calcd. For C H ClIN : C, 42.02; H, 2.98; N, 11.31.
1
3
11
3
Found: C, 41.95; H, 3.10; N, 11.39.
-Nitro-2-(1-methyl)pyridinium-3-yl-1H-benzimidazole Iodide
4d).
This compound was obtained as yellow powder, yield 92 %,
mp 265-266°; ir (potassium bromide): 3060 (CH), 1530, 1345
C H N Cl(229.0407), MS: m/z = 229.0401.
12 8 3
5
(
Anal. Calcd. For C H N Cl: C, 62.76; H, 3.51; N, 18.30.
1
2 8 3
Found: C, 62.32; H, 3.60; N, 17.95.
5
-Nitro-2-pyridin-3-yl-1H-benzimidazole (3d).
-
1 1
This compound was obtained as yellow powder, yield 65 %,
cm ; H nmr (DMSO-d ): δ 9.79 (s, 1H, C2'-H), 9.18 (2xd,
6
mp 273-274°; ir (potassium bromide): 3110 (CH), 1520, 1340
2H, C6'-H, C4'-H), 8.58 (d, 1H, C4-H, J = 2.0 Hz), 8.42 (dd,
1H, C5'-H, J = 6.2 Hz, 8.1 Hz), 8.22 (d, 1H, C6-H, J = 2.0 Hz,
-1 1
cm ; H nmr (DMSO-d ): δ 9.37 (d, 1H, C2'-H), 8.75 (dd, 1H,
6

Jan-Feb 2003
Synthesis of 2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)benzimidazoles
41
+
8
.9 Hz), 7.92 (d, 1H, C7-H, J = 8.9 Hz), 4.54 (s, 3H, N CH );
5-Nitro-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-benzim-
idazole (5d).
3
1
3
C nmr (DMSO-d ): δ 150.0 (C-2), 146.5 (C-6'), 144.6 (C-5),
6
1
43.7 (C-2'), 141.7 (C-4'), 129.0 (C-5'), 128.3 (C-3'), 119.2
This compound was obtained as brown powder, yield 47 %,
mp 130-131°; ir (potassium bromide): 2940 (CH), 1650, 1330
+
(
arom. C), 48.8 (N CH ); C13H11N IO (-CH I)(240.0647),
3
4
2
3
MS: m/z = 240.0646.
-1 1
cm ; H nmr (CD OD): δ 8.37 (d, 1H, C4-H, J = 2.0 Hz), 8.12
3
Anal. Calcd. For C H N IO : C, 40.86; H, 2.90; N, 14.66.
1
3
11
4
2
(dd, 1H, C6-H, J = 2.0 Hz, 8.9 Hz), 7.58 (d, 1H, C7-H, J = 8.9
Found: C, 40.97; H, 2.94; N, 14.51.
Hz), 6.89 (m, 1H, C4'-H), 3.60 (m, 2H, C2'-H), 2.78 (m, 2H, C6'-
1
3
H), 2.58 (s, 3H, NCH ), 2.58 (m, 2H, C5'-H); C nmr (CD OD):
General Procedure for Preparation of 1-Methyl-1,2,5,6-tetrahy-
dropyridin-3-ylbenzimidazoles (5a-d).
3
3
δ 156.6 (C-2), 145.1 (C-5), 134.2 (C-3'), 127.4 (C-4'), 119.8
arom. C), 54.6 (C-2'), 52.1 (C-6'), 45.8 (NCH ), 27.1 (C-5');
(
3
To a cooled (-20 °C) and stirred suspension of (4a-d) (4.0
mmol) in methanol (40 ml) was added portion-wise sodium boro-
hydride (4.5 mmol). After stirring for 2 hours at room tempera-
ture, the solvent was evaporated. The residue was dissolved in
ethyl acetate and washed with aqueous NaHCO solution. The
organic layer was washed with brine and dried over anhydrous
C H N O (258.1117), MS: m/z = 258.1112.
1
3 14 4 2
Anal. Calcd. For C H N O •(CO H) •H O: C, 49.18; H,
1
3
14
4
2
2
2
2
4
.95; N, 15.29. Found: C, 49.58; H, 5.09; N, 15.64.
General Procedure for Preparation of 1-Methyl-2-pyridinylbenz-
imidazoles (6a-d).
3
MgSO . The solvent was removed in vacuo and the residue was
purified by flash column chromatography on silica gel (methyl-
ene chloride:methanol) to give the title compounds 5a-d.
To a stirred suspension of potassium hydroxide (10 mmol) in
50 ml acetone was added 3a-d (2 mmol) and added methyl iodide
(6 mmol). After stirring at room temperature for 2 hours, the
reaction mixture was poured into toluene. The separated organic
layer was washed with brine, dried over anhydrous sodium sul-
fate, and concentrated under reduced pressure. The residue was
purified or isomers separated by flash column chromatography
on silica gel to give the title compounds 6a-d.
4
2
-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-benzimidazole
(5a).
This compound was obtained as yellow powder, yield 95 %,
mp 204-206°; ir (potassium bromide): 3090 (CH), 1660, 1455
-1 1
cm ; H nmr (CDCl ): δ 7.27-7.18 (m, 4H, arom. H), 6.59 (m,
3
1-Methyl-2-pyridin-3-yl-1H-benzimidazole (6a).
1
2
1
H, C4'-H), 3.59 (d, 2H, C2'-H, J = 1.9 Hz), 2.60 (m, 2H, C6'-H),
1
3
This compound was obtained by flash column chromatography
.44 (s, 3H, NCH ), 2.36 (m, 2H, C5'-H); C nmr (CDCl ): δ
3
3
51.6 (C-2), 128.0 (C-3'), 127.8 (C-4'), 123.1 (arom. C), 54.7
on silica gel (methylene chloride:methanol) as pale yellow pow-
der, yield 93 %, mp 143-145°; ir (potassium bromide): 3160
(
(
C-2'), 51.6 (C-6'), 46.1 (NCH ), 26.7 (C-5'); C13H15N3
213.1266), MS: m/z = 213.1272.
3
-1 1
(
CH), 1730, 1580 cm ; H nmr (CDCl ): δ 9.05 (d, 1H, C2'-H),
3
8
.73 (dd, 1H, C6'-H), 8.11 (m, 1H, C4'-H), 7.83-7.30 (m, 4H, C4-
Anal. Calcd. For C H N •(CO H) •H O: C, 56.07; H, 5.96;
1
3
15
3
2
2
2
13
H, C5-H, C6-H, C7-H), 7.46 (m, 1H, C5'-H), 3.87 (NCH3);
C
N, 13.08. Found: C, 55.66; H, 5.63; N, 12.86.
nmr (CDCl ): δ 150.6 (C-2), 150.5 (C-6'), 149.8 (C-2'), 142.9,
3
5
-Methoxy-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-ben-
136.5 (C-8, C-9), 136.8 (C-4'), 126.5 (C-3'), 123.6 (C-5'), 123.3,
zimidazole (5b).
122.8, 120.0, 109.8 (arom. C), 31.7 (NCH );
3
C H N (209.0953), MS: m/z = 209.0952.
This compound was obtained as yellow powder, yield 45 %,
mp 143-145°; ir (potassium bromide): 3390 (CH), 1690, 1620
13 11 3
Anal. Calcd. For C13H N : C, 74.62; H, 5.30; N, 20.08.
11
3
Found: C, 74.71; H, 5.28; N, 20.20.
-1 1
cm ; H nmr (CD OD): δ 7.23 (d, 1H, C7-H, J = 8.6 Hz), 6.83
3
(
s, 1H, C4-H), 6.66 (d, 1H, C6-H, J = 8.6 Hz), 6.52 (m, 1H,
5-Methoxy-1-methyl-2-pyridin-3-yl-1H-benzimidazole (6Ab).
C4'-H), 3.63 (s, 3H, OCH ), 3.32 (br s, 2H, C2'-H), 2.47 (br s,
3
The mixture of 5-/6-isomers (1:1) was separated by flash col-
umn chromatography on silica gel (n-hexane:acetone) to give
Ab and 6Bb. Compound 6Ab was obtained as yellow powder,
1
3
2
1
H, C6'-H), 2.31 (br s, 5H, NCH , C5'-H); C nmr (CD OD): δ
58.5 (C-5), 152.0 (C-2), 128.5 (C-3'), 128.1 (C-4'), 113.7 (arom.
3 3
6
C), 56.4 (OCH ), 54.9 (C-2'), 52.3 (C-6'), 46.0 (NCH ), 27.2
3
3
yield 40 %, mp 118°; ir (potassium bromide): 3050 (CH), 1630,
(
C-5'); C H N O(243.1372), MS: m/z = 243.1379.
14 17 3
-1 1
1
1
(
3
2
4
570 cm ; H nmr (CDCl ): δ 9.01 (br d, 1H, C2'-H), 8.74 (dd,
3
Anal. Calcd. For C H N O•(CO H) •2H O: C, 52.03; H,
1
4
17
3
2
2
2
H, C6'-H), 8.12 (dt, 1H, C4'-H), 7.48 (br dd, 1H, C5'-H), 7.30
6
5
.28; N, 11.38. Found: C, 51.92; H, 6.23; N, 11.03.
m, 2H, C4-H, C7-H), 7.01 (dd, 1H, C6-H), 3.89 (s, 3H, OCH ),
3
1
3
.88 (s, 3H, NCH3); C nmr (CDCl ): δ 156.5 (C-5), 150.7 (C-
-Chloro-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-benz-
3
), 150.4 (C-6'), 149.7 (C-2'), 143.7, 131.2 (C-8, C-9), 136.7 (C-
'), 126.6 (C-3'), 123.5 (C-5'), 113.5, 110.1, 101.8 (arom. C), 55.7
imidazole (5c).
This compound was obtained as yellow powder, yield 67 %,
mp 174-175°; ir (potassium bromide): 2920 (CH), 1670, 1430
(
OCH ), 31.7 (NCH ).
3 3
Anal. Calcd. For C H N O: C, 70.28; H, 5.48; N, 17.56.
1
4 13 3
-1 1
cm ; H nmr (CD OD): δ 7.33 (d, 1H, C4-H, J = 1.9 Hz), 7.30
3
Found: C, 70.07; H, 5.47; N, 17.74.
(d, 1H, C7-H, J = 8.6 Hz), 7.02 (dd, 1H, C6-H, J = 1.9 Hz, 8.6
Crystal Data and Structure Refinement for 6Ab.
Hz), 6.62 (m, 1H, C4'-H), 3.38 (m, 2H, C2'-H), 2.56 (m, 2H, C6'-
1
3
H), 2.37 (s, 3H, NCH ), 2.37 (m, 2H, C5'-H); C nmr (CD OD):
3
3
Empirical formula
Formula weight
C14H13N O
239.27
3
δ 153.7 (C-2), 130.2 (C-3'), 129.4 (C-5), 127.6 (C-4'), 124.5
arom. C), 54.8 (C-2'), 52.2 (C-6'), 45.9 (NCH ), 27.1 (C-5');
(
3
Temperature
297(2) K
C H N Cl(247.0876), MS: m/z = 247.0870.
13
14
3
Wavelength
0.71073 Å
Anal. Calcd. For C H N Cl•(CO H) •1/2H O: C, 51.96; H,
Crystal system, space group
Unit cell dimensions
Triclinic, P-1
a = 6.7973(8) Å α = 83.694(14)°.
1
3
14
3
2
2
2
4
.94; N, 12.12. Found: C, 52.15; H, 5.10; N, 12.02.

42
M. H. Jung, J. M. Park, I.-Y. Choi-Lee, and M. Ahn
Vol. 40
b = 7.4976(12) Å β = 80.852(7)°.
c = 12.2434(17) Å γ = 89.746(10)°.
612.25(15) Å , 2
5/6-Nitro-1-methyl-2-pyridin-3-yl-1H-benzimidazole (6ABd).
3
The title compound was obtained as a mixture of 5-/6-isomers
as dark yellow powder, yield 90 %, mp 232-234°; ir (potassium
Volume, Z
3
Calculated density
Absorption coefficient
F(000)
1.298 Mg/m
0.085 mm
252
-1
bromide): 2920 (CH), 1505, 1350 cm ; H nmr (DMSO-d ): δ
-1 1
6
9.10 (br s, 2H, C2'-H), 8.80 (br d, 2H, C6'-H, J = 4.8 Hz), 8.34 (br
d, 2H, C4'-H, J = 7.8 Hz), 7.66 (dd, 2H, C5'-H, J = 4.8 Hz, 7.8
Crystal size
0.3 x 0.5 x 0.4 mm
2.73 to 26.00°
-8 ≤ h ≤ 1, -9 ≤ k ≤ 9, -15 ≤ l ≤ 15
3042
θ range for data collection
Limiting indices
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R indices (all data)
Largest diff. peak and hole
Hz), 8.72, 8.61, 8.24, 8.17, 7.90 (m, 6H, arom. H), 4.04, 3.99 (s,
13
6
H, NCH3); C nmr (DMSO-d ): δ 155.8 (C-2), 151.5 (C-6'),
6
1
50.0 (C-2'), 143.2, 136.3 (C-8, C-9), 137.3 (C-4'), 125.7, 124.1,
2406 [Rint = 0.0229]
Full-matrix least-squares on F
1
19.8, 118.1, 111.8, 108.4 (C-3', C-5', arom. C), 32.6 (NCH3);
2
C H N O (254.0804), MS: m/z = 254.0808.
2406/0/213
1.050
13 10 4 2
Anal. Calcd. For C H N O : C, 61.41; H, 3.96; N, 22.04.
13 10 4 2
R1 = 0.0717, wR2 = 0.1646
R1 = 0.0787, wR2 = 0.1710
Found: C, 61.25; H, 3.99; N, 21.80.
General Procedure for Preparation of (7a-d).
-3
0.690 and -0.311 e.A
The compounds (7a-d) were prepared following the procedure
described for pyridinium salts (4a-d), and were used for the next
reaction without further purification.
6
-Methoxy-1-methyl-2-pyridin-3-yl-1H-benzimidazole (6Bb).
This compound was obtained as yellow powder, yield 42 %,
mp 109-110°; ir (potassium bromide): 2980 (CH), 1600, 1450
1-Methyl-2-(1-methyl)pyridinium-3-yl-1H-benzimidazole
Iodide (7a).
-1 1
cm ; H nmr (CDCl ): δ 9.00 (br d, 1H, C2'-H), 8.73 (dd, 1H,
C6'-H), 8.12 (dt, 1H, C4'-H), 7.72 (d, 1H, C4-H), 7.47 (m, 1H,
C5'-H), 6.99 (dd, 1H, C5-H), 6.85 (d, 1H, C7-H), 3.92 (s, 3H,
3
This compound was obtained as yellow powder, yield 76 %,
mp 215-217°; ir (potassium bromide): 3000 (CH), 1560, 1450
-1 1
cm ; H nmr (CD OD): δ 9.45 (s, 1H, C2'-H), 9.09 (d, 1H, C6'-
3
1
3
OCH ), 3.89 (s, 3H, NCH ); C nmr (CDCl ): δ 157.0 (C-6),
3
3
3
H), 9.01 (d, 1H, C4'-H), 8.30 (br t, 1H, C5'-H), 7.76, 7.67 (2xd,
1
1
50.3 (C-6'), 149.8 (C-2), 149.6 (C-2'), 137.5, 137.2 (C-8, C-9),
36.6 (C-4'), 126.6 (C-3'), 123.5 (C-5'), 120.5, 112.1, 93.1 (arom.
2
H, C4-H, C7-H), 7.41 (m, 2H, C5-H, C6-H), 4.57 (s, 3H,
+
13
N CH ), 4.06 (s, 3H, N -CH ); C nmr (CD OD): δ 148.1,
3
1
3
3
C), 55.8 (OCH ), 31.7 (NCH ); C H N O (239.1058), MS:
m/z = 239.1058.
3
3
14 13
3
147.5, 147.4, 146.5 (C-2, C-2', C-5', C-6'), 143.8, 138.4 (C-9, C-
), 132.3, 129.7 (C-3', C-4'), 126.0, 125.1, 120.8, 112.4 (arom.
C), 50.2 (N+CH ), 32.9 (s, 3H, N -CH ); C14H14N I(-
8
Anal. Calcd. For C H N O: C, 70.28; H, 5.48; N, 17.56.
1
4
13
3
3
1
3
3
Found: C, 69.90; H, 5.43; N, 17.12.
CH I)(209.0953), MS: m/z = 209.0943.
3
Anal. Calcd. For C H N I•1/2H O: C, 46.68; H, 4.20; N,
1.67. Found: C, 46.97; H, 4.00; N, 11.56.
1
4
14
3
2
5-Chloro-1-methyl-2-pyridin-3-yl-1H-benzimidazole (6Ac).
1
The mixture 5-/6-isomers (1:1) was separated by flash column
5
-Methoxy-1-methyl-2-(1-methyl)pyridinium-3-yl-1H-benzimi-
chromatography on silica gel (n-hexane:acetone) to give 6Ac and
Bc. Compound 6Ac was obtained as yellow powder, yield 35 %,
mp 142-143°; ir (potassium bromide): 3050 (CH), 1475, 1420
dazole Iodide (7Ab).
6
This compound was obtained as yellow powder, yield quanti-
tative, mp 227-229°; ir (potassium bromide): 3030 (CH), 1620,
-1 1
cm ; H nmr (CDCl ): δ 9.00 (d, 1H, C2'-H, J = 1.9 Hz), 8.77
3
-1 1
1500 cm ; H nmr (DMSO-d ): δ 9.54 (s, 1H, C2'-H), 9.13 (d,
(
dd, 1H, C6'-H, J = 1.6 Hz, 5.0 Hz), 8.12 (dt, 1H, C4'-H, J = 1.9
6
1
H, C6'-H), 9.03 (d, 1H, C4'-H), 8.32 (dd, 1H, C5'-H), 7.66 (d,
Hz, 7.8 Hz), 7.80 (s, 1H, C4-H), 7.49 (dd, 1H, C5'-H, J = 5.0 Hz,
1
3
1H, C4-H), 7.26 (d, 1H, C7-H), 7.05 (dd, 1H, C6-H), 4.50 (s, 3H,
N CH ), 4.01 (s, 3H, N -CH ), 3.83 (s, 3H, OCH ); C nmr
7
(
(
1
.8 Hz), 7.33 (s, 2H, C6-H, C7-H), 3.90 (s, 3H, NCH3); C nmr
+
13
CDCl ): δ 151.8 (C-2), 150.9 (C-6'), 149.7 (C-2'), 143.7, 135.2
3
1
3
3
3
(DMSO-d ): δ 156.4 (C-5), 146.7 (C-6'), 145.6 (C-2'), 144.2 (C-
C-8, C-9), 136.9 (C-4'), 128.4 (C-5), 126.1 (C-3'), 123.6 (C-5'),
23.7, 119.7, 110.6 (arom. C), 31.9 (NCH3).
6
4
'), 143.3, 131.7 (C-8, C-9), 130.1 (C-3'), 127.9 (C-5'), 114.2,
+
111.9, 94.1 (arom. C), 55.8 (OCH ), 48.6 (N CH ), 32.2 (N -
3
3
1
Anal. Calcd. For C H N Cl: C, 64.07; H, 4.14; N, 17.24.
1
3 10 3
CH ); C H IN O(-CH I)(239.1057), MS: m/z = 239.1057.
3
15 16
3
3
Found: C, 63.72; H, 4.14; N, 17.10.
Anal. Calcd. For C15H16IN O•H O: C, 45.13; H, 4.54; N,
3
2
6-Chloro-1-methyl-2-pyridin-3-yl-1H-benzimidazole (6Bc).
10.53. Found: C, 44.79; H, 4.11; N, 10.16.
This compound was obtained as yellow powder, yield 33 %,
6-Methoxy-1-methyl-2-(1-methyl)pyridinium-3-yl-1H-benzimi-
dazole Iodide (7Bb).
mp 146-147°; ir (potassium bromide): 2925 (CH), 1465, 1415
-1 1
cm ; H nmr (CDCl ): δ 9.01 (d, 1H, C2'-H, J = 1.9 Hz), 8.76
3
This compound was obtained as yellow powder, yield quantita-
tive, mp 225-226°; ir (potassium bromide): 3050 (CH), 1620, 1490
(
dd, 1H, C6'-H, J = 1.2 Hz, 5.0 Hz), 8.12 (m, 1H, C4'-H), 7.73 (d,
H, C4-H, J = 8.4 Hz), 7.49 (dd, 1H, C5'-H, J = 5.0 Hz, 7.8 Hz),
1
7
8
1
1
-1 1
cm ; H nmr (DMSO-d ): δ 9.54 (s, 1H, C2'-H), 9.11 (d, 1H, C6'-
6
.40 (d, 1H, C7-H, J = 1.6 Hz), 7.29 (dd, 1H, C5-H, J = 1.6 Hz,
H), 9.03 (d, 1H, C4'-H), 8.31 (dd, 1H, C5'-H), 7.65 (s, 1H, C4-H),
1
3
.4 Hz), 3.87 (s, 3H, NCH3); C nmr (CDCl ): δ 151.4 (C-2),
+
3
7.31 (d, 1H, C7-H), 6.95 (dd, 1H, C5-H), 4.50 (s, 3H, N CH ),
4
3
50.8 (C-6'), 149.7 (C-2'), 141.5, 137.1 (C-8, C-9), 136.8 (C-4'),
29.0 (C-6), 126.0 (C-3'), 123.6 (C-5'), 123.4, 120.8, 109.9
arom. C), 31.8 (NCH3).
13
.02 (s, 3H, N -CH ), 3.88 (s, 3H, OCH ); C nmr (DMSO-d ): δ
1 3 3 6
157.2 (C-6), 145.8 (C-6'), 145.4 (C-2), 145.3 (C-2'), 144.0 (C-4'),
(
137.9, 136.9 (C-8, C-9), 130.2 (C-5'), 127.9 (C-3'), 120.4, 113.3,
+
Anal. Calcd. For C H N Cl: C, 64.07; H, 4.14; N, 17.24.
94.1 (arom. C), 56.0 (OCH ), 48.6 (N CH ), 32.2 (N -CH );
1
3
10
3
3
3
1
3
Found: C, 63.78; H, 4.16; N, 17.41.
C H IN O(-CH I)(239.1057), MS: m/z = 239.1055.
15 16 3 3

Jan-Feb 2003
Synthesis of 2-(1-Methyl-1,2,5,6-tetrahydropyridin-3-yl)benzimidazoles
43
C6'-H), 2.53 (m, 2H, C5'-H), 2.49 (s, 3H, NCH ); 13C nmr
Anal. Calcd. For C H IN O•2H O: C, 43.18; H, 4.83; N,
1
5
16
3
2
3
1
5
0.07. Found: C, 43.13; H, 4.43; N, 9.73.
(CD OD): δ 153.5 (C-2), 143.0, 137.6 (C-8, C-9), 133.0 (C-4'),
3
1
5
27.5 (C-3'), 124.5, 124.0, 119.7, 111.5 (arom. C), 56.2 (C-2'),
2.1 (C-6'), 45.8 (NCH ), 32.4 (N -CH ), 27.0 (C-5');
-Chloro-1-methyl-2-(1-methyl)pyridinium-3-yl-1H-benzimida-
3
1
3
zole Iodide (7Ac).
C H N (227.1422), MS: m/z = 227.1427.
1
4 17 3
This compound was obtained as yellow powder, yield 96 %,
mp 243-244°; ir (potassium bromide): 3000 (CH), 1640, 1470
Anal. Calcd. For C H N •(CO H) •1/2H O: C, 58.89; H,
14 17 3 2 2 2
6.18; N, 12.88. Found: C, 58.61; H, 5.92; N, 12.56.
-Methoxy-1-methyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-
-1 1
cm ; H nmr (DMSO-d ): δ 9.58 (s, 1H, C2'-H), 9.17 (d, 1H,
6
5
C6'-H), 9.05 (d, 1H, C4'-H), 8.35 (br t, 1H, C5'-H), 7.86 (s, 1H,
C4-H), 7.83 (d, 1H, C7-H), 7.45 (d, 1H, C6-H), 4.51 (s, 3H,
yl)-1H-benzimidazole (8Ab).
+
13
N CH ), 4.04 (s, 3H, N -CH ); C nmr (DMSO-d ): δ 148.4
This compound was obtained as yellow powder, yield 61 %,
3
1
3
6
-1
(C-2), 146.1 (C-6'), 145.9 (C-2'), 144.7 (C-4'), 143.8, 135.2 (C-9,
mp 91-93°; ir (potassium bromide): 2950 (CH), 1630, 1450 cm ;
1
C-8), 129.7 (C-3'), 128.0 (C-5), 127.5 (C-5'), 124.2, 119.1, 113.1
H nmr (CD OD): δ 7.34 (d, 1H, C7-H, J = 8.9 Hz), 7.11 (d, 1H,
3
+
(
arom. C), 48.7 (N CH ), 32.4 (s, 3H, N -CH ); C H N ClI-
C4-H, J = 2.3 Hz), 6.93 (dd, 1H, C6-H, J = 2.3 Hz, 8.9 Hz), 6.34
3
1
3
14 13 3
(
-CH I)(243.0563), MS: m/z = 243.0558.
(m, 1H, C4'-H), 3.82, 3.81 (2xs, 6H, OCH , N -CH ), 3.43 (ABq,
3
3 1 3
Anal. Calcd. For C H N ClI•1/2H O: C, 42.61; H, 3.58; N,
0.65. Found: C, 42.79; H, 3.35; N, 10.54.
2H, C2'-H), 2.72 (t, 2H, C6'-H), 2.51 (m, 2H, C5'-H), 2.49 (s, 3H,
1
4
13
3
2
1
3
1
6
NCH3); C nmr (CD3OD): δ 158.4 (C-5), 153.6 (C-2), 143.8,
32.2 (C-8, C-9), 132.6 (C-4'), 127.7 (C-3'), 114.5, 112.0, 101.9
arom. C), 56.6 (C-2'), 56.4 (OCH ), 52.2 (C-6'), 45.8 (NCH ),
1
-Chloro-1-methyl-2-(1-methyl)pyridinium-3-yl-1H-benzimida-
zole Iodide (7Bc).
(
3
3
3
2.4 (N -CH ), 27.1 (C-5'); C H N O(257.1528), MS: m/z =
1 3 15 19 3
This compound was obtained as yellow powder, yield 86 %,
mp 236-237°; ir (potassium bromide): 3050 (CH), 1650, 1450
257.1526.
Anal. Calcd. For C15H19N3O•(CO2H)2•1/2H2O: C, 57.29; H,
6.22; N, 11.79. Found: C, 57.19; H, 5.93; N, 11.67.
-1
1
cm ; H nmr (DMSO-d ): δ 9.58 (s, 1H, C2'-H), 9.17 (d, 1H,
6
C6'-H), 9.05 (d, 1H, C4'-H), 8.36 (br t, 1H, C5'-H), 7.97 (s, 1H,
C7-H), 7.80 (d, 1H, C4-H), 7.36 (d, 1H, C5-H), 4.50 (s, 3H,
6
-Methoxy-1-methyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-
yl)-1H-benzimidazole (8Bb).
+
13
N CH ), 4.03 (s, 3H, N -CH ); C nmr (DMSO-d ): δ 148.2
3
1
3
6
(C-2), 146.2 (C-6'), 146.1 (C-2'), 144.7 (C-4'), 141.3, 137.8 (C-9,
This compound was obtained as pale yellow powder, yield 60
C-8), 129.6 (C-3'), 128.6 (C-5'), 128.2 (C-6), 123.7, 121.3, 111.8
%, mp 99-100°; ir (potassium bromide): 3920 (CH), 1745, 1630
cm-1; 1H nmr (CD OD + CDCl ): δ 7.48 (d, 1H, C4-H, J = 8.9
+
(
arom. C), 48.8 (N CH ), 32.5 (s, 3H, N -CH ); C H N ClI-
3
3
3
1
3
14 13 3
(
-CH I)(243.0563), MS: m/z = 243.0564.
Hz), 7.00 (d, 1H, C7-H, J = 2.2 Hz), 6.88 (dd, 1H, C5-H, J = 2.2
Hz, 8.9 Hz), 6.36 (m, 1H, C4'-H), 3.87, 3.82 (2xs, 6H, OCH , N -
3
Anal. Calcd. For C H N ClI•1/2H O: C, 42.61; H, 3.58; N,
3
1
1
4
13
3
2
CH ), 3.47 (br s, 2H, C2'-H), 2.77 (t, 2H, C6'-H), 2.55 (m, 2H,
1
1
0.65. Found: C, 42.70; H, 3.35; N, 10.44.
3
13
C5'-H), 2.52 (s, 3H, NCH3); C nmr (CD OD + CDCl ): δ 158.5
3
3
-Methyl-5/6-nitro-2-(1-methyl)pyridinium-3-yl-1H-benzimida-
(C-5), 152.2 (C-2), 138.0, 137.0 (C-8, C-9), 131.7(C-4'), 127.0 (C-
zole Iodide (7ABd).
3
'), 120.0, 113.3, 94.3 (arom. C), 56.2 (C-2', OCH ), 51.8 (C-6'),
3
4
5.4 (NCH ), 32.2 (N -CH ), 26.6 (C-5'); C H N O(257.1528),
This compound was obtained as yellow powder, yield 76 %,
mp 258-261°; ir (potassium bromide): 3150 (CH), 1520, 1490
3
1
3
15 19 3
MS: m/z = 257.1525.
Anal. Calcd. For C H N O·(CO H) ·1/2H O: C, 57.29; H,
6.22; N, 11.79. Found: C, 56.91; H, 5.93; N, 11.59.
-1 1
cm ; H nmr (DMSO-d ): δ 9.63, 9.62 (2xs, 2H, C2'-H), 9.23,
15 19
3
2
2
2
6
9
2
.21 (2xbr d, 2H, C6'-H), 9.09 (m, 2H, C4'-H), 8.83, 8.66 (2xd,
H, C4-H/C7-H), 8.39 (m, 2H, C5'-H), 8.31, 8.23 (2xdd, 2H, C5-
5
1
-Chloro-1-methyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-
H-benzimidazole (8Ac).
H/C6-H), 8.04, 7.99 (2xd, 2H, C7-H/C4-H), 4.52 (s, 6H,
+
13
N CH ), 4.15, 4.10 (2xs, 6H, N -CH ); C nmr (DMSO-d ): δ
3
1
3
6
This compound was obtained as pale yellow powder, yield 73
1
1
6
51.9, 151.1 (C-2), 146.8, 146.7, 146.4, 146.3, 145.2, 145.1,
43.8, 143.7, 142.3, 141.4, 141.0, 136.3 (C-2', C-4', C-5, C-5', C-
, C-6', C-8, C-9), 129.1, 128.1 (C-3', C-5), 120.2, 119.2, 118.4,
%
, mp 113-116°; ir (potassium bromide): 3080 (CH), 1660, 1500
-1 1
cm ; H nmr (CD OD): δ 7.58 (d, 1H, C4-H, J = 2.3 Hz), 7.47
(d, 1H, C7-H, J = 8.9 Hz), 7.28 (dd, 1H, C6-H, J = 2.3 Hz, 8.9
Hz), 6.45 (m, 1H, C4'-H), 3.87 (s, 3H, N -CH ), 3.51 (ABq, 2H,
C2'-H), 2.80 (t, 2H, C6'-H), 2.56 (m, 2H, C5'-H), 2.55 (s, 3H,
NCH3); C nmr (CD OD): δ 154.8 (C-2), 143.8, 136.4 (C-8, C-
9
3
+
115.9, 112.4, 108.9 (arom. C), 48.7 (N CH ), 32.7 (s, 3H, N -
3 1
CH ); C H IN O (-CH I)(254.0804), MS: m/z = 254.0809.
1
3
3
14 13
4
2
3
Anal. Calcd. For C H IN O ·1/2H O: C, 41.50; H, 3.48; N,
1
4
13
4
2
2
1
3
1
3.83. Found: C, 41.86; H, 3.31; N, 13.62.
3
), 133.6 (C-4'), 129.6 (C-3'), 127.0 (C-5) 124.8, 119.3, 112.8
General Procedure for Preparation of (8a-d).
(arom. C), 56.3 (C-2'), 52.0 (C-6'), 45.6 (NCH ), 32.7 (N -CH ),
3
1
3
2
6.0 (C-5'); C H ClN (261.1033), MS: m/z = 261.1028.
The reduction of compounds (7a-d) was prepared following
the procedure described for 1-methyl-1,2,5,6-tetrahydropyridin-
-ylbenzimidazoles (5a-d).
14 16 3
Anal. Calcd. For C H ClN •(CO H) : C, 54.63; H, 5.16; N,
14 16
3
2
2
11.94. Found: C, 54.53; H, 5.17; N, 11.68.
3
6
1
-Chloro-1-methyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-
H-benzimidazole (8Bc).
1
-Methyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-benz-
imidazole (8a).
This compound was obtained as white powder, yield 69 %, mp
This compound was obtained as yellow powder, yield 63 %,
mp 84-85°; ir (potassium bromide): 2950 (CH), 1645, 1450 cm ;
-1 1
-1
89-90°; ir (potassium bromide): 3020 (CH), 1640, 1460 cm ; H
nmr (CD OD): δ 7.57-7.54 (m, 2H, C4-H, C7-H), 7.23 (dd, 1H,
1
H nmr (CD OD): δ 7.62-7.22 (m, 4H, arom. H), 6.38 (m, 1H,
3
3
C4'-H), 3.84 (s, 3H, N -CH ), 3.46 (br s, 2H, C2'-H), 2.75 (t, 2H,
C5-H), 6.41 (m, 1H, C4'-H), 3.83 (s, 3H, N -CH ), 3.41 (br s, 2H,
1 3
1
3

44
M. H. Jung, J. M. Park, I.-Y. Choi-Lee, and M. Ahn
Vol. 40
C2'-H), 2.70 (t, 2H, C6'-H), 2.52 (m, 2H, C5'-H), 2.48 (s, 3H,
REFERENCES AND NOTES
NCH3); 13C nmr (CD OD): δ 154.5 (C-2), 141.5, 138.1 (C-8,
3
C-9), 133.2 (C-4'), 129.9 (C-3'), 127.3 (C-6), 124.2, 120.5, 111.5
[1a] R. Xu, M.-K. Sim and M.-L. Go, J. Med. Chem., 41, 3220
(1998); [b] J. R. Prous, Cognition-enhancing drugs. In: The Year’s
Drug News-Therapeutic Targets, 1995 Edition, Prous Science
Publishers, Barcelona, 91-113 (1995).
(
arom. C), 56.3 (C-2'), 52.0 (C-6'), 45.6 (NCH ), 32.4 (N -CH ),
3 1 3
2
6.9 (C-5'); C H ClN (261.1033) MS: m/z = 261.1027.
14 16 3
Anal. Calcd. For C H ClN •(CO H) : C, 54.63; H, 5.16; N,
1
4
16
3
2
2
1
1.94. Found: C, 54.44; H, 5.16; N, 11.55.
[2] R. M. Moltzen, R. E. Pederson, K. P. Bogeso, E. Meier, K.
Frederiksen, C. Sanchez and H. L. Lembol, J. Med. Chem., 37, 4085
5
1
/6-Nitro-1-methyl-2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-
H-benzimidazole (8ABd).
(1994).
[3] E. Toja, C. Bonetti and A. Butti, Eur. J. Med. Chem., 27,
5
19 (1992).
This compound was obtained as pale yellow powder, yield 50 %,
mp 114-116°; ir (potassium bromide): 2930 (CH), 1525, 1455 cm ;
-1
[4a] J. E. Christie, A. Shering, J. Ferguson and A. I. Glen, Br. J.
1
Psychiatry, 138, 46 (1981); [b] J. M. Palacios and R. Spiegel, Prog.
Brain Res., 70, 485 (1986).
H nmr (CD OD): δ 8.40, 8.38 (2xd, 2H, C4-H/C7-H), 8.15, 8.11
3
(
2
2
2xdd, 2H, C5-H/C6-H), 7.66, 7.61 (2xd, 2H, C7-H/C4-H), 6.52 (m,
[5] L. Jeppesen, P. H. Olesen, L. Hansen, M. J. Sheardown, C.
H, C4'-H), 3.93, 3.92 (2xs, 6H, N -CH ), 3.46 (br s, 4H, C2'-H),
1 3
Thomsen, T. Rasmussen, A. F. Jensen, M. S. Christensen, K.
Rimvall, J. S. Ward, C. Whitesitt, D. O. Calligaro, F. P. Bymaster, N.
W. Delapp, C. C. Felder, H. E. Shannon and P. Sauerberg, J. Med.
Chem., 42, 1999 (1999).
[6a] M. H. Jung, J.-G. Park, B.-S. Ryu and K.-W. Cho, J.
Heterocyclic Chem., 36, 429 (1999); [b] M. H. Jung, J.-G. Park, K.-
W. Cho and H.-G. Cheon, Korean J. Med. Chem., 9, 8 (1999).
13
.73 (t, 4H, C6'-H), 2.57 (m, 4H, C5'-H), 2.56 (s, 6H, NCH3);
C
nmr (CD OD): δ 157.5 (C-2), 145.3, 135.1 (C-8, C-9), 142.4, 141.8
3
(
1
C-5, C-6), 134.6 (C-4'), 127.3 (C-3'), 119.9, 119.8, 119.4, 116.0,
12.0 (arom. C), 56.4 (C-2'), 52.0 (C-6'), 45.8 (NCH ), 33.0 (N -
3
1
CH ), 27.2 (C-5'); C H N O (272.1273) MS: m/z = 272.1269.
3
14 16 4 2
Anal. Calcd. For C H N O ·(CO H) ·1/2H O: C, 51.75; H,
1
4
16
4
2
2
2
2
5
.16; N, 15.09. Found: C, 52.04; H, 4.94; N, 14.81.
[7] M. H. Jung, S.-W. Choi and K.-W. Cho, J. Heterocyclic
Chem., 37, 969 (2000).
Acknowledgments.
[8] J. J. Baldwin, P. K. Lumma, F. C. Novello, G. S. Ponticello
We wish to thank Mrs. B. H. Lee for providing the X-ray crys-
tallography data and this work was supported the Korea Ministry
of Science and Technology, Kolon Ltd. and KOSEF (R03-2001-
and J. M. Sprague, J. Med. Chem., 20, 1189 (1977).
[9] L. J. Mathias and C. G. Overberger, J. Org. Chem., 43,
3526 (1978).
000-00025-0) research projects.
[10] Y. Kikugawa, Synthesis, 124 (1981).