Synthesis of N-aryl-2-substituted tetrahydrobenzimidazoles via direct N-arylation

Article abstract of DOI:10.1080/00397910601168249

A series of novel N-aryl-2-substituted tetrahydrobenzimidazoles has been synthesized via direct N-arylation of 2-substituted tetrahydrobenzimidazoles, which was accomplished by a medium aryl electrophile, 4- methylsulfonylfluorobenze, in the presence of 3

Full text of DOI:10.1080/00397910601168249

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Synthesis of N‐Aryl‐2‐substituted
Tetrahydrobenzimidazoles via Direct
N‐Arylation
Mei‐Ying Li a , He Liu a & Bo‐Hua Zhong a
a Department of Medicinal Chemistry , Beijing Institute of Pharmacology and
Toxicology , Beijing, China
Published online: 24 Feb 2007.
To cite this article: Mei‐Ying Li , He Liu & Bo‐Hua Zhong (2007) Synthesis of N‐Aryl‐2‐substituted
Tetrahydrobenzimidazoles via Direct N‐Arylation, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 37:6, 1001-1009, DOI: 10.1080/00397910601168249
To link to this article: http://dx.doi.org/10.1080/00397910601168249
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Synthetic Communicationsw, 37: 1001–1009, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601168249
Synthesis of N-Aryl-2-substituted
Tetrahydrobenzimidazoles via Direct
N-Arylation
Mei-Ying Li, He Liu, and Bo-Hua Zhong
Department of Medicinal Chemistry, Beijing Institute of Pharmacology
and Toxicology, Beijing, China
Abstract: A series of novel N-aryl-2-substituted tetrahydrobenzimidazoles has
been synthesized via direct N-arylation of 2-substituted tetrahydrobenzimidazoles,
which was accomplished by a medium aryl electrophile, 4-methylsulfonylfluorobenze,
in the presence of 37% KF/Al2O3 and 18-crown-6 in fair yields under mild
reaction conditions. Meanwhile, the hydrogenation of 2-phenylbenzimidazole was
studied.
Keywords: N-arylation, hydrogenation, selective cyclooxygenase-2 inhibitors,
tetrahydrobenzimidazole
INTRODUCTION
Selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to be
clinically effective anti-inflammatory and analgesic drugs with reduced gas-
trointestinal toxicity as compared to classic NSAIDs.[1] The most widely
studied class is that of the compounds in which the pharmacophore is charac-
terized by two aromatic moieties attached to adjacent atoms in a bridging
heterocyclic five-membered ring.[2–4] For optimal COX-2 inhibitory
Received in Japan April 6, 2006
Address correspondence to Mei-Ying Li, Department of Medicinal Chemistry,
Beijing Institute of Pharmacology and Toxicology, Beijing, China. E-mail:
greenwater79@126.com
1001

1002
M.-Y. Li, H. Liu, and B.-H Zhong
activity, one of the two aromatic rings is substituted in the para-position by a
methylsulphonyl[2] or a sulfonamide group.[3,4] To find potent and selective
cyclooxygenase-2 (COX-2) inhibitors with a safer profile, a series of novel
N-arylation of 2-substituted tetrahydrobenzimidazoles containing a methylsul-
phonyl group in the para-position of N-aromatic ring has been designed in our
anti-inflammatory program. Here we report the synthesis of these compounds
(see Schemes 1 and 2). The preliminary COX-2 inhibitory activity data of
some compounds are also given.
1,2-Arylimidazoles can be prepared by cyclization of diarylamidines with
strong electrophiles such as 3-bromo-1,1,1-trifluoroacetone and following
dehydration,[5] but such methodology was ultimately proved to be ineffective
for our target molecules because of the weak electrophilicity of 2-bromocyclo-
hexanone. Because diaryl benzimidazoles can be easily synthesized by cycli-
zation of N-phenyl-o-phenylenediamine with appropriate benzoyl chloride,[6]
we wanted to prepare our target compounds by selective hydrogenation of
diaryl benzimidazoles. However, the substituted benzene ring but not the
fused one was first hydrogenated for 2-phenylbenzimidazole, as shown in
Scheme 1. Hydrogenation of 2-phenylbenzimidazole, catalyzed by 5%
22
.
Rh/C at 1208C under 100 Kg cm
2-cyclo-hexanotetrahydrobenzimidazole 1a. When decreasing the pressure
using 2 N HCl as solvent, gave
to 50 Kg cm22 and using 50% acetic acid as solvent, 2-cyclohexanobenzimi-
.
dazole 1b was obtained.
We here report a new method for synthesizing the target compounds via
direct N-arylation of 2-aryl tetrahydrobenzimidazoles 3, which were prepared
through the method described in the literature.[7] Traditional strategies for the
Scheme 1. (I) H2, 5% Rh/C, 2 N HCl, 1208C, 100 Kg cm22; (II) H2, 5% Rh/C, 50%
.
HOAc, 1208C, 50 Kg cm22; (III) 4-methylsulfonylfluorobenze, DMSO, 37% KF/
.
basic Al2O3, 18-crown-6, 1208C.

N-Aryl-2-substituted Tetrahydrobenzimidazoles
1003
.
Scheme 2. (I) Excess Cu(OAc)2, NH3 H2O, MeOH, reflux; (II) 4-methylsulfonyl
fluorobenze, DMSO, 37% KF/basic Al2O3, 18-crown-6, 1208C.
construction of the N-arylimidazole moiety include the Ullmann coupling
reaction[8] and nucleophilic aromatic substitution.[9] Unfortunately, the use
of the Ullmann coupling reaction usually leads to difficult purification
issues, with concomitant low yields. Nucleophilic aromatic substitution as
an effective method for the N-arylation of imidazole notwithstanding, the
method usually requires a strong base and is limited to aryl fluorides with
strongly electron-withdrawing ortho and/or para groups. Strongly basic con-
ditions tend to cleave the imidazole.[10] Furthermore, there is severe steric
hindrance for the N-arylation of 3, and 4-methylsulfonylfluorobenze is just
a medium aryl electrophile. Therefore, an efficient method for the N-
arylation of 3 is desired. W. J. Smith III has reported a novel and selective
method for the N-arylation of indoles mediated by KF/Al2O3.[11] In our
work, we modified the method to achieve the N-arylation of imidazoles. It
was proved that all the object compounds were obtained in fairly good
yields (50–60%) by intermediates 3 reacting with 4-methylsulfonylfluoro-
benze in the presence of 37% KF/Al2O3 and 18-crown-6 in DMSO at
1208C for 8 h.
To compare the new method (method A, based on Smith protocol) with
traditional methods of nucleophilic aromatic substitution (method B,
reaction conditions: NaH, DMSO, 1208C) and the Ullmann coupling
reaction (method C, reaction conditions: anhydrous K2CO3, Cu power,
DMF, 1508C), the latter two methods were also performed (see Table 1).
Through method B, the purified yield was about 40%, but the reaction time
was too long. No product was obtained by method C. In conclusion, the
new method is a simpler and more expedient approach with short reaction
time and fair yield for N-arylation of imidazoles and is even suitable for the
N-arylation of imidazoles with bulky steric hindrance.
Because it was reported that the cyclohexyl group could substitute for the
aromatic ring without a methylsulphonyl group in the para-position for some
selective cyclooxygenase-2 (COX-2) inhibitors,[12] we also employed the new
method to synthesize two novel compounds 2.
Through the new method, a series of novel N-aryl-2-substituted tetrahy-
drobenzimidazoles has been synthesized. The structures of all compounds
have been established by nuclear magnetic resonance (NMR), mass spec-
troscopy (MS), and elemental analysis.

1004
M.-Y. Li, H. Liu, and B.-H Zhong
Table 1. Comparison of the N-arylation methods
Method A
Method B
Entry
4
R
Time (h)
Yield (%)a
Time (h)
Yield (%)a
1
2
a
b
c
d
e
f
H
4-Me
4-Cl
8
8
8
8
8
8
8
8
8
8
8
55
55
57
53
50
52
48
50
51
51
71
120
120
120
120
120
120
120
120
120
120
120
39
41
3
42
40
4
3-Cl
2-Cl
5
38
35
6
2,5-Cl
2,4-Me
3,-4-Me
4-F
7
g
h
i
30
8
NDb
22
9
10
11
j
2,3-OMe
2-Me
NDb
ND
k
aThe purified yield.
bND means that the experiment was not done.
EXPERIMENTAL
Solvents were purified by standard procedures. Melting points were deter-
mined using a RY-1 apparatus and are uncorrected. NMR spectra were
recorded on Varian Unity Inova 600-MHz or JNM-ECA-400 400-MHz instru-
ment in the solvent indicated later. Chemical shift values are reported in parts
per million (ppm) relative to that for tetramethylsilane (TMS) used as an
internal reference standard. Spectral splitting patterns are designated as
follows: s, singlet; br, broad; d, doublet; t, triplet; m, multiplet. Mass
spectra were obtained using API3000 instruments. Elemental analysis was
carried at the CarloErba-1106.
All reactions were monitored by thin-layer chromatography (TLC) on
25 ꢀ 75 mm glass sheets precoated with silica gel (GF254) to a thickness
of 0.25 mm and viewed at 254 nm UV light.
2-Cyclohexanotetrahydrobenzimidazole 1a
To a solution of 4.85 g of 2-phenylbenzimidazole (25 mmol) in 50 mL of 2 N
HCl, 5% rhodium on carbon (0.3 g) was added. The mixture was hydrogenated
22
.
at 1208C under 100 Kg cm until the hydrogen was not absorbed in an
autoclave. The catalyst was then removed by filtration and washed with
water. The filtrate was evaporated to dryness and then dissolved with 30 mL
of water. Then the solution was adjusted to pH 14 using 30% NaOH. The
resulting precipitate was filtrated off, washed with water, and then dried to

N-Aryl-2-substituted Tetrahydrobenzimidazoles
1005
1
give 1a (5.1 g, 100% yield) as a white solid. Mp 266–2678C. H NMR
(CDCl3) d: 8.0–9.0 (1H, br, NH), 2.65 (1H, m), 2.54 (4H, br, CH2), 2.02–
2.05 (2H, d, J ¼ 12.32 Hz, CH2), 1.79–1.83 (5H, m, CH2), 1.71 (1H, d,
J ¼ 12.60 Hz, CH2), 1.21–1.54 (6H, m, CH2). ESI-MS: 205.1 (M þ 1).
Anal. calc. for C13H20N2 (204.16): C, 76.42; H, 9.87; N, 13.71; found: C,
76.58; H, 9.99; N, 13.85.
2-Cyclohexanobenzimidazole 1b
To a solution of 3.88 g of 2-phenylbenzimidazole (20 mmol) in 30 mL of 50%
HOAc, 5% rhodium on carbon (0.2 g) was added. The mixture was hydrogen-
ated at 1208C under 50 Kg cm22 for 1.5 h in an autoclave. The catalyst was
.
then removed by filtration and washed with water. The filtrate was evaporated
to about 20 mL, and then 30% NaOH was added until pH ¼ 9. The resulting
precipitate was filtrated and washed with water. Recrystallizing with ethanol
1
gave 1b (3.83 g, 95% yield) as a white solid. Mp 284–2868C. H NMR
(DMSO-d6) d: 12.11 (1H, br, NH), 7.44 (2H, d, J ¼ 8.6 Hz, ArH), 7.09
(2H, d, J ¼ 8.6 Hz, ArH), 2.83 (1H, m), 1.99–2.02 (2H, m, CH2), 1.77–
1.82 (2H, m, CH2), 1.55–1.71 (3H, m, CH2), 1.23–1.44 (3H, m, CH2).
ESI-MS: 201.0 (M þ 1). Anal. calc. for C13H16N2 (200.13): C, 77.96; H,
8.05; N, 13.99; found: C, 77.88; H, 7.99; N, 14.11.
General Procedure for N-Arylation of Imidazoles
Method A
Under an N2 atmosphere, 10% weight equivalent 18-crown-6, 1 weight equiv-
alent 37% potassium fluoride absorbed onto basic alumina, and 4-methylsul-
fonylfluorobenze (5 mmol) in 20 mL DMSO were added successively to the
20-mL DMSO solution of 3 (5 m mol). The mixture was stirred and heated
to 1208C until the reaction was completed, for about 8 h. The reaction
progress was monitored by TLC. Then, the mixture was filtrated. The
filtrate was poured into ice and stirred. The resulting precipitate was
filtrated off and washed by water. The crude reaction mixture was purified
by silica-gel column chromatography to give 4.
Method B
Under an N2 atmosphere, 5 m mol NaH (60% on mineral oil) were added to
the solution of 3 (5 m mol) in 20 mL DMSO at 158C. After stirring for 1 h,
4-methylsulfonylfluorobenze (5 m mol) was added. The resulting mixture
was heated to 1208C and stirred until the reaction was completed. The
reactive solution was poured into ice and stirred. The resulting precipitate

1006
M.-Y. Li, H. Liu, and B.-H Zhong
was filtrated off and washed by water. The crude reaction mixture was purified
by silica-gel column chromatography to give 4.
Data
1-(4-Methylsulfonylphenyl)-2-cyclohexanotetrahydrobenzimidazole (2a).
1
White solid. Yield: 58%. Mp 230–2328C. H NMR (CDCl3) d: 8.09 (2H, d,
J ¼ 8.4 Hz, ArH), 7.42 (2H, d, J ¼ 8.4 Hz, ArH), 3.16 (3H, s, SO2CH3),
2.65 (2H, t, J ¼ 5.18 Hz, CH2), 2.44 (1H, m, CH), 2.26 (2H, t, J ¼ 5.76 Hz,
CH2), 1.75–1.85 (10H, m, CH2), 1.12–1.31 (4H, m, CH2). 13C NMR
(CDCl3): d151.17, 141.47, 140.30, 135.36, 128.87, 128.04, 125.57, 45.72,
44.40, 35.83, 32.32, 26.18, 25.52, 23.94, 23.20, 22.93, 21.41. ESI-MS: 359
(M þ 1). Anal. calc. for C20H26N2O2S, (358.12): C, 67.01; H, 7.31; N, 7.81;
found: C, 66.84; H, 7.20; N, 7.50. Elution solvent for the column is
petroleum ether/ethyl acetate (1:1, v/v); Rf ¼ 0.62. The inhibitory rate to
COX-2 is 26.36% at the concentration of 3 mmol/L.
1-(4-Methylsulfonylphenyl)-2-cyclohexanobenzimidazole (2b). White
solid. Yield: 54%. Mp 166–1688C. 1H NMR (CDCl3) d: 8.20 (2H, d,
J ¼ 8.4 Hz, ArH), 7.82 (1H, d, J ¼ 8.12 Hz, ArH), 7.61 (2H, d, J ¼ 8.4 Hz,
ArH), 7.22–7.31 (2H, m, ArH), 7.00 (1H, d, J ¼ 8.12 Hz, ArH), 3.21 (3H,
s, SO2CH3), 2.67–2.72 (1H, m, CH), 1.82–1.89 (6H, m, CH2), 1.19–1.35
(4H, m, CH2). ESI-MS: 355.2 (M þ 1). Anal. calc. for C20H22N2O2S
(354.14): C, 67.77; H, 6.26; N, 7.90; found: C, 67.30; H, 6.26; N, 7.52.
Elution solvent for the column is petroleum ether/ethyl acetate (1 : 1, v/v);
Rf ¼ 0.58.
1-(4-Methylsulfonylphenyl)-2-phenyltetrahydrobenzimidazole (4a). Light
yellow solid. Yield: 55%. Mp 214–2168C. 1H NMR (DMSO-d6) d: 8.00 (2H,
d, J ¼ 8.72 Hz, ArH), 7.54 (2H, d, J ¼ 8.72 Hz, ArH), 7.23–7.29 (5 H, m,
ArH), 3.30 (3H, s, SO2CH3), 2.57 (2H, t, J ¼ 5.60 Hz, CH2), 2.38 (2H, t,
J ¼ 5.60 Hz, CH2), 1.71–1.81 (4H, m, CH2). ESI-MS: 353.0 (M þ 1). Anal.
calc. for C20H20N2O2S (352.12): C, 68.16; H, 5.72; N, 7.95; found: C,
68.16; H, 5.66; N, 7.58. Elution solvent for the column is cyclohexane/
CHCl3/ethylenediamine (25:15:4, v/v/v); Rf ¼ 0.55. The inhibitory rate to
COX-2 is 26.19% at the concentration of 3 mmol/L.
1-(4-Methylsulfonylphenyl)-2-(4-methylphenyl)tetrahydrobenzimidazole
1
(4b). White solid. Yield: 55%. Mp 204.5–2078C. H NMR (CDCl3) d: 7.98
(2H, d, J ¼ 8.52 Hz, ArH), 7.35 (2H, d, J ¼ 8.4 Hz, ArH), 7.17 (2H, d,
J ¼ 8.4 Hz, ArH), 7.03 (2H, d, J ¼ 8.52 Hz, ArH), 3.11 (3H, s, SO2CH3),
2.73 (2H, t, J ¼ 5.74 Hz, CH2), 2.42 (2H, t, J ¼ 5.74 Hz, CH2), 2.30 (3H, s,
CH3), 1.83–1.90 (4H, m, CH2). 13C NMR (CDCl3) d:145.76, 142.42,
139.67, 138.28, 137.41, 129.09, 128.73, 128.35, 127.92, 127.77, 127.22,

N-Aryl-2-substituted Tetrahydrobenzimidazoles
1007
44.43, 24.17, 23.19, 23.02, 21.99. ESI-MS: 367.8 (M þ 1, 2). Anal. calc. for
C21H22N2O2S (366.14): C, 68.82; H, 6.05; N, 7.64; found: C, 68.49; H,
5.87; N, 7.58. Elution solvent for the column is cyclohexane/CHCl3/ethyle-
nediamine (25:15:4, v/v/v); Rf ¼ 0.61.
1-(4-Methylsulfonylphenyl)-2-(4-chlorophenyl)tetrahydrobenzimidazole
1
(4c). Light yellow solid. Yield: 57%. Mp 201–2038C. H NMR (CDCl3) d:
8.01 (2H, d, J ¼ 8.4 Hz, ArH), 7.36 (2H, d, J ¼ 8.4 Hz, ArH), 7.20–7.24
(4H, m, ArH), 3.12 (3H, s, SO2CH3), 2.72 (2H, t, J ¼ 5.74 Hz, CH2), 2.41
(2H, t, J ¼ 5.74 Hz, CH2), 1.81–1.88 (4H, m, CH2). Anal. calc. for
C20H19ClN2O2S (386.09): C, 62.09; H, 4.95; N, 7.24; found: C, 62.39; H,
4.87; N, 7.14. Elution solvent for the column is petroleum ether/ethyl
acetate/ethylenediamine (1 : 1.4 : 0.1, v/v/v); Rf ¼ 0.37.
1-(4-Methylsulfonylphenyl)-2-(3-chlorophenyl)tetrahydrobenzimidazole
1
(4d). Light yellow solid. Yield: 53%. Mp 197–1998C. H NMR (CDCl3) d:
8.02 (2H, d, J ¼ 8.4 Hz, ArH), 7.36–7.40 (3H, m, ArH), 7.22 (1H, d,
J ¼ 7.88 Hz, ArH), 7.14 (1H, t, J ¼ 7.84 Hz, ArH), 7.05 (1H, d,
J ¼ 7.84 Hz, ArH), 3.12 (3H, s, SO2CH3), 2.74 (2H, t, J ¼ 5.72 Hz, CH2),
2.41 (2H, t, J ¼ 5.72 Hz, CH2), 1.84–1.90 (4H, m, CH2). 13C NMR
(CDCl3) d: 144.01, 141.93, 140.25, 137.89, 134.42, 131.78, 129.57, 128.97,
128.72, 128.43, 128.34, 127.95, 126.23, 44.47, 24.11, 23.12, 22.92, 21.88.
Anal. calc. for C20H19ClN2O2S (386.09): C, 62.09; H, 4.95; N, 7.24; found:
C, 62.56; H, 5.25; N, 6.78. Elution solvent for the column is petroleum
ether/ethyl acetate/ethylenediamine (2 : 1 : 0.1, v/v/v); Rf ¼ 0.57. The
inhibitory rate to COX-2 is 8.74% at the concentrate of 3 mmol/L.
1-(4-Methylsulfonylphenyl)-2-(2-chlorophenyl)tetrahydrobenzimidazole
(4e). White solid. Yield: 50%. Mp 163–1648C. 1H NMR (CDCl3) d: 7.88 (2H,
d, J ¼ 8.44 Hz, ArH), 7.50 (1H, dd, J ¼ 8.96 Hz, ArH), 7.24–7.30 (5H, m,
ArH), 3.06 (3H, s, SO2CH3), 2.76 (2H, t, J ¼ 5.60 Hz, CH2), 2.50 (2H,
t, J ¼ 5.60 Hz, CH2), 1.84–1.93 (4H, m, CH2). Anal. calc. for
C20H19ClN2O2S (386.09): C, 62.09; H, 4.95; N, 7.24; found: C, 62.26; H,
5.08; N, 6.91. Elution solvent for the column is petroleum ether/ethyl
acetate/ethylenediamine (1 : 1.4 : 0.1, v/v/v); Rf ¼ 0.35.
1-(4-Methylsulfonylphenyl)-2-(2,5-chlorophenyl)tetrahydrobenzimidazole
(4f). White solid. Yield: 52%. Mp 191–1938C. 1H NMR (CDCl3) d: 7.92 (2H,
d, J ¼ 8.68 Hz, ArH), 7.56 (1H, d, J ¼ 2.52 Hz, ArH), 7.26–7.30 (3H, m,
ArH), 7.19 (1H, d, J ¼ 8.68 Hz, ArH), 3.08 (3H, s, SO2CH3), 2.76 (2H, t,
J ¼ 5.76 Hz, CH2), 2.49 (2H, t, J ¼ 5.76 Hz, CH2), 1.86–1.92 (4H, m,
CH2). ESI-MS: 421.2 (M þ 1). Anal. calc. for C20H18Cl2N2O2S (420.05): C,
57.01; H, 4.31; N, 6.65; found: C, 57.00; H, 4.54; N, 6.48. Elution solvent
for the column is petroleum ether/ethyl acetate/ethylenediamine
(1 : 1.4 : 0.1, v/v/v); Rf ¼ 0.30.

1008
M.-Y. Li, H. Liu, and B.-H Zhong
1-(4-Methylsulfonylphenyl)-2-(2,4-methylphenyl)tetrahydrobenzimidazole
(4g). White solid. Yield: 48%. Mp 118–1218C. 1H NMR (CDCl3) d: 7.87 (2H,
d, J ¼ 8.40 Hz, ArH), 7.20 (2H, d, J ¼ 8.4 Hz, ArH), 7.04 (1H, d,
J ¼ 7.56 Hz, ArH), 6.93 (1H, s, ArH), 6.89 (1H, d, J ¼ 7.84 Hz, ArH), 3.06
(3H, s, SO2CH3), 2.73 (2H, t, J ¼ 5.72 Hz, CH2), 2.28 (2H, t, J ¼ 5.72 Hz,
CH2), 1.85–1.91 (4H, m, CH2). Anal. calc. for C22H24N2O2S (380.16): C,
69.44; H, 6.36, N, 7.36; found: C, 69.32; H, 6.44; N, 7.05. Elution solvent
for the column is petroleum ether/ethyl acetate/ethylenediamine (1:1.4:0.1,
v/v/v); Rf ¼ 0.47.
1-(4-Methylsulfonylphenyl)-2-(3,4-methylphenyl)tetrahydrobenzimidazole
(4h). White solid. Yield: 50%. Mp 240–2418C. 1H NMR (CDCl3) d: 7.98 (2H,
d, J ¼ 8.4 Hz, ArH), 7.36 (2H, d, J ¼ 8.4 Hz, ArH), 7.30 (1H, s, ArH), 6.91
(1H, d, J ¼ 7.84 Hz, ArH), 6.76 (1H, dd, J ¼ 7.84 Hz, ArH), 3.11 (3H, s,
SO2CH3), 2.73 (2H, t, J ¼ 5.74 Hz, CH2), 2.42 (2H, t, J ¼ 5.74 Hz, CH2),
2.21 (3H, s, CH3), 2.17 (3H, s, CH3), 1.83–1.89 (4H, m, CH2). Anal. calc.
for C22H24N2O2S (380.16): C, 69.44; H, 6.36; N, 7.36; found: C, 69.40; H,
6.32; N, 7.36. Elution solvent for the column is petroleum ether/ethyl
acetate/ethylenediamine (1:1.6:0.08, v/v/v); Rf ¼ 0.41.
1-(4-Methylsulfonylphenyl)-2-(4-fluorophenyl)tetrahydrobenzimidazole
(4i). White solid. Yield: 51%. Mp 211–2138C. 1H NMR (CDCl3) d: 8.01 (2H,
d, J ¼ 8.4 Hz, ArH), 7.36 (2H, d, J ¼ 8.4 Hz, ArH), 7.28–7.32 (2H, m, ArH),
6.95 (2H, t, J ¼ 8.68 Hz, ArH), 3.12 (3H, s, SO2CH3), 2.75 (2H, t,
J ¼ 5.74 Hz, CH2), 2.41 (2H, t, J ¼ 5.74 Hz, CH2), 1.84–1.90 (4H, m,
CH2). Anal. calc. for C20H19FN2O2S (370.12): C, 64.85; H, 5.17; N, 7.56;
found: C, 64.83; H, 5.48; N, 7.38. Elution solvent for the column is
petroleum ether/ethyl acetate/ethylenediamine (1:1:0.06, v/v/v); Rf ¼ 0.41.
1-(4-Methylsulfonylphenyl)-2-(2,3-methyloxyphenyl)tetrahydrobenzimi-
1
dazole (4j). White solid. Yield: 51%. Mp 211–2138C. H NMR (CDCl3) d:
7.85 (2H, d, J ¼ 8.68 Hz, ArH), 7.26 (2H, d, J ¼ 8.68 Hz, ArH), 7.05 (2H,
m, ArH), 6.91 (1H, m, ArH), 3.77 (3H, s, OCH3), 3.49 (3H, s, OCH3), 3.04
(3H, s, SO2CH3), 2.73 (2H, t, J ¼ 5.74 Hz, CH2), 2.46 (2H, t, J ¼ 5.74 Hz,
CH2), 1.83–1.89 (4H, m, CH2). Anal. calc. for C22H24N2O4S (412.15): C,
64.06; H, 5.86; N, 6.79; found: C, 64.21; H, 6.02; N, 6.97. Elution solvent
for the column is petroleum ether/ethyl acetate/ethylenediamine (1:1.4:0.1,
v/v/v); Rf ¼ 0.27.
1-(4-Methylsulfonylphenyl)-2-(2-methylphenyl)tetrahydrobenzimidazole
(4k). White solid. Yield: 71%. Mp 204–2078C. 1H NMR (CDCl3) d: 7.87 (2H,
d, J ¼ 8.4 Hz, ArH), 7.21 (2H, d, J ¼ 8.4 Hz, ArH), 7.07–7.18 (4H, m, ArH),
3.06 (3H, s, SO2CH3), 2.74 (2H, t, J ¼ 5.74 Hz, CH2), 2.50 (2H, t,
J ¼ 5.74 Hz, CH2), 2.10 (3H, s, CH3), 1.86–1.92 (4H, m, CH2). Anal. calc.
for C21H22N2O2S (366.14): C, 68.82; H, 6.05; N, 7.64; found: C, 69.09; H,

N-Aryl-2-substituted Tetrahydrobenzimidazoles
1009
5.87; N, 7.58. Elution solvent for the column is petroleum ether/ethyl acetate/
ethylenediamine (1:1.4:0.1, v/v/v); Rf ¼ 0.57.
REFERENCES
1. Dannhardt, G.; Kiefer, W. Cyclooxygenase inhibitors—Current status and future
prospects. Eur. J. Med. Chem. 2001, 36 (2), 109–126.
2. Friesen, R. W.; Brideau, C.; Chan, C.-C.; Charleson, S.; Deschenes, D.; Dube, D.;
Ethier, D.; Fortin, R.; Gauthier, J. Y.; Girard, Y.; Gordon, R.; Greig, G.;
Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L. J.;
Young, R. N. 2-Pyridinyl-3-(4-methylsulfonyl)phenylpyridines: Selective and
orally active cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 1998, 8,
2777–2782.
3. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.;
Doctor, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.;
Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.;
Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. Synthesis and biological evalu-
ation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification
of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfona-
mide (SC-58635, celecoxib). J. Med. Chem. 1997, 40 (9), 1347–1365.
4. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.;
Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.;
Zweifel, B. S.; Seibert, K. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfona-
mide, valdecoxib: A potent and selective inhibitor of COX-2. J. Med. Chem.
2000, 43 (5), 775–777.
5. Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X.; Koszyk, F. J.; Collins, P. W.;
Koboldt, C. M.; Veenhuizen, A. W.; Perkins, W. E.; Casler, J. J.;
Masferrer, J. L.; Zhang, Y. Y.; Gergory, S. A.; Seibert, K.; Isakkson, P. 1,2-Dia-
rylimidazole as potent and cyclooxygenase-2 selective inhibitors, and orally
active anti-inflammatory agents. J. Med. Chem. 1997, 40, 1634–1647.
6. Lunn, W. H. W.; William, H. W.; Monn, J. A.; Zimmerman, D. M. US Patent,
1999, 5,552,426.
7. Wasserman, H. H.; Wolff, M. S.; Ktiller, H.; Aaito, I.; Pickett, J. E. The dye-
sensitized photooxidation of imidazoles. Tetrahedron 1981, 37 suppl. 1, 191–200.
8. Khan, M. A.; Polya, J. B. Syntheses of heterocyclic compounds, part II: N-aryli-
midazoles by Ullmann condensation. J. Chem. Soc. 1970, 85–90.
9. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Pergamon
Press: Oxford, 1984; Vol. 5, p. 390.
10. Begtrup, M. Reactions of 4-halogeno- and 4-methylthio-imidazolium salts with
sulphide and methanethiolate ions. J. Chem. Soc. Perkin Trans. 1979, 521–527.
11. Smith, W. J., III; Sawyer, J. S. A novel and selective method for the N-arylation of
indoles mediated by KF/Al2O3. Tetrahedron Lett. 1996, 37 (3), 299–302.
12. Hashimoto, H.; Imamura, K.; Haruta, J.; Wakitani, K. 4-(4-Cycloalkyl/aryl-
oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors:
Enhancement of the selectivity by introduction of a fluorine atom and identifi-
cation of a potent, highly selective, and orally active COX-2 inhibitor JTE-
522(1). J. Med. Chem. 2002, 45 (7), 1511–1517.