Synthesis of 1,2-disubstituted imidazoles viacross-coupling and substitution reactions

Article abstract of DOI:10.3987/COM-05-10531

Lithiation of imidazole compound (1) in position 2 and subsequent quenching with electrophiles provided a route to 1,2-diaryl-, 1-aryl-2-cycloalkyl- and 1-aryl-2-heterocyclyl-substituted imidazoles.

Full text of DOI:10.3987/COM-05-10531

HETEROCYCLES, Vol. 65, No. 11, 2005
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HETEROCYCLES, Vol. 65, No. 11, 2005, pp. 2721 - 2728
Received, 28th July, 2005, Accepted, 15th September, 2005, Published online, 16th September, 2005
SYNTHESIS OF 1,2-DISUBSTITUTED IMIDAZOLES VIA
CROSS-COUPLING AND SUBSTITUTION REACTIONS
Ingo Langhammer and Thomas Erker*
Department of Medicinal/ Pharmaceutical Chemistry, University of Vienna,
Althanstraße 14, A-1090 Wien, Austria
thomas.erker@univie.ac.at
Abstract - Lithiation of imidazole compound (1) in position 2 and subsequent
quenching with electrophiles provided a route to 1,2-diaryl-, 1-aryl-2-cycloalkyl-
and 1-aryl-2-heterocyclyl-substituted imidazoles.
Introduction
Diarylimidazoles have been described as pharmacologically active compounds in several publications over
the last twenty years. Certain 1,2-diarylimidazoles for example showed COX-2-inhibiting activity.1,2 All of
these 1,2-diarylimidazoles were prepared by condensating amidines with α-halogen ketones. This paper
describes an alternative approach to 1,2-disubstituted imidazoles, starting from imidazole compound (1)
and utilising cross-coupling reactions and substitution reactions to form C-C-bonds and C-N-bonds.
Results
Starting from 1-(4-methylsulfanylphenyl)-1H-imidazole (1)3 we prepared compound (2) via lithiation of
substance (1), followed by quenching with cyclohexanone. Refering to experiments presented in
literature4-6 we assumed a selective lithiation of the imidazole ring of compound (1) onto position 2. The
real structural evidence for the substitution in position 2 was confirmed by 1H and 13C NMR data.
1. n-BuLi
2.
HO
N
N
R
O
Oxone
(91%)
N
N
(50%)
Me
Me
1
2
S
S

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HETEROCYCLES, Vol. 65, No. 11, 2005
As a methylsulfone moiety is desireable for COX-enzyme affinity, substance (2) was oxidized to 3 with
Oxone®. Dehydration of 3 with Ac2O / AcOH yielded 4.
HO
Ac2O / AcOH
(69%)
N
N
N
N
Me
Me
3
S
S
4
O
O
O
O
Lithiation of 1 and subsequent quenching with hexachloroethane gave product (5). Sulfide (5) was oxidized
with Oxone® to yield 6. The 2-chloro-substituted 6 proved to be a good substrate for nucleophilic
substitutions. Heating 6 with piperidine or morpholine in an autoclave gave products (7) or (8) respectively.
Cl
N
1. n-BuLi
2. C2Cl6
N
R
Oxone
(76%)
N
N
(95%)
Me
Me
5
1
S
S
X
X
Cl
HN
N
N
N
N
N
200°C
Me
S
Me
6
S
-CH -
-O-
7: X =
8: X =
(56%)
(65%)
O
O
O
O
2
Whilst compounds (2) and (5) could be easily oxidized with Oxone®, 2-iodo-substituted 9 turned out to be
not stable enough for oxidation. Frequent deiodination of 9 to 10 forced us to put back the oxidation step

HETEROCYCLES, Vol. 65, No. 11, 2005
2723
until formation of a C-C-bond in position 2 had been accomplished. Thus we reacted compound (9) with
3-methoxyphenylboronic acid under Suzuki conditions which gave 11 in good yield. Oxidation of 11 with
Oxone® finally yielded 12.
N
I
N
N
1. n-BuLi
2. I2
R
N
Oxone
N
N
-
I2
(79%)
10
Me
9
Me
1
Me
S
S
S
O
O
Me
O
B(OH)2
(78%)
Me
Me
Me
Me
N
N
O
O
R
Oxone
N
N
12
11
S
S
O
O
Very recently, direct coupling reactions of 1-aryl-1H-imidazoles with aryl halides has been reported by
Bellina et al..7 This work has demonstrated, that a variety of 1,5-diaryl-1H-imidazoles can be selectively
synthesized in moderate yields by direct palladium catalyzed C-arylation of 1-aryl-1H-imidazoles with aryl
iodides or bromides. The electrophilic attack of the arylpalladium halide species occur onto position C-5 of
the heteroaromatic ring.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker Avance DPx200 spectrometer, using TMS as an
internal standard. MS spectra were recorded on a Shimadzu QP 5000. Column chromatography was
performed on Merck silica gel 60, 0.063 - 0.200 mm. Melting points were determined with a Kofler melting
point apparatus and are uncorrected. Microanalyses were determined by Johannes Theiner at the Institute of
Physical Chemistry of the University of Vienna.

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HETEROCYCLES, Vol. 65, No. 11, 2005
1-[1-(4-Methylsulfanylphenyl)-1H-2-imidazolyl]-1-cyclohexanol (2)
To 0.381 g (0.002 mol) of 1 in 30 mL of anhydrous THF at -78°C under argon 1.4 mL (0.0022 mol) of 1.6
M n-BuLi in hexane was slowly added. After 15 min 0.25 mL (0.0024 mol) of cyclohexanone was added.
The reaction mixture was stirred 30 min at -78°C and then allowed to warm to rt. Then the reaction mixture
was washed with 70 mL of a saturated aqueous solution of ammonium chloride. The aqueous phase was
extracted twice with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous
sodium sulfate and evaporated. The crude product was recrystallized from ethanol to yield 0.288 g (50%) of
1
2; mp 122 - 143°C; MS: m/z (rel. int.) 288 (M+, 53), 245 (100), 217 (57), 137 (43), 69 (35); H-NMR
(CDCl3): δ = 7.36 - 7.17 (m, 4H, ArH), 7.03 - 6.93 (m, 1H, ArH), 6.90 - 6.80 (m, 1H, ArH), 2.74 (br s, 1H,
-OH), 2.53 (s, 3H, -CH3), 1.96 - 1.02 (m, 10H, -C5H10-); 13C-NMR (CDCl3): δ = 152.7 (ArC), 139.7 (ArC),
136.1 (ArC), 127.9 (ArCH), 126.0 (ArCH), 123.9 (ArCH), 71.7 (carbinol C), 37.3 (-CH2-), 25.2 (-CH2-),
21.8 (-CH2-), 15.4 (-CH3); one ArCH signal was not detectable; Anal. Calcd for C16H20N2OS: C, 66.63; H,
6.99; N, 9.71. Found: C, 66.51; H, 7.05; N 9.49.
1-[1-(4-Methylsulfonylphenyl)-1H-2-imidazolyl]-1-cyclohexanol (3)
A solution of Oxone® (1.230 g, 0.002 mol) in 10 mL of water was added to a solution of 2 (0.288 g, 0.001
mol) in 15 mL of methanol. The reaction is slightly exothermic, and the temperature of the reaction was
prevented from rising by a surrounding water bath. After being stirred at rt for 1 h, the mixture was treated
with dilute ammonium hydroxide (10%, 13 mL). The contents were stirred for 1 h and then the methanol
was evaporated. The aqueous phase was extracted four times with 20 mL of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and evaporated. The crude product was
recrystallized from ethanol to yield 0.292 g (91 %) of 3; mp 148 - 163°C; MS: m/z (rel. int.) 320 (M+, 23),
277 (100), 249 (66), 223 (39), 95 (50); 1H-NMR (CDCl3): δ = 8.07 - 7.96 (m, 2H, ArH), 7.74 - 7.62 (m, 2H,
ArH), 7.02 (s, 1H, ArH), 6.91 (s, 1H, ArH), 2.71 (br s, 1H, -OH), 3.13 (s, 3H, -CH3), 2.03 - 1.11 (m, 10H,
-C5H10-); 13C-NMR (DMSO-d6): δ = 152.4 (ArC), 144.1 (ArC), 140.1 (ArC), 128.4 (ArCH), 127.4 (ArCH),
126.3 (ArCH), 123.7 (ArCH), 70.6 (carbinol C), 43.3 (-CH3), 37.3 (-CH2-), 25.2 (-CH2-), 21.8 (-CH2-);
Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C, 59.93; H, 6.51; N 8.54.
2-(1-Cyclohexenyl)-1-(4-methylsulfonylphenyl)-1H-imidazole (4)
A solution of 3 (0.320 g, 0.001 mol) in a mixture of Ac2O (7.5 mL, 0.079 mol) and AcOH (15 mL) was
refluxed for 4 h at 130°C. After cooling to rt the volatiles were evaporated under reduced pressure. The
crude product was recrystallized from ethanol to yield 0.209 g (69%) of 4; mp 140 - 142°C; MS: m/z (rel.

HETEROCYCLES, Vol. 65, No. 11, 2005
2725
int.) 302 (M+, 81), 301 (100), 287 (11), 273 (39), 133 (27); 1H-NMR (CDCl3): δ = 8.14 - 7.94 (m, 2H, ArH),
7.64 - 7.44 (m, 2H, ArH), 7.20 - 7.10 (m, 1H, ArH), 7.09 - 6.97 (m, 1H, ArH), 5.83 - 5.70 (m, 1H, -C=CH-),
3.13 (s, 3H, -CH3), 2.38 - 2.18 (m, 2H, -CH2-), 2.12 - 1.93 (m, 2H, -CH2-),1.76 - 1.48 (m, 4H, -CH2-);
13C-NMR (CDCl3): δ = 148.7 (ArC), 143.4 (ArC), 139.5 (ArC), 132.7 (ArCH), 128.9 (ArCH), 128.8
(ArCH), 127.8 (ArC) 125.8 (ArCH / -C=CH-), 121.1 (ArCH / -C=CH-), 44.4 (-CH3), 27.3 (-CH2-), 25.4
(-CH2-), 22.3 (-CH2-) 21.5 (-CH2-); Anal. Calcd for C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26. Found: C,
63.78; H, 6.30; N, 9.14.
2-Chloro-1-(4-methylsulfanylphenyl)-1H-imidazole (5)
To 0.951 g (0.005 mol) of 1 in 100 mL of anhydrous THF at -78°C under argon 3.3 mL (0.0052 mol) of 1.6
M n-BuLi in hexane was slowly added. After 15 min 3.551 g (0.015 mol) of hexachloroethane dissolved in
15 mL of anhydrous THF were added. The reaction mixture was stirred 30 min at -78°C and then allowed to
warm to rt. Then the reaction mixture was washed with 70 mL of a saturated aqueous solution of
ammonium chloride. The aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was subjected to
column chromatography with ethyl acetate/n-hexane/TEA (60 + 35 + 5). The product was recrystallized
from ethanol to yield 1.067 g (95 %) of 5; mp 80 - 83°C; MS: m/z (rel. int.) 224 / 226 (M+, 100 / 27), 209
(51), 162 (48), 108 (28), 75 (59); 1H-NMR (CDCl3): δ = 7.40 - 7.22 (m, 4H, ArH), 7.12 - 7.03 (m, 2H, ArH),
2.53 (s, 3H, -CH3); 13C-NMR (CDCl3): δ = 140.1 (ArC), 133.0 (ArC), 131.8 (ArC), 128.6 (ArCH), 126.6
(ArCH), 125.9 (ArCH), 122.4 (ArCH), 15.4 (-CH3); Anal. Calcd for C10H9N2ClS: C, 53.45; H, 4.04; N,
12.47. Found: C, 53.64; H, 4.24; N, 12.38.
2-Chloro-1-(4-methylsulfonylphenyl)-1H-imidazole (6)
A solution of Oxone® (1.230 g, 0.002 mol) in 10 mL of water was added to a solution of 5 (0.225 g, 0.001
mol) in 15 mL of methanol. The reaction is slightly exothermic, and the temperature of the reaction was
prevented from rising by a surrounding water bath. After being stirred at rt for 1 h, the mixture was treated
with dilute ammonium hydroxide (10%, 13 mL). The contents were stirred for 1 h and then the methanol
was evaporated. The aqueous phase was extracted four times with 20 mL of ethyl acetate. The combined
organic layers were evaporated. The residue was subjected to column chromatography with ethyl acetate/
TEA (95 + 5). The product was recrystallized from ethanol to yield 0.195 g (76%) of 6; mp 125 - 133°C;
MS: m/z (rel. int.) 256 / 258 (M+, 100 / 36), 241 (9), 177 (38), 150 (25), 116 (57); 1H-NMR (CDCl3): δ =
8.18 - 8.01 (m, 2H, ArH), 7.70 - 7.54 (m, 2H, ArH), 7.21 - 7.04 (m, 2H, ArH), 3.14 (s, 3H, -CH3); 13C-NMR
(CDCl3): δ = 140.6 (ArC), 140.5 (ArC), 131.4 (ArC), 129.4 (ArCH), 128.9 (ArCH), 126.3 (ArCH), 122.1

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HETEROCYCLES, Vol. 65, No. 11, 2005
(ArCH), 44.4 (-CH3); Anal. Calcd for C10H9N2O2ClS: C, 46.79; H, 3.53; N, 10.91. Found: C, 46.79; H,
3.53; N 10.91.
1-[1-(4-Methylsulfonylphenyl)-1H-2-imidazolyl]piperidine (7)
A solution of 6 (0.257 g, 0.001 mol) in piperidine (15 mL) was put in an autoclave and heated at 200°C for
36 h. After cooling to rt the piperidine was evaporated under reduced pressure. The residue was dissolved in
ethyl acetate and washed with water. The organic phase was evaporated under reduced pressure and the
residue was subjected to column chromatography with ethyl acetate / methanol / TEA (90 + 5 + 5). The
crude product was recrystallized from ethanol to yield 0.171 g (56 %) of 7; mp 164 - 167° C; MS: m/z (rel.
int.) 305 (M+, 82), 276 (100), 249 (29), 122 (87), 96 (97); 1H-NMR (CDCl3): δ = 8.12 - 7.97 (m, 2H, ArH),
7.89 - 7.77 (m, 2H, ArH), 6.98 - 6.83 (m, 2H, ArH), 3.12 (s, 3H, -CH3), 3.07 - 2.91 (m, 4H, -CH2-), 1.55 (br
s, 6H, -CH2-); 13C-NMR (CDCl3): δ = 152.4 (ArC), 142.9 (ArC), 138.3 (ArC), 128.8 (ArCH), 126.4
(ArCH), 123.4 (ArCH), 117.2 (ArCH), 51.2 (-CH2-), 44.4 (-CH3), 25.3 (-CH2-), 23.8 (-CH2-); Anal. Calcd
for C15H19N3O2S: C, 58.99; H, 6.27; N, 13.76. Found: C, 59.01; H, 6.51; N, 13.67.
4-[1-(4-Methylsulfonylphenyl)-1H-2-imidazolyl]morpholine (8)
A solution of 6 (0.257 g, 0.001 mol) in morpholine (15 mL) was put in an autoclave and heated at 200°C for
36 h. After cooling to rt the piperidine was evaporated under reduced pressure. The residue was dissolved in
ethyl acetate and washed with water. The organic phase was evaporated under reduced pressure and the
residue was subjected to column chromatography with ethyl acetate / methanol / TEA (90 + 5 + 5). The
crude product was recrystallized from ethanol to yield 0.200 g (65 %) of 8; mp 184 - 191°C; MS: m/z (rel.
int.) 307 (M+, 25), 250 (100), 170 (29), 138 (48), 108 (37); 1H-NMR (CDCl3): δ = 8.11 - 8.01 (m, 2H, ArH),
7.88 - 7.76 (m, 2H, ArH), 6.99 - 6.87 (m, 2H, ArH), 3.79 - 3.65 (m, 4H, -CH2-), 3.12 (s, 3H, -CH3), 3.09 -
2.99 (m, 4H, -CH2-); 13C-NMR (CDCl3): δ = 151.0 (ArC), 142.4 (ArC), 138.8 (ArC), 129.0 (ArCH), 126.6
(ArCH), 123.8 (ArCH), 117.9 (ArCH), 66.3 (-CH2-), 50.2 (-CH2-), 44.4 (-CH3); Anal. Calcd for
C14H17N3O3S: C, 54.71; H, 5.57; N, 13.67. Found: C, 54.66; H, 5.66; N, 13.53.
2-Iodo-1-(4-methylsulfanylphenyl)-1H-imidazole (9)
To 0.381 g (0.002 mol) of 1 in 30 mL of anhydrous THF at -78°C under argon 1.4 mL (0.0022 mol) of 1.6
M n-BuLi in hexane was slowly added. After 15 min 0.508 g (0.002 mol) I2 dissolved in 15 mL of dry THF
was added. The reaction mixture was stirred 30 min at -78°C and then allowed to warm to rt. Then the
reaction mixture was washed with 20 mL of a saturated aqueous solution of ammonium chloride. The

HETEROCYCLES, Vol. 65, No. 11, 2005
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aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic layers were dried
over anhydrous sodium sulfate and evaporated. The residue was subjected to column chromatography with
ethyl acetate/ TEA (95 + 5). The product was recrystallized from ethanol to yield 0.500 g (79 %) of 9; mp
122 - 143°C; mp 83 - 85°C; MS: m/z (rel. int.) 316 (M+, 100), 301 (3), 189 (4), 174 (15), 142 (78); 1H-NMR
13
(CDCl3): δ = 7.40 - 7.12 (m, 6H, ArH), 2.54 (s, 3H, -CH3); C-NMR (CDCl3): δ = 140.4 (ArC), 135.0
(ArC), 132.8 (ArCH), 127.0 (ArCH), 126.4 (ArCH), 124.7 (ArCH), 90.5 (ArC), 15.4 (-CH3); Anal. Calcd
for C10H9N2IS: C, 37.99; H, 2.87; N, 8.86. Found: C, 38.21; H, 3.13; N, 8.78.
2-(3-Methoxyphenyl)-1-(4-methylsulfanylphenyl)-1H-imidazole (11)
A mixture of 9 (0.316 g, 0.001 mol), 3-methoxyphenylboronic acid (0.182 g, 0.0012 mol),
tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.0001 mol), toluene (18 mL), methanol (3.6 mL) and
2M potassium carbonate (1 mL) was refluxed for 16 h under argon atmosphere. The reaction mixture was
cooled to rt and washed with 10 mL of a saturated aqueous solution of ammonium chloride. The organic
layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to column
chromatography with ethyl acetate/TEA (95 + 5). The product was recrystallized from ethanol to give 0.231
g (78%) of 11; mp 103 - 110°C; MS: m/z (rel. int.) 296 (M+, 100), 280 (21), 222 (14), 147 (43), 77 (23);
1H-NMR (CDCl3): δ = 7.32 - 7.08 (m, 8H, ArH), 6.93 - 6.79 (m, 2H, ArH), 3.71 (s, 3H, -OCH3), 2.50 (s,
13
3H, -SCH3); C-NMR (CDCl3): δ = 159.2 (ArC), 146.4 (ArC), 139.1 (ArC), 135.4 (ArC), 131.4 (ArC),
129.1 (ArCH), 128.9 (ArCH), 126.7 (ArCH), 126.1 (ArCH), 122.9 (ArCH), 120.9 (ArCH), 114.9 (ArCH),
113.2 (ArCH), 55.1 (-OCH3), 15.5 (-SCH3); Anal. Calcd for C17H16N2OS: C, 68.89; H, 5.44; N, 9.45.
Found: C, 68.65; H, 5.69; N 9.25.
2-(3-Methoxyphenyl)-1-(4-methylsulfonylphenyl)-1H-imidazole (12)
A solution of Oxone® (1.230 g, 0.002 mol) in 10 mL of water was added to a solution of 11 (0.296 g, 0.001
mol) in 15 mL of methanol. The reaction is slightly exothermic, and the temperature of the reaction was
prevented from rising by a surrounding water bath. After being stirred at rt for 1 h, the mixture was treated
with dilute ammonium hydroxide (10%, 13 mL). The contents were stirred for 1 h and then the methanol
was evaporated. The aqueous phase was extracted four times with 20 mL of ethyl acetate. The combined
organic layers were evaporated. The residue was subjected to column chromatography with ethyl acetate /
methanol / TEA (90 + 5 + 5). The product was recrystallized from ethanol (70%) to yield 0.151 g (46%) of
1
12; mp 146 - 150°C; MS: m/z (rel. int.) 328 (M+, 100), 312 (6), 248 (42), 89 (16), 63 (14); H-NMR
(CDCl3): δ = 8.05 - 7.92 (m, 2H, ArH), 7.48 - 7.37 (m, 2H, ArH), 7.34 - 6.73 (m, 6H, ArH), 3.75 (s, 3H,

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HETEROCYCLES, Vol. 65, No. 11, 2005
-OCH3), 3.10 (s, 3H, -SCH3); 13C-NMR (CDCl3): δ = 159.5 (ArC), 146.7 (ArC), 142.9 (ArC), 139.7 (ArC),
130.8 (ArC), 129.8 (ArCH), 129.4 (ArCH), 128.8 (ArCH), 126.3 (ArCH), 122.3 (ArCH), 121.1 (ArCH),
115.1 (ArCH), 113.8 (ArCH), 55.2 (-OCH3), 44.4 (-SO2CH3); Anal. Calcd for C17H16N2O3S: C, 62.18; H,
4.91; N, 8.53. Found: C, 62.05; H, 4.74; N, 8.49.
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