Delest et al.
Synthesis of 4-Iodo-1-methyl-2-phenylthio-1H-imidazole
(18). To a solution of trimethyloxonium tetrafluoroborate22 (54 mg,
0.3664 mmol, 5 equiv) in 1.5 mL of extra dry dichloromethane
was slowly added a solution of 1-(N,N-dimethylsulfamoyl)-2-
phenylthio-5-iodo-1H-imidazole 10 (30 mg, 0.0733 mmole) in 1
mL of extra dry dichloromethane. The addition was performed over
a period of 15 h by means of a syringe pump. The resulting mixture
was then stirred for 4 days at room temperature. Butylmethylamine
(87.5 µL, 0.7327 mmol, 10 equiv) was added at once, and the
solution was stirred for 15 h. Dichloromethane (20 mL) was added,
and the solution was washed three times with water. The organic
phase was dried (MgSO4) and concentrated in vacuo. The crude
product was obtained as a mixture of regioisomers 18/15 in a 83/
17 ratio. The two regioisomers can be separated by flash chroma-
tography over silica with dichloromethane/acetone 99/1 as eluent,
1-methyl-4-iodo-2-phenylsulfonylimidazole (18, 50 mg, 0.14 mmol,
1 equiv), naphthalen-2-yl-boronic acid (27 mg, 0.16 mmol, 1.1
equiv), and Cs2CO3 (70 mg, 0.22 mmol, 1.5 equiv) were dissolved
in dry DMF (6 mL). A flow of Ar was passed through the solution
for 20 min. The solution was transferred into a sealed tube and
heated under microwave for 4 h at 80 °C. The reaction mixture
was poured into water, and ethyl acetate was added. The solution
was filtered on Celite. The layers were separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Flash chromatography over silica with ethyl
acetate/cyclohexane 30/70 as eluent affords the desired product.
Yield: 47%; mp 168-169 °C; 1H NMR (300 MHz, CDCl3) δ 8.28
(s, 1H), 8.14-8.10 (m, 2H), 7.88-7.79 (m, 4H), 7.68-7.55 (m,
3H), 7.35 (s, 1H), 4.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
142.4, 140.2, 133.9, 133.5, 133.0, 129.7, 129.4, 128.3, 128.2, 128.1,
127.7, 126.3, 125.9, 123.9, 123.5, 121.9, 77.2, 35.6; HRMS calcd
for C20H16N2O2NaS 371.0830, found 371.0824.
1
which gave pure 18: mp 63-64 °C; H NMR (300 MHz, CDCl3)
δ 7.30-7.24 (m, 2H), 7.22-7.15 (m, 3H), 7.16 (s, 1H), 3.62 (s,
1
3H); H NMR (300 MHz, acetone-d6) δ 7.52 (s, 1H), 7.36-7.30
1
(m, 2H), 7.28-7.17 (m, 3H), 3.71 (s, 3H); H NMR (300 MHz,
Synthesis
of
2-(But-3-enyloxy)-5-iodo-1-methyl-1H-
CD2Cl2) δ 7.35-7.19 (m, 5H), 7.22 (s, 1H), 3.64 (s, 3H); 1H NMR
(300 MHz, C6D6) δ 7.11-7.08 (m, 2H), 6.86-6.78 (m, 3H), 6.21
(s, 1H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 140.1, 134.2,
129.7, 129.5, 128.4, 127.1, 82.0, 34.1; GC (140 °C for 5 min and
then f 290 at 10 °C/min) 18.6 min; HRMS calcd for C10H10IN2S
316.9609, found 316.9599.
imidazole (22). 3-Buten-1-ol (900 µL, 750 mg, 10.40 mmol, 5
equiv) was added to a solution of sodium hydride (383 mg of a
60% suspension in mineral oil, 9.58 mmol, 4.6 equiv) in dry THF
(7 mL), under argon. The solution was stirred until no more gas
evolution was observed and then added to a solution of 1-methyl-
5-iodo-2-phenylsulfonylimidazole (16, 725 mg, 2.08 mmol, 1 equiv)
in dry THF (35 mL). The reaction mixture was transferred into a
sealed tube and heated under microwave for 6.5 h at 80 °C. Ethyl
acetate (50 mL) and 10% sodium hydroxide solution (30 mL) were
successively added. The organic phase was further washed twice
with a 10% solution of sodium hydroxide (30 mL). Combined
aqueous phases were extracted with ethyl acetate (20 mL). The
combined organic phases were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. Flash chromatography over
silica with dichloromethane/methanol 99/1 as eluent affords a
colorless oil (Rf ) 0.3). Yield: 78%; 1H NMR (300 MHz, CDCl3)
δ 6.73 (s, 1H), 5.84 (tdd, 1H, J ) 6.7, 10.2, 17.0 Hz), 5.06-5.19
(m, 2H), 4.37 (t, 3H, J ) 6.6 Hz), 3.32 (s, 3H), 2.52 (tq, 2H, J )
1.3, 6.7 Hz); 13C NMR (75 MHz, CDCl3) 153.7, 134.0, 130.3, 117.4,
68.8, 63.6, 33.5, 31.2; IR (cm-1) ν 3115, 2982, 2947, 1639, 1539,
1496, 1473, 1407, 1369, 1254; MS-APCI m/z ) 279, 225; HRMS
calcd for C8H11N2ONaI 300.9814, found 300.9811.
Synthesis
of
4-Iodo-1-methyl-2-phenylsulfonyl-1H-
imidazole (19). m-CPBA 70% (307 mg, 1.25 mmol, 2.2 equiv)
was added to a solution of 1-methyl-2-phenylthio-4-iodo-1H-
imidazole (18, 179 mg, 0.57 mmol, 1 equiv) in 10 mL of
dichloromethane, in a flask surrounded by aluminum foil to protect
the solution from light. After 8 h at room temperature, sodium
bisulfite (131 mg, 1.25 mmol, 2.2 equiv), water (4 mL), and a
saturated sodium bicarbonate solution (6 mL) were successively
added. Phases were separated, and the organic phase was washed
with saturated sodium bicarbonate. The aqueous phases were
extracted three times with dichloromethane. The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
in vacuo to give 191 mg of pure product as a white solid. Yield:
1
97%; mp 91-92 °C; H NMR (300 MHz, CDCl3) δ 8.03 (d, 2H,
J ) 9.4 Hz), 7.5-7.7 (m, 3H), 7.04 (s, 1H), 3.95 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 144.7, 139.6, 134.4, 131.4, 129.6, 128.3, 82.5,
35.6; MS (APCI) m/z 349; HRMS calcd for C10H9IN2O2SNa
370.9327, found 370.9317.
Synthesis
of
2-(But-3-enyloxy)-4-iodo-1-methyl-1H-
imidazole (23). 3-Buten-1-ol (185 µL, 156 mg, 2.15 mmol, 5 equiv)
was added to a solution of sodium hydride (47.5 mg of a 60%
suspension in mineral oil, 1.98 mmol, 4.6 equiv) in dry THF (2
mL), under argon. The solution was stirred until no more gas
evolution was observed and then added to a solution of 1-methyl-
4-iodo-2-phenylsulfonylimidazole (19, 150 mg, 0.43 mmol, 1 equiv)
in dry THF (7 mL). The reaction mixture was transferred into a
sealed tubes and heated under microwave for 6.5 h at 80 °C. Ethyl
acetate (30 mL) and 10% sodium hydroxide solution (10 mL) were
successively added. The organic phase was further washed twice
with a 10% solution of sodium hydroxide (10 mL). Combined
aqueous phases were extracted with ethyl acetate (10 mL). The
combined organic phases were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. Flash chromatography over
silica with dichloromethane/methanol 99/1 as eluent affords 62 mg
Synthesis of 1-Methyl-5-(naphthalene-3-yl)-2-phenylsulfonyl-
1H-imidazole (20). Pd(PPh3)4 (5 mg, 0.04 mmol, 0.03 equiv),
1-methyl-5-iodo-2-phenylsulfonylimidazole (16, 50 mg, 0.14 mmol,
1 equiv), naphthalen-2-ylboronic acid (27 mg, 0.16 mmol, 1.1
equiv), and Cs2CO3 (70 mg, 0.22 mmol, 1.5 equiv) were dissolved
in dry DMF (6 mL). A flow of Ar was passed through the solution
for 20 min. The solution was transferred into a sealed tube and
heated under microwave for 4 h at 80 °C. The reaction mixture
was poured into water, and ethyl acetate was added. The solution
was filtered on Celite. The layers were separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Flash chromatography over silica with ethyl
acetate/cyclohexane 30/70 as eluent affords the desired product.
Yield: 70%; 1H NMR (300 MHz, acetone-d6) δ 8.10-7.95 (m, 6H),
7.80-7.57 (m, 6H), 7.28 (s, 1H), 4.04 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 144.2, 140.1, 138.5, 134.4, 133.5, 133.4, 129.7, 129.4,
129.1, 128.7, 128.5, 128.2, 127.6, 127.4, 126.7, 125.6, 77.6, 33.7;
MS-APCI: m/z ) 350; HRMS calcd for C20H16N2O2NaS 371.0830,
found 371.0832.
1
of a colorless oil (Rf ) 0.3). Yield: 52%; H NMR (300 MHz,
CDCl3) δ 6.60 (s, 1H), 5.81 (m, 1H), 5.10-5.18 (m, 2H), 4.39 (t,
3H, J ) 6.6 Hz), 3.36 (s, 3H), 2.51 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 153.2, 134.2, 122.0, 117.6, 74.3, 69.4, 33.7, 30.8; MS-
APCI m/z ) 279, 225; HRMS calcd for C8H11N2ONaI 300.9814,
found 300.9816.
Synthesis of 1-Methyl-4-(naphthalene-3-yl)-2-phenylsulfonyl-
1H-imidazole (21). Pd(PPh3)4 (5 mg, 0.04 mmol, 0.03 equiv),
Acknowledgment. This work was supported by the Fonds
de la Recherche Scientifique - FNRS (F.R.S.-FNRS) and the
Region Bruxelles-Capitale. Authors thank Drs. E. Van Quaque-
beke and L. Ingrassia for fruitful comments on this manuscript.
(22) Me3O · BF4 was purchased from Acros and purified prior to use
(following the procedure described by: Curphey, T. J. Org. Synth. 1971, 51,
142–147.
6822 J. Org. Chem. Vol. 73, No. 17, 2008