4042
I. C. Gonzꢀalez et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4037–4043
reaction mixture was held at )70 °C for 2 h, allowed to
water (0.5 mL) diluted in water (0.5 mL) was added. After
30 min the reaction mixture was filtered, and the filtrate
was extracted with DCM. The organic phase was washed
with saturated solution of NaCl, dried over MgSO4,
filtered, and concentrated. Chromatography (silica, hex-
ane/EtOAc ¼ 95/5) provided 23 as an oil (12 mg,
warm to ꢀ35 °C over 2 h, and added to a mixture of
NH4Cl in ice. The organic phase was separated, the
aqueous phase was re-extracted with Et2O, and the
combined ether solutions were washed with saturated
solution of NaCl, dried over MgSO4, filtered, and
concentrated Column chromatography (silica, hexane/
1
0.05 mmol, 36%): H NMR (CDCl3, 400 MHz): d 1.43 (t,
EtOAc ¼ 95/5) gave
4
as
a
colorless liquid (1.15 g,
3H, J ¼ 7:4 Hz), 3.10 (q, 2H, J ¼ 7:4 Hz), 7.16–7.20 (m,
2H), 7.31 (s, 1H), 7.58–7.62 (m, 2H); GC–MS 263 [M]þ.
10. Rosowsky, A.; Mota, C. E.; Wright, J. E.; Freisheim,
J. H.; Heusner, J. J. J. Med. Chem. 1993, 36, 3103.
11. Crochet, R. A.; DeWitt Blanto, C., Jr. Synthesis 1974, 1,
55.
1
5.14 mmol, 83%): H NMR (CDCl3, 400 MHz): d 1.32 (t,
3H, J ¼ 7:4 Hz), 2.86 (q, 2H, J ¼ 7:4 Hz), 7.05 (d, 1H,
J ¼ 1:2 Hz), 7.26 (d, 1H, J ¼ 1:2 Hz). To a stirred solution
of 4 (0.20 g, 0.89 mmol) in ethylene glycol dimethyl ether
(4 mL) and Pd(PPh3)4 (0.05 g, 0.05 mmol) were added
Na2CO3 (0.25 g, 2.33 mmol) in water (2 mL) and
p-fluorophenylboronic acid (0.16 g, 1.16 mmol). After
stirring at 80 °C for 24 h, Pd(PPh3)4 (0.05 g, 0.05 mmol)
was added to the reaction mixture followed by Na2CO3
(0.12 g, 1.16 mmol) in water (1 mL) and p-fluorophenyl-
boronic acid (0.08 g, 0.58 mmol). After stirring at 80 °C for
8 h, the reaction mixture was cooled to room temperature,
diluted with water, and extracted with EtOAc. The organic
phase was washed with saturated solution of NaCl, dried
over MgSO4, filtered, and concentrated. Chromatography
(silica, hexane/EtOAc ¼ 97/3) provided 6 as an oil (0.12 g,
€
12. Alvarez-Insua, A. S.; Conde, S.; Corral, C. J. Heterocycl.
Chem. 1982, 19, 713.
13. DiBiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, R. A.;
Gokel, G. W. J. Org. Chem. 1979, 44, 4640.
14. Dijkstra, H. P.; ten Have, R.; van Leusen, A. M. J. Org.
Chem. 1998, 63, 5332.
15. Synthesis of pyrroles 44 and 45: n-BuLi (2.5 M in hexane,
2.83 mL, 7.09 mmol) was added dropwise to a solution of
tosylmethyl isocyanide (0.66 g, 3.38 mmol) in THF (50 mL)
at )78 °C. After 5 min Me3SnCl (1.41g, 7.09mmol) in THF
(2 mL) was added dropwise. After another 5 min, a
solution of 41 (0.49 g, 3.38 mmol) in THF (2 mL) was
added dropwise. The temperature of the reaction mixture
was allowed to rise to room temperature in 30 min, and
stirring was continued for 4 h. Water was added, and the
mixture was extracted with EtOAc. The combined extracts
were washed with water and with saturated solution of
NaCl, dried over MgSO4, filtered, and concentrated.
Chromatography (alumina, CH2Cl2) gave 42 (0.47 g,
1
0.49 mmol, 55%): H NMR (CDCl3, 400 MHz): d 1.32 (t,
3H, J ¼ 7:4 Hz), 2.86 (q, 2H, J ¼ 7:4 Hz), 7.06–7.09 (m,
2H), 7.35 (d, 1H, J ¼ 1:6 Hz), 7.37 (d, 1H, J ¼ 1:6 Hz),
7.48–7.52 (m, 2H); HRMS calculated for C12H11FS2 [M]þ
238.0286, found 238.0290; HPLC [column Zorbax SB-C-
18 (4.6 ꢁ 75 mm, 3.5 lm), T ¼ 22 °C, linear gradient: 10–
90%B (25 min), 90%B (5 min) (A ¼ 0.05% TFA in water,
B ¼ CH3CN), 1.5 mL/min] tR ¼ 23:5 min.
1
Using a similar procedure from 4 (50 mg, 0.22 mmol)
compound 18 was obtained as an oil (24 mg, 0.11 mmol,
50%): 1H NMR (CDCl3, 400 MHz): d 1.32 (t, 3H,
J ¼ 7:4 Hz), 2.88 (q, 2H, J ¼ 7:4 Hz), 7.32 (ddd, 1H,
J1 ¼ 0:8, J2 ¼ 5:2, J3 ¼ 8 Hz), 7.39 (d, 1H, J ¼ 1:6 Hz),
7.51 (d, 1H, J ¼ 1:6 Hz), 7.82 (ddd, 1H, J1 ¼ 1:6, J2 ¼ 2:4,
J3 ¼ 8 Hz), 8.53 (dd, 1H, J1 ¼ 1:6, J2 ¼ 5:2 Hz), 8.83 (dd,
1H, J1 ¼ 0.8, J2 ¼ 2:4 Hz); HRMS calculated for
C11H11NS2 [M]þ 221.0333, found 221.0332; HPLC [HPLC
conditions as for 6] tR ¼ 10:5 min.
1.35 mmol, 40%) as an oil: H NMR (CDCl3, 400 MHz):
d 0.49 (s, 9H), 7.06–7.11 (m, 3H), 7.56–7.59 (m, 2H). A
solution of KOH (50% in water, 3.35 mL) was added to a
solution of 42 (0.39 g, 1.23 mmol), benzyltriethylammo-
nium chloride (0.04 g, 0.17 mmol), and MeI (0.56 mL,
9.01 mmol) in CH2Cl2 (11 mL). The suspension was stirred
vigorously for 1 h. Water was added, and the organic layer
was separated, dried over MgSO4, filtered, and concen-
trated. Chromatography (alumina, hexane/EtOAc ¼ 90/
10) gave 4-(4-fluorophenyl)-1-methyl-2-trimethylstannyl-
1H-pyrrole-3-carbonitrile (0.22 g, 0.62 mmol, 52%) as an
Compounds 5 and 7–17 were prepared by reacting 4 with
appropriate arylboronic acids by Suzuki coupling as
similarly described for compound 6. Compounds 7–8
and 10–17 were synthesized in parallel using a QUEST
instrument and yields were not optimized.
1
oil: H NMR (CDCl3, 400 MHz): d 0.52 (s, 9H), 3.72 (s,
3H), 6.89 (s, 1H), 7.05–7.09 (m, 2H), 7.52–7.55 (m, 2H). A
solution of 4-(4-fluorophenyl)-1-methyl-2-trimethylstan-
nyl-1H-pyrrole-3-carbonitrile (0.22 g, 0.62 mmol) in THF
(4 mL) was cooled to )78 °C. NBS (0.12 g, 0.68 mmol) was
added in small portions and the reaction mixture was
stirred for 30 min at )78 °C. The mixture was allowed to
warm to 0 °C and after 20 h water was added and the
mixture was extracted with Et2O. The combined organic
layers were washed with saturated solution of NaCl, dried
over MgSO4, filtered, and concentrated. Chromatography
(alumina, hexane/EtOAc ¼ 85/15) gave 43 (0.11 g,
8. Ahluwalia, V. K.; Arora, K. K.; Kaur, G.; Mehta, B.
Synth. Commun. 1987, 17, 1441.
9. Synthesis of thiophene 23: NBS (0.19 g, 1.05 mmol) was
added in portions to a solution of 6 (0.10 g, 0.42 mmol) in
THF (5 mL) at )20 °C. The mixture was allowed to warm
to room temperature. After 24 h the reaction mixture was
concentrated, diluted with water and extracted with
EtOAc. The combined extracts were washed with satu-
rated solution of NaCl, dried over MgSO4, filtered, and
concentrated. The oil obtained was dissolved in AcOH–
THF–H2O (2.5:1:7) (0.85 mL), Zn dust (35 mg, 0.54 mmol)
was added and the reaction mixture was heated at reflux
for 8 h. The mixture was cooled to room temperature,
diluted with water, and extracted with EtOAc. The organic
phase was washed with saturated solution of NaCl, dried
over MgSO4, filtered, and concentrated. Chromatography
(silica, hexane) provided 22 (42 mg, 0.13 mmol, 31%) as an
oil. CuCN (17 mg, 0.19 mmol) was added to a solution of
22 (40 mg, 0.13 mmol) in NMP (1 mL). After 3 h of stirring
at reflux, CuCN (17 mg, 0.19 mmol) was added. The
reaction mixture was stirred at reflux for 5 h, allowed to
cool to room temperature. A solution of 28% NH3 in
1
0.38 mmol, 62%) as an oil: H NMR (CDCl3, 400 MHz):
d 3.69 (s, 3H), 6.86 (s, 1H), 7.06–7.11 (m, 2H), 7.51–7.54
(m, 2H). n-BuLi (2.5 M in hexane, 72 lL, 0.18 mmol) was
added dropwise to a stirred solution of 43 (48 mg,
0.17 mmol) in dry ether (1 mL) at )78 °C. After 0.5 h,
dimethyl disulfide (57 lL, 0.19 mmol) was added. The
reaction mixture was held at )70 °C for 0.5 h, allowed to
warm to room temperature in 4 h, and added to a mixture
of NH4Cl in ice. The organic phase was separated, the
aqueous phase was re-extracted with Et2O, and the
combined ether solutions were washed with saturated
NaCl solution, dried over MgSO4, filtered, and concen-
trated. Column chromatography (silica, hexane/
EtOAc ¼ 90/10) gave 44 as an oil (25 mg, 0.10 mmol,