Peruncheralathan et al.
1, 100). Anal. Calcd for C16H14N2S (266.37): C, 72.15; H, 5.30;
N, 10.52. Found: C, 72.05; H, 5.18; N, 10.45.
a stirring suspension of (Ph3P)2NiCl2 (0.2 g, 30 mol %) in 25
mL of dry benzene under a nitrogen atmosphere, and the
mixture was refluxed for 15 min. After the catalyst reduction,
1.90 mmol of the required Grignard reagent (4-MeOC6H4MgBr/
MeMgI) and a solution of pyrazoles 2a or 3a (1.0 mmol) in
dry benzene (20 mL) were added to the reaction mixture and
refluxed for 12 h. It was then cooled, poured into 50 mL of
saturated NH4Cl solution, and extracted with CH2Cl2 (3 × 50
mL). The organic layer was dried (anhydrous Na2SO4) and
evaporated to give crude products 12a and 13a or 14a and
15a, which were purified by column chromatography using
hexane-EtOAc as eluent.
1,3-Diphenyl-5-(4′-methoxyphenyl)-1H-pyrazole (12a).
Yield 68% (0.22 g); yellow viscous liquid (lit. 77-78 °C);27 Rf
0.41 (9.2:0.8 hexanes-EtOAc). IR (CH2Cl2): 3052, 2929, 1612,
1519, 1495, 1458, 1361, 1293, 1250 cm-1. 1H NMR (400 MHz,
CDCl3): δ 7.83 (dd J ) 6.7, 2.0 Hz, 2H), 7.29-7.35 (m, 4H),
7.19-7.24 (m, 4H), 7.09 (dd, J ) 6.8, 2.0 Hz, 2H), 6.74 (dd, J
) 6.8, 2.0 Hz, 2H), 6.67 (s, 1H), 3.69 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 159.5, 151.8, 144.2, 140.2, 133.1, 129.9, 128.9,
128.6, 127.9, 127.3, 125.8, 125.3, 122.9, 113.9, 104.7, 55.2. MS
(m/z, %): 327 (M + 1, 100), 326 (M+, 60). Anal. Calcd for
C22H18N2O (326.39): C, 80.96; H, 5.56; N, 8.58. Found: C,
81.07; H, 5.63; N, 8.46.
1,5-Diphenyl-3-(4′-methoxyphenyl)-1H-pyrazole (14a).
Yield 71% (0.23 g); colorless solid; mp 132-133 °C (lit. 138
°C);5,28 Rf 0.38 (9.2:0.8 hexanes-EtOAc). IR (KBr): 3055, 2839,
1603, 1494, 1445, 1352, 1292, 1248 cm-1. 1H NMR (400 MHz,
CDCl3): δ 7.85 (d, J ) 8.6 Hz, 2H), 7.25-7.35 (m, 10H), 6.96
(d, J ) 8.6 Hz, 2H), 6.75 (s, 1H), 3.84 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 159.5, 151.8, 144.3, 140.1, 130.6, 128.9, 128.7,
128.4, 128.2, 127.3, 127.0, 125.8, 125.2, 113.9, 104.8, 55.3. MS
(m/z, %): 327 (M + 1, 100), 326 (M+, 90). Anal. Calcd for
C22H18N2O (326.39): C, 80.96; H, 5.56; N, 8.58. Found: C,
80.85; H, 5.65; N, 8.67.
1-(4′-Fluorophenyl)-3,4-diphenyl-5-(methylthio)-1H-
pyrazole (7d). Yield 80% (1.44 g); colorless solid; mp 91-92
°C; Rf 0.43 (9.2:0.8 hexanes-EtOAc). IR (KBr): 3060, 2926,
1602, 1506, 1433, 1376, 1347 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.70 (ddd, J ) 6.8, 4.6, 2.2 Hz, 2H), 7.46-7.48 (m,
2H), 7.33-7.38 (m, 5H), 7.23-7.26 (m, 3H), 7.19 (t, J ) 8.5
Hz, 2H), 1.92 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 162.1 (d,
J ) 246.8), 150.1, 135.8, 134.5, 132.7, 132.6, 130.4, 128.3,
128.2, 128.0, 127.8, 127.5 (d, J ) 8.2 Hz), 127.3, 125.8, 115.7
(d, J ) 23.0 Hz), 18.7. MS (m/z, %): 361 (M + 1, 100), 360
(M+, 70). Anal. Calcd for C22H17FN2S (360.45): C, 73.31; H,
4.75; N, 7.77. Found: C, 73.42; H, 4.89; N, 7.95.
3-Isopropyl-5-(methylthio)-1-phenyl-1H-pyrazole (2g).
Yield 71% (0.82 g); yellow liquid; Rf 0.65 (9.2:0.8 hexanes-
EtOAc). IR (CH2Cl2): 2962, 2925, 1596, 1507, 1458, 1424, 1371
cm-1. 1H NMR (400 MHz, CDCl3): δ 7.56 (dt, J ) 7.2, 1.2 Hz,
2H), 7.42 (dt, J ) 7.2, 2.0 Hz, 2H), 7.29-7.34 (m, 1H), 6.17 (s,
1H), 3.02 (sept, J ) 7.2 Hz, 1H), 2.34 (s, 3H), 1.29 (d, J ) 7.2
Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 159.9, 139.6, 137.5,
128.8, 127.4, 124.6, 104.9, 27.9, 22.7, 17.9. MS (m/z, %): 233
(M + 1, 100), 232 (M+, 50). Anal. Calcd for C13H16N2S
(232.34): C, 67.20; H, 6.94; N, 12.06. Found: C, 67.11; H, 7.01;
N, 12.17.
General Procedure for Preparation of 1-Aryl-3-(me-
thylthio)-4,5-substituted/annulated Pyrazoles 3, 11. A
solution of respective â-oxodithioesters 9 (5 mmol) and aryl-
hydrazine (6 mmol) in 50 mL of EtOH was heated at refluxed
for 5-6 h with constant stirring, the reaction being monitored
by TLC. The solvent was removed under reduced pressure and
poured into ice-cold water, extracted with DCM (3 × 50 mL),
washed with H2O (2 × 50 mL) and brine (1 × 50 mL), and
dried over anhydrous Na2SO4. The solvent was evaporated
under vacuum to give pyrazoles 3 and 11, which were purified
by column chromatography over silica gel using hexane-
EtOAc (10:1) as eluent.
1,5-Diphenyl-3-(methylthio)-1H-pyrazole (3a). Yield 81%
(1.08 g); colorless solid; mp 59-60 °C; Rf 0.57 (9.2:0.8 hexanes-
EtOAc). IR (KBr): 3063, 2927, 1597, 1539, 1499, 1451, 1419,
1364, 1317 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.20-7.26 (m,
8H), 7.15-7.18 (m, 2H), 6.39 (s, 1H), 2.55 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 148.2, 144.3, 139.7, 130.0, 128.8, 128.6,
128.4, 128.3, 127.2, 124.9, 107.5, 15.7. MS (m/z, %): 267 (M +
1, 100), 266 (M+, 40). Anal. Calcd for C16H14N2S (266.37): C,
72.15; H, 5.30; N, 10.52. Found: C, 72.24; H, 5.22; N, 10.43.
1-(4′-Fluorophenyl)-4,5-diphenyl-3-(methylthio)-1H-
pyrazole (11d). Yield 88% (1.58 g); white solid; mp 145-147
°C; Rf 0.64 (9.2:0.8 hexanes-EtOAc). IR (KBr): 3259, 3059,
2924, 1604, 1509, 1444, 1385, 1267, 1227 cm-1. 1H NMR (400
MHz, CDCl3): δ 7.22-7.31 (m, 10H), 7.06 (d, J ) 7.7 Hz, 2H),
6.99 (dt, J ) 7.7, 2.2 Hz, 2H), 2.59 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 161.3 (d, J ) 246 Hz), 146.9, 141.1, 135.9, 131.8,
130.2, 129.6, 129.5, 128.5 (× 2C), 128.2, 126.7 (d, J ) 6.6 Hz),
126.6, 121.3, 115.6 (d, J ) 23.0 Hz), 15.0. MS (m/z, %): 361
(M + 1, 100), 360 (M+, 60). Anal. Calcd for C22H17FN2S
(360.45): C, 73.31; H, 4.75; N, 7.77. Found: C, 73.22; H, 4.64;
N, 7.89.
Procedure for Preparation of 1,5-Diphenyl-4-ethyl-3-
(methylthio)-1H-pyrazole (20l) and 4-Ethyl-5-(4-meth-
oxyphenyl)-3-(methylthio)-1-phenyl-1H-pyrazole (20m).
A solution of â-oxodithioesters 9l or 9m (5 mmol) and phenyl-
hydrazine (0.65 g, 6 mmol) in 50 mL of EtOH was refluxed for
5 h with constant stirring (monitored by TLC). The solvent
was removed under reduced pressure and poured into ice-cold
water, extracted with CH2Cl2 (3 × 50 mL), washed with H2O
(2 × 50 mL) and brine (1 × 50 mL), and dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum to give
pyrazoles 20l,m, which were purified by column chromatog-
raphy over silica gel using hexane-EtOAc (10:1) as eluent.
1,5-Diphenyl-4-ethyl-3-(methylthio)-1H-pyrazole (20l).
Yield 75% (1.10 g); colorless solid; mp 66-67 °C; Rf 0.45 (9.2:
0.8 hexanes-EtOAc). IR (KBr): 3065, 2958, 2921, 1593, 1498,
1
1435, 1393, 1354 cm-1. H NMR (400 MHz, CDCl3): δ 7.34-
7.37 (m, 3H), 7.23-7.28 (m, 3H), 7.18-7.23 (m, 4H), 2.65 (s,
3H), 2.49 (q, J ) 7.6 Hz, 2H), 1.15 (t, J ) 7.6 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 146.8, 140.8, 139.9, 130.6, 129.8,
128.6, 128.5, 128.3, 126.5, 124.4, 122.5, 16.9, 15.6, 15.2. MS
(m/z, %): 295 (M + 1, 100), 294 (M+, 90). Anal. Calcd for
C18H18N2S (294.41): C, 73.43; H, 6.16; N, 9.51. Found: C,
73.52; H, 6.26; N, 9.43.
4-Ethyl-5-(4′-methoxyphenyl)-3-(methylthio)-1-phenyl-
1H-pyrazole (20m). Yield 72% (1.17 g); red viscous liquid; Rf
0.47 (9.2:0.8 hexanes-EtOAc). IR (CH2Cl2): 2963, 2927, 1612,
5-Isopropyl-3-(methylthio)-1-phenyl-1H-pyrazole (3g).
Yield 45% (0.52 g); orange liquid; Rf 0.58 (9.2:0.8 hexanes-
EtOAc). IR (CH2Cl2): 2966, 2927, 1595, 1527, 1500, 1453, 1358
1597, 1575, 1505, 1459, 1433, 1391, 1353, 1289, 1176 cm-1
.
1
cm-1. H NMR (400 MHz, CDCl3): δ 7.34-7.45 (m, 5H), 6.13
1H NMR (400 MHz, CDCl3): δ 7.18-7.29 (m, 5H), 7.09 (d, J
) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 3.82 (s, 3H), 2.66 (s,
3H), 2.46 (q, J ) 7.6 Hz, 2H), 1.13 (t, J ) 7.6 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 159.6, 146.6, 140.9, 139.5, 131.0,
129.7, 126.7, 124.6, 122.4, 122.3, 114.0, 55.2, 16.9, 15.8, 15.1.
MS (m/z, %): 325 (M + 1, 100), 324 (M+, 40). Anal. Calcd for
(s, 1H), 2.97 (sept, J ) 6.8 Hz, 1H), 2.51 (s, 3H), 1.14 (d, J )
6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 152.0, 147.4, 139.5,
129.1, 128.1, 125.8, 102.9, 25.5, 22.8, 15.6. MS (m/z, %): 233
(M + 1, 100), 232 (M+, 90). Anal. Calcd for C13H16N2S
(232.34): C, 67.20; H, 6.94; N, 12.06. Found: C, 67.31; H, 6.81;
N, 12.15.
General Procedure for Nickel-Catalyzed Cross-Coup-
ling Reactions of 2a and 3a with Grignard Reagents.
Synthesis of 12a, 13a, 14a, and 15a. A solution of respective
Grignard reagent (0.10 mmol) in Et2O was added dropwise to
(27) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4,
3995.
(28) Sedqui, A.; Lakhlifi, T.; Vebrel, J.; Laude, B. C. R. Acad. Sci.
Paris Ser. II 1990, 310, 505.
10034 J. Org. Chem., Vol. 70, No. 24, 2005