JOURNAL OF CHEMICAL RESEARCH 2008 439
MS (EI): m/z 315 (M+, 11), 313 (100). Anal. calcd for C21H14ClN: C,
79.87; H, 4.47; N, 4.44; found: C, 79.65; H, 4.46; N, 4.45%.
2-(4-Chlorophenyl)-4-methoxy-3-phenylquinoline (3c): Compound
2c (0.5 g, 1.42 mmol) and sodium methoxide (0.5M in MeOH, 2.14
mmol, 4.3 ml) in DMF (10 ml) was treated as described for 3a.
Workup and column chromatography (3:2 EtOAc–hexane, v/v)
afforded 3c as a solid (0.29 g, 60%) m.p. 133–136°C (EtOH). IR:
Ȟmax 1563, 1486, 1360, 1090, 986, 806, 758 cm-1. NMR (CDCl3ꢄꢋꢀįH
3.54, (3H, s), 7.16–7.34 (9H, m), 7.58 (1H, tt, J = 1.2 and 7.8 Hz),
7.74 (1H, tt, J = 1.5 and 7.8 Hz), 8.16 (1H, dd, J = 0.9 and 8.2 Hz),
8.18 (1H, J = ꢉꢅꢌꢀDQGꢀꢍꢅꢎꢀ+]ꢄꢃꢀįC 61.3, 122.3, 122.8, 125.3, 126.6,
127.4, 127.9, 128.3, 129.5, 130.1, 131.0, 131.2, 133.9, 135.1, 139.0,
148.7, 159.2, 161.5. MS (EI): m/z 346 (M+, 50), 345 (72), 344 (100);
HRMS (EI): calcd for C22H16NO35Cl, 345.9955; found: 346.0004.
Anal. calcd for C22H1635ClNO: C, 76.41; H, 4.66; N, 4.05; found: C,
76.32; H, 4.56; N, 4.01%.
ꢃꢀ&KORURꢀꢄꢀꢅꢃꢆꢀÀXRURSKHQ\OꢁꢀꢂꢀSKHQ\OTXLQROLQHꢇ (2b): Compound
1b (0.65 g, 1.69 mmol), phenylboronic acid (0.25 g, 2.03 mmol),
Pd(PPh3)4 (0.10 g, 0.08 mmol) and Na2CO3 (2M, 3.4 ml) in DMF
(10 ml) were treated as described above. Workup and column
chromatography (10:1 hexane–EtOAc, v/v) afforded 2b as a solid
(0.31 g, 55%) m.p. 120–122°&ꢀꢆ(W2+ꢄꢅꢀ,5ꢋꢀȞmax 1597, 1555, 1537,
1506, 1470, 1342, 1219, 1157, 1085, 983, 876, 826, 756, 727 cm-1.
NMR (DMSO-d6ꢄꢋꢀįH 6.90 (2H, d, J ꢀꢍꢅꢈꢀ+]ꢄꢁꢀꢈꢅꢇꢌꢀꢆꢐ+ꢁꢀPꢄꢁꢀꢈꢅꢐꢍ±
7.35 (5H, m), 7.68 (1H, dt, J ꢀꢇꢅꢐꢀDQGꢀꢈꢅꢍꢀ+]ꢄꢁꢀꢈꢅꢍꢉꢀꢆꢇ+ꢁꢀGWꢁ J = 1.2
and 7.8 Hz), 8.19 (1H, d, J = 8.4 Hz), 8.32 (1H, d, J = ꢈꢅꢍꢀ+]ꢄꢃꢀįC
2
114.8 (d, JCFꢀ ꢀꢐꢇꢅꢎꢀ+]ꢄꢁꢀꢇꢐꢎꢅꢈꢁꢀꢇꢐꢑꢅꢑꢁꢀꢇꢐꢈꢅꢈꢁꢀꢇꢐꢈꢅꢍꢁꢀꢇꢐꢍꢅꢐꢁꢀꢇꢐꢌꢅꢌꢁꢀ
3
130.4, 130.7, 131.7 (d, JCFꢀ ꢀꢍꢅꢊꢀ+]ꢄꢁꢀꢇꢊꢐꢅꢍꢁꢀꢇꢊꢏꢅꢊꢀꢆGꢁꢀ4JCFꢀ ꢀꢐꢅꢌꢀ
Hz), 136.9, 142.1, 147.6, 158.0, 162.5 (d, 1JCFꢀ ꢀꢐꢎꢏꢅꢍꢀ+]ꢄꢅꢀ06ꢀꢆ(,ꢄ
m/z 333 (M+, 2), 314 (100); HRMS (EI) calcd for C21H1335ClFN:
333.0721, found: 333.0694. Anal. calcd for C21H13ClFN: C, 75.57;
H, 3.92; N, 4.00; found: C, 75.55; H, 3.77; N, 3.95%.
4-Methoxy-2-(4'-methoxyphenyl)-3-phenylquinoline
(3d):
Compound 2d (0.45 g, 1.30 mmol) and sodium methoxide (0.5M in
MeOH, 1.95 mmol, 3.9 ml) in DMF (10 ml) was treated as described
for 3a. Workup and column chromatography (3:2 EtOAc–hexane,
v/v) afforded 3d as a solid (0.29 g, 65%) m.p. 135–137°C (EtOH).
,5ꢋꢀȞmax 1607, 1580, 1515, 1485, 1360, 1244, 1108, 1069, 1032, 986,
833, 758 cm-1. NMR (CDCl3ꢄꢋꢀįH 3.52 (3H, s), 3.77 (3H, s), 6.73 (2H,
d, J = 9.0 Hz), 7.21–7.33 (7H, m), 7.54 (1H, dt, J = 1.5 and 7.8 Hz),
7.72 (1H, dt, J = ꢇꢅꢑꢀDQGꢀꢈꢅꢍꢀ+]ꢄꢁꢀꢍꢅꢇꢊꢂꢍꢅꢇꢏꢀꢆꢐ+ꢁꢀPꢄꢃꢀįC 55.2, 61.2,
113.1, 122.3, 122.6, 125.5, 126.1, 127.1, 128.1, 129.5, 129.8, 131.0,
131.3, 133.1, 135.7, 148.9, 159.3, 160.1, 161.3. MS (EI): m/z 341
(M+, 86), 340 (100), 325 (28), 69 (42), 28 (52). HRMS (EI): calcd for
C23H19NO2 340.1338, found 340.1341. Anal. calcd for C23H19NO2:
C, 80.92; H, 5.61; N, 4.10; found: C, 81.01; H, 5.80; N, 3.97%.
4-Chloro-2-(4'-chlorophenyl)-3-phenylquinoline (2c): Compound
1c (0.65 g, 1.63 mmol), phenylboronic acid (0.24 g, 1.96 mmol),
Pd(PPh3)4 (0.10 g, 0.08 mmol) and Na2CO3 (2M, 3.4 ml) in DMF
(10 ml) were treated as described for 2a. Workup and column
chromatography (10:1 hexane–EtOAc, v/v) afforded 2c as solid
(0.28 g, 50%) m.p. 145–148°&ꢀꢆ(W2+ꢄꢅꢀ,5ꢀꢆQHDWꢄꢋꢀȞmax/cm-1 1550,
1476, 1398, 1339, 1086, 1013, 826, 754, 700 cm-1. NMR (CDCl3ꢄꢋꢀįH
7.16–7.21 (4H, m), 7.26–7.29 (2H, m), 7.31–7.37 (3H, m), 7.68 (1H,
dt, J = 1.2 and 7.8 Hz), 7.80 (1H, dt, J = 1.5 and 7.8 Hz), 8.19 (1H,
dd, J = 0.9 and 8.7 Hz), 8.32 (1H, dd, J = ꢇꢅꢐꢀDQGꢀꢍꢅꢎꢀ+]ꢄꢃꢀįC 124.7,
125.5, 127.9, 128.0, 128.0, 128.3, 129.9, 130.5, 130.7, 131.1, 132.8,
134.2, 136.8, 138.7, 142.2, 147.6, 157.8. MS (EI) m/z 353 (7), 351
(39), 349 (M+, 75), 348 (100); HRMS (EI) calcd for C21H1335Cl2N:
349.0425, found: 349.0426. Anal. calcd for C21H13Cl2N: C, 72.02; H,
3.74; N, 4.00; found: C, 72.08; H, 3.85; N, 3.98%.
Synthesis of 2-aryl-3-iodo-4-methoxyquinolines 4a–d from 1: typical
procedure
3-Iodo-4-methoxy-2-phenylquinoline (4a):
A stirred mixture of
1a (0.50 g, 1.37 mmol) and sodium methoxide (0.5M in MeOH,
ꢊꢅꢉꢇꢀPPROꢁꢀꢏꢅꢉꢀPOꢄꢀLQꢀ7+)ꢀꢆꢇꢉꢀPOꢄꢀZDVꢀUHÀX[HGꢀIRUꢀꢇꢍꢀKRXUVꢅꢀ7KHꢀ
mixture was allowed to cool to room temperature and then poured
into ice-cold water. The product was extracted into chloroform and
the combined chloroform extracts were dried (MgSO4ꢄꢁꢀ¿OWHUHGꢀDQGꢀ
HYDSRUDWHGꢀ XQGHUꢀ UHGXFHGꢀ SUHVVXUHꢅꢀ 7KHꢀ UHVLGXHꢀ ZDVꢀ SXUL¿HGꢀ E\ꢀ
column chromatography (1:4 EtOAc–hexane, v/v) to afford 4a as a
white solid (0.30 g, 60%), m.p. 153–155°&ꢀꢆ(W2+ꢄꢅꢀ,5ꢋꢀȞmax 1566,
1485, 1361, 1072, 980, 894, 763 cm-1. NMR (CDCl3ꢄꢋꢀįH 4.10 (3H,
s), 7.44–7.52 (3H, m), 7.56–7.63 (3H, m), 7.75 (1H, tt, J = 1.5 and
7.7 Hz), 8.10 (1H, t, J = ꢌꢅꢉꢀ+]ꢄꢃꢀįC 62.0, 88.0, 121.9, 127.1, 127.9,
128.7, 129.2, 129.6, 130.6, 142.7, 149.0, 163.1, 164.8. MS (EI) m/z
361 (M+, 100), 331 (30), 204 (35); HRMS (EI) calcd for C16H12INO:
360.9964, found: 360.9964. Anal. calcd for C16H12INO: C, 53.23; H,
3.35; N, 3.88; found: C, 53.07; H, 3.29; N, 3.68%.
4-Chloro-2-(4'-methoxyphenyl)-3-phenylquinoline (2d): 1d (0.65 g,
1.65 mmol), phenylboronic acid (0.24 g, 1.98 mmol), Pd(PPh3)4
(0.10 g, 0.08 mmol) and Na2CO3 (2M, 3.3 ml) in DMF (10 ml) was
treated as described above. Workup and column chromatography
(10:1 hexane–EtOAc, v/v) afforded 2d as a solid (0.30 g, 53%)
m.p. 110–112°&ꢀ ꢆ(W2+ꢄꢅꢀ ,5ꢋꢀ Ȟmax 1605, 1567, 1513, 1470, 1338,
1242, 1179, 1027, 833, 770, 746 cm-1. NMR (CDCl3ꢄꢋꢀįH 3.76 (3H,
s), 6.73 (2H, d, J = 9.0 Hz), 7.19–7.23 (2H, m), 7.26–7.34 (5H, m),
7.64 (1H, dt, J = 1.2 and 7.8 Hz), 7.78 (1H, dt, J = 1.2 and 7.8 Hz),
8.19 (1H, dd, J = 0.6 and 8.7 Hz), 8.30 (1H, dd, J = 0.6 and 8.4 Hz);
įC 55.2, 113.2, 124.6, 125.3, 127.4, 127.6, 128.1, 129.7, 130.2,
130.7, 131.2, 132.7, 132.8, 137.6, 141.8, 147.7, 158.7, 159.4. MS
(EI): m/z 347 (25), 346 (48), 345 (M+, 72), 344 (100). Anal. calcd for
C22H16ClNO: C, 76.41; H, 4.66; N, 4.05; found: C, 76.42; H, 4.70;
N, 3.89%.
2-(4'-Fluorophenyl)-3-iodo-4-methoxyquinoline (4b): A mixture
of 1b (0.50 g, 1.30 mmol) and sodium methoxide (0.5M in MeOH,
2.87 mmol, 5.7 ml) in THF (10 ml) was treated as described in
the preparation of 4a. Workup and column chromatography (1:4
EtOAc–hexane, v/v) afforded 4b as a white solid (0.34 g, 70%) m.p.
140–142°&ꢀꢆ(W2+ꢄꢅꢀ,5ꢋꢀȞmax 1590, 1570, 1509, 1487, 1364, 1218,
1075, 982, 831, 768 cm-1. NMR (CDCl3ꢄꢋꢀįH 4.10 (3H, s), 7.17 (2H,
t, J = 8.9 Hz), 7.55–7.65 (3H, m), 7.76 (1H, dt, J = 1.2, and 7.8 Hz),
8.10 (1H, td, J = 0.9 and 5.6 Hz), 8.13 (1H, td, J = 0.9 and 5.6 Hz);
Methoxydechlorination of the 4-chloroquinolines 2 with sodium
methoxide in DMF: typical procedure
4-Methoxy-2,3-diphenylquinoline (3a): A stirred mixture of 2a (0.50 g,
1.58 mmol) and sodium methoxide (0.5M in MeOH, 2.38 mmol,
ꢎꢅꢍꢀPOꢄꢀLQꢀ'0)ꢀꢆꢇꢉꢀPOꢄꢀZDVꢀKHDWHGꢀXQGHUꢀUHÀX[ꢀIRUꢀꢇꢍꢀKRXUVꢅꢀ7KHꢀ
mixture was allowed to cool and quenched with ice-cold water.
The product was extracted into chloroform and the combined organic
phases were dried ( Mg2SO4ꢄꢁꢀ¿OWHUHGꢀDQGꢀHYDSRUDWHGꢅꢀ7KHꢀUHVLGXHꢀZDVꢀ
SXUL¿HGꢀE\ꢀFROXPQꢀFKURPDWRJUDSK\ꢀꢆꢊꢀꢋꢀꢐꢀ(W2$F±KH[DQHꢁꢀYꢒYꢄꢀWRꢀDIIRUGꢀ
3a as a solid (0.27 g, 55%) m.p. 132–134°&ꢀꢆ(W2+ꢄꢅꢀ,5ꢋꢀȞmax 1615,
1555, 1483, 1360, 1136, 1105, 1065, 984, 760 cm-1. NMR (CDCl3):
įH 3.54 (3H, s), 7.20–7.35 (10H, m), 7.57 (1H, tt, J = 1.5 and 7.5 Hz),
7.74 (1H, tt, J = ꢇꢅꢑꢀDQGꢀꢈꢅꢍꢀ+]ꢄꢁꢀꢍꢅꢇꢈ±ꢍꢅꢐꢐꢀꢆꢐ+ꢁꢀPꢄꢃꢀįC 61.3, 122.3,
122.8, 125.3, 126.6, 126.4, 127.9. 128.2, 129.6, 130.1, 131.0, 131.2,
133.9, 135.1, 139.1, 148.8, 159.2, 161.5. Anal. calcd for C22H17NO: C,
84.86; H, 5.50; N, 4.50; found: C, 84.70; H, 5.65; N, 4.23%.
į
C 62.0, 87.9, 122.3, (d, 2JCFꢀ ꢀꢐꢇꢅꢏꢀ+]ꢄꢁꢀꢇꢐꢇꢅꢌꢁꢀꢇꢐꢐꢅꢈꢁꢀꢇꢐꢈꢅꢐꢁꢀꢇꢐꢌꢅꢑꢁꢀ
130.7, 131.3 (d, 3JCFꢀ ꢀꢍꢅꢏꢀ+]ꢄꢁꢀꢇꢊꢍꢅꢈꢀꢆGꢁꢀ4JCFꢀ ꢀꢊꢅꢑꢀ+]ꢄꢁꢀꢇꢎꢌꢅꢉꢁꢀꢇꢏꢐꢅꢉꢁꢀ
163.0 (d, JCFꢀ ꢀꢐꢎꢏꢅꢍꢀ+]ꢄꢁꢀꢇꢏꢎꢅꢌꢃꢀ06ꢀꢆ(,ꢄꢋꢀm/z 379 (M+, 100), 349
1
(26), 222 (31); HRMS (EI): calcd for C16H11FINO: 378.9866, found
378.9869. Anal. calcd for C16H11FINO: C, 50.71; H, 2.92; N, 3.69;
found: C, 50.53; H, 2.79; N, 3.57%.
2-(4'-Chlorophenyl)-3-iodo-4-methoxyquinoline (4c): Compound
1c (0.50 g, 1.25 mmol) and sodium methoxide (0.5M in MeOH,
2.75 mmol, 5.5 ml) in THF (10 ml) were treated as described for
4a. Workup and column chromatography (1:4 EtOAc–hexane, v/v)
afforded 4c as a white solid (0.38 g, 77%) m.p. 178–180°C (EtOH).
,5ꢋꢀȞmax 1557, 1534, 1341, 1090, 824, 757 cm-1. NMR (CDCl3ꢄꢋꢀįH
4.10 (3H, s), 7.46 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7.8 Hz),
7.60–7.65 (1H, m), 7.76 (1H, dt, J = 1.2 and 7.8 Hz), 8.09–8.10
ꢆꢇ+ꢁꢀ Pꢄꢁꢀ ꢍꢅꢇꢇ±ꢍꢅꢇꢊꢀ ꢆꢇ+ꢁꢀ Pꢄꢃꢀ įC 62.0, 87.5, 122.0, 122.8, 127.3,
128.2, 129.6, 130.7, 130.8, 134.8, 141.0, 149.1, 161.8, 165.0. MS
(EI) m/z 395 (M+, 45), 379 (100), 349 (29), 222 (37). HRMS (EI):
calcd for C16H1135ClINO 394.9596, found 394.9574. Anal. calcd for
C16H11ClINO: C, 48.66; H, 2.81; N, 3.55; found: C, 48.70; H, 2.79;
N, 3.61%.
2-(4'-Fluorophenyl)-4-methoxy-3-phenylquinoline (3b): A mixture
of 2b (0.45 g, 1.36 mmol) and sodium methoxide (0.5M in MeOH,
2.04 mmol, 4.1 ml) in DMF (10 ml) was treated as described above.
Workup and column chromatography (3:2 EtOAc–hexane, v/v)
afforded 3b as a solid (0.26 g, 58%) m.p. 123–125°C (EtOH). IR:
Ȟmax 1594. 1503, 1474, 1333, 1223, 1157, 835, 765 cm-1. NMR
(CDCl3ꢄꢋꢀįH 3.54 (3H, s), 6.90 (2H, t, J = 8.7 Hz), 7.19–7.23 (2H,
m), 7.27–7.36 (5H, m), 7.58 (1H, tt, J = 1.2 and 7.7 Hz), 7.75 (1H, tt,
J = 1.2 and 7.8 Hz), 8.17 (1H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 1.2
DQGꢀꢍꢅꢊꢀ+]ꢄꢃꢀįC 61.4, 114.7 (d, 2JCFꢀ ꢀꢐꢇꢅꢊꢀ+]ꢄꢁꢀꢇꢐꢐꢅꢎꢁꢀꢇꢐꢐꢅꢍꢁꢀꢇꢐꢑꢅꢐꢁꢀ
3
126.6, 127.4, 128.2, 129.2, 130.2, 131.0, 131.0, 131.7 (d, JCFꢀ ꢀꢍꢅꢇꢀ
4
Hz), 135.1 (d, JCFꢀ ꢀꢐꢅꢌꢀ+]ꢄꢁꢀꢇꢎꢍꢅꢐꢁꢀꢇꢑꢌꢅꢊꢁꢀꢇꢏꢇꢅꢈꢁꢀꢇꢏꢐꢅꢑꢀꢆGꢁꢀ1JCFꢀ ꢀ
3-Iodo-4-methoxy-2-(4'-methoxyphenyl)quinoline (4d): A mixture
of 1d (0.50 g, 1.26 mmol) and sodium methoxide (0.5M in MeOH,
2.78 mmol, 5.6 ml) in THF (10 ml) was treated as described for 4a.
246.7 Hz). Anal. calcd for C22H16FNO: C, 80.23; H, 4.90; N, 4.25;
found: C, 80.37; H, 4.77; N, 4.34%.