4202
G. Qi et al. / Tetrahedron 66 (2010) 4195–4205
CDCl3)
d
: 2.73–2.82 (1H, m, 1ꢂH40), 2.92 (1H, d, J¼Hz, 1ꢂH40),
141.2, 157.9 (15ꢂaromatic C), 161.6 (NCON). Mass (ESI) calcd for
3.32–3.43 (2H, m, H30), 3.52 (1H, d, J¼14.4 Hz, NCHH), 3.91 (1H,
d, J¼14.1 Hz, NCHH), 5.60 (1H, s, H10), 6.61 (1H, d, J¼7.8 Hz, aro-
matic H), 6.72 (1H, d, J¼9.0 Hz, aromatic H), 6.91 (1H, t, J¼7.5 Hz,
aromatic H), 7.11 (1H, t, J¼7.4 Hz, aromatic H), 7.19 (1H, d, J¼6.9 Hz,
aromatic H), 7.56–7.69 (3H, m, 3ꢂaromatic H), 7.83–7.86 (2H, m,
2ꢂaromatic H), 7.97 (1H, dd, J¼9.0 Hz, 2.7 Hz, aromatic H), 8.16 (1H,
d, J¼8.4 Hz, aromatic H), 8.54 (1H, d, J¼5.7 Hz, aromatic H). 13C NMR
C
24H27N3O: 373.22, found 374.13 (Mþ1). HPLC (Chiralcel OD-H col-
umn): hexane/IPA¼95/5, 1.0 mL/min, 25 ꢀC, 254 nm, t1¼17.51 min
25
for (þ) and t2¼26.26 min for (ꢁ). [
a
]
þ298.7 (c 0.91, CH2Cl2).
D
4.7.2.3. Preparation of (þ)-N0-naphthyl-1,10-bisisoquinoline-20-
carboxamide (þ)-14. Compound (þ)-1 (65 mg, 0.25 mmol) was
reacted with 1-naphthyl isocyanate (36 ml, 0.25 mmol) in CH2Cl2
(75.6 MHz, CDCl3)
d
: 29.0 (C40), 48.9 (C30), 58.0 (NCH2Ph), 69.0 (C10),
(3 mL) to give a white solid that was purified by column chroma-
tography (EtOAc/hexane¼1/9) to give (þ)-N0-naphthyl-1,10-bisiso-
quinoline-20-carboxamide (þ)-14 as white powder (100.9 mg, 94%).
Mp 153–157 ꢀC. FTIR (KBr) nmax: 3276, 3053, 1619, 1525, 1502, 1389,
116.5, 121.5, 122.1, 125.1, 125.2, 125.3, 126.5, 126.9, 127.2, 127.3,
127.91, 127.94, 129.0, 130.4, 133.5, 136.1, 137.3, 140.0, 142.0, 160.2,
163.7 (21ꢂaromatic C). Mass (ESI) calcd for C25H21N3O3: 411.16,
found 412.07 (Mþ1). HPLC (Chiralcel OD-H column): hexane/
1248, 1224, 824, 790, 773, 745 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d:
IPA¼95/5, 1.0 mL/min, 25 ꢀC, 254 nm, t1¼26.17 min for (ꢁ) and
3.13 (1H, apparent d, J¼16.2 Hz, 1ꢂH40), 3.29 (1H, ddd, J¼16.5 Hz,
16.2 Hz, 5.4 Hz, 1ꢂH40), 3.67 (1H, td, J¼12.6 Hz, 3.3 Hz, 1ꢂH30), 4.62
(1H, apparent dd, J¼10.5 Hz, 3.0 Hz, 1ꢂH30), 6.98 (1H, d, J¼7.8 Hz,
aromatic H), 7.10 (1H, s, H10), 7.11 (1H, t, J¼7.2 Hz, aromatic H), 7.27
(1H, t, J¼7.5 Hz, aromatic H), 7.36 (1H, d, J¼7.8 Hz, aromatic H),
7.40–7.54 (4H, m, 4ꢂaromatic H), 7.61 (1H, d, J¼8.1 Hz, aromatic H),
7.65 (1H, t, J¼7.2 Hz, aromatic H), 7.71 (1H, d, J¼5.7 Hz, aromatic H),
7.81–7.89 (3H, m, 3ꢂaromatic H), 8.07(1H, d, J¼8.7 Hz, aromatic H),
8.12 (1H, d, J¼8.1 Hz, aromatic H), 8.55 (1H, d, J¼5.7 Hz, aromatic
25
t2¼29.72 min for (þ). [
a]
þ62.5 (c 0.77, CH2Cl2).
D
4.7.2. Urea derivatives (þ)-12–16. General procedure: Isocyanates
were added to a solution of (þ)-1 in dry CH2Cl2 under nitrogen
atmosphere and the mixture was stirred overnight. The reaction
mixture was washed with brine, the organic phase was separated,
dried over MgSO4, and filtered and the solvent was removed under
vacuum. The residue was subjected to column chromatography to
give the pure urea derivative.
H), 9.03 (1H, br s, CONH). 13C NMR (75.6 MHz, CDCl3) : 29.2 (C40),
d
38.8 (C30), 60.8 (C10), 119.9, 121.7, 121.8, 124.2, 125.6, 125.7, 125.9,
126.3, 126.62, 126.63, 127.2, 127.5, 127.56, 127.64, 127.7, 128.5, 129.5,
130.2, 134.3, 134.6, 134.8, 134.9, 137.9, 141.0, 156.4 (25ꢂaromatic C),
4.7.2.1. Preparation of (þ)-N0-(2-chlorophenyl)-1,10-bisisoquino-
line-20-carboxamide (þ)-12. Compound (þ)-1 (130 mg, 0.5 mmol)
was reacted with 2-chlorophenyl isocyanate (76.8 mg, 0.5 mmol) in
CH2Cl2 (4 mL) to give an off-white solid that was purified by column
chromatography (EtOAc/hexane¼1/9) to give (þ)-N0-(2-chlor-
ophenyl)-1,10-bisisoquinoline-2-carboxamide (þ)-12 as light gray
foam (205.0 mg, 99%). Mp 170–173 ꢀC. FTIR (KBr) nmax: 3231, 1656,
1591,1502,1438,1383,1288,1220, 821, 746 cmꢁ1. 1H NMR (300 MHz,
161.0 (NCON). Mass (ESI) calcd for C29H23N3O: 429.18, found 430.27
25
(Mþ1). [
a]
þ342.4 (c 1.04, CH2Cl2).
D
4.7.2.4. Preparation of (þ)-N0-(3,5-di-trifluoromethylphenyl)-1,10-
bisisoquinoline-20-carboxamide (þ)-15. Compound (þ)-1 (65 mg,
0.25 mmol) was reacted with 3,5-di-trifluoromethylphenyl iso-
CDCl3)
d
: 3.21–3.25 (2H, m, H40), 3.90–3.99 (1H, m,1ꢂH30), 4.15–4.22
cyanate (43.5 ml, 0.25 mmol) in CH2Cl2 (3 mL) to give a white solid
(1H, m, 1ꢂH30), 6.93 (1H, m, aromatic H), 7.02 (1H, d, J¼7.5 Hz, ar-
omatic H), 7.10 (1H, m, aromatic H), 7.18–7.33 (5H, m, H10 and
4ꢂaromatic H), 7.57 (1H, m, aromatic H), 7.60 (1H, d, J¼5.4 Hz, aro-
matic H), 7.67 (1H, m, aromatic H), 7.84 (1H, d, J¼8.1 Hz, aromatic H),
8.09 (1H, dd, J¼8.4 Hz,1.5 Hz, aromatic H), 8.15 (1H, br s, CONH), 8.43
(1H, d, J¼8.7 Hz, aromatic H), 8.47 (1H, d, J¼5.7 Hz, aromatic H). 13C
that was purified by column chromatography (EtOAc/hexane¼0.5/
9.5) to give (þ)-N0-(3,5-di-trifluoromethylphenyl)-1,10-bisisoqui-
noline-20-carboxamide (þ)-15 as white foam (115.5 mg, 90%). Mp
103–107 ꢀC. FTIR (KBr) nmax: 3328, 3058, 1654, 1560, 1474, 1444,
1376, 1278, 1179, 1131, 934, 883, 829, 747 cmꢁ1. 1H NMR (300 MHz,
CDCl3)
d
: 2.98–3.17 (2H, m, H40), 3.55 (1H, apparent t, J¼14.0 Hz,
NMR (75.6 MHz, CDCl3)
d
: 28.8 (C40), 39.9 (C30), 57.8 (C10), 121.0,
1ꢂH30), 4.51 (1H, apparent d, J¼12.3 Hz, 1ꢂH30), 6.90 (1H, d,
J¼7.8 Hz, aromatic H), 6.92 (1H, d, J¼4.5 Hz, aromatic H), 7.04 (1H, t,
J¼7.4 Hz, aromatic H), 7.18–7.27 (2H, m, 2ꢂaromatic H), 7.37 (1H, t,
J¼7.8 Hz, aromatic H), 7.45 (1H, s, H10), 7.57 (1H, t, J¼6.9 Hz, aro-
matic H), 7.63 (1H, d, J¼5.7 Hz, aromatic H), 7.78 (1H, d, J¼8.1 Hz,
aromatic H), 7.98 (3H, s, 3ꢂaromatic H), 8.49 (1H, d, J¼5.7 Hz, ar-
122.0, 123.0, 123.3, 125.8, 126.5, 126.7, 127.1, 127.46, 127.53, 127.6,
127.7, 128.9, 129.3, 130.1, 134.6, 135.3, 136.3, 137.3, 141.5, 154.8
(21ꢂaromatic C), 160.9 (NCON). Mass (ESI) calcd for C25H20ClN3O:
413.13, found 414.13 (Mþ1). HPLC (Chiralcel OD-H column): hexane/
IPA¼95/5, 1.0 mL/min, 25 ꢀC, 254 nm, t1¼14.16 min for (þ) and
25
t2¼15.64 min for (ꢁ). [
a
]
þ310.4 (c 0.91, CH2Cl2).
omatic H), 9.78 (1H, br s, CONH). 13C NMR (75.6 MHz, CDCl3)
d: 29.0
D
(C40), 38.6 (C30), 60.5 (C10), 115.6 (1ꢂCF3), 119.2 (1ꢂCF3), 121.6,122.1,
125.2,126.0,126.5,126.8,127.3,127.4,127.8,129.5,130.4,131.7,132.1,
134.16, 134.20, 137.9, 140.6, 141.6, 155.2 (21ꢂaromatic C), 160.5
(NCON). Mass (ESI) calcd for C27H19F6N3O: 515.14, found 516.07
(Mþ1). HPLC (Chiralcel OD-H column): hexane/IPA¼95/5, 1.0 mL/
4.7.2.2. Preparation of (þ)-N0-pentyl-1,10-bisisoquinoline-20-car-
boxamide (þ)-13. Compound (þ)-1 (65 mg, 0.25 mmol) was reacted
with pentyl isocyanate (32.5 ml, 0.25 mmol) in CH2Cl2 (3 mL) to give
an off-white solid that was purified by column chromatography
(EtOAc/hexane¼1/9) to give (þ)-N0-pentyl-1,10-bisisoquinoline-20-
carboxamide (þ)-13 as white foam (88.9 mg, 96%). Mp 139–142 ꢀC.
FTIR (KBr) nmax: 3282, 3057, 2953, 2926, 2859, 1610, 1543, 1250, 826,
min, 25 ꢀC, 254 nm, t1¼9.18 min for (ꢁ) and t2¼9.79 min for (þ).
25
[a
]
þ375.7 (c 1.05, CH2Cl2).
D
740 cmꢁ1. 1H NMR (300 MHz, CDCl3)
d
: 0.86 (3H, t, J¼6.9 Hz, H500),
4.7.2.5. Preparation of (þ)-N0-(2,4,6-trimethylphenyl)-1,10-bi-
1.16–1.35 (4H, m, H400 and H300), 1.45 (2H, p, J¼7.1 Hz, H200), 3.05–3.08
(2H, m, H40), 3.11–3.30 (2H, m, H100), 3.66–3.75 (1H, m, 1ꢂH30), 4.14
(1H, m, 1ꢂH30), 5.72 (1H, br s, CONH), 6.88 (1H, d, J¼7.8 Hz, aromatic
H), 6.99 (1H, s, H10), 7.04 (1H, t, J¼7.5 Hz, aromatic H), 7.17 (1H, t,
J¼7.4 Hz, aromatic H), 7.23 (1H, d, J¼7.5 Hz, aromatic H), 7.52 (1H,
apparent t, J¼7.2 Hz, aromatic H), 7.57 (1H, d, J¼5.4 Hz, aromatic H),
7.63 (1H, t, J¼7.5 Hz, aromatic H), 7.81 (1H, d, J¼8.1 Hz, aromatic H),
8.39 (1H, d, J¼7.5 Hz, aromatic H), 8.41 (1H, d, J¼5.4 Hz, aromatic H).
sisoquinoline-20-carboxamide (þ)-16. Compound (þ)-1 (65 mg,
0.25 mmol) was reacted with 2,4,6-trimethylphenyl isocyanate
(40.3 mg, 0.25 mmol) in CH2Cl2 (3 mL) to give a white solid that
was purified by column chromatography (EtOAc/hexane¼1/9) to
give (þ)-N0-(2,4,6-trimethylphenyl)-1,10-bisisoquinoline-20-carbox-
amide (þ)-16 as white powder (97.1 mg, 92%). Mp 223–227 ꢀC.
FTIR (KBr) nmax: 3260, 3024, 2942, 1625, 1509, 1396, 1292, 1238,
842, 831, 740 cmꢁ1. 1H NMR (300 MHz, CDCl3) : 2.01 (6H, s, 200-
d
13C NMR (75.6 MHz, CDCl3)
d
: 14.0 (C500), 22.4 (C400), 28.9 (C300), 29.1
CH3 and 600-CH3), 2.23 (3H, s, 400-CH3), 3.03 (1H, m, 1ꢂH40), 3.17
(1H, ddd, J¼16.2 Hz, 13.8 Hz, 5.1 Hz, 1ꢂH40), 3.66 (1H, m, 1ꢂH30),
4.36 (1H, dd, J¼13.2 Hz, 2.7 Hz, 1ꢂH30), 6.82 (2H, s, H300 and H500),
(C200), 29.8 (C40), 38.9 (C100), 41.0 (C30), 58.4 (C10), 120.9, 126.1, 126.3,
126.7, 126.8, 127.4, 127.50, 127.55, 129.1, 130.0, 134.8, 135.6, 137.2,