Deconvolution of Pyridinopolyamine Libraries
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 713
removed under vacuum. The residue was dissolved in H2O
and CH2Cl2. The separated organic phase was washed with
brine, dried (Na2SO4), and concentrated. The crude oil was
purified by flash chromatography using 8:2 to 10:0 EtOAc-
hexanes and then 9:1 to 8:2 EtOAc-MeOH as eluents to give
6.37 g (78%) of product 60 as a pale-yellow oil: silica gel TLC
Rf 0.38 (9:1 EtOAc-MeOH); 1H NMR (CDCl3) δ 0.87-0.94 (m,
2H), 1.26-1.39 (m, 2H), 1.43 (s, 9H), 2.04 (br, 1H, NH), 2.73-
2.76 (m, 2H), 3.22-3.38 (m, 4H), 3.54 (br, 1H, OH), 3.84 (s,
2H), 5.00 (s, 2H), 7.10-7.16 (m, 2H), 7.59-7.61 (m, 1H), 7.88-
7.89 (m, 2H), 7.90-7.91 (m, 2H); 13C NMR (CDCl3) δ 10.9, 14.0,
23.0, 23.8, 28.4, 30.4, 38.8, 43.0, 47.9, 54.5, 58.5, 68.2, 80.1,
119.5, 120.9, 123.5, 128.8, 130.9, 132.2, 134.1, 137.2, 155.0,
159.2, 168.13; HRMS (FAB) m/z 601.143 (M + Cs)+ (C25H32N4O5-
Cs requires 601.142).
127.8, 128.2, 128.8, 129.4, 130.9, 132.0, 137.1, 138.9, 140.0,
156.9, 158.3, 159.3; HRMS (FAB) m/z 891.269 (M + Cs)+
(C41H48N4O3F6Cs requires 891.268).
P r ep a r a tion of Com p ou n d 64. A solution of 2-nitroben-
zenesulfonyl chloride (2.33 g, 10.5 mmol, 1.16 equiv) in 30 mL
of CH2Cl2 was added dropwise to a stirred solution of 62 (4.0
g, 9.0 mmol) and Et3N (3.2 g, 3.2 mmol) in 60 mL of CH2Cl2 at
0 °C. The resulting reaction mixture was stirred at room
temperature for 2 h, diluted with 200 mL of CHCl3, and
washed with water and brine. The organic phase was dried
(Na2SO4) and concentrated. The residue was purified by flash
chromatography on a silica gel column. Elution with 2:1, 1:1,
and then 0:1 hexanes-EtOAc afforded 3.60 g (63%) of product
64 as a pale-yellow oil: silica gel TLC Rf 0.41 (1:4 hexanes-
1
EtOAc); H NMR (CDCl3) δ 1.28 (s, 9H), 1.40-1.65 (m, 2H),
2.32 (s, 3H), 2.56 (t, 2H, J ) 7.0 Hz), 3.10-3.35 (m, 4H), 3.40-
3.72 (m, 6H), 4.37 (s, 2H), 6.80-8.05 (m, 11H); 13C NMR
(CDCl3) δ 21.4, 28.3, 30.5, 43.1, 44.9, 48.0, 52.3, 58.3, 59.0,
60.1, 80.0, 119.9, 121.5, 125.2, 125.7, 127.9, 128.3, 129.4, 130.8,
132.6, 133.4, 137.2, 137.9, 138.9, 147.8, 153.5, 156.8, 159.7;
MS (FAB) m/z 760 (M + Cs)+; HRMS (FAB) m/z 628.281 (M +
H)+ (C31H42N5O7S requires 628.280).
P r ep a r a tion of Com p ou n d 61. A mixture of compound
60 (7.29 g, 15.5 mmol), anhydrous K2CO3 (25.8 g, 186.7 mmol,
1.2 equiv), and R-bromo-m-xylene (2.52 mL, 18.6 mmol, 1.2
equiv) in 300 mL of anhydrous CH3CN was stirred at room
temperature overnight. The solvent was evaporated, and the
residue was dissolved in a mixture of H2O and CH2Cl2. The
organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography using 2:8 to 6:4
EtOAc-hexanes as eluents to afford 8.11 g (91%) of product
61 as a colorless oil: silica gel TLC Rf 0.54 (100% EtOAc); 1H
NMR (CDCl3) δ 1.30 (s, 9H), 1.37-1.53 (m, 4H), 2.32 (s, 3H),
2.54-2.61 (m, 2H), 3.12-3.27 (m, 4H), 3.40-3.46 (m, 2H), 3.58
(s, 2H), 3.71 (s, 2H), 4.99 (s, 2H), 7.04-7.26 (m, 5H), 7.33-
7.36 (m, 1H), 7.57-7.60 (m, 1H), 7.71-7.76 (m, 2H), 7.86-
7.90 (m, 2H); 13C NMR (CDCl3) δ 21.4, 28.3, 30.5, 42.7, 44.9,
52.0, 58.3, 59.1, 60.0, 80.0, 119.3, 120.4, 123.5, 127.8, 128.2,
129.4, 132.3, 134.1, 137.1, 137.8, 139.1, 154.5, 156.9, 159.8;
HRMS (FAB) m/z 705.206 (M + Cs)+ (C33H40N4O5Cs requires
705.205).
P r ep a r a tion of Com p ou n d 62. Hydrazine (0.10 mL, 1.96
mmol, 3.0 equiv) was added to a stirred solution of compound
61 (0.374 g, 0.65 mmol) in 3.4 mL of CH2Cl2. The reaction
mixture was stirred at room temperature for 2 h, and the
solvent was removed under vacuum. The residue was dis-
solved in a mixture of H2O and CH2Cl2. The separated organic
phase was washed with brine, dried (Na2SO4), and concen-
trated. The crude product was further purified by flash
chromatography using 9:1 to 1:1 EtOAc-MeOH as eluents to
afford 0.12 g (42%) of product 62 as a colorless oil: silica gel
TLC Rf 0.51 (100:1 MeOH-30% NH4OH); 1H NMR (CDCl3) δ
1.31 (s, 9H), 1.41-1.44 (m, 2H), 1.55-1.56 (m, 2H), 2.34 (s,
3H), 2.62-2.66 (m, 2H), 3.21-3.23 (m, 2H), 3.30-3.32 (m, 2H),
3.46-3.48 (m, 2H), 3.63 (s, 2H), 3.77 (s, 2H), 3.94 (s, 2H), 7.04-
7.20 (m, 3H), 7.36-7.38 (m, 1H), 7.61-7.65 (m, 1H); 13C NMR
(CDCl3) δ 10.9, 14.0, 21.4, 22.9, 23.7, 28.2, 30.5, 38.7, 43.0,
44.9, 47.6, 52.1, 58.2, 59.2, 60.5, 68.1, 80.0, 119.4, 120.7, 125.7,
127.8, 128.2, 129.4, 137.02, 137.9, 138.9, 156.8, 159.4, 160.9;
HRMS (FAB) m/z 465.283 (M + Na)+ (C25H38N4O3Na requires
465.284).
P r ep a r a tion of Com p ou n d 65. A mixture of 64 (3.60 g,
5.73 mmol), anhydrous K2CO3 (10.0 g, 72 mmol), and R′-bromo-
R,R,R-trifluoro-m-xylene (1.66 g, 6.9 mmol, 1.2 equiv) in 110
mL of CH3CN was stirred at room temperature overnight. The
reaction mixture was worked up using the same procedure as
described above for library 42. The crude product was purified
by flash chromatography on a silica gel column. Elution with
3:1, 1:1, and then 1:2 hexanes-EtOAc afforded 3.60 g (80%)
of product 65 as a pale-yellow oil: silica gel TLC Rf 0.45 (1:4
1
hexanes-EtOAc); H NMR (CDCl3) δ 1.29 (s, 9H), 1.45-1.65
(m, 2H), 2.31 (s, 3H), 2.56 (t, 2H, J ) 7.0 Hz), 3.10-3.38 (m,
4H), 3.40-3.50 (m, 2H), 3.53 (s, 2H), 3.56 (s, 2H), 4.55 (s, 2H),
4.63 (s, 2H), 6.98-7.60 (m, 14H), 7.94 (d, 1H, J ) 7.3 Hz); 13
C
NMR (CDCl3) δ 21.4, 28.2, 30.4, 43.0, 44.9, 51.2, 52.2, 52.6,
58.2, 58.9, 60.2, 80.0, 120.7, 121.4, 124.2, 124.6, 125.0, 125.7,
127.9, 128.2, 129.1, 129.4, 130.9, 131.7, 131.8, 133.7, 136.6,
137.2, 137.9, 138.9, 147.8, 154.5, 156.8, 159.8; MS (FAB) m/z
918 (M + Cs)+; HRMS (FAB) m/z 786.316 (M + H)+
(C39H47N5O7SF3 requires 786.314).
P r ep a r a tion of Com p ou n d 66. Compound 66 was syn-
thesized as described above for libraries 52 and 43 from 65
(3.50 g, 4.45 mmol), thiophenol (0.59 g, 5.35 mmol, 1.2 equiv),
and anhydrous K2CO3 (3.0 g, 21.7 mmol) in 60 mL of DMF.
Flash chromatographic purification by using 100% EtOAc and
then 10:1 EtOAc-MeOH as eluents afforded 2.20 g (82%) of
product 66 as a pale-yellow oil: silica gel TLC Rf 0.47 (20:1
EtOAc-MeOH); 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.50-1.65
(m, 2H), 2.32 (s, 3H), 2.64 (t, 2H, J ) 6.8 Hz), 3.15-3.40 (m,
4H), 3.47 (t, 2H, J ) 5.5 Hz), 3.63 (s, 2H), 3.78 (s, 2H), 3.88 (s,
4H), 7.00-7.70 (m, 11H); 13C NMR (CDCl3) δ 21.4, 28.3, 30.6,
43.1, 45.0, 52.2, 53.0, 54.3, 58.3, 59.2, 60.5, 80.0, 120.5, 120.9,
123.8, 125.0, 125.8, 127.0, 127.9, 128.2, 128.8, 129.0, 129.5,
130.4, 131.0, 131.6, 137.0, 137.9, 139.1, 141.2, 156.8, 158.5,
159.7; MS (FAB) m/z 601 (M + H)+; HRMS (FAB) m/z 733.237
(M + Cs)+ (C33H43N4O3F3Cs requires 733.234).
P r ep a r a tion of Com p ou n d 72. Compound 72 was syn-
thesized as described above for libraries 42 from 40 (2.70 g,
5.1 mmol), anhydrous K2CO3 (13.0 g, 94.0 mmol), and R′-
bromo-R,R,R-trifluoro-m-xylene (2.90 g, 12.1 mmol, 2.37 equiv)
in 120 mL of CH3CN. Flash chromatographic purification by
using 5:1 and then 1:1 hexanes-EtOAc as eluents afforded
2.59 g (60%) of product 72 as a colorless oil: silica gel TLC Rf
0.55 (1:4 hexanes-EtOAc); 1H NMR (CDCl3) δ 1.30 (s, 9H),
1.45-1.68 (m, 2H), 2.60 (t, 2H, J ) 6.8 Hz), 3.10-3.40 (m, 4H),
3.42-3.55 (m, 2H), 3.62 (s, 2H), 3.64 (s, 2H), 4.58 (s, 2H), 4.63
(s, 2H), 7.11 (d, 1H, J ) 7.2 Hz), 7.27-7.68 (m, 13H), 7.97 (d,
1H, J ) 7.4 Hz); 13C NMR (CDCl3) δ 28.2, 30.5, 43.1, 45.0,
51.3, 52.3, 52.8, 58.4, 59.7, 60.2, 80.1, 120.9, 121.5, 124.0, 124.2,
124.6, 125.1, 126.5, 126.9, 128.8, 129.1, 130.4, 131.0, 131.6,
133.6, 136.6, 137.3, 140.4, 147.9, 154.8, 156.7, 159.2; MS (FAB)
m/z 840 (M + H)+; HRMS (FAB) m/z 972.187 (M + Cs)+
(C39H43N5SO7F6Cs requires 972.184).
P r ep a r a tion of Com p ou n d 63. A mixture of compound
62 (0.40 g, 0.90 mmol), anhydrous K2CO3 (1.49 g, 10.8 mmol,
12.0 equiv), and R′-bromo-R,R,R-trifluoro-m-xylene (0.47 g, 1.97
mmol, 2.2 equiv) in 30 mL of anhydrous CH3CN was stirred
at room temperature overnight. The solvent was evaporated,
and the residue was dissolved in a mixture of H2O and CH2-
Cl2. The organic phase was separated, and the aqueous phase
was extracted with CH2Cl2. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by flash chromatography using 8:2 to 7:3
EtOAc-hexanes as eluents to afford 0.41 g (60%) of product
63 as a colorless oil: silica gel TLC Rf 0.66 (3:7 hexanes-
1
EtOAc); H NMR (CDCl3) δ 1.26 (s, 9H), 1.29-1.55 (m, 4H),
2.32 (s, 3H), 2.58-2.65 (m, 2H), 3.18-3.33 (m, 4H), 3.40-3.52
(m, 2H), 3.60 (s, 2H), 3.66 (s, 4H), 3.72 (s, 2H), 3.75 (s, 2H),
7.04-7.18 (m, 4H), 7.34-7.71 (m, 11H); 13C NMR (CDCl3) δ
10.9, 14.0, 21.4, 23.0, 23.7, 28.2, 28.9, 30.3, 38.7, 42.9, 44.9,
52.2, 58.1, 59.1, 59.8, 60.5, 68.1, 80.1, 120.9, 124.0, 125.4, 125.7,