2732 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 17
Tsou et al.
a brown solid was obtained. An analytical sample was pre-
pared by preparative TLC (silica gel, 35% MeOH in CHCl3):
1H NMR (DMSO-d6) δ 10.47 (s, 1H), 9.94 (s, 1H), 8.85 (s, 1H),
8.58 (s, 1H), 8.18 (m, 1H), 7.88 (m, 2H), 7.79 (d, J ) 8.7 Hz,
1H), 7.33 (m, 2H), 6.91 (m, 1H), 6.37 (d, J ) 15.6 Hz, 1H),
3.71 (m, 1H), 3.26 (s, 3H), 3.15 (m, 3H), 3.02 (m, 1H), 2.66 (m,
1H), 2.21 (m, 1H), 1.88 (m, 1H), 1.71 (m, 2H), 1.52 (m, 1H);
1H), 7.88 (d, J ) 7.5 Hz, 1H), 7.33 (m, 2H), 5.94 (d, J ) 0.7
Hz, 1H), 5.62 (d, J ) 1.02 Hz, 1H), 2.02 (s, 3H); MS (ESI) m/z
383, 385 (M + H)+. Anal. (C18H15BrN4O‚0.25H2O) C, H, N.
(2E)-N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-2-
bu ten a m id e (18). A solution of 6 (1.58 g, 5 mmol) and
pyridine (0.5 mL, 0.489 g; 6.2 mmol) in N-methylpyrrolidone
(15 mL) was stirred and cooled in an ice bath. To this was
added dropwise a solution of trans-crotonyl chloride (0.53 mL,
0.57 g, 5.5 mmol) in CH3CN (15 mL). Cooling and stirring were
continued for 1 h, and the reaction was poured into saturated
NaHCO3 (50 mL). The resulting solid was collected and
chromatographed on silica gel. Elution with a gradient of 2:1
EtOAc-hexanes to EtOAc gave 1.32 g (68%) of 18 as a white
HRMS (EI) m/z calcd for
C24H26BrN5O2 495.1261, found
495.1269 (M+•). Anal. (C24H26BrN5O2‚0.6CHCl3) C, H, N; N:
25
calcd, 12.32; found, 11.89; [R]D ) 23 (c 0.449, MeOH).
(2E)-N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-4-
[(2-m eth oxyeth yl)(m eth yl)a m in o]-2-bu ten a m id e (16q).
Using a procedure similar to 16b, 1.21 g (50%) of the product
was obtained from 15 (2.31 g, 5 mmol) and (2-methoxyethyl)-
(methyl)amine (4.15 g, 46.6 mmol): 1H NMR (DMSO-d6) 10.42
(s, 1 H), 9.92 (s, 1 H), 8.84 (s, 1 H), 8.58 (s, 1 H), 8.17 (m, 1 H),
7.88 (m, 2 H), 7.80 (d, J ) 9 Hz, 1 H), 7.35 (dd, J ) 7.8, 7.8
Hz, 1 H), 7.29 (m, 1 H), 6.84 (td, J ) 15.3, 5.7 Hz, 1 H), 6.36
(d, J ) 15.3 Hz, 1 H), 3.46 (t, J ) 5.9 Hz, 2 H), 3.34 (s, 3 H),
3.22 (d, J ) 5.7 Hz, 2 H), 2.55 (t, J ) 5.9 Hz, 2 H), 2.23 (s, 3
H); HRMS (ESI) m/z calcd for C22H24BrN5O2 470.1192, found
470.1177 (M + H)+. Anal. (C22H24BrN5O2‚0.5 H2O) C, H, N.
1
solid: mp 267-269 °C; H NMR (DMSO-d6) δ 10.58 (s, 1H),
8.92 (s, 1H), 8.68 (s, 2H), 8.09 (m, 1H) 7.83 (m, 2H), 7.39 (m,
3H), 6.91 (m, 1H), 6.27 (m, 1H), 1.92 (d, J ) 6.7 Hz, 3H); MS
(ESI) m/z 383, 385 (M + H)+. Anal. (C18H15BrN4O‚0.25 H2O)
C, H, N.
(2E)-N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-4-
m eth oxy-2-bu ten a m id e (19). To a stirred solution of 6 (1 g,
3.17 mmol) and N,N-diisopropylethylamine (0.62 g, 4.80 mmol)
in THF (21 mL) at 0 °C was added 4-methoxycrotonyl
chloride17 (0.62 g, 4.76 mmol). The mixture was stirred at 0
°C for 1.5 h and then at room temperature for 10 min. The
mixture was poured into saturated NaHCO3-brine and ex-
tracted with EtOAc. The organic solution was dried (MgSO4),
filtered through silica gel, and evaporated. The residue was
recrystallized from n-BuOH to give 1.25 g (95%) of 19 as a
yellow solid: 1H NMR (DMSO-d6) δ 10.46 (s, 1H), 9.95 (bs,
1H), 8.83 (s, 1H), 8.59 (s, 1H), 8.17 (bs, 1H), 7.86 (m, 3H), 7.33
(m, 2H), 6.91 (dt, J ) 3.9, 15.6 Hz, 1H), 6.43 (d, J ) 15.6 Hz,
1H), 4.15 (m, 2H), 3.33 (s, 3H); MS (ESI) m/z 413 (M + H)+.
Anal. (C19H17BrN4O2‚0.33H2O) C, H, N.
N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-1-m eth -
yl-1,2,5,6-tetr a h yd r o-3-p yr id in eca r boxa m id e (20). Using
the method described above for 19, 6 (0.75 g, 2.38 mmol), N,N-
diisopropylethylamine (1.54 g, 11.9 mmol), and N-methyl-
1,2,5,6-tetrahydronicotinyl chloride hydrochloride18 (0.61 g, 3.1
mmol) gave 0.9 g (87%) of 20 as a light yellow powder: 1H
NMR (DMSO-d6) δ 10.11 (bs, 1H), 9.90 (bs, 1H), 8.78 (d, J )
1.8 Hz, 1H), 8.59 (s, 1H), 8.20 (bs, 1H), 7.94 (dd, J ) 1.8, 9.0
Hz, 1H), 7.92 (d, J ) 9.0 Hz, 1H), 7.79 (d, J ) 9 Hz, 1H), 7.30
(m, 2H), 6.87 (t, J ) 1.59, 1H), 3.50-2.90 (m’s, 6H), 2.35 (s,
3H); MS (ESI) m/z 438.3, 440.3 (M + H)+. Anal. (C21H20BrN5O‚
0.5H2O) C, H, N.
N-{4-[(3-Br om oph en yl)am in o]-6-qu in azolin yl}-2-(4-m or -
p h olin ylm eth yl)a cr yla m id e (23). A solution of 2-(4-mor-
pholinylmethyl)acrylic acid 2119 (2.06 g, 12 mmol) in THF (25
mL) was stirred and cooled in an ice bath. To this was added
isobutyl chloroformate (1.56 mL, 1.64 g, 12 mmol) and then
N-methylmorpholine (1.32 mL, 1.22 g, 12 mmol), giving the
mixed anhydride 22 as a precipitate. This mixture was stirred
for 2 min and then 6 (3.15 g, 10 mmol) in pyridine (25 mL)
was added in one portion. The reaction was stirred and cooled
for 0.5 h and then it was poured onto ice and EtOAc. The
EtOAc layer was dried (Na2SO4) and evaporated. The residue
was chromatographed on silica gel. Elution with a gradient
from 1:1 EtOAc-hexane to 1:19 EtOAc-MeOH gave 0.733 g
(15%) of 23 as a cream-colored solid: mp 158-166 °C; 1H NMR
(DMSO-d6) δ 11.17 (s, 1H), 9.94 (s, 1H), 8.81 (d, J ) 1.8 Hz,
1H), 8.60 (s, 1H) 8.19 (dd, J ) 4.2 Hz, J ) 1.8 Hz, 1H), 7.87
(m, 3H), 7.31 (m, 2H), 6.15 (d, J ) 1.2 Hz, 1H), 5.63 (s, 1H),
3.68 (m, 4H), 3.36 (m, 6H); MS (ESI) m/z 468.1 (M + H)+. Anal.
(C22H22BrN5O2‚H2O) C, H, N.
(2E)-N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-3-
(d im eth yla m in o)-2-p r op en a m id e (25a ). To a stirred solu-
tion of 6 (3.0 g, 9.52 mmol) and N,N-diisopropylethylamine
(1.23 g, 9.52 mmol) in THF (26 mL) at 0 °C was added trans-
3-chloroacryloyl chloride (1.85 g, 14.9 mmol) in THF (5 mL).
After 1 h, dimethylamine (2M in THF, 71.4 mL) was added
and the mixture was stirred an additional 1.5 h. The solvent
was evaporated and the residue was dissolved in a mixture of
EtOAc and THF. The solution was washed with saturated
NaHCO3, dried (MgSO4), and passed through a short silica gel
(2E)-N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-4-
[(2-h ydr oxyeth yl)(m eth yl)am in o]-2-bu ten am ide (16r ). This
compound was prepared by the reaction of 15 (0.550 g, 1.19
mmol) and (2-hydroxyethyl)(methyl)amine (0.107 g, 1.43 mmol)
as previously described for 16b. The chromatography solvent
was 30-35% MeOH in EtOAc, and 0.130 g (24%) of yellow
solid was obtained: 1H NMR (DMSO-d6) δ 10.44 (s, 1H), 9.93
(s, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 8.19 (m, 1H), 7.89 (m, 2H),
7.79 (d, J ) 9 Hz, 1H), 7.32 (m, 2H), 6.86 (m, 1H), 6.36 (d, J
) 15.6 Hz, 1H), 4.44 (t, J ) 5.4 Hz, 1H), 3.51 (m, 2H), 3.22 (d,
J ) 5.01 Hz, 2H), 2.46 (t, J ) 6.36 Hz, 2H), 2.23 (s, 3H); MS
(ESI) m/z 456.0, 457.9 (M + H)+; HRMS (ESI) m/z calcd for
C
21H22BrN5O2 456.102 97, found 456.103 16 (M + H)+. Anal.
(C21H22BrN5O2‚1.2H2O) C, H, N; H: calcd, 5.45; found, 5.02.
(2E)-4-(1,4′-Bip ip er id in -1′-yl)-N-{4-[(3-b r om op h en yl)-
a m in o]-6-qu in a zolin yl}-2-bu ten a m id e (16s). This com-
pound was prepared by the reaction of 15 (0.700 g, 1.52 mmol)
and 4-piperidinopiperidine (0.305 g, 1.82 mmol) as previously
described for 16b. The chromatography solvent was 1:1
EtOAc-MeOH, followed by 1:1 EtOAc-MeOH + 1% Et3N, and
0.300 g (35%) of brown solid was obtained: 1H NMR (DMSO-
d6) δ 10.54 (s, 1H), 9.97 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.21
(m, 1H), 7.90 (m, 2H), 7.78 (d, J ) 9 Hz, 1H), 7.28 (m, 2H),
6.80 (m, 1H), 6.32 (d, J ) 15.3 Hz, 1H), 3.60 (m, 11H), 3.07 (d,
J ) 5.43 Hz, 1H), 2.86 (d, J ) 11.2 Hz, 1H), 1.91 (t, J ) 15.9
Hz, 1H), 1.70 (d, J ) 11.2 Hz, 1H), 1.45 (m, 6H); HRMS (EI)
m/z calcd for C28H33BrN6O 548.1899, found 548.1882 (M+.)
Anal. (C28H33BrN6O‚1.5H2O) C, N; H: calcd, 6.28; found, 5.86.
(2E)-N-{4-[(3-Br om op h en yl)a m in o]-6-qu in a zolin yl}-4-
(1H -p yr a zol-1-yl)-2-b u t en a m id e (16t ). Using the method
described above for 15, 6 (3.00 g, 9.52 mmol), N,N-diisopro-
pylethylamine (1.41 g, 10.95 mmol), and 4-bromocrotonyl
chloride (2.01 g, 10.95 mmol) in THF (36 mL) were condensed.
Pyrazole (3.89 g, 57.1 mmol) was added and the reaction was
refluxed for 8 h. After work up as before and chromatography
on silica gel using CHCl3-EtOAc-MeOH mixtures, 1.3 g (31%)
of the product was obtained as a light tan solid: 1H NMR
(DMSO-d6) δ 10.48 (bs, 1H), 9.97 (bs, 1H), 8.82 (bs, 1H), 8.60
(s, 1H), 8.17 (bs, 1H), 7.82 (m, 5H), 7.37 (m, 3H), 7.02 (dt, J )
3, 12 Hz, 1H), 6.02 (d, J ) 12 Hz, 1H), 5.07 (m, 2H); MS (ESI)
m/z 450.9 (M + H)+. Anal. (C21H17BrN6O‚0.5 H2O) C, H, N.
N-{4-[(3-Br om op h en yl)a m in o]-6-q u in a zolin yl}-2-m e-
th yla cr yla m id e (17). A solution of 6 (1.58 g, 5 mmol) in
pyridine (15 mL) was cooled in an ice bath and a solution of
methacryloyl chloride (0.59 mL, 0.63 g, 6 mmol) in Et2O (6
mL) was added dropwise. After stirring and cooling for 2 h,
the solvents were removed in vacuo. The residue was washed
with water and the resulting solid was taken up in warm
n-BuOH. Addition of Et2O to the cooled solution gave 0.44 g
(23%) of 17: mp 240-245 °C: 1H NMR (DMSO-d6) δ 10.19 (s,
1H), 10.15 (d, J ) 6.7 Hz, 1H), 8.80 (d, J ) 2.1, 1H), 8.61 (s,
1H), 8.18 (s, 1H), 7.97 (d, J ) 2.2 Hz, 1H), 7.94 (d, J ) 2.2 Hz,