3572 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Cappelli et al.
dichloromethane cooled at 0-5 °C was added the appropriate
amine (2 equiv of diethylamine, dipropylamine, or N-methyl-
benzylamine), and the resulting mixture was stirred at room
temperature for a suitable time (typically 0.5 h) while the
reaction progress was monitored by TLC. The reaction mixture
was concentrated under reduced pressure and partitioned
between CH2Cl2 and water. The organic layer was dried over
sodium sulfate and concentrated under reduced pressure, and
the residue was used in the next step or purified when
necessary.
N-Benzyl-2-chloro-N-methylquinoline-4-carboxam-
ide (30). This compound was obtained as a pale-yellow oil that
crystallized on standing (yield 64%, mp 60-62 °C). Since the
amide nitrogen of this compound bears two different substit-
uents, the 1H NMR spectrum of the compound shows the
presence of two different rotamers in equilibrium. For the sake
of simplification the integral intensities have not been given.
1H NMR (CDCl3): δ 2.73 (s), 3.16 (s), 4.30 (s), 4.86 (s), 7.16
(m), 7.39 (m), 7.61 (m) 7.80 (m), 8.06 (m).
General Procedure for the Preparation of Target 2-(4-
Methyl-1-piperazinyl)quinoline Derivatives 5 and 6. A
mixture of the appropriate 2-chloroquinoline derivatives 13-
35 (1.0 mmol) with N-methylpiperazine (5 mL) was heated at
130-140 °C under argon for a suitable time (1-7 h), and the
reaction progress was monitored by TLC. When the 2-chloro-
quinoline derivative disappeared from the chromatogram, the
reaction mixture was then poured into ice-water (250 mL)
and extracted with chloroform. The organic layer was washed
with water, dried over sodium sulfate, and evaporated under
reduced pressure. Purification of the residue by flash chro-
matography with ethyl acetate-triethylamine (8:2) as the
eluent gave the expected 2-(4-methyl-1-piperazinyl)quinoline
derivatives 5 and 6 showing a suitable degree of purity as
confirmed by 1H NMR spectroscopy, TLC analysis, and el-
emental (C, H, N) analysis. In some instances the final
compound was recrystallized from the appropriate solvent.
2,3-Dihydro-2-methyl-4-(4-methyl-1-piperazinyl)-1H-
pyrrolo[3,4-c]quinolin-1-one (5a). This compound was pre-
pared by applying the general procedure to imidoyl chloride
36 (reaction time, 1 h). Compound 5a was recrystallized from
acetone to obtain an off-white solid (yield 58%, mp 193-194
°C). 1H NMR (CDCl3): δ 2.37 (s, 3H), 2.59 (t, J ) 4.9, 4H),
3.26 (s, 3H), 3.71 (t, J ) 4.9, 4H), 4.50 (s, 2H), 7.41 (m, 1H),
7.62 (m, 1H), 7.83 (m, 1H), 8.97 (m, 1H). MS (ESI): m/z 297
(M + H+). Anal. (C17H20N4O‚H2O) C, H, N.
standing (yield 52%, mp 86-88 °C). 1H NMR (CDCl3): δ 0.94
(t, J ) 7.3, 3H), 1.43 (t, J ) 6.9, 3H), 1.62 (m, 2H), 2.35 (s,
3H), 2.60 (t, J ) 4.7, 4H), 2.73 (m, 2H), 3.28 (t, J ) 4.7, 4H),
4.51 (q, J ) 7.2, 2H), 7.33 (m, 1H), 7.53 (m, 2H), 7.86 (m, 1H).
MS (ESI): m/z 342 (M + H+). Anal. (C20H27N3O2) C, H, N.
2-(4-Methyl-1-piperazinyl)-N,N,3-tripropylquinoline-
4-carboxamide (6fc). This compound was obtained from
amide 26 (reaction time, 2 h) as a pale-yellow oil (yield 97%).
1H NMR (CDCl3): δ 0.58 (t, J ) 7.3, 3H), 0.97 (t, J ) 7.3, 3H),
1.05 (t, J ) 7.4, 3H), 1.40 (m, 2H), 1.77 (m, 4H), 2.37 (s, 3H),
2.45-2.78 (m, 6H), 2.93 (m, 2H), 3.29 (m, 4H), 3.42-3.78 (m,
2H), 7.33 (m, 1H), 7.54 (m, 2H), 7.86 (m, 1H). MS (ESI): m/z
397 (M + H+). Anal. (C24H36N4O‚1/2H2O) C, H, N.
3,4-Bis(hydroxymethyl)-2-(4-methyl-1-piperazinyl)quin-
oline (6m). To a suspension of lithium aluminum hydride
(0.13 g, 3.4 mmol) in anhydrous THF (10 mL) cooled at 0-5
°C was added a solution of 5f (0.24 g, 0.85 mmol) in anhydrous
THF (10 mL). After the mixture was stirred for 30 min at 0-5
°C and 30 min at room temperature, the hydride was hydro-
lyzed by addition of water and the inorganic material was
filtered off and washed with THF. The filtrate was washed
with brine, dried over sodium sulfate, and evaporated under
reduced pressure to give 6m as an oil that crystallized
spontaneously (0.22 g, yield 90%). An analytical sample
recrystallized from ethyl acetate melted at 153-155 °C. 1H
NMR (CDCl3): δ 2.34 (s, 3H), 2.58 (t, J ) 4.6, 4H), 3.35 (t, J
) 4.7, 4H), 4.96 (s, 2H), 5.16 (s, 2H), 7.42 (t, J ) 7.1, 1H), 7.61
(t, J ) 7.1, 1H), 7.89 (d, J ) 8.6, 1H), 8.05 (d, J ) 8.6, 1H).
MS (EI): m/z 287 (M+, 10). Anal. (C16H21N3O2) C, H, N.
General Procedure for the Preparation of 4-Chloro-
pyrrolo[3,4-c]quinoline Derivatives 36-40. A mixture of
ester 14 (0.37 g, 1.5 mmol) in 30 mL of CCl4 with N-
bromosuccinimide (0.27 g, 1.5 mmol) and dibenzoyl peroxide
(0.03 g, 0.12 mmol) was heated at reflux under argon for 3 h.
The solvent was then removed under reduced pressure, and
the residue was diluted with a small portion of the same
solvent. The insoluble succinimide was filtered off, and the
solvent was removed under reduced pressure. The residue was
dissolved in 15 mL of absolute ethanol (or methanol), and the
appropriate amine (methylamine, ethylamine, propylamine,
sec-butylamine, or benzylamine) was added. The resulting
mixture was stirred at room temperature under argon for a
suitable time (from 1.5 h to 4 days), and the reaction progress
was monitored by TLC. The resulting precipitate was collected
by filtration, washed with water and ethanol, and dried under
reduced pressure.
4-(4-Methyl-1-piperazinyl)furo[3,4-c]quinolin-1(3H)-
one (5f). This compound was prepared by applying the general
procedure to imidoyl chloride 41 (reaction time, 1 h). Com-
pound 5f was recrystallized from acetone to obtain a yellow
4-Chloro-2,3-dihydro-2-methyl-1H-pyrrolo[3,4-c]quino-
lin-1-one (36). This compound was prepared following the
general procedure with a 8 M solution of methylamine-
methanol (2 mL, 16 mmol) and methanol as the solvent
(reaction time, 1.5 h). Compound 36 was obtained as a white
solid (0.18 g, yield 52%, mp 217-220 °C). 1H NMR (CDCl3): δ
3.31 (s, 3H), 4.51 (s, 2H), 7.78 (m, 2H), 8.12 (m, 1H), 9.05 (m,
1H). Anal. (C12H9ClN2O) C, H, N.
1
solid (yield 81%, mp 173-175 °C). H NMR (CDCl3): δ 2.38
(s, 3H), 2.59 (t, J ) 4.9, 4H), 3.70 (t, J ) 5.0, 4H), 5.43 (s, 2H),
7.43 (m, 1H), 7.65 (m, 1H), 7.85 (d, J ) 8.4, 1H), 8.74 (d, J )
7.8, 1H). MS (ESI): m/z 284 (M + H+). Anal. (C16H17N3O2) C,
H, N.
4-Benzoyl-3-methyl-2-(4-methyl-1-piperazinyl)quino-
line (6a). This compound was obtained from compound 43
(reaction time, 7 h) as a pale-yellow oil that crystallized on
standing. Recrystallization from ethyl acetate gave an analyti-
cal sample melting at 174-175 °C (yield 59%). 1H NMR
(CDCl3): δ 2.21 (s, 3H), 2.37 (s, 3H), 2.62 (t, J ) 4.6, 4H), 3.36
(m, 4H), 7.26 (m, 2H), 7.40-7.64 (m, 4H), 7.78 (m, 2H), 7.90
(m, 1H). MS (ESI): m/z 346 (M + H+). Anal. (C22H23N3O) C,
H, N.
4-Chlorofuro[3,4-c]quinolin-1(3H)-one (41). A mixture
of ester 14 (1.0 g, 4.0 mmol) in 50 mL of CCl4 with N-
bromosuccinimide (0.71 g, 4.0 mmol) and dibenzoyl peroxide
(0.10 g) was heated at reflux under argon for 3 h. The solvent
was then removed under reduced pressure, and the residue
was diluted with a small portion of the same solvent. The
insoluble succinimide was filtered off, and the solvent was
removed under reduced pressure. The residue was dissolved
in 20 mL of 2-methoxyethanol, and 3 N hydrochloric acid (20
mL) was added. The resulting mixture was heated at reflux
for 24 h under argon. The cooled reaction mixture was then
diluted with water, and the precipitate was collected by
filtration, washed with water, and dried under reduced pres-
sure. A mixture of the solid in POCl3 (10 mL) was heated at
reflux for 2.5 h under argon. The cooled reaction mixture was
then poured into ice-water, and the precipitate was extracted
with CHCl3. The combined extracts were dried over sodium
sulfate and evaporated under reduced pressure. Purification
of the residue by flash chromatography with n-hexane-ethyl
acetate (8:2) as the eluent gave pure 41 as a white solid (0.51
Ethyl 2-(4-Methyl-1-piperazinyl)-4-quinolinecarboxyl-
ate (6ba). This compound was obtained from ester 13 (reaction
time, 3 h) as a pale-yellow oil that crystallized on standing
1
(yield 55%, mp 74-76 °C). H NMR (CDCl3): δ 1.44 (t, J )
6.9, 3H), 2.34 (s, 3H), 2.53 (t, J ) 4.9, 4H), 3.77 (t, J ) 4.9,
4H), 4.47 (q, J ) 7.2, 2H), 7.27 (m, 1H), 7.48 (s, 1H), 7.54 (m,
1H), 7.72 (m, 1H), 8.37 (m, 1H). MS (EI): m/z 299 (M+, 13).
Anal. (C17H21N3O2) C, H, N.
Ethyl 2-(4-Methyl-1-piperazinyl)-3-propyl-4-quinoline-
carboxylate (6bc). This compound was obtained from ester
16 (reaction time, 3 h) as a colorless oil that crystallized on