6552 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Bruno et al.
with CHCl3. The organic layer was dried (MgSO4), filtered,
and evaporated to give yellowish oils. Amines in excess were
distilled under vacuum. The obtained crude oils were puri-
fied as follows: compound 4a was chromatographed on
silica gel (hexane/diethyl ether (5:95)) and then precipitated
as hydrochloride; compounds 4b, 4c, 4d were crystalli-
zed from diethyl ether; compound 4e was precipitated as
hydrochloride.
In the case of piperazine derivative (compound 4f), the
procedure was modified as follows: to a solution of piper-
azine (2.06 g, 3.98 mmol) in absolute ethanol (6 mL), warmed
at 45-50 °C, the epoxide 9 (1.16 g, 3.98 mmol) in absolute
ethanol (2 mL) was added dropwise. The reaction mix-
ture was stirred at 45-50 °C for 2 h. After cooling, the
mixture was treated as above-mentioned to give an oil that
was purified by chromatography on silica gel (methanol/
chloroform (5:90)). Compound 4f was characterized as
dihydrochloride.
Analytical Ddata of 2-[({[3-(Cyclopentyloxy)-4-meth-
oxyphenyl]methylene}amino)oxy]-1-(morpholin-4-ylmethyl)
Ethyl Benzoate (3c). Yield 70% . 1H NMR (CDCl3): δ
1.30-1.95 (m, 8H, 4CH2 cyclopent), 2.30-2.78 (m, 6H, 3
CH2-N), 3.60 (t, J=4.6 Hz, 4H, 2 O-CH2 morph), 3.78 (s,
3H, OCH3), 4.25-4.50 (m, 2H, O-CH2), 4.57-4.75 (m, 1H,
CH cyclopent), 5.39-5.56 (m, 1H, CHOCOPh), 6.70 (d, J=
7.8 Hz, 1H, H-5 Ar), 6.91 (dd, J=1.6, 7.8 Hz, 1H, H-6 Ar),
7.12 (d, J=1.6 Hz, H-2 Ar), 7.20-7.57 and 7.89-8.10 (2m,
6H, 5 H benzoyl þ CHdN). IR (film): cm-1 1714 (CdO).
Anal. Calcd for C27H34N2O6.
General Procedure for 3-(Cyclopentyloxy)-4-methoxyben-
zaldehyde O-[2-Chloro-3-(cycloamin-4-yl)propyl]-oxime (5a,
b). To a solution of the appropriate amino-alcohol (1c, 4a)
(3.12 mmol) in dichloromethane (3 mL) anhydrous triethy-
lamine (0.43 mL, 3.12 mmol) and thionyl chloride (0.27 mL,
3.74 mmol) were added dropwise at room temperature. After
the addition the mixture was stirred at rt for 4 h. The solvent
and excess thionyl chloride were removed under vacuum, the
residue was diluted with dichloromethane (10 mL) and
washed three times with water; the organic layer was dried
(MgSO4), filtered, and evaporated to give an oil which
was purified by chromatography on silica gel (chloroform/
hexane (9:1)).
Analytical Data of 3-(Cyclopentyloxy)-4-methoxybenzal-
dehyde O-[2-Chloro-3-(morpholin-4yl)propyl]-oxime (5a).
Yield 70%. 1H NMR (CDCl3): δ 1.50-2.05 (m, 8H, 4 CH2
cyclopent), 2.60-2.91 (m, 4H, 2 CH2 morph), 2.95-3.13 (m,
1H, CH), 3.48-3.79 (m, 6H, 2CH2 morph þ CH2), 3.84 (s,
3H, OCH3), 4.22-4.45 (m, 2H, CH2-O), 4.70-4.85 (m, 1H,
CH cyclopent), 6.80 (d, J=8.4 Hz, 1H, H-5 Ar), 6.98 (dd, J=
2.2, 8.4 Hz, 1H, H-6 Ar), 7.18 (d, J=2.2 Hz, H-2 Ar), 7.98 (s,
1H, CHdN). Anal. Calcd for C20H29ClN2O4.
Synthesis and Analytical Data of 3-(Cyclopentyloxy)-4-
methoxybenzaldehyde O-(2-Bromoacetyl)oxime (10). To a
mixture of 3-(cyclopentyloxy)-4-methoxybenzaldehyde
oxime 8 (1.45 g, 6.16 mmol) solved in dichloromethane
(6 mL) and anhydrous potassium carbonate (1.70 g, 12.32
mmol) cooled at 0-5 °C, a solution of bromoacetyl bromide
(0.64 mL, 7.39 mmol) in dichloromethane (2 mL) was added
dropwise, over 20 min period, with stirring. After the addi-
tion, the mixture was filtered and the residue washed several
times with dichloromethane; the filtrate was evaporated
under vacuum to yield a yellowish solid that was washed
more times with diethyl ether, giving a white solid.
Analytical Data of 3-(Cyclopentyloxy)-4-methoxybenzal-
dehyde O-[3-(2,6-Dimethyl-morpholin-4-yl)-2-hydroxypropyl]-
oxime (4a). Yield 79%; mp for C22H34N2O5 HCl 110 °C. 1H
3
NMR (CDCl3): δ 1.05 (d, J=6.0 Hz, 3H, CH3 morph), 1.09
(d, J=6.2 Hz, 3H, CH3 morph), 1.49-2.02 (m, 10H, 4 CH2
cyclopent þ N-CH2), 2.29-2.44 and 2.50-2.82 (2m, 4H, 2
N-CH2), 3.50-3.70 (m, 2H, 2 CH morph), 3.79 (s, 3H,
OCH3), 3.91-4.24 (m, 3H, CH2 þ CH-OH), 4.67-4.80 (m,
1H, CH cyclopent), 6.78-7.15 (3m, 3H, Ar), 7.97 (s, 1H,
CHdN). IR (KBr): cm-1 3400-3200 (OH). Anal. Calcd for
C22H34N2O5 HCl.
3
General Procedure for 2-[({[3-(Cyclopentyloxy)-4-meth-
oxyphenyl]methylene}amino)oxy]-1-(cycloamin-ylmethyl)
Ethyl Acetates (2a-c). To a solution of the suitable amino-
alcohols (1a-c) (1.93 mmol) in acetic anhydride (2 mL)
anhydrous sodium acetate (0.2 g, 2.44 mmol) was added
and the mixture was stirred for 3-5 h at 40-50 °C, monitor-
ing the formation of the product by TLC. After cooling, the
mixture was poured into water and extracted three times with
CHCl3. The combined organic layers were washed twice with
1 M NaOH solution and then several times with water, dried
(MgSO4), filtered, and evaporated to give yellow oils which
were chromatographed on Florisil (100-200 mesh) (diethyl
ether).
Analytical Data of 2-[({[3-(Cyclopentyloxy)-4-meth-
oxyphenyl]methylene}amino)oxy]-1-(morpholin-4-ylmethyl)
Ethyl Acetate (2c). Yield 81%. 1H NMR (CDCl3): δ
1.40-1.95 (m, 8H, 4 CH2 cyclopent), 1.99 (s, 3H, CH3),
2.30-2.60 (m, 6H, 3 N-CH2), 3.60 (t, J=4.6, 4H, 2 O-CH2
morph), 3.78 (s, 3H, OCH3), 4.10-4.32 (m, 2H, O-CH2),
4.70-4.80 (m, 1H, CH cyclopent), 5.18-5.31 (m, 1H,
CHOCOCH3), 6.74 (d, J=8.0 Hz, 1H, H-5 Ar), 6.95 (dd,
J=1.8, 8.4 Hz, 1H, H-6 Ar), 7.14 (d, J=1.8 Hz, H-2 Ar), 7.92
(s, 1H, CHdN). IR (film): cm-1 1738 (CdO). Anal. Calcd
for C22H32N2O6.
General Procedure for 2-[({[3-(Cyclopentyloxy)-4-meth-
oxyphenyl]methylene}amino)oxy]-1-(cycloamin-ylmethyl)
Ethyl Benzoates (3a-c). To a solution of the suitable amino-
alcohols (1a-c) (1.6 mmol) in pyridine (2 mL) benzoylchlor-
ide (0.3 mL, 2.24 mmol) was added and the reaction solution
was stirred for 16 h at 40-50 °C. After cooling, the reaction
mixture was diluted with CHCl3 (10 mL), washed three times
with 1N HCl solution, and then several times with water. The
organic layer was dried (MgSO4), filtered, and evaporated to
yield yellow oils which were chromatographed on Florisil
(100-200 mesh) (diethyl ether).
Yield: 84%; mp 126 °C. 1H NMR (CDCl3): δ 1.40-2.12
(m, 8H, 4 CH2 cyclopent), 3.87 (s, 3H, OCH3), 3.97 (s, 2H,
CH2Br), 4.71-4.90 (m, 1H, CH cyclopent), 6.86 (d, J=8.2
Hz, 1H, H-5 Ar), 7.15 (dd, J=2.0, 8.2 Hz, 1H, H-6 Ar), 7.32
(d, J=2.0 Hz, 1H, H-2, Ar), 8.28 (s, 1H, CHdN). IR (KBr):
cm-1 1768 (CdO). Anal. Calcd for C15H18BrNO4.
General Procedure for 3-(Cyclopentyloxy)-4-methoxyben-
zaldehyde O-(2-Cycloamino-acetyl)oximes (6a,b). To a sus-
pension of suitable amine (morpholine or 2,6-
dimethylmorpholine) (5.05 mmol, 1.5 equiv), anhydrous
potassium carbonate (0.86 g, 6.7 mmol, 2 equiv) and potas-
sium iodide (0.02 g, 0.10 mmol, 0.03 equiv) in dichloro-
methane (4 mL), the intermediate 10 (1.2 g, 3.37 mmol,
1equiv), solved in dichloromethane (2 mL), was added
dropwise. The reaction mixture was refluxed for 3 h. After
cooling, the mixture was filtered and the residue was washed
several times with dichloromethane; the solvent was evapo-
rated under reduced pressure and the obtained oil was
diluted with diethyl ether, washed with water, and extracted