Piperazines with High Nootropic Activity
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4505
from 1-propylpiperazine and 4-fluorobenzenesulfonyl chloride,
title compound was obtained in 85% yield after column
chromatography purification (eluting solvent: petroleum ether/
CHCl3/Et2O/absolute EtOH/NH4OH, 450:180:180:45:2.5): mp
50-51 °C from petroleum ether; IR (neat) ν 1600 (aromatic
CH), 1350 and 1160 (SO2) cm -1; 1H NMR (CDCl3) δ 0.86 (t, J
) 7.2 Hz, 3H, CH3), 1.38-1.50 (m, 2H, CH2), 2.30 (t, J ) 7.4
Hz, 2H, CH2), 2.50-2.55 (m, 4H, CH2), 3.02-3.12 (m, 4H, CH2),
7.17-7.28 (m, J H-F ) 8.6 Hz, 2H, aromatics), 7.74-7.81 (m,
J H-F ) 5.0 Hz, 2H, aromatics); 13C NMR (CDCl3) δ 13.76 (q),
21.82 (t), 47.99 (t), 54.07 (t), 62.02 (t), 118.26 (d, J C-F ) 22.0
Hz), 132.50 (d, J C-F ) 9.0 Hz), 133.34 (d, J C-F ) 3.2 Hz), 167.21
(d, J C-F ) 255.1 Hz). Anal. (C13H19FN2O2S) C, H, N.
1-Acetyl-3-m eth ylp ip er a zin e (39). Acetic anhydride (1.02
g, 10 mmol) in 4 mL of CH2Cl2 was added to a solution of
2-methylpiperazine (1 g, 10 mmol) in 8 mL of CH2Cl2, heated
at 50 °C. The mixture was allowed to cool at room temperature,
then the solvent was evaporated, the residue treated with 2
N HCl and extracted with CHCl3. The aqueous layer was then
made alkaline with 10% NaOH and extracted with CHCl3.
Evaporation of the dried solvent gave an oil that was used as
such in the following reaction: IR (neat) ν 3300-3500 (NH),
1
1640 (CdO) cm -1; H NMR (CDCl3) δ 1.07 (d, J ) 5 Hz, 3H,
3-CH3) 1.76 (bs, 1H, NH), 2.10 (s, 3H, CH3CO), 2.57-2.87 (m,
3H, CHCH3, CHN), 2.98-3.22 (m, 2H, CHN), 3.56-3.67 (m,
1H, CHN), 4.42-4.53 (m, 1H, CHN).
In the same way, starting from propionic anhydride, 3-m eth -
1-Ben zoyl-3-m eth ylp ip er a zin e (36). A solution of 1 g
(0.01 mol) of commercially available 2-methylpiperazine and
3.78 g (0.045 mol) of NaHCO3 in 13 mL of H2O was diluted
with 8 mL of acetone and cooled in an ice bath. Then a solution
of benzoyl chloride (0.011 mol) in 4 mL of acetone was added
dropwise and the mixture was allowed to warm to room
temperature and stirred for further 1.5 h. The mixture was
concentrated under vacuum and extracted with CH2Cl2. The
product was purified by flash chromatography with CH2Cl2/
MeOH 95:5 as eluent to give 59% yield of the desired product
yl-1-p r op ion ylp ip er a zin e (38) was obtained.25
1-Ben zoyl-2-m eth yl-4-pr opion ylpiper azin e (34). Meth od
A: Starting from 38 and following the general procedure
described above, the title compound was obtained in 67% yield
as a low-melting solid, purified by silica gel chromatography
using CHCl3/MeOH 95:5 as eluent: IR (neat) ν 1650 (CdO)
cm -1; 1H NMR (mixture of conformers) (CDCl3) δ 1.16 (t) and
1.17 (t) (J ) 7.4 Hz, 3H, CH3CH2), 1.28 (d, J ) 6.6 Hz, 3H,
2-CH3), 2.28-2.42 (m, 2H, CH3CH2), 2.61-2.87 (m, 1H, CH),
3.14-3.36 (m, 2H, CH), 3.61-3.84 (m, 2H, CH), 4.37-4.61 (m,
2H, CH3CH + CH), 7.26-7.45 (m, 5H, aromatics); 13C NMR
(CDCl3) δ 9.79 (q), 9.90 (q), 15.85 (q), 16.11 (q), 26.56 (t), 26.83
(t), 42.13 (t), 45.79 (t), 46.10 (t), 49.99 (d), 126.89 (d), 126.98
(d), 129.00 (d), 130.19 (d), 130.30 (d), 136.01 (s), 171.05 (s),
173.47 (s). Anal. (C15H20N2O2) C, H, N.
as a thick oil that was used as such in the following reaction:
-1
IR (neat) ν 3200-3500 (NH), 1630 (CdO) cm
;
1H NMR
(CDCl3) δ 1.05 (d, J ) 6.0 Hz, 3H, 3-CH3), 1.74 (bs, 1H, NH),
2.51-3.06 (m, 6H, CH2), 3.52-3.63 (m, 1H, CH), 7.33-7.42
(m, 5H, aromatics).
In the same way, using 4-fluorobenzenesulfonyl chloride,
1-(4-flu or oben zen esu lfon yl)-3-m eth ylp ip er a zin e (37) was
obtained in 64% yield as a thick oil that was used as such in
the following reaction: IR (neat) ν 3200-3500 (NH), 1350
Meth od B: Starting from 1-benzoyl-2-methylpiperazine (42)
and following the method described for 32, title compound was
obtained as a mixture that was purified by chromatography
with Et2O/petroleum ether/absolute EtOH/CHCl3/NH4OH 180:
450:45:180:2.5 as eluent (92% yield).
1
(SO2), 1170 (SO2) cm -1; H NMR (CDCl3) δ 1.04 (d, J ) 6.2
Hz, 3H, 3-CH3), 1.56 (bs, 1H, NH), 1.91 (t, J ) 10.0 Hz, 1H,
CH), 2.25-2.36 (m, 1H, CH), 2.88-3.06 (m, 3H, CH), 3.59-
3.65 (m, 2H, CH), 7.18-7.28 (m, J H-F ) 10.9 Hz, 2H, aromat-
ics), 7.74-7.81 (m, J H-F ) 5.1 Hz, 2H, aromatics).
4-Acet yl-1-(4-flu or ob en zen esu lfon yl)-2-m et h ylp ip er -
a zin e (35). Meth od A: Following the general procedure
described above and starting from 39, title compound was
obtained in 50% yield after purification by silica gel chroma-
tography with CHCl3/MeOH 95/5 as eluent: mp 86-88 °C from
petroleum ether; IR (neat) ν 1650 (CdO), 1350 (SO2), 1150
1-Ben zoyl-3-m eth yl-4-pr opion ylpiper azin e (32). Meth od
A: 0.2 g (1 mmol) of 1-benzoyl-3-methylpiperazine (36) and 0.4
mL of NEt3 (3 mmol) in CH3CN, cooled in an ice bath, were
added of 0.95 mL (1.1 mmol) of propionyl chloride. After 1 h
at 0 °C the mixture was washed with H2O and extracted with
Et2O. The product was purified by flash chromatography with
CH2Cl2/MeOH 95:5 as eluent (yield 70%): low-melting solid;
1
(SO2) cm -1; H NMR (mixture of conformers) (CDCl3) δ 0.97
(d) and 1.05 (d) (J ) 6.6 Hz, 3H, 2-CH3), 2.04 (s) and 2.09 (s)
(3H, CH3CO), 2.64 (td, J ) 13.0 and J ) 6.2 Hz) and 2.82 (dd,
J ) 6.4 Hz) (1H, CH), 3.00-3.46 (m, 2H, CH), 3.47-3.74 (m,
2H, CH), 4.12-4.23 (m, 1H, CH3CH), 4.26-4.37 (m) and 4.51-
4.61 (m) (1H, CH), 7.16-7.28 (m, J H-F ) 8.9 Hz, 2H, aromat-
ics), 7.78-7.88 (m, J H-F ) 4.8 Hz, 2H, aromatics); 13C NMR
(CDCl3) δ14.50 (q), 14.72 (q), 21.44 (q), 21.57 (q), 40.14 (t),
40.52 (t), 46.22 (t), 49.30 (d), 49.70 (d), 51.45 (t), 116.88 (d,
(M+) 260; IR (neat) ν 1630 (CON) cm-1 1H NMR (CDCl3) δ
;
1.00-1.18 (m, 6H, CH3CH2 and 3-CH3), 2.15-2.29 (m, 2H,
CH3CH2), 2.75-3.72 (m, 5H, CH), 4.26-4.67 (m, 2H, CH3CH
and CH), 7.27-7.36 (m, 5H, aromatics); 13C NMR (CDCl3) δ
9.79 (q), 18.75 (q), 26.78 (t), 27.09 (t), 44.95 (t), 49.03 (d), 58.31
(t), 127.29 (d), 127.80 (d), 128.69 (d), 128.93 (d), 130.28 (d),
135.50 (s), 171.56 (s), 172.72 (s). Anal. (C15H20N2O2) C, H, N.
J C-F ) 21.9 Hz), 130.00 (d, J C-F ) 10.6 Hz), 136.56 (d, J C-F
)
3.6 Hz), 165.31 (d, J C-F ) 254.6 Hz), 169.88 (s). Anal. (C13H17
-
FN2O3S) C, H, N.
Meth od B: To a solution of 0.150 g (0.96 mmol) of 2-methyl-
1-propionylpiperazine (45) in CH3CN (10 mL) were added 0.27
mL (1.92 mmol) of NEt3 and 0.12 mL (0.96 mmol) of benzoyl
chloride. After 3 h at room temperature, the mixture was
washed with water, extracted with chloroform and purified
by chromatography (Et2O/petroleum ether/absolute EtOH/
CHCl3/NH4OH 180/450/45/180/2.5) to give 0.21 g (70% yield)
of the desired product.
4-Acet yl-1-(4-flu or ob en zen esu lfon yl)-3-m et h ylp ip er -
a zin e (33). Starting from 37 and acetyl chloride, the title
compound was obtained following the procedure described for
32 (method A): yield 86%; mp 98-100 °C from petroleum ether;
IR ν 1650 (CON), 1350,1160 (SO2); 1H NMR (mixture of
conformers) (CDCl3) δ 1.28 (d) and 1.39 (d) (J ) 6.0 Hz, 3H,
3-CH3), 2.03 (s, 3H, CH3CO), 2.22-2.40 (m, 2H, CH), 2.93-
3.05 (m) and 4.83-4.93 (m) (1H, CH), 3.57-3.76 (m, 3H, CH),
3.98-4.12 (m) and 4.43-4.55 (m) (1H, CH), 7.18-7.27 (m, J H-F
) 8.4 Hz, 2H, aromatics), 7.70-7.78 (m, J H-F ) 5.1 Hz, 2H,
aromatics); 13C NMR (CDCl3) 15.41 (q), 16.49 (q), 21.60 (q),
22.06 (q), 35.84 (t), 41.22 (t), 43.87 (t), 46.42 (t), 49.43 (d), 50.78
(d), 116.68 (d, J C-F ) 21.9 Hz), 130.68 (d, J C-F ) 9.1 Hz), 131.89
(d, J C-F ) 2.7 Hz), 165.69 (d, J C-F ) 255.5 Hz), 169.10 (s). Anal.
(C13H17FN2O3S) C, H, N.
Meth od B: A solution of 0.21 g (0.81 mmol) of 1-(4-fluoro-
benzenesulfonyl)-2-methylpiperazine (43) in CHCl3 (15 mL)
was heated at 50 °C and added with 0.08 g (0.81 mmol) acetic
anhydride in CHCl3 (5 mL). At the end of the addition the
mixture was cooled, made alkaline by NaHCO3 (solution in
water) and extracted. After drying over sodium sulfate, the
solvent was evaporated and purified by chromatography with
Et2O/petroleum ether/absolute EtOH/CHCl3/NH4OH 180/450/
45/180/2.5 as eluent (53% yield). Compound 35 and its isomer
33 show different Rf using NH4OH/Et2O/petroleum ether/
absolute EtOH/CH2Cl2 9.9/360/900/180/360 as eluent (Rf ) 0.53
for 33 and 0.44 for 35).
4-Ben zyl-1-(4-flu or ob en zen esu lfon yl)-2-m et h ylp ip er -
a zin e (41). To a solution of 0.3 g (1.58 mmol) of 1-benzyl-3-
methylpiperazine, obtained as reported in the literature13 and
0.32 g (3.16 mmol) of triethylamine in 10 mL of CH3CN was
added 0.31 g (1.58 mmol) of 4-fluorobenzenesulfonyl chloride
at 0 °C and the mixture was allowed to warm to room
temperature. Then water was added and the mixture was
extracted with Et2O obtaining, in 63% yield, the desired
product that was used as such in the following reaction: 1H
NMR (CDCl3) δ 1.17 (d, J ) 7.8 Hz, 3H, 2-CH3), 1.97-2.20