108 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 1
Biswas et al.
Ar-N(CH2)2), 6.85–6.88 (t, 1H, J ) 7.6 Hz, Ar-H), 6.92–6.94 (d,
J ) 7.6 Hz, Ar-H), 7.25–7.29 (m, 2H, Ar-H).
mmol), NaCNBH3 (0.57 g, 9.12 mmol), and HOAc (0.14 mL) in
1,2-dichloroethane (20 mL) to yield compound 3c (1.42 g, 55%)
(procedure C): 1H NMR (400 MHz, CDCl3) δ 1.60–1.75 (m, 1H),
1.76–1.86 (m, 2H), 2.03–2.06 (m, 2H), 2.46–2.51 (m, 2H),
2.56–2.70 (m, 5H), 2.74–2.84 (m, 4H), 2.94–3.02 (m, 1H),
3.10–3.21 (m, 4H), 3.73–3.74 (m, 3H, -OCH3), 6.58-6.68 (m,
2H), 6.86–7.0 (m, 4H), 7.25–7.29 (m, 2H).
Synthesis of 4-(4-Phenylpiperazin-1-yl)butanenitrile (1c). 1-Phe-
nylpiperazine (12 g, 73.96 mmol) was treated with chlorobutyroni-
trile (21.28 mL, 221.89 mmol) (procedure A) to afford 1c (12.8 g,
75.6%): 1H NMR (400 MHz, CDCl3) δ 1.83–1.89 (q, 2H, J ) 6.8
Hz, CH2CH2CH2CN), 2.43–2.47 (t, 2H, J ) 7.2, N-CH2CH2-
CH2CN), 2.49–2.53 (t, 2H, J ) 7.2 Hz, CH2CH2CH2CN), 2.59–2.61
(t, 4H, J ) 4.8 Hz, CH2N(CH2)2), 3.19 (t, 4H, J ) 4.8 Hz, Ar-
N(CH2)2), 6.85–6.88 (t, 1H, J ) 7.6 Hz, Ar-H), 6.92–6.94 (d, J )
7.6 Hz, Ar-H), 7.25–7.29 (m, 2H, Ar-H).
Synthesis of 7-Methoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3d). Compound 2a (0.81
g, 3.95 mmol) was reacted with 7-methoxy-2-tetralone (0.73 g, 4.14
mmol), NaCNBH3 (0.99 g, 15.78 mmol), and HOAc (0.26 mL) in
1,2-dichloroethane (30 mL) to yield 3d (1.0 g, 69.44%) (procedure
Procedure B. Synthesis of 2-(4-Phenylpiperazin-1-yl)ethyl-
amine (2a). A solution of compound 1a in methanol (12.5 g, 62.1
mmol) was hydrogenated in a Parr hydrogenator apparatus in the
presence of Raney nickel catalyst at a pressure of 60 psi for 12 h.
The reaction mixture was passed through Celite, dried over Na2SO4,
evaporated, and purified over a silica gel column using the solvent
system ethyl acetate/methanol/triethylamine (80:15:5) to afford
1
C): H NMR (400 MHz, CDCl3) δ 1.60–1.68 (m, 2H), 2.60–2.63
(m, 6H, CH2N(CH2)2), 2.76–3.04 (m, 7H), 3.16–3.20 (t, J ) 4.8
Hz, N(CH2)2), 3.77 (s, 3H, OCH3), 6.62–6.71 (m, 2H, Ar-H),
6.64–7.02 (m, 4H, Ar-H), 7.24–7.30 (m, 2H, Ar-H).
Synthesis of 6,7-Dimethoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3e). 6,7-Dimethoxy-2-
tetralone was prepared from 2-(3,4-dimethoxyphenyl) acetic acid
by following a previously described procedure.51 Compound 2a
(0.358 g, 1.75 mmol) was reacted with 6,7-dimethoxy-2-tetralone
(0.3 g, 1.46 mmol), sodium triacetoxyborohydride (Na(OAc)3BH)
(0.925 g, 4.37 mmol), and HOAc (0.5 mL) in 1,2-dichloroethane
(30 mL) (procedure C). The crude product was purified by flash
chromatography (EtOAc/MeOH/Et3N ) 80:15:5) to yield com-
pound 3e (0.53 g, 92%): 1H NMR (400 MHz, CDCl3) δ 1.58–1.68
(m, 2H), 2.58–2.65 (m, 6H), 2.74–2.98 (m, 7H), 3.16–3.18 (t, J )
4.8 Hz, 4H, N(CH2)2), 3.81 (s, 3H, OCH3), 3.82 (s, 3H, OCH3),
6.56–6.57 (m, 2H, Ar-H), 6.82–6.87 (m, 1H, Ar-H), 6.90–6.92 (m,
2H, Ar-H), 7.23–7.27 (m, 2H, Ar-H).
1
compound 2a (8.9 g, 70%): H NMR (400 MHz, CDCl3) δ 2.48
(t, 2H, J ) 6.4 HZ), 2.69 (t, 4H, J ) 4.8 Hz), 2.89 (t, 2H, J ) 6.4
Hz), 3.14 (t, 4H, J ) 4.8 Hz, Ph-NCH2), 6.82 (t, 1H, J ) 8.0 Hz,
Ar-H), 6.89 (d, 2H, J ) 8.0 Hz, Ar-H), 7.21–7.27 (m, 2H, Ar-H).
Synthesis of 3-(4-Phenylpiperazin-1-yl)propan-1-amine
(2b). Compound 2b was synthesized from compound 1b (12 g,
55.74 mmol) according to procedure B to afford 2b (9.0 g, 74%):
1H NMR (400 MHz, CDCl3) δ 1.76–1.83 (q, 2H, J ) 6.4 Hz),
2.56 (t, 2H, J ) 6.4 Hz), 2.65 (t, 2H, J ) 5.2 Hz), 2.96 (t, J ) 6.0
Hz), 3.19 (t, 4H, J ) 5.2 Hz, Ph-NCH2), 6.86 (t, 1H, J ) 7.2 Hz,
Ar-H), 6.90–6.92 (d, 2H, J ) 8.4 Hz, Ar-H), 7.24–7.27 (m, 2H,
Ar-H).
Synthesis of 4-(4-Phenylpiperazin-1-yl)butan-1-amine (2c).
Compound 2c was synthesized from compound 1c (12 g, 52.33
mmol) according to procedure B to afford 2c (9.2 g, 75%): 1H
NMR (400 MHz, CDCl3) δ 1.45–1.61 (m, 4H), 2.39–2.42 (t, 2H,
J ) 7.2 Hz, NCH2), 2.59–2.62 (t, 4H, J ) 4.5 Hz, CH2N(CH2)2),
2.70–2.74 (t, 2H, CH2NH2), 3.19–3.22 (t, 4H, J ) 4.6 Hz, Ar-
N(CH2)2), 6.83–6.87 (t, 1H, J ) 7.2 Hz, Ar-H), 6.92–6.94 (d, J )
7.6 Hz, Ar-H), 7.24–7.28 (m, 2H, Ar-H).
Synthesis of 6,7-Dimethoxy-N-[4-(4-phenylpiperazin-1-yl)bu-
tyl]-1,2,3,4-tetrahydronaphthalen-2-amine (3f). Compound 2c
(0.340 g, 1.46 mmol) was reacted with 6,7-dimethoxy-2-tetralone
(0. 250 g, 1.21 mmol), Na(OAc)3BH (0.771 g, 3.64 mmol), and
HOAc (0.5 mL) in 1,2-dichloroethane (20 mL) (procedure C) to
furnish 3f (0.467 g, 91%): 1H NMR (400 MHz, CDCl3) 1.65 (br s,
6H), 2.44–2.48 (m, 2H), 2.63–2.65 (m, 4H), 2.76–2.81 (m, 4H),
2.99–3.01 (m, 2H), 3.19–3.22 (t, J ) 4.8 Hz, 4H, N(CH2)2), 3.82
(s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.55–6.57 (m, 2H, Ar-H),
6.84–6.87 (m, 1H, Ar-H), 6.91–6.93 (m, 2H, Ar-H), 7.24–7.28 (m,
2H, Ar-H).
Procedure D. Synthesis of N-(5-Methoxy-1,2,3,4-tetrahy-
dronaphthalen-2-yl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]propi-
onamide (4a). Propionyl chloride (0.49 mL, 5.75 mmol) was added
into a solution of compound 3a (0.70 g, 1.92 mmol) and Et3N (2.0
mL) in anhydrous methylene chloride at 0 °C under N2 atmosphere
and then stirred at room temperature for 4 h. The reaction was
diluted with CH2Cl2 and washed with water and brine, and the
organic layer was dried over Na2SO4, evaporated, and purified by
flash chromatography (EtOAc/MeOH/Et3N ) 95:4:1) to yield 4a
(0.4 g, 59.5%): 1H NMR (400 MHz, CDCl3) δ 1.13–1.17 (t, 3H, J
) 7.2 Hz, -NCOCH2CH3), 1.85–2.04 (m, 2H), 2.36–2.46(m, 2H),
2.59–2.68 (m, 7H), 2.78–2.88 (td, 1H, J1 ) 16.6 Hz, J2 ) 4.0 Hz),
2.97–3.06 (m, 2H), 3.20 (t, 4H, J ) 4.8 Hz, Ar-N(CH2)2), 3.41–3.55
(m, 2H), 3.81–3.82 (d, 3H, J ) 5.6 Hz, -OCH3), 3.98–4.03 (m,
1H, -NCH), 6.65–6.71 (m, 2H), 6.82–6.93 (m, 3H), 7.07–7.15 (m,
1H), 7.23–7.28 (m, 2H).
Synthesis of N-(6-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-[2-(4-phenylpiperazin-1-yl)ethyl]propionamide (4b). Com-
pound 3b (0.29 g, 0.79 mmol) was reacted with propionyl chloride
(0.21 mL, 2.38 mmol) and Et3N (1.0 mL) in CH2Cl2 (10 mL)
(procedure D). The crude product was purified by flash chroma-
tography using solvent system EtOAc/MeOH ) 90:10 to yield pure
compound 4b (0.4 g, 90.64%): 1H NMR (400 MHz, CDCl3) δ
1.14–1.18 (t, 3H, J ) 7.6 Hz, -NCOCH2CH3), 1.93–2.00 (m, 2H),
2.39–2.45 (m, 2H), 2.56–2.99 (m, 10H), 3.19–3.26 (m, 4H, Ar-
N(CH2)2), 3.40–3.54 (m, 2H), 3.77–3.28 (d, 3H, J ) 4.8 Hz,
-OCH3), 4.01–4.05 (m, 1H, -NCH), 6.63–6.74 (m, 2H, Ar-H),
6.85–7.01 (m, 3H, Ar-H), 7.25–7.29 (m, 3H, Ar-H).
Procedure C. Synthesis of 5-Methoxy-N-[2-(4-phenylpiper-
azin-1-yl)ethyl]-1,2,3,4-tetrahydronaphthalen-2-amine (3a). A
mixture of compound 2a (0.4 g, 1.95 mmol), 5-methoxy-2-tetralone
(0.38 g, 2.14 mmol), and glacial acetic acid (HOAc) (0.14 mL) in
1,2-dichloroethane (20 mL) was stirred at room temperature under
N2 atmosphere for 20 min. Sodium cyanoborohydride (NaCNBH3)
(0.49 g, 7.79 mmol) dissolved in a minimum volume of methanol
was added to the reaction mixture. The reaction mixture was stirred
at room temperature under nitrogen atmosphere for 12 h. The
solvent was evaporated, and saturated NaHCO3/H2O (20 mL) was
added to the mixture, which was then extracted with ethyl acetate
(3 × 100 mL). The combined organic phase was dried over Na2SO4
and evaporated to afford the crude product, which was purified by
flash chromatography (EtOAc/MeOH/Et3N ) 95:4:1) to give the
product 3a (0.65 g, 91.3%): 1H NMR (400 MHz, CDCl3) δ
1.73–1.83 (m, 1H), 2.02–2.09 (m, 1H), 2.23 (m, 1H), 2.6–2.78 (m,
5H), 2.87–3.22 (m, 7H), 3.31–3.33 (m, 1H), 3.76 (s, 2H), 3.8 (s,
3H, -OCH3), 4.05–4.15 (m, 1H, -NH-CH), 6.65–6.71 (m, 3H),
6.84–6.90 (m, 2H), 7.08–7.13 (td, 1H, J1 ) 7.8 Hz, J2 ) 2.8 Hz),
7.26 (t, 2H, J ) 7.2 Hz).
Synthesis of 6-Methoxy-N-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3b). Compound 2a (0.28
g, 1.37mmol) was reacted with 6-methoxy-2-tetralone (0.27 g, 1.50
mmol), NaCNBH3 (0.34 g, 5.47mmol), and HOAc (0.09 mL) in
1,2-dichloroethane (20 mL) to yield 3b (0.45 g, 90%) (procedure
1
C): H NMR (400 MHz, CDCl3) δ 1.72–1.84 (m, 1H), 2.02–2.08
(m, 1H), 2.23 (m, 1H), 2.6–2.78 (m, 5H), 2.87–3.25 (m, 7H),
3.31–3.33 (m, 1H), 3.76 (s, 2H), 3.8 (s, 3H, -OCH3), 4.05–4.15
(m, 1H, -NH-CH), 6.63–6.74 (m, 2H), 6.85–7.01 (m, 3H),
7.25–7.29 (m, 3H).
Synthesis of 7-Methoxy-N-[3-(4-phenylpiperazin-1-yl)propyl]-
1,2,3,4-tetrahydronaphthalen-2-amine (3c). Compound 2b (0.50
g, 2.28 mmol) was reacted with 7-methoxy-2-tetralone (0.44 g, 2.51
Synthesis of N-(7-Methoxy-1,2,3,4-tetrahydronaphthalen-2-
yl)-N-[3-(4-phenylpiperazin-1-yl)propyl]propionamide (4c). Com-