Synthesis of a New Model of Arylpiperazines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4447
(C4-phenyl), 124.5 (C5-phenyl), 138.4 (C1-phenyl), 152.0 (C2-
phenyl), 153.8 (C3), 173.3 (C1). Anal. (C21H30N4O3‚2HCl‚3H2O)
C, H, N.
212 °C (ethanol); IR (KBr, cm-1) 1760 (CON), 1700 (NCON),
1600, 1500, 1470 (Ar); 1H-NMR (Me2SO-d6/CF3COOH) δ 1.55-
1.75 (m, 5H, -(CH2)2-, H7), 1.96-2.15 (m, 3H, 2H6, H7), 3.13-
3.33 (m, 7H, CH2-Npip, 2CH2-pip, H5), 3.40 (t, J ) 6.6 Hz, 2H,
NCH2), 3.47-3.58 (m, 3H, H5, CH2-pip), 3.80-3.85 (m, 2H,
CH2-pip), 4.21 (t, J ) 8.0 Hz, 1H, H7a), 6.88 (t, J ) 7.6 Hz, 1H,
H4-phenyl), 7.19 (d, J ) 7.6 Hz, 2H, H2- and H6-phenyl), 7.32
(t, J ) 7.6 Hz, 2H, H3- and H5-phenyl); 13C-NMR (Me2SO-d6/
CF3COOH) δ 21.5 (CH2CH2-Npip), 25.4 (NCH2CH2), 26.8 (C6),
27.1 (C7), 38.0 (NCH2), 45.5 (C5), 47.1 (2CH2-pip), 51.2 (2CH2-
pip), 56.0 (CH2-Npip), 63.6 (C7a), 117.2 (C2- and C6-phenyl),
121.5 (C4-phenyl), 129.7 (C3- and C5-phenyl), 149.8 (C1-phenyl),
161.3 (C3), 174.5 (C1). Anal. (C20H28N4O2‚2HCl) C, H, N.
2-[4-[4-(o-Meth oxyp h en yl)p ip er a zin -1-yl]bu tyl]-1,3-d i-
oxoper h ydr opyr r olo[1,2-c]im idazole (4b): yield 2.5 g (50%);
mp 178-180 °C (ethanol); IR (KBr, cm-1) 1780 (CON), 1720
(NCON), 1625, 1530, 1500 (Ar); 1H-NMR (Me2SO-d6) δ 1.55-
1.84 (m, 5H, -(CH2)2-, H7), 1.96-2.23 (m, 3H, 2H6, H7), 3.11-
3.33 (m, 7H, CH2-Npip, 2CH2-pip, H5), 3.38 (t, J ) 6.6 Hz, 2H,
NCH2), 3.43-3.52 (m, 5H, H5, 2CH2-pip), 3.81 (s, 3H, OCH3),
4.20 (t, J ) 8.7 Hz, 1H, H7a), 6.91-7.10 (m, 4H, H3-, H4-, H5-,
and H6-phenyl); 13C-NMR (Me2SO-d6) δ 20.4 (CH2CH2-Npip),
24.9 (NCH2CH2), 26.8 (C6, C7), 37.7 (NCH2), 45.3 (C5), 47.1
(2CH2-pip), 50.9 (2CH2-pip), 55.0 (CH2-Npip), 55.6 (OCH3), 63.0
(C7a), 112.3 (C6-phenyl), 118.8 (C3-phenyl), 121.0 (C4-phenyl),
124.4 (C5-phenyl), 138.5 (C1-phenyl), 152.0 (C2-phenyl), 160.5
(C3), 174.1 (C1). Anal. (C21H30N4O3‚2HCl) C, H, N.
2-[4-[4-(m -Ch lor op h en yl)p ip er a zin -1-yl]b u t yl]-1,3-d i-
oxoper h ydr opyr r olo[1,2-c]im idazole (4c): yield 1.8 g (35%);
mp 192-194 °C (ethanol); IR (KBr, cm-1) 1770 (CON), 1710
(NCON), 1610, 1480 (Ar); 1H-NMR (Me2SO-d6/CF3COOH) δ
1.58-1.88 (m, 5H, -(CH2)2-, H7), 2.02-2.13 (m, 3H, 2H6, H7),
3.16-3.38 (m, 6H, CH2-Npip, 2CH2-pip), 3.40-3.56 (m, 5H,
H5, NCH2, CH2-pip), 3.60 (br t, 2H, CH2-pip), 3.82-3.87 (m,
1H, H5), 4.14 (t, J ) 8.1 Hz, 1H, H7a), 6.92 (d, J ) 7.8 Hz, 1H,
H6-phenyl), 6.95 (d, J ) 7.8 Hz, 1H, H4-phenyl), 7.08 (s, 1H,
H2-phenyl), 7.27 (t, J ) 7.8 Hz, 1H, H5-phenyl); 13C-NMR (Me2-
SO-d6/CF3COOH) δ 22.9 (CH2CH2-Npip), 27.1 (NCH2CH2), 28.8
(C6), 29.2 (C7), 37.6 (NCH2), 47.5 (C5), 48.2 (2CH2-pip), 53.3
(2CH2-pip), 58.1 (CH2-Npip), 65.4 (C7a), 117.2 (C6-phenyl),
118.7 (C2-phenyl), 123.2 (C4-phenyl), 132.9 (C5-phenyl), 136.9
(C3-phenyl), 152.5 (C1-phenyl), 163.0 (C3), 176.4 (C1). Anal.
(C20H27ClN4O2‚2HCl) C, H, N.
2-[3-[4-(m -Ch lor op h en yl)p ip er a zin -1-yl]p r op yl]-1,3-d i-
oxop er h yd r oim id a zo[1,5-a ]p yr id in e (3i): yield 1.6 g (31%);
mp 173-175 °C (ethanol/ethyl acetate); IR (KBr, cm-1) 1755
(CON), 1700 (NCON), 1595, 1500 (Ar); 1H-NMR (Me2SO-d6) δ
1.26-1.55 (m, 3H, H6ax, H7ax, H8ax), 1.63-1.68 (m, 1H, H6eq),
1.81-1.86 (m, 1H, H7eq), 1.98-2.07 (m, 3H, H8eq, -CH2-), 2.83
(td, J ) 12.6, 3.0 Hz, 1H, H5ax), 3.12 (m, 4H, CH2-Npip, CH2-
pip), 3.24 (t, J ) 12.3 Hz, 2H, CH2-pip), 3.44 (t, J ) 6.6 Hz,
2H, NCH2), 3.49-3.53 (m, 2H, CH2-pip), 3.86-4.00 (m, 4H,
CH2-pip, H5eq, H8a), 6.93 (d, J ) 7.8 Hz, 1H, H6-phenyl), 6.97
(d, J ) 8.4 Hz, 1H, H4-phenyl), 7.06 (s, 1H, H2-phenyl), 7.27
(t, J ) 8.1 Hz, 1H, H5-phenyl); 13C-NMR (Me2SO-d6) δ 22.3
(C7), 22.7 (-CH2-), 24.7 (C6), 27.1 (C8), 35.5 (NCH2), 38.9 (C5),
45.0 (2CH2-pip), 50.4 (2CH2-pip), 53.1 (CH2-Npip), 56.7 (C8a),
114.4 (C6-phenyl), 115.5 (C2-phenyl), 119.4 (C4-phenyl), 130.8
(C5-phenyl), 134.1 (C3-phenyl), 151.0 (C1-phenyl), 153.9 (C3),
173.3 (C1). Anal. (C20H27ClN4O2‚2HCl) C, H, N.
2-[3-[4-[m-(Tr iflu or om eth yl)p h en yl]piper a zin -1-yl]p r o-
p yl]-1,3-d ioxop er h yd r oim id a zo[1,5-a ]p yr id in e (3j): yield
1.2 g (20%); mp 206-208 °C (ethanol/ethyl acetate); IR (KBr,
1
cm-1) 1760 (CON), 1710 (NCON), 1650, 1605, 1465 (Ar); H-
NMR (Me2SO-d6) δ 1.26-1.51 (m, 3H, H6ax, H7ax, H8ax), 1.63-
1.68 (m, 1H, H6eq), 1.82-1.87 (m, 1H, H7eq), 1.97-2.09 (m, 3H,
H8eq, -CH2-), 2.84 (td, J ) 12.6, 3.3 Hz, 1H, H5ax), 3.12-3.14
(m, 4H, CH2-Npip, CH2-pip), 3.30 (t, J ) 12.0 Hz, 2H, CH2-
pip), 3.45 (t, J ) 6.6 Hz, 2H, NCH2), 3.51-3.55 (m, 2H, CH2-
pip), 3.93-4.00 (m, 4H, CH2-pip, H5eq, H8a), 7.16 (d, J ) 7.5
Hz, 1H, H6-phenyl), 7.27 (s, 1H, H2-phenyl), 7.30 (d, J ) 8.4
Hz, 1H, H4-phenyl), 7.48 (t, J ) 8.1 Hz, 1H, H5-phenyl); 13C-
NMR (Me2SO-d6) δ 22.3 (C7), 22.7 (-CH2-), 24.8 (C6), 27.1 (C8),
35.5 (NCH2), 38.9 (C5), 45.0 (2CH2-pip), 50.5 (2CH2-pip), 53.1
3
(CH2-Npip), 56.8 (C8a), 111.9 (q, J C-F ) 4.0 Hz, C2-phenyl),
3
115.9 (q, J C-F ) 5.0 Hz, C4-phenyl), 119.5 (C6-phenyl), 124.8
1
2
(q, J C-F ) 263.7 Hz, CF3), 130.2 (q, J C-F ) 32.2 Hz,
C3-phenyl), 130.4 (C5-phenyl), 150.1 (C1-phenyl), 153.9 (C3),
173.3 (C1). Anal. (C21H27F3N4O2‚2HCl‚4H2O) C, H, N.
2-[3-[4-(p-F lu or op h en yl)p ip er a zin -1-yl]p r op yl]-1,3-d i-
oxoper h ydr oim idazo[1,5-a ]pyr idin e (3k): yield 1.1 g (23%);
mp 205-207 °C (ethanol/ethyl acetate); IR (KBr, cm-1) 1750
1
(CON), 1700 (NCON), 1615, 1510, 1485 (Ar); H-NMR (Me2-
SO-d6) δ 1.25-1.50 (m, 3H, H6ax, H7ax, H8ax), 1.63-1.68 (m, 1H,
H6eq), 1.81-1.87 (m, 1H, H7eq), 1.97-2.05 (m, 3H, H8eq, -CH2-),
2.83 (td, J ) 12.6, 3.0 Hz, 1H, H5ax), 3.12-3.19 (m, 4H, CH2-
Npip, CH2-pip), 3.44 (t, J ) 7.0 Hz, 2H, NCH2), 3.51-3.53 (m,
2H, CH2-pip), 3.70-3.73 (m, 4H, 2CH2-pip), 3.91-3.99 (m, 2H,
2-[4-[4-[m -(Tr iflu or om eth yl)p h en yl]p ip er a zin -1-yl]bu -
tyl]-1,3-d ioxop er h yd r op yr r olo[1,2-c]im id a zole (4d ): yield
2.6 g (48%); mp 176-178 °C (ethanol); IR (KBr, cm-1) 1775
1
(CON), 1710 (NCON), 1610, 1500, 1470 (Ar); H-NMR (CD3-
OD) δ 1.71-1.83 (m, 5H, -(CH2)2-, H7), 2.07-2.24 (m, 3H,
2H6, H7), 3.20-3.32 (m, 7H, CH2-Npip, 2CH2-pip, H5), 3.53 (br
t, 2H, NCH2), 3.57-3.71 (m, 3H, H5, CH2-pip), 3.92-3.95 (m,
2H, CH2-pip), 4.21 (t, J ) 7.8 Hz, 1H, H7a), 7.20 (d, J ) 7.5
Hz, 1H, H6-phenyl), 7.29 (m, 2H, H2- and H4-phenyl), 7.47 (t,
J ) 7.5 Hz, 1H, H5-phenyl); 13C-NMR (CD3OD) δ 22.2 (CH2-
CH2-Npip), 26.2 (NCH2CH2), 28.1 (C6), 28.3 (C7), 38.8 (NCH2),
46.5 (C5), 47.6 (2CH2-pip), 52.9 (2CH2-pip), 57.4 (CH2-Npip),
64.8 (C7a), 114.1 (q, 3J C-F ) 4.0 Hz, C2-phenyl), 118.6 (q, 3J C-F
) 4.0 Hz, C4-phenyl), 121.3 (C6-phenyl), 125.6 (q, 1J C-F ) 271.9
4
H5eq, H8a), 7.02 (dd, J ) 9.2 Hz, J H-F ) 3.0 Hz, 2H, H2- and
3
H6-phenyl), 7.10 (t, J ) 9.2 Hz, J H-F ) 9.2 Hz, 2H, H3- and
H5-phenyl); 13C-NMR (Me2SO-d6) δ 22.3 (C7), 22.6 (-CH2-), 24.7
(C6), 27.1 (C8), 35.4 (NCH2), 38.8 (C5), 46.2 (2CH2-pip), 50.6
2
(2CH2-pip), 53.0 (CH2-Npip), 56.7 (C8a), 115.6 (d, J C-F ) 22.2
3
Hz, C3- and C5-phenyl), 117.9 (d, J C-F ) 7.1 Hz, C2- and C6-
1
phenyl), 146.6 (C1-phenyl), 153.8 (C3), 156.6 (d, J C-F ) 236.7
Hz, C4-phenyl), 173.2 (C1). Anal. (C20H27FN4O2‚2HCl) C, H,
N.
2
2-[3-[4-(p-Nitr op h en yl)p ip er a zin -1-yl]p r op yl]-1,3-d iox-
op er h yd r oim id a zo[1,5-a ]p yr id in e (3l): yield 1.0 g (20%);
mp 118-120 °C (ethanol/ethyl acetate); IR (KBr, cm-1) 1765
(CON), 1700 (NCON), 1600 (Ar); 1H-NMR (CDCl3) δ 1.22-1.51
(m, 3H, H6ax, H7ax, H8ax), 1.67-1.72 (m, 1H, H6eq), 1.92-1.98
(m, 1H, H7eq), 2.06-2.10 (m, 1H, H8eq), 2.24 (qt, J ) 7.2 Hz,
2H, -CH2-), 2.80 (td, J ) 12.6, 3.3 Hz, 1H, H5ax), 3.16 (t, J )
7.2 Hz, 2H, CH2-Npip), 3.59 (t, J ) 7.2 Hz, 2H, NCH2), 3.59-
3.69 (m, 1H, H8a), 3.75-3.77 (m, 2H, CH2-pip), 3.79-3.81 (m,
2H, CH2-pip), 3.86 (m, 4H, 2CH2-pip), 4.03-4.08 (m, 1H, H5eq),
6.82 (d, J ) 9.3 Hz, 2H, H2- and H6-phenyl), 8.02 (d, J ) 9.3
Hz, 2H, H3- and H5-phenyl); 13C-NMR (CDCl3) δ 22.4 (C7), 22.9
(-CH2-), 24.6 (C6), 27.3 (C8), 35.5 (NCH2), 39.2 (C5), 44.2 (2CH2-
pip), 51.0 (2CH2-pip), 54.6 (CH2-Npip), 57.3 (C8a), 113.7 (C2-
and C6-phenyl), 125.6 (C3- and C5-phenyl), 139.5 (C4-phenyl),
153.2 (C1-phenyl), 153.9 (C3), 173.3 (C1). Anal. (C20H27N5O4‚-
2HCl) C, H, N.
Hz, CF3), 131.3 (C5-phenyl), 132.6 (q, J C-F ) 31.6 Hz,
C3-phenyl), 151.3 (C1-phenyl), 161.3 (C3), 162.4 (C1). Anal.
(C21H27F3N4O2‚2HCl) C, H, N.
2-[4-[4-(p-F lu or op h en yl)p ip er a zin -1-yl]bu tyl]-1,3-d iox-
op er h yd r op yr r olo[1,2-c]im id a zole (4e): yield 1.8 g (35%);
mp 194-196 °C (ethanol); IR (KBr, cm-1) 1780 (CON), 1720
1
(NCON), 1530, 1470 (Ar); H-NMR (CD3OD) δ 1.70-1.92 (m,
5H, -(CH2)2-, H7), 2.09-2.27 (m, 3H, 2H6, H7), 3.27-3.36 (m,
5H, CH2-Npip, CH2-pip, H5), 3.46 (br t, 2H, CH2-pip), 3.57 (t,
J ) 6.9 Hz, 2H, NCH2), 3.65 (dt, J ) 11.1, 7.5 Hz, 1H, H5),
3.78 (m, 4H, 2CH2-pip), 4.25 (dd, J ) 9.4, 7.3 Hz, 1H, H7a),
3
7.16 (t, J ) 8.7 Hz, J H-F ) 8.7 Hz, 2H, H3- and H5-phenyl),
7.28-7.33 (m, 2H, H2- and H6-phenyl); 13C-NMR (CD3OD) δ
23.2 (CH2CH2-Npip), 27.2 (NCH2CH2), 29.1 (C6), 29.3 (C7), 39.8
(NCH2), 47.5 (C5), 50.7 (2CH2-pip), 53.4 (2CH2-pip), 58.4
2
(NCH2), 65.9 (C7a), 118.3 (d, J C-F ) 22.8 Hz, C3- and C5-
3
phenyl), 122.5 (d, J C-F ) 8.0 Hz, C2- and C6-phenyl), 144.6
2-[4-(4-P h en ylpiper a zin -1-yl)bu tyl]-1,3-d ioxoper h yd r o-
p yr r olo[1,2-c]im id a zole (4a ): yield 1.6 g (34%); mp 210-
(C1-phenyl), 161.1 (d, 1J C-F ) 242.3 Hz, C4-phenyl), 162.5 (C3),
176.7 (C1). Anal. (C20H27FN4O2.2HCl‚2H2O) C, H, N.