S. Dei et al. / European Journal of Medicinal Chemistry 147 (2018) 7e20
17
2.60 (bs, 4H, CH2); 2.40 (bs, 4H, CH2); 2.31e2.20 (m, 2H, CH2);
2.19e2.10 (m, 2H, CH2); 1.91 (td, J ¼ 8.0 Hz, J ¼ 4.4 Hz, 1H, CHH);
1.60e1.53 (m, 1H, CHH); 1.22 (d, J ¼ 6.7 Hz, 3H, CH3); 1.18e1.12 (m,
1H, CH); 0.79 (d, J ¼ 6.7 Hz, 3H, CH3) ppm. 13C NMR (CDCl3):
(CH arom.); 109.58 (CH arom.); 103.35 (CH arom.); 60.88 (OCH3);
60.88 (CH2); 57.92 (CH2); 56.03 (OCH3); 56.01 (OCH3); 55.99
(OCH3); 55.90 (OCH3); 53.37 (C); 53.13 (CH2); 53.02 (CH2); 37.84
(CH); 35.68 (CH2); 22.93 (CH2); 18.96 (CH3); 18.59 (CH3) ppm.
Dihydrochloride. Low melting solid. Anal: C32H47Cl2N3O5 (C, H, N).
d
138.00 (C); 129.45 (CH arom.); 128.79 (CH arom.); 127.66 (CH
arom.); 126.36 (CH arom.); 121.17 (CN); 120.90 (CH arom.); 114.58
(CH arom.); 65.53 (CH2); 57.54 (C); 56.97 (C); 53.68 (CH2); 52.97
(CH2N); 52.95 (CH2); 37.74 (CH); 35.34 (CH2); 22.52 (CH2); 18.95
(CH3); 18.61 (CH3) ppm. Dihydrochloride. Mp: 208e212 ꢀC. Anal:
C26H37Cl2N3O (C, H, N).
5.1.4.7. 2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-{4-[2-(3,4,5-
trimethoxyphenoxy)ethyl]piperazin-1-yl}-pentanenitrile
base: chromatographic eluent: CH2Cl2/MeOH/NH4OH 95:5:0.5.
Yield: 80%. IR (neat):
2233 (CN), cmꢁ1.1H NMR (CDCl3):
6.94e6.87 (m, 1H, arom.); 6.86e6.78 (m, 2H, arom.); 6.14 (s, 2H,
7. Free
n
d
5.1.4.3. 1-(4,4-Diphenylbutyl)-4-(2-phenoxyethyl)piperazine
3.
arom.); 4.02 (t, J ¼ 6.0 Hz, 2H, OCH2); 3.87 (s, 3H, OCH3); 3.86 (s, 3H,
OCH3); 3.81 (s, 6H, OCH3); 3.76 (s, 3H, OCH3); 2.75 (t, J ¼ 6.0 Hz, 2H,
CH2); 2.55 (bs, 4H, CH2); 2.37 (bs, 4H, CH2); 2.27 (t, J ¼ 7.2 Hz, 2H,
CH2); 2.14e1.77 (m, 4H, CH2); 1.54e1.23 (m, 1H, CH); 1.15 (d,
J ¼ 3.4 Hz, 3H, CH3); 0.77 (d, J ¼ 3.4 Hz, 3H, CH3) ppm. 13C NMR
Free base: chromatographic eluent: abs. EtOH./NH4OH/CH2Cl2/
ethyl ether/petroleum ether 180:9.9:360:360: 900. Mp: 75e77 ꢀC.
Yield: 50%. 1H NMR (CDCl3):
d 7.32e7.26 (m, 10H, arom.); 7.21e7.17
(m, 2H arom.); 6.99e6.92 (m, 3H arom.); 4.13 (t, J ¼ 5.9 Hz, 2H,
CH2O); 3.93 (t, J ¼ 7.8 Hz, 1H, CH); 2.84 (t, J ¼ 5.9 Hz, 2H, CH2); 2.63
(bs, 4H, CH2); 2.48 (bs, 4H, CH2); 2.40 (t, J ¼ 7.5 Hz, 2H, CH2); 2.10 (q,
J ¼ 7.8 Hz, 2H, CH2); 1.52e1.47 (m, 2H, CH2) ppm. 13C NMR (CDCl3):
(CDCl3): d 155.38 (C); 153.67 (C); 149.02 (C); 148.30 (C); 130.65 (C);
121.37 (CN); 118.71 (CH arom.); 111.12 (CH arom.); 109.53 (CH
arom.); 92.36 (CH arom.); 66.15 (OCH2); 61.01 (OCH3); 57.93
(CH2N); 57.21 (NCH2); 56.08 (OCH3); 55.99 (OCH3); 53.59 (CH2);
53.38 (CCN); 52.99 (CH2); 37.86 (CH); 35.76 (CH2); 22.95 (CH2);
18.97 (CH3); 18.61 (CH3) ppm. Dihydrochloride. Mp: 90e92 ꢀC.
Anal: C31H47Cl2N3O6 (C, H, N).
d
158.77 (C); 145.04 (C); 129.45 (CH arom.); 128.44 (CH arom.);
127.86 (CH arom.); 126.12 (CH arom.); 120.80 (CH arom.); 114.62
(CH arom.); 65.79 (CH2); 58.55 (CH2); 57.25 (CH2); 53.62 (CH2N);
53.14 (CH2N); 51.36 (CH); 33.61 (CH2); 25.38 (CH2) ppm. Anal:
C
28H34N2O (C, H, N).
5.1.4.8. 1-[4,4-Bis-(4-methoxyphenyl)-butyl]-4-[2-(3,4,5-
trimethoxyphenoxy)ethyl]piperazine 8. Free base: chromatographic
eluent: CH2Cl2/MeOH/NH4OH 95:5:0.5. Yield: 73%. 1H NMR
5.1.4.4. 1-Cinnamyl-4-(4,4-diphenylbutyl)piperazine 4. Free base:
chromatographic eluent: CHCl3/MeOH 95:5. Mp: 105e107 ꢀC.
Yield: 56%. 1H NMR (CDCl3):
d
7.42e7.38 (m, 2H arom.); 7.37e7.26
(CDCl3):
d
7.14 (d, J ¼ 4.4 Hz, 4H, arom.); 6.80 (d, J ¼ 4.4 Hz, 4H,
(m, 11H arom.); 7.22e7.18 (m, 2H arom.); 6.58e6.56 (d, J ¼ 15.9 Hz,
1H, CH¼CH); 6.35e6.28 (m, 1H, CH¼CH); 3.94 (t, J ¼ 7.8 Hz, 1H, CH);
3.19 (d, J ¼ 6.8 Hz, 2H, CH2); 2.50 (bs, 6H, CH2); 2.41 (t, J ¼ 7.5 Hz, 4H,
arom.); 6.15 (s, 2H, arom.); 4.05 (t, J ¼ 7.6 Hz, 2H, OCH2); 3.82 (s, 7H,
CH and OCH3); 3.78 (s, 3H, OCH3); 3.75 (s, 6H, OCH3); 2.78 (t,
J ¼ 6.8 Hz, 2H, CH2); 2.58 (bs, 4H, CH2); 2.44 (bs, 4H, CH2); 2.35 (t,
J ¼ 6.8 Hz, 2H, CH2); 2.04e1.92 (m, 2H, CH2); 1.52e1.48 (m, 2H,
CH2); 2.10 (q, J ¼ 7.8 Hz, 2H, CH2); 1.55e1.47 (m, 2H, CH2) ppm. 13
C
NMR (CDCl3):
d
145.04 (C); 136.96 (C); 133.08 (CH); 128.57 (CH
CH2) ppm. 13C NMR (CDCl3): d 157.81 (C); 155.42 (C); 153.68 (C);
arom.); 128.43 (CH arom.); 127.86 (CH arom.); 127.49 (CH); 126.59
(CH arom.); 126.33 (CH arom.); 126.11 (CH arom.); 61.08 (CH2);
58.56 (CH2); 53.19 (CH2N); 51.36 (CH); 33.63 (CH2); 25.40 (CH2)
ppm. Anal: C29H34N2 (C, H, N).
137.60 (C); 128.62 (CH arom.); 113.79 (CH arom.); 92.39 (CH arom.);
66.15 (OCH2); 61.02 (OCH3); 58.58 (CH2N); 57.25 (CH2N); 56.09
(OCH3); 55.22 (OCH3); 53.66 (CH2); 53.14 (CH2); 49.58 (CH); 33.95
(CH2); 25.42 (CH2) ppm. Dihydrochloride. Mp: 161e163 ꢀC. Anal:
C33H46Cl2N2O6 (C, H, N).
5.1.4.5. 1-(4,4-Bis(4-fluorophenyl)butyl)-4-cinnamylpiperazine
Free base: chromatographic eluent: CHCl3/MeOH 95:5.Yield: 56%.
1H NMR (CDCl3):
7.41e7.37 (m, 2H arom.); 7.35e7.28 (m, 2H
5.
5.1.4.9. (E)-1-[4,4-Bis-(4-methoxyphenyl)butyl]-4-[3-(3,4,5-
trimethoxyphenyl)allyl]piperazine 9. Free base: chromatographic
eluent: CH2Cl2/MeOH/NH4OH 95:5:0.5. Yield: 60%. 1H NMR
d
arom.); 7.26e7.23 (m, 1H arom.); 7.20e7.16 (m, 4H arom.);
7.01e6.96 (m, 4H arom.); 6.54 (d, J ¼ 15.8 Hz, 1H, CH¼CH);
6.33e6.26 (m, 1H, CH¼CH); 3.89 (t, J ¼ 7.7 Hz, 1H, CH); 3.18 (d,
J ¼ 6.8 Hz, 2H, CH2); 2.55e2.48 (bs, 6H, CH2); 2.39 (t, J ¼ 7.4 Hz, 4H,
2CH2); 2.02 (q, J ¼ 7.8 Hz, 2H, CH2); 1.47 (q, J ¼ 8.0 Hz, 2H, CH2) ppm.
(CDCl3):
d
7.12 (d, J ¼ 8.8 Hz, 4H, arom.); 6.84 (d, J ¼ 8.8 Hz, 4H,
arom.); 6.60 (s, 2H, arom.); 6.43 (d, J ¼ 15.6 Hz, 1H, CH¼CH); 6.19
(dt, J ¼ 15.6 Hz, 6.8 Hz, 1H, CH¼CH); 3.85 (s, 6H, OCH3); 3.83 (s, 3H,
OCH3); 3.78e3.82 (m, 1H, CH); 3.75 (s, 6H, OCH3); 3.13 (d,
J ¼ 6.8 Hz, 2H, CH2); 2.47 (bs, 8H, CH2); 2.36 (t, J ¼ 7.6 Hz, 2H, CH2);
2.05e1.93 (m, 2H, CH2); 1.58e1.48 (m, 2H, CH2) ppm. 13C NMR
13C NMR (CDCl3):
d
161.35 (d, J ¼ 243 Hz, CF); 140.53 (C); 136.94 (C);
133.08 (CH); 129.10 (d, J ¼ 7 Hz, CHF); 128.57 (CH arom.); 127.50
(CH); 126.57 (CH arom.); 126.32 (CH arom.); 115.26 (d, CHF,
J ¼ 21 Hz); 61.06 (CH2); 58.45 (CH2); 53.20 (CH2-N); 49.76 (CH);
33.84 (CH2); 25.31 (CH2) ppm. Dihydrochloride. Mp: 244e248 ꢀC.
Anal: C29H34Cl2F2N2 (C, H, N).
(CDCl3):
d
157.81 (C); 133.31 (C); 137.60 (C); 132.88 (C¼C); 132.66
(C); 128.61 (CH arom.); 126.22 (C¼C); 113.78 (CH arom.); 103.34
(CH arom.); 60.96 (OCH3); 60.92 (CH2); 58.59 (CH2); 55.21 (OCH3);
53.24 (OCH3); 53.24 (CH2); 53.19 (CH2); 49.58 (CH); 33.97 (CH2);
25.42 (CH2) ppm. Dihydrochloride. Mp: 101e103 ꢀC. Anal:
C34H46Cl2N2O5 (C, H, N).
5.1.4.6. (E)-2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-{4-[3-(3,4,5-
trimethoxyphenyl)allyl]piperazin-1-yl}pentanenitrile 6. Free base:
chromatographic eluent: CH2Cl2/MeOH/NH4OH 95:5:0.5. Yield:
5.1.4.10. 1-[4,4-Bis(4-methoxyphenyl)butyl]-4-(3,4,5-
trimethoxybenzyl)piperazine 10. Free base: chromatographic
eluent: CH2Cl2/MeOH/NH4OH 97:3:0.3. Yield: 52%. 1H NMR
62%. IR (neat): n d 6.92e6.90 (m,
2233 (CN), cmꢁ1. 1H NMR (CDCl3):
1H, arom.); 6.89 (s, 2H, arom.); 6.59 (s, 2H, arom.); 6.42 (d,
J ¼ 16.0 Hz, 1H, CH¼CH); 6.17 (dt, J ¼ 16.0 Hz, J ¼ 6.8 Hz, 1H,
CH¼CH); 3.91e3.82 (m, 15H, OCH3); 3.12 (d, J ¼ 6.8 Hz, 2H, CH2);
2.65e2.32 (m, 8H, CH2); 2.29 (t, J ¼ 7.2 Hz, 2H, CH2); 2.18e2.02 (m,
2H, CH2); 1.81e1.70 (m, 2H, CH2); 1.49e1.62 (m, 1H, CH); 1.18 (d,
J ¼ 6.4 Hz, 3H, CH3); 0.78 (d, J ¼ 6.8 Hz, 3H, CH3) ppm. 13C NMR
(CDCl3):
d
7.12 (d, J ¼ 8.4 Hz, 4H, arom.); 6.80 (d, J ¼ 8.4 Hz, 4H,
arom.); 6.55 (s, 2H, arom.); 3.85 (s, 6H, OCH3); 3.83 (s, 3H, OCH3);
3.80 (t, J ¼ 8.0 Hz, 1H, CH); 3.75 (s, 6H, OCH3); 3.42 (s, 2H, CH2);
2.44 (bs, 6H, CH2); 2.38e2.29 (m, 4H, CH2); 2.03e1.94 (m, 2H,
CH2); 1.49e1.38 (m, 2H, CH2) ppm. 13C NMR (CDCl3):
d 157.80 (C);
(CDCl3):
d
153.29 (C); 149.03 (C); 148.30 (C); 132.61 (CH); 132.59
153.06 (C); 137.51 (C); 136.87 (C); 134.05 (C); 128.61 (CH arom.);
113.78 (CH arom.); 105.83 (CH arom.); 63.28 (CH2); 60.85 (OCH3);
(C); 130.65 (C); 126.07 (C¼C); 121.35 (C); 118.69 (CH arom.); 111.14