N.A.-E. El-Sayed, et al.
Bioorganic Chemistry 93 (2019) 103312
−
1
(
(
(
υ
max, cm ): 3065 (CH-Ar.), 2920 (CH aliph.), 2203 and 2183
4.1.3.1. 6-Amino-5-(4-phenylpiperazine-1-carbonyl)-2,3-dihydro-1H-
1
2C^N), 1659 (C]O); H NMR (DMSO‑d
6
, 400 MHz): δ 1.98–2.05
pyrrolizine-7-carbonitrile(4a). Yield: 78%; m.p.: 219–221 °C; IR (υmax
,
−
1
m, 2H, CH
2
of pyrrolidine), 2.96–3.00 (m, 4H, CH
2
of pyrrolidine and
of piperazine, J = 4.40 Hz), 3.49
of piperazine,
of pyrrolidine,
C]O), 6.84 (d, 2H, Ar-Hs,
cm ): 3391 and 3333 (NH
2
), 3032 (CH-Ar.), 2978 (CH aliph.), 2222
1
CH
2
of piperazine), 3.06 (t, 2H, 1CH
2
(C^N), 1643 (C]O); H NMR (DMSO‑d
6
, 400 MHz): δ 2.36–2.40 (m,
of pyrrolizine, J = 7.38 Hz),
(
t, 2H, CH
2
of piperazine, J = 4.72 Hz), 3.61 (t, 2H, CH
2
2H, CH
3.17 (t, 4H, CH
piperazine, J = 4.9 Hz), 3.98 (t, 2H, CH
5.00 (s, 2H, NH exchanged with D O), 6.81 (t, 1H, Ar-H, J = 7.24 Hz),
6.97 (d, 2H, Ar-Hs, J = 7.92 Hz), 7.23 (t, 2H, Ar-Hs, J = 7.34 Hz);
NMR (DMSO‑d , 100 MHz): δ 24.96, 25.32, 45.07, 48.51, 49.05, 75.25,
106.12, 116.31, 119.67, 129.44, 141.73, 145.90, 151.38, 162.86 (C]
2
of pyrrolizine), 2.87 (t, 2H, CH
2
J = 4.64 Hz), 3.69 (s, 3H, OCH
3
), 3.72 (t, 2H, CH
2
2
of piperazine, J = 4.74 Hz), 3.57 (t, 4H, CH of
2
J = 7.20 Hz), 4.70 (s, 2H, NeCH
2
2
of pyrrolizine, J = 7.10 Hz),
1
3
J = 9.08 Hz), 6.92 (d, 2H, Ar-Hs, J = 9.08 Hz); C NMR (DMSO‑d
6
,
2
2
1
3
1
5
1
6
00 MHz): δ 19.68, 36.28, 42.21, 43.41, 44.46, 49.41, 49.84, 50.16,
5.65 (OCH ), 59.54, 114.77, 116.51, 118.14, 118.52, 145.52, 153.81,
C
3
6
64.19 (C]O), 172.35 (C]C-2C^N); Anal. Calcd for C20
H
23
N
5
O : C,
2
5.73; H, 6.34; N, 19.16 Found: C, 65.90; H, 6.45; N, 19.43.
O); Anal. Calcd for C19
H
21
N O: C, 68.04; H, 6.31; N, 20.88. Found: C,
5
6
8.04; H, 6.48; N, 21.09.
4
.1.2.5. 2-{1-(2-[4-(4-Chlorobenzyl)piperazin-1-yl]-2-oxoethyl)
4
.1.3.2. 6-Amino-5-[4-(4-fluorophenyl)piperazine-1-carbonyl]-2,3-
pyrrolidin-2-ylidene}malononitrile(3e). Yield: 74%; yellow oil; IR (υmax
,
−
1
dihydro-1H-pyrrolizine-7-carbonitrile(4b). Yield: 85%; m.p.: 227–229 °C;
cm ): 3040 (CH-Ar.), 2947 (CH aliph.), 2203 and 2187 (2C^N), 1670
−1
1
IR (υ , cm ): 3387 and 3333 (NH ), 3051 (CH-Ar.), 2940 (CH
1
(
C]O); H NMR (DMSO‑d
6
, 400 MHz): δ 1.98–2.02 (m, 2H, CH
of piperazine), 2.40 (s, br., 2H, CH
2
2
of
of
max
2
aliph.), 2222 (C^N), 1643 (C]O); H NMR (DMSO‑d
.36–2.40 (m, 2H, CH of pyrrolizine), 2.87 (t, 2H, CH
J = 7.38 Hz), 3.11 (t, 4H, CH of piperazine, J = 4.56 Hz), 3.56 (t, 4H,
CH of piperazine, J = 4.82 Hz), 3.97 (t, 2H, CH of pyrrolizine,
6
, 400 MHz): δ
pyrrolidine), 2.37 (s, br., 2H, CH
2
2
2
2
of pyrrolizine,
piperazine), 2.97 (t, 2H, CH
benzylic CH ), 3.47 (s, br., 4H, CH
pyrrolidine, J = 7.36 Hz), 4.64 (s, 2H, NeCH
2
of pyrrolidine, J = 7.82 Hz), 3.35 (s, 2H,
of piperazine), 3.68 (t, 2H, CH
C]O), 7.34 (d, 2H, Ar-
2
of
2
2
2
2
2
2
1
3
J = 7.08 Hz), 5.00 (s, 2H, NH exchanged with D O), 6.96–6.99 (dd,
Hs, J = 8.40 Hz), 7.39 (d, 2H, Ar-Hs, J = 8.40 Hz); C NMR (DMSO‑d
6
,
2
2
4
1
3
2
H, Ar-Hs,
J
F-H = 4.56 and 6.80 Hz), 7.07 (t, 2H, Ar-Hs,
J
F-
1
5
1
00 MHz): δ 19.67, 36.27, 42.23, 43.39, 44.41, 49.36, 52.19, 52.51,
9.50, 61.30 (benzylic CH ), 116.44, 118.13, 128.65, 131.05, 132.00,
3
H
=
8.86 Hz); C NMR (DMSO‑d
6
, 100 MHz): δ 24.96 , 25.32, 45.09,
2
2
4
8.51, 49.84, 75.26, 106.11, 115.78 ( JF-C = 22.00 Hz), 116.31, 118.14
37.45, 164.11 (C]O), 172.29 (C]C-2C^N); Anal. Calcd for
3
1
(
J
F-C = 7.00 Hz), 141.75, 145.92, 148.28, 156.68 ( JF-C = 234.00 Hz),
C
20
H
22ClN O: C, 62.58; H, 5.78; N, 18.24. Found: C, 62.71; H, 5.99;
5
1
62.86 (C]O); Anal. Calcd for C19
H
20FN O: C, 64.58; H, 5.70; N,
5
N, 18.47.
1
9.82. Found: C, 64.79; H, 5.88; N, 19.74.
4
.1.2.6. 2-{1-(2-[4-(2,5-Dimethoxybenzyl)piperazin-1-yl]-2-oxoethyl)
4
.1.3.3. 6-Amino-5-[4-(4-chlorophenyl)piperazine-1-carbonyl]-2,3-
pyrrolidin-2-ylidene}malononitrile(3f). Yield: 68%; yellow oil; IR (υmax
,
dihydro-1H-pyrrolizine-7-carbonitrile(4c). Yield: 85%; m.p.: 224–226 °C;
−
1
cm ): 3009 (CH-Ar.), 2963 (CH aliph.), 2207 and 2187 (2C^N), 1669
−
1
IR (υmax, cm ): 3445 and 3352 (NH
2
), 3067 (CH-Ar.), 2967 (CH
, 400 MHz): δ
of pyrrolizine,
of piperazine), 3.55 (s, br., 4H, CH
of pyrrolizine, J = 7.02 Hz), 5.00 (s,
O), 6.98 (d, 2H, Ar-Hs, J = 8.92 Hz), 7.25
1
(
C]O); H NMR (DMSO‑d
6
, 400 MHz): δ 1.98–2.01 (m, 2H, CH
2
of
of
1
aliph.), 2207 (C^N), 1645 (C]O); H NMR (DMSO‑d
6
2
pyrrolidine), 2.38–2.39 (m, 4H, CH
2
of piperazine), 2.96 (t, 2H, CH
2
2
.36–2.39 (m, 2H, CH
J = 7.32 Hz), 3.18 (s, br., 4H, CH
of piperazine), 3.97 (t, 2H, CH
H, NH exchanged with D
2
of pyrrolizine), 2.86 (t, 2H, CH
pyrrolidine, J = 7.81 Hz), 3.39 (s, 2H, benzylic CH
2
), 3.46 (s, br., 4H,
2
2
CH
2
of piperazine), 3.70 (s, 5H, CH
H, OCH ), 4.63 (s, 2H, NeCH
.89–6.91 (m, 2H, Ar-Hs); C NMR (DMSO‑d
6.27, 42.30, 43.36, 44.47, 49.34, 50.11, 52.68, 55.72 (OCH
), 59.50, 59.92 (benzylic CH ), 112.36, 112.63, 116.27, 118.15,
27.09, 151.97, 153.50, 164.07 (C]O), 172.29 (C]C-2C^N); Anal.
: C, 64.53; H, 6.65; N, 17.10. Found: C, 64.67; H,
2
2
of pyrrolidine and OCH
C]O), 6.78–6.81 (m, 1H, Ar-H),
, 100 MHz): δ 19.65,
), 56.34
3
), 3.72 (s,
2
3
6
3
3
2
2
2
1
3
6
1
3
(
d, 2H, Ar-Hs, J = 8.84 Hz); C NMR (DMSO‑d
6
, 100 MHz): δ 24.96 ,
3
2
1
5.31, 44.91, 48.51, 48.79, 75.25, 106.08, 116.31, 117.71, 123.13,
(
OCH
3
2
29.13, 141.77, 145.94, 150.17, 162.86 (C]O); Anal. Calcd for
1
C
19
H
20ClN O: C, 61.70; H, 5.45; N, 18.94. Found: C, 61.94; H, 5.63;
5
Calcd for C22
H
27
N O
5 3
N, 19.25.
6
.89; N, 17.27.
4
.1.3.4. 6-Amino-5-[4-(4-methoxyphenyl)piperazine-1-carbonyl]-2,3-
4
1
3
.1.2.7. N-(1-Benzylpiperidin-4-yl)-2-[2-(dicyanomethylene) Pyrrolidin-
dihydro-1H-pyrrolizine-7-carbonitrile(4d). Yield: 79%; m.p.: 233–235 °C;
−1
-yl]acetamide(8). Yield: 68%; m.p.: 159–161 °C; IR (υmax, cm ):
−1
IR (υmax, cm ): 3449 and 3356 (NH
2
), 3076 (CH-Ar.), 2951 (CH
, 400 MHz): δ
of pyrrolizine,
of piperazine), 3.56 (s, br., 4H, CH
), 3.97 (t, 2H, CH of pyrrolizine,
exchanged with D O), 6.83 (d, 2H, Ar-
364 (NH), 3065 (CH-Ar.), 2928 (CH aliph.), 2210 and 2195
1
aliph.), 2203 (C^N), 1645 (C]O); H NMR (DMSO‑d
6
2
1
(
(
2C^N), 1701 (C]O); H NMR (DMSO‑d
6
, 400 MHz): δ 1.37–1.44
2
.34–2.41 (m, 2H, CH
J = 7.30 Hz), 3.03 (s, br., 4H, CH
of piperazine), 3.69 (s, 3H, OCH
J = 7.02 Hz), 4.98 (s, 2H, NH
2
of pyrrolizine), 2.86 (t, 2H, CH
m, 2H, CH
.96–2.04 (m, 4H, CH
m, 2H, CH of piperidine), 2.95 (t, 2H, CH
J = 7.76 Hz), 3.45 (s , 2H, benzylic CH ), 3.57–3.58 (m, 1H, CH of
piperidine), 3.69 (t, 2H, CH of pyrrolidine, J = 7.18 Hz), 4.31 (s, 2H,
NeCH C]O), 7.24–7.34 (m, 5H, Ar-Hs), 8.04 (d, 1H, NH exchanged
2
of piperidine), 1.72–1.74 (m, 2H, CH
of piperidine and CH of pyrrolidine), 2.72–2.75
of pyrrolidine,
2
of piperidine),
2
3
2
1
2
2
2
(
2
2
2
2
13
2
Hs, J = 9.08 Hz), δ 6.92 (d, 2H, Ar-Hs, J = 8.96 Hz);
C NMR
, 100 MHz): 24.96 , 25.32, 45.23, 48.52, 50.54, 55.65
), 75.26, 106.15, 114.73, 116.31, 118.42, 141.71, 145.73,
45.88, 153.68, 162.83 (C]O); Anal. Calcd for C20 : C,
5.73; H, 6.34; N, 19.16. Found: C, 66.02; H, 6.51; N, 19.40.
2
(
(
DMSO‑d
6
2
2
OCH
3
1
3
with D
O); C NMR (DMSO‑d
3.82, 36.40, 43.33, 50.04, 50.11, 52.07, 59.38, 62.31 (benzylic CH
16.16, 116.31, 118.27, 127.51, 128.66, 129.34, 164.99 (C]O),
72.30 (C]C-2C^N); Anal. Calcd for C21 O: C, 69.40; H, 6.93;
6
, 100 MHz): δ 19.62, 21.57, 31.57,
1
6
H
23
N O
5 2
3
1
1
2
),
H N
25 5
4
.1.3.5. 6-Amino-5-[4-(4-chlorobenzyl)piperazine-1-carbonyl]-2,3-
N, 19.27. Found: C, 69.73; H, 6.85; N, 19.51.
dihydro-1H-pyrrolizine-7-carbonitrile(4e). Yield: 85%; m.p.: 170–172 °C;
−1
IR (υmax, cm ): 3395 and 3337 (NH
2
), 3054 (CH-Ar.), 2936 (CH
, 400 MHz): δ
1
4.1.3. General synthetic procedure for 4a–f and 9
aliph.), 2214 (C^N), 1643 (C]O); H NMR (DMSO‑d
6
Compounds 3a–f or 8 (4.5 mmol) were treated with 1% NaOC
H
2 5
2.38 (s, br., 6H, CH
CH of pyrrolizine, J = 7.28 Hz), 3.42 (s, br., 4H, CH
3.48 (s, 2H, benzylic CH ), 3.95 (t, 2H, CH
J = 7.00 Hz), 4.91 (s, 2H, NH exchanged with D O), 7.34 (d, 2H, Ar-
13
2
of pyrrolizine and CH of piperazine), 2.85 (t, 2H,
2
(
30 mL), allowed to stir at room temperature for 24 h. The obtained
2
2
of piperazine),
of pyrrolizine,
crystals were collected, washed with ethanol, dried and recrystallized
from ethanol to obtain the targeted compounds 4a–f and 9, respec-
tively.
2
2
2
2
Hs, J = 8.28 Hz), 7.39 (d, 2H, Ar-Hs, J = 8.24 Hz); C NMR (DMSO‑d ,
6
9