S.F.P. Braga et al. / Bioorganic & Medicinal Chemistry xxx (2017) xxx–xxx
9
obtained after evaporation was added distilled water and the mix-
ture was neutralized with 1 M HCl solution. The product was
extracted with 2 ꢁ 15 mL CH2Cl2, washed with distilled water
and the organic layer dried (Na2SO4), filtered and the solvent
removed under reduced pressure. The product was obtained as a
yellow semi-solid, 54% yield; IR (neat, cmꢀ1) 3139, 3032, 2947,
2893, 1667, 1594, 1570, 1542, 1457, 1233; 1H NMR (400 MHz,
CDCl3) d 8.63 (s, 1H), 8.21 (d, 1H, J = 6.2), 7.21–7.17 (m, 4H), 6.52
(dd, 1H, J = 6.2, 1.1), 4.73 (s, 2H), 3.83 (t, 2H, J = 5.8), 2.95 (t, 2H,
J = 5.8); 13C NMR (100 MHz, MeOD-d4) d 160.8, 158.1, 155.3,
134.9, 133.1, 128.2, 126.8, 126.5, 126.4, 102.9, 45.8, 41.6, 28.6;
HRMS (m/z) 212.1185 [M+H] , calcd 212.1183 C13H14N3.
alkalinized with a saturated NaHCO3 solution to pH 10 and
extracted with 20 mL of AcOEt. The organic layers were combined,
dried with Na2SO4, filtered and the solvent evaporated under
reduced pressure to yield the desired product 6c as amber oil,
84% yield; IR (neat, cmꢀ1) 3421, 3177, 3030, 1679, 1611, 1512;
1H NMR (200 MHz, CDCl3) d 9.05 (broad s, 1H), 7.45 (d, 2H,
J = 8.3), 7.12 (d, 2H, J = 8.3), 3.11 (s, 2H), 2.64 (apparent t, 4H),
2.51 (broad s, 4H), 2.31 (s, 6H); 13C NMR (50 MHz, CDCl3) d
167.9, 134.8, 133.5, 129.2, 119.2, 61.6, 54.9, 53.1, 45.7, 20.6; HRMS
(m/z) 248.1754 [M+H] , calcd 248.1757 C14H22N3O .
4.1.4.3. 2-((3-Morpholinopropyl)amino)-N-phenylacetamide (8a). In
addition to the general procedure, the aqueous layer was alkalin-
ized with an 1 M NaOH solution to pH 12 and extracted with
20 mL of AcOEt. The organic layers were combined, dried with Na2-
SO4, filtered and the solvent evaporated under reduced pressure,
4.1.2.3. 4-[N-(3-(4-morpholinyl)propyl)]pyrimidine (4c). Obtained
from the general procedure as a brown oil, after purification by col-
umn chromatography previously saturated with triethylamine
(CH2Cl2/MeOH/Et3N 97.5:2.5:0.5 ? 95:5:0.5), 49% yield; IR (neat,
cmꢀ1) 3373, 2924, 1600, 1316, 1112; 1H NMR (400 MHz, CDCl3) d
8.52 (s, 1H), 8.12 (d, 1H, J = 5.9), 6.30 (dd, 1H, J = 5.9, 0.8), 6.26
(broad s, 1H), 3.74 (t, 4H, J = 4.7), 3.42 (broad s, 2H), 2.51–2.49
(m, 6H), 1.80 (qt, 2H, J = 6.4); 13C NMR (100 MHz, CDCl3) d 162.0,
158.6, 154.9, 66.9, 57.2, 53.7, 40.6, 24.9; HRMS (m/z) 223.1549
[M+H] , calcd 223.1553 C11H19N4O .
providing the product as an amber oil, 36% yield; IR (neat, cmꢀ1
)
3280, 3060, 1669, 1599, 1523, 1442; 1H NMR (200 MHz, CDCl3) d
9.37 (broad s, 1H), 7.57 (d, 2H, J = 7.6), 7.32 (t, 2H, J = 7.6), 7.09
(t, 1H, J = 7.6), 3.69 (t, 4H, J = 4.5), 3.36 (s, 2H), 2.71 (t, 2H,
J = 6.7), 2.62 (broad s, 1H), 2.52–2.32 (m, 6H), 1.70 (qt, 2H,
J = 6.7); 13C NMR (50 MHz, CDCl3) d 169.8, 137.4, 128.7, 123.9,
119.3, 66.6, 56.8, 53.5, 52.7, 48.5, 26.2; HRMS (m/z) 278.1863 [M
+H] , calcd 278.1863 C15H24N3O2.
4.1.3. Preparation of 7-chloro-4-[4-(aminoacetyl)morpholinyl]
quinoline (5k)
4.1.4.4.
N-(4-chlorophenyl)-2-((3-morpholinopropyl)amino)ac-
In a round-bottom flask containing 5 mL of ethanol were added
4,7-dichloroquinoline (1 eq.), 4-(aminoacetyl)morpholine38 (3 eq.)
and triethylamine (3 eq.). The reaction mixture was refluxed under
magnetic stirring at 90 °C. The completion of the reaction was
observed by TLC. The solvent was removed under reduced pressure
and the resulting solid was purified by column chromatography
(AcOEt/MeOH/NH4OH 97:2:1). The 4-aminoquinoline 5k was
obtained as a pale solid, 48% yield; m.p. 183.8–185.6 °C; IR (neat,
cmꢀ1) 3200, 3060, 3008, 1651, 1580, 1107; 1H NMR (200 MHz,
DMSO-d6) d 8.40 (d, 1H, J = 5.3), 8.19 (d, 1H, J = 9.0), 7.82 (d, 1H,
J = 1.8), 7.47 (dd, 1H, J = 9.0, 1.8), 7.34 (broad s, 1H), 6.42 (d, 1H,
J = 5.3), 4.20 (d, 1H, J = 4.0), 3.30–3.80 (m, 8H); 13C NMR (DMSO-
d6, 50 MHz) d 167.3, 152.2, 150.4, 149.2, 133.8, 127.9, 124.8,
124.1, 117.7, 100.1, 66.4, 45.0, 44.1, 42.3; HRMS (m/z) 306.1003
[M+H]+, calcd 306.1009 C15H17ClN3O2.
etamide (8b). In addition to general procedure, after removal of
the acetonitrile, 10 mL of distilled water was added to the residue,
the solution was alkalinized with an 1 M NaOH solution to pH 12
and extracted with 20 mL of AcOEt, followed by 20 mL of CH2Cl2.
The organic layers were combined, dried with Na2SO4, filtered
and the solvents removed under reduced pressure, to yield the
desired product 8b as an amber oil, 98% yield; IR (neat, cmꢀ1
)
3283, 3110, 2938, 1688, 1595, 1512, 1398; 1H NMR (200 MHz,
CDCl3) d 9.66–9.29 (m, 1H), 7.69–7.44 (m, 2H), 7.28 (d, 2H,
J = 8.6), 3.70 (t, 4H, J = 4.0), 3.42 (s, 2H), 2.89 (broad s, 1H), 2.77
(t, 2H, J = 6.3), 2.53–2.37 (m, 6H), 1.73 (qt, 2H, J = 6.3); 13C NMR
(50 MHz, CDCl3) d 169.4, 136.1, 128.9, 121.0, 120.7, 66.8, 57.2,
53.7, 52.6, 49.0, 26.0; HRMS (m/z) 312.1471 [M+H] , calcd
312.1473 C15H23N3O2Cl .
4.1.4.5.
2-((3-Morpholinopropyl)amino)-N-(4-methylphenyl)ac-
4.1.4. General procedure for the preparation of 2-amine-N-
arylacetamides 6b-c and 8a-c
etamide (8c). In addition to the general procedure, after removal
of the acetonitrile, 10 mL of distilled water was added to the resi-
due, the solution was alkalinized with an 1 M NaOH solution to pH
12 and extracted with 20 mL of AcOEt. The organic layer was dried
with Na2SO4, filtered and the solvent evaporated under reduced
pressure, to yield the desired product 8c as an amber oil, 87% yield;
IR (neat, cmꢀ1) 3265, 3037, 1684, 1608, 1514; 1H NMR (200 MHz,
CDCl3) d 9.58 (broad s, 1H), 7.48 (d, 2H, J = 8.6), 7.12 (d, 2H,
J = 8.6), 3.99 (broad s, 1H), 3.72 (t, 4H, J = 4.5), 3.53 (s, 2H), 2.84
(t, 2H, J = 6.3), 2.53–2.49 (m, 6H), 2.31 (s, 3H), 1.78 (qt, 2H,
J = 6.3); 13C NMR (50 MHz, CDCl3) d 169.3, 169.0, 134.9, 133.8,
129.4, 119.9, 119.5, 66.8, 57.1, 53.6, 52.5, 48.9, 25.9, 20.8; HRMS
(m/z) 292.2016 [M+H] , calcd 292.2020 C16H26N3O2.
In
a
round-bottom flask containing the 2-chloro-N-
phenylacetamide,39 2-chloro-N-(4-chlorophenyl)acetamide40 or
2-chloro-N-(methylphenyl)acetamide39 (1 eq.) in acetonitrile, the
corresponding amine (1.05 eq.) and triethylamine (1.05 eq.) were
added. The reaction was left stirring under reflux for 2–6 h. Upon
completion, the acetonitrile was removed under reduced pressure
and the remaining residue was dissolved in 20 mL of AcOEt and
washed with 2 ꢁ 10 mL of distilled water. The organic layer was
collected, dried with Na2SO4, filtered and the solvent evaporated
under reduced pressure to yield the desired product.
4.1.4.1.
N-(4-chlorophenyl)-2-(4-methylpiperazin-1-yl)acetamide
(6b). Obtained from the general procedure as a yellow oil, 80%
yield; IR (neat, cmꢀ1) 3283, 3110, 3057, 1688, 1595, 1512, 1491;
1H NMR (200 MHz, CDCl3) d 9.14 (broad s, 1H), 7.51 (d, 2H,
J = 8.8), 7.27 (d, 2H, J = 8.8), 3.12 (s, 2H), 2.75–2.41 (m, 8H), 2.31
(s, 3H); 13C NMR (50 MHz, CDCl3) d 168.3, 136.1, 129.0, 128.9,
120.6, 61.7, 55.1, 53.9, 45.9; HRMS (m/z) 268.1209 [M+H] , calcd
268.1211 C13H19N3OCl .
4.1.5. Preparation of 1-((1H-pyrrol-2-yl)methyl)-4-methylpiperazine
(9b)
In a round-bottom flask containing methylpiperazine (1.1 eq.)
glacial acetic acid was added in an ice bath and left under stirring
until complete solubilization. Then, 1 eq. of 35% formaldehyde
aqueous solution was added, followed by dropwise addition of pyr-
role (1 eq.). The ice bath was removed and the reaction was kept
under magnetic stirring until the completion of the reaction was
detected by TLC (1–2 h). Then, in an ice bath, the reaction was alka-
linized with 20% NaOH aqueous solution to pH 10–11. The solution
4.1.4.2.
2-(4-Methylpiperazin-1-yl)-N-(4-methylphenyl)acetamide
(6c). In addition to the general procedure, the aqueous layer was