1220
L. PIEMONTESE ET AL.
4.3.11. (1-benzylpiperidin-4-yl)methanamine (13)
(300 MHz, DMSO-d6), d (ppm): 2.08–2.50 (m, 10H, 8 piperazine and
CON–CH2CH2), 3.17–3.44 (m, 2H, CON–CH2CH2), 3.49 (s, 2H,
NCH2Ph), 6.85–6.97 (m, 1H, Phbenzofuran), 7.05–7.12 (m, 2H,
Phbenzofuran), 7.23–7.34 (m, 5H, CH2Ph), 7.42 (s, 1H, benzofuran),
8.41 (t, 1H, J ¼ 5.3 Hz, NHCO); 13C-NMR (75.5 MHz, DMSO-d6), d
(ppm): 36.3, 52.6, 52.8, 56.9, 62.1, 109.7, 112.2, 112.4, 124.4, 126.9,
128.2, 128.9, 129.0, 138.3, 143.8, 143.8, 148.8, 158.2. ESI-MS (posi-
tive, m/z): 380 (M þ 1); HPLC-HRMS: tR ¼ 4.76 min, calculated
380.1962, found 380.1930.
Starting from 2-((1-benzylpiperidin-4-yl)methyl)isoindoline-1,3-
dione (335 mg, 13a), yield 37%. 1H NMR (300 MHz, DMSO-d6), d
(ppm): 1.00–1.23, 1.61–1.65, 1.82–1.89 and 2.37–2.39 (m, 9H, piperi-
dine), 2,77 (d, 2H, J ¼ 11.5 Hz, NCH2CH) 3.41 (s, 2H, NCH2Ph),
7.20–7.33 (m, 5H, aromatics, Ph–CH2); m/z (ESI-MS): 205 (M þ H)þ.
4.3.12. General method for the synthesis of compounds 1–3
(method a)
To a solution of the carboxylic acid derivatives, 2-(2-hydroxy-
phenyl)-1H-benzo[d]imidazole-5-carboxylic acid (8) or 7-hydroxy-
benzofuran-2-carboxylic acid (11) (1 eq), and the amine
derivatives, (1-benzylpiperidin-4-yl)methanamine (13) or 2-(4-ben-
zyl-1-piperazinyl)ethanamine (12), (1 eq) in dry DMF, was added
N-hydroxysuccinimide (115 mg, 1 eq) and DCC (206 mg, 1 eq) and
the reaction mixture was left stirring for 40 h at RT. Then, the
obtained white precipitate was filtered off and the liquid phase
was diluted with ethyl acetate and washed with brine (3 times),
dried over anhydrous Na2SO4, concentrated under reduced pres-
sure, and purified through column chromatography affording
a solid.
4.3.16. General method for synthesis of the compounds 4–7
(method B)
A mixture of benzofuran-2-carboxylic acid (9) or 7-methoxybenzo-
furan-2-carboxylic acid (10) (1 eq), NMM (294 mg, 2.5 eq), and T3P
(477 mg, 1.5 eq) was stirred in anhydrous DCM under N2 atmos-
phere. After 30 min, the amine derivatives 2-(4-benzyl-1-piperazi-
nyl)ethanamine (12) or (1-benzylpiperidin-4-yl)methanamine (13)
(1 eq) were added and the reaction mixture was stirred at RT
overnight. To the resulting solution was then added water and
ethyl acetate, and extracted. The aqueous layer was extracted
with ethyl acetate (3 times), and the organic layers were com-
bined, washed with 1 N NaOH (3 times) and brine (3 times), dried
over anhydrous sodium sulphate, and then concentrated under
reduced pressure. The crude was purified by column chromatog-
raphy (eluent: DCM/MeOH 98:2 for compounds 4, 6; 92:8 for com-
pounds 5, 7) affording the title compounds.
4.3.13. N-((1-benzylpiperidin-4-yl)methyl)-2-(2-hydroxyphenyl)-1H-
benzo[d]imidazole-5-carboxamide (1)
Starting from 2-(2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carbox-
ylic acid (8) (254 mg) and (1-benzylpiperidin-4-yl)methanamine
(13), (204 mg) eluent: DCM/MeOH 95:5, then 100% ethyl acetate.
The title compound was obtained as a yellow solid, yield ¼71%;
4.3.17. N-((1-benzylpiperidin-4-yl)methyl)benzofuran-2-carboxamide (4)
Starting from benzofuran-2-carboxylic acid (9) (162 mg) and (1-
benzylpiperidin-4-yl)methanamine (13) (204 mg), the title com-
1
m.p.¼265–267 ꢀC. H NMR (300 MHz, DMSO-d6), d (ppm): 1.18–1.23
and 1.58–1.93 (m, 9H, piperidine), 2.81 (d, 2H, J ¼ 10.7 Hz, 2
NHCH2CH), 3.43 (s, 2H, CH2Ph), 6.98–7.04, 7.23–7.41, 7.64–7.79, and
8.08–8.16 (m, 12H, aromatics), 8.48 (t, 1H, J ¼ 5.0 Hz, NHCO); 13C-
NMR (75,5 MHz, DMSO-d6): 29.9, 35.8, 45.0, 53.1, 62.5, 113.1, 117.2,
119.1, 122.1, 126.5, 126.6, 126.8, 128.1, 128.7, 131.8, 138.8, 154.0,
158.2, 166.6. ESI-MS (positive, m/z): 441 (M þ 1), 880 (2M þ 1);
HPLC-HRMS: tR¼5.00 min, calculated 456.2394 found 456.2375.
HPLC-HRMS: tR¼4.84 min, calculated 441.2285, found 441.2266.
pound was obtained as
a
white solid, yield ¼30.5%;
m.p.¼91–93 ꢀC. 1H NMR (300 MHz, DMSO-d6), d (ppm): 1.16–1.23,
1.61–1.65, 1.84–1.91 and 3.14–3.18 (m, 9H, piperidine), 2.78 (d, 2H,
J ¼ 11.1 Hz, CH2CH), 3.42 (s, 2H, NCH2Ph), 7.22–7.77 (m, 10H, aro-
matics), 8.73 (t, 1H, J ¼ 5.7 Hz, NHCO); 13C NMR (75.5 MHz, CDCl3),
d (ppm): 29.8, 36.0, 44.8, 53.2, 63.2, 110.4, 111.8, 122.8, 123.8,
126.9, 127.3, 127.7, 128.3, 129.4, 137.6, 148.8, 154.8, 159.1. m/z,
ESI-MS (positive, m/z): 349 (M þ 1); HPLC-HRMS: tR¼4.94 min, calcu-
lated 349.1911, found 349.1897.
4.3.14. N-(2-(4-benzylpiperazin-1-yl)ethyl)-2-(2-hydroxyphenyl)-1H-
benzo[d]imidazole-5-carboxamide (2)
4.3.18
N-(2-(4-benzylpiperazin-1-yl)ethyl)benzofuran-2-carboxa-
Starting from 2-(2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carbox-
ylic acid (8) (254 mg) and 2-(4-benzyl-1-piperazinyl)ethanamine
(12) (220 mg), eluent: DCM/MeOH 95:5, the title compound was
mide (5)
Starting from benzofuran-2-carboxylic acid (9) (162 mg) and 2-(4-
benzyl-1-piperazinyl)ethanamine (12) (220 mg), the title com-
pound was obtained as a white solid, yield ¼40%; m.p.¼89–91 ꢀC;
1H NMR (400 MHz, CDCl3), d (ppm): 2.38–2.52 (m, 8H, piperazine),
2.56 (t, 2H, J ¼ 6.0 Hz, NH2–CH2CH2N), 3.47 (s, 2H, NCH2Ph),
3.50–3.53 (m, 2H, NH2–CH2CH2N), 7.15–7.45 and 7.58–7.60 (m,
10H, aromatics); 13C NMR (100.5 MHz, CDCl3), d (ppm): 36.0, 53.0,
53.1, 56.5, 63.1, 110.3, 111.9, 122.8, 123.7, 126.8, 127.2, 127.8,
128.4, 129.3, 138.1, 149.0, 154.9, 159.0. ESI-MS (positive, m/z): 364
(M þ 1), 386 (M þ Na); HPLC-HRMS: tR¼4.97 min, calculated
364.2020, found 364.2003.
1
obtained as a yellow solid, yield ¼21%; m.p.¼249–252 ꢀC. H NMR
(400 MHz, DMSO-d6), d (ppm): 2.34–2.47 (m, 10H, 8 piperazine and
2
NH2–CH2CH2N), 3.36–3.41 (m, 4H,
2
NCH2Ph and
2
NH2–CH2CH2N), 6.99–7.40, 7.66–7.79, and 8.07–8.14 (m, 12H, aro-
matics), 8.41 (t, 1H, J ¼ 5.3 Hz, NHCO). 13C-NMR (100.5 MHz,
DMSO-d6), d (ppm): 37.0, 52.7, 52.9, 57.1, 62.2, 112.5, 117.3, 119.3,
122.4, 126.6, 126.9, 128.2, 128.6, 129.4, 132.2, 138.3, 153.3, 158.1,
166.4. ESI-MS (positive, m/z): 456 (M þ 1); HPLC-HRMS:
tR¼5.00 min, calculated 456.2394, found 456.2375.
4.3.15. N-(2-(4-benzylpiperazin-1-yl)ethyl)-7-hydroxybenzofuran-2-
carboxamide (3)
4.3.19 N-((1-benzylpiperidin-4-yl)methyl)-7-methoxy-benzofuran-2-
carboxamide (6)
Starting from 7-hydroxybenzofuran-2-carboxylic acid (11) (178 mg)
and 2-(4-benzyl-1-piperazinyl)ethanamine (12) (220 mg), eluent:
DCM/MeOH 95:5, then acetonitrile/water 19:1, afforded the title
Starting from 7-metoxy-benzofuran-2-carboxylic acid (10) (192 mg)
and (1-benzylpiperidin-4-yl)methanamine (13) (204 mg), the title
compound was obtained as a colourless oil, yield ¼26%. 1H NMR
product as a white solid, yield ¼14.2%, m.p.¼84–85 ꢀC; 1H NMR (300 MHz, DMSO-d6), d (ppm): 1.06–1.23, 1.55–1.64, 1.84–1.91 and