8266 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26
Tangallapally et al.
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continued as described in general procedure I to afford 619
mg of amine 12g in 93% yield. 1H NMR (300 MHz, CDCl3): δ
2.38 (3H, s), 2.6 (4H, t, J ) 5.0 Hz), 3.32 (4H, t, J ) 5.14 Hz),
7.2 (1H, dd, J ) 2.16, 8.26 Hz), 7.39 (1H, t, J ) 8.14 Hz), 7.67
(1H, dd, J ) 1.43, 8.01 Hz). ESI-MS: 222.4 (M + 1).
General Procedure II, for Preparation of 13a-j, Ex-
cept 13c and 13h. The substituted nitro compound (1 equiv
in a mixture of methanol-ethyl acetate, 1:2, 20 mL) was
treated with 10% Pd-carbon (5% w/w). The reaction was
subjected to hydrogenation under 50 psi hydrogen gas pressure
at room temperature and the reaction was monitored by TLC.
After completion of the reaction, the mixture was filtered
through a Celite bed and concentrated in a vacuum to afford
pure product in quantitative yields.
afford 755 mg of amide 3c in 93% yield. H NMR (500 MHz,
CDCl3): δ2.66-2.76 (4H, bs), 3.26-3.33 (4H, bs), 3.64-3.7 (2H,
bs), 7.99 (2H, d, J ) 9.03 Hz), 7.32-7.37 (2H, m), 7.38-7.46
(4H, m), 7.47 (1H, d, J ) 3.90), 7.61 (2H, d, J ) 9.03 Hz), 8.14
(1H, bs); 13C NMR (300 MHz, CDCl3-DMSO-D6, 5:1): 48.13,
51.98, 61.85, 111.94, 114.87, 114.91, 121.36, 126.12, 127.29,
128.12, 128.67, 137.17, 147.65, 148.11, 150.69, 153.39. ESI-
MS: 407.5 (M + 1). Anal. (C22H22N4O4) C, H, N.
5-Nitrofuran-2-carboxylic Acid [4-(4-Benzylpiperidin-
1-yl)phenyl]amide (3d). 5-Nitrofuran-2-carbonyl chloride
(438 mg, 2.5 mmol) in CH2Cl2 (10 mL) was added to a mixture
of amine 13d (532 mg, 2.0 mmol) in Et3N (1.04 mL, 7.5 mmol)
and the reaction continued as described in general procedure
1
IV to afford 728 mg of amide 3d in 90% yield. H NMR (500
MHz, CDCl3): δ1.50-1.65 (3H, m), 1.65-1.85 (2H, m), 2.6-
2.8 (4H, m), 3.68 (2H, d, J ) 10.98 Hz), 6.9-7.02 (2H, bs),
7.2-7.3 (3H, m), 7.3-7.39 (2H, m), 7.41 (1H, d, J ) 3.66), 7.47
(1H, t, J ) 2.1, 3.6), 7.515-7.65 (2H, bs), 8.12-8.22 (1H, bs).
13C NMR 300 MHz, (CDCl3): 31.37, 37.26, 42.58, 49.36, 112.13,
115.74, 116.16, 121.15, 125.38, 127.34, 127.70, 128.59, 139.84,
147.74, 149.11, 153.06. ESI-MS: 406.4 (M + 1). Anal.
(C23H23N3O4): C, H, N.
4-(4-Benzylpiperidin-1-yl)phenylamine (13d). 4-Benzyl-
1-(4-nitrophenyl)piperidine 12d (600 mg, 2.02 mmol) was
treated with 10% Pd-carbon (5% w/w) under the conditions
described in general procedure II to afford amine 13d in
1
quantitative yield. H NMR (500 MHz, CD3OD): δ 1.44 (2H,
q, J ) 9.27, 21.23 Hz), 1.6-1.7 (1H, m), 1.75 (1H, d, J ) 12.2
Hz), 2.55 (2H, t, J ) 11.47 Hz), 2.6 (2H, d, J ) 7.08 Hz), 3.39
(2H, d, J ) 11.23 Hz), 6.71 (2H, d, J ) 7.81 Hz), 6.87 (2H, d,
J ) 8.05 Hz), 7.16-7.21 (3H, m), 7.28 (2H, t, J ) 7.07 Hz).
ESI-MS: 267.1 (M + 1).
5-Nitrofuran-2-carboxylic Acid (3-Morpholin-4-ylphe-
nyl)amide (3f). 5-Nitrofuran-2-carbonyl chloride (438 mg, 2.5
mmol) in CH2Cl2 (10 mL) was added to a mixture of amine
13f (356 mg, 2.0 mmol) in Et3N (1.04 mL, 7.5 mmol) and the
reaction continued as described in general procedure IV to
3-Morpholin-4-ylphenylamine (13f). 4-(3-Nitrophenyl)-
morpholine 12f (600 mg, 2.88 mmol) was treated with 10%
Pd-carbon (5% w/w) under the conditions described in general
procedure II to afford amine 13f in quantitative yield. 1H NMR
(300 MHz, CDCl3): δ 3.145 (4H, t, J ) 4.79 Hz), 3.86 (4H, t,
J ) 4.89 Hz), 6.24-6.29 (2H, m), 6.37 (1H, ddd, J ) 0.73, 2.21,
8.20 Hz), 7.08 (1H, t, J ) 8.28). ESI-MS: 201.3 (M + 23).
3-(4-Methylpiperazin-1-yl)phenylamine (13g). 1-Meth-
yl-4-(3-nitrophenyl)piperazine 12g (600 mg, 2.71 mmol) was
treated with 10% Pd-carbon (5% w/w) under the conditions
described in general procedure II to afford amine 13g in
quantitative yield. 1H NMR (300 MHz, CDCl3): δ 2.36 (3H,
s), 2.57 (4H, t, J ) 4.94 Hz), 3.2 (4H, t, J ) 5.11 Hz), 3.59-
3.67 (2H, bs), 6.22 (1H, dd, J ) 2.07, 8.41 Hz), 6.28 (1H, t, J
) 2.21 Hz), 6.39 (1H, dd, J ) 1.89, 7.82 Hz), 7.06 (1H, t, J )
8.02 Hz). ESI-MS: 192.1 (M + 1).
General Procedure III, for preparation of 13c and 13h.
SnCl2‚H2O (1.125 g/mmol) was added to a solution of the
substituted nitrobenzene in ethyl acetate (10 mL/mmol). The
solution was refluxed for 2 h. The cooled solution was diluted
with water and the pH was adjusted to 8 by addition of a
saturated NaHCO3 solution. The aqueous phase was extracted
with EtOAc (3 × 75 mL), and the combined organic extracts
were thoroughly washed with brine and dried over Na2SO4.
The products obtained after the removal of the solvent were
used without further purification.
1
afford 494 mg of amide 3f in 78% yield. H NMR (500 MHz,
CDCl3): δ 3.23 (4H, t, J ) 4.63 Hz), 3.89 (4H, t, J ) 4.88 Hz),
6.77 (1H, dd, J ) 2.19, 8.3 Hz), 7.1 (1H, dd, J ) 1.46, 7.81
Hz), 7.30 (1H, t, J ) 8.05 Hz), 7.38 (1H, d, J ) 3.66 Hz), 7.46-
7.5 (2H, m), 8.20 (1H, bs). 13C NMR (300 MHz, CDCl3): 51.75,
69.37, 110.78, 114.99, 115.26, 115.31, 119.17, 132.16, 140.47,
150.80, 154.44, 157.39. ESI-MS: 318.3 (M + 1). Anal.
(C15H15N3O5): C, H, N.
5-Nitrofuran-2-carboxylic Acid [3-(4-Methylpiperazin-
1-yl)phenyl]amide (3g). 5-Nitrofuran-2-carbonyl chloride
(438 mg, 2.5 mmol) in CH2Cl2 (10 mL) was added to a mixture
of amine 13g (382 mg, 2.0 mmol) in Et3N (1.04 mL, 7.5 mmol)
and the reaction continued as described in general procedure
1
IV to afford 593 mg of amide 3g in 90% yield. H NMR (500
MHz, CDCl3): δ 2.38 (3H, s), 2.60 (4H, t, J ) 4.64 Hz), 3.28
(4H, t, J ) 4.51 Hz), 6.8 (1H, d, J ) 8.3 Hz), 7.08 (1H, d, J )
8.05 Hz), 7.25-7.32 (2H, m), 7.37-7.45 (2H, m), 7.48 (1H, dd,
J ) 1.22, 3.66 Hz), 8.17 (1H, bs). 13C NMR (300 MHz, CD3-
OD): 44.16, 47.92, 53.98, 107.99, 111.48, 111.70, 112.26,
115.49, 128.50, 137.57, 147.55, 151.16, 154.73. ESI-MS: 331.3
(M + 1). Anal. (C16H18N4O4): C, H, N.
4-(4-Methylpiperazin-1-yl)benzonitrile (14b). 1-Meth-
ylpiperazine (1.36 mL, 12.38 mmol) was added to a mixture
of 4-fluorobenzonitrile 8 (1.0 g, 8.25 mmol) and K2CO3 (2.27
mg, 16.51 mmol) in dimethyl sulfoxide (7 mL) and the reaction
continued as described in general procedure I to afford amine
1.54 g of 14b in 93% yield. 1H NMR (500 MHz, CDCl3): δ 2.36
(3H, s), 2.55 (4H, t, J ) 4.88 Hz), 3.35 (4H, t, J ) 4.88 Hz),
6.87 (2H, d, J ) 8.78 Hz), 7.49 (2H, d, J ) 8.78 Hz). ESI-MS:
202.1 (M + 1).
3-(4-Benzylpiperidin-1-yl)benzonitrile (14g). 1-Meth-
ylpiperazine (2.17 mL, 12.38 mmol) was added to a mixture
of 3-fluorobenzonitrile 9 (1.0 g, 8.25 mmol) and K2CO3 (2.27
mg, 16.51 mmol) in dimethyl sulfoxide (7 mL) and the reaction
continued as described in general procedure I to afford amine
2.05 g of 14g in 90% yield. 1H NMR (500 MHz, CDCl3): δ 1.43
(2H, dq, J ) 3.9, 12.45 Hz), 1.73-1.86 (3H, m), 2.65 (2H, d, J
) 6.83 Hz), 2.88 (2H, dt, J ) 2.68, 12.45 Hz), 3.73 (2H, d, J )
12.45 Hz), 7.1 (1H, td, J ) 0.97, 7.56 Hz), 7.14-7.17 (2H, m),
7.22 (2H, d, J ) 6.83 Hz), 7.27 (1H, t, J ) 7.32 Hz), 7.34-7.38
(3H, m). ESI-MS: 299.5 (M + 23).
4-(4-Benzylpiperazin-1-yl)phenylamine (13c). 1-Benzyl-
4-(4-nitrophenyl)piperazine 12c (750 mg, 2.52 mmol) was
treated with SnCl2‚H2O (14.4 g, 63.9 mmol) under the condi-
tions described in general procedure III to afford 552 mg of
1
amine 13c in 82% yield. H NMR (300 MHz, CDCl3): δ 2.6-
2.8 (4H, bs), 3.11 (4H, t, J ) 4.38 Hz), 3.64 (2H, s), 6.66 (2H,
d, J ) 8.76 Hz), 6.82 (2H, d, J ) 8.76 Hz), 7.25-7.45 (5H, m).
ESI-MS: 268.2 (M + 1).
General Proceure IV, for Preparation of 2 and 3a-j.
5-Nitrofuran-2-carbonyl chloride (438 mg, 2.5 mmol) in CH2-
Cl2 (10 mL) was added to a mixture of amine (2.0 mmol) in
Et3N (1.04 mL, 7.5 mmol). The mixture was stirred for 12 h
at room temperature and was followed by TLC. After comple-
tion of reaction, 100 mL of ethyl acetate was added to the
reaction mixture, and it was sequentially washed with satu-
rated aqueous NaHCO3 (2 × 50 mL), water (2 × 50 mL), and
brine (2 × 50 mL). The organic phase was dried over Na2SO4,
filtered, concentrated, and purified by flash column chroma-
tography to provide the corresponding pure amides.
5-Nitrofuran-2-carboxylic Acid [4-(4-Benzylpiperazin-
1-yl)phenyl]amide (3c). 5-Nitrofuran-2-carbonyl chloride
(438 mg, 2.5 mmol) in CH2Cl2 (10 mL) was added to amine
13c (534 mg, 2.0 mmol) in Et3N (1.04 mL, 7.5 mmol) and the
reaction continued as described in general procedure IV to
4-Thiomorpholin-4-ylbenzonitrile (14h). Thiomorpho-
line (2.35 mL, 24.79 mmol) was added to a mixture of
4-fluorobenzonitrile 8 (2.0 g, 16.52 mmol) and K2CO3 (4.56 mg,
33.05 mmol) in dimethyl sulfoxide (10 mL) and the reaction
continued as described in general procedure I to afford amine
2.93 g of 14h in 87% yield. 1H NMR (300 MHz, CDCl3): δ 2.71