M. A. Matulenko et al. / Bioorg. Med. Chem. 12 (2004) 3471–3483
3479
(64% yield) of the title compound, 6c: white solid; mp
99–101 ꢁC; Rf 0.23 (50% EtOAc–hexane; UV). 1H NMR
(300 MHz, DMSO-d6) d 2.28 (s, 3H), 2.68 (m, 4H), 3.19
(s, 2H), 3.68 (m, 4H), 6.88 (br d, J ¼ 7:8, 1H), 6.93 (dd,
J ¼ 7:8, 4.8, 1H), 7.18 (dd, J ¼ 7:5, 7.5, 1H), 7.44 (br d,
J ¼ 8:2, 1H), 7.47 (br s, 1H), 8.07 (dd, J ¼ 7:8, 2.0, 1H),
8.42 (dd, J ¼ 5:1, 2.0, 1H), 9.68 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6) d 21.0 (q), 47.7 (t), 52.3 (t), 61.4
(t), 94.3 (s), 114.6 (d), 116.6 (d), 117.8 (s), 120.0 (d),
124.0 (d), 128.4 (d), 137.8 (s), 138.4 (s), 144.2 (d), 151.9
(d), 160.2 (s), 167.9 (s). MS (DCI/NH3) m=z 336
(M+H)þ. Anal. Calcd for C19H21N5O: C, 68.04; H, 6.31;
N, 20.88. Found: C, 68.19; H, 6.36; N, 21.15.
2H), 3.65 (m, 4H), 6.97 (dd, J ¼ 7:5, 4.8, 1H), 7.36 (dd,
J ¼ 7:8, 7.8, 1H), 7.69 (d, J ¼ 7:5, 1H), 7.73 (dd,
J ¼ 8:1, 8.1, 1H), 8.10 (dd, J ¼ 8:1, 2.0, 1H), 8.21 (d,
J ¼ 8:5, 1H), 8.44 (dd, J ¼ 4:7, 2.3, 1H), 9.89 (br s, 1H).
MS (DCI/NH3) m=z 390 (M+H)þ.
Maleate salt: 622 mg (47% yield); white solid, mp 143–
145 ꢁC. 1H NMR (400 MHz, DMSO-d6) d 2.99 (m, 4H),
3.61 (s, 2H), 3.73 (m, 4H), 6.18 (s, 2H), 6.98 (dd,
J ¼ 7:7, 4.9, 1H), 7.40 (dd, J ¼ 7:7, 7.7, 1H), 7.70 (dd,
J ¼ 7:8, 7.8, 1H), 7.74 (d, J ¼ 7:7, 1H), 8.00 (br d,
J ¼ 8:0, 1H), 8.09 (dd, J ¼ 7:7, 1.8, 1H), 8.44 (dd,
J ¼ 4:8, 2.0, 1H), 10.05 (br s, 1H). 13C NMR (100 MHz,
DMSO-d6) d 46.9 (t), 52.1 (t), 59.4 (t), 95.3 (s), 115.4 (d),
117.5 (s), 123.8 (s, JCF ¼ 272:8), 125.7 (d), 126.0 (s, ob-
scured JCF ; overlapped d), 126.3 (d, JCF ¼ 5:3), 132.1
(d), 133.4 (d), 134.7 (s), 144.2 (d), 152.0 (d), 160.1 (s),
5.1.27. 2-Chloro-N-(4-methylphenyl)acetamide (5d).
Compound 5d was completed using a similar proce-
dure outlined for compound 5b substituting 4-methyl-
aniline for 2-methylaniline to provide 697 mg (70%
yield) of the title compound, 5d: white solid; mp 162–
166.8
(s),
167.2
(s).
Anal.
Calcd
for
C19H18F3N5OÆ1.0C4H4O4: C, 54.65; H, 4.39; N, 13.86.
Found: C, 54.61; H, 4.32; N, 13.83.
1
165 ꢁC; Rf 0.60 (50% EtOAc–hexane; UV). H NMR
(300 MHz, CDCl3) d 2.33 (s, 3H), 4.18 (s, 2H), 7.16
(AA0BB0, J ¼ 8:1, 2H), 7.42 (AA0BB0, J ¼ 8:5, 2H), 8.16
(br s, 1H). 13C NMR (100 MHz, DMSO-d6) d 20.4 (q),
43.5 (t), 119.3 (d), 129.1 (d), 132.8 (s), 135.9 (s), 164.3 (s).
MS (DCI/NH3) m=z 201 (M+NH4)þ. Anal. Calcd for
C9H10ClNO: C, 58.86; H, 5.49; N, 7.63. Found: C,
58.82; H, 5.33; N, 7.56.
5.1.30.
2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]-N-(3-
trifluoromethylphenyl)acetamide (6f). Compound 6f was
completed using a similar procedure outlined for com-
pound 6a substituting N-chloroacetyl-3-(trifluoro-
methyl)aniline for 2-chloro-N-phenylacetamide to
1
provide the title compound, 6f: yellow oil. H NMR
(300 MHz, DMSO-d6) d 2.69 (m, 4H), 3.25 (s, 2H), 3.69
(m, 4H), 6.93 (dd, J ¼ 7:8, 4.7, 1H), 7.41 (br d, J ¼ 7:8,
1H), 7.56 (dd, J ¼ 7:8, 7.8, 1H), 7.90 (br d, J ¼ 8:4, 1H),
8.07 (dd, J ¼ 7:8, 2.1, 1H), 8.15 (br s, 1H), 8.42 (dd,
J ¼ 4:7, 1.7, 1H), 10.11 (br s, 1H). MS (DCI/NH3) m=z
390 (M+H)þ.
5.1.28.
2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]-N-(4-
methylphenyl)acetamide (6d). Compound 6d was com-
pleted using a similar procedure outlined for compound
6a substituting compound 5d for 2-chloro-N-phenylac-
etamide to provide 514 mg (70% yield) of the title
1
compound, 6d: yellow oil. H NMR (300 MHz, CDCl3)
Maleate salt: tan solid; mp 157–158 ꢁC. 1H NMR
(300 MHz, DMSO-d6) d 3.07 (br s, 4H), 3.73 (br s, 2H),
3.79 (br s, 4H), 6.15 (s, 2H), 7.00 (dd, J ¼ 7:4, 4.7, 1H),
7.46 (br d, J ¼ 7:8, 1H), 7.59 (dd, J ¼ 7:8, 7.8, 1H), 7.85
(br d, J ¼ 8:2, 1H), 8.13 (m, 2H), 8.45 (dd, J ¼ 4:7, 2.0,
1H), 10.48 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) d
46.2 (t), 51.9 (t), 59.1 (t), 95.1 (s), 115.4 (d), 115.7 (d,
JCF ¼ 3:8), 117.5 (s), 120.2 (d, JCF ¼ 3:8), 123.1 (d),
124.0 (s, JCF ¼ 272:0), 129.5 (s, JCF ¼ 31:8), 130.1 (d),
133.0 (d), 138.9 (s), 144.3 (d), 152.0 (s), 159.9 (s), 166.1
(s), 166.9 (s). Anal. Calcd for C19H18F3N5OÆ1.0C4H4O4:
C, 54.56; H, 4.39; N, 13.86. Found: C, 54.30; H, 4.42; N,
13.42.
d 2.32 (s, 3H), 2.84 (m, 4H), 3.26 (s, 2H), 3.82 (m, 4H),
6.82 (dd, J ¼ 7:6, 4.9, 1H), 7.14 (AA0BB0, J ¼ 8:1, 2H),
7.47 (AA0BB0, J ¼ 8:5, 2H), 7.80 (dd, J ¼ 7:6, 1.9, 1H),
8.37 (dd, J ¼ 4:9, 1.9, 1H), 9.10 (br s, 1H). MS (DCI/
NH3) m=z 336 (M+H)þ.
1
Maleate salt: light tan solid; mp 156–158 ꢁC. H NMR
(400 MHz, DMSO-d6) d 2.25 (s, 3H), 3.20 (m, 4H), 3.82
(m, 4H), 3.84 (s, 2H), 6.12 (s, 2H), 6.99 (dd, J ¼ 7:5, 4.8,
1H), 7.13 (AA0BB0, J ¼ 8:0, 2H), 7.49 (AA0BB0, J ¼ 8:3,
2H), 8.10 (dd, J ¼ 7:7, 1.8, 1H), 8.44 (dd, J ¼ 4:8, 1.7,
1H), 10.20 (br s, 1H). 13C NMR (100 MHz, DMSO-d6) d
20.4 (q), 45.9 (t), 51.8 (t), 58.5 (t), 95.3 (s), 115.6 (d),
117.5 (s), 119.6 (d), 129.2 (d), 133.0 (s), 133.7 (d), 135.5
(s), 144.3 (d), 152.0 (d), 160.0 (s), 164.4 (s), 167.0 (s).
Anal. Calcd for C19H21N5OÆ1.0C4H4O4Æ0.20 H2O: C,
60.70; H, 5.63; N, 15.39. Found: C, 60.33; H, 5.55; N,
15.10.
5.1.31.
2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]-N-(4-
trifluoromethylphenyl)acetamide (6g). Compound 6g
was completed using a similar procedure outlined for
compound 6a substituting N-chloroacetyl-4-(trifluoro-
methyl)aniline (Maybridge) for 2-chloro-N-phenyl-
acetamide to provide 1.05 g (78% yield) of the title
compound, 6g: white solid; mp 147–150 ꢁC; Rf 0.24 (50%
EtOAc–hexane; UV). 1H NMR (300 MHz, DMSO-d6) d
2.69 (m, 4H), 3.26 (s, 2H), 3.68 (m, 4H), 6.93 (dd,
J ¼ 7:5, 4.7, 1H), 7.68 (AA0BB0, J ¼ 8:8, 2H), 7.88
(AA0BB0, J ¼ 8:5, 2H), 8.07 (dd, J ¼ 7:8, 2.0, 1H), 8.42
(dd, J ¼ 4:7, 2.0, 1H), 10.14 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6) d 47.7 (t), 52.3 (t), 61.4 (t), 94.3
5.1.29.
2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]-N-(2-
trifluoromethylphenyl)acetamide (6e). Compound 6e
was completed using a similar procedure outlined
for compound 6a substituting N-chloroacetyl-2-(triflu-
oromethyl)aniline (Apollo) for 2-chloro-N-phenylaceta-
mide to provide the title compound, 6e: colorless oil. 1H
NMR (300 MHz, DMSO-d6) d 2.74 (m, 4H), 3.27 (s,