Journal of Medicinal Chemistry
Article
165.9; HRMS (ESI+) m/z calcd for C22H25F2N4O4S2 [M + H]+
511.1280, found: 511.1269. Anal. Calcd for C22H24F2N4O4S2: C,
51.75; H, 4.74; N, 10.97. Found: C, 51.73; H, 4.64; N, 10.92.
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(2-
(hydroxyimino)-3-(4-(methylthio)phenyl)propanamide) (11l).
11l (114 mg, 20% from acid 10f) was obtained as an amorphous
light yellow solid after purification by flash column chromatography
(acetone:PE40−60, 3:7 then MeOH:CH2Cl2 1:9). Rf 0.4 (aceto-
ne:PE40−60, 4:6); IR (neat) 1653, 1625, 1523, 1492, 1424, 1000
cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.42 (s, 6H), 2.81 (t, J = 6.7
Hz, 4H), 3.41 (m, 4H), 3.76 (s, 4H), 7.15 (m, 8H), 8.06 (br t, J = 5.4,
2H), 11.85 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 14.9, 28.3,
36.9, 38.1, 126.1, 129.3, 133.5, 135.4, 151.6, 163.2; HRMS (ESI+) m/z
calcd for C24H31N4O4S4 [M + H]+ 567.1223, found: 567.1230. Anal.
Calcd for C24H30N4O4S4: C, 50.86; H, 5.34; N, 9.89. Found: C, 50.91;
H, 5.30; N, 9.81.
C26H32I2N4O8S2: C, 36.89; H, 3.81; N, 6.62. Found: C, 36.92; H, 3.79;
N, 6.57.
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(3-(3-
bromo-4,5-dimethoxyphenyl)-2-(hydroxyimino)propanamide)
(11q). 11q (339 mg, 45% from acid 10k) was obtained as an
amorphous white solid after purification by flash column chromatog-
raphy (gradient acetone:PE40−60, 3:7 to 4:6). Rf 0.35 (acetone:PE40−60
,
4:6); IR (neat) 1656, 1625, 1528, 1487, 1413, 1271, 1138, 1044, 998
cm−1; 1H NMR (400 MHz, CD3OD) δ 2.82 (t, J = 6.7 Hz, 4H), 3.52
(t, J = 6.7 Hz, 4H), 3.74 (s, 6H), 3.81 (s, 6H), 3.85 (s, 4H), 6.93 (d, J
= 1.8 Hz, 2H), 7.03 (d, J = 1.8 Hz, 2H). 13C NMR (100 MHz,
CD3OD) δ 29.5, 38.7, 39.6, 56.6, 60.9, 114.3, 118.0, 126.1, 135.7,
146.1, 152.7, 154.8, 165.8; HRMS (ESI+) m/z calcd for
C26H33Br2N4O8S2 [M + H]+ 751.0101, found: 751.0117. Anal. Calcd
for C26H32Br2N4O8S2: C, 41.50; H, 4.29; N, 7.45. Found: C, 41.45; H,
4.21; N, 7.48.
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(3-
(3,4-dimethoxyphenyl)-2-(hydroxyimino)propanamide) (11r).
11r (115 mg, 13% from acid 10l) was obtained as an amorphous
light yellow solid after purification by flash column chromatography
(gradient acetone:PE40−60, 3:7 to 4:6). Important degradation was
observed during the final deprotection step for reaction times superior
to 2 h. Only partial conversion to the product (and recovery of the
starting material) was achieved during the deprotection step, avoiding
degradation and allowing efficient purification of the product. Rf 0.25
(acetone:PE40−60, 4:6); IR (neat) 1658, 1628, 1511, 1419, 1259, 1233,
1141, 1022 cm−1; 1H NMR (400 MHz, CD3OD) δ 2.79 (t, J = 6.7 Hz,
4H), 3.50 (t, J = 6.7 Hz, 4H), 3.76 (s, 6H), 3.77 (s, 6H), 3.85 (s, 4H),
6.76−6.84 (m, 4H), 6.90 (d, J = 1.5 Hz, 2H). 13C NMR (100 MHz,
CD3OD) δ 29.5, 38.7, 39.6, 56.4, 56.6, 113.1, 114.3, 122.7, 131.0,
149.1, 150.3, 153.5, 166.1; HRMS (ESI+) m/z calcd for
C26H35N4O8S2 [M + H]+ 595.1891, found: 595.1897. Anal. Calcd
for C26H34N4O8S2: C, 52.51; H, 5.76; N, 9.42. Found: C, 52.54; H,
5.72; N, 9.49.
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(2-
(hydroxyimino)-3-(3-iodo-4-methoxyphenyl)propanamide)
(11m). 11m (428 mg, 36% from acid 10g) was obtained as an
amorphous light yellow solid after purification by flash column
chromatography (gradient acetone:PE40−60, 3:7 to 4:6). Rf 0.45
(acetone:PE40−60, 4:6); IR (neat) 1657, 1624, 1527, 1487, 1437,
1
1279, 1251, 1047, 1014, 981 cm−1; H NMR (400 MHz, CD3OD) δ
2.80 (t, J = 6.7 Hz, 4H), 3.50 (t, J = 6.7 Hz, 4H), 3.79 (s, 6H), 3.81 (s,
4H), 6.79 (d, J = 8.5 Hz, 2H), 7.24 (dd, J = 8.5, 2.2 Hz, 2H), 7.67 (d, J
= 2.2 Hz, 2H). 13C NMR (100 MHz, CD3OD) δ 28.6, 38.7, 39.6, 56.9,
86.2, 112.0, 131.5, 132.3, 141.0, 153.1, 158.3, 165.9; HRMS (ESI+) m/
z calcd for C24H29I2N4O6S2 [M + H]+ 786.9612, found: 786.9631.
Anal. Calcd for C24H28I2N4O6S2: C, 36.65; H, 3.59; N, 7.12. Found: C,
36.73; H, 3.48; N, 7.07.
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(3-(3-
bromo-4-fluorophenyl)-2-(hydroxyimino)propanamide) (11n).
11n (201 mg, 30% from acid 10h) was obtained as an amorphous
white solid after purification by flash column chromatography
(gradient acetone:PE40−60, 3:7 to 4:6). Rf 0.55 (acetone:PE40−60
,
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(3-(3-
bromo-5-nitrophenyl)-2-(hydroxyimino)propanamide) (11t).
11t (123 mg, 11% from acid 10n) was obtained as an amorphous
white solid after purification by flash column chromatography
4:6); IR (neat) 1655, 1623, 1528, 1491, 1427, 1404, 1242, 1358, 1013,
1
984 cm−1; H NMR (400 MHz, CD3OD) δ 2.82 (t, J = 6.7 Hz, 4H),
3.53 (t, J = 6.7 Hz, 4H), 3.87 (s, 4H), 7.06 (app-t, J = 8.6 Hz, 2H),
7.27 (ddd, J = 8.4, 4.7, 2.2 Hz, 2H), 7.51 (dd, J = 6.7, 2.2 Hz, 2H). 13C
NMR (100 MHz, CD3OD) δ 29.0, 38.6, 39.6, 109.2 (d, JCF = 21.1
Hz), 117.2 (d, JCF = 22.5 Hz), 131.2 (d, JCF = 6.9 Hz), 135.1, 136.1 (d,
JCF = 3.5 Hz), 152.5, 159.1 (d, JCF = 245 Hz), 165.7; HRMS (ESI+)
m/z calcd for C22H23Br2F2N4O4S2 [M + H]+ 666.9490, found:
666.9500. Anal. Calcd for C22H22Br2F2N4O4S2: C, 39.53; H, 3.32; N,
8.38. Found: C, 39.58; H, 3.30; N, 8.28.
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(3-(3-
bromo-4-(methylthio)phenyl)-2-(hydroxyimino)propanamide)
(11o). 11o (270 mg, 25% from acid 10i) was obtained as an
amorphous light yellow solid after purification by flash column
chromatography (gradient acetone:PE40−60, 3:7 to 1:1). Rf 0.25
(acetone:PE40−60, 3:7); IR (neat) 1655, 1623, 1526, 1462, 1432,
1026 cm−1; 1H NMR (400 MHz, CD3OD) δ 2.41 (s, 6H), 2.80 (t, J =
6.7 Hz, 4H), 3.51 (t, J = 6.7 Hz, 4H), 3.85 (s, 4H), 7.09 (d, J = 8.2 Hz,
2H), 7.25 (dd, J = 8.2, 1.8 Hz, 2H), 7.45 (d, J = 1.8 Hz, 2H). 13C
NMR (100 MHz, CD3OD) δ 15.8, 29.1, 38.7, 39.6, 122.4, 126.8,
130.1, 134.2, 136.3, 138.9, 152.7, 165.8; HRMS (ESI+) m/z calcd for
C24H29Br2N4O4S4 [M + H]+ 722.9433, found: 722.9441. Anal. Calcd
for C24H28Br2N4O4S4: C, 39.78; H, 3.90; N, 7.73. Found: C, 39.73; H,
3.85; N, 7.67.
(gradient acetone:PE40−60, 3:7 to 4:6). Rf 0.25 (acetone:PE40−60
,
3:7); IR (neat) 1655, 1620, 1526, 1426, 1344, 1026, 988 cm−1; H
NMR (400 MHz, CD3OD) δ 2.83 (t, J = 6.7 Hz, 4H), 3.53 (t, J = 6.7
Hz, 4H), 4.02 (s, 4H), 7.84−7.87 (m, 2H), 8.12−8.15 (m, 2H), 8.20
(m, 2H). 13C NMR (100 MHz, CD3OD−DMSO-d6) δ 29.8, 38.7,
39.6, 123.3, 124.1, 125.5, 139.4, 142.8, 150.2, 151.7, 165.0; HRMS
(ESI+) m/z calcd for C22H23Br2N6O8S2 [M + H]+ 720.9380, found:
720.9412. Anal. Calcd for C22H22Br2N6O8S2: C, 36.58; H, 3.07; N,
11.63. Found: C, 36.64; H, 3.01; N, 11.68.
1
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(3-
(3,5-dibromo-4-hydroxyphenyl)-2-(hydroxyimino)-
propanamide) (11u). 11u (270 mg, 22% from acid 10o) was
obtained as an amorphous light yellow solid after purification by flash
column chromatography (gradient acetone:PE40−60, 35:65 to 50:50).
Rf 0.3 (acetone:PE40−60, 4:6); IR (neat) 1653, 1625, 1520, 1544, 1474,
1406, 1159 cm−1; 1H NMR (400 MHz, CD3OD) δ 2.82 (t, J = 6.7 Hz,
4H), 3.53 (t, J = 6.7 Hz, 4H), 3.79 (s, 4H), 7.39 (s, 4H). 13C NMR
(100 MHz, CD3OD) δ 28.5, 38.6, 39.6, 112.0, 132.3, 134.0, 150.7,
152.6, 165.7; HRMS (ESI+) m/z calcd for C22H23Br4N4O6S2 [M +
H]+ 818.7787, found: 818.7811. Anal. Calcd for C22H22Br4N4O6S2: C,
32.14; H, 2.70; N, 6.81. Found: C, 32.08; H, 2.70; N, 6.74.
(2E,2′E)-N,N′-(Hexane-1,6-diyl)bis(3-(3-bromo-4-hydroxy-
phenyl)-2-(hydroxyimino)propanamide) (11w). 11w (44 mg)
was obtained in 12% yield from acid 10a and hexane-1,6-diamine 16,
after purification by flash column chromatography (AcOEt:PE40−60).
Amorphous white solid; 11w has been previously reported in the
literature35 and our data matched reported ones. Rf 0.1
(2E,2′E)-N,N′-(2,2′-Disulfanediylbis(ethane-2,1-diyl))bis(2-
(hydroxyimino)-3-(3-iodo-4,5-dimethoxyphenyl)-
propanamide) (11p). 11p (295 mg, 23% from acid 10j) was
obtained as an amorphous light yellow solid after purification by flash
column chromatography (gradient acetone:PE40−60, 3:7 to 4:6). Rf
0.15 (acetone:PE40−60, 3:7); IR (neat) 1657, 1528, 1480, 1413, 1268,
1
1
1137, 1041, 993 cm−1; H NMR (400 MHz, CD3OD) δ 2.82 (t, J =
(AcOEt:PE40−60, 1:1); H NMR (400 MHz, CD3OD) δ 1.22−1.32
6.7 Hz, 4H), 3.51 (t, J = 6.7 Hz, 4H), 3.71 (s, 6H), 3.80 (s, 6H), 3.83
(s, 4H), 6.95 (d, J = 1.7 Hz, 2H), 7.23 (d, J = 1.7 Hz, 2H). 13C NMR
(100 MHz, CD3OD) δ 29.2, 38.7, 39.6, 56.4, 60.8, 92.5, 115.3, 131.9,
136.5, 148.7, 152.8, 153.7, 165.8; HRMS (ESI+) m/z calcd for
C26H33I2N4O8S2 [M + H]+ 846.9824, found: 846.9858. Anal. Calcd for
(m, 4H), 1.42−1.52 (m, 4H), 3.20 (t, J = 7.0 Hz, 4H), 3.79 (s, 4H),
6.76 (d, J = 8.3 Hz, 2H), 7.06 (dd, J = 8.3, 2.1 Hz, 2H), 7.36 (d, J = 2.1
Hz, 2H). 13C NMR (100 MHz, CD3OD) δ 27.5, 28.8, 30.4, 40.2,
110.5, 117.1, 130.4, 130.7, 134.5, 153.6, 153.8, 165.8; HRMS (ESI+)
m/z calcd for C24H29Br2N4O6 [M + H]+ 627.0448, found: 627.0470.
1743
dx.doi.org/10.1021/jm2016182 | J. Med. Chem. 2012, 55, 1731−1750