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B. Parrino et al. / European Journal of Medicinal Chemistry 94 (2015) 149e162
2H, NH2), 6.10 (dd, 1H, J ¼ 8.5, 2.5 Hz, H-50), 6.30 (d, 1H, J ¼ 2.5 Hz,
H-30), 6.98 (d, 1H, J ¼ 8.5 Hz, H-60), 7.02e7.14 (m, 2H, H-5, H-4), 7.58
(dt, 1H, JF ¼ 2.5 Hz, J ¼ 6.7 Hz, H-6), 7.87 (1H, d, JF ¼ 2.5 Hz, H-3),
69.38; H, 5.03; N, 14.07.
4.1.1.22. 4-Methylisoindolo[2,1-a]quinoxalin-6(5H)-iminium acetate
9.52 (s,1H, OH); 13C NMR (50 MHz, DMSO-d6)
d: 92.1 (d, JF ¼ 2.8 Hz),
(1c). Yellow solid; yield: 95%; m.p: 210e212 ꢀC; IR (cmꢁ1) 3309,
101.6 (d), 103.7 (d), 108.1 (dd, JF ¼ 16.7 Hz), 114.0 (s), 114.7 (s), 117.9
(dd, JF ¼ 4.3 Hz), 121.1 (d, JF ¼ 18 Hz), 122.4 (dd, JF ¼ 6.4 Hz), 123.7
(d), 126.7 (d, JF ¼ 6.7 Hz), 128.7 (d), 145.3 (s), 153.7 (d, JF ¼ 248 Hz),
159.3 (s). Anal. Calcd for C15H10FN3O: C, 67.41; H, 3.77; N, 15.72.
Found: C, 67.70; H, 4.06; N, 15.96.
3320; 1H NMR (200 MHz, DMSO-d6)
d:1.91 (s, 3H, CH3), 2.60 (s, 3H,
CH3), 6.81 (bs, 2H, NH2), 7.17e7.37 (m, 4H, H-1, H-2, H-3, H-7),
7.85e7.89 (m, 1H, H-9), 8.22 (d, 1H, J ¼ 7.7 Hz, H-8), 8.43e8.48 (m,
1H, H-10), 8.89 (s, 1H, H-11), 11.96 (bs, 1H, NH); 13C NMR (50 MHz,
DMSO-d6) d:21.02 (q), 18.23 (q), 99.49 (d), 107.97 (s), 113.39 (d),
119.36 (d), 119.51 (s), 120.23 (d), 121.58 (d), 122.15 (s), 122.54 (d),
123.05 (d), 123.28 (s), 123.83 (s), 127.59 (d), 133.39 (s), 150.37 (s),
171.97 (s). Anal. Calcd for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67.
Found: C, 70.14; H, 5.51; N, 13.89.
4.1.1.17. 2-(2-Amino-4-hydroxyphenyl)-6-methoxy-2H-isoindole-1-
carbonitrile (5p). Conditions: 3 h rt before and 24 h rt after KCN
addition. Brown solid; yield: 43%; m.p.: 211e212 ꢀC; IR (cmꢁ1);
3430, 3345, 3303, 2200 1H NMR (200 MHz, DMSO-d6)
d: 3.79 (s, 3H,
OCH3), 4.92 (bs, 2H, NH2), 6.10 (dd, 1H, J ¼ 8.5, 2.5 Hz, H-50), 6.30 (d,
1H, J ¼ 2.5 Hz, H-30), 6.94 (d, 1H, J ¼ 8.5 Hz, H-60), 6.96 (dd, 1H,
J ¼ 9.1, 2.2, Hz, H-5), 7.07 (d, 1H, J ¼ 2.2 Hz, H-7), 7.54 (d, 1H,
J ¼ 9.1 Hz, H-4), 7.58 (s, 1H, H-3), 9.49 (s, 1H, OH); 13C NMR (50 MHz,
4.1.1.23. 3-Methoxyisoindolo[2,1-a]quinoxalin-6(5H)-iminium aꢁce1-
tate (1d). Yellow solid, yield: 99%; m.p.: 243e244 ꢀC; IR (cm
)
3303, 3500; H NMR (200 MHz, DMSO-d6) d: 1.92 (s, 3H, CH3), 3.86
(s, 3H, OCH3), 6.83 (bs, 2H, NH2), 6.93 (dd, 1H, J ¼ 8.9, 2.8 Hz, H-2),
7.04 (d, 1H, J ¼ 2.8 Hz, H-4), 7.28e7.33 (m, 2H, H-1, H-8), 7.82e7.87
(m, 1H, H-9), 8.29 (d, 1H, J ¼ 9.0 Hz, H-7), 8.40e8.44 (m, 1H, H-10),
8.82 (s, 1H, H-11), 12.04 (bs, 1H, NH); 13C NMR (50 MHz, DMSO-d6)
DMSO-d6) d: 55.0 (q), 94.5 (s), 98.2 (d), 101.6 (d), 103.7 (d), 114.2 (s),
115.3 (s), 118.9 (d), 120.0 (d), 121.3 (d), 124.3 (s), 127.1 (s), 128.6 (d),
145.2 (s), 155.1 (s), 159.0 (s). Anal. Calcd for C16H13N3O2: C, 68.81; H,
4.69; N, 15.05. Found: C, 69.12; H, 5.03; N, 15.32.
d: 21.1 (q), 55.3 (q), 107.5 (d), 107.5 (d), 110.4 (d), 116.6 (d), 117.9 (s),
118.6 (s), 119.2 (d), 119.5 (s), 120.0 (d), 122.4 (d), 122.8 (d), 125.7 (s),
129.9 (s), 151.7 (s), 158.2 (s), 172.0 (s). Anal. Calcd for C18H17N3O3: C,
66.86; H, 5.30; N, 13.00. Found: C, 66.63; H, 5.36; N, 12.71.
4.1.1.18. 2-(2-Amino-4-hydroxyphenyl)-5-methoxy-2H-isoindole-1-
carbonitrile (5q). Conditions: 3 h rt before and 24 h rt after KCN
addition. Brown solid; yield: 40%; m.p: 194e196 ꢀC; IR (cmꢁ1) 3475,
3372, 3266, 2198; 1H NMR (200 MHz, DMSO-d6)
d: 3.84 (s, 3H,
4.1.1.24. 2,3-Dimethylisoindolo[2,1-a]quinoxalin-6(5H)-iminium ac-
OCH3), 4.97 (bs, 2H, NH2), 6.09 (dd, 1H, J ¼ 8.5, 2.5 Hz, H-50), 6.29 (d,
1H, J ¼ 2.5 Hz, H-30), 6.79 (dd, 1H, J ¼ 9.0 2.2 Hz, H-5), 6.89 (d, 1H,
J ¼ 2.2 Hz, H-7), 6.93 (d, 1H, J ¼ 8.5 Hz, H60), 7.64 (d, 1H, J ¼ 9.0 Hz,
H-4), 7.66 (s, 1H, H-3), 9.47 (s, 1H, OH); 13C NMR (50 MHz, DMSO-
etate (1e). Brown solid; yield: 90%; m.p.: 238e239 ꢀC; IR (cmꢁ1
)
3362, 3401; 1H NMR (200 MHz, DMSO-d6)
d: 1.92 (s, 3H, CH3), 2.34
(s, 3H, CH3), 2.40 (s, 3H, CH3), 6.71 (bs, 2H, NH2), 7.25e7.30 (m, 2H,
H-8, H-9), 7.37 (s, 1H, H-4), 7.83e7.88 (m, 1H, H-7), 8.11 (s, 1H, H-1),
8.39e8.43 (m, 1H, H-10), 8.83 (s, 1H, H-11) 11.95 (s, 1H, NH); 13C
d6) d: 55.2 (q), 93.8 (s), 94.7 (d), 101.6 (d), 103.7 (d), 114.7 (s), 115.3
(s), 116.9 (d), 120.0 (s), 121.3 (d), 123.0 (d), 128.6 (d), 132.3 (s), 145.2
(s), 157.9 (s), 159.0 (s). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69;
N, 15.05. Found: C, 69.10; H, 4.77; N, 15.33.
NMR (50 MHz, DMSO-d6)
d
: 21.1 (q), 55.3 (q ꢂ 2), 106.9 (d),108.1 (s),
115.8 (d), 119.3 (d), 119.4 (s), 120.1 (d), 121.5 (s), 122.3 (d), 122.9 (d),
125.7 (s), 125.7 (d), 131.0 (s), 135.5 (s), 136.4 (s), 151.0 (s), 172.0 (s).
Anal. Calcd for C19H19N3O2: C, 71.01; H, 5.96; N, 13.08. Found: C,
70.75; H, 5.75; N, 12.82.
4.1.1.19. General procedure for isoindolo[2,1-a]quinoxalin-6(5H)-
iminium acetates (1aei,mep). A solution of suitable 2-(20-amino-
phenyl)-2H-isoindole-1-carbonitrile 5aei,mep (3 mmol) in acetic
acid (10 mL) was stirred under reflux for 30 min. The precipitate
formed after cooling was filtered, collected and crystallized in
ethanol to gave the desired compounds 1aei,mep.
4.1.1.25. 1,4-Dimethoxyisoindolo[2,1-a]quinoxalin-6(5H)-iminium
acetate (1f). Yellow solid; yield: 90%; m.p.: 272e273 ꢀC; IR (cmꢁ1
)
3352, 3339; 1H NMR (200 MHz, DMSO-d6)
d: 1.92 (s, 3H, CH3), 3.87
(s, 3H, OCH3), 4.06 (s, 3H, OCH3), 6.87e7.02 (m, 4H, NH2, H-2, H-3),
7.25e7.35 (m, 2H, H-8, H-9), 7.90e7.95 (m, 1H, H-7), 8.41e8.45 (m,
1H, H-10), 9.38 (s, 1H, H-11). 11.01 (s, 1H, NH); 13C NMR (50 MHz,
4.1.1.20. 2-Methoxyisoindolo[2,1-a]quinoxalin-6(5H)-iminium aꢁce1-
tate (1a). Yellow solid; yield: 99%; m.p.: 182 -182 ꢀC; IR (cm
)
DMSO-d6) d: 21.0 (q), 55.8 (q), 56.4 (q), 103.3 (d), 107.5 (d), 108.3 (s),
3500, 3347; 1H NMR (200 MHz, DMSO-d6)
d: 1.91 (s, 3H, CH3), 3.94
113.9 (d), 114.9 (s), 118.2 (s), 119.7 (d), 119.7 (d), 122.7 (d), 122.9 (d),
125.2 (s), 130.9 (s), 144.6 (s), 147.4 (s), 150.7 (s), 172.9 (s). Anal. Calcd
for C19H19N3O4: C, 64.58; H, 5.42; N, 11.89. Found: C, 64.32; H, 5.28;
N, 11.84.
(s, 3H, OCH3), 6.70 (bs, 2H, NH2), 7.12 (dd, 1H, J ¼ 8.9, 2.7 Hz, H-3),
7.28e7.33 (m, 2H, H-8, H-9), 7.53 (d, 1H, J ¼ 8.9 Hz, H-4), 7.86e7.90
(m, 1H, H-7), 7.91 (d, 1H, J ¼ 2.7 Hz, H-1), 8.41e8.45 (m, 1H, H-10),
8.98 (s, 1H, H-11), 11.93 (s, 1H, NH); 13C NMR (50 MHz, DMSO-d6)
d:
21.0 (q), 55.9 (q), 99.2 (d), 108.1 (d), 115.6 (d). 116.7 (s), 119.6 (d),
120.4 (d), 122.6 (d), 123.8 (d), 125.8 (s), 126.3 (d), 131.7 (s), 149.8 (s),
155.2 (s), 155.7 (s), 159.7 (s), 172.0 (s). Anal. Calcd for C18H17N3O3: C,
66.86; H, 5.30; N, 13.00. Found: C, 66.66; H, 5.25; N, 12.73.
4.1.1.26. 2,3-Dichloroisoindolo[2,1-a]quinoxalin-6(5H)-iminium aꢁce1-
3557, 3398; 1H NMR (200 MHz, DMSO-d6)
d: 1.92 (s, 3H, CH3), 7.14
tate (1g). Yellow solid; yield: 99%; m.p.: 242e243 ꢀC; IR (cm
)
(bs, 2H, NH2), 7.30e7.35 (m, 2H, H-8, H-9), 7.69 (s, 1H, H-4),
7.83e7.89 (m, 1H, H-10), 8.45 (s, 1H, H-7), 8.77 (s, 1H, H-1), 9.03 (s,
4.1.1.21. Isoindolo[2,1-a]quinoxalin-6(5H)-iminium acetate (1b).
Yellow solid; yield: 99%; m.p: 249e250 ꢀC; IR (cmꢁ1) 3501, 3367; 1H
NMR (200 MHz, DMSO-d6) d:1.91 (s, 1H, CH3), 6.87 (bs, 2H, NH2),
1H, H-11), 11.07 (s, 1H, NH); 13C NMR (50 MHz, DMSO-d6)
d: 21.02
(q), 99.34 (s), 107.7 (d), 109.2 (s), 117.6 (s), 119.7 (s), 119.9 (d), 120.1
(s), 123.1 (d), 123.3 (s), 123.5 (d), 123.5 (s), 125.9 (s), 128.9 (d), 138.8
(d), 152.3 (d) 172.0 (s). Anal. Calcd for C17H13Cl2N3O2: C, 56.37; H,
3.62; N, 11.60. Found: C, 56.14; H, 3.33; N, 11.86.
7.28e7.36 (m, 3H, H-1, H-4, H-2), 7.46 (dt, 1H, J ¼ 7.0, 2.0, Hz, H-3),
7.58 (dd,1H, J ¼ 8.1,1.2, Hz, H-7), 7.86e7.90 (m, 1H, H-9), 8.38 (d,1H,
J ¼ 8.1 Hz, H-8), 8.42e8.47 (m, 1H, H-10), 8.93 (s, 1H, H-11), 11.90 (s,
1H, NH); 3C NMR (50 MHz, DMSO-d6)
d:21.1 (q), 117.7 (d), 108.0 (s),
4.1.1.27. 3-Methoxy-8,9-dimethylisoindolo[2,1-a]quinoxalin-6(5H)-
115.64 (d),119.4 (d),119.5 (s),120.2 (d),122.1 (d),122.7 (d),123.1 (d),
123.6 (s), 125.5 (d), 125.7 (s), 126.9 (d), 138.4 (s), 151.4 (s), 172.0 (s).
Anal. Calcd for C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C,
iminium acetate (1h). Yellow solid; yield: 95%; m.p: 243e244 ꢀC; IR
(cmꢁ1) 3399, 3398; 1H NMR (200 MHz, DMSO-d6)
d: 1.91 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 2.42 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 6.74 (bs,