108
C.-M. Abuhaie et al. / European Journal of Medicinal Chemistry 59 (2013) 101e110
J ¼ 7.2 Hz, 3H, CO2CH2CH3), 3.21 (s, 6H, N(CH3)2), 4.08 (q, J ¼ 7.2 Hz,
2H, CO2CH2CH3), 6.66 (d, J ¼ 7.2 Hz, 2H, PyH) 7.07e7.13 (m, 2H,
ArH), 7.21 (d, J ¼ 8.0 Hz, 2H, ArH), 7.31 (d, J ¼ 7.2 Hz, 1H, ArH), 7.50
(d, J ¼ 8.0 Hz, 1H, ArH), 7.71 (d, J ¼ 7.2 Hz, 2H, PyH), 7.80 (s, 1H,
142.7 (CH), 144.0 (CH), 145.6 (CH), 147.9 (CH), 164.2 (C), 167.0 (C).
Anal. calcd for C26H21N3O3S: C, 68.49; H, 4.60; N, 9.21; S, 7.02.
Found: C, 68.55; H, 4.82; N, 9.20%.
CH]), 7.87 (s,1H, ArH). 13C NMR (CDCl3,100 MHz)
d
14.6 (CH3), 40.2
4.1.2.10. 3-(2-Cyanoacrylonitrile)-10H-phenothiazin-10-yl-carbonyl-
4-methoxypyridinium methylide (13j). Yellow solid; 50% yield; mp
242e245 ꢁC. IR nmax/cmꢂ1: 2181, 2170, 1625, 1511, 1238, 1167, 1124,
(2CH3), 59.8 (CH2), 68.1 (C), 106.9 (2CH), 110.3 (C), 120.2 (C), 124.0
(CH), 124.3 (CH), 125.4 (CH), 125.8 (CH), 127.6 (CH), 127.9 (CH), 128.1
(CH), 129.0 (C), 130.3 (C), 133.0 (C), 141.6 (C), 142.3 (C), 144.2 (CH),
146.5 (2CH), 156.2 (C), 165.7 (C), 167.1 (C). Anal. calcd for
938, 746, 595. 1H NMR (CDCl3, 400 MHz)
d ppm: 4.06 (s, 3H, OCH3),
7.07 (d, J ¼ 7.2 Hz, 2H, pyridine ArH), 7.08 (s, 1H, CH]), 7.15 (t,
J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.27e7.32 (m, 4H, phenoth. ArH), 7.71
(d, J ¼ 7.6 Hz, 2H, phenoth. ArH), 8.03 (d, J ¼ 7.2 Hz, 2H, pyridine
C
27H23ClN4O3S: C, 62.41; H, 4.43; N, 10.78; S, 6.16. Found: C, 62.08;
H, 4.26; N, 10.39%.
ArH). 13C NMR (CDCl3, 100 MHz)
d: 43.0 (C), 57.7 (CH3), 112.4 (2CH),
4.1.2.6. 3-(2-Cyanoacrylonitrile)-10H-phenothiazin-10-yl-carbonyl-
pyridinium methylide (13f). Orange solid; 36% yield; mp 292e
294 ꢁC. IR nmax/cmꢂ1: 2193, 2172, 1631, 1542, 1458, 1358, 1284,
118.0 (2C), 120.2 (C), 125.0 (2CH), 126.3 (2CH), 127.6 (2CH), 127.9
(2CH),131.4 (2C),140.4 (2C), 144.7 (CH),149.9 (2CH),163.5 (C), 170.7
(C). Anal. calcd for C24H16N4O2S: C, 67.84; H, 3.76; N, 13.19; S, 7.53;
Found: C, 67.41; H, 3.66; N, 12.90%.
1256, 1174, 746, 589. 1H NMR (DMSO-d6, 400 MHz)
d ppm: 6.84 (s,
1H, CH]), 7.22 (t, J ¼ 7.6 Hz, 2H, ArH), 7.35 (t, J ¼ 7.6 Hz, 2H, ArH),
7.40 (d, J ¼ 7.6 Hz, 2H, ArH), 7.86 (d, J ¼ 8.0 Hz, 2H, ArH), 8.01 (t,
J ¼ 6.8 Hz, 2H, PyH), 8.50 (t, J ¼ 7.6 Hz, 1H, PyH), 8.93 (d, J ¼ 6.0 Hz,
4.1.2.11. 3-(2-Cyanoethylacrylate)-10H-phenothiazin-10-yl-carbonyl-
4-methoxypyridinium methylide (13k). Yellow solid; 41% yield; mp
211e213 ꢁC. IR nmax/cmꢂ1: 2181, 1674, 1624, 1512, 1455, 1312, 1185,
2H, PyH). 13C NMR (DMSO-d6, 100 MHz)
d 40.2 (C), 114.0 (C), 116.9
(C) 120.4 (C), 125.1 (2CH), 126.3 (2CH), 127.5 (2CH), 127.7 (2CH),
127.8 (2CH), 130.3 (2C), 140.0 (2C), 142.5 (CH), 145.6 (CH), 149.1
(2CH), 162.6 (C). Anal. calcd for C23H14N4OS: C, 69.96; H, 3.54; N,
14.19. Found: C, 69.58; H, 3.97; N, 13.90%.
1103, 748, 593. 1H NMR (CDCl3, 400 MHz)
d
ppm: 1.22 (t, J ¼ 7.2 Hz,
3H, CO2CH2CH3), 4.02 (s, 3H, OCH3), 4.09 (q, J ¼ 7.2 Hz, 2H,
CO2CH2CH3), 7.05e7.19 (m, 4H, 2H pyridine and 2H phenoth. ArH),
7.24 (t, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.30 (d, J ¼ 7.6 Hz, 2H, phenoth.
ArH), 7.71 (d, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.82 (s, 1H, CH]), 8.07
4.1.2.7. 3-(2-Cyanoethylacrylate)-10H-phenothiazin-10-yl-carbonyl-
pyridinium methylide (13g). Orange solid; 42% yield; mp 259e
261 ꢁC. IR nmax/cmꢂ1: 2181, 1644, 1615, 1560, 1334, 1232, 1195,
(d, J ¼ 6.8 Hz, 2H, pyridine ArH). 13C NMR (CDCl3, 100 MHz)
d 14.6
(CH3), 57.5 (CH2), 59.8 (CH3), 67.4 (C), 111.0 (C), 112.3 (2CH), 120.0
(C), 124.7 (2CH), 125.8 (2CH), 127.4 (2CH), 127.7 (2CH), 131.2 (2C),
140.9 (2C), 143.1 (CH), 149.9 (2CH), 164.7 (C), 167.0 (C), 170.4 (C).
Anal. calcd for C26H21N3O4S: C, 66.16; H, 4.45; N, 8.90. Found: C,
66.41; H, 4.28; N, 8.91%.
1098, 754, 596. 1H NMR (CDCl3, 400 MHz)
d
ppm: 1.23 (t, J ¼ 7.0 Hz,
3H, CO2CH2CH3), 4.11 (q, J ¼ 7.0 Hz, 2H, CO2CH2CH3), 7.12 (t,
J ¼ 7.6 Hz, 2H, PyH) 7.20e7.35 (m, 4H, ArH), 7.70e7.80 (m, 4H, ArH),
7.92 (s, 1H, CH]), 8.20 (t, J ¼ 7.6 Hz, 1H, PyH), 8.32 (d, J ¼ 6.0 Hz, 2H,
PyH). 13C NMR (CDCl3, 100 MHz)
d
14.6 (CH3), 60.0 (CH2), 68.1 (C),
4.1.2.12. 3-(2-Cyanoacrylonitrile)-10H-phenothiazin-10-yl-carbonyl-
3,5-dimethylpyridinium methylide (13l). Yellow solid; 57% yield; mp
266e269 ꢁC. IR nmax/cmꢂ1: 2194, 2171, 1639, 1536, 1456, 1255, 1029,
112.3 (C), 119.4 (C), 124.8 (2CH), 126.0 (2CH), 126.9 (2CH), 127.5
(2CH), 127.8 (2CH), 131.3 (2C), 140.7 (2C), 142.7 (CH), 143.5 (CH),
148.5 (2CH), 164.2 (C), 166.9 (C). Anal. calcd for C25H19N3O3S: C,
67.94; H, 4.30; N, 9.51; S, 7.24. Found: C, 67.6; H, 4.54; N, 9.48%.
759, 594. 1H NMR (DMSO-d6, 400 MHz)
d ppm: 2.30 (s, 6H, 2CH3),
7.13 (s, 1H, CH]), 7.20 (t, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.32e7.36
(m, 4H, phenoth. ArH), 7.85 (d, J ¼ 7.6 Hz, 2H, phenoth. ArH), 8.06
(s, 1H, pyridine ArH), 8.53 (s, 2H, pyridine ArH). 13C NMR (DMSO-d6,
4.1.2.8. 3-(2-Cyanoacrylonitrile)-10H-phenothiazin-10-yl-carbonyl-
3-methylpyridinium methylide (13h). Orange solid; 49% yield; mp
170e174 ꢁC. IR nmax/cmꢂ1: 2193, 2171, 1632, 1537, 1455, 1353, 1280,
100 MHz) d 17.5 (2CH3), 40.7 (C), 114.4 (C), 117.1 (C), 120.7 (C), 125.1
(2CH), 126.2 (2CH), 127.5 (2CH), 127.7 (2CH), 130.5 (2C), 137.1 (2C),
139.6 (2C), 142.2 (CH), 145.2 (2CH), 145.8 (CH), 162.4 (C). Anal. calcd
for C25H18N4OS: C, 71.00; H, 4.26; N, 13.25; S, 7.57. Found: C, 70.77;
H, 4.31; N, 13.25%.
1250, 1170, 754, 589. 1H NMR (DMSO-d6, 400 MHz)
d ppm: 2.39 (s,
3H, CH3), 6.92 (s, 1H, CH]), 7.20 (dt, J ¼ 7.6, 0.8 Hz, 2H, phenoth.
ArH), 7.31e7.38 (m, 4H, phenoth. ArH), 7.78e7.87 (m, 3H, 1H pyri-
dine and 2H phenoth. ArH), 8.27 (d, J ¼ 8.0 Hz, 1H, H-4 pyridine
ArH), 8.69 (d, J ¼ 6.0 Hz, 1H, H-6 pyridine ArH), 8.75 (s, 1H, H-2
4.1.2.13. 3-(2-Cyanoethylacrylate)-10H-phenothiazin-10-yl-carbonyl-
3,5-dimethylpyridinium methylide (13m). Orange solid; 61% yield;
mp 245e246 ꢁC. IR nmax/cmꢂ1: 2190, 1672, 1628, 1522, 1457, 1188,
pyridine ArH). 13C NMR (DMSO-d6, 100 MHz)
d 17.6 (CH3), 40.5 (C),
114.2 (C), 117.0 (C), 120.5 (C), 125.1 (2CH), 126.2 (2CH), 126.7 (CH),
127.6 (2CH),127.8 (2CH),130.4 (2C),138.0 (C),139.8 (2C),142.4 (CH),
145.6 (CH), 146.2 (CH), 147.9 (CH), 162.5 (C). Anal. calcd for
1021, 755, 598. 1H NMR (CDCl3, 400 MHz)
d
ppm: 1.25 (t, J ¼ 6.8 Hz,
3H, CO2CH2CH3), 2.38 (s, 6H, 2CH3), 4.14 (q, J ¼ 6.8 Hz, 2H,
CO2CH2CH3), 7.10 (t, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.21 (d, J ¼ 7.6 Hz,
2H, phenoth. ArH), 7.26 (t, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.69 (s, 1H,
CH]), 7.81 (d, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.87 (s, 2H, pyridine
C
24H16N4OS: C, 70.50; H, 3.91; N, 13.70; S, 7.83. Found: C, 70.40; H,
4.39; N, 13.28%.
4.1.2.9. 3-(2-Cyanoethylacrylate)-10H-phenothiazin-10-yl-carbonyl-
3-methylpyridinium methylide (13i). Red solid; 43% yield; mp 220e
224 ꢁC. IR nmax/cmꢂ1: 2181, 1658, 1635, 1527, 1475, 1231, 1196, 764,
ArH), 8.09 (s, 1H, pyridine ArH). 13C NMR (100 MHz, CDCl3)
d 14.6
(CH3), 18.5 (2CH3), 59.9 (CH2), 68.0 (C), 112.3 (C), 119.4 (C), 124.9
(2CH), 125.8 (2CH), 127.4 (2CH), 127.5 (2CH), 131.0 (2C), 137.2 (2C),
140.5 (2C), 142.4 (CH), 144.7 (CH), 144.9 (2CH), 164.1 (C), 167.2 (C).
Anal. calcd for C27H23N3O3S: C, 69.00; H, 4.89; N, 8.94. Found: C,
68.87; H, 4.64; N, 8.75%.
597. 1H NMR (CDCl3, 400 MHz)
CO2CH2CH3), 2.46 (s, 3H, ArCH3), 4.09 (q, 7.2 Hz, 2H,
d
ppm: 1.23 (t, J ¼ 7.2 Hz, 3H,
J
¼
CO2CH2CH3), 7.11 (t, J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.20e7.30 (m, 4H,
phenoth. ArH), 7.59 (t, J ¼ 6.8 Hz, 1H, pyridine ArH), 7.78 (d,
J ¼ 7.6 Hz, 2H, phenoth. ArH), 7.94 (d, J ¼ 6.8 Hz, 1H, pyridine ArH),
8.00 (s, 1H, CH]), 8.07 (s, 1H, pyridine ArH), 8.12 (d, J ¼ 6.8 Hz, 1H,
4.1.3. General procedure for the synthesis of compounds 14aed, 15,
16 and 17
DBU (1 equiv) was added to a solution of cycloimmonium salt
(1 equiv) in a minimum volume of DMF. The reaction media
become yellow. This corresponded to the formation in situ of the
pyridine ArH). 13C NMR (CDCl3, 100 MHz)
d
14.6 (CH3), 18.7 (CH3),
60.0 (CH2), 68.2 (C), 112.3 (C), 119.4 (C), 124.8 (2CH), 125.9 (2CH),
126.2 (CH), 127.5 (2CH), 127.7 (2CH), 131.2 (2C), 138.1 (C), 140.7 (2C),