R. Majeed et al. / European Journal of Medicinal Chemistry 63 (2013) 782e792
789
9), 1.47 and 1.86 (1H each, m, H-22), 1.46 and 2.09 (1H each, m, H-
16),1.49 (1H, m, H-18),1.54 (2H, m, H-2),1.70 (3H, s, H-30), 2.28 (1H,
m, H-13), 3.03 (1H, m, H-19), 3.17 (1H, m, H-3), 3.89 (3H, s, eOCH3),
4.60 and 4.74 (1H each, s, H-29), 5.25 and 5.36 (1H each, d,
J ¼ 12.0 Hz, eOCH2e), 6.98 (1H, d, J ¼ 8.01 Hz, AreH), 7.26 (1H, d,
J ¼ 8.0 Hz, AreH), 7.33 (1H, s, AreH), 7.42 (1H, dd, J ¼ 8.0, 8.01 Hz,
(1H, d, J ¼ 1.80 Hz, AreH), 7.74 (1H, dd, J ¼ 8.0, 1.80 Hz, AreH), 7.85
(1H, s, NeCH). 13C NMR (100 MHz, CDCl3):
176.17, 150.34, 143.25,
d
138.87, 137.24, 134.54, 133.26, 133.05, 125.66, 109.71, 90.08, 78.91,
56.91, 56.57, 55.34, 50.46, 49.44, 46.95, 42.33, 40.70, 38.85, 38.70,
38.31, 37.17, 36.91, 34.23, 31.95, 30.55, 29.60, 27.99, 27.37, 25.49,
20.85, 19.38, 18.33, 17.68, 16.35, 15.85, 15.45, 14.68. IR gmax (neat):
3345, 3221, 2992, 2868, 1711, 1617, 1463, 1376, 1244, 1192, 1133,
1077, 1039, 941, 883, 810, 620 cmꢃ1. MS (%) for C40H56IN3O3 at m/z
752.3531 [M ꢃ H]þ, 752 (100), 725 (4.2), 670 (9.1), 645 (29.5), 610
(7.7), 580 (21.1), 567 (23.9), 518 (25.3), 493 (90), 455 (55.6), 374
(28.1), 340 (19.7), 327 (73.2), 310 (71.8), 282 (97.1), 265 (32.3), 254
(76.0), 235 (57.7), 198 (59.1), 134 (25.5). HRMS m/z calcd. for
AreH), 8.08 (1H, s, NeCH). 13C NMR (100 MHz, CDCl3):
d 176.24,
160.61, 150.43, 143.86, 137.90, 130.54, 122.60, 114.74, 112.44, 109.71,
106.43, 78.95, 57.02, 56.65, 56.56, 55.26, 50.44, 49.48, 47.00, 42.31,
40.61, 38.83, 38.66, 38.35, 37.12, 36.87, 34.15, 31.98, 30.58, 29.68,
27.96, 27.35, 25.47, 20.83, 19.38, 18.19, 16.00, 15.68, 15.35, 14.67. IR
gmax (neat): 3514, 3335, 2942, 2869, 1721, 1631, 1611, 1462, 1376,
1256, 1157, 1107, 1086, 1042, 855, 776, 684 cmꢃ1. MS (%) for
C
40H56IN3O3 [M þ H]þ 754.3439, found 754.3389.
C
40H57N3O4 at m/z 643.4449 [M ꢃ H]þ, 643 (53.4), 576 (17), 526
(36.9), 519.9 (17.8), 486 (10.2), 453 (17.6), 439 (17.8), 429.7 (54.7),
377 (31.5), 365 (31.5), 347.9 (23.2), 339 (35.6), 325 (58.9), 313 (64.3),
278 (72.6), 226 (34.4), 256 (34.2), 248 (63), 226 (31.5), 174 (69.8),
112 (37.6), 278 (72.6), 248 (64.3). HRMS m/z calcd. for C40H57N3O4
[M þ H]þ 644.4422, found 639.4390.
4.1.5.10. Synthesis of 3{1N(3-methyl-5-hydroxyphenyl)-1H-1,2,3-
triazol-4yl}methyloxy betulinic acid (12). The title compound pre-
pared by the reaction of propargylated betulinic acid (100 mg,
0.20 mmol) and 3-azido-5-methylphenol (45 mg, 0.3 mmol) as per
the method described in Section 4.1.5 to furnish 12 (121 mg, 94%
yield), mp 267e270 ꢂC. 1H NMR (200 MHz, CDCl3):
d 0.64 (1H, m, H-
4.1.5.8. Synthesis of 3{1N(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-
4yl}methyloxy betulinic acid (10). The title compound prepared by
the reaction of propargylated betulinic acid (120 mg, 0.24 mmol)
and 1-azido-3,4,5-methoxy benzene (52 mg, 0.3 mmol) as per the
method described in Section 4.1.5 to furnish 10 (155 mg, 92% yield),
5), 0.67 (3H, s, H-25), 0.72 (3H, s, H-24), 0.73 (3H, s, H-26), 0.89 and
1.51 (1H each, m, H-1), 0.93 and 0.95 (3H each, s, H-23 and H-27),
1.09 and 1.84 (1H each, m, H-11), 1.21 and 1.59 (1H each, m, H-12),
1.16 and 1.45 (1H each, m, H-15), 1.24 and 1.50 (1H each, m, H-6),
1.26 and 1.38 (1H each, m, H-7), 1.27 and 1.64 (1H each, m, H-21),
1.20 (1H, m, H-9), 1.47 and 1.86 (1H each, m, H-22), 1.46 and 2.09
(1H each, m, H-16), 1.49 (1H, m, H-18), 1.54 (2H, m, H-2), 1.69 (3H, s,
H-30), 2.13 (3H, s, AreCH3), 2.26 (1H, m, H-13), 3.01 (1H, m, H-19),
3.16 (1H, m, H-3), 4.61 and 4.75 (1H each, s, H-29), 5.25 and 5.36
(1H each, d, J ¼ 12.0 Hz, eOCH2e), 7.01 (1H, s, AreH), 7.18 (1H, s,
AreH), 7.33 (1H, s, AreH), 8.08 (1H, s, NeCH). 13C NMR (125 MHz,
mp 221e223 ꢂC. 1H NMR (400 MHz, CDCl3):
d 0.62 (1H, m, H-5),
0.63 (3H, s, H-25), 0.71 (3H, s, H-24), 0.72 (3H, s, H-26), 0.88 and
1.50 (1H each, m, H-1), 0.93 and 0.94 (3H each, s, H-23 and H-27),
1.09 and 1.85 (1H each, m, H-11), 1.21 and 1.59 (1H each, m, H-12),
1.16 and 1.45 (1H each, m, H-15), 1.24 and 1.50 (1H each, m, H-6),
1.26 and 1.38 (1H each, m, H-7), 1.27 and 1.64 (1H each, m, H-21),
1.20 (1H, m, H-9), 1.47 and 1.86 (1H each, m, H-22), 1.46 and 2.06
(1H each, m, H-16), 1.49 (1H, m, H-18), 1.54 (2H, m, H-2), 1.70 (3H, s,
H-30), 2.28 (1H, m, H-13), 3.03 (1H, m, H-19), 3.18 (1H, m, H-3), 3.89
(6H, s, 2ꢁ eOCH3), 3.82 (3H, s, eOCH3), 4.60 and 4.74 (1H each, s, H-
29), 5.25 and 5.36 (1H each, d, J ¼ 12.0 Hz, eOCH2e), 6.93 (2H, s,
CDCl3):
d 179.63, 154.53, 151.54, 147.25, 138.60, 130.23, 126.68,
124.08, 120.36, 118.24, 109.68, 86.75, 56.62, 55.99, 55.77, 50.48,
49.29, 46.90, 43.26, 40.07, 38.54, 38.47, 38.39, 37.42, 37.15, 34.32,
32.41, 30.48, 29.59, 28.09, 27.19, 25.51, 22.96, 20.89, 19.35, 18.12,
16.26, 16.15, 16.07, 14.68. IR gmax (neat): 3544, 2993, 2871, 1699,
1619, 1465, 1377, 1246, 1195, 1131, 1097, 1009, 945, 891, 868,
723 cmꢃ1. MS (%) for C40H57N3O4 at m/z 644.9847 [M þ H]þ, 644
(6.4), 621 (65.6), 561 (66.0), 621 (65.6), 536 (51.5), 501 (48.4), 471
(100), 414 (65.6), 356 (56.2), 324 (31.2), 28 (56.2), 208 (34.3), 178
(37.5). HRMS m/z calcd. for C40H57N3O4 [M þ H]þ 644.4422,
found 644.4393.
AreH), 8.08 (1H, s, NeCH). 13C NMR (125 MHz, CDCl3):
d 176.36,
153.89 (2ꢁ C), 150.34, 143.75, 138.29, 132.73, 122.62, 109.74, 98.31
(2ꢁ CH), 78.96, 61.07, 56.64, 56.54, 56.12 (2ꢁ OCH3), 55.21, 50.37,
49.42, 47.01, 42.30, 40.59, 38.80, 38.63, 38.33, 37.09, 36.85, 34.12,
31.95, 30.55, 29.70, 28.42, 27.28, 25.76, 20.82, 19.34, 18.20, 16.07,
15.60, 15.35, 14.66. IR gmax (neat): 3468, 3236, 2940, 2869, 1715,
1623, 1615, 1512, 1472, 1376, 1233, 1129, 1042, 1007.5, 881, 828,
618 cmꢃ1. MS (%) for C42H61N3O6 at m/z 702.4517 [M ꢃ H]þ, 702
(100), 657 (57.1), 611 (53.9), 551 (57.1), 490 (87.3), 464 (69.8), 417
(76.1), 412 (71.4), 315 (50.7), 264 (36.5), 204 (41.2), 152 (58.7).
4.1.5.11. Synthesis of 3{1N(5-hydroxy-naphth-1yl)-1H-1,2,3-triazol-
4yl}methyloxy betulinic acid (13). The title compound prepared by
the reaction of propargylated betulinic acid (75 mg, 0.15 mmol) and
5-azidonaphthalen-1-ol (37 mg, 0.2 mmol) as per the method
described in Section 4.1.5 to furnish 13 (98 mg, 97% yield), mp 238e
HRMS m/z calcd. for
found 704.4593.
C
42H61N3O6 [M
þ
H]þ 704.4633,
240 ꢂC. 1H NMR (400 MHz, CDCl3):
d 0.63 (1H, m, H-5), 0.68 (3H, s,
4.1.5.9. Synthesis of 3{1N(5-iodo-2-methylphenyl)-1H-1,2,3-triazol-
4yl}methyloxy betulinic acid (11). The title compound prepared by
the reaction of propargylated betulinic acid (85 mg, 0.17 mmol) and
2-azido-4-iodo-1-methylbenzene (55 mg, >0.2 mmol) as per the
method described in Section 4.1.5 to furnish 11 (122 mg, 96% yield),
H-25), 0.70 (3H, s, H-24), 0.73 (3H, s, H-26), 0.89 and 1.51 (1H each,
m, H-1), 0.93 and 0.95 (3H each, s, H-23 and H-27), 1.09 and 1.84
(1H each, m, H-11), 1.21 and 1.59 (1H each, m, H-12), 1.16 and 1.45
(1H each, m, H-15), 1.24 and 1.50 (1H each, m, H-6), 1.26 and 1.38
(1H each, m, H-7), 1.27 and 1.64 (1H each, m, H-21), 1.20 (1H, m, H-
9), 1.47 and 1.86 (1H each, m, H-22), 1.46 and 2.19 (1H each, m, H-
16),1.49 (1H, m, H-18),1.54 (2H, m, H-2),1.69 (3H, s, H-30), 2.29 (1H,
m, H-13), 3.01 (1H, m, H-19), 3.18 (1H, m, H-3), 4.16 and 4.58 (1H
each, s, H-29), 5.35 and 5.44 (1H each, d, J ¼ 12.0 Hz, eOCH2e), 6.97
(1H, d, J ¼ 8.0 Hz, AreH), 7.05 (1H, d, J ¼ 8.0 Hz, AreH), 7.28 (1H, d,
J ¼ 8.0 Hz, AreH), 7.50e7.57 (2H, m, AreH), 8.05 (1H, s, NeCH), 8.45
mp 230e233 ꢂC. 1H NMR (400 MHz, CDCl3):
d 0.65 (1H, m, H-5),
0.69 (3H, s, H-25), 0.74 (3H, s, H-24), 0.79 (3H, s, H-26), 0.88 and
1.50 (1H each, m, H-1), 0.94 and 0.95 (3H each, s, H-23 and H-27),
1.09 and 1.85 (1H each, m, H-11), 1.21 and 1.59 (1H each, m, H-12),
1.16 and 1.45 (1H each, m, H-15), 1.24 and 1.50 (1H each, m, H-6),
1.26 and 1.38 (1H each, m, H-7), 1.27 and 1.64 (1H each, m, H-21),
1.20 (1H, m, H-9), 1.47 and 1.86 (1H each, m, H-22), 1.46 and 2.09
(1H each, m, H-16), 1.49 (1H, m, H-18), 1.54 (2H, m, H-2), 1.70 (3H, s,
H-30), 2.17 (3H, s, AreCH3), 2.28 (1H, m, H-13), 3.01 (1H, m, H-19),
3.17 (1H, m, H-3), 4.60 and 4.73 (1H each, s, H-29), 5.25 and 5.37 (1H
each, d, J ¼ 12.0 Hz, eOCH2e), 7.12 (1H, d, J ¼ 8.0 Hz, AreH), 7.67
(1H, d, J ¼ 8.0 Hz, AreH). 13C NMR (100 MHz, CDCl3):
d 176.28,
152.67, 150.36, 143.07, 133.05, 129.75, 128.23, 127.03, 125.73, 125.08,
124.10, 123.76, 113.75, 109.74, 109.64, 79.16, 60.53, 57.03, 56.65,
55.27, 50.46, 49.47, 46.99, 42.34, 40.66, 38.82, 38.66, 38.33, 37.12,
36.94, 34.17, 32.01, 30.58, 29.64, 27.98, 27.29, 25.47, 21.08, 20.83,