J. García-Rodríguez et al. / Bioorg. Med. Chem. 22 (2014) 1285–1302
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ArCH3), 2.09 (s, 6H, 3 ꢃ AdCH2), 2.04 (s, 3H, 3 ꢃ AdCH), 1.73 (s, 6H,
3 ꢃ AdCH2) ppm. 13C NMR (100.62 MHz, DMSO-d6): d 168.3 (s),
165.7 (s), 157.7 (s), 140.6 (d), 136.0 (s), 135.6 (s), 134.7 (s), 133.9
(s), 130.0 (d, 2ꢃ), 128.6 (s), 128.1 (d), 126.2 (d, 2ꢃ), 122.9 (s),
119.4 (d), 52.2 (q), 39.9 (t, 3ꢃ), 36.6 (t, 3ꢃ), 35.9 (s), 28.4 (d, 3ꢃ),
7.99 (d, J = 8.2 Hz, 2H, H2 + H6), 7.82 (d, J = 8.2 Hz, 2H, H3 + H5),
7.74 (d, J = 1.4 Hz, 1H, H200), 7.64 (dd, J = 8.3, 1.4 Hz, 1H, H600),
6.90 (d, J = 8.3 Hz, 1H, H500), 2.11 (s, 6H, 3 ꢃ AdCH2), 2.06 (s, 3H,
3 ꢃ AdCH), 1.74 (s, 6H, 3 ꢃ AdCH2) ppm. 13C NMR (100.62 MHz,
DMSO-d6): d 168.2 (s), 166.8 (s), 158.8 (s), 141.0 (d), 136.3 (s),
135.7 (s), 135.2 (s), 130.2 (d, 2ꢃ), 129.8 (s), 126.1 (d, 2ꢃ), 125.2
(d), 124.7 (d), 123.9 (s), 117.0 (d), 39.7 (t, 3ꢃ), 36.5 (t, 3ꢃ), 36.3
21.1 (q) ppm. IR:
m 3300–3000 (br, O–H), 2902 (m, C–H), 2881
(m, C–H), 1708 (s, C@O), 1603 (m), 1435 (m), 1402 (m), 1278 (s),
1248 (m), 1183 (m), 1107 (m), 1021 (s), 1001 (s), 765 (s) cmꢁ1
.
(s), 28.3 (d, 3ꢃ) ppm. IR:
m 3582 (w, O–H), 3400–2800 (br, O–H),
MS (ESI+): m/z (%) 460 ([M+H]+, 100), 397 (14), 379 (18), 359
(16), 327 (16), 326 (55), 319 (33). HRMS (ESI+): calcd for C28H30-
NO3S [M+H]+ 460.1941; found: 460.1937.
2898 (m, C–H), 2877 (m, C–H), 2849 (m, C–H), 1681 (s, C@O),
1604 (s), 1425 (m), 1391 (s), 1297 (s), 1250 (m), 1187 (m), 1100
(m), 817 (m), 766 (m) cmꢁ1. MS (ESI+): m/z (%) 432 ([M+H]+,
100). HRMS (ESI+): calcd for C26H26NO3S [M+H]+ 432.1628; found:
432.1624. Elem. Anal. calcd for C26H25NO3Sꢀ1/2H2O C, 70.88; H,
5.95; N, 3.18; found: C, 71.19; H, 5.44; N, 3.29.
5.7.24. Methyl 4-[2-(3-adamantan-1-yl-4-[(2-methoxyethoxy)
methoxy]phenyl)thiazol-5-yl]benzoate (25c)
Following the general procedure for the microwave-assisted Su-
zuki reaction, bromothiazole 23c (0.03 g, 0.06 mmol) and 4-
(methoxycarbonyl)phenylboronic acid (0.02 g, 0.09 mmol) were
heated at 120 °C for 10 min. The residue was purified by column
chromatography (SiO2, 75:25 hexane/EtOAc), to give 25c (0.02 g,
61%) as a yellow solid, mp 157–158 °C (hexane/CHCl3). 1H NMR
(400.13 MHz, CDCl3): d 8.07 (s, 1H, H40), 8.06 (d, J = 8.2 Hz, 2H,
H2 + H6), 7.89 (d, J = 1.8 Hz, 1H, H200), 7.74 (dd, J = 8.5, 1.8 Hz, 1H,
H600), 7.66 (d, J = 8.2 Hz, 2H, H3 + H5), 7.22 (d, J = 8.5 Hz, 1H,
H500), 5.38 (s, 2H, OCH2O), 3.94 (s, 3H, OCH3), 3.9–3.8 (m, 2H,
OCH2), 3.6–3.5 (m, 2H, OCH2), 3.40 (s, 3H, OCH3), 2.16 (s, 6H,
3 ꢃ AdCH2), 2.10 (s, 3H, 3 ꢃ AdCH), 1.79 (s, 6H, 3 ꢃ AdCH2) ppm.
13C NMR (100.62 MHz, CDCl3): d 169.0 (s), 166.5 (s), 158.4 (s),
140.2 (d), 139.2 (s), 136.9 (s), 136.0 (s), 130.4 (d, 2ꢃ), 129.3 (s),
126.8 (s), 126.1 (d, 2ꢃ), 125.4 (d), 125.3 (d), 114.9 (d), 93.2 (t),
71.5 (t), 68.0 (t), 59.1 (q), 52.2 (q), 40.5 (t, 3ꢃ), 37.2 (s), 37.0 (t,
5.7.27. 4-[2-(5-Adamantan-1-yl-4-hydroxy-2-methylphenyl)
thiazol-5-yl]benzoic acid (8b)
According to the general procedure for the hydrolysis of esters,
25b (0.02 g, 0.05 mmol) gave, after crystallization, acid 8b (0.02 g,
77%) as a yellow solid, mp >300 °C (hexane/CHCl3). 1H NMR
(400.13 MHz, DMSO-d6): d 9.87 (s, 1H, OH), 8.39 (s, 1H, H40), 7.99
(d, J = 8.3 Hz, 2H, H2 + H6), 7.83 (d, J = 8.2 Hz, 2H, H3 + H5), 7.59
(s, 1H, H600), 6.75 (s, 1H, H300), 2.50 (s, 3H, ArCH3), 2.09 (s, 6H,
3 ꢃ AdCH2), 2.04 (s, 3H, 3 ꢃ AdCH), 1.73 (s, 6H, 3 ꢃ AdCH2) ppm.
13C NMR (100.62 MHz, DMSO-d6): d 168.1 (s), 166.8 (s), 157.6 (s),
140.4 (d), 136.2 (s), 135.2 (s), 134.7 (s), 133.9 (s), 130.2 (d, 2ꢃ),
129.8 (s), 128.1 (d), 126.1 (d, 2ꢃ), 122.9 (s), 119.4 (d), 39.9 (t,
3ꢃ), 36.6 (t, 3ꢃ), 35.9 (s), 28.3 (d, 3ꢃ), 21.1 (q) ppm. IR:
m 3400–
3000 (br, O–H), 2902 (m, C–H), 2874 (m, C–H), 2849 (m, C–H),
1697 (s, C@O), 1605 (s), 1388 (s), 1259 (s), 1234 (s), 1180 (m),
1124 (m), 1020 (m), 976 (s), 850 (s), 773 (s) cmꢁ1. MS (ESI+): m/z
(%) 446 ([M+H]+, 100), 373 (11), 331 (29), 327 (19), 326 (91). HRMS
(ESI+): calcd for C27H28NO3S [M+H]+ 446.1784; found: 446.1785.
Calcd for C27H27NO3Sꢀ1/5H2O C, 64.91; H, 6.66; N, 2.80; found: C,
65.35; H, 6.29; N, 2.69.
3ꢃ), 29.0 (d, 3ꢃ) ppm. IR:
m 2874 (m, C–H), 2846 (w, C–H), 1717
(s, C@O), 1603 (m), 1434 (m), 1385 (m), 1275 (s), 1220 (m), 1184
(m), 1106 (s), 1071 (m), 979 (s), 836 (s) cmꢁ1. MS (ESI+): m/z (%)
534 ([M+H]+, 100). HRMS (ESI+): calcd for C31H36NO5S [M+H]+
534.2309; found: 534.2296.
5.7.25. Methyl 4-[2-(5-adamantan-1-yl-4-[(2-methoxyethoxy)
methoxy]-1-methylphenyl)thiazol-5-yl]benzoate (25d)
5.7.28. 4-[2-(3-Adamantan-1-yl-4-[(2-methoxyethoxy)methoxy]
phenyl)thiazol-5-yl]benzoic acid (8c)
Following the general procedure for the microwave-assisted Su-
zuki reaction, bromothiazole 23d (0.03 g, 0.06 mmol) and 4-
(methoxycarbonyl)phenylboronic acid (0.02 g, 0.09 mmol) were
heated at 120 °C for 10 min. The residue was purified by column
chromatography (SiO2, 80:20 hexane/EtOAc and SiO2-C18, 5:95
CH2Cl2/CH3CN), to give 25d (0.02 g, 61%) as a yellow solid, mp
116–117 °C (hexane/CHCl3). 1H NMR (400.13 MHz, CDCl3): d 8.12
(s, 1H, H40), 8.07 (d, J = 8.6 Hz, 2H, H2 + H6), 7.69 (s, 1H, H600),
7.67 (d, J = 8.6 Hz, 2H, H3 + H5), 7.08 (s, 1H, H300), 5.38 (s, 2H, OCH2-
O), 3.94 (s, 3H, OCH3), 3.9–3.8 (m, 2H, OCH2), 3.6–3.5 (m, 2H,
OCH2), 3.42 (s, 3H, OCH3), 2.60 (s, 3H, ArCH3), 2.13 (s, 6H,
3 ꢃ AdCH2), 2.08 (s, 3H, 3 ꢃ AdCH), 1.78 (s, 6H, 3 ꢃ AdCH2) ppm.
13C NMR (100.62 MHz, CDCl3): d 168.6 (s), 166.6 (s), 157.3 (s),
139.6 (d), 137.5 (s), 136.5 (s), 136.0 (s), 135.5 (s), 130.4 (d, 2ꢃ),
129.3 (s), 128.7 (d), 126.2 (d, 2ꢃ), 125.9 (s), 117.3 (d), 93.1 (t),
71.5 (t), 68.0 (t), 59.1 (q), 52.2 (q), 40.7 (t, 3ꢃ), 37.0 (t, 3ꢃ), 36.8
According to the general procedure for the hydrolysis of esters,
25c (0.01 g, 0.02 mmol) gave, after crystallization, acid 8c (0.09 g,
99%) as a white solid, mp 275 ꢁ276 °C (hexane/CHCl3). 1H NMR
(400.13 MHz, DMSO-d6): d 8.40 (s, 1H, H40), 8.00 (d, J = 8.5 Hz,
2H, H2 + H6), 7.84 (d, J = 8.5 Hz, 2H, H3 + H5), 7.83 (d, J = 2.3 Hz,
1H, H200), 7.78 (dd, J = 8.6, 2.3 Hz, 1H, H600), 7.19 (d, J = 8.6 Hz, 1H,
H500), 5.39 (s, 2H, OCH2O), 3.8–3.7 (m, 2H, OCH2), 3.5–3.4 (m, 2H,
OCH2), 3.24 (s, 3H, OCH3), 2.12 (s, 6H, 3 ꢃ AdCH2), 2.08 (s, 3H,
3 ꢃ AdCH), 1.76 (s, 6H, 3 ꢃ AdCH2) ppm. 13C NMR (100.62 MHz,
DMSO-d6): 167.5 (s), 166.8 (s), 157.8 (s), 141.2 (d), 138.4 (s),
136.5 (s), 135.0 (s), 130.2 (d, 2ꢃ), 130.0 (s), 126.2 (d, 2ꢃ), 125.9
(s), 125.3 (d), 124.5 (d), 114.9 (d), 92.9 (t), 71.0 (t), 68.0 (t), 58.1
(q), 39.9 (t, 3ꢃ), 36.7 (s), 36.4 (t, 3ꢃ), 28.3 (d, 3ꢃ) ppm. IR:
m
2902 (m, C–H), 2848 (w, C–H), 1690 (w, C@O), 1585 (m), 1546
(s), 1415 (s), 1223 (s), 1101 (s), 983 (s), 849 (m), 785 (s) cmꢁ1
.
MS (ESI+): m/z (%) 559 ([M+K+H]+, 82), 520 ([M+H]+, 100), 459
(16), 455 (9), 445 (9), 415 (17), 401 (9), 371 (8), 210 (21). HRMS
(ESI+): calcd for C30H34NO5S [M+H]+ 520.2152; found: 520.2145.
Calcd for C30H33NO5Sꢀ1/2 [CH3)2SO] C, 66.64; H, 5.51; N, 2.51;
found: C, 66.12; H, 5.51; N, 2.62.
(s), 29.0 (d, 3ꢃ), 21.3 (q) ppm. IR:
m 2899 (m, C–H), 2848 (w, C–
H), 1713 (s, C@O), 1603 (m), 1444 (m), 1271 (s), 1239 (m), 1161
(s), 1110 (s), 1018 (m), 979 (s), 848 (s), 770 (s) cmꢁ1. MS (ESI+):
m/z (%) 548 ([M+H]+, 100). HRMS (ESI+): calcd for C32H38NO5S
[M+H]+ 548.2465; found: 548.2452.
5.7.29. 4-[2-(5-Adamantan-1-yl-4-[(2-methoxyethoxy)
5.7.26. 4-[2-(3-Adamantan-1-yl-4-hydroxyphenyl)thiazol-5-yl]
benzoic acid (8a)
According to the general procedure for the hydrolysis of esters,
25a (0.01 g, 0.02 mmol) gave, after crystallization, acid 8a (0.09 g,
99%) as a yellow solid, mp >310 °C (hexane/CHCl3). 1H NMR
(400.12 MHz, DMSO-d6): d 10.06 (s, 1H, OH), 8.35 (s, 1H, H40),
methoxy]-2-methylphenyl)thiazol-5-yl]benzoic acid (8d)
According to the general procedure for the hydrolysis of esters,
25d (0.02 g, 0.03 mmol) gave, after crystallization, acid 8d (0.01 g,
94%) as a yellow solid, mp 235–236 °C (hexane/CHCl3). 1H NMR
(400.13 MHz, DMSO-d6): d 8.43 (s, 1H, H40), 7.99 (d, J = 8.4 Hz,
2H, H2 + H6), 7.84 (d, J = 8.4 Hz, 2H, H3 + H5), 7.66 (s, 1H, H600),