642
Z.-G. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 632e648
5.1.26. (Z)-3-(5-Fluoro-1-(4-isopropylbenzylidene)-2-methyl-1H-
inden-3-yl)propanenitrile (16)
ether ¼ 1:2). Compound (Z)-19 is a yellow solid (63%). The data for
(Z)-19: M.p. 199e200 ꢂC (hexane/EtOAc). IR (film): nmax 3289, 2957,
Compound 16 was synthesized according to the general proce-
dure E, and purified by flash column chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ¼ 1:20). Yellow solid, yield:
53%. M.p. 108e109 ꢂC (hexane/EtOAc). IR (film): nmax 2957, 2927,
2866, 2247, 1598, 1464, 1199, 1162, 1138, 1055, 1016 cmꢁ1; 1H NMR
2869, 1647, 1601, 1467, 1409, 1262, 1162, 1055 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
1.31 (d, J ¼ 6.9 Hz, 6H, CH(CH3)2), 2.20 (s, 3H,
C]CCH3), 2.76 (d, J ¼ 4.8 Hz, 3H, NCH3), 2.97 (sept, J ¼ 6.9 Hz, 1H,
CH(CH3)2), 3.51 (s, 2H, CH2CO), 5.85 (q, J ¼ 4.8 Hz, 1H, CONH), 6.57e
6.64 (m, 1H, AreH), 6.83e6.88 (m, 1H, AreH), 7.22 (s, 1H, vinyleH),
7.27e7.32 (m, 2H, AreH), 7.40e7.48 (m, 3H, AreH) ppm; 13C NMR
(400 MHz, CDCl3)
d
1.32 (d, J ¼ 6.9 Hz, 6H, CH(CH3)2), 2.24 (s, 3H,
C]CCH3), 2.60 (t, J ¼ 7.4 Hz, 2H, CH2CH2CN), 2.93 (t, J ¼ 7.4 Hz, 2H,
CH2CH2CN), 2.98 (sept, J ¼ 6.9 Hz, 1H, CH(CH3)2), 6.58e6.65 (m, 1H,
AreH), 6.75e6.80 (m, 1H, AreH), 7.21 (s, 1H, vinyleH), 7.28e7.33
(m, 2H, AreH), 7.39e7.48 (m, 3H, AreH) ppm; 13C NMR
(100 MHz, CDCl3)
d: 10.5, 23.8, 26.4, 33.4, 33.9, 105.5 (d, JCe
¼ 23.0 Hz), 110.7 (d, JCeF ¼ 22.0 Hz), 123.76 (d, JCeF ¼ 9.0 Hz),
F
126.5 (2C), 129.3 (2C), 129.85, 129.87, 131.1 (2C), 133.5, 139.0,
139.5, 146.0 (d, JCeF ¼ 9.0 Hz), 149.4, 163.0 (d, JCeF ¼ 244.0 Hz),
169.9 ppm; MS (ESI) m/z 372.2 (M þ Naþ, 100%); HRMS (ESI)
calcd for C23H24FNNaOþ [M þ Naþ]: 372.1734; found: 372.1733.
Compound (E)-20 is a yellow solid (23%). The data for (E)-20: M.p.
135e136 ꢂC (hexane/EtOAc). IR (film): nmax 3296, 2957, 1644, 1598,
1470, 1409, 1202, 1150, 1049, 1013 cmꢁ1; 1H NMR (400 MHz, CDCl3)
(100 MHz, CDCl3)
d 10.5, 16.6, 21.6, 23.9, 34.0, 104.7 (d, JCe
¼ 23.0 Hz), 110.6 (d, JCeF ¼ 22.0 Hz), 119.1, 124.0 (d, JCe
F
¼ 8.0 Hz), 126.5 (2C), 129.4 (2C), 130.2, 131.1, 133.68, 133.78,
F
138.2, 139.6, 145.47 (d, JCeF ¼ 8.0 Hz), 149.3, 163.0 (d, JCe
¼ 244.0 Hz) ppm; MS (ESI) m/z 354.2 (M þ Naþ, 100%); HRMS
F
(ESI) calcd for C23H22FNNaþ [M þ Naþ]: 354.1628; found: 354.1625.
d
1.29 (d, J ¼ 6.9 Hz, 6H, CH(CH3)2), 1.89 (s, 3H, C]CCH3), 2.75 (d,
J ¼ 4.8 Hz, 3H, NCH3), 2.95 (sept, J ¼ 6.9 Hz, 1H, CH(CH3)2), 3.51 (s,
2H, CH2CO), 5.60 (q, J ¼ 4.8 Hz, 1H, CONH), 6.84e6.92 (m, 2H, Are
H), 7.23e7.33 (m, 4H, AreH), 7.50e7.56 (m, 1H, AreH), 7.63 (s, 1H,
5.1.27. 2-(5-Fluoro-1-(4-isopropylbenzylidene)-2-methyl-1H-
inden-3-yl)acetamide (17 and 18)
A solution of compound 3 (Z/E ¼ 2.5:1) (140.0 mg, 0.42 mmol),
HOBt (72 mL, 0.53 mmol), and EDCI (101 mg, 0.53 mmol) in CH2Cl2
(4 mL) was stirred at room temperature under argon for 1 h and
cooled to 0 ꢂC. Then to the solution was added NH3$H2O (0.1 mL),
and stirred for 12 h at room temperature. The reaction was
quenched with 1.0 N citric acid, and extracted with CH2Cl2
(5 mL ꢃ 3). The combined organic layers were washed with brine,
saturated NHCO3, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent: ethyl acetate/petroleum
ether ¼ 1:1) to give compound (Z)-17 as a yellow solid (82 mg, 58%),
and compound (E)-18 as a yellow solid (26 mg, 19%). The data for
(Z)-17: M.p. 138e139 ꢂC (hexane/EtOAc). IR (film) nmax 3393, 3195,
2960, 2860, 1659, 1601, 1464, 1409, 1272, 1165, 1131, 1052,
vinyleH) ppm; 13C NMR (100 MHz, CDCl3)
d 14.2, 23.9, 26.5, 33.5,
33.9, 105.5 (d, JCeF ¼ 23.0 Hz), 111.35 (d, JCeF ¼ 23.0 Hz), 119.5 (d, JCe
¼ 9.0 Hz), 126.2 (2C), 129.6 (2C), 130.2, 133.3, 133.5, 135.3, 136.4,
F
138.8, 143.18 (d, JCeF ¼ 9.0 Hz), 149.2, 163.2 (d, JCeF ¼ 244.0 Hz),
169.7 ppm; MS (ESI) m/z 372.2 (M þ Naþ, 100%). HRMS (ESI)
calcd for C23H24FNNaOþ [M þ Naþ]: 372.1734; found: 372.1732.
5.1.29. 2-(4-Fluorobenzylidene)butanoic acid (40)
Compound 40 was synthesized according to the general pro-
cedure A. White solid, yield: 50%. M.p. 113e114 ꢂC (hexane/EtOAc).
IR (film): nmax 3425, 2957, 1668, 1595, 1506, 1424, 1308, 1257, 1223,
1162, 1141 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.22 (t, J ¼ 7.4 Hz, 3H,
CH2CH3), 2.56 (q, J ¼ 7.4 Hz, 2H, CH2CH3), 7.06e7.15 (m, 2H, AreH),
7.35e7.45 (m, 2H, AreH), 7.76 (s, 1H, vinyleH) ppm; 13C NMR
1016 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.32 (d, J ¼ 6.9 Hz, 6H,
(100 MHz, CDCl3)
d
13.6, 20.5, 115.66 (d, JCeF ¼ 22.0 Hz), 131.3 (d, JCe
CH(CH3)2), 2.21 (s, 3H, C]CCH3), 2.98 (sept, J ¼ 6.9 Hz, 1H,
CH(CH3)2), 3.51 (s, 2H, CH2CO), 5.75 (s, 1H, CONH2), 6.28 (s, 1H,
CONH2), 6.57e6.64 (m, 1H, AreH), 6.85e6.90 (m, 1H, AreH), 7.22 (s,
1H, vinyleH), 7.28e7.32 (m, 2H, AreH), 7.40e7.48 (m, 3H, Are
¼ 8.0 Hz), 131.5 (d, JCeF ¼ 4.0 Hz), 133.7, 139.6, 162.8 (d, JCe
F
¼ 249.0 Hz), 174.0 ppm; MS (ESI) m/z 193.1 (M ꢁ Hþ); HRMS
F
ꢁ
(ESI) calcd for C11H10FO2 [M ꢁ Hþ]: 193.0670; found: 193.0667.
H) ppm; 13C NMR (100 MHz, CDCl3)
d
10.5, 23.8, 33.2, 33.9, 105.5
5.1.30. 2-(4-Fluorobenzyl)butanoic acid (41)
(d, JCeF ¼ 24.0 Hz), 110.8 (d, JCeF ¼ 23.0 Hz), 123.79 (d, JCeF ¼ 9.0 Hz),
126.5 (2C), 129.3 (2C), 129.85, 129.87, 131.2, 133.5, 138.8, 139.5, 145.9
(d, JCeF ¼ 8.0 Hz), 149.3, 163.0 (d, JCeF ¼ 244.0 Hz), 172.4 ppm; MS
Compound 41 was synthesized according to the general pro-
cedure B. Colorless oil, yield: 90%. IR (film): nmax 3415, 2969, 1705,
1598, 1509, 1458, 1415, 1229, 1149 cmꢁ1 1H NMR (400 MHz,
;
(ESI) m/z 358.2 (M
þ
Naþ, 100%); HRMS (ESI) calcd for
CDCl3)
d
0.96 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.52e1.72 (m, 2H,
C22H22FNNaOþ [M þ Naþ]: 358.1578; found: 358.1572. The data for
CH2CH3), 2.52e2.63 (m, 1H, CH2CH), 2.73 (dd, J ¼ 13.8, 6.6 Hz, 1H,
CH2CH), 2.93 (dd, J ¼ 13.8, 8.2 Hz, 1H, CH2CH), 6.92e7.00 (m, 2H,
AreH), 6.09e7.17 (m, 2H, AreH), 10.40 (br s, 1H, COOH) ppm; 13C
(E)-18: M.p. 169e170 ꢂC (hexane/EtOAc). IR (film): nmax 3393, 3192,
2961, 2918, 2872, 1656, 1607, 1461, 1397, 1257, 1147, 1113 cmꢁ1 1H
;
NMR (400 MHz, CDCl3)
d
: 1.29 (d, J ¼ 6.9 Hz, 6H, CH(CH3)2), 1.90 (s,
NMR (100 MHz, CDCl3) d 11.6, 24.8, 36.9, 49.1, 115.2 (d, JCe
3H, C]CCH3), 2.96 (sept, J ¼ 6.9 Hz, 1H, CH(CH3)2), 3.50 (s, 2H,
CH2CO), 5.60 (s, 1H, CONH2), 6.87 (s, 1H, CONH2), 6.83e6.90 (m, 1H,
AreH), 6.90e6.95 (m, 1H, AreH), 7.23e7.33 (m, 4H, AreH), 7.49e
7.54 (m, 1H, AreH), 7.63 (s, 1H, vinyleH) ppm; 13C NMR
¼ 21.0 Hz, 2C), 130.26 (d, JCeF ¼ 8.0 Hz, 2C), 134.78 (d, JCe
F
¼ 3.0 Hz), 162.6 (d, JCeF ¼ 243.0 Hz), 181.7 ppm; MS (ESI) m/z
F
ꢁ
195.1 (M ꢁ Hþ); HRMS (ESI) calcd for C11H12FO2 [M ꢁ Hþ]:
195.0827; found: 195.0824.
(100 MHz, CDCl3)
d
14.2, 23.9, 33.2, 33.9, 105.4 (d, JCeF ¼ 24.0 Hz),
111.3 (d, JCeF ¼ 23.0 Hz), 119.5 (d, JCeF ¼ 9.0 Hz), 126.2 (2C), 129.6
(2C), 130.3, 133.3, 133.5, 135.3, 136.2, 138.8, 143.07 (d, JCeF ¼ 9.0 Hz),
149.2, 163.16 (d, JCeF ¼ 243.0 Hz), 171.9 ppm; MS (ESI) m/z 358.2
(M þ Naþ, 100%); HRMS (ESI) calcd for C22H22FNNaOþ [M þ Naþ]:
358.1578; found: 358.1581.
5.1.31. 2-Ethyl-6-fluoro-2,3-dihydro-1H-inden-1-one (42)
Compound 42 was synthesized according to the general pro-
cedure C, and purified by flash column chromatography on silica gel
(eluent: ethyl acetate/petroleum ether ¼ 1:40). Colorless oil, yield:
85%. IR (film): nmax 2967, 2930, 2872, 1717, 1613, 1482, 1439, 1287,
1263, 1229, 1162 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.00 (t,
5.1.28. 2-(5-Fluoro-1-(4-isopropylbenzylidene)-2-methyl-1H-
inden-3-yl)-N-methylacetamide (19 and 20)
Following the procedure described for 17 and 18, compounds 19
and 20 were synthesized respectively, and purified by flash column
chromatography on silica gel (eluent: ethyl acetate/petroleum
J ¼ 7.4 Hz, 3H, CH2CH3), 1.48e1.61 (m, 1H, CH2CH3), 1.90e2.01 (m,
1H, CH2CH3), 2.62e2.70 (m, 1H, CH2CH), 2.78 (dd, J ¼ 17.0, 3.7 Hz,
1H, CH2CH), 3.28 (dd, J ¼ 17.0, 7.8 Hz, 1H, CH2CH), 7.25e7.32 (m, 1H,
AreH), 7.34e7.38 (m, 1H, AreH), 7.39e7.44 (m, 1H, AreH) ppm; 13C
NMR (100 MHz, CDCl3)
d 11.5, 24.4, 31.7, 49.6, 109.5 (d, JCe