250
H.-J. Fang et al. / European Journal of Medicinal Chemistry 101 (2015) 245e253
40F) in CH2Cl2:MeOH (2:1) as eluent to afford the target com-
pounds 12a,be14a,b and 18a,be20a,b.
(d, J ¼ 8.3 Hz, AreC),125.8 (4-C),124.3 (d, J ¼ 2.8 Hz, AreC),115.6 (d,
J ¼ 21.1 Hz, AreC),113.9 (d, J ¼ 21.0 Hz, AreC), 61.3 (NeCH2-Ar), 59.3
(9-C), 55.9 (6-C), 47.6 (2-C), 42.2 (10-C), 36.1 (1-C), 27.9 (11-C), 27.3
(12-C), 23.6 (13-C). HR-ESIMS m/z 316.2074 [MþH]þ, calcd for
4.1.18. (R,E)-4-(3-[(2-fluorobenzyl) (methyl)amino]prop-1-en-1-
yl)-3,5,5-trimethylcyclohex-2-en-1-one (12a)
C20H27FNO, 316.2077.
Yield 58.3%, orange oil, ½aꢂ2D0 þ116.6 (c 1.134, ethanol). 1H NMR
(400 MHz, CDCl3):
d
7.35 (m, 1H, AreH), 7.23 (m, 1H, AreH), 7.11 (m,
4.1.22. (R,E)-4-(3-[(4-fluorobenzyl) (methyl)amino]prop-1-en-1-
yl)-3,5,5-trimethylcyclohex-2-en-1-one (14a)
1H, AreH), 7.03 (m, 1H, AreH), 5.89 (br s, 1H, 4-H), 5.70 (dt,
J ¼ 15.2 Hz, 6.4 Hz, 1H, 8-H), 5.53 (dd, J ¼ 15.2 Hz, 9.2 Hz, 1H, 7-H),
3.57 (br s, 2H, NeCH2), 3.07 (d, J ¼ 6.4 Hz, 2H, 9-H), 2.56 (d,
J ¼ 9.2 Hz, 1H, 6-H), 2.34 (d, J ¼ 16.7 Hz, 1H, 2-H), 2.22 (s, 3H, 10-H),
2.08 (d, J ¼ 16.7 Hz, 1H, 2-H), 1.90 (d, J ¼ 1.0 Hz, 3H, 13-H), 1.03 (s,
Yield 47.2%, orange oil, ½aꢂ2D0 þ115.8 (c 1.054, ethanol). 1H NMR
(400 MHz, CDCl3):
d 7.26 (m, 2H, AreH), 7.00 (m, 2H, AreH), 5.89
(br s, 1H, 4-H), 5.67 (dt, J ¼ 15.2 Hz, 6.4 Hz, 1H, 8-H), 5.51 (dd,
J ¼ 15.2 Hz, 9.2 Hz, 1H, 7-H), 3.45 (br s, 2H, NeCH2), 3.02 (d,
J ¼ 6.4 Hz, 2H, 9-H), 2.55 (d, J ¼ 9.2 Hz, 1H, 6-H), 2.33 (d, J ¼ 16.8 Hz,
1H, 2-H), 2.17 (s, 3H, 10-H), 2.08 (d, J ¼ 16.8 Hz, 1H, 2-H), 1.90 (d,
J ¼ 1.2 Hz, 3H, 13-H), 1.03 (s, 3H, 11-H), 0.96 (s, 3H, 12-H). 13C NMR
3H, 11-H), 0.97 (s, 3H, 12-H). 13C NMR (100 MHz, CDCl3):
d 199.1 (3-
C), 161.9 (5-C), 161.4 (d, J ¼ 244.9 Hz, AreC), 132.0 (8-C), 131.5 (d,
J ¼ 4.4 Hz, AreC),130.4 (7-C),128.8 (d, J ¼ 8.0 Hz, AreC),125.8 (4-C),
125.4 (d, J ¼ 14.6 Hz, AreC), 123.9 (d, J ¼ 3.5 Hz, AreC), 115.3 (d,
J ¼ 22.0 Hz, AreC), 59.4 (9-C), 56.0 (6-C), 54.1 (NeCH2-Ar), 47.6 (2-
C), 42.0 (10-C), 36.2 (1-C), 27.9 (11-C), 27.3 (12-C), 23.5 (13-C). HR-
ESIMS m/z 316.2074 [MþH]þ, calcd for C20H27FNO, 316.2077.
(100 MHz, CDCl3):
d
199.2 (3-C), 162.0 (d, J ¼ 243.4 Hz, AreC), 161.9
(5-C), 134.4 (AreC), 131.9 (8-C), 130.5 (d, J ¼ 7.9 Hz, AreC), 130.3 (7-
C),125.8 (4-C), 115.1 (d, J ¼ 21.1 Hz, AreC), 61.0 (NeCH2-Ar), 59.2 (9-
C), 55.9 (6-C), 47.6 (2-C), 42.0 (10-C), 36.1 (1-C), 27.9 (11-C), 27.3
(12-C), 23.6 (13-C). HR-ESIMS m/z 316.2074 [MþH]þ, calcd for
4.1.19. (S,E)-4-(3-[(2-fluorobenzyl) (methyl)amino]prop-1-en-1-
yl)-3,5,5-trimethylcyclohex-2-en-1-one (12b)
C20H27FNO, 316.2077.
Yield 51.1%, orange oil, ½aꢂ2D0 ꢁ115.1 (c 1.062, ethanol). 1H NMR
4.1.23. (S,E)-4-(3-[(4-fluorobenzyl) (methyl)amino]prop-1-en-1-
yl)-3,5,5-trimethylcyclohex-2-en-1-one (14b)
(400 MHz, CDCl3): d 7.34 (m, 1H, AreH), 7.23 (m, 1H, AreH), 7.10 (m,
1H, AreH), 7.02 (m, 1H, AreH), 5.88 (br s, 1H, 4-H), 5.69 (dt,
J ¼ 15.2 Hz, 6.4 Hz, 1H, 8-H), 5.52 (dd, J ¼ 15.2 Hz, 9.2 Hz, 1H, 7-H),
3.55 (br s, 2H, NeCH2), 3.07 (d, J ¼ 6.4 Hz, 2H, 9-H), 2.55 (d,
J ¼ 9.2 Hz, 1H, 6-H), 2.33 (d, J ¼ 16.4 Hz, 1H, 2-H), 2.21 (s, 3H, 10-H),
2.07 (d, J ¼ 16.4 Hz, 1H, 2-H), 1.90 (d, J ¼ 1.2 Hz, 3H, 13-H), 1.02 (s,
Yield 53.7%, orange oil, ½aꢂ2D0 ꢁ113.9 (c 1.036, ethanol). 1H NMR
(400 MHz, CDCl3):
d 7.26 (m, 2H, AreH), 7.00 (m, 2H, AreH), 5.89
(br s, 1H, 4-H), 5.67 (dt, J ¼ 15.2 Hz, 6.4 Hz, 1H, 8-H), 5.51 (dd,
J ¼ 15.2 Hz, 9.2 Hz, 1H, 7-H), 3.45 (br s, 2H, NeCH2), 3.02 (d,
J ¼ 6.4 Hz, 2H, 9-H), 2.55 (d, J ¼ 9.2 Hz, 1H, 6-H), 2.33 (d, J ¼ 16.8 Hz,
1H, 2-H), 2.17 (s, 3H, 10-H), 2.08 (d, J ¼ 16.8 Hz, 1H, 2-H), 1.90 (d,
J ¼ 0.8 Hz, 3H, 13-H), 1.03 (s, 3H, 11-H), 0.96 (s, 3H, 12-H). 13C NMR
3H, 11-H), 0.96 (s, 3H, 12-H). 13C NMR (100 MHz, CDCl3):
d 199.2 (3-
C), 162.0 (5-C), 161.4 (d, J ¼ 244.8 Hz, AreC), 132.0 (8-C), 131.5 (d,
J ¼ 4.5 Hz, AreC),130.4 (7-C),128.8 (d, J ¼ 8.3 Hz, AreC),125.7 (4-C),
125.3 (d, J ¼ 14.5 Hz, AreC), 123.9 (d, J ¼ 3.6 Hz, AreC), 115.3 (d,
J ¼ 22.1 Hz, AreC), 59.4 (9-C), 55.9 (6-C), 54.1 (NeCH2-Ar), 47.6 (2-
C), 42.0 (10-C), 36.1 (1-C), 27.9 (11-C), 27.3 (12-C), 23.6 (13-C). HR-
ESIMS m/z 316.2076 [MþH]þ, calcd for C20H27FNO, 316.2077.
(100 MHz, CDCl3):
d
199.2 (3-C), 162.0 (d, J ¼ 243.5 Hz, AreC), 161.9
(5-C), 134.5 (AreC), 132.0 (8-C), 130.5 (d, J ¼ 7.9 Hz, AreC), 130.3 (7-
C), 125.8 (4-C), 115.1 (d, J ¼ 21.1 Hz, AreC)), 61.0 (NeCH2-Ar), 59.2
(9-C), 55.9 (6-C), 47.6 (2-C), 42.0 (10-C), 36.1 (1-C), 27.9 (11-C), 27.3
(12-C), 23.6 (13-C). HR-ESIMS m/z 316.2080 [MþH]þ, calcd for
C20H27FNO, 316.2077.
4.1.20. (R,E)-4-(3-[(3-fluorobenzyl) (methyl)amino]prop-1-en-1-
yl)-3,5,5-trimethylcyclohex-2-en-1-one (13a)
4.1.24. (R)-4-(3-[(2-fluorobenzyl) (methyl)amino]propyl)-3,5,5-
trimethylcyclohex-2-en-1-one (18a)
Yield 48.1%, orange oil, ½aꢂ2D0 þ113.6 (c 1.035, ethanol). 1H NMR
(400 MHz, CDCl3):
d
7.26 (m, 1H, AreH), 7.05 (m, 2H, AreH), 6.94
Yield 49.7%, orange oil, ½aꢂ2D0 þ121.8 (c 1.079, ethanol). 1H NMR
(m, 1H, AreH), 5.90 (br s, 1H, 4-H), 5.68 (dt, J ¼ 15.2 Hz, 6.8 Hz, 1H,
8-H), 5.51 (dd, J ¼ 15.2 Hz, 9.2 Hz, 1H, 7-H), 3.48 (br s, 2H, NeCH2),
3.03 (d, J ¼ 6.8 Hz, 2H, 9-H), 2.56 (d, J ¼ 9.2 Hz, 1H, 6-H), 2.33 (d,
J ¼ 16.8 Hz, 1H, 2-H), 2.19 (s, 3H, 10-H), 2.08 (d, J ¼ 16.8 Hz, 1H, 2-H),
1.90 (s, 3H, 13-H), 1.03 (s, 3H, 11-H), 0.96 (s, 3H, 12-H). 13C NMR
(400 MHz, CDCl3): d 7.34 (m, 1H, AreH), 7.23 (m, 1H, AreH), 7.10 (m,
1H, AreH), 7.02 (m, 1H, AreH), 5.80 (br s, 1H, 4-H), 3.55 (br s, 2H,
NeCH2), 2.39 (d, J ¼ 17.2 Hz, 1H, 2-H), 2.35 (m, 2H, 9-H), 2.21 (s, 3H,
10-H), 2.01 (d, J ¼ 17.2 Hz,1H, 2-H),1.97 (d, J ¼ 1.2 Hz, 3H,13-H),1.84
(m, 1H, 6-H), 1.72 (m, 1H, 7-H), 1.60 (m, 2H, 8-H), 1.40 (m, 1H, 7-H),
1.04 (s, 3H, 11-H), 1.00 (s, 3H, 12-H). 13C NMR (100 MHz, CDCl3):
(100 MHz, CDCl3):
d
199.1 (3-C), 163.0 (d, J ¼ 243.8 Hz, AreC), 161.9
(5-C), 141.7 (d, J ¼ 6.9 Hz, AreC), 132.0 (8-C), 130.3 (7-C), 129.7 (d,
J ¼ 8.2 Hz, AreC), 125.8 (4-C), 124.3 (d, J ¼ 2.5 Hz, AreC), 115.6 (d,
J ¼ 21.1 Hz, AreC), 113.9 (d, J ¼ 20.9 Hz, AreC), 61.3 (NeCH2-Ar),
59.3 (9-C), 55.9 (6-C), 47.6 (2-C), 42.2 (10-C), 36.1 (1-C), 27.9 (11-C),
27.3 (12-C), 23.6 (13-C). HR-ESIMS m/z 316.2080 [MþH]þ, calcd for
d
199.5 (3-C), 165.8 (5-C), 161.4 (d, J ¼ 244.7 Hz, AreC), 131.5 (d,
J ¼ 4.6 Hz, AreC), 128.8 (d, J ¼ 8.1 Hz, AreC), 125.3 (d, J ¼ 13.8 Hz,
AreC), 125.0 (4-C), 123.8 (d, J ¼ 3.6 Hz, AreC), 115.3 (d, J ¼ 22.2 Hz,
AreC), 57.6 (9-C), 54.6 (NeCH2-Ar), 51.2 (6-C), 47.1 (2-C), 42.2 (10-
C), 36.4 (1-C), 28.8 (12-C), 27.9 (7-C), 27.3 (8-C), 27.2 (11-C), 24.7
(13-C). HR-ESIMS m/z 318.2236 [MþH]þ, calcd for C20H29FNO,
318.2233.
C
20H27FNO, 316.2077.
4.1.21. (S,E)-4-(3-[(3-fluorobenzyl) (methyl)amino]prop-1-en-1-
yl)-3,5,5-trimethylcyclohex-2-en-1-one (13b)
4.1.25. (S)-4-(3-[(2-fluorobenzyl) (methyl)amino]propyl)-3,5,5-
trimethylcyclohex-2-en-1-one (18b)
Yield 50.1%, orange oil, ½aꢂ2D0 ꢁ118.0 (c 1.110, ethanol). 1H NMR
(400 MHz, CDCl3):
d
7.27 (m, 1H, AreH), 7.05 (m, 2H, AreH), 6.94
Yield 54.7%, orange oil, ½aꢂ2D0 ꢁ124.9 (c 1.009, ethanol). 1H NMR
(m, 1H, AreH), 5.89 (br s, 1H, 4-H), 5.68 (dt, J ¼ 15.2 Hz, 6.4 Hz, 1H,
8-H), 5.51 (dd, J ¼ 15.2 Hz, 9.2 Hz, 1H, 7-H), 3.48 (br s, 2H, NeCH2),
3.03 (d, J ¼ 6.4 Hz, 2H, 9-H), 2.56 (d, J ¼ 9.2 Hz, 1H, 6-H), 2.33 (d,
J ¼ 16.8 Hz, 1H, 2-H), 2.19 (s, 3H, 10-H), 2.09 (d, J ¼ 16.8 Hz, 1H, 2-H),
(400 MHz, CDCl3): d 7.33 (m,1H, AreH), 7.22 (m,1H, AreH), 7.09 (m,
1H, AreH), 7.01 (m, 1H, AreH), 5.80 (br s, 1H, 4-H), 3.54 (br s, 2H,
NeCH2), 2.38 (d, J ¼ 17.2 Hz, 1H, 2-H), 2.35 (m, 2H, 9-H), 2.20 (s, 3H,
10-H), 2.00 (d, J ¼ 17.2 Hz,1H, 2-H), 1.96 (s, 3H,13-H), 1.83 (m, 1H, 6-
H), 1.71 (m, 1H, 7-H), 1.59 (m, 2H, 8-H), 1.40 (m, 1H, 7-H), 1.04 (s, 3H,
1.90 (d, J ¼ 1.2 Hz, 3H, 13-H), 1.03 (s, 3H, 11-H), 0.96 (s, 3H, 12-H). 13
C
NMR (100 MHz, CDCl3):
161.9 (5-C), 141.7 (d, J ¼ 7.0 Hz, AreC), 132.0 (8-C), 130.3 (7-C), 129.7
d
199.2 (3-C), 163.0 (d, J ¼ 243.8 Hz, AreC),
11-H), 1.00 (s, 3H, 12-H). 13C NMR (100 MHz, CDCl3):
d
199.4 (3-C),
165.7 (5-C), 161.4 (d, J ¼ 244.4 Hz, AreC), 131.5 (d, J ¼ 4.6 Hz, AreC),