O. Bobileva et al. / Bioorg. Med. Chem. 22 (2014) 3654–3669
3663
8.34 (d, J = 8.5 Hz, 1H), 12.01 (s, 1H). 13C NMR (CDCl3) d: 14.4, 21.8,
22.0, 24.5, 28.8, 56.3, 60.5, 61.4, 61.7, 104.5, 105.5, 119.2, 119.5,
127.1, 131.0, 141.5, 141.8, 146.2, 146.9, 152.5, 152.8, 156.5,
163.8, 170.2. LCMS (ESI) m/z: 441.4 [M+H]+.
water (25 ml), and at ice-bath temperature the pH of the medium
was decreased to 2–3 by adding 6 N HCl. The precipitate was
filtered and the solid material was purified by column chromatog-
raphy on silica gel with chloroform-methanol (gradient up to
85:15) as eluent to give compounds 3, 8–10, 21, and 23–26 as
white or slightly yellowish crystalline substances.
4.1.4.2.6. (E)-Ethyl 2-(3-(2-chloroquinolin-3-yl)acrylamido)cyclo-
hex-1-enecarboxylate (36n). Compound 36n was obtained from
2-chloroquinoline-3-carbaldehyde (eluent EtOAc–petroleum ether,
gradient 1:3 to 1:2), yield 76%. 1H NMR (CDCl3) d: 1.33 (t, J = 7.1 Hz,
3H), 1.59–1.72 (m, 4H), 2.33–2.39 (m, 2H), 3.08–3.14 (m, 2H), 4.22
(q, J = 7.1 Hz, 2H), 6.64 (d, J = 15.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H),
7.75 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 8.01 (d,
J = 8.3 Hz, 1H), 8.10 (d, J = 15.6 Hz, 1H), 8.40 (s, 1H), 12.06 (s, 1H).
Compound contains ca. 13% of the corresponding Z-isomer—1H
NMR (CDCl3) d: 1.23 (t, J = 7.1 Hz, 3H), 1.59–1.72 (m, 4H), 2.22–
2.27 (m, 2H), 2.90–2.98 (m, 2H), 4.08 (q, J = 7.1 Hz, 2H), 6.27 (d,
J = 12.2 Hz, 1H), 7.10 (d, J = 12.2 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H),
7.70 (t, J = 7.7 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.5 Hz,
1H), 8.44 (s, 1H), 11.80 (s, 1H). LCMS (ESI) m/z: 385.2 [M+H]+.
4.1.4.2.7. (E)-Ethyl 2-(3-(2-chloro-6-methoxyquinolin-3-yl)acry-
lamido)cyclohex-1-enecarboxylate (36o). Compound 36o was
4.1.5.1.1.
(E)-2-(3-(Naphthalen-2-yl)acrylamido)cyclohex-1-
enecarboxylic acid (3). Compound 3 was obtained from ester
36a, yield 78%. Mp 153–156 °C. HPLC purity 95.0%. 1H NMR
(DMSO-d6) d: 1.51–1.69 (m, 4H), 2.25–2.31 (m, 2H), 2.92–2.98
(m, 2H), 6.86 (d, J = 15.7 Hz, 1H), 7.54–7.59 (m, 2H), 7.68 (d,
J = 15.7 Hz, 1H), 7.89 (dd, J = 8.6, 1.5 Hz, 1H), 7.91–7.98 (m, 3H),
8.18 (s, 1H), 11.85 (s, 1H), 12.58 (br s, 1H). 13C NMR (DMSO-d6)
d: 21.4, 21.5, 24.5, 28.2, 105.8, 122.8, 124.1, 126.7, 127.1, 127.6,
128.4, 128.4, 129.4, 131.9, 132.9, 133.6, 141.4, 150.6, 163.2,
171.1. HRMS m/z calcd for C20H19NO3Na [M+Na]+, 344.1263, found,
344.1280.
4.1.5.1.2. (E)-2-(3-(6-Methoxynaphthalen-2-yl)acrylamido)cyclo-
hex-1-enecarboxylic acid (8). Compound 8 was obtained from
ester 36b, yield 35%. Mp 174 °C. HPLC purity 95.0%. 1H NMR
(DMSO-d6) d: 1.51–1.65 (m, 4H), 2.24–2.33 (m, 2H), 2.91–2.97
(m, 2H), 3.89 (s, 3H), 6.77 (d, J = 15.6 Hz, 1H), 7.20 (dd, J = 8.9,
2.5 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 15.6 Hz, 1H), 7.83
(m, 2H), 7.87 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 11.93 (br s, 1H),
12.59 (br s, 1H). HRMS m/z calcd for C21H21NO4Na [M+Na]+,
374.1368, found, 374.1342.
4.1.5.1.3. (E)-2-(3-(Quinolin-4-yl)acrylamido)cyclohex-1-enecarb-
oxylic acid (9). Compound 9 was obtained from ester 36i (the pH
of the medium upon the isolation procedure was decreased to 4
with AcOH) and purified by column chromatography (eluent chlo-
roform–methanol, 9:1), yield 20%. Mp 176.7–179.6 °C. HPLC purity
99.0%. 1H NMR (CDCl3) d: 1.52–1.67 (m, 4H), 2.27–2.33 (m, 2H),
2.92–2.97 (m, 2H), 7.01 (d, J = 15.6 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9,
1.2 Hz, 1H), 7.83 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.90 (d, J = 4.5 Hz,
1H), 8.09 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 15.6 Hz, 1H), 8.26 (d,
J = 8.4 Hz, 1H), 8.94 (d, J = 4.5 Hz, 1H), 11.95 (s, 1H), 12.70 (br s,
1H). HRMS m/z calcd for C19H19N2O3 [M+H]+, 323.1396, found,
323.1389.
obtained
from
2-chloro-6-methoxyquinoline-3-carbaldehyde
(eluent chloroform-methanol, gradient from 100:1 to 20:1), yield
82%. 1H NMR (CDCl3) d: 1.32 (t, J = 7.1 Hz, 3H), 1.59–1.72 (m, 4H),
2.34–2.39 (m, 2H), 3.08–3.13 (m, 2H), 3.94 (s, 3H), 4.22 (q,
J = 7.1 Hz, 2H), 6.62 (d, J = 15.6 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H),
7.39 (dd, J = 9.3, 2.8 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 8.08 (d,
J = 15.6 Hz, 1H), 8.30 (s, 1H), 12.06 (s, 1H). Compound contains
ca. 12% of the corresponding Z-isomer—1H NMR (CDCl3) d: 1.24
(t, J = 7.1 Hz, 3H), 1.59–1.72 (m, 4H), 2.23–2.28 (m, 2H), 2.91–
2.97 (m, 2H), 3.91 (s, 3H), 4.09 (q, J = 7.1 Hz, 2H), 6.25 (d,
J = 12.2 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 7.08 (d, J = 12.2 Hz, 1H),
7.34 (dd, J = 9.2, 2.8 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 8.37 (s, 1H),
11.79 (s, 1H). 13C NMR (CDCl3) d: 14.4, 21.8, 22.0, 24.5, 28.7,
55.8, 60.6, 105.3, 105.8, 124.3, 126.6, 127.9, 128.3, 129.9, 134.7,
137.4, 144.0, 147.8, 152.6, 158.6, 163.0, 170.4. LCMS (ESI) m/z:
415.2 [M+H]+.
4.1.4.2.8. (E)-Ethyl 2-(3-(3,4-dimethoxyphenyl)acrylamido)cyclo-
hex-1-enecarboxylate (36p). Compound 36p was obtained from
3,4-dimethoxybenzaldehyde (eluent chloroform–methanol, 20:1),
yield 73%. 1H NMR (CDCl3) d: 1.32 (t, J = 7.1 Hz, 3H), 1.57–1.70
(m, 4H), 2.32–2.38 (m, 2H), 3.06–3.11 (m, 2H), 3.91 (s, 3H), 3.93
(s, 3H), 4.21 (q, J = 7.1 Hz, 2H), 6.37 (d, J = 15.5 Hz, 1H), 6.85 (d,
J = 8.3 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 8.3, 1.9 Hz,
1H), 7.59 (d, J = 15.5 Hz, 1H), 11.83 (s, 1H). LCMS (ESI) m/z: 360.3
[M+H]+.
4.1.4.2.9. Ethyl 2-((2E,4Z)-4-bromo-5-phenylpenta-2,4-dienami-
do)cyclohex-1-enecarboxylate (43). Compound 43 was obtained
from alpha-bromocinnamaldehyde (42) (eluent petroleum ether–
ethyl acetate, 2:1), yield 80%. 1H NMR (CDCl3) d: 1.31 (t,
J = 7.1 Hz, 3H), 1.57–1.70 (m, 4H), 2.32–2.37 (m, 2H), 3.03–3.08
(m, 2H), 4.20 (q, J = 7.1 Hz, 2H), 6.43 (d, J = 14.2 Hz, 1H), 7.26 (s,
1H), 7.33–7.42 (m, 3H), 7.44 (d, J = 14.2 Hz, 1H), 7.74–7.78 (m,
2H), 11.86 (s, 1H). 13C NMR (CDCl3) d: 14.4, 21.8, 22.0, 24.5, 28.7,
60.5, 105.6, 120.6, 127.1, 128.4, 129.4, 130.1, 134.9, 138.6, 142.9,
152.3, 163.5, 170.1. LCMS (ESI) m/z: 404.1 [M+H]+.
4.1.5.1.4. (E)-2-(3-(Quinolin-2-yl)acrylamido)cyclohex-1-enecarb-
oxylic acid (10). Compound 10 was obtained from ester 36c, yield
27%. Mp 184 °C (dec.). HPLC purity 98.5%. 1H NMR (DMSO-d6) d:
1.52–1.66 (m, 4H), 2.26–2.33 (m, 2H), 2.90–2.96 (m, 2H), 7.19 (d,
J = 15.7 Hz, 1H), 7.64 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.68 (d,
J = 15.7 Hz, 1H), 7.81 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.94 (d,
J = 8.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H),
8.43 (d, J = 8.6 Hz, 1H), 12.05 (s, 1H). HRMS m/z calcd for
C
19H19N2O3 [M+H]+, 323.1396, found, 323.1419.
4.1.5.1.5. (E)-2-(3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acrylami-
do)cyclohex-1-enecarboxylic acid (21). Compound 21 was
obtained from ester 36d, yield 64%. Mp 168 °C. HPLC purity
99.0%. 1H NMR (DMSO-d6) d: 1.50–1.63 (m, 4H), 2.22–2.30 (m,
2H), 2.87–2.94 (m, 2H), 4.23–4.30 (m, 4H), 6.56 (d, J = 15.6 Hz,
1H), 6.88 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4, 1.9 Hz, 1H), 7.24 (d,
J = 1.9 Hz, 1H), 7.40 (d, J = 15.6 Hz, 1H), 11.73 (s, 1H), 12.55 (br s,
1H). 13C NMR (DMSO-d6) d: 21.4, 2 1.5, 24.5, 28.2, 63.9, 64.3,
105.4, 116.6, 117.4, 120.5, 121.9, 127.8, 141.2, 143.5, 145.2,
150.7, 163.4, 171.1. LCMS (ESI) m/z: 330.2 [M+H]+.
4.1.5.1.6. (E)-2-(3-(2-Chloro-3,4-dimethoxyphenyl)acrylamido)cyc
lohex-1-enecarboxylic acid (23). Compound 23 was obtained from
ester 36e, yield 61%. Mp 168 °C. HPLC purity 99.0%. 1H NMR
(DMSO-d6) d: 1.51–1.64 (m, 4H), 2.23–2.31 (m, 2H), 2.88–2.95
(m, 2H), 3.76 (s, 3H), 3.89 (s, 3H), 6.67 (d, J = 15.6 Hz, 1H), 7.12
(d, J = 8.9 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 15.6 Hz, 1H),
11.84 (s, 1H), 12.61 (br s, 1H). 13C NMR (DMSO-d6) d: 21.3, 21.5,
24.5, 28.2, 56.2, 60.1, 105.9, 111.8, 123.3, 123.5, 125.1, 128.2,
4.1.5. The hydrolysis of amidocyclohex-1-ene carboxylic acid
esters 36a–p and 43 to the corresponding acids 3, 8–13, 15–19,
and 21–26
4.1.5.1. General procedure of the synthesis of amidocyclohex-1-
ene carboxylic acids 3, 8–10, 21, and 23–26. To a suspension of
substituted acrylamidocyclohex-1-ene carboxylic acid ethyl ester
(36a–i) (0.5 mmol) in isopropanol (15 ml) 5 N NaOH solution
(0.4 ml, 2.0 mmol) was added and the resulting mixture was stir-
red at 62–65 °C until the starting material disappeared (ca.
40 min). The solvent was evaporated, the residue was mixed with