Journal of Medicinal Chemistry
Article
15.8, 1.4 Hz, 1H), 2.80 (t, J = 7.7 Hz, 2H), 2.66−2.56 (m, 2H). 13C
NMR (125 MHz, CDCl3) δ 195.2, 151.7, 141.1, 140.7, 133.5, 131.3,
130.9, 129.1, 128.7, 128.5, 127.3, 126.4, 119.5, 34.6, 34.3. HRMS
(ESI): m/z [M + H]+ calcd for C17H16BrO: 315.0385; found:
315.0367. Retention time 2.80 min, HPLC purity > 99%.
(E)-5-(4-Bromophenyl)-1-phenylpent-2-en-1-one (24). The title
compound was prepared as a yellow solid using a method similar to
that described for compound F11 in 77% yield. 1H NMR (400 MHz,
CDCl3) δ 7.91−7.85 (m, 2H), 7.56 (dd, J = 10.5, 4.3 Hz, 1H), 7.51−
7.40 (m, 4H), 7.12−6.99 (m, 3H), 6.86 (t, J = 8.4 Hz, 1H), 2.81 (t, J
= 7.6 Hz, 2H), 2.66−2.59 (m, 2H). 13C{1H} NMR (125 MHz,
CDCl3) δ 190.7, 147.7, 139.7, 137.8, 132.8, 131.6, 130.2, 128.6, 126.8,
120.0, 34.3, 33.9. HRMS (ESI): m/z [M + H]+ calcd for C17H16BrO:
315.0385; found: 315.0373. Retention time 3.32 min, HPLC purity >
98%.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18ONa: 273.1255;
found: 273.1245. Retention time 2.86 min, HPLC purity > 96%.
(E)-5-Phenyl-1-(p-tolyl)pent-2-en-1-one (29). The title compound
was prepared as a colorless oil using a method similar to that
1
described for compound F11 in 90% yield. H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 8.2 Hz, 2H), 7.33−7.37 (m, 2H), 7.30−7.24
(m, 5H), 7.11 (dt, J = 15.3, 6.8 Hz, 1H), 6.91 (dt, J = 15.4, 1.3 Hz,
1H), 2.88 (t, J = 7.7 Hz, 2H), 2.71−2.64 (m, 2H), 2.45 (s, 3H). LR-
MS (ESI) m/z 273.1 [M + Na]+. Retention time 3.23 min, HPLC
purity > 95%.
(E)-1-(2-Methoxyphenyl)-5-phenylpent-2-en-1-one (30). The title
compound was prepared as a colorless oil using a method similar to
that described for compound F11 in 92% yield. 1H NMR (300 MHz,
CDCl3) δ 7.52−7.40 (m, 2H), 7.35−7.16 (m, 5H), 7.05−6.84 (m,
3H), 6.75−6.65 (m, 1H), 3.83 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 2.59
(dd, J = 14.6, 7.4 Hz, 2H). Retention time 2.27 min, HPLC purity >
98%.
(E)-1-(3-Methoxyphenyl)-5-phenylpent-2-en-1-one (31). The title
compound was prepared as a colorless oil using a method similar to
that described for compound F11 in 94% yield.1H NMR (300 MHz,
CDCl3) δ 7.45−7.27 (m, 5H), 7.25−7.20 (m, 3H), 7.07 (dd, J = 14.9,
7.3 Hz, 2H), 6.85 (d, J = 15.3 Hz, 1H), 3.86 (s, 3H), 2.85 (t, J = 7.7
Hz, 2H), 2.65 (dd, J = 14.6, 7.6 Hz, 2H). Retention time 2.59 min,
HPLC purity > 96%.
(E)-1-(4-Methoxyphenyl)-5-phenylpent-2-en-1-one (32). The title
compound was prepared as a colorless oil using a method similar to
that described for compound F11 in 88% yield. 1H NMR (300 MHz,
CDCl3) δ 7.89 (d, J = 8.9 Hz, 2H), 7.34−7.13 (m, 5H), 7.12−6.81
(m, 4H), 3.83 (s, 3H), 2.83 (t, J = 7.6 Hz, 2H), 2.67−2.56 (m, 2H).
Retention time 2.76 min, HPLC purity > 99%.
(E)-5-Phenyl-1-(piperidin-1-yl)pent-2-en-1-one (25). To a suspen-
sion of sodium hydride (0.9 g, 60 wt% in mineral oil) in dry THF (30
mL) at 0 °C was added ethyl 2-(diethoxyphosphoryl)acetate (4.4 mL,
22.4 mmol). After stirring at this temperature for 1.5 h, a solution of
3-phenylpropanal (2.0 g, 14.9 mmol) in THF was added. Then, the
reaction mixture was allowed to warm to rt and stirred for 4 h. Upon
completion, the reaction was quenched with a saturated solution of
NH4Cl and extracted with diethyl ether. The organic phase was
separated, washed with brine, dried over sodium sulfate, filtered, and
evaporated to give the intermediate ester, which was hydrolyzed using
the general procedure (NaOH/EtOH) to yield (E)-5-phenylpent-2-
enoic acid as a yellow solid (2.4 g, 90% yield for two steps), 1H NMR
(300 MHz, CD3OD) δ 7.34−7.23 (m, 2H), 7.20−7.14 (m, 3H), 6.96
(dt, J = 15.3, 6.9 Hz, 1H), 5.78 (d, J = 15.6 Hz, 1H), 2.77 (t, J = 7.6
Hz, 2H), 2.52 (q, J = 7.4 Hz, 2H). To a suspension (E)-5-phenylpent-
2-enoic acid (200 mg, 1.1 mmol) in CH2Cl2 (10 mL) at rt were added
EDCI (383 mg, 2.0 mmol), DMAP (122 mg, 1.0 mmol), and Et3N
(0.6 mL, 4.0 mmol). After stirring at rt for 30 min, piperidine (92 μL,
1.0 mmol) was added and stirred overnight. The mixture was diluted
with H2O and extracted by CH2Cl2. The organic phase was
concentrated and purified by column chromatography on silica gel
to afford (E)-5-phenyl-1-(piperidin-1-yl)pent-2-en-1-one as a yellow
(E)-1-(2-Fluorophenyl)-5-phenylpent-2-en-1-one (33). The title
compound was prepared as a colorless oil using a method similar to
that described for compound F11 in 85% yield. 1H NMR (300 MHz,
CDCl3) δ 7.68 (t, J = 7.5 Hz, 1H), 7.48 (dd, J = 12.9, 6.0 Hz, 1H),
7.36−6.94 (m, 8H), 6.74 (d, J = 15.5 Hz, 1H), 2.88−2.79 (m, 2H),
2.62 (dd, J = 14.6, 7.6 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
189.7, 189.6, 162.1 (d, JCF = 252.5 Hz), 149.2, 140.9, 133.7 (d, JCF
8.7 Hz), 130.9 (d, JCF = 2.6 Hz), 130.1 (d, JCF = 5.6 Hz), 128.54 (d,
CF = 38.8 Hz), 128.52 (d, JCF = 16.3 Hz), 128.45, 128.4, 127.1 (d, JCF
=
1
oil (60.8 mg, 25%). H NMR (400 MHz, CDCl3) δ 7.27−7.21 (m,
J
2H), 7.19−7.14 (m, 3H), 6.87−6.74 (m, 1H), 6.18 (d, J = 15.1 Hz,
1H), 3.61−3.47 (m, 2H), 3.37−3.29 (m, 2H), 2.74 (t, J = 7.7 Hz,
2H), 2.49 (dd, J = 14.5, 7.3 Hz, 2H), 1.65−1.40 (m, 6H).
= 13.6 Hz), 126.3, 124.5 (d, JCF = 3.4 Hz), 116.5 (d, JCF = 22.5 Hz),
34.5. HRMS (ESI): m/z [M + H]+ calcd for C17H16FO: 255.1180;
found: 255.1179. Retention time 2.84 min, HPLC purity > 96%.
(E)-1-(3-Fluorophenyl)-5-phenylpent-2-en-1-one (34). The title
compound was prepared as a colorless oil using a method similar to
that described for compound F11 in 89% yield. 1H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.55 (ddd, J = 9.5, 2.5, 1.6 Hz,
1H), 7.42 (td, J = 8.0, 5.5 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.26−
7.18 (m, 4H), 7.09 (dt, J = 15.4, 6.9 Hz, 1H), 6.80 (dt, J = 15.4, 1.4
Hz, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.68−2.60 (m, 2H). 13C{1H}
(E)-5-Phenyl-1-(o-tolyl)pent-2-en-1-one (26). The title compound
was prepared as a colorless oil using a method similar to that
1
described for compound F11 in 82% yield. H NMR (300 MHz,
CDCl3) δ 7.36−7.23 (m, 4H), 7.21−7.13 (m, 5H), 6.72 (dt, J = 15.7,
6.7 Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 2.77 (t, J = 7.6 Hz, 2H), 2.56
(dd, J = 14.9, 7.0 Hz, 2H), 2.35 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ 197.2, 150.33, 150.31, 140.8, 138.9, 136.8, 131.4, 131.3,
130.4, 128.6, 128.5, 128.2, 126.3, 125.4, 34.5, 34.4, 20.2. HRMS
(ESI): m/z [M + Na]+ calcd for C18H18ONa: 273.1255; found:
273.1243. Retention time 2.63 min, HPLC purity > 96%.
NMR (125 MHz, CDCl3) δ 189.6 (d, JCF = 1.9 Hz), 162.9 (d, JCF
247.8 Hz), 149.36, 140.77, 140.1 (d, JCF = 6.2 Hz), 130.3 (d, JCF = 7.7
Hz), 128.6 (d, JCF = 17.9 Hz), 126.3 (d, JCF = 5.4 Hz), 124.3 (d, JCF
=
=
(E)-1-(2,6-Dimethylphenyl)-5-phenylpent-2-en-1-one (27). The
2.8 Hz), 119.7 (d, JCF = 21.5 Hz), 115.4 (d, JCF = 22.3 Hz), 34.6, 34.5.
HRMS (ESI): m/z [M + H]+ calcd for C17H16FO: 255.1180; found:
255.1186. Retention time 2.60 min, HPLC purity > 99%.
title compound was prepared as a colorless oil using a method
1
similar to that described for compound F11 in 80% yield. H NMR
(400 MHz, CDCl3) δ 7.26 (t, J = 7.4 Hz, 2H), 7.21−7.08 (m, 4H),
7.00 (d, J = 7.5 Hz, 2H), 6.49 (dt, J = 15.9, 6.8 Hz, 1H), 6.28 (dt, J =
15.9, 1.3 Hz, 1H), 2.75 (t, J = 7.6 Hz, 2H), 2.59−2.51 (m, 2H), 2.12
(s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ 201.4, 151.5, 140.6,
140.0, 134.0, 133.0, 128.7, 128.6, 128.5, 127.6, 126.4, 34.38, 34.35,
19.4. HRMS (ESI): m/z [M + Na]+ calcd for C19H20ONa: 287.1412;
found: 287.1405. Retention time 3.08 min, HPLC purity > 97%.
(E)-5-Phenyl-1-(m-tolyl)pent-2-en-1-one (28). The title com-
pound was prepared as a colorless oil using a method similar to
that described for compound F11 in 92% yield. 1H NMR (400 MHz,
CDCl3) δ 7.72−7.69 (m, 2H), 7.41−7.31 (m, 4H), 7.27−7.24 (m,
3H), 7.10 (dt, J = 15.4, 6.8 Hz, 1H), 6.89 (dt, J = 15.4, 1.3 Hz, 1H),
2.88 (t, J = 7.7 Hz, 2H), 2.71−2.64 (m, 2H), 2.44 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 191.2, 148.3, 141.0, 138.4, 138.1, 133.5,
129.2, 128.6, 128.5, 128.5, 126.9, 126.3, 125.9, 34.6, 34.6, 21.5.
(E)-1-(4-Fluorophenyl)-5-phenylpent-2-en-1-one (35). The title
compound was prepared as a colorless oil using a method similar to
that described for compound F11 in 81% yield. 1H NMR (300 MHz,
CDCl3) δ 7.92−7.81 (m, 2H), 7.30−7.13 (m, 4H), 7.11−7.03 (m,
3H), 7.02−6.95 (m, 2H), 3.20 (ddd, J = 7.2, 2.8, 1.6 Hz, 2H), 2.47 (t,
J = 7.9 Hz, 2H). Retention time 2.51 min, HPLC purity > 97%.
(E)-1-([1,1′-Biphenyl]-2-yl)-5-phenylpent-2-en-1-one (36). The
title compound was prepared as a colorless oil using a method
1
similar to that described for compound F11 in 60% yield. H NMR
(400 MHz, CDCl3) δ 7.49−7.53 (m, 2H), 7.42 (d, J = 7.4 Hz, 2H),
7.37−7.24 (m, 8H), 7.04 (d, J = 6.9 Hz, 2H), 6.58 (dt, J = 15.7, 6.8
Hz, 1H), 5.96 (d, J = 15.7 Hz, 1H), 2.49−2.41 (m, 2H), 2.30−2.22
(m, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ 197.4, 148.6, 140.93,
140.90, 140.7, 139.7, 131.1, 130.6, 130.1, 129.3, 128.8, 128.7, 128.6,
128.6, 128.4, 128.3, 127.8, 127.4, 126.2, 34.4, 34.2. HRMS (ESI): m/z
L
J. Med. Chem. XXXX, XXX, XXX−XXX