10.1002/cmdc.201900281
ChemMedChem
FULL PAPER
0.24 mmol), nicotinamide (34 mg, 0.28 mmol, 1.2 eq.), K3PO4
(61 mg, 0.28 mmol, 1.2 eq.), Pd(OAc)2 (1.0 mg, 4.6 μmol, 2
mol%), L1 (3.3 mg, 6.8 μmol, 3 mol%), H2O (0.17 μL, 4 mol%)
and t-BuOH (0.3 mL) was heated at 110 °C for 2 h. The product
was purified by column chromatography (SiO2, hexane/acetone
1:1) affording 23g (44 mg, 63% yield) as a yellow solid (m.p.
131-134 °C). IR (cm-1): 3283, 1649, 1591, 1525, 1409, 1326,
yellow solid (m.p. 113-116 °C). IR (cm-1): 3251, 1650, 1610,
1531, 1511, 1325, 914. 1H NMR (500 MHz, Acetone-d6) δ = 9.74
(s, 1H), 8.01 – 7.97 (m, 2H), 7.58 (t, J=7.3, 1H), 7.50 (t, J=7.3,
2H), 7.28 (s, 1H), 7.25 (d, J=8.5, 2H), 6.91 (d, J=8.5, 2H), 6.49
(d, J=15.9, 1H), 6.11 (dd, J=15.9, 6.4, 1H), 5.90 (ddt, J=17.2,
10.2, 7.0, 1H), 5.18 – 4.92 (m, 2H), 4.33 – 4.17 (m, 1H), 3.90 (s,
1H), 2.41 – 2.28 (m, 2H). 13C NMR (126 MHz, Acetone) δ 167.6,
150.0, 136.3, 134.1, 132.5, 130.6, 130.0, 129.9, 129.3, 128.2,
127.9, 116.8, 114.0, 72.7, 43.2. HRMS (ESI) m/z: calcd. for
[C19H20N2O2 – H2O + H]+ 291.1497, found 291.1518.
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703. H NMR (500 MHz, Chloroform-d) δ = 9.09 (d, J=1.7, 1H),
8.78 (dd, J=4.8, 1.7, 1H), 8.21 (dt, J=8.0, 1.7, 1H), 7.86 (s, 1H),
7.61 (d, J=8.5, 2H), 7.45 (ddd, J=8.0, 4.9, 0.9, 1H), 7.41 (d,
J=8.5, 2H), 6.60 (dd, J=16.0, 1.3, 1H), 6.23 (dd, J=16.0, 6.3,
1H), 5.87 (ddt, J=17.1, 10.2, 7.1, 1H), 5.28 – 5.09 (m, 2H), 4.45
– 4.32 (m, 1H), 2.55 – 2.30 (m, 2H). 13C NMR (126 MHz, CDCl3)
δ 163.8, 152.7, 147.9, 137.0, 135.5, 134.2, 133.7, 131.5, 130.8,
129.7, 127.4, 123.9, 120.6, 118.7, 71.8, 42.2. HRMS (ESI) m/z:
calcd. for [C18H18N2O2 + H]+ 295.1447, found 295.1431.
(E)-1-(4-(But-3-en-1-ylamino)phenyl)hexa-1,5-dien-3-ol (23k):
Following General Procedure A, a mixture of 19b (60 mg, 0.24
mmol), 3-butenylamine hydrochloride (30.6 mg, 0.284 mmol, 1.2
eq.), K3PO4 (61 mg, 0.28 mmol, 1.2 eq.), Pd2(dba)3 (2.22 mg,
2.35 μmol, 1 mol%), L1 (2.9 mg, 6.0 μmol, 2.5 mol%) and t-
BuOH (0.3 mL) was heated to 110 °C for 16 h. The product was
purified by column chromatography (SiO2, hexane/AcOEt 8:2),
affording 23k (31.7 mg, 55% yield) as a yellow solid (m.p. 69-70
°C). IR (cm-1): 3282, 2919, 2848, 1642, 1611, 1518, 1317, 1280,
1245, 1181, 1082, 914. 1H NMR (500 MHz, Acetone-d6) δ = 7.18
(d, J=8.5, 2H), 6.58 (d, J=8.5, 2H), 6.43 (dd, J=15.9, 1.1, 1H),
6.01 (dd, J=15.9, 6.6, 1H), 5.97 – 5.81 (m, 2H), 5.18 – 4.96 (m,
4H), 4.96 – 4.85 (m, 1H), 4.22 (dt, J=11.4, 5.9, 1H), 3.78 (d,
J=4.3, 1H), 3.18 (q, J=7.0, 2H), 2.91 (s, 1H), 2.41 – 2.27 (m,
4H). 13C NMR (126 MHz, Acetone) δ 149.3, 137.1, 136.4, 130.4,
128.8, 128.2, 126.4, 116.7, 116.6, 113.1, 72.8, 43.6, 43.3, 34.3.
HRMS (ESI) m/z: calcd. for [C16H21NO – H2O + H]+ 226.1596,
found 226.1595.
(E)-N-(4-(3-Hydroxyhexa-1,5-dien-1-yl)phenyl)-2-
phenylhydrazine-1-carboxamide (23h): Following General
Procedure B, a mixture of 19b (60 mg, 0.24 mmol), 1-
phenylsemicarbazide (43 mg, 0.28 mmol, 1.2 eq), K3PO4 (61
mg, 0.28 mmol, 1.2 eq.), Pd(OAc)2 (1.0 mg, 4.6 μmol, 2 mol%),
L1 (3.3 mg, 6.8 μmol, 3 mol%), H2O (0.17 μL, 4 mol%) and t-
BuOH (0.3 mL) was heated at 110 °C for 2 h. The product was
purified by column chromatography (SiO2, hexane/acetone 1:1)
affording 23h (38.3 mg, 50% yield) as a yellow solid (m.p. 135-
136 °C). IR (cm-1): 3340, 3274, 1668, 1602, 1584, 1531, 1519,
1
1494. H NMR (400 MHz, Acetone-d6) δ = 8.55 (s, 1H), 7.60 (d,
J=8.5, 2H), 7.44 (s, 1H), 7.30 (d, J=8.5, 2H), 7.27 – 7.19 (m,
2H), 7.17 (s, 1H), 6.94 – 6.86 (m, 2H), 6.87 – 6.80 (m, 1H), 6.52
(dd, J=15.9, 1.2, 1H), 6.19 (dd, J=15.9, 6.3, 1H), 5.90 (ddt,
J=17.2, 10.2, 7.0, 1H), 5.17 – 4.94 (m, 2H), 4.33 – 4.18 (m, 1H),
3.89 (d, J=4.5, 1H). 13C NMR (101 MHz, Acetone) δ 157.4,
149.9, 140.0, 136.3, 132.2, 132.1, 129.8, 129.6, 127.4, 121.1,
119.7, 116.9, 114.0, 72.5, 43.2. HRMS (ESI) m/z: calcd. for
[C19H21N3O2 + H]+ 324.1712, found 324.1710.
(E)-1-(4-Benzamidophenyl)hexa-1,5-dien-3-yl acrylate (28a):
A solution of alcohol 23a (60.0 mg, 0.205 mmol) in anhydrous
DCM (0.5 mL) was treated with Et3N (86.6 μL, 0.615 mmol, 3
eq.) and DMAP (2.5 mg, 10 mg, 10 mol%), and the mixture was
cooled to 0 °C. A solution of acryloyl chloride (22.6 μL, 0.267
mmol, 1.3 eq.) in DCM (3 mL) was slowly added to the solution
containing the alcohol 23a, and the reaction mixture was stirred
for 2 h at room temperature. After completion of the reaction, the
solution was concentrated and the product was purified by
column chromatography (SiO2, hexane/AcOEt 1:1, 1% Et3N)
affording 28a (37.0 mg, 52% yield) as a yellow solid (m.p. 127-
129 °C). IR (cm-1): 3345, 1720, 1656, 1522, 1405, 1188, 1181.
1H NMR (400 MHz, Chloroform-d) δ = 7.92 – 7.83 (m, 3H), 7.62
(d, J=8.7, 2H), 7.58 – 7.52 (m, 1H), 7.51 – 7.45 (m, 2H), 7.38 (d,
J=8.7, 2H), 6.61 (d, J=15.9, 1H), 6.43 (dd, J=17.3, 1.5, 1H), 6.21
– 6.09 (m, 2H), 5.90 – 5.73 (m, 2H), 5.55 (q, J=6.5, 1H), 5.19 –
5.07 (m, 2H), 2.60 – 2.46 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
165.7, 165.6, 137.8, 135.0, 133.2, 132.7, 132.2, 132.1, 130.9,
129.0, 128.8, 127.5, 127.1, 126.4, 120.2, 118.3, 74.2, 39.3.
HRMS (ESI) m/z: calcd. for [C22H21NO3 – C3H3O2 – H2O + H]+
276.1388, found 276.1375.
1,3-Bis(4-((E)-3-hydroxyhexa-1,5-dien-1-yl)phenyl)urea (23i):
Following General Procedure A, a mixture of 19b (60 mg, 0.24
mmol), urea (7.1 mg, 0.12 mmol, 0.5 eq.), K3PO4 (61 mg, 0.28
mmol, 1.2 eq.), Pd2(dba)3 (2.22 mg, 2.35 μmol, 1 mol%), L2 (2.9
mg, 6.0 μmol, 2.5 mol%) and t-BuOH (0.3 mL) was heated to
110 °C for 16 h. The product was purified by column
chromatography (SiO2, hexane/acetone 1:1), affording 23i (67
mg, 70% yield) as a yellow solid (m.p. > 250 °C). IR (cm-1):
1
3314, 1644, 1593, 1553, 1512, 1410, 1314, 1239, 966. H NMR
(400 MHz, Acetone-d6) δ = 8.14 (s, 1H), 7.50 (d, J=8.7, 2H),
7.34 (d, J=8.7, 2H), 6.54 (dd, J=15.9, 1.4, 1H), 6.21 (dd, J=15.9,
6.2, 1H), 5.91 (ddt, J=17.2, 10.2, 7.0, 1H), 5.15 – 4.96 (m, 2H),
4.33 – 4.21 (m, 1H), 3.88 (d, J=4.5, 1H), 2.40 – 2.29 (m, 2H). 13
C
NMR (101 MHz, Acetone) δ 153.2, 140.1, 136.3, 132.2, 129.6,
127.6, 119.4, 116.9, 72.5, 43.2. HRMS (ESI) m/z: calcd. for
[C25H28N2O3 + H]+ 405.2178, found 405.2161.
(E)-1-(4-Isobutyramidophenyl)hexa-1,5-dien-3-yl
acrylate
(28b): A solution of alcohol 23b (33.0 mg, 0.127 mmol) in
anhydrous DCM (0.5 mL) was treated with anhydrous Et3N (53.6
μL, 0.381 mmol, 3 eq.) and DMAP (1.5 mg, 10 mol%), and the
mixture was cooled to 0 °C. A solution of acryloyl chloride (14
μL, 0.16 mmol, 1.3 eq.) in DCM (1.5 mL) was slowly added to
the solution containing the alcohol 23b, and the reaction mixture
was stirred for 2 h at room temperature. After completion of the
reaction, the solution was concentrated and the product was
purified by column chromatography (SiO2, hexane/AcOEt 6:4,
(E)-N'-(4-(3-Hydroxyhexa-1,5-dien-1-
yl)phenyl)benzohydrazide (23j): Following General Procedure
A, a mixture of 19b (60 mg, 0.24 mmol), benzhydrazide (38.7
mg, 0.284 mmol, 1.2 eq.), K3PO4 (61 mg, 0.28 mmol, 1.2 eq.),
Pd2(dba)3 (2.22 mg, 2.35 μmol, 1 mol%), L2 (2.9 mg, 5.6 μmol,
2.5 mol%) and t-BuOH (0.3 mL) was heated to 110 °C for 16 h.
The product was purified by column chromatography (SiO2,
hexane/AcOEt 1:1), affording 23j (63,6 mg, 87% yield) as a
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