Page 29 of 42
Journal of Medicinal Chemistry
1
2
3
4
5
6
7
8
DCM, affording the product (0.31 g, 0.87 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ 7.86 – 7.78 (m, 2H), 7.74 (d, J
= 16.2 Hz, 1H), 7.62 – 7.51 (m, 2H), 7.37 – 7.28 (m, 3H), 7.28 – 7.19 (m, 4H), 3.63 (q, J = 7.0 Hz, 2H), 2.89 (t, J =
7.1 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 185.33, 161.12, 146.13, 138.34, 136.52, 134.25, 131.84, 130.63,
128.88, 128.82, 127.72, 126.88, 123.27, 119.96, 40.78, 35.59. HRMS [C18H16BrNO2 + H]+: 358.0437 calculated,
358.0437 found.
9
(E)-4-([1,1'-Biphenyl]-3-yl)-2-oxo-N-phenethylbut-3-enamide (42). A round bottom flask was charged with aryl
bromide 41 (0.20 g, 0.56 mmol, 1 eq) and toluene/EtOH (4:1, 3 mL) and degassed for 20 min with sonication.
Pd(PPh3)4 (13 mg, 0.01 mmol, 2 mol%), phenylboronic acid (0.10 g, 0.84 mmol, 1.5 eq) and K2CO3 (0.46 g, 3.4
mmol, 6 eq) were added and the reaction was stirred for 16 h at 80 oC. The reaction mixture was filtered over a
pad of Celite and concentrated under reduced pressure. The crude residue was purified by silica gel column
chromatography (EtOAc/pentane) affording the product (0.15 g, 0.42 mmol, 75%). 1H NMR (300 MHz, CDCl3) δ
8.03 (d, J = 16.2 Hz, 1H), 7.94 – 7.78 (m, 2H), 7.73 – 7.18 (m, 14H), 3.67 (q, J = 6.9 Hz, 2H), 2.93 (t, J = 7.1 Hz,
2H). 13C NMR (75 MHz, CDCl3) δ 185.46, 161.38, 148.00, 142.21, 140.23, 138.39, 134.95, 130.35, 129.57,
129.02, 128.85, 128.81, 128.04, 127.94, 127.91, 127.24, 126.82, 118.96, 40.76, 35.59. HRMS [C24H21NO2 + H]+:
356.1645 calculated, 356.1641 found.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(4-Methylphenethyl)-2-oxo-5-phenylpentanamide (43). The title compound was prepared according to
general procedure D using -ketoacid 60c (57 mg, 0.29 mmol, 1 eq), 2-(p-tolyl)ethan-1-amine (47 μL, 0.32
mmol, 1.1 eq), EDC·HCl (85 mg, 0.44 mmol, 1.5 eq), HOBt (60 mg, 0.44 mmol, 1.5 eq) in DCM. Column
1
chromatography (2.5% -> 20% EtOAc in pentane) afforded the product (18 mg, 58 mol, 20%). H NMR (400
MHz, CDCl3) δ 7.39 – 7.22 (m, 3H), 7.22 – 7.14 (m, 3H), 7.12 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.01 –
6.86 (m, 1H), 3.52 (q, J = 7.0 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H), 2.80 (t, J = 7.1 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.32
(s, 3H), 1.93 (p, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 199.02, 160.11, 141.47, 136.44, 135.16, 129.56,
128.65, 128.61, 128.56, 126.21, 126.16, 40.68, 36.24, 35.13, 24.94, 21.18. HRMS [C20H23NO2 + H]+: 310.1802
calculated, 310.1803 found.
N-(4-Methoxyphenethyl)-2-oxo-5-phenylpentanamide (44). The title compound was prepared according to
general procedure D using -ketoacid 60c (89 mg, 0.46 mmol, 1 eq), 2-(4-methoxyphenyl)ethan-1-amine (75 l,
0.51 mmol, 1.1 eq), EDC·HCl (0.13 g, 0.69 mmol, 1.5 eq), HOBt (94 mg, 0.69 mmol, 1.5 eq) in DCM. Column
1
chromatography (2.5% -> 40% EtOAc in pentane) afforded the product (13 mg, 40 mol, 9%). H NMR (300
MHz, CDCl3) δ 7.32 – 7.24 (m, 2H), 7.23 – 7.14 (m, 3H), 7.10 (d, J = 8.6 Hz, 2H), 7.04 – 6.90 (m, 1H), 6.85 (d, J =
8.6 Hz, 2H), 3.79 (s, 3H), 3.50 (q, J = 6.9 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H), 2.65 (t, J = 7.6 Hz,
2H), 1.93 (p, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 199.03, 160.10, 158.52, 141.45, 130.25, 129.75, 128.60,
128.54, 126.15, 114.27, 55.39, 40.77, 36.23, 35.14, 34.65, 24.94. HRMS [C20H23NO3 + H]+: 326.1751 calculated,
326.1752 found.
N-(3,4-Dimethoxyphenethyl)-2-oxo-5-phenylpentanamide (45). The title compound was prepared according
to general procedure D using -ketoacid 60c (57 mg, 0.30 mmol, 1 eq), 2-(3,4-dimethoxyphenyl)ethan-1-amine
(56 L, 0.33 mmol, 1.1 eq), EDC·HCl (86 mg, 0.45 mmol, 1.5 eq), HOBt (61 mg, 0.45 mmol, 1.5 eq) in DCM.
1
Column chromatography (2.5% -> 40% EtOAc in pentane) afforded the product (6 mg, 17 mol, 6%). H NMR
(400 MHz, CDCl3) δ 7.31 – 7.26 (m, 2H), 7.22 – 7.11 (m, 3H), 7.03 – 6.91 (m, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.77 –
6.66 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.52 (q, J = 7.0 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.1 Hz, 2H),
2.65 (t, J = 7.6 Hz, 2H), 1.93 (p, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 199.04, 160.13, 149.01, 147.96,
141.44, 130.77, 128.56, 126.17, 120.73, 111.86, 111.53, 56.02, 40.69, 36.25, 35.16, 24.95. HRMS [C21H25NO4 +
H]+: 356.1856 calculated, 356.1858 found.
N-(4-Hydroxyphenethyl)-2-oxo-5-phenylpentanamide (46). The title compound was prepared according to
general procedure D using -ketoacid 60c (98 mg, 0.51 mmol, 1 eq), 4-(2-aminoethyl)phenol (77 mg, 0.56
mmol, 1.1 eq), EDC·HCl (0.15 g, 0.77 mmol, 1.5 eq), HOBt (0.10 g, 0.77 mmol, 1.5 eq) in DCM. Column
chromatography (10% -> 60% EtOAc in pentane) afforded the product (18 mg, 58 mol, 20%). 1H NMR (400
29
ACS Paragon Plus Environment