16
J. D. Williams et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
4.1.2.84.
N-[(Benzofuran-5-yl)methyl]-2-(2,4-dichlorophen-
mp 198–201 °C; Rf 0.19 (1:1 hexane/EtOAc); 1H NMR (DMSO-d6) d
11.58 (s, br, 1H), 8.63 (t, 1H), 8.09 (d, 1H), 7.71 (s, 1H), 7.59 (d, 1H),
7.45 (t, 1H), 7.27 (dd, 1H), 6.96 (d, 1H), 6.38 (dd, 1H), 4.80 (q, 1H),
4.37 (d, 2H), 1.48 (d, 3H); m/z expected 363.1 found 364.4 (M+H)+.
oxy)propanamide (34p). General synthesis HI was followed
using 5-aminomethylbenzofuran (74 mg, 0.50 mmol) to provide
86 mg (55%) of product as a beige powder: mp 125–132 °C; Rf
0.69 (1:1 hexane/EtOAc); 1H NMR (CDCl3) d 7.62 (s, 1H), 7.45–
7.36 (m, 3H), 7.17–7.14 (m, 2H), 6.99 (s, br, 1H), 6.85 (d, 1H),
6.72 (s, 1H), 4.74 (q, 1H), 4.60–4.50 (m, 2H), 1.65 (d, 3H); m/z
expected 363.0 found 364.1 (M+H)+.
4.1.2.92.
N-[(6-Fluoropyridin-3-yl)methyl]-2-(2,4-dichloro-
phenoxy)propanamide (34x). General synthesis H was followed
using 3-aminomethyl-6-fluoropyridine (63 mg, 0.50 mmol) to pro-
vide 52 mg (35%) of product as an off-white solid: mp 55-59 °C; Rf
0.36 (1:1 hexane/EtOAc); 1H NMR (CDCl3) d 8.03 (d, 1H), 7.78–7.72
(m, 2H), 7.45 (dd, 1H), 6.94 (dd, 1H), 6.86 (d, 1H), 4.74 (q, 1H), 4.47
(d, 2H), 1.62 (d, 3H); m/z expected 342.0 found 343.1 (M+H)+.
4.1.2.85. N-[(Benzimidazol-5-ylmethyl])-2-(2,4-dichlorophen-
oxy)propanamide (34q). General synthesis HI was followed
using 5-aminomethylbenzimidazole (74 mg, 0.50 mmol) to pro-
vide 43 mg (27%) of product as a colorless glass: mp 71–77 °C; Rf
0.17 (1 EtOAc); 1H NMR (CDCl3) d 8.07 (s, 1H), 7.59 (d, 1H), 7.51
(s, 1H), 7.33 (d, 1H), 7.17–7.14 (m, 3H), 6.84 (d, 1H), 5.08 (s, br,
1H), 4.73 (q, 1H), 4.68–4.55 (m, 2H), 1.63 (d, 3H); m/z expected
363.1 found 363.9 (M+H)+.
4.1.2.93.
N-[(5-Fluoropyridin-2-yl)methyl]-2-(2,4-dichloro-
phenoxy)propanamide (34y). General synthesis H was followed
using 2-aminomethyl-5-fluoropyridine (63 mg, 0.50 mmol) to pro-
vide 101 mg (68%) of product as a white powder: mp 78–82 °C; Rf
0.30 (1:1 hexane/EtOAc); 1H NMR (CDCl3) d 8.38 (s, 1H), 7.76 (s, br,
1H), 7.40–7.34 (m, 2H), 7.26–7.15 (m, 2H), 6.86 (d, 1H), 4.75 (q,
1H), 4.58 (d, 2H), 1.64 (d, 3H); m/z expected 342.0 found 343.1
(M+H)+.
4.1.2.86.
N-[(Indol-5-yl)methyl]-2-(2,4-dichlorophenoxy)pro-
panamide (34r). General synthesis H was followed using 5-ami-
nomethylindole (73 mg, 0.50 mmol) to provide 75 mg (48%) of
product as a light brown crystalline solid: mp 91–95 °C; Rf 0.56
(1:1 hexane/EtOAc); 1H NMR (CDCl3) d 7.21 (s, br, 1H), 7.48 (d,
1H), 7.35–7.32 (m, 2H), 7.24 (dd, 1H), 7.16 (dd, 1H), 7.06 (dd, 1H),
6.93 (s, br, 1H), 6.84 (d, 1H), 6.52–6.50 (m, 1H), 4.73 (q, 1H), 4.64–
4.50 (m, 2H), 1.65 (d, 3H); m/z expected 362.1 found 363.1 (M+H)+.
4.1.2.94. (R)-2-[(3,5-dichloropyridin-2-yl)oxy]butanoic acid
(36).
To a solution of 3,5-dichloropyridin-2-one (18.3 g,
111 mmol) and triphenyl phosphine (38.0 g, 145 mmol in dry
DMF (120 mL) was added (S)-methyl 2-hydroxybutanoate (17.1 g,
145 mmol). The solution was cooled to ꢁ20 °C (ice/salt bath) and
diisopropyl azodicarboxylate (DIAD; 29.3 g, 145 mmol) was added
dropwise over 45 min at ꢁ20 °C. After addition, the resulting solu-
tion was warmed to room temperature and was stirred at that
temperature for 16 h. The solvent was then removed under vac-
uum, and the residue was subjected to flash chromatography on
silica gel with 0–15% EtOAc/hexane. Product-containing fractions
were pooled and evaporated to provide a pale yellow oil that
was dissolved in MeOH (100 mL). A solution of potassium hydrox-
ide (8.40 g, 150 mmol) in water (20 mL) was added to the metha-
nolic solution at ꢁ20 °C over 10 min. The solution was warmed
to room temperature over 2 h, then the solvent was removed under
reduced pressure, and the residue diluted with water (150 mL).
The aqueous solution was washed with Et2O (150 mL ꢀ 2), then
the aqueous solution was acidified (pH 4) with aqueous HCl
(3.0 M). The resulting suspension was extracted with EtOAc
(150 mL ꢀ 6), and the combined organic extracts were dried over
MgSO4, filtered, and evaporated to provide 21.0 g (80%) of product
as a white solid: mp 87–90 °C; Rf 0.38 (4:1 hexane/EtOAc w/2%
AcOH); 1H NMR (CDCl3) d 11.0–10.0 (s, br, 1H), 7.94 (dd, 1H),
7.67 (dd, 1H), 5.15 (t, 1H), 2.08 (quint, 2H), 1.13 (t, 3H).
4.1.2.87.
N-[(Indol-6-yl)methyl]-2-(2,4-dichlorophenoxy)pro-
panamide (34s). General synthesis H was followed using 6-ami-
nomethylindole (73 mg, 0.50 mmol) to provide 71 mg (46%) of
product as a beige powder: mp 120–123 °C; Rf 0.53 (1:1 hexane/
EtOAc); 1H NMR (CDCl3) d 8.21 (s, br, 1H), 7.58 (d, 1H), 7.35 (d,
1H), 7.23–7.14 (m, 3H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.54–6.52
(m, 1H), 4.73 (q, 1H), 4.65–4.09 (m, 2H), 1.64 (d, 3H); m/z expected
362.1 found 363.1 (M+H)+.
4.1.2.88.
N-[(Indol-4-yl)methyl]-2-(2,4-dichlorophenoxy)pro-
panamide (34t). General synthesis H was followed using 4-ami-
nomethylindole (73 mg, 0.50 mmol) to provide 81 mg (52%) of
product as a pale pink powder: mp 107–111 °C; Rf 0.55 (1:1 hex-
ane/EtOAc); 1H NMR (CDCl3) d 8.28 (s, br, 1H), 7.38 (d, 1H), 7.35
(d, 1H), 7.21 (t, 1H), 7.20–7.09 (m, 2H), 6.99–6.95 (m, 2H), 6.80
(d, 1H), 6.54–6.52 (m, 1H), 4.79–4.70 (m, 3H), 1.64 (d, 3H); m/z
expected 362.1 found 363.1 (M+H)+.
4.1.2.89.
N-[(Indol-2-yl)methyl]-2-(2,4-dichlorophenoxy)pro-
panamide (34u). General synthesis IH was followed using 2-
aminomethylindole (73 mg, 0.50 mmol) to provide 93 mg (60%)
of product as a pink glass: mp 95–102 °C; Rf 0.54 (1:1 hexane/
EtOAc); 1H NMR (CDCl3) d 8.88 (s, br, 1H), 7.57 (d, 1H), 7.38–7.33
(m, 2H), 7.19–7.05 (m, 3H), 6.81 (d, 1H), 6.36 (s, 1H), 4.73 (q, 1H),
4.56 (d, 2H), 1.61 (d, 3H); m/z expected 362.1 found 363.2 (M+H)+.
4.1.2.95. (R)-N-[(Benzothiophene-5-yl)methyl]-2-[(3,5-dichloro-
pyridin-2-yl)oxy]butanamide (37a). General synthesis I was
followed
using
5-aminomethylbenzothiophene
(98 mg,
0.60 mmol) to provide 89 mg (45%) of product as a white powder:
mp 110–119 °C; Rf 0.73 (1:1 hexane/EtOAc); 1H NMR (CDCl3) d 7.99
(d, 1H), 7.80 (d, 1H), 7.65 (d, 2H), 7.45 (d, 1H), 7.26 (d, 1H), 7.20
(dd, 1H), 6.69 (s, br, 1H), 5.47 (t, 1H), 4.60 (dd, 2H), 2.12–2.06
(m, 2H), 1.03 (t, 3H); m/z expected 394.0 found 395.1 (M+H)+.
4.1.2.90. N-[(1-Methylindol-5-yl)methyl]-2-(2,4-dichlorophen-
oxy)propanamide (34v). General synthesis
H was followed
using 5-aminomethyl-1-methylindole (80 mg, 0.50 mmol) to pro-
vide 144 mg (89%) of product as a white powder: mp 146–152 °C;
Rf 0.67 (1:1 hexane/EtOAc); 1H NMR (CDCl3) d 7.46 (d, 1H), 7.34
(d, 1H), 7.27–7.25 (m, 1H), 7.15 (dd, 1H), 7.10–7.05 (m, 2H), 6.91
(s, br, 1H), 6.84 (d, 1H), 6.43 (q, 1H), 4.72 (q, 1H), 4.58–4.55 (m, 2H),
3.78 (s, 3H), 1.64 (d, 3H); m/z expected 376.1 found 377.1 (M+H)+.
4.1.2.96. (R)-N-[(Indol-5-yl)methyl]-2-[(3,5-dichloropyridin-2-
yl)oxy]butanamide (37b). General synthesis I was followed
using 5-aminomethylindole (86 mg, 0.60 mmol) to provide 52 mg
(28%) of product as an off-white powder: mp 86–88 °C; Rf 0.34
(3% MeOH/CH2Cl2); 1H NMR (CDCl3) d 8.23 (s, br, 1H), 7.98 (d,
1H), 7.64 (d, 1H), 7.47 (s, 1H), 7.32 (d, 1H), 7.22 (t, 1H), 7.05 (dd,
1H), 6.61 (s, br, 1H), 6.50 (t, 1H), 5.46 (t, 1H), 4.56 (d, 2H), 2.04–
2.12 (m, 2H), 1.02 (t, 3H); m/z expected 377.1 found 378.3 (M+H)+.
4.1.2.91. N-[(Pyrrolo[2,3-b]pyridin-5-yl)methyl]-2-(2,4-dichlo-
rophenoxy)propanamide (34w).
General synthesis H was
followed using 5-aminomethylpyrrolo[2,3-b]pyridine (74 mg,
0.50 mmol) to provide 61 mg (39%) of product as a white powder: