10.1002/cmdc.202000548
ChemMedChem
2-Methyl-N-(naphth-1-ylethyl]benzamide (4b): This compound was
synthesized according to the general procedure Ac. 863 mg, 3.13 mmol,
yield: 98%. mp: 134 °C. 1H NMR (400 MHz, CDCl3) δ = 2.48 (s, 3H), 5.10
(d, J = 5.31 Hz, 2H), 5.98 (s, 1H), 7.14 (td, J = 7.58, 0.51 Hz, 1H), 7.20 (d,
J = 7.58 Hz, 1H), 7.28 (td, J = 7.58, 1.26 Hz, 2H), 7.32 (dd, J = 7.58,
1.01 Hz, 1H), 7.39–7.49 (m, 1H), 7.49–7.64 (m, 3H), 7.85 (d, J = 8.08 Hz,
1H), 7.87–7.96 (m, 1H), 8.15 (d, J = 8.59 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 19.8, 42.2, 123.6, 125.4, 125.7, 126.1, 126.6, 126.7,
127.0, 128.8, 129.9, 131.0, 131.4, 133.5, 134.0, 136.2, 136.2, 169.6 ppm.
MS (ESI): m/z calcd for C19H17NO [M+H]+ 276.13, found 276.2. Purity (LC,
300 nm): > 99%.
7.76–7.96 (m, 3H), 8.14 (d, J = 8.08 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ = 16.7, 17.5, 44.7, 122.2, 123.3, 124.8, 125.0, 125.6, 126.1,
126.6, 126.9, 128.3, 128.5, 129.0, 130.2, 131.6, 134.1, 135.5, 136.4,
172.7 ppm. (ESI): m/z calcd for C20H19NO [M+H]+ 290.16, found 290.2.
Purity (LC, 254 nm): 98.8%.
N-(2-Fluorphenyl)-2-naphth-1-ylpropanamide (11b): This compound
was synthesized according to the general procedure B. 70 mg, 0.24 mmol,
yield: 60%. mp: 116 °C. 1H NMR (400 MHz, CDCl3) δ = 1.81 (d,
J = 7.15 Hz, 3H), 4.54 (q, J = 7.15 Hz, 1H), 6.90–7.01 (m, 2H), 7.09 (t,
J = 7.40 Hz, 1H), 7.26 (s., 1H), 7.48–7.63 (m, 4H), 7.86 (d, J = 8.16 Hz,
1H), 7.89–7.94 (m, 1H), 8.12 (d, J = 8.28 Hz, 1H), 8.29 (t, J = 7.59 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 17.9, 44.8, 114.6, 121.6, 123.0,
124.2, 124.4, 125.0, 125.7, 126.1, 126.3, 126.9, 128.6, 129.2, 131.5,
134.2, 136.2, 172.8 ppm. MS (ESI): m/z calcd for C19H16FNO [M+H]+
294.13, found 294.2. Purity (LC, 254 nm): 96.0%.
N-(Diphenylmethyl)-2-methylbenzamide
(4c):
1,1-
diphenylmethanamine (53.7 µL, 57.2 mg, 0.312 mmol, 1 eq.), TEA
(100 µL, 78 mg, 0.77 mmol, 2.5 eq.) and 2-methylbenzoyl chloride (50 µL,
60 mg, 0.39 mmol, 1.25 eq.) were added to dichloromethane (10 mL). The
reaction was monitored by TLC. After the reaction was completed, the
mixture was washed with 1 m hydrochloric acid (3x 5 mL). The organic
phase was dried, and the solvent was evaporated under reduced pressure.
The crude product was purified by silica gel column chromatography to
yield 4c (65 mg, 0.22 mmol, yield: 69%). mp: 179 °C. Rf = 0.62 (CH/EtOAc
3:1). 1H NMR (400 MHz, CDCl3) δ = 2.45 (s, 3H), 6.35 (d, J = 7.78 Hz, 1H),
6.47 (d, J = 8.03 Hz, 1H), 7.19–7.25 (m, 2H), 7.28–7.40 (m, 11H), 7.41–
7.45 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 19.9, 57.2, 125.8,
126.6, 127.4, 127.6, 128.7, 130.0, 131.1, 136.1, 136.4, 141.5, 169.0 ppm.
MS (ESI): m/z calcd for C21H19NO [M+H]+ 302.16, found 302.2. Purity (LC,
215 nm): 93.9%.
2-Naphth-1-yl-N-(4-sulfamoylphenyl)propanamide
(11c):
This
compound was synthesized according to the general procedure B. 27 mg,
0.08 mmol, yield: 19%. mp: 206 °C. Rf = 0.8 (EtOAc). 1H NMR (400 MHz,
acetone-d6) δ = 1.62 (d, J = 7.07 Hz, 3H), 4.68 (q, J = 6.82 Hz, 1H), 6.43
(s., 2H), 7.42–7.64 (m, 4H), 7.79 (s, 4H), 7.83 (d, J = 8.08 Hz, 1H), 7.93–
7.97 (m, 1H), 8.22 (d, J = 8.59 Hz, 1H), 9.59 (s., 1H) ppm. 13C NMR
(100 MHz, acetone-d6) δ = 19.2, 44.1, 119.7, 119.8, 124.3, 125.3, 126.6,
126.7, 127.2, 128.0, 128.5, 129.9, 132.3, 135.2, 139.0, 139.4, 143.6,
173.9 ppm. MS (ESI): m/z calcd for C19H18N2O3S [M-H]- 353.09, found
353.2. Purity (LC, 254 nm): 98.6%.
2-Methyl-N-[(1S)-1-naphth-1-ylethyl]benzamide (4d): To a solution of
(1S)-1-Naphth-1-ylethylamine (50 µL, 53.4 mg, 0.312 mmol, 1 eq.) and
TEA (100 µL, 78 mg, 0.77 mmol, 2.5 eq.) in dichloromethane (2 mL), 2-
Methylbenzoyl chloride (50 µL, 60 mg, 0.39 mmol, 1.25 eq.) was added
dropwise. After 1 h, the resulting precipitate was filtered off and washed
with dichloromethane. The filtrate was freed from solvent and the residue
was dissolved in ethyl acetate (10 mL). The solution was washed with 10%
citric acid solution (3x 5 mL) followed by saturated sodium chloride solution
(5 mL). The organic phase was evaporated under reduced pressure and
the crude product was recrystallized twice from ethyl acetate to yield 4d
(61 mg, 0.21 mmol, yield: 68%). mp: 160 °C. Rf = 0.48 (CH/EtOAc 3:1). 1H
NMR (400 MHz, CDCl3) δ = 1.81 (d, J = 6.65 Hz, 3H), 2.45 (s, 3H), 5.99
(d, J = 7.78 Hz, 1H), 6.09–6.24 (m, 1H), 7.09–7.22 (m, 2H), 7.24–7.31 (m,
2H), 7.43–7.65 (m, 4H), 7.83 (d, J = 8.16 Hz, 1H), 7.86–7.95 (m, 1H), 8.26
(d, J = 8.53 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 19.7, 20.6, 44.9,
122.6, 123.6, 125.2, 125.6, 126.0, 126.5, 126.6, 128.5, 128.8, 129.8,
130.9, 131.2, 134.0, 136.1, 136.4, 138.0, 168.9 ppm. MS (ESI): m/z calcd
for C20H19NO [M+H]+ 290.16, found 290.2. Purity (LC, 254 nm): 98.6%.
N-Cyclohexyl-2-naphth-1-ylpropanamide (11d): This compound was
synthesized according to the general procedure B. 53 mg, 0.19 mmol,
yield: 47%. mp: 151 °C. Rf = 0.3 (CH/EtOAc 3:1). 1H NMR (400 MHz,
CDCl3) δ = 0.78–0.87 (m, 2H), 1.14–1.36 (m, 4H), 1.50 (m, 2H), 1.64–1.78
(m, 2H), 1.70 (d, J = 7.15 Hz, 3H), 3.64–3.82 (m, 1H), 4.28 (q, J = 7.19 Hz,
1H), 5.08 (s., 1 H), 7.40–7.58 (m, 4H), 7.78–7.83 (m, 1H), 7.86–7.92 (m,
1H), 8.01–8.07 (m, 1H) ppm. 13C NMR (100 MHz, acetone-d6) δ = 18.0,
24.6, 25.4, 32.7, 32.7, 43.9, 48.1, 123.4, 124.9, 125.6, 125.9, 126.5, 128.1,
129.0, 131.5, 134.0, 137.3, 173.7 ppm. MS (ESI): m/z calcd for C19H23NO
[M+H]+ 282.19, found 282.3. Purity (LC, 254 nm): 94.8%.
4-Methyl-2-[(1R)-1-naphth-1-ylethyl]-2,3-dihydro-1H-isoindol
hydrochloride (14a): This compound was synthesized according to the
general procedure E. 84 mg, 0.17 mmol, yield: 23% as off-white solid. mp:
247 °C. Rf = 0.75 (CH/EtOAc 3:1). 1H NMR (400 MHz, MeOD) δ = 1.94 (d,
J = 6.65 Hz, 3H 46%), 1.97 (d, J = 6.65 Hz, 3H 54%), 2.03 (s, 3H 46%),
2.39 (s, 3H 54%), 4.24–4.42 (m, 2H), 4.90–5.26 (m, 2H), 5.82 (q,
J = 6.65 Hz, 1H), 6.91–7.37 (m, 3H), 7.56–7.74 (m, 3H), 7.96–8.10 (m,
3H), 8.32 (t, J = 8.03 Hz, 1H) ppm. 13C NMR (100 MHz, MeOD) δ = 18.6,
18.9, 20.4, 58.5, 58.7, 59.7, 59.8, 61.6, 121.3, 123.3, 126.2, 127.0, 127.8,
128.9, 130.5, 130.6, 131.1, 131.5, 132.3, 133.8, 134.1, 134.3, 134.4,
134.5, 134.8, 135.0, 135.8 ppm. MS (ESI): m/z calcd for C21H22ClN [M+H]+
288.18, found 288.1. Purity (LC, 280 nm): > 99%.
N-(2-Hydroxy-1-naphth-1-ylethyl)-2-methylbenzamide (8): S4 (107 mg,
0.25 mmol, 1 eq.) and lithium hydroxide monohydrate (210 mg, 5.0 mmol,
20 eq.) were dissolved in THF/H2O (3:1, 30 mL) and heated under reflux
for 2 d. THF was evaporated under reduced pressure and residual
aqueous solution was extracted with ethyl acetate (3x 10 mL) The
combined organic extracts were dried over sodium sulfate and evaporated
under reduced pressure. The crude product was purified by silica gel
column chromatography to afford 8 (56 mg, 0.18 mmol, yield: 73%) as an
off-white solid. mp: 97 °C. Rf = 0.31 (CH/EtOAc 1:1). 1H NMR (400 MHz,
CDCl3) δ = 2.45 (s, 3H), 2.98 (s., 1H), 4.05–4.21 (m, 2H), 6.08 (dt, J = 7.28,
5.08 Hz, 1H), 6.61 (d, J = 7.28 Hz, 1H), 7.11–7.26 (m, 2H), 7.28–7.61 (m,
6H), 7.82 (d, J = 7.91 Hz, 1H), 7.86–7.93 (m, 1H), 8.16 (d, J = 8.41 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3) δ = 19.8, 52.0, 65.6, 122.9, 123.5,
125.1, 125.7, 126.0, 126.7, 126.7, 128.7, 129.0, 130.1, 130.9, 131.0,
134.1, 134.4, 135.9, 136.2, 170.5 ppm. ESI (MS) m/z: calcd for C20H19NO2
[M+H]+ 306.15, found 306.1. Purity (LC, 300 nm): 97.9%.
4-Fluor-2-[(1R)-1-naphth-1-ylethyl]-2,3-dihydro-1H-isoindol chloride
(14b): This compound was synthesized according to the general
procedure E. 46 mg, 0.14 mmol, yield: 8% as colorless solid. mp: decomp.
> 260 °C. Rf = 0.66 (PE/EtOAc 6:1). 1H NMR (400 MHz, acetone-d6 and
D2O) δ = 1.96 (d, J = 6.78 Hz, 3H), 4.41 (s, 2H), 5.02 (d, J = 11.80 Hz, 1H),
5.11–5.39 (m, 1H), 5.83 (q, J = 6.73 Hz, 1H), 6.98–7.55 (m, 3H), 7.59–7.75
(m, 3H), 7.91 (d, J = 7.40 Hz, 1H), 8.05 (dd, J = 10.67, 8.53 Hz, 2H), 8.31
(d, J = 8.53 Hz, 1H) ppm. 13C NMR (100 MHz, acetone-d6 and D2O)
δ = 20.2, 55.7, 58.9, 61.1, 116.0, 119.8, 123.0, 126.0, 126.1, 126.8, 127.3,
128.3, 130.1, 130.8, 131.4, 132.3, 133.8, 134.8, 138.2 ppm. MS (ESI): m/z
calcd for C20H19ClFN [M+H]+ 292.15, found 292.1. Purity (LC, 280 nm):
> 99%.
N-(2-Methylphenyl)-2-naphth-1-ylpropanamide (11a): This compound
was synthesized according to the general procedure B. 52 mg, 0.18 mmol,
yield: 45%. mp: 151 °C. 1H NMR (400 MHz, CDCl3) δ = 1.54 (s, 3H), 1.87
(d, J = 7.33 Hz, 3H), 4.54 (q, J = 7.33 Hz, 1H), 6.78 (s., 1H), 6.93–7.02 (m,
2H), 7.10–7.21 (m, 1H), 7.48–7.61 (m, 3H), 7.63 (d, J = 6.82 Hz, 1H),
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