8
G. Zhang et al. / European Journal of Medicinal Chemistry 182 (2019) 111626
Method B as a white solid. 1H NMR (CDCl3)
3.40e3.20 (m, 2H), 1.81e1.68 (m, 1H), 1.60e1.44 (m, 2H); 13C NMR
(CD3OD)
d
7.53e7.30 (m, 5H),
4.12. (þ)-[(1R,2R)-2-(3-chlorophenyl)-2-fluorocyclopropyl]
methanamine hydrochloride ((þ)-21d)
d
139.36 (d, J ¼ 20.8 Hz), 129.64 (s, 2C), 129.15 (s), 125.67
(d, J ¼ 6.4 Hz, 2C), 82.24 (d, J ¼ 217.6 Hz), 39.65 (d, J ¼ 9.8 Hz), 23.68
Obtained from the intermediate (-)-20d employing General
(d, J ¼ 11.2 Hz), 19.17 (d, J ¼ 12.3 Hz); HRMS (ESI) calculated for
Method B as a white solid. 1H NMR (CD3OD)
d 7.46e7.34 (m, 3H),
20
C
10H13FN ([MþH]þ): m/z 166.1027; found: 166.1008. [
a
]
-67.4 (c
7.28 (d, J ¼ 7.5 Hz, 1H), 3.39e3.33 (m, 1H), 3.24 (dd, J ¼ 13.4, 8.1 Hz,
D
0.2, MeOH).
1H), 1.81e1.68 (m, 1H), 1.66e1.48 (m, 2H); 13C NMR (CD3OD)
d
141.84 (d, J ¼ 21.3 Hz), 135.69 (s), 131.31 (s), 129.08 (d, J ¼ 9.7 Hz),
4.8. (þ)-[(1R,2R)-2-fluoro-2-(m-tolyl)cyclopropyl]methanamine
hydrochloride ((þ)-21b)
125.64 (d, J ¼ 7.6 Hz), 123.66 (d, J ¼ 6.8 Hz), 81.66 (d, J ¼ 218.5 Hz),
39.48 (d, J ¼ 9.8 Hz), 24.19 (d, J ¼ 10.9 Hz), 19.42 (d, J ¼ 12.1 Hz); 19
F
NMR (CD3OD)
d
ꢀ194.37 (s); HRMS (ESI) calculated for C10H12ClFN
20
Obtained from the intermediate (-)-20b employing General
([MþH]þ): m/z 200.0637; found: 200.0626. [
a
]
D
þ38.2 (c 0.2,
Method B as a white solid. 1H NMR (CD3OD)
d
7.30 (t, J ¼ 7.6 Hz, 1H),
MeOH).
7.24e7.13 (m, 3H), 3.37e3.30 (m, 1H), 3.24 (dd, J ¼ 13.3, 8.2 Hz, 1H),
2.38 (s, 3H), 1.73e1.61 (m, 1H), 1.60e1.41 (m, 2H); 13C NMR (CD3OD)
4.13. (-)-[(1R,2R)-2-(3-chlorophenyl)-2-fluorocyclopropyl]
d
139.56 (s), 139.25 (d, J ¼ 20.3 Hz), 129.87 (s), 129.53 (d,
methanamine hydrochloride ((-)-21d)
J ¼ 10.7 Hz), 126.28 (d, J ¼ 6.4 Hz), 122.77 (d, J ¼ 6.5 Hz), 82.22 (d,
J ¼ 217.7 Hz), 39.68 (d, J ¼ 9.9 Hz), 23.63 (d, J ¼ 11.2 Hz), 21.43 (s),
Obtained from the intermediate (þ)-20d employing General
19.02 (d, J ¼ 12.5 Hz); 19F NMR (CD3OD)
d
ꢀ192.4 (s); HRMS (ESI)
Method B as a white solid. 1H NMR (CD3OD)
d 7.46e7.34 (m, 3H),
calculated for C11H15FN ([MþH]þ): m/z 180.1183; found: 180.1176.
7.28 (d, J ¼ 7.5 Hz, 1H), 3.39e3.33 (m, 1H), 3.24 (dd, J ¼ 13.4, 8.0 Hz,
20
[
a
]
þ53.6 (c 0.5, MeOH).
1H), 1.81e1.68 (m, 1H), 1.66e1.48 (m, 2H); 13C NMR (CD3OD)
D
d
141.84 (d, J ¼ 21.3 Hz), 135.69 (s), 131.31 (s), 129.08 (d, J ¼ 9.7 Hz),
4.9. (-)-[(1S,2S)-2-fluoro-2-(m-tolyl)cyclopropyl]methanamine
hydrochloride ((-)-21b)
125.64 (d, J ¼ 7.6 Hz), 123.66 (d, J ¼ 6.8 Hz), 81.66 (d, J ¼ 218.5 Hz),
39.48 (d, J ¼ 9.8 Hz), 24.19 (d, J ¼ 10.9 Hz), 19.42 (d, J ¼ 12.0 Hz); 19
F
NMR (CD3OD)
d
ꢀ194.37 (s); HRMS (ESI) calculated for C10H12ClFN
20
Obtained from the intermediate (þ)-20b employing General
([MþH]þ): m/z 200.0637; found: 200.0626. [
a
]
-37.8 (c 0.2,
D
Method B as a white solid. 1H NMR (CD3OD)
d
7.30 (t, J ¼ 7.6 Hz, 1H),
MeOH).
7.25e7.13 (m, 3H), 3.37e3.30 (m, 1H), 3.24 (dd, J ¼ 13.3, 8.0 Hz, 1H),
2.38 (s, 3H), 1.73e1.62 (m, 1H), 1.60e1.41 (m, 2H); 13C NMR (CD3OD)
4.14. (þ)-[(1R,2R)-2-(2-bromophenyl)-2-fluorocyclopropyl]
methanamine hydrochloride ((þ)-21e)
d
139.56 (s), 139.25 (d, J ¼ 20.3 Hz), 129.87 (s), 129.53 (d,
J ¼ 10.7 Hz), 126.28 (d, J ¼ 6.4 Hz), 122.77 (d, J ¼ 6.5 Hz), 82.22 (d,
J ¼ 217.6 Hz), 39.68 (d, J ¼ 9.9 Hz), 23.63 (d, J ¼ 11.2 Hz), 21.43 (s),
4.14.1. Obtained from the intermediate (-)-20e employing General
Method B as a white solid
19.02 (d, J ¼ 12.5 Hz); 19F NMR (CD3OD)
d
ꢀ192.4 (s); HRMS (ESI)
calculated for C11H15FN ([MþH]þ): m/z 180.1183; found: 180.1175.
1H NMR (CD3OD)
d
7.72 (d, J ¼ 7.9 Hz, 1H), 7.60 (dt, J ¼ 7.6, 1.9 Hz,
[
a
]
20 -49.8 (c 0.1, MeOH).
1H), 7.45 (t, J ¼ 7.5 Hz, 1H), 7.38 (m, 1H), 3.52 (dd, J ¼ 13.4, 6.2 Hz,
D
1H), 3.19 (ddd, J ¼ 13.4, 8.7, 1.2 Hz, 1H), 1.72e1.61 (m, 1H), 1.60e1.45
4.10. (þ)-[(1R,2R)-2-fluoro-2-(3-fluorophenyl)cyclopropyl]
methanamine hydrochloride ((þ)-21c)
(m, 2H); 13C NMR (CD3OD)
d
136.51 (d, J ¼ 19.0 Hz), 134.54 (s),
133.15 (d, J ¼ 2.3 Hz), 132.76 (d, J ¼ 2.4 Hz), 128.93 (s), 126.94 (s),
82.88 (d, J ¼ 218.9 Hz), 39.94 (d, J ¼ 8.4 Hz), 21.70 (d, J ¼ 11.8 Hz),
4.10.1. Obtained from the intermediate (-)-20c employing General
Method B as a white solid
7.48e7.39 (m, 1H), 7.19e7.13 (m, 2H),
7.13e7.05 (m, 1H), 3.39e3.34 (m, 1H), 3.23 (dd, J ¼ 13.4, 8.1 Hz, 1H),
1.78e1.68 (m, 1H), 1.65e1.48 (m, 2H); 13C NMR (CD3OD)
164.40 (d,
17.40 (d, J ¼ 13.3 Hz); 19F NMR (CD3OD)
d
ꢀ181.76 (s); HRMS (ESI)
calculated for
C
10H12BrFN ([MþH]þ): m/z 244.0132; found:
20
1H NMR (CD3OD)
d
244.0105. [
a
]
þ80.3 (c 0.2, MeOH).
D
d
4.15. (-)-[(1R,2R)-2-(2-bromophenyl)-2-fluorocyclopropyl]
J ¼ 245.1 Hz), 142.39 (dd, J ¼ 21.6, 7.5 Hz), 131.65 (d, J ¼ 8.4 Hz),
120.89 (d, J ¼ 4.3 Hz), 115.72 (d, J ¼ 21.4 Hz), 112.45 (dd, J ¼ 23.9,
7.8 Hz), 81.69 (d, J ¼ 218.7 Hz), 39.50 (d, J ¼ 9.9 Hz), 24.34 (d,
methanamine hydrochloride ((-)-21e)
Obtained from the intermediate (þ)-20e employing General
J ¼ 11.0 Hz), 19.56 (d, J ¼ 11.9 Hz); 19F NMR (CD3OD)
d
ꢀ114.77
Method B as a white solid. 1H NMR (CD3OD)
d
7.72 (d, J ¼ 8.0 Hz,1H),
(s), ꢀ194.54 (s); HRMS (ESI) calculated for C10H12F2N ([MþH]þ): m/z
7.60 (dt, J ¼ 7.6, 1.9 Hz, 1H), 7.45 (t, J ¼ 7.5 Hz, 1H), 7.38 (m, 1H), 3.52
20
184.0932; found: 184.0948. [
a
]
þ40.8 (c 0.2, MeOH).
(dd, J ¼ 13.4, 6.2 Hz, 1H), 3.19 (ddd, J ¼ 13.4, 8.7, 1.2 Hz, 1H),
D
1.72e1.62 (m, 1H), 1.60e1.45 (m, 2H); 13C NMR (CD3OD)
d 136.51 (d,
4.11. (-)-[(1S,2S)-2-fluoro-2-(3-fluorophenyl)cyclopropyl]
methanamine hydrochloride ((-)-21c)
J ¼ 19.0 Hz), 134.54 (s), 133.15 (d, J ¼ 2.3 Hz), 132.76 (d, J ¼ 2.4 Hz),
128.93 (s), 126.94 (s), 82.88 (d, J ¼ 218.9 Hz), 39.94 (d, J ¼ 8.4 Hz),
21.70 (d, J ¼ 11.8 Hz), 17.40 (d, J ¼ 13.3 Hz); 19F NMR (CD3OD)
Obtained from the intermediate (þ)-20c employing General
d
ꢀ181.76 (s); HRMS (ESI) calculated for C10H12BrFN ([MþH]þ): m/z
Method B as a white solid. 1H NMR (CD3OD)
d
7.48e7.39 (m, 1H),
244.0132; found: 244.0110. [
a
]
-85.6 (c 0.1, MeOH).
20
D
7.19e7.13 (m, 2H), 7.13e7.05 (m, 1H), 3.39e3.34 (m, 1H), 3.23 (dd,
J ¼ 13.4, 8.0 Hz, 1H), 1.78e1.68 (m, 1H), 1.65e1.48 (m, 2H); 13C NMR
4.16. (þ)-1-[(1R,2R)-2-fluoro-2-phenylcyclopropyl]-N-
methylmethanaminehydrochloride ((þ)-22)
(CD3OD)
d
164.40 (d, J ¼ 245.2 Hz), 142.39 (dd, J ¼ 21.6, 7.5 Hz),
131.65 (d, J ¼ 8.4 Hz), 120.89 (d, J ¼ 4.3 Hz), 115.72 (d, J ¼ 21.4 Hz),
112.45 (dd, J ¼ 23.9, 7.8 Hz), 81.69 (d, J ¼ 218.7 Hz), 39.50 (d,
J ¼ 9.9 Hz), 24.34 (d, J ¼ 11.0 Hz), 19.56 (d, J ¼ 11.9 Hz); 19F NMR
To a solution of (-)-21a (23 mg, 0.09 mmol) in THF (12 mL) was
added NaH (60% dispersion in mineral oil, 6 mg, 0.13 mmol). The
mixture was stirred at room temperature for 30 min, and then
methyl iodide (20 mg, 0.13 mmol) was added. The reaction mixture
was stirred overnight at room temperature, quenched with water,
(CD3OD)
C
0.1, MeOH).
d
ꢀ114.77 (s), ꢀ194.54 (s); HRMS (ESI) calculated for
10H12F2N ([MþH]þ): m/z 184.0932; found: 184.0935. [
a]
20 -42.6 (c
D