Fluorinated Phenylcyclopropylamines
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7 1803
by the same method as described for the cis isomer 14b
stirring for 15 min at 0 °C. All volatiles were removed under
1
(yield: 0.91 g, 79%). Data for 14a : mp 63 °C; H NMR (CDCl
3
)
vacuum. The product was recrystallized from Et
2
O/ethanol (4:
δ 1.24-1.40 (2 H, m, CH
A
H
B
), 1.59-1.71 (1 H, m, CH
O), 7.19-7.81 (9 H, m,
) δ 17.9 (dt, J ) 12.7 Hz, CH ),
), 23.4 (dd, J ) 11.4 Hz, CH ), 69.0 (dt, J ) 10.2
X
), 2.42
1) and isolated as a white powder (yield: 56 mg, 26%). Data
1
(
3 H, s, CH ), 4.20-4.45 (2 H, m, CH
3
2
for 8b: mp 170 °C; H NMR (CD
3
OD) δ 1.08-1.28 (2 H, m,
CH ), 2.80-2.96 (2 H, m, CH
), 7.36-7.47 (5 H, m, aromatic);
OD) δ 15.9 (dt, J ) 13.0 Hz, CH ), 22.9 (dd, J )
15.1 Hz, CH ), 28.0 (t, CH CH ), 40.1 (t, CH
1
3
aromatic); C NMR (CDCl
1.6 (q, CH
Hz, CH
3
A
H
B
CH
NH
A
H
B
), 1.42-1.80 (3 H, m, CH
X
2
2
-
C
+
+
13
2
3
X
3
), 4.88 (3 H, s, NH
3
2
O), 80.8 (ds, J ) 220.0 Hz, CF), 124.7 (dd, J ) 6.4 Hz,
NMR (CD
3
A B
H
+
aromatic), 127.8 (d, aromatic), 128.5 (d, aromatic), 129.8 (d,
X
X
2
NH ), 83.3 (ds,
2 3
aromatic), 133.4 (s, aromatic), 137.8 (ds, J ) 20.3 Hz, aro-
J ) 221.4 Hz, CF), 129.0 (d, aromatic), 129.8 (d, aromatic),
1
9
19
matic), 144.7 (s, aromatic); F NMR (CDCl
3
) δ -190.30 (m).
129.9 (d, aromatic), 136.5 (ds, J ) 23.0 Hz, aromatic); F NMR
MS m/z (%) 321 (1), 205 (7), 171 (3), 165 (2), 155 (19), 148 (100),
3
(CD OD) δ -161.31 (m); MS/ESI m/z (%) 180 (100), 163 (7),
1
7
35 (9), 133 (43), 127 (36), 115 (28), 105 (48), 99 (43), 91 (30),
7 (22), 75 (48), 57 (58), 51 (24); IR (NaCl) ν˜ 3072 (w), 3040
160 (66), 143 (12), 132 (11), 117 (53); IR (KBr) ν˜ 3057-2901
(br), 2583 (w), 2494 (w), 2032 (br), 1620 (m), 1607 (m), 1527
(m), 1475 (w), 1457 (m), 1385 (w), 1344 (w), 1322 (w), 1265
(m), 1202 (m), 1176 (m), 1068 (w), 1018 (m), 982 (w), 905 (m),
(w), 2964 (w), 2926 (w), 1639 (w), 1618 (w), 1597 (w), 1500
w), 1457 (m), 1412 (w), 1364 (s), 1336 (m), 1192 (m), 1174 (s),
(
-
1
1
8
5
099 (w), 1038 (w), 998 (w), 944 (s), 839 (s), 874 (m), 839 (s),
22 (m), 793 (m), 748 (m), 696 (s), 670 (s), 588 (m), 556 (s),
867 (m), 767 (s), 702 (s), 604 (w) cm .
tr a n s-(2-F lu or o-2-p h en ylcyclop r op yl)eth yla m in e Hy-
d r och lor id e (8a ). trans-(2-Fluoro-2-phenylcyclopropyl)ethyl-
amine hydrochloride (8a ) was synthesized from the corre-
sponding trans nitrile 15a (175 mg, 1 mmol) by the same
method as described for the cis isomer 8b (yield: 75 mg, 35%).
-
1
38 (m) cm . Anal. (C17
3
H17FO S) C, H.
cis-(2-F lu or o-2-p h en ylcyclop r op yl)a ceton itr ile (15b).
To a solution of cis tosylate 14b (0.64 g, 2.0 mmol) dissolved
in anhydrous DMF (20 mL) was added NaCN (0.21 g, 4.0
mmol). The solution was stirred at room temperature for 22 h
Data for 8a : mp 175 °C; 1H NMR (DMSO-d
1.19-1.28 (1 H, m, CH ), 1.33-1.39 (1 H, m, CH
1.50 (1 H, m, CH ), 1.85-2.01 (2 H, m, CH CH ), 2.81-2.98
, 400 MHz) δ
6
and then poured into 5% aqueous NaHCO
3
(50 mL). The
A
H
B
A B
H
), 1.42-
solution was extracted with cyclohexane (×4), and the com-
X
X
2
+
+
bined organic layer was washed with brine and dried over
(2 H, m, CH NH ), 3.40 (3 H, s, NH3 ), 7.27-7.41 (5 H, m,
2
3
aromatic); 13C NMR (DMSO-d ), δ 19.3 (dt, J ) 10.2 Hz,
4
MgSO . All volatiles were removed under vacuum, and the
residue was purified by silica gel chromatography (cyclohex-
ane/ethyl acetate, 15:1) to give the cis nitrile 15b as an oil
6
CH H ), 23.0 (dd, J ) 11.4 Hz, CH ), 25.5 (dt, J ) 7.6 Hz,
A
B
X
+
3
CH CH ), 38.7 (t, CH NH ), 81.3 (ds, J ) 216.2 Hz, CF), 124.0
X
2
2
(
0.31 g, 89%). (When the reaction was performed at 100 °C
(dd, J ) 6.8 Hz, aromatic), 127.5 (d, aromatic), 128.6 (d,
1
9
19
cis/trans isomerization was detected by F NMR.) Data for
aromatic), 139.6 (ds, J ) 21.6 Hz, aromatic); F NMR (DMSO-
-
2
1
1
1
2
7b: bp 131-133 °C, 6.5 × 10 mbar; H NMR (CDCl
3
) δ
), 1.89-
CN), 7.37-7.50 (5 H, m, aromatic);
) δ 15.1 (dt, J ) 12.8 Hz, CH ), 17.4 (t,
), 81.6 (ds, J ) 217.4 Hz,
d ) δ -192.31 (m); GC/MS m/z (%) 179 (5), 162 (2), 155 (12),
6
.17-1.25 (1 H, m, CH
A
H
B
), 1.55-1.70 (1 H, m, CH
A
H
B
149 (10), 147 (9), 135 (9), 125 (11), 115 (12), 109 (18), 99 (60),
97 (33), 95 (22), 91 (7), 83 (58), 78 (21), 77 (15), 71 (68), 69
(72), 60 (44), 57 (100), 55 (100), 51 (16); IR (KBr) ν˜ 3031-2976
(br), 2035 (br), 1600 (w), 1499 (s), 1454 (m), 1305 (w), 1242
(w), 1148 (w), 1119 (w), 1072 (m), 1031 (w), 1015 (w), 988 (w),
X 2
.13 (3 H, m, CH and CH
1
3
C NMR (CDCl
3
A B
H
CH
2
CN), 19.7 (dd, J ) 17.8 Hz, CH
X
CF), 117.8 (s, CN), 128.3 (dd, J ) 3.8 Hz, aromatic), 128.8 (d,
-
1
1
1
aromatic), 129.5 (dd, J ) 2.5 Hz, aromatic), 133.0 (ds, J ) 20.3
913 (w), 753 (s), 697 (s), 616 (m), 536 (w) cm . H- H COSY
1
9
1
13
Hz, aromatic); F NMR (CDCl
3
) δ -160.99 (m). GC/MS m/z
and H- C correlation spectra supported the analysis results
1 13
(
(
(
%) 175 (9), 154 (5), 135 (100), 115 (64), 109 (12), 83 (7), 77
of H NMR and C NMR.
7), 75 (7), 63 (7), 51 (9), 39 (6); IR (NaCl) ν˜ 3094 (m), 3067
m), 2252 (s), 1608 (w), 1504 (m), 1453 (s), 1419 (s), 1383 (m),
tr a n s- a n d cis-(2-F lu or o-1-p h en ylcyclop r op yl)m eth a -
n ol (18a , 18b). A mixture of ethyl trans- and cis-(2-fluoro-1-
phenyl-cyclopropane)carboxylate (17a , 17b) (2 g, 9.6 mmol),
1
345 (s), 1298 (m), 1231 (m), 1198 (s), 1133 (m), 1103 (m), 1067
-
1
(m), 976 (m), 884 (m), 809 (w), 768 (s), 703 (s), 605 (m) cm
.
12
prepared as previously described, was dissolved in anhydrous
Anal. (C11H10FN) C, H, N.
toluene (20 mL) and stirred at -74 °C. DIBAL was added
slowly, and the reaction solution was stirred for 4 h at the
same temperature. The cooling bath was removed, and the
solution was stirred overnight at room temperature. The
solution was then cooled to 0 °C, and a toluene/methanol
mixture (1:1) was added slowly. This was followed by the
addition of 2 N aqueous HCl, and the mixture was then
extracted with ether (×3). The ether layer was washed with
tr a n s-(2-Flu or o-2-ph en ylcyclopr opyl)aceton itr ile (15a).
The trans nitrile 15a was synthesized from the corresponding
trans tosylate 14a (0.64 g, 2.0 mmol) by the same method as
described for the cis isomer 15b (yield: 0.32 g, 92%). Data for
-
2
1
1
1
7a : bp 113 °C, 7.2 × 10 mbar; H NMR (CDCl
3
) δ 1.26-
.63 (3 H, m, CH and CH ), 2.69 (2 H, d, J ) 6.9 Hz, CH -
A
H
B
X
2
1
3
CN), 7.24-7.40 (5 H, m, aromatic); C NMR (CDCl
3
) δ 16.1
CN), 20.9
), 80.2 (ds, J ) 222.0 Hz, CF), 118.4 (s,
(
(
dt, J ) 10.2 Hz, CH
dd, J ) 11.5 Hz, CH
A
H
B
), 18.9 (dt, J ) 11.4 Hz, CH
2
saturated NaHCO3 and brine and dried over MgSO . After
4
evaporation, the obtained residue was purified and cis and
trans isomers were separated by silica gel chromatography
(ethyl acetate/n-hexane, 1:5). The products were obtained as
oils (yield: trans isomer 18a , 1.0 g, 63%; cis isomer 18b, 0.3
X
CN), 124.6 (dd, J ) 6.4 Hz, aromatic), 128.2 (d, aromatic), 128.6
1
9
(
(
(
d, aromatic), 137.6 (ds, J ) 21.6 Hz, aromatic); F NMR
CDCl ) δ -190.69 (m); GC/MS m/z (%) 175 (12), 155 (7), 147
8), 135 (100), 115 (57), 109 (13), 83 (6), 77 (7), 63 (7), 51 (9),
3
g, 19%). Data for 18a : 1H NMR (CDCl
3
) δ 1.17 (1H, ddd, J )
), 1.31 (1H, ddd, J )
), 1.62 (1H, broad,
OH), 3.49 (1H, dd, J ) 11.4 Hz, 2.4 Hz, -CHH-OH), 3.56
1H, d, J ) 11.4 Hz, -CHH-OH,), 4.69 (1H, ddd, J ) 64.8
3
2
9 (6); IR (NaCl) ν˜ 3093 (m), 3066 (m), 3036 (m), 2970 (w),
935 (w), 2254 (s), 1607 (m), 1502 (s), 1456 (s), 1421 (s), 1399
1
2
-
(
1.1 Hz, J ) 6.3 Hz, J ) 7.2 Hz, CH
A B
H
1.9 Hz, J ) 7.2 Hz, J ) 2.7 Hz, CH
A
H
B
(
1
m), 1318 (m), 1291 (m), 1242 (s), 1116 (s), 1080 (m), 1057 (w),
034 (s), 1006 (s), 880 (m), 802 (w), 758 (s), 699 (s), 623 (m).
Anal. (C11 10FN) C, H, N.
H
Hz, J ) 6.3 Hz, J ) 2.7 Hz, CFH), 7.26-7.41 (5H, m, aromatic);
1
3
cis-(2-F lu or o-2-p h en ylcyclop r op yl)eth yla m in e Hyd r o-
ch lor id e (8b). To a solution of cis-(2-fluoro-2-phenylcyclopro-
C NMR (CDCl
3
) δ 15.82 (d, J ) 10.3 Hz, CH
2
A
H
B
), 33.00 (d,
2
OH), 74.43
J ) 9.2 Hz, Ph(CH
OH)C<), 68.12 (d, 2.3 Hz, -CH
pyl)acetonitrile (15b) (175 mg, 1 mmol) in anhydrous Et
2
O (10
(d, J ) 225.0 Hz, FHC), 127.71 (s, aromatic), 128.76 (s,
mL) stirred under argon was added slowly a 1 M borane/THF
solution (2 mL). The reaction mixture was refluxed for 2 h and
cooled to room temperature, and 2 mL of concentrated HCl
was added. The mixture was concentrated under vacuum, and
the remaining aqueous phase was neutralized with 40% NaOH
aromatic), 130.87 (s, aromatic), 136.79 (d, J ) 3.5 Hz,
aromatic). 19F NMR (CDCl
, 282 MHz, relative to CF
δ -137.03 (ddd, J ) 67.1, 24.5, 12.4 Hz); IR (CH Cl
(br), 2919 (s), 2849 (s), 2360 (w), 1463 (m), 1036 (m), 701 (m);
COOH),
3
3
2
2
) 3420
+
1
GC/MS (EI) m/z 166 (M ), 147, 118, 91. Data for 18b: H NMR
(CDCl
CH
and extracted with Et
2
O (×3). The combined organic layers
3
) δ 1.29 (1H, ddd, J ) 10.8 Hz, J ) 7.2 Hz, J ) 6.3 Hz,
B
were dried over Na SO
2
4
. The obtained solution was concen-
A
H
), 1.35 (1H, ddd, J ) 22.8 Hz, J ) 7.2 Hz, J ) 2.7 Hz,
), 1.64 (1H, broad, -OH), 3.91 (1H, dd, J ) 11.7 Hz,
trated under vacuum to a volume of 20 mL. Gaseous HCl was
passed through this solution at 0 °C. A white solid formed with
CH
A
H
B
1.5 Hz, -CHH-OH), 4.04 (1H, d, J ) 11.7 Hz, -CHH-OH),