Fluorination of 3-(3-(Piperidin-1-yl)propyl)indoles
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12 2099
dissolved in EtOAc (25 mL) and hydrogenated over 10% Pd-C
(0.8 g) at room temperature and 1 atm H2 for 1.5 h. The
mixture was filtered and concentrated to yield 1-tert-butyloxy-
carbonyl-4-(2-phenylprop-1-yl)-4-hydroxypiperidine 57 (1.47 g,
87%) as a pale yellow glass: δH (250 MHz, CDCl3) 1.27 (3 H,
d, J ) 7), 1.36-1.60 (13 H, m), 1.73 (1 H, dd, J ) 15 and 4),
2.01 (1 H, dd, J ) 15 and 10), 2.98-3.06 (3 H, m), 3.60-3.88
(2 H, m), 7.16-7.36 (5 H, m); m/z (ES+) 320 (M + H+). This
material (1.47 g, 4.60 mmol) was reacted following a method
similar to that described for 46 to give 58 (0.65 g, 44%): δH
(250 MHz, CDCl3) 1.28 (3 H, d, J ) 7), 1.43 (9 H, s), 1.47-
2.11 (6 H, m), 2.93-3.07 (3 H, m), 3.76-3.86 (2 H, m), 7.15-
7.33 (5 H, m); m/z (ES+) 322 (M + H+).
1.54 (1 H, qd, J ) 12 and 4), 1.83 (1 H, m), 2.54-2.76 (3 H,
m), 3.11 (1 H, m), 3.88 (2 H, m), 4.73 (1 H, m), 7.23-7.37 (5
H, m).
cis-4-Ben zyla m in o-3-flu or o-1-(3-(5-(1,2,4-t r ia zol-4-yl)-
1H-in d ol-3-yl)p r op yl)p ip er id in e (65). Compound 63 was
coupled using a method similar to that described for 8 to give
65 as a colorless oil (0.21 g, 39%): oxalate salt, mp 141-149
°C (MeOH-Et2O); δH (360 MHz, DMSO-d6) 1.86-2.00 (4 H,
m), 2.34 (1 H, m), 2.60-2.75 (5 H, m), 3.10-3.26 (2 H, m),
3.40 (1 H, m), 4.12 (2 H, m), 5.13 (1 H, d, J ) 48), 7.30-7.33
(2 H, m), 7.38-7.43 (3 H, m), 7.48-7.51 (3 H, m), 7.78 (1 H, d,
J ) 2), 11.14 (1 H, s); m/z (ES+) 433 (M + H+). Anal. (C25H29
FN6‚2(C2H2O4)‚1.7(H2O)) C, H, N.
-
4-F lu or o-4-(2-p h en ylp r op -1-yl)-1-(3-(5-(1,2,4-tr ia zol-4-
yl)-1H-in d ol-3-yl)p r op yl)p ip er id in e (16). The piperidine 58
(0.64 g, 1.99 mmol) was treated in the same way as 47 to give
4-(2-phenylprop-1-yl)-4-fluoropiperidine (0.37 g, 85%): δH (360
MHz, CDCl3) 1.28 (3 H, d, J ) 7), 1.35-1.60 (2 H, m), 1.70-
1.79 (2 H, m), 1.83-2.09 (2 H, m), 2.79-2.93 (4 H, m), 3.03 (1
H, qt, J ) 7 and 7), 7.15-7.22 (3 H, m), 7.26-7.31 (2 H, m);
m/z (ES+) 222 (M + H+). This material was reacted following
a method similar to that described for the preparation of 8 to
give 16 (0.12 g, 32%): oxalate salt, mp 87-91 °C (EtOH-
Et2O); δH (360 MHz, DMSO-d6) 1.21 (3 H, d, J ) 7), 1.60-
2.10 (10 H, m), 2.75 (2 H, t, J ) 8), 2.90-3.12 (4 H, m), 3.26-
3.28 (1 H, m), 7.16-7.20 (1 H, m), 7.24-7.35 (6 H, m), 7.50 (1
H, d, J ) 9), 7.79 (1 H, s), 9.01 (2 H, s), 11.17 (1 H, s); m/z
(ES+) 446 (M + H+). Anal. (C27H32N5F‚2(C2H2O4)) C, H, N.
1-ter t-Bu toxyca r bon yl-1,2,3,6-tetr a h yd r o-4-(tr im eth yl-
silyloxy)p yr id in e (59). To a stirred solution of 43 (10.13 g,
50.8 mmol) in dry DMF (20 mL) under argon was added
TMSCl (7.74 mL, 61.0 mmol) and then dry Et3N (17.0 mL, 122
mmol), and the mixture was stirred at 80 °C for 16 h under
argon. The mixture was diluted with hexane (60 mL) and
washed with cold saturated NaHCO3 (aqueous) (3 × 30 mL).
The organic layer was dried and concentrated. Flash chroma-
tography using EtOAc-petroleum ether (10:90) as eluent gave
59 (11.84 g, 86%) as a colorless oil: δH (250 MHz, CDCl3) 0.20
(9 H, s), 1.47 (9 H, s), 2.11 (2 H, m), 3.52 (2 H, t, J ) 5.8), 3.87
(2 H, m), 4.80 (1 H, m).
1-ter t-Bu toxyca r bon yl-3-flu or o-4-p ip er id on e (60). To a
stirred solution of 59 (3.98 g, 14.7 mmol) in dry MeCN (160
mL) under N2 was added Selectfluor reagent (5.74 g, 16.2
mmol), and the mixture was stirred for 75 min. The mixture
was poured into EtOAc (600 mL), washed with dilute brine
(300 mL) and then saturated brine (100 mL), dried, and
concentrated. Flash chromatography on alumina using MeOH-
EtOAc (0:100 then 5:95) as eluent gave 60 (2.91 g, 91%) as a
colorless oil: δH (250 MHz, CDCl3) 1.50 (9 H, s), 2.52-2.64 (2
H, m), 3.22-3.38 (2 H, m), 4.18 (1 H, m), 4.45 (1 H, m), 4.83
(1 H, m).
cis -4-Ben zyla m in o-1-ter t-bu toxyca r bon yl-3-flu or op i-
p er id in e (61) a n d tr a n s-4-Ben zyla m in o-1-ter t-bu toxy-
ca r bon yl-3-flu or op ip er id in e (62). A mixture of 60 (0.11 g,
0.509 mmol), benzylamine (61 µL, 0.559 mmol), and NaB-
(OAc)3H (0.1628 g, 0.768 mmol) in dry 1,2-dichloroethane (2
mL) was stirred at room temperature under N2 for 135 min.
The reaction mixture was quenched with saturated K2CO3
(aqueous) (20 mL) and extracted with EtOAc (2 × 20 mL). The
combined organic extracts were dried and evaporated. Flash
column chromatography using EtOAc-hexane (50:50 then 100:
0) as eluent gave 61 (cis isomer) (99.5 mg, 63%) and 62 (trans
isomer) (12.7 mg, 8%) as colorless oils. 61 (cis isomer): δH (360
MHz, DMSO-d6) 1.38 (9 H, s), 1.44 (1 H, m), 1.68 (1 H, m),
2.64 (1 H, m), 2.74 (1 H, m), 2.96 (1 H, m), 3.78 (1 H, m), 4.14
(1 H, m), 4.78 (1 H, m), 7.21 (1 H, m), 7.28-7.36 (4 H, m); m/z
(ES+) 309 (M + H+). 62 (trans isomer): δH (360 MHz, DMSO-
d6) 1.34 (1 H, m), 1.39 (9 H, s), 1.81 (1 H, m), 2.74 (1 H, m),
3.14 (1 H, m), 3.30 (1 H, m), 3.48 (1 H, m), 3.69 (1 H, m), 3.77
(2 H, m), 4.39 (1 H, m), 7.22 (1 H, m), 7.28-7.35 (4 H, m); m/z
(ES+) 309 (M + H+).
cis-4-(N-Ben zyl-N-m eth yla m in o)-3-flu or o-1-(3-(5-(1,2,4-
tr ia zol-4-yl)-1H-in d ol-3-yl)p r op yl)p ip er id in e (17). Glacial
AcOH (64 µL, 1.12 mmol), formaldehyde (37 wt % solution)
(25 µL, 0.338 mmol), and NaCNBH3 (0.02 g, 0.33 mmol) were
added to a solution of 65 (0.12 g, 0.281 mmol) in dry MeOH (4
mL) under argon, and the mixture was stirred at room
temperature for 3 h. The reaction was quenched with saturated
K2CO3 (aqueous) (10 mL), and the products were extracted
with EtOAc (2 × 25 mL). The combined extracts were dried
and concentrated. Flash chromatography using CH2Cl2-
MeOH-NH3 (aqueous) (94:6:0.6 then 93:7:0.7) as eluent gave
17 as a colorless oil (0.12 g, 93%): oxalate salt, mp 111-115
°C (MeOH-Et2O); δH (360 MHz, DMSO-d6) 1.87-2.12 (4 H,
m), 2.24 (3 H, s), 2.74-3.04 (7 H, m), 3.38 (1 H, m), 3.59 (1 H,
m), 3.71 (2 H, m), 5.24 (1 H, d, J ) 50), 7.25-7.35 (7 H, m),
7.50 (1 H, d, J ) 8.5), 7.80 (1 H, d, J ) 2), 11.17 (1 H, s); m/z
(ES+) 447 (M + H+). Anal. (C26H31FN6‚2(C2H2O4)) C, H, N.
The trans isomers 64 and 66 were prepared using chemistry
similar to that described for the preparation of the cis isomers
63 and 65.
The following compounds were prepared using similar
procedures.
t r a n s-4-(N -Be n zyl-N -m e t h yla m in o)-3-flu or o-1-(3-(5-
(1,2,4-tr ia zol-4-yl)-1H-in d ol-3-yl)p r op yl)-p ip er id in e (18):
oxalate salt, mp 98-100 °C (MeOH-Et2O); δH (360 MHz,
DMSO-d6) 1.7-1.85 (1 H, m), 1.9-2.06 (3 H, m), 2.25 (3 H, s),
2.50-2.80 (4 H, m), 2.80-3.00 (3 H, m), 3.20-3.30 (1 H, m),
3.48-3.60 (1 H, m), 3.74 (2 H, q, J ) 17), 4.96 (1 H, broad d,
J ) 46), 7.26-7.34 (7 H, m), 7.49 (1 H, d, J ) 7), 7.79 (1 H, d,
J ) 4), 9.01 (2 H, s), 11.14 (1 H, s); m/z (ES+) 447 (M + H+).
Anal. (C26H31FN6‚2.5(C2H2O4)‚H2O) C, H, N.
cis -3-F lu or o -4-(N-m et h yl-N-(2-(t r iflu or om et h yl)b en -
zyl)am in o)-1-(3-(5-(1,2,4-tr iazol-4-yl)-1H-in dol-3-yl)pr opyl)-
p ip er id in e (19): oxalate salt, mp 95-97 °C (MeOH-Et2O);
δH (360 MHz, DMSO-d6) 1.89 (1 H, m), 1.98-2.10 (3 H, m),
2.22 (3 H, s), 2.76-3.10 (7 H, m), 3.42 (1 H, m), 3.62 (1 H, m),
3.83 (2 H, m), 5.25 (1 H, d, J ) 48), 7.31-7.33 (2 H, m), 7.46
(1 H, t, J ) 7), 7.50 (1 H, d, J ) 9), 7.64-7.70 (2 H, m), 7.80-
7.82 (2 H, m), 9.01 (2 H, s), 11.17 (1 H, s); m/e (ES+) 515 (M
+ H+). Anal. (C27H30F4N6‚1.7(C2H2O4)) C, H, N.
tr a n s-3-F lu or o-4-(N-m eth yl-N-(2-(tr iflu or om eth yl)ben -
zyl)a m in o)-1-(3-(5-(1,2,4-tr ia zol-4-yl)-1H-in d ol-3-yl)p r o-
p yl)p ip er id in e (20): oxalate salt, mp 80-96 °C (MeOH-
Et2O); δH (360 MHz, DMSO-d6) 1.76 (1 H, m), 1.88-2.00 (3 H,
m), 2.21 (3 H, s), 2.58-2.84 (7 H, m), 3.18 (1 H, m), 3.52 (1 H,
m), 3.94 (2H, s), 4.89 (1 H, m), 7.30-7.32 (2 H, m), 7.45 (1 H,
t, J ) 8), 7.49 (1 H, d, J ) 9), 7.64-7.69 (2 H, m), 7.80-7.83
(2 H, m), 9.01 (2 H, s), 11.13 (1 H, s); m/z (ES+) 515 (M + H+).
Anal. (C27H30F4N6‚1.5(C2H2O4)‚0.25(C4H10O)) C, H, N.
cis-3-F lu or o-1-(3-(5-(1,2,4-t r ia zol-4-yl)-1H -in d ol-3-yl)-
p r op yl) - 4 - (2 - (t r iflu or om e t h yl)b e n zyla m in o)p ip e r i-
d in e (21): oxalate salt, mp 116-120 °C (MeOH-Et2O); δH (360
MHz, DMSO-d6) 1.81 (1 H, m), 1.92-2.03 (3 H, m), 2.69-3.12
(7 H, m), 3.30 (1 H, m), 3.60 (1 H, m), 3.99 (2 H, s), 5.04 (1 H,
d, J ) 46), 7.31-7.33 (2 H, m), 7.48-7.51 (2 H, m), 7.66-7.71
(2 H, m), 7.79 (1 H, s), 7.84 (1 H, d, J ) 7), 9.01 (2 H, s), 11.17
(1 H, s); m/ z (ES+) 501 (M + H+). Anal. (C26H28F4N6‚
2(C2H2O4)) C, H, N.
cis-4-Ben zyla m in o-3-flu or op ip er id in e (63). A solution
of 61 (0.91 g, 2.95 mmol) was deprotected as described for 47
to give 63 as a colorless oil (0.58 g, 94%): δH (250 MHz, CDCl3)
tr a n s-3-Flu or o-1-(3-(5-(1,2,4-tr ia zol-4-yl)-1H-in d ol-3-yl)-
p r op yl) - 4 - (2 - (t r iflu or om e t h yl)b e n zyla m in o)p ip e r i-
d in e (22): oxalate salt, mp 127-129 °C (MeOH-Et2O); δH (360