Synthesis of 3-aminomethyl-3-fluoropiperidines

Article abstract of DOI:10.1055/s-0029-1217360

A synthetic route toward new 1-alkyl-3-aminomethyl-3-fluoropiperidines, which are of high interest as building blocks in medicinal chemistry, is described. The successful approach consists of the fluorination of ethyl 3-chloropropyl-2-cyanoacetate with Nf

Full text of DOI:10.1055/s-0029-1217360

LETTER
1765
Synthesis of 3-Aminomethyl-3-fluoropiperidines
S
ynthesis of 3-A
v
minomethy
a
l-3-fluoropiperidin
V
e
s
an Hende,a Guido Verniest,a,1 Jan-Willem Thuring,b Gregor Macdonald,b Frederik Deroose,b
Norbert De Kimpe*a
a
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax +32(0)92646243; E-mail: norbert.dekimpe@ugent.be
Johnson & Johnson, Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Turnhoutseweg 30,
2340 Beerse, Belgium
b
Received 4 March 2009
zene resulting in 3-fluoro-2,2-diphenylpiperidine.13 Re-
cently, the synthesis of a wide range of optically active 3-
fluoropiperidines was developed starting from prolinols
Abstract: A synthetic route toward new 1-alkyl-3-aminomethyl-3-
fluoropiperidines, which are of high interest as building blocks in
medicinal chemistry, is described. The successful approach consists
of the fluorination of ethyl 3-chloropropyl-2-cyanoacetate with N-
by treatment with DAST or Deoxo-FluorTM 14
Nonethe-
.
fluorodibenzenesulfonimide (NFSI) and transformation of the ester less, access to 3-aminomethyl-3-fluoropiperidines is not
moiety into different amides, yielding N-alkyl-5-chloro-2-cyano-2-
fluoropentanamides. Ring closure was achieved under basic condi-
available, although these compounds are of high interest
since they can easily be incorporated into compounds
tions, yielding 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles.
of pharmaceutical interest. Here, a general route to 1-
After reduction of the obtained lactams with borane, the desired 3-
alkyl- and 1-arylmethyl-3-aminomethyl-3-fluoropiperi-
aminomethyl-3-fluoropiperidines were obtained in good yields.
dines starting from ethyl cyanoacetate is described.
Key words: ring closure, NFSI, 3-fluoropiperidines, fluorine
In a first step, various attempts were made to synthesize 5-
halo-2-cyanopentanoates as starting material for the syn-
thesis of the desired 3-fluoropiperidines. Because the di-
rect fluorination of ethyl cyanoacetate using NFSI
resulted in mixtures of mono- and difluorinated com-
pounds, it was decided to alkylate cyanoacetate 2 first and
subsequently fluorinate the obtained alkylated cyanoace-
tate 3. At first, the chloroalkylation of ethyl cyanoacetate
(2) was performed by reaction with one equivalent of
K2CO3 and one equivalent of 1-bromo-3-chloropropane at
room temperature in DMF. After 18 hours, the reaction
mixture was analyzed by GC-MS, to reveal that a mixture
of starting material 2 (8%), ethyl 5-chloro-2-cyanopen-
tanoate (3; 43%) and the corresponding dialkylated
cyanoacetate 4 (49%) was obtained. In no cases could
selective monoalkylation be achieved when using
equimolar quantities of ethyl cyanoacetate, base and
either 1-bromo-3-chloropropane or 3-chloro-1-iodopro-
pane. However, the reaction of three equivalents of
cyanoacetate and three equivalents of 1,8-diazabicyc-
lo[5.4.0]undec-7-ene (DBU) with one equivalent of 3-
chloro-1-iodopropane at 10 °C in benzene yielded pre-
dominantly monoalkylated cyanoacetate 3, together with
unreacted starting material 2.
chemistry, heterocycles
The beneficial effects of fluorine as a substituent in organ-
ic compounds stimulated intense research into organo-
fluorine chemistry during the last decade. This is reflected
by the numerous papers in this area in recent years and the
commercial applications of organofluorine compounds in
pharmaceutical chemistry and agrochemistry.2–8 More
specifically, fluorinated heterocycles attract widespread
attention as important components of agrochemicals and
pharmaceuticals.9 3-Fluoropiperidines 1 are recognised as
T-type calcium channel antagonists and are useful in the
treatment and prevention of neurological and psychiatric
disorders (Figure 1).10
O
R2
R3
R1
N
H
F
N
R4
R5
1
T-type calcium channel antagonists
Indeed, it is known that the use of DBU in benzene can be
successful for the monoalkylation reactions of cyanoace-
tates.15 GC-analysis of the crude reaction mixture
revealed a product ratio of ethyl 5-chloro-2-cyanopen-
tanoate (3) to the corresponding dialkylation product 4 of
5 to 1, respectively. From this mixture, 5-chloro-2-cyano-
pentanoate (3) could be easily separated by fractional dis-
tillation (106–110 °C) under reduced pressure (1.5
mmHg), yielding pure cyanopentanoate 3 in 50% yield
(based on the recovery of the starting material, Scheme 1).
Although a low yield was obtained, the ease of the reac-
tion, combined with the easy separation of compound 3,
Figure 1
Only a limited number of synthetic routes toward these in-
teresting 3-fluoropiperidines are available.11 One method
proceeds via a-fluorination of 4-piperidone12 followed by
TfOH-catalyzed double electrophilic substitution to ben-
SYNLETT 2009, No. 11, pp 1765–1768
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217360; Art ID: G08009ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

1766
E. Van Hende et al.
LETTER
O
9a–d, after purification by flash chromatography on silica
gel.
CN
O
These piperidones 9 proved to be good substrates for re-
duction by borane in THF to give the desired 1-alkyl-3-
aminomethyl-3-fluoropiperidines 10a–d. Purification of
the obtained piperidines could be performed in an elegant
way via precipitation from diethyl ether as the trifluoro-
acetic acid salts, followed by filtration of the white crys-
talline salts. After treatment with aqueous NaHCO3 and
extraction, pure 3-aminomethyl-3-fluoropiperidines 10a–
d were obtained (Scheme 3).
2 (3 equiv)
Cl(CH2)3I (1.0 equiv)
DBU (3.0 equiv)
benzene, 10 °C, 10 h
O
O
CN
CN
O
O
+
Cl
Cl
Cl
It should be noted that the cyclization reaction conditions
used to synthesize lactams 9 need to be performed in an-
hydrous solvents, as the presence of water gives rise to
varying yields of cyclization product 11 (Scheme 4). As
an example, when compound 8a was reacted with t-BuOK
in wet THF (i.e. not dried over sodium benzophenone
ketyl) at room temperature, significant hydrolysis of the
nitrile function occurred, giving rise to a mixture of lac-
tams 11 and 9a (Scheme 4).
3
4
28%, after dist.
50%, based on
recovery of 2
3%, after dist.
6%, based on
recovery of 2
81–85 °C; 0.6 mbar
111–118 °C; 0.6 mbar
Scheme 1
resulted in a straightforward, multi-gram scale prepara-
tion of up to 5 g of the desired starting material. Although
a selective monoalkylation of ethyl cyanoacetate with 1,3-
dibromopropane in DMF, in the presence of 2.5 equiva-
lents of K2CO3, has been described rather recently for the
synthesis of ethyl 5-bromo-2-cyanopentanoate 5,15 in our
hands, this reaction (with or without the presence of the
catalytic imidazolium salt 1-butyl-3-methylimidazolium
tetrafluoroborate) always gave rise to the formation of the
corresponding substituted cyclobutane 616 (Scheme 2).
O
O
K2CO3 (1.2 equiv)
NFSI (1.2 equiv)
DMF, r.t., 20 h
CN
F
O
CN
O
Cl
7 71%
3
Cl
RNH2 (1 equiv)
CH2Cl2, r.t., 5 h
The problematic selective monoalkylation of ethyl cy-
anoacetate (2) has already been discussed in the literature,
where the use of masking groups for one of the acidic hy-
drogens is deviced.17
R
O
K2CO3 (1.2 equiv)
DMSO, Δ, 1 h
CN
F
N
O
R
N
H
F
O
CN
Br(CH2)3Br (1.1 equiv)
K2CO3 (2.5 equiv)
Cl
O
CN
O
8a R = C6H5 57%
9a R = C6H5 54%
9b R = propyl 62%
9c R = C6H5CH2 36%
CN
DMF, r.t.,
12–24 h
O
8b R = propyl 68%
8c R = C6H5CH2 43%
8d R = 4-MeC6H4 57%
2
9d R = 4-MeC6H4 69%
Br
5
R
N
F
O
a) BH3 in THF (5 equiv)
THF, r.t., 16 h
b) TFA
Et2O, r.t., 16 h
c) NaHCO3, CH2Cl2
CN
O
6 50%
NH2
Scheme 2
10a R = C6H5 57%
10b R = propyl 91%
10c R = C6H5CH2 78%
10d R = 4-MeC6H4 73%
In a next step, the fluorination of ethyl 5-chloro-2-cyano-
pentanoate (3) using 1.2 equivalents of N-fluorodiben-
zenesulfonimide (NFSI) and 1.2 equivalents of K2CO3 in
DMF at room temperature during 20 hours, nicely gave
rise to the corresponding fluorinated cyanopentanoate 7 in
71% yield. The material was sufficiently pure for further
use in the next step (purity of 7: 85%). The reaction of 7
with N-alkyl- and N-arylmethylamines resulted in the for-
mation of a-fluorinated amides 8a–d, which were subject-
ed to ring closure conditions. The reaction of 8a–d with
1.2 equivalents of K2CO3 in DMSO during one hour gave
rise to 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles
Scheme 3
In conclusion, a straightforward synthesis of 3-amino-
methyl-3-fluoropiperidines was designed, yielding new 1-
alkyl and 1-arylmethyl-3-aminomethyl-3-fluoropipe-
ridines, starting from ethyl cyanoacetate, in moderate to
good yields. This five-step procedure is a convenient
route for the large-scale preparation of 3-aminomethyl-3-
Synlett 2009, No. 11, 1765–1768 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Aminomethyl-3-fluoropiperidines
1767
m/z (%) = 207/9 (M+, 0.01/0.003), 162 (M+, 5), 135 (36), 100 (61),
72 (100).
O
1) KOt-Bu (1 equiv)
wet THF, 0 °C to r.t., 4.5 h
N
N
H
F
2) 0.5 M NaOH
N-Benzyl-5-chloro-2-cyano-2-fluoropentanamide (8a); Typical
Procedure
The synthesis of amide 8a is given as a representative example for
the synthesis of amides 8a–d. A solution of ethyl 5-chloro-2-cyano-
2-fluoropentanoate (7; 3.3 g, 16 mmol) and benzylamine (1.7 g, 16
mmol) in dichloromethane (40 mL) was stirred for 5 h at r.t.. Evap-
oration of the solvent yielded the crude N-benzyl-5-chloro-2-cyano-
2-fluoropentanamide (8a). Purification was performed by flash
chromatography over silica gel (EtOAc–hexane, 9:1; Rf = 0.01),
yielding pure N-benzyl-5-chloro-2-cyano-2-fluoropentanamide.
Cl
8a
HN
F
O
N
O
F
+
O
HN
11 45%
CN
1
Yield: 2.51 g (57%); viscous colourless oil. H NMR (300 MHz,
9a 16%
CDCl3): d = 1.92–2.15 (2 H, m, ClCH2CH2), 2.26–2.53 (2 H, m,
CFCH2), 3.57 (2 H, t, J = 6.3 Hz, CH2Cl), 4.49 (2 H, d, J = 5.8 Hz,
CH2NH), 6.85 (1 H, s, NH), 7.26–7.40 (5 H, m, 5 × CHar). 13C NMR
(75 MHz, CDCl3, int. ref.: 77.4 ppm): d = 26.3 (d, J = 2.3 Hz,
CH2CH2Cl), 34.5 (d, J = 21.9 Hz, CH2CF), 43.4 (CH2Cl), 43.9
(CH2NH), 89.3 (d, J = 199.6 Hz, CF), 114.4 (d, J = 33.5 Hz, CN),
127.8 (2 × CHar), 128.1 (CHar), 129.0 (2 × CHar), 136.6 (Cq,ar),
163.1 (d, J = 21.9 Hz, C=O). 19F NMR (282 MHz, CDCl3): d =
–158.74 (1 F, t, J = 23.7 Hz). IR (NaCl): 3336 (nNH), 2253 (nCN),
1689 (nCO), 1539, 1444 cm–1. MS (ES+): m/z (%) = 286/8 (M +
Scheme 4
fluoropiperidines 10, which are compounds with high po-
tential as building blocks in medicinal chemistry.
Ethyl 5-Chloro-2-cyanopentanoate (3)
To a solution of ethyl cyanoacetate (17.0 g, 0.15 mol) and DBU
(22.8 g, 0.15 mol) in anhydrous benzene (500 mL), was added a so-
lution of 3-chloro-1-iodopropane (10.2 g, 0.05 mol) in benzene (50
mL) at 10 °C during 30 min. After stirring for 10 h at 10 °C, the re-
sulting yellow reaction mixture was poured into H2O (300 mL) and
extracted with Et2O (5 × 100 mL). The combined organic phases
were washed with brine (3 × 200 mL) and dried over MgSO4. After
filtration of the drying agents and evaporation of the solvents, the
crude mixture was fractionally distilled, yielding starting material 2
(7.81 g; bp 45–50 °C at 1.0 mbar) and ethyl 5-chloro-2-cyanopen-
tanoate (3; 7.60 g; bp 81–85 °C at 0.6 mmHg). Yield: 50% (based
+
NH4 , 100/32). Anal. Calcd. for C13H14ClFN2O: C, 58.1; H, 5.3; N,
10.4. Found: C, 58.0; H, 5.1; N, 10.2.
1-Benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a); Typical
Procedure
The synthesis of 1-benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile
(9a) is given as a representative example for the synthesis of 1-
alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles 9a–d. A solution of
N-benzyl-5-chloro-2-cyano-2-fluoropentanamide (8a; 0.27 g, 16
mmol) and K2CO3 (2.6 g, 19 mmol, 1.2 equiv) in DMSO (20 mL)
was heated under reflux for 1 h. The resulting mixture was poured
into H2O (10 mL) and extracted with dichloromethane (3 × 10 mL).
The combined organic layers were dried (MgSO4) and, after evapo-
ration of the solvent, crude 1-benzyl-3-fluoro-2-oxopiperidine-3-
carbonitrile (9a) was obtained. Purification was performed by flash
chromatography over silica gel (EtOAc–hexane, 8:2; Rf = 0.14) to
give 1-benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a). Yield:
2.05 g (54%); white crystals; mp 53 °C. 1H NMR (300 MHz,
CDCl3): d = 1.90–2.14 (2 H, m, CH2CH2N), 2.46 (2 H, dt, J = 6.2
Hz, J = 17.3 Hz, CH2CF), 3.30 (2 H, dt, J = 6.1 Hz, J = 1.2 Hz,
CH2CH2N), 4.55 (1 H, d, J = 14.6 Hz, NCHaHb), 4.67 (1 H, d,
J = 14.6 Hz, NCHaHb), 7.18–7.38 (5 H, m, 5 × CHar). 13C NMR (75
MHz, CDCl3, int. ref.: 77.4 ppm): d = 18.0 (d, J = 4.6 Hz,
CH2CH2N), 32.9 (d, J = 23.1 Hz, CH2CF), 46.6 (CH2CH2N), 51.1
(Cq,arCH2), 84.6 (d, J = 188.1 Hz, CF), 115.6 (d, J = 35.8 Hz, CN),
128.1 (CHar), 128.3 (2 × CHar), 129.0 (2 × CHar), 135.2 (Cq,ar),
160.0 (d, J = 23.1 Hz, C=O). 19F NMR (282 MHz, CDCl3): d =
–148.87 (1 F, t, J = 17.8 Hz). IR (KBr): 3400, 2239 (nCN), 1673
1
on the recovery of the starting material); colourless oil. H NMR
(300 MHz, CDCl3): d = 1.34 (3 H, t, J = 7.2 Hz, CH3), 1.92–2.24
(4 H, m, ClCH2CH2CH2CF), 3.56–3.63 (3 H, m, CH2Cl and
CHCN), 4.28 (2 H, q, J = 7.2 Hz, CH2CH3). 13C NMR (75 MHz,
CDCl3, int. ref.: 77.4 ppm): d = 14.1 (CH3), 27.3 (CH2CH2Cl or
CH2CH), 29.5 (CH2CH or CH2CH2Cl), 37.0 (CH), 43.7 (CH2Cl),
63.2 (CH3CH2), 116.3 (CN), 165.9 (C=O). IR (NaCl): 2985, 2251
(nCN), 1745 (nCO), 1448, 1370 cm–1. MS (ES–): m/z (%) = 189/91
(M – H+, 100/31). Anal. Calcd. for C8H12ClNO2: C, 50.7; H, 6.4; N,
7.4. Found: C, 50.6; H, 6.3; N, 7.3.
5-Chloro-2-cyano-2-fluoropentanoate (7)
To a solution of ethyl 5-chloro-2-cyanopentanoate (3; 2.0 g, 10.6
mmol) and K2CO3 (1.6 g, 11.6 mmol) in DMF (40 mL) in a 100 mL
flask, was added N-fluorodibenzenesulfonimide (NFSI) (4.0 g, 12.7
mmol, 1.1 equiv). After stirring the reaction mixture for 20 h and fil-
tration of the solids, the filtrate was poured into H2O (30 mL) and
extracted with Et2O (3 × 30 mL). The combined organic phases
were washed with brine (3 × 20 mL) and subsequently dried over
MgSO4. Filtration of the drying agents and evaporation of the sol-
vent yielded ethyl 5-chloro-2-cyano-2-fluoropentanoate (7), which
was sufficiently pure for further use in the next step. Yield: 1.55 g
(71%); purity: 85%. For analytical purposes, a sample was purified
by flash chromatography over silica gel (EtOAc–hexane, 9:1;
Rf = 0.45). Yield: 58%; colourless oil. 1H NMR (300 MHz, CDCl3):
d = 1.39 (3 H, t, J = 7.2 Hz, CH3), 1.95–2.19 (2 H, m, ClCH2CH2),
2.27–2.47 (2 H, m, CFCH2), 3.62 (2 H, t, J = 6.2 Hz, CH2Cl), 4.40
(2 H, q, J = 7.2 Hz, CH2CH3). 13C NMR (75 MHz, CDCl3): d = 14.0
(CH3), 26.2 (d, J = 2.3 Hz, CH2CH2Cl), 34.5 (d, J = 23.1 Hz,
CH2CF), 43.3 (CH2Cl), 64.4 (CH2O), 86.5 (d, J = 196.1 Hz, CF),
113.9 (d, J = 34.6 Hz, CN), 163.2 (d, J = 26.5 Hz, C=O). 19F NMR
(282 MHz, CDCl3): d = –158.61 (1 F, t, J = 6.2 Hz). IR (NaCl):
2987, 2253 (nCN), 1773 (nCO), 1583, 1451, 1400 cm–1. GC-MS (EI):
+
(nCO), 1496, 1455 cm–1. MS (ES+): m/z (%) = 250 (M + NH4 , 100),
233 (M + H+, 31).
3-Aminomethyl-1-benzyl-3-fluoropiperidine (10a); Typical
Procedure
The synthesis of 3-aminomethyl-1-benzyl-3-fluoropiperidine (10a)
is given as a representative example for the synthesis of 1-alkyl-3-
aminomethyl-3-fluoropiperidines 10a–d. To a solution of 1-butyl-
3-fluoro-2-oxopiperidine-3-carbonitrile (9a; 0.19 g, 0.8 mmol) in
THF (10 mL) under a nitrogen atmosphere, was added carefully
BH3 (1 M in THF, 4 mL, 4 mmol, 5 equiv). After stirring for 16 h at
r.t., MeOH was carefully added until the evolution of hydrogen gas
stopped. This mixture was stirred for 1 h at r.t., and subsequently,
the solvents were evaporated. The crude mixture was taken up in
Et2O (3 mL), and 1 M HCl (1 mL) was added. The organic layer was
Synlett 2009, No. 11, 1765–1768 © Thieme Stuttgart · New York

1768
E. Van Hende et al.
LETTER
Eur. Pat. Appl. EP 1923397, 2008; A1 20080521.
extracted with 1 M HCl (2 × 3 mL) and the combined aqueous lay-
ers were then neutralized to pH 7 with 1 M NaOH and extraction
was performed with EtOAc (3 × 5 mL). Drying (MgSO4), filtration
and evaporation of the solvent yielded the crude 3-aminomethyl-1-
butyl-3-fluoropiperidine (10a), which was purified by dissolving
the piperidine in anhydrous Et2O, and adding an excess of trifluoro-
acetic acid (0.5 mL). After stirring for 16 h at r.t., the precipitated
3-aminomethyl-1-benzyl-3-fluoropiperidine trifluoroacetate was
filtered and dried at high vacuum. Yield: 70%; white crystals; mp
175 °C. 1H NMR (300 MHz, D2O): d = 1.52–1.76 (1 H, m,
CH2CHaHbCF), 1.86–2.01 (2 H, m, CH2CH2CF), 2.02–2.16 (1 H,
m, CH2CHaHbCF), 2.90–3.06 (1 H, m, NCHaHbCH2), 3.16–3.32
(3 H, m, NCHaHbCF and CH2NH2), 3.42–3.61 (2 H, m,
NCHaHbCH2 and NCHaHbCF), 4.27 (1 H, d, J = 13.2 Hz, CHaHb-
(b) Grabstein, K. H.; Wang, A.; Nairn, N.; Winblade, G.;
Thomas, J. U.S. Pat. Appl. Publ. US 2008096819, 2008;
A1 20080424. (c) Edmondson, S. D.; Mastracchio, A.;
Mathvink, R. J.; He, J.; Harper, B.; Park, Y.-J.; Beconi, M.;
Di Salvo, J.; Eiermann, G. J.; He, H.; Leiting, B.; Leone,
J. F.; Levorse, D. A.; Lyons, K.; Patel, R. A.; Patel, S. B.;
Petrov, A.; Scapin, G.; Shang, J.; Roy, R. S.; Smith, A.; Wu,
J. K.; Xu, S.; Zhu, B.; Thornberry, N. A.; Weber, A. E.
J. Med. Chem. 2006, 49, 3614. (d) Celanire, S.; Quere, L.;
Denonne, F.; Provins, L. PCT Int. Appl. WO 2007048595,
2007; A1 20070503. (e) Keith, J. M.; Gomez, L. A.; Letavic,
M. A.; Ly, K. S.; Jablonowski, J. A.; Seierstad, M.; Barbier,
A. J.; Wilson, S. J.; Boggs, J. D.; Fraser, I. C.; Mazur, C.;
Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem.
Lett. 2007, 17, 702. (f) Parker, J. C.; Hulin, B. US Pat. Appl.
Publ. US 2005043292, 2005; A1 24/02/2005; Chem. Abstr.
2005, 142, 261783.
Cq,ar), 4.36 (1 H, d, J = 13.2 Hz, CHaHbCq,ar), 7.35–7.48 (5 H, m,
5 × CHar). 13C NMR (75 MHz, D2O): d = 17.7 (CH2CH2N), 27.8 (d,
J = 20.8 Hz, CH2CH2CF), 44.1 (d, J = 19.6 Hz, CH2NH2), 51.5
(CH2CH2N), 54.4 (d, J = 21.9 Hz, CFCH2N), 61.1 (Cq,arCH2), 91.0
(d, J = 177.7 Hz, CF), 116.5 (q, J = 291.9 Hz, CF3), 127.8 (Cq,ar),
129.4 (2 × CHar), 130.5 (CHar), 131.6 (2 × CHar), 163.0 (q, J = 35.4
Hz, C=O). 19F NMR (282 MHz, D2O): d = –165.39 (br s, 1 F, CF),
–75.38 (br s, 3 F, CF3). IR (KBr): 3400, 3013, 1677 (nCO), 1429,
1203 cm–1. MS (ES+): m/z (%) = 223 (M + H+, 100). In order to ob-
tain the free amine, the obtained TFA salt was treated with sat. aq
NaHCO3 (3 mL) and extracted with EtOAc (3 × 3 mL). The com-
bined organic layers were dried (MgSO4), filtered and, after evapo-
ration of the solvent, pure 3-aminomethyl-1-benzyl-3-
fluoropiperidine (10a) was obtained. Yield: 0.10 g (82%); colour-
(3) (a) Fluorine in Bioorganic Chemistry; Welch, J. T.;
Eswarakrishnan, S., Eds.; Wiley-Interscience: New York,
1991. (b) Bioorganic and Medicinal Chemistry of Fluorine;
Bégué, J. P.; Bonnet-Delpon, D., Eds.; John Wiley & Sons,
Inc.: New Jersey, 2008.
(4) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(5) O' Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(6) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320.
(7) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(8) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(9) Differding, E.; Frick, W.; Lang, R. W.; Martin, P.; Schmit,
C.; Veenstra, S.; Greuter, H. Bull. Soc. Chim. Belg. 1990, 99,
647.
(10) Barrow J. C., Lindsley C. W., Shipe W. D., Yang Z.: PCT
Int. Appl. WO/2007/002361, 2007; Chem. Abstr. 2007, 146,
121830.
(11) Verniest, G.; Surmont, R.; Van Hende, E.; Deweweire, A.;
Deroose, F.; Thuring, J. W.; De Kimpe, N. J. Org. Chem.
2008, 73, 5458.
(12) Van Niel, M. B.; Collins, I.; Beer, M. S.; Broughton, H. B.;
Cheng, S. K. F.; Goodacre, S. C.; Heald, A.; Locker, K. L.;
MacLeod, A. M.; Morrison, D. J. Med. Chem. 1999, 42,
2087.
(13) Sun, A.; Lankin, D. C.; Hardcastle, K.; Snyder, J. P. Chem.
Eur. J. 2005, 11, 1579.
(14) Dechamps, I.; Gomez Pardo, D.; Cossy, J. Eur. J. Org.
Chem. 2007, 4224.
1
less liquid. H NMR (300 MHz, CDCl3): d = 1.44–1.85 (6 H, m,
NH2 and CH2CH2CF and CH2CH2CF), 2.31–2.54 (4 H, m,
CH2CH2CF and NCH2CH2), 2.73–2.97 (2 H, m, CH2NH2), 3.50
(1 H, d, J = 13.2 Hz, CHaHbCq,ar), 3.59 (1 H, d, J = 13.2 Hz, CHaH-
bCq,ar), 7.21–7.34 (5 H, m, 5 × CHar). 13C NMR (75 MHz, CDCl3,
int. ref.: 77.4 ppm): d = 22.5 (d, J = 6.9 Hz, CH2CH2N), 31.7 (d,
J = 20.8 Hz, CH2CH2CF), 48.2 (d, J = 23.1 Hz, CH2NH2), 53.6
(CH2CH2N), 58.3 (d, J = 24.2 Hz, CFCH2N), 63.0 (Cq,arCH2), 94.8
(d, J = 171.9 Hz, CF), 127.4 (CHar), 128.6 (2 × CHar), 129.2
(2 × CHar), 138.3 (Cq,ar). 19F NMR (282 MHz, CDCl3): d = –160.81
(br s, 1 F, CF). IR (NaCl): 3393, 2943, 1683, 1454 cm–1. MS (ES+):
m/z (%) = 223 (M + H+, 100).
Acknowledgment
The authors are indebted to the Research Foundation – Flanders
(FWO-Flanders), Ghent University (GOA, BOF) and John-
son&Johnson Pharmaceutical Research & Development, a Division
of Janssen Pharmaceutica NV, for financial support.
(15) (a) Ono, N.; Yoshimura, T.; Saito, T.; Tamura, R.; Tanikaga,
R.; Kaji, A. Bull. Chem. Soc. Jpn. 1979, 52, 1716.
(b) Muthusamy, S.; Gnanaprakasam, B. Tetrahedron Lett.
2005, 46, 635.
(16) Zefirov, N. S.; Kuznetsova, T. S.; Kozhushkov, S. I.;
Surmina, L. S.; Rashchupkina, Z. A. Zh. Org. Khim. 1983,
19, 541.
References and Notes
(1) Postdoctoral Fellow of the Research Foundation – Flanders
(FWO-Vlaanderen)
(2) For examples, see: (a) Papeo, G. M. E.; Caronni, D.; Dalvit,
C.; Giordano, P.; Mongelli, N.; Veronesi, M.; Ciprandi, F.
(17) Grossman, R. B.; Varner, M. A. J. Org. Chem. 1997, 62,
5235.
Synlett 2009, No. 11, 1765–1768 © Thieme Stuttgart · New York