A convenient one-pot preparation of N-substituted 4-phenylpiperidines

Article abstract of DOI:10.3987/COM-07-11206

N-Substituted 4-phenylpiperidines were readily synthesized by one-pot cyclization of diols with amines via bis-triflate intermediates. The new synthesis under mild conditions gave various N-substituted 4-phenylpiperidines in moderate to good yields.

Full text of DOI:10.3987/COM-07-11206

HETEROCYCLES, Vol. 75, No. 1, 2008
183
HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 183 - 188. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd August, 2007, Accepted, 27th September, 2007, Published online, 28th September, 2007. COM-07-11206
A CONVENIENT ONE-POT PREPARATION OF N-SUBSTITUTED
4-PHENYLPIPERIDINES
Shigehiro Asano and Hitoshi Ban*
Dainippon Sumitomo Pharma Co., Ltd. Enoki 33-94, Suita, Osaka, 564-0053,
Japan. e-mail: hitoshi-ban@ds-pharma.co.jp
Abstract – N-Substituted 4-phenylpiperidines were readily synthesized by
one-pot cyclization of diols with amines via bis-triflate intermediates. The new
synthesis
under
mild
conditions
gave
various
N-substituted
4-phenylpiperidines in moderate to good yields.
INTRODUCTION
N-Substituted 4-phenylpiperidines are very important motifs in the range of medicines, particularly those
used for central nervous system disorders, such as pethidine1 and difenoxin.2 Two typical synthetic routes
for N-Substituted 4-phenylpiperidines are reported. One is cyclization of appropriate phenylacetonitriles
with N-substituted bis(2-haloethyl)amines.1,3,4 The other is cyclization of primary amines with
α,α-bis(2-haloethyl)phenylacetonitrile5,6 or α,α-bis(formylmethyl)phenylacetonitrile.7 However, the use
of these methods is limited to the preparation of some N-substituted piperidine derivatives. In addition,
the former method requires the preparation of N-substituted bis(2-haloethyl)amine derivatives through
multi-reaction steps, while the later method is not useful for the synthesis of piperidines substituted with
N-aryl or N-sterically hindered alkyl groups.
In order to prepare various piperidine derivatives easily, new useful synthetic methods are desired. In this
report, we present a convenient method for the synthesis of N-substituted 4-phenylpiperidines using
bis-triflate as a key intermediate (Scheme 1).
Scheme 1. Piperidine Formation via Bis-triflate
R2NH2
Tf2O
HO
TfO
R1
R1
R1
N
R2
OH
OTf

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RESULTS AND DISCUSSION
Initially, a stepwise cyclization using bis-mesylate or bis-bromide precursor with aniline was attempted.
The diol 1 was readily synthesized from commercially available phenylacetonitrile and
2-(2-bromoethoxy)tetrahydro-2H-pyran by alkylation5 and methanolysis.8 The diol 2 was obtained by the
reduction of 3-phenylgurutalic acid according to the reported method.9 The precursors were prepared
from diols 1 and 2 by mesylation10 or bromination using CBr4/PPh3. Despite screening various bases and
solvents, the ensuing cyclization with aniline did not give sufficient yields (3‐28%) of the corresponding
piperidines. Therefore, we turned our attention to bis-triflate precursors possessing more reactive leaving
groups. The cyclization was conducted without isolating bis-triflate 3 because of its instability at room
temperature.
Table 1. The one-pot cyclization of diol with aniline
then
Tf2O (2.1 eq)
base (2.1 eq)
aniline (1.2 eq)
HO
TfO
R1
R1
R1
N
solvent
base (2.1 eq)
OH
-30 ℃, 15 min.
OTf
-30 ℃→r.t., 3 h
1 : R1 = CN
2 : R1 = H
3
4 : R1 = CN
5 : R1 = H
Diol
Entry
Isolated yield (%)
Base
Solvent
MeCN
CH2Cl2
toluene
EtOAc
EtOAc
EtOAc
MeCN
TEA
TEA
TEA
TEA
1
2
3
1
1
1
51
22
7
4
5
6
7
8
1
1
1
2
2
67
18
81
78
78
pyridine
DIPEA
DIPEA
DIPEA
EtOAc
In the presence of triethylamine (TEA) (2.1 eq.), diol 1 (1.0 eq.) and trifluoromethanesulfonic anhydride
(Tf2O) (2.1 eq.) were reacted in acetonitrile (MeCN) at -30 ℃ for 15 min. Without isolating the
bis-triflate precursor, aniline (1.2 eq.) and TEA (2.1 eq.) were then added. After one hour at the same

HETEROCYCLES, Vol. 75, No. 1, 2008
185
temperature, the reaction mixture was stirred at ambient temperature for 2 hours. The resulting piperidine
4 was obtained in 51% yield (Entry 1 in Table 1). As a result of extensive screening of various bases and
solvents, the stability of the key intermediate 3 in the reaction turned out to be important, since 3 was
gradually decomposed in the presence of pyridine (Entry 5 in Table 1). The use of dichloromethane or
toluene as reaction solvents gave poor yields due to the low solubility of 1 (Entries 2 and 3 in Table 1).
When Hünig’s base (DIPEA) was used, the reaction proceeded to completion and the one-pot cyclization
gave a satisfactory result (Entry 6). The reaction of 3-phenyl-1,5-pentanediol 2 with aniline under the
same conditions gave the desired product 5 in good yields (Entries 7 and 8).
Table 2. The one-pot cyclization of 1 with various amines
Tf2O (2.1 eq)
then
DIPEA (2.1 eq)
R2-NH2 (1.2 eq)
HO
CN
CN
EtOAc
DIPEA (2.1 eq)
N
R2
-30 ℃, 15 min.
-30 ℃→r.t., 3 h
OH
1
Entry
Isolated yield (%)
R2
Product
o-MeO-C6H4
m-MeO-C6H4
p-MeO-C6H4
p-F-C6H4
1
2
3
4
5
6
7
8
66
85
70
78
73
39
82
79
6
7
8 3
9
p-MeO2C-C6H4
p-NO2-C6H4
Bn
10
11
12 1
13
Ph2CH
14 11
15 4
n-Bu
t-Bu
9
78
70
10
Based on the results above, one-pot cyclizations of 1 with various amine nucleophiles were conducted,
and N-substituted 4-phenylpiperidines were obtained in moderate to high yields as shown in Table 2. The
reaction with anisidines, possessing an electron-donating group gave good yields (Entries 1, 2 and 3),
even if the methoxy group was located at the ortho-position. The presence of electron-withdrawing
groups, such as a fluorine atom or a methoxy carbonyl group, did not affect the chemical yield (Entries 4

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and 5). Furthermore, piperidines with N-aliphatic substituents could be obtained in good yields regardless
of the amine’s steric barrier (Entries 7, 8, 9 and 10). The N-benzyl groups in 12 and 13 were readily
removed by the common method for preparing un-substituted piperidines (not shown).1 Although a
variety of amine nucleophiles possessing electron-donating, electron-withdrawing, or sterically hindered
substituent underwent the cyclization reaction, reaction with the less nucleophilic 4-nitroaniline resulted
in an exceptionally moderate yield (Entry 6).
CONCLUSION
In summary, we developed a convenient, one-pot synthetic method of N-substituted 4-phenylpiperidines
via bis-triflate starting from 3-aryl-1,5-pentanediols. This method does not require individual multi-steps
preparation of N-substituted bis(2-haloethyl)amine derivatives as cyclization precursors. Furthermore, we
found that electron-poor and sterically hindered amines react readily under mild conditions.
EXPERIMENTAL
Melting points were determined on an Electrothermal apparatus without correction. 1H NMR spectra were
recorded on a JEOL JNM-LA300 spectrometer using CDCl3 as solvent and TMS as internal standard.
Chemical shifts (σ) are expressed in ppm. Mass spectra were recorded on a Bruker Daltonics
esquire3000plus MS equipment. Elemental analysis was performed on a CE Instrument EA1110 and a
Yokokawa analytical system IC7000.
General Preparation of Piperidine. To a solution of the diol (0.487 mmol) in dry EtOAc (2.0 mL) at ‐
30 ℃was slowly added trifluoromethanesulfonic anhydride (Tf2O) (1.02 mmol) followed by addition of
diisopropylethylamine (DIPEA) (1.02 mmol). The reaction mixture was maintained at an internal reaction
temperature of‐30 ℃ for 15 min. The primary amine (0.585 mmol) was then added, followed by
addition of DIPEA (1.02 mmol). The reaction mixture was kept at ‐30 ℃for 1h and then warmed to rt
for 2 h. The reaction was quenched by adding water and extracted with EtOAc. The organic layer was
washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed
in vacuo, and the residue was purified by silica gel column chromatography and recrystallized to give
piperidine products in the yields indicated.
4-Cyano-1-(2-methoxyphenyl)-4-phenylpiperidine 6 (Entry 1 in Table 2)
1
This compound was obtained as white needle-like crystals (MeOH), mp 97‐ 98 ℃; H NMR
(CDCl3): δ 2.23 (2H, m), 2.37 (2H, m), 3.13 (2H, m), 3.59 (2H, m), 3.89 (3H, s), 6.88 (1H, m), 6.96 (1H,
m), 7.05 (2H, m), 7.35 (1H, m), 7.45 (2H, m), 7.56 (2H, m); MS: m/z 293 (M+). Anal. Calcd for
C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 77.91; H, 6.90; N, 9.58.

HETEROCYCLES, Vol. 75, No. 1, 2008
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4-Cyano-1-(3-methoxyphenyl)-4-phenylpiperidine 7 (Entry 2 in Table 2)
1
This compound was obtained as white needle-like crystals (Et2O-hexane), mp 67‐68 ℃; H NMR
(CDCl3): δ 2.21 (4H, m), 3.25 (2H, m), 3.77 (2H, m), 3.81 (3H, s), 6.48 (1H, dd, J = 8.2, 2.1 Hz), 6.54
(1H, dd, J = 2.1, 2.1 Hz), 6.59 (1H, dd, J = 8.2, 2.1 Hz), 7.21 (1H, dd, J = 8.2, 8.2 Hz), 7.32-7.45 (3H, m),
7.51 (2H, m); MS: m/z 293 (M+). Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C,
77.93; H, 6.89; N, 9.61.
4-Cyano-1-(4-fluorophenyl)-4-phenylpiperidine 9 (Entry 4 in Table 2)
1
This compound was obtained as white needle-like crystals (Et2O-hexane), mp 71‐72 ℃; H NMR
(CDCl3): δ 2.26 (4H, m), 3.20 (2H, m), 3.62 (2H, m), 6.93-7.03 (4H, m), 7.33-7.46 (3H, m), 7.53 (2H,
m); MS: m/z 281 (M+). Anal. Calcd for C18H17FN2: C, 77.12; H, 6.11; F, 6.78; N, 9.99. Found: C,
77.06; H, 6.09; F, 6.51; N, 10.02.
4-Cyano-1-(4-methoxycarbonylphenyl)-4-phenylpiperidine 10 (Entry 5 in Table 2).
1
This compound was obtained as white needle-like crystals (MeOH), mp 115‐117 ℃; H NMR
(CDCl3): δ 2.14 (2H, m), 2.19 (2H, m), 3.37 (2H, m), 3.88 (3H, s), 3.97 (2H, m), 6.96 (2H, d, J = 9.0 Hz),
7.33-7.46 (3H, m), 7.49 (2H, m), 7.94 (2H, d, J = 9.0 Hz); MS: m/z 321 (M+). Anal. Calcd for
C20H20N2O2: C, 74.98; H, 6.29; N, 8.74. Found: C, 74.68; H, 6.24; N, 8.69.
4-Cyano-1-(4-nitrophenyl)-4-phenylpiperidine 11 (Entry 6 in Table 2).
1
This compound was obtained as yellow crystals (i-PrOH), mp 180‐182 ℃; H NMR (CDCl3): δ 2.16
(2H, m), 2.26 (2H, m), 3.47 (2H, m), 4.06 (2H, m), 6.94 (2H, d, J = 9.2 Hz), 7.37-7.51 (5H, m), 8.15 (2H,
d, J = 9.2 Hz); MS: m/z 308 (M+). Anal. Calcd for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67. Found: C,
69.62; H, 5.49; N, 13.55.
4-Cyano-1-diphenylmethyl-4-phenylpiperidine 13 (Entry 8 in Table 2)
1
This compound was obtained as white needle-like crystals (MeOH), mp 133‐135 ℃; H NMR
(CDCl3): δ 2.08 (2H, m), 2.16 (2H, m), 2.37 (2H, m), 2.99 (2H, m), 4.37 (1H, s), 7.19 (2H, m), 7.26-7.45
(11H, m), 7.51 (2H, m); MS: m/z 353 (M+). Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95.
Found: C, 84.71; H, 6.77; N, 8.02.
ACKNOWLEDGEMENTS
We are grateful to Ms. K. Bando for performing the elemental analysis, and Ms. K. Sakamoto for
recording MS spectra.

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