Development of κ opioid receptor agonists by focusing on phenyl substituents of 4-dimethylamino-3-phenylpiperidine derivatives: Structure-activity relationship study of matrine type alkaloids

Article abstract of DOI:10.1248/cpb.c15-00963

A series of new κ opioid receptor (KOR) agonists were developed from the lead compound 4-dimethylamino-1-pentanoylpiperidine (3), a matrine-type alkaloid. Derivatives of 3 were synthesized with a variety of phenyl substituents and evaluated for their anti

Full text of DOI:10.1248/cpb.c15-00963

420
Chem. Pharm. Bull. 64, 420–431 (2016)
Vol. 64, No. 5
Regular Article
Development of κ Opioid Receptor Agonists by Focusing on Phenyl
Substituents of 4-Dimethylamino-3-phenylpiperidine Derivatives:
Structure–Activity Relationship Study of Matrine Type Alkaloids
Hiroyoshi Teramoto, Takayasu Yamauchi,* Shigeru Sasaki, and Kimio Higashiyama*
Institute of Medicinal Chemistry, Hoshi University; Ebara, Shinagawa-ku, Tokyo 142–8501, Japan.
Received November 30, 2015; accepted January 20, 2016
A series of new κ opioid receptor (KOR) agonists were developed from the lead compound 4-dimethyl-
amino-1-pentanoylpiperidine (3), a matrine-type alkaloid. Derivatives of 3 were synthesized with a variety of
phenyl substituents and evaluated for their antinociceptive effects. Additionally, their selectivity for an opioid
receptor was investigated for cis-4c and d, and trans-4g, all of which had high activity exerted through the
KOR.
Key words antinociceptive effect; kappa opioid receptor; piperidine; matrine; writhing test; mouse
We previously reported that (+)-matrine (1) and (+)-allo- figuration of these diastereomers were assigned by comparison
matrine (2), a typical matrine type lupine alkaloid isolated to literature data and using the coupling constants from the
from some Sophora plants (Leguminosae), have antinocicep- 1H-NMR spectra.14) Amine 11e, which has a chloro group on
tive properties identical to those of pentazocine1) (Fig. 1). The the para position of the benzene ring, was obtained by reduc-
effects of (+)-matrine are mediated mainly through activation tion with LiAlH4 since dechlorination occurred during reduc-
of κ opioid receptors (KOR) and partially through μ receptors tion with metal sodium.
(MOR), while the effects of (+)-allomatrine are mediated only
An alternative synthetic route for 11f and g was designed
through activation of KOR.2) Because the skeleton of the ma- because only a trace of the expected allyl alcohol was ob-
trine type alkaloids differs from those of conventional KOR tained by the Shapiro reaction (Chart 2). Amidation of carbox-
agonists, such as ethylketocyclazocine,3) U-504884,5) and nal- ylic acids 12f and g and amine 13 in the presence of 1-ethy-3-
furafine (TRK-820),6) they have the potential to be derivatized (3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)
into novel KOR agonists that may not induce side effects such and 4-dimethylaminopyridine (DMAP) yielded amides 14f
as dysphoria and psychotomimetic actions7,8) (Fig. 2). In fact, and g, which was followed by Dieckmann condensation15) with
the structure–activity relationship (SAR) between the antino- NaOEt to obtain β-keto lactam 15f and g.
ciceptive effects of these alkaloids and their structures is very
Separable amines cis- and trans-11f and g were obtained by
interesting. During the development of new KOR agonists, reduction of oximes 16f and g, which were oximated from the
compound 3 was identified as a lead compound by determin- ketones 15f and g. The relative configuration of cis- and trans-
ing the essential structure required for the antinociceptive 11f and g were also assigned from the coupling constant in the
effects of (+)-matrine.9–11) When compound 3 was derivatized 1H-NMR spectra.
and tested, the antinociceptive effects of 4-dimethylamino-
As shown in Chart 3, the final synthetic steps involved
1-pentanoyl-3-phenylpiperidine (4a) were more potent than treatment with HCHO and HCO2H to afford the dimethylated
those of the lead compound 3. On the basis of the Topliss amines cis- and trans-17a–g. After debenzylation, the target
method,12) we designed and synthesized phenyl derivatives compounds cis- and trans-4a–g were obtained by N-acylation.
of 4a in an effort to further improve the activity. Herein, we To avoid dechlorination by reduction, debenzylation of the
report the synthesis of the derivatives of 4a and their pharma- precursors cis- and trans-4e–g having the chloro group were
cological effects.
carried out by using 1-chloroethyl chloroformate and MeOH.16)
Biological Evaluation To evaluate the antinociceptive
potencies of the compounds, the writhing test was performed
Synthesis
The synthetic route to the intermediates, cis- and trans- via subcutaneous (s.c.) administration of cis- and trans-4a–g
11a–e, is shown in Chart 1. Hydrazones 7a–e were prepared in mice. A single s.c. administration of all synthesized com-
by condensation of commercially available 2,4,6-triisopropyl- pounds produced a dose-dependent antinociceptive effect. The
benzenesulfonyl hydrazide 5 and the respective acetophenones ED50 values of cis- and trans-4a–g are shown in Table 1. In
6a–e. Allylic alcohols 8a–e were obtained through the Shapiro the writhing test, the antinociceptive effects of cis-4c, d and
reaction with acrolein.13) Oxidation of 8a–e with MnO2 yield- trans-4g were strikingly different compared with those of
ed the respective dienones, followed by cyclization via a dou- pentazocine, which is a well-known selective KOR agonist.
ble aza-Michael reaction with benzylamine using microwave Common to matrine-type and allomatrine-type derivatives,
irradiation to give piperidones 9a–e.13) Piperidones 9a–e were generally the compounds with a substituent at the ortho or
converted to oximes 10a–e and subsequently reduced with meta position on the benzene ring had higher antinociception,
metal sodium in EtOH to yield the separable diastereomers except for the compound having the fluoro substituent (4d).
cis- and trans-11a–d, the 3,4-cis (matrine type) and 3,4-trans For example, cis-4f and g had higher activity than cis-4e,
configuration compounds (allomatrine type). The relative con- the activities of the trans compounds were also the same as
*To whom correspondence should be addressed. e-mail: yamauchi@hoshi.ac.jp; kimio@hoshi.ac.jp
© 2016 The Pharmaceutical Society of Japan

Vol. 64, No. 5 (2016)
Chem. Pharm. Bull.
421
Fig. 1. Structure of (+)-Matrine Derivatives
Fig. 2. Structure of Conventional κ-Opioid Receptor Agonists
Reagents and reaction conditions: (a) THF, rt, 67–81%; (b) n-BuLi, acrolein, THF, −78°C, 82–97%; (c) activated MnO2, CH2Cl2, rt; (d) BnNH2, MeCN, 100°C, MW, two
steps, 67–92%; (e) NH2OH–HCl, AcONa, EtOH, H2O, reflux, 95–99%; (f) Na, EtOH, reflux, 56–85%; (g) LiAlH4, THF, reflux, 59–85%.
Chart 1
those of the cis compounds. From the results, we speculated cis-4c, d and trans-4g, the three compounds with the highest
that steric and electronic effects were more important than the antinociception, as shown in Fig. 3. The assessment of the se-
type of substituent in determining the compound’s potency. lectivity was carried out using the writhing test with the MOR
This observation may be explained by the restriction of free antagonist β-funaltrexamine (β-FNA), the δ-opioid receptor
rotation of the benzene ring containing a substituent caused by (DOR) antagonist naltrindole (NTI), or the KOR antagonist
steric hindrance between the benzene ring and dimethylamino nor-BNI (norbinaltorphimine) as control compounds. In the
moiety. Further studies are required to confirm this hypothesis. presence of the synthesized compounds, there were scarcely
Next, we investigated the opioid receptor selectivity of any changes in the antinociceptive effects with β-FNA and

422
Chem. Pharm. Bull.
Vol. 64, No. 5 (2016)
Reagents and reaction conditions: (a) EDC, DMAP, CH2Cl2, 0°C, 99%; (b) NaOEt, toluene, reflux; (c) NH2OH–HCl, AcONa, EtOH, H2O, reflux; (d) LiAlH4, THF, re-
flux, three steps, 17–30%.
Chart 2
Reagents and reaction conditions: (a) 36% HCHO, HCO2H, reflux, 41–99%; (b) 10% Pd–C, HCO2NH4, MeOH, reflux; (c) 1-chloroethyl chloroformate, CH2Cl2, rt, then
MeOH, reflux; (d) BuCOCl, Et3N, CH2Cl2, rt, two steps, 12–76%.
Chart 3
of the control antagonists.
Table 1. ED50 Value in mg/kg of cis-4a–g and trans-4a–g for 30–40
In summary, we succeeded in synthesizing the 4-dimethyl-
amino-3-phenylpiperidine derivatives cis- and trans-4a–g. The
phenyl derivatives cis-4c, d and trans-4g showed high antino-
ciceptive effects mediated through the activation of KOR. The
results are valuable in providing a starting point toward the
development of a novel KOR selective agonist.
Mice in Each Group
R
ED50 in mg/kg
Pentazocine
1
3.80
4.70
5.47
8.07
0.91
0.97
6.44
4.18
2.21
5.89
4.80
8.33
5.78
1.52
4.92
3.59
0.60
cis-4a
H
cis-4b
cis-4c
4′-Me
3′-Me
4′-F
4′-Cl
3′-Cl
2′-Cl
Experimental
Chemistry 1H- (400MHz) and 13C-NMR (100MHz) spec-
tra were obtained on a Bruker AVIII-400 instrument, and
chemical sifts are reported in ppm on the δ-scale from inter-
nal tetramethylsilane. Signal splitting patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), septet (sept), mul-
tiplet (m) or broad (br), with coupling constants (J) in hertz
(Hz). MS spectra were measured with a JEOL JMS D-600
and JMS T-100LP spectrometer by using the chemical ioniza-
tion (CI) with isobutene, the electron impact (EI) methods,
and electrospray ionization (ESI) methods. All melting points
were measured with a Yanagimoto Micro melting point appa-
ratus without collection. IR spectra were recorded on Perkin-
Elmer Spectrum Two. Microwave irradiation were carried out
cis-4d
cis-4e
cis-4f
cis-4g
2
trans-4a
trans-4b
trans-4c
trans-4d
trans-4e
trans-4f
trans-4g
H
4′-Me
3′-Me
4′-F
4′-Cl
3′-Cl
2′-Cl
NTI, but their effects were violently antagonized with nor- on Biotage Initiator. Column chromatography was performed
BNI. We assumed that the effects of cis-4c and d, matrine- on Silica gel 60 (100–210µm, Kanto Chemical Co., Inc.).
type compounds, were only slightly antagonized by β-FNA
because the antinociceptive effects of (+)-matrine (1) are par- zone (7a) Acetophenone (2.00g, 16.7mmol) was added to
tially mediated through MOR. The selectivity results were in solution of 2,4,6-triisopropylbenzenesulfonyl hydrazide
agreement with what was expected from the known behavior (5.00g, 16.7mmol) in tetrahydrofuran (THF). After being
Acetophenone (2,4,6-Triisopropylbenzene)sulfonylhydra-
a

Vol. 64, No. 5 (2016)
Chem. Pharm. Bull.
423
(CDCl3) δ: 1.24 (6H, d, J=6.9Hz), 1.30 (12H, d, J=6.8Hz),
2.15 (3H, s), 2.32 (3H, s), 2.88 (1H, sept, J=6.9Hz), 4.33 (2H,
sept, J=6.8Hz), 7.10 (2H, d, J=8.1Hz), 7.16 (2H, s), 7.52 (2H,
d, J=8.1Hz), 7.84 (1H, br). 13C-NMR (CDCl3) δ: 13.0, 21.2,
24.8, 24.8, 30.0, 34.2, 123.7, 126.2, 128.8, 131.4, 134.6, 139.5,
150.7, 151.3, 153.3. IR (KBr) cm−1: 813, 1167, 1332, 1599,
2965, 3240. MS (ESI+) m/z: 415 (M+H+, base peak). High
resolution (HR)-MS (ESI+) m/z: Found 415.2432 (Calcd for
C24H35N2O2S (M+H+) 415.2419).
3′-Methylacetophenone (2,4,6-Triisopropylbenzene)sul-
fonylhydrazone (7c)
Prepared According to Procedure for the Preparation of 7a
Yield: 76%, colorless solid, mp 159–161°C. 1H-NMR
(CDCl3) δ: 1.24 (6H, d, J=6.9Hz), 1.30 (12H, d, J=6.8Hz),
2.16 (3H, s), 2.31 (3H, s), 2.89 (1H, sept, J=6.9Hz), 4.32 (2H,
sept, J=6.8Hz), 7.13–7.21 (4H, m), 7.39 (1H, d, J=7.7Hz), 7.49
(1H, s), 7.71 (1H, br). 13C-NMR (CDCl3) δ: 13.1, 21.3, 23.5,
24.8, 29.9, 34.2, 123.4, 123.8, 126.8, 128.0, 130.1, 131.4, 137.2,
137.8, 150.7, 151.3, 153.3. IR (KBr) cm−1: 907, 1166, 1331,
1600, 2964, 3244. MS (ESI+) m/z: 415 (M+H+, base peak).
HR-MS (ESI+) m/z: Found 415.2444 (Calcd for C24H35N2O2S
(M+H+) 415.2419).
4′-Fluoroacetophenone (2,4,6-Triisopropylbenzene)sul-
fonylhydrazone (7d)
Prepared According to Procedure for the Preparation of 7a
Yield: 70%, colorless solid, mp 177–179°C. 1H-NMR
(CDCl3) δ: 1.24 (6H, d, J=6.9Hz), 1,29 (12H, d, J=6.8Hz),
2.15 (3H, s), 2.89 (1H, sept, J=6.9Hz), 4.29 (2H, sept,
J=6.8Hz), 6.96–7.01 (2H, m), 7.10 (2H, s), 7.59–7.63 (2H,
m). 13C-NMR (CDCl3) δ: 13.2, 23.5, 24.8, 29.9, 34.1, 115.0
(d, J=21.7Hz), 123.8, 128.1 (d, J=8.4Hz), 131.3, 133.6 (d,
J=3.2Hz), 149.6, 151.4, 153.4, 163.4 (d, J=249.5Hz). IR (KBr)
cm−1: 836, 1169, 1511, 1600, 2959, 3241. MS (ESI+) m/z: 419
(M+H+, base peak). HR-MS (ESI+) m/z: Found 419.2200
(Calcd for C23H32FN2O2S (M+H+) 419.2169).
4′-Chloroacetophenone (2,4,6-Triisopropylbenzene)sul-
fonylhydrazone (7e)
Prepared According to Procedure for the Preparation of 7a
Yield: 71%, colorless solid. All spectroscopic and analytical
data were consistent with the literature.18)
2-Phenyl-1,4-pentadien-3-ol (8a) A solution of n-BuLi
(3.44mL, 5.50mmol, 1.6M, in n-hexane) was added dropwise
to a solution of 7a (1.00g, 2.50mmol) in THF (10mL) at
−78°C under the nitrogen atmosphere. The reaction mixture
was stirred at −78°C for 30min, then warmed to 0°C and
further stirred for 15min. Acrolein (578mg, 9.30mmol) was
added to the reaction mixture at −78°C. After being stirred
for 1h, the reaction mixture was quenched with saturated
aqueous NaHCO3 and extracted with EtOAc. The combined
organic layer was dried over anhydrous Na2SO4 and evapo-
rated. The resulting residue was purified by chromatography
on SiO2 (n-hexane–EtOAc=8:1) to yield the 8a (345mg,
Fig. 3. The Blockage of Antinociceptive Effect of cis-4c, d and trans-
4g (3mg/kg, s.c.) after Pretreatment with MOR Antagonist β-FNA
(40mg/kg, s.c.), DOR Antagonist NTI (3.2mg/kg, s.c.) or KOR Antago-
nist nor-BNI (3.2mg/kg, s.c.) at 24h, 15min and 4h before Administra-
tion of the Test Drug, Respectively, in the Acetic Acid-Induced Abdomi-
nal Constriction Assay in Mice1,2)
Each column represents the mean shown with the S.E.M. for 10 mice in each
group. *p<0.05 (cis-4c), **p<0.01 (cis-4d or trans-4g) versus the compound alone.
stirred at room temperature (rt) for 3h, the solvent was evapo- 2.16mmol, 86%) as a colorless oil. All spectroscopic and ana-
rated. The resulting residue was purified by recrystallization lytical data were consistent with the literature.19)
with EtOH to yield 7a (5.40g, 13.5mmol, 81%) as a colorless
solid. All spectroscopic and analytical data were consistent
with the literature.17)
2-(4-Methylphenyl)-1,4-pentadien-3-ol (8b)
Prepared According to Procedure for the Preparation of 8a
1
Yield: 82%, colorless oil. H-NMR (CDCl3) δ: 2.35 (3H, s),
4′-Methylacetophenone (2,4,6-Triisopropylbenzene)sul- 5.12 (1H, d, J=5.4Hz), 5.18 (1H, dt, J=10.4, 1.4Hz), 5.31–5.36
fonylhydrazone (7b)
(2H, m), 5.37 (1H, br), 5.96 (1H, ddd, J=17.2, 10.4, 5.4Hz),
Prepared According to Procedure for the Preparation of 7a
7.15 (2H, d, J=8.1Hz), 7.33 (2H, d, J=8.1Hz). 13C-NMR
Yield: 67%, colorless solid, mp 145–147°C. 1H-NMR (CDCl3) δ: 21.1, 74.5, 112.9, 115.9, 126.8, 129.0, 136.3, 137.5,

424
Chem. Pharm. Bull.
Vol. 64, No. 5 (2016)
139.0, 149.7. IR (film) cm−1: 920, 1513, 3025, 3389. MS (EI) (Calcd for C19H22NO (M+H+) 280.1701).
m/z: 174 (M+) 119 (base peak). HR-MS (EI) m/z: Found
174.1022 (Calcd for C12H14O (M+) 174.1045).
2-(3-Methylphenyl)-1,4-pentadien-3-ol (8c)
1-N-Benzyl-3-(3-methylphenyl)-4-piperidone (9c)
Prepared According to Procedure for the Preparation of 9a
Yield: 67% over two steps, light yellow oil. 1H-NMR
(CDCl3) δ: 2.32 (3H, s), 2.48–2.55 (1H, m), 2.61–2.71 (2H, m),
Prepared According to Procedure for the Preparation of 8a
1
Yield: 86%, colorless oil. H-NMR (CDCl3) δ: 2.36 (3H, 2.78 (1H, dd, J=11.4, 9.7Hz), 3.02–3.09 (1H, m), 3.15 (1H, ddd,
s), 5.12 (1H, br), 5.19 (1H, dt, J=10.4, 1.4Hz), 5.34 (1H, dt, J=11.4, 5.7, 2.3Hz), 3.65 (2H, s), 3.76 (1H, dd, J=9.7, 5.7Hz),
J=17.2, 1.4Hz), 5.37–5.38 (2H, m), 5.97 (1H, ddd, J=17.2, 7.01–7.07 (3H, m), 7.20 (1H, t, J=7.6Hz), 7.22–7.28 (1H, m),
10.4, 5.7Hz), 7.10–7.13 (1H, m), 7.22–7.24 (3H, m). 13C-NMR 7.31–7.38 (4H, m). 13C-NMR (CDCl3) δ: 21.4, 40.7, 53.5, 56.3,
(CDCl3) δ: 21.3, 74.2, 113.2, 115.6, 123.9, 127.5, 128.0, 128.3, 59.6, 61.9, 125.9, 127.3, 127.9, 128.2, 128.4, 128.9, 129.6,
137.7, 138.9, 139.3, 149.9. IR (film) cm−1: 1487, 1602, 3396. 136.6, 137.8, 137.9, 208.2. IR (film) cm−1: 1454, 1715, 2915.
MS (CI) m/z: 175 (M+H+), 157 (base peak). HR-MS (CI) m/z: MS (ESI+) m/z: 280 (M+H+, base peak). HR-MS (ESI+) m/z:
Found 175.1137 (Calcd for C12H15O (M+H+) 175.1123).
2-(4-Fluorophenyl)-1,4-pentadien-3-ol (8d)
Found 280.1670 (Calcd for C19H22NO (M+H+) 280.1701).
1-N-Benzyl-3-(4-fluorophenyl)-4-piperidone (9d)
Prepared According to Procedure for the Preparation of 8a
Yield: 82%, colorless oil. H-NMR (CDCl3) δ: 5.06 (1H,
Prepared According to Procedure for the Preparation of 9a
1
Yield: 92% over two steps, light yellow oil. 1H-NMR
d, J=5.0Hz), 5.17 (1H, dt, J=10.4, 1.3Hz), 5.31 (1H, dt, (CDCl3) δ: 2.47–2.56 (1H, m), 2.63–2.76 (3H, m), 3.07–3.11
J=17.2, 1.4Hz), 5.35 (1H, s), 5.38 (1H, s), 5.92 (1H, ddd, (1H, m), 3.17 (1H, ddd, J=11.4, 5.6, 2.4Hz), 3.67 (2H, s), 3.80
J=17.2, 10.4, 5.8Hz), 6.98–7.03 (2H, m), 7.37–7.42 (2H, m). (1H, dd, J=9.8, 5.6Hz), 6.97–7.03 (2H, m), 7.17–7.20 (2H,
13C-NMR (CDCl3) δ: 74.4, 113.5, 114.9 (d, J=21.3Hz), 115.8, m), 7.28–7.39 (5H, m). 13C-NMR (CDCl3) δ: 40.6, 53.3, 55.4,
128.5 (d, J=7.7Hz), 135.3 (d, J=3.2Hz), 138.7, 148.7, 162.2 59.7, 61.8, 115.2 (d, J=21.2Hz), 127.4, 128.4, 129.0, 130.4 (d,
(d, J=246.5Hz). IR (film) cm−1: 1509, 1599, 1686, 3440. MS J=7.9Hz), 132.3, 137.4, 161.9 (d, J=245.5Hz), 207.8. IR (film)
(ESI−) m/z: 177 (M−H+), 61 (base peak). HR-MS (ESI−) m/z: cm−1: 1511, 1602, 1717. MS (ESI+) m/z: 284 (M+H+), 91
Found 177.0716 (Calcd for C11H10FO (M−H+) 177.0716).
2-(4-Chlorophenyl)-1,4-pentadien-3-ol (8e)
(base peak). HR-MS (ESI+) m/z: Found 284.1474 (Calcd for
C18H19FNO (M+H+) 284.1451).
Prepared According to Procedure for the Preparation of 8a
1-N-Benzyl-3-(4-chlorophenyl)-4-piperidone (9e)
Prepared According to Procedure for the Preparation of 9a
Yield: 67% over two steps, light yellow oil. 1H-NMR
1
Yield: 97%, colorless oil. H-NMR (CDCl3) δ: 5.08 (1H, d,
J=5.7Hz), 5.19 (1H, dt, J=10.4, 1.4Hz), 5.32 (1H, dt, J=17.2,
1.4Hz), 5.39 (1H, br), 5.43 (1H, t, J=1.1Hz), 5.93 (1H, ddd, (CDCl3) δ: 2.46–2.55 (1H, m), 2.57–2.70 (2H, m), 2.74 (1H, dd,
J=17.2, 10.4, 5.7Hz), 7.30 (2H, d, J=8.7Hz), 7.37 (2H, d, J=11.4, 9.8Hz), 3.07–3.10 (1H, m), 3.16 (1H, ddd, J=11.4, 5.7,
J=8.7Hz). 13C-NMR (CDCl3) δ: 74.5, 114.2, 116.2, 128.3, 2.4Hz), 3.66 (2H, s), 3.79 (1H, dd, J=9.8, 5.7Hz), 7.15 (2H,
128.4, 133.5, 137.7, 138.6, 148.6. IR (film) cm−1: 1012, 1091, d, J=8.4Hz), 7.26–7.30 (3H, m), 7.32–7.38 (4H, m). 13C-NMR
1491, 3376. MS (ESI−) m/z: 193 (M−H+), 113 (base peak). (CDCl3) δ: 40.7, 53.4, 55.7, 59.6, 61.9, 127.5, 128.4, 128.5,
HR-MS (ESI−) m/z: Found 193.0415 (Calcd for C11H10ClO 128.9, 130.3, 133.1, 135.1, 137.8, 207.7. IR (film) cm−1: 1492,
(M−H+) 193.0420).
1717, 2806. MS (ESI+) m/z: 300 (M+H+, base peak). HR-MS
1-N-Benzyl-3-phenyl-4-piperidone (9a) Activated MnO2 (ESI+) m/z: Found 300.1171 (Calcd for C18H19ClNO (M+H+)
(4.00g, 46.0mmol) was added portionwise to a solution of 8a 300.1155).
(250mg, 1.56mmol) in CH2Cl2 (15mL). After being stirred
1-N-Benzyl-3-phenyl-4-hydroxyiminopiperidine
(10a)
at rt for 4h, the reaction mixture was filtered through Celite NaOAc (1.94g, 23.7mmol) and NH2OH–HCl (1.65g, 23.7
pad and evaporated. The resulting residue was used in the mmol) were added to a solution of 9a (630mg, 2.37mmol) in
subsequent reaction without further purification. Benzylamine EtOH–H2O 1:1 (20mL). After being stirred at reflux for 3h,
(212mg, 1.99mmol) was added to a solution of the residue in the reaction mixture was alkalized with saturated aqueous
CH3CN (10mL). After being irradiated to microwave (100°C Na2CO3 and extracted with CHCl3. The combined organic
for 1h), the reaction mixture was poured on H2O and extract- layer was dried over anhydrous Na2SO4 and evaporated to
ed with CHCl3. The combined organic layer was dried over yield 10a (650mg, 2.32mmol, 98%) as a brown oil and was
anhydrous Na2SO4 and evaporated. The resulting residue was used without further purification. 1H-NMR shows double
purified by chromatography on SiO2 (n-hexane–EtOAc=2:1) signal set (isomer A and B, ratio 2:1). All spectroscopic and
to yield 9a (310mg, 1.17mmol, 75% over two steps) as a light analytical data were consistent with the literature.13)
yellow oil. All spectroscopic and analytical data were consis-
1-N-Benzyl-4-hydroxyimino-3-(4-methylphenyl)piperidine
(10b)
tent with the literature.13)
1-N-Benzyl-3-(4-methylphenyl)-4-piperidone (9b)
Prepared According to Procedure for Preparation of 9a
Prepared According to Procedure for the Preparation of 10a
1
Yield: 99%, brown oil. H-NMR shows a doubled signal set
Yield: 70% over two steps, light yellow oil. 1H-NMR (isomer A and B, ratio 2:1). H-NMR (CDCl3) δ: 2.15–2.23
(CDCl3) δ: 2.32 (3H, s), 2.46–2.56 (1H, m), 2.62–2.71 (2H, m), (2H of isomer B, m), 2.31 (3H of isomer A, s), 2.32 (3H of
2.76 (1H, dd, J=11.4, 10.0Hz), 3.05–3.10 (1H, m), 3.17 (1H, isomer B, s), 2.40–2.54 (3H; 2H of isomer A, m, 1H of isomer
ddd, J=11.4, 5.7, 2.4Hz), 3.66 (2H, s), 3.78 (1H, dd, J=10.0, B, m), 2.71–2.80 (3H; 2H of isomer A, m, 1H of isomer B,
5.7Hz), 7.09–7.14 (4H, m), 7.26–7.29 (1H, m), 7.31–7.38 (4H, m), 2.84–2.96 (2H of isomer A, m), 3.04–3.08 (1H of isomer
m). 13C-NMR (CDCl3) δ: 21.1, 40.7, 53.5, 56.0, 59.8, 61.9, B, m), 3.32 (1H of isomer B, dt, J=12.0, 1.8Hz), 3.54 (2H of
127.3, 128.4, 128.7, 128.9, 129.1, 133.6, 136.8, 137.9, 208.4. isomer B, s), 3.56 (1H of isomer A, d, J=13.2Hz), 3.60 (1H
IR (film) cm−1: 1351, 1453, 1718, 2802. MS (ESI+) m/z: 280 of isomer A, d, J=13.2Hz), 3.64 (1H of isomer A, dd, J=8.4,
(M+H+, base peak). HR-MS (ESI+) m/z: Found 280.1724 4.7Hz), 4.64 (1H of isomer B, d, J=3.8Hz), 7.10 (2H of isomer
1

Vol. 64, No. 5 (2016)
Chem. Pharm. Bull.
425
B, d, J=8.0Hz), 7.11 (2H of isomer A, d, J=8.0Hz), 7.21 (2H (2H of isomer B, m), 2.39–2.45 (1H of isomer B, m), 2.53–2.61
of isomer A, d, J=8.0Hz), 7.27–7.36 (10H, 5H of isomer A, (2H of isomer A, m), 2.67–2.71(1H of isomer A, m), 2.76–2.86
m, 5H of isomer B, m), 7.45 (2H of isomer B, d, J=8.0Hz). (4H, 3H of isomer A, m, 1H of isomer B, m), 3.05–3.09 (1H
13C-NMR (CDCl3), (isomer A) δ: 21.0, 23.5, 46.6, 52.5, 58.9, of isomer B, m), 3.27 (1H of isomer B, dt, J=12.0, 1.7Hz),
62.6, 127.2, 128.3, 128.5, 128.9, 129.1, 136.0, 136.3, 137.9, 3.52 (1H of isomer B, d, J=12.9Hz), 3.57 (1H of isomer B,
159.7; (isomer B) δ: 21.0, 29.2, 37.5, 53.7, 56.1, 62.8, 127.2, d, J=12.9Hz), 3.58 (2H of isomer A, s), 3.64 (1H of isomer
128.2, 128.3, 128.9, 129.1, 135.8, 137.2, 138.2, 159.0. IR (film) A, dd, J=7.2, 5.0Hz), 4.63 (1H of isomer B, d, J=3.8Hz),
cm−1: 951, 1453, 1513, 3277. MS (ESI+) m/z: 295 (M+H+, 7.23–7.34 (16H, 9H of isomer A, m, 7H of isomer B, m), 7.51
base peak). HR-MS (ESI+) m/z: Found 295.1827 (Calcd for (2H of isomer B, d, J=8.4Hz). 13C-NMR (CDCl3), (isomer
C19H23N2O (M+H+) 295.1810).
1-N-Benzyl-4-hydroxyimino-3-(3-methylphenyl)piperidine 130.0, 132.5, 137.4, 137.6, 159.4; (isomer B) δ: 29.1. 37.3, 53.7,
A) δ: 23.4, 46.3, 52.4, 58.5, 62.6, 127.3, 128.3, 128.3, 129.2,
(10c)
55.9, 62.8, 127.3, 128.2, 128.3, 129.1, 129.9, 132.1, 138.0, 138.8,
Prepared According to Procedure for the Preparation of 10a 158.5. IR (film) cm−1: 1091, 1493, 3270. MS (ESI+) m/z: 315
Yield: 99%, brown oil. H-NMR shows a doubled signal set (M+H+, base peak). HR-MS (ESI+) m/z: Found 315.1252
1
(isomer A and B, ratio 2:1). H-NMR (CDCl3) δ: 2.20–2.25 (Calcd for C18H20ClN2O (M+H+) 315.1264).
1
(2H of isomer B, m), 2.32 (6H, 3H of isomer A, s, 3H of iso-
cis- and trans-4-Amino-1-N-benzyl-3-phenylpiperidine
mer B, s), 2.39 (1H of isomer A, dd, J=12.0, 4.4Hz), 2.47–2.61 (cis-, trans-11a) Pieces of sodium metal (1.30g, 56.5mmol)
(3H, 2H of isomer A, m, 1H of isomer B, m), 2.70–2.74 (1H of was added portionwise to a solution of 10a (200mg,
isomer A, m), 2.83–2.89 (3H, 2H of isomer A, m, 1H of iso- 0.71mmol) in EtOH (10mL). After being stirred at reflux for
mer B, m), 3.06–3.10 (1H of isomer B, m), 3.34 (1H of isomer 20h, the reaction mixture was cooled until rt and acidified
B, dt, J=12.0, 1.9Hz), 3.50 (1H of isomer B, d, J=13.0Hz), with 10% aqueous HCl and evaporated. The resulting residue
3.56 (1H of isomer A, d, J=13.3Hz), 3.60 (1H of isomer A, d, was alkalized with 1M aqueous NaOH and extracted with
J=13.3Hz), 3.61–3.65 (2H, 1H of isomer A, m, 1H of isomer CHCl3. The organic layer was dried over anhydrous Na2SO4
B, m), 4.64 (1H of isomer B, d, J=4.2Hz), 7.01–7.05 (2H, 1H and evaporated. The resulting residue was purified by chroma-
of isomer A, m, 1H of isomer B, m), 7.12–7.21 (5H, 2H of iso- tography on SiO2 (CHCl3–MeOH=10:1) to yield the primary
mer A, m, 3H of isomer B, m), 7.24–7.37 (11H, 6H of isomer amine (161mg, 0.61mmol, 85%, cis–trans=2:3) perspective
A, m, 5H of isomer B, m). 13C-NMR (CDCl3), (isomer A) δ: as a yellow oil. All spectroscopic and analytical data of cis-
1
21.4, 23.5, 46.9, 52.6, 58.7, 62.6, 125.7, 127.2, 127.5, 128.1, 11a were consistent with the literature.13) trans-11a: H-NMR
128.3, 128.7, 129.2, 137.8, 137.9, 138.9, 159.6; (isomer B) δ: (CDCl3) δ: 1.43 (2H, br), 1.58 (1H, dq, J=12.8, 4.2Hz), 1.95
21.5, 29.3, 37.8, 54.0, 55.8, 62.8, 125.4, 126.9, 127.1, 127.2, (1H, ddd, J=12.8, 6.9, 2.6Hz), 2.13 (1H, t, J=11.4Hz), 2.16
128.2, 129.0, 129.4, 137.7, 138.3, 140.0, 159.0. IR (film) cm−1: (1H, dt, J=12.0, 2.6Hz), 2.57 (1H, dt, J=10.8, 3.7Hz), 2.86
1454, 1716, 2924. MS (ESI+) m/z: 295 (M+H+, base peak). (1H, dt, J=10.8, 4.2Hz), 2.93 (1H, ddd, J=11.4, 3.7, 2.1Hz),
HR-MS (ESI+) m/z: Found 295.1784 (Calcd for C19H23N2O 2.96–3.02 (1H, m), 3.54 (2H, s), 7.21–7.25 (4H, m), 7.28–7.33
(M+H+) 295.1810).
(6H, m). 13C-NMR (CDCl3) δ: 34.6, 52.8, 53.0, 53.6, 59.8, 62.8,
1-N-Benzyl-3-(4-fluorophenyl)-4-hydroxyiminopiperidine 126.9, 127.0, 128.2, 128.2, 128.6, 129.1, 138.2, 141.6. IR (film)
(10d)
cm−1: 1450, 1500, 2920. MS (CI) m/z: 267 (M+H+, base peak).
Prepared According to Procedure for the Preparation of 10a HR-MS (CI) m/z: Found 267.1884 (Calcd for C18H23N2 (M+H+)
1
Yield: 95%, brown oil. H-NMR shows a doubled signal set 267.1861).
1
(isomer A and B, ratio 2:1). H-NMR (CDCl3) δ: 2.15–2.23
cis- and trans-4-Amino-1-N-benzyl-3-(4-methylphenyl)-
(2H of isomer B, m), 2.39–2.56 (4H, 2H of isomer A, m, 2H piperidine (cis-, trans-11b)
of isomer B, m), 2.68–2.80 (2H of isomer A, m), 2.82–2.88
(2H of isomer A, m), 3.04–3.08 (1H of isomer B, m), 3.25–3.28
Prepared According to Procedure for the Preparation of 11a
Yield: 56% (cis–trans=2:3). cis-11b: yellow oil. H-NMR
1
(1H of isomer B, m), 3.52 (1H of isomer B, d, J=13.0Hz), 3.56 (CDCl3) δ: 1.21 (2H, br), 1.66–1.73 (1H, m), 1.91–1.97 (1H,
(1H of isomer B, d, J=13.0Hz), 3.58 (2H of isomer A, s), 3.65 m), 2.31 (3H, s), 2.47–2.55 (2H, m), 2.68–2.77 (2H, m),
(1H of isomer A, dd, J=8.0, 4.6Hz), 4.61 (1H of isomer B, d, 3.02–3.06 (1H, m), 3.18–3.21 (1H, m), 3.54 (1H, d, J=13.1Hz),
J=3.9Hz), 6.93–6.99 (4H, 2H of isomer A, m, 2H of isomer B, 3.60 (1H, d, J=13.1Hz), 7.11 (2H, d, J=7.9 Hz), 7.19–7.24
m), 7.24–7.34 (12H, 7H of isomer A, m, 5H of isomer B, m), (3H, m), 7.28–7.36 (4H, m). 13C-NMR (CDCl3) δ: 20.9, 32.7,
7.54 (2H of isomer B, dd, J=8.5, 5.6Hz). 13C-NMR (CDCl3), 46.0, 48.7, 49.6, 52.5, 63.5, 126.9, 128.2, 128.3, 128.9, 129.1,
(isomer A) δ: 23.4, 46.0, 52.3, 58.6, 62.5, 114.9 (d, J=21.0Hz), 135.9, 138.5, 138.8. IR (film) cm−1: 810, 1453, 1513, 2919.
127.3, 128.3, 129.2, 130.1 (d, J=7.8Hz), 134.7 (d, J=3.3Hz), MS (ESI+) m/z: 281 (M+H+, base peak). HR-MS (ESI+)
137.3, 159.0, 161.6 (d, J=245.0Hz); (isomer B) δ: 29.0, 37.1, m/z: Found 281.2036 (Calcd for C19H25N2 (M+H+) 281.2018).
1
53.6, 56.0, 62.7, 114.8 (d, J=20.8Hz), 127.2, 128.2, 129.0, trans-11b: yellow oil. H-NMR (CDCl3) δ: 1.37 (2H, br), 1.56
130.0 (d, J=7.8Hz), 136.0 (d, J=3.0Hz), 138.0, 158.3, 161.4 (d, (1H, dq, J=12.7, 4.2Hz), 1.93 (1H, ddd, J=12.7, 6.9, 2.6Hz),
J=244.4Hz). IR (film) cm−1: 1509, 1601, 3277. MS (ESI+) m/z: 2.09 (1H, t, J=11.4Hz), 2.14 (1H, dt, J=12.0, 2.6Hz), 2.31
299 (M+H+, base peak). HR-MS (ESI+) m/z: Found 299.1581 (3H, s), 2.52 (1H, dt, J=10.8, 3.8Hz), 2.82 (1H, dt, J=10.8,
(Calcd for C18H20FN2O (M+H+) 299.1560).
4.2Hz), 2.90 (1H, ddd, J=11.4, 3.8, 2.1Hz), 2.95–3.00 (1H, m),
1-N-Benzyl-3-(4-chlorophenyl)-4-hydroxyiminopiperidine 3.53 (2H, s), 7.09–7.13 (4H, m), 7.20–7.31 (5H, m). 13C-NMR
(10e)
(100MHz, CDCl3) δ: 21.0, 34.6, 52.3, 53.0, 53.6, 60.0, 62.9,
Prepared According to Procedure for the Preparation of 10a 126.9, 128.0, 128.2, 129.1, 129.3, 136.4, 138.2, 138.5. IR (film)
1
Yield: 99%, brown oil. H-NMR shows a doubled signal set cm−1: 811, 1513, 2797, 2918. MS (ESI+) m/z: 281 (M+H+), 264
1
(isomer A and B, ratio 2:1). H-NMR (CDCl3) δ: 2.16–2.25 (base peak). HR-MS (ESI+) m/z: Found 281.2024 (Calcd for

426
Chem. Pharm. Bull.
Vol. 64, No. 5 (2016)
1
C19H25N2 (M+H+) 281.2018).
trans=4:1). cis-11e: yellow oil. H-NMR (CDCl3) δ: 1.39 (2H,
cis- and trans-4-Amino-1-N-benzyl-3-(3-methylphenyl)- br), 1.64–1.71 (1H, m), 1.87–1.93 (1H, m), 2.50–2.56 (2H, m),
piperidine (cis-, trans-11c) 2.66 (1H, dd, J=10.8, 2.9Hz), 2.78 (1H, t, J=9.8Hz), 3.01–3.05
Prepared According to Procedure for the Preparation of 11a (1H, m), 3.17–3.20 (1H, m), 3.55 (1H, d, J=13.1Hz), 3.59 (1H,
1
Yield: 72% (cis–trans=2:3). cis-11c: yellow oil. H-NMR d, J=13.1Hz), 7.22–7.36 (9H, m). 13C-NMR (CDCl3) δ: 32.5,
(CDCl3) δ: 1.31 (2H, br), 1.68–1.74 (1H, m), 1.93–1.99 (1H, m), 45.7, 49.0, 49.5, 52.7, 63.3, 126.9, 128.1, 128.2, 128.9, 129.9,
2.33 (3H, s), 2.50–2.58 (2H, m), 2.70–2.79 (2H, m), 3.03–3.07 132.0, 138.3, 140.1. IR (film) cm−1: 1090, 1491, 2808, 2933.
(1H, m), 3.20–3.23 (1H, m), 3.56 (1H, d, J=13.1Hz), 3.61 MS (ESI+) m/z: 301 (M+H+, base peak). HR-MS (ESI+) m/z:
(1H, d, J=13.1Hz), 7.03 (1H, d, J=7.4Hz), 7.10–7.12 (2H, Found 301.1472 (Calcd for C18H22ClN2 (M+H+) 301.1472).
1
m), 7.17–7.25 (2H, m), 7.29–7.37 (4H, m). 13C-NMR (CDCl3) trans-11e: yellow oil. H-NMR (CDCl3) δ: 1.46 (2H, br), 1.58
δ: 21.3, 32.5, 46.1, 48.4, 49.4, 52.3, 63.3, 125.2, 126.7, 126.9, (1H, dq, J=12.7, 4.2Hz), 1.93 (1H, ddd, J=12.7, 6.9, 2.6Hz),
127.9, 128.0, 128.9, 129.0, 137.5, 138.4, 141.7. IR (film) 2.08 (1H, t, J=11.4Hz), 2.15 (1H, dt, J=12.0, 2.6Hz), 2.55
cm−1: 699, 1453, 1492, 2918. MS (ESI+) m/z: 281 (M+H+, (1H, dt, J=10.8, 3.7Hz), 2.82 (1H, dt, J=10.8, 4.2Hz), 2.88
base peak). HR-MS (ESI+) m/z: Found 281.2000 (Calcd for (1H, ddd, J=11.4, 3.7, 2.1Hz), 2.96–3.00 (1H, m), 3.53 (2H, s),
1
C19H25N2 (M+H+) 281.2018). trans-11c: yellow oil. H-NMR 7.16 (2H, d, J=8.4Hz), 7.23–7.31 (7H, m). 13C-NMR (CDCl3)
(CDCl3) δ: 1.57 (1H, dq, J=12.7, 4.1Hz), 1.73 (2H, br), 1.93 δ: 34.6, 52.0, 52.9, 53.6, 59.7, 62.8, 127.0, 128.2, 128.7, 129.0,
(1H, ddd, J=12.7, 6.8, 2.6Hz), 2.10 (1H, t, J=11.4Hz), 2.14 129.5, 132.5, 138.1, 140.1. IR (film) cm−1: 1090, 1492, 2799,
(1H, dt, J=12.0, 2.6Hz), 2.31 (3H, s), 2.53 (1H, dt, J=10.8, 2932. MS (ESI+) m/z: 301 (M+H+, base peak). HR-MS (ESI+)
3.7Hz), 2.83 (1H, dt, J=10.8, 4.1Hz), 2.90 (1H, ddd, J=11.4, m/z: Found 301.1447 (Calcd for C18H22ClN2 (M+H+) 301.1472).
3.7, 2.1Hz), 2.94–2.99 (1H, m), 3.52 (2H, s), 6.99–7.03 (3H,
3-{N-Benzyl-N-[2-(3-chlorophenyl)-acetyl]-amino}-pro-
m), 7.18 (1H, t, J=7.8Hz), 7.21–7.24 (1H, m), 7.26–7.31 (4H, pionic Acid Ethyl Ester (14f) 3-Chlorophenylacetic acid
m). 13C-NMR (CDCl3) δ: 21.4, 34.3, 52.4, 52.9, 53.5, 59.7, (2.47g, 14.5mmol) and ethyl 3-(N-benzylamino)propionate
62.8, 125.1, 126.9, 127.5, 128.1, 128.4, 128.9, 129.0, 138.1, (3.00g, 14.5mmol) and DMAP (2.65g, 21.8mmol) were dis-
138.1, 141.3. IR (film) cm−1: 704, 1454, 2918. MS (ESI+) m/z: solved in CH2Cl2 (150mL) at 0°C under nitrogen atmosphere.
281 (M+H+), 264 (base peak). HR-MS (ESI+) m/z: Found After being stirred for 1h, EDC (3.31g, 17.4mmol) was
281.1982 (Calcd for C19H25N2 (M+H+) 281.2018).
added to the reaction mixture and stirred for 15h. The reac-
cis- and trans-4-Amino-1-N-benzyl-3-(4-fluorophenyl)- tion mixture was washed with saturated aqueous KHSO4 and
piperidine (cis-, trans-11d) dried over anhydrous Na2SO4 and evaporated. The resulting
Prepared According to Procedure for the Preparation of 11a residue was purified by chromatography on SiO2 (n-hexane–
1
Yield: 68% (cis–trans=1:1). cis-11d: yellow oil. H-NMR EtOAc=2:1) to yield 14f (5.18g, 14.4mmol, 99%) as a light
(CDCl3) δ: 1.65–1.71 (1H, m), 1.87–1.95 (1H, m), 2.51–2.57 yellow oil. The NMR spectra of 14f showed a mixture of
1
(2H, m), 2.66 (1H, dd, J=10.8, 3.0Hz), 2.77 (1H, t, J=9.6Hz), two rotamers. The ratio of two rotamers was 13:7. H-NMR
3.02–3.06 (1H, m), 3.16–3.20 (1H, m), 3.55 (1H, d, J=13.1Hz), (CDCl3) δ: 1.22 (3H of rotamer A, t, J=7.2Hz), 1.25 (3H of
3.59 (1H, d, J=13.1Hz), 6.97–7.01 (2H, m), 7.22–7.36 (7H, m). rotamer B, t, J=7.1Hz), 2.43 (2H of rotamer B, t, J=7.2Hz),
13C-NMR (CDCl3) δ: 32.3, 45.5, 49.7, 53.5, 56.7, 63.4, 115.0 2.64 (2H of rotamer A, t, J=6.9Hz), 3.56 (2H of rotamer B,
(d, J=11.1Hz), 127.1, 128.3, 129.1, 130.1, 137.3, 138.3, 161.6 t, J=7.2Hz), 3.64–3.68 (4H of rotamer A, m), 3.84 (2H of
(d, J=244.8Hz). IR (film) cm−1: 1222, 1509, 2933. MS (ESI+) rotamer B, s), 4.06–4.15 (4H, 2H of rotamer A, m, 2H of ro-
m/z: 285 (M+H+), 267 (base peak). HR-MS (ESI+) m/z: Found tamer B, m), 4.60 (2H of rotamer A, s), 4.62 (2H of rotamer
285.1770 (Calcd for C18H22FN2 (M+H+) 285.1767). trans-11d: B, s), 7.07–7.39 (18H, 9H of rotamer A, m, 9H of rotamer B,
1
yellow oil. H-NMR (CDCl3) δ: 1.59 (1H, dq, J=12.5, 4.1Hz), m). 13C-NMR (CDCl3) δ: 14.1, 32.6, 33.3, 40.2, 40.2, 42.8,
1.92–1.96 (1H, m), 2.06–2.18 (2H, m), 2.57 (1H, dt, J=10.8, 43.3, 48.1, 52.5, 60.5, 60.9, 126.1, 127.0, 127.0, 127.1, 127.4,
3.7Hz), 2.81 (1H, dt, J=10.8, 4.1Hz), 2.90 (1H, ddd, J=11.4, 127.7, 127.9, 128.6, 128.9, 128.9, 129.0, 129.7, 129.8, 134.3,
3.7, 2.1Hz), 2.97–3.00 (1H, m), 3.54 (2H, s), 6.97–7.02 (2H, 134.4, 136.5, 136.7, 136.9, 137.1, 170.4, 170.9, 171.9. IR (film)
m), 7.16–7.22 (2H, m), 7.23–7.31 (5H, m). 13C-NMR (CDCl3) cm−1: 1190, 1450, 1650, 1730. MS (ESI+) m/z: 382 (M+Na+,
δ: 34.4, 51.6, 52.9, 53.8, 59.9, 62.9, 115.6 (d, J=21.1Hz), 127.2, base peak). HR-MS (ESI+) m/z: Found 382.1234 (Calcd for
128.4, 129.2, 129.6 (d, J=7.7Hz), 137.2 (d, J=3.1Hz), 138.1, C20H22ClNNaO3 (M+Na+) 382.1186).
161.9 (d, J=244.9Hz). IR (film) cm−1: 1509, 1603, 2802, 2934.
3-{N-Benzyl-N-[2-(2-chlorophenyl)-acetyl]-amino}-
MS (ESI+) m/z: 285 (M+H+), 250 (base peak). HR-MS (ESI+) propionic Acid Ethyl Ester (14g)
m/z: Found 285.1775 (Calcd for C18H22FN2 (M+H+) 285.1767).
cis- and trans-4-Amino-1-N-benzyl-3-(4-chlorophenyl)-
Prepared According to Procedure for the Preparation of 14f
Yield: 99%. Light yellow oil. The NMR spectra of 14g
piperidine (cis-, trans-11e) To a stirred suspension of showed a mixture of two rotamers. The ratio of two rota-
1
LiAlH4 (281mg, 7.43mmol) in THF (20mL) was added drop- mer was 13:7. H-NMR (CDCl3) δ: 1.23 (3H of rotamer A,
wise a solution of 10e (778mg, 2.48mmol) in THF (10mL) t, J=7.1Hz), 1.25 (3H of rotamer B, t, J=7.2Hz), 2.53 (2H of
at rt under nitrogen atmosphere. After being stirred at reflux rotamer B, t, J=7.4Hz), 2.66 (2H of rotamer A, t, J=6.9Hz),
for 1.5h, the reaction mixture was quenched with H2O and 3.63 (2H of rotamer B, t, J=7.4Hz), 3.67 (2H of rotamer A, t,
filtrated through Celite pad and extracted with CHCl3. The J=6.9Hz), 3.80 (2H of rotamer A, s), 3.93 (2H of rotamer B,
residue was treated with THF and refluxed for 30min. After s), 4.07–4.16 (4H, 2H of rotamer A, m, 2H of rotamer B, m),
filtration, the combined organic layers were dried over an- 4.65 (2H of rotamer B, s), 4.66 (2H of rotamer A, s), 7.18–7.40
hydrous Na2SO4 and evaporated. The resulting residue was (18H, 9H of rotamer A, m, 9H of rotamer B, m). 13C-NMR
purified by chromatography on SiO2 (CHCl3–MeOH=10:1) (CDCl3) δ: 14.1, 32.6, 33.4, 38.0, 38.2, 42.8, 43.2, 48.4, 52.5,
to yield the primary amine (581mg, 1.94mmol, 78%, cis– 60.5, 60.9, 126.3, 126.9, 126.9, 127.4, 127.6, 128.0, 128.3,

Vol. 64, No. 5 (2016)
Chem. Pharm. Bull.
427
128.4, 128.5, 128.9, 129.3, 129.4, 130.9, 131.1, 133.3, 133.4, (9H, m). 13C-NMR (CDCl3) δ: 24.2, 42.6, 50.7, 51.8, 126.7,
134.0, 134.0, 136.6, 137.3, 170.1, 170.5, 170.9, 172.0. IR (film) 127.7, 128.3, 128.7, 128.9, 129.7, 132.6, 133.9, 134.0, 136.5,
cm−1: 1375, 1445, 1651, 1731. MS (ESI+) m/z: 360 (M+H+, 155.3, 167.8. IR (film) cm−1: 754, 1446, 1643, 3300. MS (ESI+)
base peak). HR-MS (ESI+) m/z: Found 360.1415 (Calcd for m/z: 329 (M+H+, base peak). HR-MS (ESI+) m/z: Found
C20H23ClNO3 (M+H+) 360.1367).
1-N-Benzyl-3-(3-chlorophenyl)-2,4-piperidinedione (15f)
329.1102 (Calcd for C18H18ClN2O2 (M+H+) 329.1057).
cis- and trans-4-Amino-1-N-benzyl-3-(3-chlorophenyl)-
To a stirred suspension of NaOEt (2.85g, 41.8mmol) in piperidine (cis-, trans-11f)
toluene (200mL) was slowly added a solution of 14f (5.00g,
13.9mmol) in toluene (40mL) at rt under nitrogen atmosphere.
Prepared According to Procedure for the Preparation of 11e
Yield: 30% over three steps (cis–trans=3:1). cis-11f: yel-
1
After being stirred at reflux for 4h, the reaction mixture was low oil. H-NMR (CDCl3) δ: 1.34 (2H, br), 1.65–1.72 (1H, m),
acidified with 1M aqueous HCl and extracted with EtOAc. The 1.89–1.94 (1H, m), 2.54–2.67 (3H, m), 2.79 (1H, t, J=9.9Hz),
combined organic layer was dried over anhydrous Na2SO4 and 3.02–3.06 (1H, m), 3.20–3.22 (1H, m), 3.57 (2H, s), 7.19–7.26
evaporated to give 15f and was used without further purifica- (4H, m), 7.30–7.37 (5H, m). 13C-NMR (CDCl3) δ: 18.4, 32.3,
tion. For measurement of spectroscopic data, 15f mixture was 46.0, 49.7, 57.6, 63.3, 126.6, 126.9, 127.0, 128.2, 128.9, 129.1,
purified by chromatography on SiO2 (n-hexane–EtOAc=2:3) 129.3, 134.0, 138.3, 143.7. IR (film) cm−1: 698, 1453, 1595,
1
to gain a colorless solid, mp 118–120°C. H-NMR (CDCl3) δ: 2931. MS (ESI+) m/z: 301 (M+H+, base peak). HR-MS (ESI+)
2.64–2.67 (2H, m), 3.45–3.56 (2H, m), 4.53 (1H, s), 4.72 (1H, m/z: Found 301.1506 (Calcd for C18H22ClN2 (M+H+) 301.1472).
1
d, J=14.5Hz), 4.79 (1H, d, J=14.5Hz), 7.07–7.09 (1H, m), trans-11f: yellow oil. H-NMR (CDCl3) δ: 1.54–1.63 (1H, m),
7.18–7.19 (1H, m), 7.28–7.40 (7H, m). 13C-NMR (CDCl3) δ: 1.94 (1H, ddd, J=12.9, 6.9, 2.6Hz), 2.10 (1H, t, J=11.4Hz),
37.7, 41.6, 50.7, 63.7, 127.1, 128.1, 128.2, 128.3, 128.6, 128.9, 2.16 (1H, dt, J=12.0, 2.6Hz), 2.56 (1H, dt, J=10.8, 3.8Hz),
130.0, 134.2, 134.7, 136.1, 167.0, 202.7. IR (KBr) cm−1: 1381, 2.84 (1H, dt, J=10.8, 4.2Hz), 2.90 (1H, ddd, J=11.4, 3.8,
1479, 1603, 1661. MS (ESI+) m/z: 314 (M+H+, base peak). 2.1Hz), 2.96–3.01 (1H, m), 3.54 (2H, s), 7.09–7.12 (1H, dt,
HR-MS (ESI+) m/z: Found 314.0976 (Calcd for C18H17ClNO2 J=6.9, 1.7Hz), 7.20–7.26 (4H, m), 7.28–7.31 (4H, m). 13C-NMR
(M+H+) 314.0948).
(CDCl3) δ: 34.5, 52.3, 52.9, 53.5, 59.5, 62.8, 126.5, 127.0,
1-N-Benzyl-3-(2-chlorophenyl)-2,4-piperidinedione (15g) 127.1, 128.1, 128.2, 129.1, 129.9, 134.4, 138.0, 143.7. IR (film)
Prepared According to Procedure for the Preparation of 15f cm−1: 698, 1453, 1595, 2932. MS (ESI+) m/z: 301 (M+H+,
Colorless solid, mp 163–166°C. 1H-NMR (CDCl3) δ: base peak). HR-MS (ESI+) m/z: Found 301.1505 (Calcd for
2.71–2.83 (2H, m), 3.48–3.55 (1H, m), 3.71 (1H, ddd, J=13.5, C18H22ClN2 (M+H+) 301.1472).
8.6, 5.1Hz), 4.61 (1H, d, J=14.6Hz), 4.65 (1H, s), 4.90 (1H,
cis- and trans-4-Amino-1-N-benzyl-3-(2-chlorophenyl)-
d, J=14.6Hz), 7.23–7.25 (1H, m), 7.29–7.39 (7H, m), 7.41–7.43 piperidine (cis-, trans-11g)
(1H, m). 13C-NMR (CDCl3) δ: 38.59, 41.71, 50.8, 62.9, 127.0,
Prepared According to Procedure for the Preparation of 11e
127.9, 128.4, 128.9, 129.4, 129.7, 132.3, 133.2, 133.8, 136.3,
Yield: 17% over three steps (cis–trans=3:2). cis-11g: yel-
1
166.5, 201.8. IR (KBr) cm−1: 1380, 1480, 1596, 1670. MS low oil. H-NMR (CDCl3) δ: 1.53 (2H, br), 1.59–1.69 (1H, m),
(ESI+) m/z: 314 (M+H+, base peak). HR-MS (ESI+) m/z: 1.96–2.00 (2H, m), 2.18 (1H, dt, J=12.0, 2.5Hz), 2.90–2.95
Found 314.0981 (Calcd for C18H17ClNO2 (M+H+) 314.0948).
(2H, m), 2.97–3.02 (1H, m), 3.27–3.29 (1H, m), 3.56 (2H, s),
1-N-Benzyl-3-(3-chlorophenyl)-4-hydroxyimino-2- 7.15 (1H, ddd, J=7.9, 6.9, 2.1Hz), 7.22–7.33 (7H, m), 7.37 (1H,
piperidone (16f)
dd, J=7.9, 1.1Hz). 13C-NMR (CDCl3) δ: 29.7, 32.3, 42.6, 48.6,
Prepared According to Procedure for the Preparation of 10a 51.8, 63.5, 126.5, 127.0, 127.5, 128.2, 129.1, 129.2, 129.7, 134.3,
1
Brown oil. H-NMR shows a doubled signal set (isomer A 138.3, 139.2. IR (film) cm−1: 749, 1473, 2925. MS (ESI+) m/z:
1
and B, ratio 4:1). H-NMR (CDCl3) δ: 2.56 (1H of isomer B, 301 (M+H+, base peak). HR-MS (ESI+) m/z: Found 301.1507
dt, J=15.0, 5.0Hz), 2.61–2.69 (2H, 1H of isomer A, dt, J=18.5, (Calcd for C18H22ClN2 (M+H+) 301.1472). trans-11g: yellow
1
4.5, 1H of isomer B, m), 2.81 (1H of isomer A, ddd, J=18.5, oil. H-NMR (CDCl3) δ: 1.59 (1H, dq, J=12.8, 4.2Hz), 1.95
9.5, 6.9Hz), 3.11–3.24 (2H of isomer A, m), 3.31 (1H of isomer (1H, ddd, J=12.8, 6.8, 2.7Hz), 2.10–2.20 (2H, m), 2.57 (1H,
B, ddd, J=12.4, 9.4, 5.0Hz), 3.41 (1H of isomer B, dt, J=12.4, dt, J=10.8, 3.7Hz), 2.86 (1H, dt, J=10.8, 4.2Hz), 2.93 (1H,
5.2Hz), 4.55 (1H of isomer B, d, J=14.5Hz), 4.62 (1H of iso- ddd, J=11.4, 3.7, 2.1Hz), 2.97–3.02 (1H, m), 3.54 (2H, s),
mer A, s), 4.68 (2H of isomer A, s), 4.83 (1H of isomer B, d, 7.21–7.33 (9H, m). 13C-NMR (CDCl3) δ: 34.6, 47.6, 52.8, 53.2,
J=14.5Hz), 5.33 (1H of isomer B, s), 7.16–7.19 (1H of isomer 58.7, 62.5, 127.0, 127.1, 127.7, 128.2, 128.3, 129.0, 129.3, 129.9,
A, m), 7.23–7.37 (17H, 8H of isomer A, m, 9H of isomer B, 138.1, 138.8. IR (film) cm−1: 753, 1474, 2927. MS (ESI+) m/z:
m). 13C-NMR (CDCl3), (isomer A) δ: 23.9, 42.1, 50.4, 53.2, 301 (M+H+, base peak). HR-MS (ESI+) m/z: Found 301.1511
125.5, 127.4, 127.8, 128.0, 128.2, 128.7, 130.0, 134.7, 136.2, (Calcd for C18H22ClN2 (M+H+) 301.1472).
136.9, 154.5, 169.0; (isomer B) δ: 26.9, 44.4, 47.4, 50.7, 126.3,
cis-1-N-Benzyl-4-N,N-dimethylamino-3-phenylpiperidine
127.5, 127.7, 128.1, 128.7, 128.7, 129.9, 134.4, 136.2, 138.0, (cis-17a) Thirty-seven percent HCHO (0.63mL, 7.50mmol,
153.4, 167.9. IR (film) cm−1: 972, 1485, 1635, 3215. MS (ESI+) in aqueous solution) and HCO2H (0.79mL, 15.0mmol) were
m/z: 351 (M+Na+, base peak). HR-MS (ESI+) m/z: Found added to cis-11a (200mg, 0.75mmol). After being stirred at
351.0900 (Calcd for C18H17ClN2NaO2 (M+Na+) 351.0876).
reflux for 24h, the reaction mixture was alkalized with 1
1-N-Benzyl-3-(2-chlorophenyl)-4-hydroxyimino-2- aqueous NaOH and extracted with CHCl3. The combined or-
piperidone (16g) ganic layer was dried over anhydrous Na2SO4 and evaporated
M
Prepared According to Procedure for the Preparation of 10a to yield cis-17a (205mg, 0.70mmol, 93%) as a brown oil and
Brown oil. 1H-NMR shows a single isomer. 1H-NMR was used without further purification. 1H-NMR (CDCl3) δ:
(CDCl3) δ: 2.87 (2H, t, J=6.0Hz), 3.39–3.54 (2H, m), 4.57 (1H, 1.68–1.72 (1H, m), 1.93–2.08 (2H, m), 2.11 (6H, s), 2.35–2.42
d, J=14.6Hz), 4.74 (1H, s), 4.84 (1H, d, J=14.6Hz), 7.20–7.42 (2H, m), 2.98 (1H, dt, J=11.4, 2.3Hz), 3.05–3.08 (1H, m),

428
Chem. Pharm. Bull.
Vol. 64, No. 5 (2016)
3.15 (1H, d, J=2.7Hz), 3.42 (1H, d, J=13.3Hz), 3.47 (1H, d, 132.0, 133.0, 138.1, 139.7. IR (film) cm−1: 1490, 2767, 2941.
J=13.3Hz), 7.18–7.22 (2H, m), 7.23–7.24 (1H, m), 7.25–7.30 MS (ESI+) m/z: 329 (M+H+, base peak). HR-MS (ESI+) m/z:
(5H, m), 7.77 (2H, d, J=7.2Hz). 13C-NMR (CDCl3) δ: 25.0, Found 329.1793 (Calcd for C20H26ClN2 (M+H+) 329.1785).
43.0, 43.7, 53.3, 59.1, 63.1, 66.6, 126.1, 126.8, 127.6, 128.1,
cis-1-N-Benzyl-3-(3-chlorophenyl)-4-N,N-dimethylamino-
128.8, 130.6, 138.9, 143.0. IR (film) cm−1: 1460, 1500, 2760, piperidine (cis-17f)
2940. MS (EI) m/z: 294 (M+H+), 91 (base peak). HR-MS (EI)
m/z: Found 294.2072 (Calcd for C20H26N2 (M+H+) 294.2096).
cis-1-N-Benzyl-4-N,N-dimethylamino-3-(4-methylphen-
yl)piperidine (cis-17b)
Prepared According to Procedure for the Preparation of
cis-17a
1
Yield: 97%. Brown oil. H-NMR (CDCl3) δ: 1.68–1.73 (1H,
m), 1.91 (1H, dq, J=12.4, 4.1Hz), 2.05–2.11 (1H, m), 2.13 (6H,
Prepared According to Procedure for the Preparation of s), 2.31–2.39 (2H, m), 2.93 (1H, dt, J=11.5, 2.3Hz), 3.07–3.11
cis-17a
(2H, m), 3.42 (1H, d, J=13.2Hz), 3.47 (1H, d, J=13.2Hz),
1
Yield: 99%. Brown oil. H-NMR (CDCl3) δ: 1.66–1.70 (1H, 7.19–7.33 (8H, m), 7.53–7.55 (1H, m). 13C-NMR (CDCl3) δ:
m), 1.94–2.07 (2H, m), 2.12 (6H, s), 2.28–2.36 (1H, m), 2.32 24.5, 42.9, 42.9, 53.1, 58.4, 62.8, 66.3, 126.1, 126.8, 128.0,
(3H, s), 2.39 (1H, dd, J=11.4, 3.4Hz), 2.97 (1H, d, J=11.4Hz), 128.5, 128.7, 128.7, 130.6, 133.2, 138.5, 144.8. IR (film) cm−1:
3.04 (1H, d, J=10.0Hz), 3.11 (1H, br), 3.39 (1H, d, J=13.2Hz), 698, 1473, 1595, 2769, 2940. MS (ESI+) m/z: 329 (M+H+,
3.48 (1H, d, J=13.2Hz), 7.10 (2H, d, J=7.8Hz), 7.18–7.28 (5H, base peak). HR-MS (ESI+) m/z: Found 329.1816 (Calcd for
m), 7.66 (2H, d, J=7.8Hz). 13C-NMR (CDCl3) δ: 21.0, 25.1, 43.2, C20H26ClN2 (M+H+) 329.1785).
43.3, 53.2, 59.3, 63.1, 66.7, 126.8, 128.1, 128.3, 128.8, 130.4,
cis-1-N-Benzyl-3-(2-chlorophenyl)-4-N,N-dimethylamino-
135.4, 138.9, 140.0. IR (film) cm−1: 1453, 1512, 2764, 2940. MS piperidine (cis-17g)
(ESI+) m/z: 309 (M+H+), 264 (base peak). HR-MS (ESI+) m/z:
Found 309.2351 (Calcd for C21H29N2 (M+H+) 309.2331).
cis-1-N-Benzyl-4-N,N-dimethylamino-3-(3-methylphen-
yl)piperidine (cis-17c)
Prepared According to Procedure for the Preparation of
cis-17a
Yield: 99%. Brown oil. 1H-NMR (CDCl3) δ: 1.84–1.88
(1H, m), 2.12 (6H, s), 2.13–2.19 (2H, m), 2.36–2.44 (2H, m),
Prepared According to Procedure for the Preparation of 2.86 (1H, dt, J=11.6, 2.6Hz), 3.00–3.01 (1H, m), 3.41 (1H,
cis-17a d, J=13.6Hz), 3.46 (1H, d, J=13.6Hz), 3.71–3.74 (1H, m),
1
Yield: 99%. Brown oil. H-NMR (CDCl3) δ: 1.68–1.72 (1H, 7.12–7.22 (7H, m), 7.25 (1H, dt, J=7.6, 1.5Hz), 7.32 (1H, dd,
m), 1.96–2.10 (2H, m), 2.12 (6H, s), 2.34–2.37 (1H, m), 2.36 J=7.9, 1.5Hz). 13C-NMR (CDCl3) δ: 22.1, 30.0, 38.0, 53.4,
(3H, s), 2.40 (1H, dd, J=11.4, 3.6Hz), 2.97 (1H, dt, J=11.4, 54.3, 58.5, 63.4, 126.3, 126.9, 127.2, 127.9, 128.2, 129.3, 129.5,
2.3Hz), 3.05–3.11 (2H, m), 3.41 (1H, d, J=13.2Hz), 3.47 134.7, 138.1, 139.8. IR (film) cm−1: 740, 1471, 2767, 2949. MS
(1H, d, J=13.2Hz), 7.03 (1H, d, J=7.5Hz), 7.15–7.23 (2H, (ESI+) m/z: 329 (M+H+, base peak). HR-MS (ESI+) m/z:
m), 7.25–7.33 (4H, m), 7.56 (1H, d, J=7.8Hz), 7.63 (1H, s). Found 329.1833 (Calcd for C20H26ClN2 (M+H+) 329.1785).
13C-NMR (CDCl3) δ: 21.5, 24.8, 43.0, 43.5, 53.1, 58.9, 62.9,
trans-1-N-Benzyl-4-N,N-dimethylamino-3-phenylpiper-
66.5, 126.6, 126.7, 127.2, 127.5, 127.9, 128.6, 131.2, 136.5, idine (trans-17a)
138.8, 142.7. IR (film) cm−1: 1453, 2765, 2940. MS (ESI+) m/z:
Prepared According to Procedure for the Preparation of
309 (M+H+), 264 (base peak). HR-MS (ESI+) m/z: Found cis-17a
309.2309 (Calcd for C21H29N2 (M+H+) 309.2331).
Yield: 92%. Brown oil. 1H-NMR (CDCl3) δ: 1.68 (1H,
cis-1-N-Benzyl-4-N,N-dimethylamino-3-(4-fluorophen- dq, J=12.1, 3.7Hz), 1.80–1.83 (1H, m), 1.96–2.12 (2H, m),
yl)piperidine (cis-17d)
Prepared According to Procedure for the Preparation of m), 3.02–3.05 (1H, m), 3.48 (1H, d, J=13.2Hz), 3.52 (1H, d,
cis-17a
J=13.2Hz), 7.18–7.23 (4H, m), 7.25–7.29 (6H, m). 13C-NMR
2.16 (6H, s), 2.75 (1H, dt, J=11.2, 2.8Hz), 2.90–2.99 (2H,
1
Yield: 97%. Brown oil. H-NMR (CDCl3) δ: 1.69–1.73 (1H, (CDCl3) δ: 22.9, 40.3, 46.6, 53.2, 62.1, 62.9, 64.9, 126.4, 127.0,
m), 1.91 (1H, dq, J=12.4, 4.1Hz), 2.07 (1H, dt, J=11.6, 2.9Hz), 127.9, 128.2, 128.3, 129.1, 138.1, 142.8. IR (film) cm−1: 1450,
2.12 (6H, s), 2.29–2.34 (1H, m), 2.37 (1H, dd, J=11.5, 3.6Hz), 2920. MS (CI) m/z: 295 (M+H+), 116 (base peak). HR-MS (CI)
2.94 (1H, dt, J=11.5, 2.3Hz), 3.05–3.10 (1H, m), 3.13 (1H, br), m/z: Found 295.2163 (Calcd for C20H27N2 (M+H+) 295.2174).
3.44 (2H, s), 6.95–6.99 (2H, m), 7.20–7.29 (5H, m), 7.73–7.77
trans-1-N-Benzyl-4-N,N-dimethylamino-3-(4-methylphen-
(2H, m). 13C-NMR (CDCl3) δ: 24.7, 42.7, 43.0, 53.4, 58.9, yl)piperidine (trans-17b)
63.0, 66.5, 114.2 (d, J=20.5Hz), 126.8, 128.1, 128.8, 131.9 (d,
Prepared According to Procedure for the Preparation of
J=7.4Hz), 138.5 (d, J=3.3Hz), 138.7, 161.5 (d, J=244.0Hz). cis-17a
1
IR (film) cm−1: 1453, 1507, 2767, 2940. MS (ESI+) m/z: 313
Yield: 99%. Brown oil. H-NMR (CDCl3) δ: 1.66 (1H, dq,
(M+H+), 250 (base peak). HR-MS (ESI+) m/z: Found 313.2112 J=12.4, 3.8Hz), 1.78–1.82 (1H, m), 2.00–2.06 (2H, m), 2.16
(Calcd for C20H26FN2 (M+H+) 313.2080).
(6H, s), 2.29 (3H, s), 2.72 (1H, dt, J=11.1, 3.3Hz), 2.88–2.95
cis-1-N-Benzyl-3-(4-chlorophenyl)-4-N,N-dimethylamino- (2H, m), 3.03 (1H, d, J=11.0Hz), 3.47 (1H, d, J=13.3Hz),
piperidine (cis-17e) 3.51 (1H, d, J=13.3Hz), 7.06–7.11 (4H, m), 7.19–7.28 (5H, m).
Prepared According to Procedure for the Preparation of 13C-NMR (CDCl3) δ: 21.1, 22.7, 40.3, 46.2, 53.2, 62.2, 62.9,
cis-17a
64.9, 126.9, 127.6, 128.1, 129.0, 129.1, 135.7, 138.1, 139.8. IR
1
Yield: 99%. Brown oil. H-NMR (CDCl3) δ: 1.75–1.78 (1H, (film) cm−1: 1038, 1453, 1514, 2776, 2935. MS (ESI+) m/z:
m), 2.02 (1H, dq, J=12.4, 4.0Hz), 2.14 (1H, dt, J=11.6, 2.5Hz), 309 (M+H+), 264 (base peak). HR-MS (ESI+) m/z: Found
2.23 (6H, s), 2.46 (1H, dd, J=11.6, 3.5Hz), 2.93–2.98 (2H, 309.2343 (Calcd for C21H29N2 (M+H+) 309.2331).
m), 3.14–3.17 (1H, m), 3.36 (1H, br), 3.47 (2H, s), 7.23–7.31
(7H, m), 7.85 (2H, d, J=8.5Hz). 13C-NMR (CDCl3) δ: 22.8,
41.2, 41.6, 52.7, 58.8, 62.8, 65.8, 127.1, 128.3, 128.3, 128.9,

Vol. 64, No. 5 (2016)
Chem. Pharm. Bull.
429
trans-1-N-Benzyl-4-N,N-dimethylamino-3-(3-methylphen-
yl)piperidine (trans-17c)
trans-1-Benzyl-3-(2-chlorophenyl)-4-N,N-dimethylamino-
piperidine (trans-17g)
Prepared According to Procedure for the Preparation of
cis-17a
Yield: 94%. Brown oil. H-NMR (CDCl3) δ: 1.68 (1H, dq,
Prepared According to Procedure for the Preparation of
cis-17a
Yield: 41%. Brown oil. H-NMR (CDCl3) δ: 1.72 (1H, dq,
1
1
J=12.4, 3.9Hz), 1.82 (1H, ddd, J=12.4, 6.3, 2.9Hz), 2.01–2.08 J=12.1, 3.9Hz), 1.82–1.92 (2H, m), 2.08 (1H, dt, J=11.4,
(2H, m), 2.17 (6H, s), 2.32 (3H, s), 2.76 (1H, dt, J=11.1, 3.9Hz), 2.7Hz), 2.18 (6H, s), 2.78–2.83 (1H, m), 2.94 (1H, ddd, J=11.3,
2.88–2.95 (2H, m), 3.02–3.05 (1H, m), 3.48 (1H, d, J=13.2Hz), 3.5, 2.1Hz), 3.05 (1H, ddd, J=11.4, 5.9, 3.1Hz), 3.51 (1H, d,
3.52 (1H, d, J=13.2Hz), 6.99–7.01 (3H, m), 7.16 (1H, t, J=13.3Hz), 3.56 (1H, d, J=13.3Hz), 3.56–3.59 (1H, m), 7.11
J=7.7Hz), 7.21–7.26 (1H, m), 7.29–7.30 (4H, m). 13C-NMR (1H, ddd, J=7.9, 7.2, 1.8Hz), 7.19–7.33 (8H, m). 13C-NMR
(CDCl3) δ: 21.5, 22.8, 40.4, 46.6, 53.3, 62.1, 62.9, 64.9, 124.9, (CDCl3) δ: 22.0, 40.3, 41.9, 52.9, 60.5, 62.5, 64.0, 126.6,
127.0, 127.3, 128.2, 128.2, 128.6, 129.1, 137.7, 138.2, 142.8. IR 126.9, 127.2, 128.1, 128.2, 128.9, 129.5, 134.1, 138.0, 139.5. IR
(film) cm−1: 1454, 2777, 2935. MS (ESI+) m/z: 309 (M+H+), (film) cm−1: 750, 1036, 1453, 2780, 2936. MS (ESI+) m/z: 329
264 (base peak). HR-MS (ESI+) m/z: Found 309.2313 (Calcd (M+H+), 284 (base peak). HR-MS (ESI+) m/z: Found 329.1833
for C21H29N2 (M+H+) 309.2331).
trans-1-Benzyl-4-N,N-dimethylamino-3-(4-fluorophen-
yl)piperidine (trans-17d)
(Calcd for C20H26ClN2 (M+H+) 329.1785).
cis-4-N,N-Dimethylamino-1-N-pentanoyl-3-phenylpiper-
idine (cis-4a) Pd–C (10mg, 10% (w/w)) and HCO2NH4
Prepared According to Procedure for the Preparation of (69mg, 1.09mmol) were added to a solution of cis-17a (50mg,
cis-17a 0.17mmol) in MeOH (3mL). After being stirred at reflux
1
Yield: 74%. Brown oil. H-NMR (CDCl3) δ: 1.66 (1H, dq, for 4h, the reaction mixture was filtrated through Celite pad
J=12.4, 4.0Hz), 1.82 (1H, ddd, J=12.4, 6.5, 3.0Hz), 1.98–2.07 and poured on H2O and extracted with CHCl3. The com-
(2H, m), 2.16 (6H, s), 2.69 (1H, dt, J=11.2, 3.8Hz), 2.87–2.97 bined organic layer was dried over anhydrous Na2SO4 and
(2H, m), 3.02–3.06 (1H, m), 3.48 (1H, d, J=13.1Hz), 3.52 (1H, evaporated. The resulting residue was used in the subsequent
d, J=13.1Hz), 6.94–6.98 (2H, m), 7.14–7.18 (2H, m), 7.23–7.33 reaction without further purification. Et3N (53µL, 0.60mmol)
(5H, m). 13C-NMR (CDCl3) δ: 22.6, 40.4, 46.1, 53.3, 62.3, 63.0, and BuCOCl (36µL, 0.30mmol) were added to a solution
65.2, 115.3 (d, J=21.1Hz), 127.2, 128.3, 129.2, 129.3, 138.2, of crude in CH2Cl2 (3mL). After being stirred at rt for 18h,
138.5 (d, J=3.3Hz), 161.5 (d, J=243.8Hz). IR (film) cm−1: the reaction mixture was alkalized with 1M aqueous NaOH
1453, 1509, 2779, 2935. MS (ESI+) m/z: 313 (M+H+), 268 and extracted with CHCl3. The combined organic layer was
(base peak). HR-MS (ESI+) m/z: Found 313.2124 (Calcd for dried over anhydrous Na2SO4 and evaporated. The resulting
C20H26FN2 (M+H+) 313.2080).
trans-1-N-Benzyl-3-(4-chlorophenyl)-4-N,N-dimethylamino- MeOH=10:1) to yield cis-4a (20mg, 0.07mmol, 41% over two
residue was purified by chromatography on SiO2 (CHCl3–
1
piperidine (trans-17e)
Prepared According to Procedure for the Preparation of t, J=6.9Hz), 1.18–1.27 (3H, m), 1.44 (1H, dd, J=13.3, 3.3Hz),
cis-17a 1.52–1.59 (3H, m), 1.75–1.90 (3H, m), 1.94 (6H, s), 2.24 (1H,
steps) as a light yellow oil. H-NMR (C6D6, 80°C) δ: 0.81 (3H,
1
Yield: 77%. Brown oil. H-NMR (CDCl3) δ: 1.66 (1H, dq, dt, J=11.7, 4.5Hz), 2.51–2.56 (1H, m), 2.88 (1H, m), 2.93 (1H,
J=12.4, 3.9Hz), 1.82 (1H, ddd, J=12.4, 6.4, 2.7Hz), 2.00 (1H, dd, J=13.4, 3.7Hz), 7.04 (1H, tt, J=7.4, 1.5Hz), 7.12 (2H, t,
t, J=11.0Hz), 2.04 (1H, dt, J=11.8, 2.7Hz), 2.16 (6H, s), 2.70 J=7.4Hz), 7.31–7.32 (2H, m). 13C-NMR (C6D6, 60°C) δ: 14.0,
(1H, dt, J=11.0, 3.8Hz), 2.86–2.96 (2H, m), 3.03–3.06 (1H, 22.7, 25.7, 27.5, 30.1, 32.6, 43.0, 59.8, 66.3, 78.1, 126.6, 128.2,
m), 3.48 (1H, d, J=13.4Hz), 3.52 (1H, d, J=13.4Hz), 7.13 130.0, 141.9, 171.0. IR (film) cm−1: 1050, 1450, 1640, 2960. MS
(2H, d, J=8.4Hz), 7.24 (2H, d, J=8.4Hz), 7.24–7.32 (5H, m). (EI) m/z: 288 (M+), 84 (base peak). HR-MS (EI) m/z: Found
13C-NMR (CDCl3) δ: 22.3, 40.3, 46.2, 53.2, 61.9, 62.9, 65.0, 288.2209 (Calcd for C18H28N2O (M+) 288.2201).
127.0, 128.2, 128.5, 129.1, 129.1, 131.9, 138.0, 141.3. IR (film)
cis-4-N,N-Dimethylamino-3-(4-methylphenyl)-1-N-
cm−1: 1091, 1492, 2780, 2936. MS (ESI+) m/z: 329 (M+H+, pentanoylpiperidine (cis-4b)
base peak). HR-MS (ESI+) m/z: Found 329.1818 (Calcd for
C20H26ClN2 (M+H+) 329.1785).
trans-1-N-Benzyl-3-(3-chlorophenyl)-4-N,N-dimethylamino-
piperidine (trans-17f)
Prepared According to Procedure for the Preparation of
cis-4a
Yield: 27% over two steps. Light yellow oil. 1H-NMR (C6D6,
80°C) δ: 0.81 (3H, t, J=6.9Hz), 1.22–1.36 (4H, m), 1.44–1.46
Prepared According to Procedure for the Preparation of (1H, m), 1.57–1.58 (2H, m), 1.80–1.90 (3H, m), 1.96 (6H, s),
cis-17a 2.10 (3H, s), 2.25–2.27 (1H, m), 2.53 (1H, br), 2.90–2.96 (2H,
1
Yield: 92%. Brown oil. H-NMR (CDCl3) δ: 1.66 (1H, dq, m), 6.96 (2H, d, J=7.8Hz), 7.24 (2H, d, J=7.8Hz). 13C-NMR
J=12.4, 3.8Hz), 1.82 (1H, ddd, J=12.4, 6.0, 2.9Hz), 1.99–2.08 (C6D6, 60°C) δ: 14.0, 20.9, 22.8, 25.5, 27.6, 30.2, 32.7, 42.9,
(2H, m), 2.17 (6H, s), 2.71 (1H, dt, J=11.3, 3.8Hz), 2.87–2.96 50.6, 66.4, 77.9, 129.1, 130.0, 136.0, 138.8, 171.1. IR (film)
(2H, m), 3.04 (1H, ddd, J=11.0, 6.0, 3.8Hz), 3.50 (2H, s), 7.08 cm−1: 1439, 1513, 1644, 2956. MS (ESI+) m/z: 303 (M+H+,
(1H, dt, J=7.3, 1.5Hz), 7.14–7.20 (4H, m), 7.22–7.31 (4H, m). base peak). HR-MS (ESI+) m/z: Found 303.2467 (Calcd for
13C-NMR (CDCl3) δ: 22.4, 40.3, 46.5, 53.1, 61.7, 62.8, 64.9, C19H31N2O (M+H+) 303.2436).
126.1, 126.6, 127.0, 127.9, 128.2, 129.1, 129.6, 134.0, 138.0,
cis-4-N,N-Dimethylamino-3-(3-methylphenyl)-1-N-
144.9. IR (film) cm−1: 698, 1453, 2781, 2935. MS (ESI+) m/z: pentanoylpiperidine (cis-4c)
329 (M+H+, base peak). HR-MS (ESI+) m/z: Found 329.1795
(Calcd for C20H26ClN2 (M+H+) 329.1785).
Prepared According to Procedure for the Preparation of
cis-4a
Yield: 26% over two steps. Light yellow oil. 1H-NMR
(C6D6, 80°C) δ: 0.81 (3H, t, J=7.3Hz), 1.18–1.26 (3H, m),

430
Chem. Pharm. Bull.
Vol. 64, No. 5 (2016)
1.44–1.60 (4H, m), 1.80–1.92 (3H, m), 1.97 (6H, s), 2.17 (3H, IR (film) cm−1: 1439, 1644, 2931. MS (ESI+) m/z: 303 (M+H+,
s), 2.24 (1H, dt, J=11.6, 4.5Hz), 2.55–2.58 (1H, m), 2.87 (1H, base peak). HR-MS (ESI+) m/z: Found 303.2413 (Calcd for
m), 2.97 (1H, dd, J=13.5, 3.7Hz), 6.89 (1H, d, J=7.6Hz), 7.06 C19H31N2O (M+H+) 303.2436).
(1H, t, J=7.9Hz), 7.16–7.21 (2H, m). 13C-NMR (C6D6, 60°C)
trans-4-N,N-Dimethylamino-3-(4-fluorophenyl)-1-N-
δ: 13.9, 21.5, 22.8, 25.7, 27.5, 30.1, 32.6, 43.0, 50.9, 66.4, 78.0, pentanoylpiperidine (trans-4d)
127.1, 127.4, 128.2, 130.8, 137.5, 141.9, 171.0. IR (film) cm−1:
Prepared According to Procedure for the Preparation of
1439, 1644, 2956. MS (ESI+) m/z: 303 (M+H+, base peak). cis-4a
HR-MS (ESI+) m/z: Found 303.2423 (Calcd for C19H31N2O
Yield: 76% over two steps. Light yellow oil. 1H-NMR
(C6D6, 80°C) δ: 0.89 (3H, t, J=7.3Hz), 1.14–1.23 (2H, m),
(M+H+) 303.2436).
cis-4-N,N-Dimethylamino-3-(4-fluorophenyl)-1-N- 1.31–1.40 (2H, m), 1.44–1.51 (2H, m), 1.68–1.75 (2H, m), 1.93
pentanoylpiperidine (cis-4d) (6H, s), 2.15 (2H, t, J=7.5Hz), 2.49–2.51 (4H, m), 6.80–6.88
Prepared According to Procedure for the Preparation of (4H, m). 13C-NMR (C6D6, 60°C) δ: 14.1, 22.9, 27.9, 33.0, 40.2,
cis-4a
40.3, 48.9, 52.8, 65.5, 78.5, 115.4 (d, J=21.0Hz), 129.7 (d,
Yield: 21% over two steps. Light yellow oil. 1H-NMR J=7.6Hz), 137.9 (d, J=3.2Hz), 162.1 (d, J=244.0Hz), 170.7.
(C6D6, 80°C) δ: 0.82 (3H, t, J=7.3Hz), 1.19–1.28 (2H, m), IR (film) cm−1: 1439, 1510, 1643, 2868, 2932. MS (ESI+) m/z:
1.37–1.41 (3H, m), 1.51–1.71 (4H, m), 1.92 (6H, s), 1.95–1.97 307 (M+H+), 160 (base peak). HR-MS (ESI+) m/z: Found
(1H, m), 2.14 (1H, dt, J=11.7, 4.5Hz), 2.46–2.52 (1H, m), 2.78 307.2218 (Calcd for C18H28FN2O (M+H+) 307.2186).
(1H, br), 2.84 (1H, dd, J=13.5, 3.4Hz), 6.80 (2H, t, J=8.7Hz),
cis-3-(4-Chlorophenyl)-4-N,N-dimethylamino-1-N-
7.19 (2H, br). 13C-NMR (C6D6, 60°C) δ: 14.0, 22.8, 25.4, 27.6, pentanoylpiperidine (cis-4e) 1-Chloroethyl chloroformate
30.2, 32.7, 42.9, 50.7, 66.4, 77.8, 115.0 (d, J=20.6Hz), 131.5 (d, (75 µL, 0.69mmol) was added to a solution of cis-17e in
J=7.4Hz), 137.4, 162.2 (d, J=245.0Hz), 171.1. IR (film) cm−1: CH2Cl2 (4mL). After being stirred at rt for 2h, the reac-
1439, 1509, 1643, 2769, 2932. MS (ESI+) m/z: 307 (M+H+, tion mixture was evaporated and alkalized with 1M aqueous
base peak). HR-MS (ESI+) m/z: Found 307.2219 (Calcd for NaOH and extracted with CHCl3. The combined organic
C18H28FN2O (M+H+) 307.2186).
layer was dried over anhydrous Na2SO4 and evaporated.
trans-4-N,N-Dimethylamino-1-N-pentanoyl-3-phenylpiper- The resulting residue was briefly purified by chromatogra-
idine (trans-4a) phy on SiO2 (CHCl3–MeOH=40:1) to give brown oil. The
Prepared According to Procedure for the Preparation of oil was dissolved in methanol (15mL) and stirred at reflux
cis-4a
for 1h. The reaction mixture was evaporated, the resulting
Yield: 43% over two steps. Light yellow oil. 1H-NMR residue was used in the subsequent reaction without further
(C6D6, 80°C) δ: 0.88 (3H, t, J=7.4Hz), 1.21–1.39 (5H, m), 1.52 purification. Et3N (0.18mL, 1.26mmol) and BuCOCl (76µL,
(1H, ddd, J=12.8, 6.1, 2.9Hz), 1.67–1.75 (2H, m), 1.96 (6H, s), 0.63mmol) were added to a solution of the residue in CH2Cl2
2.12–2.17 (2H, m), 2.44 (1H, br), 2.59–2.67 (3H, m), 7.04–7.07 (3mL). After being stirred at rt for 24h, the reaction mixture
(3H, m), 7.14–7.18 (2H, m). 13C-NMR (C6D6, 60°C) δ: 14.0, was alkalized with 1M aqueous NaOH and extracted with
22.9, 27.8, 30.1, 32.9, 40.1, 48.1, 53.1, 65.5, 77.7, 126.8, 128.1, CHCl3. The combined organic layer was dried over anhydrous
128.6, 142.1, 170.4. IR (film) cm−1: 1060, 1440, 1640, 2930. Na2SO4 and evaporated. The resulting residue was purified
MS (EI) m/z: 288 (M+), 104 (base peak). HR-MS (EI) m/z: by chromatography on SiO2 (CHCl3–MeOH=10:1) to yield
Found 288.2183 (Calcd for C18H28N2O (M+) 288.2201).
trans-4-N,N-Dimethylamino-3-(4-methylphenyl)-1-N- low oil. 1H-NMR (C6D6, 80°C) δ: 0.82 (3H, t, J=7.2Hz),
pentanoylpiperidine (trans-4b) 1.20–1.35 (5H, m), 1.50–1.62 (4H, m), 1.89 (6H, s), 1.95–1.96
Prepared According to Procedure for the Preparation of (1H, m), 2.20 (1H, br), 2.47 (1H, br), 2.81 (2H, br), 7.10 (2H,
cis-4e (30mg, 0.09mmol, 15% over three steps) as light yel-
cis-4a
d, J=8.2Hz), 7.14 (2H, br). 13C-NMR (C6D6, 60°C) δ: 13.9,
Yield: 20% over two steps. Light yellow oil. 1H-NMR 22.7, 24.9, 27.5, 30.1, 32.7, 42.6, 50.6, 66.2, 77.7, 128.5, 131.4,
(C6D6, 80°C) δ: 0.89 (3H, t, J=7.4Hz), 1.23–1.39 (5H, m), 132.9, 139.9, 171.1. IR (film) cm−1: 1093, 1445, 1643, 2957.
1.54–1.57 (1H, m), 1.68–1.75 (2H, m), 1.99 (6H, s), 2.14 (3H, s), MS (ESI+) m/z: 323 (M+H+, base peak). HR-MS (ESI+) m/z:
2.14–2.18 (2H, m), 2.46 (1H, br), 2.57–2.68 (3H, m), 6.99 (4H, Found 323.1925 (Calcd for C18H28ClN2O (M+H+) 323.1890).
br). 13C-NMR (C6D6, 60°C) δ: 14.0, 20.9, 22.9, 27.9, 30.1, 33.0,
cis-3-(3-Chlorophenyl)-4-N,N-dimethyl-1-N-pentanoyl-
40.2, 47.5, 52.8, 65.6, 77.6, 127.9, 129.4, 136.1, 139.1, 170.4. IR piperidine (cis-4f)
(film) cm−1: 1438, 1645, 2929. MS (ESI+) m/z: 303 (M+H+,
Prepared According to Procedure for the Preparation of
base peak). HR-MS (ESI+) m/z: Found 303.2451 (Calcd for cis-4e
1
C19H31N2O (M+H+) 303.2436).
Yield: 27% over three steps. Light yellow oil. H-NMR
trans-4-N,N-Dimethylamino-3-(3-methylphenyl)-1-N- (C6D6, 80°C) δ: 0.83 (3H, t, J=7.3Hz), 1.15–1.48 (4H, m),
pentanoylpiperidine (trans-4c) 1.57–1.63 (3H, m), 1.89 (6H, s), 1.90–1.94 (3H, m), 2.11 (1H,
Prepared According to Procedure for the Preparation of dt, J=11.6, 4.5Hz), 2.45–2.51 (1H, m), 2.74–2.81 (2H, m), 6.87
cis-4a
(1H, t, J=7.9Hz), 7.02–7.05 (1H, m), 7.20–7.22 (1H, m), 7.45
Yield: 63% over two steps. Light yellow oil. 1H-NMR (1H, s). 13C-NMR (C6D6, 60°C) δ: 13.9, 22.8, 27.5, 30.1, 32.7,
(C6D6, 80°C) δ: 0.88 (3H, t, J=7.3Hz), 1.16–1.39 (5H, m), 1.54 33.8, 42.8, 53.5, 66.3, 77.6, 126.9, 129.2, 129.4, 130.3, 134.3,
(1H, ddd, J=12.9, 6.2, 3.1Hz), 1.68–1.75 (2H, m), 1.99 (6H, 143.8, 171.1. IR (film) cm−1: 1435, 1643, 2956. MS (ESI+) m/z:
s), 2.14–2.16 (2H, m), 2.17 (3H, s), 2.46 (1H, br), 2.57–2.70 323 (M+H+, base peak). HR-MS (ESI+) m/z: Found 323.1935
(3H, m), 6.89–6.94 (3H, m), 7.11 (1H, t, J=7.5Hz). 13C-NMR (Calcd for C18H28ClN2O (M+H+) 323.1890).
(C6D6, 60°C) δ: 14.0, 21.5, 22.8, 27.9, 30.0, 33.0, 40.2, 45.1,
52.9, 65.5, 78.3, 125.2, 127.6, 128.5, 129.0, 137.9, 142.1, 170.5.

Vol. 64, No. 5 (2016)
Chem. Pharm. Bull.
431
cis-3-(2-Chlorophenyl)-4-N,N-dimethyl-1-N-pentanoyl- mice (Tokyo Laboratory Animals Science, Tokyo, Japan)
piperidine (cis-4g) weighing approximately 25–35g (5–6 weeks old). Mice had
Prepared According to Procedure for the Preparation of free access to food and water in an animal room that was
cis-4e maintained at 24 1°C with a 12h light–dark cycle (lights on
1
Yield: 25% over three steps. Light yellow oil. H-NMR 8:00a.m.). Each mouse was injected i.p. with 0.7% acetic acid
(C6D6, 80°C) δ: 0.76 (3H, t, J=7.3Hz), 1.13–1.18 (2H, m), in a volume of 10mL/kg 30min after administration of the
1.31–1.55 (5H, m), 1.82–1.91 (3H, m), 2.03 (6H, s), 2.28 (1H, test drug dissolved in saline. After 10min mice were observed
br), 2.54 (1H, m), 3.02–3.05 (1H, m), 3.61 (1H, dd, J=8.6, for an additional 10min during which abdominal contractions
3.7Hz), 6.78 (1H, dt, J=7.7, 1.5Hz), 6.86 (1H, dt, J=7.8, were counted. The % antinociception was calculated from the
1.3Hz), 7.21 (1H, dd, J=7.8, 1.5Hz), 7.53 (1H, d, J=7.7Hz). mean number of contractions in each test group and control
13C-NMR (C6D6, 60°C) δ: 13.9, 22.8, 27.2, 27.5, 30.2, 39.8, group (% antinociception=[(mean control responses−test re-
43.2, 49.3, 65.2, 77.7, 126.4, 127.9, 129.9, 131.9, 134.6, 138.9, sponses)/(mean control responses)]×100). ED50 values for each
170.8. IR (film) cm−1: 1037, 1440, 1650, 2957. MS (ESI+) m/z: compound were determined by linear regression techniques.
323 (M+H+, base peak). HR-MS (ESI+) m/z: Found 323.1936 The statistical significance of differences between groups was
(Calcd for C18H28ClN2O (M+H+) 323.1890).
assessed with analysis of variance followed by the Bonfer-
trans-3-(4-Chlorophenyl)-4-N,N-dimethylamino-1-N- roni–Dunnett test.
pentanoylpiperidine (trans-4e)
Prepared According to Procedure for the Preparation of
cis-4e
Yield: 13% over three steps. Light yellow oil. H-NMR sities, 2014–2018 (Grant No. S1411019).
Acknowledgment This work was MEXT-Supported Pro-
gram for the Strategic Research Foundation at Private Univer-
1
(C6D6, 80°C) δ: 0.89 (3H, t, J=7.5Hz), 1.31–1.40 (5H, m),
1.43–1.49 (1H, m), 1.68–1.75 (2H, m), 1.92 (6H, s), 2.15 (2H, t,
J=7.5Hz), 2.43–2.49 (4H, m), 6.80 (2H, d, J=8.5Hz), 7.12 (2H, interest.
d, J=8.5Hz). 13C-NMR (C6D6, 60°C) δ: 14.0, 22.9, 27.8, 30.1,
Conflict of Interest The authors declare no conflict of
32.9, 40.0, 46.6, 51.6, 65.5, 77.7, 128.8, 129.5, 132.6, 140.5,
170.4. IR (film) cm−1: 1189, 1454, 1643, 2956. MS (ESI+) m/z:
323 (M+H+, base peak). HR-MS (ESI+) m/z: Found 323.1937
(Calcd for C18H28ClN2O (M+H+) 323.1890).
trans-3-(3-Chlorophenyl)-4-N,N-dimethyl-1-N-pentanoyl-
piperidine (trans-4f)
References
1) Xiao P., Kubo H., Ohsawa M., Higashiyama K., Nagase H., Yan
Y.-N., Li J.-S., Kamei J., Ohmiya S., Planta Med., 65, 230–233
(1999).
2) Kamei J., Xiao P., Ohsawa M., Kubo H., Higashiyama K., Taka-
hashi H., Li J.-S., Nagase H., Ohmiya S., Eur. J. Pharmacol., 337,
223–226 (1997).
3) Piercey M. F., Varner K., Schroeder L. A., Eur. J. Pharmacol., 80,
283–284 (1982).
4) Lahti R. A., VonVoigtlander P. F., Barsuhn C., Life Sci., 31, 2257–
2260 (1982).
5) Piercey M. F., Lahti R. A., Schroeder L. A., Einspahr F. J., Barsuhn
C., Life Sci., 31, 1197–1200 (1982).
6) Seki T., Awamura S., Kimura C., Ide S., Sakano K., Minami M.,
Nagase H., Satoh M., Eur. J. Pharmacol., 376, 159–167 (1999).
7) Millan M. J., Trends Pharmacol. Sci., 11, 70–76 (1990).
8) Endoh T., Matsuura H., Tajima A., Izumimoto N., Tajima C., Su-
zuki T., Saitoh A., Suzuki T., Narita M., Tseng L., Nagase H., Life
Sci., 65, 1685–1694 (1999).
9) Kobashi S., Kubo H., Yamauchi T., Higashiyama K., Biol. Pharm.
Bull., 25, 1030–1034 (2002).
10) Kobashi S., Takizawa M., Kubo H., Yamauchi T., Higashiyama K.,
Biol. Pharm. Bull., 26, 375–379 (2003).
Prepared According to Procedure for the Preparation of
cis-4e
1
Yield: 18% over three steps. Light yellow oil. H-NMR
(C6D6, 80°C) δ: 0.89 (3H, t, J=7.4Hz), 1.14–1.19 (1H, m),
1.30–1.47 (5H, m), 1.66–1.74 (2H, m), 1.90 (6H, s), 2.13 (2H, t,
J=7.4Hz), 2.40–2.51 (4H, m), 6.81 (1H, d, J=7.7Hz), 6.89 (1H,
t, J=7.7Hz), 7.04 (1H, d, J=7.7Hz), 7.16 (1H, s). 13C-NMR
(C6D6, 60°C) δ: 14.0, 22.9, 27.8, 30.1, 32.9, 40.0, 46.2, 50.9,
65.4, 77.7, 118.9, 126.4, 127.1, 129.9, 134.7, 144.3, 170.5. IR
(film) cm−1: 1454, 1643, 2957. MS (ESI+) m/z: 323 (M+H+,
base peak). HR-MS (ESI+) m/z: Found 323.1902 (Calcd for
C18H28ClN2O (M+H+) 323.1890).
trans-3-(2-Chlorophenyl)-4-N,N-dimethyl-1-N-pentanoyl-
piperidine (trans-4g)
Prepared According to Procedure for the Preparation of
cis-4e
11) Kobashi S., Kubo H., Yamauchi T., Higashiyama K., Yakugaku
Zasshi, 123, 337–347 (2003).
1
Yield: 12% over three steps. Light yellow oil. H-NMR
12) Topliss J. G., J. Med. Chem., 15, 1006–1011 (1972).
13) Rosiak A., Hoenke C., Christoffers J., Eur. J. Org. Chem., 2007,
4376–4382 (2007).
14) Schramm H., Christoffers J., Tetrahedron Asymmetry, 20, 2724–
2727 (2009).
15) Hanessian S., Sailes H., Munro A., Therrien E., J. Org. Chem., 68,
7219–7233 (2003).
16) Yang B. V., O’Rourke D., Li J., Synlett, 1993, 195–196 (1993).
17) Addie M. S., Taylor R. K., ARKIVOC, 5, 660–666 (2000).
18) Yang M.-H., Matikonda S. S., Altman R. A., Org. Lett., 15, 3894–
3897 (2013).
(C6D6, 80°C) δ: 0.89 (3H, t, J=7.4Hz), 1.24–1.40 (5H, m), 1.52
(1H, ddd, J=12.9, 6.4, 2.9Hz), 1.70–1.78 (2H, m), 1.97 (6H,
s), 2.14–2.22 (1H, m), 2.27–2.36 (2H, m), 2.49 (1H, m), 2.71
(1H, dt, J=11.1, 3.5Hz), 3.32 (1H, dt, J=10.9, 4.2Hz), 6.79 (1H,
dt, J=7.6, 1.7Hz), 6.96 (1H, dt, J=7.6, 1.2Hz), 7.02 (1H, dd,
J=7.9, 1.7Hz), 7.20 (1H, dd, J=7.9, 1.2Hz). 13C-NMR (C6D6,
60°C) δ: 14.0, 22.9, 27.8, 30.1, 33.0, 40.1, 44.0, 51.6, 64.5,
77.7, 126.9, 127.9, 128.9, 130.0, 134.6, 138.9, 170.6. IR (film)
cm−1: 1035, 1438, 1644, 2931. MS (ESI+) m/z: 323 (M+H+,
base peak). HR-MS (ESI+) m/z: Found 323.1934 (Calcd for
C18H28ClN2O (M+H+) 323.1890).
19) Rosiak A., Frey W., Christoffers J., Eur. J. Org. Chem., 2006,
4044–4054 (2006).
Acetic Acid-Induced Abdominal Contraction Assay
(Writhing Test)1,2) Evaluation for antinociceptive effects
were carried out by acetic acid writhing test using male ICR