Synthesis of (3-N-substituted-piperidin-4-ylidene)acetic acid ethyl esters

Article abstract of DOI:10.1002/jccs.201100619

A convenient preparation of skeletons 2Aand 2B (cyclic γ,δ- diamino-α,β-unsaturated esters) is reported by a three-step synthetic route based on a sequence of NBS-mediated one-pot α-bromination/Wittig olefination of piperidin-4-one 3, nucleophilic additio

Full text of DOI:10.1002/jccs.201100619

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of (3-N-substituted-piperidin-4-ylidene)acetic Acid Ethyl Esters
Meng-Yang Chang* and Tein-Wei Lee
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
(Received: Oct. 21, 2011; Accepted: Jan. 2, 2012; Published Online: ??; DOI: 10.1002/jccs.201100619)
A convenient preparation of skeletons 2A and 2B (cyclic g,d-diamino-a,b-unsaturated esters) is reported
by a three-step synthetic route based on a sequence of NBS-mediated one-pot a-bromination/Wittig
olefination of piperidin-4-one 3, nucleophilic addition with NaN3, and followed by PPh3-promoted
Staudinger reduction/substitution or CuI-catalyzed Huisgen 1,3-dipolar cycloaddition.
Keywords: Piperidines; a-Bromination; Staudinger reaction; Huisgen 1,3-dipolar cycloaddition.
INTRODUCTION
Substituted piperidine is a leading structural motif
sis of dienylamine,3a,4a,6a organometallic,6b Lewis acid-me-
diated4c or NaN3-promoted addition of aziridines,7 the
Overman rearrangement of an allylic trichloroacetimi-
date,4b and hydrogenation of functionalized 3-aminopyri-
dine.3c While their derivatives with this specific substitu-
tion pattern have been developed in several synthetic steps,
the new and shorter-step method for their preparation is
needed.
that serves as a crucial building block for numerous synthe-
ses of nitrogen heterocycles. The related progress on the
preparation of functionalized piperidine has been previ-
ously reviewed.1 In our previous work on the preparation
of substituted piperidine building blocks,2 a substitute,
aminopiperidine, was chosen as the key focus. 3-Amino-
4-alkylpiperidines have attracted increasing interest as
synthetic targets due to their important activity as phar-
macophores in several biologically active compounds.3,4,5
For example, 4-methyl-3-N-substituted-piperidine is a nu-
cleus of CP-690550 (1a), a potent and selective Janus
kinase 3 (Jak3a) inhibitor for autoimmune disease and
transplant patients,3a and 4-ethyl-3-aminopiperidinyl quin-
olone 1b is 32-fold more active against S. aureus (MRCR)
than gatifloxacin.4a Some factor Xa5a inhibitors and the CC
chemokine receptor 2 (CCR2)5b antagonists contain such
type of motifs (Fig. 1).
RESULTS AND DISCUSSION
Herein, an easy and rapid synthetic strategy was in-
vestigated for preparing a series of (3-N-substituted-piperi-
din-4-ylidene)acetic acid ethyl esters 2A and 2B. These
3-amino substituents include alkylamide, arylamide, al-
kenylamide, sulfonamide, carbamate, and triazole. Scheme
I shows a convenient three-step synthesis of skeletons 2A
and 2B from ketone 3. It involves (i) a one-pot synthesis of
a motif bearing a-bromo and a,b-unsaturated ester func-
According to the literature reports,6,7 fewer general
synthetic strategies are available for preparing the struc-
tural framework of 3-N-substituted-4-alkylpiperidine. In
general, these limited articles use the ring-closing metathe-
A three-step synthetic approach to the skel-
Scheme I
etons 2A and 2B
Fig. 1. Structures of 3-amino-4-alkylpiperidinyl com-
pounds.
* Corresponding author. Tel: +886-7-3121101 ext 2220; Fax: +886-7-3125339; E-mail: mychang@kmu.edu.tw
J. Chin. Chem. Soc. 2012, 59, 000-000
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1

Article
Chang and Lee
Scheme III Nucleophilic substitution of compound 4
tionalities by a-brominating ketone 3 with NBS in HOAc,
followed by Wittig olefination; (ii) C-3 nucleophilic substi-
tution with NaN3; and (iii) Staudinger reaction of the re-
sulting azide with PPh3, followed by N-substitution with
acyl and sulfonyl chloride or isocyanate derivatives or
Huisgen 1,3-dipolar cycloaddition reaction with different
alkynes.
In previous studies (see Scheme II), we explored the
synthetic application of N-benzenesulfonylpiperidin-4-one
3 to generate the structural framework of piperidin-3-ol 3A
with 4,4-dialkoxy groups8a and piperidine 3B with 3,4-di-
aminobenzene (quinoxaline).8b Herein, a synthetic ap-
proach to 2A and 2B with the skeleton of 3-amino-4-al-
kenyl piperidine from the piperidin-4-one 3 was further
studied.
longed reaction time, elevated temperature, different sol-
vents). Changing the nucleophile to sodium toluenesulfinic
salt (for f), the reaction mixture 5f with exo- and endo-
olefinic isomers (1:1 ratio) was isolated in a 45% yield via
SN2 type substitution reaction and followed by olefinic mi-
gration. It was inferred that stronger nucleophile could not
be easily introduced into the C-3 position of compound 4
via an intermolecular nucleophilic substitution.
Synthetic application toward piperidin-4-
Scheme II
one 3
Furthermore, a convenient synthesis of skeleton 2A
was achieved via a one-pot transformation of Staudinger
reduction9 with PPh3 followed by acylation or sulfonyla-
tion reaction with Et3N. Six commercially available materi-
als (a, acetyl chloride; b, benzoyl chloride; c, 3-methoxy-
benzoyl chloride; d, cinnamoyl chloride; e, methanesul-
fonyl chloride; f, phenylisocyanate) were examined in the
preparation of skeleton 2A. After changing the substituent,
six compounds 2Aa~2Af were provided in 74~86% yields,
as shown in Scheme IV. The distribution yields of the iso-
lated products with different N-substituents were similar to
the one-pot facile PPh3-promoted Staudinger reduction/
First, treatment of compound 3 with NBS in HOAc,
followed by Wittig olefination with Ph3P=CHCO2Et was
examined in a one-pot reaction. As shown in Scheme III,
the formations of a g-bromo group and an a,b-unsaturated
acetate group on the C-3 and C-4 position of piperidinyl
skeleton 4 with an E-geometric conformation were easily
generated from ketone 3 in a 65% yield of two-steps via a
one-pot transformation. Based on the results, nucleophilic
substitition of compound 4, with different nucleophile, was
next investigated. Initially, the treatment of compound 4
with NaN3 (for a) in acetone isolated compound 5a with a
76% yield.
Scheme IV Synthesis of compounds 2A and 2B
When compound 4 was, respectively, subjected to
different nucleophile (b, NaCN; c, NaOEt), the starting ma-
terial 4 was recovered and the expected 3-S-substituted
piperidine 5d or 5e was generated at a low yield (d, NaSPh,
11%; e, KSCN, 61%) under a number of conditions (pro-
2
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Synthesis of (3-N-substituted-piperidin-4-ylidene)acetic Acid Ethyl Esters
Table 1. Crystal data for compound 2Bd
acylation, reduction/sulfonation, and reduction/isocyana-
tion. Under the above conditions, the reaction of skeleton
2A was treated with alkyl halide (eg. methyl iodide or allyl
bromide), and no alkylamine product was isolated. There-
fore, attempts to extend this approach to one-pot reduc-
tion/alkylation were unsuccessful. The structural skeleton
of cyclic diamino ester has attracted considerable attention
because of its interesting biological activities.10 In the syn-
thesis of peptidomimetics for rational design of a therapeu-
tic agent, diamino esters can be employed to establish opti-
mum conformation and a binding site for a protein for high
binding affinity and selectivity against a target protein.11
As a model of a cycloaddition reaction for the prepar-
ing skeleton 2B, reaction of compound 5a and ethyl pro-
piolate at 80 oC for 10 h in the presence of CuI without the
addition of other substrates was examined. Compound 2Ba
was obtained in only 44% yield. When 2.0 equivalents of
Et3N was added the reaction mixture at 80 oC for 10 h, the
product yield was isolated in a 74% yield. The result con-
firms that the addition of Et3N could increase the yield and
shorten the reaction time efficiently. For synthesizing skel-
eton 2B, compounds 2Bb~2Bd with 3-triazolyl group
could also be provided in 62~87% yields via the CuI-cata-
lyzed regioselective 1,3-dipolar cycloaddition reactions of
six commercially available alkynes (R3 = H, R2 = a, CO2Et;
b, COMe; c, (CH2)3OH; d, Ph; e, 4-MePh; f, R3 = R2 =
CO2Et) under click chemistry conditions.12 The CuI-pro-
moted process provides convenient access to structural di-
versification for medicinal chemistry. Chaiken et al. re-
ported that a 3-triazolyl proline-based peptide conjugate
could bind to the gp120 protein of HIV-1 and prevent the
HIV virus from docking with CD4 cells.13 The structural
framework of synthetic product 2Bd was similar to the re-
ported motif of 3-triazolyl proline.
Empirical formula
Formula weight
Crystal system
Space group
a (Å)
b (Å)
C23H24N4O4S
452.52
Monoclinic
P 1 21/c 1
24.0130 (7)
9.6962 (3)
9.8711 (2)
90
97.389 (2)
90
2279.25 (11) / 4
296 (2)
c (Å)
a (°)
b (°)
g (°)
Volume (Å3) / Z
Temperature (K)
Dc (Mg/m3)
1.319
0.179
Absorption coefficient (mm-1)
Crystal size (mm)
q range for data collection (°)
Reflections collected
Independent reflections
RF, Rw(F2) (all data)a
RF, Rw(F2) (I > 2s(I))a
GOF
0.20 ´ 0.20 ´ 0.18
0.86 to 26.41
18154
4669 (Rint = 0.0371)
0.1009, 0.2099
0.0602, 0.1588
1.048
a RF = S|Fo-Fc|/S=|Fo|; RW (F2) = [SW|Fo -Fc2|2/ SW Fo ]
.
2
4 1/2
during the process. The protocol is broadly applicable for
the preparation of 1,2,3-triazoles. To the best of our knowl-
edge, there are few literature reports considering the prepa-
ration of the framework of 3-triazolyl piperidine.7
In summary, we have successfully presented a con-
cise three-step synthetic methodology for producing a se-
ries of novel 3-N-substituted piperidines 2Aand 2B involv-
ing NBS-mediated one-pot a-bromination/Wittig olefina-
tion, NaN3 nucleophilic addition, and PPh3-mediated one-
pot Staudinger reduction/N-substitution or the CuI-cata-
The structure of compound 2Bd was determined us-
ing single-crystal X-ray analysis (Figure 2).14 The crystal
belongs to monoclinic crystal system and P 1 21/c 1 space
group with unit-cell parameters of a = 24.0130(7), b =
9.6962(3), c = 9.8711(2) Å (Table 1). Single-crystal X-ray
diffraction analysis was obtained to prove the constitution
and relative configuration of the isolated product. The
ORTEP plot clearly shows the triazole moiety in the 3-posi-
tion of the piperidine ring. Moreover, carboxylate group in
the 4-position of the piperidine ring are in relative E-con-
figuration as expected for the only regiochemistry of CuI-
catalyzed Huisgen 1,3-dipolar cycloaddition. The other
triazole regioisomer (R2 = H, R3 = Ph) was not observed
Fig. 2. X-Ray structure of compound 2Bd.
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Article
Chang and Lee
1
lysed Huisgen 1,3-dipolar cycloaddition reaction. Impor-
tantly, no regioisomers have been isolated in our ap-
proaches. The overall prepared procedures are shorter and
more efficient than the reported methods for synthesizing
the highly useful skeleton of 4-alkyl-3-aminopiperidine.
388.0219; H NMR (400 MHz): d 7.77-7.75 (m, 2H),
7.61-7.57 (m, 1H), 7.54-7.50 (m, 2H), 5.94 (s, 1H), 4.64
(dd, J = 3.2, 4.0 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.72
(ddd, J = 1.6, 3.6, 12.8 Hz, 1H), 3.58-3.52 (m, 1H), 3.38
(dt, J = 4.0, 14.8 Hz, 1H), 3.20-3.12 (m, 2H), 2.78-2.72 (m,
1H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz): d
165.36, 151.82, 136.37, 133.04, 129.15 (2x), 127.41 (2x),
118.06, 60.40, 53.71, 49.46, 46.14, 25.06, 14.05; Anal.
Calcd for C15H18BrNO4S: C, 46.40; H, 4.67; N, 3.61.
Found: C, 46.61; H, 4.82; N, 3.78.
EXPERIMENTAL SECTION
General
THF was distilled prior to use. All other reagents and
solvents were obtained from commercial sources and used
without further purification. Reactions were routinely car-
ried out under an atmosphere of dry nitrogen with magnetic
stirring. Products in organic solvents were dried with anhy-
drous magnesium sulfate before concentration in vacuo.
Melting points were determined with a SMP3 melting ap-
paratus. Infrared spectra were recorded with a Perkin
A representative procedure of skeleton 5 is as follows
Different nucleophile (1.0 mmol) was added to a
stirred solution of compound 4 (115 mg, 0.3 mmol) in the
co-solvent of acetone/water (10 mL, v/v = 9/1; a, NaN3; d,
KSCN), THF/water (10 mL, v/v = 9/1; c, NaOEt; e, NaSPh),
or 1,4-dioxane/water (10 mL, v/v = 4/1; b, NaCN; f,
NaSO2Tol) at rt. The reaction mixture was stirred at reflux
for 6~10 h. The reaction solvent was concentrated. The res-
idue was extracted with EtOAc (3 ´ 30 mL). The combined
organic layers were washed with brine, dried, filtered and
evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc = 6/1~1/1) af-
forded skeleton 5.
1
Elmer 100 series FTIR spectrometer. H and 13C NMR
spectra were recorded on a Varian INOVA-400 spectrome-
ter operating at 200/400 and at 50/100 MHz, respectively.
Chemical shifts (d) are reported in parts per million (ppm)
and the coupling constants (J) are given in Hertz. High res-
olution mass spectra (HRMS) were measured with a mass
spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray
crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD). Elemental
analyses were carried out with Heraeus Vario III-NCSH,
Heraeus CHN-OS-Rapid Analyzer or Elementar Vario EL
III.
(1-Benzenesulfonyl-3-azidopiperidin-4-ylidene)acetic
acid ethyl ester (5a)
Yield 76% (79 mg); Colorless oil; IR (CHCl3) 3121,
2976, 2356, 1778, 1105, 894 cm-1; HRMS (ESI, M++1)
1
calcd for C15H19N4O4S 351.1127, found 351.1129; H
(1-Benzenesulfonyl-3-bromopiperidin-4-ylidene)acetic
acid ethyl ester (4)
NMR (400 MHz): d 7.78-7.74 (m, 2H), 7.60-7.56 (m, 1H),
7.53-7.48 (m, 2H), 5.92 (br d, J = 0.8 Hz, 1H), 4.14 (q, J =
7.2 Hz, 2H), 3.96-3.93 (m, 1H), 3.57 (ddd, J = 1.6, 3.6, 11.6
Hz, 1H), 3.47-3.42 (m, 1H), 3.16-3.09 (m, 1H), 3.00-2.87
(m, 2H), 2.53 (dd, J = 4.0, 12.0 Hz, 1H), 1.25 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz): d 165.51, 151.03, 136.18,
133.13, 129.24 (2x), 127.46 (2x), 116.80, 60.75, 53.80,
50.76, 46.24, 26.56, 14.11.
NBS (200 mg, 1.1 mmol) was added to a solution of
compound 3 (240 mg, 1.0 mmol) acetic acid (3 mL) at rt.
The reaction mixture was stirred at 60 oC for 2 h. The reac-
tion mixture was cooled to rt. CHCl3 (10 mL) was added to
the reaction mixture at rt. Furthermore, Ph3P=CHCO2Et
(420 mg, 1.2 mmol) was added to the reaction mixture at rt.
The reaction mixture was stirred at reflux for 1 h. Saturated
NaHCO3(aq) (5 mL) was added to the reaction mixture and
the solvent was concentrated under reduced pressure. The
residue was extracted with EtOAc (3 ´ 30 mL). The com-
bined organic layers were washed with brine, dried, filtered
and evaporated to afford crude product under reduced pres-
sure. Purification on silica gel (hexanes/EtOAc = 6/1~4/1)
afforded compound 4 (253 mg, 65%) as a yellowish solid.
M.p. = 116-117 oC (recrystallized from hexanes and EtOAc);
IR (CHCl3) 3078, 2982, 1769, 1158, 782 cm-1; HRMS
(ESI, M++1) calcd for C15H19BrNO4S 388.0218, found
(1-Benzenesulfonyl-3-thiocyanatopiperidin-4-ylidene)-
acetic acid ethyl ester (5e)
Yield 61% (66 mg); Colorless oil; IR (CHCl3) 3218,
3020, 2964, 2289, 1762, 1184, 1047, 902, 742 cm-1; HRMS
(ESI, M++1) calcd for C16H19N2O4S2 367.0786, found
1
367.0788; H NMR (400 MHz): d 7.79-7.73 (m, 2H),
7.67-7.52 (m, 3H), 5.89 (d, J = 1.6 Hz, 1H), 4.14 (q, J = 7.2
Hz, 2H), 4.09 (t, J = 2.8 Hz, 1H), 3.94 (dt, J = 3.2, 12.8 Hz,
1H), 3.84-3.79 (m, 1H), 3.73 (dt, J = 2.8, 15.2 Hz, 1H),
2.97 (dd, J = 2.8, 12.8 Hz, 1H), 2.90-2.83 (m, 1H), 2.50 (dt,
J = 3.6, 11.6 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR
4
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Synthesis of (3-N-substituted-piperidin-4-ylidene)acetic Acid Ethyl Esters
(100 MHz): d 164.80, 148.84, 133.45, 129.39 (2x), 129.16,
127.64 (2x), 120.03, 110.62, 60.69, 52.71, 50.65, 46.30,
24.15, 14.06.
3.2, 14.4 Hz, 1H), 2.02 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz): d 169.44, 165.88, 152.10, 135.63,
132.11 (2x), 129.29, 128.55 (2x), 127.53, 60.16, 51.61,
50.83, 46.72, 25.31, 23.29, 14.11.
[1-Benzenesulfonyl-3-(toluene-4-sulfonyl)piperidin-4-
ylidene]acetic acid ethyl ester and [1-Benzenesulfonyl-
5-(toluene-4-sulfonyl)-1,2,3,6-tetrahydropyridin-4-
yl]acetic acid ethyl ester (5f)
(1-Benzenesulfonyl-3-benzoylaminopiperidin-4-ylidene)
acetic acid ethyl ester (2Ab)
Yield 74% (127 mg); White solid; M.p. = 150-151 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3320, 3090, 2969, 1758, 1669, 1189, 732, 660 cm-1; HRMS
(ESI, M++1) calcd for C22H25N2O5S 429.1484, found
Yield 45% (62 mg); Colorless oil; HRMS (ESI,
M++1) calcd for C22H26NO6S2 464.1202, found 464.1204;
For exo-olefinic isomer: 1H NMR (400 MHz): d 7.83 (d, J =
8.8 Hz, 2H), 7.78-7.70 (m, 2H), 7.60-7.58 (m, 1H), 7.55-
7.48 (m, 2H), 7.37 (d, J = 8.8 Hz, 2H), 5.80 (d, J = 2.0 Hz,
1H), 4.47 (dt, J = 2.0, 13.2 Hz, 1H), 4.15-4.11 (m, 1H), 4.09
(q, J = 7.2 Hz, 2H), 3.65-3.62 (m, 1H), 2.74 (dd, J = 5.2,
13.6 Hz, 1H), 2.46 (s, 3H), 2.40-2.36 (m, 1H), 2.33-2.23
(m, 2H), 1.26 (t, J = 7.2 Hz, 3H). For endo-olefinic isomer:
1H NMR (400 MHz): d 7.76 (d, J = 8.8 Hz, 2H), 7.73-7.69
(m, 2H), 7.63-7.58 (m, 1H), 7.55-7.48 (m, 2H), 7.38 (d, J =
8.8 Hz, 2H), 4.14 (dt, J = 1.6, 5.6 Hz, 2H), 4.11 (q, J = 7.2
Hz, 2H), 3.89 (s, 2H), 3.66 (s, 2H), 3.20 (t, J = 5.6 Hz, 2H),
2.44 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H).
1
429.1485; H NMR (400 MHz): d 7.77-7.74 (m, 2H),
7.72-7.69 (m, 2H), 7.59-7.54 (m, 1H), 7.52-7.43 (m, 3H),
7.39-7.34 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 5.90 (s, 1H),
4.75-4.71 (m, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.41-3.35 (m,
2H), 3.29-3.23 (m, 1H), 3.07 (dd, J = 3.6, 12.0 Hz, 1H),
3.00-2.93 (m, 1H), 2.88-2.82 (m, 1H), 1.17 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz): d 166.69, 165.71, 152.31,
135.61, 133.39, 131.70, 129.18, 129.14 (2x), 128.40 (2x),
127.28 (2x), 127.01 (2x), 116.97, 60.00, 51.21, 51.05,
46.46, 25.59, 13.94; Anal. Calcd for C22H24N2O5S: C,
61.66; H, 5.65; N, 6.54. Found: C, 61.82; H, 5.97; N, 6.78.
[1-Benzenesulfonyl-3-(3-methoxybenzoylamino)piperi-
din-4-ylidene]acetic acid ethyl ester (2Ac)
A representative procedure of skeleton 2A is as fol-
lows
PPh3 (262 mg, 1.0 mmol) and Et3N (200 mg, 2.0
mmol) were added to a solution of compound 5a (140 mg,
0.4 mmol) THF (15 mL) at rt. The reaction mixture was
stirred at reflux for 10 h. The reaction mixture was cooled
to rt. Et3N (200 mg, 2.0 mmol) was added to the reaction
mixture at rt. Furthermore, different acyl chloride, sulfonyl
chloride or phenyl isocyanate (2.0 mmol) was added to the
reaction mixture at rt. The reaction mixture was stirred at rt
for 10 h. Saturated NaHCO3(aq) (5 mL) was added to the re-
action mixture and the solvent was concentrated under re-
duced pressure. The residue was extracted with EtOAc (3´
30 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated to afford crude product
under reduced pressure. Purification on silica gel (hex-
anes/EtOAc = 2/1~1/2) afforded skeleton 2A.
Yield 78% (143 mg); White solid; M.p. = 140-141 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3323, 3163, 3029, 1762, 1633, 1103, 774, 692 cm-1; HRMS
(ESI, M++1) calcd for C23H27N2O6S 459.1590, found
459.1591; 1H NMR (400 MHz): d 7.75-7.72 (m, 2H), 7.61-
7.57 (m, 1H), 7.55-7.49 (m, 2H), 7.36 (br s, 1H), 7.33-7.29
(m, 2H), 7.05-6.99 (m, 2H), 5.96 (s, 1H), 4.75-4.71 (m,
1H), 4.07 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 3.58-3.51 (m,
2H), 3.45-3.40 (m, 1H), 3.01 (dd, J = 3.2, 12.0 Hz, 1H),
2.91-2.76 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz): d 166.53, 165.77, 159.74, 152.13, 135.94, 134.97,
133.16, 129.58, 129.22 (2x), 127.37 (2x), 118.81, 118.08,
117.55, 112.35, 60.10, 55.33, 51.41, 51.27, 46.60, 25.55,
14.02; Anal. Calcd for C23H26N2O6S: C, 60.25; H, 5.72; N,
6.11. Found: C, 60.42; H, 5.58; N, 6.34.
[3-Acetylamino-1-(4-bromobenzenesulfonyl)piperidin-
4-ylidene]acetic acid ethyl ester (2Aa)
[1-Benzenesulfonyl-3-(3-phenylacryloylamino)piperi-
din-4-ylidene]acetic acid ethyl ester (2Ad)
Yield 86% (126 mg); Colorless oil; IR (CHCl3) 3303,
3108, 3018, 2940, 1766, 1673, 1178, 718, 683 cm-1; HRMS
(ESI, M++1) calcd for C17H23N2O5S 367.1328, found
Yield 82% (149 mg); White solid; M.p. = 176-177 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3287, 3153, 2982, 1774, 1659, 1053, 770 cm-1; HRMS
(ESI, M++1) calcd for C24H27N2O5S 455.1641, found
1
367.1330; H NMR (400 MHz): d 7.75-7.72 (m, 2H),
1
7.66-7.59 (m, 3H), 6.41 (d, J = 8.0 Hz, 1H), 5.89 (s, 1H),
4.60-4.56 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.58-3.52 (m,
1H), 3.48-3.42 (m, 2H), 2.86-2.76 (m, 2H), 2.66 (dt, J =
455.1643; H NMR (400 MHz): d 7.78-7.75 (m, 2H),
7.65-7.60 (m, 2H), 7.56-7.47 (m, 4H), 7.39-7.34 (m, 3H),
6.55 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 5.97 (s,
J. Chin. Chem. Soc. 2012, 59, 000-000
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5

Article
Chang and Lee
1H), 4.74-4.70 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.69-3.51
(m, 3H), 2.86 (dd, J = 3.2, 12.0 Hz, 1H), 2.82-2.76 (m, 1H),
afford crude product under reduced pressure. Purification
on silica gel (hexanes/EtOAc = 2/1~1/2) afforded skeleton
2B.
2.64 (dt, J = 3.6, 11.2 Hz, 1H), 1.21 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz): d 165.87, 165.15, 152.10, 142.15,
135.52, 134.53, 133.27, 129.87, 129.30 (2x), 128.80 (2x),
127.89 (2x), 17.54 (2x), 119.83, 117.85, 60.16, 51.67,
50.98, 46.80, 25.20, 14.09; Anal. Calcd for C24H26N2O5S:
C, 63.42; H, 5.77; N, 6.16. Found: C, 63.64; H, 5.98; N,
6.39.
1-(1-Benzenesulfonyl-4-ethoxycarbonylmethylenepip-
eridin-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl
ester (2Ba)
Yield 74% (132 mg); Colorless oil; IR (CHCl3) 3287,
3102, 2934, 1780, 1763, 1177, 1023, 892, 671 cm-1; HRMS
(ESI, M++1) calcd for C20H25N4O6S 449.1495, found
449.1497; 1H NMR (400 MHz): d 8.33 (s, 1H), 7.78-7.76
(m, 2H), 7.67-7.63 (m, 1H), 7.59-7.56 (m, 2H), 5.32-5.29
(m, 1H), 5.32 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.09 (q, J =
7.2 Hz, 2H), 3.73 (d, J = 6.0 Hz, 2H), 3.43-3.37 (m, 2H),
3.17-3.12 (m, 1H), 3.04-3.00 (m, 1H), 1.43 (t, J = 7.2 Hz,
3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz): d
164.94, 160.36, 149.71, 140.42, 135.49, 133.54, 129.48
(2x), 127.63, 127.57 (2x), 118.53, 61.55, 61.50, 60.65,
50.04, 46.42, 26.45, 14.29, 14.04.
(1-Benzenesulfonyl-3-methanesulfonylaminopiperidin-
4-ylidene)acetic acid ethyl ester (2Ae)
Yield 82% (132 mg); Colorless oil; IR (CHCl3) 3352,
3188, 2981, 1773, 1632, 1070, 732, 623 cm-1; HRMS (ESI,
M++1) calcd for C16H23N2O6S2 403.0998, found 403.0997;
1H NMR (400 MHz): d 7.74-7.71 (m, 2H), 7.67-7.58 (m,
3H), 5.99 (s, 1H), 5.04 (d, J = 8.4 Hz, 1H), 4.05 (q, J = 7.2
Hz, 2H), 3.82-3.77 (m, 1H), 3.66-3.61 (m, 1H), 3.29-3.14
(m, 2H), 3.06 (s, 3H), 2.88-2.75 (m, 2H), 2.65-2.59 (m,
1H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz): d
166.13, 153.72, 135.29, 134.06 (2x), 132.84, 129.02 (2x),
127.64, 59.81, 53.35, 52.27, 46.66, 46.44, 26.29, 14.08.
1-Benzenesulfonyl-3-(3-phenylureido)piperidin-4-yli-
dene]acetic acid ethyl ester (2Af)
Yield 77% (136 mg); White solid; M.p. = 168-169 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3348, 3162, 3010, 1757, 1639, 1189, 892, 740 cm-1; HRMS
(ESI, M++1) calcd for C22H26N3O5S 444.1593, found
444.1595; 1H NMR (400 MHz): d 7.78-7.73 (m, 2H), 7.64-
7.52 (m, 4H), 7.36-7.32 (m, 2H), 7.28-7.26 (m, 2H), 7.17
(br s, 1H), 7.03-6.99 (m, 1H), 5.93 (br s, 1H), 4.62-4.49 (m,
1H), 4.10 (q, J = 7.2 Hz, 2H), 3.62-3.46 (m, 3H), 2.81-2.69
(m, 2H), 2.57 (dt, J = 3.2, 10.8 Hz, 1H), 1.20 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz): d 166.05, 154.40, 153.02,
135.47, 138.62, 133.28, 129.32 (2x), 129.06 (2x), 127.53
(2x), 123.25, 119.85 (2x), 117.30, 60.12, 52.18, 51.64,
46.91, 25.06, 14.11.
[3-(4-Acetyl-[1,2,3]triazol-1-yl)-1-benzenesulfonylpip-
eridin-4-ylidene]acetic acid ethyl ester (2Bb)
Yield 86% (144 mg); White solid; M.p. = 143-144 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3320, 3164, 2983, 1776, 1738, 1132, 1043, 839, 712 cm-1;
HRMS (ESI, M++1) calcd for C19H23N4O5S 419.1389,
1
found 419.1391; H NMR (400 MHz): d 8.28 (s, 1H),
7.79-7.72 (m, 2H), 7.67-7.53 (m, 3H), 5.32-5.28 (m, 1H),
5.29 (s, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.77-3.67 (m, 2H),
3.45-3.39 (m, 2H), 3.12-3.09 (m, 1H), 3.02-2.97 (m, 1H),
2.70 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz):
d 192.46, 164.90, 149.75, 148.00, 135.51, 133.51, 129.47
(2x), 127.54 (2x), 125.63, 118.42, 61.50, 60.66, 50.05,
46.39, 27.25, 26.49, 14.04.
{1-Benzenesulfonyl-3-[4-(3-hydroxypropyl)-[1,2,3]tri-
azol-1-yl]piperidin-4-ylidene}acetic acid ethyl ester
(2Bc)
Yield 87% (151 mg); Colorless oil; IR (CHCl3) 3489,
3122, 2978, 1769, 1188, 1039, 856, 728 cm-1; HRMS (ESI,
M++1) calcd for C20H27N4O5S 435.1702, found 435.1703;
1H NMR (400 MHz): d 7.79-7.75 (m, 2H), 7.67-7.54 (m,
3H), 7.61 (s, 1H), 5.30 (s, 1H), 5.20 (dt, J = 1.2, 4.8 Hz,
1H), 4.08 (dt, J = 1.6, 7.2 Hz, 2H), 3.74-3.66 (m, 4H),
3.45-3.38 (m, 2H), 3.12-3.07 (m, 1H), 2.99-2.96 (m, 1H),
2.88 (t, J = 7.2 Hz, 2H), 2.04 (br s, 1H), 1.98 (ddd, J = 1.2,
6.4, 7.6 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz): d 165.23, 150.65, 147.57, 135.63, 133.44, 129.45
(2x), 127.53 (2x), 121.42, 117.96, 61.82, 61.12, 60.51,
A representative procedure of skeleton 2B is as fol-
lows
CuI (190 mg, 1.0 mmol), Et3N (200 mg, 2.0 mmol)
and different alkyne (1.0 mmol) were added to a solution of
compound 5a (140 mg, 0.4 mmol) DMF (4 mL) at rt. The
reaction mixture was stirred at 80 oC for 10 h. The reaction
mixture was cooled to rt. Saturated NaHCO3(aq) (5 mL) was
added to the reaction mixture and the solvent was concen-
trated under reduced pressure. The residue was extracted
with EtOAc (3 ´ 30 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated to
6
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J. Chin. Chem. Soc. 2012, 59, 000-000

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of (3-N-substituted-piperidin-4-ylidene)acetic Acid Ethyl Esters
1-(1-Benzenesulfonyl-4-ethoxycarbonylmethylenepip-
eridin-3-yl)-1H-[1,2,3]triazole-4,5-dicarboxylic acid di-
ethyl ester (2Bf)
50.15, 46.49, 31.75, 26.60, 22.06, 14.06; Anal. Calcd for
C20H26N4O5S: C, 55.28; H, 6.03; N, 12.89. Found: C,
55.46; H, 6.29; N, 13.02.
Yield 82% (171 mg); Colorless oil; IR (CHCl3) 3302,
3128, 2892, 1781, 1776, 1768, 1138, 1103, 1049, 873, 780
cm-1; HRMS (ESI, M++1) calcd for C23H29N4O8S 521.1706,
found 521.1709; 1H NMR (400 MHz): d 7.70-7.68 (m, 2H),
7.59-7.53 (m, 1H), 7.50-7.46 (m, 2H), 6.88 (t, J = 3.2 Hz,
1H), 5.93 (d, J = 2.0 Hz, 1H), 4.52-4.40 (m, 4H), 4.11-4.08
(m, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.99-3.95 (m, 1H), 3.57-
3.54 (m, 1H), 3.11 (dd, J = 4.0, 13.6 Hz, 1H), 2.80 (dt, J =
4.0, 12.0 Hz, 1H), 2.51 (dt, J = 2.8, 14.8 Hz, 1H), 1.43 (t, J
= 7.2 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz): d 164.55, 160.17, 158.70,
148.07, 139.48, 136.63, 133.02, 129.48, 129.16 (2x),
127.45 (2x), 121.99, 62.89, 61.78, 60.56, 53.48, 49.56,
45.36, 32.99, 14.18, 13.99, 13.87.
[1-Benzenesulfonyl-3-(4-phenyl-[1,2,3]triazol-1-yl)pip-
eridin-4-ylidene]acetic acid ethyl ester (2Bd)
Yield 62% (112 mg); White solid; M.p. = 156-158 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3289, 3219, 2967, 1770, 1081, 739 cm-1; HRMS (ESI,
M++1) calcd for C23H25N4O4S 453.1597, found 453.1598;
1H NMR (400 MHz): d 8.05 (s, 1H), 7.86-7.83 (m, 2H),
7.79-7.76 (m, 2H), 7.66-7.61 (m, 1H), 7.58-7.53 (m, 2H),
7.46-7.41 (m, 2H), 7.37-7.33 (m, 1H), 5.35 (s, 1H), 5.29
(ddd, J = 0.8, 4.0, 7.6 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H),
3.80 (dd, J = 4.4, 12.0 Hz, 1H), 3.71 (dd, J = 8.0, 12.0 Hz,
1H), 3.52-3.43 (m, 2H), 3.12-3.05 (m, 1H), 2.98-2.91 (m,
1H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz): d
165.17, 150.64, 147.74, 135.55, 133.40, 129.99, 129.40
(2x), 128.85 (2x), 128.40, 127.49 (2x), 125.76 (2x),
119.94, 117.84, 61.13, 60.45, 50.11, 46.44, 26.58, 13.99;
Anal. Calcd for C23H24N4O4S: C, 61.05; H, 5.35; N, 12.38.
Found: C, 61.38; H, 5.62; N, 12.49. Single-crystal X-Ray
diagram: crystal of compound 2Bd was grown by slow dif-
fusion of EtOAc into a solution of compound 2Bd in DCM
to yield colorless prism. The compound crystallizes in the
monoclinic crystal system, space group P 1 21/c 1, a =
24.0130(7) Å, b = 9.6962(3) Å, c = 9.8711(2) Å, V =
2279.25(11) Å3, Z = 4, dcalcd = 1.319 g/cm3, F(000) = 952,
2q range 0.86~26.41°, R indices (all data) R1 = 0.1009,
wR2 = 0.2099.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science
Council of the Republic of China for its financial support
(NSC 99-2113-M-037-006-MY3).
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Yield 68% (127 mg); White solid; M.p. = 184-185 oC
(recrystallized from hexanes and EtOAc); IR (CHCl3)
3270, 3192, 2904, 1766, 1075, 893, 702 cm-1; HRMS (ESI,
M++1) calcd for C24H27N4O4S 467.1753, found 467.1755;
1H NMR (400 MHz): d 7.98 (s, 1H), 7.79-7.73 (m, 4H),
7.66-7.54 (m, 3H), 7.26-7.23 (m, 2H), 5.34 (s, 1H), 5.27
(dd, J = 4.0, 7.6 Hz, 1H), 4.08 (q, J = 6.8 Hz, 2H), 3.83 (dd,
J = 4.4, 12.0 Hz, 1H), 3.69 (dd, J = 8.0, 12.0 Hz, 1H),
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d 165.22, 150.74, 147.88, 138.33, 135.67, 133.40, 129.55
(2x), 129.42 (2x), 127.53 (2x), 127.20, 125.70 (2x),
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12.01. Found: C, 61.94; H, 5.83; N, 12.49.
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www.jccs.wiley-vch.de
7

Article
Chang and Lee
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J. Chin. Chem. Soc. 2012, 59, 000-000