Synthesis of 4,4-dialkoxy-3-piperidinols. Application to the synthesis of γ-acetate dehydropipecolinonitrile

Article abstract of DOI:10.1016/j.tet.2011.04.102

The synthesis of 4,4-dialkoxy-3-piperidinols 7 was carried out by the α-bromination of piperidin-4-one 5 with N-bromosuccinimide in acetic acid and alkoxide ion-mediated α,α-dialkoxyhydroxylation. Under acidic condition, trimethyl orthoformate-mediated re

Full text of DOI:10.1016/j.tet.2011.04.102

Tetrahedron 67 (2011) 4892e4896
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 4,4-dialkoxy-3-piperidinols. Application to the synthesis of
dehydropipecolinonitrile
g-acetate
*
Meng-Yang Chang , Tein-Wei Lee, Chung-Han Lin
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2011
Received in revised form 18 April 2011
Accepted 29 April 2011
Available online 7 May 2011
The synthesis of 4,4-dialkoxy-3-piperidinols 7 was carried out by the
5 with N-bromosuccinimide in acetic acid and alkoxide ion-mediated
a
a,a
-bromination of piperidin-4-one
-dialkoxyhydroxylation. Under
acidic condition, trimethyl orthoformate-mediated reaction of compound 7a yielded aminodienylester
8 in the presence of Ph3P]CHCO2Et. The -acetate dehydropipecolinonitrile 4 was also synthesized via
g
boron trifluoride etherate-promoted addition of compound 8 with trimethylsilyl cyanide and N-bro-
mosuccinimide and selective hydrogenation.
Keywords:
N-Bromosuccinimide
Sodium alkoxide
Ó 2011 Elsevier Ltd. All rights reserved.
4,4-Dialkoxy-3-piperidinols
g-Acetate dehydropipecolinonitrile
1. Introduction
CO Et
2
O
MeO OMe
OH
1) NBS, HOAc
Functionalized piperidines are prevalent scaffolds that serve as
crucial building blocks for numerous syntheses of nitrogen hetero-
cycles and have been previously reviewed.1 In addition to their utility
as synthetic precursors or targets, these functionalized piperidines
are important intermediates present in a wide of natural products
and pharmaceutically key compounds, such as hydroxypiperidine
skeleton.2,3 In the general preparation process of the substituted
piperidinol skeleton, common synthetic methods include oxidation
of tetrahydropyridine.3 In this letter, we report a simple route for the
synthesis of piperidin-3-ol with geminal dialkoxy groups, which
three steps
2) NaOMe, THF
N
S
Ph
N
S
N
S
CN
O
O
O
O
O
O
Ph
Ph
Scheme 1. Synthesis of 4,4-dimethoxy-3-piperidinol. Preparation of
g-acetate
dehydropipecolinonitrile.
these compounds are also important intermediates for the synthesis
of azasugars and alkaloids. The molecular framework of pipecolic
acid has been used as a core template to design various molecular
targets. Cyclic a-amino nitriles are not only versatile intermediates in
organic synthesis but also exhibit a valuable dual reactivity, which
has been utilized in a broad range of synthetic applications (Fig. 1).
consists in the
succinimide in acetic acid, followed by alkoxide ion-mediated
-dialkoxyhydroxylation. The methodology was employed to pre-
pare the skeleton of -acetate dehydropipecolinonitrile (2-cyano-4-
a-bromination of piperidin-4-one with N-bromo-
a,a
g
acetate-piperidine) with a pipecolinonitrile/glutamate combination.
The synthetic approach is shown in Scheme 1.
NH
2
N
N
The pipecolic acid and a related derivative (e.g., a-amino nitrile)
PO H
CO Et
2
3
2
NH
with an important bioactive component are key ingredients in
therapeutic agents for pharmaceutical research.4 Most of these
pipecolates are derived from natural or non-natural amino acids and
offer a significant potential as peptidomimetics in which the torsion
N
N
H
CO H
2
N
H
CO H
2
N
H
CO H
N
S
CN
O
2
angle between the
a carbon and the nitrogen of the amino acid is
O
defined by the cyclic rigid ring and the position of the alkene. Some of
Ph
4
5
6
8
LY233053 1
(Ornstein)
Selfotel 2
3
(this work)
(Hutchison)
(Etayo)
* Corresponding author. Tel.: þ886 7 3121101x2220; e-mail address: mychang@
kmu.edu.tw (M.-Y. Chang).
Fig. 1. Biological active substituted pipecolates.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.102

M.-Y. Chang et al. / Tetrahedron 67 (2011) 4892e4896
4893
The synthesis of LY233053 1, a potent and selective NMDA re-
ceptor antagonist, was reported by Ornstein et al.5 Hutchison et al.
described Selfotel (CGS 19755) 2 as potent and selective NMDA re-
ceptor antagonist activity in biological testing.6,7 Etayo et al. syn-
thesized
a conformationally constrained pipecolic acid/lysine
chimera 38,9
; however, there are few syntheses of dehy-
dropipecolinate analogs 4.10
2. Results and discussion
To initiate our work,
a-bromination of piperidin-4-one
5 (1.0 mmol) with N-bromosuccinimide (2.2 equiv) provided
a mixture of 3-bromopiperidin-4-one 6 (51%) and 5-bromodihy-
dropyridin-4-one 6a (32%). It was confirmed that excess amounts of
N-bromosuccinimide assisted the formation of enone 6a. Further-
more, byadjusting the equivalent of N-bromosuccinimide (1.1 equiv),
the yield of a-bromoketone 6 (82%) was increased (Equation 1).
O
O
O
Br
Br
NBS, HOAc
+
N
S
Ph
N
S
Ph
N
S
Ph
O
O
O
O
O
O
NBS (2.2 eq) : 6 (51%)
NBS (1.1 eq) : 6 (82%)
6a (32%)
6a (trace)
5
Equation 1. NBS-mediated a-bromination of piperidin-4-one 5.
Treatment of
a-bromoketone 6 with sodium methoxide
(4.0 equiv) in tetrahydrofuran (10 mL) yielded compound 7a at
a yield of 56% (Scheme 2). The Favorskii-type rearranged product
was not observed under this reaction condition.11 The structural
framework of compound 7a was determined using single-crystal
X-ray analysis (Fig. 2).12
Fig. 2. X-ray structure of compound 7a.
O
O
RO
RO
O
MeO OMe
O
O
4
Br
Br
RONa
HC(OMe) , p-TsOH,
OH
Br
NaOMe, THF
(56%)
3
Ph P=CHCO Et, DCM
N
S
N
S
Ph
3
2
N
S
N
S
Ph
N
S
Ph
(61%)
O
O
O
O
O
O
O
O
O
Ph
Ph
6
I
R = Me, Et, n-Bu, allyl, benzyl
6
7a (X-Ray)
RO OR
7f, R = Ph (nd)
7g, R = i-Pr (nd)
7h, R = t-Bu (nd)
7a, R = Me (56%)
OH
RONa
EtO C
2
H
EtO C
H
CO Et
2
7b, R = Et (45%)
2
7c, R = n-Bu (38%)
4
BF -OEt , NBS,
H , Pd/C
2
3
2
N
S
Ph
7d, R = allyl (33%)
nd: not detected
7e, R = benzyl (21%)
2
TMS-CN, DCM
(72%)
EA (66%)
O
O
N
S
N
S
CN
N
S
CN
O
O
O
O
O
Scheme 3. A possible mechanism for synthesis of 4,4-dialkoxy-3-piperidinols 7.
O
Ph
Ph
Ph
8 (X-Ray)
9
4
reaction with iodine or iodobenzene diacetate in the structural
framework of piperidin-4-one.3c,d But, the use of bromine instead of
iodine failed to afford any skeleton 7.
Scheme 2. Synthetic strategy toward compound 4.
Furthermore, seven commercially available sodium alkoxides
(R¼b, ethyl; c, n-butyl; d, allyl; e, benzyl; f, phenyl; g, i-propyl; h, tert-
butyl) were examined in the reaction. After changing the nucleo-
phile, four 4,4-dialkoxypiperidin-3-ols 7bee were provided in
21e45% yields by the alkoxide ion-mediated rearrangement of bro-
mide 6, asshowninScheme3. But,attemptstoextendthisreactionto
the three sodium alkoxides, including phenoxide, i-propoxide, and
tert-butoxide were unsuccessful due to steric hindrance and the in-
sufficient nucleophilic ability. During the process, the desired skel-
eton 7 was isolated in low or moderate yields among the complex
product mixture. To the best of our knowledge, there are two liter-
A possible explanation for the transformation would be that so-
dium alkoxide might attack the carbonyl group at the C-4 position
and generate the epoxide ring via an intramolecular debrominative
ring-closure. In the next step, the ring-opening of intermediate
I would occur to provide skeleton 7 by introducing the second
equivalent of sodium alkoxide. Our pervious study attempted to
increasetheyield of skeleton 7 bythe addition of somereagents(e.g.,
crown ether or hexamethylphosphoric triamide), failed under
anumberofconditions (prolongedreaction time, differentsolvents).
With the results in hand, compound 7a was treated with ethyl
triphenylphosphoranylidene acetate (2.0 equiv) and trimethyl
ature reports on the alkoxide-mediated a,a-dialkoxyhydroxylation

4894
M.-Y. Chang et al. / Tetrahedron 67 (2011) 4892e4896
orthoformate (4.0 equiv) in the presence of p-toluenesulfonic acid
(1.0 equiv) to give compound 8 at a yield of 61%.13 The resulting
structural framework of cyclic aminodienylester 8 exhibited a con-
formationally restricted character of an enaminic and s-trans
(2Z,4E)-diene conformer with the electronic ‘pushepull’ nature.14
The reaction mechanism was proposed as follows (Scheme 4): (i)
intermediate II was first generated by hydrolysis of compound 7a
under acidic condition, (ii) stereoselective olefination of
a
-hydroxyketone generated (E)-intermediate III, and then (iii) di-
ene 8 was isolated by trimethyl orthoformate-promoted de-
hydration of intermediate IV. In the absence of trimethyl
orthoformate, the complex product mixture was isolated. We
envisioned that the function of trimethyl orthoformate might en-
hance the dehydration condition for constructing this carbon
framework. While poring over recent literature,15 we found that
aspergilone A, containing similar rigid structure to a pushepull
functional group, not only possessed in vitro selective cytotoxicity
but also showed potent antifouling activity.
Me
MeO O
Me
O
MeO
OMe
OH
H
HC(OMe) ,
3
OH
OH
olefination
p-TsOH
N
S
Ph
N
S
Ph
N
S
Ph
Fig. 3. X-ray structures of compounds 8 and 9a.
MeO
Me
O
O
O
O
O
O
OMe
O
II
7a
H
ion from endo- or exo-olefin. For the endo-olefin motif of diene 8,
the lone-pair of nitrogen atoms promoted the ring-opening of the
brominium ion to form intermediate V. Cyanide can trap the imi-
nium ion and lead the reaction to produce intermediate VI, which
could eliminate bromide by a-hydrogen abstraction to form com-
pound 9. In another way, bromination of the exo-olefin motif was
converted to intermediate VII, which could stabilize the iminium
MeO
OH
Me
O
EtO C
EtO C
EtO2C
dehydration
H
O
2
2
H
O
OMe
O
N
N
S
Ph
N
S
Ph
H
Me
S
Ph
O
O
O
O
O
ion by a-hydrogen abstraction to form compound 9a. In compari-
III
IV
8
son with the yield ratios both endo- and exo-olefin on the skeleton
of s-trans diene 8, we found that the endo-olefin motif performed
a better bromination priority. Furthermore, by treating compound
8 with an excess N-bromosuccinimide (2.2 equiv) under the above-
mentioned conditions, a complex mixture was observed. Finally,
selective hydrogenation was accomplished by treatment of com-
pound 9 with hydrogen on 10% Pd-activated carbon in ethyl acetate
to yield compound 4 at a yield of 66%.16 In particular, fully hydro-
genated piperidine 4a could also be provided at a yield of 9% under
these conditions.
Scheme 4. A possible mechanism for the formation of compound 8.
Next, boron trifluoride etherate promoted the efficient addition
of enamine 8 with trimethylsilyl cyanide and N-bromosuccinimide
(1.2 equiv) resulted in a-amino nitrile 9 (72%) and a-bromo ester 9a
(10%), as shown in Scheme 5. The structures of compounds 8 and 9a
were determined using single-crystal X-ray analysis (Fig. 3).12 Be-
tween C-3 hydrogen and C-5 hydrogen or C-5 bromo group, this
syn-geometric conformation was shown on the push-pull skeleton.
EtO C
2
H
EtO C
EtO C
2
2
3. Conclusion
H
Br
Br
endo-olefin
In summary, we present a simple synthesis of
dropipecolinonitrile via the key alkoxide ion-mediated
g
-acetate dehy-
N
S
Ph
CN
N
S
Ph
N
S
Ph
CN
a,a-dialkox-
H
O
TMS-CN
EtO C
2
H
syn
O
O
O
O
O
yhydroxylation reaction. This method started from inexpensive
starting material and reagents, installed the carboxylic equivalent
functional groups through a short sequence, thus provided a poten-
tial intermediate for chemical biology research. Further investigation
is required regarding their structureeactivity of the desulfonated
compounds of 4, 8, and 9.
5
BF -OEt ,
H
3
2
9 (72%)
V
VI
NBS,
N
S
Ph
8
TMS-CN,
DCM
H
O
O
EtO C
2
EtO C
2
Br
syn
Br
5
H
3
4. Experimental section
4.1. General
exo-olefin
N
S
Ph
VII
N
S
Ph
H
O
O
O
O
9a (10%, X-Ray)
Tetrahydrofuran (THF) was distilled prior to use. All other
reagents and solvents were obtained from commercial sources and
used without further purification. Reactions were routinely carried
out under an atmosphere of dry nitrogen with magnetic stirring.
Products in organic solvents were dried over anhydrous magn-
esium sulfate before concentration in vacuo. Melting points were
Scheme 5. Reaction of compound 8.
The transformation from compound 8 to 9 and 9a was a regio-
selective bromination, followed by debromocyanation reaction. The
initial event might be considered as the formation of the bromnium

M.-Y. Chang et al. / Tetrahedron 67 (2011) 4892e4896
4895
3
ꢀ
ꢀ
ꢀ
determined with a SMP3 melting apparatus. Infrared spectra were
recorded with a PerkineElmer 100 series FTIR spectrometer. 1H and
13C NMR spectrawere recorded on a Varian INOVA-400 spectrometer
operating at 200/400 and at 50/100 MHz, respectively. Chemical
b¼10.0918 (2) A, c¼11.1626 (3) A, V¼720.59 (3) A , Z¼2,
Dcalcd¼1.389 g/cm3, F(000)¼320, 2
q
range 1.85e26.38ꢀ, R indices
(all data) R1¼0.0539, wR2¼0.1470.
shifts (
d
) are reported in parts per million (ppm) and the coupling
4.3.2. 1-Benzenesulfonyl-4,4-diethoxy-piperidin-3-ol
(7b). White
constants (J) are given in hertz. High resolution mass spectra (HRMS)
were measured with a mass spectrometer Finnigan/Thermo Quest
MAT 95XL. X-ray crystal structures were obtained with an
EnrafeNonius FR-590 diffractometer (CAD4, Kappa CCD). Elemental
analyses were carried out with Heraeus Vario III-NCSH, Heraeus
CHNeOSeRapid Analyzer or Elementar Vario EL III.
solid; mp¼79e80 ꢀC (recrystallized from hexane and ethyl acetate);
IR (CHCl3) 3629, 2937, 1149 cmꢂ1; rms (ESI, Mþþ1) calcd for
C15H24NO5S 330.1375, found 330.1378; 1H NMR (400 MHz):
d
7.79e7.76 (m, 2H), 7.61e7.50(m, 3H), 3.76 (brs,1H), 3.62 (ddd, J¼2.0,
4.0,12.4 Hz,1H), 3.56e3.34 (m, 5H), 2.86 (dd, J¼2.0,12.0 Hz, 1H), 2.60
(dt, J¼2.8,12.4 Hz,1H), 2.40 (br s,1H),1.97e1.89 (m,1H),1.82e1.76 (m,
1H), 1.15 (t, J¼7.2 Hz, 3H), 1.05 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
4.2. 1-Benzenesulfonyl-3-bromopiperidin-4-one (6) and
1-benzenesulfonyl-5-bromo-2,3-dihydro-1H-pyridin-4-one (6a)
d
136.95, 132.71, 128.99 (2ꢁ), 127.47 (2ꢁ), 98.11, 67.07, 55.84, 55.46,
48.75, 42.96, 28.37, 15.23, 15.10. Anal. Calcd for C15H23NO5S: C, 54.69;
H, 7.04; N, 4.25. Found: C, 54.88; H, 4.54; N, 4.43.
N-Bromosuccinimide (400 mg, 2.2 mmol) was added to a solu-
tion of compound 5 (240 mg, 1.0 mmol) in acetic acid (5 mL) at rt.
The reaction mixture was stirred at 60 ꢀC for 2 h. Saturated sodium
bicarbonate solution (2 mL) and dichloromethane (10 mL) were
added to the reaction mixture and the solvent was concentrated.
The residue was extracted with dichloromethane (3ꢁ20 mL). The
combined organic layers were washed with brine, dried, filtered,
and evaporated to afford crude product. Purification on silica gel
(hexane/AcOEt¼6/1e4/1) afforded compounds 6 (162 mg, 51%) and
6a (100 mg, 32%). For compound 6: white solid; mp¼86e88 ꢀC
(recrystallized from hexane and ethyl acetate); IR (CHCl3) 3288,
2940, 1767, 1132 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C11H13BrNO3S
4.3.3. 1-Benzenesulfonyl-4,4-di-n-butoxy-piperidin-3-ol
(7c). Viscous oil; IR (CHCl3) 3638, 2949, 1152 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C19H32NO5S 386.2001, found 386.2003; 1H NMR
(400 MHz):
d 7.80e7.77 (m, 2H), 7.62e7.57 (m, 1H), 7.55e7.51 (m,
2H), 3.77 (br s, 1H), 3.65e3.59 (m, 1H), 3.56e3.25 (m, 5H), 2.86 (dd,
J¼2.4, 12.0 Hz, 1H), 2.59 (dt, J¼3.2, 12.0 Hz, 1H), 1.98e1.89 (m, 1H),
1.83e1.75 (m, 1H), 1.66 (br s, 1H), 1.59e1.47 (m, 2H), 1.44e1.28 (m,
2H), 1.22e1.12 (m, 2H), 1.05e0.95 (m, 2H), 0.89 (t, J¼7.2 Hz, 3H),
0.81 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 136.81, 132.69, 128.96
(2ꢁ), 127.58 (2ꢁ), 97.88, 67.14, 60.07, 59.81, 48.80, 43.00, 31.81,
31.77, 28.22, 19.42, 19.38, 13.87, 13.78.
317.9800, found 317.9803; 1H NMR (200 MHz):
d 7.81e7.76 (m, 2H),
7.63e7.53 (m, 3H), 4.58e4.55 (m,1H), 3.98e3.89 (m,1H), 3.62e3.55
(m, 1H), 3.42e3.22 (m, 2H), 2.98e2.84 (m, 1H), 2.59e2.66 (m, 1H).
For compound 6a: viscous gum; IR (CHCl3) 3240, 2934, 1756,
1120 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C11H11BrNO3S 315.9643,
4.3.4. 1-Benzenesulfonyl-4,4-diallyloxy-piperidin-3-ol (7d). Viscous
oil; IR (CHCl3) 3634, 2924, 1143 cmꢂ1; HRMS (ESI, Mþþ1) calcd for
C17H24NO5S 354.1375, found 354.1382; 1H NMR (400 MHz):
d
7.79e7.77 (m, 2H), 7.60e7.51 (m, 3H), 5.99e5.73 (m, 2H),
found 315.9644; 1H NMR (400 MHz):
d
8.10 (s, 1H), 7.86e7.84 (m,
5.32e5.06 (m, 4H), 4.67 (d, J¼16.4 Hz, 1H), 4.50 (d, J¼16.4 Hz, 1H),
4.06e3.86 (m, 3H), 3.82e3.79 (m, 1H), 3.65e3.60 (m, 1H),
3.58e3.46 (m, 1H), 2.93 (dd, J¼2.4, 12.0 Hz, 1H), 2.67 (dt, J¼3.2,
12.0 Hz, 1H), 2.09e1.97 (m, 1H), 1.86e1.81 (m, 1H); 13C NMR
2H), 7.72e7.70 (m, 1H), 7.64e7.60 (m, 2H), 3.79 (t, J¼7.2 Hz, 2H),
2.69 (t, J¼7.2 Hz, 2H); 13C NMR (100 MHz):
d 184.46, 143.40, 137.66,
134.50, 129.95 (2ꢁ), 127.36, 127.28, 102.02, 44.06, 35.18.
(100 MHz):
d
136.99, 134.05, 134.01, 132.77, 129.03 (2ꢁ), 127.50
4.3. A representative procedure of skeleton 7 is as follows
(2ꢁ), 116.87, 116.33, 98.78, 67.27, 61.73, 61.46, 48.84, 42.92, 28.58.
Sodium alkoxide (RONa, 2.0 mmol) was added to a stirring
solution of 3-bromopiperidin-4-one 6 (160 mg, 0.5 mmol) in the co-
solvent of different alcohol (ROH,1 mL) and tetrahydrofuran (10 mL)
at rt. The reaction mixture was stirred at reflux temperature for 12 h.
The total procedure was monitored by TLC until the reaction was
completed. Water (1 mL) was added to the reaction mixture and the
solvent was concentrated under reduced pressure. The residue was
extracted with ethyl acetate (3ꢁ20 mL). The combined organic
layers were washed with brine, dried, filtered, and evaporated to
afford crude product under reduced pressure. Purification on silica
gel (hexane/ethyl acetate¼4/1 to 1/1) afforded compounds 7.
4.3.5. 1-Benzenesulfonyl-4,4-dibenzyloxy-piperidin-3-ol
(7e). Viscous oil; IR (CHCl3) 3630, 2938, 1132 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C25H28NO5S 454.1688, found 454.1670; 1H NMR
(200 MHz): d 8.01e7.42 (m, 15H), 4.88e4.62 (m, 3H), 3.98e3.72 (m,
2H), 3.88e3.66 (m, 1H), 3.52e3.46 (m, 1H), 3.44e3.38 (m, 1H), 2.88
(dd, J¼2.8, 12.4 Hz, 1H), 2.70 (dt, J¼2.8, 12.4 Hz, 1H), 1.99e1.94 (m,
1H), 1.80e1.77 (m, 1H).
4.4. (1-Benzenesulfonyl-2,3-dihydro-1H-pyridin-4-ylidene)
acetic acid ethyl ester (8)
Trimethyl orthoformate (215 mg, 2.0 mmol) was added to
a stirring solution of compound 7a (150 mg, 0.5 mmol) in the
dichloromethane (10 mL) at rt. p-Toluenesulfonic acid (TsOH,
86 mg, 0.5 mmol) was added to the reaction mixture. The reaction
mixture was stirred at rt for 20 min. Furthermore, ethyl triphe-
nylphosphoranylidene acetate (Ph3P]CHCO2Et, 348 mg, 1.0 mmol)
was added to the reaction mixture. The reaction mixture was stir-
red at reflux temperature for 22 h. The total procedure was moni-
tored by TLC until the reaction was completed. Water (1 mL) was
added to the reaction mixture and the solvent was concentrated
under reduced pressure. The residue was extracted with ethyl ac-
etate (3ꢁ20 mL). The combined organic layers were washed with
brine, dried, filtered, and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexane/ethyl
acetate¼4/1 to 1/1) afforded compound 8 (94 mg, 61%) as a white
solid. Mp¼99e100 ꢀC (recrystallized from hexane and ethyl
4.3.1. 1-Benzenesulfonyl-4,4-dimethoxy-piperidin-3-ol (7a). White
solid; mp¼113e114 ꢀC (recrystallized from hexane and ethyl ace-
tate); IR (CHCl3) 3623, 2936, 1141 cmꢂ1; HRMS (ESI, Mþþ1) calcd
for C13H20NO5S 302.1062, found 302.1066; 1H NMR (400 MHz):
d
7.80e7.76 (m, 2H), 7.62e7.51 (m, 3H), 3.80e3.78 (m, 1H), 3.65
(ddd, J¼2.0, 3.6, 12.4 Hz, 1H), 3.57e3.48 (m, 1H), 3.22 (s, 3H), 3.13 (s,
3H), 2.83 (dd, J¼2.0, 12.4 Hz, 1H), 2.56 (dt, J¼3.2, 12.4 Hz, 1H), 2.10
(br s, 1H), 1.96e1.89 (m, 1H), 1.85e1.79 (m, 1H); 13C NMR
(100 MHz):
d
136.85, 132.81, 129.08 (2ꢁ), 127.51 (2ꢁ), 98.25, 66.46,
48.92, 48.10, 47.82, 42.89, 27.40. Anal. Calcd for C13H19NO5S: C,
51.81; H, 6.35; N, 4.65. Found: C, 52.08; H, 6.71; N, 4.92. Single-
crystal X-ray diagram: crystal of compound 7a was grown by
slow diffusion of ethyl acetate into a solution of compound 7a in
dichloromethane to yield colorless prism. The compound crystal-
ꢀ
lizes in the triclinic crystal system, space group Pꢂ1, a¼6.7112 (2) A,

4896
M.-Y. Chang et al. / Tetrahedron 67 (2011) 4892e4896
acetate); IR (CHCl3) 3418, 2940,1768,1133 cmꢂ1; HRMS (ESI, Mþþ1)
ethyl acetate¼4/1 to 2/1) afforded compound 4 (65 mg, 66%). Vis-
cous oil; IR (CHCl3) 3434, 2938, 2158, 1777, 1145 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C16H19N2O4S 335.1066, found 335.1068; 1H NMR
calcd for C15H18NO4S 308.0957, found 308.0961; 1H NMR
(400 MHz):
d
7.78e7.74 (m, 2H), 7.62e7.48 (m, 3H), 6.98 (dd, J¼1.2,
8.4 Hz, 1H), 6.81 (dd, J¼0.4, 8.4 Hz, 1H), 5.29 (t, J¼0.4 Hz, 1H), 4.08
(400 MHz): d 7.92e7.89 (m, 2H), 7.68e7.63 (m, 1H), 7.59e7.52 (m,
(q, J¼7.2 Hz, 2H), 3.39 (t, J¼6.4 Hz, 2H), 2.48 (dt, J¼1.2, 6.8 Hz, 2H),
2H), 6.06 (d, J¼3.6 Hz, 1H), 4.11 (q, J¼7.2 Hz, 2H), 3.72 (ddd, J¼3.6,
6.4, 14.0 Hz, 1H), 3.43 (ddd, J¼2.8, 9.6, 14.0 Hz, 1H), 2.74e2.66 (m,
1H), 2.23 (dd, J¼6.4, 16.0 Hz, 1H), 2.15 (dd, J¼8.0, 16.0 Hz, 1H), 1.75
(ddt, J¼2.8, 6.4, 13.2 Hz, 1H), 1.23 (t, J¼7.2 Hz, 3H), 1.19e1.16 (m, 1H);
1.19 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 166.55, 146.56, 136.89,
133.38, 129.32 (2ꢁ), 126.88 (2ꢁ), 112.58, 110.44, 105.88, 59.59,
42.66, 24.71, 14.07. Anal. Calcd for C15H17NO4S: C, 58.61; H, 5.57; N,
4.56. Found: C, 58.88; H, 5.90; N, 4.89. Single-crystal X-ray diagram:
crystal of compound 8 was grown by slow diffusion of ethyl acetate
into a solution of compound 8 in dichloromethane to yield colorless
prism. The compound crystallizes in the triclinic crystal system,
13C NMR (100 MHz):
127.51 (2ꢁ), 114.51, 113.57, 60.93, 44.18, 38.36, 30.35, 25.94, 14.11.
d
170.65, 162.82, 137.77, 133.71, 129.45 (2ꢁ),
Acknowledgements
ꢀ
ꢀ
ꢀ
space group Pꢂ1, a¼8.1105 (3) A, b¼8.1143 (3) A, c¼12.6883 (4) A,
V¼730.14 (4) A , Z¼2, Dcalcd¼1.398 g/cm3, F(000)¼324, 2
q
range
3
ꢀ
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). The project is also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q100004).
1.65e26.40ꢀ, R indices (all data) R1¼0.0348, wR2¼0.0930.
4.5. (1-Benzenesulfonyl-6-cyano-2,3-dihydro-1H-pyridin-4-
ylidene)acetic acid ethyl ester (9) and (1-benzenesulfonyl-2,3-
dihydro-1H-pyridin-4-ylidene)-bromo-acetic acid ethyl ester (9a)
References and notes
N-Bromosuccinimide (90 mg, 0.5 mmol) was added to a solution
of compound 8 (123 mg, 0.4 mmol) with trimethylsilyl cyanide
(3 mL) in dichloromethane (10 mL) at rt. The reaction mixture was
stirred at rt for 5 min. Boron trifluoride etherate (w0.1 mL) was
added to the reaction mixture. The reaction mixture was stirred at
rt for 3 h. Saturated sodium bicarbonate solution (2 mL) was added
to the reaction mixture and the solvent was concentrated under
reduced pressure. The residue was extracted with ethyl acetate
(3ꢁ30 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/ethyl acetate¼6/1
to 3/1) afforded compounds 9 (96 mg, 72%) and 9a (16 mg, 10%). For
compound 9: white solid; mp¼64e65 ꢀC (recrystallized from
hexane and ethyl acetate); IR (CHCl3) 3424, 2948, 2134, 1771,
1138 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C16H17N2O4S 333.0909,
1. For reviews on the synthesis of piperidine, see:(a)Buffat, M. G. P. Tetrahedron 2004,
60,1701; (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron
2003, 59, 2953; (c) Sorbera, L. A.; Serradell, N.; Bolos, J.; Rosa, E.; Bozzo, J. Drugs
Future 2007, 32, 674; (d) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
2. For reviews, see: (a) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601; (b)
Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2010, 2831.
3. (a) Bursavich, M. G.; West, C. W.; Rich, D. H. Org. Lett. 2001, 3, 2317; (b) Plietker,
B. Tetrahedron: Asymmetry 2005, 16, 3453; (c) Zacuto, M. J.; Cai, D. Tetrahedron
Lett. 2005, 46, 447; (d) Surmont, R.; Verniest, G.; de Groot, A.; Thuring, J. W.; de
Kimpe, N. Adv. Synth. Catal. 2010, 352, 2751.
4. (a) Kadouri-Puchot, C.; Comesse, S. Amino Acids 2005, 29, 101; (b) Watanabe, L.
A.; Haranaka, S.; Jose, B.; Yoshida, M.; Kato, T.; Moriguchi, M.; Soda, S.; Nishino,
N. Tetrahedron: Asymmetry 2005, 16, 903 and references cited herein; (c) Car-
ballo, R. M.; Valdomir, G.; Purino, M.; Martin, V. S.; Padron, J. I. Eur. J. Org. Chem.
2010, 2304; (d) Leon, L. G.; Carballo, R. M.; Vega-Hernandez, M. C.; Martín, V. S.;
Padron, J. I.; Padron, J. M. Bioorg. Med. Chem. Lett. 2007, 17, 2681; (e) Enders, D.;
Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359 and references cited herein.
5. For synthesis of LY233053, see: (a) Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.;
Leander, J. D.; Lodge, D.; Paschal, J. W.; Elzey, T. J. Med. Chem. 1991, 34, 90; (b)
Ornstein, P. L.; Schaus, J. M.; Chambers, J. W.; Huser, D. L.; Leander, J. D.; Wong,
D. T.; Paschal, J. W.; Jones, N. D.; Deeter, J. B. J. Med. Chem. 1989, 32, 827; (c)
Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Jones, N. D.; Deeter, J. B.; Lodge, D.;
Leander, J. D. J. Med. Chem. 1992, 35, 3111; (d) Ornstein, P. L. U.S. Patent
4,968,678, 1990.
6. For synthesis of selfotel (CGS 19755), see: Hutchison, A. J.; Williams, M.; Angst,
C.; de Jesus, R.; Blanchard, L.; Jackson, R. H.; Wilusz, E. J.; Murphy, D. E.; Ber-
nard, P. S.; Scheider, J.; Campbell, T.; Guida, W.; Sills, M. A. J. Med. Chem. 1989,
32, 2171.
7. (a) Skiles, J. W.; Giannousis, P. P.; Fales, K. R. Bioorg. Med. Chem. Lett. 1996, 6,
963; (b) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2001, 3, 953; (c) Pilli, R. A.; Correa, I. R., Jr.; Maldaner, A. O.; Rosso, G. B. Pure
Appl. Chem. 2005, 77, 1153; (d) Etayo, P.; Badorrey, R.; Diaz-Villegas, M. D.;
Galvez, J. A. Synlett 2010, 2799.
8. Etayo, P.;Badorrey, R.;Diaz-Villegas, M. D.;Galvez, J. A. Eur. J. Org. Chem. 2008, 3474.
9. (a) Ganorkar, R.; Natarajan, A.; Mamai, A.; Madalengoitia, J. S. J. Org. Chem. 2006,
71, 5004; (b) Barkallah, S.; Schneider, S. L.; McCafferty, D. G. Tetrahedron Lett.
2005, 46, 4985; (c) Quancard, J.; Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle,
S.; Karoyan, P. J. Org. Chem. 2004, 69, 7940.
10. (a) Lu, S. P.; Lewin, A. H. Tetrahedron 1998, 54, 15097; (b) Osipov, S. N.; Kolo-
miets, A. F.; Bruneau, C.; Picquet, M.; Dixneuf, P. H. Chem. Commun. 1998, 2053.
11. (a) Giblin, G. M. P.; Jones, C. D.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1998,
3689; (b) Xu, R.; Chu, G.; Bai, D. Tetrahedron Lett. 1996, 37, 1463.
found 333.0912; 1H NMR (400 MHz):
d 7.96e7.93 (m, 2H),
7.69e7.65 (m, 1H), 7.60e7.56 (m, 2H), 6.32 (s, 1H), 5.74 (s, 1H), 4.14
(q, J¼7.2 Hz, 2H), 3.70 (t, J¼6.0 Hz, 2H), 2.93e2.90 (m, 2H), 1.25 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 165.36, 143.54, 137.92, 134.05,
129.68 (2ꢁ), 128.67, 127.42 (2ꢁ), 119.71, 115.86, 114.06, 60.51, 44.83,
24.97, 14.12. Anal. Calcd for C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43.
Found: C, 58.01; H, 5.10; N, 8.78. For compound 9a: white solid;
mp¼107e108 ꢀC (recrystallized from hexane and ethyl acetate); IR
(CHCl3) 3432, 2931, 1760, 1122 cmꢂ1
;
1H NMR (200 MHz):
d
7.81e7.78 (m, 2H), 7.60e7.53 (m, 3H), 7.11 (d, J¼8.0 Hz, 1H), 6.01
(d, J¼8.0 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 3.40 (t, J¼6.6 Hz, 2H), 3.04
(t, J¼6.6 Hz, 2H), 1.28 (t, J¼7.2 Hz, 3H). Anal. Calcd for
C15H16BrNO4S: C, 46.64; H, 4.18; N, 3.63. Found: C, 46.82; H, 4.49; N,
3.79. Single-crystal X-ray diagram: crystal of compound 9a was
grown by slow diffusion of ethyl acetate into a solution of com-
pound 9a in dichloromethane to yield colorless prism. The com-
pound crystallizes in the monoclinic crystal system, space group P 1
ꢀ
ꢀ
ꢀ
21/c 1, a¼10.0231 (10) A, b¼5.4646 (6) A, c¼28.654 (3) A, V¼1568.7
(3) A , Z¼4, Dcalcd¼1.636 g/cm3, F(000)¼784, 2
q
range 1.42e26.44ꢀ,
3
ꢀ
12. CCDC 806211 (7a), 806222 (8), and 806564 (9a) contain the supplementary
crystallographic data for this paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB21EZ, UK; fax: þ441223 336033; e-mail: deposit@ccdc.cam.ac.uk).
13. (a) Padmapriya, A. A.; Just, G.; Lewis, N. G. Synth. Commun. 1985, 15, 1057; (b)
Rettenbacher, A. S.; Schantl, J. G. ARKIVOC 2001, v, 36.
14. (a) Koike, T.; Tanabe, M.; Takeuchi, N.; Tobinaga, S. Chem. Pharm. Bull. 1997, 45,
243; (b) Rajappa, S. Tetrahedron 1981, 37, 1453; (c) Bagley, M. C.; Glover, C.;
Merritt, E. A.; Xiong, X. Synlett 2004, 811.
15. Shao, C. L.; Wang, C. Y.; Wei, M. Y.; Gu, Y. C.; She, Z. G.; Qian, P. Y.; Lin, Y. C.
Bioorg. Med. Chem. Lett. 2011, 21, 690.
16. (a) Ohashi, A.; Imamoto, T. Org. Lett. 2001, 3, 373; (b) Shultz, C. S.; Dreher, S. D.;
Ikemoto, N.; Williams, J. M.; Grabowski, E. J. J.; Krska, S. W.; Sun, Y.; Dormer, P.
G.; DiMichele, L. Org. Lett. 2005, 7, 3405.
R indices (all data) R1¼0.0603, wR2¼0.1562.
4.6. (1-Benzenesulfonyl-6-cyano-1,2,3,4-tetrahydropyridin-4-yl)
acetic acid ethyl ester (4)
Palladium on activated carbon (10%, 5 mg) was added to a solu-
tion of compound 9 (100 mg, 0.3 mmol) in ethyl acetate (10 mL).
Then hydrogen was bubbled into the mixture for 10 min, and stirring
occurred at rt for 20 h. The reaction mixture was filtered and
evaporated to yield crude product. Purification on silica gel (hexane/