Asymmetric synthesis of highly enantioenriched 2-substituted piperidines and 6-substituted piperidine-2-ones by a combination enantioselective hydrazone allylation with ring closing metathesis

Article abstract of DOI:10.1016/j.tet.2012.06.061

An efficient method for the asymmetric synthesis of highly optically pure 2-substituted piperidines and 6-substituted piperidine-2-ones from aldehydes was developed by a sequence of enantioselective hydrazone allylation and ring closing metathesis. This m

Full text of DOI:10.1016/j.tet.2012.06.061

Tetrahedron 68 (2012) 7050e7055
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of highly enantioenriched 2-substituted piperidines
and 6-substituted piperidine-2-ones by a combination enantioselective
hydrazone allylation with ring closing metathesis
*
Fengnu Piao, Mithilesh Kumar Mishra, Doo Ok Jang
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 May 2012
Received in revised form 14 June 2012
Accepted 15 June 2012
Available online 23 June 2012
An efficient method for the asymmetric synthesis of highly optically pure 2-substituted piperidines and
6-substituted piperidine-2-ones from aldehydes was developed by a sequence of enantioselective hy-
drazone allylation and ring closing metathesis. This method was found to be effective for a variety of
substrates, showing substrate generality. The method’s synthetic utility was illustrated in concise syn-
thesis of the alkaloid (R)-(ꢀ)-coniine.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Piperidine
Piperidinone
Homoallylamine
Allylation
Hydrazone
Ring closing metathesis
1. Introduction
to the nitrogen atom.5,6 To the best of our knowledge, only a few
procedures have operated in a catalytic enantioselective manner.7
The optically pure 2-substituted piperidine skeleton is ubiqui-
tous in a wide range of natural products and medicinal drugs.1 It has
been used as a building block in the synthesis of biologically active
compounds. Stereoselective construction of a chiral carbon center
adjacent to the ring nitrogen atom in 2-substituted piperidines has
been an important issue in organic synthesis.2 Among strategies
reported in the literature, one reliable route to enantio-enriched
2-substituted piperidines is ring closing metathesis of chiral
dienes.3 The ring closing metathesis reaction has been widely used
in organic synthesis and provides a powerful synthetic method for
producing nitrogen-containing heterocycles. The route to chiral
2-substituted piperidines by ring closing metathesis requires chiral
homoallylamines (Scheme 1). Various methods have been reported
for asymmetric homoallylamine synthesis.4 The asymmetric addi-
tion of allylindium reagents into C]N bonds has been a powerful
method for the synthesis of chiral homoallylamines because ally-
lindium reagents have low basicity, high chemoselectivity, and low
toxicity. However, many of these synthesis reactions rely on chiral
auxiliaries and a stoichiometric amount of chiral reagents to
establish the desired stereochemistry at the chiral center adjacent
We reported recently that a stereogenic center adjacent to the
nitrogen atom was readily established by indium-mediated enan-
tioselective allylation of N-benzoylhydrazones derived from alde-
hydes in the presence of a catalytic amount of protonated chiral
amine (PCA) with a high level of enantioselectivity (Scheme 2).8
The present work continues our research on developing asym-
metric synthetic methods for optically pure compounds.9 Here,
we present the asymmetric synthesis of highly optically pure
2-substituted piperidines and 6-substituted 2-piperidinones by
combining highly enanatioselective allylation of hydrazones with
ring closing metathesis.
2. Results and discussion
As outlined in Scheme 1, the chiral dienes used for ring closing
metathesis were accessed by a synthetic sequence of enantiose-
lective hydrazone allylation, NeN bond cleavage, and N-allylation.
Enantioselective addition of allylindium reagent (3 equiv) to
aldehyde-derived N-benzoylhydrazones in the presence of pro-
tonated chiral amine (0.33 equiv) gave the corresponding homo-
allylamines in high chemical yields with high enantioselectivities
(Table 1). Optically pure homoallylamines from aryl aldehyde-
* Corresponding author. E-mail address: dojang@yonsei.ac.kr (D.O. Jang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.061

F. Piao et al. / Tetrahedron 68 (2012) 7050e7055
7051
Scheme 1. Retrosynthesis for 2-substituted piperidines.
Scheme 2. Structure of PCA.
mediated catalytic enanatioselective allylation of substrates with
alkyl chains.7
We reasoned that the high enantioselectivity is the consequence
of the interaction of PCA with N-benzoylhydrazone via hydrogen
Table 1
Enantioselective allylation of aldehyde-derived N-benzoylhydrazones in the pres-
ence of protonated chiral amine PCA
bonding and pep interaction, providing a chiral environment. The
allylindium nucleophile generated in situ attacks at the less hin-
dered Si-face of the C]N bond.
After obtaining the optically pure amines, the next synthesis
step was investigated. Compound 3 was obtained by NeN bond
cleavage of compound 2 performed with SmI2 and followed by
allylation.10 The results are summarized in Table 2. Deprotected
amines were converted into the corresponding dienes 3 by reaction
with allyl bromide in the presence of sodium hydride. The sub-
sequent reactions afforded dienes 3 in more than 80% yield in all
cases. The dienes 3 obtained were then subjected to ring closing
metathesis. Free amines are known to be detrimental to Grubbs’
catalyst.11 However, when the ring closing metathesis reaction of
dienes 3 in dichloromethane in the presence of benzylidene
bis(tricyclohexylphosphine)-dichlororuthenium (Grubbs’ second
generation catalyst) was carried out, the desired products 4 were
obtained in more than 91% yield and showed generality of sub-
strates. Optical purity was examined with HPLC analysis using
a chiral column, proving not altering the stereochemistry at the
sterogenic center. To the best of our knowledge, the levels of
enantioselectivity and substrate generality reported herein are the
highest among all those previously reported.3
The reaction scope was then extended to asymmetric synthesis
of 6-substituted piperidine-2-ones, which are important building
blocks for the synthesis of 2-substituted piperidines12 and bioactive
molecules.13 The results are summarized in Table 3. After NeN bond
cleavage using SmI2, homoallylamine acylation with acryloyl
chloride in the presence of triethylamine afforded the corre-
sponding amides in more than 80% yields in all cases over two
steps. The resulting amides 5 were then subjected to ring closing
metathesis with Grubbs’ catalyst to afford enantioenriched 6-
substituted piperidine-2-one motifs in high yields. The optical
purity of homoallylamines was retained in compound 6.
Entry Substrate R
Temp (ꢁC) Time (h) Product Yield (%)a ee (%)b
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1g
1h
1i
Phe
4-FePhe
4-NO2ePhe rt
3-ClePhe
2-BrePhe
rt
rt
12
12
12
12
12
12
12
58
58
58
2a
2b
2c
2d
2e
2f
91
91
93
92
92
92
92
93
92
93
99 (S)c
99 (S)c
99 (S)c
99 (S)c
99 (S)c
99 (S)c
80 (R)
99 (R)
99 (S)
99 (S)
rt
rt
2-MeOePhe rt
CH3(CH2)2e rt
CH3(CH2)2e ꢀ30
2g
2g
2h
2i
(CH3)3Ce
ꢀ30
CH3CH]CHe ꢀ30
a
Isolated yield.
b
Enantiomeric excess was determined by HPLC analysis using a chiral column
(Daicel Chiralpak IA) with hexaneeisopropanol as solvent.
c
8
From Ref.
.
derived N-benzoylhydrazones were synthesized, regardless of
substituent positions and whether the substituent was electron-
withdrawing or electron-donating (entries 1e6). N-benzoylhy-
drazones derived from aliphatic aldehydes underwent allylation at
room temperature with relatively low enantioselectivity (entry 7).
To improve the optical purity of homoallylamines, the reaction was
performed at ꢀ30 ꢁC. This resulted in increased enantioselectivity
up to 99% ee, although prolonged reaction times were required to
complete the corresponding addition transformation (entry 8).
Interestingly, sterically hindered pivalaldehyde also afforded the
corresponding addition product in 92% yield with 99% ee (entry 9).
An a,ß-unsaturated aldehyde-derived N-benzoylhydrazone exclu-
sively gave the 1,2-addition product in high yield with high enan-
tioselectivity (entry 10). The reaction of organometallic reagents
with imines derived from aliphatic aldehydes with a-hydrogen is
complicated by poor stereoselectivity due to enamine formation.
The present method represents the best example to date of indium-
To illustrate the utility of the methodology, (R)-(ꢀ)-coniine was
prepared by hydrogenation of compound 4g. (R)-(ꢀ)-Coniine is
a poisonous alkaloid found in poison hemlock and a neurotoxin
that disrupts the peripheral nervous system.14 Catalytic

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F. Piao et al. / Tetrahedron 68 (2012) 7050e7055
Table 2
NeN bond cleavage, N-allylation, and ring closing metathesis
Entry
Substrate
R
Product 3
Yield (%)a
Product 4
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Phe
4-FePhe
3a
3b
3c
3d
3e
3f
3g
3h
3i
81
81
83
82
80
81
81
80
80
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
91
93
92
92
92
92
93
91
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (R)
99 (S)
99 (S)
4-NO2ePhe
3-ClePhe
2-BrePhe
2-MeOePhe
CH3(CH2)2e
(CH3)3Ce
CH3CH]CHe
a
Isolated yield.
b
Enantiomeric excess was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA) with hexaneeisopropanol as solvent.
Table 3
NeN bond cleavage, acylation, and ring closing metathesis
Entry
Substrate
R
Product 5
Yield (%)a
Product 6
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Phe
4-FePhe
5a
5b
5c
5d
5e
5f
5g
5h
5i
81
80
81
81
81
82
81
80
81
6a
6b
6c
6d
6e
6f
6g
6h
6i
93
94
93
93
93
93
92
93
91
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (R)
99 (S)
99 (S)
4-NO2ePhe
3-ClePhe
2-BrePhe
2-MeOePhe
CH3(CH2)2e
(CH3)3Ce
CH3CH]CHe
a
Isolated yield.
b
Enantiomeric excess was determined by HPLC analysis using a chiral column (Daicel Chiralpak IA) with hexaneeisopropanol as solvent.
hydrogenation of 4g with Pd/C in ethyl acetate at room temperature
gave 92% yield of (R)-(ꢀ)-coniine. The enantiomeric purity was
determined to be 99% ee by HPLC analysis using a chiral column
Scheme 3.
generality of substrates. The process provides a pathway for the
synthesis of optically pure bioactive alkaloids that contain piperi-
dine skeletons with a stereogenic center adjacent to the ring ni-
trogen atom.
Scheme 3. Synthesis of (R)-(ꢀ)-coniine.
3. Conclusions
4. Experimental section
4.1. General
In conclusion, we have developed an efficient method for the
asymmetric synthesis of highly optically pure 2-substituted piper-
idines and 6-substituted piperidine-2-ones from aldehydes. This
method involves a sequence of enantioselective hydrazone allyla-
tion and ring closing metathesis with excellent yields. This ap-
proach was found to be effective for a variety of substrates, showing
Unless otherwise specified, chemicals were purchased from
commercial suppliers and used without further purification. Col-
umn chromatography was performed using silica gel (230e400
mesh, Merck). TLC was performed on glass sheets pre-coated with

F. Piao et al. / Tetrahedron 68 (2012) 7050e7055
7053
silica gel (Kieselgel 60 PF254, Merck). Mps were determined with
(m, 1H), 7.38e7.73 (m, 5H), 8.03(s, 1H); 13C NMR (CDCl3)
d¼170.0,
a FishereJohns melting point apparatus and were uncorrected. The
1H- and 13C NMR spectra were generated using a Bruker 400 NMR
spectrometer operated at 400 MHz for 1H and 100 MHz for 13C
nuclei. The spectra were internally referenced to residual protio
solvent signals. Chemical shifts were reported in parts per million
(ppm). IR spectra were collected on a PerkineElmer 16 PC FTIR
spectrometer. Specific rotations were measured on a JASCO P-2000
polarimeter. Microanalyses were performed on a CE instrument
EA1110 elemental analyzer. High performance liquid chromatog-
raphy (HPLC) analyses were performed using a Younglin SP930D
instrument with a Daicel Chiralpak IA column (250ꢂ4.6 mm). UV
absorption was monitored at 254 nm. PCA and 2aef were synthe-
sized by using the previously reported methods.8 4a,3a 4g,15 6a,3b
and 6b3b were reported in literature.
138.2,135.8,134.2,131.7,129.8,117.8,112.2, 60.0, 38.0,14.5; IR (neat) n
3306, 1649, 1578, 1316, 859 cmꢀ1; Anal. Calcd for C14H18N2O: C,
73.01; H, 7.88; N, 12.16. Found: C, 73.38; H, 7.48; N, 12.14.
4.1.5. General procedure for NeN bond cleavage and N-allylation of
homoallylamines. Hydrazine derivatives 2 (0.6 mmol) were dis-
solved in MeOH (1 mL) and treated with SmI2 (18 mL, 1.8 mmol,
0.1 M THF solution) at room temperature for 4 h under argon. After
reaction completion, the mixture was diluted with CH2Cl2, washed
with distilled water, and dried over anhydrous MgSO4. After solvent
filtration and evaporation, the product was used for the next step
without further purification.
4.1.6. General procedure for N-allylation of homoallylamines. NaH
(55 mg, 1.35 mmol, 60% dispersion in mineral oil) was suspended in
dry THF (10 mL) and cooled to 0 ꢁC under argon. A solution of the
homoallylamines (0.45 mmol) in dry THF (5 mL) was added and the
reaction mixture was allowed to warm to room temperature. After
30 min, allyl bromide (0.12 mL, 1.35 mmol) was added and stirred
for 10 h. After reaction completion, the product was diluted with
CH2Cl2, washed with saturated NH4Cl, and dried over anhydrous
MgSO4. After solvent filtration and evaporation, the residue was
purified by flash chromatography on silica gel affording the corre-
sponding products 3.
4.1.1. General procedure for allylation of N-benzoylhydrazones.8
A
mixture of PCA (194 mg, 0.30 mmol) and N-benzoylhydrazones 1
(0.90 mmol) in methanol (4 mL) was stirred at room temperature or
ꢀ30 ꢁC for 1 h under argon. Allyl bromide (0.23 mL, 2.67 mmol) and
indium powder (306 mg, 2.67 mmol) were added to the above
mixture, which was then stirred under argon at either room tem-
perature or -30 ꢁC. The reaction was monitored by TLC and pro-
ceeded for the indicated time. The mixture was diluted with CH2Cl2,
washed with saturated NaHCO3 solution, and dried over anhydrous
MgSO4. After solvent filtration and evaporation, the residue was
purified by flash chromatography on silica gel, affording the cor-
responding addition products 2. Enantiomeric excess was de-
termined by chiral HPLC analysis and compared with the authentic
racemic material.
4.1.7. General procedure for acylation of homoallylamines. A solu-
tion of homoallylamines (0.6 mmol), acryloyl chloride (0.15 mL,
1.80 mmol), and triethylamine (0.13 mL, 0.9 mmol) in acetonitrile
(5 mL) was heated to reflux for 10 h under argon. After reaction
completion, the solution was diluted with CH2Cl2, washed with
saturated NH4Cl, and dried over anhydrous MgSO4. After solvent
filtration and evaporation, the residue was purified by flash chro-
matography on silica gel affording the corresponding products 5.
4.1.2. (R)-N0-(Hept-1-en-4-yl)benzohydrazide (2g). Following the
general procedure above, 2g was obtained as a yellow oil in 93% yield
after flash chromatography (silica gel: ethyl acetate/hexane¼2/8)
and in 99% ee as determined by HPLC [Daicel Chiralpak IA,
hexane/iPrOH¼95/5, 0.7 mL minꢀ1
,
l
¼254 nm, tr (major)¼15.2 min,
4.1.8. General procedure for ring closing metathesis. A solution of 3
or 5 (0.6 mmol) and Grubbs’ catalyst (15.3 mg, 0.017 mmol) in dry
toluene (5 mL) was stirred at 50 ꢁC for 14 h under argon. After the
reaction finished, the product was diluted with CH2Cl2, washed
with distilled water, and dried over anhydrous MgSO4. After solvent
filtration and evaporation, the residue was purified by flash chro-
matography on silica gel affording the corresponding products 4 or
6. Enantiomeric excess was determined by chiral HPLC analysis and
was compared with the authentic racemic material.
tr (minor)¼12.3 min]. ½a D20
ꢃ
¼þ68.4 (c 0.10, CHCl3); 1H NMR (CDCl3)
d
¼0.88 (t, J¼7.2 Hz, 3H), 1.39e1.56 (m, 4H), 2.24e2.36 (m, 2H), 3.54
(t, J¼7.2 Hz, 1H), 5.03e5.20 (m, 3H), 5.91e5.99 (m, 1H), 7.01(s, 1H),
7.35e7.66 (m, 5H); 13C NMR (CDCl3)
¼167.7, 133.4, 132.1, 129.0,
3300, 1639, 1579,
d
127.4, 117.6, 60.0, 33.1, 32.2, 30.2, 29.6; IR (neat)
n
1315, 872 cmꢀ1; Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N,
12.06. Found: C, 72.74; H, 8.33; N, 12.14.
4.1.3. (S)-N0-(2,2-Dimethylhex-5-en-3-yl)benzohydrazide
(2h). Following the general procedure above, 2h was obtained as
a yellow oil in 92% yield after flash chromatography (silica gel: ethyl
acetate/hexane¼2/8) and in 99% ee as determined by HPLC [Daicel
4.1.9. (2S)-2-(4-Fluorophenyl)-1,2,3,6-tetrahydropyridine
(4b). Following the general procedure above, 4b was obtained as
a yellow oil in 91% yield after flash chromatography (silica gel: ethyl
acetate/hexane¼5/6) and in 99% ee as determined by HPLC [Daicel
Chiralpak IA, hexane/iPrOH¼95/5, 0.7 mL minꢀ1
,
l¼254 nm, tr
(major)¼14.4 min, tr (minor)¼11.3 min]. ½a D20
ꢃ
¼þ72.4 (c 0.10,
Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
CHCl3); 1H NMR (CDCl3)
d
¼0.98 (s, 9H), 2.10e2.16 (m, 1H),
(major)¼46.4 min, tr (minor)¼43.3 min]. ½a D20
ꢃ ¼ꢀ91.4 (c¼0.01,
2.37e2.42 (m, 1H), 2.42e2.73 (m, 1H), 5.02e5.12 (m, 2H), 5.21
CHCl3). 1H NMR (CDCl3)
d
¼2.29 (m, 1H), 2.36 (m, 1H), 3.54 (m, 1H),
(s, 1H), 5.97e6.01 (m, 1H), 7.33e7.71 (m, 5H), 8.11(s, 1H); 13C NMR
3.63 (m, 1H), 3.87 (dd, J¼3.5, J¼10.0 Hz, 1H), 5.69 (m, 1H), 5.74
(s, 1H), 5.85 (m, 1H), 7.23e7.46 (m, 4H); 13C NMR (CDCl3)
¼165.3,
131.8, 130.3, 127.3, 125.7, 114.7, 57.6, 43.1, 25.8; IR (neat) n 3412,
(CDCl3)
18.5, 17.5; IR (neat)
d
¼167.0, 136.3, 132.8, 131.6, 128.5, 126.7, 117.0, 64.3, 29.3,
3302, 1636, 1577, 1312, 862 cmꢀ1; Anal. Calcd
d
n
for C15H22N2O: C, 73.13; H, 9.00; N, 11.37. Found: C, 73.38; H, 8.69;
N, 11.44.
3008, 1516, 908 cmꢀ1; Anal. Calcd for C11H12FN: C, 74.55; H, 6.83; N,
7.90. Found: C, 74.95; H, 6.52; N, 7.93.
4.1.4. (S,E)-N0-(Hepta-1,5-dien-4-yl)benzohydrazide (2i). Following
the general procedure above, 2i was obtained as a yellow oil in 93%
yield after flash chromatography(silica gel: ethylacetate/hexane¼2/
8) and in 99% ee as determined by HPLC [Daicel Chiralpak IA,
4.1.10. (2S)-2-(4-Nitrophenyl)-1,2,3,6-tetrahydropyridine
(4c). Following the general procedure above, 4c was obtained as
a yellow oil in 93% yield after flash chromatography (silica gel: ethyl
acetate/hexane¼4/6) and in 99% ee as determined by HPLC [Daicel
hexane/iPrOH¼95/5, 0.7 mL minꢀ1
,
l
¼254 nm, tr (major)¼15.5 min,
Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
tr (minor)¼12.5 min]. ½a D20
ꢃ
¼þ76.7 (c 0.10, CHCl3); 1H NMR (CDCl3)
(major)¼45.2 min, tr (minor)¼42.4 min]. ½a D20
ꢃ ¼ꢀ89.5 (c¼0.01,
d
¼1.65 (d, J¼7.2 Hz, 3H), 2.24e2.29 (m, 2H), 3.49e3.50 (m, 1H),
CHCl3). 1H NMR (CDCl3)
d
¼2.21 (m, 1H), 2.27 (m, 1H), 3.58 (m, 1H),
5.07e5.14 (m, 3H), 5.29e5.35 (m,1H), 5.60e5.65 (m,1H), 5.79e5.82
3.67 (m, 1H), 3.82 (t, J¼8.6 Hz, 1H), 5.79 (m, 1H), 5.85 (m, 1H), 5.91

7054
F. Piao et al. / Tetrahedron 68 (2012) 7050e7055
(s, 1H), 7.26e7.43 (m, 4H); 13C NMR (CDCl3)
d
¼142.2, 135.3, 128.8,
3421, 3011, 1602,
(CDCl3)
d
¼136.1, 132.3, 129.1, 127.5, 60.1, 38.1, 32.3, 14.6; IR (neat)
n
128.5, 128.4, 127.0, 59.3, 37.6, 32.0; IR (neat)
n
3228, 1546, 828 cmꢀ1; Anal. Calcd for C8H13N: C, 77.99; H, 10.64; N,
11.37. Found: C, 78.02; H, 10.67; N, 11.31.
1208 cmꢀ1; Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.98; H, 5.52; N, 13.77.
4.1.16. (S)-5,6-Dihydro-6-(4-chlorophenyl)pyridin-2(1H)-one
(6c). Following the general procedure above, 6c was obtained as
a colorless oil in 93% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by
4.1.11. (2S)-2-(3-Chlorophenyl)-1,2,3,6-tetrahydropyridine
(4d). Following the general procedure above, 4d was obtained as
a yellow oil in 92% yield after flash chromatography (silica gel: ethyl
acetate/hexane¼4/6) and in 99% ee as determined by HPLC [Daicel
HPLC [Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
l
¼254 nm, tr (major)¼47.2 min, tr (minor)¼44.4 min]. ½a D20
ꢃ ¼ꢀ107.6
(major)¼46.0 min, tr (minor)¼42.5 min]. ½a D20
ꢃ
¼ꢀ78.6 (c¼0.01,
(c¼0.10, CHCl3). 1H NMR (CDCl3)
d
¼2.50 (m, 1H), 2.66 (m, 1H), 4.77
CHCl3). 1H NMR (CDCl3)
d
¼2.29 (m, 1H), 2.34 (m, 1H), 3.59 (m, 1H),
(t, J¼6.9 Hz, 1H), 6.03 (d, J¼7.2 Hz, 1H), 6.28 (s, 1H), 6.65 (m, 1H),
3.68 (m, 1H), 3.87 (m, 1H), 5.79 (m, 1H), 5.87 (m, 2H), 7.23e7.49
(m, 4H); 13C NMR (CDCl3)
¼142.1, 135.3, 132.9, 131.9, 128.7, 128.4,
128.4, 125.9, 59.2, 37.5, 34.3; IR (neat)
3424, 3014, 1621, 889 cmꢀ1
7.35e7.41 (m, 4H); 13C NMR (CDCl3)
d
¼166.2, 140.5, 133.4, 131.8,
d
127.5, 127.5, 62.8, 39.2; IR (neat) n 3387, 2930, 1670, 1611, 1493,
n
;
1089, 823 cmꢀ1; Anal. Calcd for C11H10N2O3: C, 60.55; H, 4.62; N,
12.84. Found: C, 60.87; H, 4.24; N, 12.84.
Anal. Calcd for C11H12ClN: C, 68.22; H, 6.25; N, 7.23. Found: C, 68.62;
H, 5.92; N, 7.30.
4.1.17. (S)-5,6-Dihydro-6-(3-chlorophenyl)pyridin-2(1H)-one
(6d). Following the general procedure above, 6d was obtained as
a colorless oil in 93% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by
4.1.12. (2S)-2-(2-Bromophenyl)-1,2,3,6-tetrahydropyridine
(4e). Following the general procedure above, 4e was obtained as
a yellow oil in 92% yield after flash chromatography (silica gel: ethyl
acetate/hexane¼4/6) and in 99% ee as determined by HPLC [Daicel
HPLC [Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
l
¼254 nm, tr (major)¼46.4 min, tr (minor)¼43.5 min].
(major)¼46.3 min, tr (minor)¼43.4 min]. ½a D20
ꢃ
¼ꢀ82.6 (c¼0.01,
½
a 2D0
ꢃ
¼ꢀ125.6 (c¼0.10, CHCl3). 1H NMR (CDCl3)
¼2.50 (m, 1H), 2.66
d
CHCl3). 1H NMR (CDCl3)
d
¼2.38 (m, 1H), 2.49 (m, 1H), 3.54 (m, 1H),
(m, 1H), 4.77 (t, J¼6.9 Hz, 1H), 6.03 (d, J¼8.6 Hz, 1H), 6.26 (s, 1H),
3.67 (m, 1H), 3.91 (t, J¼7.2 Hz, 1H), 5.79 (m, 1H), 5.88 (m, 1H), 5.91
(s, 1H), 7.23e7.41 (m, 4H); 13C NMR (CDCl3)
¼138.3, 134.2, 132.4,
3429,
6.65 (m, 1H), 7.35e7.45 (m, 4H); 13C NMR (CDCl3)
d¼166.8, 133.5,
d
129.2, 128.3, 126.6, 126.5, 115.2, 115.0, 57.4, 37.7; IR (neat) n 3358,
131.2, 128.1, 127.6, 127.2, 126.3, 63.2, 39.9, 28.0; IR (neat)
n
2960, 1680, 1620, 1510, 1060, 820 cmꢀ1; Anal. Calcd for C11H10ClNO:
C, 63.62; H, 4.85; N, 6.75. Found: C, 63.98; H, 4.48; N, 6.73.
3014, 1578, 936 cmꢀ1; Anal. Calcd for C11H11BrN: C, 55.48; H, 5.08;
N, 5.88. Found: C, 55.68; H, 4.69; N, 6.04.
4.1.18. (S)-5,6-Dihydro-6-(2-bromophenyl)pyridin-2(1H)-one
(6e). Following the general procedure above, 6e was obtained as
a colorless oil in 93% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by
4.1.13. (2S)-2-(2-Methoxyphenyl)-1,2,3,6-tetrahydropyridine
(4f). Following the general procedure above, 4f was obtained as
a yellow oil in 92% yield after flash chromatography (silica gel: ethyl
acetate/hexane¼4/6) and in 99% ee as determined by HPLC [Daicel
HPLC [Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
l
¼254 nm, tr (major)¼47.3 min, tr (minor)¼44.4 min].
(major)¼45.2 min, tr (minor)¼42.4 min]. ½a D20
ꢃ
¼ꢀ90.4 (c¼0.01,
½
a 2D0
ꢃ
¼ꢀ131.2 (c¼0.10, CHCl3). 1H NMR (CDCl3)
¼2.50 (m, 1H), 2.60
d
CHCl3). 1H NMR (CDCl3)
d
¼2.29 (m, 1H), 2.36 (m, 1H), 3.54 (m, 1H),
(m, 1H), 4.77 (t, J¼8.6 Hz, 1H), 6.00 (d, J¼6.9 Hz, 1H), 6.60 (m, 1H),
3.67 (m, 1H), 3.80 (s, 3H), 3.84 (t, J¼8.6 Hz, 1H), 5.64 (m, 1H), 5.76
(m, 1H), 6.60 (s, 1H), 7.26 -7.51 (m, 4H); 13C NMR (CDCl3)
¼167.2,
143.8, 138.9, 134.8, 133.1, 131.9, 127.0, 118.1, 63.8, 40.5, 28.6, 15.6; IR
(neat)
3431, 3014, 1548, 1146 cmꢀ1; Anal. Calcd for C12H15NO: C,
6.17 (s, 1H), 7.09e7.47 (m, 4H); 13C NMR (CDCl3)
d¼168.9, 136.7,
d
136.2, 133.5, 130.5, 130.2, 128.4, 119.5, 117.1, 45.9, 31.2; IR (neat) n
3387, 2930, 1670, 1611, 1493, 1089, 823 cmꢀ1; Anal. Calcd for
C11H10BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 52.65; H, 3.87; N,
5.56.
n
76.16; H, 7.99; N, 7.40. Found: C, 76.53; H, 7.57; N, 7.41.
4.1.14. (S)-2-tert-Butyl-1,2,3,6-tetrahydropyridine (4h). Following
the general procedure above, 4h was obtained as a colorless oil in
93% yield after flash chromatography (silica gel: ethyl acetate/
hexane¼4/6) and in 99% ee as determined by HPLC [Daicel Chir-
4.1.19. (S)-5,6-Dihydro-6-(2-methoxyphenyl)pyridin-2(1H)-one
(6f). Following the general procedure above, 6f was obtained as
a colorless oil in 93% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by
alpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
HPLC [Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
(major)¼40.3 min, tr (minor)¼37.6 min]. ½a D20
ꢃ
¼þ61.5 (c 0.10,
l
¼254 nm, tr (major)¼46.2 min, tr (minor)¼43.4 min]. ½a D20
ꢃ ¼ꢀ127.8
CHCl3); 1H NMR (CDCl3)
d
¼0.97 (s, 9H), 2.18 (m, 1H), 2.20 (s, 1H),
(c¼0.10, CHCl3). 1H NMR (CDCl3)
d
¼2.50 (m, 2H), 3.79 (s, 3H), 4.67
2.23 (m, 1H), 2.98 (t, J¼7.2 Hz, 1H), 3.26 (m, 1H), 3.34 (m, 1H), 5.61
(m, 1H), 5.69 (m, 1H); 13C NMR (CDCl3)
¼129.9, 128.0, 69.5, 64.7,
59.6, 41.4, 38.9; IR (neat)
3234, 1544, 802 cmꢀ1; Anal. Calcd for
(t, J¼7.2 Hz, 1H), 5.96 (d, J¼6.9 Hz, 1H), 6.10 (s, 1H), 6.60 (m,1H),
d
6.99e7.37 (m, 4H); 13C NMR (CDCl3) 168.0, 160.0, 135.5, 132.7, 129.7,
n
129.6, 127.7, 118.9, 114.9, 56.2, 41.3, 30.6; IR (neat) n 3442, 2980,
C9H17N: C, 77.63; H, 12.31; N, 10.06. Found: C, 78.01; H, 11.95; N,
10.07.
1682, 1615, 1516, 1250, 1060, 846 cmꢀ1; Anal. Calcd for C12H13NO2:
C, 70.92; H, 6.45; N, 6.89. Found: C, 71.31; H, 6.34; N, 6.95.
4.1.15. (S,E)-2-(Prop-1-enyl)-1,2,3,6-tetrahydropyridine
(4i). Following the general procedure above, 4i was obtained as
a colorless oil in 91% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by HPLC
4.1.20. (R)-6-Propyl-5,6-dihydropyridin-2(1H)-one (6g). Following
the general procedure above, 6g was obtained as a colorless oil in
92% yield after flash chromatography (silica gel: ethyl acetate/
hexane¼4/6) and in 99% ee as determined by HPLC [Daicel Chir-
[Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
alpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l¼254 nm, tr
l
¼254 nm, tr (major)¼42.3 min, tr (minor)¼39.5 min]. ½a D20
ꢃ
¼þ58.6
(major)¼41.3 min, tr (minor)¼38.4 min]. ½a D20
ꢃ ¼þ89.5 (c 0.10,
(c 0.10, CHCl3); 1H NMR (CDCl3)
d
¼2.04 (d, J¼7.2 Hz, 3H), 2.18
CHCl3); 1H NMR (CDCl3)
d
¼1.09 (t, J¼7.2 Hz, 3H), 1.44 (m, 4H), 2.04
(m, 2H), 2.32 (s, 1H), 3.34 (m, 1H), 3.44 (m, 1H), 3.62 (t, J¼7.2 Hz,
(m, 1H), 2.39 (m, 1H), 3.14 (t, J¼7.2 Hz, 1H), 5.71 (m, 1H), 5.78
1H), 5.06 (m, 1H), 5.59 (m, 1H), 5.69 (m, 1H), 5.81 (m, 1H); 13C NMR
(m, 1H), 5.94 (s, 1H); 13C NMR (CDCl3)
d
¼161.7, 134.9, 126.9, 53.4,

F. Piao et al. / Tetrahedron 68 (2012) 7050e7055
7055
32.0, 31.3, 22.7, 14.2; IR (neat)
n
3218, 1687, 1546, 798 cmꢀ1; Anal.
References and notes
Calcd for C8H13NO: C, 69.03; H, 9.41; N, 10.06. Found: C, 69.32; H,
9.59; N, 10.21.
1. (a) Buckingham, J.; Baggaley, K. H.; Roberts, A. D.; Szab, L. F. Dictionary of
Alkaloids, 2nd ed.; CRC: Boca Raton, 2010; (b) Cordell, G. A., Ed. ; Academic: San
Diego, 2000; vol. 54; (c) Schneider, M. J. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, NY, 1996; vol. 10; Chapter 3,
pp 155e315.
4.1.21. (S)-6-tert-Butyl-5,6-dihydropyridin-2(1H)-one
(6h). Following the general procedure above, 6h was obtained as
a colorless oil in 93% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by
2. Asymmetric synthesis of 2-substituted piperidines: (a) Liu, J.-D.; Chen, Y.-C.;
Zhang, G.-B.; Li, Z.-Q.; Chen, P.; Du, J.-Y.; Tu, Y.-Q.; Fan, C.-A. Adv. Synth. Catal.
2011, 353, 2721e2730; (b) Monaco, M. R.; Renzi, P.; Scarpino Schietroma, D. M.;
Bella, M. Org. Lett. 2011, 13, 4546e4549; (c) Colpaert, F.; Mangelinckx, S.; De
Kimpe, N. J. Org. Chem. 2011, 76, 234e244; (d) Coldham, I.; Raimbault, S.;
Whittaker, D. T. E.; Chovatia, P. T.; Leonori, D.; Patel, J. J.; Sheika, N. S. Chem.dEur.
J. 2011, 16, 4082e4090; (e) Redd, L. R.; Das, S. G.; Liu, Y.; Prashad, M. J. Org. Chem.
HPLC [Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
l
¼254 nm, tr (major)¼38.2 min, tr (minor)¼35.5 min]. ½a D20
ꢃ ¼þ91.8
(c 0.10, CHCl3); 1H NMR (CDCl3)
d
¼1.17 (s, 9H), 1.41e1.49 (m, 1H),
ꢀ
2010, 75, 2236e2246; (f) Etayo, P.; Badorrey, R.; Díaz-de-Villegas, M. D.; Galvez,
2.45e2.50 (m, 1H), 3.96 (t, J¼7.2 Hz, 1H), 5.36e5.46 (m, 2H), 5.86
(s, 1H); 13C NMR (CDCl3)
¼167.2, 145.2, 123.7, 54.3, 36.2, 30.6, 27.9;
IR (neat)
3214, 1656, 1546, 814 cmꢀ1; Anal. Calcd for C9H15N: C,
J. A. Eur. J. Org. Chem. 2008, 3474e3478; (g) Tang, T.; Ruan, Y.-P.; Ye, J.-L.; Huang,
P.-Q. Synlett 2005, 231e234; (h) Kanda, Y.; Onomura, O.; Maki, T.; Matsumura, Y.
Chirality 2003, 15, 89e94; (i) Sano, S.; Yokoyama, K.; Teranishi, R.; Shiro, M.;
d
n
ꢀ
ꢀ
Nagao, Y. Tetrahedron Lett. 2002, 43, 281e284; (j) Andres, J. M.; Herraiz-Sierra, I.;
70.55; H, 9.87; N, 9.14. Found: C, 70.24; H, 10.69; N, 9.07.
ꢀ
Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem. 2000, 1719e1726.
3. Examples of ring closing metathesis for 2-substituted-piperidines: (a) Hietanen,
A.; Saloranta, T.; Rosenberg, S.; Laitinen, E.; Leino, R. T.; Kanerva, L. Eur. J. Org.
Chem. 2010, 909e919; (b) Fiorelli, C.; Savoia, D. J. Org. Chem. 2007, 72,
6022e6028; (c) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett.
2007, 9, 2473e2476; (d) Lesma, G.; Crippa, S.; Danieli, B.; Passarella, D.; Sacchetti,
A.; Silvani, A.; Virdis, A. Tetrahedron 2004, 60, 6437e6442; (e) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693e3712; (f) Hunt, J. C. A.; Laurent, P.;
Moody, C. J. J. Chem. Soc., PerkinTrans.12002, 2378e2389; (g) Agami, C.; Couty, F.;
Evano, G. Tetrahedron: Asymmetry 2000, 11, 4639e4643.
4.1.22. (S,E)-6-(Prop-1-enyl)-5,6-dihydropyridin-2(1H)-one
(6i). Following the general procedure above, 6i was obtained as
a colorless oil in 91% yield after flash chromatography (silica gel:
ethyl acetate/hexane¼4/6) and in 99% ee as determined by
HPLC [Daicel Chiralpak IA, hexane/iPrOH¼80/20, 0.7 mL minꢀ1
,
a 20
l
¼254 nm, tr (major)¼44.3 min, tr (minor)¼41.5 min]. ½ ꢃD ¼þ95.6
(c 0.10, CHCl3); 1H NMR (CDCl3)
d
¼1.22 (d, J¼7.2 Hz, 3H), 1.84e1.92
ꢀ
ꢀ
4. For a review Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111,
7774e7854.
(m, 1H), 2.88e2.94 (m, 1H), 4.03e4.11 (m, 1H), 4.35e4.39 (m, 1H),
4.57e4.62 (m 1H), 5.80e5.89 (m, 2H), 6.57 (s, 1H); 13C NMR (CDCl3)
5. For a review Kargbo, R. B.; Cook, G. R. Curr. Org. Chem. 2007, 11, 1287e1309.
6. (a) Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun. 2012, 2543e2545; (b)
d
¼168.2, 142.7, 135.5, 128.7, 127.8, 54.4, 30.7, 17.0; IR (neat)
n 3224,
ꢀ
ꢀ
Gonzalez-Gomez, J. C.; Medjahdi, M.; Foubelo, F.; Yus, M. J. Org. Chem. 2010, 75,
6308e6311; (c) Samanta, D.; Kargbo, R. B.; Cook, G. R. J. Org. Chem. 2009, 74,
7183e7186; (d) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Sinada, T.; Ohfune, Y.
J. Org. Chem. 2005, 70, 3464e3471; (e) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry
2004, 15, 3823e3825; (f) Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6,
1741e1743; (g) Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Sridharan, V.; Thornton-
Pett, M. Tetrahedron Lett. 2003, 44, 403e405; (h) Cooper, I. R.; Grigg, R.; MacLa-
chlan, W. S.; Thornton-Pett, M.; Sridharan, V. Chem. Commun. 2002, 1372e1373.
7. (a) Kargbo, R.; Takahashi, Y.; Bhor, S.; Cook, G. R.; Lloyd-Jones, G. C.; Shep-
person, I. R. J. Am. Chem. Soc. 2007, 129, 3846e3847; (b) Tan, K. L.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2007, 46, 1315e1317; (c) Cook, G. R.; Kargbo, R.; Maity, B.
Org. Lett. 2005, 7, 2767e2770.
1675, 1546, 812 cmꢀ1; Anal. Calcd for C8H11NO: C, 70.04; H, 8.08; N,
10.21. Found: C, 70.02; H, 8.07; N, 10.31.
4.2. Synthesis of R-(L)-coniine
A mixture of compound 4g (100 mg, 0.80 mmol) and 10% palla-
dium on charcoal (85.1 mg, 0.80 mmol) in ethyl acetate (5 mL) was
stirred at room temperature under 5 bar of hydrogen for 20 h. The
mixture was filtered through Celite pad and the solvent was re-
moved by evaporation to give the title compound (93.6 mg, 92%)
in 99% ee as determined by HPLC [Daicel Chiralpak IA,
8. Kim, S. J.; Jang, D. O. J. Am. Chem. Soc. 2010, 132, 12168e12169.
9. (a) Kim, S. Y.; Kim, S. J.; Jang, D. O. Chem.dEur. J. 2010, 16, 13046e13048; (b)
Jang, D. O.; Kim, S. Y. J. Am. Chem. Soc. 2008, 130, 16152e16153; (c) Cho, D. H.;
Jang, D. O. Chem. Commun. 2006, 5045e5047.
10. For examples, of N-N cleavage with SmI2: (a) Makino, K.; Kubota, S.; Hara, S.;
Sakaguchi, M.; Hamajima, A.; Hamada, Y. Tetrahedron 2009, 65, 9468e9473; (b)
Jacobsen, M. F.; Ionita, L.; Skrydstrup, T. J. Org. Chem. 2004, 69, 4792e4796; (c)
Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266e6267.
hexane/iPrOH¼80/20, 0.7 mLminꢀ1
¼254 nm, tr (major)¼36.3min,
,
l
tr (minor)¼33.4 min]. ½a D20
ꢃ
¼ꢀ7.8 (c 0.10, CHCl3); [lit.16
½ ꢃ ¼ꢀ9.7
a 2D0
(c 0.93, CHCl3) All other spectroscopic data as reported.
11. Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856e9857.
12. (a) Diez, A.; Mavel, S.; Teulade, J. C.; Chavignon, O.; Sinibaldi, M. E.; Troin, Y.;
Rubiralta, M. Heterocycles 1993, 36, 2451e2463; (b) Comins, D. L.; LaMunyon,
D. H. J. Org. Chem. 1992, 57, 5807e5809; (c) Rubiralta, M.; Giralt, E.; Diez, A.
Piperidine Structure, Preparation, Reactivity and Synthetic Applications of Piperi-
dine and Its Derivatives; Elsevier: Amsterdam, 1991; (d) Rubiralta, M.; Diez, A.;
Vila, C.; Troin, Y.; Feliz, M. J. Org. Chem. 1991, 56, 6292e6298.
13. Kudzma, L. V.; Severnak, S. A.; Benvenga, M. J.; Ezell, E. F.; Ossipov, M. H.;
Knight, V. V.; Rudo, F. G.; Spencer, H. K.; Spaulding, T. C. J. Med. Chem. 1989, 32,
2534e2542.
14. (a) Enders, D.; Tiebes, J. Liebigs Ann. 1993, 173e177; (b) Mehmandoust, M.;
Marazano, C.; Bhupesh, C. J. Chem. Soc., Chem. Commun. 1989, 1185e1187.
15. Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H.
Synlett 2002, 1146e1148.
Acknowledgements
This work was supported by a Korea Research Foundation
Grant (KRF-2009-0074839 and KRF-2011-0021279), which was
funded by the Korean Government.
Supplementary data
HPLC analysis data are available as supplementary data. Sup-
plementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.06.061.
16. Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi, P.; Riva, S.; Sacchetti, A.; Silvani,
A.; Danieli, B. Tetrahedron: Asymmetry 2005, 16, 2225e2229.