Domino imino-aldol-aza-Michael reaction: One-pot diastereo- and enantioselective synthesis of piperidines

Article abstract of DOI:10.1021/jo101680f

Addition of α-arylmethylidene- or α-alkylidene-β-keto ester enolate to N-activated aldimines via the imino aldol pathway followed by intramolecular aza-Michael reaction in a domino fashion has been developed, and a highly diastereoselective route to subst

Full text of DOI:10.1021/jo101680f

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Domino Imino-Aldol-Aza-Michael Reaction: One-Pot Diastereo- and
Enantioselective Synthesis of Piperidines
Manas K. Ghorai,* Sandipan Halder, and Raj Kumar Das
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
mkghorai@iitk.ac.in
Received August 26, 2010
Addition of R-arylmethylidene- or R-alkylidene-β-keto ester enolate to N-activated aldimines via the
imino aldol pathway followed by intramolecular aza-Michael reaction in a domino fashion has been
developed, and a highly diastereoselective route to substituted piperidines is reported. Enantiopure
piperidines are synthesized from chiral sulfinyl imines. Formation and the observed stereoselectivity
of the products have been rationalized by mechanistic and computational studies.
Introduction
and anti-HIV properties, etc.2n Immense synthetic and
pharmacological utilities of such piperidines have inspired
researchers to develop new strategies for their syntheses.
Piperidine rings are prevalent in the core structure of many
naturally occurring alkaloids and drugs.1 Substituted piper-
idines, particularly, 2- and/or 2,6-disubstituted piperidines
are synthetically very important2,3 and exhibit a wide spec-
trum of biological activities such as antibacterial, antifungal,
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DOI: 10.1021/jo101680f
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Published on Web 10/08/2010
J. Org. Chem. 2010, 75, 7061–7072 7061
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Ghorai et al.
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Toward this end, several efforts have been devoted4-13 mostly
from substituted pyridines,5a amino alcohols,5b-f imines,5g-k
aldol reaction,5l reductive amination reactions,5m-p ring ex-
pansion and heterocyclic rearrangements,5q-u aza-conjugate
additions,6 various metal- and acid-catalyzed cyclizations,7
Mannich-type reactions,8 olefin metathesis,9 and hetero-
Diels-Alder reactions,10 etc. It is still challenging for organic
chemists to develop more efficient synthetic routes toward
functionalized piperidines with structural diversity and high
diastereo- as well as enantioselectivity.
protocol involving ketones or 1,3-dicarbonyl compounds,
aldehydes, and amines. However, this approach has limita-
tions in terms of the substrate scope and formation of
racemic products. Previously, we reported the synthesis of
racemic monosubstituted piperidines from the correspond-
ing δ-amino-β-keto esters generated from the reaction of
1,3-dicarbonyl dianion of ethyl acetoacetate and imines.13 In
continuation of our research activity in enolate14 and dian-
ion13 chemistry, we anticipated that a simple strategy involv-
ing a domino intermolecular imino-aldol followed by an
intramolecular aza-Michael reaction would lead to the stereo-
selective formation of 2,6-disubstituted piperidines. In recent
years, domino reactions15 have become very fascinating and
promising tools in synthetic organic chemistry over classical
reactions considering reaction time, purification of the inter-
mediates, and selectivity. We have successfully developed a
simple one-pot, two-step strategy for the synthesis of highly
funcionalized piperidines in diastereo- as well as enantiopure
forms employing imino-aldol and aza-Michael reactions in a
domino fashion (Scheme 1). Herein, we report our results in
detail.
In this regard, Noller et al. and others have made sig-
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Results and Discussion
Our strategy involves (i) the synthesis of R-arylmethyli-
dene- (1a,b) and R-alkylidene-β-keto ester (1c) as the pre-
cursor compounds and (ii) generation of the enolate from 1
followed by reaction with N-sulfonylaldimines. For this
purpose, the precursors 1a-c have been synthesized on the
basis of literature procedures.16 We have judiciously utilized
these substrates as nucleophiles as well as electrophiles in the
same reaction sequence, although 1a has been used earlier as
a good Michael acceptor.17 To evaluate the feasibility of our
approach, first the enolate was generated from compound
(E)-1a by the treatment with LDA at -50 °C in THF and
reaction with 2-phenyl-N-tosylaldimine 3a to afford the
corresponding 2,6-disubstituted piperidine 6a in 65% yield
as a single diastereomer (Scheme 1) with 2,6 cis-appendages
as confirmed by X-ray crystallographic data.
Formation of cis-6a as the only diastereomer was con-
firmed by the 1H NMR spectrum of the crude reaction
mixture as it indicated the absence of other diastereomer.
Presumably, the reaction followed a domino imino-aldol-
aza-Michael reaction sequence. Interestingly, (Z)-1a pro-
duced the identical product (6a) under the same reaction
conditions with lower yield. To generalize the methodology,
a number of activated aldimines were reacted with compound
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SCHEME 1. Reaction of R-Arylmethylidene-β-keto Ester with 2-Aryl-N-sulfonylaldimines via Domino Imino-Aldol-Aza-Michael
Sequence
TABLE 1. Synthesis of 2,6-Disubstituted Piperidines
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SCHEME 2. Synthesis of 2-Alkenyl-N-tosylaldiminesa
SCHEME 3. Reaction of r-Benzylidene-β-keto Ester with
2-Alkenyl-N-tosylaldiminesa
aYields of isolated products after column chromatographic purification.
(E)-1a, and the results are shown in Table 1. The structures of
other piperidines 6e and 6j as well as the cis-stereochemistry
between the substituents at the 2 and 6 positions were
confirmed by X-ray crystallographic data.18 Furthermore,
the piperidines 6 were found to exist in enol forms.
Next, the substrate scope of the strategy was explored by
studying the reaction with aliphatic imines. To prepare such
imines following an identical procedure used by us for
aromatic imines, when aliphatic aldehyde 7 was treated with
aProduct was obtained as a single diastereomer in both cases. bYields
of isolated products after column chromatographic purification.
SCHEME 4. Reaction of R-Benzylidene-β-keto Ester with
2-Aryl-N-sulfinylaldimines
p-toluenesulfonamide in the presence of catalytic BF3 OEt2
3
in refluxing benzene, interestingly, the expected imine 8 was
not formed; instead the imine 11 from the corresponding
aldehyde 10 arising from the aldol condensation of aldehyde
7 was formed in good yield (Scheme 2). Formation of such a
type of imine was precedented using a stoichiometric amount
of trifluoroacetic anhydride, R-hydrogen-containing alipha-
tic aldehyde, and p-toluenesulfonamide.19
When the enolate of compound (E)-1a reacted with the
imine 11a following identical reaction conditions as shown in
Scheme 1, the corresponding piperidine 12a was obtained in
58% yield as a single diastereomer. Once again, the relative
stereochemistry at the 2 and 6 positions was found to be cis from
X-ray crystallographic data.15 A similar result was obtained
from (E)-1a and 11b in the same reaction sequence (Scheme 3).
To demonstrate the synthetic potential of the strategy,
next the reaction was explored with sulfinyl imine as a chiral
source. Earlier sulfinyl imines were utilized by Davis et al.2e-m,20
for the synthesis of nonracemic piperidines by an alternate
strategy. Following our approach when the enolate gener-
ated from compound (E)-1a was treated with 2-phenyl-N-
sulfinylaldimine 13a the corresponding 2,6-disubstituted
piperidine 14a was obtained as a single diastereomer in
enantiopure form (dr >99:1, er >99:1).
respectively, in enantiopure forms (Scheme 5), and the er
was determined by chiral HPLC analysis (see the Supporting
Information). From these results, it is apparent that the
compounds 14a-d were produced in enantiomerically pure
forms.
Crystal structures reveal that the piperidine molecules 6a,
6e, 6j, 12a, and 14c exist in half-chair conformations where
the 2,6-substituents occupy pseudoaxial and axial positions,
respectively, and remain almost parallel to each other prob-
ably because of a favorable π-π stacking interaction be-
tween them.
On the basis of the experimental results, NMR studies,22
and X-ray crystallographic data,18 the proposed mechanism
for the formation of N-tosyl-2,6-diphenylpiperidine 6a is
shown in Scheme 6. The enolate 2 reacts with 2-phenyl-N-
tosylaldimine 3a to form the adduct 15, which undergoes
intramolecular aza-Michael reaction through the more fa-
vorable transition state 16a to furnish 6a via the intermediate
17a. However, because of allylic strain between the phenyl
and the CO2Et groups, 17a becomes less stable and flips to
the thermodynamically more stable diaxial isomer 6a, which
is stabilized by a strong π-π stacking interaction23 between
the Ph groups. Since 16a0 is the less favorable transition state
probably because of a 1,3-diaxial interaction between the
phenyl and hydrogen groups, the trans-isomer 6a0 does not
form at all.
However, the reaction with sulfinyl imines takes a longer
time and requires larger amounts of enolate (2.5 equiv)
compared to sulfonyl imines. Further generalization to this
approach was made with other sulfinylimines (Scheme 4,
Table 2). Similar to previous cases, the cis-stereochemistry
between the substituents at the 2- and 6-positions of piper-
idines 14a-d was confirmed by the crystal structure of 14c18
as a representative example, and its absolute configuration
was determined to be (2R,6R).
The methodology was further extended to the alkylidene
substrate 1c. When R-cyclohexylmethylidene-β-keto ester
(E)-1c was reacted with 2-phenyl-N-tosylaldimine 3a, inter-
estingly the corresponding piperidine 18a was formed with
Furthermore, 14c and 14d were oxidized21 to the cor-
responding tosyl derivatives (2R,6R)-6d and (2R,6R)-6f,
(18) For details of X-ray crystallographic analysis of 6a,e,j, 12a, 14c, and
18a,b, see the Supporting Information.
(19) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003, 44, 1231.
(20) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995, 60,
7037.
(22) The equatorial protons at the 2,6-positions of piperidine are far
apart; they did not show any NOE interaction although they are cis to each
other.
(23) For a recent study on π-π stacking interaction supported by
molecular modeling, see: Catak, S.; D’hooghe, M.; De Kimpe, N.;
Waroquier, M.; Speybroeck, V. V. J. Org. Chem. 2010, 75, 885.
(21) Davis, F. A.; Srirajan, V. J. Org. Chem. 2000, 65, 3248.
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TABLE 2. Synthesis of Chiral Piperidines from 2-Aryl-N-sulfinylaldimines
aProduct was obtained as a single diastereomer in all cases. bYields of isolated products after column chromatographic purification. cYield of the
product was determined after oxidation of sulfinyl group to tosyl group.
SCHEME 5. Oxidation of N-Sulfinyl 2,6-Disubstituted
Piperidines to N-Tosyl 2,6-Disubstituted Piperidines
from (E )-1c reacts with 3a to form the adduct 19a, which
undergoes intramolecular aza-Michael reaction through
the more favorable transition state 20a to produce the cis-
piperidine 18a via the intermediate 21a. Probably because
of the allylic strain between the equatorial cyclohexyl and
CO2Et groups, 21a is less stable and it flips to the thermo-
dynamically most stable diaxial isomer 18a, which is stabi-
lized by a C-H-π stacking interaction between the axial
hydrogen of the cyclohexyl ring and the axial phenyl group.
The other possible TS 20a0 is less stabilized than 20a probably
because of 1,3-diaxial interaction between axial hydrogen
and cyclohexyl groups; moreover, there is no π-π stacking
interaction between the Ph and Ts groups as discussed below
for TS 20b. Hence, the trans-piperidine 18b did not form.
In the case of (Z)-1c the trans-piperidine 18b was formed
solely as the kinetically controlled product through the more
favorable transition state 20b at lower temperature (-50 °C).
Probably because of a weak π-π stacking interaction be-
tween the Ph and Ts groups, 20b is more stabilized than the
other possible TS 20b0. Hence, the cis-piperidine 18a did not
form at lower temperature.
2,6 cis-appendages whereas (Z)-1c produced the correspond-
ing piperidine 18b with trans-stereochemistry as observed in
its crystal structure (Scheme 7).18
It is worth noting that the piperidine 6a has been formed as the
sole product in the case of 1a (Eand Z), whereasfor1c (Eand Z),
different diastereomeric products (18a and 18b) have been ob-
served depending on the double-bond geometry of the substrate.
The mechanism for the formation of 18a,b from 1c is
shown in Scheme 8. Compound 1c (E and Z) follows a simi-
lar mechanism as described above for (E)-1a. The enolate
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SCHEME 6. Proposed Mechanism and Favorable Transition State for the Formation of 6a
SCHEME 7. Reaction of (E )- and (Z)-R-Cyclohexylmethyli-
dene-β-keto Ester with 2-Phenyl-N-tosylaldimine
ture (25 °C), the thermodynamically more stable isomer 18a
started forming. After the same mixture was reacted at room
temperature for 7 h both 18a and 18b were formed in ∼1:1
ratio (Scheme 8).25
Conclusion
In conclusion, we have developed a simple diastereo- as
well as enantioselective synthetic route to highly functiona-
lized piperidines via a domino imino-aldol-aza-Michael
reaction sequence. This strategy has been generalized for
aromatic, heteroaromatic, aliphatic, as well as chiral sulfinyl
imines. It is possible to obtain 2,6 cis- or trans-disubstituted
piperidines depending on the substrates (R-arylmethylidene-
or R-alkylidene-β-keto ester) and their E/Z geometry. For-
mation and the observed stereoselectivity of the products
have been explained by plausible mechanisms and further
supported by computational studies. Further synthetic and
mechanistic studies are in progress.
These observations are further supported by the computa-
tional studies.24 In the cases of both diaryl- and cyclohexyl-
aryl-substituted piperidines, the cis-isomer is found to be
thermodynamically more stable and remains in a diaxial
conformation. But the energy difference between the cis- and
trans-isomers of diaryl piperidines (1.71 kcal/mol for 6a) is
found to be larger compared to the cyclohexyl-aryl analo-
gue (0.66 kcal/mol for 18). For this reason, in the case of
diarylpiperidines, the cis-product 18a was always observed.
In the case of substrate (Z)-1c, the trans-product 18b was
observed as the only product at lower temperature (-50 °C).
Since the energy difference between the cis- and trans-
isomers of cyclohexylphenylpiperidines (18a and 18b) is very
small, it is expected that at higher temperature the thermo-
dynamically more stable cis-isomer will be formed along with
the trans-isomer. This is, in fact, supported by experimental
results. In a separate experiment when the temperature of the
reaction mixture from (Z)-1c was raised to room tempera-
Experimental Section
Procedure for the Synthesis of Ethyl 2-Benzylidene-3-oxobu-
tanoate (1a).16b To a solution of L-proline (0.33 g, 2.83 mmol)
in 15.0 mL of dry DMSO was added 0.95 mL of benzaldehyde
(1.0 g, 9.42 mmol), the mixture was stirred for 8-10 min at room
temperature, and then ethyl acetoacetate (1.44 mL, 11.31 mmol)
was added slowly into it at the same temperature and stirred for
12-14 h. After completion of the reaction as monitored by TLC,
20.0 mL of ethyl acetate was added, the mixture was stirred for a
few minutes, and then the reaction was quenched with cold
water. The organic and aqueous layers were separated, and the
aqueous layer was extracted with ethyl acetate (3 ꢀ 15.0 mL),
washed with brine, and dried over anhydrous sodium sulfate.
After removal of the solvent under reduced pressure, the crude
(25) Following an identical procedure as described for 6a in the Experi-
mental Section, after the addition of the imine at -50 °C, the reaction was
warmed to room temperature and stirred at the same temperature for
additional 7 h. After usual workup, the 1H NMR of the crude reaction
mixture indicated the formation of 18a and 18b in ∼1:1 ratio. See the
Supporting Information for the 1H NMR spectrum of the crude reaction
mixture containing 18a and 18b.
(24) Computational study of the compounds 6a, trans-6a, and 18a,b has
been performed with the Gaussian 03 program using the B3LYP exchange
corelation functional with a 6-31G* basis set. For more details, see the
Supporting Information.
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SCHEME 8. Proposed Mechanism and Favorable Transition States for the Formation of 18a and 18b
reaction mixture was purified by flash column chromatography
on silica gel (230-400 mesh) using 5% ethyl acetate in petro-
leum ether to afford 1a (1.54 g) in 75% yield as a mixture of two
diastereomers (E)-1a (0.42 g) and (Z)-1a (1.12 g) in a ratio of
1:2.7 (determined by 1H NMR spectra of the crude product).
(E)-Ethyl 2-Benzylidene-3-oxobutanoate ((E)-1a). The general
procedure described above was followed to afford (E)-1a as a
light yellow solid: mp 45-46 °C; Rf 0.46 (20% ethyl acetate in
petroleum ether); IR νmax (KBr, cm-1) 3385, 3059, 3028, 2981,
2926, 2121, 1959, 1884, 1697, 1620, 1449, 1379, 1353, 1319, 1294,
1256, 1212, 1183, 1086, 1061, 1024, 969, 943, 862, 773, 755, 711,
693, 619, 528, 476, 446; 1H NMR (400 MHz, CDCl3) δ 1.34 (t,
3H, J = 7.1 Hz), 2.35(s, 3H), 4.3 (q, 2H, J = 7.1 Hz), 7.39 (s, 5H),
7.67 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 31.2, 61.5,
128.9, 129.6, 130.4, 132.9, 134.1, 140.5, 164.4, 203.3;HRMS(ESI)
calcd for C13H15O3 (M þ Hþ) 219.1021, found 219.1021.
Procedure for the Synthesis of Ethyl 2-(4-Cyanobenzylidene)-
3-oxobutanoate (1b)16c. To a suspension of Mg(ClO4)2 (0.64
mmol) and MgSO4 (1.27 mmol) in 10.0 mL of THF were added
4-cyanobenzaldehyde (1.0 g, 7.63 mmol) and ethyl acetoacetate
(0.81 mL, 6.35 mmol) at room temperature, and the mixture was
stirred at the same temperature for 70 h. After completion of the
reaction, as monitored by TLC, 15.0 mL of CH2Cl2 was added,
and the reaction mixture was filtered through Celite. The solvent
was evaporated under reduced pressure to afford the crude
reaction mixture as a mixture of two diastereomers which was
purified by flash column chromatography on silica gel (230-400
mesh) using 8% ethyl acetate in petroleum ether to afford 1b
(1.42 g) in 76% yield as a mixture of two diastereomers (E)-1b
(0.41 g) and (Z)-1b (1.01 g) in a ratio of 1:2.5 (determined by 1H
NMR spectra of the crude product).
(E )-Ethyl 2-(4-Cyanobenzylidene)-3-oxobutanoate ((E )-1b).
The general procedure described above was followed to afford
(E)-1b as a white solid: mp 64-65 °C; Rf 0.44 (30% ethyl acetate
in petroleum ether); IR νmax (KBr, cm-1) 3442, 2984, 2229, 1730,
(Z)-Ethyl 2-Benzylidene-3-oxobutanoate ((Z)-1a). The gen-
eral procedure described above was followed to afford (Z)-1a
as a light yellow solid: mp 46-48 °C; Rf 0.34 (20% ethyl acetate
in petroleum ether); IR νmax (KBr, cm-1) 3432, 3089, 3051, 2985,
2935, 2873, 1974, 1905, 1724, 1658, 1616, 1572, 1494, 1450, 1399,
1347, 1330, 1315, 1291, 1243, 1222,1205, 1189, 1153, 1116, 1085,
1039, 1014, 948, 933, 899, 874, 861, 837, 812, 761, 693, 611, 588,
545, 465; 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H, J = 7.1 Hz),
2.43 (s, 3H), 4.34 (q, 2H, J = 7.1 Hz), 7.39 - 7.47 (m, 5H), 7.58
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8, 26.4, 61.6, 128.8,
129.4, 130.6, 132.8, 134.5, 141.2, 167.7, 194.6; HRMS (ESI)
calcd for C13H15O3 (M þ Hþ) 219.1021, found 219.1029.
1
1669, 1504, 1383, 1297, 1244, 1042, 828, 559; H NMR (400
MHz, CDCl3) δ 1.28 (t, 3H, J = 7.1 Hz), 2.29 (s, 3H), 4.20-4.30
(m, 2H), 7.19 (s, 1H), 7.52-7.63 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 31.2, 61.9, 113.6, 118.0, 129.9, 132.5, 136.9,
138.0, 138.5, 163.8, 202.1; HRMS (ESI) calcd for C14H14NO3
(M þ Hþ) 244.0973, found 244.0972.
(Z )-Ethyl 2-(4-Cyanobenzylidene)-3-oxobutanoate ((Z )-1b).
The general procedure described above was followed to afford
(Z)-1b as a white solid: mp 66-68 °C; Rf 0.37 (30% ethyl acetate
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in petroleum ether); IR νmax (KBr, cm-1) 3443, 2983, 2226, 1732,
1661, 1627, 1385, 1298, 1249, 1224, 1206, 1043, 923, 828, 560; 1H
NMR (400 MHz, CDCl3) δ 1.19 (t, 3H, J = 7.1 Hz), 2.37 (s, 3H),
4.22-4.28 (m, 2H), 7.41-7.62 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 13.8, 26.8, 62.0, 113.7, 118.0, 129.6, 132.4, 137.6,
138.5, 166.8, 193.8; HRMS (ESI) calcd for C14H14NO3 (M þ
Hþ) 244.0973, found 244.0975.
on silica gel (230-400 mesh) using 4% ethyl acetate in petro-
leum ether to afford the pure piperidines 6a-k as a white solid.
All these compounds exist in enol form as indicated by 1H NMR
spectra and crystal structure.
Compound (E)-1a and compound (Z)-1a were two diastere-
omers when separately reacted with 2-phenyl-N-tosylaldimine
3a. Following same procedure described above, compound 6a
was obtained as the only product, and the relative stereochemi-
stry in both cases was confirmed by 1H NMR spectra and X-ray
crystallographic analysis. The yield of product 6a was different
in both the cases (starting from of (E)-1a, the yield was 65% but
from (Z)-1a it was only 40%).
4-Hydroxy-2,6-diphenyl-1-(toluene-4-sulfonyl)-1,2,5,6-tetra-
hydropyridine-3-carboxylic Acid Ethyl Ester (6a). The general
procedure described above was followed when the enolate of
(E)-1a (100.0 mg, 0.46 mmol) was reacted with 119.0 mg (0.46
mmol) of 3a (0.46 mmol) at -50 °C for 3.0 h to afford 6a (142.8
mg, 65% yield) as a white solid: mp 162-164 °C; Rf 0.5 (20%
ethyl acetate in petroleum ether); IR νmax (KBr, cm-1) 3423,
3058, 2925, 1650, 1621, 1494, 1451, 1427, 1406, 1379, 1360, 1343,
1295, 1261, 1223, 1186, 1162, 1096, 1076, 1027, 992, 954, 917, 848,
814, 779, 753, 726, 696, 683, 656, 626, 578, 560, 531;1H NMR(500
MHz, CDCl3) δ 1.05 (t, 3H, J = 7.3 Hz), 2.34 (dd, 1H, J = 6.9,
17.6 Hz), 2.45 (s, 3H), 2.62 (dd, 1H, J = 5.4, 17.6 Hz), 4.02-4.14
(m, 2H), 5.06-5.10 (m, 1H), 6.13 (s, 1H), 6.96-7.02 (m, 5H),
7.03-7.06 (m, 3H), 7.10-7.14 (m, 2H), 7.30 (d, 2H, J = 8.0 Hz),
7.78 (d, 2H, J = 8.4 Hz), 12.27 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 21.6, 31.2, 54.1, 55.3, 60.8, 98.1, 126.7, 127.2,
127.3, 127.6, 127.7, 127.9, 129.8, 136.6, 139.3, 139.7, 143.8, 170.0,
170.7; HRMS (ESI) calcd for C27H28NO5S (M þ Hþ) 478.1688,
found 478.1686.
Procedure for the Synthesis of Ethyl 2-(Cyclohexylmethylene)-
3-oxobutanoate (1c)16b. To a solution of L-proline (0.31 g, 2.7
mmol) in 15.0 mL of dry DMSO was added 1.08 mL of cyclo-
hexyl carboxaldehyde (1.0 g, 8.92 mmol), the resulting solution
was stirred for 8-10 min at room temperature, and then ethyl
acetoacetate (1.36 mL, 10.7 mmol) was added slowly at the same
temperature followed by stirred for 12-14 h. After completion
of the reaction as monitored by TLC, 20.0 mL ethyl acetate was
added, the mixture was stirred for a few minutes, and then the
reaction was quenched with cold water. The organic and aqu-
eous layers were separated, and the aqueous layer was extracted
with ethyl acetate (3 ꢀ 15.0 mL), washed with brine, and dried
over anhydrous sodium sulfate. After removal of the solvent
under reduced pressure, the crude reaction mixture was purified
by flash column chromatography on silica gel (230-400 mesh)
using 5% ethyl acetate in petroleum ether to afford 1c (1.56 g) in
78% yield as a mixture of two diastereomers (E)-1c (0.58 g) and
(Z)-1c (0.98 g) in a ratio of 1:1.7 (determined by 1H NMR
spectra of the crude product).
(E)-Ethyl 2-(Cyclohexylmethylene)-3-oxobutanoate ((E)-1c).
The general procedure described above was followed to afford
(E)-1c as a colorless liquid: Rf 0.56 (15% ethyl acetate in
petroleum ether); IR νmax (neat, cm-1) 3386, 2981, 2929, 2854,
1706, 1634, 1449, 1373, 1303, 1273, 1253, 1226, 1148, 1101, 1054,
966, 863, 762, 619, 565; 1H NMR (400 MHz, CDCl3) δ
1.09-1.24 (m, 3H), 1.28 (t, 3H, J = 7.1 Hz), 1.64-1.73 (m,
6H), 2.29-2.33 (m, 1H), 2.35 (s, 3H), 4.17-4.30 (m, 2H), 6.69 (d,
1H, J = 10.5 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 25.2,
25.6, 26.9, 31.8, 39.3, 61.1, 135.3, 152.5, 166.7, 201.3; HRMS
(ESI) calcd for C13H21O3 (M þ Hþ) 225.1490, found 225.1499.
(Z)-Ethyl 2-(Cyclohexylmethylene)-3-oxobutanoate ((Z)-1c).
The general procedure described above was followed to afford
(Z)-1c as a colorless liquid: Rf 0.48 (15% ethyl acetate in
petroleum ether); IR νmax (neat, cm-1) 3331, 2981, 2930, 2853,
1732, 1697, 1672, 1634, 1449, 1380, 1305, 1273, 1260, 1210, 1150,
1104, 1035, 967, 947, 909, 854, 792, 620, 564, 543; 1H NMR (400
MHz, CDCl3) δ 1.06-1.24 (m, 6H), 1.27 (t, 3H, J = 7.3 Hz),
1.60-1.69 (m, 4H), 2.24 (s, 1H), 2.28-2.34 (m, 1H), 4.24 (q,
2H, J = 7.3 Hz), 6.56 (d, 1H, J = 10.3 Hz); 13C NMR (100
MHz, CDCl3) δ 14.1, 25.1, 25.6, 26.8, 31.7, 39.2, 60.1, 135.2,
152.6, 166.6, 195.4; HRMS (ESI) calcd for C13H21O3 (M þ Hþ)
225.1490, found 225.1496.
Procedure for the Synthesis of N-Tosyl 2,6-Disubstituted
Piperidines. To a solution of diisopropylamine (0.08 mL, 0.55
mmol) in 2.0 mL of dry THF was added 2.0 M n-BuLi (0.28 mL,
0.55 mmol) at 0 °C and the mixture stirred for 30 min under
argon atmosphere. The color of the solution changed to yellow,
the temperature was dropped to -50 °C, compound (E)-1a (100
mg, 0.46 mmol) dissolved in 1.0 mL of dry THF was added
slowly, and the resulting mixture was stirred for 1 h to allow the
formation of enolate. Then 2-aryl-N-sulfonylaldimine 3a-j
(0.46 mmol) dissolved in 1.5 mL of dry THF was added and
the mixture stirred for an additional 2-4 h at the same tem-
perature. After completion of the reaction as monitored by
TLC, the reaction was quenched with saturated aqueous am-
monium chloride solution. The organic and aqueous layers were
separated, and the aqueous layer was extracted with ethyl
acetate (3 ꢀ 5.0 mL). The combined organic extracts were
washed with brine and dried over anhydrous sodium sulfate.
After removal of the solvent under reduced pressure, the crude
reaction mixture was purified by flash column chromatography
6-(2-Chlorophenyl)-4-hydroxy-2-phenyl-1-(toluene-4-sulfonyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic AcidEthyl Ester(6b). The
generalproceduredescribedabove was followed when the enolate
of (E)-1a (100.0 mg, 0.46 mmol) was reacted with 135.0 mg of 3b
(0.46 mmol) at -50 °C for 3.5 htoafford 6b (155.4 mg, 66%yield)
as a white solid: mp 175-178 °C; Rf 0.45 (20% ethyl acetate in
petroleum ether); IR νmax (KBr, cm-1) 3425, 3065, 2924, 2855,
1662, 1632, 1597, 1493, 1451, 1411, 1356, 1290, 1262, 1230, 1164,
1090, 1042, 954, 817, 756, 734, 701, 661, 622, 564, 544, 470; 1H
NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J = 7.1Hz), 2.28 (dd, 1H,
J = 11.2, 16.4 Hz), 2.44 (s, 3H), 2.59 (dd, 1H, J = 5.8, 16.4 Hz),
4.10-4.30 (m, 2H), 5.13-5.21 (m, 1H), 6.25 (s, 1H), 6.90-7.11
(m, 3H), 7.15-7.32 (m, 4H), 7.33-7.41 (m, 2H), 7.53 (d, 2H, J =
7.3 Hz), 7.79 (d, 2H, J = 8.3 Hz), 11.97 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 14.3, 21.6, 34.4, 55.4, 56.7, 60.9, 98.7, 127.2,
127.6, 127.9, 128.4, 128.5, 128.7, 129.2, 129.6, 131.5, 134.6, 139.5,
139.9, 144.0, 169.3, 172.2; HRMS (ESI) calcd for C27H27ClNO5S
(M þ Hþ) 512.1298, found 512.1296.
6-(3-Bromophenyl)-4-hydroxy-2-phenyl-1-(toluene-4-sulfonyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6c). The
general procedure described above was followed when the
enolate of (E)-1a (100.0 mg, 0.46 mmol) was reacted with
155.0 mg of 3c (0.46 mmol) at -50 °C for 3.5 h to afford 6c
(161.0 mg, 63% yield) as a white solid: mp 128-130 °C; Rf 0.47
(20% ethyl acetate in petroleum ether); IR νmax (KBr, cm-1
)
3424, 3056, 2924, 2854, 1667, 1624, 1432, 1403, 1372, 1346,
1301, 1224, 1158, 1094, 1075, 1026, 993, 958, 902, 813, 774, 741,
704, 660, 625, 561, 462; 1H NMR (500 MHz, CDCl3) δ 1.06 (t,
3H, J = 7.3 Hz), 2.33 (dd, 1H, J = 7.3, 17.9 Hz), 2.44 (s, 3H),
2.55 (dd, 1H, J = 5.4, 17.9 Hz), 4.03-4.15 (m, 2H), 5.04-5.07
(m, 1H), 6.11 (s, 1H), 6.83-6.89 (m, 1H), 6.94 (d, 1H, J = 7.7
Hz), 7.02-7.14 (m, 7H), 7.30 (d, 2H, J = 8.0 Hz), 7.75 (d, 2H,
J = 8.0 Hz), 12.25 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9,
21.6, 30.7, 54.0, 54.7, 60.9, 98.1, 122.2, 125.8, 127.1, 127.2,
127.5, 127.8, 129.5, 129.9, 130.4, 130.6, 136.5, 139.3, 141.5,
144.0, 169.9, 170.2; HRMS (ESI) calcd for C27H27BrNO5S
(M þ Hþ) 556.0793, found 556.0794.
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6-(4-Chlorophenyl)-4-hydroxy-2-phenyl-1-(toluene-4-sulfonyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6d).
The general procedure described above was followed when the
enolate of (E)-1a (100.0 mg, 0.46 mmol) reacted with 135.0 mg of
3d (0.46 mmol) at -50 °C for 3.0 h to afford 6d (160.0 mg, 68%
yield) as a white solid: mp 145-148 °C; Rf 0.45 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm-1) 3444, 3063,
2924, 1656, 1621, 1494, 1433, 1405, 1343, 1298, 1222, 1162, 1095,
1029, 993, 957, 884, 825, 751, 715, 686, 657, 578, 541; 1H NMR
(400 MHz, CDCl3) δ 1.05 (t, 3H, J = 7.1 Hz), 2.32 (dd, 1H, J =
7.1, 17.6 Hz), 2.45 (s, 3H), 2.57 (dd, 1H, J = 5.1, 17.8 Hz),
4.02-4.14 (m, 2H), 5.06-5.09 (m, 1H), 6.11 (s, 1H), 6.86-6.97
(m, 4H), 7.04-7.13 (m, 5H), 7.31 (d, 2H, J = 8.1 Hz), 7.76 (d,
2H, J = 8.3 Hz), 12.27 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
13.9, 21.6, 30.8, 54.0, 54.5, 60.9, 98.1, 126.8, 127.2, 127.5, 127.8,
128.0, 128.7, 129.9, 136.5, 137.8, 139.5, 144.0, 169.9, 170.3;
HRMS (ESI) calcd for C27H27ClNO5S (M þ Hþ) 512.1298,
found 512.1296.
4-Hydroxy-6-(4-nitrophenyl)-2-phenyl-1-(toluene-4-sulfonyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6e).
The general procedure described above was followed when the
enolate of (E)-1a (100.0 mg, 0.46 mmol) reacted with 140.0 mg
of 3e (0.46 mmol) at -50 °C for 3.0 h to afford 6e (168.2 mg,
70% yield) as a white solid: mp 175-179 °C; Rf 0.33 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm-1) 3447, 2981,
1659, 1628, 1600, 1517, 1494, 1435, 1404, 1345, 1307, 1267,
1227, 1186, 1162, 1092, 1024, 1007, 987, 923, 890, 851, 802, 741,
700, 679, 654, 619,564, 547, 464; 1H NMR (400 MHz, CDCl3) δ
1.07 (t, 3H, J = 7.1 Hz), 2.38 (dd, 1H, J = 7.1, 17.8 Hz), 2.46 (s,
3H), 2.61 (dd, 1H, J = 5.4, 17.8 Hz), 4.02-4.19 (m, 2H),
5.14-5.18 (m, 1H), 6.14 (s, 1H), 7.03-7.08 (m, 3H), 7.09-7.20
(m, 4H), 7.33 (d, 2H, J = 8.0 Hz), 7.77 (d, 2H, J = 8.0 Hz), 7.84
(d, 2H, J = 8.8 Hz), 12.27 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 13.9, 21.6, 30.7, 54.2, 54.8, 61.0, 98.2, 123.1, 127.2,
127.6, 127.9, 128.2, 130.0, 136.1, 139.2, 144.3, 146.8, 169.7;
HRMS (ESI) calcd for C27H26N2O7SNa (M þ Naþ) 545.1358,
found 545.1357.
(s, 1H), 6.90-6.99 (m, 8H), 7.05-7.08 (m, 2H), 7.42-7.48 (m,
2H), 7.52-7.57 (m, 1H), 7.83 (d, 2H, J = 8.6 Hz), 12.16 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 13.9, 31.2, 54.3, 55.5, 60.8,
98.1, 127.3, 127.6, 127.7, 127.8, 128.0, 129.2, 133.0, 139.3,
139.5, 169.9, 170.8; HRMS (ESI) calcd for C26H26NO5S
(M þ Hþ) 464.1531, found 464.1533.
1-Benzenesulfonyl-4-hydroxy-6-(4-methoxyphenyl)-2-phenyl-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6h).
The general procedure described above was followed when the
enolate of (E)-1a (100.0 mg, 0.46 mmol) reacted with 126.0 mg
of 3h (0.46 mmol) at -50 °C for 3.5 h to afford 6h (140.8 mg,
62% yield) as a white solid: mp 144-146 °C; Rf 0.32; (20%
ethyl acetate in petroleum ether); IR νmax (KBr, cm-1) 3448,
2929, 1654, 1618, 1513, 1448, 1404, 1348, 1301, 1253, 1226,
1162, 1096, 1077, 1029, 990, 880, 829, 802, 753, 738, 695, 628,
576, 551, 465.; 1H NMR (400 MHz, CDCl3) δ 0.98 (t, 3H, J =
7.1 Hz), 2.24 (dd, 1H, J = 7.1, 17.8 Hz), 2.53 (dd, 1H, J = 5.1,
17.8 Hz), 3.62 (s, 3H), 3.92-4.09 (m, 2H), 5.00-5.04 (m, 1H),
6.05 (s, 1H), 6.44 (d, 2H, J = 8.8 Hz), 6.80 (d, 2H, J = 8.3 Hz),
6.95-7.06 (m, 5H), 7.42-7.49 (m, 2H), 7.52-7.58 (m, 1H),
7.82 (d, 2H, J = 8.3 Hz), 12.18 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 31.1, 54.1, 54.7, 55.2, 60.8, 98.0, 113.3, 127.2,
127.5, 127.6, 128.5, 128.6, 129.2, 131.1, 132.9, 139.7, 158.7,
170.0, 170.8; HRMS (ESI) for calcd C27H28NO6S (M þ Hþ)
494.1637, found 494.1633.
4-Hydroxy-2-phenyl-6-styryl-1-(toluene-4-sulfonyl)-1,2,5,6-
tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6i). The gen-
eral procedure described above was followed when the enolate
of (E)-1a (100.0 mg, 0.46 mmol) reacted with 131.0 mg of 3i
(0.46 mmol) at -50 °C for 3.0 h to afford 6i (145.9 mg, 63%
yield) as a white solid: mp 122-124 °C; Rf 0.48 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm-1) 3448, 3030,
2925, 1653, 1623, 1493, 1450, 1425, 1404, 1342, 1304, 1260,
1219, 1184, 1160, 1092, 1021, 975, 917, 818, 801, 731, 695, 673,
613, 576, 551, 473; 1H NMR (400 MHz, CDCl3) δ 1.08 (t, 3H,
J = 7.1 Hz), 2.34-2.39 (m, 2H), 2.43 (s, 3H), 4.03-4.20 (m,
2H), 4.78-4.82 (m, 1H), 5.53-5.61 (m, 1H), 6.12 (s, 1H), 6.20
(d, 1H, J = 16.1 Hz), 6.83-6.91 (m, 2H), 7.12-7.23 (m, 5H),
7.25-7.30 (m, 3H),7.37 (d, 2H, J = 7.3 Hz), 7.74 (d, 2H, J =
8.3 Hz), 12.31 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 14.0,
21.5, 30.2, 53.0, 53.3, 60.8, 97.9, 126.4, 127.0, 127.1, 127.6,
128.0, 128.1, 128.2, 129.7, 129.8, 130.6, 136.0, 137.1, 140.6,
143.8, 170.3; HRMS (ESI) calcd for C29H29NO5SNa (M þ
Naþ) 526.1664, found 526.1667.
6-Furan-2-yl-4-hydroxy-2-phenyl-1-(toluene-4-sulfonyl)-1,2,5,6-
tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6j). The gen-
eral procedure described above was followed when the enolate
of (E)-1a (100.0 mg, 0.46 mmol) reacted with 115.0 mg of 3j
(0.46 mmol) at -50 °C for 3.0 h to afford 6j (141.9 mg, 66%
yield) as a white solid: mp 172-176 °C; Rf 0.46 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm-1) 3449, 2979,
2924, 1656, 1495, 1452, 1409, 1379, 1350, 1302, 1227, 1185,
1163, 1093, 1028, 966, 913, 886, 810, 733, 701, 672, 621, 595,
570, 549; 1H NMR (400 MHz, CDCl3) δ 0.92 (t, 3H, J = 7.1
Hz), 2.37 (s, 3H), 2.43 (dd, 1H, J = 7.6, 18.1 Hz), 2.55 (dd, 1H,
J = 2.7, 18.3 Hz), 3.91-4.08 (m, 2H), 5.21 (d, 1H, J = 5.8 Hz),
5.78 (d, 1H, J = 3.2 Hz), 5.84-5.87 (m, 1H), 6.0 (s, 1H), 6.77 (s,
1H), 6.92-7.01 (m, 4H), 7.19-7.24 (m, 3H), 7.70 (d, 2H, J =
8.3 Hz) 12.34 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9,
21.7, 28.9, 47.9, 53.1, 60.8, 97.5, 108.6, 110.2, 126.4, 127.3,
127.5, 127.6, 129.9, 137.2, 139.7, 142.2, 143.9, 150.7, 169.9,
170.4; HRMS (ESI) calcd for C25H25NO6SNa (M þ Naþ)
490.1300, found 490.1306.
4-Hydroxy-6-(4-methoxyphenyl)-2-phenyl-1-(toluene-4-sulfonyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (6f).
The general procedure described above was followed when the
enolate of (E)-1a (100.0 mg, 0.46 mmol) reacted with 133.0 mg
of 3f (0.46 mmol) at -50 °C for 4.0 h to afford 6f (135.4 mg,
58% yield) as a white solid: mp 148-152 °C; Rf 0.4 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm-1) 3448, 2924,
2854, 1741, 1657, 1513, 1458, 1426, 1403, 1376, 1343, 1300,
1256, 1232, 1160, 1097, 1031, 883, 813, 752, 731, 702, 686, 655,
623, 557, 465; 1H NMR (400 MHz, CDCl3) δ 0.97 (t, 3H, J =
7.1 Hz), 2.25 (dd, 1H, J = 6.6, 17.3 Hz), 2.38 (s, 3H), 2.53 (dd,
1H, J = 4.9, 17.6 Hz), 3.61 (s, 3H), 3.92-4.09 (m, 2H),
4.99-5.02 (m, 1H), 6.03 (s, 1H), 6.43(d, 2H, J = 8.8 Hz),
6.80 (d, 2H, J = 8.8 Hz), 6.93-7.04 (m, 4H), 7.19 -7.27 (m,
3H), 7.70 (d, 2H, J = 8.3 Hz), 12.20 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 13.9, 21.6, 30.9, 53.9, 54.5, 55.2, 60.7, 98.0,
113.3, 126.5, 127.2, 127.5, 127.6 128.5, 129.8, 131.1, 136.8,
139.9, 143.7, 158.6, 170.1, 170.7; HRMS (ESI) calcd for
C
28H29NO6SNa (M þ Naþ) 530.1613, found 530.1618.
1-Benzenesulfonyl-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydro-
pyridine-3-carboxylic Acid Ethyl Ester (6g). The general pro-
cedure described above was followed when the enolate of
(E)-1a (100.0 mg, 0.46 mmol) reacted with 113.0 mg of 3g
(0.46 mmol) at -50 °C for 2.5 h to afford 6g (136.4 mg, 64%
yield) as a white solid: mp 184-186 °C; Rf 0.43 (20% ethyl
acetate in petroleum ether); IR νmax (KBr, cm-1) 3447, 3034,
2925, 2855, 1963, 1663, 1630, 1496, 1451, 1425, 1402, 1370,
1341, 1302, 1233, 1163, 1096, 1026, 987, 925, 882, 782, 747, 692,
629, 578, 552, 464; 1H NMR (400 MHz, CDCl3) δ 0.99, (t, 3H,
J = 7.1 Hz), 2.27 (dd, 1H, J = 7.1, 17.6 Hz), 2.56 (dd, 1H, J =
5.6, 17.8 Hz), 3.93-4.09 (m, 2H), 5.01-5.05 (m, 1H), 6.07
Ethyl 2-(4-Cyanophenyl)-4-hydroxy-6-phenyl-1-tosyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (6k). The general procedure
described above was followed when the enolate of 1b (100.0 mg,
0.41 mmol) reacted with 106.0 mg of 3a (0.41 mmol) at -50 °C
for 3.5 h to afford 6k (128 mg, 62% yield) as a white solid: mp
J. Org. Chem. Vol. 75, No. 21, 2010 7069

Ghorai et al.
JOCFeatured Article
163-165 °C; Rf 0.32 (20% ethyl acetate in petroleum ether); IR
νmax (KBr, cm-1) 2924, 2853, 2228, 1737, 1658, 1602, 1498,
1453, 1409, 1351, 1303, 1259, 1230, 1161, 1093, 1020, 954, 812,
756, 692, 659, 606, 554; 1H NMR (400 MHz, CDCl3) δ 0.87 (t,
3H, J = 7.1 Hz), 2.1 (dd, 1H, J = 7.3, 18.3 Hz), 2.40 (s, 3H), 2.62
(dd, 1H, J = 2.0, 18.6 Hz), 3.90-4.06 (m, 2H), 5.20-5.22 (m,
1H), 6.0 (s, 1H), 6.82-6.95 (m, 5H), 6.99 (d, 2H, J = 8.3 Hz),
7.12 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J = 7.8 Hz), 7.72 (d, 2H,
J = 8.0 Hz), 12.39 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.9,
21.8, 28.5, 52.9, 53.2, 61.1, 96.4, 109.9, 119.1, 127.1, 127.7, 127.8,
128.1, 128.3, 128.8, 130.3, 131.1, 136.9, 137.2, 144.4, 145.8,
170.0, 170.9; HRMS (ESI) calcd for C28H27N2O5S (M þ Hþ)
503.1640, found 503.1647.
extracted with ethyl acetate (3 ꢀ 5.0 mL). The combined organic
extract was washed with brine and dried over anhydrous sodium
sulfate. After removal of the solvent under reduced pressure, the
crude reaction mixture was purified by flash column chroma-
tography on silica gel (230-400 mesh) using 3-4% ethyl acetate
in petroleum ether as eluent to afford the pure piperidines 12a,b
as a white solid. All these compounds exist in enol form as
indicated by 1H NMR spectra and crystal structure.
Ethyl 4-Hydroxy-6(E)-(pent-2-en-2-yl)-2-phenyl-1-tosyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (12a). The general procedure
described above was followed when the enolate of (E)-1a (100.0
mg, 0.46 mmol) reacted with 115.0 mg of 11a (0.46 mmol) at
-50 °C for 6 h to afford 12a (125.0 mg, 58% yield) as a white
solid: mp 154-156 °C; Rf 0.43 (20% ethyl acetate in petroleum
ether); IR νmax (KBr, cm-1) 3443, 3059, 2960, 2930, 2872, 1656,
1621, 1492, 1451, 1408, 1344, 1297, 1233, 1184, 1162, 1094,
1026, 993, 963, 894, 809, 749, 701, 687, 655, 627, 561; 1H NMR
(500 MHz, CDCl3) δ 0.82 (t, 3H, J = 7.6 Hz), 0.95-1.01 (m,
6H), 1.48-1.55 (m, 1H), 1.63-1.71 (m, 1H), 2.07 (dd, 1H, J =
7.3, 18.4 Hz), 2.39-2.46 (m, 4H), 4.01-4.16 (m, 2H), 4.38 (d,
1H, J = 6.9 Hz), 4.95-5.01 (m, 1H), 6.07 (s, 1H), 7.13-7.21
(m, 3H), 7.25-7.29 (m, 4H), 7.73 (d, 2H, J = 8.5 Hz), 12.38 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 13.4, 14.0, 14.2, 21.3, 21.7,
28.4, 53.5, 56.0, 60.7, 96.4, 126.8, 127.1, 127.3, 128.7, 129.7,
129.9, 132.4, 137.4, 140.0, 143.8, 170.6, 170.9; HRMS (ESI)
calcd for C26H32NO5S (M þ Hþ) 470.2001, found 470.2004.
Ethyl 6-(E)-Hept-3-en-3-yl)-4-hydroxy-2-phenyl-1-tosyl-1,2,5,6-
tetrahydropyridine-3-carboxylate (12b). The general procedure
described above was followed when the enolate of (E)-1a (100.0
mg, 0.46 mmol) reacted with 128.0 mg of 11b (0.46 mmol) at
-50 °C for 6.5 h to afford 12b (128.0 mg, 56% yield) as a white
solid: mp 142-144 °C; Rf 0.46 (20% ethyl acetate in petroleum
ether); IR νmax (KBr, cm-1) 3426, 3059, 2963, 2929, 1660, 1606,
1495, 1459, 1427, 1403, 1368, 1344, 1295, 1223, 1161, 1095,
1029, 987, 812, 751, 703, 656, 590, 560, 536, 457; 1H NMR (500
MHz, CDCl3) δ 0.70 (t, 3H, J = 7.5 Hz), 0.82 (t, 3H, J = 7.5
Hz), 0.99 (t, 3H, J = 7.8 Hz), 1.10-1.31 (m, 3H), 1.43-1.54 (m,
2H), 1.59-1.68 (m, 1H), 2.15 (dd, 1H, J = 7.4, 18.3 Hz),
2.34-2.40 (m, 1H), 2.43 (s, 3H), 4.01-4.16 (m, 2H), 4.52 (d,
1H, J = 7.5 Hz), 4.90-4.96 (m, 1H), 6.04 (s, 1H), 7.11 -7.20
(m, 3H), 7.23-7.32 (m, 4H), 7.74 (d, 2H, J = 8.0 Hz), 12.40 (s,
1H); 13C NMR (125 MHz, CDCl3) δ 12.8, 13.9, 14.0, 20.1, 21.6,
22.2, 28.4, 29.7, 52.6, 53.1, 53.2, 60.6, 96.3, 126.5, 127.0, 128.0,
128.1, 128.6, 129.8, 137.3, 138.7, 139.7, 143.7, 170.5, 170.9;
HRMS (ESI) calcd for C28H36NO5S (M þ Hþ) 498.2314,
found 498.2315.
Procedure for the Synthesis of 2-Alkenyl-N-tosylaldimines.
p-Toluenesulfonamide (2.0 g, 11.68 mmol) and aliphatic alde-
hyde 7 (17.52 mmol) were taken in 15.0 mL of benzene, and then
BF3 OEt2 (0.15 mL, 1.2 mmol) was added at room temperature
3
and heated to reflux at 85-90 °C with a Dean-Stark apparatus
for 5-6 h. After completion of the reaction as monitored by
TLC, the solvent was evaporated under reduced pressure, and
then the crude reaction mixture was purified by flash column
chromatography on silica gel (230-400 mesh) using 10% ethyl
acetate in petroleum ether as eluent to obtain pure aldimines
11a,b as a white solid.
4-Methyl-N-((E)-2-methylpent-2-enylidene)benzenesulfonamide
(11a). The general procedure described above was followed
when 1.3 mL of propionaldehyde 7a (1.02 g, 17.52 mmol) was
reacted with 2.0 g of p-toluene sulfonamide (11.68 mmol) to
afford 11a (1.9 g, 65% yield) as a white solid: mp 40-42 °C;
Rf 0.38 (20% ethyl acetate in petroleum ether); IR νmax (KBr,
cm-1) 3437, 2968, 2930, 2875, 1922, 1631, 1569, 1493, 1450,
1402, 1317, 1262, 1229, 1156, 1088, 1042, 913, 883, 843, 810,
772, 675, 607, 550, 491, 466; 1H NMR (400 MHz, CDCl3)
δ 1.09 (t, 3H, J = 7.6 Hz), 1.84 (s, 3H), 2.34-2.42 (m, 2H),
2.43 (s, 3H), 6.52 (t, 1H, J = 7.3 Hz), 7.33 (d, 2H, J = 8.1 Hz),
7.83 (d, 2H, J = 8.3 Hz), 8.51 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 10.8, 12.7, 21.6, 23.0, 127.8, 129.6, 134.7, 135.6,
144.2, 158.4, 174.1; HRMS (ESI) calcd for C13H18NO2S (M þ
Hþ) 252.1058, found 252.1059.
N-((E)-2-Ethylhex-2-enylidene)-4-methylbenzenesulfonamide
(11b). The general procedure described above was followed
when 1.6 mL of butyraldehyde 7b (1.3 g, 17.52 mmol) was
reacted with 2.0 g of p-toluenesulfonamide (11.68 mmol) to
afford 11b (2.18 g, 67% yield) as a white solid: mp 53-55 °C; Rf
0.42 (20% ethyl acetate in petroleum ether); IR νmax (KBr,
cm-1) 3439, 2958, 2870, 1631, 1570, 1462, 1398, 1317, 1288,
1237, 1210, 1164, 1085, 1042, 915, 863, 815, 778, 707, 673, 628,
Procedure for the Synthesis of N-Sulfinyl 2,6-Disubstituted
Piperidines. To a solution of diisopropylamine (0.08 mL, 0.55
mmol) in 2.0 mL of dry THF was added n-BuLi 2.0 M) (0.28 mL,
0.55 mmol) at 0 °C and the mixture stirred for 30 min. The color
of the solution changed to yellow, the temperature was dropped
to -50 °C, compound (E)-1a (100.0 mg, 0.46 mmol) dissolved in
1.0 mL of dry THF was added, and the mixture was stirred for
1 h to allow the formation of enolate. Then 2-aryl-N-sulfiny-
laldimine 13a-d (0.183 mmol) dissolved in 1.0 mL of dry THF
was added and the mixture stirred for an additional 8-10 h at
the same temperature. After completion of the reaction as
monitored by TLC, the reaction was quenched with saturated
aqueous ammonium chloride solution. The organic and aqu-
eous layers were separated, and the aqueous layer was extracted
with ethyl acetate (3 ꢀ 5.0 mL). The combined organic extract
was washed with brine and dried over anhydrous sodium
sulfate. After removal of the solvent under reduced pressure,
the crude reaction mixture was purified by flash column chro-
matography on silica gel (230-400 mesh) using 8% ethyl acetate
in petroleum ether to afford the pure piperidines 14a-d. All
1
584, 561, 543, 467; H NMR (400 MHz, CDCl3) δ 0.86-0.93
(m, 6H), 1.45 (q, 2H, J = 7.3 Hz), 2.24-2.32 (m, 4H), 2.36 (s,
3H), 6.40 (t, 1H, J = 7.3 Hz), 7.20-7.29 (m, 2H), 7.74-7.77
(m, 2H), 8.4 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.1, 13.8,
18.6, 21.6, 21.9, 31.3, 127.7, 129.6, 135.8, 141.2, 144.1, 156.8,
173.6; HRMS (ESI) calcd for C15H22NO2S (M þ Hþ)
280.1371, found 280.1370.
Procedure for the Synthesis of N-Tosylalkenyl-Substituted
Piperidines. To a solution of diisopropylamine (0.08 mL, 0.55
mmol) in 2.0 mL of dry THF was added 2.0 M n-BuLi (0.28 mL,
0.55 mmol) at 0 °C and the mixture stirred for 30 min. The color
of the solution changed to yellow, the temperature was dropped
to -50 °C, compound (E)-1a (100.0 mg, 0.46 mmol) dissolved in
1.0 mL of dry THF was added slowly, and the mixture was
stirred for 1 h to allow the formation of enolate. Then 2-alkenyl-
N-tosylaldimine 11a,b (0.46 mmol), dissolved in 1.0 mL of dry
THF, was added, and the mixture was stirred for an additional
6-6.5 h at the same temperature. After completion of the
reaction as monitored by TLC, the reaction was quenched with
saturated aqueous ammonium chloride solution. The organic
and aqueous layers were separated, and the aqueous layer was
1
these compounds exist in enol form as indicated by H NMR
spectra and crystal structure.
7070 J. Org. Chem. Vol. 75, No. 21, 2010

Ghorai et al.
JOCFeatured Article
4-Hydroxy-2,6-diphenyl-1-(toluene-4-sulfinyl)-1,2,5,6-tetra-
hydropyridine-3-carboxylic Acid Ethyl Ester (14a). The general
procedure described above was followed when the enolate of
(E)-1a (100.0 mg, 0.46 mmol) reacted with 44.6 mg of 13a (0.18
mmol) at -50 °C for 8.0 h to afford 14a (47.0 mg, 55% yield) as
a white solid: mp 120-122 °C; Rf 0.58 (30% ethyl acetate in
petroleum ether); [R]25D = -73.3 (c 0.685 in CHCl3); IR νmax
(KBr, cm-1) 3446, 2922, 2853, 1655, 1493, 1453, 1404, 1301,
1264, 1225, 1182, 1071, 1018, 910, 813, 754, 695, 570, 469, 432;
1H NMR (500 MHz, CDCl3) δ 1.05 (t, 3H, J = 7.3 Hz), 2.37 (s,
3H), 2.73 (dd, 1H, J = 5.4, 17.2 Hz), 2.97 (dd, 1H, J = 7.3, 17.2
Hz), 4.02-4.15 (m, 2H), 4.95-5.0 (m, 1H), 5.58 (s, 1H), 6.51 (d,
2H, J = 7.3 Hz), 6.80-6.84 (m, 2H), 6.87-6.92 (m, 1H),
7.14-7.24 (m, 5H), 7.29 (d, 2H, J = 6.9 Hz), 7.46 (d, 2H,
J = 8.0 Hz), 12.36 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
13.8, 21.3, 34.8, 51.5, 59.1, 60.6, 101.2, 125.8, 125.9, 127.2,
127.3, 127.6, 127.8, 128.4, 129.3, 140.1, 140.4, 141.6, 142.6,
170.2, 170.3; HRMS (ESI) calcd for C27H28NO4S (M þ Hþ)
462.1739, found 462.1735.
4-Hydroxy-6-(4-nitrophenyl)-2-phenyl-1-(toluene-4-sulfinyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (14b).
The general procedure described above was followed when the
enolate of (E)-1a (100.0 mg, 0.46 mmol) reacted with 52.8 mg of
13b (0.183 mmol) at -50 °C for 8.5 h to afford 14b (53.0 mg,
58% yield) as a light yellow solid: mp 148-152 °C; Rf 0.44
(30% ethyl acetate in petroleum ether); [R]25D = þ23.3 (c 0.85
in CHCl3); IR νmax (KBr, cm-1) 3446, 2922, 1656, 1518, 1449,
1403, 1382, 1347, 1298, 1224, 1169, 1094, 1075, 988, 889, 850,
814, 752, 702, 461; 1H NMR (400 MHz, CDCl3) δ 0.99 (t, 3H,
J = 7.1 Hz), 2.44 (s, 3H), 2.65 (dd, 1H, J = 6.4, 17.8 Hz), 2.86
(dd, 1H, J = 4.6, 17.8 Hz), 4.0-4.16 (m, 2H), 4.97-5.03 (m,
1H), 5.64 (s, 1H), 6.5 (d, 2H, J = 7.6 Hz), 6.75-6.93 (m, 3H),
7.25-7.35 (m, 4H), 7.58 (d, 2H, J = 7.8 Hz), 7.89 (d, 2H, J =
8.5 Hz), 12.50 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.8,
21.5, 32.2, 53.2, 55.9, 60.8, 100.2, 123.2, 125.6, 126.4, 127.1,
127.3, 128.8, 129.8, 140.2, 141.0, 142.3, 146.9, 147.0, 169.5,
170.1; HRMS (ESI) calcd for C27H27N2O6S (M þ Hþ)
507.1589, found 507.1595.
reaction mixture was purified by flash column chromatography
on silica gel (230-400 mesh) using 8% ethyl acetate in petro-
leum ether to afford (2R,6R)-6d,f as a white solid.
(2R,6R)-Ethyl-6-(4-chlorophenyl)-4-hydroxy-2-phenyl-1-tosyl-
1,2,5,6-tetrahydropyridine-3-carboxylate [(2R,6R)-6d]. The gen-
eral procedure described above was followed when the piperidine
14c (25 mg 0.05 mmol) was reacted with m-chloroperbenzoic acid
(17.5 mg, 0.1 mmol) at room temperature for 2.5 h to afford
(2R,6R)-6d (16.8 mg, 65% yield) as a white solid: [R]25D = -29.8
(c 0.275 in CHCl3). For detailed spectral data, see compound 6d.
(2R,6R)-Ethyl 4-Hydroxy-6-(4-methoxyphenyl)-2-phenyl-1-to-
syl-1,2,5,6-tetrahydropyridine-3-carboxylate [(2R,6R)-6f]. The
general procedure described above was followed when the piper-
idine 14d (25 mg 0.05 mmol) was reacted with m-chloroperben-
zoic acid (17.5 mg, 0.1 mmol) at room temperature for 3.0 h to
afford (2R,6R)-6f (17 mg, 65% yield) as a white solid: [R]25
=
D
-12.9 (c 0.255 in CHCl3). For detailed spectral data, see com-
pound 6f.
Procedure for the Synthesis of N-Tosyl 2,6-Disubstituted
Piperidines from 1c. To a solution of diisopropylamine (0.08
mL, 0.54 mmol) in 2.0 mL of dry THF was added 2.0 M n-BuLi
(0.27 mL, 0.54 mmol) at 0 °C and the mixture stirred for 30 min
under argon atmosphere. The color of the solution changed to
yellow, the temperature was dropped to -50 °C, compound 1c
(E-Z) (100.0 mg, 0.45 mmol) dissolved in 1.0 mL dry THF was
added slowly, and the mixture was stirred for 1 h to allow the
formation of enolate. Then 2-phenyl-N-tosylaldimine 3a 117.0
mg (0.45 mmol), dissolved in 1.5 mL of dry THF, was added and
the mixture stirred for an additional 6 h at the same temperature.
After completion of the reaction as monitored by TLC, the
reaction was quenched with saturated aqueous ammonium
chloride solution. The organic and aqueous layers were sepa-
rated, and the aqueous layer was extracted with ethyl acetate
(3 ꢀ 5.0 mL). The combined organic extract was washed with
brine and dried over anhydrous sodium sulfate. After removal of
the solvent under reduced pressure, the crude reaction mixture
was purified by flash column chromatography on silica gel
(230-400 mesh) using 5% ethyl acetate in petroleum ether to
afford the pure piperidines 18a,b as a white solid. These com-
pounds exist in enol form as indicated by the 1H NMR spectrum
and crystal structure.
6-(4-Chlorophenyl)-4-hydroxy-2-phenyl-1-(toluene-4-sulfinyl)-
1,2,5,6-tetrahydropyridine-3-carboxylic Acid Ethyl Ester (14c).
The general procedure described above was followed when the
enolate of (E)-1a (100 mg, 0.46 mmol) reacted with 50.8 mg of
13c (0.183 mmol) at -50 °C for 10 h to afford 14c (56 mg, 62%
yield) as a white solid: mp 164-168 °C; Rf 0.52 (30% ethyl
acetate in petroleum ether); [R]25D = -32.8 (c 0.75 in CHCl3);
IR νmax (KBr, cm-1) 3421, 3030, 2977, 2925, 1958, 1717, 1658,
1492, 1453, 1404, 1368, 1301, 1260, 1227, 1180, 1089, 1015, 983,
Ethyl 2-Cyclohexyl-4-hydroxy-6-phenyl-1-tosyl-1,2,5,6-tetra-
hydropyridine-3-carboxylate (18a). The general procedure de-
scribed above was followed when the enolate of (E)-1c (100.0
mg, 0.45 mmol) reacted with 117.0 mg of 3a (0.45 mmol) at
-50 °C for 6 h to afford 18a (132.0 mg, 61% yield) as a white
solid: mp 132-133 °C; Rf 0.43 (20% ethyl acetate in petroleum
ether); IR νmax (KBr, cm-1) 3432, 2922, 2852, 1649, 1619, 1494,
1451, 1428, 1408, 1332, 1277, 1222, 1163, 1090, 1074, 1026, 989,
1
910, 815, 701, 628, 518; H NMR (400 MHz, CDCl3) δ 0.95
(t, 3H, J = 7.1 Hz), 2.33 (s, 3H), 2.61 (dd, 1H, J = 5.8, 17.6 Hz),
2.80 (dd, 1H, J = 6.1, 17.6 Hz), 3.93-4.08 (m, 2H), 4.83-4.89
(m, 1H), 5.51 (s, 1H), 6.41 (d, 2H, J = 7.8 Hz), 6.74-6.80 (m,
2H), 6.83-6.89 (m, 1H), 7.01-7.10 (m, 4H), 7.16 (d, 2H, J =
8.1 Hz), 7.43 (d, 2H, J = 8.3 Hz), 12.34 (s, 1H); 13C NMR (125
MHz, CDCl3) δ 13.9, 21.5, 33.8, 52.2, 57.5, 60.8, 100.8, 125.9,
126.1, 127.3, 127.4, 128.5, 129.3, 129.6, 133.4, 138.7, 140.2,
141.9, 142.0, 170.1, 170.3; HRMS (ESI) calcd for C27H27-
ClNO4S (M þ Hþ) 496.1349, found 496.1349.
1
947, 896, 877, 818, 750, 737, 675, 654, 607, 561, 544, 462; H
NMR (500 MHz, CDCl3) δ 0.83-1.13 (m, 6H), 1.30 (t, 3H, J =
7.3 Hz), 1.52-1.65 (m, 4H), 1.73-1.79 (m, 1H), 2.32 (s, 3H),
2.46 (dd, 1H, J = 6.9, 16.8 Hz), 2.66 (dd, 1H, J = 10.7, 16.8 Hz),
4.0-4.21 (m, 2H), 4.57 (d, 1H, J = 10.7 Hz), 4.64-4.69 (m, 1H),
7.13 (d, 2H, J = 8.1 Hz), 7.18-7.24 (m, 1H), 7.28-7.35 (m, 4H),
7.57 (d, 2H, J = 8.4 Hz), 11.76 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.3, 21.5, 26.0, 26.2, 26.5, 30.0, 31.2, 34.9, 43.3, 58.3,
58.5, 60.6, 100.4, 126.4, 127.4, 127.6, 128.6, 129.3, 135.4, 143.2,
143.5, 169.9; HRMS (ESI) calcd for C27H34NO5S (M þ Hþ)
484.2157, found 484.2157.
Ethyl 2-Cyclohexyl-4-hydroxy-6-phenyl-1-tosyl-1,2,5,6-tetra-
hydropyridine-3-carboxylate (18b). The general procedure de-
scribed above was followed when the enolate of (Z)-1c (100.0
mg, 0.45 mmol) reacted with 117.0 mg of 3a (0.45 mmol) at
-50 °C for 6 h to afford 18b (141.5 mg, 65% yield) as a white
solid: mp 145-147 °C; Rf 0.45; (20% ethyl acetate in petroleum
ether); IR νmax (KBr, cm-1) 3442, 2928, 2851, 1640, 1497, 1452,
1403, 1356, 1337, 1323, 1262, 1229, 1217, 1182, 1151, 1091, 1059,
Procedure for the Synthesis of Chiral N-Tosyl 2,6-Disubsti-
tuted Piperidines from N-Sulfinyl 2,6-Disubstituted Piperidines.
To a solution of 14c,d in 1.5 mL of dry CH2Cl2 was added
m-chloroperbenzoic acid and the mixture stirred at room tem-
perature for 2-3 h. After completion of the reaction as mon-
itored by TLC, the reaction was quenched with saturated
aqueous sodium bicarbonate solution. The organic and aqueous
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 2.0 mL). The combined organic extracts were
washed with brine and dried over anhydrous sodium sulfate.
After removal of the solvent under reduced pressure, the crude
J. Org. Chem. Vol. 75, No. 21, 2010 7071

Ghorai et al.
JOCFeatured Article
1030, 1010, 937, 895, 862, 811, 766, 735, 724, 696, 659, 601, 584,
548; 1H NMR (400 MHz, CDCl3) δ 1.01-1.19 (m, 6H), 1.32 (t,
3H, J = 7.1 Hz), 1.60-1.81 (m, 4H), 1.96-2.06 (m,1H), 2.25 (s,
3H), 2.62 (dd, 1H, J = 5.4, 17.4 Hz), 3.07 (dd, 1H, J = 9.3, 17.4
Hz), 4.17-4.32 (m, 2H), 4.85-4.95 (m, 2H), 6.88 (d, 2H, J = 8.5
Hz), 7.0-7.12 (m, 7H), 12.27 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.3, 21.3, 26.2, 26.5, 26.6, 30.0, 31.0, 33.0, 44.7,
54.5, 58.0, 60.8, 100.9, 126.7, 127.6, 127.9, 128.4, 128.6, 137.1,
139.4, 142.1, 170.8, 170.9; HRMS (ESI) calcd for C27H34NO5S
(M þ Hþ) 484.2157, found 484.2157.
Acknowledgment. M.K.G. is grateful to DST, India, and
IIT Kanpur for financial support. S.H. and R.K.D. are thank-
ful to UGC and CSIR, India, respectively, for their senior
research fellowships.
Supporting Information Available: X-ray crystallographic
data of 6a,e,j, 12a, 14c, and 18a,b, copies of 1H and 13C spectra
for all compounds, and HPLC chromatograms for er determi-
nation. This material is available free of charge via the Internet
at http://pubs.acs.org
7072 J. Org. Chem. Vol. 75, No. 21, 2010