Imino-Diels-Alder reactions of 1-aryl-3-(trialkylsiloxy)-1,3-butadienes in solution and the solid phase

Article abstract of DOI:10.1002/ejoc.200800284

Imino-Diels-Alder reactions between 1-aryl- or 1-heteroaryl-3- (trialkylsiloxy)-1,3-butadienes and imines derived from ethyl glyoxylate have been studied. When an achiral imine was used, the diastereoselectivity depended on the nature of the aryl or heter

Full text of DOI:10.1002/ejoc.200800284

FULL PAPER
DOI: 10.1002/ejoc.200800284
Imino-Diels–Alder Reactions of 1-Aryl-3-(trialkylsiloxy)-1,3-butadienes in
Solution and the Solid Phase
Esther Caballero,*[a] Javier Figueroa,[a] Pilar Puebla,[a] Rafael Peláez,[a] Fernando Tomé,[a]
and Manuel Medarde[a]
Keywords: 1-Aryl-3-siloxy-1,3-butadienes / Pipecolic acid / Diastereoselectivity / Solid-phase synthesis / Diels–Alder reactions
Imino-Diels–Alder reactions between 1-aryl- or 1-heteroaryl-
3-(trialkylsiloxy)-1,3-butadienes and imines derived from
ethyl glyoxylate have been studied. When an achiral imine
was used, the diastereoselectivity depended on the nature
of the aryl or heteroaryl system; diastereoselectivities Ͼ 90%
were observed with methoxyphenyl or indolyl substituents,
selectivities were also achieved if a chiral imine derived from
methylbenzylamine was used as the dienophile. Solid-
supported imine dienophiles yielded the N-deprotected cy-
cloadducts by direct cleavage from the resin with no dia-
stereoselectivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
but were much lower for nitro substituents. High diastereo- Germany, 2008)
group.[9] These compounds are interesting building blocks
Introduction
for the synthesis of polycyclic compounds and have been
used in Diels–Alder reactions for the synthesis of analogues
of anthracyclines and indolocarbazole alkaloids.[10] Re-
cently, we started to study the imino-Diels–Alder (IDA) re-
actions of these dienes, which yield cycloaddition products;
the reactivity of these products with different hydrazines
has recently been published, although the details of the
IDA reaction and the stereochemistry of the cycloadducts
has not been discussed yet.[11]
In the study reported herein, the Diels–Alder reactions of
the substituted dienes 1–6 with activated imines (Figure 1),
obtained from ethyl glyoxylate, have been examined in order
to explore its usefulness in the synthesis of new 6-aryl-4-
oxopipecolic acid derivatives. The diastereoselectivity of the
reaction between unsubstituted 1-phenyl-3-(trialkylsiloxy)-
1,3-butadiene and different α-substituted alkylimines de-
pends on the bulkiness of the α-substituent of the imine,
the trans diastereomers being detected as the major reaction
products in all cases.[12] The result of different substituents
on the imine in the hetero-Diels–Alder reaction with 3-(tert-
The aza-Diels–Alder reaction of imines is a well-estab-
lished procedure for obtaining differently substituted piper-
idines.[1] A large number of dienes that can be used in the
Diels–Alder reaction with imines are described in the litera-
ture, among which Danishefsky’s diene stands out due to
its high reactivity, especially in the presence of Lewis acid
catalysts. This diene has been employed in the synthesis of
2,3-dihydro-4-pyridones, which are starting materials for
the synthesis of natural and non-natural products of inter-
est.[2] According to this methodology, 2-phenyl-2,3-dihydro-
4-pyridones have been synthesized from benzaldimines and
analogues of Danishefsky’s diene.[3] The asymmetric aza-
Diels–Alder reaction of Danishefsky’s diene with imines has
also been performed by a number of different approaches,
for example, with chiral imines,[4] chiral catalysts,[5] or chiral
ionic liquids[6] as the chiral medium, to produce 2,3-dihy-
dro-4-pyridones with regio-, diastereo-, and enantioselec-
tive control. The reaction has also been studied from a
theoretical viewpoint.[7]
Among other applications of the aza-Diels–Alder reac-
tion, the synthesis of enantiopure pipecolic acids and their
derivatives continues to attract interest due to their impor-
tant role in physiological processes.[8]
Based on the reactivity and utility of Danishefsky’s diene,
several years ago we designed a new series of dienes with
the 1-aryl-3-(trialkylsiloxy)-1,3-butadiene structure, but
with an aromatic substituent instead of the 1-methoxy
[a] Laboratorio de Química Orgánica y Farmacéutica, Facultad de
Farmacia,
Figure 1. Structure of 1-aryl- and 1-heteroaryl-3-(trialkylsiloxy)-
1,3-butadienes 1–6 and imines 7 and 8.
Campus Miguel de Unamuno, 37007 Salamanca, Spain
E-mail: escab@usal.es
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Imino-Diels–Alder Reactions of 1-Aryl-3-(trialkylsiloxy)-1,3-butadienes
butyldimethylsiloxy)-1-phenyl-1,3-butadiene has recently ZnCl2 is the most frequently used to promote this reac-
been investigated under Brønsted acid catalysis condi- tion.[15] Also the effect of various catalysts on the formation
tions.[13] Nevertheless, to the best of our knowledge, the ef- of cycloaddition versus Mannich-type products has been
fect on reactivity and diastereoselectivity produced by sub- studied.[16]
stituents on the phenyl group or the presence of other aro-
matic rings at the 1-position of the diene has not been in the presence of 10% anhydrous ZnCl2 as catalyst
studied so far. (Scheme 1). A single diastereomer (9) was formed according
We carried out the reaction between diene 1 and imine 7
1
During these studies on the IDA reaction an unexpected to H NMR spectroscopy. After isolation, the regiochemis-
difficulty in N-deprotection was observed. Therefore, the try and trans relationship between the carboxylate and tri-
use of solid-supported imines as dienophiles has been methoxyphenyl groups were unequivocally established by
studied with the aim of determining their effect on the single-crystal X-ray analysis (Figure 2). A preferred pseudo-
stereoselectivity of the reaction and their utility in the de- equatorial disposition of the trimethoxyphenyl moiety and
protection step. Finally, the chiral reaction with the imine a pseudoaxial disposition for the ethyl carboxylate was ob-
obtained from α-methylbenzylamine and ethyl glyoxylate served.[17] The 1D and 2D NMR spectroscopic data for
has been studied to determine its effect on the stereoselecti- compound 9 were used for comparisons with other related
vity of the process.
products in order to assign their stereochemistries. In ad-
dition to 9, the cis stereoisomer 10 and a 1:1 mixture of
trans and cis debenzylated cycloadducts 11 and 12 were iso-
1
lated in very low yields (Scheme 1). The H and 13C NMR
Results and Discussion
spectra of the two diastereomers are very similar, the major
The influence of the aryl substituent on C-1 of the diene difference being the shielding of the benzylic methylene car-
on the IDA reaction has been explored using dienes 1–4 bon atom in the trans isomer (δ Ͻ 55 ppm) in comparison
with activating (methoxy) or deactivating (nitro) groups on to the cis isomer (δ Ͼ 57 ppm).
the phenyl ring, and dienes 5 and 6 that have indolyl moie-
ties in that position (Figure 1).
Similar results (Scheme 1) were obtained with diene 2
and imine 7. Cycloadduct 13 was isolated in a dia-
As has been described previously, the reactive imine 7, stereomeric excess Ͼ 95%. In these reactions, no product
activated by the electron-withdrawing carboxylate group on from a Mannich-type addition was detected. The regio-
the carbon atom, has been used with simple dienes and chemistry of the products was as expected for activated
TFA as catalyst,[14] yielding products from endo attack, al- imines reacting with electron-rich 2-siloxydienes; the trans
though the reaction with Danishefsky’s diene failed due to stereochemistry has been obtained for many related imino-
diene decomposition. Among other Lewis acid catalysts, Diels–Alder reactions.[12,18]
Scheme 1. Synthesis of 9–18.
Figure 2. ORTEP drawing of crystal structures of 9 and 24.
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E. Caballero et al.
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After the imino-Diels–Alder reaction of dienes 1 and 2, 16) is maintained in dichloroethane under these reaction
reactions with siloxydienes 3 and 4 were carried out to de- conditions, complete elimination reaction eventually takes
termine the effect of the nitro group. In both cases, the reac- place.
tion was slower than with dienes 1 or 2, and longer reaction
Deprotection of compound 9 to ketone 20 was carried
times were required for the diene to completely disappear. out with 2  hydrochloric acid in THF or with 1.3 equiv. of
Interestingly, in these reactions the trans (14 and 15) and TBAF, which gave better yields. The other adducts were
cis (16 and 17) cycloadducts were formed in a 6:4 ratio. treated under the latter conditions to give the ketones 21–
They were separated and fully characterized by NMR spec- 24 (Scheme 3). The structure of the cis compound 24 was
troscopy, their relative stereochemistries being directly es- confirmed by X-ray diffraction studies, which showed a
tablished by comparison with 9 and 10. After the high dia- semi-boat conformation with the ester group in a pseudo-
stereoselectivity (trans Ͼ 90%) observed for the cycload- axial disposition and the nitrophenyl in a pseudoequatorial
dition reactions of aryl dienes 1 and 2, no stereoselectivity disposition (Figure 2).
was observed for the reactions of 1-(2-nitrophenyl)- and 1-
In order to investigate the effect of the indolyl group as a
(3-nitrophenyl)-3-(trialkylsiloxy)butadienes (3 and 4). Steric substituent at the 1-position in the siloxydiene, we prepared
and electronic effects and reaction conditions can influence dienes 5 and 6. Under the same conditions as those used in
the second cyclization step, the step that is responsible for the previous reactions, diene 5 was transformed into the
the relative stereochemistry of the product, and contribute corresponding enone, and no signals corresponding to the
to the loss of stereoselectivity.[19]
formation of the cycloadduct could be detected by 1H
To determine the effect of temperature and other solvents NMR spectroscopy. However, the presence of the with-
on the reaction of diene 3 (Scheme 2), dichloromethane and drawing sulfonyl group stabilized the diene 6, which does
dichloroethane were used at reflux. The evolution of the not decompose, and its total transformation into the cy-
reaction was monitored by 1H NMR spectroscopy for 24 h. cloadduct was observed. The major reaction product (dia-
No effect was produced on the stereochemical course of the stereomeric excess Ͼ 90%) was the trans isomer 18, and its
reaction under the former conditions, and elimination to treatment with TBAF yielded the ketone 23. These stereo-
dienone 19 was observed in dichloroethane from the begin- chemical results are similar to those obtained with dienes 1
ning of the reaction. If a mixture of cycloadducts (14 and and 2, as commented above.
Scheme 2. Effect of solvent and temperature on the reaction products.
Scheme 3. Deprotection of the adducts to yield ketones 20–24.
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Imino-Diels–Alder Reactions of 1-Aryl-3-(trialkylsiloxy)-1,3-butadienes
Hydrogenolysis of the synthesized 1-benzyl-4-oxopiper-
To test the reproducibility of the reaction and to improve
idines was attempted under a variety of common condi- the yields, different preparations of imine-resin, diene (2 or
tions. Nevertheless, only 20 afforded the free amine 25 in a 4), imine-resin molar ratios, and reaction times were used.
moderate yield with Pd/C in a mixture of formic acid and In all the experiments, deprotected cycloadducts (27 or 28)
methanol (Scheme 4).[20] Taking into consideration the fact were obtained after filtration and concentration of the fil-
that solid-phase synthesis has been successfully applied to trate. It is noticeable that the yield of cycloadduct 27 was
the preparation of pyridones using imines supported on increased to 71%.
polymers, we decided to extend the IDA study and to profit
from the easy cleavage of the cycloadducts from the resin
and also to study the diastereoselectivity of the reaction.[21]
Under the conditions required for the solid-phase IDA
reaction, no diastereoselectivity was observed. Heating of
the CH2Cl2 at reflux was necessary for the evolution of the
reaction, and this probably also had a strong effect on the
stereochemical results. A mixture of stereoisomers of the 4-
oxopipecolate derivative 29, produced by treatment of 26
with TBAF, was also observed.
In this new contribution to solid-phase IDA reactions, it
is especially noteworthy that all the cycloadducts were iso-
lated as N-deprotected products, independent of the nature
of substituents on the phenyl ring, and also good total
yields were observed relative to those produced by a two-
step process. The direct cleavage from the resin can be ex-
plained by the use of the crude product of the diene prepa-
ration, which contained an excess of TBDMSOTf in the
medium, which has also been reported to catalyze the
Diels–Alder reaction.[9b]
With the aim of determining the effect of chiral imines
on the diastereoselectivity, we decided to study the reactions
of the poorly diastereoselective (2-nitrophenyl)butadiene 3
and the highly diastereoselective indolylbutadiene 6 with
chiral imines (Scheme 6). It is well established in the litera-
ture that a highly enantioselective synthesis of piperidines
can be achieved by using chiral imines.[25] The reaction of
chiral imines derived from chiral benzylamines has been
studied with Danishefsky’s diene under different conditions
to determine their applicability in diastereoselective reac-
tions.[26] Accordingly, we decided to prepare imine 8 from
(R)-α-methylbenzylamine and ethyl glyoxylate.[27]
Scheme 4. Formation of 25.
The imine can be generated from a polymer-bound benz-
aldehyde or polymer-bound aryl/benzylamines.[22] In this
work, the supported imine was prepared by mixing the
polymer-bound benzylamine with ethyl glyoxylate and mo-
lecular sieves (4 Å) in CH2Cl2 at room temperature under
different conditions (see Table 1 and the Experimental Sec-
tion). The formation of the 7-bound imine resins (I–III de-
pending on the reaction conditions) was monitored by IR
spectroscopy.[23] For the solid-phase IDA we used the same
conditions as those employed in solution: ZnCl2 as catalyst
and CH2Cl2 as solvent (Scheme 5). First, the reaction be-
tween I and 3 was carried out at room temperature, but no
evolution was detected. Next, the reaction was performed
at reflux. The mixture was filtered, washed with CH2Cl2
and the filtrate concentrated. In this filtrate the cycloadduct
26 was isolated in 35% yield. Cleavage of the cycloadduct
from the resin was attempted by treatment with different
mixtures of TFA/CH2Cl2 or TBDMSOTf, but no further
amounts of compound 26 were recovered.[24]
We applied the same reaction conditions as those used
previously. However, after 30 h only a partial transforma-
Table 1. Conditions used for the formation of imine resin and reaction conditions for the synthesis of 26–28.
Ethyl glyoxylate
[mmol]
Resin[a]
[mmol]
t
[h]
Imine-resin[b]
Imine-resin/diene
(molar ratio)
t
[h]
Product
Yield
[%]
1.96
1.96
1.96
1.96
5
24
I
I/3 (1:1)
II/4 (1:1)
II/2 (1:1)
III/4 (2:1)
24
72
72
72
26
27
28
27
35
25
48
71
II
2.50
1.67
5
III
[a] Loading 4.0 mmol/g. [b] 7-bound.
Scheme 5. IDA reactions with polymer-bound imine 7.
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E. Caballero et al.
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Scheme 6. Diels–Alder reactions of dienes 3 and 6 with imine 8.
tion of diene 3 was detected, although when the reaction other cis diastereomer which would have allowed a defin-
was maintained at reflux a total transformation occurred. itive identification of the facial stereodifferentiation in this
Greater crowding due to the presence of an additional case.
methyl group on the benzylamine can explain the lower re-
activity observed in this case. HPLC analysis showed the
presence of three compounds in a ratio of 7:4.5:1. The reac-
tion product was treated with TBAF and then purified to
give trans and cis diastereomers 30a,b and 30c or 30d in a
11:1 ratio.
Spectroscopic analysis of 30a,b revealed a mixture of the
corresponding diastereomers in a 6:4 ratio. The major spec-
troscopic differences between 30a and 30b correspond to
the chemical shifts of the benzylic methyl groups (δ = 1.26
Figure 3. Representation of 30c and 30d, with the assignment of
each of the observed NOEs.
vs. 1.07 ppm), 5-H (δ = 3.32/3.18 vs. 2.51 ppm), and 3-H
1
protons (δ = 2.85/2.76 vs. 2.73/2.51 ppm) in the H NMR
spectra.
1
Compound 30c (or 30d) showed signals in the H and
These results confirmed the possible shift of the equilib-
13C NMR spectra that correspond to a single stereoisomer. rium for the cis/trans preference to a higher yield of the
Taking into consideration the similarity between the NMR trans cycloadduct. For imine 7 a 6:4 ratio of trans-14/cis-16
spectroscopic data for the related compounds 24 and 30c isomers was observed, whereas for chiral imine 8 a ratio of
(or 30d), which indicates a close relationship between the 11:1 for trans-30a,b/cis-30c (or 30d) was produced due to
conformations of the two piperidones, the cis structure was the effect of the C-7 methyl group. The facial selectivity
assigned to this isomer, although no stereochemical assign- was,however,nothighlyaffectedbythepresenceofthisstereo-
ment could be made from NOE difference experiments differentiating element. These results agree with the absence
(Table 2, Figure 3) because the observed effects can be pro- of facial selectivity in other examples of the hetero-Diels–
duced in both diastereomers 30c (2S,6R,1ЈR) and 30d Alder reaction of imine 8.[26d]
(2R,6S,1ЈR). The low yields of the cis cycloadducts and
As we have described above, the reaction of the indolyl-
their ketones prevented the isolation or detection of the diene 6 with the nonchiral imine 7 gave trans cycloadduct
Table 2. Observed NOEs for compound 30c (or 30d).
Saturated[a]
Assignment
Observed[a]
Assignment
1.45
3.83–3.86
5.08
7-Me
2-H/7-H
6-H
3.83–3.86, 5.08, 7.2–7.4
1.45, 2.77, 5.08, 7.2–7.4, 8.68
1,45, 2.74, 3.83–3.86
2-H/7-H, 6-H, Ph
7-Me, 3-H, 6-H, Ph, 6Ј-H
7-Me, 5-Heq, 2-H/7-H
5-Hax, Ph, 5Ј-H
8.68
6Ј-H
2.95, 7.2–7.4, 7.77
[a] δ in ppm.
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Imino-Diels–Alder Reactions of 1-Aryl-3-(trialkylsiloxy)-1,3-butadienes
18. We therefore decided to study the stereochemical course
As the direction of the attack of the diene can explain
of the reaction using the chiral imine 8 to determine the selectivity for the (R) absolute stereochemistry at C-2,
whether diastereomeric discrimination occurred in this case. the preference for the trans versus the cis diastereomer
We carried out the reaction in CH2Cl2 at reflux, and the could be explained by the relative stabilities of the two
reaction product was treated directly with TBAF, yielding products that result from the formation of the bond be-
a major product that was purified by chromatography. This tween the nitrogen atom and C-6 during the second step of
product (31) showed signals for a single compound, again the cyclization process.[29] In order to investigate the differ-
corresponding to a trans disposition (31a or 31b) of the ences between the two possibilities, we minimized[30] the
indolyl and ester groups. The formation of only one trans structures of the four diastereomers of the two cycload-
diastereomer reflects the occurrence of facial discrimi- dition products from imine 8 (silylenol ethers from diene 3,
nation. On this occasion, the absolute stereochemistry was which produce 30a,b,c, or d upon deprotection, and silyl-
assigned according to the NOEs observed, as shown in Fig- enol ethers from diene 6, which yield 31a,b,c, or d by the
ure 4 in which the key effects are depicted.
deprotection reaction). The results are presented in Table 3.
For the 2-nitrophenyl derivatives, the differences between
the trans and cis diastereomers with the same configuration
at C-2 are smaller, which accounts for the appearance of a
cis diastereomer as the reaction product. In the case of the
enantioselective reaction that yields the indolyl derivatives
31 after deprotection, Figure 5 accounts for the (S) configu-
ration at C-2. The final product must derive from the two
possible diastereomers with this configuration, the trans
diastereomer b and the cis diastereomer c. The difference in
their stability (the trans compound is more stable by
12.63 kJ/mol) accounts for the observed presence and isola-
tion of diastereomer 31b as the unique reaction product in
this case.
Figure 4. NOEs observed for 31b.
The facial differentiation can be explained by the attack
of the diene taking place through the less hindered face ac-
The whole process is presented in Scheme 7 starting with
cording to a Felkin–Anh model,[28] which corresponds to the activation of the imine by the zinc catalyst, followed
the approach of the diene to the imine closer to the benzylic by the Mannich addition, and finally by cyclization to the
hydrogen atom (si-facial selectivity) instead of the alterna- reaction products. This mechanism has previously been pro-
tive approach, close to the benzylic methyl group (re-facial posed for related imino-Diels–Alder reactions with acti-
selectivity, Figure 5).
vated dienes.[31]
Figure 5. Facial selectivity leading to compound 31.
Table 3. Calculated relative stabilities [kJ/mol] of the four possible diastereomeric cycloadducts (a–d) obtained from diene 3 and diene 6.
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E. Caballero et al.
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Scheme 7. Proposed mechanism for the stereochemical course of the reaction.
silica gel (0.040–0.063 mm). Solvents of analytical grade were used
as purchased and, when necessary, dried by using standard pro-
cedures.
Conclusions
Reported in this work is a very attractive imino-Diels–
Alder reaction that allows the preparation of 6-aryl(indol-
yl)-4-oxopipecolic acid derivatives with very high diastereo-
selectivity. The effect of different substituents on the 1-
phenyl group of the butadienes on the diastereoselectivity
of the reaction has been studied, with a loss of diastereo-
selectivity observed on replacing a methoxy by a nitro
group. Furthermore, replacing the methoxyphenyl group
with indolyl moieties maintains the diastereomeric effect
observed in the former cases. A diastereoselective effect on
the trans/cis ratio was also observed when the chiral imine
derived from α-methylbenzylamine was used as the dien-
ophile.
Materials: Dienes 1–6 and imines 7 and 8 were prepared according
to previously reported procedures.[9,26]
General Procedure for the Preparation of the Dienes: To the corre-
sponding enone (1 mmol) in CH2Cl2 under Ar, Et3N (5.4 mmol),
and triisopropylsilyl triflate (4 mmol) were added dropwise. The
reaction mixture was allowed to react at 50 °C for 2 h, and then
Et3N (1 mmol) was added. The mixture was diluted in CH2Cl2,
washed with aqueous saturated NaHCO3 solution and brine, dried,
and the solvent evaporated.
Imino-Diels–Alder Reaction. General Procedure: ZnCl2 (10%) was
mixed with the imine (1 equiv.) in dry CH2Cl2 under argon. After
stirring for 10 min, 1 equiv. of the diene was added, and the mixture
was stirred at room temperature for 24 h (dienes 1, 2, 5, and 6) or
36 h (dienes 3 and 4). The reaction mixture was washed with an
aqueous saturated NaHCO3 solution, extracted with CH2Cl2,
washed with brine, and dried with anhydrous Na2SO4. The crude
extract was concentrated to dryness and subjected directly to col-
umn chromatography (hexane/EtOAc, 8:2) to afford compounds 9–
18.
Attempts at adduct deprotection were sometimes unsuc-
cessful. However, the use of a solid-supported imine as the
dienophile has a remarkable effect on the cleavage of the
N-protecting group, directly yielding the pipecolic acid de-
rivatives in the free amino form.
(؎)-Ethyl (2S,6S)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(3,4,5-tri-
methoxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (9): White
solid (396 mg, 73%). M.p. 93–94 °C (hexane). 1H NMR
(400 MHz): δ = 7.27–7.20 (m, 5 H), 6.70 (s, 2 H), 4.80 (t, J =
2.4 Hz, 1 H), 4.65 (q, J = 2.3 Hz, 1 H), 4.18 (m, 2 H), 3.83 (s, 6
H), 3.82 (s, 3 H), 3.74 (s, 2 H), 3.66 (dd, J = 6.4, 2.3 Hz, 1 H), 2.64
(ddt, J = 16.8, 6.4, 2.3 Hz, 1 H), 2.35 (dt, J = 16.8, 2.3 Hz, 1 H),
1.29 (t, J = 7.2 Hz, 3 H), 0.90 (s, 9 H), 0.11 (s, 6 H) ppm. 13C NMR
Experimental Section
General: Melting points were determined with a Büchi 510 instru-
ment and are uncorrected. NMR spectra were recorded with a
Bruker 400 MHz DRX and/or a 200 MHz AC spectrometer in
CDCl3 as solvent with TMS as the internal standard. Mass spectra
were obtained by the electrospray method with a VGTS-240 mass
spectrometer. Flash chromatography was performed with Merck 60
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Imino-Diels–Alder Reactions of 1-Aryl-3-(trialkylsiloxy)-1,3-butadienes
(100 MHz): δ = 172.6, 153.0, 146.3, 140.1, 139.5, 136.8, 128.4 (ϫ2),
128.2 (ϫ2), 126.9, 107.8, 104.9, 61.6, 60.3, 60.2, 55.9 (ϫ2), 55.8,
54.0, 32.8, 25.6 (ϫ3), 17.9, 14.3, –4.3 (ϫ2) ppm. HRMS: calcd. for
C30H43NO6Si [M + H]+ 542.2960; found 542.2992.
HRMS: calcd. for C27H36N2O5Si [M + H]+ 497.2466; found
497.2484.
(؎)-Ethyl (2S,6R)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(2-nitro-
phenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (16): Orange oil
(174 mg, 35%). 1H NMR (400 MHz): δ = 7.71 (d, J = 7.9 Hz, 1
H), 7.69 (dd, J = 8.1, 1.1 Hz, 1 H), 7.46 (td, J = 8.0, 1.0 Hz, 1 H),
7.30 (td, J = 8.0, 1.0 Hz, 1 H), 7.30–7.20 (m, 5 H), 5.03 (br. s, 1
H), 4.99 (d, J = 3.9 Hz, 1 H), 3.89 (d, J = 13.7 Hz, 1 H), 3.79 (d,
J = 13.7 Hz, 1 H), 3.48 (t, J = 5.2 Hz, 1 H), 3.33 (m, 2 H), 2.51
(dd, J = 16.0, 5.2 Hz, 1 H), 2.21 (dd, J = 16.0, 5.2 Hz, 1 H), 1.10
(t, J = 7.2 Hz, 3 H), 0.94 (s, 9 H), 0.18 (s, 6 H) ppm. 13C NMR
(100 MHz): δ = 172.6, 150.1, 148.5, 138.0, 137.5, 131.8, 130.8, 129.0
(ϫ2), 128.1 (ϫ2), 127.5, 127.2, 123.7, 102.6, 60.6, 59.3, 58.0, 57.6,
28.3, 25.6 (ϫ3), 17.9, 13.6, –4.3 (ϫ2) ppm. HRMS: calcd. for
C27H36N2O5Si [M + H]+ 497.2466; found 497.2436.
(؎)-Ethyl (2S,6R)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(3,4,5-
trimethoxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate
(10):
1
Orange oil (11 mg, 2%). H NMR (400 MHz): δ = 7.31–7.20 (m,
5 H), 6.52 (s, 2 H), 4.80 (d, J = 2.8 Hz, 1 H), 4.21 (d, J = 2.8 Hz,
1 H), 3.89 (m, 2 H), 3.83 (s, 6 H), 3.82 (m, 1 H), 3.80 (s, 3 H), 3.59
(m, 2 H), 2.65 (dd, J = 16.4, 7.2 Hz, 1 H), 2.30 (dd, J = 16.4,
4.8 Hz, 1 H), 1.05 (t, J = 7.7 Hz, 3 H), 0.94 (s, 9 H), 0.11 (s, 6 H)
ppm. 13C NMR (100 MHz): δ = 173.1, 155.6, 147.5, 138.9, 137.8,
136.7, 128.8 (ϫ2), 127.8 (ϫ2), 126.8, 105.8, 105.6, 62.7, 60.6 (ϫ2),
60.4 (ϫ2), 57.2, 55.9, 31.6, 25.6 (ϫ3), 17.9, 13.8, –4.3 (ϫ2) ppm.
(؎)-Ethyl (2S,6S)/(2S,6R)-4-(tert-Butyldimethylsiloxy)-6-(3,4,5-
(؎)-Ethyl (2S,6R)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(3-nitro-
phenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (17): Orange oil
trimethoxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (11/12):
1
Orange oil (18 mg, 4%). H NMR (200 MHz): δ = 6.65/6.60 (s, 2
1
(139 mg, 28%). H NMR (400 MHz): δ = 8.16 (s, 1 H), 8.01 (dd,
H), 5.47/5.15 (m, 2 H), 5.01/4.89 (m, 1 H), 4.20 (q, J = 7.2 Hz, 2
H), 4.50–4.20 (m, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.84 (s, 3 H),
2.0–2.7 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H), 0.95 (s, 9 H), 0.21 (s, 6
H) ppm. 13C NMR (50 MHz): δ = 173.9, 153.0 (ϫ2), 148.2, 136.7,
106.7, 106.1, 105.3/104.9, 77.8/74.1, 73.7/69.0, 61.7, 61.2, 56.0 (ϫ2),
32.6/32.2, 25.6, 18.0, 14.4, –4.3 ppm.
J = 8.0, 1.2 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.39 (t, J = 7.6 Hz,
1 H), 7.26–7.16 (m, 5 H), 4.73 (d, J = 2.0 Hz, 1 H), 4.36 (d, J =
2.0 Hz, 1 H), 3.85 (d, J = 14.4 Hz, 1 H), 3.76 (d, J = 14.4 Hz, 1
H), 3.72 (m, 2 H), 3.68 (dd, J = 7.2, 4.8 Hz, 1 H), 2.68 (dd, J =
16.8, 7.2 Hz, 1 H), 2.32 (dd, J = 16.8, 4.8 Hz, 1 H), 1.13 (t, J =
7.1 Hz, 3 H), 0.92 (s, 9 H), 0.15 (s, 6 H) ppm. 13C NMR (100 MHz):
δ = 172.4, 148.1, 148.0, 145.5, 137.7, 134.7, 128.7 (ϫ2), 128.6, 128.0
(ϫ2), 127.1, 123.6, 122.0, 104.5, 62.3, 60.7 (ϫ2), 57.6, 31.8, 25.5
(ϫ3), 17.9, 13.8, –4.3 (ϫ2) ppm. HRMS: calcd. for C27H36N2O5Si
[M + H]+ 497.2466; found 497.2448.
(؎)-Ethyl (2S,6S)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(2-meth-
oxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (13): Orange
oil (347 mg, 72%). 1H NMR (200 MHz): δ = 7.69 (dd, J = 7.8,
1.8 Hz, 1 H), 7.24 (m, 5 H), 7.20 (m, 1 H), 6.99 (t, J = 7.6 Hz, 1
H), 6.86 (d, J = 8.4 Hz, 1 H), 5.37 (q, J = 2.5 Hz, 1 H), 4.83 (t, J
= 2.5 Hz, 1 H), 4.24 (m, 2 H), 3.83 (s, 3 H), 3.82 (d, J = 13.8 Hz,
1 H), 3.75 (d, J = 13.8 Hz, 1 H), 3.69 (dd, J = 6.2, 2.5 Hz, 1 H),
2.67 (ddt, J = 16.4, 6.2, 2.5 Hz, 1 H), 2.34 (dt, J = 16.4, 2.5 Hz, 1
H), 1.31 (t, J = 7.2 Hz, 3 H), 0.90 (s, 9 H), 0.05 (s, 6 H) ppm. 13C
NMR (50 MHz): δ = 172.9, 157.6, 146.1, 139.8, 132.3, 129.0, 128.7
(ϫ2), 128.2 (ϫ2), 127.7, 126.8, 120.7, 110.5, 107.8, 60.1, 55.9, 55.4,
54.2, 53.1, 33.2, 25.7 (ϫ3), 18.0, 14.5, –4.1 (ϫ2) ppm. HRMS:
calcd. for C28H39NO4Si [M]+· 482.2648; found 482.2688.
(؎)-Ethyl (2S,6S)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-[1-(phen-
ylsulfonyl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridine-2-carboxylate
1
(18): Brown oil (346 mg, 55%). H NMR (200 MHz): δ = 7.96 (d,
J = 8.0 Hz, 1 H), 7.75 (d, J = 8.2 Hz, 1 H), 7.70–7.10 (m, 11 H),
7.53 (s, 1 H) 4.94 (dd, J = 2.6, 2.6 Hz, 1 H), 4.77 (t, J = 2.6 Hz, 1
H), 4.18 (q, J = 7.3 Hz, 2 H), 3.78 (d, J = 13.5 Hz, 1 H), 3.71 (t, J
= 4.9 Hz, 1 H), 3.66 (d, J = 13.5 Hz, 1 H), 2.65 (ddt, J = 6.8, 4.9,
2.6 Hz, 1 H), 2.46 (dd, J = 16.8; 4.8 Hz, 1 H), 1.28 (t, J = 7.3 Hz,
1 H), 1.02 (m, 18 H) ppm. 13C NMR (50 MHz): δ = 172.6, 147.8,
139.2, 138.1, 136.1, 133.6, 130.0, 129.9 (ϫ2), 128.6 (ϫ4), 128.3
(ϫ2), 127.0, 126.1, 124.9, 124.8, 123.0, 121.5, 113.8, 104.0, 60.4,
55.8, 54.1, 53.6, 32.2, 17.9/17.8 (ϫ6), 14.4, 12.6/12.4 (ϫ3) ppm.
(؎)-Ethyl (2S,6S)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(2-nitro-
phenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (14): Orange oil
(199 mg, 40%). 1H NMR (400 MHz): δ = 8.01 (d, J = 7.9 Hz, 1
H), 7.70 (dd, J = 8.2, 1.2 Hz, 1 H), 7.59 (dt, J = 7.8, 1.0 Hz, 1 H),
7.35 (dt, J = 7.8, 1.0 Hz, 1 H), 7.25–7.15 (m, 5 H), 5.28 (q, J =
2.3 Hz, 1 H), 4.89 (t, J = 2.3 Hz, 1 H), 4.18 (m, 2 H), 3.82 (d, J =
13.7 Hz, 1 H), 3.65 (dd, J = 6.4, 2.0 Hz, 1 H), 3.57 (d, J = 13.7 Hz,
1 H), 2.70 (ddt, J = 16.4, 6.4, 2.3 Hz, 1 H), 2.35 (dt, J = 16.4,
2.0 Hz, 1 H), 1.30 (t, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 6 H)
ppm. 13C NMR (100 MHz): δ = 172.4, 150.4, 147.2, 139.3, 138.5,
132.5, 130.4, 128.3 (ϫ2), 128.0 (ϫ2), 127.7, 127.1, 123.3, 106.7,
60.4, 56.3, 55.8, 54.8, 33.3, 25.5 (ϫ3), 17.9, 14.3, –4.5 (ϫ2) ppm.
HRMS: calcd. for C27H36N2O5Si [M]+ 497.2466; found 497.2442.
Ethyl (2E,5E)-6-(2-Nitrophenyl)-4-oxohexa-2,5-dienoate (19): Ac-
cording to the previous imino-Diels–Alder procedure at reflux in
dichloroethane, compound 19 (275 mg, 100 %) was isolated. 1H
NMR (200 MHz): δ = 8.13 (d, J = 15.8 Hz, 1 H), 8.08 (d, J =
7.5 Hz, 1 H), 7.46 (d, J = 15.8 Hz, 1 H), 6.83 (d, J = 15.8 Hz, 2
H), 7.70–7.50 (m, 3 H), 4.28 (q, J = 7.0 Hz, 2 H), 1.33 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (50 MHz): δ = 188.2, 165.4, 148.5,
141.0, 137.6, 133.8, 132.0, 130.9, 130.5, 129.5, 129.2, 125.2, 61.5,
14.2 ppm.
Deprotection of the Cycloadducts. Method A: Compound 9 (200 mg,
(؎)-Ethyl (2S,6S)-1-Benzyl-4-(tert-butyldimethylsiloxy)-6-(3-nitro- 0.6 mmol), dissolved in CH2Cl2 (10 mL), was treated with 2  HCl
phenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (15): Orange oil (5 mL) and then stirred for 24 h. The reaction mixture was washed
(149 mg, 30%). 1H NMR (400 MHz): δ = 8.34 (t, J = 2.0 Hz, 1 H), with aqueous saturated NaHCO3 solution, dried, and the solvents
8.08 (ddd, J = 8.0, 2.0, 2.0 Hz, 1 H), 7.77 (dt, J = 8.0, 2.0 Hz, 1
H), 7.47 (t, J = 7.6 Hz, 1 H), 7.30–7.20 (m, 5 H), 4.85 (q, J =
were evaporated. The residue was purified by column chromatog-
raphy (hexane/EtOAc, 7:3) to afford 20 (46 mg, 30%). Method B:
2.8 Hz, 1 H), 4.75 (t, J = 2.8 Hz, 1 H), 4.20 (m, 2 H), 3.82 (d, J = The corresponding compound (0.1 mmol) was dissolved in THF
13.6 Hz, 1 H), 3.66 (dd, J = 6.4, 2.8 Hz, 1 H), 3.65 (d, J = 13.6 Hz,
1 H), 2.70 (ddt, J = 16.8, 6.4, 2.8 Hz, 1 H), 2.38 (dt, J = 16.8,
2.8 Hz, 1 H), 1.30 (t, J = 7.7 Hz, 3 H), 0.89 (s, 9 H), 0.09 (s, 6 H)
(5–10 mL), and TBAF (0.13 mmol in THF solution) was added to
the solution. The reaction mixture was stirred at room temperature
for 20 h, quenched with water, extracted with CH2Cl2, dried, and
ppm. 13C NMR (100 MHz): δ = 172.5, 148.5, 147.8, 147.5, 138.7, the solvents were evaporated. The reaction product was purified
134.5, 129.3, 128.4 (ϫ2), 128.0 (ϫ2), 127.3, 123.3, 122.4, 106.7,
by chromatography on silica (hexane/EtOAc, 1:1) to give the pure
61.3, 60.5, 55.8, 54.4, 33.1, 25.6 (ϫ3), 18.0, 14.4, –4.5 (ϫ2) ppm. compounds 20–24.
Eur. J. Org. Chem. 2008, 4004–4014
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4011

E. Caballero et al.
FULL PAPER
(؎)-Ethyl (2S,6S)-1-Benzyl-4-oxo-6-(3,4,5-trimethoxyphenyl)piper- umn chromatography (diethyl ether/EtOAc, 10:1) to afford 25
1
idine-2-carboxylate (20): Orange oil (342 mg, 80 %). 1H NMR
(400 MHz): δ = 7.40–7.20 (m, 5 H), 6.71 (s, 2 H), 4.38 (dd, J = 9.6,
(215 mg, 64%) as a brown oil. H NMR (400 MHz): δ = 6.63 (s, 2
H), 4.21 (q, J = 6.9 Hz, 2 H), 3.87 (s, 6 H), 3.84 (s, 3 H), 3.80–4.0
4.6 Hz, 1 H), 4.27 (m, 2 H), 3.92 (dd, J = 6.6, 2.2 Hz, 1 H), 3.86 (m, 1 H), 3.72 (dd, J = 11.7, 3.6 Hz, 1 H), 2.75 (dd, J = 14.6,
(s, 6 H), 3.80 (d, J = 14.0 Hz, 1 H), 3.80 (s, 3 H), 2.77 (dd, J =
14.8, 6.6 Hz, 1 H), 2.69 (dd, J = 15.2, 4.6 Hz, 1 H), 2.59 (dd, J =
15.2, 9.6 Hz, 1 H), 2.51 (dd, J = 14.8, 2.2 Hz, 1 H), 3.31 (d, J =
14.0 Hz, 1 H), 1.32 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz):
δ = 205.8, 171.5, 153.6 (ϫ2), 138.6 (ϫ2), 137.3, 128.4 (ϫ2), 128.3
(ϫ2), 127.3, 103.9 (ϫ2), 63.0, 60.8 (ϫ2), 58.6, 56.1 (ϫ2), 54.2, 49.2,
42.8, 14.4 ppm. HRMS: calcd. for C24H29NO6 [M + H]+ 428.2067;
found 428.2055.
3.7 Hz, 1 H), 2.60–2.40 (m, 2 H), 1.29 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (100 MHz): δ = 206.6, 170.9, 153.8 (ϫ2), 137.6 (ϫ2),
137.6, 103.4 (ϫ2), 61.7, 60.8, 60.6, 57.9, 56.2 (ϫ2), 50.4, 43.9,
14.8 ppm. HRMS: calcd. for C17H23NO6 [M]+· 337.1525; found
337.1555.
General Procedure for Imine Formation on a Solid Support: To a
suspension of the polymer-bound benzylamine (1 mmol) (Aldrich,
473677) and molecular sieves (4 Å) (50 mg) in CH2Cl2 (15 mL) at
room temperature under nitrogen was added ethyl glyoxylate in the
molar proportion shown in Table 1. The corresponding imine-resin
was filtered off and washed with CH2Cl2. The imine-resins (I, II or
III) show an absorption at 1740 cm–1 in IR spectra.
(؎)-Ethyl (2S,6S)-1-Benzyl-6-(2-nitrophenyl)-4-oxopiperidine-2-
1
carboxylate (21): Orange oil (286 mg, 75%). H NMR (400 MHz):
δ = 8.03 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.67 (t, J
= 8.0 Hz, 1 H), 7.43 (t, J = 8.1 Hz, 1 H), 7.30–7.24 (m, 5 H), 4.99
(dd, J = 8.0, 5.6 Hz, 1 H), 4.26 (q, J = 7.2 Hz, 2 H), 3.88 (dd, J =
6.4, 2.0 Hz, 1 H), 3.61 (d, J = 13.6 Hz, 1 H), 3.46 (d, J = 13.6 Hz,
1 H), 2.99 (dd, J = 15.6, 5.6 Hz, 1 H), 2.75 (dd, J = 14.8, 6.4 Hz,
1 H), 2.60 (dd, J = 14.8, 2.0 Hz, 1 H), 2.58 (dd, J = 15.6, 8.0 Hz,
1 H), 1.33 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz): δ =
204.7, 171.2, 149.9, 137.5, 137.4, 133.2, 128.8, 128.6 (ϫ5), 127.5,
124.1, 61.1, 58.2, 56.8, 55.0, 47.3, 42.7, 14.3 ppm. HRMS: calcd.
for C21H22N2O5 [M]+· 382.1529; found 382.1536.
General Procedure for the Imino-Diels–Alder Reaction on a Solid
Support (see Table 1): Diene 2–4 (1 mmol) and dry ZnCl2 (20%)
were added to the resin (I, II, or III) (1–2 mmol) in dry CH2Cl2
(15–20 mL) under nitrogen. The reaction mixture was heated at
reflux for 24 h or 72 h. After that, the resin was filtered off and
washed with CH2Cl2. The filtrate was concentrated, and the reac-
tion product purified by flash chromatography to give 26, 27, or
28.
(؎)-Ethyl (2S,6S)-1-Benzyl-6-(3-nitrophenyl)-4-oxopiperidine-2-
carboxylate (22): Orange oil (278 mg, 73%). H NMR (200 MHz):
(؎)-Ethyl (2S,6S)/(2S,6R)-4-(tert-Butyldimethylsiloxy)-6-(2-nitro-
phenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (26): Brown oil
(137 mg, 35%). H NMR (200 MHz): δ = 8.0–7.1 (m, 4 H), 6.17/
5.80 (m, 1 H), 5.04 (m, 1 H), 4.43 (m, 1 H), 4.20 (q, J = 7.2 Hz, 2
H), 2.7–2.0 (m, 2 H), 1.30 (t, J = 7.2 Hz, 3 H), 0.90 (s, 9 H), 0.12
(s, 6 H) ppm. 13C NMR (50 MHz): δ = 170.8/170.3, 148.2/148.9,
147.9, 137.2/136.5, 133.7/132.7, 129.6/129.3, 128.6/128.4, 124.4/
124.1, 105.6/103.5, 72.4/69.2, 73.6/70.8, 61.4, 32.6/31.5, 25.6, 18.0,
14.2, –4.5 ppm. HRMS: calcd. for C21H30N2O5Si [M + H]+
419.1924; found 419.1976.
1
δ = 8.43 (t, J = 1.8 Hz, 1 H), 8.17 (dd, J = 8.0, 2.1 Hz, 1 H), 7.83
(dt, J = 8.0, 2.1 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.25–7.30 (m,
5 H), 4.64 (dd, J = 9.5, 4.7 Hz, 1 H), 4.27 (m, 2 H), 3.93 (dd, J =
6.6, 2.6 Hz, 1 H), 3.67 (d, J = 13.5 Hz, 1 H), 3.37 (d, J = 13.5 Hz,
1 H), 2.70–2.40 (m, 4 H), 1.33 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(50 MHz): δ = 204.5, 171.5, 148.9, 146.0, 138.0, 133.4, 130.1, 128.6
(4), 127.7, 123.0, 122.5, 62.2, 61.1, 58.7, 54.8, 48.5, 42.8, 14.4 ppm.
MS: calcd. for C21H22N2O5 382.15; found 382.10.
1
(؎)-Ethyl (2S,6S)-1-Benzyl-4-oxo-6-[1-(phenylsulfonyl)-1H-indol-3-
yl]piperidine-2-carboxylate (23): Brown oil (289 mg, 56 %). 1H
NMR (200 MHz): δ = 8.02 (d, J = 8.2 Hz, 1 H), 7.83 (d, J = 8.2 Hz,
1 H), 7.50–7.10 (m, 12 H), 7.60 (s, 1 H), 4.69 (dd, J = 10.0, 4.3 Hz,
1 H), 4.20 (m, 2 H), 3.89 (dd, J = 6.2, 2.5 Hz, 1 H), 3.72 (d, J =
13.5 Hz, 1 H), 3.39 (d, J = 13.5 Hz, 1 H), 3.00–2.50 (m, 4 H), 1.33
(t, J = 6.9 Hz, 3 H) ppm. 13C NMR (50 MHz): δ = 205.7, 171.3,
137.9 (ϫ2), 137.9, 136.0, 134.0, 129.4 (ϫ2), 128.9 (ϫ2), 128.5 (ϫ2),
127.4, 126.7 (ϫ3), 126.7, 125.5, 124.4, 123.8, 123.5, 120.9, 114.1,
61.1, 58.3, 55.0, 54.0, 45.9, 42.3, 14.5 ppm. HRMS: calcd. for
C29H28N2O5S [M]+· 516.1719; found 516.1723.
(؎)-Ethyl (2S,6S)/(2S,6R)-4-(tert-Butyldimethylsiloxy)-6-(3-nitro-
phenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (27): Brown oil
(288 mg, 71%). H NMR (200 MHz): δ = 8.3–7.4 (m, 4 H), 5.61/
5.32 (m, 1 H), 5.02 (t, J = 2.8 Hz, 1 H), 4.84 (t, J = 2.8 Hz, 1 H),
4.5–4.2 (m, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 2.7–2.2 (m, 2 H), 1.25
(t, J = 7.2 Hz, 3 H), 0.90 (s, 9 H), 0.12 (s, 6 H) ppm. 13C NMR
(50 MHz): δ = 170.8/170.1, 148.9/148.7, 148.4, 143.5, 134.1/133.7,
129.5, 123.1, 122.8/122.6, 105.0/102.9, 77.7/73.0, 73.6/69.4, 61.4,
32.7/32.0, 25.6, 18.0, 14.2, –4.3 ppm.
1
(؎)-Ethyl (2S,6S)/(2S,6R)-4-(tert-Butyldimethylsiloxy)-6-(2-meth-
oxyphenyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (28): Yellow oil
(؎)-Ethyl (2S,6R)-1-Benzyl-6-(2-nitrophenyl)-4-oxopiperidine-2-car-
1
(195 mg, 48%). H NMR (200 MHz): δ = 7.5–6.8 (m, 4 H), 6.00/
1
boxylate (24): Orange oil (305 mg, 80%). H NMR (200 MHz): δ
5.68 (m, 1 H), 4.96/4.91 (m, 1 H), 4.5–4.3 (m, 1 H), 4.20 (q, J =
7.2 Hz, 2 H), 3.86/3.81 (s, 3 H), 2.8–2.2 (m, 2 H), 1.30 (t, J =
7.2 Hz, 3 H), 0.90 (s, 9 H), 0.12 (s, 6 H) ppm.
= 8.48 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 8.2 Hz, 1 H), 7.70 (t, J =
8.0 Hz, 1 H), 7.42 (t, J = 8.2 Hz, 1 H), 7.24–7.20 (m, 5 H), 4.65
(dd, J = 9.6, 5.2 Hz, 1 H), 4.06 (q, J = 7.0 Hz, 2 H), 3.84 (t, J =
4.8 Hz, 1 H), 3.73 (d, J = 14.4 Hz, 1 H), 3.62 (d, J = 14.4 Hz, 1 H),
2.79 (m, 2 H), 1.21 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (50 MHz): δ
= 205.8, 173.4, 149.9, 137.8, 137.0, 133.5, 128.9 (ϫ2), 128.8 (ϫ3),
127.7, 127.4, 124.0, 61.4, 58.8, 58.6, 57.5, 46.1, 39.5, 14.1 ppm.
(؎)-Ethyl (2S,6S)/(2S,6R)-6-(2-Nitrophenyl)-4-oxopiperidine-2-
carboxylate (29): According to Method B described previously, 26
1
gave 29 as a brown oil (175 mg, 60%). H NMR (200 MHz): δ =
8.2–7.3 (m, 4 H), 5.37 (dd, J = 11.4, 2.8 Hz, 1 H), 4.55 (dd, J =
11.0, 4.0 Hz, 1 H), 4.28 (q, J = 7.2 Hz, 2 H), 3.1–2.4 (m, 2 H), 1.30
(t, J = 7.2 Hz, 3 H) ppm. HRMS: calcd. for C14H16N2O5 [M]+·
292.1059; found 292.1096.
(؎)-Ethyl (2S,6S)-4-Oxo-6-(3,4,5-trimethoxyphenyl)piperidine-2-
carboxylate (25): Formic acid (1.0 mL) and Pd/C (10 %, 22 mg)
were added to a stirred solution of 20 (90 mg, 0.27 mmol) in MeOH
(5.4 mL). The mixture was stirred under argon overnight, the Pd/
C was filtered off, and the ethanol was evaporated in vacuo. The
residue was dissolved in CH2Cl2 and washed with aqueous satu-
rated NaHCO3 solution. The organic layer was dried with Na2SO4,
and the solvents were evaporated. The residue was purified by col-
Imino-Diels–Alder Reaction and Deprotection: ZnCl2 (10%) was
mixed with the chiral imine 8 (1 equiv.) in dry CH2Cl2 (15 mL)
under argon. After stirring for 10 min, diene 3 or 6 (1 equiv.) was
added, and the mixture was stirred at reflux for 20 h. The resulting
mixture was poured into aqueous saturated NaHCO3 solution and
4012
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4004–4014

Imino-Diels–Alder Reactions of 1-Aryl-3-(trialkylsiloxy)-1,3-butadienes
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(hexane/EtOAc, 1:1) to give the pure compounds 30 and 31.
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ethyl]piperidine-2-carboxylate (30a and 30b): Orange oil (135 mg,
34%). 1H NMR (400 MHz): δ = 7.92/7.95 (d, J = 8.0 Hz, 1 H),
7.80/7.70 (d, J = 8.0 Hz, 1 H), 7.43 (m, 1 H), 7.30 (m, 1 H), 7.22–
7.40 (m, 5 H), 5.45 (m, 1 H), 4.20 (m, 2 H), 3.99 (m, 1 H), 3.99–
3.89 (m, 1 H), 3.32 (dd, J = 15.6, 8.0 Hz, 1 H)/3.18 (ddd, J = 15.6,
6.4, 1.6 Hz, 1 H), 2.85/2.76 (ddd, J = 16.0, 7.6, 1.6 Hz, 1 H), 2.73/
2.51 (dd, J = 16.0, 6.4 Hz, 1 H), 2.51 (dd, J = 16.0, 6.4 Hz, 2 H),
1.32/1.17 (t, J = 7.1 Hz, 3 H), 1.26/1.07 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (100 MHz): δ = 205.5, 174.3/173.5, 149.5, 141.6, 138.3,
132.9/133.0, 129.1/128.8, 128.5 (ϫ2)/128.4 (ϫ2), 127.5 (ϫ2)/127.4
(ϫ2), 127.0 (ϫ2), 124.0/124.6, 61.2/60.9, 57.3/56.5, 55.4/54.8, 54.0,
47.6/46.8, 43.9, 21.3, 13.9/13.4 ppm. HRMS: calcd. for
C22H24N2O5 [M + H]+ 397.1685; found 397.1735.
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Ethyl (2S,6R)/(2R,6S)-6-(2-Nitrophenyl)-4-oxo-1-[(R)-1-phenyl-
ethyl]piperidine-2-carboxylate (30c or 30d): Orange oil (12 mg, 3%).
1H NMR (400 MHz): δ = 8.68 (d, J = 8.0 Hz, 1 H), 7.79 (d, J =
8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H),
7.40–7.20 (m, 5 H), 5.08 (dd, J = 12.4, 3.6 Hz, 1 H), 3.98 (m, 2 H),
3.86 (q, J = 6.8 Hz, 1 H), 3.83 (t, J = 4.4 Hz, 1 H), 2.95 (dd, J =
17.6, 12.4 Hz, 1 H), 2.77 (d, J = 4.4 Hz, 1 H), 2.74 (dd, J = 17.6,
3.6 Hz, 1 H), 1.45 (d, J = 6.8 Hz, 3 H), 1.08 (t, J = 7.2 Hz, 3 H)
ppm. 13C NMR (100 MHz): δ = 206.1, 174.4, 149.6, 141.5, 138.8,
133.4, 130.6, 129.1 (ϫ2), 128.1 (ϫ2), 127.7, 127.2, 123.6, 61.0, 57.6,
53.8, 52.7, 46.6, 41.8, 13.9, 11.2 ppm.
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sulfonyl)-1H-indol-3-yl]piperidine-2-carboxylate (31b): Brown oil
(132 mg, 25%). 1H NMR (400 MHz): δ = 8.03 (d, J = 8.4 Hz, 1
H), 7.96 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.6 Hz, 2 H), 7.62 (s, 1
H), 7.49 (d, J = 8.2 Hz, 1 H), 7.48–7.10 (m, 9 H), 5.18 (dd, J =
9.6, 4.4 Hz, 1 H), 4.20 (q, J = 7.0 Hz, 2 H), 4.00 (q, J = 7.0 Hz, 1
H), 3.79 (dd, J = 6.7, 2.4 Hz, 1 H), 2.94 (dd, J = 15.2, 9.6 Hz, 1
H), 2.60 (dd, J = 14.8, 6.7 Hz, 1 H), 2.58 (dd, J = 15.2, 4.4 Hz, 1
H), 2.35 (dd, J = 14.8, 2.4 Hz, 1 H), 1.31 (t, J = 7.0 Hz, 3 H), 1.20
(d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz): δ = 205.9, 174.1,
141.8, 137.9, 136.1, 133.9, 129.2 (ϫ2), 128.6, 128.5 (ϫ2), 127.8
(ϫ2), 127.4, 127.2, 126.6 (ϫ2), 125.4, 123.4 (ϫ2), 120.8, 114.2, 60.9,
56.1, 54.8, 52.4, 46.6, 44.0, 13.9, 12.2 ppm. HRMS: calcd. for
C30H30N2O5S [M]+· 530.1875; found 530.1915.
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CCDC-635623 (9) and -635622 (12) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
Financial support was received from the Junta de Castilla y León
(SA048/03, SA129A06), the Spanish MEC (CTQ2004-00369) and
European FEDER funds.
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Received: March 17, 2008
Published Online: June 11, 2008
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4014
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