Synthesis of tetrahydro- and dihydropyridines by hetero diels-alder reactions of enantiopure α,β-unsaturated sulfinimines

Article abstract of DOI:10.1002/(sici)1099-0690(199808)1998:8<1629::aid-ejoc1629>3.0.co;2-y

Intermolecular hetero Diels-Alder reactions of the enantiopure sulfinimine 11 with the enol ethers 12-16 at 20 °C and 11 kbar lead to the tetrahydropyridines 18-22 in high yield, with very good to good endo/exo selectivities, and with an induced diastereoselectivity of up to 2.1:1. The sulfinyl group in the adducts can be removed with MeLi followed by treatment with acetyl chloride or dimethyl sulfate. According to this procedure, 21 gives either N-acetyltetrahydropyridine 29 or the N-methyldihydropyridine 32. The intramolecular Diels-Alder reaction of 26 yields 27, which is transformed into 33 and 34, respectively.

Full text of DOI:10.1002/(sici)1099-0690(199808)1998:8<1629::aid-ejoc1629>3.0.co;2-y

FULL PAPER
Synthesis of Tetrahydro- and Dihydropyridines by Hetero Diels-Alder
Reactions of Enantiopure ␣,β-Unsaturated Sulfinimines
Lutz F. Tietze* and Ansgar Schuffenhauer
Institut für Organische Chemie der Georg-August-Universität,
Tammannstraße 2, D-37077 Göttingen, Germany
Fax: (internat.) ϩ 49(0)551/399476
E-mail: ltietze@gwdg.de
Received March 23, 1998
Keywords: Asymmetric induction / Azabutadienes / Calculations / Conformation analysis / Diels-Alder reactions, inter-
and intramolecular / High pressure / Pyridines, dihydro- and tetrahydro- / Sulfinimines
Intermolecular hetero Diels-Alder reactions of the
enantiopure sulfinimine 11 with the enol ethers 12–16 at 20
°C and 11 kbar lead to the tetrahydropyridines 18–22 in high
yield, with very good to good endo/exo selectivities, and with
treatment with acetyl chloride or dimethyl sulfate. According
to this procedure, 21 gives either N-acetyltetrahydropyridine
29 or the N-methyldihydropyridine 32. The intramolecular
Diels-Alder reaction of 26 yields 27, which is transformed
an induced diastereoselectivity of up to 2.1:1. The sulfinyl into 33 and 34, respectively.
group in the adducts can be removed with MeLi followed by
Introduction
Scheme 1
The synthesis of 6-membered N heterocycles is of general
interest since they often show a pronounced biological ac-
tivity. One of the most versatile methods for preparing such
compounds is the hetero Diels-Alder reaction using either
aza-dienophiles or aza-dienes.[1] Thus, α,β-unsaturated sul-
fonimines have been employed for the preparation of tetra-
hydropyridines.[2] In these reactions, however, racemic
products are obtained since the starting material is achiral.
Herein we describe the use of α,β-sulfinimines in inter- and
intramolecular hetero Diels-Alder reactions leading to the
formation of N heterocycles. Sulfinimines are interesting
substrates in synthesis[3] since they can be obtained in en-
antiopure form from menthyl toluenesulfinate.[4] They show
many similarities with vinyl sulfoxides, which have already
been employed in asymmetric Diels-Alder reactions.[5] In
these reactions, good asymmetric inductions are obtained
as a result of a stereoelectronic stabilization due to the syn-
coplanar orientation of the SϪO group and the CϪC
double bond.[6][7] On the other hand, formation of a chelate
with a Lewis acid allows a reversal of the facial selectivity.
Table 1. Energies of the conformers of 1 and 2
Structure Dihedral angle B3LYP/6-311ϩG* Relative energy
CϭXϪSϪO
energy [au]
[kcal molϪ1
]
1a
12°
117°
Ϫ88°
89°
Ϫ607.39871
Ϫ607.38900
Ϫ607.37921
Ϫ607.38865
Ϫ591.34498
Ϫ591.34233
Ϫ607.33560
Ϫ607.33792
0
1b
6.1
12.2
6.3
0
1c (TS)
1d (TS)
2a
9°
2b
133°
Ϫ74°
70°
1.7
5.9
4.4
2c (TS)
2d (TS)
only more than three times as high as that calculated for
the vinyl sulfoxide 2, but is also only 0.2 kcal molϪ1 lower
in energy than the transition structure 1d that separates the
minima 1a and 1b. Moreover, the second transition struc-
ture 1c is found to be twice as high in energy as in the case
Results and Discussion
Calculations on the Conformation of Sulfinimines
For vinyl sulfoxide 2, it was shown that the syncoplanar of the vinyl sulfoxide 2. This clearly demonstrates that there
orientation of the SϪO group and the CϪC double bond must be an additional stabilizing factor for the syncoplanar
as the ground-state conformation is stabilized by 1.7 kcal conformation 1a in the sulfinimines. Second-order pertur-
molϪ1 [6][7] We assumed that the conformation of sulfinim- bation analysis theory of the Fock matrix in the NBO[10]
.
ines might be controlled by similar effects as found for the basis shows that the πCϭN-σ*SϪCH3, πCϭN-RdS, π*CϭN
-
vinyl sulfoxides and calculated the rotational potential en- σSϪCH3, and the π*CϭN-nS interactions contribute to the
ergy surface (PES) of sulfinimine 1 with the B3LYP func- stabilization of 1a with the same order of magnitude as the
tional[8] and the 6-311ϩG* basis set.[9]
corresponding interactions for the vinyl sulfoxide. The ad-
However, at 6.1 kcal molϪ1, the B3LYP/6-311ϩG* en- ditional stabilization of 1a is in fact the result of the nN-
ergy of the second local minimum 1b relative to 1a is not σ*SϪO interaction, which further stabilizes the ground-state
Eur. J. Org. Chem. 1998, 1629Ϫ1637
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0808Ϫ1629 $ 17.50ϩ.50/0
1629

L. F. Tietze, A. Schuffenhauer
FULL PAPER
Figure 1. B3LYP/6-311ϩG* rotational potential energy surface of
1 and 2
The negative results indicate that in these Diels-Alder re-
actions with inverse electron demand, the LUMO energies
and coefficients of the sulfinimines 3 and 5 are not appro-
priate. We therefore calculated the LUMO energies of 3 and
4 by the PM3 method[11] and obtained values of Ϫ0.9 and
Ϫ1.0 eV, respectively. The respective LUMO coefficients of
3 and 4 were found to be Ϫ0.44 and Ϫ0.22 at C-3, and
Ϫ0.37 and Ϫ0.18 at the nitrogen atoms. Since the LUMO
energy of 3 is only slightly higher than that of the corre-
sponding sulfonimine 4, and the LUMO coefficients of 3 at
C-3 and at the nitrogen atom are twice as high as those
found for 4, these calculations offer no explanation as to
the lack of reactivity of 3 compared to 4. Indeed, the calcu-
lations serve only to illustrate the limited reliability of such
semiempirical approaches in the realm of hypervalent sul-
fur compounds.
For Diels-Alder reactions of 1-oxa-1,3-butadienes, we
conformation by 3.9 kcal molϪ1, giving rise to a shortening have previously demonstrated the accelerating effect of an
˚
˚
of the NϪS bond from 1.80 A in 1b to 1.78 A in 1a. The electron-withdrawing group at the 3-position of the diene,
X-ray structure of sulfinimine 3 corresponds very well with which causes a decrease of the LUMO energy and favour-
the calculations on 1a; the CϭNϪSϪO dihedral angles de- able coefficients.[12] We therefore prepared 11, bearing a cy-
viate by only 6°.
ano group at the 3-position of the 1-azabutadiene moiety,
Figure 2. Stabilization of 1a and 1b
Diels-Alder Reactions of α,β-Unsaturated Sulfinimines
Scheme 2
Since the aforementioned calculations had shown the sul-
finimines to be conformationally rigid, we expected them to
give high asymmetric induction in hetero Diels-Alder reac-
tions, even in the absence of a chelating Lewis acid. The
reaction of the α,β-unsaturated sulfinimine 3 with ethyl vi-
nyl ether seemed to be a suitable starting point for our in-
vestigations since it is known that α,β-unsaturated sulfoni-
mines such as 4 cyclize with ethyl vinyl ether at 12 kbar in
high yield with endo selectivity.[2] However, we found that
even after heating the reactants to 60°C under high pressure
up to 11 kbar for 48 h, the desired cycloadduct was not from the aldehyde 8 and menthyl toluenesulfinate 9. The
formed. Addition of Lewis acids such as AlClMe2, aldehyde 8 was synthesized from benzaldehyde 6 and iso-
AlCl2Me, SnCl4 or TMSOTf at Ϫ78°C did not change the xazole 7.[13] The usual procedure for the synthesis of sulfini-
picture; only decomposition of the enol ether was observed. mines reported by Davis,[4] in which an excess of the alde-
The intramolecular Diels-Alder reaction of 5 was likewise hyde is added to the crude mixture of 10 after the addition
unsuccessful under the conditions mentioned above.
of LiHMDS to 9, proved to be unsuitable for the synthesis
1630
Eur. J. Org. Chem. 1998, 1629Ϫ1637

Hetero Diels-Alder Reactions of Enantiopure α,β-Unsaturated Sulfinimines
FULL PAPER
of sulfinimine 11. We suspect that a Michael addition of
the formed menthoxide to the aldehyde 8 occurred. How-
ever, upon addition of acetic acid to the crude mixture of
10, the desired sulfinimine 11 was obtained in high yield.
Using this procedure, it was not necessary to employ an
excess of the aldehyde 8.
Table 2. Cycloaddition of 11 to various dienophiles 12Ϫ17
Dieno- Cyclo- R1
phile adduct
R2
R3 Yield exo/endo endo I/endo II
[%]
(/exo I/exo II)
12
13
14
15
16
17
18
19
20
21
22
23
OEt
SPh
H
H
H
96
80
99
76
98
0
1:100
1:100
13:87
1:100
24:76
Ϫ
1.7:1
H
1.9:1
OtBu H
H
2.3:1(:0.3:0.2)
1.8:1
1.1:1(:0.4:0.3)
Ϫ
SMe SMe
OMe Me
Me
H
Scheme 3
H
Me
Me
The structural assignment of the diastereomeric cycload-
ducts is representatively shown for 20. It is based on an X-
ray analysis of the minor endo adduct 20b. The NOESY
spectra of the two main products 20a and 20b both show a
strong NOE between 4-H and 6-H, which is only possible
if the two hydrogen atoms are in a cis orientation. A differ-
entiation of the two exo products was not possible on the
basis of the spectroscopic data; however, considering the
facial selection in forming the endo product 20a, it was as-
sumed that the main exo product is also formed by an at-
tack of the dienophile anti to the p-tolyl group.
Cycloadditions of 11 to various electron-rich dienophiles
12Ϫ16 at room temperature under a pressure of 11 kbar
gave the cycloadducts 18؊22 in almost quantitative yields
(Table 2). In those cases where the dienophiles could not be
removed by distillation, thus necessitating chromatographic
purification, the yields of the isolated products were around
80%. Dienophiles without electron-donating substituents,
such as the simple alkene 17, did not react. In most cases,
the endo products were formed highly preferentially, the ex-
ceptions being the reaction of 14, which contains a bulky
tert-butoxy group, and that of 16, which has a methyl group
at C-1 of the enol ether. In contrast, the induced diastereo-
selectivities were found to be rather low, ranging from 1.1:1
to 2.3:1 for the endo products, with a preferential attack
anti to the p-tolyl group. Some of the major products could
be separated by column chromatography. The reaction of
11 and 12 was also performed using different Lewis acids
at atmospheric pressure. However, decomposition of the
enol ether occurred prior to product formation.
Pressure Dependence of the Diastereoselectivity
Recently, we observed a pronounced pressure dependence
of up to ∆∆V϶ ϭ 7 cm3 molϪ1 on the diastereoselectivities
of cycloadditions of some 1-oxa-1,3-butadienes at high
pressures.[14] Such an effect is only found if there is strong
steric hindrance in the endo transition structure. The cyclo-
addition of 11 to tert-butyl vinyl ether was performed under
various pressures ranging from 2 to 12 kbar. The ratio of
the diastereomeric products 20a؊d was determined by ana-
1
lyzing the H-NMR signals of the methyl group of the p-
toluyl moiety and those of the tert-butoxy group. A marked
decrease of the conversion rate with decreasing pressure was
observed, which corresponds to the well known fact that
Diels-Alder reactions have a strong negative activation vol-
ume ∆V϶. According to ElЈyanowЈs equation,[15] the differ-
ences of the activation volumes ∆∆V϶ were determined
from plots of ln(endo I/endo II) and ln(endo I/exo I) versus
Ψ(p). A ∆∆V϶ value of Ϫ(2.0 ± 0.4) cm3 molϪ1 was found
for the formation of the endo I and exo I cycloadducts,
which is consistent with the expected stabilization of the
more crowded endo transition structure under high pres-
sure. Somewhat unexpected, however, is the preferential for-
mation of the endo I cycloadduct compared to endo II with
a ∆∆V϶(endo I Ϫ endo II) ϭ Ϫ(1.8 ± 0.5) cm3 molϪ1. This
would imply that the attack of the dienophile anti to the
tolyl group in 11, the less hindered approach, is actually
stabilized under high pressure.[16] Though the ∆∆V϶ values
are significant, they are too small to indicate a pronounced
pressure-induced enhancement of the diastereoselectivity in
these cycloadditions.
Scheme 4
Intramolecular Hetero Diels-Alder Reactions of Sulfinimines 26
Intramolecular reactions often occur with a much higher
stereoselectivity than the corresponding intermolecular
transformations. We therefore prepared the sulfinimine 26,
Eur. J. Org. Chem. 1998, 1629Ϫ1637
1631

L. F. Tietze, A. Schuffenhauer
FULL PAPER
Figure 3. Pressure dependence of the diastereoselectivity of the assumption that, in analogy to the cycloaddition of 11, the
cycloaddition of 11 and 14
attack anti to the tolyl group should be preferred. The main
product should therefore be 27a. Interestingly, in the intra-
molecular reaction of 26, the induced diastereoselectivity is
higher, while the endo/exo selectivity is lower, compared to
the intermolecular Diels-Alder reaction of 11.
Cleavage of the Sulfininyl Group
Attempts to reductively cleave the sulfinyl group in 20
with LiAlH4 or Raney Ni were unsuccessful, leading only
to decomposition. However, the sulfinyl group could
smoothly be removed by a nucleophilic substitution with
MeLi at Ϫ78°C, giving the enamide ion 28 and methyl tol-
uyl sulfoxide. 28 was quenched with acetyl chloride to fur-
nish 29. In contrast, dimethyl sulfate was found to be insuf-
ficiently reactive to allow a methylation of 28 at Ϫ78°C. At
room temperature, however, the methylation does take
place, although it is accompanied by elimination of the tert-
butoxide. Thus, as the final product, the dihydropyridine 32
was isolated.
Scheme 6
bearing a cyano group at C-3, starting from aldehyde 24.
The hetero Diels-Alder reaction of 26 was performed under
high pressure at room temperature in dichloromethane, to
give the cycloadducts 27aϪd in almost quantitative yield as
a mixture of the four possible diastereomers in a ratio of
8.8:2.3:4.4:1.0. The mixture could be separated by column
chromatography into two fractions containing 27a/27b and
27c/27d, respectively. The cycloadducts 27a and 27b are the
two endo products, while 27c and 27d are the two exo prod-
1
ucts. Thus, upon analysis of the H-NMR spectra of 27a
and 27b, 4a-H shows only a diaxial coupling with 5-Ha,
whereas in 27c and 27d this proton shows diaxial couplings
with both 5-Ha and 10b-H. A differentiation of the two
endo and two exo products on the basis of the spectroscopic
data was not possible. Thus, the assignment stems from the
Scheme 5
1632
Eur. J. Org. Chem. 1998, 1629Ϫ1637

Hetero Diels-Alder Reactions of Enantiopure α,β-Unsaturated Sulfinimines
FULL PAPER
The cleavage of the sulfinyl group in 27 could be per- mild conditions and give high yields and excellent endo sel-
formed in a similar manner as described for 20. Reaction ectivities in most cases.
of 27 with MeLi led to the corresponding enamide ion,
Figure 4. Proposed mechanism for the cycloaddition of 11 and die-
which was quenched with acetyl chloride or methyl iodide
nophiles
to give the tetrahydropyridines 33 and 34, respectively, by
attack at the nitrogen atom. Using the mixture of 27aϪd,
two diastereomers were obtained in each case in a ratio cor-
responding to the endo/exo selectivity. The isomers 35 and
36, which might have been formed by reaction at C-3 in 27,
were not observed.
Scheme 7
We thank the Deutsche Forschungsgemeinschaft (SFB 416) and
the Fonds der Chemischen Industrie for their generous support.
Experimental Section
Computational Methods: The PM3 calculations using MO-
PAC [11] were performed with a PC. The density functional calcu-
lations and NBO analysis with GAUSSIAN94[19] were performed
with an IBM RS6000 Work Station and an SGI PowerChallenge.
All starting geometries were pre-optimized with the MMX force
Conclusion
The asymmetric induction associated with the cycload-
dition of enantiopure α,β-unsaturated sulfinimines to enol
ethers is rather low. This is in contrast to calculations, which field within PC-MODEL.[20]
show a strong stabilization of a conformation with a Cϭ
NϪSϪO dihedral angle of about 0°, which is in agreement
General: All reactions were carried out under a positive pressure
of nitrogen or argon in dried solvents. Unless stated otherwise, col-
with an X-ray structure. It could be argued that the sulfini-
umn chromatography was performed with mixtures of tBuOMe/
mines are conformationally less rigid than calculated. How- petroleum ether as eluent on silica gel with mesh 0.032Ϫ0.063 mm
from Macherey-Nagel. Reactions under high pressure were carried
out in sealed Teflon tubes using a high-pressure cell built by the
Institute of Physical Chemistry of the Polish Academy of Sciences.
Sulfinimine 3 was prepared according to the procedure of Davis.[4]
Aldehydes 8 and 24, as well as the thioketene acetal 15, were pre-
pared according to the literature.[13][21][22] Ϫ IR: Bruker IFS. Ϫ
NMR: Varian XL200, VXR 200, UNITY 300, INOVA 500, and
Bruker AMX-300; solvent CDCl3 with TMS as internal standard.
Ϫ MS: Varian MAT 311A and MAT 731. The X-ray structures of 3
and 20b have been deposited with the CCDC under the depository
ever, ground-state calculations are usually quite accurate
nowadays. Therefore, another aspect must be discussed, na-
mely the mechanism of the cycloaddition. The α,β-unsatu-
rated sulfinimine can cyclize either in a concerted manner
via B-TS (Figure 4), or by a stepwise mechanism in which
the CϪC bond is formed before the CϪN bond. For the
model reaction of 1-aza-1,3-butadiene with ethene, UHF/6-
31ϩG* calculations have shown that the stepwise mecha-
nism is favoured.[17] Following the concerted reaction path,
one would expect a high asymmetric induction since bond number 101157.
formation with the generation of a stereogenic centre occurs
Aldehyde 25: To a solution of sodium methoxide (2.53 ml of a 5.4
 solution in methanol, 14 mmol) in methanol (2.4 ml) at Ϫ10°C,
isoxazole (0.94 g, 14 mmol) was added dropwise, followed, after
in close proximity to the chiral sulfinyl group. In contrast,
following the stepwise reaction path, the new stereogenic
centre is generated far away from the inducing stereogenic stirring for 1 h, by aldehyde 24 (2.6 g, 14 mmol). The mixture was
stirred for 4 d at 0°C, then poured into iced water (15 ml), and
neutralized with 20% HCl. The resulting mixture was extracted
with CH2Cl2 (3 ϫ 50 ml), and the combined organic phases were
washed with brine, dried with Na2SO4, and the solvent was re-
moved in vacuo at 20°C. Chromatographic purification furnished
centre, resulting in a low asymmetric induction. On the
other hand, a strong acceleration of the reaction with in-
creasing pressure is usually interpreted as an indication of a
concerted reaction.[18] We therefore think that the described
cycloadditions are concerted, but highly asynchronous.
Though the induced diastereoselectivity has to be im-
proved, the described aza Diels-Alder reactions of sulfinim-
ines represent a very efficient approach to chiral tetrahydro-
and dihydropyridines in only three steps, starting from com-
1.80 g (53%) of 25 as the main product, and 0.59 g (35%) of the
˜
intramolecular cycloadduct of 25 as a by-product. Ϫ IR (film): ν ϭ
3110 cmϪ1, 2830 (CϪH), 2220 (CN), 1694 (CHO), 1594. Ϫ UV
(CH3CN): λmax (lg ε) ϭ 216.5 (4.06), 300.5 (4.11), 366.0 (4.03). Ϫ
1H NMR (200 MHz, CDCl3): δ ϭ 1.77 [d, J ϭ 1.2 Hz, 3 H, prenyl-
mercially available substrates. The reactions proceed under (Z)-CH3], 1.83 [d, J ϭ 1.2 Hz, 3 H, prenyl-(E)-CH3], 4.65 (d, J ϭ
Eur. J. Org. Chem. 1998, 1629Ϫ1637 1633

L. F. Tietze, A. Schuffenhauer
FULL PAPER
6.8 Hz, 2 H, prenyl-CH2), 5.49 (ddt, J ϭ 6.8, 1.2, 1.2 Hz, 1 H,
Diels-Alder Reactions Under High Pressure. Ϫ General Pro-
prenyl-CH), 7.00 (d, J ϭ 7.8 Hz, 1 H, 3Ј-H), 7.08 (dd, J ϭ 8.0, 7.8 cedure: Cycloadditions of the sulfinimines 11 (0.2 mmol) to the
Hz, 1 H, 5Ј-H), 7.56 (ddd, J ϭ 7.8, 7.8, 1.2 Hz, 1 H, 4Ј-H), 8.40 dienophiles 12Ϫ16 (1.0 mmol) and of 26 (0.2 mmol) were per-
(dd, J ϭ 8.0, 1.2 Hz, 1 H, 6Ј-H), 8.48 (s, 1 H, 3-H), 9.56 (s, 1 H, formed in CH2Cl2 (1 ml) at 11 kbar, with reaction times of 2 d.
1-H). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 18.28 [prenyl-(Z)-CH3], Evaporation of the solvent and excess dienophile in vacuo or chro-
25.78 [prenyl-(E)-CH3], 65.78 (prenyl-CH2), 111.49 (C-2), 112.59
matographic separation gave the cycloadducts 18Ϫ22 and 27,
(C-3Ј), 114.44 (CN), 118.55 (C-5Ј), 120.62 (C-1Ј), 121.05 (prenyl- respectively.
CH), 129.62 (C-6Ј), 136.17 (C-4Ј), 139.14 [prenyl-C(CH3)2], 153.74
Tetrahydropyridine 18: Reaction of sulfinimine 11 (58 mg, 0.2
(C-3), 158.79 (C-2Ј), 187.63 (CHO). Ϫ MS (70 eV, FD); m/z (%):
241.2 (8) [Mϩ], 198.2 (16), 145.2 (26) [Mϩ Ϫ CN Ϫ C5H9], 69.1
(100) [C5H9ϩ]. Ϫ C15H15NO2 (241.28): calcd. C 74.67, H 6.27;
found C 74.89, H 6.35.
mmol) with ethyl vinyl ether (12) (72 mg, 1.0 mmol) gave the cyclo-
adducts 18a and 18b (70 mg, 96%) as a 1.7:1 mixture in the form
1
of a yellow oil. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.64 (t, J ϭ
7.0 Hz, 3 H, Et-CH3, II), 0.84 (t, J ϭ 7.0 Hz, 3 H, Et-CH3, I),
Synthesis of Sulfinimines. Ϫ General Procedure: To a stirred solu-
1.10Ϫ1.40 (m, 1 H, 5-Ha, I and II), 1.94 (ddd, J ϭ 14.0, 7.5, 3.0
tion of menthyl sulfinate 9 in THF (60 ml/mmol), LiHMDS (1.5 Hz, 1 H, 5-Hb, I), 2.06 (ddd, J ϭ 14.0, 7.4, 2.7 Hz, 1 H, 5-Hb, II),
equiv. of a 1  solution) was slowly added at Ϫ78°C and stirring 2.43 (s, 3 H, Tol-CH3, II), 2.47 (s, 3 H, Tol-CH3, I), 2.90 (dq, J ϭ
was continued at room temp. for 1 h. The solution was then cooled
15.5, 7.0 Hz, 1 H, Et-CH2a, II), 3.00Ϫ3.20 (m, 1 H, Et-CH2b, I
to Ϫ78°C once more and HOAc (1.5 equiv.) was added from a and II), 3.45 (dq, J ϭ 16.0, 7.0 Hz, 1 H, Et-CH2a, I), 4.65Ϫ3.75
microlitre syringe. After warming to 0°C, the aldehyde (1 equiv.) (m, 1 H, 4-H, I and II), 4.97 (dd, J ϭ 3.0, 2.7 Hz, 1 H, 6-H, I),
and CsF (2.0 equiv.) were added, and stirring was continued until
5.03 (dd, J ϭ 2.6, 2.3 Hz, 1 H, 6-H, II), 7.11 (s, 1 H, 2-H, I), 7.17
completion of the transformation (TLC control, ca. 14 h). The re- (s, 1 H, 2-H, II), 7.18Ϫ7.38 (m, 5 H, Ph-H, I and II), 7.35 (d, J ϭ
action was then quenched by the addition of water (a quarter of
the reaction volume) and the mixture was extracted with Et2O (3
ϫ 30 ml). The combined organic phases were washed with brine
8.3 Hz, 2 H, Tol-m-H, II), 7.40 (d, J ϭ 8.0 Hz, 2 H, Tol-m-H, I),
7.53 (d, J ϭ 8.3 Hz, 2 H, Tol-o-H, II), 7.59 (d, J ϭ 8.0 Hz, 2 H,
I). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 14.17 (Et-CH3, II), 14.47
and dried with Na2SO4, the solvent was removed in vacuo, and the (Et-CH3, I), 21.41 (Tol-CH3, II), 21.45 (Tol-CH3, I), 33.97 (C-5,
residue was purified by chromatography or crystallization.
II), 34.04 (C-5, I), 36.80 (C-4, I), 36.88 (C-4, II), 63.04 (Et-CH2,
II), 63.15 (Et-CH2, I), 82.02 (C-6, II), 82.93 (C-6, I), 91.40 (C-3,
I), 91.48 (C-3, II), 119.18 (CN, I and II), 125.32, 125.36, 126.58,
126.67, 127.72, 127.83, 128.00, 128.04, 130.00, 130.23, 138.60,
138.66, 138.93, 139.06, 140.50, 140.66, 142.95, 143.05 (aryl-C and
C-2).
Sulfinimine 11: Reaction of 9 (1.00 g, 3.3 mmol) and 8 (0.53 g,
3.3 mmol) gave 11 (0.74 g, 76%) after purification by column fil-
tration and crystallization from tBuOMe/CH2Cl2, m.p. 133°C (de-
˜
20
comp.). Ϫ [α]D ϭ ϩ343 (c ϭ 1, CHCl3). Ϫ IR (film): ν ϭ 3060
cmϪ1 (ArϪH), 3032, 2918, 2228, 2208 (CN), 1598, 1590 (CϭN),
1070 (SϪO), 544. Ϫ UV (CH3CN): λmax (lg ε) ϭ 192.0 (4.84), 226.5
Tetrahydropyridine 19: Reaction of sulfinimine 11 (58 mg, 0.2
mmol) with phenyl vinyl sulfide (13) (54 mg, 0.4 mmol) gave cyclo-
1
(1.50), 315.5 (2.43). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 2.42 (s,
3 H, Tol-CH3), 7.33 (d, J ϭ 7.9 Hz, 2 H, m-Tol-H), 7.50Ϫ7.53 (m, adduct 19 (86 mg, 80%) as a 1.9:1 mixture of the endo dia-
3 H, o,p-Ph-H), 7.61 (s, 1 H, 3-H), 7.64 (d, J ϭ 7.9 Hz, 2 H, o-Tol- stereomers I and II. The product was obtained as a yellow oil,
H), 7.95Ϫ8.00 (m, 2 H, m-Ph-H), 8.45 (s, 1 H, 1-H). Ϫ 13C NMR which was found to contain residual 13. The diastereomer ratio
(50 MHz, CDCl3): δ ϭ 21.42 (Tol-CH3), 109.32 (C-2), 114.58 (CN), was determined from the C-4, C-5, C-6 signals in the 13C-NMR
1
124.75, 129.33, 129.52, 130.7, 131.87, 133.19, 140.70, 142.03 (aryl- spectrum. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 2.30Ϫ2.55 (m, 2
C), 154.96 (C-3), 158.01 (C-1). Ϫ MS (70 eV, FD); m/z (%): 294.3 H, 5-H, I and II), 2.36 (s, 3 H, Tol-CH3, I), 2.41 (s, 3 H, Tol-CH3,
(5) [Mϩ], 155.1 (14) [Mϩ Ϫ TolSO], 139.1 (100) [TolSOϩ], 91.1 (6)
II), 3.67 (dd, J ϭ 5.7, 5.7 Hz, 1 H, 4-H, I), 3.73 (dd, J ϭ 5.8, 5.8
[Tolϩ], 77.1 (4) [Phϩ]. Ϫ C17H14N2OS (294.37): calcd. C 69.36, H Hz, 1 H, 4-H, II), 5.00 (dd, J ϭ 6.0, 3.8 Hz, 1 H, 6-H, I), 5.35 (dd,
4.79; found C 69.14, H 4.83.
J ϭ 5.3, 4.6 Hz, 6-H, II), 6.89 (d, J ϭ 0.9 Hz, 1 H, 2-H, II), 7.10
(d, J ϭ 1.7 Hz, 1 H, 2-H, I), 7.10Ϫ7.55 (m, 14 H, aryl-H). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 21.42 (Tol-CH3, I and II), 36.79 (C-
5, I), 37.37 (C-5, II), 38.27 (C-4, II), 38.76 (C-4, I), 62.80 (C-6, I),
64.67 (C-6, II), 92.39 (C-3, I), 92.89 (C-3, II), 118.75 (CN, II),
118.83 (CN, I), 124.99, 125.72, 126.97, 127.28, 127.97, 128.03,
128.44, 128.50, 128.79, 129.06, 129.17, 130.09, 130.22, 130.30,
132.00, 132.28, 133.30, 133.42, 139.02, 139.11, 137.81, 138.64,
139.76, 139.81, 143.17 (aryl-C).
Sulfinimine 26: Reaction of 9 (1.00 g, 3.3 mmol) with 25 (0.84 g,
3.3 mmol) gave 26 (1.04 g, 83%) as a yellow solid after chromato-
20
graphic purification. Ϫ [α]D ϭ ϩ596 (c ϭ 0.5, CHCl3). Ϫ IR
˜
(film): ν ϭ 3036 cmϪ1 (ArϪH), 2972, 2224 (CN), 1592, 1590 (Cϭ
N), 1070, 1046 (SϪO). Ϫ UV (CH3CN): λmax (lg ε) ϭ 233.5 (3.01),
306.0 (3.05), 367.5 (3.03). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ
1.76 [s, 3 H, prenyl-(Z)-CH3], 1.84 [s, 3 H, prenyl-(E)-CH3], 2.41
(s, 3 H, Tol-CH3), 4.59 (d, J ϭ 6.6 Hz, 2 H, prenyl-CH2), 5.49 (t,
J ϭ 6.6 Hz, 1 H, prenyl-CH), 6.96 (d, J ϭ 8.3 Hz, 1 H, 3Ј-H), 7.05
(dd, J ϭ 8.0, 7.6 Hz, 1 H, 5Ј-H), 7.32 (d, J ϭ 8.5 Hz, 2 H, m-
Tetrahydropyridine 20: The reaction of sulfinimine 11 (135 mg,
0.5 mmol) with tert-butyl vinyl ether (15) (163 mg, 1.6 mmol) gave
TolϪH), 7.49 (ddd, J ϭ 8.3, 7.6, 1.2 Hz, 1 H, 4Ј-H), 7.64 (d, J ϭ cycloadduct 20 (181 mg, 99%) as a white solid consisting of a mix-
8.5 Hz, 2 H, o-Tol-H), 8.24 (s, 1 H, 3-H), 8.35 (dd, J ϭ 8.0, 1.2 ture of endo I/endo II/exo I/exo II in a ratio of 2.3:1.0:0.2:0.3. The
Hz, 1 H, 6Ј-H), 8.49 (s, 1 H, 1-H). Ϫ 13C NMR (50 MHz, CDCl3): ratio was determined from the p-Tol-CH3 and tBuO signals in the
δ ϭ 18.27 [prenyl-(Z)-CH3], 21.42 (Tol-CH3), 25.84 [prenyl-(E)-
1H-NMR spectrum. By means of column chromatography with
CH3], 65.54 (prenyl-CH2), 108.15 (C-2), 112.23 (C-3Ј), 114.99 tBuOMe/petroleum ether (3:7) as eluent, the endo I (41 mg) and
(CN), 118.60 (C-5Ј), 120.86 (prenyl-CH), 121.21 (C-1Ј), 124.80, endo II (28 mg) diastereomers could be obtained in a pure form,
˜
129.03, 129.88, 134.94 (aryl-C), 139.21 [prenyl-C(CH3)2*], 140.98, and exo I and exo II as a mixture (12 mg). Ϫ IR (film): ν ϭ 3056
141.92 (aryl-C), 149.96 (C-3), 158.40 (C-2Ј), 158.98 (C-1). Ϫ MS cmϪ1 (CϪH), 2206 (CN), 1626 (enamine), 1098, 1040 (SϪO). Ϫ
(70 eV, FD); m/z (%): 378.7 (3) [Mϩ], 278.4 (37), 239.4 (21) [Mϩ Ϫ UV (CH3CN): λmax (lg ε) ϭ 258.5 (4.25). Ϫ MS (70 eV, FD); m/z
TolSO], 171.2 (23) [Mϩ Ϫ TolSO Ϫ prenyl], 139.1 (100) [TolSOϩ], (%): 394.4 (12) [Mϩ], 338.3 (7) [Mϩ Ϫ C4H8], 139.1 (100) [TolSOϩ],
91.1 (6) [Tolϩ], 69.1 (4) [prenylϩ]. Ϫ C22H22N2O2S (378.48): calcd. 91.1 (10) [Tolϩ], 57.1 (52) [C4H9ϩ]. Ϫ C23H26N2O2S (394.53): calcd.
C 69.81, H 5.86; found C 69.87, H 5.90.
C 70.02, H 6.64; found C 70.28, H 6.91.
1634
Eur. J. Org. Chem. 1998, 1629Ϫ1637

Hetero Diels-Alder Reactions of Enantiopure α,β-Unsaturated Sulfinimines
FULL PAPER
20
endo I. Ϫ Tetrahydropyridine 20a: [α]D ϭ ϩ178.0 (c ϭ 0.5,
127.90, 127.98, 129.06, 130.43, 130.57, 137.54, 137.80, 138.89,
1
CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.99 (s, 9 H, tBuO), 138.98, 139.31, 140.15, 143.09, 149.13 (aryl-C and C-2). Ϫ MS (70
2.13 (ddd, J ϭ 13.6, 6.8, 2.6 Hz, 1 H, 5-Ha), 2.25 (ddd, J ϭ 13.6, eV, FD); m/z (%): 389.1 (12) [Mϩ Ϫ CN], 352.2 (13) [Mϩ Ϫ MeS
4.9, 4.9 Hz, 1 H, 5-Hb), 2.39 (s, 3 H, Tol-CH3), 3.64 (ddd, J ϭ 6.8, Ϫ Me], 350.2 (100) [Mϩ Ϫ MeS Ϫ Me Ϫ H2], 273.1 (67) [Mϩ
Ϫ
4.9, 1.0 Hz, 1 H, 4-H), 5.26 (dd, J ϭ 4.9, 2.6 Hz, 1 H, 6-H), 6.87 TolSO Ϫ H2], 139.1 (30) [TolSOϩ], 77.1 (6) [Phϩ]. Ϫ C21H22N2OS3
(d, J ϭ 1.0 Hz, 1 H, 2-H), 7.1Ϫ7.3 (m, 5 H, Ph-H), 7.21 (d, J ϭ (414.40): calcd. C 60.86, H 5.35; found C 61.04, H 5.63.
7.9 Hz, 2 H, m-Tol-H), 7.43 (d, J ϭ 7.9 Hz, 2 H, o-Tol-H). Ϫ 13C
Tetrahydropyridine 22: Reaction of sulfinimine 11 (29 mg, 0.1
NMR (75 MHz, CDCl3): δ ϭ 21.39 (Tol-CH3), 27.90 (tBu-CH3),
mmol) with the enol ether 16 (20 mg, 0.5 mmol) gave cycloadduct
37.89 (C-4), 38.18 (C-5), 75.80 [tBu-C(CH3)3], 79.48 (C-6), 92.74
22 (26 mg, 98%) as a yellow oil consisting of a mixture of four
(C-3), 119.12 (CN), 125.42, 126.74, 127.90, 128.20, 130.26, 138.85,
139.25, 140.58, 142.75 (aromatic and C-2).
diastereomers IϪIV in a ratio of 1.1:1.0:0.4:0.3. The ratio was de-
termined from the MeO and C-5 signals in the 13C-NMR spectrum.
˜
Ϫ IR (film): ν ϭ 3030 cmϪ1, 2976 (CϪH), 2208 (CN), 1618 (enam-
20
endo II. Ϫ Tetrahydropyridine 20b: [α]D ϭ Ϫ12.4 (c ϭ 0.5,
1
ine), 1072 (SϪO). Ϫ UV (CH3CN): λmax (lg ε) ϭ 257.5 (4.08). Ϫ
1H NMR (500 MHz, CDCl3): δ ϭ 1.69 (s, 3 H, 6-Me, II), 1.81 (s,
3 H, 6-Me, I), 1.82 (s, 3 H, 6-Me, III), 1.91 (s, 3 H, 6-Me, IV),
2.00Ϫ2.50 (m, 1 H, 5-Ha, IϪIV), 2.43 (s, 3 H, Tol-CH3, III and
IV), 2.47 (s, 3 H, Tol-CH3, II), 2.49 (s, 3 H, Tol-CH3, I), 2.80Ϫ3.40
(m, 1 H, 5-Hb, IϪIV), 3.31 (s, 3 H, MeO, I), 3.36 (s, 3 H, MeO,
II), 3.40 (s, 3 H, MeO, III), 3.47 (s, 3 H, MeO, IV), 3.60 (ddd, J ϭ
9.6, 5.8, 1.8 Hz, 1 H, 4-H, II), 3.70 (ddd, J ϭ 10.5, 5.7, 1.7 Hz, 1
H, 4-H, I), 3.84 (ddd, J ϭ 12.1, 6.3, 2.1 Hz, 1 H, 4-H, III), 4.09 (s,
J ϭ 16.2, 10.0, 2.3 Hz, 1 H, 4-H, IV), 6.73 (d, J ϭ 2.3 Hz, 1 H, 2-
H, IV), 6.82 (d, J ϭ 2.1 Hz, 1 H, 2-H, III), 6.87 (d, J ϭ 1.8 Hz, 1
H, 2-H, II), 6.89 (d, J ϭ 1.7 Hz, 1 H, 2-H, I), 7.10Ϫ7.62 (m, 9 H,
aryl-H, IϪIV). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 21.47 (Tol-
CH3, II), 21.51 (Tol-CH3, I and III), 21.98 (Tol-CH3, IV), 22.77 (6-
CH3, IV), 23.92 (6-CH3, III), 25.44 (6-CH3, I), 26.72 (6-CH3, II),
26.88 (C-4, III), 37.58 (C-4, IV), 39.12 (C-4, II), 40.10 (C-4, II),
40.48 (C-5, II), 40.77 (C-5, I), 43.37 (C-5, III), 45.05 (C-5, IV),
49.85 (MeO, IV), 50.13 (MeO, II), 50.62 (MeO, III), 50.93 (MeO,
I), 88.04 (C-3, IV), 88.23 (C-3, III), 89.65 (C-3, II), 90.04 (C-3, I),
91.13 (C-6, II), 92.77 (C-6, I), 95.34 (C-6, IV), 95.64 (C-6, III),
116.83, 118.56, 118.83, 125.09, 125.17, 125.39, 125.47, 125.86,
125.90, 127.11, 127.16, 127.49, 127.53, 127.60, 127.74, 128.86,
128.95, 130.16, 130.36, 130.55, 130.59, 137.02, 137.98, 138.36,
139.05, 139.42, 139.62, 139.81, 139.86, 140.00, 140.27, 142.89,
142.99, 143.02, 143.18 (CN, aryl-C and C-2). Ϫ MS (70 eV, FD);
m/z (%): 366.5 (4) [Mϩ], 278.4 (39), 227.4 (13) [Mϩ Ϫ TolSO],
194.3, 139.2 (100) [TolSOϩ]. Ϫ C21H22N2O2S (366.47): calcd.
366.1402; found 366.1402 (MS).
CHCl3). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.99 (s, 9 H, tBuO),
2.20 (dd, J ϭ 6.4, 3.4 Hz, 1 H, 5-Ha), 2.21 (dd, J ϭ 4.9, 4.1 Hz, 1
H, 5-Hb), 2.42 (s, 3 H, Tol-CH3), 3.69 (dd, J ϭ 6.4, 4.9 Hz, 1 H,
4-H), 5.35 (dd, J ϭ 4.1, 3.4 Hz, 1 H, 6-H), 6.84 (s, 1 H, 2-H),
7.1Ϫ7.25 (m, 5 H, Ph-H), 7.36 (d, J ϭ 7.9 Hz, 2 H, m-Tol-H), 7.56
(d, J ϭ 7.9 Hz, 2 H, o-Tol-H). Ϫ 13C NMR (75 MHz, CDCl3):
δ ϭ 21.47 (Tol-CH3), 28.25 (tBu-CH3), 37.57 (C-4), 38.53 (C-5),
75.69 [tBu-C(CH3)3], 79.06 (C-6), 91.69 (C-3), 119.16 (CN), 125.94,
126.80, 127.70, 128.70, 130.31, 138.81, 139.35, 140.65, 142.87 (aryl-
C and C-2).
exo I and exo II. Ϫ Tetrahydropyridine 20c and 20d: 1H NMR
(300 MHz, CDCl3): δ ϭ 1.31 (s, 9 H, tBuO, exo I), 1.35 (s, 9 H,
tBuO, exo II), 1.67Ϫ1.76 (m, 1 H, 5-Ha, exo I), 1.81 (ddd, J ϭ
13.2, 6.4, 3.4 Hz, 1 H, 5-Ha, exo II), 2.09Ϫ2.16 (m, 1 H, 5-Hb, exo
I and exo II), 2.39 (s, 3 H, Tol-CH3, exo II), 2.46 (s, 3 H, Tol-CH3,
exo I), 3.72 (ddd, J ϭ 12, 6.4, 4.9 Hz, 1 H, 4-H, exo II), 3.80Ϫ3.85
(m, 1 H, 4-H, exo I), 5.36 (dd, J ϭ 2.6, 1.9 Hz, 1 H, 6-H, exo I),
5.41 (dd, J ϭ 2.6, 2.2 Hz, 1 H, 6-H, exo II), 6.70 (d, J ϭ 1.9 Hz,
1 H, 2-H, exo II), 6.92 (d, J ϭ 1.9 Hz, 1 H, 2-H, exo I), 7.10Ϫ7.35
(m, 5 H, Ph-H, exo I and exo II), 7.34 (d, J ϭ 8.3 Hz, 2 H, m-Tol-
H, exo I), 7.38 (d, J ϭ 8.3 Hz, 2 H, m-Tol-H, exo II), 7.50 (d, J ϭ
8.3 Hz, 2 H, o-Tol-H, exo I), 7.50 (d, J ϭ 8.3 Hz, 2 H, o-Tol-H,
exo II). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 21.35 (Tol-CH3, I),
26.95 (Tol-CH3, II), 29.88 (tBu-CH3, I), 31.18 (tBu-CH3, II), 39.56
(C-4, I and II), 49.44 (C-5, I and II), 76.47 [tBu-C(CH3)3, I and
II], 82.60 (C-6, I and II), 100.80 (C-3, I), 109.60 (C-3, II), 115.30
(CN, II), 115.33 (CN, I), 124.81, 125.26, 125.91, 127.57, 127.57,
128.44, 129.15, 129.33, 129.44, 129.57, 134.28, 134.74, 136.47,
141.11, 142.04, 143.59 (aryl-C and C-2).
Cycloadducts 27: Reaction of 26 (21 mg, 0.06 mmol) in CH2Cl2
at 11 kbar for a period of 4 d gave 27 (20 mg, 95%) as a yellow
Tetrahydropyridine 21: Reaction of sulfinimine 11 (88 mg, 0.3 solid consisting of a mixture of diastereomers endo I/endo II/exo I/
mmol) with the thioketene acetal 15 (54 mg, 0.5 mmol) gave the exo II in the ratio 8.5:2.3:4.9:1.0. The ratio was determined from
1
cycloadduct 21 (93 mg, 76%) as a white solid consisting of a mix-
the methyl signals in the H-NMR spectrum of the crude product.
ture of the two diastereomers I and II in a ratio of 1.8:1. The ratio
By means of column chromatography, the exo and the endo dia-
was determined from the SCH3 and 2-H signals in the 1H-NMR stereomers could be separated in amounts suitable for recording
˜
˜
spectrum. Ϫ IR (film): ν ϭ 3442 cmϪ1, 2920 (CϪH), 2208 (CN), 1H-NMR spectra. Ϫ IR (film): ν ϭ 3626 cmϪ1, 2978 (CϪH), 2206
1612 (enamine), 1254, 1238, 1102 (SϪO), 702. Ϫ UV (CH3CN): (CN), 1608 (enamine), 1490, 1454, 1286 (aryl ether), 1100, 1072
1
λmax (lg ε) ϭ 258.0 (4.20), 254.4 (4.20), 264.5 (4.18). Ϫ H NMR
(SϪO). Ϫ UV (CH3CN): λmax (lg ε) ϭ 195.0 (4.79), 262.0 (4.26).
Ϫ
(200 MHz, CDCl3): δ ϭ 2.10Ϫ2.30 (m, 1 H, 5-Ha, I and II), 2.25
13C NMR (75 MHz, CDCl3): δ ϭ 21.33 (Tol-CH3, endo I and
(s, 3 H, MeSa, I), 2.28 (s, 3 H, MeSa, II), 2.35 (s, 3 H, MeSb, II), exo I), 21.40 (Tol-CH3, endo II and exo II), 24.72 (4-CH3a, exo I),
2.39 (s, 3 H, MeSb, I), 2.46 (s, 3 H, Tol-CH3, II), 2.49 (s, 3 H, Tol- 24.91 (4-CH3b, exo I and exo II), 25.88 (4-CH3a, endo II), 26.40 (4-
CH3, I), 2.40Ϫ2.50 (m, 1 H, 5-Hb, II), 2.58 (dd, J ϭ 14.0 Hz, 5.6
CH3a, exo II), 26.88 (4-CH3a, endo I), 28.09 (4-CH3b, endo II),
Hz, 5-Hb, I), 3.80Ϫ4.00 (m, 1 H, 4-H, I and II), 6.74 (d, J ϭ 2.2 29.08 (4-CH3b, endo I), 31.63 (C-10b, endo I), 31.69 (C-10b, exo I),
Hz, 1 H, 2-H, II), 6.87 (d, J ϭ 1.8 Hz, 1 H, 2-H), 7.16 (d, J ϭ 8.3 31.75 (C-10b, endo II), 31.86 (C-10b, exo II), 39.30 (C-4a, endo I),
Hz, 2 H, Tol-m-H, I), 7.23 (d, J ϭ 8.3 Hz, 2 H, Tol-m-H, II), 40.80 (C-4a, exo II), 45.89 (C-4a, exo I), 49.36 (C-4a, endo I), 58.27
7.20Ϫ7.48 (m, 5-H, Ph-H, I and II), 7.63 (d, J ϭ 8.3 Hz, 2 H, Tol-
(C-4, endo II), 58.36 (C-4, endo I), 60.43 (C-4, exo I), 62.50 (C-5,
o-H, II), 7.64 (d, J ϭ 8.3 Hz, 2 H, Tol-o-H, I). Ϫ 13C NMR (75 endo I), 62.61 (C-5, endo II), 62.24 (C-5, exo I), 72.69 (C-5, exo II),
MHz, CDCl3): δ ϭ 13.30 (MeSa, II), 13.52 (MeSa, II), 14.8 (MeSb, 89.75 (C-1, exo I), 91.36 (C-1, endo I), 92.66 (C-1, endo II), 116.41
I and II), 21.52 (Tol-CH3, I and II), 38.62 (C-4, II), 39.25 (C-4, I), (C-7, endo II), 116.52 (C-7, endo I), 116.97 (C-7, exo II), 117.10 (C-
40.95 (C-5, II), 43.95 (C-5, I), 77.97 (C-6, I and II), 92.60 (C-3, II),
7, exo I), 118.96, 119.00, 120.48, 120.66 (CN), 120.75, 121.0, 121.09
93.85 (C-3, I), 118.15 (CN, II), 118.19 (CN, I), 125.72, 127.80, (C-9), 125.29, 125.43, 125.79, 127.11, 128.21, 128.41, 129.00,
Eur. J. Org. Chem. 1998, 1629Ϫ1637
1635

L. F. Tietze, A. Schuffenhauer
FULL PAPER
130.40, 130.46, 121.36, 131.43, 138.51, 138.97, 139.40, 141.28, o-C and Ph-p-C), 138.78 (C-2), 141.42 (Ph-ipso-C), 167.40 (Ac-
141.41, 142.88, 142.97, 143.09 (Tol-C and C-10), 153.64 (C-6a, endo
CO). Ϫ MS (70 eV, FD); m/z (%): 298.4 (12) [Mϩ], 242.3 (13) [Mϩ
I and endo II), 154.12 (C-6a, exo I and exo II). Ϫ MS (70 eV, FD); Ϫ C4H8], 224.3 (47) [Mϩ Ϫ C4H8O], 200.3 (100) [Mϩ Ϫ C4H8 Ϫ
m/z (%): 378.1 (13) [Mϩ], 278.0 (37), 240.1 (29) [Mϩ Ϫ TolSO],
139.1 (100) [TolSOϩ], 91.1 (30) [Tolϩ]. Ϫ C22H22N2O2S (378.48):
calcd. C 69.81, H 5.86; found C 69.56, H 6.04.
C2H2O], 182.2 (56), 57.1 (67) [C4H9ϩ], 43.1 [Acϩ]. Ϫ C18H22N2O2
(298.38): calcd. 298.1681; found 298.1681 (MS).
Dihydropyridine 32: Cycloadduct 20 (39 mg, 0.1 mmol) was
endo I and endo II. Ϫ 27a and 27b: 1H NMR (300 MHz, CDCl3):
δ ϭ 1.48 (s, 3 H, 4-CH3a, I), 1.63 (s, 3 H, 4-CH3a, II), 1.82 (s, 3 H,
4-CH3b, II), 1.83 (s, 3 H, 4-CH3b, I), 2.14 (ddd, J ϭ 11.2, 5.5, 3.6
Hz, 1 H, 4a-H, I), 2.18 (ddd, J ϭ 11.2, 4.9, 3.5 Hz, 1 H, 4a-H, II),
2.43 (s, 3 H, Tol-CH3, II), 2.47 (s, 3 H, Tol-CH3, I), 3.54 (dd, J ϭ
11.2, 11.0 Hz, 1 H, 5-Hax, II), 3.60 (d, J ϭ 6.0 Hz, 1 H, 10b-H, I),
3.68 (d, J ϭ 5.3 Hz, 1 H, 10b-H, II), 3.70 (dd, J ϭ 11.2, 11.2 Hz,
1 H, 5-Hax, I), 4.36 (ddd, J ϭ 11.2, 3.7, 1.9 Hz, 1 H, 5-Heq, I), 4.43
(ddd, J ϭ 11.0, 3.1, 1.6 Hz, 5-Heq, II), 6.66 (d, J ϭ 2.0 Hz, 1 H,
2-H, I), 6.68 (d, J ϭ 2.0 Hz, 1 H, 2-H, II), 6.81 (d, J ϭ 8.3 Hz, 1
H, 7-H, II), 6.83 (d, J ϭ 8.3 Hz, 1 H, 7-H, I), 6.94 (dd, J ϭ 7.6,
7.4 Hz, 1 H, 9-H, I), 6.65 (dd, J ϭ 7.6, 7.0 Hz, 1 H, 9-H, II),
7.16Ϫ7.20 (m, 1 H, 8-H, I and II), 7.32 (d, J ϭ 7.6 Hz, 2 H, Tol-
m-H, II), 7.35Ϫ7.40 (m, 1 H, 10-H, I and II), 7.39 (d, J ϭ 8.4 Hz,
2 H, Tol-m-H, I), 7.44 (d, J ϭ 7.6 Hz, 2 H, Tol-o-H, II), 7.49 (d,
J ϭ 8.4 Hz, 2 H, Tol-o-H, I).
1
treated with MeLi and (MeO)2SO4 to give 32 (9 mg, 50%). Ϫ H
NMR (200 MHz, CDCl3): δ ϭ 3.04 (s, 3 H, NMe), 4.32 (d, J ϭ
3.9 Hz, 1 H, 4-H), 4.78 (dd, J ϭ 8.0, 3.9 Hz, 1 H, 5-H), 5.86 (d,
J ϭ 8.0 Hz, 1 H, 6-H), 6.47 (s, 1 H, 2-H), 7.25Ϫ7.40 (m, 5 H, Ph-
H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 39.27 (NϪCH3), 41.01
(C-4), 82.77 (C-3), 105.81 (C-5), 120.99 (CN), 127.15 (C-6), 127.73
(Ph-o-C), 127.93 (Ph-p-C), 128.74 (Ph-m-C), 141.93 (C-2), 145.41
(Ph-ipso-C). Ϫ MS (70 eV, FD); m/z (%): 196.1 (19) [Mϩ], 119.1
(100) [M Ϫ Phϩ]. Ϫ C13H12N2 (196.25).
Tetrahydropyridine 33: Cycloadduct 27 (38 mg, 0.1 mmol) was
treated with MeLi and acetyl chloride to give 33 (28 mg, 98%) as
a mixture of the endo and exo diastereomers in a ratio of 2:1. Ϫ
˜
IR (film): ν ϭ 2934 cmϪ1 (CϪH), 2204 (CN), 1704 (acetyl), 1618
(enamine), 1292 (aryl ether), 760. Ϫ UV (CH3CN): λmax (lg ε) ϭ
194.5 (4.59), 264.0 (4.29). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ
1.42 (s, 3 H, 4-CH3a, exo), 1.48 (s, 3 H, 4-CH3a, endo), 1.79 (s, 3
H, 4-CH3b, endo), 1.81 (s, 3 H, 4-CH3b, exo), 2.00Ϫ2.20 (m, 1 H,
4a-H, endo and exo), 2.27 (s, 3 H, Ac-CH3, endo), 2.32 (s, 3 H, Ac-
CH3, exo), 3.60Ϫ3.75 (m, 1 H, 10b-H, endo and exo), 3.70 (d, J ϭ
11.0, 11.0 Hz, 1 H, 5-Hax endo), 3.81 (dd, J ϭ 10.8, 10.5 Hz, 1 H,
5-Hax, exo), 4.39 (dd, J ϭ 10.8, 3.4 Hz, 1 H, 5-Heq, exo), 4.40 (dd,
J ϭ 11.0, 3.4 Hz, 5-Heq, endo), 6.84 (dd, J ϭ 8.2, 1.2 Hz, 1 H, 7-
H, endo), 6.90 (dd, J ϭ 8.2, 1.3 Hz, 1 H, 7-H, exo), 6.98 (dd, J ϭ
7.5, 7.5 Hz, 1 H, 9-H, endo), 7.03 (dd, J ϭ 7.5, 7.5 Hz, 1 H, 9-H,
exo), 7.05Ϫ7.30 (m, 2 H, 2-H and 8-H, exo and endo), 7.35 (d, J ϭ
7.5 Hz, 1 H, 10-H, endo), 7.79 (d, J ϭ 7.5 Hz, 1 H, 10-H, exo). Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 16.91 (Ac-CH3, exo), 20.98
(Ac-CH3, endo), 21.91 (4-CH3a, exo), 21.98 (4-CH3b, exo), 22.27
(4-CH3a, endo), 23.51 (4-CH3b, endo), 28.28 (C-10b, exo), 28.44 (C-
10b, endo), 39.32 (C-4a, endo), 44.64 (C-4a, exo), 54.07 (C-4, endo),
57.23 (C-4, exo), 59.57 (C-5, endo), 63.02 (C-5, exo), 89.25 (C-1,
endo), 90.29 (C-1, exo), 113.63 (C-7, endo), 114.23 (C-7, exo),
115.74 (CN, exo), 116.10 (CN and C-10a, endo), 116.66 (C-10a
exo), 117.68 (C-9, endo), 118.19 (C-9, exo), 125.59 (C-8, exo),
126.07 (C-10, exo), 126.17 (C-8, endo), 128.27 (C-8, exo), 134.17
(C-2, endo), 139.19 (C-2, exo), 150.72 (C-6a, endo), 151.61 (C-6a,
exo), 166.09 (Ac-CO, endo), 166.67 (Ac-CO, exo). Ϫ MS (70 eV,
FD): m/z (%) ϭ 282.2 (100) [Mϩ], 240.1 (68) [Mϩ Ϫ C2H2O], 225.1
(55), 43.1 (37) [Acϩ]. Ϫ C17H18N2O2 (282.43): calcd. 283.1368;
found 283.1368 (MS).
1
exo I and exo II. Ϫ 27c and 27d: H NMR (300 MHz, CDCl3):
δ ϭ 1.29 (s, 3 H, 4-CH3a, I), 1.41 (s, 3 H, 4-CH3a, II), 1.76 (s, 3 H,
4-CH3b, II), 1.82 (s, 3 H, 4-CH3b, I), 2.12 (ddd, J ϭ 11.3, 11.2, 3.6
Hz, 1 H, 4a-H, II), 2.14 (ddd, J ϭ 11.3, 11.3, 3.4 Hz, 1 H, 4a-H,
I), 2.40 (s, 3 H, Tol-CH3, II and I), 3.48 (dd, J ϭ 11.5, 1.8 Hz, 1
H, 10b-H, II), 3.49 (dd, J ϭ 11.5, 1.8 Hz, 1 H, 10b-H, 1 H, I), 3.69
(dd, J ϭ 11.2, 11.2 Hz, 1 H, 5-Hax, II), 3.81 (dd, J ϭ 10.8, 10.8
Hz, 1 H, 5-Hax, I), 4.29 (dd, J ϭ 11.2, 3.6 Hz, 1 H, 5-Heq, II), 4.31
(ddd, J ϭ 10.8, 3.4 Hz, 5-Heq, I), 6.59 (d, J ϭ 1.8 Hz, 1 H, 2-H,
I), 6.62 (d, J ϭ 1.8 Hz, 1 H, II), 6.76 (d, J ϭ 8.2 Hz, 1 H, 7-H,
II), 6.80 (d, J ϭ 8.3 Hz, 1 H, 7-H, I), 6.82Ϫ6.93 (m, 9-H, I and
II), 7.16Ϫ7.20 (m, 1 H, 8-H, I), 7.12 (dd, J ϭ 7.3, 1.8 Hz, 1 H, 10-
H, I), 7.22Ϫ7.35 (m, 1 H, 8-H, II), 7.25 (dd, J ϭ 7.7, 1.4 Hz, 1 H,
10-H, II), 7.32 (d, J ϭ 8.3 Hz, 1 H, Tol-m-H, II), 7.37 (d, J ϭ 8.3
Hz, 2 H, Tol-m-H, I), 7.41 (d, J ϭ 8.3 Hz, 2 H, Tol-o-H, I), 7.75
(d, J ϭ 8.3 Hz, 2 H, Tol-o-H, II).
Removal of the Sulfinyl Groups in 20 and 27. Ϫ General Pro-
cedure: To a solution of the sulfinyl-substituted cycloadduct 20 or
27 (as a mixture of diastereomers) in THF (5 ml) at Ϫ78°C, 1.5
equiv. of methyllithium (as a 1.6  solution in Et2O) was added,
and the mixture was stirred for 1 h at this temperature. Then, 1.5
equiv. of the electrophile [CH3I or (MeO)2SO2 or AcCl] was added
and stirring was continued for 1 h at Ϫ78°C, and, if the reaction
was incomplete (TLC control), for a further 1 h at room tempera-
ture. The solution was then diluted with brine (2 ml) and extracted
with Et2O (3 ϫ 5 ml). The combined organic phases were dried
(Na2SO4), the solvent was removed in vacuo, and the residue was
purified by column chromatography in order to remove the by-
product methyl tolyl sulfoxide.
Tetrahydropyridine 34: Cycloadduct 27 (19 mg, 0.05 mmol) was
treated with MeLi and methyl iodide to give 34 (8 mg, 60%) as a
mixture of the endo and exo diastereomers in a ratio of 2:1. The by-
product methyl tolyl sulfoxide could not be completely removed in
this case. Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.10 (s, 3 H, 4-CH3
,
a
Tetrahydropyridine 29: Cycloadduct 20 (78 mg, 0.2 mmol) was
exo), 1.20 (s, 3 H, 4-CH3b, exo), 1.28 (s, 3 H, 4-CH3a, endo),
treated with MeLi and acetyl chloride to give 29 (34 mg, 56%) 1.40 (s, 3 H, 4-CH3b, endo), 2.00Ϫ2.20 (m, 1 H, 4a-H, endo and
(endo configuration). Ϫ UV (CH3CN): λmax (lg ε) ϭ 258.0 (3.38). exo), 2.89 (s, 3 H, NϪCH3, endo), 2.95 (s, 3 H, NϪCH3, exo),
˜
Ϫ IR (film): ν ϭ 2976 cmϪ1 (CϪH), 2208 (CN), 1694 (COϪNR2), 3.60Ϫ3.75 (m, 1 H, 10b-H, endo and exo), 3.76 (d, J ϭ 11.3, 11.2
1624 (enamine). Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 0.86 (s, 9 H, Hz, 1 H, 5-Hax, endo), 3.84 (dd, J ϭ 10.6, 10.6 Hz, 1 H, 5-Hax,
tBuO), 2.09 (ddd, J ϭ 14.0, 7.6, 2.4 Hz, 1 H, 5-Hax), 2.30 (s, 1 H,
exo), 4.27 (ddd, J ϭ 10.8, 3.4, 1.9 Hz, 1 H, 5-Heq, endo), 4.37 (dd,
J ϭ 10.2, 3.4 Hz, 5-Heq, exo), 6.57 (s, 1 H, 2-H, endo and exo),
Ac), 2.38 (ddd, J ϭ 14.0, 3.2, 1.2 Hz, 1 H, 5-Heq), 3.75 (dd, J ϭ
7.4, 1.2 Hz, 1 H, 4-H), 6.01 (m, 1 H, 6-H), 7.20Ϫ7.35 (m, 5 H, Ph- 6.81 (dd, J ϭ 8.0, 1.9 Hz, 1 H, 7-H, endo), 6.84 (dd, J ϭ 8.0, 1.9
H), 7.59 (s, 1 H, 2-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 21.81 Hz, 1 H, 7-H, exo), 6.94 (ddd, J ϭ 8.5, 7.1, 1.9 Hz, 1 H, 9-H,
(Ac-CH3), 28.01 (tBu-CH3), 36.07 (C-5), 36.87 (C-4), 74.99 [tBu- endo), 6.98 (ddd, J ϭ 8.5, 7.1, 1.9 Hz, 1 H, 9-H, exo), 7.16 (ddd,
C(CH3)3], 93.37 (C-3), 119.42 (CN), 126.45 (Ph-m-C), 128.05 (Ph- J ϭ 8.0, 7.1, 1.9 Hz, 1 H, 8-H, exo and endo), 7.35 (dd, J ϭ 7.5,
1636
Eur. J. Org. Chem. 1998, 1629Ϫ1637

Hetero Diels-Alder Reactions of Enantiopure α,β-Unsaturated Sulfinimines
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