Stereoselective synthesis of 1,2- and 1,4-dihydropyridines by using cation-π interaction as a conformation-controlling tool

Article abstract of DOI:10.1016/S0040-4039(02)01166-8

Selective shielding of one side of the pyridinium face by way of intramolecular cation-π complex formation enabled nucleophiles to attack the pyridinium ring from the non-shielded side. As a result, 1,2- and 1,4-dihydropyridines were formed in good stereoselectivities. ¹H NMR analysis and ab initio calculations at the RHF/3-21G* level supported the existence of cation-π interaction between the pyridinium and the aromatic ring of the chiral auxiliary.

Full text of DOI:10.1016/S0040-4039(02)01166-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5853–5857
Stereoselective synthesis of 1,2- and 1,4-dihydropyridines by
using cation–p interaction as a conformation-controlling tool
Shinji Yamada,* Momoe Saitoh and Tomoko Misono
Department of Chemistry, Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
Received 1 May 2002; revised 10 June 2002; accepted 14 June 2002
Abstract—Selective shielding of one side of the pyridinium face by way of intramolecular cation–p complex formation enabled
nucleophiles to attack the pyridinium ring from the non-shielded side. As a result, 1,2- and 1,4-dihydropyridines were formed in
1
good stereoselectivities. H NMR analysis and ab initio calculations at the RHF/3-21G* level supported the existence of cation–p
interaction between the pyridinium and the aromatic ring of the chiral auxiliary. © 2002 Elsevier Science Ltd. All rights reserved.
Aromatic interactions have been utilized as a confor-
mation-controlling tool in a variety of regio- and
stereoselective syntheses.1 However, although cation–p
interactions have recently received considerable atten-
tion in various fields of chemistry and biochemistry,2
little has been known about their synthetic applications
except for recent reports of asymmetric acylation of
sec-alcohols,3,4 stereoselective b-galactosylation,5 pho-
tooxidation of alkenes,6 and photoisomerization of
diphenylcyclopropane.7
ketone 4b4 according to reported procedures. Acylation
of 5a–e with nicotinoyl chloride gave the nicotinic
amides 6a–e (Scheme 2). Similarly, the enantiomer of 6e
was prepared from 8 that is a diastereomer of 4b
(Scheme 3). After conversion of these amides into the
corresponding pyridinium salts with methyl chlorofor-
mate in CH2Cl2, addition of a ketene silyl acetal, 1-
methoxy-2-methyl-1-[(trimethylsilyl)oxy]-1-propene, at
0°C gave 1,4-adducts 9 as major products with a small
amount of 1,6-adducts 10.12 The results are summarized
in Table 1. Since most of the reported methods for the
synthesis of chiral 1,4-dihydropyridines13 are conducted
Continuing our research on the synthesis of chiral
1,4-dihydropyridines,8,9 we focused on catalysis 1 for
the asymmetric acylation of racemic sec-alcohols devel-
oped by Kawabata and his colleagues,3,4 where interme-
diary pyridinium salt 2 forms a closed conformation
(Scheme 1). We considered that if pyridinium salt 3
possessing a similar chiral auxiliary has a closed confor-
mation due to cation–p interaction, it can be applicable
to the synthesis of chiral 1,2- and 1,4-dihydropyridines
as shown in Fig. 1. Thus, the selective shielding of one
side of the pyridinium face with the aromatic part
would make nucleophiles possible to attack from the
non-shielded side to give 1,2- or 1,4-dihydropyridines
stereoselectively. We report here a new entry for the
synthesis of chiral 1,2- or 1,4-dihydropyridines using a
cation–p complex10 as a key intermediate.
OH
(i-PrCO)2O
OH
H
H
H
H
O
N
N
N
N
1
2
Scheme 1.
The chiral auxiliaries 5a–e possessing various sub-
stituents were prepared from a ketone 4a3,11 or a chiral
Keywords: pyridinium salts; cation–p interaction; stereocontrol; face-
selective addition; 1,4-dihydropyridines; neighbouring group effects.
* Corresponding author. Tel.: +81-3-5978-5349; fax: +81-3-5978-5715;
e-mail: yamada@cc.ocha.ac.jp
Figure 1. Strategy for the face-selective addition of nucle-
ophiles to a pyridinium salt.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01166-8

5854
S. Yamada et al. / Tetrahedron Letters 43 (2002) 5853–5857
Scheme 2. Reagents and conditions: (i) RLi or RMgX, 73–92% yield; (ii) Pd(OH)2, H2, 82–88% yield; (iii) nicotinoyl chloride,
Et3N, 81–97% yield; (iv) MeI, 65–80% yield.
H
H
H
H
H
i, ii
iii
N
N
OH
OH
N
H H
Ph
O
N
O
8
ent-5e
ent-6e
Scheme 3. Reagents and conditions: (i) BuLi, 2-methylnaphthalene, 52% yield; (ii) Pd(OH)2, H2, 86% yield; (iii) nicotinoyl chloride,
Et3N, 85% yield.
Table 1. Addition of a ketene silyl acetal to the pyridinium salt of 6a
Entry
Substrate
Yield (%)
Ratio (9:10)b
de (%) of 9b
de (%) of 10b
1
2
3
4
5
6a
6b
6c
6d
6e
28
40
63
57
67
71:29
88:12
76:24
95:5
14
56
92
99
85
12
18
8
32
2
84:16
a CH2Cl2 was used as a solvent.
b Determined by 1H NMR spectroscopy.
under coordination- or chelation-controlling condi-
tions, ketene silyl acetals are rarely employed except for
our previously reported method.8a,9 Determination of
32% de despite through 1,7-asymmetric induction pro-
cess (entry 4).
1
the regio- and stereoselectivities was performed by H
When allyltributyltin was used as a nucleophile,14 1,2-
adducts 11 were obtained as major products with 1,6-
adducts 12 as minor products (Table 2). The
stereoselectivity for 11 is also considerably dependent
on the substituent at the chiral auxiliary similar to the
reaction with the ketene silyl acetal as described above;
when compound 6 has an aromatic substituent, higher
selectivity was observed (entries 3, 4 and 6). The fact
that whether the chiral auxiliary has an aromatic sub-
stituent or not is critical for the stereoselectivity
strongly suggests the participation of the aromatic ring
in the transition state of the addition reaction as shown
in Fig. 1. The solvents employed also had a significant
effect on the reaction rate and stereoselectivity; addi-
tion of 10 volume% of toluene to CH2Cl2 drastically
slowed down the reaction rate and led to diminished
NMR analysis based on the chemical shifts and their
integration of the olefinic protons and the methine
proton next to the nitrogen atom at the chiral auxiliary.
The diastereomer ratio of 9 was significantly dependent
on the substituents at the chiral auxiliary. Thus, when
compound 6 possesses an aromatic moiety at the chiral
auxiliary, higher selectivity was observed (entries 3–5).
In particular, 6d having a benzyl group was the most
effective and resulted in excellent selectivity (entry 4).
The substituent seems to affect not only the stereoselec-
tivity but also the regioselectivity; addition to 6d also
gave the highest regioselectivities. Although the
diastereoselectivity for the minor product 10 was much
lower than that of the major adduct 9, it is worthwhile
noting that the stereoselectivity of 1,6-adduct 10d was

S. Yamada et al. / Tetrahedron Letters 43 (2002) 5853–5857
Table 2. Addition of allyltributyltin to the pyridinium salt of 6a
5855
Entry
Substrate
Yield (%)b
Ratio (11:12)c
de (%) of 11c
1
2
3
4
5
6
6a
6b
6c
6d
6dd
6e
65 (33)
71 (40)
84 (46)
88 (56)
79 (24)
79 (61)
82:18
70:30
73:27
75:25
62:38
78:22
14
30
84
86
34
60
a CH2Cl2 was used as a solvent unless otherwise noted.
b Conversion yield. Isolated yield is given in parentheses.
c Determined by 1H NMR spectroscopy.
d A 10:1 mixture of CH2Cl2 and toluene was used as a solvent.
stereoselectivity (entry 5), and no reaction proceeded
when toluene was used as a solvent. This unusual effect
of toluene may be ascribed to the shielding of the
pyridinium ring, which would prevent the nucleophiles
from attacking the pyridinium face.
mediate pyridinium salts. The differential NOE experi-
ments for 6e and 7e led to evidence of their significant
conformational differences. While no NOE was
observed for 6e, 5% NOE between the 5H of the
pyridinium proton and the 1H or 4H of naphthyl group
in 7e was detected, suggesting the preferred conforma-
tion of 7e to be a closed conformation. Table 3 shows
Dl(6e–b) and Dl(7e–b) values at various temperatures.
The very small values of Dl(6e–b) at 293 K imply that
the pyridine and aromatic rings are apart from each
other and there is no intramolecular p–p interaction in
the neutral molecule 6e. On the other hand, the Dl(7e–
b) values were much larger than the Dl(6e–b) values
and received substantial temperature effect; lowering
the temperature decreased the Dl(7e–b) values, indicat-
ing that the pyridinium protons receive a shielding
effect from the aromatic moiety. Since the shifts of the
pyridinium protons to higher magnetic field are
observed in various cation–p or p–p complexes,16 the
preferred conformation for 7e is also suggested to be a
closed conformation as described in Fig. 1.
The absolute configuration of the stereogenic center at
C4 of 9e was determined by comparison with authentic
samples 14 and 15, which were prepared by the acyl
transfer reaction of stereochemically known compound
139 with chiral auxiliaries 5e and ent-5e4 (Scheme 4).
Comparison of their 1H NMR spectra and specific
rotations15 with those of 9e and ent-9e clarified ent-9e
to be identical with 15; therefore, the newly produced
chiral center of ent-9e is R and that of 9e is S. The
absolute configuration of the major product 11 would
perhaps be R in analogy with the case of 9e.
To elucidate the geometrical differences between the
nicotinic amide 6 and the corresponding pyridinium
1
salts, H NMR analyses were carried out for 6b and 6e,
and their N-methyl salts 7b and 7e as models of inter-
H
MeO2C
N
OH
H
5e
O
CH3CN / reflux
3days 34%
MeO2C
N
S
O
CO2Me
14
N
S
H
H
N
Bn
MeO2C
CO2Me
N
ent-5e
OH
13
O
CH3CN / reflux
3days 55%
N
CO2Me
15
Scheme 4.

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S. Yamada et al. / Tetrahedron Letters 43 (2002) 5853–5857
Table 3. Dl(6e–b) and Dl(7e–b) values (ppm) for pyridine or pyridinium protons at various temperaturesa
Temp (K)
Dl
H2
H4
H5
0.00
−0.15
−0.28
H6
0.00
−0.06
−0.22
293
293
223
Dl(6e–b)
Dl(7e–b)
Dl(7e–b)
+0.01
+0.01
−0.05
+0.01
−0.06
−0.15
a 270 MHz in CDCl3.
Figure 2. Conformers A and B obtained by ab initio calculations at the RHF/3-21G* level.
Figure 3. Working model for the nucleophilic addition.
Since all the pyridinium salts synthesized are unfortu-
nately oily compounds, X-ray analysis could not be
carried out to confirm their geometry. However, geomet-
rical optimization for 3 by ab initio calculations at the
RHF/3-21G* level provided supporting data for the
predicted conformation in Fig. 1.17 Thus, comparison of
the energies between two stable closed conformers 3A and
3B suggests that 3B is more stable than 3A by 3.20
kcal/mol, which would be sufficient energy to give high
face-selectivity in the addition reactions (Fig. 2).
Acknowledgements
We wish to express our gratitude to Professor T. Kawa-
bata in Kyoto University for his helpful instruction and
suggestions on the synthesis of the chiral auxiliaries. This
work was financially supported by Japan Society for the
Promotion of Science (13650901).
All of the foregoing data provide the following working
model for the face-selective addition to the pyridinium
as shown in Fig. 3: (a) conversion of a pyridine moiety
into a pyridinium salt forms a cation–p complex, where
the one side of the pyridinium face is selectively shielded;
(b) a nucleophile attacks this complex from the non-
shielded side to give a dihydropyridine stereoselectively.
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