Regio- and stereoselective synthesis of 1,4-dihydropyridines by way of an intramolecular interaction of a thiocarbonyl or carbonyl with a pyridinium nucleus

Article abstract of DOI:10.1016/S0040-4020(01)00892-4

Chiral 1,4-dihydropyridines were prepared by the regio- and stereoselective addition of ketene silyl acetals and organometallic reagents to pyridinium salts. In the addition reaction, an intramolecular interaction between the thiocarbonyl or carbonyl with

Full text of DOI:10.1016/S0040-4020(01)00892-4

TETRAHEDRON
Pergamon
Tetrahedron 57 >2001) 8939±8949
Regio- and stereoselective synthesis of 1,4-dihydropyridines by
way of an intramolecular interaction of a thiocarbonyl or carbonyl
with a pyridinium nucleus
Shinji Yamada,p Tomoko Misono, Mayumi Ichikawa and Chisako Morita
Department of Chemistry, Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
Received 9 August 2001; accepted 4 September 2001
AbstractÐChiral 1,4-dihydropyridines were prepared by the regio- and stereoselective addition of ketene silyl acetals and organometallic
reagents to pyridinium salts. In the addition reaction, an intramolecular interaction between the thiocarbonyl or carbonyl with the pyridinium
nucleus plays an important role in bringing about the selectivities. The absolute con®guration of the newly produced stereogenic center of the
1,4-dihydropyridines was determined by X-ray analysis and CD Cotton effects after conversion into the appropriate derivatives. The working
model for the stereoselectivity was proposed based on the ab initio calculations at the RHF/3-21Gp level. q 2001Elsevier Science Ltd. All
rights reserved.
1. Introduction
chiral auxiliary with the pyridinium nucleus15 plays a
critical role in the regio- and stereoselectivities.
Chiral 1,4-dihydropyridines1 have been employed as the
synthetic intermediates for a wide variety of compounds
such as natural products,2,3 calcium channel blockers,4 and
NADH models.5 Moreover, they have potential utility for
obtaining various nitrogen containing chiral 6-membered
heterocycles.6,7 Among various methods for the preparation
of chiral 1,4-dihydropyridines, faceselective nucleophilic
addition to the pyridinium nucleus is an attractive method
because of its synthetic convenience. Several types of
pyridinium salts having a chiral oxazoline,8 an aminal,9 or
an iron acyl10 moiety at the 3-position have been utilized
for the synthesis of them. In addition, 2,3-fused bicyclic
pyridinium salts possessing a carbonyl group in the ring11
and a bridged pyridinium12 are also proved to be good
precursors for chiral 1,4-dihydropyridines.
Recently, Comins and his coworkers have attained face-
selective 1,2-addition by way of an intramolecular inter-
action between a pyridinium and a phenyl group to hinder
one of the pyridinium faces.13 We report here a new entry
for the stereoselective synthesis of 1,4-dihydropyridines by
regio- and stereoselective nucleophilic addition to the
pyridinium salts having a 1,3-thiazolidine-2-thione14 or a
1,3-oxazolidine-2-one moiety, where an intramolecular
interaction of the thiocarbonyl or carbonyl group of the
2. Results and discussion
As substrates we employed N-benzylnicotinium salts 1a±
1c, and nicotinic amides 2a±2d and 3a±3c. First, we studied
the regioselectivity in the addition of ketene silyl acetal 4a
to N-benzylnicotinic amides 1a±1c because an intra-
molecular interaction between the thiocarbonyl and the
Keywords: pyridinium salts; stereoselection; addition reaction; thiocarbo-
nyl compounds; oxazolidinones; neighbouring group effects.
1
pyridinium ring in 1a was predicted by H NMR studies
and X-ray analysis.15 The reaction of the pyridinium salts
1a and 1b with 1.5 equiv. of ketene silyl acetal 4a was
p
Corresponding author. Tel.: 181-3-5978-5349; fax: 181-3-5978-5715;
e-mail: yamada@cc.ocha.ac.jp
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020>01)00892-4

8940
S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
Table 1. Reaction of pyridinium salts 1a±1c with a ketene silyl acetal
Salts
Solvents
Time >h)
Yield >%)
Ratio >5:6:7)
1a
1b
1c
1a
1b
1c
CD3CN
CD3CN
CD3CN
DMSO-d6
DMSO-d6
DMSO-d6
4
3
4
2
2.5
2.5
77
93
73
79
97
83
96:4:0
94:6:0
35:56:9
51:49:0
57:43:0
38:54:8
conducted at 08C for 2±4 h in CD3CN or DMSO-d6. The
results are summarized in Table 1. In CD3CN, the addition
to 1a and 1b gave 1,4-adducts 5 as a major product with a
small amount of 1,6-adduct 6. The regioselectivity is much
higher than that reported for similar reactions with ketene
silyl acetals.16 In contrast, the addition to standard 1c
provided 1,6-adduct 6 as a major product accompanied
with 1,4-adduct 5 and a small amount of 1,2-adduct 7.
The isomer ratio was readily determined by 1H NMR
analysis based on the chemical shifts of the dihydropyridine
moiety; 4H, 5H and 6H of 5b in CD3CN appeared at d 4.01
>d, Jˆ5.5 Hz), 4.77 >dd, Jˆ5.5, 7.6 Hz), and 6.03 >dd,
Jˆ1.2, 7.6 Hz), respectively, whereas those of 6b appeared
at d 6.63 >d, Jˆ9.6 Hz), 4.96 >dd, Jˆ5.6, 9.6 Hz) and 4.59
>d, Jˆ5.6 Hz), respectively. It is remarkable that the
selectivity was signi®cantly dependent on the solvent
employed; when the reaction was conducted in DMSO-d6,
the selectivities for 1a and 1b signi®cantly decreased,
whereas that for 1c scarcely changed. Since the existence
of an intramolecular interaction between the thiocarbonyl
and the pyridinium ring of 1a has been clari®ed by 1H NMR
studies and X-ray analyses,15 this signi®cant substituent
dependence in the amido moiety on the regioselectivity
would be attributable to the intramolecular CvS´´´Py1
interaction. The remarkable solvent effect can be explained
by the difference in the coordinating property of the solvents
employed; since DMSO has a stronger coordinating prop-
erty than CD3CN, it may effectively disturb the intramole-
cular interactions by solvation of the pyridinium ring.
Next, we investigated the stereoselectivity in the addition of
various ketene silyl acetals to the pyridinium salts posses-
sing chiral thiazolidine-2-thiones or oxazolidine-2-ones.
Chiral nicotinic amides 2b±2d were readily prepared from
>S)-4-phenyl-, >S)-4-benzyl17-, and >S)-4-tert-butyl18-1,3-
thiazolidine-2-thiones with nicotinoyl chloride in the
presence of Et3N. On the other hand, 3b and 3c were
successfully prepared by the reaction of >S)-4-phenyl- and
>S)-4-benzyl-1,3-oxazolidine-2-ones with nicotinic pivalic
anhydride, respectively. Since most faceselective nucleo-
philic 1,4-additions to pyridinium salts have been performed
under chelation controlled conditions,8±11 ketene silyl
acetals have scarcely been employed for such reactions.
The addition of ketene silyl acetal 4a to the intermediary
pyridinium salts formed by the reaction of 2b±2d with
methyl chloroformate gave 1,4-adduct 8a±8c as major
Table 2. Reaction of pyridinium salts of 2 and 3 with ketene silyl acetals 4a±4c
Entry
Amide
Nucleophile
Solvents
Time >h)
Products
Yield >%)a
>8:9) or >10:11)
dr of 8 or 10
1
2
3
4
5
6
7
8
2b
2b
2c
2d
3b
3c
2c
2c
4a
4a
4a
4a
4a
4a
4b
4c
CH3CN
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3Cl2
CH3CN
1.5
46
8a, 9a
8a, 9a
8b, 9b
8c, 9c
10a, 11a
10b, 11b
8d, 9d
8e, 9e
89
44
9178:22
9157:43
91
67:33
47:53
92:8
56:44
86:14
73:27
47:53
96:4
86:14
45:55
1.0
1.0
2.0
1.5
2.5
3.5
87:13
6
9184:1
99
84:16
97:3c
67>98)b
a
Isolated yield.
Conversion yield.
No syn±anti isomers was observed.
b
c

S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
8941
Scheme 1.
products and minor 1,6-adducts 9a±9c >Table 2, entries 1±
4). The relatively lower regioselectivity compared to the
case of the N-benzylpyridinium salts described above is
unclear, but the difference in the steric and electronic effects
of the N-substituents may affect the regioselectivity. The
diastereomer ratios for the major products were determined
can be attributable to intramolecular CvS´´´Py1 or
CvO´´´Py1 interaction. If the interaction occurs face-
selectively, the nucleophile will attack the complex from
the opposite side of the thiocarbonyl or carbonyl group,
which would result in good stereoselectivity >Scheme 1).
The faceselective complexation is indeed predicted by ab
initio calculations as described later. The importance of the
neighboring thiocarbonyl group in the stereoselectivity in
various reactions containing carbocation intermediates
is known.20±22 However, since in the present system, no
bonding between the sulfur atom of the thiocarbonyl and
1
based on H NMR chemical shifts of 2H, 5H and 6H of
dihydropyridine moiety. The absolute con®guration at C4
was determined to be R based on CD Cotton effects as
described later. The stereoselectivity was dependent on
the chiral auxiliary; among 2b±2d, amide 2c was the most
effective >entry 3), whereas amide 2d having the bulkiest
substituent was the least effective >entry 4). The reactions
with amides 3b and 3c also gave similar results to the case
of amide 2 >entries 5 and 6). The other ketene silyl acetals
4b and 4c also acted as faceselective nucleophiles >entries 7
and 8). The addition of 4b also proceeded in good stereo-
selectivity albeit with insuf®cient regioselectivity. Excellent
regio- and stereoselectivities were obtained when using 4c
as a nucleophile. The diastereomer ratio with respect to the
C4 of 1,4-adducts 8e is 97:3 and no syn±anti isomers based
on the another chiral center next to C4 was observed. Inter-
estingly, use of toluene as a solvent resulted in signi®cant
slower reaction rate, and both the regio- and stereo-
selectivities were reversed >entry 2). This may be due to
intermolecular cation±p interaction;19 toluene would face
the pyridinium plane and disturb the attack of a nucleophile.
1
the pyridinium carbon was detected by H and 13C NMR
spectroscopies, the interaction between the thiocarbonyl and
the pyridinium may be a through-space electrostatic inter-
action such as a cation±p interaction.19
Organometallic reagents also worked as stereoselective
nucleophiles. After the amides 2 and 3 were converted in
situ into the corresponding pyridinium salts with acid
chlorides or chloroformates, the addition of nucleophiles
to the pyridinium salts was carried out. The results are
shown in Table 3. The reaction of the pyridinium salts of
2b with MeCu23 gave a 93:7 mixture of 12a and 13a. The
diastereomer ratio of 12a was 67:33 >entry 1). This
preference in the 1,4-addition of organocopper reagents is
in agreement with reported observations.24 Addition of
PhCu to the pyridinium salts proceeded with higher
stereoselectivity than that of MeCu >entry 2). Use of benzoyl
chloride instead of methyl chloroformate to make an inter-
mediary pyridinium salt improved both regio- and stereo-
selectivities in the addition reaction >entries 3±5), indicating
The fact that the reaction with ketene silyl acetals yielded
high stereoselectivity indicates that the reaction proceeded
under non-chelation control. Thus, these stereoselectivities
Table 3. Reaction of the pyridinium salts of 2 and 3 with organometallic reagents
Entry
Amide
R2
Nucleophilea
Yield >%)b
Products
>12:13)c or >14:15)
drc of 12 or 14
1
2
3
4
5
6
7
8
2b
2b
2b
2c
2d
2b
3b
3b
OMe
OMe
Ph
Ph
Ph
OMe
OMe
OMe
MeCu
PhCu
PhCu
PhCu
PhCu
BnSnMe3
PhCu
BnSnMe3
68>61)
70>46)
76>59)
59>48)
85>68)
72
12a, 13a
12b, 13b
12c, 13c
12d, 13d
12e, 13e
12f, 13f
14a, 15a
14b, 15b
93:7
95:5
67:33
84:16
88:12
88:12
91:9
80:20
60:40
64:36
100:0
100:0
100:0
100:0
72:28
100:0
70>47)
51
a
1.1 equiv. of reagent was used.
Conversion yield. Isolated yield is shown in parentheses.
Determined by 1H NMR spectroscopy.
b
c

8942
S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
that the bulky substituent around the N-atom enhances
the 1,4-selectivity by hindering the addition to C6. The
difference in the substituents at the chiral center of the
thiazolidine-2-thione moiety did not have a signi®cant effect
on the stereoselectivity >entries 3±5). This is in contrast to
the addition of ketene silyl acetals as described above,
where the substituents of the chiral auxiliary affect the
stereoselectivity. This nucleophile-dependent stereo-
selectivity is unclear, but the difference in the coordination
effect to substrates between ketene silyl acetals and organo-
copper reagents may be one reason. Trimethylbenzyltin
also worked as a 1,4-selective nucleophile similar to the
literature25 to give 12f in good regio- and stereoselectivities
>entry 6). Amide 3b having an oxazolidinone moiety as a
chiral auxiliary also reacts with organocopper and organotin
reagents to give the corresponding 14a and 14b similar to
the reaction of amide 2b >entries 7 and 8). However, the
stereoselectivities are much lower than those obtained in the
corresponding reactions of 2b >entry 2 vs 7 and entry 6 vs 8).
This would be ascribed to the difference in the coordinating
ability of the carbonyl of 3b and the thiocarbonyl of 2b to
organometallic reagents; the coordination will disturb the
intramolecular CvO´´´Py1 interaction.
The absolute con®guration of the newly-produced stereo-
genic center for the major product of 12c was determined
by X-ray analysis after conversion of 12c >R1ˆPh, R2ˆPh)
into 19 >Scheme 2). The chiral auxiliary of 12c >an 88:12
diastereomeric mixture) was removed by treatment with
NaOMe to produce a methyl ester 16. Catalytic hydrogena-
tion of 16 with PtO2 in EtOH resulted in partially reduced
tetrahydropiperidine 17. Further reduction was carried out
in the presence of acetic acid to give a 9:1 cis and trans
Scheme 2.
To gain insight into the working model for the stereo-
selectivity, geometrical optimization of the intermediary
pyridinium salt generated from 2b with methyl chloro-
formate was carried out by semiempirical AM1methods
for each structure obtained from MMFF calculations in
conjunction with Monte Carlo searching. Four typical
conformers A±D obtained were further optimized by ab
initio calculations at RHF/3-21Gp level. Their structures
and the relative energies based on the most stable conformer
A are shown in Fig. 3. Each conformer has a helical
structure about the C4±C3±CO±N±CvS moiety. The
thiocarbonyl groups of A and B are close to C2 of the
pyridinium nucleus, whereas those of C and D are close to
the corresponding C4. The geometries of C and D are very
similar to the X-ray structure of 1a.15 Both interatomic
distances between the S atom of the thiocarbonyl and C4
1
mixture of 18, the ratio of which was determined by H
NMR spectroscopy based on the methyl protons. After
conversion of 18 into crystalline menthyloxycarbamates
19, several recrystallizations provided a single crystal for
X-ray analysis.26 The X-ray structure of 19 was given in
Fig. 1, which unequivocally showed that the 4-position
possesses R con®guration, and the phenyl and the methoxy-
carbonyl groups have cis orientation; therefore, the absolute
con®guration at the 4-position of dihydropyridine 12c
was determined to be S. Comparison of the signs of
speci®c rotation of 16 derived from 12d, 12e and 14a with
that of 16 obtained from 12c described above clearly
showed that 12d, 12e and 14a possess the same con®gu-
ration with 12c.
Determination of the absolute con®guration at C4 of 8b and
12f, which are the adducts of a ketene silyl acetal and
trimethylbenzyltin, respectively, was performed based on
their CD Cotton effects. The chiral center at C4 will govern
the directionality of the rotation about the C3±C>O) bond,
which is important in the sign of the CD Cotton effect.
The chiral auxiliaries of 8b, 12c, and 12f were readily
removed by the reaction with dimethylamine27 to afford
the corresponding dimethylamides 20a±20c in good yields
>Scheme 3). The CD spectrum of 20b derived from 12c
having S con®guration showed a negative Cotton effect
based on p±pp absorption at 244 nm as shown in Fig. 2.
A similar negative Cotton effect was observed for 20a and
20c at 245 and 242 nm, suggesting that their absolute
con®guration is R.28
Figure 1. X-Ray structure of 19.

S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
8943
faces around C4 are blocked by a carbonyl or a thiocarbonyl
group. Similarly, the carbonyl, thiocarbonyl and phenyl
groups of conformer D also hinder both faces of the
pyridinium ring. As a result, conformer C, one of the
pyridinium faces of which is not hindered, would be a key
intermediate for the addition reaction. Therefore, the
following working model for the stereoselectivity can be
proposed; the intramolecular CvS´´´Py1 or CvO´´´Py1
interaction restricts the conformation of the intermediary
quarternary pyridinium salts, which enables nucleophiles
to attack conformer C having the most unhindered
pyridinium face from the opposite side of the thiocarbonyl
group as shown in Scheme 1. The con®guration predicted by
this working model is consistent with those determined by
X-ray analysis and CD spectra.
Scheme 3.
3. Conclusion
Addition of ketene silyl acetals and organocopper and
organotin reagents to quarternary pyridinium salts
possessing 1,3-thiazolidine-2-thione or 1,3-oxazolidine-2-
one proceeded regio- and stereoselectively to give chiral
1,4-dihydropyridines. In the nucleophilic addition reactions,
the intramolecular CvS´´´Py1 or CvO´´´Py1 interaction
plays key roles to bring about the regio- and stereo-
selectivities. Thus, the intramolecular interaction restricts
the molecular motion and hinders one of the pyridinium
faces, in addition, the interaction would change the
electronic properties of the pyridinium nucleus, which
will enable nucleophiles to attack at C4 faceselectively.
Since the reaction proceeds under non-chelation con-
trolling conditions, the present method is complimentary
to the published ones for the synthesis of chiral 1,4-dihydro-
pyridines.
Figure 2. The CD spectra of dihydropyridines 20a >Ð), 20b>- - -), and 20c
>-´-´-) in EtOH.
Ê
>3.153 and 3.195 A, respectively), are signi®cantly shorter
than the sum of van der Waals radii of the carbon and sulfur
atoms,29 suggesting the intramolecular interaction between
the thiocarbonyl and the pyridinium nucleus.
4. Experimental
4.1. General
Conformers A and B have less preferable geometries for
nucleophilic attack to C4 because both the pyridinium
Melting points are uncollected. Column chromatography
Figure 3. RHF/3-21Gp optimized geometries for the pyridinium salt generated from 2b with methyl chloroformate.

8944
S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
was carried out using a Merck Silica gel 60. TLC was
carried out on a Merck Silica gel 60 PF254. IR spectra
were obtained as KBr pellets. 1H NMR spectra were
recorded at 270 or 400 MHz as dilute solutions in CDCl3,
CD3CN or DMSO-d6 and the chemical shifts were reported
relative to internal TMS. 13C NMR spectra were recorded at
67.8 or 100.4 MHz as dilute solutions in CDCl3 and the
chemical shifts were reported relative to internal TMS.
High and low-resolution mass spectra were recorded at an
ionizing voltage of 70 eV by electron impact. CD spectra
were recorded as dilute solution in EtOH.
>100), 78 >70); HRMS calcd for C9H8ON2S2 224.0078,
found 224.0084.
4.2.2. 04S)-04-Phenyl-2-thioxo-1,3-thiazolidin-3-yl)-pyri-
din-3-yl-methanone 02b). 85% yield; mp 133.5±134.58C;
22
[a]D ˆ12068 >c 1.1, CHCl3); IR >KBr) 3034, 1666, 1586,
1
1309 cm21; H NMR >270 MHz, CDCl3) d 3.54 >1H, dd,
Jˆ11.4, 7.3 Hz), 3.89 >1H, dd, Jˆ11.4, 7.6 Hz), 5.98 >1H,
dd, Jˆ7.6, 7.3 Hz), 7.32±7.48 >6H, m), 7.97 >1H, ddd,
Jˆ8.1, 2.2, 1.6 Hz), 8.71 >1H, dd, Jˆ4.9, 1.6 Hz), 8.94
>1H, dd, Jˆ2.2, 0.7 Hz); 13C NMR >100 MHz) d 38.2,
71.4, 123.4, 126.2, 129.1, 129.3, 130.2, 136.8, 137.8,
150.3, 152.9, 169.6, 202.5; MS m/z 300 >M1, 66%), 106
>100), 78 >60); HRMS found 300.0409, calcd for
C15H12N2OS2 300.0391.
4.1.1. Preparation of 0S)-4-phenyl-1,3-thiazolidine-2-
thione. Concentrated sulfuric acid >3.0 ml, 54 mmol) was
added dropwise to a round bottom ¯ask containing >S)-2-
phenylglicinol >2.1g, 15.3 mmol) at 0 8C, and the mixture
was vigorously stirred for 2 h. After potassium O-ethyl
dithiocarbonate >4.2 g, 26 mmol) was added, the solution
was adjusted to pH 9 with 2N NaOH, and the solution
was heated at 508C for 3 h. Then, potassium O-ethyl dithio-
carbonate >2.1g, 13 mmol) was again added and the reac-
tion mixture was stirred for further 6 h. After cooling to
room temperature, the solution was acidi®ed with 2N HCl
and extracted with three 50 ml portions of CHCl3. The
combined extracts were washed with water and dried over
anhydrous MgSO4. Evaporation of the solvent gave a crude
compound, which was subjected to column chromatography
on silica gel to give two crystalline compounds. The less
polar fraction was >S)-4-phenyl-1,3-thiazolidine-2-thione
4.2.3. 04S)-04-Benzyl-2-thioxo-1,3-thiazolidin-3-yl)-pyri-
din-3-yl-methanone 02c). 92% yield; mp 94.0±95.08C;
22
[a]D ˆ21558 >c 1.1, CHCl3); IR >KBr) 3026, 1666,
1
1587, 1322 cm21; H NMR >270 MHz, CDCl3) d 3.13±
3.19 >2H, m), 3.53±3.60 >2H, m), 5.18±5.22 >1H, m),
7.28±7.41>6H, m), 7.92 >1H, ddd, Jˆ7.8, 2.2, 1.7 Hz),
8.72 >1H, dd, Jˆ4.9, 1.7 Hz), 8.83 >1H, dd, Jˆ2.2,
0.7 Hz); 13C NMR >67.8 MHz, CDCl3) d 33.9, 36.9, 69.2,
123.0, 127.3, 129.0, 129.4, 130.2, 136.0, 136.3, 149.6,
152.3, 168.8, 201.4; MS m/z 314 >M1, 74%), 106 >100),
78 >65); HRMS calcd for C16H14N2OS2 314.0547, found
314.0527.
22
4.2.4. 04S)-04-tert-Butyl-2-thioxo-1,3-thiazolidin-3-yl)-
pyridin-3-yl-methanone 02d). 94% yield; mp 141.5±
>1.27 g, 50%): [a]D ˆ11828 >c 1.0, CHCl3); mp 194.5±
195.08C; IR >KBr) 3121, 1493, 1259, 1050 cm21 1H
;
22
142.58C; [a]D ˆ14978 >c 1.0, CHCl3); IR >KBr) 2971,
NMR >270 MHz, CDCl3) d 3.52 >dd, Jˆ11.2, 8.3 Hz,
1H), 3.86 >dd, Jˆ11.2, 8.1 Hz, 1H), 5.31 >dd, Jˆ8.3,
8.1Hz, 1H), 7.26±7.45 >5H, m); 13C NMR >67.8 MHz,
CDCl3) d 41.6, 67.4, 126.2, 129.1, 129.2, 137.9, 201.4;
MS m/z 195 >M1, 100%); HRMS calcd for C9H9NS2
195.0177, found 195.0182. The polar fraction was >S)-4-
phenyl-1,3-oxazolidine-2-thione >0.4 g, 17%): 1H NMR
>270 MHz) d 4.50 >dd, Jˆ8.6, 6.3 Hz, 1H), 5.01 >dd,
Jˆ9.0, 8.6 Hz, 1H), 5.31 >dd, Jˆ9.0, 6.3 Hz, 1H), 7.31±
7.45 >m, 5H).
1703, 1585 cm21 1H NMR >270 MHz, CDCl3) d 1.12
;
>9H, s), 3.31>H1, dd,
Jˆ11.7, 2.1 Hz), 3.77 >1H, dd,
Jˆ11.7, 9.3 Hz), 5.26 >1H, dd, Jˆ9.3, 2.1Hz), 7.36
>1H, dd, Jˆ7.9, 4.9 Hz), 7.98 >1H, dd, Jˆ7.9, 2.2,
1.6 Hz), 8.71 >1H, dd, Jˆ4.9, 1.6 Hz), 8.93 >1H, dd,
Jˆ2.2, 0.7 Hz); 13C NMR >67.8 MHz, CDCl3) d 26.9,
31.4, 38.2, 74.2, 122.9, 130.2, 136.8, 150.3, 152.4,
169.4, 203.4; MS m/z 280 >M1, 66%), 106 >100), 78
>71); HRMS calcd for C13H16N2OS2 280.0704, found
280.0703.
4.2. General procedure for the synthesis of nicotinic
amides from 1,3-thiazolidine-2-thiones with nicotinoyl
chloride
4.3. General procedure for the synthesis of nicotinic
amides from 1,3-oxazolidine-2-ones with nicotinic acid
To a solution of nicotinoyl chloride hydrochloride >3 equiv.)
in dry CH2Cl2 >4 ml for 1mmol) was added Et 3N >9 equiv.)
under nitrogen atmosphere. Then, 1,3-thiazolidine-2-thione
>1equiv.) in CH 2Cl2 >4 ml for 1mmol) was added dropwise
at 08C, and the reaction mixture was stirred for 4.5 h at room
temperature. Usual work up gave a crude amide, which was
chromatographed on silica gel >AcOEt/CHCl3ˆ1:1±2:1) to
afford a pure nicotinic amide.
To a solution of nicotinic acid >1.0 g, 8.1 mmol) in dry THF
>20 ml) and triethylamine >1.7 ml) added pivaloyl chloride
>1.0 ml, 8.1 mmol) at 08C. After the suspension was stirred
for 1 h, a mixture of 1,3-oxazolidine-2-one >1.2 mmol), and
DMAP >0.5 mmol) in dry THF >12 ml) was added to the
suspension. Then, the mixture was stirred for 21h. Succes-
sive operations of evaporation of the solvent, neutralization
with NH4Cl, and extraction with CHCl3 gave a crude
product, which was puri®ed by column chromatography to
give a pure amide.
4.2.1. 02-Thioxo-1,3-thiazolidin-3-yl)-pyridin-3-yl-metha-
none 02a). 96% yield; mp 103.0±104.08C; IR >KBr) 2362,
1677, 1588 cm21; 1H NMR >400 MHz, CDCl3) d 8.87 >dd,
Jˆ2.2, 0.8 Hz, 1H), 8.71 >ddd, Jˆ5.8, 4.9, 1.6 Hz, 1H), 7.95
>ddd, Jˆ8.0, 2.2, 1.6 Hz, 1H), 7.35 >ddd, Jˆ8.0, 4.9, 0.8 Hz,
1H), 4.58 >t, Jˆ7.3 Hz, 2H), 3.50 >t, Jˆ7.3 Hz, 2H); 13C
NMR >100 MHz, CDCl3) d 29.7, 56.2, 130.0, 136.6,
149.9, 152.6, 169.4, 202.3; MS m/z 224 >M1, 93), 106
4.3.1. 3-0Pyridine-3-carbonyl)-1,3-oxazolidin-2-one 03a).
45% yield; mp 122.5±123.28C; IR >KBr) 1772, 1682, 1586,
1483, 1380, 1333, 1213 cm21; 1H NMR >400 MHz, CDCl3)
d 8.87 >s, 1H), 8.75 >dd, Jˆ5.0, 1.5 Hz, 1H), 7.95 >dt, Jˆ7.9,
1.8 Hz, 1H), 7.38 >ddd, Jˆ7.9, 5.0, 0.8 Hz, 1H), 4.52 >t,
Jˆ7.9 Hz, 2H), 4.21>t,
Jˆ7.6 Hz, 2H); 13C NMR

S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
8945
>100 MHz, CDCl3) d 167.70, 153.15, 152.68, 149.75,
136.51, 128.82, 122.67, 62.43, 43.44; MS m/z 192 >M1,
12), 148 >100), 78 >89); HRMS calcd for C9H8O3N2
192.0535, found 192.0539.
78 >24); HRMS calcd for C9H8O3N2 >[M2Br±Bn]1)
192.0534, found 192.0539.
4.4.3. 1-Benzyl-3-dimethylcarbamoylpyridinium bromide
01c). 92% yield; mp 158.0±159.08C; IR >KBr) 2911, 1645,
1495, 1455, 1401 cm21; 1H NMR >400 MHz, CDCl3) d 3.03
>s, 3H), 3.09 >s, 3H), 6.42 >s, 2H), 7.38±7.26 >m, 3H), 7.79
>d, Jˆ4.9 Hz, 2H), 8.19 >dd, Jˆ7.9, 6.1Hz, 1H), 8.57 >d,
Jˆ7.9 Hz, 1H), 9.75 >d, Jˆ6.1 Hz, 1H), 9.79 >s, 1H); 13C
NMR >100 MHz, CDCl3) d 35.8, 40.1, 63.9, 128.7, 129.5
129.7, 129.9, 133.0, 136.4, 143.2, 144.1, 145.7, 163.8; MS
m/z 150 >[M2Br±Bn]1, 15), 106 >29), 91 >100), 78 >18);
HRMS calcd for C8H10N2O >[M2Br±Bn]1) 150.0793,
found 150.0754.
4.3.2. 04S)-4-Phenyl-3-0pyridine-3-carbonyl)-1,3-oxazoli-
22
din-2-one 03b). 79% yield; [a]D ˆ11308 >c 0.35, CHCl3);
1
mp 184.0±184.58C; IR >KBr) 2970, 1799, 1685 cm21; H
NMR >270 MHz, CDCl3) d 4.37 >dd, Jˆ9.0, 6.8 Hz, 1H),
4.81>dd, Jˆ9.0, 8.8 Hz, 1H), 5.64 >dd, Jˆ8.8, 6.8 Hz, 1H),
7.34±7.44 >m, 6H), 7.96 >ddd, Jˆ7.8, 1.8, 1.7 Hz, 1H), 8.74
>dd, Jˆ4.9, 1.7 Hz, 1H), 8.89 >d, Jˆ1.8 Hz, 1H); 13C NMR
>100 MHz, CDCl3) d 58.6, 70.1, 122.8, 126.4, 128.9, 129.2,
129.4, 136.7, 137.5, 150.0, 153.0, 153.5, 167.3; MS m/z 268
>M1, 6%), 106 >100), 78 >94); HRMS calcd for C15H12N2O3
268.0848, found 268.0842.
4.5. General procedure for the addition of ketene silyl
acetals to the pyridinium salts
4.3.3. 04S)-4-Benzyl-3-0pyridine-3-carbonyl)-1,3-oxazoli-
din-2-one 03c). 64% yield; mp 122.0±122.58C;
To a solution of the pyridinium salt 1 >1equiv.) and Et 3N
>2 equiv.) in the appropriate solvent was added 1-methoxy-
2-methyl-1-[>trimethylsilyl)oxy]-1-propene >2 equiv.). After
being stirred for 3 h, the reaction mixture was concentrated
to afford an oil, which was puri®ed by silica gel column
chromatography.
28
[a]D ˆ11448 >c 0.49, CHCl3); IR >KBr) 2914, 1781,
1684 cm21 1H NMR >270 MHz, CDCl3) d 2.99 >dd,
;
Jˆ13.5, 9.0 Hz, 1H), 3.44 >dd, Jˆ13.5, 3.4 Hz, 1H), 4.28
>dd, Jˆ9.0, 5.3 Hz, 1H), 4.38>1H, dd, Jˆ9.0, 8.3 Hz, 1H),
4.88±4.93>m, 1H), 7.23±7.41 >m, 6H), 7.92 >ddd, Jˆ8.1,
1.8, 1.7 Hz, 1H), 8.76 >dd, Jˆ4.9, 1.7 Hz, 1H), 8.85 >d,
Jˆ1.8 Hz, 1H); 13C NMR >67.8 MHz, CDCl3) d 37.6,
55.7, 66.6, 122.6, 127.5, 129.0, 129.4, 134.6, 136.4, 149.6,
152.6, 153.0, 167.7; MS m/z 282 >M1, 99), 106 >100), 78
>97); HRMS calcd for C16H14N2O3 282.1005, found
282.1025.
4.5.1. 2-[1-Benzyl-3-02-thioxo-1,3-thiazolidine-3-carbon-
acid
yl)-1,4-dihydropyridin-4-yl]-2-methyl-propionic
methyl ester 05a). Addition of 4a to 1a gave 5a as a
major product: An oil; IR >Neat) 2947, 1722, 1660, 1569,
1423, 1395, 1244 cm21; 1H NMR >400 MHz, CDCl3) d 7.76
>s, 1H), 7.36±7.30 >m, 5H), 6.02 >d, Jˆ7.6 Hz, 1H), 4.89
>dd, Jˆ7.6, 5.6 Hz, 1H), 4.54±4.43 >m, 3H), 4.25±4.17 >m,
1H), 4.07 >d, Jˆ5.6 Hz, 1H), 3.65 >s, 3H), 3.48±3.26 >m,
2H), 0.89 >s, 3H), 0.99 >s, 3H); 13C NMR >67.8 MHz,
CDCl3) d 177.2, 170.1, 148.4, 135.2, 128.8, 128.7, 128.2,
127.5, 107.4, 100.5, 58.6, 57.1, 51.8, 49.7, 39.1, 29.7, 22.3,
19.2; MS m/z 416 >M1, 0.04), 315 >70), 106 >46), 91 >100),
78 >15); HRMS calcd for C16H15ON2S2 >M12101),
315.0670, found 315.0675.
4.4. General procedure for the synthesis of pyridinium
salts with benzyl bromide
To a solution of a nicotinic amide >2.77 mmol) in dry
CH2Cl2 >10 ml) was added BnBr >430 ml, 3.62 mmol),
and the solution was stirred for 16 h at 508C. Concentration
of the solution resulted in the precipitation of the benzyl salt,
which was ®ltered to give a colorless solid >2.36 mmol).
4.5.2. 2-[1-Benzyl-3-02-oxo-1,3-oxazolidine-3-carbonyl)-
1,4-dihydropyridin-4-yl]-2-methyl-propionic acid methyl
ester 05b). Addition of 4a to 1b gave 5b as a major product:
An oil; IR >Neat) 2980, 2948, 1772, 1723, 1669, 1652, 1587,
4.4.1. 1-Benzyl-3-02-thioxo-1,3-thiazolidine-3-carbonyl)-
pyridinium bromide 01a). 85% yield; mp 197.3±198.2
8C; IR >KBr) 3374, 3031, 1681, 1364, 1329, 1232 cm21
;
1H NMR >400 MHz, CDCl3, 508C) d 3.89 >t, Jˆ7.3 Hz,
2H), 4.71>t, Jˆ7.3 Hz, 2H), 6.12 >s, 2H), 7.59 >m, 3H),
7.64 >m, 2H), 7.91>dd, Jˆ7.6, 5.9 Hz, 1H), 8.51 >d,
Jˆ7.6 Hz, 1H), 8.93 >d, Jˆ5.9 Hz, 1H), 10.81 >s, 1H); 13C
NMR >100 MHz, CDCl3) d 31.2, 56.9, 64.5, 127.7, 129.7,
129.8, 130.4, 132.1, 134.9, 143.9, 144.2, 147.4, 164.3,
204.9; MS m/z 224 >[M2Br±Bn]1, 48), 213 >15), 123
>28), 106 >92), 91 >100), 78 >51); HRMS calcd for
C9H8N2OS2 >[M2Br±Bn]1) 224.0078, found 224.0084.
1
1385, 1328, 1282, 1257, 1214, 1182, 1133, 1078 cm21; H
NMR >400 MHz, CDCl3) d 7.36±7.22 >m, 5H), 7.12 >s,1H),
6.02 >dd, Jˆ1.3, 7.8 Hz, 1H), 4.77 >dd, Jˆ7.9, 5.6 Hz, 1H),
4.46±4.07 >m, 5H), 4.10 >d, Jˆ5.6 Hz, 1H), 3.77 >m, 1H),
3.61 >s, 3H), 1.09 >s, 3H), 1.04 >s, 3H); 13C NMR
>67.8 MHz, CDCl3) d 177.2, 169.8, 153.9, 144.1, 136.2,
129.3, 128.7, 127.8, 127.1, 104.5, 99.8, 62.0, 60.3, 58.0,
51.6, 49.3, 43.8, 40.1, 21.5, 19.3; MS m/z 384 >M1, 1%),
283 >100), 228 >20), 106 >4), 91 >79); HRMS calcd for
C21H24O5N2 384.1685, found 384.1694.
4.4.2. 1-Benzyl-3-02-oxo-1,3-oxazolidine-3-carbonyl)pyri-
dinium bromide 01b). 82% yield; mp 108.9±109.28C; IR
4.5.3.
2-01-Benzyl-3-dimethylcarbamoyl-1,4-dihydro-
>KBr) 1783, 1684, 1633, 1363, 1201 cm21 1H NMR
;
pyridin-4-yl)-2-methyl-propionic acid methyl ester 05c).
Addition of 4a to 1c gave a 35:56:9 mixture of 5c, 6c and 7c,
which were separated by preparative TLC. 5c: An oil; IR
>Neat) 2931, 1725, 1671, 1602, 1385, 1260, 1160,
>400 MHz, CDCl3) d 10.43 >s, 1H), 9.33 >d, Jˆ6.3 Hz,
1H), 8.63 >d, Jˆ7.9, 1H), 8.01 >t, Jˆ6.6 Hz, 1H), 7.66 >m,
2H), 7.38 >m, 3H), 6.15 >s, 2H), 4.69 >t, Jˆ7.7 Hz, 2H), 4.24
>t, Jˆ7.7 Hz, 2H);13C NMR >100 MHz, CDCl3) d 167.7,
153.2, 152.7, 149.8, 136.5, 128.8, 122.7, 62.4, 43.4; MS
m/z 192 >[M2Br±Bn]1, 3), 148 >18), 106 >44), 91 >100),
1135 cm21; H NMR >400 MHz, CDCl3) d 7.36±7.17 >m,
1
6H), 6.04 >d, Jˆ7.6 Hz, 1H), 4.58 >q, 1H), 4.31 >s, 2H), 3.97
>d, Jˆ5.2 Hz, 1H), 3.58 >s, 3H), 3.00 >s, 6H), 1.10 >s, 3H),

8946
S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
1.06 >s, 3H); 13C NMR >67.8 MHz, CDCl3) d 177.3, 172.9,
137.3, 135.7, 128.6, 127.5, 127.0, 103.6, 100.1, 57.3, 51.6,
49.1, 42.3, 37.4, 20.9, 20.6; MS m/z 342 >M1, 7.2%), 241
>92), 146 >35), 91 >100), 72 >26); HRMS calcd for
C20H26O3N2 342.1943, found 342.1914. 6c: 1H NMR
>400 MHz, CDCl3) d 7.36±7.17 >m, 6H), 6.45 >d,
Jˆ10 Hz, 1H), 4.86 >m, 1H), 4.50 >d, Jˆ4.6 Hz, 1H), 4.39
>d, Jˆ16 Hz, 1H), 4.24 >d, Jˆ16 Hz, 1H), 3.71 >s, 3H), 2.98
>s, 6H), 1.30 >s, 3H), 1.15 >s, 3H). 7c: 1H NMR >400 MHz,
CDCl3) d 7.32±7.18 >m, 5H), 6.36 >d, Jˆ6.1Hz, 1H), 6.24
>d, Jˆ6.7 Hz, 1H), 5.18 >s, 1H), 4.91 >m, 1H), 4.45 >d,
Jˆ16 Hz, 1H), 4.33 >d, Jˆ16 Hz, 1H), 3.60 >s, 3H), 3.05
>s, 6H), 1.20 >s, 3H) 1.13 >s, 3H).
d 7.92 >s, 1H), 7.31±7.26 >m, 5H), 6.89 >d, Jˆ8.2 Hz, 1H),
5.81±5.71 >m, 1H), 5.30 >dd, Jˆ8.2, 4.9 Hz, 1H), 4.20 >q,
Jˆ7.3 Hz, 4H), 3.75 >s, 3H), 3.52±3.36 >m, 3H), 3.17±2.97
>m, 3H), 1.28 >m, 6H); 1H NMR >270 MHz, CDCl3) for 9d d
7.80 >s, 1H), 6.31 >d, Jˆ9.6 Hz, 1H), 5.53 >m, 1H), 4.95 >m,
1H), 4.20 >q, Jˆ7.3 Hz, 4H), 3.75 >s, 3H), 3.52±3.36 >m,
3H), 3.17±2.97 >m, 3H), 1.28 >t, Jˆ7.3 Hz, 6H); MS m/z
532 >M1, 5%), 373 >70), 314 >26), 295 >17), 231 >27), 106
>100), 91 >5); HRMS calcd for C25H28O7N2S2 532.1338,
found 532.1294.
4.5.8. 04S,40S)-4-01-Methoxycarbonyl-1-phenylmethyl)-
3-040-phenyl-20-thioxo-10,30-thiazolidine-30-carbonyl)-4H-
pyridine-1-carboxylic acid methyl ester 08e). Addition of
4c to 2c in the presence of methyl chloroformate gave 8e as
a major product >67%): 1H NMR >270 MHz, CDCl3) d 7.58
>s, 1H), 7.41±7.23 >m, 10H), 6.64 >d, Jˆ7.6 Hz, 1H), 5.24
>m, 1H), 5.00 >m, 1H), 4.30 >t, Jˆ5.3 Hz, 1H), 4.16±4.08
>m, 2H), 3.79 >s, 3H), 3.68 >s, 3H), 3.45±3.32 >m, 2H),
3.23±3.16 >m, 1H), 2.99±2.91 >m, 1H); MS m/z 522 >M1,
0.65%), 373 >100), 285 >17), 196 >25), 182 >21), 106 >93), 91
>22), 59 >15); HRMS calcd for C27H26O5N2S2 522.1284,
found 522.1306.
4.5.4. 04S,40S)-4-01-Methoxycarbonyl-1-methylethyl)-3-
040-phenyl-20-thioxo-10,30-thiazolidine-30-carbonyl)-4H-
pyridine-1-carboxylic acid methyl ester 08a). Addition of
4a to 2b in the presence of methyl chloroformate gave 8a as
a major product: An oil; 1H NMR >400 MHz, CDCl3, 508C)
d 0.87 >3H, s), 0.95 >3H, s), 3.32 >1H, dd, Jˆ11.0 Hz,
4.9 Hz), 3.61>3H, s), 3.82±3.87 >1H, m), 3.87 >3H, s),
3.94 >1H, dd, Jˆ11.0, 7.0 Hz), 5.04 >1H, dd, Jˆ7.9,
5.5 Hz), 5.75 >1H, dd, Jˆ7.0, 4.9 Hz), 6.91>H1, d,
Jˆ7.9 Hz), 7.27±7.40 >5H, m), 7.78 >1H, s); MS m/z
460>M1, 2%), 359 >100), 106 >81); HRMS calcd for
C22H24N2O5S2 460.1127, found 460.1110.
4.5.9. 04S,40S)-4-01-Methoxycarbonyl-1-methylethyl)-3-
020-oxo-40-phenyl-10,30-oxazolidine-30-carbonyl)-4H-pyri-
dine-1-carboxylic acid methyl ester 010a). Addition of 4a
to 3d in the presence of methyl chloroformate gave 10a as a
4.5.5. 04S,40S)-3-040-Benzyl-20-thioxo-10,30-thiazolidine-
30-carbonyl)-4-01-methoxycarbonyl-1-methylethyl)-4H-
pyridine-1-carboxylic acid methyl ester 08b). Addition of
4a to 2c in the presence of methyl chloroformate gave a
78:22 mixture of 8b and 9b, which was puri®ed by prepara-
1
major product: H NMR >400 MHz, CDCl3, 508C) d 1.04
>3H, s), 1.12 >3H, s), 3.61 >3H, s), 3.89 >3H, s), 3.95 >1H, d,
Jˆ5.3 Hz), 4.27 >1H, dd, Jˆ9.2, 8.6 Hz), 4.71>1H, dd,
Jˆ9.2, 8.9 Hz), 4.99 >1H, dd, Jˆ7.9, 5.3 Hz), 5.58 >1H,
dd, Jˆ8.9, 8.6 Hz), 6.89 >1H, d, Jˆ7.9 Hz), 7.29±7.37
>5H, m), 7.71>1H, s); MS m/z 327 >M12101, 100%), 106
>91); HRMS calcd for C17H15N2O5 >M12C5H9O2)
327.0981, found 327.0972.
25
tive TLC to give pure 8b: an oil; [a]D ˆ23928 >c 1.0,
CHCl3); IR >CHCl3) 2959, 1736, 1682, 1606, 1276 cm21
;
1H NMR >400 MHz, CDCl3, 508C) d 1.13 >3H, s), 1.14 >3H,
s), 2.99 >1H, dd, Jˆ11.1, 1.5 Hz), 3.11 >1H, dd, Jˆ13.3,
11.1 Hz), 3.49±3.54 >2H, m), 3.65 >3H, s), 3.88 >3H, s),
3.94 >1H, d, Jˆ5.8 Hz), 4.84±4.89 >1H, m), 5.02 >1H, dd,
Jˆ7.8, 5.8 Hz), 6.94 >1H, d, Jˆ7.8 Hz), 7.20±7.35 >5H, m),
7.67 >1H, s); 13C NMR >67.8 MHz, CDCl3, 508C) d 21.4,
21.6, 33.4, 37.2, 41.8, 48.9, 51.9, 54.2, 70.5, 108.5, 113.7,
123.9, 127.1, 128.9, 129.4, 135.0, 136.8, 151.4, 170.6,
177.0, 200.2; MS m/z 474 >M1, 3%), 373>100), 106>89);
HRMS calcd for C23H26N2O5S2 474.1283, found 474.1284.
4.5.10. 04S,40S)-3-040-Benzyl-20-oxo-10,30-oxazolidine-30-
carbonyl)-4-01-methoxycarbonyl-1-methylethyl)-4H-pyri-
dine-1-carboxylic acid methyl ester 010b). Addition of 4a
to 3c in the presence of methyl chloroformate gave 10b as a
major product, which was puri®ed by preparative TLC to
24
give pure 10b: [a]D ˆ11718 >c 0.60, CHCl3); IR >CHCl3)
1
2955, 1782, 1735, 1685, 1618 cm21; H NMR >270 MHz,
CDCl3, 508C) d 1.11 >3H, s), 1.16 >3H, s), 2.76 >1H, dd,
Jˆ13.2, 9.2 Hz), 3.31 >1H, dd, Jˆ13.2, 3.5 Hz), 3.65 >3H,
s), 3.87 >3H, s), 4.07 >1H, d, Jˆ5.3 Hz), 4.11±4.30 >2H, m),
4.81±4.92 >1H, m), 5.06 >1H, dd, Jˆ8.2, 5.3 Hz), 6.95>1H,
d, Jˆ8.2 Hz), 7.17±7.33 >5H, m), 7.58 >1H, s); 13C NMR
>67.8 MHz, CDCl3, 508C) d 20.2, 22.3, 38.2, 40.9, 48.6,
51.9, 54.2, 55.1, 66.6, 108.4, 111.5, 123.9, 127.3, 128.9,
129.3, 134.2, 135.2, 151.5, 153.3, 169.7, 176.9; MS m/z
341>M 12101, 100%), 106 >96); HRMS calcd for
C18H17N2O5 >M12C5H9O2) 341.1137, found 341.1115.
4.5.6. 04S,40S)-4-01-Methoxycarbonyl-1-methylethyl)-3-
040-tert-butyl-20-thioxo-10,30-thiazolidine-30-carbonyl)-
4H-pyridine-1-carboxylic acid methyl ester 08c). Addi-
tion of 4a to 2d in the presence of methyl chloroformate
1
gave 8c as a major product: H NMR >400 MHz, CDCl3,
508C) d 1.10 >9H, s), 1.12 >3H, s), 1.18 >3H, s), 3.22 >1H, dd,
Jˆ11.4, 2.1 Hz), 3.65 >3H, s), 3.77 >1H, dd, Jˆ11.4,
8.5 Hz), 3.79 >1H, d, Jˆ5.8 Hz), 3.87 >3H, s), 4.75 >1H,
dd, Jˆ8.5, 2.1Hz), 5.02 >1H, dd, Jˆ7.9, 5.8 Hz), 6.94
>1H, d, Jˆ7.9 Hz), 7.58 >1H, s); MS m/z 440 >M1, 1%),
339 >100), 106>72); HRMS calcd for C20H28N2O5S2
440.1440, found 440.1435.
4.6. General procedure for the addition of organocopper
reagents to the pyridinium salts
4.5.7. 04S,40S)-2-[1-Methoxycarbonyl-3-040-phenyl-20-thi-
oxo-10,30-thiazolidine-30-carbonyl)-1,4-dihydropyridin-
4-yl]-malonic acid diethyl ester 08d). Addition of 4b to 2c
in the presence of methyl chloroformate gave a 47:53
To a solution of a nicotinic amide >130 mg) in dry THF
>1.0 ml) was added acid chloride >1.1 equiv.) at 08C, and
the solution was stirred for 1h. After the solution was
cooled to 2708C, an organocopper reagent >1.2 equiv.) in
THF prepared from RLi >1equiv.) with CuBr´SMe 2
1
mixture of 8d and 9d: H NMR >270 MHz, CDCl3) for 8d

S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
8947
>2 equiv.) was added to the solution. The solution was stir-
red for 2 h and then allowed to warm to room temperature.
Hydrolysis of the reaction mixture was done with saturated
ammonium chloride solution by stirring for 1h. The solu-
tion was extracted with ether to give a crude product, which
was subjected to column chromatography on silica gel to
give a pure 1,4-dihydropyridine.
dd, Jˆ9.0, 5.0 Hz), 4.60 >1H, dd, Jˆ4.6, 1.0 Hz), 5.37 >1H,
dd, Jˆ8.2, 4.6 Hz), 7.12±7.62 >11H, m), 7.90 >1H, d,
Jˆ1.5 Hz); MS m/z 462 >M1, 4%), 259 >91), 182 >33),
111 >100); HRMS calcd for C26H26N2O2S2 462.1436,
found 462.1466.
4.6.6. 04S,40S)-3-020-Oxo-40-phenyl-10,30-oxazolidine-30-
carbonyl)-4-phenyl-4H-pyridine-1-carboxylic acid methyl
ester 014a). Addition of PhCu to the nicotinium salt of 3a
formed by treatment with benzoyl chloride afforded 14a as a
4.6.1. 04S,40S)-4-Methyl-3-040-phenyl-20-thioxo-10,30-thi-
azolidine-30-carbonyl)-4H-pyridine-1-carboxylic
acid
1
major product: H NMR >270 MHz, CDCl3, 508C) d 3.88
methyl ester 012a). Addition of MeCu to the nicotinium
salt of 2a formed by treatment with methyl chloroformate
afforded 12a as a major product: 1H NMR >270 MHz,
CDCl3, 508C) d 0.84 >3H, d, Jˆ6.8 Hz), 3.27±3.31>1H,
m), 3.55 >1H, dd, Jˆ11.2, 8.8 Hz), 3.72 >1H, dd, Jˆ11.2,
7.3 Hz), 3.91>3H, s), 5.07 >1H, dd, Jˆ8.2, 4.7 Hz), 5.70
>1H, dd, Jˆ8.8, 7.3 Hz), 6.67 >1H, d, Jˆ8.2 Hz), 7.30±
7.42 >5H, m), 7.78 >1H, s); MS m/z 374 >M1, 29%), 359
>28), 180 >89), 151 >100), 106 >41); HRMS calcd for
C18H18N2O3S2 374.0759, found 374.0801.
>3H, s), 3.95 >1H, d, Jˆ5.1Hz), 4.66±4.73 >2H, m), 4.99
>1H, dd, Jˆ5.1, 7.9 Hz), 5.58 >1H, Jˆ7.6, 7.9 Hz), 6.87>1H,
d, Jˆ7.9 Hz), 7.28±7.38 >10H, m), 7.69 >1H, s); MS m/z 404
>M1, 25%), 327 >54), 213 >100), 182 >39); HRMS calcd for
C23H20N2O5 404.1372, found 404.1347.
4.7. General procedure for the addition of trimethyl-
benzyltin to the pyridinium salts
A solution of the amide >1equiv.) in dry CH 2Cl2 was cooled
to 08C under nitrogen atmosphere. An acylating agent
>1.5 equiv.) was added dropwise to the solution, and the
solution was stirred for 1h at 0 8C. After addition of benzyl-
trimrthyltin >2 equiv.), the solution was stirred for 23 h at
room temperature. KF >20 mg) and H2O >10 drops) were
added to the solution, and the solution was stirred for
15 h. The reaction mixture was ®ltered, and the ®ltrate
was dried over anhydrous MgSO4. Evaporation of the
solvent gave a crude 1,4-adduct as an oil, which was puri®ed
by silica gel column chromatography to give a dihydro-
pyridine >hexane/AcOEt/CH2Cl2ˆ10:2:5).
4.6.2. 04S,40S)-4-Phenyl-3-040-phenyl-20-thioxo-10,30-thi-
azolidine-30-carbonyl)-4H-pyridine-1-carboxylic
acid
methyl ester 012b). Addition of PhCu to the nicotinium
salt of 2a formed by treatment with methyl chloroformate
afforded 12b as a major product: 1H NMR >270 MHz,
CDCl3, 508C) d 3.17 >1H, dd, Jˆ11.0, 5.4 Hz), 3.33 >1H,
dd, Jˆ11.0, 7.3 Hz), 3.92 >3H, s), 4.77 >1H, d, Jˆ3.2 Hz),
5.10±5.16 >2H, m), 6.78 >1H, d, Jˆ8.1Hz), 7.02±7.40
>10H, m), 8.00 >1H, s); MS m/z 436 >M1, 11%), 242 >97),
213 >100), 182 >51); HRMS calcd for C23H20N2O3S2
436.0915, found 436.0891.
4.6.3. 04S,40S)-01-Benzoyl-4-phenyl-1,4-dihydropyridin-
3-yl)-040-phenyl-20-thioxo-10,30-thiazolidin-30-yl)metha-
none 012c). Addition of PhCu to the nicotinium salt of 2a
formed by treatment with benzoyl chloride afforded 12c: 1H
NMR >270 MHz, CDCl3, 508C) d 3.06 >1H, dd, Jˆ11.0,
5.4 Hz), 3.29 >1H, dd, Jˆ11.0, 7.6 Hz), 4.82 >1H, dd,
Jˆ4.2, 1.5 Hz), 5.10 >1H, dd, Jˆ7.6, 5.4 Hz), 5.23 >1H,
dd, Jˆ8.3, 4.2 Hz), 6.95±7.64 >16H, m), 7.89 >1H, d,
Jˆ1.2 Hz); MS m/z 482 >M1, 8%), 259 >93), 182 >51),
111 >100); HRMS calcd for C28H22N2O2S2 482.1122,
found 482.1141.
4.7.1. 04S,40S)-4-Benzyl-3-040-phenyl-20-thioxo-10,30-thi-
azolidine-30-carbonyl)-4H-pyridine-1-carboxylic
acid
methyl ester 012f). 134 mg >72%); An oil; 1H NMR
>270 MHz, CDCl3, 508C) d 2.41>1H, dd, Jˆ13.2, 7.6 Hz),
2.62 >1H, dd, Jˆ13.2, 4.9 Hz), 3.44 >1H, dd, Jˆ10.2,
8.3 Hz), 3.52±3.65 >2H, m), 3.84 >3H, s), 4.99 >1H, dd,
Jˆ8.2, 5.1Hz), 5.55 >1H, dd, Jˆ8.3, 7.6 Hz), 6.66 >1H, d,
Jˆ8.2 Hz), 6.86±6.90 >2H, m), 7.10±7.44 >8H, m), 7.74
>1H, s); MS m/z 450 >M1, 2%), 359 >87), 256 >89), 106
>100); HRMS calcd for C24H22N2O3S2 450.1072, found
450.1046.
4.6.4. 04S,40S)-01-Benzoyl-4-phenyl-1,4-dihydropyridin-
3-yl)-04-benzyl-20-thioxo-10,30-thiazolidin-30-yl) metha-
none 012d). Addition of PhCu to the nicotinium salt of 2b
formed by treatment with benzoyl chloride afforded 12d: 1H
NMR >400 MHz, CDCl3, 508C) d 2.63 >1H, dd, Jˆ11.3,
6.6 Hz), 2.70 >1H, dd, Jˆ11.3, 1.8 Hz), 2.93 >1H, dd,
Jˆ13.4, 11.0 Hz), 3.32 >1H, dd, Jˆ13.4, 3.4 Hz), 4.08±
4.14 >1H, m), 5.00 >1H, br s), 5.20 >1H, dd, Jˆ8.2,
3.7 Hz), 7.03±7.64 >16H, m), 7.86 >1H, s); MS m/z
496>M1, 6%), 259 >91), 183 >49), 182 >46), 111 >100);
HRMS calcd for C29H24N2O2S2 496.1279, found 496.1302.
4.7.2. 04S,40S)-4-Benzyl-3-020-oxo-40-phenyl-10,30-oxazoli-
dine-30-carbonyl)-4H-pyridine-1-carboxylic acid methyl
ester 014b). 145 mg >85%); an oil; H NMR >270 MHz,
CDCl3, 508C) d 2.71±2.74 >2H, m), 3.59 >1H, dd, Jˆ11.7,
5.5 Hz), 3.82 >3H, s), 4.17 >1H, dd, Jˆ8.5, 6.7 Hz), 4.55
>1H, dd, Jˆ8.5, 7.8 Hz), 5.06 >1H, dd, Jˆ8.3, 5.5 Hz),
5.27 >1H, dd, Jˆ7.8, 6.7 Hz), 6.73 >1H, d, Jˆ8.3 Hz),
6.94±6.97 >2H, m), 7.15 >2H, dd, Jˆ5.1, 2.0 Hz), 7.27±
7.44 >6H, m), 7.61>1H, s); MS m/z 327>M1291%), 106
>56), 105 >100); HRMS calcd for C17H15N2O5 >M1-C7H7)
327.0981, found 327.0973.
1
4.6.5. 04S,40S)-01-Benzoyl-4-phenyl-1,4-dihydro-pyridin-
3-yl)-040-methyl-20-thioxo-10,30-thiazolidin-30-yl)metha-
none 012e). Addition of PhCu to the nicotinium salt of 2c
formed by treatment with benzoyl chloride afforded 12e: 1H
NMR >270 MHz, CDCl3, 508C) d 0.73 >9H, s), 3.06 >1H, dd,
Jˆ11.5, 5.0 Hz), 3.23 >1H, dd, Jˆ11.5, 9.0 Hz), 4.47 >1H,
4.7.3. Synthesis of 0S)-4-phenyl-1,4-dihydropyridine-3-
carboxylic acid methyl ester 016). To a solution of
dihydropyridine 12c >0.95 g, 2.0 mmol) in dry THF
>40 ml) was added 0.50 moll21 sodium methoxide solution
in methanol >8.8 ml, 4.4 mmol) was added, and the solution
was then stirred at rt for 7.5 h. Saturated ammonium

8948
S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
23
hexane to yield analytical specimen: [a]D ˆ11018 >c
;
1690 cm21 1H NMR >270 MHz, CDCl3, 508C) d 0.80
chloride solution was added to the reaction mixture at 08C,
and the pH adjusted to 8±9 and extracted three times with
CH2Cl2. The combined extracts were concentrated to give a
crude product which was subjected to column
chromatography using CH2Cl2 as an eluent solvent, afford-
ing 16 >269 mg, 66%): decomposition point 83.08C; IR
0.52, CHCl3); mp 96.0±97.08C; IR >KBr) 2917, 1725,
>3H, d, Jˆ6.8 Hz), 0.89 >3H, d, Jˆ5.6 Hz), 0.91>3H, d,
Jˆ5.4 Hz), 0.94±2.13 >10H, m), 2.55±2.70 >1H, m),
2.87±3.02 >3H, m), 3.22 >1H, dd, Jˆ13.8, 4.0 Hz), 3.44
>3H, s), 4.29±4.33 >2H, m), 4.58 >1H, dt, Jˆ10.7, 4.4 Hz),
7.19±7.29 >5H, m); 13C NMR >67.8 MHz, CDCl3, 508C) d
16.7, 21.0, 22.2, 23.9, 26.1, 26.4, 31.6, 34.7, 41.7, 43.4,
44.1, 45.6, 46.2, 47.7, 51.2, 75.4, 126.7, 127.4, 128.3,
142.4, 155.1, 171.9; MS m/z 401>M 1, 2%), 264 >87), 262
>35), 218 >100), 214 >92); HRMS calcd for C24H35NO4
401.2566, found 401.2563.
>CHCl3) 3474, 2953, 1696 cm21 1H NMR >270 MHz,
;
CDCl3) d 3.58 >3H, s), 4.51>1H, d, Jˆ4.9 Hz), 4.87 >1H,
ddd, Jˆ7.6, 4.9, 1.6 Hz), 5,71 >1H, br s), 6.03 >1H, dd, Jˆ
7.6, 4.4 Hz), 7.14±7.37 >6H, m); 13C NMR >67.8 MHz,
CDCl3) d 38.6, 51.0, 102.5, 107.6, 122.4, 126.2, 127.6,
128.2, 136.3, 148.1, 168.3; MS m/z 215 >M1, 28%), 214
>90), 213 >79), 182 >100); HRMS calcd for C13H13NO2
215.0946, found 215.0930.
4.8. General procedure for the synthesis of 3-dimethyl-
carbamoyl-1,4-dihydropyridines
4.7.4. Synthesis of 0S)-4-phenyl-1,4,5,6-tetrahydropyri-
dine-3-carboxylic acid methyl ester 017). Dihydropyridine
16 >286 mg, 1.33 mmol) was dissolved in ethanol >10 ml)
and PtO2 >49 mg) was added to the solution. The solution
was stirred for 43 h under 1atm of hydrogen atmosphere.
This was subjected to column chromatography using a 4:2:1
mixture of hexane, ethyl acetate and dichloromethane as an
eluent solvent to yield pure 17 >220 mg, 76%). Recrystal-
lization of 17 from diethyl ether gave an analytical speci-
men: mp 135.0±136.08C; IR >CHCl3) 3469, 2952, 1675,
To a solution of a 1,4-dihydropyridine in ether >2 ml)
dimethylamine >40 wt% solution in water, 100±250 ml)
was added, and the solution was stirred for 2 h at rt. After
dried over anhydrous MgSO4, the solution was concentrated
and the residue was separated by preparative TLC using a
1:1mixture of hexane and ethyl acetate or a 4:1mixture of
CH2Cl2 and ethyl acetate as an eluent solvent to afford an
oily pure 3-dimethylcarbamoyl-1,4-dihydropyridine.
1627 cm21 1H NMR >270 MHz, CDCl3) d 1.81±1.86
;
>1H, m), 1.98 >1H, tt, Jˆ12.7, 4.9 Hz), 2.96 >1H, dt,
Jˆ12.5, 3.7 Hz), 3.09±3.15 >1H, m), 3.58 >3H, s), 4.03
>1H, d, Jˆ5.1 Hz), 4.59 >1H, br s), 7.14±7.31 >5H, m),
7.75 >1H, d, Jˆ6.3 Hz); 13C NMR >67.8 MHz, CDCl3) d
29.1, 36.4, 36.5, 50.7, 96.9, 125.8, 127.7, 128.0, 143.4,
146.4, 168.6; MS m/z 217 >M1, 82%), 213 >74), 182
>100), 158 >95); HRMS calcd for C13H15NO2 217.1103,
found 217.1100.
4.8.1. 0R)-2-03-Dimethylcarbamoyl-1,4-dihydropyridine-
4-yl)-2-methylpropionic acid methyl ester 020a). Amino-
lysis of 8b >7.1mg) with dimethylamine >131 ml) gave 20a
>2.7 mg) in 58% yield: IR >Neat) 2933, 1711, 1627,
1
1604 cm21; H NMR >270 MHz, CDCl3, 508C): d 7.12 >br
s, 1H), 6.88 >br d, Jˆ8.10 Hz, 1H), 5.00 >dd, Jˆ5.4, 8.1Hz,
1H), 3.89 >d, Jˆ5.4 Hz, 1H), 3.84 >s, 3H), 3.60 >s, 3H), 3.07
>s, 6H); CD >EtOH) 245 nm >D1ˆ11.8); MS m/z >rerative
intensity) 295 >M12Me, 1), 209 >M12101, 100), 165 >41),
106 >9); HRMS calcd for C10H13N2O3 >M12101) 209.0926,
found 209.0877.
4.7.5. Synthesis of 03R,4R)-4-phenylpiperidine-3-car-
boxylic acid methyl ester 018). Tetrahydropiperidine 17
>220 mg, 1.01 mmol) was dissolved in ethanol >5 ml) and
acetic acid >5 ml), and PtO2 >43 mg) was added to the solu-
tion. The solution was stirred under 1atm of hydrogen
atmosphere for 67 h. After ®ltration, saturated NaHCO3
was added and extracted with dichloromethane for three
times. The combined extracts were dried over anhydrous
MgSO4 and the solvent was removed under reduced pres-
sure to give a crude cis and trans mixture of 18, which was
4.8.2. 0S)-4-Phenyl-1,4-dihydropyridine-3-carboxylic acid
dimethylamide 020b). Aminolysis of 12c >18 mg) with
dimethylamine >200 ml) gave 20b >9.4 mg) in 78% yield:
IR >Neat) 2960, 2934, 1727, 1625 cm21
;
11H NMR
>270 MHz, CDCl3, 508C) d 7.57±7.19 >m, 10H), 7.08 >m,
2H), 5.18 >dd, Jˆ3.8, 8.2 Hz, 1H), 4.71 >d, Jˆ3.8 Hz, 1H),
2.74 >s, 6H); CD >EtOH) 242 nm >D1ˆ4.6); MS m/z
>rerative intensity) 256 >5), 226 >M12106, 22), 182 >100),
105 >47); HRMS calcd for C14H14N2O >M1106) 226.1106,
found 226.1155.
1
used in the next reaction without further puri®cation: H
NMR >270 MHz, CDCl3); d 1.57±3.40 >m, 9H), 3.43 and
3.68 >each s, 2.6H and 0.4H, respectively), 7.19±7.35 >m,
5H).
4.7.6. Synthesis of 03R,4R,10S,20R,50S)-3-methoxylcar-
bonyl-4-phenylpiperidine-1-carboxylic acid menthyl
ester 019). To a solution of a crude 18 and triethylamine
>1.2 ml, 8.6 mmol) in dry dichloromethane >5.0 ml) >1)-
menthyl chloroformate >0.85 ml, 4.0 ml) was added drop-
wise at rt. After the solution was stirred for 19 h, the reaction
mixture was extracted with dichloromethane. This was
washed with brine and dried over anhydrous MgSO4.
Evaporation of the solvent gave a crude oily product,
which was puri®ed by silica gel column chromatography
using a 10:1:5 mixture of hexane, ethyl acetate and
dichloromethane as a eluent solvent to give pure 19
>281mg, 69% from 17). This was recrystallized from
4.8.3. 0R)-4-Benzyl-1,4-dihydropyridine-3-carboxylic acid
dimethylamide 020c). Aminolysis of 12f >29.7 mg) with
dimethylamine >250 ml) gave 20c >15.7 mg) in 80% yield:
1
IR >Neat) 2959, 2920, 1723, 1683, 1610 cm21; H NMR
>270 MHz, CDCl3, 508C): d 7.27 >m,1H), 7.23 >d,
Jˆ4.6 Hz, 2H), 7.17 >t, Jˆ4.6, 6.6 Hz, 2H), 6.96 >br s,
1H), 6.74 >br d, Jˆ5.4 Hz, 1H), 4.92 >dd, Jˆ4.0, 5.4 Hz,
1H), 3.81 >s, 3H), 3.76 >ddd, Jˆ4.0, 5.1, 8.9 Hz, 1H), 2.97
>s, 6H), 2.84 >dd, Jˆ5.1, 13.2 Hz, 1H), 2.66 >dd, Jˆ8.9,
13.2, 1H); CD >EtOH) 244 nm >D1ˆ1.3); MS m/z >rerative
intensity) 240 >M1260, 61), 195 >100), 167 >26), 106 >20);
HRMS calcd for C15H16N2O >M1260) 240.1263, found
240.1298.

S. Yamada et al. / Tetrahedron 57 -2001) 8939±8949
8949
12. Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 122, 4563.
13. >a) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem.
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14. Preliminary communication Yamada, S.; Ichikawa, M.
Tetrahedron Lett. 1999, 40, 4231.
4.9. Methods of calculation
All calculations on geometries and energies were performed
with the program package PC SPARTAN Pro. Geometry
optimizations were carried out by semiempirical AM1
methods for each structure obtained from MMFF calcula-
tions in conjunction with Monte Carlo searching. The four
typical conformers obtained were selected, and their
geometries and energies were optimized by ab initio calcu-
lations at RHF/3-21Gp level.
15. Yamada, S.; Misono, T. Tetrahedron Lett. 2001, 42, 5497.
16. Akiba, K-y.; Ohtani, A.; Yamamoto, Y. J. Org. Chem. 1986,
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Acknowledgements
19. For a review see: Ma, J. C.; Dougherty, D. A. Chem. Rev.
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Financial support, in the form of Grant-in-Aid for Scienti®c
Research >10640574) from Japan Society for the Promotion
of Science and Research >11304045) from ministry of
Education, Science, and Culture, Japan are acknowledged.
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Ê
Ê 3
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Zˆ4, rcalcdˆ1.163 M g23
,
mˆ0.623 mm21 >Cu Ka, lˆ
Ê
1.54178 A), F>000)ˆ872, Tˆ293 K. A total of 1710 unique
data for 2Qmaxˆ1208 was collected of which 1710 were inde-
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hydrogen atoms were re®ned anisotropically by full-matrix
least squares method. All the H atoms were treated isotropic.
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