Highly selective and facile synthesis of dihydro- and tetrahydropyridine dicarboxylic acid derivatives using electroreduction as a key step

Article abstract of DOI:10.1016/S0040-4020(01)00058-8

Electroreduction of pyridinedicarboxylic acid derivatives 1a-g in methanol containing ammonium chloride using a divided cell brought about highly selective hydrogenation to give the corresponding dihydropyridines in good yields. From the electrolysis of d

Full text of DOI:10.1016/S0040-4020(01)00058-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2095±2102
Highly selective and facile synthesis of dihydro- and
tetrahydropyridine dicarboxylic acid derivatives using
electroreduction as a key stepq
Yoshio Kita,b Hirofumi Maekawa,a Yasuhiro Yamasakib and Ikuzo Nishiguchia,p
aDepartment of Chemistry, Nagaoka University of Technology, 1603-1, Kamitomioka-cho, Nagaoka, Niigata 940-2188, Japan
bOrient Chemical Industries, 8-1, Sanrahigashi-machi, Neyagawa, Osaka 572-8581, Japan
Received 17 November 2000; accepted 10 January 2001
AbstractÐElectroreduction of pyridinedicarboxylic acid derivatives 1a±g in methanol containing ammonium chloride using a divided cell
brought about highly selective hydrogenation to give the corresponding dihydropyridines in good yields. From the electrolysis of dimethyl
2,3- and 2,5-pyridinedicarboxylates 1a,c, only the corresponding 1,2-dihydropyridine derivatives 2a,c were obtained in a regioselective
manner while that of 2,4-, 2,6-, and 3,4- disubstituted pyridines 1b,d,e afforded the corresponding 1,4-dihydropyridines 2b,d,e selectively in
good yields. Further hydrogenation of the resultant dihydropyridines by several methods led to the selective and facile formation of the
corresponding tetrahydropyridines 6. Furthermore, Mg-promoted hydrosilylation of the N-acetylated product 5a gave C-silylated tetra-
hydropyridines in a stereoselective manner. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
pyridines in aqueous solution gave the corresponding piperi-
dines,10,11 or 1,4-dihydro-isomers12 although the processes
were generally inferior to catalytic hydrogenation or base-
catalyzed condensation.2
Direct and selective hydrogenation of pyridine rings is
important in the synthesis of dihydro- and tetrahydropyri-
dine skeletons, being useful as synthetic intermediates of
nitrogen-containing biologically active substances.1
Among the dihydropyridine skeletons, 3,5-disubstituted-
1,4-dihydropyridine derivatives can be prepared by base-
catalyzed condensation between aromatic aldehydes, 1,3-
We have already reported that regioselective and ef®cient
hydrogenation of ring-substituted phthalic acid derivatives
was successfully accomplished by electroreduction in
aqueous acidic solvent to give the corresponding 1,2-di-
hydrophthalic acid derivatives in good to excellent yields.13
dicarbonyl compounds and amines including ammonia,2
3±5
reduction of pyridinium salts
addition.6
or photochemical cyclo-
In this study, we present selective, facile and ef®cient syn-
thesis of dihydropyridine derivatives 2 from pyridinedicar-
boxylic acid derivatives 1 by electroreduction in methanol
containing ammonium chloride using a divided cell (Eq. 1
Most of the known methods for this purpose, however, have
suffered from some disadvantages, particularly unsatis-
factory yield and/or formation of mixtures of the regio-
isomers or that of mixtures of dihydro-, tetrahydro- and
hexahydro-isomers.7±9 For example, the NaBH3CN-reduc-
tion of dimethyl and diethyl 3,5-pyridinedicarboxylates was
reported to afford the corresponding 1,4-dihydro-isomers
selectively in 77% yields. A mixture of the 1,4- and 1,2-
dihydro-isomers (the ratio of 1,4- and 1,2-dihydro-isomers:
78±79/22±21) was obtained in 54±35% yields by the cata-
lytic hydrogenation or diborane-reduction of dimethyl and
diethyl 3,5-pyridinedicarboxylates.9 Electroreduction of
q See Ref. 1.
Keywords: electroreduction; dihydropyridinedicarboxylic acids; hydroge-
nation.
p
Corresponding author. Tel.: 181-258-47-9307; fax; 181-258-47-9300;
e-mail: nishiiku@vos.nagaokaut.ac.jp
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00058-8

2096
Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
Table 1. Electroreductve hydrogenation of dimethyl 2,3-pyridinedicarboxylate 1a
Entry
Supporting electrolyte
Cathode material
Temperature
Additive
Yield of 2a
1
2
3
4
5
6
7
8
9
10
H2SO4
KF
Pt
Pt
Pt
Pt
SUS
C
Pb
Pt
Pt
Pt
rta
rt
rt
rt
rt
rt
rt
±
±
±
±
±
±
±
±
0
0
19
36
32
0
AcOH±NEt3
Et4NOTs
Et4NOTs
Et4NOTs
Et4NOTs
Et4NOTs
Et4NOTs
Et4NOTs
0
5±108C
5±108C
5±108C
48
83
89
NH4Cl
AcOH
a
rt: Room temperature; current density: 15±20 mA/cm2
in Scheme 1).14 Subsequent reduction of some of the
products 2 by various methods brought about selective
transformation to the corresponding tetrahydropyridines 6
(Eq. 2) which were also useful nitrogen-containing hetero-
cycles.15 Furthermore, Mg-promoted reductive C-silylation
of dimethyl N-acetyl-1,2-dihydropyridine dicarboxylate 5a
with various trialkylchlorosilanes in DMF led to regio- and
stereoselective hydrosilylation to give the corresponding
4-trialkylsilylated tetrahydropyridines 7a±9a in good yields
(Eq. 3).
Use of tetraethylammonium p-toluenesulfonate (Et4NOTs)
as the supporting electrolyte and platinum (Pt) as the cath-
ode material gave dimethyl 1,2-dihydro-2,3-pyridinedicar-
boxylate (2a) as the main product in a relatively better (36±
89%) yield (Entries 1±10). Moreover, reaction temperature
and pH of the reaction medium gave large in¯uences on
yield and selectivity of the product 2a (Entries 4, 8±10).
Thus, 2a was obtained in a 36% yield from electroreduction
of 1a at room temperature without any additives while the
same reaction at 5±108C gave 2a in a 48% yield (Entries 4,
8). It was noteworthy that the addition of a weak acid such
as NH4Cl or acetic acid into the reaction system brought
about the increase in the yield of 2a from 48 to 83±89%
(Entries 8±10). This remarkable improvement may be eluci-
dated by the fact that the weakly acidic conditions inhibited
the decomposition of the product 2a, which was unstable
under the basic conditions, possibly caused by electro-
generated bases.
2. Results and discussion
2.1. Electroreduction of dimethyl pyridinedicarb-
oxylates (1a±e)
Electroreduction of ®ve kinds of dimethyl pyridinedicar-
boxylates (2,3-(CO2Me)2(1a), 2,4-(CO2Me)2(1b), 2,5-
(CO2Me)2(1c), 2,6-(CO2Me)2(1d), and 3,4-(CO2Me)2(1e))
in methanol was usually carried out using a divided cell
under the constant current conditions (current density: 15±
20 mA/cm2). Some reaction conditions were studied using
dimethyl 2,3-pyridinedicarboxylate (1a) as a model starting
substrate (Table 1).
Under the optimum conditions, electroreduction of various
ring-substituted dimethyl pyridinedicarboxylates (1a±e) led
to highly selective and facile hydrogenation to give the
corresponding dihydropyridinedicarboxylates (2a±e) in
good to excellent yields (Table 2). A remarkable high
regioselectivity was observed in the present electrochemical
hydrogenation. Thus, dimethyl 1,2-dihydro 2,3- and
Table 2. Electrochemical reduction of various pyridinecarboxylic acid derivatives
Substrate
Reduction potential
(V vs Ag/AgCl)
Product
Type
Yield (%)
Dimethyl 2,3-Pyridinedicarboxylate
Dimethyl 2,4-Pyridinedicarboxylate
Dimethyl 2,5-Pyridinedicarboxylate
Dimethyl 2,6-Pyridinedicarboxylate
Dimethyl 3,4-Pyridinedicarboxylate
1a
1b
1c
1d
1e
21.98
B
A
B
A
A
2a
2b
2c
2d
2e
83
67
77
92
79
21.71
21.60
21.96
21.87
Preparative electrolysis was carried out in methanol containing Et4NOTs and NH4Cl, using a divided cell equipped with a Pt plate as the cathode, a carbon rod
as the anode, and ceramic cylinder as a diaphragm at 5±108C under the constant current conditions.

Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
2097
Scheme 2.
2,5-pyridinedicarboxylates (2a and 2c) were obtained from
the electroreduction of dimethyl 2,3- and 2,5-pyridinedicar-
boxylates (1a and 1c) in 83 and 77% yields, respectively. In
contrast to this result, dimethyl 1,4-dihydro 2,4-, 2,6- and
3,4-pyridinedicarboxylates (2b, 2d and 2e) were afforded
from the same reaction of dimethyl 2,4-, 2,6- and 3,4-pyri-
dinedicarboxylates (1b, 1d and 1e) in 67, 92 and 79%
yields, respectively. It may be interesting that the nitrogen
atoms of all the products (2a±e) were protonated. Pyridi-
nium salts such as N-methyl (1f) and N-benzyl pyridinium
salts (1g) ef®ciently underwent hydrogenation by electrore-
duction to give the corresponding 1,4-dihydro-products 2f
and 2g in 87 and 80% yields, respectively (Scheme 2).
Methyl nicotinate could not be hydrogenated because of
its more negative reduction potential. Among these
dihydro-products, 2b and 2c were very unstable at room
temperature, and were easily subjected to air-oxidation to
the original pyridine compounds.
Scheme 3.
and 1e were 21.98, 21.96 and 21.87 V (vs Ag/AgCl),
respectively, and their reversal oxidation peaks were negli-
gible. On the other hand, the reduction potentials of 1b and
1c indicated more positive values, that is, 21.71 and
21.60 V (vs Ag/AgCl), respectively, their oxidation peaks
being observed in part. These results show that the former
compounds are relatively dif®cult to reduce. Therefore, we
suggest that the electrogenerated radical anions abstract
protons very quickly from the medium methanol. Con-
versely, the latter compounds may give relatively stable
anionic species whose lifetime is suf®ciently long since
the corresponding oxidation peak can be observed on the
reverse cyclic voltammetric sweep.
Cyclic voltammogram of these pyridine compounds 1a±e
showed that they were readily accessible to usual electro-
reduction (Fig. 1). Thus, the reductive potentials of 1a, 1d
One of the plausible mechanism may be postulated for the
present hydrogenation of pyridinedicarboxylates 1 by
electroreduction, as shown in Scheme 3. Particularly, the
difference in regioselectivity of the hydrogenated position
of 2 depends on the position of the carboxylate groups in 1.
The ®rst electron transfer to the starting substrates 1
generates the corresponding radical anions 3, which can
be protonated at the 2-position (A-path) or the 4-position
(B-path) of the pyridine ring, followed by the second elec-
tron transfer affording the corresponding the hydrogenated
N-anion species 4a,c or 4b,d,e. Then, the ®nal products, 1,2-
and 1,4-dihydrogenated isomers, 2a,c and 2b,d,e, were
formed through the subsequent protonation to 4a,c and
4b,d,e, respectively.
The most important effect for regioselectivity in the hydro-
genation of 1 may be speculated to be the distribution of
anion or radical on the nitrogen atom and each of the carbon
atoms of the pyridine ring in radical anions (or dianions) 3
and N-anion species 4. Thus, for each of 3a±e, the structures
shown at the upper row of Scheme 4 would be more
important for protonation than those of the lower row, in
which anion or radical on the carbon atom possessing a
methoxycarbonyl group (E) and at the more remote position
from the nitrogen atom would be more stable. On the basis
of this hypothesis, 1,2-dihydro-isomers 2a,c and 1,4-di-
hydro-isomers 2b,e would be formed from those structures
according to the Scheme 4.
Since 1d showed rather negative reduction potential, both of
the radical anion 3d and the nitrogen anion species 4d are so
unstable, that the more stable product, 1,4-dihydro-isomer
Figure 1. Cyclic voltammogram of various pyridinedicarboxylic acid
derivatives.

2098
Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
Scheme 5.
electroreduction (Method B) and catalytic hydrogenation
(Method C), as shown in Table 3.
In Method A, 5a, prepared by usual N-acetylation of 2a in a
60% yield, was hydrogenated selectively in THF to give
dimethyl 1,2,3,4-tetrahydropyridine-2,3-dicarboxylates 6a
in a 81% yield. However, the reduction of 2d by Method
A yielded a mixture of tetra- and hexa-hydrogenated
products while Method B (electroreduction in a mixed
solvent of DMF/MeOHˆ9/1) for 2d afforded dimethyl
1,2,3,4-tetrahydropyridine-2,6-dicarboxylate 6d selectively
in a 43% yield.
Moreover, Method C (catalytic hydrogenation by Rh-C
catalyst) gave the corresponding tetrahydropyridines
among these three methods of all the dihydropyridines
5a,2d,e,g in a wide range of yields. Especially, the reduction
of the dihydropyridines 2e and 2g afforded the correspond-
ing tetrahydropyridine 6e and 6g quantitatively only by the
method C among these three methods.
Scheme 4.
2d, would be formed exclusively through thermodynamic
control between 4d and 4d0 as shown in Scheme 4.
2.2. Selective transformation to tetrahydropyridinedi-
carboxylates 615
Interestingly, the electroreduction of dimethyl pyridine-2,6-
dicarboxylate 1d gave different products depending upon
the reaction conditions. Thus, the reduction in methanol at
5±108C gave dihydropyridine 2d in a 92% yield. On the
other hand, electroreduction in DMF/MeOH (9/1) at
2408C resulted in direct formation of tetrahydropyridine
(44% yield), while that at 5±108C led to exclusive formation
of tarry products (Scheme 5).
As one of synthetic applications, some of dihydropyridines
5a,2d,e,g obtained were transformed selectively to the
corresponding tetrahydropyridines 6a,d,e,g by three kinds
of reduction methods, i.e. NaBH4 reduction (Method A),
Table 3. The synthesis of tetrahydropyridine by selective hydrogenation of
dihydropyridine
2.3. Stereo- and regioselective hydrosilylation of
dimethyl N-acetyl-1,2-dihydropyridine-2,3-dicarb-
oxylate(5a)
Substrate
Methoda
Tetrahydropyridine/%
5a
A
B
C
81 (cis/transˆ3/2)
Complex mixture
31 (cis/transˆ2/5)
Mixture
43
12
We have already reported that the Mg-promoted hydrosilyl-
ation of a,b-unsaturated esters such as ethyl cinnamate,
with trialkylchlorosilanes in DMF effects reductive cross-
coupling to give the corresponding b-silylated compounds
in good to excellent yields.16
2d
2e
A
B
C
A
B
C
No reaction
No reaction
98
It was found that when the reaction system was applied to
dihydropyridine 5a that has a conjugated diene skeleton,
tetrahydropyridines 7a±9a were obtained as the sole
products regio- and stereoselectively. As shown in Table
4, the yield of the silylated product 7a is dependent upon
reaction temperatures and the amounts of trialkylchloro-
silanes. Thus, the reaction at 5±108C gave better yield of
the product 7a than that at room temperature (Entries 1 and
2g
A
B
C
No reaction
No reaction
100
a
Method A: NaBH4, THF, room temperature. Method B: electroreduction
(Pt±C, divided cell, DMF/MeOHˆ9/1, Et4NOTs, NH4Cl, 2408C.
Method C: H2 (l atm), Rh-C, EtOH (AcOEt was used in the case of 2d).

Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
Table 4. Mg-promoted hydrosilylation of dihydropyridine 5a
2099
Entry
R1R2R3SiCl (equiv.)
Mg/equiv.
Temperature
Product (yield %)
1
2
3
4
5
6
Me3SiCl (10)
Me3SiCl (10)
Me3SiCl (7)
Me3SiCl (3)
EtMe2SiCl (10)
Et3SiCl (10)
5
5
3.5
1.5
5
rt
7a (35)
7a (64)
7a (40)
7a (23)
8a (51)
9a (32)
5±108C
5±108C
5±108C
5±108C
5±108C
5
at the 2-position possessing coordination of Me3SiCl with
the Mg21 cation to generate a more stable a-carbanion after
very fast or almost simultanous second electron transfer.
And it is considered that the product is ®nally formed by
subsequent protonation from the sterically less hindered
opposite side of the Mg21 ion (Scheme 7).
Scheme 6.
In conclusion, a new method for synthesis of dimethyl 1,2-
or 1,4-dihydropyridine-dicarboxylates has been success-
fully developed through electroreduction of dimethyl pyri-
dinedicarboxylates in this study. Particularly, 1,2-dihydro-
isomers have been ®rst synthesized by this electrochemical
method, which is characterized with good yield, convenient
procedure, mild conditions, high chemoselectivity and
speci®c regioselectivity depending on the position of the
carboxylate groups in the starting substrates. Furthermore,
the corresponding C-silylated tetrahydropyridines were
obtained by Mg-promoted regio- and stereoselective trans-
formation of the resultant 1,2-dihydro-derivative 5a.
2), and the yield of 7a increased with the increase in the
amount of trimethylchlorosilane (Entries 2±4). Use of ethyl-
dimethyl- and triethylchlorosilane instead of trimethyl-
chlorosilane under the similar reaction conditions gave the
analogous b-silylated tetrahydropyridines 8a, 9a as the sole
products but in decreased yields (Entries 5,6).
The stereochemistry of the 4-silylated product 7 was deter-
mined by 1H NMR spectrometry of the hydrogenated piperi-
dine 10, as shown in Scheme 6. The coupling constant
between H2 and H3 was 8.0 Hz and that between H3 and
H4 was 3.4 Hz. From these results, the stereochemistry of
H2±H3 and H3±H4 was determined to be trans and cis
conformation, respectively.17
3. Experimental
3.1. General
From the experimental results, the following reaction
mechanism may be proposed for the present Mg-promoted
regio- and stereoselective b-silylation of dihydropyridine
5a. The ®rst electron transfer from Mg-metal to dihydro-
pyridine 5a generated the anion radical coordinated with an
Mg21 cation from the sterically less hindered opposite side
of the carbomethoxy group at the 2-position. Subsequently,
electrophile attack of trimethylchlorosilane to the b-carbon
occurred from the opposite side of the carbomethoxy group
Methanol (MeOH) was distilled from Mg. N,N-Dimethyl-
formamide (DMF) was distilled from CaH2. Tetrahydro-
furan (THF) was distilled from LiAlH4 prior to use.
Unless otherwise mentioned, all the materials commercially
obtained were used without further puri®cation. Organic
extracts were dried over anhydrous MgSO4 and concen-
trated under reduced pressure on a rotary evaporator.
Flash chromatography was carried out using Merck 60
(Mesh 230±400) silica gel. Reactant and chromatography
fractions were analyzed using precoated silica gel 60 F254
plates (Merck). 1H NMR spectra at 400 MHz were
measured in the CDCl3 solutions. Chemical shifts are
expressed in ppm down®eld from internal tetramethylsilane
(0 ppm). The apparatus of cyclic voltammetry was
HABF501 (Hokuto Denko).
3.2. Cyclic voltammetry analysis
Cyclic voltammogram was measured in a beaker-type cell
equipped with Pt electrodes as the both electrodes, a refer-
ence electrode (Ag/AgCl) at room temperature. The solvent
was DMF containing 2 wt% Bu4NClO4 as a supporting
electrolyte. Sweep rate was 200 mV/s.
Scheme 7.

2100
Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
3.3. General procedure for the synthesis of dimethyl
dihydropyridinedicarboxylates 2a±2g
(2e).6 1H NMR (CDCl3, 400 MHz): d 3.68 (s, 3H), 3.71
(s, 3H), 7.27 (d, 1H, Jˆ4.8 Hz), 4.83 (dd, 1H, Jˆ4.8,
7.8 Hz), 6.08 (dd, 1H, Jˆ4.4, 7.8 Hz), 6.57 (bs, 1H), 7.35
(d, 1H, Jˆ5.8 Hz) ppm. 13C NMR (CDCl3): d 39.5, 51.1,
52.1, 97.0, 100.7, 125.4, 137.7, 168.2, 174.2, 207.1 ppm. IR
(nujol) 3330, 1730, 1660, 1510, 1440, 1235, 1100 cm21. MS
(EI) m/z 197 (M1, 3), 138 (100), 78 (83), 52 (62). Mp 82.0±
84.08C.
Electroreduction of pyridinedicarboxylic acid derivatives
(1a±g) (5 mmol) was carried out in methanol (40 ml)
containing Et4NOTs (2.0 g) as the supporting electrolyte
and NH4Cl (0.25 g) as the pH buffer at 5±108C under the
constant current conditions (current density; 15±20 mA/
cm2) using a divided cell equipped with a Pt plate
(12 cm2) as the cathode and a carbon rod as the anode,
and a ceramic cylinder as the diaphragm until 7 F/mol of
electricity passed through the reaction system. After the
electrolysis, the solution was poured into saturated aqueous
NaHCO3 and then the solution was extracted with AcOEt.
The organic layer was washed with H2O, saturated aqueous
NaCl, dried, ®ltered and evaporated to give the crude
products. Column chromatographic treatment of the
reaction mixture gave the dihydropyridine derivatives 2
exclusively as the almost sole products.
3.3.6. Dimethyl N-Methyl-1,4-dihydro-3,4-pyridinedi-
carboxylate (2f). H NMR (CDCl3,400 MHz): d 2.98 (s,
1
3H), 3.61 (s, 3H), 3.63 (s, 3H), 4.16 (d, 1H, Jˆ4.8 Hz),
4.81 (dd, 1H, Jˆ4.8, 8.0 Hz), 5.81 (dd, 1H, Jˆ1.6,
8.0 Hz), 7.14 (d, 1H, Jˆ1.6 Hz) ppm. 13C NMR (CDCl3):
d 38.9, 40.8, 50.9, 52.0, 96.6, 101.9, 130.0, 141.5, 167.7,
173.6 ppm. IR (neat) 2950, 1740, 1690, 1635, 1590, 1440,
1310, 1260, 1200, 700 cm21. MS (EI) m/z 211 (M1, 2), 152
(100), 92 (49). Anal. Calcd for C10H13NO4: C, 56.86; H,
6.20; N, 6.63. Found: C, 57.00; H, 6.01; N, 6.54.
3.3.7. Dimethyl N-benzyl-1,4-dihydro-3,4-pyridinedicar-
boxylate (2g). 1H NMR (CDCl3, 400 MHz): d 3.68 (s, 3H),
3.72 (s, 3H), 4.28 (d, 1H, Jˆ4.9 Hz), 4.40 (s, 2H), 4.92 (ddd,
1H, Jˆ1.5, 4.9, 7.8 Hz), 5.91 (dd, 1H, Jˆ1.5, 7.8 Hz), 7.34
(s, 1H), 7.21±7.38 (m, 5H) ppm. 13C NMR (CDCl3): d 39.7,
51.5, 52.5, 57.9, 97.9, 102.9, 127.3, 128.3, 129.3, 129.7,
136.9, 141.7, 168.2, 173.9 ppm. IR (nujol) 2950, 1740,
1700, 1680, 1600, 1210, 1170 cm21. MS (EI) m/z 287
(M1, 94), 91 (100), 65 (40). Anal. Calcd for C16H17NO4:
C, 66.89; H, 5.96; N, 4.88. Found: C, 66.92; H, 6.12; N,
4.68. Mp 68.0±68.98C.
3.3.1. Dimethyl 1,2-dihydro-2,3-pyridinedicarboxylate
(2a). H NMR (CDCl3, 400 MHz): d 3.69 (s, 3H), 3.78 (s,
1
3H), 5.03 (ddd, 1H, Jˆ1.5, 6.3, 6.4 Hz), 5.16 (d, 1H,
Jˆ3.4 Hz), 5.36 (m, 1H), 6.68 (dd, 1H, Jˆ5.8, 6.4 Hz),
7.19 (d, 1H, Jˆ6.3 Hz) ppm. 13C NMR (CDCl3): d 51.5,
51.6, 52.3, 95.8, 108.2, 135.3, 139.2, 166.6, 173.4 ppm. IR
(neat) 3320, 1730, 1455, 1440, 1250 cm21. MS (EI) m/z 197
(M1, 2), 166 (3), 138 (100), 78 (29). Anal. Calcd for
C9H11NO4: C, 54.82; H, 5.62; N, 7.10. Found: C, 54.76;
H, 5.49; N, 7.25.
3.3.2. Dimethyl 1,4-dihydro-2,4-pyridinedicarboxylate
(2b). H NMR (CDCl3, 400 MHz): d 3.73 (s, 3H), 3.80 (s,
1
3.4. The preparation of dimethyl N-acetyl-1,2-dihydro-
2,3-pyridinedicarboxylate (5a)
3H), 4.12 (dd, 1H, Jˆ3.6, 4.0 Hz), 4.51 (m, 1H), 5.63 (ddd,
1H, Jˆ2.0, 2.8, 4.0 Hz), 5.88 (bs, 1H), 6.20 (dd, 1H, Jˆ4.8,
8.0 Hz) ppm. 13C NMR (CDCl3): d 40.0, 52.2, 52.3, 93.8,
102.9, 127.1, 129.8, 163.4, 173.4 ppm. IR (neat) 3405,
2950, 1730, 1440, 1260, 1260 cm21. MS (EI) m/z 195
((M2H2)1, 2), 137 (100), 59 (35). 2b was not stable enough
to perform elemental analysis.
To a slurry of NaH (1.46 g, 60% oil suspension, 24.4 mmol,
washed twice with hexane) in DMF (20 ml) was added the
DMF (20 ml) solution of 2a 4.0 g: 20.3 mmol) at 2408C.
After 10 min, the solution of acetyl chloride (1.91 g:
24.4 mmol) was added and stirred for 1.5 h at 2408C. The
reaction mixture was poured into cold water and extracted
with Et2O. Organic layer was washed with H2O, saturated
aqueous NaCl, dried, ®ltered and evaporated to give crude
mixture. Recrystallization from a mixed solvent of hexane±
AcOEt gave 5a as a pale yellow crystal (yield 60%).
3.3.3. Dimethyl 1,2-dihydro-2,5-pyridinedicarboxylate
(2c). H NMR(CDCl3, 400 MHz): d 3.69 (s, 3H), 3.78 (s,
1
3H), 4.90 (ddd, 1H, Jˆ1.6, 2.0, 4.0 Hz), 5.26 (ddd, 1H, Jˆ
2.0, 4.0, 10.0 Hz), 5.53 (bs, 1H), 6.47 (ddd, 1H, Jˆ1.6, 2.0,
10.0 Hz), 7.48 (dd, 1H, Jˆ1.6, 6.4 Hz) ppm. 13C NMR
(CDCl3): d 50.4, 52.2, 54.1, 97.2, 108.0, 123.4, 143.0,
166.3, 171.5 ppm. IR (neat) 3375, 2950, 1730, 1680,
3.4.1. Dimethyl N-acetyl-1,2-dihydro-2,3-pyridinedicar-
boxylate (5a). 1H NMR (CDCl3,400 MHz): d 2.33 (s, 3H),
3.68 (s, 3H), 3.83 (s, 3H), 5.54 (dd, 1H, Jˆ5.9, 7.3 Hz), 6.41
(s, 1H), 6.96 (d, Jˆ7.3 Hz, 1H), 7.13 (d, 1H, Jˆ5.9 Hz)
ppm. 13C NMR (CDCl3): d 21.3, 50.9, 52.4, 53.1, 105.9,
119.3, 131.4, 132.2, 165.5, 169.6, 169.8 ppm. IR (nujol)
1640, 1440, 1290, 1110 cm21
. MS (EI) m/z 195
((M2H2)1, 1) 137 (100), 59 (29). 2c was not stable enough
to perform elemental analysis.
1740, 1705, 1690, 1550, 1440, 1320, 1300, 1230 cm21
.
3.3.4. Dimethyl 1,4-dihydro-2,6-pyridinedicarboxylate
(2d). 1H NMR (CDCl3, 400 MHz): d 3.20 (t, 2H, Jˆ
3.9 Hz), 3.80 (s, 3H), 5.48 (dt, 2H, Jˆ1.5, 3.9 Hz), 6.11
(broad s, 1H) ppm. 13C NMR (CDCl3): d 24.2, 52.0,
104.9, 130.5, 162.9 ppm. IR (nujol) 3320, 1730, 1455,
1440, 1250 cm21. MS (EI) m/z 196 ((M-H)1, 100), 136
(96), 105 (48), 78 (61). Anal. Calcd for C9H11NO4: C,
54.82; H, 5.62; N, 7.10. Found: C, 54.99; H, 5,80; N,
7.33. Mp 74.0±75.88C.
MS (EI) m/z 239 (M1, 1), 180 (30), 138 (100), 78 (94), 43
(86). Anal. Calcd for C11H13NO5: C, 55.23; H, 5.48; N, 5.86;
O, 33.44. Found: C, 55.32; H, 5.60; N, 5.62. Mp 80.5±
81.78C.
3.5. Reduction of dihydropyridines using NaBH4
(Method A)
To a solution of dihydropyridine (5 mmol) in THF (10 ml)
was added NaBH4 (0.152 g: 4 mmol), and stirred for 14 h at
3.3.5. Dimethyl 1,4-dihydro-3,4-pyridinedicarboxylate

Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
2101
room temperature. The reaction mixture was poured into
aqueous NH4Cl and extracted with AcOEt. The organic
layer was washed with H2O, saturated aqueous NaCl,
dried, ®ltered, evaporated to give the crude mixture. The
crude mixture was puri®ed by column chromatography
(hexane±AcOEt).
3375, 2950, 1730, 1670, 1615, 1440, 1350, 1180,
1100 cm21. MS (EI) m/z 199 (M1, 13), 140 (100), 80
(45). Anal. Calcd for C9H13NO4: C, 54.26; H, 6.58; N,
7.03. Found: C, 54.00; H, 6.83; N, 7.22.
3.7.4. Dimethyl N-benzyl-1,4,5,6-tetrahydro-3,4-pyridine-
dicarboxylate (6g). H NMR (CDCl3, 400 MHz): d 1.81
1
(ddt, 1H, Jˆ4.4, 5.6, 13.6 Hz), 2.07 (ddt, 1H, Jˆ3.2, 3.6,
13.6 Hz), 2.97 (ddd, 1H, Jˆ3.2, 4.4, 12.4 Hz), 3.18 (ddd,
1H, Jˆ3.2, 5.6, 12.4 Hz), 3.58 (dd, 1H, Jˆ3.6, 4.4 Hz), 3.68
(s, 3H), 3.69 (s, 3H), 4.41 (s, 2H), 7.21±7.38 (m, 5H), 7.67
(s, 1H) ppm. 13C NMR (CDCl3): d 24.0, 36.0, 42.3, 50.7,
52.0, 59.7, 92.4, 127.2, 127.8, 128.8, 136.4, 146.9, 168.2,
175.4 ppm. IR (neat) 2950, 1740, 1680, 1620, 1430, 1360,
1275, 1190, 1160 cm21. MS (EI) m/z 289 (M1, 11), 230
(92), 91 (100). Anal. Calcd for C16H19NO4: C, 66.42; H,
6.62; N, 4.84. Found: C, 66.49; H, 6.85; N, 4.99.
3.6. Electroreduction of dihydropyridines (Method B)
Electroreduction of dihydropyridine (5 mmol) was carried
out in a mixed solvent of DMF and MeOH (9/1) (40 ml)
containing Et4NOTs (2.0 g) as the supporting electrolyte
and NH4Cl (0.25 g) as the pH buffer at 5±108C under the
constant current conditions (current density; 17 mA/cm2)
using a divided cell equipped with a Pt plate (12 cm2) as
the cathode and a carbon rod as the anode, and a ceramic
cylinder as the diaphragm until 4 F/mol of electricity passed
through the reaction system. The procedure for work-up was
the same as that for the preparation of dihydropyridines. The
crude mixture was puri®ed by column chromatography
(hexane±AcOEt).
3.8. Direct preparation of 6d by electroreduction of 1d
The electrolysis conditions were almost the same as those
for Method B except temperature (2408C) and supplied
electricity (9 F/mol).
3.7. Catalytic hydrogenation of dihydropyridines
(Method C)
3.9. General procedure of the Mg-promoted hydro-
silylation of 5a
To a solution of dihydropyridine (1 mmol) in EtOH (40 ml)
was added 5%-Rh/C (10 mg) and stirred until the dihydro-
pyridine was consumed under the H2 atmosphere (1 atm) at
room temperature. The reaction solution was ®ltered
through Celite and evaporated to give the crude mixture.
The crude mixture was puri®ed by column chromatography
(hexane±AcOEt).
To a suspension of trialkylchlorosilane (25 mmol) and Mg
turning (0.3 g: 12.5 mmol) in DMF (10 ml) was added drop-
wise a solution of 5a (0.7 g: 2.5 mmol) in DMF (10 ml) at
58C, and stirring was continued until 5a was consumed
completely at 58C. The reaction mixture was poured into
saturated NaHCO3. Organic layer was extracted with AcOEt
and washed with H2O, saturated aqueous NaCl, dried,
®ltered and evaporated to give the crude products, which
was puri®ed by column chromatography (hexane±AcOEt).
3.7.1. Dimethyl N-acetyl-1,2,3,4-tetrahydro-2,3-pyridine-
dicarboxylate (6a). 1H NMR (CDCl3, 400 MHz): d 2.23 (s,
3H), 2.31 (m, 2H), 2.82 (ddd, 1H, Jˆ4.0, 8.8, 10.0 Hz), 3.65
(s, 3H), 3.75 (s, 3H), 4.99 (ddd, 1H, Jˆ3.6, 4.0, 8.4 Hz),
5.87 (d, 1H, Jˆ4.0 Hz), 6.60 (d, 1H, Jˆ8.4 Hz) ppm. 13C
NMR (CDCl3): d 21.3, 21.4, 39.9, 52.5, 52.6, 52.6, 106.4,
124.8, 168.1, 169.2, 171.3 ppm. IR (neat) 2950, 1745, 1680,
1650, 1420, 1380, 1220, 1015 cm21. MS (EI) m/z 241
(M1, 17), 140 (100), 80 (74). Anal. Calcd for C11H15NO5:
C, 54.77; H, 6.27; N, 5.81. Found: C, 54.90; H, 6.40; N,
5.70.
3.9.1.
N-Acetyl-4-trimethylsilyl-2,3-dicarbomethoxy-
1,2,3,4-tetrahydropyridine (7a). 1H NMR (CDCl3,
400 MHz): d 20.01 (s, 9H), 2.04 (bs, 1H), 2.18 (s, 3H),
3.18±3.21 (m, 1H), 3.64 (s, 3H), 3.66 (s, 3H), 4.95±4.99
(m, 1H), 5.36±5.37 (m, 1H), 6.54 (d, 1H, Jˆ8.3 Hz) ppm.
13C NMR (CDCl3): d 21.2, 21.1, 25.0, 42.6, 51.4, 52.0,
53.2, 108.6, 122.5, 167.9, 169.0, 170.4 ppm. IR (neat)
2950, 1750, 1680, 1650, 1380, 1250, 1220, 1020 cm21
.
3.7.2. Dimethyl 1,4,5,6-tetrahydro-2,6-pyridinedicar-
1
MS (EI) m/z 313 (M1, 3), 80 (73), 43 (100). Anal. Calcd
for C14H23NO5Si: C, 53.65; H, 7.40; N, 4.47. Found: C,
53.48; H, 7.53; N, 4.52.
boxylate (6d). H NMR (CDCl3, 400 MHz): d 1.93±1.96
(m, 1H), 2.11±2.15 (m, 1H), 2.21±2.27 (m, 2H), 3.75 (s,
3H), 3.78 (s, 3H), 3.92±3.93 (m, 1H), 4.41 (bs, 1H), 5.71 (t,
1H, Jˆ4.1 Hz) ppm. 13C NMR (CDCl3): d 21.4, 24.3, 52.3,
52.6, 53.7, 107.4, 133.0, 164.9, 173.5 ppm. IR (nujol) 3420,
2950, 1740, 1720, 1645, 1440, 1270, 1220 cm21. MS (EI)
m/z 199 (M1, 21), 140 (97), 108 (100), 80 (62), 53 (44).
Anal. Calcd for C9H13NO4: C, 54.26; H, 6.58; N, 7.03.
Found: C, 54.38; H, 6.65; N, 7.12. Mp 37.0±38.18C.
3.9.2. N-Acetyl-4-ethyldimethylsilyl-2,3-dicarbomethoxy-
1,2,3,4-tetrahydropyridine (8a). 1H NMR (CDCl3,
400 MHz): d 20.04 (s, 3H), 0.01 (s, 3H), 0.51±0.59 (m,
2H), 0.90±0.95 (m, 3H), 2.06±2.09 (m, 1H), 2.21 (s, 3H),
3.24 (dd, 1H, Jˆ4.8, 6.0 Hz), 3.67 (s, 3H), 3.68 (s, 3H), 4.99
(dd, 1H, Jˆ4.4, 8.4 Hz), 5.30 (d, 1H, Jˆ4.4 Hz), 6.57 (dd,
1H, Jˆ2.4, 8.4 Hz) ppm. 13C NMR (CDCl3): d 23.7, 23.6,
7.4, 7.5, 21.5, 24.1, 43.0, 51.7, 52.4, 54.1, 108.9, 123.1,
168.4, 169.4, 170.7 ppm. IR (neat) 2950, 1750, 1740,
1670, 1640, 1410, 1250, 1010 cm21. MS (EI) m/z 327
(M1, 18), 268 (34), 80 (80), 59 (100). Anal. Calcd for
C15H25NO5Si: C, 55.02; H, 7.70; N, 4.28. Found: C,
54.94; H, 7.60; N, 4.37.
3.7.3. Dimethyl 1,4,5,6-tetrahydro-3,4-pyridinedicar-
boxylate (6e). H NMR (CDCl3, 400 MHz): d 1.84 (dddd,
1
1H, Jˆ5.2, 5.6, 10.8, 13.6 Hz), 2.15 (ddd, 1H, Jˆ3.0, 6.8,
13.6 Hz), 3.19±3.28 (m, 2H), 3.59 (dd, 1H, Jˆ3.0, 5.6 Hz),
3.66 (s, 3H), 3.73 (s, 3H), 5.14 (bs, 1H), 7.60 (d, 1H,
Jˆ6.4 Hz) ppm. 13C NMR (CDCl3): d 23.6, 36.7, 37.6,
50.6, 51.9, 92.8, 143.93, 168.4, 175.7 ppm. IR (neat)

2102
Y. Kita et al. / Tetrahedron 57 (2001) 2095±2102
G. W., Gilchrist, T. L., Eds.; Elsevier: Oxford, 1998; pp 216±
N-Acetyl-4-triethylsilyl-2,3-dicarbomethoxy-
3.9.3.
1,2,3,4-tetrahydropyridine (9a). 1H NMR (CDCl3,
400 MHz): d 0.60 (q, 6H, Jˆ7.8 Hz), 0.96 (t, 9H, Jˆ
7.8 Hz), 2.03±2.06 (m, 1H), 2.21 (s, 3H), 3.26 (dd, 1H,
Jˆ4.9, 5.4 Hz), 3.65 (s, 3H), 3.70 (s, 3H), 4.81 (d, 1H,
Jˆ4.9 Hz), 5.03 (dd, 1H, Jˆ3.4, 7.8 Hz), 6.61 (dd, 1H,
Jˆ2.4, 7.8 Hz) ppm. 13C NMR (CDCl3): d 2.9, 7.6, 21.7,
21.9, 42.5, 51.7, 52.4, 56.5, 108.1, 124.3, 168.8, 169.3,
170.9 ppm. IR (neat) 2950, 2875, 1740, 1680, 1640, 1440,
1380, 1260, 1210, 1010 cm21. MS (EI) m/z 355 (M1, 25),
296 (49), 122 (53), 80 (96), 59 (100). Anal. Calcd for
C17H29NO5Si: C, 57.43; H, 8.22; N, 3.94. Found: C,
57.29; H, 8.12; N, 3.85.
250 (and others cited therein).
2. Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem. 1981, 20,
762.
3. Burnett, J. N.; Underwood, A. L. J. Org. Chem. 1965, 30,
1154.
4. Wenkert, E.; Dave, K. G.; Stevens, R. V. J. Am. Chem. Soc.
1968, 90, 6177.
5. Genisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993,
58, 2052.
6. Tietze, L. F.; Bergmann, A.; Bruggemann, K. Tetrahedron
Lett. 1983, 24, 3579.
7. Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1.
8. Eisner, U. J. Chem. Soc. D, Chem. Commun. 1969, 1348.
9. Booker, E.; Eisner, U. J. Chem. Soc., Perkin Trans. 1 1975,
929.
3.9.4.
N-Acetyl-2,3-dicarbomethoxy-4-trimethylsilyl-
1
piperidine (10). H NMR (CDCl3, 400 MHz): d 0.01 (s,
9H), 0.90±1.01 (m, 1H), 1.65±1.81 (m, 2H), 2.11 (s, 3H),
3.28 (dd, 1H, Jˆ3.4, 8.0 Hz), 3.67 (s, 3H), 3.68 (s, 3H),
3.70±3.80 (m, 2H), 4.88 (d, 1H, Jˆ8.0 Hz) ppm. 13C
NMR (CDCl3): d 22.90, 21.31, 21.42, 22.70, 40.99,
42.20, 51.65, 52.06, 56.85, 170.09, 170.58, 173.03 ppm.
10. Karilyus, I. V.; Murzatova, G. K.; Sokolskii, D. V. (AS KAZA
METAL Chem.), SU 657,026 (1979); Chem. Abstr. 1979, 91,
5121d.
11. Matoba, S. B. (Monomer Res. Dev.), SU 1,004,369 (1983);
Chem. Abstr. 1979, 99, 53607d.
IR (nujol) 2950, 1750, 1725, 1650, 1440, 1200, 840 cm21
.
12. Lund, H. Acta Chem. Scand. 1963, 17, 2325.
13. Ohno, T.; Ozaki, M.; Inagaki, A.; Hirashima, T.; Nishiguchi, I.
Tetrahedron Lett. 1993, 34, 2629.
MS (EI) m/z 315 (M1, 5), 272 (64), 256 (87), 73 (100). Anal.
Calcd for C14H25NO5Si: C, 53.31; H, 7.99; N, 4.44. Found:
C, 53.40; H, 7.67; N, 4.24. Mp 64.5±65.18C.
14. Kita, Y.; Maekawa, H.; Yamasaki, Y.; Nishiguchi, I.
Tetrahedron Lett. 1999, 40, 8587.
15. Other methods for preparation of tetrahydropyridine: (a)
Chrystal, E. J. T.; Couper, L.; Robins, D. J. Tetrahedron
1995, 51, 10241. (b) Genisson, Y.; Marazano, C.; Das, B. C.
J. Org. Chem. 1993, 58, 2052.
Acknowledgements
This work was supported by a Grant-in-Aid for Scienti®c
Research on Priority Area No. 10208205 from Ministry of
Education, Science, Sports and Culture, Japan.
16. Nishiguchi, I.; Kita, Y.; Sawada, M.; Ohno, T.; Ishino, Y.;
Maekawa, H.; Yamasaki, Y. (in press).
17. Silverstein, R. M.; Bassler, C. C.; Morrill, T. C. In Spectro-
metric Identi®cation of Organic Compounds, 5th ed., Wiley:
New York, 1991; pp 196±197.
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