Dithionite adducts of pyridinium salts: Regioselectivity of formation and mechanisms of decomposition

Article abstract of DOI:10.1016/j.tet.2005.07.096

¹H and ¹³C NMR spectroscopy has been used to detect and to characterize the adducts formed, in alkaline solutions, by the attack of dithionite anion on 3-carbamoyl or 3-cyano substituted pyridinium salts. In all studied cases, only 1,4-dihydropyridine-4-sulfinates, formed by attack of dithionite oxyanion on the carbon 4 of pyridinium ring, were found. This absolute regioselectivity seems to suggest a very specific interaction between the pyridinium cation and the dithionite through the formation of a rigidly oriented ion pair, determining the position of attack. In weak alkaline solution, the adducts decompose according to two mechanisms S_Ni and S_Ni′: the S_Ni path is operative in all studied cases and preserves the 1,4-dihydro structure yielding the corresponding 1,4-dihydropyridines, whereas the S_Ni′ path involves the shift of 2,3 or 5,6 double bonds yielding 1,2- or 1,6-dihydropyridines, respectively. The formation of 1,2- or 1,6-dihydropyridines, in addition to 1,4-dihydro isomers, depends on their respective thermodynamic stabilities.

Full text of DOI:10.1016/j.tet.2005.07.096

Tetrahedron 61 (2005) 10331–10337
Dithionite adducts of pyridinium salts: regioselectivity of
formation and mechanisms of decomposition
*
Vincenzo Carelli, Felice Liberatore, Luigi Scipione, Barbara Di Rienzo and Silvano Tortorella
`
Department of ‘Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive’, Universita ‘La Sapienza’, Piazzale Aldo Moro, 5,
00185 Rome, Italy
Received 27 April 2005; revised 12 July 2005; accepted 28 July 2005
Available online 13 September 2005
Abstract—1H and 13C NMR spectroscopy has been used to detect and to characterize the adducts formed, in alkaline solutions, by the attack
of dithionite anion on 3-carbamoyl or 3-cyano substituted pyridinium salts. In all studied cases, only 1,4-dihydropyridine-4-sulfinates,
formed by attack of dithionite oxyanion on the carbon 4 of pyridinium ring, were found. This absolute regioselectivity seems to suggest a
very specific interaction between the pyridinium cation and the dithionite through the formation of a rigidly oriented ion pair, determining the
position of attack. In weak alkaline solution, the adducts decompose according to two mechanisms SNi and SNi0: the SNi path is operative in
all studied cases and preserves the 1,4-dihydro structure yielding the corresponding 1,4-dihydropyridines, whereas the SNi0 path involves the
shift of 2,3 or 5,6 double bonds yielding 1,2- or 1,6-dihydropyridines, respectively. The formation of 1,2- or 1,6-dihydropyridines, in addition
to 1,4-dihydro isomers, depends on their respective thermodynamic stabilities.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
occur according to an intramolecular hydrogen transfer
mechanism associated with sulfur dioxide evolution,
leading to the formation of 1,4-dihydropyridines with high
regioselectivity.
Sodium dithionite reduction has been largely applied to
pyridinium salts bearing, in the 3- or 3,5-positions, electron-
withdrawing groups such as –CN, –CONH2, –COOR, and
chiefly affords the corresponding 1,4-dihydropyridines.1–7
Thermodynamic factors accounted for this high regioselec-
tivity, since theoretical studies such as, for example, the
calculation of the heats of formation using AM1 molecular
orbital methods,8a,b demonstrated the greater thermodyn-
amic stability of the 1,4-dihydropyridines in comparison
with the isomeric 1,2- and 1,6-dihydroderivatives.9 Inter-
mediate adducts, identified by some authors1,5,7 as sulfinate
anions (Scheme 1, A), are found in the dithionite reduction.
These adducts are stable at alkaline pH, while in neutral or
weakly alkaline medium they undergo fast protonation and
conversion to 1,4-dihydropyridines.
However, it has been reported7 that in the dithionite
reduction of some 4- and 4,6-methyl substituted N-Benzyl
and N-(2,6-dichlorobenzyl)-nicotinamide salts, 1,2- and
1,6-dihydropyridines were formed in addition to the
isomeric 1,4-dihydro derivatives.
During our studies on the dithionite reduction of pyridinium
salts, in some instances we also noticed the presence of
variable amounts of 1,2- or 1,6-dihydropyridines besides the
predominant 1,4-dihydropyridines.
These findings led us to perform a careful examination of
the dithionite reduction of a significant number of
pyridinium salts in order to ascertain: (a) if the formation
In a recent work10 we have shown, in accordance with H,
1
13C and 17O NMR spectroscopic evidence, that dithionite
adducts are S-anions of esters of sulfinic acid (Scheme 1, B),
originated by attack of the dithionite oxyanion at the carbon
4 of the pyridinium salts. We have also proposed that the
decomposition of these esters, after protonation, may
Keywords: Pyridinium salts; Dithionite adducts; Adduct decomposition;
SNi and SNi0 mechanisms; Dihydropyridines.
*
Corresponding author. Tel.: C39 649913226; fax: C39 649913888;
e-mail: vincenzo.carelli@uniroma1.it
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.096

10332
V. Carelli et al. / Tetrahedron 61 (2005) 10331–10337
of 1,2- and 1,6 -dihydropyridines, in addition to the 1,
4-dihydroderivatives, is a common occurrence and the
extent of the phenomenon; (b) if the formation of 1,2- or 1,
6-dihydropyridines follows the decomposition of corre-
sponding dithionite adducts at position 2 or 6 of the
dihydropyridine system.
position of attack of the dithionite on the pyridinium cation
and in all the reactions studied have allowed us to establish,
beyond doubt, that the unique intermediate adduct present
was the sulfinic ester (S-anion) formed by attack of the
dithionite oxyanion at carbon 4 of the pyridinium salt. The
formation of this sole adduct was always observed even
when the final reduction products were, besides the 1,4-
dihydropyridines, also the isomeric 1,2- or 1,6-dihydro
derivatives.
2. Results and discussion
Several pyridinium salts (1a–m, Scheme 2) have been used
as model compounds for the present study.
Similar examples of absolute regioselectivity in the reaction
of a nucleophile with a pyridinium salt were previously
reported and concerned the exclusive attack of nitroalkane
carbanions at the 4 position of the pyridinium rings.11
The results of an accurate 1H NMR analysis (Tables 1 and 5)
performed directly on the chloroform extracts obtained from
dithionite reduction of salts 1a–m, were compared with the
1H NMR data of known dihydroderivatives reported in the
literature. In this way, it was possible to ascertain that the
reduction sometimes led to a 1,4-dihydropyridine as unique
product, in other cases to mixtures of 1,4- and 1,2- or 1,4-
and 1,6-dihydropyridines. When not previously known, the
dihydroderivatives obtained, such as the 1,4-dihydropyri-
dines 3h,i,l and the 1,2-dihydropyridines 4h,i, were
unambiguously identified and their relative abundances
determined by means of HPLC, 1H and 13C NMR analyses
(Tables 1 and 2).
As we have already reported,10 carbons 4 of the dithionite
adducts are strongly deshielded with respect to the carbons
in the 4 position of the corresponding 1,4-dihydropyridines.
Indeed, the chemical shifts of carbons in the 4 position in
adducts 2a,b,c,d,h–m (Scheme 2, Table 4) are all comprised
in the 62–68 ppm range, and display, in comparison with the
chemical shifts of 4-position carbons in corresponding 1,4-
dihydropyridines (Table 2, Ref. 12–14), a downfield shift
effect variable from ca. 32 to 46 ppm. Such a downfield shift
suggests that carbon atoms are directly bonded to an oxygen
atom. Indeed, the downfield effect of an oxygen atom on the
13C chemical shift of the carbon to which is bonded, ranges
in alkane and cycloalkanes from 49 to 42 ppm ca.,
respectively.15,16
The structure of the dithionite adducts 2a–m has been
1
determined from the H and 13C NMR analyses, directly
carried out on the reduction mixtures (Tables 3 and 4). In
order to prevent a possible decomposition of the adducts
even in strongly alkaline medium, a particular procedure has
been adopted for the preparation of the samples before their
submission to NMR analyses (see Section 3). As stressed
previously by us,10 1H and 13C NMR spectroscopies
represent highly diagnostic techniques for identifying the
Similarly, the H4 in the adducts are significantly deshielded
as well (downfield shift 0.5–0.8 ppm, Table 3) with respect
to H4 in the corresponding 1,4-dihydropyridines (Table 5).
The presence of adducts deriving from the dithionite attack
to carbons 2 or 6 of the pyridinium ions would give rise in
Scheme 2.

V. Carelli et al. / Tetrahedron 61 (2005) 10331–10337
Table 1. H NMR chemical shifts of the 1,2-dihydropyridines 4h,i and 1,6-dihydropyridines 5a–f
10333
1
H2
H4
H5
H6
N–CH3
2.86s
N–CH2
4-CH3
1.59s
6-CH3
1.95s
J2,4
J2,5
J4,5
J4,6
J5,6
4ha
3.92
2Hs
4.73s
4ia, b
5aa
3.99
2Hs
6.68dd
4.93s
4.51s
2.00s
2.08s
5.79m
5.80m
6.13m
6.09m
5.01m
5.00m
4.99dt
4.94dt
4.11
2Hdd
4.03
2Hdd
4.03
2.80s
2.84s
1.2
1.6
0.8
0.8
10.0
10.0
10.0
9.8
1.6
1.6
1.6
1.6
3.2
3.2
3.2
3.2
5ba, b
5ca
6.86dd
4.15s
4.16s
7.08s
2Hdd
3.93
5da, b
1.2
0.8
c
2Hdd
3.85m
3.93d
5eb, d, e
5fb, d, f
7.16d
7.17s
4.74m
4.74m
4.20s
4.49s
1.98s
1.96s
5.0
4.5
a CDCl3.
b Aromatic proton signals are in the range 7.20–7.50 ppm.
c Overlapped with aromatic signals.
d DMSO-d6.
e CONH2 5.46s, J2,6Z1.5.
f
CONH2 5.20s.
Table 2. 13C NMR chemical shifts of the 1,4-dihydropyridines 3h–m and 1,2-dihydropyridines 4h,i
C2
C3
C4
C5
C6
N–CH3
38.6q
N–CH2
4-CH3
6-CH3
CN
CONH2
3ha
145.4d
144.1d
139.4d
136.1d
52.3d
82.1s
80.7s
102.4s
104.3s
80.6s
80.2s
30.4s
30.1s
26.2s
27.0s
151.2s
151.1s
105.4d
105.2d
105.3d
107.6d
100.2d
100.9d
133.4s
140.9s
138.3s
135.4s
153.6s
152.4s
20.6q
20.3q
20.0q
18.3q
20.6q
20.1q
20.6q
20.3q
20.0q
24.6q
20.6q
20.1q
123.1s
121.2s
3ia,b
3lb,c
3mb,c
4ha
53.6t
52.6t
47.8t
169.1s
168.8s
38.1q
121.3s
121.5s
4ia,b
47.3d
52.9t
13C NMR spectra were obtained with Gate decoupled pulse sequence.
a CDCl3.
b Aromatic carbon signals are in the range 125–140 ppm.
c DMSO-d6.
1
Table 3. H NMR chemical shifts of the adducts 2a–m
H2
H4
H5
H6
N–CH3
N–CH2
4-CH3
6-CH3
J2,6
J4,5
J5,6
Ha
Hb
2aa
7.08s
7.16d
3.68d
3.59d
3.98d
3.85 br s 4.75m
—
—
3.99d
—
—
—
—
4.92dd
4.90dd
4.93dd
6.22d
6.23dd
6.27d
6.05d
6.19dd
6.26d
—
3.07s
—
3.08s
—
—
—
—
3.15s
—
—
—
4.42s
—
4.39s
4.40s
4.70s
4.49s
—
—
—
—
—
1.30s
1.35s
—
1.30s
1.43s
1.41s
1.34s
—
—
—
—
—
—
1.66s
1.90s
1.91s
2.65s
2.73s
—
1.1
—
—
1.6
—
—
5.7
5.3
5.6
e
7.6
8.1
7.7
e
2bb, c
2ca
d
2da, c
2eb, c
2fb, c
2gb, c
2hb
d
7.18d
7.24s
7.02s
7.15s
7.23s
7.21s
6.87s
4.49d
4.46d
4.53d
4.49s
4.56s
4.37s
4.38s
—
—
5.4
—
—
—
—
7.9
7.9
—
—
—
—
—
2ib, c
2lb, c
2mb, c
—
—
—
4.70s
—
—
—
4.59df
4.66d
g
a D2O.
b D2O/DMSO-d6 1:1.
c Aromatic proton signals are in the range 7.30–7.50 ppm.
d Exchange with D2O.
e Broad signals.
f
Ja,b 17.0 Hz.
g Obscured by D2O signal.
the 13C NMR spectrum to signals in the 85–95 ppm range,
with an analogous substituent downfield shift effect of ca.
30–45 ppm in comparison with the chemical shifts of
carbon 2 or 6 of the corresponding 1,2- or 1,6-
dihydropyridines.
Therefore, on the whole, the 1H and 13C NMR spectroscopic
data clearly demonstrate the 1,4-dihydropyridine structure
of the dithionite adducts.
The above findings leave some questions open: (a) how can
it be explained the absolute regioselectivity of the dithionite
attack, which, in all cases examined, leads to the formation
of only 1,4-dihydro-4-pyridine sulfinates; (b) how can the
In all cases examined no signals were ever observed in 85–
95 ppm range of the 13C NMR spectra.

10334
V. Carelli et al. / Tetrahedron 61 (2005) 10331–10337
Table 4. 13C NMR chemical shifts of the adducts 2a,c,d,h–m
C2
C3
C4
C5
C6
CN
CONH2
N–CH2
N–CH3
43.2q
d
2aa
149.5d
145.4d
146.0d
143.9d
148.0d
150.3d
144.3d
142.8d
74.6s
72.9s
96.9s
99.6s
80.5s
82.2s
108.1s
105.6s
66.7d
64.1d
65.9d
68.5d
62.3s
61.6s
64.2s
64.6s
100.3d
98.0d
99.4d
101.2d
103.2d
105.1d
109.2d
107.8d
135.0d
129.5d
133.9d
134.1d
138.1s
139.2s
136.5s
142.3s
125.8s
120.2s
2bb, c
2cb
54.1t
59.5t
174.2s
175.4s
2da, c
2hb, c, e
2ib, c, e
2lb, c, e
2mb, c, e
d
123.0s
121.0s
54.5t
62.8t
49.3t
168.7s
173.5s
13C NMR spectra were obtained with Gated decoupled pulse sequence.
a D2O.
b D2O/ DMSO-d6 1:1.
c Aromatic carbon signals are in the range 128–137 ppm.
d Obscured by solvent signal (DMSO-d6).
e The incomplete H/D exchange in 4 and 6-CH3 gives rise to broad peaks at about 20 ppm.
Table 5. 1H NMR chemicals shift of the 1,4-dihydropyridines 3a–m
H2
H4
H5
H6
N–
CH3
N–CH2
Ha Hb
4-CH3 6-CH3 J2,4
J2,6
J4,5
J4,6
J5,6
Ja,b
JCH ,
3
H4
3aa
6.
54dd
6.
41dd
6.83d
3.12
2Hdd
3.08
2H dd
3.03
2H dd
3.12
2H dd
4.66m 5.70m 2.90s
4.63m 5.61m
0.6
0.8
1.6
1.6
1.2
1.6
1.5
1.5
3.6
3.2
3.2
3.4
5.0
5.0
3.2
1.6
1.6
1.5
1.6
8.20
8.0
8.0
8.0
8.0
7.7
3ba, b
3ca
4.24s
4.69m 5.73m 2.88s
4.71m 5.70m
3da, b
3ea, b
3fb, c
3gb, c
7.11d
7.18d
7.29
4.24s
4.36s
4.77s
4.47s
3.28m 4.
85dd
3.30m 4.
79dd
4.57m
5.
1.13d
1.03d
6.5
6.0
80dd
6.
05dd
7.15s
3.21
1.
2Hm
71md
1.80s
1.75s
1.70s
1.92s
3ha
6.48s
6.85s
7.08s
3.22m 4.42m
3.27m 4.91d
3.25m 4.52d
3.13m 4.54d
2.98s
1.18d
1.23d
0.98d
0.82d
3.2
5.1
5.1
5.1
6.3
3ia, b
3la, b
4.79d
4.54d
4.69d
4.83d
4.58d
4.78d
16.9
16.7
14.34
3mb, c 6.66s
a CDCl3.
b Aromatic proton signals are in the range 7.20–7.60 ppm.
c DMSO-d6.
d JCH ,H5Z2.8.
3
decomposition of a unique adduct also lead to the formation
of 1,2- or 1,6-dihydropyridines, together with the isomeric
1,4-dihydroderivatives.
The collapse of the ion pair (Fig. 1) would then give rise
to the formation of the C4-sulfinate bound with elimination
of SO2.
In our opinion, the absolute regioselectivity of the reaction
between dithionite and pyridinium salts seems to suggest the
idea of a particular orientation of the two reagents
determining the position of attack. A very specific
interaction between the reagents through the formation of
a rigidly oriented ion pair (Fig. 1), before the nucleophilic
dithionite attacks the electrophilic carbon 4, may be
supposed.
An answer to the second question may be given bearing in
mind the analogy existing between the decomposition of the
dithionite adducts of the pyridinium salts and that of the
allyl chlorosulfinates resulting from the reaction of allyl
alcohols with thionyl chloride. Indeed, it is well known that
two mechanisms, SNi18,19 or SNi0,20 may be operative in
In this connection, it should be born in mind that, as shown
by the X-ray structure of the dithionite anion,17 the distance
between the two nucleophilic centres located on the two
˚
oxygen atoms measures 2.868 A, which is structurally
consistent with the occurrence of a strong interaction with
both the ring NC cation and the C4 electrophilic site
˚
(calculated distance ca. 2.87 A) but not with the analogous
C
pairs C2-ring N (1.51 A) or C6-ring N (1.51 A).
C
˚
˚
Figure 1.

V. Carelli et al. / Tetrahedron 61 (2005) 10331–10337
10335
Table 6. Calculated heats of formation of all the dihydroderivatives, which could theoretically form in the dithionite reduction of salts 1a–m; the table also lists
the dihydropyridines actually formed and their relative abundances
Sale
1,2-DHP
DHf (Kcal/mol)
1,4-DHP
DHf (Kcal/mol)
1,6-DHP
DHf (Kcal/mol)
1a
1b
1c
1d
1e
1f
1g
1h
1i
4a —
4b —
4c —
4d —
4e —
4f —
4g —
4h 70%
4i 48%
4l
64.061
91.137
K5.022
21.960
16.026
6.558
17.200
50.947
79.869
9.583
3a 92%
3b 94%
3c 82%
3d 95%
3e 90%
3f 50%
3g 100%
3h 30%
3i 52%
60.781
87.770
K7.914
19.412
15.973
5.726
14.225
51.309
79.782
8.778
5a 8%
5b 6%
5c 18%
5d 5%
5e 10%
5f 50%
5g —
5h —
5i —
5l —
5m —
63.011
90.466
K5.829
21.426
16.345
5.708
18.560
52.587
80.513
11.634
1.176
1l
1m
3l 100%
3m 100%
4m
2.031
0.432
such decompositions: the SNi mechanism leads to the
preservation of the structure by the simple substitution of
the sulfinate group with the chlorine atom, while the SNi0
mechanism involves a structural rearrangement with
migration of the double bond and shift of the chlorine
atom to the carbon g from the original position of the
sulfinate. In both cases SO2 is eliminated.
uncorrected. IR spectra were registered with a Perkin Elmer
mod. 281 spectrophotometer. 1H and 13C NMR were taken
with a Bruker AVANCE 400 spectrometer, data were
elaborated by using the WINNMR Bruker Daltonik GmbH,
version 6.1.0.0 software. Chemical shifts are reported as
ppm (d) from TMS as internal standard when the solvent
was DMSO-d6 or CDCl3 and from the D2O signals (dZ
4.78 ppm) for D2O solutions. Coupling constants are given
in Hz. The HPLC analyses were performed with a Perkin
Elmer Series 200 liquid chromatograph equipped with a
Perkin Elmer series 200 diode array detector, HPLC data
were elaborated by using TURBOCHROM NAVIGATOR,
version 6.1.2.0.1 software. Preparative HPLC were per-
formed on a Perkin Elmer series 3 apparatus equipped with a
spectophotometric UV–vis Perkin Elmer LC55B detector
and an analogic HP3390A integrator.
Path SNi R-CH]CH–CH2–OSOCl/R-CH]CH–CH2–
ClCSO2
Path SNi0 R-CH]CH–CH2–OSOCl/R-CH(Cl)–CH]
CH2CSO2
Analogously, the decomposition of the 1,4-dihydropyridine-
4-sulfinates 0may proceed according to the two mechanisms
SNi or SNi . In the first case, intramolecular hydrogen
transfer occurs from the sulfinic SH group to the adjacent
carbon atom 4 with SO2 elimination and preservation of the
1,4-dihydropyridine structure, while the decomposition
according to SNi0 mechanism involves instead an intra-
molecular hydrogen transfer to atoms 2 or 6 with ensuing
shift of the 2,3 or 5,6 double bonds to positions 3,4 or 4,5,
respectively, and SO2 elimination (Scheme 2). Thus, the
possibility for the dithionite adducts of decomposing
according to these mechanisms, may provide, in our
opinion, a convincing explanation for the formation of all
the three possible dihydroderivatives starting from an
unique intermediate adduct. 0 The occurrence of the
decomposition mechanism SNi , which leads to 1,2- or
1,6-dihydropyridines, besides mechanism SNi, which
affords 1,4-dihydropyridines, depends on the respective
thermodynamic stability of the dihydroderivatives.
The column used were HPLC Lab Service Analytic
Hypersil 5-NH2 250/4.6 mm (5 mm) for the analytical
determinations and 250/10 mm (5 mm) for the preparative
determinations.
Formation enthalpies were calculated by AM1 molecular
orbital methods8a,b making use of the Hyperchem version
7.0 software. Structure were minimised by using a Fletcher-
Reeves algorithm with a convergence limit of 0.1 kcal/mol.
3.2. Pyridinium salts
3-Cyano-1-methylpyridinium iodide 1a,21 1-benzyl-3-cyano-
pyridinium bromide 1b,22 3-carbamoyl-1-methylpyridinium
iodide 1c,23 1-benzyl-3-carbamoylpyridinium bromide 1d,24
1-benzyl-3-carbamoyl-4-metylpyridinium bromide 1e,25
3-carbamoyl-1-(2,6-dichlorobenzyl)-4-methylpyridinium
bromide 1f,7 1-benzyl-3-carbamoyl-6-metylpyridinium
bromide 1g26 and 3-carbamoyl-1-(2,6-dichlorobenzyl)-4,6-
dimethylpyridinium bromide 1m,7 were prepared according
to literature procedures and displayed the expected NMR
properties.
As may be seen from Table 6, in which the formation heats
of dihydropyridines, calculated according to the AM1
molecular orbital methods,8a,b are summarized, 1,2- or
1,6-dihydropyridines are produced when their relative heats
of formation are lower or very close to those of the
corresponding 1,4-dihydro derivatives.
3.3. General procedures for the preparation of
pyridinium salts 1h–l
3. Experimental
3.1. Materials and methods
To
a
solution of 3-cyano-4,6-dimethylpyridine27
(10.0 mmol) or 3-carbamoyl-4,6-dimetylpyridine27
(10.0 mmol) in 20 ml of warm acetonitrile, 14.0 mmol of
methyl iodide or 10.0 mmol of benzyl bromide was added
and the mixture was refluxed for 12 h. To the cold solution,
Chemical reagents and solvents were purchased from
Aldrich Chemical Co. and were of analytical grade. Melting
points were determined with a Tottoli apparatus and are

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V. Carelli et al. / Tetrahedron 61 (2005) 10331–10337
Et2O (50 ml) was then added: the precipitate was collected,
washed with Et2O and recrystallised from methanol.
3.5. Dithionite reduction of pyridinium salts 1h–l,
identification of the dihydro derivatives obtained and
determination of their relative abundances
3.3.1. 3-Cyano-1,4,6-trimethylpyridinium iodide 1h.
3.5.1. Reduction of salt 1h. To a solution of NaHCO3
(400 mg) and Na2S2O4 (300 mg) in 40 ml of H2O, 50 ml of
CHCl3 were added at 4–5 8C under argon flow and strong
stirring, followed by addition of 150 mg of salt 1h. After 3 h
the chloroform layer was separated and the aqueous phase
repeatedly extracted with CHCl3 (4!20 ml). The combined
organic extracts, after drying over Na2SO4, were brought to
dryness and the residue was submitted to HPLC analysis
employing a 90:10 hexane/CH2Cl2C2% MeOH mixture
(flow 1 ml/min): the elution profile showed two major
peaks. A preparative HPLC carried out on 20 mg of residue,
adopting the same eluent (flow 5 ml/min), led to the
separation of two fractions having retention time of 7.5
and 8.9 min, respectively, the purity, of which was
determined as better than 97%. Both fractions were
examined by 1H and 13C NMR and unambiguously
identified. The first fraction (tRZ7–5 min) consisted of
3-cyano-1,4,6-trimethyl-1,2-dihydropyridine 4h (Tables 1
and 2), while the second fraction (tRZ8.9 min) was
identified as 3-cyano-1,4,6-trimethyl-1,4-dihydropyridine
3h (Tables 5 and 2).
Yield 70%, mp 228–9 8C; IR (nujol) cmK1: 3175, 2245,
1650; H NMR (DMSO-d6), d: 2.71 (3H, s, 4-CH3), 3.31
1
(3H, s, 6-CH3), 4.20 (3H, s, N-CH3), 8.19 (1H, s, H5), 9.60
(1H, s, H2). Anal. Calcd for C9 H11 N2 I: C, 39.44; H, 4.05;
N, 10.22. Found: C, 39.75; H, 3.86; N, 10.01.
3.3.2. 1-Benzyl-3-cyano-4,6-dimethylpyridinium bro-
mide 1i. Yield 75%; mp 252–4 8C; IR (nujol) cmK1
:
1
3180, 2245, 1650; H NMR (DMSO-d6) d: 2.74 (3H, s,
4-CH3), 3.32 (3H, s, 6-CH3), 5.92 (2H, s, N-CH2), 7.30-7.45
(5H, m, Ar), 8.25 (1H, s, H5), 9.85 (1H, s, H2). Anal. Calcd
for C15 H15 N2 Br: C, 59.42; H, 4.99; N, 9.24. Found: C,
59.69; H, 5.10; N, 8.97.
3.3.3. 1-Benzyl-3-carbamoyl-4,6-dimethylpyridinium
:
bromide 1l. Yield 95%; mp 225–7 8C; IR (nujol) cmK1
1
3200, 3030, 1690; H NMR (DMSO-d6) d: 2.63 (3H, s,
4-CH3), 2.67 (3H, s, 6-CH3), 5.92 (2H, s, N–CH2), 7.32-7.45
(5H, m, Ar), 8.43 (1H, s, H5), 9.30 (1H, s, H2). Anal. Calcd
for C15 H17 N2 O Br: C, 56.09; H, 5.33; N, 8.72. Found: C,
55.87; H, 5.65; N, 8.55.
Anal. Calcd for C9 H12 N2: C, 72.94; H, 8.16; N, 18.90.
Compound 3h. Found: C, 72.73; H, 7.87; N, 18.68.
Compound 4h. Found: C, 73.41; H, 7.92; N, 18.53.
3.4. General procedure for the dithionite reduction of
pyridinium salts 1a–g,m
To a stirred solution of NaHCO3 (2.5 mmol) and Na2S2O4
(2.5 mmol) in H2O (30 ml), chloroform (30 ml) and then
slowly 0.5 mmol of the pyridinium salt were added at
4–5 8C and under argon flow. After 3 h, the organic phase
was separated from the aqueous one, which was repeatedly
extracted with chloroform (4!20 ml). The combined
chloroform extracts were dried over anhydrous Na2SO4
and analyzed by 1H NMR spectroscopy.
The relative abundance of dihydropyridines 3h and 4h,
determined by 1H NMR analysis of the crude CHCl3 extract
obtained directly from the reduction, resulted to be 30% and
70%, respectively (Table 6).
3.5.2. Reduction of salt 1i. From the reduction of 1i carried
out in the same conditions described above for 1h, a crude
residue was obtained, which, submitted to HPLC analysis
(eluent: 90:10 hexane/CH2Cl2C2% MeOH, flow 1 ml/min)
gave an elution profile characterized from two major peaks.
A preparative HPLC carried out on 25 mg of residue using
the same elution system (flow 5 ml/min), led to the
separation of two fractions having retention times of 6.5
and 7.6 min, respectively, with an analytically controlled
purity degree higher than 97%. Both fractions were
The spectral parameters listed in Tables 1 and 5, compared
with the H NMR data reported in literature, allowed to
1
identify the dihydropyridine or the dihydropyridine mixture
formed in every reduction run and to determine their relative
abundances (Table 6).
The pyridinium salts 1a–g,m were reduced according to the
general procedure described above giving rise to the
dihydropyridines listed below in the relative abundances
near indicated:
1
examined by H and 13C NMR. The first fraction (tRZ
6.5 min) consisted of 1-benzyl-3-cyano-4,6-dimethyl-1,2-
dihydropyridine 4i (Tables 1 and 2), while the second
fraction (tRZ7.6 min) was identified as the 1-benzyl-3-
cyano-4,6-dimethyl-1,4-dihydropyridine 3i (Tables 5 and 2).
Salt 1a gave the 1,4-dihydropyridine 3a12 92% and the
1,6-dihydropyridine 5a12 8%. Salt 1b afforded the 1,4-
dihydropyridine 3b22 94% and the 1,6-dihydropyridine 5b28
6%. Salt 1c yielded the 1,4-dihydropyridine 3c13 82% and
the 1,6-dihydropyridine 5c29 18%. Salt 1d gave the 1,4-
dihydropyridine 3d25 95% and the 1,6-dihydropyridine 5d25
5%. Salt 1e afforded the 1,4-dihydropyridine 3e30 90% and
the 1,6-dihydropyridine 5e30 10%. Salt 1f yielded the 1,4-
dihydropyridine 3f7 50% and the 1,6-dihydropyridine 5f7
50%. Salt 1g gave as unique product the 1,4-dihydropyri-
dine 3g.26 Salt 1m afforded as unique product the 1,4-
dihydropyridine 3m.7
Anal. Calcd for C15 H16 N2: C, 80.32; H, 7.19; N, 12.49.
Compound 3i. Found: C, 80.63; H, 6.97; N, 12.25.
Compound 4i. Found: C, 80.06; H, 7.02; N, 12.18.
The relative abundance of dihydropyridines 3i and 4i,
determined by 1H NMR analysis of the crude CHCl3 extract
obtained directly from the reduction, resulted to be 30% and
48%, respectively (Table 6).

V. Carelli et al. / Tetrahedron 61 (2005) 10331–10337
10337
4. Kosower, E. M.; Bauer, S. J. Am. Chem. Soc. 1960, 82,
2191–2194.
3.5.3. Reduction of salf 1l. From the reduction of salt 1l
carried out according the procedure described above for 1a,
a chloroform extract was obtained, the 1H NMR analysis of
which revealed the presence of a unique product, which was
unambiguously identified, by 1H and 13C NMR spec-
troscopy, as 1-benzyl-3-carbamoyl-4,6-dimethyl-1,4-dihy-
dropyridine 3l (Tables 2 and 5).
5. Caughey, W. S.; Shellenberg, K. J. Org. Chem. 1966, 31,
1978–1982.
6. Biellmann, J. F.; Callot, H. J. Bull. Soc. Chim. Fr. 1968,
1154–1159.
7. Biellmann, J. F.; Callot, H. J. Bull. Soc. Chim. Fr. 1968,
1159–1165.
Anal. Calcd for C15 H18 N2 O: C, 74.35; H, 7.49; N, 11.56.
Found: C, 74.48; H, 7.27; N, 11.34.
8. (a) Dewar, M. J. S.; Stork, D. M. J. Am. Chem. Soc. 1985, 107,
3898–3902. (b) Dewar, M. J. S.; Zoebish, E. G.; Healy, E. I.;
Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902–3909.
9. Pop, E.; Brewster, M. E.; Bodor, N.; Huang, M. J. J. Mol.
Struct. (Theochem) 1993, 283, 27–32.
1
3.6. H and 13C NMR analysis of the dithionite adducts
2a–m
10. Carelli, V.; Liberatore, F.; Scipione, L.; Musio, R.; Sciacov-
elli, O. Tetrahedron Lett. 2000, 41, 1235.
In a typical procedure for the preparation of an adduct
sample for NMR examination, a solution of Na2S2O4
(0.11 mmol) in 0.25 ml of 2 M NaOD (in D2O) or 2 M
Na2CO3 (in D2O) was prepared in a NMR tube and
subsequently cooled down to K20 8C. Over this frozen
solution, kept at K20 8C, was then stratified the pyridinium
salt solution (0.06 mmol of salt in 0.25 ml of D2O or 0.25 ml
of DMSO-d6), which was afterwords frozen. The tube was
finally sealed in vacuo always keeping the temperature at
K20 8C. At the moment of performing the NMR analysis,
the tube temperature was increased to 20 8C in order to
cause the thawing of the solutions and their mixing.
11. Damij, S. W. H.; Fyfe, C. A.; Smith, D.; Sharom, F. J. J. Org.
Chem. 1979, 44, 1761–1765.
12. Butt, G. L.; Deady, L. W. J. Heterocycl. Chem. 1984, 21,
981–984.
13. Bossaerts, J. D.; Dommisse, R. A.; Alderweireldt, F. C.;
Gerlings, P. J. Chem. Res. (miniprint) 1987, 9, 2360–2384.
14. Micheletti-Moracci, F.; Liberatore, F.; Carelli, V.; Arnone, A.;
Carelli, I.; Cardinali, M. E. J. Org. Chem. 1978, 43,
3420–3422.
15. Breitmeir, E.; Bauer, G. 13C NMR spectroscopie.; Georg
Thieme: Struttgart, 1977; pp 52–54.
The 1H and 13C NMR parameters of adducts 2 are
summarized in Tables 3 and 4.
16. Schneider, H. J.; Hoppen, V. J. Org. Chem. 1978, 43,
3866–3873.
17. Dunitz, J. D. Acta Crystallogr. 1956, 9, 579–586.
18. Cowdrey, W. A.; Hughes, E. D.; Ingold, C. K.; Masterman, S.;
Scott, A. D. J. Chem. Soc. 1937, 1252–1271.
19. Sharman, S. H.; Caserio, F. F.; Nystrom, R. E.; Leak, J. C.;
Young, W. G. J. Am. Chem. Soc. 1958, 80, 5965–5971.
20. Roberts, J. D.; Young, W. G.; Winstein, S. J. Am. Chem. Soc.
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It was impossible to record 13C NMR spectra on adducts
2e–g, because of insufficient concentrations achievable both
in NaOD and Na2CO3 solutions. Indeed, pyridinium salts
1e–g displayed extreme reactivity towards aqueous NaOH,
giving rise to mixtures of dihydropyridines and pyridones.31
On the other hand, adducts 2e–g rapidly decomposed, in
aqueous Na2CO3, yielding 1,4-dihydropyridine and 1,4- and
1,6-dihydropyridine mixtures.
21. Schenker, K.; Druey, J. Helv. Chim. Acta 1959, 42,
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23. Kosower, E. M.; Klinedinst, P. E. J. Am. Chem. Soc. 1956, 78,
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Acknowledgements
This work was financially supported by funds from
`
‘Ministero dell’Istruzione, dell’Universita e della Ricerca’:
‘Progetti di Ricerca di Interesse Nazionale’.
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27. Wallenfels, K.; Schu¨ly, H. Justus Liebig Ann. Chem. 1959,
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