A novel one-pot, three-component reaction: Formation of tricyclic 1,2-dihydropyridines via mesomeric betaines

Article abstract of DOI:10.1016/S0040-4039(03)01838-0

A one-pot, three-component reaction of pyridine, thiophthalimide and acyl chloride gives novel tricyclic 1,2-dihydropyridines regio- and stereoselectively, in which a mesomeric betaine would be a key intermediate for [4+2]-cycloaddition reaction with thiocarbonyl compounds.

Full text of DOI:10.1016/S0040-4039(03)01838-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7365–7367
A novel one-pot, three-component reaction: formation of tricyclic
1,2-dihydropyridines via mesomeric betaines
Shinji Yamada,* Tomoko Misono, Chisako Morita and Noriko Nunami
Department of Chemistry, Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
Received 9 June 2003; revised 22 July 2003; accepted 25 July 2003
Abstract—A one-pot, three-component reaction of pyridine, thiophthalimide and acyl chloride gives novel tricyclic 1,2-dihydropy-
ridines regio- and stereoselectively, in which a mesomeric betaine would be a key intermediate for [4+2]-cycloaddition reaction
with thiocarbonyl compounds.
© 2003 Elsevier Ltd. All rights reserved.
One-pot, multi-component reactions continue to be of
great interest in the synthesis of various compounds
containing particularly nitrogen atoms1 owing to the
fast assembly of poly-substituted systems without isola-
tion of unstable intermediates. The importance of these
one-pot reactions in such syntheses has been demon-
strated in the Mannich, Ugi,1a,2 Biginelli,1b and aza-
product (Scheme 1). This suggests that a mesomeric
betaine,6 produced from N-acylpyridinium salt, would
be a key intermediate that undergoes [4+2]-cycloaddi-
tion reaction with a thiocarbonyl group. In this com-
munication, we describe
a new one-pot, three-
component reaction leading to tricyclic 1,2-
dihydropyridines.
Baylis–Hillman3
dihydropyridine synthesis.4
reactions,
and
in
Hantzsch
The reaction of pyridine (1), dithiophthalimide (4) and
2 equiv. of propionyl chloride (8b) in the presence of
Et3N gave tricyclic compound 9b in 62% yield (Table
During our attempted synthesis of N-acyldithiophtha-
limides, as part of continuing research program of
structural studies of twisted amides,5 we unexpectedly
obtained an tricyclic 1,2-dihydropyridine as a major
1
1),7,8 the structure of which was determined by H and
13C NMR and IR spectra, and X-ray crystallographic
analysis. Figure 1 shows the ORTEP drawing,9 which
Scheme 1.
Keywords: one-pot, three-component reaction; mesomeric betaine; 1,2-dihydropyridine; [4+2]-cycloaddition reaction; heterocyclic compound.
* Corresponding author. Tel.: +81-3-5978-5349; fax: +81-3-5978-5715; e-mail: yamada@cc.ocha.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01838-0

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S. Yamada et al. / Tetrahedron Letters 44 (2003) 7365–7368
Table 1. One-pot, three-component reactions of pyridine, thiophthalimide and acyl chloride
Entry
Pyridine
Phthalimide
Acyl chloride
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
3
1
1
4
4
4
5
4
5
5
6
7
8a
8b
8c
8b
8b
8b
(Ac2O)
8b
8b
9a
9b
9c
10b
11b
12b
13a
10b
nr
19
62
18
60
49
27
40b
61
0
a Isolated yields.
b Yields based on 1H NMR spectroscopy.
clearly reveals that it consists of 1,2-dihydropyridine,
six-membered lactam and N-acyl spirothiolactam moi-
eties. Characteristic stereochemical features are trans
relationship between 2-H of the dihydropyridine moiety
and the methyl group in the six-membered lactam ring,
and syn orientation between the dihydropyridine and
the phenyl ring. An additional important feature is that
the sulfur atom is incorporated into the six-membered
ring at the b-position of the carbonyl group. Surprising
is that the reaction provided an almost single product
despite having three stereogenic centers.7
yields, respectively, which seems to be a result of
reverse cycloaddition reaction (Scheme 2). Formation
of no regio- and stereoisomers in this one-pot reaction
also suggest the participation of a cycloaddition reac-
tion. These results led us to presume that a mesomeric
betaine A would be a key intermediate (Scheme 3). The
formation of a similar betaine has been reported in the
reaction of pyridine with ketene12 and was postulated
during some cyclization reactions.6,13 Since mesomeric
betaines have been known to behave as 1,3-dipoles, the
postulated betaine and the thiocarbonyl group would
undergo a cycloaddition reaction. The observed higher
reactivity of the thiocarbonyl than that of the carbonyl
group is in agreement with the general feature of signifi-
cant reactivity of thiocarbonyl compounds in the
cycloaddition reaction.10
To elucidate the generality of this one-pot reaction, we
employed several pyridine, acyl chloride and phthal-
imide analogues. The three-component reactions pro-
ceeded smoothly in dichloromethane at rt, and were
completed within 1–3 h. Table 1 lists the results of the
reactions. The reactions with acetyl chloride and isobu-
tyryl chloride gave the corresponding adducts 9a and 9c
with relatively lower yields than in the case using
propionyl chloride (entries 1 and 3). The reaction of
monothiophthalimide (5) having both a carbonyl and a
thiocarbonyl group afforded 10b containing the sulfur
atom in the lactam ring (entry 4), indicating the higher
reactivity of the thiocarbonyl than that of the carbonyl
group.10 The structure of the product 9c was also
confirmed to have the same framework as that of 9b by
X-ray analysis.11
A plausible pathway that satisfies all of the foregoing
results is shown in Scheme 3. The key intermediary
betaine may arise either from N-acylpyridinium with
Et3N or directly from pyridine and a ketene produced
When 4-methylpyridine (2) was used as a substituted
pyridine, similar adducts 11b and 12b were obtained in
49% and 27% yields, respectively (entries 5 and 6). The
reaction of 4-dimethylaminopyridine (3) with an acyl
chloride gave no expected product, but acetic anhydride
was effective to give 13a in 40% yield (entry 7).
Despite using N-propionylmonothiophthalimide (6)
instead of 5 in the case of entry 4, the same compound
10b was obtained in 61% yield (entry 8). On the other
hand, no product was observed in the reaction of
N-methylmonothiophthalimide (7) (entry 9). These
results indicate a necessity of the N-acyl group in this
cyclization reaction.
Figure 1. ORTEP drawing of 9b at the 30% probability level.
It may be noted that upon heating the product 9b at
60°C for 3 h, N-propionyldithiophthalimide (14) and
dithiophthalimide (4) were produced in 29% and 59%
Scheme 2.

S. Yamada et al. / Tetrahedron Letters 44 (2003) 7365–7368
7367
Scheme 3.
from an acyl chloride. The betaine reacts with N-
acyldithiophthalimide to afford a six-membered lactam
ring via [4+2]-cycloaddition reaction,14 which results in
trans stereochemistry between 2-H and the methyl group.
The syn orientation about the dihydropyridine ring and
the phenyl group may be due to intermolecular cation-p
interaction15,16 of the pyridinium cation with the p-elec-
tron of the aromatic moiety of N-acylthiophthalimide in
the cyclization step.
(53.5 mg, 0.3 mmol) and Et3N (125 ml, 0.9 mmol) in CH2Cl2
was added 2 equiv. of propionyl chloride (52 ml, 0.6 mmol)
at 0°C and the solution was stirred for 3 h at rt. After
additionofsatdNaHCO3 solution, thereactionmixturewas
extracted three times with CH2Cl2 (3×5 ml), and the
combined extract was washed with brine and dried over
anhydrous sodium sulfate. Evaporation of the solvent gave
a crude compound, which was subjected to silica gel column
chromatography using a 6:1 mixture of hexane and ethyl
acetate as an eluent to yield pure 9b as a solid (69.2 mg,
0.187 mmol).
In summary, we have found a new one-pot, three-com-
ponent reaction of thio- or dithiophthalimide, a pyridine
derivative and an acyl chloride leading to a novel tricyclic
1,2-dihydropyridine derivative. The key step in this
reaction presumably involves [4+2]-cycloaddition reac-
tion of the mesomeric betaine with a thiocarbonyl group.
9. Crystal data: Compound 9b: C19H18N2O2S2, M=370.47,
monoclinic, P21/a, v=2.897 mm−1, a=15.193(2), b=
,
8.7767(9), c=13.2074(13) A, i=98.589(8)°, V=1741.4(3)
3
A , T=293 K, Z=4, Dcalcd=1.413 g cm−1, a total of 3376
,
reflections were collected and 3169 are unique (Rint
=
0.0328). R1 and wR2 are 0.0403 [I>2|(I)] and 0.1397 (all
data), respectively. CCDC 207126.
10. For a review, see: Weinreb, S. M.; Staib, R. R. Tetrahedron
1982, 38, 3087–3128.
Acknowledgements
This work was financially supported by a Grant-in-Aid
from Japan Society for the Promotion of Science (No.
13650901).
11. Compound 9c: C21H22N2O2S2, M=398.53, monoclinic,
P21/n, v=2.543 mm−1, a=31.501(4), b=7.515(2), c=
3
,
,
17.356(3) A, i=101.510(12)°, V=4026.0(13) A , T=293
K, Z=8, Dc=1.315 g cm−1, a total of 6098 reflections were
collected and 5976 are unique (Rint=0.0219). R1 and wR2
are 0.0382 [I>2|(I)] and 0.1796 (all data), respectively.
CCDC 207127.
References
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