A new synthesis of dihydropyridin-2-ones from Brassard's diene and imines

Article abstract of DOI:10.3987/COM-08-S(N)51

A new method for the synthesis of dihydropyridin-2-ones from various N-2-nitrobenzenesulfonyl (nosyl) imines and 1,3-diethoxy-1-trimethylsiloxy-1,3- butadiene (Brassard's diene) under weakly-basic conditions is described. This synthesis of dihydropyridin-

Full text of DOI:10.3987/COM-08-S(N)51

HETEROCYCLES, Vol. 76, No. 1, 2008
221
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 221 - 225. © The Japan Institute of Heterocyclic Chemistry
Received, 24th March, 2008, Accepted, 28th April, 2008, Published online, 1st May, 2008. COM-08-S(N)51
A NEW SYNTHESIS OF DIHYDROPYRIDIN-2-ONES FROM
BRASSARD’S DIENE AND IMINES
Teruaki Mukaiyama,*1 Yuji Maruyama,2 and Takayuki Kitazawa1
1Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima,
Kita-ku, Tokyo 114-0003, Japan and Kitasato Institute for Life Sciences, Kitasato
University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
2Department of Applied Chemistry, Faculty of Science, Tokyo University of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
E-mail; mukaiyam@abeam.ocn.ne.jp
Dedicated to Professor Dr. Ryoji Noyori on the occasion of his 70th birthday.
Abstract – A new method for the synthesis of dihydropyridin-2-ones from
various N-2-nitrobenzenesulfonyl (nosyl) imines and 1,3-diethoxy-1-
trimethylsiloxy-1,3-butadiene (Brassard’s diene) under weakly-basic conditions
is described. This synthesis of dihydropyridin-2-ones involves the initial addition
reaction of Brassard’s diene to imines to afford the adducts followed by a
cyclization reaction that forms the corresponding 4-ethoxy-5,6-dihydro-1H-
pyridin-2-ones in moderate to good yields after deprotection of its nosyl group
from the adducts.
INTRODUCTION
The derivatives of dihydropyridin-2-one that are often found in many biologically active compounds such
as pharmaceuticals, agrochemicals and natural products are employed as useful building blocks of
synthetic procedures of natural products. Aza Diels-Alder reactions between Brassard’s diene and imines
are considered to be the general method for the synthesis of the above compounds. This reaction is
usually promoted by using stoichiometric amounts of Lewis acid such as boron trifluoride etherate,
diethylaluminium chloride and ethylaluminium dichloride, and dihydropyridin-2-ones are afforded in
good yields.1 Recently, a reaction by using a catalytic amount of Brønsted acid was reported to promote
the aza Diels-Alder reaction of Brassard’s diene and imines.2 However, those that use substrate having

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HETEROCYCLES, Vol. 76, No. 1, 2008
basic moieties such as amino or pyridyl groups were still considered difficult under these acidic
conditions. Therefore, to develop a method which is applicable to the imine compounds was desired.
The imines having electron-withdrawing group on the nitrogen atom are well-known to be useful
electrophiles in nucleophilic addition reactions. Also, it was reported from our laboratory that the addition
reactions of organosilyl compounds such as Mannich-type reactions,3 Strecker-type reactions,4
trifluoromethylations5 and cyanomethylations6 proceeded under weakly Lewis basic conditions when
N-sulfonyl imines7 were used. Based on these results, a new synthesis of dihydropyridin-2-ones by using
Brassard’s diene and imines under neutral conditions was studied. Various dihydropyridin-2-ones were
obtained under neutral conditions by the initial addition reaction of Brassard’s diene to imines without
using any additives, which was followed by cyclization under mild basic conditions.
RESULTS AND DISCUSSION
In the first place, reactions between Brassard’s diene and various imines derived from benzaldehyde were
tried at room temperature in THF, whose results are summarized in Table 1. When imines having an
electron-withdrawing group such as N-tosyl (Ts) or N-nosyl (Ns) groups were used, addition reactions
proceeded smoothly and the corresponding adducts were obtained in high yields with high (E) olefin
selectivities (Entries 1 and 2). When N-tert-butoxycarbonyl (Boc) imine was used, the desired adduct was
also obtained in moderate yield (Entry 3). As shown in entries 4 and 5, N-benzyl (Bn) and
N-p-methoxyphenyl (PMP) imines did not give the corresponding products. Then, it was found that the
reactions between N-sulfonyl imines and Brassard’s diene without using Lewis acid or Lewis base
proceeded smoothly and the expected adducts were obtained in high yields.
Table 1. Effects of substituents
OSiMe3
OEt
R
OEt
NH OEt
R
Brassard's diene
(1.5 equiv.)
NH OEt O
R
H
Ph
+
N
OEt
Ph
THF, rt
EtO
E isomer
2a−2e
O
Ph
Z isomer
3a−3e
1a−1e
Entry
Time/h
Product
E/Z
R
Yielda/%
98
1
>99:1
95: 5
82:18
−
1a:
1b:
1c:
1d:
1e:
Ts
Ns
1
2a & 3a
2b & 3b
2c & 3c
2d & 3d
2e & 3e
2b
>99
1
3
72
Boc
Bn
10
24
24
N.R.c
N.R.c
4
−
5
PMP
aIsolated yield. b1.2 equiv. of Brassard's diene was used. cNo reaction.

HETEROCYCLES, Vol. 76, No. 1, 2008
223
Next, cyclizations of 2a and 2b were examined. Dihydropyridin-2-one was not obtained from 2a because
the deprotection of the tosyl group did not proceed under some conditions while 2b gave the desired
cyclic compound (4b) in 92% after the deprotection of the nosyl group according to the Fukuyama’s
procedure8 (Scheme 1). Therefore, the nosyl group was chosen as a nitrogen protecting group.
Ts
NH OEt
deprotection
not detected
Ph
EtO
O
2a
Ns
Ph
O
PhSH (1.2 equiv.)
K2CO3 (3.0 equiv.)
NH2 OEt
NH OEt
HN
Ph
Ph
toluene, reflux,
1 h
DMF, rt, 10 h
OEt
EtO
O
EtO
O
2b
4b 92%
Scheme 1. Deprotection and cyclization reactions of adduct 2a and 2b
Table 2. Addition reactions of Brassard's diene with various nosyl imines
OSiMe3
OEt
OEt
Ns
R
NH OEt
EtO
Ns
R
Brassard's diene
(1.2 equiv.)
NH OEt O
Ns
H
N
R
+
OEt
THF, rt, 1 h
O
E isomer
2f−2n
Z isomer
3f−3n
1f−1n
E/Z
Entry
1
R
Product
Yielda/%
94
93:7
2f & 3f
1f:
1g:
1h:
1i:
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2g & 3g
2h & 3h
2i & 3i
2
3
98
92
95:5
95:5
95:5
94:6
97:3
97:3
86:14
95:5
4
92
96
94
97
90
74
4-O2NC6H4
2-MeC6H4
E)-Ph-CH=CH
3-Pyridyl
5
2j & 3j
1j:
2k & 3k
2l & 3l
6
(
1k:
1l:
7
8b
2m & 3m
4-Me2NC6H4
1m:
2n & 3n
1n:
9
t-Bu
aIsolated yield. bThe reaction was carried out for 5 h.

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HETEROCYCLES, Vol. 76, No. 1, 2008
The addition reactions of Brassard’s diene with various N-nosyl imines were next tried (Table 2).
N-Nosyl imines derived from aromatic aldehydes having electron-donating or -withdrawing groups
reacted smoothly and afforded the corresponding adducts in high yields (Entries 1 - 4). Ortho-substituted
imine also reacted smoothly to give the expected adduct in a high yield (Entry 5). In the case when
α,β-unsaturated imine was used, the desired 1,2-addition product was obtained in a high yield (Entry 6). It
is noteworthy that the imines having basic moieties such as pyridyl or dimethylamino groups were
applicable in this reaction since these imines had not been used easily in the conventional Lewis acid- or
Brønsted acid- mediated aza Diels-Alder reactions (Entries 7 and 8). Furthermore, an aliphatic imine
prepared from pivalaldehyde gave the adduct in a moderate yield (Entry 9).
Next, cyclization reactions after the deprotection of the nosyl group of E-isomers were tried (Table 3).
The deprotections were carried out with benzenethiol and potassium carbonate at room temperature in
DMF, and then the cyclizations were conducted under refluxing in toluene to afford the corresponding
dihydropyridin-2-ones. Both reactions of aromatic and aliphatic adducts gave the expected products in
good to high yields, respectively. Adducts having a basic moiety such as pyridyl or dimethylamino
groups also cyclized smoothly (Entries 7 and 8).
Table 3. Deprotection and cyclization reactions of E-isomers
Ns
R
O
PhSH (1.2 equiv.)
K2CO3 (3.0 equiv.)
NH OEt
NH2 OEt
EtO
HN
R
toluene, reflux,
1-12 h
DMF, rt, 10 h
OEt
R
EtO
O
O
2f−2n
4f−4n
Product Yielda/%
Entry
R
Product Yielda/%
Entry
R
4-MeC6H4
(E)-Ph-CH=CH
1
2
3
4
5
92
94
94
88
88
6
7
8
9
2k:
2l:
94
86
82
92
2f:
4f
4g
4h
4i
4k
4l
2g:
4-MeOC6H4
3-Pyridyl
2h: 4-ClC6H4
4-Me2NC6H4
2m:
2n:
4m
4n
4-O2NC6H4
2-MeC6H4
2i:
2j:
t
-Bu
4j
aIsolated yield.
A new method for the preparation of 4-ethoxy-5,6-dihydro-1H-pyridin-2-ones was thus established by the
reaction between Brassard’s diene and N-nosyl imines. This synthetic procedure is applied conveniently
to the substrates having basic moieties because the addition reactions with Brassard’s diene proceeded
under neutral conditions without using any additives and the following deprotection of the nosyl group
proceeded under weakly-basic conditions.

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