Lewis base catalyzed aza-diels-alder type reactions between danishefsky's dienes in the presence of lewis base catalysts. An efficient method for the synthesis of substituted 2,3-dihydropyridin-4-ones

Article abstract of DOI:10.3987/COM-07-S(U)65

Aza-Diels-Alder type reactions of various imines with 1-methoxy-3-trimethylsilyloxy-l,3-butadiene (Danishefsky's diene) derivatives catalyzed by Lewis bases such as lithium methoxide are described. The reaction proceeds via a stepwise pathway, i.e. first by an imino-aldol reaction followed by the acid mediated annulation to afford the corresponding 2,3-dihydropyridin-4-ones in high yields. An appropriate choice of the substituents on nitrogen plays important roles both in addition of the silyl enolates and in the subsequent annulation to form the desired cycloadducts.

Full text of DOI:10.3987/COM-07-S(U)65

HETEROCYCLES, Vol. 73, 2007
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HETEROCYCLES, Vol. 73, 2007, pp. 255 - 261. © The Japan Institute of Heterocyclic Chemistry
Received, 11th July, 2007, Accepted, 4th October, 2007, Published online, 9th October, 2007. COM-07-S(U)65
LEWIS BASE CATALYZED AZA-DIELS-ALDER TYPE REACTIONS
BETWEEN DANISHEFSKY’S DIENES IN THE PRESENCE OF LEWIS
BASE CATALYSTS.
AN EFFICIENT METHOD FOR THE SYNTHESIS OF
SUBSTITUTED 2,3-DIHYDROPYRIDIN-4-ONES
Takayuki Kitazawa, Yuji Maruyama, and Teruaki Mukaiyama*
Center 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
Dedicated to Professor Ivar Ugi.
Abstract – Aza-Diels-Alder type reactions of various imines with 1-methoxy-3-
trimethylsilyloxy-1,3-butadiene (Danishefsky’s diene) derivatives catalyzed by
Lewis bases such as lithium methoxide are described. The reaction proceeds via a
stepwise pathway, i.e. first by an imino-aldol reaction followed by the acid
mediated annulation to afford the corresponding 2,3-dihydropyridin-4-ones in high
yields. An appropriate choice of the substituents on nitrogen plays important roles
both in addition of the silyl enolates and in the subsequent annulation to form the
desired cycloadducts.
Among the biologically active compounds such as pharmaceuticals, agrochemicals and natural products,
2,3-dihydropyridin-4-ones are often recognized as key intermediates to form piperidine alkaloids. To
obtain 2,3-dihydropyridin-4-ones, one of the most fundamental methods is to allow
1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky’s Diene) to react with imines, that is the well
known aza-Diels-Alder reaction.1 Since aza-Diels-Alder reactions promoted by Lewis acid catalyst were
first reported, even more effective Lewis acid catalysts have been developed (Scheme 1).2 On the other

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HETEROCYCLES, Vol. 73, 2007
hand, there are no reports on Lewis base mediated aza-Diels-Alder reactions. Recently, it was reported
from our laboratory that silyl enolates are activated by Lewis base catalysts,3 and particularly,
Danishefsky’s dienes are effectively activated by a catalytic amount of Lewis base such as lithium
methoxide and afforded 2,3-dihydropyran-4-ones in high yields on treatment with carbonyl compounds.4
As a course of our continuous study on Lewis base catalyzed reactions, this method was next applied to
the reactions with imines in place of the above mentioned carbonyl compounds (Scheme 2). In this
communication, the first example of Lewis base catalyzed aza-Diels-Alder type reactions is described.
PG
NH
O
R
OMe
PG
H
PG
R
OSiMe3
N
N
Lewis acids
+
OMe
R
O
OMe
N
PG
R
OSiMe3
Scheme 1. Lewis Acid Catalyzed Aza-Diels-Alder Reactions
H+
Lewis base
PG
H
PG
R
PG
R
OSiMe3
N
NH
O
N
+
OMe
R
OMe
O
Scheme 2. Lewis Base Catalyzed Aza-Diels-Alder Reactions
In the first place, a reaction between Danishefsky’s diene and imines derived from benzaldehyde was
tried in the presence of a catalytic amount of lithium methoxide in DMF, which was previously proved to
be the best reaction conditions of hetero Diels-Alder type reactions (Table 1).

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257
Table 1. Lithium methoxide catalyzed aza-Diels-Alder
reactions of various imines with Danishefsky's diene
1) 20 mol % LiOMe
2) TFA
PG
H
Y
N
OSiMe
3
N
+
DMF, 0 °C
OMe
Ph
Ph
O
(1.5 equiv.)
Entry
1
PG
Ts
o-Ns complex mixture
Yield (%)
Entry
PG
P(O)Ph
Yield (%)
trace
complex mixture
5
2
2
3
4
6
7
8
Benzyl
trace
trace
89*
PMP
Ph
trace
trace
Allyl
t
CO Bu
2
o-Ns = o-nitrobenznesulfonyl, PMP = p-methoxyphenyl
* PG = H in cycloadduct
Y = H in entry 8
The substituents on imine nitrogen atom were chosen for the protective groups to be removed easily by
well known procedures. When imines having strong electron withdrawing N-sulfonyl group were used,
the starting materials disappeared after 24 hours, which was checked by TLC analysis. However,
several spots besides the target adduct were also observed by the TLC analysis (entries 1 and 2). In
addition, it was shown that the acid mediated cyclization was not successful due to the low
nucleophilicity of the sulfonamide. The addition of Danishefsky’s diene to N-aryl imines and
N-diphenylphosphinoyl imine proceeded very sluggishly and the desired pyridones were not obtained
(entries 3-5). As shown in entries 6 and 7, N-benzyl imine and N-allyl imine were non-reactive. When
N-t-Butoxycarbonyl (Boc) imine was used, the desired 2,3-dihydropyridin-4-one was obtained in 89 %
overall yield with the deprotection of Boc group during the acid mediated annulation (entry 8). When
the reaction was carried out at room temperature, the reaction mixture became complex and the yield of
the desired cycloadduct became lower.
Next, effects of other Lewis base catalysts were examined (Table 2). The alkoxide anions except
ammonium methoxide showed similar activities to lithium methoxide (entries 1-5). When Lewis bases
such as phenoxide anion and carboxylate anion were used, only a trace amount of the desired product was

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HETEROCYCLES, Vol. 73, 2007
obtained (entries 6-9). Tetrabutylammonium fluoride, a commonly used fluoride anion source, was not
effective (entry 10).
Table 2. Effects of various Lewis base ctalysts
in the aza-Diels-Alder reactions
1) 20 mol % Lewis base
2) TFA
Boc
H
N
OSiMe3
N
+
DMF, 0 °C
Ph
H
OMe
(1.4 equiv.)
Ph
O
Entry
1
Lewis Base Yield (%)
Entry
6
Lewis Base Yield (%)
LiOMe
LiOMe
89
69
LiOPh
Bu4NOPh
LiOAc
N.R.
trace
N.R.
trace
10
2*
3
7
8
NaOMe
Bu4NOMe
KOtBu
54
4
trace
37
9
Bu4NOAc
TBAF
5
10
* 10 mol% LiOMe was used.
Then, effect of solvents was examined (Table 3). When the reaction was carried out in DMSO or
pyridine, the reaction proceeded similarly to afford the pyridone in good yields (entries 2 and 3), but
solvents such as CH2Cl2, THF, and toluene were not applicable under this reaction conditions (entries
4-6). Because of the low solubility of lithium methoxide in these solvents, it was considered that the
Lewis base catalysts did not dissolve in the reaction media and thus, no reaction proceeded at all.
The above aza-Diels-Alder type reactions were next examined by using other substrates (Table 4).
N-Boc imines derived from the substituted benzaldehydes reacted as smoothly as well under the
optimized conditions and afforded the pyridones in high yields (entries 1-4). Imines derived from
hetero-aromatic aldehydes also gave the corresponding cycloadducts in good yields (entries 5 and 6).
Not only the above imines prepared from aromatic aldehydes, those derived from aliphatic aldehydes
gave the cycloadducts in good yields (entry 7). In addition to N-Boc imines, the imine derived from
ethyl glyoxylate and p-anisidine was also applicable to this aza-Diels-Alder type reaction and afforded the
N-PMP protected pyridones in good yield (entry 8).

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259
Table 3. Effects of solvents in lithium methoxide
catalyzed aza-Diels-Alder reactions.
1) 20 mol % Lewis base
Boc
H
N
OSiMe3
2) TFA
N
+
solvent, 0 °C, 24 h
Ph
H
OMe
(1.4 equiv.)
Ph
O
Entry
1
Solvent
Yield (%)
89
Entry
4
Solvent
CH2Cl2
Yield (%)
N.R.
DMF
DMSO
pyridine
5
6
THF
N.R.
N.R.
2
3
72
50
toluene
Table 4. Lithium methoxide catalyzed
aza-Diels-Alder reactions
1) 10 or 20 mol % LiOMe
2) TFA
Boc
Y
R
N
OSiMe
3
N
+
R
H
OMe
(1.4 equiv.)
DMF, 0 °C, 24 h
O
Entry
1
R
Yield (%)
89
Entry
R
Yield (%)
Ph
2-furyl
3-pyridyl
80
5*
6
2
4-MeOC H
73
46
82
37
61
73
6
4
t
Bu
7*
8
3
4-BrC H
6 4
1
2-MeC H
4*
6
4
PMP
H
* 10 mol% LiOMe was used
Y = H in entries 1-7
Y = PMP in entry 8
N
1
EtO C
2
Next, this aza-Diels-Alder type reaction was tried by using other Danishefsky’s dienes5 (Table 5). Then,
the Danishefsky’s diene with methyl groups at 2- and 4-positions was also activated effectively to afford
the desired products in excellent yields, but the observed diastereoselectivities turned out to be low. The
diastereoselectivities were slightly improved when α-benzyloxy substituted Danishefsky’s diene6 was
used.

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HETEROCYCLES, Vol. 73, 2007
Table 5. Aza-Diels-Alder reactions Using
Substituted Danishefsky's dienes
1) 20 mol % LiOMe
PG
Y
R
R2
O
N
OSiMe3
2) TFA
N
R1
+
DMF, 0 °C
R
H
OR3
R2
R1
(1.4 equiv.)
Entry Imine
R1
R2
R3
Y
H
Yield (%)
91
d.r.
1
1
Me
Me
Me
77 / 23
2
3
4
1
2
2
BnO
Me
H
Me
H
tBu
Me
tBu
H
86
>99
70
81 / 19
73 / 27
79 / 21
PMP
PMP
BnO
Boc
PMP
N
N
2
1
H
EtOOC
H
It is noted that the lithium methoxide catalyzed aza-Diels-Alder type reactions using aldimines proceeded
smoothly to construct the corresponding 2,3-dihydro-4-pyridin-2-one skeletons, frequently found
structures in such biologically active compounds as pharmaceuticals and natural products, in good to
excellent yields under mild Lewis basic conditions. Further studies on this type of reactions are in
progress.
ACKNOWLEDGEMENTS
This study was supported in part by the Grant of the 21st Century COE Program from Ministry of
Education, Culture, Sports, Science and Technology (MEXT), Japan.
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