A base-catalyzed Diels-Alder reaction of N-tosyl-3-hydroxy-2-pyridone

Article abstract of DOI:10.1016/S0040-4039(00)01444-1

A Diels-Alder reaction of N-tosyl-3-hydroxy-2-pyridone with an electron deficient dienophile was catalyzed by base. The reactivity, stereoselectivity and mechanism of this reaction are described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01444-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8317–8321
A base-catalyzed Diels–Alder reaction of
N-tosyl-3-hydroxy-2-pyridone
Hiroaki Okamura,* Hiroshi Nagaike, Tetsuo Iwagawa and Munehiro Nakatani
Department of Chemistry and Bioscience, Faculty of Science, Kagoshima University, 1-21-35 Korimoto,
Kagoshima 890-0065, Japan
Received 23 June 2000; revised 10 August 2000; accepted 25 August 2000
Abstract
A Diels–Alder reaction of N-tosyl-3-hydroxy-2-pyridone with an electron deficient dienophile was
catalyzed by base. The reactivity, stereoselectivity and mechanism of this reaction are described. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: base-catalyzed Diels–Alder reaction; 2-pyridone; endo selective; stereospecific reaction.
1
The Diels–Alder (DA) reaction is one of the most useful CꢀC bond forming reactions. To
improve its reactivity and selectivities, many catalysts have been developed, and most are Lewis
acids. Recently, however, we reported the base-catalyzed DA reaction of 3-hydroxy-2-pyrone
2
(
1), using a base-activated diene (Eq. (1)). This type of DA reaction is quite rare, and its
mechanism, which involves activation of the diene moiety by a base, is completely opposite the
usual mechanism, activation of a dienophile by Lewis acid.
(1)
In our continuous effort to find other base-catalyzed DA reactions, we found that the reaction
of N-tosyl-3-hydroxy-2-pyridone (2) with an electron deficient dienophile (3) was catalyzed by a
base, and afforded cycloadducts (4 and 5) in good yield (Eq. (1)). This paper describes the
characteristic features of this reaction.
*
Corresponding author. Fax: +81 99 285 8117; e-mail: okam@sci.kagoshima-u.ac.jp
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01444-1

8318
Compound 2 was easily derived from commercially available 2,3-pyridinediol by the modified
3
,4
Posner’s method. Table 1 summarizes the base-catalyzed cycloaddition of 2 with electron
deficient dienophiles (3a–c). The reactivity of the diene 2 itself was very low (entries 1, 10, and
1
2). Even in the reaction with the most reactive N-methylmaleimide (3a), only a trace amount
5
of adduct 4a was obtained (entry 1). However, the addition of Et N as a base catalyst
3
dramatically accelerated the reaction and an almost quantitative amount of 4a was formed
within 30 min (entry 2). The yield of this reaction depended on the amount of the catalyst and
the type of solvent. Decreasing the amount of base catalyst decreased the yields of the adduct
(
5
entries 2–4). When the reaction was carried out in the THF, the yield was also reduced (entry
). Other amine bases worked as well as Et N and the adduct was obtained in good yields
3
(
entries 8 and 9).
Table 1
a
Base-catalyzed reactions of 2 with dienophiles
The base catalyst was effective for the reactions with the less reactive dienophiles, methyl
acrylate (3b) and 3-buten-2-one (3c), and the corresponding adducts were obtained in fair yields
(
entries 11 and 13).
The endo selectivity of these reactions was very high, probably because the sterically bulky
N-Ts group produced an unfavorable interaction with the dienophile during its exo approach.
The bulkiness of the base catalyst also sterically influenced the approaching dienophile. Indeed,
a slightly lower endo selectivity was observed for the reaction using the sterically less hindered
t-BuNH (entry 8). The reaction with 3-buten-2-one (3c), however, afforded a mixture of the
2
endo and exo isomers (4c and 5c, entry 13). This exceptional example could be explained by base
induced epimerization via enolization of the carbonyl group. Indeed, the Et N treatment (rt, 24
3
h, in CH Cl ) of pure 4c and 5c afforded the mixtures in 1.0:1.1 and 1.0:1.3 ratios, respectively.
2
2

8319
Bases that contained alkali metals could also be used for the reaction with 3a and these were
more effective catalysts than the amine catalysts (Table 2). The yields of the reactions catalyzed
by 0.1 equiv. Of these bases were higher than that of the reaction catalysed by Et N under the
3
same conditions (entries 2–5). For the reaction with the less reactive dienophile 3b, however,
n-BuLi was not effective, probably due to the base instability of the dienophile (entry 6).
Table 2
a
Base-catalyzed reaction of 2 under various conditions
Koerner and Rickborn proposed two categories of [4+2] cycloaddition under basic conditions:
7b
base-induced and base-catalyzed cycloaddition. The former reaction gives an anionic adduct
8
from anionic substrate, and a typical example of this type is the reaction of a Michael acceptor
and a dienolate anion, which is usually generated from LDA treatment of an a,b-unsaturated
8
a
carbonyl compound (Eq. (2)). Most [4+2] cycloadditions using bases are classified into this
category, and their reaction mechanisms generally involve a stepwise double-Michael reaction or
9
a Michael–aldol reaction. On the other hand, the base-catalyzed reaction gives neutral
2
a
(
(
protonated) adducts, and the base-catalyzed reaction of 1 is a good example. As shown in Eq.
3) initially formed anionic diene reacts with dienophile to give anionic adduct, which is
immediately protonated by ammonium salt, and thus the base works as a catalyst. Reactions of
2
,7,10
this type are quite rare.
DA reactions by both Rickborn and Koerner and by our group.
More interestingly, two of them are reported to be base-catalyzed
2,7
These reactions are
completely opposite the ordinary acid catalyzed DA reaction, and thus they are potentially new
method for catalyzed DA reaction.
(
(
2)
3)

8320
According to the above definition, the reaction of 2 with dienophile is classified as a
base-catalyzed reaction. Determining whether its reaction mechanism is a concerted DA
mechanism or a stepwise Michael–aldol mechanism was difficult, but the formation of the
Michael adduct and the stereospecificity of this reaction were appropriate criteria to estimate the
mechanism. If the reaction proceeds via the stepwise pathway, the Michael adduct could be
formed, and the stereospecificity can be lost because of free rotation of the CꢀC bond
corresponding to the C-7–C-8 position in intermediate 7. However, in all the cases we examined,
no Michael adduct was observed, and the stereospecificity of this reaction was also confirmed
from the reactions of dimethyl maleate (3d) and dimethyl fumalate (3e), which, respectively, gave
the syn (4d) and anti products (4e and 5e) in almost complete selectivity (Schemes 1 and 2).
Although a small amount of the anti isomer 5e was formed from the reaction with 3d, this was
supposedly due to the base induced epimerization, as well as the epimerization between 4c and
5
c. Indeed, Et N treatment of a 24:1 mixture of 4d and 5e decreased the ratio to 12:1 after 48
3
h. These observations are not direct evidence to determine the reaction mechanism, but they
strongly suggest that this reaction proceeded via the concerted DA reaction mechanism.
Scheme 1. Two plausible reaction mechanisms
Scheme 2. Stereospecific base-catalyzed DA reaction
In conclusion, we found a new base-catalyzed DA reaction system using 2 as a diene. Since
the resulting cycloadducts have various functional groups, including nitrogen, and the rigid

8321
bicyclic structure, these compounds are attractive building blocks for the synthesis of biologi-
cally active compounds such as aminosugars and alkaloids. Further investigation to determine
the detailed features of this reaction and application for syntheses are now in progress.
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