Inverse-electron-demand Diels-Alder reactions of α,β-unsaturated hydrazones with 3-methoxycarbonyl α-pyrones

Article abstract of DOI:10.1039/c8ob02132e

Inverse-electron-demand Diels-Alder reactions of 3-electron-withdrawing group substituted α-pyrones with α,β-unsaturated hydrazones as electron-rich counterparts are catalyzed by Eu(hfc)₃ to afford bicyclic lactone cycloadducts. This is an example of umpolung cycloaddition based on functional transformation of carbonyls to hydrazones. A subsequent dehydrazonation reaction enables indirect synthesis of carbonyl group-containing bicyclic lactones, which cannot be easily obtained by the cycloaddition of α-pyrones and enals.

Full text of DOI:10.1039/c8ob02132e

Organic &
Biomolecular Chemistry
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Inverse-electron-demand Diels–Alder reactions
of α,β-unsaturated hydrazones with
Cite this: Org. Biomol. Chem., 2018,
6, 8913
1
3
-methoxycarbonyl α-pyrones†
Received 30th August 2018,
Accepted 2nd November 2018
Yoshimitsu Hashimoto,
Ryo Abe, Nobuyoshi Morita and Osamu Tamura
*
DOI: 10.1039/c8ob02132e
rsc.li/obc
Inverse-electron-demand Diels–Alder reactions of 3-electron- group at the 3-position with α,β-unsaturated carbonyl
withdrawing group substituted α-pyrones with α,β-unsaturated compounds.
hydrazones as electron-rich counterparts are catalyzed by Eu(hfc)
3
Carbonyl umpolung (polarity inversion) using hydrazone,
to afford bicyclic lactone cycloadducts. This is an example of which has an electron-donating nitrogen atom in an imine
9
umpolung cycloaddition based on functional transformation of functionality, is often applied in synthetic chemistry.
carbonyls to hydrazones. A subsequent dehydrazonation reaction Additionally, there are a few reports on its electron-donating
enables indirect synthesis of carbonyl group-containing bicyclic ability extension to conjugated olefins. For example, a Povarov-
lactones, which cannot be easily obtained by the cycloaddition of type inverse-electron-demand aza-Diels–Alder reaction of
α-pyrones and enals.
α,β-unsaturated hydrazones with aromatic imines afforded tet-
1
0
rahydroquinolines. We focused on this umpolung approach
to enhance the reactivity of α,β-unsaturated carbonyl com-
pounds with α-pyrones I (Scheme 1D). That is, α,β-unsaturated
hydrazones II, which have higher HOMO levels than the
parent enals because of the electron-donating ability of the
An inverse-electron-demand Diels–Alder reaction is frequently
used for the construction of various six-membered rings. For
example, cycloaddition of electron-deficient α-pyrones with
electron-rich olefins has been reported and applied for total
1
2
3
synthesis of natural products. Despite many reports on this
type of cycloaddition of α-pyrones having an electron-with-
drawing group at the 3-position I with enolethers and enam-
ines having a high HOMO level owing to the presence of an
4
electron-donating group (Scheme 1A), there are few reports on
cycloaddition of α-pyrones I with alkyl-substituted alkenes,
probably because these compounds have a lower HOMO level,
and the reactions often require high temperature or high
5
pressure (Scheme 1B). Furthermore, α,β-unsaturated carbonyl
compounds having low HOMO levels are poorly reactive with
α-pyrones I due to the mismatch of their frontier orbitals
6
,7
(
Scheme 1C). In fact, although the reaction of 3-methoxycar-
bonyl α-pyrones with indenones is known, this reaction
required extremely high pressure conditions with very high
concentrations probably due to low reactivity, selectively
affording anti cycloadducts (head-to-tail cycloadducts) with
opposite regiochemistry to that of a matched combination
8
(
A). Accordingly, there is no efficient synthetic method for
syn adducts of α-pyrones having an electron-withdrawing
Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
E-mail: tamura@ac.shoyaku.ac.jp
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Cycloaddition of 3-electron-withdrawing group substituted
α-pyrones.
c8ob02132e
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amino group, should react with electron-deficient α-pyrones I Table 1 Optimization of Lewis acid for α-pyrone activation
having low LUMO levels with matching frontier orbitals.
Moreover, the regio-selectivity can be expected to be syn,
because the orbital coefficient at the 6-position will be larger
than that at the 3-position in the LUMO of α-pyrone I and the
orbital coefficient will also be large at the β position in the
HOMO of α,β-unsaturated hydrazone II. Here, we report
inverse-electron-demand Diels–Alder reactions of electron-
Run
Catalyst
ZnCl
Mol%
Temp.
Time
Yield
3 : 4
deficient α-pyrones I with α,β-unsaturated hydrazones II to
afford cycloadducts III with high syn and endo selectivity.
Our studies began with examination of the reactions of
methyl 2-oxo-2H-pyran-3-carboxylate (1a) with acrolein deriva-
tives without any additive, in order to compare their reactiv-
ities (Scheme 2). Firstly, α-pyrone 1a failed to react with acro-
1
2
3
4
5
6
2
30
30
30
30
10
5
rt
rt
0 °C
rt
rt
30 h
50 h
4 h
17 h
26 h
20 h
33%
27%
76%
90%
86%
75%
80 : 20
89 : 11
94 : 6
97 : 3
92 : 8
AlCl
Eu(fod)
Eu(hfc)3
3
3
Eu(hfc)
Eu(hfc)
3
3
rt
90 : 10
lein (2a) at 80 °C. In contrast, the reaction with the corres- Recovery of α-pyrone 1a: 7% (run 1), 43% (run 2).
1
1
ponding dimethylhydrazone derivative 2b
0 °C to produce only syn cycloadducts, as expected, in moder-
ate yield as a 92 : 8 mixture of endo-adduct 3ab and exo-adduct Eu(hfc) (run 5), whereas 5 mol% Eu(hfc) resulted in a slight
proceeded at
4
3
3
4
ab. The structures of the two isomers were determined by reduction of the yield (run 6). Gradual lowering of the endo-
means of NOESY experiments, as shown in Fig. 1. The syn selectivity was observed when the amount of the catalyst was
selectivity can be explained in terms of frontier orbital theory reduced. Taking into account the yield, selectivity, and catalyst
as described above. We also examined the reaction with oxime loading, we chose 10 mol% Eu(hfc) in dichloroethane as the
3
1
2
16
derivative 2c as another polarity-inverted enal, but no reac- optimum conditions.
tion occurred.
Next, the substrate scope of this reaction for α-pyrones was
Next, we investigated whether a Lewis acid catalyst would studied (Table 2). The reaction of 3-p-toluenesulfonyl-substi-
1
7
improve the conversion (Table 1). Although the use of ZnCl or tuted α-pyrone 1b
with acrolein dimethylhydrazone (2b)
resulted in degradation (runs 1 and 2), lanthanide cata- catalyzed by 10 mol% of Eu(hfc) successfully afforded cyclo-
2
AlCl
lyst Eu(fod)
Furthermore, Eu(hfc) , which is occasionally used for the (run 1). In contrast, the reaction of 5-methoxycarbonyl-
3
3
3
increased the product yield to 76% (run 3). adducts 3bb and 4bb quantitatively with good endo selectivity
3
1
3
cycloaddition of α-pyrone-3-carboxylate,
adducts in 90% yield with perfect endo selectivity (run 4).
These results can be explained by the oxophilic nature of hard the lower affinity of 5-methoxycarbonyl α-pyrone 1c for the
afforded cyclo- substituted α-pyrone 1c was slow, and gradual decomposition
14
was observed (run 2). This result can be explained in terms of
1
5
lanthanide catalysts. Next, we examined whether the catalyst Lewis acid catalyst, as compared with 3-methoxycarbonyl
loading could be lowered. The endo cycloadduct 3ab was α-pyrone 1a, due to its lack of bidentate chelation ability with
obtained in high yield and selectivity by using 10 mol% the Eu complex. In this reaction, only a trace amount of
exo-adduct 4cb was isolated from the complex mixture. As the
reaction of non-substituted α-pyrone 1d was very slow even at
80 °C (run 3), as expected, this cycloaddition reaction appears
to be an inverse-electron-demand Diels–Alder reaction.
Next, we examined the scope of α,β-unsaturated hydrazones
1
1
(
Table 3). The reaction of methacrolein hydrazone 2d gave
Table 2 Substrate scope: α-pyrones
Scheme 2 Cycloaddition with acrolein derivatives without a Lewis acid.
1
2
Run
R
R
Temp.
Time
Yield
3 : 4
1
2
3
SO
H
H
2
p-tol
H
CO
H
50 °C
rt
80 °C
10 h
48 h
40 h
99%
2%
9%
83 : 17
Only 4cb
Only 3db
2
Me
Fig. 1 Structure determination by means of NOESY experiments.
Recovery of α-pyrone 1d: 78% (run 3).
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Table 3 Substrate scope: α,β-unsaturated hydrazones
Scheme 4 Dehydrazonation of cycloadduct 3ab.
1
2
Run
R
R
Temp.
Time
Yield
3 : 4
1
2
3
Me
H
H
H
Me
Ph
rt
50 °C
80 °C
4.5 h
16 h
26 h
67%b
72%
17%
52 : 48
96 : 4
>95 : trace
Conclusions
a
We have developed an inverse-electron-demand Diels–Alder
reaction of α-pyrones bearing a 3-electron-withdrawing group
with α,β-unsaturated hydrazones as a new type of electron-rich
olefin. The reaction was catalysed by the oxophilic lanthanide
a
b
trans : cis = 89 : 11. cis-Alkene derived isomer (4%) was excluded.
3
cycloadducts in moderate yields with poor stereoselectivity complex Eu(hfc) and showed high endo selectivity. This
(
run 1). In contrast, the cycloaddition with crotonaldehyde method enabled us to synthesize a hydrazone-containing
9
hydrazone 2e selectively afforded the endo adduct in good cycloadduct that can undergo hydrazone-specific reactions.
yield (run 2). Surprisingly, the cycloaddition of cinnamalde- To our knowledge, this is the first report of an all-carbon
1
8
hyde hydrazone 2f was not complete even after 26 hours at inverse-electron-demand
Diels–Alder
reaction
using
8
0 °C, and the endo-cycloadduct 3af was obtained in low yield α,β-unsaturated hydrazone as a dienophile apart from the reac-
1
9
concomitantly with gradual decomposition of 1a (run 3). We tions of 1,2-diazepine. We also succeeded in dehydrazona-
established that the reason why the reaction did not proceed tion to afford the corresponding aldehyde, which cannot be
to completion was the occurrence of retrocycloaddition easily obtained by the cycloaddition of α-pyrone and enal.
(
Scheme 3). When the cycloadduct 3af was treated under the Studies to develop an asymmetric version of this cycloaddition
same reaction conditions, α-pyrone 1a (59%) and are ongoing.
α,β-unsaturated hydrazone 2f (70%) were obtained along with
the starting cycloadduct 3af (30%) (eqn (1)). This experiment
clearly showed the occurrence of equilibration of the cyclo- Conflicts of interest
addition with 2f. Therefore, we tried to improve the yield by
loading an excess amount of α-pyrone to move the equili-
There are no conflicts to declare.
brium. The cycloaddition of α-pyrone 1a (10 equiv.) and cinna-
maldehyde hydrazone 2f (1 equiv.) gave endo cycloadduct 3af
in moderate yield with high selectivity, accompanied by the
Acknowledgements
recovery of the starting materials (eqn (2)).
This work was supported by a Grant-in-Aid for Young
Scientists of Showa Pharmaceutical University (Y. H.) and JSPS
KAKENHI Grant Number 17K08221 (O. T.).
Finally, we examined the indirect synthesis of aldehyde 3aa,
which is the equivalent of the syn–endo-cycloadduct between
α-pyrone-3-carboxylate 1a and acrolein (2a), by dehydrazona-
tion of cycloadduct 3ab (Scheme 4). Under hydrazone
exchange conditions (HCl and aq. HCHO), 3ab gave aldehyde
Notes and references
3
aa quantitatively.
1
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Scheme 3 Retrocycloaddition and improvement of the yield.
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7
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3
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3
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