Synthesis of polysubstituted α-pyrones using zinc-catalyzed addition-cyclization reactions

Article abstract of DOI:10.1002/jhet.1698

Various polysubstituted α-pyrone derivatives have been directly synthesized via a hydroalkylation of Michael additional reaction following a cyclized process catalyzed by the Lewis acid of Zn(OAc)₂. This protocol provides a new convenient and s

Full text of DOI:10.1002/jhet.1698

September 2014
Synthesis of Polysubstituted a-Pyrones Using Zinc-Catalyzed
Addition–Cyclization Reactions
1541
a
a
a
b
*
*
Wei-Bing Liu, Cui Chen, Qing Zhang, and Zhi-Bo Zhu
aSchool of Chemistry and Life Science, Guangdong University of Petrochemical Technology, 2 Guangdu Road, Maoming
525000, China
bCollege of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
*
E-mail: lwb409@yahoo.com.cn
Additional Supporting Information may be found in the online version of this article.
Received February 8, 2012
DOI 10.1002/jhet.1698
Published online 18 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
O
CO2R2
O
O
O
Zn(OAc)2 ( 0.2 equiv.)
R1
R3
+
R3
R4
100 oC, 6 h
DMF (2mL)
R1
O
R4
1
2
3
1a ( R1=CO2Et; R2=Et )
1b ( R1=Ph; R2=Et )
2a ( R3=Ph; R4=Ph )
2b ( R3=Ph; R4=Me )
2c ( R3=Me; R4=Me )
2d ( R3=Me; R4=OEt )
1c ( R1=n-C5H11; R2=Me )
1d ( R1=CO2Me; R2=Me )
Various polysubstituted a-pyrone derivatives have been directly synthesized via a hydroalkylation of
Michael additional reaction following a cyclized process catalyzed by the Lewis acid of Zn(OAc)2. This
protocol provides a new convenient and step-economical route to construct heterocycles. Fourteen examples
are obtained from easily available materials with moderate to good yields.
J. Heterocyclic Chem., 51, 1541 (2014).
INTRODUCTION
that 6 h proved to be the optimal reaction time (entries 13–14).
Furthermore, 0.2 equivalent of Zn(OAc)2 turned out to be
the sacrificial amount of choice (entries 13 and 15).
Increasing the amount of Zn(OAc)2 cannot enhance the
yield obviously.
a-Pyrones and their analogs are found in numerous
natural products that display important biological activ-
ities [1–10] and are also widely used as intermediates in
organic and pharmaceutical synthesis [11–15]. There-
fore, they have attracted much attention by researchers
for the design and synthesis of polysubstituted and
highly functionalized a-pyrones [16–24]. On the basis
of our research, the various polysubstituted a-pyrones
and their analogs were obtained by the reaction of
alkynoates with activated methylene compounds in the
presence of NaOH at a certain temperature (Scheme 1)
[25]. In continuation of our studies, we became inter-
ested in exploring catalysts for addition–cyclization of
alkynes by 1.3-dicarbonyl compounds, on which we
report herein (Scheme 2).
Subsequently, we investigated the scope of the
reaction substrates under the optimized conditions, as
shown in Table 2. From the results, we can see that
the electron-deficient internal alkynes with two strong
electron-withdrawing groups were the good partners of
alkynes and proved to be more suitable for this
protocol than the alkynes with one strong electron-
withdrawing group. For example, diethyl but-2-ynedio-
ate (1a) and dimethyl but-2-ynedioate (1d) were the
better substrates than ethyl 3-phenylpropiolate (1b) and
methyl oct-2-ynoate (1c) for this transformation (Table 2
entries 1–14). This implied electron-deficient effect of
alkynes had a positive influence on the reaction. As
well as, the symmetrical 1,3-dicarbonyl compounds
were the better substrates for this addition–cyclization
reaction than asymmetrical 1,3-dicarbonyl compounds,
as was verified with their corresponding yields. For
instance, benzoylacetate (2b) and ethyl acetoacetate
(2d) both gave lower yield to the corresponding product
than dibenzoylmethane (2a) and acetylacetone (1c)
(Table 2 entries 1–14). Finally, the experimental results sug-
gested that this synthetic route includes the zinc(II)-catalyzed
addition of activated methylenes of 1,3-dicarbonyl com-
pounds to alkynoates to give the enolic adduct 5 [26,27],
RESULTS AND DISCUSSION
We initiated our studies by optimizing reaction
conditions for the addition–cyclization of diethyl
acetylenedicarboxylate (1a) by dibenzoylmethane (2a)
(Table 1). As shown in Table 1, Zn(OAc)2 proved to
be more effective than the other tested Lewis acids or
without any catalyst in dioxane at 100ꢀC for 4 h (entries
1–7). Yet, among a set of representative solvents,
dimethylformamide was chosen as the most effective
solvent for the reactions (entries 8–12). It is noteworthy
© 2014 HeteroCorporation

1542
W.-B. Liu, C. Chen. Q. Zhang and Z.-B. Zhu
Vol 51
which served as precursor to form the ethyl 5-acetyl-6-
methyl-2-oxo-2H-pyran-4-carboxylate (3ac) by dealcoholic
reaction (Scheme 3).
Scheme 1. Synthesis of six-membered heterocycles based on alkynoates.
O
O
R
R1
CO2Et
CH2(EWG)2
EWG
O
H
R
CO2Et
CONCLUSION
CH2(EWG)2
R
O
In conclusion, we have developed an efficient method
for the synthesis of polysubstituted and highly functiona-
lized a-pyrones using Zn(OAc)2 as the catalyst. This
protocol provides a convenient and step economical route
to construct a-pyrones from easily available 1,3-dicarbonyl
compounds and electron-deficient internal alkynes via a
sequential addition–cyclization process.
R
GWE EWG
Scheme 2. Synthesis of a-pyrones.
O
CO2R2
O
O
O
Zn(OAc)2
heat
R1
R3
Acknowledgments. The authors are grateful to the Guangdong
University of Petrochemical Technology of China for financial
support of this work.
+
R3
R4
R1
O
R4
Table 1
Optimization of reaction conditions.a
O
CO2Et
O
O
O
Cat. Sol.
100oC
+
Ph
Ph
EtO2C
Ph
CO2Et
O
Ph
3a
2a
1a
Entry
Catalyst (0.2 equiv)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
FeCl3
CuCl2
ZnCl2
ZnO
Zn(OAc)2
ZnBr2
None
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CH3CN
DMF
DMSO
THF
Toluene
DMF
59
51
68
65
75
70
42
74
79
66
71
62
85
85
85
9
10
11
12
13c
14d
15c,e
DMF
DMF
aUnless otherwise specified, all the reactions were carried out using 0.25 mmol of 1a, 0.25 mmol of 2a in 2.0 mL of solvent at 100ꢀC for 4 h.
bGC yield.
cReactional time: 6 h.
dReactional time: 8 h.
eZn(OAc)2: 1.0 equiv.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014
Synthesis of Polysubstituted a-Pyrones Using Zinc-Catalyzed
Addition–Cyclization Reactions
1543
Table 2
Zn(OAc)2-induced domino synthesis of polysubstituted a-pyrones.a
O
CO2R2
O
O
O
Zn(OAc)2 ( 0.2 equiv.)
R1
R3
+
R3
R4
100 oC, 6 h
DMF (2mL)
R1
O
R4
1
2
3
1a ( R1=CO2Et; R2=Et )
1b ( R1=Ph; R2=Et )
2a ( R3=Ph; R4=Ph )
2b ( R3=Ph; R4=Me )
2c ( R3=Me; R4=Me )
2d ( R3=Me; R4=OEt )
1c ( R1=n-C5H11; R2=Me )
1d ( R1=CO2Me; R2=Me )
Entry
1
2
3
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2b
2d
3aa
3ab
3ac
3ad
3ba
3bb
3bc
3bd
3ca
3cb
3cc
78
75
82
73
75
71
80
66
71
65
72
67
82
83
9
10
11
12
13
14
3cd
3db
3dd
aAll the reactions were carried out using 1.0 mmol of 1, 1.0 mmol of 2, 0.2 equivalent of Zn(OAc)2 in 2.0 mL of DMF at 100ꢀC for 4 h.
bIsolated yield.
Scheme 3. Hypothesized reaction pathway.
1a
O
O
O
O
O
Zn(OAc)2
EtO2C
CO2Et
H
Zn(OAC)2
EtO2C
O
CO2Et
2c
4
O
EtOH
O
O
EtO2C
OH
CO2Et
EtO2C
O
3ac
5
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