Novel 2-pyrone synthesis via the nucleophilic addition of active methine compounds to 2-alkynone

Article abstract of DOI:10.1016/S0040-4039(03)00211-9

Novel 2-pyrone synthesis via the nucleophilic addition of active methine compounds to 2-alkynone has been developed. The reaction of active methine compounds with 2-alkynone provided 2-pyrones in good yields.

Full text of DOI:10.1016/S0040-4039(03)00211-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2061–2063
Novel 2-pyrone synthesis via the nucleophilic addition of active
methine compounds to 2-alkynone
Iwao Hachiya, Hitoshi Shibuya and Makoto Shimizu*
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 8 December 2002; revised 9 January 2003; accepted 17 January 2003
Abstract—Novel 2-pyrone synthesis via the nucleophilic addition of active methine compounds to 2-alkynone has been developed.
The reaction of active methine compounds with 2-alkynone provided 2-pyrones in good yields. © 2003 Elsevier Science Ltd. All
rights reserved.
The development of the synthetic method of functional-
ized 2-pyrone is important as a result of the large
number of biologically active compounds containing a
2-pyrone structure1 and as dienes in Diels–Alder
cycloadditions.2 Many synthetic methods of 2-pyrone
have been reported to date.3 As a recent example, Ma
reported the efficient synthesis of a-pyrone derivatives
by a K2CO3-catalyzed Michael addition–lactonization
reaction of 1,2-allenyl ketones with substituted acetates
with electron-withdrawing groups.4 We have recently
reported novel 2-pyridone synthesis via the nucleophilic
addition of malonic esters to alkynyl imines (Scheme 1,
Eq. (1)).5 We found that 3,4,5,6-tetrasubstituted-2-
pyrones were obtained when nucleophilic additions of
malonic esters were carried out with 2-alkynones
instead of alkynyl imines. In this paper, we describe
novel 2-pyrone synthesis via the nucleophilic addition
of active methine compounds to 2-alkynones (Scheme
1, Eq. (2)).
The effects of bases in the model reaction of diethyl
methylmalonate
1
(R1=Me) with tert-butyl 2-
phenylethynyl ketone 2 (R2=Ph, R3=tBu) are shown
in Table 1. In every case, the reaction proceeded in
1,4-dioxane under reflux for 1 h to give 5-ethoxycar-
bonyl-2-pyrone 3 accompanied by its decarboxylated
2-pyrone 4. Among the bases tested, sodium hydride
and sodium ethoxide were effective (entries 1 and 2).
Next, we investigated the effect of the substituent R3 of
2-alkynone 2. The reaction of methyl 2-phenylethynyl
ketone 2 (R2=Ph, R3=Me) gave only the 1,4-adduct 5
(R1=Me, R2=Ph, R3=Me) in 58% yield (entry 4). On
the other hand, ethyl and isopropyl ketones afforded
2-pyrones 3, their decarboxylated 2-pyrones 4, and
1,4-adducts 5, respectively (entries 5 and 6). In the case
of tert-butyl and phenyl ketones, 2-pyrones 3 and their
decarboxylated 2-pyrones 4 were obtained, respectively
(entries 1 and 7).
Several examples of the present 2-pyrone synthesis via
the nucleophilic addition of malonic esters to 2-
alkynones were examined.6 tert-Butyl 2-(1-cyclohex-
enyl) ketone 2 (R2=1-cyclohexenyl, R3=tBu) having a
double bond gave 2-pyrone 3 (R1=Me, R2=1-cyclo-
hexenyl, R3=tBu) in 87% yield (entry 8). In the case of
2-alkynone 2 (R2=TBS(CH2)3 or TBDPS(CH2)3, R3=
tBu), decarboxylated 2-pyrones 4 were obtained as
major products (entries 9 and 10). However, the reac-
tion of diethyl allylmalonate 1 (R1=allyl) gave the
desired 2-pyrone 3 (R1=allyl, R2=Ph, R3=tBu) in low
yield (entry 11).7 We next examined a b-ketoester as a
Scheme 1.
* Corresponding author. Tel.: +81-59-231-9413; fax: +81-59-231-9413;
e-mail: mshimizu@chem.mie-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00211-9

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I. Hachiya et al. / Tetrahedron Letters 44 (2003) 2061–2063
Table 1. 2-Pyrone synthesis using malonic estersa
Entry
R1
R2
R3
Base
Yield (%)
3
4
5
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Allyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
tBu
tBu
tBu
Me
Et
NaH
75
80
53
9
7
4
NaOEt
KOtBu
NaOEt
NaOEt
NaOEt
NaOEt
NaOEt
NaH
58
25
17
19
49
56
87
20
24
9
10
13
8
iPr
Ph
1-Cyclohexenyl
TBSO(CH2)3
TBDPSO(CH2)3
Ph
tBu
tBu
tBu
tBu
9
10
11
43
50
NaH
NaH
a For reaction conditions, see Ref. 6.
nucleophile instead of malonic esters. While under the
conditions reported5 the reaction of b-ketoesters with
alkynyl imines provided 2-pyridones in good yields,8
that of ethyl 2-methyl-3-oxobutanoate 6 (R=Me) with
tert-butyl 2-phenylethynyl ketone proceeded to give
5-acetyl-2-pyrone 7 (R=Me) in 60% yield along with its
deacetylated 2-pyrone 8 (R=Me) in 6% yield (Table 2,
entry 1). Even by increasing the steric bulk of the
nucleophile with ethyl 2-(2-propenyl)-3-oxobutanoate 6
(R=allyl), 5-acetyl-2-pyrone 7 (R=allyl) was obtained
in 58% yield.
We propose a plausible reaction mechanism as shown
in Scheme 2. Metalloallenoate 11 would be generated
via the 1,4-addition reaction of the active methine
compound sodium salts 9 to 2-alkynone 10 and would
undergo
intramolecular
cyclization
to
give
cyclobutenoxide intermediate 12. The cyclobutenoxide
intermediate 12 would be transformed into the metal-
enolate 13 via ring-opening, and the subsequent cycliza-
tion would give 2-pyrone 14 (Path A). Metalloallenoate
11 would undergo protonation to give a,b-unsaturated
ketone 15. The decarboxylated 2-pyrone 16 would be
formed via the nucleophilic addition of sodium alkox-
ide to the carbonyl group of 15 and the subsequent
cyclization (Path B).9
Table 2. 2-Pyrone synthesis using b-keto estersa
To obtain decarboxylated 2-pyrone, 2-methyl Mel-
drum’s acid 17 was used as a nucleophile (Eq. (3)). The
reaction of 17 with tert-butyl 2-phenylethynyl ketone
using NaHMDS as a base gave only 2-pyrone 18 in
79% yield.
(3)
We suggest a possible reaction mechanism as shown in
Scheme 3. Metalloallenoate 20 would be generated via
the 1,4-addition reaction of 2-methyl Meldrum’s acid
sodium salts 19 to tert-butyl 2-phenylethynyl ketone.
Metalloallenoate 20 would undergo protonation to give
a,b-unsaturated ketone 21. The decarboxylated 2-
pyrone 18, acetone and carbon dioxide would be
formed via the thermolysis of a,b-unsaturated ketone
21 and the subsequent cyclization.
Entry
R
Yield (%)
7
8
1
2
Me
Allyl
60
58
6
Trace
a For reaction conditions, see Ref. 6.

I. Hachiya et al. / Tetrahedron Letters 44 (2003) 2061–2063
2063
Scheme 2.
D. M. A.; Baldwin, E. T.; Erickson, J. W.; Sawyer, T. K.
J. Am. Chem. Soc. 1994, 116, 6989.
2. Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H.
Tetrahedron 1992, 48, 9111.
3. Staunton, J. In Comprehensive Organic Chemistry; Sammes,
P. G., Ed.; Pergamon Press: Oxford, 1979; Vol. 4, pp.
629–658.
4. Ma, S.; Yin, S.; Li, L.; Tao, F. Org. Lett. 2002, 4, 505 and
references cited therein.
5. Hachiya, I.; Ogura, K.; Shimizu, M. Org. Lett. 2002, 4, 2755.
6. A typical experimental procedure of the reaction of 2-
alkynone with an active methine compound: To 60% NaH
or sodium ethoxide (0.400 mmol) was added a solution of
an active methine compound (0.500 mmol) in 1,4-dioxane
(2.0 mL) and a solution of 2-alkynone (0.200 mmol) in
1,4-dioxane (2.0 mL) successively at room temperature. The
reaction mixture was stirred under reflux for 1 h and then
cooled to room temperature. Brine (10 mL) was added to
quench the reaction. The mixture was extracted with
dichloromethane (15 mL×3). The combined organic layers
were dried over sodium sulfate. The solvents were evapo-
rated in vacuo, and then the residue was purified by
preparative TLC on silica gel to give 2-pyrone and decar-
boxylated 2-pyrone.
7. When dimethyl allylmalonate was used instead of diethyl
allylmalonate, the desired 2-pyrone and its decarboxylated
2-pyrone were obtained in 24 and 6% yields, respectively.
8. For example, the reaction of ethyl 2-methyl-3-oxobutanoate
6 (R=Me) with the imine derived from 3-phenyl-2-propynal
and 4-methoxyaniline gave N-(4-methoxyphenyl)-5-acetyl-
3-methyl-4-phenyl-2-pyridone in 64% yield. The details of
the 2-pyridone synthesis via nucleophilic addition of b-
ketoesters to alkynyl imines will be reported in a full paper.
9. In the case of malonic esters as a nucleophile, it would be
possible to generate cyclobutenone 22. See Ref. 5.
Scheme 3.
In summary, we have found a novel method for 2-
pyrone synthesis by the 1,4-addition of active methine
compounds to 2-alkynone. Although numerous meth-
ods for the synthesis of 2-pyrones are available, in the
present reactions, 3,4,6-trialkyl-5-ethoxycarbonyl or 5-
acetyl-2-pyrones can be easily obtained via a novel
reaction mechanism including cyclobutenoxide interme-
diates because 2-alkynones and active methine com-
pounds such as malonic esters and b-ketoesters,
respectively, are readily available. The synthetic appli-
cation of 2-pyrones is now in progress.
References
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Pharm. Sci. 1967, 56, 1535; (b) Kupchan, S. M.; Moniot,
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36, 2611; (c) Hayashi, Y.; Yuki, Y.; Matsumoto, T.; Sakan,
T. Tetrahedron Lett. 1977, 18, 3637; (d) Prasad, J. V. N. V.;
Para. K. S.; Lunney, E. A.; Ortwine, D. F.; Dunbar, J. B.,
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Domagala, J. M.; Humblet, C.; Bhat, T. N.; Liu, B.; Guerin,