Stille couplings of 3-(trimethylstannyl)-5-bromo-2-pyrone for the syntheses of 3-aryl-5-bromo-2-pyrones and their ambident dienyl characters

Article abstract of DOI:10.1016/S0040-4039(02)01182-6

3-(Trimethylstannyl)-5-bromo-2-pyrone underwent facile Stille coupling reactions with aryl halides to produce various 3-substituted 5-bromo-2-pyrones. The resulting 3-aryl-2-pyrone derivatives underwent both normal and inverse electron demand D-A cycloadd

Full text of DOI:10.1016/S0040-4039(02)01182-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5779–5782
Stille couplings of 3-(trimethylstannyl)-5-bromo-2-pyrone for the
syntheses of 3-aryl-5-bromo-2-pyrones and their ambident
dienyl characters
a
a
b
a,
Jin-Hee Lee, Won-Suk Kim, Young Yiol Lee and Cheon-Gyu Cho *
a
Department of Chemistry, College of Natural Science, Hanyang University, 133-791 Seoul, South Korea
b
Department of Internal Medicine, College of Medicine, Hanyang University, 133-791 Seoul, South Korea
Received 14 May 2002; revised 14 June 2002; accepted 19 June 2002
Abstract—3-(Trimethylstannyl)-5-bromo-2-pyrone underwent facile Stille coupling reactions with aryl halides to produce various
-substituted 5-bromo-2-pyrones. The resulting 3-aryl-2-pyrone derivatives underwent both normal and inverse electron demand
3
Diels–Alder cycloadditions depending on the type of the dienophiles being reacted. © 2002 Elsevier Science Ltd. All rights
reserved.
Substituted 2-pyrones are important structural subunits1
present in a number of naturally occurring products.
Also as versatile synthetic building blocks, they have2
been used for the syntheses of many useful molecules.
In many cases, they have interesting physiological activ-
ities and have thus drawn much attention for their
The coupling reactions of 2a were investigated under
various catalytic conditions as summarized in Table 2.
Table 1. Stannylations of 3,5-dibromo-2-pyrone
3
synthesis. Due to the labile internal ester bond, how-
ever, direct substitutions onto the 2-pyrone ring have
4
been scarcely reported.
We have recently reported that 3,5-dibromo-2-pyrone
undergoes Sonogashira coupling reactions with various
terminal alkynes, regioselectively at the C3 position. In
HMDT
Conditions
2a (%)
2b (%)
5
addition, trimethyltin group could be introduced either
selectively at the C3 or both C3 and C5 positions,
depending on the reaction conditions (Table 1).
1
.2 equiv.
Toluene, 80°C, 4 h
THF, 100°C, 2 h
67
13
6
71
2.5 equiv.
Those stannylated 2-pyrones, readily separable with
column chromatography, would be useful reagents for
the introduction of various functionalities onto the
pyrone rings to produce structurally diverse 3-substi-
tuted and 3,5-disubstituted 2-pyrones.
Table 2. Stille couplings of 2a under various conditions
Herein, we report the Stille coupling reactions of 2a
with various aryl and hetero-aryl halides for the synthe-
sis of a series of previously unknown 3-aryl-5-bromo-2-
pyrone derivatives. Noteworthy is that all of the
Entry
Conditionsa
Yield (%)
1
2
3
4
5
Pd(PPh ) /toluene/100°C, 24 h
33
45
73
35
50
3
4
3
-substituted-5-bromo-2-pyrones are potent ambident
Pd(PPh ) Cl /DMF/50°C, 3 h
3
2
2
dienes endowed from the presence of the bromine atom
Pd(PPh ) Cl /CuI/DMF/50°C, 3 h
3 2 2
6
at the C5 position.
Pd(PPh ) Cl /CuI/MeCN/50°C, 8 h
3 2 2
Pd(PPh ) Cl /CuI/THF/50°C, 10 h
3
2
2
*
Corresponding author. Tel.: +82-2-2290-0936; fax: +82-2-2299-0762;
e-mail: ccho@hanyang.ac.kr
a
In all reactions, 5 mol% of Pd catalysts were used.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01182-6

5
780
J.-H. Lee et al. / Tetrahedron Letters 43 (2002) 5779–5782
As it turned out, the condition in entry 3 was best
suited for our Stille coupling reaction. The presence of
well proceeded, but not with aryl triflate under the
literature conditions. Couplings with hetero-aryl halides
provided 3-heteroaryl-5-bromo-2-pyrones, in moderate
yields as shown in Table 4.
+
1
catalytic amount of Cu led to substantial increases of
7
the rates and chemical yields. Use of less polar solvents
such as MeCN and THF did not give much improve-
ment. Table 3 summarizes the results on the Stille
couplings of 2a with various aryl halides using 5 mol%
of Pd catalyst.
The bis-stannylated 2-pyrone 2b also underwent facile
Stille coupling reactions with various aryl halides. The
reaction at the C5 position was significantly slower than
at C3. As shown below, either mono-coupled 4a or
bis-coupled product 4b can be obtained as a major
product by controlling reaction time and temperature
Oxidative additions of Pd(0) at C5 of 3-(trimethyltin)-5-
bromo-2-pyrone (2a) were sufficiently slow to suppress
otherwise problematic oligomerizations. The couplings
with both electron rich and deficient aryl halides were
(
Table 5). Second couplings at C5 of 4a would generate
other structurally interesting 2-pyrones containing two
different aryl groups.
Table 3. Stille couplings of 2a with selected aryl halides
In the essence, all the coupled products are potentially
ambident dienes due to the presence of the bromine
atom at C5 position. As shown in Scheme 1, 3-phenyl-
5
-bromo-2-pyrone 1a underwent both normal and
inverse electron demand Diels–Alder cycloadditions,
reacting with both methyl acrylate and benzyl vinyl
ether to provide the corresponding cycloadducts with
good to excellent diastereoselectivity and chemical
yields.
Table 4. Couplings with hetero-aryl halides
Table 5. Synthesis of mono- or bis-aryl-2-pyrones
Reaction time (h)
Temp. (°C)
Yield (%)
4
a
4b
8
4
50
100
59
17
Trace
67
8

J.-H. Lee et al. / Tetrahedron Letters 43 (2002) 5779–5782
5781
Br
Br
CO Me
2
O
CO Me +
O
2
o
tol/100 C/7h
O
O
O
8
7%
7a
8a
7b CO Me
2
(>99:1)
O
Br
Br
Br
OBn
3a
O
+
O
OBn
o
tol/100 C/12h
O
O
OBn
9
9%
8b
(70:30)
Scheme 1. Diels–Alder cycloadditions of 3a with MA and BVE.
Introduction of proper functional groups on the aryl
groups may modulate their dienyl characters. Thus, in
principle, electron donating substituents on the aryl
group may shift the resulting 2-pyrones to favor normal
electron demand Diels–Alder cycloadditions over the
other, and vice versa. A few competition experiments,
however, showed that the shifts were only minimal as
seen in Scheme 2. In these experiments, an equimolar
mixture of 3b and 3d was heated with 3 equiv. of
dienophile; methyl acrylate (MA) and benzyl vinyl ether
The stannylated 2-pyrones themselves may function as
dienes. As presented in Scheme 3, they indeed under-
went Diels–Alder cycloadditions with methyl acrylate
to produce the corresponding stannylated bicyclolac-
tones. Only a trace amount of the cycloadducts were
detected from the reactions with electron-rich, benzyl
vinyl ether, even after heating for 4 days.
In summary, we have shown that 3-(trimethylstannyl)-
2-pyrone readily prepared from regioselective stannyla-
tion of 3,5-dibromo-2-pyrone underwent facile Stille
coupling reactions with various aryl and hetero-aryl
(
BVE), respectively. The reactions were halted before
the completion.
OMe
NO2
Br
Br
MA
+
3
b and 3d
O
CO Me
O
CO Me
2
2
toluene
(1:1)
o
O
O
1
00 C
9
1
(1.2 : 1)
10
OMe
+
NO2
BVE
Br
Br
3b and 3d
O
OBn
O
OBn
toluene
(1:1)
o
1
00 C
O
O
1
12
(1.2 : 1)
Scheme 2. Competitive Diels–Alder cycloadditions of 3b and 3d.
O
Br
Br
SnMe3
CO Me
2
SnMe3
CO Me +
SnMe3
O
O
O
O
2
o
tol/100 C/24h
O
O
CO Me
Br
9
7%
2
9a
90:10)a
9b
(
2a
O
CO Me
SnMe3
2
Me Sn
3
Me Sn
3
SnMe3
CO Me +
SnMe3
OBn
o
O
O
2
O
O
tol/100 C/24h
54%
SnMe3
1
0a
(68:32)b
10b
2b
1
(
a) H NMR ratio; (b) Isolated ratio
Scheme 3. Diels–Alder cycloadditions of 2a and 2b.

5
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J.-H. Lee et al. / Tetrahedron Letters 43 (2002) 5779–5782
halides to furnish various 3-substituted-5-bromo-2-
pyrones. Second coupling reactions would generate 2-
pyrones substituted with two different aryl groups. The
resulting products cycloadded with both electron
deficient and rich dienophiles. We are currently investi-
gating other transition metal-catalyzed coupling reac-
tions on 3,5-dibromo-2-pyrone including aminations
and amidations as well as synthetic applications of the
resulting products.
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Acknowledgements
This work was supported by a grant of the Korea
Health 21 R&D Project, Ministry of Health & Welfare,
Republic of Korea.
4
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