Regioselective Stille coupling reactions of 3,5-dibromo-2-pyrone with various aryl and vinyl stannanes

Article abstract of DOI:10.1016/S0040-4039(02)02305-5

3,5-Dibromo-2-pyrone underwent facile regioselective Stille coupling reactions with aryl, heteroaryl and vinyl stannanes to produce various 3-substituted, 5-bromo-2-pyrones. Addition of a catalytic amount of CuI greatly increased the selectivity and chemical yield of the desired 3-aryl-5-bromo-2-pyrone. Second Stille coupling reactions on the resulting 3-aryl-2-pyrones gave rise to a series of potentially useful 2-pyrones with two different functionalities at C3 and C5 position in good to excellent isolated yields. 2-Pyrones with pyridyl groups at C3 position can undergo Lewis acid catalyzed Diels-Alder cycloaddition reactions with benzyl vinyl ether.

Full text of DOI:10.1016/S0040-4039(02)02305-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9015–9017
Regioselective Stille coupling reactions of 3,5-dibromo-2-pyrone
with various aryl and vinyl stannanes
Won-Suk Kim, Hyung-Jin Kim and Cheon-Gyu Cho*
Department of Chemistry, Hanyang University, Seoul 133-791, South Korea
Received 29 September 2002; accepted 16 October 2002
Abstract—3,5-Dibromo-2-pyrone underwent facile regioselective Stille coupling reactions with aryl, heteroaryl and vinyl stannanes
to produce various 3-substituted, 5-bromo-2-pyrones. Addition of a catalytic amount of CuI greatly increased the selectivity and
chemical yield of the desired 3-aryl-5-bromo-2-pyrone. Second Stille coupling reactions on the resulting 3-aryl-2-pyrones gave rise
to a series of potentially useful 2-pyrones with two different functionalities at C3 and C5 position in good to excellent isolated
yields. 2-Pyrones with pyridyl groups at C3 position can undergo Lewis acid catalyzed Diels–Alder cycloaddition reactions with
benzyl vinyl ether. © 2002 Elsevier Science Ltd. All rights reserved.
In connection with our current interest in 3,5-dibromo-
2-pyrone, which stems from its ambident dienyl charac-
ter,1–7 we have studied various other transition metal
catalyzed coupling reactions on this compound.
Recently, we have reported Pd-catalyzed regioselective
alkynylations and stannylations of 3,5-dibromo-2-
pyrone.1 Also reported was that the resulting 3-
(trimethylstannyl)-5-bromo-2-pyrone underwent Stille
coupling reactions with various aryl halides to furnish a
series of previously unknown 3-aryl-5-bromo-2-pyrones
in a highly regioselective manner.2 With this method,
we were able to prepare a wide variety of synthetically
useful 3-substituted-5-bromo and 3,5-disubsituted-2-
pyrones (Scheme 1).
not effective in the couplings with heteroaryl halides
such as 2-bromopyridine, 2-bromothiophene and 2-bro-
mofuran. For synthetic inconvenience and aforemen-
tioned ineffectiveness, we have studied direct Stille
coupling reactions of 3,5-dibromo-2-pyrone with vari-
ous stannyl reagents.
Herein, we wish to report regioselective Stille coupling
reactions of 3,5-dibromo-2-pyrone with aryl, heteroaryl
and vinyl stannanes. A set of experiments showed that
the condition B gave best results in terms of chemical
yields and regioselectivity (Table 1). Addition of a
catalytic amount of CuI (10 mol%) greatly increased
the regioselectivity and chemical yield of the desired
3-phenyl-5-bromo-2-pyrone (4a).
Table 1. Stille coupling reaction of 3,5-dibromo-2-pyrone
with tributylphenyltin under different reaction conditions
Scheme 1. Stille couplings of 3-(trimethylstannyl)-5-bromo-2-
pyrone with various aryl halides.
Although quite useful, this approach requires a sepa-
rate preparation of 3-trimethylstannyl-5-bromo-2-
pyrone for the synthesis of 3-substituted, 5-bromo-
2-pyrones. In addition, the stannylated 2-pyrone was
Condition
4a (%)
4a% (%)
A
B
C
D
E
Pd(PPh3)4/toluene/100°C/30 min
Pd(PPh3)4/CuI/toluene/100°C/30 min
Pd(PhCN)2Cl2/AsPh3/NMP/20°C/5 h
Pd(PPh3)4/THF/100°C/40 min
Pd2(dba)3/THF/100°C/4 h
81
94
60
64
30
16
Trace
Trace
11
* Corresponding author. Tel.: +82-2-2290-0936; fax: +82-2-2299-0762;
e-mail: ccho@hanyang.ac.kr
5
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02305-5

9016
W.-S. Kim et al. / Tetrahedron Letters 43 (2002) 9015–9017
Table 2. Stille couplings with various other stannanes
Second coupling reactions of the resulting 3-substi-
tuted-5-bromo-2-pyrones generated a series of struc-
turally interesting 2-pyrones bearing two different
groups in 50–79% isolated yields (Table 3), much better
than the similar cases in the literature where 5-bromo-
2-pyrone was coupled with vinyl or aryl stannanes in
41–43% yields.9
All the products shown in the Table 2 are potentially
ambident dienes, capable of undergoing Diels–Alder
cycloadditions with either electron poor or rich
dienophiles.2 Of particular interest is that 2-pyrone
derivatives with 2-pyridine substituent at 3-position can
undergo Diels–Alder cycloadditions with electron rich
dienophiles in the presence of Lewis acids. As shown in
Scheme 2 as a representative case, the product 4h
underwent Zn+2 catalyzed Diels–Alder cycloaddition
Table 3. Stille coupling reactions of 4h with selected aryl
halides
Under the condition B, we undertook coupling reac-
tions with various other aryl, heteroaryl and vinyl
stannyl reagents (Table 2).8
The coupling reaction with vinyltin (entry 1) gave virtu-
ally no coupling product under the condition B, but did
proceed under the condition C to give 4b in 57% yield.
As mentioned previously, 3-(trimethylstannyl)-5-
bromo-2-pyrone is not effective in the coupling reac-
tions with 2-bromopyridine, 2-bromothiophene and
2-bromofuran. Use of 3,5-dibromo-2-pyrone as elec-
trophilic partner in this way gave much better results,
providing the corresponding 3-heteroaryl-5-bromo-2-
pyrones in 51–72% isolated yields (entries 5, 6, and 7).
Scheme 2. ZnBr2 catalyzed Diels–Alder cycloaddition of 3-(2-
pyridyl)-5-bromo-2-pyrone with benzyl vinyl ether.

W.-S. Kim et al. / Tetrahedron Letters 43 (2002) 9015–9017
9017
with benzyl vinyl ether to furnish the endo-cycloadduct
6a as an essentially single product in 81% yield after 48
h at −20°C. No cycloaddition was, however, observed
with electron deficient methyl acrylate under the same
reaction conditions, understandable based on electronic
requirement.
Zn+2 catalyzed Diels–Alder cycloadditions with electron
rich benzyl vinyl ether, but not with electron deficient
methyl acrylate. We are currently screening various
chiral ligands for their asymmetric Diels–Alder
reactions.
Mono-coordinating BF3 etherate did not give the
cycloadduct. The cycloaddition proceeds in a catalytic
manner, presumably through the intermediate 5. The
2-pyrones 4f and 4g were much poorer diene, perhaps
due to their inability to form tight Zn-chelates. After 12
h at rt, they gave the corresponding cycloadducts in
30–40% yields under the identical conditions.
Acknowledgements
This work was supported by IMT-2000 Program of
Ministry of Information & Communication, Republic
of Korea.
References
The di-substituted 2-pyrones 5a–d also underwent yet
smooth Zn+2 catalyzed cycloadditions with benzyl vinyl
ether, providing the endo-cycloadducts 6a–d with no
detectable exo-adducts produced (Table 4).10
1. Lee, J.-H.; Park, J.-S.; Cho, C.-G. Org. Lett. 2002, 4,
1171.
2. Lee, J.-H.; Kim, W.-S.; Lee, Y. Y.; Cho, C.-G. Tetra-
hedron Lett. 2002, 43, 5779.
3. Min, S.-H.; Kim, Y.-W.; Choi, S.; Park, K. B.; Cho,
C.-G. Bull. Korean Chem. Soc. 2002, 23, 1021.
4. Lee, H.-S.; Kim, D.-S.; Won, H.; Choi, J. H.; Lee, H.;
Cho, C.-G. Tetrahedron Lett. 2002, 43, 5591.
5. Cho, C.-G.; Kim, Y.-W.; Lim, Y.-K.; Park, J.-S.; Lee, H.
J. Org. Chem. 2002, 67, 290.
In summary, we have found that 3,5-dibromo-2-pyrone
underwent highly regioselective Stille coupling reactions
with various aryl, heteroaryl and vinyl stannanes to
furnish 3-substituted, 5-bromo-2-pyrones. Subsequent
second Stille couplings on the resulting 2-pyrones gen-
erated 3,5-disubstituted 2-pyrones.11 2-Pyrones with
pyridyl group at C3 position undergo diastereospecific
6. Cho, C.-G.; Park, J.-S.; Jung, I.-H.; Lee, H. Tetrahedron
Lett. 2001, 42, 1065.
Table 4. ZnBr2 catalyzed Diels–Alder cycloadditions of
5a–d with benzyl vinyl ether
7. Cho, C.-G.; Kim, Y.-W.; Kim, W.-K. Tetrahedron Lett.
2001, 42, 8193.
8. Typical procedure: A mixture of 30 mg (0.12 mmol) of
3,5-dibromo-2-pyrone, 52 mg (0.14 mmol) of trib-
utylphenyltin, 7 mg (5 mol%) of Pd(PPh3)4, 2 mg (10
mol%) of CuI and 1 mL of toluene was heated at 100°C
for 0.5 h. Upon cooling to rt, the reaction mixture was
treated with saturated KF (aq.), diluted with Et2O, and
filtered through a plug of Celite. The filtrate was dried
over MgSO4, concentrated and purified by column chro-
matography (hexanes:EtOAc, 20/1) provided 28 mg of 1a
in 94% yield.
9. (a) Danieli, B.; Lesma, G.; Martinelli, M.; Passarella, D.;
Peretto, I.; Silvani, A. Tetrahedron 1998, 54, 14081; (b)
Liu, Z.; Meinwald, J. J. Org. Chem. 1996, 61, 6693.
10. Typical procedure: A mixture of 35 mg (0.14 mmol) of
4h, 38 mg (2 equiv.) of benzyl vinyl ether, 3 mg (10
mol%) of ZnBr2 in CH2Cl2 was stirred for 48 h at −20°C.
The reaction mixture was concentrated and purified by
column chromatography (hexanes:EtOAc) to provide 44
mg of 6a in 81% yield.
11. All new 2-pyrone derivatives prepared were fully charac-
1
terized with H, 13C NMR, FT-IR and HRMS.