Regioselectivity in the Stille Coupling Reactions of 3,5-Dibromo-2-pyrone

Article abstract of DOI:10.1021/ja037043a

The Stille couplings of 3,5-dibromo-2-pyrone normally take place regioselectively at C3, lower in electron density than C5, thus oxidative addition proceeds faster . When the reactions are carried out with Cu(I) in DMF or other polar aprotic solvent, however, the couplings occur predominantly at C5. The observed regiochemical reversal is attributed to the preferred formation of 5-pallado-2-pyrone intermediate which, in addition, turned out to be more reactive than 3-pallado-2-pyrone intermediate. Copyright

Full text of DOI:10.1021/ja037043a

Published on Web 11/01/2003
Regioselectivity in the Stille Coupling Reactions of 3,5-Dibromo-2-pyrone
Won-Suk Kim, Hyung-Jin Kim, and Cheon-Gyu Cho*
Department of Chemistry, Hanyang UniVersity, Seoul 133-791, Korea
Received July 3, 2003; E-mail: ccho@hanyang.ac.kr
Table 1. Stille Reactions under Various Reaction Conditions
The Stille coupling reaction is a widely used carbon-carbon
bond-forming synthetic method.1 Many important advances have
been reported in the literature, further expanding its scope and
versatility, with the development of efficient Pd catalysts and
ligands.2 Despite the extensive usage, however, there is no standard
entry
conditions
time
2a (%)
3a (%)
4a (%)
protocol for a given coupling reaction in terms of selecting an
appropriate set of reaction conditions as the reported procedures
employ a wide variety of solvents, catalysts, and additives for the
reactions.1c One of the synthetic limitations in the Stille reaction
would be its high steric demand, which often slows down the
subsequent Sn/Pd transmetalation in the catalytic cycle. Liebeskind
et al. have reported that the addition of CuI can increase the reaction
rate.3,4 The exact nature of the rate-enhancing “copper effect” is,
however, not fully understood. They suggested that the added Cu(I)
salt would increase the otherwise slow transmetalation by forming
organocopper species from the organotin reagent via a Sn/Cu
transmetalation, when the reaction is carried out with a weak ligand
in a polar solvent. The resulting organocopper species is believed
to undergo Cu/Pd transmetalation at a higher rate than organotin
reagents. In ethereal solvents, the CuI would facilitate the formation
of the coordinatively unsaturated Pd-species formed in the oxidative
addition step.5 There are a few contrasting cases in the literature
where organotin undergoes cross coupling reactions with the action
of Cu(I) alone.6
In connection to our ongoing research program on the chemistry
of 3,5-dibromo-2-pyrone, we have reported its Stille, Sonogashira,
and Pd-catalyzed amination reactions, all of which underwent
substitutions regioselectively at C3 over C5 position.7 The observed
regioselectivity at C3 is attributed to the lower electron density at
C3, proceeding via a faster oxidative addition of Pd(0) at this
position. The 13C NMR spectrum of 3,5-dibromo-2-pyrone clearly
indicates that C3 is more deshielded than C5 (C3: 113.8; C5: 100.0
ppm). The Stille coupling reaction with phenyl tributyltin in fact
provided 3-phenyl-5-bromo-2-pyrone 2a in 94% yield when the
reaction was carried out with CuI (10 mol %) in refluxing toluene
(Table 1, entry 2).7b Quite surprisingly, however, the Stille coupling
reaction gave rise to 3-bromo-5-phenyl-2-pyrone 3a in 75% yield
when the coupling was performed with 1.0 equiv of CuI in DMF
(entry 5). The structures of 2a and 3a were fully characterized
spectroscopically and confirmed upon chemical transformations into
the corresponding cycloadducts.8 In this account, we present the
details of the Stille coupling reactions of 3,5-dibromo-2-pyrone,
the first report showing that the Stille couplings can be made to
occur at either of two chemically different bromides, depending
on the reaction conditions.
1
2
Pd(PPh3)4/tol/100 °C
Pd(PPh3)4/CuI (0.1 equiv)/
tol/100 °C
Pd(PPh3)4/CuI (1.0 equiv)/
tol/100 °C
Pd(PPh3)4/CuI (0.1 equiv)
/DMF/50 °C
Pd(PPh3)4/CuI (1.0 equiv)/
DMF/50 °C
Pd(PPh3)4/DMF/50 °C
Pd(PPh3)4/LiCl(1.0 equiv)/
DMF/50 °C
CuI (1.0 equiv)/
DMF/50 °C
0.5 h
0.5 h
81
94
trace
trace
16
trace
3
4
5
2 h
5 h
2 h
71
6
4
34
20
75
trace
trace
trace
6
7
4 d
1 d
41
50
2
trace
1
9
8
3 d
trace
3
trace
Table 2. Effect of CuI in DMFa
entry
CuI
time
ratio (2a:3a)
total yield (%)
1
2
3
4
5
6
7
none
0.1
0.2
0.3
0.4
0.5
1.0
4 d
5 h
5 h
4.5 h
2.5 h
2.5 h
2 h
100:0
63:37
45:55
19:81
15:85
0:100
0:100
41
54
76
64
66
64
75
a Reaction condition: Pd(PPh3)4/DMF/50 °C.
Table 3. Effect of Solvent Polarity with 1 Equiv of CuIa
entry
solvent
temp/time
ratio (2d:3d)9
total yield (%)
1
2
3
4
5
6
toluene
100 °C/1.5 h
100 °C/1.5 h
100 °C/0.5 h
50 °C/0.5 h
50 °C/5 min
50 °C/5 min
86:14
81:19
77:23
12:88
8:92
71
53
97
68
39
46
1,4-dioxane
CH2Cl2
DMF
DMSO
NMPb
39:61
a Pd(PPh3)4 (5 mol %). b PdCl2(PhCN)2 (5 mol %)/AsPh3.
observed in toluene, regardless of the amount of CuI (data not
shown).
With 1.0 equiv of CuI, the ratio (3d:2d) increases as the solvent
polarity increases (Table 3). In these experiments, we used 2-furyl
tributyltin instead of phenyl tributyltin for easier chromatographic
separation of the two regioisomeric products.
A similar trend was observed with other stannanes (Table 4).
Condition C was used for the coupling with vinyltin (entry 9) as
the product decomposes under condition A.10 In entry 2, no isolable
products were seen under condition B. Apparently, the Stille
couplings took place at the electron-rich C5, rather than the usual
C3 position under condition B, which may not be readily explain-
able with the level of current mechanistic understanding.11
In toluene, the added CuI has no effect on the regiochemistry.
The addition of CuI not only increases the reaction rate, but also
changes the course of the reaction, providing more of 3a than 2a
when the reaction was conducted in DMF (entry 5).
In DMF, the ratio of 3a to 2a increases in proportion to the
equivalents of CuI (Table 2). No regiochemical changes were
9
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J. AM. CHEM. SOC. 2003, 125, 14288-14289
10.1021/ja037043a CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 4. Regiocontrolled Stille Couplings with Other Stannanesa
In summary, we have found that 3,5-dibromo-2-pyrone undergoes
Stille coupling reactions regioselectively at either C3 or C5,
depending on the reaction conditions. The preferred formation of
the Pd intermediate 6 and its higher reactivity would account for
the regioselective substitutions at C5 when the Stille couplings are
conducted under condition B. Further study is underway to elucidate
the exact nature of the Cu(I) effect on the oxidative addition of
Pd(0) in a polar solvent.
Acknowledgment. We thank the financial support of Korea
Health 21 R&D (01-PJ1-PG1-01CH03-0003) and Center for
Bioactive Molecular Hybrid. We also thank Professor M. S. Lah
for the X-ray crystallographic study. K.W.S. and K.H.J. thank the
BK21 fellowship.
Supporting Information Available: Spectral data for 2a-2j,
3a-3j, 5a, 5b, and 6 (PDF) and X-ray structures of 5a, 5b, and 6 in
CIF format.This material is available free of charge via the Internet at
http://pubs.acs.org.
References
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a A: Pd(PPh3)4/CuI (0.1 equiv)/PhMe/100 °C, B: Pd(PPh3)4/CuI (1.0
equiv)/DMF/50 °C, C: Pd2dba3/P(t-Bu)3/PhMe/rt2.
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entry
conditions
toluene/100 °C
toluene/CuI(1.0 equiv)/100 °C
DMF/50 °C
ratio (5:6)12
1
2
3
4
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100:0
100:0
30:70
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DMF/CuI(1.0 equiv)/50 °C
(8) 2a and 3a produced 7a-endo and 8a-endo, respectively, upon cycload-
ditions with methyl acrylate. The cycloadduct from the cycloaddition of
1 with methyl acrylate has been shown to undergo the coupling reaction
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Lee, H.-S.; Kim, D.-S.; Won, H.; Choi, J. H.; Lee, H.; Cho, C.-G.
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A set of control experiments demonstrated that it is the favorable
oxidative addition of “PdL2” at C5, together with higher reactivity
of the resulting Pd intermediate 6 (vide infra) that determines the
regiochemical outcome under condition B. Table 5 summarizes the
effects of solvent and CuI on the regiochemistry of the oxidative
adducts. Heating in toluene without CuI provided exclusively 5a
(entry 1), accompanied with small amount 5b formed from the
halogen exchange on Pd when CuI was added (entry 2), with no
traceable 6 in either case. In DMF, CuI plays a decisive role,
providing mainly 6 under the conditions representing the actual
catalytic conditions (entry 4). The palladium complexes 5a, 5b,
and 6 are sufficiently stable for the silica gel column chromatog-
raphy and subsequent recrystallization for X-ray crystallography.
The isolated 5a produced 2a in 91% yield when reacted with
phenyltributyltin, while the same reaction with 6 provided 3a in
99% yield.
(9) 2d: 3-(2-furyl)-5-Br-2-pyrone, 3d: 5-(2-furyl)-3-Br-2-pyrone.
(10) The initially formed coupling product underwent dimerization via a Diels-
Alder cycloaddition during the column chromatography.
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Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978. (c) Cotter,
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Sterzo, C. L. J. Am. Chem. Soc. 2002, 124, 1060. (f) Ghosh, I.; Jacobi, P.
A. J. Org. Chem. 2002, 67, 9304.
The Pd intermediate 6 undergoes much faster coupling reaction
than 5; an equimolar mixture of 5a (or 5b), 6, and phenyltributyltin
provided exclusively 3a in quantitative yield after 30 min at 50 °C
in DMF (5a or 5b remained intact). Similar regiochemical outcomes
were obtained when CuBr was used in lieu of CuI, excluding the
possible involvement of iodine in the reaction.
(12) The ratio was determined by 1H NMR spectroscopy and isolation.
JA037043A
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