1814
K. C. Y. Lau, P. Chiu / Tetrahedron Letters 48 (2007) 1813–1816
Table 1. Stille coupling reactions with organostannanes
products have been obtained in palladium-catalyzed
reactions in yields varying from 4% to 58%.
5% Pd(PhCN)2Cl2
X
R
10% Ligand, RSnBu3
This Pd-aryl/P-aryl exchange process has been produc-
tively exploited by Chan and co-workers to synthesize
functionalized arylphosphines12 and arylarsines.13 The
exchange reactions resulted in 25–68% yields of the
functionalized phosphines or arsines, which were iso-
lated from an excess of Ph3P or Ph3As typically by con-
ventional column chromatography.
dioxane, reflux, 18 h
R'
Entry
R'
R
X
R0
Liganda
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Vinyl
Vinyl
Vinyl
Ph
Ph
Ph
Br
Br
Br
Br
Br
Br
I
H
H
AsPh3
88 (83)c
95 (81)c
(82)
69
72
74
1
1
1
1
1
1
1
1
1
1
2
2
2
2
CHO
OMe
Cl
Ph
H
In the Stille reactions using 1 as a ligand, the Pd-aryl/
P-aryl exchange would result in a modification in the
structure of the polymer-supported arsine. If this new
reagent 10 could be successfully recycled and reemployed
in Stille reactions involving the same aryl halide, the
scrambling process should have a diminished effect on
the yield of the desired coupling product, since the
cross-coupling product and the scrambled product
would effectively be the same. Alternatively, pretreating
1 with an aryl halide in the presence of palladium should
also lead to a similar modification of the arsine polymer
(Eq. 1). This pretreatment could serve as a way to
‘prime’ 1 to promote the formation of the desired het-
ero-coupling product. Without resorting to conven-
tional isolation techniques such as chromatography, by
taking advantage of the ease of recovery of the poly-
mer-supported arsine, we demonstrate the exploitation
of this scrambling process to modify 1 to 10.
72 (61)
91d
OTf
Br
I
H
Cl
Cl
87e
93e
Br
Br
Br
I
Ph
Cl
Ph
H
(86)e
61
67
33
99d
Ph
OTf
H
a NCPS–AsPh3 (1); NCPS–PPh3 (2).
b Yields determined by GC; yields in brackets are isolated yields.
c Reaction time was 5 h.
d 2.5% Pd2(dba)3, 100 °C, NMP.
e 2.5% Pd2(dba)3, 80 °C, NMP.
The effectiveness of 1 as a ligand was surveyed for vari-
ous Stille reactions of electron-rich and electron-defi-
cient substrates, aryl halides and triflates (Table 1,
entries 3–8). All reactions occurred under typical reac-
tion conditions as expected. The Stille coupling of vinyl-
tributylstannane proceeded with excellent yields (Table
1, entries 9–11). In each case, removal of the arsine
was done by precipitation. The product mixture was
concentrated and redissolved in a minimum amount of
hot THF, then added to 20% ether in hexane to precip-
itate 1. Compound 1 can then be isolated by suction fil-
tration, with a recovery of about 90–95%. The rest of the
product mixture was washed with saturated aqueous KF
before GC analysis and/or purification by column
chromatography.
(
)
(
1
(
)
(
1
)
8
)
8
Ph
Ph
Stille conditions
or cat. Pd, Ar-X
ð1Þ
AsPh2
As
Ar(n= 1,2)
Ph(2-n)
To examine the efficiency and effect of recycling 1, the
Stille reaction using 4-bromoanisole as an electron-rich
aryl halide substrate was carried out using a higher-
than-usual loading of 1 (20 mol %), for the purpose of
observing a more pronounced effect of scrambling.
When fresh 1 was used as a ligand in the first run, only
a 43% yield of p-methoxybiphenyl was obtained, to-
gether with 37% of the biphenyl side product (Table 2,
cycle 1). The subsequent reaction using recycled 1 re-
sulted in an increase in the yield of 4-methoxybiphenyl
with a concomitant decrease in the yield of biphenyl of
about 20%, clearly demonstrating that the use of recy-
cled 1 enhanced the yield of the cross-coupling product
(Table 2, cycle 2). The yields of both products did not
further increase or decrease in subsequent cycles 3–5.
The 15–20% yield of biphenyl that was still produced
in the reactions using recycled 1 is attributed to the
homocoupling of tributylphenyltin. This was quantified
by experiment, where a 16% yield of biphenyl was ob-
tained under the Stille conditions without the addition
of any aryl bromide.
Comparison was also made with NCPS–PPh3 reagent
(2) as a ligand for Stille reactions (Table 1, entries
12–15). The observations by Farina and co-workers that
the arsine ligand was generally superior was confirmed
for the soluble polymer-supported reagents as well.2
In Stille arylation reactions using phenyltributylstann-
ane, biphenyl was consistently found as a side product.
Biphenyl could result from two other reactions. One
was the homocoupling of PhSnBu3 itself.2c,10 Another
was the Stille reaction after the exchange of aryl groups
between ligand 1 and the aryl halide. Segelstein et al.
have reported that, especially in Stille coupling reactions
involving less reactive, electron-rich substrates, phenyl
groups on Ph3P exchange with the electron-rich aryl
group of the organopalladium intermediate, and then
proceeded to couple with the organostannane to gener-
ate biphenyl, and result in a lower yield of the desired
cross-coupling product.11 Such scrambled coupling
A second set of recycling experiments examined the
Stille reaction of 4-bromochlorobenzene (Table 3). A
yield enhancement of about 10% was observed using