Significant enhancement of the Stille reaction with a new combination of reagents-copper(I) iodide with cesium fluoride

Article abstract of DOI:10.1002/chem.200401162

A systematic investigation for enhancement of Stille reaction using the combination of copper(I) iodide and cesium fluoride was described. Initial route to the target compound involved a double Stille coupling in the carbon-carbon bond formation of the key intermediate 1. Homocoupling has often been observed in this reaction especially when electron-withdrawing substituents are present in conjugation with tin. After extensive optimization, a variety of electronically unfavourable and sterically hindered substrates were coupled in very high yields under mild conditions.

Full text of DOI:10.1002/chem.200401162

Significant Enhancement of the Stille Reaction with a New Combination of
Reagents—Copper(i) Iodide with Cesium Fluoride
Simon P. H. Mee, Victor Lee, and Jack E. Baldwin*[a]
Abstract: The combination of copper(i) iodide and cesium fluoride significantly
À
Keywords: C C coupling · cesium
enhances the Stille reaction. After extensive optimisation, a variety of electronical-
ly unfavourable and sterically hindered substrates were coupled in very high yields
under mild conditions.
fluoride
·
copper(i) iodide
·
palladium · Stille coupling
Table 1. Optimisation of the double Stille coupling leading to the devel-
opment of a new set of conditions for the Stille reaction.
Introduction
Over the last several decades palladium-mediated coupling
reactions have proved to be indispensable in organic synthe-
sis. In particular, the Stille coupling[1] of organotin reagents
with organic electrophiles has emerged as one of the most
popular methods for carbon–carbon bond formation.[2] This
is due in large measure to the air- and moisture-stability of
the organotin substrates and the compatibility of the process
with virtually any functional group.[3]
The reaction process for the Stille coupling is not trivial
and often extensive experimentation is required to pinpoint
the optimal conditions for a given reaction. We recently en-
countered a troublesome coupling reaction in our total syn-
thesis of the proposed structure of a natural product isolated
from the red beetroot.[4] A systematic investigation to en-
hance this particular coupling reaction led to the discovery
of a new set of conditions for the Stille reaction: copper(i)
salts in combination with the fluoride ion. We have previ-
ously communicated this work[5] and herein we report the
full details of our investigation.
Entry
Reagents
Conditions
Temp time
Yield
[%][a]
[8C]
[h]
1
2
3
4
2, 3, [Pd(PPh3)4], CuBr, THF
4, 5, [Pd(PPh3)4], CuBr, THF
4, 5, [Pd2(dba)3], AsPh3, CuBr, THF
4, 5, [Pd(PPh3)4], CuI, CsF, DMF
50
50
85
40
5
10
30
55
92
15
15
2
[a] Isolated yield of 1.
Our initial route to the target compound involved a
electron-withdrawing substituents are present in conjugation
with tin.[7] To overcome this problem we reversed the polari-
ties and hence the functional groups on the coupling part-
ners, which included developing a new efficient synthesis of
3,4-bis(tri-n-butylstannyl)furan (5).[8] Couplings of this furan
5 with the required aryl halide 4 gave an improved yield of
1, but the reaction was slow and was only half complete
after 15 h at 858C. During optimisation of this transforma-
tion, we discovered that the combination of CsF and CuI in
DMF greatly enhanced this reaction, affording 92% of the
desired product 1 after just 2 h at 408C (Table 1).
À
double Stille coupling in the central carbon carbon bond
formation of the key intermediate 1 (Table 1). Originally at-
tempts were made to couple the aryl stannane 2 with 3,4-di-
bromofuran (3); however, homocoupling of the stannane 2
was the main reaction in all attempts. Homocoupling has
often been observed in Stille reactions[6] especially when
[a] S. P. H. Mee, Dr. V. Lee, Prof. J. E. Baldwin
Chemistry Research Laboratory, University of Oxford
Mansfield Road, Oxford OX1 3TA (UK)
Fax : (+44)186-527-5632
Both copper(i) salts[9–14] and fluoride sources[15–19] have
been used previously to promote Stille reactions, but until
E-mail: jack.baldwin@chem.ox.ac.uk
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DOI: 10.1002/chem.200401162
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FULL PAPER
now there have been no reports of a Stille reaction that em-
ploys both reagents at the same time.
planations could be valid, depending on the conditions of
the reaction.[13]
With ethereal solvents they suggested that the copper
effect could be explained by the “ligand association” mecha-
nism (Scheme 2). In this proposal, the active species is
formed by loss of a ligand from the initial palladium(ii) spe-
cies (A) that is generated after oxidative addition. The role
of copper(i) is to facilitate this loss of ligand by coordination
to the excess ligand in solution, which otherwise causes au-
toretardation of the required ligand loss.
The Stille mechanism: The generally accepted mechanism
for the Stille reaction[20] involves oxidative addition of Pd0
into the aryl halide (or triflate) bond, transmetallation of
the organotin reagent followed by reductive elimination to
2
2
0
À
form the sp sp bond and regenerate the catalytic Pd spe-
cies (Scheme 1).
Scheme 2. The “ligand association” mechanistic explanation for the
copper effect.
Scheme 1. A simplified outline of the Stille reaction mechanism.
The transmetallation step is generally assumed to be rate-
limiting[21] and requires the substitution of a ligand at palla-
dium by R2.[22] This requirement has promoted attempts to
facilitate the removal of a ligand from the palladium(ii) spe-
cies, which has been the main thrust of efforts to enhance
the Stille reaction. Much of this effort involves “ligand tai-
loring”, where particular properties of the ligand are pro-
posed to encourage dissociation. The rationalisation for the
observed rate increase with AsPh3 as compared to PPh3 is
Recently Espinet et al. carried out kinetic studies relating
to the above mechanistic proposal.[12,26] In one report[26] they
suggest that the transmetallation does not actually involve a
dissociative mechanism as outlined above, but a more “SN2-
type” mechanism with a cyclic associative transition state
TS(A) involving the active palladium(ii) species PdR1L2X,
or an open associative transition state TS(B) involving
PdR1 L2Y, depending on the conditions (Figure 1).
À
the lower Pd As bond enthalpy, which allows AsPh3 to dis-
sociate more easily than PPh3, enhancing the transmetalla-
tion.[22]
Copper(i) in the Stille reaction: The first mention of cop-
per(i) being used in a Stille reaction was by Marino et al., al-
though no emphasis was drawn to it.[9] Subsequently Liebes-
kind et al. highlighted that CuI, as a co-catalyst to [Pd-
(PPh3)2Cl2], enhanced Stille couplings of a range of io-
dides.[10] Mention was made of a preliminary transmetalla-
Figure 1. Espinetꢁs proposed associative transition states for transmetalla-
tion.
tion from the organostannane to
a
more reactive
organocopper intermediate as a possible mechanistic explan-
ation. It is well known that the Sonogashira[23] coupling of
alkynes with aryl and vinyl halides is co-catalysed by cop-
per(i) and it is often presumed that the role of copper(i) is
to form a copper acetylide species.[24] However another
mechanistic explanation for the role of copper(i) was given
by Hobbs et al., who observed that a palladium to copper
ratio of 1:2 was the most effective when using [Pd(PPh3)4] in
Sonagashira couplings.[25] They suggested that copper(i)
might facilitate removal of PPh3 from palladium, resulting
in a more reactive catalyst. Liebeskind and Farina et al.
later examined the “copper effect” on the Stille reaction
more thoroughly and proposed that both mechanistic ex-
The autoretardation effect of excess ligand (the basis of
Liebeskind and Farinaꢁs proposed disassociative mechanism
in Scheme 2) is still accommodated with Espinetꢁs associa-
tive pathways. Another study by Espinet et al. attempted a
quantitative evaluation of the “copper effect” in THF.[12]
Their report shows that the rate-enhancing effect of CuI is
linked to the autoretardation effect caused by the release of
two equivalents of ligand when PdL4 undergoes oxidative
addition to afford PdRL2X. They concluded that CuI coordi-
nates to “free” ligand, but does not directly promote the dis-
sociation of ligand from the palladium(ii) species. They also
pointed out that the effect revealed in their study (con-
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J. E. Baldwin et al.
ducted in THF) is not the only proposed role of copper salts
and that a Sn/Cu transmetallation mechanism may also op-
erate.[10,13]
has been used to enhance the coupling of aryl chlorides[18]
and couplings involving alkynes.[19]
This Sn/Cu “preliminary transmetallation” mechanism
was suggested by Liebeskind and Farina et al. to operate in
highly polar solvents and in the absence of strong ligand
donors like PPh3[13] (Scheme 3).
Copper(i) and fluoride combined: Our rationale for combin-
ing fluoride with copper(i) began with consideration of the
possible role of copper(i) in the Stille reaction. As outlined
above, one mechanistic model for the acceleration afforded
by copper(i) is that copper(i) takes part in a preliminary
transmetallation with the organotin reagent, producing a
more reactive organocopper intermediate. If this process
does take place one could propose that the two organome-
tallic reagents would be in equilibrium—particularly when
iodides, bromides or triflates are used. Such an equilibrium
would be shifted unfavourably towards the organotin sub-
strate as concentrations of Bu3SnX increased, retarding the
effect of copper(i) on the reaction. In a copper only-cata-
lysed coupling of organostannanes and alkenyl iodides, Lie-
beskind et al. observed that the reaction rate was initially
fast and then slowed considerably as the reaction approach-
ed 50% completion.[32] The addition of one equivalent of
Bu3SnCl prevented reaction altogether. These observations
are consistent with the proposal of a preliminary transmetal-
lation from tin to copper that is inhibited by increasing con-
centrations of Bu3SnX.
If this “preliminary transmetallation” is taking place, we
hypothesised that the presence of fluoride might drive the
equilibrium towards the more reactive organocopper inter-
mediate by removing the Bu3SnX by-product from the equi-
librium as polymeric Bu3SnF. Reaction mixtures containing
Bu3SnCl are often purified by treatment with fluoride ion
followed by filtration of the insoluble Bu3SnF that forms.[33]
Thus our rationale for using fluoride was not to hypercoor-
dinate with the organotin reagent, but to enhance the
copper effect (Scheme 4).
Scheme 3. The “preliminary transmetallation” mechanistic explanation
for the copper effect.
Liebeskind and Farina et al. observed that Stille couplings
with CuI that were carried out in the highly polar solvent
NMP displayed kinetics that was not first-order. This is in
contrast to the equivalent reaction performed in dioxane,
which showed first-order kinetics. Although this change in
kinetics could be attributable to catalyst decomposition, it
can also be due to a succession of two transmetallations.
This study also included 119Sn NMR experiments, which dis-
closed that in highly polar solvents such as NMP and DMF,
CuI reacts with vinyltributyltin and phenyltributyltin to pro-
duce Bu3SnI and presumably the corresponding organocop-
per species. Another observation that could support a Sn/Cu
transmetallation mechanism is that addition of CuI affects
the group transfer selectivity from the organostannane, and
that this selectivity occurs during the transmetallation step
of the catalytic cycle.[13]
Tin to copper transmetallation has also been suggested in
other studies utilising organostannanes in conjunction with
copper.[27–30] In particular, couplings of organostannanes with
organohalides can be mediated by copper salts alone,[28–30]
indicating that a transmetallation from the organostannane
to a copper species has taken place. However it remains un-
clear whether this involves CuX or the copper complex
comprising the organohalide–RCuX2.
Fluoride in the Stille reaction: The use of fluoride in the
Stille reaction was first reported by Stille himself in the cou-
pling of vinyl triflates.[15] The observation was made that tet-
rabutylammonium fluoride (TBAF) enhanced the reaction.
More recently fluoride has been used as an additive in the
Stille reaction based on the rationale that it could coordi-
nate to the organotin reagent, due to the well-known fluoro-
philicity of tin,[31] creating a hypervalent organotin species.
This hypervalent tin species should then be more nucleo-
philic, thus facilitating the transmetallation. Preformed hy-
percoordinate species[16] have also been used in these studies
in addition to in situ formation with TBAF.[17] Recently CsF
Scheme 4. Rationalisation for combining copper(i) and fluoride in the
Stille reaction.
Results and Discussion
To investigate the effect of copper(i) and fluoride on the
Stille coupling a test reaction was chosen in which the trans-
metallation is expected to be rate-limiting. As iodides under-
go oxidative addition rapidly,[22] 4-iodotoluene (8) was se-
lected as the electrophile. An electron-deficient aryl stan-
nane should undergo transmetallation more slowly,[34] so 4-
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Significant Enhancement of the Stille Reaction
FULL PAPER
(tri-n-butylstannyl)nitrobenzene (7) was chosen as the nu-
cleophile component. The stannane 7 was synthesised from
4-iodonitrobenzene 6 in 63% yield by treatment with [Pd-
(PPh3)4] and Bu6Sn2 in toluene (Scheme 5).[35]
may be that copper(i) and fluoride are operating in a differ-
ent way than that described in our working model, and it
may be that the two additives are enhancing the reaction by
more than one distinct mechanism. Detailed mechanistic
studies will be required to elucidate the precise mechanism
for the combination of copper(i) and fluoride in the Stille re-
action. Nonetheless the improvement they afford is signifi-
cant whatever the mechanistic details may be.[38] It is inter-
esting to note that CsF is used as a base in Suzuki coupling
reaction,[39] while the palladium-catalysed coupling between
cyclic silyl ethers and aryl iodides is promoted by a combi-
nation of CsF and CuI.[40]
Scheme 5. Preparation of 4-(tri-n-butylstannyl)nitrobenzene (7): a) [Pd-
(PPh3)4], Bu6Sn2, toluene, 1208C, 48 h, 63%.
With the required stannane 7 in hand, a series of cou-
plings with 8 were carried out to determine the individual
effects of CsF and CuI and then the combined effect of both
additives (Table 2). Only a very small amount of product
Optimisation
Solvent: To establish the optimal conditions using copper(i)
and fluoride, the effect of different solvents on the coupling
of 8 and 7 was initially investigated (Table 3). When the re-
Table 2. Effect of CsF and/or CuI on the coupling of 8 and 7.
Table 3. Effect of the solvent on the coupling of 4-iodotoluene (8) and 4-
(tri-n-butylstannyl)nitrobenzene (7).
Entry
Reagents[a]
Yield[b] [%]
1
2
3
4
5
[Pd(PPh3)4]
2
8
46
98
0
[Pd(PPh3)4], CsF
[Pd(PPh3)4], CuI
[Pd(PPh3)4], CsF, CuI
CsF, CuI
Entry
Solvent
Yield [%][a]
1
2
3
4
5
6
toluene
THF
dioxane
NMP
DMSO
DMF
6
45
48
95
96
98
[a] [Pd(PPh3)4] (10%), CuI (20%), CsF (2.0 equiv). [b] Isolated yields
are given and are the average of two repeat experiments. Remaining
mass balance is recovered starting materials.
[a] Yield of isolated product. Remaining mass balance is recovered start-
ing materials.
9[36] was isolated after two hours at 408C using [Pd(PPh3)4]
alone, and most of the starting materials were recovered
(Table 2, Entry 1). The addition of CsF increased the yield
marginally, with most of the starting materials again being
recovered (Table 2, entry 2). When the reaction was carried
out with CuI as a co-catalyst a significant increase in yield
was observed, and the reaction was almost half complete
after two hours (Table 2, entry 3). With both CuI and CsF
present, the reaction proceeded to completion in almost
quantitative yield (Table 2, entry 4). CuI salts have been re-
ported to promote the coupling of stannanes with organic
electrophiles,[28,30,37] so to address this possibility the reaction
was repeated using CuI, CsF, and in the absence of Pd0. No
product formation was observed demonstrating that CuI is
not directly catalysing this reaction (Table 2, entry 5). It is
clear that in the presence of palladium, CuI and CsF pro-
duce a combined effect that considerably enhances this reac-
tion.
action was carried out using toluene as the solvent, only a
very small amount of product 9 was isolated (Table 3,
entry 1). When using either THF (Table 3, entry 2) or diox-
ane (Table 3, entry 3), the reaction proceeded to almost
50% completion after two hours. Highly polar solvents were
by far the most effective, with NMP, DMSO and DMF de-
livering essentially quantitative yields of the product
(Table 3, entries 4, 5 and 6). A possible explanation for
these observations is that the solubility of CsF is highest in
highly polar solvents. For further optimisation studies DMF
was selected as the solvent because of its ease of removal
under reduced pressure compared with NMP and DMSO
during the work up of the reaction.
Fluoride source: With an optimum solvent found, alterna-
tive fluoride sources were considered using the same cou-
pling reaction of 8 and 7 (Table 4). Both LiF (Table 4,
entry 1) and NaF (Table 4, entry 2) had basically no effect
on the reaction, affording similar yields to the corresponding
reaction conducted in the absence of fluoride (see Table 2,
entry 3). There was some effect observed with KF (Table 4,
Our working model for combining copper(i) and fluoride
outlined in Scheme 4 does provide one possible explanation
for the greatly improved reaction outcome, however the
effect observed in Table 2 does not necessarily suggest the
involvement of the alleged organocopper intermediate. It
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Table 4. Effect of the fluoride source on the coupling of 4-iodotoluene
(8) and 4-(tri-n-butylstannyl)nitrobenzene (7).
(Table 5, entry 4). Liebeskind et al. observed in their study
of the ’copper effect’, that increasing the amount of cop-
per(i) above a copper(i):ligand ratio of 1:2 caused a decrease
in yield.[13] The explanation was that too much copper(i)
binds up all the ligand causing catalyst decomposition. How-
ever their reactions were carried out in THF while ours use
DMF, and in their study they pointed out that copper(i)
could operate with different mechanisms in THF and DMF.
It is possible that catalyst decomposition is more facile in
entry 4 than entry 3 (Table 5), in accordance with Liebe-
skindꢁs proposal, but in this case the effect is not observed
because the reaction is very rapid.
Entry
Fluoride source
Yield [%][a]
1
2
3
4
5
6
7
LiF
NaF
KF
CsF
TBAF
TBAF[b]
NH4F
44
46
62
98
98
96
54
Ligand type: To investigate the palladium catalyst with the
associated ligands the doubly-deactivated system of 4-bro-
moanisole 10 and 4-(tri-n-butylstannyl)nitrobenzene 7 was
employed. We began by examining a variety of different li-
gands (Table 6). When the coupling of 10 and 7 was carried
[a] Yield of isolated product. Remaining mass balance is recovered start-
ing materials. [b] THF was used as the reaction solvent.
entry 3), but the most effective fluoride sources were CsF
and TBAF (Table 4, entries 4 and 5). This trend can perhaps
be explained by the availability of fluoride in terms of lat-
tice energies. LiF has the highest lattice energy (LiF
1030 kJmolÀ1, NaF 910 kJmolÀ1, KF 808 kJmolÀ1, CsF
744 kJmolÀ1),[41] which would disfavour solubility as com-
pared to CsF, and hence CsF would more easily deliver the
fluoride ion. Interestingly, TBAF was equally effective in
either DMF or THF (Table 4, entry 6), unlike CsF which is
only effective in highly polar solvents (Table 4, entry 4 cf.
Table 3). Recently TBAF was shown to be a better fluoride
donor than CsF.[42] NH4F did not significantly enhance the
reaction under the conditions examined, which is unfortu-
nate as it is inexpensive (Table 4, entry 7). CsF was chosen
as the fluoride source for further optimisation because
TBAF comes as a solution in THF which might mean limit-
ing subsequent reaction temperatures to 658C.
Table 6. Effect of the ligand type on the coupling of 4-bromoanisole (10)
and 4-(tri-n-butylstannyl)nitrobenzene (7).
Entry
Ligand type
Yield [%][a]
1
2
3
4
PPh3
AsPh3
P(2-furyl)3
PCy3
PtBu3
PtBu3
11
13
15
55
89
49
[b]
5
6[c]
[a] Yield of isolated product. Remaining mass balance is recovered start-
ing materials. [b] Cy=cyclohexyl. [c] Reaction excluded CuI.
Copper(i) source: Copper(i) sources were also investigated
using the coupling of 8 and 7 (Table 5). There was no signifi-
cant difference between CuCl, CuBr and CuI (Table 5, en-
tries 1, 2 and 3) on the coupling of 8 and 7 under the condi-
tions examined. Also of note was the observation that in-
creased amounts of CuI did not adversely effect the reaction
out using Pd(OAc)2 and PPh3 as the ligand, only a small
amount of the product 11[43] was isolated after 15 h (Table 6,
entry 1). Both AsPh3 and P(2-furyl)3 proved to be no more
effective than PPh3 at enhancing the reaction (Table 6, en-
tries 2 and 3). AsPh3 and P(2-furyl)3 are believed to enhance
Stille couplings by increasing the rate of transmetallation,[22]
which could imply that in entries 1, 2 and 3 (Table 6) the
rate-limiting step might be oxidative addition rather than
transmetallation. With this possibility in mind, electron-rich
PCy3 was investigated as a ligand that might promote oxida-
tive addition by increasing the nucleophilicity of the palladi-
um(0) species. When the reaction was carried out with PCy3
the yield increased significantly to 55% after 15 h reaction
time (Table 6, entry 4). When the electron-rich ligand PtBu3
was employed the reaction proceeded almost to completion
after 15 h (Table 6, entry 5). Without further investigation it
is not easy to assert which step of the catalytic cycle is rate-
limiting for entry 5 (Table 6). However, when the reaction
was repeated in the absence of CuI (Table 6, entry 6) the
Table 5. Effect of the copper(i) source on the coupling of 4-iodotoluene
(8) and 4-(tri-n-butylstannyl)nitrobenzene (7).
Entry
Copper(i) source
Yield [%][a]
1
2
CuCl
CuBr
CuI
95
98
98
96
3
4[b]
CuI
[a] Yield of isolated product. [b] 50% CuI.
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Significant Enhancement of the Stille Reaction
FULL PAPER
yield dropped by almost half, suggesting that CuI is either
involved in the rate-limiting step or the exclusion of CuI
changes which step is rate-limiting.
the Pd(OAc)2 is reduced from palladium(ii) to the active
palladium(0) by PtBu3,[52] resulting in the effective palladi-
um/ligand ratio being decreased to some degree. Thus a pal-
ladium/ligand ratio of 1:2 using PdII might be equivalent to
a palladium/ligand ratio of 1:1 using Pd0. Irrespective of the
mechanistic details, a palladium:ligand ratio of 1:2 provided
the necessary effect for the coupling of 10 and 7, and so this
ratio was selected for further optimisation.
As a ligand PtBu3 is clearly effective and has been used
before in a variety of palladium-catalysed processes. Koie
et al. initially demonstrated the high activity of PtBu3 as a
ligand in the palladium-catalysed amination of aryl hal-
ides.[44] Since then PtBu3 has been applied in the hydroxyla-
tion of aryl halides,[45] a-carbonyl arylation,[46] Suzuki,[47] Ne-
gishi,[48] Heck,[49] Sonogashira[50] and Stille couplings.[18] The
effectiveness of the ligand might be due to two characteris-
tics. The first is that the ligand is electron-rich and as men-
tioned above, this property should facilitate the oxidative
addition. The second attribute is the steric bulk or cone
angle of the ligand, and this property might enhance the
transmetallation step of the catalytic cycle. The reasoning
behind this suggestion is that the transmetallation step re-
quires substitution of a ligand by the organostannane (or or-
ganocopper) reagent, and PtBu3 might disassociate more
readily as a result of steric acceleration.
Palladium source: The final variable considered with the
coupling of 10 and 7 was the palladium source (Table 8).
The least effective source of palladium investigated was [Pd-
Table 8. Effect of the palladium source on the coupling of 4-bromoani-
sole (10) and 4-(tri-n-butylstannyl)nitrobenzene (7).
Palladium/ligand ratio: Having established that PtBu3 was
the most effective ligand for the coupling of 10 and 7, the
effect of changing the palladium/ligand ratio was examined
(Table 7). With a palladium/ligand ratio of 1:1, 53% of the
Entry
Palladium source
Yield [%][a]
1
2
3
4
[Pd(MeCN)2Cl2]
[Pd2(dba)3]
Pd(OAc)2
PdCl2
56
64
89
97
[a] Yields are isolated and are the average of two repeat experiments.
Remaining mass balance is recovered starting materials.
Table 7. Effect of the Pd:PtBu3 ratio on the coupling of 4-bromoanisole
(10) and 4-(tri-n-butylstannyl)nitrobenzene (7).
(MeCN)2Cl2], which resulted in only 56% of the product 11
after 15 h (Table 8, entry 1). [Pd2(dba)3] (dba=dibenzylide-
neacetone) proved to be slightly better (Table 8, entry 2),
but was still not as efficient as Pd(OAc)2 (Table 8, entry 3).
The most effective palladium source investigated was PdCl2,
which delivered an almost quantitative yield of the product
11 (Table 8, entry 4). One explanation for the results out-
lined in Table 8 is that the ’preligands’ associated with the
palladium source will have differing degrees of coordinative
ability to palladium, and this could interfere with the forma-
tion of the active Pd0 species.[53] In [Pd2(dba)3] the palladium
metal is in the Pd0 oxidation state, and so the dibenzylide-
neacetone will invariably have coordinative properties to
Pd0, which could hinder the formation of Pd(PtBu3)2. Studies
showed that the species formed from [Pd2(dba)3] and PPh3
is quite different from [Pd(PPh3)4],[54] and Beller et al. re-
cently observed reduced catalytic activity in Suzuki cou-
plings when using ligands such as dba.[51] However there are
Entry
Pd/PtBu3 ratio
Yield [%][a]
1
2
3
4
1:1
1:2
1:3
1:4
53
89
90
86
[a] Yield of isolated product. Remaining mass balance is recovered start-
ing materials.
product 11 was isolated after 15 h (Table 7, entry 1), whereas
a palladium/ligand ratio of 1:2 gave 89% of 11 (Table 7,
entry 2). Increasing the palladium/ligand ratio to 1:3
(Table 7, entry 3), or 1:4 (Table 7, entry 4) virtually did not
change the yield of 11. Other groups who have used PtBu3
in palladium-catalysed processes, report that a palladium/
ligand ratio of 1:1 gives the highest rate of reaction„[18,46]
however a palladium/ligand ratio of 1:2,[18,50] or 1:4[51] is
often used, presumably to provide more stability to the cata-
lyst. In the system we investigated, a palladium/ligand ratio
of 1:1 (Table 7, etry 1) might give a higher reaction rate
than a ratio of 1:2 (Table 7, etry 2), but a lower yield due to
catalyst decomposition. Another explanation could be that
[18]
reports where [Pd2(dba)3] is more efficient than Pd(OAc)2
and others where the effectiveness of these two palladium
sources is solvent dependant.[55] [Pd(MeCN)2Cl2], Pd(OAc)2
and PdCl2 are all PdII species rather than Pd0 species, but
they still have coordinating ligands. However PdCl2 contains
only the hard ClÀ ion, which would not be expected to have
a high binding affinity for the soft Pd0, and this might allow
the most effective formation of Pd(PtBu3)2 in situ under the
conditions studied. We emphasise here that the explanation
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J. E. Baldwin et al.
we provided is highly simplified since the mechanism of
Stille coupling reaction has been shown to be very com-
plex.[56]
palladium-catalysed addition of Bu3SnH to alkyne 20[59]
(Scheme 6).
Having optimised the main variables of the reaction, we
established two sets of conditions. For the coupling of aryl
iodides and triflates we would employ conditions A ([Pd-
(PPh3)4] (5%), CuI (10%), CsF (2 equiv), DMF, 458C), and
for the less reactive aryl bromides and chlorides we would
employ conditions B (PdCl2 (2%), PtBu3 (4%), CuI (4%),
CsF (2 equiv), DMF, 458C). These were not the only condi-
tions that could be used however. DMSO and NMP were ef-
fective as solvents, CuBr and CuCl both enhanced the reac-
tion and TBAF was as effective as a fluoride source.
Scheme 6. Synthesis of vinyl stannane 13: a) propargyl alcohol, [Pd-
(PPh3)2Cl2], piperidine, CuI, benzene, RT, 2 h, 92%; b) Bu3SnH, [Pd-
(PPh3)2Cl2], THF, RT, 20 min, 39%.
The coupling of hindered iodide 12 and hindered stan-
nane 13 to give 14 has previously been achieved in an opti-
mised yield of only 27%, and that was after reaction for
15 h at 808C.[57] When conducted under our new conditions,
this same reaction returned an excellent yield of 92%
(Table 9, entry 1). It is noteworthy that with CuI and CsF
present, the reaction between 12 and 13 was complete after
8 h at just 458C. Similarly, reaction of iodide 15 and stan-
nane 13 afforded 16 in 94% yield indicating that deactivated
iodides can be coupled efficiently with the new conditions.
The previously reported best yield of this reaction was a
moderate 42%[57] (Table 9,
Scope
Coupling of iodides: Generally iodides undergo coupling re-
actions reasonably well, but sometimes if one or both of the
coupling partners are sterically hindered or deactivated,
they can be reluctant to couple efficiently. Two such exam-
ples reported in the literature to be somewhat difficult[57]
were attempted using our conditions (Table 9). The vinyl
stannane 13 was synthesised by a Sonogashira reaction be-
tween aryl iodide 15 and propargyl alcohol,[58] followed by
entry 2). As mentioned in the
introduction, 3,4-bis(tri-n-butyl-
Table 9. Coupling of iodides using conditions A.[a]
Entry
Halide/Triflate
Stannane
Product
Time [h]
8
Yield [%][b]
stannyl)furan
5 reacted with
two equivalents of ortho-substi-
tuted aryl iodide 4 in high yield
using our new conditions
(Table 9, entry 3). The disubsti-
tuted product 1 was obtained
1
92
exclusively,[4]
demonstrating
that our conditions can accom-
modate sterically hindered stan-
nanes in conjunction with steri-
cally hindered iodides. The
almost quantitative coupling of
4-iodotoluene 8 with 4-(tri-n-
2
8
2
94
92
butylstannyl)nitrobenzene
7
(used in the initial test reaction)
illustrates that reactions em-
ploying electronically disfav-
oured aryl stannanes can also
proceed in high yield (Table 9,
entry 4). The effect of heterocy-
cles on the coupling of iodides
with our conditions was as-
sessed by reaction of 3-iodopyr-
idine (17) with 2-(tri-n-butyl-
stannyl)thiophene (18). Satisfy-
ingly the coupled product 19[60]
was isolated in 99% yield, dis-
playing that heterocyclic io-
dides can also undergo coupling
efficiently (Table 9, entry 5).
3[c]
4[d]
2
1
98
99
5
[a] Conditions A: [Pd(PPh3)4] (5%), CuI (10%), CsF (2 equiv), DMF, 458C. [a] Yields are isolated and are the
average of two repeat experiments. [b] Iodide (2.1 equiv), organostannane (1 equiv), [Pd(PPh3)4] (10%), CuI
(20%), CsF (4 equiv). [c] [Pd(PPh3)4] (10%), CuI (20%), CsF (2 equiv).
3300
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Significant Enhancement of the Stille Reaction
FULL PAPER
The couplings of iodides could be carried out at room tem-
perature, although the reaction times were longer. For ex-
ample, when the coupling of 17 with 18 was performed at
room temperature the reaction took 2 h to proceed to com-
pletion.
Reaction of vinyl triflate 27 with tri-n-butylvinylstannane
(28) again progressed very quickly under our conditions af-
fording the conjugated diene 29[64] in almost quantitative
yield (Table 10, entry 3). Even when the reaction represent-
ed in entry 3 was performed at room temperature it was
complete after one hour.
Coupling of triflates: Because triflates are readily available
from the corresponding phenol or enolate, they have
become important coupling partners,[31,61] in synthesis. This
easy access to triflates has allowed quick assembly of struc-
tures such as conjugated dienes, by coupling vinyl triflates
with vinyl stannanes. For the coupling of triflates, [Pd-
(PPh3)4] was sufficient using our conditions and the reac-
tions investigated proceeded to completion rapidly
(Table 10).
Coupling of bromides: For the coupling of bromides the cat-
alytic system employing PdCl2 and PtBu3 was used (condi-
tions B). Recently Fu et al. reported a procedure for the
Stille coupling that also makes use of PtBu3.[18] To investi-
gate whether our conditions B provide an improvement
over the procedure described by Fu et al. for the coupling of
bromides, a series of reactions were carried out on the chal-
lenging coupling of electron-rich 4-bromoanisole (10) and
electron-deficient 4-(tri-n-butylstannyl)nitrobenzene (7)
(Table 11).
Table 10. Coupling of triflates using conditions A.[a]
Entry Halide/Triflate Stannane
Product
Time Yield
[h]
[%][b]
Table 11. Evaluating alternative conditions on the coupling of 10 and 7.
1
2
95
2
3
2
1
91
98
Entry
Reagents[a]
Yield [%][b]
1[c]
2
PdCl2, PtBu3, CuI, CsF, DMF
PdCl2, PtBu3, CsF, DMF
[Pd2(dba)3], PtBu3, CsF, dioxane
[Pd2(dba)3], PtBu3, CuI, CsF, dioxane
92
29
16
10
3[d]
4
[a] PdCl2 (2%) or [Pd2(dba)3] (1%), PtBu3 (4%), CuI (4%), CsF
(2.0 equiv). [b] Yields are isolated yields and are the average of two
repeat experiments. Remaining mass balance is recovered starting mate-
rials. [c] Conditions B. [d] Reagent combination reported by Fu et al.[18]
[a] Conditions A: [Pd(PPh3)4] (5%), CuI (10%), CsF (2 equiv), DMF,
458C. [b] Yields are isolated and are the average of two repeat experi-
ments.
When 10 and 7 were coupled under conditions B, a 92%
yield of the desired product 11 was isolated after 4 h at
458C (Table 11, entry 1). To address the question of whether
or not CuI is necessary when using PtBu3 under conditions
B, the coupling of 10 and 7 was repeated without CuI. Only
29% of the coupled product 11 was isolated after the same
reaction time, with the remaining starting material being re-
covered (Table 11, entry 2). This demonstrates that CuI is
still necessary to provide the highest yields, even though a
coordinatively unsaturated catalytic system is generated
under conditions B. When the coupling of 10 and 7 was car-
ried out using the reagent combination described by Fu
et al.[18] at 458C for 4 h, a 16% yield of the coupled product
11 was isolated. The reaction had not proceeded to comple-
tion during this time and the remaining starting materials
were recovered (Table 11, entry 3). Interestingly, the addi-
tion of CuI in the same reaction resulted in a slight decrease
in the isolated yield (Table 11, entry 4). This particular ob-
servation is supported by our optimisation studies where we
observed that the synergic effect of CuI and CsF requires
highly polar solvents. Our optimisation studies also revealed
4-Acetophenyl trifluoromethanesulfonate (21) reacted
rapidly with the vinylstannane 22 to give the coupled prod-
uct 23[18b] in 95% yield (Table 10, entry 1). The biaryl cou-
pling carried out between 4-methoxyphenyl trifluorometha-
nesulfonate (24) and phenyltributylstannane (25) also pro-
ceeded rapidly and gave 26[62] in high yield, demonstrating
that deactivated triflates also respond well to our conditions
(Table 10, entry 2). The preparation of 4-phenyl-1-cyclohex-
en-1-yl triflate (27)[63] proceeded from 4-phenyl-1-cyclohexa-
none (30) in 97% yield by treatment with potassium hexam-
ethyldisilazide followed by N-phenyltrifluoromethanesulfo-
nimide (Scheme 7).
Scheme 7. Preparation of vinyl triflate 27: a) KHMDS, THF, À788C, then
RT, 1 h, PhN(OTf)2, RT, 2 h, 97%.
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J. E. Baldwin et al.
that PdCl2 was superior to [Pd2(dba)3] as a palladium source
when using DMF as the solvent.
Having established the validity of conditions B, a range of
bromides were successfully coupled with a variety of stan-
nanes and in all cases investigated the yields were very high
(Table 12). 4-(Tri-n-butylstannyl)toluene (32)[65] was synthes-
ised in 94% yield by reaction of 4-tolylmagnesium bromide
(44) with tributylstannyl chloride (Scheme 8). Reaction of
aryl stannane 32 with bromobenzene (31) provided 4-phe-
nyltoluene (33)[66] in almost quantitative yield (Table 12,
entry 1). The couplings with bromides were carried out over-
night for convenience, but the reactions did not necessarily
require this extended period. This is evident from the elec-
tronically disfavoured coupling of electron-rich bromide 10
and electron-deficient stannane 7. Overnight the reaction af-
Scheme 8. Preparation of 4-(tri-n-butylstannyl)toluene (32): a) Bu3SnCl,
THF, 308C, 3 h, 94%.
forded a 97% yield of the product 11 (Table 12, entry 2),
however it was essentially complete after 4 h (92%) as dem-
onstrated above in Table 11 (entry 1). The successful cou-
pling led to an attempt at an extremely challenging reaction,
which is both sterically hindered and electronically disfav-
oured. Gratifyingly 2,4-dimethoxybromobenzene 34 and 4-
(tri-n-butylstannyl)nitrobenzene 7 reacted to deliver 35 in
high yield, establishing that even highly deactivated bro-
mides will couple with electron-deficient stannanes under
our conditions (Table 12, entry 3). Although considerably
sterically hindered, di-ortho-substituted 9-bromoanthracene
(36) efficiently underwent reaction with tri-n-butylvinylstan-
nane (28) affording the product 37[67] in an excellent yield of
96% (Table 12, entry 4). This is higher than the previously
reported yield of 66%,[18] although our reaction was carried
out at a higher temperature and for a longer time. In our
hands the coupling of 36 and 28 under Fuꢁs conditions ([Pd2-
(dba)3], PtBu3, toluene, RT, 3 h) gave 54% of the product
37, whereas when the reaction was repeated by using our
catalytic system under identical conditions (RT, 3 h) a 68%
yield of the product 37 was isolated. In both cases the re-
maining mass balance was largely recovered starting materi-
als. To carry out an example of a biscoupling, (E)-1,2-bis(tri-
n-butylstannyl)ethene (39) was prepared by radical addition
of tri-n-butylstannylhydride to ethynyltri-n-butylstannane,[68]
then coupled with bromoquinoline 38.[69] Two quinoline moi-
eties were readily incorporated onto the bis-tin ethene 39
giving a very good yield of the desired disubstituted product
40 (Table 12, entry 5). To investigate the tolerance of hetero-
cyclic bromides under our conditions, 2-bromo-6-methylpyri-
dine (41) was subjected to a coupling with phenyltri-n-butyl-
stannane (25) and satisfyingly reacted smoothly giving 91%
of the product 42 (Table 12, entry 6). This yield is signifi-
cantly higher than the previously reported yield of 61%
even though the previous protocol employed higher temper-
atures (135–1408C) and the more reactive phenyltrimethyl-
stannane.[70] Heterocyclic stannanes were also tolerated well
by our conditions, which was demonstrated by the near-
quantitative coupling of 2-(tri-n-butylstannyl)thiophene (18)
with 2-bromo-6-methylpyridine (41) to give 43[71] (Table 12,
entry 7).
Table 12. Coupling of bromides using conditions B for 15 h.[a]
Entry Halide/Triflate
Stannane
Product
Yield
[%][b]
1
98
2
97
3
89
96
4[c]
5[d]
93
6
7
91
98
Coupling of chlorides: The coupling of aryl chlorides proved
to be significantly more difficult than for aryl bromides, with
elevated reaction temperatures required to effect coupling.
Aryl chlorides are believed to be poor coupling partners
due to the reluctance of Pd0 to undergo oxidative addition
to the strong carbon–chloride bond.[72] The bond dissociation
energy for Ph–Cl is 96 kcalmolÀ1, compared with
[a] Conditions B: PdCl2 (2%), PtBu3 (4%), CuI (4%), CsF (2 equiv),
DMF, 458C. [b] Isolated yields. [c] Organostannane (1.3 equiv). [d] Bro-
mide (2.1 equiv), organostannane (1 equiv), PdCl2 (4%), PtBu3 (8%),
CuI (8%), CsF (4 equiv).
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Significant Enhancement of the Stille Reaction
FULL PAPER
81 kcalmolÀ1 for Ph–Br and 65 kcalmolÀ1 for Ph–I. To eval-
uate how chlorides would respond to our conditions we car-
ried out couplings with an activated and a deactivated aryl
chloride (Table 13).
uct was excellent. Furthermore, our conditions are mild and
compatible with a wide variety of functional groups. This
combination of copper(i) iodide and cesium fluoride should
allow the synthesis of sterically hindered systems and pro-
mote electronically disfavoured coupling reactions, expand-
ing the scope of the Stille reaction in synthetic organic
chemistry.
Table 13. Coupling of chlorides using conditions B for 15 h at 1008C.[a]
Entry Halide/Triflate Stannane
Product
Yield [%][b]
1
81
Experimental Section
General experimental: Tetrahydrofuran (THF) was distilled over sodium/
benzophenone ketyl under nitrogen. PE refers to the fraction of light pe-
troleum ether boiling between 408C and 608C, and was distilled before
use. Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and N-
methylpyrrolidine (NMP) were distilled from calcium hydride under
argon or reduced pressure and stored over 4 ꢂ molecular sieves under
argon until used. Toluene was dried over 4 ꢂ molecular sieves under
argon. All water used was distilled. Solvents were evaporated at 408C or
below on a Bꢃchi R114 Rotavaporator.
2
40–60
[a] Conditions B: PdCl2 (2%), PtBu3 (4%), CuI (4%), CsF (2 equiv),
DMF. [a] Yields are isolated and are the average of two repeat experi-
ments (entry 2 shows the range). Remaining mass balance is recovered
starting materials.
Thin-layer chromatography (TLC) was performed by using Merck alumi-
nium foil backed plates pre-coated with silica gel 60 F254 (1.05554). Re-
tention factors (Rf) are reported to two decimal places. Column chroma-
tography was performed by using ICN silica 32–63, 60 ꢂ or basic Laporte
Actal U.G. alumina.
With these substrates it was observed that the electronic
effect of the substituents on the aromatic ring of the aryl
chloride has considerable influence on the reactivity of the
substrate. Reaction of electron-deficient aryl chloride 45
with stannane 25 provided the coupled product 46[73] in a re-
spectable 81% yield (Table 13, entry 1). The coupling of the
electron-rich chloride 47 to stannane 25 proceeded in lower
yields, ranging between 40% and 60% (Table 13, entry 2).
In both cases, coupling of the aryl chlorides did not proceed
to completion even with extended reaction times, suggesting
that the catalytic system may be decomposing under the
more forcing conditions. Thus our new conditions appear ef-
fective for the coupling of electron-deficient aryl chlorides,
but less effective when it comes to electron-rich aryl chlor-
ides.[74]
1H NMR spectra were recorded on a Brꢃker DPX400 spectrometer at
400 MHz and 13C NMR spectra at 100.6 MHz and are referenced accord-
ing to IUPAC recommendations, 2001.[75] Proton spectra assignments are
1
supported by H–1H COSY where necessary. Carbon spectra assignments
are supported by DEPT analysis and 1H–13C correlations where necessa-
ry.
Low-resolution mass spectra were recorded by using a TRIO-1 GCMS
spectrometer, a Micromass Platform (APCI or ES) Spectrometer, Micro-
mass Autospec spectrometer (CI+) and a micromass ZAB spectrometer
(CI+, EI). Only molecular ions (M+), fragments from molecular ions and
other major peaks are reported. High-resolution mass spectra were re-
corded on a Micromass Autospec spectrometer and are accurate to Æ
5 ppm. Microanalyses were carried out by Elemental Microanalysis Lim-
ited, and are quoted to the nearest 0.1%.
Experimental procedures
General procedure for Stille reactions: A mixture of the organohalide
(or triflate) (0.840 mmol) and the organotin (0.930 mmol) reagent was
dissolved in DMF (2 mL), then caesium fluoride (256 mg, 1.69 mmol)
was added. The palladium catalyst and copper(i) iodide (conditions A:
[Pd(PPh3)4] (5%), CuI (10%); conditions B: PdCl2 (2%), PtBu3 (4%),
CuI (4%)) were added and the flask was evacuated and refilled with
argon five times. The mixture was stirred at 458C for the required time,
then diluted with dichloromethane (DCM) (50 mL) and water (20 mL).
After vigorous shaking, the mixture was filtered through Celite with
DCM/EtOAc (200 mL, 1:1). The organic layer was separated, dried over
Na2SO4/MgSO4 and the solvent was removed under reduced pressure.
The residue was purified by column chromatography.
Conclusion
The combination of copper(i) and the fluoride ion has
proved to be particularly effective in enhancing the Stille re-
action. Mechanistic studies would need to be undertaken to
conclusively elucidate the mechanism operating. Optimisa-
tion studies revealed that the most effective conditions were
Pd cat./CuI/CsF in DMF, with a palladium/ligand ratio of
1:2, a palladium/copper ratio of 1:2 and two equivalents of
CsF, although these were not the only conditions that could
be used. Highly polar solvents like DMSO and NMP were
effective and TBAF appeared similar to CsF as a fluoride
source. The most effective palladium catalyst for coupling
bromides was PdCl2/PtBu3, but it was not necessary when
coupling iodides or triflates, which were effectively coupled
with [Pd(PPh3)4]. A range of reactions were then carried out
which included sterically hindered and electronically disfav-
oured coupling partners. In all cases investigated by using
iodides, triflates or bromides, the yield of the desired prod-
3-(4’-Methoxyphenyl)-2-propyn-1-ol (20): [Pd-
(PPh3)2Cl2] (0.300 g, 0.430 mmol) was added to
a solution of 4-methoxyiodobenzene 15 (10.0 g,
42.7 mmol), propargyl alcohol (2.70 mL,
46.4 mmol), piperidine (9.30 mL, 93.9 mmol)
and copper(i) iodide (80 mg, 0.42 mmol) in
benzene (20 mL) under argon. The solution
was stirred at room temperature for 2 h then diluted with DCM
(100 mL). The solution was washed with water (50 mL), dried over
Na2SO4/MgSO4 and the solvent removed under reduced pressure. The
residue was purified by column chromatography (DCM/EtOAc, 19:1) to
give 20 (6.38 g, 92%) as a white solid.
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J. E. Baldwin et al.
Rf =0.26 (DCM/EtOAc, 19:1); m.p. 62–638C; lit. [58] 61–638C; 1H NMR
(400 MHz, CDCl3): d=2.54 (s, 1H; OH), 3.80 (s, 3H; OCH3), 4.48 (s,
2H; H1), 6.82 (d, J=9.0 Hz, 2H; H3’, 5’), 7.37 ppm (d, J=9.0 Hz, 2H;
H2’, 6’); 13C NMR (100.6 MHz, CDCl3): d=51.5 (C1), 55.3 (OCH3), 85.5
(C3), 86.0 (C2), 113.9 (C3’, 5’), 114.7 (C4’), 133.2 (C2’, 6’), 159.7 ppm
(C1’); IR (KBr): n˜max =3258 (br m, OH str), 2965 (w), 2898 (w), 2838 (w),
2231 (w, CC alkyne str), 1604 (s), 1509 (s), 1441 (m), 1292 (m), 1250 (s),
1174 (m), 1110 (w), 1028 (s), 949 (w), 837 cmÀ1 (s); MS (CI+): m/z (%):
163.2 ([MH]+, 100), 144.8 (46), 133.1 (32), 122.2 (19), 112.1 (13), 95.6
(14); HRMS ([MH]+) requires m/z 163.0759, found: 163.0767.
(m), 2934 (m), 2836 (m), 1607 (s), 1511 (s), 1463 (m), 1287 (m), 1248 (s),
1175 (s), 1033 (s), 835 (s), 756 cmÀ1 (m); MS (ES+): m/z ([MH+ÀH2O])
252.8 (100%); HRMS ([MH+ÀH2O) requires m/z 253.1229, found
253.1234.
3,4-Bis(3,4-dibenzyloxy-2-nitrophenyl)furan
(1):
4,5-Dibenzyloxy-2-nitroiodobenzene
(4; 406 mg, 0.880 mmol) and 3,4-bis(tri-n-
butylstannyl)furan (5; 271 mg, 0.420 mmol)
were coupled by using the general proce-
dure with conditions A [Pd(PPh3)4] (49 mg,
0.042 mmol), CuI (16 mg, 0.084 mmol), CsF
(255 mg, 1.68 mmol), DMF (2 mL)] for 2 h.
Column chromatography (DCM/PE, 7:3)
(Z)-3-(4’-Methoxyphenyl)-3-(tri-n-butylstannyl)-2-
propyn-1-ol (13):[59] Bu3SnH (3.65 mL, 13.6 mmol)
was added slowly to a solution of 3-(4’-methoxy-
gave 1 (284 mg, 92%) as a solid yellow foam.
phenyl)-2-propyn-1-ol (20; 2.00 g, 12.3 mmol) and
Rf =0.44 (DCM/PE, 7:3); m.p. 55.5–568C; 1H NMR (400 MHz, CDCl3):
d=5.15, (s, 4H; CH2 of Bn), 5.17 (s, 4H; CH2 of Bn), 6.87 (s, 2H; H6’,
6’’), 7.30–7.53 ppm (m, 24H; H2, H5, H3’, H3’’, Ar-H of Bn); 13C NMR
(100.6 MHz, CDCl3): d=71.1 and 71.4 (CH2 of Bn), 110.4 (C3’, 3’’), 117.0
(C6’, 6’’), 120.8 and 123.7 (quat. C), 127.2, 127.3, 127.4, 127.5, 128.17,
128.24, 128.3, 128.6 and 128.7 (Ar-CH of Bn), 135.7 and 135.9 (ipso-C of
Bn), 140.0 (C2, 5), 141.6, 147.9 and 152.3 ppm (quat. C); IR (KBr): n˜max
=3089 (w), 3063 (w), 1573 (m), 1519 (s, NO2 str), 1454 (m), 1342 (s, NO2
str), 1280 (s), 1203 (m), 1086 (m), 1023 (m), 868 (m), 738 (m), 696 cmÀ1
(m); MS (ES+): m/z (%): 752.3 ([MNH4]+, 100), 702.2 (33); HRMS
([MNH4]+) requires m/z 752.2608, found 752.2612.
[Pd(PPh3)2Cl2] (0.17 g, 0.24 mmol) in THF
(20 mL) under argon at room temperature. The dark brown mixture was
stirred for 20 min then the solvent was removed under reduced pressure.
The residue was purified by column chromatography (DCM/EtOAc,
19:1) to give 13 (2.18 g, 39%) as a pale yellow liquid.
1
Rf =0.41 (DCM/EtOAc, 19:1); H NMR (400 MHz, CDCl3): d=0.82–0.97
(m, 15H; CH2CH3 and SnCH2), 1.28 (sextet, J1 =7.0 Hz, 6H; CH2CH3),
1.37–1.53 (m, 6H; CH2CH2CH3), 1.61 (br s, 1H; OH), 3.79 (s, 3H;
OCH3), 4.13 (t, J=5.5 Hz, 2H; H1), 5.96 (t, J=6.0 Hz, 1H; H2), 6.80–
6.88 ppm (m, 4H; Ar CH); 13C NMR (100.6 MHz, CDCl3): d=10.0
(SnCH2), 13.6 (CH2CH3), 27.3 (CH2CH3), 28.9 (CH2CH2CH3), 55.2
(OCH3), 60.5 (C1), 113.5 and 136.2 (Ar CH), 136.2 (quat. C), 139.9 (C2),
148.2 and 157.5 ppm (quat. C); IR (thin film): n˜max = 3322 (br m, OH
str), 2955 (s), 2926 (s), 2871 (s), 2853 (s), 1602 (m), 1505 (s), 1464 (m),
1283 (m), 1244 (s), 1173 (m), 1036 (s), 864 cmÀ1 (m); MS (CI+): m/z
(%): 453.3 ([MH]+, (15)) 437.3 (35), 395.3 (92), 381.2 (75), 291.2 (72),
203.2 (37), 163.2 (54), 146.9 (100), 134.8 (33).
4-(Tri-n-butylstannyl)nitrobenzene (7):[35] A mixture
of 4-iodonitrobenzene (6; 5.00 g, 20.1 mmol), Bu6Sn2
(15.0 mL, 29.7 mmol) and [Pd(PPh3)4] (1.16 g,
1.00 mmol) in toluene (50 mL) was heated to reflux
under argon for 48 h. Saturated aqueous KF solution
(50 mL) was added to the cooled mixture and then it was stirred rapidly
at room temperature for 1 h. The mixture was filtered through Celite
with toluene washings (200 mL), then the organic layer was separated,
dried over Na2SO4/MgSO4 and the solvent removed under reduced pres-
sure. The residue was purified by column chromatography (PE/DCM,
9:1) to give 7 (5.21 g, 63%) as a yellow oil.
Rf =0.27 (PE/DCM, 9:1); 1H NMR (400 MHz, CDCl3): d=0.90 (t, J=
7.5 Hz, 9H; CH3), 1.04–1.22 (m, 6H; SnCH2), 1.34 (sextet, J=7.0 Hz,
6H; CH2CH3), 1.45–1.62 (m, 6H; CH2CH2CH3), 7.59–7.71 (m, 2H; H3,
5), 8.13 ppm (d, J=8.5 Hz, 2H; H2, 6); 13C NMR (100.6 MHz, CDCl3);
d=9.8 (SnCH2), 13.6 (CH3), 27.3 (CH2CH3), 29.0 (CH2CH2CH3), 121.9
(C2, 6), 137.0 (C3, 5), 148.1 and 153.3 ppm (quat. C); IR (thin film):
n˜max = 3031 (w), 2957 (s), 2928 (s), 2871 (s), 2853 (s), 1518 (s, NO2 str),
1347 (s, NO2 str), 850 cmÀ1 (m); MS (CI+): m/z (%): ([MNH4]+) 431.2
(15), 373.2 (18), 356.2 (36), 326.2 (27), 308.2 (29), 291.2 (57), 150.2 (23),
94.2 (100).
3-(2’-Carboxylic acid methyl ester)-3-(4’’-methox-
yphenyl)-2-propen-1-ol (14):[57] Methyl 2-iodoben-
zoate (12; 220 mg) and (Z)-3-(4’-methoxyphenyl)-
3-(tri-n-butylstannyl)-2-propyn-1-ol (13; 422 mg)
were coupled by using the general procedure
with conditions A for 8 h. Column chromatogra-
phy (DCM/EtOAc, 9:1) gave 14 (231 mg, 92%)
as a white solid.
Rf =0.20 (DCM/EtOAc, 9:1); m.p. 89–908C; 1H NMR (400 MHz,
CDCl3): d= 3.59 (s, 3H; OCH3), 3.79 (s, 3H; OCH3), 4.35 (d, J=7.0 Hz,
2H; H1), 5.85 (t, J=7.0 Hz, 1H; H2), 6.82 (d, J=8.0 Hz, 2H; H3’’, 5’’),
7.04 (d, J=7.5 Hz, 2H; H2’’, 6’’), 7.32–7.38 (m, 2H; H4’, 6’), 7.43–7.49
(m, 1H; H5’), 7.69 ppm (d, J=7.5 Hz, 1H; H3’); 13C NMR (100.6 MHz,
CDCl3): d= 51.9 and 55.2 (OCH3), 60.3 (C1), 113.1 (C3’, 5’), 127.4 (Ar
CH), 128.5 (C2), 129.5 (C3’’), 131.0, 131.2 and 131.3 (Ar CH), 131.4,
143.4, 143.8 and 158.9 (quat. C), 168.7 ppm (C=O), (one Ar CH and one
quat. C not seen); IR (KBr): n˜max =3427 (br m, OH str), 3007 (m), 2951
(m), 2838 (m), 1721 (s, C=O str), 1608 (s), 1511 (s), 1294 (s), 1250 (s),
1180 (m), 1127 (m), 1084 (m), 1031 (s), 838 (m), 761 cmÀ1 (s); MS
(ES+): m/z : ([MH+ÀH2O]) 280.8 (100%); HRMS ([MH]+) requires
m/z 281.1178, found 281.1172.
4’-Methyl-4-nitrobiphenyl (9): 4-Iodotoluene
8
(183 mg) and 4-(tri-n-butylstannyl)nitrobenzene 7
(383 mg) were coupled by using the general pro-
cedure with 10% [Pd(PPh3)4], 20% CuI and
2 equiv CsF for 2 h at 408C. Column chromatog-
raphy (PE/DCM, 1:1) gave 9 (176 mg, 98%) as a
cream solid.
3,3-Bis(4’-Methoxyphenyl)-2-propen-1-ol (16):[57]
4-Iodoanisole (15; 197 mg) and (Z)-3-(4’-methox-
yphenyl)-3-(tri-n-butylstannyl)-2-propyn-1-ol (13;
422 mg) were coupled by using the general proce-
dure with conditions A for 8 h. Column chroma-
tography (DCM/EtOAc, 19:1) gave 16 (213 mg,
94%) as a pale yellow liquid.
Rf =0.41 (PE/DCM, 1:1); m.p. 135–1378C; lit. [36] 138–1398C; 1H NMR
(400 MHz, CDCl3): d=2.44 (s, 3H; Ar CH3), 7.32 (d, J=8.0 Hz, 2H;
H3’, 5’), 7.53 (d, J=8.0 Hz, 2H; H2’, 6’), 7.71 (d, J=9.0 Hz, 2H; H2, 6),
8.28 ppm (d, J=9.0 Hz, 2H; H3, 5); 13C NMR (100.6 MHz, CDCl3): d=
21.2 (Ar CH3), 124.1 (C3, 5), 127.2 and 127.4 (C2, 2’, 6, 6’), 129.9 (C3’,
5’), 135.8, 139.1 146.8 and 147.5 ppm (quat. C); IR (KBr): n˜max =1594
(m), 1513 (s, NO2 str), 1484 (m), 1338 (s, NO2 str), 1107 (m), 824 (s),
754 cmÀ1 (m); MS (CI+): m/z (%): 231.2 ([MNH4]+, 20), 213.1 ([MH]+,
100), 183.1 (49), 165.1 (30), 152.1 (41); HRMS ([MH]+) requires m/z
213.0790, found 213.0790.
Rf =0.24 (DCM/EtOAc, 19:1); 1H NMR
(400 MHz, CDCl3): d=1.82 (s, 1H; OH), 3.80 (s,
3H; OCH3), 3.84 (s, 3H; OCH3), 4.21 (d, J=7.0 Hz, 2H; H1), 6.11 (t, J=
7.0 Hz, 2H; H2), 6.82 (d, J=9.0 Hz, 2H; H3’ and 5’ or 3’’ and 5’’), 6.90
(d, J=9.0 Hz, 2H; H3’ and 5’ or 3’’ and 5’’), 7.09 (d, J=9.0 Hz, 2H; H2’
and 6’ or 2’’ and 6’’), 7.20 ppm (d, J=9.0 Hz, 2H; H2’ and 6’ or 2’’ and
6’’); 13C NMR (100.6 MHz, CDCl3): d=55.2 (2ꢄOCH3), 60.7 (C1), 113.5
(C3’, 5’), 125.5 (C2), 128.9 and 131.0 (C2’, 6’), 131.6, 134.8, 143.4, 159.0
and 159.2 ppm (quat. C); IR (thin film): n˜max =3394 (br m, OH str), 3004
3-Thiophen-2-yl-pyridine (19):[60] 3-Iodopyridine (17;
172 mg) and 2-(tri-n-butylstannyl)thiophene (18; 347 mg)
were coupled by using the general procedure with condi-
tions
A for 1 h. Column chromatography (PE/diethyl
ether, 3:7) gave 19 (134 mg, 99%) as a pale yellow liquid.
3304
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 3294 – 3308

Significant Enhancement of the Stille Reaction
FULL PAPER
Rf =0.29 (PE/diethyl ether, 3:7); 1H NMR (400 MHz, C6D6): d= 6.74
(dd, J1 =4.5, J2 =8.0 Hz, 1H; Ar CH), 6.78–6.81 (m, 1H; Ar CH), 6.90–
6.92 (m, 1H; Ar CH), 6.98–7.02 (m, 1H; Ar CH), 7.26 (s, 1H; Ar CH),
7.45 (dt, J1 =2.0, J2 =8.0 Hz, 1H; Ar CH), 8.50 (d, J=4.0 Hz, 1H; H6),
9.10 ppm (s, 1H; H2); 13C NMR (100.6 MHz, C6D6): d= 123.7, 124.5,
126.1 and 128.5 (Ar CH), 130.6 (quat. C), 132.7 (Ar CH), 141.0 (quat. C),
147.6 (C2), 149.1 ppm (C6); IR (thin film): n˜max =3074 (m), 3030 (m),
1565 (w), 1475 (s), 1433 (m), 1413 (s), 1328 (w), 1264 (w), 1124 (w), 1023
(m), 851 (m), 801 (s), 705 cmÀ1 (s); MS(ES+): m/z (%): 161.6 ([MH]+,
100).
(s), 1247 (s), 1209 (s), 1142 (s), 1054 (s), 1026 (s), 894 (s), 861 (s), 760
(m), 700 (s), 617 cmÀ1 (s); MS (GC CI+): m/z (%): 324.1 ([MNH4]+, 4),
190.1 (15), 173.1 (16), 157.1 (7), 104.1 (100); HRMS ([MNH4]+) requires
m/z 324.0881, found 324.0865.
4-Phenyl-1-vinyl-1-cyclohexene
(29):[64]
4-
Phenyl-1-cyclohexen-1-yl triflate (27; 257 mg)
and tri-n-butylvinylstannane (28; 295 mg) were
coupled by using the general procedure with
conditions A for 1 h. Column chromatography
(PE) gave 29 (152 mg, 98%) as a colourless
liquid.
1-[4’-(1’’-ethoxyvinyl)phenyl]-ethanone (23):[18b] 4-
Acetophenyl
trifluoromethanesulfonate
(21;
Rf =0.39 (PE); 1H NMR (400 MHz, CDCl3): d= 1.79–1.91 (m, 1H),
2.06–2.14 (m, 1H), 2.26–2.54 (m, 4H), 2.80–2.91 (m, 1H), 5.01 (d, J=
11.0 Hz, 1H; H8a), 5.17 (d, J=17.5 Hz, 1H; H8b), 5.90 (apparent d, J=
4.5 Hz, 1H; H2), 6.47 (d, J1 =11.0, J2 =17.5 Hz, 1H; H7), 7.20–7.40 ppm
(m, 5H; Ar CH); 13C NMR (100.6 MHz, CDCl3): d= 24.4 (CH2), 29.6
(CH2), 34.0 (CH2), 40.3 (CH), 110.4 (C8), 126.1, 126.9 and 128.4 (Ar
CH), 129.1 (C7), 135.9 (quat. C), 139.7 (C2), 146.8 ppm (quat. C); IR
(thin film): n˜max =3086 (m), 3061 (m), 3027 (m), 3002 (m), 2919 (s), 2835
(m), 1644 (m), 1605 (s), 1497 (m), 1453 (m), 989 (m), 894 (s), 829 (m),
760 (s), 699 cmÀ1 (s); MS (GC CI+): m/z (%): 185.1 ([MH]+, 100), 170.1
(42), 104.1 (25); HRMS ([MH]+) requires m/z 185.1330, found 185.1329.
225 mg) and vinylstannane 22 (336 mg) were cou-
pled by using the general procedure with condi-
tions A for 2 h. Column chromatography (PE/
DCM, 3:7) gave 23 (145 mg, 95%) as a colourless
liquid.
Rf =0.31 (PE/DCM, 3:7); 1H NMR (400 MHz, CDCl3): d= 1.44 (t, J=
7.0 Hz, 3H; CH2CH3), 2.60 (s, 3H; H2), 3.94 (q, J=7.0 Hz, 2H;
CH2CH3), 4.32 (d, J=3.0 Hz, 1H; H2’’a), 4.77 (d, J=3.0 Hz, 1H; H2’’b),
7.12 (d, J=8.5 Hz, 2H; H3’, 5’), 7.92 ppm (d, J=8.5 Hz, 2H; H2’, 6’); 13C
NMR (100.6 MHz, CDCl3): d=14.5 (CH2CH3), 26.6 (C2), 63.5
(CH2CH3), 84.3 (C2’’), 125.4 (C3’, 5’), 128.2 (C2’, 6’), 136.7, 141.0 and
158.8 (quat. C), 197.7 ppm (C1); IR (thin film): n˜max =2980 (m), 2931
(m), 1719 (m), 1685 (s, C=O str), 1608 (s), 1406 (m), 1358 (m), 1267 (s),
1130 (m), 1111 (m), 1056 (m), 1016 (m), 958 (m), 847 (m), 808 (m),
770 cmÀ1 (m); MS (GC CI+): m/z(%): 191.1 ([MH]+, 100), 162.1 (18),
148.1 (92), 147.1 (45), 131.1 (7), 70.1 (11); HRMS ([MH]+) requires m/z
191.1072, found 191.1079.
4-(Tri-n-butylstannyl)toluene (32):[65] p-Tolylmagnesi-
um bromide (44) in diethyl ether (28.0 mL of a 1.0m
solution, 280 mmol) and Bu3SnCl (5.00 mL, 184 mmol)
were stirred in THF (25 mL) at 308C under argon for
3 h. MeOH (25 mL) was slowly added to the cooled so-
lution, and the mixture was stirred at room tempera-
ture for an additional 30 min. The solvent was removed under reduced
pressure and the residue was dissolved in DCM (100 mL). The DCM so-
lution was then washed with water (100 mL), dried over Na2SO4/MgSO4
and the solvent was removed under reduced pressure. The residue was
purified by column chromatography (PE) to give 32 (6.60 g, 94%) as a
colourless liquid.
Rf =0.48 (PE); 1H NMR (400 MHz, CDCl3): d= 0.98 (t, J=7.5 Hz, 9H;
CH2CH3), 1.04–1.22 (m, 6H; SnCH2), 1.42 (sextet, J=7.5 Hz, 6H;
CH2CH3), 1.53–1.74 (m, 6H; CH2CH2CH3), 2.41 (s, 3H; Ar CH3), 7.23
(d, J=8.0 Hz, 2H; H2, 6), 7.45 ppm (d, J=8.0 Hz, 2H; H3, 5); 13C NMR
(100.6 MHz, CDCl3): d= 9.6 (SnCH2), 13.8 (CH2CH3), 21.5 (Ar-CH3),
27.5 (CH2CH3), 29.2 (CH2CH2CH3), 128.9 (C2, 6), 136.5 (C3, 5), 137.7
and 137.9 ppm (quat. C); IR (KBr): n˜max =3061 (w), 3006 (w), 2957 (s),
2925 (s), 2871 (m), 2854 (m), 1464 (m), 1069 (m), 790 cmÀ1 (m); MS (GC
CI+): m/z (%): 342.1 ([M(120Sn)NH4]+ÀC4H10, 22), 325.1 ([M(120Sn)H]+
ÀC4H10, 21), 308.1 (100), 291.1 (63); HRMS ([M(120Sn)H]+ÀC4H10) re-
quires m/z 325.0978, found 325.0965.
4-Methoxybiphenyl (26): Method A: 4-Methoxy-
phenyl trifluoromethanesulfonate (24; 215 mg) and
phenyltri-n-butylstannane (25; 341 mg) were cou-
pled by using the general procedure with conditions
A for 2 h. Column chromatography (PE/DCM, 3:7)
gave 26 (142 mg, 91%) as a white solid.
Method B: 4-Chloroanisole (47; 120 mg) and tri-n-butylphenylstannane
(25; 341 mg) were coupled by using the general procedure with condi-
tions B at 1008C for 15 h. Column chromatography (PE/DCM, 3:7) gave
26 (62–93 mg, 40–60%) as a white solid.
Rf =0.39 (PE:DCM, 3:7); m.p. 86.5–878C; lit. [64] 868C; 1H NMR
(400 MHz, CDCl3): d= 3.90 (s, 3H; OCH3), 7.04 (d, J=9.0 Hz, 2H; Ar
CH), 7.39 (t, J=7.5 Hz, 2H; Ar CH), 7.99 (t, J=7.5 Hz, 2H; Ar CH),
7.58–7.64 ppm (m, 4H; Ar CH); 13C NMR (100.6 MHz, CDCl3): d= 55.4
(OCH3), 114.3, 126.7, 126.8, 128.2 and 128.8 (Ar CH), 133.8, 140.9 and
159.2 ppm (quat. C); IR (KBr): n˜max =3033 (w), 3002 (w), 2961 (w), 2836
(w), 1606 (s), 1522 (s), 1488 (s), 1464 (w), 1438 (w), 1288 (m), 1270 (m),
1251 (s), 1201 (s), 1184 (m), 1035 (s), 834 (s), 760 (s), 688 cmÀ1 (s); MS
(GC CI+): m/z (%): 184.1 ([MH]+, 100), 169.1 (22), 148.1 (25), 141.1
(22), 115.1 (16); HRMS ([MH]+) requires m/z 184.0888, found 184.0883.
4-Methylbiphenyl (33): Bromobenzene (31; 132 mg) and
4-(tri-n-butylstannyl)toluene (32; 354 mg) were coupled
by using the general procedure with conditions B for
15 h. Column chromatography (PE) gave 33 (138 mg,
98%) as a white solid.
Rf =0.36 (PE); m.p. 43–448C; lit. [66] 44.5–46.58C; 1H
NMR (400 MHz, CDCl3): d= 2.50 (s, 3H; CH3), 7.32–
4-Phenyl-1-cyclohexen-1-yl triflate (27):[63] KHMDS
in toluene (5.00 mL of a 0.5m solution, 2.50 mmol)
was added slowly to a solution of 4-phenyl-1-cyclo-
hexanone (30; 0.400 g, 2.30 mmol) in THF (10 mL)
7.37 (m, 2H; Ar CH), 7.40–7.47 (m, 1H; Ar CH), 7.50–
at À788C under argon. The solution was allowed to
7.57 (m, 2H; Ar CH), 7.57–7.62 (m, 2H; Ar CH), 7.67–7.72 ppm (m, 2H;
Ar CH); 13C NMR (100.6 MHz, CDCl3): d= 21.2 (CH3), 127.06, 127.08,
128.80, 128.84 and 129.6 (Ar CH), 137.1, 138.4 and 141.2 ppm (quat. C);
IR (KBr): n˜max =3030 (w), 2915 (w), 1487 (m), 823 (m), 804 (w), 755 (s),
735 (w), 690 cmÀ1 (m); MS (GC CI+): m/z (%): 168.1 ([MC]+, 100), 70.1
(28); HRMS ([MC]+) requires m/z 168.0939, found 168.0943.
warm to room temperature, then it was stirred for
1 h. The reaction mixture was cooled to À788C and a solution of N-phe-
nyltrifluoromethanesulfonimide (0.940 g, 2.63 mmol) in THF (5 mL) was
added by syringe. The reaction mixture was allowed to warm to room
temperature, then it was stirred for 2 h. The solvent was removed under
reduced pressure and the residue was purified by column chromatogra-
phy (PE/DCM, 9:1) to give 27 (0.680 g, 97%) as a colourless liquid.
4’-Methoxy-4-nitrobiphenyl (11): 4-Bromoani-
sole (10; 157 mg) and 4-(tri-n-butylstannyl)ni-
trobenzene (7; 383 mg) were coupled by using
the general procedure with conditions B for
15 h. Column chromatography (PE/DCM, 1:1)
gave 11 (187 mg, 97%) as a yellow solid.
1
Rf =0.24 (PE/DCM, 9:1); H NMR (400 MHz, CDCl3): d= 1.95–2.04 (m,
1H), 2.08–2.15 (m, 1H), 2.34–2.64 (m, 4H), 2.85–2.94 (m, 1H), 5.90 (dt,
J1 =2.0, J2 =3.0 Hz, 1H; H2), 7.20–7.32 (m, 3H; Ar CH), 7.35–7.40 ppm
(m, 2H; Ar CH); 13C NMR (100.6 MHz, CDCl3): d= 27.9 (CH2), 29.7
(CH2), 31.6 (CH2), 38.7 (CH), 118.1 (C2), 118.6 (q, JCF =320 Hz, CF3),
126.7, 126.8 and 128.6 (Ar CH), 144.6 (quat. C), 149.0 ppm (quat. C); IR
(thin film): n˜max =3064 (w), 3031 (w), 2925 (m), 1692 (m), 1495 (w), 1418
Rf =0.31 (PE/DCM, 1:1); m.p. 105–105.58C;
lit. [43] 106–107; 1H NMR (400 MHz, CDCl3):
Chem. Eur. J. 2005, 11, 3294 – 3308
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3305

J. E. Baldwin et al.
d= 3.87 (s, 3H; OCH3), 7.01 (apparent d, J=9.0 Hz, 2H; H3’, 5’), 7.58
(apparent d, J=9.0 Hz, 2H; H2’, 6’), 7.67 (apparent d, J=9.0 Hz, 2H;
H2, 6), 8.24 ppm (apparent d, J=9.0 Hz, 2H; H3, 5); 13C NMR
(100.6 MHz, CDCl3): d= 55.4 (OCH3), 114.6 (C3’, 5’), 124.1 (C3, 5),
127.0 (C2, 6), 128.5 (C2’, 6’), 131.0, 146.5, 147.1 and 160.5 ppm (quat. C);
IR (KBr): n˜max =2967 (w), 2930 (w), 2835 (w), 1600 (m), 1508 (s, NO2
str), 1343 (s, NO2 str), 1251 (s), 1186 (m), 1107 (w), 1033 (w), 1014 (w),
838 (w), 756 (w), 722 cmÀ1 (w); MS (CI+): m/z (%): 247.1 ([MNH4]+,
60), 229.0 ([MC]+, 51), 214.0 (24), 200.1 (100), 186.1 (50).
2-Phenyl-6-methylpyridine (42):[70] 2-Bromo-6-methyl-
pyridine (41; 144 mg) and phenyltri-n-butylstannane
(25; 341 mg) were coupled by using the general proce-
dure with conditions B for 15 h. Column chromatogra-
phy (DCM) gave 42 (129 mg, 91%) as a pale yellow
liquid.
Rf =0.27 (DCM); 1H NMR (400 MHz, CDCl3): d= 2.65 (s, 3H; CH3),
7.11 (d, J=7.5 Hz, 1H; Ar CH), 7.38–7.55 (m, 4H; Ar CH), 7.64 (t, J=
7.5 Hz, 1H; Ar CH), 7.98–8.01 ppm (m, 2H; Ar CH); 13C NMR
(100.6 MHz, CDCl3): d= 24.8 (CH3), 117.6, 121.6, 127.0, 128.7 and 136.9
(Ar CH), 139.8, 157.0 and 158.4 ppm (quat. C); IR (thin film): n˜max =3061
(w Ar CH str), 2956 (w), 2923 (w), 1591 (s), 1572 (s), 1459 (s), 1160 (w),
1029 (w), 805 (m), 757 (s), 694 cmÀ1 (s); MS (ES+): m/z (%): 169.5
([MH]+, 100).
2-(Thiophen-2’-yl)-6-methylpyridine (43):[71] 2-Bromo-
6-methylpyridine (41; 144 mg) and 2-(tri-n-butylstan-
nyl)thiophene (18; 347 mg) were coupled by using the
general procedure with conditions B for 15 h. Column
chromatography (PE/DCM, 1:1) gave 43 (144 mg,
98%) as a pale yellow liquid.
Rf =0.35 (PE/DCM, 1:1); 1H NMR (400 MHz, CDCl3): d= 2.59 (s, 3H;
CH3), 7.00 (d, J=7.5 Hz, 1H; Ar CH), 7.11 (dd, J1 =3.5, J2 =5.0 Hz, 1H;
Ar CH), 7.38 (dd, J1 =1.0, J2 =5.0 Hz, 1H; Ar CH), 7.45 (d, J=8.0 Hz,
1H; Ar CH), 7.54 (dd, J1 =4.0, J2 =7.5 Hz, 1H; Ar CH), 7.58 ppm (d,
J1 =1.0, J2 =3.5 Hz, 1H; Ar CH); 13C NMR (100.6 MHz, CDCl3): d=
24.6 (CH3), 115.9, 121.5, 124.4, 127.2, 127.9 and 136.8 (Ar CH), 145.2,
151.9 and 158.4 ppm (quat. C); IR (thin film): n˜max =3071 (w), 2959 (w),
2922 (w), 1587 (s), 1574 (s), 1532 (m), 1456 (s), 1434 (m), 1290 (w), 1232
(m), 1161 (m), 993 (w), 910 (m), 859 (m), 837 (m), 787 (s), 734 (s),
705 cmÀ1 (s); MS (ES+): m/z (%): 175.6 ([MH]+, 100); HRMS ([MH]+)
requires m/z 176.0534, found 176.0539.
2’,4’-Dimethoxy-4-nitrobiphenyl (35): 2,4-Di-
methoxybromobenzene (34; 182 mg) and 4-
(tri-n-butylstannyl)nitrobenzene (7; 383 mg)
were coupled by using the general procedure
with conditions B for 15 h. Column chroma-
tography (PE/DCM, 3:7) gave 35 (194 mg,
89%) as a bright yellow solid.
Rf =0.38 (PE/DCM, 3:7); m.p. 124–1258C; 1H
NMR (400 MHz, CDCl3): d= 3.84 (s, 3H; CH3), 3.88 (s, 3H; CH3), 6.57–
6.63 (m, 2H; H3’, 5’), 7.28 (d, J=8.5 Hz, 1H; H6’), 7.67 (apparent d, J=
9.0 Hz, 2H; H2, 6), 8.24 ppm (apparent d, J=9.0 Hz, 2H; H3, 5); 13C
NMR (100.6 MHz, CDCl3): d= 55.5 and 55.6 (CH3), 99.1 and 105.1 (C3’,
5’), 121.0 (quat. C), 123.2 (C3, 5), 130.0 (C2, 6), 131.3 (C6’), 145.4, 146.2,
157.6 and 161.5 ppm (quat. C); IR (KBr): n˜max =2968 (w), 2950 (w), 2841
(w), 1615 (s), 1598 (s), 1576 (s), 1511 (s, NO2 str), 1343 (s, NO2 str), 1311
(s), 1284 (s), 1212 (s), 1166 (s), 1142 (m), 1110 (m), 1050 (m), 1030 (m),
854 (m), 825 (s), 794 (m), 754 (m), 693 cmÀ1 (m); MS (CI+): m/z (%):
277.2 [MNH4]+, 20), 260.2 (100), 244.2 (22), 230.2 (57), 214.2 (12), 198.1
(26), 183.1 (20); HRMS ([MH]+) requires m/z 260.0923, found 260.0930.
9-Vinylanthracene (37): 9-Bromoanthracene (36;
216 mg, 0.840 mmol) and tri-n-butylvinylstannane (28;
346 mg, 1.09 mmol) were coupled by using the general
procedure with conditions B for 15 h. Column chroma-
tography (PE) gave 37 (165 mg, 96%) as a pale yellow
solid.
Rf =0.27 (PE); m.p. 57–608C; lit. [67] 60–638C; 1H
NMR (400 MHz, CDCl3): d= 5.68 (d, J=18.0 Hz, 1H;
C=CHb), 6.06 (d, J=11.5 Hz, 1H; C=CHa), 7.48–7.60
4-Acetylbiphenyl (46): 4-Chloroacetophenone (45;
130 mg) and phenyltri-n-butylstannane (25; 341 mg)
were coupled by using the general procedure with
conditions B at 1008C for 15 h. Column chromatog-
raphy (PE/DCM, 1:1) gave 46 (134 mg, 81%) as a
white solid.
Rf =0.17 (PE/DCM, 1:1); m.p. 116–1178C; lit. [73]
109–1108C; 1H NMR (400 MHz, CDCl3): d= 2.64 (s, 3H; CH3), 7.42 (t,
J=7.5 Hz, 1H; Ar CH), 7.49 (t, J=7.5 Hz, 2H; Ar CH), 7.63 (d, J=
7.5 Hz, 2H; Ar CH), 7.69 (d, J=8.5 Hz, 2H; H2, 6), 8.03 ppm (d, J=
8.5 Hz, 2H; H2, 6); 13C NMR (100.6 MHz, CDCl3): d=26.7 (CH3), 127.2,
127.3, 128.3, 128.9 and 129.0 (Ar CH), 135.8, 139.8 and 145.7 (quat. C),
197.7 ppm (C=O); IR (KBr): n˜max =3072 (w), 2997 (w), 2916 (w), 1680 (s,
C=O str), 1602 (s), 1404 (m), 1358 (m), 1283 (m), 1264 (s), 1208 (m),
1180 (m), 961 (m), 842 (m), 766 (s), 720 (m), 691 (m), 596 cmÀ1 (m); MS
(GC CI+): m/z (%): 197.1 ([MH]+, 100), 196.1 (48), 181.1 (45), 152.1
(18), 131.1 (26), 87.0 (20), 71.1 (33), 70.1 (72); HRMS ([MH]+) requires
m/z 197.0966, found 197.0972; elemental analysis (%) calcd: C 85.68, H
6.16; found: C 85.33, H 6.18.
(m, 5H; Ar CH and C=CH), 8.00–8.08 (m, 2H; Ar CH), 8.35–8.40 (m,
2H; Ar CH), 8.42 ppm (s, 1H; H10); 13C NMR (100.6 MHz, CDCl3): d=
122.9 (C=CH2), 125.1, 125.4, 126.0, 126.4 and 128.6 (Ar CH), 129.2 and
131.4 (quat. C), 133.6 (C=CH), 133.7 ppm (quat. C); IR (KBr): n˜max
=
3050 (m), 1622 (m), 1442 (m), 1338 (m), 1158 (m), 991 (m), 932 (m), 884
(m), 843 (m), 734 cmÀ1 (s); MS (GC CI+): m/z (%): 205.1 ([MH]+, 100);
HRMS ([MH]+) requires m/z 205.1017, found 205.1012.
(E)-Bis(7,8-dimethoxyquinol-5-yl)ethene
(40):
(38)[69] (236 mg, 0.880 mmol) and (E)-1,2-
bis(tri-n-butylstannyl)ethene
(39)[68]
5-Bromo-7,8-dimethoxyquinoline
(255 mg, 0.420 mmol) were coupled by
using the general procedure with condi-
tions B [PdCl2 (3 mg, 0.017 mmol), PtBu3
(9 mL,
0.036 mmol),
CuI
(7 mg,
0.037 mmol), CsF (255 mg, 1.68 mmol),
DMF (2 mL)] for 15 h. Column chroma-
tography (DCM/acetone, 1:1) gave 40 (157 mg, 93%) as a yellow solid.
Acknowledgements
Rf =0.32 (DCM/acetone, 1:1); m.p. 211–2128C; 1H NMR (400 MHz,
CDCl3): d= 4.12 (s, 3H; OCH3), 4.18 (s, 3H; OCH3), 7.34 (dd, J1 =4.0,
J2 =8.5 Hz, 2H; H3’, 3’’), 7.66 (s, 2H; H1, H2, or H6’, H6’’), 7.72 (s, 2H;
H1, H2, or H6’, H6’’), 8.46 (dd, J1 =1.5, J2 =8.5, 2H; H4’, 4’’), 8.97 ppm
(dd, J1 =1.5, J2 =4.0 Hz, 2H; H2’, 2’’); 13C NMR (100.6 MHz, CDCl3):
d= 57.1 and 61.9 (OCH3), 113.3 (C1, 2, or C6’, 6’’), 119.4 (C3’, 3’’), 122.6
(quat. C), 127.8 (C1, 2, or C6’, 6’’), 130.8 (quat. C), 132.2 (C4’, 4’’),
143.59, 143.64 (quat. C), 150.5 (C2’, 2’’), 151.3 ppm (quat. C); IR (KBr):
n˜max = 2999 (w), 2935 (w), 2831 (w), 1594 (s), 1500 (m), 1476 (s), 1334
(s), 1307 (m), 1251 (m), 1165 (m), 1130 (s), 1082 (s), 790 cmÀ1 (m); MS
(ES+): m/z (%): 827.1 (51), 425.0 ([MNa]+, 45), 403.0 ([MH]+, 100);
HRMS ([MH]+) requires m/z 403.1658, found 403.1653.
This research was supported by the Overseas Research Student awards
scheme and Professor Sir Jack Baldwin.
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Received: November 17, 2004
Published online: March 22, 2005
3308
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Chem. Eur. J. 2005, 11, 3294 – 3308