Stille coupling made easier - The synergic effect of copper(I) salts and the fluoride ion

Article abstract of DOI:10.1002/anie.200352979

CsF and Cul do the trick: Stille coupling reactions of aryl/vinyl iodides, triflates, and bromides with aryl/vinyl stannanes are greatly enhanced by the inclusion of CsF and Cul in the reaction mixture (see scheme; Conditions A: [Pd(PPh₃)₄]/CsF/ Cul/DW/45 °C; Conditions B: PdCl ₂/ PtBu₃/CsF/Cul/DMF/45 °C).

Full text of DOI:10.1002/anie.200352979

Communications
Stille Coupling
Stille Coupling Made Easier—The Synergic Effect
of Copper(i) Salts and the Fluoride Ion**
Simon P. H. Mee, Victor Lee, and Jack E. Baldwin*
The union of two trigonal carbon centers through the Stille
coupling[1] is a versatile process which has found numerous
applications in organic synthesis. However the reaction
between an aryl or vinyl halide/triflate and an organostan-
nane under palladium catalysis sometimes presents difficul-
ties.[2] The choice of catalyst,ligands,additives,solvent,and
temperature can substantially affect the outcome and yield of
the reaction.
We encountered a difficult Stille reaction in the course of
a recent natural product synthesis,[3] a reaction which was very
low yielding under typical conditions. After extensive opti-
mization studies we discovered a combination of co-reagents
that has proven to be remarkably effective in promoting the
Stille reaction,that is,a copper( i) salt in conjunction with
fluoride ions.
The beneficial effect of CuI salts in the Stille coupling is
well documented[4–7] and it is believed that the function
[*] S. P. H. Mee, Dr. V. Lee, Prof. J. E. Baldwin
The Dyson Perrins Laboratory
University of Oxford
South Parks Road, Oxford OX1 3QY (UK)
Fax: (+44)1865-275-632
E-mail: jack.baldwin@chem.ox.ac.uk
[**] We thank the Overseas Research Student awards scheme for a
scholarship (to S.P.H.M.).
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DOI: 10.1002/anie.200352979
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Chemie
performed by the CuI salt in the catalytic cycle is solvent
dependent.[5] In ethereal solvents such as THF and dioxane,
the proposed role of CuI is as a scavenger for free neutral
ligand that otherwise causes autoretardation of the rate-
determining associative transmetalation.[5,6] However in
organostannane 2. A series of reactions were carried out to
determine the individual effects of CuI and CsF and then the
combined effect of these two additives on this coupling
reaction (Table 1).
highly polar solvents such as N-methylpyrrolidone (NMP)
Table 1: The individual and combined effects of CuI and CsF on the
coupling of 1 and 2.
I
and DMF,the rate-accelerating effect of Cu
has been
attributed to a preliminary transmetalation reaction from
the organostannane to generate a more reactive organo-
copper intermediate,which then takes part in the catalytic
cycle.[6,7] Stille and Scott have observed previously that the
fluoride ion increases the rate of the palladium-catalyzed
coupling reaction between vinyl triflates and organostan-
nanes.[8] It was also noted that the Bu3SnCl by-product could
be efficiently transformed into insoluble Bu3SnF,which could
be removed from the reaction mixture by filtration. More
recently others have also employed the fluoride ion to
enhance the Stille reaction.[9–11,16]
On this basis we hypothesized that if the preliminary
transmetalation between the organostannane and CuI did
exist and it was in equilibrium,then removal of the Bu 3SnI by-
product as insoluble Bu3SnF should favor the formation of the
more reactive organocopper species,resulting in enhance-
ment of the reaction (Scheme 1). To our knowledge,the
tandem use of CuI and CsF to promote the Stille reaction has
not been reported.
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 and CuI
CsF and CuI
[a] [Pd(PPh3)4] (10%), CuI (20%), CsF (2.0 equiv). [b] Yields are isolated
yields of 3 and are the average of two repeat experiments. Remaining
mass balance is recovered starting materials.
When the reaction between 1 and 2 was conducted at
408C for two hours using [Pd(PPh3)4] as catalyst,only a trace
of product 3 was isolated and most of the starting materials
were recovered (Table 1,entry 1). The addition of CsF had a
very minor positive effect on the yield of this reaction
(Table 1,entry 2). A significant improvement in the yield of 3
was observed when CuI was included as an additive; the
recovered starting materials again accounted for the remain-
ing mass balance (Table 1,entry 3). When both CuI and CsF
were present,the coupling reaction proceeded to completion
with a near-quantitative yield of 3 (Table 1,entry 4). However
no product formation was observed when the coupling
between 1 and 2 was attempted with only CuI and CsF
(Table 1,entry 5). This eliminated the possibility of CuI
directly catalyzing the coupling of 1 and 2.[13–15] It is clear that
in the presence of palladium(0),CuI and CsF exert a synergic
effect that promotes this reaction considerably.
Before exploring the scope of this combined effect,we
evaluated the optimal conditions for the reaction. Variables
investigated were: solvent,palladium source,ligands,fluoride
source,and copper( i) source. We observed that aryl iodides
and triflates undergo facile coupling with organostannanes
using a mixture of [Pd(PPh3)4]/CuI/CsF in DMF (Conditions
A). For the less reactive aryl bromides,the most effective
reagent combination has proven to be PdCl2/PtBu3/CuI/CsF
in DMF (Conditions B). However,in both cases these were
not necessarily the only conditions that gave high yields.
Highly polar solvents such as DMSO and NMP were also
effective and tetrabutylammonium fluoride (TBAF) seemed
comparable to CsF in enhancing the reaction,whereas other
fluoride sources (LiF,NaF,KF) were less effective.
Scheme 1. Hypothesis leading to the investigation of the simultaneous
use of copper(i) and fluoride in the Stille reaction.
We emphasize here that Scheme 1 presents an outline of
our hypothesis. Detailed mechanistic studies will be required
to determine the precise role of copper(i) and fluoride in the
Stille reaction. This is beyond the scope of our current
investigation; nonetheless the improvement they afford is
significant however it comes about.
To investigate the effect of CuI and CsF on the Stille
reaction we chose to couple 4-iodotoluene (1) and a
deactivated electron-deficient aryl stannane,4-(tri- n-butyl-
stannyl)nitrobenzene (2),as a model reaction. Since 1 would
be expected to undergo facile oxidative addition,[12] any
variation in the rate and yield of this reaction should reflect
the relative ease of the transmetalation step involving
Recently Fu et al. reported a procedure for the Stille
coupling that also makes use of PtBu3.[16] To investigate
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 challenging
coupling of electron-rich 4-bromoanisole (4) and electron-
deficient 4-(tri-n-butylstannyl)nitrobenzene (2; Table 2).
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Table 3: Scope of the combined copper(i)/fluoride effect on a variety of cross coupling reactions of
iodides and triflates.
The coupling of 4 and 2 under
Conditions B afforded 92% of the
desired product 5 after 4 h at 458C
(Table 2,entry 1). To demonstrate
that CuI is necessary when using
PtBu3 under Conditions B the cou-
pling of 4 and 2 was repeated in the
absence of CuI. After the same
reaction time only 29% of the
coupled product 5 was isolated,
with the remaining starting mate-
rial being recovered (Table 2,
entry 2). This indicates that even
though Conditions B generate a
coordinatively unsaturated cata-
lytic system,CuI is still necessary
to provide the highest yields. When
the coupling of 4 and 2 was carried
out using the reagent combination
described by Fu et al.,[16] a 16%
yield of the coupled product 5 was
isolated along with recovered start-
ing materials (Table 2,entry 3).
Interestingly when CuI was
included in the same reaction
there was a slight decrease in
yield (Table 2,entry 4). This obser-
vation is supported by our optimi-
zation studies in which it was dis-
covered that highly polar solvents
are necessary to ensure the syner-
Entry Iodide/Triflate
Stannane
Product
Conditions Time [h] Yield [%][a]
1
A
A
8
8
92
94
2
3
4
A
A
1
2
99
92
5
A
1
98
Conditions A: [Pd(PPh3)4] (5%), CuI (10%), CsF (2 equiv), DMF, 458C. [a] Yields are isolated yields and
are the average of two repeat experiments.
gic effect of CuI and CsF. We also observed that PdCl2 was a
superior palladium source to [Pd2(dba)3] (dba = trans,trans-
dibenzylideneacetone) when using DMF as the solvent.
To investigate the efficiency of our new conditions we
studied a number of different coupling reactions which are
summarized in Table 3 and Table 4. Some of these examples
were selected from the literature.
The coupling of hindered iodide 6 and hindered stannane
7 to give 8 has previously been achieved in an optimized yield
of only 27%,following reaction for 15 h at 80 8C.[17] When
conducted under the new conditions,this same reaction
delivered 8 in an excellent yield of 92% (Table 3,entry 1). It
is noteworthy that with CuI and CsF present,the reaction
between 6 and 7 was complete after 6 h at just 458C. Similarly,
reaction of iodide 9 and stannane 7 afforded 10 in 94% yield
(Table 3,entry 2),whereas the previously reported best yield
of this reaction was a moderate 42%.[17] Heterocycles are well
tolerated under our coupling conditions,as demonstrated by
the near-quantitative coupling of 3-iodopyridine (11) and 2-
(tributylstannyl)thiophene (12; Table 3,entry 3). Organotri-
flates were also shown to be excellent substrates under the
new conditions: reaction of deactivated triflate 14 with
stannane 15 gave the coupled product 16 in 92% yield
(Table 3,entry 4),and diene 19 was obtained in 98% yield
from coupling of vinyl triflate 17 and stannane 18 (Table 3,
entry 5).
Coupling reactions with aryl bromides or chlorides
warranted the use of PdCl2/PtBu3/CuI/CsF (Conditions B)
(Table 4). These reactions were carried out overnight for
convenience,but did not necessarily require this extended
reaction time. For example the electronically disfavored
coupling of electron-rich bromide 4 and electron-deficient
stannane 2 afforded the product 5 in 97% yield overnight
(Table 4,entry 1),however it was essentially complete after
4 h (92%) as demonstrated above in Table 2 (entry 1). The
sterically unfavorable coupling of di-ortho-substituted bro-
mide 20 and stannane 18 gratifyingly provided the coupled
product 21 in 96% yield (Table 4,entry 2). This is substan-
tially higher than the previous reported yield of 66%,[16]
although our reaction was carried out at higher temperature
and for a longer time. In our hands the coupling of 20 and 18
Table 2: Evaluating alternative conditions on the coupling of 4 and 2.
Entry
Reagents[a]
Yield [%][d]
1
2
3
4
PdCl2, PtBu3, CuI, CsF, DMF[b]
PdCl2, PtBu3, CsF, DMF
92
29
16
10
[Pd2(dba)3], PtBu3, CsF, dioxane[c]
[Pd2(dba)3], PtBu3, CuI, CsF, dioxane
[a] PdCl2 (2%) or [Pd2(dba)3] (1%), PtBu3 (4%), CuI (4%), CsF
(2.0 equiv). [b] Conditions B. [c] Reagent combination reported by Fu
et al.[16]. [d] Yields are isolated yields and are the average of two repeat
experiments. Remaining mass balance is recovered starting materials.
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Table 4: Scope of the combined copper(i)/fluoride effect on a variety of cross coupling reactions of
bromides and chlorides.
In summary,we have demon-
strated that the combination of
copper(i) iodide and cesium fluo-
ride can significantly enhance the
Stille reaction. We found that the
PdCl2/PtBu3 catalytic system with
copper(i) iodide and cesium fluo-
ride in DMF is most effective for
coupling aryl bromides,while
[Pd(PPh3)4] in combination with
copper(i) iodide and cesium fluo-
ride is optimal when coupling
iodides and triflates. Furthermore,
our conditions are mild and com-
patible with a variety of functional
groups. This combination of cop-
per(i) iodide and cesium fluoride
should widen the scope of the Stille
reaction,allowing synthesis of ster-
ically hindered systems and pro-
mote electronically disfavored cou-
pling reactions.[19]
Entry Bromide/Chloride Stannane
Product
Conditions Time [h] Yield [%][c]
1
B
B
15
15
97
96
2[a]
3
B
15
93
4[b]
B
B
15
15
81
Received: September 30,2003
Revised: December 4,2003 [Z52979]
Keywords: copper · cross-coupling ·
5[b]
40–60
.
fluorides · Stille reaction
Conditions B: PdCl2 (2%), PtBu3 (4%), CuI (4%), CsF (2 equiv), DMF, 458C. [a] 1.3 equivalents of
organostannane. [b] Reaction temperature: 1008C. [c] Yields are isolated yields and are the average of
two repeat experiments (entry 5 shows the range).
[1] a) J. K. Stille, Angew. Chem. 1986,
98,504 – 519; Angew. Chem. Int.
Ed. Engl. 1986, 25,508 – 524;
b) J. K. Stille, Pure Appl. Chem. 1985, 57,1771 – 1780.
under the conditions applied by Fu and co-workers
([Pd2(dba)3],P tBu3,toluene,RT,3 h) gave 54% of the
product 21,whereas when the reaction was repeated using
our catalytic system under identical conditions (RT,3 h) a
68% yield of the product 21 was isolated. In both cases the
remaining mass balance was largely recovered starting
materials. As an example of a double Stille coupling,the
quinoline derivative 22 and stannane 23 were subjected to our
conditions,and delivered the desired product 24 in 93% yield
(Table 4,entry 3).
We have also investigated the coupling of aryl chlorides
under the CuI/CsF conditions. With these substrates we
observed that the electronic effect of the substituents on the
aromatic ring of the aryl chloride has a considerable influence
on the reactivity of the substrate. Reaction of electron-
deficient aryl chloride 25 with stannane 15 using Conditions B
at 1008C provided 26 in a respectable 81% yield (Table 4,
entry 4). However the coupling of the electron-rich chloride
27 to stannane 15,proceeded in lower yields of 40–60%
(Table 4,entry 5). 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 decompos-
ing under the more forcing conditions. Thus our new
conditions appear effective for the coupling of electron-
deficient aryl chlorides,but less effective when it comes to
electron-rich aryl chlorides.[18]
[2] For a review of the Stille reaction see: V. Farina,V. Krishna-
murthy,W. J. Scott, Org. React. 1997, 50,1 – 652.
[3] S. P. H. Mee,V. Lee,J. E. Baldwin,unpublished results.
[4] a) L. S. Liebeskind,R. W. Fengi, J. Org. Chem. 1990, 55,5359 –
5364.
[5] V. Farina,S. Kapadia,B. Krishnan,C. Wang,L. S. Liebeskind, J.
Org. Chem. 1994, 59,5905 – 5911.
[6] A. L. Casado,P. Espinet, Organometallics 2003, 22,1305 – 1309.
[7] X. Han,B. M. Stolz,E. J. Corey, J. Am. Chem. Soc. 1999, 121,
7600 – 7605.
[8] W. J. Scott,J. K. Stille, J. Am. Chem. Soc. 1986, 108,3033 – 3040.
[9] A. García Martínez,J. Osío Barcina,A. de Fresno Cerezo,L. R.
Subramanian, Synlett 1994, 12,1047 – 1048.
[10] E. Fouquet,M. Pereyre,A. L. Rodriguez, J. Org. Chem. 1997, 62,
5242 – 5243.
¯
[11] E. Abele,K. Rubina,M. Fleicher,J. Popelis,P. Arsenyan,L.
Edmunds, Appl. Organometal. Chem. 2002, 16,141 – 147.
[12] V. Farina,B. Krishnan, J. Am. Chem. Soc. 1991, 113,9585 – 9595.
[13] S. Zhang,D. Zhang,L. S. Liebeskind, J. Org. Chem. 1997, 62,
2312 – 2313.
[14] G. D. Allred,L. S. Liebeskind, J. Am. Chem. Soc. 1996, 118,
2748 – 2749.
[15] E. Piers,T. Wong, J. Org. Chem. 1993, 58,3609 – 3610.
[16] A. F. Littke,L. Schwarz,G. C. Fu, J. Am. Chem. Soc. 2002, 124,
6343 – 6348.
[17] F. Liron,M. Gervais,J.-F. Peyrat,M. Alami,J.-D. Brion,
Tetrahedron Lett. 2003, 44,2789 – 2794.
[18] For an effective method of Stille coupling using aryl chlorides,
see reference [16].
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[19] General experimental: A mixture of the organohalide (or
triflate) (0.840 mmol) and the organotin reagent (0.930 mmol)
was dissolved in DMF (2 mL),then cesium fluoride (256 mg,
1.685 mmol) was added. The palladium catalyst and copper(i)
iodide [Conditions A: [Pd(PPh3)4] (5%),CuI (10%); Conditions
B: PdCl2 (2%),P tBu3 (4%),CuI (4%)] were added and the
flask was evacuated and refilled with argon five times. The
mixture was stirred at 458C for the specified duration,then
diluted with CH2Cl2 (50 mL) and water (20 mL). After vigorous
shaking the mixture was filtered through celite with CH2Cl2/
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 chroma-
tography.
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