A versatile protocol for Stille-Migita cross coupling reactions

Article abstract of DOI:10.1039/b805299a

The combination of catalytic amounts of [Pd(PPh₃)₄], copper thiophene-2-carboxylate (CuTC) and [Ph₂PO₂] [NBu₄] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805299a

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A versatile protocol for Stille–Migita cross coupling reactionswz
Alois Furstner,* Jacques-Alexis Funel, Martin Tremblay, Laure C. Bouchez, Cristina Nevado,
¨
Mario Waser, Jens Ackerstaff and Christopher C. Stimson
Received (in Cambridge, UK) 31st March 2008, Accepted 29th April 2008
First published as an Advance Article on the web 2nd June 2008
DOI: 10.1039/b805299a
The combination of catalytic amounts of [Pd(PPh3)4], copper
thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a
series of exigent Stille–Migita reactions to be performed with
high yields; as the protocol is fluoride free, a variety of O-silyl
and C-silyl groups remained intact.
species from the equilibrium in form of sparingly soluble
R3SnF.
Despite the success of these and related protocols,12 they
essentially met with failure when applied to various late-stage
Stille–Migita reactions planned to serve as key fragment
coupling steps of different natural product syntheses pursued
by our group. Not surprisingly, major problems arose from
the incompatibility of the fluoride additives with the silyl
protecting group regiments prevalent in target oriented synth-
esis.13 The sensitivity of certain substrates to the fairly basic
conditions caused by the presence of fluoride in the medium
constitutes another limiting factor.
Organotin derivatives are prominently featured amongst the
different nucleophiles amenable to palladium catalyzed cross
coupling reactions.1 In many cases, they constitute a good
compromise between availability, ease of handling, functional
group tolerance and desirable reactivity towards the electro-
philic partner. As a result, Stille–Migita reactions remain
widely used in advanced organic chemistry, natural product
total synthesis and material science, even though other meth-
ods for catalytic cross coupling are arguably more benign.2,3
Over the years, the original Stille–Migita protocol4 has been
considerably improved. The most noteworthy advances re-
sulted from careful optimization of the ligand sets,5 as well as
from the recognition of a significant co-catalytic effect exerted
by copper(I) salts.6–8 Although the observed rate accelerations
upon addition of CuX may have more than one cause,7a
transmetallation of the tin reagents with formation of orga-
nocopper species is almost certainly involved in reactions
performed in polar media (Scheme 1). Since organocopper
reagents are considered more nucleophilic, a positive effect on
the rate and efficiency will ensue in all cases in which the
transmetallation step of the catalytic cycle is rate determining.9
As the tin/copper exchange is likely reversible, however, the
positive influence of Cu(I) will fade away with increasing
conversion, as the built-up of R3SnX in the mixture drives
the equilibrium back to the left side.
We reasoned that these problems could be remedied by
using a less nucleophilic and essentially neutral tin scavenger.
We opted for the phosphinate salt [Ph2PO2][NBu4]14 which
had already previously been used to remove tin contaminants
from difficult to purify mixtures,12b and had also served very
well in palladium-only15 as well as in palladium free cross
coupling processes.16 To the best of our knowledge, however,
this particular additive has not been exploited in Pd/Cu co-
catalyzed Stille–Migita reactions prior to our work. We were
therefore pleased to see that replacement of CsF by
[Ph2PO2][NBu4] allowed a series of challenging Stille–Migita
cross coupling reactions to be performed with excellent results,
which could not be effected otherwise.
The examples compiled in Table 1 are representative. Entry
1 shows a particularly challenging case as the skipped diene
subunits of the substrate and the product are exceptionally
sensitive and prone to double bond isomerization with forma-
tion of conjugated trienes under acidic as well as basic condi-
tions, and even upon gentle heating;17 moreover, the terminal
TBS-ether is incompatible with fluoride additives. Whereas the
use of PdCl2(MeCN) in combination with Ph3As as a pre-
ferred ligand for Stille–Migita reactions5a led to no reaction,
the combination of [Pd(PPh3)4] (5 mol%), CuTC (1.5 eq.) and
[Ph2PO2][NBu4] (1.2 eq.) in DMF resulted in essentially
quantitative cross coupling even at ambient temperature.
Entry 2 confirms this rewarding result and shows that the
reaction still proceeds in the presence of the potential S- and
N-donor sites of a tetrazolyl thioether. Likewise, a conceivable
Heck reaction between the iodide and a terminal alkene in the
donor is not interfering (entry 3). The fact that cross coupling
occurred at ambient temperature is key to success for the
Several methods have been devised to counteract this un-
desirable effect. A simple but effective means is to employ a
large excess of CuCl ( Z 5 equiv.) in combination with LiCl
( Z 6 eq.).10 Alternatively, the use of copper thiophene-2-
carboxylate (CuTC) has been recommended,8a as the resulting
tin carboxylates might be less prone to participate in the retro-
reaction. Particularly successful was a procedure developed by
Baldwin and co-workers,11 which requires only catalytic
amounts of CuI, provided that the mixture is complemented
with CsF or TBAF (2 equiv.) to remove the generated R3SnX
Max-Planck-Institut fur Kohlenforschung, D-45470 Mulheim/Ruhr,
¨
¨
Germany. E-mail: fuerstner@mpi-muelheim.mpg.de;
Fax: +49 208 306 2994; Tel: +49 208 306 2342
w Dedicated to Prof. Andrew B. Holmes on the occasion of his 65th
birthday.
z Electronic supplementary information (ESI) available: Experimental
part including analytical and spectroscopic data of all new com-
pounds. See DOI: 10.1039/b805299a
Scheme 1 Pre-equilibrium as one of the reasons for the co-catalytic
effect of copper additives on Stille–Migita cross coupling reactions
performed in polar media.
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Table 1 Palladium/copper co-catalyzed Stille–Migita cross coupling reactions promoted by [Ph2PO2][NBu4]a
a
[Pd(PPh3)4] (5 mol%), CuTC (1.2–1.6 eq.) and [Ph2PO2][NBu4] (1.1–1.6 eq.) in DMF at RT, unless stated otherwise. bUsing 10 mol%
[Pd(PPh3)4]. cUsing [Pd(PPh3)4] (70 mol%), CuTC (3 eq.) and [Ph2PO2][NBu4] (4 eq.). d86% based on recovered starting material. eThe stannane
f
was slowly added to the mixture. In THF.
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example depicted in entry 4, as the resulting product rapidly
decomposes when heated to Z 35 1C.17
3. (a) P. Espinet and A. M. Echavarren, Angew. Chem., Int. Ed.,
2004, 43, 4704; (b) V. Farina, V. Krishnamurty and W. J. Scott,
Org. React., 1997, 50, 1; (c) T. N. Mitchell, Synthesis, 1992, 803;
(d) M. A. J. Duncton and G. Pattenden, J. Chem. Soc., Perkin
Trans. 1, 1999, 1235; (e) K. C. Nicolaou, P. G. Bulger and
D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4442.
The examples shown in entries 5–7, which model a key
fragment coupling en route to amphidinolide H,18 are also
highly demanding. Apprehensive that a previous approach to
this sensitive target based on a late-stage intramolecular
Stille–Migita reaction at the 1,3-diene site had met with fail-
ure,19 much effort was dedicated to optimize this step. Grati-
fyingly, the new protocol worked exceedingly well, providing
the sterically hindered products in good to excellent yields.
Most notable is the fact that the reaction tolerates unprotected
hydroxy epoxides, which undergo Payne rearrangement under
basic conditions. Likewise, a sensitive aldol unit remained
intact (entry 7), attesting to an essentially neutral medium
operative under the chosen conditions. As expected, various
O-silyl groups as well as a vinylsilane entity (entry 5) posed no
problems for this fluoride free protocol.
4. (a) M. Kosugi, Y. Shimizu and T. Migita, Chem. Lett., 1977, 1423;
(b) D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1979, 101,
4992.
5. (a) V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113,
9585; (b) A. F. Littke, L. Schwarz and G. C. Fu, J. Am. Chem.
Soc., 2002, 124, 6343.
6. (a) J. P. Marino and J. K. Long, J. Am. Chem. Soc., 1988, 110,
7916; (b) L. S. Liebeskind and R. W. Fengl, J. Org. Chem., 1990,
55, 5359.
7. Leading references: (a) V. Farina, S. Kapadia, B. Krishnan,
C. Wang and L. S. Liebeskind, J. Org. Chem., 1994, 59, 5905;
(b) A. L. Casado and P. Espinet, Organometallics, 2003, 22, 1305;
(c) Y. Wang and D. J. Burton, Org. Lett., 2006, 8, 1109;
(d) K. C. Nicolaou, M. Sato, N. D. Miller, J. L. Gunzner,
J. Renaud and E. Untersteller, Angew. Chem., Int. Ed. Engl.,
1996, 35, 889; (e) S.-K. Kang, J.-S. Kim and S.-C. Choi, J. Org.
Chem., 1997, 62, 4208; (f) J.-H. Li, B.-X. Tang, L.-M. Tao,
Y.-X. Xie, Y. Liang and M.-B. Zhang, J. Org. Chem., 2006, 71,
7488 and references therein.
8. The in situ formation of organocopper reagents even allows
Stille–Migita type reactions to be performed in the absence of
palladium, cf.: (a) G. D. Allred and L. S. Liebeskind, J. Am.
Chem. Soc., 1996, 118, 2748; (b) J. R. Falck, R. K. Bhatt and
J. Ye, J. Am. Chem. Soc., 1995, 117, 5973.
It is well precedented that steric hindrance adversely affects
Stille–Migita and other palladium catalyzed processes.2,3
Therefore it was rewarding to see that the congested alkenyl
triflate shown in entry 8 coupled without incident with the
hindered biaryl donor to give product 8 in good yield, which is
the key intermediate of a formal total synthesis of the marine
alkaloid haouamine A.20 The silylated alkyne terminus in 8
remained unaffected by the admixed [Ph2PO2][NBu4] salt.
Finally, we revisited the formation of compound 9 which
represents the common polyketide sector of the crocacin
family of antibiotics. Its formation was plagued by poor
reproducibility and mostly low yields when performed under
conventional conditions (Pd2(dba)3 cat., tris-(2-furyl)phos-
phine, NMP, 40–60 1C, 32%),21 whereas the 2-trimethylsilyl-
ethyl ester moiety precludes the use of fluoride based proto-
cols.11,13 In line with our expectations, the new method
delivered this product without incident (entry 9). Together
with the other model studies displayed in Table 1, this example
corroborates the notion that the use of [Ph2PO2][NBu4] in
combination with CuTC and a suitable palladium source
accounts for a valuable protocol for challenging Stille–Migita
cross coupling reactions. Although the use of each individual
ingredient has precedence, their combination is unique and
allows to cope with fragile functional groups as well as the
C- and O-silyl protecting group regimens frequently encoun-
tered in target oriented synthesis.
9. For leading mechanistic investigations see refs. 3a and 5a and the
following: C. Amatore, A. A. Bahsoun, A. Jutand, G. Meyer,
A. N. Ntepe and L. Ricard, J. Am. Chem. Soc., 2003, 125,
4212.
10. X. Han, B. M. Stoltz and E. J. Corey, J. Am. Chem. Soc., 1999,
121, 7600.
11. S. P. H. Mee, V. Lee and J. E. Baldwin, Chem.–Eur. J., 2005, 11,
3294.
12. For some advanced applications of Pd/Cu co-catalyzed Stille–
Migita reactions, see: (a) H. Fuwa, N. Kainuma, K. Tachibana
and M. Sasaki, J. Am. Chem. Soc., 2002, 124, 14983;
(b) T. E. Nielsen, S. Le Quement, M. Juhl and D. Tanner,
Tetrahedron, 2005, 61, 8013; (c) R. D. Mazzola, Jr, S. Giese,
C. L. Benson and F. G. West, J. Org. Chem., 2004, 69, 220;
(d) I. Paterson, H.-G. Lombart and C. Allerton, Org. Lett., 1999,
1, 19; (e) B. Vaz, R. Alvarez, R. Bruckner and A. R. de Lera, Org.
¨
Lett., 2005, 7, 545; (f) S. R. Dubbaka and P. Vogel, J. Am. Chem.
Soc., 2003, 125, 15292; (g) W.-S. Kim, H.-J. Kim and C.-G. Cho,
J. Am. Chem. Soc., 2003, 125, 14288.
13. For another CsF-promoted Stille–Migita protocol, see:
A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 1999, 38, 2411.
14. J. Srogl, G. D. Allred and L. S. Liebeskind, J. Am. Chem. Soc.,
1997, 119, 12376.
15. A. B. Smith, K. P. Minbiole, P. R. Verhoest and M. Schelhaas,
J. Am. Chem. Soc., 2001, 123, 10942.
Generous financial support by the MPG, the Fonds der
Chemischen Industrie, the Alexander-von-Humboldt Founda-
tion (fellowships to C. N.), NSERC Canada (fellowship to
16. T. B. Durham, N. Blanchard, B. M. Savall, N. A. Powel and
W. R. Roush, J. Am. Chem. Soc., 2004, 126, 9307.
17. All attempts to form compounds of type 1–3 by Suzuki coupling
or Heck chemistry met with failure, cf.: (a) A. Furstner,
´ ,
C. Aıssa, E. Moulin and O. Muller, J. Am. Chem. Soc., 2007,
¨
C. Nevado, M. Waser, M. Tremblay, C. Chevrier, F. Teply
M. T.), the Austrian Fonds zur Forderung der Wissenschaf-
¨
¨
129, 9150; (b) A. Furstner, C. Nevado, M. Tremblay, C. Chevrier,
¨
tlichen Forschung (fellowship to M. W.), the Swiss National
Foundation and the Roche Foundation (fellowships to L. C.
B.) is gratefully acknowledged. We thank Dr F. Beaufils, Dr
¨
´ , C. Aıssa and M. Waser, Angew. Chem., Int. Ed., 2006,
¨
F. Teply
45, 5837; (c) A. Furstner, C. Aıssa, C. Chevrier, F. Teply´
C. Nevado and M. Tremblay, Angew. Chem., Int. Ed., 2006, 45,
,
¨
¨
V. Liepins, Dr F.-H. Poree and Dr R. Gilmour for exploratory
´
and additional studies not published herein, and our NMR
and chromatography departments for excellent support.
5832.
18. A. Furstner, L. C. Bouchez, J.-A. Funel, V. Liepins, F.-H. Poree,
´
¨
R. Gilmour, F. Beaufils, D. Laurich and M. Tamiya, Angew.
Chem., Int. Ed., 2007, 46, 9265.
19. M. B. Cid and G. Pattenden, Tetrahedron Lett., 2000, 41, 7373.
Notes and references
20. A. Furstner and J. Ackerstaff, Chem. Commun., 2008, DOI:
¨
10.1039/b805295f (accompanying paper) .
1. Metal-Catalyzed Cross-Coupling Reactions, ed. A de Meijere and
F Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1–2.
2. J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
21. M. Be-sev, C. Brehm and A. Furstner, Collect. Czech. Chem.
Commun., 2005, 70, 1696.
¨
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