Use of thallium(I) ethoxide in Suzuki cross coupling reactions

Article abstract of DOI:10.1021/ol0062446

(equation presented) Thallium(I) ethoxide promotes Suzuki cross couplings for a range of vinyl-and arylboronic acids with vinyl and aryl halide partners in good to excellent yields. This reagent offers distinct advantages over thallium(I) hydroxide in terms of commercial availability, stability, and ease of use.

Full text of DOI:10.1021/ol0062446

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2691-2694
Use of Thallium(I) Ethoxide in Suzuki
Cross Coupling Reactions
Scott A. Frank, Hou Chen, Roxanne K. Kunz, Matthew J. Schnaderbeck, and
William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received June 22, 2000
ABSTRACT
Thallium(I) ethoxide promotes Suzuki cross couplings for a range of vinyl- and arylboronic acids with vinyl and aryl halide partners in good
to excellent yields. This reagent offers distinct advantages over thallium(I) hydroxide in terms of commercial availability, stability, and ease
of use.
The Suzuki reaction is an important method for the synthesis
of conjugated olefins, styrenes and biphenyls,1-3 and is
extremely useful in the context of complex natural products
synthesis.4-8 In the original version of the reaction,2,9 a vinyl
(or aryl) halide is combined with a vinyl (or aryl) boronic
acid (or ester) or dialkylborane in the presence of bases such
as NaOMe or K2CO3 and a Pd(0) catalyst in an organic
solvent at temperatures between 60 and 90 °C for 2-24 h.
In 1987 Kishi reported remarkable rate accelerations when
the Suzuki reaction was performed using TlOH as the base,
in which case the cross couplings were complete within
minutes at ambient temperature.4 We have found the TlOH
method to be superior to many other procedures especially
when 1,1-dibromoolefins or 1-iodo-1-trimethylsilylalkenes,
which easily undergo base-induced elimination of HBr or
HI, are used as the substrates.7,10-12
Despite its great utility in the Suzuki reaction, aqueous
solutions of TlOH are both air and light sensitive and have
an inferior shelf life. Moreover, commercial sources of the
reagent have virtually disappeared, and to our knowledge
only a single supplier of solid TlOH currently exists.13
Dissolution of solid TlOH in water gives an initially clear
solution from which a brown-black precipitate separates even
under careful storage conditions.14 Moreover, we have
(10) Roush, W. R.; Moriarty, K. J.; Brown, B. B. Tetrahedron Lett. 1990,
31, 6509.
(1) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem.
Soc. 1985, 107, 972.
(2) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(3) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(4) Uenishi, J.-i.; Beau, J.-M.; Armstrong, R. W.; Kishi, Y. J. Am. Chem.
Soc. 1987, 109, 4756.
(5) Nicolaou, K. C.; Ramphal, J. Y.; Palazon, J. M.; Spanevello, R. A.
Angew. Chem., Int. Ed. Engl. 1989, 28, 587.
(6) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115,
11446.
(11) Roush, W. R.; Kageyama, M.; Riva, R.; Brown, B. B.; Warmus, J.
S.; Moriarty, K. J. J. Org. Chem. 1991, 56, 1192.
(12) Roush, W. R.; Brown, B. B. J. Am. Chem. Soc. 1993, 115, 2268.
(13) While 10% aqueous solutions of TlOH have been available in the
past from a variety of commercial vendors, a recent search revealed only
a single supplier of solid TlOH. A conversation with a Johnson-Matthey
customer service representative indicated that 10% TlOH solutions exhibited
both air and light sensitivity and that they had ceased marketing the reagent
for reasons of shelf life. While TlOEt is significantly more stable than TlOH,
it is air and moisture sensitive and should be handled under inert
atmospheres.
(7) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411.
(8) Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush,
W. R. Angew. Chem., Int. Ed. 1999, 38, 1652.
(14) The identity of the brown-black precipitate is unclear, but a likely
suspect is Tl2O3: To´th, I.; Gyo˜ri, B. Encyclopedia of Inorganic Chemistry;
King, B. R., Ed.; John Wiley and Sons: New York, 1994; Vol. 8, p 4134.
(9) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 3437.
10.1021/ol0062446 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/25/2000

observed that the efficiency of Suzuki reactions promoted
by TlOH is dependent on the age of the TlOH solution, with
yields decreasing substantially with older batches of reagent.
For example, during studies focusing on completion of a total
synthesis of kijanolide,15 the Suzuki coupling of 1 and 2,
using a 0.5 M stock solution of TlOH that had been prepared
1 month earlier and which had been employed successfully
in our total synthesis of bafilomycin A,8 provided 3 in 71%
yield. However, when we repeated this reaction 4 months
later using the same TlOH solution (after removing the
brown-black precipitate by filtration), the yield of 3 fell to
50%. The next time this experiment was performed, an
additional 6 months later, we prepared a fresh 0.5 M solution
of TlOH from the same batch of solid TlOH, again with
filtration to remove insoluble dark material, but the yield of
3 was still only 52%. The latter observations suggest that
TlOH may also be somewhat unstable in the solid state. Thus,
we turned our attention to identification of a suitable
replacement for TlOH.
Although thallium(I) ethoxide (TlOEt) is an easily handled
liquid that is readily available from several commercial
suppliers at lower cost than TlOH, we are aware of only
one published account in which this reagent has been used
successfully as the base in a Suzuki cross coupling reaction.16
However, there are several examples where TlOEt failed to
give acceptable results,17,18 including Kishi’s original report.4
In the later work, Kishi indicated that TlOEt gave only a
5-fold rate enhancement compared to experiments performed
using KOH, while TlOH increased the rate a 1000-fold.
Figure 1.
In a key initial experiment (Figure 1), we found that the
Suzuki cross coupling of 1 and 2 using TlOEt in an aqueous
THF solvent system, using conditions which otherwise
mirrored the previous experiments performed using the 10%
TlOH solutions, provided 3 in 83% yield. Interestingly, there
was no significant difference in the rate of coupling of 1
and 2 using either TlOH or TlOEt.
The TlOEt-promoted Suzuki reactions summarized in
Figures 1 and 2 are very fast, with TlBr or TlI precipitating
from solution immediately upon addition of TlOEt to a
mixture of the vinyl (or aryl) halide and vinyl (or aryl)
boronic acid. Although we have not performed any detailed
kinetic measurements, qualitatively these reactions appear
to be as fast as Suzuki reactions we have previously
performed using TlOH. Moreover, these reactions are
substantially faster than those performed using AgO. For
example, the coupling of 4 and 5 in the presence of AgO in
3:1 THF-H2O gave only ca. 25% conversion to 6 after a
30 min reaction period, whereas the reaction of 4 and 5 in
the presence of TlOEt is complete almost immediately after
mixing of all reagents. Kishi reported that AgO is second
only to TlOH in terms of rate acceleration (30-fold) of the
Suzuki reaction;4 however, our results suggest that TlOEt
rivals TlOH in this capacity.
We have demonstrated that TlOEt may be used with a
range of functionalized vinyl and aryl halide and vinyl- and
arylboronic acid coupling partners, as summarized in Figure
2.19 As shown in these examples, vinyl iodides (4, 11) 1,1-
dibromo olefins (7), R-iodo vinylsilanes (14), and aryl iodides
(17, 19) are excellent coupling partners, and many potentially
sensitive functional groups such as methyl esters, geminally
alkylated malonate systems, silyl ethers, enones, etc. are fully
compatible with these reaction conditions. In the accompany-
ing paper, Chemler and Danishefsky have demonstrated that
TlOEt also gives good results in intramolecular B-alkyl
Suzuki macrocyclization reactions.20
We initiated these studies on the assumption that TlOH is
an obligatory intermediate4 and that TlOEt would be rapidly
converted to TlOH under the aqueous reaction conditions.
To determine if it is necessary to run the TlOEt-promoted
Suzuki cross couplings in the presence of water, the reaction
of 4 and 5 was performed in anhydrous THF (Figure 2).
Tetraene 6 was obtained in 92% yield, compared to 97%
for the original experiment in the 3:1 THF-H2O solvent
system, with no noticeable difference in reaction rate. A
better yield of 18 was obtained from the coupling of phenyl
(15) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58, 2162, and
references therein.
(16) Humphrey, J. M.; Aggen, J. B.; Chamberlin, A. R. J. Am. Chem.
Soc. 1996, 118, 11759.
(17) Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405.
(18) Marko´, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37,
2507.
(19) All new compounds were fully characterized by 1H and 13C NMR,
IR, and high-resolution mass spectroscopy.
(20) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695. We
thank the Sloan-Kettering group for sharing their results with us prior to
publication.
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Org. Lett., Vol. 2, No. 17, 2000

Figure 2. Representative TlOEt-promoted Suzuki reactions. Unless otherwise noted, all reactions were performed using TlOEt in 3:1
THF-H2O using the conditions described in text for the coupling of 5 and 7.
iodide and vinylboronic acid 15 in wet THF (94%) than in
anhydrous THF (83%), although the former result was
obtained using an inverse addition protocol (addition of a
mixture of 17 and Pd(PPh3)4 to a mixture of 15 and TlOEt
in wet THF; the yield of 18 was only 73% using the normal
addition). However, the aqueous reaction conditions were
essential to the successful, high-yield coupling of 19 and
20.
One variable that is critical to the success of these reactions
is the solubility of an intermediate generated from the
reaction of the vinyl(aryl)boronic acid and TlOEt. For
example, exposure of THF solutions of 15 or 20 to TlOEt
in the absence of the other reaction components leads to the
immediate precipitation of white solids, which we presume
to be the thallium ate complexes of the boronic acids.21 The
precipitate generated from 15 and TlOEt partially dissolves
Org. Lett., Vol. 2, No. 17, 2000
2693

when H2O is added; however the solid analogously generated
from 20 does not appear to dissolve at all under these
conditions, or in other solvents such as MeOH, CH3CN, or
DMF. Therefore, to maximize the yield of biphenyl 21 from
the coupling of 19 and 20, it was necessary to use 5 equiv
of the phenylboronic acid in the aqueous solvent system.
Attempts to use arylboronic acids 22 and 23 (Figure 3) in
In summary, we have demonstrated that TlOEt is an
excellent alternative to TlOH for use in Suzuki cross coupling
reactions. This reagent has advantages compared to TlOH
in terms of stability and ease of use. Most importantly, the
commercial availability of TlOEt makes it significantly more
attractive than TlOH for use in this important cross coupling
reaction.
Acknowledgment. Financial support provided by the
National Institutes of Health to W.R.R. (GM 26782) and an
NIH Postdoctoral Fellowship to H.C. (CA 76655) is grate-
fully acknowledged.
OL0062446
(22) Representative experimental procedure: A solution of 5 (0.42 g,
3.28 mmol) and 7 (0.74 g, 1.09 mmol) in THF and water (12 mL, 3:1) was
degassed thoroughly (3×) by using the freeze-pump-thaw method.
Tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) was added
as a solid, and the yellow solution was stirred for 5 min at ambient
temperature. Thallium ethoxide (0.14 mL, 1.96 mmol) was added by syringe,
and a bright yellow precipitate immediately formed. (NOTE: thallium salts
are generally quite toxic and should be handled with extreme care.) The
reaction was stirred 30 min and then was diluted with ether (25 mL) and a
1 N sodium bisulfate solution (10 mL). The biphasic mixture was filtered
through Celite, and the organic layer was separated, washed with brine,
and dried over MgSO4. Concentration of the filtrate and purification of the
crude tetraene by column chromatography afforded 0.60 g (81%) of 8.
Figure 3. Unsuccessful reaction partners.
these reactions were unsuccessful, presumably due to the
insolubility of the boronic acid-TlOEt reaction product. For
this reason, an excess of the boronic acid component was
utilized in many of the experiments summarized in Figure
2.22
(21) Dewar, M. J. S.; Jones, R. J. Am. Chem. Soc. 1967, 89, 2408.
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