Vinyl aryl ethers from copper-catalyzed coupling of vinyl halides and phenols

Article abstract of DOI:10.1016/j.tetlet.2003.09.068

A general procedure for vinyl aryl ether bond formation by direct coupling of vinyl halides and phenols under mild Ullmann-type reaction conditions has been developed. Using copper chloride as the catalyst and cesium carbonate as the base, vinyl bromides or iodides were reacted with phenols in refluxing toluene to produce vinyl aryl ethers in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2003.09.068

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8257–8259
Vinyl aryl ethers from copper-catalyzed coupling of vinyl halides
and phenolsꢀ
Zhonghui Wan,* Chauncey D. Jones, Thomas M. Koenig, Y. John Pu and David Mitchell
Global Chemical Process R&D, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 21 August 2003; revised 8 September 2003; accepted 10 September 2003
Abstract—A general procedure for vinyl aryl ether bond formation by direct coupling of vinyl halides and phenols under mild
Ullmann-type reaction conditions has been developed. Using copper chloride as the catalyst and cesium carbonate as the base,
vinyl bromides or iodides were reacted with phenols in refluxing toluene to produce vinyl aryl ethers in good to excellent yields.
© 2003 Elsevier Ltd. All rights reserved.
Vinyl aryl ethers are important intermediates or build-
ing blocks in organic synthesis1 as well as raw materials
for polymers.2 Methods for their syntheses include alco-
hol addition to acetylene under high pressure (20ꢀ50
atm) and high temperature (180ꢀ200°C),3 Michael-
type addition–elimination processes,4 transition metal
catalyzed vinyl transfer5 and allyl ether isomerization.6
Harsh reaction conditions or substrate limitations pro-
hibit the practical application of these methods.
literature reported conditions for Ullmann-type ether
formation.7a As illustrated in Scheme 1, reagents 1 and
2 were combined with CuCl (25 mol%), Cs2CO3 and the
THMD ligand 4 in refluxing toluene for 5 h to afford
the ether product 3 in 92% isolated yield. In an attempt
to find the optimum ligand for generalization of the
reaction, ligands 5 and 6 were compared to ligand 4.
Our previous work indicated that amino ethyl ethers
were efficient ligands in copper-catalyzed Ullmann
diaryl ether synthesis.10 We were interested in exploring
the use of amino ethyl ethers as ligand for Ullmann
vinyl–aryl ether formation. Surprisingly, all three lig-
ands performed about the same, and interestingly even
in the absence of a ligand the reaction was completed in
less than 5 h (Table 1).
In recent years, great progress has been made in both
palladium- and copper-catalyzed Ullmann-type diaryl
ether formation.7 To our knowledge, there are no
reports on the corresponding vinyl aryl ether formation
from vinyl halides and phenols under Ullmann-type
conditions in the literature.8,9 Mechanistically, vinyl
aryl ether formation should be similar to Ullmann-type
diaryl ether formation, and thus the reaction depicted
below (Eq. (1)) should be an efficient method to access
vinyl aryl ethers from vinyl halides and phenols.
Table 1. Ligand effect on percent of vinyl bromide
consumeda
Ligand
Reaction time
1.0 h 2.0 h
0.5 h
4.0 h
None
30.0
6.2
5.0
5.4
19.0
1.8
2.2
2.5
3.0
0.5
0.4
0.4
0
0
0
0
(1)
4
5
6
Our investigation began with the reaction of bromo-
triphenylethylene 1 with 4-methoxyphenol 2 utilizing
a Relative area% of vinyl bromide remaining determined by HPLC.
ꢀ Presented at the 225th National Meeting of the American Chemical
Society, March 2003, New Orleans, LA, USA; ORGN c580.
* Corresponding author. E-mail: wan zhonghui@lilly.com
–
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.068

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Z. Wan et al. / Tetrahedron Letters 44 (2003) 8257–8259
Scheme 1.
Table 2. Copper-catalyzed coupling of vinyl halides to phenols
To explore the generality of the vinyl coupling reaction,
tri-substituted, vicinal, and geminal olefinic bromides
were examined in combination with various phenols
including the electron deficient 4-fluorophenol, the elec-
tron rich 4-methoxy phenol and the sterically demand-
ing 2-methylphenol. Table 2 shows that the reaction
proceeded smoothly regardless of the steric or elec-
tronic properties of the reactants. With few exceptions,
the reactions were generally completed in less than 5 h
and in good to excellent yields. Even thio ethers (Table

Z. Wan et al. / Tetrahedron Letters 44 (2003) 8257–8259
8259
2, entry 9) could be formed utilizing this reaction
method, albeit in lower yield.11 The lower yield with
2-butene (Table 2, entry 6) is most likely due to the
substrates volatility. It also is important to note that
the E/Z stereochemistry of the vinyl aryl ether bond
corresponds to the starting vinyl halide (Table 2, entries
4, 6, 8, and 9). Geminal olefinic bromides produced a
1:1 mixture of 1- and 2-ethers as determined by 1H
NMR (Table 2, entries 5 and 7). Mechanistic investiga-
tion for an explanation of this phenomenon was not
pursued.
Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am.
Chem. Soc. 1991, 113, 1713–1729; (c) Longley, R. A., Jr.;
Emerson, W. S. J. Am. Chem. Soc. 1950, 72, 3079–3081;
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Organic Syntheses; Wiley & Sons: New York, 1963;
Collect. Vol. IV, pp. 816–819.
2. (a) Comprehensive Polymer Science; Allen, G., Ed.; Perg-
amon Press: New York, 1989; Vol. 3; (b) Encyclopedia of
Polymer Science and Engineering, 2nd ed.; Mark, H. F.;
Bikales, N.; Overberger, C. G.; Menges, G., Eds.; John
Wiley: New York, 1989; Vol. 16; (c) Kojima, K.;
Sawamoto, M.; Higashimura, T. Macromolecules 1989,
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3. Reppe, W. Ann. Chim. 1956, 601, 84–111.
4. Jones, D. E.; Morris, R. O.; Vernon, C. A.; White, R. F.
J. Chem. Soc. B. 1960, 2349–2366.
In conclusion, copper-catalyzed vinyl halide–phenol
coupling is an efficient method for vinyl aryl ether
formation. Generally, vinyl bromides and iodides, phe-
nols and thiols are all suitable substrates. Compared to
Ullmann diaryl ether formation reactions, the construc-
tion of the vinyl aryl ether bond appears to be more
facile and the ligand effects are less significant.
5. Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc.
2002, 124, 1590–1591.
6. Crivello, J. V.; Kong, S. J. Org. Chem. 1998, 63, 6745–
6748.
General Method: The following general method was
used for all substrates in Table 2. 1.0 equiv. vinyl
halide, 1.5 equiv. phenol, 0.25 equiv. CuCl and 0.25
equiv. ligand 5, 2.0 equiv. Cs2CO3 and toluene (5.0
mL/mmol) were combined in a round-bottom flask and
allowed to reflux until complete consumption of the
vinyl halide as determined by HPLC. After reaction
completion, the mixture was diluted with MTBE and
filtered through a plug of diatomaceous earth. The
filtrate was washed with 28% aqueous ammonium
hydroxide then dried over K2CO3. The crude products
were purified by Kugelrohr distillation under high vac-
uum or chromatography on either triethylamine deacti-
vated silica gel or neutral aluminum oxide.
7. For some recent reports on diaryl ether formation, see:
(a) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.;
Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623–
1626; (b) Gujadhur, R. K.; Bates, C. G.; Venkataraman,
D. Org. Lett. 2001, 3, 4315–4317; (c) Fagan, P. J.;
Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am.
Chem. Soc. 2000, 122, 5043–5051; (d) Marcoux, J.-F.;
Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
10539–10540; (e) Kalinin, A. V.; Bower, J. F.; Riebel, P.;
Snieckus J. Org. Chem. 1999, 64, 2986–2987; (f) Evans,
D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937–2940; (g) Palomo, C.; Oiarbide, M.; Lopez, R.;
Gomez-Bengoa, E. Chem. Commun. 1998, 2091–2092; (h)
Smith, K.; Jones, D. J. Chem. Soc., Perkin Trans. 1 1992,
407–408; (i) Wolter, M.; Nordman, G.; Job, G. E.; Buch-
wald, S. L. Org. Lett. 2002, 4, 973–976.
8. For an example of Pd-catalyzed enamine formation, see:
Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C.
Chem. Commun. 2002, 2362–2363.
9. Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 4978–4979.
10. Mitchell, D.; Pu, Y. J.; Koenig, T. M.; Wan, Z. Abstract
ORGN c580, the 225th National Meeting of the Ameri-
can Chemical Society, March 2003, New Orleans, LA.
11. For some recent reports on thioethers formation, see: (a)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4,
3517–3520; (b) Li, G. Y. J. Org. Chem. 2002, 67, 3643–
3650.
Acknowledgements
We would like to thank Professors Marvin Miller, Leo
Paquette, William Roush, Paul Wender, Peter Wipf,
and Stephen Buchwald for helpful discussions. We are
also grateful to the Lilly Physical Chemistry Group for
analytical data.
References
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