Copper-catalyzed coupling of 1,1-dibromo-1-alkenes with phenols: A general, modular, and efficient synthesis of ynol ethers, bromo enol ethers, and ketene acetals

Article abstract of DOI:10.1021/ol300491d

An efficient and general copper-catalyzed method is reported for the synthesis of phenol-derived 1-bromoenol ethers, ynol ethers, and ketene acetals by chemodivergent copper-catalyzed cross-coupling between readily available 1,1-dibromo-1-alkenes and phen

Full text of DOI:10.1021/ol300491d

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1652–1655
Copper-Catalyzed Coupling of
1,1-Dibromo-1-alkenes with Phenols:
A General, Modular, and Efficient
Synthesis of Ynol Ethers, Bromo Enol
Ethers, and Ketene Acetals
†
Kevin Jouvin, Alexandre Bayle, Frederic Legrand, and Gwilherm Evano*
†
†
,†,‡
ꢀ
ꢀ ꢀ
ꢀ
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite de Versailles
Saint-Quentin en Yvelines, 45, Avenue des Etats-Unis, 78035 Versailles Cedex, France,
and Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques,
ꢀ
Universite Libre de Bruxelles, Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
gevano@ulb.ac.be
Received February 29, 2012
ABSTRACT
An efficient and general copper-catalyzed method is reported for the synthesis of phenol-derived 1-bromoenol ethers, ynol ethers, and ketene
acetals by chemodivergent copper-catalyzed cross-coupling between readily available 1,1-dibromo-1-alkenes and phenols.
Heteroatom-substituted alkenes and alkynes are func-
tional groups that display enormous potential in organic
chemistry and high versatility. Significant advances
have been made recently in the synthesis of ynamides,1
enamides,2 phosphorus-substituted acetylenes,3 and olefins,4
which considerably expanded their synthetic utility, as ex-
emplified with the renaissance of the chemistry of nitrogen-
substituted alkynes due to the development of efficient
methods for their preparation. Alkynyl5,6 and alkenyl2,7
ethers, while possessing many of the reactivity features of
their nitrogen-substituted counterparts, have been far less
investigated because of the relatively few methods available
for their synthesis, except in the case of simple enol ethers.
Here we report an efficient, general, and chemodivergent
method for the synthesis of stable, phenol-derived 1-brom-
oenol ethers 3, ynol ethers 4, and ketene acetals 5 by
copper-catalyzed cross-coupling between readily available
1,1-dibromo-1-alkenes 1 and phenols 2 (Scheme 1).
†
ꢀ
Universite de Versailles Saint-Quentin en Yvelines.
‡
ꢀ
Universite Libre de Bruxelles.
(1) (a) Evano, G.; Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010,
49, 2840. (b) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064.
(2) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
(3) Kondoh, A.; Yorimitsu, H.; Oshima, K. Chem. Asian J. 2010, 5, 398.
(4) (a) Julienne, D.; Delacroix, O.; Gaumont, A.-C. Curr. Org. Chem.
2010, 14, 457. (b) Gaumont, A. C.; Gulea, M. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Molander, G. A.,
Ed.; Thieme: Stuttgart, 2006; Vol. 33, pp 665ꢀ694.
(5) Witulski, B.; Alayrac, C. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; de Meijere, A., Ed.; Thieme:
Stuttgart, 2005; Vol. 24, pp 933ꢀ956.
(6) For the synthesis of ynol ethers, see: (a) Darses, B.; Millet, A.;
Philouze, C.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2008, 10, 4445. (b) Sosa,
J. R.; Tudjarian, A. A.; Minehan, T. G. Org. Lett. 2008, 10, 5091. (c)
Bruckner, D. Synlett 2000, 1402. (d) Himbert, G.; Loffler, A. Synthesis 1992,
495. (e) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987, 52,
2919. (f) Pericas, M. A.; Serratosa, F.; Valenti, E. Tetrahedron 1987, 43,
2311. (g) Smithers, R. H. Synthesis 1985, 556. For selected recent transfor-
mations from ynol ethers, see: (h) Davies, P. W.; Cremonesi, A.; Martin, N.
Chem. Commun. 2011, 47, 379. (i) Hanna, R.; Daoust, B. Tetrahedron 2011,
67, 92. (j) Basheer, A.; Marek, I. Beilstein J. Org. Chem. 2011, 6, No. 77. (k)
While the use of gem-dibromoalkenes 1 in palladium
catalysis has been extensively studied,8 their use in combi-
nation with copper-based catalytic systems, which might
(7) Winternheimer, D. J.; Shade, R. E.; Merlic, C. A. Synthesis 2010,
2497.
Levin, A.; Basheer, A.; Marek, I. Synlett 2010, 329. (l) Garcı
´
a-Garcı
´
a, P.;
ꢀ
Fernandez-Rodrı
´
guez, M. A.; Aguilar, E. Angew. Chem., Int. Ed. 2009, 48,
5534. (m) Ceccon, J.; Danoun, G.; Greene, A. E.; Poisson, J.-F. Org. Biomol.
Chem. 2009, 7, 2029.
(8) (a) Chelucci, G. Chem. Rev. 2012, 112, 1344. (b) Legrand, F.;
Jouvin, K.; Evano, G. Isr. J. Chem. 2010, 50, 588.
r
10.1021/ol300491d
Published on Web 03/07/2012
2012 American Chemical Society

be especially useful for the introduction of various het-
eroatoms, has been far less developed. We have recently
shown that they are indeed versatile partners that can be
readily coupled with nitrogen or phosphorus nucleophiles,
yielding ynamides, ketene N,N-acetals, or vinylphospho-
nates with remarkable efficiency.9 Based on these results,
wefelt thattheir reaction withphenols incombination with
a suitable copper catalyst10,11 might provide an efficient
and modular entry to 1-bromo-enol ethers 3,12 ynol ethers
4, and ketene acetals 5, especially useful building blocks
with limited availability, provided that both the cross-
coupling mode (regioselective monocoupling, double cou-
pling, or alkynylative coupling) and the easy dimerization
of 1 could be controlled.
Figure 1. Ligand influence on the cross-coupling.
Scheme 1. Chemodivergent Synthesis of 1-Bromoenol Ethers,
Ynol Ethers, and Ketene Acetals from Vinyl Dibromides
alkenes 1 and phenols 2 under the optimized conditions
(Figure 2). Para-, meta-, and ortho-substituted phenols
were all readily transformed to the corresponding bromoe-
nol ethers 3, although the cross-coupling was slowed down
in the last case. The presence of electron-withdrawing or
-donating groups had virtually no effect on the outcome of
the reaction and even the challenging 4-bromophenol
could be smoothly transformed to the corresponding enol
ether 3g, without competing reaction involving the aro-
matic bromide. The reaction was found to be equally
efficient for the synthesis of alkyl- (3a-s), alkenyl- (3t)
and aryl- (3u, 3v) substituted bromoenol ethers and al-
lowed the synthesis of more complex bromoenol ethers
such as the ones derived from citronellal, 3w, or β-estra-
diol, 3x.13 Trifluoroethanol could also be used as a cross-
coupling partner in place of phenols, yielding stable bromo-
enol ethers 30 in moderate yields. In all cases, a site
selective cross-coupling involving the least hindered CꢀBr
bond occurred, favoring the formation of the Z-isomers,14
compound that cannot be obtained using other methods,
with synthetically useful levels of stereoselectivity (Z/E: 74/
26 to 96/4).15 In an attempt to further extend the scope of
this cross-coupling, the use of aliphatic alcohols was also
evaluated but, as anticipated, mostly resulted in homo-
dimerization of the starting dibromoalkene. Interestingly,
the reaction is not limited to the small scale used for the
coupling reactions described above (i.e., 0.7 mmol) as
illustrated by the gram scale synthesis of bromoenol ethers
3a and 3c.
To test this hypothesis, we initiated our studies by
examining the reaction of m-cresol 2a with 1.5 equiv of
1,1-dibromooct-1-ene 1a, in order to promote the selective
formation of the monocoupled product 3a, in the presence
of excess potassium phosphate, catalytic amounts of
copper(I) iodide, and various bidentate ligands susceptible
to promote the cross-coupling (Figure 1). Best results were
obtained with 3,4,7,8-tetramethyl-1,10-phenanthroline F
and 2,20-bipyridine G, the latter affording bromoenol ether
3a in 81% yield with a slightly better diastereoselectivity
(Z/E: 91/9). Finally, toluene and potassium phosphate
were found to be the most suitable solvent and base,
respectively, to minimize the dimerization of 1a.
Toevaluatethe scopeofthissite-selectivecrosscoupling,
we examined the reactivity of a series of 1,1-dibromo-1-
(9) (a) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G. Angew.
Chem., Int. Ed. 2009, 48, 4381. (b) Coste, A.; Couty, F.; Evano, G. Org.
Lett. 2009, 11, 4454. (c) Evano, G.; Tadiparthi, K.; Couty, F. Chem.
Commun. 2011, 47, 179.
(10) For leading references on the synthesis of enol ethers by copper-
catalyzed alkenylation of alcohols or phenols, see: (a) Kabir, M. S.;
Lorenz, M.; Namjoshi, O. A.; Cook, J. M. Org. Lett. 2010, 12, 464. (b)
Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L.
J. Org. Chem. 2008, 73, 284. (c) Ma, D.; Cai, Q.; Xie, X. Synlett 2005,
1767. (d) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
4978. (e) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973.
(11) For reviews on copper catalysis, see: (a) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. 2009, 48, 6954. (b) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054.
(12) For the synthesis of E-1-bromoenol ethers and their application in
organic synthesis, see: Yu, W.; Jin, Z. J. Am. Chem. Soc. 2000, 122, 9840.
We next turned our attention to the selective formation
of ynol ethers 4 starting from the same reaction partners 1
and 2 and found that exposure of the crude reaction
mixtures to potassium tert-butoxide after dilution with
dioxane triggered a rapid β-elimination of the intermediate
bromoenol ethers (Figure 3).16 Using this slight modification,
(13) The lower yields observed with some substrates can be attributed
to catalyst deactivation or dimerization of the dibromoalkene.
(14) The stereochemistry of bromoenol ethers 3a0 and 3c0 was as-
signed on the basis of NOE experiments. See the Supporting Informa-
tion for details.
(15) Z/E ratio from crude reaction mixtures.
Org. Lett., Vol. 14, No. 6, 2012
1653

Figure 3. Synthesis of ynol ethers by site-selective coupling/
elimination.
Figure 2. Site-selective cross-coupling to 1-bromoenol ethers.
ynol ethers 4 with representative substitution patterns could
be obtained with high efficiency, which nicely complements
their classical synthesis involving reaction with trichloroethylene
followed by a FritschꢀButtenbergꢀWiechel rearrangement.6
We finally envisioned a modification of our procedure
that would allow for a clean and selective double cross-
coupling, which would provide a straightforward entry to
phenol-derived ketene acetals 5, compounds for which
there is no general preparation to date. The optimization
of this coupling turned out to be a lot more complicated
due to problems associated to the high sensitivity of these
building blocks toward hydrolysis or during their purifica-
tion. Ketene acetals 5 could however be obtained in
virtually pure form by performing the reaction with excess
phenol in dioxane at 110 °C followed by simple removal of
the catalyst and base by filtration, concentration of the
crude mixture and elimination of excess phenol by extrac-
tion of the apolar product with pentane. Using this opti-
mized procedure, phenol- and trifluoroethanol-derived
ketene acetals 5 and 50 could be obtained with high effi-
ciency, regardless of the substitution pattern or electronic
properties of the starting materials (Figure 4).13
Figure 4. Synthesis of ketene acetals by double cross-coupling.
From a mechanistic point of view, both bromo enol
ethers 3 and ketene acetals 5 could be respectively formed
by either site-selective/double cross coupling from the
corresponding dibromoalkenes or by hydrobromination/
hydroalkoxylation of intermediate ynol ethers. To probe
the operative mechanism, deuterated (1aD and 1bD) and
nondeuterated (1a and 1b) dibromoalkenes were respec-
tively reacted with deuterated and nondeuterated phenols
under our coupling conditions optimized for the synthesis
of bromoenol ethers 3 and ketene acetals 5 (Scheme 2).
Results from these experiments unambiguously demon-
strate that the vinylic hydrogen atom of the starting
dibromides is fully retained during the reaction, clearly
(16) For the anti-β-elimination of bromoalkenes to alkynes, see:
Okutani, M.; Mori, Y. J. Org. Chem. 2009, 74, 442 and references cited
therein.
1654
Org. Lett., Vol. 14, No. 6, 2012

This result is also in agreement with the stereoselectivity
observed for the formation of 3. Bromoenol ethers 3 would
therefore arise from a regioselective cross coupling gov-
erned by the known higher reactivity of the trans CꢀBr
bond of dibromides 1 toward oxidative addition,8,17 while
a double cross-coupling would account for the formation
of ketene acetals 5.18
Scheme 2. Cross-Coupling with Deuterated Substrates
In conclusion, we have developed an efficient and gen-
eral copper-catalyzed method for the synthesis of phenol-
derived 1-bromo-enol ethers, ynol ethers, and ketene
acetals from readily available 1,1-dibromo-1-alkenes.
The outcome and chemoselectivity of the reaction are
controlled by simple modification of the reaction condi-
tions. We envision great acceptance and applicability for
these simple and practical procedures which provide
straightforward entries to highly valuable building blocks.
Further studies are underway in our laboratory to further
extend their use in organic synthesis.
Acknowledgment. We thank the CNRS, the University
of Versailles, and the ANR (Project Nos. ProteInh ANR-
07-JCJC-0025-01 and DYNAMITE ANR-2010-BLAN-
704) for financial support. K.J. acknowledges the Minis-
ꢁ
tere de la Recherche for a graduate fellowship.
indicating that β-elimination followed by hydrobromina-
tion or hydroalkoxylation is not a competitive pathway.
Supporting Information Available. Experimental pro-
cedures, characterization, and copies of 1H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.
acs.org.
ꢀ
(17) (a) Zapata, A. J.; Ruiz, J. J. Organomet. Chem. 1994, 479, C6. (b)
Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873. (c) Shen, W.; Thomas,
S. A. Org. Lett. 2000, 2, 2857.
(18) This mechanism is also supported by the formation of ketene
acetals from the corresponding bromoenol ethers when the latter were
reacted under the reaction conditions shown in Figure 4 and by the
presence of bromoenol ethers before completion of the reaction yielding
to ketene acetals.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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