The availability of structurally diverse sulfonates is much
wider than that of halides, as sulfonates are readily prepared
from phenols. During the development of our work, Alami
reported the Pd-catalyzed reaction between tosylhydrazones
and aryl triflates,5 in the context of their studies of isocom-
bretastatins,6 a new type of anticancer agents. However, the
coupling reaction with aryl triflates is restricted to the
preparation of 1,1-diarylethylenes, employing tosylhydra-
zones derived from acetophenones, and therefore, its scope
is very limited. For this reason, we decided to continue with
our study to expand the coupling reaction to more challenging
substrates. In this paper we report our progress in this
reaction, which has led to the development of a wide scope
cross-coupling between tosylhydrazones and aryl nonaflates,
which allows high yielding syntheses of di-, tri-, and
tetrasubstituted arylalkenes.
hydrolysis of the nonaflate, and olefin 5, the Bamford-Stevens
degradation product of the tosylhydrazone. Based on our
experience in other coupling reactions with tosylhydrazones,
we tested the addition of small amounts of water to the
reaction mixture.3d Indeed, when the reaction was conducted
in the presence of 5 equiv of water, complete conversion
was achieved after 4 h, leading to diarylethylene 3a in
quantitative yield.10 Noteworthy, the reaction proceeds with
total regioselectivity, giving rise exclusively to the coupling
product of the nonaflate 3a, with no traces of the alkene that
would come from coupling at the chloride position. These
reaction conditions were applied to other nonaflates and
tosylhydrazones derived from acetophenones (Scheme 3)
leading to the diarylethylenes 3 in very high yields.
From the beginning of our study, we chose aryl nonaflates
for various reasons: nonaflates exhibit similar reactivity as
triflates as electrophiles in Pd-catalyzed cross-couplings but
are more economically and easily prepared7 as well as more
user-friendly than triflates.8 Moreover, nonaflates are more
robust than triflates toward alkoxides and, therefore, provide
better results in Pd-catalyzed cross-couplings that require the
employment of these types of bases.9
Scheme 3. Synthesis of 1,1-Diarylethylenes by Pd-Catalyzed
Cross-Coupling between the Tosylhydrazones and Nonaflates
As a model reaction we selected the coupling of hydrazone
2a, derived from 4-methylacetophenone, and nonaflate 1a,
a quite demanding electrophilic component that will require
addressing steric (ortho substitution) and chemoselectivity
(ONf vs Cl) issues (Scheme 2).
However, the reaction of nonaflate 1b with hydrazone 4a,
derived from 3-phenylpropanal, under the same reaction
conditions, turned out to be very sluggish, and the coupling
product 6a was obtained in very low yield. Moreover, the
couplings with other hydrazones derived from alkyl ketones
such as 4b, 4c, and 4d did not occur at all, leading mainly
to the alkenes derived from the Bamford-Stevens degrada-
tion (Scheme 4).
Scheme 2. Pd-Catalyzed Cross-Coupling between the
Tosylhydrazone 2a and Nonaflate 1a
Scheme 4
.
Unsuccessful Reactions under the Standard
Conditions
The first experiment, employing the standard reaction
conditions previously developed for aryl halides, furnished
the cross-coupling product in a promising 60% yield after
20 h at 110 °C. Analysis of the GC/MS trace showed
significant amounts of phenol 4, which comes from the
(4) (a) Xiao, X.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009,
11, 4732. (b) Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun.
2010, 46, 1724.
Cross-coupling and Heck reactions with aryl and alkenyl
sulfonates are accelerated in the presence of added halide
(5) (a) Tre´guier, B.; Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M.
Tetrahedron Lett. 2009, 50, 6549. (b) Brachet, E.; Hamze, A.; Peyrat, J.-
F.; Brion, J.-D.; Alami, M. Org. Lett. 2010, 12, 4042.
(6) Messaoudi, S.; Tre´guier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.;
Rodrigo De Losada, J. R.; Liu, J.-M.; Bignon, J.; Wdzieczak-Bakala, J.;
Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. J. Med. Chem. 2009, 52,
4538.
(7) Aryl nonaflates are prepared with perfluoro-1-butanesulfonyl fluoride
(see Supporting Information for details) that is available at half the price
($/mmol) of anhydride triflate (Aldrich Chem. Co.).
(8) For a recent review on the advantages of the use of nonaflates in
Pd-catalyzed cross-couplings, see: Ho¨germeier, J.; Reissig, H.-U. AdV. Synth.
Catal. 2009, 351, 2747.
Org. Lett., Vol. 13, No. 3, 2011
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