Synthesis of polysubstituted olefins by Pd-catalyzed cross-coupling reaction of tosylhydrazones and aryl nonaflates

Article abstract of DOI:10.1021/ol102884g

Aryl nonaflates are employed as electrophiles in the Pd-catalyzed cross-coupling with tosylhydrazones affording di-, tri-, and tetrasubstituted olefins. Fine tunning of the reaction conditions are required to accomplish the coupling successfully, includin

Full text of DOI:10.1021/ol102884g

ORGANIC
LETTERS
2011
Vol. 13, No. 3
510-513
Synthesis of Polysubstituted Olefins by
Pd-Catalyzed Cross-Coupling Reaction
of Tosylhydrazones and Aryl Nonaflates
Jose´ Barluenga,* Luc´ıa Florentino, Fernando Aznar, and Carlos Valde´s*
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, UniVersidad de
OViedo, c/Julia´n ClaVer´ıa 8, 33006, OViedo, Spain
barluenga@unioVi.es; acVg@unioVi.es
Received November 29, 2010
ABSTRACT
Aryl nonaflates are employed as electrophiles in the Pd-catalyzed cross-coupling with tosylhydrazones affording di-, tri-, and tetrasubstituted
olefins. Fine tunning of the reaction conditions are required to accomplish the coupling successfully, including the addition of LiCl and the
presence of small amounts of water. Under the optimized conditions, the reactions proceed with high yield and also high stereoselectivity
depending on the nature of the coupling partners.
Pd-catalyzed cross-coupling reactions are currently the most
reliable methods for the creation of Csp -Csp bonds.1 Well
established methods are based on the combination of an organic
halide or sulfonate with an organometallic reagent. At present,
the judicious election of cross-coupling sequences allows the
preparation of nearly all types of substituted alkenes.2 Neverthe-
less, the incorporation of different types of coupling partners is
highly desirable, as it enables the introduction of new classes
of fragments through cross-couplings reactions.
2
2
Scheme 1
.
Pd-Catalyzed Cross-Coupling Reactions Employing
Carbonyls Mediated by Tosylhydrazide
In this context, we have recently uncovered a new Pd-
catalyzed cross-coupling reaction that employs tosylhydra-
zones as nucleophilic coupling partners (Scheme 1).3 From
our point of view, this reaction features some interesting
properties; among them: (1) the reaction proceeds without
the participation of a stoichiometric organometallic reagent;
(2) since tosylhydrazones are readily prepared from carbonyl
compounds, it represents a very simple way to transform
carbonyls into reagents for cross-coupling reactions. Indeed,
since our preliminary contribution, we and others have shown
that the Pd-catalyzed reactions with tosylhydrazones are
excellent routes for the preparation of polysubstituted olefins
by reactions with aryl3b-d and benzyl halides.4
(1) (a) Negishi, E.-i. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley-Interscience: Hoboken, NJ, 2002. (b) de Mejiere,
A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
Wiley-VCH: Weinheim, 2004. (c) Tsuji, J. Palladium Reagents and
Catalysts; Wiley: Chichester, 2004.
(2) For a recent review, see: Negishi, E.-i.; Wang, G.; Rao, H.; Xu, Z.
J. Org. Chem. 2010, 75, 3151.
(3) (a) Barluenga, J.; Moriel, P.; Valde´s, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587. (b) Barluenga, J.; Toma´s-Gamasa, M.; Moriel, P.;
Aznar, F.; Valde´s., C. Chem.sEur. J. 2008, 14, 4792. (c) Barluenga, J.;
Escribano, M.; Moriel, P.; Aznar, F.; Valde´s, C. Chem.sEur. J. 2009, 15,
3291. (d) Barluenga, J.; Escribano, M.; Aznar, F.; Valde´s, C. Angew. Chem.,
Int. Ed. 2010, 49, 6856.
To expand the scope of this reaction to a wider variety of
substrates, we decided to study the employment of sulfonates
as electrophilic components in the cross-coupling reaction.
10.1021/ol102884g  2011 American Chemical Society
Published on Web 12/23/2010

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
511

salts.11 For this reason, we studied the effect of the addition of
ionic salts to the reaction mixture. Indeed, it was found that
the addition of LiCl led to a spectacular increase in the yield.
After some experimentation it was found that the coupling
reactions could be achieved successfully by the addition of 1
equiv of LiCl and 5 equiv of H2O.12 These reaction conditions
were then applied to a set of tosylhydrazones and sulfonates
(Scheme 5, Table 1).
in these cases it was necessary to employ a 1:2 nonaflate/
hydrazone molar ratio to avoid the formation of trisub-
stituted olefins that occur by Heck reaction of the initially
formed alkene 6 with the nonaflate.13 The coupling
reactions with hydrazones derived from cyclic and acyclic
alkyl ketones also took place with very high yields (entries
5-13). It is worth noting that these reactions do not
proceed at all in the absence of LiCl.
With regard to the structure of the nonaflate, the reaction
tolerates ortho substitution and also the presence of a chlorine
substituent that may enable further derivatization through
cross-coupling reactions.
Scheme 5
.
Synthesis of Substituted Olefins by Pd-Catalyzed
Reactions with Tosylhydrazones
The coupling reaction with nonaflates retains the charac-
teristics reported for the reactions with aryl halides. For
instance, the reactions with the hydrazone derived from
2-methoxycyclohexanone give exclusively the allyl ethers
with total regioselectivity (entries 10-13), as previously
reported for the couplings with aryl bromides.3d
Moreover, the stereochemistry in the formation of the
trisubstituted alkenes is noteworthy. The reactions with
hydrazones derived from dialkyl ketones such as 3-pentanone
afford exclusively the E-alkene (entry 5).
The coupling proceeded with nearly quantitative yield
for hydrazone 4a derived from an aldehyde, giving rise
exclusively to the E-alkenes (entries 1-4). Nevertheless,
Table 1. Substituted Olefins 6 Prepared According to Scheme 5a
a Reaction conditions: Nonaflate 1, (0.5 mmol), hydrazone 4 (0.55 mmol, 1.1 equiv), LiCl (0.5 mmol), LiOtBu (2.8 equiv), H2O (5 equiv), Pd2dba3 (1-5
mol %), Xphos (1-5 mol %), dioxane (1.5 mL). b A 2:1 molar ratio hydrazone 4/nonaflate 1 was employed. c Reaction times are not optimized. d Isolated
yields after column chromatography. e Obtained as a 1:1 mixture of isomers. f Stereochemistry determined by NOESY experiments. g Obtained as a single
stereoisomer. The stereochemistry is proposed based on the previous examples.
512
Org. Lett., Vol. 13, No. 3, 2011

Interestingly, the coupling reaction with a hydrazone
derived from a propiophenone and nonaflate 1a, which
features a chlorine in the ortho position, afforded exclusively
the Z-olefin 6p (entry 16), while the reaction with meta
substituted benzenenonaflate provided a 1:1 mixture of the
two expected Z/E isomers (entry 14). The effect of the ortho
substituent is general for coupling reactions of ortho sub-
stituted nonaflates with hydrazones derived from aryl alkyl
ketones (Table 1, entries 16-18). In all cases the stereoiso-
mer was obtained that features the alkyl group and the
o-substituted arene in a cis arrangement.14 Moreover, triaryl
substituted alkenes could be prepared stereoselectively taking
advantage of the ortho-directing effect (Table 1, entries
19-20). These are interesting results indeed, as they
represent a new entry into stereochemically defined
trisubstituted olefins, not easily available through other
methods.15 A detailed justification of this ortho-directing
effect based on DFT-molecular modeling studies is
included in the Supporting Information. Finally, the
employment of the hydrazone derived from an R-branched
ketone led to the corresponding tetrasubstituted alkene,5b
also with very high yield (entry 22).
Scheme 6. Concise Formal Synthesis of Sertraline
syntheses of sertraline, protection of the hydroxy group is
not required, and therefore this represents an advance when
compared with previously reported procedures.16
In conclusion, we have developed proper conditions to
carry out the Pd-catalyzed cross-coupling reaction between
tosylhydrazones and aryl nonaflates. The process is very
general with regard to both coupling partners, the hydrazone
and the ketone, and occurs with very high yields in most of
the cases. The stereoselectivity of reactions with o-substituted
aryl nonaflates is worth noting. Taking into account the wide
availability of nonaflates that are easily prepared from
phenols, this reaction represents an important addition to the
usefulness of Pd-catalyzed cross-coupling with tosylhydra-
zones.
To illustrate the usefulness of the cross-coupling method
we prepared the dihydronaphthalene derivative 8, which is
the direct precursor of the antidepresant sertraline, in one
single step from the tosylhydrazone of 4-hydroxytetralone
7 (Scheme 6). Noteworthy, the coupling is completely
chemoselective; no coupling reaction through a chloro-
substituent is detected. Moreover, unlike in most of the
Acknowledgment. Financial support for this work by DGI
of Spain (CTQ2007-61048/BQU) and Consejer´ıa de Edu-
cacio´n y Ciencia of Principado de Asturias (IB08-088) and
a predoctoral fellowship to L.F. from FICYT of the Princi-
pado de Asturias are gratefully acknowledged.
(9) Barluenga, J.; Jime´nez-Aquino, A.; Aznar, F.; Valde´s, C. J. Am.
Chem. Soc. 2009, 131, 4031.
(10) As suggested by one referee, we conducted the coupling reaction
employing 2.8 equiv of LiOH as base, both in the presence or in the absence
of tBuOH respectively. Both reactions proceeded with 100% conversion
but led to a 88:12 mixture of 3a and the phenol that comes from hydrolysis
of the nonaflate followed by coupling at the chloride position (GC/MS).
(11) (a) Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P. O.;
Skrydstrup, T. Angew. Chem., Int. Ed. 2006, 45, 3349. (b) Roy, A. H.;
Hartwig, J. F. Organometallics 2004, 23, 194.
Supporting Information Available: Experimental details.
Characterization data for olefins 3, 6, and 8 and nonaflates
1. Justification of the ortho-directed stereoselectivity and
computational studies. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) The reaction in the presence of LiCl but without H2O proceeds
with a conversion below 50% after 20 h.
(13) The presence of a mixture of trisubstituted olefins was detected by
GC/MS.
OL102884G
(14) The stereochemistry of the double bond was determined in all cases
by NOESY experiments.
(15) For stereoselective Heck reaction, see: Blettner, C. G.; Konig,
W. A.; Stenzel, W.; Schotten, T. Tetrahedron Lett. 1999, 40, 2101.
(16) (a) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967. (b)
Krumlinde, P.; Boga´r, K.; Ba¨ckvall, J.-E. Chem.sEur. J. 2010, 16, 4031.
(c) Enr, A.; Ouizem, S.; Cheng, X.; Romanens, P.; Ku¨ndig, E. P. AdV. Synth.
Catal. 2010, 352, 2306.
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