Synthesis of 2-arylacrylates from pyruvate by tosylhydrazide-promoted Pd-catalyzed coupling with aryl halides

Article abstract of DOI:10.1002/chem.201002425

Important synthetic intermediates and direct precursors of the prophen class of anti-inflammatory agents, 2-arylacrylates are prepared in one step from ethyl pyruvate by employing the recently developed Pd-catalyzed cross-coupling between tosylhydrazones

Full text of DOI:10.1002/chem.201002425

COMMUNICATION
DOI: 10.1002/chem.201002425
Synthesis of 2-Arylacrylates from Pyruvate by Tosylhydrazide-Promoted
Pd-Catalyzed Coupling with Aryl Halides
Josꢀ Barluenga,* Marꢁa Tomꢂs-Gamasa, Fernando Aznar, and Carlos Valdꢀs*[a]
The Pd-catalyzed cross-coupling reaction between tosylhy-
drazones and aryl halides, recently developed by our group,
constitutes a very efficient way to synthesize di- and trisub-
stituted olefins.[1a] Over the last few years we have shown
that this reaction is an excellent way to employ carbonyl
compounds as the nucleophilic component of a Pd-catalyzed
cross-coupling reaction (Scheme 1).[1,2]
While the classical method for the synthesis of 2-arylacry-
lates is the condensation of the corresponding arylacetate
with paraformaldehyde,[11,12] more recently, these systems
have been prepared through different Pd-catalyzed cross-
coupling reactions: Suzuki cross-couplings with 2-chloracry-
lates,[13] and alkenyl boronates,[14] Negishi reaction with 2-
metallated acrylates,[15] and Pd-catalyzed carbonylation of
arylvinyl bromides.[16] In a very recent contribution, Wang
et al. reported a new synthesis of 2-arylacrylates by Pd-cata-
lyzed coupling between diazoesters and arylboronic acids.[17]
Herein, we present a new Pd-catalyzed cross-coupling ap-
proach to these systems that employs the tosylhydrazone of
ethyl pyruvate as nucleophilic component, and therefore ob-
viates the need for a stoichiometric organometallic reagent.
Our initial experiments showed that the coupling between
the tosylhydrazone 2, derived from ethyl pyruvate, and p-
bromotoluene proceeded in quantitative yield leading to ac-
rylate 3a by employing the reaction conditions presented in
Scheme 2. Notably, the potentially sensitive ester functional-
ity remained unaltered under the relatively harsh basic reac-
tion conditions.
Scheme 1. Pd-catalyzed cross-coupling reactions employing carbonyls
mediated by tosylhydrazide.
In the context of this study, we turned our attention to hy-
drazones derived from ethyl pyruvate (1), as a representa-
tive of a-oxoesters, in the hope that the coupling reaction
would represent a new route to 2-arylacrylates.
The importance of this motif as a synthetic intermediate
is noteworthy. For instance, 2-arylacrylates provide the main
entry into the optically active version of prophens (a-aryl-
propionic acids),[3] the widely employed nonsteroidal anti-in-
flammatory agents. Moreover, these structures are activated
olefins that are continuously employed as Michael accept-
ors,[4] dienophiles,[5] dipolarophiles,[6] alkenes for Heck and
sequential Pd-catalyzed reactions,[7] intermediates in hetero-
cyclic synthesis,[8] intermediates in the synthesis of cyclopro-
pane carboxylic acids with biological activity,[9] and key frag-
ments to generate diversity in drug discovery programs.[10]
Scheme 2. Preliminary experiment of the coupling of the hydrazone 2 de-
rived from ethyl pyruvate with an aryl bromide. Xphos: 2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl.
To develop a more practical procedure, we studied the re-
action starting directly from ethyl pyruvate (1), avoiding the
isolation of the tosylhydrazone 2. After some experimenta-
tion, a one-pot protocol was optimized. In this process, ethyl
pyruvate and tosylhydrazide were stirred for 2 h at 708C,
then the rest of the reagents were added to the reaction
mixture. Following this procedure, similar yields were ob-
[a] Prof. J. Barluenga, M. Tomꢀs-Gamasa, Prof. F. Aznar, Dr. C. Valdꢁs
Instituto Universitario de Quꢂmica Organometꢀlica “Enrique Moles”
Universidad de Oviedo, c/Juliꢀn Claverꢂa 8. Oviedo 33006 (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
acvg@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002425.
Chem. Eur. J. 2010, 16, 12801 – 12803
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12801

tained to those from the two-step protocol starting from the
hydrazone 2. The scope of this transformation was studied,
and selected examples are presented in Table 1.
Table 1. (Continued)
Entry
Ar-Br
Compound 3
Yield [%][b]
10
86
Table 1. Synthesis of 2-arylacrylates 3 from ethyl pyruvate (1) and aryl
bromides.[a]
11
12
99
98
Entry
1
Ar-Br
Compound 3
Yield [%][b]
99
[a] reaction conditions: ketone 1, 1 mmol; TsNHNH2, 1.1 mmol; dioxane,
2 h, 708C; then ArBr, 1 mmol; [Pd2A(dba)3] (dba=dibenzylideneacetone),
CTHUNGTRENNUNG
1.0 mol%; Xphos, 4 mol%; LiOtBu, 2.4 equiv, 1108C. [b] Yield of isolat-
ed products.
2
3
89
90
The reaction proceeds in very high yields for a variety of
benzene rings with electron-donating (Table 1, entries 4, 5,
12) and electron-withdrawing (Table 1, entries 3, 11) sub-
stituents, including the sterically hindered bromomesitylene
(Table 1, entry 7). As expected, the reaction with p-bromo-
chlorobenzene leads exclusively to the chlorobenzene deriv-
ative (Table 1, entry 9). The process can be accomplished
also with heterocycles (Table 1, entries 8, 10), and tolerates
the presence of a free NH group. Finally, the reaction can
be employed for the preparation of relevant molecules such
as 3 f, the direct precursor of Naproxen.
The coupling was also studied with hydrazones derived
from other 2-oxoesters (Table 2). The reactions employing
the hydrazone of ethyl 3-methyl-2-oxobutanoate provide the
substituted 2-arylacrylates with moderate yields and require
higher catalyst loading (Table 2, entries 1–4). Nevertheless,
these are the first examples of the employment of the cou-
pling reaction with tosylhydrazones in the synthesis of func-
tionalized tetrasubstituted olefins.[18] Moreover, the 3,3-dis-
ubstituted-2-arylacrylates, in spite of their simplicity, are an
unusual type of functionalized alkenes not easily available
through other methodologies.[19]
4
5
98
92
6
60
Finally, the reaction with unbranched 2-oxoesters leads to
trisubstituted alkenes as a mixture of Z/E isomers in varia-
ble ratio depending on the substrate. Interestingly, in the
particular case of the very bulky mesitylene derivative
(Table 2, entry 5), the Z/E mixture of isomers that is ob-
tained after a reaction time of 2.5 h, undergoes isomeriza-
tion by leaving the reaction for up to 12 h under the reaction
conditions, giving rise exclusively to the E isomer.
In summary, we have described a very straightforward
synthesis of 2-arylacrylates, very useful synthetic intermedi-
ates, by a Pd-catalyzed cross-coupling reaction that employs
ethyl pyruvate—a commodity chemical—as cross-coupling
partner. The reaction is experimentally simple, very effi-
cient, general, and functional-group tolerant, and therefore
7
8
9
97
89
98
12802
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Chem. Eur. J. 2010, 16, 12801 – 12803

Synthesis of 2-Arylacrylates from Pyruvate
COMMUNICATION
Table 2. Synthesis of substituted 2-arylacrylates 5 from hydrazones 4 and
aryl bromides.[a]
Keywords: arylacrylates
palladium · pyruvate
· cross-coupling · hydrazones ·
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[a] Reaction conditions: hydrazone 4, 1 mmol; ArBr, 1 mmol; [Pd2-
ACHTUNGTRENNUNG(dba)3], 2.5 mol%; Xphos 10 mol%; LiOtBu, 2.4 equiv; dioxane, 1108C.
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this new procedure undoubtedly represents a very attractive
alternative for the preparation of these systems. Moreover,
the reaction can be also applied to other 2-ketoesters, to
produce the corresponding 2-aryl-a,b-unsaturated esters. In
particular, the reaction has been employed for the prepara-
tion of functionalized tetrasubstituted alkenes.
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Acknowledgements
This work was supported by the DGI of Spain (CTQ2007-61048/BQU)
and the Consejerꢂa de Educaciꢄn y Ciencia of Principado de Asturias
(IB08-088). A FPU predoctoral fellowship to M.T.G. is gratefully ac-
knowledged.
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Received: August 20, 2010
Published online: October 13, 2010
Chem. Eur. J. 2010, 16, 12801 – 12803
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12803