Unexpected formation of aryl ketones by palladium-catalyzed coupling of aryl bromides with vinylic acetates

Article abstract of DOI:10.1021/ol7015065

A palladium-catalyzed coupling reaction of aryl bromides with vinylic acetates in the presence of tributyitin methoxide has been described. Unexpected formation of aryl ketones was obtained. Preliminary mechanistic studies indicated that the reaction proceeded by the addition of the aryl moiety in the coordination sphere of palladium to a ketene.

Full text of DOI:10.1021/ol7015065

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3623-3625
Unexpected Formation of Aryl Ketones
by Palladium-Catalyzed Coupling of Aryl
Bromides with Vinylic Acetates
Mickae1
l Jean,§ Jacques Renault,§ Philippe Uriac,*,§ Marc Capet,† and
Pierre van de Weghe*,§,‡
EA Substances Liche´niques et Photoprotection, Faculte´ de Pharmacie,
UniVersite´ de Rennes 1, 2 aVenue du Professeur Le´on Bernard,
F-35043 Rennes Cedex, France, Bioprojet-Biotech, 4 rue du Chesnay Beauregard,
BP96205, F-35762 Saint-Gre´goire, France and Laboratoire de Chimie Organique et
Bioorganique associe´ au CNRS, ENSC-Mu, UniVersite´ de Haute Alsace,
3 rue A. Werner, F-68093 Mulhouse Cedex, France
philippe.uriac@uniV-rennes1.fr; pierre.Van-de-weghe@uniV-rennes1.fr
Received June 25, 2007
ABSTRACT
A palladium-catalyzed coupling reaction of aryl bromides with vinylic acetates in the presence of tributyltin methoxide has been described.
Unexpected formation of aryl ketones was obtained. Preliminary mechanistic studies indicated that the reaction proceeded by the addition of
the aryl moiety in the coordination sphere of palladium to a ketene.
In 1983 Migita disclosed R-phenylation of ketones via tin
enolates catalyzed by a palladium complex. The reaction of
tributyltin enolates, prepared in situ from tributyltin meth-
oxide and enol acetates, with aryl bromides in the presence
of dichlorobis(tri-o-tolylphosphine)palladium was found to
give R-aryl ketones in good yields.1 In spite of its synthetic
interest, few developments and applications of this reaction
were reported.2 Recently Buchwald and Hartwig described
independently another Pd-catalyzed R-arylation of ketones,
the enolates being generated in situ from ketones and bases
like NaO-t-Bu.3 To our knowledge, there has been no report
concerning R-arylation of aldehydes. Here, we first describe
that palladium complexes efficiently catalyze intermolecular
addition of aryl bromides to various vinylic acetates in the
presence of tributyltin methoxide leading to aryl ketones.
In a preliminary experiment, we treated 1a with vinyl
acetate 2a and Bu3SnOMe in the presence of dichlorobis-
(tri-o-tolylphosphine)palladium in toluene at 100 °C. No
R-arylation of the aldehyde was observed, but acylation of
the benzothiazole was achieved affording 3a in a moderate
yield (Scheme 1). Because of this surprising inversion of
selectivity we decided to study this reaction.
We began to focus on optimizing the reaction conditions
using the 2-bromonaphthalene 1b as starting material (Table
§ Faculte´ de Pharmacie, Universite´ de Rennes 1.
† Bioprojet-Biotech.
‡ COB, Universite´ de Haute Alsace.
(1) (a) Kosugi, M.; Hagiwara, I.; Sumiya, T.; Migita, T. J. Chem. Soc.,
Chem. Commun. 1983, 344-345. (b) Kosugi, M.; Hagiwara, I.; Sumiya,
T.; Migita, T. Bull. Chem. Soc. Jpn. 1984, 57, 242-246.
(2) Selected examples: (a) Gupta, M.; Nair, V. Tetrahedron Lett. 2005,
46, 1165-1167. (b) Nicolaou, K. C.; Xu, H. Chem. Commun. 2006, 600-
602.
Scheme 1. Preliminary Experiment
(3) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108-11109. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997,
119, 12382-12383. (c) Culkin, D. C.; Hartwig, J. F. Acc. Chem. Res. 2003,
36, 234-245. (d) Hartwig, J. F. Synlett 2006, 1283-1294.
10.1021/ol7015065 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/01/2007

As shown in Table 1, the Pd-catalyzed coupling of aryl
bromides with vinylic acetates provided a general method
for the preparation of various aryl ketones. When the reaction
was carried out with vinylic acetates 2a and 2b, we obtained
lower yields than with 2c and 2d. The yield was improved
by using 5-10 equiv of these volatile enolates (bp <110
°C).4 While the coupling reaction of 1b with 2b led to 3d
with a convenable yield, no reaction occurred with the
2-chloronaphthalene and only a modest conversion was
observed with 2-triflate naphthalene. By using the more
reactive 2-iodonaphthalene, its disappearance was achieved
after 14 h at 100 °C. However, 3d was formed in a small
amount (30%) along with 2,2′-binaphthalene 5 (31%).4 The
reaction seemed to be sensitive to the electronic feature of
the aryl group. When the aryl group possesses an electro-
withdrawing group, the conversion is low (25% starting
material recovered) and the main product isolated is the result
of a butyl group transfer (entry 8).5 The reaction remained
effective in the presence of electrodonor groups even in the
ortho position (entries 9-12). It is noteworthy that the
coupling reaction works with ortho and ortho, ortho′
substituted aryl bromides with satisfactory yield (entries 13
and 14). The 2-bromopyridine and 3-bromopyridine 1j are
known to react in Pd-catalyzed cross-coupling reactions. In
our conditions only 1j afforded the aryl ketone 3o in low
yield (entry 15) whereas the 2-bromopyridine furnished only
the 2,2′-bipyridine in almost quantitative yield.
Table 1. Palladium-Catalyzed Coupling of Aryl Bromides with
Vinylic Acetates
In the early stages of this work, a mechanism containing
an acyl-palladium species was envisioned. However, no
known element in the literature allowed us to understand
the pathway with this intermediate. For a better understanding
of the catalytic process we decided to realize the coupling
reaction in the presence of the deuterated vinylic acetate 2e.
Under our reaction conditions, 1b with 2e (2 equiv) afforded
the deuterated aryl ketone 3p in 75% yield (deuterium
incorporation being superior to 90%) along with traces of 5
and less than 10% of 2-deuterionaphthalene 6 (Scheme 2).
Scheme 2. Cross-Coupling in the Presence of Deuterated
Vinylic Acetate
a Isolated yield (average of two runs). b 10-15% 2,2′-binaphthalene 5
isolated. c 28% 4-NO2-C6H4-Bu isolated. d 75-90% conversion.
On the basis of these observations we propose the
following catalytic cycle (Scheme 3). A Heck-type reaction
cannot be ruled out. However, in the absence of tributyltin
methoxide no reaction occurred. Under classical Heck
reaction conditions (1b + 2c in the presence of 10 mol %
of PdCl2[(o-Tol)3P]2 and 2 equiv of Et3N at 60 °C in DMF)
1, entry 4). After some experimentation (choice of solvent,
palladium source, and phosphine ligand),4 we found that 5
mol % of dichlorobis(tri-o-tolylphosphine)palladium in DMSO
at 100 °C in the presence of 2 equiv of propenyl acetate 2b
and 2 equiv of Bu3SnOMe are the best conditions to obtain
a complete conversion of the starting material. No reaction
occurred in the absence of palladium catalyst or tributyltin
methoxide. A study of the scope of this reaction was
undertaken and the results are collected in Table 1.
(4) See the Supporting Information.
(5) Ito, S.; Okujima, T.; Morita, N. J. Chem. Soc., Perkin Trans. 1 2002,
1896-1905.
3624
Org. Lett., Vol. 9, No. 18, 2007

coordinated to the palladium as complex C.10 Insertion of
the ketene into the aryl-palladium bond followed by a
reductive elimination gives product 3p and regenerates the
palladium catalyst. A similar aryl addition to a ketene in the
coordination sphere of palladium was previously described
by Watanabe.11 This work consolidates our proposed mech-
anism. The presence of a small amount of 5 probably resulted
from a palladium-catalyzed homocoupling of aryl bromides.12
The present work is the first example of palladium-
catalyzed coupling of aryl bromides with vinylic acetates
affording aryl ketones. Initial mechanistic studies indicated
that the reaction proceeded by the addition of the aryl group
to a ketene. Further investigations of the scope and mech-
anism, as well as synthetic applications, are currently in
progress and will be reported in due course.
Scheme 3. Working Catalytic Cycle
Acknowledgment. We gratefully acknowledge Professor
Jacques Eustache (COB, Universite´ de Haute-Alsace, France)
for fruitful discussions. The authors wish to thank the referees
for helpful suggestions. Financial support of this project by
Bioprojet-Biotech (fellowship to MJ), the Universite´ de
Rennes 1, and the CNRS is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
no reaction was observed after the reaction was stirred for
24 h.6 Thus we believe that the reaction proceeds via the
addition of the aryl group to a ketene. As described by
Migita, the classical oxidative addition of the aryl bromide
to a Pd(0) transmetallation reaction with the stannyl enolate
formed in situ from the vinylic acetate7,8 led to the intermedi-
ate B. A direct reductive elimination from B could lead to
aldehyde 7. However, in almost all cases with vinylic acetates
we have been unable to detect the formation of R-arylalde-
hyde. On the contrary we suggest that the catalytic process
carries on with a â-H elimination leading to a ketene9
OL7015065
(8) The [(2-methyl-1-propenyl)oxy]tri-n-butylstannane, prepared as de-
scribed by Pereyre, was submitted to our cross-coupling reaction conditions
with the 2-bromonaphthalene 1b. After 14 h of stirring at 100 °C, the
arylketone 3e was obtained and isolated in 72% yield. This control
experiment confirms that the tributyltin methoxide plays a similar role in
this reaction as in the Migita’s reaction (formation of the Pd-intermediate
B) and excludes an acetyl-directed addition of the palladium in the vinylic
bond. Pereyre, M.; Bellegarde, B.; Mendelsohn, J.; Valade, J. J. Organomet.
Chem. 1968, 11, 97-100.
(9) Few examples were reported describing the formation of ketenes with
the help of palladium. Okumoto, H. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons,
Inc.: New York, 2002; Chapter VI.5.2, pp 2655-2662.
(10) In the coupling reactions in the presence of the vinylic acetate 2d,
traces of cinnamaldehyde were also detected from the crude reaction mixture.
The formation of cinnamaldehyde could be the result of a â-H elimination
of a hydrogen atom at the benzylic position.
(11) Mitsudo, T.; Kadokura, M.; Watanabe, Y. J. Org. Chem. 1987, 52,
3186-3192.
(12) For example: Hennings, D. D.; Iwama, T.; Rawal, V. H. Org. Lett.
1999, 1, 1205-1208.
(6) To our knowledge the formation of vinylic aryle derivatives in a Heck-
type reaction between aryl iodide or triflate in the presence of vinyl acetate
was reported independently. Neither aldehyde nor ketone was observed in
these reaction conditions. (a) Andersson, C.-M.; Hallberg, A. J. Org. Chem.
1988, 53, 235-239. (b) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J.
Org. Chem. 1992, 57, 3558-3563.
(7) (a) Miura, K.; Fujisawa, N.; Saito, H.; Wang, D.; Hosomi, A. Org.
Lett. 2001, 3, 2591-2594. (b) Doyle, A.; Jacobsen, E. N. J. Am. Chem.
Soc. 2005, 127, 62-63.
Org. Lett., Vol. 9, No. 18, 2007
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