Practical and efficient Suzuki-Miyaura cross-coupling of 2-iodocycloenones with arylboronic acids catalyzed by recyclable Pd(0)/C

Article abstract of DOI:10.1021/jo051501b

The first Suzuki-Miyaura cross-coupling of 2-iodocycloenones with arylboronic acids catalyzed by 10% Pd(0)/C is described as an interesting alternative to classical homogeneous conditions. Most of the substrate reacted under mild condition at 25 °C under air in aqueous DME. The conditions described tolerate a wide range of iodoenones and boronic acids. Notably, the procedure features inexpensive reagents and solvents with low toxicity rendering the method environmentally benign. Additionally 10% Pd(0)/C could be recovered and efficiently reused at least five times without significant alteration of the yields of the cross-coupled product.

Full text of DOI:10.1021/jo051501b

handling. To circumvent this issue, the development of
ligandless conditions using homogeneous palladium cata-
lyst is of great interest.3 However, several drawbacks
remain to be solved: (1) the use of additives is often
required in order to obtain high yields of cross-coupled
products, and (2) the separation and recovery of pal-
ladium catalyst remain challenging if not impossible. In
this context, heterogeneous catalysis using 10% Pd(0)/C
as catalyst for Suzuki-Miyaura reactions appears as a
suitable alternative to the “classical” homogeneous condi-
tions.4 Indeed, in this case ligands and additives are
generally not required for efficient transformations, and
catalyst removal is easily performed by simple filtration.
Another important feature is the compatibility of 10%
Pd(0)/C with water as solvent or cosolvent under air.5
However, all studies using Pd/C as catalyst have been
so far realized for the preparation of biaryl compounds.
To the best of our knowledge there is no literature
precedent for the Pd/C-mediated cross-coupling reaction
of 2-halocycloenones with boronic acid partners. It should
be noted that even under homogeneous Pd catalysis the
cross-coupling of 2-haloenones with boronic acid has
attracted much less attention compared to aryl-aryl
coupling, in part because of the sensitive nature of
2-halocycloenones.6 In an effort to develop “green” trans-
formations during the course of a project requiring C-C
bonds formation between enones and aryls for the
preparation of biologically active compounds,7 it was
Practical and Efficient Suzuki-Miyaura
Cross-Coupling of 2-Iodocycloenones with
Arylboronic Acids Catalyzed by Recyclable
Pd(0)/C†
Franc¸ois-Xavier Felpin
Universite´ Bordeaux-I, Laboratoire de Chimie Organique et
Organome´tallique, 351 Cours de la Libe´ration,
33405 Talence Cedex, France
fx.felpin@lcoo.u-bordeaux1.fr
Received July 19, 2005
The first Suzuki-Miyaura cross-coupling of 2-iodocy-
cloenones with arylboronic acids catalyzed by 10% Pd(0)/C
is described as an interesting alternative to classical homo-
geneous conditions. Most of the substrate reacted under mild
condition at 25 °C under air in aqueous DME. The conditions
described tolerate a wide range of iodoenones and boronic
acids. Notably, the procedure features inexpensive reagents
and solvents with low toxicity rendering the method envi-
ronmentally benign. Additionally 10% Pd(0)/C could be
recovered and efficiently reused at least five times without
significant alteration of the yields of the cross-coupled
product.
(3) For some recent and representative examples see: (a) Wallow,
T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034-5037. (b) Darses, S.;
Jeffery, T.; Geneˆt, J.-P.; Brayer, J.-L.; Demoute, J.-P. Tetrahedron Lett.
1996, 37, 3857-3860. (c) Bumagin, N. A.; Bykov, V. V. Tetrahedron
1997, 53, 14437-14450. (d) Badone, D.; Baroni, M.; Cardamone, R.;
Ielmini, A.; Guzzi, U. J. Org. Chem. 1997, 62, 7170-7173. (e) Blettner,
C. G.; Ko¨nig, W. A.; Stenzel, W.; Schotten, T. J. Org. Chem. 1999, 64,
3885-3890. (f) Chi, S. M.; Choi, J.-K.; Yum, E. K.; Chi, D. Y.
Tetrahedron Lett. 2000, 41, 919-922. (g) Zim, D.; Monteiro, A. L.;
Dupont, J. Tetrahedron Lett. 2000, 41, 8199-8202. (h) Ma, D.; Wu, Q.
Tetrahedron Lett. 2001, 42, 5279-5281. (i) Kabalka, G. W.; Nam-
boodiri, V.; Wang, L. Chem. Commun. 2001, 775. (j) Molander, G. A.;
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35, 3277-3280. (b) Gala, D.; Stamford, A.; Jenkins, J.; Kugelman, M.
Org. Proc. Res. Dev. 1997, 1, 163-164. (c) Sengupta, S.; Bhattacharyya,
S. J. Org. Chem. 1997, 62, 3405-3406. (d) Bykov, V.; Bumagin, N.
Russ. Chem. Bull. 1997, 46, 1344-1345. (e) Ennis, D. S.; McManus,
J.; Wood-Kaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs, A. Org.
Proc. Res. Dev. 1999, 3, 248-252. (f) LeBlond, C. R.; Andrews, A. T.;
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C.; Shapland, P. D. Tiffin, P. D. Tetrahedron Lett. 2001, 42, 1765-
1767. (h) McClure, M. S.; Roschangar, F.; Hodson, S. J.; Millar, A.;
Osterhout, M. H. Synthesis 2001, 1681-1685. (i) Sakurai, H.; Tsukuda,
T.; Hirao, T. J. Org. Chem. 2002, 67, 2721-2722. (j) Heidenreich, R.
G.; Ko¨hler, K.; Krauter, J. G. E.; Pietsch, J. Synlett 2002, 1118-1122.
(k) Organ, M. G.; Mayer, S. J. Comb. Chem. 2003, 5, 118-124. (l)
Conlon, D. A.; Pipik, B.; Ferdinand, S.; LeBlond, C. R.; Sowa, J. R.
Jr.; Izzo, B.; Collins, P.; Ho, G.-J.; Williams, J. M.; Shi, Y.-J.; Sun, Y.
Adv. Synth. Catal. 2003, 345, 931-935. (m) Tagata, T.; Nishida, M. J.
Org. Chem. 2003, 68, 9412-9415. (n) Arcadi, A.; Cerichelli, G.;
Chiarini, M.; Correa, M.; Zorzan, D. Eur. J. Org. Chem. 2003, 4080-
4086. (o) Zhang, G. J. Chem. Res. 2004, 9, 593-595. (p) Cravotto, G.;
Palmisano, G.; Tollari, S.; Nano, G. M.; Penoni, A. Ultrason. Sonochem.
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Sonochem. 2005, 12, 99-102. (r) Cravotto, G.; Beggiato, M.; Penoni,
A.; Palmisano, G.; Tollari, S.; Le´veˆque, J.-M.; Bonrath, W. Tetrahedron
Lett. 2005, 46, 2267-2271. (s) Sajiki, H.; Kurita, T.; Kozaki, A.; Zhang,
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(5) Felpin, F.-X.; Landais, Y. J. Org. Chem. 2005, 70, 6441-6446.
The Suzuki-Miyaura reaction is probably one of the
most important palladium-catalyzed processes for C-C
bonds formation. Extensive studies have been made since
the pioneering works from Suzuki and Miyaura.1 The
massive interest for the Suzuki reaction can be explained
by the impressively wide range of substrates tolerated.
Additionally, the relative stability of boronic acids to air
and their low toxicity constitute a highly valuable practi-
cal advantage for both academic and industrial applica-
tions. Recently this process has reached a level of
sophistication, and admirable results can be obtained
with a homogeneous palladium catalyst (Pd(OAc)2, Pd2-
(dba)3, ...) associated to a ligand.2 However, the most
popular tertiary phosphine ligands are often sensitive to
air oxidation and therefore require careful and air-free
† This paper is dedicated with respect to my mentors Jacques
Lebreton (Universite´ de Nantes) and Robert S. Coleman (Ohio State
University).
(1) (a) Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457-2483. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (c) Miyaura, N.
In Topics in Current Chemistry; Miyaura, N., Ed.; Springer-Verlag:
Berlin, 2002; Vol. 219, p 11. (d) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633-9695.
(2) For recent brilliant results, see: (a) Littke, A. F.; Dai, C.; Fu, G.
C. J. Am. Chem. Soc. 2000, 122, 4020-4028. (b) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685-4696.
10.1021/jo051501b CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/14/2005
J. Org. Chem. 2005, 70, 8575-8578
8575

TABLE 1. Optimization of Reaction Conditions
TABLE 2. Screening of Boronic Acids
sub-
Pd/C
T
t
yielda
(°C) (h) (%)
entry strate (mol%)
base
solvent
1
2
1
1
1
1
1
1
1
1
1
1
2
2
5
5
Na2CO3 EtOH/H2O (1/1)
Na2CO3 EtOH/H2O (1/1)
25 12
80
82
70
5
3
5
Na2CO3 DME/H2O (95/5) 80 12 (75)
4
5
5
1
1
Na2CO3 DME/H2O (1/1) 25 12
86
85
5
Na2CO3 DME/H2O (1/1)
Na2CO3 DME/H2O (1/1)
Na2CO3 DME/H2O (1/1)
Na2CO3 DME/H2O (1/1)
80
5
6
25 12 (33)
7
80 12
80 12
25 12
25 12
25 12
80 12
80
81
5
64
0
0
8
0.5
5
9
Et3N
NaOH
DME/H2O (1/1)
DME/H2O (1/1)
10
11
12
5
5
Na2CO3 DME/H2O (1/1)
Na2CO3 DME/H2O (1/1)
5
a Yields are for isolated products. Conversion in brackets
found that heterogeneous 10% Pd(0)/C is a valuable
source of palladium for such a reaction. Herein, we
present our studies concerning the first cross-coupling
reaction of 2-iodocycloenones with boronic acids catalyzed
by 10% Pd(0)/C.
Optimization of Reaction Conditions. For our first
investigations on 10% Pd(0)/C-mediated Suzuki reaction
we selected 2-iodo-2-cyclohexen-1-one 1 and phenyl bo-
ronic acid as model partners (Table 1). A number of
parameters were evaluated. Under optimized conditions
2-iodo-2-cyclohexen-1-one 1 in a mixture of DME (1,2-
dimethoxyethane) and H2O (1/1) reacted with phenyl
boronic acid in the presence of 10% Pd(0)/C (5 mol %)
and Na2CO3 (2 equiv) at 25 °C to give the corresponding
cross-coupled product 3 in 86% yield (entry 4). It is
important to note that all our subsequent studies have
been carried out under air and with undistilled solvents,
rendering the method exceptionally practicable. Recent
reports highlighted the beneficial effect of alcoholic
solvent for the Pd/C-mediated cross-coupling of aryl
bromide with aryl boronic acids.4s On the basis of these
results, we first used EtOH and water as solvent system.
Although the reaction rate was faster at 80 °C, the
reaction conducted at 25 °C gave also good results
(entries 1 and 2). However, we detected some impurities
on TLC that proved to be difficult to separate by flash
chromatography. Since alcoholic solvents could be oxi-
dized by Pd/C under air atmosphere, EtOH was replaced
by DME. We found that the DME/H2O volumetric ratio
was critical for the success of the cross-coupling reactions.
Low water concentration had deleterious effects, result-
ing only in a partial conversion (entry 3). After consider-
able experimentation, we determined that the optimal
volumetric ratio was 1/1. The reaction can be run at 25
or 80 °C without any significant changes for the yields
(entries 4 and 5). Although the reaction rate was slower
at 25 °C, subsequent studies were conducted at that
temperature for the extremely mild conditions. Alterna-
a Yields are for isolated products.
tively the reaction can be efficiently conducted at low
catalyst loading (0.5 mol % of 10% Pd(0)/C) albeit at a
higher temperature (entry 8). To our knowledge, this
catalyst loading (0.5 mol %) is the lowest reported to date
for such a transformation. This finding could be useful
for large scale preparation; however, on a laboratory scale
(1.5 mmol) 5 mol % of 10% Pd(0)/C proved to simplify
handling procedure. We also screened other bases with-
out relevant success. The use of an organic base such as
Et3N resulted in a dramatically low yield due to extensive
decomposition of starting material (entry 9). On the other
hand, the inorganic base NaOH proved to be less effective
than Na2CO3 (entry 10). An important point to note is
the complete inefficiency of 2-bromo-2-cyclohexen-1-one
2 under these conditions to undergo the Suzuki-Miyaura
cross-coupling (entries 11 and 12). Only extensive de-
composition of starting materials was observed whatever
the temperature (25 or 80 °C).
(6) For some relevant examples in total synthesis of natural
products, see: (a) Yoshida, M.; Mori, K. Eur. J. Org. Chem. 2000,
1313-1317. (b) Tan, Q.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2000, 39, 4509-4511. (c) Herzon, S. B.; Myers, A. G. J. Am. Chem.
Soc. 2005, 127, 5342-5344.
(7) Felpin, F.-X. Unpublished results.
8576 J. Org. Chem., Vol. 70, No. 21, 2005

TABLE 3. Screening of 2-Iodocycloenones
a Yields are for isolated products.
Screening of Boronic Acids. Encouraged by these
promising results, we then explored the reaction of
2-iodocyclohexenone 1 with a variety of boronic acids.
Table 2 summarizes the most significant experiments of
this study. As already observed, the reaction took place
under very mild conditions at room temperature in
aqueous DME, affording excellent yields of expected
products regardless of the nature of boronic acids. For
instance, activated boronic acids (electron-rich) in ortho,
meta, or para positions reacted well (entries 2-4). Most
importantly, electron-poor boronic acids (entries 5-7)
also gave excellent results, although these substrates are
generally less reactive and sometime prone to homocou-
pling and protodeboronation in protic solvent. The reac-
tion conditions are notably compatible with fluoro-, nitro-,
and keto-aryls. We also examined the introduction of
heteroaromatic substituents, which are of great impor-
tance in pharmaceutical drug discovery processes. For
instance, thiophenyl and benzofuranyl boronic acids can
be readily cross-coupled under our conditions (entries 8
and 9). Finally, we found that the inexpensive and very
stable sodium tetraphenyl borate can advantageously be
used as an efficient alternative to phenyl boronic acid
(entry 10).
on various 2-iodocycloenones. Gratifyingly, all substrates
tested during our studies gave cross-coupled products in
high yields and most of the substitution patterns were
tolerated at room temperature. However, for the 3-sub-
stituted cycloenone 16 and the hindered steroid 19 higher
temperatures (50 and 80 °C, respectively) were required
for complete conversion (entries 6 and 9). Finally, het-
erocycloenones could be envisaged as part of the backbone
of naturally occurring biologically active compounds.
Pleasingly, these substrates were found to be highly
reactive under 10% Pd(0)/C catalysis as demonstrated in
entries 7 and 8. The major limitation of this process
results in the relative instability of some 2-iodocy-
cloenones. As illustrated in entry 4, the modest yield
obtained for 21 (46%) is due to competitive degradation
of starting material 13. Interestingly, the conversion was
total at 25 °C after 12 h of stirring, but 21 was isolated
with only 20% yield. The degradation of 13 was minored
at 80 °C by enhancing the kinetic of the cross-coupling.
Since the catalyst could be easily separated from the
reaction mixture by simple filtration, a particularly
attractive feature would be its recyclability. We examined
the cross-coupling of 2-iodo-2-cyclohexen-1-one 1 with
phenyl boronic acid and recovered the catalyst to reuse
it (Table 4). We were pleased to find that with the same
batch of 10% Pd(0)/C it was possible to carry out at least
five runs without affecting the yield. The progressive
decrease of the activity can be efficiently balanced by
increasing the temperature of the reaction.
Screening of 2-Iodocycloenones. Having estab-
lished a reasonable range of boronic acid partners, we
next examined the scope of the reaction with various
2-iodocycloenones (Table 3). The process showed excellent
tolerance toward the ring size of 2-iodocycloenones (5-7
carbons), and high yield of cross-coupled products were
obtained. Next, we studied the influence of substitutions
In conclusion, we have reported that Pd(0)/C can
efficiently catalyze the Suzuki-Miyaura cross-coupling
J. Org. Chem, Vol. 70, No. 21, 2005 8577

TABLE 4. Recycling Test
mixture was stirred for the specified time and temperature. Pd-
(0)/C was filtered, and the filtrate was diluted with H2O (4.5
mL) and extracted with Et2O (3×). The collected organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
Eventually, the catalyst was washed twice with water and
twice with Et2O, dried under vacuum (4 h), and reused in a new
run.
entry
runa
T (°C)
t (h)
yield (%)b
2-Phenylcyclohex-2-enone (3). Purification by flash chro-
matography (10% EtOAc-petroleum ether) gave 3 as a colorless
solid (222 mg, 86%): Mp 93-94 °C [lit.8 92-93 °C]. IR (KBr) ν
1662, 2933, 3016 cm-1. 1H NMR (CDCl3, 300 MHz) δ 2.09-2.17
(m, 2H), 2.53-2.64 (m, 4H), 7.06 (app t, 1H, J ) 4.1 Hz), 7.28-
7.40 (m, 5H). 13C NMR (CDCl3, 75 MHz) δ 22.9, 26.5, 39.0, 127.5,
127.9, 128.5, 136.5, 140.3, 147.9, 197.9. HRMS (EI) calcd for
C12H12O (M +) 172.0888, found 172.0886.
1
2
3
4
5
1
2
3
4
5
25
25
25
50
50
12
12
24
12
12
86
85
79
81
80
a Reaction products carried out with the same batch of Pd/C.
b Yields are for isolated products.
Acknowledgment. The author thanks Mr. Pierre
Guenot (CRMPO, Universite´ de Rennes 1) for HRMS
analysis. Thanks are also due to Mr Edouard Godineau
for helpful discussions.
of 2-iodocycloenones with arylboronic acids. We have
shown that the reaction can be mostly conducted at 25
°C in aqueous DME under air, rendering the method very
practicable. Additionally, the possibility to easily recycle
the catalyst makes the process very cheap and highly
valuable for environmental concerns.
Supporting Information Available: Detailed experi-
1
mental procedures and copies of H and 13C NMR of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Experimental Section
General Procedure for Suzuki Cross-Coupling Reac-
tion. To a solution of iodoenone (1.5 mmol) in DME (4.5 mL)
and H2O (4.5 mL) were added Na2CO3 (318 mg, 3 mmol), Ar-
B(OH) (3 mmol), and 10% Pd(0)/C (79.5 mg, 5 mol %). The
JO051501B
(8) Kraus, G. A.; Frazier, K. J. Org. Chem. 1980, 45, 2579-2581.
8578 J. Org. Chem., Vol. 70, No. 21, 2005