The α-arylation of α-bromo- and α-chloroenones using palladium-catalysed cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2006.02.134

The palladium-catalysed cross-coupling reaction of various arylboronic acids with α-bromoenones and α-chloroenones offers an operationally simple approach to the synthesis of both cyclic and acyclic α-arylenones.

Full text of DOI:10.1016/j.tetlet.2006.02.134

Tetrahedron Letters 47 (2006) 2863–2866
The a-arylation of a-bromo- and a-chloroenones using
palladium-catalysed cross-coupling
James C. Banks, David Van Mele and Christopher G. Frost*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 16 January 2006; revised 10 February 2006; accepted 23 February 2006
Available online 10 March 2006
Abstract—The palladium-catalysed cross-coupling reaction of various arylboronic acids with a-bromoenones and a-chloroenones
offers an operationally simple approach to the synthesis of both cyclic and acyclic a-arylenones.
Ó 2006 Elsevier Ltd. All rights reserved.
The catalytic a-functionalisation of enones with sp2
O
carbon groups such as aryl and alkenyl is a desirable
X
M
but challenging prospect. Although there is no general
method for this useful transformation, approaches
involving metal catalysed cross-coupling show consider-
able potential as described by Negishi in an excellent
review.1 In this context, palladium or nickel complexes
have been studied in the catalytic synthesis of a-aryl-
a,b-unsaturated carbonyl compounds by the cross-
coupling of a-organometallics with aryl halides or the
Cross-coupling of an α-organometallic
and aryl halide (M=Zn, Sn; X=I)
O
M
X
complementary
combination
of
a-halocarbonyl
compound and sp2 carbon derived organometallics
(Fig. 1). Of the many possible permutations, the most
success has been realised with a-iodoenones and organo-
zinc derivatives, although requiring strictly anhydrous
reaction conditions, yields are generally high and the
loading of palladium catalyst (typically PdCl2(PPh3)2)
are acceptably low (5–10 mol %).2 An elegant solution
avoiding transition metal catalysis has recently been
reported by Koech and Krische.3 The regiospecific
a-arylation of simple enones is achieved by nucleophilic
(phosphine) catalysis. This elegant methodology
employs triarylbismuth(V) dichlorides as aryl transfer
reagents and tolerates a wide-range of aryl substitution
with the exception of strong p-donating groups in the
para position (e.g., p-OMe). In this letter, we report an
effective method for the synthesis of a-arylenones using
a palladium catalysed cross-coupling of arylboronic
acids and either a-bromo- or a-chloroenones.4 This
Cross-coupling of an α-halocarbonyl and
aryl organometallic (M=Zn, Sn, B; X=I,
OTf)
O
M
H
Enolate arylation via nucleophilic catalysis
(M = hypervalent Bi)
Figure 1. Catalytic approaches to the synthesis of a-aryl-a,b-unsatu-
rated carbonyl compounds.
study complements the recent excellent work of Felpin
involving additions to a-iodoenones using a hetero-
geneous Pd(0)/C catalyst system.5
The substrates 1–6 were conveniently prepared
from a mixture of oxoneTM and either sodium bro-
mide or sodium chloride as described by Dieter et al.
*
Corresponding author. Tel.: +44 (0)1225 386142; fax: +44 (0)1225
386231; e-mail: c.g.frost@bath.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.134

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J. C. Banks et al. / Tetrahedron Letters 47 (2006) 2863–2866
the different palladium complexes under the reaction
O
O
O
conditions. Interestingly, Felpin notes the complete fail-
ure of a-bromocyclohexenone to undergo Suzuki–Miya-
ura coupling employing the Pd(0)/C catalyst system, an
observation attributed to substrate decomposition.5 In
our hands, the most active complex was identified as
the electron-rich PdCl2(PCy3)2 and this was employed
in subsequent reactions.
X
1. NaX, OxoneTM
2. Et3N
O
O
Br
Cl
Br
The protocol demonstrated useful scope with respect to
the boronic acid employed, the isolated yields were higher
with activated boronic acids than with electron-poor
boronic acids (Scheme 3, entries 1–6). The lower yield
of isolated product with p-chlorophenylboronic acid
(Scheme 3, entry 3) was due to a competitive polymerisa-
tion process. The less reactive m-nitrophenylboronic acid
did not afford any desired product, only evidence of pro-
todeboronation was found. Given the potential of this
approach, a number of alternative a-haloenones (2–6)
were examined with the aim of achieving a unique
cross-coupling of arylboronic acids and a-chloroenones.
Although advances in catalyst design and screening have
revealed a number of palladium-based systems for the
efficient coupling reactions of aryl chlorides, the corre-
sponding reactions of vinyl chlorides have received much
less attention.8 The reaction of a-chlorocyclohexenone 2
with phenylboronic acid was successful affording a 45%
yield of product. Unfortunately much lower isolated
yields were obtained with the a-bromocyclopentenone 3
(Scheme 3, entries 8–10). Despite the low yields of prod-
ucts, no starting material was recovered from these reac-
tions suggesting that the inherent instability of this
substrate on heating is a limiting factor. Gratifyingly,
the acyclic substrates (4 and 5) proved to be competent
substrates affording good isolated yields of product at
just 1 mol % catalyst loading (Scheme 3, entries 11–17).
Although 4 and 5 are less reactive than a-bromocyclohex-
enone 1, these acyclic substrates proved to be stable to
heating and very little degradation was observed.
1 84% Yield
2 81% Yield
3 78% Yield
O
O
O
Cl
Br
Br
Ph
Ph
4 63% Yield
Ph
5 11% Yield
6 39% Yield
Scheme 1. The preparation of a-haloenones.
(Scheme 1).6 The a-bromination of trans-4-phenyl-3-
buten-2-one afforded 4 as the major product along with
a low yield of 5 due to r-bond rotation prior to
elimination.
As a representative example, the reaction of a-bromo-
cyclohexenone 1 with phenylboronic acid was investi-
gated in aqueous solvent in the presence of various
palladium complexes.7 In all cases, 1 was completely
consumed affording the a-arylated product in varying
isolated yields, as indicated (Scheme 2, entries 1–5).
The substrate was found to undergo extensive decompo-
sition on prolonged heating and the isolated yields of
product reflects the relative activity or the longevity of
O
O
Br
We were pleased to note that good yields of product
were also obtained in the cross-coupling of electron-rich
and electron-poor boronic acids with the acyclic a-chlo-
roenone 6 (Scheme 3, entries 18–20). Again, the lower
reactivity of this substrate towards oxidative addition
was offset by the enhanced thermal stability resulting
in a useful coupling process.
Ph B(OH)2
[Pd] (1 mol%)
Cs2CO3
dioxane:water (5:1)
1
Entry
[Pd] (1 mol%)
Isolated yield (%)
1
2
3
4
5
Pd(PPh3)4
7
In conclusion, cyclic and acyclic a-arylenones can be
prepared using a palladium-catalysed cross-coupling
protocol involving a-bromo- or a-chloroenones and
commercially available boronic acids. The acyclic a-
haloenones offer the best scope as a consequence of their
increased stability.
Pd(PPh3)2Cl2
Pd(PCy3)2Cl2
Pd(PTol3)2Cl2
Pd(PtBu3)2Cl2
37
77
41
44
Reaction conditions: A mixture of cesium carbonate (2 mmol), palladium
complex, (0.01 mmol), arylboronic acid (2 mmol) and the α-haloenone (1
mmol) in 1,4-dioxane (5 ml) and water (1 ml) were stirred at reflux for 24
h. The mixture was poured into water (50 ml), extracted with EtOAc (3 x
20 ml), dried over MgSO4, evaporated under reduced pressure and purified
by flash column chromatography (SiO2, petroleum ether:EtOAc, 90:1) to
afford the product.
Acknowledgements
We would like to acknowledge the generous support of
Pfizer Global Research and Development (Sandwich)
for a summer scholarship to J.C.B. The EPSRC Mass
Spectrometry Service at the University of Wales Swan-
sea is also thanked for their assistance.
Scheme 2. The reaction of a-bromocyclohexenone with phenylboronic
acid.

J. C. Banks et al. / Tetrahedron Letters 47 (2006) 2863–2866
2865
O
O
Ar B(OH)2
X
Ar
Pd(PCy3)2Cl2 (1 mol%)
Cs2CO3 (2 equiv.)
dioxane:water (5:1)
115 oC, 24 hours
Ar
Entry
Substrate
Isolated yield (%)
Entry
1
Substrate
Ar
Isolated yield (%)
52
11
77
4
4
1
12
70
2
1
64
MeO
Cl
MeO
O
13
39
4
4
3
4
1
1
98
59
14
70
O2N
15
--
4
5
5
6
1
1
--
Cl
16
21
50
Me2N
17
45
5
6
7
8
2
3
66
64
MeO
18
18
MeO
19
15
6
9
3
3
78
51
MeO
O
20
15
6
10
Scheme 3. The scope of the palladium-catalysed coupling.
2. Negishi, E.; Tan, Z.; Liou, S. Y.; Liao, B. Q. Tetrahedron
2000, 56, 10197–10207.
Supplementary data
3. Koech, P. K.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
5350–5351.
Experimental procedures and compound characterisa-
tion data are available. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.02.134.
4. (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: Berlin, 2002; Vol. 219, p 11; (d)
Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–
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