A novel palladium-catalyzed homocoupling reaction initiated by transmetallation of palladium enolates

Article abstract of DOI:10.1016/S0040-4039(02)00328-3

Palladium-catalyzed homocoupling reaction of aryl boronic acids has been developed using a protocol similar to the well-documented crosscoupling reaction. α-Halocarbonyl compounds are applied to initiate the reaction via oxidative addition to a palladium(0) species. The resulting palladium enolate halide can promote the double transmetallation. Reductive elimination generates the desire homocoupling product.

Full text of DOI:10.1016/S0040-4039(02)00328-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2525–2528
A novel palladium-catalyzed homocoupling reaction initiated by
transmetallation of palladium enolates
Aiwen Lei and Xumu Zhang*
Department of Chemistry, 152 Davey Laboratory, Penn State University, University Park, PA 16802, USA
Received 25 January 2002; revised 14 February 2002; accepted 15 February 2002
Abstract—Palladium-catalyzed homocoupling reaction of aryl boronic acids has been developed using a protocol similar to the
well-documented crosscoupling reaction. a-Halocarbonyl compounds are applied to initiate the reaction via oxidative addition to
a palladium(0) species. The resulting palladium enolate halide can promote the double transmetallation. Reductive elimination
generates the desire homocoupling product. © 2002 Elsevier Science Ltd. All rights reserved.
2
b
Biaryls form the central core in a large number of
natural products and is an important pharmacophore
in a variety of biologically active compounds. Pd- and
a). If a homocoupling reaction is expected to proceed
in a similar manner, a second transmetallation between
1
2
2
R –M and intermediate I for forming intermediate II is
Ni-catalyzed crosscoupling reactions have been devel-
required (Scheme 1, path b). To our knowledge, there
2
1
oped to construct the biaryl compounds. Compared
are no reports that the intermediate R –M–X generated
1
1
with the enormous literature on crosscoupling reac-
tions, there have been fewer studies carried out on
by oxidative addition of R X to M can undergo dou-
ble transmetallation to form intermediate II, which can
produce the homocoupling product via reductive elimi-
nation. In the course of studying asymmetric a-aryl-
ation of ketones or esters, we serendipitously found
that a-halocarbonyl compounds can serve as this type
of reagent. The a-halocarbonyl compounds can
undergo oxidative addition with a palladium(0) species
and mediate the aforementioned double transmetalla-
tion. Homocoupling products are generated in this
process. Herein, we would like to present our results in
this area.
3
–5
Pd-catalyzed homocoupling reactions.
Generally,
crosscoupling reactions are initiated by oxidative addi-
tion, followed by transmetallation, and reductive elimi-
nation to give the coupling products (Scheme 1, path
R2 R2
M1
R1
X
The a-arylation of ketones has been explored by the
6
R1 R2
Hartwig and Buchwald groups, and its asymmetric
R1 M1
R2 M1 R2
II
X
7
version has also been achieved by Buchwald et al.
However, because the strong basic conditions are neces-
sary for the formation of palladium enolate, the reac-
tion is limited to the formation of chiral quaternary
carbon centers. Racemization of tertiary carbon centers
adjacent to a carbonyl can occur under the strong basic
conditions. In order to overcome this difficulty, we
envision that a-halocarbonyl compounds can undergo
oxidative addition to a palladium(0) species and a
palladium enolate can be formed without use of a base.
Transmetallation of the palladium enolate with an
organometallic compound and reductive elimination
can produce the a-arylation product. Under this design,
we examined a palladium-catalyzed reaction between
M2 R1
R2 M2
M2
X
R1 M1 R2
I
R2 M2
Scheme 1.
*
0
Corresponding author.
methyl a-bromophenylacetate
1
and 3,5-dimethyl
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00328-3

2
526
A. Lei, X. Zhang / Tetrahedron Letters 43 (2002) 2525–2528
8
phenyl boronic acid 2. Surprisingly, the expected cross-
coupling product 3 was not formed while the homocou-
pling compound 4a was produced as the exclusive
product. This unexpected result led us to pursue the
mechanism for the formation of 4a and to investigate
the role of a-bromophenyl acetate 1 (Scheme 2).
obtained along with compound 6, which is the reduc-
tion product of 5 (Eq. (1)). In the absence of the
a-bromo ester, no coupling product could be obtained.
Therefore, we believe that the a-bromo carbonyl com-
pound plays an important role in this reaction.
O
O
Pd2(dba)3.CHCl3
Br
Using this reaction protocol, we have examined the
+
+
reaction with a different a-bromo carbonyl compound
rac-BINAP
B(OH)2 Cs CO3
5
and found that the homocoupling product 4a was
2
Dioxane
5
4a
6
2
(1)
Under the palladium-catalyzed homocoupling condi-
tion, we have investigated the reaction of a variety of
aryl boronic substrates and readily available ethyl a-
OMe
Ph
Br
O
9
OMe
3
bromo acetate 7. A competition between homocou-
+
Ph
pling and crosscoupling reactions was observed (Table
O
B(OH)2
1
, entries 1, 3–5, 7, 9 and 12). We found that the
substitution at the a-position of the bromoester would
favor the homocoupling reaction and hinder the cross-
coupling reaction (Table 1, entries 3 and 5). In addi-
tion, water plays a dramatic role in controlling the
selectivity between homocoupling and crosscoupling
reactions. When water was added, the ratio of homo-
and crosscoupling products switched from 30:70 to
1
2
4a
Scheme 2.
Table 1. Palladium-catalyzed coupling reaction of aryl boronic acids
a
R1
Br
R1
+
3
R1
R PdCl2(rac-BINAP)
R2
+
R3
dioxane/H2O
R2
O
R1
B(OH)2
KF
O
2
1 or 7
4
8
Homo-
coupling
Cross-
coupling
Entry
Substrates
Solvent
Yields (%)
Productsb
Homo-
Cross-
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
2a
2a
2b
2b
2b
2b
2c
2c
2d
2d
2e
2f
7
1
7
7
1
1
7
1
7
1
1
7
1
7
1
1
1
Dioxane
Dioxane/H O
Dioxane
Dioxane/H O
Dioxane
Dioxane/H O
Dioxane
Dioxane/H O
Dioxane
Dioxane/H O
Dioxane/H O
Dioxane
Dioxane/H O
Dioxane
Dioxane/H O
Dioxane/H O
89
95
82
89
88
85
92
91
92
94
93
94
92
89
95
89
90
50
100
30
70
94
100
50
100
50
100
100
60
100
100
100
100
100
50
0
70
30
6
0
50
0
50
0
0
40
0
0
2
2
2
2
1
1
1
1
1
1
1
1
2
2
2f
2
2g
2g
2h
2l
0
0
0
2
2
Dioxane/H O
2
a
All reactions were performed using 2.5 mol% PdCl (rac-BINAP) and 300 mol% KF. The reactions were done at 100°C for 2–24 h and progress
2
of the reaction was monitored by TLC.
Isolated yields were reported, and the ratio of homocoupling product versus crosscoupling product was determined by NMR.
b

A. Lei, X. Zhang / Tetrahedron Letters 43 (2002) 2525–2528
2527
Br
R1
Pd0)L2
O
Ar-Ar
R2
4
Br PdL2
Br PdL2
O
R1
R1
O
R2
Ar-PdL2
Ar
R2
9A
9B
10
ArM
M=B(OH)2
7
0:30 in the reaction of ortho-methyl phenyl boronic acid
and ethyl a-bromoacetate (Table 1, entries 3 and 4).
Significantly, we obtained 100% homocoupling selectiv-
ity when methyl a-bromo phenylacetate 1 was used in the
presence of water (Table 1, entries 2, 6, 8, 10, 11 and
R1
+ MX
MO
R2
1
1
1
3–17). It is noteworthy that the present homocoupling
protocol can not only be carried out in an aqueous
condition, but also can tolerate a wide variety of func-
tional groups. Aldehyde, methoxy, and nitro groups are
compatible in the reaction (Table 1, entries 11, 12, 14,
Scheme 3.
is little known about the transmetallation between aryl
organometallic reagents and enolate anion at a palladium
center. In our study, we found several controlling factors
for the chemoselectivity between homocoupling and
crosscoupling reactions: (1) The increased yield of homo-
coupling product in aqueous medium suggests that
homocoupling reaction is preferred. It is reasonable that
the intermediate 11 is hydrolyzed in the presence of water
and this process facilitates the formation of the interme-
diate 10. (2) When methyl a-bromophenylacetate (1) was
employed in this reaction, the high homocoupling selec-
tivity may be derived from the fast tautomerization from
a C-bound palladium enolate to an O-bound palladium
enolate. (3) The dramatic homocoupling selectivity of an
ortho-methoxy group may be the result of coordination
of the methoxy group to a palladium center. This
coordination can weaken the O-bound palladium enolate
bond and make it a better leaving group, which facilitates
the second transmetallation.
1
6, 17). Another interesting phenomenon is the role of
ortho-methoxy group. The reaction of ethyl a-bromo
acetate surprisingly gave exclusive homocoupling
product over the crosscoupling product (Table 1, entry
1
4). However, if the methoxy group was not present at
the ortho position, the high selectivity for homocoupling
disappeared (Table 1, entry 12).
Compared with the extensive study and application of
crosscoupling reaction catalyzed by transition metal
complexes (Scheme 1, path a), the homocoupling reac-
tion has received little attention. Because of this scant
coverage in the literature, we feel that our discovery of
this homocoupling via a traditional crosscoupling
approach will invigorate work in this area.
In the proposed mechanism of our homocoupling reac-
tion, a palladium enolate was hypothesized as the key
intermediate. Recently, the chemistry of palladium eno-
6,7,10
In summary, we have developed a novel palladium-cat-
alyzed homocoupling reaction using a protocol similar to
the well-documented crosscoupling reaction. Further
investigation of the scope, synthetic applications, as well
as development of the asymmetric version of this palla-
dium-catalyzed homocoupling reaction to make chiral
biaryl compounds will be reported in due course.
late has received intensive attention.
Three proposed
1
1
structures are Pdꢀcarbon (h ), Pdꢀoxygen (h ) and
3
10f,11
Pdꢀoxo p-allyl (h ) enolates.
Many organic trans-
formations with palladium enolates such as protonoly-
1
0a–e
6,7
sis,
arylation of carbonyl compounds, Mannich-
10f 10g–j
type reaction,
and aldol reaction
have been
reported. Scheme 3 illustrates a proposed mechanism for
the homocoupling reaction. First, the reaction is initiated
by oxidative addition of an a-halocarbonyl compound to
Pd(0). Double transmetallation of 9 generates the
intermediate 10 and reductive elimination of 10 yields the
homocoupling product.
Acknowledgements
1
2
We thank support of a Camille and Henry Dreyfus
Teaching-Scholar Award and acknowledge a generous
loan of precious metals from Johnson Matthey Inc.
The oxidative addition of a-halocarbonyl compounds as
11
the initial step is well documented. A C-bound Pd
enolate 9A formed by oxidative addition to a palla-
dium(0) species can tautomerize to an O-bound Pd
enolate 9B. Double transmetallation of the Pd enolate is
the key step for this new coupling reaction. Compared
with transmetallation between an aryl organometallic
reagent and a halide anion at a palladium center, there
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6