Chemoselective three-component coupling via a tandem Pd-catalyzed boron-Heck and Suzuki reactions

Article abstract of DOI:10.1016/j.tetlet.2008.10.039

A new approach is herein reported to prepare biaryl derivatives via a tandem Pd-catalyzed boron-Heck and Suzuki reactions. This one-pot tandem process avoided purification or addition of extra catalyst between steps. The resulting biaryl compounds can be

Full text of DOI:10.1016/j.tetlet.2008.10.039

Tetrahedron Letters 49 (2008) 7307–7310
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Tetrahedron Letters
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Chemoselective three-component coupling via a tandem
Pd-catalyzed boron-Heck and Suzuki reactions
*
Justin O’Neill, Kyung Soo Yoo, Kyung Woon Jung
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1062, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach is herein reported to prepare biaryl derivatives via a tandem Pd-catalyzed boron-Heck
and Suzuki reactions. This one-pot tandem process avoided purification or addition of extra catalyst
between steps. The resulting biaryl compounds can be prepared with substrate variability in good to
moderate yields.
Received 18 August 2008
Revised 7 October 2008
Accepted 8 October 2008
Available online 14 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The biaryl moiety has been prevalent as a key structure of the
functional molecules in raw materials for LCD (liquid crystal dis-
play) and OLED (organic light emitting diode) scaffolds, as well
as for biologically active compounds.1 Recently, the palladium-
catalyzed reactions known as Heck–Mizoroki,2 Suzuki–Miyaura,3
Negishi,4 and Stille5 reactions have been employed as powerful
and versatile methods for biaryl synthesis. These reactions have
offered increased utility because of their mild conditions compared
to traditional biaryl synthetic methods such as the Scholl,6
Gomberg–Bachmann,7 or Ullmann-type reactions.8
Recently, our group reported general methods for the intermo-
lecular oxidative palladium-catalyzed boron-Heck cross coupling
between aryl- or alkenylboronic acids and olefins under very mild
conditions.9 In particular, we examined several examples of com-
petitive one-pot intermolecular Suzuki, Heck, and our boron-Heck
cross coupling reactions. As shown in Scheme 1, we found that
under oxidative conditions, the boron-Heck compound (5) was
formed exclusively. These results implied that under these cou-
pling conditions, Heck and Suzuki coupling reactions were sup-
pressed due to the absence of base, relatively low temperature,
and presence of oxygen atmosphere. For the same competition
reaction under nitrogen with sodium carbonate at 100 °C, there
was almost completely selective formation of the Heck product
(4) and no trace of the boron-Heck coupling product. This sug-
gested that we could simply use different atmospheres to
sequentially employ different palladium-catalyzed cross-coupling
reactions in a three-component coupling tandem reaction. There-
fore, we examined the oxidative palladium-catalyzed cross-cou-
pling reactions of 4-iodophenylboronic acid with olefins such as
tert-butyl acrylate (Eq. 1) and 2-cyclohexen-1-one (Eq. 2), because
the resulting products would become suitable substrates for ensu-
ing Suzuki couplings.
O
B(OH)
+
O
Pd(OAc)2 (10 mol %)
dmphen (11 mol %)
2
t
O Bu
t
(1)
O Bu
I
B(OH)
2
O
I
DMF, O2, rt, 16 h
I
3
7
8 (92%)
+
+
t
O Bu
H CO
3
(CH ) N
3 2
3
2
1
Pd(OAc)2 (5 mol %)
dmphen (5 mol %)
O2, DMF, rt
B(OH)
+
Pd(OAc)2 (10 mol %)
dmphen (11 mol %)
2
O
O
O
OCH
3
(2)
DMF, O2, 50 oC, 6 h
O
I
I
t
t
O Bu
7
10 (85%)
O Bu
9
(CH ) N
3 2
H CO
3
(CH ) N
3 2
4
5
6
(Heck)
(boron-Heck)
(Suzuki)
As expected, boron Heck-type products were exclusively gener-
91%
0%
0%
ated, and no other coupling products were obtained. On the basis
of these results, herein we report the development of a one-pot
chemo- and regioselective method for the preparation of biaryl
compounds via a tandem oxidative palladium-catalyzed boron-
Heck and Suzuki coupling approach.
Scheme 1.
* Corresponding author. Tel.: +1 213 740 8768; fax: +1 213 740 6270.
E-mail address: kwjung@usc.edu (K. W. Jung).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.039

7308
J. O’Neill et al. / Tetrahedron Letters 49 (2008) 7307–7310
Table 1
4-iodophenylboronic acid, tert-butyl acrylate, and phenylboronic
acid as coupling partners. As shown in Table 2, the oxidative bor-
on-Heck reaction intermediate product 8 was prepared at room
temperature, and then further reacted with phenylboronic acid in
a Suzuki coupling in the presence of NaOH under a N2 atmosphere
at 50 °C. A tandem oxidative boron-Heck/Suzuki reaction using
two equivalents of tert-butyl acrylate as an alkene formed the biar-
yl product (11) and a disubstituted acryl product (12) in a 2:1 ratio
(entry 1), because the Heck reaction took place in the second-step
reaction. Therefore, we changed the ratio of tert-butyl acrylate to a
molar equivalent, and obtained more of the oxidative boron-Heck/
Suzuki reaction product (entry 2). However, in the coupling reac-
tion of disubstituted olefins such as ethyl crotonate and b-methyl-
styrene (entries 3 and 4), only tandem oxidative boron-Heck/
Suzuki reaction products (13 and 14) were obtained in good yields,
with excellent (E)-stereoselectivity.
Employing 2-cyclohexen-1-one 9 as an olefin, a similar screen-
ing process for the boron-Heck reaction was carried out with 4-
iodophenylboronic acid, the results of which are summarized in
Table 3. At room temperature, an increase in the amount of Pd(II)
complex provided a rise in yield (entries 1 and 2). Increasing the
molar ratio of 2-cyclohexen-1-one to 4-iodophenylboronic acid
up to 2:1 increased the yield slightly (entry 3). Elevation of the
temperature to 50 °C further increased the yield, while also accel-
erating the reaction rate (entry 4). However, lowering the ratio of
2-cyclohexen-1-one to 4-iodophenylboronic acid at this higher
temperature resulted in significant decrease in yield (entry 5). Sub-
sequently, we determined that optimal conditions for the cross-
coupling reaction were to use two equivalents of 2-cylcohexen-
1-one at 50 °C in the presence of 10 mol % of the Pd(II) catalyst.
Next, we examined the Suzuki reaction of intermediate
compound (10) with phenylboronic acid. Thus, intermediate
Conditions for the selective oxidative boron-Heck reaction with acyclic alkene, tert-
butyl acrylate 3a
O
B(OH)
3
2
Pd(OAc)2
t
O Bu
dmphen
O2
I
I
7
8
Entry
Mole ratio
7
3
Pd(OAc)2 (mol %)
T (°C)
Time (h)
Yieldd (%)
1b
2c
3c
4c
1
1
1
1
1.1
1.1
2
5
23
23
23
50
16
16
16
6
81
85
92
87
10
10
10
2
a
All reactions were carried out with 7 (1.0 mmol) and various mole ratios of tert-
butyl acrylate in DMF (2.5 mL).
b
dmphen [2,9-Dimethyl phenanthroline] (5.5 mol %).
dmphen (11.0 mol %).
Isolated yields.
c
d
Initial studies focused on optimization of the boron-Heck type
coupling of 4-iodophenylboronic acid (7) and olefins such as tert-
butyl acrylate (acyclic example) and 2-cyclohexen-1-one (cyclic
example). Table 1 shows the results from the screening of various
temperatures, mole ratios, and catalyst/ligand loading amounts for
this boron-Heck-type coupling using tert-butyl acrylate. The de-
sired product (8) was formed exclusively in a high yield at room
temperature using 10 mol % of Pd(II) catalyst and two equivalents
of tert-butyl acrylate (entry 3). At 50 °C, the yield of product 8 was
diminished due to generation of 4-iodophenol as a side product
(entry 4), despite acceleration of the reaction rate.10
Next, experiments directed toward the development of a tan-
dem oxidative boron-Heck/Suzuki reaction were performed using
Table 2
One-pot tandem reactions; oxidative cross-coupling of 7 with various olefinsa and Suzuki reaction with phenylboronic acidb
Olefin
PhB(OH)2
R
B(OH)
Pd(OAc)2
2
NaOH
Product
6 h, 50 oC, N2
dmphen
16 h, rt,O2
I
I
7
8
Entry
1
Olefin
Mole equiv
2
Productc
O
O
O
OtBu
t
O Bu
OtBu
tBuO
11 (53%)
12 (26%)
O
O
O
OtBu
OtBu
O
2
3
1
tBuO
t
O Bu
(63%)
O
(15%)
O
O
OEt
2
2
OEt
13 (81%)
4
14 (80%)
a
All reactions were carried out with 7 (1.0 mmol), olefins (2.0 mmol), Pd(OAc)2 (10 mol %), and dmphen (11.0 mol %) in DMF (2.5 mL).
Phenylboronic acid (1.2 mmol) and NaOH (2.0 mmol).
Isolated yields.
b
c

J. O’Neill et al. / Tetrahedron Letters 49 (2008) 7307–7310
7309
Table 3
Table 4
Conditions for the selective oxidative boron-Heck reaction with 2-cyclohexen-1-one 9a
One-pot tandem reactions, oxidative cross-coupling of 7 with 2-cyclohexen-1-one
and Suzuki reaction with various arylboronic acidsa,b
B(OH)
9
2
a
1) Pd(OAc)2 (10 mol %)
Pd(OAc)
2
O
dmphen (11 mol %)
B(OH)2
dmphen
O
I
O2, DMF, 16 h, RT
O
I
+
2
b
7
10
2) ArB(OH)2
NaOH, N2, 6 h, 90 o
I
O
Ar
C
Entry
Mole ratio
Entry
Arylboronic acid
Product
Yieldc (%)
67
7
9
Pd/ligand (mol %)
T (°C)
Time (h)
Yieldd (%)
1b
2c
3c
4c
5c
1
1
1
1
1
1.2
1.2
2
2
1.2
5
23
23
23
50
50
16
16
16
6
61
78
80
85
65
B(OH)2
10
10
10
10
O
1
15
6
a
All reactions were carried out with 7 (1.0 mmol) and various mole ratios of
2-cyclohexen-1-one in DMF (2.5 mL).
B(OH)2
O
O
b
dmphen [2,9-Dimethyl phenanthroline] (5.5 mol %).
dmphen [2,9-Dimethyl phenanthroline] (11.0 mol %).
NMR yields.
2
3
60
51
c
H3CO
d
16
17
H3CO
H3CO
H3CO
B(OH)2
compound 10 was generated from 7, and to the crude reaction
mixture containing 10, phenylboronic acid was added and the
reaction was stirred at 50 °C under N2 in the presence of NaOH.
After 6 h, the cross-coupling reaction proceeded to give a 45% yield
of the desired biaryl product (15). Although this yield was in fact
the overall yield for the two-step one-pot tandem reaction, this
conversion was not satisfactory compared to the Suzuki reaction
of intermediate 8 under similar conditions. Subsequently, we
sought optimal conditions by screening various bases and temper-
atures to increase the Suzuki, and consequently, the overall reac-
tion conversion. In this reaction, the use of carbonate and
phosphate bases such as Na2CO3, K2CO3, and K3PO4 at 50 °C pro-
vided the biaryl coupling product 15 in low yields. Also, the use
of an organic base such as Et3N reduced the yield.11 However, at
the elevated temperature of 90 °C in the presence of NaOH, the
reaction proceeded well to afford the coupling compound in an in-
creased yield of 67% for the two-step tandem reaction (Scheme 2).
By utilizing these optimized Suzuki reaction conditions, we
examined a tandem palladium-catalyzed oxidative boron-Heck
and Suzuki reaction with 4-iodophenylboronic acid, 2-cyclohex-
en-1-one, and various arylboronic acids as summarized in Table
4. Reactions with electron-donating substituted arylboronic acids
such as 4-methoxyphenyl boronic acid, 3,4-dimethoxyphenylbo-
ronic acid, and 4-N,N-dimethylaminophenylboronic acid took place
smoothly to provide the desired compounds 16, 17, and 18 in 60%,
51%, and 59% yields, respectively (entries 2–4). Also, the reactions
with 4-nitrophenylboronic acid, 4-acetylphenyl-boronic acid, and
4-cyanophenylboronic acid possessing highly electron-withdraw-
ing groups afforded the biaryl products 19, 20, and 21 in 77%,
78%, and 63% yields, respectively (entries 5–7). The coupling reac-
tion using 2,6-dimethyl phenylboronic acid gave a 30% yield of the
desired product 22 due to steric hindrance (entry 8). In addition,
we examined the Suzuki coupling reaction of the alkenylboronic
acid, trans-styrenyl boronic acid, which proceeded to afford the
corresponding cross-coupling compound 23 in 48% yield. Overall,
these tandem reactions offered an efficient method for the prepa-
ration of biaryl compounds in a one-pot process.
H3CO
H3CO
B(OH)2
O
4
5
59
77
N
18
N
O2N
Ac
B(OH)2
O
O2N
19
B(OH)2
B(OH)2
O
6
7
78
63
Ac
20
21
O
NC
NC
O
B(OH)2
8
30
48
22
B(OH)2
O
9
23
a
All reactions were carried out with 4-Iodophenylboronic acid (1.0 mmol), 2-
cyclohexen-1-one (2.0 mmol), Pd(OAc)2 (10 mol%), and dmphen (11 mol%) in DMF
(2.5 mL).
b
Arylboronic acid (1.2 mmol) and NaOH (2.0 mmol).
c
Isolated yields.
To investigate the scope and limitation of the final coupling
partner, we sought to use different halo-arylboronic acids as the
centerpiece component for the tandem reaction. Several different
halo-arylboronic acids were used with 2-cyclohexen-1-one and
phenylboronic acid as coupling partners, using the established
optimal reaction conditions. The results of these reactions are sum-
marized in Table 5. A tandem reaction of 4-iodophenylboronic acid,
2-cyclohexen-1-one, and phenylboronic acid was converted
PhB(OH)2
Table 3, entry 4
O
O
7
NaOH, N2
6 h, 90 o
I
C
10
15 (67%)
Scheme 2.

7310
J. O’Neill et al. / Tetrahedron Letters 49 (2008) 7307–7310
Table 5
the longevity of palladium catalysts and opens up possibilities
for other tandem oxidative palladium reactions.
The effect of various halo-arylboronic acids with 2-cyclohexen-1-one 9a,b
a
Typical procedure for the tandem reaction: To an oven dried
10 mL round-bottomed flask equipped with a stir bar was charged
0.10 mmol Pd(OAc)2, and 0.11 mmol 2,9-dimethyl phenanthroline
in 2.5 mL DMF. The reaction was stirred at room temperature for
30 minutes, at which time 2.0 mmol alkene was added, followed
by 1.0 mmol halo aryl boronic acid. The reaction flask was then
fitted with an oxygen balloon and stirred at room temperature
for 16 h, or at 50 °C for 6 h. Following confirmation of consumption
of starting material by TLC, the oxygen balloon was removed and
N2 was bubbled through the solution for at least 1 min. 1.2 mmol
aryl boronic acid and 2.0 mmol NaOH were then added to the
solution, and the solution was then stirred for up to 6 h under N2
at 90 °C. The reaction mixture was then dissolved in 50 mL ethyl
acetate and washed twice with 50 mL water, once with 50 mL
brine, and dried over anhydrous sodium sulfate and concentrated
in vacuo. The crude reaction mixture was then subjected to column
chromatography using a 10:1 hexane/ethyl acetate eluent system
on silica gel (230–400 mesh).
1) Pd(OAc) (10 mol %)
2
dmphen (11 mol %)
O , DMF, 16 h, RT
2
B(OH)
+
2
O
b
2) PhB(OH)
2
O
o
NaOH, N , 6 h, 90
2
C
Ph
X
Entry
1
Arylboronic acid
Product
Yieldc (%)
<5%
B(OH)
2
O
O
Cl
15
15
B(OH)
2
2
45
Br
I
B(OH)
2
O
3
4
52
32
Acknowledgment
24
25
We acknowledge generous financial support from the National
Institutes of General Medical Sciences of the National Institutes of
Health (RO1 GM 71495).
Cl
MeO
B(OH)
2
O
O
MeO
Supplementary data
OMe
OMe
B(OH)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.10.039.
5
36
Cl
2
26
References and notes
a
All reactions were carried out with Arylboronic acid (1.0 mmol), 2-cyclohexen-
1-one (2.0 mmol), Pd(OAc)2 (10 mol%), and dmphen (11 mol%) in DMF (2.5 mL).
1. (a) Poetsch, E. Kontakte 1988, 2, 15; (b) Bemis, G. W.; Murcko, M. A. J. Med.
Chem. 1996, 39, 2887; (c) Pu, L. Chem. Rev. 1998, 98, 2405; (d) Hajduk, P. J.;
Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med. Chem. 2000, 43, 3443; (e) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (f) Croom, K. F.;
Keating, G. M. Am. J. Cardiovasc. Drugs 2004, 4, 395.
b
Phenylboronic acid (1.2 mmol) and NaOH (2.0 mmol).
c
Isolated yields.
2. (a) Hernandez, S.; SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett. 2003, 5,
1095; (b) Alberico, D.; Scott, M.; Lautens, M. Chem. Rev. 2007, 107, 174.
3. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147; (c) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633; (d) Persichini, P. J. Curr. Org. Chem. 2003, 7, 1725;
(e) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
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Rottaelander, M.; Palmer, N.; Knochel, P. Synlett 1996, 573; (c) Tilley, J. W.;
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H.; Welton, A. F. J. Med. Chem. 1989, 32, 1814; (d) Hoye, T. R.; Chen, M. J. Org.
Chem. 1996, 61, 7940.
5. (a) Kosugi, M.; Hagiwara, I.; Migita, T. Chem. Lett. 1983, 839; (b) Stille, J. K.
Angew. Chem., Int. Ed. Engl. 1986, 98, 504; (c) Stanforth, S. P. Tetrahedron 1998,
54, 263.
6. (a) Kovacic, P.; Jones, M. B. Chem. Rev. 1987, 87, 357; (b) March, J. Advanced
Organic Chemistry, 4th ed.; Wiley: New York, 1992; p 539.
7. (a) Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339; (b) March, J.
Advanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 715–171.
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Gozzi, C.; Shulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
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11. Conversion yields of the tandem reaction using various bases at 50 °C for 6 h
under N2 for the Suzuki coupling step; Na2CO3 (29%), K2CO3 (24%), K3PO4 (37%),
and triethyl-amine (25%).
efficiently to biaryl product 15 in 67% yield (Table 4, entry 1), while
chloro- and bromo-phenylboronic acid afforded the desired prod-
uct in 15% and 45% yields, respectively (entries 1 and 2). This is be-
cause aryl bromide and iodide easily react with phenylboronic acid
but chloride does not participate in coupling readily. Furthermore,
3-iodophenyl-boronic acid reacted with 2-cyclohexen-1-one, and
then phenylboronic acid to give a 52% yield of 24 (entry 3). In
the case of di-substituted arylboronic acids including 3-chloro-
4-methoxyphenyl boronic acid and 5-chloro-2-methoxyphenyl-
boronic acid, tandem reactions with 2-cyclohexen-1-one and
phenylboronic acid afforded regioselective desired products 25
and 26 in 32% and 36% yields, respectively (entries 4 and 5).
In conclusion, a tandem oxidative boron-Heck/Suzuki coupling
reaction was developed for the preparation of biaryls in good to
moderate yields. The reaction can be performed with variation at
all three coupling partners. In addition, the biaryls formed in this
study were obtained without the use of long laborious purification
or the further addition of more palladium catalyst between
coupling reactions. Furthermore, the use of different atmospheric
conditions, and consequently, different mechanisms, allows for