An improved preparation of arylboronates: Application in one-pot Suzuki biaryl synthesis

Article abstract of DOI:10.1021/jo0269114

We have developed a modification of the Miyaura arylboronate synthesis^1a by substituting a ligandless palladium catalyst for PdCl₂(dppf). Palladium acetate, free of ligand, was found highly effective for such coupling reactions. This modified procedure is advantageous over the original Miyaura synthesis in ease of workup, catalyst removal, and low catalyst cost. Furthermore, the boronates formed in this manner can be used directly for Suzuki coupling reactions in a one-pot fashion. The biaryl products have improved impurity profiles and reduced heavy metal contamination.

Full text of DOI:10.1021/jo0269114

SCHEME 1. Miya u r a On e-step Ar ylbor on a te
Syn th esis Ca ta lyzed by P d Cl2(d p p f)1
An Im p r oved P r ep a r a tion of
Ar ylbor on a tes: Ap p lica tion in On e-P ot
Su zu k i Bia r yl Syn th esis†
Lei Zhu, J ason Duquette, and Mingbao Zhang*
Department of Chemistry Research, Bayer Research Center,
400 Morgan Lane, West Haven, Connecticut 06516
procedure undesirable as a manufacturing process. In
this paper, we wish to report an improved synthesis of
arylboronates by substituting a ligandless palladium
catalyst for PdCl2(dppf). Palladium acetate, a much
cheaper palladium catalyst,4a is highly effective for such
coupling reactions. Furthermore, the boronates prepared
in this manner can be used directly for Suzuki coupling
reactions in a one-pot fashion. The resultant biaryl
products have improved impurity profiles and reduced
heavy metal contamination.
mingbao.zhang.b@bayer.com
Received December 26, 2002
Abstr a ct: We have developed a modification of the Miyaura
arylboronate synthesis1a by substituting a ligandless pal-
ladium catalyst for PdCl2(dppf). Palladium acetate, free of
ligand, was found highly effective for such coupling reac-
tions. This modified procedure is advantageous over the
original Miyaura synthesis in ease of workup, catalyst
removal, and low catalyst cost. Furthermore, the boronates
formed in this manner can be used directly for Suzuki
coupling reactions in a one-pot fashion. The biaryl products
have improved impurity profiles and reduced heavy metal
contamination.
In their pioneering study, Miyaura and co-workers
reported that potassium acetate was essential for the
palladium(0)-catalyzed aryl halide/diboron coupling reac-
tion. They thus proposed the presence of an acetoxopal-
ladium(II) intermediate in the catalytic cycle.1a We
speculated that palladium acetate would be equally
capable of catalyzing the coupling reaction by facilitating
the formation of this key intermediate, thus rendering
PdCl2(dppf) unnecessary.
Arylboronates are playing an increasingly prominent
role in Suzuki cross-coupling reactions as important
alternatives to arylboronic acids, especially when the
corresponding boronic acids are not readily available.2
The PdCl2(dppf)-catalyzed cross-coupling reaction of bis-
(pinacolato)diboron with arylhalides, first reported by
Miyaura and co-workers, is a convenient method for the
synthesis of arylboronates (Scheme 1).1a In contrast to
the more traditional organometallic approach,3 the
Miyaura procedure enables facile access to boronic acid
derivatives in the presence of sensitive functionalities
such as ester, ketone, cyano, or nitro groups. We have
found, however, in the course of a large-scale synthesis
of a lead drug candidate, that the use of PdCl2(dppf) as
a catalyst is not optimal. The quality of the arylboronates
and subsequent Suzuki coupling products are often
compromised by coloration and high residual heavy metal
content. Large-scale chromatography is often needed for
purification and high catalyst cost also makes this
The coupling reaction between arylhalides and bis-
(pinacolato)diboron was carried out in DMF at 80 °C
under argon with 3 mol % of palladium acetate (unless
otherwise specified) and 3 equiv of potassium acetate.
Under these conditions, arylbromides having electron-
withdrawing groups, such as COMe, CN, COOMe, and
NO2, underwent coupling reaction smoothly with the
diboron reagent (entries 1, 2, 5, and 7, Table 1). Consis-
tent with Miyaura’s results, arylbromides having electron-
donating groups, such as NMe2 and OMe, coupled poorly
with the diboron under the palladium acetate catalysis
conditions. Prolonged heating resulted in an insignificant
change in the reaction mixture (entries 8 and 10, Table
1). Electron-rich arylboronates can alternatively be made
from the corresponding aryliodides under the conditions
for electron-poor arylbromides (entry 9, Table 1).
Palladium removal appears to be facile with this new
palladium acetate catalyzed arylboronate formation. The
crude arylboronates (white to off-white solids) obtained
after a simple workup showed low palladium contamina-
tion (entries 1, 2, 5, 7, and 9, Table 1). In contrast, an
experiment, catalyzed with PdCl2(dppf) and worked up
identically, yielded a crude product (a dark brown solid)
that contained 350 times more palladium (entry 7, Table
1).
* Address correspondence to this author. Phone: (203) 812-5906.
Fax (203) 812-2452.
† This work was presented in part at The 10th Symposium on the
Latest Trends in Organic Synthesis, October 23-27, 2002, Gainesville,
FL.
(1) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995,
60, 7508. (b) Masuda and co-workers have reported the preparation of
pinacol arylboronates by PdCl2(dppf)-catalyzed coupling of aryl halides/
triflates with pinacolborane. This method, however, produces arene
by reduction of the aryl halides as a significant byproduct. Murata,
M.; Watanabe, S.; Masuda, Y. J . Org. Chem. 1997, 62, 6458. Murata,
M.; Oyama, T.; Watanabe, S.; Masuda, Y. J . Org. Chem. 2000, 65, 164.
(2) (a) Manickam, G.; Schluter, A. D. Synthesis 2000, 442. (b)
Firooznia, F.; Gude, C.; Chan, K.; Marcopulos, N.; Satoh, Y. Tetrahe-
dron Lett. 1999, 40, 213. (c) Firooznia, F.; Gude, C.; Chan, K.; Satoh,
Y. Tetrahedron Lett. 1998, 39, 3985. (d) Zembower, D. E.; Zhang, H.
J . Org. Chem. 1998, 63, 9300.
(3) (a) For boronic acids via organomagnesium reagents, see: Wash-
burn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A.; Cernak, E. S.
Adv. Chem. Ser. 1959, 23, 102. Washburn, R. M.; Billig, F. A.; Bloom,
M.; Albright, C. F.; Levens, E. Adv. Chem. Ser. 1961, 32, 208. Brown,
H. C.; Cole, T. E. Organometallics 1983, 2, 1316. (b) For boronic acids
via organolithium reagents, see a review: Snieckus, V. Chem. Rev.
1990, 90, 879.
In several instances, the arylboronate products were
accompanied by small amounts (5-15%) of the symmetric
(4) (a) PdCl2(dppf) $9000/mol; Pd(OAc)2 $2000/mol. Aldrich catalog
2001-2002. (b) Catalysts other than PdCl2(dppf) which have been used
for the Miyaura arylboronate reaction include PdCl2(PPh3)2 (Taka-
hashi, K.; Takagi, J .; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 126.
Iovine, P. M.; Kellett, M. A.; Redmore, N. P.; Therien, M. J . J . Am.
Chem. Soc. 2000, 122, 8717) and Pd2dba3 (Todd, M. H.; Abell, C. J .
Comb. Chem. 2001, 3, 319). We thank a reviewer for bringing this
information to our attention.
10.1021/jo0269114 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/02/2003
J . Org. Chem. 2003, 68, 3729-3732
3729

TABLE 1. Ar ylbor on a te F or m a tion Med ia ted by
Liga n d less P a lla d iu m Ca ta lysts
dure can be very valuable to synthetic chemists. To carry
out the two steps in one pot, the boronate formation needs
to be reasonably clean. Furthermore, proper selection of
solvent and base is also essential. In a typical experiment,
the first arylhalide (ArX) was converted into its boronate
via bis(pinacolato)diboron under standard conditions (Pd-
(OAc)2, KOAc, DMF, 80 °C). The Suzuki coupling partner
Ar′X was then added to the reaction mixture together
with 3 mol % of Pd(PPh3)4 and 1.5 equiv of cesium car-
bonate. The reaction mixture was then heated at 80 °C
overnight to afford the biaryl product. The results are
summarized in Table 2 and generally demonstrate sat-
isfactory yields.
Pd
Pd
reaction yield, %
time, h (isolated)b
content,
ppm
entry catalysta
aryl halide (ArX)
1
2
3
4
5
6
7
A
A
B
B
A
B
A
4-BrC6H4COMe
3-BrC6H4CN
3-BrC6H4CN
3
2
2
22
3
20
3
(86)c
(81)d
29d
57
17
NDf
ND
100
ND
35
3-BrC6H4CN
15d
4-Br-3-MeC6H3CO2Me
4-Br-3-MeC6H3CO2Me
4-BrC6H4NO2
(70)d
34d
(90)c
(12300)e
8
9
10
A
A
A
4-BrC6H4OMe
4-IC6H4OMe
4-BrC6H4NMe2
15
2
23
21c
80c
23c
ND
140
ND
In our studies, DMF was the solvent of choice because
it had proven suitable for both the arylboronate formation
and the Suzuki coupling reaction.7a Potassium acetate
was used in the arylboronate formation due to its mild
basicity, a crucial factor for this reaction.1a A stronger
base, cesium carbonate, was later introduced to promote
the Suzuki coupling.7 Although palladium acetate alone
was sufficient to catalyze both the boronate formation
and the Suzuki coupling in some cases, we found that,
in general, the addition of 3 mol % of Pd(PPh3)4 after the
boronate formation would accelerate the cross-coupling
step.7 Palladium catalysts were easily removed during
workup by filtration through a pad of Celite. The biaryl
products are usually obtained as crystalline solids in high
purity after extraction and trituration.
As expected, the outcomes of the cross-coupling reac-
tions were greatly influenced by the substituents on the
arylhalides. In the cases where both ArX and Ar′X are
electron deficient, high yields (>90%) of the biaryls were
obtained regardless of the addition order of the halides
(entries 1, 2, 7, and 8, Table 2). Significantly, nonsub-
stituted bromobenzene i coupled efficiently with the
electron-poor p-acetylbromobenzene f under these condi-
tions (entry 15, Table 2). With the same halide f,
p-bromonitrobenzene h and p-methylbromobenzoate g
underwent the cross-coupling reaction smoothly even
without the addition of Pd(PPh3)4 (entries 9 and 12, Table
2). However, bromobenzene i did not react with f under
the same conditions (entry 16, Table 2). In the absence
of both Cs2CO3 and Pd(PPh3)4, the Suzuki coupling
reactions proceeded very slowly (entries 10 and 13, Table
2). For electron-rich arylbromides, only a trace amount
of the biaryl products was obtained due to their poor
boronate formation (entries 3 and 4, Table 2), although
an aryliodide afforded the biaryl in good yield (61%, entry
5, Table 2). Reversing the roles of the coupling partners
can rectify this situation. For example, biaryls 9 and 10
were obtained in 60% and 20% yields, respectively, when
electron-rich Ar′X’s were coupled with the boronate
a
Catalyst: (A) Pd(OAc)2, 3 mol %; (B) Pd/C (Degussa, wet, 10
wt % on dry basis), 3 mol %. Estimated by 1H NMR spectroscopy
in CDCl3. Isolated yields are shown in parentheses. c Originally
made by Miyaura et al., see ref 1a for details. Spectroscopic data
(1H NMR and MS) are consistent with the desired structure and
b
d
match those reported by Miyaura et al. New compound, fully
characterized (see Experimental Section for details). e Pd content
for an experiment, catalyzed with PdCl2(dppf), and worked up
identically, is shown in parentheses. f Not determined.
1
biaryls in the reaction mixture as shown by H NMR.
Two control experiments were then carried out to probe
the origin of dimer formation (Scheme 2). In the first
experiment, p-acetylbromobenzene was treated with 1
equiv of the diboron reagent under our standard condi-
tions. 1H NMR analysis of the resultant reaction mixture
showed a 9:1 ratio of the boronate and the homo-dimer
with no presence of the starting bromide. This reaction
mixture was then kept at 80 °C for an extended period
1
of time (18 h). H NMR revealed no significant change
in the product ratio. This result showed that the aryl-
boronate was thermally stable in the reaction mixture,
and essentially ruled out the possibility of homo-coupling
of the boronate as the primary origin of the dimer
formation. In the second experiment, p-acetylbromoben-
zene was treated with 0.5 equiv of the diboron reagent.
Upon heating, under standard conditions, for the same
amount of time (18 h), the boronate:dimer ratio was 1:4
1
as shown by H NMR. This experiment clearly demon-
strated that the dimer formation resulted from Suzuki
coupling of the boronates and their halide precursors
under the reaction conditions.
We also examined Pd/C as another ligandless pal-
ladium catalyst, but it proved to be much less effective
than palladium acetate for the boronate formation. With
Pd/C, poor yields were observed for the boronates due to
significant homo-dimer formation (entries 3, 4, and 6,
Table 1). It suggests that Pd/C is more effective in
catalyzing the Suzuki coupling reaction than the boronate
formation under these conditions (vide infra).
Our success in replacing PdCl2(dppf) by a ligandless
palladium catalyst for such arylboronate formation is un-
precedented in the literature. We investigated the scope
of this reaction and elaborated the results into a conve-
nient one-pot Suzuki coupling reaction (Chart 1 and
Table 2). The strategy of using organoboranes generated
in situ for Suzuki coupling reactions was first docu-
mented by Keay,5 and was recently demonstrated to be
quite successful with arylboronates, especially in solid-
phase applications.6 Clearly, avoiding the often trouble-
some isolation of arylboronates via the Miyaura proce-
(5) (a) Maddaford, S. P.; Keay, B. A. J . Org. Chem. 1994, 59, 6501.
(b) Anderson, N. G.; Maddaford, S. P.; Keay, B. A. J . Org. Chem. 1996,
61, 9556.
(6) (a) Piettre, S. R.; Baltzer, S. Tetrahedron Lett. 1997, 38, 1197.
(b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997, 38, 3841. (c)
Brown, S. D.; Armstrong, R. W. J . Am. Chem. Soc. 1996, 118, 6331.
(d) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447. (e) Carbonnelle, A.; Zhu, J . Org. Lett. 2000, 2, 3477.
(7) The selection of base and catalyst for the Suzuki coupling step
was not a focus of this study. For reviews regarding Cs2CO3 and Pd-
(PPh3)4 in Suzuki coupling reactions, see: (a) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457. (b) Wallow, T. I.; Novak, B. M. J . Org.
Chem. 1994, 59, 5034. (c) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett
1992, 207.
3730 J . Org. Chem., Vol. 68, No. 9, 2003

SCHEME 2
CHART 1. Str u ctu r es of Ar yl Ha lid es (Ar X or Ar ′X) a n d Bia r yl P r od u cts (Ar -Ar ′)
generated in situ from the electron-poor halide f (entries
22 and 23, Table 2). Sterically hindered halides, such as
3-iodomesitylene k , coupled satisfactorily with f under
the “one-pot” conditions (entry 24, Table 2). Iodobro-
mobenzene l underwent coupling chemoselectively with
f to provide the bromobiaryl product 12 (entry 26, Table
2). The aryl chloride j failed to couple with f under these
Suzuki conditions (entries 19, 20, and 21, Table 2). In
the cases where ArX and Ar′X are both electron-rich, the
yields of the biaryls are expected to be low because of
the inability to generate the aryl boronates cleanly.
For active arylhalide Suzuki coupling partners, the
cross-coupling step can also be facilitated by addition of
Pd/C (Degussa, wet, 10 wt % on dry basis, typically 3
mol %) after the completion of the boronate formation
catalyzed by palladium acetate (Table 2) (vide supra).
Both catalysts can be easily removed together by a simple
filtration through a pad of Celite after the Suzuki
reaction. For many substrates, cesium carbonate was
unnecessary for the Suzuki coupling with Pd/C. An
exception was the unsubstituted bromobenzene i where
only 30% biaryl yield was obtained in the absence of
cesium carbonate (entry 17, Table 2). For unactivated
arylhalide Suzuki coupling partners, Pd(PPh3)4 gave
better yields for the cross-coupling step than Pd/C
(entries 24/25 and 26/27, Table 2).
We also examined the residual palladium content in
the biaryl products under various Suzuki conditions
(Table 2). J ust as expected, Pd/C resulted in the least
palladium contamination in the biaryl products among
the various Suzuki conditions examined (entries 6, 11,
14, and 18, Table 2). Removing traces of heavy metal from
a drug substance can be a nontrivial exercise in many
instances.8 Thus, our one-pot Suzuki biaryl coupling
process involving this unique combination of ligandless
palladium catalysts will find applications in drug syn-
thesis where very low heavy metal content is desired.
We have shown that palladium acetate, a better choice
than PdCl2(dppf) in terms of cost4 and catalyst removal,
effectively catalyzes the cross-coupling of a wide variety
of arylhalides with bis(pinacolato)diboron to form the
corresponding boronates. Boronates prepared in this
procedure either can be conveniently isolated or used in
situ for Suzuki cross-coupling reactions with arylhalides
to provide biaryls.
(8) Rosso, V. W.; Lust, D. A.; Bernot, P. J .; Grosso, J . A.; Modi, S.
P.; Rusowicz, A.; Sedergran, T. C.; Simpson, J . H.; Srivastava, S. K.;
Humora, M. J .; Anderson, N. G. Org. Process Res. Dev. 1997, 1, 311.
J . Org. Chem, Vol. 68, No. 9, 2003 3731

TABLE 2. On e-P ot Su zu k i Cou p lin g Rea ction s via
Ar ylbor on a tes Gen er a ted in Situ a
134.44, 138.41, 138.75. GCMS (EI), m/z 229. Anal. Calcd for
13H16BNO2: C, 68.16; H, 7.04; N, 6.11. Found: C, 67.90; H,
C
7.23; N, 6.50.
Meth yl 2-Meth yl-4-(4,4,5,5-tetr a m eth yl-1,3,2-d ioxa bor o-
la n -2-yl)b en zoa t e. This boronate was prepared in a similar
manner as described above in 70% yield. An analytically pure
sample obtained by silica gel column chromatography exhibited
the following spectroscopic data: 1H NMR (CDCl3) δ 1.37 (s,
12H), 2.58 (s, 3H), 3.91 (s, 3H), 7.79 (s, 2H), 7.81 (s, 1H); 13C
NMR (CDCl3) δ 22.99, 25.75, 52.76, 84.25, 125.65, 130.49, 131.78,
135.75, 144.85, 167.12;. GCMS (EI), m/z 276. Anal. Calcd for
C15H21BO4: C, 65.24; H, 7.67. Found: C, 65.44; H, 7.67.
Typ ica l P r oced u r e for th e On e-P ot Su zu k i Rea ction
w ith P d (P P h 3)4 via th e in Situ Gen er a ted Ar yl Bor on a te
As Illu str a ted by th e P r ep a r a tion of Bia r yl 6. To a 50-mL,
three-necked, round-bottomed flask were charged, in no specific
order, 4′-bromoacetophenone (0.52 g, 2.6 mmol, 1.0 equiv), bis-
(pinacolato)diboron (0.70 g, 2.8 mmol, 1.05 equiv), palladium
acetate (17 mg, 0.078 mmol, 3 mol %), potassium acetate (0.77
g, 7.9 mmol, 3.0 equiv), and 10 mL of DMF. The mixture was
degassed by gently bubbling argon through for 30 min at room
temperature. The mixture was then heated at 80 °C under argon
protection until completion of the reaction (2-3 h). After the
reaction mixture was cooled to room temperature, 1-bromo-4-
nitrobenzene (0.52 g, 2.6 mmol, 1.0 equiv), cesium carbonate (1.3
g, 3.9 mmol, 1.5 equiv), and Pd(PPh3)4 (90 mg, 0.078 mmol, 3
mol %) were added. The reaction mixture was then heated at
80 °C overnight under argon, then cooled to room temperature
and diluted with water (20 mL) and ethyl acetate (20 mL). Black
particles were removed by passing through a pad of Celite. The
organic layer was separated, and washed twice with 15 mL of
brine solution. After drying over sodium sulfate, the solvent was
removed at reduced pressure to afford 1-(4′-nitro-biphenyl-4-yl)-
ethanone 6 as a yellow solid (0.7 g, >99% yield, >95% purity by
1H NMR). An analytically pure sample was obtained by column
chromatography (silica gel, ethyl acetate/hexanes): light yellow
solid, mp 145.5-146.5 °C. 1H NMR (DMSO-d6) δ 8.32 (d, J )
8.8 Hz, 2H), 8.08 (d, J ) 8.7 Hz, 2H), 8.03 (d, J ) 9.1 Hz, 2H),
7.93 (d, J ) 8.6 Hz, 2H), 2.63 (s, 3H); 13C NMR (DMSO-d6) δ
198.03, 147.79, 145.86, 142.61, 137.37, 129.59, 128.88, 128.10,
124.82, 27.78. GCMS (EI), m/z 241. Anal. Calcd for C14H11NO3:
C, 69.70; H, 4.60; N, 5.81. Found: C, 69.85; H, 4.55; N, 5.59.
Typ ica l P r oced u r e for th e On e-P ot Su zu k i Rea ction
w ith P d /C As Illu str a ted by th e P r ep a r a tion of Bia r yl 6.
To a 50-mL, three-necked, round-bottomed flask were charged,
in no specific order, 4′-bromoacetophenone (0.52 g, 2.6 mmol,
1.0 equiv), bis(pinacolato)diboron (0.70 g, 2.8 mmol, 1.05 equiv),
palladium acetate (17 mg, 0.078 mmol, 3 mol %), potassium
acetate (0.77 g, 7.9 mmol, 3.0 equiv), and 10 mL of DMF. The
mixture was degassed by gently bubbling argon through for 30
min at room temperature. The mixture was then heated at 80
°C under argon until completion of the reaction (2-3 h). After
the reaction mixture was cooled to room temperature, 1-bromo-
4-nitrobenzene (0.52 g, 2.6 mmol, 1.0 equiv), cesium carbonate
(1.3 g, 3.9 mmol, 1.5 equiv), and Pd/C (Degussa, 160 mg, 0.075
mmol, 0.03 equiv) were added. The reaction mixture was then
heated at 80 °C overnight, then cooled to room temperature,
diluted with cold water (30 mL), and stirred for 10 min. Solids
were filtered through a pad of Celite, and rinsed with water (30
mL). The filter cake was stirred in 50 mL of ethyl acetate, and
filtered through a pad of Celite. After drying over sodium sulfate,
the solvent was removed at reduced pressure to afford 1-(4′-nitro-
biphenyl-4-yl)-ethanone 6 as an off-white solid (0.61 g, 98%,
>95% purity by 1H NMR).
halide pairs
biaryls
yield,
%
Suzuki
Pd content,
ppm
entry (ArX, Ar′X) (Ar-Ar′)
conditionsh
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
a , g
b, g
c, g
d , g
e, g
a , f
f, a
f, h
f, h
f, h
f, h
f, g
f, g
f, g
f, i
f, i
f, i
f, i
f, j
f, j
f, j
f, d
f, c
f, k
f, k
f, l
1
2
3
4
4
5
5
6
6
6
6
7
7
7
8
8
8
8
8
8
8
9
10
11
11
12
12
88b
A
A
A
A
A
D
A
A
B
C
D
B
C
D
A
B
D
E
NDg
ND
ND
ND
ND
60
1000
3300
ND
ND
417
208
ND
82
2500
ND
ND
149
ND
ND
ND
ND
ND
ND
ND
ND
ND
90b
tracec
tracec
61d
98b
95b
95b
90b
trace
98b
90b
trace
91b
88d
trace
30f
92b
trace
trace
trace
60d
A
D
E
A
A
A
E
20e
69d
10f
75d
A
E
f, l
50f
a
b
Refer to Chart 1 for structures. Crude yield, 90-95% purity
by 1H NMR. c Low-yielding boronate formation. Isolated yield.
d
e GC yield. f 1H NMR yield. g Not determined. Suzuki conditions:
h
(A) Pd(PPh3)4 (0.03 equiv); Cs2CO3 (1.5 equiv), 80 °C, 18 h. (B)
Cs2CO3 (1.5 equiv), 80 °C. (C) No Pd(PPh3)4, no Cs2CO3. (D) Pd/C
(Degussa, wet, 10 wt %, 0.03 equiv). (E) Pd/C (Degussa, wet, 10
wt %, 0.03 equiv), Cs2CO3 (1.5 equiv), 80 °C.
Exp er im en ta l Section
All chemicals and reagents used in this study were purchased
commercially and used without purification. NMR spectroscopic
data were recorded on a Varian (300 MHz) NMR spectrometer.
Elemental analyses were performed by Robertson Microlit Labs.
Typ ica l P r oced u r e for th e P r ep a r a tion of Ar ylbor -
on a tes As Illu str a ted by th e Syn th esis of 3-(4,4,5,5-Tet-
r a m eth yl-1,3,2-d ioxa bor ola n -2-yl)ben zon itr ile. To a 50-mL,
three-necked, round-bottomed flask were charged 3-bromoben-
zonitrile (0.95 g, 5.20 mmol), bis(pinacolato)diboron (1.43 g, 5.62
mmol), potassium acetate (1.53 g, 15.6 mmol), palladium acetate
(0.04 g, 0.16 mmol, 3 mol %), and DMF (20 mL). The mixture
was degassed by gently bubbling nitrogen for 30 min. It was
then heated in an oil bath at 85 °C until completion (ca. 5 h).
The reaction mixture was then cooled to room temperature and
diluted with water (75 mL) to induce precipitation. The gray
solid was collected by filtration, rinsed with water, and dried.
It was then dissolved in ethyl acetate (50 mL). The insoluble
material was removed by filtration through a pad of Celite. The
filtrate yielded the title compound as a white solid (0.37 g) after
removal of solvent in vacuo. The mother liquor from the first
filtration was extracted with ethyl acetate (75 mL). The organic
layer was washed with water (50 mL × 2) and dried over
anhydrous sodium sulfate. Removal of solvent yielded additional
product as a colorless oil that solidified shortly (0.60 g). The
combined yield was 81%. An analytically pure sample obtained
by recrystallization in ethyl acetate exhibited the following
spectroscopic data: 1H NMR (CDCl3) δ 1.37 (s, 12H), 7.46 (t, J
) 7.6, 1H), 7.71 (d, J ) 7.7, 1H), 8.00 (d, J ) 7.6, 1H), 8.08 (s,
1H); 13C NMR (CDCl3) δ 25.72, 84.90, 112.23, 119.00, 128.47,
Ackn owledgm en t. The authors thank Donald Wola-
nin, Xin Ma, David Miller, and Fred Ehrgott for helpful
discussions.
Su p p or tin g In for m a tion Ava ila ble: Complete charac-
terization data for biaryls 1, 2, 4, 5, 7, 8, 9, 11, and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0269114
3732 J . Org. Chem., Vol. 68, No. 9, 2003