Efficient palladium-catalyzed Suzuki-Miyaura coupling of aryl chlorides with arylboronic acids using benzoferrocenyl phosphines as supporting ligands

Article abstract of DOI:10.1016/j.tet.2007.04.057

Four monodentate benzoferrocenyl phosphines were studied as supporting ligands in palladium-catalyzed Suzuki-Miyaura coupling of aryl chlorides with arylboronic acids. Of these ligands, the more electron-rich and steric demanding benzoferrocenyl dicyclohexyl phosphine was found highly effective for the reaction followed by the benzoferrocenyl diisopropyl phosphine. The corresponding diethyl and diphenyl phosphines are much less active. When the dicyclohexyl phosphine was used, both electron-rich and electron-poor aryl chlorides were coupled with arylboronic acids within 1 h giving good to excellent yields. Chloro-substituted pyridines were also found highly reactive under these conditions giving excellent yields of biaryl products. Sterically hindered biaryls can also be prepared using the dicyclohexyl phosphine as ligand.

Full text of DOI:10.1016/j.tet.2007.04.057

Tetrahedron 63 (2007) 6879–6886
Efficient palladium-catalyzed Suzuki–Miyaura coupling of aryl
chlorides with arylboronic acids using benzoferrocenyl
phosphines as supporting ligands
*
Muralidhara Thimmaiah and Shiyue Fang
Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
Received 3 April 2007; accepted 17 April 2007
Available online 25 April 2007
Abstract—Four monodentate benzoferrocenyl phosphines were studied as supporting ligands in palladium-catalyzed Suzuki–Miyaura cou-
pling of aryl chlorides with arylboronic acids. Of these ligands, the more electron-rich and steric demanding benzoferrocenyl dicyclohexyl
phosphine was found highly effective for the reaction followed by the benzoferrocenyl diisopropyl phosphine. The corresponding diethyl
and diphenyl phosphines are much less active. When the dicyclohexyl phosphine was used, both electron-rich and electron-poor aryl chlorides
were coupled with arylboronic acids within 1 h giving good to excellent yields. Chloro-substituted pyridines were also found highly reactive
under these conditions giving excellent yields of biaryl products. Sterically hindered biaryls can also be prepared using the dicyclohexyl phos-
phine as ligand.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
scope of this reaction to aryl chlorides, Fu and co-workers
used tri-tert-butylphosphine as supporting ligand for palla-
dium-catalyzed Suzuki–Miyaura coupling. Because of the
bulkiness of the ligand, the less reactive species [Pd(PtBu3)2]
can be transformed into the more reactive [Pd(PtBu3)] dur-
ing the reaction. Together with the highly electron-rich na-
ture of the ligand, this mono-coordinated palladium(0) can
activate electron-deficient aryl chlorides at room tempera-
ture and electron-rich ones at elevated temperature allowing
Suzuki–Miyaura coupling of both electron-rich and -poor
aryl chlorides.5 Independently, Buchwald and co-workers
designed and synthesized a series of air-stable biaryl-based
electronically rich and sterically bulky ligands; using these
ligands, both electron-rich and -poor aryl chlorides were
activated for the coupling reaction at room temperature.6
Many bioactive natural products such as the vancomycin
antibiotics contain biaryl units, which increase the rigidity
of the molecule and are beneficial to or indispensable for bi-
ological function.1 As a result, the development of method-
ologies that are useful for constructing biaryl function has
received much attention in organic chemistry. Compared
with other methods for the synthesis of biaryls such as
Stille,2 Kumada,3 and Negishi2a,3,4 coupling reactions,
Suzuki–Miyaura coupling of aryl halides with arylboronic
acids has several practical advantages. The nucleophilic re-
action partner boronic acids are usually non-toxic, inert to air
and moisture, and are thermally stable; the side products
arising from them can be easily removed from the reaction
mixture; and the weak nucleophilic nature of boronic acids
makes the reaction compatible with certain functional
groups such as nitriles, ketones, and aldehydes. As to the
electrophilic reaction partner aryl halides, aryl chlorides
are most attractive because they are more available and
less expensive than aryl bromides and iodides.2a,3,4 How-
ever, until late 1990s, unactivated aryl chlorides are not
feasible substrates for Suzuki–Miyaura coupling reactions
because of their reluctance toward oxidative addition, which
is the first step of the oxidative addition, transmetallation,
and reductive elimination process. In order to extend the
Later, some other bulky electron-rich phosphine ligands
were designed and synthesized for the Suzuki–Miyaura
coupling of aryl chlorides.7 Among them, those based on
the ferrocene attracted significant attention (see Fig. 1 for
examples). Ferrocene is electron-rich as indicated by its
ability to stabilize adjacent carbocation8 and is sterically
bulky especially when additional substituent groups are at-
tached to one or both of its Cp rings; as a result, ferrocene
is an excellent starting point for making electron-rich and
sterically hindered ligands for Suzuki–Miyaura coupling
of aryl chlorides. For example, Fu and co-workers found
that 1 is an active ligand for this reaction even though 1
is a triarylphosphine, which is less electron-rich than trial-
kylphosphines; the ligand is active with both electron-rich
and -poor aryl chlorides including those with di-ortho
Keywords: Benzoferrocenyl phosphine ligand; Suzuki coupling; Aryl chlo-
ride; Chloropyridine.
* Corresponding author. Tel.: +1 906 487 2023; fax: +1 906 487 2061;
e-mail: shifang@mtu.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.057

6880
M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
FeCp
H3C
∗
tBu
FeCp
FeCp
Fe(C5Ph5)
FeCp
O
Fe
TMS
2
Ph2P
P
3
PPh2
CH3
P(tBu)2
PPh2
PCy2
PCy2
1
2
3
4
5
6
Cp* = C5(CH3)5, Cp = C5H5, Cy = C6H11
Figure 1. Examples of ferrocenyl phosphine ligands for Suzuki–Miyaura coupling.
substituted ones.9 Richards and co-workers synthesized 2
and the C3-symmetric 3;10 using 2 as ligand, coupling of
certain aryl chlorides with phenylboronic acid proceeded
at 60 ꢀC;10a when 3 was used, under optimized conditions,
coupling of electron-poor aryl chloride gave excellent yield,
but in the case of electron-rich ones, yields less than 60%
were obtained.10b Hartwig’s group used 4 in Suzuki–
Miyaura coupling and other reactions, in the most challeng-
ing case the authors reported in the paper that a di-ortho
substituted biaryl can be prepared from electron-rich aryl
chloride in 80% at 100 ꢀC.11 Hierso’s group reported using
the tetraphosphine 5 as ligands in coupling reactions involv-
ing aryl chlorides; when electron-poor substrates were used,
excellent yields could be obtained, but with electron-rich
substrates, yields were moderate; 5 is not considered elec-
tron-rich by the authors and forms bis-coordinated complex
with palladium, the authors attributed its activity in activat-
ing aryl chlorides to the stability of its palladium complex.12
Recently, Johannsen’s and Xiao’s research groups reported 6
and other similar ligands for coupling of aryl chlorides, both
electron-rich and -poor aryl chlorides were coupled with
high to excellent yields in 8–24 h;13 in the most challenging
case, a tri-ortho substituted biaryl was synthesized in 88%
yield at 100 ꢀC within 24 h;13a in addition, enantiopure 6
was applied for asymmetric synthesis of 2,20-dimethyl bi-
naphthalene from aryl bromide and arylboronic acid, the
best ee obtained was 54%.13b
2. Results and discussion
2.1. Optimization of reaction conditions
Because several bases such as CsF, KF, Cs2CO3, K2CO3, and
K3PO4 were shown to be suitable for Suzuki–Miyaura cou-
pling of aryl chlorides,5,6b,6c,7b,9,11 we first planned to iden-
tify the best one for the reaction using our ligands. Among
the four benzoferrocenyl phosphine ligands (7a–d), 7d is
most electron-rich and most sterically hindered; we reasoned
that it should offer the best results for activation of aryl chlo-
rides, which was indeed the case as shown later. As a result,
7d was chosen for the base-screening. When the electron-
neutral chlorobenzene and phenylboronic acid were used
as substrates, 1,4-dioxane as solvent, and Pd2(dba)3 as the
palladium source, both Cs2CO3 and K3PO4 gave excellent
results. At 100 ꢀC, quantitative conversions were achieved
within 1 h as shown by GC even when 1 to 1 molar ratio
of the two substrates was used and the isolated yield of the
biphenyl in both cases was 88% (Table 1, entries 1 and 2).
CsF was found equally effective (entry 3). However, when
K2CO3 and KF were used for the reaction, under these con-
ditions much less yields were obtained (entries 4 and 5).
Next, the effects of the solvent and temperature on the reac-
tion were studied. As shown in Table 2, under similar condi-
tions described above, when 1,4-dioxane, DME, and toluene
were used as solvent, good to excellent isolated yields of
biaryl product were obtained; among them, 1,4-dioxane
gave best results, within 1 h, 100% conversion was achieved
(entry 1). In contrast, longer reaction time was needed to
complete the reaction when DME or toluene was used as sol-
vents (entries 2 and 3). The more polar solvents THF, DMM,
and DMF were found unsuitable for the reaction (entries 4, 5,
and 6). We also explored the possibility of room temperature
Suzuki–Miyaura coupling of aryl chlorides, when the
Recently, we reported the synthesis and characterization of
four novel benzoferrocenyl phosphine ligands 7a–d (Fig. 2)
and demonstrated that these ligands could be easily prepared
and are chemically and configurationally stable in air and in
solution.14 In the X-ray crystal structure of 7a, we noticed
that the lone pair on the phosphorus atom points to the
endo face of the benzoferrocene. We reasoned that coordina-
tion of these ligands with palladium would favor mono-
coordinated unsaturated organometallic species; because
benzoferrocene, like ferrocene, is electron-rich, these ligands
might represent a new class of bulky electron-rich ligands
that are useful in Suzuki–Miyaura coupling of aryl chlorides
with arylboronic acids. Furthermore, the phosphorus atom is
not attached to the bulky ferrocene moiety directly; this
might provide mono-coordinated yet less hindered palladium
Table 1. Identifying suitable base for Suzuki–Miyaura coupling of aryl
chloridesa
Cl
B(OH)2
+
complexes that are suitable for coupling reactions. In this pa-
per, we report our results on this investigation.
Entry
Base
Time (h)
Yieldb (%)
1
2
3
4
5
Cs2CO3
K3PO4
CsF
K2CO3
KF
1
1
1
21
1
88
88
87
68
20
FeCp*
7a, R = Ph
7b, R = CH2CH3
7c, R = CH(CH3)2
a
7d, R = C6H11
PR2
Conditions: phenylboronic acid 1 equiv, chlorobenzene 1 equiv,
Pd2(dba)3 1.5 mol %, 7d 3.6 mol %, base 2 equiv, 1,4-dioxane, reflux.
Isolated yields.
b
Figure 2. Benzoferrocenyl phosphine ligands.

M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
6881
Table 2. Effects of solvents and temperature on Suzuki–Miyaura coupling
palladium(0) to aryl chlorides. In the case of 7a, the phos-
phorus atom is less electron-rich than those in 7b,c because
phenyl groups are less electron-donating than alkyl groups;
as a result, its palladium(0) complex is not nucleophilic
enough to activate the aryl C–Cl bonds. Ligand 7b is the
least sterically hindered among the four but it is more elec-
tron-rich than 7a; its complexes with palladium favor the bi-
coordinated L2Pd over the mono-coordinated LPd to the
extent that the latter, which is believed to be responsible for
activating aryl C–Cl bonds, does not have sufficient quantity
to catalyze the reaction. Ligands 7c,d are both electron-rich
and sterically bulky, they form mono-coordinated highly nu-
cleophilic complexes with palladium or can be transformed
into such species under reaction conditions, and therefore
are highly active for activation of aryl C–Cl bonds.
of aryl chloridesa
Cl
B(OH)2
+
Entry
Solvent
Temperature
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1,4-Dioxane
DMEc
Reflux
Reflux
Reflux
Reflux
Reflux
rt
1
24
24
1
24
8
88
84
72
45
Toluene
THF
DMMc
DMF
14
<5
<5
70
1,4-Dioxane
1,4-Dioxane
rt
50 ꢀC
24
23
a
Conditions: phenylboronic acid 1 equiv, chlorobenzene 1 equiv,
Pd2(dba)3 1.5 mol %, 7d 3.6 mol %, Cs2CO3 2 equiv, solvent.
Isolated yields.
b
c
It is interesting to note that 7b is the most active ligand in
palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-
propen-1-yl acetate with dimethyl malonate while 7c,d are
least active for this reaction.14 It is well known that the
14e L2Pd can ionize allyl acetates in allylic alkylation reac-
tions as indicated by many bidentate ligands in this applica-
tion; thus it is reasonable that 7b shows high activity in this
reaction. The reduced activity of 7c,d in allylic alkylation
was attributed to the difficulty for the substrates to access
palladium because of the bulkiness of the ligands. However,
it is not easy to understand why an LPd of 7c,d is more ste-
rically hindered than an L2Pd of 7b. One possibility is that
L2Pd of 7d predominates at room temperature, which was
the temperature we used for allylic alkylation reaction; it
can only dissociate to LPd complex with a reasonable rate
at elevated temperature and so can catalyze Suzuki–Miyaura
reaction of aryl chlorides. Another possibility is that the
mono-coordinated 12e LPd complex is less active than the
14e L2Pd in allylic alkylation reactions.
DME, dimethoxyethane; DMM, dimethoxymethane.
electron-neutral chlorobenzene was used as the substrate,
there was virtually no conversion in 24 h (entry 7). At
50 ꢀC, the reaction proceeded but at much slower rate; after
23 h, an isolated yield of only 70% was obtained (entry 8).
We also tested to pre-form the ligand–palladium complex
at elevated temperature in 1,4-dioxane and then perform the
reaction at room temperature, the reaction did not proceed.
2.2. Comparison of the activity of the four benzoferro-
cenyl phosphine ligands
After the suitable conditions for the cross-coupling reaction
were identified, we next set up to compare the activities of the
four benzoferrocenyl ligands (7a–d). Phenylboronic acid
and the electron-rich 4-chlorotoluene were chosen as sub-
strates. Under the optimized conditions shown in Table 3,
when 7a was used as ligand, only 15% yield of the biaryl
product was obtained (Table 3, entry 1). Ligand 7b was
also found not suitable for the reaction, even after 15 h,
the yield of biaryl product was less than 5% (entry 2). How-
ever, under the same conditions, ligand 7c gave very good re-
sults, within 1 h, the reaction was nearly completed and an
isolated yield of 79% was obtained (entry 3). As expected,
best results were obtained when 7d was used as the ligand
for the reaction; 100% conversion was realized within 1 h
and the isolated yield of biaryl product was 92% (entry 4).
It was reported that the conjugated double bonds in benzo-
ferrocene could participate in hydrogenation15 and Diels–
Alder16 reactions under certain conditions due to the reduced
aromaticity of the benzene ring of the indene moiety. Keep-
ing this information in mind during our investigation, we
were trying to observe if our ligands (7a–d) could participate
in Heck reaction as an alkene. Under all reaction conditions
we studied, no product arising from this reaction was de-
tected. This may be attributed to the partial aromatic nature
of the conjugated double bonds and the steric hindrance of
the ligands.
The above results are consistent with the theory that
electron-rich bulky ligands favor oxidative addition of
2.3. Substrate scope studies
Table 3. Comparison of benzoferrocenyl ligands in Suzuki–Miyaura
coupling of aryl chloridesa
Under optimized conditions (see Table 4 and Section 4)
using 7d as the supporting ligand, a wide range of aryl chlo-
rides can be coupled with various arylboronic acids. Table 4
shows substrates without any substituent in the ortho posi-
tions of the chlorides and boronic acids, this excludes steric
effect on the reaction allowing electronic effects to be stud-
ied separately. For the nucleophilic partner of the reaction,
both electron-neutral and -rich arylboronic acids coupled
with phenyl chloride with high efficiency (entries 1–3); but
when the electron-poor 4-fluorophenylboronic acid was
used, lower yield was obtained (entry 4). As to the electro-
philic reaction partner, electron-poor aryl chlorides gave
best results; in all of the examples, quantitative isolated
CH3
B(OH)2
CH3
+
Cl
Entry
Ligand
Time (h)
Yieldb (%)
1
2
3
4
7a
7b
7c
7d
1
15
1
15
<5
79
1
92
a
Conditions: phenylboronic acid 1 equiv, 4-chlorotoluene 1 equiv,
Pd2(dba)3 1.5 mol %, ligand 3.6 mol %, Cs2CO3 2 equiv, 1,4-dioxane,
reflux.
Isolated yields.
b

6882
M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
Table 4. Suzuki–Miyaura coupling of unhindered substratesa
Entry
1
Aryl chloride
Boronic acid
Product
Yieldb (%)
88
Reference
17
Cl
B(OH)2
2
95
18
Cl
H3C
B(OH)2
CH3
3
4
85
72
18
19
Cl
Cl
H3CO
F
B(OH)2
B(OH)2
OCH3
F
NC
CN
5
98
20
B(OH)2
Cl
6
7
8
96
99
98
20
20
20
CN
NC
Cl
B(OH)2
B(OH)2
B(OH)2
OHC
OHC
Cl
CHO
CHO
Cl
9
98
99
19
19
N
Cl
B(OH)2
B(OH)2
NO2
NO2
O2
O
2N
10
Cl
CH3
H3C
11
12
89
92
18
18
B(OH)2
B(OH)2
Cl
H3C
H3CO
Cl
CH3
OCH3
13
14
92
68
18
18
B(OH)2
B(OH)2
Cl
H3CO
Cl
OCH3
OCH3
H3CO
97c
21
Cl
15
B(OH)2
OCH3
H3CO
Cl
N
16
17
18
19
20
89
98
23
40
20
22
22
23
24
23
B(OH)2
B(OH)2
B(OH)2
N
Cl
N
N
S
S
Cl
S
S
B(OH)2
B(OH)2
Cl
Cl
S
S
(continued)

M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
6883
Table 4. (continued)
Entry
Aryl chloride
Boronic acid
Product
Yieldb (%)
60
Reference
17
O
B
O
21
Cl
a
Conditions: aryl chloride 1 equiv, arylboronic acid 1 equiv, Pd2(dba)3 1.5 mol %, 7d 3.6 mol %, Cs2CO3 2 equiv, 1,4-dioxane, reflux, 1 h.
Isolated yield.
Yield after 6 h; at 1 h, 86% conversion shown by GC.
b
c
yields were obtained within 1 h (entries 5–10). For electron-
challenging.6c Table 5 shows our results on this study. Under
optimized reaction conditions using 7d as ligand, arylboronic
acids with one ortho substituent all coupled with chloroben-
zene with high efficiency, isolated yields ranging from 76%
to 92% were obtained (Table 5, entries 1–5). With an ortho
substituent on aryl chlorides, the reaction is even better and
higher yields were obtained (entries 6–9); in these examples,
electron-poor chlorides gave better results than electron-rich
ones, which are consistent with our observation in studies on
electronic effects. When the di-ortho substituted 2-chloro-
1,3-dimethylbenzene was used, although the isolated yield
was lower than those obtained with unhindered substrates,
it was still high (78%, entry 10). However, when di-ortho
substituted boronic acids were used, only traces of products
could be isolated (entries 11 and 12). These observations in-
dicate that oxidative addition may not be the rate-limiting
step under our reaction conditions at least when hindered
substrates are involved, even though the aryl chloride used
here is electron-rich and is normally considered challenging
for activation. Instead, the rate-controlling step is more likely
to be transmetallation of boronic acid to palladium.
rich aryl chlorides, some of them gave excellent yields
within 1 h (entries 11–13) but for some other substrates,
longer reaction time was needed to achieve quantitative
conversion (compare entry 14 with 15).
We next investigated the coupling of heteroaromatic chlo-
rides with arylboronic acid under our reaction conditions
using 7d as ligand. As shown in Table 4, for both 2- and
3-chloropyridines coupled with phenylboronic acid with
high efficiency, excellent isolated yields were obtained
within 1 h (entries 16 and 17). However, coupling of chloro-
thiophenes with phenylboronic acid was much less effec-
tive (entries 18 and 19). The 2-thienylboronic acid and
phenylboronic acid pinacol ester were also found to be less
efficient coupling partners of this reaction under our condi-
tions (entries 20 and 21).
It is well known that Suzuki–Miyaura coupling reaction
is sensitive to steric hindrance of substrates and synthesis
of highly hindered biaryls using this method remains
Table 5. Suzuki–Miyaura coupling of substrates with one or more ortho substituentsa
Entry
Aryl chloride
Boronic acid
Product
Yieldb (%)
80
Reference
18
CH3
H3C
1
Cl
B(OH)2
Ph
Ph
2
83
25
Cl
B(OH)2
B(OH)2
3
4
5
92
82
76
26
18
27
Cl
Cl
Cl
OCH3
H3CO
F
B(OH)2
F
B(OH)2
OCH3
Cl
H3CO
NC
6
7
84
94
18
28
B(OH)2
B(OH)2
CN
Cl
(continued)

6884
M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
Table 5. (continued)
Entry
Aryl chloride
NO2
Boronic acid
Product
Yieldb (%)
99
Reference
19
O2N
8
B(OH)2
Cl
CHO
Cl
OHC
H3C
9
99
78
28
22
B(OH)2
B(OH)2
CH3
Cl
10
CH3
H3C
H3C
CH3
B(OH)2
11
12
<5
<5
22
29
Cl
Cl
CH3
H3C
H3CO
OCH3
B(OH)2
OCH3
H3CO
CH3
CH3
CH3
Cl
CH3
13
14
15
57
33
61
29
—
29
B(OH)2
CH3
CH3
H3C
CH3
CH3
Ph
Ph
Cl
B(OH)2
CH3
CH3
Cl
H3C
B(OH)2
B(OH)2
CH3
H3C
CH3
Cl
CH3
16
72c
29
CH3
H3C
a
Conditions: aryl chloride 1 equiv, arylboronic acid 1 equiv, Pd2(dba)3 1.5 mol %, 7d 3.6 mol %, Cs2CO3 2 equiv, 1,4-dioxane, reflux, 1 h.
Isolated yield.
Catalyst loading was reduced to Pd2(dba)3 0.75 mol %, 7d 1.8 mol %.
b
c
Because the oxidative addition is less sensitive to steric hin-
1–5 were not used to synthesize tri-ortho substituted bi-
aryls;9–12 6 was used for such a purpose, but long reaction
time (24 h) and high temperature (100 ꢀC) were needed,
and only two examples were given;13 and when 3 and 5
were applied for coupling electron-rich aryl chlorides,
much lower yields (less than 60%) were obtained.10b,12
However, some non-ferrocene-based ligands gave better re-
sults than ligand 7d on certain substrates.6
drance than transmetallation under our reaction conditions,
we next tested to synthesize the more challenging tri-ortho
substituted biaryls from di-ortho substituted aryl chlorides
(as opposed to from di-ortho substituted arylboronic acids).
As shown in Table 5, the isolated yield ranged from moder-
ate to good within 1 h (entries 13–15); extending the reaction
time to 24 h did not increase the yields significantly. It is re-
markable that under these conditions, the highly hindered
2,6-dimethyl-2-phenyl-1,10-biphenyl (entry 14), an un-
known compound, could be synthesized although in moder-
ate yield. We also challenged our reaction conditions by
lowering catalyst loading and using sterically hindered sub-
strates, the yield was not affected (entry 16). These results
are superior to those obtained with known ferrocene-based
catalysts discussed in Section 1.9–13 For example, ligands
Further challenges for Suzuki–Miyaura coupling that could
be overcome by our catalyst include the reaction of di-ortho
substituted aryl chlorides with di-ortho substituted arylboro-
nic acids to synthesize tetra-ortho substituted biaryls and
stereoselective coupling of aryl chlorides with alkenylboro-
nic acids to synthesize cis- and trans-vinylarenes. Because
under current reaction conditions, our catalytic system is

M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
6885
sensitive to the steric hindrance imposed by di-ortho
substituted boronic acids (see Table 5, entries 11 and 12),
the synthesis of tetra-ortho substituted biaryls was not pur-
sued. For stereoselective coupling of aryl chlorides with al-
kenylboronic acids, currently, there is no general efficient
protocol in literature;30 under reported conditions, alkene
isomerization is unavoidable and mixtures of cis- and
trans-vinylarenes are obtained.6c,31 Our preliminary studies
on coupling of aryl chlorides with cis- and trans-alkenylbor-
onic acids have shown that this challenge can be overcome
using the current catalytic protocol; a systematic study is un-
der way and results will be reported separately.
solvent (1,4-dioxane, dimethoxyethane, toluene or THF) or
an anhydrous solvent from commercial source (dimethoxy-
methane or DMF) was added to both flasks via oven-dried
syringes. Aryl chloride was added to the two-necked
round-bottomed flask via syringe if it is a liquid; otherwise,
it was dissolved in the same solvent for the reaction in an-
other round-bottomed flask and added to the two-necked
flask via a cannula. Finally, the ligand solution was added
to the two-necked flask via a cannula. The reaction mixture
was then heated to specific temperature (see Tables 1–5) and
the reaction was occasionally monitored by TLC and/or GC–
MS (but the reaction time was not minimized). After specific
time as indicated in Tables 1–5, the mixture was cooled to
room temperature gradually under nitrogen and filtered
through a pack of CeliteÒ 545, which was washed thoroughly
with Et2O. The filtrate and the washing solvent were com-
bined and evaporated to dryness under reduced pressure.
The product was then purified by flash column chromato-
graphy. All products in this study are known (references
3. Conclusion
In conclusion, we have shown that the benzoferrocenyl
phosphine ligand 7d is highly active for Suzuki–Miyaura
coupling of aryl chlorides with arylboronic acids. Under op-
timized conditions, a wide range of aryl chlorides including
the challenging electron-rich and sterically hindered ones
were coupled with arylboronic acids with high efficiency
within short reaction time. The catalytic system is also effi-
cient for the stereoselective coupling of aryl chlorides with
alkenylboronic acids, results on which will be reported
shortly. Our future studies include tuning ligand structure
to improve catalyst activity, applying this new class of li-
gands in other reactions as well as the synthesis of enantio-
pure benzoferrocenyl ligands for enantioselective catalysis.
1
are given in Tables 4 and 5) and were identified by H and
13C NMR and GC–MS except 2,6-dimethyl-2-phenyl-1,10-
biphenyl (Table 5, entry 14), which is characterized below.
4.2.1. Analytical data for 2,6-dimethyl-2-phenyl-1,10-bi-
phenyl. Colorless oil; 1H NMR (400 MHz, CDCl3)
d 7.53–7.51 (m, 1H), 7.48–7.41 (m, 2H), 7.22–7.08 (m,
7H), 7.00 (d, J¼8.0 Hz, 2H), 1.98 (s, 6H); 13C NMR
(400 MHz, CDCl3) d 141.6, 141.1, 141.0, 139.2, 136.3,
130.6, 130.4, 129.0, 127.9, 127.7, 127.6, 127.4, 127.2,
126.8, 21.1; EI-MS Calcd for C20H18 (m/z) [M+] 258, found
258; Anal. Calcd for C20H18: C 92.98, H 7.02; found: C
92.99, H 7.40.
4. Experimental
4.1. General
Acknowledgements
All reactions were performed under a nitrogen atmosphere
using standard Schlenk techniques. Reagents and solvents
available from commercial sources were used as received
unless otherwise noted. 1,4-Dioxane and THF were distilled
from Na/benzophenone ketyl. Toluene and dimethoxyethane
were distilled over CaH2. 1H and 13C NMR were measured
on a Varian UNITY INOVA spectrometer at 400 MHz.
GC–MS were measured on GCMS-QP5050A, Shimadzu;
column, DB-5MS, 0.25 mm thickness, 0.25 mm diameter,
25 m length; MS, positive EI.
Financial support from Department of Chemistry, Michigan
Tech; a Research Seed Award from Michigan Tech Research
Excellence Fund; and the assistance from Mr. Jerry L. Lutz
(NMR), Mr. Shane Crist (computation) and Mr. Dean W.
Seppala (electronics) are gratefully acknowledged. The au-
thors also thank NSF for an equipment grant (CHE-
9512445).
References and notes
4.2. General procedure for Suzuki–Miyaura
coupling of aryl chlorides
1. (a) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2097–2152; (b) Baudoin, O.
Eur. J. Org. Chem. 2005, 4223–4229; (c) Bringmann, G.;
Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384–5427;
(d) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197–3210.
2. (a) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133–173; (b)
Kosugi, M. Organomet. News 2006, 75–78; (c) De Souza,
M. V. N. Curr. Org. Synth. 2006, 3, 313–326.
3. Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic,
M. D.; Stanetty, P. Eur. J. Org. Chem. 2006, 3283–3307.
4. Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651–2710.
5. Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020–4028.
A two-necked round-bottomed flask with a magnetic stirring
bar and a reflux condenser was dried in an oven and con-
nected to nitrogen through a double bank inert gas/vacuum
manifold and cooled to room temperature. Arylboronic
acid (for quantities of materials, see Tables 1–5 and their
footnotes), Pd2(dba)3, and a base were added under positive
nitrogen pressure. The flask with the condenser was
switched from nitrogen to vacuum by turning the double ob-
lique hollow glass plug of the manifold and remained under
vacuum for about 10 min and then turned back to nitrogen
carefully. The benzoferrocenyl phosphine ligand in a one-
necked round-bottomed flask was dried under vacuum over-
night and the flask was then filled with nitrogen carefully and
remained under a nitrogen atmosphere. A freshly distilled
6. (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722–9723; (b) Wolfe, J. P.; Singer, R. A.;
Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,

6886
M. Thimmaiah, S. Fang / Tetrahedron 63 (2007) 6879–6886
9550–9561; (c) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
16. Wang, B. Q.; Mu, B.; Chen, D.; Xu, S. S.; Zhou, X. Z.
Organometallics 2004, 23, 6225–6230.
17. Nising, C. F.; Schmid, U. K.; Nieger, M.; Brase, S. J. Org.
Chem. 2004, 69, 6830–6833.
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696;
(d) Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed.
2005, 44, 6173–6177.
7. (a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X. H.;
Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen,
R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8,
1787–1789; (b) Liu, D.; Gao, W. Z.; Dai, Q.; Zhang, X. M.
Org. Lett. 2005, 7, 4907–4910; (c) Zapf, A.; Jackstell, R.;
Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann, C.;
Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun.
2004, 38–39; (d) Dai, Q.; Gao, W. Z.; Liu, D.; Kapes, L. M.;
Zhang, X. M. J. Org. Chem. 2006, 71, 3928–3934.
8. Allenmar, S. Tetrahedron Lett. 1974, 15, 371–374.
9. Liu, S. Y.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 2408–
2409.
10. (a) Roca, F. X.; Richards, C. J. Chem. Commun. 2003, 3002–
3003; (b) Pickett, T. E.; Richards, C. J. Tetrahedron Lett.
2001, 42, 3767–3769.
11. Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org.
Chem. 2002, 67, 5553–5566.
18. Stevens, P. D.; Fan, J. D.; Gardimalla, H. M. R.; Yen, M.; Gao,
Y. Org. Lett. 2005, 7, 2085–2088.
19. Li, J. H.; Liu, W. J. Org. Lett. 2004, 6, 2809–2811.
20. Tao, B.; Boykin, D. W. J. Org. Chem. 2004, 69, 4330–4335.
21. Ackermann, L.; Althammer, A. Org. Lett. 2006, 8, 3457–3460.
22. Su, W. P.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2004, 6,
1421–1424.
23. Xiong, Z. C.; Wang, N. D.; Dai, M. J.; Li, A.; Chen, J. H.; Yang,
Z. Org. Lett. 2004, 6, 3337–3340.
24. Su, W.; Urgaonkar, S.; McLaughlin, P. A.; Verkade, J. G. J. Am.
Chem. Soc. 2004, 126, 16433–16439.
25. Dong, C. G.; Hu, Q. S. J. Am. Chem. Soc. 2005, 127, 10006–
10007.
26. Cella, R.; Cunha, R. L. O. R.; Reis, A. E. S.; Pimenta, D. C.;
Klitzke, C. F.; Stefani, H. A. J. Org. Chem. 2006, 71, 244–250.
27. Liang, L. C.; Chien, P. S.; Huang, M. H. Organometallics 2005,
24, 353–357.
12. Hierso, J. C.; Fihri, A.; Amardeil, W.; Meunier, P.
Organometallics 2003, 22, 4490–4499.
28. Mino, T.; Shirae, Y.; Sakamoto, M.; Fujita, T. J. Org. Chem.
2005, 70, 2191–2194.
13. (a) Baillie, C.; Zhang, L. X.; Xiao, J. L. J. Org. Chem. 2004, 69,
7779–7782; (b) Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5,
3025–3028.
14. Thimmaiah, M.; Luck, R. L.; Fang, S. J. Organomet. Chem.
2007, 692, 1956–1962.
15. King, R. B.; Bisnette, M. B. Inorg. Chem. 1964, 3, 796–800.
29. Song, C.; Ma, Y. D.; Chai, Q.; Ma, C. Q.; Jiang, W.; Andrus,
M. B. Tetrahedron 2005, 61, 7438–7446.
30. Denmark, S. E.; Kallemeyn, J. M. J. Am. Chem. Soc. 2006, 128,
15958–15959.
31. Navarro, O.; Marion, N.; Mei, J. G.; Nolan, S. P. Chem.—
Eur. J. 2006, 12, 5142–5148.