Air-stable and catalytically active phosphinous acid transition-metal complexes

Article abstract of DOI:10.1021/om200697u

Secondary phosphane oxides R₂P(O)H are most frequently used as preligands for phosphinous acid R₂POH (R = alkyl, aryl) transition-metal complexes, which are very efficient catalysts for cross-coupling reactions. To investigate the influence of electron-deficient substituents on the catalytic activity, the coordination properties of bis(trifluoromethyl)-, bis(pentafluoroethyl)-, and bis[2,4-bis(trifluoromethyl) phenyl]phosphinous acid toward catalytically relevant metals, such as palladium and platinum, are studied. The novel phosphinous acid palladium complexes reveal a high catalytic activity in Heck and Suzuki cross-coupling reactions. Because of the strong dependence of these processes on the reaction conditions, a systematic solvent and base screening with 1-bromo-3-fluorobenzene and phenyl boronic acid as model reactants is performed. The most efficient solvent/base system consists of 2-propanol and potassium phosphate, providing a full conversion and a TON of around 10 000 after 20 h at room temperature with a catalyst loading of 0.01 mol % palladium. A catalyst loading of only 0.004 mol % palladium still leads to a nearly full conversion after 20 h at room temperature. During the catalytic reaction, the formation of the corresponding phosphinic acid R₂P(O)OH is observed. Further investigations lead to the conclusion that palladium nanoparticles represent the catalytically active species. We also succeeded in the generation of palladium nanoparticles, which exhibit an extremely high catalytic activity in Suzuki cross-coupling reaction with TONs over 60 000 and TOFs larger than 40 000.

Full text of DOI:10.1021/om200697u

ARTICLE
pubs.acs.org/Organometallics
Air-Stable and Catalytically Active Phosphinous Acid Transition-Metal
Complexes
‡
†
,‡
Boris Kurscheid, Lhoussaine Belkoura, and Berthold Hoge*
†
Department f €u r Chemie der Universit €a t zu K €o ln, Luxemburger Str. 116, 50939 K €o ln, Germany
‡
Fakult €a t f €u r Chemie, Anorganische Chemie, Universit €a t Bielefeld, Universit €a tsstr. 25, 33615 Bielefeld, Germany
ABSTRACT: Secondary phosphane oxides R P(O)H are most fre-
2
quently used as preligands for phosphinous acid R POH (R = alkyl,
2
aryl) transition-metal complexes, which are very efficient catalysts for
cross-coupling reactions. To investigate the influence of electron-
deficient substituents on the catalytic activity, the coordination proper-
ties of bis(trifluoromethyl)-, bis(pentafluoroethyl)-, and bis[2,4-bis(trifluoromethyl)phenyl]phosphinous acid toward catalytically
relevant metals, such as palladium and platinum, are studied. The novel phosphinous acid palladium complexes reveal a high catalytic
activity in Heck and Suzuki cross-coupling reactions. Because of the strong dependence of these processes on the reaction
conditions, a systematic solvent and base screening with 1-bromo-3-fluorobenzene and phenyl boronic acid as model reactants is
performed. The most efficient solvent/base system consists of 2-propanol and potassium phosphate, providing a full conversion and
a TON of around 10 000 after 20 h at room temperature with a catalyst loading of 0.01 mol % palladium. A catalyst loading of only
0
.004 mol % palladium still leads to a nearly full conversion after 20 h at room temperature. During the catalytic reaction, the
formation of the corresponding phosphinic acid R P(O)OH is observed. Further investigations lead to the conclusion that
2
palladium nanoparticles represent the catalytically active species. We also succeeded in the generation of palladium nanoparticles,
which exhibit an extremely high catalytic activity in Suzuki cross-coupling reaction with TONs over 60 000 and TOFs larger than
4
0 000.
1
1,7
’
INTRODUCTION
Although there are a variety of phosphorus ligands available,
in solution, a solvent-dependent equilibrium is observed.
8
1ꢀ3
An increasing donor number of the chosen solvent leads to an
increasing amount of the corresponding phosphinous acid
tautomer.
the motivation to design new ligands strongly depends on the
industrial demand for economical and robust, air-stable ligands for
complexes with a high catalytic activity. Commonly used complexes,
such as [Pd(PPh ) ], are highly air- and moisture-sensitive. Phos-
phane ligands, such as tri-tert-butylphosphane, P(t-Bu) , are extre-
mely efficient, but pyrophoric. Because of the air sensitivity of many
9
On the basis of the working hypothesis of Suzuki, the catalytic
cycle of cross-coupling reactions is divided into three steps. The
kinetics of each step is strongly influenced by the electronic
nature of the chosen ligands. As demonstrated by Roddick and
3
4
3
10
co-workers, an increasing electron-withdrawing effect of phos-
phane ligands leads to an acceleration of the reductive elimina-
tion step. The diphenylphosphane complex shown in eq 2
liberates biphenyl only at temperatures above 150 °C, whereas
the introduction of electron-withdrawing groups effects a re-
duced decomposition temperature and, therefore, an acceleration
of the reductive elimination step. The pentafluoroethyl-substi-
tuted complex already decomposes below room temperature.
Therefore, the question arises if transition-metal complexes of
electron-deficient phosphinous acids may exhibit an increased
catalytic activity in cross-coupling reactions.
phosphane ligands, the usage of secondary phosphane oxides
1,3
(SPOs), so-called preligands, is getting more and more popular.
Pentavalent phosphane oxides R P(O)H are related to trivalent
2
phosphinous acids R P-OH by a tautomerization process. For
2
electron-donating alkyl and aryl groups, the tautomeric equilibrium
is completely shifted to the side of the phosphane oxide (cf. eq 1).
Chatt and Heaton demonstrated in 1968 that this equilibrium can
be shifted completely to the side of the phosphinous acid by
4
coordination to suitable transition-metal complexes (cf. eq 1). In
recent years, the development of new secondary phosphane oxides
progressed and the related phosphinous acid complexes are active
1,3
catalysts in many cross-coupling reactions.
Another possibility to stabilize the unusual form of the phos-
phinous acid is the introduction of electron-withdrawing sub-
stituents, such as trifluoromethyl and pentafluoroethyl groups.
Special Issue: Fluorine in Organometallic Chemistry
5,6
The employment of less electron-withdrawing perfluoroaryl
Received: July 28, 2011
groups leads to the phosphane oxide in the solid state, whereas
Published: October 14, 2011
r 2011 American Chemical Society
1329
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|Organometallics 2012, 31, 1329–1334

Organometallics
ARTICLE
a,b
Scheme 1. Results of Heck Cross-Coupling Reactions
Scheme 2. Solvent and Base Screening with Juliphos 2 and
Bophos 3
a
19
b
Determined via integration of the F NMR resonances. Palladium
ligand ratio of 1:2.
’
RESULTS AND DISCUSSION
One of the most popular and industrially relevant reactions is
the Suzuki cross-coupling. The success of this conversion
strongly depends not only on the catalyst but also on the reaction
conditions, such as temperature, solvent, and base. Therefore, a
systematic solvent and base screening of the test system with
1-bromo-3-fluorobenzene and phenyl boronic acid is performed
at first (cf. Scheme 2). The advantage of the fluorinated benzene
derivative again is the possibility to measure the conversion rate
by F NMR spectroscopy. The solvent and base screening is
performed with 1.40 mol % Juliphos 2, which equals 2.80 mol %
palladium, leading to six base/solvent combinations with a full
conversion after 20 h at room temperature (Scheme 2). Beside
the solvent and base systems depicted in Scheme 2, additionally
carbonates, hydrocarbonates, hydrophosphates, amines, and
sodium tert-butanolate are tested with Juliphos 2 as well as
Bophos 3 in THF solution. All systems led to a conversion rate of
less than 10%. Further investigations with a lower catalyst loading
of 0.35 mol % Juliphos 2 (0.70 mol % palladium) prove the
combination of 2-propanol as a solvent and potassium phosphate
as a base to be the most efficient system. The identically
performed solvent and base screening using 1.34 mol % Bophos
In contrast to previous work in other work groups, we are
interested in the catalytic activity of transition-metal complexes
bearing electron-deficient phosphinous acids (R ) P-OH. The
reaction of (CF ) P-OH, (C F ) P-OH, and [2,4-(CF ) C H ] -
P(O)H with a slight excess of palladium dichloride initially yields
the mononuclear complexes [PdCl {(R) POH} ], which easily con-
dense to neutral dinuclear complexes [Pd (μ-Cl) {[(R) PO] H} ]
with R = CF (1), C F (2), and 2,4-(CF ) C H (3) under
liberation of HCl.
f 2
3
2
2 5 2
3 2 6 3 2
2
f 2
2
2
2
f 2
2
2
19
f
3
2
5
3 2 6 3
1
1,12
The selective synthesis of a mononuclear
palladium complex can be achieved by reacting bis(pentafluoro-
ethyl)phosphinous acid with palladium bis(hexafluoroacetyl-
acetonate), yielding 4.
12
3
(2.68 mol % palladium) also highlights the combination of
2
-propanol as a solvent and potassium phosphate as a base as the
most efficient system.
The catalytic activity of the synthesized complexes 1ꢀ4 is
tested in Heck cross-coupling reactions with the model system
consisting of n-butyl acrylate and 1-bromo-2-fluorobenzene (cf.
Scheme 1). The advantage of fluorinated benzene derivatives is
the possibility to determine the conversion rate by F NMR
spectroscopy.
After optimizing the reaction conditions, the next logical step
is the systematic test of the limiting catalyst loading with 1ꢀ4.
The stepwise reduction of the catalyst loading to 0.01 mol %
palladium affords a nearly full conversion with TONs of around
10 000 after 20 h at room temperature (Scheme 3). The high
catalytic activity is illustrated with 0.002 mol % Juliphos 2 (0.004
mol % palladium), also leading to a nearly quantitative conver-
sion with a TON of 24 500 (cf. Scheme 3).
19
Using a catalyst loading of 0.0078 mol % palladium, which
equals a loading of 0.0034 mol % Bophos 3, leads after 48 h at
1
aꢀg
1
35 °C to a turnover number (TON) of 7436. The complexes 2
These results are compared with the air-sensitive catalyst
consisting of Pd (dba) and P(t-Bu) , which, under identical
conditions, only has a conversion rate of 55.0%. It is interesting
that Pd (dba) alone leads to an increased conversion rate of
and 4 exhibit a slightly lower catalytic activity with TONs of 6958
and 6564, respectively (cf. Scheme 1). The air-sensitive catalyst
designed from Pd (dba) (dba = dibenzylideneacetone) and tri-tert-
2
3
3
1aꢀg
2
3
2
3
butylphosphane leads under the same conditions to a TON of 6900.
These results indicate the high catalytic activity of the air-stable
palladium complexes 2ꢀ4 with electron-deficient phosphinous
acids as ligands.
78.0% (cf. Scheme 3). Attempted Suzuki cross-couplings in the
absence of palladium failed.
It is noteworthy that complexes 1ꢀ4 can be handled in the air
for a few minutes, and in the case of Bophos 3, it is even possible
1
330
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Organometallics
ARTICLE
Scheme 3. Reduced Catalyst Loading in Suzuki Cross-
a
Coupling Reaction
Figure 1. TEM imaging of the Pd nanoparticles 5 in the parent solution
after 8 days: measured points, 41; average, 4.81 nm; min, 3.08 nm; max,
6.58 nm; standard degression, 0.93 nm.
relevance. It does influence, however, the redox reaction of the
phosphinous acid complexes into the phosphinic acid and the
catalytically active palladium species.
In the literature exist several reports with palladium nanopar-
13
ticles as catalysts in cross-coupling reactions. One synthetic
route to generate catalytically active palladium nanoparticles is
based on the treatment of a suspension of palladium acetate or
sodium tetrachloropalladate with polyethylene glycol (PEG)
a
19
Determined via integration of the F NMR resonances.
1
3
with an average molecular weight of around 400 Da. As our
most efficient catalytic system contains 2-propanol as a solvent, it
is conceivable to generate palladium nanoparticles solely by
contact of palladium dichloride with this alcohol. Stirring a palla-
dium dichloride suspension in 2-propanol leads, after several days
at room temperature, to an intensive red solution. To investigate
the progress of this reaction from a palladium dichloride suspen-
sion in 2-propanol, aliquots are taken every 2 days and its palla-
dium content isdetermined, afterfiltration througha 0.45μm filter
disk, via atom absorption spectroscopy (AAS). After 16 days,
nearly 70% of the starting palladium dichloride has been trans-
formed into dispersed palladium nanoparticles 5. Transmission
electron microscopy (TEM) proved the formation of palladium
nanoparticles, 5, with a diameter of 3ꢀ5 nm (cf. Figure 1).
To demonstrate the catalytic activity of the so generated nano-
particles 5, a Suzuki cross-coupling reaction using the optimized
reaction conditions given in eq 4 was conducted. The stepwise
reduction of the catalyst loading to 0.0014 mol % palladium leads to
a conversion rate of 86% with a TON of 61 400 and a TOF of 49 100
after 75 min (cf. eq 4 and Scheme 3). The high catalytic activity of
the nanoparticles 5 in solution is maintained for at least 2 months
when stored under nitrogen in the absence of light.
Scheme 4. Three Consecutive Runs of the Suzuki Reaction
Using a Single Catalyst Loading of Juliphos 2 of 0.7 mol % Pd
a
a
19
Determined via integration of the F NMR resonances.
to store the catalyst for at least 2 years under nitrogen without
loss of its activity.
19
F NMR spectroscopic investigations of the Suzuki reaction
with 2 reveal a decomposition of the complex to the correspond-
ing phosphinic acid (C F ) P(O)OH (cf. eq 3) and a new
2
5 2
palladium species [Pd].
The slow formation of nanoparticles 5 can also be illustrated by an
increased conversion with time. The use of palladium dichloride as a
catalyst (0.2 mol % palladium) leads, after 20 h at room temperature,
to a conversion rate of only 13%. A prolongation of the reaction time
up to 24 and 26 h leads to significantly increased conversion rates of
This palladium species [Pd] is still catalytically active. When
an additional amount of 1-bromo-3-fluorobenzene, phenylboro-
nic acid, and base is added to the reaction mixture, a complete
conversion occurs within 20 h at room temperature. Even a third
run in the system with 2-propanol and potassium phosphate
yields an overall conversion rate of 91% (cf. Scheme 4).
6
3% and 93%, respectively. The increased catalytic activity agrees with
the generation of highly active palladium nanoparticles.
’
FURTHER CROSS-COUPLING REACTIONS
From the formation of a noncoordinating phosphinic acid
(
Rf)2P(O)OH, it is clear that the electronic nature of the
The Suzuki cross-coupling is an important step in the indus-
trial synthesis of a variety of products, for example, the angiotensin II
substituents R of the phosphinous acids is of no catalytic
f
1
331
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Organometallics
Table 1. Synthesis of 4 -Methyl-biphenyl-2-carbonitrile
ARTICLE
0
The catalysts 2 and 3 were used under the conditions of the
optimized Suzuki cross-coupling protocol for the synthesis
of partly fluorinated biphenyls (cf. Table 2). The prod-
uct resulting from the coupling of bromopentafluoroben-
zene and 4-fluorophenylboronic acid, 2,3,4,4 ,5,6-hexafluoro-
biphenyl, was fully characterized by a single-crystal structure
(cf. eq 5) by Suzuki Cross-Coupling
a
catalyst
catalyst loading [mol % pd]
yield [%]
TON
0
Bophos, 3
0.0035
0.0035
86.4
83.9
24 685
23 971
Nadiphos II, 4
GC-MS yield.
1
6
a
analysis.
’
CONCLUSION
Table 2. Suzuki Cross-Coupling Reaction of Fluorinated Aryl
Bromides and Boronic Acids under Standard Conditions,
Using 1.34 mol % Bophos 3 (2.68 mol % Palladium)
The phosphinous acid palladium complexes 1ꢀ4 exhibit a
a,b,c,d,e
high catalytic activity with a short activation time in Heck as well
as in Suzuki cross-coupling reactions. The air-stable complexes
are obtained in very good yields on a gram scale. Complex 3 can
be stored under nitrogen for at least 2 years without loss of
catalytic activity.
These complexes, however, are not the catalytically active
species. During the catalytic process, the formation of the
corresponding phosphinic acids (R ) P(O)OH is observed.
f 2
Thereby, colloidal palladium is generated, which maintains its
catalytic activity even after three consecutive runs. From the
formation of a noncoordinating phosphinic acid (R ) P(O)OH,
f 2
it is clear that the electronic nature of the substituents R of the
f
phosphinous acids is of no catalytic relevance. It does influence,
however, the redox reaction of the phosphinous acid complexes
into the phosphinic acid and the catalytically active palladium
species.
We also succeeded in the development of a cost-efficient
synthesis of catalytically active palladium nanoparticles 5 with a
long shelf life and a convienent handling.
’
EXPERIMENTAL SECTION
All reactions are carried out under an atmosphere of dry nitrogen
using Schlenk techniques. Commercially available compounds are used
as purchased. All bases are dried in vacuum at 70 °C. The conversions are
monitored by NMR spectroscopy using a Bruker Model Avance III 300
a
Yield of the corresponding biphenyl determined via integration of the
1
9
b
31
19
13
1
F NMR resonances. Isolated yield; reaction conditions: Juliphos 2
spectrometer ( P, 111.92 MHz; F, 282.40 MHz; C, 75.47 MHz, H,
c
17
(
3.0mol %), K
2
CO
3
, THF, reflux 18 h. Side products 15% homocoupling
300.13 MHz) with positive shifts being downfield from the external
d
31
19
1
and 35% not identified. Side product pentafluorobenzene is obtained in a
4
3
standards (85% orthophosphoric acid ( P), CCl F ( F), and TMS ( H)).
e
6% yield. Side product pentafluorobenzene is obtained in a 48% yield.
The atom absorption spectroscopy (AAS) is performed with a Varian
SpectrAA 400 using Pd(NO ) in 0.5 mol/L HNO as a standard: air/
3
2
3
receptor antagonists used as a remedy for high blood pressure, such
acetylene flow, 3.5/1.5, manual/absorption; measurement time, 30 s;
stop after 30 s or 0.1% (standard and probe).
14
0
as Irbesartan (cf. eq 5). The intermediate 4 -methyl-biphenyl-
-carbonitrile can be synthesized by the reaction of 1-bromo-
-benzonitrile and p-toluene boronic acid (Table 1). Using a catalyst
2
2
EI/CI GC/MS spectra are recorded using a Varian Saturn II GC/MS
mass spectrometer equipped with an ion trap used with EI (70 eV) or CI
with internal ionization. The spectra are recorded and processed with
the Varian Saturn II Software Version 5.2 by the accumulation and
averaging of several single spectra for each GC peak using background
subtraction.
General Procedure for Heck Cross-Coupling Reaction, e.g.,
with Juliphos, 2. In a Schlenk tube, 2.70 g (21.0 mmol, 1.5 equiv) of
n-butyl acrylate and 2.91 g (21.0 mmol, 1.5 equiv) of potassium
carbonate are added to a solution of 2.45 g (14.0 mmol, 1.0 equiv) of
loading of 0.035 mol % palladium of 3and 4, TONs of around 24 000
after 20 h at room temperature are achieved (Table 2). Unfortu-
nately, a direct comparison of the results with 3and 4with other cata-
lysts is not possible because of the differences in the reaction condi-
15
tions (catalyst loading, temperatures, and microwave assistance).
1-bromo-2-fluorobenzene in 20 mL of DMF. After stirring for 120 min at
room temperature, 1.2 mg (0.84 μmol, 0.012 mol %) of [Pd (μ-Cl) -
2
2
{
2 5 2 2 2
[(C F ) PO] H} ], Juliphos 2, is added to the reaction mixture and
1
9
stirred at 135 °C for 24 h. After F NMR spectroscopic monitoring, the
solution is stirred for an additional 24 h at 135 °C. The NMR spectro-
scopic data of the isolated product are in good agreement with the
literaturedata. H NMR(300.13MHz, CDCl
1
1
8 1
2
3
): δ = 7.77 (d, J(H,H) =
2
6.2 Hz, 1H, C7-H), 7.48ꢀ7.03 (m, 4H, ArH), 6.49 (d, J(H,H) = 16.0 Hz,
3
3
1
H, C6-H), 4.18 (t, J(H,H) = 6.7 Hz, 2H, C4-H), 1.65 (tt, J(H,H) = 6.8,
1
332
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Organometallics
ARTICLE
3
3
6
0
.8 Hz, 2H, C3-H), 1.40 (qt, J(H,H) = 7.3, J(H,H) = 6.8 Hz, 2H, C2-H),
hexane and 100 mL of water, the organic layer is extracted three times
3
.92 (t, J(H,H) = 7.3 Hz, 3H, C1-H).
with brine (100 mL), dried over MgSO , and filtered off. The solvent is
4
0
removed in vacuum. 2.4 -Difluorobiphenyl (1.35 g) is obtained as a
colorless solid (70% yield, 7.0 mmol).
1
3
1
1
C{ H} NMR (75.47 MHz CDCl
3
): δ = 166.7 (s, C5), 161.3 (d, J(C,F) =
3
2
1
1
54.3 Hz, C9), 137.1 (d, J(C,F) = 3.0 Hz, C7), 131.5 (d, J(C,F) = 8.8 Hz),
28.9 (d, J(C,F) = 3.0 Hz), 124.3 (d, J(C,F) = 3.6 Hz), 122.5 (d, J(C,F) =
1.6 Hz, C8), 120.8 (d, J(C,F) = 6.5 Hz, C6), 116.1 (d, J(C,F) = 22.9 Hz,
2
4
2
1H NMR (600.13 MHz, CDCl
1H, H2), 7.25 (1H, H3), 7.45 (1H, H4), 7.57 (2H, H1 ), 7.18 (2H, H2 ).
3
): δ = 7.20 (1H, H1), 7.37
C10), 64.5 (s, C4), 30.7 (s, C3), 19.1 (s, C2), 13.9 (s, C1); an unam-
0
0
(
13
19
bigous assignment for C atoms (C11, C12, C13) could not be given.
NMR (282.40 MHz, CDCl
F
3
) ppm = ꢀ116.5 (s).
General Procedure for Suzuki Cross-Coupling Reaction,
Solvent, and Base Screening, e.g., with Juliphos, 2. A sample
of 0.17 g (1.0 mmol, 1.0 equiv) of 1-bromo-3-fluorobenzene and 0.64 g
(
0
2
3.0 mmol, 3.0 equiv) of potassium phosphate are added to a solution of
.18 g (1.5 mmol, 1.5 equiv) of phenylboronic acid in 10 mL of
-propanol. After stirring for 120 min at room temperature, 20 mg
13
1
1
0
C{ H} NMR (CDCl
3
, 75.4 MHz): δ = 162.5 (d, J(C,F) = 247.1 Hz, C4 ),
1
3
0
1
59.7 (d, J(C,F) = 247.5 Hz, C2), 131.8 (d, J(C,F) = 3.9 Hz, C1 ), 130.8 (d,
J(C,F) = 3.0 Hz, C6), 130.6 (d, J(C,F) = 2.9 Hz, C2 ), 129.1 (d, J(C,F) =
8.2 Hz, C4), 128.1 (d, J(C,F) = 13.4 Hz, C1), 124.4 (d, J(C,F) = 3.7 Hz, C5),
116.2 (d, J(C,F) = 22.6 Hz, C3), 115.4 (d, J(C,F) = 21.5 Hz, C3 ). F NMR
3
3
0
4
3
(14.8 μmol, 2.8 mol %) of [Pd
2 2 2 5 2 2 2
(μ-Cl) {[(C F ) PO] H} ], Juliphos 2,
2
is added and stirring is continued for 20 h. The conversion rate is
19
2
2
0
19
monitored by F NMR spectroscopy.
0
(
CDCl
3
, 282.40 MHz) ppm = ꢀ114.6 (m, F4 ), ꢀ118.1 (m, F2). Mass
Synthesis of 3-Fluorobiphenyl, e.g., with Juliphos, 2. Samples
of 12.27 g (70.15 mmol, 1.0 equiv) of 1-bromo-3-fluorobenzene and 44.69 g
+
spectrum (EI; 20 eV) {m/z (%) [assignment]}: 190 (100) [M ].
General Procedure for Further Suzuki Cross-Coupling
Reactions, e.g., Synthesis of 3,3 -Difluorobiphenyl. A 0.17 g
(210.50 mmol, 3.0 equiv) of potassium phosphate are added to a solution of
0
1
2
2.83 g (105.25 mmol, 1.5 equiv) of phenylboronic acid in 200 mL of
-propanol. After stirring for 240 min at room temperature, 2.112 mg
(
(
1.0 mmol, 1.0 equiv) portion of 1-bromo-3-fluorobenzene and 0.64 g
3.0 mmol, 3.0 equiv) of potassium phosphate are added to a solution
(14.8 μmol, 0.0021 mol%) of [Pd
2 2 2 5 2 2 2
(μ-Cl) {[(C F ) PO] H} ], Juliphos
of 0.21 g (1.5 mmol, 1.5 equiv) of phenylboronic acid in 25 mL of
2-propanol. After stirring for 120 min at room temperature, 30.0 mg
(
2
2
, is added and the reaction mixture is stirred at room temperature for
19
0 h. F NMR spectroscopic investigations show a quantitative trans-
0.027 μmol, 2.7 mol %) of Bophos 3 is added and the reaction mixture
formation. The NMR spectroscopic data of the isolated product are
1
9
19
1
is stirred at room temperature for 20 h. F NMR (282.40 MHz,
CDCl
F NMR Spectroscopic Data of 3,3 ,4 ,5 -Tetrafluorobiphenyl.
in good agreement with the literature data. H NMR (300.13 MHz,
CDCl
): δ = 7.67ꢀ7.61 (m, 2H, CH), 7.55ꢀ7.40 (m, 5H,CH), 7.40ꢀ
.35 (m, 1H, CH), 7.15ꢀ7.06 (m, 1H, CH). C{ H} NMR (75.47 MHz,
3
): δ = ꢀ112.7 (s).
3
1
3
1
19
0
0
0
7
1
3
19
CDCl
3
): δ = 163.2 (d, J(C,F) = 245.4 Hz), 143.5 (d, J(C,F) =
F NMR (282.40 MHz, CDCl ): δ = ꢀ112.7 (s,1F, F-3), ꢀ135.5 (m, 2F,
3
4
3
0 0
19
0
7
1
1
.6 Hz), 139.9 (d, J(C,F) = 2.2 Hz), 130.2 (d, J(C,F) = 8.3 Hz), 128.9 (s),
27.9 (s), 127.1 (s), 122.8 (d, J(C,F) = 3.4 Hz), 114.07 (d, J(C,F) = 21.8 Hz),
14.05 (d, J(C,F) = 20.9 Hz). F NMR (282.40 MHz, CDCl
F3 5 ), ꢀ162.3 (m, 1F, F4 ).
19
4
2
0
F NMR Spectroscopic Data of 3-Fluoro-3 -methoxybiphenyl.
2
19
3
) ppm = ꢀ113.1
F NMR (282.40 MHz, CDCl ): δ = ꢀ113.6 (s).
+
3
(
s). Mass spectrum (EI; 70 eV) {m/z (%) [assignment]}: 172 (100) [M] ; 154
19
F NMR Spectroscopic Data of 2,3,4,5,6-Pentafluorobiphenyl.
F NMR (282.40 MHz, CDCl
+
+
(
32) [C12
H
10] ; 152 (12) [M ꢀ HF] .
1
9
3
): δ = ꢀ134.4 (m, 2F, m-F), ꢀ156.9
General Procedure for the Isolation of the Coupling Products.
After F NMR spectroscopic investigations, the reaction mixture is
diluted with 40 mL of hexane and 50 mL of water. The organic layer is
extracted three times with brine (40 mL), dried over MgSO
off. The solvent is removed in vacuum.
Further Suzuki Cross-Coupling Reactions. Synthesis of 4 -
Methyl-biphenyl-2-carbonitrile. A 14.42 g (78.8 mmol, 1.0 equiv)
portion of 1-bromo-2-benzonitrile and 25.10 g (118.4 mmol, 1.5 equiv)
of potassium phosphate are added to a solution of 16.12 g (118.4 mmol,
2
19
(t, J(F,F) = 20.6 Hz, 1F, p-F), ꢀ163.3 (m, 2F, o-F). The NMR
spectroscopic data of the isolated product are in good agreement with
1
7
the literature data.
NMR Spectroscopic Data of 2,3,4,4 ,5,6-Hexafluorobiphenyl (6)
4
, and filtered
0
0
1.5 equiv) of p-toluene boronic acid in 150 mL of 2-propanol. After
stirring for 180 min at room temperature, 3.0 mg (1.38 μmol, 0.0035 mol %)
of Bophos 3 is added, and the reaction mixture is stirred at room tem-
1
perature for 20 h. The conversion rate is determined by GC-MS. H
1
NMR (300.13 MHz, CDCl
3
): δ = 7.80ꢀ7.75 (m, 2H, CH), 7.55ꢀ7.40
3
H NMR (300.13 MHz, CDCl ): δ = 7.44 (m, 2H, C2-H), 7.21 (m, 2H,
1
3
1
1
(
m, 1H), 7.67ꢀ7.62 (m, 1H), 7.56ꢀ7.40 (m, 4H), 7.35ꢀ7.30 (m, 2H),
3
C3-H). C{ H} NMR (75.47 MHz, CDCl ): δ = 163.3 (d, J(C,F) =
13
1
1
0
1
2
1
1
.45 (s, 3H, ꢀCH
3
). C{ H} NMR (75.47 MHz, CDCl
3
): δ = 145.5 (s),
249.8, C1), 143.8 (d, m, J(C,F) = 247.4 Hz, C2 ), 140.6 (d, m, J(C,F) =
254.1 Hz, C1 ), 137.9 (d, m, J(C,F) = 252.8 Hz, C3 ), 132.0 (d, J(C,F) =
8.4 Hz, C2), 122.3 (s, C4), 115.9 (d, J(C,F) = 22.1 Hz, C3), 114.9 (t, d
J(C,F) = 16.9 Hz, J(C,F) = 4 Hz, C4 ). F NMR (282.40 MHz, CDCl ):
0
1
0
3
38.7 (s), 135.3 (s), 133.7 (s), 132.8 (s), 130.0 (s), 129.5 (s), 128.6 (s),
27.3 (s), 118.9 (s), 111.2 (s), 21.3 (s).
2
0
2
0
19
Synthesis of 2,4 -Difluorobiphenyl. A sample of 1.75 g (10 mmol,
3
0
2
1.0 equiv) of 1-bromo-4-fluorobenzene and 4.15 g (30 mmol, 3.0 equiv)
δ = ꢀ111.3 (s, F4 ), ꢀ143.3 (m, 2F, m-F), ꢀ155.2 (t, J(F,F) = 20.6 Hz,
1F, p-F), ꢀ162.0 (m, 2F, o-F). The NMR spectroscopic data of the isolated
potassium carbonate are added to a solution of 2.09 g (15 mmol, 1.5 equiv)
of 4-fluoro-phenylboronic acid in 20 mL of THF. After stirring for
1
7
product are in good agreement with the literature data. Mass spec-
+
15 min at room temperature, 0.21 g (0.15 mmol) of Juliphos 2 is added
trum (EI; 70 eV) {m/z (%) [assignment]}: 262 (100) [M] ; 242 (18)
[M ꢀ HF] ; 193 (8).
+
and the reaction mixture is refluxed for 18 h. After adding 200 mL of
1
333
dx.doi.org/10.1021/om200697u |Organometallics 2012, 31, 1329–1334

Organometallics
ARTICLE
’
AUTHOR INFORMATION
Med. 2001, 345, 851–860. (b) Massie, B. M.; Carson, P. E.; McMurray,
J. J.; Komajda, M.; McKelvie, R.; Zile, M. R.; Anderson, S.; Donovan, M.;
Iverson, E.; Staiger, C.; Ptaszynska, A. N. Engl. J. Med. 2008, 359,
2456–2467. (c) Russell, J. C.; Kelly, S. E.; Vine, D. F.; Proctor, S. D. Br. J.
Pharmacol. 2009, 158, 1588–1596. (d) Koichi, Y.; Mitsuru, O.; Christo-
pher, H.; Theodore, K. W.; Hiromi, R. Hypertension 2009, 54, 1353–1359.
Corresponding Author
*E-mail: b.hoge@uni-bielefeld.de.
’
ACKNOWLEDGMENT
(e) Anton, F.; William, L. T.; Robert, V. A. J. Med. Chem. 2009, 52,
The Merck KGaA (Darmstadt, Germany) is acknowledged for
8038–8046.
financial support. We want to thank Dr. N. Ignatiev (Merck
KGaA), Prof. L. Weber, and Dr. J. Bader for helpful discussions.
We thank N. Allefeld and Dr. J. Bader for the generous gift of
Nadiphos I + II and Juliphos. We are grateful to Dr. A. Czybulka
for his instruction on the atom absorption spectroscopy.
(15) (a) Zhou, Y.; Xi, Z.; Chen, W.; Wang, D. Organometallics 2008,
27, 5911–5920. (b) Iwasawa, T.; Kamei, T.; Watanabe, S.; Nishiuchi, M.;
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Q.; Huang, Y. J. Mol. Catal. A: Chem. 2007, 271, 93–97. (d) Guram, A. S.;
King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.;
Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006,
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, 1787–1789. (e) Dey, R.; Sreedhar, B.; Ranu, B. C. Tetrahedron 2010,
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