Catalytic palladium phosphination: Modular synthesis of C 1-symmetric biaryl-based diphosphines

Article abstract of DOI:10.1002/chem.201101529

A new family of C₁-symmetric bis(diphenylphosphino)biphenyls have been prepared starting from readily available ortho,ortho′- dihalobiphenyl precursors by a palladium-catalyzed C-P coupling reaction. This process does not require the use of an

Full text of DOI:10.1002/chem.201101529

DOI: 10.1002/chem.201101529
Catalytic Palladium Phosphination: Modular Synthesis of C1-Symmetric
Biaryl-Based Diphosphines
Laurence Bonnafoux, Rafael Gramage-Doria, FranÅoise Colobert, and
Frꢀdꢀric R. Leroux*[a]
Abstract: A new family of C1-symmet-
ric bis(diphenylphosphino)biphenyls
cyclic phosphafluorene derivative. So
far, no synthetic pathway has been
found to avoid this intramolecular re-
action. Herein we report the first gen-
eral and external-ligand-free palladi-
um-catalyzed phosphination reaction
that allows the synthesis of a wide vari-
ety of substituted ortho,ortho’-bis(di-
phenylphosphino)biphenyls. With the
aim of illustrating the scope and effi-
ciency of this methodology, we applied
it to the establishment of a straightfor-
ward access to C1-symmetrical ana-
logues of the most powerful ligands
used in homogenous catalysis and ex-
tended it to more challenging sub-
strates.
have been prepared starting from read-
ily available ortho,ortho’-dihalobiphen-
yl precursors by a palladium-catalyzed
C–P coupling reaction. This process
does not require the use of an addition-
al ligand. To date, the synthesis of such
diphosphines, by reaction of an inter-
mediate biphenyldiyl dianion with
ClPPh2, mainly afforded the undesired
Keywords: biaryls · cross-coupling ·
lithiation · palladium · phosphorus
Introduction
ble to establish a methodology to synthesize efficiently C1-
symmetrical biphenyl diphosphine ligand families
As remarkable auxiliaries and scaffolds, chiral biaryls are
widely used in a large number of efficient stereodifferentiat-
ing reactions.[1] In particular, atropisomeric C2-symmetric bi-
naphthyl or biphenyl diphosphine ligands such as BINAP,[2]
BIPHEMP,[3] MeO-BIPHEP,[4] SEGPHOS,[5] SYNPHOS,[6]
DIFLUORPHOS[7] and their analogues are well known as
highly efficient chiral ligands for a variety of transition-
metal-catalyzed asymmetric reactions (Scheme 1, top). The
biphenyl backbone has an advantage over binaphthyl: By
controlling the size of the substituents at the 6- and 6’- posi-
tions, the dihedral angle of the biphenyl backbone can be
modulated. In fact, this angle is one of the key factors for
ligand efficiency as regards conversion and enantiomeric
excess in asymmetric catalysis.[5,7a,b,8]
On the other hand, the design of C1-symmetric diphos-
phines has attracted increasing interest in recent decades be-
cause of the improved activity of some catalytic reac-
tions.[8c,9] However, the synthesis of C1-symmetric diphos-
phine ligands based on biaryl scaffolds has been less ex-
plored due to the difficulty of their synthesis. In addition, to
elucidate the role of the ortho substituents of the biaryl
backbone and, in particular, to compare the effect of C2 and
C1 symmetry on catalytic reactions, it was considered desira-
(Scheme 1, bottom) analogous to their C2-symmetric coun-
terparts.
The synthesis of C2-symmetric tetra-ortho-substituted
biaryl diphosphines can essentially be achieved by three ap-
proaches. 1) Symmetrical bis(diphenylphosphino)biphenyls
can be obtained by Ullmann coupling between two identical
prefunctionalized aryl moieties bearing the phosphine group
in the oxidized form (which might be reduced later), as ex-
emplified in the synthesis of MeO-BIPHEP.[4] 2) A strategy
based on palladium- or nickel-catalyzed phosphination of
biaryl bis-triflates. This approach was successfully applied
for the first time to the synthesis of BINAP.[10] 3) The use of
an already pre-existing biaryl scaffold, most frequently a
2,2’-dibromobiaryl, which is submitted to halogen/metal ex-
change followed by trapping with ClPPh2, as in the case of
BIPHEMP.[3]
Unfortunately, these strategies cannot be applied to the
synthesis of less sterically demanding C1-symmetric tri-
ortho-substituted derivatives. In fact, one major drawback
was found. The use of 2,2’-dibromobiphenyl gave, after dili-
thiation followed by treatment with ClPPh2, the cyclic deriv-
ative 5-phenyl-5H-benzo[b]phosphindole (or phosphafluor-
ene)[11] instead of the expected 2,2’-bis(diphenylphosphino)-
biphenyl[12] (Scheme 2). Schlosser and co-workers repor-
ted[11b] that the formation of the phosphafluorene derivative
is a major limitation in the direct synthesis of 2,2’-bis(diphe-
nylphosphino)biphenyl starting from their dihalo precursors.
They even showed that reaction of 2,2’-biphenylylenedilithi-
um with 2 equiv of ClPPh2 affords a 1:1 mixture of phospha-
fluorene and PPh3. Apart from this study, very few investi-
gations regarding the formation of phosphafluorene as side-
[a] Dr. L. Bonnafoux, R. Gramage-Doria, Prof. F. Colobert,
Dr. F. R. Leroux
Laboratoire de stꢀrꢀochimie, UMR CNRS 7509
CNRS/University of Strasbourg, ECPM
25 Rue Becquerel, 67087 Strasbourg Cedex 02 (France)
E-mail: frederic.leroux@unistra.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101529.
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Chem. Eur. J. 2011, 17, 11008 – 11016

FULL PAPER
mobiphenyl precursors, which
can then be submitted to
double phosphination reactions
for which two strategies were
investigated: The classical phos-
phination pathway, which relies
on lithiation, and a new double
palladium-catalyzed phosphina-
tion reaction.
Synthesis of the precursors:
Substituted C1-symmetric biaryl
scaffolds were obtained by tran-
sition-metal-free “aryne” cou-
pling in excellent yields either
directly (2d–k) or by the func-
tionalization of 2,2’,6-tribromo-
biphenyl (3; Scheme 4).[16d,17]
We showed that the latter is an
excellent turntable that allows
the introduction of various
ortho substituents like OMe
Scheme 1. Common biaryl scaffolds of the most efficient 2,2’-bis(diphenylphosphino)biphenyls ligands (top)
and their C1-symmetric targeted analogues 1a–k (bottom).
(2a), NMe2 (2b), Me (2c), and Ph (2 f), which could not be
obtained directly. Regioselective bromine/lithium exchange
reactions can be performed on this substrate when submit-
ted to lithiation in THF with 1 equiv of BuLi. Under these
conditions only the bromine atom located in the most elec-
tronegative ring is selectively displaced.[18] Thus, 2,2’,6-tri-
bromobiphenyl (3) was used as a molecular platform for the
synthesis of most of the new ligands.
Scheme 2. Formation of phosphafluorene instead of the expected 2,2’-
bis(diphenylphosphino)biphenyl when using the classical methodology in
less sterically demanding biaryls.
Lithiation pathway—solvent effects: When the ortho,ortho’-
dibromobiphenyls 2 were submitted to a double halogen/
lithium exchange in THF or Et2O followed by trapping with
2 equiv of ClPPh2, whatever the nature of the ortho substitu-
ent on the 2,2’-dilithiated biphenyl (X=Me, OMe, NMe2,
Cl, OCF3, Ph, OCH2O, OCF2O, OCF2CF2O, H, F), the for-
mation of phosphafluorenes was exclusively observed. This
is consistent with the observation of Schlosser and co-work-
ers.[11b] However, we anticipated that if THF was replaced
by toluene, the outcome of the reaction could be modified
in favor of the 2,2’-bis(diphenylphosphino)biphenyls.
Indeed, it is known that aggregation plays an important role
in organolithium chemistry. Coordinating ligands such as
ethers can provide an alternative source of electron density
for the electron-deficient lithium atoms. Ethers can stabilize
aggregates by coordination to the lithium atoms and then
allow organolithiums to shift to an entropically favored
lower degree of aggregation.[19] For example, THF is a
product have been carried out and no general approach has
been developed to avoid its formation.[13]
Similarly, our group has shown that an increased torsion
angle between the two phenyl rings is necessary for the for-
mation of bis(diphenylphosphino)biphenyls to prevail and,
in some cases, the phosphafluorene has not been ob-
served.[14] Continuing our research, we have reported the
synthesis of the first C1-symmetric MeO-BIPHEP analogue
1a.[14] However, it required additional and laborious protec-
tion and deprotection of the biphenyl scaffold to avoid the
undesired phosphafluorene formation.[15] In this paper we
report on the first straightforward access to a whole family
of C1-symmetric tri-ortho-substituted bis(diphenylphosphi-
no)biphenyls 1 in which, for the first time, the undesired for-
mation of phosphafluorene is avoided.
Results and Discussion
For a rapid access to this ligand family, we devised the syn-
thetic approach depicted in Scheme 3 based on the transi-
tion-metal-free “aryne” coupling reaction that we recently
developed.[16] It allows the preparation of ortho,ortho’-dibro-
Scheme 3. Synthetic approach to C1-symmetric biaryl-based diphosphines
1.
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F. R. Leroux et al.
(temperature, order of addition,
excess of ClPPh2) had no signif-
icant influence on the ratio of
diphosphine/phosphafluorene
(1:4). All diphosphine ligands
were stable in air and at room
temperature. The low yields
were due to the formation of
phosphafluorenes as side-prod-
ucts.
In general, all the bis(diphe-
nylphosphino)biphenyls 1 were
obtained in moderate yields
varying from 10 to 47%. Never-
theless, the corresponding phos-
phafluorenes and triphenyl-
phosphine were still formed.
Scheme 4. Synthesis of ortho,ortho’-dibromobiphenyl precursors by “aryne” coupling. Reagents and condi-
tions: (a) i. tBuLi (2 equiv), THF, À1008C, 5 min then À788C, 1 h; ii. 1,2-dibromobenzene; (b) i. tBuLi
(2 equiv), THF, À788C, 1 h; ii. 1,2-dibromobenzene; (c) i. tBuLi (2 equiv.), THF, À1008C, 5 min then À788C,
1 h; ii. 1-iodo-2-bromobenzene; (d) i. BuLi (2 equiv), THF, À788C, 1 h; ii. 1-bromo-2-iodobenzene; (e) starting
from 1,2-dibromobenzene with BuLi (0.5 equiv), THF, À788C; (f) i. BuLi (1 equiv), THF, À788C, 5 min;
ii. MeI (96%); (g) i. BuLi (1 equiv), THF, À788C, 5 min; ii. BF
ACHTUNGNERTN(NUG OMe)2·Et2O; iii. NaOH, H2O2, 08C; iv. K2CO3,
MeI, acetone, 608C (68%); (h) i. BuLi (1 equiv), THF, À788C, 5 min; ii. PhSO2N3; iii. LiAlH4, Et2O, 50 8C; iv.
NaCNBH3, CH2O, AcOH, MeCN, 08C (78%); (i) i. BuLi (1 equiv), THF, À788C, 5 min; ii. I2, THF; Even if these side-products
(j) Na2CO3, PhB(OH)2, [PdACTHUNTRGNE(GNU PPh3)4], H2O/MeCN (50:50), 908C, 3 h.
could be separated from the de-
sired diphosphine by standard
chromatography on silica gel
strong decoordinating solvent producing low degrees of ag-
gregation, albeit with an increase in basicity and concomi-
tantly an increase in nucleophilicity, whereas organolithiums
in toluene or hydrocarbon solutions in general invariably
form aggregates of hexamers or tetramers. These solvents
favor the internal stabilization of lithiated species.[20]
and/or by crystallization, the ring-closing reaction to yield
phosphafluorenes remained a real limitation to the overall
synthesis.[21] In spite of the significant progress, this result
was not sufficiently satisfactory from a synthetic point of
view and we decided to investigate a new approach: The
palladium-catalyzed phosphination of halobiaryls.
Thus, when the reaction was performed in toluene, the
formation of 2,2’-bis(diphenylphosphino)biphenyls 1 was ob-
served together with phosphafluorenes 4 and triphenylphos-
phine (Table 1). The reaction conditions were chosen to
ensure the complete double halogen/lithium exchange of the
starting material and modification of the trapping conditions
Palladium-catalyzed C–P cross-coupling reaction: Over the
past few years, C–P coupling reactions have started to be
studied but less systematically than the C–C, C–N, or C–O
coupling reactions. Nevertheless, some catalytic systems
have been successfully developed. Most of them allow the
monophosphination of various substrates, in particular, sub-
stituted phenyl derivatives. However, double phosphination
reactions have rarely been described and are performed
starting from bis-triflate substrates.[10,22] Under the same re-
action conditions, biphenyl and binaphthyl substrates exhibit
different reactivities.[9e,10b,22d,e,23] In general, all these reac-
tions have some critical drawbacks: 1) They have to be
heated at reflux for 3 days, 2) triflate intermediates have to
be accessible or otherwise have to be prepared, which re-
quires two additional synthetic steps when starting from the
dihalo precursor, and 3) they require the use of additional li-
gands to allow the coupling reaction. In contrast to the
mono C–P coupling reactions mainly developed by Stelzer
and co-workers,[24] very few double C–P coupling reactions
of dihalobiphenyls have been reported so far. Murata and
Buchwald reported only one example of a C–P coupling of
2,2’-dibromobiphenyl with dicyclopentylphosphine using Pd-
Table 1. Reaction conditions for the synthesis of bis(diphenylphosphino)-
biphenyls 1a–i.
2
R
X’
n
T[a]
[equiv] [8C]
T’[b]
[8C]
Ratio
1/4
Yield of 1
[%][c]
2a
2b
2c
2d
2e
2f
2g
2h
OMe
NMe2
Me
Cl
OCF3
Ph
Br
Br
Br
Br
Br
Br
Br
I
2
2
2
2
2
2
2
3
3
110
110
110
110
110
110
110
25
50
50
50
50
50
50
50
25
25
1.3:1.0 17
1.4:1.0 44
1.9:1.0 30
1.4:1.0 23
AHCTUNGRTEG(NNUN OAc)2 and DiPPF as catalyst, which afforded after 18 h the
desired 2,2’-bis(dicyclopentylphosphino)biphenyl.[25] More
recently, a bicyclic dibromo substrate afforded under micro-
wave irradiation aza-BINAP-type ligands.[26]
n.d.
10
1.0:1.0 24
1.6:1.0 18
OCH2O
OCF2O
2.7:1:0
47
Preliminary attempts to obtain 2,2’-bis(diphenylphosphi-
no)biphenyls 1 from 2,2’-dibromobiphenyls and HPPh2 with
2i OCF2CF2O
I
25
2.0:1.0 34
[a] Metalation temperature. [b] Trapping temperature. [c] Isolated prod-
uct yield of 1 after flash-chromatography on silica gel.
catalytic amounts of PdACTHNGUTERN(UNG OAc)2 failed. Irrespective of the
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Catalytic Palladium Phosphination
FULL PAPER
Table 3. Screening of the reaction conditions for the catalytic phosphination of model
substrates 5c, 5d, and 5g.
substrate used, it was all recovered. Therefore we
considered the double C–P coupling reaction of the
diiodo analogues. To convert the dibromobiphenyls
2a–k and 3 into their diiodo analogues 5a–l, they
were submitted to a double Br/Li exchange in THF
either with 2 equiv of BuLi (conditions a) or with
4 equiv of tBuLi (conditions b) followed by the ad-
dition of 2 equiv of iodine to afford most of the in-
termediates in very good yields (Table 2).
Inspired by the studies of Rohlꢂk et al. on the
phosphination of iodoaryl phosphonates,[27]
a
screening was carried out to determine the optimal
phosphination conditions without addition of any
external ligand. For this purpose, substrates 5c, 5d,
and 5g were selected as model substrates with
structural and electronic diversity (Table 3). 2-
Chloro-2’,6-diiodobiphenyl (5d) was treated with
Entry
R
Solvent
T
KOAc
Pd
[mol%]
(OAc)2
t
5
1
4
[8C] [equiv]
[h] [%][a] [%][a] [%][a]
1
2
toluene
toluene
90 2.2
2
2
83
17
77
0
23
19 <5
3[b]
4[b]
5[b]
6
90 2.2
2
2
19
83
44
38
17 <5
56 <5
62 <5
100
HPPh2 in the presence of PdACTHUNRTGNEUNG(OAc)2 and anhydrous
toluene
toluene/ 110 1.2
DMA
90 2.2
10
2
20 <5
50
50
Cl
KOAc as base in toluene, DMA (N,N-dimethylace-
tamide), or a mixture of toluene/DMA (13:1). In
toluene, the outcome of the reaction seems to be
dependent upon the amount of palladium (Table 3,
entries 1–6). When the reactions were carried out
with a small amount of palladium, incomplete con-
version was achieved. Unexpectedly, under some
conditions the corresponding phosphafluorene was
7
2
>95
<5 <5
8
9
10
11
12
13
18
25
66
2
53
43
27
47 <5
57 <5
73 <5
DMA
DMA
DMA
130 2.2
130 2.2
130 2.2
1
2
2
2
<5 >95 <5
82 10
<5 >95 <5
OCH2O
Me
2
8
2
[a] Percentage determined by H NMR spectra. Ratio within the limits of NMR detec-
formed in a non-negligible ratio relative to the cor- tion. [b] PdACTHNUGTRNEUNG(OAc)2 and HPPh2 were mixed together in DMA before addition of re-
agents.
responding diphosphine 1 (Table 3, entries 2 and 6).
To the best of our knowledge, the formation of
phosphafluorene side-products during catalytic
phosphinations with HPPh2 has never been reported. Inter-
estingly, when DMA was used as co-solvent, the formation
of phosphafluorene was avoided but the reaction was not
complete even after 66 h (Table 3, entries 7–10). An increase
DMA was used as co-solvent or solvent. Note that attempts
at phosphination at lower temperatures (50, 75, and 1008C)
did not afford the corresponding diphosphine 1, but the
starting material 5 together with some tentatively assigned
monophosphine intermediates formed in the course of the
reaction. Finally, at 1308C, when only DMA was used as sol-
vent with 2.2 equiv of KOAc, the reaction was complete
after 2 h without any trace amounts of phosphafluorenes
(Table 3, entry 11). The same trends were observed with
in the amount of PdACTHNUTRGNEUNG(OAc)2 had no beneficial effect when
Table 2. Synthesis of 2,2’-diiodobiphenyl precursors 5.
2,2’-diiodo-6-methylbiphenyl
iodophenyl)benzo[d][1,3]dioxole (5g; Table 3, entries 12 and
13).
Once the optimal reaction conditions had been found,
(5c)
and
5-iodo-4-(2-
AHCTUNGTRENNUNG
they were applied to the diiodobiaryl series 5a–l. A large
number of target ligands were efficiently obtained and in
most cases the formation of phosphafluorenes was prevent-
ed (Table 4).[28]
Substrate
R
X’
Conditions
5
Yield [%][a]
2a
2b
2c
2d
2e
2 f
2g
2h
2j
OMe
NMe2
Me
Cl
OCF3
Ph
OCH2O
OCF2O
H
F
Br
Br
Br
Br
Br
Br
Br
Br
I
b
b
b
a
b
b
a
b
a
b
a
5a
5b
5c
5d
5e
5 f
5g
5h
5j
71
65
86
93
81
44
91
69
88
80
72
In general, the corresponding diphosphines were obtained
in good-to-excellent yields in only one step and in a very
short reaction time, even with the more sensitive fluorinated
diphosphines. 2,2’-Bis(diphenylphosphino)biphenyl (1j; R=
H) was prepared in a yield of 62%. Although this com-
pound is not useful from a catalytic point of view, it was not
possible to obtain it by lithiation and trapping with
ClPPh2.[11b] We also successfully prepared its fluorinated an-
alogue 1k in good yield (73%). The moderate yield ob-
tained when R=NMe2 (1b) can be explained by a likely co-
Br
Br
Br
2k
3
5k
5l
[a] Isolated product yield after flash chromatography.
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F. R. Leroux et al.
Table 4. Synthesis of 2,2’-bis(diphenylphosphino)biphenyl ligands by the
Table 5. Synthesis of 6 starting from 5l, 7, 8, or 3.
catalytic C–P cross-coupling reaction under optimized conditions.
Entry
Substrate
X1
X2
X3
n [eq]
Yield of 6 [%][a]
1
2
3
4
5
5l
5l
7
8
3
Br
Br
I
Br
Br
I
I
Br
Br
Br
I
I
Br
I
2.2
3.2
3.2
3.2
3.2
50
91
88
79
18
Br
Time [h] Ratio 1:4[a]
1
Yield of 1 [%][b]
[a] Isolated product yield after flash chromatography.
Entry
5
R
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
OMe
NMe2
Me
Cl
OCF3
2.0
3.0
2.0
3.0
2.0
>95:5
86:14
>95:5
>95:5
84:16
88:12
>95:5
63:37
>95:5
1a 98
1b 43
1c 73
1d 95
1e 53
1g 80
1h 48
1j 62
1k 73
curred at the bromide atom. Confirmation of its molecular
structure was achieved by a single-crystal X-ray diffraction
analysis (Figure 1). Aikawa and Mikami have used this achi-
ral triphosphine, although its synthesis was not reported.[29]
This result encouraged us to investigate the polyphosphi-
nation reactions of polyhalobiaryls (Table 5). The triple C–P
cross-coupling reaction under stoichiometric conditions af-
forded the corresponding triphosphine 6 in an excellent
yield of 91% (Table 5, entry 2). It is interesting to note that
1) three consecutive C–P coupling reactions can be per-
formed almost quantitatively and in one pot on the same
substrate and 2) that C–P coupling with a bromo substrate is
possible. Next we repeated the reaction by using the 2,2’-di-
bromo analogue 7 and in this case biphenyl-2,2’,6-triyltris(di-
phenylphosphine) (6) was obtained in a yield of 88%
(Table 5, entry 3). We also tried to determine whether the
relative position of the iodine atom on the biphenyl back-
bone has an influence on the outcome of the reaction. Thus,
we performed the reaction with 2,6-dibromo-2’-iodobiphenyl
(8) instead of 2,2’-dibromo-6-iodobiphenyl (7), but the out-
come of the reaction was the same and the product was ob-
tained once again in an excellent yield (79%; Table 5,
entry 4). Finally, we wondered whether the reaction would
5g OCH2O 3.0
5h OCF2O 1.5
5i
H
F
3.0
1.5
5k
[a] Percentage determined by 1H NMR spectroscopy. Ratio within the
limits of NMR detection. [b] Isolated yield after flash chromatography.
ordination of the nitrogen atom to palladium, which modi-
fies the nature of the catalytic species (Table 4, entry 2). We
also noticed that O-alkyl-substituted derivatives are better
substrates than their a-fluorinated ether analogues. In the
case of R=OMe, 2,2’-bis(diphenylphosphino)biphenyl 1a
was obtained in a yield of 98% (Table 4, entry 1) compared
with 53% when X=OCF3 (1e; Table 4, entry 5). Similarly,
the yield increased from 48% for 1h (R=OCF2O) to 80%
for 1g (R=OCH2O).
To date, this is the first versatile double catalytic C–P
cross-coupling protocol ever described. It allows a direct
and rapid access to 2,2’-bis(diphenylphosphino)biphenyls in
only one step in moderate-to-excellent yields and very short
reaction times, allowing us to proceed on a gram scale. In-
terestingly, it did not require the addition of an external
ligand. Moreover, in many cases (R=F, Cl, Me, OMe,
OCF2O), the formation of phosphafluorenes was completely
avoided. When R=H, NMe2, OCH2O, and OCF3, phospha-
fluorenes 4 were formed in only trace amounts and could be
easily separated from the desired ligands 1.
Probably one of the most interesting features of this
double palladium catalytic phosphination reaction was ob-
served when attempts were made to perform the reaction
with 2-bromo-2’,6-diiodobiphenyl (5l; Table 5, entry 1). Sur-
prisingly, the corresponding diphosphine was not detected at
all. Instead, the triphosphine 6 was obtained in a yield of
50% (note that the biaryl was employed in excess compared
with HPPh2). The 31P NMR spectrum of 6 displayed one
doublet at d=À12.5 ppm (d, J=23 Hz), which integrates for
two phosphorous atoms, and a triplet at d=À14.6 ppm (d,
J=23 Hz), which integrates for one phosphorous atom. This
suggests that a third unexpected phosphination reaction oc-
Figure 1. Molecular structure of compound 6 in the solid state.
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Catalytic Palladium Phosphination
FULL PAPER
be as efficient in the absence of any iodine atoms as it is
with the iodo substrates. Thus, the triple phosphination was
performed on 2,2’,6-tribromobiphenyl (3), which yielded the
triphosphine 6, but in a lower yield (Table 5, entry 5).
starting from the 2,2’-diiodo analogue 5k (Table 4, entry 9).
Thus, complete iodination of the substrate is not necessary.
The synthesis of 2,2’-bis(diphenylphosphino)biphenyl 1h
from its diiodo precursor in a yield of 48% has already been
described (Table 4, entry 7). The yield surprisingly increased
Irrespective of the substrate employed, the crude reaction
mixture was extremely clean and revealed only one product.
In general, C–P coupling reactions on these substrates were
extremely rapid. After 45 min, the trihalobiphenyls were
consumed and biphenyl-2,2’,6-triyltris(diphenylphosphine)
(6) was exclusively formed. This suggests that autocatalysis
may be responsible for the rate and efficiency of the reac-
tion. It may also be assumed that the limiting step of the
overall process is the first C–P coupling reaction. Indeed,
when the first phosphine is introduced on to the biphenyl
to
72%
starting
from
5-bromo-2,2-difluoro-4-(2-
iodophenyl)benzo[d]
AHCTUNGTRENNUNG
tetrafluorinated ligand 1i was also obtained in this way in a
yield of 47% (Table 6, entry 3). To study the limits of our
system, we studied the double phosphination of more steri-
cally hindered substrates. The reaction conditions were suc-
cessfully applied to tetra-ortho-substituted biaryls like 2-
bromo-6,6’-dichloro-2’-iodobiphenyl (10), which afforded
the corresponding diphosphine 11 in an excellent yield of
80% (Table 6, entry 4). Even a triple phosphination was ef-
ficiently performed with a global yield of 67% starting from
2,2’,6,6’-tetrasubstituted biphenyl 12 (Table 6, entry 5).
À
backbone, it can favor palladium insertion into the other C
X bonds (X=Br or I) on its skeleton. This could explain the
absence of side-products such as the mono- and/or diphos-
phines. For instance, when we applied the reaction condi-
tions to the dibromo precursor 2d (R=Cl), even after 12 h
no coupling product was observed. This means that the pres-
ence of at least one iodine atom is necessary to start the cas-
cade phosphination and to guarantee the formation of the
polyphosphinated biaryl in good yield.
Suggested mechanism for the catalytic phosphination: A
similar mechanism to those studied and described by Buch-
wald,[30] Hartwig,[31] and Barluenga[32] and their co-workers
for Csp2–N coupling[33] can be formulated for the present
double C–P cross-coupling reaction (Scheme 5). The first
step is the formation of a catalytic species involving Pd0.
After oxidative addition of the iodobiaryl (intermediate A),
HPPh2 might coordinate the metal center prior to its depro-
We then extended our study to other 2-bromo-2’-iodobiar-
yls. Starting with 9, diphosphine 1k was obtained in good
yield (70%; Table 6, entry 1), similar to the yield obtained
tonation
by
KOAc
to
give
intermediate
B
(pKa(HPPh2/ÀPPh2)=22;
(pKa(HOAc/ÀOAc) ꢀ
Table 6. Extension of the method to various 2-bromo-2’-iodobiaryls.[a]
pKa(KOAc/ÀOAc) =4).[34] Reductive elimination leads to
the formation of the first monophosphine, which remains co-
ordinated to Pd0 (intermediate C) and which can intramo-
lecularly assist the second oxidative addition to give inter-
mediate D. A second coordination/deprotonation sequence
Entry
1
Substrate
Product
Yield [%][b]
70
2
3
72
47
4
5
80
67[c]
[a] Reaction conditions: PdACHTNUTRGNE(NUG OAc)2 (2 mol%), HPPh2 (2.2 equiv), KOAc
(2.2 equiv), DMA, 1308C, 3 h. [b] Isolated yield after flash chromatogra-
phy. [c] Reaction conditions: HPPh2 (3 equiv) and KOAc (3 equiv).
Scheme 5. Proposed mechanism for the catalytic double phosphination
reaction.
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11013

F. R. Leroux et al.
of HPPh2 gives intermediate E. Then the last reductive elim-
ination leads to the formation of the 2,2’-bis(diphenylphos-
phino)biphenyl 1 with regeneration of the Pd0 catalytic spe-
cies (Scheme 5).
Conclusion
In this work we have shown how a new class of C1-symmet-
ric bis(diphenylphosphino)biphenyl ligands can be prepared
starting from a few common precursors obtained by a transi-
tion-metal-free “aryne” coupling reaction. The difficulties
previously encountered in synthesizing these kinds of li-
gands, that is, an undesired intramolecular cyclization of a
transient 2-diphenyphosphanyl-2’-biphenylyllithium to yield
a phosphafluorene, has been overcome to a certain extent
by a solvent effect on the lithiation/trapping sequence to
afford the desired diphosphine as the major product.
The trace amounts of phosphafluorenes formed can be ex-
plained by an exchange of the aryl groups bonded to the co-
ordinated phosphine in intermediate D. After aryl migra-
tion, reductive elimination gives PPh3, which was detected
in the crude reaction mixture by 31P NMR spectroscopy. Ac-
cording to Cheng and Kong, this kind of aryl exchange
occurs in [PdACHTUNGTRENNUNG
(PPh3)2(C6H4-p-CH3)I].[35] Marcuccio and co-
workers have also observed an aryl migration in Suzuki–
Miyaura coupling reactions[36] and Chenard and co-workers
reported similar observations in Stille coupling reactions.[37]
In addition, such a Pd–aryl/P–aryl exchange has been ob-
served in numerous processes[38] like Heck reactions,[39] ami-
nations,[40] amidations,[41] ketone a-arylations,[42] cyana-
tions,[43] and C–S coupling reactions.[44] Kwong and Chan
even used this exchange as the key step in the catalytic
monophosphination of biaryl triflates with PPh3 to obtain
the PYPHOS ligands.[45] On the other hand, several stud-
ies[35,46] have shown that this exchange is an equilibrium pro-
cess between different palladium species and that is con-
trolled by the steric and electronic profiles of the coordinat-
ed ligands (Scheme 6). These authors proved that the migra-
tion is favored by electron-donor substituents. This is in
agreement with our observations that phosphafluorenes are
mainly formed when R=OCF3, NMe2, and OCH2O. On the
other hand, Kong[35] noticed that additional amounts of
ligand prevent this migration. In our case, the ligand is
HPPh2 itself and/or the diphosphine 1 obtained, which is in
excess (2 equiv) relative to the palladium species. This could
explain why the phosphafluorene 4 is formed only as a
minor product in comparison with the 2,2’-bis(diphenylphos-
phino)biphenyl 1.
As an alternative, the C–P cross-coupling reactions were
performed on a series of 2,2’-diiodobiaryls and some 2-
bromo-2’-iodobiaryls under the optimized conditions. This
catalytic system turns out to be a direct and rapid route to
2,2’-bis(diphenylphosphino)biphenyls giving moderate-to-ex-
cellent yields without the addition of any ligand. To the best
of our knowledge this is the first versatile external-ligand-
free C–P coupling reaction of dihalobiaryls. It is an extreme-
ly fast double C–P cross-coupling reaction relative to the C–
P coupling reactions starting from bis(triflates) that have
been described in the literature. In particular, the reaction
time was in general reduced from 3 days to 3 h. Interesting-
ly, the formation of phosphafluorenes was avoided in most
cases. When X=H (1j), NMe2 (1b), OCH2O (1g), and
OCF3 (1e), it was only observed as a minor product and
could be easily separated chromatographically from the de-
sired diphosphine. The formation of this side-product was a
priori completely unexpected under palladium-catalyzed
conditions but can be explained by aryl migration. The
double palladium-catalyzed phosphination reaction is per-
fectly reproducible and allows the preparation of ligands in
multi-gram quantities. We also applied the same reaction
conditions to more challenging substrates and proved that it
was possible to perform up to three coupling reactions on
the same polyhalogenated substrate and to obtain the corre-
sponding polyphosphines in very good yields.
Overall, the methodology presented in this study allows
new pathways to be considered for the synthesis of more so-
phisticated diphosphines based on C1- or C2-symmetric
biaryl scaffolds. The direct synthesis of enantiomerically
pure C1-symmetric biaryl-based diphosphines is currently
under investigation, as well as the introduction of chirality
at the phosphorus atom.
Experimental Section
Full experimental details are given in the Supporting Information.
General description for the catalytic C–P coupling protocol towards bis-
AHCTUNGERTG(NNUN diphenylphosphines): An oven-dried Schlenk tube was evacuated and
refilled with argon. Potassium acetate (2.20 mmol, 0.22 g, 2.2 equiv), diio-
dobiaryl (1.00 mmol, 1 equiv), and diphenylphosphine (2.20 mmol, 0.41 g,
0.38 mL, 2.2 equiv) were added to a solution of N,N-dimethylacetamide
(9.00 mL) and then a solution of N,N-dimethylacetamide (1.00 mL) con-
taining palladium acetate (1.50 mg, 2 mol%) was added. The solution
turned red and was immediately placed in an oil bath at 1308C. Once the
Scheme 6. Pd–aryl/P–aryl exchange.
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Catalytic Palladium Phosphination
FULL PAPER
reaction had finished the reaction mixture was allowed to cool down to
room temperature. Water (40 mL) was added and the aqueous phase was
extracted with dichloromethane (3ꢃ50.0 mL). The combined organic
layers were dried over sodium sulfate. Evaporation of the solvent fol-
lowed by column chromatography on silica gel with cyclohexane/ethyl
acetate (19:1) afforded the corresponding bis(diphenylphosphino)biphen-
yls.
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X-ray crystallographic data for 6: Single crystals of 6 were obtained by
slow diffusion of pentane into a dichloromethane solution of the com-
pound. C48H37P3, Mr =706.69, orthorhombic, P21P21P21, a=12.8102(2),
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Acknowledgements
We thank the CNRS and the Ministꢅre de la Recherche of France. We
are much grateful to LONZA AG, Switzerland, for a Ph. D. grant to L.B.
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Received: May 18, 2011
Published online: August 18, 2011
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Chem. Eur. J. 2011, 17, 11008 – 11016