Ligand tailoring: The first modular assembly of atropisomeric biarylbisphosphine ligands

Article abstract of DOI:10.1055/s-2006-933107

Strategies based on highly selective halogen-metal permutations have been devised and applied enabling the modular assembly of atropisomeric biaryl bisphosphines. After resolution on chiral column, the ligands were tested in benchmark hydrogenation reactions affording good to excellent enantioselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933107

766
LETTER
Ligand Tailoring: The First Modular Assembly of Atropisomeric
Biarylbisphosphine Ligands
Ligand
T
ailori
r
ng édéric Leroux,*a Hanspeter Mettlerb
a
Laboratoire de Stéréochimie (UMR CNRS 7509), Université Louis Pasteur (ECPM), 67087 Strasbourg Cedex 2, France
Fax +33(3)90242742; E-mail: lerouxf@ecpm.u-strasbg.fr
b
LONZA AG, 3930 Visp, Switzerland
Received 19 October 2005
parts to modify the stereoelectronic profile of a ligand.
Numerous modifications of the phosphine substituent can
be found in the literature, influencing the steric hindrance
around the metal and/or the electronic properties of the
phosphorus center.21 In addition, the groups of Zhang,22
Saito13,14 and Genêt23 studied the steric modification of the
biaryl core. However, the electronic design of atropiso-
meric bisphosphine ligands has been less systematically
studied.24 One difficulty is the possibility to synthesize
atropisomeric ligand families in a modular way, as it is
done for the JOSIPHOS family. Such a modular access to
a whole ligand family allows the fine-tuning of the steric
and electronic properties of a ligand depending on specific
needs.
Abstract: Strategies based on highly selective halogen–metal per-
mutations have been devised and applied enabling the modular as-
sembly of atropisomeric biaryl bisphosphines. After resolution on
chiral column, the ligands were tested in benchmark hydrogenation
reactions affording good to excellent enantioselectivity.
Key words: lithiation, phosphorus, catalysts, hydrogenation, bi-
aryls
Chiral compounds qualifying as ligands for asymmetric
catalysis continue to be designed and synthesized at a
frenetic pace.1–3 If under such circumstances it appears
difficult to keep track of all individual structures, one
nevertheless recognizes three dominant classes which are
privileged because of their versatility and their enantio-
selective performance. Bisphosphines containing asym-
metric carbon centers were the first to supplant mono- and
bisphosphines4,5 having stereogenic phosphorus atoms
and were equally the first to gain practical importance.
DIOP,6 CHIRAPHOS7 and, more recently, the DUPHOS
family8 have been featured by most impressive results in
the area of asymmetric hydrogenation reactions. Mean-
while competitors emerged such as BINAP,9,10 arguably
the most popular of all ligands, MeOBIPHEP11,12 and
SEGPHOS.13,14 Finally, the option of planar chirality was
explored leading to paracyclophane15 and ferrocene16–18
based bisphosphines. The JOSIPHOS family19,20 belong-
ing to the latter category deserves particular attention as it
offers the so far unique advantage to enable ligand con-
struction with utmost structural flexibility.
Our objective was to apply the concept of modular
synthetic access25 to the series of atropisomeric biaryls in
order to prepare in a rational way a large family of biaryl-
bisphosphine ligands having different tunable ortho sub-
stituents. A specific goal was to make biphenylene-2,2¢-
bisphosphines accessible that carry only one substituent at
the 6-positions.
Polar organometallic chemistry is particularly suitable to
realize this goal, due to the possibility to perform highly
selective reactions. As our objective had to cope with a
high structural complexity, we decided, for reasons of lo-
gistic simplicity, that it would be advantageous to allow
for the presence of just one kind of halogen, preferably
bromine, in a common starting material in order to replace
them successively by metal and ultimately by phosphorus
groups or other substituents. This raises the question of
how to discriminate chemically between formally identi-
cal halogen atoms.
In the field of atropisomeric ligands, both the aryl phos-
phorus substituents and the biaryl backbone are tunable
X
X
X
ClPPh2
ClPPh2
– PPh3
P
Ph2P PPh2
Li Li
Ph
X = H, F, Cl, Br, OCH3, NMe2
Scheme 1
SYNLETT 2006, No. 5, pp 0766–0770
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933107; Art ID: D30805ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ligand Tailoring
767
H3CO
We decided to use 2,2¢,6,6¢-tetrabromobiphenyl as com-
mon starting material.27 The feasibility of the project
should be demonstrated on the modular synthesis of all
four 2¢-methoxy-2,6-biphenylenebisphosphines 1–4, hav-
ing a methoxy substituent, in analogy to MeOBIPHEP,
and in addition all possible permutations of bis(diaryl-
phosphine)-, bis(dialkylphosphine)- and mixed dialkyl/
diarylphosphine substituents (Figure 1).
H3CO
Cy2P PCy2
Ph2P PPh2
2
1
H3CO
H3CO
Starting from 2,2¢,6,6¢-tetrabromobiphenyl, the first halo-
gen was replaced by methoxy, affording 2,2¢,6-tribromo-
6¢-methoxybiphenyl (5; 82% yield), if the intermediate
was consecutively subjected to borylation, oxidation and
O-methylation.28 A double bromine–lithium interconver-
sion and subsequent condensation with two equivalents of
chlorodiphenylphosphine gave 6¢-bromo-2,2¢-bis(diphen-
ylphosphanyl)-6-methoxybiphenyl (6; 71% yield) which
could be readily reduced to the halogen-free bisphosphine
1 (57% yield; Scheme 2).
Cy2P PPh2
Ph2P PCy2
3
4
Figure 1
There was a major obstacle to be overcome. Any 2¢-di-
phenylphosphino-2-biphenyl lithium generated as an in-
termediate would be unable to produce a bisphosphine by
condensation with a second chlorodiorganylphosphine
component if a single fluorine, chlorine or bromine atom
or a single methyl or methoxy group occupied the 6-posi-
tion.26 The intermediate would rather undergo an instanta-
neous nucleophilic substitution at phosphorus and cyclize
under phenyllithium elimination to afford a 1H-ben-
zo[b]phosphindole (Scheme 1).
The intriguing question was whether one bromine would
be exchanged preferentially if the twofold halogen–metal
permutation was not carried out simultaneously but suc-
cessively. An effective discrimination between two bro-
mine atoms as a function of their chemical environment
has so far been observed only sporadically in such kind of
processes.29 Fortunately, the reaction occurred exclusive-
ly in the doubly halogenated ring when 2,2¢,6-tribromo-
6¢-methoxybiphenyl (5) was treated with just one
equivalent of butyllithium in tetrahydrofuran at –75 °C.
The undesired ring closure can be avoided, as we have
now found, by the introduction of a later removable
‘dummy’ substituent into the 6¢-position. Our first choice
fell on bromine.
Br Br
H3CO Br
H3CO
1) 2 equiv BuLi,
toluene, 25 °C
2) MeOH
Br Br
1) 1 equiv BuLi, THF, –75 °C
2) 1 equiv FB(OMe)·OEt2
3) NaOH/H2O2
4) H3CI
Ph2P PPh2
Ph2P PPh2
6
1
1) 2 equiv BuLi,
THF, –75 °C
2) 2 equiv ClPPh2
H3CO
H3CO
H3CO Br
1) 2 equiv BuLi,
1) 1 equiv BuLi,
THF, –75 °C
THF, –75 °C
2) 2 equiv ClPCy2
2) MeOH
Br Br
Cy2P PCy2
Br Br
5
7
2
1) 2 equiv BuLi, THF, –75 °C
2) 2 equiv I2
1) 1 equiv BuLi, THF, –75 °C
2) 1 equiv ClPCy2
H3CO
H3CO
H3CO Br
1) 1 equiv BuLi,
toluene, 0 °C
2) 1 equiv ClPCy2
Cy2P Br
Cy2P PPh2
9
8
3
I
I
1) 1 equiv BuLi, DEE, –75 °C
2) 1 equiv ClPCy2
H3CO Br
H3CO
H3CO Br
1) 1 equiv BuLi,
DEE, –75 °C
1) 2 equiv BuLi,
toluene, 25 °C
2) 1 equiv ClPPh2
2) MeOH
I
PCy2
Ph2P PCy2
Ph2P PCy2
10
11
4
Scheme 2
Synlett 2006, No. 5, 766–770 © Thieme Stuttgart · New York

768
F. Leroux, H. Mettler
LETTER
Protolysis with methanol provided 2,2¢-dibromo-6-meth- reactions. Tests were performed with two b-keto esters
oxybiphenyl (7; 92% yield) which was readily converted and two acrylates. All experiments were performed in
into 2,2¢-bis(dicyclohexylphosphanyl)-6-methoxybiphen- screening type equipment with the objective to see differ-
yl (2; 74% yield) and into the P,P-dicyclohexyl-P¢,P¢- ences between ligands for different substrates. Optimiza-
diphenylbisphosphine (3; 56% yield) by double and tion of the hydrogenation conditions was not attempted.
stepwise bromine–lithium permutation, respectively. In
the latter case the bromophosphine 8 (79%) acted as the
The racemic ligands 1–4 were separated into their enan-
tiomers by preparative HPLC chromatography using a
intermediate. Finally, 2,2¢,6-tribromo-6¢-methoxybi-
phenyl (5) was converted into the diiodo compound 9 by
double bromine–lithium interconversion and subsequent
trapping with iodine. Two consecutive unilateral halo-
gen–metal permutations, the first followed by condensa-
tion with chlorodicyclohexylphosphine, led to the P¢,P¢-
dicyclohexyl-P,P-diphenylbisphosphine (4; 62% yield)
via the bromoiodophosphine 10 (72% yield) and the bro-
mobisphosphine 11 (32% yield). The introduction of
iodine ascertains higher selectivity, as iodine is known to
be displaced faster than bromine by several powers of ten
(Scheme 2).
chiral stationary phase (CHIRALCEL® OD 20 mm, n-hep-
tane–EtOH 2000:1).
We first examined the hydrogenation reaction of acetoac-
etate and chloroacetoacetate (Scheme 3). The catalytic
tests were performed in ethanol at 50 °C, and 80 °C, re-
spectively, under 4 bar of hydrogen pressure with a sub-
strate/catalyst ratio (S/C) of 100 (Table 1). The
acetoacetate was preferentially hydrogenated using the
MeOBIPHEP (99% ee, 100% conversion) related ligand
1 with fully aryl substituted phosphorus atoms (99% ee,
100% conversion). Similar results were obtained for chlo-
roacetoacetate (88% ee, 100% conversion vs. 92% ee,
100% conversion for MeOBIPHEP). Both enantioselec-
tivity and reactivity are highest with ligand 1 and much
lower with ligand 2, the mixed aryl/alkyl ligands 3 and 4
lying in-between.
The four model compounds 1–4 are just meant to illustrate
the almost inexhaustible possibilities for creating struc-
tural diversity. The aliphatic or aromatic substituents at
phosphorus may be varied at will, the methoxy entity may
be replaced by any other carbon or hetero unit and addi-
tional groups may be introduced. All the methods em-
ployed were straightforward and expedient enough to
provide the bisphosphines 1–4 rapidly and in sufficient
amounts. The access to the target compounds 1–4 relied
on a combination of strategies, which deserve to be con-
sidered individually. First, the introduction of a remov-
able ‘dummy’ substituent and taking it along almost to the
end is essential for the success. Without the protection
against planarization any transient 6- or 6¢-methoxy-2¢-
diphenylphosphino-2-biphenylyllithium would collapse
to ‘9-phenyl-9-phosphafluorene’ (9-phenyl-1H-ben-
zo[b]phosphindole) under elimination of phenyllithium.26
Second, dilithiated biaryls can be readily generated if, and
only if, the two metal atoms are delivered to two separate
rings rather than twice to the same ring. Thus, 2,2¢,6,6¢-
tetrabromobiphenyl and 2,2¢,6-tribromo-6¢-methoxybi-
phenyl (5) produce the corresponding 2,2¢-biphenylene
dilithium neatly. Thirdly, and most importantly, all dibro-
mo- and tribromobiphenyls exhibit rigorous site selectiv-
ity when exposed to just one equivalent of butyllithium.
The halogen–metal exchange occurs exclusively in the
ring that carries the more electronegative substituents.
Such a distinct difference in permutation rates is without
precedent. All transformations allow an easy preparation
of the ligands on gram scale. The ligands are air- and
temperature-stable compounds.
O
O
[Ru]cat, ligand,
H2, 4 bar, EtOH
OH
O
OEt
OEt
R
R
Scheme 3
Table 1 Hydrogenation of b-Ketoesters Using Ruthenium
Complexes of Ligands 1–4a
R
Ru precursor
Ligand
Temp Time ee Conver-
(°C) (h) (%) sion (%)
H
H
H
H
H
RuCl3
RuCl3
RuCl3
RuCl3
RuCl3
1
2
3
4
50
50
50
50
3.5 99 100
15
15
15
88
87
4
98
95 100
MeOBIPHEP 50
3.0 99 100
Cl Ru2(p-cymene)2Cl4
Cl Ru2(p-cymene)2Cl4
Cl Ru2(p-cymene)2Cl4
Cl Ru2(p-cymene)2Cl4
1
2
3
4
80
80
80
80
2
15
2
88 100
45 98
80 100
87 100
92 100
48
1
Cl Ru2(p-cymene)2Cl4 MeOBIPHEP 80
Most atropisomeric biaryl bisphosphine ligands used for
asymmetric hydrogenations have C2-symmetry and, as a
consequence, identically substituted phosphine groups.3
The literature only shows very few C1-symmetric exam-
ples in this ligand class, none of them having a high struc-
tural or electronic diversity.21d,30–32 It was therefore highly
interesting to investigate the behavior of the biarylbis-
phosphines 1–4 as ligands in asymmetric hydrogenation
a Reaction carried out with S/C of 100. The ee values were determined
by HPLC analysis.
Next, we studied the hydrogenation of an olefin (dimeth-
ylitaconate). The hydrogenations were performed in
methanol at 2 bar hydrogen pressure with a substrate/cat-
alyst ratio (S/C) of 180 (Scheme 4).
Synlett 2006, No. 5, 766–770 © Thieme Stuttgart · New York

LETTER
Ligand Tailoring
769
[Ru]- or [Rh]catalyst,
ligand, H2, P (bar),
MeOOC
MeOOC
[Rh]cat, ligand,
COOR
Ph
COOR
O
Ph
H2, 2 bar, MeOH
HN
MeOH
HN
COOMe
COOMe
O
Scheme 4
Scheme 5
Table 2 Hydrogenation of Dimethyl Itaconate Using Rhodium
Complexes of Ligands 1–4a
tioselectivities were only moderate with the all-alkyl
ligand 2 performing best, followed by the all-aryl ligand
1. Use of the mixed ligands 3 and 4 results in very poor ee.
A completely different picture was found upon hydro-
genating 2-acetaminocinnamic acid methyl ester over Rh
catalysts at low pressure and room temperature. Here, the
mixed aryl-alkyl ligand 3 performs very well, giving high
ee as well as fast reaction rates (94% ee and 100% conver-
sion, better than MeDUPHOS). Use of the alternative
mixed ligand 4 results in a slower hydrogenation and
lower enantioselectivity (Table 3).
Rh precursor
Ligand
Temp Time ee
Conver-
sion (%)
(°C)
(h)
(%)
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
1
2
3
4
22
3
2
100
60
22
15
2
24
30
89
22
100
57
22
15
3
JOSIPHOSb 22
71–97c 100
a Reaction carried out with S/C of 180.
In summary, strategies have been devised and applied
enabling the modular assembly of chiral biarylbisphos-
phines. The four model compounds 1–4 are just meant to
illustrate the almost inexhaustible possibilities for creat-
ing structural diversity. The aliphatic or aromatic substit-
uents at phosphorus may be varied at will, the methoxy
entity may be replaced by any other carbon or hetero unit
and additional groups may be introduced. All the methods
employed were straightforward and expedient enough to
provide the bisphosphines 1–4 rapidly and in sufficient
amounts.
b 1-(S)-[1(R)-(Dicyclohexylphosphanyl)ethyl]-2-(diphenylphos-
phanyl)ferrocene.
c The ee is highly dependent on the hydrogen pressure. Reaction at 1
bar gave 97% ee, at 2 bar 71% ee.
A remarkably high diversity of the investigated ligands in
terms of enantioselectivity as well as reactivity could be
observed. While the ligands 1 and 3 give a fast and com-
plete reaction with low ee, it is the complementary ligand
4, which leads to a high enantioselectivity, albeit with a
clearly lower hydrogenation rate. The all-alkyl ligand 2
performs poor in both respects, indicating that at least one
electron-poor phosphorus atom needs to be present in the
catalyst.
The four ligands 1–4 behave very differently in the cata-
lytic hydrogenation and their relative performance is
strongly dependent on the substrate. It is interesting to
note that each ligand has the best ee performance in one of
the test reactions and that ligands 1 and/or 3 are among the
best concerning reaction rates in all cases. The findings
underline the importance to be able to prepare biarylbis-
phosphine ligands in a modular way in order to answer
rapidly and efficiently on catalytic needs.
The third benchmark system, the hydrogenation of 2-
acetaminocinnamic acid (Scheme 5), was performed in
methanol according to the conditions given in Table 3.
2-Acetaminocinnamic acid was hydrogenated over Ru
catalysts at elevated temperature and pressure. The enan-
Table 3 Hydrogenation of Acetamino Cinnamates Using Ruthenium and Rhodium Complexes of Ligands 1–4
R
Ligand
S/C
500
500
500
500
500
100
100
100
100
Temp (°C)
P (bar)
Time (h)
ee (%)
43
Conversion (%)
H
1a
40
40
40
40
40
25
25
25
25
50
50
50
50
60
2
5
15
6
100
34
H
2a
66
H
3a
8
100
84
H
4a
15
15
3.3
4.7
15
10
13
H
BINAPa
45
100
100
100
93
Me
Me
Me
Me
2b
90
3b
2
94
4b
2
81
MeDUPHOSb
2
91
100
a Catalyst precursor was Ru2(benzene)2Cl4.
b Catalyst precursor was Rh(cod)2BF4.
Synlett 2006, No. 5, 766–770 © Thieme Stuttgart · New York

770
F. Leroux, H. Mettler
LETTER
(23) (a) Duprat de Paule, S.; Champion, N.; Vidal, V.; Genêt, J.-
P.; Dellis, P. FR 2830254, 2001; Chem. Abstr. 2001, 1138,
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Genêt, J.-P.; Dellis, P. WO 2003029259, 2002; Chem. Abstr.
2001, 1138, 280367. (c) See also: Pai, C. C.; Li, Y. M.;
Zhou, Z. Y.; Chan, A. S. C. Tetrahedron Lett. 2002, 43,
2789.
Acknowledgment
The authors are indebted to the Bundesamt für Berufsbildung und
Technologie (Bern) for financial support in the framework of a KTI
project (contract 5474.1 KTS). F.L. is much indebted to Prof. M.
Schlosser, Lausanne, for countless precious advice.
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Vidal, V.; Genêt, J.-P.; Champion, N.; Dellis, P. Angew.
Chem. Int. Ed. 2004, 43, 320.
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n-BuLi (0.10 mol) in hexanes (63 mL) was added at –75 °C
to a solution of 2,2¢,6,6¢-tetrabromo-1,1¢-biphenyl (47 g,
0.10 mol) in THF (500 mL). The mixture was consecutively
treated with fluorodimethoxyborane diethyl ether (19 mL,
16 g, 0.10 mol), a 3.0 M aq solution of NaOH (36 mL) and
30% aq H2O2 (10 mL, 3.6 g, 0.10 mol). The reaction mixture
was neutralized at 25 °C with 2.0 M HCl (100 mL) and
extracted with Et2O (3 × 100 mL). The combined organic
layers were washed with a 10% aq solution of Na2SO3 (100
mL), dried over Na2SO4 and evaporated. The oily residue
was dissolved in DMSO (200 mL) before MeI (7.5 mL, 17
g, 0.12 mol) and KOH powder (6.7 g, 0.12 mol) were
consecutively added. After 1 h, H2O (500 mL) was added
and the product was extracted with Et2O (3 × 100 mL). The
organic layers were dried over Na2SO4 and evaporated.
Crystallization from EtOH (100 mL) afforded 35 g (82%)
product as colorless cubes; mp 184–185 °C. 1H NMR (400
MHz, CDCl3): d = 7.64 (d, J = 8.3 Hz, 2 H), 7.30 (m, 2 H),
7.11 (t, J = 8.1 Hz, 1 H), 6.96 (dd, J = 7.2, 2.2 Hz, 1 H), 3.77
(s, 3 H). 13C NMR (101 MHz, CDCl3): d = 157.6, 139.5,
131.5, 130.5, 130.2, 125.1, 124.6, 124.3, 110.0, 56.3. Anal.
Calcd (%) for C13H9Br3O (420.92): C, 37.09; H, 2.16.
Found: C, 37.10; H 2.03.
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