First modular synthesis of dissymmetric biaryldiphosphine ligands allowing tunable steric and electronic effects

Article abstract of DOI:10.1002/adsc.200600300

The first modular synthesis of a family of C₁-symmetric diphosphine ligands is presented. Their synthesis is based on unprecedented highly regioselective halogen/metal interconversions on a common polybrominated biaryl precursor. This methodology allows the functionalization of the ortho- and ortho'-positions of the biaryl core. Diphosphine ligands carrying only one substituent at the 6-position and the two phosphine substituents at the 2- and 2′-position become easily accessible. The two phosphine substituents may be identical (as in compounds 2 and 3) or different (as in compounds 1 and 4). All diphosphines were prepared on gram scale, and the enantiopure ligands were obtained by chromatography of the racemate on a chiral HPLC column. The asymmetric hydrogenation of β-keto esters, acetamidocinnamates and dimethyl itaconate revealed good to excellent asymmetric inductions of up to 99 % ee, and are often close to those of the well-known C₂-symmetric MeO-BIPHEP.

Full text of DOI:10.1002/adsc.200600300

FULL PAPERS
DOI: 10.1002/adsc.200600300
First Modular Synthesis of Dissymmetric Biaryldiphosphine
Ligands Allowing Tunable Steric and Electronic Effects
FrØdØric R. Lerouxa,* and Hanspeter Mettlerb
a
Laboratoire de StØrØochimie (UMR CNRS 7509), UniversitØ Louis Pasteur (ECPM), 67087 Strasbourg Cedex 2, France
Fax : (+33)-3-9024-2742; e-mail: frederic.leroux@ecpm.u-strasbg.fr
LONZA AG, 3930 Visp, Switzerland
b
Fax : (+41)-27-947-5697
Received: June 22, 2006; Published online: January 8, 2007
Abstract: The first modular synthesis of a family of phines were prepared on gram scale, and the enan-
C1-symmetric diphosphine ligands is presented. Their tiopure ligands were obtained by chromatography of
synthesis is based on unprecedented highly regiose- the racemate on a chiral HPLC column. The asym-
lective halogen/metal interconversions on a common metric hydrogenation of b-keto esters, acetamidocin-
polybrominated biaryl precursor. This methodology namates and dimethyl itaconate revealed good to ex-
allows the functionalization of the ortho- and ortho’- cellent asymmetric inductions of up to 99% ee, and
positions of the biaryl core. Diphosphine ligands car- are often close to those of the well-known C2-sym-
rying only one substituent at the 6-position and the metric MeO-BIPHEP.
two phosphine substituents at the 2- and 2’-position
become easily accessible. The two phosphine sub-
stituents may be identical (as in compounds 2 and 3) Keywords: asymmetric catalysis; atropisomerism;
or different (as in compounds 1 and 4). All diphos- biaryls; diphosphines; lithiation
Introduction
Finally, the option of planar chirality was explored
leading to paracyclophane[16] and ferrocene[17–20] based
The use of chiral transition metal complexes as homo- diphosphines. Togniꢀs JOSIPHOS ligand family[21–23]
geneous catalysts is a well established and highly at- belonging to the latter category deserves particular at-
tractive strategy for the synthesis of optically active tention, as it offers the unique advantage to enable a
products. Chiral phosphorus compounds are very effi- modular ligand construction with utmost structural
cient ligands for many important reactions involving flexibility (Scheme 1). The first variable is introduced
late transition metals. Consequently, the quest for as the aliphatic group R at the level of an (a-hydroxy-
new efficient ligand systems is a major challenge in alkyl)ferrocene which is either made by acylation of
catalysis research.[1–3]
ferrocene followed by reduction or by addition of or-
Three dominant ligand classes, privileged because
of their versatility and their enantioselective perfor-
mance, can be recognized.
Diphosphines containing asymmetric carbon cen-
ters were the first to replace mono- and diphos-
phines[4–6] having stereogenic phosphorus atoms and
were equally the first to gain practical importance.
DIOP,[7] CHIRAPHOS[8] and, more recently, the
DUPHOS family[9] have been featured by most im-
pressive results in the area of asymmetric hydrogena-
tion reactions.
Diphosphines supported on stereogenic atropiso-
meric biaryl scaffolds like MeO-BIPHEP,[10,11] SEG-
PHOS[12,13] and BINAP,[14,15] which is without any
doubt the most popular of all ligands, became very ef-
ficient chiral inductors in most stereoselective reac-
tions.
Scheme 1. Modular synthetic access to ferrocene based li-
gands.
Adv. Synth. Catal. 2007, 349, 323 – 336
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323

FrØdØric R. Leroux and Hanspeter Mettler
FULL PAPERS
ganozinc species to formylferrocene, a reaction which
may even be accomplished enantioselectively when
conducted in the presence of chiral auxiliaries. The al-
cohol is subsequently treated with acetic acid anhy-
dride and dimethylamine to afford an a-aminoferro-
cene which can be resolved in its antipodes. Butyl-
lithium-promoted deprotonation occurs exclusively at
one of the two diastereotopic sites flanking the side
chain. Using the appropriate chlorophosphine, any di-
organylphosphino group can be now attached to this
position. Finally, the dimethylamino group can be re-
placed by a second diorganylphosphino moiety or a
suitable aliphatic, aromatic or heterocyclic amine
(Scheme 1).
Scheme 2. Four target ligands demonstrating the modular
construction of biaryl-based ligands.
Such a modular access to a whole ligand family is
much more difficult to realize in the field of atropiso-
meric biaryl ligands. Few examples are known so far
and they only allow restricted structural diversity. the presence of just one kind of halogen, preferably
Both the aryl phosphorus substituents and the biaryl bromine, in a common starting material. These bro-
backbone are tunable parts to modify the stereoelec- mine atoms should be replaced successively by a
tronic profile of a ligand. So far, most modifications metal and ultimately by phosphorus groups or other
focused on the phosphorus substituents, influencing substituents. However, this raised the question of how
the steric hindrance around the metal and/or the elec- to discriminate chemically between formally identical
tronic properties of the phosphorus center.[24–27] Steric halogen atoms.[33–36]
modifications of the biaryl core were realized by
Zhang,[28] Saito[12,13] and GenÞt.[29,30] These groups
could show that the dihedral angle between the two Results and Discussion
phenyl rings correlates well with the enantioselective
performance of the ligand. However, the electronic Ligand Synthesis
design of atropisomeric diphosphine ligands has been
less systematically studied.[31,32] It remains a challenge From our preliminary studies on the synthesis of biar-
to prepare in parallel ligand families in a modular yldiphosphines, we knew that there was a major ob-
way allowing the fine-tuning of the steric and elec- stacle to be overcome. Indeed, any 2’-diphenylphos-
tronic properties of a ligand and thus to tailor the phino-2-biphenyllithium generated as an intermediate
metal complex according to specific substrate needs.
would be unable to produce a diphosphine by conden-
Our objective was to apply the concept of modular sation with a second chlorodiorganylphosphine com-
ligand assembly (well known from the ferrocene- ponent if a halogen atom, a methoxy- or a dimethyl-
based JOSIPHOS ligand family) to the series of atro- amino group occupies the 6-position (Scheme 3).[37,38]
pisomeric biaryls. A specific goal was to synthesize Due to the small torsion angle between the two
C1-symmetric diphosphines that carry only one sub- phenyl rings, the intermediate would rather undergo
stituent at the 6-positions. For historical reasons, most an instantaneous nucleophilic substitution at phospho-
of the diphosphine ligands in asymmetric catalysis are rus and cyclize under phenyllithium elimination to
C2-symmetric, although this symmetry is not a prereq- afford a “9-phosphafluorene” (1H-benzo[b]phosphin-
uisite. As a model compound we have chosen the dole).
well-known MeO-BIPHEP ligand due to its excellent
However, we could show that the undesired ring
and well documented catalytic properties. We decided closure can be avoided by the introduction of a later
to remove one of the methoxy substituents in order to removable “dummy” substituent at the 6’-position. In
get a C1-symmetric diphosphine. In addition, all possi- fact, an increasing dihedral angle between the two
ble permutations of bisdiaryl-, bisdialkyl- and mixed phenyl rings favors the diphosphine formation with
diaryl-dialkyldiphosphines should be prepared in respect to the “9-phosphafluorene” formation.
order to demonstrate the feasibility of a modular
ligand construction (Scheme 2).
Our first choice fell on bromine as “dummy” sub-
stituent. All four 2’-methoxy-2,6-biphenylenediphos-
Polar organometallic chemistry allows one to per- phines 1–4 were prepared starting from 2,2’,6,6’-tetra-
form highly selective reactions. Therefore, it seemed bromobiphenyl.[35,39] The latter can be obtained by
to us the ideal tool to realize our goal. As the objec- lithiation of 1,3-dibromobenzene, followed by copper-
tive had to cope with a high structural complexity, we mediated aryl-aryl coupling, according to a new, low-
decided, for reasons of logistic simplicity, to allow for temperature modification of the classic Ullmann cou-
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Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands
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yield of 56% by stepwise bromine/lithium permuta-
tion. The bromophosphine 8 (79%) acted hereby as
an intermediate. Finally, 2,2’,6-tribromo-6’-methoxybi-
phenyl (5) was converted into the diiodo compound 9
by double bromine/lithium interconversion and subse-
quent trapping with iodine. Two consecutive halogen/
metal permutations, the first followed by condensa-
tion with chlorodicyclohexylphosphine, led to the
second mixed diphosphine 1 (62%) via the bromoio-
dophosphine (10; 72%) and the bromodiphosphine
(11; 63%) (Scheme 4).
All the methods employed were straightforward
and expedient enough to provide the diphosphines 1–
4 rapidly and in sufficient amounts. Several transfor-
mations described above revealed an unprecedented
selectivity of the halogen/metal permutation mode.
As one can deduce from the transformation of
tribromo
A
AHCTREUNG
to the phosphine 8, it is always the halogen residing
in the more electronegatively substituted ring which is
replaced by lithium. We could show by ab initio calcu-
lations and equilibration studies, that a bromine atom
stabilizes more efficiently a carbanion in its meta posi-
tion than a methoxy substituent. This explains the re-
gioselectivity of the bromine/lithium exchange of
Scheme 3. Formation of “9-phosphafluorenes”.
tribromo(methoxy)biphenyl (5). These results will be
U
pling.[40–42] 2,2’,6,6’-Tetrabromobiphenyl undergoes published elsewhere in due course.
easily a bromine/lithium exchange using butyllithium
in tetrahydrofuran at À758C. The methoxy substitu-
ent of the target ligands was easily introduced, by Racemate Resolution
submitting the aryllithium intermediate to a boryla-
tion, oxidation and O-methylation sequence affording The four racemic ligands 1–4 were separated in their
2,2’,6-tribromo-6’-methoxybiphenyl (5; 82%).
A
enantiomers by means of semi-preparative HPLC
double bromine/lithium interconversion and subse- chromatography on a CHIRALCELꢂ OD column.
quent condensation with two equivalents of chlorodi- However, in order to avoid laborious individual reso-
phenylphosphine gave 2-bromo-6’-methoxy-2’,6-bis- lution protocols in each single case, we decided to de-
(diphenylphosphine) (6; 71%) which could be readily velop a second-generation approach (Scheme 5) using
reduced to the halogen-free diphosphine 2 (57%).
a common starting material which should be resolved
The intriguing question was whether one bromine at an early synthetic stage. Thus, 2,2’-dibromo-6-hy-
of 5 would be exchanged preferentially if the two-fold droxy-6’-(trimethylsilyl)biphenyl (12) was selected to
halogen/metal permutation was not carried out simul- become the new turntable. The trimethylsilyl group
taneously but successively. An effective discrimination had to face two problems. First to avoid the undesired
between two bromine atoms as a function of their “9-phosphafluorene” formation and second to give
chemical environment has so far been observed only rise to a resolvable biphenyl.
sporadically in such kind of processes.[34,36,43] Fortu-
Consecutive treatment of 2,2’,6,6’-tetrabromobi-
nately, the reaction occurred exclusively in the doubly phenyl with butyllithium, chlorotrimethylsilane, again
halogenated ring when 2,2’,6-tribromo-6’-methoxybi- butyllithium, fluorodimethoxyborane and alkaline hy-
phenyl (5) was treated with just one equivalent of bu- drogen peroxide produced the phenol 12 in 56%
tyllithium in tetrahydrofuran at À758C. Protolysis overall yield through 2,2’,6-tribromo-6’-(trimethylsi-
with methanol provided 2,2’-dibromo-6-methoxybi- lyl)biphenyl (15; 91%). Alternatively, the phenol (12;
phenyl (7; 92%) which was readily converted into 59% overall) was obtained from 2,2’,6,6’-tetrabromo-
2,2’-bis(dicyclohexylphosphine)-6-methoxybiphenyl
biphenyl by halogen/metal permutation followed by
(3; 74%) by double bromine/lithium exchange fol- borylation and oxidation giving 2,2’,6-tribromo-6’-hy-
lowed by trapping with two equivalents of chlorodicy- droxybiphenyl (13; 81%), protection of the latter as
clohexylphosphine. In contrast, the mixed P,P-dicyclo- the acetal (14; 88%), another halogen/metal permuta-
hexyl-P’,P’-diphenyldiphosphine 4 was obtained in a tion and subsequent silylation (to the acetal 16: 83%)
Adv. Synth. Catal. 2007, 349, 323 – 336
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325

FrØdØric R. Leroux and Hanspeter Mettler
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Scheme 4. Modular synthetic access to atropisomeric biphenyl ligands. Reagents and conditions: [a] Butyllithium (1.0 equiv.)
in tetrahydrofuran (THF) at À758C. [b] Butyllithium (2.0 equivs.) in THF at À758C. [c] (i) Fluorodimethoxyborane·diethyl
etherate; (ii) aqueous sodium hydroxide/hydrogen peroxide. [d] Methyl iodide, potassium hydroxide in dimethyl sulfoxide.
[e] Iodine (2.0 equivs.). [f] Methanol. [g] Chlorodicyclohexylphosphine (1 equiv.). [h] Chlorodicyclohexylphosphine
(2.0 equivs.). [i] Chlorodiphenylphosphine (1.0 equiv.). [j] Chlorodiphenylphosphine (2.0 equivs.). [k] Butyllithium
(2.0 equivs.) in toluene at +258C. [l] Butyllithium (1.0 equiv.) in diethyl ether (DEE) at À758C.
Efficient racemate resolution of phenol 12 was ac-
complished by preparative HPLC chromatography
using a chiral stationary phase (CHIRALCELꢂ OD
20 mm, n-heptane/2-butanol, 100:2). The pure enantio-
mers (R)-12 and (S)-12 were converted into the me-
thoxy compounds (R)-17 (96%) and (S)-17 (95%) by
alkylation with iodomethane.
When 2,2’-dibromo-6-methoxy-6’-(trimethylsilyl)bi-
phenyl (17) was treated with two equivalents of butyl-
lithium and subsequently trapped with chlorodiphe-
nylphosphine or chlorodicyclohexylphosphine, the re-
spective diphosphines 18 (89%) and 19 (76%) were
obtained (Scheme 6). Unfortunately, the protodesily-
lation underwent in the case of 18 very reluctantly
(43% of diphosphine 2) and failed completely in the
case of the diphosphine 19. Although silanes are quite
frequently used as protective groups in organometal-
lic chemistry,[44] this approach leading to chiral biaryl-
diphosphines was unsuccessful and had to be aban-
doned. Presently, we are studying the use of chiral
auxiliaries for the resolution of these biaryldiphos-
Scheme 5. Racemate resolution of a common precursor.
and deprotection. The methoxy-derivative 17 was ob- phines. These results will be presented elsewhere in
tained after alkylation of the phenol 13 with iodome- due course.
thane.
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Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands
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Scheme 6. Attempt to use silylated precursors. Reagents and conditions: [a] Butyllithium (2.0 equivs.) in toluene at À758C.
[b] Chlorodiphenylphosphine (2.0 equivs.). [b’] Chlorodicyclohexylphosphine (2.0 equivs.). [c] TBAF·H2O in DMF at 1208C,
3 days.
Benchmark Hydrogenation Studies
tography using a chiral stationary phase (CHIRAL-
CELꢂ OD 20 mm, n-heptane/EtOH, 2000:1).
Most atropisomeric biaryldiphosphine ligands used
for asymmetric hydrogenations have C2-symmetry
and, as a consequence, identically substituted phos- Hydrogenation of Ethyl Acetoacetate
phine groups.[3] The literature shows only very few C1-
symmetric examples in this ligand class, none of them The keto group in ethyl acetoacetate can be hydro-
having a high structural or electronic diversity.[27,45,46] genated with a variety of catalysts. A very simple
It was therefore intriguing to investigate the behavior method for performing this reaction with easy avail-
of the biaryldiphosphines 1–4 as ligands in asymmet- able, stable RuCl3 as precursor and in situ formation
ric hydrogenation reactions.
of the active catalyst was described by Madec et al.[47]
Good results have been reported in the literature and adopted for our benchmark studies. The refer-
for the rhodium- and ruthenium-catalyzed asymmetric ence ligand, MeO-BIPHEP gave a fast reaction with
hydrogenations of olefins and ketones. Therefore, we high ee (entry 5 in Table 1). A similar performance
chose to perform the benchmark reactions with b- was found for ligand 2 (entry 2 in Table 1), whereas
keto esters and two acryl ester substrates in order to the other ligands gave slower reactions and lower ees
gather information on the applicability range of the (entries 1, 3 and 4 in Table 1).
new catalysts. All experiments were performed in
screening type equipment with the objective to see
differences between ligands for different substrates. Hydrogenation of Ethyl 4-Chloroacetoacetate
Optimization of the hydrogenation conditions was not
attempted. The racemic ligands 1–4 were separated If a coordinative functional group such as a chloride
into their enantiomers by preparative HPLC chroma- exists in the proximity of the carbonyl group of a b-
Table 1. Hydrogenation of ethyl acetoacetate using Ru complexes of ligands 1–4.[a]
Entry S/C Ligand
Hydrogen uptake [h] Total reaction time [h] ee [%] Conversion [%] TOF [hÀ1][b]
1
2
3
4
5
158
194
158
160
160
1
2
3
4
15
3.5
15
15
15
6
15
15
95
99
8798
88
100
100
11
55
10
4
0.4
MeO-BIPHEP
3.0
799
100
53
[a]
All reactions were conducted with 1.1 mol substrate in 7mL EtOH at 4 bar hydrogen and 50 8C with RuCl3 as catalyst
precursor. The enantiomeric excesses were determined by GC analysis on a Lipodex-E column (25 m”0.25 mm).
The turnover frequency (TOF) is measured as mol of product per mol of catalyst per hour of hydrogen uptake time.
[b]
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327

FrØdØric R. Leroux and Hanspeter Mettler
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keto ester, lower enantioselectivity will be observed
Matteoli et al.[48] described the ruthenium-catalyzed
due to the competition of two different coordination hydrogenation of the free acid in MeOH in the pres-
patterns. However, the enantioselectivity can be im- ence of BINAP as ligand and the dimeric [Ru-
proved under higher reaction temperatures. Under
A
the Madec conditions with RuCl3 as precursor and they reported a very long reaction time of 113 h at
MeO-BIPHEP as ligand, the hydrogenation of ethyl 408C and 100 bar, leading to an enantioselectivity of
4-chloroacetoacetate gave 72% ee at 808C and 92% only 50%. In our case the reaction was finished after
ee at 1208C (entries 1 and 2 in Table 2). If the dimeric 29 h at 408C and 60 bar and with an S/C-ratio of 250,
[Ru(p-cymene)Cl2]2 was used as precursor, the ee giving an ee of 45% (entry 1 in Table 3). A better
G
values were 92% at 808C and 95% at 1208C (en- enantioselectivity of 66% but very slow reaction was
tries 3 and 4 in Table 2). As the enantioselectivity of found for ligand 3 (entry 4 in Table 3). Ligand 2 gave
the reaction seems to be less temperature-dependent approximately the same ee but much faster reaction
when starting from the dimeric ruthenium precursor, compared to BINAP (entry 3 in Table 3). Very low
we chose to use these conditions for the benchmark enantioselectivities were achieved when using ligands
tests. The temperature of 808C will generally not lead 1 and 4 (entries 2 and 5 in Table 3).
to the optimal ee values but is more convenient for
Holz et al.[49] have used a cationic rhodium complex
observing and measuring the reaction time and was of MeDuphos for the asymmetric hydrogenation of
therefore applied as standard for the benchmarks. the methyl ester and reported fast reactions with high
Ligand 2 performed best from the new candidates enantioselectivities in dichloromethane (98.0% ee) as
with an ee only slightly lower compared to the refer- well as in methanol (97.5% ee). We observed an ex-
ence ligand MeO-BIPHEP (entry 6 in Table 2). A tremely slow hydrogenation in dichloromethane with
similar enantioselectivity but much lower reactivity much lower enantioselectivity (entry 1 in Table 4).
was observed for ligand 1 (entry 5 in Table 2). Where- The reaction in methanol however was as expected
as ligand 4 still allowed a decent ee, ligand 3 per- (97% ee, see entry 2 in Table 4) and we chose to use
formed poor in enantioselectivity as well as reactivity these conditions for the benchmark system. The
(entries 7and 8 in Table 2).
MeO-BIPHEP ligand performed very poorly with this
substrate and gives only 27% ee (entry 3 in Table 4).
The three tested new ligands gave surprisingly high
enantioselectivities of 90–94% (entries 4–6 in Table 4)
and were reasonably active, with the exception of
ligand 1.
Hydrogenation of Acetamidocinnamic Acid
Derivatives
Acetamidocinnamic acid and its derivatives are
widely used substrates for testing new ligands in the
asymmetric hydrogenation of a carbon-carbon double Hydrogenation of Dimethyl Itaconate
bond. In general, rhodium catalysts are used and elec-
tron-rich ligands are favored for achieving high reac- Many successful ligands have been reported for the
tivity as well as enantioselectivity.
hydrogenation of dimethyl itaconate. Among them
Table 2. Hydrogenation of ethyl 4-chloroacetoacetate using Ru-complexes of ligands 1–4.[a]
Entry S/C Ligand
T [8C] Hydrogen uptake [h] Total reaction time [h] ee [%] Conversion [%] TOF [hÀ1][c]
1[b]
2[b]
3
4
5
100 MeO-BIPHEP 80
1
2
15
4
3
4
48
4
72
92
92
95
87100
88
45
100
100
100
100
99
49
324
100 MeO-BIPHEP 120
200 MeO-BIPHEP 80
200 MeO-BIPHEP 120
0.6
<0.5b
48
2
15
2
>400
200
200
1
2
3
4
80
80
80
80
4
6
100
98
100
95
13
102
7200
8
18
3
200
80
[a]
All reactions were conducted with 5 mmol substrate in 30 mL EtOH at 4 bar hydrogen with Ru2(p-cymene)2Cl4 as precur-
A
sor. The enantiomeric excesses were determined by GC-analysis on a Lipodex-E column (25 m”0.25 mm).
RuCl3 used as precursor, 15 mmol substrate, most of the substrate was hydrogenated during the heat-up phase.
The turnover frequency (TOF) is measured as mol of product per mol of catalyst per hour of hydrogen uptake time.
[b]
[c]
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Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands
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Table 3. Hydrogenation of acetamidocinnamic acid using Ru-complexes of ligands 1–4.[a]
Entry
Ligand
Hydrogen uptake [h]
Total reaction time [h]
ee [%]
Conversion [%]
TOF [hÀ1][c]
1
2
3
4
5
BINAP
<29[b]
29
15
16
15
15
45
13
43
66
8
100
84
100
34
>8
14
49
6
1
2
3
4
15
5
15
5
100
49
[a]
All reactions were conducted with 2.5 mmol substrate in 5 mL MeOH at 50 bar hydrogen and 408C with
Ru2(benzene)2Cl4 as precursor. S/C ratio was 250. The enantiomeric excesses were determined by HPLC analysis on a
ACHTREUNG
Nucleodex beta PM column.
[b]
[c]
Reaction at 60 bar pressure, exact uptake time not known due to data sampling problem.
The turnover frequency (TOF) is measured as mol of product per mol of catalyst per hour of hydrogen uptake time.
Table 4. Hydrogenation of methyl acetamidocinnamate acid using Rh-complexes of ligands 1–4.[a]
Entry Ligand
Solvent Hydrogen uptake [h] Total reaction time [h] ee [%] Conversion [%] TOF [hÀ1][d]
1
2
3
4
5
6
MeDuphos[b]
MeDuphos[b]
MeO-BIPHEP[c] MeOH
CH2Cl2 24
MeOH 2.5
24
22
24
15
15
83
6
0.3
97100
2798
93
40
25
4.0
1
3
4
MeOH 15
MeOH
MeOH
81
100
5
3.3
4.715
90
29
(COD)2BF4 as
94
100
20
[a]
All reactions were conducted with 0.5 mmol substrate in 6 mL solvent at 1 bar hydrogen and 258C with Rh
ACHTREUNG
precursor. S/C ratio was 100. The enantiomeric excesses were determined by GC analysis on a Lipodex-E column (25 m”
0.25 mm).
[b]
[c]
[d]
2 mmol substrate in 30 mL solvent, the finished [Rh
2 mmol substrate in 30 mL solvent, reaction at 4 bar hydrogen.
The turnover frequency (TOF) is measured as mol of product per mol of catalyst per hour of hydrogen uptake time.
A
G
the cationic rhodium complexes of MeDuphos Discussion of the Hydrogenation Results
(97.0% ee in THF at 1 bar pressure and 258C, see
Holz et al.[49]) and Josiphos (98.5% ee in MeOH at The ruthenium-catalyzed reduction of the keto func-
1 bar pressure and 258C, see Togni et al.[50]). We de- tion in ethyl acetoacetate works well with the known
cided to use the conditions as described by Togni for MeO-BIPHEP ligand. The relative performance of
this benchmark system. The Josiphos ligand gave a the four new ligands is ligand 2>ligand 1>ligand 4>
fast reaction and a high enantioselectivity (entry 1 in ligand 3 for stereoselectivity and ligand 2>ligand 1ꢀ
Table 5). From the new candidates, ligand 1 was the ligand 3>ligand 4 for activity. The relatively small
only one leading to a high enantioselectivity however change from MeO-BIPHEP to ligand 2 has obviously
with a very slow reaction (entry 2 in Table 5). Ligands little influence on the hydrogenation. Replacing the
2 and 4 showed a remarkably high reactivity but gave phenyl substituents against the cyclohexyl substituents
poor ees (entries 3 and 5 in Table 5). Ligand 3, finally, on one of the two phosphines leads to much lower ac-
was neither very active nor stereoselective (entry 4 in tivity and selectivity and one can differentiate be-
Table 5).
tween a matched case for ligand 1 and a mismatched
case for ligand 4. Low performance is noted with the
very electron rich all-cyclohexyl ligand 3.
The hydrogenation of 4-chloroacetoacetate follows
a similar pattern at least in terms of selectivity. The
Adv. Synth. Catal. 2007, 349, 323 – 336
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329

FrØdØric R. Leroux and Hanspeter Mettler
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Table 5. Hydrogenation of dimethyl itaconate using Rh-complexes of ligands 1–4.[a]
Entry
Ligand
Hydrogen uptake [h]
Total reaction time [h]
ee [%]
Conversion [%]
TOF [hÀ1][c]
1
2
3
4
5
Josiphos[b]
2.5
15
3
15
2
9
15
6
15
15
97100
89
2
24
30
3
577
100
60
7
1
2
3
4
59
7
89
100
[a]
All reactions were conducted with 0.9 mmol substrate in 5 mL methanol at 1 bar hydrogen and 258C with Rh(COD)2BF4
A
as precursor. S/C ratio was 180. The enantiomeric excesses were determined by GC analysis on a Lipodex-E column
(25 m”0.25 mm).
R,S-PPF-PCy2.
[b]
[c]
The turnover frequency (TOF) is measured as mol of product per mol of catalyst per hour of hydrogen uptake time.
relative performance of the four new ligands is ligand ligand 1 for activity. In this application we observe
2ꢀligand 1>ligand 4>ligand 3 for stereoselectivity the interesting fact that the two “mixed” ligands, i.e.,
and ligand 4>ligand 2>ligand 3>ligand 1 for activi- the ligands containing both cyclohexyl- and phenyl-
ty. It is most striking that ligand 4 which gave a slow phospine groups clearly outperform the other two li-
hydrogenation with ethyl acetoacetate shows the gands. The best match for enantioselectivity is ligand
highest activity for 4-chloroacetoacetate. None of the 1 with the cyclohexylphosphine located in the unsub-
four new ligands is as active and selective as the stituted phenyl ring and the best match for activity is
benchmark ligand MeO-BIPHEP under the chosen ligand 4 with the phenylphosphine located in the un-
conditions.
substituted phenyl ring.
In the rhodium-catalyzed hydrogenation of methyl
acetamidocinnamate, the relative performance of the
three tested candidates was ligand 4ꢀligand 1> Conclusions
ligand 3 for stereoselectivity and ligand 3>ligand 4>
ligand 1 for activity. It is rather surprising that all In summary, strategies have been devised and applied
three ligands give enantioselectivities of 90% or enabling the modular assembly of chiral biaryldiphos-
higher considering the much lower performance of phines. The four model compounds 1–4 are just
the related MeO-BIPHEP ligand (25%). The pres- meant to illustrate the almost inexhaustible possibili-
ence of at least one cyclohexyl-substituted phosphine ties for creating structural diversity. The aliphatic or
seems to play an important role for this application. aromatic substituents at phosphorus may be varied at
The best match for high activity is presented by the will, the methoxy entity may be replaced by any other
fully cyclohexyl-substituted ligand 3.
carbon or hetero unit and additional groups may be
Very different results are obtained in the case of introduced. All the methods employed were straight-
the ruthenium-catalyzed hydrogenation of acetoami- forward and expedient enough to provide the diphos-
docinnamic acid. Here, we find a relative perfor- phines 1–4 rapidly and in sufficient amounts.
mance of ligand 3>ligand 2>ligand 1>ligand 4 for
The access to the target compounds 1–4 relied on a
stereoselectivity and ligand 2=ligand 4>ligand 1> combination of strategies which deserve to be consid-
ligand 3 for activity. The electron rich fully cyclohex- ered individually. First, the introduction of a trime-
yl-substituted ligand 3 gives by far the highest enan- thylsilyl group or another removable “dummy” sub-
tioselectivity but, in contrast to the above benchmark, stituent is essential for the success. Without the pro-
has the lowest activity of all four tested ligands. The tection against planarization any transient 6- or 6’-me-
enantioselectivities of both MeO-BIPHEP and the re- thoxy-2’-diphenylphosphino-2-biphenylyllithium
lated ligand 2 are only mediocre with the latter show- would collapse to “9-phenyl-9-phosphafluorene” (9-
ing a much higher activity. Very poor enantioselectivi- phenyl-1H-benzo[b]phosphindene) under elimination
ties are found when applying the ligands 1 and 4 with of phenyllithium. Second, dilithiated biaryls can only
both cyclohexyl- and phenyl-substituted phosphines.
be readily generated if the two metal atoms are deliv-
In the rhodium-catalyzed hydrogenation of dimeth- ered into two separate rings rather than in the same
yl itaconate, the relative performance of the four new ring. Thus, 2,2’,6,6’-tetrabromobiphenyl,[36] and 2,2’,6-
ligands is ligand 1>ligand 4>ligand 3>ligand 2 for tribromo-6’-methoxybiphenyl (5) produce the corre-
stereoselectivity and ligand 4>ligand 2>ligand 3ꢀ sponding 2,2’-biphenylenedilithium. Thirdly and most
330
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Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands
FULL PAPERS
importantly, all dibromo- and tribromobiphenyls ex- 2’-(Dicyclohexylphosphino)-2-(diphenylphosphino)-6-
hibited rigorous site selectivity when exposed to just methoxy-1,1’-biphenyl (1)
one equivalent of butyllithium. The halogen/metal ex-
change occurred exclusively in the ring carrying the
At 08C, butyllithium (4.6 mmol) in hexanes (2.9 mL) was
added to
a solution of bromodiphosphine 11 (2.5 g,
more electronegative substituents, for example, bro-
mine as opposed to hydrogen, lithiooxy or methoxy
and methoxy as opposed to hydrogen, trimethylsilyl
or diorganylphosphino. Such a distinct difference in
permutation rates is without precedent.
3.9 mmol) in toluene (6.0 mL). After 1 h at 08C, methanol
(1 mL) was added followed by water (10 mL) and the organ-
ic layer was separated. The aqueous phase was extracted
with dichloromethane (2”20 mL) and the combined organic
layers were dried over sodium sulfate before being evapo-
rated. The residue was purified by silica gel chromatography
(hexane:ethyl acetate=9:1) affording the diphosphine 1.
Crystallization from ethyl acetate (10 mL) gave colorless
prisms; yield: 1.36 g (62%), mp 200–2038C; 1H NMR
(CDCl3, 400 MHz): d=7.50 (d, J=7.8 Hz, 1H), 7.2 (m,
12H), 6.98 (t, J=7.5 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.66
(ddd, J=7.7, 3.2, 0.9 Hz, 1H), 6.57 (ddd, J=7.5, 3.7, 1.2 Hz,
1H), 3.64 (s, 3H), 1.6 (m, 12H), 1.1 (m, 10H); 31P NMR
(CDCl3, 162 MHz): d=À8.7(d, J=13.1 Hz), À13.4 (d, J=
13.2 Hz); anal. calcd. for C37H42OP2 (564.27): C 78.70, H
7.50; found: C 78.42, H 7.65.
The racemic diphosphine 1 was separated into its enantio-
mers by preparative chromatography using a chiral station-
ary phase. The column used was CHIRALCELꢂ OD 20 mm,
the mobile phase was heptane/EtOH=2000:1. From 360 mg
racemic material 142 mg of (+)-6-dicyclohexylphosphanyl-
2’-diphenylphosphanyl-2-methoxy-1,1’-biphenyl (+)-1 and
123 mg of (À)-6-dicyclohexylphosphanyl-2’-diphenylphos-
phanyl-2-methoxy-1,1’-biphenyl (À)-1 were isolated. The en-
antiomeric purity of both compounds was 100% (measured
by HPLC on an analytic CHIRALCELꢂ OD 10 mm
column). (À)-1: [a]2D4: À1.4 (c 0.5 in CH2Cl2).
The four ligands 1–4 behave very differently in the
catalytic hydrogenation and their relative perfor-
mance is strongly dependent on the substrate. It is in-
teresting to note that each ligand has the best ee per-
formance in one of the test reactions and that ligands
1 and/or 3 are among the best concerning reaction
rates in all cases. The benchmark tests have shown
that no single ligand performs very well for a variety
of substrates. Each of the four new ligands has its
own merits and pitfalls, depending on the type of sub-
strate as well as the specific catalytic system used.
The variance in stereoselectivity and in activity
caused by switching from phenylphosphine to cyclo-
hexylphosphine is in some cases dramatic. It will now
be very intriguing to investigate how a fine-tuning of
the new ligands can be achieved by either variations
in the alkyl- and arylphosphine substituents or by
moving from 2-methoxybiphenyldiphosphines into re-
lated biphenyldiphosphines with other substituents in
the 2-position.[35,51]
2’,6-Bis(diphenylphosphino)-2-methoxy-1,1’-biphenyl
(2)
Experimental Section
At 08C, butyllithium (50 mmol) in hexanes (30 mL) was
added to a solution of compound 6 (16 g, 25 mmol) in tolu-
ene (0.1 L). After 45 min at 258C, methanol (2 mL) was
added followed by water (25 mL) and the organic layer was
separated. The aqueous phase was extracted with dichloro-
methane (2”25 mL) and the combined organic layers were
dried over sodium sulfate before being evaporated. Crystal-
lization from dichloromethane (50 mL) afforded colorless
prisms; yield: 7.9 g (57%); mp 227–2288C (decomposition);
1H NMR (CDCl3, 400 MHz): d=7.3 (m, 18H), 7.15 (dt, J=
6.8, 2.6 Hz, 4H), 7.06 (dt, J=7.3, 1.7 Hz, 2H), 6.82 (dd, J=
7.6, 4.2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.66 (dd, J=
7.9 Hz, 3.1, 1H), 3.22 (s, 3H); 13C NMR (CDCl3, 101 MHz):
d=157.1 (d, J=2 Hz), 144.1 (d, J=8 Hz), 143.8 (d, J=
8 Hz), 138.3, 137.4, 136.3 (d, J=8 Hz), 136.1 (d, J=7Hz),
134.5 (d, J=2 Hz), 133.9 (dd, J=20, 14 Hz), 133.3 (d, J=
19 Hz), 131.2 (dd, J=6, 4 Hz), 128.8, 128.4, 128.2, 128.0,
127.9 (d, J=2 Hz), 128.8, 127.6, 125.9 (d, J=2 Hz), 110.6,
54.7; 31P NMR (CDCl3, 162 MHz): d=À13.1 (d, J=
17.8 Hz), À13.6 (d, J=17.8 Hz); anal. calcd. for C37H30OP2
(552.59): C 80.42, H 5.47; found: C 80.53, H 5.52.
General Remarks
Tetrahydrofuran and diethyl ether were distilled from
sodium-benzophenone and stored under nitrogen in Schlenk
burettes. N,N-Dimethylformamide was dried by azeotropic
distillation with toluene. Butyllithium, sec-butyllithium and
tert-butyllithium were supplied by CheMetall AG, D-38685
Langelsheim. Other reagents were obtained from commer-
cial sources and checked using refraction index for liquids
and melting points for solids. Air- and moisture-sensitive
compounds were stored in Schlenk tubes or Schlenk bu-
rettes. Reactions at low temperatures were performed using
cold baths: water/ice at 08C, acetone/dry ice at À758C and
diethyl ether/liquid nitrogen at À1008C. The temperature
acetone/dry ice is consistently indicated at À758C and
“room temperature” as 258C. Melting ranges (mp) are re-
producible after resolidification unless otherwise stated
(“dec.”), and were corrected using a calibration curve.
1H NMR: Bruker DPX-400; chemical shift d in ppm relative
to tetramethylsilane (d=0.00) or relative to deuterated sol-
vent. Elemental analysis: Ilse Beetz, Microanalytisches Lab-
oratorium, D-96301 Kronach or F. Hoffmann-La Roche,
CH-4070 Basel. The expected percentages were calculated
using the atomic weight numbers listed in the 1999 IUPAC
recommendations.
The separation was performed as described for 1. (+)-
2:[a]20: 6.0 (c0.5 in CHCl3).
ThDe same ligand 2 could be prepared starting from race-
mic or enantiopure diphosphine 18 (0.62 g, 1.0 mmol) and
tetrabutylammonium fluoride hydrate (0.52 g, 2.0 mmol) in
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331

FrØdØric R. Leroux and Hanspeter Mettler
FULL PAPERS
N,N-dimethylformamide (5.0 mL). After heating at 1008C
for 20 h, 0.24 g (43%) of diphosphine 2 were obtained.
(47g, 0.10 mol) in tetrahydrofuran (500 mL). The mixture
was consecutively treated with fluorodimethoxyborane·
diethyl ether[52,53] (19 mL, 16 g, 0.10 mol), a 3.0M aqueous
solution of sodium hydroxide (36 mL) and 30% aqueous hy-
drogen peroxide (10 mL, 3.6 g, 0.10 mol). The reaction mix-
ture was neutralized at 258C with 2.0M hydrochloric acid
(100 mL) and extracted with diethyl ether (3”100 mL). The
combined organic layers were washed with a 10% aqueous
solution of sodium sulfite (100 mL), dried over sodium sul-
fate and evaporated. The oily residue was dissolved in di-
methyl sulfoxide (200 mL) before iodomethane (7.5 mL,
17g, 0.12 mol) and potassium hydroxide powder (6.7g, 0.12
mol) were consecutively added. After 1 h, water (500 mL)
was added and the product was extracted with diethyl ether
(3”100 mL). The organic layers were dried over sodium sul-
fate and evaporated. Crystallization from ethanol (0.10 L)
afforded the product as colorless cubes; yield: 35 g (82%);
2’,6-Bis(dicyclohexylphosphino)-2-methoxy-1,1’-
biphenyl (3)
At À758C, butyllithium (0.10 mol) in hexanes (63 mL) was
added to a solution of compound 7 (17g, 50 mmol) in tetra-
hydrofuran (250 mL). After the addition was completed, the
mixture was treated with a 2.0M solution of chlorodicyclo-
hexylphosphine (22 mL, 24 g, 0.10 mol) in tetrahydrofuran
(50 mL). The mixture was allowed to reach 258C and treat-
ed with a saturated aqueous solution of ammonium chloride
(100 mL). The mixture was extracted with ethyl acetate (3”
50 mL), and the combined organic layers were dried over
sodium sulfate. The diphosphine 3 was obtained after evapo-
ration of the solvents and crystallization form methanol
(100 mL) as colorless cubes; yield: 43 g (74%); mp 220–
2218C (decomposition); 1H NMR (CDCl3, 400 MHz): d=
7.56 (m sym., 1H), 7.4 (m, 3H), 7.16 (d, J=7.5 Hz, 1H),
7.08 (m sym., 1H), 6.88 (d, J=7.8 Hz, 1H), 3.66 (s, 3H), 1.7
(m, 24H), 1.2 (m, 20H). 6.99 (ddd, J=7.7, 2.9, 1.3 Hz, 1H),
6.8 (m, 3H), 6.63 (d, J=8.6 Hz, 1H), 3.01 (s, 3H); 13C NMR
(CDCl3, 101 MHz): d=157.5 (d, J=9 Hz), 148.4 (d, J=
25 Hz), 141.7, 137.8 (d, J=19 Hz), 136.2 (d, J=18 Hz),
134.0, 132.4, 127.1, 125.0, 124.1, 108.9, 54.0, 35.9 (d, J=
16 Hz), 34.0 (d, J=19 Hz), 32.5 (d, J=16 Hz), 32.1 (d, J=
20 Hz), 31.7(d, J=16 Hz), 30.6, 29.7, 28.7 (d, J=10 Hz),
28.0, 27.2, 26.4 (d, J=13 Hz); 31P NMR (CDCl3, 162 MHz):
d=À9.9 (d, J=12.1 Hz), À11.5 (d, J=12.2 Hz); anal. calcd.
for C37H54OP2 (576.79): C 77.05, H 9.44; found: C 77.17, H
9.14.
1
mp 184–1858C; H NMR (CDCl3, 400 MHz): d=7.64 (d, J=
8.3 Hz, 2H), 7.3 (m, 2H), 7.11 (t, J=8.1 Hz, 1H), 6.96 (dd,
J=7.2, 2.2 Hz, 1H), 3.77 (s, 3H); 13C NMR (CDCl3,
101 MHz): 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.
6-Bromo-2,6’-bis(diphenylphosphino)-2’-methoxy-1,1’-
biphenyl (6)
At À758C, butyllithium (0.10 mol) in hexanes (57mL) was
added to a solution of compound 5 (21 g, 50 mmol) in tetra-
hydrofuran (250 mL). The reaction mixture was treated with
a 2.0M solution of chlorodiphenylphosphine (18 mL, 22 g,
0.10 mol) in tetrahydrofuran (50 mL). The mixture was al-
lowed to reach 258C and treated with a saturated aqueous
solution of ammonium chloride (200 mL). The reaction mix-
ture was extracted with ethyl acetate (3”100 mL), and the
combined organic layers were dried over sodium sulfate.
Evaporation of the solvents and crystallization from ethyl
acetate (0.10 L) afforded colorless needles; yield: 23 g
The separation was performed as described for 1. The en-
antiomeric purity was 99.2% for the (À)-isomer and 96.9%
for the (+)-isomer (measured by HPLC on an analytic
CHIRALCELꢂ OD 10 mm column). (+)-3: [a]2D4: 16.4 (c 0.5
in CH2Cl2).
1
(71%); mp 224–2268C (decomposition); H NMR (CDCl3,
6-Dicyclohexylphosphanyl-2’-diphenylphosphanyl-2-
methoxy-1,1’-biphenyl (4)
400 MHz): d=7.56 (dd, J=8.0, 1.3 Hz, 1H), 7.38 (dt, J=7.0,
1.6 Hz, 2H), 7.3 (m, 12H), 7.1 (m, 6H), 6.99 (ddd, J=7.7,
2.9, 1.3 Hz, 1H), 6.8 (m, 3H), 6.63 (d, J=8.6 Hz, 1H), 3.01
(s, 3H); 13C NMR (CDCl3, 101 MHz): d=157.0 (dd, J=10,
2 Hz), 144.0 (dd, J=33, 7Hz), 141.2 (dd, J=13, 3 Hz), 138.4
(d, J=14 Hz), 138.1 (dd, J=10, 2 Hz), 137.3 (d, J=1 Hz),
137.2, 137.1, 136.2 (dd, J=14, 1 Hz), 135.5 (d, J=7Hz),
135.2 (d, J=6 Hz), 135.0 (d, J=11 Hz), 134.8 (d, J=7Hz),
134.6, 134.3, 134.1, 133.7(d, J=3 Hz), 133.6 (d, J=3 Hz),
133.1, 132.9, 132.8, 129.3, 128.8, 128.4, 128.2, 128.1, 127.9,
127.8, 126.6, 110.5, 54.4; 31P NMR (CDCl3, 162 MHz): d=
À10.1 (d, J=24.6 Hz), À13.9 (d, J=24.9 Hz); anal. calcd. for
C37H29BrOP2 (631.49): C 70.37, H 4.63; found: C 69.13, H
4.60.
At 08C, butyllithium (25 mmol) in hexanes (30 mL) was
added to a solution of compound 8 (11 g, 25 mmol) in tolu-
ene (100 mL). After 45 min the mixture was cooled to
À758C and a 1.0M solution of chlorodiphenylphosphine
(4.4 mL, 5.5 g, 25 mmol) in toluene (25 mL) was added. The
mixture was allowed to reach 258C. A saturated aqueous so-
lution of ammonium chloride (50 mL) was added and the or-
ganic layer was separated. The aqueous phase was extracted
with ethyl acetate (3”25 mL) and the combined organic
layers were dried over sodium sulfate before being evapo-
rated. Crystallization from methanol (50 mL) gave the di-
phosphine as colorless cubes; yield: 7.9 g (56%); mp 170–
1
1718C; H NMR (CDCl3, 400 MHz): d=7.3 (m, 16H), 6.78
(d, J=7.9 Hz, 1H), 3.23 (s, 3H); 31P NMR (CDCl3,
162 MHz): d=À11.3 (d, J=10.7Hz), À14.0 (d, J=10.8 Hz);
anal. calcd. for C37H42OP2 (564.69): C 78.70, H 7.50; found:
C 78.59, H 7.43; (À)-4: [a]2D0: À34.9 (c 0.5 in CH2Cl2).
2’,6-Dibromo-2-methoxy-1,1’-biphenyl (7)
At À758C, butyllithium (25 mmol) in hexanes (13 mL) was
added to a solution of compound 5 (11 g, 25 mmol) in tetra-
hydrofuran (200 mL). Immediately after the addition was
completed, methanol (2.0 mL) was added. After addition of
water (100 mL) the organic phase was separated and the
aqueous layer was extracted with ethyl acetate (3”30 mL).
The combined organic layers were dried over sodium sulfate
2,6,6’-Tribromo-2’-methoxy-1,1’-biphenyl (5)
Butyllithium (0.10 mol) in hexanes (63 mL) was added at
À758C to a solution of 2,2’,6,6’-tetrabromo-1,1’-biphenyl
332
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Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands
FULL PAPERS
before being evaporated. After crystallization from ethanol
treated with chlorodicyclohexylphosphine (2.2 mL, 2.3 g,
10 mmol). The mixture was allowed to reach 258C and treat-
ed with a saturated aqueous solution of ammonium chloride
(20 mL). The mixture was extracted with ethyl acetate (3”
20 mL), and the combined organic layers were dried over
sodium sulfate. After concentration of the solvent, the resi-
due was subjected to purification by silica gel chromatogra-
phy (hexane:ethyl acetate=9:1) to obtain the title com-
pound as a yellowish oil; yield: 4.2 g (72%); 1H NMR
(CDCl3, 400 MHz): d=7.58 (d, J=7.9 Hz, 1H), 7.5 (m, 2H),
7.17 (t, J=7.7 Hz, 1H), 7.01 (t, J=8.1 Hz, 1H), 6.80 (d, J=
8.3 Hz, 1H), 3.62 (s, 3H), 1.6 (m, 12H), 1.1 (m, 10H);
13C NMR (CDCl3, 101 MHz): d=159.3, 135.1 (d, J=7Hz),
131.0, 129.3, 128.7, 126.2, 125.1, 120.7, 113.0, 55.7, 35.4 (d,
J=18 Hz), 34.3 (d, J=13 Hz), 30.9 (d, J=15 Hz), 30.1 (d,
J=17Hz), 29.4 (d, J=6 Hz), 35.4 (d, J=18 Hz), 27.3, 26.4;
31P NMR (CDCl3, 162 MHz): d=À2.1 (s); anal.calcd. for
C25H31BrIOP (585.30): C 51.30, H 5.34; found: C 51.58, H
5.45.
(25 mL) 2’,6-dibromo-2-methoxy-1,1’-biphenyl was obtained
1
as colorless cubes; yield: 7.9 g (92%) mp 93–958C; H NMR
(CDCl3, 400 MHz): d=7.67 (d, J=8.0 Hz, 1H), 7.38 (t, J=
7.5 Hz, 1H), 7.3 (m, 4H), 6.92 (d, J=8.1 Hz, 1H), 3.73 (s,
3H); 13C NMR (CDCl3, 101 MHz): d=157.9, 138.8, 132.3,
131.6, 131.4, 129.9, 129.1, 127.5, 127.1, 124.5, 124.2, 110.0,
56.1; anal. calcd. for C13H10Br2O (342.03): C 45.32, H 2.95;
found: C 45.32, H 2.85.
(2’-Bromo-6-methoxy-1,1’-biphenyl-2-yl)dicyclohexyl-
phosphine (8)
At À758C, butyllithium (0.10 mol) in hexanes (63 mL) was
added to a solution of compound 7 (34 g, 0.10 mol) in tetra-
hydrofuran (500 mL). After the addition was completed, the
mixture was treated with a 2.0M solution of chlorodicyclo-
hexylphosphine (22 mL, 24 g, 0.10 mol) in tetrahydrofuran
(100 mL). The mixture was allowed to reach 258C and treat-
ed with a saturated aqueous solution of ammonium chloride
(200 mL). The mixture was extracted with ethyl acetate (3”
100 mL), and the combined organic layers were dried over
sodium sulfate. Evaporation of the solvents and crystalliza-
tion from a 9:1 mixture (v/v) hexanes/ethyl acetate (50 mL)
afforded colorless needles; yield: 36 g (79%); mp 100–
2-Bromo-6-(dicyclohexylphosphino)-2’-(diphenyl-
phosphino)-6’-methoxy-1,1’-biphenyl (11)
At À758C, butyllithium (10 mmol) in hexanes (6.3 mL) was
added to a solution of 10 (5.9 g, 10 mmol) in diethyl ether
(20 mL). After 15 min chlorodiphenylphosphine (1.8 mL,
2.2 g, 25 mmol) was added. The mixture was allowed to
reach 258C. A saturated aqueous solution of ammonium
chloride (20 mL) was added and the organic layer was sepa-
rated. The aqueous phase was extracted with ethyl acetate
(3”20 mL) and the combined organic layers were dried
over sodium sulfate before being evaporated. The residue
was subjected to purification by silica gel chromatography
(cyclohexane as eluent) to obtain the title compound as yel-
1
1028C; H NMR (CDCl3, 400 MHz): d=7.61 (d, J=7.8 Hz,
1H), 7.38 (t, J=7.9 Hz, 1H), 7.33 (t, J=7.3 Hz, 1H), 7.21
(dt, J=7.9, 1.5 Hz, 2H), 7.14 (dd, J=7.6, 1.8 Hz, 1H), 6.96
(d, J=8.2 Hz, 1H), 3.72 (s, 3H), 1.7 (m, 12H), 1.2 (m,
10H); 13C NMR (CDCl3, 101 MHz): d=157.8, 133.1 (d, J=
4 Hz), 132.0, 128.6, 128.1, 126.2, 125.1, 124.7, 111.0, 55.8,
35.4 (d, J=18 Hz), 34.3 (d, J=13 Hz), 30.9 (d, J=15 Hz),
30.1 (d, J=17Hz), 29.4 (d, J=6 Hz), 35.4 (d, J=18 Hz),
27.3, 26.4; 31P NMR (CDCl3, 162 MHz): d=À13.8 (s); anal.
calcd. for C25H32BrOP (459.41): C 65.36, H 7.02; found: C
65.52, H 7.07.
1
lowish oil; yield: 4.1 g (63%); H NMR (CDCl3, 400 MHz):
d=7.46 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.33
(dd, J=7.7, 2.4 Hz, 1H), 7.2 (m, 12H), 6.82 (d, J=7.4 Hz,
1H), 3.65 (s, 3H), 1.6 (m, 12H), 1.0 (m, 10H); anal. calcd.
for C37H41BrOP2 (643.57): C 69.05, H 6.42; found C 69.33, H
6.66; 31P NMR (CDCl3, 162 MHz): d=À8.7(d, J=13.1 Hz),
À13.4 (d, J=13.2 Hz).
2-Bromo-2’,6-diiodo-6’-methoxy-1,1’-biphenyl (9)
Butyllithium (30 mmol) in hexanes (19 mL) was added at
À758C to a solution of 5 (6.3 g, 15 mmol) in tetrahydrofuran
(75 mL). After 45 min, a solution of iodine (7.7 g, 30 mmol)
in tetrahydrofuran (20 mL) was added. At 258C, a 10%
aqueous solution of sodium thiosulfate was added (100 mL)
followed by extraction with ethyl acetate (3”50 mL). The
organic layer was dried over sodium sulfate before being
evaporated to dryness. Crystallization from a 9:1 mixture
(v/v) hexanes/ethyl acetate (30 mL) afforded colorless nee-
dles; yield 6.0 g (78%); 1H NMR (CDCl3, 300 MHz): d=
7.90 (dd, J=7.9, 1.1 Hz, 1H), 7.67 (dd, J=8.0, 1.1 Hz, 1H),
7.57 (dd, J=7.9, 0.9 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 6.99
(d, J=8.3 Hz, 1H), 6.93 (t, J=7.9 Hz, 1H), 3.78 (s, 3H);
13C NMR (CDCl3, 75 MHz): d=156.9, 145.8, 138.0, 132.5,
130.9 (2 C), 130.8, 130.5, 123.7, 111.0, 101.0, 100.7, 56.2;
anal. calcd. for C13H9BrI2O (514.92): C 30.32, H 1.76; found:
C 30.61, H 1.83.
2’,6-Dibromo-6’-(trimethylsilyl)-1,1’-biphenyl-2-ol (12)
At À758C butyllithium (50 mmol) in hexanes (32 mL) was
added to a solution of silane (15) (23 g, 50 mmol) in tetrahy-
drofuran (200 mL). The mixture was consecutively treated
with fluorodimethoxyborane·diethyl ether[52,53] (9.5 mL,
8.0 g, 50 mmol), a 3.0M aqueous solution of sodium hydrox-
ide (18 mL) and 30% aqueous hydrogen peroxide (5.0 mL,
1.8 g, 50 mmol). At 258C, the mixture was neutralized with
2.0M hydrochloric acid (50 mL) and extracted with diethyl
ether (3”50 mL). The combined organic layers were washed
with a 10% aqueous solution of sodium sulfite (50 mL),
dried over sodium sulfate and evaporated. Crystallization
form hexanes (50 mL) afforded 11 as colorless needles;
yield: 13 g (64%); mp 93–958C; 1H NMR (CDCl3,
400 MHz): d=7.78 (dd, J=7.9, 1.2 Hz, 1H), 7.69 (dd, J=
7.3, 1.3 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.28 (dd, J=7.9,
1.4 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.98 (dd, J=8.0,
1.2 Hz, 1H), 4.56 (s, 1H), 0.06 (s, 9H); anal. calcd. for
C15H16Br2OSi (400.17): C 45.02, H 4.03; found C 44.96, H
4.27.
2-Bromo-6-(dicyclohexylphosphino)-2’-iodo-6’-meth-
oxy-1,1’-biphenyl (10)
At À758C, butyllithium (10 mmol) in hexanes (6.3 mL) was
added to a solution of 9 (5.2 g, 10 mmol) in diethyl ether
(50 mL). After the addition was completed, the mixture was
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FrØdØric R. Leroux and Hanspeter Mettler
FULL PAPERS
The same silane 12 was obtained in a 84% yield (3.36 g),
when solution of acetal 14 (4.5 g, 10 mmol) in tetrahydrofur-
an (20 mL) was treated with a 3.0M hydrochloric acid
(20 mL) for 2 h. The racemic silane 12 was separated into its
enantiomers by preparative chromatography using a chiral
stationary phase. The column used was CHIRALCELꢂ OD
20 mm, the mobile phase was n-heptane/2-butanol=100:1.
The enantiomeric purity of both compounds was 100%
(measured by HPLC on an analytic CHIRALCELꢂ OD
10 mm column). (+)-12: [a]2D0: +37.8 (c 1 in CHCl3) and (À)-
12: [a]2D0: À39.4 (c 1 in CHCl3).
with diethyl ether (3”100 mL). The combined organic
layers were dried over sodium sulfate and evaporated. After
chromatography on silica (100 mL, 0.50 kg) with hexanes as
eluent, 15 was obtained as a colorless oil. Crystallization
from methanol afforded colorless platelets; yield: 41 g
(88%); mp 175–1798C; 1H NMR (CDCl3, 400 MHz): d=
7.76 (dd, J=7.7, 1.1 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.66
(d, J=8.0 Hz, 2H), 7.64 (dd, J=7.7, 1.3 Hz, 1H), 7.31 (t, J=
7.7 1H), 7.15 (t, J=8.0 Hz, 1H), 0.06 (s, 9H); 13C NMR
(CDCl3, 101 MHz) : d=146.2, 143.3, 141.8, 134.1, 133.2,
131.6, 130.4, 129.1, 125.7, 124.6, À0.1; anal. calcd. for
C15H15Br3Si (463.08): C 38.91, H 3.27; found: C 38.84, H
3.04.
2,6,6’-Tribromo-1,1’-biphenyl-2-ol (13)
At À758C, butyllithium (50 mmol) in hexanes (31 mL) was
added to a solution of 2,2’,6,6’-tetrabromo-1,1’-biphenyl
(24 g, 50 mmol) in tetrahydrofuran (200 mL). The mixture
was consecutively treated with fluorodimethoxyborane·
diethyl ether[52,53] (9.5 mL, 8.0, 50 mmol), a 3.0M aqueous
solution of sodium hydroxide (18 mL) and 30% aqueous hy-
drogen peroxide (5.0 mL, 1.8 g, 50 mmol). At 258C, the mix-
ture was neutralized with 2.0M hydrochloric acid (50 mL)
and extracted with diethyl ether (3”50 mL). The combined
organic layers were washed with a 10% aqueous solution of
sodium sulfite (50 mL), dried over sodium sulfate and
evaporated. Crystallization form hexanes afforded 13 as
slightly red prisms; yield: 17g (81%); mp 118–119 8C;
1H NMR (CDCl3, 400 MHz): d=7.70 (d, J=8.1 Hz, 2H),
7.29 (dd, J=7.9, 1.2 Hz, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.19
(t, J=7.9 Hz, 1H), 6.95 (dd, J=8.3, 1.2 Hz,1H), 4.85 (s,
1H); 13C NMR (CDCl3, 101 MHz) : d=153.3, 139.2, 137.5,
132.2, 131.3, 130.9, 125.9, 124.9, 123.9, 114.9; anal. calcd. for
C12H7Br3O (406.90): C 35.42, H 1.73; found: C 35.31, H 1.73.
Trimethyl(6,2’-dibromo-6’-methoxymethoxy-1,1’-
biphenyl-2-yl)silane (16)
At À758C butyllithium (25 mmol) in hexanes (16 mL) was
added to a solution of acetal (14) (11 g, 25 mmol) in tetrahy-
drofuran (120 mL). Immediately after the addition was com-
pleted, the mixture was treated with chlorotrimethylsilane
(3.3 mL, 2.8 g, 25 mmol). At 258C, water was added
(100 mL) and the mixture was extracted with diethyl ether
(3”100 mL). The combined organic layers were dried over
sodium sulfate and evaporated. Crystallization from metha-
nol afforded colorless platelets; yield: 9.22 g (83%); mp 90–
928C; 1H NMR (CDCl3, 400 MHz): d=7.78 (dd, J=8.0,
1.5 Hz, 1H), 7.74 (dd, J=7.5, 1.5 Hz, 1H), 7.37 (m, 4H),
5.29 (d, J=7.0 Hz, 1H), 5.10 (d, J=7.0 Hz, 1H), 3.41 (s,
3H), 0.08 (s, 9H); 13C NMR (CDCl3, 101 MHz): d=156.2,
155.3, 143.6, 142.4, 133.7, 133.0, 130.1, 128.5, 125.9, 125.6,
125.4, 113.2, 94.5, 56.2, À0.2; anal.calcd. for C17H20Br2O2Si
(444.24): C 45.96, H 4.54; found: C 46.06, H 4.13.
Trimethyl(6,2’-Dibromo-6’-methoxy-biphenyl-2-
yl)silane (17)
2,6,6’-Tribromo-2’-methoxymethoxy-1,1’-biphenyl (14)
A solution of phenol 13 (10 g, 25 mmol) in tetrahydrofuran
(25 mL) was added to a 60% suspension of sodium hydride
in mineral oil (1.0 g, 25 mmol) in tetrahydrofuran (25 mL) at
258C. After 30 min, a solution of chloromethyl methyl ether
(2.2 mL, 2.2 g, 28 mmol) in tetrahydrofuran (10 mL) was
added at 08C. The reaction mixture was allowed to reach
258C before water (50 mL) was added followed by extrac-
tion with ethyl acetate (3”50 mL). The combined organic
layers were dried over sodium sulfate and evaporated. Crys-
tallization from methanol afforded colorless platelets; yield:
Iodomethane (1.9 mL, 4.3 g, 30 mmol) was added to a sus-
pension of phenol 12 (8.0 g, 20 mmol) and potassium car-
bonate (6.9 g, 50 mmol) in acetone (100 mL). The reaction
mixture was heated at reflux for 12 h, before water
(100 mL) was added followed by extraction with ethyl ace-
tate (3”100 mL). The combined organic solvents were dried
and evaporated. Crystallization from methanol afforded col-
1
orless prisms; yield: 7.29 g (88%); mp 184–1858C; H NMR
(CDCl3, 400 MHz): d=7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.60
(dd, J=7.5, 1.0 Hz, 1H), 7.26 (m, 3H), 6.92 (dd, J=9.0,
2.5 Hz, 1H), 3.74 (s, 3H); 13C NMR (CDCl3, 101 MHz): d=
158.7, 144.0, 142.7, 134.1, 133.5, 132.5, 130.5, 129.0, 126.6,
125.9, 124.8, 109.9, 56.1, 0.1; anal. calcd. for C16H18Br2OSi
(414.21): C 46.39, H 4.38; found: C 46.43, H 4.41.
Starting with enantiopure (+)- or (À)-12 the correspond-
ing methyl ethers (+)-17: [a]2D0: +13.1 (c 1 in CHCl3) and
(À)-17: [a]2D0: À13.5 (c 1 in CHCl3) were obtained.
1
9.92 g (88%); mp 142–1438C; H NMR (CDCl3, 400 MHz):
d=7.66 (d, J=8.0 Hz, 2H), 7.38 (dd, J=7.7, 1.3 Hz, 1H),
7.28 (t, J=8.2 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.14 (t, J=
8.0 Hz, 1H), 5.13 (s,2H), 3.42 (s, 3H); 13C NMR (CDCl3,
101 MHz) : d=155.0, 139.6, 131.7, 131.5, 130.5, 130.2, 125.6,
125.0, 124.2, 113.2, 94.3, 56.2; anal. calcd. for C14H11Br3O2
(450.95): C 37.29, H 2.46; found: C 37.35, H 2.58.
Trimethyl(2’,6,6’-tribromo-1,1’-biphenyl-2-yl)silane
(15)
2,2’-Bis-diphenylphosphanyl-6-methoxy-6’-
trimethylsilanylbiphenyl (18)
At À758C, butyllithium (0.10 mol) in hexanes (63 mL) was
added to a solution of 2,2’,6,6’-tetrabromo-1,1’-biphenyl
(47g, 0.10 mol) in tetrahydrofuran (500 mL). Immediately
after the addition was completed, the mixture was treated
with chlorotrimethylsilane (13 mL, 11 g, 0.10 mol). At 258C,
water was added (100 mL) and the mixture was extracted
At 08C, butyllithium (25 mmol) in hexanes (16 mL) was
added to a solution of silane 17 (10 g, 25 mmol) in toluene
(50 mL). After 45 min, the reaction mixture was treated
with a 2.0M solution of chlorodiphenylphosphine (9.0 mL,
11 g, 50 mmol) in toluene (25 mL). The mixture was allowed
334
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Modular Synthesis of Dissymmetric Biaryldiphosphine Ligands
FULL PAPERS
to reach 258C and treated with a saturated aqueous solution References
of ammonium chloride (200 mL). The reaction mixture was
extracted with ethyl acetate (3”100 mL), and the combined
organic layers were dried over sodium sulfate. Evaporation
of the solvents and crystallization from ethyl acetate afford-
ed colorless cubes; yield: 13.9 g (89%); mp 214–2168C;
1H NMR (CDCl3, 400 MHz): d=7.59 (dd, J=7.4, 1.6 Hz,
1H), 7.5 (m, 4H), 7.3 (m, 16H), 7.09 (ddd, J=7.4, 3.5,
1.3 Hz, 1H), 7.04 (symm. m, 3H), 6.58 (d, J=8.32 Hz, 1H),
3.08 (s, 3H), À0.36 (s, 9H); 13C NMR (CDCl3, 101 MHz):
d=157.1 (d, J=2 Hz), 144.1 (d, J=8 Hz), 143.8 (d, J=
8 Hz), 138.3, 137.4, 136.3 (d, J=8 Hz), 136.1 (d, J=7Hz),
134.5 (d, J=2 Hz), 133.9 (dd, J=20, 14 Hz), 133.3 (d, J=
19 Hz), 131.2 (dd, J=6, 4 Hz), 128.8, 128.4, 128.2, 128.0,
127.9 (d, J=2 Hz), 128.8, 127.6, 125.9 (d, J=2 Hz), 110.6,
54.7; 31P NMR (CDCl3, 162 MHz): d=À12.2 (d, J=
38.1 Hz), À14.9 (d, J=38.8 Hz); anal. calcd. for C40H38OP2Si
(624.78): C 76.90, H 6.13; found: C 76.59, H 6.02.
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(11 mL, 12 g, 50 mmol) in toluene (25 mL). The mixture was
allowed to reach 258C and treated with a saturated aqueous
solution of ammonium chloride (0.20 L). The reaction mix-
ture was extracted with ethyl acetate (3”100 mL), and the
combined organic layers were dried over sodium sulfate.
Evaporation of the solvents and crystallization from ethyl
acetate afforded colorless cubes; yield: 12.3 g (76%); mp
173–1758C; 1H NMR (CDCl3, 400 MHz): d=7.55 (d, J=
8.3 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.30 (t, J=7.4 Hz,
2H), 7.04 (d, J=7.7 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 3.63
(s, 3H), 1.6 (m, 21H), 1.2 (m, 23H), À0.10 (s, 9H);
13C NMR (CDCl3, 101 MHz): d=157.5 (d, J=9 Hz), 148.4
(d, J=25 Hz), 141.7, 137.8 (d, J=19 Hz), 136.2 (d, J=
17Hz), 134.0, 132.4, 127.1, 125.0, 124.1, 108.9, 54.0, 35.9 (d,
J=16 Hz), 34.0 (d, J=19 Hz), 32.5 (d, J=16 Hz), 32.1 (d,
J=20 Hz), 31.7(d, J=16 Hz), 30.6, 29.7, 28.7 (d, J=10 Hz),
28.0, 27.2, 26.4 (d, J=13 Hz), 0.48; 31P NMR (CDCl3,
162 MHz): d=À10.4 (d, J=45 Hz), À11.3 (d, J=45 Hz);
anal. calcd. for C40H62OP2Si (648.97): C 74.03, H 9.63;
found: C 73.78, H 9.71.
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Acknowledgements
The authors are indebted to the Bundesamt für Berufsbildung
und Technologie (Bern) for financial support in the frame-
work of a KTI project (contract 5474.1 KTS) and the COST-
D24 action WG0006–02. F.L. is much indebted to Prof. M.
Schlosser, Lausanne, for countless precious advice.
Adv. Synth. Catal. 2007, 349, 323 – 336
ꢁ 2007Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
335

FrØdØric R. Leroux and Hanspeter Mettler
FULL PAPERS
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