Synthesis of new water-soluble atropisomeric ligands derived from the MeOBIPHEP skeleton: Applications for asymmetric C-H bond formation and mechanistic studies

Article abstract of DOI:10.1002/adsc.201100535

We have extended the methodology developed for the preparation of atropisomeric chiral ligands derived from the MeOBIPHEP ligand to water-soluble ones. The hydrophilic ligands bearing sodium carboxylate and methylammonium chloride moieties were easily synthesized under mild conditions in a short sequence and in high yields. Their solubility and acid/base properties were also determined. The ruthenium(II) catalysts contain- ing 4-CO₂Na- and 3,5-(CO₂Na)₂-substituted MeOBIPHEP analogues showed excellent activities and led to the desired hydrogenated products derived from dimethyl itaconate and 2-(4-fluorophenyl)-3-methylcrotonic acid in ees≥92%. An investigation of the asymmetric hydrogenation of the latter substrate in D₂O as solvent afforded an insight into the mechanism. Copyright

Full text of DOI:10.1002/adsc.201100535

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DOI: 10.1002/adsc.201100535
Synthesis of New Water-Soluble Atropisomeric Ligands Derived
from the MeOBIPHEP Skeleton: Applications for Asymmetric
À
C H Bond Formation and Mechanistic Studies
Lucie Leseurre,a Kurt Pꢀntener,b Jean-Pierre GenÞt,a Michelangelo Scalone,b,*
and Vꢁronique Micheleta,*
a
Chimie ParisTech, Laboratoire Charles Friedel (LCF), UMR 7223, 11 rue P. et M. Curie, 75231 Paris Cedex 05, France
Fax : (+33)-1-4407-1062; e-mail: veronique-michelet@chimie-paristech.fr
Process Research & Synthesis CoE Catalysis, F. Hoffmann-La Roche AG, 4070 Basel, Switzerland
b
Fax : (+41)-61-688-1670; e-mail: michelangelo.scalone@roche.com
Received: July 7, 2011; Revised: September 12, 2011; Published online: November 29, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100535.
Abstract: We have extended the methodology de-
veloped for the preparation of atropisomeric chiral
ligands derived from the MeOBIPHEP ligand to
water-soluble ones. The hydrophilic ligands bearing
sodium carboxylate and methylammonium chloride
moieties were easily synthesized under mild condi-
tions in a short sequence and in high yields. Their
solubility and acid/base properties were also
determined. The ruthenium(II) catalysts contain-
growth in the synthesis of water-soluble ligands.[3]
Whereas a flurry of achiral water-soluble ligands has
been prepared by original strategies, the synthesis of
chiral hydrophilic ligands has been more limited,
which can be explained by the difficult and long se-
quences needed for their preparation.[4] Atropisomer-
ic ligands bearing sulfonated water-soluble moieties
are quite common due to the fact that their syntheses
relied generally on the regioselective sulfonation
of the “parent” ligand (Scheme 1). BINAP and
MeOBIPHEP derivatives 1a, 1b[5] and 2[6] have been
prepared via sulfonation in the presence of an SO3/
H2SO4 mixture. Alternatively, Roche scientists have
described in 1992 a sulfonated ligand 3[7,8] according
to a conceptually different 5-step strategy (52% iso-
lated yield) and have studied various hydrogenation
reactions under aqueous conditions[8] (Scheme 2).
Moreover, starting from binaphthol, atropisomeric
cationic ligands 4 and 5 have been described, respec-
tively by GenÞtꢂs and Lemaireꢂs groups.[9] Neutral
phosphonic acid-substituted water-soluble ligands 6a
and 6b were also prepared according to a similar
strategy.[10,11] We recently described a novel synthesis
of chiral atropisomeric ligands based on the MeOBI-
PHEP skeleton starting from chiral bisphosphonate
ing
4-CO2Na-
and
3,5-(CO2Na)2-substituted
MeOBIPHEP analogues showed excellent activities
and led to the desired hydrogenated products de-
rived from dimethyl itaconate and 2-(4-fluorophen-
yl)-3-methylcrotonic acid in eesꢀ92%. An investi-
gation of the asymmetric hydrogenation of the
latter substrate in D2O as solvent afforded an in-
sight into the mechanism.
Keywords: asymmetric catalysis; atropisomeric li-
gands; bis-phosphanes; phosphorus; rhodium;
ruthenium; water-soluble ligands
Transition metal-catalyzed reactions and specifically 7.[12] We envisioned that this methodology would offer
asymmetric homogeneous catalysis have given a con- a unique opportunity to easily prepare water-soluble
siderable impetus to the progress in the areas of or- ligands and more precisely to synthesize analogues of
ganometallic, organic and industrial chemistry.[1] 3. We wish therefore to describe our results concern-
Among them, carbon-hydrogen and carbon-carbon ing the synthesis of novel water-soluble ligands and
À
bond formation reactions using water-soluble organo- our preliminary results in asymmetric C H bond for-
metallic catalysts are fundamentally important as they mation reactions.
bear the potential to provide solutions to both envi-
Initially, we anticipated that alkoxycarbonyl-substi-
ronmental and economic concerns, for example, by fa- tuted ligands might be good precursors for anionic
cilitating the product/catalyst separation.[2] The last water-soluble MeOBIPHEP analogues. We recently
fifteen years therefore have witnessed tremendous described a Pd-catalyzed reaction of various alkoxy-
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Scheme 1.
Scheme 2.
carbonyl-substituted iodides with bis-phosphane butyl esters 10, 11 and 13, carboxylic acid 12 and a
ligand (R)-9 or (S)-9 (prepared from 7[13]) and the re- cyano group 14 were efficiently prepared in good to
sults are gathered in Table 1. Ligands bearing tert- excellent yields and high enantiomeric purities.[12a]
The tert-butyl esters were then converted to carbox-
ylic acids in the presence of trifluoroacetic acid in di-
Table 1. Pd-catalyzed P-C coupling of aryl iodides with
bisphosphane ligand 9.
chloromethane in quantitative yields [Scheme 3, Eq.
(1)]. Finally, the corresponding sodium salts were
then prepared by addition of sodium hydride in tetra-
hydrofuran at 08C. With this procedure ligands 15,[14]
16 and 17 were obtained in high overall yields. A cat-
ionic ligand was also synthesized using a 2-step syn-
thesis involving the reduction of the cyano functional-
ities to methylamino groups followed by ammonium
formation in the presence of hydrogen chloride. Ac-
cordingly, the tetra(methylammonium)-substituted
ligand 18 was isolated in 93% yield over 2 steps
[Scheme 3, Eq. (2)].
We further characterized the ligands by measuring
their solubility in water; the results are collected in
Table 2. The hydrophilic ligands 15, 16, 17 and 18
have similar solubilities ranging between 1.3·102 g/L
and 3.85·102 g/L (for comparison, the water solubility
of both triphenylphosphane analogues TPPTS[15,16]
and m-TPPTC[17] are 1.1 kg/L, that of 3 is 3–3.5 g/L).
Entry Ar
Ligand Yield[a] [%] ee[b] [%]
1
2
3
4
5
6
7
8
4-t-BuO2C-C6H4
(R)-10 88
(S)-10 82
(R)-11 94
(R)-12 70
99
99
98
99
>99
>99
>99
>99
4-t-BuO2C-C6H4
3-t-BuO2C-C6H4
4-HO2C-C6H4
3,5-(t-BuO2C)2-C6H3 (R)-13 76
3,5-(t-BuO2C)2-C6H3 (S)-13 67
4-NC-C6H4
4-NC-C6H4
(R)-14 89
(S)-14 89
[a]
[b]
Isolated yield.
Determined by HPLC analysis.
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Synthesis of New Water-Soluble Atropisomeric Ligands Derived from the MeOBIPHEP Skeleton
Scheme 3.
Table 2. Physical characterization of ligands.
[c]
Entry
Ligand
Solubility[a] [102 g/L]
pKa in H2O[b]
pKa in MeOHaq
1
2
3
4
15
16
17
18
1.75
1.30
3.85
1.10
3.5 and 7.5
3.7 and 7.8
3.4 and 8.0
5.1 and 10.1
3.9, 5.0, 5.2 and 5.8
3.3, 4.7, 5.3 and 6.1
<3, <3, 3.5, 4.5, 4.9, 5.5, 5.7 and 6.5
nd
[a]
Determined in water.
[b]
15 mg of ligand were dissolved in 5 mL of H2O and acidified except for 18. The solution was dosed with aqueous sodium
hydroxide (1ꢄ10À2 M).
Determined in aqueous methanol solution (57%); nd: not determined
[c]
The acid/base behaviours of the polycarboxylic acid salts-functionalized ligands 15, 16, 17 and the tetra-
forms of ligands 15, 16 and 17 were determined in
ACHTUNGTREN(NGNU methylammonium)-substituted ligand 18 to build up
water and in aqueous methanol.[18] In water, the tetra- in situ the catalytic species. We were pleased to find
carboxylic acid moieties derived from ligands 15 and
16 present similar pKa values for the corresponding
first two acidities (3.5 and 3.7, respectively). The re-
maining two carboxylic groups (out of 4 present in
the molecules) are less acidic and have measured
pKas equal to 7.5 and 7.8, respectively. In aqueous
methanol, the four steps were independently deter-
mined and stayed in the same ranges for para- and
meta-substituted ligands. In the case of the octasubsti-
tuted ligand 17, four carboxylic groups have pKa
values close to 3.4, whereas the four others lie at ca.
8.0 in water. In aqueous methanol solution, the first
two pKa values of the acid moieties could not be mea-
sured whereas the six remaining were clearly deter-
Table 3. Ru-catalyzed hydrogenation of dimethyl itaconate.
Entry Ligand
Solvent
Conv.[a] ee[b]
[%]
[%]
1
2
3
4
5
6
(R)-15
(R)-16
(R)-17
(R)-18
(R)-3
H2O
H2O
H2O
H2O
H2O
100
46
100
32
92
84
89
87
mined. The tetraACHTNUGTRNEUNG(methylammonium) substituted
100
95
ligand 18 presents two pKa values in water, one at 5.1
corresponding to one NH3Cl/NH2 function and one at
10.1 for the three remaining functions.
Having in hand these novel water-soluble ligands
we chose to study the asymmetric hydrogenation re-
action of a standard substrate such as dimethyl itaco-
nate 19[19] in water (Table 3). We selected the sodium
(R)-6b
EtOH/H2O/hexane 99
(5/1/5)
MeOH
79[11b]
AHCTUNGTRENNUNG
7
8
(R)-12
(R)-H8-17 MeOH
95
27
86
91
[a]
[b]
Determined by gas chromatography.
Determined by HPLC analysis.
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Table 4. Ru-catalyzed hydrogenation of 2-(4-fluorophenyl)-3-methyl-crotonic acid 21.
Entry
Ligand
Solvent
Base (equiv.)
Conv.[a] [%]
15 h
ee[b] [%] (configuration)
2 h
1
2
3
4
5
6
7
8
(R)-12
(R)-15
(R)-16
(R)-17
(R)-3
(R)-12
(R)-12
(R)-17
(R)-17
(R)-17
(R)-17
(R)-12
(R)-H4-16
(S)-H8-17
(S)-12
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
MeOH
MeOH
MeOH
Et3N (0.6)
Et3N (0.6)
Et3N (0.6)
Et3N (0.6)
Et3N (0.6)
DBU (0.6)
NaOH (0.6)
–
NaOH (0.1)
NaOH (0.6)
NaOH (0.9)
Et3N (0.6)
Et3N (0.6)
Et3N (0.6)
Et3N (0.6)
–
–
–
–
–
–
–
42
85
100
46
–
–
–
–
99
88 (S)
85 (S)
79 (S)
95 (S)
84 (S)
87 (S)
88 (S)
95 (S)
95 (S)
95 (S)
95 (S)
88 (S)
88 (S)
85 (R)
88 (R)
100
100
100
100
95
99
80
9
100
100
100
100
100
100
100
10
11
12
13
14
15[c]
[a]
Determined by gas chromatography.
Determined by HPLC analysis, after 15 h.
S/C=1000.
[b]
[c]
that with all tested catalysts the desired diester 20 was in the synthesis of Mibefradil, a calcium channel
obtained within 20 h under 10 bar of dihydrogen in blocker developed by Roche for the treatment of hy-
water. The presence of the sodium carboxylate moiet- pertension and chronic angina pectoris.[20,21] The hy-
ies in para positions of the phenyl groups bound to drogenation of 2(4-fluorophenyl)-3-methylcrotonic
phosphorus was crucial whereas lower conversion and acid 21 was performed in water in the presence of the
enantiomeric excess were obtained in the presence of tetrasulfonated ligand 3 and led to the desired prod-
the meta-substituted ligand 16 (Table 3, entries 1 and uct 22 in 84% enantiomeric excess (Table 4, entry 5).
2). The catalyst containing the octasubstituted ligand With the catalysts containing the water-soluble ligands
17 led to a total conversion and 89% enantiomeric 12, 15, 16 and 17 excellent activities were observed in
excess (Table 3, entry 3). The presence of the cationic all cases (Table 4, entries 1–4). The enantioselectivi-
water-soluble functionality (ligand 18) induced a low ties ranged from 79% to 95%, the best enantiomeric
conversion but an enantiomeric excess of 87%, that excess being obtained in the case of the 3,5-dicar-
is, comparable to that obtained with anionic ligands boxylated ligand 17.
(Table 3, entry 4). With the para-substituted tetrasul-
Switching from triethylamine to DBU (Table 4,
fonate ligand 3 (Table 3, entry 5) similar results were entry 6) or NaOH (Table 4, entry 7) had a minimal, if
obtained as with the ligand 15, thus rendering 15 a any, influence on the conversion or the enantioselec-
convenient alternative to 3. Itꢂs noteworthy that the tivity in the case of ligand 12. The presence of lower
results obtained with these new ligands compared fa- or higher amounts of NaOH did not have an impact
vourably with the previously published results in the on the enantiomeric excess for ligand 17 (Table 4, en-
presence of phosphonic acid derivative 6b (Table 3, tries 8–11), but influenced the conversion. The lower
entry 6).
conversion at 0.9 equivalents of NaOH after 2 h
We also compared the para- and di-meta-substitut- might have various origins, a strong coordination of
ed ligands 12 and H8-17 (carboxylic acid form of the base to the organometallic complex being a rea-
ligand 17) to the reaction conditions in methanol. In sonable one. When the hydrogenation was conducted
this solvent, a lower activity was observed compared in MeOH, lower enantiomeric excesses were obtained
to the reactions in water, but the ee values remained (Table 4, entries 12–15). The catalyst loading could be
comparable (Table 3, entries 7 and 8).
reduced (S/C ratio=1000) without erosion of either
We also tackled the preparation of (S)-2-(4-fluoro- the conversion or the ee (Table 4, entry 15).
phenyl)-3-methylbutanoic acid 22, a key intermediate
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Synthesis of New Water-Soluble Atropisomeric Ligands Derived from the MeOBIPHEP Skeleton
Table 5. Ru-catalyzed hydrogenation of 2-(4-fluorophenyl)-3-methylcrotonic acid 21 in D2O.
Entry
Concentration (mol/L)
22-d0
22-d1b
22-d1a
22-d2
1
2
1.55
0.7
24%
40%
39%
40%
13%
10%
24%
10%
The mechanism of hydrogenation of a,b-unsaturat- determining: one in an activation step of the catalyst
ed carboxylic acid has been described by Halpern,[22] leading to species B1 and the other in the catalytic
Noyori,[23] Erkey[24] and recently Bergens[25] by study- cycle for the regeneration of the monohydride ruthe-
ing the reduction of tiglic acid under H2 or D2 pres- nium complex B1. Based on this postulated mecha-
sure in MeOH or MeOD as solvent. Depending on nism, the formation of 22-d0 would come from 1,2-in-
À
the dihydrogen pressure, the rate-limiting step is sertion in the Ru H bond of intermediate B1 fol-
either the formation of the dicarboxylate ruthenium lowed by hydrogenolysis of the five-membered heter-
monohydride complex (via the heterolytic cleavage of ometallacycle C1. The formation of 22-d1b would be
À
H2) or the reaction of the monohydride complex with explained by the 1,2-insertion in the Ru H bond of
the alkene (at high pressure). As part of the study of intermediate B1 followed by solvolysis of the five-
the hydrogenation reaction in water of 2-(4-fluoro- membered heterometallacycle C1. The obtention of
phenyl)-3-methylcrotonic acid, deuteration experi- both 22-d1a and 22-d2 would arise from similar pro-
ments were conducted in the presence of the catalyst cesses involving B1’ in lieu of B1.
containing ligand 17. The reduction was carried out in
Under the usual reaction conditions (C=1.55 mol/
D2O in the presence of triethylamine at two concen- L), the products resulting from the 1,2-insertion in the
À
trations in substrate. The various deuterated products Ru H bond (22-d0 and 22-d1b) represent 63% of the
and their proportions, as determined by 1H NMR total amount 22 (Table 5, entry 1). The equilibrium
spectroscopy and mass spectrometry are collected in B1/B1’ would be in favour of B1,[28] the H/D exchange
Table 5.
of the monohydride complexes B1/B1’ being similar as
These observations and the results described in the compared to what has been described in the literature
literature[22–25] led us to postulate the mechanism de- for tiglic acid at high pressure in MeOD.[22,23,25] Fur-
scribed in Scheme 4 for the hydrogenation reaction of thermore, the hydrogenolysis (22-d0 and 22-d1a) would
the acid 2-(4-fluorophenyl)-3-methylcrotonic 21 in represent 37% of the cleavage of the five-membered
water. From the in situ generated ruthenium bisace- heterometallacycle C1 affording E1. When the reac-
tate precursor, two steps involving the heterolytic tion was conducted in a volume twice as large, an en-
cleavage of dihydrogen gas and ligand exchange be- hancement of these phenomena (Table 5, entry 2) was
tween acetate and the substrate 21 would lead to observed. Indeed, considering that the volume of the
ruthenium monohydride complex B1, which is in equi- autoclave was fixed assuming the validity of Henryꢂs
librium with the species B1’. Monohydride complex B1 law, the amount of dissolved dihydrogen in water is
(or B1’) would then undergo a 1,2-insertion step of the two times larger in 2 mL than in 1 mL of D2O. This
double bond of the substrate leading to the five-mem- leads to an increase in the proportion of products re-
bered heterometallacycle C1. Two ways are then pos- sulting from hydrogenolysis of the five-membered
sible for the evolution of C1 species, either the hydro- heterometallacycle C1 (22-d0 +22-d1a: 50%) and a
genolysis generating the monohydride species E1, or slowdown in the equilibrium of solvolysis between
the solvolysis to form the biscarboxylate intermediate complexes B1 and B1’ (22-d1a +22-d2: 20%).
D1. Through a new cleavage of dihydrogen gas, the
complex D1 would be converted to species E1.
Given this work, the positive influence of the addi-
tion of a base on the reaction rate could be rational-
In the final step ligand exchange between the sub- ized by considering the coordination of the substrate
strate 21 and the product 22 would regenerate the in- on the monohydride ruthenium complex as the rate-
termediate B1. Accordingly, two steps would be rate- determining step under these conditions. The addition
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Scheme 4. Mechanistic rationale.
of a base would accelerate this step via the formation (CO2Na)2-substituted
MeOBIPHEP
analogues
of the carboxylate ion derived from 21. It is notewor- showed high reactivities and enantioselectivities, lead-
thy that a similar assumption on the effect of base ad- ing to the desired products in ꢀ92% ee.
dition was put forward by Ojimaꢂs group in a study of
Finally, the hydrogenation of 2-(4-fluorophenyl)-3-
the hydrogenation reaction of a,b-unsaturated acids methylcrotonic acid in D2O confirmed the simultane-
in the presence of rhodium complexes.[29] The acids ous existence of a hydrogenolysis and a solvolysis var-
and bases species being in equilibrium, the exchange iant of the mechanism and suggested an interpreta-
of carboxylated ligands would thus be facilitated.
The successful development of asymmetric transfor-
mations in organo-aqueous medium depends on the in enantioselective C H or C C bond formation reac-
ability to design inexpensive chiral ligands that are tions in water. Current efforts are focused on expand-
easy to prepare. We have extended the methodology ing the scope of this methodology and to develop re-
developed for the preparation of MeOBIPHEP-based cyclable systems.
tion of the role of the added base.
These results pave the way for further applications
À
À
atropisomeric chiral ligands to congeners bearing car-
boxylate and methylammonium groups as water-solu-
ble templates. These hydrophilic ligands were synthe-
Experimental Section
sized under mild conditions by a short sequence and
in high yields; their solubility and acid/base properties
were also determined. During the study of the asym-
metric hydrogenation of dimethyl itaconate and 2-(4-
fluorophenyl)-3-methylcrotonic acid in water, the
General Remarks
1
All manipulations were carried out under argon. H NMR,
13C NMR and 31P NMR were recorded on a Bruker AV 300
ruthenium catalysts containing the 4-CO2Na- and 3,5- instrument. All signals were expressed as ppm (d and inter-
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Synthesis of New Water-Soluble Atropisomeric Ligands Derived from the MeOBIPHEP Skeleton
nally referenced to residual protio solvent signals. Coupling
constants (J) are reported in Hz and refer to apparent peak
multiplicities. Mass spectroscopy and high resolution mass
spectra were performed at Hoffmann-La Roche AG
(Basel). Ligands 10–14 were prepared according to pub-
lished procedures.[12a]
(2CH3), 112.1 (2CH), 126.6 (2CH), 128.5 (4CH), 129.3
(2CH), 129.6 (2CH), 130.0 (2CH, C4, 4C), 130.6 (2C), 133.2
(br. s, 2CH), 134.3 (br. s, 2CH), 135.7 (br. s, 2CH), 136.4
(br. s, 2CH), 137.4 (6C), 156.7 (2C), 174.8 (2C), 175.0 (2C);
31P NMR (D2O, 121 MHz): d=À15.9; ESI/MS: m/z=781.1
(M+3HÀ3Na)+; [a]25: +20.2 (c 1.00, H2O) (R).
(R)- or (S)-6,6’-DDimethoxy-P2,P2,P2’,P2’-tetrakis-[3,5-di-
A
mp
1
>2608C; H NMR (DMSO, 300 MHz): d=3.43 (s, 6H), 6.54
Synthesis of Sodium Salts 15, 16, 17
(d, 2H, J=7.8 Hz), 7.05 (d, 2H, J=8.4 Hz), 7.38 (t, 2H,
3J=8.0 Hz), 7.72 (m, 4H), 7.91 (m, 4H), 8.18 (s, 2H), 8.41
(s, 2H), 13.1 (br. s, 8H); 13C NMR (DMSO, 75 MHz): d=
54.9 (2CH3), 112.2 (2CH), 125.9 (2C), 129.9 (4CH), 130.3
(2CH), 131.1 (4C), 131.4 (4C), 132.5 (2C), 132.8 (2C),
To a solution of tert.-butyl ester ligand (1 equiv.) in dry and
degassed dichloromethane (0.5M), trifluoroacetic acid
(0.5M in dichloromethane) was slowly added at 08C. The
mixture was stirred at room temperature under argon
during 2 h until completion, water was then added and the
reaction mixture was extracted twice with EtOAc. The com-
bined organic fractions were dried over magnesium sulfate,
filtered and concentrated under reduced pressure. The prod-
uct was washed twice with 10 mL of dichloromethane and
dried under vacuum and used directly in the next step with-
out purification. After washing twice with pentane, sodium
hydride (4 or 8 equiv, M=24) was dried 30 min under
vacuum. A solution of the acid ligand (1 equiv.) in dry and
degassed THF (0.2M) was carefully added to NaH at 08C
under argon. The reaction mixture was degassed and stirred
at room temperature during 5 h, then concentrated under
vacuum.
133.1 (2C), 136.0 (2C), 136.6 (t, JC,P =10.9 Hz, 4CH), 137.4
(t, JC,P =11.0 Hz, 4CH), 156.9 (2C), 165.8 (4C), 166.1 (4C);
31P NMR (DMSO, 121 MHz): d=À14.6; ESI/MS: m/z=
935.3 (M+H)+; HR-MS: m/z=957.0942, calcd. for
C46H32NaO18P2: 957.0956; [a]25: +11.7 (c 0.99, MeOH) (S).
(R)- or (S)-6,6’-DimethoxDy-P2,P2,P2’,P2’-tetrakis-[3,5-di-
(carbonyloxy)phenyl]-biphenyl-2,2’-bisphosphine
sodium
1
salt (17): mp 2508C (decomp.); H NMR (D2O, 300 MHz):
3
d=2.83 (s, 6H), 6.67 (d, 2H, J=8.0 Hz), 6.71 (br. d, 2H,
3
3J=7.6 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.74 (m, 4H), 7.92 (m,
4H), 8.19 (s, 2H), 8.23 (s, 2H); 13C NMR (D2O, 75 MHz):
d=54.5 (2CH3), 111.7 (2CH), 125.5 (2CH), 129.6 (2CH,
2C), 130.2 (2CH), 130.4 (2CH), 134.8 (2C), 136.0 (t, JC,P
10.5 Hz, 4CH), 136.3 (4C), 136.5 (4C), 136.8 (4C), 137.8 (t,
2JC,P =11.2 Hz, 4CH), 157.0 (2C), 174.3 (4C), 174.6 (4C);
31P NMR (D2O, 121 MHz): d=À12.3; ESI/MS: m/z=957.4
(M+8HÀ7Na)+; [a]D25: +34.3 (c 0.99, H2O) (S).
2
=
(R)- or (S)-6,6’-Dimethoxy-P2,P2,P2’,P2’-tetrakis-[4-(car-
bonyloxy)phenyl]-biphenyl-2,2’-bisphosphine sodium salt
1
(15): mp 2508C (decomp.); H NMR (D2O, 300 MHz): d=
3
3
3.06 (s, 6H), 6.78 (br. d, 2H, J=7.9 Hz), 6.91 (d, 2H, J=
8.0 Hz), 7.08 (m, 4H), 7.21 (m, 4H), 7.34 (t, 2H, 3J=
3
3
7.9 Hz), 7.66 (d, 4H, J=7.4 Hz), 7.73 (d, 4H, J=7.7 Hz);
13C NMR (D2O, 75 MHz): d=54.7 (2CH3), 112.1 (2CH),
126.6 (2C), 128.8 (4CH), 130.0 (2CH), 131.9 (4CH) 132.9
(t, 2JC,P =10.4 Hz, 4CH), 133.9 (t, 2JC,P =10.4 Hz, 4CH),
136.5 (2C), 136.9 (2C), 137.0 (2C), 137.3 (2C), 138.7 (2C),
139.5 (2C), 155.7 (2C), 174.9 (2C), 175.1 (2C); 31P NMR
(D2O, 121 MHz): d=À16.3; ESI/MS: m/z=781.3 (M+
C42H32NaO10P2: 781.1370; [a]2D5: + 14.2 (c 1.00, H2O) (R).
(R)- or (S)-6,6’-Dimethoxy-P2,P2,P2’,P2’-tetrakis-[3-(car-
bonyloxy)phenyl]-biphenyl-2,2’-bisphosphine: mp 1938C
(decomp.); 1H NMR (DMSO, 300 MHz): d=3.16 (s, 6H),
(S)-6,6’-Dimethoxy-P2,P2,P2’,P2’-tetrakis-[4-(meth-
ylamino)phenyl]-biphenyl-2,2’-bisphosphine Chloride
Salt (18)
To a solution of 1 g of (S)-6,6’-dimethoxy-P2,P2,P2’,P2’-tet-
rakis-[4-(cyano)phenyl]-biphenyl-2,2’-bisphosphine
(14)
3HÀ3Na)+;
HR-MS:
m/z=781.1366,
calcd.
for
(1.466 mmol, 1 equiv., M=682.64) in 15 mL of degassed and
distilled THF, 334 mg of lithium aluminum hydride
(8.796 mmol, 6 equiv., M=38) were added in small portions.
The reaction mixture was degassed and stirred at room tem-
perature under argon during 4 h then treated at 08C by
adding alternatively 1.5 mL of distilled and degassed water
and 1.5 mL of 1N NaOH. The resulting mixture was filtered
through a short pad of celite [(i-Pr)2O] and concentrated
under reduced pressure. (S)-6,6’-Dimethoxy-P2,P2,P2’,P2’-
tetrakis-[4-(methylamino)phenyl]-biphenyl-2,2’-bisphosphine
was obtained as an unstable pale brown solid and directly
used for the next step; yield: 954 mg (93%).
3
3
6.55 (br. d, J=7.6 Hz), 6.88 (d, 2H, J=8.2 Hz), 7.18 (m,
3
2H), 7.32 (m, 6H), 7.44 (t, 2H, J=7.6 Hz), 7.65 (m, 2H),
7.72 (m, 2H), 7.81 (d, 2H, 3J=7.8 Hz), 7.90 (d, 2H, 3J=
7.7 Hz), 11.80 (br. s, 4H); 13C NMR (CD3OD, 75 MHz): d=
55.3 (2CH3), 112.3 (2CH), 127.0 (2CH), 129.4 (4CH), 130.3
(2CH), 130.6 (2CH), 131.0 (2CH), 131.9 (4C), 134.0 (2C),
2
2
135.3 (t, 2CH, JC,P =9.8 Hz), 136.5 (t, 2CH, JC,P =11.2 Hz),
2
2
138.8 (t, 2CH, JC,P =11.2 Hz), 139.4 (t, 2CH, JC,P =9.8 Hz),
137.8 (6C), 159.0 (2C), 169.6 (4C); 31P NMR (DMSO,
121 MHz): d=À14.9; ESI/MS: m/z=759.5 (M+H)À; HR-
MS: m/z=759.1537, calcd. for C42H33O10P2: 759.1543; [a]2D5:
À12.0 (c 0.96, MeOH) (R).
A solution of 954 mg of (S)-6,6’-dimethoxy-P2,P2,P2’,P2’-
tetrakis-[4-(methylamino)phenyl]-biphenyl-2,2’-bisphosphine
(1.366 mmol, 1 equiv., M=698.29) in 11 mL of HCl
(5.5 mmol, 4 equiv., 0.5M in methanol) was stirred under
argon during 3 h. After concentration, (S)-6,6’-dimethoxy-
P2,P2,P2’,P2’-tetrakis-[4-(methylamino)phenyl]-biphenyl-
2,2’-bisphosphine chloride salt 18 was obtained as an orange
solid; yield: 1.08 g (quantitative); mp >2608C (decomp.).
1H NMR (D2O, 300 MHz): d=3.11 (s, 6H), 4.07 (s, 4H),
(R)- or (S)-6,6’-Dimethoxy-P2,P2,P2’,P2’-tetrakis-[3-(car-
bonyloxy)phenyl]-biphenyl-2,2’-bisphosphine sodium salt
(16): mp >2608C; 1H NMR (D2O, 300 MHz): d=3.14 (s,
3
3
6H), 6.78 (br. d, 2H, J=7.4 Hz), 6.89 (d, 2H, J=8.2 Hz),
3
3
3
7.11 (m, 2H), 7.23 (m, 4H), 7.32 (t, 4H, J=8.3 Hz), 7.54
(br. s, 2H), 7.61 (br. s, 2H), 7.66 (d, 2H, J=8.0 Hz), 7.76
4.13 (s, 4H), 6.80 (dd, 2H, J=7.2 Hz, JH,P =2.5 Hz), 6.95
(d, 2H, 3J=8.3 Hz), 7.10 (m, 4H), 7.27 (m, 8H, H5’, H6),
7.37 (m, 6H, H3, H6’); 13C NMR (D2O, 75 MHz): d=42.6
3
(d, 2H, 3J=7.7 Hz); 13C NMR (D2O, 75 MHz): d=54.8
Adv. Synth. Catal. 2011, 353, 3269 – 3277
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3275

Lucie Leseurre et al.
COMMUNICATIONS
(2CH2), 54.8 (2CH3), 112.2 (2CH), 126.5 (2C), 128.9
Jacobsen, A. Pfaltz, H. Yamamoto, (Eds.), in: Compre-
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P. M. Maitlis, in: Metal-Catalysis in Industrial Organic
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2
(8CH), 130.1 (2CH), 131.6 (2C), 133.1 (2C), 133.6 (t, JC,P
=
9.0 Hz, 4CH), 134.6 (t, 2JC,P =10.5 Hz, 4CH), 136.3 (4C),
137.1 (4C), 156.8 (2 C). 31P NMR (D2O, 121 MHz): d=
À17.0; ESI/MS: m/z=699.2 (MÀ4HCl+H)+; [a]D25: +19.1 (c
1.00, H2O) (S).
Hydrogenation Reactions
In a glass tube and inside a glove box, ruthenium precursor
(1 mol%) and diphosphine (1.1 mol%) were stirred in a dry
and degassed solvent for 3 h under argon atmosphere before
addition of the hydrogenation substrate. The reactor tube
was put in an autoclave where hydrogen was introduced at
the desired pressure. The reaction mixture was stirred at
258C and at the end of the reaction, dihydrogen was evacu-
ated. If the reaction was carried out in water, the reaction
mixture was extracted with n-hexane or ethyl acetate, dried
over magnesium sulfate and concentrated under reduced
pressure. If the reaction was carried out in MeOH, the reac-
tion mixture was directly concentrated under reduced pres-
sure. Crude materials were analyzed by 1H NMR spectrosco-
py and chiral GC or HPLC.
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Dimethyl methylsuccinate (20): 1H NMR (CDCl3,
3
3
400 MHz): d=1.22 (d, J=7.2 Hz, 3H), 2.41 (dd, J=6.0 Hz,
2J=24.8 Hz, 1H), 2.76 (dd, 3J=8.0 Hz, 2J=24.8 Hz, 1H),
2.92 (m, 1H), 3.68 (s, 3H), 3.70 (s, 3H); Chiral GC (column
BGB-176, T0 =608C, T30 =1508C): tr1 =13.49 min, tr2 =
13.70 min, trSM =15.21.
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2-(4-Fluorophenyl)-3-methylbutanoic acid (22): 1H NMR
3
3
(CDCl3, 400 MHz): d=0.70 (d, J=6.8 Hz, 3H), 1.07 (d, J=
6.4 Hz, 3H), 2.28 (app. h, 3J=6.4 Hz, 1H), 3.13 (d, 3J=
3
3
10.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.4 Hz,
1H), 7.28 (d, 3J=8.4 Hz, 1H), 7.30 (d, 3J=8.8 Hz, 1H);
Chiral HPLC [column Chiralpak IC, n-heptane/0.1% TFA
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211 nm]: tr1 =5.35 min, tr2 =5.81 min, trSM =7.83.
À
Dellis, French Patent 15,217, 1999; e) for C C bond
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Acknowledgements
This work was supported by the Centre National de la Re-
cherche Scientifique (CNRS). L.L. is grateful to the CNRS
and F. Hoffmann-La-Roche AG for financial support (2006–
2009). Thanks to Rudolf Schmid and Michel Lalonde for
making available the ligand (R)-3, to Bjçrn Wagner, Joseph
Schneider, Jean-Claude Jordan and Marcel Althaus (all F.
Hoffmann-La Roche AG, Basel) for analytical support.
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À
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have
[HRu(MeOBIPHEP
MeOBIPHEP(C6H6)]BF4 in CD3OD and compared the
dissolved
two
Ru
hydride
complexes
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
À
À
evolution of the Ru H signal towards an aromatic C
H signal (in analogy to Halpernꢂs work[22]). For both
complexes, after 24 h no change had occurred. Addi-
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Adv. Synth. Catal. 2011, 353, 3269 – 3277
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3277