Difluorphos, an Electron-Poor Disphosphane: A Good Match between Electronic and Steric Features

Article abstract of DOI:10.1002/anie.200352453

The π acidity makes the difference: The fluorinated diphosphane, difluorphos, is synthesized (see structure: purple = P, red = O, green = F, gray = C) and its stereoelectronic features are evaluated in theoretical and experimental studies. Its unusual π acidity explains the excellent results obtained with it in ruthenium-mediated asymmetric hydrogenation of fluorinated β-functionalized ketones. These results are better than those obtained with other biphenyl-based diphosphanes.

Full text of DOI:10.1002/anie.200352453

Communications
Asymmetric Hydrogenation
Difluorphos, an Electron-Poor Diphosphane:
A Good Match Between Electronic and Steric
Features**
SØverine Jeulin, SØbastien Duprat de Paule,
Virginie Ratovelomanana-Vidal,* Jean-Pierre GenÞt,*
Nicolas Champion, and Philippe Dellis*
The design and synthesis of new chiral ligands, which display
high activity and enantioselectivity, is still a significant
challenge in the development of transition-metal-catalyzed
asymmetric reactions. In recent years, chelating diphosphanes
supported by an atropisomeric scaffold, have proved to be
among the most active, selective and versatile ligands in this
area.[1] Leading diphosphanes such as binap[2] and more
recently MeO-biphep[3] have shown excellent results, espe-
cially in the field of ruthenium-mediated asymmetric hydro-
genation.[4] Many research groups have devoted their efforts
toward the discovery of new efficient atropisomeric ligands[5]
with unusual stereoelectronic profiles. Both the aryl phos-
phorus substituents and the biaryl backbone are tunable parts
in this family of ligands (Figure 1). Replacing the phenyl
Figure 1. General stereoelectronic tunable features of a C2-symmetric
atropisomeric diphosphane.M=transition metal center, b=bite angle,
q=dihedral angle.
[*] S. Jeulin, Dr. S. Duprat de Paule, Dr. V. Ratovelomanana-Vidal,
Prof. Dr. J.-P. GenÞt
Laboratoire de Synth›se SØlective Organique et Produits Naturels
Ecole Nationale SupØrieure de Chimie de Paris
11, rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
Fax: (+33)144-071-062
E-mail: gvidal@ext.jussieu.fr
genet@ext.jussieu.fr
Dr. N. Champion, Dr. P. Dellis
SYNKEM S.A.S., 47, rue de Longvic
21301 Chenôve Cedex (France)
Fax: (+33)380-447-270
E-mail: p.dellis@fr.fournierpharma.com
[**] CNRS and SYNKEM S.A.S. are gratefully acknowledged for doctoral
fellowships (S.J. and S.D.P.). We thank Dr A. SolladiØ-Cavallo, from
the Department of Fine Organic Chemistry (ECPM, Strasbourg,
France), for her kind permission to use molecular modeling
facilities. We also acknowledge a generous gift of (R)- and (S)-MeO-
biphep from Dr. R. Schmid (Hoffmann-LaRoche).
Supporting information (experimental details and analytical data)
for this article is available on the WWW under http://www.ange-
wandte.org or from the author.
320
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352453
Angew. Chem. Int. Ed. 2004, 43, 320 –325

Angewandte
Chemie
phosphorus substituents by bulkier aromatics (p-Tol- binap,[6]
DTBM-segphos[7]), electronically modified substituents (p-F-
binap, Cy-binap)[6] or heteroaromatics (a-furyl-MeO-
biphep[3c]), can modify the steric hindrance around the
metal and/or the electronic properties of the phosphorus
centers and create more selective ligands. Structural varia-
tions of the biaryl backbone are at the origin of the wide
diversity in the field of atropisomeric diphosphanes. The
steric design of the biaryl core has been extensively explored:
Cn-TunaPhos[8] by Zhang and co-workers, segphos[7] by Saito
and co-workers, and recently synphos[9] by our group have
been specially targeted because they displayed a (tunable or)
narrow dihedral angle, a steric condition postulated as
essential to obtain good enantioselectivities in asymmetric
hydrogenation.[7b] However, the electronic design of atropi-
someric diphosphanes has been less systematically studied:
the more effective ligands designed to date bear an atropiso-
meric core, which is often electronically richer than that in
binap[3,7–9] and there are only few examples of effective
electrodeficient atropisomeric diphosphanes. Most of them
are based on a biheteroaryl skeleton (binapFu,[10] tetraMe-
bitianp[11]) and electron-poor biphenyl-based ligands have
rarely displayed satisfactory enantioselectivities (bifup,
fupmop).[12] Moreover, in the field of ruthenium-mediated
enantioselective hydrogenation, electrodeficiency has some-
times been considered as a drawback for catalytic activity,[12,13]
but its influence on enantioselectivity has
Scheme 1. Typical diphosphane ligands
was performed by heating with an excess of HSiCl3 in xylene
in the presence of tributylamine in 91% yields for (R)-5 and
(S)-5 ((R)-difluorphos and (S)- difluorphos).[16] Subsequent
oxidation of diphosphanes (R)-5 and (S)-5 with hydrogen
rarely been underlined.
Following our interest in ligand design,[9a,14]
we report herein the synthesis of a new
atropisomeric diphosphane, based on a seg-
phos-like backbone, which has a narrow dihe-
dral angle and electron-withdrawing substitu-
ents,
hereafter
named
difluorphos[9a]
(Scheme 1). In addition, we describe studies
regarding its steric and electronic features. Its
performance in ruthenium-mediated asymmet-
ric hydrogenation, compared to other electron-
rich atropisomeric diphosphanes, has also been
preliminary evaluated.
Our synthetic approach to enantiopure (R)-
and (S)-[4,4’-bi(2,2-difluoro-1,3-benzodioxol)-
5,5’-diyl]bis(diphenylphosphane) (5; difluor-
phos) is depicted in Scheme 2. Phosphorylation
of commercially available 1 was through the
organomagnesium formation, followed by the
addition of chlorodiphenylphosphane oxide.
Phosphane oxide 2 was obtained in 66%
yield. Ortho-lithiation of 2 by LDA at ꢀ788C
and further iodination with I2 furnished 3 in
88% yield. Iodide 3 was subjected to an
Ullmann-type coupling[15] with copper in
DMF at 1308C and afforded the bis(phosphane
oxide) 4 in 69% yield. The optical resolution of
(RS)-4 was by chiral preparative HPLC using a
Chirose C3 Column in 90% yield based on
(RS)-4. (ꢀ)-4 and (+)-4 were enantiomerically
pure (> 99% ee) according to HPLC (Chiral-
Scheme 2. Reagents and conditions: a) Mg, THF, 608C!RT; then ClP(O)Ph2, 208C; b) LDA, THF,
ꢀ788C, 2 h; then I2, ꢀ788C to RT; c) Cu, DMF, 1308C; d) Chiral preparative HPLC, Chirose C3
pak AD column). Reduction of the resolved 4 Column; e) HSiCl3, Bu3N, xylene, 1408C. LDA=lithium diisopropylamide.
Angew. Chem. Int. Ed. 2004, 43, 320 –325
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
321

Communications
peroxide showed that no racemization had occurred during
the reduction process, in accord with the enantiomeric
purities determined by HPLC. Therefore, both enantiomers
of this new ligand were obtained on a multigram scale in five
steps with an overall yield of 33%.
Having generated a new atropisomeric diphosphane,
whose backbone was structurally close to existing electron-
rich ligands (synphos or segphos), but with potentially
different electronic properties, we performed a preliminary
evaluation of its geometric and electronic profiles.
Scheme 3. Synthesis of diphosphane selenides.
The quantification of steric properties of atropisomeric
diphosphanes is conveniently achieved by measuring the
dihedral angle (q) of the biaryl backbone. In transition-metal
complexes, this parameter is geometrically related to the bite
angle (b)[17] and controls directly the asymmetric spatial
environment around the metal center (Figure 1). In asym-
metric hydrogenation, the influence of q on enantioselectivity
has only recently been described by Zhang and co-workers,[8]
Saito and co-workers[7b] and our group.[18] Based on steric
considerations, but not on electronic properties, the narrowest
dihedral angle seems to provide the highest selectivities. We
used computer modeling to estimate the dihedral angle of
difluorphos and five other atropisomeric diphosphanes,
binap, biphemp, MeO-biphep, synphos and the closely related
segphos (Scheme 1). We took particular care to model all
ligands with the same Molecular Mechanics program[19] and
parameter set,[20] so as to highlight a correct trend in dihedral
angles. As expected, difluorphos and segphos have almost the
same dihedral angle (67.6 and 67.28, respectively), which is
the narrowest of the series, followed by synphos (70.78), MeO-
biphep (72.38), biphemp (74.58), and then binap (86.28). These
results are in agreement with our previous results[18] and those
obtained by Saito and co-workers on minimized structures of
Ikariya-type ruthenium complexes.[7b] Therefore the original
segphos-modified bi(difluorobenzodioxole) core gives
difluorphos, a priori, ideal steric properties for asymmetric
hydrogenation, but we expected its electronic profile to differ
radically from usual diphosphanes.
the diphosphanes with elemental selenium in refluxing
chloroform. The value for binap (738 Hz, entry 1) is in good
agreement with literature.[21a] Atropisomeric diphosphanes of
entries 1–5 are less basic than triphenylphosphane (entry 6).
Whereas binap, MeO-biphep, synphos, and segphos display
equivalent s-basicities (1JP, Se around 740 Hz), difluorphos
(749 Hz, entry 5) has a significantly lower s-donor ability.
Electronic donor–acceptor properties of these diphos-
phanes have also been investigated by studying the carbonyl
stretching frequencies of [RhCl(diphosphane)(CO)] com-
plexes B which were prepared by the reaction of
[{RhCl(CO)2}2] with diphosphane ligands (Scheme 4).[22] The
higher the carbonyl stretching frequency, the higher the p-
acidic character of the diphosphane. Results are in Table 2.
Scheme 4. Synthesis of [RhCl(diphosphane)(CO)] complexes B.
Table 2: Carbonyl stretching frequencies of [RhCl(diphosphane)(CO)]
complexes B.
Diphosphane ligand
n(CO)[a] in B [cmꢀ1
]
binap
2017
2014
2012
2016
2023
A simple way of evaluating the s-donor ability of a
phosphane group is to measure the magnitude of JP, Se in the
1
MeO-biphep
synphos
77Se isotopomer of the corresponding phosphane-sele-
nide.[10,21] Allen and Taylor have reported[21a] that an increase
in this coupling constant indicates an increase in the
s character of the phosphorus lone-pair orbital (i.e., a less
basic phosphane). To estimate the donor ability of phospho-
rus centers in difluorphos and compare it with other
atropisomeric diphosphanes (Table 1), we prepared the
corresponding diselenides A (Scheme 3) by simply treating
segphos[b]
difluorphos
[a] in CHCl3. [b] (R)-segphos was prepared according to the reported
procedure.[7]
The five diphosphanes ordered by decreasing p acidity are as
follows: difluorphos > binap and segphos > MeO-biphep >
synphos. The electron-poor bi(difluorobenzodioxole) back-
bone of difluorphos is responsible for its higher p-back-
donation ability, compared to nonfluorinated analogues, such
as segphos or synphos.
Of the five ligands of this electronic comparative study,
difluorphos is the poorest s donor and the best p acceptor.
Moreover, if we superimpose steric and electronic scales and
line them up on binap (Figure 2), one can observe that
oxygenated diphosphanes, such as MeO-biphep, segphos, or
synphos, are systematically electron-richer than binap and
Table 1: 31P–77Se coupling constants in compounds A.
Entry
Diphosphane ligand
1JP,Se in A [Hz]
1
2
3
4
5
6
binap
738
742
740
738
749
MeO-biphep
synphos
segphos[a]
difluorphos
P
P
732[21a]
h
3
[a] (R)-segphos was prepared according to reported procedure.[7]
322
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 320 –325

Angewandte
Chemie
hydrogenation of ethyl benzoylacetate.
Interestingly, the difluorphos ligand
showed an unexpected efficiency in
the Ru-catalyzed hydrogenation of
ethyl 4-chloro-acetoacetate, a b-keto
ester bearing a chelating substituent
(entry 4). Under 10 bar hydrogen, at
1108C, ethyl (3R)-hydroxy-4-chloro-
butyrate was obtained quantitatively
in 97% ee using 1 mol% [RuBr2{(S)-
difluorphos}]. This result is in good
agreement with work by the Noyori
and Saito groups on other biphenyl
Figure 2. Comparative steric and electronic scales of binap, MeO-biphep, synphos, segphos, and
difluorphos.
have narrower dihedral angles. On the contrary, difluorphos
does not follow the same trend and is placed at opposite ends
of steric and electronic scales, with the narrowest dihedral
angle and the most p-acidic character, which confers on it a
totally unusual stereoelectronic profile.
To evaluate the performance of difluorphos in ruthenium-
mediated asymmetric hydrogenation we followed our con-
venient procedure,[23] and prepared catalysts from
[(cod)Ru(h3-(CH2)2CCH3)2] (cod = cyclooctadiene) and
difluorphos by addition of a methanolic solution of HBr in
acetone (Scheme 5). The hydrogenations were carried out on
a 1 mmol scale using 1 mol% catalyst, in a stainless steel
autoclave. The conversions were determined by 1H NMR
Scheme 5. General procedure for ruthenium-mediated asymmetric
hydrogenation reactions using difluorphos.
spectroscopy and enantiomeric excesses of the products were
determined by chiral GC (Table 3).
In all cases, complete conversion was obtained. The test
substrate methyl acetoacetate was reduced in 99% ee using
the [RuBr2{(S)-difluorphos}] catalyst under 4 bar of hydrogen
at 508C (entry 1). We were pleased to notice that ethyl
benzoylacetate and ethyl (4-fluoro)benzoylacetate were also
reduced efficiently (10 bar, 808C) to afford the corresponding
b-hydroxy esters with 92and 95% ee, respectively (entries 2
and 3). In our hands, using the same hydrogenation con-
ditions, [RuBr2{(R)-binap}] provided only 88% ee in the
ligands, such as binap (97% ee using [RuBr2{(S)-binap}]
under 100 bar and 1008C)[24,4a] and segphos (98% ee using
[{RuCl[(R)-segphos]}2(m-Cl)3][NH2Me2] under 30 bar and
908C).[7b]
These good results obtained with difluorphos in the
hydrogenation of standard substrates encouraged us to
investigate more carefully the hydrogenation of “tricky”
substrates, especially fluorinated b-functionalized ketones.
Table 3: Hydrogenation results using the difluorphos ligand.
Entry
1
Substrate[a]
Ligand[a]
Config.
Solvent
MeOH
pH2
[bar]
T
[8C]
t
[h]
Product[b]
ee[c]
[%]
Config.
S
R
4
50
80
24
24
99
92
S
2
EtOH
10
S
3
4
R
S
MeOH
EtOH
10
10
80
24
3
95
97
S
R
110
[a] Reactions were conducted on a 1-mmol scale, using 1 mol% of in situ prepared[23] [RuBr2{(R)-or (S)-difluorphos}] as catalyst. [b] All conversions
were 100%, according to 1H NMR spectroscopy. [c] Enantiomeric excesses were determined by chiral gas chromatography (Lipodex A column).
Angew. Chem. Int. Ed. 2004, 43, 320 –325
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
323

Communications
We[25] and others[26] have already described low enantioselec-
based on a bi(difluorobenzodioxole) backbone, displayed a
narrow dihedral angle combined with an unusual p-acidity.
Comparison of difluorphos with other leading biphenyl-based
ligands (binap, MeO-biphep, synphos and segphos) in ruthe-
nium-mediated hydrogenation revealed that its electrodefi-
ciency was crucial in obtaining high levels of enantioselection
in the hydrogenation of challenging substrates. Theoretical
and experimental studies are currently under investigation in
order to rationalize the unusual behavior of difluorphos
ligand in asymmetric catalysis.
tivities in the ruthenium-mediated asymmetric hydrogenation
of ethyl 4,4,4-trifluoroacetoacetate and ethyl pentafluoropro-
pionylacetate using biphenyl atropisomeric diphosphanes,
even at high temperature. Therefore we performed a com-
parative study between five diphosphanes in the asymmetric
hydrogenation of substrates 6a–c (Scheme 6). We conducted
the hydrogenation reactions at least twice under strictly the
same conditions for the five diphosphanes: hydrogen pres-
sure, temperature, substrate concentration (0.5m), substrate/
catalyst ratio (S/C = 100; Table 4).
Experimental Section
Experimental procedures and characterization
data for compounds 2–5, A, and B are given in
the Supporting Information.
Typical procedure for asymmetric hydroge-
nation: (S)-difluorphos (7.5 mg, 0.011 mmol) and
[(cod)Ru(h3-(CH2)2CCH3)2] (3.2mg, 0.01 mmol)
Scheme 6. Asymmetric hydrogenation of fluorinated substrates. P*P=(S)-binap, (S)-MeO-biphep,
(S)-synphos, (R)-segphos, or (S)-difluorphos.
were placed in a 10-mL flask, and degassed
anhydrous acetone (1 mL) was added dropwise.
A methanolic solution of HBr (122 mL, 0.18m)
was added dropwise to the suspension. The
reaction mixture was stirred at room temperature
for about 30 min and an orange suspension
formed. The solvent was removed under
vacuum. The orange solid residue was used with-
out further purification as a catalyst for the
hydrogenation reaction of the desired substrate
(1 mmol) in MeOH or EtOH (2mL). The reac-
tion vessel was placed in a 500-mL stainless steel
autoclave, which was adjusted at the desired
pressure and warmed to the desired temperature
for 24 h. The solvent was evaporated and the
crude product was purified on a short pad of silica
gel, eluting with cyclohexane:ethyl acetate (1:1).
Conversion and enantiomeric excess were deter-
mined by 1H NMR spectroscopy and chiral GC,
respectively.
Table 4: Comparative study of difluorphos and other ligands in the ruthenium-catalyzed hydrogenation
of fluorinated b-functionalized ketones.
Substrate Conditions[a]
ee [%][b]
synphos
Product
binap
MeO-
segphos[c] difluorphos Config.
biphep
6a
6b
6c
10 bar, 1108C, 23
1 h, EtOH
10 bar, 1108C, 44
40
57
87
49
63
85
59
76
88
70
81
98
R
R
1 h, EtOH
50 bar, 508C,
91
R,R
24 h, MeOH
(de=77%) (de=71%) (de=67%) (de=71%) (de=86%)
[a] Reactions were conducted on a 1-mmol scale, using 1 mol% of in situ prepared[23] [RuBr2{S ligand}]
1
as catalyst. [b] All conversions were 100%, according to H and 19F NMR spectroscopy. Enantiomeric
and diastereomeric excesses were determined by chiral gas chromatography (Lipodex A column).
[c] (R)-segphos was prepared according to the reported procedure.[7]
Received: July 23, 2003 [Z52453]
Note, for b-keto esters 6a and 6b, the enantiomeric excess
is lineally related to the dihedral angle of the diphosphane:
Keywords: asymmetric catalysis · atropisomerism · fluorinated
ligands · hydrogenation · ruthenium
.
the narrower the dihedral angle (q(binap) > q(MeO-
biphep) > q(synphos) > q(segphos) = q(difluorphos)), the
better the enantioselectivities (ee(binap) < ee(MeO-
biphep) < ee(synphos) < ee(segphos) < ee(difluorphos)).
However, despite the geometric similarity between segphos
and difluorphos, the latter provides the best enantiomeric
excesses for the three substrates: b-hydroxy esters 7a and 7b
were obtained in 70 and 81% ee, respectively, and diol 7c was
obtained with very satisfactory diastereo- and enantioselec-
tivity (86% de and 98% ee for the R,R anti diol). To our
knowledge, this is the best reported ee values for the
ruthenium-catalyzed hydrogenation of 6a,[27] 6b and 6c[28]
using biphenyl-based diphosphanes. In this particular case,
the superiority of difluorphos over its nonfluorinated
analogue segphos lies in the atypical combination of a
narrow dihedral angle and a stronger electrodeficient char-
acter.
[1] For a review on axially chiral bidentate ligands, see : M.
McCarthy, P. J. Guiry, Tetrahedron 2001, 57, 3809.
[2] a) R. Noyori, H. Takaya, Acc. Chem. Res. 1990, 23, 345; b) H.
Takaya, T. Ohta, R. Noyori, Catalytic Asymmetric Synthesis
(Ed.: I. Ojima), VCH, New York, 1993.
[3] a) R. Schmid, M. Cereghetti, B. Heiser, P. Schönholzer, H.-J.
Hansen, Helv. Chim. Acta 1988, 71, 897; b) R. Schmid, J.
Foricher, M. Cereghetti, P. Schönholzer, Helv. Chim. Acta 1991,
74, 370; c) R. Schmid, E. A. Broger, M. Cereghetti, Y. Crameri,
J. Foricher, M. Lalonde, R. K. Müller, M. Scalone, G. Schoettel,
U. Zutter, Pure Appl. Chem. 1996, 68, 131.
[4] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994, pp. 1 – 93; b) “Reductions in Organic Syn-
thesis”: J.-P. Genet, ACS Symp. Ser. 1996, 641, 31 – 51; c) T.
Ohkuma, M. Kitamura, R. Noyori in Catalytic Asymmetric
Synthesis (Ed.: I. Ojima), 2000, pp. 1 – 110; d) R. Noyori, T.
Ohkuma, Angew. Chem. 2001, 113, 41; Angew. Chem. Int. Ed.
2001, 40, 40; e) J.-P. Genet, Pure Appl. Chem. 2002, 74, 77; f) H.-
In summary, we have described an efficient synthesis of a
new electrodeficient atropisomeric diphosphane, difluorphos.
We have shown that its original stereoelectronic structure,
324
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 320 –325

Angewandte
Chemie
U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer,
Adv. Synth. Catal. 2003, 345, 103.
[5] For a recent review on new chiral phosphorus ligands for
asymmetric hydrogenation, see: W. Tang, X. Zhang, Chem. Rev.
2003, 103, 3029.
[6] a) K. Mashima, K. Kusano, N. Sato, Y. Matsumura, K. Nozaki,
H. Kumobayashi, N. Sayo, Y. Hori, T. Ishizaki, S. Akutagawa, H.
Takaya, J. Org. Chem. 1994, 59, 3064; b) H. Kumobayashi, T.
Miura, N. Sayo, T. Saito, X. Zhang, Synlett 2001, 1055.
[7] a) T. Saito, N. Sayo, Z. Xiaoyaong, T. Yokozawa (Takasago
International Corporation), EP 0850945, 1998; b) T. Saito, T.
Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura, H.
Kumobayashi, Adv. Synth. Catal. 2001, 343, 264.
[23] a) J.-P. Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart, X.
Pfister, M. C. Caꢂo de Andrade, J. A. Laffitte, Tetrahedron:
Asymmetry 1994, 5, 665; b) J.-P. Genet, C. Pinel, V. Ratovelo-
manana-Vidal, S. Mallart, X. Pfister, L. Bischoff, M. C. Caꢂo
de Andrade, S. Darses, C. Galopin, J. A. Laffitte, Tetrahedron:
Asymmetry 1994, 5, 675.
[24] M. Kitamura, T. Ohkuma, H. Takaya, R. Noyori, Tetrahedron
Lett. 1988, 29, 1555.
[25] a) D. Blanc, V. Ratovelomanana-Vidal, J.-P. Gillet, J.-P. Genet, J.
Organomet. Chem. 2000, 603, 128. b) J. Madec, X. Pfister, P.
Phansavath, V. Ratovelomanana-Vidal, J.-P. Genet, Tetrahedron
2001, 57, 2563.
[26] N. Sayo, S. Akutagawa, T. Saito, R. Noyori, H. Kumobayashi, H.
Takaya, (Takasago International Corporation), EP 295109, 1988.
[27] For Ru-catalyzed hydrogenation of ethyl 4,4,4-trifluoro-acetoa-
cetate using biheteroaromatic diphosphanes, see: T. Benincori,
E. Cesarotti, O. Piccolo, F. Sannicolꢀ, J. Org. Chem. 2000, 65,
2043.
[28] Noyori has reported obtaining (R,R)-1,1,1,5,5,5-hexafluoro-2,3-
pentandiol with 70% de and 70% ee using [Ru{(S)-(ꢀ)-p-
Tolbinap}](PF6)2 as catalyst: N. Sayo, T. Saito, H. Kumobayashi,
S. Akutagawa, R. Noyori, H. Takaya, (Takasago International
Corporation), EP 297752, 1989.
[8] Z. Zhang, H. Qian, J. Longmire, X. Zhang, J. Org. Chem. 2000,
65, 6223.
[9] a) S. Duprat de Paule, N. Champion, V. Vidal, J.-P. Genet, P.
Dellis (SYNKEM), FR 2830254, 2001; S. Duprat de Paule, N.
Champion, V. Vidal, J.-P. Genet, P. Dellis (SYNKEM), WO
03029259, 2003. b) See also: C. C. Pai, Y. M. Li, Z. Y. Zhou,
A. S. C. Chan, Tetrahedron Lett. 2002, 43, 2789.
[10] N. G. Andersen, M. Parvez, B. A. Keay, Org. Lett. 2000, 2, 2817.
[11] a) T. Benincori, E. Brenna, F. Sannicolꢀ, L. Trimarco, P.
Antognazza, E. Cesarotti, J. Chem. Soc. Chem. Commun. 1995,
685; b) T. Benincori, E. Brenna, F. Sannicolꢀ, L. Trimarco, P.
Antognazza, E. Cesarotti, F. Demartin, T. Pilati, J. Org. Chem.
1996, 61, 6244.
[12] M. Murata, T. Morimoto, K. Achiwa, Synlett 1991, 827.
[13] T. Benincori, O. Piccolo, S. Rizzo, F. Sannicolꢀ, J. Org. Chem.
2000, 65, 8340.
[14] a) P. Guerreiro, V. Ratovelomanana-Vidal, J.-P. Genet, P. Dellis,
Tetrahedron Lett. 2001, 42, 3423; b) G. Michaud, M. Bulliard, L.
Ricard, J.-P. Genet, A. Marinetti, Chem. Eur. J. 2002, 8, 3327.
[15] a) F. Ullmann, J. Bielecki, Ber. Dtsch. Chem. Ges. 1901, 34, 2174;
b) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359.
[16] (+)-(S)-difluorphos ((S)-5): m.p. > 2608C ; 1H NMR (300 MHz,
CDCl3): d = 6.89 (dt, J = 1.5, 8.2Hz, 2H), 7.02 (d, J = 8.2Hz,
2H), 7.10–7.22 (m, 8H), 7.23–7.35 ppm (m, 12H); 31P NMR
(162MHz, CDCl 3, H3PO4 (85%)): d = ꢀ12.23 ppm; 19F NMR
(376 MHz, CDCl3): d = ꢀ49.90 ppm (dd, J = 160.8, 93.4 Hz); MS
(EI): m/z: 683 [M+H]+; HR-MS: calculated for C38H25F4O4P2
[M+H] 683.1164, found 683.1147; [a]2D0 = + 2 0 c( = 0.1 in ben-
zene). The reduction of (+)-(R)-4 afforded (ꢀ)-(R)-difluorphos
((R)-5) in 91% yield as a white solid. All analytical data were
identical to the corresponding spectra of (+)-(S)-5. R enan-
tiomer: [a]2D0 = ꢀ2 0 (c = 0.1 in benzene).
[17] a) P. Dierkes, P. W. N. M. van Leeuwen, J. Chem. Soc. Dalton
Trans. 1999, 1519; b) P. W. N. M. van Leeuwen, P. C. J. Kamer,
J. N. H. Reek, P. Dierkes, Chem. Rev. 2000, 100, 2741.
[18] a) S. Duprat de Paule, S. Jeulin, V. Ratovelomanana-Vidal, J.-P.
Genet, N. Champion, P. Dellis, Tetrahedron Lett. 2003, 44, 82 3;
b) S. Duprat de Paule, S. Jeulin, V. Ratovelomanana-Vidal, J.-P.
Genet, N. Champion, G. Deschaux, P. Dellis, Org. Process Res.
Dev. 2003, 7, 399; c) S. Duprat de Paule, S. Jeulin, V. Ratovelo-
manana-Vidal, J.-P. Genet, N. Champion, P. Dellis, Eur. J. Org.
Chem. 2003, 1931.
[19] CAChe (Computer Aided Chemistry) program.
[20] Force field parameters: MM2; calculation type: structure
optimization; optimization method: conjugate gradient for no
more than 3000 updates or until convergence to 10ꢀ4 kcalmolꢀ1
.
[21] a) D. W. Allen, B. F. Taylor, J. Chem. Soc. Dalton Trans. 1982, 51;
b) A. Suꢁrez, M. A. Mendez-Rojas, A. Pizzano, Organometallics
2002, 21, 4611.
[22] a) L. Vallarino, J. Chem. Soc. 1957, 2287; b) A. Sanger, J. Chem.
Soc. Dalton Trans. 1977, 120; c) K. Mashima, K. Kusano, N. Sato,
Y. Matsumura, K. Nozaki, H. Kumobayashi, N. Sayo, Y. Hori, T.
Ishizaki, S. Akutagawa, H. Takaya, J. Org. Chem. 1994, 59, 3064.
Angew. Chem. Int. Ed. 2004, 43, 320 –325
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
325