A straightforward and modular synthesis of enantiopure C2- and C1-symmetrical 2,2″-phosphino-1,1″-biferrocenes

Article abstract of DOI:10.1016/S0957-4166(01)00194-X

A new practical and highly flexible synthesis of enantiopure C₂- and C₁-symmetrical 2,2″-phosphino-1,1″-biferrocenes is presented. The structural properties of two of their PdCl₂ complexes and preliminary Ru-catalysed hydrogenations using the biferrocene ligands, giving anantioselectivities of up to 82%, are described.

Full text of DOI:10.1016/S0957-4166(01)00194-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1105–1108
A straightforward and modular synthesis of enantiopure C - and
2
C -symmetrical 2,2%%-phosphino-1,1%%-biferrocenes
1
a
b
c
a,
Li Xiao, Kurt Mereiter, Felix Spindler and Walter Weissensteiner *
a
Institut f u¨ r Organische Chemie, Universit a¨ t Wien, W a¨ hringer Straße 38, A-1090 Vienna, Austria
b
Institute of Mineralogy, Crystallography and Structural Chemistry, Vienna University of Technology, Getreidemarkt 9,
A-1060 Vienna, Austria
c
Solvias AG, Catalysis Research, PO Box, CH-4002 Basel, Switzerland
Received 26 March 2001; accepted 27 April 2001
Abstract—A new practical and highly flexible synthesis of enantiopure C - and C -symmetrical 2,2%%-phosphino-1,1%%-biferrocenes
2
1
is presented. The structural properties of two of their PdCl complexes and preliminary Ru-catalysed hydrogenations using the
2
biferrocene ligands, giving enantioselectivities of up to 82%, are described. © 2001 Elsevier Science Ltd. All rights reserved.
1
2
1
. Introduction
of R "R . Coupling of the iodides led to the 2,2%%-bis-
(
phosphinyl)-1,1%%-biferrocenes III, which on reduction
with trichlorosilane gave the final products IV.
Axially chiral diphosphines as exemplified by 2,2%-bis-
diphenylphosphino)-1,1%-binaphthyl (BINAP) are
widely used in enantioselective catalysis. Surprisingly
little attention has been paid to their biferrocene ana-
logues, although ferrocene based ligands have proved
to be highly efficient in many catalytic enantioselective
(
1
,2
I
O
O
P
P
Fe
R2
Fe
R2
R1
R1
3
,4
reactions. Almost 10 years ago, Ito et al. described
the synthesis of 2,2%%-bis(diphenylphosphino)-1,1%%-bifer-
I
II
5
,6
rocene (BIFEP), but to the best of our knowledge
neither structural nor catalytic results have been pub-
lished. Only very recently a few additional examples
with P-stereogenic phosphino substituents were synthe-
7
sised by Nettekoven. In allylic aminations using the
Fe
Fe
8
ligands, products having up to 93% e.e. were obtained.
PR1R2
1
P(O)R R2
1
PR R2
P(O)R R2
1
Fe
Fe
Both the original synthesis of BIFEP and that of its
P-stereogenic analogues followed a similar strategy to
that outlined in Scheme 1. Ferrocenylphosphineoxide I
was ortho-magnesiated and transformed into the
respective 2-iodo-ferrocenylphosphineoxide II. A race-
IV
III
1
2
Scheme 1.
mate was obtained for R =R =Ph, while
diastereomers were formed in up to 94% d.e. in the case
In the case of BIFEP, resolution of (±)-2,2%%-bis-
diphenylphosphinyl)-1,1%%-biferrocene was necessary,
while both the coupling reaction of the P-stereogenic
-iodoferrocenylphosphineoxides and the final reduc-
(
2
tion step led to partial epimerisation at phosphorus.
These facts severely limit the applicability of this reac-
tion sequence.
*
0
Corresponding author. Tel.: 43-1-4277-52148; fax: 43-1-4277-9521;
e-mail: walter.weissensteiner@univie.ac.at
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00194-X

1
106
L. Xiao et al. / Tetrahedron: Asymmetry 12 (2001) 1105–1108
2
0
1
We now describe a new modular synthesis of BIFEP
and analogues avoiding the need for a resolution step
and allowing for the stepwise addition of different
phosphino groups to an enantiopure biferrocene inter-
mediate (Scheme 2). In a solid state reaction iodide 1
was coupled with Cu powder giving enantiopure
(30%, [h] =+125.5 (c=0.40, CHCl )); C : R =3,5-
D
3
1
2
dimethyl-4-methoxyphenyl,
phenyl, 8 (42%, [h] =+1.63 (c=0.43, CHCl ))).
R =3,5-trifluoromethyl-
2
0
§
D
3
9,10
The (S ,S ) absolute configuration of biferrocenes 2–8
p
p
follows directly from the absolute configuration of
starting material 1, known to be (S ,R ).
9
(
2
S ,S ,S ,S )-2,2%%-bis-(p-tolylsulfinyl)-1,1%%-biferrocene,
c
c
p
p
c
p
†
20
(130°C, 16 h, yield 77%, [h] =−393.0 (c=0.50,
D
CHCl )), which served as the central intermediate
3
With respect to their intended application in enantiose-
lective catalysis the palladium dichloride complexes of
biferrocenes 6 (6·PdCl ) and 8 (8·PdCl ) were prepared
allowing the stepwise replacement of both p-tolylsulfi-
nyl units. Reaction of 2 in THF with tert-Bu-Li (1.2
equiv.) in THF (−78°C, 5 min) and quenching with
2
2
by reacting the respective ligands with (CH CN) PdCl
3
2
2
chloro(diaryl)phosphine led to (S ,S ,S )-2-diarylphos-
c
p
p
in benzene. Solvated single crystals suitable for X-ray
diffraction could be obtained from both complexes on
crystallisation from appropriate solvent mixtures (Figs.
1
phino-2%%-p-tolyl-sulfinyl-1,1%%-biferrocenes: R =Ph, 3
2
0
1
(
60%, [h] =+60.6 (c=0.50, CHCl )); R =3,5-
D 3
20
dimethylphenyl,
4
(80%, [h] =−27.0 (c=0.52,
D
1
and 2).
1
CHCl )); R =3,5-dimethyl-4-methoxyphenyl, 5 (66%,
h] =−14.4 (c=0.50, CHCl )). In a subsequent step
3
2
0
[
¶
D
3
The X-ray study not only proved the structural
integrity of ligands 6 and 8 and the cis-coordination to
Pd but also in both cases the (S ,S ) absolute configura-
tion. A particularly interesting feature is the biferrocene
conformation. Unlike for BINAP, at the laboratory
time scale, for ligands 6–8 a free rotation about the
biferrocene bond must be assumed. Hence, their PdCl2
complexes may exist as two conformers differing in the
biferrocene arrangement.
the second sulfinyl group was removed by treatment of
–5 in THF with tert-Bu-Li in THF (−78°C, 5 min)
followed again by reaction with a chloro(diaryl)-
3
p
p
1
0
phosphine.
I
Fe
O
S
R
Cu
S(O)R
Fe
S(O)R
Fe
A comparison of the molecular structures depicted in
(Sc,Rp) - 1
(Sc,Sc,Sp,Sp) - 2
Figs. 1 and 2 indeed shows that in complex 6·PdCl
biferrocene unit adopts a (P)-shaped conformation
while 8·PdCl prefers an (M)-shaped biferrocene back-
bone. Obviously, the biferrocene shape in the preferred
2
the
tBuLi / ClPR1
2
2
Fe
Fe
PR2
tBuLi
S(O)R
2
PR1
ClPR2
PR1
2
2
2
Fe
Fe
‡
§
1
NMR data for 7: H NMR (CDCl , 400 MHz) l 1.78 (s, 12H,
3
(
Sp,Sp)
(Sc,Sp,Sp)
CH ), 2.34 (s, 12H, CH ), 3.97 (m, 2H, Cp-H), 4.00 (s, 10H, Cp-H),
.51 (m, 2H, Cp-H), 4.90 (m, 2H, Cp-H), 6.26 (d, J=7.3 Hz, 4H,
Ph-H), 6.45 (s, 2H, Ph-H), 7.03 (s, 2H, Ph-H), 7.20 (d, J=8.3 Hz,
H, Ph-H); P NMR l −22.42; MS (EI, 100°C) m/z=850 (M ).
3
3
4
1
2
R1= Ph
R = R = Ph
6
7
3
4
5
31
+
4
1
3
,5-(CH3)2Ph
3,5-(CH3)2Ph
3,5-(CH3)2-4-(OCH3)Ph
NMR data for 8: H NMR (CDCl , 400 MHz) l 1.75 (s, 6H, CH ),
3
3
R1= 3,5-(CH3)2-4-(OCH3)Ph
R2= 3,5-(CF3)2Ph
2.29 (s, 6H, CH
3
), 3.38 (s, 3H, OCH
), 3.75 (s, 3H, OCH
3
3
), 3.85 (m,
8
1H, Cp-H), 3.96 (br s, 6H, Cp-H), 4.05 (s, 5H, Cp-H), 4.56 (m, 1H,
Cp-H), 4.68 (m, 1H, Cp-H), 4.80 (m, 1H, Cp-H), 5.06 (m, 1H,
Cp-H), 6.26 (d, J=7.0 Hz, 2H, Ph-H), 7.06 (d, J=5.6 Hz, 2H,
Ph-H), 7.13 (d, J=8.1 Hz, 2H, Ph-H), 7.43 (s, 1H, Ph-H), 7.91 (d,
J=7.0 Hz, 2H, Ph-H), 7.98 (s, 1H, Ph-H); P NMR l −25.93,
19.09; MS (FAB) m/z=1126 (M ).
R = 4-(CH3)Ph
3
1
Scheme 2.
+
−
¶
Crystal data for 6·PdCl ·2CHCl ·H O: C H Cl Fe OP Pd (red
2
3
2
46 40
8
2
2
prisms from CHCl /EtOH+H O), M=1172.42, monoclinic, a=
3
2
1
,
0.270(3), b=22.142(6), c=10.282(3) A, i=100.96(2)°, U=2296(1)
A , T=223 K, space group P2 (no. 4), Z=2, v(Mo-K )=1.58
mm , 33075 reflections measured (umax=30°), 12764 unique (Rint=
0.051) which were used in all calculations. The final wR(F ) was
0.1086 (all data). The investigated crystals were pseudo-merohedral
twins (twin matrix 0 0 1/0 −1 0/1 0 0) showing orthorhombic pseu-
dosymmetry with C2221 as the pseudo-space group.
,
Depending on the phosphine used, either C - or C -
3
2
1
1
a
−
1
symmetrical biferrocenes all of (S ,S ) configuration
p
p
1
2
20
D
2
were obtained (C : R =R =Ph, 6 (49%, [h] =+150.5
2
1
2
‡
(
c=0.22, CHCl )); R =R =3,5-dimethylphenyl,
7
3
Crystal data for 8·PdCl ·solv.: C H Cl F Fe O P Pd (solvent
2
54 44
2
12
2
2 2
containing red prisms from EtOEt/CH Cl ; solvent badly disordered
2
2
and therefore omitted from chemical formula, M, and v), M=
1
303.83, orthorhombic, a=13.883(3), b=15.914(3), c=26.242(5) A
,
,
†
1
3
NMR data for 2: H NMR (400 MHz, CDCl ) l 2.44 (s, 6H, CH ),
U=5798(2) A
,
, T=297 K, space group P2 2 2 (no. 19), Z=4,
3
3
1 1 1
−
1
4
7
.01 (m, 2H, Cp-H), 4.37 (br s, 12H, Cp-H), 5.14 (m, 2H, Cp-H),
.31 (d, J=8.1 Hz, 4H, Ph-H), 7.68 (d, J=7.8 Hz, 4H, Ph-H); MS
EI, 200°C) m/z=646 (M ).
v(Mo-K )=1.49 mm , 60296 reflections measured (umax=25°),
10183 unique (Rint=0.068), which were used in all calculations. The
a
+
2
(
final wR(F ) was 0.1091 (all data).

L. Xiao et al. / Tetrahedron: Asymmetry 12 (2001) 1105–1108
1107
conformer of bis(diarylphosphino)–biferrocene com-
plexes depends on the steric requirements of the
diarylphosphino groups. In solution, the presence of
interconverting conformers cannot be excluded.
In summary, we have developed a straightforward syn-
thesis of enantiopure 2,2%%-phosphino-1,1%%-biferrocenes
via 2,2%%-bis-(p-tolylsulfinyl)-1,1%%-biferrocene as the
intermediate. Consecutive replacement of the sulfinyl
groups allowed the introduction of either equivalent or
non-equivalent phosphino substituents. In general, this
modular approach is also expected to be applicable to
electrophiles other than phosphine. Preliminary asym-
metric hydrogenations of ethyl acetylacetate with in situ
prepared Ru catalysts gave the product in up to 82%
e.e. X-Ray diffraction studies on two biferroceno–
Although conformational flexibility of the biferrocenyl
backbone might be considered a disadvantage, some
preliminary, but promising, results in the hydrogena-
tion of ethyl acetylacetate were obtained (Table 1).
Ruthenium complexes prepared in situ from [RuI (p-
2
cymene)] and ligands 6–8 were used and enantioselec-
2
tivities of up to 82% could be reached.
PdCl complexes revealed that conformers with either a
2
(
P)- or a (M)-shaped biferroceno unit are accessible,
When a 0.43 M solution of ethyl acetylacetate in etha-
depending on the substitution pattern of the phosphino
units.
nol containing a catalyst prepared in situ from [RuI (p-
2
cymene)] , 6 and HCl (1 M; 60 mL) was stirred under 80
2
bar pressure of H at 80°C for 16 h, (R)-ethyl-3-
2
hydroxybutyrate was produced in 82% e.e. and >99.5%
yield. Interestingly, the application of catalysts with the
Acknowledgements
C -symmetrical ligands 6 or 7 gave the hydrogenation
2
product in markedly higher enantioselectivity than
This work was kindly supported by Osterreichische
8
reactions with the C -symmetrical ligand 8 (20% e.e.).
Nationalbank (project 7516) and by Acci o´ n Integrada
(project 18/2000). A PhD grant of the Bundesminis-
terium f u¨ r Ausw a¨ rtige Angelegenheiten (Nord-S u¨ d-
Dialog Stipendienprogramm) is kindly acknowledged
by L.X.
1
With the use of ligand 6 at the lower temperature of
60°C the enantiomeric purity of the hydrogenation
product, (R)-ethyl-3-hydroxybutyrate, decreased from
2 to 70% e.e.
8
Figure 1. Molecular structure of C -symmetric 6·PdCl2 in 6·PdCl ·2CHCl ·H O with hydrogen bonded CHCl and H O
2
2
3
2
3
2
molecules. Characteristic torsion angles: P(1)ꢀC(1)ꢀC(6)ꢀP(2)=32.8(3)°, C(2)ꢀC(1)ꢀC(6)ꢀC(7)=29(1)°.

1
108
L. Xiao et al. / Tetrahedron: Asymmetry 12 (2001) 1105–1108
Figure 2. Molecular structure of C -symmetrical 8·PdCl in 8·PdCl ·solv. Characteristic torsion angles: P(1)ꢀC(1)ꢀC(6)ꢀP(2)=−
1
2
2
55.4(2)°, C(2)ꢀC(1)ꢀC(6)ꢀC(7)=−58.4(7)°.
Table 1. Catalytic hydrogenation of ethyl acetylacetate
2. Noyori, R. Asymmetric Catalysis in Organic Synthesis;
with H /Ru/ligands 6–8
Wiley: New York, 1994.
2
3
. Ferrocenes, Homogeneous Catalysis, Organic Synthesis,
Material Science; Togni, A.; Hayashi, T., Eds.; VCH:
Weinheim, 1995.
Ligand
Temp. (°C) Conversion
%)
E.e. (%)
Configuration
(
4
5
6
. Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; pp. 801–856.
. Sawamura, M.; Yamauchi, A.; Takegawa, T.; Ito, Y. J.
Chem. Soc., Chem. Commun. 1991, 874.
6
6
7
8
80
60
80
80
\99.5
\99.5
\98
96
82
70
68
20
R
R
R
R
. Ito, Y.; Sawamura, M., Japanese Patent, JP 04283596,
Reaction conditions: ethyl acetylacetate: (0.84 g, 6.45 mmol); catalyst:
RuI (p-cymene)] +Ligand (PP:Ru=1.05); s/c: 1000; solvent: etha-
1992, Sumitomo Chemical Co., Ltd.
7. Nettekoven, U. Doctoral Thesis, University of Amster-
dam, 2000.
[
2
2
nol (15 mL); HCl (1 M, 60 mL); p(H ): 80 bar; reaction time: 16 h.
2
8
. Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Mereiter, K.; Lutz, M.; Spek, A.
L. Organometallics 2000, 19, 2299.
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