Synthesis of novel 1,1′-bis(oxazolinyl)metallocenes and their application in the asymmetric phenyl transfer from organozincs to aldehydes

Article abstract of DOI:10.1016/S0022-328X(00)00906-2

Two novel C₂-symmetric 1,1′-bis(oxazolinyl)metallocenes bearing two catalytic sites each have been employed in the asymmetric phenyl transfer from organozincs to aldehydes. Both, ferrocene (3) and ruthenocene (10) give very good yields and high

Full text of DOI:10.1016/S0022-328X(00)00906-2

Journal of Organometallic Chemistry 624 (2001) 157–161
www.elsevier.nl/locate/jorganchem
Synthesis of novel 1,1%-bis(oxazolinyl)metallocenes and their
application in the asymmetric phenyl transfer from organozincs to
aldehydes
C. Bolm *, N. Hermanns, M. Kesselgruber, J.P. Hildebrand
Institut fu¨r Organische Chemie der RWTH Aachen, Professor Pirlet Strasse 1, 52056 Aachen, Germany
Received 4 October 2000; accepted 15 November 2000
Dedicated to Professor Jean Normant on the occasion of his 65th birthday
Abstract
Two novel C2-symmetric 1,1%-bis(oxazolinyl)metallocenes bearing two catalytic sites each have been employed in the asymmetric
phenyl transfer from organozincs to aldehydes. Both, ferrocene (3) and ruthenocene (10) give very good yields and high
enantioselectivities in the title reaction affording optically active diarylmethanols with up to 96% ee. © 2001 Elsevier Science B.V.
All rights reserved.
Keywords: 1,1%-bis(Oxazolinyl)metallocenes; Asymmetric phenyl transfer; Organozincs; Aldehydes
1. Introduction
catalyst system for the phenyl transfer from organo-
zincs to aldehydes consisting of ferrocene 1 and mix-
tures of ZnPh2 and ZnEt2 [9,10]. The best enantiomeric
excesses were obtained with a catalyst loading of 10
mol%. In order to achieve a reduction of the required
catalyst amount, we now investigated the use of metal-
locenes bearing duplicate catalytically active sites in a
single molecule. Considering a strategy introduced by
Park, Ahn [11] and Ikeda [12] in the ferrocene series
(preparation of C2 symmetric diphosphine 2) several
years ago, we expected a straighforward synthesis of the
desired 1,1%,2,2%-tetrasubstituted ferrocene 3 by elec-
trophilic quench of the dianion of 4 with benzophenone
[13]1. Other metallocenes having this substitution pat-
Asymmetric catalysis has become a powerful tool in
organic synthesis in recent years [1]. Among the vast
variety of ligands, planar chiral ferrocenes [2] belong to
the most successful which have also been applied in
industrial processes [3]. Numerous compounds have
been described [4], and it was found that the element of
planar chirality often had a decisive influence on the
stereoselectivity and efficiency of the resulting catalytic
system [5]. In order to introduce planar chirality into
the molecules, the ability of oxazolines to act as direct-
ing groups for diastereoselective ortho-lithiation [6] has
frequently been applied, leading — after subsequent
quenches with appropriate electrophiles — to the de-
sired products in high yield and excellent stereochemi-
cal control [7]. Furthermore, the oxazoline moiety itself
proved to be an excellent stereo-directing element in
asymmetric catalysis, and thus in planar chiral systems
its usefulness has exceeded the application as internal
chiral auxiliary [8].
Recently, we reported on a highly enantioselective
Fig. 1.
1 After submission of this manuscript (September 29, 2000) a paper
appeared in which the synthesis of 3 and its application in diethylzinc
additions to benzaldehyde was described.
* Corresponding author. Tel.: +49-241-804675; fax +49-241-
8888391.
E-mail address: carsten.bolm@oc.rwth-aachen.de (C. Bolm).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00906-2

158
C. Bolm et al. / Journal of Organometallic Chemistry 624 (2001) 157–161
Table 1
Catalyzed phenyl transfer to various aldehydes with ferrocenes 1 and 3 a
Entry
Substrate
Catalyst amount (mol%)
Ee (%) b of products 6a–c using
Absolute config. c
Ferrocene 1
Ferrocene 3
1
2
3
4
5
6
7
5a
5a
5a
5b
5b
5c
5c
10
5
2
10
5
10
5
97
95
92
96
96
75
75
96
94
86
95
95
72
71
R
R
R
R
R
S
S
number of oxazoline diphenylhydroxymethyl units the
catalyses with 3 even showed slightly inferior results. A
possible explanation of this behavior was seen in a
mutual interference of the two catalytic sites during the
catalysis.
In order to disfavor and minimize such negative
interaction, we prepared ruthenocene 10. With respect
to ferrocenes, the two cyclopentadienyl rings of
Scheme 1.
,
ruthenocenes are ca. 0.34 A further apart [14], thus
increasing the spatial separation of the two catalytic
tern were hoped to be accessible in an analogous man-
ner (Fig. 1).
sites. The synthesis of 10 was accomplished in the same
manner as for ferrocene
3 starting from 1,1%-
ruthenocene dicarboxylic acid (7), which was obtained
via carboxylation of dilithiated ruthenocene [15]
(Scheme 2). The diacid was reacted with an excess of
oxalyl chloride, and the resulting 1,1%-bis(chlorocar-
bonyl)ruthenocene was treated with (S)-tert-leucinol to
afford the corresponding bisamide 8. Cyclization of 8
following the Appel protocol [16] gave 1,1%-bis(oxa-
zolinyl)ruthenocene (9). Directed ortho-metalation of 9
with sec-butyllithium and subsequent quenching of the
resulting dianion with benzophenone in the same man-
ner as in the ferrocene series gave a diastereomeric
mixture of ruthenocene 10 in a ratio of 9:1. The
diastereomers were separated by flash chromatography,
and diastereomerically pure (S,S,Rp,Rp)-10 was used
for further studies [13]2.
2. Results and discussion
Known 1,1%-bis(oxazolinyl)ferrocene (4) was prepared
in two steps from 1,1%-bis(chlorocarbonyl)ferrocene fol-
lowing literature procedures [12a]. As hoped for, the
synthesis of 3 was accomplished by dilithiation of 4
with sec-butyllithium in THF at −78°C and subse-
quent quenching of the dimetallated species with ben-
zophenone (Scheme 1).
A 9:1 mixture of diastereomers was obtained in good
yield, favoring of the product with (R,R)-configuration
with respect to planar chirality. Preparative HPLC gave
diastereomerically pure (S,S,Rp,Rp)-3 which was subse-
quently used in asymmetric phenyl transfers to alde-
hydes according to our new protocol [9b]. Results of
these catalyses are summarized in Table 1.
Compared to catalyses with ferrocene 1, use of 10
mol% of C2-symmetric 3 gave almost identical results
with respect to both yield and enantioselectivity. Unfor-
tunately, reactions with a lower catalyst loading led to
a decrease in enantioselectivity. Based on an identical
2 In the synthesis of 3 the stereochemical assignment is based on the
results by Ahn (Ref. [11b]) and Ikeda (Ref. [12a]). The analogous
behavior of the Ru complex was established independently. The C2
symmetry of complexes 3 and 10 is further suggested by the highly
symmetrical NMR spectra.

C. Bolm et al. / Journal of Organometallic Chemistry 624 (2001) 157–161
159
Table 2
Catalyzed phenyl transfer to various aldehydes with ruthenocene 10 a
c
Entry
Substrate
Catalyst amount (mol%)
Ee (%) b of products 6a–c using ruthenocene 10
Absolute config.
1
2
3
4
5
6
7
5a
5a
5a
5b
5b
5c
5c
10
5
2
10
5
10
5
96
95
90
94
93
74
72
R
R
R
R
R
S
S
a All reactions gave good to quantitative yields on a 0.25 mmol scale.
b Determined by HPLC using a column with chiral stationary phase.
c Determined by comparison of the order of peak elution during HPLC with literature values, or tentatively assigned by assumption of an
identical reaction pathway (entries 4,5).
3. Conclusion
In conclusion, we introduced new C2-symmetric
metallocenes 3 and 10 which catalyze the asymmetric
phenyl transfer from organozincs to aldehydes with
high enantioselectivities. Based on the number of oxa-
zoline units present in the catalytic system, ferrocene 3
is inferior to its mono-substituted analogue 1.
Ruthenocene 10 showed comparable selectivities and
yields.
4. Experimental
All manipulations except workup and purification
Scheme 2.
were conducted under an inert atmosphere of Ar using
standard Schlenk techniques. Diphenylzinc was ob-
tained from Strem and handled in a glovebox under Ar.
Tetrahydrofuran and toluene were distilled from
sodium/benzophenone ketyl radical, dichloromethane
from calciumhydride prior to use. sec-Butyllithium was
The results of catalyses with the new ruthenocene 10
are summarized in Table 2. To our delight, we noted
that compared to ferrocene 3, ruthenocene 10 showed
purchased from Fluka as a 1.3 M solution in cyclohex-
slightly better selectivities in the phenyl transfer to
ane. 1H- and 13C-NMR spectra were recorded on a
4-chlorobenzaldehyde (5a) at lower catalyst loadings
Varian Gemini 300 spectrometer at 300 and 75 MHz,
(entries 2 and 3). The same accounted for transforma-
tions of 3-phenylpropanal (5c). However, additions to
4-methoxybenzaldehyde (5b) were less efficient giving
slightly lower enantioselectivies with 10 than with 3,
and again, ferrocene 1 having only a single catalytic site
was more selective than ruthenocene 10 with two.
As a consequence of these results, we believe that
possible steric interactions of the two catalytic sites in 3
respectively, and on a Varian Inova 400 spectrometer at
400 and 100 MHz, respectively. Chemical shifts are
given in ppm with internal referencing to the solvent
peaks. IR spectra were measured on a Perkin Elmer
1760 S as KBr pellets, MS spectra on a Varian MAT
212 or a Finnigan SSQ7000 mass spectrometer with EI
ionization. All experiments were conducted at least
twice to ensure reproducibility.
and 10 are not the sole reasons for the lower enantiose-
lectivities observed in catalyses with these 1,1%,2,2%-tetra-
substituted bis(oxazolinyl) metallocenes. Other factors
might as well have an important impact, and current
studies are directed towards a deeper understanding of
the underlying principles of this synthetically useful
C–C bond-forming catalysis.
4.1. (S,S,Rp,Rp)-1,1%-bis-[(4-tert-Butyloxazolin-2-yl)]-
2,2%-bis(diphenylhydroxymethyl)ferrocene (3)
To a solution of 250 mg (0.57 mmol) of 4 in 10 ml of
tetrahydrofuran is added 1.15 ml (1.50 mmol) of sec-
butyllithium at −78°C. After stirring the mixture at

160
C. Bolm et al. / Journal of Organometallic Chemistry 624 (2001) 157–161
4.3. (S,S)-1,1%-bis-[4-tert-Butyl-oxazolin-2-yl]-
ruthenocene (9)
this temperature for 2 h, and then at 0°C for 20 min,
271 mg (1.45 mmol) of benzophenone is added in one
portion. Stirring is continued overnight, allowing the
temperature to rise to ambient temperature. The reac-
tion is then quenched with 10 ml of water and extracted
with diethylether (3×25 ml). The collected organic
layers are dried (MgSO4) and evaporated. The crude
product is obtained in a diastereomeric ratio of 9:1. The
diastereomers were separated by preparative HPLC
(silica gel; 10 mm; eluent: hexanes:MTBE=9:1) to yield
277 mg (53%) of the title compound as an orange solid:
To a solution of 822 mg (1.59 mmol) of 8 in 60 ml of
acetonitrile is added 3.1
g
(11.80 mmol) of
triphenylphosphine, 2.0 ml of triethylamine and 2.6 ml
of tetrachloromethane. The mixture is stirred overnight
at ambient temperature, then quenched with 100 ml of
water and extracted with diethylether (4×80 ml). The
collected organic layers are dried (MgSO4) and evapo-
rated. Purification by column chromatography (silica
gel; pentane:diethylether=1:2) yields 605 mg (79%) of
the title compound as a light yellow solid. m.p. 191–
193°C. [h]D= –117° [c=1.0, CHCl3]. 1H-NMR
(CDCl3): l 0.90 (s, 18H), 3.80 (dd, J=7.1 Hz, 9.2 Hz,
2H), 4.04–4.20 (m, 4H), 4.67 (b, 4H), 5.05 (b, 2H), 5.15
(b, 2H). 13C-NMR (CDCl3): l 25.8, 33.9, 68.2, 72.0,
72.2, 73.3, 73.3, 75.9, 75.9, 163.8. MS (EI, 70 eV): m/z
(%) 482 (21, [M+]), 425 (100), 325 (53). IR (KBr):
w=3433, 2960, 2225, 1660, 1483. HRMS Calc. for
C24H32N2O2Ru: 482.1501. Found: 482.1503.
1
m.p. 241–243°C. [h]D= −125° [c=0.25, CHCl3]. H-
NMR (CDCl3): l 0.98 (s, 18H), 3.54 (dd, J=1.6 Hz,
2.5 Hz, 2H), 3.58 (dd, J=9.6 Hz, 2H), 4.07 (dd, J=9.3
Hz, 2H), 4.15 (dd, J=8.8 Hz, 10.2 Hz, 2H), 4.59 (dd,
J=1.6 Hz, 2.5 Hz, 2H), 5.17 (dd, J=2.7 Hz, 2H),
7.00–7.20 (m, 20H), 9.13 (s, 2H). 13C-NMR (CDCl3): l
26.5, 33.3, 67.9, 69.0, 72.0, 75.1, 75.6, 77.2, 78.6, 100.9,
126.5, 127.1, 127.3, 123.3, 127.4, 127.4, 145.3, 148.9,
167.1. MS (EI, 70 eV): m/z (%) 800 (26, [M+]), 600
(70), 356 (100), 327 (30), 298 (958), 105 (20). IR (KBr):
w=2957, 1652, 700. HRMS Calc. for C50H52N2O4Fe:
800.3276. Found: 800.3275.
4.4. (S,S,Rp,Rp)-1,1%-bis-[4-tert-Butyloxazolin-2-yl]-
2,2%-bis(diphenylhydroxymethyl)ruthenocene (10)
To a solution of 100 mg (0.21 mmol) of 9 in 4 ml of
tetrahydrofuran is added 0.42 ml (0.54 mmol) of sec-
butyllithium at −78°C. After stirring the mixture at
this temperature for 2 h, and then at 0°C for 20 min,
100 mg (0.55 mmol) of benzophenone is added in one
portion. The reaction is quenched after 2 h at 0°C with
10 ml of water and extracted with diethylether (3×10
ml). The collected organic layers are dried (MgSO4) and
evaporated. The crude product is obtained in a
diastereomeric ratio of 9:1. Purification by flash chro-
matography (silica gel; pentane:diethylether=6:1)
yields 130 mg (74%) of the title compound as a light
4.2. (S,S)-1,1%-bis-[N-(1-tert-Butyl-2-hydroxyethyl)-
amido]ruthenocene (8)
A suspension of 1.00 g (3.13 mmol) of 1,1%-
ruthenocenedicarboxylic acid (7) in 15 ml of
dichloromethane is treated with 2.18 ml (25.06 mmol)
of oxalyl chloride. Three drops of pyridine are added
and the mixture is refluxed under ultrasonic irradiation
until it becomes a clear solution (ca. 3 h). The solvent
is removed into a trap, the residue is dried for 2 h and
dissolved in 10 ml of dichloromethane. The solution is
added slowly via cannula to a mixture of 1.31 g (11.11
mmol) of (S)-tert-leucinol and 2.30 ml (16.42 mmol) of
triethylamine in 10 ml of dichloromethane. After stir-
ring at ambient temperature overnight 20 ml of water
are added. The organic layer is separated and the
aqueous layer is extracted with dichloromethane (3×
20 ml). The combined organic phases are dried
(MgSO4), evaporated and purified by column chro-
matography (silica gel; ethylacetate) to yield 931 mg
(57%) of the title compound as a light yellow solid.
m.p. 243–245°C (dec). [h]D= −148° [c=1.0, CHCl3].
1H-NMR (CDCl3): l 0.95 (s, 18H), 3.57–4.10 (m, 6H),
4.75 (b, 4H), 4.83 (b, 2H), 5.20 (b, 2H), 5.91–6.00 (m,
2H). 13C-NMR (CDCl3): l 26.9, 34.4, 58.8, 61.3, 77.8,
72.1, 73.2, 73.5, 82.2, 168.7. MS (EI, 70 eV): m/z (%)
518 (3, [M+]), 402 (35), 303 (71), 257 (56), 231 (55), 86
(99), 60 (100). IR (KBr): w=3334, 2963, 1626, 1539.
HRMS Calc. for C18H22NO3Ru (C24H36N2O4Ru–
C6H14NO): 402.0637. Found: 402.0638.
1
yellow syrup. [h]D= −179° [c=1.0, CHCl3]. H-NMR
(CDCl3): l 0.90 (s, 18H), 3.50–3.60 (m, 2H), 3.84 (b,
2H), 3.98–4.15 (m, 4H), 5.01 (b, 2H), 5.15 (b, 2H),
6.90–7.30 (m, 20H), 8.90 (s, 2H). 13C-NMR (CDCl3): l
26.4, 33.9, 69.2, 73.1, 74.2, 75.5, 77.1, 77.1, 81.8, 105.4,
126.4, 126.6, 126.9, 127.2, 127.3, 127.8, 145.5, 148.5,
166.4. MS (EI, 70 eV): m/z (%) 847 (15, [M+]), 829
(26), 75 (55), 287 (22), 183 (28), 105 (100). IR (KBr):
w=3086, 2960, 1656, 1448. HRMS Calc. for
C50H52N2O4Ru: 846.2964. Found: 846.2964.
4.5. Standard procedure for the asymmetric phenyl
transfer to aldehydes
In a glovebox, a well-dried Schlenk flask is charged
with diphenylzinc (36 mg, 0.16 mmol). The flask is
sealed and removed from the glovebox. Freshly distilled
toluene (3 ml) is added, followed by diethylzinc (33 ml,
0.33 mmol). After stirring for 30 min at room tempera-
ture the metallocene is added and the resulting solution

C. Bolm et al. / Journal of Organometallic Chemistry 624 (2001) 157–161
161
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[3] For accounts on the importance of ferrocene type ligands for
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Chimia 51 (1997) 300.
is cooled to 10°C. Stirring is continued for additional
10 min at this temperature, and then the aldehyde (0.25
mmol) is added in one portion. The Schlenk flask is
sealed and the reaction mixture stirred at 10°C
overnight. The solution is quenched with water, ex-
tracted with diethylether (3×10 ml), dried (MgSO4)
and evaporated. Column chromatography (silica gel;
eluent: pentane/diethylether) affords the pure secondary
alcohol.
[4] C.J. Richards, A.J. Locke, Tetrahedron: Asymmetry 9 (1998)
2377.
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4.6. HPLC analysis of the secondary alcohols
a-(4-Chlorophenyl)phenylmethanol (5a): Chiralcel
OB, heptane/i-PrOH, 80:20, 0.9 ml min−1, (R): 8.8,
(S): 13.3 min.
a-(3-Methoxyphenyl)phenylmethanol (5b): Chiralcel
OD, heptane/i-PrOH, 95:5, 0.8 ml min−1, (S): 35.0,
(R): 54.3 min.
1,3-Diphenyl-1-propanol (5c): Chiralcel OD, hep-
tane/i-PrOH, 95:5, 0.9 ml min−1, (S): 24.3, (R): 27.3
min.
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Acknowledgements
We are grateful to the Fonds der Chemischen Indus-
trie and the Deutsche Forschungsgemeinschaft (DFG)
within the Collaborative Research Center (SFB) 380
‘Asymmetric Synthesis by Chemical and Biological
Methods’ for financial support. MK acknowledges
DFG for a predoctoral fellowship (Graduiertenkolleg,
GK-440). We thank Degussa and Witco for donations
of chemicals.
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therein.
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