Stereoselective substitution of α-aminoalkylferrocenes with diorganozincs. A fast synthesis of new chiral FERRIPHOS ligands for asymmetric catalysis

Article abstract of DOI:10.1016/S0957-4166(99)00182-2

A direct stereoselective substitution of α-aminoalkylferrocenes of type 3 with organozinc reagents provides chiral ferrocenes which can be converted to the FERRIPHOS ligands of type 1 in a one-pot procedure. These FERRIPHOS ligands have been used for the Rh-catalyzed asymmetric hydrogenation of an enol acetate with 94.9% ee.

Full text of DOI:10.1016/S0957-4166(99)00182-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1839–1842
Stereoselective substitution of α-aminoalkylferrocenes with
diorganozincs. A fast synthesis of new chiral FERRIPHOS
ligands for asymmetric catalysis
Matthias Lotz,a Tania Ireland,a Juan J. Almena Perea b and Paul Knochel a,∗
aInstitut für Organische Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany
bDegussa-Hüls AG, Fine Chemicals Division, Wolfgang Site, Rodenbacher Chaussee 4, D-63403 Hanau, Germany
Received 12 April 1999; accepted 11 May 1999
Abstract
A direct stereoselective substitution of α-aminoalkylferrocenes of type 3 with organozinc reagents provides
chiral ferrocenes which can be converted to the FERRIPHOS ligands of type 1 in a one-pot procedure. These
FERRIPHOS ligands have been used for the Rh-catalyzed asymmetric hydrogenation of an enol acetate with
94.9% ee. © 1999 Elsevier Science Ltd. All rights reserved.
Chiral ferrocenylphosphines are important ligands for asymmetric catalysis.1 Recently, we have repor-
ted a new class of such ligands: the FERRIPHOS ligands of type 12–4 (Scheme 1). These diphosphines
proved to be very efficient for the asymmetric hydrogenation of α-acetamidoacrylic acid derivatives
affording high enantioselectivities (>97% ee).2
Scheme 1.
The preparation of the ligands 1 required the synthesis of the sensitive diacetoxyferrocene derivatives
of type 2 which were obtained from the stable and easy to handle diaminoferrocene derivatives of type 3.
We have examined the direct substitution of the dimethylamino groups of 3 with diorganozincs since it
would avoid the synthesis and handling of the diacetates 2. Herein, we wish to report the successful direct
stereoselective substitution reaction as well as some new applications of the FERRIPHOS catalysts for
the asymmetric reduction of enol acetates. A recent publication by Salzer et al. has shown that benzylic
∗
Corresponding author. E-mail: knochel@ps1515.chemie.uni-marburg.de
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00182-2

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dimethylaminochromium complexes undergo enantiospecific nucleophilic substitutions with chloride
ions5 using ethyl chloroformate to activate the dimethylamino group. In preliminary experiments, we
have examined the substitution of the monodimethylaminoferrocene derivative 4 (97–98% ee) with
organozinc reagents in the presence of various acid chlorides (Table 1). We found that a range of
acylating agents were efficient for this nucleophilic substitution with dimethylzinc (THF, −30°C, 12 h).
The stereoselectivity of the reaction was optimal using acetyl chloride leading to the substitution product
5a with 96.5% ee (ca. 98% retention of configuration; entry 2 of Table 1).
Table 1
Nucleophilic substitution of the dimethylaminoferrocene derivative 4 with Me2Zn and an acylating
agent
Under these conditions, reactive organozinc halides like 2-picolylzinc bromide 6 prepared by the
lithiation of 2-picoline followed by a transmetallation with zinc bromide6 undergo a smooth substitution
with ca. 98% retention of configuration. However, unreactive organozinc halides like 4-acetoxybutylzinc
iodide7 7 furnish a moderate yield and low enantioselectivity (47% ee; see Scheme 2). This can
be explained by the generation of the configurationally unstable α-ferrocenyl carbocation. Next, we
examined the substitution with the FERRIPHOS precursors of type 3 (R=Ph, Me) and were pleased to
find that the double substitution occurs with complete retention of configuration furnishing the expected
chiral ferrocene derivatives 8 (see Table 2). The ferrocenes 3a–b were converted in a one-pot procedure
to the desired FERRIPHOS ligands 1a–b.
Scheme 2.

M. Lotz et al. / Tetrahedron: Asymmetry 10 (1999) 1839–1842
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Table 2
C2-symmetrical ferrocene derivatives 8a–d obtained by the stereoselective substitution of the amino-
ferrocenes 3a–b with organozinc reagents in the presence of CH3COCl
Thus, the treatment of 3a–b with n-BuLi (3.0 equiv., THF, −70°C, 20 min) furnishes the corresponding
lithiated intermediates which by the reaction with ClPPh2 (3.5 equiv., −70°C to rt, 1 h) provide the
FERRIPHOS 1a (42%) and 1b (50%) in enantiomerically pure form (>99% ee) (Scheme 3).
Scheme 3.
The catalytic activity of the new FERRIPHOS ligands was tested in the rhodium catalyzed asymmetric
reduction of the enol acetate 9.8a,8b A smooth hydrogenation took place [1 bar H2, Rh(COD)2BF4 (1
mol%), acetone, 1a (1 mol%); 25°C, 12 h] providing the 2-acetoxyester 10 in 95% yield and 94.9%
ee (Scheme 4). Interestingly, the ligand of type 1 bearing dimethylamino groups (R=NMe2) was not a
catalyst for this reaction.9
In summary, we have developed a direct substitution10 of aminoferrocene derivatives with organozinc
reagents allowing a more straightforward synthesis of FERRIPHOS ligands. We have also demonstrated
the utility of these new diphosphines for the asymmetric reduction of an enol acetate.

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M. Lotz et al. / Tetrahedron: Asymmetry 10 (1999) 1839–1842
Scheme 4.
Acknowledgements
We thank the DFG (SFB 260, Graduiertenkolleg, Leibniz program), the Fonds der Chemischen
Industrie and Degussa-Hüls AG (Hanau) for generous support. We also thank BASF AG (Ludwigshafen),
Chemetall (Frankfurt) for the generous gift of chemicals. J.J.A. thanks the Alexander von Humboldt
Foundation for a fellowship before moving to Degussa-Hüls AG.
References
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2. Almena Perea, J. J.; Börner, A.; Knochel, P. Tetrahedron Lett. 1998, 39, 8073.
3. Almena Perea, J. J.; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry 1999, 10, 375.
4. Kang, J.; Lee, J. H.; Anh, S. H.; Choi, J. S. Tetrahedron Lett. 1998, 39, 5523.
5. Englert, U.; Salzer, A.; Vasen, D. Tetrahedron: Asymmetry 1998, 9, 1867.
6. Walter, L. A. Org. Synth. 1955, Vol. III, 757.
7. Rozema, M. J.; Eisenberg, C.; Lütjens, H.; Ostwald, R.; Belyk, K.; Knochel, P. Tetrahedron Lett. 1993, 34, 3115.
8. (a) Wolinsky, J.; Novak, R.; Vasileff, R. J. Org. Chem. 1964, 29, 3596. (b) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518.
9. Unpublished results
10. Typical procedure: In a 50 mL flask equipped with an argon-inlet, the ferrocenyl diamine 3a (500 mg, 0.83 mmol) was
dissolved in THF (20 mL) under argon and cooled to −30°C. Via a syringe Zn(i-Pr)2 (1.47 M in THF, 1.67 mL, 2.46
mmol) and acetyl chloride (0.14 mL, 1.97 mmol) was added in this order. The reaction mixture was allowed to warm to
room temperature overnight. After aqueous work-up and extraction with t-butyl methyl ether, the combined organic layers
were dried (MgSO4), filtrated and the solvent was evaporated under reduced pressure. The crude product was purified by
filtration over silica gel (n-pentane) affording compound 8a [379 mg, 0.62 mmol, 76% yield, >99% ee; HPLC: OD, 0.5%
i-PrOH, 0.6 mL/min, 215 nm, tR/min=6.81 (RR), 8.09 (SS)].