Table 1 Conditions applied for lithiation of 1-ferrocenyl-ethanol
Base
Solvent
Temp./1C
Time/h
Main product
d.r.a
Yield [%] (S,pR)-3a
t-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
Et2O
THF
C6H12
Et2O
Et2O
Et2O
ꢀ60
ꢀ60
5
ꢀ50
ꢀ20
0
2
2
2
10
10
10
Several
Several
(S,pR)-3a
(S,pR)-3a
(S,pR)-3a
(S,pR)-3a
n.d.
n.d.
60 : 40
99 : 1
95 : 5
95 : 5
Inseparable
Inseparable
Inseparable
25
79
60
a
1
Determined by HPLC and H-NMR analysis.
Scheme 3 Lithiation of phenyl- and cyclohexyl-ferrocenyl alcohols.
Scheme 2 Synthesis of ortho-substituted ferrocenyl alcohols.
Encouraged by these results and with optimised conditions
in hand, we tested the scope of our method by reacting the
dilithiated ferrocenyl alcohol (S,pR)-2 with different electro-
philes (Scheme 2, Table 2).
Table 3 Diastereoselective lithiation of phenyl- and cyclohexyl-
ferrocenyl alcohols
6
R
Yield [%]
d.r.a
Yields were generally good, and the diastereomeric ratio
was again in the range of 95 : 5. In the case of t-butyl sulfide 3c
only, low yield and massive formation of 10-substituted by-
product were observed, probably due to steric hindrance
caused by the bulky t-butyl group. Comparison of the NMR
spectra of 3b and 3e with literature values18 proved their
configuration to be (S,pR), which is in accordance with the
established stereochemical model for ferrocene lithiation.19
In this manner, a variety of interesting new planar chiral
ferrocene derivatives were prepared, which could find use in
asymmetric catalysis. Compounds 3a–e feature a Lewis basic
heteroatom in the 2-position as well as a free hydroxy group,
which makes them promising candidates for the emerging field
of hydrogen-bond assisted nucleophilic catalysis.20 Chiral
ferrocene diol 3f could find application in reactions usually
catalysed by Binol or Taddol derivatives.
a
b
Phenyl
Cyclohexyl
66
81
495 : 5
495 : 5
a
1
Determined by H-NMR spectroscopy.
In summary, we have established the free hydroxy-function
as a new ortho-directing group for diastereoselective ortho-
metalation of ferrocene. This method opens up an efficient and
flexible approach to novel planar chiral ferrocene derivatives.
The easy preparation of enantiopure ferrocenyl-ethanol makes
it an interesting alternative to the popular Ugi amine. The
obtained planar chiral ferrocenyl alcohols can easily be ela-
borated further to known and new ligands, and are promising
new lead structures for hydrogen bond assisted nucleophilic
catalysis. Research along these lines is underway and will be
reported in due course.
Next, we turned our attention to other ferrocenyl alcohols,
to explore the generality of the lithiation method. Satisfyingly,
phenyl- and cyclohexyl-ferrocenyl alcohols 4a and 4b gave
single diastereomers in good yields after lithiation and quench-
ing with benzophenone (Scheme 3, Table 3).
Notes and references
1. (a) Three issues dedicated to ferrocene chemistry in J. Organomet.
Chem., 2001, 637–639, 1–875; (b) C. J. Richards and A. J. Locke,
Tetrahedron: Asymmetry, 1998, 9, 2377; (c) A. Togni and
T. Hayashi, Ferrocenes – Homogeneous Catalysis, Organic Synth-
esis, Material Science, VCH, Weinheim, 1995; (d) A. Togni and
R. L. Halterman, Metallocenes, Wiley-VCH, Weinheim, 1998,
vol. 2.
2. (a) O. B. Sutcliffe and M. R. Bryce, Tetrahedron: Asymmetry,
2003, 14, 2297; (b) T. J. Colacot, Chem. Rev., 2003, 103, 3101;
(c) R. C. J. Atkinson, V. C. Gibson and N. J. Long, Chem. Soc.
Rev., 2004, 33, 313; (d) R. G. Arrayas, J. Adrio and
J. C. Carretero, Angew. Chem., 2006, 118, 7836.
3. (a) D. Markarding, H. Klusacek, G. Gokel, P. Hoffmann and
I. Ugi, J. Am. Chem. Soc., 1970, 92, 5389; (b) T. Hayashi,
K. Yamamoto and M. Kumada, Tetrahedron Lett., 1974, 4405.
4. (a) F. RebiZre, O. Riant, L. Ricard and H. B. Kagan, Angew.
Chem., Int. Ed. Engl., 1993, 105, 644; F. RebiZre, O. Riant,
L. Ricard and H. B. Kagan, Angew. Chem., Int. Ed. Engl., 1993,
32, 568; (b) N. M. Lagneau, Y. Chen, P. M. Robben, H.-S. Sin,
K. Tasaku, J.-S. Chen, P. D. Robinson and D. H. Hua, Tetra-
hedron, 1998, 54, 7301.
These compounds were prepared only in racemic form, and
their configuration cannot yet be assigned. However, in ana-
logy to compounds 3a–f we assume their relative configuration
to be also (S,pR)/(R,pS), respectively.
Table
ferrocenyl alcohols
2
Diastereoselective
synthesis
of
ortho-substituted
3
Electrophile
R
Yield [%]
d.r.
a
b
c
d
e
f
(Ph-S)2
–S-Ph
–S-Me
–S-t-butyl
–Se-Ph
–P(Ph)2
79
64
21
77
63
75
95 : 5ab
94 : 6a
n.d.
(Me-S)2
(t-Butyl-S)2
(Ph-Se)2
Ph2PCl
95 : 5a
493 : 7a
95 : 5a
Ph2CQO
–C(Ph)2OH
5. (a) O. Riant, O. Samuel and H. B. Kagan, J. Am. Chem. Soc.,
1993, 115, 5835; (b) O. Riant, O. Samuel, T. Flessner, S. Taudien
a
b
Determined by NMR spectroscopy. Determined by HPLC analysis.
and H. B. Kagan, J. Org. Chem., 1997, 62, 6733; (c) H. Wolfle,
¨
ꢁc
This journal is The Royal Society of Chemistry 2008
3288 | Chem. Commun., 2008, 3287–3289