electronic tuning option thus leads to even more adaptable
ligand systems as compared to oxazolines,7 and the imida-
zoline derived catalyst systems were often superior to the
corresponding oxazolines in terms of the enantioselectivity
of the catalysis product.5
Our main interest in the preparation of ferrocenyl-
substituted imidazolines 3 results from the anticipated
enrichment of electron density at the imino nitrogen atom
due to the strongly electron-donating properties of the
ferrocenyl moiety in the 2-position of the heterocyclic
system. The electron-rich amidine group8 should thus be an
even stronger σ-donor ligand, base, and nucleophile9 than
in conventional imidazolines. Herein, we present the first
synthesis of optically active, chiral ferrocenylimidazolines10
and their diastereoselective ortho-metalation giving rise to
novel planar chiral systems.
corresponding sulfamidates 5 in high yield utilizing a
modified literature procedure13 using just 0.1 mol % of
RuCl3.14 Sulfamidates 5 were then regio- and diastereo-
selectively ring opened by nucleophilic attack of potassium
phthalimide using SN2 type conditions. Deprotection of
phthalimides 6 by hydrazinolysis revealed the free primary
amino group. This synthetic sequence is amenable to
multigram preparations.15
The synthesis of chiral ferrocenylimidazolines started from
commercially available ferrocenyl carboxylic acid 8, which
was converted to primary amide 9 via a modified literature
procedure (Scheme 2).16 Compound 9 was then activated by
Scheme 2
To realize the preparation of imidazolines 3, synthetic
access to optically active 1,2-diamines 7 possessing a primary
and a secondary amino group was a prerequisite.11 We have
thus developed a practical four-step sequence starting from
(-)-ephedrine 4a and (+)-pseudoephedrine 4b (Scheme 1)
Scheme 1
O-alkylation with 1 equiv of Et3O+BF4- generating iminium
ether tetrafluoroborate salt 10. The formation of the hetero-
cyclic system by condensation of 10 with 7 was ac-
complished at room temperature without the need for
isolating 10. The resulting amidinium salt was converted to
the free base with 1.0 N NaOH. When 0.1 N NaOH was
employed, the heterocyclic moiety was still partly protonated
indicating its highly basic character.17
The optically pure heterocyclic systems, which were
prepared without the need for chromatographic purifications,
were then investigated in diastereoselective ortho-lithiations18
avoiding any chromatographic purification.12 The enantio-
merically pure amino alcohols were converted into the
(11) Our attempts to prepare 3 directly from amino alcohols failed.
(12) For previous syntheses, see: (a) Gust, R.; Gelbcke, M.; Angermeier,
B.; Bachmann, H.; Krauser, R.; Scho¨nenberger, H. Inorg. Chim. Acta 1997,
264, 145. (b) Tytgat, D.; Gelbcke, M.; Smith, D. F. Pharmazie 1990, 45,
835.
(13) Williams, A. J.; Chakthong, S.; Gray, D.; Lawrence, R. M.;
Gallagher, T. Org. Lett. 2003, 5, 811.
(5) (a) Botteghi, C.; Schionato, A.; Chelucci, G.; Brunner, H.; Ku¨rzinger,
A.; Obermann, U. J. Organomet. Chem. 1989, 370, 17. (b) Morimoto, T.;
Tachibana, K.; Achiwa, K. Synlett 1997, 783. (c) Davenport, A. J.; Davies,
D. L.; Fawcett, J.; Russell, D. R. J. Chem. Soc., Perkin Trans. 1 2001,
1500. (d) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713.
(e) Busacca, C. A. U.S. Patent 6,316,620, 2001. (f) Busacca, C. A.;
Grossbach, D.; So, R. C.; O’Brien, E. M.; Spinelli, E. M. Org. Lett. 2003,
5, 595. (g) Casey, M.; Smyth, M. P. Synlett 2003, 102.
(14) Review about the synthesis and reactivity of sulfamidates: Mele´n-
dez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581.
(6) Further selected examples: (a) Bastero, A.; Ruiz, A.; Claver, C.;
Castillo´n, S. Eur. J. Inorg. Chem. 2001, 3009. (b) Bastero, A.; Ruiz, A.;
Claver, C.; Milani, B.; Zangrando, E. Organometallics 2002, 21, 5820. (c)
Bastero, A.; Claver, C.; Ruiz, A.; Castillo´n, S.; Daura, E.; Bo, C.; Zangrando,
E. Chem. Eur. J. 2004, 10, 3747.
(7) The N substituent also influences the ligand geometry due to steric
interaction with the ligand backbone.
(15) This new route for the preparation of optically active diamines is
not restricted to ephedrines. The full scope will be presented separately.
(16) Arimoto, F. S.; Haven, A. C., Jr. J. Am. Chem. Soc. 1955, 77, 6295.
(17) The basicity is thus markedly increased by the ferrocenyl moiety
in comparison to conventional imidazolines (typical pKHA values are 6-10,
see ref 8).
(18) For previous stereoselective ortho metalations of ferrocene deriva-
tives, see ref 3 and: (a) Marquarding, D.; Klusacek, H.; Gokel, G.;
Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389. (b) Riant, O.;
Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B. J. Org. Chem. 1997,
62, 6733. (c) Ganter, C.; Wagner, T. Chem. Ber. 1995, 128, 1157. (d) Riant,
O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H. B. J. Org. Chem.
1998, 63, 3511. (e) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Taylor, N. J.;
Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685. (f) Enders, D.; Peters, R.;
Lochtman, R.; Runsink, J. Eur. J. Org. Chem. 2000, 2839.
(8) Ferna`ndez, B.; Perillo, I.; Lamdan, S. J. Chem. Soc., Perkin Trans.
2 1973, 1371.
(9) Basic/nucleophilic planar chiral ferrocenes: Mermerian, A. H.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 5604 and references therein.
(10) Only one achiral ferrocenyl imidazoline (3 with R, R1-4, E ) H)
has been described so far: Nametkin, N. S.; Shvekhgeimer, G. A.; Tyurin,
V. D.; Tutubalina, A. I.; Kosheleva, T. N. IzV. Akad. Nauk SSSR, Ser. Khim.
1971, 1567.
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