Preparation and diastereoselective ortho-metalation of chiral ferrocenyl imidazolines: Remarkable influence of LDA as metalation additive

Article abstract of DOI:10.1021/ol051437k

(Chemical Equation Presented) The preparation of optically pure ferrocenyl imidazolines starting from ferrocenecarboxylic acid and the application to diastereoselective ortho-metalations is described highlighting the remarkable influence of lithium dialky

Full text of DOI:10.1021/ol051437k

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4137-4140
Preparation and Diastereoselective
Ortho-Metalation of Chiral Ferrocenyl
Imidazolines: Remarkable Influence of
LDA as Metalation Additive
Rene´ Peters* and Daniel F. Fischer
Laboratorium fu¨r Organische Chemie, ETH Zu¨rich, Ho¨nggerberg HCI E111,
Wolfgang-Pauli-Str. 10, CH-8093 Zu¨rich, Switzerland
peters@org.chem.ethz.ch
Received June 21, 2005
ABSTRACT
The preparation of optically pure ferrocenyl imidazolines starting from ferrocenecarboxylic acid and the application to diastereoselective
ortho-metalations is described highlighting the remarkable influence of lithium dialkylamides, especially LDA, as metalation additives (in
combination with tert-butyllithium) on the diastereoselectivity.
Chiral oxazolines1 as well as planar chiral ferrocenes2 are
among the most successful ligand motifs in homogeneous
asymmetric catalysis, and the combination of both concepts
within planar chiral ferrocenyl oxazolines3 1 (Figure 1) has
emerged as an excellent ligand system.4
Recently, several groups have disclosed their studies using
chiral bidentate imidazoline ligands 2 in asymmetric cataly-
sis.5 Replacing an oxazoline oxygen atom by a group NR
allows for the accurate adjustment of the electron density
on the imino-type nitrogen atom by selecting either electron-
withdrawing or -donating residues R.6 This additional
(1) (a) Ghosh, A. K.; Mathivanen, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1. (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336.
(2) (a) Ferrocenes; Hayashi, T., Togni, A., Eds.; VCH: Weinheim,
Germany, 1995. (b) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry
1998, 9, 2377.
(3) (a) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995,
60, 10. (b) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B.
Synlett 1995, 74. (c) Nishibayashi, Y.; Uemura, S. Synlett 1995, 79.
(4) Selected examples: (a) Sammakia, T.; Stangeland, E. L. J. Org.
Chem. 1997, 62, 6104. (b) Bolm, C.; Mun˜iz Fernandez, K.; Seger, A.; Raabe,
G.; Gu¨nther, K. J. Org. Chem. 1998, 63, 7860. (c) Arikawa, Y.; Ueoka,
M.; Matoba, K.; Nishibayashi, Y.; Uemura, Y. J. Organomet. Chem. 1999,
572, 163. (d) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M. Organo-
metallics 1999, 18, 2291.
Figure 1. Imidazolines 3 complementing ligands 1 and 2.
10.1021/ol051437k CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/25/2005

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.
4138
Org. Lett., Vol. 7, No. 19, 2005

Scheme 3
(Scheme 3, Table 1, and Supporting Information). In contrast
combined with alkyllithium bases: the configuration of the
major isomer with regard to the planar chirality could thus
be reversed for 11 (Table 1, entries 3, 4, 8, and 9) or at least
significantly increased for 12 (Table 1, entry 11).
to the related oxazolines 1 (E ) H), deprotonations using
simple alkyllithium bases in ethereal solvents at low tem-
perature did not induce high diastereoselectivities (Table 1,
The most selective base/additive combination in our case
consists of 0.95-1.00 equiv of t-BuLi and 1.00-1.50 equiv
of LDA in THF at -78 °C (Table 1, entries 4 and 11) giving
access to planar chiral imidazolines 13 or 14 with diaste-
reoselectivities ranging from 12:1 to 31:1 (Table 2). To the
Table 1. Screening of the Effect of Lithium Amides as
Metalation Additives on the Diastereoselective
Ortho-Metalations of 11 and 12
t-BuLi
(equiv)
amide
(equiv)
conva
(%)
entry
product
dra
Table 2. Diastereoselective Ortho-Metalations of 11 and 12
1
2
3
4
5
6
7
8
9
13aA
1.10
72
0
5:1
n.a.
1:9
1:12
3:1
2:1
1:2
1:4
1:5
1:3
1:31
1:1
t-BuLi LDA
dra yieldb
LDA (1.10)
LDA (1.05)
LDA (1.50)
LDA (1.05)
LDA (2.10)
LTMP (1.10)
LiNCy2 (1.10)
LiNEt2 (1.10)
13bA
13bA
13aA
13aA
13bA
13bA
13bA
14bA
14bA
14A
1.00
0.95
1.50
2.10
1.10
1.10
1.05
1.00
1.00
2.20
76
79
92
93
95
26
55
43
80
80
entry product (equiv) (equiv)
EX
MeI
1.50 MeI
a/b
(%)
drc
1
2
13aA
13bA
13aB
13bB
13bC
13bD
14bA
14bA
14bB
14bB
1.10
0.95
1.10
0.95
0.95
0.95
1.00
1.00
1.00
1.00
5:1
1:12
61
66
34
50
50
53
nd
41
nd
41
20:1d
1:>99d
19:1e
3
4
5
6
Ph2CO 4:1
1.50 Ph2CO 1:12
1.50 Ph2PCl 1:7
1.50 (TolS)2 1:17
1:>99e
1:8d
1:10d
10
11
12
7
8
MeI
1.00 MeI
1:3
1:31
LDA (1.00)
LDA (2.00)
1:150e
9
10
Ph2CO 1:2
1.00 Ph2CO 1:21
1:>99e
a Based on H NMR of the crude reaction mixture.
1
a Based on H NMR of the crude reaction mixture. b Yield of isolated
1
1
product after column chromatography or trituration. c Based on H NMR
of the isolated product purified by column chromatography or trituration.
d Diastereomeric ratio after column chromatography. e Diastereomeric ratio
after trituration.
entries 1 and 10). For that reason, several metalation additives
were screened. Enders, Peters, et al. had previously shown
that LiClO4 in THF has a positive influence on ortho-
lithiations of optically pure ferrocenoyl hydrazones regarding
yield and regioselectivity.19 In the case of 11 and 12,
however, LiClO4 had in most cases a detrimental influence
on diastereoselectivity and conversion. While lithium tet-
ramethylpiperidide (LTMP) effected ortho-deprotonation
with low stereoselectivity, other lithium amides such as
lithium diisopropylamide (LDA, Table 1, entry 2) were not
basic enough. The dialkylamides were, however, found to
have a major influence on the diastereoselectivity when
best of our knowledge, this is the first reported example for
the remarkable influence of lithium dialkylamide additives
on the diastereoselective generation of planar chiral sys-
tems.20 The influence of lithium amides (and also of lithium
alkoxides and other lithium salts) on the reactivity and
selectivity of organolithium species usually results from the
formation of hetero-aggregates [(RLi)x(R′NLi)y], which are
2
more stable than the homo-aggregate species (RLi)n and
(19) (a) Enders, D.; Peters, R.; Lochtman, R.; Raabe, G. Angew Chem.,
Int. Ed. 1999, 38, 2421. (b) Enders, D.; Peters, R.; Lochtman, R.; Raabe,
G.; Runsink, J.; Bats, J. W. Eur. J. Org. Chem. 2000, 3399.
(20) We are currently investigating if this a general effect for the
generation of planar chiral ferrocenes and if it is also valid for ferrocenyl-
oxazolines and Ugi-type amines.
Org. Lett., Vol. 7, No. 19, 2005
4139

(LiX)n.21 We have reason to assume that the mixed aggregate
formation of LDA and t-BuLi is probably not the only
rationalization in the present studies, since, e.g., the selectiv-
ity dropped significantly, when 2 equiv of t-BuLi and the
same amount of LDA were used (Table 1, entries 6 and 12).
Here, the same mixed aggregate should have been formed
as with 1 equiv of each component (Table 1, entries 3 and
11). This could indicate that the generated lithiated ferrocene
derivatives are also primarily involved in the aggregation
process, thus influencing the configurational outcome. It is
important to note the reproducibly high diastereoselectivities
were only obtained, when the freshly prepared LDA solutions
were aged for several hours (2-48 h) at 0 °C prior to use.
Silica gel column chromatography or trituration allowed
in most cases to further improve the dr (Table 2, entries 1-5,
8, and 10). The absolute configuration could be determined
by X-ray analyses for 13bB22 and 14bB (Figure 2).23 Since
In conclusion, we have presented the preparation of the
first optically active ferrocenyl imidazolines starting from
commercially available ferrocenyl carboxylic acid via a high
yielding operationally simple three-step procedure. To realize
this task, we have developed a practical four-step sequence
to optically active 1,2-diamines possessing a primary and a
secondary amino group. Investigation of diastereoselective
ortho-lithiations has revealed that LDA, as a metalation
additive in combination with t-BuLi, has a significant
influence on the configuration of the reaction product with
regard to the planar chirality. This method provides access
to a novel class of chiral ligands, bases, and nucleophiles
for further study.
Acknowledgment. This work was supported by ETH
Research Grant No. TH-30/04-2 and by the member com-
panies of the Kontaktgruppe fu¨r Forschungsfragen (KGF):
Ciba Specialty Chemicals, Novartis, F. Hoffmann-La Roche,
Serono, and Syngenta. Moreover, we are thankful to F.
Hoffmann-La Roche for the donation of laboratory equip-
ment. Prof. Erick M. Carreira (ETHZ) and Dr. Martin Karpf
(F. Hoffmann-La Roche) are acknowledged for critically
reading this manuscript and Dr. B. Schweizer for the
determination of the X-ray structures.
Supporting Information Available: Experimental pro-
cedures, full characterization data for all new products, and
further results of the metalation screening. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051437K
Figure 2. Crystal structures of 13bB (left) and 14bB (right).
(22) X-ray data for 13bB (crystal size: plate 0.16 × 0.14 × 0.04 mm):
C34H32FeN2O; Mr ) 540.490; monoclinic, P21; a ) 7.2470(2) Å, b )
20.1918(7) Å, c ) 9.7910(4) Å; R ) 90.00°, â ) 104.179(2)°, γ ) 90.00°;
V ) 1389.07(8) Å3; Z ) 2; Dx ) 1.292 g cm-3; Mo KR radiation λ )
0.71073; 172 K. Structure refinement with SHELXL-97; H atoms are
calculated; R(all) ) 0.0786; 4442 observed reflections.
the diastereoselective formation of the ortho-lithiated inter-
mediate is responsible for the configuration of the planar
chiral product, the absolute configuration for all compounds
can be assigned.24
(23) X-ray data for 14bB (crystal size: plate 0.40 × 0.40 × 0.38 mm):
C34H32FeN2O; Mr ) 540.490; orthorhombic, P212121; a ) 9.8803(2) Å, b
) 13.2759(2) Å, c ) 20.8422(4) Å; R ) 90.00°, â ) 90.00°, γ ) 90.00°;
V ) 2733.87(9) Å3; Z ) 4; Dx ) 1.313 g cm-3; Mo KR radiation λ )
0.71073; 173.2 K. Structure refinement with SHELXL-97; H atoms are
calculated; R(all) ) 0.0535; 7049 observed reflections.
(21) (a) Gossage, R. A.; Jastrzebski, J. T. B. H.; van Koten, G. Angew.
Chem., Int. Ed. 2005, 44, 1448. (b) Seebach, D. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1624.
(24) However, we have found that the diastereoselectivity also depends
on the electrophile to some degree (see Table 2).
4140
Org. Lett., Vol. 7, No. 19, 2005