Catalytic and stereoselective ortho-lithiation of a ferrocene derivative

Article abstract of DOI:10.1002/anie.201303650

N,N-Dimethylferrocenylmethylamine can be lithiated stereoselectively by iPrLi in pentane/Et₂O using catalytic amounts of the chiral auxiliary (R,R)-TMCDA. In homogenous reactions, high e.r. values were obtained upon crystallization of the lithiated species. The catalytic activity of TMCDA is made possible by its release from the stereomerically pure lithioferrocene as it dimerizes to a homochiral dimeric etherate. Copyright

Full text of DOI:10.1002/anie.201303650

Angewandte
Chemie
Communications
Chiral Metallocenes
P. Steffen, C. Unkelbach, M. Christmann,
W. Hiller, C. Strohmann*
&&&& — &&&&
Catalytic and Stereoselective ortho-
Lithiation of a Ferrocene Derivative
N,N-Dimethylferrocenylmethylamine can
be lithiated stereoselectively by iPrLi in
pentane/Et2O using catalytic amounts of
the chiral auxiliary (R,R)-TMCDA. In
homogenous reactions, high e.r. values
were obtained upon crystallization of the
lithiated species. The catalytic activity of
TMCDA is made possible by its release
from the stereomerically pure lithioferro-
cene as it dimerizes to a homochiral
dimeric etherate.
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DOI: 10.1002/anie.201303650
Chiral Metallocenes
Catalytic and Stereoselective ortho-Lithiation of a Ferrocene
Derivative**
Patricia Steffen, Christian Unkelbach, Mathias Christmann, Wolf Hiller, and
Carsten Strohmann*
Dedicated to Professor Werner Uhl on the occasion of his 60th birthday
Planar chiral ferrocene derivatives are important ligands for
a variety of catalysts in asymmetric synthesis.[1] Commonly,
the stereoinformation is introduced into the ferrocene by
a diastereo-differentiating lithiation in the ortho-position to
a chiral directing group.[2] A large variety of heteroatom-
based chiral directing groups have been evaluated in the
past.[3] In contrast, achiral substituted ferrocenes that do not
bear defined chiral information require the presence of an
external chiral auxiliary in the lithiation step to achieve their
stereoselective desymmetrization.[4]
auxiliaries. Herein lies a principal problem that has limited its
use as a prochiral building block to date: procedures for the
asymmetric lithiation of 2 suffer from low conversion and/or
stereoselectivities,[7] and even the racemic ortho-metalation of
2 has to rely on a bimetallic superbasic mix to achieve high
yields.[8]
However, past investigations by Uemura and co-workers
revealed that the diamine ligand (R,R)-tetramethyl-1,2-cyclo-
hexanediamine (TMCDA, 4)[9] shows some potential as
a
chiral additive in the desymmetrization of 2.[7] As
(R)-N,N-Dimethyl-1-ferrocenylethylamine (1), or Ugiꢀs
amine, is certainly the best-known example of a ferrocene
derivative with a chiral directing group, as its ortho-lithiation
proceeds with high stereoselectivity.[5] Consequently, since the
inception of its lithiation it has evolved into a crucial entry
point for routes to important and efficient ferrocene-based
chiral ligands (see Scheme 1).[6]
N,N-Dimethylferrocenylmethylamine (2) is an inexpen-
sive, achiral analogue of Ugiꢀs amine. Therefore, its desym-
metrization by ortho-lithiation has to be mediated by chiral
TMCDA is a readily available chiral auxiliary, this prompted
us to reinvestigate its application in the asymmetric lithiation
of the achiral aminomethylferrocene derivative 2. Herein, our
primary objective was to devise an efficient, one-pot desym-
metrization route of 2 that combines high stereoselectivity
and high yields.
Initially, we investigated the combination of TMCDAwith
different commercially available alkyl lithium reagents for the
stereoselective ortho-lithiation of 2. Benzophenone was
selected as a suitable electrophile, as the racemic quenching
product, carbinol 5, is known.[10] Additional experiments were
performed with dimethoxy(diphenyl)silane as an alternative
electrophile (Scheme 2).
Scheme 1. Above: Ortho-lithiation of chiral Ugi’s amine (R)-1 as an
important route to chiral 1,2-functionalized ferrocenylphoshine cata-
lysts.[5,6] Below: Alternative route starting from achiral analogue 2 in
the presence of a chiral additive, such as (R,R)-TMCDA (4).[7]
Scheme 2. TMCDA-mediated ortho-lithiation/quenching sequence of 2
with different metalation conditions and electrophiles (see Table 1).
During the initial screening of commercially available
alkyl lithium using a two-fold excess of TMCDA in hydro-
carbon/Et2O mixtures (Table 1, entries 1–4), we quickly found
that nBuLi/4 afforded some stereoselectivity (e.r. 84:16) but
suffered from low conversion. In comparison, tBuLi/4 proved
the most reactive mixture but the ortho-lithiation proceeded
with nearly no stereoselectivity (e.r. 53:47). sBuLi/4 afforded
a slightly improved stereoselectivity and a higher conversion
at lower temperatures compared to nBuLi.[4b]
[*] M. Sc. P. Steffen, Dr. C. Unkelbach, Prof. Dr. M. Christmann,
Dr. W. Hiller, Prof. Dr. C. Strohmann
Fakultꢀt fꢁr Chemie und Chemische Biologie
Technische Universitꢀt Dortmund
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
E-mail: mail@carsten-strohmann.de
[**] We are grateful to the Deutsche Forschungsgemeinschaft and the
European Research Area for financial support.
To our delight, switching from butyllithium reagents to
iPrLi improved both the conversion and stereoselectivity
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303650.
2
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Table 1: Representative reaction conditions for the asymmetric, TMCDA-
mediated lithiation of 2 and consecutive quenching with benzophenone
to yield carbinol (Rp)-5.
contains one complete molecule of the aggregate. [(Sp)-
3]2·Et2O exhibits a slightly skewed cisoid arrangement (angle
between the two planes of the two substituted Cp rings 22.48)
of the two homochiral lithioferrocene units. Both amino-
methyl side-arms display lithium coordination as can be
expected for an ortho-directing, coordinating group.[13] Only
one lithium center is four-coordinate owing to the contact to
the oxygen of a Et2O donor. The other lithium center only has
a coordination number of three as the two neighboring
ferrocene ligands shield the fourth possible coordination site
(Figure 1).[14]
Entry RLi
Equiv Solvent
4
t [h]
T
%
e.r.[b]
[8C] Yield[a]
1
2
3
nBuLi
tBuLi
sBuLi
2
2
2
hexane/Et2O
6
3
6
À30 28
À30 77
À60 56
84:16
53:47
87:13
pentane/Et2O
cyclohexane/
Et2O
pentane/Et2O
pentane/THF
pentane/toluene
4
5
6
iPrLi
iPrLi
iPrLi
2
2
2
6
6
6
À60 90[c]
95:5
50:50
–
À60 90[c]
[d]
À30
–
[a] Isolated product. [b] Determined by chiral-phase HPLC. [c] Yield of
crude product was more than 95% (determined by NMR spectroscopy).
[d] Starting material recovered.
considerably. Using iPrLi/4, carbinol 5 was obtained in
a stereomeric ratio of 95:5 and 90% yield after a lithiation
time of 6 h at À608C.
If THF was used instead of Et2O, ortho-lithiation occurred
as well, albeit without any degree of stereodifferentiation.
This can be attributed to the strongly coordinating properties
of THF which suppress coordination of the chiral auxiliary.[11]
Toluene did not promote ortho-lithiation of 2, as it underwent
benzylic lithiation in the presence of TMCDA (Table 1,
entries 5 and 6).
The Rp configuration of the 1,2-substituted quenching
products was ascertained by reaction of aminocarbinol (Rp)-5
with BH3 and subsequent X-ray structural analysis of the
resulting aminoborane derivative (Scheme 3). Switching from
Figure 1. Left: Monoetherate of the homochiral dimer [(Sp)-3]2·Et2O.
Right: Dietherate of the racemic analogue (rac-3·Et2O)2 (Heteroatoms
and lithiated carbon centers are labeled, hydrogen atoms omitted for
clarity). Selected bond lengths [ꢂ] and angles [8]: [(Sp)-3]2·Et2O C6–Li2
2.089(3), C6–Li1 2.289(3), C19–Li2 2.174(3), C19–Li1 2.225(3), Li1–N1
2.132(4), Li2–N2 2.0373; Li2-C6-Li1 66.4(1), C19-Li1-C2 108.5(1), C6-
Li2-C19 118.4(2). rac-(5·Et2O)2 C6–Li2 2.130(5), C6–Li1 2.272(5), C19–
Li1 2.145(5), C19–Li2 2.366(5), Li1–N1 2.302(5), Li2–N2 2.236(5); Li2-
C6-Li1 70.17(17), C15-Li1-C6 112.1(2).
For the purpose of comparison, the racemic lithiated
intermediate was crystallized as well. Compound 2 was
treated with tBuLi in Et2O at À308C. Storage of the reaction
mixture at À788C for 3 d afforded lithiated species 5 as red
crystalline blocks, which were identified as (rac-3·Et2O)2, the
dietherate of dimeric 3.
The racemic dimer (rac-3·Et2O)2 crystallizes from pen-
tane/Et2O in the monoclinic crystal system, space group C2/c.
The asymmetric unit contains one complete molecule of the
dimeric species and one half of a co-crystallized Et2O solvent
molecule. The central structural motif of the pseudo-C2-
Scheme 3. Derivatization of the 1,2-disubstituted ferrocenes (Rp)-5 and
(Rp)-6 and consecutive determination of the absolute configuration by
X-ray structural analysis.
benzophenone to dimethoxydiphenylsilane as the electro-
phile afforded the corresponding silylated ferrocene (Rp)-6 in
excellent yields (92%) and identical stereoselectivities. The
absolute configuration of (Rp)-6 was confirmed by hydrolysis
to and complete characterization of the resulting novel silanol
(Rp)-7.[12]
The lithiated intermediate of the stereoselective ortho-
metalation could be successfully crystallized. Storage of the
reaction mixture at À788C for 3 d afforded a crop of bright
red plates of the lithiated compound. To our surprise, the
obtained aggregate was not the lithioferrocene (Sp)-3 coordi-
nated by TMCDA, but rather an ether-coordinated dimeric
aggregate.
À
symmetric dimer is a four-membered C Li ring comprised of
the two lithium centers and the two carbanionic centers of the
substituted cyclopentadienyl moiety. With an angle of 123.88
between the planes of the two substituent-bearing Cp rings of
the ferrocenyl moieties, the two halves of the dimer adopt
a substantially more tilted, trans-like arrangement in relation
À
to the central C Li ring as compared to [(Sp)-3]2·Et2O. Thus,
the two ferrocenyl moieties are able to evade the spatial
demand of their respective counterpart to accommodate for
a second coordinating Et2O molecule, resulting in a coordi-
nation number of four for both lithium centers.[15]
As the presence of a ligand-centered or intramolecular
center of defined chirality is an important feature to induce
one preferred configuration in stereomerically enriched
organolithium species,[11] we were surprised to note that the
The homochiral lithioferrocene crystallizes as the dimeric
etherate [(Sp)-3]2·Et2O from pentane/Et2O in the monoclinic
crystal system, space group P21.[22] The asymmetric unit
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lithiated intermediate [(Sp)-3]2·Et2O does not feature coordi-
nation of the lithium centers by the chiral additive that had
been used in its synthesis. Thus, despite its role in the
asymmetric ortho-lithiation step, TMCDA apparently does
not play a role for the aggregation of the resulting lithiated
species.
TMCDA afforded an e.r. of 85:15 coupled with nearly
quantitative conversion and a short reaction time (entry 6).
Interestingly, the substitution of Et2O for MTBE under
identical conditions resulted in a decrease of stereoselectivity
(e.r. = 67:33; Table 2, entry 8).
If the reaction mixture was stored for longer periods at
À788C, crystallization of the stereomerically enriched aggre-
gate occurred. This could be proven by separation of the
crystals from the mother liquor. Quenching them afforded the
highly stereomerically enriched product (Rp)-6 (e.r. > 99:1) in
an yield of 68% (entry 7).[19] The combination of sBuLi and
catalytic amounts of TMCDA resulted in a decrease of
conversion and a slightly lower stereoselectivity comparable
to the respective stoichiometric runs described above
(entries 9, 10).
Quantum-chemical calculations were performed to eluci-
date the proposed selectivity and catalytic activity of TMCDA
during the ortho-lithiation cycle. For the abstraction of the
two prochiral ortho-hydrogen atoms, the respective stereo-
differentiating transition states were computed in the pre-
lithiation complex [2·TMCDA·iPrLi].[20] In fact, the deproto-
nation leading to (Sp)-configuration in the lithiated inter-
mediate is favored by 7 kJmolÀ1 in comparison to the other
transition state. This difference in energies corresponds
satisfactorily to the enantiomeric ratios observed in the
products after quenching of metalation runs with stoichio-
metric amounts of TMCDA (e.r. = 86:14).
In the possible prelithiation complex [2·TMCDA·RLi],
iPrLi seems to provide the ideal combination of sterical
demand and reactivity to necessitate a highly stereoselective
ortho-lithiation. In comparison, primary alkyl lithium nBuLi
seems to be too small and tBuLi too bulky to induce the high
selectivities that are observed when using iPrLi.[20]
This prompted us to investigate the stereoselectivity of the
ortho-metalation of 2 using sub-stoichiometric amounts of
TMCDA. While the use of catalytic amounts of chiral lithium
amides in stereoselective deprotonation reactions has
attracted considerable attention,[16] similar examples for
workable deprotonation reactions involving organolithium
reagents with substoichiometric amounts of chiral ligands are
still comparatively scarce:[17] To the best of our knowledge,
only one example of a stereoselective catalytic deprotonation
reaction utilizing alkyl lithium bases has been previously
reported. OꢀBrien and co-workers developed a (À)-sparteine/
bispidine-based asymmetric catalytic lithiation of N-Boc
pyrrolidine or phosphinoboranes, albeit in the presence of
stoichiometric amounts of an achiral auxiliary bispidine,
which supplants sparteine from the lithiated substrate.[18]
Thus, we investigated the catalytic stereoselective ortho-
lithiation of 2 (Table 2). We found that 0.2 equiv TMCDA and
1.3 equiv iPrLi at À788C in a mixture of pentane/Et2O
resulted in a near-quantitative conversion of 2 after 96 h, and
upon quenching with benzophenone, in an e.r. of 81:19. If only
0.05 equiv TMCDAwas used, the e.r. decreased to 71:29 while
the conversion remained nearly quantitative (Table 2,
entries 1 and 3). This indicates that at low temperatures in
Et2O, iPrLi is capable of slowly metalating 2 even in the
absence of the coordinating diamine.
This non-stereoselective background reaction obviously
competes with the stereoselective metalation mediated by
sub-stoichiometric amounts of the chiral auxiliary. Interest-
ingly, the reaction did not proceed quantitatively with
catalytic amounts of TMCDA if no Et2O was added to the
reaction mixture, but only to the mole fraction of the additive
(Table 2, entry 4). Et2O is obviously essential for the promo-
tion of the catalytic activity of TMCDA. Consequently, the
stereoselectivity of the reaction could be improved by low-
ering the amount of Et2O in the reaction solvent: Performing
the lithiation in a 12:1 pentane/Et2O mixture with 0.2 equiv
For TMCDA to be catalytically active, it has to be
released from the enantiomerically enriched ortho-lithiated
species (Sp)-3·TMCDA to be available for the formation of
further pre-lithiation complexes with unreacted starting
material and iPrLi. From complex [2·TMCDA·iPrLi], another
stereo-differentiating lithiation step can occur. The molecular
structure of the lithiated intermediate suggests a possible
mechanism for the release of TMCDA: Obviously, upon
aggregation of the lithioferrocene 3 to a more stable dimer,
a bidentate amine such as TMCDA
is unsuitable to coordinate the
Table 2: Catalytic asymmetric, TMCDA-mediated lithiation of 2 and consecutive quenching with
benzophenone to yield carbinol (Rp)-5.
lithium centers in the dimer owing
to its increased steric demand in
comparison to monodentate ether
donors. In contrast, as soon as the
formation of an etherate or dieth-
erate is considered, the dimeriza-
tion becomes highly favorable.
This releases the chiral catalyst
TMCDA from the lithiated inter-
mediate and its further activity in
the catalytic cycle (Scheme 4).
Entry
RLi
Equiv 4
Solvent
t [h]
T [8C]
% yield[a]
e.r.[b]
1
2
3
4
5
6
7
8
9
10
iPrLi
iPrLi
iPrLi
iPrLi
iPrLi
iPrLi
iPrLi
iPrLi
sBuLi
sBuLi
0.2
0.1
0.05
0.2
0.2
0.2
0.2
0.2
0.2
0.2
pentane/Et2O (1:1)
pentane/Et2O (1:1)
pentane/Et2O (1:1)
pentane
pentane/Et2O (12:1)
pentane/Et2O (12:1)
pentane/Et2O (1:1)
pentane/MTBE (1:1)
cyclohexane/Et2O (1:1)
cyclohexane/Et2O (1:1)
96
96
96
96
96
2
192
2
96
2
À78
À78
À78
À78
À78
À78[e]
À78
À78[e]
À78
À78[e]
86[c]
82[c]
83[c]
17[d]
93[c]
94[c]
68[f]
87[c]
41
81:19
78:22
71:29
82:18
86:14
85:15
>99:1
67:33
80:20
67:33
87
The solvent-mediated propen-
sity of the lithiated substrate for
dimerization constitutes the driv-
ing force behind the release of the
[a] Isolated product. [b] Determined by chiral-phase HPLC. [c] Yield in crude product was more than
95% (determined by NMR spectroscopy). [d] Yield of crude product was about 20%. [e] Intermediary
warming to RT. [f] Obtained upon separation of crystals from mother liquor.
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to the etherate [(Sp)-3]2·Et2O under release of the chiral auxiliary
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chiral catalyst and as such constitutes another example for the
importance of the structure–reactivity relationship in organo-
lithium chemistry.
Herein, we presented an approach for the efficient and
highly stereoselective desymmetrization of N,N-dimethylfer-
rocenylmethylamine (2) by ortho-lithiation as a feasible
alternative to the established lithiation of its chiral derivative,
namely Ugiꢀs amine. Furthermore, we could demonstrate that
this reaction is possible in the presence of substoichiometric
amounts of chiral auxiliary, marking this reaction as a new and
promising example for a catalytic and stereoselective depro-
tonation reaction in organolithium chemistry. Ferrocene 2 can
be efficiently lithiated by secondary alkyl lithium species in
the presence of substoichiometric amounts of the chiral
auxiliary (R,R)-TMCDA. The reaction proceeds with stereo-
selectivities between 85:15 (0.2 equiv TMCDA) and 71:29
(0.05 equiv TMCDA) in homogenous runs but can be boosted
to more than 99:1 by separation of the enantiomerically
enriched lithiated species by crystallization. The catalytic
cycle is made possible by the release of the chiral promoter
from the lithiated species upon its dimerization.
[14] Similar structural motifs are found for substituted aryllithums
and lithioferrocenophanes: a) J. Belzner, D. Schꢂr, U. Dehnert,
D. Noltemeyer, Organometallics 1997, 16, 285 – 288; b) C. Chen,
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3253.
[15] The Supporting Information contains information on an iso-
structural dimeric structure of the racemic lithioferrocene,
featuring THF coordination of each lithium center obtained
from a pentane/THF reaction mixture.
[16] a) P. Dinꢃr, Tetrahedron: Asymmetry 2010, 21, 2733 – 2739;
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Hoboken, NJ, United States, 2013, pp. 317 – 635.
Received: April 29, 2013
Published online: && &&, &&&&
Keywords: carbanions · lithiation · metallocenes ·
.
stereoselective catalysis · structure elucidation
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