A highly diastereomerically enriched, silyl-substituted alkyl lithium, configurationally stable at room temperature

Article abstract of DOI:10.1002/anie.200462141

The opening or blocking of a coordination site at the lithium center (for example by attachment of THF, see picture; left) leads to diastereodivergent courses in the reactions of a highly diastereomerically enriched alkyl lithium with Me₃SnCl. At room temperature in noncoordinating solvents the reagent is configurationally stable and epimerizes in the presence of THF. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200462141

Communications
Organolithium Compounds
(chloromethyl)silane 1. A chlorine–iodine exchange by a
Finkelstein reaction is necessary in the second step for the
introduction of the optically active amine (S)-2-(methoxyme-
thyl)pyrrolidine (SMP; Scheme 1).
A Highly Diastereomerically Enriched, Silyl-
Substituted Alkyl Lithium, Configurationally
Stable at Room Temperature**
Carsten Strohmann,* Bors C. Abele, Klaus Lehmen,
and Daniel Schildbach
Dedicated to Professor Johann Weis
on the occasion of his 60th Birthday
Over the last 20 years, a number of enantiomerically and
diastereomerically enriched[1] alkyl lithium compounds have
been reported.[2,3] For most of the compounds the config-
uration of the metalated stereogenic carbon center is only
stable at low temperatures (À788C). However, more recently,
corresponding compounds have been synthesized which have
proved to be configurationally stable for a few minutes at
higher temperatures, including examples from Hoppe et al.
and from our own group.[2,4,5] In a few cases the absolute
configuration of the alkyl lithium and the reaction products
have been determined unambiguously by single-crystal X-ray
structural analysis,[6] which allows conclusions that are free
from speculation to be drawn on the stereochemical course of
the reaction of the alkyl lithium with electrophilic reaction
partners. We recently described the highly stereoselective
lithiation of an (aminomethyl)benzylsilane, the molecular
structure of the corresponding alkyl lithium compound, and
the stereochemical course of its reactions.[5,6g,7]
We now report the synthesis of the highly diastereomeri-
cally enriched silyl-substituted alkyl lithium compound (R,S)-
6, its different structures in the solid state, determined on
crystals from coordinating and non-coordinating solvent
mixtures, and the diastereodivergent stereochemical course
of the reactions of (R,S)-6 with chlorotrimethylstannane in
relation to the solvent used. Diastereodivergent reactions of
alkyl lithium compounds by variation of the electrophile have
already been described, however a control of the stereo-
chemical course of the reaction by choice of solvent is to our
knowledge unknown.
Scheme 1. Synthesis of the starting compound (S)-5. For full experi-
mental details see the Supporting Information.
The lithiation of (S)-5 occurred in the first case by reaction
with sec-butyllithium in toluene/cyclohexane over 30 days at
À808C (Schema 2, path 1). After warming to room temper-
ature and being left to stand for 60 min the mixture was
cooled to À908C and treated with chlorotrimethylstannane
(Me3SnCl reacts rapidly as a selective trapping reagent even
at low temperatures). The 1H NMR spectra of the crude
product 7 showed a diastereomeric ratio d.r. = 91:9 for the tin
compound (Scheme 2). The absolute configuration of the
main stereoisomer (R,S)-7 was determined by derivatization
to the ammonium stannate [Ph2{(Me3Si)(Me3Sn)CH}-
SiCH2N(H)C6H12O][Me3SnCl2] ((R,S)-8) and subsequent
single-crystal X-ray analysis.[8]
If the described procedure of lithiation and substitution
was carried out in toluene/cyclohexane but after the addition
of sec-butyllithium warming to room temperature was carried
out within only 5 min, the tin compounds were formed with a
diastereomeric ratio of only d.r. = 63:37 (Scheme 2, path 2).
This diastereomeric relationship was not influenced by the
standing time of the lithium compound (R,S)-6 at room
temperature, since the reactions of the lithium compound
with the electrophile both immediately after warming to room
temperature and after 60 min standing time at room temper-
ature gave the same result. It follows from this result that the
diastereomeric ratio of the lithium compound 6 is dependent
almost exclusively upon the conditions of the deprotonation
(kinetically controlled diastereotopos-differentiating depro-
tonation). In addition, it can be deduced that the config-
uration at the stereogenic, metalated carbon center of (R,S)-6
is stable for at least 60 min at room temperature (Scheme 2).
We made a striking observation on the stereochemical
course of the lithiation–substitution sequence when it was
carried out in a toluene/cyclohexane/THF mixture under
otherwise identical conditions (Scheme 2, path 3). The single-
crystal X-ray structural analysis of the two alkyl lithium
compounds (R,S)-6 and (R,S)-6·THF do indeed show in each
case an R configured metalated carbon center (Figures 1 and
2). The 1H NMR spectroscopic investigation of the crude
product of the reaction of (R,S)-6·THF with chlorotrimethyl-
The synthesis of the starting compound, the optically
active (aminomethyl)[(trimethylsilyl)methyl]silane (S)-5,
occurs in good yields in four steps starting from dichloro-
[*] Priv.-Doz. Dr. C. Strohmann, Dr. B. C. Abele, Dr. K. Lehmen,
Dr. D. Schildbach
Institut fꢀr Anorganische Chemie
Universitꢁt Wꢀrzburg
Am Hubland, 97074 Wꢀrzburg (Germany)
Fax: (+49)931-888-4605
E-mail: mail@carsten-strohmann.de
[**] We thank the Deutsche Forschungsgemeinschaft, the Graduierten-
kolleg 690, and the Fonds der Chemischen Industrie for the
financial support of this work and Wacker-Chemie GmbH for
generous gifts of chemicals.
Supporting information for this article (full experimental details) is
available on the WWW under http://www.angewandte.com or from
the author.
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DOI: 10.1002/anie.200462141
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Angewandte
Chemie
tion by the silicon centers (a effect). The
sum of the angles of 348.2 and 345.68 for
the “carbanionic units” of (R,S)-6 and
(R,S)-6·THF show a pyramidalization of
the metalated center, which is illustrated
by the Si1-C1-Si2 bond angles of 127.2(2)
and 125.6(2)8. In (R,S)-6 the shortest
contact involving the lithium center
(1.970(7) ꢀ) is to the oxygen atom of
the SMP handle. In (R,S)-6·THF the
shortest Li–O contact of 1.955(8) ꢀ is to
the coordinated THF molecule, the dis-
tance to the oxygen atom of the SMP
handle is increased to 2.079(8) ꢀ.
Whereas (R,S)-6 is the result of a
kinetically controlled diastereotopos-dif-
ferentiating deprotonation, (R,S)-6·THF
can be formed in a thermodynamically
controlled epimerization at room temper-
ature. Examination of the C1–Li bond
axis shows that in the stereoisomer (R,S)-
6·THF, the trimethylsilyl group and the
THF molecule distance themselves spa-
tially from each other and the crystallized
Scheme 2. Lithiation of (S)-5 and diastereodivergent reaction pathway. For full experimental
details see the Supporting Information.
stannane shows, however, a diastereomeric ratio of d.r. = 92:8
for the tin compound formed in favor of the (S,S)-7
diastereomer. Thus the substitution with (R,S)-6 in the
presence of THF occurs with inversion of the configuration,
whereas in the noncoordinating toluene/cyclohexane mixture
retention of configuration is observed. Moreover, the addi-
tion of a few drops of THF to the only slightly diastereomeri-
cally enriched sample of (R,S)-6 (d.r. = 63:37) at room
temperature in an analogous trapping reaction at À908C
also produces the tin compound (S,S)-7 with d.r. = 92:8
(Scheme 2, path 4). Thus, this fourth form of the reaction is
a thermodynamically controlled epimerization at room tem-
perature. Reactions of isolated (R,S)-6 in toluene and (R,S)-
6·THF in THF gave the same results.
The molecular structures of (R,S)-6 (Figure 1) and (R,S)-
6·THF (Figure 2) were determined by single-crystal X-ray
structural analysis. The stereochemical homogeneity of the
samples was confirmed in that identical lattice constants were
obtained for each of ten randomly chosen crystals.[8] Both
(R,S)-6 and (R,S)-6·THF crystallize as monomers with only
one C–Li contact of 2.176(6) ((R,S)-6) and 2.195(8) ꢀ ((R,S)-
6·THF). Both molecules have an R configuration at the
metalated carbon center C1. The lithium centers show in each
case a contact to the metalated carbon center C1 and are also
coordinated by both a nitrogen and oxygen center of the SMP
ligand. A fourth coordination site on the lithium in (R,S)-
6·THF is occupied by a THF molecule from the solvent,
whereas in the case of (R,S)-6 short contacts to the hydrogen
atoms H3b (2.281 ꢀ) and H3c (2.014 ꢀ) of a methyl group of
the neighboring molecule are observed with formal formation
of a coordination polymer. Common to both structures are
short Si1–C1 and Si2–C1 bonds of between 1.789 and 1.808 ꢀ,
which result from the polarization-induced charge stabiliza-
Figure 1. Molecular structure of compound (R,S)-6 (Schakal represen-
tation).[9a] Selected bond lengths [ꢂ] and angles [8]: Si1-C1 1.800(4),
Si2-C1 1.808(4), Li-C1 2.176(6), N-Li 2.098(7), O-Li 1.970(7); C1-Si1-C5
109.7(2).
Figure 2. Molecular structure of compound (R,S)-6·THF (left), detail
representation (right; Schakal representation).[9a] Selected bond
lengths [ꢂ] and angles [8]: Si1-C1 1.789(4), Si2-C1 1.797(4), Li-C1
2.195(8), N-Li 2.106(7), O1-Li 2.079(8), O2-Li 1.955(8); C1-Si1-C5
109.6(2).
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Communications
diastereomer thus represents the thermodynamically most
sponding HOMO (the orbital coefficients at C1 are almost
equally large; Figure 4). In contrast, with a free coordination
site, substitution with retention of configuration is conceiv-
able after precoordination at the formally triply coordinated
stable isomer (Figure 2 right). A quantum chemical estima-
tion of the relative energies of (R,S)-6·THF and (S,S)-6·THF
at the B3LYP/6-31 + G(d) level shows an energetic prefer-
ence for (R,S)-6·THF over (S,S)-6·THF of 8 kJmolÀ1, which
corresponds to the trend found experimentally.[10]
The 13C NMR spectrum of (R,S)-6·THF in [D6]benzene at
room temperature shows only one set of signals in which a
1
quartet with J13C,7Li = 16.0 Hz is observed for the metalated
carbon center (Figure 3). The line shape of the quartet is
Figure 4. B3LYP/6-31+G(d)-optimized structure of (R,S)-6·THF and
visualization of the highest occupied molecular orbital (Molekel repre-
[9b]
sentation;
the numbering corresponds to that in Figure 1).
Figure 3. Section from the 13C NMR spectrum of (R,S)-6·THF in
[D6]benzene at room temperature.
lithium center in solution (just as high selectivities in
deprotonations can be explained by complex-induced prox-
imity effects (CIPE)).[13] Thus the choice of solvent, and with
it the coordination sphere of the lithium center, decides the
stereochemical course of the reaction of (R,S)-6 with the
electrophile Me3SnCl.
Our studies show that the choice of the solvent can have a
considerable effect on the (stereochemical) reaction behavior
of an alkyl lithium. Therefore only an unambiguous exper-
imental determination of the absolute configuration can form
the basis for an explanation of the stereochemical course of
the reaction of diastereomerically enriched alkyl lithium
compounds. Quantum mechanical methods can be of assis-
tance in comparing the mechanisms involved. The next
question is whether this observation in our system (R,S)-6
can be confirmed by reactions with other electrophiles.
produced by superimposition of the 13C–7Li coupling pattern
with the 13C–6Li coupling pattern. This result suggests the
presence of 6 as a monomer in solution with the lithium center
static on the NMR time scale at room temperature. NMR
spectroscopy studies by Fraenkel and Reich in polar solvents,
usually THF, show that inversion barriers which play a role in
the racemization of chelated alkyl lithium compounds lie in
an energy range of 18–80 kJmolÀ1,[11], however an SMP
handle allows particularly strong chelation. Thus, fixation of
the lithium center in THF and the high stability of the
configuration in nonpolar solvents for (S)-5 are not surprising.
In contrast a 13C–7Li coupling could not be resolved for
(R,S)-6 in [D8]toluene, neither at room temperature nor
between 20 and À508C. Owing to the high quadrupole
7
moment of Li (nuclear spin I = 3= ) corresponding couplings
Received: September 28, 2004
Revised: January 2, 2005
Published online: April 18, 2005
2
are not always observed, even in “frozen” exchange proc-
esses. Through the shortening of the carbon–lithium contact
during a reduction in temperature, the resolution of the C–Li
coupling, which is caused by the increasing quadrupole
interaction, becomes worse and the coupling pattern often
disappears again.[12] The same effect is observed in low-
temperature 13C NMR spectroscopy investigations with (R,S)-
6·THF in [D8]toluene, in which a strong broadening of the
signal for the metalated carbon center is observed with falling
temperature.
How can the experimentally observed stereochemical
course be explained? In the case of a coordinated donor
molecule, as in (R,S)-6·THF, it emerges that a rear attack of
the electrophile with inversion of configuration is possible.
This possibility is also shown by visualization of (R,S)-6·THF
(optimized at the B3LYP/6-31 + G(d) level) with the corre-
Keywords: carbanions · chirality · lithium · silanes
.
[1] In general we refer to the stereogenic metalated carbon center
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A zero correction resulting from these frequency calculations
increased the energy difference between (R,S)-6·THF and (S,S)-
6·THF by 0.9 kJmolÀ1. Absolute electronic energies without
zero correction (B3LYP/6-31 + G(d)) from the quantum chem-
ical calculations in atomic units: (R,S)-6·THF: À1846.00502703,
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[8] Diffractometer: StoeIPDS; MoKa radiation, l = 0.71073 ꢀ, T=
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Gꢂttingen, 1990 and 1997); the refinement of the absolute
structure was additionally ensured by refinement of the Flack
parameter for the determination of the relative configuration.
a) (R,S)-6·THF (colorless plates from n-pentane/THF, 0.3 ꢄ 0.3 ꢄ
0.2 mm3): C27H42LiNO2Si2, Mr = 475.74, orthorhombic, space
group P212121, a = 10.7958(16), b = 14.037(3), c = 18.920(3) ꢀ,
V= 2867.2(8) ꢀ3, Z = 4, 1 = 1.102 MgmÀ3, 2q range: 4.3–48.08.
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24064 reflections, of which 4501 were independent (Rint
=
0.2199). R1 = 0.0661, wR2 = 0.1188 (all data). Flack parameter:
À0.01(18); b) (R,S)-6 (orange-yellow needles from n-pentane,
0.4 ꢄ 0.4 ꢄ 0.3 mm3): C23H34LiNOSi2, Mr = 403.63, monoclinic,
space group P21, a = 10.971(7), b = 10.677(6), c = 11.162(8) ꢀ,
b = 112.07(7), V= 1211.7(13) ꢀ3, Z = 2, 1 = 1.106 MgmÀ3, 2q
range: 4.4–54.08. 8374 reflections, of which 4441 were independ-
ent (Rint = 0.0544). R1 = 0.0458, wR2 = 0.0899 (all data). Flack
parameter: 0.02(14); c) (R,S)-8 (colorless needles, 0.4 ꢄ 0.3 ꢄ
0.2 mm3): C29H53Cl2NOSi2Sn2, Mr = 796.18, triclinic, space
group P1, a = 9.504(2), b = 10.292(3), c = 10.865(4) ꢀ, a =
68.70(4), b = 70.81(4), g = 81.71(3)8, V= 934.7(5) ꢀ3, Z = 1, 1 =
1.414 MgmÀ3, 2q range: 4.2–52.08. 13687 reflections, of which
6918 independent (Rint = 0.0507). R1 = 0.0434, wR2 = 0.1169 (all
data). Flack parameter: À0.02(3). CCDC-250458 ((R,S)-6),
CCDC-250459 ((R,S)-6·THF), and CCDC-250460 ((R,S)-8)
contain the detailed crystallographic data for this publication.
The data can be obtained free of charge from the Cambridge
Crystallographic Data Centre under www.ccdc.cam.ac.uk/data_
request/cif.
[9] a) E. Keller, Schakal99, Universitꢃt Freiburg, 1999; b) S. Port-
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