Kinetic and NMR spectroscopic studies of chiral mixed sodium/lithium amides used for the deprotonation of cyclohexene oxide

Article abstract of DOI:10.1002/chem.200500121

The mixed-metal complex formed from n-butylsodium, n-butyllithium, and a chiral amino ether has been studied by NMR spectroscopy. Three different mixed-metal amides were used as chiral bases for the deprotonation of cyclohexene oxide. The selectivity and initial rate of reaction were compared for sodium-amido ethers, lithium-amido ethers, and mixtures of sodium and lithiumamido ethers in diethyl ether and tetrahydrofuran, respectively. The mixed sodium/lithium amides are more reactive than the single sodium and lithium amides, whereas the stereoselectivities are higher when lithium amides are used. The alkali-metal/γ-amido ethers exhibit both higher initial reaction rates and stereoselectivities than their β-amido ether analogues. NMR spectroscopic studies of mixtures of n-butylsodium (nBuNa), n-butyllithium (nBuLi), and the γ-amino ethers in diethyl ether show the exclusive formation of dimeric mixed-metal amides. In diethyl ether, the lithium atom of the mixed-metal amide is internally coordinated and the sodium atom is exposed to solvent; however, in tetrahydrofuran, both metals are internally coordinated.

Full text of DOI:10.1002/chem.200500121

FULL PAPER
Kinetic and NMR Spectroscopic Studies of Chiral Mixed Sodium/Lithium
Amides Used for the Deprotonation of Cyclohexene Oxide
Richard Sott, Johan Granander, Carl Williamson, and Gçran Hilmersson*[a]
Abstract: The mixed-metal complex
formed from n-butylsodium, n-butyl-
lithium, and a chiral amino ether has
been studied by NMR spectroscopy.
Three different mixed-metal amides
were used as chiral bases for the depro-
tonation of cyclohexene oxide. The se-
lectivity and initial rate of reaction
were compared for sodium–amido
ethers, lithium–amido ethers, and mix-
tures of sodium and lithiumamido
ethers in diethyl ether and tetrahydro-
furan, respectively. The mixed sodium/
lithium amides are more reactive than
the single sodium and lithium amides,
whereas the stereoselectivities are
higher when lithium amides are used.
The alkali-metal/g-amido ethers exhibit
both higher initial reaction rates and
stereoselectivities than their b-amido
ether analogues. NMR spectroscopic
studies of mixtures of n-butylsodium
(nBuNa), n-butyllithium (nBuLi), and
the g-amino ethers in diethyl ether
show the exclusive formation of dimer-
ic mixed-metal amides. In diethyl
ether, the lithium atom of the mixed-
metal amide is internally coordinated
and the sodium atom is exposed to sol-
vent; however, in tetrahydrofuran,
both metals are internally coordinated.
Keywords: amides
·
asymmetric
synthesis · lithium · mixed-metal
complexes · NMR spectroscopy
Introduction
action may require more than 24 h for completion.[5] How-
ever, the use of the heavier alkali metals sodium or potassi-
um, instead of lithium, results in a more powerful base from
which the rate of deprotonation should be considerably
higher than that of the corresponding lithium amide.[6] An-
drews and co-workers have reported that the use of sodium
diisopropylamide (NDA) for the deprotonation of ketones
gives a higher selectivity for the kinetically favored enolate
than lithium diisopropylamide (LDA).[7] Despite the fact
that sodium and potassium amides are common reagents in
organic synthesis, the use of heavy alkali metal amides in
asymmetric synthesis has not been explored. To the best of
our knowledge, the study by Johansson and Davidsson has
generated the only report in which mixed sodium/lithium
amides derived from chiral 1,2-diamines have been used in
stereoselective deprotonation of cyclohexene oxide
(Scheme 1).[8]
The asymmetric deprotonation of prochiral ketones and ep-
oxides by chiral lithium amides derived from 1,2-diamines
has received much attention.[1,2] There has also been a
steady growth of structural and mechanistic knowledge of
these systems gained by X-ray diffraction analysis, NMR
spectroscopy, kinetic studies, and computational methods.[3]
These reactions are useful in organic synthesis even though
they often require stoichiometric amounts of the chiral lithi-
um amide. Recently, the use of less reactive achiral “bulk”
bases has resulted in catalytic deprotonations with high ste-
reoselectivities, although the observed selectivity often
drops when less than 10% of the chiral base is used.[1,4] The
reaction rates for the enantioselective deprotonation reac-
tions by chiral lithium amides are generally low and the re-
The study showed that the mixed-metal amide gives a sig-
nificantly lower selectivity in the reaction (10% enatiomeric
excess (ee) compared to 70% ee when the lithium amide is
used). Based on various NMR observations, it was suggested
that a lithium chelate is formed and that sodium is exposed
to the diethyl ether (Et2O) solvent. The selectivity with such
a complex is expected to be lower in the epoxide-opening
reaction, since the epoxide coordinates to the larger sodium
[a] R. Sott, J. Granander, C. Williamson, Prof. G. Hilmersson
Department of Chemistry, Gçteborg University
41296 Gçteborg (Sweden)
Fax : (+46)31-7723840
E-mail: hilmers@chem.gu.se
Supporting Information for this article is available on the WWW
1
under http://www.chemeurj.org/ or from the author. The H and
13C NMR shifts for the lithium–amide complex Li-1 and the Li,1H -
6
À
À
cation. The lithium oxygen and lithium nitrogen bond
lengths in crystal structures are approximately 2.0 Š, while
HOESY spectra for the lithium–amide complexes in Et2O and THF
are presented in the Supporting Information.
Chem. Eur. J. 2005, 11, 4785 – 4792
DOI: 10.1002/chem.200500121
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4785

These results suggest that it should be possible to design
amide dimers with sodium internally chelated and lithium
exposed to the solvent and, therefore, also the incoming ep-
oxide (Scheme 3). The larger sodium cation and the six-
membered chelate would then push the chiral centers closer
to the lithium cation and ultimately form a compound that
combines the stereoselectivity of the lithium amide and the
reactivity of the sodium amide.
Scheme 1. The stereoselective deprotonation of cyclohexene oxide medi-
ated by chiral lithium, sodium, and sodium/lithium amide complexes in
Et2O.
Here, we report on the NMR studies of lithium and
mixed sodium/lithium amides formed from the chiral g-
À
the sodium oxygen and so-
À
dium nitrogen bond lengths
are approximately 2.5 Š,[7,9,10]
that is, the considerably longer
À
sodium oxygen bond length
should force the stereogenic
center of the amide away from
the approaching epoxide.
Mixed complexes of organo-
lithium and organosodium
compounds have been found
in the solid state. Mulvey and
co-workers have reported on
the crystal structure of a mixed
lithium/sodium–benzyl
com-
pound and a mixed tetrameric
ladder structure, with a central
ring containing lithium and the
outer ring containing so-
dium.[11] Furthermore, Williard
Scheme 3. The desired chiral mixed-metal lithium/sodium amide with coordination of the cyclohexene oxide to
the lithium metal.
and Nichols have characterized mixed lithium/sodium, lithi-
um/potassium and sodium/potassium amides of hexamethyl-
disilazane in the solid state and in solution by NMR spec-
troscopy.[10,12]
More recently we reported that the chelate ring size con-
trols the positioning of nBuNa in chiral mixed-metal
amides.[13] Tridentate amines with the ability to form five- or
six-membered chelates were treated with a mixture of
nBuNa and nBuLi. This led to the exclusive formation of
complexes with lithium in the five-membered chelate and
sodium in the six-membered chelate (Scheme 2).
amino ether 1 in both Et2O and tetrahydrofuran (THF). The
mixed-metal amide is capable of forming six-membered che-
lates. Along with the NMR studies, we also report the initial
rate and enantioselectivity of the deprotonations of cyclo-
hexene oxide by using the lithium, sodium, and mixed-metal
amides of the chiral g-amino ethers 1 and 2, and the chiral
b-amino ether 3 in Et2O and THF.
This indicates that the larger sodium cation prefers to
occupy the six-membered chelate, while the smaller lithium
prefers the five-membered chelate. The six-membered che-
late is also more flexible than the corresponding five-mem-
bered chelate as the “bite-angles” are allowed to adjust to
sodium.
Results and Discussion
Synthesis of the chiral amino ethers: The synthesis of the
chiral g-amino ethers 1 and 2 was achieved through the re-
duction of common chiral a-amino acids that subsequently
had the amine functionality protected by a tert-butoxycar-
bonyl (tBOC) group and the alcohol converted into a p-
tosyl leaving group. The homologation was carried out by
using sodium cyanide with subsequent acid hydrolysis to
convert the resulting nitriles into carboxylic acids and to
Scheme 2. Observed metal arrangement in the mixed complex formed by
nBuNa, nBuNa, and a chiral tridentate amine.
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Asymmetric Synthesis
FULL PAPER
remove the tBOC group.[14] After reduction to the corre-
sponding primary g-amino alcohols, alkylation of both the
amine and alcohol functionalities yielded the desired sec-
ondary g-amino ethers (Scheme 4). The synthesis of the b-
amino ether 3 has previously been published.[15]
amides, as deduced from experiments conducted with the
corresponding lithium amides. However, employing the
sodium amides as opposed to the more reactive mixed-
metal complexes had no detrimental effect on the enantiose-
lectivity. When Et2O was used as solvent, the stereoselectivi-
ties were generally significantly lower for the lithium amides
than for the corresponding sodium amides; however, amine
1 was an exception.
The comparison of the reactivity and selectivity of the
metal amides of the chiral g-amino ether 2 and the chiral b-
amino ether 3, both derived from valine, gave an idea of
what effects the homologation of the amino ether had on
the reaction. The initial rates were significantly higher by
using the lithium, sodium, and the mixed-metal complexes
of 2 than those of 3 in THF. In Et2O the initial rates were of
the same magnitude for the metal amides of both amines.
The same trend held for the enantioselectivity, which in
THF was higher when the chiral g-amino ether 2 was used.
In Et2O the observed difference in enantioselectivity when 2
and 3 were employed was very small.
Scheme 4. Synthesis of the b- and g-amino ethers.
NMR studies of mixtures of nBuLi and compound 1: To
study of the mixed-metal amide formed by the chiral g-
amino ether 1, nBuNa, and nBuLi by NMR spectroscopy, it
is necessary to first characterize the lithium amide. The sec-
tions below describe the NMR spectroscopic study of the
complexes formed by 1 and nBuLi in Et2O and THF, fol-
lowed by characterization of the mixed-metal complex.
Deprotonation of cyclohexene oxide by mixed sodium/lithi-
um–amide complexes: The asymmetric deprotonation reac-
tions were performed by adding nBuLi and/or nBuNa to a
solution of the chiral amino ether in Et2O or THF at
À788C. After a few minutes at À788C, the solution was
equilibrated at 208C and the cyclohexene oxide was added.
Aliquots of the reaction mixture were quenched and the re-
action monitored by the appearance of the enantiomers of
the 2-cyclohexene-1-ol, by means of chiral gas chromatogra-
phy. The initial rates of the reactions in Et2O and THF are
given in Table 1.
The sodium amides were significantly more reactive than
the corresponding lithium amides as expected; however, the
mixed-metal complexes were even more reactive in both
THF and Et2O. It should be noted that the high initial rates
of the mixed-metal amides tended to decrease after a few
percent conversion when the reaction was carried out in
Et2O. This was not the case in THF, as the enantioselectivity
was lower using the mixed-metal amides and the sodium
Characterization of lithium amides in Et2O: Addition of
[6Li]nBuLi (0.1 mmol) to
1 (0.07 mmol) in [D10]Et2O
(0.6 mL) at À788C resulted in a mixture of the dimeric C2-
symmetric lithium amide (Li-1)2, characterized by two
6Li NMR signals at d=1.5 and 2.0 ppm, and the mixed com-
plex nBuLi/Li-1, characterized by two 6Li NMR signals at
d=2.3 and 2.7 ppm (see Figure 1). In the 13C NMR spectra
the a-carbon signal at d=12.3 ppm from the mixed complex
1
was a quintet with J(13C,6Li)=8.9 Hz. The signals from the
mixed complex and free nBuLi increased, while those of the
(Li-1)2 complex decreased upon further addition of nBuLi
(0.03 mmol). The equilibrium constant (K) was estimated to
be 0.02m from the signal inten-
6
sities in the Li NMR spectrum
at À778C.
Table 1. Initial rates and enantioselectivities obtained from the deprotonation of cyclohexene oxide
(0.10 mmol) after 10 min of reaction (less than 15% conversion) using different lithium, sodium, and mixed-
metal complexes (0.20 mmol) in THF and Et2O (1.0 mL) at 20.08C.
The two-dimensional (2D)
6Li,1H HOESY experiment has
previously been utilized in sev-
eral detailed structural investi-
gations of organolithium com-
pounds and was used to mea-
sure heteronuclear Overhauser
effects between lithium and
protons at short distances.[16]
THF
Et2O
Amine
Alkali metal
reagent
Initial
ee [%]
Initial
ee [%]
rate [MsÀ1
]
rate [MsÀ1
]
(S)-1
(S)-1
(S)-1
(R)-2
(R)-2
(R)-2
(S)-3
(S)-3
(S)-3
nBuLi
nBuNa
nBuLi/nBuNa
nBuLi
nBuNa
nBuLi/nBuNa
nBuLi
nBuNa
2.1”10À6
10.6”10À6
14.1”10À6
5.2”10À6
21.6”10À6
28.2”10À6
1.6”10À6
6.5”10À6
9.0”10À6
46(R)
24(R)
25(R)
48(S)
30(S)
27(S)
33(S)
25(S)
23(S)
2.5”10À6
6.6”10À6
27(R)
17(R)
9(R)
3(S)
19(S)
19(S)
4(S)
13.7”10À6 [a]
3.3”10À6
13.9”10À6
21.5”10À6[a]
3.8”10À6
6
The Li,1H HOESY of the mix-
12.5”10À6
13.6”10À6[a]
22(S)
8(S)
ture of (Li-1)2, nBuLi/Li-1, and
free nBuLi in Et2O at À778C
revealed NOEs between the
nBuLi/nBuNa
[a] Average initial rates after 5 minutes of reaction (less than 5% conversion).
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G. Hilmersson et al.
Figure 2. The 6Li NMR spectrum of the (Li-1)2 complex (0.12m) in equi-
librium with the mixed complex nBuLi/Li-1 (0.04m) in 0.6 mL [D8]THF
at À878C (left), and the poorly resolved a-carbon signal of the nBuLi/Li-
1 complex in the 13C NMR spectrum (right).
Figure 1. The 6Li NMR spectrum of the (Li-1)2 complex (0.03m) in equi-
librium with the mixed complex nBuLi/Li-1 (0.02m) in 0.6 mL [D10]Et2O
at À778C (left), and the region of the 13C NMR spectrum showing the a-
carbon of the nBuLi/Li-1 complex (right).
in both Et2O and THF. Consequently, the upfield lithium
signal of the THF-solvated Li-1/nBuLi was assigned to the
methoxy chelate.
lithium atoms and the protons of 1 in addition to NOEs be-
tween the lithium atoms and the butyl a-protons of nBuLi/
Li-1. Both the lithium amide and the mixed complex
showed NOEs between the upfield lithium and the methoxy
protons.
NMR studies of the mixed sodium/lithium amide (Li-1/Na-
1): The sodium amides formed by nBuNa and compound 1
in Et2O and THF were studied by NMR spectroscopy. In
1
Characterization of lithium amides in THF: There were
three signals, at d=0.8, 1.2, and 1.8 ppm in the 6Li NMR
spectrum from a mixture of [6Li]nBuLi (0.1 mmol) and com-
plex 1 (0.1 mmol) in [D8]THF (0.6 mL) at À878C (see
Figure 2). These signals were assigned to two different struc-
tures of the dimeric lithium amide, either with the methoxy
coordination to only one of the lithium atoms (yielding two
6Li signals) or with a symmetric coordination to both lithium
atoms (one 6Li signal). THF coordinates lithium more
strongly than Et2O, and therefore THF promotes symmetri-
cally coordinated amides in which both lithium atoms are
coordinated by solvent. The intensity ratio between the
THF, two sets of signals appeared in the 13C and H spectra
from what seems to be the Na-1 complex and the mixed
nBuNa/Na-1 complex with the nBuNa proton signals at d=
À1.0 ppm. In Et2O, only the Na-1 complex was observed, in
addition to the homo aggregate of nBuNa, which appeared
at d=À1.1 ppm in the 1H spectrum. Unfortunately, these
sodium amide complexes could not be fully characterized.
6
The Li NMR spectrum of a solution of a mixture of 1
(0.18 mmol), nBuNa (0.09 mmol), and nBuLi (0.09 mmol) in
[D10]Et2O (0.6 mL) has only one 6Li NMR signal d=
1
1.3 ppm at À888C. Both the 13C and H spectra showed the
presence of only one set of signals (Table 2), different from
those of the corresponding lithium amides. This indicated
that all of the amine must be complexed within one mixed-
metal complex (Li-1/Na-1), since there is only one half
equivalent of lithium and sodium cations per amine. There
was only one set of NMR signals at all temperatures (À60
to À1008C), suggesting that there was only one major di-
meric complex. The single set of 13C NMR resonances from
the Li-1/Na-1 complex indicated that it had C2 symmetry.
6
three Li signals, two from the asymmetric complex and one
from the symmetric complex, was approximately 1:1:1. The
6
two Li NMR signals from the mixed complex Li-1/nBuLi at
6
d=1.9 and 1.8 ppm appeared in the Li spectrum upon fur-
ther addition of nBuLi (0.1 mmol). In the 13C NMR spec-
trum the a-carbon at d=13.6 ppm from complexed nBuLi
appeared as a poorly resolved quintet (1J(13C,6Li)=8.7 Hz).
The 6Li,1H HOESY of the mixture of the two dimeric
complexes of Li-1 in THF at À878C showed NOEs between
the lithium atoms and the protons of 1 for both complexes.
The symmetrically coordinated Li-1 showed an NOE cross-
peak between the lithium atom and the methoxy protons,
while the asymmetric Li-1
6
Heteronuclear Li,1H NOEs were employed to determine
the position of the lithium cation in the mixed complex. The
6Li,1H HOESY spectra of the mixed-metal complex Li-1/
Na-1 in [D10]Et2O were recorded at À888C with mixing
showed an NOE between the
Table 2. Chemical shifts for the mixed-metal complex (Li-1/Na-1) formed by
(0.09 mmol), nBuLi (0.09 mmol), and THF (0.11 mmol) in Et2O (0.6 mL) at À888C.
1 (0.18 mmol), nBuNa
upfield lithium atom and the
methoxy protons. The chelated
lithium signal appeared more
upfield than that of the sol-
vent-coordinated lithium atom
OCH3
OCH2
CHCH2
PhCH
NCH
CHCH3
CHCH3
THF
d 1H [ppm]:
d13C [ppm]:
3.36
60.0
3.5, 3.8
76.2
2.26
39.4
3.64
70.0
2.60
50.4
1.05
23.1
1.11
28.6
3.43, 1.7
68.1, 26.2
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Asymmetric Synthesis
FULL PAPER
times of 0.7 and 1.0 s. Surprisingly, NOEs were observed be-
tween the lithium signal and the proton signals of the me-
thoxy group at d=3.40 ppm. We also observed several
6Li,1H NOE cross-peaks between the methoxy, CH2, CH3,
and PhCH protons of 1 and lithium, supporting the forma-
tion of a mixed-alkali complex. This indicated that lithium
was internally coordinated, contrary to what was expected.
However, this does not exclude the possibility that these
NOEs appear as a result of a rapid exchange of sodium with
lithium. This was further examined by the addition of one
equivalent of protonated THF (0.11 mmol) per lithium atom
to a solution of 1 (0.18 mmol), nBuNa (0.07 mmol), and
nBuLi (0.11 mmol) in [D10]Et2O (0.65 mL) followed by
6Li,1H HOESY experiments. The THF ligand has a greater
affinity for alkali metals and is expected to replace Et2O.
This difference in coordination has been observed by signifi-
cant changes in 6Li chemical
sodium exchange, one would also expect a strong NOE be-
tween the lithium and protons of THF.
To ensure that not all of the added THF molecules were
coordinated to the lithium amide, an additional three equiv-
alents of THF were added per Li. This made no difference
to the 6Li NMR spectrum, or to the cross-peaks observed
for the mixed-metal amide in the corresponding 6Li,1H -
HOESY spectrum. These observations showed that the
mixed-metal amide in Et2O must be an asymmetric dimer
with methoxy coordinated to lithium, leaving sodium ex-
posed to THF solvent coordination.
Upon further addition of THF, some of the C2-symmetric
Li-1/Na-1 turned into a complex in which both metals were
exposed to the solvent (Scheme 5). The lithium signal of the
dimeric mixed-metal amide shifted continuously upfield
with increasing THF concentration. With 12 equivalents of
shifts of various chiral lithium
amides.[17] The presence of
only a few equivalents of THF
had no significant effect on the
6Li spectrum, indicating that it
does not disrupt the C2-sym-
metric structure.
With one equivalent of THF
per lithium added, the Li,1H -
HOESY spectrum revealed no
cross-peaks between the THF
protons and the lithium atom
6
Scheme 5. Addition of more than four equivalents of THF (per lithium) to the Et2O-solvated (Li-1/Na-1) com-
plex results in a complex in which both metals are coordinated by solvent.
6
of the mixed-metal complex (Figure 3). The THF protons
and the OCH2 and OCH3 protons of 1 had similar shifts, but
careful examination revealed that the cross-peaks were re-
THF (per lithium) added, the Li,1H HOESY spectrum re-
vealed strong cross-peaks between the lithium atom of the
mixed-metal amide at d=1.1 ppm and the THF protons at
d=3.58 ppm, as well as the protons of the methoxy group of
1 at d=3.36 ppm. In the THF-solvated mixed-metal dimer
both lithium and sodium atoms were coordinated by me-
thoxy groups, in agreement with our previous studies of
chiral lithium amides derived from a-amino acids.[17] The
possible formation of a mixed-
solved. In comparison, strong NOEs appeared in the Li,1H -
6
HOESY spectrum between the downfield signal of lithium
in Li-1 and the protons of THF at d=3.44 ppm. If the lithi-
um cation occupies the chelated position it should not show
any NOE to the protons of the THF, but under fast lithium–
metal amide with methoxy co-
ordination at only the lithium
atom was excluded, since such
a complex would not produce
the observed NOE between
the lithium atom and the THF
protons in the 6Li,1H HOESY
spectrum. This is most likely to
be the reactive complex that
coordinates to cyclohexene
oxide in THF, with possible re-
action sites both at lithium and
sodium atoms.
Further addition of nBuLi
(0.05 mmol) resulted in the for-
mation of a mixed nBuLi/Na-1
complex, indicated by a signal
at d=1.7 ppm in the Li NMR
spectrum and a new set of sig-
Figure 3. 6Li,1H HOESY spectrum of 1 (0.18 mmol), nBuNa (0.07 mmol), nBuLi (0.11 mmol), and THF
(0.11 mmol) in [D10]Et2O (0.6 mL) at À888C, with scale expansion of the 1H spectral region (d=3.2–3.8 ppm)
shown on the right.
6
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G. Hilmersson et al.
nals in the 13C spectrum (Figure 4). The nBuLi a-carbon
tion to lithium is much stronger than that to sodium, and
this is suggested to be the reason for the reported structure.
These complexes significantly increased the reactivity in
the deprotonation of cyclohexene oxide. They are therefore
promising precursors for the development of dimers with
the sodium atom internally chelated and the lithium atom
exposed to the solvent. Diamines are better chiral bases for
the asymmetric deprotonation of cyclohexene oxide than
amino ethers. We therefore aim to develop such mixed-
metal amides with amine chelates. Such mixed amides are
potentially more reactive than the lithium analogue, while
they also mediate the reactions with high enantioselectivity.
1
signal at d=12.6 ppm was split into a 1:1:1 triplet with J-
(13C,6Li)=7.7 Hz. Further addition of nBuLi resulted in the
formation of the mixed nBuLi/Li-1 complex, dimeric (Li-1)2,
and more mixed nBuLi/Na-1 complex.
Experimental Section
Synthesis of chiral amino ethers: NMR spectra were recorded on a
Varian 400 MHz spectrometer by using CDCl3 as solvent. Optical rota-
tions were measured using a Perkin–Elmer 341 LC polarimeter. IR spec-
tra were recorded on a Perkin–Elmer 1600 Series FTIR spectrometer.
Melting points were determined using a Büchi Melting Point B-545 and
are uncorrected. Dried solvents were distilled from sodium/benzophe-
none. High-resolution mass spectroscopy was carried out on a Micromass
LCT spectrometer.
6
Figure 4. The Li NMR spectrum of the Li-1/Na-1 complex in equilibrium
with the mixed complex nBuLi/Na-1 in Et2O/THF (0.6/0.1 mL) at À878C
(left), and the region of the 13C NMR spectrum showing the a-carbon of
the nBuLi/Na-1 complex (right).
The chiral amino acids used as starting materials, (R)-phenylglycine and
(S)-valine, were purchased from Sigma–Aldrich and their reduction to
amino alcohols,[18] protection as tBOC amido alcohols,[19] and conversion
to tosylates[20] were made according to literature procedures. The synthe-
sis of the chiral b-amino ether (S)-2-isopropylamino-1-methoxy-3-methyl-
butane (3) has been described previously.[15]
In pure [D8]THF, the spectral line of the mixed lithium/
sodium amide appeared at d=1.0 ppm in the Li spectrum
at À878C. This signal was split into two (2:3 intensity ratio)
upon lowering the temperature below À958C. This suggests
that both symmetrical and asymmetrical mixed-metal
dimers are formed in THF.
6
(S)-3-(N-tert-Butoxycarbonylamino)-3-phenylpropanenitrile:
A mixture
of (R)-2-(N-tert-butoxycarbonylamino)-2-phenylethyl tosylate (18.87 g,
45.3 mmol, 1.0 equiv) dissolved in DMF (125 mL) was added to a suspen-
sion of finely ground NaCN (6.66 g, 136 mmol, 3.0 equiv) in DMF
(125 mL) and the mixture stirred overnight at room temperature. A solu-
tion of NaOH (2.0m, 200 mL) was added and the mixture extracted with
dichloromethane (3”100 mL). The combined organic extract was washed
with water (3”100 mL) and concentrated in vacuo. The residue was dis-
solved in ethyl acetate/hexane (1:1, 200 mL), washed again with water
(3”100 mL), dried over Na2SO4, and concentrated in vacuo yielding a
pale yellow oil that quickly crystallized (10.59 g, 95%). Spectral data
were consistent with those reported in the literature.[14]
Conclusion
We have shown that the mixed-metal amides generated
from chiral g-amino ethers are potentially useful chiral
amides for enantioselective synthesis. The sodium and
mixed-metal amides exhibit a significantly higher reactivity
in the asymmetric deprotonation of cyclohexene oxide than
the corresponding lithium amides in either Et2O or THF.
Surprisingly, the mixed-metal amides are even more reactive
than the sodium amides. In THF, the increased reactivity of
the sodium and mixed-metal amides occurs at the expense
of a decreased enantioselectivity, but in Et2O some of the
enantioselectivities increase upon replacing the lithium
amide with a sodium amide.
(R)-3-(N-tert-Butoxycarbonylamino)-4-methylpentanenitrile: The same
procedure was used as for the preparation of (S)-3-(N-tert-butoxycarbon-
ylamino)-3-phenylpropanenitrile, but with (R)-2-(N-tert-butoxycarbinol-
amino)-3-methylbutyl tosylate. Yield 72% as a white solid. The spectral
data were consistent with those reported in the literature.[14]
(S)-3-Amino-3-phenylpropanol: The nitrile, (S)-3-(N-tert-butoxycarbonyl-
amino)-3-phenylpropanenitrile (8.68 g, 35.2 mmol, 1.0 equiv) was added
to hydrochloric acid (6m, 200 mL, 1.23 mol, 35 equiv), and the mixture
was refluxed overnight. The solution was cooled to 08C, washed with di-
chloromethane (2”100 mL) and concentrated in vacuo. The residue was
dissolved in water, made basic with a solution of NaOH (5m), washed
with dichloromethane (2”50 mL), and concentrated in vacuo. The result-
ing white powder was dried using benzene. The dry sodium carboxylate
salt of the g-amino acid was added to an ice-cooled suspension of LiAlH4
(4.01 g, 105 mmol, 3.0 equiv) in dry THF (250 mL). The mixture was al-
lowed to reach room temperature and then refluxed overnight. The mix-
ture was cooled to 08C and the excess LiAlH4 was quenched with a solu-
tion of NaOH (2m, 30 mL). The precipitate was filtered off and extracted
with THF (4”25 mL). The combined organic extract was concentrated in
vacuo, and the residue was dissolved in a solution of NaOH (2m, 70 mL)
and extracted with dichloromethane (3”50 mL). The combined organic
extract was washed with brine (50 mL), dried over Na2SO4, and concen-
Mixing Na-1 with Li-1 leads to the complete formation of
a mixed amide dimer as shown by the NMR experiments.
However, our attempts to form dimers with the sodium
atom internally chelated and the lithium atom exposed to
6
the solvent were unsuccessful, as indicated by the Li,1H -
HOESYNMR spectra. In Et2O a dimeric mixed-metal com-
plex with sodium exposed to solvent is formed, while both
lithium and sodium are coordinated by the solvent in the
mixed-metal amide in THF. It appears that the ether chela-
4790
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www.chemeurj.org
Chem. Eur. J. 2005, 11, 4785 – 4792

Asymmetric Synthesis
FULL PAPER
trated in vacuo yielding a clear, colorless oil (2.77 g, 52%). The spectral
data were consistent with those reported in the literature.[21]
(R)-2-Isopropylamino-4-methoxy-1-methylpentane (2): Same procedure
as for the preparation of (S)-1-isopropylamino-3-methoxy-1-phenylpro-
pane, but with (R)-3-isopropylamino-4-methylpentanol. Yield 40% as a
clear colorless oil. B.p. 358C, 0.02 mbar; [a]2D0 =+14.08 (c=1.03 in di-
chloromethane); IR (thin film): n˜ =3340, 2959, 2931, 2872, 1465, 1380,
(R)-3-Amino-4-methylpentanol: The same procedure as for the prepara-
tion of (S)-3-amino-3-phenylpropanol was used, but with (R)-3-(N-tert-
butoxycarbonylamino)-4-methylpentanenitrile. Yield 64% as
a pale
1
1171, 1119 cmÀ1; H NMR (400 MHz, CDCl3): d=0.86 (d, J=6.6 Hz, 3H;
yellow oil. Spectral data were consistent with those reported in the litera-
ture.[22]
(CH3)2CH), 0.88 (d, J=6.6 Hz, 3H; (CH3)2CH), 1.01 (d, J=6.1 Hz, 3H;
(CH3)2CHN), 1.03 (d, J=6.1 Hz, 3H; (CH3)2CHN), 1.42 (m, 1H;
(CH3)2CH), 1.67 (m, 1H; CH2CH2O), 1.77 (m, 1H; CH2CH2O), 2.47 (m,
1H; CHCH2CH2O), 2.82 (septet, J=6.1 Hz, 1H; (CH3)2CHN), 3.33 (s,
3H; CH3O), 3.47 ppm (m, 2H; CH2O); 13C NMR (100 MHz, CDCl3): d=
17.8 ((CH3)2CH), 19.0 ((CH3)2CH), 23.5 ((CH3)2CHN), 24.1
((CH3)2CHN), 30.9 ((CH3)2CH), 31.7 (CH2CH2O), 46.7 ((CH3)2CHN),
57.5 (CHCH2CH2O), 58.8 (CH3O), 71.2 ppm (CH2O); HRMS (ESI+):
m/z calcd for C10H24NO: 174.1858; found: 174.1850.
(S)-3-Isopropylamino-3-phenylpropanol: The amino alcohol (S)-3-amino-
3-phenylpropanol (2.77 g, 18.3 mmol, 1.0 equiv) and acetone (10.63 g,
13.44 mL, 183 mmol, 10 equiv) were dissolved in benzene (125 mL) and
refluxed for six hours. The solution was allowed to cool to room tempera-
ture and concentrated in vacuo. The residue was dissolved in dry ethanol
(125 mL) and NaBH4 (1.38 g, 36.6 mmol, 2.0 equiv) was added. The mix-
ture was stirred overnight at room temperature. Water (50 mL) was
added and the ethanol removed under reduced pressure. The remaining
aqueous phase was extracted with dichloromethane (3”50 mL). The
combined organic extract was washed with brine (50 mL), dried over
Na2SO4, and concentrated in vacuo resulting in a white solid (3.48 g,
98%). M.p. 858C; [a]2D0 =À77.38 (c=0.99 in dichloromethane); IR (KBr):
n˜ =3262, 3196, 2971, 2926, 2864, 1490, 1452, 1384, 1178, 1055, 1035, 892,
Kinetics: Reaction vessels and syringes were thoroughly oven-dried
before use. THF, Et2O, hexane, and toluene were distilled from sodium
benzophenone and kept inside a glovebox. n-Decane, 1-hexanol and cy-
clohexene oxide were distilled from calcium hydride and kept inside a
glovebox. Stock solutions of cyclohexene oxide in n-decane (2.00m) and
1-hexanol in toluene (3.53 mm) were prepared inside the glovebox and
used in the experiments. The concentrations of the nBuLi (2.45m in
hexane) and the nBuNa suspension (0.53m in hexane) were determined
by employing double Gilman titrations.[23] GC analyses were carried out
by using a Varian Star 3400CXgas chromatograph equipped with a
chiral stationary-phase column (CP-Chirasil-DEXCB, 25 m, 0.32 mm)
from Chrompack. Analyses were performed using He (1.5 mLminÀ1) as
carrier gas (injector 2258C, detector 2508C).
761, 700 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.00 (d, J=6.3 Hz, 3H;
;
(CH3)2CH), 1.09 (d, J=6.3 Hz, 3H; (CH3)2CH), 1.76 (m, 1H;
CH2CH2OH), 1.94 (m, 1H; CH2CH2OH), 2.63 (septet, J=6.3 Hz, 1H;
(CH3)2CH), 3.81 (m, 1H; PhCH), 3.91 (m, 2H; CH2OH), 7.23–7.38 ppm
(m, 5H; Ar); 13C NMR (100 MHz, CDCl3): d=21.7 ((CH3)2CH), 24.4
((CH3)2CH), 39.1 (CH2CH2OH), 45.5 ((CH3)2CH), 61.6 (PhCH), 63.5
(CH2OH), 126.4 (o-Ar), 127.5 (p-Ar), 128.9 (m-Ar), 143.5 ppm (i-Ar);
HRMS (ESI+): m/z calcd for C12H20NO: 194.1545; found: 194.1544.
Synthesis of n-butylsodium: Inside the glovebox sodium tert-butoxide
(1.5 g, 15.6 mmol, 1.0 equiv) was added to the reaction vessel equipped
with a magnetic stirring bar. Dry hexane (10 mL) was added and the
vessel sealed and taken out of the glovebox and cooled to 08C in an ice
bath. n-Butyllithium (2.45m in hexane, 12.49 mL, 31.2 mmol, 2.0 equiv)
was added dropwise through a septum, and the suspension was stirred for
one hour at 08C before being allowed to warm up to room temperature
and was then stirred for an additional 6 h. The resulting suspension was
centrifuged and the precipitate was washed with dry hexane (5”10 mL).
The precipitate was then suspended in hexane (10 mL) and transferred to
another airtight vessel and stored at À208C. The concentration of the
nNaBu suspension was determined to be 0.53m as evidenced from a
double Gilman titration.
(R)-3-Isopropylamino-4-methylpentanol: The same procedure as for the
preparation of (S)-3-isopropylamino-3-phenylpropanol was used, but
with (S)-3-amino-4-methylpentanol. Yield 86% as a clear colorless oil.
B.p. 60 8C, 0.05 mbar; [a]2D0 =+60.58 (c=1.01 in dichloromethane); IR
(thin film): n˜ =3274, 2961, 2870, 1466, 1382, 1370, 1171, 1076, 855,
678 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=0.84 (d, J=6.9 Hz, 3H;
(CH3)2CH), 0.93 (d, J=6.9 Hz, 3H; (CH3)2CH), 1.07 (d, J=6.1 Hz, 6H;
(CH3)CHN), 1.42 (m, 1H; CH2CH2OH), 1.52 (m, 1H; CH2CH2OH), 1.95
(m, J=4.2, 6.9 Hz, 1H; (CH3)2CH), 2.70 (m, 1H; CHCH2CH2OH), 2.96
(septet, J=6.1 Hz, 1H; (CH3)CHN), 3.79 (m, 1H; CH2OH), 3.86 ppm
(m, 1H; CH2OH); 13C NMR (100 MHz, CDCl3): d=16.3 ((CH3)2CH),
20.4 ((CH3)2CH), 22.4 ((CH3)2CHN), 22.5 ((CH3)2CHN), 28.9
((CH3)2CH),
29.7
(CH2CH2OH),
45.2
((CH3)2CHN),
61.8
Typical kinetic procedure: The chiral amine (0.20 mmol) was dissolved in
dry solvent (THF or Et2O), in amounts making the total volume of the
reaction 1 mL, in an airtight reaction vessel inside the glovebox. The re-
action vessel was sealed and taken out of the glovebox, placed under a
nitrogen atmosphere and the solution cooled to À788C in a dry ice/ace-
tone cooling bath. The nBuNa suspension was sonicated briefly in order
to make it homogenous and a portion (0.53m, 0.10 mmol) was withdrawn
by syringe. This homogenous suspension was then added dropwise to the
reaction vessel. The mixture was allowed to react for 5 min before nBuLi
(2.45m, 0.10 mmol) was added dropwise using a syringe. The mixture was
allowed to react for a further 5 min and then allowed to reach room tem-
perature, and was placed in a thermostat bath and equilibrated to 20.08C
for 5 min. The reaction was started by addition of a solution of cyclohex-
ene oxide (2.0m, 0.10 mmol) in n-decane (0.050 mL) with a syringe. Sam-
ples of the reaction mixture were quenched in hydrochloric acid (0.64m,
100 ml) at even intervals with a syringe and extracted with toluene
(500 ml) containing an internal standard of 1-hexanol (3.53 mm). The or-
ganic phases were transferred to vials and analysed by capillary gas chro-
matography.
(CHCH2CH2OH), 63.8 ppm (CH2OH); HRMS (ESI+): m/z calcd for
C9H22NO: 160.1701; found: 160.1703.
(S)-1-Isopropylamino-3-methoxy-1-phenylpropane (1): The amino alco-
hol (S)-3-isopropylamino-3-phenylpropanol (3.48 g, 18.0 mmol, 1.0 equiv)
dissolved in dry THF (50 mL) was added dropwise to a suspension of
NaH (60% in mineral oil, 0.94 g, 23.4 mmol, 1.3 equiv) in dry THF
(50 mL). The mixture was warmed at 508C for 1 h before being cooled to
room temperature. Methyl iodide (3.32 g, 1.46 mL, 23.4 mmol, 1.3 equiv)
dissolved in dry THF (10 mL) was added dropwise and the mixture al-
lowed to react overnight at room temperature. Water (50 mL) was added
and the mixture concentrated in vacuo. The remaining aqueous phase
was extracted with dichloromethane (3”50 mL) and the combined organ-
ic extract was washed with brine (50 mL), dried over Na2SO4, and con-
centrated in vacuo yielding a clear yellow oil. The product was purified
using flash chromatography on Al2O3 with ethyl acetate/hexane 1:4 as
eluent, followed by short-path distillation, yielding a clear colorless oil
(1.28 g, 34%). B.p. 758C, 0.07 mbar; [a]2D0 =À33.48 (c=1.00 in dichloro-
methane); IR (thin film): n˜ =3337, 2964, 2927, 2869, 1453, 1380, 1174,
1119, 702 cmÀ1 1H NMR (400 MHz, CDCl3): d=0.97 (d, J=6.3 Hz, 3H;
;
NMR sample preparation: The solution studies of the lithium amides and
the mixed sodium/lithium amides were performed in deuterated Et2O
and THF solvents using 6Li-labeled nBuLi. The nBuNa suspension in
hexane (0.53m) was transferred to an NMR tube under N2 atmosphere.
The hexane was removed under reduced pressure and deuterated solvent
was added followed by rapid cooling of the sample at À788C.
(CH3)2CH), 1.02 (d, J=6.3 Hz, 3H; (CH3)2CH), 1.79 (m, 1H;
CH2CH2O), 2.00 (m, 1H; CH2CH2O), 2.59 (septet, J=6.3 Hz, 1H;
(CH3)2CH), 3.23 (m, 1H; CH2O), 3.29 (s, 3H; CH3O), 3.34 (m, 1H;
CH2O), 3.87 (t, J=7.0 Hz, 1H; PhCH), 7.23–7.35 ppm (m, 5H; Ar);
13C NMR (100 MHz, CDCl3): d=22.3 ((CH3)2CH), 24.5 ((CH3)2CH), 38.6
(CH2CH2O), 45.8 (CH3)2CH), 57.8 (PhCH), 58.8 (CH3O), 70.4 (CH2O),
127.1 (p-Ar), 127.3 (Ar), 128.6 (Ar), 144.5 ppm (i-Ar); HRMS (ESI+):
m/z calcd for C13H22NO: 208.1701; found: 208.1699.
NMR studies: All NMR spectra were recorded using a Varian Unity500
spectrometer equipped with three channels using 5 mm 13C, 6Li, or 1H
Chem. Eur. J. 2005, 11, 4785 – 4792
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4791

G. Hilmersson et al.
triple-resonance probe-heads, built by the Nalorac Company. We used
measuring frequencies of 500 MHz (1H), 125 MHz (13C), and 73 MHz
(6Li). The 1H and 13C NMR spectra were referenced to the solvent
[7] P. C. Andrews, N. D. R. Barnett, R. E. Mulvey, W. Clegg, P. A.
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[10] P. G. Williard, M. A. Nichols, J. Am. Chem. Soc. 1991, 113, 9671.
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[D10]Et2O signals at d=1.33 ppm (1H CH2) and d=65.5 ppm (13C
À
1
À
À
CH2), and the [D8]THF signals at d=1.72 ppm ( H CH2) and d=
67.6 ppm (13C CH2), respectively. Probe temperatures were measured
À
after more than one hour of temperature equilibrium with both a cali-
brated methanol–freon NMR spectroscopy thermometer and the stan-
dard methanol thermometer supplied by Varian instruments.[24] 6Li,1H -
HOESY experiments were performed with tM =1.0 s in both THF and
Et2O. For further data of the 6Li,1H HOESY experiments, see previous
studies.[17,25]
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[14] R. Caputo, E. Cassano, L. Longboard, G. Palumbo, Tetrahedron
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Financial support from The Swedish Research Council is gratefully ac-
knowledged, and the Knut and Alice Wallenberg Foundation is also
gratefully acknowledged for the funding of our glovebox. We thank
Docent Ö. Davidsson and Dr. G. Hulte at AstraZeneca Research and
Development, Mçlndal (Sweden), for the mass spectrometry analysis.
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Received: February 3, 2005
Published online: June 1, 2005
4792
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4785 – 4792