Influence of steric factors on chiral lithium amide aggregates

Article abstract of DOI:10.1021/ja4123957

The solution structures of three mixed aggregates dissolved in toluene-d₈ consisting of the lithiated amides derived from (S)-N-isopropyl-1-((triisopropylsilyl)oxy)propan-2-amine, (R)-N-(1-phenyl-2- ((triisopropylsilyl)oxy)ethyl)propan-2-amine, or (S)-N-isobutyl-3-methyl-1- ((triisopropylsilyl)oxy)butan-2-amine and n-butyllithium are characterized by various NMR experiments including diffusion-ordered NMR spectroscopy with diffusion coefficient-formula weight correlation analyses (D-FW) and other one- and two-dimensional NMR techniques. We report that steric hindrance of R ₁ and R₂ groups of the chiral lithium amide controls the aggregation state of the mixed aggregates. With a less hindered R₂ group, lithium (S)-N-isopropyl-1-((triisopropylsilyl)oxy)propan-2-amide forms mostly a 2:2 ladder-type mixed aggregate with n-butyllithium. Increase of steric hindrance of the R₁ and R₂ groups suppresses the formation of the 2:2 mixed aggregate and promotes formation of a 2:1 mixed aggregate. We observe that lithium (S)-N-isobutyl-3-methyl-1- ((triisopropylsilyl)oxy)butan-2-amide forms both a 2:2 mixed aggregate and a 2:1 mixed trimer with n-butyllithium. Further increase in the steric hindrance of R₁ and R₂ groups results in the formation of only 2:1 mixed aggregate as observed with lithium (R)-N-(1-phenyl-2-((triisopropylsilyl) oxy)ethyl)propan-2-amide.

Full text of DOI:10.1021/ja4123957

Article
pubs.acs.org/JACS
Influence of Steric Factors on Chiral Lithium Amide Aggregates
Chicheung Su, Russell Hopson, and Paul G. Williard*
Department of Chemistry, Brown University, 324 Brook Street, Providence, Rhode Island 02912 United States
S
* Supporting Information
ABSTRACT: The solution structures of three mixed
aggregates dissolved in toluene-d8 consisting of the lithiated
amides derived from (S)-N-isopropyl-1-((triisopropylsilyl)-
oxy)propan-2-amine, (R)-N-(1-phenyl-2-((triisopropylsilyl)-
oxy)ethyl)propan-2-amine, or (S)-N-isobutyl-3-methyl-1-
((triisopropylsilyl)oxy)butan-2-amine and n-butyllithium are
characterized by various NMR experiments including
diffusion-ordered NMR spectroscopy with diffusion coeffi-
cient-formula weight correlation analyses (D-FW) and other
one- and two-dimensional NMR techniques. We report that
steric hindrance of R1 and R2 groups of the chiral lithium
amide controls the aggregation state of the mixed aggregates.
With a less hindered R2 group, lithium (S)-N-isopropyl-1-
((triisopropylsilyl)oxy)propan-2-amide forms mostly a 2:2 ladder-type mixed aggregate with n-butyllithium. Increase of steric
hindrance of the R1 and R2 groups suppresses the formation of the 2:2 mixed aggregate and promotes formation of a 2:1 mixed
aggregate. We observe that lithium (S)-N-isobutyl-3-methyl-1-((triisopropylsilyl)oxy)butan-2-amide forms both a 2:2 mixed
aggregate and a 2:1 mixed trimer with n-butyllithium. Further increase in the steric hindrance of R1 and R2 groups results in the
formation of only 2:1 mixed aggregate as observed with lithium (R)-N-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl)propan-2-amide.
Scheme 1. Trimeric 2:1 Complexes 2 and 3 and the
Homodimer 4
INTRODUCTION
■
Organolithium amide bases such as lithium diisopropylamide
and lithium hexamethyldisilazide are generally used to
deprotonate weakly acidic organic compounds such as ketones,
esters, etc.1 Chiral lithium amide bases have also been
developed for use in asymmetric deprotonation and addition
reactions.2 As a representative example, Koga and co-workers
reported a highly enantioselective aldol reaction in the presence
of chiral lithium amide bases strongly implicating the influence
of mixed aggregates.3 Several groups including Collum,4
Davidsson,5 Duhamel,6 Hilmersson,7 McGarrity,8 Maddaluno,9
Reich,10 Strohmann,11 and Thomas12 also reported the
formation of mixed aggregates that incorporate lithium amide
bases.
We previously reported the crystal structures of mixed
trimers containing two equivalents of the chiral lithium amide
derived from N-isopropyl valinol 1 and one equivalent of the
alkyl lithium reagents depicted as structure 2 in Scheme 1.13
Later, we also reported both the solid state structure and the
solution state characterization of a similar trimeric complex
consisting of two equivalents of the chiral lithium amide and 3-
pentanone lithium enolate depicted as complex 3.14 More
recently we reported the homodimeric solution structure 4 of
the pure lithiated chiral amine 1 in the absence of any
additional reagents in hydrocarbon solvent.15 Most recently, we
reported the four-rung ladder structures 6a−d (Scheme 2) of
mixed aggregates consisting of a 2:2 stoichiometric ratio of the
chiral lithium amide derived from N-ethyl-O-triisopropylsilyl
valinol 5 and either n-butyllithium (n-BuLi), sec-butyllithium (s-
BuLi), or isopropyllithium (i-PrLi) or cyclopentyllithium.16
Since the amino acid derived chiral amides are shown to be
useful in asymmetric addition and deprotonation reactions,17
and also since the reactivity and stereoselectivity of chiral
lithium mixed aggregates depend on the aggregation state of
the reagents,6,7,10,18 the aggregation state determination of
these chiral lithium mixed aggregates is crucial in controlling
Received: December 5, 2013
Published: January 22, 2014
© 2014 American Chemical Society
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Scheme 2. The 2:2 Ladder Structure Mixed Aggregates 6
the mechanism of reactions in which they are employed and in
designing new chiral lithium reagents. A comprehensive review
of the extant breadth and scope of the influence of mixed
aggregates on reactivity containing single and multiple anions
and single and multiple cations has recently been published.19
In an attempt to rationalize the formation of completely
different mixed aggregates, we synthesized chiral amines 7, 8,
and 9 (Scheme 3) and characterized the mixed aggregates of
Scheme 3. Chiral Amines 7, 8, and 9
Figure 1. 1H NMR spectra of chiral amine 7 titration of 0.2 M n-Bu6Li
toluene-d8 solution at −40 °C. H represents the resonance of n-Bu6Li
hexamer; I represents the resonances of impurities and mixed
aggregates of n-Bu6Li and n-BuO6Li; 10 represents the resonances of
the 2:2 mixed aggregate 10.
lithium amides derived from 7, 8, and 9 with n-BuLi. We report
that the steric factors of R1 and R2 groups dictate the formation
of 2:2 mixed aggregates or 2:1 mixed trimers. With a sterically
less hindered methyl group at the R2 position, lithiated chiral
amine 7 forms exclusively 2:2 mixed aggregate with the same
motif as aggregates 6. When the methyl group is replaced by a
sterically more hindered isobutyl group at the R2 position,
lithiated chiral amine 8 forms both 2:2 mixed aggregate and 2:1
mixed trimer similar to the structure of complex 2a. Further
increase in the steric hindrance of the R2 group prevents the
formation of 2:2 mixed aggregate, as lithiated chiral amine 9
with a phenyl group at its R2 position forms 2:1 mixed trimer
and only a small amount of homodimer resembling the
structure of complex 4. No 2:2 mixed aggregate is observed
with chiral amide derived from 9.
RESULTS AND DISCUSSION
Figure 2. 6Li NMR spectra of chiral amine 7 titration of 0.2 M n-Bu6Li
toluene-d8 solution at −40 °C. H represents the resonance of n-Bu6Li
hexamer; I represents the resonances of impurities and mixed
aggregates of n-Bu6Li and n-BuO6Li; 10 represents the resonances of
the 2:2 mixed aggregate 10.
■
Solution State Characterization of the 2:2 Mixed
Aggregate of Lithiated Chiral Amine 7 and n-BuLi. Chiral
amine 7 was easily synthesized from (S)-alanine in three steps
following the procedure we have used previously to prepare the
N-isopropyl-O-triisopropylsilyl valinol.13 The sample for NMR
studies was prepared in situ by titrating (S)-N-isopropyl-1-
((triisopropylsilyl)oxy)propan-2-amine 7 into a toluene-d8
BuLi equals 1:1.5, the peak at −0.59 ppm dominates the α-
methylene region of n-BuLi.
6
solution of Li labeled n-BuLi at −40 °C. The titration was
monitored by 1H and 6Li NMR as depicted in Figures 1 and 2,
respectively.
In the Li NMR spectra, n-BuLi exhibits one major peak
6
corresponding to a hexamer and a minor broad peak
corresponding to some unknown aggregate(s) of n-BuLi and
n-BuOLi. The spectra show clearly the decrease of the
resonance of the unsolvated hexameric n-BuLi aggregate and
the rise of two sharp peaks with 1:1 ratio upon addition of
chiral amine 7. These two sharp peaks dominate when the ratio
of lithiated chiral amine 7 to n-BuLi equals 1:1.5. These spectra
are consistent with a 2:2 mixed aggregate structure 10 depicted
in Figure 2.
Before the addition of chiral amine 7, n-BuLi exists mostly as
hexamer (−0.92 ppm)20 and a small amount of n-BuLi/ n-
butoxide (n-BuOLi) mixed aggregate (at approximately −0.55
ppm). Alkyllithium reagents are known to form mixed
aggregates with lithium alkoxide.8,12,21 Upon addition of chiral
amine 7, a new peak at −0.50 ppm increases significantly
simultaneously with a decrease of the peaks due to the hexamer
of n-BuLi. When the mole ratio of lithiated chiral amine 7 to n-
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1
Figure 3. H DOSY of mixed aggregate 10 in toluene-d8 at −40 °C.
Figure 4. Crystal structure of mixed aggregate 2a.
1
The H{6Li} HMBC spectrum confirms the formation of a
weight of mixed aggregate 10 is 667 g/mol, a 2.4% difference
from the expected formula weight of the 2:2 mixed aggregate
10 (683.3 g/mol). Details of the D-FW experiment are outlined
in the Supporting Information..
6
mixed aggregate because both sharp peaks in the Li correlate
to the protons of lithiated chiral amine 7 and the α-methylene
protons of n-BuLi. 1H and 13C NMR experiments including 1H
NMR, 13C NMR, COSY, HSQC, HMBC confirm the H and
1
Overall, our NMR experiments confirm that when the mole
ratio of chiral lithium amide to n-BuLi is approximately 1:1, the
solution structure of the mixed aggregate between lithiated,
chiral amine 7 and n-BuLi in toluene is the 2:2 mixed aggregate
10. This resembles the structure of mixed aggregate 6b.
Previously we reported that lithiated chiral amine 1b forms
the 2:1 mixed trimer 2a with n-BuLi, whereas lithiated chiral
amine 5, with simple substitution of the R1 isopropyl group of
1b to an ethyl group, forms 2:2 mixed aggregate 6b.
Interestingly, the results of this study illustrate that lithiated
chiral amine 7, with simple replacement of the R2 isopropyl
group of 1b to a methyl group, also forms a 2:2 mixed
aggregate. This latter substitution represents a change from
valine to alanine as the starting substrate. This observation
13C chemical shift assignments given in the Supporting
Information.22
To distinguish a 2:2 mixed aggregate from a 1:1 mixed
aggregate, diffusion-ordered NMR spectroscopy and diffusion
coefficient-formula weight (D-FW) correlation analysis were
performed.15,16,17a,23 In this experiment, benzene (BEN, 78.11
g/mol), cyclooctene (COE, 110.2 g/mol), 1-tetradecene (TDE,
196.4 g/mol), and squalene (SQU, 410.7 g/mol) were added to
the sample solution as internal molecular weight references. As
1
seen in the H DOSY spectrum (Figure 3), the α-methylene
protons of n-BuLi and distinct peaks from lithiated chiral amine
7 have very similar diffusion coefficients. This result establishes
complexation between the lithiated chiral amine 7 and n-BuLi.
From the D-FW experiment, the average predicted formula
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Figure 5. Crystal structure of mixed aggregate 6a.
prompted us to compare the crystal structures of 2a13b and 6a16
more carefully.
As depicted in Figures 4 and 5, the distances from C(3) and
C(1′) carbon to C(1) (Scheme 4) in structure 6a are 2.92 and
steric effect between R1, R2 groups and C(1) methylene group
is significantly reduced when a 2:1 mixed trimer is formed
instead of a 2:2 mixed aggregate. Thus, we propose that the
steric bulk of the R1 and R2 groups, especially the hindrance on
the C(3) and C(1′) carbons, predetermines the formation of
2:2 mixed aggregate or 2:1 mixed trimer. With relatively less
hindered R1 and R2 groups, lithiated chiral amines 5 and 7 form
2:2 mixed aggregates with n-BuLi, while lithiated chiral amines
1a and 1b containing relatively hindered R1 and R2 groups form
2:1 mixed trimers with n-BuLi. To verify our hypothesis, we
synthesized and characterized lithiated chiral amine 8, which
has an isobutyl R2 group and is sterically less hindered than
chiral amine 1b in its C(3) position.
Scheme 4. Numbering and Labeling Scheme of Chiral
Amines
Solution State Characterization of the Mixed Aggre-
gates of Lithiated Chiral Amine 8 and n-BuLi (12 and
13). Chiral amine 8 was easily synthesized from (S)-leucine in
three steps. The sample for NMR studies was prepared by
titrating (S)-N-isobutyl-3-methyl-1-((triisopropylsilyl)oxy)-
2.57 Å, respectively, while the corresponding distances in
structure 2a are 3.74 and 2.54 Å, respectively. Therefore, the
1
Figure 6. H NMR spectra of chiral amine 8 titration of 0.2 M n-Bu6Li toluene-d8 solution at −40 °C. H represents the resonance of n-Bu6Li in
hexamer; I represents the resonances of impurities and mixed aggregates of n-Bu6Li and n-BuO6Li; 11 represents the resonances of the 2:2 mixed
aggregate 11; 12 represents the resonances of the 2:1 mixed trimer 12.
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Figure 7. Li NMR spectra of chiral amine 8 titration of 0.2 M n-Bu6Li toluene-d8 solution at −40 °C. H represents the resonance of n-Bu6Li in
hexamer; I represents the resonances of impurities and mixed aggregates of n-Bu6Li and n-BuO6Li; 11 represents the resonances of the 2:2 mixed
aggregate 11; 12 represents the resonances of the 2:1 mixed trimer 12.
1
Figure 8. H{6Li} HMBC of 11 and 12 in toluene-d8 at −40 °C.
6
butan-2-amine 8 into a toluene-d8 solution of Li labeled n-
butyllithium at −40 °C. The number of peaks is double the
number of peaks of nonlithiated chiral amine 8, implicating the
formation of more than one type of lithiated, chiral-amine
peaks correspond to 2:1 mixed trimer 12 as depicted in Figure
7.
To verify the existence of the putative mixed aggregates 11
and 12, we obtained the 1H {6Li} HMBC spectrum. As
depicted in Figure 8, Li(1) shows a strong correlation to the α-
methylene protons of n-BuLi (−0.52 ppm) and the proton of
the methine (3.16 ppm) group adjacent to nitrogen. Addition-
ally, Li(2) also shows a strong correlation to the α-methylene
protons of n-BuLi and one of the protons of the methylene
(3.42 ppm) group adjacent to oxygen. Moreover, Li(3) shows a
6
aggregate, see Figure 6. The Li NMR shows very clearly the
emergence and rise of two downfield sharp peaks with 1:1
intensity upon addition of chiral amine 8, as well as two sharp
peaks with 1:2 intensity slightly upfield of the 1:1 sharp peaks,
see Figure 7. From our previous work,13,16 we postulate that the
1:1 peaks correspond to 2:2 mixed aggregate 11 and the 1:2
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strong correlation to the proton of the methine (2.98 ppm)
group adjacent to nitrogen while Li(4) shows a strong
correlation to the α-methylene protons of n-BuLi (−0.58
ppm) and the proton of the methine (3.12 ppm) group
adjacent to nitrogen. These results are consistent with Li(1)
and Li(2) representing the 2:2 mixed complex 11 between n-
BuLi and the lithiated chiral amine 8 and Li(3) and Li(4)
representing the 2:1 mixed trimer 12.
consequence of the interaction of C(6) with two equivalent 6Li
atoms.
Four distinct peaks of the two different putative complexes
from δ 2.9 to δ 4.1 ppm were utilized for our D-FW analysis
because other resonances overlapped. The 1H DOSY spectrum
(Figure 10) shows that the putative complexes diffuse
considerably slower than squalene, indicating that the formula
weights of these complexes are significantly higher than the
formula weight of squalene.
This D-FW experiment yields a predicted formula weight of
712 g/mol for the 2:2 mixed aggregate 11 and an average
predicted formula weight of 758 g/mol for the mixed aggregate
12. These results differ by 7.2% from the expected formula
weight of the 2:2 mixed aggregate 11 (765.5 g/mol) and 7.7%
from the expected formula weight of the 2:1 mixed aggregate
11 (704.4 g/mol). Thus, these D-FW experiments unambig-
uously define the aggregation state of the species in solution
with molecular weights in the range 700−750. However, these
D-FW results alone cannot distinguish between the aggregates
11 and 12.
1
1
A series of H and 13C NMR experiments including H
1
NMR, 13C NMR, COSY, HSQC, HMBC confirm the H and
13C chemical shift assignments of complexes 11 and 12.22
Notably the α-methylene carbon (carbon atom 1) of n-BuLi
within the mixed aggregate 11 is a quintet (J = 10.2 Hz) at 11.7
ppm (Figure 9). This suggests that C(1) of n-BuLi interacts
Taken together, our NMR data support the existence of both
2:2 mixed aggregate 11 and 2:1 mixed trimer 12 between
lithiated chiral amine 8 and n-BuLi in toluene when the mole
ratio of n-BuLi to chiral lithium amide 8 is more than 1:1.5.
Solution State Characterization of the Mixed Aggre-
gate of Lithiated Chiral Amine 9 and n-BuLi 13 and
Homodimer 14. Chiral amine 9 was synthesized from (R)-
phenylglycine in three steps. Compound 9 is more sterically
hindered than chiral amine 8 at the C(3) position. An NMR
sample was prepared by titrating (R)-N-(1-phenyl-2-
((triisopropylsilyl)oxy)ethyl)propan-2-amine into a toluene-d8
Figure 9. 13C NMR of carbon atoms 1 and 7 of mixed aggregates 11
and 12 in toluene-d8 at −40 °C.
6
solution of Li labeled n-butyllithium at −40 °C. The number
of peaks in the 2.9−4.5 ppm region is double the number of
peaks of nonlithiated chiral amine 9, suggesting that lithiated
chiral amine 9 forms more than one type of aggregate, see
6
with two Li atoms. Moreover, as depicted in Figure 9, the α-
methylene carbon (carbon atom 7) of n-BuLi within the mixed
aggregate 12 at 13.7 ppm is also a quintet (J = 10.4 Hz) as a
6
Figure 11. As depicted in Figure 12, the Li NMR also shows
1
Figure 10. H DOSY of mixed aggregates 11 and 12 in toluene-d8 at −40 °C.
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Figure 11. H NMR spectra of chiral amine 9 titration of 0.2 M n-Bu6Li toluene-d8 solution at −40 °C. H represents the resonance of n-Bu6Li in
hexamer; I represents the resonances of impurities and mixed aggregates of n-Bu6Li and n-BuO6Li; 13 represents the resonances of the 2:1 mixed
trimer 13; 14 represents the resonances of homodimer 14.
6
Figure 12. Li NMR spectra of chiral amine 9 titration of 0.2 M n-Bu6Li toluene-d8 solution at −40 °C. H represents the resonance of n-Bu6Li in
hexamer; I represents the resonances of impurities and mixed aggregates of n-Bu6Li and n-BuO6Li; 13 represents the resonances of the 2:1 mixed
trimer 13; 14 represents the resonances of homodimer 14.
very clearly the emergence and rise of two sharp peaks with 1:2
intensity upon addition of chiral amine 9, as well as a minor
sharp peak slightly upfield of the 1:2 peaks. These three sharp
peaks dominate when the mole ratio of lithiated chiral amine 9
to n-BuLi equals 1:0.9. These results are similar to the titration
results of chiral amine 1b with n-BuLi.13,15 Thus, we suggest
that the 1:2 peaks correspond to the 2:1 mixed trimer 13 and
the minor upfield peak corresponds to the homodimer 14..
The 1H{6Li} HMBC spectrum (see Figure S32 in Supporting
Information) shows a strong correlation from Li(1) to the
proton of the methine (4.26 ppm) group adjacent to nitrogen
while Li(2) shows a strong correlation to the α-methylene
protons of n-BuLi and the proton of another methine (2.91
ppm) group adjacent to nitrogen. Meanwhile, Li(3) shows a
strong correlation to the proton of methine groups (4.45, 3.07
ppm) adjacent to nitrogen. These results are consistent with
the assignment of Li(1) and Li(2) to the 2:1 mixed trimer 13
between n-BuLi and the lithiated chiral amine 9 and Li(3) to
the homodimer 14.
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All assignments of H and 13C resonances for aggregates 13
and R2 groups are summarized in Table 1. When R1 and R2
groups are relatively unhindered, a 2:2 mixed aggregate is the
and 14 are summarized in the Supporting Information. As
illustrated in Figure 13, the α-methylene carbon (carbon atom
Table 1. Aggregation States of Different Lithium Chiral
Amide/n-BuLi Complexes
R1 group
R2 group
aggregation state
isopropyl
ethyl
methyl
dominantly 2:2 mixed aggregate
dominantly 2:2 mixed aggregate
2:2 mixed aggregate and 2:1 mixed trimer
majorly 2:1 mixed trimer
isopropyl
isobutyl
phenyl
isopropyl
isopropyl
isopropyl
isopropyl
majorly 2:1 mixed trimer
Figure 13. 13C NMR of carbon atoms 1 of mixed trimer 13 in toluene-
d8 at −40 °C.
dominant species as with chiral amine 5 and 7. A 2:1 mixed
trimer is observed when the steric hindrance of R1 and R2
groups increases. Lithiated chiral amine 8 forms a significant
amount of both 2:2 mixed aggregate and 2:1 mixed trimer with
n-butyllithium. Further increase in the steric hindrance at C(3)
position inhibits the formation of 2:2 mixed aggregate;
therefore, lithiated chiral amines 1b and 9 preferably form
2:1 mixed trimers with n-butyllithium.
1) of n-BuLi of the putative mixed trimer 13 is a quintet (J =
10.1 Hz) at 13.5 ppm. This pattern indicates that carbon atom
6
1 in n-BuLi is J-coupled to two Li atoms.
Diffusion-ordered NMR spectroscopy (Figure 14) and D-
FW analysis reveal that the major peaks of the lithiated chiral
amine 9 from 2.9 to 4.3 ppm and n-butyllithium (−0.54 ppm)
diffuse at a very similar rate. The average experimentally
determined formula weight for the mixed aggregate 13 is 678
g/mol, an 8.8% difference from the expected formula weight for
the 2:1 mixed aggregate 13 (743.4 g/mol). Moreover, the
average experimentally determined formula weight for the
homodimer 14 is 649 g/mol, a 4.7% difference from the
expected formula weight of homodimer 14 (681.2 g/mol).
Overall, the combination of all these NMR experiments
supports the formation of the 2:1 mixed trimer 13 between
lithiated chiral amine 9 and n-BuLi, as well as the formation of
homodimer 14 in toluene when the mole ratio of n-BuLi to
chiral lithium amide is more than 1:0.9.
CONCLUSION
■
The size of R1 and R2 groups significantly influences the
aggregation state of the mixed complexes between lithiated
chiral amines and n-BuLi. When the R1 and R2 groups are
relatively unhindered, a 2:2 mixed aggregate dominants.
Increase in the steric hindrance of R1 and R2 groups inhibits
the formation of this 2:2 mixed aggregate and promotes the
formation of the 2:1 mixed trimer.
It is well-established that lithiated N-isopropyl-O-triisopro-
pylsilyl valinol 1b forms a 2:1 mixed trimer with n-BuLi and
that this mixed aggregate is responsible for the enantioselec-
tivity of asymmetric addition of n-BuLi in the mixed aggregate
to aldehydes.17 Hence, knowledge of the aggregation state of
The aggregation states of the mixed complexes between n-
butyllithium and different lithium chiral amides with various R1
1
Figure 14. H DOSY of mixed trimer 13 and homodimer 14 in toluene-d8 at −40 °C.
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mmol, 82.0%). H NMR (Tol-d8, 400 MHz) δ 3.65 (dd, 1H, J = 4.7,
9.5 Hz), 3.51 (dd, 1H, J = 4.4, 9.5 Hz), 2.92 (septet, 1H, J = 6.2 Hz),
2.70 (m, 1H), 1.83 (m, 1H), 1.41−1.29 (m, 2H), 1.13−1.00 (m, 28H),
0.99−0.92 (m, 6H). 13C NMR (Tol-d8, 100 MHz) δ 66.4, 54.8, 46.1,
43.3, 25.5, 24.7, 24.1, 24.0, 23.4, 18.7, 12.8. HRMS-ESI m/z: [M + H]+
calcd for C18H42NOSi, 316.3036; found, 316.3035.
mixed aggregates is crucial in unveiling the origin of the
enantioselectivity of chiral lithium amides. Moreover, the ability
to predict the formation of different mixed aggregates enables
us to design chiral amines with desired enantioselectivity most
efficiently. Extensive work on both enantioselectivity and
mechanism of the asymmetric addition of the alkyllithium
moiety to electrophiles using these chiral lithium amide/
alkyllithium mixed aggregates to various electrophiles is in
progress.
Synthesis of (R)-N-(1-Phenyl-2-((triisopropylsilyl)oxy)ethyl)-
propan-2-amine 9. (R)-N-(1-Phenyl-2-((triisopropylsilyl)oxy)-
ethyl)propan-2-amine 8 was synthesized using the same method
described above from N-isopropyl (R)-phenylglycinol (2.40 g, 13.4
mmol). Purification (bp = 163 °C, 5 mm Hg) gave a colorless oil (3.58
g, 10.7 mmol, 79.6%). 1H NMR (Tol-d8, 400 MHz) δ 7.44 (d, 2H, J =
7.28 Hz), 7.24−7.10 (m, 3H), 3.99 (dd, 1H, J = 4.1, 8.9 Hz), 3.74 (dd,
1H, J = 4.1, 9.6 Hz), 3.71−3.59 (m, 1H), 2.71 (septet, 1H, J = 6.28
Hz), 1.75 (br, 1H), 1.12−0.97 (m, 27H). 13C NMR (Tol-d8, 100
MHz) δ 143.1, 128.9, 128.5, 127.9, 70.0, 63.8, 47.0, 25.2, 22.9, 18.6,
12.7. HRMS-ESI m/z: [M + H]+ calcd for C20HNOSi, 336.2723;
found, 336.2715.
EXPERIMENTAL SECTION
Procedures for NMR Experiments. NMR samples were prepared
in tubes sealed with rubber septa caps and parafilm. NMR tubes were
■
1
evacuated in vacuo, flame-dried, and filled with argon before use. H
chemical shifts were referenced to toluene-d8 at 7.09 ppm, and 13C
chemical shifts were referenced to toluene-d8 at 137.86 ppm. All NMR
experiments except DOSY experiments were acquired on a 600 MHz
spectrometer. DOSY experiments were acquired on a 600 or 400 MHz
spectrometer equipped with a z-axis gradient amplifier with a z-axis
gradient coil. Maximum gradient strength was 0.5 T/m and 0.214 T/
m, respectively. 1H DOSY was performed using the standard
programs, employing a double stimulated echo sequence, bipolar
gradient pulses for diffusion, and 3 spoil gradients. Diffusion time was
200 ms, and the rectangular gradient pulse duration was 700 μs
(lithiated chiral amine 8) and 1000 μs (lithiated chiral amine 7 and 9).
Gradient recovery delays were 200 μs. Individual rows of the quasi-2-D
diffusion databases were phased and baseline corrected. Actual
diffusion coefficients used for D-FW analysis were obtained using
the T1/T2 analysis module in commercially available software.
The 6Li labeled n-butyllithium samples were prepared by laboratory
Synthesis of n-Bu6Li. The n-Bu6Li solution was prepared in
heptane according to the method that our group has published
previously.15
ASSOCIATED CONTENT
■
S
* Supporting Information
Supplemental NMR spectra and data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
pgw@brown.edu
6
synthesized Li labeled n-butyllithium heptane solution. About 40 μL
Notes
of the 2.4 M n-butyllithium heptane solution was added via syringe to
a NMR tube. After the addition, the NMR tube was evacuated in vacuo
for 10−30 min at 0 °C in order to remove the heptane. After filling
with argon, toluene-d8 was added via syringe to bring the total volume
up to 500 μL.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported through NSF Grant 1058051. We
thank Mr. Chang Liu for synthesizing the chiral amines used in
this study.
The internal references (in a ratio of 1:3:3:1 for BEN, COE, TDE,
and SQU, respectively) were titrated into the NMR tube and
1
monitored by H NMR. The titration was stopped when the peak
intensity of benzene was about the same as the α-methylene protons of
n-BuLi for lithiated chiral amine 7, about 0.67 times the intensity as
the α-methylene protons of n-BuLi for lithiated chiral amine 8 and
about 1.5 times the intensity as the α-methylene protons of n-BuLi for
lithiated chiral amine 9.
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3254
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