Rare-Earth-Metal-Catalyzed Kinetic Resolution of Chiral Aminoalkenes via Hydroamination: The Effect of the Silyl Substituent of the Binaphtholate Ligand on Resolution Efficiency

Article abstract of DOI:10.1002/ejoc.201900107

The kinetic resolution of α-substituted aminopentenes via intramolecular hydroamination was investigated using various 3,3′-silyl-substituted binaphtholate yttrium catalysts. High efficiencies in the kinetic resolution were observed for methyl-, benzyl-, and phenyl-substituted substrates utilizing the cyclohexyldiphenylsilyl-substituted catalyst 2c with resolution factors reaching as high as 90(5) for hex-5-en-2-amine (3a). Kinetic analysis of the enantioenriched substrates with the matching and mismatching catalyst revealed that the efficiency of catalyst 2c benefits significantly from a favorable Curtin–Hammett pre-equilibrium and by a large k_fast/k_slow ratio. Other binaphtholate catalysts were less efficient due to a less favorable Curtin–Hammett pre-equilibrium, which often favored the mismatching substrate-catalyst combination. Cyclization of the matched substrate proceeds generally with large trans-selectivity, whereas the trans/cis-ratio for mismatched substrates is significantly diminished, favoring the cis-cyclization product isomer in some instances.

Full text of DOI:10.1002/ejoc.201900107

A Journal of
Accepted Article
Title: Rare-Earth Metal-Catalyzed Kinetic Resolution of Chiral
Aminoalkenes via Hydroamination: The Effect of the Silyl-
Substituent of the Binaphtholate Ligand on Resolution Efficiency
Authors: Hiep N Nguyen and Kai Hultzsch
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900107
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900107
Supported by

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
Rare-Earth Metal-Catalyzed Kinetic Resolution of Chiral
Aminoalkenes via Hydroamination: The Effect of the Silyl-
Substituent of the Binaphtholate Ligand on Resolution Efficiency
Hiep N. Nguyen[b] and Kai C. Hultzsch*[a]
Abstract: The kinetic resolution of -substituted aminopentenes via
intramolecular hydroamination was investigated using various 3,3’-
silyl-substituted binaphtholate yttrium catalysts. High efficiencies in
the kinetic resolution were observed for methyl-, benzyl-, and phenyl-
substituted substrates utilizing the cyclohexyldiphenylsilyl-substituted
catalyst 2c with resolution factors reaching as high as 90(5) for hex-
5-en-2-amine (3a). Kinetic analysis of the enantioenriched substrates
with the matching and mismatching catalyst revealed that the
efficiency of catalyst 2c benefits significantly from a favorable Curtin-
asymmetric intra-[12] and intermolecular[12e,f,13] hydroamination of
alkenes. In particular 3,3’-bis(silyl)-substituted binaphtholate rare-
earth metal complexes (Figure 1) exhibited high activity and
enantioselectivities of up to 96% ee in intramolecular reactions
and up to 66% ee in intermolecular reactions.[12d,f,13]
SiAr3
Me2N
SiR3
Me2N
O
O
O
O
Hammett pre-equilibrium and by
a large kfast/kslow ratio. Other
Ln
Y
binaphtholate catalysts were less efficient due to a less favorable
Curtin-Hammett pre-equilibrium, which often favored the mismatching
substrate-catalyst combination. Cyclization of the matched substrate
proceeds generally with large trans-selectivity, whereas the trans/cis-
ratio for mismatched substrates is significantly diminished, favoring
the cis-cyclization product isomer in some instances.
Me2N
Me2N
Ph
Ph
SiAr3
SiR3
Ph
2a
(R)- , SiR3
=
1a Ln
(R)-
-
, SiAr3 = SiPh3
(R)-1b-Ln, SiAr3 = Si(3,5-xylyl)3
Si
Ln = Sc, Y, Lu
2b
(R)- , SiR3 = Sit-BuPh2
(R)-2c, SiR3 = SiCyPh2
2d
(R)- , SiR3 = Si(iPr)3
Introduction
(R)-2e, SiR3 = SiCy2Ph
Nitrogen-containing compounds are widely found in nature and
biological systems; therefore, this class of organic compounds is
of high importance in fundamental research, as well as
pharmaceutical and chemical industry.[1] The metal-catalyzed
hydroamination of olefins, in which an amine N-H functionality
adds directly to an unsaturated carbon-carbon bond, provides one
of the simplest routes to amine products with 100% atom
efficiency.[2] Significant research efforts have resulted in the
development of a large variety of catalyst systems for the
hydroamination of olefins;[3–8] however, many challenges remain,
in particular with respect to asymmetric hydroamination
reactions.[9–11]
Figure 1. Rare-earth metal complexes based on 3,3’-bis(silyl)-binaphtholate
ligands for asymmetric hydroamination reactions.
Moreover, complexes 1a and 1b were also applied in the catalytic
kinetic resolution of chiral aminoalkenes via the asymmetric
hydroamination/cyclization (Scheme 1).[12c,d,f,14–17]
H
N
H
N
R
2 mol% (R)-cat.
R
NH2
+
[D6]benzene
R
We have developed biphenolate, binaphtholate and NOBIN-
based aminophenolate rare-earth metal catalysts for the
cis
(minor)
trans
(major)
ca. 50% conv.
R = alkyl, aryl
NH2
+
[a]
[b]
Univ.-Prof. Dr. K. C. Hultzsch
Universität Wien, Fakultät für Chemie,
Institut für Chemische Katalyse
Währinger Straße 38, 1090 Wien (Austria)
E-mail: kai.hultzsch@univie.ac.at
Homepage: https://chemcat.univie.ac.at/
Hiep N. Nguyen, PhD
R
(recovered)
Scheme 1. General scheme of the kinetic resolution of -substituted
aminoalkenes.
Rutgers, The State University of New Jersey
Department of Chemistry and Chemical Biology
610 Taylor Road, Piscataway, New Jersey 08854-8087, USA
Previously we have shown that resolution factors f as high as 19
can be achieved for a phenyl-substituted aminopentene using
(R)-1a-Lu at 40 °C (Scheme 1, R = Ph).[12d,15] The hydroamination
products of aryl-substituted aminopentenes using the
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
binaphtholate catalysts 1a and 1b displayed high trans:cis
diastereoselectivity of up to 50:1. Moreover, the kinetic study of
the kinetic resolution process revealed that the Curtin-Hammett
pre-equilibrium favors the matching substrate-catalyst complex
for α-substituted aminopentenes containing aryl substituents, as
indicated by a pre-equilibrium constant Kdias > 1 (vide infra).
However, the kinetic resolution of aminoalkene substrates
containing aliphatic substituents in the α-position of the amine
was significantly less efficient with these catalysts, primarily as a
result of a shifted Curtin-Hammett pre-equilibrium in favor of the
mismatching substrate-catalyst complex (Kdias < 1).
Herein we report the kinetic resolution process using the yttrium
catalysts (R)-2a−e[12f] based on binaphtholate ligands with a
variety of bulky trisarylsilyl-, trisalkylsilyl-, and alkylarylsilyl-
substituents in the 3 and 3’ position (Figure 1). Our previous
studies have shown that the sterically demanding silyl groups in
the binaphtholate catalysts are responsible for catalyst stability as
well as high catalytic activity and selectivity, but herein we will
show that subtle changes in these silyl-substituents can have a
significant influence on the kinetic resolution process, especially
on the Curtin-Hammett pre-equilibrium.
complexes 1 and 2 with a resolution factor f > 50[18] for 3a (Table
1, entry 4). Although the silyl groups in the 3 and 3’ positions of
the binaphtholate ligands had a pronounced effect on catalytic
activity as well as the resolution factors in the cyclization of 3a,
the trans:cis diastereoselectivities were rather unaffected,
showing consistently low ratios in the range of 7:1 to 9:1.
Higher trans:cis selectivities of up to 20:1 were observed for the
benzyl-substituted aminopentene 3b (Table 1, entries 6−9).
However, the cyclization of 3b proceeded at a much lower rate
using the tert-butyldiphenylsilyl-substituted binaphtholate catalyst
(R)-2b in comparison to (R)-1a-Y (42.3 h at 25 °C for (R)-2b vs 9
h at 22 °C for (R)-1a-Y to obtain 50% conversion; see Table 1,
entries 6 and 8). This is in contrast to our observation that (R)-2b
generally displayed similar catalytic activity as (R)-1a-Y in the
cyclization of aminopentenes.[12f] Despite the slow rate of
cyclization, (R)-2b resolved 3b more efficiently than (R)-1a-Y.
Similar to the previous observation, the resolution of 3b was
generally less efficient than the resolution of 3a with the same
rare-earth metal binaphtholate catalyst (for example, compare
Table 1, entry 4 and 9). Nevertheless, catalyst (R)-2c resolved 3b
with a still impressive resolution factor of 43.
The kinetic resolution of the phenyl-substituted aminopentene 3c
was performed at 40 °C using catalysts (R)-2a−e with good
turnover rates, giving consistently high trans:cis selectivities
≥50:1 (Table 1, entries 11−15). Complexes (R)-2a, (R)-2b, and
(R)-2c displayed similar catalytic activity in the cyclization of 3c
(Table 1, entries 11−13), but as for substrates 3a and 3b, the
highest resolution factor (f >50) was observed for the
cyclohexyldiphenylsilyl-substituted binaphtholate complex (R)-2c.
As expected, the triisopropylsilyl-substituted binaphtholate
catalyst (R)-2d exhibited the lowest activity as well as the lowest
efficiency in the resolution of 3c (Table 1, entry 14) in agreement
to its general performance in the hydroamination/cyclization of
Results and Discussion
Previously we had observed that the cyclization of -substituted
aminopentenes proceeds significantly faster using the
triphenylsilyl-substituted
binaphtholate
catalyst
(R)-1a-Y
compared to (R)-1a-Lu and that (R)-1a-Y displayed slightly higher
efficiency in the kinetic resolution of the sterically less demanding
substrate 3a in comparison to the smaller ionic radius metal
complex (R)-1a-Lu (Table 1, entries 1, 2).[12c,d,15] We therefore
decided to focus our kinetic resolution studies on the more active
and presumably more efficient yttrium catalysts (R)-2a−e. A broad
range of substrates for intra- and intermolecular asymmetric
hydroamination reactions unrelated to the kinetic resolution
process has been reported for these catalysts recently.[12f] For the
purpose of this study we investigated the kinetic resolution of the
racemic α-substituted 1-aminopent-4-enes 3a−d (Table 1). These
substrates feature aliphatic as well as aromatic substituents which
had been kinetically resolved with low (resolution factor f = 2–6
for 3b, 3d) to moderate (f = 6–19 for 3a, 3c) efficiency using
catalysts (R)-1a-Ln and (R)-1b-Ln.[12c,d,15]
achiral
aminopentenes.[12f]
The
dicyclohexylphenylsilyl-
substituted complex (R)-2e exhibited the highest activity in the
cyclization of 3c at three times the rate compared to (R)-2a–c
(Table 1, entries 11–13 vs entry 15), but unfortunately at the
expense of resolution efficiency.
Previous studies have shown that the sterically more demanding
α-alkyl substrates, such as the benzyl-substituted 3b and the
cyclohexyl-substituted 3d exhibit significantly diminished
resolution
factors
using
the
bis(triarylsilyl)-substituted
binaphtholate catalysts (R)-1a-Ln and (R)-1b-Ln.[15] This
observation is also true for 3d using the cyclohexyldiphenylsilyl-
substituted binaphtholate catalyst (R)-2c (Table 1, entry 19).
Interestingly, the least reactive, triisopropylsilyl-substituted
catalyst (R)-2d resolved 3d most effectively among our available
binaphtholate catalysts, with a resolution factor of 8.9 (Table 1,
entry 20). Among all the tested substrates, cyclization of 3d
proceeded with the lowest trans:cis diastereoselectivity in the
range of 5:1−10:1.
(Insert Table 1 here)
For the sterically least demanding methyl-substituted
aminopentene 3a, the structurally rigid dibenzosilole-substituted
complex (R)-2a was more efficient than the triphenylsilyl-
substituted binaphtholate catalysts (R)-1a-Y and (R)-1a-Lu
(Table 1, entries 1–3). The sterically more demanding
dicyclohexylphenylsilyl-substituted binaphtholate complex (R)-2e
showed significantly diminished kinetic resolution efficiency
(Table 1, entry 5), while exhibiting a significant higher rate of
cyclization in comparison to the other catalysts. Remarkably, the
cyclohexyldiphenylsilyl-substituted binaphtholate complex (R)-2c
was significantly more efficient than all other binaphtholate
In order to identify the factors governing the high efficiency of the
cyclohexyldiphenylsilyl-substituted binaphtholate complex (R)-2c
in the kinetic resolution process, we started a more detailed
investigation of the kinetic resolution of aminoalkenes using the
general model (Scheme 2).[12d,15,19]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
Kdias = kSR/kRS
kSR
[R]
+
[cat-S]
[cat-R]
+
[S]
kRS
kR
kS
(R)-product
(S)-product
Scheme 2. The general model for the kinetic resolution of aminoalkenes ([S],
[R] = substrate enantiomers; [cat-S], [cat-R] = substrate-catalyst complex of
respective substrate enantiomer).
The two diastereomeric substrate-catalyst complexes [cat-S] and
[cat-R] readily interconvert with an equilibrium constant Kdias (Eq.
1) and each of the complexes reacts with a corresponding rate
constant (kR and kS) to give the corresponding hydroamination
products. The rate of interconversion between the two substrate-
catalyst complexes is rapid even at low temperatures and
significantly higher than both rates of cyclization.[12d]
Figure 3. Dependence of enantiomeric excess of recovered starting material on
conversion in the kinetic resolution of 3a with (R)-2c at 25 °C. The line was fitted
to a resolution factor f = 90.
Inspired by the high resolution factor for the methyl-substituted
aminopentene 3a obtained with the cyclohexyldiphenylsilyl-
substituted binaphtholate catalyst (R)-2c at 25 °C, a large-scale
kinetic resolution of 3a was performed with (S)-2c, giving (S)-3a
(95% ee) in 38% re-isolated yield at 52% conversion. The yield of
(S)-3a is lower than expected due to its volatility (b.p. 114−116 °C
at 760 Torr). The enantioenriched α-substituted aminopentenes
3b−3d were also prepared using (R)-2c and the resolution data
are summarized in Table 2.
ꢉ
ꢏꢉ ꢏ
ꢆꢇꢈ
ꢊꢋꢌ ꢍ ꢎ ꢐ
ꢀꢁꢂꢃꢄ
ꢅ
ꢅ
(1)
ꢉ
ꢏꢉ ꢏ
ꢊꢋꢌ ꢍ ꢐ ꢎ
ꢆꢈꢇ
The resolution factor f is determined by the equilibrium constant
Kdias and the cyclization rate constants of the two diastereomeric
substrate-catalyst complexes (Eq. 2),[20] which may be
determined independently.
ꢆꢈ
ꢑ ꢅ ꢀꢁꢂꢃꢄ
(2)
ꢆꢇ
For pseudo-first-order reactions the resolution factor can be
expressed as a function of conversion C and ee of recovered
substrate (Eq. 3).[19]
Table 2. Large-scale preparation of enantioenriched α-substituted
aminopentenes via kinetic resolution using binaphtholate catalyst 2c.[a]
ꢉꢔ
ꢖꢔ
ꢖꢏ
ꢖꢏ
ꢒꢓ 1 ꢍ ꢕ
1
ꢗꢗ
(3)
ꢑ ꢅ
ꢉꢔ
ꢖꢔ
ꢒꢓ 1 ꢍ ꢕ 1 ꢍ ꢗꢗ
Subst.
Cat.
T [°C]
t [h]
f[b]
Conv.
[%]
Yield
(ee,
According to Eq. 3, the resolution factor f for 3a using the
binaphtholate catalyst (R)-2c can be determined by plotting
ln[(1−C)(1−ee) vs ln[(1−C)(1+ee) (Figure 2). The relationship
between conversion and enantiomeric excess ee is expressed by
Figure 3.
config.) [%][c]
38 (95, S)
40 (95, S)
40 (97, S)
18 (95, S)
3a
3b
3c
3d
(S)-2c
(R)-2c
(R)-2c
(R)-2c
25
25
40
25
9
90(5)
43
52
57
54
77
22.5
31
>50
9.5
5.6(3)
[a] General reaction conditions: 0.8–1.5 g racemic aminoalkene ([sub.] =
0.9–1.3 M), 2 mol% cat., benzene, Ar. [b] Taken from Table 3 (for 3a and
3d) and Table 1 (for 3b and 3c). [c] Isolated yield and ee value of recovered
(S)-3. All recovered aminoalkenes have (S) configuration, because the CIP
priorities differ between substrate 3a on the one side and substrate 3b−d on
the other side. Thus, the (S)-catalyst enantiomer is the matching catalyst for
substrate (R)-3a, while it is the (R)-catalyst enantiomer for substrates (R)-
3b−d.
The rate constants kfast and kslow for the cyclization of the matching
and mismatching substrate-catalyst combination, respectively,
were obtained via kinetic measurements of the cyclization rates
of enantioenriched (S)-3a using (R)-2c (Figure 4) in the
temperature range of 25–50 °C for the faster matching substrate-
catalyst combination, respectively the cyclization of (S)-3a using
(S)-2c (Figure 5) in the temperature range of 25–55 °C for the
slower mismatching substrate-catalyst combination.
Figure 2. Plot of ln[(1−C)(1−ee) versus ln[(1−C)(1+ee) for the kinetic resolution
of 3a using binaphtholate catalyst (R)-2c at 25 °C.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
in the cyclization of (S)-3a using (R)-2c (Figure 6, trace a,
trans/cis = 39:1 for the matching substrate-catalyst pair) and (S)-
3a using (S)-2c (Figure 6, trace b, trans/cis = 1:1.2 for the
mismatching substrate-catalyst pair) account for the low trans/cis
selectivities observed in the kinetic resolution of racemic 3a
(trans/cis = 7−9:1, Table 1, entries 3–5). Additionally, the trans/cis
ratios decrease gradually as the resolution reaction proceeds
(Figure 7). It is noteworthy that the reaction of (S)-3a using (S)-2c
(mismatching substrate-catalyst pair) preferentially produced the
cis-product at all reaction temperatures in the range of 25−50 °C
(Table 3, entries 3−6).
(Insert Table 3 here)
Figure 4. Time dependence of the substrate concentration in the
hydroamination of (S)-3a using (R)-2c (matching pair; [(S)-3a]0 = 0.140 mol L−1
,
[(R)-2c] = 2.73 mmol L−1). The straight lines represent the least square linear
regression.
Figure 6. 1H NMR spectra of hydroamination products 4a obtained with the
matching substrate-catalyst pair (S)-3a and (R)-2c (trace a) and with the
mismatching substrate-catalyst pair (S)-3a and (S)-2c (trace b).
Figure 5. Time dependence of the substrate concentration in the
hydroamination of (S)-3a using (S)-2c (mismatching pair; [(S)-3a]0 = 0.140 mol
L−1, [(S)-2c] = 2.73 mmol L−1). The straight lines represent the least square linear
regression.
The kinetic data and resolution parameters of α-substituted
aminopentenes were determined with the alkylarylsilyl-substituted
binaphtholate catalysts 2b, 2c, and 2e (Table 3). In agreement
with the kinetic measurements reported previously for the methyl-
substituted 3a using the triphenylsilyl-substituted binaphtholate
catalyst 1a-Y,[15] the Curtin-Hammett pre-equilibrium favors the
mismatching substrate-catalyst combination (Kdias < 1) when 3a is
paired with catalysts 2b and 2e (Table 3, entries 1, 2 and 7). On
the contrary, the equilibrium for the cyclohexyldiphenylsilyl-
substituted binaphtholate catalyst 2c and substrate 3a favors the
matching substrate-catalyst complex (Kdias > 1); thus, effectively
enhancing the efficiency of the kinetic resolution process. The
relative rate kfast/kslow remains in the range of 9.1(3)−18.9(2) for
the methyl-substituted aminopentene 3a with our novel
binaphtholate catalysts 2b, 2c, and 2e at temperatures ranging
from 25 to 50 °C, with the highest ratio being achieved with 2c at
25 °C. Dramatic differences in the trans/cis diastereoselectivities
Figure 7. Trans/cis ratio of 4a formed in the kinetic resolution of rac-3a using 2
mol% of (R)-2c at 25 °C as a function of conversion. The line is drawn as a
guide for the eye.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
In agreement to the observations for 3a, the mismatching
substrate-catalyst combination was favored in the Curtin-
Hammett pre-equilibrium in the resolution of the benzyl-
substituted aminopentene 3b with catalyst 2b (Table 3, entry 9).
The high efficiency in the kinetic resolution of 3b with 2c was
achieved through a combination of high relative rate, kfast/kslow
,
and a Curtin-Hammett pre-equilibrium in favor of the matching
substrate-catalyst pair (Kdias > 1) (Table 3, entry 10). Although the
pre-equilibrium was slightly in favor of the matching substrate-
catalyst pair for catalyst 2e, the low kfast/kslow ratio resulted in an
overall low efficiency of the kinetic resolution of substrate 3b
(Table 3, entry 11). While the diastereoselectivities remained high
for the matching pair of substrate (S)-3b and the (S)-catalyst,
significantly lower trans/cis diastereoselectivities were observed
for the mismatching pair with all tested catalysts (Table 3, entries
9–11), in contrast to previous observations for catalyst (S)-1a-
Y.[15]
Figure 8. Eyring plot for the hydroamination/cyclization of (S)-3a using (R)-2c
(matching pair) and (S)-2c (mismatching pair).
High diastereoselectivities of up to 50:1 were observed for the
phenyl-substituted aminopentene 3c with all binaphtholate
catalysts (Table 3, entries 12–16). Although the cyclization rate of
the matching substrate-catalyst pair, involving substrate (S)-3c
and catalyst (S)-1a-Y, was about three times faster than that of
(S)-3c and (S)-2c at 60 °C, a higher kfast/kslow ratio was observed
for 3c with 2c (kfast/kslow = 15.7(7) vs 7.1 with 1a-Y) (Table 3,
entries 12 and 14). As a result, the cyclohexyldiphenylsilyl-
substituted binaphtholate catalyst 2c was more efficient in the
kinetic resolution of 3c in comparison to 1a-Y.
Stereomodel for the kinetic resolution of α-substituted
aminopentenes. According to the proposed stereomodel for the
kinetic resolution of α-substituted aminopentenes using
binaphtholate rare-earth metal catalysts, the diastereomers can
be obtained via possible cyclization pathways as depicted in
Scheme 3.[12d,15]
Kdias
The alkylarylsilyl-substituted binaphtholate catalysts 2b, 2c, and
2e behaved quite differently in the kinetic resolution of the
cyclohexyl-substituted aminopentene 3d compared to the
triphenylsilyl-substituted binaphtholate catalyst 1a-Y. The
NH2
L
L
O
O
O
O
H
H
R
R
N
Y
N
Y
*
*
NH2
R
R
k
fast/kslow ratios were significantly lower for 2b, 2c, and 2e
mismatched
kslow
matched
kfast
B
C
A
compared to 1a-Y; however, this deficiency is overcompensated
by a Curtin-Hammett pre-equilibrium in favor of the matching
substrate-catalyst pair for 2b, 2c, and 2e (Kdias > 1), whereas in
case of 1a-Y[15] the pre-equilibrium favors the mismatching
substrate-catalyst pair (compare Table 3 entries 18–20 with entry
17). As a result, 2b, 2c, and 2e are slightly more efficient catalysts
for the kinetic resolution of 3d in comparison to 1a-Y.
R
R
HN
NH
HN
Y
H
R
Y
Y
L
L
L
The Eyring plot for kfast and kslow (Figure 8) provided an access to
the activation parameters for the hydroamination/cyclization of
H
H
H
N
N
N
R
R
R
(S)-3a using (R)-2c (matching substrate-catalyst pair) (ΔH‡
=
minor
43(6) kJ mol−1, ΔS‡ = −137(18) J mol−1 K−1). Because the reaction
of (S)-3a and (S)-2c (mismatching substrate-catalyst pair)
afforded the products with low trans/cis diastereoselectivities, the
activation parameters for each diastereomer were obtained
(trans: ΔH‡ = 52(3) kJ mol−1, ΔS‡ = −138(8) J mol−1 K−1; cis: ΔH‡
= 52(5) kJ mol−1, ΔS‡ = −135(16) J mol−1 K−1). The activation
parameters for the matching and mismatching seem to be in a
similar range to those obtained previously for 3a with catalyst 1a-
Y (matching pair: ΔH‡ = 47.3(3.5) kJ mol−1, ΔS‡ = −128(11) J mol−1
K−1; mismatching pair: ΔH‡ = 54.9(3.1) kJ mol−1, ΔS‡ = −121(9) J
mol−1 K−1).[15] The negative activation entropy is indicative of a
highly organized transition state.[12d,15,21]
trans
(2R,5R) for 4a
(2R,5S) for 4b–d
cis
major
(2S,5S) for 4a
(2S,5R) for 4b–d
(2S,5R) for 4a
(2S,5S) for 4b–d
Scheme 3. Proposed stereomodel for the kinetic resolution of α-substituted
aminopentenes with (R)-binaphtholate yttrium catalysts.[12d,15] L = aminoalkene
substrate or hydroamination product
The stereomodel for the kinetic resolution is in agreement with the
general stereomodel for enantioselective intramolecular
hydroamination of aminopentenes by (R)-binaphtholate rare-
earth metal catalysts, in which the Ln−N bond preferentially
approaches the re face of the olefin.[12d] In case of the matching
substrate-catalyst pair, the α-substituent of the aminoalkene rests
in an equatorial position of the seven-membered chair-like
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
transition state in the conformation that facilitates the approach of
the Ln−N bond to the olefin from the re face (Scheme 3, pathway
C). In case of the mismatching substrate-catalyst combination,
the sterically unfavorable interaction between the substrate and
the alkylarylsilyl-substituent of the binaphtholate ligand restricts
the approach of the Ln−N bond to the olefin from the si face
(Scheme 3, pathway A). Pathway B provides an alternative to
pathway A, allowing the mismatching substrate-catalyst complex
to avoid the steric interaction between the substrate and the bulky
silyl group. However, pathway B requires the α-substituent of the
aminopentene to rest in an axial position, which leads to an
unfavorable 1,3-diaxial interaction in the chair-like transition state
and possibly steric interaction between the α-substituent R of the
substrate and an alkylarylsilyl-substituent of the binaphtholate
ligand, if the α-substituent R is sufficiently large.
equilibrium in favor of the matching substrate-catalyst
combination and a high kfast/kslow ratio.
Experimental Section
General Considerations. All operations were performed under an inert
atmosphere of nitrogen or argon using standard Schlenk-line or glovebox
techniques. Solvents and reagents were purified as stated previously.[12d]
Complexes 2a–2e,[12f] substrates hex-5-en-2-amine (3a),[23] 1-phenylhex-
5-en-2-amine (3b),[12d] 1-phenylpent-4-en-1-amine (3c),[12d] and 1-
cyclohexylpent-4-en-1-amine (3d),[15] were prepared according to
previously described procedures. The substrates were distilled twice from
finely powder CaH2, stored over molecular sieves, and kept in the fridge of
a
glovebox. (S)-(+)--Methoxy--trifluoro-methylphenylacetic acid
(Mosher acid) was transformed to the corresponding (R)-Mosher acid
chloride using oxalyl chloride/DMF in hexanes.[24] Enantiomeric excess for
3a–3d was measured by 19F NMR spectroscopy of the corresponding
Mosher amides as reported previously.[12d,15]
Pathway
B
accounts for the significantly reduced
diastereoselectivities which were observed for the mismatching
substrate-catalyst combinations when using catalysts 2b, 2c, and
2e. Moreover, the cyclization of the mismatching substrate-
catalyst pairs (S)-3a with (S)-2c, (S)-3d with (S)-2b, and (S)-3d
with (S)-2c generated predominantly the cis-pyrrolidine products;
General procedure for NMR-scale kinetic resolution of chiral α-
substituted aminopentenes. In a glove box, a screw cap NMR tube was
charged with racemic aminoalkene (20.0 mg, 0.10−0.20 mmol), ferrocene
(3.0 mg, 16.1 µmol), [D6]benzene (to give a total volume of 0.5 mL), and
catalysts (2.0 mol% with respect to racemic aminoalkene, 2.0−4.0 µmol,
0.060 M in [D6]benzene). The NMR tube was capped, immediately
removed from the glovebox, and shaken well to dissolve ferrocene. The
reaction mixture was heated in a thermostatic oil bath, if required. The
conversion was monitored by 1H NMR spectroscopy by following the
disappearance of the olefinic signals of the substrate relative to the internal
standard ferrocene. The reaction was stopped after ca. 50% conversion
was achieved. The aminoalkene starting material was isolated in form of
the hydrochloride salt and enantiomeric excess was determined using the
previously reported procedure.[12c,d]
thus, pathway
B becomes the preferred pathway. The
exceptionally high efficiency in the kinetic resolution of the methyl-
substituted aminopentene 3a with 2c results from the Curtin-
Hammett pre-equilibrium in favor of the matching substrate-
catalyst complex and a high kfast/kslow ratio.
The large trans/cis diastereoselectivities, exceeding 50:1,
observed for the phenyl-substituted aminopentene 3c in
comparison to the alkyl-substituted aminopentenes 3a, 3b, and
3d, may result from a coordinative interaction of the phenyl-
substituent of 3c with the metal center[22] or a π-interaction of the
phenyl-substituent with a naphthyl ring of the binaphtholate ligand.
General procedure for preparation of chiral α-substituted
aminopentenes by kinetic resolution. In a glovebox, a 20 mL vial was
charged with the racemic aminoalkenes (3c: 0.80 g, 5.0 mmol; 3a, 3b, and
3d: 1.50 g, 8.0−9.0 mmol), benzene (5.0 mL), and 2c (0.5−0.9 mL of
solution, 0.20 M in benzene, 0.10−0.18 mmol, 2.0 mol%). The vial was
kept at 25 °C (3a, 3b, and 3d) or heated to 40 °C (3c). Small aliquots (20
µL) were syringed to NMR tubes, which was then diluted with CDCl3 (0.55
mL), and a 1H NMR spectrum was recorded to monitor the conversion. The
reaction was stopped after enantiomeric excess of the starting material
reached at least 95 %ee, determined by 19F NMR spectroscopy of its
corresponding Mosher amide at 40−65°C. The chiral α-substituted
aminopentenes were isolated by the standard benzaldimine work-up
procedure[12c,d] and were purified by vacuum distillation from CaH2.
Conclusions
The kinetic resolution of α-substituted aminopentenes via
asymmetric hydroamination/cyclization was studied using rare-
earth metal catalysts based on 3,3’-bis(alkylarylsilyl)-substituted
binaphtholate ligands. In general the cyclohexyldiphenylsilyl-
substituted binaphtholate catalyst (R)-2c displays high efficiency
in the kinetic resolution of the methyl-, benzyl-, and phenyl-
substituted substrates 3a, 3b, and 3c, respectively. The highest
resolution factor of up to 90(5) was observed for 3a using (R)-2c.
Despite having a favorable Curtin-Hammett pre-equilbrium, the
cyclohexyl-substituted aminopentene 3d exhibits low efficiency in
the kinetic resolution with all binaphtholate catalysts screened in
this study as a result of a low kfast/kslow ratio.
The activation parameters for the cyclization of (S)-3a with
complex (R)-2c (matching substrate-catalyst pair) and (S)-3a with
complex (S)-2c (mismatching substrate-catalyst pair) are in line
with the previously reported data obtained for the cyclization of 3a
using complex 1a-Y.[15] It is noteworthy that the mismatching
substrate-catalyst combination of (S)-3a and (S)-2c preferentially
affords the cis-product. The kinetic resolution parameters show
that high efficiency in the kinetic resolution of the methyl-
substituted 3a with 2c stems from the Curtin-Hammett pre-
(2S)-Hex-5-en-2-amine ((S)-3a). This compound was prepared by kinetic
resolution using (S)-2c at 25 °C, 52% conversion after
9 h. The
enantioenriched starting material was recovered as colorless oil (38% yield,
bp 114−116 °C at 760 Torr, 95% ee). The NMR spectra are in agreement
with those of rac-hex-5-en-2-amine [23]
.
(2S)-1-Phenylhex-5-en-2-amine ((S)-3b). This compound was prepared
by kinetic resolution using (R)-2c at 25 °C, 57% conversion after 22.5 h.
The enantioenriched starting material was recovered as colorless oil (40%
yield, 95% ee, bp 103 °C at 0.2 mmHg). The NMR spectra are in
[12d]
agreement with those of rac-1-phenylhex-5-en-2-amine
.
(1S)-1-Phenylpent-4-en-1-amine (3c) This compound was prepared by
kinetic resolution using (R)-2c at 40 °C, 54% conversion after 31 h. The
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
enantioenriched starting material was recovered as colorless oil (40% yield,
97% ee). The NMR spectra are in agreement with those of rac-1-
phenylpent-4-enylamine.[12d]
[5]
[6]
Reviews on alkali and alkaline-earth metal-catalyzed hydroaminations:
a) J. Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal. 2002,
344, 795–813; b) S. Harder, Chem. Rev. 2010, 110, 3852–3876; c) A. G.
M. Barrett, M. R. Crimmin, M. S. Hill, P. A. Procopiou, Proc. R. Soc. A
2010, 466, 927–963; d) M. R. Crimmin, M. S. Hill, Top. Organomet.
Chem. 2013, 45, 191–241.
(1S)-1-Cyclohexylpent-4-en-1-amine ((S)-3d). This compound was
prepared by kinetic resolution using (R)-2c at 25 °C, 77% conversion after
9.5 hours. The enantioenriched starting material was recovered as
colorless oil (18% yield, 95% ee, bp 80 °C at 0.2 mmHg). The NMR
spectra are in agreement with those of rac-1-cyclohexylpent-4-en-1-
Reviews on late transition metal-based catalysts: a) M. Beller, C. Breindl,
M. Eichberger, C. G. Hartung, J. Seayad, O. R. Thiel, A. Tillack, H.
Trauthwein, Synlett 2002, 1579–1594; b) J. F. Hartwig, Pure Appl. Chem.
2004, 76, 507–516; c) R. A. Widenhoefer, X. Han, Eur. J. Org. Chem.
2006, 4555–4563; d) J. J. Brunet, N. C. Chu, M. Rodriguez-Zubiri, Eur.
J. Inorg. Chem. 2007, 4711–4722; e) K. D. Hesp, M. Stradiotto,
ChemCatChem 2010, 2, 1192–1207; f) J. Jenter, A. Lühl, P. W. Roesky,
S. Blechert, J. Organomet. Chem. 2010, 695, 406–418; g) V. Rodriguez-
Ruiz, R. Carlino, S. Bezzenine-Lafollee, R. Gil, D. Prim, E. Schulz, J.
Hannedouche, Dalton Trans. 2015, 44, 12029–12059; h) L. Huang, M.
Arndt, K. Gooßen, H. Heydt, L. J. Gooßen, Chem. Rev. 2015, 115, 2596–
2697; i) For a recent example of an iron-catalyzed hydroamination of
aminoalkenes, see: C. Lepori, E. Bernoud, R. Guillot, S. Tobisch, J.
Hannedouche, Chem. Eur. J. 2019, 25, 835–844.
amine [15]
.
General procedure for kinetic catalytic hydroamination/cyclization
reactions. In a glovebox, a screw cap NMR tube were charged with a
solution of the enantioenriched α-substituted aminopentene (2.0 w% in
[D6]benzene, 200−375 µL, 58.0−74.0 µmol), ferrocene (3.0 mg),
[D6]benzene (to give a total volume of 500 µL), and catalyst (2.0 mol%,
1.16−1.48 µmol, 21−24 µL stock solution in [D6]benzene). The tube was
placed in either 400 or 500 MHz NMR thermostatic probe with temperature
of 25−55 °C and an arrayed experiment was set up to record 1H NMR
spectra automatically in time intervals (30 sec., 1 min., 3 min., 5 min., or
10 min.). The conversion was determined based on the disappearance of
the olefinic signals of the substrate relative to the internal standard
ferrocene. The linear part of the data was fit by least square analysis and
kobs. was determined from the slope α of a plot of concentration of amine
(M) versus time (min.).
[7]
[8]
For reviews on photocatalytic hydroaminations see: (a) K. A. Margrey, D.
A. Nicewicz, Acc. Chem. Res. 2016, 49, 1997–2006; b) D. Menigaux, P.
Belmont, E. Brachet, Eur. J. Org. Chem. 2017, 2008–2055.
a) For a review on the asymmetric formal hydroamination of alkenes
using copper hydride catalysts see: M. T. Pirnot, Y. M. Wang, S. L.
Buchwald, Angew. Chem. Int. Ed. 2016, 55, 48–57; Angew. Chem. 2016,
128, 48–57; b) For a review on the Cope-type hydroamination see: A. M.
Beauchemin, Org. Biomol. Chem. 2013, 11, 7039-7050.
[9]
For reviews on asymmetric hydroamination see: a) P. W. Roesky, T. E.
Müller, Angew. Chem. Int. Ed. 2003, 42, 2708–2710; Angew. Chem.
2003, 115, 2812–2814; b) K. C. Hultzsch, Adv. Synth. Catal. 2005, 347,
367–391; c) I. Aillaud, J. Collin, J. Hannedouche, E. Schulz, Dalton Trans.
2007, 5105–5118; d) G. Zi, Dalton Trans. 2009, 9101–9109; g) S. R.
Chemler, Org. Biomol. Chem. 2009, 7, 3009–3019; e) G. Zi, J.
Organomet. Chem. 2011, 696, 68–75; f) J. Hannedouche, J. Collin, A.
Trifonov, E. Schulz, J. Organomet. Chem. 2011, 696, 255–262; g) J.
Hannedouche, E. Schulz, Chem. Eur. J. 2013, 19, 4972–4985; h) A. L.
Reznichenko, A. J. Nawara-Hultzsch, K. C. Hultzsch, Top. Curr. Chem.
2014, 343, 191–260; i) C. Michon, M. A. Abadie, F. Medina, F. Agbossou-
Niedercorn, J. Organomet. Chem. 2017, 847, 13–27.
Acknowledgments
This work was supported by the National Science Foundation
through a NSF CAREER Award (CHE 0956021).
Keywords: asymmetric catalysis • hydroamination • kinetic
resolution • reaction mechanisms • rare earths
[1]
[2]
a) A. Ricci, Modern Amination Methods, Wiley-VCH, 2000; b) A. Ricci,
Amino Group Chemistry: From Synthesis to the Life Sciences, Wiley-
VCH, 2008; c) Chiral Amine Synthesis: Methods, Developments and
Applications; Nugent, T, Ed.; Wiley-VCH: Weinheim, Germany, 2010.
For general reviews on hydroamination see: a) T. E. Müller, M. Beller,
Chem. Rev. 1998, 98, 675–704; b) J. J. Brunet, D. Neibecker in Catalytic
Heterofunctionalization from Hydroamination to Hydrozirconation, (Eds.
A. Togni, H. Grützmacher), Wiley-VCH, Weinheim, 2001, pp. 91–141; c)
T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem. Rev.
2008, 108, 3795–3892; d) S. Doye in Science of Synthesis, Vol. 40a (Ed.
D. Enders), Thieme, Stuttgart, 2009, pp. 241–304; e) A. L. Reznichenko,
K. C. Hultzsch, Top. Organomet. Chem. 2013, 43, 51–114; f) N. Nishina,
Y. Yamamoto, Top. Organomet. Chem. 2013, 43, 115–143; g) A. L.
Reznichenko, K. C. Hultzsch in Organic Reactions, Vol. 88 (Eds. S. E.
Denmark, A. Charette), Wiley: Hoboken, NJ, 2016, pp. 1–554.
[10] For selected examples of highly enantioselective intramolecular
hydroamination of aminoalkenes see: a) M. C. Wood, D. C. Leitch, C. S.
Yeung, J. A. Kozak, L. L. Schafer, Angew. Chem. Int. Ed. 2007, 46, 354–
358; Angew. Chem. 2007, 119, 358–362. b) X. Shen, S. L. Buchwald,
Angew. Chem. Int. Ed. 2010, 49, 564–567; Angew. Chem. 2010, 122,
574–577; c) K. Manna, M. L. Kruse, A. D. Sadow, ACS Catal. 2011, 1,
1637–1642; d) Y. Zhang, W. Yao, H. Li, Y. Mu, Organometallics 2012,
31, 4670–4679; e) X. Zhang, T. J. Emge, K. C. Hultzsch, Angew. Chem.
Int. Ed. 2012, 51, 394–398; Angew. Chem. 2012, 124, 406–410; f) K.
Manna, W. C. Everett, G. Schoendorff, A. Ellern, T. L. Windus, A. D.
Sadow, J. Am. Chem. Soc. 2013, 135, 7235–7250; g) Z. Chai, D. Hua,
K. Li, J. Chu, G. Yang, Chem. Commun. 2014, 50, 177–179; h) L.
Hussein, N. Purkait, M. Biyikal, E. Tausch, P. W. Roesky, Chem.
Commun. 2014, 50, 3862–3864; i) X. Zhou, B. Wei, X. L. Sun, Y. Tang,
Z. Xie, Chem. Commun. 2015, 51, 5751–5753; j) For the highly
enantioselective intermolecular hydroamination of cyclopropenes see: H.
L. Teng, Y. Luo, B. Wang, L. Zhang, M. Nishiura, Z. Hou, Angew. Chem.
Int. Ed. 2016, 55, 15406–15410; Angew. Chem. 2016, 128, 15632–
15636.
[3]
[4]
Reviews on rare-earth metal-catalyzed hydroaminations: a) S. Hong, T.
J. Marks, Acc. Chem. Res. 2004, 37, 673–686; b) A. L. Reznichenko, K.
C. Hultzsch, Struct. Bonding (Berlin) 2010, 137, 1–48; c) A. A. Trifonov,
I. V. Basalov, A. A. Kissel, Dalton Trans. 2016, 45, 19172–19193.
Reviews on Group 4- and actinide-catalyzed hydroaminations: a) I.
Bytschkov, S. Doye, Eur. J. Org. Chem. 2003, 935–946; b) F. Pohlki, S.
Doye, Chem. Soc. Rev. 2003, 32, 104–114; c) S. Doye, Synlett 2004,
1653–1672; d) A. L. Odom, Dalton Trans. 2005, 225–233; e) R. Severin,
S. Doye, Chem. Soc. Rev. 2007, 36, 1407–1420; f) A. V. Lee, L. L.
Schafer, Eur. J. Inorg. Chem. 2007, 2243–2255; g) P. Eisenberger, L. L.
Schafer, Pure Appl. Chem. 2010, 82, 1503–1515; h) T. Andreas, M. S.
Eisen, Chem. Soc. Rev. 2008, 37, 550–567.
[11] For selected examples of highly enantioselective intramolecular
hydroamination reactions of aminodienes and aminoallenes see: a) R. L.
LaLonde, B. D. Sherry, E. J. Kang, F. D. Toste, J. Am. Chem. Soc. 2007,
129, 2452–2453; b) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste,
Science 2007, 317, 496–499; c) Z. Zhang, C. F. Bender, R. A.
Widenhoefer, Org. Lett. 2007, 9, 2887–2889; d) R. L. LaLonde, Z. J.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
Wang, M. Mba, A. D. Lackner, F. D. Toste, Angew. Chem. Int. Ed. 2010,
49, 598–601; Angew. Chem. 2010, 122, 608–611; e) N. D. Shapiro, V.
Rauniyar, G. L. Hamilton, J. Wu, F. D. Toste, Nature 2011, 470, 245–
249.; f) O. Kanno, W. Kuriyama, Z. J. Wang, F. D. Toste, Angew. Chem.
Int. Ed. 2011, 50, 9919–9922; Angew. Chem. 2011, 123, 10093-10096.
[12] a) D. V. Gribkov, K. C. Hultzsch, F. Hampel, Chem. Eur. J. 2003, 9,
4796–4810; b) D. V. Gribkov, F. Hampel, K. C. Hultzsch, Eur. J. Inorg.
Chem. 2004, 4091–4101; c) D. V. Gribkov, K. C. Hultzsch, Chem.
Commun. 2004, 730–731; d) D. V. Gribkov, K. C. Hultzsch, F. Hampel,
J. Am. Chem. Soc. 2006, 128, 3748–3759; e) A. L. Reznichenko, K. C.
Hultzsch, Organometallics 2013, 32, 1394–1408; f) H. N. Nguyen, H. Lee,
S. Audörsch, A. L. Reznichenko, A. J. Nawara-Hultzsch, B. Schmidt, K.
C. Hultzsch Organometallics 2018, 37, 4358–4379. See also: g) X. Yu,
T. J. Marks, Organometallics 2007, 26, 365–376.
L. Teng, Y. Luo, M. Nishiura, Z. Hou, J. Am. Chem. Soc. 2017, 139,
16506–16509.
[17] For rare-earth metal-catalyzed kinetic resolution processes other than
hydroamination, see for example: a) M.-H. Lin, T. V. RajanBabu, Org.
Lett. 2002, 4, 1607–1610; b) C. I. Maxwell, K. Shah, P. V. Samuleev, A.
A. Neverov, R. S. Brown, Org. Biomol. Chem. 2008, 6, 2796–2803; c) L.
Zhou, X. Liu, J. Ji, Y. Zhang, X. Hu, L. Lin, X. Feng, J. Am. Chem. Soc.
2012, 134, 17023–17026; d) L. Zhou, X. Liu, J. Ji, Y. Zhang, W. Wu, Y.
Liu, L. Lin, X. Feng, Org. Lett. 2014, 16, 3938–3941; e) Y. Zhang, X. Liu,
L. Zhou, W. Wu, T. Huang, Y. Liao, L. Lin, X. Feng, Chem. Eur. J. 2014,
20, 15884–15890; f) B. Wu, J. C. Gallucci, J. R. Parquette, T. V.
RajanBabu, Chem. Sci. 2014, 5, 1102–1117; g) Y. Xu, K. Kaneko, M.
Kanai, M. Shibasaki, S. Matsunaga, J. Am. Chem. Soc. 2014, 136, 9190–
9194; h) T. Huang, L. Lin, X. Hu, J. Zheng, X. Liu, X. Feng, Chem.
Commun. 2015, 51, 11374–11377; i) N. Li, B. T. Guan, Adv. Synth. Catal.
2017, 359, 3526–3531; j) H. K. Kisan, R. B. Sunoj, ACS Catalysis 2018,
8, 7633–7644.
[13] A. L. Reznichenko, H. N. Nguyen, K. C. Hultzsch, Angew. Chem. Int. Ed.
2010, 49, 8984–8987; Angew. Chem. 2010, 122, 9168–9171.
[14] For reviews on kinetic resolution see: a) H. B. Kagan, J. C. Fiaud, Top.
Stereochem. 1988, 18, 249–330; b) E. Vedejs, M. Jure, Angew. Chem.
Int. Ed. 2005, 44, 3974–4001; Angew. Chem. 2005, 117, 4040–4069; c)
H. Pellissier, Adv. Synth. Catal. 2011, 353, 1633–1666.
[18] Resolution factors >50 are difficult to determine with sufficient precision
based on a single data point. A better estimate for these large f values
can be obtained from linear regression of several data points (vide infra).
[19] For the detailed derivation of the underlying equations see refs. [12d] and
[15].
[15] A. L. Reznichenko, F. Hampel, K. C. Hultzsch, Chem. Eur. J. 2009, 15,
12819–12827. For the application of NOBIN-based aminophenolate
complexes in the kinetic resolution of aminoalkenes see ref. [12e].
[16] a) For the gold-catalyzed dynamic kinetic resolution of aminoallenes via
hydroamination/cyclization see: Z. Zhang, C. F. Bender, R. A.
Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148–14149; b) For the
stereoconvergent, intermolecular asymmetric hydroamination of racemic
allenes see: K. L. Butler, M. Tragni, R. A. Widenhoefer, Angew. Chem.
Int. Ed. 2012, 51, 5175–5178; Angew. Chem. 2012, 124, 5265–5268; c)
For the desymmetrization of aminodialkenes and aminodialkynes see: K.
Manna, N. Eedugurala, A. D. Sadow, J. Am. Chem. Soc. 2015, 137, 425–
[20] For simplification we assume that kR/kS represents kfast/kslow for all
substrates. Note however, that for substrate 3a the S enantiomer is the
faster reacting enantiomer when using the (R)-binaphtholate catalysts.
[21] M. R. Gagné, C. L. Stern, T. J. Marks, J. Am. Chem. Soc. 1992, 114,
275–294.
[22] M. N. Bochkarev, Chem. Rev. 2002, 102, 2089–2117.
[23] J. Y. Kim, T. Livinghouse, Org. Lett. 2005, 7, 4391–4393.
[24] P. M. Smith, E. J. Thomas, J. Chem. Soc. Perkin Trans. 1 1998, 3541–
3556.
435;
d)
For
the
diastereodivergent
asymmetric
carboamination/annulation of cyclopropenes with aminoalkenes see: H.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Asymmetric hydroamination
Hiep N. Nguyen, Kai C. Hultzsch*
Page No. – Page No.
Rare-Earth Metal-Catalyzed Kinetic
Resolution of Chiral Aminoalkenes
via Hydroamination: The Effect of the
Silyl-Substituent of the Binaphtholate
Ligand on Resolution Efficiency
The efficiency in the kinetic resolution of chiral aminoalkenes via intramolecular
hydroamination can be improved significantly in comparison to previous catalysts
by introduction of a cyclohexyldiphenylsilyl-substituent in the catalyst leading to a
shift of the Curtin-Hammett pre-equilibrium in favor of the matching substrate-
catalyst pair.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
Table 1. Catalytic kinetic resolution of α-substituted 1-aminopent-4-enes[a]
Entry
Subst.
Cat.
T [°C]
22
t [h]
25.5
42
Conv. [%]
trans/cis[b]
11:1
10:1
9:1
ee [%][c]
72
f
1
2
3
4
5
6
7
8
9
(R)-1a-Y
(R)-1a-Lu
(R)-2a
53
55
49
48
50
50
52
50
48
9.5[d]
8.4[d]
14
22
73
25
29.5
13.0
4
71
(R)-2c
25
7:1
86
>50
2.8
(R)-2e
25
8:1
34.5
42
(R)-1a-Y
(R)-1b-Y
(R)-2b
22
9
20:1
20:1
20:1
20:1
3.6[d]
2.9[d]
8.6
22
27
38
25
42.3
17.8
64
(R)-2c
25
82
43
10
11
12
13
14
15
16
17
18
19
20
21
(R)-1a-Y
(R)-2a
(R)-2b
(R)-2c
(R)-2d
(R)-2e
(R)-1a-Y
(R)-1b-Y
(R)-2b
(R)-2c
(R)-2d
(R)-2e
22
40
40
40
40
40
22
22
25
25
25
25
95
41.0
39
39
82
14
8
50
50
54
46
50
45
56
59
54
51
58
50
≥50:1
≥50:1
≥50:1
≥50:1
≥50:1
≥50:1
---
74
77
86
78
30
57.5
49
54
56
57
80
41
15[d]
18
18
>50
2.4
10
3.5[e]
3.6[e]
4.8
5.9
8.9
3.5
46
3.3
4.3
16
5.5
---
5:1
7:1
10:1
6:1
[a] General reaction conditions: 0.10−0.20 mmol substrate ([sub.] = 0.2–0.5 M), 2 mol% cat., [D6]benzene, Ar atm. [b] Trans/cis
ratio of products. [c] Enantiomeric excess of recovered starting material 3a–d. [d] Data from ref. [12d]. [e] Data from ref. [15].
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900107
European Journal of Organic Chemistry
FULL PAPER
Table 3. Kinetic resolution parameters of α-substituted aminopentenes[a]
kfast
[10−3 s−1
trans/cis
fast (slow, conv.[d] [%])
Entry
Subst.
Cat.
T [°C]
kslow
[10−3 s−1
kfast/kslow
f [c]
Kdias
[b]
]
]
1
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
3c
3d
3d
3d
3d
1a-Y
2b
30
25
25
30
40
50
25
30
40
40
40
60
70
60
70
70
30
25
25
25
8.5
1.12
7.6
6.4
0.84
>30:1.0 (2.8:1.0, 100)[e]
35:1.0 (2.2:1.0, 77)
39:1.0 (1:1.2, 100)
38:1.0 (1:1.25, 100)
38:1.0 (1:1.3, 100)
38:1.0 (1:1.2, 100)
35:1.0 (1.5:1.0, 60)
>30:1.0 (>30.0:1.0, 85)[e]
24:1.0 (4.0:1.0, 65)
25:1.0 (1.0:1.0, 70)
21:1.0 (1.7:1.0, 77)
>50:1.0 (8.8:1.0, 99)[f]
>50:1.0 (3.2:1.0, 45)
>50:1.0 (7.0:1.0, 30)
>50:1.0 (6.9:1.0, 30)
>50:1.0 (2.2:1.0, 100)
9.0:1.0 (1.4:1.0, 90)[e]
24:1.0 (1.0:2.4, 100)
20:1.0 (1.0:1.9, 100)
21:1.0 (1.2:1.0, 100)
2
2.31(1)
7.35(5)
0.215(2)
0.388(4)
0.730(1)
1.64(1)
3.19(1)
0.34(1)
0.26
10.7(1)
18.9(2)
14.1(1)
11.8(1)
14.8(2)
9.1(3)
9.6
5.8(1)
90(5)
77(5)
46(2)
23.7(4)
2.8(1)
2.6
0.54(1)
4.8(3)
5.5(4)
3.9(2)
1.60(3)
0.31(1)
0.27
3
2c
4
2c
10.26(5)
19.3(1)
47.2(6)
3.08(1)
2.5
5
2c
6
2c
7
2e
8
1a-Y
2b
9
3.15(4)
5.7(1)
0.432(4)
0.437(8)
0.542(7)
1.59
7.3(1)
13.0(3)
5.2(1)
7.1
6.1(4)
32(1)
5.5(1)
11.5
0.84(6)
2.5(1)
1.06(3)
1.6
10
11
12
13
14
15
16
17
18
19
20
2c
2e
2.84(6)
11.3
1a-Y
2b
5.35(2)
3.76(2)
6.90(6)
3.91(3)
8.5
0.48(1)
0.24(1)
0.46(1)
0.65(1)
1.0
11.2(2)
15.7(7)
15.0(4)
6.0(1)
8.5
11.6(6)
24.6(3)
16.6(8)
7.6(3)
2.7
1.04(5)
1.57(7)
1.11(6)
1.27(5)
0.32
2c
2c
2e
1a-Y
2b
4.47(5)
3.12(1)
1.93(1)
1.19(2)
0.790(3)
1.11(1)
3.76(8)
3.95(2)
1.74(2)
4.7(2)
5.6(3)
3.6(1)
1.25(6)
1.42(8)
2.07(4)
2c
2e
[a] General reaction conditions: 58–74 mol (S)-3a–d ([sub.] = 0.11–0.14 M), 2 mol% cat., [D6]benzene, Ar. [b] kfast = kR for the reaction of (S)-3a
with (R)-catalyst; kfast = kS for the reaction of (S)-3b, (S)-3c, (S)-3d with (S)-catalyst. [c] Determined from the slope of plot of ln(1−C)(1−ee) versus
ln(1−C)(1+ee), with at least three data points. [d] Conversion for mismatching substrate at which trans/cis ratio was determined. [e] Data from ref.
[15]. [f] Data from ref. [12d].
This article is protected by copyright. All rights reserved.