Kinetic resolution of aminoalkenes by asymmetric hydroamination: A mechanistic study

Article abstract of DOI:10.1002/chem.200902229

The kinetic resolution of chiral aminoalkenes by hydroamination-cyclization was studied by using 3,3'-bis(triarylsilyl)-substituted binaphtholate rare-earth-metal complexes. The resolution of 1-arylaminopentenes proceeds with high efficiency and high irans-diastereoselectivity, whereas the resolution process of 1-alkylaminopentenes suffers from decreasing resolution efficiency with increasing steric demand of the aliphatic substituent. Kinetic studies of the matching and mismatching substrate-catalyst pair by using enantiopure substrates and either the (R)- or (S)-binaphtholate catalysts revealed that the difference in resolution efficiency stems from a shift of the Curtin-Hammett pre-equilibrium. Al-though 1-arylaminopentenes favor the matching substrate-catalyst complex, preference for the mismatching substrate-catalyst complex for 1-alkylaminopentenes diminishes resolution efficiency. Nevertheless, the relative cyclization rate for the two diastereomeric substrate-catalyst complexes remains in a typical range of 7-10:1. Plausible attractive π interactions between the aryl substituent and either the metal center or the aromatic system of the bis(triarylsilyl)-substituted binaphtholate ligand may explain increased sta-bility of the matching substrate-catalyst complex. Incidentally, the methoxymethyl (MOM)-substituted aminopentene 3g also exhibited a strong preference for the matching substrate-catalyst complex, possibly due to the chelating nature of the MOM substituent. The proximity of the stereocenter to the amino group in the aminoalkene substrate was crucial to achieve good kinetic resolution efficiency. The more remote β-phenyl substituent in 2-phenylpent-4-en-l-amine (5) resulted in diminished discrimination of the substrate enantiomers with respect to the relative rate of cyclization of the two substrate-catalyst complexes and a Curtin-Hammett preequilibrium close to unity.

Full text of DOI:10.1002/chem.200902229

FULL PAPER
DOI: 10.1002/chem.200902229
Kinetic Resolution of Aminoalkenes by Asymmetric Hydroamination:
A Mechanistic Study
Alexander L. Reznichenko,[a] Frank Hampel,[b] and Kai C. Hultzsch*[a]
Abstract: The kinetic resolution of
chiral aminoalkenes by hydroamina-
tion–cyclization was studied by using
3,3’-bis(triarylsilyl)-substituted binaph-
tholate rare-earth-metal complexes.
The resolution of 1-arylaminopentenes
proceeds with high efficiency and high
trans-diastereoselectivity, whereas the
resolution process of 1-alkylaminopen-
tenes suffers from decreasing resolu-
tion efficiency with increasing steric
demand of the aliphatic substituent.
Kinetic studies of the matching and
mismatching substrate–catalyst pair by
using enantiopure substrates and either
the (R)- or (S)-binaphtholate catalysts
revealed that the difference in resolu-
tion efficiency stems from a shift of the
Curtin–Hammett pre-equilibrium. Al-
though 1-arylaminopentenes favor the
matching substrate–catalyst complex,
preference for the mismatching sub-
strate–catalyst complex for 1-alkylami-
nopentenes diminishes resolution effi-
ciency. Nevertheless, the relative cycli-
zation rate for the two diastereomeric
substrate–catalyst complexes remains
in a typical range of 7–10:1. Plausible
attractive p interactions between the
aryl substituent and either the metal
center or the aromatic system of the
bis(triarylsilyl)-substituted binaphtho-
late ligand may explain increased sta-
bility of the matching substrate–cata-
lyst complex. Incidentally, the
methoxymethyl (MOM)-substituted
aminopentene 3g also exhibited
AHCTUNGTRENNUNG
a
strong preference for the matching sub-
strate–catalyst complex, possibly due to
the chelating nature of the MOM sub-
stituent. The proximity of the stereo-
center to the amino group in the ami-
noalkene substrate was crucial to
achieve good kinetic resolution effi-
ciency. The more remote b-phenyl sub-
stituent in 2-phenylpent-4-en-1-amine
(5) resulted in diminished discrimina-
tion of the substrate enantiomers with
respect to the relative rate of cycliza-
tion of the two substrate–catalyst com-
Keywords: asymmetric catalysis
·
hydroamination · kinetic resolution ·
reaction mechanisms · rare earths
plexes and
a Curtin–Hammett pre-
equilibrium close to unity.
Introduction
bonds, either in an intermolecular (Scheme 1a) or intramo-
lecular (Scheme 1b) fashion, generates amines in a waste-
free, highly atom-economical manner starting from simple
and inexpensive precursors.
In particular, the generation of new stereogenic centers
constitutes an attractive application of the hydroamination
process, but the development of chiral catalysts for the
asymmetric hydroamination of alkenes (AHA) has re-
mained challenging.[3,4]
The importance of nitrogen-containing compounds in bio-
logical systems and industrially relevant basic and fine
chemicals has sparked significant research efforts to develop
efficient synthetic protocols.[1] One of the simplest ap-
proaches, hydroamination, has only found significant atten-
tion in recent years with the development of more efficient
transition-metal-based catalyst systems.[2] The addition of
ꢀ
amine N H functionalities to unsaturated carbon–carbon
[a] A. L. Reznichenko, Prof. Dr. K. C. Hultzsch
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
610 Taylor Road, Piscataway, NJ 08854-8087 (USA)
Fax : (+1) 732-445-5312
E-mail: hultzsch@rci.rutgers.edu
[b] Dr. F. Hampel
Institut fꢀr Organische Chemie
Friedrich-Alexander Universitꢁt Erlangen-Nꢀrnberg
Henkestr. 42, 91054 Erlangen (Germany)
Scheme 1. Inter- (a) and intramolecular (b) hydroamination of alkenes.
Chem. Eur. J. 2009, 15, 12819 – 12827
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12819

Table 1. Kinetic resolution parameters of a-substituted aminopentenes[a]
Among the various catalyst systems developed over the
past two decades,[2,5] rare-earth-metal complexes are among
the most active and widely applicable catalysts.[2l,6–8]
In recent years, limitations in the enantioselectivities ob-
tained with chiral lanthanocene-based hydroamination cata-
lysts[3,9] sparked the development of novel, chiral, non-met-
allocene-based rare-earth-metal hydroamination cata-
lysts.[10–13] Our investigations have focused on the develop-
ment of chiral biphenolate and binaphtholate rare-earth-
metal hydroamination catalysts.[11] In particular, complexes
based on sterically demanding 3,3’-bis(triarylsilyl)-substitut-
ed binaphtholate ligands[11c,d] have proven to be highly
active and enantioselective, achieving up to 95% enantio-
meric excess (ee) in hydroamination–cyclization of aminoal-
kenes. Furthermore, these complexes were also efficient in
the catalytic kinetic resolution of chiral aminoalkenes by hy-
droamination–cyclization (Scheme 2).[14,15]
Entry Subst. Cat.
t [h]
T [8C] Conv. [%] ee [%][b]
f
1
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3c
3d
3d
3d
3d
3d
3d
3e
3e
3e
3e
3e
3e
3 f
3 f
3 f
3 f
3 f
3 f
3g
3g
3g
3g
1–Y
95
15
18
40
8
26
35
14
24
22
18
17
22
10
21
24
9
22
40
40
22
40
40
50
40
40
50
40
40
50
40
40
50
22
22
40
22
22
40
50
52
52
52
50
47
55
34
52
51
50
55
60
51
50
49
50
50
64
52
70
55
53
55
51
52
51
50
56
47
75
59
46
47
50
59
45
56
74
83
63
59
78
70
69
40
70
54
71
77
81
80
68
68
42
32
60
38
42
47
72
73
73
80
75
73
49
51
67
54
44
32
33
9
15[c]
19[c]
7[c]
6[c]
19[c]
18
2
3
1–Lu
2–Y
4
5
2–Lu
1–Y
6
7
8
1–Lu
1–Sc
2–Y
7
12
11
9
2–Lu
2–Sc
1–Y
1–Lu
1–Sc
2–Y
2–Lu
2–Sc
1–Y
1–Lu
1–Sc
2–Y
2–Lu
2–Sc
1–Y
1–Lu
1–Sc
2–Y
2–Lu
2–Sc
1–Y
1–Lu
1–Sc
2–Y
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
6
12[c]
10
8
19
11
12
3.6[c]
2.6
Scheme 2. Kinetic resolution by hydroamination–cyclization.
26
40
27
13
33
3.5
2.9[c]
2.0
Kinetic resolution of chiral a-substituted aminoalkenes
containing aryl substituents proceeded smoothly with high
diastereoselectivity (trans/cis up to 50:1) and high resolution
factors (f up to 19). Unfortunately, kinetic resolution of
chiral a-substituted aminoalkenes containing aliphatic sub-
stituents proceeded with deteriorating efficiency, but in-
creasing trans/cis diastereoselectivity, with increasing steric
demand of the alkyl substituent. Herein, we disclose results
from a detailed kinetic study of this kinetic resolution pro-
cess, which sheds some light on the mechanism of this cata-
lytic asymmetric hydroamination and the mode of operation
of the chiral binaphtholate catalysts.
3.5
25.5 22
9.5[c]
8.4[c]
42
94
26
22
40
22
12[c]
16[c]
14[c]
14[c]
3.5
6.0
2.9
3.6
4.7
2.8
2.7
1.2
2.0
1.2
24.5 22
94
8
23
34
46
47
49
85
40
22
22
40
22
22
40
40
40
40
40
2–Lu
2–Sc
1–Y
1–Lu 120
2–Y
180
94
20
9
Results and Discussion
2–Lu
[a] Reaction conditions: 2 mol% cat., [D6]benzene, Ar atm, 0.5–1m sub-
strate (subst.). Conv.=conversion. [b] ee value of recovered 3. [c] Data
from ref. [11d].
During our previous studies, we have demonstrated that
chiral rare-earth-metal binaphtholate complexes 1–Ln and
2–Ln (Ln=Sc, Y, Lu) are
active in both hydroamination–
cyclization and kinetic resolu-
tion of 1-substituted aminopen-
tenes.[11c,d]
eral trends in (nonkinetic-resolution-type) asymmetric hy-
droamination reactions, the efficiency in kinetic resolution
often increases with the ionic radius size of the rare-earth
metal. For example, the triphenylsilyl-substituted binaphtho-
late yttrium complex 1–Y was superior for the 4-methoxy-
phenyl-substituted aminopentene 3b (Table 1, entry 5),
whereas the sterically more congested tris(3,5-xylyl)silyl-
substituted binaphtholate yttrium complex 2–Y was most ef-
ficient for the electron-withdrawing 4-chlorophenyl-substi-
tuted aminopentene 3c (Table 1, entry 14).
In an extension of our previ-
ous study we surveyed a broad-
er set of a-substituted aminoal-
kenes with six different binaph-
tholate rare-earth-metal com-
plexes
1–Ln
and
2–Ln
(Table 1). As noted previously, the highest resolution factors
were observed for the a-aryl-substituted aminoalkenes 3a–c,
with 1–Lu being most efficient for 3a.[11d] In contrast to gen-
For a-alkyl-substituted aminoalkenes, high selectivities
are only observed for the sterically least demanding sub-
12820
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12819 – 12827

Kinetic Resolution of Aminoalkenes
FULL PAPER
strate 3e by using the sterically more demanding tris(3,5-xy-
lyl)silyl-substituted catalyst 2 in general and, in particular,
the yttrium complex 2–Y. Sterically more demanding a-alkyl
substrates, such as the benzyl-substituted 3d and the cyclo-
hexyl-substituted 3 f, exhibit significantly diminished resolu-
tion factors. Both scandium and yttrium complexes show
slightly higher kinetic resolution efficiency for 3d, whereas
the opposite observation (highest selectivity for 1–Lu,
Table 1, entry 30) is true for 3 f. The cyclization of the me-
thoxymethyl (MOM)-substituted aminoalkene 3g is signifi-
cantly retarded, clearly due to the chelating nature of the
pending ether functionality. Contrary to our expectations,
the chelating donor group did not improve the kinetic reso-
lution efficiency, with essentially no kinetic discrimination of
the two substrate enantiomers for lutetium catalysts and
only slightly better efficiencies for yttrium catalysts. Again,
the highest selectivity was observed for 1–Y (Table 1,
entry 35).
resolution factor can be expressed as a function of the con-
version (C) and the ee value of the recovered substrate
[(Eq. (6)]:
d½Rꢁ
ð4Þ
ð5Þ
ꢀ
¼ kR½cat: ꢀ Rꢁ
¼ kS½cat: ꢀ Sꢁ
dt
d½Sꢁ
ꢀ
dt
lnð½Rꢁ=½Rꢁ Þ ln½ð1 ꢀ CÞð1 þ eeÞꢁ
lnð½Sꢁ=½Sꢁ00Þ ln½ð1 ꢀ CÞð1 ꢀ eeÞꢁ
ð6Þ
f ¼
¼
A plot of ln
[(1ꢀC)
E
G
N
vides the resolution factor f (Figure 1), while kinetic mea-
According to the general model for the kinetic resolution
of racemic aminoalkenes by catalytic hydroamination
(Scheme 3),[11d] the total amount of the catalyst [Ln] is dis-
Figure 1. Plot of ln
resolution of 3e by using (R)-1–Y as a catalyst at various temperatures
[(1ꢀC)
E
[(1ꢀC)
G
&
*
^
(
=308C, =408C, =508C).
Scheme 3. General model for catalytic kinetic resolution.
AHCTUNGTREGsNNNU urements obtained by using an enantiopure substrate and
either the (R)- or (S)-catalyst gives access to the zero-order
reaction rate constants kR and kS for the matching (Fig-
ure 2a) and mismatching (Figure 2b) substrate–catalyst com-
bination. Enantiopure substrates were obtained either
through large-scale kinetic resolution (3a–3 f, Table 2) by
using the best resolution catalysts for each particular sub-
strate or by fractional crystallization of the ammonium salt
with (R)-(ꢀ)-mandelic acid (3g).[17] The kinetic data and res-
olution parameters obtained for substrates 3a–3g by using
(R)-1–Y and (S)-1–Y are summarized in Table 3.
In agreement with our previous findings for the phenyl-
substituted substrate 3a,[11d] the aryl-substituted substrates
3b and 3c both exhibit an equilibrium constant Kdias in favor
of the matching substrate–catalyst complex (Kdias >1). Thus,
Kdias and the kR/kS ratio both favor the resolution process.
Also, cyclization of 3b and 3c proceeded with the same high
diastereoselectivities as that for 3a.
tributed between two substrate–catalyst complexes [cat.-S]
and [cat.-R] [Eq. (1)], which readily interconvert with an
equilibrium constant, Kdias, determined by Equation (2).
Each of the complexes reacts with a corresponding rate con-
stant (kR and kS) to give the corresponding hydroamination
products. Previous NMR spectroscopic investigations of 1–Y
and 2–Y have revealed that the rate of interconversion be-
tween the two diastereomeric substrate–catalyst complexes
is rapid, even at low temperatures, and significantly higher
than both rates of cyclization.[11d]
½Lnꢁ ¼ ½cat:-Sꢁ þ ½cat:-Rꢁ
kSR ½cat: ꢀ Rꢁ½Sꢁ
ð1Þ
ð2Þ
Kdias
¼
¼
kRS
½cat: ꢀ Sꢁ½Rꢁ
The resolution factor f depends on three independent pa-
rameters: the equilibrium constant (Kdias) and the cyclization
rate constants of both substrate–catalyst complexes
[Eq. (3)],[16] which may be determined independently.
The cyclization of the N-deuterated aminoalkene [D2]3a
proceeded with a significant primary kinetic isotope effect
(KIE, kH/kD =3.8 at 508C and 5.4 at 608C), which is in
agreement with previous findings on the hydroamination–
cyclization of achiral aminopentenes.[6a,11d] Although no N
ꢀ
kR
kS
H bond breaking is involved in the rate-determining olefin-
insertion step according to the generally accepted mecha-
nism for the hydroamination–cyclization of amino-
f ¼ Kdias
ð3Þ
For pseudo-first-order reactions [Eqs. (4) and (5)], the
alkenes,[2l,6a] it has been proposed that partial proton trans-
ACHTUNGTRENNUNG
Chem. Eur. J. 2009, 15, 12819 – 12827
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12821

K. C. Hultzsch et al.
Table 3. Kinetic resolution parameters of a-substituted aminopentenes
determined with 1–Y.
[b]
Subst. T [8C]
f
kfast
[10ꢀ3 sꢀ1
]
kfast/kslow
Kdias trans/cis
fast (slow)[c]
[a]
U
1
2
3
4
5
6
7
8
9
3a
3a
50
60
12.8 5.45
11.5 11.3
11.0 1.42
9.1 2.10
18.1 0.81
13.2 4.5
2.6 2.5
6.4 8.5
5.2 14.0
4.1 30.4
2.7 8.5
4.1 2.2
6.6 5.1
6.6
7.1
5.3
4.9
9.5
4.2
9.6
7.6
7.1
7.0
8.5
3.2
3.4
1.9
1.6
2.1
1.9
1.9
3.1
>50:1 (9.2:1)[d]
>50:1 (8.8:1)[d]
>50:1 (15:1)
>50:1 (15:1)
>50:1 (>50:1)
>50:1 (>50:1)
[D2]3a 50
[D2]3a 60
3b
3c
3d
3e
3e
40
40
30
30
40
50
30
50
60
0.27 >30:1 (>30:1)
0.84 >30:1 (2.8:1)
0.73 >30:1 (2.2:1)
0.59 >30:1 (2.1:1)
0.32
1.28
1.93
10 3e
11 3 f
12 3g
13 3g
9:1 (1.4:1)
6:1 (2:1)
5:1 (1.8:1)
[a] kfast =kR for 3a–3d, 3 f, and 3g; kfast =kS for 3e. [b] kfast/kslow =kR/kS for
3a–3d, 3 f, and 3g; kfast/kslow =kS/kR for 3e. [c] Determined by integration
of CHN proton signals of pyrrolidines in the 1H NMR spectra after full
conversion. [d] Kinetic data from ref. [11d].
Figure 2. Time dependence of substrate consumption in the hydroamina-
tion–cyclization of (R)-3e with a) (S)-1–Y (matching pair;[16] [cat.]=
0.00228m) and b) (R)-1–Y (mismatching pair;[16] [cat.]=0.00833m) in
~
&
*
^
[D6]benzene; [3e]0 =0.152m ( =308C, =408C, =508C, =608C).
equilibrium in favor of the mismatching substrate–catalyst
complex, while achieving high trans/cis-diastereoselectivities.
Although the equilibrium constant is strongly affected by
the a-substituent, the relative reaction rate kR/kS remains in
the range of 7–10 for all of the substrates, except 3c and 3g.
The activation parameters for the matching (DH° =
(47.3ꢂ3.5) kJmolꢀ1, DS° =(ꢀ128ꢂ11) JKꢀ1 molꢀ1) and mis-
Table 2. Preparation of highly enantioenriched a-substituted aminopen-
tenes by kinetic resolution.
Subst.
Cat.
T [8C]
f
Conv. [%]
Yield (ee) [%][a]
[D2]3a
3b
3c
3d
3e
(R)-1–Lu
(R)-1–Lu
(R)-2–Y
(R)-1
(R)-2–Y
(R)-1–Lu
40
40
40
25
25
25
19
18
19
5
15
6
61
60
61
83
64
84
34 (98)
36 (98)
30 (97)
12 (>98)
30 (97)
9 (98)
matching
(DH° =(54.9ꢂ3.1) kJmolꢀ1,
DS° =(ꢀ121ꢂ
9) JKꢀ1 molꢀ1) substrate–catalyst combination for the cycli-
zation of 3e were obtained from the Eyring plot for kfast and
kslow (Figure 3). The data compare well with the parameters
obtained previously for 3a (matching: DH° =(52.2ꢂ
3 f
[a] Yield and ee value of recovered 3.
fer from a coordinated amine may stabilize the four-mem-
bered-ring olefin-insertion transition state.[6a] Despite this
pronounced KIE, both reaction channels are affected to a
similar extent and the resulting resolution parameters seem
to be similar to those of the nondeuterated substrate 3a.
Compared with the aryl-substituted aminoalkenes 3a–3c,
the alkyl- and benzyl-substituted aminopentenes 3d–3 f be-
haved quite differently. Here, the Curtin–Hammett pre-
equilibrium favored the mismatching substrate–catalyst
complex (Kdias <1), thus, effectively reducing the efficiency
of the kinetic resolution process. A notable exception is the
MOM-substituted substrate 3g, which displayed a prefer-
ence for the matching substrate–catalyst complex, possibly
as a result of the coordinating donor substituent. Diastereo-
selectivities were lower for substrates 3e–3g than for 3a–3d
and the mismatching substrate–catalyst combination exhibit-
ed significantly reduced diastereoselectivities. Interestingly,
the benzyl-substituted aminoalkene 3d combines properties
of both substrate families, that is, a Curtin–Hammett pre-
2.8) kJmolꢀ1, DS° =(ꢀ127ꢂ8) JKꢀ1 molꢀ1
;
mismatching:
DH° =
(57.7ꢂ1.3) kJmolꢀ1,
DS° =(ꢀ126ꢂ
Figure 3. Eyring plot for the hydroamination–cyclization of (R)-3e by
2
*
using (S)-1–Y ( , matching, y=ꢀ5691.3xꢀ15.496, R =0.989) and (R)-1–
2
^
Y ( , mismatching, y=ꢀ6608.9xꢀ14.518, R =0.9939).
12822
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12819 – 12827

Kinetic Resolution of Aminoalkenes
FULL PAPER
4) JKꢀ1 molꢀ1).[11d] The negative activation entropy is a
strong indicator of a highly organized transition state.[6a,11d]
X-ray crystallographic and optical rotational evidence
show that the (R)-binaphtholate catalysts react faster with
(R)-3a–3d and (S)-3e. A comparison of the 19F NMR spec-
tra of the Mosher amides also indicates that (R)-3 f and (R)-
3g are the matching substrates for these catalysts. A stereo-
model for the binaphtholate rare-earth-metal-catalyzed ki-
netic resolution of a-substituted aminoalkenes by intramo-
lecular hydroamination in agreement with these findings has
been proposed (Scheme 4).[11d] According to this model, the
3g. Interestingly, the equilibrium constant Kdias for 3g in-
creases with increasing temperature, whereas the aryl-substi-
tuted 3a displays the opposite behavior.
The decreased trans/cis diastereoselectivity observed for
the mismatched substrate–catalyst combination for 3a, 3e,
and 3 f can be rationalized with an alternative approach of
the metal–amide bond to the re face of the alkene moiety, in
which the a substituent rests in an axial position (Scheme 4,
C). Interestingly, substrates 3b–3d exhibit the same high
level of trans diastereoselectivity, suggesting that unfavora-
ble steric interactions of these larger, more extended a sub-
stituents with the triarylsilyl substituent of the binaphtholate
ligand preclude reaction pathway C becoming an alternative
to pathway B.
To investigate the general influence of the position of the
aryl substituent in the substrate on the resolution process,
we investigated the kinetic resolution of the b-phenyl-substi-
tuted aminopentene 5 (Table 4).
Table 4. Kinetic resolution of 5 ([subst.]0 =2.0m) by using 2 mol% bi-
naphtholate catalysts 1–Ln and 2–Ln at 258C.
Cat.
Conv. [%][a]
trans/cis[b]
ee [%][c]
f
(R)-1–Y
(R)-1–Lu
(R)-1–Sc
(R)-2–Y
(R)-2–Lu
(R)-2–Sc
53
51
54
47
55
50
1:1.3
1:1.3
1:1.3
1:1.2
1:1.2
1:1.2
17
26
34
17
31
11
1.6
2.1
2.5
1.8
2.2
1.4
[a] Determined by 1H NMR spectroscopy using ferrocene as an internal
Scheme 4. Stereomodel for kinetic resolution of a-substituted aminopen-
tenes. For the matching substrate only the pathway leading to the pre-
ferred trans isomer is shown.
1
standard. [b] Determined by H NMR spectroscopy. [c] ee value of recov-
ered 5, determined by 19F NMR spectroscopy of the corresponding
Mosher amide.
rare-earth-metal amide preferentially approaches the alkene
moiety from the re face (Scheme 4, A), whereas the ap-
proach from the si face of the alkene is hampered due to un-
favorable repulsive interactions between the substrate alkyl
chain and the sterically demanding triarylsilyl substituent of
the (R)-binaphtholate ligand (Scheme 4, B). Each of the two
diastereomeric substrate–catalyst complexes has two possi-
ble cyclization pathways.
The high trans diastereoselectivities observed for aryl-sub-
stituted aminopentenes suggests that these substrates pref-
erably cyclize through a transition state with an equatorial
orientation of the aryl substituent in both substrate–catalyst
complexes. This may be explained either by a potential coor-
dinative interaction of the phenyl ring with the metal[18] or a
p interaction with a naphthyl ring of the binaphtholate
ligand, thus providing additional stabilization to the equato-
rial complex. Furthermore, this weak attractive interaction
of the aryl substituent in 3a–3c may explain the slight pref-
erence for the matching substrate–catalyst complex over the
mismatching complex (Kdias >1) and similar donor–metal in-
teractions can be proposed for the methyl ether substituted
Although the preparative-scale kinetic resolution of 5
could not be achieved due to the low resolution factors, we
succeeded in isolating enantiopure (S)-5 after repeated re-
crystallization of the corresponding (R)-mandelate. The ab-
solute configuration was established by X-ray crystallo-
graphic analysis of the corresponding Mosher amide.[19]
19F NMR spectroscopic analysis of the Mosher amide of 5,
recovered from the kinetic resolution reaction, carried out
by using complexes (R)-1 and (R)-2, was thus identified to
be the (R)-enantiomer, indicating that (S)-5 reacts faster
with the (R)-binaphtholate catalysts. With (S)-5 in hand, we
began to study the kinetics and diastereoselectivity of the
matching and mismatching substrate–catalyst pairs (Table 5)
by using 1–Y as the catalyst.
Table 5 illustrates that, in contrast to 3a–3g, kinetic reso-
lution of 5 proceeded with very low reaction rate difference,
kfast/kslow, between the matching and mismatching substrate–
catalyst pair. Furthermore, with Kdias ꢃ0.9, the mismatching
substrate–catalyst complex is slightly favored in the Curtin–
Hammett pre-equilibrium. Overall, the more remote place-
Chem. Eur. J. 2009, 15, 12819 – 12827
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12823

K. C. Hultzsch et al.
Table 5. Kinetic resolution parameters for 5 by using 1–Y.[a]
the allylic position relative to the alkene moiety. We antici-
pated that the closer proximity to the alkene might increase
the influence on the outcome of the kinetic resolution. Un-
fortunately, the kinetic resolution of 7 led to partial double
bond isomerization. Nevertheless, enantioenriched (S)-7 was
recovered from the reaction mixture at approximately 50%
conversion (Table 6).
[a]
T [8C]
f
kfast [10ꢀ3 sꢀ1
]
kfast/kslow Kdias trans/cis
matching (mismatching)
30
40
50
1.5 0.58
1.5 1.32
1.4 3.00
1.64
1.73
1.48
0.92 1:1.3 (6:1)
0.87 1:1.4 (7:1)
0.95 1:1.4 (7:1)
[a] The rates for the matching and mismatching substrate–catalyst combi-
nation were determined with (S)-5 by using either (R)-1–Y (matching
combination) or (S)-1–Y (mismatching combination).
Table 6. Attempted NMR-scale kinetic resolution of 7 at 308C.
ment of the phenyl substituent in the b position to the
amino group significantly diminishes its influence on the ki-
netic resolution. However, it is noteworthy that the trans/cis
diastereomeric ratio shifts dramatically going from the
matching to the mismatching substrate–catalyst pair. The
matching substrate–catalyst combination indicates a slight
preference for formation of the cis-pyrrolidine diastereomer,
which is in agreement with a preferred equatorial orienta-
tion of the phenyl substituent in the approach of the metal
amide to the re face of the alkene moiety (Scheme 5, A).
The strong preference for the trans-pyrrolidine product in
the case of the mismatching substrate–catalyst combination
may be explained by the presence of an additional steric in-
teraction between the equatorial phenyl substituent and the
triarylsilyl-substituted binaphtholate ligand in the approach
of the metal amide bond to the si face of the alkene leading
to the cis-pyrrolidine (Scheme 5, C). Alternatively, the ap-
proach to the re face (Scheme 5, D) leading to the trans-
pyrrolidine puts the phenyl substituent in an axial position
without disadvantageous steric interactions with the binaph-
tholate ligand. Thus, in contrast to 3a–3c, there is no ten-
dency to keep the phenyl ring in an equatorial position.
We then directed our attention to the kinetic resolution of
3-phenylpent-4-en-1-amine (7), which features a phenyl sub-
stituent in the g position relative to the amino group and in
Cat.
Conv. [%]
8:7’
ee [%][a]
f
(R)-1–Y
(R)-2–Y
47
51
7:1
6:1
39
65
3.7
8.2
[a] ee value of recovered 7, determined by chiral phase HPLC of the 2-
naphthoyl amide of 7 recovered from the reaction mixture.
In our previous study, we reported the kinetic resolution
of hept-6-en-2-amine with a moderate resolution factor of
3.3 using (R)-2–Y at 808C.[11d] We hoped that better resolu-
tion factors may be achieved in the kinetic resolution of the
aryl-substituted aminohexene 9, but, unfortunately, the reso-
lution factor was limited to less than three for this substrate
(Table 7), which was insufficient for a preparative-scale ki-
netic resolution.
Conclusion
Kinetic investigations into the kinetic resolution of chiral
aminopentenes with sterically hindered triarylsilyl-substitut-
ed binaphtholate rare-earth-
metal complexes 1 and 2 were
carried out. These indicated
that substrates with substituents
in the a position that can inter-
act with the metal center (or
the aromatic ring system of the
binaphtholate ligands), for ex-
ample, through p–arene coordi-
nation or an ether donor group,
favor the matching substrate–
catalyst complex, resulting in
good efficiencies in the kinetic
resolution process. Simple ali-
phatic substituents, on the other
hand, favor the mismatching
substrate–catalyst
complex,
which significantly diminishes
the efficiency in the kinetic res-
olution.
Scheme 5. Proposed transition states in the kinetic resolution of 5.
12824
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12819 – 12827

Kinetic Resolution of Aminoalkenes
FULL PAPER
Table 7. Kinetic resolution of aminohexene 9 ([subst.]0 =2.0m) by using
binaphtholate catalysts (R)-1 and (R)-2 at 808C.
extracts were dried over KOH and the solvent was evaporated in vacuo.
The residue was treated with finely powdered CaH2 for 2 h and was then
distilled twice from CaH2 at reduced pressure to give 3 f as a colorless
liquid (4.20 g, 62%). B.p. 1208C at 1 mmHg; 1H NMR (400 MHz,
CDCl3): d=5.85–5.75 (m, 1H; =CH), 5.01–4.87 (m, 2H; =CH2), 2.50–2.43
(m, 1H; CHNH2), 2.22–2.02 (m, 2H; CH2), 1.72–1.51 (m, 6H; CH2),
1.28–0.83 ppm (m, 9H; CH2); 13C{1H} NMR (75.5 MHz, CDCl3): d=138.8
(=CH), 114.3 (=CH2), 55.5, 43.9, 34.0, 30.8, 29.6, 27.8, 26.6, 26.5,
26.4 ppm; HRMS m/z: [M]+ calcd for C11H22N: 168.1752 [MꢀH]+;
found: 168.1747; Mosher adduct 19F NMR (CDCl3, 258C): d=ꢀ69.08
(R), ꢀ69.25 ppm (S).
Cat.
Conv. [%][a]
trans/cis[b]
ee [%][c]
f
(R)-1–Y
(R)-1–Lu
(R)-1–Sc
(R)-2–Y
(R)-2–Lu
(R)-2–Sc
45
51
47
72
55
60
1:3
1:6
1:7
1:2.5
1:5
1:4
11
26
18
11
31
47
1.5
2.1
1.5
1.3
2.2
2.9
1-(Methoxymethyl)pent-4-enylamine (3g): Methoxyacetonitrile (7.11 g
0.10 mol) was added dropwise over 15 min at RT to a solution of but-3-
enemagnesium bromide prepared from 4-bromobut-1-ene (13.5 g,
0.10 mol) and magnesium turnings (2.43 g, 0.10 mol) in THF (100 mL).
The dark-red reaction mixture was stirred at reflux for 2 h. The mixture
was then cooled and quenched with a saturated solution of aqueous am-
monium chloride (100 mL). The product was extracted with diethyl ether
(2ꢃ70 mL). The combined organic layers were washed with water, brine,
and dried over Na2SO4. The solvent was evaporated in vacuo and the res-
idue was dissolved in MeOH (200 mL). Ammonium acetate (61 g,
0.80 mol) and NaBH3CN (3.76 g, 60 mmol) were added in one portion at
room temperature. The mixture was stirred at room temperature for 1 d.
Concentrated HCl was added carefully until pH<2 was reached and the
solvent was removed in vacuo. The residue was dissolved in water
(15 mL) and extracted with diethyl ether (20 mL). The aqueous solution
was brought to pH>12 with solid KOH and extracted with diethyl ether
(3ꢃ20 mL). The combined extracts were dried over KOH and the solvent
was evaporated in vacuo. The residue was treated with finely powdered
calcium hydride for 2 h and was then distilled twice from CaH2 at re-
duced pressure to give 3g as a colorless liquid (4.50 g, 35%). B.p. 95–
[a] Determined by 1H NMR spectroscopy based on an internal standard.
[b] Determined by 1H NMR spectroscopy. [c] ee of recovered 9 deter-
mined by 19F NMR spectroscopy of the corresponding Mosher amide.
Experimental Section
General: All operations were performed under an inert atmosphere of
nitrogen or argon by using standard Schlenk-line or glove box techniques.
Solvents and reagents were purified as stated previously.[11] Complexes 1–
Ln and 2–Ln (Ln=Sc, Y, Lu),[11d] substrates 3a–3d,[11d] 3e,[7i] 5,[7i] and, 7[20]
were prepared according to previously described procedures. (R)-(+)-a-
Methoxy-a-trifluoromethylphenylacetic acid was transformed to its acid
chloride by using oxalyl chloride/DMF in hexanes.[21] Enantiomeric
excess for 3a–3g was measured by 19F NMR spectroscopy of the corre-
sponding Mosher amides as reported previously.[11d] The enantiomeric
excess for 7 was measured by chiral phase HPLC of the corresponding 2-
naphthoyl amide on a Chiralcel OD column, eluent hexane/isopropyl al-
1
1048C at 200 mmHg; H NMR (300 MHz, CDCl3): d=5.86–5.76 (m, 1H;
=CH), 5.04–4.91 (m, 2H; =CH2), 3.34–3.30 (m, 4H, CH3; OCH2), 3.16–
3.11 (m, 1H; OCH2) 2.96–2.92 (m, 1H; CHN), 2.20–2.02 (m, 2H; CH2),
1.50–1.42 (m, 1H; CH2), 1.39–1.30 (m, 1H; CH2), 1.25 ppm (brs, 2H;
NH2); 13C NMR (100 MHz, CDCl3): d=138.4 (=CH), 114.6 (=CH2), 78.2,
58.9, 50.3, 33.4, 30.3 ppm; Mosher adduct 19F NMR ([D6]benzene, 708C):
d=ꢀ69.41 (S), ꢀ69.48 ppm (R).
cohol=90:10, flow rate 1 mLminꢀ1
, retention times 39.0 min (major
isomer obtained from the R catalyst); 41.2 min (minor isomer). The abso-
lute configuration of enantioenriched 7 was established by comparison of
the optical rotation sign of the N-benzoyl derivative with the literature
data.[22]
1-Phenyl-hex-5-en-1-amine (9): Copper(I) iodide (0.19 g, 1.0 mmol) was
[D2]-1-Phenylpent-4-en-1-amine ([D2]3a):
A mixture of 3a (1.60 g,
added to
a solution of benzoyl chloride (4.20 g, 30 mmol) in THF
9.9 mmol), hexanes (5 mL), and D2O (2 mL) was stirred in a sealed flask
at 608C overnight. After cooling to room temperature, the aqueous layer
was separated and discarded. The procedure was repeated twice with
fresh aliquots of D2O (2 mL). The organic layer was dried over molecular
sieves and the solvent was removed in vacuo. The residue was distilled
twice from CaH2 at reduced pressure to give [D2]3a (1.20 g, 74%) as a
colorless liquid (b.p. 1208C, 1 mmHg) with >95% of isotopic substitution
according to 1H NMR spectroscopy. Mosher adduct: 19F NMR
([D6]benzene, 608C): d=ꢀ69.35 (R), ꢀ69.47 ppm (S).
1-Cyclohexylpent-4-en-1-amine (3 f): Copper(I) iodide (200 mg,
1.05 mmol) was added to a solution of cyclohexanecarboxylic acid chlo-
ride (5.84 g, 39.8 mmol) in THF (100 mL). The resulting suspension was
cooled to ꢀ308C and a solution of but-3-enemagnesium bromide pre-
pared from 4-bromobut-1-ene (5.40 g, 40.0 mmol) and magnesium turn-
ings (0.96 g, 39.5 mmol) in THF (100 mL) was added dropwise over 1 h,
while the temperature was maintained below ꢀ208C. The mixture was
stirred at the same temperature for 2 h and was then allowed to warm to
room temperature. The solvent was removed in vacuo, the residue was
dissolved in CH2Cl2 (70 mL) and 1m aqueous HCl (50 mL). The organic
layer was separated, filtered to remove precipitated copper salts, washed
with 10% aqueous NaHCO3, and dried over Na2SO4. The solvent was re-
moved by rotary evaporation and the residue was dissolved in absolute
MeOH. Ammonium acetate (15 g, 200 mmol) and NaBH3CN (1.0 g,
15 mmol) were added in one portion at room temperature. The mixture
was stirred at room temperature for 1 d. Concentrated HCl was added
carefully until pH<2 was reached and the solvent was removed in vacuo.
The residue was dissolved in water (50 mL) and extracted once with
diethyl ether (20 mL). The aqueous solution was brought to pH>12 with
solid KOH and extracted with diethyl ether (3ꢃ20 mL). The combined
(100 mL). The resulting suspension was cooled to ꢀ308C and a solution
of pent-4-enemagnesium bromide prepared from 5-bromopent-1-ene
(4.47 g, 30 mmol), and magnesium turnings (0.72 g, 30 mmol) in THF
(50 mL) was added dropwise over 1 h, while the temperature was main-
tained below ꢀ208C. The mixture was stirred at the same temperature
for 2 h and was then allowed to reach room temperature. The solvent
was removed in vacuo and the residue was dissolved in dichloromethane
(70 mL) and 1m aqueous HCl (50 mL). The organic layer was separated,
filtered to remove precipitated copper salts, washed with 10% aqueous
NaHCO3, and dried over Na2SO4. The solvent was removed in vacuo and
the residue was dissolved in absolute MeOH (100 mL). Ammonium ace-
tate (15 g, 200 mmol) and NaBH3CN (2.0 g, 30 mmol) were added in one
portion at room temperature. The mixture was stirred at room tempera-
ture for 1 d. Concentrated HCl was added carefully until pH<2 was
reached and the solvent was removed in vacuo. The residue was dissolved
in water (50 mL) and extracted once with diethyl ether (20 mL). The
aqueous solution was brought to pH>12 with solid KOH and extracted
with diethyl ether (3ꢃ20 mL). The combined extracts were dried over
KOH and the solvent was evaporated in vacuo. The residue was treated
with finely powdered calcium hydride for 2 h and was then distilled twice
from CaH2 at reduced pressure to yield 9 as a colorless liquid (3.70 g,
1
70%). B.p. 95–998C at 0.5 mmHg; H NMR (400 MHz, CDCl3): d=7.36–
7.25 (m, 5H; aryl-H), 5.85–5.75 (m, 1H; =CH), 5.03–4.94 (m, 2H; =CH2),
3.93 (t, 3J
ACHTNUTRGNEU(GN H,H)=10.3 Hz, 1H; CH), 2.13–2.07 (m, 2H; CH2), 1.76–1.69
(m, 2H; CH2), 1.52–1.45 ppm (m, 4H; CH2 and NH2); 13C{1H} NMR
(75.5 MHz, CDCl3): d=146.7 (aryl), 138.6 (=CH), 128.4, 126.9, 126.3
(aryl), 114.6 (=CH2), 56.2, 39.1, 33.7, 25.8 ppm; Mosher adduct 19F NMR
(CDCl3, 258C): d=ꢀ69.29 (R), ꢀ69.40 ppm (S).
Chem. Eur. J. 2009, 15, 12819 – 12827
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12825

K. C. Hultzsch et al.
General procedure for analytical kinetic resolution: In the glove box, a
screw cap NMR tube was charged with the catalyst (20 mmol),
[D6]benzene (0.5 mL), the substrate (1.00 mmol), and ferrocene (2 mmol)
as the internal standard. The NMR tube was heated in a thermostat-con-
trolled oil bath where required. The conversion was then monitored by
NMR spectroscopy and the reactions were stopped after an appropriate
conversion had been reached. Separation of the product pyrrolidine and
the aminoalkene was achieved by aqueous extraction of the secondary
ammonium acetate from the primary amine benzaldimine.[11c,d]
Acknowledgements
Partial financial support of this research by the Deutsche Forschungsge-
meinschaft (DFG) is gratefully acknowledged. The authors thank Prof.
Daniel Seidel and Eric Klauber for their kind assistance with obtaining
HPLC data.
[1] a) A. Ricci, Modern Amination Methods, Wiley-VCH, Weinheim,
2000; b) A. Ricci, Amino Group Chemistry: From Synthesis to the
Life Sciences, Wiley-VCH, Weinheim, 2008.
General procedure for preparative-scale kinetic resolution: In the glove
box, a flask was charged with the catalyst (0.1 mmol), C6H6 (10 mL), and
substrate (15.00 mmol). The conversion and enantiomeric excess of the
starting material was then monitored by NMR spectroscopy and the reac-
tions were stopped after a minimum of 98% ee had been reached. After
a standard benzaldimine workup procedure,[11c,d] chiral amines were puri-
fied by vacuum distillation from CaH2.
[2] For general reviews on hydroamination, see: a) R. Taube in Applied
Homogeneous Catalysis, Vol. 1, 1st ed. (Eds.: B. Cornils, W. A. Herr-
mann), VCH, Weinheim, 1996, p. 507; b) T. E. Mꢀller, M. Beller,
Chem. Rev. 1998, 98, 675; c) T. E. Mꢀller, M. Beller, Transition
Metals for Organic Synthesis, Vol. 2 (Eds.: M. Beller, C. Bolm),
Wiley-VCH, Weinheim, 1998, p. 316; d) J. J. Brunet, D. Neibecker in
Catalytic Heterofunctionalization from Hydroamination to Hydrozir-
conation (Eds.: A. Togni, H. Grꢀtzmacher), Wiley-VCH, Weinheim,
2001, p. 91; e) M. Nobis, B. Drießen-Hçlscher, Angew. Chem. 2001,
113, 4105; Angew. Chem. Int. Ed. 2001, 40, 3983; f) J. Seayad, A.
Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal. 2002, 344, 795;
g) M. Beller, C. Breindl, M. Eichberger, C. G. Hartung, J. Seayad,
O. R. Thiel, A. Tillack, H. Trauthwein, Synlett 2002, 1579; h) J. F.
Hartwig, Pure Appl. Chem. 2004, 76, 507; i) F. Pohlki, S. Doye,
Chem. Soc. Rev. 2003, 32, 104; j) I. Bytschkov, S. Doye, Eur. J. Org.
Chem. 2003, 935; k) S. Doye, Synlett 2004, 1653; l) S. Hong, T. J.
Marks, Acc. Chem. Res. 2004, 37, 673; m) A. L. Odom, Dalton
Trans. 2005, 225; n) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36,
1407; o) T. E. Mꢀller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Rev. 2008, 108, 3795.
[3] a) P. W. Roesky, T. E. Mꢀller, Angew. Chem. 2003, 115, 2812;
Angew. Chem. Int. Ed. 2003, 42, 2708; b) K. C. Hultzsch, Adv. Synth.
Catal. 2005, 347, 367; c) K. C. Hultzsch, Org. Biomol. Chem. 2005, 3,
1819; d) K. C. Hultzsch, D. V. Gribkov, F. Hampel, J. Organomet.
Chem. 2005, 690, 4441; e) I. Aillaud, J. Collin, J. Hannedouche, E.
Schulz, Dalton Trans. 2007, 5105; f) G. Zi, Dalton Trans. 2009, DOI:
10.1039/b906588a; g) A. L. Reznichenko, K. C. Hultzsch in Chiral
Amine Synthesis (Ed.: T. Nugent), Wiley-VCH, Weinheim, in press.
[4] Sequential alkyne hydroamination–asymmetric hydrosilylation (or
asymmetric transfer hydrogenation) represents an alternative to
asymmetric hydroamination, see: a) A. Heutling, F. Pohlki, I. By-
tschkov, S. Doye, Angew. Chem. 2005, 117, 3011; Angew. Chem. Int.
Ed. 2005, 44, 2951; b) X.-Y. Liu, C.-M. Che, Org. Lett. 2009, 11,
4204.
[D2]-(1S)-1-Phenylpent-4-en-1-amine ([D2]3a): Prepared from (1S)-3a in
an analogous procedure to that used to prepare racemic ([D2]3a). Com-
pound (1S)-3a was resolved from 3a by using (R)-1–Lu as described pre-
viously.[11d]
(1S)-1-(4-Methoxyphenyl)-pent-4-en-1-amine ((S)-3b): Compound (S)-3b
was resolved from 3b by (R)-1–Y (f=18), as a colorless liquid in 36%
yield, b.p. 1058C at 0.2 mmHg. Spectroscopic properties are in agreement
with literature data.[11d]
(1S)-1-(4-Chlorophenyl)-pent-4-en-1-amine ((S)-3c): Compound (S)-3c
was resolved from 3c by (R)-2–Y (f=19), as a colorless liquid in 30%
yield, b.p. 100–1108C at 0.2 mmHg. Spectroscopic properties are in agree-
ment with literature data.[11d]
(2S)-1-Phenylhex-5-en-2-amine ((S)-3d): Compound (S)-3d was resolved
from 3d by (R)-1–Y (f=5), as a colorless liquid in 12% yield, b.p. 1038C
at 0.2 mmHg. Spectroscopic properties are in agreement with literature
data.[11d]
(2R)-Hex-5-en-2-amine ((R)-3e): Compound (R)-3e was resolved from
3e by (R)-2–Y (f=15), as a colorless liquid in 30% yield, b.p. 1148C at
760 mmHg. [a]2D0 =ꢀ5.6 (c=0.5 in MeOH). Spectroscopic properties are
in agreement with literature data.[7i]
(1S)-1-(Cyclohexyl)-hex-5-en-1-amine ((S)-3 f): Compound (S)-3 f was re-
solved from 3 f by (R)-1–Lu (f=6), as a colorless liquid in 9% yield, b.p.
808C at 0.2 mmHg. Spectroscopic properties are identical to those of rac-
emic 3 f.
(1R)-1-(Methoxymethyl)pent-4-enylamine ((R)-3g):[17] A hot solution of
3g (3.48 g, 27 mmol) and (R)-(ꢀ)-mandelic acid (4.12 g, 34 mmol) in iso-
propyl alcohol (40 mL) was allowed to cool slowly to 08C. The precipitat-
ed salt was filtered off after 12 h, dried in air, and recrystallized again.
After 12 recrystallizations, more than 92% ee was achieved, according to
19F NMR spectroscopy of the Mosher amide. The salt was treated with
10% aqueous NaOH (20 mL) and the amine was extracted with diethyl
ether (2ꢃ40 mL). The combined extracts were dried over KOH and the
diethyl ether was evaporated. The residue was distilled twice from CaH2
under reduced pressure to give (R)-3g as a colorless liquid (0.45 g, 12%),
b.p. 94–1028C at 200 mmHg. Spectroscopic properties are identical to
those of racemic 3g.
[5] For some recent examples, see: a) A. Tillack, V. Khedkar, H. Jiao,
M. Beller, Eur. J. Org. Chem. 2005, 5001; b) J. Takaya, J. F. Hartwig,
J. Am. Chem. Soc. 2005, 127, 5756; c) C. S. Yi, S. Y. Yun, I. A.
Guzei, J. Am. Chem. Soc. 2005, 127, 5782; d) J.-J. Brunet, N. C. Chu,
O. Diallo, Organometallics 2005, 24, 3104; e) A. M. Johns, M. Utsu-
nomiya, C. D. Incarvito, J. F. Hartwig, J. Am. Chem. Soc. 2006, 128,
1828; f) O. Jimenez, T. E. Mꢀller, C. Siever, A. Spirkl, J. A. Lercher,
Chem. Commun. 2006, 2974; g) R. L. LaLonde, B. D. Sherry, E. J.
Kang, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 2452; h) J. Zhou,
J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 12220; i) Z. Zhang, S. D.
Lee, R. A. Widenhoefer, J. Am. Chem. Soc. 2009, 131, 5372.
[6] For hydroamination catalyzed by cyclopentadienyl rare-earth-metal
complexes, see: a) M. R. Gagnꢄ, C. L. Stern, T. J. Marks, J. Am.
Chem. Soc. 1992, 114, 275; b) Y. Li, T. J. Marks, J. Am. Chem. Soc.
1996, 118, 9295; c) Y. Li, T. J. Marks, J. Am. Chem. Soc. 1998, 120,
1757; d) A. T. Gilbert, B. L. Davis, T. J. Emge, R. D. Broene, Orga-
nometallics 1999, 18, 2125; e) V. M. Arredondo, S. Tian, F. E. McDo-
nald, T. J. Marks, J. Am. Chem. Soc. 1999, 121, 3633; f) G. A. Mo-
lander, E. D. Dowdy, J. Org. Chem. 1999, 64, 6515; g) V. M. Arre-
dondo, F. E. McDonald, T. J. Marks, Organometallics 1999, 18, 1949;
h) G. A. Molander, E. D. Dowdy, S. K. Pack, J. Org. Chem. 2001, 66,
4344; i) G. A. Molander, S. K. Pack, Tetrahedron 2003, 59, 10581;
j) G. A. Molander, S. K. Pack, J. Org. Chem. 2003, 68, 9214; k) J.-S.
Ryu, G. Y. Li, T. J. Marks, J. Am. Chem. Soc. 2003, 125, 12584; l) J.
(2S)-2-Phenyl-pent-4-en-1-amine ((S)-5): A hot solution of racemic 5
(5.44 g, 34 mmol) and (R)-(ꢀ)-mandelic acid (5.19 g, 34 mmol) in ethanol
(40 mL) was allowed to cool slowly to 08C. The precipitated salt was fil-
tered off, dried in air, and recrystallized again. After 13 recrystallizations,
ꢄ98% ee was reached according to 19F NMR spectroscopy of the Mosher
amide. The salt was treated with 20% aqueous NaOH (20 mL) and the
amine was extracted with Et2O (2ꢃ40 mL). The combined extracts were
dried over KOH and the diethyl ether was evaporated in vacuo. The re-
sulting residue was distilled twice from CaH2 under reduced pressure
(b.p. 1028C at 0.1 mmHg) to give (S)-5 as a colorless liquid (0.75 g,
13%). Spectroscopic data are in agreement with the data reported in the
literature.[7i]
12826
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 12819 – 12827

Kinetic Resolution of Aminoalkenes
FULL PAPER
Zhao, T. J. Marks, Organometallics 2006, 25, 4763; m) S. B. Amin,
S. Y. Seo, T. J. Marks, Organometallics 2008, 27, 2411; n) H. F. Yuen,
T. J. Marks, Organometallics 2009, 28, 2423.
Scott, Dalton Trans. 2004, 2251; f) J. Y. Kim, T. Livinghouse, Org.
Lett. 2005, 7, 1737; g) J. Collin, J.-D. Daran, O. Jacquet, E. Schulz,
A. Trifonov, Chem. Eur. J. 2005, 11, 3455; h) D. Riegert, J. Collin, A.
Meddour, E. Schulz, A. Trifonov, J. Org. Chem. 2006, 71, 2514; i) N.
Meyer, A. Zulys, P. W. Roesky, Organometallics 2006, 25, 4179; j) H.
Kim, Y. K. Kim, J. H. Shim, M. Kim, M. Han, T. Livinghouse, P. H.
Lee, Adv. Synth. Catal. 2006, 348, 2609; k) X. Yu, T. J. Marks, Orga-
nometallics 2007, 26, 365; l) R. Heck, E. Schulz, J. Collin, J.-F. Car-
pentier, J. Mol. Catal. A 2007, 268, 163; m) D. Riegert, J. Collin, J.-
D. Daran, T. Fillebeen, E. Schulz, D. Lyubov, G. Fukin, A. Trifonov,
Eur. J. Inorg. Chem. 2007, 1159; n) L. Xiang, Q. Wang, H. Song, G.
Zi, Organometallics 2007, 26, 5323; o) J. Hannedouche, I. Aillaud, J.
Collin, E. Schulz, A. Trifonov, Chem. Commun. 2008, 3552; p) G.
Zi, L. Xiang, H. Song, Organometallics 2008, 27, 1242; q) I. Aillaud,
D. Lyubov, J. Collin, R. Guillot, J. Hannedouche, E. Schulz, A. Tri-
fonov, Organometallics 2008, 27, 5929; r) Q. Wang, L. Xiang, H.
Song, G. Zi, Inorg. Chem. 2008, 47, 4319.
[7] For achiral, non-metallocene, rare-earth-metal-based hydroamina-
tion catalysts, see: a) M. R. Bꢀrgstein, H. Berberich, P. W. Roesky,
Organometallics 1998, 17, 1452; b) M. R. Bꢀrgstein, H. Berberich,
P. W. Roesky, Chem. Eur. J. 2001, 7, 3078; c) Y. K. Kim, T. Living-
house, J. E. Bercaw, Tetrahedron Lett. 2001, 42, 2933; d) Y. K. Kim,
T. Livinghouse, Angew. Chem. 2002, 114, 3797; Angew. Chem. Int.
Ed. 2002, 41, 3645; e) Y. K. Kim, T. Livinghouse, Y. Horino, J. Am.
Chem. Soc. 2003, 125, 9560; f) F. Lauterwasser, P. G. Hayes, S.
Brꢁse, W. E. Piers, L. L. Schafer, Organometallics 2004, 23, 2234;
g) K. C. Hultzsch, F. Hampel, T. Wagner, Organometallics 2004, 23,
2601; h) T. K. Panda, A. Zulys, M. T. Gamer, P. W. Roesky, Organo-
metallics 2005, 24, 2197; i) J. Y. Kim, T. Livinghouse, Org. Lett. 2005,
7, 4391; j) S. Bambirra, H. Tsurugi, D. van Leusen, B. Hessen,
Dalton Trans. 2006, 1157; k) H. Kim, T. Livinghouse, J. H. Shim,
S. G. Lee, P. H. Lee, Adv. Synth. Catal. 2006, 348, 701; l) M. Rastꢁt-
ter, A. Zulys, P. W. Roesky, Chem. Eur. J. 2007, 13, 3606; m) E. Lu,
W. Gan, Y. Chen, Organometallics 2009, 28, 2318.
[8] For catalyst systems for the hydroamination of aminoalkenes based
on metals other than rare-earth metals, see: a) A. Ates, C. Quinet,
Eur. J. Org. Chem. 2003, 1623; b) P. D. Knight, I. Munslow, P. N.
OꢅShaughnessy, P. Scott, Chem. Commun. 2004, 894; c) D. V. Grib-
kov, K. C. Hultzsch, Angew. Chem. 2004, 116, 5659; Angew. Chem.
Int. Ed. 2004, 43, 5542; d) J. A. Bexrud, J. D. Beard, D. C. Leitch,
L. L. Schafer, Org. Lett. 2005, 7, 1959; e) C. F. Bender, R. A. Widen-
hoefer, J. Am. Chem. Soc. 2005, 127, 1070; f) M. R. Crimmin, I. J.
Casely, M. S. Hill, J. Am. Chem. Soc. 2005, 127, 2042; g) H. Kim,
P. H. Lee, T. Livinghouse, Chem. Commun. 2005, 5205; h) N. Meyer,
K. Lçhnwitz, A. Zulys, P. W. Roesky, M. Dochnahl, S. Blechert, Or-
ganometallics 2006, 25, 3779; i) R. K. Thomson, J. A. Bexrud, L. L.
Schafer, Organometallics 2006, 25, 4069; j) D. A. Watson, M. Chiu,
R. G. Bergman, Organometallics 2006, 25, 4731; k) P. Horrillo-Martꢆ-
nez, K. C. Hultzsch, F. Hampel, Chem. Commun. 2006, 2221;
l) M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, L. L. Schafer,
Angew. Chem. 2007, 119, 358; Angew. Chem. Int. Ed. 2007, 46, 354;
m) A. L. Gott, A. J. Clarke, G. J. Clarkson, P. Scott, Organometallics
2007, 26, 1729; n) B. D. Stubbert, T. J. Marks, J. Am. Chem. Soc.
2007, 129, 4253; o) B. D. Stubbert, T. J. Marks, J. Am. Chem. Soc.
2007, 129, 6149; p) T. Ogata, A. Ujihara, S. Tsuchida, T. Shimizu, A.
Kaneshige, K. Tomioka, Tetrahedron Lett. 2007, 48, 6648; q) C. Liu,
J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 1570; r) C. F. Bender,
W. B. Hudson, R. A. Widenhoefer, Organometallics 2008, 27, 2356;
s) C. Quinet, P. Jourdain, C. Hermans, A. Ates, I. Lucas, I. E.
Markꢇ, Tetrahedron 2008, 64, 107; t) A. L. Gott, A. J. Clarke, G. J.
Clarkson, P. Scott, Chem. Commun. 2008, 1422; u) A. L. Gott, G. J.
Clarkson, R. J. Deeth, M. L. Hammond, C. Morton, P. Scott, Dalton
Trans. 2008, 2983; v) P. Horrillo-Martꢆnez, K. C. Hultzsch, Tetrahe-
dron Lett. 2009, 50, 2054; w) K. Lçhnwitz, M. J. Molski, A. Lꢀhl,
P. W. Roesky, M. Dochnahl, S. Blechert, Eur. J. Inorg. Chem. 2009,
1369; x) M. R. Crimmin, M. Arrowsmith, A. G. M. Barrett, I. J.
Casely, M. S. Hill, P. A. Procopiou, J. Am. Chem. Soc. 2009, 131,
9670.
[11] a) D. V. Gribkov, K. C. Hultzsch, F. Hampel, Chem. Eur. J. 2003, 9,
4796; b) D. V. Gribkov, F. Hampel, K. C. Hultzsch, Eur. J. Inorg.
Chem. 2004, 4091; c) D. V. Gribkov, K. C. Hultzsch, Chem.
Commun. 2004, 730; d) D. V. Gribkov, K. C. Hultzsch, F. Hampel, J.
Am. Chem. Soc. 2006, 128, 3748.
[12] For general reviews on the application of chiral rare-earth-metal cat-
alysts in organic synthesis, see: a) K. Mikami, M. Terada, H. Matsu-
zawa, Angew. Chem. 2002, 114, 3704; Angew. Chem. Int. Ed. 2002,
41, 3554; b) H. C. Aspinall, Chem. Rev. 2002, 102, 1807; c) M. Shiba-
saki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187; d) S. Kobayashi, M.
Sugiura, H. Kitagawa, W. W.-L. Lam, Chem. Rev. 2002, 102, 2227.
[13] For general reviews on the chemistry of cyclopentadienyl-free rare-
earth-metal complexes, see: a) F. T. Edelmann, Angew. Chem. 1995,
107, 2647; Angew. Chem. Int. Ed. Engl. 1995, 34, 2466; b) F. T. Edel-
mann, D. M. M. Freckmann, H. Schumann, Chem. Rev. 2002, 102,
1851; c) W. E. Piers, D. J. H. Emslie, Coord. Chem. Rev. 2002, 233–
234, 131.
[14] For the gold-catalyzed dynamic kinetic resolution of aminoallenes
through hydroamination–cyclization, see: Z. Zhang, C. F. Bender,
R. A. Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148.
[15] The (dynamic) kinetic resolution of racemic amines can be effected
by using various enzymatic methodologies; for selected examples,
see: a) F. van Rantwijk, R. A. Sheldon, Tetrahedron 2004, 60, 501;
b) C. J. Dunsmore, R. Carr, T. Fleming, N. J. Turner, J. Am. Chem.
Soc. 2006, 128, 2224; c) A. N. Parvulescu, P. A. Jacobs, D. E. De Vos,
Chem. Eur. J. 2007, 13, 2034; d) C. E. Hoben, L. Kanupp, J.-E. Bꢁck-
vall, Tetrahedron Lett. 2008, 49, 977; e) A. N. Parvulescu, P. A.
Jacobs, D. E. De Vos, Adv. Synth. Catal. 2008, 350, 113; f) H. Ismail,
R. M. Lau, F. van Rantwijk, R. A. Sheldon, Adv. Synth. Catal. 2008,
350, 1511; g) M. D. Truppo, N. J. Turner, J. D. Rozzell, Chem.
Commun. 2009, 2127.
[16] For the sake of simplicity kR/kS represents kfast/kslow for all substrates.
Note, however, that for substrate 3e the S enantiomer is the faster
reacting enantiomer when using the (R)-binaphtholate catalysts.
[17] A preliminary X-ray crystallographic analysis of the ammonium salt
of (R)-3g with (R)-(ꢀ)-mandelic acid confirmed the assigned abso-
lute configuration relative to the known configuration of mandelic
acid. Also, the 19F NMR spectroscopic chemical shift of the Mosher
amide of 3g obtained in the fractional crystallization is in agreement
with this assignment.
[9] For asymmetric hydroamination catalyzed by cyclopentadienyl rare-
earth-metal complexes, see: a) M. A. Giardello, V. P. Conticello, L.
Brard, M. R. Gagnꢄ, T. J. Marks, J. Am. Chem. Soc. 1994, 116,
10241; b) M. R. Douglass, M. Ogasawara, S. Hong, M. V. Metz, T. J.
Marks, Organometallics 2002, 21, 283; c) S. Hong, A. M. Kawaoka,
T. J. Marks, J. Am. Chem. Soc. 2003, 125, 15878; d) J.-S. Ryu, T. J.
Marks, F. E. McDonald, J. Org. Chem. 2004, 69, 1038; e) D. V. Vita-
nova, F. Hampel, K. C. Hultzsch, J. Organomet. Chem. 2007, 692,
4690.
[10] a) P. N. OꢅShaughnessy, P. D. Knight, C. Morton, K. M. Gillespie, P.
Scott, Chem. Commun. 2003, 1770; b) P. N. OꢅShaughnessy, P. Scott,
Tetrahedron: Asymmetry 2003, 14, 1979; c) S. Hong, S. Tian, M. V.
Metz, T. J. Marks, J. Am. Chem. Soc. 2003, 125, 14768; d) J. Collin,
J.-D. Daran, E. Schulz, A. Trifonov, Chem. Commun. 2003, 3048;
e) P. N. OꢅShaughnessy, K. M. Gillespie, P. D. Knight, I. Munslow, P.
[18] M. N. Bochkarev, Chem. Rev. 2002, 102, 2089.
[19] CCDC-739753 contains the supplementary crystallographic data for
the (R)-Mosher amide of (S)-5. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[20] Q. Yang, J. E. Ney, J. P. Wolfe, Org. Lett. 2005, 7, 2575.
[21] P. M. Smith, E. J. Thomas, J. Chem. Soc. Perkin Trans. 1 1998, 3541.
[22] M. Gao, D.-X. Wang, Q.-Y. Zheng, M.-X. Wang, J. Org. Chem. 2006,
71, 9532.
Received: August 11, 2009
Published online: October 15, 2009
Chem. Eur. J. 2009, 15, 12819 – 12827
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12827