Non-metallocene rare earth metal catalysts for the diastereoselective and enantioselective hydroamination of aminoalkenes

Article abstract of DOI:10.1016/j.jorganchem.2004.11.058

In this short review we summarize our work on new cyclopentadienyl-free rare earth metal catalysts for the diastereoselective and enantioselective hydroamination of aminoalkenes. Non-metallocene rare earth metal catalysts based on diamidoamine, biphenolate and binaphtholate ligands are readily available through alkane and amine elimination procedures. Diamidoamine yttrium complexes are efficient catalysts for the highly diastereoselective cyclization of 1-methyl-pent-4-enylamine to yield trans-2,5-dimethyl-pyrroldine with trans to cis ratios of up to 23:1. The X-ray crystal structural analysis of [((2,6-Et₂C₆H₃NCH₂CH ₂)₂NMe)Y{N(SiMe₃)₂}] is reported in which yttrium is coordinated in a highly distorted tetrahedral fashion. 3,3′-Di-tert-butyl substituted biphenolate complexes tend to form phenolate-bridged hetero- and homochiral dimers. The low steric demand of the tert-butyl substituents resulted also in low enantioselectivities in hydroamination/cyclization reactions. Binaphtholate complexes with sterically more demanding tris(aryl)silyl substituents were more efficient catalysts; giving enantioselectivities of up to 83% ee. These catalysts could also be applied in kinetic resolution of chiral aminoalkenes giving k_rel values as high as 16. Catalyst activities strongly depend on the reactivity of the leaving group which is protolytically exchanged for the substrate during the initiation step. Complexes with bis(dimethylsilyl)amido ligand initiate rather sluggishly because of the low basicity of this amido ligand and appreciable catalytic activity is only observed at elevated temperatures. Aryl and Alkyl complexes showed significant better rates comparable in magnitude to lanthanocene catalysts.

Full text of DOI:10.1016/j.jorganchem.2004.11.058

Journal of Organometallic Chemistry 690 (2005) 4441–4452
www.elsevier.com/locate/jorganchem
Non-metallocene rare earth metal catalysts for the
diastereoselective and enantioselective hydroamination
of aminoalkenes q
*
Kai C. Hultzsch , Denis V. Gribkov, Frank Hampel
Institut fu¨r Organische Chemie, Friedrich-Alexander Universita¨t, Erlangen-Nu¨rnberg, Henkestr. 42, D-91054 Erlangen, Germany
Received 29 September 2004; received in revised form 11 November 2004; accepted 11 November 2004
Available online 16 February 2005
Abstract
In this short review we summarize our work on new cyclopentadienyl-free rare earth metal catalysts for the diastereoselective
and enantioselective hydroamination of aminoalkenes. Non-metallocene rare earth metal catalysts based on diamidoamine,
biphenolate and binaphtholate ligands are readily available through alkane and amine elimination procedures. Diamidoamine
yttrium complexes are efficient catalysts for the highly diastereoselective cyclization of 1-methyl-pent-4-enylamine to yield
trans-2,5-dimethyl-pyrroldine with trans to cis ratios of up to 23:1. The X-ray crystal structural analysis of [((2,6-Et2C6-
H3NCH2CH2)2NMe)Y{N(SiMe3)2}] is reported in which yttrium is coordinated in a highly distorted tetrahedral fashion. 3,30-
Di-tert-butyl substituted biphenolate complexes tend to form phenolate-bridged hetero- and homochiral dimers. The low steric
demand of the tert-butyl substituents resulted also in low enantioselectivities in hydroamination/cyclization reactions. Binaphth-
olate complexes with sterically more demanding tris(aryl)silyl substituents were more efficient catalysts; giving enantioselectivities
of up to 83% ee. These catalysts could also be applied in kinetic resolution of chiral aminoalkenes giving krel values as high as 16.
Catalyst activities strongly depend on the reactivity of the leaving group which is protolytically exchanged for the substrate
uring the initiation step. Complexes with bis(dimethylsilyl)amido ligand initiate rather sluggishly because of the low basicity
of this amido ligand and appreciable catalytic activity is only observed at elevated temperatures. Aryl and Alkyl complexes
showed significant better rates comparable in magnitude to lanthanocene catalysts.
ꢀ 2005 Elsevier B.V. All rights reserved.
Keywords: Asymmetric catalysis; Hydroamination; Rare earth metals; Non-metallocene complexes
1. Introduction
synthesis of basic and fine chemicals, pharmaceuticals
and other industrially relevant building blocks starting
from inexpensive precursors [1].
The hydroamination is a highly atom economical
process in which an amine N–H bond is added to an
unsaturated carbon–carbon bond (Eqs. 1 and 2). This
reaction is of great potential interest for the waste-free
R2
R1
R1
R2
N
H
N
ð1Þ
ð2Þ
+
N H
q
This paper was first presented at the XIVth International Confer-
ence on Homogeneous Catalysis, Munich, July 7, 2004.
R
R
H
*
N H
Corresponding author. Fax: +49 9131 852 6865.
E-mail address: hultzsch@chemie.uni-erlangen.de (K.C. Hultzsch).
0022-328X/$ - see front matter ꢀ 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.11.058

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K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
The transition metal catalyzed hydroamination has
like transition state (for n = 1). This step is approximately
thermoneutral [9] and it is usually also the rate determin-
ing step, giving rise to a zero order rate dependence on
substrate concentration and first order rate dependence
on catalyst concentration. The resulting rare earth metal
alkyl species undergoes fast protonolysis with a second
amine molecule, regenerating the rare earth metal amido
species and releasing the heterocyclic product.
The first asymmetric hydroamination catalysts based
on chiral rare earth metal amido complexes were re-
ported by Marks and coworkers in 1992 [10]. Unfortu-
nately, these C1-symmetric chiral ansa-lanthanocenes
underwent facile epimerization under the conditions of
catalytic hydroamination via reversible protolytic cleav-
age of the metal cyclopentadienyl bond (Scheme 2) [10–
12]. Obviously, such an epimerization process is highly
unfavourable for efficient asymmetric catalysis. In fact,
the enantiomeric excess and absolute configuration of
the hydroamination product was independent of the dia-
stereomeric purity of the chiral lanthanocene precatalyst
employed [10c]. Furthermore, enantiomeric excess of
hydroamination products obtained with these catalysts
was limited below 75% ee.
A configurationally stable catalyst seemed to us a sine
qua non for efficient asymmetric catalysis. We therefore
decided to develop hydroamination catalyst systems
based on non-cyclopentadienyl ligand sets [13], which
should have comparable catalytic activity to the lant-
hanocene systems, but should not epimerize under the
reaction conditions of catalytic hydroamination. A sec-
ond advantage of non-cyclopentadienyl ligands would
be that chiral ligands are usually more easily accessible
and can be readily modified [14].
the significant advantage that stereo- and regiochemistry
(e.g., Markovnikov/anti-Markovnikov addition) of the
hydroamination product may be controlled by tuning
the steric and electronic properties of the ligand frame-
work. In particular the generation of new stereogenic
centers during the hydroamination process constitutes
an attractive application of this reaction, but the devel-
opment of chiral catalysts for the asymmetric hydroam-
ination of alkenes (AHA) has remained challenging [2].
Over the past two decades catalyst systems based on
early (groups 3–5, as well as lanthanides and actinides)
[1h,1i,1j,1k,3] and late (groups 8–10) [1g,4] transition
metals have been developed [5]. Unfortunately, most
systems suffer from restrictions in the choice of sub-
strates. Commonly only alkynes, activated alkenes
(e.g., alkenes with electron withdrawing groups at-
tached, vinyl arenes, 1,3-dienes or ring-strained alkenes)
and certain types of amines (e.g., anilines) react. Marks
and coworkers on the other hand have pioneered cata-
lyst systems based on rare earth metals that are highly
reactive towards simple alkene substrates [1k,6,7],
although the number of reports on intermolecular rare
earth metal catalyzed reactions are limited [8] and most
investigations have focused on intramolecular hydroam-
ination reactions.
The mechanism of the rare earth metal catalyzed intra-
molecular hydroamination involves a metal amido spe-
cies, which is generated in an activation step via
protolytic exchange of an alkyl or amido ligand in the pre-
catalyst by the aminoalkene substrate (Scheme 1) [6,9]. In
the first step of the catalytic cycle the alkene inserts into
the metal amido bond through a seven-membered chair-
H2N
n = 1, 2
n
[Ln]
X
X = alkyl, aryl, amido
HX
Catalyst Activation
H
N
H
N
[Ln]
*
n
Olefin Insertion
n
∆H ~ 0 kcal/mol
Protonolysis
H
N
∆H ~ -13 kcal/mol
[Ln]
n
H2N
H
N
n
[Ln]
*
n
Scheme 1. Simplified mechanism for rare earth metal catalyzed hydroamination/cyclization.

K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
4443
- H NR
NHR
NH2R
(S)
+ H NR
2
2
NHR
NHR
NHR
NH2R
(R)
Si
Ln
Si
Ln
Si
Ln
+ H NR
- H NR
2
2
R*
NH2R
R*
H
R*
Scheme 2. Epimerization of chiral lanthanocene complexes during the hydroamination reaction (R* = (ꢁ)-menthyl, (ꢁ)-phenylmenthyl, (+)-
neomenthyl) [10,12].
When we began our studies in 2001, the number of
non-metallocene rare earth metal hydroamination
catalyst systems was limited [15]. Since then, however,
several reports have appeared on the application
of non-metallocene rare earth metal catalysts in
diastereoselective [16] and enantioselective [17]
hydroamination.
ing a-olefin polymerization catalysis [18]. The complexes
could be prepared conveniently in good to excellent
yield via amine or arene elimination starting from
tris(amido) yttrium or tris(o-C6H4CH2NMe2) yttrium
precursors (Scheme 3) [19]. Whereas the bis(dimethylsi-
lyl)amido complex 1 was obtained under mild reaction
conditions, the corresponding bis(trimethylsilyl)amido
complexes 2 required much harsher reaction conditions
because of formation of undesired by-products at lower
reaction temperatures. The amido complexes 1 and 2
showed high thermal stability, but aryl complex 3a
decomposed at room temperature (t1/2 ꢀ 6 h), probably
via C–H activation of the ortho-methyl group of the
mesityl substituent. Indicative for this assumption was
the decreased rate of decomposition for the sterically
2. Diamidoamine catalysts for diastereoselective
hydroamination of aminoalkenes
2.1. Synthesis and structure of diamidoamine complexes
As one of our first non-chiral model systems we chose
complexes based on tridentate diamidoamine ligands,
which had been successfully applied in group 4 metal liv-
more demanding ethyl substituted complex 3b (t1/2
2.5 d) and the absence of decomposition in case of the
ꢀ
Me
Me
Me
O
Me
Me
N
+ [Y{N(SiHMe2)2}3(THF)2]
Me
Y
N
1
N(SiHMe2)2
Me
N
toluene, 50 ˚C, 2 d
R'
R'
R'
R'
R
R
R
N
H
N(SiMe3)2
R
R
R
N
+ [Y{N(SiMe3)2}3]
N
R
Y
N
H
N
N
toluene, 120 ˚C, 1 d
Me
R
2a-c
a R = R' = Me
b R = Et, R' = H
c R = Cl, R' = H
R'
R'
Me
R
Me
N
R
R
N
+ [Y(o-C6H4CH2NMe2)3]
toluene, 25 ˚C, 3 - 4 h
R
Y
N
N
Me
3a-c
Scheme 3. Synthesis of diamidoamine complexes via amine or arene elimination.

4444
K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
2,6-dichlorophenyl substituted complex 3c after 4 d at
25 ꢁC and 1 h at 70 ꢁC.
Complexes 1 and 3b have distorted trigonal bipyrami-
dal geometries with a diamidoamine ligand adopting a
fac coordination mode (Figs. 1 and 2) [19]. The structure
of four coordinate complex 2b [20] can be seen as being
intermediate between tetrahedral and seesaw geometry
(Fig. 3). The geometry of the diamidoamine ligand in
2b is very similar to that in 1 and 3b, despite the lower
coordination number of yttrium in this complex (Table
1). Furthermore the bond length of yttrium to the diam-
idoamine ligand are only slightly shorter in 2b than in 1,
but comparable to those in 3b. The unsaturation of yt-
trium is manifested in two short contacts with methyl
groups of the bis(trimethylsilyl)amido ligand, suggesting
Fig. 3. Structure of four coordinate diamidoamine complex 2b.
Table 1
Comparison of selected bond lengths (A), atomic distances (A) and
˚
˚
angles (ꢁ) for diamidoamine yttrium complexes 1, 2b and 3b
1
2b
3b
Y1–N1
Y1–N2
Y1–N3
Y1–N4
2.240(3)
2.480(3)
2.245(3)
2.263(3)
2.223(4)
2.492(3)
2.185(3)
2.233(3)
2.172(4)
2.466(3)
2.219(4)
2.527(3)
Y1ꢂ ꢂ ꢂC32
Y1ꢂ ꢂ ꢂC42
Y1ꢂ ꢂ ꢂSi1
Y1ꢂ ꢂ ꢂSi2
3.019(5)
3.064(6)
3.560(1)
3.195(1)
3.2657(12)
3.3101(11)
N1–Y1–N2
N1–Y1–N3
N2–Y1–N3
N1–Y1–N4
N2–Y1–N4
N3–Y1–N4
Si1–N4–Si2
Y1–N4–Si1
Y1–N4–Si2
71.08(10)
117.55(10)
72.94(10)
111.98(10)
99.80(9)
73.63(14)
117.58(13)
72.37(12)
118.28(14)
144.24(12)
120.04(14)
134.1(2)
73.67(12)
119.51(14)
71.96(12)
118.34(13)
167.48(13)
102.71(12)
Fig. 1. Structure of five coordinate diamidoamine complex 1.
123.23(10)
125.32(16)
127.31(15)
106.63(13)
111.86(17)
114.08(18)
the presence of b-SiC agostic interactions similar to pre-
viously characterized bis(trimethylsilyl)amido com-
plexes [21].
2.2. Catalytic hydroamination/cyclization of
aminoalkenes
Complexes 2 and 3 displayed good catalytic activity
in the cyclization of aminoalkene 4 at room temperature
(TOF 7.6–10 hꢁ1 for 2a,b and 3a,b; 1.2 hꢁ1 for 2c and
3c, Eq. (3)) which is close to that of homoleptic
[Y{N(SiMe3)2}3] (10 hꢁ1). The bis(dimethylsilyl)amido
complex 1 on the other hand showed diminished cata-
lytic activity and required higher reaction temperatures
(1.3 hꢁ1 at 40 ꢁC). The catalytic activity of 2a and 3a
Fig. 2. Structure of five coordinate diamidoamine complex 3b.

K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
4445
the metal. However, no ligand dissociation was observed
for both catalysts in catalytic reactions of the sterically
more demanding gem-dimethyl substituted 4.
[Ln] NR2
H2N
Keq
+
Keq < 1 for R = SiHMe2
Keq >> 1 for R = SiMe3
Cyclization of 1-methyl-pent-4-enylamine (8) leads to
cis-and trans-2,5-dimethyl-pyrrolidine (9). Therefore,
this substrate was chosen to quantify catalytic activity
as well as diastereoselectivity of the catalysts. The pre-
ferred formation of the trans diastereomer can be ex-
plained with minimal 1,3-diaxial interactions in the
cyclization transition state (Fig. 4) [6,24]. Simple homo-
leptic tris(amido) complexes [Ln{N(SiMe3)2}3] are infe-
rior catalysts for this particular substrate [15c,16a,19],
requiring high reaction temperatures and giving poor
diastereoselectivities.
Livinghouse et al. reported the facile cyclization of
this substrate under relative mild conditions (60 ꢁC) with
high diastereoselectivities (up to 19:1) using a catalyst
system generated in situ from [Ln{N(SiMe3)2}3] and a
vicinal diamine [16]. Unfortunately, information on
the nature of the catalytically active species remained
limited [25], hampering the elucidation of structure–
reactivity/selectivity relationships.
The well-defined diamidoamine complexes 2 and 3
displayed not only good catalytic activity even at room
temperature, but also excellent trans:cis diastereoselec-
tivity of up to 23:1 (Table 3). The sterically least demand-
ing 2,6-dichlorophenyl substituted diamidoamine
complexes gave the lowest trans to cis ratio of 14:1.
Catalysts 2 and 3 were also shown to be reactive
towards secondary amines in the bicyclization of
aminodiene 10 (Scheme 5), producing 1-aza-bicy-
clo[2.2.1]heptane derivatives. The first cyclization step
generated pyrrolidine 11 with turnover frequencies
>55 hꢁ1 at room temperature, but low diastereoselec-
tivities (61.4:1). The second cyclization usually requires
heating to 60 ꢁC and the aza-bicyclic product 12 was
generated as a mixture of (endo:exo) and (exo:exo)
H
N
+ HNR2
[Ln]
Scheme 4. Equilibrium of catalyst activation.
was only slightly diminished in the presence of a few
equivalents of THF, indicating that the low catalytic
activity of 1 is not a result of catalyst deactivation by
coordinated THF. In fact, the lower basicity of the
bis(dimethylsilyl)amido ligand in comparison to the
bis(trimethylsilyl)amido ligand [22] results in an incom-
plete initiation (Scheme 4) and only a small amount
(<20%) of the precatalyst enters the catalytic cycle.
H
N
2 - 3 mol% 2 or 3
NH2
ð3Þ
25 ˚C
TOF up to 10 h-1
4
5
The Thorpe–Ingold-effect [23] favors the cyclization
of gem-dialkyl substituted 4 in comparison to unsubsti-
tuted aminopentene 6, resulting in a 2- to 10-fold in-
crease in the cyclization rate for most catalyst systems.
However, the mesityl substituted complex 3a showed
essentially no activity in the cyclization of 6, similar to
the tris(amido) complex [Y{N(SiMe3)2}3] (Table 2). In
contrast to that, complex 3c catalyzed the cyclization
of 6 with significant better activity. An explanation for
this unexpected difference in reactivity of the two diam-
idoamine catalysts 3a and 3c was uncovered by NMR
spectroscopic investigations, which showed that in case
of catalyst 3a the tridentate diamidoamine ligand was
protolytically cleaved from the metal by substrate 6.
In case of catalyst 3c on the other hand, the less
basic diamidoamine ligand with electron withdrawing
dichlorophenyl substituents remained coordinated to
isomers
(1.4:1
for
2b).
Bicyclization
using
[Y{N(SiMe3)2}3] proceeded faster (4 h, 60 ꢁC, >98%
conv.), but afforded an equimolar mixture of the two
aza-bicyclic diastereomers.
H
N
H
N
Me
[Ln]
[Ln]
Table 2
Cyclization of pent-4-enylamine (6)
Me
H
N
favored
disfavored
3 mol% cat.
NH2
H
N
H
N
7
6
Catalyst
T (ꢁC)
t (h)
Conversion (%)
cis-9
trans-9
3a
3c
90
60
80
30
60
4
97
6
Fig. 4. Plausible cyclization transition states for the preferred forma-
tion of trans-2,5-dimethyl-pyrrolidine (9).
[Y{N(SiMe3)2}3]
216

4446
K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
Table 3
Catalytic hydroamination/cyclization of 1-methyl-pent-4-enylamine (8)
within one lanthanum-biphenolate chelate (La1–O11)
˚
is 0.10–0.14 A longer than the La–O bond to the other
H
N
H
N
lanthanum-biphenolate moiety (La1–O110). The geome-
try of the biphenolate ligand is strongly dependent on
the coordination number of the metal. Hence, the bite
angle of the biphenolate ligand (O11–La1–O21) and
the dihedral angle between the two phenolate rings is in-
creased upon going from five coordinate (R,S)-14b to
four coordinate (R,R)-15.
3 mol% cat.
NH2
+
8
cis-9
trans-9
Catalyst
T (ꢁC)
TOF (hꢁ1
)
d.r.(trans:cis)
2a
2b
2ca
3a
3b
3c
25
25
25
25
25
25
90
5.2
6.2
9.1
7.8
4.3
6.8
22:1
19:1
14:1
22:1
23:1
13.5:1
4:1b
3.2. Asymmetric hydroamination/cyclization of
aminoalkenes
[La{N(SiMe3)2}3]
a
Our initial catalytic investigations revealed that the
biphenolate yttrium bis(dimethylsilyl)amido complex
(R)-13 exhibited only low catalytic activity even at ele-
vated temperatures (Table 5). A slight improvement in
catalytic activity was observed for the binaphtholate
complex (R)-17, in which the 2,6-diisopropylphenyl sub-
stituents effectively prevent formation of phenolate-
bridged dimeric species. However, enantioselectivities
remained moderate, reaching 57% ee for pent-4-enyl-
amine (6).
1.6 mol% cat.
>99% conv. after 13 h.
b
3. Biphenolate and binaphtholate catalysts for
enantioselective hydroamination of aminoalkenes
3.1. Synthesis of chiral non-metallocene complexes
Our first chiral rare earth metal complexes were based
on the biphenolate ligand Biphen2ꢁ with stereodirecting
tert-butyl substituents in 3 and 30 positions (Scheme 6)
[26–29]. The monomeric yttrium complex 13 could be
prepared via amine elimination in enantiopure and race-
mic form. However, the tert-butyl substituents were not
sterically demanding enough to prevent dimer forma-
tion. Upon heating of (rac)-13 the phenolate-bridged
heterochial dimer (R,S)-14a was formed. Furthermore,
lanthanum formed exclusively the heterochiral dimer
(R,S)-14b (Fig. 5) because of its larger ionic radius,
and an enantiopure complex could not be prepared.
Yet, enantiopure biphenolate lanthanum complexes
were obtained via alkane elimination utilizing the homo-
leptic tris(alkyl) [La{CH(SiMe3)2}3] (Scheme 6) [27,28].
The initial THF-free product is the homochiral pheno-
late-bridged dimer (R,R)-15 (Fig. 6). Addition of THF
generates the monomeric species (R)-16 coordinated by
three THF ligands.
O
O
Y
N(SiHMe2)2
O
O
(R)-17
Both complexes were highly thermally robust and
even at 100 ꢁC no significant loss in enantioselectivity
was observed. Because intermolecular ligand redistribu-
tion reactions would lead to achiral catalytically active
species, such redistribution reactions must be insignifi-
cant even under these drastic conditions and the
biphenolate and binaphtholate complexes are configu-
rational stable at least on the timescale of the catalytic
reaction.
Both dimeric lanthanum biphenolate complexes exhi-
bit similar structural features for the La2O2-metallacycle
with an unsymmetrical bridging of the phenolates (Table
4). The lanthanum to bridging phenolate bond length
H
N
3 mol% 2b
60 ˚C
30 h, 93% conv.
+
NH2
N
N
C6D6, 25 ˚C
37 min, >98% conv.
TOF >55 h-1
(endo,exo)-12
(exo,exo)-12
10
11
dr = 1.3:1
dr = 1.4:1
Scheme 5. Preparation of 1-aza-bicyclo[2.2.1]heptanes via bicyclization of aminodienes.

K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
4447
O
2 [Y{N(SiHMe2)2}3(THF)2]
toluene, 2 h, 60 ˚C
OH
OH
O
O
2
2
Y
N(SiHMe2)2
O
13
H2(Biphen)
racemic
complex
toluene
20 min, 110 ˚C
2 [La{CH(SiMe3)2}3]
–10 ˚C→ 25 ˚C
toluene,1 h
O
O
O
Ln
O
Z
X
La
O
O
O
O
La
Ln
Z
X
O
O
X = CH(SiMe3)2
Z = N(SiHMe2)2
(R,R)-15
(R,S)-14a Ln = Y
(R,S)-14b Ln = La
CH(SiMe3)2
O
6 equiv THF
O
O
2
La
O
O
(R)-16
Scheme 6. Synthesis of chiral biphenolate rare earth metal complexes.
Fig. 5. Structure of heterochiral dimer (R,S)-14b.
Fig. 6. Structure of homochiral dimer (R,R)-15.

4448
K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
Table 4
effect of the tert-butyl substituents is even less effective
˚
Structural comparison of selected bond lengths (A), and angles (ꢁ) for
phenolate-bridged dimers (R,S)-14b and (R,R)-15
for the larger lanthanum in comparison to yttrium.
We concluded that a significant increase in the steric
demand of the 3 and 30 substituent in the diolate ligand
was necessary to improve catalyst selectivity. Indeed,
binaphtholate yttrium aryl complexes (R)-18a and (R)-
18b with tris(aryl)silyl substituents in 3 and 30 position
performed cyclization of 4 and 6 with good rates at
room temperature and better enantioselectivities com-
pared to other biphenolate and binaphtholate complexes
[30]. The highest enantioselectivities of up to 83% ee was
observed for the most hindered catalyst (R)-18b. The
large tris(aryl)silyl substituent did not only enhance
the stereodirecting effect of the ligand, but also
prevented undesired formation of phenolate-bridged
dimeric species.
(R,S)-14b
(R,R)-15
La1–O21
La1–O11
La1–O110
2.234(2)
2.503(2)
2.407(2)
88.83(7)
71.10(8)
108.90(8)
87.8(4)
2.169(4)
2.506(3)
2.364(3)
O11–La1–O21
O11–La1–O110
La1–O11–La10
Biphenolate dihedral angle
95.86(12)
73.24(11)
105.39(11)
ꢁ97.0(7)
Catalysts (R)-13 and (R)-17 suffered from similar ini-
tiation inefficiencies and low catalytic activity as diami-
doamine complex 1, which was also indicated by their
kinetic behaviour. Whereas (R)-17 gave rise to a first or-
der rate dependence on substrate concentration, (R)-13
showed a second order rate dependence, contrasting
the commonly observed zero order rate dependence on
substrate concentration in accordance with olefin inser-
tion into the Ln–N bond being the rate determining step
[1k,6,9].
R
R
3
Si
3
Si
O
Me2N
Y
Indeed, biphenolate alkyllanthanum complexes
(R,R)-15 and (R)-16 displayed significant higher cata-
lytic activity at room temperature, comparable in mag-
nitude to lanthanocene complexes, e.g., 95 hꢁ1 for
substrate 4 with ½CpꢃLaCHðSiMe3Þ ꢄ at 25 ꢁC [6]. The
O
O
O
O
La
CH(SiMe3)2
Me2N
O
Ph
SiAr3
SiAr3
2
2
(R)-19
(R)-18a: R = H
catalytic activity of the monomeric tris(THF)-adduct
(R)-16 was almost twice that of the homochiral dimer
(R,R)-15, suggesting that the dimeric structure of the
precatalyst (R,R)-15 remains intact under the catalytic
reaction conditions in the absence of THF. Further-
more, both catalysts showed the expected zero order
rate dependence on substrate concentration.
(R)-18b: R = Me
Addition of a few equivalents of THF diminished cat-
alytic activity only slightly, but had a positive effect on
the enantiomeric excess for substrate 4, whereas no effect
was observed for aminopentene 6 (Table 5) [31]. Obvi-
ously, in case of the sterically more demanding gem-
dimethyl substituted aminoalkene 4, THF can more
Unfortunately, the pyrrolidine cyclization products
were obtained essentially in racemic form using (R,R)-
15 and (R)-16, indicating that the stereodifferentiating
Table 5
Catalytic asymmetric hydroamination/cyclization of aminoalkenes
Catalyst
Substrate
[cat.]/[s] (%)
T (ꢁC)
t (h)
Conversion (%)
TOF (hꢁ1
)
% ee
(R)-13
4
4
4
4
4
4
4
4
4
6
6
6
6
6
6
6
6
4
2
2
4
4
4
1.5
4
3
2
2
4
4
4
1
4
3
70
25
25
60
100
22
25
22
22
60
60
70
100
22
25
22
22
22
1.5
1
77
95
2.5
35
36
8
(R,R)-15
(R)-16
(R)-17
98
92
61
13.5
8
7
28.3
28.0
43
52
53
31
2
(R)-17
0.75
3
>99
P98
P98
P98
P98
>99
98
(R)-18a
(R)-18a + 2THF
(R)-18b
(R)-19
8
6
21
2
14
94
5
0.5
19
25
43
16
24
54
20
1.4
(R,R)-15
(R)-16
(R)-17
5.3
0
91
57
52
69
67
83
72
(R)-17
>99
P98
P98
P98
P98
(R)-18a
(R)-18a + 2THF
(R)-18b
(R)-19
1.2
2
2.2
37

K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
4449
effectively compete with the substrate for empty coordi-
matched
mismatched
nation sites on the metal, changing the geometries and
relative energies of the two diastereomeric cyclization
transition states leading to the two enantiomeric pyrrol-
idine products.
Increasing the ionic radius from yttrium to lantha-
num (complex (R)-19) significantly increased catalytic
activity [31], although this rate improvement went along
with a slight erosion in catalyst selectivity.
NH2
NH2
R
R
NH
HN
R
k1
O
O
O
Y
O Y
R
k-1
slow
k2,R
k2,S
fast
H
N
H
N
3.3. Kinetic resolution of chiral aminoalkenes
R
R
Asymmetric intramolecular hydroaminations are
commonly performed by differentiation of enantiotopic
faces of the alkene in achiral aminoalkene substrates.
Chiral aminoalkenes on the other hand should be kinet-
ically resolved, if the two enantiomers of the substrate
have different rates of cyclization. That is, at 50% con-
version one would obtain an enantioenriched azacyclic
product and recover the aminoalkene starting material
enriched with the slower reacting enantiomer.
Marks and coworkers [10c] attempted to apply chiral
lanthanocene catalysts for kinetic resolution of 8, but
only low enantiomeric excess (<20% ee) at various ex-
tents of conversion was observed. Binaphtholate com-
plexes (R)-17, (R)-18a and (R)-18b on the other hand
were found to be significantly more effective in the ki-
netic resolution of a-substituted chiral aminopentenes
(Table 6) with krel values [32] as high as 16 and enantio-
meric excess for recovered starting material reaching
80% ee at conversions close to 50% [30]. The 2,5-disub-
stituted pyrrolidines were obtained in good to excellent
trans diastereoselectivity, depending on the steric de-
(2S,5S)-9
(R = Me)
Fig. 7. Proposed stereomodel for kinetic resolution of chiral amino-
alkenes with an equatorial approach of the olefin.
mand of the a-substituent. The sterically more hindered
binaphtholate catalyst (R)-18b was more effective in the
kinetic resolution process of the sterically less demand-
ing 8, whereas sterically more encumbered 20 was more
efficiently kinetically resolved using (R)-18a.
A plausible stereomodel explaining the observed pre-
ferred formation of (2S, 5S)-9 using (R)-18b as catalyst
was proposed (Fig. 7). A rapid exchange of matching
and mismatching aminoalkene prior to cyclization is
necessary for an effective kinetic resolution process.
Cyclization of (R)-8 is believed to be impeded by a steric
unfavorable interaction of the vinylic methylene protons
with a tris(aryl)silyl substituent in the chair-like transi-
tion state. Detailed kinetic investigations are currently
in progress to clarify the mechanism of this reaction.
Table 6
Catalytic kinetic resolution of chiral aminopentenes
H
N
H
N
2 mol% cat.
C D , 22 ˚C
NH2
R
R
+
R
6 6
trans
cis
8
R = Me
9
R = Me
20 R = Ph
22 R = CH Ph
21 R = Ph
23 R = CH Ph
2
2
a
krel
Substrate
Catalyst
t (h)
Conversion (%)
trans:cis
% ee of recov. start. mat.
% ee of trans product (sign)
8
8
(R)-17b
(R)-18a
(R)-18b
(R)-18a
(R)-18b
(R)-18a
(R)-18b
1.5
25.5
26
61
53
52
50
52
50
52
6.4:1
11:1
43
72
80
74
63
42
38
35
68
2.6
9.5
8
13:1
78 (ꢁ)c
16
20
20
22
22
a
95
18d
P50:1
P50:1
20:1
(+)
15
7
9
27
40 (ꢁ)
3.6
2.9
20:1
34
Based on starting material.
5 mol% cat., 90 ꢁC.
A (ꢁ) optical rotation corresponds to a (2S, 5S) absolute configuration.
b
c
d
At 40 ꢁC.

4450
K.C. Hultzsch et al. / Journal of Organometallic Chemistry 690 (2005) 4441–4452
3.4. Intermolecular hydroamination
251073. Copies of the data can be obtained free of
charge from the Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (int code) +44 1223/
336 033 or E-mail: deposit@ccdc.cam.ac.uk or www:
http://www.ccdc.cam.ac.uk.
The intermolecular hydroamination catalyzed by rare
earth metal complexes has remained a significant chal-
lenge and efficiencies are two to three orders of magni-
tude smaller than for intramolecular hydroamination
reactions [8]. The first order rate dependence on olefin
concentration results in rather uneconomical long reac-
tion times. Therefore, intermolecular hydroamination
reactions have been commonly performed with a larger
excess of olefin in order to operate in a pseudo zero
order regime.
Preliminary studies have revealed recently that the
highly active lanthanum catalyst (R)-19 catalyzes the
selective anti-Markovnikov addition of n-propylamine
under relative mild reaction conditions even if only
equimolar amounts of styrene and amine are used
(Eq. (4)) [31], albeit rather long reaction times were
required.
Acknowledgement
Generous financial support by the Deutsche Fors-
chungsgemeinschaft (DFG) and the Fonds der Chemis-
chen Industrie is gratefully acknowledged. K.C.H. is a
DFG Emmy Noether fellow (2001–2005) and thanks
Professor John A. Gladysz for his generous support.
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˚
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˚
˚
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