3,3′-Bis(trisarylsilyl)-substituted binaphtholate rare earth metal catalysts for asymmetric hydroamination

Article abstract of DOI:10.1021/ja058287t

Chiral 3,3′-bis(trisarylsilyl)-substituted binaphtholate rare earth metal complexes (R)-[Ln{Binol-SiAr₃}(o-C₆H ₄CH₂NMe₂)(Me₂NCH₂Ph)] (Ln = Sc, Lu, Y; Binol-SiAr₃ = 3,3′-bis(trisarylsilyl)-2,2′- dihydroxy-1,1′-binaphthyl; Ar = Ph (2-Ln), 3,5-xylyl (3-Ln)) and (R)-[La{Binol-Si(3,5-xylyl)₃}{E(SiMe₃)₂}(THF) ₂] (E = CH (4a), N (4b)) are accessible via facile arene, alkane, and amine elimination. They are efficient catalysts for the asymmetric hydroamination/cyclization of aminoalkenes, giving TOF of up to 840 h ^-1 at 25 °C for 2,2-diphenyl-pent-4-enylamine (5c) using (R)-2-Y. Enantioselectivities of up to 95% ee were achieved in the cyclization of 5c with (R)-2-Sc. The reactions show apparently zero-order rate dependence on substrate concentration and first-order rate dependence on catalyst concentration, but rates depend on total amine concentrations. Activation parameters for the cyclization of pent-4-enylamine using (R)-2-Y (ΔH(S)? = 57.4-(0.8) kJ mol^-1 and ΔS(S)? = -102(3) J K^-1 mol^-1; ΔH(R)? = 61.5(0.7) kJ mol^-1 and ΔS(R)? = -103(3) J K^-1 mol ^-1) indicate a highly organized transition state. The binaphtholate catalysts were also applied to the kinetic resolution of chiral α-substituted aminoalkenes with resolution factors f of up to 19. The 2,5-disubstituted aminopentenes were formed in 7:1 to ≥50:1 trans diastereoselectivity, depending on the size of the α-substituent of the aminoalkene. Rate studies with (S)-1-phenyl-pent-4-enylamine ((S)-15e) gave the activation parameters for the matching (ΔH? = 52.2(2.8) kJ mol ^-1, ΔS? = -127(8) J K^-1 mol^-1 using (S)-2-Y) and mismatching (ΔH? = 57.7(1.3) kJ mol ^-1, ΔS? = -126(4) J K^-1 mol^-1 using (R)-2-Y) substrate/catalyst combination. The absolute configuration of the Mosher amide of (2S)-2-methyl-4,4-diphenyl-pyrrolidine and (2R)-methyl-(5S)- phenyl-pyrrolidinium chloride, prepared from (S)-15e, were determined by crystallographic analysis. Catalyst (R)-4a showed activity in the anti-Markovnikov addition of n-propylamine to styrene.

Full text of DOI:10.1021/ja058287t

Published on Web 03/02/2006
3,3′-Bis(trisarylsilyl)-Substituted Binaphtholate Rare Earth
Metal Catalysts for Asymmetric Hydroamination
Denis V. Gribkov, Kai C. Hultzsch,* and Frank Hampel
Contribution from the Institut fu¨r Organische Chemie, Friedrich-Alexander UniVersita¨t
Erlangen-Nu¨rnberg, Henkestrasse 42, D-91054 Erlangen, Germany
Received December 6, 2005; E-mail: hultzsch@chemie.uni-erlangen.de
Abstract: Chiral 3,3′-bis(trisarylsilyl)-substituted binaphtholate rare earth metal complexes (R)-[Ln{Binol-
SiAr3}(o-C6H4CH2NMe2)(Me2NCH2Ph)] (Ln ) Sc, Lu, Y; Binol-SiAr3 ) 3,3′-bis(trisarylsilyl)-2,2′-dihydroxy-
1,1′-binaphthyl; Ar ) Ph (2-Ln), 3,5-xylyl (3-Ln)) and (R)-[La{Binol-Si(3,5-xylyl)3}{E(SiMe3)2}(THF)2] (E )
CH (4a), N (4b)) are accessible via facile arene, alkane, and amine elimination. They are efficient catalysts
for the asymmetric hydroamination/cyclization of aminoalkenes, giving TOF of up to 840 h-1 at 25 °C for
2,2-diphenyl-pent-4-enylamine (5c) using (R)-2-Y. Enantioselectivities of up to 95% ee were achieved in
the cyclization of 5c with (R)-2-Sc. The reactions show apparently zero-order rate dependence on substrate
concentration and first-order rate dependence on catalyst concentration, but rates depend on total amine
concentrations. Activation parameters for the cyclization of pent-4-enylamine using (R)-2-Y (∆H(S)q ) 57.4-
(0.8) kJ mol-1 and ∆S(S)q ) -102(3) J K-1 mol-1; ∆H(R)q ) 61.5(0.7) kJ mol-1 and ∆S(R)q ) -103(3) J
K-1 mol-1) indicate a highly organized transition state. The binaphtholate catalysts were also applied to
the kinetic resolution of chiral R-substituted aminoalkenes with resolution factors f of up to 19. The 2,5-
disubstituted aminopentenes were formed in 7:1 to g50:1 trans diastereoselectivity, depending on the size
of the R-substituent of the aminoalkene. Rate studies with (S)-1-phenyl-pent-4-enylamine ((S)-15e) gave
the activation parameters for the matching (∆Hq ) 52.2(2.8) kJ mol-1, ∆Sq ) -127(8) J K-1 mol-1 using
(S)-2-Y) and mismatching (∆Hq ) 57.7(1.3) kJ mol-1, ∆Sq ) -126(4) J K-1 mol-1 using (R)-2-Y) substrate/
catalyst combination. The absolute configuration of the Mosher amide of (2S)-2-methyl-4,4-diphenyl-
pyrrolidine and (2R)-methyl-(5S)-phenyl-pyrrolidinium chloride, prepared from (S)-15e, were determined
by crystallographic analysis. Catalyst (R)-4a showed activity in the anti-Markovnikov addition of n-
propylamine to styrene.
Introduction
amines in a waste-free, highly atom-economical manner starting
from simple and inexpensive precursors.
The importance of nitrogen-containing compounds in biologi-
cal systems and industrially relevant basic and fine chemicals
has sparked significant research efforts to develop efficient
synthetic protocols.1 One of the simplest approaches, the
hydroamination, has found significant attention only in recent
years with the development of more efficient transition metal
based catalyst systems.2 The addition of amine N-H function-
alities to unsaturated carbon-carbon bonds, either in an
intermolecular (eq 1) or intramolecular (eq 2) fashion, generates
(1) Malpass, J. R. In ComprehensiVe Organic Chemistry; Barton, D., Ollis,
W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 2, p 1.
Transition metal based hydroamination catalysts have the
significant advantage that they permit facile tuning of catalytic
properties via adjustment of sterical and electronic features of
the ligand framework, thereby controlling the stereo- and
regiochemistry of the hydroamination product. 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 remained challenging.3
(2) For general and comprehensive reviews on this topic see: (a) Taube, R. In
Applied Homogeneous Catalysis; Cornils, B., Herrmann, W. A., Eds.;
VCH: Weinheim, 1996; Vol. 1, p 507. (b) Mu¨ller, T. E.; Beller, M. Chem.
ReV. 1998, 98, 675. (c) Mu¨ller, T. E.; Beller, M. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
1998; Vol. 2, p 316. (d) Brunet, J. J.; Neibecker, D. In Catalytic
Heterofunctionalization from Hydroamination to Hydrozirconation; Togni,
A., Gru¨tzmacher, H., Eds.; Wiley-VCH: Weinheim, 2001; p 91. (e) Nobis,
M.; Driessen-Ho¨lscher, B. Angew. Chem., Int. Ed. 2001, 40, 3983. (f)
Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth. Catal. 2002,
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9
3748
J. AM. CHEM. SOC. 2006, 128, 3748-3759
10.1021/ja058287t CCC: $33.50 © 2006 American Chemical Society

Rare Earth Metal Catalysts for Hydroamination
A R T I C L E S
Catalyst systems based on alkali and alkaline earth metals,2a-d,f,4
as well as early (groups 3-5, lanthanides and actinides)2i-m,5,6
and late (groups 8-10)2g,h,7 transition metals have been devel-
oped. Unfortunately, many of these systems can be applied only
to a limited set of substrates. Commonly, only activated alkenes
[e.g. alkenes with electron-withdrawing groups attached, vinyl
arenes, 1,3-dienes, or ring-strained alkenes], alkynes, or cer-
tain types of amines [e.g., anilines] can be applied. Rare earth
metals based catalyst systems are reactive toward simple
alkene substrates, predominantely in intramolecular reac-
tions.2l,8-10
was limited due to a facile epimerization process via reversible
protolytic cleavage of the metal cyclopentadienyl bond under
the reaction conditions of catalytic hydroamination.9b-e The
configuration of the hydroamination products was independent
of diastereomeric purity of the lanthanocene precatalysts,
requiring a catalyst redesign if the opposite enantiomer of the
hydroamination product is desired.9b
We therefore decided to develop hydroamination catalyst
systems based on non-cyclopentadienyl ligand sets,12 which
should have comparable catalytic activity to the lanthanocene
systems but should retain their configurational integrity under
the reaction conditions of catalytic hydroamination. Furthermore,
chiral non-cyclopentadienyl ligand sets are usually easily
accessible and can be readily modified.13 Increased interest in
this area in recent years has surfaced in several reports on non-
metallocene rare earth metal based catalyst systems14 for
enantioselective3b-d,15-17 hydroamination.
The first chiral rare earth metal based hydroamination
catalysts were reported by Marks and co-workers in 1992.9a,b,11
Although enantioselectivities of up to 74% ee were achieved,
the application of these C1-symmetric chiral ansa-lanthanocenes
(4) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005, 127,
2042.
(5) For some examples using actinide-based catalysts, see: (a) Straub, T.;
Haskel, A.; Neyroud, T. G.; Kapon, M.; Botoshansky, M.; Eisen, M. S.
Organometallics 2001, 20, 5017. (b) Wang, J.; Dash, A. K.; Kapon, M.;
Berthet, J.-C.; Ephritikhine, M.; Eisen, M. S. Chem. Eur. J. 2002, 8, 5384.
(c) Stubbert, B. D.; Stern, C. L.; Marks, T. J. Organometallics 2003, 22,
4836.
In our initial studies on biphenolate and binaphtholate rare
earth metal hydroamination catalysts16 we realized that sterically
demanding substituents in 3 and 3′ positions of the diolate ligand
are an indispensable requirement for a monomeric catalyst
structure and effective asymmetric induction. We therefore
anticipated that an increase in steric bulk of these substituents
would increase enantioselectivity. In this paper we report the
synthesis of 3,3′-bis(trisarylsilyl)-substituted binaphtholate rare
earth metal complexes and their application as hydroamination
catalysts.17 Schaverien reported the synthesis of similar binaph-
tholate alkyllanthanum complexes more than a decade ago,18
but their catalytic potential has remained unexplored to date.
(6) For some recent examples using group 4- and group 5-based catalyst
systems, see: (a) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem.
Soc. 2003, 125, 11956. (b) Knight, P. D.; Munslow, I.; O’Shaughnessy, P.
N.; Scott, P. Chem. Commun. 2004, 894. (c) Ackermann, L.; Kaspar, L.
T.; Gschrei, C. J. Org. Lett. 2004, 6, 2515. (d) Anderson, L. L.; Arnold, J.;
Bergman, R. G. Org. Lett. 2004, 6, 2519. (e) Ramanathan, B.; Keith, A.
J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6, 2957. (f) Heutling, A.;
Pohlki, F.; Doye, S. Chem. Eur. J. 2004, 10, 3059. (g) Pohlki, F.; Bytschkov,
I.; Siebeneicher, H.; Heutling, A.; Ko¨nig, W. A.; Doye, S. Eur. J. Org.
Chem. 2004, 1967. (h) Lorber, C.; Choukroun, R.; Vendler, L. Organo-
metallics 2004, 23, 1845. (i) Hoover, J. M.; Petersen, J. R.; Pikul, J. H.;
Johnson, A. R. Organometallics 2004, 23, 4614. (j) Gribkov, D. V.;
Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 44, 5542. (k) Bexrud, J. A.;
Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959. (l)
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5001.
(7) For some recent examples using late transition metal catalyst systems,
see: (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.
(b) Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
4366. (c) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 1622. (d) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J.
F. J. Am. Chem. Soc. 2003, 125, 5608. (e) Utsunomiya, M.; Hartwig, J. F.
J. Am. Chem. Soc. 2004, 126, 2702. (f) Vo, L. K.; Singleton, D. A. Org.
Lett. 2004, 6, 2469. (g) Tillack, A.; Khedkar, V.; Beller, M. Tetrahedron
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Soc. 2005, 127, 1070. (i) Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 5756. (j) Yi, C. S.; Yun, S. Y.; Guzei, I. A. J. Am. Chem. Soc.
2005, 127, 5782. (k) Brunet, J.-J.; Chu, N. C.; Diallo, O. Organometallics
2005, 24, 3104. (l) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lo¨hnwitz, K.;
Herrmann, J.-S.; Roesky, P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005,
44, 7794.
(8) For hydroamination catalyzed by cyclopentadienyl rare earth metal
complexes see: (a) Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989,
111, 4108. (b) Gagne´, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc.
1992, 114, 275. (c) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118,
9295. (d) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757. (e)
Gilbert, A. T.; Davis, B. L.; Emge, T. J.; Broene, R. D. Organometallics
1999, 18, 2125. (f) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks,
T. J. J. Am. Chem. Soc. 1999, 121, 3633. (g) Molander, G. A.; Dowdy, E.
D. J. Org. Chem. 1999, 64, 6515. (h) Arredondo, V. M.; McDonald, F. E.;
Marks, T. J. Organometallics 1999, 18, 1949. (i) Molander, G. A.; Dowdy,
E. D.; Pack, S. K. J. Org. Chem. 2001, 66, 4344. (j) Molander, G.; Pack,
S. K. Tetrahedron 2003, 59, 10581. (k) Molander, G. A.; Pack, S. K. J.
Org. Chem. 2003, 68, 9214.
(9) For asymmetric hydroamination catalyzed by cyclopentadienyl rare earth
metal complexes see: (a) Gagne´, M. R.; Brard, L.; Conticello, V. P.;
Giardello, M. A.; Marks, T. J.; Stern, C. L. Organometallics 1992, 11,
2003. (b) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne´, M. R.;
Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241. (c) Douglass, M. R.;
Ogasawara, M.; Hong, S.; Metz, M. V.; Marks, T. J. Organometallics 2002,
21, 283. (d) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc.
2003, 125, 15878. (e) Ryu, J.-S.; Marks, T. J.; McDonald, F. E. J. Org.
Chem. 2004, 69, 1038.
(11) For reviews on the application of chiral rare earth metal catalysts in organic
synthesis, see: (a) Mikami, K.; Terada, M.; Matsuzawa, H. Angew. Chem.,
Int. Ed. 2002, 41, 3554. (b) Aspinall, H. C. Chem. ReV. 2002, 102, 1807.
(c) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187. (d)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV.
2002, 102, 2227.
(12) For general reviews on the chemistry of cyclopentadienyl-free rare earth
metal complexes see: (a) Edelmann, F. T. Angew. Chem., Int. Ed. Engl.
1995, 34, 2466. (b) Edelmann, F. T.; Freckmann, D. M. M.; Schumann,
H. Chem. ReV. 2002, 102, 1851. (c) Piers, W. E.; Emslie, D. J. H. Coord.
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(13) Even simple modifications to the ligand structure of cyclopentadienyl ligands
can require tedious multistep procedures; see for example: (a) Halterman,
R. L. Chem. ReV. 1992, 92, 2, 965. (b) Halterman R. L. In Metallocenes;
Togni, A., Halterman, R. L., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 1,
p 455.
(14) For achiral non-metallocene rare earth metal based hydroamination catalysts,
see: (a) Bu¨rgstein, M. R.; Berberich, H.; Roesky, P. W. Organometallics
1998, 17, 1452. (b) Bu¨rgstein, M. R.; Berberich, H.; Roesky, P. W. Chem.
Eur. J. 2001, 7, 3078. (c) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E.
Tetrahedron Lett. 2001, 42, 2933. (d) Kim, Y. K.; Livinghouse, T. Angew.
Chem., Int. Ed. 2002, 41, 3645. (e) Kim, Y. K.; Livinghouse, T.; Horino,
Y. J. Am. Chem. Soc. 2003, 125, 9560. (f) Lauterwasser, F.; Hayes, P. G.;
Bra¨se, S.; Piers, W. E.; Schafer, L. L. Organometallics 2004, 23, 2234.
(g) Hultzsch, K. C.; Hampel, F.; Wagner, T. Organometallics 2004, 23,
2601. (h) Panda, T. K.; Zulys, A.; Gamer, M. T.; Roesky, P. W.
Organometallics 2005, 24, 2197. (i) Kim, J. Y.; Livinghouse, T. Org. Lett.
2005, 7, 4391. (j) Bambirra, S.; Tsurugi, H.; van Leusen, D.; Hessen, B.
Dalton Trans 2006, 1157.
(15) (a) O’Shaughnessy, P. N.; Knight, P. D.; Morton, C.; Gillespie, K. M.;
Scott, P. Chem. Commun. 2003, 1770. (b) O’Shaughnessy, P. N.; Scott, P.
Tetrahedron Asymmetry 2003, 14, 1979. (c) Hong, S.; Tian, S.; Metz, M.
V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768. (d) Collin, J.; Daran,
J.-D.; Schulz, E.; Trifonov, A. Chem. Commun. 2003, 3048. (e)
O’Shaughnessy, P. N.; Gillespie, K. M.; Knight, P. D.; Munslow, I.; Scott,
P. Dalton Trans. 2004, 2251. (f) Kim, J. Y.; Livinghouse, T. Org. Lett.
2005, 7, 1737. (g) Collin, J.; Daran, J.-D.; Jacquet, O.; Schulz, E.; Trifonov,
A. Chem. Eur. J. 2005, 11, 3455.
(16) (a) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. Chem. Eur. J. 2003, 9,
4796. (b) Gribkov, D. V.; Hampel, F.; Hultzsch, K. C. Eur. J. Inorg. Chem.
2004, 4091.
(10) Most investigations utilizing rare earth metal catalysts have focused on
intramolecular hydroamination reactions, whereas the number of reports
on intermolecular hydroamination are limited, see: (a) Li, Y.; Marks, T.
J. Organometallics 1996, 15, 3770. (b) Ryu, J.-S.; Li, G. Y.; Marks, T. J.
J. Am. Chem. Soc. 2003, 125, 12584.
(17) A preliminary account of the results presented herein has been com-
municated, see: Gribkov, D. V.; Hultzsch, K. C. Chem. Commun. 2004,
730.
(18) Schaverien, C. J.; Meijboom, N.; Orpen, A. G. J. Chem. Soc., Chem.
Commun. 1992, 124.
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A R T I C L E S
Scheme 1
Gribkov et al.
Figure 1. Ionic radius dependence of enantiomeric excess for pyrrolidines
obtained from aminopentenes 5a and 5b with binaphtholate catalysts (R)-
2-Ln, (R)-3-Ln (Ln ) Sc, Lu, Y), and (R)-4a. The lines are drawn as a
guide for the eye.
Results
Synthesis of Binaphtholate Complexes. Binaphtholate rare
earth metal complexes of the smaller rare earth elements,
scandium, yttrium, and lutetium, were prepared via arene
elimination from the readily available homoleptic tris(aryl)
complexes [Ln(o-C6H4CH2NMe2)3] (Ln ) Sc, Y, Lu)19 using
the tris(aryl)silyl binaphthols20 (R)-1a and (R)-1b (Scheme 1).
Complexes (R)-2-Ln and (R)-3-Ln retained one equivalent of
N,N-dimethylbenzylamine coordinated to the metal center (by
NMR spectroscopy). Although the reactions proceeded cleanly
by NMR spectroscopy (see Supporting Information), removal
of traces of free N,N-dimethylbenzylamine proved to be difficult
in preparative-scale reactions.21 Therefore, the catalysts were
often prepared in situ or stored as a frozen stock solution in
C6D6 at -35 °C. Exchange between coordinated and free
benzylamine was slow on the NMR time scale. However, the
coordinated N,N-dimethylbenzylamine could be readily dis-
placed by harder donors, such as THF.22
Tris(3,5-xylyl)silyl-substituted binaphtholate complexes of the
larger lanthanum metal were accessible either from the tris-
(alkyl) complex [La{CH(SiMe3)2}3]23a at room temperature or
the tris(amido) complex [La{N(SiMe3)2}3]23b at 80 °C (Scheme
1).24 While (R)-4a was cleanly formed in the presence of 2.5
equiv of THF, in the case of the less reactive amido complex
[La{N(SiMe3)2}3] a large excess of THF was required to obtain
(R)-4b as the sole product.25 Furthermore, removal of solvent
from (R)-4b led to the formation of a yet unidentified second
species.26,27
Asymmetric Hydroamination of Aminoalkenes. All bi-
naphtholate complexes displayed high catalytic activity at room
temperature in the hydroamination/cyclization of aminopentenes
5a-d, while aminohexenes 7a and 7b required elevated reaction
temperatures (Table 1). Complexes based on the smallest rare
earth metal, scandium, were less active and required higher
reaction temperatures (in some cases) to achieve appreciable
turnover frequencies. Catalytic activity increased with increasing
ionic radius. The lanthanum catalyst (R)-4a displayed the highest
turnover rates for the unactivated aminopentene 5a (37 h-1 at
22 °C) and the gem-dimethyl-substituted 5b (94 h-1 at 22 °C).
Cyclization of 5c proceeded with rates as high as 840 h-1 at
25 °C using (R)-2-Y, as a result of the significant Thorpe-
Ingold effect28 of the gem-diphenyl substituents.
Enantioselectivity of the pyrrolidine products generally
increased with decreasing ionic radius of the metal (see trends
for 5a and 5b in Figure 1). 5a and 5b were cyclized more
efficiently (with respect to rate and enantioselectivity) using the
sterically more hindered tris(3,5-xylyl)silyl-substituted binaph-
tholate complexes (R)-3-Ln in comparison to using the corre-
sponding triphenylsilyl-substituted binaphtholate complexes (R)-
2-Ln of the same rare earth metal. The opposite trend was
observed for the sterically more demanding substrates 5c and
5d. An exception in this series of complexes was the scandium
complex (R)-3-Sc, as it displayed generally lower selectivity
and slower rates than (R)-2-Sc and the lutetium complex (R)-
3-Lu, most likely due to steric overcrowding of the coordination
sphere around scandium.
(19) (a) Ln ) Y: Booij, M.; Kiers, N. H.; Heeres, H. J.; Teuben, J. H. J.
Organomet. Chem. 1989, 364, 79. (b) Ln ) Lu: Wayda, A. L.; Rogers, R.
D. Organometallics 1985, 4, 1440. (c) Ln ) Sc: Manzer, L. E. J. Am.
Chem. Soc. 1978, 100, 8068.
(20) (a) Maruoka, K.; Itoh, T.; Araki, Y.; Shirasaka, T.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1988, 61, 2975. (b) Gong, L.-Z.; Pu, L. Tetrahedron Lett.
2000, 41, 2327.
(21) The complexes were commonly obtained as glassy solids after removal of
the solvent. Precipitation from pentane or hexanes did not improve the
purity of the complexes, and we have thus far been unable to obtain single
crystals suitable for X-ray crystallographic analysis. Also, derivatization
of complexes (R)-2 and (R)-3 either via substitution of the coordinated
N,N-dimethylbenzylamine by other donors (e.g., Et2O, THF) or by
protonolysis of the yttrium-aryl bond with an amine (e.g., HN(SiMe3)2,
HN(CH2CH2OMe)2) did not lead to a better isolable product.
(22) Reaction of (R)-2-Y with 2 equiv n-propylamine also led to a replacement
of the coordinated N,N-dimethylbenzylamine, concomitant with rapid
protolytic cleavage of the yttrium-aryl bond and formation of a diolate
amido amine species.
Interestingly, the most reactive substrate 5c was also cyclized
with the highest selectivity (up to 95% ee using (R)-2-Sc). The
less reactive aminopentene 5a was cyclized in 92% ee using
(25) Reaction of [La{N(SiMe3)2}3] and (R)-1b in the absence of THF or in the
presence of only a few equivalents of THF led to the formation of a species
which did not contain any amido ligand and which we therefore assign to
be of dimeric or oligomeric nature with more than one binaphtholate ligand
per metal center. Also, [La{CH(SiMe3)2}3] and (R)-1b did not form a clean
product in the absence of THF.
(26) The close proximity of several aromatic substituents suggest that one of
the aromatic rings of the trisarylsilyl binaphtholate ligands could form a
π-arene complex with the metal center as a result of partial loss of THF.
For a review on π-arene rare earth metal complexes see: Bochkarev, M.
N. Chem. ReV. 2002, 102, 2089.
(27) Note that addition of aminoalkene substrate to this mixture of two species
generated a single catalytically active species, which was presumably
identical to that formed from the corresponding bis(THF) adduct of the
precatalyst.
(28) Jung, M. E.; Pizzi, G. Chem. ReV. 2005, 105, 1735.
(29) Ringdahl, B.; Pereira, W. E., Jr.; Craig, J. C. Tetrahedron 1981, 37, 1659.
(23) (a) Hitchcock, P. B.; Lappert, M. F.; Smith, R. G.; Bartlett, R. A.; Power,
P. P. J. Chem. Soc., Chem. Commun. 1988, 1007. (b) Bradley, D. C.; Ghotra,
J. S.; Hart, F. A. J. Chem. Soc., Dalton Trans. 1973, 1021.
(24) We have been unable to generate the corresponding enantiopure triphenyl-
silyl binaphtholate lanthanum complex cleanly starting from (R)-1a and
[La{CH(SiMe3)2}3] under the conditions reported by Schaverien for the
corresponding racemic complex.18
9
3750 J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006

Rare Earth Metal Catalysts for Hydroamination
A R T I C L E S
Table 1. Catalytic Hydroamination/Cyclization of Aminoalkenes
1
entry
cat.
substrate
[cat.]/[subst.] (%)
T (°
C)
t (h)
yield (%)a
Nt (h-
)
ee (%)b
1
2
3
4
5
6
7
8
(R)-2-Sc
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-3-Lu
(R)-2-Y
(R)-2-Y
(R)-2-Y+ 3 THF
(R)-3-Y
(R)-4a
(R)-4b
(R)-2-Sc
(R)-3-Sc
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-2-Y
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5c
5c
5c
5c
5c
5c
5d
5d
5d
5d
5d
5d
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
2
2
2
5
4
2
2
1
4
3
1.7
2
2
2.5
2
3
4
3
1.5
2
4
3.5
1
2
2
2
2
2
2
2
2
2
2
2
2
2
60
60
60
22
96
27
4
96
95
96
93
92
95
95
96
94
89
95
93
91
94
94
95
95
92
95
94
95
95
95
94
96
96
96
96
94
97
96
95
95
97
97
95
94
95
94
92
97
97
96
97
97
0.5
1.5
18
1.7
0.13
2.6
93
2.0
2.2
37
g 33
13
0.3
5.5
2.4
3.1
8
480
5.6
2.1
80
87
72
90
92
70
66
70
83
72
71
73
58
56
69
68
43
65
38
31
53
31
24
95
74
93
80
84
77
85
61
83
78
63
69
16
43
40
55
46
40
61
42
40
36
16.5
0c
190
24
0.8
53.5
20
1.4
5.5
5.5
25
60
22
22
22
22
60
22
60
22
22
22
60
22
22
22
22
22
25
25
25
25
25
25
25
25
25
25
25
25
80
80
80
80
80
60
60
60
60
60
9
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
39
40
41
42
43
44
45
192
10.5
27.5
14
3
0.07
22
24
2
0.45
5
(R)-2-Y
(R)-2-Y + 3 THF
(R)-2-Y + 300 THFd
(R)-3-Y
(R)-4a
(R)-4b
(R)-2-Sc
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-2-Y
14
94
g 60
110
0.6
3
20
0.25
0.1
0.06
0.06
6
g 180
g 500
g 840
g 760
11
(R)-3-Y
(R)-2-Sc
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-2-Y
13
5.0
0.11
0.5
0.2
0.3
460
100
420
240
(R)-3-Y
(R)-2-Sc
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-3-Y
(R)-2-Sc
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-3-Y
84
0.65
2
2
2
2
2
2
2
2
23
14
21
40
20
64
7.5
7.5
20
2.2
4.0
2.1
1.6
4.1
0.9
6.4
6.8
2.9
2
a NMR yield determined relative to ferrocene internal standard. b Enantiomeric excess determined by 19F NMR of Mosher amides. Pyrrolidines prepared
with (R)-binaphtholate catalysts have (S) configuration according to the X-ray crystallographic analysis of the Mosher amide of (S)-6c (Supporting Information)
and the observed positive ORD for 6a and 6b. [R]20 ) -20.0° for (R)-6a, see ref 29. [R]20 ) -24.3° for (R)-6b, see ref 9b. c In toluene-d8. d Substrate:
D
D
THF ) 1:6.
(R)-3-Lu at 0 °C (90% ee at 22 °C). Overall, the enantiomeric
excess of pyrrolidines 5a and 5c depended only slightly on the
reaction temperature (∆ee ≈ 1.5% ee/10 °C in the range of
0-60 °C for 5a, Figure S4).30 However, it is noteworthy that
the enantiomeric excess of 6b increased with increasing tem-
perature using (R)-2-Y as catalyst to level out at a maximum
value of 66% ee at 100 °C (Figure S9),30 concomitant with the
observation of increased rates after about the first half-life (vide
infra).
The (R)-binaphtholate catalysts furnished the pyrrolidine pro-
ducts preferentially with (S) configuration.31 Similar to lanthano-
cene catalyst systems,8b the catalytic activity of binaphtholate rare
earth metal complexes was affected only slightly by the addition
of THF, which is indicative of a stronger binding of the
aminoalkene substrate in comparison to ethereal donors. Fur-
thermore, catalyst enantioselectivity was affected markedly only
in the presence of a large excess of THF (Table 1, entry 20).
(31) See X-ray crystallographic analysis of the Mosher amide of 6c in the
(30) See Supporting Information for details.
Supporting Information.
9
J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006 3751

A R T I C L E S
Gribkov et al.
Table 2. Catalytic Hydroamination/Cyclization of Aminoalkenes
a NMR yield determined relative to ferrocene internal standard.
Whereas pyrrolidines 6a-d were formed quite selectively
using the binaphtholate catalysts 2-Ln and 3-Ln, cyclization
of aminohexenes 7a and 7b produced piperidines 8a and 8b
with moderate selectivity (up to 55% ee for 8a using (R)-3-Lu,
up to 61% ee for 8b using (R)-3-Sc).
Cyclization of the aminodiolefin 9 (Table 2) proceeded with
high selectivity using (R)-2-Sc (88 and 78% ee) but only low
diastereoselectivity (2.7:1). Interestingly, the minor diastereomer
of pyrrolidine 10 exhibited a significantly lower enantiomeric
excess than the major diastereomer for all triphenylsilyl-
substituted binaphtholate complexes (R)-2-Ln, while both
diastereomers where obtained with essential identical enantio-
meric excess using tris(3,5-xylyl)silyl-substituted binaphtholate
complexes (R)-3-Ln. The triphenylsilyl-substituted binaphtholate
complexes were also more successful in the cyclization of the
1,2-disubstituted olefin 11 (Table 2, entries 6, 7). Steric
congestion around nitrogen, as found in the secondary ami-
noalkene 13, resulted in significantly reduced selectivities in
comparison to that of the primary aminoalkene analogue 5a,
and only the scandium catalysts gave an appreciable enantio-
meric excess.
Figure 2. Time dependence of substrate concentration in the hydroami-
nation/cyclization of 5a ([subst.]0 ) 0.50 mol L-1) with (R)-2-Y ([Ln] )
0.01 mol L-1) at variable temperatures in C6D6. The lines through the data
points represent the least-squares fit for all data.
Kinetics of Hydroamination/Cyclization. In accordance
with the generally accepted mechanism of hydroamination/
cyclization,8b in which the olefin insertion step is rate determin-
ing, most reactions showed apparent zero-order rate dependence
on substrate concentration up to three half-lives for a given initial
substrate concentration (Figure 2). Some plots showed a slight
curvature (Figure S5, see also Figure 6),30 indicating a slight
rate acceleration during the catalytic reaction prior the onset of
Further evidence for the high catalytic activity of diolate rare
earth metal hydroamination catalysts provided the anti-Mark-
ovnikov32 addition of n-propylamine to styrene mediated by the
lanthanum complex 4a with an initial turnover frequency of
0.7 h-1 ([styrene] ) 0.8 mol L-1) at 60 °C (eq 3).
(32) Rare earth and alkali metal catalyzed hydroamination reactions of vinyl
arenes generally proceed with anti-Markovnikov selectivity,2b,f,10 whereas
late transition metals2h,7a or Broenstedt acid catalysts furnish the Mark-
ovnikov products; see: (a) Anderson, L. L.; Arnold, J.; Bergman, R. G. J.
Am. Chem. Soc. 2005, 127, 14542. (b) Kaspar, L. T.; Fingerhut, B.;
Ackermann, L. Angew. Chem., Int. Ed. 2005, 44, 5972.
9
3752 J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006

Rare Earth Metal Catalysts for Hydroamination
A R T I C L E S
Figure 5. Dependence of turnover frequency (Nt) on initial substrate
concentration ([subst.]0) in the cyclization of 5a with (R)-2-Y ([Ln] ) 0.02
mol L-1) at 40 °C. The line represents the best fit for k1 ) 29.7(1.2) h-1
and Kdorm ) 2.50(0.12) mol-1 L.30
Figure 3. Rate dependence on catalyst concentration for the hydroami-
nation/cyclization of 5a ([subst.]0 ) 0.50 mol L-1) with (R)-2-Y in C6D6
at 40 °C.
Scheme 2
proposed for the lanthanocene catalysts. The two diastereomeric
cyclization transition states differ by ∆∆Hq ) 4.1(0.8) kJ mol-1
in their activation enthalpies, but show essentially the same
degree of order (∆∆Sq ) 1(3) J K-1 mol-1).
The signals of 5a in the 1H NMR spectra of catalytic
experiments showed significant line broadening as well as an
upfield shift of the R- and â-methylene protons (Figure S7, trace
d), which increased with increasing conversion,30 indicating a
strong binding of the substrate to the metal center and a fast
exchange on the NMR time scale between coordinated amine
and amido ligands and free amine.33 The signals of the product
heterocycle 6a showed a similar line broadening (Figure S7,
trace d).30
Although the reactions show an apparent zero-order rate
dependence on substrate concentration, decreasing reaction rates
were observed with increasing initial substrate concentrations
(Figure 5).34 The reactions are impeded by the presence of
coordinating bases, but the observation of an apparent zero-
order rate dependence on substrate concentration suggests that
the starting aminoalkene and pyrrolidine product bind with
equilibrium constants of similar order of magnitude to the metal
center (Scheme 2), at least for the substrate/catalyst combination
discussed herein.35
Figure 4. Eyring plot for the hydroamination/cyclization of 5a ([subst.]0
) 0.50 mol L-1, kR: 0, kS: 9) using (R)-2-Y ([Ln] ) 0.01 mol L-1). The
rate constants kR and kS were determined according to kR ) k1(1 - ee)/2
and kS ) k1(1 + ee)/2.
product inhibition observed at high conversion (>85% conver-
sion). However, catalyst activation () protonolysis of Ln-X
by the aminoalkene substrate, where X is an alkyl, aryl, or amido
substituent) was generally instantaneous and irreversible, except
in the case of the amido complex 4b, where the precatalyst is
regenerated at high conversions concomitant with a decrease
in the rate of cyclization. The first-order rate dependence on
catalyst concentration over an 8-fold range (Figure 3) is
indicative of a monomeric catalytically active species.
The activation parameters for the lower transition state leading
to pyrrolidine (S)-6a (∆H(S)q ) 57.4(0.8) kJ mol-1 and ∆S(S)q
) -102(3) J K-1 mol-1) and the activation parameters for the
higher transition state leading to pyrrolidine (R)-6a (∆H(R)q )
61.5(0.7) kJ mol-1 and ∆S(R)q ) -103(3) J K-1 mol-1) were
obtained from the Eyring plot (Figure 4). They are in good
agreement with the activation parameters reported by Marks
for the achiral lanthanocene catalyst [Cp*2LaCH(SiMe3)2] (∆Hq
) 12.7(1.4) kcal mol-1 = 53(6) kJ mol-1, ∆Sq ) -27(4.6) eu
= -113(19) J K-1 mol-1),8b indicating that the hydroamination/
cyclization involves a similar highly ordered transition state as
The rate depression was also clearly visible when the substrate
was added in two batches (Figure 6). Cyclization of 5a (0.50
mol L-1) in the presence of product heterocycle 6a (0.50 mol
L-1) with (R)-2-Y (0.02 mol L-1) showed a reduced rate (8.4
h-1 vs 15.0 h-1 for the first run in the absence of 6a) of apparent
zeroth order.34b
(33) In catalytic and stoichiometric experiments no discrete catalyst species could
be observed.
9
J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006 3753

A R T I C L E S
Gribkov et al.
Therefore, the rate law for the catalytic hydroamination/
cyclization of aminoalkenes using binaphtholate rare earth metal
catalysts can be approximated by eq 5, with L being the
combined concentrations of amine bases and Kdorm the equilib-
rium constant between the catalytically active amido amine
species and the dormant amido diamine species (vide infra).36
The experimental values for the turnover frequencies Nt (Nt )
rate/[Ln]) plotted vs the initial concentration of substrate were
approximated with eq 530 to give k1 ) 29.7(1.2) h-1 and Kdorm
) 2.50(0.12) mol-1 L at 40 °C, respectively k1 ) 113(4) h-1
and Kdorm ) 0.89(0.06) mol-1 L at 60 °C.
k1[Ln]
1 + Kdorm[L]
d[subst.]
rate ) -
)
(5)
dt
High substrate concentrations were also slightly detrimental
to product enantioselectivity. Cyclization of 5a using (R)-2-Y
proceeded with 72% ee in a dilute substrate solution ([subst.]0
) 0.19 mol L-1), while a concentrated solution furnished 6a in
only 68% ee ([subst.]0 ) 0.98 mol L-1, [Ln] ) 0.02 mol L-1
in both cases). However, the enantiomeric excess of 6a prepared
with (R)-2-Y was invariant at various extents of conversion,
and no influence of catalyst concentration on product enantio-
selectivity was observed.
Cyclization of 5b with (R)-2-Y showed significantly more
pronounced rate acceleration than observed for 5a (Figure S8),30
indicating a stronger substrate inhibition and weaker binding
of the product heterocycle 6b to the metal center for this
substrate/catalyst combination. Concomitant to these observa-
tions the enantiomeric excess increased with increasing reaction
temperature (vide supra and Figure S9).
Cyclization of the nitrogen deuterated substrate 5a-d2 pro-
ceeded significantly more slowly than the non-deuterated 5a
(3.6 h-1 at 40 °C for 5a-d2 vs 15 h-1 for 5a using 4 mol %
(R)-2-Y, [Ln] ) 0.02 mol L-1), indicating a primary kinetic
isotope effect of 4.2. This kinetic isotope effect is comparable
to the value of 2.7 observed for [Cp*2LaCH(SiMe3)2] at 60 °C.8b
However, enantioselectivity was not affected (70% ee for 6a-
d2 vs 69% ee for 6a). Furthermore, cyclization was irreversible
at room temperature, as neither the isotopic substitution pattern
in 6a-d2 nor the enantiomeric excess changed after 45 days at
25 °C.
Kinetic Resolution of Chiral Aminoalkenes. The catalytic
kinetic resolution is an important methodology in organic
synthesis for the preparation of enantioenriched compounds.37
Kinetic resolution of chiral aminoalkenes via asymmetric
hydroamination on the other hand has not been performed
successfully prior to our studies.17,38 Attempts to resolve 15a
Figure 6. Time dependence of substrate concentration in the hydroami-
nation/cyclization of 5a using (R)-2-Y ([Ln] ) 0.02 mol L-1) at 40 °C. A)
First run ([subst.]0 ) 0.50 mol L-1). B) Second run with a second batch of
substrate 5a ([subst.]0 ) 0.50 mol L-1) added. C) Independent kinetic run
with [subst.]0 ) 1.00 mol L-1. The lines through the data points represent
the least-squares fit for the linear part of the data.
with chiral lanthanocene complexes gave only low enantiomeric
excess (<20% ee) at various extents of conversion.9b However,
binaphtholate catalysts 2-4 were successfully employed in the
kinetic resolution of chiral aminoalkenes (Table 3, Figure 7)
with a resolution factor f (f ) Kdias(kfast/kslow), vide infra) of up
to 19.
A simple protocol allowed the convenient separation of
aminoalkene starting material and pyrrolidine product by
aqueous extraction of the secondary ammonium acetate from
the benzaldimine of the primary amine (Scheme 3).
The resolution factor for the sterically least demanding
methyl-substituted substrate 15a increased slightly in the order
Lu e Y < Sc using triphenylsilyl-substituted binaphtholate
catalysts (R)-2-Ln and had a maximum value of 12 for catalyst
(R)-2-Sc with the smallest rare earth element. The sterically
more encumbered binaphtholate complexes (R)-3-Ln were
(36) (a) The presence of coordinating bases to the catalytically active species
has been argued by Marks and co-workers for lanthanocene complexes
based on kinetic and mechanistic studies (e.g. effects of exogenous bases
on reaction rates and diastereoselectivity, paramagnetic line broadening of
substrate and product signals in the NMR spectra of catalytic hydroami-
nation reactions, kinetic isotope effects).8b,9b (b) The number of amines
coordinated to species A and B (see Scheme 6) could not be determined
yet, as these species could not be observed independently by NMR
spectroscopy.33 However, on the basis of the preference of diolate rare earth
metal complexes to form five-coordinate complexes (e.g. in complexes 2
and 3, see also ref 16a) we believe species B to be a coordinatively saturated
diamine amido complex, while species A should possess an empty
coordination site required for the olefin insertion step. This proposal would
also be in agreement with the significantly reduced catalytic activity
observed for diolate diamine complexes.15a,e,f (c) [L] ) [subst.] +
[pyrrolidine] ≈ [subst.]0 -3 [Ln]. Three equivalents of amine are consumed
per molecule of precatalyst in the formation of the amido diamine species
B (Scheme 6), which is thought to be the dominant resting state of the
catalyst in solution in the presence of a large excess of amine bases.30
(37) (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (b) Keith,
J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5. (c)
Kagan, H. B. Tetrahedron 2001, 57, 2449. (d) Vedejs, E.; Jure, M. Angew.
Chem., Int. Ed. 2005, 44, 3974.
(38) Chiral amines can be resolved efficiently via enzymatic acylation; see: (a)
v. Rantwijk, F.; Sheldon, R. A. Tetrahedron 2004, 60, 501. For nonenzy-
matic kinetic resolutions of amines, see: (b) Arai, S.; Bellemin-Laponnaz,
S.; Fu, G. C. Angew. Chem., Int. Ed. 2001, 40, 234. (c) Al-Sehemi, A. G.;
Atkinson, R. S.; Fawcett, J.; Russell, D. R. Tetrahedron Lett. 2000, 41,
2239. (d) Miyano, S.; Lu, L. D.-L.; Viti, S. M.; Sharpless, K. B. J. Org.
Chem. 1985, 50, 4350. Preparation of chiral amines via asymmetric imine
hydrogenation and hydrosilylation: (e) Viso, A.; Lee, N. E.; Buchwald, S.
L. J. Am. Chem. Soc. 1994, 116, 9373. (f) Yun, J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 767.
(34) (a) In catalytic experiments with [Cp*2LaCH(SiMe3)2] we did not observe
a rate dependence on overall substrate concentration within the margin of
experimental error under the same reaction conditions. Furthermore, the
1H NMR signals of the substrate and product remained sharp throughout
the catalytic experiments, indicating a significant weaker binding of the
amine bases to the sterically more hindered metallocene complex in
comparison to the sterically more accessible binaphtholate catalysts. (b)
Marks observed a similar rate depression in the cyclization of an aminodiene
substrate using a constrained geometry catalyst,9d indicating a substantial
binding of the heterocyclic product to the metal center.
(35) (a) Other substrate/catalyst combinations can have different binding
constants for substrate and product, as the increased rates observed at high
conversion in the cyclization of 5b using (R)-2-Y indicate (Figure S8). (b)
Variable-temperature NMR studies of reaction mixtures containing (R)-
2-Y and 3 equiv of 6a in toluene-d8 showed broad features over a large
temperature range (-60 to +80 °C), even in the presence of the
noncyclizable primary amine n-propylamine (see Figures S1 and S2).30 No
decoalescence was observed even at -90 °C.
9
3754 J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006

Rare Earth Metal Catalysts for Hydroamination
A R T I C L E S
Table 3. Catalytic Kinetic Resolution of Chiral Aminopentenesa
entry
catalyst
substrate
t (h)
conversion (%)
% yield of SM; prod.b
trans:cis
recovered 15: ee (%)
16: ee (%)
f c
1
2
3
4
5
6
7
8
(R)-2-Sc
15a
15a
15a
15a
15a
15a
15a
15a
15b
15b
15c
15c
15d
15d
15e
15e
15e
15e
15f
94d
94d
42
24.5
25.5
15
26
25
4.5
6
6
24
9
27
15d
40
95
18d
18d
8d
51
50
55
51
53
52
52
50
51
51
50.5
51
50
52
52
52
50
52
50
50
39; 45
38; 44
37; 50
38; 47
39; 49
40; 47
39; 46
40; 44
42; 47
39; 46
40; 49
46; 47
45; 39
44; 46
42; 51
46; 51
47; 41
41; 50
44; 48
43; 47
10:1
7:1
10:1
9:1
11:1
8:1
13:1
7:1
16:1
20:1
18:1
7:1
20:1
20:1
g50:1
g50:1
g50:1
g50:1
g50:1
g50:1
73
73
73
75
72
68
80
65
51
57
37
44
42
38
83
59
74h
63
71
78
64
71
58
73
68
12
14
8.4
14
9.5
8.7
16
9.1
4.7
5.9
3.0
3.7
3.6
2.9
(R)-3-Sc
(R)-2-Lu
(R)-3-Lu
(R)-2-Y
(R)-2-Y+2 THF
58
(R)-3-Y
78 (-)e
73
(R)-4bf
9
(R)-2-Yg
(R)-3-Yg
(R)-2-Yf
(R)-3-Yf
(R)-2-Yf
(R)-3-Y
-
10
11
12
13
14
15
16
17
18
19
20
-
-
-
40 (-)
34
(R)-2-Lu
(R)-3-Luf
(R)-2-Y
(R)-3-Y
(R)-2-Y
-
-
19
6
15
7
12
19
63 (+)i
-
-
-
(R)-2-Y
15g
a Reaction conditions: 2 mol % cat., C6D6, Ar atm, 22 °C. b Isolated yield of starting material (SM) and product. Volatile amines were isolated as
hydrochloride salts. c Resolution factor f ) Kdias × kfast/kslow
.
d At 40 °C. e A (-) optical rotation corresponds to a (2S,5S) absolute configuration, see ref 39.
f 1.5 mol % cat. g 1.0 mol % cat. h [R]22 ) +12.9° for enantiopure (S)-15e‚HCl, [R]22 ) -41.9° for (2R,5S)-16e. i Determined by chiral HPLC.
D
D
Scheme 3 a
Figure 7. Dependence of enantiomeric excess of recovered starting material
on conversion in the kinetic resolution of 15e with (R)-2-Y at 30 °C. The
line was fitted using eq 12 to a resolution factor f ) 14.5.30
consistently more efficient for 15a with resolution factors as
high as 16 for the middle sized yttrium, while (R)-4b with the
larger lanthanum metal was the least effective resolution catalyst.
Addition of THF was slightly detrimental for diastereoselectivity
and kinetic resolution of 15a (Table 3, entry 6). Both series of
catalysts, (R)-2-Ln and (R)-3-Ln, exhibited similar catalytic
activity in cyclization of 15a, which increased with increasing
ionic radius of the metal.
Substrates with sterically more demanding R-alkyl substitu-
ents were increasingly less efficiently kinetically resolved,
although again the sterically more hindered (R)-3-Y was slightly
more effective than (R)-2-Y. The resolution factors decreased
in the following sequence of substrates: 15a (R ) Me, Table
3, entries 5 and 7) > 15b (R ) Et, entries 9 and 10) > 15c
a
Reagents and conditions: (a) 0.55 equiv AcOH; (b) 0.6 equiv PhCHO,
25 °C, 2 h; (c) extraction with benzene/hexanes/water (1/1/2); (d) organic
layer: 2N HCl, Et2O, 25 °C, 24 h; (e) aq NaOH; (f) aqueous layer: aq
NaOH.
(R ) iPr, entries 11 and 12) ≈ 15d (R ) CH2Ph, entries 13
and 14). However, aryl-substituted substrates 15e-g were
more efficiently resolved using catalysts (R)-2-Ln (Ln ) Lu,
Y, Table 3, entries 15, 17, 19, and 20) having the sterically
less demanding 3,3′-bis(triphenylsilyl)-substituted binaphtholate
ligand.
The 2,5-disubstituted pyrrolidines were obtained in moderate
to excellent trans diastereoselectivity, depending on the steric
hindrance of the R-substituent. Diastereoselectivity for methyl-
9
J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006 3755

A R T I C L E S
Scheme 4
Gribkov et al.
Scheme 5
fore, the rate law for each enantiomer is defined by eqs 8 and
9.41
d[R]
dt
-
-
) kR[cat.-R]
) kS[cat.-S]
(8)
(9)
substituted 15a ranged from 7:1 for catalysts (R)-3-Sc and (R)-
4b, up to 13:1 for (R)-3-Y. Sterically more demanding alkyl-
substituted substrates 15b-15d exhibited higher trans/cis
selectivities (trans/cis ) 16:1-20:1, except for entry 12). The
highest diastereoselectivity was observed for aryl-substituted
substrates 15e-g, which gave consistently high trans/cis
selectivities g50:1.
d[S]
dt
Combination of eqs 6-9 and integration30 leads to
kR ln([R]/[R]0)
f ) Kdias
)
(10)
kS
ln([S]/[S]0)
Resolution of p-chlorophenyl-substituted 15f occurred with
(R)-2-Y slightly less efficient than resolution of 15e, whereas
a higher selectivity was observed for the p-methoxyphenyl-
substituted 15g. Interestingly, the presence of the methoxy group
in 15g did not diminish the rate of cyclization. In fact,
cyclization of 15g proceeded at least twice as fast as 15f. These
examples indicate that the electron density at the aromatic ring
influences the rate as well as selectivity of cyclization.
The resolution factor can be expressed as a function of
conversion C and enantiomeric excess ee.
ln[(1 - C)(1 - ee)]
ln[(1 - C)(1 + ee)]
f )
(11)
Note that eq 11 is identical to that obtained for kinetic resolution
with a first-order rate dependence in substrate concentration,
except that in the latter case the parameter f is determined only
by the ratio between kR and kS.37a
Rearrangement of eq 11 leads to an expression for the
conversion as a function of the enantiomeric excess ee and the
resolution factor f, which is in good agreement with the
experimental data (Figure 7).
Kinetic resolution of 15e using 1 mol % (R)-2-Lu gave
enantiopure (S)-15e (g99% ee) in 33% re-isolated yield at 64%
conversion. The absolute configuration was determined by X-ray
crystallographic analysis of the ring-closed pyrrolidine hydro-
chloride (2R,5S)-16e‚HCl (Supporting Information) prepared
with (S)-2-Y. Therefore, in agreement with observations made
for substrates 5a-5d, the cyclization of chiral aminoalkenes
15a-15g proceeds with (R)-binaphtholate catalysts preferen-
tially through an approach of the Ln-N bond to the re face of
the olefin.
1/(f-1)
1 - ee
(1 + ee)
C ) 1 -
(12)
f
(
)
Kinetic resolution of 1-methylhex-5-enylamine (17) required
elevated temperature and exhibited a low resolution factor for
(R)-2-Y as well as a poor cis/trans ratio for the piperidine
product. (Scheme 4).
Kinetic measurements of the cyclization rates of enantiopure
(S)-15e using either (R)-2-Y or (S)-2-Y provided the rate
constants kslow and kfast for the cyclization of the mismatching
and matching substrate/catalyst combination (Figure 8).42 The
Kinetics of the Resolution Process. According to the general
model for the kinetic resolution of aminoalkenes (Scheme 5)
the total amount of catalyst [Ln] is distributed among two
substrate/catalyst complexes [cat.-R] and [cat.-S] (eq 6), which
readily interconvert in the presence of both enantiomers of the
substrate with rate constants kSR and kRS significantly larger than
the rates of cyclization.40 The equilibrium constant Kdias is
defined by eq 7.
(39) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J. J. Org. Chem. 1999, 64,
1979.
(40) Addition of 10 equiv of n-propylamine to (R)-2-Y gave only one broad
signal set for the propyl group, while two separate signal sets for the propyl
amido group and the coordinated propylamine were observed when only 2
equiv of n-propylamine were added. Marks and co-workers observed similar
exchange processes with amido amine lanthanocene complexes.8b
(41) Note that kR and kS are the apparent rate constants for a certain initial
substrate concentration. According to the overall rate law in eq 5, they
depend on the total base concentration.
(42) In the beginning of the kinetic resolution of rac-15e with (R)-2-Y (at <50%
conversion) the rate of the reaction approaches the zero-order rate of the
matching substrate/catalyst combination41 because, predominantly, the
matching substrate enantiomer is consumed. At higher conversions (>60%)
most of the matching substrate enantiomer is consumed, and the mismatch-
ing substrate enantiomer is consumed with a zero-order rate approaching
that of the mismatching substrate/catalyst combination. A smooth transition
between these two limiting cases results from the shift of the equilibrium
between the two diastereomeric substrate/catalyst complexes (Scheme 5)
in favor of the mismatching substrate/catalyst complex during the course
of the reaction. The overall time dependence of the concentration of the
(S) and (R) enantiomers during the kinetic resolution process can be
expressed by the following equations:30
[Ln] ) [cat.-S] + [cat.-R]
(6)
(7)
kSR
kRS
[cat.-R][S]
[cat.-S][R]
Kdias
)
)
The rate of hydroamination/cyclization is first order in catalyst
concentration, which corresponds here to the concentration of
the substrate/catalyst complexes [cat.-R] and [cat.-S]. There-
[S]0 - [S] + Kdias [R]0/[S]0 1/f ([S]0 - [S]f) ) kS[Ln]‚t
f
f
[R]0 - [R] + 1/Kdias [S]0/[R]0 f([R]0 - [R]1/f) ) kR[Ln]‚t.
1/f
1/f
9
3756 J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006

Rare Earth Metal Catalysts for Hydroamination
A R T I C L E S
2-Y on the other hand remained constant at an approximately
13:1 ratio up to 80% conversion, but dropped to an 8.8:1 final
ratio (Figure S15).30
Discussion
The binaphtholate catalysts 2-4 combine high activity and
good enantioselectivity. They have catalytic activity similar to
highly active lanthanocene catalysts. Cyclization of 5b with (R)-
4a (94 h-1 at 22 °C) proceeded with a turnover frequency
identical within margin of error to that of [Cp*2LaCH(SiMe3)2]
(95 h-1 at 25 °C).8b Cyclization of 5a catalyzed by (R)-4a (37
h-1 at 22 °C) and (R)-2-Y (2.6 h-1 at 25 °C, 93 h-1 at 60 °C)
should be compared to [Cp*2LaCH(SiMe3)2] (140 h-1 at 60
°C),8b [(R,S)-neomenthylNdCH(SiMe3)2] (93 h-1 at 25 °C),9b
and [(R,S)-neomenthylYCH(SiMe3)2] (4 h-1 at 25 °C).9b
The enantioselectivities observed for catalysts (R)-2-Ln and
(R)-3-Ln are among the highest reported thus far for rare earth
metal based hydroamination catalysts. Livinghouse recently
reported the application of an aminothiophenolate catalyst
system which gave up to 89% ee,15f although catalytic activity
was significantly lower than for catalysts 2-4.44 The two
additional amine donors of the amino(thio)phenolate ligands in
the catalyst systems reported by Scott15a and Livinghouse15f
seem to reduce catalytic activity, as the metal center becomes
less electropositive. Note, however, that one additional amine
donor in the ligand, as found in diamidoamine hydroamination
catalysts,14g does not seem to have a detrimental effect on
catalytic activity. The bis-oxazolinato catalyst system reported
by Marks was quite catalytically active but failed to give
enantioselectivities exceeding 67% ee.45 Collin, Trifonov, and
co-workers reported up to 70% ee using diamidobinaphthylate
complexes15d,g for the cyclization of the highly activated
substrate 5d.
Figure 8. Time dependence of trans-product concentration in the cycliza-
tion of (S)-15e using (S)-2-Y (9) or (R)-2-Y ([), as well as in the kinetic
resolution of (rac)-15e using (R)-2-Y (2) at 60 °C ([Ln] ) 0.0066 mol
L-1; [subst.]0 ) 0.335 mol L-1).42
The apparent zero-order rate dependence on substrate con-
centration, the first-order rate dependence on catalyst concentra-
tion, and the observed activation parameters are in accordance
with the generally accepted mechanism for rare earth metal
catalyzed hydroamination/cyclizations, in which the insertion
of the olefin moiety into the rare earth metal amido bond in a
chairlike transition state is the rate-limiting step of the catalytic
cycle (Scheme 6).8b,46 However, the impediment of the reaction
at high initial substrate concentrations indicates that a catalyti-
cally active binaphtholate amido amine species A is in equi-
librium with a catalytically inactive or significantly less active
binaphtholate amido diamine species B.36a,b Although lantha-
nocene catalysts are also slightly inhibited by the presence of
external bases, such as n-propylamine or THF, they do not show
Figure 9. Eyring plot for the hydroamination/cyclization of (S)-15e using
(S)-2-Y (2) and (R)-2-Y ([).
Eyring plot for kfast and kslow (Figure 9) provided the activation
parameters for the matching substrate/catalyst combination (∆Hq
) 52.2(2.8) kJ mol-1, ∆Sq ) -127(8) J K-1 mol-1) and for
the mismatching substrate/catalyst combination (∆Hq ) 57.7-
(1.3) kJ mol-1, ∆Sq ) -126(4) J K-1 mol-1). The difference
in the activation enthalpy is ∆∆Hq ) 5.5(3.0) kJ mol-1, while
the activation entropy for both transition states is identical within
experimental error.
Extrapolation of the Eyring plot gave a relative rate kfast/kslow
) 8.2 at 30 °C. Based on the resolution factor f ) 14.5 the
equilibrium constant of the two substrate/catalyst complexes was
estimated to Kdias ) 1.8, indicating that the equilibrium favors
the matching substrate/catalyst diastereomeric complex in this
example.
reduced rates with increasing substrate concentration.8b,34
A
significant difference of the binding constants of the aminoalk-
ene starting material and pyrroldine product would result in self-
inhibition or self-acceleration due to a shift in the equilibrium
of species A and B.47 The observation of a zero-order rate
The trans/cis ratio for the matching substrate/catalyst com-
bination (S)-15e/(S)-2-Y was g50:1 throughout the reaction,
similar to the selectivity observed in the kinetic resolution of
racemic 15e up to 50% conversion.43 The trans/cis selectivity
of the mismatching substrate/catalyst combination (S)-15e/(R)-
(44) Cyclization of 5b using 5 mol % of an aminothiophenolate yttrium catalyst
required 23 d at 30 °C and 15 h at 60 °C to achieve >95% conversion,15f
suggesting approximate turnover rates of 0.04 h-1, respectively 1.3 h-1
.
(45) Cyclization of 5b using 5 mol % of a bisoxazolinato lanthanum catalyst
proceeded with 67% ee and 25 h-1 at 23 °C, whereas 5a was cyclized in
40% ee with 0.09 h-1 15c
.
(46) (a) Motta, A.; Lanza, G.; Fragala`, I. L.; Marks, T. J. Organometallics 2004,
23, 4097. (b) Note, however, that in case of the hydroamination/cyclization
of aminodienes Tobisch recently proposed turnover-limiting protonolysis
of the η3-butenyl-Ln functionality; see: Tobisch, S. J. Am. Chem. Soc.
2005, 127, 11979.
(43) Additionally, cyclization of racemic 15a with (R)-2-Y proceeded with 11:1
diastereoselectivity up to 50% conversion, but dropped to 3.4:1 at 100%
conversion.
9
J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006 3757

A R T I C L E S
Scheme 6
Gribkov et al.
Figure 10. Stereomodel for enantioselective hydroamination/cyclization
of aminoalkene 5a by binaphtholate rare earth metal catalysts with an
equatorial approach of the olefin.
dependence on substrate concentration is therefore indicative
of a relative nonspecific binding of the amine bases to the metal
center in this example.
The slightly increased catalytic activity of sterically more
encumbered 3,3′-bis(tris(3,5-xylyl)silyl)-substituted binaphtho-
late catalysts (R)-3-Ln in comparison to that of sterically less
demanding 3,3′-bis(triphenylsilyl)-substituted binaphtholate cata-
lysts (R)-2-Ln can therefore be explained with a weaker binding
of amines to (R)-3-Ln, thereby shifting the equilibrium from
the dormant species B to the catalytically active species A.
Since the equilibrium between species A and B is shifted at
high initial substrate concentrations or in the presence of excess
THF, the reaction is channeled more and more through the
significantly less active species B. The slightly reduced enan-
tioselectivities observed under these conditions could therefore
be explained with a less enantioselective cyclization process in
species B, due to a more crowded coordination environment
around the metal center.
The unusual temperature dependence of enantioselectivity in
the cyclization of substrate 5b (Figure S9) is also in agreement
with a less selective species B, as the equilibrium between
species A and B is shifted at elevated temperatures in favor of
the more selective species A.
The rate- and stereo-determining olefin insertion step can be
proposed to involve an approach of the olefin from the equatorial
position to the axial Ln-N bond (Figure 10).48 The transition
state for an approach of the Ln-N bond to the si face of the
olefin, leading to the (R)-pyrrolidine product, is hampered by
sterically unfavorable interactions of the substrate with one of
the sterically demanding tris(aryl)silyl substituents, whereas no
Figure 11. Proposed stereochemical model for the kinetic resolution of
R-substituted 1-aminopent-4-enes.
such interaction occurs if the olefin approaches with the opposite
re face to give the observed (S) stereochemistry. The effect of
different bases coordinated to species A (either aminoalkene
substrate, pyrrolidine product, or THF) can be expected to have
only a minimal influence on the stereoselection process, as the
exogenous base coordinates trans to the axial Ln-N bond,
which is also in accordance with conversion-independent product
enantioselectivities.
In agreement with these observations, the cyclization of chiral
aminoalkenes 15a-g proceeded also preferentially through an
approach of the Ln-N bond to the re face of the olefin. In
case of the matching substrate/catalyst combination the R-sub-
stituent preferentially rests in an equatorial position, locking
the conformation of the seven-membered cyclization transition
state, and allowing a facile approach of the Ln-N bond to the
re face of the olefin (Figure 11). In case of the mismatching
substrate/catalyst combination the approach to the si face of
the olefin with an equatorial R-substituent is hindered by
sterically unfavorable interactions between the substrate and the
tris(aryl)silyl substituent. An approach to the re face of the olefin
on the other hand, favored by diminished steric interactions with
the tris(aryl)silyl substituents of the binaphtholate ligand,
requires an R-substituent in axial position and leads to the cis
(47) (a) As noted above, the cyclization of 5a by (R)-2-Y performed at 25 °C
showed a slight sign of curvature (acceleration, see Figures 6 and S5),
suggesting that the binding constant of the pyrrolidine product is slightly
smaller than that of the aminoalkene. (b) Sterically open ansa-lanthanocene
complexes and constrained geometry catalysts display product inhibition
(apparent first-order kinetics),8b,9b,d,e while self-acceleration has been
observed in the cyclization of aminodiene derivatives using sterically more
encumbered catalysts.9d (c) For product inhibition in rare earth metal
catalyzed hydrophosphination, see: Douglass, M. R.; Stern, C. L.; Marks,
T. J. J. Am. Chem. Soc. 2001, 123, 10221.
(48) A similar model has been proposed by Marks and co-workers for their
bisoxazolinato rare earth metal hydroamination catalyst system.15c Molecular
modeling studies indicated that the opposite (minor) pyrrolidine enantiomer
should form if the olefin approaches from the apical position to an equatorial
Ln-N bond. A change of the approach of the olefin was suggested to be
responsible for the reversal of product absolute configuration when catalysts
with alkyl-substituted bisoxazolinato ligands were used instead of catalysts
with aryl-substituted bisoxazolinato ligands.
9
3758 J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006

Rare Earth Metal Catalysts for Hydroamination
A R T I C L E S
pyrrolidine product. This competition between enantiomorphic
site control and substrate control explains the lower trans/cis
diastereoselectivity observed in the cyclization of the mismatch-
ing aminoalkene/catalyst combination (S)-15e and (R)-2-Y.
The kinetic resolution process of substrate 15e is assisted by
the equilibrium between the two diastereomeric substrate/catalyst
complexes, which lies in favor of the matching substrate/catalyst
combination. The low efficiency in the kinetic resolution of
alkyl-substituted aminoalkenes 15b-d on the other hand could
result from a less favorable position of the substrate/catalyst
complexation equilibrium (e.g., Kdias e 1).49
A plausible explanation for the high trans/cis ratio and high
efficiency in the kinetic resolution of aryl-substituted substrates
15e-15g in comparison to that of alkyl-substituted substrates
15b-15d could stem from a π-interaction of the aryl substituent
with the metal center or one of the aromatic substituents of the
binaphtholate ligand. Further evidence for this proposal is
indicated by the increased rate of cyclization and improved
resolution efficiency in the presence of the electron-donating
p-methoxy group in 15g, in comparison to the electron-
withdrawing p-chloro-substituted 15f.50 Similar aryl-directing
effects have been shown to be crucial for high regioselectivity
in intermolecular vinylarene hydroamination and ring opening
of unsymmetrical phenylmethylenecyclopropanes.10b
systems, and enantioselectivities of up to 95% ee were achieved
in the cyclization of achiral aminopentenes. The hydroamination
mechanism for the binaphtholate catalyst system is similar to
that proposed for lanthanocene catalysts, based on the rate
dependencies on substrate and catalyst concentrations and the
observed activation parameters. However, the binaphtholate
complexes are more prone to base coordination, as exemplified
by the dependence of catalytic activity on initial substrate
concentration. Further studies will focus on the scope, selectivity,
and functional group tolerance of the binaphtholate rare earth
metal complexes in asymmetric hydroamination and other
catalytic σ-bond metathesis reactions. The initial experiments
of the anti-Markovnikov addition of n-propylamine to styrene
indicate that the highly active lanthanum catalysts (R)-4a and
(R)-4b are the most promising candidates for asymmetric
intermolecular hydroamination reactions.
Acknowledgment. Generous financial support by the Deut-
sche Forschungsgemeinschaft (DFG), the Fonds der Chemischen
Industrie, and the Dr. Otto Ro¨hm Geda¨chtnisstiftung is gratefully
acknowledged. K.C.H. is a DFG Emmy Noether fellow (2001-
2006) and thanks Professor John A. Gladysz for his continual
support. We thank Patricia Horrillo Mart´ınez for the preparation
of substrates 5c and 5d, Rebekka Park for assistance in the
preparation of substrates 15f and 15g and some kinetic resolution
experiments, as well as Dmitri Denysenko for helpful discus-
sions.
Conclusion
Rare earth metal complexes with sterically demanding tris-
(aryl)silyl-substituted binaphtholate ligands are efficient catalysts
for asymmetric hydroamination/cyclization of aminoalkenes and
the kinetic resolution of R-substituted aminopentenes. Catalytic
activities are comparable to those of lanthanocene catalyst
Supporting Information Available: Experimental procedures
and spectral and analytical data for complexes, substrates and
products, derivation of equations, kinetic diagrams, and crystal-
lographic data (in CIF format) for (2R,5S)-16e‚HCl and the
Mosher amide of (S)-6c. This material is available free of charge
via the Internet at http://pubs.acs.org.
(49) Further kinetic studies will address this subject.
(50) The fact that the p-methoxy functionality in substrate 15g is tolerated by
(R)-2-Y without detrimental effect on the rate of cyclization can be
explained by the remote position of the methoxy substituent.
JA058287T
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J. AM. CHEM. SOC. VOL. 128, NO. 11, 2006 3759