Kinetic resolution of chiral aminoalkenes via asymmetric hydroamination/cyclisation using binaplitholate yttrium complexes

Article abstract of DOI:10.1039/b316096c

Chiral binaphtholate yttrium aryl complexes are highly active and enantioselective catalysts for the asymmetric hydroamination of aminoalkenes, as well as the kinetic resolution of α-substituted 1-aminopent-4-enes to give trans-2,5-disubstituted pyrrolidines with good enantiomeric excess and high k_rel.

Full text of DOI:10.1039/b316096c

Kinetic resolution of chiral aminoalkenes via asymmetric
hydroamination/cyclisation using binaphtholate yttrium complexes†
Denis V. Gribkov and Kai C. Hultzsch*
Institut für Organische Chemie, Friedrich-Alexander Universität Erlangen-Nürnberg, Henkestr. 42, D-91054
Erlangen, Germany. E-mail: hultzsch@chemie.uni-erlangen.de
Received (in Cambridge, UK) 11th December 2003, Accepted 26th January 2004
First published as an Advance Article on the web 20th February 2004
Chiral binaphtholate yttrium aryl complexes are highly active
and enantioselective catalysts for the asymmetric hydro-
amination of aminoalkenes, as well as the kinetic resolution of
a-substituted 1-aminopent-4-enes to give trans-2,5-disubsti-
tuted pyrrolidines with good enantiomeric excess and high
binaphtholate ligand to transmit its chirality onto the substrate
during the cyclisation step. Cyclisation of 2-allyl-2-methyl-pent-
4-enylamine (6) proceeded with almost identical enantiomeric
excess for both catalysts, although 1a gave a slightly better
diastereomeric ratio.
We then began to investigate the kinetic resolution of a-
substituted 1-aminopent-4-enes (Scheme 2, Table 2). Both catalysts
show moderate (Table 2, entries 1 and 2) to high (Table 2, entries
3 and 4) trans selectivity depending on the steric bulk of the
substituent a to the amino group. Cyclisation of 2-aminohex-5-ene
(8) is known to yield predominantly trans-2,5-dimethylpyrrolidine
(9),9,10 which can be explained with minimal 1,3-diaxial inter-
actions in the cyclisation transition state.11
krel
.
The hydroamination reaction in general1 and its asymmetric variant
in particular2 constitute an important goal in current research due to
their relevance to the synthesis of nitrogen-containing fine
chemicals and pharmaceuticals. Rare earth metal catalysts have
proven to be competent catalysts in various hydroamination
reactions. However, chiral catalysts based on planar chiral
cyclopentadienyl ligands were hampered by facile catalyst epimer-
isation.3 Only recently have new chiral rare earth metal catalysts
based on non-cyclopentadienyl ligands evolved.4 However, en-
antioselectivities have not been improved markedly compared to
lanthanocene catalysts and catalyst activity was unsatisfactory. In a
previous study4b we observed the first example of a kinetic
resolution of 2-aminohex-5-ene, albeit with a rather low krel‡ value
of only 2.6. Herein we communicate the synthesis of new
binaphtholate yttrium aryl complexes which show significantly
improved catalytic activity for aminoalkene hydroamination/
cyclisation with unprecedented enantioselectivities, which are also
capable of promoting efficient kinetic resolution of a-substituted
1-aminopent-4-enes.5
The sterically more hindered catalyst 1b gave a good krel for
sterically less hindered substrate 8, but inferior selectivity for more
bulky substrates 10 and 12, for which catalyst 1a gave better
values.
Our previous study had shown that steric bulk in the 3- and 3A-
positions of the biphenolate or binaphtholate is an indispensable
requirement for a monomeric catalyst structure and effective
asymmetric induction. We anticipated that a further increase in
steric bulk of these substituents would increase the enantioselectiv-
ity. We decided that 3,3A-bis(tris(aryl)silyl)-substituted binaph-
tholate ligands6 would be suitable candidates to provide sufficient
steric bulk. Although analogous binaphtholate lanthanum alkyl
complexes have been reported,7 their catalytic activity remains
unexplored. Suitable yttrium complexes were prepared by arene
elimination starting from [Y(o-C6H4CH2NMe2)3]8 (Scheme 1).
Complexes 1a and 1b retain one equivalent of N,N-di-
methylbenzylamine.
Scheme 1
Initial experiments with a few hydroamination/cyclisation
benchmark substrates (Table 1) showed that the two binaphtholate
yttrium complexes display good catalytic activity at room tem-
perature of comparable magnitude to that of lanthanocene cata-
lysts.3,9 The rate is only slightly depressed in the presence of THF
(3.2 h21 for substrate 2 using 1a plus 3 equivalents of THF,
compared with 8 h21 in the absence of THF). Although enantiose-
lectivities for 2,2-dimethyl-pent-4-enylamine (2) are rather moder-
ate, higher enantioselectivities were observed for 1-aminopent-
4-ene (4). Additionally, enantioselectivities using catalyst 1b are up
to 14% higher than those observed with sterically less hindered 1a.
Complex 1b delivers 2-methylpyrrolidine (5) in unprecedented
83% ee, the highest enantioselectivity observed with a chiral rare
earth metal catalyst to date.2–4 The remote methyl groups on the
aromatic substituents of silicon clearly increase the efficiency of the
Table 1 Catalytic hydroamination/cyclisation reactionsa
Entry Substrate
Cat.
t/h
Conv. (%)
TOF/h21 ee (%)
1
2
3
4
5
6
2
2
4
4
6
6
1a
1b
1a
1b
1ab
1bb
3
2
24
20
1
498
498
498
498
498
498
8
14
1.2
2.2
75
70
43
53
69
83
63, 53c
65, 65d
1.2
† Electronic supplementary information (ESI) available: experimental
procedures and characterising data for all new complexes and substrates.
See http://www.rsc.org/suppdata/cc/b3/b316096c/
a Reaction conditions: 4 mol% cat., C6D6, Ar atm, 22 °C. b 2 mol% cat. c dr
= 1.8:1. d dr = 1.4:1.
730
C h e m . C o m m u n . , 2 0 0 4 , 7 3 0 – 7 3 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Catalytic kinetic resolution of chiral aminopentenesa
% ee of
recovered
reactant
% ee of
productb
c
Entry
Substrate
Cat.
t/h
Conv. (%) trans:cis
krel
1
2
3
4
5
6
8
8
10
10
12
12
1a
1b
1a
1b
1a
1b
25.5
26
95
18f
9
53
52
50
52
50
52
11:1
13:1
450:1
450:1
20:1
72
80
74
63
42
38
68
9.5
16
15
7
3.6
2.9
78 (2)d
—e (+)
––e
40 (2)
34
27
20:1
a Reaction conditions: 2 mol% cat., C6D6, Ar atm, 22 °C. b Sign of optical rotation given in parentheses. c Based on starting material. d (2S,5S) absolute
configuration. e Not determined. f At 40 °C.
A simple protocol allowed the convenient separation of the
aminoalkene starting material and pyrrolidine product by aqueous
extraction of the secondary amine acetate from the primary amine
benzimine (Scheme 2).
A working model for the observed stereodifferentiation explain-
ing the preferred formation of (2S,5S)-9 is depicted in Fig. 1.
Efficient kinetic resolution is only possible if the initial exchange of
matching and mismatching substrates is significantly faster than
cyclisation. Slower cyclisation of (R)-8 results from sterically
unfavourable interactions of the vinylic methylene protons with one
triphenylsilyl substituent in the seven-membered transition state.
In conclusion, the synthesis of chiral trans-2,5-disubstituted
pyrrolidines via kinetic resolution of a-substituted 1-aminopent-
4-enes represents a new promising application of asymmetric
hydroamination in organic synthesis. We are confident that this
general route can be applied to other chiral aminoalkenes allowing
the facile synthesis of enantiopure nitrogen-containing hetero-
cycles. Modification of the substitution pattern of the binaphtholate
ligands as well as the ionic radius of the rare earth metal can be
expected to result in even more active and enantioselective
hydroamination catalysts.
Generous financial support by the Deutsche Forschungsge-
meinschaft (DFG) and the Fonds der Chemischen Industrie is
gratefully acknowledged. K. C. H. is a DFG Emmy Noether fellow
and thanks Professor John A. Gladysz for generous support.
Notes and references
‡ krel denotes the relative ratio between the faster and slower reacting
enantiomer of the substrate. See: H. B. Kagan and J. C. Fiaud, Top.
Stereochem., 1988, 18, 249.
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Scheme 2 Reagents and conditions: i, 0.55 equiv. AcOH; ii, 0.6 equiv.
PhCHO, 25 °C, 2 h; iii, extraction with benzene/hexanes/water (1:1:2); iv,
organic layer: 2 N HCl, Et2O, 25 °C, 24 h; v, aq. NaOH; vi, aqueous layer:
aq. NaOH.
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complements the synthesis of cis-2,5-disubstituted pyrrolidines via
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Fig. 1 Proposed stereochemical model for the kinetic resolution of a-
substituted 1-aminopent-4-enes.
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C h e m . C o m m u n . , 2 0 0 4 , 7 3 0 – 7 3 1
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