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Enantioselective Catalytic Hydroamination of Alkenes.

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Asymmetric Synthesis of Amines
Enantioselective Catalytic Hydroamination of Alkenes
Peter W. Roesky* and Thomas E. Mller*
asymmetric synthesis · chiral ligands · homogeneous
catalysis · hydroamination · iridium · lanthanides
The catalytic addition of an organic
amine R2NH bond to alkenes or alkynes (hydroamination) to give nitrogen
containing molecules is of great interest
for academic and industrial research.
Since today most amines are made in
multistep syntheses, hydroamination
would offer the most attractive alternative synthetic route. It was shown, that
hydroamination can be catalyzed by
transition metals (d- and f-block) and
alkali metals.[1] Depending on the catalytic system either an activation of the
CC multiple bond or the NH bond
takes place. Alkene or alkyne activation
is usually accomplished with late-transition metals through coordination of
the CC multiple bond to the metal
center. In contrast, the amino function
can be activated by alkali or early
transition metals, which generate an
amido species, or by NH oxidative
addition to electron-rich transition metals. Depending on the nature of the
catalysts and the substrates either Markovnikov or anti-Markovnikov products
are obtained [Eq. (1)]. The scope of
[*] Prof. Dr. P. W. Roesky
Institut fr Chemie
Freien Universit"t Berlin
Fabeckstrasse 34–36
14195 Berlin (Germany)
Fax: (+ 49) 30-838-52440
catalytic hydroamination has been reviewed recently.[1–6]
Today, the vast number of enantioselective syntheses of molecules bearing
an amine functionality use classical
stoichiometric reactions with chiral auxiliaries or utilize enantiomerically pure
starting materials.[7] As a result of the
increasing interest in the hydroamination reaction some research groups have
started to investigate the enantioselective R2NH addition to CC double
bonds. In early transition-metal chemistry Marks et al. implemented C1-symmetric organolanthanide ansa-metallocene catalysts of the type [Me2Si(h5C5Me4)(h5-C5H3R*)LnE(SiMe3)2] (1)[8–10]
(R* = ()-menthyl,
()-phenylmenthyl; Ln = La, Nd, Sm,
Y, Lu; E = CH, N) and [Me2Si(h5OHF)(h5-C5H3R*)LnN(SiMe3)2] (2)[11]
(OHF = octahydrofluorenyl; R* = ()menthyl; Ln = Sm, Y, Lu) in the enan-
tioselective and diastereoselective hydroamination/cyclization of aminoalkenes. Compounds 1 and 2 catalyze the
cyclization of, for example, 1-amino-4pentenes to 2-methylpyrrolidines and of
1-amino-5-hexenes to 2-methylpiperidines, generating a new asymmetric
center adjacent to the heterocyclic nitrogen atom [Eq. (2)].
Using 1 as the catalyst 2,2-dimethyl1-aminopent-4-ene is cyclized with
53 % ee at 25 8C (74 % ee at 30 8C)
and turnover frequencies as high as
93 h1. In general, the turnover frequencies decrease with decreasing ion radius
of the metal center. The configuration of
the product and the enantiomeric excess
depends on the chiral group R* and the
ion radius of the lanthanide metal. The
product stereochemistry can be understood in terms of olefin insertion via a
chairlike, seven-membered transition
Compound 2 was used to convert 1amino-5-hexenes into 2-methylpiperidines with enantioselectivities up to
67 %. Compared to 1, compound 2 only
provides greater enantioselectivities
with sterically encumbered substrates.
In both cases the reaction kinetics were
zero order in substrate and first order in
catalyst concentration over at least three
half-lives. The kinetics are thus in agreement with activation of the amine and
rate-determining insertion of the alkene
group.[12] Compound 2 (Ln = Sm) was
also used for the enantioselective hydroamination/cyclization of aminodienes.
Preliminary studies reveal that the cyclization of 1-amino-5,7-octadiene to the
corresponding piperidine proceeds with
up to 69 % ee.[13]
Togni et al.[14, 15] developed an enantioselective version of the known iridium-catalyzed hydroamination reaction.[16, 17] The binuclear, chloride bridged complexes 3–7 which have chiral
chelating diphosphanes in their coordi-
DOI: 10.1002/anie.200301637
Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710
Dr. T. E. Mller
Institut fr Technische Chemie II
Technische Universit"t Mnchen
Lichtenbergstrasse 4
85747 Garching (Germany)
Fax: (+ 49) 89-28913544
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
nation spheres were prepared. The unseparated cis/trans mixtures of these
compounds were used as catalyst precursors in the intermolecular hydroamination of norbornene with aniline
[Eq. (3)].
catalyst precursors in the intermolecular
hydroamination of norbornene with aniline. The study compared the complexes
8 (employed as inseparable cis/trans
mixture) with the corresponding ferrocene-based Josiphos-ligated complexes
Addition of fluoride ions (as
1,1,1,3,3,3-hexakis(dimethylamino)diphosphazenium fluoride) as cocatalyst
increased the activity and enantioselectivities. Using 6 as the catalyst, up to
95 % enantiomeric excess were observed. The highest turnover frequencies of 3.4 h1 were observed when 3 was
employed as catalyst. These reactions
were performed without solvent and at a
catalyst concentration of 1 or 2 mol % Ir.
In a similar approach planar chiral
arene chromium tricarbonyl complexes,
[{h6-(pR,R)[(PR2)CHMe]C6H4PPh2}Cr(CO)3] (R = Cy (cyclohexyl), Ph), were
used as ligands to generate binuclear,
chloride-bridged iridium complexes
8.[18, 19] The compounds 8 were used as
3 and its tBu derivative. Reactions were
performed in aniline at 60 8C for 96 h
using 0.1 mol % of catalyst. An even
higher enantiomeric excess (up to 70 %)
was obtained in comparison to the
ferrocene ligated complexes (13 % and
64 % ee), however, only traces of product were isolated.
In contrast to the results found for
the iridium-based catalysts, the bidentate ferrocenyl Josiphos system did not
afford active catalysts for nickel systems.
On the other hand NiII complexes containing the chiral tridentate ferrocenyl
Pigiphos ligand, [Ni(Pigiphos)(thf)](ClO4)2 have been found to efficiently
catalyze the enantioselective hydroamination of activated olefins with both
anilines and aliphatic amines [Eq. (4);
EWG = electron-withdrawing group] at
Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710
room temperature.[20] The most remarkable result in this series concerns
the hydroamination of methacrylonitrile with morpholine that gave the
product in quantitative yield and
69 % ee.
The palladium catalyzed hydroamination of anilines to 1,3-dienes was
investigated by Hartwig et al.[21] This
group evaluated a large number of
potential catalysts for the hydroamination reaction by a colorimetric method
which allowed the rapid determination
of the concentration of unreacted anilines at the end of the reaction. Anilines
(educt) but not allylic amines (product)
react with furfural to give a red product.
The experiments showed that complexes formed in situ from [{Pd(p-allyl)Cl}2] and PPh3 in the presence of
10 % trifluoracetic acid (TFA) are very
active for the hydroamination of aromatic amines. Experiments with optically active phosphanes instead of PPh3
showed good conversions but little or
no stereoselectivity. Although slower,
the same reaction with the chiral phosphane ligand 9, but without acid as
cocatalyst, showed a promising stereoselectivity and conversion of various
[Eq. (5)].
Under optimized reaction conditions enantioselectivities up to 95 %
were observed. In a more detailed study,
it was shown that—in the presence of
acid, the catalyst [{Pd(p-allyl)Cl}2], and
9—at the metal center, the product
exchanges with free amine as fast as it
is formed, and therefore, loses its optical
activity. Thus, the kinetic selectivity of
the catalytic system may be the same in
the presence and absence of acid; the
exchange process leads to the apparent
reduction in selectivity.[22]
Also, the enantioselective addition
of aniline to vinylarenes can be per-
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
formed with palladium catalysts.[23] As
outlined above this requires irreversible
addition of the amine to the olefin.
Reaction of aniline with p-trifluoromethylstyrene catalyzed by [((R)-binap)Pd(OSO2CF3)2] at 25 8C gave the addi-
have only limited applications. As a
result of the increasing research efforts
in the enantioselective catalytic hydroamination new and spectacular examples of this reaction will most likely
follow in the near future.
tion product in 81 % yield and 81 %
enantioselectivity [Eq. (6)]. Analysis of
the enantioselectivity throughout the
reaction showed a constant value at
both low and high conversion. Reaction
of vinylnaphthalene with aniline at 45 8C
with the same catalyst gave quantitative
yields and 64 % enantioselectivity.
The enantioselective catalytic hydroamination is one of the major challenges in synthetic organic and organometallic chemistry. An enantioselective
hydroamination offers a very attractive
synthetic pathway to chiral amines. As
shown herein only a few catalysts for the
enantioselective hydroamination are
known to date. So far, these systems
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Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710
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catalytic, enantioselectivity, hydroamination, alkenes
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