Intermolecular, catalytic asymmetric hydroamination of bicyclic alkenes and dienes in high yield and enantioselectivity

Article abstract of DOI:10.1021/ja803523z

A set of catalytic, intermolecular hydroaminations of strained bicyclic olefins and dienes are reported that occur in both high yield and high enantioselectivity. These reactions occur with a catalyst generated from [Ir(cyclooctene)Cl]₂, sterically hindered and electron-rich derivatives of the Segphos and BIPHEP family of ligands, and a soluble base. This system catalyzes the addition of various anilines to norbornene, norbornadiene, and other bicyclic olefins. The products from addition of p-anisidine can be transformed to BOC-protected norbornylamine and to substituted cyclopentanes in nearly enantiopure form. Mechanistic studies show that addition of aniline-d₂ occurs in a syn fashion and suggest that the catalytic cycle comprises oxidative addition of aniline to form a bis-anilide hydride complex, followed by migratory insertion of olefin and reductive elimination of product in a series of steps involving iridium complexes containing ancillary bisphosphine and arylamide ligands. Copyright

Full text of DOI:10.1021/ja803523z

Published on Web 08/21/2008
Intermolecular, Catalytic Asymmetric Hydroamination of Bicyclic Alkenes and
Dienes in High Yield and Enantioselectivity
Jianrong (Steve) Zhou and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois Urbana-Champaign, 600 South Matthews AVenue, Box 58-6,
Urbana, Illinois 61801
Received May 12, 2008; E-mail: jhartwig@uiuc.edu
Scheme 1
Asymmetric hydroamination of olefins would be an efficient
means to access chiral, nonracemic alkylamines,1 and development
of stereoselective catalysts for these processes has been a long-
standing challenge.2 Only recently have intramolecular, catalytic
hydroaminations of alkenes and allenes been reported with a high
level of enantioselection.3 However, no example of intermolecular
hydroamination of alkenes has been reported with both high yield
and high enantioselectivity.4
Table 1. Effect of Ligands on the Asymmetric Hydroamination of
Norbornene with m-Xylylamine under the Conditions of Scheme 1
Roughly a decade ago, the beneficial effect of a fluoride anion5
on the hydroamination of aniline with norbornene10 was reported.
The origin of this effect was never deduced, and additions occurred
in either high yield or high enantioselectivity, but not both. Here,
we report asymmetric hydroaminations of bicyclic alkenes and
dienes with a series of aromatic amines in high yields and
enantioselectivities using an organic base in place of the fluoride.
This process creates an enantioselective route to 2-norbornylamine,
which is a common building block in medicinal chemistry,6 and to
enantioenriched cyclopentylamines containing at least three defined
stereocenters and two additional functionalities for further manipu-
lations (eq 1). The effect of base and the reactivity of potential
intermediates provide a mechanistic foundation for the hydroami-
nation activities of the iridium catalysts.
a DM ) 3,5-dimethylphenyl; DTBM ) 3,5-di-tert-butyl-4-methoxy-
phenyl. b Values from Jeulin, S.; de Paule, S. D.; Ratovelomanana-Vidal,
V.; Genet, J. P.; Champion, N.; Dellis, P. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5799.
bulky, electron-rich P-aryl groups were particularly reactive. A
sequential increase in steric bulk and electron donation of the P-aryl
group led to a smooth increase in yield while maintaining high
enantioselectivity (Table 1, entries 3-5 and 6-8). Under similar
conditions, reactions catalyzed by complexes generated from
Josiphos ligands containing di-tert-butyl-, dicyclohexyl-, and dia-
rylphosphino groups5 formed <15% yield of the product with
22-96% ee.
The scope of the reaction of different aromatic amines with
bicyclic olefins is shown in Table 2. In general, both electron-poor
and -rich anilines were less reactive than electron-neutral anilines
toward this hydroamination catalyzed by the complex of DM-
Segphos.8 Most reactions occurred in high yield and ee using
DTBM-Segphos under neat conditions, but in some cases a change
in ligand created higher selectivities. X-ray crystallography on the
bromoaniline addition product showed that the absolute stereo-
chemistry of the product was (2S) when (R)-DTBM-Segphos was
used as ligand.
These catalysts significantly increase the synthetic utility of this
hydroamination by catalyzing additions to norbornadiene. This
diene, which often chelates low-valent metals, could be envisioned
to poison the catalyst. However, m-xylylamine and p-anisidine
added to norbornadiene in high yield and enantioselectivity in the
presence of the catalyst generated from (R)-DTBM-Segphos. No
product from addition to the second olefin unit was detected by
GCMS.9 Reactions of p-anisidine with both olefins also occurred
with just 0.5 mol % of iridium, although a longer reaction time
was needed. Both benzo-fused and imide-containing bicyclic olefins
Our initial experiments were based on the hypothesis that the
fluoride used in previous studies might have served as a base to
generate small amounts of arylamide and could be replaced with a
soluble organic base. To test this hypothesis, we conducted reactions
between m-xylylamine and norbornene in the presence of cata-
lysts generated from a combination of [Ir(cyclooctene)2Cl]2, DM-
Segphos, and disilylamide base. These and related data are sum-
marized in Scheme 1. Indeed, added KHMDS base dramatically
increased turnover numbers and enantioselectivity for the reactions
of a substituted aniline with norbornene.7 We next considered that
KHMDS simply produced catalytic amounts of KNHXylyl. Con-
sistent with this logic, the reaction conducted with 1 mol % of added
KNHXylyl occurred with yields and enantioselectivities that were
similar to those with added KHMDS.
Studies of this reaction catalyzed by complexes of other types
of biaryl bisphosphine ligands (Table 1) showed that the backbone
dihedral angle and substituents on the P-aryl groups both influenced
catalyst activity. Reactions conducted with the catalyst containing
BINAP or 3,5-xylyl-BINAP occurred with low turnover numbers
(Table 1, entries 1 and 2). Complexes of Seg-phos and MeOBI-
PHEP, which have smaller backbone dihedral angles than BINAP,
were more active catalysts (Table 1, entries 3 and 6 vs 1). Catalysts
generated from members of these two ligand families containing
9
12220 J. AM. CHEM. SOC. 2008, 130, 12220–12221
10.1021/ja803523z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Proposed Catalytic Cycle for the Hydroamination
Table 2. Scope of Asymmetric Hydroaminations of Olefins
The stereochemistry of the addition implies that the reaction
occurs by a pathway involving migratory insertion of the alkene,
followed by reductive elimination. The data obtained with different
catalyst precursors imply that a monomeric, neutral anilide complex
catalyzes the reaction. We tentatively postulate that protonation of
the anionic anilide complex in the presence of alkene allows entry
into the catalytic cycle and that the catalyst deactivates by forming
the neutral dimeric [Ir(L2)(NHmXylyl)]2.12 If this proposal is correct
and the mechanism in Scheme 2 is followed, then each intermediate
contains an arylamide ligand. The arylamide would then serve as
a reactive and ancillary ligand.
a 100 °C, 12 h. b exo-(2S) configuration was determined by X-ray
crystallography. c 0.5 mol % [Ir]; 40 h. d 1 mol % [Ir]; 12 h. e triMeO )
3,4,5-trimethoxyphenyl. f 1.2 equiv of olefin. g 1.2 equiv of m-
xylylamine.
In summary, we have reported a series of intermolecular
enantioselective hydroaminations that occur in high yield and ee.
Studies are underway to design catalysts to improve reaction scope
based on the hypothesis that the arylamide serves as both a reactive
and ancillary ligand.
reacted in high yield and enantioselectivity. The product of the latter
reaction contains fiVe new stereocenters.
Reactions of more hindered and more basic amines formed
hydroamination products in lower yields. o-Toluidene reacted with
norbornene at the ortho methyl group, and o-anisidine did not react,
even at 100 °C. Alkylamines, such as octylamine or N-methyla-
niline, also did not react with norbornene under these conditions.
The synthetic manipulations in eqs 2 and 3 illustrate the utility
of the addition products. The p-methoxyphenyl (PMP) group of
the anisidine adduct can be converted in high yield to the Boc-
protected norbornylamine. In addition, the unreacted olefin moiety
of norbornadiene adducts can be cleaved by ozonolysis or ring-
opening cross metathesis to generate stereochemically defined
aminocyclopentane derivatives.
Acknowledgment. We thank the DOE for support of this work
and Takasago for gifts of chiral phosphines.
Supporting Information Available: Experimental procedures,
product characterization, and complete ref 6a (PDF, CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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Although preliminary, a few pieces of mechanistic data point to
the pathway in Scheme 2.10 First, the reaction of m-XylylND2 with
norbornene formed the syn addition product (eq 4).10 Second, the
anionic bisanilide K[Ir(L2)(NHmXylyl)2] (1, L2 ) DM-segphos),
formed from [Ir(DM-Segphos)Cl]211 and 2 equiv of KNHmXylyl,
catalyzed the reaction of XylylNH2 with norbornene in <5% yield,
but this complex in combination with an equimolar amount of
m-XylylNH3+ led to an active catalyst (eq 5). Finally, this reaction
catalyzed by the neutral dimeric [Ir(L2)(NHmXylyl)]2 occurred in
<5% yield.
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(7) Reactions conducted with LiHMDS and NaHMDS as base occurred to lower
conversions.
(8) A full set of data is provided in the Supporting Information.
(9) The origin of the selectivity for addition of a single amine is unclear.
(10) Additions catalyzed by Ir(PEt3)3Cl and ZnCl2 occurred with syn
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