Asymmetric hydrogenation of aromatic olefins catalyzed by iridium complexes of proline derived phosphine-oxazoline ligands

Article abstract of DOI:10.1016/S0040-4039(02)02747-8

The synthesis of a series of phosphine-oxazoline ligands is reported. This ligands are synthesized by reaction of a phosphine chloride with the secondary nitrogen of proline. Upon coordination to iridium the resulting complexes can be used in the asymmetric hydrogenation of simple olefins. The effect of different counter ions and substitution at the oxazoline and the phosphine is reported.

Full text of DOI:10.1016/S0040-4039(02)02747-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 953–955
Asymmetric hydrogenation of aromatic olefins catalyzed by
iridium complexes of proline derived phosphine–oxazoline ligands
Guopin Xu and Scott R. Gilbertson*
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Received 22 October 2002; accepted 3 December 2002
Abstract—The synthesis of a series of phosphine–oxazoline ligands is reported. This ligands are synthesized by reaction of a
phosphine chloride with the secondary nitrogen of proline. Upon coordination to iridium the resulting complexes can be used in
the asymmetric hydrogenation of simple olefins. The effect of different counter ions and substitution at the oxazoline and the
phosphine is reported. © 2003 Elsevier Science Ltd. All rights reserved.
Over the past 5 years we have been involved in the
development of phosphine–oxazoline ligands for a vari-
ety of reactions. One system we have developed uses
proline as one of the chiral elements. The initial ligands
were based on trans-hydroxy proline (1) and were
synthesized by substitution of the hydroxyl group with
phosphine.1–3 More recently, we have reported proline-
based ligands where the phosphorus is attached to the
proline through a PꢀN bond (2).4 Such ligands have an
advantage in that the phosphorus group can be readily
modified since formation of the P-heteroatom bond is
quite facile.5 We have synthesized a series of iridium
complexes with our proline derived ligands and tested
these complexes in the asymmetric hydrogenation of
simple olefins (Fig. 1).
Reported here is a series of ligands based on proline.
These catalysts were varied in three locations: at the
oxazoline, the phosphine and by altering the counter
ion. Based on our experience, as well as the work of
Pfaltz and others, the R group on the oxazoline was
chosen to be either iso-propyl or tert-butyl.9,12 It should
be noted that, since the oxazoline is derived from an
Figure 1. Two proline based ligands.
Table 1. Catalyst systems screened
In the area of asymmetric hydrogenation, the reduction
of unfunctionalized olefins has been less developed than
the hydrogenation of alkenes containing heteroatoms.
Much of the initial success in this area utilized
cyclopentadienyl ligands with either titanium or zirco-
nium. The most successful early examples were reported
by Buchwald, using Brintzinger type ligands.6,7 More
recently, a number of workers, Pfaltz and Burgess
particularly have found that PꢀN iridium complexes
can be highly effective in the asymmetric hydrogenation
of styrene derivatives.5,8–15 In a number of cases these
systems provide selectivities as high as 99:1 enan-
tiomeric ratio (er). Additionally these systems proceed
with low catalyst loadings.
Cpd c
Ar
R
X
3
Ph
i-Pr
PF6
4
5
6
7
8
9
10
Ph
Ph
o-Tol
o-Tol
2-Ethylphenyl
2,3-Dimethylphenyl
2,4-Dimethylphenyl
i-Pr
BARF
BARF
PF6
BARF
BARF
BARF
BARF
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
* Corresponding author. Tel.: 1-314-935-6357; fax: 1-314-935-4481;
e-mail: srg@wuchem.wustl.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02747-8

954
G. Xu, S. R. Gilbertson / Tetrahedron Letters 44 (2003) 953–955
amino acid, there are a wide variety of R groups
available for this position. The aromatic group on the
phosphine was varied with different substituted benzene
derivatives. Sterics were the primary consideration used
in making the choices for this position. Additionally,
two different counter ions were used, PF6 and tetra-
kis[3,5-bis(trifluoromethyl)phenyl]-borate
(BARF)
(Table 1).
The ligands were readily available by reaction of pro-
line ester with a phosphine chloride followed by protec-
tion of the phosphine with sulfur (Scheme 1). Cleavage
of the benzyl ester to the acid by reaction with lithium
iodide was followed by amide formation with an amino
alcohol. Amide formation was then followed by cycliza-
tion to the oxazoline. Prior to metalation, the phos-
phine sulfide was converted to the free phosphine by
reaction with Raney nickel.1,16,17
Scheme 1. Synthesis of proline based ligands.
In the synthesis of new phosphine ligands, generally the
most difficult step is the incorporation of the phosphine
by formation of a phosphorusꢀcarbon bond. One of the
important features of the chemistry reported here is
that the phosphorus is incorporated into the molecule
through the formation of a phosphorusꢀamine bond.
The necessary phosphine chlorides are available by
reaction of variety of aryl Grignards with PCl3.18,19 This
allows for the synthesis of a variety of different phos-
phorus components without the need for the generation
of carbanions or phosphide anions.
Table 2. Hydrogenation of methylstilbene analogs
Entry
R
Catalyst (mol%) Conversion (%) era R:S
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
MeO
MeO
MeO
MeO
MeO
3 (4.0)
4 (0.3)
5 (0.3)
6 (4.0)
7 (0.3)
8 (0.3)
9 (0.3)
10 (0.3)
5 (0.3)
7 (0.3)
8 (0.3)
8 (0.2)
9 (0.3)
99
99
99
50
99
99
99
99
99
99
99
99
99
99
73:17
85:15
93:7
92:8
95:5
96:4
95:5
93:7
94:6
96:4
96:4
97:3
95:5
95:5
The initial substrate that was examined, trans-a-methyl-
stilbene (16), has been examined by a number of
groups. It was observed in this system that the selectiv-
ity was dependent on all three possible variables (Table
2). The best counter ion in terms of selectivity and
lowest catalyst loading is BARF. When BARF was
used as the counter ion a catalyst loading of 0.3 mol%
was generally used. The need to use BARF as a counter
ion has also been observed by Pfaltz and Burgess.9–11
Complexes with PF6 as the counter ion result in slow
reaction with catalyst loading as high as 10 mol%. In a
number of cases no reaction was observed with PF6
complexes. NMR studies in the literature indicate that
when PF6 is the counter ion the catalytically inactive
bridging iridium hydride is more readily formed than
with the sterically larger BARF counter ion.20
9
10
11
12b
13
14
MeO 10 (0.3)
a The enantiomeric ratios were determined by HPLC on Chiralcel OJ
column, entries 1–8, Hex/iPrOH=99:1; entries 9–14, Hex/iPrOH,
95:5, flow rate=0.5 mL/min, 20°C.
b 20 bar H2 at 0°C.
the highest selectivity with all of the substrates tested,
giving a selectivity of 97:3 enantiomeric ratio with
para-methoxymethylstilbene (17) and 96:4 er with
trans-a-methylstilbene (16) (Fig. 2).
As is generally true for oxazoline-based ligands, the
group on the oxazoline has the most significant impact
on the selectivity of the ligand. In this case tert-butyl
gave better selectivity than the ligands with iso-propyl
on the oxazoline. It was determined early in this study
that the optimal oxazoline stereochemistry was the (R)
configuration. The diastereoisomer of ligand 5 with the
oxazoline in the (S) configuration and BARF as the
counter ion give an 17:83 (R:S) enantiomer ratio. Sub-
stitution on the phosphine also influences the selectivity
of the catalyst. The ligand with ethyl in the ortho
position (8) gave higher selectivity than the simple
benzene case (5). This ligand was also more selective
than the ligands with methyl at the ortho position (7, 9,
and 10). Ligand 8 proved to be the ligand that provided
Catalyst from ligand 8 was examined with a number of
styrene derivatives. In general trisubstituted double
bonds proceed with fair to good selectivity. When the
double bond is in a ring (20 and 21) a ratio of enan-
tiomers as high as 84 to 16 was obtained. The reaction
proceeds with low selectivity as well as slow rate with
tetrasubstituted olefins (22). Additionally, terminal dou-
ble bonds give low selectivity (25). Reaction with the
trisubstituted allyl alcohol (27) proceeded with good
selectivity, giving a 97 to 3 ratio of enantiomers.

G. Xu, S. R. Gilbertson / Tetrahedron Letters 44 (2003) 953–955
955
also gratefully acknowledge the Washington University
High-Resolution NMR Facility, partially supported by
NIH 1S10R02004, and the Washington University
Mass Spectrometry Resource Center, partially sup-
ported by NIHRR00954, for their assistance.
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In this paper we report the synthesis of a new proline-
derived ligand that when coordinated to iridium, pro-
vides a catalyst that gives good selectivity in the
hydrogenation of simple unfunctionalized olefins. We
are currently working on methods to synthesize this
system with more hindered phosphines. Additionally a
number of other reactions are being examined.
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This work was partially supported by the National
Science Foundation (Grant No. CHE-9316821). We