SimplePHOX, a readily available chiral ligand system for iridium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ol049235w

Equation presented. New Ir-SimplePHOX complexes Ir-6-Ir-9 catalyze the quantitative, highly enantioselective hydrogenation of a range of unfunctionalized and functionalized olefins. Synthesis, catalytic results, and X-ray crystal structures are presented

Full text of DOI:10.1021/ol049235w

ORGANIC
LETTERS
2004
Vol. 6, No. 12
2023-2026
SimplePHOX, a Readily Available Chiral
Ligand System for Iridium-Catalyzed
Asymmetric Hydrogenation
Sebastian P. Smidt, Frederik Menges, and Andreas Pfaltz*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
andreas.pfaltz@unibas.ch
Received April 26, 2004
ABSTRACT
New Ir−SimplePHOX complexes Ir-6−Ir-9 catalyze the quantitative, highly enantioselective hydrogenation of a range of unfunctionalized and
functionalized olefins. Synthesis, catalytic results, and X-ray crystal structures are presented here.
Iridium complexes with chiral P,N-ligands1 have emerged
as a new class of hydrogenation catalysts that are largely
complementary to the well-known rhodium and ruthenium
catalysts.2 In contrast to their Rh and Ru counterparts, they
do not require a coordinating group next to the CdC bond
for efficient, highly enantioselective alkene hydrogenation.
In addition to unfunctionalized alkenes, high enantiomeric
excesses were also obtained with several classes of func-
tionalized olefins for which no suitable catalysts were
available. Originally, we used iridium(I)-COD complexes
derived from chiral phosphinooxazoline (PHOX) ligands3 as
precatalysts. The choice of the counterion of these cationic
complexes proved to be crucial. Coordinating anions, even
very weak ligands such as triflate, almost completely inhibit
the catalyst. The best results were obtained with tetrakis-
stable and can be stored at ambient temperature for months
without loss of activity.
The encouraging results obtained with Ir-PHOX catalysts
prompted us as well as other groups to investigate new
classes of chiral P,N-ligands containing a chiral oxazoline
ring or, alternatively, a pyridine or quinoline system con-
nected to a chiral backbone.4 Some of these new ligands,
especially phosphinite-oxazolines such as ThrePHOX, have
considerably enhanced the application range of Ir-catalyzed
hydrogenation. In connection with our work on Pd-catalyzed
allylic substitution, we have developed phosphite and phos-
phoramidite ligands of type A derived from a readily
accessible oxazolinyl alcohol and an additional chiral unit
such as BINOL, TADDOL, or a chiral 1,2-diamine.5 In view
(4) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed.
1998, 37, 2897-2899. (b) Blackmond, D. G.; Lightfoot, A.; Pfaltz, A.;
Rosner, T.; Schnider, P.; Zimmermann, N. Chirality 2000, 12, 442-449.
(c) Blankenstein, J.; Pfaltz, A. Angew. Chem., Int. Ed. 2001, 40, 4445-
4447. (d) Cozzi, P. G.; Zimmermann, N.; Hilgraf, R.; Schaffner, S.; Pfaltz,
A. AdV. Synth. Catal. 2001, 343, 450-454. (e) Menges, F.; Pfaltz, A. AdV.
Synth. Catal. 2002, 344, 40-44. (f) Drury, W. J., III; Zimmermann, N.;
Keenan, M.; Hayashi, M.; Kaiser, S.; Goddard, R.; Pfaltz, A. Angew. Chem.,
Int. Ed. 2004, 43, 70-74. (g) Hou, D.-R.; Reibenspies, J. H.; Burgess, K.
J. Org. Chem. 2001, 66, 206-215. (h) Hou, D.-R.; Reibenspies, J.; Colacot,
T. J.; Burgess, K. Chem. Eur. J. 2001, 7, 5391-5400. (i) Tang, W.; Wang,
W.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 943-946. (j) Liu, D.;
Tang, W.; Zhang, X. Org. Lett. 2004, 6, 513-516. (k) Bunlaksananusorn,
T.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 3941-3943.
-
[3,5-(trifluoromethyl)phenyl]borate (BArF ), which became
our standard anion for subsequent work. Iridium complexes
with this anion are easy to handle as they are air and moisture
(1) Pfaltz, A.; Blankenstein, J.; Ho¨rmann, E.; McIntyre, S.; Menges, F.;
Hilgraf, R.; Scho¨nleber, M.; Smidt, S. P.; Wu¨stenberg, B.; Zimmermann,
N. AdV. Synth. Catal. 2003, 345, 33-43.
(2) (a) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. I, pp
121-182. (b) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008-2022.
(c) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998-2007.
(3) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345.
10.1021/ol049235w CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/18/2004

of the excellent results obtained with ThrePHOX ligands,
we decided to prepare phosphinite analogues of ligands A,
which we called SimplePHOX, because they are readily
prepared in just two steps from simple precursors.
The synthesis of four SimplePHOX derivatives is sum-
marized in Scheme 1. Condensation of the enantiomerically
be grown from diethyl ether or dichloromethane solutions,
respectively, that were layered with pentane.
Iridium complexes Ir-6-Ir-9 were tested in the enantio-
selective hydrogenation of a series of unfunctionalized al-
kenes, an acrylic ester, and an allylic alcohol. The observed
enantioselectivities were compared to those obtained with
iridium-PHOX complexes Ir-10 and Ir-11,7 which are
among the most selective catalysts developed so far. Unless
stated otherwise, catalytic reactions were performed with 0.1
mmol of substrate and 1 mol % catalyst in 0.5 mL of CH2Cl2
at 50 bar H2 for 2 h. Full conversion was routinely achieved.
Scheme 1. Synthesis of SimplePHOX Ligands and Their
Iridium-COD Complexes.
(E)-1,2-Diphenyl-1-propene (13) is hydrogenated with high
enantioselectivities by many iridium-P,N catalysts. With
SimplePHOX catalyst Ir-7, too, a high ee of 98% ee was
achieved, which is in the same range of selectivity as with
the benchmark catalysts Ir-10 and Ir-11 (Table 1).
Table 1. Enantioselective Hydrogenation of Trisubstituted,
Unfunctionalized Olefins with Catalysts Ir-6-Ir-11a
pure amino alcohols 2 and 3 with hydroxy acid 1 in refluxing
xylene under azeotropic removal of water led to oxazolinyl
alcohols 4 and 5.5a,6 Deprotonation of the alcohol with
butyllithium and subsequent reaction with the appropriate
chloro- or bromophosphine afforded the desired phosphinites
6-9 in 30-60% yield. Weaker bases such as triethylamine/
DMAP, which work well for phosphinite formation from less
hindered alcohols, could not be used in this case.
a All reactions were performed using 0.1 mmol of alkene and 0.5 mL of
dichloromethane at 50 bar of hydrogen pressure at room temperature
(reaction time: 2 h). b Conversions were determined by GC. In all cases, a
clean reaction was observed with a single product peak in the GC.
c Determined by HPLC (see ref 4a,b).
Following standard procedures, iridium complexes Ir-6-
Ir-9 were synthesized. Single crystals of compounds Ir-6
and Ir-8 suitable for X-ray crystallographic analysis could
Hydrogenation of (E)-2-(4-methoxyphenyl)-2-butene (14)
with SimplePHOX complexes gives selectivities around 90%
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Org. Lett., Vol. 6, No. 12, 2004

ee, between the ee values obtained with Ir-10 (81% ee) and
Ir-11 (99% ee).
selectivity and cannot compete with the phosphinite complex
Ir-11 (90% ee).
(Z)-2-(4-Methoxyphenyl)-2-butene 15 is a more demand-
ing substrate that normally reacts with lower enantioselec-
tivity than the corresponding (E)-isomer. Hydrogenation of
the (E)- and (Z)-isomers always leads to opposite enantio-
mers. Interestingly, catalyst Ir-8 outperforms the other
SimplePHOX complexes in this case. For this particular sub-
strate, sterically less demanding substituents in the oxazoline
ring and at the P atom seem better suited, whereas in most
other reactions analogous complexes with tert-butyl- and
o-tolyl-substituted ligands induce higher enantioselectivities
than Ir-8. With 89% ee catalyst Ir-8 induces respectable ee
levels, close to the best value (95% ee) observed so far.1 In
the hydrogenation of the cyclic substrate 6-methoxy-1-
methyl-3,4-dihydronaphthalene (16) complex Ir-7 is clearly
the most effective catalyst among the four SimplePHOX
complexes. The observed ee of 95% is one of the best values
recorded for this substrate.
The SimplePHOX complex Ir-7 proved to be an excellent
catalyst for the hydrogenation of the trisubstituted acrylic
ester 18 and allylic alcohol 19. The observed enantioselec-
tivities of 94 and 97% ee, respectively, are among the highest
values observed for these substrates.4e,j The same catalyst
also gave high enantioselectivities for a range of trisubstituted
alkenes bearing heteroaromatic rings at the CdC bond.1,8
Crystal structures of the two SimplePHOX complexes Ir-6
and Ir-8 are shown in Figure 1. The two structures are very
Terminal alkenes are highly reactive substrates, giving full
conversion with high rates even at the low hydrogen pressure
of 1 bar. For this substrate class, the enantioselectivity drops
significantly with increasing pressure, in contrast to the
hydrogenation of trisubstituted alkenes, which shows little
pressure dependence. With the Ir-PHOX complex Ir-10,
e.g., the ee decreases from 61% to essentially 0% in the
hydrogenation of 2-(4-methoxyphenyl)-1-butene, when the
pressure is raised from 1 to 50 bar (Table 2). The Simple-
Figure 1. Comparison of the crystal structures of the cations of
Ir-6 (left) and Ir-8 (right). COD and hydrogen atoms have been
omitted for clarity.
similar with a characteristic boatlike conformation of the six-
membered chelate ring. In both structures, the substituent in
the oxazoline ring and the axial P-phenyl group point in the
same direction. The only notable variation is the different
rotational angle of the equatorial P-phenyl groups. However,
in terms of energy, this difference is hardly significant. NMR
studies of analogous P-(o-tolyl) derivatives show that the
P-aryl groups rotate freely around the P-C bond, suggesting
that the conformation of the phenyl groups is readily altered
by minor effects such as crystal packing forces.
Table 2. Enantioselective Hydrogenation of Terminal and
Functionalized Olefins with Catalysts Ir-6-Ir-11a
The coordination geometry as well as the chiral pocket
formed by the P,N-ligand are very similar in the two
SimplePHOX complexes Ir-6 and Ir-8 and the PHOX
complex Ir-12 (see Table 3 and Supporting Information).
However, compared to PHOX complexes, which form a
rather rigid chelate ring due to the geometric constraint of
the bridging phenyl group, the chelate ring in analogous
phosphinite ligand complexes such as Ir-6, Ir-8, or Ir-11 is
more flexible. NMR and X-ray studies of complex Ir-11 and
related derivatives show that the energetic differences
between different boat- and chairlike conformations are
small. In some phosphinite complexes, a chairlike conforma-
tion of the chelate ring is actually preferred in the solid state.4c
Therefore, it seems dangerous to draw conclusions concern-
ing the enantioselectivity induced by a particular precatalyst
on the basis of crystal structure data.
a,b,c See Table 1. d Second set of results was obtained in 2 mL of
dichloromethane at 1 bar hydrogen pressure, 30 min reaction time.
(6) (a) Pridgen, L. N.; Miller, G. J. Heterocycl. Chem. 1983, 20, 1223-
1230. (b) Allen, J. V.; Williams, J. M. J. Tetrahedron: Asymmetry 1994,
5, 277-282.
(7) Complex Ir-11 is commercially available from Strem, Inc.
(8) Wu¨stenberg, B. Ph.D. Dissertation, University of Basel, Basel,
Switzerland, 2003.
PHOX complexes perform significantly better at 50 bar;
however, at 1 bar, they show only a modest increase in
(5) (a) Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814-1816. (b) Escher, I.
H.; Pfaltz, A. Tetrahedron 2000, 56, 2879-2888.
Org. Lett., Vol. 6, No. 12, 2004
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hydrogenation of olefins. Particularly high ee values of
94-97% were obtained in the hydrogenation of a cyclic
unfunctionalized alkene, an acrylic ester, and an allylic
alcohol. Our results indicate a considerable potential of this
ligand class in asymmetric catalysis.9
Table 3. Comparison of Structural Parameters in Crystal
Structures of Ir Complexesa
complex
Ir -6
Ir -8
Ir -12
R/Rw [%]
Ir-N [pm]
Ir-P [pm]
P-O/P-C [pm]b
P-Ir-N [deg]
Ir-(CdC) trans to P [pm]c
Ir-(CdC) trans to N [pm]c
4.3/4.8
208.8(4)
224.9(1)
161.1(4)
85.6(1)
212
3.1/3.6
208.7(3)
223.9(1)
160.7(4)
85.1(1)
211
6.0/6.8
211.9(7)
226.6(3)
182.0(9)
85.0(2)
211
Acknowledgment. We thank Markus Neuburger and Dr.
Silvia Schaffner, University of Basel, for X-ray crystal-
lographic analyses. Financial support by the Swiss National
Science Foundation, the Federal Commission for Technology
and Innovation (KTI Project No. 5189.2 KTS), and Solvias
AG (Basel) is gratefully acknowledged. S.P.S. thanks the
Gottlieb Daimler and Carl Benz Foundation and the German
Academic Exchange Service (DAAD) for Ph.D. fellowships.
F.M. thanks the Fonds der Chemischen Industrie (Frankfurt)
and the German Federal Ministry for Science and Technology
(BMBF) for a Kekule´ Fellowship.
201
202
202
a Parameters are averaged for independent crystallographic moieties
present in the unit cell. Crystallographic estimated standard deviations are
given in parentheses. b P-C bond in the chelate ring of Ir-12. c Distances
between iridium and the CdC bonds.
The Ir-P and Ir-N bonds, as well as the distances be-
tween Ir and the CdC bonds of the COD ligand, are re-
markably similar in length in the two SimplePHOX com-
plexes Ir-6 and Ir-8 and the PHOX complex Ir-12 (Table
2), suggesting that the electronic properties of the phosphine
and phosphinite ligands are comparable.
In summary, we have developed a readily accessible class
of chiral modular P,N-ligands consisting of a chiral oxazoline
ring tethered to a phosphinite group. These ligands, which
are prepared in just two steps from simple starting materials,
induce high enantioselectivities in the iridium-catalyzed
Supporting Information Available: Experimental pro-
cedures, characterization of unknown compounds, references
to known compounds, tables, and additional figures for the
X-ray crystal structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL049235W
(9) Ligand 7 and catalyst Ir-7 will be soon available from Strem, Inc.
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Org. Lett., Vol. 6, No. 12, 2004