Rationally designed ligands for asymmetric iridium-catalyzed hydrogenation of olefins

Article abstract of DOI:10.1021/ja0464241

A new class of chiral N,P-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes has been developed. These new ligands proved to be highly efficient and tolerates a broad range of substrates. The enantiomeric excesses are in the range of the best ever reported. The results can be rationalized with the proposed selectivity model. Copyright

Full text of DOI:10.1021/ja0464241

Published on Web 10/13/2004
Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogenation
of Olefins
Klas Ka¨llstro¨m,† Christian Hedberg,† Peter Brandt,‡ Annette Bayer,§ and Pher G. Andersson*,†
Organic Chemistry, Department of Chemistry, Uppsala UniVersity, Box 599, 751 24, Uppsala, Sweden,
Department of Structural Chemistry, BioVitrum AB, 112 76 Stockholm, Sweden, and
Department of Chemistry, Faculty of Science, UniVersity of Tromsø, 9037, Tromsø, Norway
Received June 17, 2004; E-mail: pher.andersson@kemi.uu.se
Enantioselective hydrogenation is one of the most powerful
methods in asymmetric catalysis. While ruthenium- and rhodium-
catalyzed asymmetric hydrogenations of chelating olefins have a
long history,1 unfunctionalized olefins still represent a challenging
class of substrates. During the past few years, Pfaltz and others2a-h
have developed chiral mimics of Crabtree’s catalyst,3 which have
been used successfully for asymmetric hydrogenation of arylalkenes.
Figure 1. Selectivity model applied in ligand design.
However, iridium-catalyzed asymmetric hydrogenation is still highly
substrate dependent, and the development of new efficient chiral
ligands that tolerate a broader range of substrates remains a
challenge.
In this Communication, we report a new class of phosphinite-
oxazole iridium complexes 1a-c, which are highly enantioselective
for a wide range of substrates. Moreover, one single complex, 1b,
was able to reduce a large variety of substrates and gave results in
the range of the best ever reported.4
Figure 2. General ligand structure.
Scheme 1. Synthesis of Complex 1a-ca
Since very little was known about the mechanism and the
enantioselectivity-determining factors of asymmetric iridium-
catalyzed hydrogenations, our group recently undertook a kinetic
and computational study of the hydrogenation of (E)-1,2-diphenyl-
1-propene 6 with the Pfaltz iridium-PHOX complex.5 Our findings
encouraged us to design a new class of N,P-ligands with the
following specifications: the ligand should (i) contain a nitrogen
atom and a phosphorus atom to get a significant trans effect and
reaction site discrimination, (ii) be able to form a six-membered
chelate ring upon complex formation, (iii) contain a rigid backbone
a Conditions and reagents: (a) benzonitrile, Rh2(OAc)4 (0.17 mol %),
fused to the aromatic heterocycle to reduce conformational flex-
60 °C, 2 h. (b) BH3‚Me2S, (R)-Me-CBS-oxazaborolidine (10 mol %), THF,
ibility, and (iv) form a chiral environment to the substrate, as
depicted in Figure 1.
With these criteria in mind, we envisioned the ligand structure
in Figure 2. Retrosynthetic analysis of the structure in Figure 2
resulted in a four-step synthesis from readily available starting
materials (Scheme 1).
2 h, room temperature. (c) TMEDA, BuLi, THF, -78 °C to room
temperature, 1 h, then R2PCl, room temperature, 16 h. (d) [IrCl(COD)]2,
CH2Cl2, reflux, 30 min, then NaBArF, H2O, room temperature, 30 min;
BArF ) (tetrakis[3,5-bis(trifluoromethyl)phenyl]borate).
are stable, crystalline compounds and can be stored for months
without detectable decomposition.
Following this synthetic scheme, we prepared complexes 1a-c
with different aromatic groups on the phosphorus atom. Rhodium-
catalyzed conversion of diazodimedone6 2 in the presence of
benzonitrile gave the keto oxazole7 3 in 52% yield. Catalytic
enantioselective reduction of keto oxazole 3 with (R)-Me-CBS-
borane provided the (S)-alcohol8 4 in 91% yield and 90% ee. One
single recrystallization with 85% recovery of the alcohol increased
the ee to >99%. The phosphinites were prepared according to a
published procedure,2b and 5a-c were obtained in good yields (60-
80%). Due to the lability of 5a-c, these compounds were filtered
through a short plug of silica and subjected to complex formation2a
without further purification. The resulting iridium complexes 1a-c
Hydrogenation of 6 using 0.5 mol % of 1a under standard
conditions2a at different pressures showed 30 bar to be optimal for
this substrate. At 1 bar, no conversion could be detected after 2 h.
For substrate 13 the ee increased slightly, from 91% ee to 93% ee,
on going from 30 to 50 bar. The standard pressure was therefore
set to 50 bar.
These new complexes also proved to be highly efficient in the
hydrogenation of other substrates (Table 1, entries 2-9), with
complex 1b as the overall best. As expected, 2-p-methoxyphenyl-
3-methylbut-2-en 10 (entry 5) showed poor enantioselectivity.
The success of these catalysts for enantioselective reduction of
substituted styrenes could be rationalized in terms of the selectivity
model in Figure 1. To get a firmer hold of the catalyst-ligand
interactions in the selectivity-determing transition state, we opti-
mized the coupled migratory insertion/oxidative addition for
† Uppsala University.
‡ Biovitrum AB.
§ UiT.
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J. AM. CHEM. SOC. 2004, 126, 14308-14309
10.1021/ja0464241 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Iridium-Catalyzed Hydrogenation of Substrates 3-10a
primarily based on discrimination between a larger and a smaller
geminal substituent. Thus, due to the pseudo-C2 symmetry of the
reactive site, only one large substituent is required on the alkene,
but two large substituents in trans configuration will perform better.
The nonsubstituted position on the alkene will preferentially be
oriented toward the bulky phenyl substituent of the oxazole part in
the catalyst. Thus, tetra-substituted alkenes are poor substrates for
this catalyst, i.e., alkene 10. For alkenes with the most bulky
substituents cis, such as 9, the selectivity could be compromised.
R,â-Unsaturated esters add a complicating electronic effect to the
selectivity. B3LYP/LACVP calculations on trans-methyl crotonate
suggest a strong preference for â-addition of the hydride (5 kcal/
mol). This results in low converversion and poor enantioselectivity
in the reduction of methyl R-methyl cinnamate.
In conclusion, we have used a computationally derived selectivity
model to design new catalysts for hydrogenation of disubstituted
styrenes. This new class of catalysts is highly selective and
applicable to a wide range of substrates. The enantioselectivities
reported here are in the range of the best previously reported.
Acknowledgment. This work was supported by grants from
the Swedish Research Council (VR) and SELCHEM graduate
program. A.B. thanks the Norwegian Research Council (grant
151722/V30) and NorFA for financial support. We are also very
grateful to Professor Lars Kristian Hansen (University of Tromsø)
for performing the X-ray analysis.
Supporting Information Available: Experimental procedures for
the preparations of the ligands, complexes, hydrogenation procedures,
characterization data, and chiral separation data (PDF, CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
a Conditions: pressure, 30 bar (entry 1), 50 bar (entries 2-4, 6-9), 100
bar (entry 5); all reactions were run at room temperature for 2 h, except for
entries 5 and 6, where the reaction was run overnight instead; catalyst
loading, 0.5 mol %, except for entries 5 and 6, where 1 mol % was used
instead; all reactions were run in CH2Cl2 as 0.25 M solutions.
References
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(8) Absolute configuration of alcohol 4 was determined by X-ray analysis of
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4,5,6,7-tetrahydrobenzooxazol-4-yl ester (15). Crystallographic data have
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Figure 3. (Left) Structure of the selectivity-determining transition state of
the coupled migration insertion/oxidative addition of dihydrogen. (Right)
Selectivity model using the ligand structure of the optimized transition state
and a schematic substrate molecule.
substrate 6 being hydrogenated by catalyst 1a (Figure 3).9 The
calculated structure, being very similar to those previously reported,5
clearly shows a chiral pocket well suited to accommodate an alkene
with large trans substituents. The enantiofacial selectivity is
(9) Transition-state optimization was performed at the B3LYP/LACVP level
of theory in the Jaguar program. For details, see ref 5.
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