Biaryl phosphite-oxazolines from hydroxyl aminoacid derivatives: Highly efficient modular ligands for Ir-catalyzed hydrogenation of alkenes

Article abstract of DOI:10.1039/b806891g

High enantioselectivities and activities are achieved in the Ir-catalyzed hydrogenation of several unfunctionalized olefins using modular biaryl phosphite-oxazoline ligands from hydroxyl aminoacid derivatives; the presence of a biaryl phosphite group is crucial to this success. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806891g

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Biaryl phosphite-oxazolines from hydroxyl aminoacid derivatives: highly
efficient modular ligands for Ir-catalyzed hydrogenation of alkenesw
a
a
a
b
´
Montserrat Dieguez,* Javier Mazuela, Oscar Pamies, J. Johan Verendel and
Pher G. Andersson*b
Received (in Cambridge, UK) 23rd April 2008, Accepted 20th May 2008
First published as an Advance Article on the web 3rd July 2008
DOI: 10.1039/b806891g
High enantioselectivities and activities are achieved in the Ir-
catalyzed hydrogenation of several unfunctionalized olefins using
modular biaryl phosphite-oxazoline ligands from hydroxyl ami-
noacid derivatives; the presence of a biaryl phosphite group is
crucial to this success.
The asymmetric hydrogenation of olefins has been widely used
in stereoselective organic synthesis and some processes have
Fig. 1 Phosphite-oxazoline ligands 1 and 2 and phosphinite-oxazo-
found industrial applications. In this respect, the asymmetric
hydrogenation of unfunctionalized olefins still represents a
challenging class of substrates.1 Iridium complexes with chiral
P,N ligands have become established as efficient catalysts for
the hydrogenation of unfunctionalized olefins, with scope
complementary to that of Rh- and Ru-diphosphine com-
plexes.2 Unlike Rh- and Ru-catalysts, they do not require a
coordinating polar group adjacent to the CQC group. The
first chiral ligands developed for this process were the phos-
phine-oxazolines, which are chiral mimics of Crabtree’s cata-
lyst. These ligands have been used successfully for the
asymmetric hydrogenation of a limited range of alkenes.3
Recently, the composition of the ligands has been extended
by the discovery of new mixed P,N ligands that have con-
siderably broadened the scope of Ir-catalyzed hydrogenation.4
Of them all, the most successful ligands contain a phosphinite
moiety as P-donor group and either an oxazoline, oxazole or
pyridine as N-donor group.4b–d,g
line ligands.
more limited and their enantioselectivities and activities were
lower than those of related phosphinite/phosphine-oxazoline
ligands. They also required higher catalyst loadings (4 mol%)
and higher pressures (100 bar) to achieve full conversions. The
second report was published recently and presented the suc-
cessful application of pyranoside phosphite-oxazoline ligands
2 (Fig. 1).6b However it is unclear whether this success is due to
the pyranoside-sugar backbone or the introduction of a biaryl
phosphite moiety.
To address this point, we took one of the most successful
ligand families for this process (ligands 3, Fig. 1) and replaced
the phosphinite moiety with a biaryl phosphite moiety (ligands
L1–L6a–e, Fig. 2). In this communication we present the
application of this phosphite-oxazoline ligand library
(L1–L6a–e, Fig. 2)7 in the asymmetric Ir-catalyzed hydroge-
nation of several unfunctionalized olefins. Another advantage
of this new ligand library design is that it enables more ligand
parameters to be studied than in our first phosphite-oxazoline
ligand library 2. These parameters are important for the
hydrogenation reactions, and because they are easy to intro-
duce they are easy to study. With this library (Fig. 2), we
investigated the effect of systematically varying the substitu-
ents in the oxazoline moiety (R1) and the alkyl backbone chain
(R3). We also studied the presence of a second stereogenic
In the last few years, phosphite-containing ligands have
demonstrated that they are potentially extremely useful in
many transition-metal catalyzed reactions.5 Their highly mod-
ular construction, facile synthesis from readily available chiral
alcohols, greater resistance to oxidation than phosphines and
p-acceptor capacity have proved to be highly advantageous.
Despite this, they have rarely been used in the Ir-catalyzed
hydrogenation of olefins. So far only two reports have been
published that use phosphite ligands.6 One of these reports
described the application of TADDOL-based phosphite-oxa-
zoline ligands 1 (Fig. 1).6a However, their substrate range was
a
´
´
`
Departament de Quımica Fısica i Inorganica, Universitat Rovira i
Virgili, C/ Marcelli Domingo, s/n. 43007 Tarragona, Spain. E-mail:
montserrat.dieguez@urv.cat; Fax: +34-977559563; Tel: +34-
977558780
b Department of Biochemistry and Organic Chemistry, Uppsala
University, BOX 576, 751 23 Uppsala, Sweden. E-mail:
pher.andersson@kemi.uu.se
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of [Ir(cod)(L)]BArF (L = L1–L6a–e)
complexes. See DOI: 10.1039/b806891g
Fig. 2 Phosphite-oxazoline ligands L1–L6a–e.
ꢀc
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3888 | Chem. Commun., 2008, 3888–3890

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Table 1 Ir-catalyzed asymmetric hydrogenation of S1 using ligands
L1–L6a–ea
mol%
Ir
%
Conv.b
Entry
L
% eec
1
2
3
4
5
6
7
8
L1a
L1b
L1c
L1d
L1e
L2a
L3a
L4a
L5a
L6a
L1d
2
2
2
2
2
2
2
2
100
100
100
100
100
100
100
100
100
80
97 (R)
94 (R)
98 (R)
99 (R)
94 (R)
95 (R)
90 (R)
92 (R)
91 (R)
81 (R)
99 (R)
Fig. 3 Selected hydrogenation results. Reaction conditions: 0.2 mol%
a
catalyst, CH2Cl2 as solvent, 50 bar H2, 2 h. 1 mol% catalyst.
9
2
2
0.2
10
11
a
100
b
Reactions carried out using 1 mmol of S1. Conversion measured
1
by H-NMR. Enantiomeric excesses determined by chiral HPLC.
c
centre in the heterocycle ring (R2) and the substituents and
configurations in the biaryl phosphite moiety (a–e). By care-
fully selecting these elements, we achieved high enantioselec-
tivities and activities in a wide range of substrates.
Fig. 4 Selected hydrogenation results. Reaction conditions: 0.2 mol%
catalyst, CH2Cl2 as solvent, 1 bar H2, 30 min.
hydrogenation of terminal olefins S9–S11 (Fig. 4). The en-
antioselectivity in this substrate class is more difficult to
control than for the E trisubstituted olefins S1–S3. Therefore,
few catalytic systems have provided high enantioselectivities.9
Interestingly, we achieved high activities and enantioselectiv-
ities at low catalyst loadings (0.2 mol%) under mild reaction
conditions (1 bar of H2). Enantiomeric excesses for substrates
S9 and S10 are among the best values reported to date.9 Of
particular note is the excellent enantioselectivity (499% ee)
obtained for the most sterically hindered substrate S11, which
surpasses the best values obtained to date.6b Again, the
replacement of a phosphinite moiety by a phosphite group
in the ligand design leads to higher enantioselectivity (i.e. 97%
ee vs. 94% ee9a for S10).
To make the initial evaluation of this new type of ligands
(L1–L6a–e), we chose the Ir-catalyzed hydrogenation of trans-a-
methylstilbene S1 (Table 1). As this reaction was carried out with
a wide variety of ligands carrying different donor groups, we were
able to compare the efficacy of the various ligand systems.
The catalyst precursors [Ir(cod)(L)]BArF (L = L1–L6a–e)
were prepared following a standard protocol3d and used with-
out further purification. The results (Table 1) indicate that
enantioselectivity is affected by the substituents at the oxazo-
line and in the alkyl backbone chain, the presence of a second
stereogenic centre in the oxazoline ring and the substituents/
configuration in the biaryl phosphite moiety. The best result
(100% conversion; 99% ee) was therefore obtained with ligand
L1d (entry 4), which contains the optimal combination of
ligand parameters. These results show the efficiency of using
highly modular scaffolds in the ligand design.
In summary, we have described the successful application of
modular phosphite-oxazoline ligands in the Ir-catalyzed asym-
metric hydrogenation of several unfunctionalized olefins. We
have demonstrated that the introduction of a biaryl phosphite
moiety into the ligand design is highly adventitious in terms of
catalytic activity and substrate versatility. Therefore, they
provided higher enantioselectivities and activities for a wider
range of di- and tri-substituted substrates than their phosphi-
nite-oxazoline counterparts. We have also found that the
effectiveness at transferring the chiral information in the
product can be tuned by suitably choosing the ligand compo-
nents (phosphite, oxazoline and backbone substituents). This
means that these catalyst systems are extremely attractive for
further research. Because of the modular construction of these
phosphite-oxazoline ligands, structural diversity is easy to
achieve, so activities and enantioselectivities can be maximized
for each new substrate as required. Studies of this kind, as well
as mechanistic studies, are currently under way.
We also performed the reaction at low catalyst loading (0.2
mol%) using ligand L1d (entry 11). The excellent enantio-
selectivity (99% (R) ee) and activity (100% conversion after
2 h at room temperature) were maintained.
The subsequent screening of other potential substrates showed
that these catalysts also allow the asymmetric hydrogenation of
several other trisubstituted unfunctionalized linear S2–S4 and
cyclic S5 olefins, a,b-unsaturated ester S6, allylic alcohol S7 and
acetate S8 (Fig. 3). The enantioselectivities are among the best
observed for these substrates.2 It should be noted that if ligands
are appropriately tuned, high enantioselectivities can also be
obtained for the more demanding Z-isomer S4, which usually
reacts with a lower enantioselectivity than that of the correspond-
ing E-isomer S3. These phosphite-oxazolines also provided higher
enantioselectivities in a wider range of substrates at lower catalyst
loadings than their related phosphinite-oxazoline counterparts 3,
one of the most successful ligand classes.8
We thank the Spanish Government (CTQ2007-62288/BQU),
the Catalan Government (2005SGR007777, 2006BE-210167
and Distinction to M.D.), COST D40, Vetenskapsradet (VR)
To further study the potential of these readily available
ligands, we also tested the Ir-L1d catalyst in the asymmetric
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3888–3890 | 3889

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and Astra Zeneca for support. We are grateful to Paivi
¨
Kaukoranta for assistance with chiral analyses.
Ed., 2006, 45, 5194; (d) K. Kallstrom, C. Hedberg, P. Brandt, P.
¨ ¨
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Co and T.-J. Kim, Chem. Commun., 2006, 3537.
Notes and references
5 For some representative examples see: (a) C. Claver, M. Die
O. Pamies and S. Castillon, in Catalytic Carbonylation
Reactions, ed. M. Beller, Springer-Verlag, Berlin, 2006,
pp. 35–64; (b) M. Dieguez, O. Pamies, A. Ruiz and C.
´
guez,
1 (a) I. Ojima, Catalytic Asymmetric Synthesis, Wiley-VCH, New
York, 2nd edn, 2000; (b) R. Noyori, Asymmetric Catalysis in
Organic Synthesis, Wiley, New York, 1994; (c) H.-U. Blaser and
E. Schmidt, Asymmetric Catalysis on Industrial Scale, Wiley, New
York, 2004; (d) J. M. Brown, in Comprehensive Asymmetric
Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto,
Springer-Verlag, Berlin, 1999, vol. 1.
´
´
Claver, in Methodologies in Asymmetric Catalysis, ed. S. V. Mal-
hotra, ACS, Washington, 2004, pp. 161–174; (c) M. Yan, Z.-Y.
Zhou and A. S. C. Chan, Chem. Commun., 2000, 115; (d) O.
Pamies, M. Die
3646; (e) Y. Mata, O. Pamies and M. Die
2007, 13, 3296.
6 (a) R. Hilgraf and A. Pfaltz, Adv. Synth. Catal., 2005, 347, 61; (b)
M. Dieguez, J. Mazuela, O. Pamies, J. J. Verendel and P. G.
´
guez and C. Claver, J. Am. Chem. Soc., 2005, 127,
2 For recent reviews, see: (a) K. Kallstrom, I. Munslow and
¨
¨
´
guez, Chem.–Eur. J.,
P. G. Andersson, Chem.–Eur. J., 2006, 12, 3194; (b) S. J.
Roseblade and A. Pfaltz, Acc. Chem. Res., 2007, 40, 1402;
(c) T. L. Church and P. G. Andersson, Coord. Chem. Rev.
2008, 252, 513; (d) X. Cui and K. Burgess, Chem. Rev., 2005,
105, 3272.
´
Andersson, J. Am. Chem. Soc., 2008, 130, 7208.
7 Ligands L1–L6a–e have been successfully used in Pd-catalyzed
3 See for instance: (a) W. Tang, W. Wang and X. Zhang, Angew.
Chem., Int. Ed., 2003, 42, 943; (b) D.-R. Hou, J. Reibenspies, T. J.
Colacot and K. Burgess, Chem.–Eur. J., 2001, 7, 5391; (c) P. G.
Cozzi, F. Menges and S. Kaiser, Synlett, 2003, 833; (d) A. Lighfoot,
P. Schnider and A. Pfaltz, Angew. Chem., Int. Ed., 1998, 37, 3897; (e)
F. Menges, M. Neuburger and A. Pfaltz, Org. Lett., 2002, 4, 4713; (f)
D. Liu, W. Tang and X. Zhang, Org. Lett., 2004, 6, 513; (g) W. J.
Drury III, N. Zimmermann, M. Keenan, M. Hayashi, S. Kaiser, R.
Goddard and A. Pfaltz, Angew. Chem., Int. Ed., 2004, 43, 70.
4 (a) M. C. Perry, X. Cui, M. T. Powell, D.-R. Hou, J. H.
Reibenspies and K. Burgess, J. Am. Chem. Soc., 2003, 125, 5391;
(b) J. Blankestein and A. Pfaltz, Angew. Chem., Int. Ed., 2001, 40,
4445; (c) S. Kaiser, S. P. Smidt and A. Pfaltz, Angew. Chem., Int.
allylic substitution, see: M. Die
2008, 14, 3653.
´
guez and O. Pamies, Chem.–Eur. J.,
8 The related phosphinite-oxazoline ligands 3 afforded 499% ee
for S3, 92% ee for S4, 85% ee for S5, 94% ee for S6 and
92% ee for S7 at 1 mol% Ir-catalyst. See: (a) ref. 4g; (b) S. P.
Smidt, F. Menges and A. Pflatz, Org. Lett., 2004,
6
2023. There are no data reported for substrates S2 and
S8.
¨
9 For successful applications, see: (a) S. McIntyre, E. Hormann,
F. Menges, S. P. Smidt and A. Pfaltz, Adv. Synth. Catal.
2005, 347, 282 (ee’s up to 94% for S10); (b) ref. 4d (ee’s up to
97% for S10); (c) ref. 6b (97% ee for S11).
ꢀc
This journal is The Royal Society of Chemistry 2008
3890 | Chem. Commun., 2008, 3888–3890