Indium-catalyzed asymmetric hydrogenation of unfunctionalized tetrasubstituted olefins

Article abstract of DOI:10.1002/anie.200702555

(Chemical Equation Presented) Even notoriously unreactive substrates such as tetrasubstituted unfunctionalized olefins can be hydrogenated with high efficiency and excellent enantioselectivity using readily accessible chiral Ir catalysts. In this way, two adjacent stereogenic centers can be introduced in a single step (see scheme for an example; BAr_F = tetrakis(3,5- di(trifluoromethyl)-phenyl)borate, o-Tol = ortho-tolyl).

Full text of DOI:10.1002/anie.200702555

Communications
DOI: 10.1002/anie.200702555
Asymmetric Catalysis
Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized
Tetrasubstituted Olefins**
Marcus G. Schrems, Eva Neumann, and Andreas Pfaltz*
Table 1: Ir-catalyzed hydrogenation of 5.[a]
Iridium complexes with chiral N,P ligands have emerged as a
new class of highly efficient catalysts for asymmetric hydro-
genation with an application range that is largely comple-
mentary to rhodium and ruthenium diphosphane com-
plexes.[1–3] They have been used successfully for the hydro-
genation of a wide range of functionalized and unfunction-
alized di- and trisubstituted olefins. Unlike Rh and Ru
diphosphane complexes, they do not require the presence of a
Ligand L
p [bar]
Conversion [%][b]
ee [%][d]
1a
1b
2a
2b
3a
3b
(S)-4a
(S)-4b
(S)-4c
(S)-4d
50
50
50
50
50
50
50
50
50
50
5
>99
65
55
95
95
79 (À)
2 (+)
5 (À)
=
coordinating group near the C C bond, so even purely alkyl-
substituted olefins can be hydrogenated with high enantiose-
lectivity.[3] However, to date no practical catalysts are known
for the asymmetric hydrogenation of unfunctionalized tetra-
substituted olefins. Although Buchwald and co-workers have
obtained high enantioselectivities in the hydrogenation of
tetrasubstituted aryl alkenes using a chiral zirconocene
complex,[4] high catalyst loadings, long reaction times, and
high sensitivity of the catalyst have prevented widespread use
of this method. Ir catalysts based on chiral phosphanyl
oxazoline (phox) ligands 1,[5] on the other hand, showed high
82 (À)
14 (À)
14 (+)
88 (À)
80 (À)
92 (À)
92 (À)
96 (À)
97 (À)
71 (À)
74 (À)
27 (À)
85 (À)
84 (À)
62 (À)
40 (À)
58 (À)
69 (À)
30 (À)
62 (À)
73 (+)
48 (À)
42 (À)
79 (À)
83
>99
>99
>99
>99
>99[c]
99
>99
>99
>99
>99
>99
>99
>99
>99
>99[c]
>99
60
1
(S)-4e
(S)-4 f
(S)-4g
(S)-4h
(S)-4i
(S)-4j
(S)-4k
50
50
50
50
50
50
50
10
5
50
50
50
50
50
50
(S)-4l
(S)-4m
(R)-4n
(S)-4o
(S)-4p
(S)-4q
>99
86
>99
>99
[a] See above equation and the Supporting Information for conditions;
BArF =3,5-di(trifluoromethyl)phenyl)borate. [b] Conversion was deter-
mined by GC. [c] t=8 h. [d] Determined by GCon a chiral column.
activity in the hydrogenation of tetrasubstituted aryl alkenes
such as 5, but enantiomeric excesses were at best moderate
(Table 1).[1a,6]
We have recently found that Ir complexes based on the
structurally simple and readily accessible phosphanyl oxazo-
lines 4 are much better suited for such reactions.[7]
A
subsequent study with a wide range of ligands 4 and
phosphinite oxazoline ligands of types 2 and 3 revealed that
5 and other tetrasubstituted olefins can be hydrogenated with
high enantioselectivity at remarkably low catalyst loadings.
Herein, we report the results of this study, which has led to
highly efficient and practical Ir catalysts for the asymmetric
hydrogenation of tetrasubstituted unfunctionalized olefins.
Although the phosphanylmethyloxazoline 4k was
reported by Sprinz and Helmchen[8] many years ago, ligands
of this type have not, to date, received much attention.[9]
Using a modified synthetic route starting from two sets of
secondary phosphanes and chloromethyloxazoline com-
[*] M. G. Schrems, Dr. E. Neumann, Prof. Dr. A. Pfaltz
Department of Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
[**] Financial support from the Swiss National Science Foundation and
the Federal Commission for Technology and Innovation (KTI) is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8274
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Angewandte
Chemie
pounds derived from chloroacetyl chloride and amino alco-
hols,[10] we readily prepared a library of ligands 4a–q (Cy =
cyclohexyl, Bn = benzyl, o-Tol = ortho-tolyl). Among these
17 ligands, derivatives 4c and 4d gave ee values above 90% in
the hydrogenation of substrate 5 (Table 1). With ligand 1b
and with phosphinites 2a, 3a, and 3b, which had all been
successfully used for the hydrogenation of trisubstituted
olefins,[1a] the reaction was slower and led to nearly racemic
product. Ligand 1a, which gives only moderate to low
enantioselectivities with trisubstituted olefins, clearly outper-
forms the sterically more demanding derivative 1b. Obvi-
ously, the optimum ligand structures for tri- and tetrasub-
stituted olefins differ strongly. Interestingly, ligand 2b with
cyclohexyl groups at the P atom led to 95% conversion and a
respectable 82% ee, whereas the analogous Ph2P-substituted
derivative 2a gave only 55% conversion and 5% ee. In
general, ligands with dialkylphosphanyl substituents seem to
be better suited for this substrate than diarylphosphanyl
oxazolines. Ligand 4d showed the best overall performance
for this substrate. Surprisingly, the enantiomeric excess
increased from 92% at 50 bar to 97% when the pressure
was lowered to 1 bar, while the reaction was still sufficiently
fast to allow essentially full conversion under standard
conditions.
Scheme 1. Selected hydrogenation results; for reaction conditions, see
Equation (1) and the Supporting Information. [a] 5.0 bar H2, 8 h.
[b] Over 99.8% cis, conversion includes 3% 1,2-dimethylnaphthalene.
[c] Over 99.8% cis, conversion includes 11% 1,2-dimethylnaphthalene.
[d] 99% cis, conversion includes 4% 1,2-dimethylnaphthalene. [e] Only
cis, conversion includes traces of 2-methyl-1-phenylnaphthalene (less
than 1%).
The analogous para-fluorophenyl-substituted alkene 7
turned out to be a more difficult substrate. The maximum
enantiomeric excess at 50 bar was 79% using ligand 4d,
whereas at 5 bar up to 89% ee could be obtained with ligand
4e (Scheme 1). We next tested a series of cyclic olefins 8–16[4]
(Scheme 1). The 2,3-disubstituted indenes 8–11 readily
reacted, yielding high enantioselectivities under the condi-
tions given in Equation (1). Among the phosphanylmeth-
50 bar, 73% ee at 5 bar with catalyst Ir-4k), whereas the
phenyl-substituted analogue 16 gave up to 91% ee, albeit with
low conversion.[15] Surprisingly, in the hydrogenation of
olefins 12–15, the sense of asymmetric induction depended
on the structure of the R2 substituent at the stereogenic center
of the ligand. For example, dihydronaphthalene 15 was
converted to the (À)-product in 65% ee by (S)-Ir-4k (R2 =
iPr), while (S)-Ir-4m (R2 = CH2tBu) gave the (+)-product in
39% ee under the same conditions. Apparently, the coordi-
nation mode of the olefin depends crucially on the oxazoline
substituent.
yloxazolines 4a–q, ligand 4k gave the best results for this class
of substrates with 95% ee for indene 11. However, the
previously developed phosphinite oxazolines 3a and 3b[11]
also proved to be efficient ligands, which outperformed ligand
4k in the hydrogenation of 8–10. Indenes 12–14 reacted with
similarly high enantioselectivities using Ir-4k, but conversions
were low. Importantly, no isomerization at the benzylic
position was observed with Ir-4, so the relative configuration
of the products was exclusively cis.[14]
We found that in many cases high enantioselectivities and
conversions could be obtained at catalyst loadings of 0.1–
0.5 mol% [Eq. (2), Scheme 2]. In the hydrogenation of olefin
As observed with substrate 5, we obtained higher
ee values at lower hydrogen pressures in the hydrogenation
of olefins 8–11 using Ir-4k. For olefin 8 the enantiomeric
excess increased from 86% at 50 bar to 93% at 10 bar. At
5 bar the ee value reached 94% with full conversion after a
reaction time of 8 h. Buchwald and co-workers, on the other
hand, observed the opposite trend for their zirconocene
catalyst, which performed best at high pressures of up to
138 bar.[4]
11, for example, the ee value did not change when the amount
of catalyst was reduced from 2.0 to 0.1 mol%, while
conversion after the standard reaction time of 4 h decreased
to 84%. Dihydronaphthalene 15, on the other hand, still gave
full conversion with 0.1 mol% of catalyst, but the enantio-
meric excess decreased from 65% with 2 mol% of catalyst to
58%. Olefin 5 gave poor results at catalyst loadings below
2 mol%, possibly because of deactivating impurities.
Only moderate enantioselectivities could be achieved in
the hydrogenation of dihydronaphthalene 15 (65% ee at
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8275

Communications
with the simple, commercially available phox ligand 1a was an
even more effective catalyst and allowed the reaction to be
carried out at low catalyst loadings of 0.1 mol% with
excellent results. At 5 bar hydrogen pressure ligand 4p
performed best, giving 96% ee.
In conclusion, we have found a set of efficient, readily
accessible catalysts for the asymmetric hydrogenation of
tetrasubstituted unfunctionalized olefins. The remarkably
high catalytic activity towards this notoriously unreactive
substrate class and the option to introduce two adjacent
stereogenic centers in a single step open up new possibilities
in asymmetric hydrogenation.
Received: June 12, 2007
Published online: September 21, 2007
Scheme 2. Catalyst loading for selected substrates using [Ir(L)cod]-
BArF; see Equation (2) and the Supporting Information for reaction
conditions. [a] Over 99.8% cis, conversion includes 3% 1,2-dimethyl-
naphthalene.
Keywords: asymmetric catalysis · hydrogenation · iridium ·
.
N,P ligands · tetrasubstituted olefins
The tricyclic ring system of 18 is found in a variety of
natural products. The utility of compounds of this type as
synthetic building blocks was recently demonstrated by
Banwell et al., who synthesized the tetracyclic carbon frame-
work of gibberellins from a racemic methoxy-substituted
derivative of 18.[12] We envisaged that asymmetric hydro-
genation of tricycle 17, which is easily prepared from cyclo-
hexanone and benzaldehyde in three steps,[13] would provide
an efficient enantio- and diastereoselective route to structure
18.
[1]a) A. Pfaltz, J. Blankenstein, R. Hilgraf, E. Hörmann, S.
McIntyre, F. Menges, M. Schönleber, S. P. Smidt, B. Wüstenberg,
N. Zimmermann, Adv. Synth. Catal. 2003, 345, 33 – 43; b) X. Cui,
K. Burgess, Chem. Rev. 2005, 105, 3272 – 3297; c) K. Källström, I.
Munslow, P. G. Andersson, Chem. Eur. J. 2006, 12, 3194 – 3200.
[2]S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. 2006, 118, 5318 –
5321; Angew. Chem. Int. Ed. 2006, 45, 5194 – 5197.
[3]S. Bell, B. Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A.
Pfaltz, Science 2006, 311, 642 – 644.
[4]M. V. Troutman, D. H. Appella, S. L. Buchwald, J. Am. Chem.
Soc. 1999, 121, 4916 – 4917.
Indeed, substrate 17 reacted smoothly with Ir catalysts
based on ligands 4k or 4p to afford the desired product with
high enantioselectivity and full conversion under standard
screening conditions (Table 2). Surprisingly, the Ir complex
[5]G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336 – 345.
[6]Co and Kim reported 88% ee for olefin 5 recently; however, the
conversion was very low (21%, 24 h): T. T. Co, T.-J. Kim, Chem.
Commun. 2006, 3537 – 3539.
[7]E. Neumann, Dissertation, University of Basel, 2006.
[8]J. Sprinz, G. Helmchen, Tetrahedron Lett. 1993, 34, 1769 – 1772.
[9]P. Braunstein, C. Graiff, F. Naud, A. Pfaltz, A. Tiripicchio, Inorg.
Chem. 2000, 39, 4468 – 4475; P. Braunstein, F. Naud, C. Graiff, A.
Tiripicchio, Chem. Commun. 2000, 897 – 898; P. Braunstein,
M. D. Fryzuk, M. Le Dall, F. Naud, S. J. Rettig, F. Speiser, J.
Chem. Soc. Dalton Trans. 2000, 1067 – 1074.
Table 2: Ir-catalyzed hydrogenation of 18.[a]
[10]Ligands
4 were prepared by nucleophilic substitution of
L
Catalyst
loading [mol%]
p [bar]
Conversion [%][b]
ee [%][d]
chloromethyloxazolines with BH3-protected metalated dialkyl-
or diarylphosphanes; see the Supporting Information.
[11]S. P. Smidt, F. Menges, A. Pfaltz, Org. Lett. 2004, 6, 2023 – 2026.
[12]M. G. Banwell, A. T. Phillis, A. C. Willis, Org. Lett. 2006, 8,
5341 – 5344.
[13]a) J. Colonge, J. Sibeud, Bull. Soc. Chim. Fr. 1952, 786 – 789; b) J.
Colonge, J. Sibeud, Bull. Soc. Chim. Fr. 1953, 75 – 78.
[14]In the hydrogenation of 15, trans product was detected in some
cases (Ir-3b: 13%); see the Supporting Information.
[15]In the hydrogenation of dihydronaphthalenes 15 and 16, small
amounts of aromatization product were detected; see the
Supporting Information.
1a
2.0
1.0
0.5
0.1
2.0
2.0
2.0
2.0
50
50
50
50
5
50
50
5
>99
>99
>99
>99
>99[c]
>99
>99
>99[c]
94 (+)
93 (+)
93 (+)
90 (+)
94 (+)
90 (+)
93 (+)
96 (+)
4k
4p
[a] For reaction conditions, see the above equation and the Supporting
Information. [b] Conversion was determined by GC. [c] t=8 h. [d] Deter-
mined by GCon a chiral column.
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