Diphenylphosphanylsulfoximines as ligands in iridium-catalyzed asymmetric imine hydrogenations

Article abstract of DOI:10.1002/anie.200502482

(Chemical Equation Presented) Easily accessible phosphine-substituted sulfoximines 2 have been applied in Ir-catalyzed asymmetric hydrogenations of acylic N-arylated imines 1. The amines 3 are formed under mild conditions in high yields with excellent ee

Full text of DOI:10.1002/anie.200502482

Communications
Crabtreeꢀs catalyst,[8] have attracted particular attention. For
example, Zhang and co-workers reported enantioselective
hydrogenations of N-aryl imines (with up to > 99% ee) by
applying an iridium catalyst bearing a chiral 1,1’-bisphospha-
nylferrocene (f-binaphane).[9] Phosphanyloxazoline com-
plexes with noncoordinating anions have been used by
several group to afford products with up to 90% ee.[10]
Industrially relevant in this context is the asymmetric hydro-
genation of an acyclic N-aryl imine as key step in the synthesis
of the herbicide (S)-metolachlor by Syngenta.[11] Although
only moderate enantioselectivities are achieved, the excep-
tionally high turnover numbers (TON) and turnover frequen-
cies (TOF) of the iridium-ferrocenylphosphine catalyst
allowed this imine reduction to become one of the largest
catalytic enantioselective industrial processes to date.
Chiral sulfoximines are versatile ligands for asymmetric
catalysis,[12] and highly enantioselective hetero-Diels–Alder
reactions,[13] Mukaiyama-type aldol,[14] and carbonyl-ene
reactions[15] with sulfoximine-based catalysts have recently
been described. In all these catalytic reactions, dinitrogen
chelates such as 1 or 2 with sulfoximine units linked to
quinoline or aniline moieties were applied. We thus focused
our attention on the synthesis and use of phosphine-substi-
tuted sulfoximines 3, which on the basis of conclusions from
solution and solid-state studies[13c,16] were expected to be good
metal binders through their P and Ndonor sites.
Asymmetric Hydrogenations
DOI: 10.1002/anie.200502482
Diphenylphosphanylsulfoximines as Ligands in
Iridium-Catalyzed Asymmetric Imine
Hydrogenations**
Christian Moessner and Carsten Bolm*
Chiral amines are ubiquitous in natural products and drugs,
and their synthesis by asymmetric hydrogenation of carbon–
nitrogen double bonds has attracted much attention.[1] How-
ever, the search for and development of efficient catalysts for
enantioselective C–Ndouble bond hydrogenations with high
enantioselectivity at a reasonable catalyst loading proved
=
=
much more difficult than for the reduction of C C and C O
groups.[2–5] Furthermore, most of those catalysts are only
suitable for asymmetric hydrogenations of cyclic substrates,
whereas acyclic imines still represent challenging com-
pounds.[6] In this case, one of the major problems for achieving
a high enantiomeric excess is the equilibrium between the E
and Z isomer of the imine,[7] which makes it difficult for the
catalyst to convert all stereoisomers in a uniform and selective
manner. Consequently, the first successful chiral catalysts for
this important transformation have only recently been
described. Among them, homogenous Ir complexes with
chiral P,P- or P,N-ligands, which are structurally analogous to
For the preparation of diphenylphosphanyl sulfoximines
3, phosphine oxide 4, which can be obtained by palladium-
catalyzed cross-coupling of 2-bromo-1-iodobenzene with
diphenylphosphane, served as starting material.[17] Applica-
tion of the newly developed copper-mediated N-arylation
reaction[18] afforded products 6a–f from 4 and sulfoximines
5a–f, respectively, in moderate to good yields (Scheme 1).
Reductive deoxygenation of 6 with trichlorosilane gave
diphenylphosphanylsulfoximines 3 as solid, air-stable prod-
ucts in 55–81% yield.
Guided by the successful applications of other P,N-ligands
as effective hydrogenation catalysts,[3–5,19] the novel sulfox-
imine derivatives 3 were tested in Ir-catalyzed asymmetric
imine hydrogenations. For the initial screening and optimizing
process, acetophenone-derived imine 7a was selected as
substrate. To our delight we found that the catalyst generated
by mixing [{Ir(cod)Cl}2] (0.5 mol%) with sulfoximine 3a
(1.1 mol%) followed by the addition of iodine (2.0 mol%) led
to full conversion of 7a under H2 into 8a with rather
encouraging 79% ee (Scheme 2).
[*] Dipl.-Chem. C. Moessner, Prof. Dr. C. Bolm
Institut für Organische Chemie
Rheinisch-Westfälische Technische Hochschule Aachen
Landoltweg 1, 52056 Aachen (Germany)
Fax: (+49)241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
[**] We are grateful to the Fonds der Chemischen Industrie and to the
Deutsche Forschungsgemeinschaft (DFG) within the SFB 380
“Asymmetric Synthesis by Chemical and Biological Methods” for
financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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the activity and the enantioselectivity of the resulting
catalysts. Thus, use of 3b and 3c bearing S-isopropyl or S-
cyclopentyl groups resulted in low conversions of 7a
(<40%), even after extended reaction times, to give 8a with
66 and 10% ee, respectively (Table 1, entries 2 and 3).
Surprisingly, however, the effect of branching at the b position
of the sulfoximine alkyl group was opposite, and the catalyst
efficiency increased remarkably! Thus, with isobutyl-substi-
tuted sulfoximine 3d an excellent conversion of 7a was
achieved after only 4 h, and the enantioselectivity of the
resulting amine 8a reached an unprecedented 96% ee
(Table 1, entry 4). Sulfoximines 3e and 3 f, which have
modified S-aryl groups, led to active catalysts as well
(99% conversion after 12 h; Table 1, entries 5 and 6), but
in these cases the enantioselectivities were lower (50 and
88% ee, respectively) than those attained with 3d.
Scheme 1. Synthesis ofthe diphenylphosphanylsulof ximines 3.
As the Ir catalyst with sulfoximine ligand 3d
performed exceptional well in the test reaction
(Scheme 2), we briefly studied its catalytic behavior
under modified reaction conditions. A decrease in the
Scheme 2. Ir-catalyzed asymmetric imine hydrogenation.
Table 1: Influence of the ligand structure on the asymmetric
hydrogenation ofimine 7a.[a]
Subsequent experiments revealed that no reaction occur-
red in the absence of iodine, which indicated that the IrI
complex formed in situ was only a precatalyst, which most
likely was further oxidized by iodine.[20] Hydrogenations of
analogous substrates showed that the aryl group on the imine
nitrogen atom had a strong effect on the reactivity and
selectivity of the catalyst. The best result was achieved with
the imine bearing the N-(p-methoxy)phenyl (PMP) group,
which can easily be removed by oxidative methods. Use of the
N-(o-methoxy)phenyl-protected substrate 9a led to lower
reactivity and enantioselectivity (58% ee after 20 h). No
reaction occurred with imine 10a bearing the N-mesityl
group.
Entry
Sulfoximine
t [h]
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(R)-3e
(R)-3 f
4
8
20
4
12
12
99
40
<20
99
99
99
79 (À)
66 (À)
10 (À)
96 (À)
50 (+)
88 (+)
[a] Reaction conditions: imine 7a (0.5 mmol), [{Ir(cod)Cl}2]
(0.0025 mmol), sulfoximine 3 (0.0055 mmol), iodine (0.01 mmol), H2
(20 bar), toluene (0.5m), room temperature. [b] Determined by 1H NMR
spectroscopy. [c] The enantiomer ratios were determined by HPLC by
using a column with a chiral stationary phase (Chiralcel OD-H). The
direction ofthe optical rotation of 8a is given in parenthesis.
catalyst loading to 0.5 mol% did not result in any change in
the enantioselectivity. With 0.1 mol% of catalyst, the hydro-
gen pressure had to be increased to 50 bar to achieve full
conversion.[21] Toluene was the solvent of choice, and lowering
the reaction temperature led to a slight increase in enantio-
selectivity (97% ee at 08C).[22]
To explore the scope of the Ir-catalyzed asymmetric
hydrogenation with the catalyst based on sulfoximine 3d, a
series of imines with 4-methoxyphenyl groups on the imine
nitrogen atom were reduced under the optimized reaction
conditions (Table 2).
The data can be summarized as follows: Substrates with
meta- or para-substituents on the arene (e.g. 7d, 7e, 7g–i)
reacted equally well as unsubstituted 7a to afford the
corresponding aryl-protected amines with enantioselectivities
in the range 93–96% ee (Table 2, entries 4, 5, 7–9). Although
ortho-substituted imines 7c, 7 f, and 7j were applied as
mixtures of double-bond isomers, they also gave products
with excellent enantioselectivities (90–98% ee; Table 2,
entries 3, 6, and 10). Imine 7b, which was derived from
propiophenone (and isolated as a 7:1 mixture of E/Z isomers),
Next, the influence of the ligand structure on the catalyst
performance in the test reaction depicted in Scheme 2 was
studied. Increasing the steric bulk of the alkyl substituent of
the sulfoximine a to the sulfur atom drastically lowered both
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Table 2: Ir-catalyzed asymmetric hydrogenations ofimines 7.[a]
solid (344 mg, 81%) after flash chromatography (SiO2; pentane/
acetone 10:1). For analytical data, see the Supporting Information.
General procedure: Under an argon atmosphere [{Ir(cod)Cl}2]
(1.7 mg, 0.0025 mmol) and sulfoximine 3d (2.5 mg, 0.0055 mmol)
were placed in a 10-mL test tube equipped with a stirrer bar. After the
addition of dry toluene (0.5 mL), the yellow solution was stirred for
30 min. Iodine (2.5 mg, 0.010 mmol) was then added, and the solution
turned red within 30 min. To this catalyst solution was added the
imine (0.5 mmol) and additional toluene (0.5 mL). The test tube was
placed in an argon-filled steel autoclave, which was purged three
times with hydrogen (5 bar) and finally pressurized to 20 bar. The
reaction mixture was stirred for the indicated period of time. Then,
the hydrogen gas was released and the reaction quenched by addition
of pentane (3 mL). The product was filtered through a short plug of
silica (3 cm) and eluted with pentane/acetone (20:1).
Entry
Imine
t [h]
ee [%][b]
1
2
3
4
5
7a
7b[c]
7c[c]
7d
7e
4
4
6
4
4
96 (À)
92 (À)
94 (+)
93 (À)
96 (À)
90 (+)
96 (À)
94 (À)
95 (À)
98 (+)
69 (À)
75 (+)
91 (À)
6
7
7f[c]
7g
6
4
8
9
10
11
12
13
7h
7i
4
4
6
4
12
4
The conversions were determined by 1H NMR spectroscopy, and
the enantiomer ratio analyzed with analytical HPLC by using chiral
columns. For details, see the Supporting Information.
7j[c]
7k
9i
11
Received: July 16, 2005
Published online: October 10, 2005
[a] Reaction conditions: imine
7
(0.5 mmol), [{Ir(cod)Cl}2]
(0.0025 mmol), sulfoximine 3d (0.0055 mmol), iodine (0.01 mmol), H2
(20 bar), toluene (0.5m), room temperature. In all cases, full conversion
was achieved. [b] The enantiomer ratios were determined by HPLC using
a column with a chiral stationary phase (Chiralcel OD-H). The directions
ofthe optical rotations ofamines 8 are given in parentheses. [c] Mixture
of isomers; for details see the Supporting Information.
Keywords: amines · asymmetric catalysis · hydrogenation ·
imines · sulfoximines
.
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[22] For details, see the Supporting Information.
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