Well-defined chiral spiro iridium/phosphine-oxazoline cationic complexes for highly enantioselective hydrogenation of imines at ambient pressure

Article abstract of DOI:10.1021/ja063444p

New chiral phosphine-oxazoline ligands (7, SIPHOX) with a rigid and bulky spirobiindane scaffold were synthesized, starting with optically pure 7-diphenylphosphino-7′-trifluoromethanesulfonyloxyl-1,1′- spirobiindane, in four steps in 40-64% overall yield.

Full text of DOI:10.1021/ja063444p

Published on Web 09/06/2006
Well-Defined Chiral Spiro Iridium/Phosphine-Oxazoline
Cationic Complexes for Highly Enantioselective
Hydrogenation of Imines at Ambient Pressure
Shou-Fei Zhu, Jian-Bo Xie, Yong-Zhen Zhang, Shen Li, and Qi-Lin Zhou*
Contribution from the State Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai UniVersity, Tianjin 300071, China
Received May 17, 2006; E-mail: qlzhou@nankai.edu.cn
Abstract: New chiral phosphine-oxazoline ligands (7, SIPHOX) with a rigid and bulky spirobiindane scaffold
were synthesized, starting with optically pure 7-diphenylphosphino-7′-trifluoromethanesulfonyloxyl-1,1′-
spirobiindane, in four steps in 40-64% overall yield. Iridium complexes of 7, the chiral analogues of the
Crabtree catalyst, were generated by coordination of ligands 7 and [Ir(COD)Cl]2 in the presence of sodium
tetrakis-3,5-bis(trifluoromethyl)phenylborate. The complexes were characterized by NMR, ESI-MS, and X-ray
diffraction analysis. The Ir-SIPHOX complexes can catalyze the hydrogenation of acyclic N-aryl ketimines
under ambient pressure with excellent enantioselectivities (up to 97% ee) and full conversions. This result
represents the highest enantioselectivity and the first example of the hydrogenation of imines catalyzed by
chiral analogues of the Crabtree catalyst at ambient pressure. Studies on the stability of the catalysts revealed
that the catalysts Ir-SIPHOX are very stable and resistant to the formation of inactive trimers under
hydrogenation conditions. On the basis of the X-ray diffraction analysis of the structures of catalysts and
amine products, a rational explanation for the enantiocontrol of the chiral catalysts in the hydrogenation of
imines is proposed.
cyclic sulfonamides.7 The Ru-DuPhos-DACH complex was
Introduction
applied in the hydrogenation of acetophenone aniline imine with
The catalytic asymmetric hydrogenation of imines has drawn
much attention recently, since it provides one of the most
efficient routes to the synthesis of chiral amines, which are
widely used in pharmaceutical and agrochemical substances.1
Although great efforts have been made in recent decades,
catalytic asymmetric hydrogenation of imines remains a chal-
lenge in modern synthesis, in contrast to the relative ease of
asymmetric hydrogenation of olefins and ketones.
In the past decade, several chiral transition metal complexes,
such as Ti, Rh, Ru, and Ir complexes, have been investigated
and exhibited promising results in the asymmetric hydrogenation
of imines. The chiral titanocene developed by Buchwald et al.2
was found to be highly enantioselective in the hydrogenation
of a variety of cyclic imines. Rhodium complexes of chiral
bidentate phosphines have proven to be effective catalysts in
the asymmetric hydrogenation of benzylimines,3 N-acylhydra-
zone,4 and N-diphenylphosphinyl ketimines.5 Ru-BINAP was
successfully used in the hydrogenation of N-tosylimines6 and
high enantioselectivity.8 Since neutral [Ir(COD)Cl]2/xyliphos
was successfully applied in the industrial synthesis of the
herbicide (S)-metolachlor,9 a number of iridium complexes of
chiral diphosphine ligands have been developed for the hydro-
genation of cyclic and acyclic imines and quinolines in high
enantioselectivities.10 One of the most notable examples was
reported by Zhang et al.10b in the hydrogenation of acyclic
imines with up to >99% ee by using Ir/f-Binaphane catalyst.
Very recently, neutral Ir complexes of P,N-ligands were also
found to be highly enantioselective catalysts in the hydrogena-
tion of N-aryl ketimines and quinolines with I2 as an additive.11
In 1997, Pfaltz et al.12 developed a chiral analogue of the
Crabtree catalyst,13 the cationic iridium/(S)-2-(2-(diphenylphos
(6) Charette, A. B.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669.
(7) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron
Lett. 1990, 31, 4117.
(8) Cobley, C. J.; Henschke, J. P. AdV. Synth. Catal. 2003, 345, 195.
(9) Blaser, H.-U. AdV. Synth. Catal. 2002, 344, 17.
(10) (a) Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1995, 6, 2661. (b)
Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (c) Wang,
W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem.
Soc. 2003, 125, 1053. (d) Vargas, S.; Rubio, M.; Suarez, A.; del Rio, D.;
Alvarez, E.; Pizzano, A. Organometallics 2006, 25, 961. (e) Dervisi, A.;
Carcedo, C.; Ooi, L. AdV. Synth. Catal. 2006, 348, 175. (f) Imamoto, T.;
Iwadate, N.; Yoshida, K. Org. Lett. 2006, 8, 2289.
(1) For reviews, see: (a) Blaser, H.-U.; Spinder, F. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 1, p 248. (b) Kobayashi, S.; Ishitani, H. Chem.
ReV. 1999, 99, 1069. (c) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(d) Blaser, H.-U.; Malan, C.; Pugin, B.; Spinder, F.; Steiner, H.; Studer,
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(b) Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564.
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Pfaltz, A. Chem. Eur. J. 1997, 3, 887. (b) Lightfoot, A.; Schnider, P.; Pfaltz,
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12886
J. AM. CHEM. SOC. 2006, 128, 12886-12891
10.1021/ja063444p CCC: $33.50 © 2006 American Chemical Society

Catalytic Enantioselective Hydrogenation of Imines
A R T I C L E S
(SPINOL),19 several routes can be considered to construct the
chiral spiro phosphine-oxazoline ligands (abbreviated SI-
PHOX). As we have had intermediate 2 in the previous synthesis
of chiral spiro diphosphine (SDP) ligands,18d two routes were
advanced to synthesize ligands 7 from compound 2 (Scheme
1). The shorter route, including only two steps, was tried first.
The palladium-catalyzed cyanation of 2 ran smoothly to provide
compound 3 in 88% yield (step a). However, the next step, the
condensation of cyano group with 2-amino alcohols catalyzed
by anhydrous ZnCl2 (step b), was completely suppressed. The
alternative four-step route was then tested, and satisfying results
were obtained. Compound 2 was converted to esters 4 by Pd-
catalyzed carbonylation20 in 85-91% yield (step c). The
carboxylates 4 were hydrolyzed by aqueous KOH in methanol
to provide acids 5 in 67-99% yield (step d). The condensation
of acids 5 with enantiomerically pure 2-amino alcohols in the
presence of 1-hydroxylbenzotriazole (HOBt) and N,N′-dicyclo-
hexylcarbodiimide (DCC) in tetrahydrofuran (THF) gave amides
6 in 87-100% yield (step e). Finally, the target ligands 7 were
obtained by cyclization of the amides 6 in 69-76% yield (step
f).21 The phosphine-oxazoline ligands 7 are stable and can be
purified by silica gel column chromatography.
Figure 1. Cationic iridium catalysts with chiral P,N-ligands.
phino)phenyl)-4-alkyl-4,5-dihydrooxazole ((S)-PHOX) complex
(Figure 1). There are three crucial features of Pfaltz’s catalyst:
(1) Simple synthesis and high stability make the purification
and manipulation easier. (2) The ease of growing single crystals
for X-ray diffraction analysis makes catalysts well-defined; this
is beneficial to the study of the mechanism.14 (3) High reactivity
and enantioselectivity are observed in the hydrogenation of
imines and unfunctionalized olefins.15 Following Pfaltz’s pio-
neering work, many chiral cationic iridium catalysts with
different P,N-ligands16 have been prepared and applied in the
hydrogenation of imines, and some of them were proven to be
efficient.17 However, most of those catalysts gave only a modest
enantioselectivity.
Synthesis of Cationic Iridium Catalysts 1. In the Pfaltz
procedure for the preparation of cationic iridium catalysts with
chiral P,N-ligands, [Ir(COD)Cl]2 was first reacted with P,N-
ligands to form the complex [Ir(COD)(P,N)]Cl. The anion Cl-
was then exchanged to BARF- by treatment with aqueous
solutions of NaBARF (BARF ) tetrakis-3,5-bis(trifluoromethyl)-
phenylborate).12c Although this procedure has been commonly
used in the synthesis of cationic iridium catalysts and various
P,N-ligands were reported to coordinate with [Ir(COD)Cl]2
within several hours,15b the spiro phosphine-oxazoline ligand
7a cannot completely coordinate to iridium under the standard
conditions. When the mixture of [Ir(COD)Cl]2 and ligand 7a
([Ir(COD)Cl]2/7a ) 0.5:1) was refluxed in CH2Cl2 for 1 h
(method A), 31P NMR analysis (Figure 2) showed that the
coordination of ligand 7a to the iridium dimer was incomplete,
leaving about 50% free ligand (δ -20.4 ppm). Two coordinated
phosphorus signals at lower field (δ 22.2 and 16.4 ppm)
indicated that two complexes were formed in the reaction.
Prolonging the reaction time to more than 3 days, or carrying
out the reaction in refluxing 1,2-dichloroethane (DCE) did not
contribute to the complete coordination of ligand 7a to iridium
but rather induced decomposition of the ligand. However, as
the ratio of [Ir(COD)Cl]2/7a was increased to 1:1 (method B),
a complete coordination of ligand 7a to iridium was achieved
in refluxing CH2Cl2, giving the same two complexes as those
obtained via method A. The results from methods A and B
clearly indicated that only one of two iridium atoms in the [Ir-
(COD)Cl]2 was coordinated with ligand 7a. It was found that,
if [Ir(COD)Cl]2, ligand 7a, and NaBARF‚3H2O ([Ir(COD)Cl]2/
7a/NaBARF ) 0.5:1:1.5, method C) were mixed together, the
coordination of ligand 7a to iridium could be completed at room
temperature. A compound with a 31P NMR peak at 15.2 ppm
was isolated in 85% yield, which was identified to be the
During our investigation of the chiral spirobiindane-backbone
phosphorous ligands, we became aware that the spirobiindane
scaffold is extremely rigid and bulky.18 We therefore envisaged
that the phosphine-oxazoline ligands bearing a spirobiindane
scaffold would be crowded and perhaps could prevent the
deactivation of their iridium complexes by inhibiting the
formation of the inactive trimer, which was one of the drawbacks
of the reported Ir/P,N catalysts. Herein we report the synthesis
of chiral phosphine-oxazoline ligands containing a spirobiin-
dane scaffold and their well-defined cationic iridium complexes
1, and their application in asymmetric hydrogenation of acyclic
N-aryl ketimines at ambient pressure with excellent enantiose-
lectivities (up to 97% ee).
Results and Discussion
Synthesis of Chiral Spiro Phosphine-Oxazoline Ligands
7. Starting from the optically pure 1,1′-spirobiindane-7,7′-diol
(14) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592.
(15) For reviews, see: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33,
336. (b) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Hormann, E.; McIntyre,
S.; Menges, F.; Schonleber, M.; Smidt, S. P.; Wustenberg, B.; Zimmermann,
N. AdV. Synth. Catal. 2003, 345, 33.
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Tommasino, M. L.; Lemaire, M. Chem. ReV. 2000, 100, 2159. (b) Guiry,
P. J.; Saunders, C. P. AdV. Synth. Catal. 2004, 346, 497.
(17) (a) Cahill, J. P.; Lightfoot, A. P.; Goddard, R.; Rust, J.; Guiry, J. P.
Tetrahedron: Asymmetry 1998, 9, 4301. (b) Menges, F.; Pfaltz, A. AdV.
Synth. Catal. 2002, 344, 40. (c) Cozzi, P. G.; Menges, F.; Kaise, S. Synlett
2003, 833. (d) Blanc, C.; Agbossou-Niedercorn, F.; Nowogrocki, G.
Tetrahedron: Asymmetry 2004, 15, 2159. (e) Ezhova, M. B.; Patrick, B.
O.; James, B. R.; Waller, F. J.; Ford, M. E. J. Mol. Chem. A: Chem. 2004,
224, 71. (f) Trifonova, A.; Diesen, J. S.; Chapman, C. J.; Andersson, P. G.
Org. Lett. 2004, 6, 3825. (g) Solinas, M.; Pfaltz, A.; Cozzi, P. G.; Leitner,
W. J. Am. Chem. Soc. 2004, 126, 16142. (h) Legault, C. Y.; Charette, A.
B. J. Am. Chem. Soc. 2005, 127, 8966. (i) Trifonova, A.; Diesen, J. S.;
Andersson, P. G. Chem. Eur. J. 2006, 12, 2318.
(18) (a) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Chem.
Commun. 2002, 480. (b) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang,
L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348. (c) Zhou, H.;
Wang, W.-H.; Fu, Y.; Xie, J.-H.; Shi, W.-J.; Wang, L.-X.; Zhou, Q.-L. J.
Org. Chem. 2003, 68, 1582. (d) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-
F.; Fan, B.-M.; Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125,
4404. (e) Fu, Y.; Hou, G.-H.; Xie, J.-H.; Xing, L.; Wang, L.-X.; Zhou,
Q.-L. J. Org. Chem. 2004, 69, 8157. (f) Zhu, S.-F.; Yang, Y.; Wang, L.-
X.; Liu, B.; Zhou, Q.-L. Org. Lett. 2005, 7, 2333. (g) Shi, W.-J.; Zhang,
Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.; Zhou, Q.-L. J. Am. Chem. Soc.
2006, 128, 2780.
(19) (a) Birman, V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron: Asymmetry
1999, 10, 125. (b) Zhang, J.-H.; Liao, J.; Cui, X.; Yu, K.-B.; Deng, J.-G.;
Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L.; Chung, L.-W.; Ye, T. Tetrahedron:
Asymmetry 2002, 13, 1363.
(20) Hotta, H.; Suzuki, T.; Miyano, S.; Inoue, Y. J. Mol. Catal. 1989, 54, L5.
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A R T I C L E S
Zhu et al.
Figure 2. 31P NMR studies on the coordination via three methods. (S,S)-7a reacted with [Ir(COD)Cl]2 in dichloromethane for 1 h.
Scheme 1. Synthesis of Chiral Spiro Phosphine-Oxazoline Ligands 7a
a Reagents and conditions: (a) 10 mol % Pd(PPh3)4, Zn(CN)2, dimethylformamide, 130 °C; (c) 15 mol % Pd(OAc)2, 15 mol % dppp, CO (1 atm), Et3N,
DMSO, MeOH, 70 °C; (d) 40-60% KOH, methanol, reflux; (e) 2-amino alcohol, DCC, HOBt, room temperature; (f) MsCl, Et3N, DMAP, CH2Cl2, 0 °C
to room temperature.
complex 1a. Furthermore, by adding 1.5 equiv of NaBARF‚
3H2O to the mixtures in methods A and B, complex 1a, identical
to the authentic sample from method C, was produced in 80%
yield.
On the basis of the experimental results, it was reasonable to
assume that coordination of ligand 7a to an iridium dimer cannot
release the monomeric iridium complex; that is, the chlorine
bridges still existed after a ligand was coordinated to one of the
two iridium atoms in [Ir(COD)Cl]2. Thus, a rational process for
the coordination of ligand 7a with [Ir(COD)Cl]2 was proposed
and is illustrated in Scheme 2. The two 31P NMR peaks at lower
field in methods A and B might represent the coordination
modes CI and CII. Whenever the P,N-ligand is small or flexible
enough, the second ligand can coordinate to the second iridium
atom in [Ir(COD)Cl]2, and the dimeric iridium complex will
be scissioned into two monomeric iridium chlorides, as sug-
gested in the literature.12c However, if the P,N-ligand was rigid
and bulky, like SIPHOX, it would be very difficult for a second
ligand to coordinate to the second iridium atom in [Ir(COD)-
Cl]2, even under harsh conditions. In the presence of NaBARF,
the complexes CI and CII were dechlorinated to release [Ir-
(COD)]+ species, which was coordinated easily by P,N-ligand
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Catalytic Enantioselective Hydrogenation of Imines
A R T I C L E S
Scheme 2. Proposed Coordination Pathway
Scheme 3. Synthesis of Cationic Iridium Complexes of SIPHOX
Ligands
from the biindane skeleton, while in the complex (S,R)-1a the
isopropyl group is directed toward and repulsed by the biindane
skeleton.
Asymmetric Hydrogenation of Imines with Catalysts 1.
The hydrogenation of N-(1-phenylethylidene)aniline (8a) was
chosen to test the reactivity and enantioselectivity of catalysts
1. The reaction was performed in CH2Cl2 with 1 mol % of
catalyst under 20 atm hydrogen pressure at 25 °C. The catalysts
1, with different substituents on the oxazoline ring of the ligands,
were compared first, and the results are listed in Table 1. By
using catalyst (S,S)-1a, the imine 8a was hydrogenated with
96% conversion, affording the product 9a in 76% ee (Table 1,
entry 1). The reaction catalyzed by (S,R)-1a gave a racemic
product with a very low conversion, showing that the chiralities
on the spirobiindane backbone and oxazoline ring in this catalyst
are mismatched (entry 2). Catalyst 1b, bearing a phenyl group
on the oxazoline ring, also gave a good enantioselectivity (74%
ee), although the conversion was only 18% (entry 3). A better
result was achieved by using catalyst 1c, which has a benzyl
group on the oxazoline ring (entry 4, 98% conversion and 81%
ee). The solvent effect was studied in the reaction catalyzed by
1c. It was found that weakly polar solvents such as CH2Cl2,
toluene, ether, and tert-butyl methyl ether (TBME) were suitable
for obtaining high conversion and enantioselectivity.
to yield the monomeric iridium complex. It should be pointed
out that other coordination models, such as those with one P,N-
ligand coordinated to two iridiums in [Ir(COD)Cl]2, are also
possible. Thus, all the Ir/SIPHOX complexes 1 were prepared
in high yields according to the simple and efficient method C
(Scheme 3). All the iridium complexes 1 were stable in the
atmosphere.
Structure Analysis of Chiral Iridium Complexes 1. The
complexes (S,S)-1a and (S,R)-1a were easily crystallized from
alcohol/water solvent and afforded crystals suitable for X-ray
diffraction analysis. The X-ray diffraction analysis (Figure 3)
revealed that the ligand 7a coordinated iridium with phosphorus
and nitrogen atoms. The ligand acted as a rigid pincer, and the
iridium atom was clamped into a nine-membered heterometal
ring. The spirobiindane backbone, P-phenyl groups, and iso-
propyl group on the oxazoline ring formed a relatively crowded
and rigid environment around the central metal atom. The large
chelate rings made the bite angle (P-Ir-N) values of both com-
plexes (S,S)-1a and (S,R)-1a larger than those in the analogous
Ir/(S)-PHOX complex [(S,S)-1a, 87.91°; (S,R)-1a, 92.20°; (S)-
PHOX, 85.88° 12a]. Although the Ir-N bond length in 1a was
in the normal range compared to Ir/(S)-PHOX complex [(S,S)-
1a, 2.082 Å; (S,R)-1a, 2.109 Å; Ir/(S)-PHOX, 2.097 Å], the
Ir-P bond in 1a was apparently longer than that in the Ir/(S)-
PHOX complex [(S,S)-1a, 2.349 Å; (S,R)-1a, 2.344 Å; Ir/(S)-
PHOX, 2.305 Å]. This might be attributed to the steric hindrance
of ligands and the electronic difference of the P atoms in the
ligands. The SIPHOX ligands are more crowded and have a
higher electronic density on the P atom than that in the PHOX
ligand, which has an electron-withdrawing group (oxazoline)
at the ortho position. The differences between complexes (S,S)-
1a and (S,R)-1a, especially the difference in the bite angle, were
mainly caused by the orientation of the isopropyl group on the
oxazoline ring. The isopropyl in the complex (S,S)-1a departs
By introducing substituents into the P-phenyl ring of the
catalyst 1c, another two catalysts, 1d and 1e, were synthesized.
It can be seen from the data in Table 1 that the substituent on
the P-phenyl ring had a negligible effect on the enantioselectivity
of the catalyst (entries 9-11). However, the reactivity of the
catalyst was remarkably increased in the case of 1e, which bears
3,5-dimethyl groups on the P-phenyl ring. By using 1e, the
catalyst loading could be reduced to 0.5 mol % (entry 12) and
the hydrogenation could be performed under ambient hydrogen
pressure at 10 °C (entry 14). Catalyst 1e was one of the few
efficient chiral catalysts that could hydrogenate imines at
ambient pressure.10e,f
Under the optimal reaction conditions, a variety of N-aryl
ketimines can be hydrogenated at ambient hydrogen pressure
in excellent enantioselectivities (>90% ee) with full conversions.
From the data in Table 2, it can be seen that the introduction of
an electron-donating group on the R-phenyl ring of ketimine
slightly increased the enantioselectivity (entries 2, 3, and 8).
However, an electron-withdrawing substituent on the N-phenyl
ring led to higher enantioselectivity (entries 10, 11, and 13).
The highest enantioselectivity (97% ee) was achieved in the
hydrogenation of N-(1-phenylethylidene)-4-chloroaniline (8j,
entry 10). This result represents, to the best of our knowledge,
9
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A R T I C L E S
Zhu et al.
Table 1. Asymmetric Hydrogenation of
N-(1-Phenylethylidene)aniline Catalyzed by 1a
entry
catalyst
solvent
conversion (%)b
ee (%)c
1
2
3
4
5
6
7
8
(S,S)-1a
(S,R)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1c
(S,S)-1d
(S,S)-1e
(S,S)-1e
(S,S)-1e
(S,S)-1e
(S,S)-1e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
EtOAc
MeOH
ether
ether
ether
ether
ether
96
7
18
98
65
98
40
8
99
76
0
Figure 3. Crystal structures of (S,S)-1a and (S,R)-1a; the anion BARF-
and hydrogen atoms are omitted for clarity.
74
81
79
82
74
ndd
87
88
90
89
90
93
93
9
10
11
12e
13f
14g
15g,h
99
>99
>99
70
>99
>99
ether
tBuOMe
a Reaction conditions: 0.2 mmol scale, [substrate] ) 0.2 M, 1 mol %
catalyst, 20 atm H2 pressure, 25 °C, 20 h. b Determined by GC using an
HP-5 column. c Determined by chiral HPLC using a Chiracel AS or OD-H
column. The absolute configuration is R.22 d Not determined. e With 0.5
mol % catalyst. f With 0.1 mol % catalyst. g Under ambient hydrogen
pressure at 10 °C. h 80 mg of 4 Å MS was added.
Figure 4. Structure of complex (S,S)-1a and proposed model for the
stereochemistry in the asymmetric hydrogenation of imines (the hydrogen
atoms, anion, and COD are omitted for clarity). (A) View from the front
side of catalyst 1a. (B) Selectivity model for hydrogenation of imines.
Table 2. Asymmetric Hydrogenation of N-Aryl Ketimines
Catalyzed by 1e under Ambient Hydrogen Pressurea
SIPHOX catalysts, we investigated the stability of 1a under
hydrogen pressure. After treatment of catalyst 1a under 50 atm
of hydrogen for 3 h, ESI-MS analysis showed only the monomer
(7a + Ir, m/z ) 708), and no trimeric molecule (with two
positive charges,23 m/z ) 1066) was formed. This pre-
hydrogenated catalyst was taken to catalyze the hydrogenation
of N-(1-phenylethylidene)aniline (8a), giving the product 9a in
74% ee with a full conversion, which was similar to that
obtained by using the original catalyst, (S,S)-1a. This experiment
clearly demonstrated that the iridium complex with SIPHOX
ligand was resistant to the formation of inactive trimer even
when exposed to a high pressure of hydrogen, which was
consistent with what we expected in the catalyst design.
entry
substrate
R
R
′
product
ee (%)b
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
8g
8h
8i
H
H
H
H
H
H
H
H
H
4-Me
4-Cl
4-Br
3-Me
3-Br
9a
9b
9c
9d
9e
9f
9g
9h
9i
93 (R)
94 (-)
94 (-)
90 (-)
91 (R)
93 (-)
92 (-)
94 (-)
93 (-)
97 (-)
96 (+)
91 (-)
94 (-)
4-MeO
4-Me
4-Cl
4-Br
3-Cl
3-Br
3,4-diMe
H
H
H
H
H
To explain the stereochemistry in the asymmetric hydrogena-
tion of N-aryl ketimines catalyzed by Ir-SIPHOX complexes
1, a model for the coordination of substrate to the catalyst was
proposed, based on the crystal structure of catalyst 1a. As shown
in Figure 4, the iridium atom in the catalyst 1a is surrounded
by the ligand. In the four quadrants in front of iridium, the upper-
right quadrant is strongly hindered by the spirobiindane
backbone, the low-left quadrant is semi-hindered by one of the
P-phenyls, and the other two quadrants are relatively open. The
ketimine substrate must coordinate to iridium with the Si face
so that its two bulky aryl groups can be located in the two open
quadrants, as illustrated in Figure 4. According to this model,
hydrogen was added to the substrate from its Si face, leading
to the formation of amine product with R configuration, which
was consistent with the experimental results (see Supporting
Information).
9
10
11
12
13
8j
8k
8l
9j
9k
9l
8m
9m
a Reaction conditions: 0.2 mmol of substrate, 1 mL of TBME, 80 mg
of 4 Å MS, 1 mol % catalyst, ambient H2 pressure, 10 °C, 20 h. Conversions
were >99.5% in all reactions. b Determined by chiral HPLC using a Chiracel
OD-H column.
the highest enantioselectivity in the asymmetric hydrogenation
of ketimines using chiral cationic iridium catalysts.
Study on the Stability of Catalysts under a Hydrogen
Atmosphere and Explanation of Stereochemistry in the
Hydrogenation of Imines with Catalysts 1. It was reported
that the cationic iridium catalysts deactivate easily under a
hydrogen atmosphere by forming inactive trimers.13,23 To
measure whether the trimerization also takes place in our Ir-
(22) Kanth, J. V. B.; Periasamy. M. J. Org. Chem. 1993, 58, 3156.
(23) Smidt, S. P.; Pfaltz, A.; Martinez-Viviente, E.; Pregosin, P. S.; Albinati,
A. Organometallics 2003, 22, 1000.
9
12890 J. AM. CHEM. SOC. VOL. 128, NO. 39, 2006

Catalytic Enantioselective Hydrogenation of Imines
A R T I C L E S
monitored with TLC for a complete conversion. The crude product
was purified by chromatography on a silica gel column with ethyl ace-
tate/petroleum ether and 2% (v/v) of triethylamine to give ligands 7.
Preparation of Iridium Complexes 1. Method A. A mixture of
ligand 7a (62 mg, 0.12 mmol) and [Ir(COD)Cl]2 (40 mg, 0.06 mmol)
in CH2Cl2 (3 mL) was stirred in a Schlenk tube under an argon
atmosphere to a homogeneous solution. The solution was heated at
the reflux temperature for 1 h. TLC and NMR showed that free ligand
was still present. After the solution cooled to room temperature,
NaBARF‚3H2O (170 mg, 0.18 mmol) was added, and the mixture was
stirred vigorously for 1 h. TLC indicated that coordination of the ligand
to iridium was complete. Next, 2 mL of water was added, and the
mixture was stirred for 30 min. The organic layer was separated, and
the aqueous phase was extracted with CH2Cl2 (2 × 10 mL). The
combined organic extracts were concentrated under reduced pressure,
and the resulting residue was purified by flash column chromatography
on silica gel with CH2Cl2/petroleum ether to afford the orange-yellowish
catalyst 1a in 80% yield.
Conclusion
In conclusion, novel chiral phosphine-oxazoline ligands
SIPHOX with a rigid and bulky spirobiindane scaffold were
synthesized in good yields. The coordination behavior of the
SIPHOX toward [Ir(COD)Cl]2 was studied for development of
the corresponding cationic iridium catalysts. Comparison of three
different coordination methods indicated that formation of [Ir-
(COD)(SIPHOX)]+ catalyst occurred only in the presence of
NaBARF. X-ray diffraction analysis showed that the SIPHOX
constructed a crowded and efficient chiral environment around
the iridium metal in the Ir-SIPHOX catalysts. The Ir-SIPHOX
catalysts were highly efficient for the hydrogenation of acyclic
N-aryl ketimines under ambient hydrogen pressure, providing
chiral amines in excellent enantiomeric excesses (up to 97%
ee) and full conversions. NMR and ESI-MS analysis of catalysts
revealed that the Ir-SIPHOX catalysts are stable under the
reaction conditions by preventing the formation of inactive
trimer. The excellent reactivity and enantioselectivity of these
Ir-SIPHOX complexes in the hydrogenation of imines showed
a high potential for wide application of this rigid and bulky
P,N-ligand in transition metal-catalyzed asymmetric reactions.
Method B. A mixture of ligand 7a (62 mg, 0.12 mmol) and [Ir-
(COD)Cl]2 (80 mg, 0.12 mmol) in CH2Cl2 (3 mL) was stirred in a
Schlenk tube under an argon atmosphere to a homogeneous solution.
The solution was refluxed for 1 h. TLC and NMR showed no free
ligand remained. NaBARF‚3H2O (340 mg, 0.36 mmol) was added at
room temperature, and the mixture was stirred vigorously for 1 h.
Catalyst 1a was isolated in 80% yield by flash column chromatography
on silica gel with CH2Cl2/petroleum ether.
Experimental Section
Synthesis of Phosphine-Oxazoline Ligands 7. General Procedure
for the Synthesis of 4. A mixture of triflates 2 (11.3 mmol), Pd(OAc)2
(381.7 mg, 1.70 mmol), dppp (701.1 mg, 1.70 mmol), MeOH (60 mL),
dimethyl sulfoxide (DMSO, 90 mL), and Et3N (24 mL) was saturated
with CO and stirred under a CO atmosphere at 70 °C. The reaction
mixture was monitored by TLC for full conversion. After cooling to
room temperature, the mixture was concentrated at reduced pressure.
The residue was chromatographed on silica gel with ethyl acetate/
petroleum ether to afford esters 4.
General Procedure for the Synthesis of 5. A mixture of esters 4
(6.49 mmol), MeOH (75 mL), and 40-60% KOH (15 mL) was heated
to 100 °C under an argon atmosphere and monitored with TLC for full
conversion. Concentrated hydrochloric acid was carefully added with
vigorous stirring to pH 2. The mixture was diluted with water (100
mL) and extracted with ethyl acetate (3 × 100 mL). The organic layers
were combined, washed with saturated brine, and dried over anhydrous
Na2SO4. After evaporation under reduced pressure, the residue was
subjected to chromatography on silica gel with ethyl acetate/petroleum
ether to give acids 5.
Method C. A mixture of ligand 7a (62 mg, 0.12 mmol), [Ir-
(COD)Cl]2 (40 mg, 0.06 mmol), and NaBARF‚3H2O (170 mg,
0.18 mmol) in CH2Cl2 (3 mL) was stirred in a Schlenk tube under
an argon atmosphere at room temperature for 1 h. TLC and NMR
showed no free ligand remained. Catalyst 1a was isolated in 85% yield
by flash column chromatography on silica gel with CH2Cl2/petroleum
ether.
Asymmetric Hydrogenation of Imines. General Procedure. A
mixture of catalyst 1e (3.8 mg, 2 µmol), substrate 8a (39 mg, 0.2 mmol),
4 Å molecular sieves (MS, 80 mg), and TBME (1 mL) in a Schlenk
tube was stirred under argon at room temperature for 10 min. The
mixture was degassed with three freezing/vacuum cycles and finally
filled with hydrogen in a balloon. The hydrogenation was performed
with stirring at 10 °C for 20 h and monitored with GC (HP-5 column)
for full conversion. The crude product was purified by column
chromatography on a silica gel column with ethyl acetate/petroleum
ether (1:12, v/v) to give pure amine 9a in 99% yield.
General Procedure for the Synthesis of 6. A mixture of acids 5
(1.12 mmol), amino alcohol (3.50 mmol), HOBt (380 mg, 2.48 mmol),
and DCC (664 mg, 3.22 mmol) in THF (60 mL) was stirred under an
argon atmosphere at room temperature. The reaction mixture was
monitored by TLC for a full conversion. After the solvent was
evaporated under reduced pressure, the residue was subjected to
chromatography on silica gel with ethyl acetate/petroleum ether to afford
amides 6.
General Procedure for the Synthesis of Ligands 7. To a solution
of 6 (1.13 mmol), triethylamine (0.34 mL), and 4-methylaminopyridine
(5 mg, 0.041 mmol) in dichloromethane (70 mL) was added methane-
sulfonyl chloride (130 µL) at 0 °C. The mixture was stirred for 30
min, and another portion of triethylamine (1.45 mL) was added. The
resulting mixture was warmed to room temperature. The reaction was
Acknowledgment. We thank the National Natural Science
Foundation of China, the Ministry of Education of China, and
the Committee of Science and Technology of Tianjin City for
financial support.
Supporting Information Available: Analytical data and
spectra of the ligands, complexes, imines; determination of
enantiomeric excesses and graphic for amine products; and
selective X-ray diffraction analysis data, in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA063444P
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