Efficient enantioselective hydrogenation of arylimines using aminophosphine-oxazoline iridium catalysts

Article abstract of DOI:10.1016/j.tetasy.2004.05.015

The preparation and characterization of cationic iridium complexes bearing chiral aminophosphine-oxazoline auxiliaries of general formula [Ir(COD)L*]X [X: PF₆ and B(Ar^F)₄] is reported. These complexes have been applied to the asymmetric hydrogenation of two imines: N-(phenylethylidene)aniline S1 and N-(phenylethylidene)benzylamine S2 providing the corresponding chiral amines in up to 90% and 82% ee, respectively.

Full text of DOI:10.1016/j.tetasy.2004.05.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2159–2163
Efficient enantioselective hydrogenation of arylimines using
aminophosphine-oxazoline iridium catalysts
Catherine Blanc,a Francine Agbossou-Niedercorna,* and Guy Nowogrockib
aLaboratoire de Catalyse de Lille, UMR CNRS 8010, ENSCL, BP 108, 59652 Villeneuve d’Ascq Cedex, France
bLaboratoire de Cristallographie et Physicochimie duSolide, UMR CNRS 8012, ENSCL, BP 108,
59652 Villeneuve d’Ascq Cedex, France
Received 21 April 2004; accepted 6 May 2004
Available online 11 June 2004
Abstract—The preparation and characterization of cationic iridium complexes bearing chiral aminophosphine-oxazoline auxiliaries
of general formula [Ir(COD)L*]X [X: PF6 and B(ArF)4] is reported. These complexes have been applied to the asymmetric
hydrogenation of two imines: N-(phenylethylidene)aniline S1 and N-(phenylethylidene)benzylamine S2 providing the corresponding
chiral amines in upto 90% and 82% ee, respectively.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
example, to reach very high enantioselectivities (up to
>99% ee) in the hydrogenation of acyclic imines cata-
lyzed by Ir-f-Binaphthane complexes.9 On the other
side, the potential of bitopic ligands of the P,N type has
been demonstrated in a multitude of enantioselective
catalytic reactions.1a Particularly, the phosphine-oxaz-
olines (phox ligands) developed initially by Pfaltz,
Williams and Helmchen10 have been applied successfully
in many different processes,11 and induced also high
enantioselectivities in the hydrogenation of imines.12 As
a representative example, N-(phenylethylidene)aniline
and related imines are hydrogenated in the presence of
The highly enantioselective hydrogenation of C@C and
C@O bonds has been accomplished frequently in the
presence of rhodium and ruthenium catalysts.1 Con-
versely, the hydrogenation of imines is often less effec-
tive using identical or closely related catalysts.2;3 Yet, the
reduction of C@N bonds represents an important pro-
cess for obtaining enantiomerically pure amines. In fact,
chiral amines are often important functionalities in
biologically active compounds and they are produced
for industrial purposes.4;5 The largest scale industrial
enantioselective catalytic process involves an imine
hydrogenation reaction. The produced amine is the
precursor to the chiral herbicide (1S)-Metolachlor.6
12a
the mentioned catalysts with upto 89% ee.
We have already reported on the synthesis of a class of
P,N ligands, the aminophosphine-oxazolines (Scheme
1).13 These auxiliaries are readily prepared from two
optically active aminoacids. One is providing the chiral
Among the significant successes met in the area of
enantioselective reduction of imines, Buchwald et al.
have developed an ansa-titanocene catalyst for a highly
effective hydrogenation of cyclic ketimines (upto 98%
ee).7 On the other hand, as mentioned above, several
transition metal catalysts of groupVIII have also been
applied more or less successfully to the hydrogenation of
imines2 but iridium complexes bearing phosphorus
based chiral auxiliaries appeared more appropriate for
that transformation.6;8 Xiao and Zhang were able, for
O
O
N
N
N
N
1a
2a
1b
3a
PPh2
O
PPh2
O
N
N
N
N
PPh2
PPh2
* Corresponding author. Tel.: +33-03-20-43-49-27; fax: +33-03-20-43-
65-85; e-mail: francine.agbossou@ensc-lille.fr
Scheme 1.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.015

2160
C. Blanc et al. / Tetrahedron: Asymmetry 15 (2004) 2159–2163
oxazoline unit and the second one the chiral amino-
phosphine end. Three aminoacids have been selected to
prepare these ligands that is
acid (for ligands 1a and 1b),
1,2,3,4-D-tetrahydroisoquinoline-3-carboxylic acid (for
D
-indoline-2-carboxylic
D-proline (for 2a), and
3a). These ligands appeared to be very efficient in both
the asymmetric allylic alkylation13 and the conjugate
addition to enones.14
Here, we report on the preparation of cationic iridium(I)
complexes bearing aminophosphine-oxazolines and on
their use in the asymmetric hydrogenation of imines.
2. Results and discussion
The cationic iridium complexes 4a, 4b, 5a, and 6a are
easily prepared, in separate experiments, through reac-
tion of 2 equiv of ligands 1a, 1b, 2a, and 3a with 1 equiv
of [Ir(COD)Cl]2 in CH2Cl2 at reflux for 3 h followed by
the exchange of the chloride, which is performed in the
presence of AgPF6 at room temperature. After filtration
of the resulting mixture, the expected complexes are
isolated in high yields (Scheme 2).15
Figure 1. Crystal structure of 7a. The H atom and PF6 are omitted for
clarity.
ium and the two heteroatoms [Ir–N, 2.04(2) vs
ꢀ
ꢀ
2.106(3) A; Ir–P, 2.251(7) vs 2.3009(12) A] are quite
close. Compared to other closely related complexes and
because of the higher flexibility of ligand 1a, there is a
deviation of the chelate ring from planarity and a twist-
boat conformation is observed in 7a. The phenyl rings
are placed in pseudoequatorial and pseudoaxial posi-
tions, as is often encountered in other diphenylpho-
phane complexes.12a
1) [IrCl(COD)]2
+
O
O
H
PF -
(0.5 equiv.)
CH2Cl2
6
N
Ir
N
N
N
P
2) AgPF6
PPh2
Ph2
These iridium complexes were next applied in the
enantioselective hydrogenation of two imines, that is N-
(phenylethylidene)aniline S1, and N-(phenylethylid-
ene)benzylamine S2 (Scheme 4).20 The hydrogenation
results are reported in Table 1. Hydrogenation carried
out on S1 in the presence of the original PHOX auxil-
iary19 is also reported for comparison.
1a
1b
2a
3a
4a
4b
5a
6a
Scheme 2.
We also prepared complex 7a where the PF6 anion has
16
been replaced with B(ArF)4 through reaction of the
intermediate complex toward 4a with sodium tetra-
kis[3,5-bis(trifluoromethyl)phenyl]borate instead of
AgPF6 in a biphasic system (Scheme 3).15 The crystal
structure of 7a has been determined by X-ray diffraction
(Fig. 1).17
Ph
Ph
"IrL*" (cat.)
"IrL*" (cat.)
*
Ph
Ph
N
+ H2
+ H2
Ph
Ph
N
H
S1
*
N
S2
Ph
N
H
Ph
Complex 7a presents characteristics quite similar to
those of other iridium complexes reported in the litera-
ture even though small differences are observed.12a;18 The
complex presents a square-planar as coordination
geometry of the iridium atom. The P–Ir–N angle is
slightly larger than in the analogous PHOX ligand19
(88.0(7)° vs 85.6(1)°). The bond distances between irid-
Scheme 4.
The initial hydrogenation experiments have been carried
out on S1 at room temperature and under 50 bar of
hydrogen for 12 h in dry degassed CH2Cl2 in the presence
-
+B(ArF)4
O
O
1) [IrCl(COD)]2
(0.5 equiv.)
CH2Cl2
N
Ir
N
N
N
P
7a
Ph2
1a
2) NaB(ArF)4
PPh2
Scheme 3.

C. Blanc et al. / Tetrahedron: Asymmetry 15 (2004) 2159–2163
Table 1. Asymmetric hydrogenation of S1 and S2a
2161
Entry
Substrate
Ligand
Complex
PH2 (bar)
Temp( °C)
S/Ir
Conv. (%)b
Ee (%) (Config.)c
1
S1
1a
1b
2a
3a
PHOX
1a
3a
1a
2a
1a
1a
2a
3a
1a
1a
1a
1a
1a
2a
3a
1a
4a
4b
5a
50
50
50
50
50
50
50
50
50
20
5
25
25
25
25
25
25
25
0
50
80
50
50
50
50
30
50
30
50
50
50
30
50
50
50
50
50
50
50
50
98
83
80 (S)
14 (R)
72 (S)
68 (S)
68 (S)
ndg
2
3
100
94
4
5d
6a
e
36
14
f
6
g
7
<5
nd
8
4a
5a
4a
4a
5a
6a
7a
7a
7a
7a
4a
5a
6a
7a
100
82
84 (S)
85 (S)
86 (S)
81 (S)
73 (S)
72 (S)
83 (S)
87 (S)
89 (S)
90 (S)
81 (S)
62 (S)
60 (S)
82 (S)
9
0
10
11
12
13
14
15h
16
17
18
19
20
21
25
25
25
25
25
25
0
100
100
100
91
20
30
50
1
91
39
50
20
50
50
50
50
100
100
100
100
100
100
25
25
25
25
25
S2
a The hydrogenations were carried out during 12 h in freshly distilled CH2Cl2 in the conditions mentioned in the table following the general procedure
given in Ref. 20.
b Conversions were determined by GC and 1H NMR.
c Ee were determined by HPLC using a Chiralcel OD column (hexane/isopropanol: 90/10; 1 mL minÀ1).
d Reaction time of 2 h.
e [Ir(COD)(PHOX)]PF6 prepared as complex 4a from [IrCl(COD)]2 and commercially available (S)-2-(2-diphenylphosphanyl-phenyl)-4-isopropyl-
4,5-dihydro-oxazole.
f The catalyst was prepared in situ by reacting [IrCI(COD)]2 and 1a in toluene.
g Tetra(terbutyl)ammonium iodide was added (10 mol %) to the reaction mixture containing [IrCl(COD)]2 and ligand 3a.
h Reaction time of 4 h.
of 4a and 4b. We found that 4a, which is bearing ligand
1a with a (R) configuration on the oxazoline ring and (S)
on the aminophosphine residue, induced a higher selec-
tivity (80% ee, entry 1) than its diastereomeric complex
4b carrying a ligand with a (S) configuration on the ox-
azoline unit (14% ee, entry 2). In addition, the antipode
amines are obtained with these two chiral auxiliaries.
This clearly points out the great impact of the stereogenic
center of the oxazoline unit on the selectivity of the
reaction. A further variation of the selectivity is expected
while investigating the substituent effect on the stereo-
genic center. Generally, high conversions and good to
high enantioselectivities (over 68% ee) are obtained un-
der 50 bar of H2 at room temperature. The PHOX aux-
iliary is providing an enantioselectivity identical to that
induced by ligand 3a (68% ee) (entries 4 and 5). As al-
ready noticed for the other catalytic reactions (asym-
metric allylic alkylation and conjugate addition to
enones), the more rigid ligands 1a and 2a are leading to
the best results in terms of enantioselectivity.13;14
gand 3a, the process slowed down significantly
(conversion <5%, entry 7). This is not surprising as the
resulting neutral iridium iodide species [IrI{1a}]2 is ex-
pected to exhibit properties close to those of the neutral
complex [IrCl{1a}]2 (entry 6). Also, the beneficial effect
of iodine on the hydrogenation of imines has been re-
ported when neutral catalysts are involved.9 In our case,
the addition of iodine to a catalytic mixture containing
[IrCl{1a}]2 is providing a catalyst inducing less than 5%
ee during the hydrogenation of S1. The temperature and
the hydrogen pressure have an influence on the efficiency
of the process. Indeed, while lowering the temperature
to 0 °C, the selectivity increased for 4a (Dee ¼ 4%, en-
tries 1 and 8) and for 5a (Dee ¼ 12:5%, entries 2 and 9).
On the other side, reducing the hydrogen pressure from
50 to 30 or further to 20 bar led to an increase of the
selectivity. For example, for 4a, a 6% ee increase was
obtained (entries 1 and 10). A similar enhancement was
observed for 6a (Dee ¼ 4%, entries 4 and 13). Lowering
further the hydrogen pressure became detrimental (entry
11). The effect of the counterion of the iridium cationic
complex has been reported in the case of the hydroge-
nation of tetrasubstituted alkenes.21 Thus replacing PF6
by B(ArF)4 enhances generally the selectivity of the
reaction. An identical enhancement of the selectivity has
been obtained while using complex 7a instead of 4a
ðDee ¼ 4%, entries 17 vs 10). Thus, the adjustment of the
catalytic conditions led to 90% ee as the best result
(entry 17).
We next varied the catalytic conditions. For example,
while performing the hydrogenation of S1 with the
neutral precursor [IrCl{1a}]2 prepared in situ in toluene
through reaction of [IrCl(COD)]2 with 1a, the reaction
became very slow (entry 6). On the other side, when
terbutylammonium iodide was added to the catalytic
mixture (entry 7) containing the neutral precatalyst ob-
tained from a reaction between [IrCl(COD)]2 with li-

2162
C. Blanc et al. / Tetrahedron: Asymmetry 15 (2004) 2159–2163
Transition Metals for Organic Synthesis; Beller, M., Bolm,
C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, p69.
6. (a) Togni, A. Angew. Chem., Int. Ed. 1996, 35, 1475; (b)
Spindler, F.; Blaser, H. U. Enantiomer 1999, 4, 557; (c)
Blaser, H.-U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer,
M.; Togni, A. Top. Catal. 2002, 19, 3.
7. (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc.
1992, 114, 7562; (b) Willoughby, C. A.; Buchwald, S. L.
J. Org. Chem. 1993, 58, 7627; (c) Willoughby, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952; (d)
Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc.
1994, 116, 11703.
Substrate S2 (N-(phenylethylidene)benzylamine) was also
hydrogenated efficiently in the presence of the cationic
iridium precatalysts but with a slightly lower selectivity
than S1, that is from 62% to 82% ee (entries 18–21). For
this substrate S2, again complexes 4a and 7a, which are
bearing the more rigid and more sterically demanding
ligand of the series, 1a, are providing the best results.
3. Conclusion
8. (a) Chan, Y. N. C.; Osborn, J. A. J. Am. Chem. Soc. 1990,
112, 9400; (b) Spindler, F.; Pugin, B.; Blaser, H. U. Angew.
Chem., Int. Ed. Engl. 1990, 29, 558; (c) Morimoto, T.;
Nakajima, N.; Achiwa, K. Synlett 1995, 748; (d) Tani, K.;
Onouchi, J.; Yamagata, Y.; Kataoka, Y. Chem. Lett. 1995,
955; (e) Satoh, K.; Inenaga, M.; Kanai, K. Tetrahedron:
Asymmetry 1998, 9, 2657; (f) Cahill, J. P.; Lightfoot, A. P.;
Goddard, R.; Rust, J.; Guiry, P. J. Tetrahedron: Asymme-
try 1998, 9, 4307; (g) Broger, E. A.; Burkart, W.; Hennig,
M.; Scalone, M.; Schmid, R. Tetrahedron: Asymmetry
In conclusion, we have demonstrated that cationic irid-
ium complexes with chiral aminophosphine-oxazolines
are efficient catalysts for the enantioselective hydroge-
nation of imines. The complexes are readily accessible
and air-stable. In the hydrogenation of N-(phenylethyl-
idene)aniline S1, upto 90% ee could be reached. The
hydrogenation of substrate S2 provided the corre-
sponding amine with up to 82% ee. These chiral induc-
tions compare very well to the best results obtained with
phosphine-oxazolines on the same substrates. The sub-
strate scope for imine hydrogenation as well as applica-
tions of this family of ligands to other asymmetric
transformations are under investigation in our labora-
tory.
~
1998, 9, 4043; (h) Guiu, E.; Munoz, B.; Castillon, S.;
Claver, C. Adv. Synth. Catal. 2003, 345, 169.
ꢁ
9. Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40,
3425.
10. (a) Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1993, 32, 566; (b) Dawson, G. J.; Frost, C. G.; Williams, J.
M. J. Tetrahedron Lett. 1993, 34, 3194; (c) Sprinz, J.;
Helmchen, G. Tetrahedron Lett. 1993, 34, 1769.
11. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
Acknowledgements
ꢁ ^
12. (a) Schnider, P.; Koch, G.; Pretot, R.; Wang, G.; Bohnen,
€
F. M.; Kruger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887;
(b) Kainz, S.; Brikmann, A.; Leitner, W.; Pfaltz, A. J. Am.
Chem. Soc. 1999, 121, 6421; (c) Pfaltz, A. Chimia 2001, 55,
708; (d) Cozzi, P. G.; Menges, F.; Kaiser, S. Synlett 2003,
833.
We thank CNRS and MEN (grant to C.B.) for financial
support.
13. Blanc, C.; Hannedouche, J.; Agbossou-Niedercorn, F.
Tetrahedron Lett. 2003, 44, 6469.
References and notes
14. Blanc, C.; Agbossou-Niedercorn, F. Tetrahedron: Asym-
metry 2004, 15, 757.
15. Iridium complexes 31P NMR (121 MHz, CD2Cl2, d ppm):
4a: 51.0 (s); 4b: 51.0 (s); 5a: 51.3 (s); 6a: 51.0 (s); 7a: 51.3
1. (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed., 2nd ed.;
Wiley-VCH: New York, 2000; (b) Comprehensive Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 1999; (c) Noyori, R.; Ohkuma,
T. Angew. Chem., Int. Ed. 2001, 40, 40; (d) Blaser, H. U.;
Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Sterder, M.
Adv. Synth. Catal. 2003, 345, 103.
(s). 7a: 1H NMR (300 MHz, CD2Cl2):
d 0.21 (d,
J ¼ 6:6 Hz, 3H); 0.73 (d, J ¼ 7:1 Hz, 3H); 0.92 (m, 2H);
1.28 (m, 3H); 1.58 (m, 2H); 1.84 (m, 1H); 2.13 (m, 2H);
2.48 (m, 4H); 3.00 (m, 1H); 3.38 (m, 1H); 3.70 (m, 2H);
4.08 (m, 1H); 4.36 (m, 1H); 4.58 (dd, J ¼ 4:9 and 9.5 Hz,
1H); 4.67 (t, J ¼ 9:8 Hz, 1H); 4.98 (m, 1H); 5.18 (m, 1H);
5.73 (m, 1H); 5.82 (d, J ¼ 7:8 Hz, 1H); 6.73 (t, J ¼ 7:8 Hz,
1H); 6.85 (m, 1H); 7.23 (d, J ¼ 6:8 Hz, 1H); 7.34–7.45 (m,
8H); 7.82 (m, 3H).
ꢁ
ꢁ
2. (a) Bakos, J.; Toth, I.; Heil, B.; Marko, I. J. Organomet.
Chem. 1985, 279, 23; (b) Becalski, A. G.; Cullen, W. R.;
Fryzuk, M. D.; James, B. R.; Kang, G.-J.; Rettig, S. J.
Inorg. Chem. 1991, 30, 5002; (c) Bakos, J.; Orosz, A.; Heil,
B.; Laghmari, M.; Lhoste, P.; Sinou, D. J. Chem. Soc.,
Chem. Commun. 1991, 1684; (d) Amrami, Y.; Leconte, L.;
Sinou, D.; Bakos, J.; Toth, I.; Heil, B. Organometallics
1989, 8, 542; (e) Lensink, C.; de Vries, J. G. Tetrahedron:
Asymmetry 1992, 3, 235; (f) Tararov, V. I.; Kadyrov, R.;
16. Nishida, H.; Takada, N.; Yoshimura, M.; Sonoda, T.;
Kobayashi, H. Bull. Chem. Soc. Jpn. 1984, 57, 2600; For
reviews on ‘noncoordinating’ ions, see: (a) Strauss, S. H.
Chem. Rev. 1993, 93, 927; (b) Krossing, I.; Raabe, I.
Angew. Chem., Int. Ed. 2004, 43, 2066.
€
Riermeier, T. H.; Holz, J.; Borner, A. Tetrahedron:
17. Burnett, M. N.; Johnson, C. K. ORTEP-III: Oak Ridge
Thermal Ellipsoid Plot Program for Crystal Structure
Illustrations, Oak Ridge National Laboratory Report
ORNL-6895, 1996. CCDC number 238864.
18. Menges, F.; Pfaltz, A. Adv. Synth. Catal. 2002, 344, 40.
19. PHOX auxiliary used: commercially available (S)-2-
(2-diphenylphosphanyl-phenyl)-4-isopropyl-4,5-dihydro-
oxazole.
Asymmetry 1999, 10, 4009; (g) Sablong, R.; Osborn,
J. A. Tetrahedron Lett. 1996, 37, 4937.
3. For transfer hydrogenation of imines, see: (a) Uematsu,
N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 4916; (b) Mao, J.; Baker, D. C.
Org. Lett. 1999, 1, 841; (c) Vedejs, E.; Trapencieris, P.;
Suna, E. J. Org. Chem. 1999, 64, 6724.
4. Imwinkelried, R. Chimia 1997, 51, 300.
5. (a) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.;
20. General procedure for the iridium-catalyzed hydrogena-
tion of imines: A glass flask equipped with a magnetic
stir bar was charged with N-(phenylethylidene)aniline
S1 (70 mg, 0.35 mmol) and placed in a stainless-steel
€
Keßeler, M.; Sturmer, R.; Zelinski, T. Angew. Chem., Int.
Ed. 2004, 43, 788; (b) Spindler, F.; Blaser, H.-U. In

C. Blanc et al. / Tetrahedron: Asymmetry 15 (2004) 2159–2163
2163
autoclave (50 mL). The autoclave was purged with N2.
Under nitrogen, precatalyst 4a (6 mg, 0.007 mmol) was
dissolved in freshly distilled and degassed methylene
chloride (5 mL) and transferred via cannula to the
autoclave. Then, the autoclave was pressurized with H2
(50 bar) and stirred overnight at room temperature. After
depressurization and evaporation of the solvent, the
resulting slurry was filtered through a short pad of silica
gel. The hydrogenated product (S)-N-phenyl-1-phenyl-
ethylamine was isolated in 96% yield (68 mg). The
enantiomeric excess was determined by HPLC using a
Chiralcel OD column (i-PrOH/hexane: 90/10; flow rate:
1 mL/min; detection UV at 254 nm; tRðSÞ ¼ 9:6 min,
tRðRÞ ¼ 11:3 min).
21. Lightfoot, A.; Schider, P.; Pfaltz, A. Angew. Chem., Int.
Ed. 1998, 37, 2897.