Chiral phosphine-phosphoramidite ligands for highly efficient Ir-catalyzed asymmetric hydrogenation of sterically hindered N-arylimines

Article abstract of DOI:10.1021/ol301618r

A mild and general iridium-catalyzed, highly enantioselective hydrogenation of sterically hindered N-arylimines with a new H₈-BINOL-derived phosphine-phosphoramidite ligand has been developed. The present catalytic system features high turnover numbers (up to 100000) and good to perfect enantioselectivities (up to 99% ee) for the hydrogenation of a variety of sterically hindered N-arylimines.

Full text of DOI:10.1021/ol301618r

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3554–3557
Chiral PhosphineÀPhosphoramidite
Ligands for Highly Efficient Ir-Catalyzed
Asymmetric Hydrogenation of Sterically
Hindered N-Arylimines
Chuan-Jin Hou,†,‡ Ya-Hui Wang,† Zhuo Zheng,† Jie Xu,† and Xiang-Ping Hu*,†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan
Road, Dalian 116023, China, and School of Light Industry and Chemical Engineering,
Dalian Polytechnic University, 1 Qinggongyuan, Dalian 116034, China
xiangping@dicp.ac.cn
Received June 12, 2012
ABSTRACT
A mild and general iridium-catalyzed, highly enantioselective hydrogenation of sterically hindered N-arylimines with a new H8-BINOL-derived
phosphineÀphosphoramidite ligand has been developed. The present catalytic system features high turnover numbers (up to 100000) and good
to perfect enantioselectivities (up to 99% ee) for the hydrogenation of a variety of sterically hindered N-arylimines.
Chiral amines are important synthetic intermediates in
the preparation of many physiologically active com-
pounds. As a result, significant efforts have been devoted
to the asymmetric synthesis of these compounds via cata-
lytic methods.1 For its inherent efficiency and atom econ-
omy, catalytic asymmetric hydrogenation of prochiral
imines has emerged as one of the most direct and con-
venient approaches to chiral amines and their derivatives.2
Todate, a variety of imine frameworks includingcyclicand
acyclic imines have proven to be suitable substrates.3 How-
ever, asymmetric hydrogenation of sterically hindered
imines remains scarely explored,4 despite the fact that the
corresponding chiral amines are important building blocks
in organic synthesis and agrochemistry. Except for a
relevant example on the industrial production of the key
intermediate for chiral herbicide (S)-metolachlor,5 the
most impressive example in this area was described by
Zhang et al.,6 in which high enantioselectivities were
observed in the hydrogenation of some sterically hindered
N-arylalkylarylimines employing an Ir catalyst with a
ferrocenyldiphosphine ligand, (R,R)-f-binaphane. How-
ever, incomplete conversion was observed by using 2 mol %
of a IrÀf-binaphane complex and under a H2 pressure of
1000 psi. In addition, this catalytic system failed in the
hydrogenation of sterically hindered N-aryldialkylimines.
Therefore, the development of a highly efficient catalytic
system that successfully addressed the challenges of low
reactivity, narrow substrate scope, and harsh hydrogena-
tion conditions encountered in the hydrogenation of
† Dalian Institute of Chemical Physics.
‡ Dalian Polytechnic University.
(1) Chiral Amine Synthesis: Methods, Developments and Applications;
Nugent, T. C., Ed.; Wiley-VCH: Weinheim, 2010.
(2) Blaser, H.-U.; Spinder, F. In Handbook of Homogeneous Hydro-
genation; de Vries, J. G.; Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007.
(3) For recent reviews, see: (a) Fleury-Bregeot, N.; de la Fuente, V.;
Castillon, S.; Claver, C. ChemCatChem 2010, 2, 1346–1371. (b) Xie,
J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713–1760.
(4) (a) Chan, Y. N. C.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112,
9400–9401. (b) Sablong, R.; Osborn, J. A. Tetrahedron: Asymmetry
1996, 7, 3059–3062. (c) Schnider, P.; Koch, G.; Pretot, R.; Wang, G.;
Bohnen, F. M.; Kruger, C.; Pfaltz, A. Chem.;Eur. J. 1997, 3, 887–892.
(d) Blaser, H.-U.; Buser, H.-P.; Hausel, R.; Jalett, H.-P.; Spindler, F.
J. Organomet. Chem. 2001, 621, 34–38.
(5) (a) Blaser, H.-U.; Buser, H.-P.; Loers, K.; Hanreich, R.; Jalett,
H. P.; Jelsch, E.; Pugin, B.; Schneider, H. D.; Spindler, F.; Wagmann, A.
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r
10.1021/ol301618r
Published on Web 06/27/2012
2012 American Chemical Society

sterically hindered imines would represent a significant
advancement.
Recently, we have developed a family of unsymmetrical
hybrid phosphineÀphosphoramidite ligands, (Sc,Sa)-PEA-
Phos 1 and (Rc,Ra)-THNAPhos 2 (Figure 1), which are
highly efficient for the Rh-catalyzed asymmetric hydroge-
nation of various functionalized olefins.7 A drive to further
explore the potential of these ligands prompted us to
investigate its application in the Ir-catalyzed asymmetric
hydrogenation of imines, focusing on the challenging
sterically hindered N-arylimines. Although phosphineÀ
phosphoramidite ligands can generate highly active and
enantioselective catalysts with different metal centers,8À13
to the best of our knowledge, their application in the Ir-
catalyzed asymmetric hydrogenation of acyclic imines has
not yet been reported. Herein we described a mild and
general iridium-catalyzed, highly enantioselective hydro-
genation of sterically hindered N-arylimines with a new
H8-BINOL-derived phosphineÀphosphoramidite ligand,
in which high turnover numbers (up to 100000) and good
to excellent enantioselectivities (up to 99% ee) were
achieved.
Figure 1. Chiral phosphineÀphosphoramidite ligands (Sc,Sa)-
PEAPhos 1, (Rc,Ra)-THNAPhos 2, and (Rc,Ra)-3.
in the presence of 1 mol % of catalyst prepared in situ
from [Ir(COD)Cl]2 and 2.2 equiv of chiral ligand with KI
as an additive and under a H2 pressure of 60 bar, and
some representative results are shown in Table 1. To our
delight, (Sc,Sa)-PEAPhos 1a displayed a promising per-
formance in this challenging hydrogenation, in which
full conversion and 88% ee were achieved (entry 1).
However, the use of (Sc,Sa)-PEAPhos 1b and (Rc,Ra)-
THNAPhos 2 gave incomplete conversion, although a
slightly improved ee value was observed with (Sc,Sa)-
PEAPhos 1b (entries 2 and 3). These results suggested
that the increased steric hindrance on the amino moiety
and chiral carbon center of this ligand motif had a
negative effect on the catalytic activity. We therefore
decided to modify the binaphthyl backbone in a purpose
to further improve the overall catalytic performance.
New H8-BINOL derived phosphine-phosphoramidite
ligands, (Rc,Ra)-3a and (Rc,Ra)-3b, were then prepared
and subjected to the model hydrogenation. The partially
hydrogenated naphthalene rings contain sp3 hybridized
carbons that can increase the steric bulkiness of bi-
naphthyl frameworks and change the biaryl dihedral
angle, which may be beneficial to improve the
enantioselectivity.14 Using 3a as the ligand, the substrate
was fully converted with 97% ee (entry 4). Again, the
introduction of a methyl group into the amino moiety of
ligand led to a devastating decrease in catalytic activity
(<10% conversion) (entry 5). These results indicated
that the presence of an N-H proton on the amino moiety
and a H8-binaphthyl moiety on this ligand motif is
crucial for achieving high catalytic activity and enan-
tioselectivity in this challenging hydrogenation. Better
results obtained with the ligand bearing an N-H proton
are presumably caused by the substrate orientation from
a hydrogen bond between the ligand and the substrate as
proposed by Reek et al.15
With N-(2,6-dimethylphenyl)-1-phenylethylidenea-
mine 4a as a model substrate, an initial attempt at the
Ir-catalyzed asymmetric hydrogenation was carried out
(7) (a) Huang, J.-D.; Hu, X.-P.; Duan, Z.-C.; Zeng, Q.-H.; Yu, S.-B.;
Deng, J.; Wang, D.-Y.; Zheng, Z. Org. Lett. 2006, 8, 4367–4370.
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Z.-C.; Xu, X.-F.; Zheng, Z. Angew. Chem., Int. Ed. 2007, 46, 7810–7813.
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(8) For Rh-catalyzed asymmetric reactions, see: (a) Francio, G.;
Faraone, F.; Leitner, W. Angew. Chem., Int. Ed. 2000, 39, 1428–1430.
(b) Jia, X.; Li, X.; Lam, W. S.; Kok, S. H. L.; Xu, L.; Lu, G.; Yeung,
C.-H.; Chan, A. S. C. Tetrahedron: Asymmetry 2004, 15, 2273–2278.
(c) Hu, X.-P.; Zheng, Z. Org. Lett. 2004, 6, 3585–3588. (d) Hu, X.-P.;
Zheng, Z. Org. Lett. 2005, 7, 419–422. (e) Vallianatou, K. A.; Kostas,
I. D.; Holz, J.; Boner, A. Tetrahedron Lett. 2006, 47, 7947–7950.
(f) Zhang, W.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 5515–5518.
(g) Zhang, W.; Zhang, X. J. Org. Chem. 2007, 72, 1020–1023. (h) Yan,
Y.; Zhang, X. J. Am. Chem. Soc. 2006, 128, 7198–7202. (i) Wassenaar, J.;
Kuil, M.; Reek, J. N. H. Adv. Synth. Catal. 2008, 350, 1610–1614.
(j) Wassenaar, J.; Reek, J. N. H. J. Org. Chem. 2009, 74, 8403–8406.
(k) Yu, S.-B.; Huang, J.-D.; Wang, D.-Y.; Hu, X.-P.; Deng, J.; Duan,
Z.-C.; Zheng, Z. Tetrahedron: Asymmetry 2008, 19, 1862–1866.
(l) Wassenaar, J.; Kuil, M.; Lutz, M.; Spek, A. L.; Reek, J. N. H.
Chem.;Eur. J. 2010, 16, 6509–6517. (m) Wassenaar, J.; de Bruin, B.;
Reek, J. N. H. Organometallics 2010, 29, 2767–2776. (n) Pullmann, T.;
Engendahl, B.; Zhang, Z.; Holscher, M.; Zanotti-Gerosa, A.; Dyke, A.;
Francio, G.; Leitner, W. Chem.;Eur. J. 2010, 16, 7517–7526.
(o) Hintermair, U.; Hofener, T.; Pullmann, T.; Francio, G.; Leitner,
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Yu, S.; Ji, B.; Zhang, X. Chem.;Eur. J. 2010, 16, 871–877. (q) Zhang,
X.; Cao, B.; Yu, S.; Zhang, X. Angew. Chem., Int. Ed. 2010, 49, 4047–
4050. (r) Chikkali, S. H.; Bellini, R.; de Bruin, B.; van der Vlugt, J. I.;
Reek, J. N. H. J. Am. Chem. Soc. 2012, 134, 6607–6616.
(9) For Ru-catalyzed asymmetric reaction, see: Burk, S.; Francio, G.;
Leitner, W. Chem. Commun. 2005, 3460–3462.
(10) For Ag-catalyzed asymmetric reaction, see: Yu, S.-B.; Hu, X.-P.;
Deng, J.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry
2009, 20, 621–625.
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D.; Clavier, H.; Crevisy, C.; Mauduit, M. Tetrahedron: Asymmetry 2006,
17, 2726–2729. (b) Hou, C.-J.; Guo, W.-L.; Hu, X.-P.; Deng, J.; Zheng,
Z. Tetrahedron: Asymmetry 2011, 22, 195–199.
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van Zutphen, S.; Mora, G.; Le Floch, P.; Siegler, M. A.; Spek, A. L.;
Reek, J. N. H. Organometallics 2009, 28, 2724–2734. (b) Wassenaar, J.;
Jansen, E.; van Zeist, W.-J.; Bickelhaupt, F. M.; Siegler, M. A.; Spek,
A. L.; Reek, J. N. H. Nat. Chem. 2010, 2, 417–421.
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(13) For Rh-, Ru-, Ir-catalyzed asymmetric hydrogenation, see:
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Org. Lett., Vol. 14, No. 13, 2012
3555

Table 1. Ligand Screeninga
Table 2. Screening of Hydrogenation Conditionsa
entry
ligand
convb (%)
eec (%)
entry
additive
solvent
H2 (bar)
convb (%)
eec (%)
1
2
3
4
5
(Sc,Sa)-1a
(Sc,Sa)-1b
(Rc,Ra)-2
>99
84
88
90
51
1
2
none
KI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
toluene
THF
60
60
60
60
60
60
60
20
90
20
20
20
60
80
33
>99
>99
84
61
97
96
83
89
61
59
97
86
3
I2
(Rc,Ra)-3a
(Rc,Ra)-3b
>99
<10
97
d
4
NIS
Bu4NI
CSA
PA
5
75
6
14
a Hydrogenation was carried out with 5 mol % of KI and 1 mol % of
Ir catalyst at rt for 24 h, unless otherwise specified. b Determined by GC.
c Determined by HPLC using a chiral stationary phase. d Not determined
due to low conversion.
7
24
8
KI
>99
>99
<10
12
9
KI
97
d
10
11
12
13e
14f
KI
KI
80
91
97
93
The success of (Rc,Ra)-3a encouraged us to investigate
the effects of the additive, solvent, and H2 pressure to
obtain optimal conditions, and some representative results
are shown in Table 2. Initially, the additive was investi-
gated because of its significant influence on the asymmetric
catalysis.16 In Zhang’s report, the additive was deleterious
to the Ir-catalyzed hydrogenation of sterically hindered
imines, resulting in dramatically decreased conversion and
enantioselectivity.6 Our study disclosed, however, that the
use of various I additives could significantly increase the
reactivity and enantioselectivity. Thus, without any addi-
tives, the Ir/(Rc,Ra)-3a catalyst showed low activity and
moderate enantioselectivity (entry 1). By use of KI, I2,
Bu4NI, and NIS, significantly increased performance was
obtained (entries 2À5). Among these I additives, KI and I2
were optimal, by which perfect performance was achieved
(entries 2 and 3). Except for I additives, however, other
additives tested proved to have no positive effect on this
hydrogenation (entries 6 and 7). H2 pressure showed no
apparent effect on the catalytic performance. Full conver-
sions and 97% ee were achieved no matter the hydrogena-
tion was performed under a H2 pressure of 20, 60, or 90 bar
(entries 2, 8, and 9). The effect of the solvent was next
investigated, and an obvious solvent dependency was
observed. However, no result surpassed that obtained in
CH2Cl2 (entries 10À12). Lowering the catalyst loading to
0.1 mol % had no effect in the hydrogenation performance
(entry 13). Good performance (>99% conversion and
93% ee) can be achieved even when the hydrogenation
was performed at a catalyst loading of 0.01 mol % (entry
14), representing the most efficient catalytic system in the
hydrogenation of sterically hindered N-arylalkylaryli-
mines reported so far.
KI
46
KI
CH2Cl2
CH2Cl2
>99
>99
KI
a Hydrogenation was carried in CH2Cl2 with 5 mol % of KI and
1 mol % of Ir catalyst at rt for 24 h, unless otherwise specified.
b Determined by GC. c Determined by HPLC using a chiral stationary
phase. d Not determined. e Using 0.1 mol % of Ir catalyst. f Using
0.01 mol % of Ir catalyst at 90 °C for 36 h.
this catalytic system was efficient to a variety of N-arylalk-
ylarylimines, N-aryldialkylimines, and R-imino esters,
which were hydrogenated in good to excellent enantios-
electivities. For N-arylalkylarylimines 4aÀh, the hydroge-
nations proceeded to completion and afforded the cor-
responding chiral amines in high yields (92À99%) and
excellent enantioselectivities (95À99% ee) (entries 1À8).
The electronic property of the substituent on the phenyl
ring showed a limited influence on the enantioselectivity.
Outstanding selectivity of up to 99% ee was achieved in the
hydrogenation of 1-(3-nitrophenyl)ethylideneamine 4f
(entry 6). It is noteworthy that the hydrogenations of
N-aryldialkylimines 4iÀk were conducted smoothly with
good enantioselectivities (69%, 88% ee, and 96% ee,
respectively), representing the best result reported so far
(entries 9À11). More importantly, the present catalytic
system was efficient for the hydrogenation of methyl
2-(2,6-dimethylphenylimino)propanoate 4l, providing the
corresponding amino acid derivative 5l in 86% ee, which is
the first successful example in the Ir-catalyzed asymmetric
hydrogenation of R-imino ester substrates (entry 12).
Methyl 2-(2,6-dimethylphenylamino)propanoate 5l can
be used as an intermediate for the preparation of the
fungicide (S)-metalaxyl. The hydrogenation of the sub-
strate bearing a β-substituent proved to be more difficult.
Performing the hydrogenation at 60 °C and under a H2
pressure of 80 bar for 36 h, the substrate 4m with a
β-methyl group could be hydrogenated completely in
90% ee (entry 13). These results demonstrated high effi-
ciency of the present Ir/(Rc,Ra)-3a catalytic system in the
hydrogenation of sterically hindered imines.
Having established the optimized hydrogenation condi-
tions, we then examined the scope of this Ir/(Rc,Ra)-3a
catalytic system by employing a range of sterically hin-
dered N-arylimines. The results in Table 3 indicated that
(16) For a review, see: Fagnou, K.; Lautens, M. Angew. Chem., Int.
Ed. 2002, 41, 26–47.
3556
Org. Lett., Vol. 14, No. 13, 2012

Table 3. Substrate Scope of Sterically Hindered Iminesa
entry
imine
yieldb (%) eec (%)
1
2
4a: R1 = Ph, R2 = H
98
98
98
98
99
98
98
92
94
97
95
96
97
97
97
98
96
96
99
98
95
69
88
96
86
90
4b: R1 = 4-MeC6H4, R2 = H
4c: R1 = 4-ClC6H4, R2 = H
4d: R1 = 4-BrC6H4, R2 = H
4e: R1 = 4-NO2C6H4, R2 = H
4f: R1 = 3-NO2C6H4, R2 = H
4g: R1 = 3-MeOC6H4, R2 = H
4h: R1 = 6-MeO-2-naphthyl, R2 = H
4i: R1 = Et, R2 = H
3
4d
5
Figure 2. Effect of N-aryl group on the hydrogenation.
Scheme 1. Synthesis of Chiral Herbicide (1S)-Metolachlor
6
7
8
9
10d
11
12
13e
4j: R1 = i-Pr, R2 = H
4k: R1 = MeOCH2, R2 = H
4l: R1 = CO2Me, R2 = H
4m: R1 = Ph, R2 = Me
a All hydrogenations were carried out with 5 mol % of KI and 1 mol %
of Ir catalyst at rt for 24 h, unless otherwise specified. b Yields of isolated
product. c Determined by HPLC or GC using a chiral stationary phase.
d Performed at 60 °C under a H2 pressure of 60 bar. e Performed at 60 °C
under a H2 pressure of 80 bar for 36 h.
A different N-aryl group on the imine substrates was
also investigated under the optimized conditions, and
some representative results are showed in Figure 2. No
apparent effect on the catalytic activity and enantioselec-
tivity was observed. Besides various sterically hindered
N-aryl groups, the substrate 4q with an N-phenyl substituent
was also suitable to this hydrogenation, giving the hydro-
genation product 5q in 95% ee and 96% yield.
A practical application of this methodology as the key
step in the enantioselective synthesis of the chiral herbicide
(1S)-metolachlor was examined as shown in Scheme 1. The
hydrogenation was performed on a 50 g scale at 100 °C for
18 h under a H2 pressure of 80 bar with Bu4NI as the
additive by employing a catalyst loading of 0.001 mol %
(S/C = 100000). MEA imine 6 was completely trans-
formed into the corresponding MEA amine 7 in up to
80% ee. Restricted by the hydrogenation apparatus in our
laboratory, we did not investigate the feasibility of the
hydrogenation of MEA imine 6 under lower catalyst
loading. Because of the ready availability and the low cost
of chiral ligand, the present catalytic system should be a
competent alternative for the use in the industrial produc-
tion of chiral herbicide (1S)-metolachlor.
suggested that the presence of an N-H proton and a H8-
binaphthyl moiety on the ligand motif is crucial for this
hydrogenation to obtain high catalytic activity and enan-
tioselectivity. The present catalytic system features high
turnover numbers (up to 100000) and good to perfect
enantioselectivities (up to 99% ee) for the hydrogenation
of a variety of sterically hindered N-arylimines, represent-
ing the most versatile catalyst in the hydrogenation of
sterically hindered imines. The utility of this catalytic
system was demonstrated by the synthesis of the chiral
herbicide (1S)-metolachlor at a catalyst loading of 0.001
mol %. Further application of the present catalytic system
is still underway.
Acknowledgment. Support for this research from the
Dalian Institute of Chemical Physics (CAS) and the
Planned Science and Technology Project of Dalian
(2011J21DW010) is gratefully acknowledged.
Supporting Information Available. Experimental de-
tails, characterization data, NMR spectra, and HPLC or
GC data for ee analysis. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a mild, practical, and
general iridium-catalyzed, highly enantioselective hydro-
genation of sterically hindered N-arylimines with a new
chiral phosphineÀphosphoramidite ligand. The results
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3557