Application of monodentate secondary phosphine oxides, a new class of chiral ligands, in Ir(I)-catalyzed asymmetric imine hydrogenation

Article abstract of DOI:10.1021/ol034282u

(Matrix presented) Secondary phosphine oxides were prepared from R ¹PCl₂ and R²MgBr, followed by hydrolysis. They were obtained in an enantiopure form by preparative chiral HPLC. These new monodentate ligands were tested in the iridium-catalyzed hydrogenation of imines at 25 bar. Enantioselectivities up to 76% were obtained at L/lr = 2. Addition of pyridine (Pyr/lr = 1:2) raised the ee to 83%. Using pyridine as an additive allowed reduction of the L/lr ratio to 1 without reduction of ee.

Full text of DOI:10.1021/ol034282u

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1503-1506
Application of Monodentate Secondary
Phosphine Oxides, a New Class of
Chiral Ligands, in Ir(I)-Catalyzed
Asymmetric Imine Hydrogenation
,†
,†
Xiao-bin Jiang,† Adriaan J. Minnaard,* Bart Hessen,† Ben L. Feringa,*
Alexander L. L. Duchateau,‡ Jean G. O. Andrien,‡ Jeroen A. F. Boogers,‡ and
,†,‡
Johannes G. de Vries*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747AG Groningen, The Netherlands, and
DSM Research, Life Sciences s AdVanced Synthesis & Catalysis, P.O. Box 18,
6160 MD Geleen, The Netherlands
hans-jg.Vries-de@dsm.com
Received February 18, 2003
ABSTRACT
1
2
Secondary phosphine oxides were prepared from R PCl2 and R MgBr, followed by hydrolysis. They were obtained in an enantiopure form by
preparative chiral HPLC. These new monodentate ligands were tested in the iridium-catalyzed hydrogenation of imines at 25 bar.
Enantioselectivities up to 76% were obtained at L/Ir ) 2. Addition of pyridine (Pyr/Ir ) 1:2) raised the ee to 83%. Using pyridine as an additive
allowed reduction of the L/Ir ratio to 1 without reduction of ee.
Asymmetric catalysis is in principle the most desirable
method for producing enantiopure chemicals.1 This is due
to the high atom economy as compared to methods based
on the resolution of racemates. Asymmetric hydrogenation,
based on the use of enantiopure transition metal complexes
as catalysts, has been particularly prevalent in the past 30
years, and many successful examples are known.2 However,
recent analyses show that the application of asymmetric
hydrogenation for the production of fine chemicals is
limited.3,4 Two major factors that hamper its use are the cost
and the availability of the catalysts, in particular of the ligand
that is often prepared in a tedious multistep synthesis. For
this reason, we have embarked on a program aimed at the
development of enantiopure ligands that are easily prepared
(2) (a) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; VCH Publishers, Inc.: New York, 2000;
p 1. (b) Laneman, S. A. In Handbook of Chiral Chemicals; Ager, D. J.,
Ed.; Marcel Dekker: New York, 1999; p 143. (c) Brown, J. M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H. Eds.; Springer: Berlin, 1999; Vol. 1, p 121. (d) Bo¨rner, A.; Holz,
J. In Transition Metals for Organic Synthesis. Building Blocks and Fine
Chemicals; Beller, M., Bolm, C. Eds.; Wiley-VCH: Weinheim, Germany,
1998; Vol. 2, p 3. (e) Burk, M. J.; Bienewald, F. In Transition Metals for
Organic Synthesis. Building Blocks and Fine Chemicals; Beller, M., Bolm,
C.; Wiley-VCH: Weinheim, Germany, 1998; Vol. 2, p 13. (f) No´gra´di, M.
StereoselectiVe Synthesis; VCH: Weinheim, Germany, 1987; p 53. (g)
Koenig, K. E. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic
Press: Orlando, 1985; Vol. 5, p 71.
† University of Groningen.
‡ DSM Research.
(1) Jacobsen, E. N.; Pfaltz, A.; Yamamoto H. ComprehensiVe Asymmetric
Catalysis; Springer-Verlag: Berlin, 1999; Vols. 1-3.
(3) Blaser, H.-U.; Spindler, F.; Studer, M. Appl. Catal., A 2001, 221,
119.
10.1021/ol034282u CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/04/2003

in 1-3 synthetic steps.5 A recent breakthrough has been the
development of monodentate phosphoramidites for the highly
enantioselective hydrogenation of R- and â-dehydroamino
acids6 and enamides.7 Other groups have developed mono-
dentate phosphonites,8 phosphites,9 and phosphines10 that also
perform well in asymmetric hydrogenation.
Scheme 1. Tautomeric Forms of SPOs
An area that remains underdeveloped is the asymmetric
hydrogenation of imines.11 Although catalysts are known that
give rise to high enantioselectivities in the hydrogenation of
acetophenone-based imines such as rhodium/monosulfonated
bdpp12 and of cyclic imines using ansa-titanocene,13 the rate
of these is still too low for industrial use. A very fast iridium
catalyst was developed by Blaser et al. for the asymmetric
hydrogenation of an intermediate for the herbicide (S)-
Metolachlor.14 However, the enantioselectivity did not exceed
80%. Nevertheless, this process is used industrially. Enan-
tioselective transfer hydrogenation of imines has been
developed recently and seems to have great potential.15
In this paper, we report our results on the application of
secondary phosphine oxides,16,17 an entirely new class of
enantiopure monodentate ligands, in the iridium-catalyzed
asymmetric hydrogenation of acetophenone-based imines.
Secondary Phosphine Oxides (SPOs). In solution, SPOs
exist in equilibrium between pentavalent (phosphine oxide
form) and trivalent (phosphinite form) tautomeric structures
(Scheme 1).17 Although at room temperature the phosphine
oxide form is the more stable one,18 it is the phosphinite
form that coordinates to the transition metal.19
SPOs are easily prepared in a two-step one-pot procedure
from readily available starting materials16-20 and are thus
highly suited to a modular or a combinatorial approach. They
are air and moisture stable. Nonchiral or racemic SPOs have
been used as ligands in Pt-catalyzed hydroformylation,21 in
Pt-catalyzed hydrolysis22 and amination23 of nitriles, and in
Pd-catalyzed aromatic substitution reactions.24 Enantiopure
SPOs have been obtained by classical resolution using (S)-
mandelic acid18,25 or a three-step resolution procedure
developed by Chan.26a They do not racemize easily.17 It is
thus very surprising that they have been used only as
intermediates in the preparation of chiral phosphines and
bisphosphines.26 We have not been able to find any reports
on their application in asymmetric catalysis.
(4) de Vries, J. G. In Encyclopedia of Catalysis; Horvath, I. T., Ed.;
John Wiley & Sons: New York, 2003; Vol. 3, p 295. See also the on-line
version: http://www.mrw.interscience.wiley.com/enccat/.
We have prepared a range of monodentate SPOs (1-7)
by reaction of R2MgBr with R1PCl2 (reversed addition)
followed by hydrolysis (Scheme 2). Ligand 8 was prepared
(5) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(6) (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.;
de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000,
122, 11539. (b) van den Berg, M.; Minnaard, A. J.; de Vries, J. G.; Feringa,
B. L. (DSM N. V.). WO 02/04466, 2002. (c) van den Berg, M.; Minnaard,
A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma, A.; Feringa, B.
L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.; Boogers,
J. A. F.; Henderickx, H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003,
345, 308. (d) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J.
Am. Chem. Soc. 2002, 124, 14552. (e) Zeng, Q.; Liu, H.; Mi, A.; Jiang, Y.;
Li, X.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron 2002, 58, 8799.
(7) (a) van den Berg, M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H.
M.; de Vries, J. G.; Feringa, B. L. AdV. Synth. Catal. 2002, 344, 1003. (b)
Jia, X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002,
43, 5541.
Scheme 2. Synthesis of tert-Butyl-phenylphosphine Oxide
(8) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961.
(9) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889.
(10) (a) Guillen, F.; Fiaud, J.-C. Tetrahedron Lett. 1999, 40, 2939. (b)
Junge, K.; Oehme, G.; Monsees, A.; Riermeier, T.; Dingerdissen, U.; Beller,
M. Tetrahedron Lett. 2002, 43, 4977.
from Taddol by treatment with PCl3 followed by hydrolysis.
Ligand 9 was prepared following the procedure of Fiaud et
al. (Figure 1).10a
(11) (a) Spindler, F.; Blaser, H.-U. In Transition Metals for Organic
Synthesis. Building Blocks and Fine Chemicals; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, Germany, 1998; Vol. 2, p 69. (b) Spindler, F.;
Blaser, H.-U. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, p 248.
(12) (a) Bakos, J.; Orosz, A.; Heil, B.; Laghmari, M.; Lhoste, P.; Sinou,
D. J. Chem. Soc., Chem. Commun. 1991, 1684. (b) Lensink, C.; de Vries,
J. G. Tetrahedron: Asymmetry 1992, 3, 235. (c) Lensink, C.; Rijnberg, E.;
de Vries, J. G. J. Mol. Catal. A: Chem. 1997, 116, 199.
(13) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
8952.
(14) (a) Bader, R. R.; Baumeister, P.; Blaser, H.-U. Chimia 1996, 50,
99. (b) Spindler, F.; Pugin, B.; Jalett, H.-P.; Buser, H.-P.; Pittelkow, U.;
Blaser, H.-U. In Catalysis of Organic Reactions; Malz, R. E., Jr., Ed.; Marcel
Dekker: New York, 1996; p 153.
(15) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 4916. (b) Sugi, K. D.; Nagata, T.; Yamada,
T.; Mukaiyama, T. Chem. Lett. 1997, 493.
(16) Kleiner, H.-J. In Houben-Weyl, Methoden der Organischen Chemie,
4 Auflage; Regitz, M., Ed.; Georg Thieme Verlag: Stuttgart, 1982; Band
E1, p 240.
(17) Gallagher, M. J. In The Chemistry of the Organophosphorus
Compounds; Hartley, F. R., Ed.; John Wiley & Sons: Chichester, UK, 1992;
Vol. 2, p 53.
Figure 1. Secondary phosphine oxides.
Org. Lett., Vol. 5, No. 9, 2003
1504

SPO 1 was conveniently resolved using preparative chiral
HPLC. As the separation between the two peaks was very
large (4.3 min), 100 mg could be separated per run. SPOs
2-7 and 9 were all separated in the same manner, although
none of these ligands afforded the same spectacular separa-
tion achieved with 1.
chloride-containing iridium catalyst precursor gave both the
highest rates and the highest enantioselectivity. High rates
were obtained with SPO/Ir ratios of 1, but the enantioselec-
tivity in the hydrogenation of 10 was only 10% (Table 1,
Iridium/SPO-Catalyzed Imine Hydrogenation. It is
conceivable that the acidic proton of SPOs has an accelerat-
ing effect upon the transition metal-catalyzed hydrogenation
of imines.27 We thus tested the hydrogenation of a range of
acetophenone-based imines and N-diphenylphosphinyl-imine
1528 (Figure 2) at 25 bar at room temperature in CH2Cl2.
Table 1. Iridium/SPO-Catalyzed Hydrogenation of Iminesa
entry
imine
ligand
t (h)
conversion (%)b
ee (%)c
1d
2e
3
4f
5g
6
7
8
9
10
10
10
10
10
10
10
10
11
15
17
10
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
6
7
8
9
0.8
24
51
72
114
24
24
48
24
24
100
75
>95
100
89
100
100
>95
>95
100
100
100
10 (S)
45 (S)
69 (S)
4 (S)
70 (S)
7
2
9
51
70
10h
11
12i
1 (R)
1 (R)
1 (R)
24
168
0
76 (S)
a General conditions: [Ir(COD)Cl]2/SPO/imine ) 2.5:10:100, 25 bar H2,
toluene, room temperature. b Conversion was determined by 1H NMR
(CDCl3). c Ee was determined by HPLC (chiralpak AD or OD, heptane/2-
propanol ) 95/5 or 90/10) on the N-acetyl derivatives. Configuration is
unknown when none is shown. d CH2Cl2 as solvent, Ir/1 )1:1. e CH2Cl2
as solvent. f [Ir(COD)2]BF4 as a precursor. g CF3C6H5 as a solvent. h Tem-
perature ) 40 °C. i H2 (1 bar; balloon).
Figure 2. Imines.
Initial tests with [Ir(COD)Cl]2, [Rh(COD)Cl]2, [Ir(COD)2]-
BF4, and [Rh(COD)2]BF4 showed that use of the neutral
entry 1). The enantioselectivity could be increased by raising
the SPO/Ir ratio to 2, though this reduced the rate of the
reaction markedly. Next, a range of solvents (Et2O, EtOAc,
THF, MeOH, iPrOH, benzene, R,R,R-trifluorotoluene, CH3-
CN, and c-hexane) were tested using [Ir(COD)Cl]2/1 in the
hydrogenation of 10. From these tests, toluene and R,R,R-
trifluorotoluene emerged as the best solvents (entries 3 and
5). Changes in the ligand structure did not lead to any
improvement in enantioselectivity (entries 6-9). Of the other
imines tested (entries 9-11), only the phosphinylated imine
15 could be hydrogenated with reasonable enantioselectivity.
The N-phenyl imine 17 always gave racemic product under
a variety of conditions. A rather surprising feature of these
catalysts is their ability to hydrogenate imines at 1 bar H2,
although at this pressure the rate becomes very low (entry
12).
(18) Wang, F.; Polavarapu, P. L.; Drabowitz, J.; Mikolajczyk, M. J. Org.
Chem. 2000, 65, 7561.
(19) (a) Goerlich, J. R.; Fischer, A.; Jones, P. G.; Schmutzler, R., Z.
Naturforsch., B: Chem. Sci. 1994, 49, 801. (b) Heuer, L.; Jones, P. G.;
Schmutzler, R. New J. Chem. 1990, 14, 891. (c) Dixon, K. R.; Tattray, A.
D.; Can. J. Chem. 1971, 49, 3997.
(20) (a) Hoffmann, H.; Schellenbeck, P. Chem. Ber. 1966, 99, 1134. (b)
Farnham, W. B.; Lewis, R. A.; Murray, R. K.; Mislow, J. K. J. Am. Chem.
Soc. 1970, 92, 5808. (c) Horner, L.; Beck, P.; Toscano, V. G. Chem. Ber.
1961, 94, 1317.
(21) Van Leeuwen, P. W. N. M.; Roobeek, C. F. In Homogeneous
Transition Metal Catalalyzed Reactions. Advances in Chemistry Series 230;
American Chemical Society: Washington, DC, 1992; p 367.
(22) Ghaffar, T.; Parkins, A. W. Tetrahedron Lett. 1995, 36, 8657.
(23) Cobley, C. J.; Heuvel, M. van den; Abbadi, A.; de Vries, J. G.
Tetrahedron Lett. 2000, 41, 2467.
(24) (a) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677. (b) Li, G. Y.; Fagan, P. J.; Watson, P. L. Angew. Chem., Int. Ed.
2001, 40, 1513-1516. (c) Li, G. Y. (E. I. Du Pont de Nemours and
Company, USA). U.S. Patent 6,124,462, 2000. (d) Li, G. Y. (E. I. Du Pont
de Nemours and Company, USA). U.S. Patent 6,291,722 B1, 2001.
(25) Drabowicz, J.; Lyzwa, P.; Omelanczuk, J.; Pietrusiewicz, K. M.;
Mikolayczyk, M. Tetrahedron: Asymmetry 1999, 10, 2757.
(26) (a) Haynes, R. K.; Au-Yeung, T. L.; Chan, W. K.; Lam, W. L.; Li,
Z. Y.; Yeung, L. L.; Chan, A. S. C.; Li, P.; Koen, M.; Mitchell, C. R.;
Vonwiller, S. C. Eur. J. Org. Chem. 2000, 3205. (b) Haynes, R. K.; Lam,
W. W.; Yeung, L. L. Tetrahedron Lett. 1996, 37, 4729. (c) Haynes, R. K.;
Lam. W. W.; Williams, I. D.; Yeung, L. L. Chem. Eur. J. 1997, 3, 2052.
(d) Kawashima, T.; Iwanga, H.; Okazaki, R. Chem. Lett. 1993, 1531. (e)
Kawashima, T.; Iwanga, H.; Okazaki, R. Heteroatom Chem. 1995, 6, 235.
(27) It has been suggested that protic solvents are a prerequisite for
rhodium-catalyzed imine hydrogenation since the proton of the solvent
bound to rhodium aids in shifting the imine from its n-bonded form to the
π-bonded form that is required for its migratory insertion into the Rh-H
bond. See: Longley, C.; Goodwin, T. J.; Wilkinson, G. Polyhedron 1986,
5, 1625.
Not satisfied with these results, we decided to test the
effects of additives such as I2,29 n-Bu4NI,30 K2CO3, t-BuOK,
Na2CO3, primary amines,31 phthalimide,32 AgCOOCF3,33 and
(28) Spindler, F.; Blaser, H. U. AdV. Synth. Catal. 2001, 343, 68.
(29) (a) Vastag, S.; Bakos, J.; Toros, S.; Takach, N. E.; King, R. B.;
Heil, B.; Marko, L. J. Mol. Catal. 1984, 22, 283. (b) Spindler, F.; Pugin,
B.; Blaser, H.-U. Angew. Chem., Int. Ed. Engl. 1990, 29, 558. (c) Becalski,
A. G.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kang, G. J.; Rettig, S.
J. Inorg. Chem. 1991, 30, 5002.
(30) Morimoto, T.; Nakajima, N.; Achiwa, K. Synlett 1995, 748.
(31) Murata, S.; Sugimoto, T.; Matsuura, S. Heterocycles 1987, 26, 763.
(32) Morimoto, T.; Suzuki, N.; Achiwa, K. Heterocycles 1996, 43, 2557.
Org. Lett., Vol. 5, No. 9, 2003
1505

with full conversion after 24 h (Table 2, entry 1). Surpris-
ingly, when 1 equiv of ligand was used in combination with
2 equiv of pyridine, the reaction worked equally well (entry
2). This seems to imply that pyridine exerts its effect as a
ligand. When larger amounts of pyridine (5 or 10 equiv) were
used, the hydrogenation proceeded slower with a small drop
in ee. Other pyridine derivatives performed somewhat more
poorly. A slight improvement in ee could be obtained by
lowering the temperature to 0 °C, though at the expense of
rate (entries 4, 5). Substituted N-benzyl acetophenone imines
could all be hydrogenated with medium-high enantioselec-
tivity (entries 3, 5-8). However, addition of pyridine did
not improve the hydrogenation of the phosphinylated imine
15 (entry 9) but led to the opposite enantiomer instead. The
more hindered N-benzhydryl imine 16 could only be
hydrogenated at higher pressure (entry 10). The use of higher
pressure did not have an appreciable influence on the rate
of hydrogenation of 10, although the ee was somewhat lower
(entry 11). Use of ligands other than 1 did not lead to any
improvements (entries 15-22).
Table 2. Ir/SPO/Pyridine-Catalyzed Hydrogenation of Iminesa
entry
imine
ligand
t (h)
conversion (%)b
ee (%)c
1
2d
3
10
10
11
10
11
12
13
14
15
16
10
10
11
11
11
11
11
10
10
10
10
10
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
3
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
1 (R)
2
3
4
5
6
7
8
9
24
24
24
120
120
24
24
17
139
48
48
24
72
10
17
17
17
17
24
24
48
24
100
>98
100
75
80
85
75
76
85
50
78 (S)
78 (S)
80
82 (S)
83
76
77
62
12
4e
5e
6
7
8
9
10f
11f
12g
13h
14i
15
16
17
18
19
20
21j
22
57
100
30
73 (S)
68 (S)
76
73
33
100
100
>95
>95
60
>95
100
100
100
>95
In conclusion, we have developed a new class of mono-
dentate ligands, enantiopure secondary phosphine oxides that
show good performance in the iridium-catalyzed asymmetric
hydrogenation of imines. The enantioselectivities obtained
are comparable to the best results obtained so far in iridium-
catalyzed hydrogenation of similar imines.35
68
70
66 (S)
7 (S)
4 (S)
1 (S)
23 (S)
Acknowledgment. We thank Mr. M. B. van Gelder and
Mr. E. P. Schudde for technical support and Mr. M. van
den Berg and Dr. A. H. M. de Vries for useful discussions.
Financial support from DSM and the Dutch Ministry of
Economic Affairs under the EET scheme (Grants EE-
TK97107 and EETK99104) is gratefully acknowledged.
a General conditions:: [Ir(COD)Cl]2/SPO/pyridine/imine ) 2.5:10:10:
100, 25 bar H2, toluene, room temperature. b Conversion was determined
by 1H NMR (CDCl3). c Ee determination: see Table 1. d Ir/SPO ) 1:1.
e Temperature ) 0 °C. f H2 (70 bar). g Cyclohexane as a solvent. h Benzene
as a solvent. i Temperature 40 °C. j [Ir(COD)2]BF4 as a precusor.
AgBF4. All of these were found to have a negative effect on
the Ir/SPO-catalyzed imine hydrogenations, however. When
I2 was used, acetophenone was found as the only decomposi-
tion product.
Inspired by Crabtree’s catalyst, [Ir(COD)(PCy3)Py]PF6,
which shows high activity in alkene hydrogenation,34 we
decided to test the effectiveness of pyridine as an additive.
Using 2 equiv of pyridine with respect to iridium, the
hydrogenation becomes faster and the ee increases to 78%
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL034282U
(33) Sablong, R.; Osborn, J. A. Tetrahedron Asymmetry 1996, 7, 3059.
(34) Crabtree, R. H. Acc. Chem. Res. 1979, 12, 331.
(35) Schnider, P.; Koch, G.; Pre´toˆt, A.; Wang, G.; Bohnen, F. M.; Kruger,
C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887.
1506
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