Polymer-immobilized catalyst for asymmetric hydrogenation of racemic α-(N-benzoyl-N-methylamino)propiophenone

Article abstract of DOI:10.1021/jo802339t

Asymmetric hydrogenation of α-(N-benzoyl-N-methylami-no)propiophenone through dynamic kinetic resolution was performed by using a polymer-immobilized chiral diamine-ruthenium-BINAP-t-BuOK system in order to yield syn-β-amidealcoholexclusivelywithnearlyperfectenantioselectivity.

Full text of DOI:10.1021/jo802339t

The dynamic kinetic discrimination6 of the stereoisomers for such
a racemic ketone is achievable. Although asymmetric hydrogena-
tion under the conditions of dynamic kinetic resolution has been
applied to some types of racemic ketones such as R-alkylcyclo-
hexanone7 and R-ketoethers,8 the reaction involving R-nitrogen
substituted ketones has not been studied extensively. A few
examples of such a system have been reported. Noyori et al. and
Hamada et al. reported on the hydrogenation of R-amino-ꢀ-keto
ester involving the use of BINAP9-Ru complex.10,11 The carbonyl
group in the substrate structure is necessary for attaining high
diastereoselectivity in the reaction. Ohkuma recently reported on
the asymmetric hydrogenation of R-branched aromatic ketones with
TolBINAP12/DMAPEN13-Ru(II) complex.14 The dynamic kinetic
resolution of racemic 2-tert-butoxycarbonylaminocyclohexanone
by hydrogenation to produce 1,2-cis-configurated 2-tert-butoxy-
carbonylaminocyclohexanol in 82% ee was described.15 In our
study, to synthesize enantiopure pseudoephedrine derivatives, we
focused on the asymmetric hydrogenation of racemic R-amide
ketone rac-1 by utilizing dynamic kinetic resolution (Scheme 1).
Polymer-Immobilized Catalyst for Asymmetric
Hydrogenation of Racemic
r-(N-Benzoyl-N-methylamino)propiophenone
Vinia Ipai Chiwara, Naoki Haraguchi, and Shinichi Itsuno*
Department of Materials Science, Toyohashi UniVersity of
Technology, Tempaku-cho, Toyohashi 441-8580, Japan
itsuno@tutms.tut.ac.jp
ReceiVed October 18, 2008
SCHEME 1. Asymmetric Hydrogenation of Racemic
r-Amide Ketone 1
Asymmetric hydrogenation of R-(N-benzoyl-N-methylami-
no)propiophenone through dynamic kinetic resolution was
performed by using a polymer-immobilized chiral diamine-
ruthenium-BINAP-t-BuOK system in order to yield syn-
ꢀ-amidealcoholexclusivelywithnearlyperfectenantioselectivity.
From the perspective of employing a green, sustainable
synthetic method, the use of polymer-immobilized catalysts
should be considered always mainly because they can easily
be separated from the reaction mixture and because of their
recyclability.16 However, the dynamic kinetic resolution of
R-amide ketone by using a polymer-immobilized chiral catalyst
has not yet been reported. We developed a polymer-immobilized
Certain ꢀ-amino alcohols such as pseudoephedrine and its
derivatives (2) are valuable constituents of a variety of biologi-
cally active products and medicinally important compounds.1
In addition, pseudoephedrine has been used as an efficient chiral
auxiliary for asymmetric reactions.2 Such optically active
ꢀ-amino alcohols having two adjacent stereogenic centers have
been synthesized by using several methods, including the
diastereoselective addition of organometallic reagents to R-ami-
no aldehydes,3 diastereoselective reduction of R-amino ketones,4
and diastereoselective reduction of R-alkoxy imines.5 In these
reactions, the corresponding enantiopure starting materials
produce optically active products. Moreover, these reactions
preferentially produce anti isomers, and pseudoephedrine pos-
sesses a syn-ꢀ-amino alcohol structure.
(6) (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36–55. (b) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry 2003,
14, 1407–1446. (c) Noyori, R.; Ohkuma, T. Pure Appl. Chem. 1999, 71, 1493–
1501. (d) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73.
(7) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R. J. Org.
Chem. 1996, 61, 4872–4873.
(8) (a) Matsumoto, T.; Murayama, T.; Mitsuhashi, S.; Miura, T. Tetrahedron
Lett. 1999, 40, 5043–5046. (b) Studer, M.; Blaser, H. U.; Burkhardt, S. AdV.
Synth. Catal. 2002, 344, 511–515.
(9) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl.
(10) (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi,
H. J. Am. Chem. Soc. 1989, 111, 9134–9135. (b) Kitamura, M.; Tokunaga, M.;
Noyori, R. J. Am. Chem. Soc. 1993, 115, 144–152. (c) Noyori, R.; Tokunaga,
M; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68, 36–56.
(11) (a) Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y. Tetrahedron:
Asymmetry 2001, 1, 1757–1762. (b) Makino, K.; Goto, T.; Hiroki, Y.; Hamada,
Y. Angew. Chem., Int. Ed. 2004, 43, 882–884. (c) Makino, K.; Hiroki, Y.;
Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784–5785.
An alternative method to obtain chiral ꢀ-amino alcohol involves
the stereoselective hydrogenation of racemic R-nitrogen substituted
ketones that contain configurational labile R-stereogenic centers.
(12) TolBINAP ) 2,2′-bis(di-4-tolylphosphino)-1,1′-binaphthyl.
(13) DMAPEN ) 2-dimethylamino-1-phenyethylamine.
(14) Arai, N.; Ooka, H.; Azuma, K.; Yabuuchi, T.; Kurono, N.; Inoue, T.;
Ohkuma, T. Org. Lett. 2007, 9, 939–941.
(1) Sweetman, S. C.; Martindale. In W. Martindale: the Complete Drug
Reference, 35th ed.; Pharmaceutical Press: London, UK, 2007.
(2) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(3) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990,
55, 1439–1446.
(4) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 547–550.
(5) Lida, H.; Yamazaki, N.; Kibayashi, C. J. Chem. Soc., Chem. Commun.
1987, 746–748.
(15) Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000,
122, 6510–6511.
(16) (a) Itsuno, S. In Handbook of Asymmetric Heterogeneous Catalysis;
Ding, K., Uozumi, Y., Eds.; Wiley-VCH: Weinheim, Germany, 2008; Chapter
3. (b) Itsuno, S. In Acid Catalysis in Modern Organic Synthesis; Yamamoto,
H., Ishihara, K., Eds.; Wiley-VCH: Weinheim, Germany, 2008; Vol. 2, pp 1019-
1060. (c) El-Shehawy, A. A.; Itsuno, S. In Current Topics in Polymer Research;
Bress, R. K., Ed.; Nova Science Publisher: New York, 2005, pp 1-69.
10.1021/jo802339t CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1391–1393 1391

TABLE 1. Asymmetric Hydrogenation of rac-1 by Using
N-Substituted Diamine-RuCl2-BINAP in 2-Propanola
CHART 2. Polymer-Immobilized Chiral 1,2-Diamine
Ligand
N-benzoyl pseudoephedrine
entry diamine BINAP time, h conv. %b de %b ee %c config.
1
2
3
4
(S,S)-3a
(R,R)-3b
(R,R)-3b
(R,R)-3c
S
S
R
S
17
1
17
2
100
100
100
100
>99
>99
>99
>99
72
91
42
99.4
S,S
R,R
R,R
S,S
a Reactions conducted at room temperature in 2-propanol.
[Diamine]:[RuCl2]:[(S)-BINAP] ) 2:1:1, S/C ) 500. b Determined by
HPLC and H NMR analysis. c Determined by chiral HPLC analysis.
1
CHART 1. Chiral 1,2-Diamine Ligand
chiral 1,2-diamine as a polymeric chiral ligand for the
Noyori-Ohkuma-type catalyst. The polymeric chiral precatalyst
was efficiently used for the asymmetric hydrogenation of rac-1
via dynamic kinetic resolution.
TABLE 2. Asymmetric Hydrogenation of rac-1 by Using
Polymer-Immobilized Complexa
N-benzoyl pseudoephedrine
entry
polymeric diamine
conv,b
%
de,b
%
ee,c %
config.
Because
the
catalytic
system
prepared
from
BINAP-RuCl2-DPEN17 (3a)-t-BuOK in 2-propanol, which
was originally developed by Noyori and Ohkuma, provides one
of the most efficient hydrogenation activities for simple ketone
reduction to a secondary alcohol,18 we apply this system to the
dynamic kinetic resolution of rac-1.19 The racemic R-amide
ketone is smoothly hydrogenated with (S,S)-3a-(R)-
BINAP-RuCl2-t-BuOK in 2-propanol to produce the corre-
sponding syn-ꢀ-amide alcohol (S,S)-2 in a quantitative yield with
72% ee (Table 1, entry 1).20 In the hydrogenation of simple
ketones, the use of N-substituted 1,2-diamine ligand decreases
the catalytic activity. However, in the case of the dynamic
kinetic resolution of rac-1, we observe that mono N-benzyl
DPEN (R,R)-3b (Chart 1) is a rather effective chiral ligand for
the catalyst system, as shown in Table 1. By using the
precatalyst containing (R,R)-3b and (S)-BINAP/RuCl2, the
asymmetric hydrogenation of rac-1 produces syn-ꢀ-amide
alcohol (R,R)-2 in quantitative conversion with 91% ee (entry
2). When (R)-BINAP is used instead of (S)-BINAP, both the
reactivity and enantioselectivity decrease (entry 3). A combina-
tion of (S)-BINAP and (R,R)-N-substituted DPEN appears to
be the matched pair required to produce (R,R)-ꢀ-amide alcohol.
The mono N-benzylated DPEN ligand 3b is readily prepared
by the reaction between 3 equiv of DPEN and benzylic bromide.
Under such reaction conditions, 3b is exclusively obtained and
the insoluble hydrobromide can easily be separated from the
reaction mixture.
1d
2e
3e
4e
5d
6f
7
8
9
10
4a
4a
4b
4c
4c
4c
4d
4e
4f
0
7
10
100
0
100
100
81.5
100
100
>99
>99
>99
61.7
88.5
99.8
R,R
R,R
R,R
>99
>99
>99
>99
>99
90.0
99.5
99.6
92.0
95.5
R,R
R,R
R,R
R,R
R,R
4g
a Reactions conducted at room temperature in 2-propanol/DMF (1:1)
for
2 h. [Diamine]:[RuCl2]:[(S)-BINAP] ) 2:1:1, S/C ) 500.
b Determined by HPLC and 1H NMR analysis. c Determined by chiral
HPLC analysis. d Reaction carried out in 2-propanol. e 24 h. f Reaction
carried out in DMF.
tivity (99.4% ee), as shown in Table 1. The results obtained
encouraged us to prepare the polymer-immobilized chiral ligand.
Because the chiral monomer (R,R)-3c contains styrenic double
bonds, various types of vinyl monomers can be copolymerized
with 3c. The properties of the chiral copolymers often influence
the catalytic activity in the asymmetric reaction. We selected
styrene, 2-hydroxyethyl methacrylate, methyl methacrylate,
N-isopropylacrylamide, and 4-hydroxymethylstyrene as achiral
vinyl monomers. In many cases of using the polymer-im-
mobilized catalyst, the degree of cross-linking and the structure
of the cross-linking agent affect the catalytic activity of the
polymeric catalyst. Divinylbenzene (DVB) and ethyleneglycol
dimethacrylate (EGDMA) were used as cross-linking agents.
The terpolymerization of the chiral ligand monomer 3c (10 mol
%), achiral monomer (88 mol %), and cross-linking agent (2
mol %) smoothly proceeded under radical polymerization
conditions in DMF to produce various types of the correspond-
ing polymer-immobilized chiral 1,2-diamine ligands 4 (Chart
2). The insoluble cross-linked polymers 4 were used as the chiral
polymeric ligand of the RuCl2-BINAP complex.
To prepare the polymer-immobilized version of mono N-
benzylated DPEN ligand, we synthesized 4-(4-vinylbenzyloxy-
)benzyl DPEN 3c as a chiral ligand monomer by using the same
method employed for the preparation of 3b. The precatalyst
prepared from (R,R)-3c exhibited a high level of enantioselec-
(17) DPEN ) 1,2-diphenylethylenediamine.
(18) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 2675–2676.
(19) Racemic R-(N-benzoyl-N-methylamino)propiophenone 1 was obtained
from Nippon Soda Co. Ltd.
(20) Obtained amide alcohol 2 was treated with 20% NaOH aqueous solution
in reflux ethanol for 2 h to give the syn amino alcohol, (-)-(R,R)-pseudoephe-
drine. Methyl protons of the syn isomer appeared at 0.94 ppm in 1H NMR spectra
of the amino alcohol with no peak at 0.88 ppm for the anti isomer.
Table 2 shows the results obtained from the dynamic kinetic
resolution of rac-1 via hydrogenation by using the polymeric
catalyst. First, we used the polystyrene-based polymeric chiral
ligand 4a in 2-propanol. Unfortunately, no reaction occurred
in this solvent (Table 2, entry 1), mainly due to the strong
1392 J. Org. Chem. Vol. 74, No. 3, 2009

hydrophobicity of the polymer support. The polymeric complex
prepared from 4a shrunk in the alcoholic solvent and this
prevented the catalytic activity (entry 1). We encountered the
same problem when we developed the different types of
polymeric catalysts that were applied to the asymmetric
hydrogenation of simple ketones.21 We used a mixed solvent
of 2-propanol and DMF to solve this problem.22 However, the
precatalyst prepared from 4a produced a very low conversion
with 61.7% ee (entry 2) in the mixed solvent of 2-propanol and
DMF. By using the polar cross-linking agent (EGDMA), a slight
improvement was observed (entry 3). When the hydrophilic
achiral monomer, hydroxyethyl methacrylate, was incorporated
(4c) into the polymer support, the reactivity of the polymeric
precatalyst prepared from 4c dramatically increased to yield syn-
ꢀ-amide alcohol exclusively. The enantioselectivity obtained
approached 100% ee (entry 4) in 2-propanol/DMF. The solvent
used in this system strongly influenced both the reactivity and
enantioselectivity. The repeated use of a single solvent of
2-propanol showed no conversion with this catalyst (entry 5).
On the other hand, the same reaction smoothly occurred in DMF
alone with lowering of the enantioselectivity (entry 6). In the
case of 2-hydroxyethyl methacrylate used as an achiral monomer
in the polymer-support preparation, the influence of the cross-
linking structure was not so important. The DVB cross-linkage
significantly promoted the asymmetric hydrogenation (entry 7).
Although the use of poly(methyl methacrylate) as a polymer
support showed excellent enantioselectivity in the same reaction,
the polymeric catalyst yielded slightly lower conversion under
the same reaction conditions (entry 8). Other hydrophilic
polymer supports such as poly(acrylamide) and poly(4-hy-
droxymethylstyrene) yielded the corresponding chiral ꢀ-amide
alcohol (R,R)-2 in quantitative conversion with high enantiose-
lectivities (entries 9 and 10).
poly(hydroxyethyl methacrylate) exhibited excellent perfor-
mance in the dynamic kinetic resolution of racemic R-amide
ketone rac-1 via hydrogenation to yield the corresponding syn-
ꢀ-amide alcohol (R,R)-2 in quantitative conversion with nearly
perfect enantioselectivity. In addition, the polymer-immobilized
catalyst could be reused several times without loss of catalytic
activity.
Experimental Section
General Procedure for Preparation of Polymers 4a-g by
Radical Polymerization. A glass ampule equipped with a magnetic
stirrer chip was charged with 3d (0.23 mmol, 0.1 g), comonomer
(2.02 mmol), cross-linking agent (0.046 mmol), AIBN (97 µmol),
and DMF (1 mL). After three vacuum freeze-thaw cycles, the
ampule was sealed under liquid nitrogen. Polymerization was
performed at 70 °C for 48 h. The ampule was opened and the
resulting mixture was poured into methanol. The polymer afforded
was collected over a glass filter, washed with THF and methanol,
and dried in vacuo at 40 °C.
Asymmetric Hydrogenation of r-Amide Ketone. A 20-mL
Schlenk vessel equipped with a Teflon-coated magnetic stirrer bar
was charged with a polymer-supported chiral diamine ligand (0.015
mmol), RuCl2/(S)-BINAP(dmf)n (0.007 g, 0.0075 mmol), and dry
DMF (1 mL). The mixture was degassed and heated at 80 °C for
2 h. The DMF was removed under reduced pressure, and the solid
obtained was transferred together with R-amide ketone (0.2 g, 0.75
mmol) to a 100-mL autoclave equipped with a pressure gauge and
hydrogen gas inlet tube. The autoclave was flushed with argon to
replace air after which a degassed solution of a 1:1 mixture of
2-propanol (1 mL)/DMF (1 mL) and 1.0 M t-BuOK solution in
t-BuOH (0.075 mL) was added. Hydrogen was then introduced into
the autoclave and then it was pressurized up to 1 MPa. The reaction
mixture was stirred at room temperature for 2 h. After carefully
venting the hydrogen gas, the reaction mixture was filtered through
a silica gel column (ethyl acetate/methanol as eluent) to remove
the insoluble polymeric catalyst. The purified product was further
concentrated and dried under reduced pressure. The conversion was
determined by using 1H NMR, and the enantioselectivity was
determined by using HPLC analysis (Chiralcel OJ-H, Daicel;
hexane/2-propanol/ethanol ) 8:1:1, 0.3 mL/min, rt, tR(R,R) ) 27.35
min, tR(S,S) ) 23.80 min). (1R,2R)-2: 1H NMR (300 MHz, DMSO-
d6) δ 0.97 (d, J ) 6.9 Hz), 2.89 (s, 3H), 4.58 (br, 1H), 5.26 (br,
1H), 7.23-7.40 (m, 10H). 13C NMR (75 MHz, DMSO-d6) δ 15.0,
26.8, 59.2, 73.5, 126.7, 127.4, 128.1, 128.6, 137.7, 143.4, 171.4.
One of the important advantages of using polymer-im-
mobilized catalysts is the recyclability of the catalyst. The
polymeric chiral complex could be easily separated from the
reaction mixture and then recovered by filtration after the
hydrogenation was completed. Thus, we studied the recycle
experiment by using the polymeric precatalyst prepared from
4c. We confirmed that recycling can be carried out at least five
times without any loss of catalytic activity of the polymeric
catalyst. Under the reaction conditions for entry 4 using the
catalyst derived from 4c, we obtained (R,R)-2 in the quantitative
yield with 99.8%, 99.8%, 99.8%, 99.8%, and 99.8% ee values
for five recycling experiments.
Acknowledgment. This study was partially supported by a
Grant-in-Aid for Scientific Research on Priority Area “Advanced
Molecular Transformation of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
In conclusion, we successfully prepared various types of
polymer-immobilized chiral 1,2-diamine 4. The polymeric
precatalyst prepared from hydrophilic polymer support such as
Supporting Information Available: Details on the experi-
1
ment and the H and 13C NMR spectra of all new compounds.
(21) (a) Itsuno, S.; Tsuji, A.; Takahashi, M. J. Polym. Sci., Part A: Polym.
Chem. 2004, 42, 4556–4562. (b) Takahashi, M.; Haraguchi, N.; Itsuno, S.
Tetrahedron: Asymmetry 2008, 19, 60–66.
(22) Ohkuma, T.; Takeno, H.; Honda, Y.; Noyori, R. AdV. Synth. Catal. 2001,
343, 369–375.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802339T
J. Org. Chem. Vol. 74, No. 3, 2009 1393