Highly diastereoselective hydrogenation of imines by a bimetallic Pd-Cu heterogeneous catalyst

Article abstract of DOI:10.1021/op1001325

An efficient and practical heterogeneous bimetallic Pd-Cu/C catalyst was identified as an alternative to Raney nickel for the highly diastereoselective hydrogenation of imines prepared from prochiral ketones and α- phenylethylamines. Chiral amines were ob

Full text of DOI:10.1021/op1001325

Organic Process Research & Development 2010, 14, 890–894
Highly Diastereoselective Hydrogenation of Imines by a Bimetallic Pd-Cu
Heterogeneous Catalyst
Jale Mu¨slehiddinog˘lu,* Jun Li,* Srinivas Tummala, and Rajendra Deshpande
Process Research and DeVelopment, Bristol-Myers Squibb Co., One Squibb DriVe, New Brunswick,
New Jersey, U.S.A. 08903-0191
Abstract:
initially used in the hydrogenation of 1 to provide 2 with high
selectivity (94% de) (Scheme 2). However, drawbacks to this
process included the requirement for a high catalyst loading
(∼ 60% wt/wt) resulting in poor suspension as well as special
handling to remove water from the pyrophoric catalyst prior to
the hydrogenation in order to minimize hydrolysis of the imine
substrate. This prompted us to investigate safer and more
process-friendly catalysts that would also deliver high facial
selectivity during the hydrogenation. Herein, we report a highly
diastereoselective hydrogenation of imines prepared from a
variety of acetophenones and R-phenylethylamine chiral aux-
iliaries using a heterogeneous Pd-Cu/C bimetallic catalyst
(A701023-4 from Johnson Matthey) as a safe and economical
alternative to Raney nickel.
An efficient and practical heterogeneous bimetallic Pd-Cu/C
catalyst was identified as an alternative to Raney nickel for the
highly diastereoselective hydrogenation of imines prepared from
prochiral ketones and r-phenylethylamines. Chiral amines were
obtained with diastereomeric excess (de) up to 94% using Pd-Cu/
C, while conventional Pd-C catalysts afforded only 72% de.
Optimization showed that a robust process required a palladium/
copper ratio of 4:1. Evidence for the influence of catalyst pre-
treatment which may change the structure of the catalyst and/or
metal oxidation states on the selectivity of the reaction is discussed.
The bimetallic catalyst system provided consistent results on scale
and performed reliably on a variety of substrates.
Results and Discussion
Various catalysts and methods were screened for the
reduction of 1. Hydrogenations performed with palladium on
Introduction
Chiral R-phenylalkylamines are key building blocks for the
synthesis of many pharmaceuticals.1 Among different asym-
metric approaches1,2 to this class of chiral amines, auxiliary-
directed diastereoselective hydrogenation of imines using
heterogeneous metal catalysts has been a subject of strong
interest.3 Bringmann et al. reported an approach which involved
Raney nickel-catalyzed, highly diastereoselective reduction of
acetophenone imines bearing an inexpensive R-phenylethy-
lamine chiral auxiliary.3a,b The chiral primary amines were
subsequently obtained by a highly regioselective hydrogenolysis
of the bis-benzylic amines (Scheme 1).3b-f,h,i,4 Nugent et al. have
expanded the methodology to a wide array of substrates.3g,h,j
During the process development of peliglitazar (4),5 a potent
dual peroxisome proliferator-activated receptors (PPARs) R/γ
agonist for the treatment of type 2 diabetes, Raney nickel was
(3) For Raney nickel/R-phenylethylamine/prochiral ketone: (a) Bringmann,
G.; Geisler, J.-P Tetrahedron Lett. 1989, 30, 317. (b) Bringmann, G.;
Geisler, J.-P.; Geuder, T.; Kunkel, G; Kinzinger, L. Liebigs Ann. Chem.
1990, 795. (c) Gutman, A. L.; Etinger, M.; Nisnevich, G.; Polyak, F.
Tetrahedron: Asymmetry 1998, 9, 4369. (d) Li, H.-Y.; Anzalone, L.;
Waltermire, R. E. U.S. Patent 5,932,749, 1999. (e) Storace, L.;
Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.;
Giangiordano, M.; Haley, J. J.; Kamholz, K.; Li, H.-Y.; Ma, P.;
Nugent, W. A.; Parsons, R. L.; Sheeran, P. J.; Silverman, C. E.;
Waltermire, R. E.; Wood, C. C. Org. Process Res. DeV. 2002, 6, 54.
(f) Wu, Y.-J.; He, H.; Sun, L.-Q.; Wu, D.; Gao, Q.; Li, H.-Y. Bioorg.
Med. Chem. Lett. 2003, 13, 1725. (g) Nugent, T. C.; Wakchaure, V.
N; Ghosh, A. K.; Mohanty, R. R. Org. Lett. 2005, 7, 4967. (h) Nugent,
T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R. AdV. Synth.
Catal. 2006, 348, 1289. (i) Lukin, K.; Hsu, M. C.; Chambournier, G.;
Kotecki, B.; Venkatramani, C. J.; Leanna, M. R. Org. Process Res.
DeV. 2007, 11, 578. (j) Nugent, T. C.; El-Shazly, M.; Wakchaure,
V. N. J. Org. Chem. 2008, 73, 1297. (k) For palladium on charcoal/
R-phenylethylamine/prochiral ketone: Eleveld, M. B.; Hogeveen, H.;
Schudde, E. P. J. Org. Chem. 1986, 51, 3635. (l) Torok, B.; Surya
Prakash, G. K. AdV. Synth. Catal. 2003, 345, 165. (m) Alexakis, A.;
Gille, S.; Prian, F.; Rosset, S.; Ditrich, K. Tetrahedron Lett. 2004,
45, 1449. (n) For Raney nickel/ketoester: Blacklock, T. J.; Shuman,
R. F.; Butcher, J. W.; Shearin, W. E., Jr.; Budavari, J.; Grenda, V. J.
J. Org. Chem. 1988, 53, 836. (o) Huffman, M. A.; Reider, P. J.
Tetrahedron Lett. 1999, 40, 831.
* To whom correspondence should be addressed. E-mail: jun.li1@bms.com;
jale.muslehiddinoglu@bms.com.
(1) (a) Chiral Amine Synthesis, Methods, DeVelopments and Applications;
Nugent, T. C., Ed.; Wiley-VCH: Weinheim, 2010. (b) Nugent, T. C.;
El-Shazly, M. AdV. Synth. Catal. 2010, 352, 753. (c) Nugent, T. C.
Chiral Amine Synthesis - Strategies, Examples, and Limitations. In
Process Chemistry in the Pharmaceutical Industry, 2nd ed.; Braish,
T. F., Gadamasetti, K., Eds.; CRC Press-Taylor and Francis Group:
Boca Raton, 2007; Vol. 2: Challenges in an EVer-Changing Climate,
pp 137-156. (d) Turner, N. J.; Carr, R. Biocatalytic Routes to
Nonracemic Chiral Amines. In Biocatalysis in Pharmaceutical and
Biotechnology Industries; Patel, R. N., Ed.; CRC Press-Taylor and
Francis Group: Boca Raton, 2006; pp 743-756.
(2) For general review: (a) Kukula, P.; Rins, R. Top. Catal. 2003, 25, 29.
(b) Heitbaum, M.; Glorius, F. Escher, I. Angew. Chem., Int. Ed. 2006,
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H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103. (d) Besson, M.;
Pinel, C. Top.Catal. 2003, 25, 43. (e) Ellman, J. A. Pure Appl. Chem.
2003, 75, 39. (f) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y.
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Higashiyama, K.; Ishii, A. Org. Lett. 2003, 5, 1007.
(5) (a) Chen, S.; Qu, F.; Devasthale, P.; Lai, Z.; Shao, C.; Wang, W.;
Wu, S.; Zhang, H.; Farrelly, D.; Moore, L.; Gu, L.; Sun, W.; Flynn,
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233rd ACS National Meeting, Chicago, IL, March 25-29, 2007. (b)
Deshpande, R.; Staab, A.; Petsch, D.; Pesti, J.; Li, H.-Y.; Kolla, L.;
Spangler, L.; Li, J.; Littke, A.; Marchetti, M.; Escobar, C.; Mu¨sle-
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Meeting, Boston, MA, August 19-23, 2007. (c) Cheng, P. T. W.;
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2001.
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Vol. 14, No. 4, 2010 / Organic Process Research & Development
10.1021/op1001325  2010 American Chemical Society
Published on Web 06/10/2010

Scheme 1. Catalytic reduction of r-phenylethylamine-substituted imines to chiral amines
Scheme 2. Setting the chiral benzylic center of peliglitazar
Table 1. Diastereomeric excess (de) in the hydrogenation of
charcoal (Pd-C) provided 2 in only modest diastereomeric
excess (72% de). To improve diastereoselectivity, two ap-
proaches were pursued. First, chiral additives were screened to
investigate the possibility of exerting double stereodifferentia-
tion. Chiral additives are known to induce enantioselectivity
during achiral imine hydrogenations over Pd-C.6 However,
to our knowledge, there are no analogous examples reported
in the literature on the improvement of diastereoselectivity of
chiral imine hydrogenations over heterogeneous catalysts modi-
fied with chiral additives.7 Application of this approach to 2
led to the finding that Pd-C catalyst modified with (-)-
cinchonidine improved selectivity to 90% de (Table 1). No
improvements in de were observed when D-alanine or L-tartaric
acid were used as chiral additives. We next examined the impact
of using Pd catalysts modified by nonchiral additives or other
metals.3j,o While marginal improvements in diastereoselectivity
were observed using DABCO, interestingly, two heterogeneous
bimetallic catalysts, Pd-Cu and Pd-Na (both on activated
chiral iminesa
entry
1
catalyst (additive)
Raney-nickel
Pd-C
de (%)
94
72
70
72
88
90
82
94
92
2
3
4
5
6
7
8
9
Pd-C (L-tartatic acid)
Pd-C (D-alanine)
Pd-C ((-)-cinchonidine)
Pd-C ((-)-cinchonidine) premixed
Pd-C DABCO
Pd-Cu/C
Pd-Na/C
a NaBH4 afforded 78% de. Conversions for all entries are between 90-100%.
carbon), demonstrated excellent diastereoselectivity (94% de).
The influence of the cometal on the catalyst performance in
bimetallic palladium catalysts are known.8a To our knowledge,
enhancements to the diastereoselectivity of imine reductions
using bimetallic palladium catalysts have not been reported. The
closest example in the literature is a report by Klabunovskii et
al.8b on the use of Pd-Cu in the asymmetric hydrogenation of
ethyl acetoacetate in the presence of L-tartaric acid to introduce
(6) Gobolos, S.; Tfirst, E.; Margitfalvi, J. L.; Hayes, K. S. J. Mol. Catal.
A: Chem 1999, 146, 129.
(7) A noteworthy example is that good diastereomeric excess was achieved
in the hydrogenation of an imine bearing an R-phenylethylamine chiral
auxiliary with a rhodium-chiral phosphine ligand, albeit a homoge-
neous catalysis system, see: Lensink, C.; de Vries, J. G. Tetrahedron:
Asymmetry 1993, 4, 215.
(8) (a) Coq, B.; Figueras, F. J. Mol. Catal. A: Chem 2001, 173, 117. (b)
Kuznetsova, T. I.; Murina, I. P.; Vedenyapin, A. A.; Akimov, V. M.;
Klabunovskii, E. I. React. Kinet. Catal. Lett. 1988, 37, 363.
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891

Table 2. Elemental analysisa of hydrogenation catalysts
Cu/(Pd +
Al Pd-Cu Cu) (%)
on the representative binding energies for Pd, PdO, Cu, Cu2O,
and CuO (335, 336.3, 932.4, 932.5, and 933.7 eV, respectively).
To test the hypothesis that higher levels of metal oxides might
be a factor, Pd-Cu/alumina catalyst was pretreated with pure
oxygen at 170 °C for 14 h prior to the hydrogenation. However,
it should be noted that this treatment may affect both the
oxidation state and the surface structure. Under hydrogenation
conditions, the palladium oxide is readily reduced,11 but copper
stays in the oxide form.12 When this catalyst was used for the
hydrogenation of 1, the de improved to 92%, while untreated
catalyst gave 86% de. This experiment suggested that the
pretreatment of the catalyst resulted in changing the surface in
terms of structure and/or chemical state of the copper and had
an effect on the selectivity by possibly changing adsorption
properties of the substrate on the catalyst. It is known from the
literature that surface structure and oxidation state of the metal
may play a role in selectivity.13
From the above findings, the most attractive options available
to support plant scale-up for the hydrogenation of 1 with high
facial selectivity were as follows: (a) Employment of alumina
supported bimetallic catalyst following oxygen pretreatment or
(b) a dry carbon-supported 5% Pd-Cu (palladium/copper
weight ratio ∼4:1) catalyst. On the basis of the higher de
obtained with the latter, Pd-Cu/C was selected to demonstrate
the efficiency of the process on a 400-g scale.
The imine was prepared by azeotropic distillation in the
presence of Ti(OiPr)4. It should be noted that imine formation
was required versus using one-pot reductive amination due to
the low conversion observed in the reductive amination. The
hydrogenation of imine was carried out in a toluene/methanol
(50:50) solution to afford 2 with 94% de. No debenzylation
was observed in the Pd-Cu/C catalyzed hydrogenation. The
reaction mixture was debenzylated through regioselective hy-
drogenolysis with 10% Pd-C,3a affording 6 in 73% isolated
yield (Scheme 3). The manifestation of this result is that the
Pd-Cu bimetallic system is scalable to provide an efficient and
practical approach to prepare chiral amines with high diaste-
reoselectivity.
sample
Pd-Cu-Al2O3 0.6 2.9 3.1 56.5 36.9 4.8/1
Pd-Cu-C 0.7 2.7 94.7 1.2 3.9/1
Cu Pd
C
O
17
20
0
a Elemental analysis of Pd-Cu on alumina and Pd-Cu on carbon catalysts.
modest enantioselectivity. Due to the superior diastereoselec-
tivity observed with the Pd-Cu and Pd-Na, we studied the
chiral imine hydrogenation using these catalysts.
During process optimization using Pd-Na/C and Pd-Cu/C
catalysts, it was observed that diastereoselectivity was not
reproducible from batch to batch. While increasing the levels
of sodium did not yield consistent de, increasing the amount
of copper on the solid support from 0.03 wt % to 1.0 wt % led
to consistently high de, although a decrease in catalytic activity
of the Pd-Cu/C catalyst was noted at higher copper loading.
The total time to achieve 99.5% conversion increased from 3 h
at 0.03 wt % Cu to 11 h at 1.0 wt % Cu. These observations
led us to focus on further optimization of the Pd-Cu bimetallic
catalyst system.
Carbon-supported Pd-Cu bimetallic catalysts typically
contain 50-60 wt % water. To prevent the hydrolysis of imine
substrates to the corresponding ketones, it was necessary to use
the dry catalysts, which can be obtained from Johnson Matthey.
For improved safety, substitution of the carbon support for
noncombustible alumina was explored. However, dry Pd-Cu/
alumina catalysts consistently resulted in slightly lower de
(86%). To improve the selectivity of these catalysts, additional
factors were explored. Elemental analysis (Table 2) showed that
the Pd-Cu ratio is slightly higher for the Pd-Cu/alumina
catalyst. The marginal difference of copper (∼ 3%) suggested
surface composition should not be the primary factor for low
de. This prompted us to consider the various oxidation states
present in our bimetallic catalyst. To do this we examined the
surface oxidation states using X-ray photoelectron spectroscopy
(XPS) (also called electron spectroscopy for chemical analysis
(ESCA))10 (Figure 1). In comparison to the ESCA spectra of
Pd-Cu/C catalyst (red line), Pd-Cu/alumina spectra (black
line) showed lower levels of copper and palladium oxides based
In addition to demonstrating the scalability of the Pd-Cu/C
bimetallic catalyst system, we were interested in expanding the
Figure 1. X-ray photoelectron spectra of Pd-Cu/C and Pd-Cu/alumina (untreated with O2).
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Scheme 3. Conversion of the ketone precursor to the chiral benzylic primary amine 6
Table 3. Exploration of different acetophenone substrates scope using Pd-Cu/C catalysta
a (R)-R-phenylethylamine was used. Note: all the E/Z configurations were determined by proton NMR and diastereomeric excess by GC as well as proton NMR.
substrate scope (Table 3). A variety of aryl ketimines 7 were
synthesized from the corresponding aryl ketones in the presence
of Ti(OiPr)4. The hydrogenation reactions were carried out at
25 psig and ambient temperature in the presence of 5%
palladium-copper (palladium/copper weight ratio ∼4:1) on
activated carbon. The hydrogenated products were obtained in
de ranging between 86 to 94% with the exception of entry 6.
Notably, both electron-rich and -deficient aryl ketones were
successfully hydrogenated. The E/Z ratio of the ketimines 7
and diastereoisomeric excess of secondary amines 8 were
determined by proton NMR on the basis of chemical shift
correlations.3k It is plausible that (S,S) resulted from hydrogena-
tion at the less hindered side of E configuration of the ketimine
and (R,S) resulted from Z configuration of the ketimine (Scheme
4). In the case of entry 4 (Table 3), a high de (92%) was
(9) Boyd, D. R.; Jennings, W. B.; Waring, L. C. J. Org. Chem. 1986, 51,
992.
(10) Satterfield, C. Heterogeneous Catalysis in Industrial Practice, 2nd ed.;
McGraw-Hill: New York, 1991; p 165.
(12) Kim, M. H.; Ebner, J. R.; Friedman, R. M.; Vannice, M. A. J. Cat.
2002, 208, 381.
(11) McKinney, P. V. J. Am. Chem. Soc. 1933, 55, 3626.
(13) Somorjai, G. A.; Park, J. Y. Angew. Chem. Int. Ed 2008, 47, 9212.
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893

Scheme 4
observed despite the low E/Z ratio (77/23) of the starting
ketimine. This effect is possibly attributed to rapid E/Z isomer-
ization9 coupled with slow kinetically controlled hydrogenation
(Curtin-Hammett principle).
was stirred for 15 min, followed by addition of 3 L of water.
After phase split, the product-rich aqueous solution was added
into 2.6 L of 2 N NaOH to afford a slurry. The slurry was then
filtered and dried to 0.64% LOD to obtain 6 (293 g, 73%
isolated yield) as a white solid with HPLC area purity of 96%
and enantiomeric purity of 94% ee. [R]2D5 -13.99° (c 10, DCM);
1H NMR (400 MHz, CDCl3): δ 7.97 (dd, J ) 2.0, 8.3 Hz, 2H),
7.38-7.44 (m, 3H), 7.24 (d, J ) 8.8 Hz, 2H), 6.86 (d, J ) 8.8
Hz, 2H), 4.23 (t, J ) 6.8 Hz, 2H), 4.05 (q, J ) 6.3 Hz, 1H),
2.97 (t, J ) 6.8 Hz, 2H), 2.37 (s, 3H), 1.56 (s, N-H, 2H), 1.34
(d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 158.7,
156.9, 144.4, 139.5, 132.3, 129.3, 128.2, 127.3, 126.2, 125.5,
114.1, 66.8, 50.8, 26.8, 26.1, 10.8; HRMS ESI Calcd for
C20H22N2O2: (M + H)+ 323.1760; found 323.1758.
Experimental Section
Screening Conditions (Table 1). All the reactions (entries
1-9) were carried out in a 5-mL solution of toluene/methanol
(1:1 (v/v)) with an Endeavor Catalyst Screening System
(Biotage) on a 500 mg scale at 25 psig and 25 °C for 16 h.
Raney nickel (60 wt %) (Grace Davidson 2800) was used for
entry 1. Entries 2-7 used 10 wt % of 5% Pd-C from Johnson
Matthey. Entries 3-6 used 0.3 equiv of chiral additives. Entry
6 used a Pd-C and (-)-cinchonidine premix prepared by
stirring 0.3 equiv of (-)-cinchonidine with 10 wt % 5% Pd-C
in methanol for 30 min and leaving overnight, followed by
filtration through a Whatman filtering paper. The wet catalyst
was used as is. Entry 7 used 0.15 equiv of DABCO. Entry 8
used 10 wt % of 5% Pd/0.03 wt % Cu/C from Johnson Matthey.
Entry 9 used 5 wt % of 3% Pd/0.01 wt % Na/C from Engelhard.
Diastereomeric excess was determined by GC on a DB-1 HT
column (15 m × 0.32 mm) and proton NMR. GC program for
diastereoisomers 2 and 3: Tinj ) 250 °C and Tdet ) 300 °C,
carrier gas He flow 1.6 mL/min, 150 °C, then 10 °C/min to
280 °C, then 20 °C/min to 350 °C (hold 5 min), retention time
for 2 (13 min), and 3 (13.1 min). For product primary amine 6,
the enantiomeric excess was determined by Chiral HPLC using
a Chiralcel OD-H 5 µm 4.6 mm × 150 mm column. LOD (loss
on drying) was determined by Mettler Toledo moisture analyzer.
Scale-Up. (S)-1-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethox-
y)phenyl)ethanamine (6). To a 4-L toluene solution was added
ketone 5 (400 g, 1.24 mol, 1.0 equiv), (S)-R-phenylethylamine
(181 g, 1.49 mol, 1.2 equiv), and Ti(OiPr)4 (91.6 g, 0.322 mol,
0.26 equiv). The reaction mixture was refluxed under azeotropic
distillation to achieve 99.1% conversion after 23 h. The reaction
mixture was cooled and inverse quenched to a 2 N NaOH
solution. After filtration and phase split, the toluene solution
was concentrated to 2 L. To the above toluene concentrate was
added 2 L of methanol and 5% Pd-Cu/C dry catalyst with
Pd-Cu (w/w) ratio of 4:1 from Johnson Matthey (A701023-
4) (25 g, 6.25 wt/wt% based on ketone 5) in a 5-L Buchi reactor.
The reaction was carried out at 25 °C under 25 psig of hydrogen.
Reaction was complete after 10.5 h to afford diastereomeric
excess of 94%. The reaction mixture was filtered through a 0.5
µm polypropylene Cuno filter to remove the catalyst. To the
filtrate was added 30 wt % of 10% Pd-C (Degussa NE/W
E101), followed by the addition of acetic acid (149 g, 2.48 mol,
2.0 equiv). The debenzylation reaction was carried out at 50
°C and 40 psig. Isolation was carried out in a 10-L Chemglass
reactor. Methanol was distilled off, followed by the addition of
400 mL of isopropanol and 150 mL of acetic acid. The mixture
Conclusions
In summary, high diastereoselectivities were observed in the
hydrogenation of imines with a bimetallic Pd-Cu/C catalyst.
Key advantages of this new method are improved safety
compared with those of Raney nickel, no issues with catalyst
suspension, and enhanced operational scalability. It was dem-
onstrated that a reliable process resulted from using a bimetallic
5% Pd-Cu/C catalyst with Pd-Cu (w/w) ratio of 4:1.
Preliminary data from X-ray photoelectron spectroscopy suggest
that diastereoselectivity could be influenced by the oxidation
states at both palladium and copper. Effectiveness of the
bimetallic Pd-Cu system was demonstrated on a plant scale
for our key peliglitazar intermediate, offering a practical
approach to prepare chiral amines with high diastereoselectivity.
Note Added after Print Publication: In the version
published June 10, 2010, Jale Mu¨slehiddinog˘lu should have
been designated a corresponding author. This has been
corrected in this version posted August 24, 2010.
Acknowledgment
We thank Dr. David Kronenthal for a critical review of the
manuscript, Dr. Joerg Deerberg, Dr. Jaan Pesti, and Dr. Lopa
Desai for their review of the manuscript, and Robert McNair
(Johnson Matthey) and Ramesh Subramarian for their significant
contributions for the development of the bimetallic catalyst and
Dr. Otute Akiti, Melissa Marchetti and Dr. Adam Littke for
their support for the development of the process. We also thank
Penn State University for providing the X-ray photoelectron
spectroscopy data for the catalysts. We are grateful to Shirley
Wong and Merrill Davies for analytical support of this project.
Received for review May 13, 2010.
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