Towards a zinc-catalyzed asymmetric hydrogenation/transfer hydrogenation of imines

Article abstract of DOI:10.1002/asia.201200309

The first asymmetric hydrogenation/transfer hydrogenation of imines to amines using zinc(II) triflate in combination with chiral ligands is described. The monodentate binaphthophosphepine ligand (3 g) provided the highest enantioselectivities. Using diffe

Full text of DOI:10.1002/asia.201200309

DOI: 10.1002/asia.201200309
Towards a Zinc-Catalyzed Asymmetric Hydrogenation/Transfer
Hydrogenation of Imines
Svenja Werkmeister, Steffen Fleischer, Kathrin Junge, and Matthias Beller*[a]
Abstract: The first asymmetric hydrogenation/transfer hydrogenation of imines to
amines using zinc(II) triflate in combination with chiral ligands is described. The
monodentate binaphthophosphepine ligand (3g) provided the highest enantiose-
lectivities. Using different imines, the corresponding amines were obtained in mod-
erate yields and enantioselectivities.
Keywords: asymmetric synthesis ·
amines · hydrogenation · imines ·
zinc
Introduction
achieved especially using precious metal-based catalysts, for
example, Ir,[7] Ru,[8] Rh,[9] and Pd[10] complexes. However,
catalytic hydrogenations with non-precious metal complexes
are far less developed. During our investigations on iron-
catalyzed enantioselective imine hydrogenations,[11] we dis-
covered that similar reductions proceed in the presence of
catalytic amounts of simple zinc(II) triflate.[12] Most recently,
we were able to perform atom-efficient reductive hydroami-
nations of alkynes with this unique catalyst. However, to the
best of our knowledge no asymmetric hydrogenations using
zinc catalysts are known. Herein, we describe the first exam-
ples of both zinc-catalyzed hydrogenations and transfer hy-
drogenations of imines to amines.
The development of improved methods for the synthesis of
enantiomerically pure amines is of continuing industrial and
academic interest owing to their importance in agrochemi-
cals, pharmaceuticals, chiral auxiliaries, and biological sys-
tems.[1,2] Notably, in 2010 more than 45% of the top 200
brand-name drugs by US retail sales contained at least one
stereogenic center, and 20% of which represented chiral
amines. Selected examples of these products are shown in
Figure 1.[3]
Results and Discussion
While testing different Lewis acids for the hydrogenation of
para-methoxy-N-(1-phenylethylidene)aniline
1a
(p-me
thoxyphenyl=PMP) to give the corresponding amine 2a, to
our surprise ZnACTHNUTRGNEUNG(OTf)2 was discovered as a suitable cata-
lyst.[12] In Table 1, selected reactions from the previous opti-
mization studies are shown. For example, using 5 mol% of
simple ZnACHTUNGRTNENG(U OTf)2 without any ligand at 1008C afforded 2a in
72% yield (Table 1, entry 1). By increasing the catalyst load-
ing to 10 mol% 2a was obtained in 95% yield (Table 1,
Figure 1. Selection of the top 200 brand-name drugs by US retail sales in
2010.
Table 1. Optimization of zinc triflate as a hydrogenation catalyst.[a]
Among the different catalytic methods known for the
asymmetric synthesis of amines, hydrogenation of imines/en-
amines is an important and environmentally friendly ap-
proach.[4–6] In the past decades, impressive progress has been
Entry
Zn(OTf)2 [mol%]
T [8C]
Conv. [%][b]
Yield [%][b]
1
2
3
4
5
5
10
5
2
1
100
100
120
120
120
83
95
>99
74
38
72
95
92
47
4
[a] S. Werkmeister, S. Fleischer, Dr. K. Junge, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
E-mail: matthias.beller@catalysis.de
[a] Reaction conditions: 1a (0.5 mmol), ZnACHTUNGRTENUNG(OTf)2, toluene (0.5 mL), H2
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200309.
(80 bar), T, 24 h. [b] Conversion and yield were determined by GC meth-
ods using hexadecane as an internal standard.
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
&
&
&
These are not the final page numbers! ÞÞ

FULL PAPER
entry 2). On the other hand, at 1208C in the presence of
5 mol% of ZnACHTUNGTRENNUNG(OTf)2, 1a was converted into 2a with a simi-
the bidentate ligand (S,S)-deguphos (3b), while the ob-
served enantiomeric excess with this ligand was only 12%.
Increasing the ligand loading to 10 mol%, the desired amine
1b was produced in 46% yield and 17% ee.
lar product yield of 92% (Table 1, entry 3). To perform the
enantioselective hydrogenation reactions,[13] we used
Zn
(OTf)2 in combination with a variety of chiral nitrogen-
In the presence of other chiral P-ligands such as 3a, 3c–
3 f, and 3h–3j, low to moderate yields between 6% and
39% were observed as well as low enantioselectivities of up
to 10% ee. However, using 5 mol% of the monodentate bi-
naphthophosphepine ligand 3g gave a moderate yield of
34% and 17% ee. The enantiomeric excess could be in-
creased to 22% by using a higher concentration of the phos-
phepine ligand 3g. Unfortunately, repeating the reaction
and phosphorous-based ligands for the enantioselective re-
duction of N-(1-phenylethyl)aniline 1b. As shown in
Figure 2, we initially tested different chiral P-containing li-
with combinations of ZnACTHNUTRGNE(UNG OTf)2/3g or 3b at 808C did not
afford amine 2b. Hence, a correlation between enantioselec-
tivity and reaction temperature can therefore not be dis-
cussed. Temperatures >1008C are required for the activa-
tion of molecular hydrogen mediated by ZnACTHNURTGNENG(U OTf)2. Further-
more, it should be noted that the low yields resulted mostly
from aldol condensations of the imine 1b, which were ob-
served as side reactions.
Next, we tested different N-containing ligands such as pyr-
idinebisoxazoline (pybox) and pyridinebisimidazoline
(pybim; Figure 3); these ligands have recently been em-
ployed successfully for enantioselective zinc-catalyzed hy-
drosilylations and ruthenium-catalyzed transfer hydrogena-
tions of ketones.[13a,15] Unfortunately, either traces or no
amine 2b was formed in the presence of 4a–e, 5a, and 5b.
Additionally, three different diamine ligands were tested.
The product 2b was obtained in 30% yield with an enantio-
selectivity of 13% using ligand 6a. The reaction gave a simi-
lar yield (31%) and ee (11%) in the presence of 6c. The
hemilabile ligand 7a gave a moderate yield of 22%, howev-
er, the ee was significantly lower (5%).
As none of the tested chiral ligands revealed satisfying re-
sults, we considered the use of chiral Brønsted acids as co-
catalysts. Recently, chiral 1,1’-binaphthalene-2,2’-diol phos-
phoric acids have been used successfully in the enantioselec-
tive reduction of C=X bonds using Hantzsch esters as reduc-
ing agents.[16] Consequently, we combined zinc(II) triflate
with different phosphoric acids 8 for the hydrogenation of
imine 1b (Table 2). The highest yield (31%) of amine 2b
was obtained using (R)-TRIP 8d as the ligand, albeit race-
mically. Notably, in the presence of H8-1,1’-binaphthyl-2,2’-
diyl hydrogen phosphate 8e almost no hydrogenation took
place. The chiral Brønsted acids 8a–8c and 8 f led to low
product yields between 10% and 26%; a chiral induction of
up to 15% ee was detected for 8a (Table 2, entry 1). To
prove the highest possible enantioselectivity with the tested
ligands, we performed hydrogenation experiments of N-(1-
phenylethylidene)-aniline (1b) using stoichiometric amounts
of zinc(II) triflate with ligands 3b, 3g, and 3h. As shown in
Scheme 1, good yields between 72% and 84% of 2b were
achieved. In the presence of ligand 3b only a slight increase
in the ee from 17% to 19% was obtained, and 3h produced
amine 2b as a racemate. However, the best enantioselectivi-
Figure 2. Zn-catalyzed hydrogenation of 1b in the presence of different
chiral P-containing ligands 3 (GC yields are presented).
gands, which are well-known for hydrogenation reaction-
s.[13a,i,14] Without any ligand, the hydrogenation of 1b to 2b
proceeded in 87% isolated yield. However, employing
chiral P-ligands such as 3a–3j decreased the product yield
significantly. The highest yield of 61% was achieved with
Abstract in German: Die ersten asymmetrischen Hydrie
rungen bzw. Transfer-hydrierungen von Iminen zu Aminen
in Gegenwart von Zinktriflat und chiralen Liganden werden
beschrieben. Beste Enantioselektivitꢁten werden mit dem
Binaphthophosphepin-Liganden 3g erhalten. Verschiedene
Imine konnten so zu den entsprechenden Aminen mit mo
deraten Ausbeuten und Enantioselektivitꢁten umgesetzt
werden.
ty of 37% ee was achieved with Zn
ACHTUNGRTEN(NUGN OTf)2/3g. Reducing the
temperature to 808C to obtain higher enantioselectivity
&
&
&2
&
www.chemasianj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Zinc-Catalyzed Asymmetric Hydrogenations
Figure 3. Different chiral N-containing ligands 4, 5, 6, and 7 for imine hydrogenation reactions (GC yields are presented).
Table 2. Variation of different chiral Brønsted acids for the hydrogena-
tion of imine 1b.[a]
Entry
Brønsted acid [mol%]
Yield of 2b [%][b]
ee [%][c]
1
2
3
4
5
6
8a
8b
8c
8d
8e
8 f
10
26
16
31
3
15
5
racemic
racemic
n.d.
17
7
[a] Reaction conditions: 1b (0.25 mmol), ZnACTHNUTRGNEUNG(OTf)2, Brønsted acid 8, tolu-
ene (1 mL), H2 (80 bar), 1208C, 24 h. [b] The yield was determined by
GC methods using hexadecane as an internal standard. [c] The ee was de-
termined by chiral HPLC analysis. n.d.=not determined.
Scheme 1. Reduction of 1a with stoichiometric amounts of ZnACHTUNGTRENNUNG(OTf)2 and
selected ligands.
using ZnACHTUNGTRENNUNG(OTf)2/3g led to a lower yield (14%) of 2b with an
enantioselectivity of 34% ee. Noticeably, the lower tempera-
ture reduces the yield, whereas the enantiomeric excess re-
mains nearly the same as that at 1208C (37% ee).
lar rate or the chiral catalyst system Zn
stable during the reaction.
ACHTUNGRTEN(NUNG OTf)2/3g is not
These results indicate that a non-asymmetric reduction of
Obviously, Zn
However, as already discussed in our previous work,[12] we
analyzed Zn(OTf)2 by inductively coupled plasma spectrom-
etry, where no detectable amounts of Ru, Rh, Ir, and Pd
ACHTUNGRTENN(UNG OTf)2 is a unique hydrogenation catalyst.
the imine mediated by Zn
the enantioselective hydrogenation catalyzed by Zn
3g. Possibly, the former catalytic reaction proceeds at a simi-
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
were observed. Furthermore, several samples of ZnACHTUNGTRENNUNG(OTf)2
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
3
&
&
&
These are not the final page numbers! ÞÞ

Matthias Beller et al.
FULL PAPER
tion reagents (Table 3). Besides, a typical Hantzsch ester,
which gave nearly full conversion after 1 h (Table 3,
entry 1), both iPrOH/KOtBu and HCOOH/NEt3 have been
used as hydrogen donors. Using iPrOH as the hydrogen
source and KOtBu as the base resulted in no reaction
(Table 3, entries 2 and 3). HCOOH/NEt3 produced the
amine 2a in a low yield of 7% after 1 h and in 8% yield
after 24 h (Table 3, entries 4 and 5), thus showing that the
catalyst is not stable under these reaction conditions.
Unfortunately, no enantioselectivity was observed using
the Hantzsch ester in the presence of zinc(II) triflate and
different ligands (Table 4). Notably, in the absence of
ZnACTHNUTRGEN(NUG OTf)2 and ligand, no reaction was observed.
Table 4. Transfer hydrogenation of imine 1a with Hantzsch ester.[a]
Figure 4. Substrate scope of the Zn/3g-catalyzed hydrogenation of
imines.
from various suppliers showed identical results for the hy-
drogenation of 1a to 2a.
Entry ZnACHTUNGTRNEUNG
(OTf)2 [mol%] Ligand [mol%] T [8C] Yield[b] [%] ee[b] [%]
1
2
3
4
5
6
7
8
–
2
2
2
1
3
5
5
5
5
2
–
60
60
60
60
60
60
60
80
80
80
80
–
–
Finally, the optimized catalyst system was applied in the
reduction of seven different imines 1 to the corresponding
amines 2. As shown in Figure 4, the hydrogenation of differ-
ent meta- and para-substituted aromatic imines bearing elec-
tron-donating as well as electron-withdrawing groups gave
the corresponding amines in low to moderate isolated yields
between 28% and 49%.
Furthermore, a disubstitued substrate was employed to
furnish the desired amine 2g (Figure 4). Notably, the ach-
ieved enantiomeric excesses (up to 27%) are not satisfying
for synthetic applications. Nevertheless, to our knowledge,
these reactions constitute the first examples of enantioselec-
tive zinc-catalyzed hydrogenations.
3b [5]
3g [5]
6a [5]
3g [5]
3g [5]
3g [5]
–
3g [5]
3g [10]
3g [5]
80
90
89
90
93
95
>99
97
98
93
racemic
racemic
racemic
racemic
5
racemic
–
racemic
racemic
racemic
9
10
11
[a] Reaction conditions: 1a (0.25 mmol), ZnACTHNUTRGENUG(N OTf)2 (5 mol%), chiral
ligand, Hantzsch ester (0.7 mmol, 1.4 equiv), toluene (1.0 mL), 608C for
1 h. [b] Yield determined by GC methods using hexadecane as an inter-
nal standard. [c] The ee was determined by chiral HPLC analysis.
To perform the catalytic hydrogenation under milder re-
action conditions, we also tested typical transfer hydrogena-
Conclusions
Table 3. Zn-catalyzed transfer hydrogenation of imine 1a.
The first enantioselective zinc-catalyzed hydrogenations of
imines are presented. Moderate to good yields are obtained
in the presence of different Zn/phosphine catalyst systems,
although the obtained enantioselectivities of up to 27% ee
are too low to be synthetically useful. Nevertheless, our
work demonstrates for the first time that such asymmetric
hydrogenations are possible. We hope that this work will in-
spire other research groups to improve the stereoselectivity
with improved ligands. In addition, zinc-catalyzed transfer
hydrogenations of imines using a Hantzsch ester as a reduc-
ing agent are demonstrated.
Entry
1[a]
H2 source
t [h]
Yield[c] [%]
95
ee[d] [%]
1
racemic
Hantzsch ester
iPrOH/KOtBu
iPrOH/KOtBu
HCOOH/NEt3
HCOOH/NEt3
2[b]
3[b]
4[b]
5[b]
1
24
1
–
–
7
8
n.d.
n.d.
racemic
racemic
24
[a] Reaction conditions: 1a (0.5 mmol), 5 mol% Zn
Hantzsch ester (0.7 mmol, 1.4 equiv), toluene (1 mL), 608C for 1 h.
[b] Reaction conditions: 1a (0.5 mmol), 5 mol% Zn(OTf)2, 5 mol% 3g,
iPrOH (1 mL)/10 mol% KOtBu or HCOOH/NEt3 (1 mL), 608C for 1 h.
[c] Yield determined by GC methods using hexadecane as an internal
standard. [d] The ee was determined by chiral HPLC analysis.
ACHTUNGRTEN(NUNG OTf)2, 5 mol% 3g,
Experimental Section
A
Unless otherwise stated, all reactions were carried out under an argon at-
mosphere with exclusion of moisture from reagents and glassware using
standard techniques for manipulating air-sensitive compounds. All isolat-
1
ed compounds were characterized by H NMR and 13C NMR spectrosco-
&
&
&4
&
www.chemasianj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Zinc-Catalyzed Asymmetric Hydrogenations
py, high resolution mass spectrometry (HRMS), and HPLC. NMR spec-
tra were recorded on Bruker AV 300 or AV 400 spectrometers. All chem-
ical shifts (d) are reported in ppm and coupling constants (J) in Hz. All
chemical shifts are related to solvent peaks (chloroform: 7.26 (1H), 77.00
(13C)). All measurements were carried out at room temperature unless
otherwise stated. Mass spectra were generally recorded on a Finnigan
MAT 95-XP (Thermo Electron) or on a 6210 Time-of-Flight LC/MS
(Agilent). Gas chromatography was performed on a HP 6890 with a HP5
column (Agilent). The enantioselectivities were recorded with chiral
HPLC on a HP 1100 (Hewlett Packard) or with a chiral GC on HP6890
(Hewlett Packard/Agilent).
Asymmetric Hydrogenation of Imines with iPrOH/KOtBu or HCOOH/
NEt3
Under an argon atmosphere, a glass vial was charged with ZnACHTUNGTRENNUNG(OTf)2
(4.5 mg, 0.0125 mmol), chiral ligand 3g (0.0125 mmol), imine 1a
(0.25 mmol), iPrOH (1 mL)/10 mol% KOtBu or HCOOH/NEt3 (1 mL),
and
a magnetic stirring bar. Afterwards, the vial was capped with
a septum equipped with a syringe and set in the alloy plate. The reaction
mixture was heated up to 608C for 1 hour to give the corresponding
amine 2a. After the reaction had finished, the yield was determined by
GC and the ee with chiral HPLC.
General Information
Unless otherwise stated, commercial reagents were used without purifica-
tion. All catalytic hydrogenation experiments using molecular hydrogen
were carried out in a Parr Instruments 4560 series autoclave (300 mL)
containing an alloy plate with wells for seven 4 mL glass vials.
Acknowledgements
This research has been funded by the State of Mecklenburg-Western
Pomerania, the BMBF and the DFG (Leibniz Prize). We thank Dr. W.
Baumann, Dr. C. Fischer, S. Buchholz, S. Schareina, and S. Smyczek (all
at the LIKAT) for their excellent technical and analytical support.
Non-Asymmetric Hydrogenation of Imines with Hydrogen
Under an argon atmosphere, a glass vial was charged with Zn
(9.1 mg, 0.025 mmol), imine 1a (0.5 mmol), toluene (0.5 mL), and a mag-
netic stirring bar. Afterwards, the vial was capped with septum
ACHTUNGERTN(NUNG OTf)2
a
equipped with a syringe and set in the alloy plate, which was then placed
into the autoclave. Once sealed, the autoclave was purged 3 times with
hydrogen, then pressurized to 80 bar and heated at 1208C for 24 h to
give the corresponding amine 2a. After the reaction had finished, the au-
toclave was cooled to 258C, depressurized, and the reaction mixture was
analyzed by GC.
[1] J. J. Brunet, D. Neibecker, in Catalytic Heterofunctionalization from
Hydroamination to Hydrozirconation, (Eds.: A. Togni, H. Grꢀtz-
macher), Wiley VCH, Weinheim, 2001, pp. 91–141.
[2] a) T. E. Mꢀller, M. Beller, Chem. Rev. 1998, 98, 675–703; b) J.
Seayad, A. Tillack, C. G. Hartung, M. Beller, Adv. Synth. Catal.
2002, 344, 795–813; c) F. Pohlki, S. Doye, Chem. Soc. Rev. 2003, 32,
104–114; d) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36, 1407–
1420; e) T. E. Mꢀller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada,
Chem. Soc. Rev. 2008, 108, 3795–3892.
Asymmetric Hydrogenation of Imines with Hydrogen
Under an argon atmosphere, a glass vial was charged with Zn
ACHTUNGERTN(NUNG OTf)2
[3] D. J. Mack, M. L. Weinrich, E. Vitaku, J. T. Njardarson, Top 200
Brand Name Drugs by US retail sales in 2010; compiled and pro-
duced by the Njardarson group, http://cbc.arizona.edu/njardarson/
group/sites/default/files/Top%20200%20Brand-name%20Drugs%20-
by %20US%20Retail%20Sales%20in%202010sm_0.pdf.
(4.5 mg, 0.0125 mmol), chiral ligand 3, 4, 5, 6, 7, or (0.0125 or
8
0.025 mmol), imine 1 (0.25 mmol), toluene (1 mL), and a magnetic stir-
ring bar. Afterwards, the vial was capped with a septum equipped with
a syringe and set in the alloy plate, which was then placed into the auto-
clave. Once sealed, the autoclave was purged 3 times with hydrogen,
then pressurized to 80 bar and heated at 1208C for 24 h to give the corre-
sponding amine 2. After the reaction had finished, the autoclave was
cooled to 258C, depressurized, and the yield was determined by GC and
the ee by HPLC or chiral GC.
[4] For reviews on this topic, see: a) F. Spindler, H.-U. Blaser, in: Tran-
sition Metals for Organic Synthesis, Vol. 2, 2nd ed. (Eds.: M. Beller,
C. Bolm), Wiley-VCH, Weinheim, 2004, p. 113; b) H.-U. Blaser, F.
Spindler, in Handbook of Homogeneous Hydrogenation, Vol. 3
(Eds: J. G. de Vires, C. J. Elsevier), Wiley-VCH, Weinheim, 2007,
pp. 1193ff; c) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry 1999,
10, 2045–2061; d) H.-U. Blaser, C. Malan, B. Pugin, F. Spinder, H.
Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103–151; e) W.
Tang, X. Zhang, Chem. Rev. 2003, 103, 3029–3069; f) T. C. Nugent,
M. EI-Shazly, Adv. Synth. Catal. 2010, 352, 753–819; g) M. Rueping,
E. Sugiono, F. R. Schoepke, Synlett 2010, 852–865; h) N. Fleury-Brꢃ-
geot, V. de La Fuente, S. Castillꢄn, C. Claver, ChemCatChem 2010,
2, 1346–1371; i) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011,
111, 1713–1760; j) C. Wang, B. Villa-Marcos, J. Xiao, Chem.
Commun. 2011, 47, 9773–9780.
Asymmetric Hydrogenation of Imines with Hydrogen–Substrate Scope
Under an argon atmosphere, a glass vial was charged with ZnACTHNUTRGNEUNG(OTf)2
(4.5 mg, 0.0125 mmol), chiral ligand 3g (0.025 mmol), imine
1 (0.25 mmol), toluene (1 mL), and a magnetic stirring bar. Afterwards,
the vial was capped with a septum equipped with a syringe and set in the
alloy plate, which was then placed into the autoclave. Once sealed, the
autoclave was purged 3 times with hydrogen, then pressurized to 80 bar
and heated at 1208C for 24 h to give the corresponding amine 2. After
the reaction had finished, the autoclave was cooled to 258C, depressur-
ized, and the reaction mixture was purified by column chromatography
on silica gel (heptane/ethyl acetate=9:1). The isolated compounds 2a–2 f
were then analyzed by NMR spectroscopy, HRMS, and HPLC or chiral
GC.
[5] a) P. A. Chaloner, M. A. Esteruelas, F. Joꢄ, L. A. Oro, Homogeneous
Hydrogenation, Kluwer Academic Publishers, Band 15, Niederlande
1994.
[6] a) H.-U. Blaser, F. Spindler, Comprehensive Asymetric Catalysis
(Eds.: E. Jacobsen, A. Pfaltz, H. Yamamoto), Springer Berlin, 1999,
p. 247; b) H.-U. Blaser, Adv. Synth. Catal. 2002, 344, 17–31; c) H.-U.
Blaser, B. Pugin, F. Spindler, A. Togni, C. R. Chim. 2002, 5, 379–
385; d) H.-U. Blaser, B. Pugin, F. Spindler, M. Thommen, Acc.
Chem. Res. 2007, 40, 1240–1250; e) C. Claver, E. Fernꢅndez in
Modern Reduction Methods (Eds.: Ph. Anderson, I. Munslow),
Asymmetric Hydrogenation of Imines with Hantzsch Ester
Under an argon atmosphere, a glass vial was charged with ZnACTHNUTRGNEUNG(OTf)2
(4.5 mg, 0.0125 mmol), chiral ligand 3b, 3g, or 6a (0.0125 mmol), imine
1a (0.25 mmol), Hantzsch ester (1.4 equiv, 0.7 mmol), toluene (1 mL),
and
a magnetic stirring bar. Afterwards, the vial was capped with
a septum equipped with a syringe and set in the alloy plate. The reaction
mixture was heated up to 608C for 1 hour to give the corresponding
amine 2a. After the reaction had finished, the yield was determined by
GC and the ee with chiral HPLC.
ˇ
Wiley-VCH, Weinheim, 2008, p. 237; f) J. G. de Vries, N. Mrsic,
Catal. Sci. Technol. 2011, 1, 727–735.
[7] For applications of Ir catalysts, see: a) F. Spindler, B. Pugin, H.-U.
Blaser, Angew. Chem. 1990, 102, 561–562; Angew. Chem. Int. Ed.
Engl. 1990, 29, 558–559; b) A. Togni, Angew. Chem. 1996, 108,
1581–1583; Angew. Chem. Int. Ed. Engl. 1996, 35, 1475–1477; c) R.
Sablong, J. A. Osborn, Tetrahedron: Asymmetry 1996, 7, 3059–3062;
d) G. Zhu, X. Zhang, Tetrahedron: Asymmetry 1998, 9, 2415–2418;
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
5
&
&
&
These are not the final page numbers! ÞÞ

Matthias Beller et al.
FULL PAPER
e) C. Bianchini, P. Barbaro, G. Scapacchi, E. Farnetti, M. Graziani,
Organometallics 1998, 17, 3308–3310; f) D. Xiao, X. Zhang, Angew.
Chem. 2001, 113, 3533–3536; Angew. Chem. Int. Ed. 2001, 40, 3425–
3428; g) X.-B. Jiang, A. J. Minnaard, B. Hessen, B. L. Feringa,
A. L. L. Duchateau, J. G. O. Andrien, J. A. Boogers, J. G. de Vries,
Org. Lett. 2003, 5, 1503–1506; h) E. Guiu, B. MuÇoz, S. Castillon, C.
Claver, Adv. Synth. Catal. 2003, 345, 169–171; i) C. Moessner, C.
Bolm, Angew. Chem. 2005, 117, 7736–7739; Angew. Chem. Int. Ed.
2005, 44, 7564–7567; j) T. Imamoto, N. Iwadate, K. Yoshida, Org.
Lett. 2006, 8, 2289–2292; k) S.-F. Zhu, J.-B. Xie, Y.-Z. Zhang, S. Li,
Q.-L. Zhou, J. Am. Chem. Soc. 2006, 128, 12886–12891; l) M. T.
Reetz, O. Bondarev, Angew. Chem. 2007, 119, 4607–4610; Angew.
Chem. Int. Ed. 2007, 46, 4523–4526; m) C. Li, C. Wang, B. Villa-
Marcos, J. Xiao, J. Am. Chem. Soc. 2008, 130, 14450–14451; n) C.
Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2009, 131, 6967–
6969; o) S. Shirai, H. Nara, Y. Kayaki, T. Ikariya, Organometallics
2009, 28, 802–809; p) Z. Han, Z. Wang, X. Zhang, K. Ding, Angew.
Chem. 2009, 121, 5449–5453; Angew. Chem. Int. Ed. 2009, 48, 5345–
5349; q) W. Li, G. Hou, M. Chang, X. Zhang, Adv. Synth. Catal.
nenberg, F. Marras, S. Gladiali, M. Beller, Tetrahedron: Asymmetry
2007, 18, 1288–1298; c) S. Enthaler, G. Erre, K. Junge, K. Schrçder,
D. Addis, D. Michalik, M. Hapke, D. Redkin, M. Beller, Eur. J. Org.
Chem. 2008, 3352–3362; d) G. Erre, K. Junge, S. En
thaler, D. Addis, D. Michalik, A. Spannenberg, M. Beller, Chem.
Asian J. 2008, 3, 887–894; e) N. S. Shaikh, S. Enthaler, K. Junge, M.
Beller, Angew. Chem. 2008, 120, 2531–2535; Angew. Chem. Int. Ed.
2008, 47, 2497–2501; f) G. Erre, S. Enthaler, K. Junge, D. Addis, M.
Beller, Adv. Synth. Catal. 2009, 351, 1437–1441; g) K. Junge, B.
Wendt, S. Enthaler, M. Beller, ChemCatChem 2010, 2, 453–458;
h) K. Junge, B. Wendt, D. Addis, S. Zhou, S. Das, M. Beller, Chem.
Eur. J. 2010, 16, 68–73; i) K. Junge, B. Wendt, D. Addis, S. Zhou, S.
Das, S. Fleischer, M. Beller, Chem. Eur. J. 2011, 17, 101–105; j) G.
Wienhçfer, I. Sorribes, A. Boddien, F. Westerhaus, K. Junge, H.
Junge, R. Llusar, M. Beller, J. Am. Chem. Soc. 2011, 133, 12875–
12879.
[14] Selected manuscripts: a) R. Noyori, T. Ohkuma, M. Kitamura, H.
Takaya, N. Sayo, H. Kumobayashi, S. Akutagawa, J. Am. Chem. Soc.
1987, 109, 5856–5858; b) M. Kitamura, T. Ohkuma, S. Inoue, N.
Sayo, H. Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya, R.
Noyori, J. Am. Chem. Soc. 1988, 110, 629–631; c) K. Junge, G.
Oehme, A. Monsees, T. Riermeier, U. Dingerdissen, M. Beller, Tet-
rahedron Lett. 2002, 43, 4977–4980; d) K. Junge, G. Oehme, A.
Monsees, T. Riermeier, U. Dingerdissen, M. Beller, J. Organomet.
Chem. 2003, 675, 91–96; e) K. Junge, B. Hagemann, S. Enthaler, G.
Oehme, M. Michalik, A. Monsees, T. Riermeier, U. Dingerdissen,
M. Beller, Angew. Chem. 2004, 116, 5176–5179; Angew. Chem. Int.
Ed. 2004, 43, 5066–5069; f) K. Junge, B. Hagemann, S. Enthaler, A.
Spannenberg, M. Michalik, G. Oehme, A. Monsees, T. Riermeier,
M, Beller, Tetrahedron: Asymmetry 2004, 15, 2621–2631; g) S. En
thaler, B. Hagemann, K. Junge, G. Erre, M. Beller, Eur. J. Org.
Chem. 2006, 2912–2917; h) Z. Lu, S. Mah, Angew. Chem. 2008, 120,
264–303; Angew. Chem. Int. Ed. 2008, 47, 258–297; i) M. El-Sha
zlya, T. C. Nugenta, Adv. Synth. Catal. 2010, 352, 753–819.
ˇ ´
2009, 351, 3123–3127; r) N. Mrsic, A. J. Minnaard, B. L. Feringa,
J. G. deVries, J. Am. Chem. Soc. 2009, 131, 8358–8359; s) G. Hou, F.
Gosselin, W. Li, J. C. McWilliams, Y. Sun, M. Weisel, P. D. OꢆShea,
C.-Y. Chen, I. W. Davies, X. Zhang, J. Am. Chem. Soc. 2009, 131,
9882–9883; t) A. Baeza, A. Pfaltz, Chem. Eur. J. 2010, 16, 4003–
4009; u) G. Hou, R. Tao, Y. Sun, X. Zhang, F. Gosselin, J. Am.
Chem. Soc. 2010, 132, 2124–2125; v) B. Villa-Marcos, C. Li, K. Mul-
holland, P. J. Hogan, J. Xiao, Molecules 2010, 15, 2453–2472.
[8] For use of Ru catalysts, see: a) W. Oppolzer, M. Wills, M. Starke-
mann, G. Bernardinelli, Tetrahedron Lett. 1990, 31, 4117–4120;
b) N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1996, 118, 4916–4917; c) K. Abdur-Rashid, A. J. Lough,
R. H. Morris, Organometallics 2001, 20, 1047–1049; d) C. J. Cobley,
J. P. Henschke, Adv. Synth. Catal. 2003, 345, 195–201; e) D. Guijar
ro, ꢇ. Pablo, M. Yus, Tetrahedron Lett. 2009, 50, 5386–5388.
[9] For use of Rh catalysts, see: a) A. G. Becalski, W. R. Cullen, M. D.
Fryzuk, B. R. James, G.-J. Kang, S. R. Rettig, Inorg. Chem. 1991, 30,
5002–5008; b) M. J. Burk, J. E. Feaster, J. Am. Chem. Soc. 1992,
114, 6266–6267; c) J. Mao, D. C. Baker, Org. Lett. 1999, 1, 841–843;
d) F. Spindler, H.-U. Blaser, Adv. Synth. Catal. 2001, 343, 68–70;
e) R. Kadyrov, T. H. Riermeier, Angew. Chem. 2003, 115, 5630–
5632; Angew. Chem. Int. Ed. 2003, 42, 5472–5474; f) G. Shang, Q.
Yang, X. Zhang, Angew. Chem. 2006, 118, 6508–6510; Angew.
Chem. Int. Ed. 2006, 45, 6360–6362.
[15] K. Junge, K. Mçller, B. Wendt, S. Das, D. Gçrdes, K. Thurow, M.
Beller, Chem. Asian J. 2012, 7, 314–320.
[16] For selected examples see: a) M. Rueping, E. Sugiono, C. Azap, T.
Theissmann, M. Bolte, Org. Lett. 2005, 7, 3781–3783; b) S. Hoff-
mann, A. M. Seayad, B. List, Angew. Chem. 2005, 117, 7590–7593;
Angew. Chem. Int. Ed. 2005, 44, 7424–7427; c) M. Rueping, A. P.
Antonchik, T. Theissmann, Angew. Chem. 2006, 118, 3765–3768;
Angew. Chem. Int. Ed. 2006, 45, 3683–3686; d) M. Rueping, S. P.
Antonchik, T. Theissmann, Angew. Chem. 2006, 118, 6903–6907;
Angew. Chem. Int. Ed. 2006, 45, 6751–6755; e) S. Hoffmann, M.
Nicoletti, B. List, J. Am. Chem. Soc. 2006, 128, 13074–13075; f) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem. Soc.
2006, 128, 84–86; g) G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc.
2007, 129, 5830–5831; h) V. N. Wakchaure, J. Zhou, S. Hoffmann, B.
List, Angew. Chem. 2010, 122, 4716–4718; Angew. Chem. Int. Ed.
2010, 49, 4612–4614; i) V. N. Wakchaure, M. Nicoletti, L. Batjen, B.
List, Synlett 2010, 2708–2710.
[10] For use of Pd catalysts, see: a) H. Abe, H. Amii, K. Uneyaama, Org.
Lett. 2001, 3, 313–315; b) Q. Yang, G. Shang, W. Gao, J. Deng, X.
Zhang, Angew. Chem. 2006, 118, 3916–3919; Angew. Chem. Int. Ed.
2006, 45, 3832–3835; c) Y.-Q. Wang, S.-M. Lu, Y.-G. Zhou, J. Org.
Chem. 2007, 72, 3729–3734.
[11] S. Zhou, S. Fleischer, K. Junge, M. Beller, Angew. Chem. 2011, 123,
5226–5230; Angew. Chem. Int. Ed. 2011, 50, 5120–5124.
[12] S. Werkmeister, S. Fleischer, S. Zhou, K. Junge, M. Beller, ChemSu-
sChem 2012, 5, 777–782.
[13] a) S. Enthaler, B. Hagemann, S. Bhor, G. Anilkumar, M. K. Tse, B.
Bitterlich, K. Junge, G. Erre, M. Beller, Adv. Synth. Catal. 2007, 349,
853–860; b) S. Enthaler, G. Erre, K. Junge, D. Michalik, A. Span
Received: April 8, 2012
Revised: June 15, 2012
Published online: && &&, 0000
&
&
&6
&
www.chemasianj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

FULL PAPER
Hydrogenation
Svenja Werkmeister, Steffen Fleischer,
Kathrin Junge,
Matthias Beller*
&&&& — &&&&
Towards a Zinc-Catalyzed Asymmetric
Hydrogenation/Transfer Hydrogena-
tion of Imines
Let’s do it with Zinc: The first exam-
ples of zinc-catalyzed enantioselective
hydrogenations of imines to amines
are presented with moderate to good
yields.
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
7
&
&
&
These are not the final page numbers! ÞÞ