Iridium-catalyzed asymmetric hydrogenation of imines

Article abstract of DOI:10.1002/chem.200903418

We have evaluated a wide range of iridium complexes derived from chiral oxazoline-based N,P ligands for the asymmetric hydrogenation of imines and identified three efficient catalysts. These catalysts are readily synthesized by straightforward convenient routes and are air and moisture stable. In the reduction of acetophenone N-arylimines and related acyclic substrates, excellent enantioselectivities (up to 96 % ee) were obtained by using 0.1-0.5 mol % of catalyst at -20°C and 5-50 bar hydrogen pressure.

Full text of DOI:10.1002/chem.200903418

FULL PAPER
DOI: 10.1002/chem.200903418
Iridium-Catalyzed Asymmetric Hydrogenation of Imines
Alejandro Baeza and Andreas Pfaltz*[a]
Abstract: We have evaluated a wide range of iridium complexes derived from
chiral oxazoline-based N,P ligands for the asymmetric hydrogenation of imines
and identified three efficient catalysts. These catalysts are readily synthesized by
straightforward convenient routes and are air and moisture stable. In the reduction
of acetophenone N-arylimines and related acyclic substrates, excellent enantiose-
lectivities (up to 96% ee) were obtained by using 0.1–0.5 mol% of catalyst at
À208C and 5–50 bar hydrogen pressure.
Keywords: asymmetric catalysis
·
asymmetric hydrogenation · imines ·
iridium · N,P ligands
Introduction
tion of acetophenone N-phenylimine, up to 89% ee was ach-
ieved by using 0.1 mol% catalyst at 58C. Subsequently,
many different iridium catalysts with chiral N,P ligands were
developed in other laboratories (see Scheme 1).[5–15] The suc-
cess we had with modified PHOX and related oxazoline-
based N,P ligands in the asymmetric hydrogenation of ole-
fins,[20] including enamines,[21] prompted us to reinvestigate
imine hydrogenations with a wide range of Ir–N,P ligand
complexes that have been developed in our group during
the last 10 years. Herein we report the results of this study,
in which we identified several readily accessible, highly effi-
cient catalysts for the asymmetric reduction of acyclic N-
Chiral amines occur as structural elements in many biologi-
cally active natural and unnatural products. They are also of
importance as chiral auxiliaries, catalysts, and resolving
agents. Consequently, the asymmetric hydrogenation of
imines has found much attention as a direct, atom-economi-
cal route to optically active amines. During the last two de-
cades, various highly enantioselective chiral catalysts have
been reported for this transformation, many of them based
on iridium (see Scheme 1).[1–19] The potential for industrial
application is demonstrated by the well-known process for
the multiton-scale production of the herbicide (S)-metola-
chlor from an imine precursor.[12] The catalyst used in this
process, an iridium–Josiphos complex (Scheme 1, structure
IX), stands out for its extremely high activity and efficiency
with a turnover number exceeding one million. However,
most other catalysts are much less active and require rela-
tively high loadings compared with the standards reached in
asymmetric hydrogenations of olefins and ketones. An addi-
tional problem is the generally narrow application range.
Therefore, the search for new catalysts for the asymmetric
hydrogenation of imines remains an important area of re-
search.
arylACTHNUTRGNEiUNG mines.
Results and Discussion
Initial experiments were performed on the imine 1a, which
results from the condensation of aniline and acetophenone.
The reaction was carried out under 5 bar hydrogen pressure
for 4 h, with 1 mol% iridium–N,P ligand catalyst in a range
of solvents. The catalysts chosen were Ir–PHOX complex 3a
and Ir–ThrePHOX complex 4a; the latter is commercially
available (Table 1).[22] The best enantioselectivities were ob-
tained with the Ir–PHOX complex 3a. Among the solvents
tested, CH2Cl2 and toluene (Table 1, entries 1–4) gave the
best results. Although both solvents worked equally well, di-
chloromethane was selected as the solvent of choice because
the catalysts were more soluble in this medium. tert-Butyl
methyl ether (TBME)[7] gave lower enantioselectivities
(Table 1, entries 5 and 6), and MeOH or MeOH/toluene
mixtures, which gave excellent results for this reaction with
other iridium complexes,[8] led to a dramatic drop in both
In 1997 we reported that cationic iridium–PHOX com-
plexes (Scheme 1, structure I) are efficient catalysts for the
asymmetric hydrogenation of N-arylimines.[4] In the reduc-
[a] Dr. A. Baeza, Prof. A. Pfaltz
Department of Chemistry, University of Basel
St. Johanns Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
Chem. Eur. J. 2010, 16, 4003 – 4009
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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previous work.[4] In the hydro-
genation of unfunctionalized
olefins, much larger turnover
numbers are achieved when
BArF instead of hexafluoro-
phosphate salts are employed
and, consequently, BArF salts
have become the catalysts of
choice.[24] The positive effect of
BArF is much less pronounced
in the hydrogenation of imines.
Preliminary tests showed only a
slightly higher rate and no dif-
ference in ee value for the BArF
salt 3c relative to the corre-
sponding hexafluorophosphate.
However, the BArF salts have
the advantage that they are
more soluble in apolar media.
In addition, they are less mois-
ture sensitive and easier to
handle and, therefore, were
chosen as standard catalysts.
Scheme 1. Selected examples of catalysts successfully applied in the asymmetric hydrogenation of imines.
COD=1,5-cyclooctadiene, BArF =tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
Ir–PHOX complexes 3a–c all
reacted with full conversion
and enantioselectivities of 82–
AHCTUNGTRENNUNG
Table 1. Solvent influence in the catalytic hydrogenation of imines.
Entry
Catalyst
Solvent
Conv. [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
3a
4a
3a
4a
3a
4a
3a
3a
CH2Cl2
CH2Cl2
PhCH3
>99
>99
>99
>99
>99
>99
5
85
67
85
67
72
69
44
30
PhCH3
TBME[c]
TBME[c]
MeOH
PhCH3/MeOH (4/1)
10
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see the Ex-
perimental Section for details). [c] tert-Butyl methyl ether.
Scheme 2. Catalysts employed in the screening of asymmetric hydrogena-
tion of imines.
conversion and enantioselectivity (Table 1, entries 7 and 8).
The use of additives, such as iodine[6,10] or phthalimide,[23]
often employed in these reactions, was also tested but gave
poor results.
Subsequently, a series of different catalysts was screened
under standard conditions in CH2Cl2 at 5 bar hydrogen pres-
sure (Scheme 2 and Table 2). In general, we used BArF salts
in this study rather than hexafluorophosphates, as in our
85% ee (Table 2, entries 1–3). In contrast, the sterically
more demanding catalyst 3d with a tert-butyl group in the
oxazoline ring and a bis(ortho-tolyl)-substituted P atom
(Table 2, entry 4) gave only 90% conversion and a lower ee
value. This is in line with previous work, which had shown
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Chem. Eur. J. 2010, 16, 4003 – 4009

Asymmetric Imine Hydrogenation
FULL PAPER
Table 2. Asymmetric hydrogenation of imines: Catalyst screening.
Table 3. Asymmetric hydrogenation of imines: Variation of the tempera-
ture.
Entry
Catalyst
Conv. [%][a]
ee [%][b]
Entry
Catalyst
T [8C]
Conv. [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
5a
5b
6a
6b
7a
7b
7c
8
>99
>99
>99
90
>99
>99
90
85
82
84
72
67
63
79
60
88
74
82
89
5
1
2
3
4
5
6
7
8
3a
6a
7b
8
3a
6a
7b
8
3a
6a
3a
6a
0
0
0
>99
>99
>99
>99
95
>99
80
>99
10
90
92
92
90
0
À20
À20
À20
À20
À40[c]
À40[c]
40
93
95.5
95.5
94
94
97
5
9
>99
>99
>99
>99
5
>99
80
>99
10
11
12
13
14
15
16
9
10
11
12
80
>99
>99
84
86
40
85
60
83
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see the Ex-
perimental Section for details). [c] 6 h reaction time.
9
10
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see the Ex-
perimental Section for details).
ried out at À408C with complexes 3a and 6a (Table 3, en-
tries 9 and 10), but in both cases the reaction did not go to
completion, even when the reaction time was increased to
6 h, and only a slight improvement in enantioselectivity was
observed. However, these results demonstrated that catalyst
6a is more active than 3a. At 408C, almost the same ee
values were obtained as those at room temperature
(Table 3, entries 11 and 12, compare with Table 2, entries 1
and 9).
We next studied the effects of catalyst loading and hydro-
gen pressure (Table 4). At 0.5 mol% catalyst loading and
5 bar hydrogen pressure at 08C, full conversion and the
same ee value as with 1 mol% catalyst was achieved by
using complex 3a. By using the same catalyst loading and
pressure, the more reactive complex 8 gave 98% conversion
that large substituents at these positions led to lower reac-
tivity and enantioselectivity. As expected, other complexes
with a tert-butyl group at the stereogenic center, such as the
phosphanyl–imidazoline complexes 5a, 5b, and 7c, also
gave unsatisfactory results (Table 2, entries 7, 8, 13). Ir–
ThrePHOX complexes 4a and 4b gave full conversion, but
only moderate enantioselectivity (Table 2, entries 5 and 6).
Very promising results (full conversion and 88% ee) were
achieved with the Ir–SimplePHOX complex 6a, with an
electron-rich dicyclohexyl-substituted P atom, whereas the
corresponding diphenylphosphanyl derivative 6b gave only
74% ee (Table 2, entries 9 and 10). The imidazoline ana-
logues 7a and 7b, the recently developed NeoPHOX com-
plex 8,[25] and catalyst 10[26] with a thiophene backbone also
performed well, with ee values between 82 and 89%
(Table 2, entries 11, 12, 14, 16). Complex 9, on the other
hand, which is an excellent catalyst for the hydrogenation of
tetrasubstituted olefins,[27] gave poor results.
Table 4. Asymmetric hydrogenation of imines: Optimization of reaction
conditions.
Overall, complexes with an isopropyl group at the stereo-
genic center showed the best performance irrespective of
the ligand backbone. On the other hand, no clear trends
emerged for the substituents on the P atom. Based on these
results, the most promising catalysts 3a, 6a, 7b, and 8 were
selected for further optimization of the reaction conditions.
We first studied the influence of the reaction temperature
(Table 3). At 08C (Table 3, entries 1–4), full conversion and
a considerable improvement in enantioselectivity was ach-
ieved in all cases (ee values were around 4–5% higher than
at room temperature). When the temperature was decreased
to À208C, the enantioselectivity increased even further
(Table 3, entries 5–8). However, catalysts 3a and 7b gave
only 95 and 80% conversion, respectively, under these con-
ditions (Table 3, entries 5 and 7). The reaction was also car-
Entry
Catalyst
([mol%])
T
[8C]
H2 pressure
[bar]
t
Conv.
[%][a]
ee
G
G
[h]
[%][b]
1
2
3
4
5
6
7
8
9
3a (0.5)
6a (0.5)
7b (0.5)
8 (0.5)
3a (0.5)
6a (0.5)
7b (0.5)
6a (0.1)
8 (0.1)
0
À20
0
À20
À20
À20
À20
À20
À20
5
5
5
5
10
10
10
50
50
7
8
7
8
6
6
6
6
6
>99
67
88
98
25
>99
54
94
90
95.5
92
94
93
95.5
95
96
>99
94
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see the Ex-
perimental Section for details).
Chem. Eur. J. 2010, 16, 4003 – 4009
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www.chemeurj.org
4005

A. Pfaltz and A. Baeza
and 94% ee at À208C (Table 4, entry 4). With 0.5 mol% of
complex 6a, the hydrogen pressure had to be increased to
10 bar, to achieve full conversion at À208C (Table 4,
entry 6). Complex 7b gave unsatisfactory conversion at À20
and 08C and 0.5 mol% catalyst loading (Table 4, entry 7).
Excellent enantioselectivities were also obtained when the
reaction was performed by using 0.1 mol% of the most
active catalysts 6a and 8 at À208C, although 50 bar of hy-
drogen pressure was needed to reach high conversion
(Table 4, entries 8 and 9). In conclusion, the influence of the
catalyst loading and hydrogen pressure on the enantioselec-
tivity seems to be negligible. Based on these results, the sub-
strate scope of catalysts 3a, 6a, and 8 was evaluated under
the optimized conditions.
more strongly to the iridium catalyst than the less basic
analogous phenylamine 2a. It is known that coordinating
species deactivate the catalyst.[4]
Hydrogenations with the more reactive catalyst 6a were
carried out at À208C (Table 6). With all substrates tested,
the enantioselectivities were consistently higher than with
Table 6. Asymmetric hydrogenation of imines using catalyst 6a.
Hydrogenations with complex 3a were carried out with
0.5 mol% catalyst loading at 08C and 5 bar hydrogen pres-
sure (Table 5). Introduction of a 4-chloro or 4-methoxy sub-
stituent in the N-aryl group of the acetophenone imine had
no significant influence on the enantioselectivity and conver-
sion (Table 5, entries 1–3). N-phenylimines of 4-chloro- and
4-methoxyacetophenone also gave essentially the same ee
value and conversion as the unsubstituted imine 1a (Table 5,
entries 4 and 5). The N-phenylimine of ethyl phenyl ketone,
on the other hand, reacted with lower enantioselectivity but
full conversion (79% ee, Table 5, entry 7, compared with
90% ee for 1a; Table 4, entry 1). A possible explanation[2]
for the lower ee value in this case could be the lower E/Z
ratio of the starting imine (E/Z 91:9) compared with 1a,
Entry R1
R2
R3
2
Conv. [%][a] ee [%][b]
1
Ph
Ph
4-ClC6H4
4-(MeO)C6H4 Me 2c
Ph
Me 2a
Me 2b
>99
>99
85
95.5
93.5
95
2
Ph
3
Ph
4
4-ClC6H4
Me 2d
Me 2e
>99
99
95.5
94
5
4-(MeO)C6H4 Ph
6
Ph
PhCH2
Ph
Ph
4-(MeO)C6H4 Me 2c
Ph Me 2d
Me 2 f[c] >99
81
7
Ph
Ph
Ph
4-ClC6H4
Et 2g[d] >99
91.5
96
95.5
95.5
8[e]
9[e]
10[e]
Me 2a
94
56
>99
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see the Ex-
perimental Section for details). [c] The starting imine was isolated as 92:8
E/Z isomer mixture. [d] The starting imine was isolated as 91:9 E/Z
isomer mixture. [e] The reaction was carried out using 0.1 mol% of cata-
lyst under 50 bar of H2 pressure.
1
which (according to H NMR spectroscopic analysis) exists
in solution as pure E isomer. Hydrogenation of N-benzyl-
ACHTUNGTRENNUNGimine 1 f proved to be slower, resulting in low conversion
and only 74% ee (Table 5, entry 6). The low reactivity of
this substrate is likely to be due to the higher basicity of the
hydrogenation product 2 f, which is expected to coordinate
catalyst 3a, exceeding 90% ee, except for the N-benzylimine
1 f (Table 6, entry 6), which gave 2 f with 81% ee but this
time full conversion. With 0.5 mol% catalyst and 10 bar hy-
drogen pressure, the reaction went to completion in all cases
with the exception of the 4-methoxyphenyl imine 1c
(Table 6, entry 3), which gave only 85% conversion even at
longer reaction times. At 50 bar hydrogen pressure, high
conversion and excellent enantioselectivities were achieved
in the hydrogenation of the acetophenone and 4-chloroace-
tophenone imines 1a and 1d, (Table 6, entries 1 and 4),
even at catalyst loadings of 0.1 mol%, making this catalyst
attractive for applications on a larger scale. The less reactive
4-methoxyphenyl imine 1c gave only moderate conversion
under these conditions.
The Ir–NeoPHOX complex 8 gave similar results to those
recorded for the SimplePHOX complex 6a (Table 7). Essen-
tially full conversions were obtained for all substrates with
the exception of the less reactive 4-methoxyphenyl imine 1c
(Table 7, entries 3 and 9). In general, the enantioselectivities
were only slightly lower than with catalyst 6a; only the
imine derived from phenylethyl ketone 2g gave a signifi-
cantly lower ee value (82% ee, Table 7, entry 7, compared
with 91.5% ee with catalyst 6a, Table 6, entry 7). With
0.1 mol% catalyst at 50 bar hydrogen pressure, higher con-
Table 5. Asymmetric hydrogenation of imines using catalyst PHOX 3a.
Entry R1
R2
R3
2
Conv. [%][a] ee [%][b]
1
2
3
4
5
6
7
Ph
Ph
Ph
4-ClC6H4
4-(MeO)C6H4 Ph
Ph
Ph
Ph
4-ClC6H4
4-(MeO)C6H4 Me 2c
Ph
Me 2a
Me 2b
>99
>99
99
>99
98
90
88.5
89
90
88.5
74
Me 2d
Me 2e
Me 2 f[c]
PhCH2
Ph
20
Et 2g[d] >99
79
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see Exper-
imental Section for details). [c] The starting imine was isolated as 92:8 E/
Z isomer mixture. [d] The starting imine was isolated as 91:9 E/Z isomer
mixture.
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Asymmetric Imine Hydrogenation
FULL PAPER
Table 7. Asymmetric hydrogenation of imines by using catalyst 8.
terms of enantioselectivity, catalytic activity, and turnover
numbers, they rival the best catalysts reported to date. Due
to their high activity, reactions proceed smoothly even at
low catalyst loading, low temperature, and moderate hydro-
gen pressure.
Experimental Section
Entry R1
R2
R3
2
Conv. [%][a] ee [%][b]
1
2
3
4
5
6
7
Ph
Ph
Ph
4-ClC6H4
4-(MeO)C6H4 Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-(MeO)C6H4 Me 2c
Ph
Me 2a
Me 2b
98
>99
85
>99
98
94
92
94
95
90
77
82
94
93.5
95
General: All reactions involving air- or moisture-sensitive reagents were
performed under argon by using standard Schlenk techniques or under
purified N2 gas in an MBraun glove box. All solvents and reagents were
obtained from Fluka, Aldrich, or Alfa Aesar and were used without fur-
ther purification. Iridium complexes were prepared according to litera-
ture procedures.[28] 1H and 13C NMR spectra were recorded at 258C on a
400 MHz Bruker Avance spectrometer, using CDCl3 as solvent and TMS
as internal standard; chemical shifts are given in ppm, unless otherwise
stated. Mass spectra (EI) were recorded on a VG70-250 machine. Chiral
HPLC analyses were performed on a Shimadzu Class-VP Version 5.0 in-
strument equipped with a chiral Daicel Chiralcel OD-H column; the re-
tention time of the major isomer is highlighted in bold. Optical rotations
were measured on a Perkin–Elmer 341 polarimeter. Imine conversions
were determined by GC analysis on a Carlo Erba Instrument GC 8000
Top using a Macherey–Nagel Optima 5-Amin column (30 m x 0.25 mm x
0.5 mm). IR spectra were recorded on a Perkin–Elmer FTIR RX1 instru-
ment and only the most structurally relevant peaks are listed. Melting
points were measured with a Bꢁchi 535 melting point apparatus and are
not corrected. Elemental analyses were carried out by the Micro-Analyti-
cal laboratory of the Department of Chemistry of the University of
Basel. Analytical TLC was performed on Macherey–Nagel Polygram Sil
G/UV254 plates and Merck silica gel 60 (0.0040–0.0063 mm) was em-
ployed for flash chromatography.
Me 2d
Me 2e
PhCH2
Ph
Ph
4-(MeO)C6H4 Me 2c
Ph Me 2d
Me 2 f[c] >99
Et 2g[d] >99
8[e]
9[e]
10[e]
Me 2a
>99
85
>99
Ph
4-ClC6H4
[a] Determined by GC analysis of the reaction mixture after removal of
the catalyst (see the Experimental Section for details). [b] Determined by
chiral HPLC analysis using a Daicel Chiralcel OD-H column (see the Ex-
perimental Section for details). [c] The starting imine was isolated as 92:8
E/Z isomer mixture. [d] The starting imine was isolated as 91:9 E/Z
isomer mixture. [e] The reaction was carried out using 0.1 mol% of cata-
lyst under 50 bar of H2 pressure for 6 h.
versions and almost the same enantioselectivities were ach-
ieved compared with the reactions with catalyst 6a (Table 7,
entries 8–10).
The cyclic imine 11 gave high conversion with catalysts
3a, 6a, and 8, but the enantioselectivities were lower than
with analogous acyclic imines (Scheme 3). The most selec-
tive catalyst in this case was complex 6a, which gave amine
12 with 82% ee under standard conditions. Imines derived
from dialkylketones gave only low conversion and enantio-
selectivity, whereas cyclic imines with a C=N bond in a five-
or six-membered ring showed no reactivity.
General procedure for the preparation of imines 1: Imines 1 were pre-
pared following literature procedures (for example, see reference [4]).
The analytical data given below is for the only imine (11) not described
in the literature, and may be taken as representative.
(E)-N-(6-methoxy-3,4-dihydronaphthalen-1-(2H)-ylidene)benzylamine
(11): Slightly yellow solid. M.p.94–958C; Rf =0.72 (hexane/ethyl acetate
5/1); 1H NMR (400 MHz, CDCl3): d=1.90 (q, J=6.1 Hz, 2H; CH2), 2.48
and 2.86 (2ꢂt, J=6.1 Hz, 2ꢂ2H; 2ꢂCH2), 3.85 (s, 3H; OCH3), 6.68 (d,
J=2.5 Hz, 1H; ArH), 6.79 (d, J=7.3 Hz, 2H; ArH), 6.84 (dd, J=2.6,
8.7 Hz, 1H; ArH), 7.05 (t, J=7.6 Hz, 1H; ArH), 7.32 (t, J=7.6 Hz, 2H;
ArH), 8.26 ppm (d, J=8.6 Hz, 1H; ArH); 13C NMR (101 MHz, CDCl3):
d=23.2, 29.9, 30.5 (CH2), 55.5 (CH3), 112.8, 113.2, 119.9, 122.9, 127.2,
128.5, 129.0, 143.4, 161.6, 165.2 (ArC), 152.0 ppm (C=N); IR (KCl): n=
1591, 1496, 1248 cmÀ1; MS (EI): m/z (%): 251 (100) [M]+, 223 (58), 208
(13), 180 (32), 77 (35); elemental analysis calcd (%) for C17H17NO: C
81.24, H 6.82, N 5.57; found: C 81.38, H 6.79, N 5.44.
General procedure for the iridium-catalyzed asymmetric hydrogenation
of imines: A solution of imine (0.2 mmol) and iridium complex (1–
0.1 mol%) in dry dichloromethane (1 mL) under inert atmosphere was
placed in an autoclave, which was sealed and placed in a bath for 1 h at
the appropriate temperature. After this time, the autoclave was purged
with hydrogen gas, pressurized to the desired hydrogen pressure and
stirred at the corresponding temperature for the indicated time. After
this time, the solvent was evaporated and the catalyst was removed by fil-
tration through a short silica gel column (3ꢂ1 cm) with a mixture of pen-
tane and diethyl ether (1:1) as eluent to give the amine product as a pure
compound after evaporation of the solvent. For the amine 10c, which
was not obtained as a pure product after workup, flash chromatography
(15ꢂ3 cm) was needed, using a mixture of pentane and ethyl acetate
(97:3) as eluent.
Scheme 3. Asymmetric hydrogenation of exocyclic imine 11.
Conclusion
By screening various iridium complexes derived from chiral
oxazoline-based N,P ligands that were developed in our lab-
oratory, we have identified three efficient catalysts for the
asymmetric hydrogenation of imines derived from arylalkyl
ketones. These catalysts are readily accessible by a short,
convenient synthesis and are air and moisture stable. In
For catalyst screening, reactions were performed on a 0.1 mmol scale.
The absolute configuration of the resulting amines 2a, 2c, 2 f, and 2g was
found to be R and was assigned by comparison with known literature
values,[4,5,11] for optical rotation and HPLC retention times.
Chem. Eur. J. 2010, 16, 4003 – 4009
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4007

A. Pfaltz and A. Baeza
Analytical data are given below. For known products, only [a]D, 1H,
(l=225, 254 nm, 208C, n-heptane/2-propanol 99/1, 0.5 mLminÀ1; tr =27.7
and 39.6 min); 1H NMR (400 MHz, CDCl3): d=1.75–2.03 (m, 4H; 2ꢂ
CH2), 2.72–2.84 (m, 2H; CH2), 3.80 (s, 3H; OCH3), 3.84 (s, 1H; NH),
4.60 (t, J=4.5 Hz, 1H; CH), 6.65–6.76 (m, 5H; ArH), 7.18–7.23 (m, 2H;
ArH), 7.31 ppm (d, J=8.6 Hz, 1H; ArH); 13C NMR (101 MHz, CDCl3):
d=19.2, 28.7, 29.7 (CH2), 50.4 (CH), 55.2 (CH3), 112.5, 112.8, 113.2,
116.9, 129.3, 130.4, 130.5, 138.9, 147.4, 158.5 ppm (ArC); IR (KCl): n=
3399, 2932, 1601, 1499, 1249 cmÀ1; MS (EI): m/z (%): 253 (14) [M]+, 162
(14), 161 (100); elemental analysis calcd (%) for C17H19NO: C 80.60, H
7.56, N 5.53; found: C 80.78, H 7.64, N 5.39.
13C NMR, and HPLC data are listed.
(R)-N-Phenyl-1-phenylethylamine (2a):[4] [a]D20 =À27.8 (c=1 in CH2Cl2);
95.5% ee from HPLC Daicel Chiralcel OD-H (l=225, 254 nm, 208C, n-
heptane/2-propanol 99/1, 0.5 mLminÀ1; tr =24.4 and 32.7 min); 1H NMR
(400 MHz, CDCl3): d=1.51 (d, J=6.6 Hz, 3H; CH3), 4.03 (brs, 1H;
NH), 4.48 (q, J=6.6 Hz, 1H; CH), 6.49–6.52 (m, 2H; ArH), 6.62–6.66
(m, 1H; ArH), 7.07–7.11 (m, 2H; ArH), 7.21–7.38 ppm (m, 5H; ArH);
13C NMR (101 MHz, CDCl3): d=25.0 (CH3), 53.4 (CH), 113.2, 117.2,
125.8, 126.8, 128.6, 129.1, 145.2, 147.2 ppm (ArC).
(À)-N-(4-Chlorophenyl)-1-phenylethylamine (2b):[10] [a]D20 =À5.1 (c=1 in
CH2Cl2); 93.5% ee from HPLC Daicel Chiralcel OD-H (l=225, 254 nm,
208C, n-heptane/2-propanol 98/2, 0.5 mLminÀ1; tr =19.3 and 27.2 min);
1H NMR (400 MHz, CDCl3): d=1.50 (d, J=6.6 Hz, 3H; CH3), 4.05 (brs,
1H; NH), 4.43 (q, J=6.6 Hz, 1H; CH), 6.41 (dd, J=2.1, 6.7 Hz, 2H;
ArH), 7.01 (dd, J=2.1, 6.7 Hz, 2H; ArH), 7.20–7.24 (m, 1H; ArH), 7.29–
7.34 ppm (m, 4H; ArH); 13C NMR (101 MHz, CDCl3): d=25.0 (CH3),
53.6 (CH), 114.3, 121.8, 125.7, 127.0, 128.7, 128.9, 144.7, 145.7 ppm (ArC).
(R)-N-(4-Methoxyphenyl)-1-phenylethylamine (2c):[5] [a]D20 =À21.3 (c=1
in CH2Cl2), [a]2D0 =+1.9 (c=1 in CHCl3); 95% ee from HPLC Daicel
Chiralcel OD-H (l=225, 254 nm, 208C, n-heptane/2-propanol 99/1,
0.5 mLminÀ1; tr =31.2 and 35.3 min); 1H NMR (400 MHz, CDCl3): d=
1.49 (d, J=6.8 Hz, 3H; CH3), 3.69 (s, 3H; OCH3), 3.74 (brs, 1H; NH),
4.40 (q, J=6.8 Hz, 1H; CH), 6.46 (dd, J=2.1, 6.7 Hz, 2H; ArH), 6.68
(dd, J=2.1, 6.7 Hz, 2H; ArH), 7.20–7.25 (m, 1H; ArH), 7.29–7.37 ppm
(m, 4H; ArH); 13C NMR (101 MHz, CDCl3): d=25.1 (CH3), 54.2 (CH),
55.7 (OCH3), 114.5, 114.7, 125.9, 126.8, 128.6, 141.5, 145.4, 151.9 ppm
(ArC).
(À)-N-Phenyl-1-(4-chlorophenyl)-ethylamine (2d):[7] [a]D20 =À15.3 (c=1
in CH2Cl2), [a]2D0 =+3.2 (c=1 in CHCl3); 95.5% ee from HPLC Daicel
Chiralcel OD-H (l=225, 254 nm, 208C, n-heptane/2-propanol 98/2,
0.5 mLminÀ1; tr =26.7 and 35.9 min); 1H NMR (400 MHz, CDCl3): d=
1.48 (d, J=6.8 Hz, 3H; CH3), 4.00 (brs, 1H; NH), 4.44 (q, J=6.8 Hz,
1H; CH), 6.47 (d, J=7.6 Hz, 2H; ArH), 6.65 (t, J=7.4 Hz, 1H; ArH),
7.08 (m, 2H; ArH), 7.25–7.31 ppm (m, 4H; ArH); 13C NMR (101 MHz,
CDCl3): d=25.1 (CH3), 53.0 (CH), 113.3, 117.5, 127.2, 128.8, 129.1, 132.4,
143.8, 146.9 ppm (ArC).
Acknowledgements
A.B would like to thank the Spanish Ministerio de Educaciꢃn, Ciencia y
Deporte (MECD) and Fundaciꢃn EspaÇola para la Ciencia y la Tecnolo-
gꢄa (FECYT) for a postdoctoral fellowship. Support of this work by the
Swiss National Science Foundationand the Federal Commission for Tech-
nology and Innovation (KTI) is gratefully acknowledged.
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(À)-N-Phenyl-1-(4-methoxyphenyl)-ethylamine (2e):[11] [a]D20 =À15.5 (c=
1 in CH2Cl2); 94% ee from HPLC Daicel Chiralcel OD-H (l=225,
254 nm, 208C, n-heptane/2-propanol 99/1, 0.5 mLminÀ1
;
tr =32.4 and
1
37.4 min); H NMR (400 MHz, CDCl3): d=1.49 (d, J=6.6 Hz, 3H; CH3),
3.78 (s, 3H; OCH3), 4.01 (brs, 1H; NH), 4.44 (q, J=6.8 Hz, 1H; CH),
6.51 (dd, J=1.0, 8.6 Hz, 2H; ArH), 6.64 (t, J=7.3 Hz, 1H; ArH), 6.85
(dd, J=2.0, 6.6 Hz, 2H; ArH), 7.07–7.11 (m, 2H; ArH), 7.25–7.29 ppm
(m, 2H; ArH); 13C NMR (101 MHz, CDCl3): d=25.0 (CH3), 52.8 (CH),
55.2 (OCH3), 113.3, 114.0, 117.1, 126.9, 129.1, 137.2, 147.3, 158.4 ppm
(ArC).
(R)-N-Benzyl-1-phenylethylamine (2 f):[4] [a]D20 =+29.5 (c=1 in CHCl3);
81% ee from HPLC Daicel Chiralcel OD-H (l=225, 254 nm, 208C, n-
heptane/2-propanol 99/1, 0.5 mLminÀ1; tr =12.3 and 14.4 min); 1H NMR
(400 MHz, CDCl3): d=1.37 (d, J=6.7 Hz, 3H; CH3), 1.61 (s, 1H; NH),
3.59 and 3.66 (2ꢂd, J=13.2 Hz, 2ꢂ1H; CH2Ph), 3.81 (q, J=6.6 Hz, 1H;
CH), 7.24–7.36 ppm (m, 10H; ArH); 13C NMR (101 MHz, CDCl3): d=
24.5 (CH3), 51.6 (CH2), 57.5 (CH), 127.7, 127.8, 127.9, 128.1, 128.3, 128.4,
140.8, 145.5 ppm (ArC).
(R)-N-Phenyl-1-phenylpropylamine (2g):[5] [a]D20 =+20.5 (c=1 in
CHCl3); 91.5% ee from HPLC Daicel Chiralcel OD-H (l=225, 254 nm,
208C, n-heptane/2-propanol 98/2, 0.5 mLminÀ1; tr =14.2 and 17.2 min);
1H NMR (400 MHz, CDCl3): d=0.95 (t, J=7.3 Hz, 3H; CH3), 1.61 (m,
2H; CH2), 4.06 (brs, 1H; NH), 4.22 (t, J=6.6 Hz, 1H; CHPh), 6.51 (m,
2H; ArH), 6.62 (t, J=7.3 Hz, 1H; ArH), 7.08 (t, J=7.4 Hz, 2H; ArH),
7.20–7.35 ppm (m, 5H; ArH); 13C NMR (101 MHz, CDCl3): d=10.8
(CH3), 31.6 (CH2), 59.7 (CH), 113.2, 117.1, 126.4, 126.8, 128.5, 129.0,
143.9, 147.5 ppm (ArC).
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=
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4008
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Chem. Eur. J. 2010, 16, 4003 – 4009

Asymmetric Imine Hydrogenation
FULL PAPER
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Received: December 14, 2009
Published online: March 10, 2010
Chem. Eur. J. 2010, 16, 4003 – 4009
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4009