Novel chiral tetraaza ligands: synthesis and application in asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.tetasy.2007.03.013

Novel chiral tetraaza ligands, N¹,N²-bis(2-(piperidin-1-yl)benzylidene)cyclohexane-1,2-diamine 1 and N¹,N²-bis(2-(piperidin-1-yl)benzyl)cyclohexane-1,2-diamine 2, have been synthesized and fully characterized by

Full text of DOI:10.1016/j.tetasy.2007.03.013

Tetrahedron: Asymmetry 18 (2007) 729–733
Novel chiral tetraaza ligands: synthesis and application
in asymmetric transfer hydrogenation of ketones
Wei-Yi Shen, Hui Zhang, Hua-Lin Zhang and Jing-Xing Gao*
State Key Laboratory of Physical Chemistry of Solid Surfaces and Department of Chemistry,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, PR China
Received 5 January 2007; accepted 12 March 2007
1
2
1
2
Abstract—Novel chiral tetraaza ligands, N ,N -bis(2-(piperidin-1-yl)benzylidene)cyclohexane-1,2-diamine 1 and N ,N -bis(2-(piperidin-
-yl)benzyl)cyclohexane-1,2-diamine 2, have been synthesized and fully characterized by analytical and spectroscopic methods. The
1
structure of (R,R)-1 has been established by X-ray crystallography. Asymmetric transfer hydrogenation of aromatic ketones with the
catalysts prepared in situ from [IrHCl (COD)] and the chiral tetraaza ligands in 2-propanol gave the corresponding optically active sec-
2
2
ondary alcohols in high conversions and good ees (up to 91%) under mild reaction conditions.
2007 Published by Elsevier Ltd.
ꢀ
1
2
1. Introduction
tetraaza ligands, N ,N -bis(2-(piperidin-1-yl)benzylidene)-
1
2
cyclohexane-1,2-diamine 1 and N ,N -bis(2-(piperidin-
1-yl)benzyl)cyclohexane-1,2-diamine 2, which were used
in the Ir-catalyzed asymmetric transfer hydrogenation of
aromatic ketones, giving the corresponding optically active
secondary alcohols in high chemical yields and in fair to
good ees.
The realization of most homogeneous asymmetric catalysis
should need chiral metal complexes, which act as templates
to regulate organic reactions. Generally, chiral metal com-
1
plexes contain various metal centers and chiral organic
ligands which allow good stereocontrol and modify the
reactivity and selectivity of the metal center in catalytic
processes. For the past decades, chiral phosphine ligands
are becoming some of the more important and popular
2
,3
ligands in asymmetric catalysis. It should be noted, how-
ever, in the field of asymmetric transfer hydrogenation
reaction, the most used chiral auxiliaries contain nitrogen,
N
N
N
N
H
H
4–6
N
N
N
N
not phosphorus, as the donor atom. Recently, chiral tetra-
aza ligands have received much attention because of their
simple synthesis from easily available inexpensive precur-
sors, less toxic than phosphine ligands, and providing
(R,R
)-1
(R,R)-2
7
multi-coordination sites on the metal center. Chiral tetra-
aza ligands have been successfully used as chiral auxiliaries
for a wide range of reactions, such as asymmetric allylic
8
–12
13,14
alkylation,
asymmetric hydrosilylation,
asymmetric
However,
1
5,16
17,18
cyanosilylation
and dialkylzinc addition.
2
. Results and discussion
when chiral tetraaza ligands were used for asymmetric
transfer hydrogenation of aryl ketones, the results were
unsatisfactory, and only gave low enantiomeric ex-
2
.1. Synthesis of ligands 1 and 2
7
,19,20
cesses.
Recently, we have synthesized two novel chiral
The synthesis of chiral tetraaza ligands (R,R)-1 and (R,R)-2
is outlined in Scheme 1. According to the literature proce-
2
1
*
Corresponding author. Tel.: +86 592 2180116; fax: +86 592 2183047;
e-mail addresses: jxgao@xmu.edu.cn; cuihua@xmu.edu.cn
dure, 2-(piperidin-1-yl)benzaldehyde 4 can be conve-
niently prepared by nucleophilic displacement of the
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.03.013

730
W.-Y. Shen et al. / Tetrahedron: Asymmetry 18 (2007) 729–733
O
F
O
N
N
H
a
H
b
N
N
N
3
4
(R,R)-1
N
N
H
c
H
N
N
(
R,R)-2
2 3
Scheme 1. Synthesis of tetraaza ligands (R,R)-1 and (R,R)-2. Reagents and conditions: (a) K CO , DMF, piperidine, reflux; (b) (R,R)-1,2-
diaminocyclohexane, CH CH OH, reflux; (c) NaBH , CH CH OH, reflux.
3
2
4
3
2
activated fluorine in 2-fluorobenzaldehyde with piperidine
in refluxing dimethylformamide (83% yield). The imine
ligand (R,R)-1 was synthesized by the condensation of
Ru, Rh or Ir complexes with ligand (R,R)-1 or (R,R)-2 as
catalyst precursors have been tested for this reduction.
The catalyst systems were generated in situ by mixing
ligand (R,R)-1 or (R,R)-2 and various metal complexes in
refluxing 2-propanol, which were directly used for reduc-
tion of propiophenone. Typical results are listed in Table 1.
(
(
R,R)-1,2-diaminocyclohexane with 4 in refluxing ethanol
74% yield). Ligand (R,R)-1 is stable in air and water.
The IR spectrum of (R,R)-1 exhibited a strong C@N
ꢀ
1
1
stretch at 1637 cm . The H NMR spectrum presented a
singlet at d 8.55 for the imino protons. The geometry of this
compound was confirmed by the X-ray crystal structure
analyses (Fig. 1). Reduction of the imino ligand (R,R)-1
The Ru(DMSO) Cl /(R,R)-1 system showed only low
4
2
activity and enantioselectivity (Table 1, entry 1), while
ligand (R,R)-2 was used, the activity improved but the ee
remained low (Table 1, entry 2). When catalyst systems,
with excess NaBH was carried out in refluxing ethanol
4
to afford the amine ligand (R,R)-2 in 70% yield.
coupled with [RhCl(COD)] and either (R,R)-1 or (R,R)-2
2
were applied, no reaction was observed (Table 1, entries
3
and 4). While iridium complexes [IrCl(COD)]2 or
[
IrHCl (COD)] was employed as the metallic precursor,
2
2
the [IrHCl (COD)] /(R,R)-1 system gave the best result
2
2
(97% yield and 67% ee). We also found this system to be
stable in air and the catalytic reactions can be performed
under air atmosphere.
2
.2.2. Asymmetric transfer hydrogenation of aromatic
ketones. The aforementioned catalytic system [IrHCl2-
COD)] /(R,R)-1 has been further examined for the asym-
(
2
metric transfer hydrogenation of various aromatic ketones.
The results are summarized in Table 2. A variety of aro-
matic ketones can be reduced to the corresponding opti-
cally active secondary alcohols with high chemical yields
and good enantiomeric excesses under air atmosphere.
We found that the reaction rate and enantioselectivity were
affected by the steric property of the substrates in alkyl
moiety. As the bulkiness of the alkyl group increased from
methyl, ethyl, propyl to n-butyl, the enantioselectivity
gradually increased (76–91% ee, Table 2, entries 1–5), but
the reduction of isobutyrophenone proceeded slowly with
lower ee (Table 2, entry 6). The electronic properties and
position of the groups in ring substituent also affected the
enantioselectivity of the reduction reaction. ortho-Substi-
tuted acetophenone was reduced smoothly with 90% ee
(Table 2, entries 7 and 8), while a lower ee for meta-methyl
acetophenone (Table 2, entry 9) was obtained. The intro-
duction of an electron-donating substituent, such as a
Figure 1. Molecular structure of (R,R)-1.
2
2
.2. Asymmetric transfer hydrogenation of various ketones
.2.1. Asymmetric transfer hydrogenation of propiophe-
none. In an initial experiment, the transfer hydrogenation
of propiophenone was chosen as a model reaction. Some

W.-Y. Shen et al. / Tetrahedron: Asymmetry 18 (2007) 729–733
731
a
Table 1. Influence of the catalyst precursors on the asymmetric transfer hydrogenation of propiophenone
O
OH
OH
O
metal complex
R,R)-1 or 2, KOH, r.t.
+
+
(
b
b
c
Entry
Precursor
Ligand
Temperature (ꢁC)
Time (h)
Conversion (%)
ee (%)
Configuration
1
2
4
Ru(DMSO) Cl
2
(R,R)-1
(R,R)-2
25
25
24
6
8
60
10
12
(S)
(S)
3
4
[RhCl(COD)]
2
(R,R)-1
(R,R)-2
25
25
3
3
Trace
Trace
—
—
—
—
5
6
[IrCl(COD)]
2
(R,R)-1
(R,R)-2
25
25
5
2
97
82
57
55
(S)
(S)
7
8
[IrHCl
2
(COD)]
2
(R,R)-1
(R,R)-2
25
25
2
3
97
27
67
56
(S)
(S)
a
b
c
Reaction conditions: propiophenone, 1.0 mmol; [M]:[ligand]:[KOH]:[propiophenone] = 1:1.2:10:100; 2-propanol, 10 mL.
Conversions and enantiomeric excesses were determined by GC analysis using a chiral G-TA column.
The configurations were determined by comparison of the retention times of the enantiomers on the GC traces with literature values.
meta-methoxyl group in acetophenone gave higher conver-
sion but lower ee (Table 2, entry 10). The ketone having an
electron-withdrawing substituent, ortho- or para-chloro-
acetophenone gave 99% chemical yield with moderate ee
trometer. Mass spectra were recorded on a Finnigan LCQ
mass spectrometer. Elemental analyzes were carried out on
a Carlo Erba 1110 analyzer. The yields and ee values were
determined by GC analysis with a chiral G-TA column.
Column chromatography was carried out on a silica gel
(
Table 2, entries 11 and 12).
(140 mesh) using ethyl acetate/petroleum ether as eluent.
In order to determine the role of the piperidinyl group in
The solvents were dried and purified according to standard
methods.
the phenyl ring of ligand 1, we synthesized the chiral
1
2
ligand,
(1R,2R)-N ,N -dibenzylidenecyclohexane-1,2-di-
2
2
amine, which does not contain any substituent in the 2-
position of the phenyl ring. This ligand has been examined
in the asymmetric transfer hydrogenation of 2 -methyl-
4.2. Synthesis of the chiral tetraaza ligands
0
4.2.1. 2-(Piperidin-1-yl)benzaldehyde 4. This compound
acetophenone, with lower conversion and ee achieved
was synthesized according to literature procedures in 83%
2
1
1
(
35% conversion, 78% ee). This result indicated that the
yield, as a yellow oil (6.28 g, 83% yield).
H NMR
piperidinyl group in the phenyl ring of ligand 1 played an
important role in asymmetric transfer hydrogenations.
(400 MHz, CDCl ): d 1.62–1.67 (m, 2H), 1.73–1.78 (m,
3
4H), 3.05 (t, J = 5.2 Hz, 4H), 7.04–7.10 (m, 2H), 7.49–
1
3
7.51 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 10.30 (s, 1H).
C
NMR (100 MHz, CDCl ): d 24.05, 26.20, 55.61, 118.98,
3
3. Conclusion
121.95, 128.62, 129.16, 134.81, 156.98, 191.65. IR (neat,
NaCl) m 3067, 2936, 2851, 2701, 1687, 1596, 1482, 1452,
1378, 1283, 1228, 925, 825, 764, 648 cm .
ꢀ
1
The new chiral tetraaza ligands (R,R)-1 and (R,R)-2 have
been prepared and the molecular structure of (R,R)-1
established. These ligands were employed for the first time
to catalyze the enantioselective reduction of a variety of
aromatic ketones with high chemical yields and satisfactory
enantioselectivities under an air atmosphere. Although the
enantioselectivity remains to be further improved, the pres-
ent study shows that chiral tetraaza ligands can be also
used in asymmetric transfer hydrogenation. These results
provide a useful insight for the design of more efficient
1
2
4.2.2. (1R,2R)-N ,N -bis(2-(piperidin-1-yl)benzylidene)cyclo-
hexane-1,2-diamine (R,R)-1. A solution of (R,R)-1,2-dia-
minocyclohexane (0.856 g, 0.0075 mmol) and 2-(piperidin-
1-yl)benzaldehyde 4 (2.840 g, 0.015 mmol) in ethanol
(20 mL) was refluxed with stirring for 72 h. A yellow solu-
tion was obtained and then cooled to room temperature,
concentrated under reduced pressure to ca. 5 mL. The res-
idue was then cooled to ꢀ18 ꢁC to give acicular crystals
1
2
chiral catalytic system, based on C -symmetric tetraaza
(1R,2R)-N ,N -bis(2-(piperidin-1-yl)benzylidene)cyclohex-
ane-1,2-diamine (R,R)-1 (2.74 g, 80% yield). Mp 152–
2
ligands.
2
D
0
1
1
(
53 ꢁC. ½aꢁ ¼ þ85:5 (c 1.0, CHCl3).
H
NMR
400 MHz, CDCl ): d 1.52–1.55 (m, 6H), 1.62–1.72 (m,
3
4. Experimental
8H), 1.83–1.90 (m, 6H), 2.79 (s, 8H), 3.48 (s, 2H), 6.91–
.96 (m, 4H), 7.24–7.29 (m, 2H), 7.78 (d, J = 7.6 Hz,
6
1
3
4
.1. General methods
2H), 8.55 (s, 2H). C NMR (100 MHz, CDCl ): d 24.19,
3
24.64, 26.27, 33.13, 54.44, 74.54, 118.40, 122.10, 127.84,
NMR spectra were recorded on a Bruker AV 400 instru-
129.73, 130.55, 153.96, 159.06. IR (KBr): m 3067, 2932,
2853, 1637, 1595, 1483, 1449, 1281, 1227, 763 cm . EIMS
ꢀ1
ment using TMS as an internal standard in CDCl . IR
3
spectra were recorded on a Nicolet Avatar 360 FT-IR spec-
(m/z): 457 (M+1). Anal. Calcd for C H N : C, 78.90; H,
3
0
40
4

732
W.-Y. Shen et al. / Tetrahedron: Asymmetry 18 (2007) 729–733
a
2 2
Table 2. Asymmetric transfer hydrogenation of various ketones catalyzed by [IrHCl (COD)] /1
b
b
c
Entry
Substrate
Time (h)
1.3
Conversion (%)
ee (%)
Configuration
O
1
2
98
97
76
80
(S)
(S)
O
O
O
O
O
1.5
3
1.3
1.3
1
99
93
98
46
88
87
91
64
(S)
(R)
(S)
(S)
d
4
5
6
1.6
O
O
7
1.5
94
90
(S)
d
8
1.5
1.3
1.3
93
94
97
90
80
77
(R)
(S)
(S)
O
9
O
H CO
1
0
3
O
Cl
1
1
1
2
1.3
1.3
99
99
70
68
(S)
(S)
O
Cl
a
b
c
Reaction conditions: ligand, (R,R)-1; ketone, 1.0 mmol; [M]:[ligand]:[KOH]:[ketone] = 1:1.2:300:100; 2-propanol, 15 mL; air atmosphere.
Conversions and enantiomeric excesses were determined by GC analysis using a chiral G-TA column.
The configurations were determined by comparison of the retention times of the enantiomers on the GC traces with literature values.
Ligand, (S,S)-1.
d
8
.83; N, 12.27. Found: C, 79.03; H, 8.69; N, 12.28. In an
1 (2.283 g, 5.0 mmol) and NaBH (7.566 g, 200 mmol) in
4
analogous manner, using (S,S)-1,2-diaminocyclohexane
instead of (R,R)-1,2-diaminocyclohexane, ligand (S,S)-1
absolute ethanol (60 mL) was refluxed with stirring for
72 h. The solution was cooled to room temperature and
H O (25 mL) was added to destroy any excess NaBH .
2
0
was also prepared. ½aꢁ ¼ ꢀ85:3 (c 1.0, CHCl3).
D
2
4
The mixture solution was extracted with CH Cl
2
2
1
2
.2.3. (1R,2R)-N ,N -bis(2-(piperidin-1-yl)benzyl)cyclo-hex-
4
(60 mL · 3). The combined extracts were washed with sat-
1
2
ane-1,2-diamine (R,R)-2. A solution of (1R,2R)-N ,N -
urated NH Cl solution (15 mL · 3) and the organic layer
4
bis(2-(piperidin-1-yl)benzylidene)cyclohexane-1,2-diamine
dried over anhydrous MgSO , followed by filtration, con-
4

W.-Y. Shen et al. / Tetrahedron: Asymmetry 18 (2007) 729–733
733
centrated to ca. 8 mL and cooled to ꢀ18 ꢁC to yield a pale
yellow solid. Purification of the crude product by flash
chromatography (EtOAc/petrol ether 1:1) gave (R,R)-2 as
vacuo. The residue was purified by flash chromatography
on a silica gel column to afford (S)-1-phenylphentan-1-ol
in 98% conversion with 91% ee.
20
a white solid (1.61 g, 70% yield). Mp 52 ꢁC. ½aꢁ ¼ ꢀ55:4
D
1
(
(
c 1.0, CHCl ). H NMR (400 MHz, CDCl ): d 1.14–1.27
3 3
m, 2H), 1.34–1.61 (m, 14H), 1.75 (d, J = 7.6 Hz, 2H),
Acknowledgements
2
4
.10 (d, J = 12 Hz, 2H), 2.37–2.49 (m, 2H), 2.50–2.65 (m,
H), 2.68–2.88 (m, 4H), 3.76 (d, J = 12.8 Hz, 2H), 4.24
We would like to thank the National Natural Science
Foundation of China (20373056, 20423002), the Fujian
Provincial Science and Technology Commission
(2005YZ1020) for financial support.
(
d, J = 13.2 Hz, 2H), 7.04–7.13 (m, 4H), 7.18–7.23 (m,
1
3
2
2
1
3
1
H), 7.26–7.33 (m, 2H). C NMR (100 MHz, CDCl ): d
3
3.95, 24.27, 26.54, 29.10, 47.62, 54.29, 59.31, 121.01,
24.61, 129.44, 130.90, 131.12, 152.99. IR (KBr): 3429,
060, 3023, 2932, 2852, 2800, 1598, 1491, 1450, 1223,
ꢀ
1
104, 1030, 765 cm . EIMS (m/z): 461 (M + 1). Anal.
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3
0
44
4
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˚
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1
1
4.4. Typical procedure for asymmetric transfer
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2
2
9
003.
ligand (R,R)-1 (5.5 mg, 0.012 mmol) in 2-propanol
10 mL) was heated to 80 ꢁC for 30 min under air atmo-
sphere. After cooling to room temperature, valerophenone
1 mmol) was added, followed by KOH (3 mmol) in 2-pro-
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(
(
panol (5 mL). The asymmetric transfer hydrogenation was
conducted at room temperature for the time indicated
2
3. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.
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2
(
monitored by GC). The resulting solution was quenched
with 1 M HCl and the organic phase concentrated in