Synthesis of novel chiral tetraaza ligands and their application in enantioselective transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.cclet.2012.01.021

Novel chiral tetraaza ligands (R)-N, N′-bis[2-(piperidin-1-yl) benzylidene]propane-1, 2-diamine 6 and (S)-N-[2-(piperidin-1-yl)benzylidene]-3- {[2-(piperidin-1-yl)benzylidene]amino}-alanine sodium salt 7 have been synthesized and fully characterized by NM

Full text of DOI:10.1016/j.cclet.2012.01.021

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 395–398
www.elsevier.com/locate/cclet
Synthesis of novel chiral tetraaza ligands and their application
in enantioselective transfer hydrogenation of ketones
*
Shen Luan Yu, Yan Yun Li , Zhen Rong Dong, Jing Xing Gao
*
State Key Laboratory of Physical Chemistry of Solid Surfaces, National Engineering Laboratory for Green Chemical Productions of Alcohols-
Ethers-Esters and Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
Received 18 October 2011
Available online 3 March 2012
Abstract
Novel chiral tetraaza ligands (R)-N, N0-bis[2-(piperidin-1-yl)benzylidene]propane-1, 2-diamine 6 and (S)-N-[2-(piperidin-1-
yl)benzylidene]-3-{[2-(piperidin-1-yl)benzylidene]amino}-alanine sodium salt 7 have been synthesized and fully characterized by
NMR, IR, MS and CD spectra. The catalytic property of the ligands was investigated in Ir-catalyzed enantioselective transfer
hydrogenation of ketones. The corresponding optical active alcohols were obtained with high yields and moderate ees under mild
reaction conditions.
# 2012 Yan Yun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Asymmetric catalysis; Iridium; Ketones; Tetraaza ligand; Asymmetric transfer hydrogenation
Asymmetric catalysis with transition metal complexes is a research area which has grown enormously in the past
twenty years. Chiral ligands containing N, P, O, S or their mixed moieties played a key role in the catalytic reaction [1–
5]. Among the widely used chiral ligands, nitrogen-based ligands were particularly attractive due to their simple and
inexpensive synthesis, more stability than phosphines ligands and versatile coordinated chemistry properties [6–8].
Chiral bisoxazolines (Box) 1 and pyridine bisoxazolines (Pybox) 2 represented a class of ligands which were
successfully employed in metal-catalyzed asymmetric synthesis (Scheme 1) [9–13]. Another well known nitrogen-
based ligand is TsDPEN 3 [14–18] which was first applied in Ru-catalyzed asymmetric transfer hydrogenation (ATH)
of aromatic ketones developed by Noyori and co-workers.
In recent years, chiral tetraaza ligands have been studied as chiral auxiliaries for a wide range of reactions. Trost
et al. applied ligand 4 and its analogues in Mo-catalyzed asymmetric allylic alkylation with extraordinary levels of
regio- and enantioselectivity [19,20]. Luis and co-workers reported a series of bis(amino amide) ligands which
showed excellent enantioselectivities (up to 99% ee) in asymmetric alkylation of dialkylzinc to aromatic aldehydes
[21]. Feng et al. applied the C2-symmetric chiral tetraaza-Ti(IV) complexes to asymmetric cyanosilylation of
aldehydes and ketones with excellent activity [22]. In 2007, we reported the synthesis of a tetraaza ligand derived
from (R,R)-1,2-diaminocyclohexane and its successful application in ATH of aromatic ketones [23]. To extend
our study, we herein describe the synthesis of chiral ligands 6 and 7, derived from the schiff-base condensation of
* Corresponding authors.
E-mail addresses: yanyunli@xmu.edu.cn (Y.Y. Li), jxgao@xmu.edu.cn (J.X. Gao).
1001-8417/$ – see front matter # 2012 Yan Yun Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2012.01.021

396
S.L. Yu et al. / Chinese Chemical Letters 23 (2012) 395–398
Me Me
O
O
O
O
O
O
N
NH HN
O
S
N
N
N
N
H2N
HN
N
N
tBu
tBu
R1
O
R1
4
2 (Pybox)
1 (Box)
3 (TsDPEN)
Scheme 1. Chiral nitrogen-based ligands.
2-(piperidin-1-yl)benzaldehyde 5 [24] and various chiral diamines and their further application in the Ir-catalyzed
enantioselective transfer hydrogenation of ketones (Scheme 2).
Ligand 6 was synthesized by the condensation of (R)-propane-1, 2-diamine with 2-(piperidin-1-yl)benzaldehyde in
refluxing ethanol for 48 h. It was obtained as white solid in 49% yield, featuring the MS signals at 417.3 (M+1) [25].
The 1H NMR spectrum presented two singlets at d 8.56 and 8.60 for the imino protons. The CD spectra of the two
enantiomers of chiral ligand 6 have been measured in methanol as solvent and exhibited the mirror-image relationship
with Demax = 62.27 molꢀ1 Lcmꢀ1 at l = 248 nm (Fig. 1).
The interaction of (S)-2,3-diaminopropionic acid hydrogen chloride with two equivalents of sodium hydroxide
gave (S)-2,3-diaminopropionate sodium salt in quantitative, which was further reacted with 2-(piperidin-1-
yl)benzaldehyde 5 in refluxing methanol for 48 h. After crystallization of methanol, ligand 7 was obtained as
yellowish solid, featuring the MS signals at 468.9 (M+Na). The ligand was stable in solid state but unstable in its
methanol solution with the color turned dark, which was also confirmed by mass spectra analysis. The ligand was
slightly soluble in water but hard to dissolve in chlorinated solvents and toluene. The 1H NMR spectrum presented two
singlets at d 8.51 and 8.54 for the imino protons.
In order to examine the chiral induction abilities of chiral tetraaza ligands 6 and 7, we explored the enantioselective
transfer hydrogenation of various ketones in the presence of Ir-based catalyst. The results were summarized in Table 1.
Obviously, no enantioselectivity was observed without chiral ligand (Table 1, entry 1). Coupled with IrCl(CO)(PPh3)2,
chiral tetraaza ligand 6 exhibited high activity (99% conv.) and 34% ee in the ATH of propiophenone (Table 1, entry
10). Under the same conditions, the tetraaza ligand 7 derived from (S)-2,3-diaminopropionic acid, showed low
enantioselectivity (Table 1, entry 11), which might attributed to the carboxyl group next to the chiral center. Next, we
investigated the ATH of ketones with ligand 6 as chiral auxiliary. Various aromatic ketones were reduced smoothly
with high yields and moderate enantioselectivities. Acetophenone derivatives with substituents on the aromatic rings
at ortho position were reduced smoothly with improved enantioselectivities (Table 1, entries 3, 6 and 9). And reaction
activities were obviously impacted by electronic properties of the substituents. Substrates with electron-donating
substituent on the aromatic rings displayed inferior activities (Table 1, entries 3–9). Furthermore, the substituents on
the aromatic rings at different positions had observable effects on the enantioselectivity of the products. The ortho
position substituents showed much higher enantioselectivity than meta or para position ones (Table 1, entries 3 vs. 4
H
CH3
NH2
H
CH3
N
H2N
N
b
N
N
CHO
N
CHO
F
a
6
H
COONa
N
5
N
c
N
N
H
COOH
NH2
HCl
H2N
7
Scheme 2. Synthesis of novel chiral tetraaza ligands. Reagent and conditions: (a) K2CO3, DMF, piperidine, 160 8C, 4 h; (b) C2H5OH, reflux, 48 h;
(c) NaOH (2 eq.), MeOH, reflux, 48 h.

S.L. Yu et al. / Chinese Chemical Letters 23 (2012) 395–398
397
75
50
(R)-6
25
0
-25
(S)-6
-50
-75
250
300
350
400
450
(nm)
Fig. 1. The CD spectra of chiral ligand 6.
and 5, 6 vs. 7 and 8), probably because the ortho substituted substrates are more likely to coordinate with the ligand.
These results are in accordant with our previous investigations [23]. More rigid and hindered ketones, however, would
need much longer reaction time than acetophenone and its derivatives (Table 1, entries 10 and 12–14). For the
reduction of 1,1-diphenylacetone, the corresponding optical active alcohol was obtained with 97% yield and 50% ee at
75 8C for 5 h (Table 1, entry 15).
In conclusion, the novel chiral tetraaza ligands 6 and 7 were successfully synthesized and fully characterized by
physical and chemical methods. And the ligands were easily prepared from commercially available materials.
Furthermore, they were firstly applied in the iridium-catalyzed asymmetric transfer hydrogenation of aromatic
ketones. High activities (up to >99%) and moderate ees have been achieved with catalytic system generated in situ
from IrCl(CO)(PPh3)2 and ligand 6 in the presence of base. Further mechanism study is underway in our laboratory.
Table 1
Ir-catalyzed asymmetric transfer hydrogenation of various ketones with chiral tetraaza ligands.a .
O
OH
IrCl(CO)(PPh3)2/Ligand 6
KOH/i-PrOH
R1
R2
*
R1
R2
Entry
R1
R2
Time/h
Conv.b (%)
eeb (%)
Config.c
1d
2
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
5
5
85
93
0
21
48
16
11
52
20
13
27
34
3
–
Ph
R
R
R
R
R
R
R
R
R
S
3
o-Cl-Ph
m-Cl-Ph
p-Cl-Ph
o-Me-Ph
m-Me-Ph
p-Me-Ph
o-OMe-Ph
Ph
5
>99
>99
>99
95
4
5
5
5
6
5
7
5
80
8
5
67
9
5
>99
99
10
11e
12
13
14
15
10
10
10
10
10
5
Ph
Et
98
Ph
n-Pr
96
32
30
25
50
R
R
R
R
Ph
n-Bu
Cy
98
Ph
99
(Ph)2CH
Me
97
a
Reaction conditions: ketone, 0.5 mmol; i-PrOH, 10 mL; propiophenone:ligand 6:IrCl(CO)(PPh3)2:KOH = 100:1.5:1:2, molar ratio; 75 8C.
Conversions and enantiomeric excesses were determined by GC analysis using a CP-Chirasil-Dex CB column.
The configurations were determined by comparison of the retention times of the enantiomers on the GC traces with literature values.
Without ligand.
b
c
d
e
Ligand 7 was used instead of ligand 6.

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S.L. Yu et al. / Chinese Chemical Letters 23 (2012) 395–398
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Nos. 20423002, 20923004, and 21173176),
Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1036) and State Key
Laboratory of Physical Chemistry of Solid Surfaces for financial support.
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20
[25] Compound 6: mp 104–105 8C; ½aꢁD ꢀ56.5 (c 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 1.36 (d, 3H, J = 6.4 Hz), 1.46–1.58 (m, 4 H), 1.58–
1.74 (m, 8 H), 2.75–2.90 (m, 8 H), 3.75–3.95 (m, 3 H), 6.92–7.02 (m, 4 H), 7.26–7.34 (m, 2 H), 7.81–7.88 (m, 2 H), 8.56 (s, 1 H), 8.60 (s, 1 H);
13C NMR (100 MHz, CDCl3): d 20.63, 24.19, 26.29, 54.53, 54.63, 66.91, 68.80, 118.46, 118.63, 122.32, 122.36, 127.71, 127.91, 129.48,
129.58, 130.82, 130.93, 154.05, 154.20, 159.16, 161.03; IR (KBr) n: 3451, 2969, 2948, 2926, 2853, 2832, 2802, 2735, 1634, 1597, 1481, 1448,
1378, 1363, 1326, 1280, 1231, 1158, 1140, 1100, 1024, 927, 777, 762, 750, 652 cmꢀ1; EIMS (m/z): 417.3 (M+1). Compound 7: mp 216 8C
20
(dec.); ½aꢁD þ 9:5 (c 1.0, MeOH); 1H NMR (400 MHz, CD3OD): d 1.46–1.70 (m, 12 H), 2.65–2.81 (m, 8 H), 3.93 (t, 1H, J = 10.8 Hz,), 4.25
(dd, 1H, J = 10.8 Hz and 3.2 Hz), 4.38–4.47 (m, 1 H), 6.91–7.04 (m, 4 H), 7.26–7.34 (m, 2 H), 7.72 (dd, 1H, J = 7.6 Hz and 1.6 Hz), 7.91 (dd,
1H, J = 7.6 Hz and 1.6 Hz), 8.51 (s, 1 H), 8.54 (s, 1 H); 13C NMR (100 MHz, CD3OD): d 25.19, 25.20, 27.33, 27.38, 55.79, 55.83, 65.69, 78.68,
119.74, 120.02, 123.34, 123.43, 128.66, 129.19, 130.14, 130.42, 132.36, 132.63, 155.86, 155.91, 163.27, 164.11, 178.14; IR (KBr) n: 3424,
2936, 2847, 2786, 2738, 1628, 1591, 1481, 1448, 1372, 1286, 1222, 1158, 1024, 927, 756, 747 cmꢀ1; MS (ESI) m/z: [M+Na]+ 468.9.