Highly efficient chiral PNNP ligand for asymmetric transfer hydrogenation of aromatic ketones in water

Article abstract of DOI:10.1016/j.tetlet.2006.03.197

Chiral PNNP ligand II and [IrHCl₂(COD)]₂ were applied for the first time in the asymmetric transfer hydrogenation of aromatic ketones with HCOONa in water, giving the corresponding optical alcohols in high yield and excellent enantio

Full text of DOI:10.1016/j.tetlet.2006.03.197

Tetrahedron Letters 47 (2006) 4501–4503
Highly efficient chiral PNNP ligand for asymmetric
transfer hydrogenation of aromatic ketones in water
Yan Xing, Jian-Shan Chen, Zhen-Rong Dong, Yan-Yun Li and Jing-Xing Gao*
The State Key Laboratory of Physical Chemistry of Solid Surfaces and Department of Chemical and Biochemical
Engineering, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, PR China
Received 17 January 2006; revised 30 March 2006; accepted 31 March 2006
Available online 11 May 2006
Abstract—Chiral PNNP ligand II and [IrHCl2(COD)]2 were applied for the first time in the asymmetric transfer hydrogenation of
aromatic ketones with HCOONa in water, giving the corresponding optical alcohols in high yield and excellent enantioselectivity
(up to 99% ee). Particularly, the reduction of propiophenone proceeded smoothly at a substrate to catalyst molar ratio of 8000,
without compromising the ee values obtained.
ꢀ 2006 Published by Elsevier Ltd.
Asymmetric transfer hydrogenation (ATH) of ketones
has emerged as an attractive method for the production
of chiral alcohols due to its operational simplicity and
easy availability of hydrogen sources.1 The solvent for
ATH is usually 2-propanol,2 HCOOH–Et3N,3 or water.4,5
Among these solvents, involvement of 2-propanol in
ketone/alcohol equilibrium deteriorates the enantio-
selectivity and prevents a complete conversion,4f while
using HCOOH–Et3N as an organic solvent is harmful
and contaminates the environment.6 In the context of
using alternative solvents for green synthesis, water is
certainly the most outstanding solvent.7 Recently, some
effective chiral ligands of N,N-4 and N,O-type5 have
been applied in ATH using HCOONa as hydrogen
source in water. However, chiral polydentate PNNP
ligands have found little utility for ATH in water.5
Initially, various conditions were trailed to determine
the potential applicability of chiral PNNP-type ligands
for ATH of propiophenone (Scheme 1). The chiral
diiminodiphosphine ligand I exhibited good catalytic
activity (85% yield) but low enantioselectivity (34%
ee), while the chiral diaminodiphosphine ligand II hav-
ing two NH groups gave good to excellent results (Table
1, entry 1). This suggests that the NH function plays a
crucial role for the high conversion and good ee. These
results are similar to the case where 2-propanol is used
as solvent.8,9 When ligand II was used, increasing the
amount of HCOONa from 5 to 10 equiv had little effect
(entry 2). The effect of temperature was investigated; a
temperature change from 60 to 40 ꢁC greatly decreased
H
H
In the earlier studies, we reported the synthesis and
catalytic property of the well-designed PNNP-type
ligand II8 (Fig. 1), which exhibited high enantioselec-
tivity and activity in ATH of ketones using 2-propa-
nol as solvent and hydrogen source.9 Recently, we
found that this chiral ligand could also be applied in
ATH using HCOONa as the reductant in aqueous
media.
N
P
N
P
N
N
P
Ph2
P
Ph2
Ph2 Ph2
I C6P2N2
II C6P2(NH)2
Figure 1.
O
OH
*
[IrHCl2(COD)]2, Ligand II
Keywords: Chiral ligand; Aromatic ketone; Asymmetric transfer
hydrogenation.
H2O, HCOONa,
*
Corresponding author. Tel.: +86 592 2180929; fax: +86 592
2183047; e-mail: cuihua@jingxian.xmu.edu.cn
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.03.197

4502
Y. Xing et al. / Tetrahedron Letters 47 (2006) 4501–4503
Table 1. Asymmetric transfer hydrogenation of propiophenone catalyzed by [IrHCl2(COD)]2/ligand II system in aqueous media10
Entry
S/C
HCOONa (equiv)
Temp (ꢁC)
Time (h)
Yielda (%)
ee (%)a
1
2
3
4
5b
6c
7
100/1
100/1
100/1
200/1
200/1
200/1
4000/1
8000/1
5
10
5
5
5
5
5
5
60
60
40
60
60
60
60
60
9
9
99
99
40
98
92
99
99(95d)
88(80d)
88
87
85
88
89
88
86
85
60
21
39
51
77
101
8
a Determined by GC analysis on a G-TA column.
b Carried out in air.
c Water was not degassed.
d Isolated yield.
Table 2. Asymmetric transfer hydrogenation catalyzed by [IrHCl2(COD)]2/(R,R)- or (S,S)-C6P2(NH)2 systems in aqueous mediaa
O
O
O
O
O
2
3
8
5
6
4
O
O
O
O
Cl
O
Cl
Cl
9
11
7
10
Entry
Substrate
Ligand
Time (h)
Yieldb (%)
eeb (%)
Conf.c
1
2
3
4
5
6
7
8
9
2
(S,S)
(R,R)
(S,S)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(S,S)
(R,R)
(S,S)
(R,R)
33
30
50
39
47
39
36
33
47
34
39
39
99
95
99
85
99
86
99
98
98
48
95
98
99
99
96
92
62
88
82
51d
55
76
82
64
R
S
R
S
S
R
R
S
R
S
S
R
2
3
3
4
5
6
7
8
10
11
12
9
10
11
a The reactions were carried out at 60 ꢁC with 5 mol % of PPNCl and a S/C/HCOONa ratio of 100/1/500.
b Determined by GC equipped with a G-TA column (25 m) unless otherwise noted.
c The configurations were determined by comparison of the GC retention times for product mixtures with known literature values.
d Determined by HPLC analyses with a Chiralcel OD column.
the yield without loss of enantioselectivity (entries 3 and
4). When the catalytic reaction was carried out in air, the
activity slowed down but did not affect the ee value (89%
ee, entry 5). Interestingly, if water was not degassed, the
reaction time would be dramatically prolonged from 21
to 51 h in order to obtain the same yield (entry 6). The
reaction, notably, was also feasible at a higher substrate
to catalyst molar ratio (S/C) of 8000 (To the best of our
knowledge, the highest S/C ratio reported to date does
not exceed 2000.4a,d,e), with high isolated yield and good
enantioselectivity (entry 8), which allows for potential
practical application.
additives, only very low conversions were obtained in
60–72 h. In order to overcome this drawback, several
phase transfer catalysts (PTC), such as tetrabutyl
ammonium bromide (TBAB), cetyltrimethyl ammonium
bromide (CATB), and bis(triphenylphosphoranyl-
idene)ammonium chloride (PPNCl), were investigated.
We were pleased to discover that the enantioselectivities
and reactivities of the transfer hydrogenation were
enhanced highly in the presence of PPNCl. Generally,
the enantiomeric excess and the reaction rate in the
reduction of alkyl aryl ketones have been found to be
dependent on both steric and electronic factors.9b The
ee value was noticeably increased by increasing the steric
hindrance of ketones (entries 1–4). The best results (99%
yield and 99% ee, entries 1 and 2) were obtained in the
asymmetric reduction of 1-tetralone (2). ATH of alkyl
aryl ketones 5 and 6 proceeded rapidly to the
Encouraged by the results obtained with [IrHCl2
(COD)]2/C6P2(NH)2, we then applied this system to a
wide range of aromatic ketones (Table 2). When the
reactions were performed in water without any

Y. Xing et al. / Tetrahedron Letters 47 (2006) 4501–4503
4503
3. For recent reports of ATH in HCOOH–Et3N: (a) Wu, X. F.;
Li, X. G.; Frank, K.; Xiao, J. L. Angew. Chem., Int. Ed.
2005, 44, 3407–3411; (b) Matsunaga, H.; Ishizuka, T.;
Kunieda, T. Tetrahedron Lett. 2005, 46, 3645–3648; (c)
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Am. Chem. Soc. 2005, 127, 7318–7319; (d) Liu, P. N.; Gu, P.
M.; Wang, F.; Tu, Y. Q. Org. Lett. 2004, 6, 169–172; (e)
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corresponding chiral alcohols in good ee’s (entries 6 and
7). The introduction of electron-withdrawing
substituents, such as –Cl in the ortho- or meta-position
of the aryl ketone, resulted in higher rates but slightly
lower enantioselectivities compared with para-substi-
tuted substrates (entries 8–10). The reactivity was also
delicately influenced by electron-donating substituents
on the aromatic ring, with the enantioselectivity for
ortho-substitution being higher than that for meta-
substituted ketones (entries 11 and 12).
4. For literatures about aqueous-phase ATH of ketones, see:
(a) Wang, F.; Liu, H.; Cun, L. F.; Zhu, J.; Deng, J. G.;
Jiang, Y. Z. J. Org. Chem. 2005, 70, 9424–9429; (b) Wu,
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6. Pohanish, R. P.; Greene, S. A. McGraw-Hill’s Hazardous
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In summary, this work demonstrates that the catalytic
system generated in situ from [IrHCl2(COD)]2 and
PNNP ligand is an excellent catalyst for the asymmetric
transfer hydrogenation of various aromatic ketones
using HCOONa in water. The best result was obtained
in the reduction of 1-tetralone, giving 99% yield and
99% ee. In addition, even with a molar ratio of
propiophenone to catalyst of up to 8000/1, the reduction
proceeded smoothly in excellent enantioselectivity.
These experimental results provide an attractive method
for conducting ATH in a less costly, simpler and
‘greener’ manner.
Acknowledgements
´
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The authors thank the National Natural Science
Foundation of China (No. 20373056) and Fujian
Provincial Science and Technology Commission (No.
2002F016) for the financial support.
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10. General procedure for the asymmetric transfer hydroge-
nation of ketones: [IrHCl2(COD)]2 (1.9 mg, 0.0025 mmol)
and (R,R)-ligand II (5.0 mg, 0.0055 mmol) were dissolved
in 2 ml of degassed water under a N2 atmosphere. The
mixture was stirred at 60 ꢁC for 1 h, HCOONa (130 mg,
1.25 mmol) was then added to the solution. After the
solution was stirred for a further 10 min, propiophenone
(0.033 ml, 0.25 mmol) was introduced and the resulting
solution allowed to react for the predetermined reaction
time. At the end of the experiment, the reaction products
were extracted by a mixed solvent (3 · 5 ml) of n-hexane
and diethyl ether (v/v, 5:1). The extracted liquor was dried
over Na2SO4 and analyzed by GC.
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