Synthesis and characterization of novel chiral bidentate P,N-containing ligands and ruthenium(II) complex. the application in asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.jorganchem.2014.04.007

Novel chiral bidentate P,N-containing ligands have been easily synthesized by Schiff-base condensation of o-(diphenylphosphino)benzaldehyde and modified chiral diamine, (R,R)-2-(2,5-dimethyl-pyrrol-1-yl)-cyclohexylamine, further reduction with NaBH₄. The chiral ruthenium(II) complex could be successfully prepared from the reaction between chiral bidentate aminophosphine ligand and RuCl₂(PPh₃)₃. The chiral bidentate P,N-containing ligands and ruthenium(II) complex were fully characterized by NMR, IR, HRMS and single-crystal X-ray diffraction studies. In the presence of KOH, the asymmetric transfer hydrogenation (ATH) of various ketones catalyzed by the chiral ruthenium(II) complex proceeded smoothly under mild conditions, affording corresponding chiral secondary alcohols with up to 99% conversion and up to 60% ee. Additive such as NH₄I was found to be helpful to promoting the enantioselectivity.

Full text of DOI:10.1016/j.jorganchem.2014.04.007

Accepted Manuscript
Synthesis and Characterization of Novel Chiral Bidentate P,N-Containing Ligands and
Ruthenium(II) Complex. The Application in Asymmetric Transfer Hydrogenation of
Ketones
Li Zeng, Fang Wu, Yan-Yun Li, Zhen-Rong Dong, Jing-Xing Gao
PII:
S0022-328X(14)00177-6
10.1016/j.jorganchem.2014.04.007
JOM 18542
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 4 February 2014
Revised Date: 31 March 2014
Accepted Date: 3 April 2014
Please cite this article as: L. Zeng, F. Wu, Y.-Y. Li, Z.-R. Dong, J.-X. Gao, Synthesis and
Characterization of Novel Chiral Bidentate P,N-Containing Ligands and Ruthenium(II) Complex. The
Application in Asymmetric Transfer Hydrogenation of Ketones, Journal of Organometallic Chemistry
(2014), doi: 10.1016/j.jorganchem.2014.04.007.
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ACCEPTED MANUSCRIPT
Synthesis and Characterization of Novel Chiral Bidentate
P,N-Containing Ligands and Ruthenium(II) Complex. The
Application in Asymmetric Transfer Hydrogenation of
Ketones
Li Zeng, Fang Wu, Yan-Yun Li,* Zhen-Rong Dong, Jing-Xing Gao
Novel chiral bidentate P,N-containing ligands and corresponding
five-coordinated chiral ruthenium(II) complex have been successfully
synthesized and characterized. The asymmetric transfer hydrogenation
(ATH) of various ketones catalyzed by the chiral ruthenium(II) complex
proceeded smoothly with up to 99% conversion and up to 60% ee.
N
O
OH
R2
Cl
(R,R)-3
NH
P
R1
R2
R1
KOH, iPrOH
*
PPh3
Ru
Ph2 Cl
(R,R)-3

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1
2
3
4
Synthesis and Characterization of Novel Chiral Bidentate
P,N-Containing Ligands and Ruthenium(II) Complex. The
Application in Asymmetric Transfer Hydrogenation of
Ketones
5
6
7
Li Zeng, Fang Wu, Yan-Yun Li*, Zhen-Rong Dong, Jing-Xing Gao
8
9
College of Chemistry and Chemical Engineering, State Key Laboratory
of Physical Chemistry of Solid Surfaces, National Engineering
Laboratory for Green Chemical Productions of Alcohols, Ethers and
Esters, Xiamen University, Xiamen 361005, People’s Republic of China
10
11
12
13
14
15
16
17 *Corresponding author. Tel.: (+86)-592-2180929
18 E-mail: yanyunli@xmu.edu.cn
19
20
21
1

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22 Abstract
Novel chiral bidentate P,N-containing ligands have been easily
24 synthesized by Schiff-base condensation of
23
25 o-(diphenylphosphino)benzaldehyde and modified chiral diamine,
26 (R,R)-2-(2,5-dimethyl-pyrrol-1-yl)-cyclohexylamine, further reduction
27 with NaBH4. The chiral ruthenium(II) complex could be successfully
28 prepared from the reaction between chiral bidentate aminophosphine
29 ligand and RuCl2(PPh3)3. The chiral bidentate P,N-containing ligands and
30 ruthenium(II) complex were fully characterized by NMR, IR, HRMS and
31 single-crystal X-ray diffraction studies. In the presence of KOH, the
32 asymmetric transfer hydrogenation (ATH) of various ketones catalyzed
33 by the chiral ruthenium(II) complex proceeded smoothly under mild
34 conditions, affording corresponding chiral secondary alcohols with up to
35 99% conversion and up to 60% ee. Additive such as NH4I was found to
36 be helpful to promoting the enantioselectivity.
37
38 Keywords
39 Chiral bidentate P,N-containing ligands; Ruthenium(II) complex;
40 Asymmetric transfer hydrogenation; Ketones; Propiophenone
41
42
2

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43 1. Introduction
44
Asymmetric catalysis catalyzed by transition metal is a powerful
45 method to obtain chiral compounds, which are important building blocks
46 in the pharmaceuticals, agrochemicals, and fragrances industries [1–5]. In
47 asymmetric catalysis, ligands coordinated to the transition metal induce
48 asymmetry in a reaction, not just through steric factors, but also by
49 generating electronic asymmetry on the metal centre through the presence
50 of different donor atoms. Therefore, the design and synthesis of efficient
51 chiral ligands is a long-term challenge in asymmetric catalysis [6–8].
52
In the past few decades, the chiral aminophosphine ligands which bear
53 both “soft” phosphorus atom and “hard” nitrogen atom as their donor
54 atoms attracted more and more attention. The π-acceptor character of the
55 phosphorus can stabilize a metal centre in a low oxidation state, while the
56 σ-donor ability of nitrogen makes the metal more susceptible to oxidative
57 addition reactions [9-26]. This combination can help to stabilize metal
58 center and provide special chiral coordination environments during a
59 catalytic cycle. In 1996, we successfully synthesized C2-symmetric chiral
60 P2N2 ligands and employed the corresponding chiral ruthenium(II)
61 complexes to the asymmetric transfer hydrogenation (ATH) of aromatic
62 ketones [27]. Since then, a new class of chiral aminophosphine ligands,
63 such as P2N2-, PN4- and P2N4-type ligands has been successively
64 synthesized. Coupled with ruthenium, rhodium, iridium, or iron
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65 complexes, their catalytic performance for asymmetric reaction has been
66 studied in detail by us and other groups [28-49]. Despite the encouraging
67 progress in synthesis and application of chiral aminophosphine ligands,
68 the development of novel and effective chiral P,N-containing ligands is
69 still an important task to meet different demands of various asymmetric
70 reaction. In continuation of our study on chiral aminophosphine ligands
71 and related catalysis, we aim to develop a series of P,N-ligands, including
72 bidentate, tridentate, tetradentate, and multidentate P,N-ligands from
73 readily available starting material chiral diaminocyclohexane. We would
74 investigate the effects of steric and electronic factors of these ligands on
75 the asymmetric catalytic behavior. Herein we described the synthesis of
76 novel chiral bidentate P,N-containing ligands (R,R)-1 and (R,R)-2
77 (Scheme 1). By the introducing π-electron conjugated pyrrolyl ring with
78 two methyl groups into the P,N-backbone, it is thus possible to influence
79 the steric configuration and electronic properties of resulting chiral
80 P,N-ligands. The chiral ruthenium(II) complex (R,R)-3 (Scheme 1) was
81 also synthesized, characterized and investigated the catalytic behavior in
82 ATH of ketones.
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N
N
Cl
NH
N
N
NH
P
PPh3
Ru
P
Ph2
P
Ph2
Ph2 Cl
(R,R)-1
(R,R)-3
(R,R)-2
83
84
85
Scheme 1 Novel chiral bidentate P,N-containing ligands and chiral ruthenium(II)
complex
86
87 2. Experimental
88 2.1 General comments
89
All experiments were carried out under a nitrogen atmosphere using a
90 vacuum line and standard Schlenk techniques. All solvents were dried and
91 purified according to the standard methods before use. Optical rotations
92 were measured with a Perkin-Elmer 341 polarimeter. NMR spectra were
1
93 recorded on a Varian Unity-500 or Varian Unity-400 spectrometer. H
94 NMR chemical shifts were reported in ppm relative to TMS. Mass spectra
95 were obtained on Bruker En Apex ultra 7.0T FT-MS. IR spectra were
96 recorded on a Nicolet Avatar 360 FTIR spectrometer. X-Ray diffraction
97 data were collected on an Agilent Supernova CCD diffractometer.
98 2.2 Synthesis of (R,R)-2-(2,5-dimethyl-pyrrol-1-yl)-cyclohexylamine
O
CH3OH
50oC
+
H2N
NH2
O
H2N
N
99
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100
(R,R)-2-(2,5-Dimethyl-pyrrol-1-yl)-cyclohexylamine was prepared
101 according to the published procedure [50]. In a 250 mL round-bottomed
102 flask under nitrogen, a mixture of (R,R)-diaminocyclohexane (2.25 g,
103 19.7 mmol), 2,5-hexanedione (2.3 mL) and acetic acid (1.13 mL) was
104 dissolved in methanol (113 mL). After stirring the reaction mixture at
105 50 °C for 12 h and then cooling to room temperature, the solvent was
106 removed under reduced pressure to obtain orange oil. The oil was washed
107 with CH2Cl2 (375 mL), NaOH (4 M, 375 mL) and CH2Cl2 (60 mL × 3),
108 successively. The organic layers were combined and dried over anhydrous
109 MgSO4. After filtration and removing the solvent in vacuum, the crude
110 product was purified by chromatography on silica using CH2Cl2/CH3OH
111 (95:5) solution as an eluent. The solvent was removed to give an orange
1
112 oil (3.40 g, 89% yield). Anal. for C12H20N2 : 192.3 g/mol; H NMR (400
113 MHz, CDCl3): δ (ppm) 5.75 (s, 1 H), 5.72 (s, 1 H), 3.58 (td, 1 H, J = 10.8
114 Hz and 4.8 Hz), 3.23 (td, 1 H, J = 10.8 Hz and 4.4 Hz), 2.34 (s, 3 H), 2.21
115 (s, 3 H), 2.03-1.99 (m, 1 H), 1.95-1.74 (m, 4 H), 1.41-1.29 (m, 2 H),
116 1.23-1.13 (m, 1 H), 0.99 (br s, 2 H).
117 2.3 Synthesis of chiral iminophosphine ligand (R,R)-1
CHO
P
N
N
Na2SO4
+
H2N
CH2Cl2, rt, 3 days
P
Ph2
N
Ph2
(R,R)-1
118
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119
To a mixture of o-(diphenylphosphino)benzaldehyde (0.86 g, 3.0 mmol)
120 and anhydrous Na2SO4 (10.0 g, 70.0 mmol) in CH2Cl2 (25 mL) was
121 added (R,R)-2-(2,5-dimethyl-pyrrol-1-yl)-cyclohexylamine (0.68 g, 3.5
122 mmol). The mixture was stirred at room temperature for 3 days. The
123 resulting solution was filtrated and the solvent was removed under
124 vacuum to obtain a yellow solid (R,R)-1 (1.30 g, 93% yield). Anal. for
125 C31H33N2P : 464.58 g/mol; [α]2D0 = −36.0 (c 1.0, CH2Cl2). 1H NMR (400
126 MHz, CDCl3):
δ (ppm) 8.49 (d, 1 H, J = 4.8 Hz), 7.65-7.62 (m, 1 H),
127 7.34-7.28 (m, 7 H), 7.25-7.19 (m, 5 H), 6.81-6.78 (m, 1 H), 5.49 (br s, 2
128 H), 4.09 (td, 1 H, J = 9.6 Hz and 5.6 Hz), 3.50 (td, 1 H, J = 10.4 Hz and
129 4.8 Hz), 2.22 (br s, 6 H), 2.08-2.02 (m, 1 H), 1.90-1.85 (m, 1 H),
13
130 1.77-1.70 (m, 2 H), 1.65-1.50 (m, 2 H), 1.46-1.26 (m, 2 H); C NMR
131 (100 MHz, CDCl3):
δ (ppm) 159.32 (d, J = 22 Hz), 139.97, 139.79,
132 136.97, 136.79, 136.56, 136.47 (d, J = 2 Hz), 136.38, 134.20, 133.98 (d, J
133 = 5 Hz), 133.75, 133.12, 129.99 (d, J = 1 Hz), 129.15 (d, J = 4 Hz),
134 128.96, 128.79, 128.74 (d, J = 3 Hz), 128.63, 128.57 (d, J = 2 Hz), 128.51,
135 127.37 (d, J = 3 Hz), 107.77, 104.59, 72.04, 60.17, 34.22, 30.86, 26.22,
31
136 24.42, 15.56, 13.81; P NMR (162 MHz, CDCl3):
δ (ppm) −14.40; IR
137 (KBr) ν: 3052.1, 2928.1, 2855.2, 1637.2, 1478.2, 1434.3, 1396.4, 1292.3,
138 1193.3, 1117.6, 1069.6, 1025.1, 744.4, 722.9, 695.5, 545.6, 503.8 cm−1;
139 HRMS (ESI, m/z): 465.2454.
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140 2.4 Synthesis of chiral aminophosphine ligand (R,R)-2
N
NH
NaBH4
N
N
EtOH, 50 oC, 2 days
P
Ph2
P
Ph2
(R,R)-1
(R,R)-2
141
142
A mixture of (R,R)-1 (0.50 g, 1.1 mmol) and NaBH4 (1.0 g, 26.4 mmol)
143 in absolute EtOH (30 mL) was heated at 50 °C with stirring for 2 days.
144 Then, H2O (20 mL) was added and the solvent was removed under
145 reduced pressure. The residue was extracted repeatedly with CH2Cl2 (60
146 mL × 3) and the combined extracts were neutralized by saturated NH4Cl
147 solution. The solution was washed with saturated NH4Cl solution, H2O
148 and saturated brine solution, successively. The organic layers were
149 combined and dried over anhydrous Na2SO4. Removal of the solvent
150 afforded a pale yellow solid (R,R)-2 (0.42 g, 82% yield). Anal. for
151 C31H35N2P: 466.59 g/mol; [α]2D0 = −19.7 (c 1.0, CH2Cl2). 1H NMR (400
152 MHz, CDCl3):
δ (ppm) 7.61-7.41 (m, 1 H), 7.38-7.26 (m, 6 H), 7.25-7.22
153 (m, 1 H), 7.21-7.16 (m, 4 H), 7.12-7.08 (m, 1 H), 6.86-6.83 (m, 1 H), 5.75
154 (br s, 2 H), 3.87-3.70 (m, 3 H), 3.00 (td, 1 H, J = 10.8 Hz and 4.4 Hz),
155 2.22 (s, 3 H), 2.14 (s, 3 H), 1.96-1.89 (m, 1 H), 1.87-1.77 (m, 3 H),
156 1.73-1.69 (m, 1 H), 1.38-1.28 (m, 1 H), 1.27-1.17 (m, 1 H), 1.14-1.06 (m,
13
157 1 H), 1.03-0.89 (m, 1 H); C NMR (100 MHz, CDCl3):
δ (ppm) 144.65
158 (d, J = 3 Hz), 136.74, 136.64, 135.57, 135.43, 133.99 (d, J = 7 Hz),
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159 133.79 (d, J = 7 Hz), 133.40, 132.12, 132.03, 131.86, 131.76, 128.99,
160 128.67, 128.64, 128.58, 128.52, 128.45, 127.08, 108.05, 105.42, 61.09,
161 58.13, 48.39 (d, J = 22 Hz), 32.43, 31.42, 29.71, 26.22, 24.61, 15.12,
162 13.60; 31P NMR (162 MHz, CDCl3):
δ (ppm) −16.31; IR (KBr) ν: 3422.3,
163 3052.9, 2930.2, 2855.8, 1476.7, 1435.5, 1384.6, 1291.5, 1181.6, 1118.0,
164 1070.3, 1026.5, 747.1, 721.8, 696.8, 545.7, 506.3 cm−1; HRMS (ESI, m/z):
165 467.2621.
166 2.5 Synthesis of chiral ruthenium(II) complex (R,R)-3
N
RuCl2(PPh3)3
CH2Cl2, 35 oC, 1 day
NH
Cl
N
NH
P
PPh3
Ru
P
Ph2
Ph2 Cl
(R,R)-2
(R,R)-3
167
168
In a 100 mL Schlenk tube, a mixture of (R,R)-2 (0.57 g, 1.21 mmol)
169 and RuCl2(PPh3)3 (0.53 g, 0.55mmol) was dissolved in CH2Cl2 (50 mL)
170 under nitrogen. After stirring the reaction mixture at 35 °C for 24 h and
171 then cooling to room temperature, the solvent was removed under
172 reduced pressure. The crude product was recrystallized from CH2Cl2/Et2O
173 solution to give dark green solid (R,R)-3 (0.33 g, 67% yield). Anal. for
1
174 C49H50Cl2N2P2Ru: 900.8 g/mol; H NMR (400 MHz, CDCl3):
δ (ppm)
175 7.64-7.60 (m, 6 H), 7.34-7.29 (m, 4 H), 7.27-7.26 (m, 1 H), 7.23-7.12 (m,
176 10 H), 6.96-6.87 (m, 5 H), 6.70-6.66 (m, 1 H), 6.43-6.38 (m, 2 H), 5.93 (s,
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177 1 H), 5.87 (s, 1 H), 4.47 (td, 1 H, J = 11.2 Hz and 1.6 Hz), 4.36 (ddd, 1 H,
178 J = 13.6 Hz, 10.8 Hz and 2.8 Hz), 3.95 (td, 1 H, J = 12 Hz and 3.6 Hz),
179 3.85 (td, 1 H, J = 10.8 Hz and 4 Hz), 2.77-2.73 (m, 1 H), 2.44 (s, 3 H),
180 2.22 (s, 3 H), 2.13-2.03 (m, 1 H), 1.87-1.84 (m, 1 H), 1.77-1.74 (m, 1 H),
13
181 1.63-1.55 (m, 2 H), 1.29-1.17 (m, 3 H); C NMR (100 MHz, CDCl3):
δ
182 (ppm) 140.58 (d, J = 13 Hz), 135.50, 135.11, 134.98, 134.88, 134.82
183 134.73, 134.68, 134.58, 134.04 (d, J = 3 Hz), 132.67, 132.19, 131.82,
184 131.73, 131.01 (d, J = 3 Hz), 130.47 (d, J = 2 Hz), 130.26, 129.98 (d, J =
185 3 Hz), 129.74, 129.64 (d, J = 3 Hz), 129.05 (d, J = 2 Hz), 128.67, 128.15,
186 128.07, 127.79, 127.60, 127.51, 127.48, 126.92, 126.82, 108.83, 106.78,
187 60.81 (d, J = 2 Hz), 60.32 (d, J = 2 Hz), 53.26 (d, J = 4 Hz), 32.92, 31.58,
31
188 25.46, 24.07, 15.51, 14.01; P NMR (162 MHz, CDCl3):
δ (ppm) 68.27
189 (d, J = 35.6 Hz), 41.41 (d, J = 35.6 Hz); IR (KBr) ν: 3207.4, 3052.6,
190 2929.7, 2858.3, 1624.8, 1572.2, 1511.4, 1481.5, 1434.3, 1389.7, 1291.0,
191 1192.0, 1155.9, 1130.2, 1092.6, 1027.8, 994.0, 908.0, 877.2, 746.4, 697.7,
192 621.0, 546.1, 521.3, 467.3, 419.2 cm−1; MS (m/z): 899.2 (M-1).
193 Elemental analysis for C49H50Cl2N2P2Ru, calcd. (found): C, 65.33 (64.92);
194 H, 5.59 (5.39); N, 3.11 (2.95).
195 2.6 ATH of ketones catalyzed by chiral ruthenium(II) complex
196
A typical procedure for the ATH was as follows: Under a nitrogen
197 atmosphere, the chiral ruthenium(II) complex (R,R)-3 (4.5 mg, 0.005
198 mmol) were added in a Schlenk tube equipped with a Teflon-coated
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199 magnetic stirring bar. Isopropyl alcohol (iPrOH) was then introduced and
200 the mixture was stirred at 65 °C for 30 min. An appropriate amount of
201 KOH/iPrOH solution was then added, and the mixture was continually
202 stirred for another 10 min. Ketone was then introduced and the mixture
203 was stirred at the desired temperature for the required reaction time. At
204 the end of the reaction, the product was determined by GC using a chiral
205 CP-Chiralsil-Dex CB column.
206
207 3. Results and Discussion
208 3.1 Synthesis and characterization of chiral P,N-ligands
209
The chiral bidentate iminophosphine ligand (R,R)-1 could be easily
210 obtained by the condensation of o-(diphenylphosphino)benzaldehyde and
211 (R,R)-2-(2,5-dimethyl-pyrrol-1-yl)-cyclohexylamine at room temperature
212 in 93% yield. The IR spectrum of (R,R)-1 presented a strong C=N stretch
213 at 1637 cm-1. The 1H NMR spectrum exhibited a doublet (J = 4.8 Hz) at
δ
214 8.49 ppm for the imino proton. These spectroscopic data and results of
215 HRMS supported the proposed structure and indicated that (R,R)-1
31
216 contains imino group. The P NMR spectrum of (R,R)-1 exhibited a
217 singlet at
δ
−14.40 ppm, which represented the phosphine atom of PPh2
31.38 ppm implied that minor oxidation of the
218 group. And the singlet at
δ
219 phosphine group occured during the reaction. Reduction of (R,R)-1 with
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220 excess NaBH4 was carried out in EtOH at 50 °C, affording the
221 corresponding amine ligand (R,R)-2 as a pale yellow solid in 82% yield.
222 The presence of multiple peak at
δ 1.96-1.89 ppm for the NH proton in
1
223 the H NMR spectrum of (R,R)-2 and the disappearance of infrared band
224 at 1637 cm-1 indicated that the imino group was reduced to the
225 corresponding amino group. The 31P NMR spectrum presented a singlet at
226
δ −16.31 ppm standing for the phosphine atom of PPh2 group in the
227 compound. There was also minor phosphine oxide (singlet at
228 ppm).
δ 31.88
229 3.2 Synthesis and characterization of chiral ruthenium(II) complex
Previously, we successfully synthesized the six-coordinated chiral
230
231 ruthenium(II) complex by the reaction of chiral tetradentate P2N2-type
232 ligands with RuCl2(DMSO)4 in refluxing toluene [27]. Thus, we tried to
233 obtain the chiral ruthenium(II) complex by the reaction of chiral bidentate
234 P,N-containing ligand (R,R)-2 with RuCl2(DMSO)4 but could not succeed.
235 However, when we chose RuCl2(PPh3)3 as ruthenium precursor, the
236 five-coordinated complex (R,R)-3 was fortunately obtained. The 31P NMR
237 spectrum of (R,R)-3 exhibited signals at δ 68.27 (d, J = 35.6 Hz) and
238 41.41 (d, J = 35.6 Hz) ppm, indicating that both phosphino groups were
239 coordinated to the ruthenium center. Dark-green crystals of (R,R)-3
240 suitable for X-ray diffraction were obtained from CH2Cl2/Et2O. The
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241 structure of (R,R)-3 was established by single-crystal X-ray diffraction
242 study, which revealed that the two chloro atoms were mutually trans to
243 each other and (R,R)-2 ligand behaved as a bidentate ligand around the
244 Ru center (Fig. 1). The structure is analogous to those of RuCl2(PPh3)3
245 and the ruthenium(II) complex reported by Cullen [51, 52].
246
247
248
249
250
251
252
Fig. 1 The structure of chiral ruthenium(II) complex (R,R)-3 (some H atoms omitted
for clarity). Selected bond lengths (Å) and angles (°): Ru-P(1) 2.1935(7), Ru-P(2)
2.3164(7), Ru-N(1) 2.209(2), Ru-Cl(1) 2.3997(7), Ru-Cl(2) 2.3858(7); P(1)-Ru-Cl(1)
96.29(3), P(1)-Ru-P(2) 97.38(3), P(1)-Ru-N(1) 92.27(6), P(l)-Ru-Cl(2) 97.90(3),
Cl(1)-Ru-N(1) 81.48(6), N(1)-Ru-Cl(2) 86.95(6), Cl(2)-Ru-P(2) 90.01(3),
P(2)-Ru-Cl(1) 99.09(2), P(2)-Ru-N(1) 170.19(6), Cl(1)-Ru-Cl(2) 162.01(2).
253 3.3 Catalytic behavior of chiral ruthenium(II) complex
The five-coordinated chiral ruthenium(II) complex (R,R)-3 was
254
255 evaluated as catalyst for the ATH reaction of ketones using iPrOH as the
256 hydrogen source. We chose propiophenone as a model substrate at first
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257 (Table 1). It could be seen that the ATH of propiophenone carried out
258 smoothly to afford (R)-1-phenylpropan-1-ol, with 99% conversion and
259 37% ee (Table 1, entry 1). In our previous study, we found that the ATH
260 reaction could be promoted by addition of ammonium salt such as NH4Cl,
261 although the role of ammonium salt in the catalytic cycle is still unclear
262 [37]. Therefore, we examined the influence of additive on ATH of
263 propiophenone. It was interesting that the enantioselectivity also
264 increased by addition of ammonium halide (Table 1, entries 2-5). With 5
265 eq. (related to catalyst) of NH4I as additive, in the presence of 10 eq.
266 (related to catalyst) of KOH, 56% ee was obtained for the ATH of
267 propiophenone with slightly decreased catalytic activity (Table 1, entry 5).
268 However, when NH4PF6 was used as additive, the reaction was almost
269 stopped, affording only 4% conversion (Table 1, entry 6). The
270 enantioselectivity was slightly affected by addition of ammonium acetate,
271 ammonium carbonate or ammonium sulfate (Table 1, entries 7-9).
272 However, using ammonium carbonate as additive caused great decrease
273 of activity (Table 1, entry 9). Moreover, addition of sodium halide or
274 potassium halide increased the enantioselectivity somewhat (Table 1,
275 entries 10-15).
276
277
278
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279 Table 1 The influence of additive on ATH of propiophenone a
O
OH
(R,R)-3 (1 mol%)
KOH, iPrOH
280
Entry
1
Additive
Conv. (%) b Ee (%) b
--
NH4F
99
99
99
98
96
4
37
39
44
50
56
12
38
35
35
38
39
42
39
36
42
2
3
NH4Cl
NH4Br
NH4I
4
5
6
NH4PF6
CH3COONH4
(NH4)2SO4
(NH4)2CO3
NaCl
7
96
94
57
99
99
99
99
99
97
8
9
10
11
12
13
14
15
NaBr
NaI
KCl
KBr
KI
a
281
282
283
Reaction conditions: propiophenone (0.5 mmol), (R,R)-3 (0.005 mmol), additive
b
(0.025 mmol), sub:cat.:KOH=100:1:10, iPrOH (10 mL), 40 °C, 5 h. Determined
by GC using a chiral CP-Chiralsil-Dex CB column.
15

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284
It is known that adding a base is crucial to the reaction of ATH or
285 asymmetric hydrogenation (AH) on reactivity and enantioselectivity.
286 Meanwhile the examples under base-free condition have been also
287 demonstrated [47, 53-55]. Table 2 presented the effect of base on the ATH
288 of propiophenone. It showed that no reaction carried out if the base was
289 absent or at low concentration (Table 2, entries 1 and 2). Both the reaction
290 rate and ee increased greatly with increasing concentration of base (Table
291 2, entry 3). With 10 eq. (related to catalyst) of KOH, the ATH afforded
292 96% conversion and 56% ee (Table 2, entry 4). However, excess base
293 would decrease the enantioselectivity (51% ee, Table 2, entry 5). In the
294 presence of tBuOK, the reaction proceeded smoothly with lower ee
295 (Table 2, entry 6). Moreover, when a weaker base, such as NaOH, K2CO3,
296 and Na2CO3 was used, a slower reaction even no reaction resulted (Table
297 2, entries 7-9). The role of the base is considered to be helpful to the
298 formation of metal hydrides [56].
299 Table 2 The influence of base on the ATH of propiophenone a
Entry
1
Base
sub:cat.:base
100:1:0
Conv. (%) b
Ee (%) b
None
--
--
2
3
KOH
KOH
100:1:4
100:1:8
--
--
71
55
16

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4
5
6
7
8
9
KOH
KOH
100:1:10
100:1:12
100:1:10
100:1:10
100:1:10
100:1:10
96
56
51
46
41
--
98
98
61
--
tBuOK
NaOH
K2CO3
Na2CO3
--
--
300
301
302
a Reaction conditions: propiophenone (0.5 mmol), (R,R)-3 (0.005 mmol), NH4I (0.025
b
mmol), iPrOH (10 mL), 40 °C, 5 h.
Determined by GC using a chiral
CP-Chiralsil-Dex CB column.
303
Furthermore, we also carried out the reaction under different
304 temperature to determine proper temperature for ATH of propiophenone.
305 It could be seen in Table 3 that the reaction was inert at lower temperature
306 (Table 3, entries 1 and 2). The reaction rate accelerated when the reaction
307 temperature increased. However, at higher temperatures, the ee dropped
308 quickly (Table 3, entries 5-7). Considering the catalytic activity as well as
309 enantioselectivity, we chose 40 °C as the optimal reaction temperature.
310 Table 3 The influence of temperature on ATH of propiophenone a
Entry Temp.( °C)
10
Conv. (%) b
--
Ee (%) b
--
1
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2
3
4
5
6
7
20
--
52
--
30
40
50
60
70
59
53
50
40
29
87
98
99
>99
311
312
313
a Reaction conditions: propiophenone (0.5 mmol), (R,R)-3 (0.005 mmol), NH4I (0.025
b
mmol) as additive, sub:cat.:KOH=100:1:10, iPrOH (10 mL), 2 h. Determined by
GC using a chiral CP-Chiralsil-Dex CB column.
314
The influence of reaction time on ATH of propiophenone catalyzed
315 by chiral ruthenium(II) complex (R,R)-3 was investigated and the results
316 were shown in Fig. 2. It indicated that the reaction proceeded rapidly at
317 the beginning and then slowed down. However, prolonged reaction time
318 led to the dropped enantioselectivity. The highest ee value (60% ee) was
319 obtained at 4 h, and the corresponding conversion was 96%.
18

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100
90
80
70
60
50
40
30
Conversion (%)
Ee (%)
0
1
2
3
4
5
6
7
Reaction time (h)
320
321
Fig. 2 Effect of reaction time on ATH of propiophenone. Reaction conditions:
propiophenone (0.5 mmol), (R,R)-3 (0.005 mmol), NH4I (0.025 mmol) as additive,
sub:cat.:KOH=100:1:10, iPrOH (10 mL), 40 °C.
322
323
324
With the optimized conditions in hand, we next examined the ATH
325 of various ketones using the chiral ruthenium(II) complex (R,R)-3 as
326 catalyst. For the ATH of acetophenone, the catalyst system showed
327 similar high activity but decreased enantioselectivities (42% ee, Table 4,
328 entry 2). Under the conditions employed, the substituted acetophenones
329 gave decreasing activities on going from the para to meta and ortho
330 substitution (Table 4, entries 3-5). Only 58% conversion and 22% ee were
331 obtained for ortho-substituted acetophenones (Table 4, entry 5). As for
332 more hindered aromatic ketone, 1,1’-diphenylpropan-2-one gave low
333 conversion and poor enantioselectivity (Table 4, entry 6). In the case of
19

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334 ATH of dialkyl ketone, 3,3-dimethylbutan-2-one also gave unsatisfied
335 result (30% conversion and 3% ee, Table 4, entry 7). These results may
336 imply that the interaction between substrate and chiral catalyst played an
337 important role in asymmetric catalysis. In the ruthenium complex, the
338 introducing pyrrolyl ring into the P,N-backbone increased the steric
339 hindrance around the metal atom, which hampered effective cooperation
340 between substrate and chiral catalyst in the catalytic cycle.
341 Table 4 ATH of various ketones catalyzed by (R,R)-3 a
Entry
Ketones
Conv. (%) b
Ee (%) b
Config. b
O
1
96
60
R
O
O
O
2
3
4
5
6
97
88
62
58
45
42
36
48
22
5
R
R
R
R
R
O
O
20

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O
7
30
3
R
a
342
343
344
345
Reaction conditions: ketone (0.5 mmol), (R,R)-3 (0.005 mmol), NH4I (0.025 mmol)
b
as additive, sub:cat.:KOH=100:1:10, iPrOH (10 mL), 40 °C, 4 h. Determined by
GC using a chiral CP-Chiralsil-Dex CB column. The absolute configuration was
determined by comparison of the retention times with the literature data.
346
It is noted that for the ATH of ketones catalyzed by chiral ruthenium(II)
347 complex (R,R)-3, lower catalyst loading is possible. Table 5 demonstrated
348 the results of various catalyst loadings for the ATH of propiophenone. For
349 instance, the reaction proceeded smoothly at S/C = 500, affording 96%
350 conversion and 24% ee in 5 h (Table 5, entry 3). At still a higher S/C ratio
351 of 1500, the propiophenone was reduced with 75% conversion in 24 h,
352 affording a turnover number (TON) of 1125 (Table 5, entry 5).
353 Table 5 Various catalyst loadings for the ATH of propiophenone a
Entry sub:cat.:KOH
Time (h) Conv. (%) b Ee (%) b TON
1
100:1:10
200:1:10
500:1:10
1000:1:16
1500:1:16
5
5
96
97
96
93
75
56
26
24
19
5
96
194
480
930
1125
2c
3c
4c
5c
5
24
24
a
354
355
Reaction conditions: (R,R)-3 (0.005 mmol), NH4I (0.025 mmol) as additive, iPrOH
(10 mL), 40 °C. b Determined by GC using a chiral CP-Chiralsil-Dex CB column. c At 70 °C.
21

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356
357 4. Conclusions
358
In summary, we have synthesized novel chiral bidentate P,N-containing
359 ligands and corresponding chiral ruthenium(II) complex from modified
360 chiral diamine, (R,R)-2-(2,5-dimethyl-pyrrol-1-yl)-cyclohexylamine
361 through a convenient transformation. The five-coordinated structure of
362 chiral ruthenium(II) complex was established by single-crystal X-ray
363 diffraction study, which revealed that the chiral P,N-containing ligand
364 (R,R)-2 behaved as a bidentate ligand around the Ru center. Using iPrOH
365 as the hydrogen source, the ATH of various ketones catalyzed by the
366 chiral ruthenium(II) complex proceeded smoothly with up to 99%
367 conversion and up to 60% ee. Although the results are certainly still quite
368 modest with respect to what can be achieved by using well-developed
369 ATH catalysts, it represents a good example for design and synthesis of
370 novel ruthenium(II) catalysts containing chiral bidentate aminophosphine
371 ligand. Efforts are underway to synthesize a larger library of chiral
372 P,N-containing ligands and corresponding metal complexes for efficient
373 asymmetric catalysis.
374
375 Acknowledgments
376
We would like to thank the National Natural Science Foundation of
22

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377 China (No. 21173176) and Program for Changjiang Scholars and
378 Innovative Research Team in University (No. IRT1036) for financial
379 support.
380
381 Appendix A. Supplementary material
382
Further characterization data and NMR spectra of chiral ligands
383 (R,R)-1, (R,R)-2 and chiral ruthenium(II) complex (R,R)-3 are given in
384 the supplementary material. CCDC 960239 (complex (R,R)-3) contains
385 the supplementary crystallographic data for this paper. These data can be
386 obtained free of charge from The Cambridge Crystallographic Data
387 Centre via www.ccdc.cam.ac.uk/data_request/cif.
388
389 References
390
391
392
393
394
395
396
397
398
[1] R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994.
[2] S.C. Stinson, Chem. Eng. News 79 (2001) 45-56.
[3] W. Tang, X. Zhang, Chem. Rev. 103 (2003) 3029-3069.
[4] P.W.N.M. van Leeuwen, Homogeneous Catalysis: Understanding the Art,
Springer-Verlag, Berlin, 2005.
[5] H. Shimizu, I. Nagasaki, K. Matsumura, N. Sayo, T. Saito, Acc. Chem. Res. 40
(2007) 1385-1393.
[6] R.A. Sheldon, Chirotechonology, Marcel Dekker, New York, 1993.
[7] E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric
23

ACCEPTED MANUSCRIPT
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
Catalysis, Vols. I–III, Springer, Berlin, New York, 1999.
[8] I. Ojima, Catalytic Asymmetric Synthesis, Wiley, New York, 2000.
[9] P. Espinet, K. Soulantica, Coord. Chem. Rev. 195 (1999) 499-556.
[10] G. Helmchen, A. Pfaltz, Acc. Chem. Res. 33 (2000) 336-345.
[11] G. Chelucci, G. Orru, G.A. Pinna, Tetrahedron 59 (2003) 9471-9515.
[12] I.D. Kostas, Curr. Org. Synth. 5 (2008) 227-249.
[13] P. von Matt, A. Pfaltz, Angew. Chem. Int. Ed. Engl. 32 (1993) 566-568.
[14] J. Sprinz, G. Helmchen, Tetrahedron Lett. 34 (1993) 1769-1772.
[15] A.H.M. de Vries, A. Meetsma, B.L. Feringa, Angew. Chem. Int. Ed. Engl. 35
(1996) 2374-2376.
[16] I. Yamada, M. Yamaguchi, T. Yamagishi, Tetrahedron: Asymmetry 7 (1996)
3339-3342.
[17] Y.T. Jiang, Q.Z. Jiang, G.X. Zhu, X.M. Zhang, Tetrahedron Lett., 38 (1997)
215-218.
[18] I. Achiwa, A. Yamazaki, K. Achiwa, Synlett 1998, 45-46.
[19] X.Q. Hu, H.L. Chen, X.M. Zhang, Angew. Chem. Int. Ed. 38 (1999) 3518-3521.
[20] Y. Wang, H. Guo, K.L. Ding, Tetrahedron: Asymmetry 11 (2000) 4153-4162.
[21] S. Bell, B. Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A. Pfaltz, Science 311
(2006) 642-644.
[22] Y.J. Yan, X.M. Zhang, J. Am. Chem. Soc. 128 (2006) 7198-7202.
[23] M. Engman, J.S. Diesen, A. Paptchikhine, P.G. Andersson, J. Am. Chem. Soc.
129 (2007) 4536-4537.
[24] S.-M. Lu, C. Bolm, Angew. Chem. Int. Ed. 47 (2008) 8920-8923.
[25] M.P. Mitoraj, A. Michalak, Inorg. Chem. 49 (2010) 578-582.
[26] C. Schotes, A. Mezzetti, Angew. Chem. Int. Ed. 50 (2011) 3072-3074.
24

ACCEPTED MANUSCRIPT
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
[27] J.-X. Gao, T. Ikariya, R. Noyori, Organometallics 15 (1996) 1087-1089.
[28] J.-X. Gao, X.-D. Yi, P.-P. Xu, C.-L. Tang, H.-L. Wan, T. Ikariya, J. Organomet.
Chem. 592 (1999) 290-295.
[29] J.-X. Gao, X.-D. Yi, P.-P. Xu, C.-L. Tang, H. Zhang, H.-L. Wan, T. Ikariya, J. Mol.
Catal. A: Chemical 159 (2000) 3-9.
[30] J.-X. Gao, H. Zhang, X.-D. Yi, P.-P. Xu, C.-L. Tang, H.-L. Wan, K.-R. Tsai, T.
Ikariya, Chirality 5 (2000) 383-388.
[31] Y.-Y. Li, H. Zhang, J.-S. Chen, X.-L. Liao, Z.-R. Dong, J.-X. Gao, J. Mol. Catal.
A: Chemical 218 (2004) 153-156.
[32] J.-S. Chen, L.-L. Chen, Y. Xing, G. Chen, W.-Y. Shen, Z.-R. Dong, Y.-Y. Li,
J.-X.Gao, Acta Chim. Sinica 62 (2004) 1745-1750.
[33] Y.-Y. Li, X.-Q. Zhang, Z.-R. Dong, W.-Y. Shen, G. Chen, J.-X. Gao, Org. Lett. 8
(2006) 5565-5567.
[34] B.-Z. Li, J.-S. Chen, Z.-R. Dong, Y.-Y. Li, Q.-B. Li, J.-X. Gao, J. Mol. Catal. A:
Chemical 258 (2006) 113-117.
[35] Z.B. Cheng, S.L. Yu, Y.Y. Li, Z.R. Dong, G.S. Sun, K.L. Huang, J.X. Gao, Chem.
Res. Chin. Univ. 27 (2011) 170-173.
[36] S.L. Yu, Y.Y. Li, Z.R. Dong, J.N. Zhang, Q. Li, J.X. Gao, Chin. Chem. Lett. 22
(2011) 1269-1272.
[37] S.L. Yu, W.Y. Shen, Y.Y. Li, Z.R. Dong, Y.Q. Xu, Q. Li, J.N. Zhang, J.X. Gao,
Adv. Synth. Catal. 354 (2012) 818-822.
[38] Y.-Q. Xu, S.-L. Yu, Y.-Y. Li, Z.-R. Dong, J.-X. Gao, Chin. Chem. Lett. 24 (2013)
527-530.
[39] R.M. Stoop, S. Bachmann, M. Valentini, A. Mezzetti, Oganometallics 19 (2000)
4117-4126.
25

ACCEPTED MANUSCRIPT
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
[40] Z. Zheng, X.-Q. Yao, C. Li, H.-L. Chen, X.-Q. Hu, Tetrahedron Lett. 42 (2001)
2847-2849.
[41] S. Bachmann, M. Furler, A. Mezzetti, Organometallics 20 (2001) 2102-2108.
[42] C. Bonaccorsi, A. Mezzetti, Organometallics 24 (2005) 4953-4960.
[43] C. Sui-Seng, F. Freutel, A.J. Lough, R.H. Morris, Angew. Chem. Int. Ed. 47
(2008) 940-943.
[44] M. Ranocchiari, A. Mezzetti, Organometallics 28 (2009) 1286-1288.
[45] R.H. Morris, Chem. Soc. Rev. 38 (2009) 2282-2291.
[46] S.-L. Zhou, S. Fleischer, K. Junge, S. Das, D. Addis, M. Beller, Angew. Chem.
Int. Ed. 49 (2010) 8121–8125.
[47] P.O. Lagaditis, A.J. Lough, R.H. Morris, J. Am. Chem. Soc. 133 (2011)
9662-9665.
[48] P.E. Sues, A.J. Lough, R.H. Morris, Organometallics 30 (2011) 4418-4431.
[49] W.W. Zuo, A.J. Lough, Y.F. Li, R.H. Morris, Science 342 (2013) 1080-1083.
[50] M.S. Taylor, E.N. Jacobsen, J. Am. Chem. Soc. 126 (2004) 10558-10559.
[51] S.J. La Placa, J.A. Ibers, Inorg. Chem. 1965, 4, 778-783.
[52] D.C. Mudalige, S.J. Rettig, B.R. James, W.R. Cullen, J. Chem. Soc., Chem.
Commun. 126, (1993) 830-832.
[53] K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem. Int. Ed.
Engl. 36 (1997) 285-288.
[54] K. Murata, T. Ikariya, R. Noyori, J. Org. Chem. 64 (1999) 2186-2187.
[55] Z.-R. Dong, Y.-Y. Li, J.-S. Chen, B.-Z. Li, Y. Xing, J.-X. Gao, Org. Lett. 7 (2005)
1043-1045.
[56] R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 66 (2001) 7931-7944.
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Synthesis and Characterization of Novel Chiral Bidentate
P,N-Containing Ligands and Ruthenium(II) Complex. The
Application in Asymmetric Transfer Hydrogenation of
Ketones
Li Zeng, Fang Wu, Yan-Yun Li,* Zhen-Rong Dong, Jing-Xing Gao
Highlights
ꢀ Novel chiral bidentate P,N-containing ligands were synthesized and
characterized.
ꢀ Novel chiral Ru(II) complex was successfully prepared and
characterized by X-ray diffraction studies.
ꢀ ATH of various ketones catalyzed by chiral Ru(II) complex proceeded
smoothly under mild conditions.

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Supporting Information
Synthesis and Characterization of Novel Chiral Bidentate
P,N-Containing Ligands and Ruthenium(II) Complex. The
Application in Asymmetric Transfer Hydrogenation of
Ketones
Li Zeng, Fang Wu, Yan-Yun Li,* Zhen-Rong Dong, Jing-Xing Gao
(College of Chemistry and Chemical Engineering, State Key Laboratory
of Physical Chemistry of Solid Surfaces, National Engineering
Laboratory for Green Chemical Productions of Alcohols, Ethers and
Esters, Xiamen University, Xiamen 361005, People’s Republic of China)
Fax: (+86)-592-2183047; Phone: (+86)-592-2180929
E-mail: yanyunli@xmu.edu.cn
S1