Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of aromatic ketones in water using novel water-soluble chiral monosulfonamide ligands

Article abstract of DOI:10.1002/hc.20641

Novel water-soluble analogues of Noyori's (R,R)-N-(p-tolylsulfonyl)-1,2- diphenylethyl- enediamine and Knochel's (R,R)-N-(p-tolylsulfonyl)-1,2- diaminocyclohexane, containing an additional quaternary ammonium group, have been synthesized. The ruthenium catalysts prepared in situ by reacting chiral monosulfonamides with [RuCl₂(p-cymene)]₂ afforded high conversion rates and enantiomeric excess (ee) values in the asymmetric transfer hydrogenation of aromatic ketones in aqueous HCOONa. Furthermore, the catalyst could be easily recovered and reused at least five times without obvious loss of ee value.

Full text of DOI:10.1002/hc.20641

Heteroatom Chemistry
Volume 21, Number 7, 2010
Ruthenium(II)-Catalyzed Asymmetric Transfer
Hydrogenation of Aromatic Ketones in Water
Using Novel Water-Soluble Chiral
Monosulfonamide Ligands
Zhongqiang Zhou, Qiong Ma, Yong Sun, Aiqing Zhang, and Lin Li
Key Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission &
Ministry of Education, Hubei Province, College of Chemistry and Materials Science, South-Central
University for Nationalities, Wuhan 430074, People’s Republic of China
Received 14 May 2010; revised 10 August 2010
cost [1–6]. The use of aqueous media in organic re-
ABSTRACT: Novel water-soluble analogues of
actions has attracted a great deal of interest because
Noyori’s (R,R)-N-(p-tolylsulfonyl)-1,2-diphenylethyl-
water is a desirable solvent with respect to envi-
enediamine and Knochel’s (R,R)-N-(p-tolylsulfonyl)-
ronmental concerns, safety, and cost [7–9]. Rhyoo
1,2-diaminocyclohexane, containing an additional
et al. [10] reported the first example of the Ru(II)-
quaternary ammonium group, have been synthesized.
catalyzed asymmetric hydrogen-transfer reduction
The ruthenium catalysts prepared in situ by reacting
of aromatic ketones in an aqueous solution. Because
chiral monosulfonamides with [RuCl2(p-cymene)]2
there is an increasing demand for atom economy and
afforded high conversion rates and enantiomeric
environmentally friendly methods, the development
excess (ee) values in the asymmetric transfer hydro-
of Ru(II)-catalyzed ATH reaction performed in wa-
genation of aromatic ketones in aqueous HCOONa.
ter has expanded significantly [11–30]. However, it
Furthermore, the catalyst could be easily recov-
is worthwhile to develop new water-soluble catalysts
ered and reused at least five times without obvious
that can simplify the purification step and be recy-
ꢀ
C
loss of ee value.
2010 Wiley Periodicals, Inc. Het-
cled and reused without significant loss of enantios-
electivity and activity. Here, we would like to report
the synthesis of novel water-soluble chiral monosul-
fonamides and their application in Ru(II)-catalyzed
ATH of aromatic ketones in neat water.
eroatom Chem 21:505–514, 2010; View this article online
at wileyonlinelibrary.com. DOI 10.1002/hc.20641
INTRODUCTION
Asymmetric transfer hydrogenation (ATH) of
prochiral ketones has emerged as a very valuable
synthetic tool to obtain optically pure secondary al-
cohols because of its operational simplicity, the easy
availability of hydrogen sources, safety, and lower
RESULTS AND DISCUSSION
Xiao recently reported that the ATH of aromatic
ketones with Knochel’s Ru-TsCYDN [(R,R)-N-(p-
toluenesulfonyl)-1,2-diaminocyclohexane] catalyst
and Noyori’s Ru-TsDPEN [(R,R)-N-(p-toluenesul-
fonyl)-1,2-diphenylethylenediamine] catalyst could
be performed using water as solvent [24,25]. How-
ever, Ru-TsCYDN and Ru-TsDPEN cannot be easily
separated from products because of the catalysts
being soluble in common solvents, which renders
catalysts separation by extraction impossible.
505
Correspondence to: Zhongqiang Zhou; e-mail: zhou-zq@
hotmail.com.
Contract grant sponsor: Natural Science Foundation of Hubei
Province.
Contract grant numbers: 2007ABA291, 2008CDB036.
2010 Wiley Periodicals, Inc.
c
ꢀ

506 Zhou et al.
This prompted us to search for an improved and
more efficient catalytic system for the ATH. To
facilitate catalyst/product separation, we have
successfully synthesized novel water-soluble chiral
monosulfonamides by the introduction of imidazo-
lium, triethylammonium, and pyridinium moiety
with (R,R)-4a in the presence of triethylamine pro-
vided monosulfonamide (R,R)-5a. The introduc-
tion of 1-methylimidazole to (R,R)-5a was achieved
to give the quaternary salt (R,R)-6a. Then re-
moval of the Boc group of (R,R)-6a by treatment
with trifluoroacetic acid provided a novel ionic lig-
and (R,R)-7a in almost quantitative yield. The lig-
ands (R,R)-7b and (R,R)-7c were similarly pre-
pared using pyridine and triethylamine, respec-
tively, instead of 1-methylimidazole (Scheme 1).
The ligands 7d–7f were similarly prepared us-
ing 3-nitrophenylsulfonyl chloride instead of 4-
nitrophenylsulfonyl chloride (Scheme 2). The lig-
ands (R,R)-7g and (R,R)-7h were similarly prepared
using (R,R)-1,2-diphenylethylenediamine instead of
(R,R)-1,2-diaminocyclohexane (Scheme 3).
to
monosulfonylated-(R,R)-1,2-diaminocyclohex-
ane or monosulfonylated-(R,R)-1,2-diphenylethyl-
enediamine. The water-soluble ruthenium catalysts
prepared from [RuCl2(p-cymene)]2 and water-
soluble chiral monosulfonamides could be easily
separated from the reaction mixture because of its
insolubility in common solvents and reused for the
following reaction.
Water-soluble chiral monosulfonamides (R,R)-7
can in general be readily prepared. (R,R)-N-Boc-Nꢁ-
(4 - aminophenylsulfonyl) - 1,2 - diaminocyclohexane
(4a) was prepared according to the literature pro-
cedure [31]. The reaction of chloroacetyl chloride
The ruthenium catalysts were prepared by re-
acting water-soluble monosulfonamide ligands with
[RuCl2(p-cymene)]2 in neat water at 40◦C for 1 h
b
a
O
S
O
H3N
NH3
H2N
HN
NO2
BocHN
HN
S
NO2
Tartrate
O
2a
O
3a
1
O
S
O
O
c
d
BocHN
HN
NH2
BocHN
HN
S
NHCCH2Cl
O
O
4a
5a
O
O
O
O
e
f
H3N
HN
S
NH
N
BocHN
HN
S
NH
Cl
N
O
O
6a
N
N
N
2CF3CO2
CH3
CH3
7a
O
O
NH
g
O
O
S
f
5a
5a
BocHN
HN
S
NH
Cl
H3N
HN
N
O
O
2CF3CO2
6b
7b
O
O
O
h
O
S
f
BocHN
HN
S
NH
Cl
N(Et)3
H3N
HN
NH
N(Et)3
O
O
7c
2CF3CO2
6c
SCHEME 1 Synthesis of ligands 7a–7c. Reagents and conditions: (a) 4-O2N-PhSO2Cl, triethylamine, CH2Cl2; (b) (Boc)2O,
triethylamine, CH2Cl2, room temperature (rt); (c) Pd/C, HCOONH4, MeOH, rt; (d) ClCH2COCl, triethylamine, CH2Cl2; (e)
1-methylimidazole, CH3CN, 80◦C; (f) CF3COOH, 0◦C; (g) pyridine, CH3CN, 80◦C; and (h) triethylamine, CH3CN, 80◦C.
Heteroatom Chemistry DOI 10.1002/hc

Ru(II)-Catalyzed Hydrogenation of Aromatic Ketones in Water with Soluble Chiral Monosulfonamide Ligands 507
NO2
NO2
a
O
S
O
S
b
H3N
NH3
Tartrate
BocHN
HN
H2N
HN
O
O
3b
1
2b
O
NH2
NHCCH2Cl
O
S
O
S
d
c
BocHN
HN
BocHN
HN
O
4b
O
5b
O
O
HN
HN
O
f
O
e
N
N
N
N
N
H3N
HN
S
BocHN
HN
S
CH3
CH3
Cl
2CF3CO2
O
O
7d
6d
O
N
O
HN
HN
HN
HN
O
S
f
f
O
S
g
5b
5b
H3N
HN
HN
BocHN
HN
HN
Cl
O
7e
2CF3CO2
O
O
6e
O
O
S
O
S
h
N(Et)3
2CF3CO2
N(Et)3
Cl
H3N
BocHN
O
7f
O
6f
SCHEME 2 Synthesis of ligands 7d–7f. Reagents and conditions: (a) 3-O2N-PhSO2Cl, triethylamine, CH2Cl2; (b) (Boc)2O,
triethylamine, CH2Cl2, room temperature (rt); (c) Pd/C, HCOONH4, MeOH, rt; (d) ClCH2COCl, triethylamine, CH2Cl2; (e)
1-methylimidazole, CH3CN, 80◦C; (f) CF3COOH, 0◦C; (g) pyridine, CH3CN, 80◦C; and (h) triethylamine,CH3CN, 80◦C.
under argon atmosphere. The resulting precatalysts
were used for the ATH without purification. On the
basis of Xiao’s work [24,25], the amount of HCOONa
and the reaction temperature were not screened. All
these catalytic reactions were carried out using 5
equiv of HCOONa at 40◦C. The ATH of acetophenone
in water has been examined using 7a–7f derived
from (R,R)-1,2-diaminocyclohexane as ligands and
the results are summarized in Table 1. The catalyst
prepared from (R,R)-7b showed the best catalytic
activity. When monosulfonamide (R,R)-7b was used
as the ligand, the reduction of acetophenone pro-
ceeded to give almost quantitative conversion with a
substrate/catalyst (S/C) ratio of 100 at 40◦C in 2-h re-
action time, furnishing (R)-1-phenylethanol in 84%
enantiomeric excess (ee) (entry 2, Table 1). The ATH
of acetophenone derivatives was investigated using
the Ru-7b catalyst. As can be seen from Table 1,
various ketones tested, including 2-substituted,
electron-deficient, and electron-rich variants, were
reduced with quantitative conversion and good ee
values, using HCOONa as a hydrogen source and
neat water as the solvent, for several hours.
The ATH of acetophenone in water has also
been examined using 7g–7h derived from (R,R)-1,2-
diphenylethylenediamine as ligands and the results
are summarized in Table 2. The Ru-7g catalyst gave
slightly higher ee than the Ru-7h catalyst in the case
of reduction of acetophenone. The ATH of acetophe-
none derivatives was investigated using the Ru-7g
catalyst. As shown in Table 2, the Ru-7g catalyst de-
livered high conversion for most of the ketones in
2-h reaction time, with ee value reaching up to 96%.
An exception was encountered for propiophenone;
the reduction of propiophenone led to a 100% con-
version in 90% ee in 4 h (entry 3, Table 2).
Heteroatom Chemistry DOI 10.1002/hc

508 Zhou et al.
Ph
Ph
Ph
Ph
Ph
Ph
b
a
O
S
O
S
H2N
NH2
H2N
HN
NO2
BocHN
HN
NO2
O
2c
O
3c
1a
Ph
BocHN
Ph
Ph
Ph
O
O
S
O
c
d
HN
NH2
BocHN
HN
S
NHCCH2Cl
O
O
5c
4c
Ph
Ph
O
Ph
BocHN
Ph
O
O
O
e
f
H3N
HN
S
NH
N(Et)3
HN
S
NH
Cl
N(Et)3
O
O
6g
2CF3CO2
7g
Ph
Ph
O
NH
Ph
BocHN
Ph
O
g
O
S
O
S
f
5c
H3N
HN
N
HN
NH
Cl
N
O
O
2CF3CO2
6h
7h
SCHEME 3 Synthesis of ligands 7g–7h. Reagents and conditions: (a) p-O2N-PhSO2Cl, triethylamine, CH2Cl2; (b) (Boc)2O,
triethylamine, CH2Cl2, room temperature (rt); (c) Pd/C, HCOONH4, MeOH, rt; (d) ClCH2COCl, triethylamine, CH2Cl2; (e)
triethylamine, CH3CN, 80◦C; (f) CF3COOH, 0◦C; (g) pyridine, CH3CN, 80◦C.
TABLE 1 Asymmetric Transfer Hydrogenation of Aromatic Ketones Promoted by 7a–7f in Watera
OH
O
[RuCl2(p-cymene)]2 / 7
R2
R2
HCOONa, H2O
R1
R1
Entry
R1
R2
Ligand
Time (h)
Conversion (%)b
ee (%)c
Configurationd
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
CH3
Cl
H
H
H
H
H
7a
7b
7c
7d
7e
7f
7b
7b
7b
7b
7b
7b
7b
7b
7b
9
2
3.5
7
8
6
4
4
4.5
4
4
4
3.5
4
4.5
>99
>99
99
90
81
87
84
85
87
84
87
67
87
87
80
87
74
70
82
89
R
R
R
R
R
R
R
S
S
R
R
R
R
S
S
H
95
CH3
Cl
Cl
H
H
H
H
Cl
Br
100
100
100
100
100
100
100
100
100
9
10
11
12
13
14
15
Br
CH3
CH3O
Cl
H
aReactions were carried out using 1 mmol of ketone, 5 equiv of HCOONa, and an S/C ratio of 100 in 2 mL of water under argon atmosphere
at 40◦C.
bDetermined by GC–MS analysis on an HP-5ms column.
cDetermined by GC, using a chiral column (Chirasil-Dex CP 7502).
dAbsolute configuration was assigned by comparison of the sign of the specific rotation with that reported [32,33].
Heteroatom Chemistry DOI 10.1002/hc

Ru(II)-Catalyzed Hydrogenation of Aromatic Ketones in Water with Soluble Chiral Monosulfonamide Ligands 509
TABLE 2 Asymmetric Transfer Hydrogenation of Aromatic Ketones Promoted by 7g–7h in Watera
OH
O
[RuCl2(p-cymene)]2 / 7
R2
R2
HCOONa, H2O
R1
R1
R2
Entry
R1
Ligand
Conversion (%)b
ee (%)c
Configurationd
1
H
H
H
H
CH3
Cl
Br
CH3
H
CH3O
Cl
H
H
CH3
Cl
Cl
H
H
H
Br
H
Cl
7g
7h
7g
7g
7g
7g
7g
7g
7g
7g
7g
100
100
100
100
100
99
100
92
100
100
100
94
92
90
95
94
94
95
94
95
96
93
R
R
R
S
S
R
R
R
S
R
S
2
3e
4
5
6
7
8
9
10
11
aUnless otherwise indicated, reactions were carried out using 1 mmol of ketone, 5 equiv of HCOONa, and an S/C ratio of 100 in 2 mL of water
under argon atmosphere at 40◦C for 2 h.
bDetermined by GC–MS analysis on an HP-5ms column.
cDetermined by GC, using a chiral column (Chirasil-Dex CP 7502).
dAbsolute configuration was assigned by comparison of the sign of the specific rotation with that reported [32,33].
eThe reaction was carried out using 1 mmol of ketone, 5 equiv of HCOONa, and an S/C ratio of 100 in 2 mL of water under argon atmosphere
at 40◦C for 4 h.
From the standpoint of green chemistry, it is
highly desirable that the catalyst can be recov-
ered and reused. To investigate the catalyst recy-
clability and reusability in neat water, we chose
HCOONa as the reductant and acetophenone as a
model substrate. On completion of the reaction, the
catalyst was easily recovered after extraction of the
reduced products with hexane. The aqueous solu-
tion containing the catalyst was used for the subse-
quent transfer hydrogenation run by adding 1 equiv
of formic acid to regenerate sodium formate. As
shown in Tables 3 and 4, catalysts Ru-7b and Ru-7g
could be used for five runs with completely main-
tained yields and enantioselectivity, although there
was gradual decrease in the reaction rates. Catalyst
recycle led to the loss of reaction rates, presum-
ably because of some decomposition of active Ru-7
complexes.
In conclusion, novel water-soluble chiral mono-
sulfonamides containing quaternary ammonium
group have been successfully synthesized in good
yields by the introduction of imidazolium, pyri-
dinium, and triethylammonium moieties to mono-
sulfonylated-(R,R)-1,2-diaminocyclohexane or mo-
nosulfonylated-(R,R)-1,2-diphenylethylenediamine.
Water-soluble ruthenium catalysts prepared in situ
from ruthenium complex [RuCl2(p-cymene)]2 and
monosulfonamide ligands were used in the ATH
of aromatic ketones and high conversion rates
and ee values were achieved using HCOONa as
TABLE 3 Recycling of Catalyst Ru-7b in Asymmetric Transfer Hydrogenation of Acetophenone in Watera
Run
Ligand
Time (h)
Conversion (%)b
ee (%)c
Configurationd
1
2
3
4
5
7b
7b
7b
7b
7b
2
2
2.5
3.5
6.5
>99
>99
>99
>99
>99
83
83
82
82
81
R
R
R
R
R
aReactions were carried out using 1 mmol of acetophenone, 5 equiv of HCOONa, and an S/C ratio of 100 in 2 mL of water under argon
atmosphere at 40◦C in the first run. Since the second run, 1 mmol of HCOOH was added to regenerate sodium formate in every recycling run.
bDetermined by GC–MS analysis on an HP-5ms column.
cDetermined by GC, using a chiral column (Chirasil-Dex CP 7502).
dAbsolute configuration was assigned by comparison of the sign of the specific rotation with that reported [32,33].
Heteroatom Chemistry DOI 10.1002/hc

510 Zhou et al.
TABLE 4 Recycling of Catalyst Ru-7g in Asymmetric Transfer Hydrogenation of Acetophenone in Watera
Run
Ligand
Time (h)
Conversion (%)b
ee (%)c
Configurationd
1
2
3
4
5
7g
7g
7g
7g
7g
2
2
2
2.5
3
100
100
100
100
100
94
93
93
93
93
R
R
R
R
R
aReactions were carried out using 1 mmol of acetophenone, 5 equiv of HCOONa, and an S/C ratio of 100 in 2 mL of water under argon
atmosphere at 40◦C in the first run. Since the second run, 1 mmol of HCOOH was added to regenerate sodium formate in every recycling run.
bDetermined by GC–MS analysis on an HP-5ms column.
cDetermined by GC, using a chiral column (Chirasil-Dex CP 7502).
dAbsolute configuration was assigned by comparison of the sign of the specific rotation with that reported [32,33].
the reductant in neat water. The catalysts could
be easily recovered and reused at least five times
without obvious loss of ee value, though a prolonged
reaction time was needed. The organic solvent-free
reaction conditions, simple experimental procedure,
ease of catalyst recovery, and efficient reusability
make this method very advantageous.
sulting solution was washed with water (3 × 50 mL)
and dried over anhydrous MgSO4. After concentra-
tion, the residue was dried to afford 2a as a pale yel-
low powder (632 mg, 84.5%). m.p. 180◦C (lit. [31],
m.p. 177.5–178◦C). [α]D = +26.7 (c = 0.49, C2H5OH).
IR (KBr), ν: 3429, 3359, 3297, 1528, 1349, 1162,
1092 cm−1.
(R,R)-N-Boc-Nꢁ-(4-nitrophenylsulfonyl)-1,2-
EXPERIMENTAL
diaminocyclohexane (3a)
Material and Instruments
(R,R)-N-Boc-Nꢁ -(4-nitrophenylsulfonyl)-1,2-diami-
nocyclohexane (3a) was prepared according to the
literature procedure [31]. Yield 75.5%, m.p. 159–
162◦C, [α]D = +42.8 (c = 0.42, C2H5OH).
Melting points were determined on a melting point
apparatus and were uncorrected. Specific rotations
were measured on a WZZ-3 digital polarimeter.
Infrared (IR) spectra were recorded on a Nicolet
Nexus 470 FTIR spectrometer. 1H NMR spectra were
recorded on a Bruker Avance III 400 spectrometer,
with tetramethylsilane as the internal standard. El-
emental analysis was performed using a Vario EL
Series III apparatus. The conversions were mea-
sured by gas chromatography–mass spectrometry
(GC–MS) on an Agilent 5973N system (HP-5ms cap-
illary column). The ee values were determined by
GC (Agilent 6890N), using a chiral column (Chirasil-
Dex CP 7502). The chemicals used in this work were
purchased from the Alfa Aesar (Tianjin, China) and
Sinopharm Chemcial Reagent Co., Ltd., (Shanghai,
China).
(R,R)-N-Boc-Nꢁ-(4-aminophenylsulfonyl)-1,2-
diaminocyclohexane (4a)
(R,R)-N-Boc-Nꢁ-(4-aminophenylsulfonyl)-1,2-diam-
inocyclohexane (4a) was prepared according to the
literature procedure [31]. Yield 95.7%, m.p. 187◦C,
[α]D = +69.6 (c = 0.39, C2H5OH).
Preparation of (R,R)-6a
To a solution of (R,R)-4a (369 mg, 1 mmol) and tri-
ethylamine (0.18 mL, 1.25 mmol) in CH2Cl2 (12 mL)
cooled in an ice bath, a solution of chloroacetyl chlo-
ride (0.1 mL, 1.3 mmol) in CH2Cl2 (12 mL) was added
dropwise. At the end of the addition, the mixture
was stirred for further 8 h at the same tempera-
ture and then stirred for 32 h at room temperature.
The mixture was washed successfully with 0.5 M cit-
ric acid, water, saturated sodium bicarbonate, and
brine and dried over anhydrous MgSO4. After con-
centration, the crude product of 5a was obtained
(434 mg, 97.4%), m.p. 183–186◦C. A mixture of 5a
(223 mg, 0.5 mmol), 1-methylimidazole (0.2 mL,
15 mmol), and acetonitrile (3 mL) was stirred for
24 h at 80◦C under argon. The solvent and excess
(R,R)-N-(4-Nitrophenylsulfonyl)-1,2-
diaminocyclohexane (2a)
Dichloromethane (10 mL) was added to
a
stirred solution of the L-tartrate salt of (R,R)-1,2-
diaminocyclohexane (1.32 g, 5 mmol) in 5.3 mL
of 2N NaOH solution. The mixture was cooled to
0◦C, and a solution of 4-nitrophenylsulfonyl chloride
(554 mg, 2.5 mmol) in 10 mL of dichloromethane
was added dropwise over 20 min. After the addition
was completed, the mixture was allowed to warm
to room temperature and stirred overnight. The re-
Heteroatom Chemistry DOI 10.1002/hc

Ru(II)-Catalyzed Hydrogenation of Aromatic Ketones in Water with Soluble Chiral Monosulfonamide Ligands 511
of 1-methylimidazole were removed under reduced
Anal. Calcd for C22H27F6N5O7S: C, 42.65; H, 4.39; N,
11.30; Found: C, 42.23; H, 4.17; N, 11.02.
pressure, and the residue was dried in vacuo to give
6a as a pale yellow solid (214 mg, 81.2%). m.p. 159–
161◦C. [α]D = +50 (c = 0.3, C2H5OH). IR (KBr), ν:
3550, 3478, 3423, 3105, 2936, 1689, 1597, 1544, 1318,
Preparation of (R,R)-7b
1
1161 cm−1. H NMR (DMSO-d6, 400 MHz): δ 0.98–
Compound 7b was prepared using the same proce-
dure as 7a, yield 99%. m.p. 132–134◦C. [α]D = +69.8
(c = 0.32, CH3OH). IR (KBr), ν: 3418, 3068, 2947,
1.76 (m, 8H), 1.38 (s, 9H), 2.86 (br s, 1H), 3.14 (br
s, 1H), 3.93 (s, 3H), 5.28 (s, 2H), 6.37 (d, J = 8 Hz,
1H), 7.44 (d, J = 8 Hz, 1H), 7.74 (d, J = 7.2 Hz, 2H),
7.76 (d, J = 6.8 Hz, 2H), 9.12 (s, 1H), 11.13 (s, 1H).
Anal. Calcd for C23H34ClN5O5S: C, 52.31; H, 6.49; N,
13.26; Found: C, 52.01; H, 6.71; N, 13.01.
1
1680, 1598, 1549, 1497, 1321, 1263, 1200 cm−1. H
NMR (DMSO-d6, 400 MHz): δ 0.96–1.97 (m, 8 H),
2.76 (br s, 1H), 2.96 (br s, 1H), 5.73 (s, 2H), 7.82 (s,
4H), 8.24 (s, 2H), 8.71 (t, J = 7.2 Hz, 1H), 9.07 (s,
2H), 11.34 (s, 1H). Anal. Calcd for C23H26F6N4O7S: C,
44.81; H, 4.25; N, 9.09; Found: C, 44.31; H, 4.47; N,
8.62.
Preparation of (R,R)-6b
Compound 6b was prepared using the same proce-
dure as 6a, yield 77.2% (two steps). m.p. 215–218◦C.
[α]D = +69.3 (c = 0.3, C2H5OH). IR (KBr), ν: 3338,
2937, 1685, 1598, 1550, 1524, 1319, 1259, 1157, 1090
cm−1. 1H NMR (DMSO-d6, 400 MHz): δ 0.97–1.75 (m,
8 H), 1.38 (s, 9 H), 2.83–2.85 (m, 1H), 3.12–3.14 (m,
1H), 5.75 (s, 2H), 6.37 (d, J = 8 Hz, 1H), 7.45 (d,
J = 8 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.80 (d, J =
9.2 Hz, 2H), 8.24 (t, J = 6.8 Hz, 2H), 8.71 (t, J = 7.6
Hz, 1H), 9.08 (d, J = 5.6 Hz, 2H), 11.51 (s, 1H). Anal.
Calcd for C24H33ClN4O5S: C, 54.90; H, 6.33; N, 10.67;
Found: C, 54.57; H, 6.61; N, 10.34.
Preparation of (R,R)-7c
Compound 7c was prepared using the same proce-
dure as 7a, yield 99%. m.p. 84–86◦C. [α]D = +47.7
(c = 0.35, CH3OH). IR (KBr), ν: 3419, 2947, 1680,
1599, 1548, 1467, 1323, 1201 cm−1. 1H NMR (DMSO-
d6, 400 MHz): δ 0.85–1.96 (m, 8 H), 1.29 (s, 9 H), 2.76
(br s, 1H), 2.96 (br s, 1H), 3.55 (d, J = 6.8 Hz, 6H),
4.29 (s, 2H), 7.84 (d, J = 9.2 Hz, 4H), 11.32 (s, 1H).
Anal. Calcd for C24H36F6N4O7S: C, 45.14; H, 5.68; N,
8.77; Found: C, 44.91; H, 5.92; N, 8.33.
Preparation of (R,R)-6c
(R,R)-N-(3-Nitrophenylsulfonyl)-1,2-
diaminocyclohexane (2b)
Compound 6c was prepared using the same proce-
dure as 6a, yield 88.4% (two steps). m.p. 152–155◦C.
[α]D = +45.3 (c = 0.3, C2H5OH). IR (KBr), ν: 3411,
2933, 1697, 1598, 1547, 1318, 1255, 1159, 1090 cm−1.
1H NMR (DMSO-d6, 400 MHz): δ 0.97–1.74 (m, 8 H),
1.29 (s, 9 H), 1.37 (s, 9 H), 2.86–2.88 (m, 1H), 3.06–
3.12 (m, 1H), 3.53 (d, J = 6 Hz, 6H), 4.37 (s, 2H), 6.37
(d, J = 5.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.78
(d, J = 8.4 Hz, 2H), 7.84 (d, J = 7.6 Hz, 2H), 11.51
(s, 1H). Anal. Calcd for C25H43ClN4O5S: C, 54.88; H,
7.92; N, 10.24; Found: C, 54.51; H, 8.21; N, 10.03.
Compound 2b was prepared using the same proce-
dure as 2a, using 3-nitrophenylsulfonyl chloride in-
stead of 4-nitrophenylsulfonyl chloride, yield 84.5%.
m.p. 110–112◦C. [α]D = −34.0 (c = 0.5, CHCl3). IR
(KBr), ν: 3570, 3375, 3302, 1670, 1534, 1352, 1324,
1164, 1099, 1082 cm−1. 1H NMR (CDCl3, 400 MHz): δ
1.17–1.68 (m, 8H), 1.91–1.97 (m, 3H), 2.38–2.41 (m,
1H), 2.68–2.73 (m, 1H), 7.74 (t, J = 8 Hz, 1H), 8.23
(d, J = 8 Hz, 1H), 8.41–8.42 (m, 1H), 8.77 (s, 1H).
Anal. Calcd for C12H17N3O4S: C, 48.15; H, 5.72; N,
14.04; Found: C, 48.27; H, 5.61; N, 14.19.
Preparation of (R,R)-7a
(R,R)-N-Boc-Nꢁ-(3-nitrophenylsulfonyl)-1,2-
Trifluoroacetic acid (4.5 mL) was added to (R,R)-6a
(264 mg, 0.5 mmol) at 0◦C under argon. After stirring
for 4 h at 0◦C, toluene (12 mL) was added to the
mixture and the volatile was removed under reduced
pressure to give 7a as a pale yellow solid (99%). m.p.
88–90◦C. [α]D = +35.8 (c = 0.5, CH3OH). IR (KBr), ν:
3418, 3114, 2947, 1680, 1598, 1549, 1323, 1201 cm−1.
1H NMR (DMSO-d6, 400 MHz): δ 0.95–1.96 (m, 8 H),
2.67–2.82 (m, 1H), 2.94 (br s, 1H), 3.87 (s, 3H), 5.27
(s, 2H), 6.62 (d, J = 8 Hz, 1H), 7.45 (d, J = 8 Hz,
1H), 7.74–7.81 (m, 4H), 9.05 (s, 1H), 11.09 (s, 1H).
diaminocyclohexane (3b)
Compound 3b was prepared using the same pro-
cedure as 3a, yield 87.3%. m.p. 115–118◦C. [α]D
=
+11.9 (c = 0.42, C2H5OH). IR (KBr), ν: 3364, 3221,
1690, 1611, 1533, 1352, 1324, 1167, 1080 cm−1. H
1
NMR (CDCl3, 400 MHz): δ 1.17–2.05 (m, 8H), 1.43 (s,
9H), 3.02–3.04 (m, 1H), 3.37–3.39 (m, 1H), 4.45 (d,
J = 7.2 Hz, 1H), 6.18 (d, J = 4.8 Hz, 1H), 7.72 (t, J =
8 Hz, 1 H), 8.20 (d, J = 8 Hz, 1H), 8.41–8.43 (m, 1H),
8.72 (t, J = 2 Hz, 1H). Anal. Calcd for C17H25N3O6S:
Heteroatom Chemistry DOI 10.1002/hc

512 Zhou et al.
C, 51.11; H, 6.31; N, 10.52; Found: C, 51.32; H, 6.13;
N, 10.39.
was added to the mixture and the volatile was re-
moved under reduced pressure to give 7d as a pale
yellow solid (99%). m.p. 80–81◦C. [α]D = +21.1 (c =
0.5, CH3OH). IR (KBr), ν: 3425, 3061, 2960, 1690,
1633, 1554, 1485, 1386, 1169 cm−1. 1H NMR (DMSO-
d6, 400 MHz): δ 0.91–1.91 (m, 8H), 2.75 (br s, 1H),
2.96 (br s, 1H), 3.94 (s, 3H), 4.62 (s, 2H), 5.28 (s,
1H), 7.58–8.26 (m, 6H), 8.62 (s, 1H), 9.11 (s, 3H).
Anal. Calcd for C22H27F6N5O7S: C, 42.65; H, 4.39; N,
11.30; Found: C, 42.37; H, 4.21; N, 11.15.
(R,R)-N-Boc-Nꢁ-(3-aminophenylsulfonyl)-1,2-
diaminocyclohexane (4b)
Compound 4b was prepared using the same pro-
cedure as 4a, yield 71.8%. m.p. 134–137◦C. [α]D
=
+44.1 (c = 0.3, CHCl3). IR (KBr), ν: 3374, 2935, 1692,
1630, 1517, 1451, 1387, 1313, 1159, 1084 cm−1. H
1
NMR (CDCl3, 400 MHz): δ 1.09–2.01 (m, 8H), 1.47
(s, 9H), 2.92 (br s, 1H), 3.32–3.34 (m, 1H), 4.50 (d,
J = 6.4 Hz, 1H), 5.52 (s, 1H), 6.85 (d, J = 6.8 Hz,
1H), 7.19 (s, 1H), 7.23 (t, J = 8 Hz, 1H), 7.28 (d, J =
4.4 Hz, 1H). Anal. Calcd for C17H27N3O4S: C, 55.26;
H, 7.37; N, 11.37; Found: C, 55.03; H, 7.12; N, 11.15.
Preparation of (R,R)-7e
Compound 7e was prepared using the same proce-
dure as 7d, yield 82% (two steps). m.p. 70–72◦C.
[α]D = +20.7 (c = 0.5, CH3OH). IR (KBr), ν: 3426,
3058, 2960, 1698, 1634, 1552, 1487, 1385, 1160, 1089
1
cm−1. H NMR (DMSO-d6, 400 MHz): δ 0.90–1.92
(R,R)-N-Boc-Nꢁ-(3-chloroacetylaminophenyl-
sulfonyl)-1,2-diaminocyclohexane (5b)
(m, 8H), 2.73 (br s, 1H), 2.95 (br s, 1H), 4.61(t, J =
6.8 Hz, 2H), 5.72 (s, 1H), 7.57–7.64 (m, 1H), 7.91
(s, 1H), 8.17 (s, 2H), 8.25–8.28 (m, 1H), 8.61 (t, J =
8 Hz, 1H), 9.11 (m, 3H), 11.12 (s, 1H). Anal. Calcd
for C23H26F6N4O7S: C, 44.81; H, 4.25; N, 9.09; Found:
C, 44.43; H, 4.41; N, 8.73.
To a solution of (R,R)-4b (900 mg, 2.44 mmol)
and triethylamine (0.44 mL, 3.05 mmol) in CH2Cl2
(12 mL) cooled in an ice bath a solution of
chloroacetyl chloride (0.25 mL, 3.3 mmol) in CH2Cl2
(15 mL) was added dropwise. At the end of the ad-
dition, the mixture was stirred for further 8 h at the
same temperature and then stirred for 32 h at room
temperature. The mixture was washed successfully
with 0.5 M citric acid, water, saturated sodium bicar-
bonate, and brine and dried over anhydrous MgSO4.
After concentration, the crude product was purified
by silica gel column chromatography (petroleum
ether/AcOEt = 1:1) to afford 5b (993 mg, 91.4%).
m.p. 143–145◦C. [α]D = +45 (c = 0.30, CHCl3). IR
(KBr), ν: 3395, 2934, 1685, 1629, 1601, 1524, 1452,
Preparation of (R,R)-7f
Compound 7f was prepared using the same proce-
dure as 7d, yield 99% (two steps). m.p. 77–79◦C.
[α]D = +27.4 (c = 0.5, CH3OH). IR (KBr), ν: 3260,
2936, 1683, 1596, 1550, 1478, 1427, 1316, 1200, 1156,
1
1086 cm−1. H NMR (DMSO-d6, 400 MHz): δ 1.01–
2.37 (m, 8H), 1.02 (t, J = 6.4 Hz, 9H), 2.60 (d, J =
6.4 Hz, 6H), 2.76 (br s, 1H), 3.13 (br s, 1H), 3.54 (s,
2H), 7.17 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H),
7.47–7.59 (m, 1H), 7.70–7.81 (m, 1H), 9.98 (s, 1H).
Anal. Calcd for C24H36F6N4O7S: C, 45.14; H, 5.68; N,
8.77; Found: C, 44.71; H, 5.85; N, 8.34.
1
1368, 1315, 1160 cm−1. H NMR (CDCl3, 400 MHz):
δ 1.20–2.07 (m, 8H), 1.39 (s, 9H), 3.07 (br s, 1H),
3.36 (br s, 1H), 4.24 (s, 2H), 4.75 (d, J = 5.2 Hz,
1H), 5.71 (s, 1H), 7.51 (t, J = 8 Hz, 1H), 7.68 (d,
J = 7.6 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 8.02
(s, 1H), 8.44 (s, 1H). Anal. Calcd for C19H28ClN3O5S:
C, 51.17; H, 6.33; N, 9.42; Found: C, 51.01; H, 6.16;
N, 9.54.
(R,R)-N-Boc-Nꢁ-(4-chloroacetylaminophenyl-
sulfonyl)-1,2-diphenylethylenediamine (5c)
(R,R)-N-Boc-Nꢁ-(4-aminophenylsulfonyl)-1,2-diphe-
nylethylenediamine (4c) was prepared according
to the literature procedure [34]. Compound 5c
was prepared from 4c, using the similar procedure
Preparation of (R,R)-7d
A mixture of (R,R)-5b (223 mg, 0.5 mmol), 1-
methylimidazole (0.2 mL, 15 mmol) and acetonitrile
(3 mL) was stirred for 24 h at 80◦C under argon.
The solvent and excess of 1-methylimidazole were
removed under reduced pressure, and the residue
was dried in vacuo to give 6d as a pale yellow pow-
der (203 mg, 77%). Trifluoroacetic acid (3 mL) was
added to (R,R)-6d (180 mg, 0.34 mmol) at 0◦C under
argon. After stirring for 4 h at 0◦C, toluene (9 mL)
as that of 5b, yield 84.7%. m.p. 235◦C. [α]D
=
+21.24 (c = 0.32, acetone). IR (KBr), ν: 3371, 3301,
1685, 1523, 1324, 1159 cm−1.1H NMR (acetone-d6,
300 MHz): δ 1.35 (s, 9H), 4.25 (s, 2H), 4.69 (t, J =
4.2 Hz, 1H), 4.92 (t, J = 4.2 Hz, 1H), 6.61 (d, J =
3.3 Hz, 1H), 7.01–7.18 (m, 10H), 7.45 (d, J = 3.9 Hz,
2H), 7.57 (d, J = 4.2 Hz, 2H), 9.62 (s, 1H). Anal.
Calcd for C27H30ClN3O5S: C, 59.61; H, 5.56; N, 7.72;
Found: C, 59.32; H, 5.41; N, 7.85.
Heteroatom Chemistry DOI 10.1002/hc

Ru(II)-Catalyzed Hydrogenation of Aromatic Ketones in Water with Soluble Chiral Monosulfonamide Ligands 513
Preparation of (R,R)-7g
Recycle experiment for the ATH of acetophenone
in water
A mixture of (R,R)-5c (270 mg, 0.496 mmol), triethy-
lamine (0.72 mL, 5 mmol), and acetonitrile (5 mL)
was stirred for 50 h at 80◦C under argon. The solvent
and excess of triethylamine were removed under re-
duced pressure, and the residue was dried in vacuo
to give 6g. Trifluoroacetic acid (4 mL) was added to
6g at 0◦C under argon. After stirring for 7 h at 0◦C,
toluene (10 mL) was added to the mixture and the
volatile was removed under reduced pressure to give
7g as a pale yellow solid (99%). m.p. 124◦C. [α]D =
+46.7 (c = 0.27, MeOH). IR (KBr), ν: 3426, 3059,
2882, 1678, 1598, 1547, 1326, 1200, 1154, 837 cm−1.
1H NMR (DMSO-d6, 400 MHz): δ 1.25 (s, 9H), 3.52
(m, 6H), 4.21 (s, 2H), 4.40 (d, J = 8.0 Hz, 1H), 4.62
(d, J = 8.4 Hz, 1H), 6.82–7.40 (m, 14H), 10.97 (s, 1H).
Anal. Calcd for C32H38F6N4O7S: C, 52.17; H, 5.20; N,
7.60; Found: C, 51.95; H, 4.83; N, 7.41.
After the organic compounds were extracted, the
residual aqueous phase containing the catalyst was
reused by adding formic acid (0.039 mL, 1.0 mmol)
to regenerate sodium formate and then acetophe-
none (120 mg, 1.0 mmol) was added into the aque-
ous solution for a new reaction cycle and the second
cycle of the reaction was started under the same con-
ditions.
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cm−1. H NMR (DMSO-d6, 400 MHz): δ 4.43 (d, J =
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for 1 h under an argon atmosphere. HCO2Na·2H2O
(520 mg, 5 mmol) and ketone (1.0 mmol) were then
added. The mixture was stirred at 40◦C for a certain
period of time. After cooling to room temperature,
the organic compounds were extracted with hexane
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