Chiral amino amides for the ruthenium(II)-catalyzed asymmetric transfer hydrogenation reaction of ketones in water

Article abstract of DOI:10.1002/chir.20723

The chiral amino amide 3 was derived from L-proline and used for the [RuCl2(p-cymene)]2-catalyzed asymmetric transfer hydrogenation of prochiral ketones performed in water. Moderate to good chemical selectivities (up to 95% yield) and enantioselectivities (up to 90% ee) were obtained in the presence of 2 mol % of TBAB (n-Bu₄NBr) as the phase transfer catalyst.

Full text of DOI:10.1002/chir.20723

CHIRALITY 22:173–181 (2010)
Chiral Amino Amides for the Ruthenium(II)-Catalyzed Asymmetric
Transfer Hydrogenation Reaction of Ketones in Water
JINCHENG MAO* AND JUN GUO
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Suzhou University, Suzhou, People’s Republic of China
ABSTRACT
[
The chiral amino amide 3 was derived from L-proline and used for the
RuCl (p-cymene)] -catalyzed asymmetric transfer hydrogenation of prochiral ketones
2
2
performed in water. Moderate to good chemical selectivities (up to 95% yield) and enantio-
selectivities (up to 90% ee) were obtained in the presence of 2 mol % of TBAB (n-Bu NBr)
4
as the phase transfer catalyst. Chirality 22:173–181, 2010. VV C 2009 Wiley-Liss, Inc.
KEY WORDS: asymmetric transfer hydrogenation; ketones; water; enantioselectivity;
ruthenium
INTRODUCTION
EXPERIMENTAL
Asymmetric hydrogenation of prochiral ketones, imines,
All reactions were carried out in air and monitored by
and activated alkenes has been considered as a direct thin layer chromatography (TLC). All ketones were pur-
route to get enantiomerically enriched chiral compounds chased from Aldrich or Acors. [RuCl (p-cymene)]2 was
2
in various manufactures of pharmaceuticals and advanced prepared following reported procedure. Sodium formate
1
–7
materials. However, the use of molecular hydrogen and was purchased from Fluka. NMR spectra were measured
hence often expensive specialized high-pressure equip- in CDCl on a Bruker DRX-400 NMR spectrometer (400
3
ment reduced its accessibility and operability. Thus, asym- MHz) with TMS as an internal reference. Optical rotations
metric transfer hydrogenation (ATH) has emerged as an were measured with a HORIBA SEPA-200 high sensitive
alternative because of its operational simplicity and the polarimeter. Enantiomeric excess (ee) determination was
8
easy availability of hydrogen source. In the past decades, carried out using HPLC with a Daicel Chiralcel OD-H or
two popular protocols have been developed by Noyori and AD-H column on an Agilent HP-1100 HPLC instrument.
i
coworkers, including KOH/ PrOH and HCOOH/Et N
systems.
3
9
,10
Nowadays, a major concern for chemists is
Synthesis of Chiral Ligands
the development and employment of economical and envi-
ronmentally friendly methodologies. Water is regarded
as a ‘‘greener’’ solvent than most organic solvents as a
medium for conducting reactions. Therefore, ATH
performed in water using HCOONa gained great atten-
A solution of proline (6) (50 mmol) in 200 ml of a H O/
dioxane/NaOH (1 M, 1:2:1) mixture was added Boc O (55
mmol) at 08C. After stirring the mixture at room tempera-
ture for overnight, the solvent was evaporated with the
residue being adjusted pH 5 9. The organic layer was
2
2
1
1–32
tion.
Various successful chiral ligands have been
1
6–32
extracted with AcOEt for three times, dried over MgSO ,
4
designed based on TsDPEN.
Recently, we have dem-
and concentrated under reduced pressure to yield the
desired product (7). This unpurified Boc-proline and tri-
ethylamine (50 mmol) was dissolved in tetrahydrofuran
and the solution was cooled down to 08C. To the solution
was added dropwise ethyl chloroformate (50 mmol) for 30
min and the pasty reaction mixture was stirred for an addi-
tional 30 min. Chiral amine (50 mmol) was added dropwise
onstrated that the low cost, commercially available (2)-
ephedrine hydrochloride (1) was an efficient catalyst for
Ru-catalyzed ATH of ketones performed in water and in
air. And high conversions (up to 99%) and good enantiose-
lectivities (up to 83% ee) were obtained. Recently, we
also found that the combination of commercially available
1
4
(
1R,2S)-cis-1-aminoindan-2-ol (2) with [RuCl (p-cymene)]2
2
is an effective catalyst for ATH of prochiral ketones in tap
water and in open vessel, providing moderate to good con-
Additional Supporting Information may be found in the online version of
this article.
versions (up to 81%) and enantioselectivities (up to 70% ee; Contract grant sponsor: National Natural Science Foundation of China;
1
5
Contract grant number: 20802046.
Contract grant sponsor: Key Laboratory of Organic Synthesis of Jiangsu
Fig. 1).
Given the interest in conducting this reaction in water, Provinces.
the search for new efficient catalysts is still a challenging *Correspondence to: J. Mao, Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering and Mate-
rials Science, Suzhou University, Suzhou, People’s Republic of China.
amides (3–5) derived from proline (6) as chiral ligands E-mail: jcmao@suda.edu.cn
work till now. We convey here the use of chiral amino
Received for publication 18 October 2008; Accepted 13 February 2009
DOI: 10.1002/chir.20723
Published online 20 April 2009 in Wiley InterScience
for Ru-catalyzed ATH of ketones in water, affording good
yields (up to 95%) and good ee values (up to 90%) of the
chiral secondary alcohols.
(www.interscience.wiley.com).
VV C 2009 Wiley-Liss, Inc.

1
74
MAO AND GUO
Fig. 1. The chiral ligands were studied in the article.
to the mixture for 30 min. The resulting solution was stirred
at 08C for 1 h, at r.t. for another 16 h, and then refluxed for 3
h. After cooling down to r.t., the mixture was filtered and the
solid was thoroughly washed with AcOEt. After the filtrate
and wash liquids were evaporated at reduced pressure, the
residue was redissolved in ethyl acetate and successively
washed with water, an aqueous Na CO , and brine. The or-
The Representative Procedure of Asymmetric
Transfer Hydrogenation of Ketones
A suspension of [RuCl (p-cymene)] (0.0125 mmol) and
2
2
ligand (0.03 mmol) in H O (2 ml) and stirred at room tem-
2
perature for 2 h. HCOONa (5.0 mmol) was then added to
the solution. After the solution was stirred for 10 min, ace-
tophenone (1.0 mmol) was then introduced. The resulting
mixture was stirred for the predetermined reaction time.
After the reaction time, the reaction products were
extracted by the mixed solvents of hexane and diethyl
ether. The extracted solvent was dried over Na SO and
2
3
ganic layer was dried over Na SO and concentrated in
2
4
vacuo to give products (8 and 9). Then to a solution of 8
7.54 mmol) in CH Cl (15 ml) was added trifluoroacetic acid
(
2
2
(
201 mmol) solution in CH Cl (15 ml) dropwise at 08C. The
2 2
2
4
mixture was stirred for 1 h at 08C. Water (10 ml) was added
enantiomeric excess (ee) determination was carried out
using HPLC with a Daicel Chiralcel OD-H or AD-H col-
umn on an Agilent HP-1100 HPLC instrument (solvent,
8:2 hexane/isopropanol; flow rate 1 ml/min; 254 nm UV
detection). The configuration was assigned by comparison
with the sign of specific rotation of the known compounds.
and aqueous layer was extracted with CH Cl . The combined
2
2
organic solvents were dried and concentrated under reduced
pressure. The residual oil was purified by flash chromatogra-
phy on silica to afford the desired pure products (3–5).
9
Characterization of the Representative Chiral Ligands
Characterization of the Chiral Secondary Alcohols
(
2S)-N-((R)-1-phenylethyl)pyrrolidine-2-carboxamide
D 1
1-Phenylethanol. Yield: 70%. Fifty-five percent ee
determined by HPLC analysis (Chiralcel OD-H column,
(
3). [a]2 5 25.5 (c 1.0, acetone); H NMR (400 MHz,
5
CDCl ) d: 1.48 (d, J 5 6.8 Hz, 3H), 1.64–1.71 (m, 1H),
3
IPA:hexane 5 8:92). Retention time: t
tmajor 5 6.12 min. H NMR (400 MHz, CDCl ) d: 1.51 (d, J
5 6.80 min,
minor
1
2
(
.87–1.91 (m, 2H), 2.07–2.17 (m, 1H), 2.84–2.90 (m, 1H),
1
3
.98–3.04 (m, 1H), 3.76 (dd, J 5 5.2, 8.8 Hz, 1H), 5.05–5.13
1
3
5 6.8 Hz, 3H), 1.82 (br, 1H), 4.91 (q, J 5 6.4 Hz, 1H),
m, 1H), 7.23–7.35 (m, 5H), 7.94 (br, 1H); C NMR (100
MHz, CDCl ) d: 22.6, 26.5, 31.1, 47.6, 48.2, 60.9, 126.2,
1
3
7
.28–7.30 (m, 1H), 7.34–7.39 (m, 4H); C NMR (100
3
MHz, CDCl ) d: 25.5, 70.7, 125.8, 127.8, 128.9, 146.2.
3
1
27.4, 128.9, 144.1, 174.5; HRMS: calcd [M1H] for
C H N O 218.1419, found 218.1419.
1
3
18
2
1
-(2-Fluorophenyl)ethanol. Yield: 83%. Forty-three
percent ee determined by HPLC analysis (Chiralcel OD-H
2R)-N-((R)-1-phenylethyl)pyrrolidine-2-carboxamide column, IPA:hexane 5 1:99). Retention time: t
(
5
minor
D
5
1
1
(
4). [a]2 5 225.9 (c 1.0, acetone); H NMR (400 MHz, 22.16 min, tmajor 5 20.45 min. H NMR (400 MHz, CDCl )
3
CDCl ) d: 1.47 (d, J 5 6.8 Hz, 3H), 1.68–1.78 (m, 2H), d: 1.51 (d, J 5 6.4 Hz, 3H), 2.04 (br, 1H), 5.19 (q, J 5 6.4
3
1
2
.90–1.98 (m, 1H), 2.01–2.19 (m, 1H), 2.87–2.93 (m, 1H), Hz, 1H), 6.99–7.04 (m, 1H), 7.15 (t, J 5 7.6 Hz, 1H), 7.21–
1
3
.98–3.03 (m, 1H), 3.71 (dd, J 5 5.6, 9.2 Hz, 1H), 5.05–5.13 7.26 (m, 1H), 7.48 (t, J 5 7.6 Hz, 1H); C NMR (100 MHz,
1
3
(
m, 1H), 7.25–7.36 (m, 5H), 7.92 (d, J 5 6.8 Hz, 1H);
C
CDCl ) d: 24.4, 64.7, 115.5–115.7 (d, J 5 21.7 Hz), 124.7,
3
NMR (100 MHz, CDCl ) d: 22.4, 26.4, 31.0, 47.4, 48.2, 127.0–127.1 (d, J 5 4.3 Hz), 129.0–129.1 (d, J 5 8.1 Hz).
3
6
0.8, 126.3, 127.3, 128.8, 143.7, 174.5; HRMS: calcd [M 1
1
-(2-Chlorophenyl)ethanol. Yield: 62%. Eighty-three
percent ee determined by HPLC analysis (Chiralcel OD-H
column, IPA:hexane 5 1:99). Retention time: t
H] for C H N O 218.1419, found 218.1428.
1
3
18
2
5
minor
(
2S,4R)-4-Hydroxy-N-((R)-1-phenylethyl)pyrrolidine-
1
2
6.30 min, tmajor 5 23.74 min. H NMR (400 MHz, CDCl )
3
d: 1.48 (d, J 5 6.4 Hz, 3H), 2.13 (br, 1H), 5.28 (q, J 5 6.4
Hz, 1H), 7.19 (t, J 5 7.6 Hz, 1H), 7.26–7.33 (m, 2H), 7.58
d, J 5 7.6 Hz, 1H); C NMR (100 MHz, CDCl ) d: 23.9,
D
1
2
-carboxamide (5). [a]2 5 11.4 (c 1.0, acetone); H
5
NMR (400 MHz, CDCl ) d: 1.48 (d, J 5 7.2 Hz, 3H), 1.84–
3
1
1
1
.91 (m, 1H), 2.20–2.23 (m, 3H), 2.73 (dd, J 5 3.2, 12.4 Hz,
H), 2.99 (dd, J 5 1.2, 12.4 Hz, 1H), 4.00 (t, J 5 8.4 Hz,
H), 4.37 (t, J 5 3.6 Hz, 1H), 5.02–5.10 (m, 1H), 7.22–7.34
13
(
3
6
7.3, 126.8, 127.6, 128.8, 129.8, 132.0, 143.5.
1
3
(
m, 5H), 8.04 (d, J 5 8.4 Hz, 1H); C NMR (100 MHz,
1-(4-Bromophenyl)ethanol. Yield: 89%. Forty-four
CDCl ) d: 22.7, 40.3, 48.5, 55.7, 60.0, 73.1, 126.2, 127.5, percent ee determined by HPLC analysis (Chiralcel OD-H
3
1
29.0, 143.9, 174.7; HRMS: calcd [M–H O 1 H] for column, IPA:hexane 5 1:99). Retention time: t
5
2
minor
1
C H N O 216.1263, found 216.1267.
42.13 min, tmajor 5 45.33 min. H NMR (400 MHz, CDCl )
3
1
3
16
2
Chirality DOI 10.1002/chir

CHIRAL AMINO AMIDES FOR KETONE REDUCTION
175
d: 1.47 (d, J 5 6.4 Hz, 3H), 1.80 (br, 1H), 4.87 (q, J 5 6.4
1-(Naphthalen-6-yl)ethanol. Yield: 87%. Sixty per-
Hz, 1H), 7.25 (d, J 5 8.4 Hz, 2H), 7.47 (d, J 5 8.4 Hz, 2H); cent ee determined by HPLC analysis (Chiralcel OD-H col-
1
3
C NMR (100 MHz, CDCl ) d: 25.5, 69.9, 121.4, 127.5, umn, IPA:hexane 5 5:95). Retention time: t
5 16.07
minor
3
1
1
31.8, 145.1.
min, tmajor 5 16.85 min. H NMR (400 MHz, CDCl ) d:
3
1
1
.57 (d, J 5 6.4 Hz, 3H), 1.85 (br, 1H), 5.07 (q, J 5 6.4 Hz,
H), 7.44–7.51 (m, 3H), 7.80–7.84 (m, 4H); C NMR (100
1
3
1
-o-Tolylethanol. Yield: 60%. Forty-seven percent ee
determined by HPLC analysis (Chiralcel OD-H column,
IPA:hexane 5 10:90). Retention time: t 5 6.66 min,
MHz, CDCl ) d: 25.5, 70.8, 124.2, 124.3, 126.2, 126.5,
128.1, 128.3, 128.7, 133.3, 133.7, 143.6.
3
minor
1
tmajor 5 6.12 min. H NMR (400 MHz, CDCl ) d: 1.47 (d, J
3
5
6.4 Hz, 3H), 1.77 (br, 1H), 2.35 (s, 3H), 5.14 (q, J 5 6.4
1,2,3,4-Tetrahydronaphthalen-1-ol. Yield:
Ninety percent ee determined by HPLC analysis (Chiralcel
78%.
1
3
Hz, 1H), 7.12–7.24 (m, 3H), 7.52 (d, J 5 7.6 Hz, 1H);
C
NMR (100 MHz, CDCl ) d: 19.3, 24.3, 67.2, 127.9, 126.8, OD-H column, IPA:hexane 5 4:96). Retention time: t
3
minor
1
1
27.5, 130.8, 134.6, 144.3.
5 9.47 min, tmajor 5 10.31 min. H NMR (400 MHz,
CDCl ) d: 1.76–1.80 (m, 1H), 1.90–2.00 (m, 3H), 4.78–4.80
3
1
-m-Tolylethanol. Yield: 60%. Forty-three percent ee
determined by HPLC analysis (Chiralcel OD-H column,
IPA:hexane 5 10:90). Retention time: t 5 5.81 min,
(
(
m, 1H), 7.09–7.12 (m, 1H), 7.18–7.23 (m, 2H), 7.42–7.44
1
3
m, 1H); C NMR (100 MHz, CDCl ) d: 19.2, 29.6, 32.5,
3
minor
68.2, 126.4, 127.7, 129.0, 129.2, 137.4, 139.1.
1
tmajor 5 5.28 min. H NMR (400 MHz, CDCl ) d: 1.49 (d, J
3
5
6.8 Hz, 3H), 1.76 (br, 1H), 2.36 (s, 3H), 4.86 (q, J 5 6.4
1-(Thiophen-2-yl)ethanol. Yield: 79%. Thirty-two per-
cent ee determined by HPLC analysis (Chiralcel OD-H col-
1
3
Hz, 1H), 7.09 (d, J 5 7.6 Hz, 1H), 7.15–7.26 (m, 3H);
C
NMR (100 MHz, CDCl ) d: 21.8, 25.5, 70.6, 122.8, 126.5, umn, IPA:hexane 5 1:99). Retention time: t
5 40.04
minor
3
1
1
28.5, 128.7, 138.4, 146.2.
min, tmajor 5 38.17 min. H NMR (400 MHz, CDCl ) d:
3
1
1
.61 (d, J 5 6.0 Hz, 3H), 1.98 (br, 1H), 5.15 (q, J 5 6.0 Hz,
H), 6.96–6.99 (m, 2H), 7.24–7.26 (m, 1H); C NMR (100
1
3
1
-(Naphthalen-4-yl)ethanol. Yield: 62%. Eighty-six
percent ee determined by HPLC analysis (Chiralcel OD-H
column, IPA:hexane 5 10:90). Retention time: t
MHz, CDCl ) d: 25.7, 66.7, 123.7, 124.9, 127.1.
3
5
minor
1
9
.29 min, tmajor 5 13.74 min. H NMR (400 MHz, CDCl )
1-p-Tolylethanol. Yield: 60%. Forty-nine percent ee
3
d: 1.68 (d, J 5 6.4 Hz, 3H), 1.96 (br, 1H), 5.69 (q, J 5 6.4 determined by HPLC analysis (Chiralcel OD-H column,
Hz, 1H), 7.47–7.55 (m, 3H), 7.68 (d, J 5 7.2 Hz, 1H), 7.78 IPA:hexane 5 1:99). Retention time: t
5 28.77 min, tma-
minor
1
(
1
1
d, J 5 8.4 Hz, 1H), 7.87–7.89 (m, 1H), 8.12 (d, J 5 8.4 Hz,
H); C NMR (100 MHz, CDCl ) d: 24.7, 67.2, 122.4, Hz, 3H), 2.34 (s, 3H), 4.86 (q, J 5 6.4 Hz, 1H), 7.16 (d, J 5
3
H NMR (400 MHz, CDCl ) d: 1.48 (d, J 5 6.8
jor 5 25.41 min. 3
1
3
1
3
23.5, 125.8, 125.9, 126.3, 128.1, 129.2, 130.6, 134.1, 141.8.
8.0 Hz, 2H), 7.26 (d, J 5 7.6 Hz, 2H); C NMR (100 MHz,
CDCl ) d: 21.5, 25.5, 70.5, 125.8, 129.5, 137.4, 143.3.
3
1
-(2-Chlorophenyl)propan-1-ol. Yield: 56%. Sixty-six
percent ee determined by HPLC analysis (Chiralcel AD-H
column, IPA:hexane 5 1:99). Retention time: t
1-(3-(Trifluoromethyl)phenyl)ethanol. Yield: 60%.
Forty-nine percent ee determined by HPLC analysis (Chir-
5
minor
1
2
4.38 min, tmajor 5 23.24 min. H NMR (400 MHz, CDCl ) alcel OD-H column, IPA:hexane 5 1:99). Retention time:
3
1
d: 0.99 (t, J 5 7.8 Hz, 3H), 1.71–1.87 (m, 2H), 1.96 (br, tminor 5 28.77 min, tmajor 5 25.41 min. H NMR (400 MHz,
1
7
H), 5.07 (dd, J 5 4.8, 7.6 Hz, 1H), 7.12–7.22 (m, 1H), CDCl ) d: 1.52 (d, J 5 6.4 Hz, 3H), 1.94 (br, 1H), 4.98 (q, J
3
1
3
.28–7.34 (m, 2H), 7.55 (dd, J 5 1.6, 6.0 Hz, 1H); C NMR 5 6.4 Hz, 1H), 7.45–7.49 (m, 1H), 7.53–7.58 (m, 2H), 7.65
1
3
(100 MHz, CDCl ) d: 10.5, 30.9, 72.3, 127.4, 127.6, 128.7, (s, 1H); C NMR (100 MHz, CDCl ) d: 25.7, 70.2, 122.6–
3
3
1
29.7, 132.4, 142.4.
122.7 (d, J 5 3.6 Hz), 124.6–124.7 (d, J 5 3.6 Hz), 129.3–
1
29.4 (d, J 5 13.8 Hz), 147.2.
1
-(4-Chlorophenyl)propan-1-ol. Yield: 95%. Twenty-
three percent ee determined by HPLC analysis (Chiralcel
4-Phenylbutan-2-ol. Yield: 65%. Thirty-one percent
OD-H column, IPA:hexane 5 5:95). Retention time: t
ee determined by HPLC analysis (Chiralcel OD-H column,
5 7.91 min,
minor
1
5
29.35 min, tmajor 5 31.46 min. H NMR (400 MHz, IPA:hexane 5 10:90). Retention time: t
minor
1
CDCl ) d: 0.90 (t, J 5 7.4 Hz, 1H), 1.68–1.83 (m, 2H), 1.90 tmajor 5 7.03 min. H NMR (400 MHz, CDCl ) d: 1.22 (d, J
3
3
1
3
(br, 1H), 4.58 (t, J 5 6.6 Hz, 1H) 7.26–7.33 (m, 4H);
C
5 6.0 Hz, 3H), 1.72-1.78 (m, 2H), 2.60–2.75 (m, 2H), 3.78–
1
3
NMR (100 MHz, CDCl ) d: 10.3, 32.2, 75.5, 127.7, 128.8, 3.86 (m, 1H), 7.09–7.29 (m, 5H); C NMR (100 MHz,
3
1
33.3, 143.4.
CDCl ) d: 23.9, 32.1, 41.4, 67.9, 128.7, 129.5, 135.6, 139.4.
3
1
-(2,4-Dichlorophenyl)propan-1-ol. Yield:
Forty-eight percent ee determined by HPLC analysis Eighty-nine percent ee determined by HPLC analysis
Chiralcel OD-H column, IPA:hexane 5 5:95). Retention (Chiralcel OD-H column, IPA:hexane 5 10:90). Retention
94%.
3,4-Dihydro-2H-thiochromen-4-ol. Yield:
81%.
(
1
1
time: tminor 5 6.04 min, tmajor 5 6.47 min. H NMR (400 time: tminor 5 8.87 min, tmajor 5 7.61 min. H NMR (400
MHz, CDCl ) d: 0.98 (t, J 5 7.2 Hz, 3H), 1.67–1.83 (m, MHz, CDCl ) d: 1.86 (br, 1H), 2.00–2.09 (m, 1H), 2.31–
3
3
2
H), 2.01 (br, 1H), 5.02 (dd, J 5 4.8, 7.6 Hz, 1H), 7.26–7.28 2.38 (m, 1H), 2.83–2.89 (m, 1H), 3.28–3.35 (m, 1H), 4.80
(
m, 1H), 7.35 (d, J 5 2.0 Hz, 1H), 7.49 (d, J 5 4.4 Hz, 1H); (t, J 5 4.0 Hz, 1H), 7.05–7.15 (m, 3H), 7.26–7.32 (m, 1H).
1
3
13
C NMR (100 MHz, CDCl ) d: 10.3, 30.9, 71.7, 127.7,
C NMR (100 MHz, CDCl ) d 21.9, 30.3, 66.6, 124.6,
3
3
1
28.5, 129.4, 132.8, 133.7, 150.0.
127.0, 128.7, 130.9, 133.5, 134.9.
Chirality DOI 10.1002/chir

1
76
MAO AND GUO
Scheme 1. Synthesis of chiral amide amine ligands.
3
3–35
2
,3-Dihydro-1H-inden-1-ol. Yield: 83%. Thirty-one steps.
The synthetic route was shown in Scheme 1.
percent ee determined by HPLC analysis (Chiralcel OD-H To study the matching between the stereogenic centers,
column, IPA:hexane 5 8:92). Retention time: t 5 7.25 ligands (3 and 4) were destined to synthesize in good
minor
1
min, tmajor 5 6.70 min. H NMR (400 MHz, CDCl ) d: yields (73% and 77%). Considering that additional hydroxyl
3
1
3
3
3
.89–2.05 (m, 2H), 2.44–2.52 (m, 1H), 2.77–2.85 (m, 1H), group in the ligand will possibly enhance its solubility in
.01–3.09 (m, 1H), 5.24 (t, J 5 6.0 Hz, 1H), 7.23–7.25 (m, water, we synthesized ligand 5 from trans-4-hydroxyl-L-pro-
1
3
H), 7.40–7.42 (m, 1H). C NMR (100 MHz, CDCl ) d: line in 68% yield (see Supporting Information).
3
0.1, 36.0, 76.5, 124.6, 125.1, 126.9, 128.5, 143.6, 145.3.
Then these chiral amide amine ligands (3–5) and the
intermediates (6–9) were investigated into the ATH per-
formed in water and the results were listed in Table 1. To
our astonishment, we did not get desired secondary alco-
hol for all of the chiral ligands (3–9) (entry 1, Table 1).
Enhanced temperature (408C) was beneficial for the reac-
tion catalyzed by ligands (3–5) (entries 2–4, Table 1),
whereas it was unfavorable for ligands (6–9) (entry 5, Ta-
1
-(Ferrocenyl)ethanol. Yield: 78%. Fifty-seven per-
cent ee determined by HPLC analysis (Chiralcel AD-H col-
umn, IPA:hexane 5 5:95). Retention time: tminor 5 17.06
min, tmajor 5 17.91 min.
RESULTS AND DISCUSSIONS
The amide amine ligands were prepared from ble 1). Although ligand 3 could afford the highest enantio-
chiral L(D)-proline or trans-4-hydroxyl-L-proline in three selectivity among them, the yield of the desired product
a
TABLE 1. Screening various chiral ligands (3–9) in the ATH of acetophenone in water
b
c
d
Entry
L* (mol %)
PTC (mol %)
Temperature (8C)
Yield (%)
ee (%)
Configuration
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
3–9 (3)
3 (3)
4 (3)
5 (3)
6–9 (3)
3 (3)
3 (3)
3 (6)
3 (12)
3 (1.5)
3 (3)
–
–
–
–
r.t.
40
40
40
40
40
r.t.
40
40
40
40
40
40
40
40
40
Trace
32
75
35
Trace
71
63
80
90
Trace
Trace
82
70
63
–
–
R
S
R
–
R
R
R
R
–
49
47
48
–
53
53
53
49
–
–
CTAB (2)
CTAB (2)
CTAB (2)
CTAB (2)
CTAB (2)
SDBS (2)
DDAC (2)
TBAB (2)
TBAB (1)
TBAB (5)
TBAB (10)
0
1
2
3
4
5
6
–
–
3 (3)
3 (3)
3 (3)
3 (3)
51
55
52
49
54
R
R
R
R
R
44
41
3 (3)
a
All the reactions were performed in 2 ml of water at room temperature for 24 h. A total of 1 mmol of acetophenone, 5 equiv of HCOONa, L*/Ru ratio of
1
.2 and S/C ratio of 40.
b
Isolated yield.
c
The enantiomeric excess was determined by chiral HPLC analysis of the corresponding products on a Chiralcel OD-H column.
d
Absolute configuration determined by comparison with reported optical rotations.
Chirality DOI 10.1002/chir

CHIRAL AMINO AMIDES FOR KETONE REDUCTION
177
a
TABLE 2. Asymmetric transfer hydrogenation of prochiral ketones performed in water using 3
b
c
d
Entry
1
Ketone
Time/Temperature (8C)
Yield (%)
70
e.e. (%)
55
Configuration
24 (40)
R
2
24 (40)
24 (40)
24 (40)
24 (40)
62
56
83
93
83
82
43
53
R
e
3
R
R
R
4
5
6
48 (80)
60
47
R
7
8
9
48 (80)
24 (40)
48 (80)
60
89
60
49
44
43
R
R
R
Chirality DOI 10.1002/chir

1
78
MAO AND GUO
TABLE 2. Continued
b
c
d
Entry
Ketone
Time/Temperature (8C)
Yield (%)
e.e. (%)
86
Configuration
10
11
12
24 (40)
24 (40)
24 (40)
62
R
f
41
65
74
90
S
e
R
1
1
1
1
3
4
5
6
36 (40)
36 (80)
36 (80)
36 (80)
87
78
85
81
60
80
82
89
R
R
R
R
e
1
1
7
8
36 (80)
24 (40)
83
56
31
66
R
R
1
9
36 (80)
95
23
R
Chirality DOI 10.1002/chir

CHIRAL AMINO AMIDES FOR KETONE REDUCTION
179
TABLE 2. Continued
b
c
d
Entry
Ketone
Time/Temperature (8C)
Yield (%)
e.e. (%)
48
Configuration
2
0
36 (80)
94
R
2
2
1
2
36 (40)
36 (80)
79
78
32
57
R
R
a
All the reactions were performed in 2 ml of water in the presence of 2 mol % of TBAB at room temperature for 24–48 h. A total of 1 mmol of ketone, 5
equiv of HCOONa, ligand 3/Ru ratio of 1.2 and S/C ratio of 40.
b
Isolated yield.
c
The enantiomeric excess was determined by chiral HPLC analysis of the corresponding products on a Chiralcel OD-H column.
d
Absolute configuration determined by comparison with reported optical rotations.
e
Ligand 5 was used instead of ligand 3.
f
Ligand 4 was used instead of ligand 3.
was not good (entry 2, Table 1). Thus, 2 mol % of cetylti- ble 2. It can be seen that the reaction rate and enantiose-
methylammonium bromide (CTAB) was used as the phase lectivity are greatly influenced by the steric and electronic
transfer catalyst (PTC). It obviously resulted in the devel- properties of prochiral ketones. For the ortho-substituted
opment of the catalytic efficiency of ligand 3 (entry 6, Ta- substrates (Table 2, enties 2–6), comparing with electron-
ble 1). The catalytic reaction performed at room tempera- donating group (such as methyl), electron-withdrawing
ture afforded slightly decreased yield (entry 7, Table 1). groups, including Cl, F, and CF gave the better results.
3
Although higher loading of the catalyst led to increased Among them, the catalytic reaction of 2-chloroacetophe-
yield, the enantioselectivity was not raised (entries 8–9, none gave the good enantioselectivity (83% ee) (entry 2,
Table 1). Reduced loading of the catalyst could not pro- Table 2). Under the same conditions, ligand 5 afforded
mote the reaction (entry 10, Table 1). In addition, other similar ee value (82% ee) (entry 3, Table 2). Meta- and
PTCs, such as SDBS (sodium dodecyl benzene sulfonate), para-substituted substrates gave similar results (entries 7–
DDAC (dimethyl dioctadecylammonium chloride), and 9, Table 2). To our delight, satisfactory results were
TBAB, were also employed under the same conditions acquired when the bulky substrates were used (entries
(
entries 11–13, Table 1). The results showed that TBAB 10–16, Table 2). For 1-acetonaphtone, as expected, ligand
gave the best enantioselectivity (55% ee) (entry 13, Table 3 gave better result than ligand 4 (entries 10 and 11, Ta-
). Changing the amount of TBAB could not get enhanced ble 2). However, for the same substrate, ligand 5 gave the
results (entries 14–16, Table 1). higher enantioselectivity (90% ee) than ligand 3 (86% ee)
1
To assess the practical usefulness of the catalytic sys- (entry 12 vs. entry 10, Table 2). In contrast, 2-acetonaph-
tem, we evaluated a number of substrates in ATH in water tone afforded inferior result (60% ee) (entry 13, Table 2).
using ligand 3 and the results obtained were shown in Ta- Aromatic cyclic ketones afforded the corresponding alco-
Scheme 2. ATH of (E)-4-phenylbut-3-en-2-one using our catalytic system.
Chirality DOI 10.1002/chir

1
80
MAO AND GUO
hol with good enantioselectivities (entries 14–16, Table 2). 11. Rhyoo HY, Park HJ, Suh WH, Chung YK. Use of surfactants in water-
soluble ruthenium(II) complex-catalyzed asymmetric hydrogen-trans-
fer reduction of aromatic ketones. Tetrahedron Lett 2002;43:269–
However, to our surprise, 1-indanone gave poor result
(
entry 17, Table 2). In addition, several propiophenones
2
72.
were employed as the substrates in ATH (entries 18–20,
Table 2). 2-Chloro-substituted ketone afforded the desired
product with 66% ee (entry 18, Table 2). In addition, heter-
1
2. Rhyoo HY, Park HJ, Chung YK. The first Ru(II)-catalysed asymmetric
hydrogen transfer reduction of aromatic ketones in aqueous media.
Chem Commun 2001;2064–2065.
ocyclic aromatic ketone has also been investigated in the 13. Alza E, Bastero A, Jansat S, Peric a` s MA. Aqueous asymmetric transfer
reaction and promising result was obtained (entry 21, Ta-
ble 2). When 1-acetylferrocene was used as the substrate,
the desired alcohol was obtained in 78% yield and 57% ee
hydrogenations using modular hydrophobic aminoalcohols. Tetrahe-
dron Asymmetry 2008;19:374–378.
1
1
1
4. Mao JC, Wan BS, Wu F, Lu SW. First example of asymmetric transfer
hydrogenation in water induced by a chiral amino alcohol hydrochlor-
ide. Tetrahedron Lett 2005;46:7341–7344.
(
entry 22, Table 2).
The interesting reduction of a ketone with both C ¼¼ O
5. Xu Z, Mao JC, Zhang YW, Guo J, Zhu JL. Inversion of stereochemistry
in the asymmetric transfer hydrogenation of ketones performed in tap
water and in open-vessel. Catal Commun 2008;9:618–623.
and C ¼¼ C bonds was performed using our catalytic
3
6
system. The question is whether carbonyl or imine
group could be reduced. GC-MS showed that the C ¼¼ C
bond was first saturated followed by the C ¼¼ O bond. The
chiral alcohol was obtained with 65% yield and 31% ee
III
6. Wu X, Li X, Zanotti-Gerosa A, Pettman A, Liu J, Mills AJ, Xiao J. Rh
III
and Ir -catalyzed asymmetric transfer hydrogenation of ketones in
water. Chem Eur J 2008;14:2209–2222.
(
Scheme 2).
17. Wu X, Xiao J. Aqeous-phase asymmetric transfer hydrogenation of
ketones—A greener approach to chiral alcohols. Chem Commun
2
007;2449–2466.
1
1
2
8. Alza E, Bastero A, Jansat S, Peric a` s MA. Aqueous asymmetric transfer
hydrogenations using modular hydrophobic aminoalcohols. Tetrahe-
dron Asymmetry 2008;19:374–378.
CONCLUSION
In summary, we have demonstrated that the combina-
tion of the readily available chiral amide amines with
RuCl (p-cymene)]2 is an effective catalytic system for
ATH in water. The desired chiral secondary alcohols were
obtained in moderate to good yields (up to 95%) and enan-
tioselectivities (up to 90% ee). To keep better conversions
of substrates, 2 mol % of TBAB as PTC was necessary.
The discovery of these new chiral ligands provides an effi-
cient method for the catalytic transfer hydrogenation using
aqueous sodium formate as the hydrogen source. The
9. Wu X, Liu J, Tommaso DD, Iggo JA, Catlow CRA, Bacsa J, Xiao J. A
multilateral mechanistic study into asymmetric transfer hydrogenation
in water. Chem Eur J 2008;14:7699–7715.
[
2
0. Arakawa Y, Chiba A, Haraguchi N, Itsuno S. Asymmetric transfer hy-
drogenation of aromatic ketones in water using a polymer-supported
chiral catalyst containing a hydrophilic pendant group. Adv Synth
Catal 2008;350:2295–2304.
2
1. Liu PN, Deng JG, Tu YQ, Wang SH. Highly efficient and recyclable
heterogeneous asymmetric transfer hydrogenation of ketones in
water. Chem Commun 2004;2070–2071.
search for more active and enantioselective ligands is 22. Liu J, Zhou Y, Wu Y, Li X, Chan ASC. Asymmetric transfer hydrogena-
ongoing in our laboratories.
tion of ketones with a polyethylene glycol bound Ru catalyst in water.
Tetrahedron Asymmetry 2008;19:832–837.
2
3. Cortez NA, Aguirre G, Parra-Hake M, Somanathan R. Ruthenium(II)
and rhodium(III) catalyzed asymmetric transfer hydrogenation (ATH)
of acetophenone in isopropanol and in aqueous sodium formate using
new chiral substituted aromatic monosulfonamide ligands derived
from (1R,2R)-diaminocyclohexane. Tetrahedron Asymmetry 2008;19:
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