Catalytic asymmetric transfer hydrogenation of ketones using [Ru(p-cymene)Cl2]2 with chiral amino alcohol ligands

Article abstract of DOI:10.1007/s10562-010-0408-y

Catalytic asymmetric transfer hydrogenation of aromatic alkyl ketones has been investigated using [Ru(p-cymene)Cl₂]₂ and new derivatives of β-amino alcohols synthesized from (S)-(-)-lactic acid and mandelic acid as ligands. Chiral secondary alcohols were obtained with good to excellent conversion (60-90%) and moderate to good enantioselectivities (40-86%).

Full text of DOI:10.1007/s10562-010-0408-y

Catal Lett (2010) 138:231–238
DOI 10.1007/s10562-010-0408-y
Catalytic Asymmetric Transfer Hydrogenation of Ketones Using
[Ru(p-cymene)Cl2]2 with Chiral Amino Alcohol Ligands
•
Sudhindra H. Deshpande Ashutosh A. Kelkar
•
•
Rajesh G. Gonnade Savita K. Shingote
•
Raghunath V. Chaudhari
Received: 12 March 2010 / Accepted: 1 July 2010 / Published online: 20 July 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Catalytic asymmetric transfer hydrogenation of
aromatic alkyl ketones has been investigated using [Ru(p-
cymene)Cl2]2 and new derivatives of b-amino alcohols
synthesized from (S)-(-)-lactic acid and mandelic acid as
ligands. Chiral secondary alcohols were obtained with
good to excellent conversion (60–90%) and moderate to
good enantioselectivities (40–86%).
has emerged as a highly efficient technique [9, 10]. The
advantages of asymmetric transfer hydrogenation using
2-propanol as a reductant are well documented in the lit-
erature [5, 9, 10]. Owing to simplicity of operation and
importance of the subject, the reaction has been extensively
investigated using various ligands and hydrogen sources in
recent years [11–15]. One of the most significant break-
throughs in transfer hydrogenation was reported by Noyori
et al. with the use of chlororuthenium (II) arene precursors
with chiral monoarylsulfonylated-1,2-diamines [16–18] or
b-amino alcohols [19] as ligands. The structurally well
defined [RuII(arene) (TsDPEN)] (TsDPEN = (1R,2R)-N-
Keywords Asymmetric transfer hydrogenation Á
Ru catalyst Á Ketones Á Amino alcohol ligand
1 Introduction
(p-tolylsulfonyl)-1,2-diphenylethylene-diamine)
system
enables highly effective reduction of a variety of ketones
with greater than 90% ee [16–18]. Noyori’s catalyst system
based on Ru(II) arene complex and simple b-amino alco-
hols such as ephedrine gives highest catalytic activity as
well as high enantioselectivity (95% yield and 91% ee in
1 h, using [RuCl2(C6Me6)]2 as a catalyst precursor) [19].
This key development has led to intense exploration of
Ru(II)arene(amino alcohol) systems with the aim
of designing new ligands and broadening the scope of
asymmetric transfer hydrogenation reaction. A variety of
b-amino alcohols were synthesized and used as ligands in
the Ru(II) catalyzed asymmetric transfer hydrogenation of
ketones. From the literature, it is found that when amino
alcohols are used as chiral auxiliaries, the best results are
obtained using 2-propanol as the hydride source. Several
research groups have reported on the incompatibility of
amino alcohols with formic acid/triethylamine as the
hydride source [6, 7, 20].
Catalytic asymmetric transfer hydrogenation of ketones is
one of the important transformations in organic chemistry
and a large number of catalytic methods are available to
achieve this goal [1–8]. Among these, transfer hydroge-
nation of prochiral ketones using 2-propanol as a reductant
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-010-0408-y) contains supplementary
material, which is available to authorized users.
S. H. Deshpande Á A. A. Kelkar Á S. K. Shingote
Chemical Engineering and Process Development Division,
National Chemical Laboratory, Pune 411 008, India
e-mail: aa.kelkar@ncl.res.in
R. G. Gonnade
Center for Materials Characterization, National Chemical
Laboratory, Pune 411 008, India
R. V. Chaudhari (&)
Andersson et al. [21–25] have successfully developed
2-Azanorboronyl based amino alcohols as ligands and used
in the Ru(II) catalyzed asymmetric transfer hydrogenation
of aryl alkyl ketones like acetophenone. Asymmetric
Department of Chemical and Petroleum Engineering, Center for
Environmentally Beneficial Catalysis, The University of Kansas,
1501 Wakarusa Dr. A Suite 110, Lawrence, KS 66047, USA
e-mail: rvc1948@ku.edu
123

232
S. H. Deshpande et al.
transfer hydrogenation using Azanorboronyl alcohol as a
ligand (Scheme 1, A) was fast and 97% conversion of
acetophenone with 96% ee was achieved in 0.25 h. A wide
variety of ketones were reduced with high enantioselec-
tivity (85–99%) using this catalyst system. Wills et al. [26–
29] have investigated transfer hydrogenation of various
ketones using (1R,2S)-cis-1-aminoindan-2-ol as a ligand
(Scheme 1, B) with high asymmetric induction (70–98%).
Van Leeuwen et al. [30, 31] have investigated various
substituted amino ethanol and norephedrine based ligands
and tetradentate ligands for transfer hydrogenation of
ketones. Best results (88% conversion of acetophenone
with 95% ee) were obtained using (1R,2S)-N-benzyl-nor-
ephedrine as a ligand (Scheme 1, C). They also found that
bidentate coordination is desirable even for tetradentate
ligand and catalytic activity decreased significantly with
tetradentate ligands. Frost et al. [32] have prepared a series
of amino alcohols (based on established amino alcohol
backbone) and found that ligand D (Scheme 1) gave best
results for transfer hydrogenation of acetophenone (91%
conversion and 95% ee at 10 °C). Watts et al. [33] have
prepared a series of terpene based amino alcohols and used
for transfer hydrogenation of various ketones using
[RuCl2(p-cymene)2]2 as a catalyst. Good to excellent yield
with moderate enantioselectivity (up to 71%) was obtained
using limonene derived amino alcohol (1S,2S,4R)-1-
methyl-4-(1-methylethenyl)-2-(methylamino)cyclohexane
(Scheme 1, E). Recently, Schiffers et al. [34] have used
2-aminocyclohexanol derivatives for transfer hydrogena-
tion of acetophenone using [RuCl2(p-cymene)2]2 as a cat-
alyst. Enantiomers of 2-aminocyclohexanol derivatives
were separated by resolution using (R)- and (S)-mandelic
acid. Best results ([95% conversion and up to 96% ee at
10 °C) were obtained using F (Scheme 1) as a ligand.
From the literature, it can be clearly seen that amino
alcohol structure and substituents significantly affect con-
version as well as selectivity, though the exact reasons for
the observed effects (steric and electronic) are still not
understood completely [9, 30, 31, 35]. From the literature,
it was observed that most of the amino alcohol derivatives
investigated have chiral centers on adjacent carbon atoms
and are mostly derived from ephedrine or norephedrine.
We decided to synthesize chiral amino alcohol ligands
starting from cheap and easily available raw materials like
(S)-(-)-lactic acid, racemic mandelic acid, benzyl amine
and (R)- and (S)- a-methyl benzyl amine. In these amino
alcohols the chiral centers will not be on the adjacent
carbon atoms. One chiral center will be on the carbon
attached to –OH group, while other chiral center will be on
the carbon attached to –N of the amino alcohol. There are
no reports on the transfer hydrogenation of ketones using
such amino alcohols as ligands. In this paper, synthesis of
new derivatives of amino alcohol ligands and their appli-
cations in Ru(II)(arene) catalyzed transfer hydrogenation
of ketones have been reported.
2 Experimental
All the experiments were carried out under inert atmo-
sphere of argon using oven-dried glassware. All the
ketones used except 2-Acetyl-6-methoxy naphthalene were
procured from Aldrich Chemicals, USA. 2-Acetyl-6-
methoxy naphthalene was obtained as a free sample from
private company and purity of the compound ([98%) was
confirmed by GC and GC–MS analysis. [Ru(p-cyme-
ne)Cl2]2 was purchased from Aldrich chemicals, USA,
while [RhCp * Cl2]2 and [IrCp * Cl2]2 were purchased
from Strem Chemicals, USA. 2-Propanol (HPLC grade)
was procured from Merck, India. [Ru(benzene)Cl2]2 was
O
H
OH
Ligand
[RuCl2(
p-cymene)]2
iPrOH, KOH or iPrOK, or tBuOK, rt
CH2Ph
NH
H3C
NH2
OH
O
1
prepared using the literature procedure [36]. The H NMR
O
NH
OH
spectra were recorded on a 200 MHz Bruker spectrometer.
13C NMR spectra were recorded on a 400 MHz Bruker
spectrometer. FTIR spectra were recorded on Shimadzu
OH
(A)
(B)
(C)
spectrometer (Model IR prestige 21) and reported in cm-1
.
OH
H
HPLC analysis was carried out using Perkin Elmer HPLC
instrument with quaternary gradient pump, diode array
detector and auto sampler. GC analysis was carried out
using Agilent GC (Agilent Technologies, USA, Model
6850) using HP-Chiral column and HP-1 column pur-
chased from Agilent Technologies. LC–MS analysis was
carried out by Thermo Fisher Scientific LC–MS (MSQ plus
Model).
N
Me
NH
HO
HN
OH
(D)
(E)
(F)
Scheme 1 Transfer hydrogenation of acetophenone using amino
alcohol ligands
123

Catalytic Asymmetric Transfer Hydrogenation of Ketones
233
13C NMR :(d in ppm) 145.6, 128.6, 127.1, 126.5, 66.4,
58.7, 54.4, 24.4, 20.6
2.1 Synthesis and Characterization of Amino Alcohol
Ligands
FT-IR: (neat) 3383, 3309, 2966, 2877, 1454, 1118, 744,
(S) Methyl lactate and methyl mandalate were prepared
using standard literature procedures.
698
LC–MS: MH?: 180
Three ligands were prepared starting from S (-) methyl
lactate and a-(S)-methyl benzyl amine, a-(R) methyl benzyl
amine or benzyl amine as reactants. Typical procedure used
for the synthesis of 2-Propanol-1-[(1-phenyl ethyl) amino]
[S, S] using S (-) methyl lactate and a-(S)-methyl benzyl
amine as reactants is presented below. Characterization
details of ligands prepared are also presented below:
2.1.2 Preparation of 2-Propanol-1-[(1-phenyl ethyl)
amino] [S,R] (Ligand-2)
The ligand was prepared using S (-) methyl lactate and
a-(R) methyl benzyl amine as reactants and same proce-
dure. Product obtained was yellowish solid (2.5 g, yield:
64%).
1H NMR: d = 1.11–1.14, 3H (d, J = 6.2 Hz),
d = 1.39–1.42, 3H (d, J = 6.6 Hz), d = 2.23–2.33, 1H
(dd, J = 9.6 Hz, 12.2 Hz), d = 2.58–2.65, 1H (dd,
J = 3 Hz, 11.8 Hz) and 2H (N–H and O–H, br, singlet),
d = 3.77–3.80, 2H (multiplet), d = 7.31–7.41, 5H
(multiplet).
2.1.1 Preparation 2-Propanol-1-[(1-phenyl ethyl) amino]
[S,S] (Ligand-1)
Step 1: S (-) methyl lactate 11.6 g (0.1 mol) and a-(S)-
methyl benzyl amine 12.1 g (0.1 mol) were taken in a
100 mL round bottom flask and refluxed for 12 h. The con-
tents were cooled to room temperature and 50 mL ice-cold
solution of 1 N HCl was added to the flask. The contents
were shaken vigorously and aqueous layer was discarded to
remove unreacted amine. Toluene (50 mL) was added to the
remaining organic layer in the flask. The contents were
heated at 70 °C for about 10 min to get clear solution. The
solution was dried over sodium sulphate and concentrated
under reduced pressure using rotary evaporator to get amide
derivative. Yield of the compound was 16 g (83%). For-
mation of the desired amide derivative was confirmed by
NMR, LC–MS analysis. Step 2: NaBH4 (3.33 g, 90 mmol)
was taken in 250 mL round bottom flask containing 100 mL
THF (dried over KOH). Amide derivative (4.2 g,
21.8 mmol) was dissolved in 50 mL THF (dried over KOH)
in a separate flask and was added slowly to NaBH4 solution.
The resulting solution was cooled to 0–5 °C using ice water
bath. BF3Áetherate 10 mL (11.4 g, 80 mmol) was taken in
dropping funnel and was added carefully to the above solution
over a period of 20 min, making sure that excessive pressure
does not develop. The solution was stirred for 1 h and allowed
to warm to room temperature. The solution was refluxed for
3 h and after cooling to room temperature 10 mL of 2 N HCl
was added carefully, followed by 30 mL distilled water, to
destroy excess NaBH4 present. The resulting solution was
concentrated to *40 mL and extracted with n-hexane
(2 9 30 mL). 5 N NaOH solutionwas added toaqueous layer
to adjust the pH to 11–12 and extracted with ethyl acetate
(3 9 30 mL), dried over sodium sulphate and concentrated to
get yellowish liquid as product (2.5 g, yield: 64%).
13C NMR: (d in ppm) 143.7, 127.5, 126.5, 125.5, 64.7,
56.7, 53.3, 23.2, 19.4
FT-IR: (KBr) 3390, 2924, 1450, 1118, 1064, 763, 702
LC–MS: MH?: 180
2.1.3 Preparation of 2-Propanol-1-(phenyl methyl)
amino)] (S) (Ligand-3)
The ligand was prepared using S (-) methyl lactate and
benzyl amine as reactants and same procedure. Product was
obtained as a yellowish liquid (2.7 g, yield: 75%).
1H NMR: d = 1.08–1.12, 3H (d, J = 6.3 Hz), d =
2.39–2.49, 1H (dd, J = 9.2 Hz, 12.0 Hz), d = 2.59–2.66,
1H (dd, J = 3.2 Hz, 12.0 Hz), d = 3.60, 2H (br, sin-
glet), d = 3.75–3.88, 3H (multiplet), d = 7.22–7.31, 5H
(multiplet)
13C NMR: (d in ppm) 138.9, 127.4, 127.1, 126.1, 64.6,
55.3, 52.6, 19.3
FT-IR: (KBr)3309, 3029, 2970, 1455, 1110, 1030, 744,
700
LC–MS: MH?: 166
Two ligands were prepared starting from methyl
mandalate and a-(S) methyl benzyl amine or a-(R) methyl
benzyl amine as reactants. Typical procedure used for the
synthesis of a-[(1-phenylethyl)amino)methyl]-benzene
ethanol] [SS] using methyl mandalate and a-(S) methyl
benzyl amine as reactants is presented below.
2.1.4 Preparation of a-[(1-phenylethyl)amino)methyl]-
benzene ethanol] [SS] (Ligand-4)
1H NMR :d = 1.06–1.09, 3H (d, J = 6.2 Hz),
d = 1.35–1.38, 3H (d, J = 6.6 Hz), d = 2.28–2.38, 1H (dd,
J = 9.0 Hz, 12.0 Hz), d = 2.44–2.52, 1H (dd, J = 3.4 Hz,
11.9 Hz), d = 2.91, 2H (br, singlet), d = 3.58–3.78, 2H
(multiplet), d = 7.19–7.31, 5H (multiplet)
Step 1: Methyl Mandalate16.7 g (0.1 mol) and a-(S)
methyl benzyl amine12.1 g (0.1 mol) were taken in a
250 mL round bottom flask and heated at 130 °C for 3 h.
123

234
S. H. Deshpande et al.
The solution was cooled to room temperature and 100 mL
of ice-cold solution of 1 N HCl was added with stirring.
Sticky solid separated on stirring for 15 min. Sticky solid
(mixture of racemic amide derivatives) was filtered and
dissolved in 30 mL warm toluene to obtain clear solution.
The clear solution obtained was cooled to 0 °C and kept
standing for 12 h to obtain white crystalline solid. White
crystalline solid was filtered and washed with toluene.
White solid obtained was pure isomer of amide derivative
(6.5 g, yield 25.5%). Purity of the epimer was confirmed by
HPLC analysis using Silica column and using 5% IPA in
n-Hexane, as mobile phase. Compound was characterized
1
by GC–MS and H NMR analysis. Step 2: NaBH4 (3.33 g,
Fig. 1 ORTEP of a-[(1-phenylethyl)amino)methyl]-benzene ethanol]
[SS] (Ligand-4) drawn at 30% displacement ellipsoids probability
level; H atoms are shown as small spheres of arbitrary radii
90 mmol) was taken in a 250 mL round bottom flask
containing 100 mL THF (dried over KOH). Amide deriv-
ative (5.2 g, 20.4 mmol) was dissolved in 50 mL THF
(dried over KOH) in a separate flask and was added slowly
to NaBH4 solution. The resulting solution was cooled to
0–5 °C using ice water bath. BF3.etherate 10 mL (11.4 g,
80 mmol) was taken in dropping funnel and was added
carefully to the above solution over a period of 20 min,
making sure that excessive pressure does not develop. The
solution was stirred for 1 h and allowed to warm to room
temperature. The solution was refluxed for 3 h and after
cooling to room temperature, 10 mL of 2 N HCl was added
carefully followed by 30 mL distilled water, to destroy
excess NaBH4 present. The resulting solution was con-
centrated to *40 mL and extracted with n-hexane
(2 9 30 mL). 5 N NaOH solution was added to aqueous
layer to adjust the pH to 11–12 and the solution was cooled
to room temperature to get white crystalline product, which
was recrystallized using methanol to get 3.5 g of the pure
product (yield: 71.2%). Compound was characterized by
2.1.5 Preparation of a-[(1-phenylethyl)amino)methyl]-
benzene ethanol] [RR] (Ligand-5)
The ligand was prepared by reaction of Methyl Mandalate
and a-(R) methyl benzyl amine using the procedure
described. White crystalline product obtained was recrys-
tallized using methanol to get 3.5 g of the pure product
(yield: 71.2%).
1H NMR: d = 1.42–1.45, 3H (d, J = 6.6 Hz),
d = 2.21, 2H (br, singlet), d = 2.62–2.68, 1H (dd,
J = 8.5 Hz, 12.2 Hz), d = 2.72–2.83, 1H (dd, J = 3.8 Hz,
12.2 Hz), d = 3.77–3.86, 1H (q, J = 6.8 Hz), d =
4.59–4.65, 1H (dd, J = 3.8 Hz, 8.4 Hz), d = 7.30–7.37,
10H (multiplet)
13C NMR: (d in ppm) 145.3, 142.5, 128.6, 128.4, 127.5,
127.1, 126.5, 125.8, 72.4, 58.5, 55.3, 24.1
1
LC–MS, H NMR as well as single crystal X-ray analysis
FT-IR: (KBr) 3290, 2920, 1454, 1064, 703
LC–MS: MH?: 242
(Fig. 1, also see supplementary material for details).
Thus pure (S,S) amide derivative crystallized out pref-
erentially from toluene solution on cooling (Step 1), while
other isomer (S,R) was soluble in toluene solution. The
separation of the desired diasteriomer of amide derivative
by preferential crystallization of one of the isomer from the
toluene solution (Step 1) is very interesting. This has
allowed us to develop an easy procedure for the synthesis
of (R,R) and (S,S) isomers starting from cheap racemic
methyl mandalate as reactant.
1H NMR: d = 1.41–1.44, 3H (d, J = 6.6 Hz), d = 2.37,
2H (br, singlet), d = 2.62–2.72, 1H (dd, J = 8.6 Hz,
12.2 Hz), d = 2.77–2.85, 1H (J = 3.9 Hz, 12.6 Hz),
d = 3.76–3.86, 1H (q, J = 6.8 Hz), d = 4.59–4.65, 1H
(dd, J = 3.8 Hz, 8.4 Hz), d = 7.30–7.35, 10H (multiplet)
13C NMR: (d in ppm) 145.3, 142.5, 128.6, 128.4, 127.5,
127.1, 126.5, 125.8, 72.4, 58.5, 55.3, 24.1
2.2 Experimental Procedure
All the reactions were carried out in a jacketed glass
reactor flushed with argon prior to the addition of reactants.
In a typical experiment, [Ru(p-cymene)Cl2]2 7.7 mg
(0.013 mmol) and ligand-4 13.4 mg (0.055 mmol) was
added to 25 mL 2-propanol in a glass reactor. Acetophe-
none 0.3 g (2.5 mmol) and stock solution of KOH
(0.086 N) 6.99 mg (0.12 mmol) were added to the glass
reactor and Argon bladder was attached to the reactor to
maintain inert conditions. The glass reactor temperature
was kept constant at 25 °C using water circulation bath.
Reaction was initiated by stirring the reaction mixture with
the help of magnetic needle. Reaction was continued for
2 h and reaction sample was withdrawn and quenched by
the addition of acetic acid. Analysis of the reaction crude
FT-IR: (KBr) 3290, 2920, 1454, 1064, 703
LC–MS: MH?: 242
123

Catalytic Asymmetric Transfer Hydrogenation of Ketones
235
O
R2
C
was carried out by chiral GC analysis (for acetophenone
reactions) using HP-Chiral column supplied by Agilent
Technologies, USA. For all other reactions enantiomeric
excess was obtained by HPLC analysis using Chiracel
OD-H column supplied by Daicel Company. Formation of
alcohol products was confirmed by GC–MS analysis.
R1
O
R1
R2
C
Δ
reflux
+
H2N
NH
OH
OH
OCH3
R3
R3
methyl (S)-(-)- lactate or
racemic methyl mandalate
Amine derivative
Amide derivative
*
Racemic mandelic acid
based ligands
(S)-(-) - Lactic acid
based ligands
Mixture of
(R,R) and (S,R) or
(R,S) and (S,S) diasteriomers
of amide derivative
R1
R2
NH
C
3 Results and Discussion
OH
Dissolve in toluene
cool to 0oC for 12 h
R3
Amino alcohol ligands
For our study we have prepared amino alcohols starting
from cheap and easily available starting materials such as
(S)-(-)-lactic acid and racemic mandelic acid. First,
methyl esters of the (S)-(-)-lactic acid and mandelic acid
were prepared by known literature methods. Condensation
of methyl esters of these acids with amines such as benzyl
amine, (R)- or (S)-a-methyl benzyl amine leads to the
formation of respective amide derivatives, which on
reduction with NaBH4 and BF3.etherate are converted to
the required amino alcohol derivatives. For amino alcohols
prepared from (S)-(-)-lactic acid, since chiral (S)-(-)-
lactic acid was used as a starting material, required chiral
amino alcohols were obtained directly by reduction of
amide derivatives. However, for amino alcohols prepared
from mandelic acid, racemic methyl mandalate was used as
a starting material. The condensation of methyl mandalate
with (R)- or (S)- a-methyl benzyl amine yields a mixture of
diasteriomers. The mixture of diasteriomers obtained was
dissolved in toluene and cooled to 0 °C for 12 h. On
cooling the solution white solid crystallized out. The white
solid obtained was filtered and washed with toluene. The
white solid obtained was pure single isomer of amide
derivative (depending on the amine used). With this simple
technique, we were able to separate pure isomer (R,R or
S,S) from the mixture of diasteriomers, while other dias-
teriomer (R,S or S,R) remained in the solution. Reduction
of the purified amide isomer gives required amino alcohol
derivative (Scheme 2). Using this strategy, 3 amino alco-
hols were prepared starting from (S)-(-)-lactic acid and 2
amino alcohols were prepared staring from racemic man-
delic acid (Scheme 3) and used for the asymmetric transfer
hydrogenation reaction.
H
B
Separation of (S,S) or (R,R) amide
derivative in pure form as white
crystalline product. Other disteriomer
remains in the solution
a
N
R1 = CH3 for lactic acid, C6H5 for mandelic acid, R2 and R3 = H for brnzyl amine
2 = H and R3 = CH3 for α-(S)- methyl benzyl amine or α-(R)- methyl benzyl amine
R
* In case of Mandelic acid α-(S)- methyl benzyl amine or α-(R)- methyl benzyl
amine were used as reactants, while benzyl Amine was not used
Scheme 2 Synthetic methodology used for the preparation of amino
alcohol ligands starting from S-(?)-methyl lactate and racemic
mandelic acid as starting materials
H3C
H3C
H3C
H
H
H
C
H
HO HN
C
HO HN
C
HO HN
CH3
CH3
1
2
3
H
H
HO HN
C
HO HN
C
CH3
CH3
5
4
Scheme 3 Various amino alcohol ligands synthesized
formed as a precatalyst (Scheme 4). Amino alcohol pre-
pared from (S)-(-)-lactic acid and benzyl amine in the
present work (Scheme 3, ligand 3) has only one chiral
center on the C atom attached to –OH group, while there is
no chiral center on the C atom attached to –N. For other
amino alcohols prepared by condensation of (S)-(-)-lactic
acid or racemic mandelic acid with (R)- or (S)-a-methyl
benzyl amine (Scheme 3, ligand nos. 1, 2, 4 and 5), second
chiral C atom is attached to –N of the amino alcohol and is
outside the coordination sphere of Ru. It will be interesting
to see the effect of only one chiral center in the amino
Amino alcohols derived from (S)-(-)-lactic acid and
mandelic acid have not been investigated in detail for
asymmetric transfer hydrogenation of ketones. Most of the
amino alcohols developed are based on ephedrine or nor-
ephedrine backbone. According to the proposed mecha-
nism for Ru catalyzed transfer hydrogenation using amino
alcohol as a ligand, precatalyst (18 electron Ru complex) is
formed by the interaction of Ru(arene) catalyst precursor
and amino alcohol ligand (Scheme 4) [24]. Thus both the
chiral centers of amino alcohol ligand (for ephedrine based
ligands) will be present in the five member Ru complex
Scheme 4 Proposed 18-elec-
tron catalyst precursor formed
by reaction of Ru(arene) com-
plex and amino alcohol ligand
[17, 30]
Ru
Cl
NH2
O
123

236
S. H. Deshpande et al.
alcohol ligand and also the effect of additional chiral center
outside the coordination sphere on the conversion and
chiral selectivity.
the results obtained using ligands prepared from (S)-(-)-
lactic acid for various catalyst precursors (Table 1, Sr. No.
2–4) clearly show that high enantioselectivity was obtained
using ligand-3, except for [RhCp * Cl2]2 catalyst (Com-
pare Table 1, Entry 4 with 1 for Rh catalyst). Enantiose-
lectivity decreased marginally for ligand-1 (with [S,S]
structure), while conversion as well as enantioselectivity
decreased for ligand-2, having [S,R] structure for all the
catalyst precursors investigated. This indicates negative
influence of the [S,R] isomer on the catalytic activity and
selectivity. Ligands 1 and 4 have same configuration except
that the methyl group in the ligand 1 is replaced by phenyl
group in the ligand-4. Results obtained for both the ligands
are comparable for Ru catalyst precursors (Table 1,
compare Sr. No. 2 and 5), while for (RhCp * Cl2)2 and
(IrCp * Cl2)2 conversion as well as enantioselectivity was
higher for ligand 4, having phenyl group. Observed results
for [Ru(benzene)Cl2]2 and [Ru(p-cymene)Cl2]2 complexes
as catalysts indicate that methyl group present on the chiral
C attached to –OH is sufficient for chiral discrimination.
Carpentier et al. also have obtained similar results for
transfer hydrogenation of tert-butylacetoacetate using
Ru(II) catalyst and ephedrine based ligands [35]. For
ligands 4 and 5 prepared from racemic mandelic acid, high
conversion ([90%) and moderate to good enantioselec-
tivity was obtained using Ru and Rh catalysts, while low
conversion and moderate enantioselectivity was obtained
using Ir complex catalyst. Ligands 4 and 5 are enantiomers
and (S)-(-)-1-phenyl ethanol was obtained in excess using
ligand 4, while (R)-(?)1-phenyl ethanol was obtained in
excess using ligand 5. Good results were obtained using
Ru(p-cymene)Cl2]2/ligand-4 combination and also, struc-
ture of the ligand-4 was confirmed by single crystal X-ray
As a first step transfer hydrogenation of acetophenone
was investigated using Ru, Rh and Ir metal complexes as
catalyst precursors with 1R,2S-ephedrine (Ep) and amino
alcohols prepared as ligands and the results are presented in
Table 1. The results clearly show that the catalysts pre-
pared with amino alcohol ligands (Table 1, Sr. No. 2–6) are
active and selective for asymmetric transfer hydrogenation
of acetophenone. From the results it can be seen that the
configuration of the product was ‘‘R’’ using Ep and ligand
4 (marked with * in the Table 1, Sr. No. 1 and 6) for all the
catalyst precursors, while for all other ligands (Table 1, Sr.
No. 2–5) the product configuration was ‘‘S’’ for all the
catalyst precursors screened. It may be noted that for
1R,2S-ephedrine (Ep) and ligand 4 the configuration of
‘‘C’’ attached to –OH group is ‘‘R’’, while for all other
ligands screened the configuration of ‘‘C’’attached to –OH
group is ‘‘S’’. This clearly indicates that the configuration
of carbon attached to –OH group is imparted to the chiral
alcohol product. The conversion of acetophenone and
chiral induction obtained using ligand-3 compares very
well with ephedrine as a ligand (Table 1, compare Sr. No.
1 and 4). As explained earlier configuration of product with
Ep as a ligand is ‘‘R’’, while that with ligand 3 is ‘‘S’’.
Ligand-3 has only one chiral center present on the C
attached to –OH group. This clearly indicates that the
chiral center at the –OH group is more important in
deciding the chiral selectivity and other chiral center
attached to –N may have minimal role in deciding the
chiral selectivity. Similar observations have already been
reported by several authors [9, 19, 32, 35]. Comparison of
Table 1 Asymmetric reduction of acetophenone using amino alcohol ligands and various catalysts
Sr. no.
Ligand
(Ru(Benz)Cl2)2
Conv. (%)
(Ru(p-cymene)Cl2)2
(RhCp * Cl2)2
Conv. (%)
(IrCp * Cl2)2
Conv. (%)
eea (%)
Conv. (%)
eea (%)
eea (%)
eea (%)
1
2
3
4
5
6
Ep
1
90
87
85
93
91
92
69b
54
81
90
59
84
91
90
92b
78
95
83
42
96
96
96
66b
77
–
41
30
20
52
51
51
78b
30
–
2
40
54
3
68
87
67
83
81b
77
61
64b
4
50
50b
76
76b
5
Reaction conditions: Catalyst: 1.3 9 10-5 mol; Ligand: 5.5 9 10-5 mol
Acetophenone: 2.5 9 10-3 mol; KOH: 1.2 9 10-4 mol; IPA: 25 cm3
Temperature: 25 °C; Reaction time: 2 h
Benz = Benzene; Cp* = C5Me5, Ep = (1R, 2S)-ephedrine
a
S configuration (confirmed by chiral GC analysis using authentic standard)
R configuration (confirmed by chiral GC analysis using authentic standard)
b
123

Catalytic Asymmetric Transfer Hydrogenation of Ketones
237
Table 2 Asymmetric reduction
Entry
Ketone
Reaction time (h)
Conv. (%)
ee (%)
of substrates using amino
alcohol ligand 4 and
[Ru(p-cymene)Cl2]2 catalyst
1
Acetophenone
2
1
1
1
2
2
2
2
2
2
1
91
99
92
95
82
38
54
74
23
–
76
52
56
57
67
74
65
62
35
–
2
4-Bromoacetophenone
4-Nitroacetophenone
4-Chloroacetophenone
4-Methylacetophenone
4-Isobutylacetophenone
4-Methoxyacetophenone
2-Acetyl 6-methoxy naphthalenea
2,5-Dimethylacetophenone
2-Acetyl pyridine
3
4
Reaction conditions:
[Ru(p-cymene)Cl2]2:
5
1.3 9 10-5 mol; Ligand 4:
5.5 9 10-5 mol ketone,
2.5 9 10-3 mol; KOH:
1.2 9 10-4 mol; IPA: 25 cm3;
Temperature: 25 °C
6
7
8
9
a
10
11
Acetonitrile (2 mL) was
added to dissolve 2-Acetyl-
6-methoxy naphthalene
3-Acetyl pyridine
99
64
analysis (See Fig. 1). Further work on the screening of
various ketones was carried out using ligand 4 and Ru
(p-cymene)Cl2]2 as a catalyst precursor.
smoothly with conversion ranging between 60 and 98%
and enantioselectivity between 40 and 86%. Good enanti-
oselectivity has been obtained using ligand having only one
chiral center on the C attached to –OH group (ligand-3),
indicating that the chiral center attached to –OH moiety is
important in deciding chiral selectivity. Ligands have been
prepared using simple procedure and starting from cheaper
raw materials such as (S)-(-)-lactic acid and racemic
mandelic acid. For ligands prepared using racemic man-
delic acid, chiral resolution of racemic amide derivative
was carried out by simple crystallization method using
toluene as a solvent. Further work on the detailed investi-
gation on asymmetric transfer hydrogenation is in progress
in our laboratory.
Various ketones were screened using [Ru(p-cyme-
ne)Cl2]2/ligand-4 catalyst system and the results are pre-
sented in Table 2. Best results were obtained for transfer
hydrogenation of acetophenone as a reactant (91% con-
version and 76% ee). With electron withdrawing substitu-
ents in the para position activity increased significantly,
while enantioselectivity decreased significantly (Table 2,
compare Sr. No. 1 with Sr. No. 2–4, conversion 92–95% in
1 h compared to 91% in 2 h; ee: 52–66 compared to 76%).
While with electron donating methyl group in Para position
conversion as well as chiral selectivity decreased margin-
ally (Table 2, Sr. No. 1 and 5). With bulkier isobutyl group
in para position, the reaction was sluggish (38% conversion
in 3 h) with 74% ee. With substituent in the ortho position,
conversion as well as chiral selectivity decreased signifi-
cantly (Table 2, Sr. No. 9 and 10). Thus, reaction did not
proceed using 2-acetyl pyridine, while 99% conversion in
1 h reaction time with 64% enantioselectivity was achieved
using 3-acetylpyridine as a reactant. 4-Methoxyacetophe-
none is known to be a challenging substrate probably
because of its low redox potential, giving lower conver-
sions and enantioselectivity [17, 23, 34]. In the present
study, transfer hydrogenation of 4-methoxyacetophenone
gave 54% conversion with 65% ee in 2 h reaction time.
Acknowledgement Authors thank CSIR for financial assistance
(project CMM0005).
References
1. Noyori R (1994) Asymmetric catalysis in organic synthesis. John
Willey, New York, Ch. 2
2. Ojima I (ed) (1993) Catalytic asymmetric synthesis. VCH, Berlin
3. Corey EJ, Helal CJ (1998) Angew Chem Int Ed 37:1986
4. Noyori R, Yamakawa M, Hashiguchi S (2001) J Org Chem
66:7931
5. Noyori R, Hashiguchi S (1997) Acc Chem Res 30:97
6. Palmer MJ, Wills M, Tetrahedron M (1999) Asymmetry 10:2045
7. Zassinovich G, Mestroni G, Gladiali S (1992) Chem Rev 92:1051
8. Ohkuma T, Noyori R, Nishiyama H, Itsuno S (1999) In: Jacobsen
EN, Pfaltz A, Yamamoto H (eds) Comprehensive asymmetric
catalysis, vol 1. Springer, Berlin, Ch. 6, 199 pp
4 Conclusions
9. Everaere K, Mortreux A, Carpentier J (2003) Adv Synth Catal
345:67
10. de Graauw CF, Peters JA, Van Bekkum H, Huskens J (1994)
Synthesis 10:1007
11. Martins JED, Clarkson GJ, Wills M (2009) Org Lett 11:847–850
12. Cortez NA, Aguirre G, Parra-Hake M, Somanathan R (2007)
Tetrahedron Lett 48(25):4335–4338
The reduction of ketones under catalytic transfer hydro-
genation conditions with 2-propanol as a hydrogen source
is a mild and highly attractive route for the formation of
secondary alcohols. We have shown that (S)-(-)-lactic
acid and mandelic acid based b-amino alcohols can be used
as ligands for catalytic asymmetric transfer hydrogenation
of various ketones. The transfer hydrogenation proceeds
13. Cortez T, Norma A, Aguirre T, Gerardo T, Parra-Hake T, Miguel
T, Somanathan T, Ratnasamy
50(19):2228–2231
T
(2009) Tetrahedron Lett
123

238
S. H. Deshpande et al.
14. Ahlford K, Ekstroem J, Zaitsev AB, Ryberg P, Eriksson L,
Adolfsson H ((2009)) Chem Eur J 15:11197
15. Zhang X-Q, Li Y-Y, Dong Z-R, Shen W-Y, Cheng Z-B, Gao J-X
(2009) J Mol Catal A Chem 307:149
16. Hashiguchi S, Fujii A, Takehara J, Ikariya T, Noyori R (1995) J
Am Chem Soc 117:7562
17. Fujii A, Hahsiguchi S, Uematsu N, Ikariya T, Noyori R (1996) J
Am Chem Soc 118:2521
26. Palmer M, Walsgrove T, Wills MJ (1997) J Org Chem 62:5226
27. Kenny JA, Palmer MJ, Smith ARC, Walsgrove T, Wills M (1999)
Synlett 11:1615
28. Wills M, Gamble M, Palmer M, Smith A, Studley J, Kenny J
(1999) J Mol Catal A Chem 146:139
29. Palmer MJ, Kenny JA, Walsgrove T, Kawamoto AM, Wills M
(2002) J Chem Soc Perkin Trans 1:416
30. Petra DGI, Kamer PCJ, Van Leeuwen PWNM, Goubitz K, Van
Loon AM, de Vries JG, Schoemaker HE (1999) Eur J Inorg Chem
12:2335
18. Haack KJ, Hashiguchi S, Fujii T, Ikariya T, Noyori R (1997)
Angew Chem Int Ed 36:285
19. Takehara J, Hashiguchi S, Fujii A, Inoue S, Ikariya T, Noyori R
(1996) Chem Commun 233
20. Kenny JA, Versilus K, Heck AJR, Walsgrove T, Wells M (2000)
Chem Commun 99
21. Alonso DA, Guijarro D, Pinho P, Temme O, Andersson PG
(1998) P G J Org Chem 63:2749
22. Alonso DA, Brandt P, Nordin SJM, Andersson PG (1999) J Am
Chem Soc 121:9580
31. Petra DGI, Reek JNH, Handgraaf JW, Meijer EJ, Dierkes P,
Kamer PCJ, Brussee J, Schoemaker HE, Van Leeuwen PWNM
(2000) Chem Eur J 6:2818
32. Frost CG, Mendonca P (2000) Tetrahedron Asymmetry 11:1845
33. Watts CC, Thoniyot P, Cappuccio F, Verhagen J, Gallagher B,
Singaram B (2006) Tetrahedron Asymmetry 17:1301
34. Schiffers I, Rantanen T, Schmidt F, Bergmans W, Zani L, Bolm
C (2006) J Org Chem 71:2320
23. Alonso DA, Nordin SJM, Roth P, Tarnai T, Andersson PG (2000)
J Org Chem 65:3116
24. Brandt P, Roth P, Andersson PG (2004) J Org Chem 69:4885
25. Nordin SJM, Roth P, Tarani T, Alonso DA, Brandt P, Andersson
PG (2001) Chem Eur J 7(7):1431
35. Everaere K, Mortreux A, Bulliard M, Brussee J, Van der Gen A,
Nowogrocki G, Carpentier JF (2001) Eur J Org Chem 2:275
36. Bennet MA, Smith A (1974) J Chem Soc Dalton Trans 233
123