Transfer hydrogenation reactions catalyzed by chiral half-sandwich Ruthenium complexes derived from Proline

Article abstract of DOI:10.1007/s12039-016-1151-8

Chiral ruthenium half-sandwich complexes were prepared using a chelating diamine made from proline with a phenyl, ethyl, or benzyl group, instead of hydrogen on one of the coordinating arms. Three of these complexes were obtained as single diastereoisomers and their configuration identified by X-ray crystallography. The complexes are recyclable catalysts for the reduction of ketones to chiral alcohols in water. A ruthenium hydride species is identified as the active species by NMR spectroscopy and isotopic labelling experiments. Maximum enantio-selectivity was attained when a phenyl group was directly attached to the primary amine on the diamine ligand derived from proline. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1151-8

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1151-8
Transfer hydrogenation reactions catalyzed by chiral half-sandwich
Ruthenium complexes derived from Proline
ARUN KUMAR PANDIA KUMAR and ASHOKA G SAMUELSON∗
Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India
e-mail: ashoka@ipc.iisc.ernet.in
MS received 5 May 2016; revised 5 July 2016; accepted 5 July 2016
Abstract. Chiral ruthenium half-sandwich complexes were prepared using a chelating diamine made from
proline with a phenyl, ethyl, or benzyl group, instead of hydrogen on one of the coordinating arms. Three of
these complexes were obtained as single diastereoisomers and their configuration identified by X-ray crystal-
lography. The complexes are recyclable catalysts for the reduction of ketones to chiral alcohols in water. A
ruthenium hydride species is identified as the active species by NMR spectroscopy and isotopic labelling exper-
iments. Maximum enantio-selectivity was attained when a phenyl group was directly attached to the primary
amine on the diamine ligand derived from proline.
Keywords. Asymmetric transfer hydrogenation; Proline diamine ligands; Half-sandwich ruthenium
complexes; Chiral alcohols; Ruthenium hydride.
1. Introduction
very high enantiomeric excesses under mild conditions.
In the case of acetophenone as a substrate, formation
of (S)-1-phenylethanol in 97% ee and 95% yield was
observed.14 Noyori and co-workers identified the origin
of enantioselectivity19 in Noyori-Ikariya type half-
Asymmetric reduction of carbonyl compounds is an
important reaction1 as it leads to chiral secondary alco-
hols, a key functional group found in several fine chem-
icals, agrochemicals2 and pharmaceuticals.3 7 In nature, sandwich complexes with C-H··· π interactions between
the arene ring and a wide range of substrates.20,21
oxidoreductases catalyze transfer hydrogenation of car-
Few studies have tested the hypothesis by comparing
very similar ligands with and without C-H··· π interac-
tions arising from the chiral ligand and substrate for
enhancing enantioselectivity.22
bonyl compounds to give stereospecific alcohols using
alcohol dehydrogenases such as horse liver dehydroge-
nase with cofactors like NADH or NADPH.8,9 In the
laboratory, transfer hydrogenation reactions are conve-
niently carried out with a wide range of catalysts which
are convenient alternatives to high pressure hydrogen-
ation which demands special vessels and hydrogen
gas.10,11 As early as in 1970, the research groups of
Ohkubo and Sinou suggested the use of [RuCl2(PPh3)3]
as a catalyst to carry out asymmetric transfer hydro-
genation (ATH) in the presence of either a chiral hydro-
gen donor or a chiral monophosphine ligand.12,13 But
only in 1995, a breakthrough was made by Noyori and
coworkers using a half-sandwich ruthenium catalyst
containing a chiral N-sulfonylated 1,2-diamine ligand
for ATH of ketones and imines.14 18 The important fea-
ture of this catalyst is that the ligand and the metal
play an active role in the transfer of two hydrogen
atoms, one of which is attached to the N of the lig-
and and hence protic in nature and the other attached
to Ru and hence considered hydridic. The bifunctional
nature of the catalyst leads to chiral alcohols with
Although the use of green solvents like water is pre-
ferable,23 solubility problems force one to use isopro-
panol14,24 or a mixture of formic acid and triethyl
amine (HCOOH:Et3N)15 for transfer hydrogenation.
Several ligands modelled after the Noyori catalyst
have been developed for the asymmetric transfer
hydrogenation reactions in water based on sulfonated
diphenylethylenediamine25,26 (TsDPEN) and sulfona-
ted-cyclohexyldiamine27,28 (Ts-CYDN) ligands using
sodium formate29 as a hydrogen source. A recent report
by Denizalti and co-workers on the asymmetric transfer
hydrogenation of ketones in water, but with added SDS,
employing in situ generated ruthenium proline amide
and diamine complexes30 prompts us to report in this
work, a closely related series of chiral half-sandwich
ruthenium(II) complexes containing (S)-N-substituted-
2-aminomethylpyrrolidine ligands, their synthesis and
use as catalysts for the asymmetric transfer hydrogena-
tion of ketones in water. We have characterized the
complexes completely through X-ray crystallography
∗For correspondence

Arun Kumar Pandia Kumar and Ashoka G Samuelson
L2 : Yield: 49%; 1H NMR (400 MHz, CDCl3): δ 3.15
(m, 1H), 2.84 (m, 2H), 2.62-2.42 (m, 4H), 1.81 (m, 1H),
1.66 (m, 2H), 1.26 (m, 1H), 1.04 (t, 3H, J = 7.2 Hz);
13C{1H}NMR (100 MHz, CDCl3) : δ 58.7, 55.7, 46.9,
44.8, 30.2, 26.2, 15.7
and shown how silver nitrate can activate sluggish cat-
alysts and how the reaction can be carried out without
using sodium dodecyl sulphate (SDS) as an additive
which they found detrimental to the enantioselectivity.
Further, we have shown the formation of a hydride
intermediate through isotopic labelling and spectros-
copy. Our systematic study by varying the substituent
on the chiral ligand suggests that phenyl groups on the
proline ring has a beneficial effect in the enantiose-
lectivity in the reduction of a variety of ketones and
supports the earlier hypothesis of Noyori.21
L3: Yield: 61%; 1H NMR (400 MHz, CDCl3): δ 7.23
(m, 1H), 7.31 (m, 4H), 3.79 (s, 2H), 3.22 (m, 1H), 2.88
(m, 2H), 2.49 (m, 2H), 1.87 (m, 1H), 1.69 (m, 2H), 1.31
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 140.9, 128.8,
128.6, 127.3, 58.8, 55.1, 54.7, 46.9, 30.2, 26.2
L4: Yield: 36%; 1H NMR (400 MHz, CDCl3): δ 3.06
(m, 1H), 2.88 (m, 2H), 2.56 (m, 2H), 1.77 (m, 3H), 1.31
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 61.5, 47.5,
46.9, 29.6, 26.2.
2. Experimental
2.1 Materials and methods
2.3 General procedure for the synthesis of chiral
half-sandwich ruthenium proline diamine complexes
All reactions and manipulations were routinely per-
formed under a nitrogen atmosphere using standard
Schlenk techniques in oven-dried glassware. L-Proline,
benzylchloroformate, benzylamine, L-prolinamide, ani-
line were obtained from Sigma-Aldrich U.S.A. All
ketone substrates were obtained from Sigma-Aldrich
U.S.A. Ethyl amine was distilled from 70% aqueous
solution and stored over potassium hydroxide pellets
at −20◦C. Tetrahydrofuran was distilled over sodium/
benzophenone. Triethylamine was distilled first over
KOH and then over LiAlH4. Analytical thin layer chro-
matography (TLC) was performed using precoated silica
gel plates supplied by Merck (60 F254). Subsequent to
elution, plates were visualized using UV radiation (254
nm). Preparative TLC was done using ChemLabs Silica
gel GF 254. Nuclear magnetic resonance spectra were
recorded on a Bruker AMX 400 spectrometer operat-
ing at 400 MHz for H, 61.3 MHz for H NMR, 100
MHz for 13C NMR. ESI-HRMS measurements were
performed on an Agilent 6538 UHD accurate-mass Q-
TOF LC/MS instrument. Elemental analyses were per-
formed by using a Thermo Finnigan Flash EA 1112
CHNS analyzer. HPLC analysis was performed using a
Chiralcel OD column and Chiralcel OJ-H column on a
Merck Hitachi Lachrome HPLC device.
To a solution of [Ru(p-cymene)Cl2]2 (0.286 mmol) in
dry isopropanol (10 mL) was added (S)-N-substituted-
2-aminomethylpyrrolidine ligand (0.573 mmol) and tri-
ethylamine (1.15 mmol). The resulting reaction mixture
was kept at 80◦C for 1 h. The solvent was removed
under vacuum, and ethanol was then added and kept for
crystallization under nitrogen atmosphere. The yellow
crystals formed were filtered and dried.
1
C1: Yield: 80%; H NMR (400 MHz, CDCl3): δ
9.20 (d, 1H, NH, J = 10.0 Hz), 7.98 (d, 2H, J =
7.76 Hz), 7.59 (q, 1H, NH, J = 7.84 Hz), 7.32 (t, 2H,
J = 7.52 Hz), 7.20 (t, 1H, J = 7.36 Hz), 5.70 (d, 1H,
J = 5.76 Hz), 5.66 (d, 1H, J = 5.76 Hz), 5.46 (d,
1H, J = 5.84 Hz), 5.44 (d, 1H, J = 5.8 Hz), 4.05 (m,
1H), 3.55 (m, 1H), 3.38 (m, 1H), 3.18 (m, 1H), 2.70
(m, 1H), 2.36 (m, 1H), 2.25 (s, 3H), 1.97 (m, 3H),
1.35 (m, 1H), 0.98 (d, 6H, J = 6.8 Hz); Anal.Calcd
for C21H30Cl2N2Ru: C 52.28; H 6.27; N 5.81, Found:
C 51.85; H 6.02; N 5.62; ESI-HRMS: m/z calcu-
lated for [C21H30N2RuCl]+: 447.1140 [M-Cl]+; found:
447.1143.
1
2
C2: Yield: 75%; 1H NMR (400 MHz, CDCl3): δ 8.26
(q, 1H, NH, J = 7.40 Hz), 6.95 (m, 1H, NH), 6.28 (d,
1H, J = 5.64 Hz), 5.86 (d, 1H, J = 5.68 Hz), 5.66 (d,
1H, J = 5.76 Hz), 5.26 (d, 1H, J = 5.96 Hz), 3.79 (m,
1H), 3.29 (m, 3H), 3.03 (m, 2H), 2.72 (m, 1H), 2.45 (s,
3H), 2.08 (q, 1H, J = 12.12 Hz), 1.96 (m, 2H), 1.78 (m,
2.2 General procedure for the synthesis of
(S)-N-substituted-2-aminomethylpyrrolidine ligands
Literature procedures were used for the preparation of 2H), 1.36 (t, 3H, J = 7.32 Hz), 1.28 (dd, 6H, J = 6.88,
L1,38 L2,39 L3,39 and L4.39
6.92 Hz); Anal. Calcd for C17H30Cl2N2Ru: C 47.00; H
1
L1: Yield: 66%; H NMR (CDCl3): δ 7.17 (t, 2H, 6.96; N 6.45, Found: C 46.32; H 6.57; N 6.17; ESI-
J = 7.44 Hz), 6.69 (t, 1H, J = 7.32 Hz), 6.63 (d, 2H, J = HRMS: m/z calculated for [C17H30N2RuCl]+: 399.1140
7.84 Hz), 3.38 (m, 1H), 3.16 (dd, 1H, J = 4.6, 4.64 Hz), [M-Cl]+; found: 399.1137.
2.92 (m, 3H), 1.74 (m, 3H), 1.46 (m, 1H); 13C NMR
C3: Yield: 82%; 1H NMR (400 MHz, CDCl3): δ 8.21
(100 MHz, CDCl3): δ 148.9, 129.6, 117.7, 113.4, 58.1, (q, 1H, NH, J = 7.36 Hz), 7.75 (d, 2H, J = 6.92 Hz),
49.1, 46.9, 30.0, 26.2
7.44 (t, 2H, J = 7.36 Hz), 7.37 (m, 1H), 7.03 (m, 1H,

Asymmetric Transfer Hydrogenation by Ruthenium Complexes
Enantiomeric excess (%) at 12 h (isopropanol/hexane
NH), 6.08 (d, 1H, J = 6.0 Hz), 5.84 (d, 1H, J = 5.6
Hz), 5.37 (d, 1H, J = 6.0 Hz), 4.50 (d, 1H, J = 6.0
Hz), 4.24 (dd, 1H, J = 6.84, 6.88 Hz), 4.03 (dd, 1H,
J = 7.2, 7.28 Hz), 3.75 (m, 1H), 3.33 (m, 1H), 3.03 (m,
2H), 2.44 (m, 1H), 2.34 (s, 3H), 2.14 (q, 1H, J = 12.28
Hz), 1.97 (m, 2H), 1.79 (m, 2H), 1.26 (dd, 6H, J =
3.4, 3.6 Hz); Anal.Calcd for C22H32Cl2N2Ru: C 53.22;
H 6.50; N 5.64. Found: C 52.36; H 6.03; N 5.38; ESI-
HRMS: m/z calculated for [C22H32N2RuCl]+: 461.1297
[M-Cl]+; found: 461.1298.
2/98 0.9 mL/min, t1 = 17.4 min for the S enantiomer,
t2 = 19.8 for the R enantiomer) C1 = 74 (S), C2 = 36
(S), C3 = 74 (S), C4 = 12 (S).
2.4c 1-Phenylpropanol:31 1H NMR(400MHz,CDCl3):
δ 7.34 (m, 5H), 4.60 (t, 1H, J = 6.4 Hz), 1.88 (1H, br),
1.72 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz); Enantiomeric
excess (%) at 12 h (ethanol/hexane 5/95 0.5 mL/min,
t1 = 16.1 min for the S enantiomer, t2 = 14.2 for the R
enantiomer) C1 = 48 (R), C2 = 15 (S), C3 = 15 (S),
C4 = 8 (S).
2.4d 1-(2-Naphthyl)ethanol:31 1H NMR (400 MHz,
CDCl3): δ 7.80 (m, 4H), 7.60 (m, 3H), 5.08 (q, 1H, J =
6.4 Hz), 1.98 (bs, 1H, OH), 1.57 (d, 3H, J = 6.4 Hz);
Enantiomeric excess (%) at 12 h (ethanol/hexane 5/95
0.5 mL/min, t1 = 26.4 min for the S enantiomer, t2 =
29.3 for the R enantiomer) C1 = 28 (R), C2 = 20 (S),
C3 = 34 (S), C4 = 4 (S).
C4: Yield: 72%; 1H NMR (400 MHz, CDCl3): δ 8.16
(q, 2H, NH2, J = 9.0 Hz), 7.19 (m, 1H, NH), 6.0 (d,
1H, J = 5.52 Hz), 5.82 (d, 1H, J = 5.6 Hz), 5.72 (d,
1H, J = 5.64 Hz), 5.70 (d, 1H, J = 5.76 Hz), 3.56 (m,
1H), 3.23 (m, 1H), 3.12 (m, 2H), 2.73 (m, 2H), 2.44
(s, 3H), 2.34 (m, 1H), 1.79 (m, 3H), 1.30 (dd, 6H, J =
6.8 Hz); Anal.Calcd for C15H26Cl2N2Ru: C 44.34; H
6.45; N 6.89, Found: C 44.81; H 6.79; N 7.13; ESI-
HRMS: m/z calculated for [C15H26N2RuCl]+: 371.0827
[M-Cl]+; found: 371.0828.
2.4e 1-(1-Naphthyl)ethanol:31 1H NMR (400 MHz,
CDCl3): δ 8.13 (d, 1H, J = 8.36 Hz), 7.88 (d, 1H, J =
7.68 Hz), 7.79 (d, 1H, J = 8.24 Hz), 7.69 (d, 1H, J =
7.28 Hz), 7.51 (m, 3H), 5.70 (q, 1H, J = 6.4 Hz), 2.08
(bs, 1H, OH) 1.68 (d, 3H, J = 6.4 Hz); Enantiomeric
excess (%) at 12 h (ethanol/hexane 5/95 0.5 mL/min,
t1 = 29.2 min for the S enantiomer, t2 = 41.0 for the R
enantiomer) C1 = 56 (R), C2 = 68 (S), C3 = 22 (S),
C4 = 2(S).
2.4f 1-Indanol:31 1H NMR (400 MHz, CDCl3): δ 7.40
(m, 1H), 7.27 (m, 3H), 5.26 (t, 1H, J = 6.0 Hz), 3.03(m,
1H), 2.82 (m, 1H), 2.51 (m, 1H), 1.96 (m, 2H); Enan-
tiomeric excess (%) at 12 h (isopropanol/hexane 2/98
0.9 mL/min, t1 = 19.8 min for the S enantiomer, t2 =
23.0 for the R enantiomer) C1 = 54 (S), C2 = 30 (S),
C3 = 22 (S), C4 = 2 (S).
2.4g 1-(4-Chlorophenyl)ethanol:32 34 1H NMR (400
MHz, CDCl3): δ 7.31 (m, 4H), 4.88 (q, 1H, J = 6.4
Hz), 1.90 (bs, 1H, OH), 1.47 (d, 3H, J = 6.4 Hz); Enan-
tiomeric excess (%) at 12 h (isopropanol/hexane 10/90
0.5 mL/min, t1 = 13.6 min for the S enantiomer, t2 =
14.5 for the R enantiomer) C1 = 22 (R), C2 = 28 (S),
C3 = 45 (S), C4 = 10 (S).
2.4 General procedure for the catalytic transfer
hydrogenation reaction
To a solution of a ruthenium catalyst (0.0168 mmol)
in degassed water (8 mL) was added a ketone (0.168
mmol) and sodium formate (0.84 mmol). The reaction
mixture was kept in a thermostat at 60◦C. 1 mL of the
solution from the reaction mixture was withdrawn at 1 h,
2 h and 12 h; extracted with 5 mL of ethyl acetate;
dried over anhydrous sodium sulphate and analyzed
1
by H NMR spectroscopy. Conversion was calculated
from the 1H NMR spectrum. Chiral alcohols were puri-
fied by preparative thin layer chromatography. Enan-
tiomeric excess (ee) was determined using the chiral
HPLC technique employing the Chiralcel OD column,
except in the case of 1-(4-Chlorophenyl)ethanol, 1-(2-
Chlorophenyl)ethanol, 1-(4-Nitrophenyl)ethanol), for
which it was determined using a Chiralcel OJ-H
column.
2.4a 1-(4-Methoxyphenyl)ethanol:31 1H NMR (400
MHz, CDCl3): δ 7.31 (d, 2H, J = 8.8 Hz), 6.89 (d, 2H,
J = 8.4 Hz), 4.87 (q, 1H, J = 6.4 Hz), 3.80 (s, 3H),
1.81 (1H, bs, OH), 1.48 (d, 3H, J = 6.4 Hz); Enan-
tiomeric excess (%) at 12 h (isopropanol/hexane 10/90
0.5 mL/min, t1 = 16.9 min for the S enantiomer, t2 =
15.9 for the R enantiomer) C1 = 50 (R), C2 = 16 (S),
C3 = 28 (S), C4 = 2 (S).
2.4h 1-(4-Bromophenyl)ethanol:32 34 1H NMR (400
MHz, CDCl3): δ 7.48 (d, 2H, J = 1.6 Hz), 7.28 (d, 2H,
J =1.2 Hz), 4.89 (q, 1H, J = 6.4 Hz), 1.85 (bs, 1H, OH),
1.49 (d, 3H, J = 6.8 Hz); Enantiomeric excess (%) at
2.4b α-Tetralol:31 1H NMR (400 MHz, CDCl3): δ 12 h (isopropanol/hexane 5/95 0.5 mL/min, t1 = 8.3 min
7.42 (m, 1H), 7.20 (m, 2H), 7.09 (m, 1H), 4.79 (q, 1H, for the S enantiomer, t2 = 9.4 for the R enantiomer)
J = 4.8 Hz), 2.73 (m, 2H), 1.92 (m, 2H), 1.76 (m, 3H). C1 = 28 (R), C2 = 12 (R), C3 = 38 (S), C4 = 2 (S).

Arun Kumar Pandia Kumar and Ashoka G Samuelson
2.4i 1-(2-Chlorophenyl)ethanol:32 34 1H NMR (400
t2 = 26.5 for the R enantiomer) C1 = 96 (S), C2 = 30
(R), C3 = 35 (S), C4 = 2 (S).
MHz, CDCl3): δ 7.58 (m, 1H), 7.31 (m, 2H), 7.20
(m, 1H), 5.30 (q, 1H, J = 6.32 Hz), 2.02 (bs, 1H, OH),
1.49 (d, 3H, J = 6.44 Hz); Enantiomeric excess (%)
at 12 h (isopropanol/hexane 10/90 0.5 mL/min, t1 =
10.9 min for the S enantiomer, t2 = 11.5 for the R
enantiomer) C1 = 38 (R), C2 = 18 (S), C3 = 24 (S),
C4 = 10 (S).
2.4m 1-(Furan-2-yl)ethanol:32 34 1H NMR (400
MHz, CDCl3): δ 7.38 (d, 1H, J = 1.94 Hz), 6.33 (d, 1H,
J = 1.4 Hz), 6.24 (d, 1H, J = 2.8 Hz), 4.90 (q, 1H, J =
6.56 Hz), 2.24 (bs, 1H, OH), 1.56 (d, 3H, J = 6.6 Hz);
Enantiomeric excess (%) at 12 h (ethanol/hexane 1/99
1.0 mL/min, t1 = 31.5 min for the S enantiomer, t2 =
28.3 for the R enantiomer) C1 = 86 (S), C2 = 36 (S),
C3 = 32 (S), C4 = 4 (S).
2.4j 1-(4-Nitrophenyl)ethanol:32 34 1H NMR (400
MHz, CDCl3): δ 8.22 (d, 2H, J = 8.8 Hz), 7.55 (d, 2H,
J = 8.4 Hz), 5.03 (q, 1H, J = 3.6 Hz), 2.10 (bs, 1H,
OH), 1.52 (d, 3H, J = 6.4 Hz); Enantiomeric excess (%)
at 12 h (ethanol/hexane 5/95 0.8 mL/min, t1 = 39.5 min
for the S enantiomer, t2 = 43.9 for the R enantiomer)
C1 = 20 (R), C2 = 20 (S), C3 = 46 (S), C4 = 6 (S).
2.5 Crystal Data
Crystals of ruthenium diamine complexes C2, C3 and
C4 suitable for X-ray diffraction study were carefully
picked and mounted on the goniometer head. The unit
cell parameters and intensity data were collected at
room temperature employing a Bruker SMART APEX
CCD diffractometer equipped with a MoKα X-ray
source (50 kV, 40 mA). Data acquisition was carried
out using SMART software and the data reduction
was carried out using SAINT software.35 The empirical
absorption corrections were carried out using the SAD-
ABS program.36 The structure was solved and refined
using the SHELXL-97 program.37 Hydrogen atoms
2.4k 4-Phenyl-2-butanol:32 34 1H NMR (400 MHz,
CDCl3): δ 7.28 (m, 3H), 7.20 (m, 2H), 3.83 (m, 1H), 2.7
(m, 2H), 1.78 (m, 2H), 1.24 (d, 3H, J = 6.2 Hz); Enan-
tiomeric excess (%) at 12 h (isopropanol/hexane 10/90
1.0 mL/min, t1 = 12.2 min for the S enantiomer, t2 =
8.6 for the R enantiomer) C1 = 84 (S), C2 = 84 (S),
C3 = 23 (S), C4 = 4 (S).
2.4l 2-Bromo-1-phenyl ethanol:32 34 1H NMR (400 were fixed in idealized positions and refined using a rid-
MHz, CDCl3): δ 7.30 (m, 5H), 4.80 (dd, 1H, J = ing model. The crystallographic details of C2, C3 and
3.2, 3.6 Hz), 2.68 (bs, 1H, OH), 3.63 (m, 2H); Enan- C4 have been summarized in Table 1. Crystallographic
tiomeric excess (%) at 12 h (isopropanol/hexane 2/98 data for C2, C3 and C4 have been deposited with the
1.0 mL/min, t1 = 22.1 min for the S enantiomer, Cambridge Crystallographic Data Centre in the cif files
Table 1. Crystal data and refinement details for C2, C3 and C4.
C2
C3
C4
Formula
Formula weight
C17H30Cl2N2Ru
434.40
C22H32Cl2N2Ru
496.47
C15H26Cl2N2Ru
406.05
Crystal system
Space group
Orthorhombic
P212121
293 (2)
9.1526 (6)
10.3465 (6)
20.2390 (12)
90.00
Orthorhombic
P212121
293 (2)
8.5597 (16)
9.354 (2)
28.647 (6)
90.00
Orthorhombic
P212121
293 (2)
8.3272 (4)
9.6615 (5)
22.0185 (9)
90.00
T (K)
a, Å
b, Å
c, Å
α, deg
β
90.00
90.00
90.00
γ
90.00
90.00
90.00
V, Å
Z
1916.6 (2)
4
1.505
2293.8 (8)
4
1.438
1771.46 (14)
4
d
calc, g cm−3
1.524
1.180
μ(mm−1
)
1.096
0.926
λ(Å)
0.71073
0.0475
0.0696
ꢀ
0.71073
0.0345
0.0785
0.71073
0.0272
0.0741
Ra
Rw
ꢀ
ꢀ
ꢀ
aR = (|Fo|- |Fc|)/ |Fo|, Rw = [ w(|Fo|- |Fc|)2/ w|Fo|2]1/2 (based on reflections with I>2σ(I)).

Asymmetric Transfer Hydrogenation by Ruthenium Complexes
1
of ligands was confirmed by H and 13C NMR spec-
troscopy.
CCDC 880005, 880004 and 885471 respectively. Data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Metal complexes were synthesized by carrying out
the reaction of ruthenium cymene dimer with chi-
ral (S)-N-substituted 2-aminomethylpyrrolidine ligands
(Scheme 4).40 The corresponding chiral ruthenium
complexes C1, C2, C3 and C4 were obtained as yellow
crystalline complexes whose structures were confirmed
by NMR, ESI-HRMS and X-ray crystallography.
The crystal structure of the ruthenium complex C1 is
already available in the literature40 while that of C2, C3
and C4 are reported in this paper. The molecular struc-
tures of three complexes are depicted in Figure 1. The
complexes were obtained as single diastereoisomers
crystallizing in the orthorhombic, chiral P212121 space
group. The configuration around the ruthenium center
3. Results and Discussion
Ligands were synthesized from the naturally occurring
chiral amino acid L-proline. (S)-N-phenyl-2-amino-
methylpyrrolidine L1 was prepared from L-proline by
reacting it with phosphorous pentachloride to give the
acid chloride. The resultant acid chloride was treated
with aniline in THF to yield N-phenyl-proline amide.
Finally, the amide was reduced with LiAlH4 to yield L1
(Scheme 1).38
The synthesis of (S)-N-ethyl L2 and (S)-N-benzyl-
2-aminomethylpyrrolidine L3 was however more cum-
bersome and involved the conversion of L-proline to
N-carbobenzoxy proline by reacting it with benzyl
chloroformate in the presence of a base. The resultant
N-carbobenzoxy proline was converted into N-carbo-
benzoxy-proline-p-nitrophenol ester using p-nitrophe-
nol and N,Nꢁ-Dicyclohexylcarbodiimide. To this ester
suitable amines (ethyl or benzyl amine) were added to
get the corresponding amides (ethyl or benzyl). The
amides thus obtained were subjected to hydrogenation
in the presence of Pd/C catalyst and molecular hydro-
gen followed by lithium aluminium hydride to give
diamine ligands as shown in Scheme 2 (ethyl L2 or
benzyl L3).39
Scheme 3. Synthesis of (S)-2-aminomethylpyrrolidine L4.
The 2-aminomethylpyrrolidine L4 ligand was pre-
pared from the L-proline amide which on reduction
with lithium aluminium hydride afforded the 2-amino-
methylpyrrolidine L4 ligand (Scheme 3).39 Formation
Scheme 4. Synthesis of chiral half-sandwich ruthenium
proline diamine complexes.
Scheme 1. Synthesis of (S)-N-phenyl-2-aminomethylpyrrolidine L1.
Scheme 2. Synthesis of (S)-N-ethyl (L2) or benzyl-2-aminomethylpyrrolidine (L3).

Arun Kumar Pandia Kumar and Ashoka G Samuelson
Figure 1. ORTEP view of C2, C3 and C4 at the 40% probability level showing selected atom labeling.
Hydrogen atoms are omitted for clarity.
based on the Cahn-Ingold-Prelog nomenclature gave S extrusion of carbon dioxide. The substrate will then
configuration in C2 and C4 wheras in C3 ruthenium coordinate to ruthenium and both H− and H+ will be
adopts the R configuration41 44 Details of the molec- transferred simultaneously to the ketone to yield the
ular structure are given in the supporting information. chiral alcohol in an intermediate such as 6. The resul-
Because the complexes are soluble in water, the transfer tant ruthenium amido complex 7 is a 16e− species that
hydrogenation reaction was carried out using sodium on reaction with sodium formate and water will regen-
formate as a reducing agent in water making the reac- erate the ruthenium sodium formate complex 3 and the
tion eco-friendly, benign, and convenient. The use of catalytic cycle continues as shown in Scheme 5.46
C1 has only been reported as a catalyst in isopropanol
and it was reported to be inactive in a mixture of triethyl stoichiometric reaction was carried out with sodium for-
amine-formic acid.45
mate and ruthenium diamine catalysts C1, C2, C3, and
To probe the formation of an intermediate like 5, a
In the proposed mechanism of transfer hydrogena- C4 as depicted in Scheme 6. The reaction was carried
tion of ketones in water, the first step is the formation out in a NMR tube where the ruthenium proline diamine
of an aqua complex 2 from the chloro complex 1, which catalyst was dissolved in 0.4 mL of D2O containing
reacts with sodium formate to form the ruthenium- sodium formate. The hydride formation was monitored
formate complex 3. The η4-mode of binding in 4 is by 1H NMR spectroscopy. Formation of the ruthenium
1
suggested to avoid the formation of a 20 electron com- hydride species was ascertained by H NMR spec-
plex en-route to the ruthenium hydride species 5 by trum where in all cases, hydride peaks were observed
Scheme 5. Proposed mechanism of transfer hydrogenation reaction of ketones in water.

Asymmetric Transfer Hydrogenation by Ruthenium Complexes
Scheme 6. Stoichiometric reaction of ruthenium proline
diamine complexes with HCOONa.
1
in the up-field region of the H NMR spectrum. The
Scheme 7. Transfer hydrogenation of acetophenone
hydride chemical shift values for 5C1: δ−6.93 ppm, employing deuterated sodium formate (DCOONa).
5C2: δ−7.63 ppm, 5C3: δ−7.43 ppm and 5C4: δ−7.46
ppm are shown in Figure 2. Formation of ruthenium in water (Scheme 7). It led to the formation of both 2a
hydride species of complex C1 was further confirmed and 2b.
1
2
by the mass spectrometry. HRMS (ESI) m/z calcu-
Formation of 2a and 2b was confirmed by H, H
lated for [C21H31N2Ru]+: 413.1530; found 413.1506. and 13C NMR spectroscopy. 2a showed a singlet in the
This study suggested that ruthenium catalysts C1, C2, 2H NMR spectrum at δ 4.88 ppm corresponding to the
C3 and C4 are forming the hydride which is probably deuterium and in the 1H decoupled 13C NMR spectrum
the active species in the reduction of ketones to form a triplet at δ 70.45 ppm corresponding to the α carbon
chiral alcohols.
attached to the deuterium atom. The C-D coupling con-
The transfer hydrogenation reaction was then stant is found to be 22.8 Hz. Ratio of 2a and 2b was
1
attempted with deuterated sodium formate (DCOONa). calculated from the H NMR spectrum. Table 2 lists
DCOONa on reaction with ruthenium proline diamine the ratio of 2a and 2b and the enantiomeric excess. In
complex will lead to the formation of ruthenium deu- the case of ruthenium catalyst C1 more of 2a was
teride species and subsequently the deuteride will observed compared to what was observed in the reac-
be transferred to the acetophenone to form 2a. If the tion with catalysts C2–C4.
deuteride attached to the Ru exchanges its deuterium
Ruthenium diamine catalysts were optimized with
with hydrogen in the solvent, it may lead to the forma- acetophenone as a model substrate. The catalyst, base,
tion of the ruthenium hydride species which will trans- and substrate were taken in 1:50:10 ratio and the reac-
fer the hydride to the acetophenone to give 2b. The tion was carried out at 60◦C. The reaction was moni-
1
reaction was carried out employing ruthenium catalysts tored by H NMR spectroscopy and the enantiomeric
C1, C2, C3, and C4 with acetophenone as a substrate excess was determined using a Chiralcel OD column.
Figure 2. 1H NMR spectra of hydrides of ruthenium diamine complexes C1, C2, C3 and C4 respectively.

Arun Kumar Pandia Kumar and Ashoka G Samuelson
Table 2. Ratio of 2a and 2b in the transfer hydrogenation reaction of
acetophenone with DCOONa.
Ratio of Productsa (%)
Entry
R
Conversion (%)
2a
2b
eeb (%)
1
2
3
4
-Ph
-Et
-CH2Ph
-NH2
96
82
82
82
89
79
78
73
11
21
22
27
22 (R)
20 (S)
24 (S)
8 (S)
1
aRatio of products are determined by H NMR and are an average of
two runs. bEnantiomeric excess is determined by chiral HPLC analysis
using Chiralcel OD column.
C1 afforded 93% of 1-phenyl ethanol with an enan- with catalysts C2, C3 and C4 were carried out without
tiomeric excess of 10% (R) at 12 h (Table 3, entry 1) silver nitrate.
but the maximum enantiomeric excess of 31% (R) was
C1 resulted in good yields of chiral alcohols with
obtained at 4h. Since the mechanism of transfer hydro- moderate to good enantioselectivities. Maximum enan-
genation reaction required generation of a vacant site at tiomeric excess of 96% (S) was obtained for 2-bromo-
ruthenium, the effect of silver ions to aid the formation 1-phenyl ethanol (entry 10, Table 4). An electron
of an aqua complex was probed. Reactions carried out withdrawing substituent on the ketone resulted in good
with 10 mol% and 20 mol% of AgNO3 showed almost yields of the chiral alcohol compared to yields with
quantitative conversion at 12 h (Table 3, entry 2 and an electron donating substituent. With difficult sub-
3). A catalyst loading of 10% appeared to be optimum strates such as α-tetralone (entry 12, Table 4) and
(Table 3, entry 4).
indanone (entry 13, Table 4), good enantioselectivi-
With C2, 85% conversion was observed after 12 h ties were observed with C1. The importance of using
and addition of AgNO3 provided little advantage. The silver nitrate as an additive appears to be more impor-
formation of S isomer of 1-phenylethanol was observed tant for sluggish substrates such as indanone. Forma-
(Table 3, entry 5 and 6). The same trend was observed tion of 1-indanol was observed with 50% conversion
with catalyst C3 (Table 3, entry 7 and 8) and C4 (Table in the presence of AgNO3, whereas reduced conversion
3, entry 9 and 10). In both cases, conversion was not was observed in the absence of an additive (entry 13,
enhanced in the presence of silver nitrate and the forma- Table 4).
tion of S isomer of 1-phenylethanol was observed. Only
Compared to C1, less conversion was observed with
with catalyst C1, silver nitrate was found to enhance C2 for most of the ketones. In the case of two substrates,
the yields. The transfer hydrogenation reaction was then the enantiomeric excess was higher with C2 than with
carried out with ketones having different electronic and C1 (entries 7 and 8, Table 4) although the yields were
steric demands. It was deemed necessary to use silver lower. The presence of AgNO3 was not enhancing
nitrate only in the case of catalyst C1 and so reactions the rate of the reaction, presumably because catalysts
Table 3. Transfer hydrogenation of acetophenone with catalysts C1, C2, C3 and C4a.
Conversionb (%)
eec (%)
4 h 12 h
Entry Catalyst amount Catalyst
Additive
4 h
12 h
Isolated Yield (%)
1
2
3
4
5
6
7
8
9
10 mol %
10 mol %
10 mol %
5 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
C1
C1
C1
C1
C2
C2
C3
C3
C4
C4
–
81
88
91
51
78
79
64
65
69
75
93
99
99
64
85
86
87
89
77
77
31 (R) 10 (R)
18 (R) 16 (R)
79
87
87
56
73
75
75
78
69
70
AgNO3 (10 mol %)
AgNO3 (20 mol %)
26 (R)
8 (R)
–
–
20 (R) 24 (R)
12 (S) 10 (S)
14 (S) 10 (S)
AgNO3 (20 mol %)
–
22 (S)
8 (S)
AgNO3 (20 mol %)
–
AgNO3 (20 mol %)
25 (S) 10 (S)
8 (S)
8 (S)
6 (S)
6 (S)
10
aReactions were carried out at 60◦C, the ratio of catalyst/ substrate/formate was 1:10:50. bThe conversion was determined by
1H NMR spectroscopy. cEnantiomeric excess was determined by chiral HPLC analysis using chiralcel OD column.

Asymmetric Transfer Hydrogenation by Ruthenium Complexes
Table 4. Transfer hydrogenation of various ketones with ruthenium catalysts C1, C2, C3 and C4.a
Conversionb (%)
Entry Catalysts
Substrate
Product
1 h
2h
12 h
% eec (R/S) Isolated Yield (%)
1
C1
C2
C3
C4
71
72
50
58
78
78
62
63
92
88
71
79
48 (R)
15 (S)
15 (S)
8 (S)
81
76
63
71
2
C1
C2
C3
C4
50
30
44
76
62
38
57
78
91
66
65
92
20 (R)
20 (S)
46 (S)
6 (S)
81
56
56
80
3
4
5
6
7
8
C1
C2
C3
C4
63
67
84
38
78
70
86
65
90
73
92
84
28 (R)
12 (R)
38 (S)
2 (S)
78
67
88
75
C1
C2
C3
C4
22
14
12
51
35
17
17
52
81
30
26
55
50 (R)
16 (S)
28 (S)
2 (S)
72
19
18
49
C1
C2
C3
C4
86
71
78
49
92
71
84
57
93
76
85
78
38 (R)
18 (S)
24 (S)
10 (S)
80
68
80
72
C1
C2
C3
C4
71
81
78
38
77
89
83
48
84
90
88
74
22 (R)
28 (S)
45 (S)
10 (S)
71
82
86
69
C1
C2
C3
C4
68
24
45
38
71
28
52
55
82
37
68
57
84 (S)
84 (S)
23 (S)
4 (S)
73
28
61
52
C1
C2
C3
C4
44
30
33
29
62
44
50
56
75
49
64
64
56 (R)
68 (S)
22 (S)
2 (S)
67
40
54
57
9
C1
C2 C3
C4
65
35 35
24
71
66 52
34
78
72 61
54
28 (R)
20 (S) 34 (S)
4 (S)
69
62 53
48
10
C1
C2
C3
C4
71
48
71
63
Quanti-tative
–
96 (S)
30 (R)
35 (S)
2 (S)
86
87
92
85
81
86
Quanti-tative
Quanti-tative
–
Quanti-tative
11
12
C1
C2
C3
C4
70
36
42
34
85
42
48
71
88
43
51
78
86 (S)
36 (S)
32 (S)
4 (S)
76
33
45
70
C1
C2
C3
C4
17
11
20
17
26
16
24
21
74
26
32
26
74 (S)
36 (S)
74 (S)
12 (S)
68
18
26
20

Arun Kumar Pandia Kumar and Ashoka G Samuelson
Table 4. (continued)
Conversionb (%)
Entry
13
Catalysts
Substrate
Product
1 h
2h
12 h
% eec (R/S)
Isolated Yield (%)
C1
C1
C2
C2
C3
C3
C4
C4
28
16d
15
38
28
17
20
16
20
17
25
50
30
27
34
23
25
32
36
54 (S)
48 (S)
30 (S)
30 (S)
22 (S)
24 (S)
2 (S)
35
19
19
28
17
20
27
29
16e
14
20e
13
16e
3 (S)
aReactions were carried out at 60◦C, the ratio of catalyst/ substrate/formate was 1:10:50. Conversion was determined by 1H
NMR spectroscopy. cEnantiomeric excess was determined by chiral HPLC analysis of the reaction mixture after 12 hrs using
d
a Chiralcel OD column excluding substrates in entries 2, 5 and 6 where chiral OJ-H column was used. Without AgNO3.
eWith AgNO3.
other catalysts exhibited no change with addition of
silver nitrate. The catalyst C1 with the phenyl group
delivers the best yield and induces higher enantioselec-
tivity compared to the other catalysts that are studied
in most cases. This suggests that the observations made
by Noyori on the influence of C-H··· π interactions
C2–C4 were readily hydrolyzed. This can be under-
stood in the reaction with indanone as a substrate (entry
13, Table 4) where the rates were limited by subsequent
slow steps. Although very good enantiomeric excess is
observed in the formation of α-tetralol 74% (S) (entry
12, Table 4) with C3, the better yield obtained with
C1 makes it a clear winner. Lower enantioselectivi- between the catalyst and the substrate leading to bet-
ties were obtained for all ketones with C4 compared to ter enantioselectivity might be a general phenomenon
C1. Interestingly, the best enantiomeric excess obtained worthy of systematic exploitation.
with catalyst C4 was in the case of α-tetralol (12% (S)
(entry 12, Table 4).
Supplementary Information (SI)
Recycling the catalyst is an added advantage while
Mass spectra of complexes (S2–S6), 1H NMR spectrum
working with precious metals. After 12 h of reaction
1
of ligands and complexes (S7–S19), H NMR spec-
with acetophenone and C1 (10 mol%) in the presence of
trum of deuterated and undeuterated 1-phenylethanol
(S20–S27) and HPLC chromatogram of chiral alcohols
(Figures S28–S42) are given in the Supporting Informa-
tion, available at www.ias.ac.in/chemsci.
HCOONa, formation of 1-phenylethanol was observed
with 92% conversion (an average of two runs). The
product and the residual starting material were removed
by extraction with ethyl acetate and a fresh batch of
the substrate was added to initiate the next cycle. Three
cycles could be run in this fashion after removal of the
organic reactants and products without significant loss
in the conversion in the subsequent batch.
Acknowledgements
A.G.S. thanks DST, New Delhi for the award of a
research grant and A.K. gratefully acknowledges a
senior research fellowship from CSIR. Authors thank
DST, New Delhi, for providing funds through the FIST
program for purchase of a 400 MHz NMR spectrometer.
4. Conclusions
Chiral half-sandwich ruthenium proline diamine com-
plexes C1, C2, C3 and C4 are readily prepared from
the proline-derived diamine ligands L1, L2, L3 and L4.
These complexes are excellent catalysts for the transfer
hydrogenation of ketones in water. Stoichiometric reac-
tion of C1, C2, C3 and C4 with sodium formate showed
the formation of a ruthenium-hydride as the most prob-
able species involved in the reduction of ketones. C1
was successfully recycled without affecting the conver-
sion during the transfer hydrogenation of acetophenone.
The yield in this reaction was enhanced in the pres-
ence of silver nitrate when C1 was the catalyst whereas
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