Biaryl diphosphine ligands and their ruthenium complexes: Preparation and use for catalytic hydrogenation of ketones

Article abstract of DOI:10.1016/j.ica.2020.119850

Procedures for the preparation of the nucleophilic diphosphine ligands (R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((R)-Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((S)-Ph-Garphos, 2b) were described. The ligands were used to prepare the ruthenium(II) Ph-Garphos complexes, chloro(p-cymene)(R)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Ph-Garphos]Cl (3)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Ph-Garphos]Cl (4)). In the presence of the chiral diamine co-ligands (1R,2R)-1,2-diphenylethane-1,2-diamine (R,R-DPEN) and (1S,2S)-1,2-diphenylethane-1,2-diamine (S,S-DPEN), complexes 3 and 4 were found to be catalyst precursors for the enantioselective reduction of aryl ketones under mild conditions (room temperature and 3–4 atm of H₂). The chiral alcohols were isolated in moderate to good yields and with enantioselectivities of up to 93percent. The ruthenium complexes chloro(p-cymene)(R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Xyl-Garphos]Cl (6)) were also prepared and used as catalyst precursors for the hydrogenation of aryl ketones in the presence of (R,R)-DPEN and (S,S)-DPEN. Significant improvements in the enantioselectivities of the alcohols (up to 98percent ee.) were afforded. A combination of 6 and (S,S)-DPEN afforded (R)-1-(3-methoxyphenyl)ethanol in 89percent yield and with 95percent ee which was shown to be a suitable precursor for the preparation of (S)-rivastigmine.

Full text of DOI:10.1016/j.ica.2020.119850

InorganicaChimicaActa511(2020)119850
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Research paper
Biaryl diphosphine ligands and their ruthenium complexes: Preparation and
use for catalytic hydrogenation of ketones
Shannen Lorrainea, Kamaluddin Abdur-Rashidb, Wenli Jiab, Kareem Abdur-Rashidb,
⁎
⁎
Paul Maragha, , Tara Dasguptaa,
a Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica
b Kamal Pharmachem Inc., 3403 American Drive, Mississauga Ontario, L4V 1T4, Canada
A R T I C L E I N F O
A B S T R A C T
Keywords:
Procedures for the preparation of the nucleophilic diphosphine ligands (R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-
diyl)bis(diphenylphosphine) ((R)-Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphe-
nylphosphine) ((S)-Ph-Garphos, 2b) were described. The ligands were used to prepare the ruthenium(II) Ph-
Garphos complexes, chloro(p-cymene)(R)-(4,4′,6,6′-tetraamethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ru-
thenium(II) chloride ([RuCl(p-cymene)(R)-Ph-Garphos]Cl (3)) and chloro(p-cymene)(S)-(4,4′,6,6′-tetra-
amethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine)ruthenium(II) chloride ([RuCl(p-cymene)(S)-Ph-Garphos]Cl
(4)). In the presence of the chiral diamine co-ligands (1R,2R)-1,2-diphenylethane-1,2-diamine (R,R-DPEN) and
(1S,2S)-1,2-diphenylethane-1,2-diamine (S,S-DPEN), complexes 3 and 4 were found to be catalyst precursors for
the enantioselective reduction of aryl ketones under mild conditions (room temperature and 3–4 atm of H2). The
chiral alcohols were isolated in moderate to good yields and with enantioselectivities of up to 93%. The ru-
thenium complexes chloro(p-cymene)(R)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-
phosphine)ruthenium(II) chloride ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5)) and chloro(p-cymene)(S)-(4,4′,6,6′-
Diphosphines
Hydrogenation
Aryl ketones
Garphos
Rivastigmine synthesis
tetramethoxybiphenyl-2,2′-diyl)bis(bis(3,5-dimethylphenyl)-phosphine)ruthenium(II)
chloride
([RuCl(p-
cymene)(S)-Xyl-Garphos]Cl (6)) were also prepared and used as catalyst precursors for the hydrogenation of aryl
ketones in the presence of (R,R)-DPEN and (S,S)-DPEN. Significant improvements in the enantioselectivities of
the alcohols (up to 98% ee.) were afforded. A combination of 6 and (S,S)-DPEN afforded (R)-1-(3-methox-
yphenyl)ethanol in 89% yield and with 95% ee which was shown to be a suitable precursor for the preparation of
(S)-rivastigmine.
1. Introduction
of ketones is the trans-RuCl2(BINAP)(diamine) system which was de-
veloped by Noyori and co-workers [6-10]. It is believed that the high
The enantioselective reduction of carbonyl and iminocarbonyl
compounds is one of the most efficient methods for the preparation of
chiral alcohols and amines which are common substructures in many
pharmaceutical products [1-3]. One such example is (R)-1-(3-methox-
yphenyl)ethanol which serves as a precursor to the drug (S)-rivas-
tigmine (Scheme 1). (S)-Rivastigmine, (S)-3-[1-(dimethylamino)ethyl]
phenyl ethyl (methyl) carbamate, represents one of the most potent
drugs for the treatment of mild-to-moderate dementia of the Alzhei-
mer’s type, Parkinson’s disease and Lewy bodies [4,5]. Consequently,
several catalytic systems which afford high efficiency and enantios-
electivity for the preparation of such chiral pharmachores have been
explored (Fig. 1).
efficiency of Noyori’s ternary catalyst originated from the donor–-
acceptor bifunctionality, and that basic (and reductive) conditions fa-
cilitated the formation of the active ruthenium dihydride catalytic
species [7,8,11-14]. Since then, ruthenium complexes of the type
RuCl2(diphosphine)(diamine) are recognized as some of the most ef-
fective catalysts for the asymmetric hydrogenation of aromatic, het-
eroaromatic and α,β-unsaturated ketones [15-26]. Over the years, di-
phosphines such as Phanephos [27,28], P-Phos [29], and Cn-TunePhos
[30] have demonstrated similar efficiency, or exceeded, that of BINAP.
The spiro diphosphine SDP ligands have also demonstrated high effi-
ciency in the asymmetric hydrogenation of racemic α-arylcyclohex-
anones, α-arylaldehydes and α,β-unsaturated acids [31,32]. The Sun-
phos class of ligands are effective for the reduction of α- and β-
One of the most efficient catalysts for the asymmetric hydrogenation
⁎ Corresponding authors.
E-mail addresses: paul.maragh@uwimona.edu.jm (P. Maragh), tara.dasgupta@gmail.com (T. Dasgupta).
https://doi.org/10.1016/j.ica.2020.119850
Received 17 December 2019; Received in revised form 12 April 2020; Accepted 19 June 2020
Availableonline23June2020
0020-1693/©2020ElsevierB.V.Allrightsreserved.

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
(60 mL) was added to a Schlenk flask (250 mL) with magnesium (1.2 g,
49.9 mmol), I2 (10 mg) and THF (40 mL). The mixture was refluxed for
2 h and then cooled to room temperature. The resulting light brown
solution was transferred to another flask (250 mL) and then cooled to
−78 °C. Chlorodiphenylphosphine (11 g, 49.9 mmol) in THF (30 mL)
was added at −78 °C. The mixture was stirred at −78 °C for 1 h, then it
was slowly warmed up to room temperature and stirred at room tem-
perature for 1 h. Water (50 mL) was added to the reaction mixture, then
H2O2 (30%, 13 mL) was added dropwise at 0 °C. The resulting mixture
was stirred for 30 min. The organic layer was separated and the aqu-
eous layer was extracted with ethyl acetate (50 mL × 2). The combined
organic layer was washed thoroughly with NaHSO3 (20%, 100 mL × 3)
and brine (100 mL × 2) and dried over MgSO4. It was filtered and the
solvent was removed to give a viscous oil which was purified with
crystallization (CH2Cl2/hexane = 1/20) to give the product as a col-
orless solid (15.2 g, Yield: 97.5%). 1H NMR (300 MHz, CD2Cl2) δ:
7.72–7.64 (m, 4H), 7.60–7.54 (m, 2H), 7.52–7.45 (m, 4H), 6.79 (dd,
2H, 1J = 2.1 Hz, 2J = 13.2 Hz), 6.64 (t, 1H, J = 2.1 Hz), 3.77 (s, 6H).
31P NMR (121.5 MHz, CD2Cl2) δ: 29.03. 13C (75 MHz, CD2Cl2) δ:
161.18 (d, J = 17.6 Hz), 135.17 (d, J = 102 Hz), 132.99 (d,
J = 103 Hz), 132.12 (d, J = 2.9 Hz), 132.11 (d, J = 9.8 Hz), 109.87 (d,
J = 10.9 Hz), 103.91 (d, J = 2.3 Hz), 55.74.
Scheme 1.
ketoesters, β-ketosulfones, polyfunctionalized ketones, aryl-pyridyl ke-
tones and substituted ferrocenyl ketones [33,34]. Despite the recent
successes however, improvements in asymmetric hydrogenations in-
clude access to more selective ligand systems, lower hydrogen pressure,
and expanding the range of substrates [35-43].
To this end, we explore the use of the diphosphine ligands (R)-
(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) ((R)-
Ph-Garphos, 2a) and (S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis
(diphenylphosphine) ((S)-Ph-Garphos, 2b) as chiral auxiliaries, and the
ruthenium(II)
Ph-Garphos
complexes
([RuCl(p-cymene)(R)-Ph-
Garphos]Cl (3) and RuCl(p-cymene)(S)-Ph-Garphos]Cl (4)) as air-stable
catalyst precursors for the asymmetric hydrogenation of ketones.
Neutral RuCl2(diphosphine)(diamine) complexes have been extensively
reviewed in the literature. However the use of cationic ruthenium(II)
complexes of the type ([RuCl(p-cymene)(diphosphine)]Cl has scarcely
received any attention. We believe these readily accessible cationic
ruthenium(II) complexes, in combination with the diamine ligands,
(R,R)-DPEN and (S,S)-DPEN, should lead to highly efficient catalytic
systems for practical applications. Furthermore, ruthenium complexes
containing the 3,5-dimethylphenyl-substituted ligands such as RuCl2-
[(S)-Xyl-BINAP][(S)-DAIPEN] and its R,R isomer [44-48], RuCl2-[(R)-
Preparation of (2-bromo-3,5-dimethoxyphenyl)diphenylpho-
sphine oxide (1b): N-bromosuccinimide (NBS) (6.7 g, 37.6 mmol) was
added to a solution of (3,5-dimethoxyphenyl)diphenylphosphine oxide
(12.3 g, 36.4 mmol) in CH2Cl2 (140 mL) at 0 °C. The resulting sus-
pension was stirred at 0 °C for 1 h. Na2CO3 (saturated, 40 mL) was
added to quench the reactions. It was stirred at room temperature for
30 min. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (40 mL × 2). The combined organic layer was
washed with brine and dried over MgSO4. It was filtered and the solvent
was removed to give the crude product as a pale yellow solid (14.3 g,
94% yield). It was sufficiently pure for the next step. The pure sample
was obtained by recrystallization from CH2Cl2/hexane (1/15). 1H NMR
(300 MHz, CD2Cl2) δ: 7.73–7.67 (m, 4H), 7.62–7.56 (m, 2H), 7.53–7.46
(m, 4H), 6.69 (d, 1H, J = 3 Hz), 6.57 (dd, 1H, 1J = 3 Hz,
2J = 14.1 Hz), 3.89 (s, 3H), 3.68 (s, 3H). 31P NMR (121.5 MHz, CD2Cl2)
δ: 30.72.
Xyl-PhanePhos][(S,S)-DPEN]
[27],
RuCl2-[(S)-Xyl-P-Phos][(R,R)-
DPEN] [29], RuCl2-[(S)-Xyl-SDP][(R,R)-DPEN] [49], amongst others
[50,51], have demonstrated remarkable activity and enantioselectivity
for the asymmetric hydrogenation of ketones. As such, the activity of
the analogous [RuCl(p-cymene)(R)-Xyl-Garphos]Cl (5) /(R,R)-DPEN)
and [RuCl(p-cymene)(S)-Xyl-Garphos]Cl (6) /(S,S)-DPEN systems, was
compared to complexes 3 and 4.
2. Experimental
Preparation of (R,S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)
bis(diphenylphosphine oxide) (1c): Copper powder (5.81 g,
91.5 mmol) was added to a solution of (2-bromo-3,5-dimethoxyphenyl)
diphenylphosphine oxide (12.7 g, 30.5 mmol) in DMF (50 mL). Iodine
(100 mg) was then added. The resulting suspension was stirred at
140 °C for 2 h after which, DMF was removed under vacuum. To the
residues, CHCl3 (200 mL) was added, and the mixture stirred for an
additional 30 min. The solid was filtered and washed with CHCl3
(20 mL). The combined filtrate was washed with aqueous ammonia
(5%, 200 mL × 2), brine (20%, 200 mL × 1) and dried over MgSO4.
The solid was filtered and washed with CHCl3 (20 mL). The solvent was
removed from the filtrate to give the crude product as an off-white solid
which was purified by recrystallization from CH2Cl2/ether (10/200) to
give the pure product as a colorless solid (6.2 g, 60.3% yield).
Resolution of (R,S)-(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)
bis(diphenylphosphine oxide) (rac-1c): L-(-)-DBTA monohydrate
(3.49 g, 9.28 mmol) in Et2O (30 mL) was added to a solution of
(4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine
oxide) (6.2 g, 9.2 mmol) in CH2Cl2 (30 mL). Another portion of Et2O
(120 mL) was added to the mixture. The resulting suspension was
stirred for 30 min. The solid was filtered, washed with ether (20 mL)
and dried to give the product as a colorless, crystalline solid which was
stirred with CH2Cl2/ether (100 mL/150 mL) for 1 h. The white crys-
talline solid was filtered and then stirred with another portion of
CH2Cl2/ether (80 mL/120 mL) for 1 h. The colorless crystalline solid
was filtered and washed with ether (20 mL) and dried under vacuum to
give a colorless solid which was dissolved in CH2Cl2 (150 mL) and
washed with NaHCO3 (saturated, 100 mL × 2). The organic layer was
All manipulations involving air- and moisture-sensitive materials
were performed under an inert, dry atmosphere of nitrogen or argon.
The solvents were purified using standard procedures [52] and, where
necessary, were distilled under argon or nitrogen atmosphere using the
appropriate drying agent. The [RuCl2(p-cymene)]2 metal precursor,
(R)- and (S)-Xyl-Garphos ligands, and the 1,2-diamine co-ligands,
TsDPEN and DPEN, were obtained from Kamal Pharmachem Inc. The
ketone substrates were obtained from commercial suppliers and used
without further purification. GC analysis was carried out on a Hewlett-
Packard 6890 gas chromatograph equipped with a 5973 MSD detector
and β-DEX 120 chiral capillary column (30 m × 0.25 mm; Supelco.,
USA). HPLC analysis was done using a Agilent Technologies 1200 Series
HPLC. 1H- and 13C NMR analysis were performed on a Bruker ACE 200,
a Bruker 400 or Bruker 500 MHz Fourier Transform (FT) spectrometer
and referenced to the residual protons in the deuterated solvents.
Chemical shifts are reported in parts per million (δ or ppm) relative to
tetramethylsilane (TMS). Optical rotation measurements were per-
formed on an Anton Parr MCP 300 polarimeter, using a sodium lamp
with a wavelength of 589 nm at 20 °C. All measurements were con-
ducted using a cell of path length 0.5 dm using dichloromethane or
chloroform as solvent and the average of 5 readings.
2.1. Preparation of Ph-Garphos ligands
Preparation
of
(3,5-dimethoxyphenyl)diphenylphosphine
oxide (1a): 1-Bromo-3,5-dimethoxybenzene (10 g, 46.1 mmol) in THF
2

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
Fig. 1. Chiral Garphos ligands.
dried over MgSO4. It was filtered and the solvent was removed from the
4J = 1.0 Hz, CH), 5.95 (d, 1H, 3J = 7 Hz, CH), 5.79 (d, 1H,
4J = 2.2 Hz, CH), 4.62 (s, 1H, CH), 4.27 (d, 1H, 3J = 7 Hz, CH), 3.65 (s,
3H, OCH3), 3.61 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 3.30 (s, 3H, OCH3),
3.07 (septet, 1H), 2.01 (s, 3H, CH3), 1.37 (d, 3H, 3J = 7 Hz, CH3), 0.10
(d, 3H, 3J = 6.5 Hz, CH3). 31P{1H} NMR (500 MHz, CDCl3): δ 41.4
(JPP = 63.7 Hz) and 27.0 (JPP = 61.7 Hz). 13C NMR (500 MHz, CDCl3):
δ 159.5, 159.4, 159.0, 157.9, 136.8, 135.8, 135.3, 134.7, 131.3, 131.1,
131.0, 130.6, 129.9, 129.3, 129.2, 128.1, 128.0, 127.8, 126.6, 125.2,
124.8, 121.7, 117.0, 112.0, 110.9, 110.5, 109.1, 105.3, 104.3, 100.9,
99.9, 96.6, 84.7, 55.9 (OCH3), 54.9 (OCH3), 54.6 (OCH3), 54.2 (OCH3),
filtrate to give (S)-Garphos oxide as a colorless solid (2.3 g, 74.2%,
99.5% ee) [ ]2D5 115. 2 (c 0.95, CH2Cl2). The combined mother liquor
°
was neutralized with NaHCO3 to give the (R)-enriched phosphine oxide
(3.9 g) which was resolved with D-(+)-DBTA (2.1 g). The enantiopure
product was freed with NaHCO3 to give the (R)-form enantiomer as a
colorless crystalline solid (2.7 g, 87.1% yield, 99.9% ee). [ ]2D5 + 114. 6°
(c 0.99, CH2Cl2). (HPLC: Chiralpak IA column 0.46 cm × 25 cm. 2-
PrOH/hexane
=
40/60,
1
mL/min, 25 °C, 254 nm. (S)-
form = 9.55 min, (R)-form = 5.88 min.
30.0 (CH3), 23.1 (CH3), 21.4 (CH3), 19.1 (CH3). [ ]2D0 + 247. 2 (c 0.1,
°
Preparation of (R)-4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl-bis
(diphenylphosphine) (2a): HSiCl3 (0.2 mL, 268 mg, 1.98 mmol) was
added to a suspension of (R)-4,4′,6,6′-tetramethoxy-biphenyl-2,2′-diyl-
bis(diphenylphosphineoxide) (50 mg, 0.074 mmol) in toluene (6 mL).
The resulting mixture was refluxed for 20 h under Ar. It was cooled to
room temperature and NaOH (2 N, 30 mL) was added and the resulting
mixture was stirred at 50 °C for 30 min. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (30 mL). The
combined organic layer was washed with brine and dried over MgSO4.
It was filtered through a silica gel pad. The solvent was removed to give
the product as a white solid (40 mg, 84%). 1H NMR (300 MHz, CD2Cl2)
δ: 7.35–7.24 (m, 16H), 7.18–7.11 (m, 4H), 6.33 (d, J = 2.1 Hz, 2H),
6.24–6.21 (m, 2H), 3.62 (s, 6H), 3.15 (s, 6H). 31P NMR (121.1 MHz,
CD2Cl2) δ: −12.32.
CHCl3).
[RuCl(p-cymene)((S)-Ph-Garphos)]Cl (4). Yield: 953 mg, 98%;
mp. 170 °C (decomp.). 1H NMR (500 MHz, CDCl3): δ 7.94 (m, 2H, aryl-
H), 7.76 (m, 2H, aryl-H), 7.61 – 7.36 (m, 14H, aryl-H), 7.00 (d, 1H,
4
3J = 5.8 Hz, CH]), 6.57 (t, 1H, JHP = 2.0 Hz, CH), 6.51 (dd, 1H,
3JHP = 11.5 Hz, CH), 6.13 (d, 1H, 4J = 1.0 Hz, CH), 5.94 (d, 1H,
3J = 7.6 Hz, CH), 5.78 (d, 1H, 4J = 2.2 Hz, CH), 4.62 (s, 1H, CH), 4.26
(d, 1H, 3J = 7 Hz, CH), 3.63 (s, 3H, OCH3), 3.59 (s, 3H, OCH3), 3.39 (s,
3H, OCH3), 3.29 (s, 3H, OCH3), 3.06 (septet, 1H), 2.00 (s, 3H, CH3),
1.35 (d, 3H, 3J = 7 Hz, CH3), 0.10 (d, 3H, 3J = 6.8 Hz, CH3). 31P{1H}
NMR (500 MHz, CDCl3):
δ 41.4 (JPP = 74.7 Hz) and 27.0
(JPP = 68.8 Hz). 13C NMR (500 MHz, CDCl3): δ 159.9, 159.5, 159.2,
158.9, 158.1, 157.8, 137.1, 136.2, 135.3, 134.5, 134.0, 132.4, 131.4,
131.2, 130.6, 129.4, 128.8, 128.0, 126.8, 126.2, 125.4, 124.4, 123.1,
122.9, 122.6, 121.5, 117.4, 117.2, 112.3, 110.2, 109.3, 105.2, 104.0,
100.9, 99.9, 96.8, 96.6, 85.7, 55.9, 55.0 (d, OCH3), 30.0 (CH3), 24.0,
23.0, 21.4 (CH3), 19.1 (CH3). [ ]2D0 277. 6° (c 0.1, CHCl3).
Preparation of (S)-4,4′,6,6′-tetramethoxybiphenyl-2,2′-diyl-bis
(diphenylphosphine) (2b): (S)-4,4′,6,6′-tetramethoxy-biphenyl-2,2′-
diyl-bis(diphenylphosphine) was prepared from (S)–4,4′,6,6′-tetra-
methoxy-biphenyl-2,2′-diyl-bis(diphenylphosphineoxide) using the
procedure outlined above. The product was isolated as a white solid
(44 mg, 92%). 1H NMR (300 MHz, CD2Cl2) δ: 7.34–7.25 (m, 16H),
7.18–7.12 (m, 4H), 6.32 (d, J = 2.1 Hz, 2H), 6.23–6.21 (m, 2H), 3.61
(s, 6H), 3.14 (s, 6H). 31P NMR (121.1 MHz, CD2Cl2) δ: −12.34.
2.3. General procedure for the hydrogenation of ketones with DPEN
In a typical catalytic run, a solid sample of t-BuOK (0.12 mmol, 10
equiv.) was added to a 100 mL Parr pressure reactor containing a stir
bar. To this, a solution of the ketone (12 mmol, 1000 equiv) dissolved in
2-propanol (5 mL) was added. The reactor was then purged 3–4 times
with hydrogen gas at 30 psi. This was followed by the addition of a
mixture of Ru(II)-Garphos (1 equiv., 0.1 mol%) and the co-ligand DPEN
(0.012 mmol, 1 equiv.) dissolved in 2-propanol (5 mL). The reactor was
then purged 3–4 times with hydrogen gas at 30 psi then pressurized
with hydrogen gas at 50–60 psi. At the end of the reaction, the mixture
was filtered through a short pad of silica gel, transferred and made up in
a volumetric flask prior to injection on the GC column. The pure pro-
duct was isolated upon removal of the solvent by vacuum distillation
and purification of the residue by silica gel chromatography using
hexane/ethyl acetate (5/1) as eluent.
2.2. Preparation of ruthenium(II) Ph-Garphos complexes
A mixture of Ph-Garphos ligand (658 mg, 1.02 mmol) and [RuCl2(p-
cymene)]2 (306 mg, 0.5 mmol) was dissolved in methanol (5 mL) under
an atmosphere of nitrogen. The mixture was then heated at 55 °C for 1 h
in a preheated water bath. At the end of the reaction, the solvent was
removed under vacuum and the residue was re-dissolved in dried
CH2Cl2 (5 mL). The mixture was slowly added to hexane (25 mL) to
precipitate a yellow to yellow-green solid which was then filtered and
dried under vacuum.
[RuCl(p-cymene)((R)-Ph-Garphos)]Cl (3). Yield: 920 mg, 98%;
mp. 170 °C (decomp.). 1H NMR (500 MHz, CDCl3): δ 7.98 (m, 2H, aryl-
H), 7.96 (m, 4H, aryl-H), 7.79 (m, 2H, aryl-H), 7.78–7.74 (dd, 4H, aryl-
H), 7.60–7.50 (m, 10H, aryl-H), 7.43–7.39 (m, 3H, aryl-H), 7.29 (m,
2.4. Preparation of (S)-Rivastigmine
3H, aryl-H), 7.00 (d, 1H, 3J
= 5.8 Hz, CH), 6.62 (dd, 1H,
3
3JHP = 11.5 Hz, CH), 6.55 (dd, 1H, JHP = 11.5 Hz, CH), 6.14 (d, 2H,
Preparation of (R)-1-(3-methoxyphenyl)ethanol (8e): A solution
3

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
Scheme 2. Synthesis of Ph-Garphos ligands.
of 1-(3-methoxyphenyl)ethanone (1.0 g, 6.7 mmol) dissolved in 2-
propanol (5 mL) was added to t–BuOK (7 mg, 0.06 mmol) in a 100 mL
Parr pressure reactor containing a stir bar. The mixture was purged 4
times with hydrogen gas at 30 psi. A mixture of 6 (7 mg, 0.007 mmol)
and (S,S)-DPEN (1.4 mg, 0.007 mmol) in 2-propanol (5 mL) was added
and the mixture was then purged 4 times with hydrogen gas at 30 psi
then pressurized with hydrogen gas at 60 psi. The mixture was stirred
for 6 h at room temperature. It was then transferred to a round bottom
flask and the solvent was removed under reduced pressure. Hexanes
was added and the solution was filtered through a short pad of silica gel
to remove the catalyst residue. The solvent was evaporated under re-
duced pressure to give the product as a colorless oil. Yield = 1.06 g
(99%); 95% ee.
(3 × 10 mL) and the combined organic layers were dried (MgSO4) and
the solvent removed under reduced pressure. The residue was purified
by flash chromatography to give the product as a pale yellow oil. Yield:
1.07 g; 91%. The NMR results are consistent with those reported in the
literature [53].
Preparation of (S)-3-(1-(dimethylamino)ethyl)phenol (10e):
Hydrogen bromide (5 mL of a 48% aqueous solution) was added to (S)-
1-(3-methoxyphenyl)-N,N-dimethylethanamine (1.0 g, 5.6 mmol) in a
Teflon-stoppered Schlenk flask and the mixture was heated for 12 h at
100 °C. It was cooled to room temperature and quenched with K2CO3
solution until the mixture was basic. The mixture was extracted with
ethyl acetate (3 × 25 mL) and the organic layers were combined and
dried over MgSO4. It was filtered and the solvent was evaporated under
reduced pressure. The crude product was purified by flash chromato-
graphy to give the product as a white solid. Yield: 0.87 g (94%). The
NMR results are consistent with those reported in the literature [53].
Preparation of (S)-3-(1-(dimethylamino)ethyl)phenyl ethyl
(methyl)carbamate (11e): Ethyl acetate (10 mL) was added to a
mixture of (S)-3-(1-dimethylaminoethyl)phenol (0.80 g, 4.8 mmol),
K2CO3 (1.00 g, 7.3 mmol) and N-ethyl-N-methyl carbamoyl chloride
(0.65 g, 5.3 mmol) under argon and the mixture refluxed for 6 h. It was
cooled to room temperature and water (10 mL) was added and the
phases were separated. The aqueous layer was extracted with ethyl
acetate (3 × 10 mL) and the combined organic layers were dried
(MgSO4) and the solvent removed under reduced pressure. The crude
product was purified by flash chromatography to give the product as a
pale yellow oil. Yield: 1.15 g (95%). The NMR results are consistent
Preparation of (S)-1-(3-methoxyphenyl)-N,N-dimethylethana-
mine (9e): Triethylamine (1.0 g, 10 mmol) was added to a solution of
(R)-1-(3-methoxyphenyl)ethanol (1.0 g, 6.6 mmol) in THF (10 mL)
under argon. The mixture was cooled to 0 °C and methanesulfonyl
chloride (1.14 g, 10 mmol) was added dropwise. The resulting sus-
pension was stirred for 3 h at room temperature. All the volatiles were
then removed under vacuum, then dimethylamine solution (20 mL of a
2.0 M in THF) was added and the mixture stirred at room temperature
for 12 h. Another portion of dimethylamine solution (20 mL) was added
and the mixture stirred for another 12 h. The mixture was then eva-
porated under vacuum and water (10 mL) was added to the residue,
followed by sodium hydroxide solution (1.0 M) until the mixture was
basic. Ethyl acetate (10 mL) was then added and the layers were se-
parated. The aqueous phase was extracted with ethyl acetate
4

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
with those reported in the literature [53].
Table 1
Asymmetric hydrogenation of acetophenone.
3. Results and discussion
It has been shown that the incorporation of small substituents such
as methyl and methoxy groups at the 6- and 6′-positions of biaryl di-
phosphine ligands confer atropisomerism [54-57]. Variations of these
biaryl diphosphines containing alkoxy substituents include (R)- and (S)-
(6,6′-dimethoxy(1,1′-diphenyl)-2,2′-diyl)bis(diarylphosphine), (R)- and
(S)-(5,5′,6,6′-tetramethoxy(1,1′-diphenyl)-2,2′-diyl)bis(diarylpho-
sphine), or (R)- and (S)-(4,4′,5,5′,6,6′-hexamethoxy(1,1′-diphenyl)-2,2′-
diyl)bis(diarylphosphine) [58]. The preparation of these biaryl dipho-
sphine ligands was originally based on copper-catalyzed Ullmann cou-
pling of halophosphonate intermediates, which were subsequently re-
duced to the respective biaryl diphospines [58]. The halophosphonate
intermediates were prepared by the ortho-lithiation of phosphine oxide
precursors followed by halogenation with molecular I2, Br2, ICl or IBr
[58]. However, attempts to prepare the halophosphonate intermediates
for the preparation of (R)- and (S)-(4,4′,6,6′-tetramethoxy-(1,1′-di-
phenyl)-2,2′-diyl)bis(diarylphosphine) using similar ortho-lithiation
and halogenation procedures were unsuccessful due to the ortho-di-
recting property of the alkoxy groups, resulting in polyhalogenated
species. It was later discovered that the desired halophosphonate in-
termediates can be readily prepared in high yields from the reaction of
the phosphonate ester and N–bromosuccinimide (NBS).
Entry
Complex
1,2-Diamine
Conv.a (%)
Yieldb (%)
eec (%)[conf.]d
1
3
3
3
–
R,R-DPEN
S,S-DPEN
none
> 99
> 99
20
80
80
–
90 [S]
28 [R]
38 [S]
–
2
3
4e
5f
6
R,R-DPEN
R,R-DPEN
R,R-DPEN
S,S-DPEN
< 5
–
–
< 10
> 99
> 99
–
–
5
6
88
98
97 [S]
95 [R]
7
Reaction conditions: Ketone (12 mmol), t-BuOK (0.12 mmol), and catalyst
(0.012 mmol). S:C ratio = 1000. aConversions determined by GC analysis.
bIsolated yields were obtained upon silica gel chromatography. cee values de-
termined by GC using a chiral Supelco β-DEX 120 column. dAbsolute config-
uration was determined by comparison of elution order with literature data.
[16,62] eIn situ reaction with [Ru(p-cymene)Cl2]2/(R)-Ph-Garphos/(R,R)-
DPEN. fIn situ reaction using [Ru(p-cymene)Cl2]2/(R,R)-DPEN in the absence of
ligand.
in yields of 87% and 91%, respectively. The ruthenium Xyl-Garphos
complexes 5 ([RuCl(p-cymene)(R)-Xyl-Garphos]Cl) and 6 ([RuCl(p-
cymene)(S)-Xyl-Garphos]Cl) were synthesized according to the proce-
dure outlined and were isolated in 52% yields.
The Ph-Garphos ligands were prepared from a readily accessible and
inexpensive starting material, 1-bromo-3,5-dimethoxybenzene, using a
similar procedure as reported in US Patent 20130184479A1 [59]. As
outlined in Scheme 2, the derived monophosphonate (1a) was treated
with NBS to yield the desired bromophosphonate (1b). Ullmann cou-
pling of the bromophosphonate (1b) in the presence of copper powder
activated with iodine at 140 °C produced a racemic mixture of the
desired bis(phosphine oxides) (rac-1c). Subsequent resolution with D-
(+)-DBTA·H2O or L-(-)-DBTA·H2O, followed by reduction with tri-
chlorosilane yielded the desired Ph-Garphos ligands, (R)-Ph-Garphos
(2a) and (S)-Ph-Garphos (2b) in moderate yields and high chiral purity.
The methoxy substituents in the 4,4′-substituents are expected to en-
hance the enantioselectivity of the phosphine ligands [44,60] (Scheme
3).
The 1H NMR and 31P{1H} spectra suggested that the ruthenium(II)
complexes are unsymmetrical. In complexes 3 and 4, the methoxy
protons resonated as four sharp singlets at chemical shifts of 3.30, 3.41,
3.61 and 3.65 ppm. Owing to the non-equivalence of the phosphorus
atoms, two pairs of doublets were also observed at 27 and 41 ppm
(JPP = 62.8 Hz).
3.1. Asymmetric hydrogenation of ketones
The model substrate, acetophenone, was used to assess the catalytic
capability of the ruthenium(II) Garphos complexes, 3–6, for the asym-
metric hydrogenation of ketones. The chiral diamine DPEN was selected
as a suitable co-ligand due to its accessibility and low cost. Complete
conversion (> 99%) of acetophenone to 1-phenylethanol (7a) was
achieved under ambient conditions and within 3 h (Table 1). The 3/
(R,R)-DPEN combination afforded the (S)-1-phenylethanol in 80% yield
and with 90% ee (entry 1). The corresponding 3/(S,S)-DPEN system
afforded the (R)-1-phenylethanol with similarly high conversions, but
lower enantioselectivity (28%, entry 2). In the absence of the 1,2-dia-
mine co-ligand, only 20% conversion was achieved and the S-alcohol
formed in 38% ee (entry 3). This finding highlights the importance of
In order to evaluate the activity of the Ph-Garphos ligands, the ru-
thenium(II) complexes, 3 and 4, were prepared from the reaction of the
dichloro(p-cymene)ruthenium(II) dimer (1 equiv.) with either the (R)-
or (S)-Ph-Garphos ligand (2 equiv.) in methanol at 55 °C for 1 h, under
inert atmosphere. Following removal of the solvent, the residue was
dissolved in the minimum amount of dichloromethane and slowly
added to hexane with stirring. The desired product precipitated, and
was isolated upon vacuum filtration as a moderately air-stable, pale
yellow to green solid. Complexes
3
([RuCl(p-cymene)(R)-Ph-
Garphos]Cl) and 4 ([RuCl(p-cymene)(S)-Ph-Garphos]Cl) were isolated
Scheme 3. Synthesis of the ruthenium(II) complexes.
5

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
Table 2
Ru(II)-catalyzed asymmetric hydrogenation of ketones 7b-7 h.
Entry
Ketone
Pre-Cat.
Time (h)
Conv.a (%)
Yieldb (%)
eec (%)[conf.]d
1
3/(R,R)-DPEN
3/(S,S)-DPEN
5/(R,R)-DPEN
6/(S,S)-DPEN
6
98
66
50
98
91
90 [S]
40 [R]
95 [S]
95 [R]
2
9
94
3e
4e
24
24
> 99
99
5
6
7
8
3/(R,R)-DPEN
3/(S,S)-DPEN
5/(R,R)-DPEN
6/(S,S)-DPEN
2
2
2
2
99
88
64
94
96
77 [S]
41 [R]
98 [S]
98 [R]
96
> 99
> 99
9
3/(R,R)-DPEN
3/(S,S)-DPEN
5/(R,R)-DPEN
6/(S,S)-DPEN
3
4
3
3
> 99
> 99
> 99
> 99
80
80
78
81
72 [S]
39 [R]
97 [S]
96 [R]
10
11
12
13
14
15f
16
3/(R,R)-DPEN
3/(S,S)-DPEN
5/(R,R)-DPEN
6/(S,S)-DPEN
2
> 99
97
94
77
88
89
93 [S]
24 [R]
98 [S]
95 [R]
3
24
6
> 99
> 99
17
18
3/(R,R)-DPEN
3/(S,S)-DPEN
8
90
97
–
–
rac
21
12
19
20
3/(R,R)-DPEN
3/(S,S)-DPEN
4
4
80
83
–
8
12
21
22
3/(R,R)-DPEN
3/(S,S)-DPEN
24
24
99
93
34
11
16
Reaction conditions: Ketone (12 mmol), t-BuOK (0.12 mmol), and catalyst (0.012 mmol. S:C ratio = 1000. aConversions were determined by NMR spectroscopy. bee
values were determined by GC using a chiral Supelco β-DEX 120 column. dAbsolute configuration was determined by comparison of elution order with literature
f
data. eHydrogenations conducted at a S:C ratio of 500 and 50 °C. Reaction time unoptimized.
the 1,2-diamine co-ligand in improving the activity and enantioselec-
tivity. This is made possible through the coordination of the diamine to
the ruthenium, and the resulting complex effectively controls the ste-
reochemical outcome and, enhances the rate of the reaction [7,61].
Matched combinations of the ruthenium (R)-Ph-Garphos complex and
(R,R)-DPEN afforded higher enantioselectivities. Furthermore, ex-
ploratory in situ hydrogenations of acetophenone using a combination
of [Ru(p-cymene)Cl2]2 dimer/(R)-Ph-Garphos/(R,R)-DPEN and [Ru(p-
cymene)Cl2]2 dimer/(R,R)-DPEN produced significantly lower conver-
sions (entries 4 and 5).
diphosphine)(S,S-diamine) combinations, respectively. The ‘mis-
matched’ ([RuCl(p-cymene)(R)-Ph-Garphos]Cl)/(S,S)-DPEN system af-
forded the (R)-configured alcohol with low ee values (28%).
Subsequently, the Ru(II)-catalyzed hydrogenation was expanded to in-
clude other ketone substrates 7b-7 h. The results are summarized in
Table 2.
In most cases, complete reduction of the aryl ketones 7b-7e was
achieved under ambient conditions, to give the corresponding chiral
alcohols in moderate to good yields and enantioselectivities (Table 2,
entries 1–16). Higher enantioselectivities were achieved with the mat-
ched ruthenium(diphosphine)(diamine) combinations than the corre-
sponding mismatched combinations. Even so, the 5/(R,R)-DPEN and 6/
(S,S)-DPEN combinations afforded the chiral alcohols with significantly
higher ee values than the analogous 3/DPEN combinations. This dif-
ference was more noticeable in the enantioselective reductions of the
para-substituted ketones 4-chloroacetopheone (7c) and 4-bromoaceto-
phenone (7d). Enantioselectivites of 77% (7c) and 72% (7d) were
achieved when 3/(R,R)-DPEN was employed (entries 5 and 9). This is in
contrast to the 5/(R,R)-DPEN and 6/(S,S)-DPEN systems which pro-
vided the para-substituted alcohols with ee’s of 96–98% (entries 7–8
and 11–12). Trabesinger et al. [64] suggested that the 3,5-dialkyl meta-
effect might be substrate dependent which could explain the vast dif-
ferences in enantioselectivity for some substrates. The chiral alcohol
(R)-1-(3-methoxyphenyl)ethanol (7e) is of industrial interest because it
is a precursor for the preparation of the acetylcholinesterase inhibitor
Rivastigmine. This alcohol was prepared in 95% ee using 6/(S,S)-DPEN
The 5/(R,R)-DPEN and 6/(S,S)-DPEN combinations were also in-
vestigated for the hydrogenation of acetophenone (entries 6 and 7).
Excellent catalytic activity, and more interestingly, high enantioselec-
tivities of up to 97% were observed. The enhanced enantioselectivity is
believed to arise from a more rigid chiral pocket, allowing for improved
interaction between substrate and catalyst. It has been reported that
increased enantioselectivity relies on the repulsive interactions between
the aryl group of the aromatic ketone and the bulky substituents on the
4,4′-positions of the diphosphine in the disfavoured transition state
[29,32,44,49]. Nonetheless, the improved enantioselectivities afforded
by the Xyl-Garphos ligands is expected, as similar results have been
observed with other diphosphines possessing the bis(xylyl)phosphine
moieties [31,44,63].
In general, the (S)- and (R)-configured alcohols were obtained in
good yields and with high enantioselectivities from the matched ru-
thenium/(R-diphosphine)(R,R-diamine)
and
ruthenium/(S-
6

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
Scheme 4. Proposed mechanism for the ruthenium-mediated hydrogenation of ketones with 3/DPEN.
(entry 16). Even though the reaction was not optimized using 5/(R,R)-
DPEN, the (S)-1-(3-methoxyphenyl)ethanol was afforded in 88% yield
and 98% ee within 24 h. The aliphatic ketones (7f-h) required longer
reaction times to effect high conversions with low enantioselectivities
(entries 17–22).
Scheme 4 highlights the proposed bifunctional mechanism in which the
polarized Hδ-Ruδ+–Nδ-–Hδ+ quadrupole of A interacts with the polar
C]O dipole of the ketone substrate [14]. The hydride of the Ru-H bond
and the amine proton are concomitantly transferred to the C]O atoms
via a pericyclic six-membered transition state B, to give the chiral al-
cohol [68]. Following the elimination of the alcohol, a molecule of H2
coordinates to the unsaturated 16e ruthenium-diphosphine-amido-
amine [8] intermediate C to form species D. Abbel et al. [66] suggested
that the heterolytic splitting of a ƞ2-dihydrogen across the ruthenium-
amido bond is the turnover rate determining step of the catalytic cycle.
The weakly coordinated ƞ2-dihydrogen subsequently cleaves, facil-
itating regeneration of the active catalytic species A (Scheme 4).
3.2. Mechanism for the hydrogenation of ketones with 1/DPEN
We anticipate that the true catalyst formed from the reaction of the
ruthenium(II) Garphos complex and DPEN, in the presence of hydrogen
gas and base, is a ruthenium(II) dihydride species, A. This is similar to
the mechanism reported for the well-established RuCl2(BINAP)(dia-
mine)-catalyzed asymmetric hydrogenation of ketones [61,65-67].
7

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
Scheme 5. Synthesis of (S)-Rivastigmine.
3.3. Application to drug synthesis
influence the work reported in this paper.
Acknowledgements
Rivastigmine (11e) is the first USFDA approved drug for the treat-
ment of mild-to-moderate dementia which can be administered in the
form of capsules or patches, [5,69]. However, only the (S)-enantiomer
exhibits the desired cholinesterase inhibition [70]. Therefore, access to
optically active intermediates (synthons) in high yields and enantios-
electivities is critical for the preparation of enantiopure target mole-
cules [71]. Herein, we report that (S)-Rivastigmine can be obtained in
high yields starting with (R)-1-(3-methoxyphenyl)ethanol, followed by
amination, then amidoesterification.
The authors extend appreciation to the Department of Chemistry
and the Office of Graduate Studies and Research at the University of the
West Indies, Mona for their financial support. We are also grateful to
Kamal Pharmachem Inc. for the provision of chemicals. We also deeply
appreciate the assistance of Dr. Mark Lawrence.
References
Scheme 5 outlines a facile four step protocol to achieve the target
molecule in high yields. Following the asymmetric reduction of 3-
methoxyacetopheone to provide the desired (R)-1-(3-methoxyphenyl)
ethanol (8e) in 95% ee, the alcohol is treated with methanesulfonyl
chloride followed by dimethylamine to produce (S)-1-(3-methox-
yphenyl)-N,N-dimethyl ethanamine (9e) in 91% yield. Demethylation
of the methoxy group of 9e using concentrated HBr solution affords (S)-
3-(1-(dimethylamino)ethyl)phenol (10e) in 94% yield. Subsequent ad-
dition of N-ethyl-N-methyl carbamoyl chloride, in the presence of a
strong base and at reflux, results in the amidoesterification of the
aminophenol 10e to give (S)-Rivastigmine (11e) in 95% yield.
[1] W.S. Knowles, Acc. Chem. Res. 16 (1983) 106–112, https://doi.org/10.1021/
ar00087a006.
[2] W.S. Knowles, R. Noyori, Acc. Chem. Res. 40 (2007) 1238–1239, https://doi.org/
10.1021/ar7000809.
[3] M. Scalone, P. Waldmeier, Org. Proc. Res. Dev. 7 (2003) 418–425, https://doi.org/
10.1021/op034006v.
[4] P.-C. Yan, G.-L. Zhu, J.-H. Xie, X.-D. Zhang, Q.-L. Zhou, Y.-Q. Li, W.-H. Shen, D.-
Q. Che, Org. Process Res. Dev. 17 (2013) 307–312, https://doi.org/10.1021/
op3003147.
[5] V.R. Arava, L. Gorentla, P.K. Dubey, Int. J. Org. Chem. 1 (2011) 26–32.
[6] T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M. Terada, R. Noyori, J.
Am. Chem. Soc. 120 (1998) 1086–1087, https://doi.org/10.1021/ja972897e.
[7] T. Ohkuma, H. Ooka, S. Hashigushi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 117
(1995) 2675–2676.
[8] R. Feng, A. Xiao, X. Zhang, Y. Tang, M. Lei, Dalton Trans. 42 (2013) 2130–2145,
https://doi.org/10.1039/c2dt32210b.
4. Conclusion
[9] H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, E. Katayama,
A.F. England, T. Ikariya, R. Noyori, Angew. Chem. Int. Ed. 37 (1998) 1703–1707,
https://doi.org/10.1002/(sici)1521-3773(19980703)37:12<1703::aid-
anie1703>3.0.co;2-i.
The (R)-Ph-Garphos ligand demonstrated exceptional catalytic effi-
ciency in the asymmetric hydrogenation of aryl ketones with the [RuCl
(p-cymene)((R)-Ph-Garphos)]Cl complex (1) and the (R,R)-DPEN co-li-
gand. Excellent conversions with moderate to high enantiomeric ex-
cesses were achieved in short reaction times. The combination of 3 and
(S,S)-DPEN gave excellent conversions with much lower ee values.
Substitution of the pendant phenyl ring with the bulkier 3,5-di-
methylphenyl moiety dramatically increased the enantioselectivities.
The 3,5-dimethyl substituted Xyl-Garphos, and their ruthenium(II)
complexes, 5 and 6, gave conversions of > 99% of the chiral alcohols
with enantioselectivities of up to 98%. The (S)- and (R)-alcohols were
the predominant isomers with the matched ruthenium(II)/(R)-dipho-
sphine/(R,R)-DPEN and mismatched ruthenium(II)/(R)-diphosphine/
(S,S)-DPEN combinations, respectively. (R)-1-(3-methoxyphenyl)
ethanol was used for the preparation of (S)-Rivastigmine in high yields.
[10] J.-H. Xie, D.-H. Bao, Q.-L. Zhou, Synthesis 47 (2015) 460–471, https://doi.org/10.
1055/s-0034-1378939.
[11] G. Ma, R. McDonald, M. Ferguson, R.G. Cavell, B.O. Patrick, B.R. James, T.Q. Hu,
Organometallics 26 (2007) 846–854, https://doi.org/10.1021/om060987z.
[12] A. Zanotti-Gerosa, W. Hems, M. Groarke, F. Hancock, Platinum Met. Rev. 49 (2005)
158–165, https://doi.org/10.1595/147106705x75421.
[13] C.A. Sandoval, Q. Shi, S. Liu, R. Noyori, Chem. Asian J. 4 (2009) 1221–1224,
https://doi.org/10.1002/asia.200900171.
[14] T. Ohkuma, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci., 86 (2010) 202-219.doi:10.
2183/pjab.86.202.
[15] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H. Kumobayashi,
S. Akutagawa, J. Am. Chem. Soc. 109 (1987) 5856–5858, https://doi.org/10.1021/
ja00253a051.
[16] Y. Jiang, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 120 (1998) 3817–3818, https://doi.
org/10.1021/ja974095p.
[17] J. Madec, X. Pfister, P. Phansavath, V. Ratovelomanana-Vidal, J.-P. Genet,
Tetrahedron 57 (2001) 2563–2568.
[18] R. Noyori, T. Ohkuma, Angew. Chem. Int. Ed. 40 (2001) 40–73.
[19] T. Ohkuma, H. Ooka, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 117 (1995)
10417–10418.
Declaration of competing interest
[20] S. Doherty, J.G. Knight, A.L. Bell, R.W. Harrington, W. Clegg, Organometallics 26
(2007) 2465–2468, https://doi.org/10.1021/om070129i.
[21] G.A. Grasa, A. Zanotti-Gerosa, J.A. Medlock, W.P. Hems, Org. Lett. 7 (2005)
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to
8

S. Lorraine, et al.
InorganicaChimicaActa511(2020)119850
1449–1451, https://doi.org/10.1021/ol047355y.
https://doi.org/10.1021/ol0000814.
[22] P. Cao, X. Zhang, J. Org. Chem. 64 (1999) 2127–2129, https://doi.org/10.1021/
jo981859q.
[48] T. Ohkuma, D. Ishii, H. Takeno, R. Noyori, J. Am. Chem. Soc. 122 (2000)
6510–6511, https://doi.org/10.1021/ja001098k.
[23] C.-Y. Chen, R.A. Reamer, J.R. Chilenski, C.J. McWilliams, Org. Lett. 5 (2003)
5039–5042, https://doi.org/10.1021/ol0360795.
[49] J.-H. Xie, L.-X. Wang, Y. Fu, S.-F. Zhu, B.-M. Fan, H.-F. Duan, Q.-L. Zhou, J. Am.
Chem. Soc. 125 (2003) 4404–4405, https://doi.org/10.1021/ja029907i.
[50] J.P. Henschke, A. Zanotti-Gerosa, P. Moran, P. Harrison, B. Mullen, G. Casy,
I.C. Lennon, Tetrahedron Lett. 44 (2003) 4379–4383, https://doi.org/10.1016/
S0040-4039(03)00940-7.
[24] X. Li, W. Chen, W. Hems, F. King, J. Xiao, Org. Lett. 5 (2003) 4559–4561, https://
doi.org/10.1021/ol0355837.
[25] D.G. Genov, D.J. Ager, Angew. Chem. Int. Ed. 43 (2004) 2816–2819, https://doi.
org/10.1002/anie.200353441.
[51] J.P. Henschke, M.J. Burk, C.G. Malan, D. Herzberg, J.A. Peterson, A.J. Wildsmith,
C.J. Cobley, G. Casy, Adv. Synth. Catal. 345 (2003) 300–307, https://doi.org/10.
1002/adsc.200390025.
[26] J. Wu, J.-X. Ji, R. Guo, C.-H. Yeung, A.S.C. Chan, Chem. Eur. J. 9 (2003)
2963–2968, https://doi.org/10.1002/chem.200204688.
[27] M.J. Burk, W. Hems, D. Herzberg, C. Malan, A. Zanotti-Gerosa, Org. Lett. 2 (2000)
4173–4176, https://doi.org/10.1021/ol000309n.
[52] W.L.F. Armarego, C.L.L. Chai, Purification of Laboratory Chemicals, 6th ed.,
Butterworth-Heinemann, Burlington, MA, 2009.
[28] D. Chaplin, P. Harrison, J.P. Henschke, I.C. Lennon, G. Meek, P. Moran,
C.J. Pilkington, J.A. Ramsden, S. Watkins, A. Zanotti-Gerosa, Org. Process Res. Dev.
7 (2003) 89–94, https://doi.org/10.1021/op025585r.
[53] V.N. Wakchaure, P.S.J. Kaib, M. Leutzsch, B. List, Angew. Chem. Int. Ed., 54 (2015)
11852-11856.doi:10.1002/anie.201504052.
[54] M. McCarthy, P.J. Guiry, Tetrahedron 57 (2001) 3809–3844.
[55] M. Charton, J. Org. Chem. 42 (1977) 2528–2529, https://doi.org/10.1021/
jo00434a048.
[29] J. Wu, H. Chen, W. Kwok, R. Guo, Z. Zhou, C. Yeung, A.S.C. Chan, J. Org. Chem. 67
(2002) 7908–7910.
[30] W. Li, X. Sun, L. Zhou, G. Hou, S. Yu, X. Zhang, J. Org. Chem. 74 (2009) 1397–1399,
https://doi.org/10.1021/jo802372w.
[56] F. Leroux, ChemBioChem 5 (2004) 644–649, https://doi.org/10.1002/cbic.
200300906.
[31] J.-H. Xie, Q.-L. Zhou, Acc. Chem. Res. 41 (2008) 581–593, https://doi.org/10.
1021/ar700137z.
[57] A. Mazzanti, L. Lunazzi, M. Minzoni, J.E. Anderson, J. Org. Chem. 71 (2006)
5474–5481, https://doi.org/10.1021/jo060205b.
[32] J.-H. Xie, S. Liu, X.-H. Huo, X. Cheng, H.-F. Duan, B.-M. Fan, L.-X. Wang, Q.-L. Zhou,
J. Org. Chem. 70 (2005) 2967–2973, https://doi.org/10.1021/jo0478712.
[33] X. Tao, W. Li, X. Ma, X. Li, W. Fan, X. Xie, T. Ayad, V. Ratovelomanana-Vidal,
Z. Zhang, J. Org. Chem. 77 (2012) 612–616, https://doi.org/10.1021/jo202204j.
[34] B. Lu, Q. Wang, M. Zhao, X. Xie, Z. Zhang, J. Org. Chem. 80 (2015) 9563–9569,
https://doi.org/10.1021/acs.joc.5b01548.
[58] R. Schmid, J. Foricher, M. Cereghetti, P. Schönholzer, Helv. Chim. Acta 74 (1991)
370–389, https://doi.org/10.1002/hlca.19910740215.
[59] K. Abdur-Rashid, W. Jia, S. Lu, R. Guo, X. Chen, D. Amoroso, Biaryl Diphosphine
Ligands, Intermediates of the same and their use in Asymmetric Catalysis. US
20130184479A1, July 18, 2013.
[60] A. Hu, H.L. Ngo, W. Lin, Angew. Chem. Int. Ed. 43 (2004) 2501–2504, https://doi.
org/10.1002/anie.200353415.
[35] M.T. Reetz, X. Li, J. Am. Chem. Soc. 128 (2006) 1044–1045.
[36] H. Guo, D. Liu, N.A. Butt, Y. Liu, W. Zhang, Tetrahedron 68 (2012) 3295–3299,
https://doi.org/10.1016/j.tet.2012.02.075.
[61] B. Zhao, Z. Han, K. Ding, Angew. Chem. Int. Ed. 52 (2013) 4744–4788, https://doi.
org/10.1002/anie.201204921.
[37] T. Irrgang, D. Friedrich, R. Kempe, Angew. Chem. Int. Ed. 50 (2011) 2183–2186,
https://doi.org/10.1002/anie.201004665.
[62] A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 118
(1996) 2521–2522, https://doi.org/10.1021/ja954126l.
[38] D.-M. Lee, S.H. Kwak, K.-I. Lee, Bull. Korean Chem. Soc. 30 (2009) 1317–1324.
[39] Y.-Q. Guan, M. Gao, X. Deng, H. Lv, X. Zhang, Chem. Commun. 53 (2017)
8136–8139, https://doi.org/10.1039/C7CC03902F.
[63] C. Barbato, S. Baldino, M. Ballico, R. Figliolia, S. Magnolia, K. Siega, E. Herdtweck,
P. Strazzolini, G. Chelucci, W. Baratta, Organometallics 37 (2018) 65–77, https://
doi.org/10.1021/acs.organomet.7b00737.
[40] J. Wu, J.X. Ji, A.S. Chan, Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 3570–3575,
https://doi.org/10.1073/pnas.0409043102.
[64] G. Trabesinger, A. Albinati, N. Feiken, R.W. Kunz, P.S. Pregosin, M. Tschoerner, J.
Am. Chem. Soc. 119 (1997) 6315–6323.
[41] Y.-Y. Yan, T.V. RajanBabu, Org. Lett. 2 (2000) 199–202, https://doi.org/10.1021/
ol991285r.
[65] C.A. Sandoval, T. Ohkuma, K. Muñiz, R. Noyori, J. Am. Chem. Soc. 125 (2003)
13490–13503, https://doi.org/10.1021/ja030272c.
[42] Z. Herseczkia, I. Gergely, C. Hegedüs, Á. Szöllősy, J. Bakos, Tetrahedron:
Asymmetry 15 (2004) 1673–1676, https://doi.org/10.1016/j.tetasy.2004.04.023.
[43] S. Wu, M. He, X. Zhang, Tetrahedron: Asymmetry 15 (2004) 2177–2180, https://
doi.org/10.1016/j.tetasy.2004.05.043.
[66] R. Abbel, K. Abdur-Rashid, M. Faatz, A. Hadzovic, A.J. Lough, R.H. Morris, J. Am.
Chem. Soc. 127 (2005) 1870–1882.
[67] P.A. Dub, N.J. Henson, R.L. Martin, J.C. Gordon, J. Am. Chem. Soc. 136 (2014)
3505–3521, https://doi.org/10.1021/ja411374j.
[44] H.L. Ngo, W. Lin, J. Org. Chem. 70 (2005) 1177–1187, https://doi.org/10.1021/
jo048333s.
[68] R. Noyori, Angew. Chem. Int. Ed. 41 (2002) 2008–2022, https://doi.org/10.1002/
1521-3773(20020617)41:12<2008::AID-ANIE2008>3.0.CO;2-4.
[69] C. Bhanja, S. Jena, J. Chem. Pharm. Res. 4 (2012) 3171–3183.
[70] J. Mangas-Sánchez, M. Rodríguez-Mata, E. Busto, V. Gotor-Fernández, V. Gotor, J.
Org. Chem. 74 (2009) 5304–5310, https://doi.org/10.1021/jo900784g.
[71] M. Hu, F.-L. Zhang, M.-H. Xie, Synth. Commun. 39 (2009) 1527–1533, https://doi.
org/10.1080/00397910802531948.
[45] T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E. Katayama,
T. Yokozawa, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 120 (1998) 13529–13530,
https://doi.org/10.1021/ja983257u.
[46] T. Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R. Noyori, Org. Lett. 2 (2000)
659–662, https://doi.org/10.1021/ol9904139.
[47] T. Ohkuma, M. Koizumi, M. Yoshida, R. Noyori, Org. Lett. 2 (2000) 1749–1751,
9