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