Supporting Information
Wiley-VCH 2013
69451 Weinheim, Germany
ChenPhos: Highly Modular P-Stereogenic C1-Symmetric Diphosphine
Ligands for the Efficient Asymmetric Hydrogenation of a-Substituted
Cinnamic Acids
Weiping Chen,* Felix Spindler, Benoit Pugin, and Ulrike Nettekoven
anie_201304472_sm_miscellaneous_information.pdf
Supporting Information:
CONTENTS:
I. Synthesis of ligands
II. Asymmetric hydrogenation
III. Plausible transition state in asymmetric hydrogenation
IV. NMR Spectra
S1
I.
Synthesis of ligands:
(RC,SFc,SP)-1-[2-(1-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-bromoferrocene [(RC,SFc,SP)-3]:
NMe2
Fe
P
Fe
Fe
Br
2
Ph
NMe2
H
(RC,SFc,SP)-3
14.5 ml (23.2 mmol) of n-BuLi (1.6 M in hexane) are added dropwise to a solution of 8 g (23.2 mmol) of
1,1’-dibromoferrocene in 30 ml of THF at a temperature of < -30 °C. The mixture is stirred for a further 30 minutes at
this temperature to give a suspension of 1-lithio-1’-bromoferrocene.
17.9 ml (23.2 mmol) of s-BuLi (1.3 M in cyclohexane) are added dropwise to a solution of 5.98 g (23.2 mmol) of
(R)-1-dimethylamino-1-ferrocenylethane in 40 ml of TBME at <-10 °C. After stirring the mixture at the same
temperature for 10 minutes, the temperature is allowed to rise to room temperature and the mixture is stirred for another
1.5 h. The mixture was cooled to -78 °C, and 3.15 ml (23.2 mmol) of phenyldichlorophosphine are added dropwise at
such a rate that the temperature does not exceed -60°C. After stirring the mixture at -78 °C for a further 10 minutes, the
temperature is allowed to rise to room temperature slowly and the mixture is stirred for another 1 h. The mixture was
cooled to <-35 °C, and the suspension of 1-lithio-1’-bromoferrocene was added via a cannula at such a rate that the
temperature does not exceed -30°C. After stirring the mixture at -30°C for a further 10 minutes, the temperature was
allowed to rise to 0°C and the mixture was stirred for another 2 hours. The reaction mixture was admixed with 20 ml of
water. The organic phase was separated off, dried over sodium sulphate and the solvent wa removed under reduced
pressure on a rotary evaporator. Chromatographic purification (silica gel 60; eluent: heptane/ethyl acetate/NEt3 =
85:10:5) gave the desired product as a mixture of two diastereomers.
The mixture was dissolved in 50 ml of toluene and refluxed for 4 hours. After distilling off the toluene, the residue was
crystallized in ethanol to give the product (8.60 g, 59%) as a yellow crystals. 1H NMR (300 MHz, CDCl3): δ 1.06 (d, 3H,
J = 6.7 Hz), 1.43 (s, 6H), 3.71 (m, 1H), 3.82 (m, 1H), 3.90 (m, 2H), 3.95 (s, 5H), 3.96 (m, 1H), 4.05 (m, 1H), 4.06 (m,
1H), 4.15 (br. s, 1H), 4.26 (m, 1H), 4.36 (m, 2H), 4.55 (m, 1H), 7.20 (m, 3H), 7.44 (m, 2H).
CDCl3): δ -35.0 (s).
S2
31
P NMR (121.5 MHz,
General procedure for the preparation of ligands 1a-1n:
Fe
P
Ph
Fe
NMe2
1) n-BuLi or s-BuLi
TBME, 0 ℃
H
Fe
2) R2PCl
NMe2
P
Br
(RC,SFc,SP)-3
Ph
Fe
PR2
1a-1n
H
1a. R = Cy, 95%
1b. R = Ph, 82.2%
1c. R = t-Bu, ~100%
1d. R = i-Pr, 95%
1e. R = Et, 91%
1f. R = 4-FC6H4, 93%
1g. R = 4-CF3C6H4, 54%
1h. R = 2-norbornyl, 89%
1i. R = 2-furyl, 83%
1j. R = o-An, 23%
1k. R = 3,5-Me2C6H3, 48%
1l. R = 3,5-(CF3)2C6H3, 86%
1m. R = 3,5-Me2-4-MeOC6H2, 92%
1n. R = 1-C10H7, 88%
1.1 mmol of n-BuLi (1.6 M in hexane) or s-BuLi (1.3 M in cyclohexane) was added dropwise to a solution of 1 mmol of
(RC,SFc,SP)-3 in TBME (5 mL) at -5 °C to 0°C. The temperature was maintained at 0 °C, the mixture was stirred for a
further one hour and 1.1 mmol of the chlorophosphine ClPR2 was then added. The temperature was allowed to rise to
room temperature; the reaction mixture was stirred for a further one hour and then admixed with 5 ml of a saturated
aqueous NaHCO3 solution. The organic phase was separated, dried over sodium sulphate and the solvent was removed
under reduced pressure on a rotary evaporator. Chromatographic purification and, if required, crystallization in methanol
gives ligands 1a-1n as pure diastereomers.
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’dicyclohexylphosphinoferrocene (1a):
1
H NMR (300 MHz, C6D6): δ 1.15 (d, 3H, J = 6.7 Hz), 1.77 (s, 6H), 1.25~2.28 (m, 22H), 4.01 (m, 1H), 4.05 (m, 1H),
4.10 (m, 1H), 4.11 (m, 1H), 4.14 (s, 5H), 4.20 (br. s, 1H), 4.26 (m, 2H), 4.36 (m, 1H), 4.37 (m, 1H), 4.49 (m, 2H), 4.75
(m, 1H), 7.24 (m, 3H), 7.80 (m, 2H). 31P NMR (121.5 MHz, C6D6): δ -35.6 (s); -7.5 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’- diphenylphosphinoferrocene
(1b):
1
H NMR (300 MHz, CDCl3): δ 1.12 (d, 3H, J = 6.6 Hz), 1.48 (s, 6H), 3.57 (m, 1H), 3.69 (m, 1H), 3.83 (m, 1H), 4.00 (s,
5H), 4.02 (m, 1H), 4.10 (m, 3H), 4.20 (br. s, 1H), 4.25 (m, 1H), 4.29 (m, 1H), 4.31 (m, 1H), 4.52 (m, 1H), 7.18~7.46 (m,
15H). 31P NMR (121.5 MHz, CDCl3): δ -35.2 (s), -16.1 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di-tert-butylphosphinoferrocene
(1c):
After addition of di-tert-butylphosphine chloride, the reaction mixture is additionally stirred at 50°C for 1 h before
addition of the NaHCO3 solution. ~90% pure. 1H NMR (300 MHz, CDCl3): δ 1.07 (s, 3H), 1.11 (s, 6H), 1.14 (d, 3H, J =
6.6 Hz), 1.15 (s, 3H), 1.20 (s, 3H), 1.25 (s, 3H),1.50 (s, 6H), 3.72 (m, 1H), 3.86 (m, 2H), 4.02 (s, 5H), 4.03 (m, 1H), 4.12
(m, 3H), 4.21 (m, 1H), 4.30 (m, 2H), 4.40 (m, 1H), 4.56 (m, 1H), 7.27 (m, 3H), 7.53 (m, 2H).
31
P NMR (121.5 MHz,
CDCl3): δ -35.0 (s), 28.4 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-diiosopropylphosphinoferrocene
(1d):
S3
1
H NMR (300 MHz, C6D6):δ 1.23~1.26 (m, 15H), 1.76 (s, 6H), 1.90 (m, 1H), 2.00 (m, 1H), 3.97 (m, 1H), 4.05 (m, 1H),
4.11 (m, 2H), 4.14 (s, 5H), 4.19 (m, 1H), 4.22 (m, 1H), 4.29 (m, 1H), 4.36 (m, 1H), 4.38 (m, 2H), 4.43 (m, 1H), 4.47 (m,
1H), 4.76 (m, 1H), 7.19 (m, 3H), 7.79 (m, 2H). 31P NMR (121.5 MHz, C6D6): δ -35.6 (s); -0.0 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-diethylphosphinoferrocene (1e):
1
H NMR (300 MHz, C6D6):δ 1.09~1.22 (m, 9H), 1.56 (m, 2H), 1.69 (m, 2H), 1.76 (s, 6H), 4.01 (m, 1H), 4.06 (m, 1H),
4.11 (m, 2H), 4.13 (s, 5H), 4.19 (m, 2H), 4.29 (m, 1H), 4.36 (m, 1H), 4.38 (m, 1H), 4.45 (m, 2H), 4.77 (m, 1H), 7.22 (m,
3H), 7.78 (m, 2H). 31P NMR (121.5 MHz, C6D6): δ -35.0 (s); -26.5 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di(4-fluorophenyl)phosphino
ferrocene (1f):
1
H NMR (300 MHz, CDCl3): δ 1.14 (d, 3H, J = 6.6 Hz), 1.50 (s, 6H), 3.47 (br. s, 1H), 3.68 (br. s, 1H), 3.84 (m, 1H),
4.02 (s, 5H), 4.12 (m, 3H), 4.20 (br. s, 1H), 4.23 (m, 2H), 4.32 (m, 1H), 4.35 (m, 1H), 4.56 (m, 1H), 6.97 (d, 2H, J = 8.7
Hz), 7.02 (d, 2H, J = 8.7 Hz), 7.25 (m, 7H), 7.43 (m, 2H). 31P NMR (121.5 MHz, CDCl3): δ -35.3 (s); -18.5 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di(4-trifluoromethylphenyl)
phosphinoferrocene (1g):
1
H NMR (300 MHz, CDCl3): δ 1.04 (d, 3H, J = 6.7 Hz), 1.40 (s, 6H), 3.42 (br. s, 1H), 3.57 (br. s, 1H), 3.73 (br. s, 1H),
3.93 (s, 5H), 4.04 (m, 2H), 4.08 (br. s, 1H), 4.11 (br. s, 1H), 4.14 (br. s, 1H), 4.17 (m, 1H), 4.26 (m, 2H), 4.48 (m, 1H),
7.11~7.48 (m, 13H). 31P NMR (121.5 MHz, CDCl3): δ -35.6 (s); -15.5 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di(2-norbornyl)phosphino
ferrocene (1h):
The product is obtained as a mixture of at least 4 diastereomers. 31P NMR (121.5 MHz, C6D6): δ -35.6 (s), -35.4 (s),
-35.3 (s), -35.1 (s); -13.8 (s), -11.3 (s), -10.8 (s), -10.1 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di(2-furyl)phosphinoferrocene
(1i):
1
H NMR (300 MHz, C6D6): δ 1.15 (d, 3H, J = 6.7 Hz), 1.74 (s, 6H), 3.14 (br. s, 1H), 3.85 (br. s, 1H), 4.05 (br. s, 1H),
4.09 (m, 1H), 4.11 (s, 5H), 4.20 (br. s, 3H), 4.30 (br. S, 1H), 4.34 (br. s, 1H), 4.36 (m, 1H), 4.41 (br. s, 1H), 4.66 (m, 1H),
4.78 (m, 1H), 6.12 (m, 2H), 6.74 (br. s, 1H), 6.77 (br. s, 1H), 7.19 (m, 3H), 7.30 (s, 1H), 7.35 (s, 1H), 7.60 (m, 2H). 31P
NMR (121.5 MHz, C6D6): δ -64.2 (s); -35.4 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di(2-methoxyphenyl)phosphino
ferrocene (1j):
1
H NMR (300 MHz, C6D6): δ 1.17 (d, 3H, J = 6.7 Hz), 1.76 (s, 6H), 3.39 (s, 3H), 3.52 (s, 3H), 3.90 (br. s, 1H), 3.94 (br.
s, 1H), 4.10 (m, 2H), 4.13 (s, 5H), 4.19 (br. s, 1H), 4.31 (br. s, 1H), 4.35 (m, 3H), 4.54 (m, 1H), 4.58 (br. s, 1H), 4.93 (br.
s, 1H), 6.62 (dd, 2H, J = 12.2 and 7.0 Hz), 6.81 (t, 1H, J = 7.3 Hz), 6.90 (t, 1H, J = 7.3 Hz), 7.19 (m, 3H), 7.38 (t, 2H, J =
5.9 Hz), 7.69 (m, 2H). 31P NMR (121.5 MHz, C6D6): δ -42.6 (s); -35.6 (s).
S4
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-bis-(3,5-dimethylphenyl)
phosphinoferrocene (1k):
1
H NMR (300 MHz, CDCl3): δ 1.48 (d, 3H, J = 6.6 Hz), 2.26 (s, 6H), 3.57 (m, 1H), 3.75 (m, 1H), 3.84 (m, 1H), 3.97 (m,
1H), 4.01 (s, 5H), 4.13 (m, 4H), 4.22 (m, 2H), 4.25 (m, 1H), 4.32 (m, 1H), 4.51 (m, 1H), 6.88 (s, 1H), 6.91 (s, 2H), 6.93
(s, 2H), 6.95 (s, 1H), 7.19 (m, 3H), 7.44 (m, 2H). 31P NMR (121.5 MHz, CDCl3): δ -35.1 (s), -16.1 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-bis[3,5-di(trifluoromethyl)phenyl]
phosphinoferrocene (1l):
1
H NMR (300 MHz, CDCl3): δ 1.10 (d, 3H, J = 6.6 Hz), 1.45 (s, 6H), 3.38 (m, 1H), 3.75 (m, 1H), 3.81 (m, 1H), 4.00 (s,
5H), 4.10 (m, 1H), 4.13 (m, 1H), 4.19 (m, 2H), 4.21 (m, 1H), 4.27 (m, 1H), 4.34 (m, 1H), 4.41 (m, 1H), 4.58 (m, 1H),
7.17 (m, 3H), 7.38 (m, 2H), 7.66 (t, 4H, J = 7.0 Hz), 7.86 (s, 2H). 31P NMR (121.5 MHz, CDCl3): δ -35.7 (s), -13.5 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-bis(3,5-dimethyl-4-methoxyphenyl)phosphinoferrocene (1m):
1
H NMR (300 MHz, CDCl3): δ 1.49 (d, 3H, J = 6.6 Hz), 2.23 (s, 6H), 3.55 (br. s, 1H), 3.71 (s, 3H), 3.72 (s, 3H), 3.85 (m,
1H), 3.95 (m, 1H), 4.01 (s, 5H), 4.14 (m, 4H), 4.21 (m, 2H), 4.25 (m, 1H), 4.32 (m, 1H), 4.53 (m, 1H), 6.90 (s, 1H), 6.93
(s, 1H), 6.95 (s, 1H), 6.98 (s, 1H), 7.21(m, 3H), 7.44 (m, 2H). 31P NMR (121.5 MHz, CDCl3): δ -35.1 (s), -18.3 (s).
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)ferrocen-1-yl]phenylphosphino-1’-di(1-naphthyl)phosphino
ferrocene (1n):
1
H NMR (300 MHz, CDCl3): δ 1.10 (d, 3H, J = 6.6 Hz), 1.45 (s, 6H), 3.53 (m, 1H), 3.62 (m, 1H), 3.72 (br. s, 1H), 3.79
(br. s, 1H), 3.94 (s, 5H), 3.95 (m, 1H), 4.02 (m, 2H), 4.05 (br. s, 1H), 4.17 (br. s, 1H), 4.26 (br. s, 1H), 4.31 (m, 1H), 4.41
(m, 1H), 7.15~7.24 (m, 5H), 7.31~7.56 (m, 8H), 7.82 (m, 4H), 8.54 (m, 1H), 8.99 (dd, 1H, J = 8.1 and 5.4 Hz). 31P NMR
(121.5 MHz, CDCl3): δ -40.4 (s), -35.3 (s).
1-Dicyclohexylphosphino-1’-bromoferrocene (6):
Br
1) n-BuLi, THF
-25~-30 ℃
Br
2) Cy2PCl, 0 ℃~rt
Fe
Br
Fe
PCy2
6
4
120 ml (0.3 mol) of n-BuLi (2.5 M in hexane) are added dropwise to a solution of 103 g (0.3 mol) of
1,1’-dibromoferrocene in 300 ml of THF at a temperature of < -30°C. The mixture is stirred at this temperature for a
further 1.5 hours. It is then cooled to -50°C and 66.2 ml (0.3 mol) of dicyclohexylphosphine chloride are added dropwise
at such a rate that the temperature does not exceed -45°C. After stirring the mixture for a further 10 minutes, the
temperature is allowed to rise to room temperature and the mixture is stirred for another one hour. After addition of
150 ml of water, the reaction mixture is shaken with hexane. The organic phases are dried over sodium sulphate and the
solvent is distilled off under reduced pressure on a rotary evaporator. The residue is crystallized in ethanol. The product
A2 is obtained in a yield of 84% (yellow solid). 1H NMR (300 MHz, C6D6): δ 1.20~2.11 (m, 22H), 3.97 (m, 2H), 4.23
(m, 2H), 4.26 (m, 2H), 4.41 (m, 2H). 31P NMR (121.5 MHz, C6D6): δ -8.3 (s).
S5
General procedure for the preparation of 1o-1r from 1-dicyclohexyl phosphino-1’-bromoferrocene:
Fe
NMe2
Br
Fe
P
PCy2
6
R' H
Fe
PCy2
1o. R' = i-Pr, 88%
1p. R' = Cy, 50%
1q. R' = 4-CF3C6H4, 60%
1r. R' = 4-MeOC6H4, 57%
1o-1r
3.85 ml (5 mmol) of s-BuLi (1.3 M in cyclohexane) was added dropwise to a solution of 1.29 g (5 mmol) of
(R)-1-dimethylamino-1-ferrocenylethane in 5 ml of TBME at <-20°C. After stirring the mixture at the same temperature
for 10 minutes, the temperature was allowed to rise to room temperature and the mixture was stirred for another 1.5
hours. The reaction mixture was then cooled to -78°C and (5 mmol) of dichloroalkyl(aryl)phosphine was added dropwise
at such a rate that the temperature does not exceed -60°C. Further stirring at -78°C for 30 minutes and subsequently at
room temperature for one hour gave a suspension comprising the chlorophosphine.
In another reaction vessel, 3.31 ml (5 mmol) of n-BuLi (1.6 M in hexane) was added dropwise to 2.31 g (5 mmol) of the
compound 6 in 10 ml of TBME at <-60 °C. After the addition, the temperature was allowed to rise to 0 °C and the mixture
was stirred at this temperature for another 30 minutes. The resulting reaction solution was then added to the cooled
suspension of the chlorophosphine prepared above, with care being taken to ensure that the temperature does not
exceed -50 °C. After the addition, the temperature was allowed to rise to room temperature and the mixture was stirred for
another 1.5 hours. After addition of 5 ml of saturated, aqueous NaHCO3 solution, the reaction mixture was extracted. The
organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure on a rotary evaporator.
This gave a mixture of the two diastereomers.
The mixture of the two diastereomers was heated without addition of solvent at 150 °C for two hours. After cooling,
chromatographic purification gave the desired ligands 1o-1r.
(RC,SFc,SP)-1-[2-(1- N,N-Dimethylaminoethyl)ferrocen-1-yl]isopropylphosphino-1’- dicyclohexylphosphinoferrocene
(1o):
1
H NMR (300 MHz, C6D6):δ 0.90~2.17 (m, 35H), 2.25 (s, 6H), 2.39 (m, 1H), 2.92 (m, 1H, J = 6.6 Hz), 3.93 (m, 1H),
4.07 (s, 5H), 4.21 (m, 1H), 4.27 (m, 1H), 4.38 (m, 3H), 4.43 (m, 4H), 4.47 (m, 1H), 4.74 (m, 1H). 31P NMR (121.5 MHz,
C6D6): δ -24.4 (s), -7.8 (s).
(RC,SFc,SP)-1-[2-(1- N,N-Dimethylaminoethyl)ferrocen-1-yl]cyclohexylphosphino-1’-dicyclohexylphosphino
ferrocene (1p):
1
H NMR (300 MHz, C6D6):δ 0.94~2.40 (m, 32H), 1.30 (d, 2H, J = 6.5 Hz), 2.63 (s, 6H), 2.72 (td, 1H, J = 12.6 and 2.7
Hz), 3.93 (m, 1H), 4.08 (s, 5H), 4.21 (m, 1H), 4.28 (m, 1H), 4.38~4.47 (m, 7H), 4.51 (m, 1H), 4.72 (m, 1H). 31P NMR
(121.5 MHz, C6D6):δ -26.9 (s), -8.4 (s).
S6
(RC,SFc,SP)-1-[2-(1- N,N-Dimethylaminoethyl)-1-ferrocenyl](4-trifluoromethylphenyl)phosphino-1’-dicyclohexyl
phosphinoferrocene (1q):
1
H NMR (C6D6, 300 MHz): δ 1.10 (d, J = 6.7 Hz, 3H), 0.96~2.36 (m, 11H), 1.65 (s, 6H), 3.80 (s, 1H), 4.00 (m, 1H), 4.02
(m, 1H), 4.10 (m, 2H), 4.13 (s, 5H), 4.19 (m, 3H), 4.28 (m, 1H), 4.34 (m, 1H), 4.43 (m, 1H), 4.48 (m, 1H), 4.70 (m, 1H),
7.50 (d, J = 8.4 Hz, 2H), 7.71 (dd, J = 8.4 and 7.7 Hz, 2H); 31P NMR (CDCl3, 101 MHz): δ -7.8 and -35.0.
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl](4-methoxyphenyl)phosphino-1’-dicyclohexyl
phosphinoferrocene(1r):
1H NMR (C6D6, 300 MHz): δ 1.18 (d, J = 6.7 Hz, 3H), 1.00~2.36 (m, 11H), 1.82 (s, 6H), 3.39 (s, 3H), 4.07 (m, 1H),
4.09 (m, 1H), 4.12 (m, 1H), 4.16 (s, 5H), 4.21 (m, 1H), 4.30 (m, 2H), 4.39 (m, 3H), 4.50 (m, 2H), 4.77 (m, 1H), 6.89 (d,
J = 8.3 Hz, 2H), 7.73 (dd, J = 8.3 and 7.7 Hz, 2H); 31P NMR (CDCl3, 101 MHz): δ -7.4 and -37.7.
General procedure for “one-pot” synthesis:
(RC,SFc,SP)-1-[2-(1-N,N-Dimethylaminoethyl)-1-ferrocenyl]cyclohexylphosphino-1’-bis[3,5-di(trifluoromethyl)
phenyl]phosphinoferrocene (1r):
NMe2
Fe
P
Fe
Fe
Br
2
Cy
Fe
P
NMe2
Cy
Fe
H
Ar2
NMe2
H
Fe
heating
P
Cy
Fe
Ar2
NMe2
H
Ar = 3,5-(CF3)3C6H3
1s
4 ml (10 mmol) of n-BuLi (2.5 M in hexane) are added dropwise to a solution of 3.44 g (10 mmol) of
1,1’-dibromoferrocene in 10 ml of tetrahydrofuran (THF) at a temperature of <-30°C. The mixture is stirred at this
temperature for a further 1.5 h to give a suspension of 1-bromo-1’-lithioferrocene.
In a second reaction vessel, 7.7 ml (10 mmol) of s-BuLi (1.3 M in cyclohexane) are added dropwise to a solution of 2.57 g
(10 mmol) of (R)-1-dimethylamino-1-ferrocenylethane in 15 ml of TBME at <-10°C. After stirring the mixture at the same
temperature for 10 min, the temperature is allowed to rise to 0°and the mixture is stirred for another 1.5 h. The reaction
mixture is then cooled to -78°C and 1.51 ml (10 mmol) of dichlorocyclohexylphosphine is added. Further stirring at -78°C
for 30 minutes and, after removal of cooling, at room temperature for another 1 h gives a suspension of the
chlorophosphine which is subsequently added at a temperature of <-10°C to the suspension of 1-bromo-1’-lithioferrocene.
The cooling is then removed and the mixture is stirred at room temperature for a further 1.5 h. After renewed cooling to
<-50°C, 4 ml (10 mmol) of n-BuLi (2.5 M in hexane) are added dropwise. After the addition, the temperature is allowed to
S7
rise to 0°C and the mixture is stirred for a further 30 min. It is then cooled to -20°C and 4.63 g (10 mmol) of
bis[3,5-di(trifluoromethyl)phenyl]chlorophosphine are added. The cooling is subsequently removed and the mixture is
stirred at room temperature for another 1.5 h. The reaction mixture is admixed with 1N NaOH and extracted. The organic
phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure on a rotary evaporator. The
residue is subsequently heated at 150°C for one hour. Chromatographic purification (silica gel 60; eluent = hexane/ethyl
acetate 8:1) gives 1s as a yellow solid (yield: 66%).1H NMR (300 MHz, C6D6): δ 1.25 (d, 3H, J = 6.7 Hz), 1.00~2.29 (m,
11H), 2.20 (s, 6H), 3.78 (m, 1H), 4.02 (m, 1H), 4.04 (s, 5H), 4.09 (m, 1H), 4.14 (m, 1H), 4.17 (m, 1H), 4.21 (m, 1H), 4.40
(m, 2H), 4.60 (m, 1H), 7.80 (d, 2H, J = 6.8 Hz), 8.00 (d, 4H, J = 6.0 Hz). 31P NMR (121.5 MHz, C6D6): δ -27.1 (s); -14.1
(s).
S8
II. Asymmetric hydrogenation:
Preparation of a rhodium complex (nbd is norbornadiene):
11 mg (0.0148 mmol) of ligand 1a and 5.4 mg (0.0144 mmol) of [Rh(nbd)2]BF4 were dissolved in 0.8 ml of CD3OD and
stirred for 10 minutes. The solution was transferred to an NMR tube for measurement. 31P NMR (121.5 MHz, CD3OD):
Two superimposed doublets. Possible assignment: δ 26.60 (d, J Rh-P = 163 Hz), 26.30 (d, JRh-P = 157 Hz).
General
procedure
for
the
hydrogenation
of
(E)-2-(3-(3-methoxypropoxy)-4-
methoxybenzylidene)-3-methylbutanoic acid:
0.0024 mmol of ligand and 0.85 mg (0.0023 mmol) of [Rh(nbd)2]BF4 are weighed into a 25 ml Schlenk vessel provided
with magnetic stirrer and rubber septum and dissolved in 2 ml of methanol. The solution is stirred for about 10 minutes.
A solution of (E)-2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid in methanol was then added
(the substrate concentration is 0.78 molar). The resulting solution was transferred under pressure by means of a cannula
into a 50 ml steel autoclave which was provided with heating and had previously been flooded with argon. The autoclave
was connected via a reducing valve to a hydrogen reservoir. The autoclave was closed and the argon was replaced by
hydrogen by two cycles of pressurization with hydrogen (60 bar) and depressurization. The autoclave was then
pressurized again with a hydrogen pressure indicated in Table and the hydrogenation was started at a temperature
indicated in Table by switching on the stirrer. After the reation time indicated in Table, the stirrer was switched off, the
autoclave was depressurized and the hydrogenation solution was taken out. The conversion and the enantiomeric excess
(ee) are determined by means of HPLC (Chirapak AD; 0.46 x 250 mm; hexane/EtOH/AcOH 950:50:1; flow =
0.7 ml/minute; 20°C.
Table 1. Hydrogenation of (E)-2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)- 3-methylbutanoic acid
Ar
CO2H
H2
Rh(NBD)2BF4
Ligand
CO2H
Ar
MeOH, 35 ℃
(R)-8
7
Ar = 3-(3-methoxypropoxy)-4-methoxyphenyl
entry
Ligand
S/C*
Tem.
[°C]
H2
[bar]
Time
[h]
Conv.
(%)
ee (%)
1
1a
2000
25
60
19.5
100
97.4
2
1a
5000
35
60
15.5
100
98.5
3
1a
8500
35
60
4
98
98.2
4
1a
8500
35
60
21
100
99.1
5
1a
8500
35
50
5
100
99.2
6
1a
12000
35
50
3.5
95
99.0
7
1a
12000
50
50
3.5
100
98.0
8
1b
2000
35
50
22
99
87.4
9
1c
5000
35
60
20.5
100
95.6
10
1c
2000
35
50
65
100
97.5
S9
entry
Ligand
S/C*
Tem.
[°C]
H2
[bar]
Time
[h]
Conv.
(%)
ee (%)
11
1e
8500
35
60
20
7
81.6
12
1f
8500
35
60
18
70
88.2
13
1g
8500
35
60
18
53
87.0
14
1h
8500
35
60
21
100
97.6
15
1h
12000
35
50
3.5
49.3
99.2
16
1i
8500
35
60
21
46
81.2
17
1j
8500
35
60
20
18
83.8
18
1k
2000
25
50
20
100
89.4
19
1l
2000
35
50
68
56
87.2
20
1m
2000
35
50
17
96
87.7
21
1n
2000
35
50
19
100
78.8
22
1o
6700
35
60
19
100
9.6
23
1p
8500
35
60
20
99
21.4
24
TriFer
8500
35
60
20
20
96.2
25
TriFer
12000
35
50
3.5
14
99.5
26
TriFer
2000
35
50
18.5
100
98.5
Hydrogenation of (E)-3-(4-benzyloxyphenyl)-2-alkoxyacrylic acid:
H2 (20 bar)
Rh(NBD)2BF4
CO2H
(RC,SFc,SP)-1h
OMe
BnO
MeOH, 40 ℃
CO2H
OMe
BnO
9
10
95.2% ee
1.87 mg (0.005 mmol) of [Rh(nbd)2]BF4 and 0.005 mmol of ligand are weighed into a 10 ml Schlenk vessel provided with
magnetic stirrer and rubber septum and dissolved in 1 ml of methanol. The solution is stirred for 10 minutes and a solution
of 143 mg (0.5 mmol) of substrate S2 in 4 ml of methanol (S/C = 100) or 285 mg (1 mmol) in 9 ml (S/C = 200) is then
added. The resulting solution is transferred under pressure via a cannula to a 50 ml steel autoclave and hydrogenated in a
manner
analogous
to
that
described
in
the
hydrogenation
of
(E)-2-(3-(3-methoxypropoxy)-4-
methoxybenzylidene)-3-methylbutanoic acid. The conversion and the enantiomeric excess (ee) are determined by means of
HPLC (Chirapak AD-H; 0.46 x 250 mm).
Preliminarily screening of the application scope of ChenPhos:
General procedure for Rh- and Ru-complexes catalyzed hydrogenation:
The hydrogenations are carried out in 1.2 ml ampoules. Instead of stirring, intensive shaking is carried out. In a glove box,
solutions having a volume of 0.5 ml and compositions shown in Table 4 are prepared in the 1.2 ml ampoules under a
nitrogen atmosphere. The catalysts are prepared in situ by mixing 1 equivalent of [Rh(nbd) 2]BF4 with 1.3 equivalents of
S10
ligand in dichloroethane and subsequently distilling off the dichloroethane under reduced pressure. The substrate is
dissolved in the hydrogenation solvent and added as a solution to the catalyst. The ampoules are fixed in place in a
pressure-rated, heatable container, the container is closed, the desired temperature is set, the nitrogen atmosphere in the
container is replaced by a hydrogen atmosphere at the desired pressure and the hydrogenation is started by switching on the
shaker. The conversion and the enantiomeric excess (ee) for the substrates S1 and S2 are determined by means of GC
(Chrasil-L-val). The hydrogenation samples from substrate S2 are derivatized beforehand by means of TMS-diazomethane.
The conversion and ee for substrate S3 are determined by means of GC (Lipodex-E). The results are summarized in Table 2.
Table 2. Preliminarily screening of Rh- and Ru-ChenPhos complexes catalyzed hydrogenation
H2 (1 bar)
[Rh(nbd)2]BF4
Ligand
NHAc
CO2Me
up to 97% ee
EtOH, rt
CO2Me
S1
H2 (1 bar)
[Rh(nbd)2]BF4
Ligand
NHAc
Ph
NHAc
CO2H
NHAc
Ph
THF, rt
S2
CO2H
up to 97% ee
O
H2 (80bar)
[RuI2(p-cymene)]2
Ligand
O
OEt
OH O
OEt
DCE, 80 °C
S3
up to 79% ee
entry
Ligand
Substrate
S/C*
Solvent
Temperature
[°C]
Pressure
[bar]
Time
[h]
Conversion
(%)
ee
(%)
1
1a
S1
100
EtOH
25
1
2
100
97
2
1b
S1
25
EtOH
25
1
2
100
94
3
1d
S1
100
EtOH
25
1
2
100
95
4
1f
S1
100
EtOH
25
1
2
100
95
5
1g
S1
100
EtOH
25
1
2
100
94
6
1a
S2
25
THF
25
1
2
100
94
7
1d
S2
25
THF
25
1
2
100
97
80
14
100
79
8*
S3
100
DCE
80
1b
* In this hydrogenation, [RuI2(p-cymene)]2 is used instead of [Rh(nbd)2]BF4.
General procedure for Ir-complexes catalyzed hydrogenation of imine:
N
O
H2 (80bar)
[Ir(cod)Cl]2
ChenPhos
HN
O
toluene, rt
4.89 mg (0.0067 mmol) of ligand 1b and 2.12 mg (0.0032 mmol) of [Ir(cod)Cl]2 are weighed into a 25 ml Schlenk vessel
provided with magnetic stirrer and rubber septum and dissolved in 2 ml of toluene. The solution is stirred for about 10
S11
minutes. A solution of 260 mg (1.27 mmol) of imine, 4.7 mg of tetrabutylammonium iodide and 30 mg of acetic acid in
3 ml of toluene is then added. The resulting solution is transferred under pressure via a cannula into a 50 ml steel autoclave
provided with heating. The hydrogenation is carried out in a manner analogous to that described in the hydrogenation of
(E)-2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid (hydrogenation time = 19 hours; room
temperature; hydrogen pressure = 80 bar). The conversion and the enantiomeric excess (ee) are determined by means of
HPLC (Chiracel OD-H). The conversion is quantitative and the ee is 31% (R configuration).
S12
III. Plausible transition state in asymmetric hydrogenation:
The generally accepted mechanism of enantioselective hydrogenation catalysed by a Rh-complex involves a substrate
coordination to the solvate Rh-complex to form a chelate catalyst-substrate complex A (Figure 1) in which the olefinic
bond and the carbonyl oxygen at the β position interact with the Rh(I) centre. To achieve high enantioselectivity and
activity, it is essential that there is a second functional group such as carbonyl group at the β position to olefinic bond
that is capable of chelation with the metal resulting in a ring system that stablises the reactive intermediate. Unlike
enamides, enol acetates and itaconates, α-substituted cinnamic acids lack such functionality at the β position to
coordinate with the metal; thus most of known chiral diphosphine ligands give low enantioselectivities and activities for
the Rh-catalysed asymmetric hydrogenation of α-substituted cinnamic acids. However, in the 1a-Rh-substrate complex B,
the dimethylamino moiety would serve to have a secondary interaction with the substrate, i.e. an electrostatic interaction
with the carboxyl unit of substrate, establishing the multi-site recognition of the substrate by the Rh-complex leading to
high enantioselectivity and activity. In addition, the catalytic activity is further enhanced by the strengthened d-σ*
interaction (acceleration of the oxidative addition of molecular hydrogen) with the bulky and electron-rich
dicyclohexylphosphino group.
Fe
R1
Z
P
R
Rh
*
P
O
Fe
R2
H
N
H
O
Ph O
P
Rh
R
Ar
P
Z = NH, O, CH2
A
B
Figure 1.
Substrate-catalyst complexes in asymmetric hydrogenation
Ligand 1t (replacement of dimethylamino group in 1a with a methoxy group) is not effective for the Rh-catalyzed
hydrogenation of (E)-2-(3-(3-methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanoic acid 7 (44% ee) (Scheme 1) due
to lacking the secondary interaction (a stable substrate-catalyst complex is unable to form). However, it is a perfect ligand
for the hydrogenation of a standard substrate methyl 2-acetamidoacrylate with a carbonyl group at the β position to olefinic
bond (>99.9% ee) (Scheme). In methyl 2-acetamidoacrylate, the secondary interaction functional group is the carbonyl
(acetyl group) at the β position of olefinic bond; the C=C bond and the carbonyl oxygen atom at the β position interact with
the RhI center to form a stable chelate catalyst–substrate complex.
S13
CO2H
Ar
H2
Rh(NBD)2BF4
1t
CO2H
Ar
MeOH, 35 ℃
Fe
(R)-8
44% ee
7
Ar = 3-(3-methoxypropoxy)-4-methoxyphenyl
NHAc
CO2Me
H2 (1 bar)
[Rh(nbd)2]BF4
1t
EtOH, rt
P
Ph
Fe
NHAc
CO2Me
> 99.9% ee
PCy2
1t
Scheme 1. Ligand 1t-Rh complex catalyzed asymmetric hydrogenation
S14
OMe
H
IV. NMR spectra:
S15
S16
S17
S18
S19
S20
S21
S22
S23
S24
S25
S26
S27
S28
S29
S30
S31
S32
S33
S34
S35
S36
S37
S38
S39
S40
S41
S42
S43
S44
S45
S46
S47
S48
S49
S50
S51
S52