Asymmetric hydrogenation of aromatic ketones using an iridium(I) catalyst containing ferrocene-based P-N-N tridentate ligands

Article abstract of DOI:10.1016/j.tetasy.2013.10.012

Six ferrocene-based P-N-N tridentate ligands have been synthesized and applied in the Ir-catalyzed asymmetric hydrogenation of aromatic ketones. A wide range of ketones are hydrogenated enantioselectively to afford the corresponding optically active alcohols in the enantioselectivities of up to 86.6% ee. The substituent groups on the P-phenyl and pyridine rings play an important role with regard to the enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2013.10.012

Tetrahedron: Asymmetry 24 (2013) 1567–1571
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric hydrogenation of aromatic ketones using an iridium(I)
catalyst containing ferrocene-based P–N–N tridentate ligands
⇑
⇑
Huifang Nie, Gang Zhou, Quanjun Wang, Weiping Chen , Shengyong Zhang
School of Pharmacy, Fourth Military Medical University, Shaanxi Province, Xi’an 710032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Six ferrocene-based P–N–N tridentate ligands have been synthesized and applied in the Ir-catalyzed
asymmetric hydrogenation of aromatic ketones. A wide range of ketones are hydrogenated enantioselec-
tively to afford the corresponding optically active alcohols in the enantioselectivities of up to 86.6% ee.
The substituent groups on the P-phenyl and pyridine rings play an important role with regard to the
enantioselectivity.
Received 29 July 2013
Revised 9 October 2013
Accepted 10 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
RuCl2(diamine)] systems, with several structurally related cata-
lysts also showing similar excellent selectivities and reactivities
The development of new asymmetric catalytic systems is still a
major challenge because of its importance in synthetic organic
chemistry and manufacturing fine chemicals.1 The reduction of ke-
tones using molecular hydrogen is a very important process in or-
ganic synthesis due to its low cost and complete atom efficiency.2
The catalytic asymmetric hydrogenation of simple ketones pro-
vides the most efficient process for the production of optically ac-
tive secondary alcohols, which in turn, are some of the most
valuable intermediates for the manufacturing of pharmaceuticals
and advanced materials. For the asymmetric hydrogenation of sim-
ple aromatic ketones, the use of [(diphosphine)RuCl2(diamine)]
type catalytic systems (Fig. 1) pioneered by Noyori et al. is one of
the most powerful and reliable procedures.3 The general definitive
feature of this catalyst is that ruthenium is coordinated with a chi-
ral diphosphine and a chiral diamine, forming a well defined chiral
trans-octahedral complex. The high degree of enantioselectivity
was considered to be the result of a synergistic effect of the chiral
diphosphine and the diamine ligands.4 Since Noyori’s original
publications, there has been much interest in [(diphosphine)-
for the reduction of acetophenone derivatives. Much effort has
been dedicated to developing efficient phosphine ligands such as
chiral phosphines, chirally flexible phosphines, and even achiral
bulky monophosphine ligands. However, most phosphines have
been used in conjunction with chiral DPEN and DAIPEN to mimic
the Noyori catalyst.5,6
Recently, Zhou et al. developed chiral iridium catalysts contain-
ing a chiral SpiroPAP ligand, and these catalysts showed excellent
enantioselectivities (up to 99.9% ee) and an extremely high TON (as
high as 4,550,000) for the hydrogenation of simple ketones.7 These
Ir-SpiroPAP catalysts (Fig. 1) are likely to have a ‘metal-ligand
bifunctional catalysis’ mechanism, similar to the [(diphos-
phine)RuCl2(diamine)] catalysts.8
We have reported on several ferrocene-based aminophosphine
ligands 1 (Fig. 2) and their application in the Ru(II)-catalyzed
asymmetric hydrogenation of ketones.9 Continuing our interest
in ferrocene-based chiral ligands and their application in
asymmetric catalysis10 as well as being inspired by Zhou’s results
in the Ir-SpiroPAP catalyzed asymmetric hydrogenation of ketones,
we herein report preliminary results regarding new ferrocene-
based P–N–N ligands 2 (Fig. 2) and their Ir-complexes-catalyzed
asymmetric hydrogenation of ketones.
Ar Ar
Ar Ar
H2
N
Cl
Cl
Ir
P
H
P
N
H
Ru
N
P
N
Cl
H2
H
Ar Ar
[(S)-BINAP-RuCl2-(S)-DPEN]
N
H
NHR
Ir-SpiroPAP
PAr2
PAr2
N
Fe
Fe
Figure 1. [(S)-BINAP-RuCl2-(S)-DPEN] and Ir-SpiroPAP.
X
1
2
⇑
Corresponding authors. Tel.: +86 29 84 776 775.
E-mail address: wpchen@fmmu.edu.cn (W. Chen).
Figure 2. Ferrocene-based ligands 1 and 2.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.10.012

1568
H. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 1567–1571
Table 1
2. Results and discussion
New ferrocene-based P–N–N ligands
Asymmetric hydrogenation of acetophenone catalyzed by Ir-2a–f complexesa
O
OH
2
were very easily
20 atm H2
[{Ir(cod)Cl}2] / L*
accessible from the readily available (R)-Ugi’s amine 3 (Scheme 1).
Thus, highly diastereoselective ortho-lithiation of amine (R)-3 fol-
lowed by treatment with ClPAr2 gave PPFA derivatives 4, which
have an (RC,SFc)-configuration. After the reaction of 4 with Ac2O
at 100 °C, followed by treatment with a large excess of ammonia
in a mixture of water, methanol, and THF at 60 °C, the dimethyl-
amino group of 4 was substituted by an amino group to form com-
pounds 5. Finally, reductive amination of 5 with picolinaldehydes
resulted in the formation of ligands 2a–f in high isolated yields.
solvent, t-BuOK, RT
S/C=2000
7a
8a
Entry
Ligand
Solvent
Time (h)
Convb (%)
eec (%)
1
2
3
4
5
6
7
8
2f
2f
2f
2f
2a
2b
2c
2d
2e
2f
MeOH
EtOH
12
18
18
24
18
18
18
18
18
36
99
99
98
97
99
99
99
99
99
96
60.1 (R)
77.0 (R)
23.1 (R)
43.0 (R)
44.1 (R)
25.1 (R)
57.6 (R)
60.5 (R)
69.8 (R)
75.0 (R)
i-PrOH
Toluene
EtOH
EtOH
EtOH
EtOH
EtOH
9
NMe2
NMe2
1) t-BuLi, 0oC
2) Ar2PCl, 0oC
1) Ac2O, 100oC
10d
EtOH
PAr2
Fe
Fe
2) NH4OH, MeOH/THF
a
Reaction conditions: 10 mmol substrate, 0.055 mol % 2, 0.025 mol %
[{Ir(cod)Cl}2], 2.5 mol % t-BuOK, solvent volume = 3 mL, room temperature (25–
30 °C). The catalysts were prepared in situ.
(R)-3
(RC,SFc)-4
b
Yield of isolated product.
Determined by HPLC using chiral columns.
a, Ar = C6H5, 72%
c
b, Ar = (3,5)-(Me)2C6H3, 58%
f, Ar = (3,5)-(t-Bu)2C6H3, 50%
d
S/C = 5000, 50 atm H2.
X
well as the 6-methyl group on the pyridine ring of the ligand were
the crucial factors with regard to the enantioselectivity. When the
catalyst Ir-2f loading was lowered to 0.02 mol % (S/C = 5000),
the hydrogenation product (R)-8a was still obtained with 75% ee
(entry 10).
NH2
N
H
OHC
N
PAr2
N
Fe
PAr2
Fe
NaBH(OAc)3, DCE, rt
X
5
2
(RC,SFc)-
(RC,SFc)-
a, Ar = C6H5, 70%
A wide range of ketones were hydrogenated over Ir-2f under
the standard reaction conditions (Table 2). All of the aromatic
ketones 7a–o tested underwent hydrogenation to afford the
corresponding chiral alcohols 8a–o in good isolated yields and
with moderate to good enantioselectivities (53.5–86.6% ee)
(Table 2, entries 1–16). Of the ketones reduced, those with
meta-substituting groups on the phenyl ring provided the best
enantioselectivities (entries 6, 7, 8, 15). Electron withdrawing
groups and electron donating groups on the phenyl ring, respec-
tively, increased and decreased the activity, but seemed to only
have a marginal effect on the ee values. When the catalyst loading
a
, Ar = C6H5, X = H, 95%
b, Ar = (3,5)-(Me)2C6H3, 63%
f, Ar = (3,5)-(t-Bu)2C6H3, 65%
b,
Ar = C6H5, X = 3-Me, 93%
c,
Ar = C6H5, X = 5,6-(CH)4, 95%
Ar = C6H5, X = 6-Me, 93%
d,
e
, Ar = (3,5)-(Me)2C6H3, X = 6-Me, 90%
f
, Ar = (3,5)-(t-Bu)2C6H3, X = 6-Me, 94%
Scheme 1. Synthesis of P–N–N ligands 2a–f.
We envisioned that the reaction of ligands 2 with [{Ir(cod)Cl}2]
under hydrogen would form complexes 6 (Fig. 3), which might be
similar to Zhou’s Ir-SpiroPAP catalysts, giving high enantioselectiv-
ity and activity in the enantioselective hydrogenation of ketones.
Table 2
H
Asymmetric hydrogenation of ketones with Ir-2fa
N
H
20 atm H2
O
OH
N
P
Ar
Fe
Ir
[{Ir(cod)Cl}2] / 2f
Ar
X
H
R1
R2
EtOH, t-BuOK, rt
S/C = 2000
R1
R2
Cl
7
8
6
Entry
R1
R2
Prod
Time (h)
Yieldb (%)
eec (%)
Figure 3. Plausible Ir-(RC,SFc)-2 catalysts.
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
2-MeOC6H4
2-BrC6H4
3-MeOC6H4
3-BrC6H4
3-CF3C6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-FC6H4
2-Furyl
1-Naphthyl
2-Naphthyl
3-BrC6H4
Me
Et
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8g
18
15
18
12
18
12
18
18
12
12
18
12
12
18
18
36
99
99
99
99
99
99
99
98
99
99
99
99
99
98
98
96
77.0 (R)
73.6 (R)
60.8 (R)
69.9 (R)
78.5 (R)
82.4 (R)
86.6 (R)
84.2 (R)
75.2 (R)
70.1 (R)
75.2 (R)
65.7 (R)
53.5 (R)
62.3 (R)
82.6 (R)
85.2 (R)
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
We initially chose acetophenone 7a as the model substrate for
evaluating the performance of ligands 2a–f in the Ir-catalyzed
asymmetric hydrogenation of ketones. All of the ligands 2a–f dis-
played high reactivity and moderate to good enantioselectivity in
the hydrogenation of acetophenone (Table 1). Thus, the complete
hydrogenation of acetophenone to (R)-1-phenylethanol (R)-8a
with 60.1% ee occurred in less than 12 h at room temperature in
MeOH under an H2 pressure of 20 atm in the presence of
0.055 mol % (RC,SFc)-2f, 0.025 mol % [{Ir(cod)Cl}2], and 2.5 mol %
t-BuOK (entry 1). The choice of solvent played an important role
in the hydrogenation; EtOH proved to be the best solvent for
Ir-2f (entries 2–4). Ligand screening results demonstrated that
substituent groups on the pyridine and phenyl rings played only
a small role in the reactivity but had a significant effect on the
enantioselectivity. Of the ligands tested, the best results were ob-
tained using 2f in 77% ee with full conversion (entry 2), which
proved that the 3,5-di-tert-butyl groups on the P-phenyl rings as
9
10
11
12
13
14
15
16d
a
Reaction conditions: 10 mmol substrate, 0.055 mol % 2, 0.025 mol %
[{Ir(cod)Cl}2], 2.5 mol % t-BuOK, solvent volume = 3 mL, room temperature
(25–30 °C). The catalysts were prepared in situ.
b
Yield of isolated product.
Determined by HPLC using chiral columns.
S/C = 5000, 50 atm H2.
c
d

H. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 1567–1571
1569
was lowered to 0.02 mol % (S/C = 5000), optically active 8g was ob-
tained in high yield and with little diminishment of the enantiose-
lectivity (entry 16).
4.2.1.3. (RC,SFc)-1-[Bis(3,5-di-tert-butylphenyl)phosphino]-2-[1-
(dimethylamino)ethyl]ferrocene 4f.
Yield: 3.33 g, 50%.
Yellow foam; ½a 2D5
ꢀ
¼ ꢁ246:8 (c 0.25, CH2Cl2); 1H NMR (500 Hz,
CDCl3) d 7.65–7.55 (m, 2H), 7.44 (s, 1H), 7.25–7.21 (m, 3H), 4.37
(s, 1H), 4.26 (s, 1H), 4.21–4.17 (m, 1H), 3.97 (s, 5H), 3.90 (s, 1H),
1.73 (s, 6H), 1.36 (s, 18H), 1.32 (d, J = 6.5 Hz, 3H), 1.26 (s, 18H);
31P NMR (202 Hz, CDCl3) d ꢁ22.79 (s); 13C NMR (126 Hz, CDCl3) d
149.8 (d, J = 7.4 Hz), 149.2 (d, J = 7.3 Hz), 138.9 (d, J = 3.8 Hz),
137.1 (d, J = 7.2 Hz), 129.5 (d, J = 22.1 Hz), 127.2 (d, J = 20.5 Hz),
122.6, 121.1, 96.2 (d, J = 22.3 Hz), 78.4 (d, J = 9.2 Hz), 71.6 (d,
J = 5.4 Hz), 69.6, 69.2 (d, J = 3.8 Hz), 67.9, 57.2 (d, J = 7.2 Hz), 39.2,
34.9, 34.7, 31.6, 31.5, 10.7; HRMS (ESI) Calcd for C42H60FeNP
[M+1]+: 666.3879, Found: 666.3875.
3. Conclusion
In conclusion, we have designed and synthesized a series of
ferrocene-based P–N–N tridentate ligands and applied them to
the Ir-catalyzed asymmetric hydrogenation of aromatic ketones.
A wide range of ketones could be hydrogenated enantioselectively
to afford the corresponding optically active alcohols in good
isolated yields and with moderate to good enantioselectivities.
The substituent groups on the P-phenyl and pyridine rings played
a significant role with regard to the reaction enantioselectivity.
Further modification of the Ar on the phosphorus and X on the
pyridine ring is currently underway.
4.2.2. General preparation of 5a, 5e, 5f
A solution of 4 (5 mmol) in Ac2O (20 mL) was heated to 100 °C
under nitrogen conditions, and the mixture was stirred for 2 h at
100 °C. After cooling to room temperature, the orange reaction
mixture was concentrated in vacuo to give an acetate. The acetate
could be used in the next step without purification. To a solution of
the acetate in an 80 mL mixture of MeOH and THF (1:1) was added
aqueous ammonia (20 mL). The reaction was then stirred at 60 °C
for 24 h. After cooling to room temperature, the mixture was
quenched by the addition of ice water. The red–brown solution
was extracted with ether, the organic phase was dried over Na2SO4,
and the solvent was removed under reduced pressure. After chro-
matographic purification, the desired products 5a, 5e, and 5f were
obtained in good yields.
4. Experimental
4.1. General
The 1H and 13C NMR spectra were recorded on a Bruker AV-500
spectrometer using TMS as an internal reference. Coupling con-
stant (J) values are given in Hz. Melting points were obtained on
Micro Melting Point Instrument (XRC-1) and are uncorrected. Opti-
cal rotation analyses were performed on a Perkin–Elmer Model
343 Polarimeter. HRMS were recorded on ZAB-HS spectrometer
with ES ionization (ESI). All commercially available reagents were
used as received. Solvents and reagents were purified and dried
by standard methods prior to use. Products were purified by flash
column chromatography on silica gel purchased from Qingdao
Haiyang Chemical Co., Ltd. All reactions involving air or moisture
sensitive species were performed under an inert atmosphere in
oven-dried glassware.
4.2.2.1. (RC,SFc)-1-(Diphenylphosphino)-2-[(1-amino)ethyl]fer-
rocene 5a9.
Yield: 1.45 g, 70%. Yellow solid; mp 132.4–
132.9 °C; ½a 2D5
ꢀ
¼ ꢁ407:2 (c 0.25, CH2Cl2); 1H NMR (500 Hz, CDCl3)
d 7.57–7.50 (m, 2H), 7.40–7.35 (m, 3H), 7.28–7.24 (m, 5H), 4.44
(s, 1H), 4.29–4.26 (m, 1H), 4.24–4.17 (m, 1H), 4.02 (s, 5H), 3.78–
3.75 (m, 1H), 1.45 (d, J = 6.5 Hz, 3H).
4.2. Synthesis of ferrocene-based tridentate ligands 2a–f
4.2.2.2.
(RC,SFc)-1-[Bis(3,5-dimethylphenyl)phosphino]-2-[(1-
4.2.1. General preparation of 4a, 4e, 4f
amino)ethyl]ferrocene 5e9.
Yield: 1.48 g, 63%. Yellow solid;
To a solution of (R)-Ugi’s amine 3 (2.57 g, 10 mmol) in TBME
(20 mL) was added 1.6 M t-BuLi solution in n-hexane (6.8 mL,
10.88 mmol) at 0 °C. After the addition was complete, the mixture
was warmed to room temperature, and stirred for 1.5 h at room
temperature. The mixture was then cooled to 0 °C again, and
Ar2PCl (11 mmol) was added in one portion. After stirring for
20 min at 0 °C, the mixture was warmed to room temperature,
and stirred for 1.5 h at room temperature. The mixture was then
quenched by the addition of saturated NaHCO3 solution (20 mL).
The organic layer was separated and dried over MgSO4, and the sol-
vent was removed under reduced pressure, after which the filtrate
was concentrated. The residue was purified by chromatography to
afford 4a, 4e, and 4f.
mp 142.3–143.1 °C; ½a D25
ꢀ
¼ ꢁ305:5 (c 0.25, CH2Cl2); 1H NMR
(500 Hz, CDCl3) d 7.25–7.15 (d, J = 8.5 Hz, 2H), 7.05 (s, 1H), 6.95–
6.85 (m, 3H), 4.30 (m, 1H), 4.30–4.20 (m, 1H), 4.07 (s, 5H), 3.62
(s, 1H), 2.36 (s, 6H), 2.26 (s, 6H), 1.88 (s, 6H), 1.49 (d, J = 6.5 Hz, 3H).
4.2.2.3.
(RC,SFc)-1-[Bis(3,5-di-tert-butylphenyl)phosphino]-2-
[(1-amino)ethyl]ferrocene 5f.
Yield: 2.07 g, 65%. Yellow
foam; ½a 2D5
ꢀ
¼ ꢁ205:6 (c 0.25, CHCl3); 1H NMR (500 Hz, CDCl3) d
7.40 (s, 1H), 7.38–7.34 (m, 2H), 7.30–7.28 (m, 1H), 7.18–7.13 (m,
2H), 4.40–4.36 (m, 1H), 4.26–4.20 (m, 1H), 4.18–4.10 (m, 1H),
4.05 (s, 5H), 3.67–3.64 (m, 1H), 1.42 (d, J = 7 Hz, 3H), 1.29 (s,
18H), 1.21 (s, 18H); 31P NMR (202 Hz, CDCl3) d ꢁ23.05 (s); 13C
NMR (126 Hz, CDCl3) d 150.4 (d, J = 6.6 Hz), 150.1 (d, J = 7.4 Hz),
138.4 (d, J = 7.8 Hz), 135.8 (d, J = 7.6 Hz), 129.1 (d, J = 21.2 Hz),
127.5 (d, J = 20.2 Hz), 122.8, 122.3, 100.0 (d, J = 10.2 Hz), 76.5 (d,
J = 7.7 Hz), 71.1 (d, J = 3.5 Hz), 69.5, 68.6, 67.8 (d, J = 3.8 Hz), 45.4
(d, J = 8.8 Hz), 34.9, 34.8, 31.5, 31.4, 22.9; HRMS (ESI) Calcd for C40-
H56FeNP [M+1]+: 638.3578, Found: 638.3571.
4.2.1.1. (RC,SFc)-1-(Diphenylphosphino)-2-[1-(dimethylamino)-
ethyl]ferrocene 4a12
.
Yield: 3.17 g, 72%. Red solid; mp
141–143 °C; ½a 2D5
ꢀ
¼ ꢁ358:9 (c 0.25, CHCl3); 1H NMR (500 Hz,
CDCl3): d 7.62–7.56 (m, 2H), 7.37–7.32 (m, 3H), 7.22–7.14 (m,
5H), 4.37 (s, 1H), 4.25–4.24 (m, 1H), 4.16–4.14 (m, 1H), 3.94 (s,
5H), 3.86 (s, 1H), 1.77 (s, 6H), 1.26 (d, J = 7 Hz, 3H).
4.2.3. Synthesis of ligands 2a–f
To a solution of ferrocenyl aminophosphine ligand 5 (1 mmol)
and NaBH(OAc)3 (2 mmol) in DCE (10 mL) was added picolinalde-
hyde (1.1 mmol) under a nitrogen atmosphere. The reaction mix-
ture obtained was stirred at room temperature for 10–18 h
(monitored by TLC). After being quenched with a saturated
NaHCO3 solution, the mixture was diluted with water and
extracted with ethyl acetate. The organic layer was dried with
4.2.1.2.
(RC,SFc)-1-[Bis(3,5-dimethylphenyl)phosphino]-2-[1-
(dimethylamino)ethyl]ferrocene 4e12
.
Yield: 2.88 g, 58%.
Red oil; ½a 2D5
ꢀ
¼ ꢁ278:9 (c 0.25, CHCl3); 1H NMR (500 Hz, CDCl3) d
7.25–7.23 (m, 2H), 6.98 (s, 1H), 6.80–6.78 (m, 3H), 4.35 (s, 1H),
4.23–4.22 (m, 1H), 4.10–4.08 (m, 1H), 3.92 (s, 5H), 3.87 (s, 1H),
2.32 (s, 6H), 2.18 (s, 6H), 1.81 (s, 6H), 1.28 (d, J = 7 Hz, 3H).

1570
H. Nie et al. / Tetrahedron: Asymmetry 24 (2013) 1567–1571
anhydrous Na2SO4 and concentrated in vacuo to afford the crude
product. After chromatography on silica-gel column, the corre-
sponding P–N–N ligands 2a–f were obtained in high yields.
4.2.3.5. (RC,SFc)-1-[Bis(3,5-dimethylphenyl)phosphino]-2-[1-N-
(6-methylpyridin-2-ylmethyl) ethyl]ferrocene 2e.
Yield:
0.52 g, 90%. Yellow foam; ½a D25
ꢀ
¼ ꢁ262:4 (c 0.25, CH2Cl2); 1H
NMR (500 Hz, CDCl3) d 7.28–7.23 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H),
7.04 (s, 1H), 6.92–6.84 (m, 3H), 6.74 (s, 1H), 6.30 (d, J = 8 Hz, 1H),
4.55 (s, 1H), 4.34–4.30 (m, 1H), 4.29–4.22 (m, 1H), 4.08 (s, 5H),
3.87–3.82 (m, 1H), 3.63 (d, 2J = 14.5 Hz, 1H), 3.61 (d, 2J = 14.5 Hz,
1H), 2.47 (s, 3H), 2.35 (s, 6H), 2.11 (s, 6H), 1.58 (d, J = 6.5 Hz,
3H); 31P NMR (202 Hz, CDCl3) d ꢁ25.14 (s); 13C NMR (126 Hz,
CDCl3) d 159.5, 157.0, 139.4 (d, J = 9.3 Hz), 137.6 (d, J = 6.7 Hz),
137.4 (d, J = 7.9 Hz), 136.8 (d, J = 8.9 Hz), 136.2, 132.6, 132.5,
130.6 (d, J = 25.1 Hz), 130.2 (d, J = 28.7 Hz), 120.7, 117.8, 97.3 (d,
J = 23.9 Hz), 75.8 (d, J = 7.8 Hz), 71.4 (d, J = 4 Hz), 69.6, 69.5 (d,
J = 3.9 Hz), 68.7, 51.8, 51.1 (d, J = 9.6 Hz), 24.4, 21.4, 21.2, 19.1;
HRMS (ESI) Calcd for C35H39FeN2P [M+1]+: 575.2279, Found:
575.2273.
4.2.3.1.
(RC,SFc)-1-(Diphenylphosphino)-2-[1-N-(pyridin-2-
ylmethyl)ethyl]ferrocene 2a.
Yield: 0.48 g, 95%. Red solid;
mp 137.3–138.2 °C; ½a D25
ꢀ
¼ ꢁ320:2 (c 0.25, CH2Cl2); 1H NMR
(500 Hz, CDCl3) d 8.40–8.35 (m, 1H), 7.65–7.55 (m, 2H), 7.42–
7.32 (m, 4H), 7.32–7.26 (m, 2H), 7.22–7.14 (m, 3H), 7.04–6.98
(m, 1H), 6.60 (d, J = 8 Hz, 1H), 4.58–4.57 (m, 1H), 4.37–4.33 (m,
1H), 4.26–4.20 (m, 1H), 4.06 (s, 5H), 3.88–3.84 (m, 1H), 3.69 (d,
2J = 14 Hz, 1H), 3.66 (d, 2J = 14 Hz, 1H), 1.60 (d, J = 7 Hz, 3H); 31P
NMR (202 Hz, CDCl3) d ꢁ25.03 (s); 13C NMR (126 Hz, CDCl3) d
159.9, 148.7, 140.1 (d, J = 10 Hz), 137.3 (d, J = 8.8 Hz), 136.0,
135.0 (d, J = 21.2 Hz), 132.6 (d, J = 18.9 Hz), 129.1, 128.3 (d,
J = 6.4 Hz), 128.1, 128.0 (d, J = 2.8 Hz), 121.5, 121.3, 97.7 (d,
J = 24.4 Hz), 75.1 (d, J = 7.7 Hz), 71.3 (d, J = 4.4 Hz), 69.6, 69.5 (d,
J = 4.4 Hz), 69.1, 52.2, 51.3 (d, J = 9.3 Hz), 19.5; HRMS (ESI) Calcd
for C30H29FeN2P [M+1]+: 505.1496, Found: 505.1485.
4.2.3.6. (RC,SFc)-1-[Bis(3,5-di-tert-butylphenyl)phosphino]-2-[1-
N-(6-methylpyridin-2-ylmethyl)ethyl]ferrocene 2f.
Yield:
0.69 g, 94%. Yellow foam; ½a D25
ꢀ
¼ ꢁ184:6 (c 0.25, CH2Cl2); 1H
4.2.3.2. (RC,SFc)-1-(Diphenylphosphino)-2-[1-N-(3-methylpyri-
NMR (500 Hz, CDCl3) d 7.42–7.37 (m, 3H), 7.24 (s, 2H), 7.23–7.21
(m, 1H), 7.17–7.10 (m, 1H), 6.81 (d, J = 7.5 Hz, 1H), 5.89 (d,
J = 8 Hz, 1H), 4.51 (s, 1H), 4.30–4.23 (m, 2H), 4.06 (s, 5H), 3.75 (s,
1H), 3.54 (d, 2J = 14.5 Hz, 1H), 3.48 (d, 2J = 14.5 Hz, 1H), 2.39 (s,
3H), 1.55 (d, J = 6.5 Hz, 3H), 1.29 (s, 18H), 1.13 (s, 18H); 31P NMR
(202 Hz, CDCl3) d ꢁ24.98 (s); 13C NMR (126 Hz, CDCl3) d 159.4 (d,
J = 5.9 Hz), 157.1, 150.5 (d, J = 6.6 Hz), 150.0 (d, J = 7.4 Hz), 138.5
(d, J = 7.7 Hz), 136.3, 135.6 (d, J = 7.3 Hz), 129.1 (d, J = 21.4 Hz),
127.4 (d, J = 20.7 Hz), 125.3, 122.7 (d, J = 20.5 Hz), 120.8, 117.8,
96.9, 75.1 (d, J = 14.1 Hz), 71.1 (d, J = 4.2 Hz), 69.6, 69.4 (d,
J = 3.8 Hz), 68.6, 51.8, 51.1 (d, J = 10.1 Hz), 34.9, 34.8, 31.5, 31.3,
24.3, 19.2; HRMS (ESI) Calcd for C47H63FeN2P [M+1]+: 743.4157,
Found: 743.4148.
din-2-ylmethyl)ethyl]ferrocene 2b.
Yield: 0.46 g, 92%. Red
solid; mp 103.2–104 °C; ½a D25
ꢀ
¼ ꢁ353:6 (c 0.25, CH2Cl2); 1H NMR
(500 Hz, CDCl3) d 8.07 (d, J = 4 Hz, 1H), 7.60–7.52 (m, 2H), 7.40–
7.32 (m, 3H), 7.23–7.16 (m, 3H), 7.13–7.03 (m, 3H), 6.92–6.87
(m, 1H), 4.57 (s, 1H), 4.33–4.30 (m, 1H), 4.18–4.12 (m, 1H), 3.97
(s, 5H), 3.88–3.84 (m, 1H), 3.66 (d, 2J = 14 Hz, 1H), 3.52 (d,
2J = 14 Hz, 1H), 1.97 (s, 3H), 1.64 (d, J = 6.5 Hz, 3H); 31P NMR
(202 Hz, CDCl3) d ꢁ24.81 (s); 13C NMR (126 Hz, CDCl3) d 156.9,
146.0, 140.0 (d, J = 9.2 Hz), 137.8 (d, J = 9.1 Hz), 136.9, 135.1 (d,
J = 21.5 Hz), 132.3 (d, J = 18.1 Hz), 130.4, 129.0, 128.1, 128.0 (d,
J = 5.8 Hz), 127.7, 121.2, 98.6 (d, J = 25.1 Hz), 74.9 (d, J = 8.3 Hz),
71.1 (d, J = 4 Hz), 69.6, 69.3 (d, J = 4.4 Hz), 69.2, 51.3 (d,
J = 9.5 Hz), 49.8, 20.8, 17.7; HRMS (ESI) Calcd for C31H31FeN2P
[M+1]+: 519.1653, Found: 519.1649.
4.3. Typical procedure for the asymmetric hydrogenation of
ketones 7a–o11
4.2.3.3.
(RC,SFc)-1-(Diphenylphosphino)-2-[1-N-(quinolin-2-
ylmethyl)ethyl]ferrocene 2c.
Yield: 0.53 g, 95%. Yellow foam;
To a 20 mL hydrogenation vessel were added the catalyst pre-
½
a 2D5
ꢀ
¼ ꢁ276:8 (c 0.25, CH2Cl2); 1H NMR (500 Hz, CDCl3) d 7.88 (d,
cursor [{Ir(cod)Cl}2] (1.7 mg, 2.53
lmol), ligand 2f (4.5 mg,
J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.65–
7.59 (m, 1H), 7.58–7.51 (m, 2H), 7.49–7.42 (m, 1H), 7.40–7.33 (m,
3H), 7.25–7.20 (m, 1H), 7.14–7.06 (m, 2H), 7.03–6.98 (m, 1H), 6.76
(d, J = 8.5 Hz, 1H), 4.58 (s, 1H), 4.34 (s, 1H), 4.33–4.25 (m, 1H), 4.01
(s, 5H), 3.90–3.80 (m, 3H), 1.62 (d, J = 6 Hz, 3H); 31P NMR (202 Hz,
CDCl3) d ꢁ25.13 (s); 13C NMR (126 Hz, CDCl3) d 147.4, 140.0 (d,
J = 9.5 Hz), 137.4 (d, J = 8.9 Hz), 136.0, 135.1, 134.9, 132.7, 132.5,
131.4 (d, J = 10.2 Hz), 129.1 (d, J = 9.5 Hz), 128.3 (d, J = 6.3 Hz),
128.1 (d, J = 8.1 Hz), 128.0, 127.4, 127.1, 125.8, 120.0, 97.2 (d,
J = 23.7 Hz), 75.2 (d, J = 8.3 Hz), 71.4 (d, J = 4.3 Hz), 69.7, 69.6 (d,
J = 4 Hz), 69.3, 52.6, 51.5 (d, J = 9.5 Hz), 19.6; HRMS (ESI) Calcd for
6.06 mol), and anhydrous EtOH (3 mL) under a nitrogen atmo-
l
sphere. The mixture was stirred for 1.0 h at 25–30 °C to give a clear
yellow solution. After placing the vessel in an autoclave, the ketone
(10 mmol) and t-BuOK (28 mg, 0.253 mmol) were added. The auto-
clave was replaced with H2 three times, and the reaction mixture
was stirred at room temperature until no obvious hydrogen pres-
sure drop was observed. After releasing the hydrogen pressure,
the reaction mixture was filtered through a short silica gel column.
The solvent in the filtrate was removed to determine the yield and
the product obtained was analyzed by HPLC to determine the
enantiomeric excess.
C
34H31FeN2P [M+1]+: 555.1653, Found: 555.1644.
Acknowledgment
4.2.3.4. (RC,SFc)-1-(Diphenylphosphino)-2-[1-N-(6-methylpyri-
din-2-ylmethyl)ethyl]ferrocene 2d.
Yield: 0.48 g, 93%. Red
We would like to thank the National Science Foundation of
China (NSFC 21172262, 20802092) for financial support of this
work.
oil; ½a 2D5
ꢀ
¼ ꢁ243:8 (c 0.65, CH2Cl2); 1H NMR (500 Hz, CDCl3) d
7.56–7.50 (m, 2H), 7.40–7.33 (m, 3H), 7.28–7.20 (m, 3H), 7.17–
7.10 (m, 3H), 6.84 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 4.53
(s, 1H), 4.33–4.28 (m, 1H), 4.25–4.17 (m, 1H), 4.00 (s, 5H), 3.85–
3.80 (m, 1H), 3.62 (s, 1H), 2.41 (s, 3H), 1.55 (d, J = 6.5 Hz, 3H); 31P
NMR (202 Hz, CDCl3) d ꢁ25.03 (s); 13C NMR (126 Hz, CDCl3) d;
159.3, 157.1, 140.1 (d, J = 9.8 Hz), 137.4 (d, J = 9.2 Hz), 136.3,
135.0 (d, J = 21.3 Hz), 132.6 (d, J = 18.6 Hz), 131.5 (d, J = 10 Hz),
129.1, 128.3 (d, J = 5.9 Hz), 128.3, 120.9, 118.3, 97.8 (d,
J = 24.3 Hz), 75.1 (d, J = 8.2 Hz), 71.3 (d, J = 4 Hz), 69.6, 69.5 (d,
J = 4.4 Hz), 69.1, 52.1, 51.3 (d, J = 9.2 Hz), 24.4, 19.4; HRMS (ESI)
Calcd for C31H31FeN2P [M+1]+: 519.1653, Found: 519.1645.
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