Scope and Mechanism on Iridium-f-Amphamide Catalyzed Asymmetric Hydrogenation of Ketones

Article abstract of DOI:10.1002/cjoc.201800129

A series of novel and easily accessed ferrocene-based amino-phosphine-sulfonamide (f-Amphamide) ligands have been developed and applied in Ir-catalyzed asymmetric hydrogenation of aryl ketones, affording the corresponding chiral secondary alcohols with excellent results (up to >99% conversion, >99% ee and TON up to 200 000). DFT calculations suggest an activating model involving an alkali cation Li⁺.

Full text of DOI:10.1002/cjoc.201800129

Scope and Mechanism on Iridium-f-Amphamide Catalyzed Asymmetric
Hydrogenation of Ketones
Zhi-Qin Liang,a Ti-Long Yang, a Guoxian Gu, a Li Dang*,a,b and Xumu Zhang *,a
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday
ABSTRACT A series of novel and easily accessed ferrocene-based amino-phosphine-sulfonamide (f-Amphamide) ligands have been developed and
applied in Ir-catalyzed asymmetric hydrogenation of aryl ketones, affording the corresponding chiral secondary alcohols with excellent results (up to >99%
conversion, >99% ee and TON up to 200,000). DFT calculations suggest an activating model involving an alkali cation Li+.
KEYWORDS aryl ketone, asymmetric, f-Amphamide, hydrogenation, iridium
Introduction
Results and Discussion
Results
Catalytic asymmetric hydrogenation of prochiral ketones is a
convenient and economical method to prepare chiral alcohols,[1]
which are significant building blocks in pharmaceuticals and
The preparation of the tridentate PNN ligand f-Amphamide is
natural products.[2] Since Noyori’s milestone work in the 1990s
very simple. The f-Amphamide ligands L1-L6 were efficiently
wherein the BINAP-ruthenium-diamine catalytic system was
originally developed for hydrogenation of ketones,[3] numerous
ligands including bidentate and tridentate ligands have been
synthesized and investigated to access chiral alcohols via metal
catalyzed asymmetric hydrogenation in the past decades.[4]
prepared by
a three-step manipulation from commercially
available (R)-Ugi’s amine (see in supporting information).[10] With
f-Amphamide ligands in hand, we began our research by
evaluating its catalytic performance in Ir-catalyzed asymmetric
hydrogenation of model substrate acetophenone 4a. With the
catalyst obtained in situ by mixing [Ir(cod)Cl]2 and ligand L1, the
solvent effect was investigated (S/C = 5,000). As shown in Table 1,
solvent was critical to achieve high conversion and enantiocontrol.
Alcohols proved to be superior to other solvents including toluene,
DCM, THF etc., and i-PrOH turned to be the best solvent in terms
of conversion and enantiocontrol (66-96% ee, Table 1, entries
1-7).
Figure 1 Selected Tridentate Ligands for Asymmetric Hydrogenation of
Further evaluation of different f-Amphamide ligands revealed
that the structure of the amino sulfonamide had important effect
on the enantioselectivity. To our surprise, L1 and L6 ligands with a
simple sulfonamide motif gave better results (L1, L6 vs L2, L3, L4,
L5). The optimal ligand L6 with two sterically hindered
3,5-di-tert-phenyl groups on P atom provided the hydrogenated
product 5a with full conversion and 98% ee (Table 1, entry 12).
Various bases were investigated for this hydrogenation reaction
Aryl Ketones
In terms of the tridentate PNN ligands, there are limited
examples for asymmetric hydrogenation of ketones. In 2011,
Zhou et al reported the tridentate spiro pyridine-aminophosphine
ligands SpiroPAP for hydrogenation of ketones, giving chiral
alcohols with excellent results in the iridium catalytic system
(Figure 1).[5] In 2013, Chen and Zhang’s group successfully
developed tridentate ferrocene-based amino-phosphine pyridine
ligands for iridium-catalyzed asymmetric hydrogenation of
ketones with encouraging results (Figure 1).[6] Subsequently, our
catalyzed by Ir-L6 (S/C
= 5,000) in i-PrOH. Moderate
enantioselectivities were obtained in the presence of KOtBu,
NaOtBu, NaOH and Cs2CO3 (80-88% ee, >99% conversions, Table 1,
entries 13-16). It revealed that LiOtBu was the best choice for this
transformation. The results retained the same level even the
catalyst loading was reduced to 0.01 mol% (S/C = 10,000, Table 1,
entry 17).
group successively developed
tridentate ligands f-amphox[7] (Figure 1), f-ampha[8] and
f-amphol[9]
which were highly efficient ligands for
a series of ferrocene-based
,
iridium-catalyzed asymmetric hydrogenation of ketones. Although
many ligands for asymmetric hydrogenation of ketones have been
developed, considering increasing industrial demand, easily
accessed and practical ones are still highly desirable. Herein, we
successfully developed a class of readily prepared and air-stable
tridentate ferrocene-based amino-phosphine sulfonamide
(f-Amphamide) ligands, which displayed excellent performance in
iridium-catalyzed asymmetric hydrogenation of aryl ketones.
Compared with other neutral PNN ligands, the sulfonamide is
acidic (pKa~10), and the new f-Amphamide is a neutral ligand.
a Department of Chemistry, Southern University of Science and Technology,
1088 Xueyuan Rd, Nanshan District, Shenzhen, Guangdong 518055, P. R.
China. Email: zhangxm@sustc.edu.cn.
b Department of Chemistry and Key Laboratory for Preparation and Application
of Ordered Structural Materials of Guangdong Province, Shantou University,
Guangdong 515063, P. R. China. Email: ldang@stu.edu.cn.
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may lead to differences between this version and the Version of Record. Please cite this
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Table 1 Reaction Condition Optimization with 4aa
catalyst loading was decreased to 0.0005 mol% (S/C = 200,000),
the transformation of acetophenone 4a on a 2.4 g scale
proceeded smoothly generating chiral alcohol 5a with full conv.
and 98% ee within 24 h at rt under a hydrogen pressure of 40
atm.
Scheme 1 Substrate Scope
entry
1
ligand
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
solvent
toluene
CH2Cl2
THF
base
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
KOtBu
NaOtBu
NaOH
Cs2CO3
LiOtBu
conv. [%]b
22
ee [%]c
94
90
75
66
93
nd
96
83
95
80
90
98
80
88
88
72
2
5
3
6
4
MeOH
EtOH
17
5
63
6
1,4-dioxane
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
nr
7
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
8
9
10
11
12
13
14
15
16
17d
Scheme 2 Gram-scale Hydrogenation of 4a
L6
i-PrOH
>99
98
a Reaction conditions: 4a (2.0 mmol), 0.02 mol% [Ir(cod)Cl]2, 0.042 mol%
L1, 1.0 mol% LiOtBu, 2.0 mL solvent, room temperature. Absolute
configuration determined by comparison of the optical rotation with that
DFT calculations were then carried out to shed light on the
insight of asymmetric hydrogenation of 4a using the novel ligand
f-Amphamide L1.[11] The sulfonamide can be deprotonated in the
presence of the inorganic base LiOtBu (Scheme S1).[12] The alkali
cation Li+ prefers to locate on the O atom of the Tosyl (Ts) group,
rather than forms an alkali amidato complex as proposed in the
hydrogenation mechanism by f-amphox.[13] Possible sites for
location of the added Li+ were examined and found that the
Ir(III)-trihydride complex I were more stable than other isomers
(Table S1 and Scheme S2). In fact, this lithium oxide successfully
promotes the hydrogenation of carbonyl group. As shown in
Figure 2, the catalytic cycle started by the active intermediate I
involves (1) enantio-determining hydride transfer from Ir center
of complex I to keto carbon of 4a and (2) the H2 activation process
to yield 5a and regenerate the catalyst I. Transition state for
hydride transfer leading to (S)-1-phenyl ethoxide anion (TS1(S)) is
more stable than the corresponding TS1(R) to (R)-1-phenyl
ethoxide anion by 2.8 kcal/mol, which indicates 98% ee. The H2
activation between the cationic Ir(III) and (S)-1-phenyl ethoxide
anion incurs a barrier of 9.6 kcal/mol via TS2(S).
b
c
known in literatures. Determined by 1H NMR. Determined by HPLC
analysis. d S/C=10,000.
Under the optimal conditions (Ir/L6, 20 atm H2/1.0 mol%
LiOtBu, S/C
= 10,000, rt), the substrate scope was then
investigated. As depicted in Scheme 1, all of aryl alkyl ketones
were transformed smoothly, providing the corresponding chiral
alcohols in quantitative conversions with 92-99% ee. The
substrates bearing either an electron-donating (Me, MeO) or
electron-withdrawing group (F, Cl, Br, CF3) on the phenyl ring
were all well tolerated and the position of the substituent groups
(ortho-, meta- and para-) on the phenyl group had little influence
on the outcome (5a-5n). Hetero-aromatic ketones 4o and 4p
were also tested and the corresponding products 5o and 5p were
both obtained in excellent conv. and ee. Howerer, the dialkyl
ketone 4q did not work well giving the corresponding alcohol 5q
with a low ee (5 % ee).
As shown in Scheme 2, a gram-scale reaction of 4a with tiny
amount of catalyst was carried out to demonstrate the potential
practicability of our catalytic system. To our delight, when the
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Figure 2 Gibbs Free Energy Profile for the Iridium-catalyzed Enantioselective Hydrogenation of 4a with L1
The enantioselectivity is due to the more steric repulsion
between Ph on P of f-Amphamide L1 and the larger group (-Ph) of
4a in TS1(R) than that in TS1(S). This larger repulsion results in
Conclusions
We have developed a series of novel and air-stable anionic
longer Ir−H and C−H distances in TS1(R) than those in TS1(S)
(Figure 3 and Figure S1). Furthermore, the repulsion leads to
better overlap between Ir−H d−σ orbital and C=O π* orbital in
HOMO-1 of TS1(S) than those in HOMO-1 of TS1(R), showing that
TS1(S) should be more stable than TS1(R). This is consistent with
the molecular orbital calculation of TS1(S) and TS1(R). More
importantly, when using ligand L6, even larger steric repulsion
between Ar on P atom and the larger group (-Ph) of 4a in TSL6(R)
than that in TSL6(S) provides more obvious evidence that TSL6(S) is
more stable than TSL6(R). The energy difference between these
two transition states is 3.1 kcal/mol, indicating an ee value of
98.9%. Our calculations are in excellent agreement with the
experimental results.
tridentate ferrocene-based amino-phosphine sulfonamide
(f-Amphamide) ligands for Ir-catalyzed enantioselective
hydrogenation of simple aryl ketones. The great efficacy (TON up
to 200,000) and the synthetic convenience to the novel
tridendate f-Amphamide ligands make this asymmetric
hydrogenation practical and user-friendly, and it should play an
important role in the field of asymmetric hydrogenation. DFT
calculations show that the electrophilicity of lithium oxide
successfully promotes the hydrogenation of carbonyl group. Less
steric repulsion in TS1(S) leads to better overlap between Ir−H
d−σ orbital and C=O π* orbital than that in TS1(R) and excellent
ee values is therefore achieved. Further investigation on
challenging substrates is underway and will be reported in due
course.
Experimental
General remark
All reactions and manipulations which are sensitive to
moisture or air were performed in an argon-filled glove box or
using standard schlenk techniques. Aromatic ketones were
purchased from commercial suppliers and purified by simple
distillation or flash column chromatography prior to use.
Anhydrous MeOH, DCM, i-PrOH were purchased from
Sigma-Adrich. Anhydrous 1, 4-dioxane, toluene, THF, Et2O were
distilled from sodium benzophenone ketyl. Anhydrous EtOH was
freshly distilled from magnesium. [Ir(COD)Cl]2 was prepared
according to the literature.[14] 1H NMR (400 MHz), 13C NMR (101
MHz) and 31P NMR (162 MHz) spectra were recorded on a Bruker
ADVANCE III spectrometer with CDCl3 as the solvent and
tetramethylsilane (TMS) as the internal standard. Chemical shifts
1
are reported up field to TMS (0.00 ppm) for H NMR and relative
to CDCl3 (77.0 ppm) for 13C NMR. HRMS were recorded on APEXII
and ZAB-HS spectrometer. HPLC analyses were performed using
an Agilent 1260 Series instrument. GC analyses were performed
using an Agilent 7890B Series instrument. GC condition : A 1 L
portion of the extract was injected onto a 30 m X 0.25 mm X 0.25
µm SUPELCO Beta Dex 120 capillary GC column maintained at 40
oC for 1 min, followed by a temperature gradient from 40 oC to
100 oC at 2 oC min-1, a temperature gradient of 100 oC to 200 oC at
10oC min-1, injector and detector temperature was 220 oC.
Column Chromatography was performed with silica gel Merck 60
(300-400 mesh).
Figure 3 The Molecular Orbital Interactions and Steric Repulsions in
TS1(S), TS1 (R), TSL6(S), and TSL6(R)
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Preparation of phosphine-amino-amide (f-Amphamide) Ligands
57.1, 46.6, 32.3, 30.0, 24.9, 24.1, 21.7, 20.2; 31P{1H} NMR (162
MHz, CDCl3) δ -24.6 (s). HRMS (ESI) calcd for C37H42FeN2O2PS
[M+H]+: 665.2049; Found: 665.2037.
(L3): Yellow solid, 60% yield. []2D0 = -160.9 (c = 1.0, CHCl3); 1H
NMR (400 MHz, Chloroform-d) δ 7.43– 7.41 (m, 2H), 7.35 – 7.24
(m, 8H), 7.22 – 7.16 (m, 2H), 7.05 – 6.95 (m, 3H), 6.91– 6.90 (m,
3H), 6.84 (t, J = 7.4 Hz, 2H), 6.73 – 6.66 (m, 2H), 6.62 – 6.55 (m,
2H), 4.30 – 4.25 (m, 1H), 4.21 (t, J = 2.6 Hz, 1H), 3.93 (d, J = 7.5 Hz,
1H), 3.86 (s, 5H), 3.65 – 3.57 (m, 2H), 3.55 – 3.51 (m, 1H), 2.25 (s,
3H), 1.07 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
142.5, 140.7 (d, J = 11.0 Hz), 138.8, 137.8 (d, J = 9.2 Hz), 135.5,
135.3, 132.9, 132.7, 129.2, 129.0, 128.7, 128.6, 128.6, 128.3,
128.2, 128.1, 127.8, 127.8, 127.7, 127.7, 127.5, 127.3, 127.1, 98.8,
74.4 (d, J = 9.5 Hz), 71.6 (d, J = 4.0 Hz), 69.9, 69.6, 69.5, 64.9, 63.4,
47.8, 29.8, 21.6, 19.8; 31P{1H} NMR (162 MHz, CDCl3) δ -23.5 (s).
HRMS (ESI) calcd for C45H44FeN2O2PS [M+H]+: 763.2205; Found:
763.2188
(L4): Yellow solid, 64% yield. []D = -228.2 (c = 1.0, CHCl3); H
NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 8.2 Hz, 2H), 7.59 –
7.51 (m, 2H), 7.44 – 7.36 (m, 3H), 7.31– 7.27 (m, 7H), 4.45 (s, 1H),
4.33 –4.31 (m, 1H), 4.06 (s, 5H), 3.99 – 3.93 (m, 1H), 3.79 (s, 1H),
2.80 – 2.74 (m, 1H), 2.71 –2.65 (m, 1H), 2.45 (s, 3H), 2.26 – 2.16
(m, 2H), 1.40 (d, J = 6.6 Hz, 3H), 0.97 – 0.83 (m, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 143.0, 139.8, 137.4, 135.0, 134.8, 133.1, 132.
9, 129.6, 129.3, 128.8, 128.7, 128.6, 128.3, 128.3, 127.2, 97.1,
75.4, 71.4, 69.8, 69.5, 69.2, 51.7, 51.6, 45.3, 43.2, 28.2, 21.6, 19.4;
31P{1H} NMR (162 MHz, CDCl3) δ -25.4 (s). HRMS (ESI) calcd for
C34H38FeN2O2PS [M+H]+: 625.1736; Found: 625.1734.
[15]
General procedure:
To a solution of (R)-Ugi’s amine (R)-1
(2.57 g, 10 mmol) in anhydrous Et2O (20 mL) was added 1.6 M
tBuLi solution in pentane (11.2 mmol, 7.0 mL) at 0 oC. After
addition was complete, the mixture was warmed to room
temperature and stirred for 2 h. The mixture was then cooled to
o
to -78 C and fresh distilled PCl3 (11.46 mmol, 1 mL) was added
drop wise, and the mixture was warmed to room temperature
overnight. The mixture was then cooled to -78 oC again, and a
suspension of RMgBr (prepared from corresponding RBr (30
mmol) and magnesium turnings (0.8 g, 33.3 mmol) in THF at
reflux temperature) was added slowly via cannula. After addition,
the mixture was stirred overnight from -78 oC to room
temperature and quenched with 20 mL saturated NH4Cl aq. The
organic layer was separated and the aqueous layer was extracted
with Et2
Na2SO4 and concentrated. The residue was purified by column
chromatography to afford the aminophosphine (Rc, Sp)-2 with
little impurity, which was used directly in the next step without
further purification.
A solution of crude aminophosphine (Rc, Sp)-2 (1 mmol) in
acetic anhydride (1.5 mL) was heated to 100oC for 1-2 h
(monitored by TLC). After the starting material was disappeared,
the volatiles were removed under reduced pressure. Toluene (2
mL) was then added and the resulting solution was concentrated.
The operation was repeated for three times to remove excess
acetic anhydride. To the residue, a small amount of i-PrOH or
EtOH was added and the mixture was subjected to ultrasound for
several minutes until the appearing of yellow solid. The alcohol
was then removed by high vaccum, and the obtained yellow solid
(> 95% yield) was pure enough for next step.
20
1
(L5): Yellow solid, 47% yield. []2D0 = -171.8 (c = 1.0, CHCl3); 1H
NMR (400 MHz, Chloroform-d) δ 7.56 – 7.49 (m, 2H), 7.42 – 7.36
(m, 3H), 7.26 – 7.22 (m, 2H), 7.17 (s, 2H), 7.14 – 7.06 (m, 3H), 4.87
(s, 1H), 4.41 (s, 1H), 4.29 (t, J = 2.5 Hz, 1H), 4.10 – 4.01 (m, 2H),
4.06 (s, 5H), 3.77– 3.76 (m, 1H), 2.99 – 2.89 (m, 1H), 2.42 (d, J =
5.6 Hz, 1H), 2.31 (t, J = 5.4 Hz, 2H), 2.24 (t, J = 7.6 Hz, 1H), 1.39 (d,
J = 6.5 Hz, 3H), 1.30 (d, J = 7.0 Hz, 6H), 1.23 (t, J = 6.8 Hz, 12H).
13C{1H} NMR (101 MHz, CDCl3) δ 152.4, 150.4, 134.9, 134.7, 133.1,
132.9, 129.2, 128.8, 128.5, 128.4, 128.3, 128.3, 123.8, 100.1, 75.5
(d, J = 6.5 Hz), 71.4 (d, J = 4.2 Hz), 69.9, 69.3 (d, J = 3.7 Hz), 69.0,
50.9, 50.8, 44.4, 42.5, 34.3, 29.6, 25.1 (d, J = 2.6 Hz), 23.8 (d, J =
2.9 Hz), 19.2. 31P{1H} NMR (162 MHz, CDCl3) δ -25.3 (s). HRMS
(ESI) calcd for C41H52FeN2O2PS [M+H]+: 723.2831; Found:
723.2816.
A
mixture of the acetate (Rc, Sp)-3 (1 mmol) and
corresponding amino sulfonamide[10b] (5 mmol) in dry MeOH (5
mL) was refluxed overnight under nitrogen. The solvent was
evaporated under reduced pressure to afford the crude product.
After column chromatography on silica-gel column with
petroleum ether/ethyl acetate (v/v= 8:1 to 5:1) as eluent, the
corresponding phosphine-amino-amide (f-amphamide) Ligands
were obtained as yellow solids in medium to good yields.
(L6): Yellow solid, 54% yield. []2D0 = -183.1 (c = 1.0, CHCl3); 1H
NMR (400 MHz, Chloroform-d) δ 7.64 (d, J= 8.3 Hz, 2H), 7.47 –
7.38 (m, 3H), 7.28 – 7.26 (m, 3H), 7.24 – 7.18 (m, 2H), 4.36 (s, 1H),
4.26 (t, J = 2.7 Hz, 1H), 4.06 (s, 5H), 3.99 – 3.92 (m, 1H), 3.70 (s,
1H), 2.43 (s, 3H), 2.41 –2.35 (m, 1H), 2.12 –2.05 (m, 3H), 1.31 (s,
18H), 1.29 (d, J = 6.5 Hz, 3H), 1.18 (s, 18H). 13C{1H}a NMR (101
MHz, CDCl3) δ 150.8 (d, J = 7.3 Hz), 150.4 (d, J = 7.3 Hz), 143.1,
138.2, 137.6, 135.0 (d, J = 7.0 Hz), 129.7, 129.1, 128.9, 128.0, 128.
8, 127.2, 123.1, 122.8, 96.2 (d, J = 23.0 Hz), 77.4, 71.2 (d, J = 4.1
Hz), 69.8, 69.1 (d, J = 3.4 Hz), 68.6, 51.1, 51.0, 44.9, 42.8, 35.1,
34.9, 31.6, 31.5, 21.6, 19.3. 31P{1H} NMR (162 MHz, CDCl3) δ -24.4
(s). HRMS (ESI) calcd for C49H68FeN2O2PS [M+H]+: 835.4083;
Found: 835.4067
(L1): Yellow solid, 72% yield. []2D0 = -247.1 (c = 1.0, CHCl3); 1H
NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 8.3 Hz, 2H), 7.57 –
7.51 (m, 2H), 7.41 – 7.37 (m, 3H), 7.29 (d, J = 7.8 Hz, 2H), 7.26 –
7.14 (m, 5H), 4.42 (d, J = 2.3 Hz, 1H), 4.30 (t, J = 2.6 Hz, 1H), 4.02
(s, 5H), 4.02 – 4.00 (m, 1H), 3.85 – 3.72 (m, 1H), 2.45 (s, 3H), 2.45
– 2.42 (m, 2H),2.29 (t, J = 5.4 Hz, 2H), 1.34 (d, J = 6.6 Hz, 3H); 13C
{1H} NMR (101 MHz, CDCl3) δ 143.1, 140.0 (d, J = 9.9 Hz), 137.3,
136.8 (d, J = 8.4 Hz), 135.0, 134.8, 132.9, 132.7, 129.9, 129.6,
129.2, 128.6, 128.5, 128.4, 128.3, 128.2, 127.2, 97.0 (d, J = 23.1
Hz), 75.3 (d, J = 6.6 Hz), 71.5 (d, J = 4.4 Hz), 69.8, 69.3, 69.2, 69.0,
50.9 (d, J = 8.8 Hz), 44.6, 42.8, 21.6, 19.2; 31P{1H} NMR (162 MHz,
CDCl3) δ -25.0 (s). HRMS (ESI) calcd for C33H36FeN2O2PS [M+H]+:
611.1579; Found: 611.1577.
Procedure for asymmetric hydrogenation of ketones
(L2): Yellow solid, 41% yield. []2D0 = -257.1 (c = 1.0, CHCl3); 1H
NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 8.3 Hz, 2H), 7.52 –
7.48 (m, 2H), 7.44 – 7.36 (m, 3H), 7.28 (d, J = 3.2 Hz, 2H), 7.22 –
7.15 (m, 1H), 7.12 – 7.02 (m, 4H), 4.52 (s, 1H), 4.37 (t, J = 2.6 Hz,
1H), 4.08 (s, 5H), 4.04 –4.01 (m, 1H),3.71 (d, J = 1.3 Hz, 1H), 2.45
(s, 3H), 2.14 – 2.09 (m, 2H), 1.97 – 1.89 (m, 1H), 1.85– 1.84 (m,
1H), 1.53 – 1.43 (m, 2H), 1.36 (d, J = 6.2 Hz, 3H), 1.08 – 1.03 (m,
2H), 0.94 – 0.76 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 142.9,
140.0 (d, J = 10.6 Hz), 137.5, 136.8 (d, J = 9.5 Hz), 135.2, 135.0,
133.0, 132.8, 129.5, 129.3, 128.5, 128.5, 128.4, 128.3, 128.3,
127.6, 98.2, 74.5, 71.3 (d, J = 4.0 Hz), 70.6, 69.8, 69.7, 69.4, 57.9,
General procedure for S/C = 10 000: To a 2.5 mL vial was
added the catalyst precursor [Ir(COD)Cl]2 (3.4 mg, 0.005 mmol),
ligand L6 (9.2 mg, 0.011 mmol) and anhydrous i-PrOH (2.0 mL)
under argon atmosphere. The mixture was stirred for 1 h at room
temperature to give a clear yellow solution. An aliquot of the
catalyst solution (20 L, 0.0002 mmol) was transferred into a 5 mL
hydrogenation vessel, LiOtBu (1.6 mg), ketone (2 mmol) and
anhydrous i-PrOH (2 mL) was added. The vessels were placed in
an autoclave which was then charged with 20 atm of H2 and
o
stirred at 25-30 C for 12 h. After slowly releasing the hydrogen
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pressure, the reaction mixture was passed through a short
column of silica gel to remove the metal complex. The product
was analyzed by 1HNMR to determine the conversion. The ee
values were determined by HPLC analysis on a chiral stationary
phase.
CHCl3), > 99% conversion, 96% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
nm; tR = 9.0 min (major), tR = 10.2 min (minor), 1H NMR (400 MHz,
CDCl3) δ 7.40 (s, 1H), 7.33 – 7.23 (m, 3H), 4.89 (q, J = 6.4 Hz, 1H),
2.02 (s, 1H), 1.50 (d, J = 6.5 Hz, 3H).
(S)-1-phenylethanol (5a): []2D0 = -59.7 (c = 1.0, CHCl3), > 99%
conversion, 98% ee. The enantiomeric excess was determined by
HPLC on Chiralcel OD-H column, hexane: isopropanol = 95:5; flow
rate = 1.0 mL/min; UV detection at 210 nm; tR= 7.5 min (minor), tR
(S)-1-(4-chlorophenyl)ethanol (5j): []2D0 = -49.4 (c = 1.0,
CHCl3), > 99% conversion, 97% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
1
= 8.6 min (major), H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 10.7,
1
4.4 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.09 – 6.95
(m, 1H), 7.08 – 6.88 (m, 1H), 5.19 (dd, J = 9.6, 4.8 Hz, 1H), 2.57 (d,
J = 15.8, 10.4 Hz, 1H), 1.51 (d, J = 6.5 Hz, 3H).[5]
nm; tR = 9.0 min (major), tR = 9.5 min (minor), H NMR (400 MHz,
CDCl3) δ 7.39 – 7.23 (m, 4H), 4.87 (q, J = 6.4 Hz, 1H), 2.27 (s, 1H),
1.47 (d, J = 6.5 Hz, 3H).
(S)-1-phenylpropan-1-ol (5b): []2D0 = -48.7 (c = 1.0, CHCl3), >
99% conversion, 99% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
(S)-1-(2-bromophenyl)ethanol (5k): []2D0 = -40.4 (c = 1.0,
CHCl3), > 99% conversion, 96% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
1
1
nm; tR = 8.7 min (major), tR = 9.3 min (minor), H NMR (400 MHz,
nm; tR = 7.7 min (major), tR = 8.2 min(minor), H NMR (400 MHz,
CDCl3) δ 7.44 – 7.33 (m, 4H), 7.34 – 7.22 (m, 1H), 4.62 (t, J = 6.6
Hz, 1H), 1.92 (d, J = 13.4 Hz, 1H), 1.90 – 1.70 (m, 2H), 0.94 (t, J =
7.4 Hz, 3H).
CDCl3) δ 7.61 (dd, J = 7.8, 1.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.36
(t, J = 7.5 Hz, 1H), 7.17 – 7.13 (m, 1H), 5.25 (q, J = 6.3 Hz, 1H), 2.25
(s, 1H), 1.50 (d, J = 6.4 Hz, 3H).
(S)-1-(p-tolyl)ethanol (5c): []2D0 = -52.1 (c = 1.0, CHCl3), > 99%
conversion, 99% ee. The enantiomeric excess was determined by
HPLC on Chiralcel OJ-H column, hexane: isopropanol = 95:5; flow
rate = 1.0 mL/min; UV detection at 210 nm; tR = 10.6 min (major),
(S)-1-(4-bromophenyl)ethanol (5l): []2D0 = -46.2 (c = 1.0,
CHCl3), > 99% conversion, 96% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OD-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 230
1
1
tR = 11.9 min (minor), H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 6.6
nm; tR = 7.5 min (major), tR = 8.0 min (minor), H NMR (400 MHz,
Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.89 (q, J = 6.1 Hz, 1H), 2.37 (s,
3H), 1.88 (s, 1H), 1.51 (d, J = 6.4 Hz, 3H).
CDCl3) δ 7.52 – 7.47 (m, 2H), 7.28 (t, J = 4.2 Hz, 2H), 4.90 (q, J = 6.1
Hz, 1H), 1.84 (s, 1H), 1.50 (d, J = 6.5 Hz, 3H).
(S)-1-(4-methoxyphenyl)ethanol (5d): []2D0 = -41.7 (c = 1.0,
CHCl3), > 99% conversion, 97% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 230
nm; tR = 18.1 min (major), tR = 19.3 min (minor), 1H NMR (400
MHz, CDCl3) δ 7.32 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 4.87
(q, J = 6.4 Hz, 1H), 3.83 (s, 3H), 1.91 (s, 1H), 1.50 (d, J = 6.4 Hz, 3H).
(S)-1-(3-methoxyphenyl)ethanol (5e): []2D0 = -44.0 (c = 1.0,
CHCl3), > 99% conversion, 99% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
nm; tR = 14.1 min (major), tR = 15.9 min (minor), 1H NMR (400
MHz, CDCl3) δ 7.29 (dd, J = 10.0, 6.1 Hz, 1H), 7.00 – 6.92 (m, 2H),
6.84 (dd, J = 8.1, 1.9 Hz, 1H), 4.89 (q, J = 6.4 Hz, 1H), 3.84 (s, 3H),
2.06 (s, 1H), 1.51 (d, J = 6.5 Hz, 3H).
(S)-1-(4-(trifluoromethyl)phenyl)ethanol (5m): []2D0 = -36.8
(c = 1.0, CHCl3), > 99% conversion, 97% ee. The enantiomeric
excess was determined by HPLC on Chiralcel OJ-H column,
hexane: isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection
at 230 nm; tR = 6.7 min (major), tR = 7.1 min (minor), 1H NMR (400
MHz, CDCl3) δ 7.63 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.98
(d, J = 6.3 Hz, 1H), 2.04 (d, J = 9.1 Hz, 1H), 1.53 (d, J = 6.5 Hz, 3H).
(S)-1-(naphthalen-2-yl)ethanol (5n): []2D0 = -52.9 (c = 1.0,
CHCl3), > 99% conversion, >99% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
nm; tR = 27.7 min (major), tR = 36.6 min (minor), 1H NMR (400
MHz, CDCl3) δ 7.94 – 7.74 (m, 4H), 7.59 – 7.44 (m, 3H), 5.07 (q, J =
6.4 Hz, 1H), 2.21 (s, 1H), 1.60 (d, J = 6.5 Hz, 3H).
(S)-1-(thiophen-2-yl)ethanol (5o): []2D0 = -26.6 (c = 1.0,
CHCl3), > 99% conversion, 96% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 250
nm; tR = 10.0 min (major), tR = 12.2 min (minor), 1H NMR (400
MHz, CDCl3) δ 7.38 – 7.18 (m, 1H), 7.08 – 6.87 (m, 2H), 5.20 – 5.11
(m, 1H), 2.08 (s, 1H), 1.63 (d, J = 6.4 Hz, 3H).
(S)-1-(2-fluorophenyl)ethanol (5f): []2D0 = -52.1 (c = 1.0,
CHCl3), > 99% conversion, 99% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 98:2; flow rate = 1.0 mL/min; UV detection at 210
nm; tR = 6.9 min (major), tR = 14.2 min (minor), 1H NMR (400 MHz,
CDCl3) δ 7.54 – 7.49 (m, 1H), 7.29 – 7.24 (m, 1H), 7.18 (t, J = 7.4
Hz, 1H), 7.09 – 7.00 (m, 1H), 5.23 (d, J = 6.1 Hz, 1H), 1.98 (s, 1H),
1.55 (d, J = 6.5 Hz, 3H).
(S)-1-(furan-2-yl)ethanol (5p): []2D0 = -45.3 (c = 1.0, CHCl3), >
99% conversion, 92% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
(S)-1-(3-fluorophenyl)ethanol (5g): []2D0 = -42.5 (c = 1.0,
CHCl3), > 99% conversion, 99% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OD-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
1
nm; tR = 8.6 min (major), tR = 9.5 min (minor), H NMR (400 MHz,
CDCl3) δ 7.39 (s, 1H), 6.34 (s, 1H), 6.24 (d, J = 3.0 Hz, 1H), 4.89 (q, J
= 6.5 Hz, 1H), 2.22 (s, 1H), 1.56 (d, J = 6.6 Hz, 3H).
1
nm; tR = 12.6 min (major), tR(R) = 13.1 min (minor), H NMR (400
MHz, CDCl3) δ 7.39 – 7.24 (m, 1H), 7.20 – 7.07 (m, 2H), 7.00 – 6.96
(m, 1H), 4.92 (q, J = 6.4 Hz, 1H), 2.00 (s, 1H), 1.51 (d, J = 6.5 Hz,
3H).
(S)-heptan-2-ol (5q): []2D0 = -2.5 (c = 1.0, CHCl3), > 99%
conversion, 5% ee (by GC). The enantiomeric excess was
determined by GC after acelation on-dex 120, tR = 28.5 min
(minor), tR = 30.3 min (major), 1H NMR (400 MHz, CDCl3) δ 3.80 (q,
J = 6.0 Hz, 1H), 1.52 – 1.23 (m, 8H), 1.19 (d, J = 6.2 Hz, 3H), 0.89 (t,
J = 6.8 Hz, 3H).
(S)-1-(2-chlorophenyl)ethanol (5h): []2D0 = -56.8 (c = 1.0,
CHCl3), > 99% conversion, 99% ee. The enantiomeric excess was
determined by HPLC on Chiralcel OJ-H column, hexane:
isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 210
Asymmetric hydrogenation of acetophenone at S/C =
200,000: To a 2.5 mL vial was added the catalyst precursor
[Ir(COD)Cl]2 (3.4 mg, 0.005 mmol), ligand L6 (8.5 mg, 0.011 mmol)
and anhydrous i-PrOH (1 mL) under argon atmosphere. The
mixture was stirred for 1 h at room temperature to give a clear
1
nm; tR = 7.6 min (major), tR = 8.1 min (minor), H NMR (400 MHz,
CDCl3) δ 7.62 – 7.60 (m, 1H), 7.35 – 7.30 (m, 2H), 7.29 – 7.20 (m,
1H), 5.31 (q, J = 6.4 Hz, 1H), 2.25 (s, 1H), 1.51 (d, J = 6.4 Hz, 3H).
(S)-1-(3-chlorophenyl)ethanol (5i): []2D0 = -40.4 (c = 1.0,
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yellow solution. An aliquot of the catalyst solution (10 L, 0.0001
mmol) was transferred into a 10 mL hydrogenation vessel, then a
solution of LiOtBu (0.8 mg, 0.01 mmol), acetophenone (20 mmol)
and anhydrous i-PrOH (1.5 mL) was added. The vessel was placed
in an autoclave which was then charged with 40 atm of H2 and
stirred at 25-30 oC for 24 h. The work-up was identical to that
described for the asymmetric hydrogenation at S/C = 10,000.
(S)-1-Phenylethanol (5a): > 99% conversion, 98% ee (S).
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The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement (optional)
This work was supported by a start-up fund from Southern
University of Science and Technology (to X. Zhang), Shenzhen
Science
and
Technology
Innovation
Committee
(KQTD20150717103157174, to X. Zhang)and National Natural
Science Foundation of China (No. 21573102, to L. Dang). We
greatly acknowledge the referees for their helpful suggestions on
the mechanistic studies.
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Entry for the Table of Contents
Page No.
Scope and Mechanism on
Iridium-f-Amphamide Catalyzed
Asymmetric Hydrogenation of Ketones
A
series of novel and easily accessed ferrocene-based amino-phosphine-sulfonamide
(f-Amphamide) ligands have been developed and applied in Ir-catalyzed asymmetric hydrogenation
of aryl ketones, affording the corresponding chiral secondary alcohols with excellent results (up
to >99% conversion, >99% ee and TON up to 200,000). DFT calculations suggest an activating
model involving an alkali cation Li+.
Zhi-Qin Liang, Ti-Long Yang, Guoxian Gu, Li
Dang* and Xumu Zhang*
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