Development of Ferrocene-Based Diamine-Phosphine-Sulfonamide Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of Ketones

Article abstract of DOI:10.1021/acs.joc.8b01276

A series of air-stable, easily accessible tridentate ferrocene-based diamine-phosphine sulfonamide (f-diaphos) ligands were successfully developed for iridium-catalyzed asymmetric hydrogenation of ketones. The f-diaphos ligands exhibited excellent enantioselectivity and superb reactivity in Ir-catalyzed asymmetric hydrogenation of ketones (for arylalkyl ketones, (S)-selectivity, up to 99.4% ee, and 100 000 TON; for diaryl ketones, (R)-selectivity, up to 98.2% ee, and 10 000 TON). This protocol could be easily conducted on gram scale, thereby providing a chance to various drugs.

Full text of DOI:10.1021/acs.joc.8b01276

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Article
Development of Ferrocene-Based Diamine-Phosphine-Sulfonamide (f-
Diaphos) Ligands for Iridium Catalyzed Asymmetric Hydrogenation of Ketones
Fei Ling, Sanfei Nian, Jiachen Chen, Wenjun Luo, Ze Wang, Yaping Lv, and Weihui Zhong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01276 • Publication Date (Web): 31 Jul 2018
Downloaded from http://pubs.acs.org on July 31, 2018
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Development of FerroceneꢀBased DiamineꢀPhosphineꢀSulfonamide (fꢀDiaphos)
Ligands for Iridium Catalyzed Asymmetric Hydrogenation of Ketones
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Fei Ling, Sanfei Nian, Jiachen Chen, Wenjun Luo, Ze Wang, Yaping Lv and Weihui Zhong*
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Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic
of China
ABSTRACT: A series of air stable, easily accessible tridentate ferroceneꢀbased diamineꢀphosphine
sulfonamide (fꢀdiaphos) ligands were successfully developed for iridiumꢀcatalyzed asymmetric hydrogenation
of ketones. The fꢀdiphos ligands exhibited excellent enantioselectivity and superb reactivity in Ir-catalyzed
asymmetric hydrogenation of ketones (for arylalkyl ketones, (S)ꢀselectivity, up to 99.4% ee and 100 000 TON;
for diaryl ketones, (R)ꢀselectivity, up to 98.2% ee and 10 000 TON). This protocol could be easily conducted on
gram scale, thereby providing a chance to various drugs.
INTRODUCTION:
Enantioenriched chiral alcohols are prevalent skeletons, not only existing in many physiologically or/and
biologically active molecules,1 such as in selective cholesterol absorption inhibitor ezetimine,2 antidepressant
duloxetine,3 cꢀMet/HGFR inhibitor crizotinib,4 selective β3ꢀadrenoceptor agonist mirabegron,5 antihistamines
orphenadrine6 and neobenodine,7 but also representing versatile building blocks in organic synthesis.8 Owing
to their great importance, the development of efficient systems for the catalytic enantioselective synthesis of
chiral alcohols is of substantial interest to both the academic community and the industrial sector.
Figure 1. Related chiral pharmaceuticals containing chiral alcohols
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OH
F
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Cl
OH
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N
N
O
N
NH
Cl
O
F
N
O
H
S
F
H2N
N
Duloxetine
Crizotinib
N(CH32
Ezetimine
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N(CH3)2
OH
CH3
O
H
N
O
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S
O
NH2
N
N
CH3
Neobenodine
H
Mirabegron
Orphenadrine
Transitionꢀmetalꢀcatalyzed asymmetric hydrogenation has emerged as a powerful tool for accessing chiral
alcohols from various ketones.9 The pioneering research work was disclosed by Noyori and Ohkuma in the
1990s, who developed a highly efficient [RuCl2(diphosphine)ꢀ(1,2ꢀdiamine)] catalytic system for asymmetric
hydrogenation of ketones with high reactivity and moderate enantioselectivity.10 Inspired by this fundamental
work, continues efforts have been devoted to creating new types of chiral ligands. In this context, tridentate
ligands exhibit unique reactivity and excellent enantioselectivity, owing to their deeper chiral concave pockets
around the metal center.11 For example, Zhou and coworkers have developed a series of axially tridentate
spiro PꢀNꢀN and PꢀNꢀS ligands, and applied them in the iridiumꢀcatalyzed reduction of ketones, affording alkyl
alcohols with up to 99.9% ee and 4 550 000 TON (Scheme 1, a).11b,11c Similarly, Kitamura and cowoker's have
created a set of tridentate binanꢀPyꢀPPh2 ligands and also achieved excellent results.11d,11e Despite their great
success that has been achieved, multistep complicated reactions were employed to synthesize these axially
tridentate ligands. Recently, ferroceneꢀbased tridentate ligands have received much attention as powerful
ligands for asymmetric hydrogenation of ketones, because of their various advantages such as potential planar
and central chiralities, cheapness, readily availability and easy modification. Remarkably, Zhang and
coworkers developed a set of privileged tridentate ligands derived from (SC, RFC)ꢀferrocene and amino acid
derivatives, and simple ketones could be hydrogenated to (R)ꢀalcohols in up to 99.9% ee and 1 000 000 TON
(Scheme 1a).12 However, in previous studies, (RC, SFC)ꢀferroceneꢀbased tridentate ligands are far less efficient
to produce chiral alcohols (<97% ee, and ≤2000 TON for (R)ꢀalcohols; 81%ee and 20% conversion for
(S)ꢀalcohols) (Scheme 1b).13,12b This distinct performance of (SC, RFC)ꢀ and (RC, SFC)ꢀferrocene skeletons made
it difficult to obtain both enantioenriched (R)ꢀ and (S)ꢀalcohols with one type of ligands, which remains an
unsolved challenge. Despite their low efficiency, (RC, SFC)ꢀferroceneꢀbased tridentate ligands are potential to
give enantioenriched (S)ꢀalcohols, which are important structures in pharmaceutical products, albeit in low
efficiency (Figure 1) 2ꢀ5
.
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Recently, our studies were focused on developing ferroceneꢀbased organocatalysts for asymmetric
transformations.14 Encouraged by these basic researches, we are interested in designing new ferroceneꢀbased
tridentate ligands, especially (RC, SFC)ꢀferroceneꢀbased tridentate ligands, thereby achieving both alcohol
enantiomers at one stroke. We are pleased to find that C2ꢀsymmetric 1,2ꢀdiamine derivatives are competent to
this challenging task, owing to their two tunable chiral centers and enhanced NH acidity (Scheme 1c). Herein,
we successfully developed a set of novel ferroceneꢀdiamineꢀphosphineꢀsulfonamide (fꢀdiaphos) ligands and
applied them in iridiumꢀcatalytic asymmetric hydrogenation of ketones. Arylalkyl ketones could be
hydrogenated to (S)ꢀalcohols with (RC, SFC)ꢀfꢀdiphos L8 in up to 99.4% ee and 100 000 TON (Scheme 1c),
while acetophenone was reduced to (R)ꢀ1ꢀphenylethanol with good results using ligand L11 as the ligand,
which is an enantiomer of (RC, SFC)ꢀfꢀdiaphos L1 (Scheme 6, 95.4% ee, and 10 000 TON). Furthermore, this
protocol could be employed for the asymmetric hydrogenation of more challenging diaryl ketones, affording
enantioenriched diaryl methanols with up to 98.2% ee, and 10 000 TON (Scheme 1d).
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Scheme 1. Ferroceneꢀbased Tridentate Ligands for Asymmetric Hydrogenation of Ketones
RESULT AND DISCUSSION
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The current developed fꢀdiaphos ligands L1−L9 could be easily obtained in 47ꢀ65% yield by treatment of
acetates (SC, RFC)ꢀ1 with 1,2ꢀdiamines in MeOH under reflux conditions (Scheme 2). In addition, we also
synthesized ligand L10, which is the diasteroisomer of ligand L1 to investigate the relationship between
enantioselectivity and configuration of ligand.
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Scheme 2. Synthetic Route of fꢀDiaphos Ligands L1−L10
With the chiral fꢀdiaphos ligands L1−L10 in hand, we began our studies by screening them for asymmetric
hydrogenation of acetophenone (1a) serving as the model substrate with the catalyst generated in situ by
i
mixing [Ir(COD)Cl]2 with ligands L1−L10 (S/C = 10 000) in PrOH (more details on investigations of solvents,
bases and temperature see SI). As shown in Table 1, majority of the fꢀdiaphos ligands exhibited extreme high
reactivity and excellent enatioselectivity, giving access to (S)ꢀ1ꢀphenylethanol (2a) in >99% conversion with up
to 97.7% ee. With an increase in steric hindrance on the benzene ring of the sulfonyl group from L1 to L2 by
switching 4ꢀmethyl to 2,4,6ꢀtrimethyl, the enantiomeric selectivity of the reaction increased from 94.3% to
97.4% ee (Table 1, entry 2). Nevertheless, further increasing the steric hindrance from 2,4,6ꢀtrimethyl to
2,4,6ꢀtriisoꢀpropionyl resulted in a decrease on ee value (Table 1, entry 3). Moreover, relatively lower
enantioselectivity was observed when the reaction was conducted with the use of
1,2ꢀdiphenylethaneꢀ1,2ꢀdiamineꢀbased ligand L4 (Table 1, entry 4). It was noteworthy that replacing the
counterparts from (R, R)ꢀ1,2ꢀdiaminocyclohexane to its enantiomer led to a significantly reduced
enantioselectivity with opposite configuration of the product (L1, 94.3% ee vs L5, ꢀ18.2% ee). In addition, the
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substituents on the Pꢀphenyl ring had a little influence on the enantioselectivity, and L8 was found to afforded
the best result with >99% conversion and 97.7% ee (Table 1, entries 6−8). On contrast, upsetting results were
obtained when ligand L9 bearing free NH2 moiety was applied into this transformation (Table 1, entry 9, 79%
conversion, 40% ee). Notably, (SC, RFC)ꢀferroceneꢀbased ligand L10 which is the diastereoisomer of ligand L1
displayed low enantioselectivity and moderate reactivity (Table 1, entry 10, 86% conversion, 16.3% ee). These
results indicated that the sulfonyl group and the configuration of the ligand are very critical for enantioselectivity
and reactivity.
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Table 1. Screening Ligands for Asymmetric Hydrogenation of 1aa
entry
1
ligand
L1
conv. (%)b
>99
>99
>99
>99
>99
>99
>99
>99
79
ee (%)c
94.3
97.4
89.3
86.1
ꢀ18.2
97.3
95.9
97.7
40.0
16.3
2
L2
3
L3
4
L4
5
L5
6
L6
7
L7
8
L8
9
L9
10
86
L10
aReaction conditions: 2 mmol scale, [substrate] = 0.2 M, 0.005 mol % [Ir(COD)Cl]2, 0.0105 mol % ligand L, 2.5
t
i
o
b
c
mol % BuOLi, 10 mL of PrOH, room temperature (25−30 C). Determined by GC analysis. Determined by
HPLC analysis.
After identifying the optimum reaction conditions (IrꢀL8/30 atm H2/2.5 mol % tBuOLi, S/C = 10 000/rt), we next
set out to determine the versatility of this reaction system in the asymmetric hydrogenation of arylalkyl ketones.
Various (S)ꢀalcohols were obtained in almost quantitative yields with 94.0−99.4% ee (Scheme 3). Substrates
bearing ethyl and propyl groups on the vicinity of the benzylic position were hydrogenated smoothly to yield the
desired alcohols in 98.4% and 98.5% ees, respectively. However, introduction of steric hindered substituent at
the benzylic position resulted in a slight reduced ee (2d, 97.9% ee and 2e, 97.4% ee). Notably, tetralone was
also compatible with the IrꢀL8 catalytic system, leading to the corresponding product 2f in 99% yield with 97.5%
ee. On the other hand, the substrates bearing electronꢀdonating groups (1g−1j) and electronꢀwithdrawing
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groups (1k−1p) on the phenyl ring were hydrogenated well with excellent results (almost all products in up to
>97% ee, 99% yield). An exception was found when the nitroꢀsubstituted ketone 1q was used, delivering the
corresponding alcohol 2q in 94% ee. In addition, the position of the substituent on the phenyl ring had slight
influence on the reaction outcome, and orthoꢀsubstituted ketones gave better results than that of metaꢀ or
paraꢀsubstituted compounds (2g, 99.0% ee vs 2h, 98.8% ee or 2i, 97.9% ee). In addition, the benzene ring
could be effectively replaced by other aromatic substituents like benzo[d][1,3]dioxolꢀ5ꢀyl (1r), naphthyl (1s),
1,1'ꢀbiphenylꢀ4ꢀyl (1t) to forge the corresponding alcohols in 98.3−99.0% ee. The best result (99% yield with up
to 99.4% ee) was observed when using 9Hꢀfluorenꢀ2ꢀyl substituted ketone (1u) as the substrate. It indicates
that the amplified asymmetric bias between the alkyl and aryl groups offers better results. Delightfully, current
protocol also tolerated with heterocyclic aromatic ketones to produce the targeted products (2v−2x) in good
enatioselectivities.
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Scheme 3. IrꢀL8 Catalysis for the Asymmetric Hydrogenation of 1a
[Ir(COD)Cl]2/L8 ( 0.01 mol %)
O
tBuOLi (2.5 mol %)
OH
R2
R2
R1
H2 (3.0 MPa), iPrOH
rt, 12 h, S/C = 10 000
R1
1
2
OH
OH
OH
OH
2b
OH
OH
2c
2a
2d
2e
97.4% ee
2f
b
97.5% eeb
98.4% ee
99% yield
97.7% ee
99% yield
98.5% ee
99% yield
97.9% ee
99% yield
98.0% yield
99% yield
OH
OH
OH
OH
OH
OH
O
Cl
F
2g
2h
2i
2j
2k
2l
99.0% ee
99% yield
98.8% ee
99% yield
97.9% ee
99% yield
97.7% ee
99% yield
95.8% ee
99% yield
97.0% ee
99% yield
OH
OH
OH
OH
Cl
OH
OH
Br
F3C
O
O
O2N
Br
Cl
2o
2m
2p
2n
CF3
2q
2r
96.5% ee
99% yield
97.6% ee
99% yield
97.5% ee
99% yield
98.3% ee
99% yield
98.6% ee
97% yield
94.0% ee
96% yield
OH
OH
OH
S
OH
OH
O
O
OH
2s
2u
2w
2t
2v
2x
97.9% ee
99% yield
98.3% eeb
94.7% ee
99% yield
95.8% ee
91% yield
99.0% ee
99% yield
99.4% ee
99% yield
99% yield
aReaction conditions were the same as those listed in Table 1, entry 8. Isolated yields. The ee was determined
by HPLC analysis. bat 60 oC.
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Intriguingly, these privileged fꢀdiaphos ligands could be further applied into the Irꢀcatalyzed asymmetric
hydrogenation of orthoꢀsubstituted diaryl ketones, leading to a variety of chiral diaryl methanols in 82.1−98.2%
ee (Scheme 4). 2ꢀBromobenzophenone was initially hydrogenated under 0.1 mol % of the IrꢀL6 catalytic
system for 12 h, giving (R)ꢀ(2ꢀbromophenyl)(phenyl)methanol 4a in 96% yield with 94.6% ee (more details on
optimization of reaction conditions, see SI). Notably, the ortho substituent greatly affected the reaction,
asymmetric bias between the two aryl groups. Thereby, the introduction of oꢀbromo or oꢀchloro unit was
conductive to higher ee values (4a, 94.6% ee; 4b, 92.7% ee) than that of oꢀfluoro or oꢀmethyl unit (4c, 82.1%
ee and 4d, 85.1% ee). Moreover, the results of the highꢀperformance liquid chromatographic (HPLC) analysis
with a chiral stationary phase indicated that the products were (R)ꢀisomers. In addition, oꢀBrꢀphenyl aryl
ketones that contained electronꢀdeficient (3e−3g) and electronꢀrich (3h−3j) aryl groups furnished the
corresponding unsymmetrical diarylmethanols with sufficient yields and ees, which indicating that fꢀdiaphos L6
can precisely recognize the orthoꢀsubstituted phenyl group. Furthermore, excellent ees, exceeding 98.2%,
were obtained when (5ꢀbromoꢀ2ꢀchlorophenyl)(4ꢀethoxyphenyl)methanone and (5ꢀbromoꢀ2ꢀchlorophenyl)(4ꢀ
florophenyl)methanone were employed as the substrates.
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Scheme 4. IrꢀL6 Catalysis for the Asymmetric Hydrogenation of 3
aReaction conditions: 1 mmol scale, [substrate] = 0.2 M, 0.05 mol % [Ir(COD)Cl]2, 0.105 mol % ligand L6, 2.5
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mol % tBuOLi, 10 mL of iPrOH, room temperature (25−30 oC). Isolated yields. The ee was determined by HPLC
analysis.
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In order to demonstrate the utility of this method, several gramꢀscale reactions with lower catalyst loading were
conducted, as shown in scheme 5. To our delight, IrꢀL8 complex exhibited good stability and excellent
reactivity. When the catalyst loading was decreased to 0.001 mol % (S/C=100 000), the asymmetric
hydrogenation still underwent smoothly with 120 g of acetophenone 1a to afford the product (S)ꢀ2a in 117 g, 98%
isolated yield and 97.4% ee within only 24 h at room temperature under hydrogen pressure of 50 atm (Scheme
5a). In addition, a gramꢀscale reduction of (2ꢀbromophenyl)(pꢀtolyl)methanone 3h was also accomplished with
our catalytic system (0.01 mol % IrꢀL6, S/C=10 000), and the (R)ꢀ(2ꢀbromophenyl)(pꢀtolyl)methanol 4h was
obtained in 93.2% ee (Scheme 5b). Subsequently debromination of 4h resulted in the formation of
(S)ꢀphenyl(pꢀtolyl)methanol 5h, which is the key intermediate of (S)ꢀneobenodine.15 Furthermore, the
debromination of 4f and 4l also underwent smoothly to produce (S)ꢀ(4ꢀchlorophenyl)(phenyl)methanol 5f (81%
yield, >99% ee) and (R)ꢀ(2ꢀchlorophenyl)(4ꢀfluorophenyl)methanol 5l (83% yield, 97% ee).
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Scheme 5. GramꢀScale Reaction and Further Transformation
To the best of our knowledge, there’s no example of controllable asymmetry hydrogenation of aryl alkyl
ketones to offer two enantiomers by using ferroceneꢀbased tridentate ligands. We are interested to see
whether current developed chiral fꢀdiaphos ligands could achieve this goal. Thus, L11, an enantiomer of (RC,
SFC)ꢀfꢀdiaphos L1, was synthesized and displayed high enantioselectivity and superb reactivity in the
Iridiumꢀcatalyzed asymmetry hydrogenation of acetophenone (1a). (R)ꢀ1ꢀphenylethanol (2a’) could be
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obtained in 99% yield with 95.4% ee (Scheme 6). This result indicates the current developed fꢀdiaphos ligands
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are capable of affording both (R) and (S) aryl alkyl methanols in high yields with excellent enantioselectivities.
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Scheme 6. IrꢀL11 Catalysis for the Synthesis of (R)ꢀ1ꢀPhenylethanol
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In order to further investigate the role of the NHTs group of the fꢀdiaphos ligand, we synthesized ligand L12 by
protecting the NH with ethyl group. Poor conversion and moderate enantioselectivity were observed under the
same conditions (L12, 78% conversion, 72.0% ee, vs L1, >99% conversion, 94.3% ee, Scheme 7a) in the
Ir/L12ꢀcatalyzed asymmetric hydrogenation of acetophenone 1a. These results indicated that the NHTs group
played a crucial role in this asymmetric hydrogenation reaction. Based on the control experiments and previous
literatures,12 two plausible transition state models were proposed to explain the different enantioselectivities in
asymmetry hydrogenation of aryl alkyl and diaryl ketones (Scheme 7b and 7c). The common active catalyst
was believed to be a Ir(III)ꢀdihydride complex A (Scheme 7b), which is derived from reaction of the Ir(I)
precursor, L6 or L8, the base, and two H2 molecules along with dissociation of the COD ligand. For aryl alkyl
ketones, the substrate 1a coordinates to A to form transition states B or C through interaction with two Hs
shown in red. The coordination of substrate to the complex A through the two Hs shown in green is disfavored
due to the steric hinderance caused by the aryl ring and the ferrocene group on P of the ligand and also the
large Ar group on NHTS. The transition state C has higher energy than transition state B, due to the steric
repulsion between the Ph ring of the 1a and the aryl ring of Pꢀcenterin transition state C. The subsequent step
is transfering of proton from the acidic −NHTs group to the substrate, leading to the (S)ꢀaryl alcohol with high ee.
Similarly, three possible transition state models (D, E and F) were proposed when using orthoꢀbromo diaryl
ketone 3a as a substrate. Transiton state D is favored over E and F, because the increased steric hindrance
caused by inner bromoꢀsubstituted benzene ring with methyl or cyclohexyl group of the ligand is disfavored in E
and F. Thus, the (R)ꢀdiaryl methanol 4a is forming via intermediate D. Notably, experiment results are in
accordance with this hypothesis: the smaller size of orthoꢀsubstituent (Br>Cl>Me>F) lead to a decreasement
on enantioselectivity (see 4a−4d).
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Scheme 7. Control Experiments and Possible Transition States
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CONCLUSION
In summary, we have successfully developed a series of novel tridentate ferroceneꢀbased diamineꢀphosphine
sulfonamide (fꢀdiaphos) ligands for iridiumꢀcatalytic asymmetric hydrogenation of various arylalkyl ketones and
diaryl ketones. Excellent enantioselectivities and superb activities (for arylalkyl ketones, up to 99.4% ee and
100 000 TON; for diaryl ketones, up to 98.2% ee and 10 000 TON) have been achieved using Ir−fꢀdiaphos
catalyst. This protocol could be easily conducted on gram scale, thereby provided a chance to synthesis
various drugs. Moreover, current process represents the first example that ferroceneꢀbased tridentate ligand
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can realize controllable asymmetry hydrogenation of aryl alkyl ketones to produce (R)ꢀ and (S)ꢀalcohols with
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excellent results.
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EXPERIMENTAL SECTION
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General information: All reactions were performed in an argonꢀfilled glovebox. Anhydrous THF and toluene
were distilled from sodium benzophenoneketyl. Anhydrous MeOH, EtOH and iPrOH were freshly distilled from
magnesium. Hydrogen gas (99.999%), aromatic ketones, [Ir(COD)Cl]2 and other chemical reagents were
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purchased from commercial suppliers. HNMR (400, 500 or 600 MHz), 13C NMR (100, 125 or 150 MHz) and
31P NMR (243 or 202 MHz) spectra were recorded on a Bruker ADVANCE II and III instruments in CDCl3 or
DMSOꢀd6 with TMS as internal standard. 1H NMR chemical shifts were referenced to tetramethylsilane signal
(0 ppm), 13C NMR chemical shifts were referenced to the solvent resonance (77.00 ppm, CDCl3). HRMS
spectra were recorded on an Agilent 1200HPLCꢀ6210TOFMS using ESI as ion source. Optical rotations were
determined using a AUTOPOL V polarimeter. HPLC analyses were performed using Agilent 1100 equipped
with OJꢀH, ODꢀH, ADꢀH and ID column.
General Procedure for the Preparation of fꢀdiaphos ligands. A solution of (Rc, SFC)ꢀ or (Sc, RFC)ꢀ1 (1
mmol), (R, R)ꢀ or (S, S)ꢀ1,2ꢀdiamine (2 mmol) in dry MeOH (1 mL) was stirred at reflux overnight. The reaction
mixture was cooled to room temperature, and then the solvent was removed under vacuum. The crude product
was purified by column chromatography on silica gel to yield L1−L11.
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fꢀDiphos L1: Orange solid, 65% yield, 432.0 mg, mp 154−155 C, [α]D = ꢀ130.0 (c = 0.5, CHCl3). 1H NMR
(600 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 2H), 7.50−7.46 (m, 2H), 7.37−7.34 (m, 3H), 7.24 (d, J = 8.4 Hz, 2H),
7.17−7.14 (m, 1H), 7.07−7.03 (m, 4H), 5.89 (s, 1H), 4.49 (s, 1H), 4.34 (t, J = 2.4 Hz, 1H), 4.05 (s, 5H),
4.00−3.99 (m, 1H), 3.68 (s, 1H), 2.42 (s, 3H), 2.14−2.06 (m, 2H), 1.91−1.89 (m, 1H), 1.83−1.81 (m, 1H),
1.47−1.42 (m, 2H), 1.33 (d, J = 6.0 Hz, 3H), 1.09−0.95 (m, 2H), 0.85−0.77 (m, 1H), 0.06 (brs, 1H), ꢀ0.26−ꢀ0.40
(m, 1H); 13C NMR (150 MHz, CDCl3) δ 142.8, 139.9 (d, J = 10.5 Hz), 137.2, 136.6 (d, J = 9.0 Hz), 135.0 (d, J =
21.0 Hz), 132.8 (d, J = 19.5 Hz), 129.4, 129.2, 128.3, 128.30, 128.2 (d, J = 7.5 Hz), 127.5, 98.1 (d, J = 22.5 Hz),
74.3 (d, J = 7.5 Hz), 71.2 (d, J = 4.5 Hz), 69.7, 69.5 (d, J = 4.5 Hz), 69.2, 57.8, 56.9, 32.1, 29.8, 24.8, 24.0, 21.6,
20.1; 31P NMR (243 MHz, CDCl3) δ ꢀ24.73 (s). HRMS (ESI) calcd for C37H42FeN2O2PS [M + H]+, 665.2049;
found: 665.2062.
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fꢀDiphos L2: Orange solid, 48% yield, 333.0 mg, mp 162ꢀ164 C, [α]D = ꢀ125.2 (c = 0.5, CHCl3). H NMR
(400 MHz, CDCl3) δ 7.51 ꢀ 7.47 (m, 2H), 7.38 ꢀ 7.35 (m, 3H), 7.16 ꢀ 7.11 (m, 1H), 7.03 (t, J = 4.4 Hz, 4H), 6.92
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(s, 2H), 5.93 (s, 1H), 4.49 (s, 1H), 4.33 (t, J = 2.8 Hz, 1H), 4.05 (s, 5H), 4.04ꢀ4.02 (m, 1H), 3.69 (s, 1H), 2.59 (s,
6H), 2.31 (s, 3H), 2.15 ꢀ 2.04 (m, 2H), 1.91 ꢀ 1.86 (m, 1H), 1.77ꢀ1.73 (m, 1H), 1.48 ꢀ 1.39 (m, 5H), 1.07 ꢀ 0.92 (m,
2H), 0.82 ꢀ 0.70 (m, 1H), ꢀ0.43 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 141.6,140.1 (d, J = 11.0 Hz), 139.1,
136.3 (d, J = 9.0 Hz), 135.0 (d, J = 21.0 Hz), 134.2, 132.6 (d, J = 19.0 Hz), 131.8, 129.2, 128.4 (d, J = 6.0 Hz),
128.2 (d, J = 8.0 Hz), 97.8 (d, J = 23.0 Hz), 74.0 (d, J = 6.0 Hz), 71.1 (d, J = 4.0 Hz), 69.7, 69.4 (d, J = 4.0 Hz),
69.2, 57.8, 57.0, 46.3 (d, J = 10.0 Hz), 32.0, 29.8, 24.9, 24.0, 23.1, 21.0, 19.9; 31P NMR (162 MHz, CDCl3) δ
ꢀ24.94 (s). HRMS (ESI) calcd for C39H46FeN2O2PS [M + H]+: 693.2362; Found: 693.2357.
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fꢀDiphos L3: Orange solid, 47% yield, 365 mg, mp 151ꢀ152 oC, [α]D20 = ꢀ52.4 (c = 0.5, CHCl3). 1H NMR (600
MHz, CDCl3) δ 7.49−7.47 (m, 2H), 7.36−7.34 (m, 3H), 7.15 (s, 2H), 7.08 (t, J = 7.2 Hz, 3H), 6.96 (t, J = 7.2 Hz,
2H), 5.96 (s, 1H), 4.50 (s, 1H), 4.27 (s, 1H), 4.07−4.01 (br, 1H), 4.04 (s, 5H), 3.64 (s, 1H), 2.92 (hept, J = 6.6 Hz,
1H), 2.19−1.97 (m, 4H), 1.49 (t, J = 9.6 Hz, 2H), 1.39 (d, J = 5.4 Hz, 3H), 1.29−1.26 (m, 7H), 1.23 (d, J = 6.6 Hz,
6H), 1.17 (d, J = 6.6 Hz, 6H), 1.07−0.98 (m, 2H), 0.90−0.82 (m, 2H), 0.14 (s, 1H), ꢀ0.19−ꢀ0.21 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 152.1, 150.3, 139.9 (d, J = 10.0 Hz), 136.4 (d, J = 8.8 Hz), 135.1 (d, J = 21.3 Hz),
133.5, 132.6 (d, J = 18.8 Hz), 129.2, 128.3 (d, J = 6.3 Hz), 128.1 (d, J = 7.5 Hz), 123.6, 97.34 (d, J = 26.3 Hz),
74.3 (d, J = 6.3 Hz), 71.2 (d, J = 3.8 Hz), 70.0 (d, J = 2.5 Hz), 69.7, 69.1, 57.3 (d, J = 17.5 Hz), 46.6 (d, J = 8.8
Hz), 34.1, 32.0, 29.8 (d, J = 17.5 Hz), 25.1 (d, J = 13.8 Hz), 23.9, 23.6 (d, J = 25.0 Hz), 19.8; 31P NMR (243
MHz, CDCl3) δ ꢀ24.96 (s). HRMS (ESI) calcd for C45H58FeN2O2PS [M + H]+, 777.3301; found: 777.3320.
fꢀDiphos L4: Orange solid, 52% yield, 397 mg, mp 92ꢀ94 oC, [α]D20 = ꢀ150.0 (c = 0.5, CHCl3). 1H NMR (600
MHz, CDCl3) δ 7.53−7.50 (m, 2H), 7.40−7.38 (m, 6H), 7.36 (d, J = 8.4 Hz, 2H), 7.29−7.28 (m, 2H), 7.13 (t, J =
6.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 2H), 7.00 (t, J = 7.8 Hz, 3H), 6.93 (t, J = 7.2 Hz, 2H), 6.79 (d, J = 7.8 Hz, 2H),
6.68 (d, J = 6.6 Hz, 2H), 6.45 (s, 1H), 4.37 (s, 1H), 4.30 (s, 1H), 4.02 (d, J = 7.8 Hz, 1H), 3.95 (s, 5H), 3.71−3.69
(m, 2H), 3.62 (d, J = 5.4 Hz, 1H), 2.34 (s, 3H), 1.51 (s, 1H), 1.16 (d, J = 3.0 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 142.4, 140.6 (d, J = 12.0 Hz), 138.6, 137.7, 135.3 (d, J = 21.0 Hz), 132.7 (d, J = 18.0 Hz), 129.1, 128.9, 128.5,
128.3, 128.1 (d, J = 7.5 Hz), 127.70, 127.65, 127.6, 127.4, 127.2, 127.0, 74.2 (d, J = 10.5 Hz), 71.5 (d, J = 4.5
Hz), 69.8, 69.6, 69.5, 64.7, 63.3, 47.6, 21.5, 19.7; 31P NMR (202 MHz, CDCl3) δ ꢀ23.54 (s). HRMS (ESI) calcd
for C45H44FeN2O2PS [M + H]+, 763.2206; found: 763.2174.
fꢀDiphos L5: Orange solid, 62% yield, 412 mg, mp 140−142 oC, [α]D20 = ꢀ72.8 (c = 0.5, CHCl3). 1H NMR (600
MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 4.8 Hz, 2H), 7.40 (s, 3H), 7.31−7.26 (m, 7H), 5.10 (s, 1H),
4.44 (d, J = 9.0 Hz, 2H), 4.05 (s, 2H), 3.93 (s, 5H), 2.45 (s, 3H), 2.42−2.40 (br, 1H), 2.01−1.93 (m, 1H), 1.83 (d,
J1 = 10.2 Hz, 2H), 1.45 (s, 3H), 1.34 (d, J = 13.2 Hz, 1H), 1.27 (d, J = 12.0 Hz, 1H), 1.00−0.85 (m, 2H),
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0.74−0.69 (m, 2H), 0.50−0.49 (br, 1H); 13C NMR (150 MHz, CDCl3) δ 142.9, 140.2 (d, J = 9.0 Hz), 137.8 (d, J =
7.5 Hz), 135.2 (d, J = 22.5 Hz), 132.7 (d, J = 19.5 Hz), 129.5, 129.2, 128.4 (d, J = 6.0 Hz), 128.1 (d, J = 3.0 Hz),
128.1, 127.3, 74.1 (d, J = 7.5 Hz), 71.0 (d, J = 3.0 Hz), 69.9, 69.7, 68.6 (d, J = 4.5 Hz), 56.9, 47.6, 31.7, 24.7,
24.0, 23.8, 21.6, 19.2; 31P NMR (243 MHz, CDCl3) δ ꢀ26.91 (s). HRMS (ESI) calcd for C37H42FeN2O2PS [M +
H]+, 665.2095; found: 665.2070.
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fꢀDiphos L6: Orange solid, 51% yield, 382 mg, mp 88−89 C, [α]D = ꢀ78.4 (c = 0.5, CHCl3). HNMR (600
MHz, CDCl3) δ 7.14 (d, J = 7.8 Hz, 2H), 7.01 (s, 1H), 6.88 (s, 2H), 6.85 (s, 1H), 6.73 (s, 2H), 5.96 (s, 1H), 4.46
(s, 1H), 4.31 (s, 1H), 4.05 (s, 5H), 4.01 (s, 1H), 3.71 (s, 1H), 2.60 (s, 6H), 2.32 (s, 6H), 2.26 (s, 3H), 2.11 (s, 6H),
2.03 (s, 2H), 1.90 (s, 1H), 1.80 (d, J = 12.6 Hz, 1H), 1.45−1.38 (m, 5H), 0.98−0.95 (m, 2H), 0.85−0.77 (m, 1H),
0.14 (s, 1H), ꢀ0.38 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 141.6, 139.5 (d, J = 9.0 Hz), 138.9, 137.9 (d, J = 7.5
Hz), 137.5 (d, J = 7.5 Hz), 136.2 (d, J = 9.0 Hz), 134.7, 132.7 (d, J = 21.0 Hz), 131.8, 130.9, 130.6 (d, J = 19.5
Hz), 130.1, 75.0 (d, J = 7.5 Hz), 71.2, 69.7, 57.6 (d, J = 61.5 Hz), 31.3, 29.8, 23.9, 22.9, 21.4, 21.2, 20.9; 31P
NMR (243 MHz, CDCl3) δ ꢀ25.04 (s). HRMS (ESI) calcd for C43H54FeN2O2PS [M + H]+, 749.2988; found:
749.3006.
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fꢀDiphos L7: Orange solid, 47% yield, 431 mg, mp 91−93 C, [α]D = ꢀ80.8 (c = 0.5, CHCl3). H NMR (400
MHz, CDCl3) δ 7.40 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.05 (d, J = 6.0 Hz, 2H), 6.86 (s, 2H), 6.00 (s,
1H), 4.48 (s, 1H), 4.31 (s, 1H), 4.08 (s, 5H), 4.00 (s, 1H), 3.59 (s, 1H), 2.60 (s, 6H), 2.27 (s, 3H), 2.06ꢀ1.99 (m,
2H), 1.89(s, 1H), 1.69 (d, J = 13.2 Hz, 1H), 1.45 (s, 3H), 1.37 (s, 2H), 1.27 (s, 19H), 1.14 (s, 18H), 0.98 ꢀ 0.94
(m, 2H), 0.79 ꢀ 0.70 (m, 1H), ꢀ0.52 ꢀ ꢀ0.55 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 150.7 (d, J = 7.5 Hz), 150.1 (d,
J = 7.5 Hz), 141.3, 138.7, 138.1 (d, J = 6.3 Hz), 135.1 (d, J = 6.3 Hz), 134.7, 131.8, 129.2 (d, J = 21.3 Hz),
127.2 (d, J = 20.0 Hz), 122.6 (d, J = 47.5 Hz), 97.0 (d, J = 22.5 Hz), 76.1 (d, J = 5.0 Hz), 70.8 (d, J = 2.5 Hz),
69.6, 69.3 (d, J = 2.5 Hz), 68.9, 57.8 (d, J = 22.5 Hz), 47.2 (d, J = 10.0 Hz), 34.8 (d, J = 22.5 Hz), 31.4 (d, J =
5.0 Hz), 31.1, 30.0, 25.2, 23.8, 22.9, 20.8 (d, J = 11.3 Hz); 31P NMR (162 MHz, CDCl3) δ ꢀ24.65 (s). HRMS (ESI)
calcd for C55H78FeN2O2PS [M + H]+, 917.4879; found: 917.4867.
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fꢀDiphos L8: Orange solid, 50% yield, 444 mg, mp 87−89 C, [α]D = ꢀ74.4 (c = 0.5, CHCl3). H NMR (600
MHz, CDCl3) δ 7.71−7.70 (m, 2H), 7.39 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.22 (d, J = 7.8 Hz, 2H),
7.06 (d, J = 7.8 Hz, 2H), 5.95 (s, 1H), 4.48 (s, 1H), 4.29 (s, 1H), 4.08 (s, 5H), 3.99−3.98 (m, 1H), 3.58 (s, 1H),
2.40 (s, 3H), 2.06−2.02 (m, 2H), 1.96−1.93 (m, 1H), 1.78 (d, J = 12.6 Hz, 1H), 1.45−1.43 (m, 1H), 1.39 (d, J =
6.6 Hz, 4H), 1.28 (s, 18H), 1.15 (s, 18H), 1.00−0.92 (m, 2H), 0.81−0.75 (m, 1H), 0.14 (s, 1H), ꢀ0.32−ꢀ0.44 (q, J
= 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 150.7 (d, J = 6.0 Hz), 150.1 (d, J = 6.0 Hz), 142.6, 138.1 (d, J =
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7.5 Hz), 135.2 (d, J = 7.5 Hz), 129.4, 129.2 (d, J = 21.0 Hz), 127.4 (d, J = 21.0 Hz), 127.1, 122.8, 122.3, 76.1 (d,
J = 6.0 Hz), 70.9 (d, J = 3.0 Hz), 69.6, 69.5, 68.9, 57.7 (d, J = 12.0 Hz), 47.1, 34.9, 34.7, 31.5, 31.4, 31.3, 30.0,
25.1, 23.8, 21.5, 20.8; 31P NMR (243 MHz, CDCl3) δ ꢀ24.42 (s). HRMS (ESI) calcd for C53H74FeN2O2PS [M +
H]+, 889.4554; found: 889.4516.
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fꢀDiphos L9: Orange oil, 56% yield, 412 mg, [α]D = ꢀ374.4 (c = 0.5, CHCl3). H NMR (600 MHz, CDCl3) δ
7.39 (s, 1H), 7.34 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 2H), 7.30 (s, 1H), 7.13 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 2H), 4.45 (s,
1H), 4.23 (t, J = 2.4 Hz, 1H), 4.14−4.13 (m, 1H), 4.07 (s, 5H), 3.55 (s, 1H), 1.97−1.95 (m, 1H), 1.90−1.86 (m,
1H), 1.70−1.68 (m, 1H), 1.52−1.48 (m, 2H), 1.47−1.44 (m, 1H), 1.37 (d, J = 6.0 Hz, 3H), 1.27 (s, 18H), 1.21 (s,
18H), 1.07−1.00 (m, 1H), 0.96−0.83 (m, 3H), ꢀ0.086−ꢀ0.015 (m, 1H); 13C NMR (150 MHz, CDCl3) δ 150.6 (d, J
= 6.0 Hz), 150.0 (d, J = 7.5 Hz), 138.3 (d, J = 7.5 Hz), 135.4 (d, J = 7.5 Hz), 129.3 (d, J = 19.5 Hz), 127.6 (d, J =
16.5 Hz), 122.5 (d, J = 64.5 Hz), 98.1 (d, J = 21.0 Hz), 76.2 (d, J = 4.5 Hz), 70.9 (d, J = 4.5 Hz), 69.5, 69.3 (d, J
= 3.0 Hz), 68.6, 60.6, 55.3, 46.7 (d, J = 9.0 Hz), 34.9, 34.8, 34.5, 31.5, 30.2, 25.6, 24.8, 20.0; 31P NMR (243
MHz, CDCl3) δ ꢀ24.22 (s). HRMS (ESI) calcd for C46H68FeN2P [M + H]+, 735.4465; found: 735.4461.
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fꢀDiphos L10: Orange solid, 64% yield, 426 mg, mp 145−146 C, [α]D = +86.0 (c = 0.5, CHCl3). H NMR
(600 MHz, CDCl3) δ 7.69 (d, J = 7.8 Hz, 2H), 7.60−7.57 (m, 2H), 7.37−7.36 (m, 3H), 7.28−7.22 (m, 7H), 5.14 (s,
1H), 4.41−4.39 (m, 2H), 4.00−3.98 (m, 2H), 3.90 (s, 5H), 2.41 (s, 3H), 2.36 (s, 1H), 1.96−1.93 (m, 1H),
1.80−1.79 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H), 1.33−1.23 (m, 3H), 0.89−0.87 (m, 1H), 0.75−0.73 (m, 1H),
0.66−0.60 (m, 1H), 0.53−0.47(m, 1H); 13C NMR (150 MHz, CDCl3) δ 142.9, 140.2 (d, J = 7.5 Hz), 137.8 (d, J =
7.5 Hz), 137.7, 135.2 (d, J = 22.5 Hz), 132.7 (d, J = 18.0 Hz), 129.5, 129.2, 128.3 (d, J = 6.0 Hz), 128.1 (d, J =
3.0 Hz), 127.3, 100.0 (d, J = 27 Hz), 74.1 (d, J = 9.0 Hz), 70.9 (d, J = 4.5 Hz), 69.9, 69.7, 68.6 (d, J = 4.5 Hz),
57.5, 56.8, 47.5 (d, J = 9.0 Hz), 32.0, 31.7, 24.8, 24.0, 23.8, 21.6; 31P NMR (243 MHz, CDCl3) δ ꢀ26.78 (s).
HRMS (ESI) calcd for C37H42FeN2O2PS [M + H]+, 665.2049; found: 665.2044.
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fꢀDiphos L11: Orange solid, 61% yield, 406 mg, mp 146−148 C, [α]D = +60.4 (c = 0.5, CHCl3). H NMR
(600 MHz, CDCl3) δ 7.70 (d, J = 6.0 Hz, 2H), 7.49−7.47 (m, 2H), 7.37 (s, 3H), 7.24 (d, J = 7.2 Hz, 2H),
7.18−7.13 (m, 1H), 7.05 (d, J = 3.0 Hz, 4H), 5.89 (s, 1H), 4.49 (s, 1H), 4.34 (d, J = 2.4 Hz, 1H), 4.05 (d, J = 2.4
Hz, 5H), 3.99 (d, J = 6.0 Hz, 1H), 3.68 (s, 1H), 2.43 (d, J = 1.2 Hz, 3H), 2.10 (t, J = 7.8 Hz, 2H), 1.91 (d, J = 12.6
Hz, 1H), 1.81 (t, J = 9.0 Hz, 1H), 1.47−1.42 (m, 2H), 1.33 (d, J = 4.2 Hz, 3H), 1.09−1.03 (m, 1H), 1.00−0.96 (m,
1H), 0.83−0.77 (m, 1H), 0.46 (brs, 1H), ꢀ0.35 (q, J= 10.8 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 142.8, 139.8 (d,
J = 10.5 Hz), 137.2, 136.6 (d, J = 9.0 Hz), 134.9 (d, J = 21.0 Hz), 132.7 (d, J = 19.5 Hz), 129.4, 129.2, 128.3 (d,
J = 6.0 Hz), 128.2 (d, J = 7.5 Hz), 127.5, 98.1 (d, J = 24.0 Hz), 74.3 (d, J = 6.0 Hz), 71.1 (d, J = 4.5 Hz), 70.4,
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69.7, 69.5 (d, J = 3.0 Hz), 69.2, 57.8, 56.9, 46.3 (d, J = 9.0 Hz), 32.1, 29.8, 24.8, 23.9, 21.6, 20.0; 31P NMR
(202 MHz, CDCl3) δ ꢀ24.63 (s). HRMS (ESI) calcd for C37H42FeN2O2PS [M + H]+, 665.2053; found: 665.2060.
fꢀDiphos L12: Orange solid, 46% yield, 318 mg, mp 77−78 oC, [α]D20 = ꢀ80.6 (c = 0.5, CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.59−7.54 (m, 2H), 7.39−7.36 (m, 3H), 7.24−7.15 (m, 7H), 4.35 (s, 1H),
4.29 (t, J = 2.8 Hz, 1H), 4.05−4.01 (m, 1H), 4.00 (s, 5H), 3.75 (s, 1H), 3.15−3.08 (m, 2H), 2.84 (s, 1H), 2.45 (s,
1H), 2.37 (s, 3H), 2.00 (d, J = 12.4 Hz, 1H), 1.61−1.45 (m, 3H), 1.42 (d, J = 6.4 Hz, 3H), 1.33−1.27 (m, 2H),
1.18 (t, J = 6.8 Hz, 3H), 0.93−0.87 (m, 2H), 0.10 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 142.3, 140.2 (d, J = 10.0
Hz), 138.8, 137.4 (d, J = 8.0 Hz), 135.3 (d, J = 21.0 Hz), 132.8 (d, J = 18.0 Hz), 129.4, 129.1, 128.1 (d, J = 3.0
Hz), 128.0 (d, J = 2.0 Hz), 127.9, 127.2, 99.7 (d, J = 24.0 Hz), 74.2 (d, J = 6.0 Hz), 70.8 (d, J = 5.0 Hz), 69.6,
69.1, 68.8, 62.8, 54.8, 46.2, 32.4, 31.7, 29.7 (d, J = 4.0 Hz), 29.4, 25.7, 24.5, 22.7, 21.6, 20.2, 16.9; 31P NMR
(162 MHz, CDCl3) δ ꢀ23.55 (s). HRMS (ESI) calcd for C39H46FeN2O2PS [M + H]+, 693.2320; found: 693.2343.
General Procedure for the asymmetric hydrogenation of aryl alkyl ketones 1. Under argon
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atomosphere, [Ir(COD)Cl]2 (8.4 mg, 0.012 mmol), L8 (22.7 mg, 0.025 mmol), anhydrous PrOH (3 mL) were
added to an ovenꢀdried vial (10 mL) and then stirred at 30 oC for 1.5 h to give a clear yellow solution. An aliquot
of the catalyst solution (25 ꢁL, 0.0002 mmol) was transferred into a 20ꢀmL hydrogenation vessel, then ketones
(2.0 mmol), tBuOLi in iPrOH (0.025 mmol/mL, 2 mL, 0.05 mmol) and anhydrous iPrOH (8 mL) were added. The
vessel was placed in an autoclave which was then charged with 30 atm of H2 and stirred at 25−30 oC for 12 h
(60 oC for 2e, 2f, 2s). After slowly releasing the hydrogen pressure, the solvent was removed, and the mixture
was purified by passing through a short column of silica gel to afforded corresponding alcohol. The ee values of
all compounds were determined by HPLC with a chiral column.
(S)ꢀ1ꢀPhenylethanꢀ1ꢀol (2a): Colorless oil, 99% yield, 242.4 mg; 97.7% ee (S); [α]D20 = ꢀ71.2 (c = 0.5, CHCl3);
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lit.16 [α]D = ꢀ48 [c = 0.17, CHCl3, 93% ee (S)]. The ee was determined by HPLC on Chiralpak OJ−H column,
hexane: isopropanol = 90:10; flow rate = 0.7 mL/min; UV detection at 210 nm; tR(S) = 11.29 min (major), tR(R) =
12.89 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.38−7.34 (m, 1H), 7.29−7.26 (m, 1H), 4.90 (q, J = 6.6 Hz, 1H),
1.81 (brs, 1H), 1.50 (d, J = 6.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 145.8, 128.5, 127.5, 125.4, 70.5, 25.2.
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(R)ꢀ1ꢀPhenylethanꢀ1ꢀol (2a’): Colorless oil, 99% yield, 242.2 mg; 95.4% ee (R); [α]D = +65.3 (c = 0.5,
CHCl3); lit.16 [α]D20 = ꢀ48 [c = 0.17, CHCl3, 93% ee (S)]. The ee was determined by HPLC on Chiralpak OJ−H
column, hexane: isopropanol = 90:10; flow rate = 0.7 mL/min; UV detection at 210 nm; tR(S) = 11.01 min
(minor), tR(R) = 12.51 min (major). 1H NMR (600 MHz, CDCl3) δ 7.38−7.34 (m, 1H), 7.29−7.26 (m, 1H), 4.90 (q,
J = 6.6 Hz, 1H), 1.81 (brs, 1H), 1.50 (d, J = 6.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 144.8, 127.5, 126.5,
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(S)ꢀ1ꢀPhenylpropanꢀ1ꢀol (2b): Colorless oil, 99% yield, 270.0 mg; 98.4% ee (S). [α]D = ꢀ40.4 (c = 0.5,
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CHCl3); lit.12c [α]D = +46.9 [c = 1.0, CHCl3, >99% ee (R)]. The ee was determined by HPLC on Chiralpak
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OJ−H column, hexane: isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 220 nm; tR(S) = 10.95 min
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(major), tR(R) = 12.02 min (minor). H NMR (600 MHz, CDCl3) δ 7.34−7.30 (m, 4H), 7.27−7.24 (m, 1H),
4.56−4.53 (m, 1H), 2.16−2.08 (br, 1H), 1.83−1.69 (m, 2H), 0.892 (t, J = 7.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 144.6, 128.4, 127.5, 126.0, 76.0, 31.9, 10.2.
(S)ꢀ1ꢀPhenylbutanꢀ1ꢀol (2c): White solid, 99% yield, 149.2 mg, 98.5% ee (S). [α]D20 = ꢀ33.2 (c = 0.5, CHCl3);
lit.17 [α]D = +51.6 [c = 0.94, CHCl3, 96.6% ee (R)].The ee was determined by HPLC on Chiralpak OJ−H
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column, hexane: isopropanol = 97:3; flow rate = 0.5 mL/min; UV detection at 220 nm; tR(S) = 21.61 min (major),
tR(R) = 23.44 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.35−7.32 (m, 4H), 7.28−7.25 (m, 1H), 4.65 (t, J = 7.2
Hz, 1H), 1.94−1.92 (br, 1H), 1.81−1.75 (m, 1H), 1.70−1.64 (m, 1H), 1.47−1.38 (m, 1H), 1.34−1.26 (m, 1H), 0.92
(t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 145.0, 128.4, 127.5, 125.9, 74.4, 41.3, 19.1, 14.0.
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(S)ꢀ1,2ꢀDiphenylethanꢀ1ꢀol (2d): White soild, 99% yield, 395.4 mg, 97.9% ee (S). [α]D = ꢀ29.6 (c = 0.5,
CHCl3); lit.18 [α]D20 = +47.6 [c = 0.5, EtOH, 94.0% ee (R)]. The ee was determined by HPLC on Chiralpak OD−H
column, hexane: isopropanol = 90:10; flow rate = 0.9 mL/min; UV detection at 210 nm; tR(R) = 9.19 min (minor),
tR(S) = 10.02 min (major). 1H NMR (600 MHz, CDCl3) δ 7.36−7.19 (m, 10H), 4.90−4.88 (m, 1H), 3.06−2.97 (m,
2H), 2.04−1.95 (br, 1H); 13C NMR (150 MHz, CDCl3) δ 143.8, 138.1, 129.6, 128.5, 128.4, 127.7, 126.7, 125.9,
75.4, 46.1.
(S)ꢀ2ꢀMethylꢀ1ꢀphenylpropanꢀ1ꢀol (2e): Colorless oil, 98% yield, 294.4 mg; 97.4% ee (S). [α]D20 = ꢀ24.8 (c =
0.5, CHCl3); lit.12c [α]D20 = +41.6 [c = 1.0, CHCl3, >99% ee (R)]. The ee was determined by HPLC on Chiralpak
OD−H column, hexane: isopropanol = 98:2; flow rate = 0.8 mL/min; UV detection at 210 nm; tR(S) = 15.26 min
(major), tR(R) = 17.85 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.34−7.25 (m, 5H), 4.35 (d, J = 7.2 Hz, 1H),
1.98−1.92 (m, 1H), 1.89−1.88 (br, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 143.7, 128.2, 127.4, 126.6, 80.1, 35.3, 19.0, 18.3.
(S)ꢀ1,2,3,4ꢀTetrahydronaphthalenꢀ1ꢀol (2f): Red solid, 99% yield, 295.4 mg, 97.5% ee (S). [α]D20 = +33.2 (c =
0.5, CHCl3); lit.17 [α]D20 = ꢀ28.6 (c = 0.88, CHCl3, 94.4% ee (R)]. The ee was determined by HPLC on Chiralpak
OJ−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 13.43 min
(major), tR(R) = 16.66 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.45−7.43 (m, 1H), 7.24−7.20 (m, 2H), 7.12 (t,
J = 4.8 Hz, 1H), 4.76 (t, J = 4.8 Hz, 1H), 2.86−2.81 (m, 1H), 2.77−2.71 (m, 1H), 2.19 (s, 1H), 2.02−1.95 (m, 2H),
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(S)ꢀ1ꢀ(oꢀTolyl)ethanꢀ1ꢀol (2g): Colorless oil, 99% yield, 271.2 mg, 99.0% ee (S). [α]D = ꢀ36.4 (c = 0.5,
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CHCl3); lit.12c [α]D = +77.0 [c = 1.0, CHCl3, >99% ee (R)]. The ee was determined by HPLC on Chiralpak
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OJ−H column, hexane: isopropanol = 99:1; flow rate = 0.5 mL/min; UV detection at 220 nm; tR(S) = 45.38 min
(minor), tR(R) = 47.79 min (major). 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H),
7.16 (td, J1 = 7.8 Hz, J2 = 1.2 Hz), 7.13−7.12 (d, J = 7.8 Hz, 2H), 5.12−5.09 (m, 1H), 2.33 (s, 3H), 1.91−1.86 (br,
1H), 1.45 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 143.9, 134.2, 130.4, 127.2, 126.4, 124.5, 66.8, 24.0,
18.9.
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(S)ꢀ1ꢀ(mꢀTolyl)ethanꢀ1ꢀol (2h): Colorless oil, 99% yield, 270.2 mg, 98.8% ee (S). [α]D = ꢀ36.0 (c = 0.5,
CHCl3); lit.19 [α]D20 = +47.8 [c = 1.0, CHCl3, 96% ee (R)]. The ee was determined by HPLC on Chiralpak OJ−H
column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 12.94 min (major),
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tR(R) = 14.31 min (minor). H NMR (600 MHz, CDCl3) δ 7.24−7.21 (m, 1H), 7.17 (s, 1H), 7.14 (d, J = 7.8 Hz,
1H), 7.08 (d, J = 7.8 Hz, 1H), 4.82 (q, J = 6.6 Hz, 1H), 2.35 (s, 3H), 2.12−2.05 (br, 1H), 1.46 (d, J = 6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 145.9, 138.2, 128.4, 128.2, 126.2, 122.5, 70.4, 25.1, 21.5.
(S)ꢀ1ꢀ(pꢀTolyl)ethanꢀ1ꢀol (2i): Colorless oil, 99% yield, 270.0 mg, 97.9% ee (S). [α]D20 = ꢀ27.6 (c = 0.5, CHCl3);
lit.16 [α]D20 = ꢀ49.0 [c = 0.33, CHCl3, 85% ee (S)]. The ee was determined by HPLC on Chiralpak OJ−H column,
hexane: isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 220 nm; tR(S) = 12.60 min (major), tR(R) =
14.88 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.84 (q, J =
6.6 Hz, 1H), 2.34 (s, 3H), 1.98−1.91 (br, 1H), 1.47 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 142.9,
137.1, 129.2, 125.4, 70.2, 25.1, 21.1.
(S)ꢀ1ꢀ(4ꢀMethoxyphenyl)ethanꢀ1ꢀol (2j): Colorless oil, 99% yield, 303.4 mg, 97.7% ee (S). [α]D20 = ꢀ51.6 (c =
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0.5, CHCl3); lit.19 [α]D = +56.8 [c = 1.0, CHCl3, 95% ee (R)]. The ee was determined by HPLC on Chiralpak
OJ−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 210 nm; tR(R) = 16.27 min
(minor), tR(S) = 18.44 min (major). 1H NMR (600 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 9.0 Hz,
2H), 4.78 (q, J = 6.0 Hz, 1H), 3.76 (s, 3H), 2.57 (brs, 1H), 1.43 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 158.9, 138.1, 126.7, 113.8, 69.8, 55.3, 25.0.
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(S)ꢀ1ꢀ(4ꢀFluorophenyl)ethanꢀ1ꢀol (2k): Colorless oil, 99% yield, 279.2 mg, 95.8% ee (S). [α]D = ꢀ29.6 (c =
0.5, CHCl3); lit.12a [α]D20 = +49.0 [c = 0.2, CH2Cl2, 99.9% ee (R)]. The ee was determined by HPLC on Chiralpak
OJ−H column, hexane: isopropanol = 97:3; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 21.68 min
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(major), tR(R) = 23.15 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.32−7.28 (m, 2H), 7.03−6.99 (m, 2H), 4.83 (q,
J = 6.6 Hz, 1H), 2.38 (s, 1H), 1.44 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 162.1 (d, 1JCꢀF = 244.5 Hz),
141.5 (d, 4JCꢀF = 3.0 Hz), 127.1 (d, 3JCꢀF = 7.5 Hz), 115.3 (d, 2JCꢀF = 21.0 Hz), 69.8, 25.3.
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(S)ꢀ1ꢀ(4ꢀChlorophenyl)ethanꢀ1ꢀol (2l): Colorless oil, 99% yield, 310.4 mg, 97.0% ee (S). [α]D20 = ꢀ5.2 (c = 0.5,
CHCl3); lit.16 [α]D20 = ꢀ38 [c = 0.28, CHCl3, 95% ee (S)]. The ee was determined by HPLC on Chiralpak OJ−H
column, hexane: isopropanol = 97:3; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 20.34 min (major),
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tR(R) = 22.49 min (minor). H NMR (600 MHz, CDCl3) δ 7.30−7.25 (m, 4H), 4.82 (q, J = 6.6 Hz, 1H), 2.40 (s,
1H), 1.43 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 144.3, 133.0, 128.6, 126.8, 69.7, 25.2.
(S)ꢀ1ꢀ(3ꢀBromophenyl)ethanꢀ1ꢀol (2m): Colorless oil, 99% yield, 398.6 mg, 97.6% ee (S). [α]D20 = ꢀ27.2 (c =
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0.5, CHCl3); lit.16 [α]D = ꢀ35 [c = 0.32, CHCl3, 99% ee (S)]. The ee was determined by HPLC on Chiralpak
OJ−H column, hexane: isopropanol = 95:5; flow rate = 1.0 mL/min; UV detection at 220 nm; tR(S) = 11.64 min
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(major), tR(R) = 14.01 min (minor). H NMR (600 MHz, CDCl3) δ 7.51 (t, J = 1.8 Hz, 1H), 7.39−7.37 (m, 1H),
7.26 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 4.82 (q, J = 6.6 Hz, 1H), 2.21 (s, 1H), 1.45 (d, J = 6.0 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 148.1, 130.5, 130.1, 128.6, 124.0, 122.6, 69.7, 25.3.
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(S)ꢀ1ꢀ(4ꢀBromophenyl)ethanꢀ1ꢀol (2n): Colorless oil, 99% yield, 398.4 mg, 97.5% ee (S). [α]D = ꢀ17.2 (c =
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0.5, CHCl3); lit.16 [α]D = ꢀ32 [c = 0.36, CHCl3, 95% ee (S)]. The ee was determined by HPLC on Chiralpak
OJ−H column, hexane: isopropanol = 98:2; flow rate = 0.8 mL/min; UV detection at 210 nm; tR(S) = 35.48 min
(major), tR(R) = 39.57 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.47−7.45 (m, 2H), 7.25−7.23 (m, 2H), 4.85 (q,
J = 6.6 Hz, 1H), 1.93 (s, 1H), 1.46 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 144.8, 131.6, 127.2, 121.2,
69.8, 25.3.
(S)ꢀ1ꢀ(2,4ꢀDichlorophenyl)ethanꢀ1ꢀol (2o): Colorless oil, 99% yield, 378.0 mg, 96.5% ee (S). [α]D20 = ꢀ21.6 (c
= 0.5, CHCl3); lit.20 [α]D25 = ꢀ52.4 [c = 0.55, CHCl3, 94% ee (S)]. The ee was determined by HPLC on Chiralpak
OD−H column, hexane: isopropanol = 98:2; flow rate = 0.6 mL/min; UV detection at 210 nm; tR(S) = 22.15 min
(major), tR(R) = 24.05 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 1.8 Hz,
1H), 7.24−7.20 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 5.15 (q, J = 6.6 Hz, 1H), 3.02 (s, 1H), 1.40 (d, J = 6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 141.7, 133.3, 132.0, 129.0, 127.5, 127.4, 66.5, 23.6.
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(S)ꢀ1ꢀ(3,5ꢀBis(trifluoromethyl)phenyl)ethanꢀ1ꢀol (2p): White soild, 97% yield, 500.8 mg, 98.6% ee (S). [α]D
=
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ꢀ10.3 (c = 0.5, CHCl3); lit.19 [α]D = +22.7 [c = 1.0, CHCl3, 93% ee (R)]. The ee was determined by HPLC on
Chiralpak OD−H column, hexane: isopropanol = 98:2; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) =
10.44 min (major), tR(R) = 11.55 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.84 (s, 2H), 7.79 (s, 1H), 5.04 (q, J
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= 6.6 Hz, 1H), 2.09 (s, 1H), 1.54 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 148.2, 131.7 (q, 2JCꢀF = 33.0
Hz), 125.6 (q, 4JCꢀF = 1.5 Hz), 123.3 (q, 1JCꢀF = 271.5 Hz), 121.4−121.2 (m), 69.3, 25.5.
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(S)ꢀ1ꢀ(4ꢀNitrophenyl)ethanꢀ1ꢀol (2q): Brown oil, 96% yield, 320.9 mg, 94.0% ee (S). [α]D = ꢀ18.0 (c = 0.5,
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CHCl3); lit.16 [α]D20 = ꢀ17.0 [c = 0.65, CHCl3, 80% ee (S)]. The ee was determined by HPLC on Chiralpak OJ−H
column, hexane: isopropanol = 96:4; flow rate = 0.8 mL/min; UV detection at 210 nm; tR(S) = 55.86 min (major),
tR(R) = 60.69 min (minor). 1H NMR (600 MHz, CDCl3) δ 8.18 (td, J1 = 8.4 Hz, J2 = 1.8 Hz, 2H), 7.54−7.52 (m,
2H), 5.01 (q, J = 6.6 Hz, 1H), 2.11 (s, 1H), 1.51 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 153.1, 147.2,
126.1, 123.8, 69.5, 25.5.
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(S)ꢀ1ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ethanꢀ1ꢀol (2r): Brown oil, 99% yield, 165.3 mg, 98.3% ee (S). [α]D = ꢀ24.8
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(c = 0.5, CHCl3); lit.21 [α]D = +32.4 [c = 0.67, CH2Cl2, 86% ee (R)]. The ee was determined by HPLC on
Chiralpak OD−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 230 nm; tR(R) =
18.91 min (minor), tR(S) = 22.78 min (major). 1H NMR (600 MHz, CDCl3) δ 6.88 (s, 1H), 6.78 (dd, J1 = 7.8 Hz, J2
= 1.8 Hz, 2H), 5.94 (s, 2H), 4.80 (q, J = 6.6 Hz, 1H), 1.95 (s, 1H), 1.45 (d, J = 6.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 147.8, 146.8, 140.0, 118.7, 108.1, 106.1, 101.0, 70.2, 25.2.
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(S)ꢀ1ꢀ(Naphthalenꢀ1ꢀyl)ethanꢀ1ꢀol (2s): White soild, 99% yield, 171.2 mg, 98.3% ee (S). [α]D = ꢀ80.4 (c =
0.5, CHCl3); lit.12a [α]D20 = +38.4 [c = 0.5, CH2Cl2, 94% ee (R)]. The ee was determined by HPLC on Chiralpak
OD−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 230 nm; tR(S) = 21.29 min
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(major), tR(R) = 38.27 min (minor). H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.89−7.88 (m, 1H),
7.79 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.54−7.47 (m, 3H), 5.66 (q, J = 6.6 Hz, 1H), 2.11 (s, 1H), 1.67
(d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 141.4, 133.8, 130.3, 128.9, 127.9, 126.1, 125.6, 125.6, 123.2,
122.0, 67.1, 24.4.
(S)ꢀ1ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀyl)ethanꢀ1ꢀol (2t): White solid, 99% yield, 394.6 mg, 99.0% ee (S). [α]D20 = ꢀ20.8 (c =
22
0.5, CHCl3); lit.22 [α]D = ꢀ41.9 [c = 1.0, CHCl3, 92% ee (S)]. The ee was determined by HPLC on Chiralpak
AD−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 254 nm; tR(S) = 15.86 min
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(major), tR(R) = 17.59 min (minor). H NMR (600 MHz, CDCl3) δ 7.61−7.59 (m, 4H), 7.45 (t, J = 7.8 Hz, 4H),
7.36 (t, J = 7.8 Hz, 1H), 4.96 (q, J = 6.6 Hz, 1H), 1.94−1.92 (br, 1H), 1.55 (d, J = 6.6 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 144.9, 140.9, 140.5, 128.8, 127.3, 127.1, 125.9, 70.2, 25.2.
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(S)ꢀ1ꢀ(9HꢀFluorenꢀ2ꢀyl)ethanꢀ1ꢀol (2u): White solid, 99% yield, 418.0 mg, 99.4% ee (S); [α]D = ꢀ33.2 (c =
25
0.5, CHCl3); lit.23 [α]D = +44.3 [c = 1.5, CHCl3, 81% ee (R)]. The ee was determined by HPLC on Chiralpak
AD−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 18.94 min
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(major), tR(R) = 22.29 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz,
1H), 7.55 (t, J = 7.2 Hz, 2H), 7.40−7.37 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 4.98 (q, J = 6.6 Hz, 1H), 3.89 (s, 2H),
2.00 (s, 1H), 1.56 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 144.6, 143.6, 143.4, 141.5, 141.2, 126.8,
126.7, 125.1, 124.2, 122.1, 119.9, 119.8, 70.7, 36.9, 25.3.
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(S)ꢀ1ꢀ(Thiophenꢀ2ꢀyl)ethanꢀ1ꢀol (2v): Colorless oil, 91% yield, 233.3 mg, 95.8% ee (S). [α]D20 = ꢀ32.8 (c = 0.5,
20
CHCl3); lit.12a [α]D = +14.6 [c = 1.25, CHCl3, 99.9% ee (R)]. The ee was determined by HPLC on Chiralpak
OJ−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 16.94 min
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(major), tR(R) = 22.46 min (minor). H NMR (600 MHz, CDCl3) δ 7.23 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H),
6.96−6.95 (m, 2H), 5.10 (q, J = 6.6 Hz, 1H), 2.48 (s, 1H), 1.58 (d, J = 6.6 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ
150.0, 126.7, 124.4, 123.2, 66.2, 25.3.
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(S)ꢀ1ꢀ(Furanꢀ2ꢀyl)ethanꢀ1ꢀol (2w): Yellow oil, 99% yield, 111.3 mg, 94.7% ee (S). [α]D = ꢀ31.2 (c = 0.5,
CHCl3); lit.12c [α]D20 = +16.6 [c = 1.0, CHCl3, 96% ee (R)]. The ee was determined by HPLC on Chiralpak OJ−H
column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 14.06 min (major),
tR(R) = 16.07 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.37−7.36 (m, 1H), 6.33 (dd, J1 = 3.0 Hz, J2 = 1.8 Hz,
1H), 6.23 (d, J = 3.0 Hz, 1H), 4.88 (q, J = 6.6 Hz, 1H), 1.97 (s, 1H), 1.54 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 157.6, 141.9, 110.1, 105.1, 63.7, 21.3.
(S)ꢀ1ꢀ(Benzofuranꢀ2ꢀyl)ethanꢀ1ꢀol (2x): Brown oil, 99% yield, 322.0 mg, 97.9% ee (S). [α]D20 = ꢀ8.0 (c = 0.5,
20
CHCl3); lit.24 [α]D = +11.6 [c = 1.0, CHCl3, 97% ee (R)]. The ee was determined by HPLC on Chiralpak ID
column, hexane: isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 215 nm; tR(R) = 8.04 min (minor),
tR(S) = 8.43 min (major). 1H NMR (600 MHz, CDCl3) δ 7.54 (d, J = 6.8 Hz, 1H), 7.47−7.46 (m, 1H), 7.28 (td, J1 =
7.2 Hz, J2 = 1.2 Hz,1H), 7.23−7.21 (m, 1H), 6.60 (s, 1H), 5.01 (q, J = 6.6 Hz, 1H), 2.28 (s, 1H), 1.64 (d, J = 6.6
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 160.2, 154.8, 128.2, 124.2, 122.8, 121.1, 111.2, 101.8, 64.2, 21.4.
Typical procedure for the asymmetric hydrogenation of diaryl ketones 3: Under argon atomosphere,
i
[Ir(COD)Cl]2 (8.4 mg, 0.012 mmol), L6 (18.7, 0.025 mmol), anhydrous PrOH (3 mL) were added to an
ovenꢀdried vial (10 mL) and then stirred at room temperature for 1.5 h to give a clear yellow solution. An aliquot
of the catalyst solution (125 ꢁL, 0.001 mmol) was transferred by syringe into a 10ꢀmL vial, then ketones (1
mmol), tBuOLi in iPrOH (0.025 mmol/mL, 1.0 mL, 0.025 mmol) and anhydrous iPrOH (4 mL) were added. The
vessel was placed in an autoclave which was then charged with 30 atm of H2 and stirred at 25−30 oC for 12 h.
After slowly releasing the hydrogen pressure, the solvent was removed, and the mixture was purified by
passing through a short column of silica gel to afforded corresponding alcohols 4a−4l. The ee values of all
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compounds were determined by HPLC with a chiral column.
(R)ꢀ(2ꢀBromophenyl)(phenyl)methanol (4a): Clear oil, 96% yield, 253.2 mg, 94.6% ee (R). [α]D20 = +46.4 (c =
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0.5, CHCl3); lit.25 [α]D = ꢀ41.6 [c = 1.4, CHCl3, 99% ee (S)]. The ee was determined by HPLC on Chiralpak
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OD−H column, hexane: isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 13.46 min
(major), tR(S) = 19.40 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz,
1H), 7.41 (d, J = 7.8 Hz, 2H), 7.36−7.33 (m, 3H), 7.28 (t, J = 7.2 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.21 (s, 1H),
2.43 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 142.5, 142.2, 132.9, 129.1, 128.5, 127.8, 127.7, 127.1, 122.8, 74.8.
HRMS (EI) calcd for C13H11BrO [M]+, 261.9993; found: 261.9998.
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(R)ꢀ(2ꢀChlorophenyl)(phenyl)methanol (4b): Clear oil, 98% yield, 215.4 mg, 92.9% ee (R). [α]D20 = +11.6 (c =
0.5, CHCl3); lit.26 [α]D20 = ꢀ15.2 [c = 1.51, CHCl3, 98% ee (S)]. The ee was determined by HPLC on Chiralpak
OD−H column, hexane: isopropanol = 97:3; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 30.65 min
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(major), tR(S) = 38.41 min (minor). H NMR (600 MHz, CDCl3) δ 7.61 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H),
7.41−7.40 (m, 2H), 7.36−7.33 (m, 3H), 7.32−7.27 (m, 2H), 7.23 (t, J1 = 7.8 Hz, J2 = 1.8 Hz,1H), 6.23 (s, 1H),
2.39 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 142.3, 141.0, 132.6, 129.6, 128.8, 128.5, 128.1, 127.8, 127.1, 126.9,
72.7. HRMS (EI) calcd for C13H11ClO [M]+, 218.0498; found: 218.0506.
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(R)ꢀ(2ꢀFluorophenyl)(phenyl)methanol (4c): Clear oil, 99% yield, 201.6 mg, 82.1% ee (R). [α]D = ꢀ3.6 (c =
20
0.5, CHCl3); lit.26 [α]D = ꢀ4.6 [c = 0.84, CHCl3, 84% ee (R)]. The ee was determined by HPLC on Chiralpak
OD−H column, hexane: isopropanol = 97:3; flow rate = 1.0 mL/min; UV detection at 220 nm; tR(R) = 18.24 min
(major), tR(S) = 20.26 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.53 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 2H),
7.37 (t, J = 7.2 Hz, 2H), 7.32−7.26 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.11 (s, 1H), 3.00 (s,
1H); 13C NMR (150 MHz, CDCl3) δ 160.0 (d, 1JCꢀF = 244.5 Hz), 142.8, 131.0 (d, 3JCꢀF = 13.5 Hz), 129.2 (d, 3JCꢀF
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= 9.0 Hz), 128.6, 127.8, 127.7 (d, JCꢀF = 4.5 Hz), 126.4, 124.4 (d, JCꢀF = 4.5 Hz), 115.4 (d, JCꢀF = 21.0 Hz),
70.1 (d, 4JCꢀF = 3.0 Hz). HRMS (EI) calcd for C13H11FO [M]+, 202.0794; found: 202.0789.
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(R)ꢀPhenyl(oꢀtolyl)methanol (4d): White soild, 98% yield, 195.1 mg, 85.1% ee (R). [α]D = ꢀ3.6 (c = 0.5,
CHCl3); lit.25 [α]D20 = +7.3 [c = 0.735, CHCl3, 98% ee (S)]. The ee was determined by HPLC on Chiralpak OJ−H
column, hexane: isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 210 nm; tR(R) = 20.83 min
(major), tR(S) = 23.26 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 4.2 Hz,
4H), 7.27−7.22 (m, 2H), 7.20−7.18 (m, 1H), 7.13 (d, J = 7.2 Hz, 1H), 5.97 (s, 1H), 2.23 (s, 3H), 2.18 (s, 1H); 13
C
NMR (150 MHz, CDCl3) δ 142.9, 141.5, 135.4, 130.6, 128.5, 127.6, 127.6, 127.1, 126.3, 126.1, 73.4, 19.4.
HRMS (EI) calcd for C14H14O [M]+, 198.1045; found: 198.1058.
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(R)ꢀ(2ꢀBromophenyl)(4ꢀfluorophenyl)methanol (4e): White soild, 94% yield, 264.6 mg, 94.1% ee (R). [α]D
=
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+21.6 (c = 0.5, CHCl3); The ee was determined by HPLC on Chiralpak OD−H column, hexane: isopropanol =
90:10; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 11.55 min (major), tR(S) = 17.42 min (minor). 1H
NMR (600 MHz, CDCl3) δ 7.58 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.54 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H),
7.38−7.34 (m, 3H), 7.16 (td, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 7.02 (t, J = 8.4 Hz, 2H), 6.16 (s, 1H), 2.56 (brs, 1H);
13C NMR (150 MHz, CDCl3) δ 162.3 (d, 1JCꢀF = 244.5 Hz), 142.4, 137.9 (d, 4JCꢀF = 3.0 Hz), 132.9, 129.3, 128.8
(d, 3JCꢀF = 9.0 Hz), 128.3, 127.8, 122.7, 115.3 (d, 2JCꢀF = 21.0 Hz), 74.2. HRMS (EI) calcd for C13H10BrFO [M]+,
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279.9899; found: 279.9911.
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(R)ꢀ(2ꢀBromophenyl)(4ꢀchlorophenyl)methanol (4f): Clear oil, 92% yield, 275.3 mg, 91.9% ee (R). [α]D
=
+59.6 (c = 0.5, CHCl3); The ee was determined by HPLC on Chiralpak OD−H column, hexane: isopropanol =
90:10; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 12.10 min (major), tR(S) = 19.41 min (minor). 1H
NMR (600 MHz, CDCl3) δ 7.55−7.52 (m, 2H), 7.34−7.32 (m, 3H), 7.30 (d, J = 8.5 Hz, 2H), 7.16 (td, J1 = 7.8 Hz,
J2 = 1.2 Hz, 1H), 6.16 (s, 1H), 2.53 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 142.2, 140.6, 133.6, 133.0, 129.4,
128.6, 128.4, 128.4, 127.9, 122.7, 74.1. HRMS (EI) calcd for C13H10BrClO [M]+, 295.9604; found: 295.9607.
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(R)ꢀ(2ꢀBromophenyl)(4ꢀbromophenyl)methanol (4g): Clear oil, 90% yield, 305.9 mg, 91.8% ee (R). [α]D
=
+13.6 (c = 0.5, CHCl3); The ee was determined by HPLC on Chiralpak OD−H column, hexane: isopropanol =
97:3; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 35.85 min (major), tR(S) = 67.70 min (minor). 1H
NMR (600 MHz, CDCl3) δ 7.54 (d, J = 7.8 Hz, 1H), 7.52 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.45 (d, J = 8.4 Hz,
2H), 7.34 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.18−7.15 (m, 1H), 6.14 (s, 1H), 2.53 (s, 1H); 13C NMR
(150 MHz, CDCl3) δ 142.1, 141.2, 133.0, 131.6, 129.4, 128.8, 128.4, 127.9, 122.7, 121.7, 74.2. HRMS (EI)
calcd for C13H10Br2O [M]+, 339.9098; found: 339.9099.
(R)ꢀ(2ꢀBromophenyl)(pꢀtolyl)methanol (4h): White soild, 97% yield, 270.2 mg, 93.2% ee (R). [α]D20 = +31.6 (c
= 0.5, CHCl3); lit.27 [α]D20 = ꢀ30.0 [c = 1.1, CHCl3, 86% ee (S)]. The ee was determined by HPLC on Chiralpak
OD−H column, hexane: isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 10.71 min
(major), tR(S) = 13.92 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.62 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.54 (dd,
J = 7.8, 1.2 Hz, 1H), 7.36−7.34 (m, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.16−7.14 (m, 3H), 6.15 (s, 1H), 2.43 (s, 1H),
2.34 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 142.7, 139.3, 137.5, 132.8, 129.2, 129.0, 128.4, 127.7, 127.1, 122.8,
74.7, 21.2. HRMS (EI) calcd for C14H13BrO [M]+, 276.0150; found: 276.0160.
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(R)ꢀ(2ꢀBromophenyl)(4ꢀmethoxyphenyl)methanol (4i): White soild, 95% yield, 280.1 mg, 93.9% ee (R). [α]D
= +11.2 (c = 0.5, CHCl3); lit.28 [α]D20 = ꢀ10.3 [c = 0.63, CH2Cl2, 85% ee (S)]. The ee was determined by HPLC on
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Chiralpak OD−H column, hexane: isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) =
17.19 min (major), tR(S) = 22.08 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.64 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz,
1H), 7.53 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 7.37−7.34 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.14 (td, J1 = 7.8 Hz, J2
= 1.2 Hz, 1H), 6.87−6.85 (m, 2H), 6.10 (s, 1H), 3.78 (s, 3H), 2.58 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 159.1,
142.7, 134.4, 132.8, 129.0, 128.5, 128.2, 127.7, 122.7, 113.9, 74.4, 55.3. HRMS (EI) calcd for C14H13BrO2 [M]+,
292.0099; found: 292.0111.
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(R)ꢀ(2ꢀbromophenyl)(3,5ꢀdimethylphenyl)methanol (4j): White soild, 99% yield, 289.5 mg, 91.7% ee (R).
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[α]D = +82.8 (c = 0.5, CHCl3); The ee was determined by HPLC on Chiralpak OD−H column, hexane:
isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(R) = 12.48 min (major), tR(S) = 39.68
min (minor). 1H NMR (600 MHz, CDCl3) δ 7.59 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.54 (dd, J1 = 7.8 Hz, J2 = 1.2
Hz, 1H), 7.36−7.33 (m, 1H), 7.15 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.01 (s, 2H), 6.92 (s, 1H), 6.13 (s, 1H), 2.30
(s, 6H), 1.57 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 142.7, 142.1, 138.0, 132.8, 129.5, 129.0, 128.6, 127.7,
124.8, 122.8, 74.8, 21.4. HRMS (EI) calcd for C15H15BrO [M]+, 290.0306; found: 290.0305.
(R)ꢀ(5ꢀBromoꢀ2ꢀchlorophenyl)(4ꢀethoxyphenyl)methanol (4k): White soild, 97% yield, 331.7 mg, 98.2% ee
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(R). [α]D = ꢀ84.6 (c = 0.5, CHCl3); The ee was determined by HPLC on Chiralpak OD−H column, hexane:
isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 225 nm; tR(R) = 8.80 min (major), tR(S) = 10.17
min (minor). 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 2.0 Hz, 1H), 7.31 (dd, J1 = 8.5 Hz, J2 = 2.5 Hz, 1H), 7.23
(d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 1H), 6.84−6.81 (m, 2H), 6.01 (s, 1H), 3.99 (q, J = 7.0 Hz, 2H), 2.47 (s,
1H), 1.38 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.8, 143.2, 133.6, 131.5, 131.2, 131.0, 130.6,
128.4, 121.0, 114.5, 72.2, 63.5, 14.8. HRMS (EI) calcd for C15H14BrClO2 [M]+, 339.9866; found: 339.9856.
(R)ꢀ(5ꢀBromoꢀ2ꢀchlorophenyl)(4ꢀfluorophenyl)methanol (4l): White soild, 98% yield, 309.5 mg, 93.2% ee (R).
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[α]D = ꢀ193.2 (c = 0.5, CHCl3); The ee was determined by HPLC on Chiralpak OJ−H column, hexane:
isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 210 nm; tR(R) = 10.95 min (major), tR(S) = 13.05
min (minor). 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 2.4 Hz, 1H), 7.36−7.33 (m, 3H), 7.19 (d, J = 8.4 Hz, 1H),
1
7.04 (t, J = 8.4 Hz, 2H), 6.10 (s, 1H), 2.39 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 162.4 (d, JCꢀF = 244.5 Hz),
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142.8, 137.3, 131.9, 131.2, 131.1, 130.7, 128.8 (d, JCꢀF = 9.0 Hz), 121.1, 115.6 (d, JCꢀF = 21.0 Hz), 71.8.
HRMS (EI) calcd for C13H9BrClFO [M]+, 313.9509; found: 313.9499.
Typical procedure for the synthesis of compound 5h. To a 5.0ꢀmL vial was added the catalyst precursor
i
[Ir(COD)Cl]2 (8.4 mg, 0.012 mmol), L6 (18.7, 0.025 mmol) and anhydrous PrOH (3 mL) under argon
atomosphere. The mixture was stirred for 1 h at room temperature to give a clear yellow solution. An aliquot of
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the catalyst solution (125 ꢁL, 0.001 mmol) was transferred into a 100ꢀmL hydrogenation autoclave, then tBuOLi
(20 mg, 0.25 mmol), 3h (2.74 g, 10 mmol) and anhydrous iPrOH (20 mL) was added. The autoclave was then
charged with 50 atm of H2 and stirred at 25−30 oC for 24 h. The workꢀup was identical to that described for the
asymmetric hydrogenation at S/C = 1 000. (R)ꢀ(2ꢀBromophenyl)(pꢀtolyl)methanol (4h): > 99% conversion,
93.42% ee (R).
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To a solution of 4h (2.70 g, 9.75 mmol) in THF (54 mL) was added nꢀBuLi (12 mL, 2.5 M in nꢀhexane) under
argon atomosphere at ꢀ78 °C. After addition was complete, the mixture was stirred for 3.0 h at ꢀ78 °C. The
mixture was quenched by the addition of H2O. The aqueous layer was extracted with CH2Cl2 (×3). The
combined organic portions were dried over Na2SO4 and evaporated in vacuo. The residue was purified by
column chromatography to give 1.92g 5h in 85% yield as a white solid. The ee values of the 5h were
determined by HPLC with a chiral column.
(S)ꢀPhenyl(pꢀtolyl)methanol (5h): White solid, 85% yield, 192 mg, 93.0% ee (S). [α]D20 = ꢀ3.6 (c = 0.5, CHCl3);
lit.29 [α]D30 = ꢀ4.0 [c = 0.76, CHCl3, 47% ee (S)]. The ee was determined by HPLC on Chiralpak OD−H column,
hexane: isopropanol = 90:10; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 12.12 min (major), tR(R) =
13.30 min (minor). 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.8 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.27 (d, J =
8.4 Hz, 3H), 7.16 (d, J = 7.8 Hz, 2H), 5.81 (s, 1H), 2.35 (s, 3H), 2.32−2.25 (br, 1H); 13C NMR (150 MHz, CDCl3)
δ 144.0, 141.0, 137.3, 129.2, 128.5, 127.5, 126.6, 126.5, 76.1, 21.1. HRMS (EI) calcd for C14H14O [M]+,
198.1045; found: 198.1060.
Compoounds 5f, 5l could be prepared under the similar reaction condition.
20
(S)ꢀ(4ꢀchlorophenyl)(phenyl)methanol (5f): Oil, 81% yield, 176.6 mg, >99% ee (S). [α]D = +42.2 (c = 0.5,
CHCl3), lit.30 [α]D30 = +18.6 (c = 0.40, CHCl3, 87% ee, S). The ee was determined by HPLC on Chiralpak AD−H
column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 16.04 min (major),
tR(R) = 17.71 min (minor). 1H NMR (400 MHz, CDCl3) δ 7.33ꢀ7.24 (m, 9H), 5.71 (s, 1H), 2.57 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 143.4, 142.2, 133.3, 128.7, 128.6, 127.92, 127.87, 126.6, 75.6. HRMS (EI) calcd for
C13H11ClO [M]+, 218.0498; found: 218.0502.
(R)ꢀ(2ꢀchlorophenyl)(4ꢀfluorophenyl)methanol (5l): Oil, 83% yield, 196.3 mg, 97.0% ee (R). [α]D20 = +5.2 (c =
20
0.5, CHCl3), lit.25 [α]D = ꢀ15.2 (c = 1.51, CHCl3, 97% ee, S). The ee was determined by HPLC on Chiralpak
AD−H column, hexane: isopropanol = 95:5; flow rate = 0.8 mL/min; UV detection at 220 nm; tR(S) = 15.74 min
1
(minor), tR(R) = 17.20 min (major). H NMR (400 MHz, CDCl3) δ 7.57 (dd, J1 = 7.6 Hz, J2 = 0.8 Hz, 1H),
7.35−7.21 (m, 5H), 7.03−6.97 (m, 2H), 6.12 (s, 1H), 3.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.2 (d, J =
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244.0 Hz), 140.8, 138.0 (d, J = 3.0 Hz), 132.4, 129.6, 128.9, 128.7 (d, J = 8.0 Hz), 127.8, 127.2, 115.3 (d, J =
22.0 Hz), 72.0. HRMS (EI) calcd for C13H10ClFO [M]+, 236.0404; found: 236.0406.
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Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.xxxxxxx
Copies of NMR spectra of ligands and products, as well as HPLC charts of products.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: weihuizhong@zjut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (Nos. 21676253 and 21706234) and Project
funded by China Postdoctoral Science Foundation (Nos. 2017M612033) for financial support.
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