Iridium-Catalyzed Enantioselective Transfer Hydrogenation of Ketones Controlled by Alcohol Hydrogen-Bonding and sp3-C?H Noncovalent Interactions

Article abstract of DOI:10.1002/adsc.202000615

Iridium-catalyzed enantioselective transfer hydrogenation of ketones with formic acid was developed using a prolinol-phosphine chiral ligand. Cooperative action of the iridium atom and the ligand through alcohol-alkoxide interconversion is crucial to facilitate the transfer hydrogenation. Various ketones including alkyl aryl ketones, ketoesters, and an aryl heteroaryl ketone were competent substrates. An attractive feature of this catalysis is efficient discrimination between the alkyl and aryl substituents of the ketones, promoting hydrogenation with the identical sense of enantioselection regardless of steric demand of the alkyl substituent and thus resulting in a rare case of highly enantioselective transfer hydrogenation of tert-alkyl aryl ketones. Quantum chemical calculations revealed that the sp³-C?H/π interaction between an sp³-C?H bond of the prolinol-phosphine ligand and the aryl substituent of the ketone is crucial for the enantioselection in combination with O?H???O/sp³-C?H???O two-point hydrogen-bonding between the chiral ligand and carbonyl group. (Figure presented.).

Full text of DOI:10.1002/adsc.202000615

Title: Iridium-Catalyzed Enantioselective Transfer Hydrogenation
of Ketones Controlled by Alcohol Hydrogen-Bonding and
sp³-C–H Noncovalent Interactions
Authors: Hiroaki Murayama, Yoshito Heike, Kosuke Higashida, Yohei
Shimizu, Nuttapon Yodsin, Yutthana Wongnongwa, Siriporn
Jungsuttiwong, Seiji Mori, and Masaya Sawamura
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000615
Link to VoR: https://doi.org/10.1002/adsc.202000615

10.1002/adsc.202000615
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Iridium-Catalyzed Enantioselective Transfer Hydrogenation of
Ketones Controlled by Alcohol Hydrogen-Bonding and sp3-C–H
Noncovalent Interactions
Hiroaki Murayama,a Yoshito Heike,a Kosuke Higashida,a,b Yohei Shimizu,a,b Nuttapon
Yodsin,c Yutthana Wongnongwa,c Siriporn Jungsuttiwong,c Seiji Mori,d* and Masaya
Sawamuraa,b*
a
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
E-mail: sawamura@sci.hokudai.ac.jp
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021,
b
Japan
c
Center for Organic Electronic and Alternative Energy, Department of Chemistry and Center of Excellence for
Innovation in Chemistry, Faculty of Science, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
Institute of Quantum Beam Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan
d
E-mail:seiji.mori.compchem@vc.ibaraki.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
abstraction of two H atoms from 2-propanol and the
Abstract. Iridium-catalyzed enantioselective transfer
hydrogenation of ketones with formic acid was developed protonative hydride reduction of the carbonyl group
resulting in the hydrogenation of simple ketones.[2d-f]
using a prolinol-phosphine chiral ligand. Cooperative action
of the iridium atom and the ligand through alcohol–alkoxide
interconversion is crucial to facilitate the transfer
hydrogenation. Various ketones including alkyl aryl ketones,
ketoesters, and an aryl heteroaryl ketone were competent
substrates. An attractive feature of this catalysis is efficient
discrimination between the alkyl and aryl substituents of the
ketones, promoting hydrogenation with the identical sense
of enantioselection regardless of steric demand of the alkyl
substituent and thus resulting in a rare case of highly
enantioselective transfer hydrogenation of tert-alkyl aryl
ketones. Quantum chemical calculations revealed that the
sp3-C–H/ interaction between an sp3-C–H bond of the
prolinol-phosphine ligand and the aryl substituent of the
ketone is crucial for the enantioselection in combination with
A few catalytic systems based on interconversion of
other functional groups in the ligands have also been
proposed,
including
cyclopentadienol–
aromatization–
cyclopentadienone,[3]
dearomatization,[4] and carboxylic acid–carboxylate.[5]
Despite the significant advances in the
enantioselective transfer hydrogenation, the reactions
are sensitive to steric bulkiness.[6,7] More specifically,
only a few catalysts induced high enantioselectivity for
the transfer hydrogenation of tert-alkyl aryl ketones,
and those catalysts did not show sufficient
enantioselectivity for the reaction of substrates with
smaller alkyl groups such as acetophenone.[6b,c] Thus,
the development of more general transfer
hydrogenation catalysts remains a challenge.
O–H···O/sp3-C–H···O
two-point
hydrogen-bonding
between the chiral ligand and carbonyl group.
Previously, we developed prolinol-phosphine chiral
ligands for use in the copper-catalyzed
enantioselective alkynylation of aldehydes and -
ketoesters with terminal alkynes, in which cooperation
of the ligand hydroxyl group and the copper center was
proven by quantum chemical calculations (Scheme
1).[8] The calculations also showed the presence of O–
H···O/sp3-C–H···O two-point hydrogen-bonding
between the chiral ligand and the carbonyl group.
Combined with these hydrogen-bonding interactions,
dispersive ligand–substrate attractions explained the
enantioselectivity of the copper catalysis.[8,9] The
prolinol-phosphine chiral ligands were also used
successfully for the enantioselective Kinugasa
reaction,[10] the copper-catalyzed coupling between
nitrones and terminal alkynes to produce
enantioenriched 1,3,4-trisubstituted -lactams, based
Keywords: transfer hydrogenation • iridium • chiral
catalyst • C–H/ interaction • nonclassical hydrogen bond
Enantioselective transfer hydrogenation of ketones has
been widely studied as a method for the synthesis of
chiral secondary alcohols. A common approach
toward developing catalysts for the transfer
hydrogenation is to employ the cooperative action of
metals and ligands for outer-sphere activation of the
ketone.[1] The Noyori–Ikariya-type chiral ruthenium
amide catalyst system is a representative approach.[2]
The key to its catalysis is the amine–amide
interconversion in the ligand that induces both the
1
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10.1002/adsc.202000615
Advanced Synthesis & Catalysis
on the assumption that O–H···O/sp3-C–H···O two-
point hydrogen-bonding between the prolinol-
phosphine and the oxyanion of the nitrone occurred as
a crucial catalyst–substrate interaction. Along this line,
we envisioned that the concept of O–H···O/sp3-C–
H···O two-point hydrogen-bonding may be extended
to metal-catalyzed outer-sphere enantioselective
hydrogenation of carbonyl compounds, in which
hydrogen-bonding between a protic site of a chiral
ligand and a carbonyl group is essential.[11]
Herein, we report the iridium-catalyzed
enantioselective transfer hydrogenation of ketones
with formic acid[12] enabled by alcohol–alkoxide
interconversion[13] of a prolinol-phosphine chiral
ligand (Scheme 1).[14,15] This catalytic system
efficiently discriminates between the aryl substituent
and the alkyl substituent of the ketone by an attractive
noncovalent interaction between a nonpolar sp3-C–H
bond of the chiral ligand and the  system of the aryl
substituent of the ketone (sp3-C–H/ interaction),
achieving excellent enantioselection of the same sense
regardless of steric demand of the alkyl substituent.
alcohol moieties did not promote the reaction at all
(entries 1, 3).[16] In contrast, L2 bearing a secondary
alcohol moiety gave chiral secondary alcohol 2a with
significant enantioselectivity (85% ee), albeit in low
yield (11%) (entry 2). Encouraged by this result,
further screening of secondary alcohol ligands was
conducted focusing on the influence of α-substituents
of the hydroxy group. Both the product yield and
enantioselectivity were slightly improved by
employing tert-butyl-substituted ligand L4 (entry 4,
19%, 89% ee). Even better yield and enantioselectivity
were obtained with L5 bearing a neopentyl group
(entry 5, 46%, 92% ee). On the other hand, the reaction
was completely inhibited by replacing the hydroxy
group of L5 with a methoxy group (L5-OMe),
indicating the critical role of the alcoholic site (entry
6).
Screening of solvents revealed that the use of
ethereal solvents was crucial, as no reaction occurred
with other types of solvents such as toluene,
dichloromethane,
2-propanol,
N,N-
dimethylformamide, and acetonitrile. The optimal
solvent was cyclopentyl methyl ether (CPME),
affording the product in 87% yield with 94% ee (entry
7). Effect of the base was also significant. While the
reaction did not proceed at all with LiOt-Bu or NaOt-
Bu (entries 8 and 9), K2CO3 improved the
enantioselectivity to 96% ee (entry 10, 82%
yield).[17,18]
Table 1. Optimization of Enantioselective Transfer
Hydrogenation.[a]
entry
ligand
solvent
base
yield
(%)[b]
0
11
0
19
46
0
87
0
ee
(%)[c]
–
85
–
89
92
–
94
–
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
THF
THF
THF
THF
THF
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
LiOt-Bu
NaOt-Bu
K2CO3
–
L5-OMe THF
L5
L5
L5
L5
L5
L5
CPME
CPME
CPME
CPME
CPME
CPME
9
0
82
0
–
96
–
10
11
12[d]
Scheme 1. Applications of Chiral Prolinol-Phosphine
Ligands for the Enantioselective Cu-catalyzed Alkynylation
of Carbonyl Compounds (Previous Work) and Ir-catalyzed
Transfer Hydrogenation of Ketones (Present Work).
–
83
95
We commenced the investigation with acetophenone
(1a) as the model substrate (Table 1). Various chiral
prolinol-phosphines (L) were examined for their
ability
to
induce
catalytic
activity
and
enantioselectivity in the reaction of 1a (0.2 mmol) and
formic acid (2.0 eq) in the presence of [IrCl(cod)]2 (1
mol%), chiral ligand (2.5 mol%), and KOt-Bu (5
mol%) in THF (1 mL) at 25 ºC over 6 h (entries 1–6).
The ligands (L1 and L3) bearing primary or tertiary
[a] Condition: [IrCl(cod)]2 (1 mol%), ligand (2.5 mol%),
base (5 mol%), 1a (0.20 mmol), HCO2H (0.40 mmol),
solvent (1 mL), 25 ºC, 6 h. [b] Yield of the isolated product.
2
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10.1002/adsc.202000615
Advanced Synthesis & Catalysis
[c] The enantiomeric excess was determined by HPLC
analysis. [d] [Ir(OMe)(cod)]2 was used instead of
[IrCl(cod)]2.
99% ee), cyclohexyl- (2s: 99%, 98% ee), and
neopentyl-substituted (2t: 90%, 98% ee) alcohols were
obtained from the corresponding ketones with the
same level of enantioselection. Conjugated enone 1u
with a bulky alkyl group also underwent smooth
hydrogenation to afford 2u (56%), although the
enantioselectivity dropped to 60% ee and the
competitive 1,4-reduction was significant (17% NMR
yield)
This reaction was applicable to 2-benzoylpyridine
(1v), affording (R)-phenyl-(2-pyridyl)methanol (2v) in
64% yield with 85% ee.[20] Since the steric demand of
the phenyl and pyridyl groups is almost the same, the
enantioselectivity is likely due to the difference in
electron density of the aromatic rings.
The following two experiments are supportive of a
mechanism involving an iridium alkoxide species.
First, the reaction did not proceed at all in the absence
of the external base additive, which was used in a
catalytic amount in the parent reaction (Table 1, entry
11). Second, the effect of [Ir(OMe)(cod)]2 in the
absence of a base additive was comparable to that of
the [IrCl(cod)]2/KOt-Bu system (entry 12).
Under the optimized conditions, various ketones
including alkyl (hetero)aryl ketones, an aryl heteroaryl
ketone, and keto esters were hydrogenated to form the
corresponding secondary alcohols in a highly
enantioselective manner. Thus, the enantioselective
transfer hydrogenation of ketones (1) with formic acid
(2 equiv) was conducted in the presence of [IrCl(cod)]2
(1 mol%), L5 (2.5 mol%), and K2CO3 (5 mol%) in
CPME at 25 ºC or 40 ºC over 6 h (Table 2). Chiral
secondary alcohols were obtained in high
enantioselectivities with both electron-donating (2b,
81%, 96% ee; 2c, 93%, 93% ee) and withdrawing (2d,
70%, 95% ee; 2e, 77%, 94% ee) substituents at the
para-position of the phenyl ring of acetophenone.
Ketone 1f bearing an ortho-methyl group on the
phenyl ring was also compatible giving 2f in >99%
yield with 97% ee. Sterically more demanding
acetonaphthones were competent (2g, 97%, 93% ee;
2h, 79%, 95% ee). Heteroaryl ketones reacted with
good enantioselectivities (2i, >99%, 86% ee; 2j, >99%,
86% ee). A cyclic ketone was also amenable (2k:
>99%, 87% ee).
Table 2. Scope of Ketones (1).[a]
Chemoselectivity was assessed using ketones
including other reducible moieties. Reduction of
ketonic carbonyl groups proceeded exclusively in the
presence of an ester moiety regardless of the relative
location of the two functional groups (2l: 97%, 96%
ee; 2m: >99%, 95% ee). Benzil 1n underwent twofold
reduction to produce (R,R)-1,2-diphenyl-1,2-diol (2n)
in a 96:4 diastereomeric ratio with 99.7% ee. However,
the isolated terminal C–C double bond in 1o was
completely reduced during the enantioselective
carbonyl hydrogenation over 24 h to give saturated
alcohol 2o (70%, 85% ee).
Excellent discrimination between the aryl group and
the bulky alkyl group with the same catalyst is a
significant feature of this reaction. The reaction of tert-
butyl phenyl ketone (1p) proceeded smoothly, giving
(S)-2,2-dimethyl-1-phenylpropanol (2p) in 99.8% ee.
Interestingly, hydrogenation of acetophenone and tert-
butyl phenyl ketone occurred on the same prochiral
face, regardless of the reversal of the relative steric
demand between the phenyl and the alkyl substituents
of the carbonyl group. This result cannot be explained
by a steric repulsion model alone, but rather, suggests
that the enantioselection is due to attractive forces
between the catalyst and the aromatic ring of the
substrate.[2e,19] Similarly, sterically demanding
adamantyl- (2q: 91%, 99% ee), isopropyl- (2r: 94%,
[a]Condition: [IrCl(cod)]2 (1 mol%), L5 (2.5 mol%), K2CO3
(5 mol%), 1 (0.20 mmol), HCO2H (0.40 mmol), CPME (1
mL), 40 oC, 6 h. Yield of the isolated product. The
enantiomeric excess was determined by HPLC analysis. [b]
Reaction was conducted at 25 oC. [c] Reaction time was 12
h. [d] Reaction time was 24 h.
3
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10.1002/adsc.202000615
Advanced Synthesis & Catalysis
Dialkyl ketones such as phenethyl methyl ketone
We performed DFT calculations at the
B3LYP+D3(BJ)/def2SVP level of theory[22] for the
hydride attack of the carbonyl group (C–D-TS–E in
Scheme 2), which is likely the enantioselectivity-
determining step, employing L5 as the ligand and 1a
as the ketone. For the pyrrolidine ring in L5, we
examined the three most stable conformers based on
our previous DFT studies on the copper-catalyzed
enantioselective alkynylation of aldehydes.[8a] The
most stable transition states (D-TS) leading to the
major [(S)-2a] (TS_major) and minor [(R)-2a]
(TS_minor) enantiomeric products are shown in
Figures 1a and 1b, respectively, with the plot of weak
noncovalent interactions given by the NCIPlOT
program[23] [see Supporting Information for the bond
critical point (BCP) analyses of the quantum theory of
atoms in molecule (QTAIM)]. The activation Gibbs
free energy leading to the major enantiomer (Scheme
2, C to D-TS) is 24.1 kJ mol–1 at 298.15 K. TS_major
is 9.8 kJ mol–1 lower in Gibbs free energy than
TS_minor, in accord with the excellent experimental
enantioselection (96% ee, Table 1, entry 10) favoring
the S product.
(1w) and cyclohexyl methyl ketone (1x) showed
decreased reactivity and enantioselectivity (2w: 25%,
42% ee; 2x: 73%, 15% ee) compared with the alkyl
aryl ketones. These results are in accord with the
proposed importance of attractive interactions
between the chiral ligand and the aryl group of the
ketones.
We propose a catalytic cycle involving alcohol–
alkoxide interconversion as shown in Scheme 2. An
iridium-L5 complex enters into the catalytic cycle in
the form of dihydridoiridium(III) formate A upon
reaction with K2CO3 and formic acid.[21] The formate
(A) undergoes decarboxylation to form iridium
trihydride B, in which prolinol-phosphine ligand L5
presents an alcoholic hydrogen bond donor site. Next,
complex B captures ketone 1 through OH···O/sp3-C–
H···O two-point hydrogen-bonding to form C.
Nucleophilic attack of one of the three hydrides on the
iridium center to the carbonyl carbon and cooperative
protonation of the developing oxyanion with the ligand
O–H group through D-TS affords alkoxoiridium(III)
complex E. Instantaneous protonation of E with
formic acid releases the secondary alcohol product 2
with regeneration of A.
As expected, one of the nonpolar sp3-C–H bonds
located  to the N atom (the 3-position of the
pyrrolidine ring) of L5 donates a nonclassical
hydrogen bond to the carbonyl oxygen of the ketone in
both transition states, resulting in O–H···O/sp3-C–
H···O two-point hydrogen-bonding, which orients the
carbonyl group to accept the nucleophilic attack of the
Ir-bound equatorial hydride cis to the N atom in a well-
defined manner (Figure 1). In addition, Figure 1a
shows that a C–H/ interaction occurs between a
nonpolar C(sp3)–H bond at the 4-position of the
pyrrolidine ring and the aromatic ring of the ketone in
TS_major and that the alkyl (Me) group is positioned
outward from the steric environment of the catalyst.
On the other hand, the aromatic substituent in
TS_minor does not cause attractive interactions,
while the alkyl group is located proximal to the
pyrrolidine framework of the chiral ligand. These
interpretations of the computational results explain the
experimental observations that only aryl ketones were
efficiently hydrogenated with high enantioselectivity,
while the reaction broadly tolerated various aryl
ketones regardless of steric demand of the carbonyl
alkyl group with the identical sense of enantioselection.
Scheme 2. Proposed Catalytic Cycle.
4
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10.1002/adsc.202000615
Advanced Synthesis & Catalysis
Figure 1. Geometrical features and plots of noncovalent interactions (NCIPlot) of the transition states leading to (a) the
major enantiomer and (b) the minor enantiomer. Atomic distances are given in Å .
The present work demonstrates that cooperative
action of a metal and ligand through alcohol–alkoxide
interconversion can facilitate enantioselective transfer
hydrogenation of ketones and shows that the O–
H···O/sp3-C–H···O two-point hydrogen-bonding
provided by the metal-bound prolinol-phosphine
chiral ligand, which was previously proposed for
copper catalysis,[8,10] is preserved in the iridium-
catalyzed enantioselective transfer hydrogenation of
ketones with formic acid. Additionally, in the present
Ir catalysis, the pyrrolidine framework of the ligand
causes an sp3-C–H/ interaction with the carbonyl-
substituted aromatic rings, allowing efficient prochiral
face selection for the reaction of various alkyl aryl
ketones. The tolerance toward various ketones
regardless of the steric demand of the alkyl group is a
significant feature of this catalysis. Thus, we
confirmed that the concept of ligand–substrate
noncovalent interactions involving nonpolar sp3-C–H
bonds serves as a versatile guiding principle for the
design of enantioselective catalysis, the significance of
which had not been previously demonstrated.
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Experimental Section
A General Procedure for Iridium(I)-Catalyzed Transfer
Hydrogenation of Ketones: In a glove box, L5 (2.2 mg,
0.0050 mmol) was placed in a screw vial containing a
magnetic stirring bar. CPME (1 mL), [IrCl(cod)]2 (1.3 mg,
0.0020 mmol) and K2CO3 (1.4 mg, 0.010 mmol) were added
to the vial and the mixture was stirred at room temperature
for 5 minutes to give a pale yellow solution. Formic acid
(18.4 mg, 0.40 mmol) and ketone 1a (24.0 mg, 0.20 mmol)
were added sequentially. The vial was sealed with a screw
cap and taken out from the glove box. After stirring for 6 h
at 25 ˚C, the mixture was quenched with saturated K2CO3
aq. and extracted with Et2O. The organic layer was dried
over anhydrous MgSO4. After filtration, the filtrate was
evaporated under reduced pressure to give a crude mixture.
Flash chromatography on silica gel (0–10% EtOAc/hexane)
gave 2a (19.7 mg, 0.16 mmol) in 82% yield. The ee value
(96% ee) was determined by HPLC analysis on a chiral
stationary phase: CHIRALCEL® OD-H column 4.6 mm ×
250 mm, Daicel Chemical Industries, hexane/2-propanol =
5:95, 1.0 mL/min, 40 ˚C, 220 nm UV detector, retention
time = 7.6 min for (R) isomer and 8.4 min for (S) isomer.
[5] J. Yu, J. Long, Y. Yang, W. Wu, P. Xue, L. W. Chung,
X.-Q. Dong, X. Zhang, Org. Lett. 2017, 19, 690–693.
[6] a) M. B. Díaz-Valenzuela, S. D. Phillips, M. B. France,
M. E. Gunn, M. L. Clarke, Chem. Eur. J. 2009, 15,
1227–1232. b) N. Meyer, A. J. Lough, R. H. Morris,
Chem. Eur. J. 2009, 15, 5605–5610. c) D. Wang, A.
Bruneau-Voisine, J.-B. Sortais, Catal. Commun. 2018,
105, 31–36.
[7] For enantioselective hydrogenations of tert-alkyl aryl
ketones using molecular hydrogen, see: a) T. Ohkuma,
C. A. Sandoval, R. Srinivasan, Q. Lin, Y. Wei, K. Muñiz,
R. Noyori, J. Am. Chem. Soc. 2005, 127, 8288–8289. b)
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Chem. Eur. J. 2010, 16, 3201–3206. f) J. E. R. Martins,
D. J. Morris, M. Wills, Tetrahedron Lett. 2009, 50 688–
692. For efficient enantioselective hydrogenation of
alkyl aryl ketones with an P,NH,N chiral ligand, see: g)
W. Wu, S. Liu, M. Duan, X. Tan, C. Chen, Y. Xie, Y.
Lan, X.-Q. Dong, X. Zhang, Org. Lett. 2016, 18, 2938–
2941.
Acknowledgements
This work was supported by MEXT KAKENHI Grant Number
JP15H05801 (to M.S.) and JP18H04233 (to S.M.) in Precisely
Designed Catalysts with Customized Scaffolding, by JSPS
KAKENHI Grant Number JP18H03906 in Grant-in-Aid for
Scientific Research (A) to M.S., and by the Sakura Science Plan
through “Collaborative research activity course“ from JST
(Number: S2018F0228129) to S.M. S.J. thanks the Center of
Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of
Higher Education, Science, Research and Innovation.
[8] a) T. Ishii, R. Watanabe, T. Moriya, H. Ohmiya, S. Mori,
M. Sawamura, Chem. Eur. J. 2013, 19, 13547–13553. b)
M. C. Schwarzer, A. Fujioka, T. Ishii, H. Ohmiya, S.
Mori, M. Sawamura, Chem. Sci. 2018, 9, 3484–3493.
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10.1002/adsc.202000615
Advanced Synthesis & Catalysis
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[18] The iridium-L5 catalyst also promoted hydrogenation
of acetophenone (1a) in the presence of hydrogen gas (2
MPa), producing (S)-1-phenylethanol (2a) with virtually
the same level of enantioselectivity (95% ee) as that of
the transfer hydrogenation.
[10] a) Y. Takayama, T. Ishii, H. Ohmiya, T. Iwai, M. C.
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[IrCl(cod)]2 (1 mol%), L5 (2.5 mol%)
K2CO3 (5 mol%)
(S)-2a
>99%, 95% ee
1a
H2 (2 MPa)
CPME, 25 oC, 15 h
[11] For sp3-C–H···O hydrogen-bonding in the Ir-catalyzed
enantioselective sp3-C–H borylation, see: R. Reyes, T.
Iwai, S. Maeda, M. Sawamura, J. Am. Chem. Soc. 2019,
141, 6817–6821.
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[12] For achiral ruthenium complex-catalyzed transfer
hydrogenation using formic acid as a hydrogen source,
see: a) Y. Watanabe, T. Ota, Y. Tsuji, Chem. Lett. 1980,
1985–1586. b) Y. Watanabe, T. Ohta, Y. Tsuji, Bull.
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system, see reference 2b.
[13] Zhang and co-workers reported iridium-catalyzed
enantioselective hydrogenation of ketones using a
P/NH/OH ligand containing a ferrocene skeleton, in
which the possibilities of both amine–amide and
alcohol–alkoxide interconversions were proposed: J. Yu,
M. Duan, W. Wu, X. Qi, P. Xue, Y. Lan, X.-Q. Dong, X.
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[21] See Supporting Information for the investigation on
the generation of active species with an isolable catalyst
precursor S1 prepared by mixing L5, [IrCl(cod)]2 and
K2CO3. The structure of S1 was determined by XRD
analysis. CCDC-2000498 contains the supplementary
crystallographic data for S1. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[14] Other P/NH/OH chiral ligands were reported by
Clarke and co-workers: a) M. B. Díaz-Valenzuela, S. D.
Phillips, M. B. France, M. E. Gunn, M. L. Clarke, Chem.
Eur. J. 2009, 15, 1227–1232. b) S. D. Phillips, J. A.
Fuentes, M. L. Clarke, Chem. Eur. J. 2010, 16, 8002–
8005. c) J. A. Fuentes, S. D. Phillips, M. L. Clarke,
Chem. Cent. J. 2012, 6, 151.
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[15] Other tridentate ligands such as P/N/OH Schiff base-
unit-containing ligands promoted asymmetric transfer
hydrogenation: a) H. L. Kwong, W.-S. Lee, T.-S. Lai,
W.-T. Wong, Inorg. Chem. Commun. 1999, 2, 66–69. b)
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[23] Noncovalent interactions such as sp3-C–
interactions are shown with a method introduced by Erin
R. Johnson et al. The program MultiWFN 3.7 and VMD
were used to visualize these areas, displayed in green.
(a) E. R. Johnson, S. Keinan, P. Mori-Sanchez, J.
Contreras-Garcia, A. J. Cohen, W. Yang, J. Am. Chem.
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[16] The catalyst with the primary alcohol ligand L1 would
form an inactive hydride-bridged iridium dimer due to
less steric hindrance around the iridium atom. On the
other hand, a large steric hindrance around the hydroxy
group of L3 would inhibit cooperation of the OH group
and the iridium atom. Thus, both L1 and L3 were totally
inactive in the transfer hydrogenation.
[17] See Supporting Information for details.
6
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10.1002/adsc.202000615
Advanced Synthesis & Catalysis
COMMUNICATION
Iridium-Catalyzed Enantioselective Transfer
Hydrogenation of Ketones Controlled by Alcohol
Hydrogen-Bonding and sp3-C–H Noncovalent
Interactions
Adv. Synth. Catal. Year, Volume, Page – Page
Hiroaki Murayama, Yoshito Heike, Kosuke
Higashida, Yohei Shimizu, Nuttapon Yodsin,
Yutthana Wongnongwa, Siriporn Jungsuttiwong,
Seiji Mori,* and Masaya Sawamura*
7
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