Iridium-Catalyzed Asymmetric Hydrogenation of Halogenated Ketones for the Efficient Construction of Chiral Halohydrins

Article abstract of DOI:10.1002/adsc.201800267

Iridium-catalyzed asymmetric hydrogenation of prochiral halogenated ketones was successfully developed to prepare various chiral halohydrins with high reactivities and excellent enantioselectivities under basic reaction condition (up to >99% conversion, 99% yield, >99% ee). Moreover, gram-scale experiment was performed well in the presence of just 0.005 mol% (S/C=20 000) Ir/f-amphox catalyst with 99% yield and >99% ee. (Figure presented.).

Full text of DOI:10.1002/adsc.201800267

Title: Iridium-Catalyzed Asymmetric Hydrogenation of Halogenated
Ketones for the Efficient Construction of Chiral Halohydrins
Authors: Congcong Yin, Weilong Wu, Yang Hu, Xuefeng Tan, Cai You,
Yuanhua Liu, Ziyi Chen, Xiu-Qin Dong, and Xumu Zhang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800267
Link to VoR: http://dx.doi.org/10.1002/adsc.201800267

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iridium-Catalyzed Asymmetric Hydrogenation of Halogenated
Ketones for the Efficient Construction of Chiral Halohydrins
Congcong Yin,†a Weilong Wu,†a Yang Hu,a Xuefeng Tan,b Cai You,a Yuanhua Liu,a
Ziyi Chen,a Xiu-Qin Dong,*a Xumu Zhang*a,b
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R. China.
Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, P. R. China.
b
† Congcong Yin and Weilong Wu contributed equally to this work.
E-mail address: xumu@whu.edu.cn; xiuqindong@whu.edu.cn.
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######.((Please
delete if not appropriate))
seldom outstanding and powerful catalytic systems
developed for the asymmetric hydrogenation of
halogenated ketones to afford excellent reactivities
and enantioselectivities.[11] The turnover numbers
(TON) of most catalytic systems is less than 5 000.
And the reaction conditions are strongly restricted to
neutral and slightly acidic conditions.[11, 12] Therefore,
the asymmetric hydrogenation of prochiral
halogenated ketones is still a challenge with great
significance, and it is necessary to develop a highly
efficient and general catalytic system for the
asymmetric hydrogenation of halogenated ketones to
access enantioenriched halohydrins. Recently, we
Abstract. Iridium-catalyzed asymmetric hydrogenation
of prochiral halogenated ketones was successfully
developed to prepare various chiral halohydrins with high
reactivities and excellent enantioselectivities under basic
reaction condition (up to >99% conversion, 99% yield,
>99% ee). Moreover, gram-scale experiment was
performed well in the presence of just 0.005 mol% (S/C =
20 000) Ir/f-amphox catalyst with 99% yield and >99% ee.
Keywords: Asymmetric hydrogenation; halogenated
ketones; chiral halohydrins; enantioselectivity; chiral
tridentate ligand
developed
aminophosphoxazoline (f-amphox) ligands[13] and
ferrorence-based amino-phosphine-alcohol (f-
a
series of tridentate ferrocene
amphol) ligands[14], which achieved excellent results
in iridium-catalyzed asymmetric hydrogenation of
prochiral ketones and derivatives.[13-14] Inspired by
these results, we herein successfully realized Ir-
catalyzed asymmetric hydrogenation of halogenated
ketones under basic reaction condition, preparing a
series of chiral halohydrins with excellent results
(Scheme 1, up to >99% conversion, 99% yield, >99%
ee, and 20 000 TON).
Chiral
halohydrins
are
highly
versatile
intermediates for the preparation of bioactive
compounds in the fields of pharmaceuticals and
agriculture.[1] For example, they can be convertible to
2]
congestive heart failure drug (R)-denopamine,[1c,
clinically potent -adrenoreceptor agonist and
sympathomimetic drug (R)-isoproterenol[3] and α1-
adrenergic receptor agonist (R)-phenylephrine[4]. In
addition, growing protocols have been developed for
the transformations of enantioenriched halohydrins
into a broad range of functional groups to construct
various useful chiral organic compounds,[5] such as
5n]
epoxides,[5a-5d,
hydroxynitriles,[5e-5g] azides,[5h-5k]
glycols[5l] and amino alcohols[1e, 5m-5n]. Therefore, the
methods introducing chiral halohydrin motifs with
excellent stereocontrol provided a powerful platform
for asymmetric synthesis.
Scheme 1. Ir-catalyzed asymmetric hydrogenation of
halogenated ketones and key transformation.
It was well-known that asymmetric reduction of
prochiral halogenated ketones is an important and
straightforward method to prepare chiral halohydrins.
Initially, we began our research by investigating
the solvent effect for the asymmetric hydrogenation
of α-chloroacetophenone 1a[15] as model substrate at
room temperature with the catalyst generated in situ
by mixing [Ir(COD)Cl]2 with ligand f-amphox L1
(S/C = 1 000) in ethanol, which can also promote
dissolution of the base K2CO3. Full conversions and
excellent enantioselectivities were achieved in a
[1a-1e,
5d,
5h,
6-11]
For examples, asymmetric
hydroboration catalyzed by chiral oxazaborolidines,
[1a-1e, 5h, 6] transfer hydrogenation through chiral Rh[7, 8a]
or Ru[8] catalysts and asymmetric reduction with
biocatalysts[5d, 9]. Owing to the highly alkaline
[10]
instability of halogenated ketones,
there are
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
mixture of toluene/EtOH and hexane/EtOH (v/v =
conversion was afforded with strong base KOtBu
10:1) (>99% conversion, 98%->99% ee, Table 1, (Table 2, entry 5). Full conversion and 93% ee
entries 5 and 10). Less satisfactory results were were obtained in the presence of Cs2CO3 (Table
afforded in pure ethanol with little impurity (98%
conversion, 98% ee, Table 1, entry 2). Poor
reactivities were observed in MeOH/EtOH,
iPrOH/EtOH, DCM/EtOH, DCE/EtOH, THF/EtOH,
2, entry 6). Poor results were observed when
using Na2CO3, KHCO3, K2HPO4 and Et3N as the
base (Table 2, entries 7-10). When the reaction
time was reduced from 12 h to 4 h, this
CHCl3/EtOH and 1,4-dioxane/EtOH (v/v = 10:1), transformation was accomplished with excellent
although good to excellent enantioselectivities can be
obtained (8%–35% conversions, 85%–98% ee, Table
1, entries 1, 3, 4, 6-9). In order to obtain the best
reaction solvent, these asymmetric hydrogenation
reactions were proceeded in toluene/EtOH and
hexane/EtOH at a lower catalyst loading (S/C = 5
000), we can obtain better results using the
hexane/EtOH as the solvents (88% conversion and
98% ee, Table 1, entry 12). Therefore, the mixture of
hexane/EtOH (10:1) was used as the reaction solvent.
enantioselectivity (98% ee, Table 2, entry 11).
Table 2. Screening ligands and bases for the
asymmetric hydrogenation of α-chloroacetophenone
[a]
1a with Ir/f-amphox L1
.
Entry
Ligand
Base
Conv.
(%)[b]
>99
>99
>99
>99
trace
>99
trace
10
Ee
(%)[c]
98
97
96
96
NA
93
NA
87
NA
NA
98
Table 1. Screening solvents for the asymmetric
hydrogenation of α-chloroacetophenone 1a with Ir/f-
amphox L1. [a]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
K2CO3
K2CO3
K2CO3
K2CO3
KOtBu
Cs2CO3
Na2CO3
KHCO3
K2HPO4
Et3N
Entry
Solvent
Conv.
(%) [b]
23 [d]
98 [d]
24 [d]
12
>99
35
9
17
8
>99
19
88
Ee
(%) [c]
90
98
85
94
98
98
89
94
90
98
98
NR
NR
>99
1
2
3
4
5
6
7
8
9
MeOH/EtOH = 10:1
EtOH
10
11 [d]
K2CO3
iPrOH/EtOH = 10:1
DCM/EtOH = 10:1
PhMe/EtOH = 10:1
DCE/EtOH = 10:1
THF/EtOH = 10:1
CHCl3/EtOH = 10:1
1,4-dioxane/EtOH = 10:1
hexane/EtOH = 10:1
PhMe/EtOH = 10:1
hexane/EtOH = 10:1
[a] Reaction conditions: [1a] = 0.2 mmol, 0.0001
mmol [Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL
hexane. The catalyst was preformed in EtOH,
hexane/EtOH (v/v) = 10:1. NR = no reaction, NA =
not available.
[b]
Determined by 1H NMR analysis.
[c] Determined by HPLC analysis.
[d] Reaction time is 4 h.
10
11 [e]
12 [e]
We further investigated the generality of this
asymmetric hydrogenation under the optimized
reaction conditions, and the results are
summarized in Table 3. The expected
98
[a] Reaction conditions: [1a] = 0.2 mmol, 0.0001 mmol
[Ir(COD)Cl]2, 0.00021 mmol ligand, solvent volume = 1.0
mL. The catalyst was preformed in EtOH (0.1 mL for each
reaction vial), solvent/EtOH (v/v) = 10:1. DCM =
hydrogenation products 2a-2r were obtained with
excellent results (>99% conversion, 93%-99%
yields, 90%->99% ee). Substituents on the phenyl
ring with different electronic properties (electron-
neutral, electron-rich and electron-deficient) and
substituted patterns (ortho-, meta-, para-) were
well tolerated in this reaction. The meta-CF3 1f
and
chloroacetophenones were slightly reduced the
enantioselectivities (90%-91% ee). The
dichloromethane, DCE
tetrahydrofuran.
=
dichloroethane, THF
=
[b] Determined by 1H NMR analysis.
[c] Determined by HPLC analysis.
[d] Containing trace impurity.
[e] S/C = 5 000.
ortho-chlorine
1j
substituted
α-
Subsequently, this Ir-catalyzed asymmetric
hydrogenation of α-chloroacetophenone 1a was
studied with various chiral f-amphox ligands L1–
L4 (S/C = 1 000) in hexane/EtOH (10:1) with
K2CO3 as the base. All of the reactions proceeded
smoothly with full conversions and excellent
enantioselectivities (>99% conversions, 96%–
98% ee, Table 2, entries 1–4), and ligand L1 was
identified as the optimal ligand with the best
enantioselectivity. Then different bases were also
screened for this transformation. Trace
challenging heterocyclic thienyl substrate 1q also
proceeded smoothly affording the desired
hydrogenation product with >99% conversion,
99% yield and 99% ee. The 2-chloro-1-
(naphthalen-2-yl)ethan-1-one
1r
was
hydrogenated successfully with excellent results
(>99% conversion, 99% yield and 99% ee). The
challenging
alkyl
substrate
1-chloro-3,3-
dimethylbutan-2-one 1s displayed poor reactivity
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
and enantioselectivity (7% conversion, 23% ee).
It is worth noting that the hydrogenation product
(S)-2-chloro-1-(3-methoxyphenyl)ethan-1-ol 2c
can be transformed to the enantiomer of the
selective α1-adrenergic receptoragonist (R)-
and
excellent
stereoselectivity
(62%
conversion, >25:1 dr, 96% ee).
4
]
phenylephrine, [ and the hydrogenation products
(S)-2-chloro-1-(4-methoxyphenyl)ethan-1-ol 2d
and
(S)-1-(4-((tert-
butyldimethylsilyl)oxy)phenyl)-2-chloroethan-1-
ol 2p are served to construct the enantiomer of
the congestive heart failure drug (R)-denopamine.
Scheme 2. The asymmetric hydrogenation of racemic
chlorinated ketone substrates catalyzed by Ir/f-amphox.
[2]
In addition, the hydrogenation product (S)-2-
chloro-1-(2-chlorophenyl)ethan-1-ol 2j can be
converted to the enantiomer of -adrenoceptor
To our delight, the asymmetric hydrogenation of
bromoketones also proceeded well in this catalytic
system. As shown in Table 4, the electronic property
of substituents on the phenyl ring had little effect on
the reaction results. The hydrogenation product
bromhydrins 2v-2y can be afforded with high yields
and excellent enantioselectivities (>99% conversion,
95%-99% yields, 98%->99% ee).

16
]
agonist (R)-tulobuterol. [
Table 3. Scope study for the asymmetric hydrogenation of
chlorinated ketones 1 with Ir/f-amphox L1. [a]
Table 4. Asymmetric hydrogenation of bromoketones 1
with Ir/f-amphox L1. [a]
[a] Reaction conditions: [Substrate] = 0.2 mmol, 0.001
mmol [Ir(COD)Cl]2, 0.0021 mmol ligand, 1.0 mL hexane.
The catalyst was preformed in EtOH, hexane/EtOH (v/v) =
1
10:1. Conversion was determined by H NMR analysis,
yield reported is the isolated yield, ee was determined by
HPLC analysis.
Our Ir/f-amphox L1 catalytic system exhibited
extremely high activity. The gram-scale asymmetric
hydrogenation
of
2-chloro-1-(4-
methoxyphenyl)ethan-1-one 1d was performed
successfully with just 0.005 mol% (S/C = 20 000)
catalyst, affording the product (S)-2-chloro-1-(4-
methoxyphenyl)ethan-1-ol 2d with 99% yield and
>99% ee (Scheme 3), which is the key intermediate
to produce the enantiomer of a useful drug (R)-
denopamine for congestive heart failure. [2]
[a] Reaction conditions: [Substrate] = 0.2 mmol, 0.0001
mmol [Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL hexane.
The catalyst was preformed in EtOH, hexane/EtOH (v/v) =
10:1. Conversion was determined by H NMR analysis,
yield reported is the isolated yield, ee was determined by
1
HPLC analysis.
[b] S/C = 500, 12 h.
[c] 12 h.
[d] Conversion and ee were determined by GC analysis.
The racemic chlorinated ketone substrates were
also investigated in this asymmetric hydrogenation,
which involved dynamic kinetic resolution process.
As shown in Scheme 2, the cyclic chlorinated ketone
2-chloro-2,3-dihydro-1H-inden-1-one 1t with steric
hindrance did not work in this asymmetric catalytic
system. The acyclic chlorinated ketone 2-chloro-1-
phenylpropan-1-one 1u displayed moderate reactivity
Scheme 3. Ir/f-amphox-catalyzed gram-scale asymmetric
hydrogenation of 2-chloro-1-(4-methoxyphenyl)ethan-1-
one 1d with high TON.
In addition, we applied our previous ferrorence-
based amino-phosphine-alcohol (f-amphol) ligands[14]
into this Ir-catalyzed asymmetric hydrogenation of
chlorinated ketones (Table 5). We can obtain good to
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
pressure. The ee value was determined by chiral HPLC
analysis of the chiral halohydrin directly.
excellent results in the hydrogenation of α-
chloroacetophenone 1a and 4-chloro-1-phenylbutan-
1-one 1za (82%-97% ee, >99% conversion).
Although very poor conversion was achieved, 99% ee
was obtained in the asymmetric hydrogenation of 3-
chloro-1-phenylpropan-1-one 1z. The asymmetric
hydrogenation of racemic cyclic chlorinated ketone
2-chloro-2,3-dihydro-1H-inden-1-one
proceeded well through dynamic kinetic resolution
process with excellent results (>99%
conversion, >25:1 dr, 96% ee).
Acknowledgements
We are grateful for financial support of the Important Sci-
Tech Innovative Project of Hubei Province (2015ACA058), the
National Natural Science Foundation of China (Grant No.
21372179, 21432007, 21502145), the Natural Science
Foundation of Hubei Province (Grant No. 2016CFB449) and
Wuhan Morning Light Plan of Youth Science and Technology
(Grant No. 2017050304010307). The Program of Introducing
Talents of Discipline to Universities of China (111 Project) is
also appreciated.
1t
was
Table 5. Ir/f-amphol-catalyzed asymmetric hydrogenation
of chlorinated ketones. [a]
References
[1] a) E. J. Corey, C. J. Helal, Angew. Chem., Int. Ed.
1998, 37, 1986-2012; b) E. J. Corey, J. O. Link,
Tetrahedron Lett. 1990, 31, 601-604; c) E. J.
Corey, J. O. Link, J. Org. Chem. 1991, 56, 442-444;
d) J. D. Bloom, M. D. Dutia, B. D. Johnson, A.
Wissner, M. G. Burns, E. E. Largis, J. A. Dolan, T.
H. Claus, J. Med. Chem. 1992, 35, 3081-3084; e) J.
Y. L. Chung, R. Cvetovich, J. Amato, J. C.
McWilliams, R. Reamer, L. DiMichele, J. Org.
Chem. 2005, 70, 3592-3601; f) A. K. Singh, J. S.
Prasad, E. J. Delaney, In Asymmetric Catalysis on
Industrial Scale: Challenges, Approaches and
Solutions; H. U. Blaser, E. Schmidt, Eds.; Wiley-
VCH: Weinheim, 2004; pp 335-348; g) P. Kumar,
R. K. Upadhyar and R. K. Pandey, Tetrahedron:
Asymmetry, 2004, 15, 3955–3959; h) L. Cao, J. T.
Lee, W. Chen and T. K. Wood, Biotechnol.
Bioeng., 2006, 94, 522–529; i) R. D. Fabio, C.
Pietra, R. J. Thomas, L. Ziviani, Bioorg. Med.
Chem. Lett., 1995, 5, 551–554; j) J. Pabel, G.
Höfner, K. T. Wanner, Bioorg. Med. Chem. Lett.,
2000, 10, 1377–1380.
[a] Reaction conditions: [Substrate] = 0.2 mmol, 0.0001
mmol [Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL hexane.
The catalyst was preformed in EtOH, hexane/EtOH (v/v) =
10:1. Conversion was determined by H NMR analysis,
yield reported is the isolated yield, ee was determined by
HPLC analysis.
1
[b] S/C = 100, 12 h.
In summary, we successfully developed a highly
efficient asymmetric hydrogenation of prochiral
halogenated ketones to produce various chiral
halohydrins with excellent results under basic
reaction condition (up to >99% conversion, 99%
yield and >99% ee). This asymmetric catalytic
methodology can provide versatile and important
intermediates, which can be used to prepare
[2] a) L. H. C. Lunts, B. G. Main, H. Tucker, In
Medicinal Chemistry, The Role of Organic
Chemistry in Drug Research; S. M. Roberts, B. J.
Price, Ed.; Academic Press: New York, 1985; pp
49-92; b) M. R. Bristow, R. E. Hershberger, J. D.
Port, W. Minobe, R. Rasmussen, Mol. Pharmacol.,
pharmaceuticals. In addition,
a
gram-scale
experiment was proceeded smoothly with only 0.005
mol% (S/C = 20 000) Ir/f-amphox catalyst with 99%
yield and >99% ee.
1989
,
35, 295-303; c) H. Yokoyama, T.
Yanagisawa, N. Taira, J. Cardiooasc. Pharmacol.,
1988, 12, 323-331.
Experimental Section
[3] a) H. Konzett, Arch. Exp. Pathol. Pharmakol. 1940
197, 27–40; b) E. Beccari, A. Beretta, J. S.
Lawendel, Science, 1953, 118, 249–250.
,
General procedure for the asymmetric hydrogenation
with S/C = 1,000: To a 4.0 mL vial was added the catalyst
precursor [Ir(COD)Cl]2 (1.4 mg, 2.0×10-3 mmol), ligand L1
(2.4 mg, 4.2×10-3 mmol) and anhydrous EtOH (2.0 mL) in
the argon-filled glovebox. The mixture was stirred for 2.0
[4] a) H. Takeda, T. Tachinami, M. Aburatani, H.
Takahashi, T. Morimoto and K. Achiwa,
Tetrahedron Lett., 1989, 30, 367-370; b) J. F.
McGarrity and A. Zanotti-Gerosa, Tetrahedron:
Asymmetry, 2010, 21, 2479-2486; c) The Merck
Index, 14th ed.; Merck and Co., Inc.: Whitehouse
o
h at 25 C giving orange red solution. And then 0.2 mmol
of α-chloro ketone, K2CO3 (1.4 mg, 0.01 mmol.) were
added into a 5 mL hydrogenation vessel. 1.0 mL anhydrous
hexane was added as solvent and a solution of Ir/f-amphox
L1 in anhydrous EtOH (100 μL) was added via an injection
port. Then the vessel was placed in an autoclave, closed it
and moved it out from golvebox. The autoclave quickly
purged with hydrogen gas for three times, then pressurized
to 50 atm H2. The reaction solution was stirred at room
temperature (25 oC-30 oC) until for 4 h, then released
pressure carefully. The solution of reaction mixture was
purified by a flash chromatography on a silical gel with
ethyl acetate and the solvent was removed under reduced
Station, NJ, USA, 2006
.
[5] Selected examples: a) E. J. Corey, S. Shibata, R. K.
Bakshi, J. Org. Chem., 1988, 53, 2861-2863; b) C.
Barbieri, L. Bossi, P. D'Arrigo, G. P. Fantoni, S.
Servi, J. Mol. Catal. B: Enzym., 2001, 11, 415-421; c)
P. Vitale, A. Digeo, F. M. Perna, G. Agrimi, A.,
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
Salomone, A. Scilimati, C. Cardellicchio, V. Capriati,
M. Hayes, M. Wills, J. Org. Chem., 2006, 71, 7035-
7044; d) S. Denizaltı, D. Mercan, B. Şen, A. G.
Gökçe, B. Çetinkaya, J. Organomet. Chem., 2015,
779, 62-66; e) R. Hodgkinson, V. Jurčík, A. Zanotti-
Gerosa, H. G. Nedden, A. Blackaby, G. J. Clarkson,
M. Wills, Organometallics, 2014, 33, 5517-5524; f)
T. Touge, T. Hakamata, H. Nara, T. Kobayashi, N.
Sayo, T. Saito, K. Kayaki, T. Ikariya, J. Am. Chem.
Soc., 2011, 133, 14960-14963; g) R. Soni, K. E.
Jolley, G. J. Clarkson, M. Wills, Org. Lett., 2013, 15,
5110-5113; h) Y. Yuki, T. Touge, H. Nara, K.
Matsumura, M. Fujiwhara, Y. Kayaki, T. Ikariya, Adv.
Catalysts, 2017, 7, 37-49; d) C. Aguirre-Pranzoni, F.
R. Bisogno, A. A. Orden, M. Kurina-Sanz, J. Mol.
Catal. B: Enzym., 2015, 114, 19-24; e) K. Isaac, J.
Stemper, P. Retailleau, J. F. Betzer, A. Marinetti, Eur.
J. Org. Chem., 2014, 19, 4099-4106; f) J. Stemper, K.
Isaac, J. Pastor, G. Frison, P. Retailleau, A. Voituriez,
J.-F. Betzer, A. Marinetti, Adv. Synth. & Catal., 2013,
355, 3613-3624; g) A. Kamal, G. R. Khanna, R.
Ramu, Tetrahedron: Asymmetry, 2002, 13, 2039-
2051; h) S. F. Lu, B. Herbert, G. Haufe, K. W. Laue,
W. L. Padgett, O. Oshunleti, J. W. Daly, K. L. Kirk,
J. Med. Chem., 2000, 43, 1611-1619; i) L. S.
Campbell-Verduyn, W. Szymański, C. P. Postema, R.
A. Dierckx, P. H. Elsinga, D. B. Janssen, B. L.
Feringa, Chem. Commun., 2010, 46, 898-900; j) S.
Kim, S. N. Cho, T. Oh, P. Kim, Bioorg. Med. Chem.
Lett., 2012, 22, 6844-6847; k) G. Zaponakis, H. E.
Katerinopoulos, Tetrahedron Lett., 1996, 37, 3045-
3048; l) J. Barluenga, J. Flórez, M. Yus, J. Chem.
Soc., Chem. Commun., 1982, 1153-1154; m) W. S.
Everson, Chem. Rev., 1949, 45, 183-345; n) D.
Tokoshima, K. Hanaya, M. Shoji, T. Sugai, J. Mol.
Catal. B: Enzym., 2013, 97, 95-99.
Synth.
&
Catal.,
2017,
359,
DOI:
10.1002/adsc.201701227.
[9] Selected examples: a) H. Lin, Y. Z. Chen, X. Y. Xu, S.
W. Xia, L. X. Wang, J. Mol. Catal. B: Enzym., 2009,
57, 1-5; b) F. G. Mutti, A. Orthaber, J. H.
Schrittwieser, J. G. de Vries, R. Pietschnig, W.
Kroutil, Chem. Commun., 2010, 46, 8046-8048; c) S.
Y. Chen, C. X. Yang, J. P. Wu, G. Xu, L. R. Yang,
Adv. Synth. & Catal., 2013, 355, 3179-3190.
[10]-Chloroacetophenone
suffers
Darzens-like
condensation in a basic alcoholic solvent: a) H. H.
Wasserman, N. E. Aubrey, H. E. Zimmerman, J. Am.
Chem. Soc. 1953, 75, 96-98; b) C. L. Stevens, R. J.
Church, V. J. Traynelis, J. Org. Chem. 1954, 19, 522-
532.
[6] Selected examples: a) S. Itsuno, Org. React. 1998, 52,
395-576; b) Y. Zhou, G. Gao, Y. Song, J. Qu,
Synthetic Commun., 2014, 44, 1515-1520; c) S. Wei,
R. Messerer, S. B. Tsogoeva, Chem.-Eur. J., 2011, 17, [11] a) M. Devocelle, A. Mortreux, F. Agbossou, J. R.
14380-14384; d) N. Hosoda, H. Kamito, M. Takano,
Y. Takebe, Y. Yamaguchi, M. Asami, Tetrahedron,
2013, 69, 1739-1746; e) W. Xu, H. Guo, Q. Zhu, X.
Ke, X. Hu, Catal. Lett., 2008, 125, 302-307; f) N. J.
Gilmore, S. Jones, M. P. Muldowney, Org. Lett.,
2004, 6, 2805-2808; g) M. Ćwiklińska, M. P.
Krzemiński, A. Tafelska-Kaczmarek, Tetrahedron:
Asymmetry, 2015, 26, 1453-1458; h) D. A. Cifuente,
C. E. Tonn, Org. Commun., 2012, 5, 77-82; i) T.
Inoue, D. Sato, K. Komura, S. Itsuno, Tetrahedron
lett., 1999, 40, 5379-5382; j) A. L. Zhang, Z. d. Yu, L.
W. Yang, N. F. Yang, D. Peng, J. Mol. Catal. A-
Chem., 2015, 398, 407-412; k) M. Azizoglu, A.
Erdogan, N. Arslan, Y. Turgut, Chirality, 2014, 26,
21-26.
Dormoy, Tetrahedron Lett., 1999, 40, 4551-4554; b)
L. Qiu, J. Wu, S. Chan, T. L. Terry, J. X. Ji, R. Guo,
C.-C. Pai, Z. Zhou, X. Li, Q.-H. Fan, A. S. C. Chan, P.
Natl. Acad. Sci. USA, 2004, 101, 5815-5820; c) L.
Qiu, F. Y. Kwong, J. Wu, W. H. Lam, S. Chan, W.-Y.
Yu, Y.-M. Li, R. Guo, Z. Zhou, A. S. C. Chan, J. Am.
Chem. Soc., 2006, 128, 5955-5965; d) T. Ohkuma, K.
Tsutsumi, N. Utsumi, N. Arai, R. Noyori, K. Murata,
Org. Lett. 2007, 9, 255-257; e) X. Wan, Q. Meng, H.
Zhang, Y. Sun, W. Fan, Z. Zhang, Org. Lett., 2007, 9,
5613-5616; f) D. Xu, Z. M. Zhou, L. Dai, L. W. Tan,
J. Zhang, Bioorg. Med. Chem. Lett., 2015, 25, 1961-
1964.
[12] a) J. P. Genêt, M. C. De Andrade, V.
Ratovelomanana-Vidal, Tetrahedron Lett., 1995, 36,
2063-2066; b) C. Mordant, C. C. de Andrade, R.
Touati, V. Ratovelomanana-Vidal, B. B. Hassine, J.
P. Genêt, Synthesis, 2003, 15, 2405-2409; c) S.
Prévost, S. Gauthier, M. C. C. de Andrade, C.
Mordant, A. R. Touati, P. Lesot, P. Savignac, T.
Ayad, P. Phansavath, V. Ratovelomanana-Vidal, J. P.
Genêt, Tetrahedron: Asymmetry, 2010, 21, 1436-
1446; d) K. E. Jolley, A. Zanotti ‐ Gerosa, F.
Hancock, A. Dyke, D. M. Grainger, J. A. Medlock,
H. G. Nedden, J. J. M. Le Paih, S. J. Roseblade, A.
Seger, V. Sivakumar, I. Prokes, D. J. Morris, V.
Sivakumar, Adv. Synth. & Catal. 2012, 354, 2545-
2555.
[7] Selected examples: a) T. Hamada, T. Torii, K. Izawa,
R. Noyori, T. Ikariya, Org. Lett. 2002, 4, 4373-4376;
b) T. Hamada, T. Torii, T. Onishi, K. Izawa, T.
Ikariya, J. Org. Chem., 2004, 69, 7391-7394; c) D. S.
Matharu, D. J. Morris, A. M. Kawamoto, G. J.
Clarkson, M. Wills, Org. Lett., 2005, 7, 5489-5491; d)
L. S. Zheng, Q. Llopis, P. G. Echeverria, C. Férard, G.
Guillamot, P. Phansavath, V. Ratovelomanana-Vidal,
J. Org. Chem., 2017, 82, 5607-5615; e) Echeverria, P.
G.; Férard, C.; Phansavath, P.; Ratovelomanana-Vidal,
V. Catal. Commun., 2015, 62, 95-99; f) N. A. Cortez,
G. Aguirre, M. Parra-Hake, R. Somanathan, A. J.
Arita, A. L. Cooksy, G. Huelgas, Synthetic Commun.,
2010, 41, 73-84.
[13] a) W. Wu, S. Liu, M. Duan, X. Tan, C. Chen, Y. Xie,
Y. Lan, X.-Q. Dong, X. Zhang, Org. Lett., 2016, 18,
2938-294; b) W. Wu, C. You, C. Yin, Y. Liu, X.-Q.
Dong, X. Zhang, Org. Lett., 2017, 19, 2548-2551; c)
W. Wu, Y. Xie, P. Li, X. Li, Y. Liu, X.-Q. Dong, X.
Zhang, Org. Chem. Front., 2017, 4, 555-559; d) Y.
[8] Selected examples: a) D. J. Bayston, C. B. Travers, M.
E. C. Polywka, Tetrahedron: Asymmetry, 1998, 9,
2015-2018; b) D. J. Cross, J. A. Kenny, I. Houson, L.
Campbell, T. Walsgrove, M. Wills, Tetrahedron:
Asymmetry, 2001, 12, 1801-1806; c) D. J. Morris, A.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
Hu, W. Wu, X. Q Dong,. X. Zhang, Org. Chem.
Front., 2017, 4, 1499-1502.
[14] J. Yu, M. Duan, W. Wu, X. Qi, P. Xue, Y. Lan, X.-Q.
Dong, X. Zhang, Chem.-Eur. J., 2017, 23, 970-975.
[15] a) J. C. Lee, Y. H. Bae, S. K. Chang, Bull. Korean
Chem. Soc., 2003, 24, 407-408; b) S. Kamila, B.
Koh, E. R. Biehl, J. Heterocyclic Chem., 2006, 43,
1609-1612.
[16] H. Kume, M. Kondo, Y. Ito, R. Suzuki, K. Yamaki,
K. Takagi, Clin. Exp. Pharmacol. Physiol. 2002, 29,
1076-1083.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800267
Advanced Synthesis & Catalysis
COMMUNICATION
Iridium-Catalyzed Asymmetric Hydrogenation of
Halogenated Ketones for the Efficient Construction
of Chiral Halohydrins
Adv. Synth. Catal. 2018, Volume, Page – Page
Congcong Yin,†a Weilong Wu,†a Yang Hu,a
Xuefeng Tan,b Cai You,a Yuanhua Liu,a Ziyi Chen,a
Xiu-Qin Dong,*a Xumu Zhang*a,b
7
This article is protected by copyright. All rights reserved.