Efficient Access to Chiral Benzhydrols via Asymmetric Transfer Hydrogenation of Unsymmetrical Benzophenones with Bifunctional Oxo-Tethered Ruthenium Catalysts

Article abstract of DOI:10.1021/jacs.6b05738

A concise asymmetric transfer hydrogenation of diaryl ketones, promoted by bifunctional Ru complexes with an etherial linkage between 1,2-diphenylethylenediamine (DPEN) and η⁶-arene ligands, was successfully developed. Because of the effective discrimination of substituents at the ortho position on the aryl group, unsymmetrical benzophenones were smoothly reduced in a 5:2 mixture of formic acid and triethylamine with an unprecedented level of excellent enantioselectivity. For the non-ortho-substituted benzophenones, the oxo-tethered catalyst electronically discerned biased substrates, resulting in attractive performance yielding chiral diarylmethanols with >99% ee.

Full text of DOI:10.1021/jacs.6b05738

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Communication
Efficient Access to Chiral Benzhydrols via Asymmetric
Transfer Hydrogenation of Unsymmetrical Benzophenones
with Bifunctional Oxo-tethered Ruthenium Catalysts
Taichiro Touge, Hideki Nara, Mitsuhiko Fujiwhara, Yoshihito Kayaki, and Takao Ikariya
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b05738 • Publication Date (Web): 27 Jul 2016
Downloaded from http://pubs.acs.org on July 27, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Efficient Access to Chiral Benzhydrols via Asymmetric Trans-
fer Hydrogenation of Unsymmetrical Benzophenones with Bi-
functional Oxo-tethered Ruthenium Catalysts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Taichiro Touge,*† Hideki Nara,† Mitsuhiko Fujiwhara,† Yoshihito Kayaki,*‡ and Takao Ikariya‡
† Corporate Research & Development Division, Takasago International Corporation, 1-4-11 Nishi-Yawata, Hiratsuka, Kana-
gawa 254-0073, Japan
‡ Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Tech-
nology, 2-12-1-E4-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Using a systematic approach to structural tuning of the bi-
functional catalysts derived from sulfonylated 1,2-
diphenylethylenediamine (DPEN), we designed a new family
of oxo-tethered Ru complexes (DENEB)—(R,R)-3 and (R,R)-
4—that exhibit excellent catalytic performance for the
asymmetric transfer hydrogenation of simple ketones.11,12
The persistent three-point coordination obtained by introduc-
ing the covalently tethered unit13 enhanced catalyst longevity
and produced the highest activity of a series of the prototypic
ABSTRACT: A concise asymmetric transfer hydrogenation of
diaryl ketones, promoted by bifunctional Ru complexes with an
etherial linkage between 1,2-diphenylethylenediamine (DPEN)
and 6-arene ligands, was successfully developed. Because of the
effective discrimination of substituents at the ortho-position on
the aryl group, unsymmetrical benzophenones were smoothly
reduced in a 5:2 mixture of formic acid and triethylamine with an
unprecedented level of excellent enantioselectivity. For the non-
ortho-substituted benzophenones, the oxo-tethered catalyst elec-
tronically discerned biased substrates, resulting in attractive per-
formance yielding chiral diarylmethanols with >99% ee.
(6-arene)Ru/Ts-DPEN catalysts, including (R,R)-
(R,R)- . Regarding the imposed coordination, conformational
1 and
2
rigidity also supported the stereodiscrimination ability of the
bifunctional catalysts. In this paper, we report the substantial
enantioselectivity of the oxo-tethered Ru complexes in the
catalytic transfer hydrogenation of diaryl ketones with a vari-
ety of substituents at ortho positions and/or other positions.
Catalytic asymmetric synthesis of secondary alcohols from ke-
tones has attracted considerable interest as a reliable method.
Since a string of Ru catalysts with 1,2-diamine scaffolds was es-
tablished for asymmetric hydrogenation or transfer hydrogenation
of acetophenone derivatives in the mid-1990s,1,2 the utility of
metal/NH cooperation has been highlighted via advances in redox
transformations of carbonyl or alcoholic compounds.3 Because of
breakthrough developments of the bifunctional catalysts, the
scope of ketone substrates has been extensively broadened; how-
ever, a high level of stereo-controlling ability of the chiral cata-
lysts is needed to access post-challenging targets.
Among aromatic ketones, unsymmetrical benzophenones have
been less frequently subjected to enantioselective reduction, in
which a catalyst must discern structural differences in the two
aromatic rings.4-8 The catalytic hydrogenation offers straightfor-
ward access to biologically and pharmaceutically valuable ben-
zhydrols without producing stoichiometric amounts of metal
waste, compared with the asymmetric catalytic addition of nucle-
ophilic arylmetals to aromatic aldehydes.9 Ohkuma and Noyori
reported that the Ru/(S)-Xylbinap/(S)-daipen catalyst can effec-
tively promote H2-hydrogenation of substituted benzophenones in
the presence of tert-BuOK under mild pressure (8 atm) and tem-
perature conditions.4a Although ortho-substituted benzophenones
were successfully converted to the corresponding diarylmethanols
with a maximum of 99% ee, the enantiomeric excesses obtained
from meta- and para-substituted substrates were lower (<47% ee).
In other asymmetric hydrogenation,4b–f hydroboration,5 hydrosi-
lylation,6 and transfer hydrogenation7 systems with reasonable
enantioselectivity, the substrate scope remains primarily limited to
ortho-functionalized and mono-substituted benzophenones.10
Figure 1. Structure of non-tethered and tethered Ru-DPEN cata-
lysts.
We initially examined asymmetric transfer hydrogenation of 2-
methylbenzophenone using 1 mol% of the DPEN-derived Ru
complexes in an azeotropic mixture of formic acid and triethyla-
mine at 60 °C. As listed in Table 1, the corresponding (S)-alcohol
was obtained in 86-98% ees after the 18 h reaction. Compared to
the prototype catalyst of (R,R)-1 and (R,R)-2 (entries 1 and 2), the
oxo-tethered Ru(II) complexes (R,R)-3, (R,R)-4 exhibited superior
activities (entries 3 and 4), and the former Ts-derivative showed
optimal catalytic performance in terms of the yield and enantiose-
lectivity.14 The attained optical purity is as high as those with a
ketoreductase enzyme.8b
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
Table 1. Asymmetric transfer hydrogenation of 2-
methylbenzophenonea
Table 2. Asymmetric transfer hydrogenation of 2-
substituted benzophenonesa
1
2
3
4
5
6
7
8
9
entry
catalyst
(R,R)-1
(R,R)-2
(R,R)-3
(R,R)-4
% yield
22
% eeb
entry R1
R2
H
R3
H
temp, °C time, h product % yield
% eeb
1
2
3
4
86(S, +)
90(S, +)
98(S, +)
94(S, +)
1
2
Cl
Br
40
60
60
40
60
60
30
40
10
30
60
30
40
17
8
6b
6c
6d
6e
6f
>99
>99
99
98(S, –)
99(S, –)
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
98
3
4c,d
CF3
OH
CH3
H
H
12
13
17
23
18
7
>99(S, –)
77(S, –)
97(S, –)
98(S, +)
99(S, –)
99(S, +)
91(S, +)
90(S, +)
99(S, –)
97(S, –)
97(S, –)
94
H
H
94
aTypical reaction conditions: catalyst (0.01 mmol), substrate (1.0 mmol),
HCO2H/Et3N=5/2 azeotropic mixture (0.5 mL). bDetermined by HPLC analysis.
5
4-CH3
H
94
6
CH3 4,5-(CH3)2
H
6g
6h
6i
98
A variety of 2-substituted benzophenones was shown to be ap-
plicable to asymmetric transfer hydrogenation with (R,R)-3, which
displayed enhanced enantioselectivities relative to the asymmetric
hydrogenation with chiral Ru catalysts,4a–f as listed in Table 2.
Mono-substituted benzophenones bearing chloro, bromo, and
trifluoromethyl groups at the ortho position were smoothly re-
duced with almost complete conversions and excellent ees, ex-
ceeding 98% (entries 1–3). The results of the high-performance
liquid chromatographic (HPLC) analysis with a chiral stationary
phase indicated that the products were (S)-isomers. In contrast to
the asymmetric hydrogenation with a diphosphine-diamine-Ru(II)
complex,4a the oxo-tethered catalyst (R,R)-4 tolerated a phenolic
7
Cl
Cl
F
4-Cl
5-NO2
5-F
H
97
8
H
>99
91
9
H
40
7
6j
10
11
12
13
F
3-CF3
perfluoro
H
H
6k
6l
>99
>99
>99
99
F
H
5
Cl
Cl
4’-Cl
4’-F
18
17
6m
6n
H
aTypical reaction condition: catalyst (0.01 mmol), substrate (1.0 mmol), HCO2H/Et3N=5/2
azeotropic mixture (0.5 mL). bDetermined by HPLC analysis. c(R,R)-4 was employed as a
catalyst. dComparable yield (99%) and ee (70%) were obtained by using (R,R)-3 under
identical conditions.
ketone
—2-hydroxybenzophenone—and provided a satisfactory ee
of 77% (entry 4). Multiply-substituted aryl phenyl ketones, in-
cluding 2,4-methyl-, 2,4,5-trimethyl-, 2,4-dichloro-, and 2-chloro-
5-nitrobenzophenone analogues, were converted to the desired
(S)-benzhydrols with sufficient conversions and ees (entries 5–8).
Although reduction of 2,5-difluoro- and 2-fluoro-3-
trifluoromethylbenzophenone produced slightly lower ees of 91%
and 90% (entries 9 and 10), 2,3,4,5,6-pentafluorobenzophenone
was completely hydrogenated with outstanding enantioselectivity
(entry 11). Transfer hydrogenation of 2,4’-dichloro- and 2-chloro-
4’-fluorobenzophenone furnished the corresponding unsymmet-
rical diarylmethanols in high yields and 97% ee (entries 12 and
13), indicating that (R,R)-3 can precisely recognize the ortho-
substituted phenyl group.
In a putative outer sphere mechanism involving H+ and H-
transfer to the C=O moiety, an attractive interaction between the
edge of an η6-arene ligand and the face of an aromatic ring15 in
ketone substrates has been considered to impose their one-sided
approach and enable remarkable asymmetric induction.16 Given
that the stereochemistry of all products from 2-substituted diaryl
ketones has an S-configuration, a sterically favorable edge-to-face
interaction away from the ortho-substituted phenyl groups is en-
visaged in the transition state, as depicted in Figure 2. The intro-
duction of the sterically less demanding fluorine atom into the
ortho position was mildly effective compared with other halogens
(entries 9 and 10).
Figure 2. Proposed interaction between 2-substituted benzo-
phenone and the oxo-tethered Ru(II) complex (R,R)-3.
Scheme 1. Synthesis of optically active 6-phenyl-6H-
benzo[c]chromene
(i) 2-Fluorophenylboronic acid (7) (1.5 equiv), Pd(PPh3)4 (2 mol%), K2CO3 (1.5
equiv), Toluene/THF = 1/1, 100 °C, 7 h (ii) tert-BuOK (1.0 equiv), THF, 20 °C, 3 h
The chiral benzohydrol product was successfully utilized in the
expedient preparation of chiral benzo[c]chromene (9), for which
only few synthetic methods have been reported (Scheme 1).17 The
The utility of (R,R)-3 was also demonstrated in the reaction of
unsymmetrical diaryl ketones with the exception of 2-substituted
benzophenones, as summarized in Table 3. From 4-
chlorobenzophenone, the corresponding (S)-alcohol was formed
with a moderate ee of 48% (11a, entry 1). The enantioselectivities
can be substantially increased to 76% and 77% ees by doubly-
halogenated substrates at the meta- and para-position (11b and
11c, entries 2 and 3). A comparable selectivity of 76% ee was
attainable in the reduction of mono-substituted 4-
nitrobenzophenone, implying an additional beneficial effect re-
Suzuki-Miyaura
coupling
reaction
of
(S)-(2-
bromophenyl)(phenyl)methanol (6c) with 2-flurorophenylboronic
acid (7) in the presence of Pd(PPh3)4 smoothly afforded the corre-
sponding adduct 8 with virtually no loss of optical purity. Subse-
quent cyclization with tert-BuOK in THF yielded the desired
benzochromene framework 9 in 70% yield and 98% ee.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
sulting from the incorporation of a strongly electron-withdrawing
The excellent enantioselectivity was also realized for other ar-
1
2
3
4
5
6
7
8
NO2 group (11d, entry 4); 3-nitro-4-chlorobenzophenone pro-
duced 93% ee and complete conversion (11e, entry 5). When
3,4,5-trifluorobenzophenone and 3,5-dinitrobenzophenone were
tested as highly biased diaryl ketones, the expected chiral alcohols
(11f and 11g, entries 6 and 7) were obtained with 95% and >99%
ees, respectively. In these cases, the (S)-enantiomers were formed,
possibly via a transition state by avoiding an interaction between
the 6-arene ligand and the relatively electron deficient ring, as
indicated in bold in Figure 3.18
omatic ketones with distinct electronic properties. As shown in
Schemes 2 and 3, the reaction of benzoylferrocene afforded (S)-
alcohol (11m) in 90% ee via a similar asymmetric induction, albe-
it producing only a 53% yield after 20 h at 60 °C. In addition, 3-
nitrophenyl 2-thienyl ketone was converted to the corresponding
(R)-product (11n) in 96% yield with almost complete enantiose-
lectivity (Scheme 3). These results provide evidence for enanti-
oselective reduction, that is, the chiral oxo-tethered catalyst accu-
rately avoids the sterically demanding and electron-poor ferrocene
moiety and establishes the thiophene ring as an electron-rich
fragment that can approach the 6-arene ligand shown in Figure 3.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Asymmetric transfer hydrogenation of non-ortho-
substituted diaryl ketonesa
Scheme 2. Asymmetric transfer hydrogenation of benzo-
ylferrocene
entry R1
R2
Cl
Cl
F
R3
H
R4
time, h product % yield
% eeb
48(S, +)
76(S, +)
77(S, +)
76(S, +)
93(S, +)
95(S, +)
>99(S, +)
5(R, +)
1
2
H
Cl
F
H
11
18
7
11a
11b
11c
11d
11e
11f
11g
11h
11i
>99
>99
>99
>99
>99
>99
90
H
H
H
Scheme 3. Asymmetric transfer hydrogenation of 3-
nitrophenyl 2-thienyl ketone
3
H
4
H
NO2
Cl
F
H
H
11
11
16
26
20
21
6
5
NO2
F
H
H
6c
7c
8d
9
F
H
NO2
H
H
NO2
H
H
H
OCH3
OCH3
OH
OCH3
OCH3
80
H
Cl
Cl
NO2
H
H
59
53(S, +)
55(S)
10
11
12
H
H
11j
11k
11l
>99
>99
92
An extensive range of unsymmetrical benzophenone deriva-
tives was successfully reduced with good to excellent ees and in
high yields, because the oxo-tethered ligand ensuring precise
recognition of ortho-substituted phenyl groups as well as differen-
tiation between electron-rich and electron-poor arene rings. Con-
sidering the combination of desirable features, including a wide
substrate scope, excellent enantioselectivity, mild reaction condi-
tions, and high stability and availability of the catalyst precursor,
we believe that this catalyst system has significant potential for
application in a practical streamlined method to obtain chiral dia-
rylmethanols.
H
H
30
9
79(R, +)
99(S, +)
NO2
NO2
aTypical reaction condition: catalyst (0.01 mmol), substrate (1.0 mmol), HCO2H/Et3N=5/2
azeotropic mixture (0.5 mL) bDetermined by HPLC analysis. cThe reaction was performed
at 10 °C. dThe reaction was performed at 60 °C.
On the other hand, 4-methoxybenzophenone produced the (R)-
11h (5% ee), as the result of a slightly better arene-arene interac-
tion with the 4-methoxyphenyl group compared to the phenyl
group (entry 8). The catalyst molecule can pointedly differentiate
between two para-substituted phenyl groups with opposite elec-
tronic character, as observed in the reaction of 4-chloro-
4’methoxybenzophenone, which yields a higher ee of 11i. A com-
parable ee with complete conversion was achieved in the reduc-
tion of 4-chloro-4’-hydroxybenzophenone, and the phenolic OH
group remained intact (11j, entry 10). Additional enhancement of
enantioselectivity by the nitro group was confirmed in the for-
mation of 11k and 11l. The ees of the obtained methoxy-
substituted alcohols—11i and 11k—were consistently increased
by 3-5 % compared with the stereochemical outcomes of 11a and
11d, which were derived from the corresponding aryl phenyl ke-
tones, possibly because the methoxyphenyl ring preferentially
interacts with the η6-arene ligand in the enantio-determining step.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.....
Experimental section, characterization data, and determination of
absolute configuration of products (6g, 6i, 6j, 6k, 11b, 11c, 11e,
11f, and 11n) by X-ray crystallographic analysis of their deriva-
tives.
AUTHOR INFORMATION
Corresponding Author
*taichiro_touge@takasago.com, ykayaki@o.cc.titech.ac.jp
Notes
The authors declare no competing interest.
ACKNOWLEDGMENT
This study was financially supported by JSPS KAKENHI Grant
Number 24350079 and 26621043 and in part by Grant for Basic
Science Research Projects from The Sumitomo Foundation. We
Figure 3. Plausible transition state in asymmetric transfer hydro-
genation of non-ortho-substituted benzophenones with (R,R)-3.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(16) (a) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000,
are grateful to Messrs. Yoshihiro Yaguchi, Akihiro Kawaraya,
Kazuhiko Sakaguchi, Jun Kurabe, Hiroaki Izumi, Masayuki Sen-
tou and Mses. Hisae Kasuga, Kyoko Zaizen, Chikako Kawata,
Seika Abe, Noriko Yamamoto of Takasago International Corpora-
tion for the measurement of NMR and mass spectra, and experi-
mental assistance. We also thank Prof. Takeshi Nakai and Prof.
Masahiro Terada for helpful discussions.
122, 1466. (b) Yamakawa, M.; Yamada, I.; Noyori, R. Angew. Chem. Int.
Ed. 2001, 40, 2818. (c) Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org.
Chem. 2001, 66, 7931. (d) Cheung, F. K.; Lin, C.; Minissi, F.; Crivillé, A.
L.; Graham, M. A.; Fox, D. J.; Wills, M. Org. Lett. 2007, 9, 4659. (e) Dub,
P. A.; Ikariya, T. J. Am. Chem. Soc. 2013, 135, 2604. (f) Matsuoka, A.;
Sandoval, C. A.; Uchiyama, M.; Noyori, R.; Naka, H. Chem. Asian J.
2015, 10, 112.
1
2
3
4
5
6
7
8
9
(17) (a) Kym, P. R.; Lane, B. C.; Pratt, J. K.; Von Geldern, T.; Winn,
M.; Brenneman, J.; Patel, J. R.; Arendsen, D. L.; Akritopoulou-zanze, I.;
Ashworth, K. L.; Hartandi, K. US20010041802 A1. (b) Edwards, J. P.;
Zhi. L.; Pooley, C. L. F.; Tegley, C. M.; West, S. J.; Wang, M.-W.; Got-
tardis, M. M.; Pathirana, C.; Schrader, W. T.; Jones, T. K. J. Med. Chem.
1998, 41, 2779. (c) Wallace, O. B.; Lauwers, K. S.; Dodge, J. A.; May, S.
A.; Calvin, J. R.; Hinklin, R.; Bryant, H. U.; Shetler, P. K.; Adrian, M. D.;
Geiser, A. G.; Sato, M.; Burris, T. P. J. Med. Chem. 2006, 49, 843. (d)
Guo, Z.-W.; Li, X.-S.; Zhu, W.-D.; Xie, J.-W. Eur. J. Org. Chem. 2012,
6924.
(18) Discussion on the edge-to-face interaction weakened by electron
withdrawing groups on the face-directed ring: (a) Jennings, W. B.;
O’Connell, N.; Malone, J. F.; Boyd, D. R. Org. Biomol. Chem. 2013, 11,
5278. (b) Gardarsson, H.; Schweized, W. B.; Trapp, N.; Diederich, F.
Chem. Eur. J. 2014, 20, 4608, and references cited therein.
REFERENCES
(1) (a) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40.
(b) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 2675. (c) Ohkuma, T.; Ooka, H.; Hashiguchi, S.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) (a) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97. (b)
Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562. (c) Haack, K.-J.; Hashiguchi, S.; Fujii, A.;
Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. Engl. 1997, 36, 285.
(3) For some reviews, see: (a) Palmer, M. J.; Wills, M. Tetrahedron:
Asymmetry 1999, 10, 2045. (b) Ikariya, T.; Blacker, J. Acc. Chem. Res.
2007, 40, 1300. (c) Ikariya, T. Bull. Chem. Soc. Jpn. 2011, 84, 1. (d)
Muñiz, K. Angew. Chem. Int. Ed. 2005, 44, 6622. (e) Zhao, B; Han, Z.;
Ding, K. Angew. Chem. Int. Ed. 2013, 52, 4744. (f) Wang, D.; Astruc, D.;
Chem. Rev. 2015, 115, 6621. (g) Zuo, W.; Morris, R. H. Nat. Protoc. 2015,
10, 241. (h) Dub, P. A.; Gordon, J. C. Dalton Trans. 2016, 45, 6756.
(4) (a) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori,
R. Org. Lett. 2000, 2, 659. (b) Wu, J.; Ji, J.-X.; Guo, R.; Yeung, C.-H.;
Chan, A. S. C. Chem. Eur. J. 2003, 9, 2963. (c) Li, Y.; Ding, K.; Sandoval,
C. A. Org. Lett. 2009, 11, 907. (d) Li, Y.; Zhou, Y.; Shi, Q.; Ding, K.;
Noyori, R.; Sandoval, C. A. Adv. Synth. Catal. 2011, 353, 495. (e) Goto,
M.; Konishi, T.; Kawaguchi, S.; Yamada, M.; Nagata, T.; Yamano, M.
Org. Process Res. Dev. 2011, 15, 1178. (f) Ito, J.-i.; Teshima, T.;
Nishiyama, H. Chem. Commun. 2012, 48, 1105. (g) Irrgang, T.; Friedrich,
D.; Kempe, R. Angew. Chem. Int. Ed. 2011, 50, 2183.
(5) (a) Kokura, A.; Tanaka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2006,
8, 3025. (b) Guo, J.; Chen, J.; Lu, Z. Chem. Commun. 2015, 51, 5725.
(6) (a) Wu, J.; Ji, J.-X.; Chan, A. S. C. Proc. Natl. Acad. Sci. USA 2005,
102, 3570. (b) Lee, C.-T.; Lipshutz, B. H. Org. Lett. 2008, 10, 4187. (c)
Sui, Y.-Z.; Zhang, X.-C.; Wu, J.-W.; Li, S.; Zhou, J.-N.; Li, M.; Fang, W.;
Chan, A. S. C.; Wu, J. Chem. Eur. J. 2012, 18, 7486.
(7) (a) Kriis, K.; Kanger, T.; Müürisepp, A.-M.; Lopp, M. Tetrahedron:
Asymmetry 2003, 14, 2271. (b) Kriis, K.; Kanger, T.; Lopp, M. Tetrahe-
dron: Asymmetry 2004, 15, 2687. (c) Yang, Y.; Weng, Z.; Muratsugu, S.;
Ishiguro, N.; Ohkoshi, S.; Tada, M. Chem. Eur. J. 2012, 18, 1142.
(8) For biocatalytic approaches: (a) Li, H.; Zhu, D.; Hua, L.; Biehl, E.
R. Adv. Synth. Catal. 2009, 351, 583. (b) Truppo, M. D.; Pollard, D.;
Devine, P. Org. Lett. 2007, 9, 335.
(9) (a) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc.
Rev. 2006, 35, 454. (b) Salvi, L.; Kim, J. G.; Walsh, P. J. J. Am. Chem.
Soc. 2009, 131, 12483. (c) Tian, P.; Dong, H.-Q.; Lin, G.-Q. ACS Catal.
2012, 2, 95. (d) Uenishi, A.; Nakagawa, Y.; Osumi, H.; Harada, T. Chem.
Eur. J. 2013, 19, 4896.
(10) Recently, asymmetric desymmetrization of diaryl methanol was
achieved by enantioselective silylation of aryl C–H bond at the ortho
position of benzophenone derivatives: Lee, T.; Wilson, T. W.; Berg, R.;
Ryberg, P.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 6742.
(11) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito,
T.; Kayaki, Y.; Ikariya, T. J. Am. Chem. Soc. 2011, 133, 14960.
(12) For industrial use of DENEB catalysts: (a) Komiyama, M.; Itoh,
T.; Takeyasu, T. Org. Process Res. Dev. 2015, 19, 315. (b) Chung, J. Y.
L.; Scott, J. P.; Anderson, C.; Bishop, B.; Bremeyer, N.; Cao, Y.; Chen,
Q.; Dunn, R.; Kassim, A.; Lieberman, D.; Moment, A. J.; Sheen, F.;
Zacuto, M. Org. Process Res. Dev. 2015, 19, 1760.
(13) Other examples of tethered Ru complexes: (a) Hannedouche, J.;
Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126, 986. (b) Soni, R.;
Hall, T. H.; Mitchel, B. P.; Owen, M. R.; Wills, M. J. Org. Chem. 2015,
80, 6784, and references cited therein.
(14) The effectiveness of the oxo-tethered catalyst 3 was also con-
firmed in the reaction of other diaryl ketone substrates by comparison with
test experiments using 1. The results are summarized in Supporting Infor-
mation (Tables S1 and S2).
(15) (a) Takahashi, O.; Kohno, Y.; Nishio, M. Chem. Rev. 2010, 110,
6049. (b) Nishio, M. Phys. Chem. Chem. Phys. 2011, 13, 13873. (c) Salo-
nen, L. M.; Ellermann, M.; Diederich, F. Angew. Chem. Int. Ed. 2011, 50,
4808.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment