Accessible Bifunctional Oxy-Tethered Ruthenium(II) Catalysts for Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.8b02157

A concise synthesis of new oxy-tethered ruthenium complexes effective for the asymmetric transfer hydrogenation of aromatic ketones is described. The oxy-tether was constructed via a defluorinative etherification arising from an intramolecular nucleophilic substitution of a perfluorinated phenylsulfonyl substituent. The obtained tethered complexes exhibited desirable catalytic activity and selectivity, especially in the asymmetric transfer hydrogenation of functionalized aromatic ketones. The robustness and rigidity of the tether contribute to their superior catalytic performance relative to the nontethered prototype complex.

Full text of DOI:10.1021/acs.orglett.8b02157

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Accessible Bifunctional Oxy-Tethered Ruthenium(II) Catalysts for
Asymmetric Transfer Hydrogenation
†
‡
‡
‡
‡
Asuka Matsunami, Marika Ikeda, Hitomi Nakamura, Minori Yoshida, Shigeki Kuwata,
,
‡
and Yoshihito Kayaki*
†Department of Chemistry and Biological Science, College of Science and Engineering, Aoyama Gakuin University, 5-10-1
Fuchinobe, Chuo-ku, Sagamihara 252-5258, Japan
‡
Department of Chemical Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology,
2
-12-1-E4-1 O-okayama, Meguro-ku, Tokyo 152-8552, Japan
*
S Supporting Information
ABSTRACT: A concise synthesis of new oxy-tethered
ruthenium complexes effective for the asymmetric transfer
hydrogenation of aromatic ketones is described. The oxy-tether
was constructed via a defluorinative etherification arising from
an intramolecular nucleophilic substitution of a perfluorinated
phenylsulfonyl substituent. The obtained tethered complexes
exhibited desirable catalytic activity and selectivity, especially
in the asymmetric transfer hydrogenation of functionalized
aromatic ketones. The robustness and rigidity of the tether
contribute to their superior catalytic performance relative to
the nontethered prototype complex.
he asymmetric transfer hydrogenation (ATH) of ketones
offers an invaluable and operationally simple approach to
made the tether bridge easily accessible; however, multistep
processes involving activation and protection/deprotection
procedures are still required, as shown in Scheme 1a and
T
chiral alcohols using 2-propanol or formic acid/formate salts as
1
6a−c,7
promising reducing agents. Since the trailblazing work by
1b.
2
Noyori, Ikariya, and co-workers in the mid-1990s, half-
In the course of our synthetic studies on half-sandwich Ru9,
Ir, and Rh complexes derived from N-sulfonyl-1,2-diamines,
the coordination of N-pentafluorobenzenesulfonyl-1,2-
diphenylethylene-1,2-diamine (FsDPEN) was found to facili-
6
sandwich Ru(η -arene) complexes bearing chiral protic amine
ligands and their analogues have received considerable
1f,3
attention as powerful bifunctional catalysts.
As a further
10
advancement of the practical applications, Wills introduced
tate unique transformations. As illustrated by an example in
Scheme 2, the carbon−fluorine bond at the ortho position of
the Fs group was selectively cleaved by an incoming hydroxide
via nucleophilic aromatic substitution to afford an oxaruthe-
4a
4b
innovatively designed modified Ru complexes (1 and 2 in
Figure 1), in which the N-sulfonyl-1,2-diamine ligand is
1
0a
nacycle.
Inspired by this cyclization, we designed a
straightforward synthesis of new oxy-tethered Ru complexes
by intramolecular substitution of the FsDPEN ligand in
hydroxyalkylated arene−Ru(II) dimers (Scheme 1c).
Following the established synthesis of the FsDPEN-
6
10a
coordinated Ru(η -p-cymene) complex (6),
chlorido-
(
amine)−Ru complexes (7a and 7b) modified with a
Figure 1. Examples of bifunctional tethered Ru complexes.
hydroxyethyl or hydroxypropyl chain on the arene moiety
were isolated in high yields of 85% and 91% by mixing the
corresponding [RuCl (η -arene)] and (S,S)-FsDPEN in the
presence of an equimolar amount of triethylamine in refluxing
THF for 2 h (Scheme 3). Analogously to that of prototype
complex 6, the F NMR spectra of 7a and 7b in CD Cl
displayed a set of three signals with relative intensities of 2:1:2,
i.e., −135.9, −153.3, and −162.7 ppm for 7a and −136.8,
6
covalently linked to the η -arene ligand. Compared to the
6
2
2
original nontethered complex, tethered complex 2 offers a
longer lifetime and higher catalytic activity due to its enhanced5
stability from the three-point coordination. Thereafter, Wills,
1
9
6
7
2 2
Mohar, and Takasago have each developed related tethered
1f
amine−Ru complexes (Figure 1). Among them, the oxy-
tethered Ru complex (5) has been well utilized in the ATH of
a range of ketonic substrates including simple alkyl aryl
ketones, α-substituted alkyl aryl ketones, and unsym-
8
7
a
7c
Received: July 10, 2018
7
b
metrical diaryl ketones. The heteroatom junction has indeed
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Synthetic Routes to Tethered Ru Complexes Having an Oxygen- or Nitrogen-Dope Linkage
Scheme 2. Oxydefluorination of FsDPEN via Intramolecular
Nucleophilic Attack
Scheme 3. Synthesis of Chlorido(amine)−Ru Complexes 7a
and 7b
When the oxydefluorination of 7a was examined in the
presence of K CO (1.2 equiv) in THF under reflux conditions
2
3
11
for 4 h (Scheme 4), the desired oxy-tethered Ru complex
8a) was successfully obtained as an orange powder in 63%
isolated yield after reprecipitation from acetonitrile and diethyl
(
1
−
154.2, and −163.8 ppm for 7b. The H NMR spectrum of 7a
showed signals for diastereomeric NH protons at 3.67 and 6.95
ppm, as well as the resonances attributable to the methylene
protons on the tether at 2.96 and 4.05 ppm.
ether. Treatment of 7b with K CO in acetonitrile at 70 °C
2
3
also afforded the corresponding oxy-tethered product (8b) in
1
9
85% isolated yield. Figure 2 shows the F NMR spectrum of
B
DOI: 10.1021/acs.orglett.8b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of Oxy-Tethered Ru Complexes 8a and
complex 8a derived from (S,S)-FsDPEN adopts a three-legged
piano-stool structure around the (R)-Ru center which attaches
8b
6
12
to the η -arene, NH , sulfonylamido, and chlorido ligands.
2
6
The η -arene ligand connects to the ortho-position of the
tetrafluorophenylsulfonyl moiety via the ethyl ether linkage.
There is no significant change in the bond lengths around the
Ru center, between the tethered and nontethered complexes;
however, 8a exhibits a comparatively greater angle of
135.14(10)° between the sulfonamido−Ru bond and the
vector passing from the Ru center to the centroid of the arene
ligand than is seen in 6 (131.01(14)° and 130.39(13)°).
Notably, the N2−S−C1−C2 dihedral angle (55.8(3)°) of 8a is
smaller than that of 6 (60.5(2)° and 63.4(2)°), implying that
the slightly tilted fluoroarene ring in 8a will compensate for the
strain caused by the junction.
The ATH of acetophenone (S1) using 0.1 mol % of oxy-
tethered complex 8a in an azeotropic mixture of formic acid
and triethylamine at 60 °C for 15 h gave (S)-1-phenylethanol
(
P1) in 97% yield with 96% ee (Table 1, run 1). Comparable
activity with a slightly lower enantioselectivity of 94% ee was
obtained with 8b (run 2). When nontethered (S,S)-FsDPEN
analogue 6 was employed under the same conditions, the yield
Table 1. Asymmetric Transfer Hydrogenation of
a
Acetophenones
Figure 2. 19F NMR spectra of 7a (a) and 8a (b) in DMSO-d6.
8
a, which exhibits four separated peaks as a result of the
1
defluorination of the Fs unit. The H and two-dimensional
1
1
1
13
NMR data ( H− H COSY and H− C HMQC) of 8a are
also consistent with the defluorinated ethereal linkage (Figures
S15, S16, and S19). The diastereotopic methylene protons on
the alkyl chain appeared as four independent multiplet signals
in the 2.69−5.09 ppm region in the spectrum of tethered
complex 8a, which is unlike the set of two triplets observed for
the nontethered complex 7a. For both 8a and 8b, a mixture of
diastereomers with the opposite chirality at the Ru center were
not observed.
Recrystallization by slow diffusion of diethyl ether into an
acetonitrile solution gave yellow crystals of oxy-tethered
complexes 8a and 8b, that were suitable for X-ray
crystallography. As shown in Figure 3, new oxy-tethered Ru
temp
time
(h)
yield
b
c
run ketone cat.
S/C
(°C)
(%)
ee (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
S1
8a
8b
6
8a
6
8a
8a
8b
8a
8a
8a
8b
8a
8a
8a
1000
1000
1000
300
300
300
300
300
500
1000
1000
1000
500
1000
50
60
60
60
40
40
40
40
40
30
60
30
30
60
60
0
15
15
24
24
24
24
24
24
24
3
97
99
52
85
67
100
97
90
96
>99
79
96 (S)
94 (S)
94 (S)
86 (S)
92 (S)
86 (S)
88 (S)
90 (S)
96 (S)
80 (R)
90 (R)
90 (R)
96 (R)
45 (R)
60 (R)
S2
S3
S4
S5
S6
0
1
2
3
4
5
24
24
24
3
88
d
S7
S8
100
100
100
24
a
Standard reaction conditions (S/C = 1000): the reaction was carried
out with substrate (2 mmol) and catalyst (0.002 mmol) in 1 mL of a
b
1
5
:2 azeotropic mixture of HCO H and Et N. Determined by H
2 3
NMR spectroscopy using 1,3,5-trimethoxybenzene (runs 1−5),
durene (runs 6−13), or benzotrifluoride (runs 14 and 15) as internal
c
standards. The ee values were determined by chiral HPLC analysis
Figure 3. X-ray crystal structure of oxy-tethered Ru complex 8a. The
hydrogen atoms, except for the coordinating amine protons, are
omitted for clarity. Thermal ellipsoids are shown at the 30%
probability level.
on Chiralcel OD-H and OJ-H columns and COSMOSIL CHiRAL 5A
d
and 5B columns. Conditions: HCO H (3 equiv) and HCO K (1
2
2
equiv) were used in a mixed solvent of EtOAc (1.5 mL) and water (2
mL).
C
DOI: 10.1021/acs.orglett.8b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of the alcohol product decreased dramatically to 52% (run 3);
however the enantioselectivity was almost identical (94% ee).
Although there are limited studies about FsDPEN-
and functionalized acetophenones. The oxy-tethered structure
could be easily obtained by a short synthesis involving a highly
selective intramolecular defluorinative aromatic substitution.
Comparison of their catalytic performance to that of
nontethered analogue 6 demonstrated the practical utility of
8a and 8b as ATH catalysts. The catalytic properties could be
finely tuned by altering the length of the tether. Further
structural modifications of the tethered complexes and an
exploration of their catalytic applications are in progress.
1
0
complexes, some positive effects of FsDPEN compared to
the original tosyl analogue have been disclosed, particularly in
13
the ATH of functionalized ketones. Desirable results were
also obtained in the ATH of substituted acetophenones using
fluorinated oxy-tethered Ru complexes 8a and 8b. In the
reduction of sterically congested acetophenone derivatives of
2
-methoxy-, 2-chloro-, and 2-bromoacetophenone (S2−S4),
which usually exhibit difficulty in being enantioselectively
reduced,
ASSOCIATED CONTENT
Supporting Information
■
5
b,14
the oxy-tethered complexes (8a and 8b) provided
*
S
the corresponding (S)-alcohols (P2−P4) in excellent yields
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02157.
with satisfactory enantioselectivities (86−92% ee; runs 4 and
6
4
−8) after the reaction with a substrate/catalyst ratio of 300 at
0 °C for 24 h. In contrast, the ATH of S2 using alkyl-tethered
Experimental details, characterization data, and copies of
NMR spectra of the products (PDF)
complex 2 was reported to give P2 with a somewhat lower
5b
enantioselectivity (79% ee) under identical conditions. The
yield of P2 decreased to 67% when nontethered complex 6,
which has an η -p-cymene ligand, was used for the ATH of S2
Accession Codes
6
CCDC 1855028−1855029 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
run 5). These results highlight the vital contribution of oxy-
tethered catalysts with appropriate structural tuning for
achieving high activities and enantioselectivities.
Other functionalized ketones including α-cyano-, α-
hydroxy-, and α-chloroacetophenone (S5−S7) were also
transformed into the desired alcohols in a good enantiose-
lective manner using tethered complexes 8a and 8b (runs 9−
AUTHOR INFORMATION
■
1
3). The enantioselectivity of the ATH of α-cyanoacetophe-
Corresponding Author
*E-mail: ykayaki@o.cc.titech.ac.jp.
ORCID
none (S5) with 8a (run 9; 96% ee, S form) was modestly
better than that with the related nontethered FsDPEN−Ir
complex (94% ee) and oxy-tethered complex 5 (95% ee).
13f
7a
The ATH of α-hydroxyacetophenone (S6) using 8a proceeded
slightly faster (quantitative yield after 3 h) than that with
commercial oxy-tethered complex 5 (98% yield after 5 h) and
resulted in good enantioselectivity of 80% ee (R) at 60 °C (run
Shigeki Kuwata: 0000-0002-3165-9882
Yoshihito Kayaki: 0000-0002-4685-8833
Notes
1
0). The enantioselectivity was increased to 90% ee when the
The authors declare no competing financial interest.
reaction was performed at 30 °C (run 11). Related complex 8b
with a longer tether provided a similar stereochemical result
with a higher yield (88% yield and 90% ee; run 12). α-
ACKNOWLEDGMENTS
■
This study was financially supported by JSPS KAKENHI Grant
Number 18K14225 and in part by a Grant for Basic Science
Research Projects from The Sumitomo Foundation and by a
Grant for Engineering Research from Mizuho Foundation for
the Promotion of Sciences and by a Sasakawa Scientific
Research Grant from the Japan Science Society. We also
acknowledge Takasago International Corporation for the
generous gifts of (S,S)-1,2-diphenylethylenediamine.
Haloketone S7 was reduced by a combination of HCO H and
2
HCO K in a mixed solvent of EtOAc/H O using the
2
2
7c
established method to prevent side reactions accompanied
by formylation of the halogenated substrate in the azeotropic
mixture of HCO H and Et N.
2
3
The ATH of 1,1,1-trifluoroacetophenone (S8) usually gives
-phenyl-2,2,2-trifluoroethanol (P8) with relatively low
1
enantioselectivity due to poor discrimination of the prochiral
5b,15
face of fluoroalkyl ketone.
By using 0.1 mol % of 8a as the
REFERENCES
■
catalyst at 60 °C, (R)-P8 was obtained quantitatively after 3 h
with a moderate ee of 45% (run 14), and the enantioselectivity
was significantly lower (22% ee) when nontethered FsDPEN-
complex 6 was used. The reaction proceeded even at 0 °C,
leading to a higher ee of 60% (run 15). In the ATH with a
nontethered original TsDPEN−Ru complex under the same
(
1) (a) Ito, J.; Nishiyama, H. Recent topics of transfer hydro-
genation. Tetrahedron Lett. 2014, 55, 3133−3146. (b) Sues, P. E.;
Demmans, K. Z.; Morris, R. H. Rational development of iron catalysts
for asymmetric transfer hydrogenation. Dalton Trans. 2014, 43,
7650−7667. (c) Foubelo, F.; Najera, C.; Yus, M. Catalytic asymmetric
́
transfer hydrogenation of ketones: recent advances. Tetrahedron:
Asymmetry 2015, 26, 769−790. (d) Wang, D.; Astruc, D. The Golden
Age of Transfer Hydrogenation. Chem. Rev. 2015, 115, 6621−6686.
15
conditions, the enantioselectivity remained below 45% ee.
For the ATH reactions of S8 with modified-DPEN catalysts
(
e) Wu, X.; Xiao, J. In Comprehensive Organic Synthesis II, 2nd ed.;
reported to date, the maximum enantioselectivity of 56% ee
5
b
Knochel, P., Molander, G. A., Eds.; Elsevier: Amsterdam, 2015; Vol. 8,
pp 198−273. (f) Nedden, H. G.; Zanotti-Gerosa, A.; Wills, M. The
Development of Phosphine-Free “Tethered” Ruthenium(II) Catalysts
for the Asymmetric Reduction of Ketones and Imines. Chem. Rec.
was achieved by using an alkyl-tethered complex; thus, the
present fluorinated oxy-tethered complex 8a was convincingly
shown to be effective for the ATH.
In summary, we have developed a new synthetic route to
oxy-tethered Ru complexes utilizing (S,S)-FsDPEN derivatives
as highly efficient and reliable catalysts for the ATH of simple
2
016, 16, 2623−2643. (g) Matsunami, A.; Kayaki, Y. Upgrading and
expanding the scope of homogeneous transfer hydrogenation.
Tetrahedron Lett. 2018, 59, 504−513.
D
DOI: 10.1021/acs.orglett.8b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
6
(2) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
SO N(Me)-(CH ) (η -Aryl) Conjugate Ligands for Asymmetric
2 2 n
Asymmetric Transfer Hydrogenation of Aromatic Ketones Catalyzed
by Chiral Ruthenium(II) Complexes. J. Am. Chem. Soc. 1995, 117,
Transfer Hydrogenation of Aryl Ketones. Adv. Synth. Catal. 2015,
357, 2540−2546. (d) Cotman, A. E.; Cahard, D.; Mohar, B.
7562−7563. (b) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
Stereoarrayed CF -Substituted 1,3-Diols by Dynamic Kinetic
3
Noyori, R. Ruthenium(II)-Catalyzed Asymmetric Transfer Hydro-
genation of Ketones Using a Formic Acid-Triethylamine Mixture. J.
Am. Chem. Soc. 1996, 118, 2521−2522.
Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydro-
genation. Angew. Chem., Int. Ed. 2016, 55, 5294−5298. (e) Rast, S.;
Modec, B.; Stephan, M.; Mohar, B. γ-Sultam-cored N,N-ligands in the
ruthenium(II)-catalyzed asymmetric transfer hydrogenation of aryl
ketones. Org. Biomol. Chem. 2016, 14, 2112−2120. (f) Jeran, M.;
Cotman, A. E.; Stephan, M.; Mohar, B. Stereopure Functionalized
Benzosultams via Ruthenium(II)-Catalyzed Dynamic Kinetic Reso-
lutionAsymmetric Transfer Hydrogenation. Org. Lett. 2017, 19,
2042−2045. (g) Cotman, A. E.; Modec, B.; Mohar, B. Stereoarrayed
2,3-Disubstituted 1-Indanol via Ruthenium(II)-Catalyzed Dynamic
Kinetic ResolutionAsymmetric Transfer Hydrogenation. Org. Lett.
2018, 20, 2921−2924.
(7) (a) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.;
Saito, N.; Kayaki, Y.; Ikariya, T. Oxo-tethered Ruthenium(II)
Complex as a Bifunctional Catalyst for Asymmetric Transfer
Hydrogenation and H2 Hydrogenation. J. Am. Chem. Soc. 2011,
133, 14960−14963. (b) Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki,
Y.; Ikariya, T. Efficient Access to Chiral Benzhydrols via Asymmetric
Transfer Hydrogenation of Unsymmetrical Benzophenones with
Bifunctional Oxo-tethered Ruthenium Catalysts. J. Am. Chem. Soc.
2016, 138, 10084−10087. (c) Yuki, Y.; Touge, T.; Nara, H.;
Matsumura, K.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T. Selective
Asymmetric Transfer Hydrogenation of α-Substituted Acetophenones
with Bifunctional Oxo-tethered Ruthenium(II) Catalysts. Adv. Synth.
Catal. 2018, 360, 568−574.
(8) (a) Komiyama, M.; Itoh, T.; Takeyasu, T. Scalable Ruthenium-
Catalyzed Asymmetric Synthesis of a Key Intermediate for the β2-
Adrenergic Receptor Agonist. Org. Process Res. Dev. 2015, 19, 315−
319. (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. Evolution of a
Manufacturing Route to Omarigliptin, A Long-Acting DPP-4
Inhibitor for the Treatment of Type 2 Diabetes. Org. Process Res.
Dev. 2015, 19, 1760−1768. (c) Wang, B.; Zhou, H.; Lu, G.; Liu, Q.;
Jiang, X. Bifunctional Oxo-tethered Ruthenium Complex Catalyzed
Asymmetric Transfer Hydrogenation of Aryl N-Heteroaryl Ketones.
Org. Lett. 2017, 19, 2094−2097. (d) Ashley, E. R.; Sherer, E. C.; Pio,
B.; Orr, R. K.; Ruck, R. T. Ruthenium-Catalyzed Dynamic Kinetic
Resolution Asymmetric Transfer Hydrogenation of β-Chromanones
by an Elimination-Induced Racemization Mechanism. ACS Catal.
2017, 7, 1446−1451. (e) Sun, G.; Zhou, Z.; Luo, Z.; Wang, H.; Chen,
L.; Xu, Y.; Li, S.; Jian, W.; Zeng, J.; Hu, B.; Han, X.; Lin, Y.; Wang, Z.
Highly Enantioselective Synthesis of syn-β-Hydroxy α-Dibenzylamino
Esters via DKR Asymmetric Transfer Hydrogenation and Gram-Scale
Preparation of Droxidopa. Org. Lett. 2017, 19, 4339−4342.
(9) (a) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Aerobic Oxidative
Kinetic Resolution of Racemic Secondary Alcohols with Chiral
Bifunctional Amido Complexes. Angew. Chem., Int. Ed. 2008, 47,
2447−2449. (b) Shirai, S.; Nara, H.; Kayaki, Y.; Ikariya, T.
Remarkable Positive Effect of Silver Salts on Asymmetric Hydro-
genation of Acyclic Imines with Cp*Ir Complexes Bearing Chiral N-
Sulfonylated Diamine Ligands. Organometallics 2009, 28, 802−809.
(c) Kamezaki, S.; Akiyama, S.; Kayaki, Y.; Kuwata, S.; Ikariya, T.
Asymmetric nitrile-hydration with bifunctional ruthenium catalysts
bearing chiral N-sulfonyldiamine ligands. Tetrahedron: Asymmetry
2010, 21, 1169−1172. (d) Moritani, J.; Hasegawa, Y.; Kayaki, Y.;
Ikariya, T. Tetrahedron Lett. 2014, 55, 1188−1191. (e) Moritani, J.;
Kayaki, Y.; Ikariya, T. Advantageous asymmetric ketone reduction
with a competitive hydrogenation/transfer hydrogenation system
using chiral bifunctional iridium catalysts. RSC Adv. 2014, 4, 61001−
61004. (f) Matsunami, A.; Kayaki, Y.; Ikariya, T. Enhanced Hydrogen
Generation from Formic Acid by Half-Sandwich Iridium(III)
Complexes with Metal/NH Bifunctionality: A Pronounced Switch
from Transfer Hydrogenation. Chem. - Eur. J. 2015, 21, 13513−
13517. (g) Matsunami, A.; Kuwata, S.; Kayaki, Y. A Bifunctional
(3) (a) Ikariya, T.; Blacker, A. J. Asymmetric Transfer Hydro-
genation of Ketones with Bifunctional Transition Metal-Based
Molecular Catalysts. Acc. Chem. Res. 2007, 40, 1300−1308. (b) Ikariya,
T. Chemistry of Concerto Molecular Catalysis Based on the Metal/
MH Bifunctionality. Bull. Chem. Soc. Jpn. 2011, 84, 1−16. (c) Zhao,
B.; Han, Z.; Ding, K. The N-H Functional Group in Organometallic
Catalysis. Angew. Chem., Int. Ed. 2013, 52, 4744−4788. (d) Eisenstein,
O.; Crabtree, R. H. Outer sphere hydrogenation catalysis. New J.
Chem. 2013, 37, 21−27. (e) Khusnutdinova, J. R.; Milstein, D. Metal-
Ligand Cooperation. Angew. Chem., Int. Ed. 2015, 54, 12236−12273.
(f) Dub, P. A.; Gordon, J. C. The mechanism of enantioselective
ketone reduction with Noyori and Noyori-Ikariya bifunctional
catalysts. Dalton Trans. 2016, 45, 6756−6781.
(4) (a) Hannedouche, J.; Clarkson, G. J.; Wills, M. A New Class of
“
Tethered” Ruthenium(II) Catalyst for Asymmetric Transfer Hydro-
genation Reactions. J. Am. Chem. Soc. 2004, 126, 986−987.
b) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. A Class
(
of Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenations
of Ketones. J. Am. Chem. Soc. 2005, 127, 7318−7319.
(5) (a) Soni, R.; Jolley, K. E.; Clarkson, G. J.; Wills, M. Direct
Formation of Tethered Ru(II) Catalysts Using Arene Exchange. Org.
k, V.; Zanotti-
Lett. 2013, 15, 5110−5113. (b) Hodgkinson, R.; Jurcí
̌
Gerosa, A.; Nedden, H. G.; Blackaby, A.; Clarkson, G. J.; Wills, M.
Synthesis and Catalytic Applications of an Extended Range of
6
Tethered Ruthenium(II)/η -Arene/Diamine Complexes. Organo-
metallics 2014, 33, 5517−5524. (c) Parekh, V.; Ramsden, J. A.;
Wills, M. Ether-tethered Ru(II)/TsDPEN complexes; synthesis and
applications to asymmetric transfer hydrogenation. Catal. Sci. Technol.
2
012, 2, 406−414. (d) Soni, R.; Hall, T. H.; Mitchell, B. P.; Owen, M.
R.; Wills, M. Asymmetric Reduction of Electron-Rich Ketones with
Tethered Ru(II)/TsDPEN Catalysts Using Formic Acid/Triethyl-
amine or Aqueous Sodium Formate. J. Org. Chem. 2015, 80, 6784−
6793. (e) Forshaw, S.; Matthews, A. J.; Brown, T. J.; Diorazio, L. J.;
Williams, L.; Wills, M. Asymmetric Transfer Hydrogenation of 1,3-
Alkoxy/Aryloxy Propanones Using Tethered Arene/Ru(II)/TsDPEN
Complexes. Org. Lett. 2017, 19, 2789−2792. (f) Soni, R.; Jolley, K. E.;
Gosiewska, S.; Clarkson, G. J.; Fang, Z.; Hall, T. H.; Treloar, B. N.;
Knighton, R. C.; Wills, M. Synthesis of Enantiomerically Pure and
Racemic Benzyl-Tethered Ru(II)/TsDPEN Complexes by Direct
Arene Substitution: Further Complexes and Applications. Organo-
metallics 2018, 37, 48−64. (g) Vyas, V. K.; Knighton, R. C.; Bhanage,
B. M.; Wills, M. Combining Electronic and Steric Effects to Generate
Hindered Propargylic Alcohols in High Enantiomeric Excess. Org.
Lett. 2018, 20, 975−978. (h) Chew, R. J.; Wills, M. Ruthenium-
Catalyzed Asymmetric Reduction of Isoxazolium Salts: Access to
4
Optically Active Δ -Isoxazolines. J. Org. Chem. 2018, 83, 2980−2985.
(
i) Hodgkinson, R.; Jurcík, V.; Nedden, H.; Blackaby, A.; Wills, M. An
̌
alternative route to tethered Ru(II) transfer hydrogenation catalysts.
Tetrahedron Lett. 2018, 59, 930−933. (j) Chen, F.; Romero-Canelon
́
,
I.; Soldevila-Barreda, J. J.; Song, J.-I.; Coverdale, J. P. C.; Clarkson, G.
J.; Kasparkova, J.; Habtemariam, A.; Wills, M.; Brabec, V.; Sadler, P. J.
Transfer Hydrogenation and Antiproliferative Activity of Tethered
Half-Sandwich Organoruthenium(II) Catalysts. Organometallics 2018,
3
(
7, 1555−1566.
6) (a) Kisic, A.; Stephan, M.; Mohar, B. Asymmetric Transfer
̌
́
Hydrogenation of 1-Naphthyl Ketones by an ansa-Ru(II) Complex of
a DPEN-SO N(Me)-(CH ) (η -p-Tol) Combined Ligand. Org. Lett.
6
2
2 2
2
013, 15, 1614−1617. (b) Kisi
c, A.; Stephan, M.; Mohar, B. ansa-
̌ ́
6
Ruthenium(II) Complexes of DPEN-SO N(Me)-(CH ) (η -aryl)
2
2 n
Conjugate Ligands for Asymmetric Transfer Hydrogenation of Aryl
Ketones. Adv. Synth. Catal. 2014, 356, 3193−3198. (c) Kisic, A.;
Stephan, M.; Mohar, B. ansa-Ruthenium(II) Complexes of DPEN-
̌
́
E
DOI: 10.1021/acs.orglett.8b02157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Iridium Catalyst Modified for Persistent Hydrogen Generation from
Formic Acid: Understanding Deactivation via Cyclometalation of a
1
(
,2-Diphenylethylenediamine Motif. ACS Catal. 2017, 7, 4479−4484.
10) (a) Dub, P. A.; Wang, H.; Matsunami, A.; Gridnev, I. D.;
Kuwata, S.; Ikariya, T. C−F Bond Breaking through Aromatic
Nucleophilic Substitution with a Hydroxy Ligand Mediated via Water
Bifunctional Activation. Bull. Chem. Soc. Jpn. 2013, 86, 557−568.
(
b) Matsunami, A.; Kayaki, Y.; Kuwata, S.; Ikariya, T. Nucleophilic
Aromatic Substitution in Hydrodefluorination Exemplified by
Hydridoiridium(III) Complexes with Fluorinated Phenylsulfonyl-
1
1
(
,2-diphenylethylenediamine Ligands. Organometallics 2018, 37,
958−1969.
11) The intramolecular oxidefluorination in Scheme 4 should be
conducted in the absence of water to prevent the formation of oxa-
ruthenacycles, as demonstrated in ref 10a.
(
12) The crystal structure of the oxy-tethered complex 8b is shown
in Figure S1 of the Supporting Information.
13) (a) Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.;
(
Wagner, A.; Mioskowski, C. Highly enantioselective synthesis via
6
dynamic kinetic resolution under transfer hydrogenation using Ru(η -
arene)-N-perfluorosulfonyl-1,2-diamine catalysts: a first insight into
the relationship of the ligand’s pK and the catalyst activity. Chem.
a
Commun. 2001, 24, 2572−2573. (b) Limanto, J.; Krska, S. W.;
Dorner, B. T.; Vazquez, E.; Yoshikawa, N.; Tan, L. Dynamic Kinetic
Resolution: Asymmetric Transfer Hydrogenation of α-Alkyl-Sub-
stituted β-Ketoamides. Org. Lett. 2010, 12, 512−515. (c) Liu, Z.;
Shultz, C. S.; Sherwood, C. A.; Krska, S.; Dormer, P. G.; Desmond,
R.; Lee, C.; Sherer, E. C.; Shpungin, J.; Cuff, J.; Xu, F. Highly
enantioselective synthesis of anti aryl β-hydroxy α-amino esters via
DKR transfer hydrogenation. Tetrahedron Lett. 2011, 52, 1685−1688.
(
d) Villacrez, M.; Somfai, P. Enantioselective synthesis of anti-β-
amido-α-hydroxy esters via asymmetric transfer hydrogenation
coupled with dynamic kinetic resolution. Tetrahedron Lett. 2013, 54,
5
266−5268. (e) Soltani, O.; Ariger, M. A.; Carreira, E. M. Transfer
Hydrogenation in Water: Enantioselective, Catalytic Reduction of
(
(
E)-β,β-Disubstituted Nitroalkenes. Org. Lett. 2009, 11, 4196−4198.
f) Soltani, O.; Ariger, M. A.; Vazquez-Villa, H.; Carreira, E. M.
́
Transfer Hydrogenation in Water: Enantioselective, Catalytic
Reduction of α-Cyano and α-Nitro Substituted Acetophenones.
Org. Lett. 2010, 12, 2893−2895.
(14) (a) Zheng, L.-S.; Llopis, Q.; Echeverria, P.-G.; Ferard, C.;
́
Guillamot, G.; Phansavath, P.; Ratovelomanana-Vidal, V. Asymmetric
Transfer Hydrogenation of (Hetero)arylketones with Tethered
Rh(III)-N-(p-Tolylsulfonyl)-1,2-diphenylethylene-1,2-diamine Com-
plexes: Scope and Limitations. J. Org. Chem. 2017, 82, 5607−5615.
(
b) Zimbron, J. M.; Dauphinais, M.; Charette, A. B. Noyori-Ikariya
catalyst supported on tetraarylphosphonium salt for asymmetric
transfer hydrogenation in water. Green Chem. 2015, 17, 3255−3259.
(
c) Echeverria, P.-G.; Ferard, C.; Phansavath, P.; Ratovelomanana-
́
Vidal, V. Synthesis, characterization and use of a new tethered Rh(III)
complex in asymmetric transfer hydrogenation of ketones. Catal.
Commun. 2015, 62, 95−99.
(15) (a) Slungård, S. V.; Krakeli, T.-A.; Thvedt, T. H. K.; Fuglseth,
E.; Sundby, E.; Hoff, B. H. Investigation into the enantioselection
mechanism of ruthenium-arene-diamine transfer hydrogenation
catalysts using fluorinated substrates. Tetrahedron 2011, 67, 5642−
̌
650. (b) Sterk, D.; Stephan, M.; Mohar, B. Highly Enantioselective
5
Transfer Hydrogenation of Fluoroalkyl Ketones. Org. Lett. 2006, 8,
5935−5938.
F
DOI: 10.1021/acs.orglett.8b02157
Org. Lett. XXXX, XXX, XXX−XXX