Enhancing effects of salt formation on catalytic activity and enantioselectivity for asymmetric hydrogenation of isoquinolinium salts by dinuclear halide-bridged iridium complexes bearing chiral diphosphine ligands

Article abstract of DOI:10.1002/chem.201405408

Asymmetric hydrogenation of 1- and 3-substituted and 1,3-disubstituted isoquinolinium chlorides using triply halide-bridged dinuclear iridium complexes [{Ir(H)(diphosphine)} ₂(μ -Cl)₃]Cl has been achieved by the strategy of HCl salt formation of isoquinolines to afford the corresponding chiral 1,2,3,4-tetrahydroisoquinolines (THIQs) in high yields and with excellent enantioselectivities after simple basic workup. The effects of salt formation have been investigated by time-course experiments, which revealed that the generation of isoquinolinium chlorides clearly prevented formation of the catalytically inactive dinuclear trihydride complex, which was readily generated in the catalytic reduction of salt-free isoquinoline substrates. Based on mechanistic investigations, including by 1H and ³¹P{¹H} NMR studies and the isolation and characterization of several intermediates, the function of the chloride anion of the isoquinolinium chlorides has been elucidated, allowing us to propose a new outer-sphere mechanism involving coordination of the chloride anion of the substrates to an iridium dihydride species along with a hydrogen bond between the chloride ligand and the N-H proton of the substrate salt.

Full text of DOI:10.1002/chem.201405408

DOI: 10.1002/chem.201405408
Full Paper
&
Asymmetric Catalysis |Hot Paper|
Enhancing Effects of Salt Formation on Catalytic Activity and
Enantioselectivity for Asymmetric Hydrogenation of
Isoquinolinium Salts by Dinuclear Halide-Bridged Iridium
Complexes Bearing Chiral Diphosphine Ligands
Yusuke Kita, Kenta Yamaji, Kosuke Higashida, Kandula Sathaiah, Atuhiro Iimuro, and
Kazushi Mashima*[a]
Abstract: Asymmetric hydrogenation of 1- and 3-substituted
and 1,3-disubstituted isoquinolinium chlorides using triply
halide-bridged dinuclear iridium complexes [{Ir(H)(diphosphi-
ne)}2(m-Cl)3]Cl has been achieved by the strategy of HCl salt
formation of isoquinolines to afford the corresponding chiral
1,2,3,4-tetrahydroisoquinolines (THIQs) in high yields and
with excellent enantioselectivities after simple basic work-
up. The effects of salt formation have been investigated by
time-course experiments, which revealed that the generation
of isoquinolinium chlorides clearly prevented formation of
the catalytically inactive dinuclear trihydride complex, which
was readily generated in the catalytic reduction of salt-free
isoquinoline substrates. Based on mechanistic investigations,
including by 1H and 31P{1H} NMR studies and the isolation
and characterization of several intermediates, the function of
the chloride anion of the isoquinolinium chlorides has been
elucidated, allowing us to propose a new outer-sphere
mechanism involving coordination of the chloride anion of
the substrates to an iridium dihydride species along with
a hydrogen bond between the chloride ligand and the N-H
proton of the substrate salt.
chiral ruthenium,[4] rhodium,[5] and palladium[6] complexes have
also been shown to be effective. Concerning the iridium cata-
lyst system, novel and efficient strategies have been developed
through chemically activating catalysts as well as substrates for
the successful asymmetric hydrogenation of N-heteroaromat-
ics.[7] Most research approaches have been directed towards
activating the catalysts.[8–10] The most common protocol is to
add iodine or a halide-containing species such as 1-bromo-3-
chloro-5,5-dimethylhydantoin to the catalyst precursors to oxi-
dize IrI precursors to catalytically active IrIII species.[11] The
second approach is the addition of secondary amines that are
converted to amido ligands that bind at the catalytically active
iridium species through an outer-sphere mechanism.[12] On the
other hand, activation of substrates has recently been target-
ed. Pre-activation of substrates by adding Brønsted acids such
as HCl and trifluoroacetic acid (Scheme 1a)[9d,13,14] and protect-
ing agents such as benzyl halides and chloroformates to N-het-
eroaromatics (Scheme 1b)[15] produces the corresponding salts,
the aromaticity and coordination ability of which are thereby
modified. Recently, we demonstrated that HX salts of quino-
lines, isoquinolines, and pyridines represented pre-activated
substrates suitable for asymmetric hydrogenation, showing en-
hanced reactivity and/or enantioselectivity when using halide-
bridged dinuclear iridium complex [{Ir(H)(diphosphine)}2(m-
Cl)3]Cl (1; Scheme 2) bearing chiral diphosphine ligands.[13] In
this context, we directed our efforts towards delineating
a mechanism to rationalize the enhanced catalytic activity and
enantioselectivity in the asymmetric hydrogenation of N-het-
Introduction
Asymmetric hydrogenation of unsaturated organic compounds
has been established as one of the most efficient synthetic
methods for obtaining chiral substrates.[1] Among various unsa-
turated substrates, the asymmetric hydrogenation of heteroar-
enes, particularly N-heteroarenes such as pyridines, quinolines,
isoquinolines, quinoxalines, pyrroles, and indoles, has attracted
recent interest since this provides a straightforward route to
a wide range of enantiomerically pure saturated N-heterocy-
cles, which are abundant motifs in many biologically active
compounds.[2] Since the pioneering work by Murata, who re-
ported the asymmetric hydrogenation of 2-methylquinoxaline
using an Rh/(S,S)-DIOP catalyst system,[3] development of this
attractive reaction paradigm has been limited owing to the
high stability of N-heteroarenes and the strong coordination
ability of both N-heteroarenes and their hydrogenated N-het-
erocycles to the catalytically active metal center. Iridium com-
plexes have typically been employed as effective catalysts for
the asymmetric hydrogenation of N-heteroaromatics, although
[a] Dr. Y. Kita, K. Yamaji, K. Higashida, Dr. K. Sathaiah, A. Iimuro,
Prof. Dr. K. Mashima
Department of Chemistry, Graduate School of Engineering Science
Osaka University, CREST
Toyonaka, Osaka 560-8531 (Japan)
E-mail: mashima@chem.es.osaka-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405408.
Chem. Eur. J. 2015, 21, 1915 – 1927
1915
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
hydrogenations of isoquinolinium salts, including a screening
of counter anions of the salt substrates, the wider substrate
scope, and mechanistic studies, in order to better understand
the significant effects of the use of salt substrates.
Results and Discussion
Anion effects on asymmetric hydrogenation of isoquinolini-
um salts by a chloride-bridged dinuclear iridium catalyst
(S)-1a
Scheme 1. Asymmetric hydrogenation of N-heteroaromatics through sub-
strate activation by (a) the HX salt formation method and (b) the alkoxycar-
bonylation and benzylation method.
With the aim of elucidating anion effects on the asymmetric
hydrogenation of isoquinolinium salts, we first studied the re-
actions of various 3-phenylisoquinolinium salts (2a-HX) cata-
lyzed by a triply-chloride-bridged dinuclear iridium complex
(S)-1a. The reaction conditions were 30 atm H2; 1,4-dioxane/
isopropyl alcohol (10:1); 20 h; 308C, and the results are sum-
marized in Table 1. We first examined the effects of chloride,
bromide, and iodide anions using the same chloride catalyst
Table 1. Screening of counter anions in the asymmetric hydrogenation of
2a-HX.[a]
Entry
X
Conv.[b] (%)
ee[c] (%)
Scheme 2. Chiral dinuclear iridium complexes.
1
2
3
4
5
6
7
Cl
Br
I
OTf
OCOCF3
OTs
NO3
>99
38
65
66
>99
98
85
52
38
68
73
84
84
eroaromatics. For the present work, we selected isoquinolines
as model substrates, which show clear effects of salt formation
when catalyst 1 is used for asymmetric hydrogenation. Specifi-
cally, hydrogenation of 3-substituted isoquinolinium salts pro-
vides easier access to chiral 3-substituted 1,2,3,4-tetrahydroiso-
quinolines (THIQs) compared with other asymmetric hydroge-
nations of salt-free substrates[15c] as well as traditional synthetic
methods,[16] and allows easy work-up by simple treatment with
base to remove HX, as described in our previous report
(Scheme 3).[13b] Moreover, isoquinolines have been regarded as
some of the most challenging substrates for asymmetric hy-
drogenation.[15,17] Herein, we report full details of asymmetric
>99
[a] Reaction conditions:
(0.24 mmol), (S)-1a (2.4 mmol), and 1,4-dioxane/iPrOH (10:1, 3 mL), under
H2 (30 atm), was heated at 308C for 20 h. [b] Determined by H NMR anal-
ysis. [c] Determined by HPLC analysis.
A mixture of 3-phenylisoquinolinium salt
1
(S)-1a, since we previously observed that the three bridging
chloride ligands of (S)-1a remained intact and did not undergo
halide-exchange with HBr and HI or with bromide and iodide
salt substrates.[13a] Asymmetric hydrogenation of 2a-HCl fol-
lowed by basic work-up afforded the corresponding product
(S)-3a with >99% conversion and 85% ee (entry 1), whereas
asymmetric hydrogenations of 2a-HBr and 2a-HI resulted in
lower conversions and rather low enantioselectivities (entries 2
and 3). The triflic acid (TfOH) salt of 3-phenylisoquinoline (2a-
HOTf) was hydrogenated with moderate conversion and 68%
ee (entry 4), and the trifluoroacetic acid (TFA) salt was fully hy-
drogenated to give the product with 73% ee (entry 5). Notably,
the tosylate (2a-HOTs) and nitrate (2a-HNO3) were suitable
substrates to produce (S)-3a with high enantioselectivity (84%
ee) (entries 6 and 7), almost matching that with 2a-HCl. Thus,
enantioselectivity was affected by the counter anion of the iso-
quinolinium salts, and we selected the HCl salt as the best in
Scheme 3. Comparison of asymmetric hydrogenations of isoquinolinium
salts and isoquinoline catalyzed by a dinuclear iridium complex.[13b]
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1916
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
terms of its high conversion and enantioselectivity as well as
its ease of handling and simple product recovery by basic
work-up.
Table 2. Asymmetric hydrogenation of 1-substituted isoquinolinium
salts.[a]
Substrate scope for asymmetric hydrogenation of isoquino-
linium chlorides
Entry
R
Conv.[b] (%)
ee[c] (%)
96 (S)
We checked the generality of the salt formation strategy in
asymmetric hydrogenations of 3-substituted and 1-substituted
isoquinolinium chlorides using iridium complex (S)-1d bearing
(S)-DIFLUORPHOS as a catalyst in a solvent of 1,4-dioxane/iso-
propyl alcohol (10:1).[13b] We have previously reported the
scope of the asymmetric hydrogenation of 3-substituted iso-
quinolinium chlorides, as outlined in Equation (1).[13b] 3-Aryl-
substituted substrates were hydrogenated with high enantio-
selectivity regardless of the electronic effect of substituents on
the phenyl group. In the case of sterically congested sub-
strates, moderate enantioselectivity was observed. In addition,
isoquinolinium chlorides bearing benzyl and cyclohexyl groups
were also good substrates for the asymmetric hydrogenation.
We found that 1-aryl isoquinolinium chlorides could be hy-
1
2
phenyl
3h
3i
99
99
Ref. [13b]
Ref. [13b]
98 (+)
3
4
5
3j
3k
3l
98[d]
98[d]
99
97 (+)
97 (+)
99 (S)
this work
this work
Ref. [13b]
6
3m
3n
3o
98[d]
94[d]
75
96 (ꢀ)
96 (R)
96 (R)
this work
this work
Ref. [13b]
7[e]
8
9[f]
10
3p
3q
63
99
85 (S)
Ref. [13b]
Ref. [13b]
79 (ꢀ)
11
3r
98
91 (S)
Ref. [13b]
[a] Reaction conditions: A mixture of isoquinolinium salt (0.24 mmol), (S)-
1d (4.8 mmol), and 1,4-dioxane/iPrOH (10:1, 3 mL), under H2 (30 atm), was
heated at 808C for 20 h. [b] Determined by 1H NMR analysis. [c] Deter-
mined by HPLC analysis. [d] Isolated yield. [e] Run for 28 h. [f] 4.8 mmol of
[{Ir(H)[(S)-DM-segphos]}2(m-Cl)3]Cl [(S)-1c] was used as catalyst.
drogenated under relatively harsh conditions (808C) to afford
the desired products with excellent enantiomeric excesses,
some of which have been reported previously (Table 2). 1-Aryl-
substituted substrates were efficiently hydrogenated regardless
of the electronic effect of the substituents on the phenyl
group (entries 2–6). On the other hand, steric effects of ortho
substituents affected the reaction rate. 2-Chlorophenylisoqui-
nolinium chloride required 28 h to reach 94% conversion
(entry 7). The high functional group tolerance of the process
was demonstrated by the successful use of an isoquinoline
bearing a bromo substituent (entry 8). Moreover, hydrogena-
tions of 1-alkyl isoquinolinium salts proceeded efficiently (en-
tries 9–11), although a benzyl-substituted substrate 2p-HCl re-
quired a change of catalyst to one bearing (S)-DM-SEGPHOS
(entry 9).
its 4-bromobenzoyl derivative. 1,3-Diaryl-, 1-aryl-3-alkyl-, and 1-
alkyl-3-aryl-substituted isoquinolinium chlorides proved to be
good substrates for the present catalytic system (entries 2–6).
Lower conversion was observed for 4d-HCl, presumably due
to weak basicity of the sp2-nitrogen owing to the presence of
two electron-withdrawing groups, resulting in easy dissociation
of HCl from its isoquinolinium salt. Enantioselectivity was only
slightly affected by the electronic nature and position of the
substituents on the aromatic substrates. Substituents at the 6-
and 7-positions had no effect on the reactivity or enantioselec-
tivity (entries 7–10). In all reactions, no peaks due to a minor
We then turned our attention to asymmetric hydrogenation
of 1,3-disubstituted isoquinolinium chlorides to produce two
stereogenic centers at the 1,3-positions, as this would repre-
sent an advantageous feature of our asymmetric hydrogena-
tion protocol for heteroaromatics.[11f,18]Table 3 shows the results
of hydrogenations of several 1,3-disubstituted isoquinolinium
salts under the optimized conditions. The asymmetric hydroge-
nation of 1,3-diphenyl substrate 4a-HCl has been reported
previously, yielding only one isomer of THIQ (1S,3S)-5a in 93%
conversion with 98% ee with complete syn-selectivity (entry 1).
The 1H NMR spectrum of (1S,3S)-5a showed signals due to
a single diastereomer, and the absolute configuration of this
product was determined by X-ray crystallographic analysis of
1
isomer could be detected in the H NMR spectra of the prod-
ucts, suggesting high diastereoselectivity (syn-selectivity based
on (1S,3S)-5a).
Other disubstitution patterns were also amenable to this cat-
alytic reaction. The reaction of 3,4-diphenylisoquinolinium
chloride 6-HCl gave the corresponding hydrogenated product
with 43% ee, and only the syn isomer was obtained [Eq. (2)].
1,4-Diphenylisoquinolinium chloride 8-HCl was hydrogenated
to afford a 4:1 mixture of syn and anti isomers with high enan-
tioselectivities [Eq. (3)]. Stereochemistries observed in the
asymmetric hydrogenation of 6-HCl and 8-HCl were rational-
ized by assuming a tautomerization between an imine form
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1917
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 3. Asymmetric hydrogenation of 1,3-disubstituted isoquinolinium
salts.[a]
Entry R1
R2
R3 R4
Yield[b] ee[c]
(%)
(%)
1[d]
phenyl
phenyl
phenyl
H
H
5a 93
98 (S,
S)
96
(+)
Scheme 5. Reaction pathways in asymmetric hydrogenation of 8-HCl.
2
H
H
H
H
H
H
5b 91
5c 93
5d 56
98
(ꢀ)
91
3
the imine, and the second reduction determined the ratio of
the syn and anti isomers of the 1,2,3,4-tetrahydroisoquinolini-
um salts. In the second reduction, the difference between the
two transition states was considered to be small, resulting in
low diastereoselectivity.
4[e]
(+)
97
(ꢀ)
98
(ꢀ)
94
(+)
92
(ꢀ)
94
(+)
97
5
6
phenyl
H
H
H
H
5e 87
5 f 80
phenyl
phenyl
phenyl
phenyl
phenyl
n-hexyl
7
phenyl
phenyl
phenyl
phenyl
H
F
5g 89
8
H
OMe 5h 88
9
F
H
H
5i 89
5j 87
10
CH3
(+)
[a] Reaction conditions: A mixture of isoquinolinium salt (0.24 mmol), (S)-
1d (4.8 mmol), and 1,4-dioxane/iPrOH (10:1, 3 mL), under H2 (30 atm), was
heated at 808C for 20 h. [b] Isolated yield. [c] Determined by HPLC analy-
sis. [d] Ref. [13b]. [e] Catalyst loading was 5 mol% and run at 1208C.
and an enamine form of the dihydroisoquinolinium salt, a half-
reduced intermediate compound, which would be consistent
with our previous deuterium-labeling experiments.[13b] As
shown in Scheme 4 for 3,4-disubstituted isoquinoline, rapid
tautomerization provided equimolar amounts of enantiomers
of the imines, subsequent hydrogenation of which proceeded
against the substituent at the C4 position to selectively form
the syn isomer. On the other hand, as shown in Scheme 5, the
reduction of the 1,4-disubstituted isoquinolinium salt 8-HCl ini-
tially induced chirality at the C1 position with high enantiose-
lectivity, as described in our previous report.[13b] Subsequent
tautomerization provided a mixture of syn and anti isomers of
Time-course study on asymmetric hydrogenation of isoqui-
noline 2a and isoquinolinium chloride 2a-HCl
In order to reveal the effects of salt formation on the asymmet-
ric hydrogenation of isoquinolines catalyzed by iridium dinu-
clear complexes, we performed time-course studies on such re-
actions of 2a and 2a-HCl under the optimized conditions.
Plots of the yield of 3a against time showed that the reaction
of 2a-HCl proceeded steadily, reaching a yield of 99% after
20 h, whereas the reaction of 2a was rather slow (Figure 1a).
This difference could be attributed to whether or not the hy-
Figure 1. Time courses of yield (a) and enantiomeric excess (b) of 3a in
asymmetric hydrogenations of 2a (triangles) and 2a-HCl (circles) catalyzed
by (S)-1d.
Scheme 4. Reaction pathways in asymmetric hydrogenation of 6-HCl.
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1918
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
drogenated product could coordinate to the iridium center. It
is noteworthy that the enantiomeric excess of 3a after basic
work-up remained unaltered during the course of the reaction
of 2a-HCl, whereas it decreased during the course of the reac-
tion of 2a (Figure 1b). This decrease in ee during the reaction
of 2a can be rationalized in terms of a change in the active
species induced by the hydrogenated product. However, such
negative effects of amine formation are as yet unclear, al-
though we previously reported that the hydrogenated prod-
ucts from 2-substituted quinoxalines afforded the correspond-
ing amide-hydride species, which served as catalysts in an
outer-sphere mechanism.[12] These experiments clearly showed
that salt formation inhibited the negative effects of the prod-
uct amines on both reactivity and enantioselectivity.
Synthesis and reactions of anionic mononuclear iridium
complexes
The time-course experiments suggested that the activity and
enantioselectivity of the iridium catalyst were highly depen-
dent on whether or not the product could coordinate to the
metal center. We thus conducted control experiments to eluci-
date any interaction of (S)-1a with 3-phenylisoquinoline (2a)
and its hydrogenated product (S)-3a together with their HCl
salts. As outlined in Scheme 6, since these mixtures were in
equilibrium and no adducts could be isolated, we used
10 equivalents of each substrate in order to shift the equilibri-
um to the adducts as much as possible. When (S)-1a and
10 equivalents of 2a were dissolved in CD2Cl2 at room temper-
ature, we observed a new hydride peak centered at d=
1
ꢀ18.3 ppm (brs) in the H NMR spectrum and two signals at
d=2.8 (br) and ꢀ5.3 ppm (br) in the 31P{1H} NMR spectrum.
This suggested that an isoquinoline-coordinated complex (S)-
10 was generated, based on comparison with signals observed
for the 2-phenylquinoxaline-coordinated iridium complex (S)-
15 [major: dH =ꢀ18.2 ppm (dd, JH-P =12.3, 17.2 Hz); dP =ꢀ5.9
(d, JP-P =19.4 Hz) and ꢀ12.9 ppm (d, JP-P =19.4 Hz); minor: dH =
ꢀ19.3 ppm (dd, JH-P =14.2, 21.7 Hz); dp =2.2 (d, JP-P =19.4 Hz)
and ꢀ4.3 ppm (d, JP-P =19.4 Hz)].[12] Similarly, (S)-3-phenyl-
1,2,3,4-tetrahydroisoquinoline [(S)-3a] (95% ee) was found to
coordinate to the iridium center in CD2Cl2 to form complex (S)-
11, which was spectroscopically characterized. The 1H NMR
spectrum featured
a double doublet centered at d=
ꢀ19.5 ppm (JH-P =17.6, 15.2 Hz) and the 31P{1H} NMR spectrum
showed two doublets centered at d=3.2 (JP-P =19.4 Hz) and
ꢀ3.1 ppm (JP-P =19.4 Hz), these peaks being comparable to
those found for the 4-methoxyaniline-coordinated iridium
complex (S)-16 [dH =ꢀ20.1 ppm (dd, JH-P =14.2, 21.4 Hz); dP =
0.3 (d, JP-P =18.6 Hz) and ꢀ5.6 ppm (d, JP-P =18.6 Hz)].[12] In
sharp contrast to these neutral substrates, the reaction of (S)-
1a and 10 equivalents of 2a-HCl gave a facial mononuclear iri-
dium trichloride-hydride complex (S)-12, which displayed
a double doublet hydride signal centered at d=ꢀ21.0 ppm
(JH-P =19.9, 14.9 Hz) and two doublets centered at d=ꢀ0.36
(JP-P =18.3 Hz) and ꢀ4.4 ppm (JP-P =18.3 Hz) in its 31P{1H} NMR
spectrum. Notable inertness of the hydride species (S)-12
toward 2a-HCl was observed, as evidenced by the absence of
Scheme 6. Controlled reactions of (S)-1a with amines or ammonium salts.
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1919
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
peaks due to a hydrogenated product in the 1H NMR spectrum.
1
The H NMR spectrum of a mixture of (S)-1a and 10 equiva-
lents of 3a-HCl in CD2Cl2 showed the same pattern as that of
12. The chemical shifts and JP-H coupling constants of a hydride
signal centered at d=ꢀ21.1 ppm (t, JH-P =18.2 Hz) and phos-
phorus signals centered at d=ꢀ0.19 (d, JP-P =18.2 Hz) and
ꢀ4.6 ppm (d, JP-P =18.2 Hz) were in good accord with those of
(S)-12, suggesting that an anionic iridium complex (S)-13 simi-
lar to (S)-12 except for the different cationic part was generat-
ed. The formation of anionic trichloro iridium complexes (S)-12
and (S)-13 was further supported by an experiment in which
a mixture of 10 equivalents of tetrabutylammonium chloride
and (S)-1a in CD2Cl2 afforded the corresponding anionic com-
Scheme 7. Reaction of in situ generated (S)-12 with H2.
complexes (S)-10 and (S)-11 in hand, solutions of these com-
plexes in CD2Cl2 were exposed to molecular hydrogen (1 atm)
for 18 h at room temperature and monitored by NMR spectros-
copy. Monitoring the reaction of in situ generated complex (S)-
12 with H2, (S)-13 was observed along with the tetrahydroiso-
1
plex (S)-14, the H NMR spectrum of which showed a hydride
signal at d=ꢀ20.6 ppm (dd, JH-P =19.1, 14.1 Hz) and two phos-
phorus signals at d=0.30 (d, JP-P =17.7 Hz) and ꢀ3.3 ppm (d,
JP-P =17.7 Hz). In sharp contrast to nBu4NCl, no new hydride
peak appeared upon adding nBu4NBF4 or nBu4NNO3
to (S)-1a in CD2Cl2 (see the Supporting Information).
As the anionic complexes 12–14 showed almost the
same NMR spectral data, it was assumed that there
was a hydrogen bond between N-H and a chloride
ligand at the iridium center. Indeed, Esteruelas et al.
reported that an anionic trichloro iridium complex 17
had a hydrogen bond between the chloride of the
anionic iridium moiety and the hydrogen atom of the
benzo[h]quinolinium cation,[19] and two hydrogen
bonds between Et2NH2Cl and the chloride ligands of
each ruthenium atom were reported to stabilize an
anionic dinuclear triply-chloride-bridged ruthenium
complex (R)-18 bearing chelating diphosphine li-
gands (Figure 2).[20]
With the anionic iridium complexes (S)-12 and (S)-
13 as well as neutral nitrogen-coordinated iridium
Scheme 8. Reaction of in situ generated (S)-10 with H2.
quinolinium salt after 1 week (Scheme 7). In contrast, exposure
of (S)-10 to hydrogen proceeded differently from that of (S)-
12, affording the trihydride dinuclear complex (S)-19, which
was reported to be catalytically inactive (Scheme 8).[12] Similar
results were obtained for the reaction of the product-coordi-
nated complex (S)-11. It should be emphasized that complex
(S)-13 did not react with H2, whereas complex (S)-11 reacted
with H2 to give the trihydride complex (S)-19. This clear reactiv-
ity difference between an anionic iridium complex and a neu-
tral nitrogen-coordinated complex is consistent with the ob-
served lower conversion (59%) of 2a compared to that of its
HCl salt (full conversion) under the catalytic conditions using
(S)-1a (Scheme 1). Moreover, it was pointed out that the trihy-
dride complex (S)-19 reacted with the salt 2a-HCl to regener-
ate
a mixture of (S)-1a and (S)-12 in 49% conversion
(Scheme 9), whereas the reaction of (S)-19 with 3a-HCl did not
regenerate a mixture of (S)-1a and (S)-13. Thus, before com-
plete consumption of the HCl salt of 3-phenylisoquinoline 2a-
HCl, the deactivation process of the catalytic reaction could be
suppressed by 2a-HCl through its reactivation of the catalyti-
cally inactive trihydride complex (S)-19, if generated during the
hydrogenation.
Figure 2.
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1920
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
at d=ꢀ9.40 (ddd,
JH-H =3.5 Hz,
JH-P =159.7, 15.6 Hz) and
ꢀ21.2 ppm (td, JH-H =3.6 Hz, JH-P =15.0 Hz) appeared. These
could be assigned to the desired iridium dihydride complex
(S)-21 as a single stereoisomer. This may provide a rationale for
the high enantioselectivity, even though the precursor dichlor-
ides (S)-20 consisted of two isomers. The aforementioned cou-
pling constants suggested that one hydride ligand was orient-
ed trans to one phosphine ligand and cis to the other, whereas
the second hydride ligand was oriented cis to both phosphine
ligands (Figure 2). Because (S)-21 could not be isolated from
the reaction mixture due to low conversion even after 25 h, we
utilized a reported synthetic method for iridium dihydride
complexes involving the reaction of an IrI complex with H2 in
the presence of donor ligands.[21] In fact, the reaction of in situ
generated [IrCl((S)-binap)]2 with H2 (1 atm) in the presence of
a-picoline in toluene at room temperature afforded the same
iridium dihydride complex (S)-21, the hydride peaks of which
were superimposed on those observed for the reaction of (S)-
1a with H2 (Eq. (4)). In order to isolate crystals for a crystallo-
graphic study, we conducted a similar reaction of an IrI com-
plex bearing SEGPHOS, [IrCl((S)-segphos)]2, with p-methoxypyri-
dine to afford a complex (S)-22, which was characterized by
Scheme 9. Regeneration of (S)-1a and the anionic complex from trihydride
complex (S)-19 by addition of isoquinolinium or ammonium salt.
Synthesis and reactivity of a dihydride iridium complex
We confirmed above that coordination of the chloride anion of
isoquinolinium chloride formed an anionic iridium complex (S)-
12, which could not hydrogenate 2a-HCl directly in the ab-
sence of H2. Next, we conducted control experiments to identi-
fy any catalytically active species in the present asymmetric hy-
drogenation of isoquinolinium salts. We have previously pro-
posed an iridium dihydride complex as a catalytically active
complex for the asymmetric hydrogenation of quinoxalines.[12]
Thus, we performed the controlled reaction of (S)-1a with H2
in the presence of a-picoline as a model donor ligand
(Figure 3). When (S)-1a and 10 equivalents of a-picoline were
NMR spectroscopy [dH =ꢀ8.61 (dd,
JP-H =18, 160 Hz),
ꢀ21.3 ppm (t, JP-H =16 Hz); dP =8.13, 0.30 ppm] and X-ray anal-
ysis. Figure 4 shows an ORTEP drawing of (S)-22, in which the
iridium atom is seen to adopt an octahedral geometry. The
overall structure of the dihydride based on NMR spectroscopy
was clearly confirmed.
1
Figure 3. Time-dependent H NMR spectra of hydride species in the reaction
of (S)-1a and a-picoline (10 equiv) under H2 (1 atm) at room temperature.
Asterisks indicate peaks due to an unidentified species.
dissolved in CD2Cl2 at room temperature, we observed new hy-
dride peaks centered at d=ꢀ18.7 (dd, JH-P =17.1, 13.0 Hz) and
ꢀ19.9 ppm (dd, JH-P =22.0, 14.3 Hz) with relative intensities of
1
78:22 in the H NMR spectrum. This suggested that two iso-
mers of a-picoline-coordinated complexes (S)-20 (Figure 2)
were generated and assigned as C-(S)-20, (major) and A-(S)-20,
(minor) based on the crystal structure of the previously report-
ed complex (S)-16.[12] After 1 h under H2 atmosphere, the sig-
nals due to (S)-20 decreased, and new hydride peaks centered
Figure 4. Crystal structure of (S)-22 (hydrogen atoms omitted for clarity).
Selected bond lengths [ꢁ] and angles [8]: Ir1ꢀP1 2.232(2), Ir1ꢀP2 2.345(2),
Ir1ꢀCl1 2.511(2), Ir1ꢀN1 2.143(6); P1-Ir1-P2 93.48(8), P2-Ir1-N1 91.74(18),
P2-Ir1-N1 173.82(19).
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1921
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Proposed mechanism for asymmetric hydrogenation of iso-
quinolinium salts
Scheme 11 shows the proposed catalytic cycle. The iridium di-
nuclear complex (S)-1, which is in equilibrium with the anionic
iridium complex A, dissociates to allow coordination by the
solvent.[12] The monohydride complex B is then formed, which
can react with H2 to form dihydride complex C with concomi-
tant formation of HCl. Displacement of the solvent by the chlo-
ride could then occur to form the anionic dihydride complex
D. Subsequent hydride attack on the isoquinolinium salt re-
generates the monohydride complex B along with the dihy-
droisoquinoline, which is trapped with HCl to form the dihy-
droisoquinolinium salt. The second reduction then proceeds in
a similar manner to give the tetrahydroisoquinolinium salts.
The counter cation of iridium trichloride complex A should be
changed from isoquinolinium to tetrahydroisoquinolinium ac-
cording to the progress of the reaction. Based on Crabtree’s
proposal that the outer-sphere pathway is the most likely hy-
drogenation mechanism of protonated quinolines by mononu-
clear iridium trihydride complex 23,[22,23] it is assumed that hy-
dride attack of the dihydride complex D also proceeds through
Scheme 10. Comparison of the efficacies of (S)-21 and (S)-1a in (a) hydride
attack on 2a-HCl and (b) asymmetric hydrogenation of 2b-HCl.
As shown in Scheme 10a, we compared the stoi-
chiometric reactions with 2a-HCl of the isolated dihy-
dride complex (S)-21 and the dinuclear iridium com-
plex (S)-1a in the absence of H2. Complex (S)-21
showed high reactivity for the insertion of the isoqui-
nolinium salt into the IrꢀH bond to afford dihydro-
and tetrahydroisoquinolinium salts, whereas (S)-1a
showed no activity. Under milder conditions, these
complexes were tested as catalysts for the asymmet-
ric hydrogenation of 2b-HCl under an H2 pressure of
30 atm (Scheme 10b). The dihydride iridium complex
(S)-21 displayed almost the same activity and selec-
tivity for the asymmetric hydrogenation of 1-substi-
tuted isoquinolinium salts as seen in the reaction
using (S)-1a. This suggests that the dihydride com-
plex could be involved in the catalytic cycle, al-
though the isolated dihydride had picoline as a stabi-
lizing ligand. Based on the observations that: (i) the
chloride anion from substrates and products coordi-
nated to the mononuclear iridium center to form
Scheme 11. Proposed catalytic cycle for the asymmetric hydrogenation of isoquinolinium
salts.
mononuclear anionic complexes, (ii) the enantiomeric
excess was sensitively affected by the counter anions
of substrate salts, and (iii) another possible mononu-
clear trihydride iridium complex 23 (Figure 5), which was re-
ported as an active species in the
hydrogenation of quinolines,[22]
was not observed in the reaction
of (S)-1a with H2, we conclude that
the dihydride complex was proba-
bly coordinated by chloride to
form a key intermediate for the hy-
an outer-sphere mechanism. The high enantioselectivity can
then be ascribed to the formation of the single isomer of the
dihydride complex, which dominantly selected the enantioface
of the isoquinolinium chlorides. The chloride counter anion of
the substrate interacts with the dihydride complex, as evi-
denced by the clear dependence of enantiomeric excess on
the nature of the counter anion of the substrate salts. Hence,
the transition state for hydride attack is proposed to be a six-
membered ring, involving the chloride and N-H proton of the
substrate salts in a new outer-sphere mechanism.
drogenation of the isoquinolinium
salts.
Figure 5. Trihydride iridium
complex.[22]
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1922
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
on JASCO UV-2075 or PU-2089 spectrometers. Optical rotations
were recorded on a JASCO DIP-370 polarimeter at 589 nm (sodium
lamp) and are given in 10ꢀ1 degcm2 gꢀ1. Mass spectra were ob-
tained on Bruker Daltonics MicroTOF II-HB and JEOL JMS-700 spec-
trometers. All melting points were recorded on a Yanaco micro
melting point apparatus. Flash column chromatography was per-
formed on silica gel 60 (40–66.3 mm, 230–400 mesh ASTM). Elemen-
tal analyses were performed on a Perkin-Elmer 2400 analyzer at
the Faculty of Engineering Science, Osaka University. Hydrogena-
tion reactions were conducted in a TAIATSU stainless steel auto-
clave or Biotage Endeavor catalyst screening system.
Conclusion
We have successfully developed the asymmetric hydrogena-
tion of isoquinolines through salt formation prior to hydroge-
nation using dinuclear iridium complexes (S)-1, which thus rep-
resent useful and versatile catalyst precursors for the synthesis
of chiral THIQs with high enantiomeric excess. We have dem-
onstrated that salt formation of the substrate is essential to
achieve high yield and high enantioselectivity. Under the opti-
mized conditions, the asymmetric hydrogenation of 1- and 3-
substituted isoquinolinium HCl salts proceeded efficiently to
afford the desired chiral THIQs in high yields and with high
enantioselectivities after simple basic work-up. The construc-
tion of two stereogenic centers in a single operation has been
achieved by asymmetric hydrogenation of disubstituted isoqui-
nolinium salts. In addition, time-course experiments have re-
vealed that salt formation prevented the catalytic performance
and enantioselectivity from being eroded by the negative ef-
fects of such substrates and their amine derivatives. Moreover,
General procedure for asymmetric hydrogenation of isoqui-
nolinium salts
An iridium dinuclear complex (2.4 mmol, 1.0 mol%) and an isoqui-
nolinium salt (0.24 mmol, 1 equiv) were placed in a glass tube in
the reactor, and the tube was flushed with argon. A mixed solvent
of dry iPrOH/1,4-dioxane (1:10; 3 mL) was added through an inlet,
and the reactor was charged with H2 to the desired pressure. The
reaction mixture was stirred for 20 h. After releasing the H2 pres-
sure, the solvent was removed in a rotary evaporator. The residue
was poured into saturated aqueous NaHCO3 solution and extracted
with ethyl acetate. The organic layer was washed with brine and
dried over Na2SO4. The conversions were determined by 1H NMR
analysis of the products after basic work-up. The enantiomeric ex-
cesses were determined by HPLC analysis. Some THIQs had to be
acetylated to determine their enantiomeric excesses. For this, a vial
was charged with the THIQ (ca. 40 mg), CH2Cl2 (2 mL), and triethyl-
amine (3 mL). The reaction mixture was cooled to 08C by immer-
sion in an ice bath, whereupon acetyl chloride (3 drops) was
added. The reaction mixture was allowed to warm to room tem-
perature and stirred overnight. After filtration through a short pad
of silica gel to remove ammonium salts, eluting with ethyl acetate,
all volatiles were removed under reduced pressure.
mechanistic studies, including by H and 31P{1H} NMR and the
1
isolation and characterization of several catalytic intermediates,
led to the following observations: (1) chloride coordination to
an iridium center prevented the formation of catalytically inac-
tive complex (S)-19, and (2) iridium dihydride complex (S)-21 is
involved in the catalytic cycle. We have proposed a conceptual-
ly new transition state involving chloride coordination to an iri-
dium center and a hydrogen bond between the chloride
ligand and N-H proton of the substrate salt to form a six-mem-
bered outer-sphere ring. Further developments for reducing N-
heteroaromatics by the HCl salt formation protocol are being
pursued by our group.
(+)-Methyl 4’-(1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (3j):
Pale-yellow solid; m.p. 93–948C; IR (KBr): n˜ =3335 (m), 2949 (s),
2803 (s), 1704 (s), 1608 (s), 1573 (w), 1434 (s), 1279 (s), 1112 (s),
1018 cmꢀ1 (m); 1H NMR (CDCl3, 400 MHz, 308C): d=8.1–8.0 (m,
2H), 7.4–7.3 (m, 2H), 7.16 (d, J=4.0 Hz, 2H), 7.1–7.0 (s, 1H), 6.70 (d,
J=7.8 Hz, 1H), 5.2 (s, 1H), 3.9 (s, 3H), 3.3–3.2 (m, 1H), 3.1–3.0 (m,
2H), 2.9–2.8 (m, 1H), 2.1 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3,
308C): d=167.1, 150.1, 137.6, 135.5, 129.9, 129.4, 129.3, 129.1,
128.1, 126.6, 125.9, 61.9, 52.6, 42.3, 29.8 ppm; MS (EI): m/z: calcd
for C17H17NO2: 267.1259; found: 267.1256; HPLC (Daicel OD-H,
hexane/iPrOH, 95:5, detector: 215 nm, temperature: 258C, flow
Experimental Section
General
All reactions and manipulations involving air- and moisture-sensi-
tive organometallic compounds were performed under argon
using standard Schlenk techniques. [{Ir(H)(chiral diphosphine)}2(m-
Cl)3]Cl complexes 1a–d were prepared according to literature pro-
cedures.[13a,24] 1,4-Dioxane was dried and deoxygenated by distilla-
tion over sodium benzophenone ketyl under argon, and methanol
and ethanol were distilled from the corresponding magnesium alk-
oxides under argon. iPrOH was distilled from calcium hydride.
CH2Cl2, Et2O, hexane, THF, and toluene were dried and deoxygenat-
ed using a Grubbs column (Glass Counter Solvent Dispensing
System, Nikko Hansen & Co., Ltd.). Other chemicals were pur-
chased and used without further purification. 1H NMR (400 MHz),
13C NMR (100 MHz), 19F NMR (376 MHz), and 31P NMR (160 MHz)
spectra were measured on a Bruker Avance III-400 spectrometer.
All 1H NMR chemical shifts were recorded in ppm (d) relative to tet-
ramethylsilane or referenced to the chemical shifts of residual sol-
vent resonances (CHCl3 (dH =7.26 ppm) or CH2Cl2 (dH =5.31 ppm)
were used as internal standards). All 13C NMR chemical shifts were
recorded in ppm (d) relative to CDCl3 (dC =77.16 ppm). 31P NMR
chemical shifts were recorded in ppm (d) relative to 85% H3PO4 as
an external standard (dP =0.00 ppm). All 19F NMR chemical shifts
were recorded in ppm (d) relative to a,a,a-trifluorotoluene as an
external standard (dF =ꢀ63.90 ppm). UV/Vis spectra were recorded
rate: 1 mLminꢀ1, t1 =20.7 min, t2 =27.4 min, major peak t2); [a]D20
+ 31.9 (c=1, CHCl3).
=
(+)-1-p-Tolyl-1,2,3,4-tetrahydroisoquinoline (3k):[25] Colorless
solid; m.p. 79–808C; IR (KBr): n˜ =3441 (w), 3013 (m), 2970 (m),
1602 (w), 1514 (m), 1491 (s), 1370 (m), 1291 (m), 1121 (s),
1036 cmꢀ1 (m); 1H NMR (CDCl3, 400 MHz, 308C): d=7.2–7.1 (m,
6H), 7.1–7.0 (m, 1H), 6.77 (d, J=7.8 Hz, 1H), 5.1 (s, 1H), 3.3–3.2 (m,
1H), 3.1–3.0 (m, 2H), 2.9–2.8 (m, 1H), 2.3 (s, 3H), 2.2 ppm (brs,
1H); 13C NMR (100 MHz, CDCl3, 308C): d=142.0, 138.5, 137.0, 135.5,
129.2, 129.1, 128.9, 128.2, 126.3, 125.7, 61.8, 42.3, 29.9, 21.2 ppm;
MS (EI): m/z: calcd for C16H17N: 223.1361; found: 223.1342; HPLC
(corresponding acetamide, Daicel OD-H, hexane/iPrOH, 99:1, detec-
tor: 222 nm, temperature: 288C, flow rate: 1 mLminꢀ1
42.3 min, t2 =49.9 min, major peak t2); [a]D20 = +11.7 (c=1, CHCl3).
(3m):
, t1 =
(ꢀ)-1-(3-Methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
Colorless solid; m.p. 105–1078C; IR (KBr): n˜ =3420 (w), 3061 (w),
2912 (m), 1612 (s), 1585 (m), 1492 (s), 1439 (m), 1336 (m),
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1923
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
1
1278 cmꢀ1 (s); H NMR (CDCl3, 400 MHz, 308C): d=7.3–7.2 (m, 1H),
t2 =16.1 min, major peak t2); [a]D20 = +37.3 (c=1.0, CHCl3) (for an ee
7.14 (d, J=4.0 Hz, 2H), 7.1–7.0 (m, 1H), 6.9–6.8 (m, 4H), 5.08 (s,
1H), 3.78 (s, 3H), 3.3–3.2 (m, 1H), 3.1–3.0 (m, 2H), 2.9–2.8 (m, 1H),
1.98 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3, 308C): d=159.8,
146.6, 138.2, 135.5, 129.5, 129.1, 128.2, 126.4, 125.8, 121.5, 114.8,
112.9, 62.2, 55.3, 42.4, 29.9 ppm; HRMS (EI): m/z: calcd for
C16H17NO: 239.1310; found: 239.1311; HPLC (corresponding acet-
amide, Daicel OD-H, hexane/iPrOH, 95:5, detector: 215 nm, temper-
ature: 108C, flow rate: 1 mLminꢀ1, t1 =24.3 min, t2 =28.2 min,
major peak t1); [a]D20 =ꢀ123.4 (c=0.5, CHCl3).
of 98%).
1,3-Bis(4-methoxycarbonylphenyl)-1,2,3,4-tetrahydroisoquino-
line (5d): Yellow solid; m.p. 31–358C; IR (KBr): n˜ =3422 (w), 2950
(w), 2368 (w), 2345 (w), 1719 (s), 1434 (m), 1279 (m), 1279 (s), 1175
(w), 1112 (m), 1018 (m), 858 (m), 743 (m), 705 (m), 621 cmꢀ1 (w);
1H NMR (CDCl3, 400 MHz, 308C): d=8.07–7.99 (m, 4H), 7.62–7.49
(m, 4H), 7.20–7.11 (m, 2H), 7.09–7.02 (m, 1H), 6.69 (d, J=7.8 Hz,
1H), 5.34 (s, 1H), 4.29 (dd, J=11.1, 3.5 Hz, 1H), 3.92 (s, 3H), 3.91 (s,
3H), 3.15 (dd, J=15.6, 11.1 Hz, 1H), 3.00 (dd, J=15.9, 3.4 Hz, 1H),
2.08 ppm (br, 1H); 13C NMR (100 MHz, CDCl3, 308C): d=166.9,
166.8, 149.6, 149.3, 137.5, 134.8, 129.9, 129.8, 129.6, 129.4, 129.2,
(+)-1-(2-Chlorophenyl)-1,2,3,4-tetrahydroisoquinoline
Pale-yellow oil; IR (neat): n˜ =3328 (w), 3061 (m), 2919 (m), 2830
(3n):[26]
(w), 1603 (m), 1570 (m), 1493 (s), 1453 (s), 1368 (m), 1292 (s),
128.8, 127.4, 126.6, 126.5, 126.0, 63.7, 58.8, 52.0, 38.8 ppm; HRMS
1
+
1024 cmꢀ1 (s); H NMR (CDCl3, 400 MHz, 308C): d=7.42 (dd, J=7.8,
(ESI): m/z: calcd for C25H24NO4
:
402.1705 [MꢀH]+; found:
1.0 Hz, 1H), 7.2–7.0 (m, 5H), 6.99 (dd, J=7.5, 1.1 Hz, 1H), 6.77 (d,
J=7.5 Hz, 1H), 5.6 (s, 1H), 3.1–3.2 (m, 1H), 3.1–2.9 (m, 2H), 2.9–2.8
(m, 1H), 2.1 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3, 308C): d=
142.2, 137.2, 135.9, 134.1, 131.2, 129.7, 129.2, 128.5, 128.1, 126.8,
126.5, 125.9, 57.7, 41.4, 29.8 ppm; MS (EI): m/z: calcd for C15H14ClN:
243.0815; found: 243.0828; HPLC (Daicel OJ-H, hexane/iPrOH, 98:2,
detector: 215 nm, temperature: 308C, flow rate: 0.7 mLminꢀ1, t1 =
12.7 min, t2 =15.2 min, major peak t2); [a]D20 = +17.9 (c=0.7,
CHCl3).
402.1701; HPLC (Daicel OD-H, temperature: 308C, hexane/iPrOH,
95:5, detector: 215 nm, flow rate 1.0 mLminꢀ1, t1 (ꢀ)=21.9 min, t2
(+)=24.8 min); [a]D20 = +11.5 (c=0.39, CHCl3) (for an ee of 91%).
1-Cyclohexyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline (5e): White
solid; m.p. 95–978C; IR (KBr): n˜ =3313 (w), 3061 (m), 2925 (s), 2854
(s), 1601 (s), 1563 (m), 1492 (s), 1455 (s), 1306 (m), 1249 (m), 1156
1
(m), 1028 cmꢀ1 (m); H NMR (CDCl3, 400 MHz, 308C): d=7.55 (d, J=
7.5 Hz, 2H), 7.5–7.4 (m, 2H), 7.3–7.2 (m, 4H), 7.13 (d, J=7.3 Hz,
1H), 4.30 (s, 1H), 4.04 (dd, J=11.0, 3.0 Hz, 1H), 3.0–2.8 (m, 2H),
2.1–2.0 (m, 1H), 1.9–1.8 (m, 1H), 1.7–1.6 (m, 4H), 1.5–1.2 ppm (m,
6H); 13C NMR (100 MHz, CDCl3, 308C): d=145.5, 138.1, 136.9, 128.8,
128.6, 127.4, 126.9, 126.1, 125.7, 125.6, 61.9, 58.0, 44.4, 39.8, 30.9,
27.3, 26.8, 26.7, 25.5 ppm; MS (EI): m/z: calcd for C21H26N:
292.2065; found 292.2049; HPLC (Daicel OD-H, hexane/iPrOH, 99:1,
detector: 215 nm, temperature: 158C, flow rate: 0.5 mLminꢀ1, t1 =
9.2 min, t2 =10.3 min, major peak t1); [a]D20 =ꢀ94.9 (c=3.0, CHCl3)
(for an ee of 97%).
1,3-Diphenyl-1,2,3,4-tetrahydroisoquinoline (5a):[13b] White solid;
m.p. 111–1128C; 1H NMR (CDCl3, 400 MHz, 308C): d=7.40 (d, J=
7.3 Hz, 2H), 7.32 (d, J=6.8 Hz, 2H), 7.3–7.1 (m, 6H), 7.1–6.9 (m,
3H), 6.64 (d, J=7.8 Hz, 1H), 5.21 (s, 1H), 4.06 (dd, J=11.0, 3.5 Hz,
1H), 3.1–3.0 (dd, J=15.8, 11.5 Hz, 1H), 2.92 (dd, J=15.8, 3.3 Hz,
1H), 2.03 ppm (brs, 1H); 13C NMR (CDCl3, 100 MHz, 308C): d=
144.8, 144.6, 138.7, 135.6, 129.4, 128.9, 128.7, 128.6, 127.8, 127.7,
127.6, 126.8, 126.3, 126.0, 64.5, 59.4, 39.2 ppm; MS (EI+): m/z: calcd
for C21H19N: 285.1517 [MꢀH]+; found: 285.1534; HPLC (correspond-
ing trifluoroacetamide, Daicel OD-H, hexane/iPrOH, 99:1, detector:
215 nm, flow rate 0.5 mLminꢀ1, t1 (+)=15.3 min, t2 (ꢀ)=16.6 min);
[a]D20 = +47.8 (c=1.5, CHCl3) (for an ee of 98%).
3-Hexyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (5 f): Colorless
oil; IR (neat): n˜ =3313 (w), 3061 (m), 2925 (s), 2854 (s), 1601 (s),
1563 (m), 1492 (s), 1455 (s), 1306 (m), 1249 (m), 1156 (m),
1028 cmꢀ1 (m); 1H NMR (CDCl3, 400 MHz, 308C): d=7.4–7.3 (m,
5H), 7.16 (d, J=4.0 Hz, 2H), 7.1–7.0 (m, 1H), 6.72 (d, J=7.8 Hz,
1H), 5.15 (s, 1H), 3.2–3.1 (m, 1H), 3.0–2.7 (m, 2H), 1.88 (brs, 1H),
1.7–1.6 (m, 2H), 1.5–1.3 (m, 8H), 0.95 ppm (t, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3, 308C): d=144.9, 139.2, 135.7, 129.3,
128.9, 128.6, 127.7, 127.6, 126.2, 125.6, 64.1, 54.6, 37.1, 36.7, 31.9,
29.6, 26.0, 22.7, 14.2 ppm; MS (EI): m/z: calcd for C21H27N:
293.2144; found: 293.2144; HPLC (Daicel OD-H, hexane/iPrOH,
1-(4-Methoxyphenyl)-3-phenyl-1,2,3,4-tetrahydroisoquinoline
(5b): White solid; m.p. 131–1338C; IR (KBr): n˜ =3310 (w), 3061 (m),
3023 (m), 3003 (m), 2956 (m), 2913 (s), 1612 (s), 1585 (m), 1509 (s),
1
1493 (s), 1336 (m), 1303 (s), 1173 (s), 1037 (s), 835 cmꢀ1 (s); H NMR
(CDCl3, 400 MHz, 308C): d=7.50 (d, J=7.5 Hz, 2H), 7.4–7.3 (m, 5H),
7.2–7.0 (m, 3H), 6.90 (d, J=8.5 Hz, 2H), 6.77 (d, J=7.5 Hz, 1H), 5.25
(s, 1H), 4.23 (dd, J=11.3, 3.3 Hz, 1H), 3.83 (s, 3H), 3.18 (dd, J=15.6,
11.5 Hz, 1H), 3.01 (dd, J=15.8, 3.0 Hz, 1H), 2.06 ppm (brs, 1H);
13C NMR (100 MHz, CDCl3, 308C): d=159.2, 144.7, 139.1, 137.1,
135.6, 130.4, 128.8, 128.7, 127.7, 127.5, 126.8, 126.3, 125.9, 113.9,
63.8, 59.4, 55.4, 39.2 ppm; MS (EI): m/z: calcd for C22H21NO:
315.1623; found 315.1627; HPLC (Daicel OD-H, hexane/iPrOH, 99:1,
detector: 215 nm, temperature: 258C, flow rate: 1 mLminꢀ1, t1 =
10.2 min, t2 =19.3 min, major peak t2); [a]D20 = +47.8 (c=1.5,
CH2Cl2) (for an ee of 96%).
99:1, detector: 215 nm, temperature: 208C, flow rate: 0.5 mLminꢀ1
,
t1 =9.3 min, t2 =13.3 min, major peak t1); [a]D20 = +18.7 (c=2.0,
CHCl3) (for an ee of 98%).
7-Fluoro-1,3-diphenyl-1,2,3,4-tetrahydroisoquinoline (5g): Yellow
oil (>95:5 diastereoselectivity); IR (KBr): n˜ =3314 (m), 3085 (m),
3061 (s), 3029 (s), 2924 (m), 2899 (m), 2800 (s), 1613 (s), 1591 (m),
1496 (s), 1455 (s), 1428 (s), 1281 (s), 1254 (s), 1220 (s), 1029 (s), 957
(s), 832 (s), 808 (s), 773 (s), 751 (s), 735 (s), 700 cmꢀ1 (s); 1H NMR
(CDCl3, 400 MHz, 308C): d=7.65–7.27 (m, 5H), 7.08 (t, J=6.5 Hz,
1H), 6.92–7.68 (m, 1H), 6.52–6.38 (m, 1H), 5.22 (s, 1H), 4.20 (dd, J=
11.2, 2.9 Hz, 1H), 3.18–2.90 (m, 2H), 2.10 ppm (brs, 1H); 13C NMR
(100 MHz, CDCl3, 308C): d=161.0 (d, J=241.9 Hz), 144.2, 144.0,
140.6 (d, J=6.6 Hz), 131.0 (d, J=2.9 Hz), 130.1 (d, J=7.5 Hz), 129.1,
128.6, 127.8, 127.5, 126.6, 114.0 (d, J=21.9 Hz), 113.4 (d, J=
21.1 Hz), 64.3 (d, J=1.6 Hz), 59.2, 38.3 ppm; 19F NMR (CDCl3,
376 MHz, 308C): d=ꢀ116.8 ppm; HRMS (ESI): m/z: calcd for
C21H19FN+: 304.1502 [MꢀH]+; found: 304.1504; HPLC (Daicel AD-H,
temperature: 308C, hexane/iPrOH, 99:1, detector: 215 nm, flow
rate 1.0 mLminꢀ1, t1 (ꢀ)=15.0 min, t2 (+)=23.6 min); [a]2D0 = +12.8
(c=1.2, CHCl3) (for an ee of 94%).
1,3-Bis(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(5c):
White solid; m.p. 204–2058C; IR (KBr): n˜ =3431 (w), 3000 (m), 2960
(m), 2915 (m), 2837 (m), 1611 (s), 1510 (s), 1302 (s), 1238 (s), 1172
1
(m), 1035 (s), 833 cmꢀ1 (s); H NMR (CDCl3, 400 MHz, 308C): d=7.38
(m, 4H), 7.2–7.0 (m, 3H), 6.9–6.8 (m, 4H), 6.76 (d, J=8.0 Hz, 1H),
5.24 (s, 1H), 4.18 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.16 (dd, J=
15.3, 11.3 Hz, 1H), 2.97 (m, 1H), 2.07 ppm (brs, 1H); 13C NMR
(100 MHz, CDCl3, 308C): d=159.2, 159.1, 139.1, 137.1, 136.8, 135.7,
130.4, 128.8, 127.9, 127.7, 126.3, 125.9, 114.0, 113.9, 63.9, 58.8, 55.5,
55.4, 39.2 ppm; MS (EI): m/z: calcd for C23H24NO2: 346.1807; found:
346.1808; HPLC (Daicel OD-H, hexane/iPrOH, 98:2, detector:
215 nm, temperature: 258C, flow rate: 1 mLminꢀ1, t1 =13.7 min,
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1924
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
7-Methoxy-1,3-diphenyl-1,2,3,4-tetrahydroisoquinoline
White solid; m.p. 88–908C; IR (KBr): n˜ =3439 (w), 3060 (m), 2829
(5h):
(m), 2808 (m), 2787 (m), 1600 (s), 1580 (m), 1492 (s), 1451 (s), 1367
(m), 1315 (m), 1283 (m), 1259 (m), 1241 (m), 1217 (s), 1179 (m),
1121 (m), 1075 (m), 1029 (m), 917 (m), 844 (m), 807 cmꢀ1 (m);
1H NMR (CDCl3, 400 MHz, 308C): cis-9: d=7.41–6.98 (m, 13H), 6.92–
6.87 (m, 1H), 5.26 (s, 1H), 4.19 (t, J=4.6 Hz, 1H), 3.41 (dd, J=7.7,
5.0 Hz, 1H), 3.25 ppm (dd, J=7.9, 4.8 Hz, 1H); trans-9: d=7.41–
6.98 (m, 13H), 6.81–6.78 (m, 1H), 5.19 (s, 1H), 4.33 (t, J=8.3 Hz,
1H), 3.49 (dd, J=6.8, 5.6 Hz, 1H), 3.14 ppm (dd, J=3.5, 8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3, 308C): d=145.5, 144.5, 138.5, 137.7,
130.4, 129.6, 129.1, 129.0, 129.0, 128.5, 128.4, 128.0, 127.8, 127.5,
127.4, 126.6, 126.5, 126.4, 126.4, 126.2, 62.6, 62.0, 51.4, 49.8, 46.2,
44.9 ppm; HRMS (ESI): m/z: calcd for C21H20N+: 286.1596 [MꢀH]+;
found: 286.1600; HPLC (syn-9: Daicel OD-H, temperature: 308C,
hexane/iPrOH, 99:1, detector: 215 nm, flow rate 1.0 mLminꢀ1, t1 =
13.8 min, t2 =16.0 min; anti-9: Daicel OD-H, temperature: 308C,
(m), 1611 (s), 1501 (s), 1454 (s), 1324 (m), 1290 (s), 1257 (s), 1157
1
(m), 1030 cmꢀ1 (s); H NMR (CD2Cl2, 400 MHz, 308C): d=7.50 (d, J=
7.5 Hz, 2H), 7.44 (d, J=7.0 Hz, 2H), 7.4–7.2 (m, 6H), 7.07 (d, J=
8.5 Hz, 1H), 6.72 (dd, J=8.5, 2.6 Hz, 1H), 6.27 (s, 1H), 5.25 (s, 1H),
4.19 (dd, J=11.0, 3.3 Hz, 1H), 3.62 (s, 3H), 3.07 (dd, J=15.0,
11.0 Hz, 1H), 2.94 (dd, J=15.6, 3.3 Hz, 1H), 2.05 ppm (brs, 1H);
13C NMR (100 MHz, CD2Cl2, 308C): d=158.1, 145.4, 145.3, 140.2,
130.0, 129.5, 128.9, 128.8, 128.2, 127.9, 127.7, 127.0, 113.3, 112.4,
64.7, 59.7, 55.5, 38.6 ppm; MS (EI): m/z: calcd for C22H21NO:
315.1623; found: 315.1606; HPLC (Daicel OD-H, hexane/iPrOH,
99:1, detector: 215 nm, temperature: 108C, flow rate: 0.4 mLminꢀ1
,
t1 =31.8 min, t2 =34.2 min, major peak t2); [a]D20 =ꢀ18.9 (c=1.0,
CHCl3) (for an ee of 92%).
hexane/iPrOH, 98.5:1.5, detector: 215 nm, flow rate 1.0 mLminꢀ1
,
6-Fluoro-1,3-diphenyl-1,2,3,4-tetrahydroisoquinoline (5i): White
solid; m.p. 65–678C; IR (KBr): n˜ =3316 (w), 3027 (m), 2827 (m),
1615 (s), 1590 (s), 1495 (s), 1438 (m), 1341 (w), 1280 (s), 1234 (s),
1143 (s), 1028 cmꢀ1 (m); 1H NMR (CDCl3, 400 MHz, 308C): d=7.50
(d, J=7.3 Hz, 2H), 7.44 (d, J=6.8 Hz, 2H), 7.4–7.3 (m, 6H), 6.84 (d,
J=9.0 Hz, 1H), 6.8–6.7 (m, 2H), 5.23 (s, 1H), 4.23 (dd, J=11.3,
3.3 Hz, 1H), 3.2–3.1 (m, 1H), 2.99 (dd, J=16.0, 2.8 Hz, 1H),
2.03 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3, 308C): d=162.5 (d,
J=245.0 Hz), 144.6, 144.2, 137.8 (d, J=7.3 Hz), 134.6 (d, J=2.9 Hz),
129.4 (d, J=8.0 Hz), 129.3, 128.7, 128.6, 127.9, 127.7, 126.8, 115.0
(d, J=20.5 Hz), 113.1 (d, J=21.3 Hz), 64.1, 59.2, 39.2 ppm; 19F NMR
(CDCl3, 376 MHz, 308C): d=ꢀ117.2 ppm; MS (EI): m/z: calcd for
C21H18NF: 303.1423; found: 303.1404; HPLC (Daicel OD-H, hexane/
iPrOH, 99:1, detector: 215 nm, temperature: 158C, flow rate:
0.5 mLminꢀ1, t1 =17.7 min, t2 =20.4 min, major peak t1); [a]2D0 = +
15.6 (c=1.0, CHCl3) (for an ee of 94%).
t1 =14.3 min, t2 =16.8 min); [a]D20 =ꢀ8.0 (c=1.1, CHCl3) (for an ee of
90% ee and 97% ee mixture). The relative configuration of 9 was
assigned after N-tosylation and comparing the 1H NMR chemical
shifts of the product with literature values.[28]
Ir(H)2Cl{(S)-binap}(2-methylpyridine) ((S)-21): A mixture of [IrCl(-
coe)2]2 (353 mg, 0.394 mmol, 1 equiv) and (S)-BINAP (503 mg,
0.808 mmol, 2.05 equiv) in toluene was stirred overnight at room
temperature. After removing the displaced coe under reduced
pressure, 2-methylpyridine (12 equiv) was added and the mixture
was stirred for several hours. Under H2 atmosphere, the color of
the solution immediately turned from red to yellow. After the reac-
tion mixture had been stirred overnight, all volatiles were removed
under reduced pressure. The residue was redissolved in dichloro-
methane, and then precipitation by adding hexane afforded (S)-21
as a yellow solid. M.p. 1068C (decomp.); IR (KBr): n˜ =2962 (m),
2917 (m), 2849 (m), 2363 (w), 1539 (w), 1260 (s), 1093 (s), 1019 (s),
6-Methyl-1,3-diphenyl-1,2,3,4-tetrahydroisoquinoline (5j): White
solid; m.p. 90–918C; IR (KBr): n˜ =3430 (w), 3028 (m), 1614 (m),
1498 (s), 1455 (s), 1354 (w), 1280 (m), 1115 (m), 1026 cmꢀ1 (m);
1H NMR (CDCl3, 400 MHz, 308C): d=7.50 (d, J=7.3 Hz, 2H), 7.44 (d,
J=7.0 Hz, 2H), 7.4–7.2 (m, 6H), 6.96 (s, 1H), 6.88 (d, J=8.0 Hz, 1H),
6.65 (d, J=7.8 Hz, 1H), 5.26 (s, 1H), 4.22 (dd, J=11.0, 3.3 Hz, 1H),
3.16 (dd, J=15.3, 11.3 Hz, 1H), 2.97 (dd, J=16.0, 3.3 Hz, 1H), 2.31
(s, 3H), 2.01 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3, 308C): d=
145.1, 144.7, 135.9, 135.8, 135.4, 129.4, 129.3, 128.6, 128.5, 127.7,
127.6, 127.5, 126.9, 126.8, 64.3, 59.4, 39.2, 21.1 ppm; MS (EI): m/z:
calcd for C22H21N: 299.1674; found: 299.1703; HPLC (Daicel OD-H,
hexane/iPrOH, 99:1, detector: 215 nm, temperature: 108C, flow
1
798 cmꢀ1 (s); H NMR ([D8]dioxane, 400 MHz): d=9.16 (s, 1H), 8.35
(m, 2H), 8.2–6.0 (m, 33H), 2.91 (s, 3H), ꢀ9.41 (dd, J(P,H)=160,
16 Hz, 1H), ꢀ20.6 ppm (t, J(P,H)=15 Hz, 1H); 31P{1H} NMR
(161 MHz, [D8]dioxane, 308C): d=15.6 (s), 2.22 ppm (s); elemental
analysis calcd (%) for C50H41ClIrNP2·1.5CH2Cl2: C 57.65, H 4.13, N
1.31; found: C 57.63, H 4.08, N 1.32.
Ir(H)2Cl{(S)-segphos}(4-methoxypyridine) ((S)-22): The title com-
plex was synthesized according to a similar procedure as used for
(S)-21. The product was recrystallized from Et2O/CH2Cl2 and was
obtained as a yellow solid. IR (KBr): n˜ =2962 (m), 2917 (m), 2849
(m), 2539 (w), 1575 (w), 1538 (w), 1260 (s), 1092 (s), 1019 (s),
1
799 cmꢀ1 (s); H NMR (CD2Cl2, 400 MHz, 308C): d=8.68 (s, 2H), 8.5–
rate: 0.5 mLminꢀ1
, t1 =13.8 min, t2 =14.9 min, major peak t1);
[a]D20 = +10.9 (c=1.5, CHCl3) (for an ee of 97%).
5.8 (m, 30H), 3.72 (s, 3H), ꢀ8.61 (dd, J(P,H)=160, 18 Hz, 1H),
ꢀ21.3 ppm (t, J(P,H)=16 Hz, 1H); 31P{1H} NMR (161 MHz, CD2Cl2,
308C): d=8.13 (s), 0.30 ppm (s); elemental analysis calcd (%) for
C44H37ClIrNO5P2·1.5CH2Cl2: C 50.75, H 3.74, N 1.30; found: C 50.38,
H 3.63, N 1.37.
cis-3,4-Diphenyl-1,2,3,4-tetrahydroisoquinoline (7): Pale-blue
solid (>95:5 diastereoselectivity); m.p. 119–1218C; IR (KBr): n˜ =
3752 (m), 3651 (m), 3356 (s), 3025 (s), 2791 (s), 1578 (m), 1492 (s),
1
1449 (s), 1361 (m), 1112 (m), 933 (m), 743 (s), 700 cmꢀ1 (s); H NMR
(CDCl3, 400 MHz, 308C): d=7.27–7.08 (m, 6H), 7.08–6.96 (m, 4H),
6.91–6.84 (m, 2H), 6.60 (d, J=6.9 Hz, 2H), 4.44 (d, J=3.9 Hz, 1H),
4.38 (s, 2H), 4.23 (d, J=3.7 Hz, 1H), 1.91 ppm (brs, 1H); 13C NMR
(100 MHz, CDCl3, 308C): d=142.0, 141.1, 138.2, 135.4, 130.6, 130.3,
127.8, 127.1, 126.8, 126.7, 126.5, 126.4, 126.0, 125.9, 62.1, 50.8,
49.3 ppm; HRMS (ESI): m/z: calcd for C21H20N+: 286.1596 [MꢀH]+;
found 286.1595; HPLC (Daicel OD-H, temperature: 308C, hexane/
iPrOH, 90:1, detector: 215 nm, flow rate 1.0 mLminꢀ1, t1 =6.1 min
(major), t2 (ꢀ)=10.1 min (minor)); [a]D20 = +185 (c=0.46, CHCl3)
(for an ee of 43%). The relative configuration of 7 was assigned
X-ray crystallographic analysis
A crystal of (S)-22 was mounted on a CryoLoop (Hampton Re-
search Corp.) with a layer of light mineral oil and placed in a nitro-
gen stream at 113(1) K. Measurements were made on a Rigaku
AFC7R/Mercury CCD detector with graphite-monochromated MoKa
(0.71075 ꢁ) radiation. Crystal data and structure refinement param-
eters are listed in the Supporting Information.
The structure of (S)-22 was solved by direct methods (SHELXS-
97)[29] and refined against F2 by the full-matrix least-squares
method using SHELXS-97. Non-hydrogen atoms were refined ani-
sotropically. H atoms were included in the refinement in calculated
positions as riding on their carrier atoms. The function minimized
1
after N-benzylation and comparing the H NMR chemical shifts of
the product with literature values.[27]
1,4-Diphenyl-1,2,3,4-tetrahydroisoquinoline (9): Yellow oil (syn:-
anti, 4:1); IR (NaCl): n˜ =3081 (m), 3060 (s), 3025 (s), 2945 (s), 2880
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1925
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
was [(Fo ꢀFc2)2] (w=1/[s2(Fo )+(aP)2 +bP]), where P=(max(Fo ,0)+
2
2
2
[7] For reviews about additive effects on asymmetric hydrogenation, see:
a) Z. Yu, W. Jin, Q. Jiang, Angew. Chem. Int. Ed. 2012, 51, 6060–6072;
Angew. Chem. 2012, 124, 6164–6177; b) T. Nagano, A. Iimuro, K. Yamaji,
Y. Kita, K. Mashima, Heterocycles 2014, 88, 103–127.
[8] For representative examples of developing chiral diphosphine ligands,
see: a) M. Sawamura, H. Hamashima, M. Sugawara, R. Kuwano, Y. Ito, Or-
ganometallics 1995, 14, 4549–4558; b) L. Qin, 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; c) D.-Y. Zhang, D.-S. Wang, M.-C.
Wang, C.-B. Yu, K. Gao, Y.-G. Zhou, Synthesis 2011, 2796–2802; d) M.
Rubio, A. Pizzano, Molecules 2010, 15, 7732–7741; e) S. E. Lyubimov, D.
Ozolin, P. Y. Ivanov, A. Melman, V. S. Velezheva, V. A. Davankov, Chirality
2014, 26, 56–60.
[9] For representative examples of developing chiral P,N ligands, see: a) S.-
M. Lu, C. Bolm, Adv. Synth. Catal. 2008, 350, 1101–1105; b) A. Baeza, A.
Pfaltz, Chem. Eur. J. 2010, 16, 2036–2039; c) D.-S. Wang, J. Zhou, D.-W.
Wang, Y.-L. Guo, Y.-G. Zhou, Tetrahedron Lett. 2010, 51, 525–528; d) J. L.
NfflÇez-Rico, J. Fernµndez-Pꢃrez, J. Benet-Buchholz, A. Vidal-Ferran, Or-
ganometallics 2010, 29, 6627–6631.
2Fc2)/3 with s2(Fo ) from counting statistics. The functions R1 and
2
wR2 were (ꢀj jFo jꢀjFc j j)/ꢀjFo j and [ꢀw(Fo ꢀFc2)2/ꢀ(wFo )]1/2, re-
spectively. The ORTEP-3 program was used to draw the mole-
cule.[30]
2
4
Acknowledgements
This work is financially supported by the Core Research for
Evolutionary Science and Technology (CREST) program of the
Japan Science and Technology Agency (JST), a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” from the Ministry
of Education, Culture, Sports, Science and Technology (MEXT),
Japan, and
a Grant-in-Aid for Young Scientists (B) (No.
[10] For an example of developing chiral phosphite and phosphoramidite li-
gands, see: M. Eggenstein, A. Thomas, J. Theuerkauf, G. Franció, W. Leit-
ner, Adv. Synth. Catal. 2009, 351, 725–732.
25810062) from the MEXT, Japan. A.I. expresses his special
thanks for the financial support provided by the JSPS Research
Fellowship for Young Scientists.
[11] For representative examples, see: a) W.-B. Wang, S.-M. Lu, P.-Y. Yang, X.-
W. Han, Y.-G. Zhou, J. Am. Chem. Soc. 2003, 125, 10536–10537; b) C.
Deport, M. Buchotte, K. Abecassis, H. Tadaoka, T. Ayad, T. Ohshima, J.-P.
GenÞt, K. Mashima, V. Ratovelomanana-Vidal, Synlett 2007, 2743–2747;
c) W. Tang, L. Xu, Q.-H. Fan, J. Wang, B. Fan, Z. Zhou, K.-h. Lam, A. S. C.
Chan, Angew. Chem. Int. Ed. 2009, 48, 9135–9138; Angew. Chem. 2009,
121, 9299–9302; d) A. M. Maj, I. Suisse, C. Mꢃliet, C. Hardouin, F. Agbos-
sou-Niedercorn, Tetrahedron Lett. 2012, 53, 4747–4750; e) L. Shi, Z.-S.
Ye, L.-L. Cao, R.-N. Guo, Y. Hu, Y.-G. Zhou, Angew. Chem. Int. Ed. 2012, 51,
8286–8289; Angew. Chem. 2012, 124, 8411–8414; f) R.-N. Guo, X.-W.
Cai, Y.-G. Zhou, Chem. Commun. 2013, 49, 8537–8539.
Keywords: asymmetric catalysis · hydrogenation · iridium ·
nitrogen heterocycles · reaction mechanisms
[1] a) G. Shang, W. Li, X. Zhang, in Catalytic Asymmetric Synthesis, 3rd ed.
(Ed.: I. Ojima), Wiley, Hoboken, 2010, Chapter 7, pp. 343–436; b) K. Pꢂn-
tener, M. Scalone, W. Bonrath, R. Karge, T. Netcher, F. Roessler, F. Spind-
ler, in Asymmetric Catalysis on Industrial Scale: Challenges, Approaches
and Solutions, 2nd ed. (Eds.: H. U. Blaser, H. J. Federsel), Wiley-VCH,
Weinheim, 2010, Chapters 2–3, pp. 13–38.
[2] For reviews, see: a) Y.-G. Zhou, Acc. Chem. Res. 2007, 40, 1357–1366;
b) R. Kuwano, Heterocycles 2008, 76, 909–922; c) D.-S. Wang, Q.-A.
Chen, S.-M. Lu, Y.-G. Zhou, Chem. Rev. 2012, 112, 2557–2590.
[12] T. Nagano, A. Iimuro, R. Schwenk, T. Ohshima, Y. Kita, A. Togni, K. Mashi-
ma, Chem. Eur. J. 2012, 18, 11578–11592.
[13] a) H. Tadaoka, D. Cartigny, T. Nagano, T. Gosavi, T. Ayad, J.-P. GenÞt, T.
Ohshima, V. Ratovelomanana-Vidal, K. Mashima, Chem. Eur. J. 2009, 15,
9990–9994; b) A. Iimuro, K. Yamaji, S. Kandula, T. Nagano, Y. Kita, K. Ma-
shima, Angew. Chem. Int. Ed. 2013, 52, 2046–2050; Angew. Chem. 2013,
125, 2100–2104; c) Y. Kita, A. Iimuro, S. Hida, K. Mashima, Chem. Lett.
2014, 43, 284–286.
[3] S. Murata, T. Sugimoto, S. Matsuura, Heterocycles 1987, 26, 763–766.
[4] For recent examples, see: a) T. Wang, L.-G. Zhou, Z. Li, F. Chen, Z. Ding,
Y. He, Q.-H. Fan, J. Xiang, Z.-X. Yu, A. S. C. Chan, J. Am. Chem. Soc. 2011,
133, 9878–9891; b) Q.-A. Chen, D.-S. Wang, Y.-G. Zhou, Y. Duan, H.-J.
Fan, Y. Yang, Z. Zhang, J. Am. Chem. Soc. 2011, 133, 6126–6129; c) J.
Qin, F. Chen, Z. Ding, Y.-M. He, L. Xu, Q.-H. Fan, Org. Lett. 2011, 13,
6568–6571; d) T. Wang, G. Ouyang, Y.-M. He, Q.-H. Fan, Synlett 2011,
939–942; e) Q.-A. Chen, K. Gao, Y. Duan, Z.-S. Ye, L. Shi, Y. Yang, Y.-G.
Zhou, J. Am. Chem. Soc. 2012, 134, 2442–2448; f) N. Ortega, S. Urban, B.
Beiring, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 1710–1713; Angew.
Chem. 2012, 124, 1742–1745; g) T. Wang, F. Chen, J. Qin, Y.-M. He, Q.-H.
Fan, Angew. Chem. Int. Ed. 2013, 52, 7172–7176; Angew. Chem. 2013,
125, 7313–7317; h) Z.-Y. Ding, T. Wang, Y.-M. He, F. Chen, H.-F. Zhou, Q.-
H. Fan, Q. Guo, A. S. C. Chan, Adv. Synth. Catal. 2013, 355, 3727–3735;
i) J. Wysocki, N. Ortega, F. Glorius, Angew. Chem. Int. Ed. 2014, 53, 8751–
8755; Angew. Chem. 2014, 126, 8896–8900.
[5] For representative examples, see: a) R. Kuwano, K. Sato, T. Kurokawa, D.
Karube, Y. Ito, J. Am. Chem. Soc. 2000, 122, 7614–7615; b) M. Studer, C.
Wedemeyer-Exl, F. Splindler, H.-U. Blaser, Monatsh. Chem. 2000, 131,
1335–1343; c) C. Bianchini, P. Barbaro, G. Scapacci, J. Organomet. Chem.
2001, 621, 26–33; d) R. Kuwano, K. Kaneda, T. Ito, K. Sato, T. Kurokawa,
Y. Ito, Org. Lett. 2004, 6, 2213–2215; e) A. Lei, M. Chen, M. He, X. Zhang,
Eur. J. Org. Chem. 2006, 4343–4347; f) P. Feiertag, M. Albert, U. Netteko-
ven, F. Spindler, Org. Lett. 2006, 8, 4133–4135; g) R. Kuwano, M. Kashi-
wabara, K. Sato, T. Ito, K. Kaneda, Y. Ito, Tetrahedron: Asymmetry 2006,
[14] a) Z. W. Li, T.-L. Wang, Y.-M. He, Z.-J. Wang, Q.-H. Fan, J. Pan, L.-J. Xu,
ˇ ´
Org. Lett. 2008, 10, 5265–5268; b) N. Mrsic, L. Lefort, J. A. F. Boogers,
A. J. Minnaard, B. L. Feringa, J. G. de Vries, Adv. Synth. Catal. 2008, 350,
ˇ ˇ
1081–1089; c) N. Mrsic, T. Jerphagnon, A. J. Minnaard, B. L. Feringa, J. G.
de Vries, Adv. Synth. Catal. 2009, 351, 2549–2552; d) D.-S. Wang, Y.-G.
Zhou, Tetrahedron Lett. 2010, 51, 3014–3017.
[15] a) S.-M. Lu, Y.-Q. Wang, X.-W. Han, Y.-G. Zhou, Angew. Chem. Int. Ed.
2006, 45, 2260–2263; Angew. Chem. 2006, 118, 2318–2321; b) Z.-S. Ye,
M.-W. Chen, Q.-A. Chen, L. Shi, Y. Duan, Y.-G. Zhou, Angew. Chem. Int. Ed.
2012, 51, 10181–10184; Angew. Chem. 2012, 124, 10328–10331; c) Z.-S.
Ye, R.-N. Guo, X.-F. Cai, M.-W. Chen, L. Shi, Y.-G. Zhou, Angew. Chem. Int.
Ed. 2013, 52, 3685–3689; Angew. Chem. 2013, 125, 3773–3777.
[16] a) I. Tellitu, D. Badía, E. Domínguez, F. J. García, Tetrahedron: Asymmetry
1994, 5, 1567–1578; b) L. Carrillo, D. Badía, E. Domínguez, F. Ortega, I.
Tellitu, Tetrahedron: Asymmetry 1998, 9, 151–155; c) F. A. Davis, Y. W.
Andemichael, J. Org. Chem. 1999, 64, 8627–8634; d) J. L. Vicario, D.
Badía, E. Domínguez, L. Carrillo, J. Org. Chem. 1999, 64, 4610–4616;
e) R. Pedrosa, C. Andrꢃs, J. M. Iglesias, M. A. Obeso, Tetrahedron 2001,
57, 4005–4014; f) S. Chandrasekhar, N. R. Reddy, M. V. Reddy, B. Jagan-
nadh, A. Nagaraju, A. R. Sankar, A. C. Kunwar, Tetrahedron Lett. 2002, 43,
1885–1888; g) M. Dubois, E. Deniau, A. Conture, P. Grandclaudon, Tetra-
hedron Lett. 2012, 68, 7140–7147; h) J. L. Vicario, D. Badía, L. Carrillo, E.
Anakabe, Tetrahedron: Asymmetry 2003, 14, 347–353; i) D. Enders, V.
Braig, M. Boudou, G. Raabe, Synthesis 2004, 2980–2990; j) T. Kawabata,
S. Majumdar, K. Tsubaki, D. Monguchi, Org. Biomol. Chem. 2005, 3,
1609–1611; k) T. Kawabata, S. Matsuda, S. Kawakami, D. Monguchi, K.
Moriyama, J. Am. Chem. Soc. 2006, 128, 15394–15395; l) J. M. Concellón,
P. Tuya, V. del Solar, S. García-Granda, M. R. Díaz, Org. Lett. 2009, 11,
3750–3753.
ˇ ´
17, 521–535; h) N. Mrsic, T. Jerphagnon, A. J. Minnaard, B. L. Feringa,
J. G. de Vries, Tetrahedron: Asymmetry 2010, 21, 7–10; i) A. M. Maj, I.
Suisse, C. Mꢃliet, F. Agbossou-Niedercorn, Tetrahedron: Asymmetry 2010,
21, 2010–2014.
[6] For a review, see: Q.-A. Chen, Z.-S. Ye, Y. Duan, Y.-G. Zhou, Chem. Soc.
Rev. 2013, 42, 497–511. For a recent example, see: a) Y. Duan, L. Li, M.-
W. Chen, C.-B. Yu, H.-J. Fan, Y.-G. Zhou, J. Am. Chem. Soc. 2014, 136,
7688–7700.
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1926
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[17] D. Zhao, F. Glorius, Angew. Chem. Int. Ed. 2013, 52, 9616–9618; Angew.
Chem. 2013, 125, 9794–9796.
[22] G. E. Dobereiner, A. Nova, N. D. Schley, N. Hazari, S. J. Miller, O. Eisen-
stein, R. H. Crabtree, J. Am. Chem. Soc. 2011, 133, 7547–7562.
[23] O. Eisenstein, R. H. Crabtree, New J. Chem. 2013, 37, 21–27.
[24] T. Yamagata, H. Tadaoka, M. Nagata, T. Hirao, Y. Kataoka, V. Ratoveloma-
nana-Vidal, J. P. GenÞt, K. Mashima, Organometallics 2006, 25, 2505–
2513.
[18] a) C.-Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005, 127, 8966–8967;
b) Y.-C. Xiao, C. Wang, Y. Yao, J. Sun, Y.-C. Chen, Angew. Chem. Int. Ed.
2011, 50, 10661–10664; Angew. Chem. 2011, 123, 10849–10852; c) D.-S.
Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan, G.-F. Hiang,
Chem. Sci. 2011, 2, 803–806; d) ref. [4]; e) Y. Duan, M. W. Chen, Q.-A.
Chen, C.-B. Yu, Y.-G. Zhou, Org. Biomol. Chem. 2012, 10, 1235–1238;
f) Z.-P. Chen, Z.-S. Ye, M.-W. Chen, Y.-G. Zhou, Synthesis 2013, 45, 3239–
3244; g) C. Li, J. Chen, G. Fu, D. Liu, Y. Liu, W. Zhang, Tetrahedron 2013,
69, 6839–6844; h) J. L. NfflÇez-Rico, H. Fernµndez-Pꢃrez, A. Vidal-Ferran,
Green Chem. 2014, 16, 1153–1157.
[19] a) R. D. Simpson, W. J. Marshall, A. A. Farischon, D. C. Roe, V. V. Grushin,
Inorg. Chem. 1999, 38, 4171–4173; b) M. A. Esteruelas, F. J. Fernµndez-
Alvarez, M. Olivµn, E. OÇate, Organometallics 2009, 28, 2276–2284.
[20] Two hydrogen bonds between Et2NH2Cl and the chloride ligand of
a ruthenium complex have been reported, see: T. Ohta, Y. Tonomura, K.
Nozaki, H. Takaya, K. Mashima, Organometallics 1996, 15, 1521–1523.
[21] H. Werner, T. Dirnberger, A. Hçhn, Chem. Ber. 1991, 124, 1957–1961.
[25] M. Chang, W. Li, X. Zhang, Angew. Chem. Int. Ed. 2011, 50, 10679–
10681; Angew. Chem. 2011, 123, 10867–10869.
[26] T. Suna, Chem. Heterocycl. Compd. 2000, 36, 287–300.
[27] S. Chandrasekhar, N. R. Reddy, M. V. Reddy, B. Jagannadh, A. Nagaraju,
A. Ravi Sankar, A. C. Kunwar, Tetrahedron Lett. 2002, 43, 1885–1888.
[28] S. Wang, Z. Chai, S. Zhou, S. Wang, X. Zhu, Y. Wei, Org. Lett. 2013, 15,
2628–2631.
[29] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112.
[30] L. J. Farrugia, Appl. Crystallogr. 1999, 32, 837.
Received: September 25, 2014
Published online on November 28, 2014
Chem. Eur. J. 2015, 21, 1915 – 1927
www.chemeurj.org
1927
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim