Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst

Article abstract of DOI:10.1021/jacs.8b11547

A novel cationic [IrH(THF)(P,N)(imine)] [BAr_F] catalyst containing a P-stereogenic MaxPHOX ligand is described for the direct asymmetric hydrogenation of N-methyl and N-alkyl imines. This is the first catalytic system to attain high enantioselectivity (up to 94% ee) in this type of transformation. The labile tetrahydrofuran ligand allows for effective activation and reactivity, even at low temperatures. Density functional theory calculations allowed the rationalization of the stereochemical course of the reaction.

Full text of DOI:10.1021/jacs.8b11547

Subscriber access provided by Kaohsiung Medical University
Communication
Direct Asymmetric Hydrogenation of N-Methyl
and N-Alkyl Imines with an Ir(III)H Catalyst
Ernest Salomo, Albert Gallen, Giuseppe Sciortino, Gregori Ujaque,
Arnald Grabulosa, Agusti Lledos, Antoni Riera, and Xavier Verdaguer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b11547 • Publication Date (Web): 26 Nov 2018
Downloaded from http://pubs.acs.org on November 27, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl
Imines with an Ir(III)H Catalyst
Ernest Salomó, † Albert Gallen, ‡ Giuseppe Sciortino,§,# Gregori Ujaque,§ Arnald Grabulosa, ‡ Agustí
Lledós,*,§ Antoni Riera, *,†,‡ Xavier Verdaguer *,†,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Baldiri Reixac 10,
08028 Barcelona, Spain.
‡ Dept. Química Inorgànica i Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.
§ Dept. de Química, Ed. C.n., Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona 08193, Spain.
# Dipt. di Chimica e Farmacia, Università di Sassari, via Vienna 2, I-07017 Sassari, Italy.
Supporting Information Placeholder
H
N
N
ABSTRACT: A novel cationic [IrH(THF)(P,N)(imine)] [BArF]
catalyst containing a P-stereogenic MaxPHOX ligand is described
for the direct asymmetric hydrogenation of N-methyl and N-alkyl
imines. This is the first catalytic system to attain high
enantioselectivity (up to 94% ee) in this type of transformation. The
labile THF ligand allows for effective activation and reactivity,
even at low temperatures. DFT calculations allowed the
rationalization of the stereochemical course of the reaction.
NH
N
O
O
Rivastigmine
dextro-Methamphetamine
F3C
H
Cl
N
Cl
Cinacalcet
Sertraline
Figure 1: Chiral N-methyl and N-alkyl amine pharmaceuticals.
Chiral N-methyl or N-alkyl amine is a frequent pharmacophore
in pharmaceutical substances (Figure 1). Examples include
sertraline (to treat depression),1 dextro-methamphetamine (to treat
ADHD and narcolepsy),2 rivastigmine (to treat Alzheimer’s and
Scheme 1. Background vs. present work on the direct
asymmetric hydrogenation of N-methyl imines.
Parkinson’s
diseases)3
and
cinacalcet
(to
treat
N
HN
hyperparathyroidism).4 Due to the importance of this moiety, many
efforts have been devoted to the asymmetric synthesis of optically
pure N-methyl amines.5 An ideal methodology to obtain this class
of compounds is the catalytic reduction of the corresponding
imines. However, the high basicity and nucleophilicity of N-methyl
amines often results in catalyst deactivation. The most successful
approaches for the asymmetric reduction of N-methyl imines are
Ti-catalyzed hydrosilylation, reported by Buchwald,6a and
Brönsted acid-catalyzed reduction using Hantzsch ester in the
presence of Boc2O, reported by List.6b In both cases, the final amine
product is protected with either a SiR3 or Boc group, thus
circumventing the basicity issue associated with the free amine.
Cat
H2
R
R
Present work
Pfaltz group
Cat =
X
X
H
Ir
P
N
O
P
N
Ir
N
Ph
4 mol%, 100 bar
58% ee
1 mol%, 3 bar
up to 94% ee
From an industrial perspective, the direct hydrogenation of
imines is a much more desirable process;7 however, in contrast to
the good results obtained with N-aryl ketimines,8,9 the
hydrogenation of N-methyl ketimines has not yet been achieved
with useful levels of enantioselectivity. Pfaltz and co-workers
reported the hydrogenation of the N-methyl imine of acetophenone
with Ir-PHOX catalysts, achieving only 58% ee (Scheme 1).10 The
conversion was complete, but harsh pressures of hydrogen (100
bar) and high catalyst loadings (4 mol%) were required. We
hypothesize that this difference between N-aryl and N-alkyl
ketimines is due to the aforementioned basicity of this class of
compounds. Here we report a novel type of Ir(III) precatalyst that
can be used directly in hydrogenation reactions and that has
allowed the direct hydrogenation of N-methyl and N-alkyl imines
in mild conditions and with high levels of selectivity (Scheme 1).
We have recently reported that cationic Ir(I)-MaxPHOX catalysts
are highly active and selective in the hydrogenation of N-aryl
imines.11,12 Here we tested whether these catalysts are also effective
for N-methyl imine substrates (Table 1). The initial attempts to
reduce the model N-methyl imine with four distinct diastereomers
of Ir-MaxPHOX catalysts (1-4) were disappointing (Table 1,
entries 1-4). A maximum enantiomeric excess of 71% was obtained
with catalyst 2, but with only 41% conversion. In 2013, Pfaltz and
co-workers reported that the catalyst in the hydrogenation of N-aryl
imines is an iridacycle that forms upon reaction with the imine
substrate.13 We have previously isolated and characterized
cyclometallated [IrHCl(MaxPHOX)(imine)] complexes.11 With
this in mind, we hypothesized that, with the addition of the proper
cyclometallating agent, a novel iridacycle would show an enhanced
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
iPr
capacity to reduce N-methyl imines. After testing a wide array of
BArF
BArF
iPr
O
1
2
3
4
cyclometallating substances (A1-A15, see SI), we identified
acetophenone N-phenyl imine (A5) as the best additive. Indeed, the
addition 2 mol % of A5 dramatically improved the reaction
outcome with respect to both the conversion and selectivity (Table
1, entries 5-8). The best result was obtained with catalyst 1,
achieving an unprecedented 90% ee (Table 1, entry 5).
HN
P
Me
tBu
O
HN
P
H
N
A5
1) H2,
2) L
iPr
N
Ir
Ir
Me
iPr
X
THF
N
Ph
5
1
6
7
8
9
Entry
Added L Yield (%)
X
Complex
Table 1. Catalyst optimization.a
1
2
3
4
CH3CN
Ph3P
Me3P
92
94
96
98
CH3CN
Ph3P
Me3P
THF
5
6
7
8
N
HN
Additive
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1 mol% cat.
N
Ethylene
*
CH3
H2, 3 bar
DCM
A5
Table 3: Catalysis with cyclometallated Ir(III)H catalysts.
Catalysts:
iPr
BArF
BArF
iPr
BArF
BArF
iPr
iPr
N
HN
O
O
O
O
HN
P
HN
HN
HN
P
cat. 1 mol %
N
P
N
P
N
N
Ir
Ir
Ir
Ir
Me
Me
iPr
iPr
Me
Me
iPr
H2 (3 bar), DCM
iPr
4
2
3
1
Entry
cat.
5
6
7
8
T (°C)
Conv. (%)a ee (%)b
Entry
Cat.
1
2
3
4
1
2
3
4
Additivea Conv. (%)b ee (conf.)c
1
2
3
4
5
6
rt
rt
rt
rt
0
100
0
100
100
0
85
-
90
91
-
1
2
3
4
5
6
7
8
-
-
-
100
41
100
6
100
100
100
36
13(R)
71(S)
9(R)
11(R)
90(S)
61(S)
78(R)
86(R)
-
7
A5
A5
A5
A5
8
0
100
1
91
a) Conversion was determined by H NMR. b) Enantiomeric
excess was determined by chiral HPLC analysis of the
corresponding trifluoroacetate.
a) 2 mol% of additive was added prior to the addition of the
imine substrate. b) Conversion was determined by H NMR. c)
Enantiomeric excess was determined by chiral HPLC analysis of
the corresponding trifluoroacetate. Absolute configuration was
determined by optical rotation of the free amine.
1
Complexes 5-8 were used as catalytic precursors in the
hydrogenation of acetophenone N-methyl imine (Table 3). We
found that complexes containing CH3CN (5), PMe3 (7) and THF
(8) provided 100% conversion at room temperature while the
catalyst containing a PPh3 (6) proved inactive (Table 3, entry 2).
Catalysts 7 and 8 provided the best selectivity, 90 and 91% ee
respectively, which parallels that achieved with the catalyst
generated in situ (Table 3, entries 3 and 4). When the reaction
temperature was lowered to 0 °C, complex 8 maintained its activity,
while the Me3P analog (7) was no longer active (Table 3, entries 5
and 6). We assumed that, in the presence of hydrogen, the solvent
fragment in 8 is quickly released, thereby allowing faster
activation.14
To achieve a reliable and robust method applicable in large- or
even industrial-scale reactions, it would be desirable to isolate a
catalyst that can be used directly in hydrogenation reactions. As
mentioned above, neutral cyclometallated Ir(III)HCl complexes
have been prepared and isolated; however, these complexes require
activation by the addition of NaBArF.11,13 We envisaged that an
active precatalyst could be achieved if the reactive coordination site
was stabilized with a transient ligand. To this end, complex 1 was
reacted, in the presence of hydrogen, with acetophenone N-phenyl
imine (A5), and the resulting complex was treated with several
stabilizing ligands (Table 2). The use of CH3CN, Ph3P and Me3P as
ligands provided a single stereoisomer of the corresponding
Using catalyst 8, we next addressed the hydrogenation of several
N-methyl and N-alkyl ketimines. The results are summarized in
Figure 2. Full conversions were obtained in all cases. Reactions at
low temperature (0–10°C) generally produced higher selectivity.
Imines derived from 4- and 3-methoxyacetophenone were less
reactive. In this regard, the hydrogenation had to be conducted at
room temperature and the enantiomeric excesses for the
corresponding amines were 91 and 89%, respectively. For the
substrates containing electron-withdrawing groups (p-Cl, p-F and
p-CF3), the temperature was decreased to ‒10 °C, which improved
selectivity, allowing up to 93-94% ee. N-Methyl imine derived
from -tetralone was hydrogenated, achieving 89% ee. Finally,
excellent results were also obtained with imines derived from N-
propyl and N-isobutyl amine. This observation thus indicates that
N-alkyl imines can be hydrogenated with high selectivity (92-94%
ee).15
cationic octahedral Ir(III) complexes 5-7, as shown by 1H and 31
P
NMR spectra. Pressurization with ethylene gas (3 bar) afforded
complex 8, also as a single stereoisomer. However, 8 did not
contain an ethylene ligand but a solvent molecule instead (Table 2,
entry 4). As expected, complex 8 could be synthesized without the
addition of ethylene, interestingly, the resulting complex was of
lower purity, as determined by 1H NMR spectroscopy (see SI). We
hypothesized that ethylene assists in the isomerization of
intermediate unsaturated species to yield the final compound. To
our delight, complexes 5-8 are stable solids that can be handled in
air and stored under nitrogen (see SI for X-ray structure of 7).
Table 2. Synthesis of Ir(III)H cyclometallated catalysts.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Figure 2: Results for the hydrogenation of N-methyl and N-
alkyl imines using catalyst 8.a,b
1
2
3
N
N
N
N
N
MeO
4
5
6
MeO
F
Cl
0 ºC
94% ee
-10 ºC
93% ee
0 ºC
91% ee
rt
rt
91% ee
89% ee
7
N
N
N
N
N
8
9
Cl
F3C
-10 ºC
93% ee
-10 ºC
94% ee
0 ºC
92% ee
-10 ºC
93% ee
-10 ºC
89% ee
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a) Hydrogenation reactions were run overnight in DCM at 3 bar
of H2 with 1 mol % of 8 at the temperature listed. 100% conversion
was obtained in all cases, as determined by 1H NMR. b)
Enantiomeric excess was determined by chiral HPLC of the
corresponding trifluoroacetamide.
The hydrogenation of N-phenyl imines has been proposed to
proceed through an outer-sphere mechanism.16 In order to
understand the stereochemical course of the reaction a DFT
mechanistic study using the B3LYP-D3 functional and including
solvent effects has been performed in the present system (see SI for
full details). The active catalyst is the iridium(III) hydride-
dihydrogen complex that results from the ligand exchange of THF
with H2. The acidic dihydrogen complex protonates the imine-
substrate and leads to an iminium ion which is not bound to the Ir
center. The stereodetermining step is the intermolecular hydride-
transfer from the resulting IrH2 to the activated substrate. This is a
lose TS in which multiple orientations of the substrate are possible.
A quadrant model that accounts for the possible orientations of the
iminium ion is depicted in Figure 3a. The most favorable TS is the
one where the phenyl ring of the substrate is placed in the SW
quadrant (Figure 3b) and leads to the S enantiomer as observed
experimentally. The most favorable TS leading to the R isomer is
1.8 kcal mol-1 above with the phenyl group in the NW quadrant
(Figure 3c). From these values the calculated enantiomeric excess
is 90%, which is in close agreement with the experimental findings.
Non-covalent interaction analysis17 shows that in the (S)-SW TS
the phenyl group of the iminium ion generates a larger 
interaction surface than the (R)-NW TS (Figure 3b,c), thus leading
to a more favorable transition sate. In support of this notion is the
fact that the reduction of a purely aliphatic substrate like
cyclohexylmethylketone N-methyl imine provided a racemate.18
In summary, we have described a novel cationic Ir(III)H catalyst
that has allowed the first direct hydrogenation of methyl and alkyl
imines in mild conditions and in high enantiomeric excess. The
catalyst contains
a
P-stereogenic MaxPHOX ligand,
a
cyclometallated imine and a THF solvent molecule. The catalyst is
a stable solid that can be stored under nitrogen. The THF ligand
allows for fast and effective activation, even at reduced
temperatures. DFT studies allowed to interpret the stereochemical
course of the reaction. We think the findings reported herein
contribute to advances in the development of hydrogenation
iridium catalysts.
Figure 3: a) DFT computed quadrant model for the hydride
transfer stereodetermining step. Transition state relative G‡
values for different orientations of the substrate phenyl group
(in green: TSs leading to S isomer; in red: TSs leading to R
isomer). The hydride transferred to the substrate is highlighted
in magenta. b) Most favorable TS leading to S isomer, G‡ =
0.0 kcal mol-1 (G‡ = 6.3 kcal mol-1 with respect to the iminium
intermediate). c) Most favorable TS leading to R isomer, G‡
= 1.8 kcal mol-1. Color code for NCI analysis: red: repulsive,
blue: attractive.
ASSOCIATED CONTENT
Supporting Information
Screening of additives data, experimental procedures, crystal data
for 7, NMR spectra for new compounds, and HPLC
chromatograms. Crystallographic data in CIF format file for 7.
Computational methods and extended description of the
computational results. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Email: xavier.verdaguer@irbbarcelona.org
Email: antoni.riera@irbbarcelona.org
Email: agusti@klingon.uab.es
ORCID
Xavier Verdaguer: 0000-0002-9229-969X
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Application of Monodentate Secondary Phosphine Oxides, a New Class of
Antoni Riera: 0000-0001-7142-7675
Agustí Lledós: 0000-0001-7909-422X
Chiral Ligands, in Ir(I)-Catalyzed Asymmetric Imine Hydrogenation. Org.
Lett. 2003, 5, 1503–1506. (e) Mršić, N.; Minnaard, A. J.; Feringa, B. L.;
Vries, J. G. de. Iridium/Monodentate Phosphoramidite Catalyzed
Asymmetric Hydrogenation of N -Aryl Imines. J. Am. Chem. Soc. 2009,
131, 8358–8359. (f) Han, Z.; Wang, Z.; Zhang, X.; Ding, K. Spiro[4,4]-1,6-
Nonadiene-Based Phosphine-Oxazoline Ligands for Iridium-Catalyzed
Enantioselective Hydrogenation of Ketimines. Angew. Chem. Int. Ed. 2009,
48, 5345–5349. (g) Li, C.; Wang, C.; Villa-Marcos, B.; Xiao, J. Chiral
Counteranion-Aided Asymmetric Hydrogenation of Acyclic Imines. J. Am.
Chem. Soc. 2008, 130, 14450–14451. (h) Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-
1
2
3
4
5
6
7
8
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank MINECO (CTQ2017-87840-P, CTQ2017-87889-P and
CTQ2015-65040-P) and IRB Barcelona for financial support. We
gratefully acknowledge institutional funding from the Spanish
Ministry of Economy, Industry and Competitiveness (MINECO)
through the Centers of Excellence Severo Ochoa award, and from
the CERCA Programme of the Catalan Government. E. S. thanks
MINECO for a fellowship.
Z.;
Li,
S.;
Zhou,
Q.-L.
Cationic
Well-Defined
Complexes
Chiral
for
Spiro
Highly
9
Iridium/Phosphine−Oxazoline
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Enantioselective Hydrogenation of Imines at Ambient Pressure. J. Am.
Chem. Soc. 2006, 128, 12886–12891.
(10) a) Schnider, P.; Koch, G.; Prétôt, R.; Wang, G.; Bohnen, F. M.;
Krüger, C.; Pfaltz, A. Enantioselective Hydrogenation of Imines with Chiral
(Phosphanodihydrooxazole)iridium Catalysts. Chem. Eur. J. 1997, 3, 887–
892. b) Baeza, A.; Pfaltz, A. Iridium-Catalyzed Asymmetric Hydrogenation
of Imines. Chem. Eur. J. 2010, 16, 4003–4009.
(11) Salomó, E.; Rojo, P.; Hernández-Lladó, P.; Riera, A.; Verdaguer,
X. P-Stereogenic and Non-P-Stereogenic Ir–MaxPHOX in the Asymmetric
Hydrogenation of N-Aryl Imines. Isolation and X-Ray Analysis of Imine
Iridacycles. J. Org. Chem. 2018, 83, 4618–4627.
REFERENCES
(1) Doogan, D. P.; Caillard, V. Sertraline: A New Antidepressant. J.
Clin. Psychiatry 1988, 49 Suppl, 46–51.
(2) Parkes, J. D.; Fenton, G. W. Levo(-) Amphetamine and Dextro(+)
Amphetamine in the Treatment of Narcolepsy. J. Neurol. Neurosurg.
Psychiatry 1973, 36, 1076–1081.
(12) (a) Salomó, E.; Orgué, S.; Riera, A.; Verdaguer, X. Highly
Enantioselective Iridium-Catalyzed Hydrogenation of Cyclic Enamides.
Angew. Chem. Int. Ed. 2016, 55, 7988–7992. (b) Orgué, S.; Flores, A.;
Biosca, M.; Pamies, O.; Diéguez, M.; Riera, A.; Verdaguer, X.
Stereospecific SN2@P Reactions: Novel Access to Bulky P-Stereogenic
Ligands. Chem. Commun. 2015, 51, 17548–17551.
(13) Schramm, Y.; Barrios-Landeros, F.; Pfaltz, A. Discovery of an
Iridacycle Catalyst with Improved Reactivity and Enantioselectivity in the
Hydrogenation of Dialkyl Ketimines. Chem. Sci. 2013, 4, 2760–2766.
(14) The integrity of the catalyst is preserved throughout the catalysis.
GC analysis of the crude mixture after the reaction showed N-methyl imine
substrate does not exchange with the cyclometallated N-phenyl imine.
Moreover, the catalyst could be recovered after the reaction by trapping it
with PMe3. See supporting information for full details.
(3) Finkel, S. I. Effects of Rivastigmine on Behavioral and Psychological
Symptoms of Dementia in Alzheimer’s Disease. Clin. Ther. 2004, 26, 980–
990.
(4) Torres, P. U. Cinacalcet HCl: A Novel Treatment for Secondary
Hyperparathyroidism Caused by Chronic Kidney Disease. J. Ren. Nutr.
2006, 16, 253–258.
(5) Chiral Amine Synthesis; Nugent, T. C., Ed.; Wiley-VCH, Weinheim,
2010.
(6) (a) Verdaguer, X.; Lange, U. E. W.; Reding, M. T.; Buchwald, S. L.
Highly Enantioselective Imine Hydrosilylation Using (S,S)-Ethylenebis(η5-
Tetrahydroindenyl)titanium Difluoride. J. Am. Chem. Soc. 1996, 118,
6784–6785. (b) Wakchaure, V. N.; Kaib, P. S. J.; Leutzsch, M.; List, B.
Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines.
Angew. Chem. Int. Ed. 2015, 54, 11852–11856.
(7) Asymmetric Catalysis on Industrial Scale: Challenges, Approaches
and Solutions, 2nd ed.; Blaser, H.-U., Federsel, H.-J., Eds.; Wiley-VCH:
Weinheim, 2010.
(8) For reviews on the metal catalyzed asymmetric hydrogenation of
imines, see: a) Hopmann, K. H.; Bayer, A. Enantioselective Imine
Hydrogenation with Iridium-Catalysts: Reactions, Mechanisms and
Stereocontrol. Coord. Chem. Rev. 2014, 268, 59–82. b) Fleury-Brégeot, N.;
de la Fuente, V.; Castillón, S.; Claver, C. Highlights of Transition Metal-
Catalyzed Asymmetric Hydrogenation of Imines. ChemCatChem 2010, 2,
1346–1371. c) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Transition Metal-
Catalyzed Enantioselective Hydrogenation of Enamines and Imines. Chem.
Rev. 2011, 111, 1713–1760.
(15) The E/Z ratio of the starting imines as determined by 1H NMR
ranges between 95:5 and 100:0. We found no direct correlation between the
E/Z ratio and the selectivity of the reaction. It is possible that the proposed
iminium ion intermediate isomerizes under the reaction conditions.
(16) (a) Tutkowski, B.; Kerdphon, S.; Limé, E.; Helquist, P.; Andersson,
P. G.; Wiest, O.; Norrby, P.-O. Revisiting the Stereodetermining Step in
Enantioselective Iridium-Catalyzed Imine Hydrogenation. ACS Catal.
2018, 8, 615–623. (b) Hopmann, K. H.; Bayer, A. On the Mechanism of
Iridium-Catalyzed Asymmetric Hydrogenation of Imines and Alkenes: A
Theoretical Study. Organometallics 2011, 30, 2483–2497.
(17) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.;
Piquemal, J.-P.; Beratan, D. N.; Yang. W. NCIPLOT: A Program for
Plotting Noncovalent Interaction Regions. J. Chem. Theory Comput. 2011,
7, 625–632.
(18) Hydrogenation of cyclohexylmethylketone N-methylimine with 1
mol% of 8 provided a racemate with 50% conversion. Similar calculations
to those reported in Figure 3 (quadrant model) for this substrate give a G‡
difference of only 0.1 kcal mol-1 between the most favorable TSs leading to
opposite enantiomers. See supporting information for further details.
(9) For examples of the Iridium catalyzed hydrogenation of N-aryl
imines, see: (a) Cheemala, M. N.; Knochel, P. New P,N-Ferrocenyl Ligands
for the Asymmetric Ir-Catalyzed Hydrogenation of Imines. Org. Lett. 2007,
9,
3089–3092.
(b)
Moessner,
C.;
Bolm,
C.
Diphenylphosphanylsulfoximines as Ligands in Iridium-Catalyzed
Asymmetric Imine Hydrogenations. Angew. Chem. Int. Ed. 2005, 44, 7564–
7567. (c) Trifonova, A.; Diesen, J. S.; Chapman, C. J.; Andersson, P. G.
Application of Phosphine−Oxazoline Ligands in Ir-Catalyzed Asymmetric
Hydrogenation of Acyclic Aromatic N-Arylimines. Org. Lett. 2004, 6,
3825–3827. (d) Jiang, X.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.;
Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
TOC Graphic
1
2
3
4
iPr
X
O
5
6
7
8
HN
P
Me
tBu
·
·
·
Stable Ir(III)H catalyst
Direct hydrogenation
Mild conditions
H
Ir
N
iPr
1 mol%
O
9
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
N
HN
3 bar H2
R
R
up to 94% ee
ACS Paragon Plus Environment