Iridium-catalyzed enantioselective reductive amination of aromatic ketones

Article abstract of DOI:10.1039/d0cy01271h

A highly efficient direct asymmetric reductive amination of aromatic ketones catalyzed by an iridium complex of Josiphos-type binaphane ligands was described. This concise and practical method provided chiral amines in high yields and enantioselectivities (up to 99% ee). This journal is

Full text of DOI:10.1039/d0cy01271h

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Chaoqiu Chen, Yong Qin et al.
Highly dispersed Pt nanoparticles supported on carbon
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DOI: 10.1039/D0CY01271H
COMMUNICATION
Iridium-catalyzed Enantioselective Reductive Amination of
Aromatic Ketones
Ruixia Liu,a+ Bin Li,b+ Jingkuo Han,a Dongxu Zhang,a Muqiong Li,a Lin Yao,a Wei Zhao,a Qiaofeng
Received 00th January 20xx,
Accepted 00th January 20xx
Wang,a Ru Jiang*a and Huifang Nie*a
DOI: 10.1039/x0xx00000x
NH2
A highly efficient direct asymmetric reductive amination of
aromatic ketones catalyzed by iridium complex of Josiphos-type
binaphane ligands was described. This concise and practical
method provided chiral amines in high yields and
enantioselectivities (up to 99 % ee).
NH2
N
NHR
I
II
III
resolving agent
chiral catalysts
selegiline
O
O
N
O
O
N
Due to their wide applications as resolving agents, chiral
auxiliaries/chiral bases and catalysts for asymmetric synthesis
(Figure 1), chiral amines are of significant commercial value in
pharmaceutical and agrochemical industry.1 Moreover, chiral
amines themselves often possess pronounced biological
activities, and hence they constitute privileged building blocks
for pharmaceuticals and agrochemicals (Figure 1).2 To satisfy
the demand for enantiomerically pure amines, the
development of efficient synthetic methods toward chiral
amines has long been a thriving field in organic chemistry.3 As
compared to the highly efficient asymmetric hydrogenation
(AH) and asymmetric transfer hydrogenation of the
corresponding imines/enamines or iminium salts, the approach
of direct asymmetric reductive amination (DARA) bypasses the
preparation of the C−N double bond substrates, and is thus
more concise, more efficient, and more promising.4
Reductive amination (RA) is one of the most widely utilized
transformations both in biological systems and synthetic
organic chemistry.5 As a privileged tool for nature, many
essential biomonomers including amino acids inside organisms
are synthesized through this effective strategy. As for synthetic
chemistry, since the first DARA reported by Blaser et al. in 1999
in the production of the herbicide metolachlor,6 some progress
has been made in the synthesis of chiral amines through
transition metal-catalyzed RA, which represents a step-
economic and efficient strategy by directly converting carbonyl
OMe
N
O
IV
V
solifenacin
metalaxyl
Figure 1 Representative important compounds containing
chiral amine unit.
compounds into amines in the presence of amine sources and
reductants.7 However, compared to numerous reports about
asymmetric imine/enamine reduction, only relatively limited
success has been achieved regarding DARA, partly due to the
incompatibility of transition-metal hydrides with ketones and
inhibition of the amines to the metal catalysts.8 Owing to the
limited advances yet promising utility of DARA for the synthesis
of chiral amines, the development of robust and efficient
catalytic system is challenging and highly desirable.
Recently, we have developed a series of Josiphos-type
binaphane ligands (RC,SFc,Sax)-1, ax-Josiphos (Figure 2), that
have shown excellent reactivities and enantioselectivities for Ir-
catalyzed AH of cyclic imines and acyclic imines.9 Furthermore,
we found these ax-Josiphos possessed surprising hydrolytic and
air stability, with no degradation after 6 months open to the air
for Ph-ax-Josiphos. As part of our ongoing studies on AH of
imines, we envisioned that this robust and efficient catalytic
system might tolerate the inhibition of the amines to the
catalysts. Herein, we report the highly efficient DARA of
aromatic ketones catalyzed by the Ir-(R)-Cy-ax-Josiphos using o-
anisidine as the nitrogen source. This transformation provides
PR2
ax-Josiphos
a. School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
e-mail: jiangru@fmmu.edu.cn; niehuifang@fmmu.edu.cn
b. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry
of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR
China.
Fe
P
1a, t
(RC,SFc,Sax)-
Bu-ax-Josiphos
1b
(RC,SFc,Sax)- , Cy-ax-Josiphos
1c,
(RC,SFc,Sax)-
Ph-ax-Josiphos
1d
(RC,SFc,Sax)- , Xyl-ax-Josiphos
+. These authors contributed equally.
Figure 2 Josiphos-type binaphane ligands (R)-ax-Josiphos
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
Table 1 Screenings for ligands and nitrogen sources.a
Table 2 Condition investigation.a
View Article Online
DOI: 10.1039/D0CY01271H
MeO
1.2 eq o-anisidine
[Ir(COD)Cl]2 0.5 mol %
1.2 eq nitrogen source
O
O
R
[Ir(COD)Cl]2 0.5 mol %
(R)-ax-Josiphos 1.1 mol %
HN
HN
(R)-Cy-ax-Josiphos 1.1 mol %
0.1 eq I2 / 1.5 eq Ti(OiPr)4
50 atm H2, 50C ,DCM, 24h
H2, solvent, additive, T, 24h
2a
2a
3
3a
nitrogen
sources
Convb
(%)
eec
(%)
Convc Eed
T/Pb
Entry
Ligand
Entry
Additive
Solvent
(%)
(%)
1
2
3
4
5
6
(R)-Cy-ax-Josiphos
(R)-Cy-ax-Josiphos benzylamine
p-anisidine
> 99
N.D.
> 99
98
99
> 99
77
–
82
11
5
10 % I2, 1.5 equiv
of Ti(OiPr)4
1
2
3
4
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50/50
50/50
50/50
50/50
50/50
> 99 82
80 53
(R)-Cy-ax-Josiphos
(R)-tBu-ax-Josiphos
(R)-Ph-ax-Josiphos
(R)-Xyl-ax-Josiphos
o-anisidine
o-anisidine
o-anisidine
o-anisidine
10 % I2
1.5 equiv of
N.D.
N.D.
–
–
Ti(OiPr)4
19
none
aReaction conditions: 0.5 mmol scale, [substrate] = 0.2 M.
bDetermined by 1H NMR.
10 % I2, 0.2 equiv
92 79
> 99 81
> 99 82
> 99 81
95 82
35 28
40 61
55 73
30 37
11 80
of Ti(OiPr)4
cEnantiomeric excesses were determined by chiral HPLC. The
absolute configuration is assigned by comparison of the
rotation sign with literature.5f
10 % I2, 0.5 equiv
of Ti(OiPr)4
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
MeOH
EtOH
50/50
50/50
50/50
50/50
50/50
50/50
50/50
50/50
10 % I2, 1.0 equiv
7
of Ti(OiPr)4
10 % I2, 2.0 equiv
of Ti(OiPr)4
the corresponding chiral amines in high yields and excellent
enantioselectivities (ee up to 99%).
8
5 % I2, 1.0 equiv of
Initially, we employed Ir-(R)-Cy-ax-Josiphos as a test catalyst
for the DARA of standard substrate acetophenone 2a according
to the literature conditions.8a Considering the removal of amino
protecting groups, we screened various anisidines (o-anisidine,
p-anisidine) and benzylamine in the model reaction to search for
the optimal nitrogen source. As shown in Table 1 (entries 1-3),
both anisidines gave moderate to good enantioselectivities, but
no product was detected when using benzylamine as the
nitrogen source. The best result was obtained using o-anisidine,
giving 3a with 98 % isolated yield and 82 % ee. At the same time,
tBu-ax-Josiphos, Ph-ax-Josiphos and Xyl-ax-Josiphos were also
evaluated in this transformation. All tested ax-Josiphos ligands
gave the similar yields, while the enantioselectivities were
obviously affected by the substituents at the phosphorus atom
of ligands. The results are summarized in Table 1 (entries 3-6).
The Cy group ligand acquired the best ee value, which was
consistent with our previous research about AH of N-aryl
9
Ti(OiPr)4
10 % I2, 1.0 equiv
of Ti(OiPr)4
10
11
12
13
14
15
16
17
18
19
20
21
10 % I2, 1.0 equiv
of Ti(OiPr)4
10 % I2, 1.0 equiv
of Ti(OiPr)4
10 % I2, 1.0 equiv
1,4-
dioxane
of Ti(OiPr)4
10 % I2, 1.0 equiv
of Ti(OiPr)4
acetone 50/50
10 % I2, 1.0 equiv
THF
50/50
50/50
50/50
60
6
of Ti(OiPr)4
10 % I2, 1.0 equiv
of Ti(OiPr)4
EtOAc
CHCl3
90 83
> 99 87
> 99 89
96 91
10 % I2, 1.0 equiv
of Ti(OiPr)4
10 % I2, 1.0 equiv
of Ti(OiPr)4
toluene 50/50
TBME 50/50
imines.9b
enantioselectivities ranging from 5 % to 19 % ee.
Other
three
ligands
furnished
poor
10 % I2, 1.0 equiv
of Ti(OiPr)4
Next, the effects of additive, solvent, temperature, and H2
pressure on catalytic activity and enantioselectivity were
examined (Table 2). In Zhang’s report, Ti(OiPr)4 and I2 were
found to be efficient accelerants for DARA of aromatic ketones.
Similarly, our study also disclosed that both the Ti(OiPr)4 and I2
were necessary for Ir-(R)-Cy-ax-Josiphos to achieve complete
conversion for asymmetric reductive amination. At the same
time, the amount of Ti(OiPr)4 and I2 have also been evaluated
(Table 2, entries 2-8). Interestingly, the phenomenon of
improvement on enantioselectivity reported by Zhang et al
didn’t occur when the amount of Ti(OiPr)4 increased from 1.0
equiv to 2.0 equiv.8a Further examinations focused on the
solvent employed, and the reactivities and enantioselectivities
were significantly affected by the choice of solvent. In general,
the strong polar solvents (CH3CN, MeOH, EtOH, 1,4-dioxane,
and acetone) gave the poor yields and ees (Table 2, entries 10-
14), and the medium polar solvents (CH2Cl2, EtOAc, CHCl3, TBME
10 % I2, 1.0 equiv
of Ti(OiPr)4
toluene 30/50
toluene 50/30
85 90
10 % I2, 1.0 equiv
95 89
of Ti(OiPr)4
aReaction conditions: 0.5 mmol scale, [substrate] = 0.2 M.
bT(°C)/P(atm
)
cDetermined by 1H NMR.
dEnantiomeric excesses were determined by chiral HPLC. The
absolute configuration is assigned by comparison of the
rotation sign with literature.5f
and toluene) afforded better results (Table 2, entries 7, 16-19).
Toluene proved to be the best solvent in terms of catalytic
reactivity and enantioselectivity. The enantioselectivity seemed
insensitive to H2 pressure and temperature. The DARA of 2a
could also be carried out under 30 atm H2 and 30 °C, giving the
similar ee value but a lower yield (Table 2, entries 20-21).
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
MeO
HN
NHBoc
1) [Ir(COD)Cl]2 0.5 mol %
(R)-Ph-ax-Josiphos 1.1 mol %
TFA,DCM, 3h;
1.2 eq o-anisidine
[Ir(COD)Cl]2 0.5 mol %
(R)-Cy-ax-Josiphos 1.1 mol %
O
View Article Online
DOI: 10.1N0H39/D0CY01271H
O
R

A
0.1 eq I2 / 1.0 eq Ti(OiPr)4
50 atm H2, 50C ,toluene, 24h
2)
4
MS, toluene
50 atm H2, 50 C, 24h
R
5
6
(S)-
2
70 % yield
84 % ee
3
MeO
HN
MeO
HN
MeO
HN
MeO
MeO
Scheme 3 An intramolecular asymmetric reductive amination of
substrate 5
F
Cl HN
HN
F
3d
3b
3c
0% yield
(3v) was still obtained in 80 % yield and 96 % ee. It is worth
mentioning that this catalytic system performed well in the
DARA of substrates 2a and 2b with ortho-substitution phenyl
ring (o-fluoro and o-chloro) at the aromatic ketone (91 % ee, 70
% ee) which appeared difficult for Chang’s catalytic system.5c
Unfortunately, the catalysts also failed to catalyze the reaction
when a bulkier aromatic ketone substrate 2d was employed.
Finally, two α-substituted acetophenones 2w and 2x were also
tested in this catalytic system and a steric effect similar to 2b-d
was found. Phenylacetone (2w) gave a moderate yield and good
enantioselectivity (61 % yield, 87 % ee), while no product was
detected when using phenyl isopropyl ketone (2x) as the
substrate.
3a
95% yield
91% ee
80% yield
70% ee
3e 95% yield
92% ee
95% yield
89% ee
MeO
MeO
MeO
MeO
HN
MeO
HN
HN
HN
HN
O2N
MeO
Br
F
3h
3j
90% yield
94% ee
3i
97% yield
3f
96% yield
97% yield
93% ee
3g
95% yield
91% ee
95% ee
95% ee
MeO
HN
MeO
HN
MeO
HN
MeO
HN
MeO
HN
Br
Cl
O2N
F3C
3o
3k
3n
97% yield
96% ee
95% yield
99% ee
3l
3m
95% yield
96% ee
96% yield
93% ee
96% yield
96% ee
MeO
HN
MeO
HN
MeO
HN
MeO
MeO
HN
HN
Cl
Cl
To demonstrate the potential utility of this DARA for the
preparation of chiral amines, a gram scale reductive amination
reaction of 2m was performed. Adduct 3m was obtained in 90
MeO
3s
95% yield
3q
3p
96% yield
90% ee
96% yield
95% ee
3r
96% yield
94% ee
3t
90% yield
89% ee
92% ee
MeO
MeO
HN
MeO
HN
MeO
HN
%
isolated yield and 96 % ee (Scheme 2). The N-o-
HN
MeO
MeO
methoxyphenyl group on the chiral amine 3m could be easily
removed by sulfuric acid and trichloroisocyanuric acid,10a and
the obtained primary amine was able to transform to CB1
receptor modulator (4) in classical and high yield reactions.10b
To further verify the practicality of this catalytic system, a highly
efficient intramolecular asymmetric reductive amination of
tert-butyl (2-(2-oxo-2-phenylethyl)benzyl)carbamate (5) in
combination with N-Boc deprotection was carried out in a one-
3u
3v
97% yield
88% ee
80% yield
96% ee
3w
3x
0% yield
61% yield
87% ee
a
2
Reaction conditions: (0.5 mmol), o-anisidine (1.2 equiv), [Ir(COD)Cl]2 (0.5 mol%), (R)-Cy-ax-Josiphos (1.1
mol%), I2 (0.1 equiv), Ti(OiPr)4 (1.0 equiv); bIsolated yields after column chromatography; cEnantiomeric
excesses were determined by chiral HPLC.
Scheme 1 Asymmetric reductive amination of aromatic ketones
2.a,b,c
Finally, the transformation catalyzed by Ir-(R)-Cy-ax-Josiphos in
toluene at 50 °C and 50 atm H2 in the presence of Ti(OiPr)4 and
I2 turned out to be optimal.
Under the optimized conditions, a wide range of aromatic
ketones 2a-x were investigated in the DARA using o-anisidine as
the nitrogen source. The results are summarized in Scheme 1.
All meta-(2e-2i) and para-(2j-2q) substituted substrates
afforded the desired products in high yields (90 % − 97 %) and
pot
process
to
prepare
(6).
chiral
Unfortunately,
3-phenyl-1,2,3,4-
low
tetrahydroisoquinoline
a
enantioselectivity (19 % ee) was obtained when Cy-ax-Josiphos
was employed as chiral ligand. Considering the excellent
catalytic activities of all ax-Josiphos ligands in the DARA of
acetophenone in combination with the different structural
characteristics of 2 and 5, we envisioned a modified catalytic
system based on ax-Josiphos may acquire good catalytic
performance in the intramolecular asymmetric reductive
amination of 5. To our delight, after screening of additive,
solvent, temperature, and H2 pressure (see the Supporting
Information, Table S1), the transformation proceeded well to
provide (S)-6 in 70 % isolated yield and 84 % ee (Scheme 3).
excellent enantioselectivities (90
% − 99 % ee). The
stereochemical outcome of the substrates 2e-2q appears to be
insensitive to the electron effect of substituents on the phenyl
ring of the aromatic ketone, providing adducts with similar
enantioselectivities.
As
expected,
the
excellent
enantioselectivities were also achieved in the substrates 2r-2u
with 3,4-disubstituted phenyl ring at the aromatic ketone block
(88 % − 94 % ee). In addition, the catalytic system was applied
to the DARA of 3,4-dihydronaphthalen-1(2H)-one (2v), and (R)-
Conclusions
In summary, we have developed a highly efficient and
enantioselective DARA catalytic system of aromatic ketones for
the preparation of chiral amines. Catalyzed by the iridium-
diphosphine complex and facilitated by Ti(OiPr)4 and I2, the
reaction led to the secondary amines in high enantioselectivities
and yields. The N-o-methoxyphenyl group could be easily
removed to afford corresponding primary amines under mild
conditions. At the same time, a gram scale reductive amination
N-(2-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
MeO
O
N
O
O
CF3
1.2 eq o-anisidine
0.5 mol % [Ir(COD)Cl]2
1.1 mol % (R)-Cy-ax-Josiphos
0.1 eq I2 / 1.0 eq Ti(OiPr)4
50 atm H2, 50C ,toluene, 24h
O
HN
N
10
N
Cl
F3C
F3C
Cl
2m
10 mmol
3m
2.66 g obtained
90% yield, 96% ee
4
Scheme 2 Gram scale asymmetric reductive amination of
aromatic ketone 2m
This journal is © The Royal Society of Chemistry 20xx
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7
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Acknowledgements
Financial support from the Key R&D Program in Shaanxi
Province of China (2020SF-202), the Natural Science Basic
Research Plan in Shaanxi Province of China (2020JZ-26), and
Fourth Military Medical University (2018XA009) is greatly
acknowledged.
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Conflicts of interest
There are no conflicts to declare.
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Catalysis Science & Technology
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DOI: 10.1039/D0CY01271H
PCy2
MeO
1.2 eq o-anisidine
[Ir(COD)Cl]2 0.5 mol %
(R)-Cy-ax-Josiphos 1.1 mol %
O
Fe
P
HN
R
0.1 eq I2 / 1.0 eq Ti(OiPr)4
R
50 atm H2, 50C ,toluene, 24h
(R)-Cy-ax-Josiphos
A highly efficient catalytic system of direct asymmetric reductive amination of
aromatic ketones.