Direct Catalytic Asymmetric Reductive Amination of Aliphatic Ketones Utilizing Diphenylmethanamine as Coupling Partner

Article abstract of DOI:10.1021/acs.orglett.7b00212

The highly efficient direct catalytic reductive amination of ketones with diphenylmethanamine catalyzed by iridium-phosphoramidite complexes is described. As an effective coupling partner, diphenylmethanamine is suitable for a wide range of ketones to pro

Full text of DOI:10.1021/acs.orglett.7b00212

Letter
pubs.acs.org/OrgLett
Direct Catalytic Asymmetric Reductive Amination of Aliphatic
Ketones Utilizing Diphenylmethanamine as Coupling Partner
Haizhou Huang, Yunfei Zhao, Yang Yang, Le Zhou, and Mingxin Chang*
College of Chemistry and Pharmacy, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, PR China
S
* Supporting Information
ABSTRACT: The highly efficient direct catalytic reductive amination of ketones
with diphenylmethanamine catalyzed by iridium−phosphoramidite complexes is
described. As an effective coupling partner, diphenylmethanamine is suitable for a
wide range of ketones to provide chiral amines in high yields and
enantioselectivity. The chiral monodentate phosphoramidite ligands are tunable
and competent to accommodate substrates with different structures.
he reductive amination reaction is one of the most
widely utilized transformations in both biological systems
Scheme 1. Comparison of Different Nitrogen Donors for
Asymmetric Ketone Reductive Amination
T
and synthetic organic chemistry.1 It chemoselectively couples
ketones and amines to form diverse C−N bonds. It is a
privileged in vivo tool for nature to enantioselectively generate
essential biomonomers. A renowned example is the formation
of the naturally occurring amino acids.1a,2 In synthetic
chemistry, some progress has been made for the synthesis
of chiral amines via transition-metal-catalyzed asymmetric
reductive amination3 since the first example was reported by
Blaser and co-workers in 1999 for the production of the
herbicide Metolachlor.4a A number of catalysts have been
examined on reductively coupling various ketones and amines.
However, successful transition-metal-catalytic systems are very
limited. One major obstacle is the inhibitory effect of coupling
partner amines on the catalysts, resulting in their low
reactivity. At the same time, the detailed mechanism of
transition-metal-catalyzed asymmetric reductive amination
remains to be elucidated.
Scheme 2. Diphenylmethanamine-Involved Reductive
Amination
For the transition-metal-catalyzed asymmetric reductive
amination, anilines are the most utilized ketone coupling
partners due to their less restrictive impact on catalysts
compared with alkyl amines.4 Other nitrogen donors include
inorganic ammonium salts,5 benzylamine,6 hydrazines,7 and
hydrazides4g,8 (Scheme 1). Simple benzylamine is more
nucleophilic compared with anilines and thus exerts more
inhibitory effect on the transition-metal center. We propose
that diphenylmethanamine, with another phenyl group on the
benzylic carbon of the simple benzylamine, would be less
likely to restrain the catalyst reactivity. Herein, we report the
application of diphenylmethanamine as a reductive amination
partner of a variety of ketones catalyzed by iridium−
monodentate phosphoramidite complexes (Scheme 2).
Chiral aliphatic amines are present in many active
pharmaceutical ingredients, and certain unfunctionalized
ones are difficult to synthesize by asymmetric catalytic
methods.9 Especially for the primary amines with linear
aliphatic chain and lower molecular weight, their large-scale
production depends on classic resolution.10 The BINOL-based
phosphoramidite MonoPhos was initiated by Pringle and
Feringa in 2000.11 This series of ligands found success in
numerous catalytic research areas, largely due to their ease of
preparation at low cost and their bench stability.12 We started
our research on the asymmetric reductive amination of the
simple 2-pentanone with diphenylmethanamine 2 to synthe-
size the corresponding chiral amines catalyzed by 1 mol %
iridium−phosphoramidite complexes. L1a worked perfectly
for the reductive coupling of phenylacetone with 2.13 As for 2-
pentanone, the reaction proceeded smoothly to give
exclusively the desired product, but only rendered 61% ee.
We then continued to develop a series of phosphoramidite
Received: January 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00212
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chiral ligands based on BINOL and H8-BINOL backbones
(Figure 1) and utilized them in the reductive amination of 2-
To explore the substrate scope of this Ir−phosphoramidite
catalytic system, a range of ketones was studied. The results
are summarized in Scheme 3. For different substrates, the
Scheme 3. Asymmetric Reductive Amination of Aliphatic
a
Ketones
Figure 1. Structures of phosphoramidite ligands.
a
Table 1. Screening of Phosphoramidite Chiral Ligands
b
c
entry
cat. (mol %)
H2 (atm)
ligand
ee (%)
1
2
3
4
5
6
7
8
1
60
60
60
60
60
60
60
60
60
60
40
30
L1a
L1b
L1c
L1d
L2a
L2c
L2d
L2e
L2e
L2e
L2e
L2e
62
6
1
1
52
38
64
63
45
86
87
86
86
86
1
1
1
1
1
d
9
1
10
11
0.1
0.1
0.1
e
12
a
Reaction conditions: [Ir]/L/1a/2 = 1:2:1000:1100, CH2Cl2 2 mL, 40
a
Reaction conditions: [Ir]/L/1a/2 = 1:2:100:110, 1a 0.2 mmol,
atm of H2, 13 h; MS 0.1 g; TFA 0.5 equiv; Ti(Oi-Pr)4 0.3 equiv. Yields
are isolated yields. Enantiomeric excesses were determined by chiral
HPLC. Catalyst loading was 0.4 mol %. Catalyst loading was 0.3 mol
%.
CH2Cl2 2 mL, 60 atm of H2, 13 h; COD = 1,5-cyclooctadiene; MS = 4
Å molecular sieves, 0.1 g; TFA = CF3COOH, 0.3 equiv; Ti(Oi-Pr)4 0.3
b
c
b
equiv. When ligand L2e was used, the TFA amount was 0.5 equiv.
c
d
Enantiomeric excesses were determined by chiral HPLC. Ir-
(COD)2Barf metal precursor was used instead of [Ir(COD)Cl]2,
e
Barf = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. Reaction yield
dropped 5%.
suitable ligand varied; e.g., for substrate 1b, L1a worked much
better than the sterically hindered L2e. This is because for
different sized substrates, according ligands are required to
accommodate their spatial demand. From the experiments, we
can see L1a functioned well for substrates 1b and 1e−h.
Increasing the substrates size by changing the alkyl
substituents from linear to branched has a positive influence
on stereocontrol. Compared with the 86% ee value of 3a, the
ee’s for 3b and 3c were improved to 99% and 95%,
respectively. The best results were obtained for cyclic alkyl
group substituted ketones 1e and 1f. The catalytic system also
worked quite well for aliphatic and aromatic hybrid ketones
1h and 1i, providing 3h and 3i in 96% and 97% ee,
respectively, and perfect yields.
To further demonstrate the practical application of this
protocol, the asymmetric reductive amination of 1h was
performed on large scale. Product 3h was obtained with 93%
isolated yield and 96% ee. The facile removal of the
diphenylmethyl group was carried out with Pd/C and H2.
The product was then derived with acetic anhydride to give 4
pentanone. The results are summarized in Table 1. The ee
values resulting from phosphoramidite ligands bearing simple
6-membered or 5-membered N-monocyclic rings were all less
than 65% (entries 2−7). In addition, the H8-BINOL-based
ligands furnished lower enantiomeric excesses than the
BINOL-based ones (entries 1−4 versus 5−7). When the N-
tricyclic ligand L2e was applied, ee was enhanced to 86% and
could be further improved to 87% (entries 8 and 9). When
0.1 mol % of iridium−L2e was utilized, the reaction
proceeded completely (entry 10). When the H2 pressure
was decreased to 40 atm, the reaction yield and ee remained
the same. Further lowering the pressure to 30 atm, the yield
for the reaction slightly dropped but the enantioselectivity was
not affected (entries 11 and 12). In comparison, we utilized
aniline and benzylamine as coupling partners (eq 1). As
expected, neither of them provided satisfactory results.
B
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in 94% yield without any erosion of the enantioselectivity
(Scheme 4).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00212.
Scheme 4. Large-Scale Reductive Amination of 1g and
Facile Deprotection
Experimental materials and procedures, NMR of
products, and HPLC for racemic and chiral products
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mxchang@nwsuaf.edu.cn.
ORCID
To gain insight into the reaction pathways, we conducted
isotopic-labeling experiments for the reductive amination of
ketones 1g and 1h with diphenylmethanamine using
Mingxin Chang: 0000-0002-5407-3403
Notes
The authors declare no competing financial interest.
1
deuterium gas (Scheme 5). From the H NMR integration,
ACKNOWLEDGMENTS
■
Scheme 5. Deuterium Incorporation Study
We thank the National Natural Science Foundation of China
(No. 21402155), Yangling Bureau of Science & Technology
(No. 2016NY-25), and Northwest A&F University
(Z109021521) for financial support. Mr. Hongli Zhang
(Northwest A&F University) is thanked for NMR analysis.
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