Communication

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Asymmetric Synthesis of Chiral Primary Amines by Ruthenium-

Catalyzed Direct Reductive Amination of Alkyl Aryl Ketones with
Ammonium Salts and Molecular H2
Xuefeng Tan,† Shuang Gao,† Weijun Zeng,† Shan Xin,† Qin Yin,*,†,‡ and Xumu Zhang*,†
†
Department of Chemistry, Southern University of Science and Technology, Shenzhen 518000, People’s Republic of China
‡
Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518000, People’s
Republic of China
*
S Supporting Information
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Scheme 1. Representative Strategies for Transition Metal-

ABSTRACT: A ruthenium/C3-TunePhos catalytic system Catalyzed ARA
has been identified for highly efficient direct reductive
amination of simple ketones. The strategy makes use of
ammonium acetate as the amine source and H2 as the
reductant and is a user-friendly and operatively simple
access to industrially relevant primary amines. Excellent
enantiocontrol (>90% ee for most cases) was achieved
with a wide range of alkyl aryl ketones. The practicability
of this methodology has been highlighted by scalable
synthesis of key intermediates of three drug molecules.
Moreover, an improved synthetic route to the optimal
diphosphine ligand C3-TunePhos is also presented.

C hiral amines are prevalent structural units in a large

number of pharmaceutical drug molecules, agrochemicals,
and commodity chemicals. Therefore, efficient synthetic routes
toward chiral amines have attracted tremendous attention.1
Transition metal-catalyzed reductive amination represents a
step-economic and efficient strategy by directly converting
carbonyl compounds into amines in the presence of amine
sources and reductants.2 However, compared to numerous
studies on asymmetric imine reduction,3 only limited success
has been achieved regarding asymmetric reductive amination
(ARA), partly due to the incompatibility of transition-metal
hydrides with ketones. Another factor that cannot be ignored
lies in coordination of the amine to the metal catalyst, often
resulting in its inhibition.4 To enhance the catalytic efficiency,
some special amines such as aryl amines,5 benzylamines6 or
others7 were used as amine sources, but these furnish secondary
amines. An additional synthetic operation to remove the aryl or
benzyl substituents is thus required to liberate the synthetically
more versatile primary amine (eq 1, Scheme 1). Asymmetric
reductive amination for the direct synthesis of chiral primary
amines from ketones and ammonia or its equivalents is highly
desirable but still underdeveloped. In 2005, Takasago company
patented an asymmetric reductive amination of β-keto esters
with NH4OAc to provide chiral β-amino esters.8 After that,
several works using a similar strategy have been reported,
including the application of different ligands such as
ClMeOBIPHEP9 and segphos.10 The syntheses of top-selling
drug sitagliptin,11 (S)-3-amino-4-methoxy-butan-1-ol12 as well
as methyl (3R)-3-aminobutyrate13 via this methodology were
also documented. In all cases, a functional group such as ester
or amide in the β-position is necessary to ensure high efficiency
(eq 2, Scheme 1). In comparison, Kadyrov’s group reported a
ruthenium-catalyzed enantioselective reductive amination of
simple aryl ketones via transfer hydrogenation. However, the
formation of undesired formylated amine could not be avoided,
thus requiring an additional hydrolysis step to achieve the
primary amine product (eq 3, Scheme 1).14 Despite the above-
mentioned state-of-the-art, a highly efficient and enantioselec-
tive asymmetric reductive amination of simple aryl ketones with
ammonia or its equivalents using molecular H2 has remained
rare15 and is a formidable challenge to be overcome (eq 4,
Scheme 1). Herein, we report our recent efforts toward
asymmetric reductive amination of simple ketones with
ammonium salts utilizing molecular H2 as the reducing reagent.
We commenced our study by testing the performance of
various combinations of ruthenium precatalysts and different
chiral diphosphine ligands in the reaction of model substrate
acetophenone (5a) and ammonium salts under 55 bar of H2.
Received: December 6, 2017
Published: January 29, 2018

© 2018 American Chemical Society 2024 DOI: 10.1021/jacs.7b12898

J. Am. Chem. Soc. 2018, 140, 2024−2027
Journal of the American Chemical Society
From an initial screening of diverse diphosphine ligands, C3-
TunePhos (4), a derivative of the Cn-TunePhos (n = 0−6)
series developed by our group in 2000,16 emerged as optimal
regarding enantiocontrol. Existing procedures17 to synthesize
these privileged ligands suffer from long synthetic routes and
limited possibilities for derivatization. An improved and
divergent preparation to five C3-TunePhos derivatives 4a−4e
is shown in Scheme 2 (for details, see the Supporting
Information).
Scheme 2. Improved Synthetic Route to C3-TunePhosa
a
Reaction conditions: (a) (2R,4R)-pentane-2,4-diol, DIAD, Ph3P,
81%; (b) n-BuLi; then CuCN; then p-benzoquinone, one pot, 55%;
(c) KOH, then NaNO2 and KI, 40% over two steps; (d) n-BuLi,
ClPAr2, 37−61%.
With these C3-TunePhos ligands in hand, further condition
optimization was conducted to improve the reaction efficiency
and selectivity, including the screening of the ruthenium source,
solvent, additive, ammonium salt, substrate concentration,
reaction temperature as well as hydrogen pressure with the
standard substrate acetophenone (5a) (Tables S1−S6). Finally,
the combination of 1 mol % Ru(OAc)2(4e) as catalyst,
trifluoroethanol (TFE) as solvent, two equivalents of
ammonium acetate as amine source, 0.5 M substrate
concentration, 55 bar of H2 at 80 °C stood out, providing
the corresponding primary amine 6a in 92% yield and 97% ee
(entry 6, Table 1). It is noteworthy that excellent conversion is
obtained when TFE is used as solvent, and possible reason is
that TFE facilitates the formation of imine intermediate.9 The
formation of secondary alcohol could be inhibited through
choosing suitable ammonium salts in TFE (see Tables S2 and
S3 for details). Interestingly, we did not observe the formation
of secondary amine arising from double reductive aminations. A
comparison of C3-TunePhos 4a with commercially available
diphosphine ligands binap and segphos is summarized in Table
1 (entry 8 vs entries 9 and 10), This demonstrates the
superiority of C3-TunePhos in this reaction. When the reaction
temperature was increased from 80 to 100 °C, similar results
were obtained in the presence of only 0.5 mol % catalyst
loading (entry 7). Further substrate scope investigation was
then carried out at 100 °C with 0.5 mol % of catalyst. The
absolute configuration of the product 6a was established by
comparison of its optical rotation with that reported in
literature (see the Supporting Information for details).
Under the optimal reaction conditions, a wide range of
simple aryl ketones were subjected to this direct reductive
amination procedure. In most cases, the ketones could be
transformed into the corresponding primary amines with
excellent enantioselectivities and moderate to high yields
(Table 2). Both electron-donating (Me, tBu or MeO as in
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Table 1. Reaction Condition Optimizationa
Entry Ru cat. Yield (%) ee (%)
1 RuCl2(4a)(DMF)n 90 78
2 RuCl2(4b)(DMF)n 88 74
3 RuCl2(4c)(DMF)n 87 76
4 RuCl2(4d)(DMF)n 93 89
5 RuCl2(4e)(DMF)n 94 94
6 Ru(OAc)2(4e) 92 97
7a Ru(OAc)2(4e) 96 96
8 Ru(OAc)2(4a) 93 75
9 Ru((R)-BINAP)(OAc)2 92 65
10 Ru((R)-SegPhos)(OAc)2 92 67
a
Reaction conditions: acetophenone 5a (0.2 mmol), NH4OAc (0.4
mmol), [Ru] (1 mol %), TFE (0.4 mL), H2 (55 bar), 80 °C, 24 h. The
pressure refers to the actual value at 80 °C. The free amine 6a was
obtained after neutralizing its corresponding acetate salt with a base.
The ee values were determined by chiral HPLC after sample acylation.
b
Reaction was carried out with 0.5 mol % catalyst loading at 100 °C.
TFE = trifluoroethanol.
5b−g) and electron-withdrawing substituents (F, Cl, Br, CF3 as
in 5h−5o) on the benzene ring were tolerated, and the
reactivity and selectivity were high throughout. The hetero-
aromatic ketone 5q reacted with decreased enantiomeric excess
probably due to a weak coordination effect of the oxygen atom.
Besides methyl ketone, ethyl ketone 5r demonstrated
comparable reactivity and selectivity, providing 6r in 78%
yield and 97% ee. It is worth mentioning that catalyst
Ru(OAc)2(4e) showed very low reactivity toward 1-benzosu-
berone (5s), whereas good conversion and enantiocontrol of 5s
could be achieved by using Ru(OAc)2 (4a) as catalyst.
Unfortunately, the dialkyl ketone 5t was not a suitable substrate
for this catalytic system, and poor yield and enantiocontrol
were obtained (20% ee, 6t).
To demonstrate the significance and practicality of this
methodology, scale-up syntheses of key intermediates of drug
molecules, including Tecalcet hydrochloride, Cinacalcet, and
Rivastigmine were performed (Scheme 3). Tecalcet hydro-
chloride and Cinacalcet are drugs that act as a calcimimetic and
used to treat secondary hyperparathyroidism, the former
currently in Phase II clinical trials18 and the latter sold by
Amgen under the trade name of Sensipar in North America and
Australia, and of Mimpara in Europe.19 The critical synthon to
Tecalcet hydrochloride is (R)-1-(3-methoxyphenyl)ethyl amine
(6g), which could be easily accessed under standard conditions
with high enantioselectivity (94% ee) and TON up to 500 (eq
1, Scheme 3). Similarly, the key chiral motif (R)-1-(naphth-1-
yl) ethyl amine in Cinacalcet could be efficiently synthesized
with high enantioselectivity (up to 98% ee) and promising
efficacy of S/C up to 1000 (eq 2, Scheme 3). The gram-scale
syntheses of these two key intermediates reveal the potential of
practical industrial application. Rivastigmine, sold under the
trade name of Exelon, is a parasympathomimetic or cholinergic
agent for the treatment of mild to moderate dementia of the
Alzheimer’s type and dementia due to Parkinson’s disease.20 As
shown in eq 3 of Scheme 3, the key intermediate to (R)-
Rivastigmine was directly synthesized via reductive amination
of 5v with high efficiency.21
DOI: 10.1021/jacs.7b12898
J. Am. Chem. Soc. 2018, 140, 2024−2027
Journal of the American Chemical Society
Table 2. Substrate Scope
a
Reaction condtions: ketone 5 (0.2 mmol), NH4OAc (0.4 mmol),
Ru(OAc)2(4e) (0.5 mol %), TFE (0.4 mL), H2 (57 bar), 100 °C, 24 h.
The pressure refers to the actual value at 100 °C. The free amines 6a-t
were obtained after neutralizing their corresponding acetate salts with
a base. The ee values were determined by chiral HPLC after sample
acylation. bRu(OAc)2(4a) was used instead of Ru(OAc)2(4e). cThe ee
was determined by chiral HPLC after sample tosylation.
Scheme 3. Scale-up Syntheses of Key Intermediates of Drug
Molecules
In conclusion, we have established a highly chemo- and
enantioselective catalytic system for the direct reductive
amination of simple ketones with ammonium salts and
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molecular H2. The use of ammonia acetate as an amine source
and H2 as reductant constitutes a facile and user-friendly
approach to versatile primary amines, which can be easily
derived into more valuable amine products. This reaction
features broad substrate scope, good functional group
compatibility and excellent enantiocontrol (up to 98% ee).
Key intermediates of three drugs can be easily accessed in gram
scale from commercially available ketones, which showcases the
potential of practical usage. In addition, an improved synthetic
route to the optimal diphosphine ligand C3-TunePhos was also
developed.
■
*
ASSOCIATED CONTENT
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b12898.
Detailed experimental procedures, spectral data, and
analytical data (PDF)
■ AUTHOR INFORMATION
Corresponding Authors
*yinq@sustc.edu.cn
*zhangxm@sustc.edu.cn
ORCID
Xuefeng Tan: 0000-0002-6121-1499
Qin Yin: 0000-0003-3534-3786
Xumu Zhang: 0000-0001-5700-0608
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We are grateful to a start-up fund from Southern University of
Science and Technology, Shenzhen Science and Technology
Innovation Committee (No. KQTD20150717103157174) and
National Natural Science Foundation of China (No. 21432007)
for financial support. We greatly acknowledge Professor Martin
Oestreich (Technische Universität Berlin) for proofreading the
paper.
■
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2027 DOI: 10.1021/jacs.7b12898

J. Am. Chem. Soc. 2018, 140, 2024−2027