Asymmetric Synthesis of Chiral Primary Amines by Ruthenium-Catalyzed Direct Reductive Amination of Alkyl Aryl Ketones with Ammonium Salts and Molecular H2

Article abstract of DOI:10.1021/jacs.7b12898

A ruthenium/C₃-TunePhos catalytic system 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.

Full text of DOI:10.1021/jacs.7b12898

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Communication
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
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12898 • Publication Date (Web): 29 Jan 2018
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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
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Xuefeng Tan,† Shuang Gao,† Weijun Zeng,† Shan Xin,† Qin Yin*,†,‡ and Xumu Zhang*,†
† Department of Chemistry, Southern University of Science and Technology, Shenzhen, 518000, P. R. China.
‡ Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, 518000, P. R.
China.
Supporting Information Placeholder
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 (Equation 3, Scheme 1).14 Despite the above-
mentioned state-of-the-art, a highly efficient and enantioselective
asymmetric reductive amination of simple aryl ketones with am-
monia or its equivalents using molecular H2 has remained rare15
and is a formidable challenge to be overcome (Equation 4,
Scheme 1). Herein, we report our recent efforts toward asymmet-
ric reductive amination of simple ketones with ammonium salts
utilizing molecular H2 as the reducing reagent.
ABSTRACT: A ruthenium/C3-TunePhos catalytic system 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 practicabil-
ity of this methodology has been highlighted by scalable synthesis
of key intermediates of three drug molecules. Moreover, an im-
proved synthetic route to the optimal diphosphine ligand C3-
TunePhos is also presented.
Scheme 1. Representative Strategies for Transition Metal-
Catalyzed ARA
Chiral 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 Howev-
er, compared to numerous studies on asymmetric imine reduc-
tion,3 only limited success has been achieved regarding asymmet-
ric 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 benzyla-
mines6 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 ( Equation 1, Scheme
1). Asymmetric reductive amination for the direct synthesis of
chiral primary amines from ketones and ammonia or its equiva-
lents is highly desirable but still underdeveloped. In 2005, Ta-
kasago 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 re-
ported, 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
(Equation 2, Scheme 1). In comparison, Kadyrov’s group reported
a ruthenium-catalyzed enantioselective reductive amination of
We commenced our study by testing the performance of vari-
ous combinations of ruthenium precatalysts and different chiral
diphosphine ligands in the reaction of model substrate acetophe-
none (5a) and ammonium salts under 55 bar of H2. 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 derivatiza-
tion. An improved and divergent preparation to five C3-TunePhos
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derivatives 4a‒4e is shown in Scheme 2 (for details see the Sup-
porting Information).
Scheme 2. Improved Synthetic Route to C3-TunePhosa
ondary amine arising from double reductive aminations. A com-
parison of C3-TunePhos 4a with commercially available diphos-
phine 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
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o
increased from 80 C to 100 C, similar results were obtained in
the presence of only 0.5 mol % catalyst loading (entry 7). Further
o
substrate scope investigation was then carried out at 100 C with
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9
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 enantioselectivi-
ties and moderate to high yields (Table 2). Both electron-donating
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t
aReaction 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%.
(Me, Bu or MeO as in 5b‒g) and electron-withdrawing substitu-
ents (F, Cl, Br, CF3 as in 5h‒5o) on the benzene ring were tolerat-
ed, and the reactivity and selectivity were high throughout. The
heteroaromatic 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 com-
parable 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-benzosuberone (5s), while
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).
Table 1. Reaction Condition Optimizationa
Table 2. Substrate Scopea
aReaction 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 oC. The free amine 6a
was obtained after neutralizing its corresponding acetate salt with
a base. The ees were determined by chiral HPLC after sample
b
acylation. Reaction was carried out with 0.5 mol% catalyst load-
ing at 100 °C. TFE = trifluoroethanol.
With these C3-TunePhos ligands in hand, further condition op-
timization was conducted to improve the reaction efficiency and
selectivity, including the screening of the ruthenium source, sol-
vent, additive, ammonium salt, substrate concentration, reaction
temperature as well as hydrogen pressure with the standard sub-
strate 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 sources,
o
0.5 M of 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 conver-
sion 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 choos-
ing suitable ammonium salts in TFE (see Tables S2 and S3 for
details). Interestingly, we did not observe the formation of sec-
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aReaction condtions: ketone 5 (0.2 mmol), NH4OAc (0.4 mmol),
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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 oC. The free
amines 6a-t were obtained after neutralizing their corresponding
acetate salts with a base. The ees were determined by chiral
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4
Detailed experimental procedures, spectral data, and
analytical data (PDF)
b
HPLC after sample acylation. Ru(OAc)2(4a) was used instead of
Ru(OAc)2(4e). cThe ee was determined by chiral HPLC after
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sample tosylation.
AUTHOR INFORMATION
To demonstrate the significance and practicality of this meth-
odology, scale-up syntheses of key intermediates of drug mole-
cules, including Tecalcet hydrochloride, Cinacalcet, and Ri-
vastigmine were performed (Scheme 3). Tecalcet hydrochloride
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 hydrochlo-
ride is (R)-1-(3-methoxyphenyl)ethyl amine (6g), which could be
easily accessed under standard conditions with high enantioselec-
tivity (94% ee) and TON up to 500 (Equation 1, Scheme 3). Simi-
larly, the key chiral motif (R)-1-(naphth-1-yl) ethyl amine in
Cinacalcet could be efficiently synthesized with high enantiose-
lectivity (up to 98% ee) and promising efficacy of S/C up to 1000
(Equation 2, Scheme 3). The gram-scale syntheses of these two
key intermediates reveal the potential of practical industrial appli-
cation. 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 Equation 3 of Scheme 3,
the key intermediate to (R)-Rivastigmine was directly synthesized
via reductive amination of 5v with high efficiency.21
Corresponding Author
*E-mail: yinq@sustc.edu.cn; zhangxm@sustc.edu.cn
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ORCID
Qin Yin: 0000-0003-3534-3786
Xumu Zhang: 0000-0001-5700-0608.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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
manuscript.
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