Copper-Catalyzed Asymmetric Hydrosilylation of β-Nitroethyl Aryl Ketones

Article abstract of DOI:10.1021/acs.orglett.9b04339

A copper-catalyzed asymmetric hydrosilylation of β-nitroethyl aryl ketones has been disclosed, and the corresponding chiral alcohols could be obtained in high yields (up to 99% yield) and excellent enantioselectivities (up to 96% ee). Moreover, the reaction worked well on a gram scale with 0.3 mol % of ligand loading, indicating that our protocol has potential applications in the synthesis of important pharmaceuticals such as Tranylcypromine and Ticagrelor.

Full text of DOI:10.1021/acs.orglett.9b04339

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Letter
Copper-Catalyzed Asymmetric Hydrosilylation of β‑Nitroethyl Aryl
Ketones
Weijun Zeng,+ Xuefeng Tan,+ Yang Yu, Gen-Qiang Chen,* and Xumu Zhang*
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ABSTRACT: A copper-catalyzed asymmetric hydrosilylation of β-
nitroethyl aryl ketones has been disclosed, and the corresponding
chiral alcohols could be obtained in high yields (up to 99% yield)
and excellent enantioselectivities (up to 96% ee). Moreover, the
reaction worked well on a gram scale with 0.3 mol % of ligand
loading, indicating that our protocol has potential applications in
the synthesis of important pharmaceuticals such as Tranylcypro-
mine and Ticagrelor.
trans-2-Arylcyclopropylamine derivatives are widely found in
many bioactive compounds or drugs including Tranylcypro-
mine,1 Ticagrelor,2 Antiallergic compounds,3 LSD1 (lysine
demethylase 1) inhibitors,4 and so on (Figure 1). Tranylcy-
Scheme 1. General Synthetic Routes of the
Cyclopropylamine Intermediate
cyclopropanation (Scheme 1, eq 2). The former route was
superior to the latter one since it avoids the use of hazardous
carbene precursors or azides, while the chiral alcohol
intermediate could be directly obtained by asymmetric
reduction of β-nitroethyl aryl ketones 1.
Although the asymmetric reduction of ketones has been well
established, the asymmetric reduction of β-nitroethyl aryl
ketone 1 was rarely reported due to the fact that β-nitroethyl
aryl ketones are not stable under basic conditions, and retro-
Michael addition as well as other side reactions will occur
(Scheme 2, eq 1). CBS reduction of β-nitroethyl aryl ketones 1
could produce the alcohol in high yield and enantioselectivity;
however, 20% catalyst loading was needed.6 A highly
enantioselective biocatalytic reduction of 1 was reported by
Turner and co-workers in 2016;7 however, very high catalyst
loading (equal amount) was needed to ensure full conversion.
Effective and enantioselective reduction of β-nitroethyl aryl
ketone 1 is still highly demanded. Herein, we disclose a highly
Figure 1. Representative examples of bioactive compounds that
contain a cyclopropyl amine unit.
promine is a nonselective and irreversible inhibitor of the
enzyme monoamine oxidase, and it is used as an antidepressant
and anxiolytic agent in the clinical treatment of mood and
anxiety disorders, respectively. Ticagrelor is an antagonist of
the P2Y12 receptor, and the drug was approved by the FDA
(Food and Drug Administration) as a platelet aggregation
inhibitor in 2011.
During the last few decades, tremendous efforts have been
devoted to the synthesis of trans-2-phenylcyclopropylamine
(CPA) derivatives.5 Generally speaking, there are two synthetic
routes for the CPA (cyclopropylamine) intermediate: one is
the intramolecular SN2 reaction followed by reduction of the
nitro group (Scheme 1, eq 1), and the other is the Hofmann-
type degradation of the cyclopropane carboxylic derivatives,
which were produced by carbene or sulfur ylide mediated
Received: December 3, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04339
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
a
Scheme 2. Asymmetric Reduction of β-Nitroethyl Aryl
Table 1. Optimization of the Reaction Conditions
Ketones
b
c
entry
ligand
solvent
T (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L9
L9
L9
L9
L9
L9
L9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
64
70
64
83
47
75
86
99
86
88
90
65
58
--
40
53
83
44
−53
−87
89
89
90
85
85
86
74
--
9
10
11
12
13
14
15
16
DCM
n-pentane
i-PrOH
toluene
toluene
toluene
--
--
−20
−20
−20
95
95
15
94
94
--
d
17
18
e
a
Reaction conditions: To a 10 mL Schlenk tube was added
Cu(OAc)2·H2O (3.6 mg, 0.018 mmol, 3 mol %), (S)-SEGPHOS
(3.7 mg, 0.006 mmol, 1 mol %), and toluene (3.0 mL), and the
resulting mixture was stirred at room temperature for 30 min. Then
the mixture was cooled to −20 °C, and PhSiH3 (65.0 mg, 0.6 mmol,
1.0 equiv) and 1a (0.6 mmol) were added successively under argon
protection. The reaction mixture was allowed to stir at −20 °C for 4
efficient and enantioselective copper-catalyzed hydrosilylation of β-
nitroethyl aryl ketones and its synthetic applications.
b
c
d
h. Isolated yield. Determined by chiral HPLC. With 0.3 mol % of
e
Our initial investigation began with reduction of compound
1a with asymmetric hydrogenation. No desired product was
obtained with f-amphox, f-amphol, and f-ampha ligands
developed recently in our group8 due to the instability of 1a
under basic conditions. The Rh(I)/diphosphine system9 could
only give poor yields and enantioselectivities (for the details
see the Supporting Information). Next, we turned our effort to
other reduction methods such as transfer hydrogenation10 and
asymmetric hydrosilylation.11 To our great delight, product 2a
was obtained in 64% yield and 40% ee in the presence of
Cu(OAc)2/L1 ((S,S)-t-Bu-DuPhos) using PhSiH3 as reductant
and toluene as solvent at 0 °C under base-free condition, and
no retro-Michael addition product was detected (entry 1,
Table 1).12 Encouraged by the promising results, we next
screened various diphosphine ligands, and only moderate
yields and enantioselectivities were achieved for electron-
donating diphosphine ligands such as L2 ((R,R)-QuinoxP*),
L3 ((S,S)-Ph-BPE), L4 ((Rc,Sp)-DuanPhos), and L5 ((R,S)-
JosiPhos) (entries 2−5, Table 1). Both the yield and
enantioselectivity improved greatly by using axially chiral
ligands such as L6 ((S)-BINAP), L7 ((R)-MeO-BIPHEP), L8
((R)-C3*-TunePhos), and L9 ((R)-SEGPHOS) (entries 6−9,
Table 1). Unexpectedly, the enantioselectivity dropped slightly
with the bulkier ligands L10 ((R)-DM-SEGPHOS) and L11
((R)-DTBM-SEGPHOS) (entries 10−11, Table 1) (Figure 2).
The solvents such as THF, DCM, n-pentane, and i-PrOH were
also screened using SEGPHOS as the ligand (entries 12−15,
Table 1), and the yields dropped sharply without any increase
in enantioselectivity in THF and DCM. No product was
detected using n-pentane or i-PrOH as solvent. When the
temperature decreased to −20 °C, the enantioselectivity was
increased to 94%. To our great surprise, the enantioselectivity
(S)-SEGPHOS, 24 h. With 0.3 mol % of (S)-SEGPHOS and 1 mol
% of Cu(OAc)2·H2O, 48 h. THF = Tetrahydrofuran, DCM =
dichloromethane.
Figure 2. Ligands screened for the asymmetric hydrosilylation.
was maintained when the ligand loading was decreased to 0.3
mol %, whereas the yield was dropped to 15% when the copper
salt was reduced to 1 mol %, indicating that ligand-accelerated
catalysis13 was probably involved in the current reaction
(entries 17 and 18, Table 1). In addition, 1 equiv of PhSiH3
was necessary to achieve full conversion probably due to the
relatively low reactivity of the second and third hydride of
PhSiH3.
B
https://dx.doi.org/10.1021/acs.orglett.9b04339
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pubs.acs.org/OrgLett
Letter
With the optimal reaction conditions in hand, we next
examined the substrate scope of the copper-catalyzed
asymmetric hydrosilylation. For substrates with an electron-
donating group (1b−1d, Scheme 3) or electron-withdrawing
Scheme 4. Gram-Scale Experiments
Scheme 3. Substrate Scope
transformed to 3i which is a key intermediate in the synthesis
of Ticagrelor.6
In conclusion, we have developed an efficient asymmetric
hydrosilylation of β-nitroethyl aryl ketones, giving the
corresponding chiral alcohols in high yields and enantiose-
lectivities. This methodology provides a highly efficient access
to the chiral trans-2-arylcyclopropylamine derivatives. More-
over, the reaction worked well on a gram scale with 0.3 mol %
of ligand loading, indicating that the method has potential
industrial applications in the synthesis of drugs and bioactive
compounds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04339.
Synthesis and characterization of detailed experimental
procedures (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Gen-Qiang Chen − Southern University of Science and
Technology, Shenzhen, People’s Republic of China;
orcid.org/0000-0003-2276-6800; Email: chengq@
sustc.edu.cn
Xumu Zhang − Southern University of Science and
Technology, Shenzhen, People’s Republic of China;
orcid.org/0000-0001-5700-0608; Email: zhangxm@
sustc.edu.cn
group (1e−1h, Scheme 3) on the para-position of the phenyl
ring, the reaction worked well to provide the corresponding
alcohols in excellent yields and enantioselectivities. It is worth
mentioning that 89% yield and 95% ee were achieved for the
3,4-difluorophenyl substrate 1i, which can be further trans-
formed to the key intermediate of Ticagrelor (Figure 1). The
current reaction also tolerates a substrate with an electron-
donating or electron-withdrawing meta-substituent on the
phenyl group (1j−1l). Relatively lower enantioselectivities
were achieved for ortho-substituted substrates, 53% ee for
compound 1m and 88% ee for compound 1n. 2-Naphthyl and
2-furyl substrates were also tested, and 33% yield, 93% ee and
90% yield, 94% ee were achieved, respectively. The
enantioselectivity dropped dramatically in the case of alkyl
substrate 1q (91% yield, 11% ee). Products such as 2c, 2g, and
2o were not obtained in high yield because the conversions
were not full. Retro-Michael addition and over-reduction of 2g
at the ester were not observed. The conversion will improve
greatly if the temperature or the catalyst loading is increased.
To further demonstrate the synthetic utility of the
methodology, the gram-scale experiment (Scheme 4) was
performed using 1i as substrate with 3 mol % of copper acetate
and 0.3 mol % of SEGPHOS. An amount of 5.79 g of product
2i was produced from 6.00 g of 1i (95% yield and 95% ee).
According to the reported procedures, compound 2i can be
Other Authors
Weijun Zeng − Southern University of Science and
Technology, Shenzhen, People’s Republic of China
Xuefeng Tan − Southern University of Science and
Technology, Shenzhen, People’s Republic of China
Yang Yu − Southern University of Science and Technology,
Shenzhen, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04339
Author Contributions
+W.Z. and X.T. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
X. Zhang is indebted to the Southern University of Science and
Technology (start-up fund), Shenzhen Science and Technol-
ogy Innovation Committee (Nos. KQTD20150717103157174
and JSGG20170821140353405), Shenzhen Nobel Prize
Scientists Laboratory Project (C17213101), and SZDRC
Discipline Construction Program for financial support. G.-Q.
Chen gratefully acknowledges the Free Exploration Fund from
C
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Letter
(6) Rasparini, M.; Taddei, M.; Cini, E.; Minelli, C.; Turner, N.;
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