Angewandte
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Chemie
were add to promote prior formation of the ketimine. The use
of alcohol solvents such as isopropanol and n-butanol was also
critical to the formation of the amine product. Under the
optimized conditions, the model reaction afforded the desired
product in 85% yield and 91% ee in the presence of a nickel/
Ph-BPE catalyst. Notably, when the model reaction was
conducted in a one-pot manner, i.e., without pre-formation of
the ketimine, the desired product was still obtained in 76%
yield in the presence of molecular sieves (see the Supporting
Information).
The ligand Ph-BPE was found to be the most stereose-
lective among the bisphosphines invented by Burk et al.,
while DuPhos and BPF were found to be less selective
(Scheme 1).[18] QuinoxP* and BenzP*[3e,19] afforded good
yields, but only moderate ee was obtained. We also tested
several Josiphos ligands,[20] but they did not provide good ee
values either. Other strongly donating bis(alkylphosphine)s
developed by Zhang et al. were also tested, but they afforded
unsatisfactory ee values. For example, a nickel catalyst with
the ligand Binapine[21] resulted in only 60% ee in the model
reaction, while DuanPhos and TangPhos led to low catalytic
activity and less than 30% ee. Less-donating bis(arylphos-
phine)s such as BINAP, Segphos, and DIPAMP did not
produce active catalysts at all.
Regarding the choice of the amine component, parent
aniline and p-anisidine gave products in 76 and 80% ee
(Scheme 2). The ee value was improved to around 90% when
Scheme 3. Asymmetric reductive amination of aromatic ketones with
3,5-dimethylanisidine (0.3 mmol scale in most cases).
Next, we examined the reductive amination of ketones
with benzhydrazide, a cheap amine source (Scheme 4a). To
our satisfaction, a diverse set of aromatic ketones reacted
efficiently to give N-benzoylhydrazine products with high ee
values in the presence of a nickel/Binapine catalyst. All of the
reactions were conducted under one-pot conditions with
molecular sieves as a dehydrating agent. Thus, no prior
formation of hydrazones was needed. For reactions of two
aliphatic ketones, a Josiphos ligand, CyPF-Cy, afforded
excellent stereoselectivity (Scheme 4b). In a test case, the
nickel catalyst loading was reduced to 1 mol%, and the
product was isolated in 95% yield and 97% ee on a 5 mmol
scale (Scheme 4c). Further reducing the catalyst loading to
0.5 mol% resulted in 70% yield without any loss of ee. The
resulting N-benzoylhydrazine products are crystalline and can
be readily crystallized to boost optical purity. In addition, the
Scheme 2. Asymmetric reductive amination of acetophenone with
several anilines (0.3 mmol scale).
bigger anilines such as 3,5-dimethoxyaniline and 3,5-
dimethyl-4-anisidine were used. The anisidine fragment in
the products can be easily removed by treatment with
oxidants.[22] Notably, we found that o-tolylamine did not
undergo the desired process.
We next explored the scope with respect to the ketones
under the optimal conditions (Scheme 3a). A series of
aromatic ketones were readily aminated with good ee
values. Both electron-donating and electron-withdrawing
groups can be present on the aryl rings of the ketones.
Furthermore, the catalytic process can be conducted with
1 mol% of the nickel catalyst (Scheme 3b). Unfortunately
though, reactions of aliphatic methyl ketones gave very low
selectivity (< 20% ee) in combination with various aryl-
amines.[23]
À
N N single bond in the products can be cleaved to release
free alkylamines with SmI2[4a] and Raney nickel.[24]
We also successfully performed double reductive amina-
tion to produce substituted tetrahydroquinoxalines directly
(Scheme 5).[25] 1,2-Diaminobenzene and a-ketoaldehydes
spontaneously condensed to form quinoxalines even without
molecular sieves. The quinoxalines were hydrogenated by
a nickel/TangPhos catalyst to give products in moderate to
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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