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Cooperative Catalysis with Iron and a Chiral Brønsted Acid
Table 2. Asymmetric reductive amination of different ke-
tones 1 with amines 2a or 2b.[a]
and enantioselectivities (Table 2, entries 2 and 3). 2-
Acetylthiophene as an example for a heteroaromatic
ketone also was transformed to the corresponding
amine 3d in high yield (88%) and good enantioselec-
tivity (73% ee) (Table 2, entry 4). Notably, more chal-
lenging aliphatic ketones were applied too and were
transformed into the corresponding amines with mod-
erate yields and good enantioselectivities (Table 2, en-
tries 5–7). It should be noted that different substitu-
ents on the aromatic ring of the ketone did not affect
the chiral induction to a significant extent (entries 8–
11). However, the best yield (90%) was observed for
ketone 1j bearing an electron-withdrawing group and
aniline 2b. For the direct asymmetric reductive amina-
tion of 2-octanone, para-chloracetophenone and 1-bi-
phenyl-4-ylethanone with 2a only low conversions
were detected by NMR spectroscopy. In these cases
chemoselectivities were not determined. Unfortunate-
ly, ortho-substituted aromatic ketones as well as
ortho-substituted anilines showed no reaction at all.
All products shown in Table 2 were also synthesized
by hydrogenation of the corresponding imine using
the combination of a molecular-defined non-chiral
iron complex 5 with a chiral Brønsted acid (TRIP)
4.[13] In general, yields and enantiomeric excess are
better compared to the results of the direct asymmet-
ric reductive amination of ketones (Supporting Infor-
mation, Table S1). Nevertheless, in some cases slightly
increased yields (3c and 3k) and enantioselectivities
(3b, 3c and 3e) were achieved using the catalytic
method presented in this publication. Moreover, the
protocol of the direct asymmetric reductive amination
allows additional variation of the amine part. Here,
a higher structure diversity of the products is accessi-
ble, which represents a huge advantage of DARA.
Therefore, the asymmetric reductive amination of
acetophenone 1b with different substituted amines
2a–2j was investigated (Table 3). meta- and para-sub-
stituted anilines with electron-donating and electron-
withdrawing groups reacted with acetophenone 1b in
high yields and led to very good to excellent enantio-
selectivities (92–99% ee).
In summary, we have developed the first iron-cata-
lyzed asymmetric reductive amination (DARA) of ke-
tones with anilines in the presence of hydrogen. Key
to success is the combination of a chiral Brønsted
acid (TRIP) catalyst and the non-chiral Knçlker com-
[a]
General reaction conditions: 0.5 mmol ketone 1,
0.5 mmol aniline 2a or 2b, 3 mol% (S)-TRIP 4, 5 mol%
5, 50 bar H2, 658C, 24 h, 2 mL toluene, molecular sieves.
[b]
The yields are determined by 1H NMR spectroscopic
analysis with dibromomethane as an internal standard.
The yield of the pure isolated product is given in brack-
ets.
[c]
The ee value was determined by HPLC on a chiral sta-
tionary phase.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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