DOI: 10.1002/chem.201402763
Communication
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Organocatalysis
Chiral Phosphoric-Acid-Catalyzed Transfer Hydrogenation of Ethyl
Ketimine Derivatives by Using Benzothiazoline
Kodai Saito,[a] Kosaku Horiguchi,[a] Yukihiro Shibata,[b] Masahiro Yamanaka,[b] and
Takahiko Akiyama*[a]
reactivity and enantioselectivity in transfer hydrogenation of
Abstract: Chiral phosphoric acid catalyzed transfer hydro-
genation of ketimines derived from propiophenone deriv-
trifluoromethylated ketimines by using those two hydrogen
donors, the mechanistic insights and stereochemical outcome
atives and reductive amination of alkyl ethyl ketone deriv-
were not discussed.[6c,j] Hantzsch ester and benzothiazoline
atives were extensively examined in the presence of two
have large structural differences (Figure 1). In benzothiazoline,
representative hydrogen donors. The excellent enantiose-
lective transfer hydrogenation was achieved by use of
benzothiazoline as a hydrogen donor. The theoretical
studies elucidated that the unsymmetrical structure of
benzothiazoline plays an important role in high enantiose-
lective hydrogenation.
Figure 1. Representative hydrogen donors for transfer hydrogenation cata-
lyzed by a Brønsted acid.
The asymmetric hydrogenation of ketimines is an efficient
method for the synthesis of chiral amines.[1] In this reaction,
molecular hydrogen is normally used as the reducing agent in
combination with chiral transition-metal catalysts.[2] A biomim-
the hydrogen atom located at the sterically hindered C(2) posi-
etic asymmetric hydrogen-transfer approach employing nico-
tinamide adenine dinucleotide (NADH) mimics was recently de-
veloped and extensively studied by many researchers.[3] The
groups of Rueping, List, and MacMillan independently reported
the transfer hydrogenation of ketimines by using Hantzsch
ester as the hydrogen donor and chiral phosphoric acid for the
first time.[4] Hantzsch ester was recognized to be the most reli-
able hydrogen donor, and a range of transfer hydrogenation
reactions, which use chiral phosphoric acid, has been
developed.[5]
tion transfers to the substrate, whereas in Hantzsch ester
having a symmetric and planar structure, the transferable hy-
drogen atom is located at the sterically less hindered C(4) posi-
tion. The steric difference between the two hydrogen donors
would be a vital factor affecting the enantioselectivity.[7]
Although the asymmetric transfer hydrogenation of keti-
mines was extensively investigated, the substrate scope was
limited to mostly acetophenone derivatives, and there are few
intensive studies on the generality and limitations of ketimines
derived from propiophenone and other aromatic ketones con-
taining long alkyl chains.[8] Herein, we report the chiral phos-
phoric acid catalyzed transfer hydrogenation of ketimine deriv-
atives obtained from ethyl ketones by using the representative
hydrogen donors. Interestingly, benzothiazoline exhibited ex-
cellent enantioselectivity in comparison with Hantzsch ester.
We also conducted a theoretical study and elucidated the dif-
ference in enantiocontrol efficiency between those two hydro-
gen donors.
In 2009, we demonstrated that benzothiazoline is an effi-
cient hydrogen donor in the chiral phosphoric-acid-catalyzed
transfer hydrogenation of ketimines.[6a] The advantages of ben-
zothiazoline lie in the ease of tuning both reactivity and enan-
tioselectivity by altering the substituent at the second position
of the molecule. The substituent effect of benzothiazoline was
confirmed in many examples of the transfer hydrogenation of
C=N bonds catalyzed by chiral phosphoric acid.[6b–j] Although
we have recently reported that there are some differences in
First, we focused on the applicability of benzothiazoline to
the asymmetric transfer hydrogenation of non-methyl aromatic
ketimine. An initial attempt of the transfer hydrogenation was
carried out with ketimine 1a prepared from propiophenone
and p-anisidine by means of chiral phosphoric acid containing
2,4,6-triisopropylphenyl group (R)-2 in benzene in the presence
of benzothiazoline 3 at room temperature (Table 1).[9] Examina-
tion of the effect of the substituent at second position of ben-
zothiazoline 3 revealed that 3b containing a 2-naphthyl group
resulted in the highest enantiomeric excess (ee; 85, 98% ee,
Table 1, entry 3).
[a] Dr. K. Saito, K. Horiguchi, Prof. T. Akiyama
Department of Chemistry, Faculty of Science, Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
[b] Y. Shibata, Prof. Dr. M. Yamanaka
Department of Chemistry and Research Center for Smart Molecules
Faculty of Science, Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402763.
Chem. Eur. J. 2014, 20, 1 – 6
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