Enantioselective Synthesis of Cycloalkylamines via Dynamic Kinetic Resolution
COMMUNICATIONS
Figure 1. TsDPEN-based catalysts.
According to the early findings by Noyori,[6] imines re-
act faster than ketones in transfer hydrogenation using
HCO2H/Et3N as the hydrogen source and type-I
Scheme 3. “One-pot” transfer hydrogenation to cycloalkyl-
amines.
Ru(II) catalysts. Therefore, we decided to explore the
selective “one-pot” transfer hydrogenation of in situ
generated allyl imines (Scheme 3). Thus, ketones 15–
17, representatives of both types of substrates, were
used directly as starting materials in “solvent-free” reac-
tions[8] carried out in the presence of an excess of allyl-
amine. The results collected using this technique (en-
toluene (60 mL) was heated to reflux overnight using a
“Dean–Stark” system in order to remove water. The reaction
mixture was concentrated and the crude product was used in
the following step without further purification.
¼
¼
tries 8–10) confirmed the expected C N/C O chemo-
selectivity: cis allylamines 18–20 were obtained with
similar overall yields and selectivities as from preformed
benzylimines. This method provides a more convenient
procedure for the operational simplicity, in particular
when the synthesis of the alternative imine precursor
is troublesome. It is in addition worth mentioning that
only Ru(II) catalyst I gave good results under these con-
ditions.
Transfer Hydrogenation of Ketimines
Method A: To a solution of catalyst I–III in a 5:2 HCO2H/Et3N
azeotropic mixture (2.4 mL) was added a solution of the crude
benzylimine 1–4 or 9–11 (5 mmol) in CH2Cl2 (7 mL). The mix-
ture was stirred at room temperature for 1–6 days and the re-
action was then diluted with CH2Cl2 (10 mL) and washed with a
solution of Na2CO3 (0.5 M, 20 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3ꢀ15 mL), the combined organic layer
was dried and concentrated, and the residue was purified by
flash chromatography.
Method B: A mixture of ketone 15–17 (4 mmol), allylamine
(8 equivs., 2.4 mL) and anhydrous MgSO4 (500 mg) was stirred
at room temperature for 1 h. A solution of catalyst I
(0.02 mmol, S/C¼200) in a 5:2 HCO2H/Et3N azeotropic mix-
ture (2.4 mL) was then added and the mixture was stirred for 6
days. The reaction mixture was then diluted with CH2Cl2
(10 mL) and washed with a solution of Na2CO3 (0.5 M, 20 mL).
The aqueous layer was extracted with CH2Cl2 (3ꢀ15 mL) and
the combined organic layer was dried (MgSO4), concentrated
and the residue was purified by flash chromatography.
Starting material, method used for the synthesis, catalyst,
eluents, yields and spectral and analytical data for compounds
5–8, 12–14, and 18–20 are described in the Supporting Infor-
mation.
Summarizing, transfer hydrogenation of a-substituted
cyclic ketimines via DKR can be accomplished by using
Noyoriꢀs Ru(arene)TsDPEN complex I, as well as relat-
ed Ir(III) and Rh(III)-based catalysts II and III, and
HCO2H/Et3N as the hydrogen source. These reactions
provide the first known examples of a DKR-based proc-
¼
ess involving reduction of C N bonds. The observed
yields and the achieved levels of diastero- and enantio-
selectivity of the products confer synthetic utility to
the methodology. A more detailed study to determine
the scope and limitations of this new synthetic tool is cur-
rently being performed in our laboratory.
Experimental Section
Acknowledgements
Synthesis of Benzylketimines 1–4 and 9–11; General
Procedure
We thank the Spanish Ministerio de Ciencia y Tecnología
(grants CTQ2004-00290 and CTQ2004-00241) and the “Junta
de Andalucía” for financial support. A. R. and A. M. thank
Bayer CropScience for predoctoral fellowships and the dona-
tion of chemicals.
A solution of the starting ketone (18 mmol), benzylamine
(1.2 equivs., 2.36 mL) and p-toluenesulfonic acid (cat.) in dry
References and Notes
[1] Reviews: a) R. Noyori, M. Tokunaga, M. Kitamura, Bull.
Chem. Soc. Jpn. 1995, 68, 36–56; b) F. F. Huertas, A. B. E.
Scheme 2. Dynamic kinetic resolution of monocyclic ket-
imines.
Adv. Synth. Catal. 2005, 347, 1917 – 1920
ꢁ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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