Guijarro et al.
JOCArticle
imine functionality and a protecting group for the nitrogen
atom of the reduction product. Furthermore, the sulfinyl
group can easily be removed under mild acidic conditions8
for further transformations. The tert-butanesulfinyl group is
particularly interesting because it has shown high levels of
asymmetric induction in a variety of processes. Since the ini-
tial studies carried out by Ellman, N-(tert-butanesulfinyl)-
imines have consolidated as excellent substrates for the
preparation of chiral primary amines.9 The diastereoselec-
tive reduction of N-(tert-butanesulfinyl)ketimines has been
achieved using several boranes,9b,c,10 sodium or lithium
borohydrides,9b,c,e,10,11 aluminum hydrides,9c,10,11 and diethyl-
zinc in the presence of Ni(acac)2.12
Among the different approaches to perform the reduction
of a carbon-heteroatom double bond, the transfer hydro-
genation protocol presents several advantages because it is
operationally simple, normally uses low catalyst loadings,
and avoids the handling of hazardous chemicals such as
metallic hydrides or molecular hydrogen. Moreover, volatile
reaction side products, such as acetone or carbon dioxide,
are formed, which facilitates the isolation of the reduction
products. The asymmetric transfer hydrogenation has widely
been applied to the synthesis of chiral secondary alcohols by
reduction of ketones.13 However, there are only a limited
number of examples of stereoselective preparation of amines
by this methodology. The asymmetric reduction of imines
bearing alkyl,13d aryl,13c,d benzyl,5c,13c,d phosphinyl,2,13d or
sulfonyl13b,d groups on the nitrogen atom and endocyclic
imines5c,13b-d by transfer hydrogenation has been published,
with the catalysts being ruthenium,14 rhodium, or iridium
complexes with chiral ligands such as monotosylated dia-
mines, β-aminoalcohols, diphosphines, and N-heterocyclic
carbenes. Some organocatalysts have also been employed in
the reduction of N-aryl- and endocyclic imines.13c,d How-
ever, to the best of our knowledge, the asymmetric transfer
hydrogenation has never been applied to the reduction of sul-
finylimines. As part of our research on the use of these useful
imines in asymmetric synthesis,15 herein we report our results
on the preparation of highly enantiomerically enriched ami-
nes by a ruthenium-catalyzed transfer hydrogenation of
N-(tert-butanesulfinyl)imines.16
Results and Discussion
The use of β-aminoalcohols as ligands for asymmetric
catalysis has been one of the subjects of our research activi-
ties during the last several years.17 Since one of the most suc-
cessful applications of these compounds has been as ligands
for ruthenium complexes used as catalysts for the transfer
hydrogenation of ketones,13 we decided to explore the pos-
sibility of extending this reduction methodology to N-(tert-
butanesulfinyl)imines. After screening several aminoalcohols,16
we found that (1S,2R)-1-amino-2-indanol18,19 3 (20 mol %)
gave a complex by reaction with [RuCl2(p-cymene)]2 (5 mol %)
that was able to catalyze the reduction of the imine derived
from acetophenone 1a (Table 1) in isopropyl alcohol at room
temperature and in the presence of KOH (50 mol %). The
yield of the reduction product 2a was quite low (31%), but we
were pleased to see that the ee was excellent (98%, Table 1,
entry 1). The high enantioselectivity obtained encouraged us
to do an optimization study of the reaction conditions since,
to the best of our knowledge, this was the first time that the
asymmetric transfer hydrogenation of an acyclic imine using
a β-aminoalcohol as a chiral ligand and isopropyl alcohol as
a hydrogen source had been achieved.20,21 Moreover, the
possibility of performing the reductions in isopropyl alcohol
was very attractive because it has been proven to be a
convenient solvent for industrial scale processes.22,23
(15) (a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry
2008, 19, 603–606. (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2008, 19, 2484–2491. (c) Almansa, R.; Guijarro, D.; Yus, M.
Tetrahedron Lett. 2009, 50, 3198–3201. (d) Almansa, R.; Guijarro, D.; Yus,
M. Tetrahedron Lett. 2009, 50, 4188–4190. (e) Almansa, R.; Collados, J. F.;
Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2010, 21, doi: 10.1016/j.
tetasy.2010.03.046.
(8) See, for instance: (a) Sun, X.; Wang, S.; Sun, S.; Zhu, J.; Deng, J.
Synlett 2005, 2776–2780. (b) Kosciolowicz, A.; Rozwadowska, M. D. Tetra-
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(16) Preliminary communication: Guijarro, D.; Pablo, O.; Yus, M.
Tetrahedron Lett. 2009, 50, 5386–5388.
(17) (a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron: Asymmetry
2007, 18, 896–899. (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron:
Asymmetry 2007, 18, 2828–2840. (c) Almansa, R.; Guijarro, D.; Yus, M.
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ꢀ
(e) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. Rev.
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(18) Both enantiomers of cis-1-amino-2-indanol have been extensively
used as ligands for the asymmetric transfer hydrogenation of ketones. See,
for instance: (a) Palmer, M.; Walsgrove, T.; Wills, M. J. Org. Chem. 1997, 62,
5226–5228. (b) Blacker, A. J.; Mellor, B. J. Patent WO 9842643A1, 1998.
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2000, 5, 4–18. (d) Palmer, M. J.; Kenny, J. A.; Walsgrove, T.; Kawamoto,
A. M.; Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 416–427. (e) Hansen,
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(19) A rhodium complex bearing N-tosyl-(1S,2R)-1-amino-2-indanol as a
ligand has been used as a catalyst for the transfer hydrogenation of an
endocyclic imine. See ref 18b.
(10) (a) Chelucci, G.; Baldino, S.; Chessa, S.; Pinna, G. A.; Soccolini, F.
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€
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€
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5266 J. Org. Chem. Vol. 75, No. 15, 2010