resent an opportunity, but they must point at two main
directions: higher chemical and stereochemical efficiency and
lower cost of the catalytic system. To obtain an enantiopure
compound with a metal-free, inexpensive catalyst would open
unexplored synthetic routes with relevant consequences also
in terms of novel patent strategies.
Even if both catalysts 2 and 3 showed excellent chemical
efficiency and interesting levels of enantioselectivity, the
control of the absolute stereochemistry was not satisfactory.
In order to improve the selectivity of the process, the
trichlorosilane-mediated reduction of acetophenone imines
(R)-4 and (S)-4 derived from (R)- and (S)-1-phenylethy-
lamine, respectively, was studied (Scheme 2).13 The reaction
In this context, we wish to report here our studies on a
low cost catalytic system, easily prepared from commercially
available products, able to promote the enantioselective
reduction of ketimines with trichlorosilane with great ef-
ficiency. A wide class of catalysts prepared by simple
condensation of picolinic acid9m or its derivatives with a
chiral amino alcohol9i,10 or diamine11 was investigated. In a
one-step procedure, several derivatives were synthesized
simply by reaction of a chiral amino alcohol or diamine with
picolinoyl chloride or picolinic acid in the presence of
condensing agents. Among the different synthesized com-
pounds, (1R,2S)-ephedrine-derived N-picolinoylamide 19i and
N-4-chloropicolinoylamide 210 and the bis(N-methyl-N-
picolinoylamide) of 1,1′-binaphthyldiamine 312 were selected
for this study (Figure 1).
Scheme 2. Stereoselective Reduction of Imine 4
product is the bis-R-methylbenzylamine, a compound that
has found numerous applications as chiral base and chiral
ligand.14 The diastereoselective reduction of these chiral
substrates through hydrogenation with different catalytic
systems has been investigated.15 However, to the best of our
knowledge, no examples of analogous studies with organo-
catalytic systems have been reported so far.
Figure 1. Catalysts for stereoselective ketimine reduction.
In the reduction of the N-benzylimine of acetophenone, by
employing 10% of catalyst 1 at 0 °C in dichloromethane the
product was isolated in 85% yield and 71% ee (Scheme 1).
(7) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407.
(8) Reviews: (a) Benaglia, M.; Guizzetti, S.; Pignataro, L. Coord. Chem.
ReV. 2008, 252, 492. (b) Denmark, S. E.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2008, 47, 1560.
Scheme 1. Enantioselective Reduction of N-Benzylimines
(9) Selected references: (a) Malkov, A. V.; Mariani, A.; MacDougal,
K. N.; Koe`ovsky´, P. Org. Lett. 2004, 6, 2253. (b) Malkov, A. V.; Stone`ius,
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Figlus, M.; Koe`ovsky´, P. J. Org. Chem. 2008, 73, 3985. (d) Matsumura,
Y.; Ogura, K.; Kouchi, Y.; Iwasaki, F.; Onomura, O. Org. Lett. 2006, 8,
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Synth. Catal. 2008, 350, 619. (h) Wu, P.; Wang, Z.; Cheng, M.; Zhou, L.;
Sun, J. Tetrahedron 2008, 64, 11304. (i) Zheng, H.; Deng, J.; Lin, W.;
Zhang, X. Tetrahedron Lett. 2007, 48, 7934. (l) Gautier, F.-M.; Jones, S.;
Martin, S. J. Org. Biomol. Chem. 2009, 7, 229. (m) For the first report
where chiral amides were used as catalysts, see: Iwasaki, F.; Onomura, O.;
Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura, Y. Tetrahedron Lett.
2001, 42, 2525.
Higher performances were obtained with ephedrine-based
4-chloropicolinamide 2 that promoted the reaction in quantita-
tive yield and 80% ee. Catalyst (S)-3 promoted the reaction in
quantitative yield and 85% ee.
(10) Guizzetti, S.; Benaglia, M. European Patent Appl. Nov 30, 2007;
PCT/EP/2008/010079, Nov 27, 2008.
(6) Reductive amination: for selected recent references for organometallic
systems see ref 2 and: (a) Reetz, M. T.; Bondarev, O. Angew. Chem., Int.
Ed. 2007, 46, 4523. (b) Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org.
Lett. 2006, 8, 1229. For organic catalysts, see: (c) Ouellet, S. G.; Walji,
A.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327. (d) Rueping,
M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45,
3683. (e) Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498. (f) Storer,
R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
128, 84. For a recent biocatalytic reductive amination, see: (g) Koszelewski,
D.; Lavandera, I.; Clay, D.; Guebitz, G. M.; Rozzell, D.; Kroutil, W. Angew.
Chem., Int. Ed. 2008, 47, 9337. (h) Koszelewski, D.; Lavandera, I.; Clay,
D.; Rozzell, D.; Kroutil, W. AdV. Synth. Catal. 2008, 350, 2761. See also:
(i) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 43, 5472.
(11) Guizzetti, S., Benaglia, M. European Patent Appl. no. EP07023240.0,
Sep 22, 2008.
(12) Guizzetti, S.; Benaglia, M.; Cozzi, F.; Rossi, S.; Celentano, G.
Chirality 2009, 21, 233.
(13) For a review on the use of methylbenzylamine, see: Juaristi, E.;
Leon-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry 1999,
10, 2441.
(14) See: Alexakis, A.; Gille, S.; Prian, F.; Rosset, S.; Ditrich, K.
Tetrahedron Lett. 2004, 45, 1449, and references cited therein.
(15) Nugent, T. C.; El-Shazly, M.; Wachaure, V. N. J. Org. Chem. 2008,
73, 1297, and references cited thereinSee also: AdV. Synth. Catal. 2006,
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