approach, which reduces the typical three-step synthesis
to a one-pot process (Scheme 1). The dehydrating prop-
erty of diorganozinc reagents was utilized to generate
imines in situ, as previously demonstrated by Hoveyda
and Snapper.3a,b We have also taken advantage of the
facile cleavage of a phosphinoyl activating group1b,8 from
amines under acidic workup conditions.
This is a very effective and general method to gain
access to free R-chiral amines directly from commercially
available reagents. The Leuckart-Wallach-type condi-
tions developed by Kadyrov and co-workers seem to be
limited to acetophenone derivatives.9 Enzymatic methods
possess the disadvantage that enzymes are substrate
specific, thus reducing the generality of the protocol.10
Multicomponent One-Pot Procedure for the
Synthesis of Free r-Chiral Amines from
Aldehydes
Alexandre Coˆte´ and Andre´ B. Charette*
De´partement de Chimie, Universite´ de Montre´al, P.O. 6128,
Station Downtown, Montre´al, Que´bec, Canada H3C 3J7
Received August 5, 2005
Optimization experiments were performed with com-
mercially available aldehydes that were not further
purified prior to use. Despite the fact that preliminary
results have shown that slightly better enantioselectivi-
ties could be obtained with neat diorganozinc reagents,
we chose to use solutions in toluene for safety (some neat
dialkylzinc reagents are pyrophoric), availability, and
economical considerations.
An examination of the stoichiometry revealed that 3
equiv of aldehyde and 5 equiv of dialkylzinc reagent,
relative to the phosphinoylamide, provided the best
compromise between economy of reagents, overall yield,
and quantity of side products formed.
The main challenge in transferring the methodology
to a parallel synthesis format was to find conditions to
effect complexation, since this typically involves mixing
The synthesis of free R-chiral amines by a one-pot multi-
component procedure from commercially available starting
materials is described. This enantioselective reaction in-
volves a catalytic asymmetric addition of dialkylzinc re-
agents to N-diphenylphosphinoylimines with use of an air-
stable precatalyst complex 1. The R-chiral amines are
prepared with a one-pot procedure from alkyl and aryl
aldehydes in good yield (41-90%) and with excellent enan-
tioselectivity (90-97% ee).
(6) (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
1692-1693. (b) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B.
J. Am. Chem. Soc. 2003, 125, 14260-14261. (c) Coˆte´, A.; Boezio, A.
A.; Charette, A. B. Proc. Natl Acad. Sci. U.S.A. 2004, 101, 5405-5410.
(d) Desrosiers, J.-N.; Coˆte´, A.; Charette, A. B. Tetrahedron 2005, 61,
6186-6192.
(7) Selected examples of catalytic enantioselective methods to
prepare protected R-chiral amines from imines: (a) Soeta, T.; Nagai,
K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2003, 68,
9723-9727. (b) Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed.
2004, 43, 2228-2230. (c) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer,
R. A.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 355-358. (d)
Dahmen, S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940-5941. (e)
Zhang, H.; Liu, H.; Cui, X.; Mi, A.; Jiang, Y.; Gong, L. Z. Synlett 2005,
615-618. (f) Wang, C.; Shi, M. J. Org. Chem. 2003, 68, 6229-6237.
(g) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett.
2005, 7, 307-310.
(8) (a) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 4712-4713. (b) Wipf, P.; Kendall, C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761-768. (c)
Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530-
2535. (d) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E. Eur. J.
Org. Chem. 1998, 1413-1423. (e) Soai, K.; Hatanaka, T.; Miyazawa,
T. J. Chem. Soc., Chem. Commun. 1992, 1097-1098.
(9) (a) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003,
42, 5472-5474. (b) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.;
Fischer, C.; Bo¨rner, A. Adv. Synth. Catal. 2004, 346, 561-565.
(10) Some examples of enzymatic transaminations: (a) He´laine, V.;
Rossi, J.; Gefflaut, T.; Alaux, S.; Bolte, J. Adv. Synth. Catal. 2001,
343, 692-697. (b) Li, T.-L.; Choroba, O. W.; Charles, E. H.; Sandercock,
A. M.; Williams, D. H.; Spencer, J. B. Chem. Commun. 2001, 1752-
1753. (c) Fotheringham, I. G.; Grinter, N.; Pantaleone, D. P.; Senkpeil,
R. F.; Taylor, P. P. Bioorg. Med. Chem. 1999, 7, 2209-2213. (d)
Harding, J. R.; Hughes, R. A.; Kelly, N. M.; Sutherland, A.; Willis, C.
L. J. Chem. Soc., Perkin Trans. 1 2000, 3406-3416. (e) Kim, K.; Cole,
P. A. J. Am. Chem. Soc. 1998, 120, 6851-6858. (f) Cox, R. J.; Jenkins,
H.; Schouten, J. A.; Stentiford, R. A.; Wareing, K. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 2023-2036. (g) Sutherland, A.; Willis, C. L. J.
Bioorg. Med. Chem. Lett. 1999, 9, 1941-1944.
The extensive use of enantiopure R-chiral amines in
food, agrochemical, biochemical, and pharmaceutical
industries has stimulated the development of methodolo-
gies to generate them.1 A one-pot multicomponent2-4
synthesis would be extremely valuable in high-through-
put processes which are amenable to automation, such
as combinatorial and parallel synthesis.5
Having recently developed a catalytic asymmetric
reaction to generate R-chiral amines,6,7 we have aimed
at finding experimental conditions that could be adapted
to a parallel synthesis format. Described herein is our
(1) (a) Bloch, R. Chem. Rev. 1998, 98, 1407-1438. (b) Kobayashi,
S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094.
(2) Review on asymmetric multicomponent reactions: Ramo´n, D.
J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602-1634.
(3) Asymmetric multicomponent addition of organometallic reagents
to imine and/or iminium: (a) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409-10410. (b)
Akullian, L. C.; Snapper, M. L.; Hoveyda A. H. Angew. Chem., Int.
Ed. 2003, 42, 4244-4247. (c) Gommermann, N.; Koradin, C.; Polborn,
K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766.
(4) Asymmetric one-pot reduction and addition to imines: (a) Borg,
G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40, 6709-6712.
(b) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092-1093.
(5) (a) Cargill, J. F.; Lebl, M. Curr. Opin. Chem. Biol. 1997, 1, 67-
71. (b) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem.,
Int. Ed. 2001, 40, 650-679. (c) Powers, D. G.; Coffen, D. L. Drug
Discovery Today 1999, 4, 377-383. (d) Dolle, R. E. J. Comb. Chem.
2003, 5, 693-753. (e) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893-930.
10.1021/jo0516483 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/18/2005
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J. Org. Chem. 2005, 70, 10864-10867