A R T I C L E S
List et al.
Enantioselective catalysis of the Mannich reaction is a rather
new concept. First examples were described by Tomioka,12
Kobayashi,13 Sodeoka,14 and Lectka.15 All of these variants use
preformed imine and enol equivalents combined with a metal-
based catalyst.16,17 A direct catalytic enantioselective three-
component Mannich reaction of propiophenone, paraformalde-
hyde, and pyrrolidine has been described by Shibasaki et al.3
However, although the product is formed in encouraging
enantioselectivity (64%), the yield is poor (16%).18
Support for our initial reaction design involving ketones,
aldehydes, and anilines came from elegant studies by Kobayashi
et al.25 In addition, we have estimated the imine/aldehyde equi-
librium ratio in the reaction of p-nitrobenzaldehyde (0.1 M) with
1
p-anisidine (0.1 M) in DMSO-d6 from H NMR to be around
1.26 Therefore, both reaction pathways seemed feasible. In our
initial experiment, we found (S)-proline to catalyze the direct
asymmetric Mannich reaction of p-nitrobenzaldehyde, p-anisi-
dine, and acetone to give the expected product (1) in 50% yield
(eq 3).4 The corresponding aldol product was formed as well
under those conditions but in much lower yield (<20%). Most
importantly, excellent enantioselectivity was observed (94% ee).
This reaction constitutes the first catalytic asymmetric three-
component Mannich reaction of a free aldehyde with an un-
modified ketone and an amine. It is also the first organocatalytic
enantioselective Mannich reaction.
Proline-Catalysis. Asymmetric catalysis with proline was
first realized in the Hajos-Parrish-Eder-Sauer-Wiechert reac-
tion,19 an enantiogroup-differentiating aldol cyclization. We have
recently discovered proline-catalyzed direct asymmetric inter-
molecular aldol reactions of ketones with aldehydes.20 The basis
of proline-catalysis in these reactions is the facile in situ
generation of chiral enolate equivalents (enamines) from ketones
and aldehydes. This particular type of catalysis, enamine cataly-
sis,21 represents a way of merging enolization and enantiose-
lective bond construction in enolate-electrophile-type reactions.22
We expected the presumed proline enamines to not only react
with carbonyl compounds in aldol reactions or with activated
olefins in Michael reactions,23,24 but also with imines in Mannich
reactions. We further hoped to conduct proline-catalyzed Man-
nich reactions as direct three-component reactions of ketones,
aldehydes, and amines without prior imine formation. Direct
aldol and Mannich reactions typically compete if imines and
enol equivalents are not preformed, and their rates depend on
the equilibrium ratio between the aldehyde and the imine (Keq)
and on their respective rate constants (kaldol vs kMannich) (eq 2).
Results and Discussion
Ketone Component. Other ketones can readily be used in
proline-catalyzed Mannich three-component reactions with
excellent results (Table 1). Reacting three different ketones
(butanone, methoxyacetone, and hydroxyacetone, each 20 vol
%) with p-anisidine (1.1 equiv) and p-nitrobenzaldehyde (1
equiv) furnished the desired products in high yields (92-96%)
and excellent ee’s of up to >99%. In addition, excellent dia-
stereoselectivities were observed. High regioselectivities gener-
ally favoring products resulting from the higher substituted
R-side of the ketone were found with oxygenated ketones, while
butanone furnished a 2.5:1 regioisomeric mixture. The chemose-
lectivity in these reactions was also high, and essentially no
aldol product was formed in all three cases.
Aldehyde Component. We have used various structurally
diverse aldehydes in three-component Mannich reactions with
p-anisidine and acetone (Table 2). In contrast to our observations
in proline-catalyzed aldol reactions and in contrast to any other
catalytic asymmetric Mannich reaction disclosed so far, R-un-
branched aldehydes were found to be efficient substrates in these
reactions. Here, acetone instead of the commonly used DMSO
was used as solvent (Table 2, entries 1-5).27 Excellent enantio-
selectivities yet modest yields were obtained in reactions of
aromatic aldehydes.28 R-Branched aldehydes, for example
isobutyraldehyde, could also be used.
(10) (a) Reference 5a. (b) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520-10524.
(11) For diasteroselective Mannich reactions, see for example: (a) Seebach,
D.; Betschart, C.; Schiess, M. HelV. Chim. Acta 1984, 67, 1593-1597. (b)
Risch, N.; Arend, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 2422-2423.
(12) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomoioka, K. J. Am.
Chem. Soc. 1997, 119, 2060-2061. (b) Kambara, T.; Hussein, M. A.;
Fujieda, H.; Iida, A.; Tomioka, K. Tetrahedron Lett. 1998, 39, 9055-9058.
(c) Tomioka, K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.;
Nomura, Y.; Motomu, K.; Koga, K. Chem. Commun. 1999, 715-716. (d)
Kambara, T.; Tomioka, K. Chem. Pharm. Bull. 1999, 47, 720-721. (e)
Hussein, M. A.; Iida, A.; Tomioka, K. Tetrahedron 1999, 55, 11219-
11228.
(13) (a) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119,
7153-7154. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc.
1998, 120, 431-432. (c) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 8180-8186.
(14) (a) Hagiwara, E.; Fujii, A.; Soeoka, M. J. Am. Chem. Soc. 1998, 120, 2474-
2475. (b) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999,
121, 5450-5458.
(15) (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc.
1998, 120, 4548-4549. (b) Ferraris, D.; Young, B.; Cox, C.; Drury, W. J.,
III; Lectka, T. J. Org. Chem. 1998, 63, 6090-6091. (c) Ferraris, D.;
Dudding, T.; Young, B.; Drury, W. J., III; Lectka, T. J. Org. Chem. 1999,
64, 2168-2169.
(20) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395-2396. (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-
7387. (c) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575.
(21) List, B. Synlett 2001, 1675-1686.
(16) For a more recent example, see: Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D.
Angew. Chem., Int. Ed. 2001, 40, 2271-2274.
(22) Evans, D. A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452-6453.
(23) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423-2425.
(24) List, B.; Castello, C. Synlett 2001, 1687-1689.
(17) For a catalytic asymmetric vinylogous Mannich reaction, see: Martin, S.
F.; Lopes, O. D. Tetrahedron Lett. 1999, 40, 8949-8953.
(18) Very recently Jørgensen et al. developed a new catalytic asymmetric
Mannich reaction of activated ketones with preformed imines. Juhl, K.;
Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995-
2997.
(25) For example, see: Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965-
1967.
(26) This equilibrium is influenced by the water concentration, and the
commercially available d6-DMSO samples we use are typically 0.1 M in
H2O.
(19) (a) Hajos, Z. G.; Parrish, D. R. Asymmetric Synthesis of Optically Active
Polycyclic Organic Compounds. German Patent DE 2102623, Jul 29, 1971.
(b) Eder, U.; Sauer, G.; Wiechert, R. Optically Active 1,5-Indanone and
1,6-Naphthalenedione. German Patent DE 2014757, Oct 7, 1971. (c) Eder,
U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496.
(d) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615.
(27) Proline can be recovered in these reactions by filtration (see Experimental
Section). Alternatively, 20 vol % acetone in chloroform can be used.
(28) After our results were published, others submitted a manuscript describing
related observations: Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas,
C. F., III. Tetrahedron Lett. 2001, 42, 199-201.
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828 J. AM. CHEM. SOC. VOL. 124, NO. 5, 2002