carbonyl compounds, which constitute various pharmaceu-
ticals, natural products, and versatile synthetic intermediates.4
Conventional protocols for three-component Mannich-type
reactions of aldehydes, amines, and ketones in organic
solvents include some severe side reactions and have some
substrate limitations, especially for enolizable aliphatic
aldehydes. Our previous DBSA-catalyzed three-component
Mannich-type reactions in colloidal dispersion systems,3g in
which silyl enolates instead of ketones are used as nucleo-
philic components,5 have extended the substrate applicability
and avoided the use of organic solvents. However, there is
still a drawback in that the silyl enolates have to be prepared
from the corresponding carbonyl compounds usually under
anhydrous conditions. From atom economical and environ-
mental points of view, therefore, it is desirable to develop a
new efficient system for Mannich-type reactions in which
the parent carbonyl compounds are directly used6 and water
is used as a solvent (Scheme 1). These three-component
noted that p-toluenesulfonic acid (TsOH) did not afford the
desired product (entry 3). DBSA formed a white turbid
reaction mixture, while TsOH formed two immiscible layers.
This result indicates that the long alkyl chain of DBSA is
necessary for formation of the colloidal dispersion which
leads to efficient catalysis. In fact, a combination of TsOH
and sodium dodecyl sulfate (SDS), which formed a colloidal
dispersion in the presence of the substrates, afforded the
adduct in a modest yield (entry 5), while SDS alone gave
the adduct in a very low yield (entry 4). The reaction
proceeds through the imine formation of the aldehyde and
the amine, protonation of the imine, and the attack of the
enol derived from the ketone to the protonated imine. This
dehydrative imine formation in water is a characteristic
feature of our colloidal dispersion system for reactions of
imines.
The reactions of various aldehydes, amines, and ketones
were found to be efficiently catalyzed by DBSA at ambient
temperature in water (Table 2).9,12
The following features are noteworthy in these reactions.
(1) A 1:1:1 mixture of benzaldehyde, p-anisidine, and
acetophenone with 10 mol % of DBSA gave the Mannich
adduct in 63% yield (entry 1), in contrast to a 30% yield by
a conventional HCl-catalyzed reaction in EtOH (18 h).6a (2)
In the case of the substrates shown in entries 3, 5, and 6,
only 1 mol % of DBSA was sufficient to catalyze the
reactions. (3) The reactivity order of the amines is p-
chloroaniline > aniline > p-anisidine, indicating the impor-
tance of the electronic nature of the amines. (4) In the
reaction of 2-butanone (entry 8), the adduct aminoalkylated
at the less substituted R-carbon was formed preferentially.
(5) Not only benzaldehyde but also heteroaromatic aldehydes
such as 2-furfural and 2-pyridinecarbaldehyde worked well
(entries 9 and 10). (6) For enolizable aliphatic aldehydes such
Scheme 1
reactions would be also useful for the synthesis of â-amino
ketone libraries.7 Here we report DBSA-catalyzed three-
component Mannich-type reactions in a colloidal dispersion
system using ketones as nucleophilic components.
The reaction of benzaldehyde, aniline, and acetophenone
in the presence of an acid catalyst in water was selected as
a model reaction. Among the Brønsted and Lewis acid
catalysts tested, DBSA8 catalyzed the reaction most ef-
ficiently (Table 1, entry 1). Interestingly, this efficient
(5) (a) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett. 1998, 39, 323. (b)
Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999, 1045. (c) Akiyama,
T.; Takaya, J.; Kagoshima, H. Synlett 1999, 1426.
(6) HCl-catalyzed three-component Mannich-type reactions of aldehydes,
amines, and ketones in EtOH have been reported. (a) Blatt, A. H.; Gross,
N. J. Org. Chem. 1964, 29, 3306. (b) Yi, L.; Zou, J.; Lei, H.; Lin, X.;
Zhang, M. Org. Prep. Proced. Int. 1991, 23, 673.
Table 1. Three-Component Mannich-Type Reactions in Water
(7) Multiple-component reactions, which can produce a diversity of
compounds, provide one of the most efficient methods for the combinatorial
synthesis of compound libraries. For example, see: Kobayashi, S. Chem.
Soc. ReV. 1999, 28, 1.
(8) Dodecylbenzenesulfonic acid (soft type) was purchased from Tokyo
Kasei Kogyo Co., Ltd., and used without further purification. This is a
mixture of several linear alkylbenzenesulfonic acids. Its molecular weight
was regarded as 326.50.
(9) All the Mannich adducts in Table 2 were adequately characterized
by 1H and 13C NMR. The adducts in entries 1,6a 2,6a 3,6 5,6b,10 7,11 and 86a
have been reported earlier. The spectral data for the other Mannich adducts
are included in the Supporting Information.
entry
catalyst
DBSA
Sc(O3SOC12H25
TsOH
SDS
TsOH + SDS
yield (%)
1
2
3
4
5
69 (9a,4b)
54
0
5
56
)
3
(10) Koslov, N. S.; Vorob’eva, G. V. Vestsi Akad. Nauk Belarus SSR,
Ser. Khim. Nauk 1968, 107.
a In MeOH. b In CH2Cl2.
(11) Kobayashi, S.; Nagayama, S. J. Org. Chem. 1997, 62, 232.
(12) General Reaction Procedure: To a solution of DBSA (0.0025-
0.075 mmol, 1-30 mol %) in H2O (1.5 mL) were added an amine (0.25
mmol), an aldehyde (0.25 mmol), and a ketone (0.25-1.25 mmol)
successively at 23 °C. After stirring at the same temperature for the period
of time listed in Table 2, a saturated aqueous NaHCO3 solution (5 mL) and
brine (5 mL) were added, and the mixture was extracted with ethyl acetate.
Purification by silica gel chromatography gave the desired product. Ten-
mmol-scale reactions were also carried out without any difficulties. For
example, the reaction of benzaldehyde (10 mmol), aniline (10 mmol), and
acetophenone (10 mmol) in the presence of 10 mol % of DBSA afforded
the product in 82% yield (24 h).
catalysis was not observed in the reactions carried out in
organic solvents such as MeOH and CH2Cl2. This solvent
effect shows the unique property of water to induce
hydrophobic interactions between the substrates and the
catalyst. Scandium tris(dodecyl sulfate), a representative
LASC, was less effective than DBSA (entry 2). It should be
1966
Org. Lett., Vol. 1, No. 12, 1999
Manabe, Kei
