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Chemistry Letters Vol.35, No.6 (2006)
Synthesis of ꢀ-Amino Ketones by Iridium(III)-catalyzed Direct-Mannich Reaction
Shunsuke Sueki, Takeyuki Igarashi, Takayuki Nakajima, and Isao ShimizuÃ
Department of Applied Chemistry, School of Science and Engineering, Waseda University,
3-4-1 Okubo, Shinjuku-ku, Tokyo 169-8555
(Received March 8, 2006; CL-060283; E-mail: shimizui@waseda.jp)
Table 1. Activity of catalysts for direct-Mannich reaction
CHO
The direct-Mannich reaction of ketones 1, aldehydes 2, and
MeO
anilines 3 was studied using catalytic amount of transition-metal
complexes. The trivalent iridium complex, [IrCl2(H)(cod)]2,
catalyzed the direct-Mannich reaction effectively to give various
ꢀ-amino kenotes in good yields under mild conditions.
O
+
O
O
HN
4a
Catalyst
NO2
2a
1a
+
DMSO, Temp.,
17 h
NO2
+
NH2
OMe
Carbon–carbon bond forming reactions utilizing transition-
metal catalysts which proceed under mild conditions are useful
tools for production of organic compounds in environmentally
benign way. In recent years, multicomponent coupling reactions
(MCRs) have attracted much attention because the complex
molecules form in one pot and chemical diversity can be achiev-
ed with ease.1 Reaction of amines and carbonyl compounds
known as the Mannich reaction involving the sequential forma-
tion of C–N bond and C–C bond is one of the most useful multi-
component coupling reactions.2 However, to execute the reac-
tion for complicated organic compounds fine tunings of reaction
conditions are necessary. So far several reactions, which are pro-
moted or catalyzed by Lewis acids,3 lanthanides,4 early transi-
tion metals,5 and organocatalysts,6 are developed. However, late
transition metals or noble metals,7 which tolerate a wide variety
of organic compounds having functional groups, are recognized
to be inactive as catalysts for the Mannich reaction. Recently,
Xia et al. reported AuCl3–PPh3 is effective for N-protected
ꢀ-amino ketone synthesis.8 In our study to develop transition
metal-catalyzed reactions, we have found a trivalent Ir complex
catalyzed the Mannich reaction although most of the late
transition metals are not effective including Ir(I) complex.
At first, reaction of acetone (1a), p-nitrobenzaldehyde (2a),
and o-anisidine (3a) was studied using catalytic amount of
transition-metal complexes. In a typical experiment, to a mixture
of the catalyst (0.025 mmol), 2a (0.5 mmol), and 3a (0.55 mmol)
in DMSO (2 mL) was added 1a (3 mL) and the mixture was
stirred for 17 h. The phosphate buffer saline was added to the
mixture and the product was extracted with ethyl acetate and
purified by column chromatography. As representative results
of the reactions are shown in Table 1, when [Rh(cod)Cl]2 and
[Ru(cod)Cl2]2 (cod = cyclooctadiene) were used as catalysts
ꢀ-amino ketone 4a was obtained in 21 and 18% yields, respec-
tively. [Ir(cod)Cl]2 and [Ir(cod)(OMe)]2 scarcely have catalytic
activity. However, the reaction using the trivalent iridium com-
plex, [IrCl2(H)(cod)]2, proceeded smoothly to give 4a in 64%
yield although IrCl3 and Ir(acac)3 (acac = acetylacetonato) are
inactive. Ytterbium triflate did not give a satisfactory result.4
Furthermore, TiCl4, a typically used Lewis acid, gave
ꢀ-amino ketone 4a in 48% yield, but the undesired enone 5 by
aldol condensation was obtained in 14% yield. When conc.
HCl was used, the enone 5 was obtained as the major product.
The reaction with [IrCl2(H)(cod)]2 proceeded at 0 ꢀC in 57%
yield, but in the reaction at 90 ꢀC the yield of 4a decreased dra-
5
3a
NO2
Yield/%a
Catalyst (mol % based on 2a)
Temp./°C
4a
5
b
b
[Rh(cod)Cl]2 (5.0)
rt
21
18
[Ru(cod)Cl2]2 (5.0)
[Ir(cod)Cl]2 (5.0)
[Ir(cod)(OMe)]2 (5.0)
IrCl3 (10)
rt
rt
rt
rt
rt
0
rt
90
rt
b
b
b
b
0
6
7
57
64
0
39
48
15
16
b
b
Ir(acac)3 (10)
[IrCl2(H)(cod)]2 (5.0)
9
54
b
Yb(OTf)3 (10)
TiCl4 (10)
conc. HCl
Blank
rt
rt
90
14
37
55
aYield based on 2a. bNot isolated, only detected by
TLC.
matically and the enone 5 was obtained in 54% yield. In the
absence of catalyst the reaction of 1, 2a, and 3a proceeded at
90 ꢀC to give the enone 5 in 55% yield. The role of the catalyst
is ambiguous. However, it should be noted that the Ir(III) cata-
lyst is not strong enough to catalyze the aldol reaction but the
imine was readily activated with an Ir(III) complex. Indeed,
reaction of 1 and 2a was carried out with [IrCl2(H)(cod)]2, no
formation of 5 was observed.
Various solvents can be used for this reaction at 0 ꢀC. Polar
solvents such as DMSO, THF, and acetonitrile, are suitable for
smooth reaction, and the product 4a was obtained in 57, 43,
and 41%, respectively. However, less polar solvent such as di-
chloromethane (26%) and toluene (24%) did not give satisfacto-
ry results. Acetone was used not only as the substrate but as sol-
vent in this case to give the product in 46% yield.
The generality of the reaction to prepare ꢀ-amino ketones
was examined using several substrates having a variety of func-
tional groups (Table 2). 4-amino-4-Aryl-2-butanones, 4a–4l
were obtained in moderate to good yields in one pot starting
from acetone and the corresponding aldehydes 2 and aromatic
amines 3. When aliphatic amines, such as cyclohexylamine, pi-
peridine, and phenethylamine, were used as amine components,
the reaction did not proceed.
Various aromatic amines were prepared in this reaction. The
primary amine can be obtained by removal of the o-methoxy-
phenyl group (OMP). As shown in Scheme 1, the OMP was re-
moved oxidatively with treatment of cerium ammonium nitrate
Copyright Ó 2006 The Chemical Society of Japan
Sueki, Shunsuke
