The direct and enantioselective, one-pot, three-component, cross-Mannich reaction of aldehydes

Article abstract of DOI:10.1002/anie.200351813

A double-crossed reaction: The use of proline as an organocatalyst enables a one-pot, direct, cross-Mannich reaction to be performed between two different aldehydes and 4-methoxyaniline in a highly syn-diastereo- and enantioselective manner (see scheme).

Full text of DOI:10.1002/anie.200351813

Angewandte
Chemie
Cross-Mannich Reaction of Aldehydes
The Direct and Enantioselective, One-Pot, Three-
Component, Cross-Mannich Reaction of
Aldehydes**
Yujiro Hayashi,* Wataru Tsuboi, Itaru Ashimine,
Tatsuya Urushima, Mitsuru Shoji, and Ken Sakai
Organocatalytic enantioselective reactions[1] have received
great attention in recent years since the discovery by List and
Barbas et al. of aldol reactions using proline as an organo-
catalyst.[2] These reactions are intermolecular variants of the
Hajos–Parrish–Eder–Sauer–Wiechert reaction.[3] Such cata-
lysts have now been successfully applied to other synthetically
important transformations such as the Mannich[4–6] and
Michael reactions,[7] a-aminations,[8] etc.[9]
The catalytic, asymmetric Mannich reaction is one of the
most powerful methods for the construction of chiral nitro-
gen-containing molecules. Recently several excellent results
were reported, some of which are based on catalytic
asymmetric additions of a preformed enolate to aldimines.[10]
Unlike such Mannich reactions of preformed enolates, the
research groups of Shibasaki,[11] Jørgensen,[12] Trost,[13] List,[4]
and Barbas[5] have developed direct, catalytic asymmetric
Mannich reactions. The former three research groups used
chiral organometallic catalysts, while the latter two employed
proline as an organocatalyst: List et al. developed a three-
component, asymmetric Mannich reaction between an alde-
hyde, 4-methoxyaniline (p-anisidine), and a ketone,[4] while
Barbas and co-workers reported a Mannich reaction of N-
PMP-protected[14] a-imino ethyl glyoxylate and an alde-
hyde.[5] Although proline-mediated reactions are synthetically
useful, and afford Mannich products with excellent enantio-
selectivity, aldehydes were not employed as the Mannich
donor in the reaction performed by List et al., while N-PMP-
protected a-imino ethyl glyoxylate was the only Mannich
acceptor examined in the reaction performed by Barbas and
co-workers. The development of a direct and enantioselective,
one-pot, three-component cross-Mannich reaction of two
different aldehydes is desirable to expand the scope of these
powerful asymmetric Mannich reactions; such a system would
comprise a Mannich reaction in which one aldehyde is
[*] Prof. Dr. Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, Dr. M. Shoji
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science, Kagurazaka
Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Prof. Dr. K. Sakai
Department of Applied Chemistry, Faculty of Science
Tokyo University of Science, Kagurazaka
Shinjuku-ku, Tokyo 162-8601 (Japan)
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Priority Areas (A; “Exploitation of Multi-Element Cyclic Molecules”)
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
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DOI: 10.1002/anie.200351813
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3677

Communications
employed as the Mannich donor and the other aldehyde is
spectroscopy (400 MHz). Possible side reactions are the self-
aldol and cross-aldol condensations, which have been
reported to proceed at 48C by Northrup and MacMillan.[2j]
The fact that the Mannich reaction proceeds at lower
temperature (À208C) than the aldol reaction (48C) indicates
that the aldimine is more electrophilic than the parent
aldehyde. This is contrary to the generally accepted notion
that an aldimine is less reactive toward nucleophilic addition
than its corresponding aldehyde.[15] Recently Yb(OTf)3,[16]
[PdCl2(PPh3)2],[17] and the combination of BF3·OEt2
and water[18] have been reported to be catalysts for the
chemoselective activation of aldimines in preference to
aldehydes, and the present catalyst also belongs to this rare
class.
The same effect of the temperature on the yield was also
observed with p-nitrobenzaldehyde: While at room temper-
ature the reaction afforded several products, with the desired
amino alcohol being formed in less than 10% yield, good
results were obtained at 08C and À108C (entries 6–8).
Solvent effects were examined next. Unlike the elegant
enantioselective cross-aldol reaction of aldehydes by
Northrup and MacMillan,[2j] in which a wide variety of
solvents can be employed, the reaction scarcely proceeded
in CH3CN, CH2Cl2, THF, and toluene. Good yields and high
enantioselectivities were obtained in DMF and NMP
(entries 4 and 5).[19]
Once the best reaction conditions had been established,
the generality of this one-pot, three-component cross-Man-
nich reaction of aldehydes was examined (Table 1). Not only
benzaldehyde, but 2-naphthaldehyde and p-tolualdehyde are
also suitable Mannich acceptor aldehydes and afford adducts
in good yield with high syn-diastereo- and enantioselectivities
(entries 12 and 13). Electron-deficient aldehydes such as p-
nitrobenzaldehyde and p-chlorobenzaldehyde react smoothly,
also providing Mannich products with good yields and
enantioselectivities (entries 8 and 11). Although the yield of
the reaction using p-bromobenzaldehyde at À208C is only
33%, because of the low solubility of the aldimine, a good
yield was obtained when the reaction was performed at
À108C (entries 9 and 10). In addition to aromatic aldehydes,
heteroaromatic aldehydes are also good Mannich acceptor
aldehydes: Furfural and p-pyridinecarbaldehyde react with
propanal to afford the adducts in good yield with high syn-
diastereo- and enantioselectivity (entries 14 and 15). The
product from the reaction of p-pyridinecarbaldehyde was
characterized after conversion into the corresponding tert-
butyldimethylsilyl ether, and the yield was 84% over three
steps. It is noteworthy that the basic pyridine moiety has no
detrimental effect on the proline catalyst. However, under the
same reaction conditions aliphatic aldehydes such as cyclo-
hexylcarbaldehyde gave a complex mixture, while the desired
product was obtained in very low yield in the reaction of
electron-rich aldehydes such as p-anisaldehyde.
utilized as a component of the Mannich acceptor to afford a
synthetically versatile intermediate, a b-amino aldehyde.
Our initial attempt gave a disappointing result. We chose
propanal as the Mannich donor and benzaldehyde as a
component of the Mannich acceptor. Following the condi-
tions used by List et al.[4] benzaldehyde, 4-methoxyaniline,
and propanal were stirred in DMSO in the presence of a
catalytic amount of l-proline at room temperature, but less
than 10% yield of the cross-Mannich product was obtained,
together with several unidentified products. As the formed b-
amino aldehyde decomposed during purification by column
chromatography on silica gel, it was isolated and character-
ized after reduction with NaBH4 to the corresponding b-
amino alcohol. As the cross-aldol condensation between
benzaldehyde and propanal is a possible side reaction,
propanal was added to a solution of aldimine generated
in situ from benzaldehyde and 4-methoxyaniline at room
temperature, but with no improvement in the yield. After
several experiments, it was found that the reaction temper-
ature is very important for this transformation. As shown in
Table 1, the amino alcohol was obtained in less than 10 and
15% yield at room temperature and 08C, respectively,
together with several unidentified products (entries 1 and
2), when N-methyl-2-pyrrolidinone (NMP) was used as a
solvent (see below). The yield increased to 50% when the
reaction was performed at À108C (entry 3), and a good yield
and high enantioselectivity (90%, 98% ee) were obtained at
À208C (entry 4). The syn isomer (see below) was selectively
generated, and no anti isomer could be detected by 1H NMR
Table 1: Three-component Mannich reaction with various acceptor
aldehydes.[a]
Entry Aldehyde
T [8C] Yield [%][b] syn:anti ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
benzaldehyde
benzaldehyde
benzaldehyde
23
0
À10
À20
À20
23
0
À10
<10
15
50
90
71
<10
89
93
85
33
n.d[d]
n.d
n.d
90
98
96
n.d
95
99
95
98
98
>95:5
>95:5
>95:5
>95:5
n.d
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
benzaldehyde
benzaldehyde[e]
p-nitrobenzaldehyde
p-nitrobenzaldehyde
p-nitrobenzaldehyde
p-bromobenzaldehyde À10
p-bromobenzaldehyde À20
p-chlorobenzaldehyde
2-naphthaldehyde
p-tolualdehyde[e]
furfural
À20
À20
À20
À20
91
59
95
96
86
84
>99
87
p-pyridinecarbaldehyde À20
84[f]
In addition to propanal, n-butanal can also be successfully
employed as the Mannich donor and affords the Mannich
products in good yield with high diastereo- and enantio-
selectivity (Table 2, entries 1 and 2). When n-pentanal was
used as the Mannich donor, however, the yield and the
enantioselectivity were decreased to 55% and 71% ee,
[a] Reaction conditions: aldehyde:4-methoxyaniline:propanal:proline=
1.0:1.1:3.0:0.1, NMP was used as the solvent except in entries 5 and
13. Reaction time: 20 h. [b] Yield of the isolated amino alcohol. [c] The
ee values were determined by chiral HPLC analysis (CHIRAPAK AD-H or
AS-H). [d] Not determined. [e] DMF was used as the solvent. [f] Yield of
the corresponding amino tert-butyldimethylsilyl ether, see text.
3678
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Table 2: Three-component Mannich reaction with various donor
aldehydes.[a]
Entry
R
Yield [%][b]
syn:anti
ee [%][c]
1
2
3
Me
Et
nPr
90
85
55
>95:5
>95:5
>95:5
98
97
71
[a] Reaction conditions: benzaldehyde:4-methoxyaniline:aldehyde:pro-
line=1.0:1.1:3.0:0.1 [b] Yield of the isolated amino alcohol. [c] ee values
were determined by chiral HPLC analysis (CHIRAPAK AD-H).
respectively (entry 3). At present it is not clear why n-
pentanal is a poor Mannich donor.
Figure 1. ORTEP diagram of the amino alcohol derived from p-chloro-
benzaldehyde.
The self-Mannich reaction of propanal also proceeds
effectively to afford the syn-3-amino-2-methylbutan-1-ol
derivative in 70% yield and 96% ee. In this reaction, all
three components (propanal, 4-methoxyaniline, and l-pro-
line) are mixed together at À208C without preformation of
the aldimine. The success of this procedure indicates that the
aldimine was formed even at À208C, and that the reaction
between the aldehyde and aldimine is faster than the self-
aldol reaction. The high diastereoselectivity (syn:anti =
> 95:5) is in strong contrast to the self-aldol reaction of
propanal, for which low diastereoselectivity (syn:anti = 4:1) is
observed [Equation (1)].[2j]
In summary, the one-pot, direct
cross-Mannich reaction of two differ-
ent aldehydes has been realized for
the first time with high syn-diastereo-
and enantioselectivities by the cata-
lytic use of l-proline as an organo-
catalyst. The success of this process
lies in the low reaction temperature
(À208C), at which side reactions,
Figure 2. Transition-
state model.
such as the aldol condensation, can be suppressed. There
are several noteworthy features of this reaction: Proline is
found to be one of the rare catalysts that activate aldimines
preferentially to aldehydes. The present method for the
selective formation of syn-b-amino-a-alkyl aldehydes is
complementary to the organometal-mediated asymmetric
catalytic Mannich reactions, in which the anti-b-amino-a-
alkyl ester or ketone is selectively produced. The b-amino-a-
alkyl aldehydes generated are versatile intermediates, the
aldehyde portion of which can be further transformed into
other functional groups.[5] The present method will be useful
for the synthesis of nitrogen-containing chiral molecules.
A good-quality single crystal of the reduction product of
the Mannich adduct of p-chlorobenzaldehyde, propanal, and
4-methoxyaniline was obtained and the relative and absolute
configurations have been determined by X-ray crystallo-
graphic analysis.[20] The 2S,3S configuration of the 3-amino-2-
methylpropan-1-ol unit (Figure 1) was determined by refine-
ment of the Flack parameter, which converged at À0.2(4) for
the configuration shown, and at 1.2(4) for the centrosym-
metrically inverted structure. This result indicates that l-
proline catalyzes a si-facial attack on the aldimine generated
in situ (Figure 2), which is in good agreement with the
transition-state model[21] for proline-catalyzed Mannich reac-
tions with ketones proposed by List et al.[4] and Barbas and
co-workers.[5] The present reaction gave the syn-b-amino-a-
alkyl aldehyde with high diastereoselectivity, which is com-
plementary to the asymmetric catalytic Mannich reactions of
Kobayashi et al.[10e] and Lectka and co-workers,[10i,k] in which
anti-b-amino-a-alkyl esters and ketones are selectively
formed.
Experimental Section
Typical experimental procedure (Table 1, entry 4): After stirring a
solution of benzaldehyde (1.0 mmol), 4-methoxyaniline (1.1 mmol),
and l-proline (0.1 mmol) in NMP (1.0 mL) for 2 h at RT, propanal
(3.0 mmol) was added to the reaction mixture at À208C, and stirring
was continued for 20 h at this temperature. The reaction was
quenched with phosphate buffer (pH 7.0), and the organic materials
were extracted with ethyl acetate (” 3), and the organic phases were
combined and washed with brine, and dried over Na2SO4. After
removal of the volatile materials under reduced pressure, the residue
was dissolved in MeOH (3.0 mL), and then NaBH4 (3.0 mmol) was
added at 08C. After stirring the mixture for 30 minutes, the reaction
was quenched with phosphate buffer (pH 7.0), and the organic
materials were extracted with ethyl acetate (” 3). The organic phases
were then combined and dried over Na2SO4. After removal of the
volatile materials under reduced pressure, the residue was purified by
thin-layer chromatography and afforded the b-amino alcohol in a
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yield of 244 mg (90%) with 98% ee, as determined by HPLC analysis
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on a chiral stationary phase.[22]
Received: May 6, 2003 [Z51813]
Keywords: aldehydes · asymmetric synthesis ·
.
enantioselectivity · organocatalysts · three-component reaction
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3680
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