Table 1. Effect of solvent and catalyst in the domino desulfonylation/
Mannich reaction[a]
with propanal to afford the Mannich products in good yield
with good anti selectivity and excellent enantioselectivity
(Table 2, entries 1–6). In the reaction of butanal, the yield in
the presence of water was not satisfactory; the aldehyde acts
not only as a nucleophile but also as a solvent to dissolve
the imine, and the dissolving ability of butanal is insufficient
for this purpose. The reaction nonetheless proceeds effi-
ciently in 1,4-dioxane to afford the Mannich product in
good yield with excellent enantioselectivity (Table 2,
entry 7).
The reaction proceeds not only with N-Ts imines but also
with N-Ns (nosyl)[11] imines. In the reaction of N-Ns imines,
when the reaction was performed in the presence of water,
the desired product was obtained in low yield because N-Ns
imine is more reactive than N-Ts imine and hydrolysis of
the imine takes place readily. However, the reaction pro-
ceeds well in 1,4-dioxane to afford the Ns-protected Man-
nich product in good yield with excellent diastereo- and
enantioselectivities (Table 2, entries 8 and 9).
The reaction was found to be applicable to imines derived
from aromatic aldehydes. Whereas the precursor of the N-
Ts imine para-toluenesulfonamido sulfone, derived from ar-
omatic aldehyde, is rather unstable, the corresponding N-Ts
imine is more stable and could be isolated. Thus, the isolat-
ed N-Ts imine was used as starting material. The reaction of
propanal and N-Ts-imine derived from benzaldehyde in the
presence of 10 mol% of catalyst 1 proceeded well to afford
the Mannich product in good yield with good diastereo- and
enantioselectivities (Table 2, entry 10). The products were
isolated as the b-amino aldehyde and also as the g-amino al-
cohol by reduction with NaBH4 (Table 2, entry 11). Imines,
not only from benzaldehyde, but also from aromatic alde-
hydes with electron-rich and electron-deficient substituents
were used as suitable substrates (Table 2, entries 12–14).
The absolute configuration was determined after conver-
sion of the Mannich product of propanal and the N-Ts
imine derived from isovaleraldehyde (Table 2, entry 2) to
the amino alcohol by comparing the optical rotation with
that reported in the literature.[12]
Entry
Catalyst
Solvent
T
[8C]
Yield
[%][b]
anti/syn[c]
ee
[%][d]
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1
2
3
4
CH2Cl2
THF
1,4-dioxane
H2O
brine
brine/CH2Cl2
brine
1,4-dioxane
brine
brine
0
0
0
0
0
0
10
10
10
10
10
38
52
62
41
60
49
76
79
20
76:24
95:5
92:8
97
98
98
96
96
97
94
96
93:7
89:11
>95:5
84:16
88:12
n.d.
8[e]
9
10
11
n.d.
n.d.
n.d.
<5
10
n.d.
n.d.
brine
[a] Reactions were performed employing a-amidosulfone 5 (0.2 mmol),
aldehyde (1.0 mmol), catalyst (0.02 mmol), NaHCO3 (0.6 mmol), and sol-
vent (0.4 mL) for 20 h. n.d.=not determined. [b] Yield of isolated prod-
uct. [c] Diastereomer ratio was determined by 1H NMR spectroscopy
after reduction with NaBH4. [d] Enantiomeric excess of the anti isomer
was determined by chiral HPLC analysis after reduction with NaBH4.
[e] The reaction time is 48 h.
Next, the reaction was performed using an isolated imine
(Scheme 2). Although a good yield and excellent enantiose-
lectivity were obtained when the reaction was carried out in
1,4-dioxane, the product was obtained in only low yield in
the presence of water. In the presence of water, low yield
was obtained in the reaction of isolated imine, whereas a
Scheme 2.
In summary, we have developed an asymmetric Mannich
reaction catalyzed by diarylprolinol silyl ether to afford the
anti-Mannich product with excellent enantioselectivity.
There are several noteworthy features associated with this
reaction: 1) This is one of the rare examples of the success-
ful catalytic asymmetric cross Mannich reaction of unmodi-
fied aldehyde as a Mannich donor and an imine derived
from an aliphatic aldehyde with a-hydrogen atoms as a
Mannich acceptor. 2) The present reaction can be success-
fully applied not only to imines derived from aliphatic alde-
hydes but also to imines from aromatic aldehydes. 3) Both
N-Ts imines and N-Ns imines can be used. 4) In the reaction
of imines derived from aliphatic aldehydes, water (without
an organic solvent) was used as a reaction medium; there-
fore this offers green reaction conditions.
good result was obtained in the domino reaction of the de-
sulfonylative preparation of imine and the Mannich reac-
tion. The reason for the successful domino reaction in the
presence of water is the gradual generation of imine, which
reacts readily with the enamine. Having determined the best
reaction conditions, the generality of the domino reaction
was investigated using brine and 1,4-dioxane as a solvent
(Table 2). The reaction is generally fast in the presence of
water and is complete within 20 h because it proceeds under
condensed conditions, whereas the reaction in 1,4-dioxane
takes 48 h. Excellent enantioselectivity was obtained in both
solvents.
As for the imines derived from aliphatic aldehydes, not
only 3-phenylpropanal but also isovaleraldehyde, isobutyral-
dehyde, cyclohexanecarbaldehyde, phenylacetaldehyde, and
benzyloxyacetaldehyde were suitable aldehydes for reaction
Previously, only b-alkyloxycarbonyl or b-aryl-substituted
b-amino aldehydes could be synthesized by the organocata-
lyst-mediated Mannich reaction of unmodified aldehyde as
8274
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8273 – 8276