Proline catalyzed two-component, three-component and self-asymmetric Mannich reactions promoted by ultrasonic conditions

Article abstract of DOI:10.1016/j.tetlet.2006.06.042

The proline catalyzed two-component and three-component asymmetric Mannich reaction with hydroxyacetone and self-Mannich reaction with propanal were performed successfully under ultrasonic conditions in 1 h to afford Mannich products in 90-98% isolated yi

Full text of DOI:10.1016/j.tetlet.2006.06.042

Tetrahedron Letters 47 (2006) 5965–5967
Proline catalyzed two-component, three-component
and self-asymmetric Mannich reactions promoted
by ultrasonic conditions
M. Lakshmi Kantam,a,* Ch. V. Rajasekhar,a G. Gopikrishna,a
K. Rajender Reddya and B. M. Choudaryb,*
aIndian Institute of Chemical Technology, Hyderabad 500 007, India
bOgene Systems(I) Pvt. Ltd., Hyderabad 500 037, India
Received 3 May 2006; revised 1 June 2006; accepted 7 June 2006
Available online 30 June 2006
Abstract—The proline catalyzed two-component and three-component asymmetric Mannich reaction with hydroxyacetone and
self-Mannich reaction with propanal were performed successfully under ultrasonic conditions in 1 h to afford Mannich products
in 90–98% isolated yields and 81–99% ees with excellent diastereoselectivities.
Ó 2006 Elsevier Ltd. All rights reserved.
The development of new stereoselective methods for the
synthesis of optically pure molecules is important due to
the increased interest in enantiopurity for drug candi-
dates. In this context, the Mannich reaction is syntheti-
cally useful for the construction of nitrogen-containing
molecules.1 A catalytic diastereo- and enantioselective
Mannich reaction is desirable because the chirality
controlling element is used in limited quantities. Metal-
containing and metal-free catalysts have led to a break-
through in the diastereo- and enantioselective Mannich
reactions.2 Readily available metal-free organocatalysts
are often preferred over chiral metal-based catalysts3
even though yields as well as diastereo- and enantioselec-
tivities are lower. L-proline is a commonly used metal-
free organocatalyst and has been extensively studied in
various reactions involving enamine intermediates.4 An
important proline catalyzed three-component Mannich
reaction was developed by List et al.5 Enolizable alde-
hydes and ketones were treated with in situ generated
imines or preformed imines to afford the Mannich prod-
ucts with good yields and excellent enantioselectivities.6
Barbas and co-workers used this strategy for direct
Mannich reaction with preformed iminoglyoxylates.7
Later, Hayashi et al. reported high pressure induced
three-component asymmetric Mannich reactions with
excellent stereoselectivities.8
The use of protected dihydroxyacetone in asymmetric
Mannich reaction was first reported by Cordova and
co-workers and subsequently Westermann reported
rapid Mannich reactions using protected dihydroxyace-
tone and various imines, initially under normal condi-
tions, and later under microwave conditions.9 Enders
has described the synthesis of selectively protected ami-
no sugars via asymmetric three-component Mannich
reactions.10
Despite the high enantioselectvity, there is a limitation
to List’s reaction where the yields are moderate with
electron-rich aldehydes when hydroxyacetone was used
as the ketone donor. Generally, chemical reactions are
invariably accelerated in ionic liquids, and under micro-
wave and ultrasonic conditions using both transition
metal complexes and heterogeneous catalysts.11 Note-
worthy advances have been made in proline catalyzed
reactions using ionic liquids in terms of reusability, im-
proved stereoselectivity and reaction time.12 Similarly,
microwave assisted proline catalyzed asymmetric Man-
nich reactions have been reported with good yields
and selectivities in short reaction times.9,13 However,
to the best of our knowledge there are no reports on
the use of ultrasound promoted organocatalytic reac-
tions. Here we report efficient and rapid two-component
Keywords: Organo catalysis; Mannich reaction; Asymmetric synthesis;
Proline; Ultrasonic conditions.
*
Corresponding authors. Tel.: +91 40 2719 3510; fax: +91 40 2716
0921 (M.L.K.); e-mail: mlakshmi@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.042

5966
M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 5965–5967
Table 2. Mannich reaction of various aldimines and hydroxyacetone
catalyzed by L-proline at ambient temperature and induced by
ultrasonic conditions
and three-component asymmetric Mannich reactions
and a self-Mannich reaction with propanal and p-anisi-
dine under normal ultrasonic conditions catalyzed by
proline.
NPMP
O
NHPMP
O
L-proline
(15 mol%)
In an initial experiment, a 4:1 mixture of DMSO/
acetone (10 mL), L-proline (17 mg) and preformed
N-(p-nitrobenzylidene)-p-anisidine was reacted under
ultrasonic conditions for 1 h, to afford the Mannich
product in 50% yield (Table 1, entry 1). Under normal
conditions at room temperature, 50% of the correspon-
ding product was obtained after 24 h. No other side
product was observed. We also employed 2-butanone
and cyclohexanone, however, the yields were poor
(Table 1, entries 2 and 3). With hydroxyacetone as the
donor, the reaction was complete in 1 h with 98% yield
(Table 1, entry 4). Lower conversion of the product
was observed when we reduced the reaction time (Table
1, entry 5).
+
H3C
H3C
DMSO
rt, 1h
OH
OH
R
R
ultrasonic conditions
Entry
R
Time (h)
Yielda (%)
Syn/antib
eec (%)
1
2
3
4
5
6
NO2
CN
Br
H
Me
OMe
1.0
1.0
1.0
1.0
1.0
1.0
98
98
96
94 (93)
90 (86)
91 (85)
94:6
96:4
94:6
90:10
85:15
75:25
99
99
98
98 (93)
98 (85)
81 (65)
a Isolated yields after silica-gel column chromatography. (The values in
parentheses are yields under conventional conditions).
b The syn/anti ratio was determined by 1H NMR spectroscopy.
c Enantiomeric excess was determined by HPLC analysis (Daicel AD-
RH column). The values in parentheses are ees under conventional
conditions.
We next examined the optical purity, using acetone as
the donor, the Mannich product was obtained with
36% ee (Table 1, entry 1). Notably, with hydroxyace-
tone, we obtained >99% ee (Table 1, entry 4). Based
on the above experiments, it can be reasoned that the
hydroxyl function in the ketone donor leads to forma-
tion of the enamine rapidly which subsequently attacks
the electrophile to produce the Mannich product under
ultrasonic conditions. With this high yielding and highly
stereoselective process in hand, we further investigated
the generality of the reaction with various preformed
imines to broaden the scope of the reaction (Table 2).
various types of amino alcohols with high optical purity.
In the case of the electron-rich aldehydes, the yields and
ees are quite impressive in comparison to those reported
under normal conditions (Table 2, entries 5 and 6).
After achieving high enantioselectivities in two-compo-
nent reactions, we performed the reactions under
three-component conditions. Three-component asym-
metric Mannich reactions also produced very good
results (Table 3) and it was noticed that ultrasonic con-
ditions not only promoted the asymmetric Mannich
reaction, but also promoted imine formation between
the aromatic aldehydes and p-anisidine in very short
intervals. However, three-component reactions pro-
duced slightly lower yields and enantioselectivities com-
pared with the two-component reactions.
In the Mannich reaction of electron-deficient aromatic
aldehydes (q-nitro, q-cyano and q-bromo) with hydroxy-
acetone, the yields, ees and des were very high. (Table 2,
entries 1–3). The reaction with benzaldehyde afforded
the product in very good yield, 94% and 98% ee with
10:1 diastereoselectivity (Table 2, entry 4). The increase
in yields and optical purity is due to the high pressure,
rapid heating and rapid cooling during ultrasonic irradi-
ation. This method has wide applicability to afford
In addition, the use of aldehydes as nucleophilic donors
offers a particularly attractive route to fuctionalized
Table 3. Three-component asymmetric Mannich reaction of various
aromatic aldehydes and p-anisidine with hydroxyacetone catalyzed by
L-proline at ambient temperature under ultrasonic conditions
Table 1. Screening of ketone donors with aromatic aldimines under
ultrasonic conditions
OMe
O
NHPMP
L-proline
(15 mol%)
O
O
NHPMP
O
L-proline
(15 mol%)
CHO
NPMP
+
H C
3
H C
3
+
R1
R1
+
DMSO
rt, 1h
OH
OH
R
R
DMSO
rt, 1 h
R2
NO2
R2
ultrasonic conditions
NH
2
O2N
ultrasonic conditions (40 Hz)
Entry
R
Time (h)
Yielda (%)
Syn/antib
eec (%)
Entry
R1
R2
Yielda
eeb (%)
1
2
3
4
5
NO2
CN
Br
H
OMe
1.0
1.0
1.0
1.0
1.0
98
98
94
90 (93)
85 (91)
94:6
96:4
94:6
90:10
75:25
99
98
96
85 (94)
66 (81)
1
2
3
4
5
CH3
CH3
(CH2)4
CH3
CH3
H
50
10
15
98
80c
36
nd
nd
99
99
CH3
(CH2)4
OH
OH
a Isolated yields after silica-gel column chromatography. (The values in
parentheses are for two-component conditions).
b The syn/anti ratio was determined by 1H NMR spectroscopy.
c Enantiomeric excess was determined by HPLC analysis (Daicel AD-
RH column). The values in parentheses are ees obtained under
conventional conditions.
nd = not determined.
a Yields were determined by 1H NMR.
b Ees were determined by HPLC analysis (Chiralcel AD and AD-RH
column).
c Yield after 45 min.

M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 5965–5967
5967
Eds.; Wiley-VCH: Weinheim, 2005; (c) Kobayashi, S.;
Ueno, M. In Comprehensive Asymmetric Catalysis Sup-
plement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 2003, Chapter 29.5.
b-amino acids and their derivatives including b-lactams
and amino alcohols. Not only does this strategy involve
the creation of two contiguous stereocenters upon
carbon–carbon bond formation, but also provides struc-
tural and functional diversity. Recently, self-Mannich
reactions were reported at low temperature with excel-
lent yields and enantioselectivity.14 After the successful
use of hydroxyacetone with imines, we proceeded with
the enamine intermediates formed from aliphatic
aldehydes as nucleophiles for stereoselective, amino
acid-catalyzed self-Mannich reactions. We examined
self-Mannich reactions of propanal with p-anisidine at
room temperature under ultrasonic conditions and
observed the formation of a single product, which upon
NaBH4 reduction gave syn-3-amino-2-methylbutane-1-
ol derivatives in 80% yield and 91% ee. This is the first
report on rapid self-Mannich reaction of propanol with
high yield and ees at room temperature.
3. (a) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003,
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OH
O
1. L-proline
NHPMP
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(15 mol%)
+
DMF
CH3
rt, 1 h
CH3
Yield 80%, de 95:5, ee 91%.
CH3
ultrasonic conditions
OMe
2. NaBH4 in methanol
15 minutes.
2 Eq.
1 Eq.
In conclusion, this ultrasonic method widens the scope
and generality of the proline catalyzed asymmetric Man-
nich reaction with better yields and enantioselectivities.
Both electron-rich and -deficient aldehydes worked well
under these conditions. The high yield, high optical pur-
ity and operational simplicity make this present method
potentially useful in organic synthesis.
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Acknowledgements
10. Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.
Chem., Int. Ed. 2005, 44, 4079–4083.
We thank the CSIR for financial support under the Task
Force Project CMM-0005. Ch.V.R.S. and G.G.K.
thank the Council of Scientific Industrial Research,
India, for their fellowships.
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