HClO4-SiO2 catalyzed stereoselective synthesis of β-amino ketones via a direct Mannich-type reaction

Article abstract of DOI:10.1016/j.tetlet.2007.07.088

The HClO₄-SiO₂ catalyzed three-component, one-pot Mannich reaction of ketones, aromatic aldehydes and aromatic amines is carried out in ethanol to afford the corresponding β-amino ketones in good yields and high stereoselectivities in favor of the anti-isomer. Three new compounds are reported.

Full text of DOI:10.1016/j.tetlet.2007.07.088

Tetrahedron Letters 48 (2007) 6801–6804
HClO4–SiO2 catalyzed stereoselective synthesis of b-amino
ketones via a direct Mannich-type reaction
Mohammad A. Bigdeli, Firouzeh Nemati* and Gholam Hossien Mahdavinia
Faculty of Chemistry, Teacher Training University, 49 Mofateh St., Tehran, Iran
Received 12 May 2007; revised 1 July 2007; accepted 12 July 2007
Available online 21 July 2007
Abstract—The HClO4–SiO2 catalyzed three-component, one-pot Mannich reaction of ketones, aromatic aldehydes and aromatic
amines is carried out in ethanol to afford the corresponding b-amino ketones in good yields and high stereoselectivities in favor
of the anti-isomer. Three new compounds are reported.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
tions using electrophiles, such as imines and stable
nucleophiles, such as enolates, enol ethers and enamines,
have been reported in the literature.5 A more desirable
version of the Mannich reaction involves the use of a
one-pot, three-component strategy that allows for a
wide range of structural variations. In this context,
recent developments in asymmetric synthesis, using a
three-component protocol, have made the Mannich
reaction very valuable.6
Solid supported reagents are unique acid catalysts that
have become popular over the last two decades. The
activity and selectivity of a reagent dispersed on the sur-
face of a support are improved as the effective surface
area of the reagent is increased significantly, and hence
they are expected to perform more effectively than the
individual reagents.1
Low toxicity, moisture resistance, air tolerance and low
prices are other common features that make the use of
solid supported reagents as attractive alternatives to
conventional Lewis acids or metal triflates.
In this work we have found HClO4–SiO2 to be an
efficient catalyst in EtOH at room temperature for the
synthesis of b-amino carbonyl compounds through a
one-pot, three-component reaction of aldehydes, amines
and ketones.
Silica supported perchloric acid (HClO4–SiO2) has
received considerable attention as an inexpensive, non-
toxic and recyclable catalyst for numerous organic
transformations, affording the corresponding products
in excellent yields and with high selectivity.2 To the best
of our knowledge, there has been no report on the use of
HClO4–SiO2 as a catalyst in the Mannich reaction.
Initially, the three-component Mannich reaction of benz-
aldehyde (2.5 mmol), aniline (2.5 mmol) and cyclohexa-
none (3 mmol) was examined. To optimize the reaction
conditions, solvents such as CH3CN, 1,4-dioxane,
Et2O, THF, toluene and EtOH were examined. Ethanol
was found to be the best solvent as far as yields and reac-
tion times were concerned. All the products precipitate in
ethanol. Further experimentation revealed that the
optimum amount of catalyst was 2 mol %, (Scheme 1).
The Mannich reaction is an important carbon–carbon
bond forming reaction in organic synthesis.3 It is used
for the synthesis of b-amino carbonyl compounds,
which are important synthetic intermediates for various
pharmaceuticals and natural products.4 Mannich reac-
The reaction of different aromatic aldehydes, anilines
and cyclohexanone gave product 4 in good to high yields
with excellent anti selectivity. The results are summa-
rized in Table 1. 4-Nitrobenzaldehyde and 4-nitroaniline
possessing strong electron-withdrawing groups did not
react. 4-Bromoaniline showed the reverse selectivity in
favor of the syn-isomer (entry 3).
Keywords: Mannich reaction; b-Amino ketones; Silica perchloric acid;
Stereoselective.
*
Corresponding author. Fax: +98 21 88820993;
firouzehnemati@yahoo.com
e-mail:
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.088

6802
M. A. Bigdeli et al. / Tetrahedron Letters 48 (2007) 6801–6804
O
O
O
NHAr2
Ar1
NHAr2
Ar1
HClO4-SiO2 (2 mol%)
EtOH (3 ml), 2-5 h
Ar1CHO
+
Ar2NH2
+
+
1
3
2
4 syn
4 anti
Scheme 1. One-pot, three-component Mannich reaction.
Table 1. Direct Mannich-type reaction of aromatic aldehydes, anilines
form between HClO4–SiO2, the imine and the enol form
of cyclohexanone (Scheme 2).8 Transition state I pro-
vides more space for the aryl groups of the aldimine
and less steric repulsion between the aryl groups and
the catalyst in the anti-isomer, that is, the most stable
transition state produces the anti-isomer.
and cyclohexanonea
Entry R1
R2
Time Yieldb anti/sync
(h)
(%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
2
2
3
2
3
5
4
4
98
90
75
80
85
90
92
83
80
nrd
nr
99:1
98:2
28:72
87:23
95:5
99:1
94:6
98:2
97:3
—
4-MeC6H4
4-BrC6H4
Ph
Ph
Ph
The one-pot, three-component Mannich reaction using
acetophenone was also studied (Scheme 3). It was found
that the corresponding b-amino carbonyl compounds
were formed in good to moderate yields. The results
are summarized in Table 2. Acetophenone was less reac-
tive than cyclohexanone and required a greater quantity
of catalyst (4 mol %) and longer reaction times to afford
the desired products.
4-MeC6H4
4-ClC6H4
1-Naphthyl
1-Naphthyl
4-BrC6H4
4-ClC6H4
4-MeC6H4
Ph
4-MeC6H4
3.5
12
4-NO2C6H4 12
10
11
4-NO2C6H4 Ph
Ph
—
a Reaction conditions: aromatic aldehyde (2.5 mmol), aromatic amine
(2.5 mmol), cyclohexanone (3 mmol), and HClO4–SiO2 (2 mol %).
b Isolated yields, products were confirmed by 1H NMR.
c Anti/syn ratio was determined by 1H NMR.
In summary, good stereoselectivity, high yields, non-
toxic solvents, very easy work-up, low catalyst loading
and no formation of by-products are the merits of this
procedure.
d No reaction.
The isomers were identified from the values of the cou-
pling constants between the vicinal protons a- and b- to
C@O. It has been reported that the J value of anti
isomers (ca. 7.5 Hz) is higher than those of syn isomers
(ca. 4.5 Hz) in these types of systems.7 The anti/syn ratio
was determined by the relative areas under the absorp-
tion peaks for Hb.
2. Experimental
2.1. A: general procedure for the synthesis of b-amino-
carbonyl compounds using cyclohexanone
A
mixture of benzaldehyde (2.5 mmol), aniline
(2.5 mmol), cyclohexanone (3 mmol) and HClO4–SiO2
(0.01 g, 2 mol %) was stirred in EtOH (3 ml) at room
temperature for 2–5 h. The reaction was monitored by
TLC. After completion of the reaction, ethyl acetate
As shown in Table 1, the anti-isomer predominated over
the syn-isomer with the exception of entry 3. A possible
transition state is proposed in which hydrogen bonds
OClO3H
O
Si
O
O
O
Ar2
OH
H
O
Ar2
H
Ar2NH2
NH
O
OClO3H
N
H
Ar1CHO
H
Ar1
H
Ar1
H
anti
I
Scheme 2. Possible transition states leading to the anti-product.
Ar2
O
HN
O
HClO4-SiO2 (4 mol%)
EtOH (3 ml), 10-17 h
Ar1
Ar1CHO
+
Ar2NH2
+
Scheme 3. Mannich-type reaction of aromatic aldehydes, anilines and acetophenone.

M. A. Bigdeli et al. / Tetrahedron Letters 48 (2007) 6801–6804
6803
Table 2. Mannich-type reactions of aromatic aldehydes, anilines and
1H, J = 8.33 Hz), 7.9 (t, 2H, J = 8.3 Hz), 7.73 (d, 1H,
J = 8.1 Hz), 7.42–7.56 (m, 3H), 6.83 (d, 2H,
J = 8.24 Hz), 6.56 (d, 2H, J = 8 Hz), 5.42 (d, 0.06H,
syn, J = 4.1 Hz), 5.3 (d, 0.94H, anti, J = 5.72 Hz), 3.2
(t, 1H, J = 4.9 Hz), 2.15–2.39 (m, 1H), 1.9–2.15 (m,
2H), 2.13 (s, 3H), 1.68–1.9 (m, 6H); 13C NMR
(75 MHz, CDCl3): d 20.33, 25.06, 28.14, 33.16, 43.05,
55.09, 56.50, 113.79, 114.44, 122.09, 125.01, 125.23,
125.81, 126.18, 126.88, 127.52, 129.46, 129.60, 131.36,
133.91, 137.09, 144.92, 213.19; Anal. Calcd for
C24H25NO: C, 83.93; H, 7.28; N, 4.08. Found: 83.99;
H, 7.65; N, 4.07.
acetophenonea
Entry R1
R2
Time Yieldb Mp (°C)
(h)
(%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
12
15
15
36
17
12
95
80
85
Nrc
75
89
90
90
168–1709
131–13210
128–1309
—
130–1318
147–1498
177–1789
165–1679
4-ClC6H4
4-MeC6H4
1-Naphthyl
4-BrC6H4
4-MeOC6H4 Ph
Ph
Ph
4-NO2C6H4 12
4-MeC6H4 10
a Reaction conditions: aldehyde (2.5 mmol), amine (2.5 mmol), aceto-
phenone (2.5 mmol) and HClO4–SiO2 (4 mol %).
b Isolated yield, products were confirmed by 1H NMR.
c No reaction.
4.2. 2-((4-Bromophenyl)(phenylamino)methyl)cylohexa-
none (Table 1, entry 8)
Mp 110–112 °C, IR (KBr): mmax/cmÀ1 3393, 1713, 1600,
was added and catalyst was removed by filtration. The
filtrate was washed with NaHCO3 (aq) and brine and
was dried over MgSO4. The solvent was removed under
reduced pressure. Pure b-amino ketone was recrystal-
lized from EtOH. In some cases, trituration in petro-
leum ether was necessary.
1493, 1275, 1011, 753; 1H NMR (300 MHz; CDCl3;
Me4Si):
d
7.4–7.44 (dd, 2H, J = 7.4Hz and
J = 2.4 Hz), 7.28 (t, 2H, J = 5.4 Hz), 7.03–7.13 (m,
3H), 6.71 (t, 1H, J = 6.9 Hz), 6.58 (d, 2H, J = 8.1 Hz),
4.72 (d, 0.02H, syn, J = 4.41 Hz), 4.57(d, 0.98H, anti,
J = 6.72 Hz), 2.86 (s, 1H), 2.34–2.43 (m, 2H), 1.6–1.9
(m, 6H); 13C NMR (75 MHz, CDCl3, mixture of diaste-
reoisomers): d 24.01, 24.89, 27.03, 27.85, 28.89, 31.53,
42.06, 42.45, 56.35, 56.96, 57.17, 57.62, 113.70, 114.08,
117.87, 117.95, 120.90, 129.11, 129.14, 129.28, 129.46,
131.45, 131.55, 131.66, 131.77, 131.83, 140.79, 146.84,
212.46; Anal. Calcd for C19H20ONBr: C, 63.70; H,
5.58; N, 3.91. Found: C, 63.69; H, 5.62, N, 4.01.
2.2. B: general procedure for the synthesis of b-amino-
carbonyl compounds from acetophenone
A
mixture of benzaldehyde (2.5 mmol), aniline
(2.5 mmol), acetophenone (2.5 mmol) and HClO4–SiO2
(0.02 g, 4 mol %) was stirred in EtOH (3 ml) at room
temperature for 10–17 h. The reaction was monitored
by TLC. The products precipitated from the reaction
mixture. The precipitate was filtered off, dissolved in
hot EtOH and the catalyst was removed by hot filtra-
tion. The filtrate was kept at room temperature and
the resulting crystallized product was collected by filtra-
tion and washed with EtOH (95%).
4.3. 2-((p-Toluidino)(4-chlorophenyl)methyl)cyclohexa-
none (Table 1, entry 9)
Mp 119–121 °C, IR (KBr): mmax/cmÀ1 3379, 1701, 1523,
1493, 1289, 813; 1H NMR (300 MHz; CDCl3; Me4Si): d
7.42 (d, 2H, J = 8.27 Hz), 7.28–7.31 (m, 2H), 7.09–7.12
(m, 1H), 6.9 (d, 2H, J = 8.17 Hz), 6.78 (d, 2H,
J = 7.6 Hz), 4.6 (d, 0.03H, syn, J = 5.5 Hz), 4.5 (d,
0.97H, anti, J = 8.22 Hz), 2.36–2.5 (m, 2H), 2.3 (s,
1H), 2.22 (s, 3H), 1.66–1.83 (m, 6H); 13C NMR
(75 MHz, CDCl3): d 20.39, 23.94, 27.81, 31.41, 41.98,
56.88, 58.48, 114.47, 127.35, 127.87, 128.64, 128.89,
129.0, 129.66, 129.94, 131.59, 132.91, 139.66, 143.65,
212.71; Anal. Calcd for C20H22NOCl: C, 73.28; H,
6.71; N, 4.27. Found: C, 73.38; H, 6.99, N, 4.25.
1
All the products were characterized by IR, H NMR
and 13C NMR, and were identified by comparison of
the spectral data and melting points with those reported
in the literature.
3. Preparation and recycling of HClO4–SiO2
HClO4–SiO2 was prepared according to Asit K. Chak-
raborti’s procedure.2a The catalyst was separated from
the reaction mixture and washed with EtOH and dried
at 100 °C for 24 h to give recycled HClO4–SiO2. The
reaction of benzaldehyde, aniline and cyclohexanone
was repeated with recycled catalyst and the yields were
found to remain in the range of 90% for five recycles.
Acknowledgement
We thank the Faculty of Chemistry of the Teacher
Training University for supporting this work.
References and notes
4. Spectral (IR, 1H NMR, 13C NMR) and analytical data
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