Highly stereoselective synthesis of β-amino ketones via a mannich reaction catalyzed by cellulose sulfuric acid as a biodegradable, efficient, and recyclable heterogeneous catalyst

Article abstract of DOI:10.1080/00397911.2010.520101

The efficient use of cellulose sulfuric acid as a heterogeneous catalyst promotes three-component, one-pot Mannich reaction of various ketones, aromatic aldehydes, and aromatic amines in ethanol to make the corresponding β-amino ketones with high stereose

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Highly Stereoselective Synthesis of β-
Amino Ketones via a Mannich Reaction
Catalyzed by Cellulose Sulfuric Acid as a
Biodegradable, Efficient, and Recyclable
Heterogeneous Catalyst
Firouzeh Nemati a , Amir Soheyl Fakhaei a , Ali Amoozadeh a & Yaser
Saeidi Hayeniaz b
a Department of Chemistry, Faculty of Science, Semnan University,
Semnan, Iran
b Faculty of Chemistry, Tarbiat Moallem University, Tehran, Iran
Accepted author version posted online: 30 Jun 2011.Version of
record first published: 16 Jun 2011.
To cite this article: Firouzeh Nemati , Amir Soheyl Fakhaei , Ali Amoozadeh & Yaser Saeidi Hayeniaz
(2011): Highly Stereoselective Synthesis of β-Amino Ketones via a Mannich Reaction Catalyzed
by Cellulose Sulfuric Acid as a Biodegradable, Efficient, and Recyclable Heterogeneous Catalyst,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:24, 3695-3702
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Synthetic Communications1, 41: 3695–3702, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.520101
HIGHLY STEREOSELECTIVE SYNTHESIS OF b-AMINO
KETONES VIA A MANNICH REACTION CATALYZED BY
CELLULOSE SULFURIC ACID AS A BIODEGRADABLE,
EFFICIENT, AND RECYCLABLE HETEROGENEOUS
CATALYST
Firouzeh Nemati,1 Amir Soheyl Fakhaei,1 Ali Amoozadeh,1 and
Yaser Saeidi Hayeniaz2
1Department of Chemistry, Faculty of Science, Semnan University,
Semnan, Iran
2Faculty of Chemistry, Tarbiat Moallem University, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract The efficient use of cellulose sulfuric acid as a heterogeneous catalyst promotes
three-component, one-pot Mannich reaction of various ketones, aromatic aldehydes, and
aromatic amines in ethanol to make the corresponding b-amino ketones with high stereo-
selectivity in favor of the anti-isomer. This protocol has several advantages such as good
yield, mild reaction conditions, no environmental hazards, and simple workup procedure.
Keywords b-Amino ketones; cellulose sulfuric acid; Mannich reaction; stereoselective
INTRODUCTION
In recent years, a large number of articles have been devoted to the introduction
and applications of valuable ecofriendly catalysts.[1] One of the most simple and use-
ful strategies for the preparation of such catalysts is the attachment of organic or
inorganic materials to different solid supports. Low toxicity, moisture resistance,
air tolerance, greater selectivity, easier handling, and low cost are some of the
Received July 7, 2010.
Address correspondence to Firouzeh Nemati, Department of Chemistry, Faculty of Science,
Semnan University, Semnan, Iran. E-mail: fnemati_1350@yahoo.com; fnemati@semnan.ac.ir
3695

3696
F. NEMATI ET AL.
beneficial features of this method that make it a viable alternative to noncatalytic
methods. The use of biopolymers and especially cellulose for support of sulfuric acid,
as an example of newly investigated solid acid catalysts, is worthy of note.[2,3]
The Mannich reaction is an important carbon–carbon bond-forming reaction
in organic synthesis.[2] It is used for the synthesis of b-amino carbonyl compounds,
which are significant synthetic intermediates for various pharmaceuticals and natural
products.[4] In addition, recent developments in using a three-component protocol
made the Mannich reaction even more valuable in asymmetric synthesis.[5–13]
In his work, we report that cellulose sulfuric acid (CSA) is an efficient catalyst
for the synthesis of b-amino carbonyl compounds in EtOH at room temperature
through a one-pot, three-component reaction of aldehydes, amines, and ketones.
RESULTS AND DISCUSSION
In continuation of our investigation of Mannich reactions,[14,15] we now intro-
duce CSA as an effective and highly stereoselective catalyst for the one-pot synthesis
of b-amino carbonyl compounds via a multicomponent reaction of aryl aldehydes,
anilines, and cyclohexanone (Scheme 1).
To establish the optimum conditions for this reaction, initially, the three-
component Mannich reaction of benzaldehyde (2 mmol), aniline (2 mmol), and
cyclohexanone (3 mmol) was examined, and various solvents such as tetrahydro-
furan (THF), H2O, EtOH, CH2Cl2, and CH3CN were chosen. Ethanol was found
to be the best solvent as far as yield, reaction rate, cost, and environmental acc-
eptability were concerned. In addition, some of the products precipitate in ethanol.
Further experiments revealed the optimum amount of catalyst to be 0.3 g.
To show the generality and scope of this new protocol, we used different
aromatic aldehydes and aromatic amines bearing electron-withdrawing and elec-
tron-donating groups in addition to cyclohexanone in the presence of 0.3 g CSA in
EtOH. The reaction gave the corresponding products (4) in good to excellent yields
(Scheme 1). The results are summarized in Table 1.
An important feature of this procedure was that strong-withdrawing substitu-
ents such as the nitro group on aromatic aldehyde and electron-donating group on
aromatic amines (Table 1, entries 4, 8, and 15) result in good yield. This is because
the electron-withdrawing substituents on benzaldehyde and electron-donating sub-
stituents on aniline have a great impact on the rate of the formation of the com-
=
pound ArCH NPh derived from the aryl aldehydes and aryl amines. According
to this explanation, benzaldehyde with strong electron-donating groups and aryla-
mine with electron-withdrawing groups would not work well (Table 1, entries 11,
Scheme 1. One-pot three-component direct Mannich reaction.

STEREOSELECTIVE SYNTHESIS OF b-AMINO KETONES
3697
Table 1. Mannich-type reaction of aromatic aldehydes, anilines, and cyclohexanonea in EtOH
Entry
Ar1
Ar
Time (h)
Yield (%)b
anti=sync
M.P. ꢀC
1
2
C6H5
Ph
Ph
6
6
80
80
99=1
99=1
99=1
33=67
99=1
99=1
70=30
99=1
—
138–140[14]
150–151[15]
120–121[14]
159–160[16]
129–131[14]
69–70[14]
110–112[14]
123–125
—
2-ClC6H4
4-MeC6H4
2-NO2C6H4
2-Naphthyl
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-OHC6H4
4-MeOC6H4
C6H5
3
Ph
Ph
12
5
75
80
4
5
Ph
Ph
7
75
6
6
75
75
7
Ph
Ph
5
8
5
80
11
12
13
14
15
Ph
Ph
12
12
7
Trace
Trace
75
—
—
98–99[17]
—
118–119[18]
4-BrC6H4
4-NO2C6H4
4-MeC6H4
99=1
—
C6H5
C6H5
12
8
No reaction
75
98=2
aReaction conditions: Aromatic aldehyde (2 mmol), aniline (2 mmol), cyclohexanone (3 mmol), CSA
(0.3 g).
bIsolated yields, products were confirmed by 1H NMR.
cAnti=syn ratio was determined by 1H NMR.
12, and 14). Interestingly, the results in Table 1 show that the anti- isomer is much
more favored than syn- one with an exception of entry 4 in Table 1. The anti- and
syn- isomers were identified by measurements of the coupling constants (J) of the
adjacent vicinal protons to C O and NH in 1H NMR spectra. The coupling
=
Scheme 2. Possible mechanism.

3698
F. NEMATI ET AL.
Scheme 3. Mannich-type reaction of aromatic aldehydes, anilines with acetophenone, and 1,3-
diphenylpropan-2-one.
constants for the anti- isomers are reported to be larger than those of the syn-
isomers.[19,20]
The observed anti- selectivity may be rationalized based on previously
reports.[14,15,19] We propose that the in situ–generated enolate attacks the in situ–
generated aldimine as shown in Scheme 2.[10] If hydrogen bonding occurs among
cellulose, aldimine, and enolate, the aryl and phenyl groups would be anti- to each
other, so there is minimum steric repulsion between the methylene group in cyclohex-
anone and aryl group, as well as cellulose and H. Therefore, this transition state
leads to an anti- isomer. In summary, we propose that powerful hydrogen bonding
exists in cellulose, imine, and enol form of cyclohexanone (Scheme 2) because of the
observed excellent anti- selectivity of the reaction.
Table 2. Mannich-type reaction of aromatic aldehydes, anilines, and acetophenone or 1,3-diphenylpro-
pan-2-onea in EtOH
Time Yield
(h)
Entry
Ketone
Ar1
Ar
(%)b anti=syn
M.P ꢀC
1
2
Acetophenone
Acetophenone
Acetophenone
C6H5
4-OMe C6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H5
C6H5
Ph
Ph
14
16
14
12
11
10
12
10
24
14
11
14
95
74
80
75
75
65
75
85
–
–
168–169[14]
148–149[14]
135–137[14]
131–133[14]
130–132[14]
104–105[21]
164–166[16]
165–167[14]
–
–
3
Ph
–
4
Acetophenone
Acetophenone
Ph
Ph
–
5
–
–
6
Acetophenone
Acetophenone
Ph
7
4-ClC6H4
4-MeC6H4
4-NO2C6H4
Ph
–
8
Acetophenone
Acetophenone
C6H5
C6H5
–
9
–
10
11
12
1,3-diphenylpropan-2-one
1,3-diphenylpropan-2-one
1,3-diphenylpropan-2-one 4-MeO C6H4
C6H5
90
80
83
99=1
88=12
99=1
168–170
148–150
132–133
4-FC6H4
Ph
Ph
aReaction conditions: Aldehyde (2 mmol), aromatic aniline (2 mmol), acetophenone (2 mmol) or
1,3-diphenylpropan-2-one (2 mmol) and CSA (0.5 g).
bIsolated yield, products were confirmed by 1H NMR.
cNo reaction.

STEREOSELECTIVE SYNTHESIS OF b-AMINO KETONES
3699
These encouraging results prompted us to test other ketones such as 1,3-
diphenylpropan-2-one (dibenzylketone) and acetophenone (Scheme 3). Corres-
ponding b-amino carbonyl compounds were formed in good yields (Table 2).
Acetophenone and 1,3-diphenylpropan-2-one are less reactive than cyclohexanone
and required a larger quantity of catalyst (0.5 g) and longer reaction time to yield
the desired products. High anti-selectivity was also observed for product 6
(Table 2, entries 10–12). The highly electron-deficient 4-nitroaniline did not work
(Table 2, entry 9). High electron-withdrawing groups such as NO2 decrease the
activity of the amine to produce the aldimine and result in a very poor yield.
In summary, three-component Mannich-type reactions of aryl aldehydes, aro-
matic amines, and ketones are efficiently catalyzed by CSA in EtOH. The reaction
works well with a wide range of structural variations in all the three components.
The most important advantages of this methodology are the mild conditions, good
yield, and high stereoselectivity. In addition, our process involves an environmen-
tally benign, cheap, and recyclable catalyst.
EXPERIMENTAL
Chemicals were purchased from the Fluka, Merck, and Aldrich chemical
companies. Melting points were determined by an Electrothermal 9100 and are
not corrected. Thin-layer chromatography (TLC) on commercial aluminum-backed
1
plates of silica gel 60 F254 was used to monitor the progress of reactions. H NMR
and 13C NMR spectra were recorded on Bruker Avance 300-MHz spectrometers
with 7–10 mM solutions in CDCl3 in the presence of tetramethylsilane as internal
standard. Infrared (IR) spectra were recorded using a Perkin-Elmer 843 spec-
trometer with KBr plates. Elemental analyses were performed by Perkin-Elmer
CHN analyzer, 2400 series II.
Preparation and Recycling of Cellulose Sulfuric Acid
CSA was prepared according to Shaabani et al.’s procedure.[2] The catalyst was
separated from the reaction mixture, washed thoroughly with chloroform and
EtOH, and dried at 80 ꢀC for 24 h to give recycled CSA. The reaction of benzal-
dehyde, aniline, and cyclohexanone was repeated with recycled catalyst, and the
yields remained in the range of 70% for three runs.
General Procedure for the Synthesis of b-Aminocarbonyl
Compounds Using Cyclohexanone
A mixture of arylaldehyde (2 mmol), aniline (2 mmol), cyclohexanone
(3 mmol), and CSA (0.3 g) was stirred in EtOH (3 mL) at room temperature for
5–12 h. The reaction was monitored by TLC. The products precipitated from the
reaction mixture. The precipitate was filtered off and dissolved in hot EtOH, and
the catalyst was removed by hot filtration.
The filtrate was kept at room temperature, and the resulting crystallized pro-
duct was collected by filtration and washed with EtOH (95%). Some products were
separated and purified by dry flash column chromatography.

3700
F. NEMATI ET AL.
General Procedure for the Synthesis of b-Aminocarbonyl
Compounds Using Acetophenone or 1,3-Diphenylpropan-2-one
A mixture of arylaldehyde (2 mmol), aniline (2 mmol), acetophenone or
1,3-diphenylpropan-2-one (2 mmol), and CSA (0.5 g) was stirred in EtOH (5 mL)
at room temperature for 10–16 h. The reaction was monitored by TLC. The products
were precipitated from the reaction mixtures, filtered off, dissolved in hot EtOH, and
left to crystallize at room temperature. The resulting crystallized product was col-
lected by filtration and washed with EtOH (95%). The b-aminocarbonyl compounds
from 1,3-diphenylpropan-2-one were separated and purified by dry flash chromato-
graphy.
1
All 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 literature.
Spectral (IR, 1H NMR, and 13C NMR) and analytical data of new compounds
are given.
Selected Data
2-[(Phenylamino)(4-nitrophenyl)methyl]cyclohexanone (Table 1, Entry 8).
1
mp 123–125 ꢀC, IR (KBr): v max=cmꢁ1: 3405, 1700, 1575, 1550, 1350; H NMR
(300 MHz, CDCl3, Me4Si): d 8.16 (d, J ¼ 8.77 Hz, 2H), 7.59 (d, J ¼ 8.68 Hz, 2H),
7.13–7.08 (m, 2H), 6.70 (t, J ¼ 7.32 Hz, 1H), 6.53 (d, J ¼ 7.92 Hz, 2H), 4.72 (d,
J ¼ 5.35 Hz, anti, 1H), 2.92–2.87 (m, 1H), 2.45–2.30 (m, 2H), 2.06–1.91 (m, 3H),
1.84–1.74 (m, 3H); 13C NMR (75 MHz, CDCl3): d 24.5, 25.0, 27.0, 27.8, 29.1,
32.0, 42.4, 56.9, 58.1, 113.8, 114.1, 118.5, 123.7, 128.3, 128.6, 129.2, 129.3, 146.3,
147.1, 149.5, 211.9. Anal. calc. for C19H20N2O3: C, 70.37; H, 6.17; N, 8.64%; Found:
C, 70.25; H, 6.01; N, 8.54%.
1,3,4-Triphenyl-4-(phenylamino)butan-2-one (Table 2, Entry 10). mp
168–170 ꢀC; IR (KBr): v max=cmꢁ1: 3405, 1710, 1601, 1320, 667; 1H NMR
(300 MHz, CDCl3, Me4Si): d 7.42–7.39 (m, 2H), 7.34–7.25 (m, 8H), 7.19–7.13 m,
3H), 6.99–6.93 (m, 2H), 6.71 (dd, J ¼ 7.19, J ¼ 1.77 Hz, 2H), 6.58 (t, J ¼ 7.3 Hz,
1H), 6.34 (dd, J ¼ 8.13, J ¼ 1 Hz, 2H), 4.98 (d, anti, J ¼ 10.15 Hz, 1H), 4.14 (d,
J ¼ 10.15 Hz, 1H), 3.31 (dd, J ¼ 20, J ¼ 16 Hz, 2H); 13C NMR (75 MHz, CDCl3): d
50.7, 59.8, 64.7, 113.9, 117.8, 126.8, 127.4, 127.6, 128.3, 128.5, 128.6, 128.8, 129.1,
129.2, 129.5, 133.0, 134.7, 142.0, 147.2, 205.4; Anal. calc. for C28H25NO; C, 85.93;
H, 6.39; N, 3.58%; Found: 85.83; H, 6.28; N, 3.45%.
4-(4-Fluorophenyl)-1,3-diphenyl-4-(phenylamino)butan-2-one (Table 2,
Entry 11). mp 148–150 ꢀC; IR (KBr): v max=cmꢁ1 3428, 1700, 1600, 1508, 750,
1
700; H NMR (300 MHz, CDCl3, Me4Si): d 7.38–7.30 (m, 7H), 7.2–7.15 (m, 3H),
7.0–6.9 (m, 4H), 6.72–6.7 (m, 2H), 6.62–6.57 (m, 1H), 6.30 (dd, J ¼ 8.5, J ¼ 1 Hz,
2H), 4.97 (d, anti, J ¼ 10.17 Hz, 0.88H), 4.87 (d, syn, J ¼ 4.73 Hz, 0.12H), 4.15 (d,
syn, J ¼ 7.59 Hz, 0.12H), 4.10 (d, anti, J ¼ 10.17 Hz, 0.88H), 3.74 (s, 1H), 3.37 (dd,
J ¼ 16.8, J ¼ 15.66 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 50.5, 58.8, 64.6, 113.6,
113.9, 115.2, 115.5, 118.0, 126.9, 128.4, 128.6, 128.8, 129.0, 129.1, 129.2, 129.3,

STEREOSELECTIVE SYNTHESIS OF b-AMINO KETONES
3701
129.4, 129.6, 132.7, 134.4, 137.6, 146.9, 163.6, 205.1. Anal. calc. for C28H24NOF: C,
82.15; H, 5.86; N, 3.42%. Found: C, 82.02; H, 5.79, N, 3.30%.
4-(4-Methoxyphenyl)-1,3-diphenyl-4-(phenylamino)butan-2-one (Table 2,
1
Entry 12). mp 132–133 ꢀC, IR (KBr): v max=cmꢁ1 3409, 1714, 1605, 1516, 760; H
NMR (300 MHz, CDCl3, Me4Si): d 7.35–7.26 (m, 7H), 7.19–7.15 (m, 3H), 6.99–6.94
(m, 2H), 6.84–6.80 (m, 2H), 6.71 (dd, J ¼ 6.71, J ¼ 1.77 Hz, 2H), 6.58 (t, J ¼ 7.3 Hz,
1H), 6.33 (dd, J ¼ 8.13, J ¼ 1 Hz, 2H), 4.98 (d, anti, J ¼ 10.15 Hz, 1H), 4.14 (d, anti,
J ¼ 10.15 Hz, 1H), 3.81 (s, 3H), 3.7 (s, br, 1H), 3.33 (dd, J ¼ 20, J ¼ 16 Hz, 2H); 13C
NMR (75 MHz, CDCl3): d 50.7, 59.8, 64.7, 113.9, 117.8, 126.9, 127.5, 127.6, 128.3,
128.5, 128.6, 128.8, 129.1, 129.2, 129.5, 133.0, 134.7, 142.1, 147.1, 205.4. Anal. calc.
for C29H27NO2: C, 82.66; H, 6.41; N, 3.32%; Found C, 82.55; H, 6.29, N, 3.25%.
ACKNOWLEDGMENT
We thank the Department of Chemistry and Center of Gifted Students of
Semnan University for supporting this work.
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