Stereoselective synthesis ofβ-Amino ketones via direct Mannich-type reaction catalyzed with SO2-4/TiO2 and SO 2-4/nano TiO2

Article abstract of DOI:10.1080/00397910902906594

At room temperature, SO^2-₄/nano-TiO₂ efficiently catalyze the direct Mannich-type reaction of varieties of in situ-generated aldimines using aldehydes and anilines with ketones in a three-component reaction under solvent-free conditions. The reaction proceeds rapidly and affords the correspondingβ-amino ketones in good to high yields with good to excellent stereoselectivity. The catalyst can be recycled for subsequent reactions without any appreciable loss of efficiency.

Full text of DOI:10.1080/00397910902906594

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Stereoselective Synthesis of
β-Amino Ketones via Direct
Mannich-Type Reaction
Catalyzed with
Masoud Samet a , Bagher Eftekhari-Sis b , Mohammed
M. Hashemi a & Fateme Farmad a
a Department of Chemistry, Sharif University of
Technology, Tehran, Iran
b Department of Chemistry, Faculty of Basic Science,
University of Maragheh, Maragheh, Iran
Published online: 12 Nov 2009.
To cite this article: Masoud Samet , Bagher Eftekhari-Sis , Mohammed M. Hashemi
& Fateme Farmad (2009) Stereoselective Synthesis of β-Amino Ketones via Direct
Mannich-Type Reaction Catalyzed with , Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 39:24, 4441-4453,
DOI: 10.1080/00397910902906594
To link to this article: http://dx.doi.org/10.1080/00397910902906594
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Synthetic Communications1, 39: 4441–4453, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902906594
Stereoselective Synthesis of b-Amino Ketones via
Direct Mannich-Type Reaction Catalyzed with
SO24ꢀ=TiO2 and SO42ꢀ=Nano TiO2
Masoud Samet,1 Bagher Eftekhari-Sis,2 Mohammed M. Hashemi,1
and Fateme Farmad1
1Department of Chemistry, Sharif University of Technology, Tehran, Iran
2Department of Chemistry, Faculty of Basic Science, University of
Maragheh, Maragheh, Iran
Abstract: At room temperature, SO24ꢀ=TiO2 and SO42ꢀ=nano-TiO2 efficiently
catalyze the direct Mannich-type reaction of varieties of in situ–generated
aldimines using aldehydes and anilines with ketones in a three-component
reaction under solvent-free conditions. The reaction proceeds rapidly and affords
the corresponding b-amino ketones in good to high yields with good to excellent
stereoselectivity. The catalyst can be recycled for subsequent reactions without
any appreciable loss of efficiency.
Keywords: b-Amino ketones, Mannich reaction, nano-TiO2, SO42ꢀ=TiO2
INTRODUCTION
b-Amino carbonyl compounds are attractive targets for chemical synth-
esis because of their prevalence and wide utility. One of their earliest
applications was in the preparation of important b-amino alcohols,
versatile synthetic intermediates for a large number of natural products,[1]
antibiotics,[2] and chiral auxiliaries.[3] Further, the b-amino carbonyl
Received January 13, 2009.
Mr. Masoud Samet is M.Sc. student.
Address correspondence to Bagher Eftekhari-Sis, Department of Chemistry,
Faculty of Basic Science, University of Maragheh, Mother Sq. Amirkabir High-
way, P.O. Box 55181-83111, Maragheh, Iran. E-mail: eftekharisis@mhec.ac.ir
4441

4442
M. Samet et al.
moiety is common in a large variety of biologically active compounds[4]
and finds use as an important intermediate for fine chemicals[5] and
pharmaceuticals.[6] Therefore, the development of new catalytic methods
for its preparation is of prime importance in organic synthesis. Catalytic
Mannich-type reactions have been reported by several groups as an
efficient method to prepare b-amino carbonyl compounds.[7]
Solid acids such as zeolites, oxides, and aluminophosphates and their
modified forms such as sulfated oxides have been extensively studied as
possible alternatives to conventional Lewis=Brønsted acid catalysts.[8]
Acidity of oxides increases on sulfate ion treatment,[9] and that of zeolites
increases by protonation.[10] The increase in acidity is due to an increase
in the number and the strength of acid sites. In several reactions the yield
and selectivity of a product depend not only on the concentration but
also on the strength of the acid sites. The solid superacids such as
SO24ꢀ=TiO2 (H0 < ꢀ11.93), which can be easily prepared, are sufficiently
stable at the elevated reaction temperature and regenerated conveniently.
Different kinds of solid superacids and the fields in which they are used
have been developed. They have been used in isomerization, alkylation,
acylation, polymerization, oligomerization, esterification, and oxidation
processes.[11]
As part of our research on chemical transformations,[12] herein we
report a simple and environmentally benign methodology for stereoselec-
tive synthesis of b-amino ketones via direct Mannich-type reaction of
aldehydes, anilines, and ketones under solvent-free conditions at room
temperature using SO24ꢀ=TiO2 as catalyst.
RESULTS AND DISCUSSION
SO24ꢀ=TiO2 was prepared, according to the literature,[13] by immersing
TiO2 in 1 N H2SO4 solution for 30 min, which was then decanted and
dried from 80 to 150ꢁC. The resulting solid was calcinated at 200 to
500ꢁC and powdered.
The SO24ꢀ=TiO2-catalyzed direct Mannich-type reaction was first
studied with performed aniline, benzaldehyde, and cyclohexanone under
solvent-free conditions for 3 h at room temperature. 2-[Phenyl(phenyla-
mino)methyl]cyclohexanone was isolated in good yield (87%), with 89%
anti-selectivity. The overall reaction is shown in Scheme 1.
To examine the optimal conditions for SO24ꢀ=TiO2-catalyzed direct
Mannich-type reaction of benzaldehyde, aniline, and cyclohexanone,
we carried out different experiments (entries 1–12, Table 1). The reaction
was carried out with aniline (1 mmol), benzaldehyde (1 mmol), and cyclo-
hexanone (3 mmol) for 3 h under different conditions. Entries 1–7 show

Stereoselective Synthesis of b-Amino Ketones
4443
Scheme 1. Direct Mannich-type reaction of aniline, benzaldehyde, and
cyclohexanone catalyzed with SO24ꢀ=TiO2.
the effect of various solvents and solvent-free conditions on the yield and
stereoselectivity of the reaction. Good to excellent anti-selectivity was
observed in ethanol (EtOH) and CH2Cl2 and under solvent-free
conditions, whereas the reaction in organic solvent showed poor yield.
N-Benzylideneaniline was the only isolated product in H2O and
n-hexane, so we chose solvent-free conditions for good yield and good
anti-selectivity of the reaction and environmental acceptability. The opti-
mum amount of catalyst (0.03 g of SO24ꢀ=TiO2) was determined from
experiments corresponding to entries 1 and 8–12. Entry 8 shows the cat-
alytic effect of SO24ꢀ=TiO2 on the reaction. Entry 10 describes the yields
of three consecutive additions leading to corresponding b-amino ketone.
In these experiments, the product was isolated by filtration, the solid
Table 1. Mannich reaction of aniline, benzaldehyde, and cyclohexanone in
different conditions
Entry
Solvent
Catalyst (g)
Yield (%)
87
Anti=syn
1
2
3
4
5
6
7
8
9
Solvent-free
H2O
EtOH
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0
0.01
0.03
0.07
0.1
89=11
—
94=6
96=4
—
—
—
—
79=21
88=12
78=22
—
a
—
35
20
—
50
30
0
73
CH2Cl2
n-Hexane
Et2O
CH3CN
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
10
11
12
92,90,89b
73
67
aMain product was imine.
bCatalyst was used over three runs.

4444
M. Samet et al.
residues were washed with dichloromethane and dried in air, and the
remaining catalyst was reloaded with fresh reagents for further runs.
No considerable decrease in the yield was observed, demonstrating
that SO24ꢀ=TiO2 can be reused as a catalyst in direct Mannich-type
reactions.
Eleven examples of the direct Mannich-type reaction of anilines, aro-
matic and heteroaromatic aldehydes, and cyclic ketones are listed in
Table 2. The reactions were performed by adding cyclic ketones (3 mmol)
to the mixture of anilines (1 mmol) and benzaldehydes (1 mmol) under
solvent-free conditions in the presence of SO24ꢀ=TiO2 (0.03 g) at room
temperature. The data in Table 2 clearly show that the reaction gave
the corresponding b-amino ketones in good to excellent yield with good
to excellent anti-selectivity for cyclohexanone at room temperature.
Interestingly, in the case of cycloheptanone the reaction show reverse
stereoselectivity, and the syn isomer was formed in good yield (entries
9 and 10).
Table 2. Mannich reaction of anilines, aldehydes, and cyclic ketones catalyzed
with SO24ꢀ=TiO2
Entry Ketone (n) Aniline (X) Aldehyde (X0) Time (h) Yield (%)a Anti=synb
1
2
3
4
5
6
7
8
9
10
1
2
2
2
2
2
2
2
3
3
H
H
H
H
H
3-Me
3-Me
3-Me
H
4-Me
H
4-Cl
4-NO2
Furfural
H
4-Cl
4-NO2
H
1
3
75
92
85
89
80
81
75
95
60
70
66=33
88=12
61=39
65=35
59=41
60=40
100=0
75=25
16=84
34=66
2.5
3.5
1.5
2.5
2.5
3
5.5
5
4-Cl
H
aYields refer to isolated products.
bDiastereomeric ratio measured by 1HNMR spectroscopy analysis of the crude
reaction mixture.

Stereoselective Synthesis of b-Amino Ketones
4445
Scheme 2. Mannich reaction of anilines, benzaldehyde, and acetophenone.
Similarly, the Mannich reaction of benzaldehydes and anilines with
acetophenone was investigated; the overall reaction is best formulated
in Scheme 2.
Also, SO24ꢀ supported on the TiO2 nanoparticles was investigated as
catalyst in the Mannich reaction of aromatic aldehydes and anilines with
cyclohexanone (Table 3). Interestingly, it was shown that in the case of
aldehyde with an electron-withdrawing group such as 4-nitro benzalde-
hyde, the anti=syn ratio decreased from 65=35 and 75=25 (Table 2, entries
4 and 8) when SO24ꢀ=TiO2 was used to 58=42 and 53=47 (Table 3, entries
3n and 6n) in the presence of SO42ꢀ=nano-TiO2. In contrast, in the case of
benzaldehyde, this ratio was increased from 88=12 and 60=40 (Table 2,
entries 2 and 6) in the presence of SO24ꢀ=TiO2 to 95=5 and 100=0
Table 3. Mannich reaction of anilines, aldehydes, and cyclic ketones catalyzed
with SO24ꢀ=nano-TiO2
Entry Ketone (n) Aniline (X) Aldehyde (X0) Time (h) Yield (%)a Anti=synb
1n
2n
3n
4n
5n
6n
2
2
2
2
2
2
H
H
H
3-Me
3-Me
3-Me
H
4-Cl
4-NO2
H
4-Cl
4-NO2
3
90
83
89
80
70
93
95=5
61=39
58=42
100=0
100=0
53=47
2.5
3.5
2.5
2.5
3
aYields refer to isolated products.
bDiastereomeric ratio measured by 1H-NMR spectroscopy analysis of the
crude reaction mixture.

4446
M. Samet et al.
Scheme 3. Chemoselectivity of cyclohexanone toward aldimine in preference to
aldehydes.
(Table 3, entries 1n and 4n) when SO24ꢀ=nano-TiO2 was used as catalyst.
No considerable changes were shown in the yield or time of reaction.
Another characteristic feature of the present protocol is the strong
chemoselectivity of cyclohexanone toward aldimines, prepared in situ
from the reaction of aldehydes and amines, in preference to aldehydes
as shown in Scheme 3.
CONCLUSION
In summary, three-component Mannich reactions of aldehydes, anilines,
and ketones are efficiently catalyzed by SO24ꢀ=TiO2 under solvent-free con-
ditions. Aromatic and heteroaromatic aldehydes can be successfully used
as the aldehyde component. Also, we have found that good to excellent
anti-selectivity was observed in the SO24ꢀ=TiO2-catalyzed Mannich reac-
tion of cyclic ketones and aromatic aldimines in very short times at room
temperature under solvent-free conditions. When SO24ꢀ=nano-TiO2 was
used as the catalyst, anti-selectivity decreased in the case of aldehyde with
electron-withdrawing groups and increased in the case of benzaldehyde.
EXPERIMENTAL
General Reaction Procedure
Benzaldehyde (1 mmol), cyclohexanone (3 equiv.), and SO24ꢀ=TiO2
(0.03 g), were added successively to aniline (1 mmol) at room temperature
(20–25ꢁC) and stirred at the same temperature for the appropriate time.
After completion of the reaction, CH2Cl2 (15 ml) was added, and
the catalyst was removed by filtration. Filtrates were concentrated to
dryness. The crude mixture was washed with hexane to afford 2-
(phenyl-phenylamino-methyl)-cyclohexanone in 92% yield as an 88=12
anti=syn mixture. Products were obtained almost in pure form. In some

Stereoselective Synthesis of b-Amino Ketones
4447
cases, further purification was carried out by column chromatography on
silica gel using petroleum ether=ethyl acetate. All products were known
and characterized by their spectroscopic data (IR and NMR) by compar-
ison with those reported in the litrature.[12a] Anti=syn ratio was deter-
1
mined by HNMR according to the literature.[12a]
Data
2-[(Phenylamino)(p-tolyl)methyl]cyclopantanone (1)
IR (KBr): n ¼ 3393 (NH), 3039, 2955, 2871 (CH), 1724 (CO), 1603, 1510
ꢀ1
=
(C C), 1313 (NH) cm
.
1H NMR (500 MHz, CDCl3): d ¼ 1.70–1.79
(m, 2H, CH2), 1.91–1.94 (m, 2H, CH2), 2.05–2.15 (m, 1H, CH2),
2.31–2.35 (m, 1H, CH2), 2.39 (s, 3H, CH3), 2.43–2.48 (m, 1H, CH), 4.1 (d,
3JH,H ¼ 7.44 Hz, 0.66 H, CH, anti isomer), 4.18 (d, JH,H ¼ 6.14Hz,
3
0.34 H, CH, syn isomer), 5.11 (s, 1H, NH), 6.55 (d, 3JH, H ¼ 7.69 Hz, 2H,
CHAr), 6.65 (t, JH,H ¼ 7.31Hz, 1H, CHAr), 7.07 (t, JH,H ¼ 7.43Hz,
3
3
2H, CHAr), 7.14 (d, JH,H ¼ 7.89Hz, 2H, CHAr), 7.29 (d, JH,H ¼ 7.98 Hz,
3
3
2H, CHAr) ppm.
2-[Phenyl(phenylamino)methyl]cyclohexanone (2)
1H NMR (500 MHz, CDCl3): d ¼ 1.73–1.76 (m, 2H, CH2), 1.89–1.98 (m,
4 H, CH2), 2.38–2.48 (m, 2H, CH2), 2.79–2.80 (m, 1H, CH), 4.66 (d,
3JH,H ¼ 4.99 Hz, 0.88 H, CH, anti isomer), 4.75 (s, 1H, NH), 4.84
3
3
(d, JH,H ¼ 3.98 Hz, 0.12H, CH, syn isomer), 6.57 (d, JH,H ¼ 8.50 Hz,
2H, CHAr), 6.66 (t, JH,H ¼ 7.50 Hz, 1H, CHAr), 7.09–7.12 (m, 2H,
3
CHAr), 7.26 (d, JH,H ¼ 7.00 Hz, 1H, CHAr), 7.34 (t, JH,H ¼ 7.50 Hz,
3
3
2H, CHAr), 7.41 (t, JH,H ¼ 8.75 Hz, 2H, CHAr) ppm.
3
2-[(4-Chlorophenyl)(phenylamino)methyl]cyclohexanone (3)
1H NMR (500 MHz, CDCl3): d ¼ 1.73–1.81 (m, 1H, CH2), 1.85–1.91 (m,
2H, CH2), 1.94–2.02 (m, 1H, CH2), 2.05–2.10 (m, 2H, CH2), 2.20–2.29
(m, 1H, CH), 2.35–2.48 (m, 1H, CH2), 2.74–2.82 (m, 1H, CH), 4.78 (d,
3
3JH,H ¼ 4.90 Hz, 0.61H, CH, anti isomer), 4.94 (d, JH,H ¼ 3.65 Hz,
3
0.39 H, CH, syn isomer), 5.04 (s, 1H, NH), 6.51 (d, JH,H ¼ 7.79 Hz, 2H,
3
CHAr), 6.70 (d, JH,H ¼ 7.40 Hz, 1H, CHAr), 7.11 (t, 3JH,H ¼ 8.11Hz, 2H,
3
3
CHAr), 7.60 (t, JH,H ¼ 8.50 Hz, 2H, CHAr), 8.20 (d, JH,H ¼ 8.67 Hz,
2H, CHAr) ppm.

4448
M. Samet et al.
2-[(p-Nitrophenyl)(phenylamino)methyl]cyclohexanone (4)
IR (KBr): n ¼ 3373 (NH), 3032, 2948, 2858 (CH), 1699 (CO), 1601
ꢀ1
.
1H NMR (500 MHz,
=
(C C), 1515, 1346 (NO2), 1287 (NH) cm
CDCl3): d ¼ 1.69–1.78 (m, 1H, CH2), 1.82–1.88 (m, 2H, CH2),
1.91–1.99 (m, 1H, CH2), 2.01–2.08 (m, 2H, CH2), 2.18–2.28 (m, 1H,
CH), 2.33–2.45 (m, 1H, CH2), 2.71–2.79 (m, 1H, CH), 4.75 (d,
3
3JH,H ¼ 4.84 Hz, 0.65 H, CH, anti isomer), 4.90 (d, JH,H ¼ 3.42Hz,
3
0.35 H, CH, syn isomer), 4.93 (s, 1H, NH), 6.48 (d, JH,H ¼ 7.77 Hz, 2H,
CHAr), 6.67 (d, 3JH,H ¼ 7.37 Hz, 1H, CHAr), 7.07 (t, 3JH,H ¼ 8.09 Hz, 2H,
3
3
CHAr), 7.58 (t, JH,H ¼ 8.49 Hz, 2H, CHAr), 8.17 (d, JH,H ¼ 8.64 Hz,
2H, CHAr) ppm.
2-[Furan-2-yl(phenylamino)methyl]cyclohexanone (5)
1H NMR (500 MHz, CDCl3): d ¼ 1.69–1.76 (m, 3H, CH2), 1.91–1.95 (m,
3H, CH2), 2.31–2.47 (m, 2H, CH2), 2.91–3.15 (m, 1H, CH), 4.61 (s, 1H,
3
NH), 4.85 (d, JH,H ¼ 5.36 Hz, 0.59 H, CH, anti isomer), 4.92
(d,3JH,H ¼ 4.90 Hz, 0.41H, CH, syn isomer), 6.23 (d, 1H, CHAr), 6.30
(d, 1H, CHAr), 6.69–6.73 (m, 3H, CHAr), 7.16–7.20 (m, 2H, CHAr),
7.34 (t, 1H, CHAr) ppm.
2-[Phenyl(m-tolylamino)methyl]cyclohexanone (6)
=
IR (KBr): n ¼ 3351 (NH), 3038, 2944 (CH), 1702 (CO), 1602, 1538 (C C),
1306 (NH) cmꢀ1. H NMR (500 MHz, CDCl3): d ¼ 1.69–1.79 (m, 2H,
1
CH2), 1.82–1.98 (m, 4 H, CH2), 2.20 (s, 3H, CH3), 2.33–2.37 (m, 1H,
CH2), 2.44–2.46 (m, 1H, CH2), 2.70–2.75 (m, 1H, CH), 4.63
3
(d, JH,H ¼ 6.96 Hz, 0.60 H, CH, anti isomer), 4.72 (br. s, 1H, NH), 4.84
3
3
(d, JH,H ¼ 3.47 Hz, 0.40 H, CH, syn isomer), 6.28 (d, JH,H ¼ 6.35 Hz,
1H, CHAr), 6.36 (s, 1H, CHAr), 6.45 (d, JH,H ¼ 7.32Hz, 1H, CHAr),
3
6.93 (t, JH,H ¼ 7.65 Hz, 1H, CHAr), 7.23 (t, JH,H ¼ 7.13Hz, 1H, CHAr),
3
3
7.32 (t, JH,H ¼ 7.41Hz, 2H, CHAr), 7.41 (d, JH,H ¼ 7.69 Hz, 2H,
3
3
CHAr) ppm.
2-[(4-Chlorophenyl)(m-tolylamino)methyl]cyclohexanone (7)
IR (KBr): n ¼ 3349 (NH), 3045, 2939, 2865 (CH), 1703 (CO), 1603, 1531
(C C), 1487, 1300 (NH), 710 (C–Cl) cmꢀ1. 1H NMR (500 MHz, CDCl3):
=
d ¼ 1.70–1.77 (m, 1H, CH2), 1.88–1.94 (m, 2H, CH2), 2.12–2.14 (m, 1H,
CH2), 2.21–2.29 (m, 2H, CH2), 2.37 (s, 3H, CH3), 2.43–2.48 (m, 1H,

Stereoselective Synthesis of b-Amino Ketones
4449
3
CH2), 2.53–2.57 (m, 1H, CH2), 2.87–2.92 (m, 1H, CH), 4.78 (d, JH,H
¼
3
5.03Hz, 1H, CH, anti isomer), 4.96 (s, 1H, NH), 6.29 (t, JH,H ¼ 7.76 Hz,
1H, CHAr), 6.38 (s, 1H, CHAr), 6.56 (t, 3JH,H ¼ 7.74 Hz, 1H, CHAr), 6.99
(t, 3JH,H ¼ 7.77 Hz, 1H, CHAr), 7.63 (d, 3JH,H ¼ 8.55 Hz, 2H, CHAr), 8.22
3
(d, JH,H ¼ 8.57 Hz, 2H, CHAr) ppm.
2-[(p-Nitrophenyl)(m-tolylamino)methyl]cyclohexanone (8)
=
IR (KBr): n ¼ 3373 (NH), 2948, 2858 (CH), 1699 (CO), 1601 (C C), 1516,
1345 (NO2), 1300, 1100 (NH) cmꢀ1 1H NMR (500 MHz, CDCl3):
.
d ¼ 1.61–1.69 (m, 1H, CH2), 1.81–1.90 (m, 2H, CH2), 2.02–2.04 (m, 1H,
CH2), 2.10–2.14 (m, 2H, CH2), 2.27 (s, 3H, CH3), 2.35–2.40 (m, 1H,
CH2), 2.44–2.48 (m, 1H, CH2), 2.85–2.90 (m, 1H, CH), 4.74 (d,
3
3JH,H ¼ 5.00 Hz, 0.75 H, CH, anti isomer), 4.89 (d, JH,H ¼ 4.00 Hz,
3
0.25 H, CH, syn isomer), 4.91 (br. s, 1H, NH), 6.27 (t, JH,H ¼ 7.78 Hz,
3
1H, CHAr), 6.36 (s, 1H, CHAr), 6.50 (t, JH,H ¼ 7.71Hz, 1H, CHAr), 6.96
3
3
(t, JH,H ¼ 7.76 Hz, 1H, CHAr), 7.61 (d, JH,H ¼ 8.53Hz, 2H, CHAr),
8.20 (d, JH,H ¼ 8.56 Hz, 2H, CHAr) ppm.
3
2-[Phenyl(phenylamino)methyl]cycloheptanone (9)
1H NMR (500 MHz, CDCl3): d ¼ 1.28–1.38 (m, 2H, CH2), 1.45–1.64 (m, 2H,
CH2), 1.73–176 (m, 1H, CH2), 1.94 (m, 3H, CH2), 2.33–2.38 (m, 1H, CH2),
2.48–2.54 (m, 1H, CH2), 2.88–2.92 (m, 1H, CH), 4.47 (d, 3J¼ 7.50, 0.16 H,
3
CH, anti isomer), 4.58 (d, J¼ 5.00, 0.84 H, CH, syn isomer), 4.99 (s, 1H,
3
3
NH), 6.49 (t, J ¼ 9.98, 2H, CHAr), 6.61 (t, J ¼ 10.00, 1H, CHAr), 7.05 (t,
3J ¼ 8.50, 2H, CHAr), 7.22–7.28 (m, 1H, CHAr), 7.3–7.39 (m, 4 H, CHAr).
2-[(4-Chlorophenylamino)(phenyl)methyl]cycloheptanone (10)
1H NMR (500 MHz, CDCl3): d ¼ 1.30–1.37 (m, 2H, CH2), 1.48–1.65 (m,
2H, CH2), 1.75–1.77 (m, 1H, CH2), 1.97–2.03 (m, 3H, CH2), 2.34–2.40
(m, 1H, CH2), 2.51–2.56 (m, 1H, CH2), 2.91–2.94 (m, 1H, CH), 4.51
3
3
(d, JH,H ¼ 7.48, 0.34 H, CH, anti isomer), 4.63 (d, JH,H ¼ 5.03, 0.66 H,
CH, syn isomer), 5.01 (s, 1H, NH), 6.53 (d, 2H, CHAr), 7.11–7.17 (m,
5 H, CHAr), 7.21–7.28 (m, 2H, CHAr).
2-[Phenyl(phenylamino)methyl]cyclohexanone (1n)
1H NMR (500 MHz, CDCl3): d ¼ 1.73–1.78 (m, 2H, CH2), 1.88–1.97 (m,
4 H, CH2), 2.38–2.47 (m, 2H, CH2), 2.79–2.81 (m, 1H, CH), 4.67

4450
M. Samet et al.
3
(d, JH,H ¼ 4.99 Hz, 0.95 H, CH, anti isomer), 4.75 (s, 1H, NH), 4.84 (d,
3
3JH,H ¼ 3.98 Hz, 0.12H, CH, syn isomer), 6.57 (d, JH,H ¼ 8.50 Hz, 2H,
3
CHAr), 6.66 (t, JH,H ¼ 7.50 Hz, 1H, CHAr), 7.09–7.12 (m, 2H, CHAr),
7.26 (d, 3JH,H ¼ 7.00 Hz, 1H, CHAr), 7.34 (t, 3JH,H ¼ 7.50 Hz, 2H, CHAr),
3
7.41 (t, JH,H ¼ 8.75 Hz, 2H, CHAr) ppm.
2-[(4-Chlorophenyl)phenylamino)methyl]cyclohexanone (2n)
1H NMR (500 MHz, CDCl3): d ¼ 1.75–1.82 (m, 1H, CH2), 1.89–1.93 (m,
2H, CH2), 1.96–2.08 (m, 1H, CH2), 2.10–2.12 (m, 2H, CH2), 2.23–2.28
(m, 1H, CH), 2.37–2.49 (m, 1H, CH2), 2.75–2.84 (m, 1H, CH), 4.75 (s,
3
1H, NH), 4.84 (d, JH,H ¼ 5.10 Hz, 0.61H, CH, anti isomer), 4.89 (d,
3
3JH,H ¼ 4.05, 0.39 H, CH, syn isomer), 6.55 (d, JH,H ¼ 7.79 Hz, 2H,
3
3
CHAr), 6.79 (d, JH,H ¼ 7.42Hz, 1H, CHAr), 7.16 (t, JH,H ¼ 8.11Hz,
2H, CHAr), 7.66 (t, 3JH,H ¼ 8.50 Hz, 2H, CHAr), 8.23 (d, 3JH,H ¼ 8.64 Hz,
2H, CHAr) ppm.
2-[(p-Nitrophenyl)(phenylamino)methyl]cyclohexanone (3n)
1H NMR (500 MHz, CDCl3): d ¼ 1.67–1.76 (m, 1H, CH2), 1.80–1.86 (m,
2H, CH2), 1.89–1.97 (m, 1H, CH2), 1.99–2.06 (m, 2H, CH2), 2.16–2.26
(m, 1H, CH), 2.31–2.43 (m, 1H, CH2), 2.69–2.77 (m, 1H, CH), 4.73 (d,
3
3JH,H ¼ 4.86 Hz, 0.58 H, CH, anti isomer), 4.88 (d, JH,H ¼ 3.44 Hz,
3
0.42H, CH, syn isomer), 4.91 (s, 1H, NH), 6.46 (d, JH,H ¼ 7.74 Hz, 2H,
3
3
CHAr), 6.65 (d, JH,H ¼ 7.34 Hz, 1H, CHAr), 7.04 (t, JH,H ¼ 8.05 Hz,
2H, CHAr), 7.50 (t, JH,H ¼ 8.47 Hz, 2H, CHAr), 8.15 (d, JH,H ¼ 8.61
3
3
Hz, 2H, CHAr) ppm.
2-[Phenyl(m-tolylamino)methyl]cyclohexanone (4n)
1H NMR (500 MHz, CDCl3): d ¼ 1.74–1.82 (m, 2H, CH2), 1.92–2.01 (m,
4 H, CH2), 2.25 (s, 3H, CH3), 2.37–2.39 (m, 1H, CH2), 2.46–2.49 (m, 1H,
CH2), 2.74–2.78 (m, 1H, CH), 4.63 (d, 3JH,H ¼ 6.96 Hz, 1H, CH, anti iso-
3
mer), 4.70 (s, 1H, NH), 6.31 (d, JH,H ¼ 6.37 Hz, 1H, CHAr), 6.38 (s, 1H,
CHAr), 6.46 (d, 3JH,H ¼ 7.34 Hz, 1H, CHAr), 6.95 (t, 3JH,H ¼ 7.66 Hz, 1H,
3
3
CHAr), 7.25 (t, JH,H ¼ 7.15 Hz, 1H, CHAr), 7.34 (t, JH,H ¼ 7.42Hz, 2H,
3
CHAr), 7.40 (d, JH,H ¼ 7.70 Hz, 2H, CHAr) ppm.
2-[(4-Chlorophenyl)(m-tolylamino)methyl]cyclohexanone (5n)
1H NMR (500 MHz, CDCl3): d ¼ 1.72–1.85 (m, 3H, CH2), 1.96–2.01
(m, 3H, CH2), 2.64 (s, 3H, CH3), 2.35–2.36 (m, 1H, CH2), 2.43–2.47

Stereoselective Synthesis of b-Amino Ketones
4451
(m, 1H, CH2), 2.72–2.75 (m, 1H, CH), 4.60 (d, 3JH,H ¼ 6.18 Hz, 1H, CH,
3
anti isomer), 4.74 (s, 1H, NH), 6.29 (d, JH,H ¼ 7.98 Hz, 1H, CHAr), 6.35
3
3
(s, 1H, CHAr), 6.48 (d, JH,H ¼ 7.43Hz, 1H, CHAr), 6.96 (t, JH,H
¼
7.72Hz, 1H, CHAr), 7.31 (d, JH,H ¼ 8.35 Hz, 2H, CHAr), 7.35 (d,
3
3JH,H ¼ 8.46 Hz, 2H, CHAr) ppm.
2-[(p-Nitrophenyl)(m-tolylamino)methyl]cyclohexanone (6n)
1HNMR (500 MHz, CDCl3): d ¼ 1.59–1.67 (m, 1H, CH2), 1.78–1.89 (m,
2H, CH2), 1.99–2.01 (m, 1H, CH2), 2.08–2.11 (m, 2H, CH2), 2.24 (s,
3H, CH3), 2.34–2.37 (m, 1H, CH2), 2.41–2.46 (m, 1H, CH2), 2.84–2.88
3
(m, 1H, CH), 4.69 (d, JH,H ¼ 5.1Hz, 0.53H, CH, anti isomer), 4.81 (d,
3JH,H ¼ 4.47 Hz, 0.47 H, CH, syn isomer), 4.85 (s, 1H, NH), 6.25 (t,
3JH,H ¼ 7.77 Hz, 1H, CHAr), 6.33 (s, 1H, CHAr), 6.49 (t, 3JH,H ¼ 7.69 Hz,
3
3
1H, CHAr), 6.94 (t, JH,H ¼ 7.75 Hz, 1H, CHAr), 7.59 (d, JH,H
¼
8.51Hz, 2H, CHAr), 8.18 (d, JH,H ¼ 8.54 Hz, 2H, CHAr) ppm.
3
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