Stereoselective synthesis of β-amino ketones via direct Mannich-type reaction catalyzed with silica sulfuric acid

Article abstract of DOI:10.1016/j.tet.2007.01.015

At room temperature, the direct Mannich-type reaction of a variety of in situ generated aldimines using aldehydes and anilines with ketones in a three-component reaction was efficiently catalyzed by silica sulfuric acid (SSA) in EtOH. This rapid reaction afforded the corresponding β-amino ketones in good yields with excellent stereoselectivities and catalyst was recyclable.

Full text of DOI:10.1016/j.tet.2007.01.015

Tetrahedron 63 (2007) 2404–2408
Stereoselective synthesis of b-amino ketones via direct
Mannich-type reaction catalyzed with silica sulfuric acid
a
c
a
a
Hui Wu,a,b, Yang Shen, Li-yan Fan, Yu Wan, Pu Zhang,
*
Cai-fa Chenb and Wen-xiang Wanga
aDepartment of Chemistry, Xuzhou Normal University, Xuzhou 221116, PR China
bKey Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Xuzhou 221116, PR China
cDepartment of Chemistry, Tongji University, Shanghai 200092, PR China
Received 23 November 2006; revised 10 January 2007; accepted 11 January 2007
Available online 13 January 2007
Abstract—At room temperature, the direct Mannich-type reaction of a variety of in situ generated aldimines using aldehydes and anilines
with ketones in a three-component reaction was efficiently catalyzed by silica sulfuric acid (SSA) in EtOH. This rapid reaction afforded
the corresponding b-amino ketones in good yields with excellent stereoselectivities and catalyst was recyclable.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
phenyl)borate,13 PS–SO3H,14 L-proline,3h have been investi-
gated. However, these methods have some drawbacks such
as long reaction time, use of costly and non-recoverable
catalysts, use of toxic reagents, and requirement of special
effort for catalyst preparation. Silica sulfuric acid is an ex-
cellent acidic catalyst, which is frequently used to promote
some important reactions.15–18 We report herein full details
of a novel, convenient, and simple procedure to realize a
one-pot three-component reaction of aldehydes, amines,
and ketones, catalyzed by SSA, for the preparation of
b-amino carbonyl compounds in EtOH (Scheme 1).
Mannich reactions are among the most important carbon–
carbon bond forming reactions in organic synthesis.1 They
provide b-amino carbonyl compounds, which are important
synthetic intermediates for various pharmaceuticals and nat-
ural products.2 Therefore, the development of new synthetic
methods leading to b-amino carbonyl compounds or their
derivatives has attracted much attention. However, the clas-
sic Mannich reaction has limited applications. To overcome
the drawbacks of the classic method, numerous modern ver-
sions of the Mannich reaction using performed electrophiles,
such as imines and stable nucleophiles, such as enolates,
enol ethers, and enamines3 have been developed. But the
preferred route is to use a one-pot three-component strategy
that gives a wide range of structural variations. Furthermore,
only a few one-pot procedures on the use of unmodified
aldehydes or ketones have been reported in the literature
and a variety of catalysts, Zn(OTf)2,4 H3PW12O40,5
ZrOCl2$8H2O,6 (S)-serine,7 DBSA,8 SDS–HCl,9–11
Bi(OTf)3$4H2O,12 sodium tetrakis(3,5-trifluoromethyl-
2. Results and discussion
Initially, the three-component Mannich reaction of benzal-
dehyde (2.0 mmol), aniline (2.0 mmol), and cyclohexanone
(2.1 mmol) was examined. To optimize reaction condition,
some solvents were screened in the model reaction. The
results are shown in Table 1. Entries 1a–1f showed the effect
of various solvents. Interestingly, the Mannich reaction
Ar' NH
Ar
O
O
Ar' NH
Ar
O
OSO3H
EtOH, r.t.
+
+
+
Ar CHO
Ar' NH2
anti
syn
1
2
3
4
5
Scheme 1. Direct Mannich-type reactions of aromatic aldehydes, anilines, and cyclohexanone.
Keywords: Direct Mannich-type reaction; b-Amino ketones; Silica sulfuric acid; Synthesis.
* Corresponding author. Tel.: +86 0516 83500349; fax: +86 0516 83403164; e-mail: wuhui72@yahoo.com.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.015

H. Wu et al. / Tetrahedron 63 (2007) 2404–2408
2405
Table 1. Mannich reactions of benzaldehyde (2.0 mmol), aniline
(2.0 mmol), and cyclohexanone (2.1 mmol) under different conditions
It has to be mentioned that our protocol used stoichiometric
cyclohexanone, while other protocols took excessive cyclo-
hexanone (1.7–6.0 equiv), for example, when H3PW12O40,5
ZrOCl2$8H2O,6 DBSA,8 SDS–HCl,9–11 etc. were used as
catalysts.
Entry
Solvent
SSA (mol %)
Yieldsa (%)
anti/syn
1a
1b
1c
1d
1e
1f
1g
1h
1i
MeOH
CH3CN
CH2Cl2
Ethyl acetate
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
0.04
0.04
0.04
0.04
0.04
0.04
0.02
0.06
0.08
0.1
53
60
50
20
nrb
96
77
59
55
18
80:20
99:1
82:12
99:1
—
85:15
84:16
80:20
80:20
81:19
The anti and syn isomers were identified by the coupling
constants (J) of the vicinal protons adjacent to C]O and
1
NH in their H NMR spectra.19 J signal of anti isomer is
higher than that of the syn one. The anti/syn ratio was
determined by 1H NMR judged by the intensity of the
H1 (Scheme 2).
1j
a
Yield of isolated products.
No reaction.
b
Ar'
Ar'
NH
O
NH
H1
O
H1
showed an intriguing solvent effect; excellent anti selectivity
was observed in CH3CN and ethyl acetate, whereas the yields
of the reaction exhibited were low (20% and 60%). Com-
pared with MeOH, CH2Cl2, and H2O, EtOH showed high
yield and good stereoselectivity. Therefore, we chose EtOH
as the solvent for high yield and good anti selectivity of the
reaction. The optimum amount of catalyst (0.04 mol %) was
determined from experiments corresponding to entries 1f–1j.
When the amount of SSA was higher than 0.04 mol %, the
yield gradually decreased.
Ar
Ar
H
H
syn
anti
Scheme 2. Identification of anti and syn isomers by 1H NMR spectroscopy.
Interestingly, the b-amino ketones in Table 2 show that the
anti isomer is much more favored than syn isomer with the
exception of entry 2n (anti/syn¼11:89). The possible transi-
tion states are proposed in Scheme 3. If hydrogen bonds are
formed among SSA, the imine and the enol form of cyclo-
hexanone, the aryl groups of aldimine would be anti to
each other and there should be less steric repulsion in _, be-
tween the methylene groups of cyclohexanone and aryl
group on the carbon atom, as well as SSA and H1. So the
most stable transition state I would produce the anti isomer
III (Scheme 3). The encouraging results prompted us to use
other ketones such as acetophenone (Scheme 4). When
0.06 mol % SSAwas used, b-amine ketones 7 were obtained
in high yields. Table 3 clearly demonstrates that SSA is a
good catalyst for Mannich reaction in EtOH. Acetophenone
was less reactive than cyclohexanone and needed more
catalyst, longer reaction time to afford the desired products.
It was found that the electronic effect of substitutes had some
influence on the yields. For example, when there was an
electron withdrawing group of aromatic aldehyde (entry 3d),
the reaction time was longer (17 h), and the yield was
lower (60%).
In our initial experiments, we found that aromatic aldehydes
1, anilines 2, and cyclohexanone 3 in EtOH were stirred in
the presence of a catalytic amount (0.04 mol %) of SSA
at room temperature for 3–6 h to give the corresponding b-
amino carbonyl compounds 4. As shown in Table 2, the
reaction of different aromatic aldehydes, anilines, and cyclo-
hexanone gave the b-amino ketone adduct in good to high
yield with good to excellent anti selectivity at room temper-
ature, but the benzaldehyde with strong electron withdraw-
ing group almost did not work (Table 2, entry 2h).
High anti selectivity was obtained with various substituted
benzaldehydes except for 4-chlorobenzaldehyde (Table 2,
entry 2l).
Table 2. Direct Mannich-type reactions of aromatic aldehydes, anilines, and
cyclohexanonea
2
Entry Ar1
Ar0
Time (h) Yieldsb (%) anti/sync
HO3SO
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2-OCH3C6H4
2-ClC6H4
2-BrC6H4
2,3-OCH3C6H3
4-OCH3C6H4
4-CH3C6H4
2,5-OCH3C6H3
4-NO2C6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5
6
6
6
4
6
6
6
3
4
5
6
6
6
89
83
81
91
90
80
75
nrd
96
89
82
83
92
85
99:1
86:14
99:1
95:5
99:1
99:1
99:1
—
85:15
99:1
99:1
75:25
99:1
11:89
O
H
Si
O
O
Ar2
Ar2 NH
Ar1
O
O
H
Ar2
H1
HN
O
N
H
Ar1
H
H
H
anti
III
Ar1
H
I
II
H
4-CH3C6H4
2-ClC6H4
4-ClC6H4
3-ClC6H4
3-CH3C6H4
Scheme 3. Possible transition states.
NH2
COCH3
Ph NH
Ar
O
OSO3H
EtOH, r.t.
a
+
Ar CHO
+
Reaction conditions: aldehydes (2 mmol), anilines (2 mmol), cyclohexa-
none (2.1 mmol), and SSA (0.04 mol %).
Yield of isolated products.
b
c
1
2
6
7
Diastereomeric ratio measured by 1H NMR spectroscopy analysis of the
crude reaction mixture.
No reaction.
Scheme 4. Mannich-type reactions of aromatic aldehydes, anilines, and
acetophenone.
d

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H. Wu et al. / Tetrahedron 63 (2007) 2404–2408
Table 3. Mannich-type reactions of aromatic aldehydes, anilines, and aceto-
4.4. Preparation and recycling of SSA
phenonea
SSA was prepared according to Mohammad Ali Zolfigol’s
procedure.20 The catalyst was separated in the first stage of
the above work up procedure. The residue was washed with
95% EtOH and dried at 110 ꢁC for 12 h to give pure SSA for
further runs.
Entry
Ar
Time (h)
Yieldsb (%)
3a
3b
3c
3d
3e
3f
C6H5
12
15
14
17
14
13
92
80
81
60
70
71
4-CH3C6H4
4-OCH3C6H4
4-BrC6H4c
2-ClC6H4
2,3-OCH3C6H3
The known compounds (entries 2f, 2i, and 2l in Table 2 and
entries 3a–3d in Table 3) have been identified by comparison
of spectral data with those reported.4–6,19d
a
Reaction conditions: aldehydes (2 mmol), amine (2 mmol), acetophenone
(2.1 mmol), and SSA (0.06 mol %).
Yield of isolated products.
b
c
SSA (0.08 mol %) was used.
4.5. Spectral data of new products
4.5.1. 2-((2-Methoxyphenyl)(phenylamino)methyl)cyclo-
hexanone (4a). H NMR (400 MHz, CDCl3) d: 7.40 (d,
1
3. Conclusion
J¼6.4 Hz, 1H), 7.20 (t, J¼8.0 Hz, 1H), 7.08 (t, J¼8.0 Hz,
2H), 6.87–6.92 (m, 2H), 6.58–6.65 (m, 2H), 5.02 (d,
J¼6.8 Hz, 1H), 2.90–2.94 (m, 1H), 2.33–2.47 (m, 2H),
1.59–1.99 (m, 6H); IR (KBr, n, cmꢀ1): 3349.19, 1698.92,
1600.50, 1516.68, 854.14; 13C NMR (100 MHz, CDCl3) d:
213.50, 156.92, 147.06, 129.13, 128.75, 128.71, 127.93,
127.75, 120.52, 116.93, 113.12, 109.91, 55.71, 55.10, 52.20,
41.57, 31.47, 27.95, 23.38; Calcd for C20H23NO2: C, 77.64;
H, 7.49; N, 4.53. Found: C, 77.60; H, 7.53; N, 4.50.
In summary, good anti selectivity has been observed in the
SSA-catalyzed direct-type Mannich reaction in EtOH. The
significant features of this procedure include: (1) high yields;
(2) good stereoselectivities; (3) facile operations; (4) recy-
clable catalysts; and (5) non-toxic solvents.
4. Experimental
4.1. General
4.5.2. 2-((2-Chlorophenyl)(phenylamino)methyl)cyclo-
hexanone (4b). H NMR (400 MHz, CDCl3) d: 7.59 (d,
1
All reagents were purchased from commercial sources and
used without further purification. TLC analysis was per-
formed with glass backed plates precoated with silica gel
and examined under UV (254 nm). NMR spectra were mea-
sured in CDCl3 with Me4Si as the internal standards on
a Bruker Advance DPX-400 at room temperature. IR spectra
were recorded on Bruker FTIR spectrometer, absorbances
are reported in cmꢀ1. Elemental analyses were performed
on a Perkin–Elmer-2400 elemental analyzer.
J¼7.2 Hz, 1H), 7.35 (d, J¼7.2 Hz, 1H), 7.09–7.22 (m,
2H), 5.36 (d, J¼3.6 Hz, 0.14H), 5.26 (br s, 1H), 4.92 (d,
J¼4.4 Hz, 0.86H), 2.95–2.99 (m, 1H), 2.30–2.41 (m, 2H),
1.96–2.14 (m, 4H), 1.59–1.85 (m, 2H); IR (KBr, n, cmꢀ1):
3396.45, 1697.69, 1601.76, 1502.64, 809.08; 13C NMR
(100 MHz, CDCl3) d: 212.91, 146.67, 138.92, 133.05,
129.57, 129.24, 129.03, 128.91, 128.77, 128.72, 127.97,
126.80, 126.68, 117.74, 117.28, 113.81, 113.07, 55.15,
55.10, 53.84, 53.03, 42.58, 42.06, 32.43, 27.86, 27.25,
26.86, 24.66, 24.55; Calcd for C19H20ClNO: C, 72.72; H,
6.42; N, 4.46. Found: C, 72.68; H, 6.32; N, 4.40.
4.2. General procedure for the synthesis of b-amino
carbonyl compounds 4
4.5.3. 2-((2-Bromophenyl)(phenylamino)methyl)cyclo-
hexanone (4c). H NMR (400 MHz, CDCl3) d: 7.61 (d,
1
A mixture of benzaldehyde (2.0 mmol), aniline (2.0 mmol),
cyclohexanone (2.1 mmol), and SSA (0.11 g, 0.04 mol %)
was stirred in EtOH (3 mL) at room temperature for 3–6 h.
The reaction was monitored in TLC. Upon and on comple-
tion, CH2Cl2 was added and catalyst was removed by filtra-
tion. Filtrates were washed with saturated NaHCO3(aq) and
brine, dried with anhydrous Na2SO4, and concentrated to
dryness. The crude mixture was subjected to flash column
chromatography.
J¼8.0 Hz, 1H), 7.53 (dd, J¼1.2, 8.4 Hz, 1H), 7.24 (t,
J¼7.6 Hz, 1H), 7.05–7.13 (m, 3H), 6.66 (t, J¼7.2 Hz, 1H),
6.54 (d, J¼8.0 Hz, 1H), 5.50 (br s, 1H), 2.98–3.01 (m,
1H), 2.96–3.02 (m, 2H), 2.29–2.96 (m, 2H), 1.99–2.20 (m,
2H), 1.75–1.85 (m, 2H); IR (KBr, n, cmꢀ1): 3390.40,
1697.71, 1600.70, 1501.84, 806.92; 13C NMR (100 MHz,
CDCl3) d: 212.89, 146.69, 140.43, 132.31, 129.01, 128.90,
128.28, 127.34, 123.61, 117.23, 113.11, 57.59, 54.99,
42.80, 32.74, 27.85, 24.80; Calcd for C19H20BrNO: C,
63.70; H, 5.63; N, 3.91. Found: C, 63.60; H, 5.69; N, 3.96.
4.3. General procedure for the synthesis of b-amino
carbonyl compounds 7
4.5.4. 2-((2,3-Dimethoxyphenyl)(phenylamino)methyl)-
cyclohexanone (4d). H NMR (400 MHz, CDCl3) d: 7.11
1
A mixture of benzaldehyde (2.0 mmol), aniline (2.0 mmol),
acetophenone (2.0 mmol), and SSA (0.17 g, 0.06 mol %)
was stirred in EtOH (3 mL) at room temperature for
12–17 h. The reaction was monitored in TLC. Upon and on
completion, CH2Cl2 was added and catalyst was removed
byfiltration. FiltrateswerewashedwithsaturatedNaHCO3(aq)
and brine, dried with anhydrous Na2SO4, and concentrated
to dryness. The crude mixture was subjected to flash column
chromatography.
(t, J¼8.0 Hz, 2H), 7.05 (d, J¼7.6 Hz, 1H), 7.00 (t,
J¼8.0 Hz, 1H), 6.79 (t, J¼7.6 Hz, 1H), 6.62–6.68 (m, 3H),
5.22 (d, J¼4.2 Hz, 0.05H), 4.96 (d, J¼7.6 Hz, 0.95H),
3.95 (s, 3H), 3.87 (s, 3H), 2.90–3.00 (m, 1H), 2.30–2.44
(m, 2H), 1.70–1.96 (m, 6H); IR (KBr, n, cmꢀ1): 3334.72,
1703.50, 1601.57, 1528.75, 813.21; 13C NMR (100 MHz,
CDCl3) d: 213.24, 151.97, 147.11, 146.53, 134.68, 128.10,
128.74, 123.53, 119.76, 117.07, 113.72, 113.26, 110.79,

H. Wu et al. / Tetrahedron 63 (2007) 2404–2408
2407
60.24, 56.29, 55.34, 53.00, 41.88, 31.95, 27.97, 23.78; Calcd
for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.21;
H, 7.48; N, 4.15.
1525.80, 829.73; 13C NMR (100 MHz, CDCl3) d: 212.46,
148.22, 140.91, 134.49, 129.76, 128.29, 127.07, 126.87,
117.11, 113.01, 111.55, 57.79, 57.07, 41.73, 31.36, 27.68,
23.60; Calcd for C19H20ClNO: C, 72.72; H, 6.42; N, 4.46.
Found: C, 72.682; H, 6.50; N, 4.41.
4.5.5. 2-((4-Methoxyphenyl)(phenylamino)methyl)cyclo-
hexanone (4e). H NMR (400 MHz, CDCl3) d: 7.27 (d,
1
J¼8.4 Hz, 2H), 7.12 (d, J¼7.6 Hz, 2H), 7.10 (t, J¼8.0 Hz,
2H), 6.64 (t, J¼7.2 Hz, 1H), 6.65 (d, J¼8.4 Hz, 2H), 4.71
(br s, 1H), 4.62 (d, J¼7.2 Hz, 1H), 2.72–2.76 (m, 1H),
2.42–2.47 (m, 1H), 2.34–2.38 (m, 1H), 1.83–1.93 (m, 4H),
1.68–1.75 (m, 3H); IR (KBr, n, cmꢀ1): 3332.42, 1707.26,
1600.92, 1532.21, 800.33; 13C NMR (100 MHz, CDCl3) d:
212.74, 147.01, 138.36, 136.45, 128.91, 128.77, 126.86,
117.16, 113.34, 57.39, 57.30, 41.43, 30.92, 27.92, 23.28,
20.81; Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.44; H, 7.59; N, 4.54.
4.5.10. 2-((m-Toluidino)(phenyl)methyl)cyclohexanone
(4n). H NMR (400 MHz, CDCl3) d: 7.39 (d, J¼7.2 Hz,
1
2H), 7.31 (t, J¼7.6 Hz, 2H), 7.23 (t, J¼7.2 Hz, 1H), 6.98
(t, J¼8.0 Hz, 1H), 6.49 (d, J¼8.0 Hz, 1H), 6.43 (s, 1H),
6.35 (d, J¼8.0 Hz, 1H), 4.82 (d, J¼4.0 Hz, 0.89H), 4.64
(d, J¼7.2 Hz, 0.11H), 4.47 (br s, 1H), 2.76–2.82 (m, 1H),
2.42–2.46 (m, 1H), 2.28–2.36 (m, 1H), 2.22 (s, 3H), 2.03–
2.09 (m, 2H), 1.91 (d, J¼6.8 Hz, 1H); IR (KBr, n, cmꢀ1):
3386.31, 1695.13, 1602.90, 1524.73, 802.64; 13C NMR
(100 MHz, CDCl3) d: 211.06, 147.21, 141.42, 138.42,
128.67, 128.62, 128.18, 128.08, 127.21, 126.95, 126.84,
126.67, 118.39, 118.23, 114.71, 110.71, 110.22, 57.24,
56.91, 56.39, 42.14, 41.46, 30.98, 28.45, 27.63, 26.77,
24.58, 23.33, 21.32; Calcd for C20H23NO: C, 81.87; H,
7.90; N, 4.77. Found: C, 81.82; H, 7.99; N, 4.76.
4.5.6. 2-((2,5-Dimethoxyphenyl)(phenylamino)methyl)-
cyclohexanone (4g). 1H NMR (400 MHz, CDCl3) d: 7.08 (t,
J¼8.0 Hz, 2H), 6.95 (d, J¼7.6 Hz, 1H), 6.8 (d, J¼8.4 Hz,
1H), 6.70 (dd, J¼2.8, 9.6 Hz, 1H), 6.62 (t, J¼7.2 Hz, 1H),
6.56 (t, J¼8.0 Hz, 2H), 5.99 (d, J¼7.2 Hz, 1H), 5.85 (br s,
1H), 3.89 (s, 3H), 3.74 (s, 3H), 2.81–2.86 (m, 1H), 2.41–2.47
(m, 1H), 2.31–2.35 (m, 1H), 1.85–2.00 (m, 4H), 1.58–1.79
(m, 2H); IR (KBr, n, cmꢀ1): 3353.70, 1702.06, 1602.54,
1531.01, 813.29; 13C NMR (100 MHz, CDCl3) d: 213.41,
153.41, 151.24, 146.98, 130.47, 128.25, 117.01, 114.72,
114.05, 113.16, 112.00, 110.76, 55.87, 55.56, 55.28,
52.14, 41.46, 31.30, 27.93, 23.26; Calcd for C21H25NO3:
C, 74.31; H, 7.42; N, 4.13. Found: C, 74.30; H, 7.53; N, 4.12.
4.5.11. 3-(2-Chlorophenyl)-1-phenyl-3-(phenylamino)-
propan-1-one (7e). H NMR (400 MHz, CDCl3) d: 8.0 (d,
1
J¼8.4 Hz, 2H), 7.55–7.61 (m, 2H), 7.50 (t, J¼7.6 Hz, 2H),
7.41–7.44 (m, 1H), 7.19–7.21 (m, 2H), 7.10 (t, J¼8.0 Hz,
2H), 6.67 (t, J¼7.6 Hz, 1H), 6.50 (d, J¼8.4 Hz, 2H), 5.33
(t, J¼4.0 Hz, 1H), 4.93 (br s, 1H), 3.65 (dd, J¼4.0,
14.4 Hz, 1H), 3.20 (dd, J¼8.8, 15.6 Hz, 1H); IR (KBr, n,
cmꢀ1): 3400.44, 1675.45, 1599.81, 1519.11, 873.80; 13C
NMR (100 MHz, CDCl3) d: 198.27, 146.19, 139.23,
136.18, 133.29, 132.07, 129.55, 128.84, 128.45, 128.27,
128.10, 127.81, 127.17, 117.60, 113.32, 51.73, 43.50; Calcd
for C21H18ClNO: C, 75.11; H, 5.40; N, 4.17. Found: C,
75.01; H, 5.50; N, 4.10.
4.5.7. 2-((p-Toluidino)(phenyl)methyl)cyclohexanone
1
(4j). H NMR (400 MHz, CDCl3) d: 7.39 (d, J¼7.2 Hz,
2H), 3.32 (t, J¼7.6 Hz, 2H), 7.23 (t, J¼7.6 Hz, 1H), 6.90
(d, J¼8.0 Hz, 2H), 6.51 (d, J¼7.6 Hz, 2H), 4.61 (d,
J¼7.6 Hz, 1H), 2.80–2.82 (m, 1H), 2.34–2.48 (m, 2H),
2.19 (s, 3H), 1.86–1.95 (m, 6H); IR (KBr, n, cmꢀ1):
3406.42, 1702.39, 1620.45, 1524.27, 805.21; 13C NMR
(100 MHz, CDCl3) d: 212.65, 144.61, 141.56, 129.27,
129.17, 126.99, 126.83, 126.40, 113.48, 57.91, 57.26,
41.41, 30.90, 27.61, 23.31, 20.05; Calcd for C20H23NO: C,
81.87; H, 7.90; N, 4.77. Found: C, 81.80; H, 7.91; N, 4.70.
4.5.12. 3-(2,3-Dimethoxyphenyl)-1-phenyl-3-(phenyl-
amino)propan-1-one (7f). H NMR (400 MHz, CDCl3) d:
1
8.07 (d, J¼8.0 Hz, 2H), 7.58 (t, J¼7.6 Hz, 1H), 7.47 (t,
J¼7.6 Hz, 2H), 7.09 (t, J¼8.0 Hz, 2H), 7.00 (t, J¼8.0 Hz,
2H), 6.85 (d, J¼7.6 Hz, 1H), 6.65 (t, J¼7.6 Hz, 1H), 6.55
(d, J¼8.0 Hz, 2H), 5.20 (t, J¼4.4 Hz, 1H), 4.70 (br s, 1H),
4.04 (s, 3H), 3.92 (s, 3H), 3.73 (dd, J¼4.4, 8.4 Hz, 1H),
3.18 (dd, J¼9.2, 14.8 Hz, 1H); IR (KBr, n, cmꢀ1): 3400.68,
1683.59, 1600.33, 1523.52, 866.12; 13C NMR (100 MHz,
CDCl3) d: 189.90, 156.19, 152.60, 152.24, 149.91, 129.68,
129.01, 128.84, 125.65, 124.03, 123.91, 120.76, 118.94,
118.25, 117.83, 114.81, 114.74, 62.11, 61.67, 55.78, 55.65;
Calcd for C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found:
C, 76.40; H, 6.53; N, 3.80.
4.5.8. 2-((2-Chlorophenylamino)(phenyl)methyl)cyclo-
hexanone (4k). H NMR (400 MHz, CDCl3) d: 7.39 (d,
1
J¼7.6 Hz, 2H), 7.33 (t, J¼7.6 Hz, 2H), 7.24–7.26 (m, 2H),
6.96 (t, J¼7.6 Hz, 1H), 6.58 (t, J¼7.6 Hz, 1H), 6.49 (d,
J¼8.0 Hz, 1H), 5.5 (br s, 1H), 4.72 (d, J¼6.4 Hz, 1H),
2.87–2.89 (m, 1H), 2.20–2.49 (m, 2H), 1.27–2.02 (m, 6H);
IR (KBr, n, cmꢀ1): 3391.50, 1701.95, 1595.43, 1500.10,
811.33; 13C NMR (100 MHz, CDCl3) d: 211.77, 142.93,
140.83, 128.78, 128.25, 127.28, 127.02, 126.96, 119.44,
117.14, 112.04, 57.56, 57.13, 41.85, 31.36, 27.65, 23.87;
Calcd for C19H20ClNO: C, 72.72; H, 6.42; N, 4.46. Found:
C, 72.68; H, 6.50; N, 4.40.
Acknowledgements
We are grateful to the foundation of the ‘Natural Science
Research Project of University in Jiangsu Province’
(No. JH03-038) and the ‘Post-doctor Foundation of Xuzhou
Normal University’ (No. 2003009).
4.5.9. 2-((3-Chlorophenylamino)(phenyl)methyl)cyclo-
hexanone (4m). H NMR (400 MHz, CDCl3) d: 7.31–7.38
1
(m, 4H), 7.25 (t, J¼6.8 Hz, 1H), 6.98 (t, J¼8.0 Hz, 1H),
6.60 (d, J¼7.6 Hz, 1H), 6.52–6.53 (m, 1H), 6.41–6.43 (m,
1H), 4.89 (br s, 1H), 4.57 (d, J¼6.4 Hz, 1H), 2.76–2.81
(m, 1H), 2.32–2.47 (m, 2H), 1.91–2.00 (m, 4H), 1.70–1.86
(m, 2H); IR (KBr, n, cmꢀ1): 3342.02, 1701.50, 1599.60,
References and notes
1. (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. 1998, 37, 1044; (b) Kobayashi, S.; Ishitani, H. Chem.

2408
H. Wu et al. / Tetrahedron 63 (2007) 2404–2408
Rev. 1999, 99, 1069; (c) Mannich, C.; Krosche, W. Arch.
Pharm. 1912, 250, 674.
2. (a) Muller, R.; Goesmann, H.; Waldmann, H. Angew. Chem.,
Int. Ed. 1999, 38, 184; (b) Bohme, H.; Haake, M. Advances
in Organic Chemistry; Taylor, E. C., Ed.; Wiley: New York,
NY, 1976; p 107.
8. Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1, 1965.
9. Akiyama, T.; Matsuda, K.; Fuchibe, K. Synlett 2005, 322.
10. Matsuda, K.; Mori, Y.; Kobayashi, S. Tetrahedron 2001, 57,
2537.
11. Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999,
1045.
3. (a) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125,
338; (b) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 4712; (c) Juhl, K.;
Gathergood, N.; Jørgensen, K. A. Angew. Chem. 2001, 113,
3083; (d) List, B. J. Am. Chem. Soc. 2000, 122, 9336; (e)
List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827; (f) Cordova, A.; Notz, W.;
Zhong, G.; Betancort, J. M.; Barbas, C. F. J. Am. Chem. Soc.
2002, 124, 1842; (g) Kobayashi, S.; Hamada, T.; Manabe, K.
J. Am. Chem. Soc. 2002, 124, 5640; (h) Hayashi, Y.; Tsuboi,
W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew.
Chem., Int. Ed. 2003, 42, 3677; (i) Wenzel, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 12964.
4. (a) Wang, Y. G.; Yang, Y. Y.; Shou, W. G. Tetrahedron 2006, 62,
10079; (b) Wang, Y. G.; Yang, Y. Y.; Shou, W. G. Tetrahedron
Lett. 2006, 47, 1845.
5. Azizi, N.; Torkiyan, L.; Saidi, M. R. Org. Lett. 2006, 8, 2079.
6. Eftekhari-Sis, B.; Abdollahifa, A.; Hashemi, M. M.; Zirak, M.
Eur. J. Org. Chem. 2006, 2006, 5152.
12. Ollevier, T.; Nadeau, E.; Guay-Begin, A. A. Tetrahedron Lett.
2006, 47, 8351.
13. Chang, C. T.; Liao, B. S.; Liu, S. T. Tetrahedron Lett. 2006, 47,
9257.
14. Iimura, S.; Nobutou, D.; Manabe, K.; Kobayashi, S. Chem.
Commun. 2003, 1644.
15. Peyman, S.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M.
Tetrahedron Lett. 2005, 46, 7051.
16. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M. B.
Tetrahedron Lett. 2003, 44, 2889.
17. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron
Lett. 2005, 46, 2105.
18. Wu, H.; Shen, Y.; Fan, L. Y.; Wan, Y.; Shi, D. Q. Tetrahedron
2006, 62, 7995.
19. (a) Loh, T. P.; Liung, S. B. K. W.; Tan, K. L.; Wei, L. L.
Tetrahedron 2000, 56, 3227; (b) Gennari, C.; Venturini, I.;
Gislon, F.; Schimperma, G. Tetrahedron Lett. 1987, 28, 227;
(c) Guanti, G.; Narisano, E.; Banfi, L. Tetrahedron Lett.
1987, 28, 4331; (d) Ollevier, T.; Nadeau, E. J. Org. Chem.
2004, 69, 9292.
7. Ibrahem, I.; Zou, W. B.; Enggvist, M.; Xu, Y. M.; Cordova, A.
Chem.—Eur. J. 2005, 11, 7024.
20. Zolfigol, M. A. Tetrahedron 2001, 57, 9509.