High stereoselective Mannich reaction catalyzed by Starch sulfonic acid in water

Article abstract of DOI:10.2174/157017809789124920

Starch sulfonic acid was used as efficient and highly stereoselective catalyst for the three-component Mannich reaction of aldehydes, amines, and ketones in water at ambient temperature to afford the corresponding β-amino ketones in good to excellent stereoselectivity and yields.

Full text of DOI:10.2174/157017809789124920

456
Letters in Organic Chemistry, 2009, 6, 456-461
High Stereoselective Mannich Reaction Catalyzed by Starch Sulfonic Acid
in Water
Yu Wana,b, Wei Lina, Xiu-Mei Chena, Yang Shena, Hai-Qiang Xina, Hua-Hong Xua, Rui Yuana,
Li-Ling Panga, Rui Maa, Cai-Hui Yuea, Wei Yina, Rong-Cheng Boa and Hui Wu*,a,b
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, P. R. China
bKey Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Xuzhou 221116, P. R. China
Received February 13, 2009: Revised May 15, 2009: Accepted May 15, 2009
Abstract: Starch sulfonic acid was used as efficient and highly stereoselective catalyst for the three-component Mannich
reaction of aldehydes, amines, and ketones in water at ambient temperature to afford the corresponding ꢀ-amino ketones
in good to excellent stereoselectivity and yields.
Keywords: Highly stereoselective, Mannich reaction, Starch sulfonic acid.
Recently the emphasis of science and technology is
shifting more towards sustainable resources and processes, in
this regard biopolymers are attractive candidates to explore
for supported catalysis. Starch is the cheapest and totally
biodegradable natural biopolymer. To the best of our
knowledge, starch has been widely used as surfactant in
organic chemistry [1]. The reports about the combinations of
starch and acid such as amino acid, fatty acid, sulfuric acid
for organic synthesis were also studied recently [2-4]. In
addition, sulfonic acid is often used as Brønsted acid to
as reactant have been reported and a variety of stereo-
selective or asymmetric catalysts such as (L)-proline [9], (S)-
proline [10], sulfonated amino acids [11], (S)- proline [12],
acyclic chiral amines and amino acids [13], and silica
sulfuric acid [14], have been investigated. In recent years,
Mannich reaction using water as media has received much
attention [15-17].
As a part of our interest in Mannich reactions, herein we
reported a SSA catalyzed highly stereoselective one-pot
three-component Mannich reaction of aldehydes, amines and
Ar' NH
Ar
O
Ar' NH
Ar
O
O
starch
OSO3H
( 0.08 g)
+
+
Ar CHO
Ar' NH2
+
Water (3 mL), r.t., 2-5h
anti
syn
3
1
2
5
4
Scheme 1. Mannich reaction of aromatic aldehydes, arylamines and cyclohexanone.
catalyze some important reactions [5]. These applications
enlightened us to synthesize starch sulfuric acid (SSA) and
use it as catalyst in organic synthesis. SSA has ever been
used as catalyst for the preparation of quinidines via
Fridedländer reaction [6]. In our previous work [7], it has
also been synthesized and successfully used as catalyst to
promote some interesting reaction.
ketones using water as the reaction medium at ambient
temperature to afford the corresponding ꢀ-amino ketones in
good to excellent stereoselectivity and yields (Scheme 1).
At the beginning, SSA and some other Brønsted and
Lewis acid was tested in the Mannich reaction of
benzaldehyde (2.0 mmol), aniline (2.0 mmol) and
cyclohexanone (2.1 mmol) (Table 1). The reaction was
carried out at room temperature in water for 2 h. No product
was detected in the control reaction. Acids including silica
sulfuric acid, TsOH and surfactant such as sodium dodecyl
sulfate (SDS) (entries 1, 4, 5, Table 1) could not catalyze this
reaction. Dodecylbenzenesulfonic acid (DBSA) (entry 2,
Table 1) and SDS-HCl (entry 3, Table 1) could promote this
reaction with good yield and stereoselectivity, but it is
difficult to separate the product from mixture due to the
formation of emulsions. SSA afforded the highest yield and
excellent anti stereoselectivity because of its combination of
high polarity and water solubility (entries 8-10, Table 1).
These two important characters are necessary to form
ꢀ-Amino carbonyl compounds prepared from Mannich
reaction are very important synthetic intermediates in the
synthesis of pharmaceuticals and natural products [8].
Therefore, much attention has been drawn to the
development of new synthetic methods to prepare these
compounds. High stereoselective or asymmetric direct
Mannich reaction using the unmodified aldehydes or ketones
*Address correspondence to this author at the School of Chemistry and
Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, P. R.
China; Tel: +86051683403163; Fax: +86051683403164;
E-mail: wuhui72@yahoo.com.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

High Stereoselective Mannich Reaction Catalyzed
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
457
Table 1. One-Pot Mannich Reaction of Benzaldehyde (2.0 mmol), Aniline (2.0 mmol), and Cyclohexanone (2.1 mmol) in Water
Entry
Catalyst
X (g)
Yield (%)a
anti:sync
1
2
silica sulfuric acid
DBSA
10
10
Nrb
97
-
74:26
99:1
-
3
SDS-HCl
10
87
4
TsOH
10
Nrb
Nrb
84
5
SDS
10
-
6
H3PMo12O40
starch sulfuric acid
starch sulfuric acid
starch sulfuric acid
starch sulfuric acid
10
63:37
-
7
0
Nrb
8
0.04
0.08
0.12
90
99:1
99:1
99:1
9
95
10
85
aIsolated yield. bNo reaction. cDiastereomeric ratio is measured by HNMR spectroscopic analysis of the crude products.
colloidal dispersion, which can increase the water solubility
of organic reactants in water. Although these organic
reactants have low solubility in water, the Mannich reactions
were successfully catalyzed by SSA at room temperature.
We thought that SSA was used not only as a Brønsted acid
but also a surfactant and the reactions took place at the
interface of organic materials in water. Double catalytic
loading of starch sulfonic acid from 0.04 g to 0.08 g
improved the yield slightly from 90% to 95% (entries 8-9,
Table 1). However, the yield decreased unexpectedly when
the amount of catalyst was over 0.08 g (Table 1, entries 10),
thus 0.08 g starch sulfonic acid is suitable choice for
optimum yield of ꢀ-amino ketones (entry 9, Table 1).
The anti and syn isomers were identified by the coupling
constants (J) value between the vicinal protons adjacent to
C=O and NH in 1H NMR spectra [18]. The anti/syn ratio was
determined by 1H NMR.
Aromatic aldehydes 1, anilines 2, and cyclohexanone 3 in
water were stirred in the presence of a catalytic amount (0.08
g) of starch sulfonic acid at room temperature for 2-5 h to
give the corresponding ꢀ-Amino carbonyl compounds
compounds (Table 2) in good to high yield with good to
excellent anti selectivity at room temperature, except the
benzaldehyde bearing strong electron withdrawing group
(entry 4h, Table 2).
Table 2. Direct Mannich-Type Reactions of Aromatic Aldehydes, Arylamines, and Cyclohexanonea
Comp.
Ar
Ar'
t (h)
Anti/synb
Yield (%)c
4a
4b
4c
4d
4e
4f
C6H5
2-OCH3C6H4
3,4,5-OCH3C6H2
4-CH3C6H4
2,3-OCH3C6H3
3,5-OCH3C6H3
2,6-OCH3C6H3
4-NO2 C6H4
C6H5
C6H5
C6H5
2
4
3
5
4
3
3
12
2
2
3
4
2
3
4
5
99:1
99:1
99:1
99:1
95:5
99:1
99:1
-
98
84
92
85
78
81
87
Nrd
78
84
78
87
98
89
82
81
C6H5
C6H5
C6H5
C6H5
4g
4h
4i
C6H5
C6H5
3-CH3C6H4
3-ClC6H4
4-CH3C6H4
3-Cl-4-FC6H3
4-ClC6H4
3-Cl-4-CH3C6H3
4-FC6H4
3-Cl-2-CH3C6H3
88:12
70:30
88:12
97:3
95:5
99:1
84:16
95:5
4j
C6H5
4k
4l
C6H5
C6H5
4m
4n
4o
4p
C6H5
C6H5
C6H5
C6H5
aReaction conditions: aldehydes (2.0 mmol), arylamines (2.0 mmol), cyclohexanone (2.1 mmol), and starch sulfonic acid (0.08 g). bDiastereomeric ratio measured by 1H NMR
spectroscopy analysis of the crude reaction mixture. cIsolated yield. dNo reaction.

458 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Wan et al.
O
O
S
Ar2
O
Ar2
O
Ar2
NH
HN
H1
H
O
O
O
O
HO3SO
O
H
O
N
H
Ar1
H
Ar1
O
O
H
H
H
O
S
Ar1
OH
I
III
II
Scheme 2. The proposed Mechanism for SSA catalyzed Mannich reaction.
It should be mentioned that all methods reported required
excess cyclohexanone (1.7-6.0 equiv.), for example, when
H3PW12O40 [19], ZrOCl2·8H2O [20], DBSA[21] , SDS-HCl
[22], (Gn[Me])-Cu(OTf)2 [23] etc. were used as catalyst.
However, only stoichiometric cyclohexanone was used in
our protocol. Moreover, no organic solvent was involved.
Therefore, the workup was easy. As the products were solid
and insoluble in water, the pure products were obtained
directly by filtration and then recrystallization from ethanol
or DMF.
This encouraging result prompted us to test ketones such
as acetophenone (Scheme 3, Table 3). As acetophenone was
less reactive than cyclohexanone, longer reaction time was
necessary to afford the desired products. When 0.08 g of
starch sulfonic acid was used, ꢀ-amino ketones were
obtained with yields ranging from 58% to 78 %. We found
that the electronic effect of substituents had no influence on
the yields.
We also tried to recycle the catalyst. After completion of
the reaction, product was extracted by ethyl acetate and the
water was used for the reaction. As shown in Scheme 4,
when the same reaction was carried out in this solution,
slightly lower yields (85%) of the product were obtained
compared with the first one, but the solution was still
effective for the reaction.
A possible reaction mechanism is outlined in Scheme 3.
We propose that the high steroselectivity of products come
from the characteristic of SSA. If hydrogen bonds are
formed between SSA and the enol form of cyclohexanone,
the aryl groups of aldimine would be anti to each other and
there should be less steric repulsion in I, between 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
2).
In summary, one-pot Mannich reaction in aqueous media
catalyzed by SSA with good anti-selectivity has been
developed. This method has several advantages including
mild reaction conditions, low catalyst loading, and no
formation of by-products such as aldol or deamination
COCH3
starch
OSO3H
( 0.08 g)
Ar' NH
Ar
O
+
Ar' NH2
+
Ar CHO
Water (3mL), r.t., 8-12h
7
1
2
6
Scheme 3. Mannich reaction of aromatic aldehydes, arylamines and acetophenone.
Table 3. Mannich-Type Reactions of Aromatic Aldehydes, Arylamines, and Acetophenonea
Comp.
Ar
Ar'
t (h)
Yield (%)b
7a
7b
7c
7d
7e
7f
C6H5
C6H5
C6H5
3-CH3C6H4
4-OCH3C6H4
4-CH3C6H4
3-ClC6H4
C6H5
12
10
10
8
78
65
58
62
67
60
76
62
61
C6H5
C6H5
C6H5
9
4-OCH3C6H4
4-CH3C6H4
4-ClC6H4
4-BrC6H4
9
7g
7h
7i
C6H5
12
10
12
C6H5
C6H5
aReaction conditions: aldehydes (2.0 mmol), arylamines (2.0 mmol), acetophenone (2.1 mmol), and starch sulfonic acid (0.08 g). bIsolated yield.

High Stereoselective Mannich Reaction Catalyzed
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
459
Ph NH
Ph
O
O
1st: 98% yield
2nd: 85% yield
3rd: 85% yield
4th: 84% yield
starch
OSO3H
( 0.08 g)
Ph CHO
+
Ph NH2
+
Water (3mL), r.t., 8-12h
Scheme 4. Recovered catalyst for Mannich reaction.
[18]
(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.
Azizi, N.; Torkiyan, L.; Saidi, M. R. Org. Lett., 2006, 8, 2079.
Eftekhari-Sis, B.; Abdollahifa, A.; Hashemi, M. M.; Zirak, M. Eur.
J. Org. Chem., 2006, 2006, 5152.
products. In addition, our process involves an
environmentally benign, cheap and easy to handle catalyst.
To the best of our knowledge, this is the first report of a
starch sulfonic acid-catalyzed direct-type Mannich reaction.
Because of its numerous benefits, the protocol should be
very useful in the synthesis of ꢀ-aminocarbonyl compounds
that might have biological activities.
[19]
[20]
[21]
[22]
Manabe, K.; Kobayashi, S. Org. Lett., 1999, 1, 1965.
(a) Akiyama, T.; Matsuda, K.; Fuchibe, K. Synlett, 2005, 322; (b)
Matsuda, K.; Mori, Y.; Kobayashi, S. Tetrahedron, 2001, 57, 2537;
(c) Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett, 1999, 1045.
Muraki, T.; Fujita, K. I.; Terakado, D. Synlett, 2006, 2646.
General procedure: All reagents were purchased from
commercial sources and used without further purification. TLC
analysis was performed with glass backed plates precoated with
silica gel and examined under UV (254 nm). NMR spectra were
measured in CDCl3 with Me4Si as the internal standards on a
Bruker Advance DPX- 400 at room temperature. IR spectra were
recorded on Bruker FT-IR spectrometer, absorbencies were
reported in cm-1. Elemental analyses were performed on a Perkin
Elmer-2400 elemental analyzer. The high-resolution electrospray
ionization (ESI) mass spectra were obtained on Bruker MSTOFQII
mass spectrometer.
General procedure for the synthesis of ꢀ-Amino carbonyl
compounds compounds 4: A mixture of aromatic aldehyde (2.0
mmol), arylamine (2.0 mmol), cyclohexanone (2.1 mmol), and
SSA (0.08 g) was stirred in H2O (3 mL) at room temperature for 2-
5 h. The reaction was monitored by TLC. Ethanol was added upon
completion and catalyst was removed by filtration. The product
was purified by recrystallization with EtOH. The analytical data for
represent compounds are shown below.
General procedure for the synthesis of ꢀ-Amino carbonyl
compounds compounds 7: A mixture of benzaldehyde (2.0
mmol), aniline (2.0 mmol), acetophenone (2.1 mmol), and SSA
(0.08 g) was stirred in H2O (3 mL) at room temperature for 8-12 h.
The reaction was monitored by TLC. Ethanol was added upon
completion and catalyst was removed by filtration. The product
was purified by recrystallization with EtOH. The analytical data for
represent compounds are shown below.
SSA was synthesized following the same procedure reported by us
[7].
The known compounds (4a, 4b, 4d, 7a, 7c, 7f, 7g, 7h, 7i) have
been identified by comparison of spectral date with those reported
[7c, 17d, 18, 19].
ACKNOWLEDGEMENTS
We are grateful for financial support from the National
Science Foundation of China (No. 20772103), Natural
Science Foundation of the Jiangsu Province (No. BK
2007028), the “Qin Lan Project in Jiangsu Province” (No.
QL200607 and No. 08QLT001) and the Post-graduate
Training Innovation Project in Xuzhou Normal University
(No. 09YLB089) for financial support.
[23]
REFERENCES AND NOTES
[1]
Anderson, J. E.; Casarini, D.; Ijeh, A. I.; Lunazzi, L.; Tocher, D. A.
J. Am. Chem. Soc., 1995, 117, 3054.
[2]
(a) Merta, J.; Torkkeli, M.; Ikonen, T.; Serimaa, R.; Stenius, P.
Macromolecules, 2001, 34, 2937; (b) Feitkenhauer, H.; Fischer, D.;
Fäh, D. Biotechnol. Prog., 2003, 19, 874; (c) Merta, J.; Garamus, V.
M.; Kuklin, A. I.; Willumeit, R.; Stenius, P. Langmuir, 2000, 16,
10061.
[3]
[4]
[5]
Ito, A.; Hattorl, M.; Yoshida, T.; Watanabe, A.; Sato, R.; Takahashi,
K. J. Agric. Food Chem., 2006, 54, 10191.
Zhang, G.; Maladen, M. D.; Hamaker, B. R. J. Agric. Food Chem.,
2003, 51, 2801.
(a) Melero, J. A.; Grieken, R.V.; Morales, G. Chem. Rev., 2006,
106, 3790; (b) Iimura, S.; Manabe, K.; Kobayashi, S. J. Org.
Chem., 2003, 68, 8723; (c) Iimura, S.; Manabe, K.; Kobayashi, S.
Org. Lett., 2003, 5, 101; (d) Iimura, S.; Nobutou, D.; Manabe, K.;
Kobayashi, S. Chem. Commun., 2003, 1644; (e) Wu, H.; Shen, Y.;
Fan, L. Y.; Wan, Y.; Shi, D. Q. Tetrahedron, 2006, 62, 7995.
Shaabani, A.; Rahmati, A.; Badri, Z. Catal. Commun., 2008, 9, 13.
Wu, H.; Chen, X. M.; Wan, Y.; Zhang, F. R.; Xin, H. Q.; Xu, H.
H.; Ma, R.; Yue, C. H.; Pang, L. L.; Yuan, R.; Lin, W.; Yin, W.;
Bo, R. C. Asian J. Chem., 2009, 21(4), 2815.
[6]
[7]
[8]
Muller, R.; Goesmann, H.; Waldmann, H. Angew. Chem., 1999,
111, 166. Angew. Chem. Int. Ed. Engl., 1999, 38, 184.
Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc.,
2003, 125, 11208.
Data
2-((3,4,5-trimethoxyphenyl)(phenylamino)methyl)cyclohexan-
one 4c. 1H NMR (400 MHz, CDCl3) ꢁ 7.11 (t, J=7.6 Hz, 2H), 6.67
(t, J=7.6 Hz, 1H), 6.62 (s, 1H), 6.57 (d, J=8.0 Hz, 2H), 4.68 (br. s,
1H), 4.53 (d, J=6.8 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 2.70-2.75 (m, 1H), 2.34-2.47 (m, 2H), 1.84-1.96 (m, 4H),
1.70-1.74 (m, 2H); 13C NMR (100 MHz, CDCl3) ꢁ 222.57, 152.95,
147.05, 137.62, 128.78, 117.39, 113.41, 103.92, 60.53, 58.25,
57.28, 55.86, 41.59, 31.01, 27.60, 23.45; IR (KBr, ꢂ, cm-1):
3336.80, 1703.03, 1592.72, 1497.75, 839.55; HRMS (ESI) calcd
for C22H27NO4 [MH]+, 370.2018; Found: 370.2035; Anal. Calcd for
C22H27NO4: C, 71.52; H, 7.37; N, 3.79 Found: C, 71.50; H, 7.38; N,
3.76%.
2-((2,3-dimethoxyphenyl)(phenylamino)methyl)cyclohexanone
4e. 1H NMR (400 MHz, CDCl3) ꢁ 7.10 (t, J=7.6 Hz, 2H), 7.01 (q,
2H), 6.79 (dd, J=8.0, 2.0 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.60 (d,
J=8.0Hz, 2H), 4.94 (d, J=6.8 Hz, 1H), 4.90 (br. s, 1H), 4.0 (s, 3H),
3.87 (s, 3H), 2.89-2.94 (m, 1H), 2.39-2.43 (m, 1H), 2.28-2.34 (m,
[9]
[10]
[11]
Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew.Chem. Int.
Ed. Engl., 2005, 44, 4079.
Wu, Y. S.; Cai, J. W.; Hu, Z. Y.; Lin, G. X. Tetrahedron Lett.,
2004, 45, 8949.
[12]
[13]
Rodríguez, B.; Bolm, C. J. Org. Chem., 2006, 71, 2888.
Ibrahem, I.; Zou, W.; Engqvist, M.; Xu, M.; Córdova, A. Chem.
Eur. J., 2005, 11, 7024.
[14]
[15]
Wu, H.; Shen, Y.; Fan, L. Y.; Wan, Y.; Zhang, P.; Chen, C. F.;
Wang, W. X. Tetrahedron, 2007, 63, 2404.
Wang, R.; Li, B. G.; Huang, T. K.; Shi, L.; Lu, X. X. Tetrahedron
Lett., 2007, 48, 2071.
[16]
[17]
Manabe, K.; Mori, Y. Tetrahedron, 2001, 57, 2537.
Ollevier, T.; Nadeau, E.; Guay-Bégin, A.-A. Tetrahedron Lett.,
2006, 47, 8351-8354.

460 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Wan et al.
1H), 1.70-1.97 (m, 6H); 13C NMR (100 MHz, CDCl3) ꢀ 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, 60.24, 56.29, 55.34, 53.00, 41.88,
31.95, 27.97, 23.78; IR (KBr, ꢁ, cm-1): 3334.72, 1703.50, 1601.57,
1528.75, 813.21. HRMS (ESI) calcd for C21H25NO3 [MH]+,
340.1913; Found: 340.1903; Anal. Calcd for C21H25NO3: C, 74.31;
H, 7.42; N, 4.13. Found: C, 74.35; H, 7.40; N, 4.10%.
(m, 1H), 6.53-6.58 (m, 1H), 6.36-6.38 (m, 1H), 4.74 (d, J=6.4 Hz,
0.97H), 2.67-2.73 (m, 1H), 2.31-2.51 (m, 2H), 1.69-1.85 (m, 4H),
1.48-1.54 (m, 2H); 13C NMR (100 MHz, CDCl3) ꢀ 212.81, 144.25,
141.02, 128.64, 128.55, 127.47, 127.44, 127.31, 127.20, 116.73,
116.52, 114.85, 112.96, 112.90, 58.81, 57.37, 42.12, 31.73, 28.00,
23.99; IR (KBr, ꢁ, cm-1): 3389.29, 1699.09, 1608.22, 1520.74,
813.10. HRMS (ESI) calcd for C19H19ClFNO [MH]+, 332.1217;
Found: 332.1208; Anal. Calcd for C19H19ClFNO: C, 68.77; H, 5.77;
N, 4.22. Found: C, 68.70; H, 5.80; N, 4.28%.
2-((3,5-dimethoxyphenyl)(phenylamino)methyl)cyclohexanone
1
4f. H NMR (400 MHz, CDCl3) ꢀ 7.26 (d, J=8.4 Hz, 1H), 7.07 (t,
1
J=7.6 Hz, 2H), 6.61 (t, J=6.8 Hz, 1H), 6.55 (d, J=8.0 Hz, 2H), 6.44
(t, J=8.0 Hz, 2H), 4.93 (d, J=6.8 Hz, 1H), 4.85 (br. s, 1H), 3.91 (s,
3H), 3.77 (s, 3H), 2.83 (m, 1H), 2.41-1.45 (m, 1H), 2.31- 2.35 (m,
1H), 1.94-1.99 (m, 4H), 1.67-1.90 (m, 2H); 13C NMR (100 MHz,
CDCl3) ꢀ 213.70, 159.47, 157.90, 147.11, 128.74, 128.47, 121.50,
116.89, 113.17, 104.05, 98.04, 55.97, 55.13, 54.99, 51.88, 41.49,
31.35, 27.98, 23.27; IR (KBr, ꢁ, cm-1): 3338.59, 1702.14, 1603.20,
1502.23, 808.22. HRMS (ESI) calcd for C21H25NO3 [MH]+,
340.1913; Found: 340.1901; Anal. Calcd for C21H25NO3: C, 74.31;
H, 7.42; N, 4.13. Found: C, 74.38; H, 7.38; N, 4.07%.
2-((2,6-dimethoxyphenyl)(phenylamino)methyl)cyclohexanone
4g. 1H NMR (400 MHz, CDCl3) ꢀ 7.08 (t, J=8.0 Hz, 2H), 6.95 (d,
J=3.2 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.70 (dd, J=9.2, 3.2 Hz,
1H), 6.62 (t, J=7.2 Hz, 1H), 6.56 (d, J=8.0 Hz, 2H), 5.00 (d, J=4.4
Hz, 1H), 4.84 (br. s, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 2.84 (q, 1 H),
2.41 (m, 1H), 2.30-2.35 (m, 1H), 1.86-1.99 (m, 4H), 1.67-1.78 (m,
2H); 13C NMR (100 MHz, CDCl3) ꢀ 213.38, 153.44, 151.26,
147.03, 130.50, 128.76, 117.02, 114.07, 113.18, 112.00, 110.78,
55.90, 55.58, 55.28, 52.15, 41.48, 31.32, 27.95, 23.28; IR (KBr, ꢁ,
cm-1): 3352.33, 1702.17, 1603.05, 1498. 68, 813.02. HRMS (ESI)
calcd for C21H25NO3 [MH]+, 340.1913; Found: 340.1915; Anal.
Calcd for C21H25NO3: C, 74.45; H, 7.40; N, 4.10. Found: C, 74.38;
H, 7.38; N, 4.07%.
2-((4-chlorophenylamino)(phenyl)methyl)cyclohexanone 4m. H
NMR (400 MHz, CDCl3) ꢀ 7.24-7.37 (m, 5H), 7.01 (d, J=8.8 Hz,
2H), 6. 46 (d, J=8.4 Hz, 2H), 4.79 (br, s, 1H), 4.56 (d, J=6.8 Hz,
1H), 2.76-2.78 (m, 1H), 2.35-2.46 (m, 2H), 1.84-1.97 (m, 4H),
1.69-1.74 (m, 2H); 13C NMR (100 MHz, CDCl3) ꢀ 212.82, 145.87,
141.27, 128.90, 128.55, 128.57, 128.48, 127.48, 127.35, 127.22,
122.13, 115.23, 114.77, 58.34, 57.41, 41.99, 31.57, 27.97, 23.87;
IR (KBr, ꢁ, cm-1): 3412.29, 1699.12, 1600.26, 1500.75, 803.99.
HRMS (ESI) calcd for C19H20ClNO [MH]+, 314.1312; Found:
314.1295; Anal Calcd for C19H20ClNO: C, 72.72; H, 6.42; N, 4.46.
Found: C, 72.70; H, 6.45; N, 4.40%.
2-((3-chloro-4-methylphenylamino)(phenyl)methyl)cyclohexan-
one 4n. 1H NMR (400 MHz, CDCl3) ꢀ 7.33-7.38 (m, 5H), 6.90 (d,
J=8.0 Hz, 1H), 6.57 (s, 1H), 6.37 (d, J=8.4 Hz, 1H), 4.73 (br. s,
1H), 4.56 (d, J=6.8 Hz 1H), 2.76-2.78 (m, 1H), 2.35-4.46 (m, 2H),
2.19 (s, 3H), 1.83-1.94 (m, 4H), 1.70-1.75 (m, 2H); 13C NMR (100
MHz, CDCl3) ꢀ 212.48, 146.12, 141.09, 134.31, 130.83, 128.26,
127.00, 126.90, 124.08, 113.68, 112.05, 57.96, 57.13, 41.65, 31.25,
27.68, 23.54, 18.56, IR (KBr, ꢁ, cm-1): 3363.19, 1705.91, 1612.66,
1513.34, 815.14. HRMS (ESI) calcd for C20H22ClNO [MH]+,
328.1468; Found: 328.1458; Anal. Calcd for C20H22ClNO: C,
73.27; H, 6.76; N, 4.27. Found: C, 73.17; H, 6.70; N, 4.29 %.
2-((4-fluorophenylamino)(phenyl)methyl)cyclohexanone 4o. 1H
NMR (400 MHz, CDCl3) ꢀ 7.33-7.38 (s, 5H), 6.76-6.81 (m, 2H),
6.46-6.51 (m, 2H), 6.42 (br, s, 1H), 4.54 (d, J=7.2 Hz, 1H), 2.74-
2.77 (m, 1H), 2.33-2.48 (m, 2H), 1.83-1.98 (m, 4H), 1.67-1.72 (m,
2H); 13C NMR (100 MHz, CDCl3) ꢀ 212.58, 156.74, 154.40,
143.30, 141.21, 128.24, 128.14, 127.20, 127.01, 115.28, 115.24,
115.06, 114.41, 114.34, 58.59, 57.21, 41.64, 31.16, 27.66, 23.53;
IR (KBr, ꢁ, cm-1): 3403.80, 1699.75, 1612.08, 1512.24, 825.47.
HRMS (ESI) calcd for C19H20FNO [ MH]+, 298.1607; Found:
298.1594; Anal. Calcd for C19H20FNO: C, 76.74; H, 6.78; N, 4.71.
Found: C, 76.65; H, 6.96; N, 4.70%.
2-((m-toluidino)(phenyl)methyl)cyclohexanone 4i. 1H NMR (400
MHz, CDCl3) ꢀ 7.38 (t, J=8.0 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.23
(t, J=7.6 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H),
6.41 (s, 1H), 6.35 (d, J=8.0 Hz, 1H), 4.82 (d, J=4.4 Hz, 0.12 H),
4.68 (br. s, 1H), 4.64 (d, J=7.2 Hz, 0.88 H), 2.74-2.77 (m, 1H),
2.42-2.47 (m, 1H), 2.32-2.38 (m, 1H), 2.20 (s, 3H), 1.87-1.94 (m,
4H), 1.68-1.75 (m, 2H); 13C NMR (100 MHz, CDCl3) ꢀ 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; IR (KBr, ꢁ, cm-1): 3386.31, 1695.13, 1602.90,
1524.73, 802.64. HRMS (ESI) calcd for C20H23NO [MH]+,
294.1858; Found: 294.1849; Anal. Calcd for C20H23NO: C, 81.87;
H, 7.90; N, 4.77. Found: C, 81.95; H, 7.78; N, 4.68%.
2-((3-chloro-2-methylphenylamino)(phenyl)methyl)cyclohexan-
one 4p. 1H NMR (400 MHz, CDCl3) ꢀ 7.24-7.38 (m, 5H), 6.93 (d,
J=8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 6.36 (m, 1H), 4.90 (d, J=6.4
Hz, 0.95 H), 4.58 (t, J=4.8 Hz, 1H), 2.82 (br, s, 1H), 2.33-2.46 (m,
2H), 2.18 (s, 3H), 1.72-1.97 (m, 6H); 13C NMR (100 MHz, CDCl3)
ꢀ 212.97, 145.95, 140.91, 132.03, 130.44, 128.35, 127.12, 126.76,
120.57, 116.33, 110.23, 57.91, 57.23, 41.70, 31.43, 27.70, 23.44,
16.89; IR (KBr, ꢁ, cm-1): 3380.93, 1698.42, 1597.24, 1516.59,
802.16. HRMS (ESI) calcd for C20H22ClNO [MH]+, 328.1468;
Found: 328.1473; Anal. Calcd for C20H22ClNO: C, 73.27; H, 6.76;
N, 4.27. Found: C, 73.17; H, 6.79; N, 4.37%.
2-((3-chlorophenylamino)(phenyl)methyl)cyclohexanone 4j. 1H
NMR (400 MHz, CDCl3) ꢀ 7.32-7.38 (m, 3H),7.23-7.26 (m, 2H),
6.96-7.26 (m, 1H), 6.61 (t, J=7.2 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H),
6.42 (d, J=8.0 Hz,1H), 4.90 (br, s, 1H), 4.67 (d, J=6.4 Hz, 0.3H),
4.57 (d, J=6.4 Hz, 0.7H), 2.75-2.81 (m, 1H), 2.32-2.46 (m, 2H),
1.91-2.00 (m, 4H), 1.69-1.86 (m, 2H); 13C NMR (100 MHz,
CDCl3) ꢀ 212.46, 148.21, 140.91, 134.49, 129.76, 128.29, 127.07,
126.86, 117.11, 113.01, 111.55, 57.79, 57.07, 41.73, 31.36, 27.68,
23.60; IR (KBr, ꢁ, cm-1): 3342.02, 1701.50, 1599.60, 1525.80,
829.73. HRMS (ESI) calcd for C19H20ClNO [MH]+, 314.1301,
Found: 314.1312; Anal. Calcd for C19H20ClNO: C, 72.72; H, 6.42;
N, 4.46. Found: C, 72.68; H, 6.48; N, 4.52%.
3-(m-tolylamino)-1,3-diphenylpropan-1-one 7b. 1H NMR (400
MHz, CDCl3) ꢀ 7.93 (d, J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H),
7.56-7.60 (m, 4H), 7.47 (t, J=6.4 Hz, 2H), 7.25-7.28 (m, 2H), 6.99
(t, J=8.0 Hz, 1H), 6.36-6.52 (m, 3H), 5.02 (t, J=6.0 Hz, 1H), 4.50
(br. s, 1H), 3.40-3.56 (m, 2H), 2.22 (s, 3H); 13C NMR (100 MHz,
CDCl3) ꢀ 198.30, 147.02, 143.09, 138.87, 136.72, 133.41, 129.01,
128.82, 128.71, 128.23, 127.32, 126.37, 118.77, 114.70, 110.78,
100.01, 54.77, 46.30, 21.60; IR (KBr, ꢁ, cm-1): 3388.35, 1667.62,
1602.38, 1520.80, 843.72. HRMS (ESI) calcd for C22H21NO
[MH]+, 316.1701; Found: 316.1668; Anal. Calcd for C22H21NO: C,
83.78; H, 6.71; N, 4.44. Found: C, 83.85; H, 6.70; N, 4.50 %.
3-(p-tolylamino)-1,3-diphenylpropan-1-one 7d. 1H NMR (400
MHz, CDCl3) ꢀ 7.94 (d, J=7.6 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.47
(t, J=6.4 Hz, 2H), 7.35 d, J=8.0 Hz, 2H), 7.09-7.16 (m, 4H), 7.68
(t, J=6.0 Hz, 1H), 6.58 (d, J=8.0 Hz, 2H), 5.00 (t, J=6.4 Hz, 1H),
4.53 (br. s, 1H), 3.39-3.55 (m, 2H), 2.33 (s, 3H); 13C NMR (100
MHz, CDCl3) ꢀ 198.06, 144.39, 142.85, 136.42, 133.11, 129.32,
128.52, 128.41, 127.93, 127.02, 126.72, 126.10, 113.71, 54.79,
46.10, 20.09; IR (KBr, ꢁ, cm-1): 3406.42, 1702.39, 1620.45,
2-((p-toluidino)(phenyl)methyl)cyclohexanone 4k. 1H NMR (400
MHz, CDCl3) ꢀ 7.38 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.24
(d, J=7.2 Hz, 1H), 6.89 (d, J=8.0Hz, 2H), 6.47 (d, J=8.0 Hz, 2H),
4.79 (d, J=3.6 Hz, 0.12H), 4.61 (d, J=7.2 Hz, 0.88H), 4.62 (br, s,
1H), 2.72-2.75 (m, 1H), 2.43-2.49 (m, 1H), 2.31-2.38 (m, 1H), 2.19
(s, 3H), 1.86-1.94 (m, 4H), 1.70-1.72 (m, 2H); 13C NMR (100
MHz, CDCl3) ꢀ 212.65, 144.61, 141.56, 129.27, 128.17, 126.99,
126.84, 126.40, 113.48, 57.91, 57.26, 41.41, 30.91, 27.61, 23.31,
20.05; IR (KBr, ꢁ, cm-1): 3406.42, 1702.39, 1620.45, 1524.27,
805.21. HRMS (ESI) calcd for C20H23NO [MH]+, 294.1858; Found:
294.1839; Anal. Calcd for C20H23NO: C, 81.87; H, 7.90; N, 4.77.
Found: C, 81.80; H, 7.98; N, 4.81 %.
2-((3-chloro-4-fluorophenylamino)(phenyl)methyl)cyclohexan-
one 4l. 1H NMR (400 MHz, CDCl3) ꢀ 7.26-7.35 (m, 5H), 6.82-6.87

High Stereoselective Mannich Reaction Catalyzed
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
461
1524.27, 805.21. HRMS (ESI) calcd for C22H21NO [MH]+,
316.1701; Found: 316.1688; Anal. Calcd for C22H21NO: C, 83.78;
H, 6.71; N, 4.44. Found: C, 83.85; H, 6.74; N, 4.40 %.
147.87, 142.05, 136.28, 134.51, 133.29, 129.81, 128.66, 128.48,
127.93, 127.28, 125.99, 117.41, 113.31, 111.66, 54.35, 45.85; IR
(KBr, ꢁ, cm-1): 3342.02, 1701.50, 1599.60, 1525.80, 829.73.
HRMS (ESI) calcd for C21H18ClNO [MH]+, 336.1155; Found:
336.1147; Anal. Calcd for C21H18ClNO: C, 75.11; H, 5.40; N, 4.17.
Found: C, 75.21; H, 5.45; N, 4.10 %.
3-(3-chlorophenylamino)-1,3-diphenylpropan-1-one 7e. 1H NMR
(400 MHz, CDCl3) ꢀ 7.93 (d, J=8.0 Hz, 2H), 7.60 (t, J=6.4 Hz,
1H), 7.03-7.50 (m, 4H), 7.45-7.48 (m, 4H), 6.97-7.28 (m, 3H), 6.99
(t, J=8.0 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 6.44 (s, 1H), 6.37 (d,
J=8.0 Hz, 1H), 5.02 (t, J=6.0Hz, 1H), 4.50 (br. s, 1H), 3.40-3.56
(m, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) ꢀ 197.81,