A new class of metal-free catalysts for direct diastereo- and regioselective Mannich reactions in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2004.09.174

Camphor sulfonic acid and three sulfonated amino acids shows to efficiently catalyze direct Mannich reactions of benzaldehyde, aniline and various ketones in aqueous media, with high diastereo- or regioselectivities. Camphor sulfonic acid is an efficient catalyst for Mannich reactions of benzaldehyde, aniline and various ketones in aqueous media, with diastereo- or regioselectivities. Meanwhile, three sulfonated amino acids can catalyze the same type of reactions effectively with high diastereo- or regioselectivities.

Full text of DOI:10.1016/j.tetlet.2004.09.174

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8949–8952
A new class of metal-free catalysts for direct diastereo- and
regioselective Mannich reactions in aqueous media
Yin-Su Wu, Jiwen Cai,* Zhi-Ya Hu and Guang-Xin Lin
School of Chemistry & Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
Received 31 May 2004; revised 7 September 2004; accepted 15 September 2004
Available online 14October 2004
Abstract—Camphor sulfonic acid is an efficient catalyst for Mannich reactions of benzaldehyde, aniline and various ketones in aque-
ous media, with diastereo- or regioselectivities. Meanwhile, three sulfonated amino acids can catalyze the same type of reactions
effectively with high diastereo- or regioselectivities.
Ó 2004 Elsevier Ltd. All rights reserved.
Mannich-type reaction is a classic protocol to synthesize
b-amino carbonyl compounds and has been investigated
extensively. The first asymmetric Mannich reaction was
diastereoselective and involved the addition of pre-
formed enolates and enamines to preformed imines.1
With the increasing interests in developing environmen-
tal benign reactions, the atom-economic catalytic proc-
ess that employs unmodified carbonyl donor, amine,
and acceptor aldehyde as an idealized Mannich-type
reaction is attracting more and more attention.1 Only
very recently, the first catalytic asymmetric 3-component
Mannich-type reaction using free aldehydes and ketones
was reported, in which L-proline was used as a catalyst
and the reaction was carried out in DMSO.2
silyl enol ethers. Herein, as part of our systematic
searching for the potential application of natural chiral
compounds, especially amino acids, in asymmetric syn-
theses carried out in aqueous media,8 we wish to report
the first direct 3-component diastereo-controlled Man-
nich-type reactions catalyzed by a series of metal-free
catalysts, using water as the only solvent. The catalysts
used in this study include D-camphor sulfonic acid (D-
CSA) and sulfonated amino acids, as shown in Figure 1.
Initially, the catalytic effect of the commercially avail-
able D-CSA in the amount of 10mmol% for the conden-
sation reaction of benzaldehyde, aniline, and,
cyclohexanone in aqueous media was evaluated. The
reaction proceeded smoothly to afford the Mannich cond-
ensation products in good yield with the anti isomer as
the only product. Encouraged by the result, the effect
of sulfonated amino acids was evaluated and the
results were presented in Table 1. It showed that, in all
cases, the b-amino carbonyl adduct was obtained in
excellent yields with the anti isomer as the dominant
Using metal-free small molecules as catalysts has been
another strategy to develop green organic reactions.3
The reported metal-free catalysts used for Mannich-type
reactions include DBSA,4 polymer-supported sulfonic
acid,5 L-proline,2 and chiral phosphoric acid deriva-
tives.6 Reactions catalyzed by the latter two in organic
media show high enantioselectivities.
Kobayashi et al. reported the first asymmetric Mannich
reaction catalyzed by chiral Lewis acid in aqueous med-
ia,7 in which ZnF2 and a chiral diamine were used as the
catalysts for the diastereoselective and enantioselective
Mannich-type condensation of a hydrazono ester with
R1 =
OH
1
L-Tyr-SO3H
L-Phe-SO3H
CH2R
SO3H
H
COOH
NH2
SO3H
SO3H
2
R2
=
O
SO3H
R3
HO3S
=
3 L-Try-SO3H
Keywords: Direct Mannich reaction; Metal-free catalyst; Aqueous
media; Sulfonated amino acid; Camphor sulfonic acid.
4 D-CSA
N
H
*
Corresponding author. Tel.: +86 20 84114215; fax: +86 20
84112245; e-mail: puscjw@zsu.edu.cn
Figure 1. The Brønsted-acid catalysts.
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.174

8950
Y.-S. Wu et al. / Tetrahedron Letters 45 (2004) 8949–8952
Table 1. Catalytic results for reactions of benzaldehyde, aniline, and cyclohexanone
Ph
Ph
O
CHO
NH2
NH
NH
O
O
H
H
Catalysts
H2O, rt
+
Ph
Ph
+
Anti 8a
Syn 8b
Producta
5
6
7a
Entry
Catalysts
Time (hr)
Yield
de (%)
1
2
D-CSA
5
5
91
90
8ab
8a, 8b
100
90
L-Tyr-SO3H
8a:8b = 95:5
8a, 8b
3
L-Try-SO3H
5
88
94
8a:8b = 97:3
8a
8a, 8b
4
5
L-Phe-SO3H
1,5nds
5
5
90
78
100
44
8a:8b = 72:28
8a, 8b
6
7
bpds
5
5
73
64
8a:8b = 82:18
nd
L-Tyr
nd
a Determined by 1H NMR.
b With ee% of 8% established by HPLC with chiral column Daicel Chiralpak AS-RH.
3-Component reaction of benzaldehyde, aniline, and
cyclopentanone did not produce the desired adduct,
probably due to the polyaminoalkylation of cyclopenta-
none. Therefore, another procedure was adopted, in
which benzaldehyde and aniline were first mixed to pro-
duce imine in situ before ketone was added, and the de-
sired adduct was generated with moderate yields and
excellent diastereoselectivities, as shown in Table 2.
Finally, the regioselectivities of these Brønsted acids
were examined and the results shown in Table 3. In all
cases, the C–C bond was formed by the less-substituted
carbon atom of the asymmetric ketones, and 10a or 11a
was obtained as the major product, which is consistent
with what was reported for DBSA.4
The reaction process could be considered to proceed via
an iminium salt generated by benzaldehyde, aniline and
the Brønsted acid, as shown in Scheme 1. It should be
noted that in aqueous media, the oxygen atoms of the
sulfonate group are hydrogen bonding acceptors while
the hydrogen atoms of the amino group are hydrogen
bonding donors. The strong hydrogen bonds formed
between these groups could dominant the intermolecular
interaction in aqueous solution, create an asymmetrical
environment enhancing the enantioseletivities,3,6 and
consequently produce the detectable (yet low) enantio-
selectivity observed in entry 1.
Figure 2. Crystal structure of the anti isomer of compound 8, showing
the racemic dimer linked by hydrogen bonds.
diastereoisomer. The structure of the anti isomer is
further confirmed by X-ray crystallography,9 as shown
in Figure 2. The anti isomers formed racemic dimer
via hydrogen bonds between the amino and carbonyl
groups.
In order to identify the structural factor contribution to
the stereoselectivities, the catalytic effect of achiral aro-
matic sulfonic acids, namely, naphthalene-1,5-disulfonic
acid (1,5nds) and 4,40-biphenyldisulfonic acids (bpds),
as well as L-tyrosine were investigated and the results
were shown as entries 5–7 in Table 1. Both 1,5nds and
bpds produced high yields but moderate diastereoselecti-
vities, which were comparable to the catalytic results
reported for the achiral catalyst DBSA.4 L-Tyrosine
did not catalyze the Mannich-type reaction under the
reaction conditions evaluated, indicating that carboxylic
acid is not acidic enough to activate the reaction. There-
fore, both sulfonic acid and the chiral nature of the reac-
tion media were crucial for effective and high
diastereoselective catalytic results.
In summary, we have identified a new group of small
organic molecules which can catalyze the 3-component
Mannich-type reaction with moderate to high yields
and high stereoselectivities, with water as the only sol-
vent at room temperature. Amino acids are readily
obtained chiral organic compounds. However, only
recently, with L-proline catalyzed successfully a series
of organic reactions,2,10 the use of natural amino acids
as chiral source for asymmetric catalysts attracted
peopleÕs attention.11 Our result reported herein shows
that amino acid derivatives can be served as effective

Y.-S. Wu et al. / Tetrahedron Letters 45 (2004) 8949–8952
Table 2. Catalytic results for reactions of benzaldehyde, aniline, and cyclopentanone
8951
Ph
NH
Ph
NH
O
O
O
Ph
H
H
Catalysts
O, rt
N
Ph
Ph
+
H
2
Ph
5 + 6
Syn 9b
Anti 9a
Yield
7b
Entry
Catalysts
Time (hr)
Producta
de (%)
8
D-CSA
1
1
1
60
60
58
9a
9a
100
100
94
9
10
L-Tyr-SO3H
L-Try-SO3H
9a, 9b
9a:9b = 97:3
9a, 9b
9a:9b = 92:8
11
L-Phe-SO3H
1
60
84
a Determined by 1H NMR.
Table 3. Reactions of benzaldehyde, aniline, and 2-butanone, 2-pentanone
Ph
NH
Ph
NH
CHO
O
NH2
O
O
Catalysts
H2O, rt
+
+
Ph
Ph
H
R
H
R
R
H
5
7c: R = Me
7d: R = Et
10a: R = Me
11a: R = Et
10b: R = Me
11b: R = Et
6
Entry
Catalyst
D-CSA
R
Time (hr)
Yield (%)
Producta
12
13
Me
Me
2475
24
10a
L-Tyr-SO3H
L-Try-SO3H
L-Phe-SO3H
65
70
72
10a, 10b
10a:10b = 90:10b
10a, 10b
10a:10b = 80:20b
10a, 10b
10a:10b = 87:13b
11a
14
15
Me
Me
24
24
16
17
18
19
D-CSA
Et
Et
Et
Et
2468
24
L-Tyr-SO3H
L-Try-SO3H
L-Phe-SO3H
68
68
68
11a
11a
24
24
11a
a Determined by 1H NMR.
b The de% of 10b is around 20% with the syn isomer as the major product.
catalysts for reactions carried out in aqueous media. It is
remarkable that in entries 1, 4, 8, 9, 12, 16–19, the reac-
tions are diastereo- or regiocontrolled, with one isomer
as the only product.
Ph
B
H
Ph
H
NH
O
N
OH
H
Ph
Sterically unfavorable
H
Ph
H
Acknowledgements
Syn 8a transition state
We are grateful for the financial support from the Sci-
ence and Technology Programs of Guangdong Province
(Grant No. 2003C104030) and the National Natural Sci-
ence Foundation of China (Grant No. 20271053).
Ph
B
H
Ph
Ph
NH
O
N
OH
H
H
Supplementary data
H
Ph
H
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.09.174. Crystallographic data (excluding struc-
ture factors) for the structures in this paper has been
Anti 8a transition state
Scheme 1. Proposed catalytic transition state for the syn and anti
isomers. Bꢀ represents the de-protonated Brønsted acid.

8952
Y.-S. Wu et al. / Tetrahedron Letters 45 (2004) 8949–8952
6. (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566–1568; (b) Uraguchi, D.;
Terada, M. J. Am. Chem. Soc. 2004, 126, 5356–
5357.
7. Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem.
Soc. 2002, 124, 5640–5641.
8. Wu, Y.-S.; Shao, W.-Y.; Zheng, C.-Q.; Huang, Z.-L.; Cai,
J.; Deng, Q.-Y. Helv. Chim. Acta 2004, 87, 1377–1384.
9. Crystal data for the anti isomer of 8, Mw = 279.37,
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
239849. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK (Fax: +44 0 1223 336033 or email:
deposit@ccdc.cam.ac.uk).
References and notes
monoclinic, space group P21/n, a = 10.309(4), b =
˚
10.726(4),
c = 14.263(5)A,
b = 95.076(7)°,
V =
1. (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102–112; (b)
´
1570.8(10)A , Z = 4 , qcalcd = 1.181gcmꢀ3, F(000) = 600,
MoKa radiation, l = 0.072mmꢀ1. Reflections collected
9776, unique 3809, R(int) = 0.0159, R1 = 0.0527,
wR2 = 0.1516 for strong reflections with I > 2r(I),
Gof = 1.022.
3
˚
´
Cordova, A. Chem. Eur. J. 2004, 10, 1987–1997.
2. List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337.
3. Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289–296.
4. Manbe, K.; Mori, Y.; Kobayashi, S. Tetrahedron 2001, 57,
2537–2544.
5. Iimura, S.; Nobutou, D.; Manabe, K.; Kobayashi, S.
Chem. Commun. 2003, 1644–1645.
10. List, B. Tetrahedron Lett. 2002, 58, 5573–5590.
11. Lindstro¨m, U. M. Chem. Rev. 2002, 102, 2751–
2772.