Mannich-type reactions in a colloidal solution formed by sodium tetrakis(3,5-trifluoromethylphenyl)borate as a catalyst in water

Article abstract of DOI:10.1016/j.tetlet.2006.10.125

Sodium tetrakis(3,5-trifluoromethylphenyl)borate [NaBAr₄^F] efficiently catalyzed the one-pot, three-component Mannich reaction of ketones with aromatic aldehydes and different anilines in water at an ambient temperature and afforded the corresponding β-amino carbonyl compounds in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.10.125

Tetrahedron Letters 47 (2006) 9257–9259
Mannich-type reactions in a colloidal solution
formed by sodium tetrakis(3,5-trifluoromethylphenyl)borate
as a catalyst in water
Chi-Tsing Chang, Bei-Sih Liao and Shiuh-Tzung Liu*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
Received 22 August 2006; revised 18 October 2006; accepted 25 October 2006
Available online 13 November 2006
Abstract—Sodium tetrakis(3,5-trifluoromethylphenyl)borate ½NaBArF4 ꢀ efficiently catalyzed the one-pot, three-component Mannich
reaction of ketones with aromatic aldehydes and different anilines in water at an ambient temperature and afforded the correspond-
ing b-amino carbonyl compounds in good to excellent yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The Mannich reaction is one of the most important car-
bon–carbon bond forming reactions in organic synthesis,
Eq. 1.1 This reaction provides the formation of b-amino
carbonyl compounds, which are important intermediates
for the construction of various nitrogen-containing nat-
ural products and pharmaceuticals.2 However, the dras-
tic reaction conditions for the classical intermolecular
Mannich reaction limit its synthetic usefulness. There-
fore, numerous modifications of this reaction have been
developed to overcome the drawbacks.1,3 Many metal
complexes have been used as Lewis acid catalysts to pro-
mote the reaction under anhydrous conditions,1–3 and
few water-compatible Lewis acids were reported.4
yashi and Manabe, they found that dodecylbenzenesulf-
onic acid could catalyze the Mannich reaction at an
ambient temperature in water to give various b-amino
ketones in good yields.6 In these surfactant-aided sys-
tems, organic substrates form emulsion droplets that
function as reaction media in water. However, the pres-
ence of a Brønsted acid is still required to carry out the
reaction in most of the instances. Here, we offer an
efficient method for the preparation of Mannich type
products in water by using sodium tetrakis(3,5-trifluoro-
methyl-phenyl)borate (½NaBArF4 ꢀ) as a catalyst under
mild and nearly neutral conditions.
F3C
O
R2
R1
NaBArF
NH
O
catalyst
R3
B
4
Na
4
1
R CHO
R2NH2
+
+
R4
R4
F3C
R3
ð1Þ
Initially, the two-component Mannich reaction of N-
benzylideneaniline (1.0 mmol) and various nucleophiles
(2 mmol) was examined (Table 1). As a preliminary
study, we found that ½NaBArF4 ꢀ did not catalyze the reac-
tion of acetophenone with benzylideneaniline in most of
the organic solvents such as THF, dichloromethane or
DMF. It was revealed that the present Mannich-type
reaction proceeded only in aqueous media. Running
the reaction of benzylideneaniline with ketone in water
at an ambient temperature gave the desired product in
an excellent yield (Table 1, entry 4). Encouraged by
the results, we examined various ketones and silyl eno-
lates to screen the scope of this new protocol. The silyl
In recent years, organic reactions in an aqueous medium
have received enormous attention, because the use of
water has several advantages as it is the easiest obtain-
able solvent, is an environmentally friendly substance,
and can be easily separated from organic products.5–7
In this context, researches focusing on the development
of new catalysts to promote organic reactions in water
have become highly desirable. In an early report Koba-
*
Corresponding author. Tel.: +8862 23660352; fax: +8862
23636359; e-mail: stliu@ntu.edu.tw
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.125

9258
C.-T. Chang et al. / Tetrahedron Letters 47 (2006) 9257–9259
Table 1. Results of Mannich reaction catalyzed by ½NaBArF4 ꢀ
Entry Ketone or silyl enol ether Solvent Time
NH2
a
CHO
Z
Y
O
Yield (%)
NaBAr4F
H2O
O
NH
1
2
3
4
5
Acetophenone
Acetophenone
Acetophenone
Acetophenone
CH2Cl2 96 h
0
0
THF
96 h
96 h
96 h
30 min
1 h
DMF
Water
Water
Trace
96
91
100
77
100
32
Z
Y
Y = -COOMe
= -COOMe
Z = I
= Cl
63 % (anti:syn = 7:4)
57 % (anti:syn = 8:5)
C6H5C(OSiMe3)@CH2
6
C6H5C(OSiMe3)@CHCH3 Water
30 min
1 h
Water 144 h
Scheme 1.
7
8
C6H5C(O)CH2CH3
Cyclohexone
The selectivity for anti-isomers is slightly favored. In
addition, the reaction of cyclohexanone and p-chloro-
aniline with 1-naphthalenecarbaldehyde yielded the
coupling product, 2-[(4-chlorophenylamino)naphtha-
len-1-ylmethyl]-cyclohexanone, in 65% (anti:syn = 1:1).
Water
3 h
100
a Reaction conditions: ½NaBArF4 ꢀ (0.005 mmol), ketone or silyl enol
ether (2 mmol), N-benzylideneaniline (1 mmol) at 30 °C.
enolate as the nucleophile in the reaction appeared to be
more reactive than the corresponding ketone com-
pounds as evidenced by the shorter reaction time and
better yields (Table 1, entries 5 and 6).
For unsymmetric ketone, the regioselectivity of the less
hindered site is observed. Thus, the reaction of 2-buta-
none, benzaldehyde, and aniline in the presence of
½NaBArF4 ꢀ in water provided Mannich products I and
II, Eq. 2. The ratio of I:II is about 85:15, indicating that
the reaction takes place at the less substituted carbon
center.
With the success of the above coupling reaction, we
examined the feasibility of the three-component
Mannich reaction. The reaction of benzaldehyde,
aniline, and acetophenone in the presence of ½NaBArF4 ꢀ
as the catalyst in water provided the desired compound
in an 81% isolated yield (Table 2, entry 1). Again, this
efficient catalyst was not observed in the reactions car-
ried out in the organic solvents. Several of the substi-
tuted anilines underwent the reaction smoothly except
for p-nitroaniline (Table 2, entry 9). By using 1H
NMR to monitor the reaction, we realized that the imine
intermediate, 4-nitrobenzylidenephenylamine, was not
formed during the reaction.
Ph
O
Ph
Ph
NH
O
O
NH
C6H5CHO + C6H5NH2 +
+
Ph
I
II
ð2Þ
It should be noted that the addition of organic substrates
to this sodium salt in water readily formed a milky sus-
pension, indicating that borate anions acted as surfac-
tants.8 In an early work, we found this salt did not
completely dissociate into free ions in dichloromethane,
with the formation of aggregation instead.9 From the
dynamic light scattering measurement, the average size
of aggregated particles of ½NaBArF4 ꢀ and organic
substrates is in the range of ꢁ1 lm. Thus the addition
of organic substrates readily forms a colloidal disper-
sion, which is similar to that of a mixture of dodecyl-
benzenesulfonic acid (DBSA) and organic reagents in
water reported by Kobayashi and Manabe.6 Apparently,
the formation of colloid particles plays an essential role
in the acceleration of the coupling reaction. In our early
study, the crystal structure of ½NaBArF4 ꢀ reveals that the
fluorine atoms of trifluoromethyl groups do coordinate
toward the metal center.9 We believe that such coordina-
tion might partially persist in an aqueous environment,
which thus increases the Lewis acidity of metal ions.
The reactions proceeded not only for acetophenone but
also for other dialkyl ketones in good yields. As illus-
trated in Scheme 1, ½NaBArF4 ꢀ did catalyze the Mannich
reaction of cyclohexone, substituted benzaldehydes, and
anilines to yield the desired b-amino ketone products.
1
The stereoselectivity was determined by H NMR spec-
troscopy and by comparison with known compounds.
Table 2. Results of the three-component Mannich reactiona
R2
CHO
NH2
O
NaBAr4F
H2O
NH
O
+
+
R1
R1
R2
Entry
R1
R2
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
F
Cl
Br
i-Propyl
CH3O
H
H
H
H
H
H
H
I
48
48
48
48
48
48
24
24
48
81
51
74
85
53
21
100
51
—
In conclusion, this procedure offers several advantages
for the Mannich reaction such as low loading of cata-
lyst, mild conditions, high yields, clean reactions, which
make it a useful and attractive methodology for organic
synthesis. Quite a number of products are solid and
insoluble in water, which can be obtained by filtration
and recrystallization. This simple work-up procedure is
also beneficial to this method. Further applications of
this catalyst to other transformations are currently
under investigation.
H
H
Me
NO2
a Reaction conditions: ½NaBArF4 ꢀ (0.005 mmol), acetophenone
(2 mmol), aniline (1 mmol), aldehyde (1 mmol) in H2O (2 mL) at
30 °C.

C.-T. Chang et al. / Tetrahedron Letters 47 (2006) 9257–9259
9259
3. Few recent examples: (a) Matsunaga, S.; Kumagai, N.;
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Acknowledgment
This research was supported by the funding of National
Science Council (NSC94-2113-M002-035).
´
K. J. Am. Chem. Soc. 2002, 124, 5640; (e) Cordova, A.;
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Supplementary data
4. (a) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem.
Soc. 2002, 124, 5640; (b) Notz, W.; Tanaka, F.; Watanabe,
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Supplementary data (spectroscopic data for the Man-
nich reaction products) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2006.10.125.
´
Ibrahem, I.; Casas, J.; Cordova, A. Angew. Chem., Int. Ed.
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