Mannich-type reaction catalyzed by silica-supported fluoroboric acid under solvent-free conditions

Article abstract of DOI:10.1080/00397910701796766

Three-component Mannich-type reaction of aldehydes, aromatic amines, and silyl enolate proceeded smoothly to afford β-amino carbonyl compounds with good yields in the presence of a catalytic amount of HBF4-SiO2. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701796766

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Mannich‐Type Reaction Catalyzed by
Silica‐Supported Fluoroboric Acid under
Solvent‐Free Conditions
WeiYi Chen a , XinSheng Li b & Jun Lu a
a College of Chemistry and Chemical Engineering of Suzhou University ,
Suzhou, China
b Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, Institute
of Physical Chemistry, Zhejiang Normal University , Jinhua, China
Published online: 27 Feb 2008.
To cite this article: WeiYi Chen , XinSheng Li & Jun Lu (2008) Mannich‐Type Reaction Catalyzed by
Silica‐Supported Fluoroboric Acid under Solvent‐Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:4, 546-552, DOI:
10.1080/00397910701796766
To link to this article: http://dx.doi.org/10.1080/00397910701796766
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Synthetic Communicationsw, 38: 546–552, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701796766
Mannich-Type Reaction Catalyzed
by Silica-Supported Fluoroboric Acid
under Solvent-Free Conditions
WeiYi Chen,1 XinSheng Li,2 and Jun Lu1
1College of Chemistry and Chemical Engineering of Suzhou University,
Suzhou, China
2Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces,
Institute of Physical Chemistry, Zhejiang Normal University, Jinhua,
China
Abstract: Three-component Mannich-type reaction of aldehydes, aromatic amines,
and silyl enolate proceeded smoothly to afford b-amino carbonyl compounds with
good yields in the presence of a catalytic amount of HBF4-SiO2.
Keywords: aldehyde, amine, HBF4-SiO2, Mannich reaction, silyl enolate
The Mannich reaction is one of the important fundamental reactions in organic
chemistry. It is a classical method in the routes for the synthesis of various
b-amino carbonyl compounds, which are versatile synthetic building blocks
for the preparation of many nitrogen-containing biological compounds.[1]
Therefore, it has found applications in the synthesis of numerous pharmaceu-
ticals and natural products.
Because of the drastic reaction conditions and long reaction times, the
classical intermolecular Mannich reaction is plagued by a number of serious
disadvantages. The Lewis acid–catalyzed condensation of silyl enol ethers
Received in the USA November 8, 2007
Address correspondence to WeiYi Chen, College of Chemistry and Chemical
Engineering of Suzhou University, Suzhou 215123, China. E-mail: suzhoucwy@
163.com
546

Mannich-Type Reaction
547
or silyl ketene acetals to imines is an excellent variant of the classical Mannich
reaction. However, this Lewis acid–catalyzed one-pot Mannich reaction quite
often had to be carried out under strict anhydrous conditions because many of
the imines are unstable in the presence of water.[2] In addition, an equimolar
amount of Lewis acid was required as a promoter because of the stronger
basicity of nitrogen. At the same time, many Lewis acids could not be used
in a one-pot reaction because of the presence of free amines and water
produced in the imine formation.
Thus, the development of Mannich reaction methods is always in high
demand. By now, several novel catalytic systems have been reported and
applied to the Mannich-type reaction.[3] Under those reaction conditions,
imines could be activated effectively, and the Mannich reaction could
proceed smoothly to afford b-amino carbonyl compounds in good yields.
However, many of those methods involved the use of expensive
reagents, extended reaction times, and harsh conditions, and also
required tedious aqueous workup, leading to the generation of a large
amount of toxic waste.
Obviously, there is an urgent need to develop safe, practical, and
environmentally friendly processes. Among the many methods, the use of
solid acid catalysts such as clay, ion-exchange resins, and zeolites has
received considerable attention in organic synthesis.[4] In recent years, solid-
supported catalysts, in which the catalysts are adsorbed onto an insoluble
inorganic or organic support (e.g., silica, alumina, clay or charcoal), have
been applied widely in organic chemistry.[5] As the effective surface area of
the catalysts dispersed on a support could be increased significantly, the
activity and selectivity of the catalysts could be improved. Meanwhile, the
use of solid-supported catalysts could offer ease of workup and opportunities
for recycling and makes a great contribution to green chemistry.
Recently, Akiyama and coworkers have found that Mannich-type reaction
of aldehydes, amines, and silyl enolate could proceed smoothly in the presence
of a catalytic amount of HBF4 (aq.).[6] To explore an alternative environmen-
tally benign condition for this reaction, we attempted to examine this reaction
in the presence of HBF4–SiO2, which could act as a weak protic acid and
might be a useful and inexpensive catalyst for the Mannich-type reaction
under mild conditions.
In a model study, the reaction of benzaldehyde (0.3 mmol), 4-fluoro-
aniline (0.3 mmol), and [(1-methoxy-2-methyl-1-propenyl)oxy]trimethylsi-
lane (0.45 mmol) was carried out in the presence of HBF4–SiO2 (30 mol%)
under various conditions. The best yield (84%) was obtained when the
reaction was tested at room temperature under solvent-free conditions.
Lower yields were obtained when the reactions were carried out in organic
solvents such as dichloromethane (DCM), MeCN, THF, MeOH, and
toluene. Meanwhile, the catalyst could be successfully recycled three times
by diluting the reaction mixture with diethyl ether, filtering, and reusing it
without significant reduction of acitivity compared to its initial use. The

548
W. Chen, X. Li, and J. Lu
Table 1. Results of Mannich-type reaction of benzaldehyde, aromatic amines, and 3
catalyzed by HBF4–SiO2
Entry
R1
Product
Yield (%)
1
2
3
4
5
6
4-FC6H4
4-ClC6H4
4-BrC6H4
C6H5
4a
4b
4c
4d
4e
4f
84
86
89
78
80
0
4-MeOC6H4
C6H5CH2
required product could be obtained in low yield (34%) using SiO2 as the
catalyst under the same reaction conditions.
Under the optimized reaction conditions, structurally diverse amines were
subjected to the Mannich-type reaction in the presence of HBF4–SiO2 under
solvent-free conditions. The results are summarized in Table 1. For the
present reaction condition, all of the desired products could be obtained in
moderate to good yields, whereas an aldimine derived from aliphatic amine
did not work well (Table 1, entry 6). In addition, the structure of 4a was
further confirmed by single-crystal X-ray crystallography (Fig. 1). All of this
evidence showed that HBF4 was a driving force for the Mannich-type
reaction, and it played a very essential role in this methodology.
To explore generality and scope, the potential of HBF4–SiO2 was further
investigated as a catalyst for the Mannich-type reaction of a range of aromatic
and aliphatic aldehydes.
Figure 1. Molecular structure of product 4a.

Mannich-Type Reaction
549
As shown in Table 2, these reactions proceeded smoothly to afford the
desired products in moderate to high yields under solvent-free conditions.
Furthermore, this protocol could work with both aromatic and aliphatic
aldehydes.
In summary, a convenient solvent-free procedure for performing
imino–aldol coupling, using HBF4 –SiO2 solid acid support, has been
developed, which could afford the b-amino ester smoothly. This method is
endowed with several merits, such as simplicity in operation, mild
reaction conditions, wide applicability, cost efficiency, and recyclability of
catalyst, which make it a convenient, economic, and user-friendly process.
Further investigations on asymmetric Mannich-type reaction catalyzed by
HBF4–SiO2 are in progress.
EXPERIMENTAL
Apparatus and Analysis
Proton nuclear magnetic resonance spectra (1H NMR) and carbon nuclear
magnetic resonance spectra (13C NMR) were obtained for solution in CDCl3
with Me4Si as internal standard on a Bruker Avance DPX 300 spectrometer.
IR spectra were obtained on a Nicolet FT-IR500 spectrophotometer using
KBr pellets. Elemental analyses were performed with a Carlo-Erba-1110
analyzer. The X-ray diffraction was performed on a Rigaku Mercury CCD
X-ray diffractometer.
Table 2. Results of Mannich-type reaction of aldehydes, aniline, and 3 catalyzed by
HBF4–SiO2
Entry
R2
Product
Yield (%)
1
2
4-MeOC6H4
4-ClC6H4
4g
4h
4i
81
84
80
89
76
75
82
85
86
80
3
4-O2NC6H4
2,4-Cl2C6H3
c-C6H13
4
4j
5
4k
4l
6
C6H5CH2CH2
C6H5CH55CH
3,4-(OCH2O)C6H3
2-Furyl
7
4m
4n
4o
4p
8
9
10
2-Thiophene

550
W. Chen, X. Li, and J. Lu
General Procedure
Benzaldehyde 1a (30 mL, 0.3 mmol), 4-fluoroaniline 2a (29 mL, 0.3 mmol), [(1-
methoxy-2-methyl-1-propenyl)oxy] trimethylsilane 3 (96 mL, 0.45 mmol), and
HBF4–SiO2 (0.18 g, 0.5 mmol HBF4 g21) were added to a bottle in quick suc-
cession. The mixture was stirred at room temperature for 2 h. The reaction
mixture was extracted with diethyl ether. After the evaporation of solvent, the
residue was purified by column chromatography on silica gel (EtOAc-
PE ¼ 1:8) to give the product 4a in 84% yield.
Spectral Data for Selected Products
3-(4-Fluoro-phenylamino)-2,2-dimethyl-3-phenyl-propionic Acid
Methyl Ester (4a)
IR (KBr): n 2924, 2852, 1714, 1510, 1136 cm21 1H NMR (CDCl3,
.
300 MHz): d 1.15 (s, 3H), 1.26 (s, 3H), 3.66 (s, 3H), 4.42 (d, J ¼ 7.71 Hz,
1H), 4.66 (d, J ¼ 7.53 Hz, 1H), 6.39–6.44 (m, 2H), 6.71–6.77 (m, 2H),
7.23–7.31 (m, 5H). 13C NMR (CDCl3, 75 MHz): d 20.5, 24.6, 47.0, 52.1,
65.1, 114.2, 114.3, 115.3, 115.6, 127.5, 128.0, 128.3, 138.9, 143.3, 177.0.
Anal. calcd. for C18H20FNO2: C, 71.74; H, 6.69; N, 4.65. Found: C, 71.72;
H, 6.71; N, 4.62.
3-(4-Bromo-phenylamino)-2,2-dimethyl-3-phenyl-propionic Acid
Methyl Ester (4c)
IR (KBr): n 2954, 2889, 1714, 1610, 1176 cm21 1H NMR (CDCl3,
.
300 MHz): d 1.15 (s, 3H), 1.28 (s, 3H), 3.65 (s, 3H), 4.41 (d, J ¼ 7.74 Hz,
1H), 4.89 (d, J ¼ 7.26 Hz, 1H), 6.36 (d, J ¼ 8.88 Hz, 2H), 7.10
(d, J ¼ 8.85 Hz, 2H), 7.21–7.28 (m, 5H). 13C NMR (CDCl3, 75 MHz): d
20.74, 24.69, 46.92, 52.16, 64.53, 108.96, 115.00, 127.67, 128.12, 128.22,
131.74, 138.71, 145.92, 162.03, 176.95. Anal. calcd. for C18H20BrNO2: C,
59.68; H, 5.56; N, 3.87. Found: C, 59.70; H, 5.61; N, 3.85.
3-(4-Methoxy-phenylamino)-2,2-dimethyl-3-phenyl-propionic Acid
Methyl Ester (4e)
1
IR (KBr): n 2931, 2847, 1724, 1606, 1510, 1176 cm21. H NMR (CDCl3,
300 MHz): d 1.16 (s, 3H), 1.24 (s, 3H), 3.66 (s, 6H), 4.45 (s, 2H), 6.45
(d, J ¼ 8.70 Hz, 2H), 6.63 (d, J ¼ 9.00 Hz, 2H), 7.21–7.29 (m, 5H).
13C NMR (CDCl3, 75 MHz): d 20.38, 24.43, 47.07, 51.99, 55.58, 65.13,
114.61, 114.67, 127.34, 127.92, 128.31, 139.31, 141.17, 151.87, 177.07.
Anal. calcd. for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.80;
H, 7.35; N, 4.52.

Mannich-Type Reaction
551
3-Benzo[1,3]dioxol-5-yl-2,2-dimethyl-3-phenylamino-propionic Acid
Methyl Ester (4n)
IR (KBr): n 2936, 2878, 1688, 1141, 1083 cm21 1H NMR (CDCl3,
.
300 MHz): d 1.17 (s, 3H), 1.27 (s, 3H), 3.66 (s, 3H), 4.38 (d, J ¼ 3.78 Hz,
1H), 4.73 (d, J ¼ 3.24 Hz, 1H), 5.91 (d, J ¼ 8.28 Hz, 2H), 6.51
(d, J ¼ 5.79 Hz, 2H), 6.59–6.63 (m, 1H), 6.71–6.75 (m, 3H), 6.76–7.08
(m, 2H); 13C NMR (CDCl3, 75 MHz): d 20.82, 24.52, 47.02, 52.08, 64.13,
100.94, 107.71, 108.29, 113.37, 117.30, 121.78, 128.99, 133.21, 146.84,
147.53, 176.98. Anal. calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28.
Found: C, 69.80; H, 6.45; N, 4.24.
Crystal Data for 4a
C18H20FNO2, F.W. 301.35, colorless crystal, triclinic, space group
o
˚
P-1, a ¼ 8.002 (2), b ¼ 9.963 (2), c ¼ 10.808 (3) A, a ¼ 73.953 (13) ,
3
b ¼ 84.084 (15)o, g ¼ 76.047 (14)o, V ¼ 803.0 (3) A
,
Z ¼ 2,
˚
Dc ¼ 1.246 mg m23
,
T ¼ 153(2) K, Mo Ka (l ¼ 0.71070 A),
˚
m ¼ 0.072 mm21, F (000) ¼ 352, R ¼ 0.0454, wR ¼ 0.1062, largest diff.
peak and hole: 253 and 271 e nm23. CCDC reference number 604093.
.
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