Utilization of Solid Acid SO42?/TiO2 as Catalyst to the Three-Component Mannich Reaction at Ambient Temperature

Article abstract of DOI:10.1002/jhet.2825

The three-component Mannich reaction of among dimethyl malonate, aromatic primary amine, and aromatic aldehyde was made successfully in the presence of solid acidic catalyst SO₄^2?/TiO₂, with excellent catalytic

Full text of DOI:10.1002/jhet.2825

Month 2017 Utilization of Solid Acid SO42ꢀ/TiO2 as Catalyst to the Three-Component
Mannich Reaction at Ambient Temperature
*
Yuanyong Yao, Meng Zhang, Shixue Chen, Mingming Xing, and Hua Shu
Institute of Material and Chemical Engineering, Tongren University, Tongren 554300, People’s Republic of China
*
E-mail: 583780805@qq.com
Additional Supporting Information may be found in the online version of this article.
Received December 21, 2015
DOI 10.1002/jhet.2825
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
The three-component Mannich reaction of among dimethyl malonate, aromatic primary amine, and
aromatic aldehyde was made successfully in the presence of solid acidic catalyst SO42ꢀ/TiO2, with excellent
2ꢀ
catalytic activity, as compared to SO42ꢀ/γ-Al2O3 and SO42ꢀ/ZnO. To the best of our knowledge, SO4
/
TiO2 prepared at varied calcination temperatures can perform different intensities of Lewis and Brønsted
acidities. Because of this point, under the optimum conditions, the effect of SO42ꢀ/TiO2 (prepared at
200°C) was much more than that of SO42ꢀ/TiO2 (prepared at 300°C or 400°C) in the three-component
Mannich reaction. In observing ionization activation mode of the three-component Mannich reaction, it
disclosed that the plausible mechanism possibly undergoes formation of aldimines and transformation of
aldimines into β-amino esters by applying solid acidic catalyst SO42ꢀ/MxOy.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
nitrogen atom with acidic proton may be envisaged.
These catalytic interactions with the electrophilic
substrate are presumably responsible for lowering the
activation energy of the overall reaction thereby
promoting the formation of the Mannich adduct
favorably. Although the activation of substrates in
various Mannich-type reactions via non-covalent
hydrogen-bond interaction has been widely exploited
[23–28], the corresponding activation of imines through
ion-pair formation has been scarcely reported. It appears
that Mannich reactions catalyzed by relatively stronger
Brønsted Lewis acids facilitate the nucleophilic attack of
enolizable carbonyls like malonate to pi-antibonding
orbital of an sp2-hybridized carbon center of electrophilic
aldimine [29–33]. In the absence of a base initiator, the
substrate under this reaction condition presumably
undergoes activation through an ionic mechanism
involving the generation of an ion-pair.
Suitably substituted amino esters and their derivatives
are considered as potent building blocks for designing
various pharmaceutical or medicinal products and their
intermediates [1,2]. In particular, certain optically active
β-amino esters with appropriate configuration of the
chiral center have been widely applied to generate
products of biological significance such as peptide
mimics, antibiotics, herbicides, pharmacological agents,
enzyme inhibitors, and catalytic antibodies [3–6]. The
prospective β-amino ester derivatives which are usually
characterized by the presence of a chiral carbon center
are conventionally synthesized by Mannich or Mannich-
type reaction of pregenerated or in situ electrophilic
aldimines (EI) with malonate esters serving as the
nucleophile (Nu). Numerous synthetic approaches to
diverse amino ester derivatives (both racemic and chiral)
have been investigated and documented in the last
10 years [7–22].
Solid acids derived from SO42ꢀ/MxOy have been
regarded as highly efficient and environment-friendly
catalysts for various organic transformations such as
isomerization and alkylation reactions. These acids which
are usually associated with two catalytic sites are able to
activate a wide range of substrates because of the
presence of both Brønsted and Lewis acidic sites. In this
Regarding mechanism of acid-catalyzed Mannich or
Mannich-type reactions, both non-covalent hydrogen-
bond activation of the imine with Brønsted Lewis acids
as well as ionic activation involving the formation of an
ion pair from the interaction of lone pair of electrons of
© 2017 Wiley Periodicals, Inc.

Y. Yao, M. Zhang, S. Chen, M. Xing, and H. Shu
Vol 000
regard, Jing and co-workers [34] had made an interesting
observation that solid acid SO42ꢀ/TiO2 prepared at
various calcination temperatures exhibited Lewis and
Brønsted acidities to different extents, as confirmed from
their in situ FIIR-pyridine absorption frequencies at
1450 cmꢀ1 and 1540 cmꢀ1 respectively. It appears that
ionic mode of mechanism is greatly assisted by the
presence of a water source which can readily convert
Lewis acidic sites into active Brønsted acids to activate
the aldimines through ion-pair formation in a typical
Mannich reaction, as depicted in Figure 1.
Furthermore, this acid catalyst can help to initiate the
Mannich reaction not only through chemical interaction
but also by offering large surface area to the reacting
components. In continuation to our synthesis of Mannich
adducts [35–38], herein, we report synthesis of β-amino
esters through Mannich-type reaction of aromatic
aldimines with dimethyl malonate catalyzed by acid
catalyst SO42ꢀ/MxOy. Under optimal conditions, in order
to account for the observed products, an ionic mechanism
of catalytic activation of the aldimines has been proposed.
RESULT AND DISCUSSION
As depicted in Figure 1, partial Lewis acidic site
originated from SO42ꢀ/MxOy can be automatically
transformed into Brønsted acidic site by absorbing H2O.
Depending on the synthetic procedures of solid acids
SO42ꢀ/MxOy reported by authors [37,38], we selected
SO42ꢀ/γ-Al2O3, SO42ꢀ/TiO2, and SO42ꢀ/ZnO as acidic
catalysts to investigate
a
model three-component
Mannich reaction of among aniline, bezenyldehyde, and
dimethyl malonate, as well as evaluate their catalytic
activities, which were depicted in Table 1. It was found
that under the same conditions, the effect of SO42ꢀ/TiO2
(prepared at 200°C, 300°C, and 400°C, respectively)
utilized in the model three-component Mannich
reaction, performing the better result of dimethyl
2-(phenyl(phenylamino)methyl)malonate 4, with 45%–
65% in yields (entries 4–9, in Table 1), was more than
that of SO42ꢀ/ZnO and SO42ꢀ/γ-Al2O3, with 34% and
26% in yields (entries 2 and 3, in Table 1). In addition,
we have known that SO42ꢀ/TiO2 prepared at different
calcination temperatures are able to perform varied
intensity of Lewis and Brønsted acidities. SO42ꢀ/TiO2 as
solid acidic catalyst prepared at 200°C, 300°C, and
400°C, respectively, was studied on the above model
three-component Mannich reaction to evaluate their
catalytic activities. The results demonstrated that the
2ꢀ
Figure 1. Plausible conversion of Lewis acid to Brønsted acid in SO4
/
TiO2 system.
Table 1
The three-component Mannich reaction promoted by solid acids SO42ꢀ/TiO2.
Entry
Cat/mol%
Solvent
Temp./°C
Time/h
Yield/%d
1
2
3
4
5
6
7
8
9
10
—
DCM
DCM
DCM
DCM
DCM
DCM
toluene
EtOH
toluene
xylene
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
24
24
trace
34
26
45
55
61
64
60
2ꢀ
SO42ꢀ/ZnOa/10 mol%
a
SO42ꢀ/γ-Al2O3 /10 mol%
a
SO4 /TiO2 /10 mol%
SO422ꢀꢀ/TiO2b/10 mol%
c
SO42ꢀ/TiO2c/10 mol%
SO42ꢀ/TiO2c/10 mol%
SO42ꢀ/TiO2c/10 mol%
SO42ꢀ/TiO2a/20 mol%
SO4 /TiO2 /10 mol%
65
21e
aPrepared at 400°C.
bPrepared at 300°C.
cPrepared at 200°C.
dIsolated yield after chromatographic purification.
eSO42ꢀ/TiO2 refluxed for 6 h in xylene to be cool down to room temperature, with equipment of dean stark.
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effect of calcination temperature of 200°C performs better
than that of 300°C and 400°C in catalytic activity of
SO42ꢀ/TiO2 under the same conditions. The resulting
amino esters 4 exhibited dramatic distinctions in yields,
with the yields of 61%, 55%, and 45%, respectively
(entries 4–6, in Table 1). While practically no product
formation was observed in the absence of any catalyst
(entry 1, in Table 1). To optimize reaction conditions for
performing better catalytic activity of SO42ꢀ/TiO2, we
further studied this model reaction using solid acidic
catalyst SO42ꢀ/TiO2 (prepared at 200°C) under different
conditions. We discovered that toluene offered better yield
(entry 7, in Table 1), as compared to other solvents such
as EtOH or dichloromethane. Additionally, by increasing
amount of solid acidic catalyst SO42ꢀ/TiO2 (prepared at
200°C) from 10 mol% to 20 mol% (entry 9, in Table 1), it
did not enhance the yield significantly at the ambient
temperature. What is more, we selected solid acidic
catalyst SO42ꢀ/TiO2 (prepared at 400°C) to be refluxed
in yields was slightly different from non-conjugated
aromatic aldehyde in yield, such as non- or mono-
substituted benzaldehyde, 2-furfuraldehyde, and 2-
formylthiophene, under the same conditions, which was
shown in entries 1–6 of Table 2. Benzothiazol primary
amine was regarded as specific hetero aromatic amine,
which was sensitive to strong Brønsted acid in the
reacting system. So, the reaction involving benzothiazol
primary amine was not to be proceeded well by applying
SO42ꢀ/TiO2 (prepared at 200°C), which had been in
agreement with experiments. Therefore, various
benzothiazol β-amino esters were afforded with not good
conversion. Simultaneously, through refluxing for some
hours in xylene, solid acid SO42ꢀ/TiO2 (prepared at
400°C) was able to exclude its Brønsted acid sites. It was
proved that the solid acid SO42ꢀ/TiO2 (prepared at
400°C) excluded Brønsted acidic sites disable to promote
the three-components Mannich reaction to carry on.
In repetition of solid acid SO42ꢀ/TiO2 (prepared at
200°C), the solid acid SO42ꢀ/TiO2 was filtrated out from
the reaction system, and then promoted at calcination
temperature of 200°C for 5 h. The renewed solid acid
SO42ꢀ/TiO2 was reused in the same Mannich reaction of
among aniline, bezenyldehyde, and dimethyl malonate
under the conditions (entry 7, in Table 1) to evaluate its
catalytic activity. The results showed that catalytic
activity of renewed SO42ꢀ/TiO2 is still kept well, with
62% in yield of product 4.
for 6 h in solvent of xylene, with equipment of dean stark,
2ꢀ
that was aimed to evaporate water away from the SO4
/
TiO2. In other words, it enabled to keep SO42ꢀ/TiO2 solid
acid’s Lewis acid sites, without Brønsted acid sites. It is
obvious that the yield of product 4 decreased dramatically
(entry 10, in Table 1). All in all, those tests proved that the
Brønsted acid site of SO42ꢀ/TiO2 is much more dominant
than the Lewis aid site in the three-component Mannich
reaction (entries 4–6, 10, in Table 1).
To further observe suitability of above mentioned solid
acidic catalyst SO42ꢀ/TiO2, the next task was to evaluate
the substrate scope, as shown as in Table 2. Utilization of
SO42ꢀ/TiO2 (prepared at 200°C), performing excellent
catalytic activity, to the three-component Mannich
reaction, in order to investigate the scope of reaction with
respect to aromatic primary amine and aldehyde, was
done under the above optimum conditions. In view of the
proposed ionization activation mode, primary amine was
used as one of three components of Mannich reaction,
which was regarded as a vital factor. Aromatic and
heteroaromatic primary amines were possibly responsible
for the effect of proposed ionization activation mode.
When hetero aromatic primary amine bearing
benzothiazol group was applied in the three-component
Mannich reaction, it performed expectations to be less,
with the range of 35%–49% in yields, as comparable to
that of aromatic primary amine of aniline. To the best of
our knowledge, heterocyclic ring primary amine could
also offer additional proton acceptor, such as nitrogen,
oxygen, and sulfur atom(s), which might disturb the
effect of the ionization activation mode. To investigate
the effect of aromatic aldehyde, the conjugated aromatic
aldehyde reacted with mono-or non-substituted
benzothiazol primary amine and dimethyl malonate to
obtain resulting amino esters 12, 13, with 49% and 48%
In order to account for ionization activation mode of the
three-component Mannich reaction in the presence of solid
acid SO42ꢀ/TiO2, we divided the three-component
Mannich reaction into two steps: one is the condensation
of aromatic primary amine with aromatic aldehyde to
form intermediate of iminiums; the other is nucleophilic
addition of dialkyl malonate to the former intermediate to
afford β-amino esters product. Setting up a model
condensation of aniline with benzyldehyde to obtain the
intermediate of iminium N-benzylideneaniline 5 with
using solid acidic catalyst SO42ꢀ/TiO2 (prepared at
200°C, 300°C, and 400°C, respectively) was made to
evaluate their catalytic activities at room temperature,
with stirring for 24 h in solvent of toluene, which was
shown as in Table 3. The intermediate of N-
benzylideneaniline 5 was afforded in yields of 63%, 61%,
and 59%, respectively, which was purified by means of
recrystallization with EtOH. It was indicated that in this
model condensation, SO42ꢀ/TiO2 (prepared at 200°C),
performing 6.964 (Brønsted acidity) and 1.568 (Lewis
acidity) identified by area value of character peaks in situ
FTIR pyridine adsorption spectrum, is not obvious
difference from others prepared at 300°C (6.206 and
1.087 in Brønsted and Lewis acidities) and 400°C (4.990
and 0.870 in Brønsted and Lewis acidities) in catalytic
activity [31]. Unfortunately, when Ar was benzothiazol
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Y. Yao, M. Zhang, S. Chen, M. Xing, and H. Shu
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Table 2
The three-component Mannich reaction induced by solid acid SO42ꢀ/TiO2 (prepared at 200°C).
Entry
1
Ar
Ar0
Product
Yield/%a
37b
2
3
35b
39b
4
5
37b
35b
6
7
38b
49b
(Continued)
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Solid Acid Applied to Organocatalysis of Mannich Reaction
Table 2
(Continued)
Entry
Ar
Ar0
Product
Yield/%a
8
48b
13
aIsolated yield after chromatographic purification.
bNewly SO42ꢀ/TiO2 prepared at 200°C.
Table 3
The model condensation of aniline with benzyldehyde by applying SO42ꢀ/TiO2.
Entry
Cat/mol%
Calcination temp./C
Yield/%a
1
2
3
4
—
—
Trace
63
61
SO42ꢀ/TiO2/10 mol%
SO42ꢀ/TiO2/10 mol%
SO42ꢀ/TiO2/10 mol%
200
300
400
59
aIsolated yield after chromatographic purification.
group, a series of benzothiazol imines derived from
performing powerful Brønsted and Lewis acidities,
benzyldehyde as electrophile was protonated to be
activated in the reaction system. The activation energy of
condensation of benzyldehyde with aniline was permitted
to be lowered. Therefore, the above condensation was put
into effect at room temperature.
What is more, in the step of formation of β-amino esters,
the nucleophilic addition of dimethyl malonate to N-
benzylideneaniline 5 to form product 4 was done in the
presence of SO42ꢀ/TiO2 (prepared at 200°C, 300°C, and
400°C, respectively), the results were almost agreeable to
corresponding data from entries 4–7, in Table 1, as
shown as in Table 4.
In view of Figures 2 and 3, it was proposed that the two
plausible mechanisms of Mannich transformation by acid
or base were discussed. In acidic catalysis, SO42ꢀ/TiO2
offering strong Brønsted acidity can protonate the
nitrogen atom of iminiums to be activated; subsequently,
the active iminiums are attacked by less amount of enol
reaction of benzothiazol amines with non-conjugated or
2ꢀ
conjugated aromatic aldehydes in the presence of SO4
/
TiO2 (prepared at 200°C, 300°C, and 400°C,
respectively) at room temperature, eventually stirring for
48 h, was not detected by TLC. This evidence indicated
that the plausible track of benzothiazol β-amino esters’
condensation does not possibly follow product of
dimethyl 2-(phenyl(phenylamino)methyl)malonate 4.
To the best of our knowledge, the condensation of
aniline with benzyldehyde is actually nucleophilic
addition–elimination.
Conventionally,
nucleophilic
addition needs increased effective collisions between
nucleophile and electrophile by heating up to reflux for
several hours to form the intermediate of corresponding
amino methanol, for example, phenyl(phenylamino)
methanol. And then, the elimination of corresponding
amino methanol is made to form carbon–nitrogen double
bond (C═N) by taking off a H2O in acidic environment,
because of its hydroxyl group protonated to be good
leaving group. Because of SO42ꢀ/TiO2 solid acid
of
dimethyl
malonate
to
complete
Mannich
transformation. Simultaneously, in base catalysis, wake
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Table 4
The two-component Mannich reaction induced by applying SO42ꢀ/TiO2.
Entry
Cat/mol%
Calcination temp./°C
Yield/%a
1
2
3
4
5
—
—
200
300
400
—
Trace
66
61
58
15
SO42ꢀ/TiO2/10 mol%
SO42ꢀ/TiO2/10 mol%
SO42ꢀ/TiO2/10 mol%
NEt3/10 mol%
aIsolated yield after chromatographic purification.
Figure 2. Proposed plausible mechanism of Mannich transformation induced by acid.
and then to attack un-activated iminiums to obtain β-
amino esters. Comparing the two activation modes, the
yield in acidic catalysis is more than that in basic
catalysis under the same conditions. By which it indicates
that active energy of the whole reaction in acid catalysis
should be lower than that in base catalysis, which is
depicted in Table 4.
CONCLUSIONS
The three-component Mannich reaction of among
dimethyl malonate, aromatic primary amine, and
2ꢀ
aldehyde in the presence of solid acidic catalyst SO4
/
Figure 3. Proposed plausible mechanism of Mannich transformation in-
duced by base.
MxOy, especially for SO42ꢀ/TiO2 (prepared at 200°C,
300°C, and 400°C, respectively) was allowed to be
continue at ambient temperature. Simultaneously,
experimental data have proved the Brønsted acidity of
SO42ꢀ/TiO2 to be dominant in the three-component
Mannich reaction. Relying on this point, it successfully
base such as triethyl amine bearing a pair of lonely
electrons can capture active proton originated from α-
carbon of dimethyl malonate to be strong nucleophile,
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Solid Acid Applied to Organocatalysis of Mannich Reaction
proved that the effect of SO42ꢀ/TiO2 (prepared at 200°C) is
much more than that of SO42ꢀ/TiO2 (prepared at 300°C
and 400°C, respectively). In observing the mechanism of
Mannich transformation induced by solid acid catalyst,
we divided the three-component Mannich reaction into
two steps: one is condensation of aromatic primary amine
with aromatic aldehyde to form the intermediate of
iminiums; the other is nucleophilic addition of dimethyl
malonate to prepared iminiums to afford product. Taking
the three-component Mannich reaction among aniline,
The second step: a mixture of imines (20 mmol) and solid
acid SO42ꢀ/TiO2 loading 10 mol% (2 mmol, 0.3524 g) in
dry toluene (5 mL) was stirred for 5 min at room tempera-
ture under argon atmosphere. And then, dimethyl malonate
3 (22 mmol) was added dropwise, and the progress of the
reaction was monitored by conducting thin layer chroma-
tography on silica gel. After 24 h, the reaction was ended.
The solid acid SO42ꢀ/TiO2 was filtered out from the reac-
tion system. The organic phase was dried with anhydrous
MgSO4. After separation out of solid, the dry organic
phase was evaporated away. The residue was submitted
to column chromatography on silica gel (petroleum
ether / EtOAc = from 10/1 to 5/1) to afford final product.
Dimethyl 2-(phenyl(phenylamino)methyl)malonate (5). As
a white solid; yield: 64%; M.p. 98–100°C. 1H–NMR
(500 MHz, CDCl3, 25°C, TMS): δ (ppm) 8.04 (d, J = 10,
1H), 7.79 (d, J = 10 Hz, 1H), 7.53–7.48 (m, 4H), 7.34–
7.26 (m, 3H), 7.23 (d, J = 5 Hz, 1H), 7.18 (t, J = 10 Hz,
1H), 6.41–6.39 (d, J = 10 Hz, 1H), 5.53–5.49 (t,
J = 20 Hz, 1H), 4.97–4.91 (dd, J = 20 Hz, 1H), 4.17–
3.98(m, 4H), 1.30 (t, J = 5 Hz, 3H), 1.15 (t, J = 5 Hz,
3H); 13C–NMR (125 MHz, CDCl3, 25°C, TMS): δ (ppm)
141.3(d), 135.6, 134.3, 128.7, 127.7(d), 126.3, 125.9,
125.2, 123.9, 120.1, 118.6, 63.5(d), 56.9, 55.7; Anal.
Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found:
C, 68.43; H, 5.85; N, 5.14.
bezenyldehyde, and dimethyl malonate for example, both
2ꢀ
of above two steps did work in the presence of SO4
/
TiO2 as solid acidic catalyst, with moderate yields.
Therefore, it was proposed that the plausible mechanism
of the three-component Mannich reaction possibly
undergoes formation of the intermediate of iminiums,
subsequently, to be activated by protonation in the
presence of SO42ꢀ/TiO2, as compared to the activation
mode of base catalysis.
EXPERIMENTAL
General experimental procedure for the three-components
Mannich reaction.
Aromatic aldehyde (20 mmol) and
solid acid SO42ꢀ/TiO2 loading 10 mol% (2 mmol,
0.3524 g) in dry toluene (5 mL) were added and stirred
for 5 min at room temperature under argon atmosphere.
And then, primary amine (16 mmol) and dimethyl
malonate 3 (22 mmol) were added in turn, and the
progress of the reaction was monitored by conducting
thin layer chromatography on silica gel. After 24 h, the
reaction was ended. The solid acid SO42ꢀ/TiO2 was
filtered out from the reaction system. The organic phase
was dried with anhydrous MgSO4. After separation out
of solid, the dry organic phase was evaporated away. The
residue was submitted to column chromatography on
silica gel (petroleum ether / EtOAc = from 10/1 to 5/1) to
afford final product.
Dimethyl-2-((6-methoxybenzo[d]thiazol-2-ylamino)(4-fluoro-
phenyl)methyl)malonate (6). As a colorless oil; yield: 12%;
1H–NMR (500 MHz, CDCl3, 25°C, TMS): δ (ppm) 7.43–
7.36 (m, 3H), 7.07 (d, J = 2.9 Hz, 1H), 7.00 (t, J = 8.6 Hz,
2H), 6.89–6.84 (m, 2H), 5.68–5.63 (m, 1H), 3.98 (d,
J = 5.2 Hz, 1H), 3.78 (m, 3H), 3.71 (s, 3H), 3.65 (s, 3H);
13C–NMR (125 MHz, CDCl3, 25°C, TMS): δ (ppm)
168.5, 167.3, 164.3, 163.4, 161.6, 155.7, 146.3, 134.6,
131.9, 128.6, 128.3, 120.0, 116.1, 115.5, 113.8, 105.4,
56.9, 55.9, 53.2, 52.9; 19F–NMR (470 MHz, CDCl3): δ
(ppm) ꢀ113.9. Anal. Calcd for C20H19FN2SO5: C, 57.41;
H, 4.58; N, 6.69. Found: C, 57.43; H, 4.75; N, 6.74.
Dimethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(2-chlorophenyl)
1
methyl)malonate (7). As a colorless oil; yield:23%; H–
General experimental procedure for the two-component
Mannich reaction.
NMR (500 MHz, CDCl3, 25°C, TMS): δ (ppm) 7.49–
7.41 (m, 1H), 7.40–7.33 (m, 2H), 7.27–7.21 (m, 3H),
7.06 (d, J = 7.4 Hz, 1H), 6.97 (t, J = 7.4 H z, 1H), 5.92
(q, J = 4.6 Hz, 1H), 4.19 (d, J = 4.6 Hz, 1H), 3.76 (m,
3H), 3.67 (s, 3H), 2.52 (s, 3H); 13C–NMR (125 MHz,
CDCl3, 25°C, TMS): δ (ppm) 168.5, 167.4, 165.3, 151.2,
129.9, 129.7, 128.5, 127.1, 126.8, 121.9, 118.5, 55.9,
54.2, 52.9, 18.6. Anal. Calcd for C20H19ClN2SO4: C,
57.34; H, 4.57; N, 6.69. Found: C, 57.21; H, 4.94; N, 6.70.
The first step: aromatic aldehyde (20 mmol) and solid acid
SO42ꢀ/TiO2 loading 10 mol% (2 mmol, 0.3524 g) in dry
toluene (5 mL) were added and stirred for 5 min at room
temperature under argon atmosphere. And then, primary
amine (16 mmol) was added, and the progress of the reac-
tion was monitored by conducting thin layer chromatogra-
phy on silica gel. After 24 h, the reaction was ended. The
solid acid SO42ꢀ/TiO2 was filtered out from the reaction
system. The organic phase was dried with anhydrous
MgSO4. After separation out of solid, the dry organic
phase was evaporated away. The residue was submitted
to column chromatography on silica gel (petroleum
ether / EtOAc =10/1) to afford intermediate of imines.
Dimethyl-2-((4-methylbenzo[d]thiazol-2-ylamino)(2-fluoro-
phenyl)methyl)malonate (8). As a colorless oil, yield: 25%;
1H–NMR (500 MHz, CDCl3, 25°C, TMS): δ (ppm) 7.46 (t,
J = 7.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23–7.31 (m,
1H), 7.05 (q, J = 7.4 Hz, 3H), 6.99 (t, J = 8.0 Hz, 1H),
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6.84 (d, J = 9.2 Hz, 1H), 5.81–5.88 (m, 1H), 4.14 (d,
J = 5.7 Hz, 1H), 3.69 (s, 3H), 3.70 (m, 3H), 2.54 (s, 3H);
13C–NMR (125 MHz, CDCl3, 25°C, TMS): δ (ppm)
168.3, 167.3, 165.2, 161.7, 159.8, 151.4, 128.7, 126.8,
124.5, 122.0, 118.4, 115.9, 115.4, 53.6, 53.2, 18.4; 19F–
NMR (470 MHz, CDCl3): δ (ppm) ꢀ117.7. Anal. Calcd
for C20H19 FN2SO4: C, 59.69; H, 4.76; N, 6.96. Found:
J = 16 Hz, 1H), 6.25–6.31(dd, 1H), 5.26–5.29(m, 1H),
3.94 (d, J = 4.6 Hz, 1H), 3.78(s, 3H), 3.72(s, 3H). 13C
NMR (125 MHz, CDCl3) δ (ppm): 168.42, 167.51,
166.10, 150.89, 135.88, 133.35, 132.00, 128.69, 128.31,
127.15, 126.81, 126.46, 125.15, 120.55, 120.02, 56.49,
55.32, 53.15, 52.99; Anal. Calcd for C21H18N2O4ClS:
C, 58.67; H, 4.22; N, 6.52; Found: C, 58.16; H, 3.98;
N, 6.21.
C, 59.27; H, 4.51; N, 6.79.
Dimethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(phenyl)methyl)
1
malonate (9). As a colorless oil, yield: 37%, H–NMR
(500 MHz, CDCl3, 25°C, TMS): δ (ppm) 7.41–7.37 (m,
3H), 7.33 (t, J = 7.7 Hz, 2H), 7.27 (t, J = 6.3 Hz, 1H),
7.07 (d, J = 6.9 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 6.87
(br, 1H), 5.64–5.63 (m, 1H), 4.04–4.03 (m, 1H), 3.68 (s,
6H), 2.52 (s, 3H); 13C–NMR (125 MHz, CDCl3, 25°C,
TMS): δ (ppm) 168.3, 167.3, 165.4, 151.2, 138.6, 129.2,
128.9, 128.2, 126.7, 126.6, 121.7, 118.3, 58.4, 57.0,
53.2, 52.9, 18.4; Anal. Calcd for C20H20N2O4S: C, 62.48;
Acknowledgments. We gratefully acknowledge financial support
from the Natural Science Foundations of Guizhou Province
(Grant No. KY (2014)317) and the Educational Ministry
Foundation of Guizhou Province (Grant No. KY (2012)069).
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