Use of Mesoporous Molecular Sieves in the Production of Fine Chemicals: Preparation of Dihydroquinolinones of Pharmaceutical Interest from 2′-Aminochalcones

Article abstract of DOI:10.1002/cctc.201501403

Solid catalysts can be an alternative to homogeneous mineral Br?nsted and Lewis acids for the synthesis of pharmaceuticals provided that the diffusional and adsorption properties of the reactants and products can be controlled. Structured micro and especi

Full text of DOI:10.1002/cctc.201501403

DOI: 10.1002/cctc.201501403
Full Papers
Use of Mesoporous Molecular Sieves in the Production of
Fine Chemicals: Preparation of Dihydroquinolinones of
Pharmaceutical Interest From 2’-Aminochalcones
María J. Climent,* Avelino Corma,* Sara Iborra, and Laura Martí[a]
Solid catalysts can be an alternative to homogeneous mineral
Brønsted and Lewis acids for the synthesis of pharmaceuticals
provided that the diffusional and adsorption properties of the
reactants and products can be controlled. Structured micro
and especially monolayered zeolites and mesoporous materials
can be active and selective for intramolecular cyclization reac-
tions and, more specifically, for intramolecular aza-Michael cy-
clizations of 2’-aminochalcones to yield aryl-2,3-dihydro-4(1H)-
quinolinones of pharmaceutical interest. However, the catalyst
deactivates by strong adsorption of the basic quinolinone
product. Product desorption has been controlled by optimizing
catalyst pore structure and surface composition, together with
a proper selection of solvent and reaction temperature. Pro-
cess intensification for the synthesis of aryl-2,3-4(1H)-quinoli-
nones of pharmaceutical interest has been achieved by prepar-
ing catalysts that allow the one-pot synthesis of the dihydro-
quinolinones starting from 2’-nitrochalcones with excellent
yields.
Introduction
2-Aryl-2,3-dihydro-4(1H)-quinolinones (or 2-aryl-1,2,3,4-tetrahy-
dro-4-quinolones) derivatives are six-membered nitrogen het-
erocyclic compounds considered as aza-analogs of flavanones.
The synthesis of these compounds has generated continuous
interest because of their wide range of biological activities,
such as hypertensive, antibacterial, anti-inflammatory, and as
anticancer and immunosuppressive agents.[1–3] They display
significant cytotoxicity against a panel of human tumor cell
lines and also have high activity toward multi-drug resistant
KB-VIN, and ovarian 1A9 cell lines. In addition, aza-analogs of
flavanones can also serve as valuable precursors for the syn-
thesis of other pharmaceutical and active compounds;[4,5] for
example, those with potent antimitotic antitumor effects,[6]
such as 2-aryl-4-quinolones derivatives[7] and 4-alcoxy-2-arylqui-
nolines,[8] which are often not readily accessible by other
routes.[9,10]
Scheme 1. Synthesis of 2-phenyl-2,3-dihydroquinolin-4(1H)-one (2) from
2’-aminochalcone (1).
ous catalysts such as piperidine, KOH,[12] l-proline,[13] as well as
Brønsted and Lewis acids such as orthophosphoric acid in
acetic acid,[7] PEG-400 (PEG=polyethylene glycol),[14] wet cya-
nuric chloride,[15] zinc chloride,[16] ytterbium(III) triflate (YbOTf)3
in ionic liquid ([bmim]BF4; bmim=1-butyl-3-methylimidazoli-
um)[17] or lithium tetrafluoroborate[18] have been used as cata-
lysts for the cyclization of 2’-aminochalcones into quinolinones.
However, many of these homogeneous processes involve the
use of corrosive reagents, require large amounts of catalyst,
long reaction times, and high temperatures, giving, in most
cases, low yields of products. This is due to the fact that
strong bases and also acids promote polymerization reactions,
while generating considerable amounts of waste. To overcome
these drawbacks, different heterogeneous Brønsted and
Lewis acid catalysts such as silica-supported phosphomolybdic
acid (PMA-SiO2),[19] silica-supported TaBr5,[20] silica-supported
NaHSO4,[21] alumina-supported CeCl3·7H2O-NaI,[22] and Mont-
morillonite K-10 clay under microwave irradiation[23] have been
proposed to promote the intramolecular aza-Michael cycliza-
tion of 2’-aminochalcones. In Table 1 the reaction conditions
and yields reported in the literature using the above catalytic
systems have been summarized.
The synthesis of 2,3-dihydro-4(1H)-quinolinones is generally
accomplished by the base or acid catalyzed intramolecular aza-
Michael cyclization of substituted 2’-aminochalcones, through
the nucleophilic attack of the amino group on the b-carbon of
the enone function, which leads to the formation of six-mem-
bered heterocyclic systems (6-endo-trig cyclization product) as
predicted from Baldwin’s rules (Scheme 1).[11] Basic homogene-
[a] Prof. M. J. Climent, Prof. A. Corma, Prof. S. Iborra, Dr. L. Martí
Instituto de Tecnología Química (UPV-CSIC)
Universitat PolitØcnica de Val›ncia
Avda dels Tarongers s/n
46022, Valencia (Spain)
Fax: (+34) 963877809
E-mail: mjcliol@qim.upv.es
acorma@itq.upv.es
As can be observed, the heterogeneous catalytic systems re-
ported present several limitations such as the use of large cata-
Supporting information for this article can be found under http://
dx.doi.org/10.1002/cctc.201501403.
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The general mechanism for the intramolecular cyclization of
2’-aminochalcone in acidic media involves the protonation, or
Lewis acid interaction, of the oxygen of the enone group. This
produces activation of the b-carbon towards nucleophilic
attack of the amino group, leading to the formation of six-
membered heterocyclic systems, in this case dihydroquinoli-
none (6-endo-trig cyclization product; Scheme 2). The mecha-
nism is in good agreement with theoretical studies recently
presented by Reyes et al.,[27] who have shown that the electro-
philic character of the b-carbon in 2’-aminochalcones increases
18% in acidic media (TFA).
Table 1. Heterogeneous catalysts and reaction conditions for the synthe-
sis of 2,3-dihydro-2-phenyl-4(1H)-quinolinone reported in the literature.[a]
Catalyst
Catalyst
amount
Solvent
T
[8C]
Time
Yield
[%]
Ref.
PMA-SiO2
TaBr5-SiO2
NaHSO4-SiO2
1 mol%
EtOH reflux 18 h
52
[19]
[20]
5–10 mol%
NaHSO4 (2 g)
SiO2 (2 g)
0.3–0.4 g
–
–
150 3–5 min 92
150 8 h
72 (95)[c] [21]
CeCl3·7H2O
NaI-Al2O3
montmorillonite 1 g[b]
–
–
70 2.5 h
98
[22]
[23]
MW 1.5 min 80
[a] 2’-Aminochalcone: 1 mmol. [b] 2’-Aminochalcone: 0.45 mmol. [c] Yield
under microwave irradiation (MW) given in parentheses.
lyst-to-substrate ratios (from 1.35 to 130.15 g catalyst per g of
2’-aminochalcone), in some cases long reaction times, and
temperatures higher than 1008C or microwave activation are
required. Additionally, in the case of acid-supported catalysts,
leaching of the acid into the reaction media could be expect-
ed, which may limit the recovery and recyclability of the cata-
lyst. Therefore, the development of efficient and stable hetero-
geneous catalysts for the aza-Michael addition is desirable.
Cascade processes involving multiple catalytic events is an
important area of research in organic chemistry as it can help
to decrease raw materials consumption and energy, producing
lower amounts of waste.[24,25] In this sense, we have recently
presented an efficient method to synthesize a variety of 2’-ami-
nochalcones through a cascade process that involves, as the
first step, the Claisen–Schmidt condensation of o-nitroaceto-
phenones and benzaldehyde derivatives followed by reduction
of the nitro group into the corresponding amino group.[26] It
would then be of much interest to develop a single cascade
process able to directly produce dihydroquinolinones from ni-
trochalcones. In the first part of this work, we will show that
this can be achieved by means of a catalyst based on micro-
and mesoporous molecular sieves. Thus, we will present how
the catalyst can be optimized to maximize the yield and cata-
lyst life during the synthesis of a variety of dihydroquinoli-
nones of pharmaceutical interest, starting from the substituted
2’-aminochalcones, with excellent activities and selectivities.
Then, in the second part of this work, a cascade process will
be presented in which hydrogenation of 2’-nitrochalcones into
aminochalcones will be coupled with their cyclization to
obtain dihydroquinolinones with a bifunctional metal–acid cat-
alyst.
Scheme 2. Intramolecular cyclization mechanism of 2’-aminochalcones in
acidic media.
Among the different potential solid acid catalysts able to
perform the aza-Michael reaction, we thought that Brønsted or
Lewis acidic aluminosilicates could be the most promising cat-
alysts as they offer high flexibility for catalyst design. They can
range from amorphous to crystalline and have micro- to meso-
porous structures that can be synthesized with different pore
sizes, acidity, and hydrophobic–hydrophilic properties.[28] More-
over, the thermal stability of aluminosilicates allows their re-
generation by simple calcination in air.
For the study of the ring-closure process, the trans-2’-amino-
chalcone was selected as a substrate model and different
structured acidic solid catalysts with different pore topologies
and dimensions were chosen. We started with large-pore mi-
croporous zeolites though, as we were expecting reactant and
product diffusional problems, as well as strong adsorption of
the slightly basic products within the micropores of the zeo-
lites. We also introduced into our catalytic study 2D zeolites
(ITQ-2) and a mesoporous structured material (MCM-41), which
should be less or not limited by reactant and product diffusion.
More specifically, we have studied the potential of a USY tri-
directional 12 ring (12R) zeolite with cavities, a tridirectional
12R zeolite without cavities (HBeta), a 12R unidirectional zeo-
lite (Mordenite), a delaminated zeolite (ITQ-2), and a structured
mesoporous aluminosilicate (MCM-41), all of them bearing
Brønsted acid sites. As this type of reaction can also be cata-
lyzed by Lewis sites, metal framework substituted Sn-Beta and
Zr-Beta zeolites and Sn-MCM-41 were also tested in the cycliza-
tion of trans-2’-aminochalcone. As a reference homogeneous
Brønsted acid, we have chosen p-toluenesulfonic acid (p-TSA)
and a mixture of acetic and orthophosphoric acid.
Results and Discussion
Influence of catalyst structure
As stated above, the most common method to obtain 2-
phenyl-2,3-dihydroquinolin-4(1H)-one (2) from 1-(2-amino-
phenyl)-3-phenylprop-2-en-1-one (2’-aminochalcone, 1) is by
means of the acid-catalyzed aza-Michael intramolecular addi-
tion (Scheme 1).
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Table 2. Physicochemical properties of the catalysts.
À1 [b]
Catalyst(Si/Al)
Vmicrop.
[cm3 gÀ1
Pore size
[nm]
BET
[m2 gÀ1
Acidity [mmolpyridine gcat
2508C
]
[a]
]
]
1508C
3508C
B
L
B
L
B
L
Mordenite(10)
HBeta(12)
0.17
0.19
0.19
0.70”0.65
0.57”0.26
0.75”0.57
0.56”0.56
0.75”0.57
0.56”0.56
0.74”0.74
cups 0.8”0.7
3.2
550
602
600
67
25
54
25
29
28
65
59
69
81
58
34
56
36
25
32
29
32
HBetanano(8)
USY(5.6)
ITQ-2(12)
0.25
0.009
–
–
–
–
–
nm
593
643
1000
732
58
57
19
17
8
–
0
0
25
27
62
31
20
–
49
37
5
3
3
–
0
0
19
18
46
27
14
–
31
16
4
0
0
–
–
–
14
13
34
20
10
–
MCM-41(15)
MCM-41(30)
MCM-41(50)
Si-MCM-41
Sn-MCM-41(146)[c]
Sn-Beta(130)[c]
3.2
3.2
3.2
3.1
730
1100
1110
470
13
10
6
0
–
–
0.75”0.57
0.56”0.56
0.75”0.57
0.56”0.56
Zr-Beta(130)[d]
nm
482
0
15
0
0
–
–
[a] Volume of micropore calculated from t-plot. [b] Acidity (mmol of pyridine per gram of catalyst) calculated by using extinction coefficients given in
ref. [50]. B: Brønsted acidity, L: Lewis acidity. [c] Si/Sn molar ratio. [d] Si/Zr molar ratio.
A blank experiment in the absence of catalyst was per-
Table 3. Results of the intramolecular aza-Michael cyclization of 2’-amino-
formed and 5% conversion was observed after 8 h. The chemi-
cal composition, textural properties, and acidity of the solid
catalysts studied are given in Table 2, and their preparations
are presented in the Experimental Section.
chalcone in the presence of acid catalysts.
Entry Catalyst
r8”102
TOF[c]
[hÀ1
t
Conv. Yield Selec.
[molhÀ1 gÀ1
]
]
[h] [%] 2 [%] 2 [%]
1
2
3
4
5
6
7
8
mordenite[a]
HBeta
nanoBeta
USY
ITQ-2
MCM-41(15)
MCM-41(30)
MCM-41(50)
Si-MCM-41
Sn-MCM-41[a]
Sn-Beta
3.40
3.67
17
508
472
2882
2807
1912
11 476
2400
3525
–
8
6
8
6
6
1
6
6
6
8
8
8
4
6
8
22
42
92
48
72
94
75
62
5
21
42
92
48
72
94
75
62
98
99
First, the 12R unidirectional zeolite (Mordenite) and two zeo-
lites with tridimensional pore topology and strong Brønsted
acidity (HBeta and USY) were selected to perform the desired
cyclization. When the cyclization reaction was carried out over
these catalysts at 1008C using toluene as a solvent, Mordenite
exhibited a similar turnover frequency (TOF) as Beta zeolite but
a higher deactivation rate could be deduced from the results
in Figure 1. Indeed, it can be seen that the conversion curve
for Mordenite stops sharply with reaction time, at still low
levels of conversion (see Table 3, entries 1 and 2). This fast de-
100
100
100
100
100
100
94
16.28
10.90
21.80
6.80
4.70
0.15
0.08
1.55
1.15
–
9
4.7
10
11
12
13
14
15
5
15
59
48
11
85
5
12
59
48
5
85
2
80
92
52
100
100
50
100
43
Zr-Beta
p-TSA[b]
–
AcH-OPA[d]
blank
–
–
Reaction conditions: 2’-aminochalcone (1 mmol), catalyst (8 wt%), tolu-
ene (0.5 mL), 1008C. [a] Catalyst: 15 wt%. [b] Catalyst: 15 wt%, at 308C.
[c] Calculated as the initial reaction rate (mmolhÀ1
) divided by the
number of Brønsted acid sites measured at 1508C. [d] A mixture of acetic
acid and orthophosphoric acid (1:1 v/v, 15 wt%) was used as the catalyst
at 1008C.
activation of the Mordenite can be attributed to the unidirec-
tionality of the pores, which can be easily plugged by strongly
adsorbed reactants and products. Better catalytic activity and
yield were achieved with the tridirectional USY zeolite (Table 3,
entry 4), with the TOF being about six times higher than in the
case of Beta zeolite, with the smaller pore diameter. These re-
sults indicate that the pore dimensions and topology, and
therefore reactant diffusion and site accessibility, play an im-
portant role for the catalytic behavior of the microporous ma-
terials. Pore dimensions and topology result in smaller geomet-
Figure 1. Kinetics curves of the yield to 2-phenyl-2,3-dihydroquinolin-4(1H)-
one obtained with different solid acid catalysts (8 wt%) starting from 2’-ami-
&
*
nochalcone (1 mmol) in toluene (0.5 mL) at 1008C. MCM-41 ( ), ITQ-2 ( ),
~
^
HBeta ( ), USY ( ), 15 wt% Mordenite (”), 15 wt% Sn-MCM-41(+).
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rical restrictions for the diffusion of reactants and/or products
in USY compared with HBeta zeolite. In fact, if one considers
the molecular dimensions of the trans-2’-aminochalcone
(0.78”0.74”0.64 nm) and dihydroquinolinone (1.07”0.59”
0.55 nm), it appears that the molecular size of the trans-2’-ami-
nochalcone is in the range of the pore sizes of USY zeolite
(0.74”0.74 nm) and is larger than the pore diameters of HBeta
(0.75”0.57 and 0.56”0.56 nm) and Mordenite (0.70”0.65 and
0.57”0.26 nm). Consequently, geometrical restrictions for reac-
tant diffusion could be expected for these three catalysts, in-
creasing in the order USY<HBeta<Mordenite. To check this
point, a nanocrystalline Beta zeolite sample with smaller crystal
size (10–20 nm; Betanano) was prepared and tested in the cycli-
zation reaction. As can be seen in Figure 2, when the zeolite
Table 4. Composition of the organic material extracted by Soxhlet.
Catalyst
Total amount[a]
[%]
Composition of organic [%][b]
Reactant (1)
Product (2)
HBeta
USY
ITQ-2
3
14
43
25
3
31
75
97
69
[a] wt% of organic material extracted by Soxhlet (with respect to the
amount of the catalyst) by using dichloromethane. [b] Product distribu-
tion of the compounds in the organic extract.
al remains on the catalyst after use, on the Beta zeolite the or-
ganic material was twofold higher (38 wt%). Moreover, analysis
of the molecules remaining adsorbed on the catalyst after re-
action (see Table 4) indicates that most of the organic materials
adsorbed correspond to the reaction product, that is, dihydro-
quinolinone.
Thus, tridirectional HBeta and USY zeolites appear not to be
suitable catalysts to carry out the aza-Michael intramolecular
cyclization owing to the existence of restricted diffusion and
enhanced adsorption of the reactants and products in the
pores, leading to a fast deactivation of the catalyst.
From all the above results, it can be inferred that solid cata-
lysts with larger pores and milder acidities should be better for
performing the aza-Michael intramolecular cyclization of trans-
2’-aminochalcone. Thus, a delaminated zeolite with large exter-
nal surface area, low micropore volume, and medium–strong
acidity (ITQ-2) was selected to perform the cyclization of trans-
2’-aminochalcone. This zeolite was prepared by delamination
of a layered MWW precursor,[29] resulting in thin zeolite sheets
(2.5 nm thick) with a hexagonal array of cups with an aperture
of 0.7 nm.
Figure 2. Yield of 2-phenyl-2,3-dihydroquinolin-4(1H)-one (2) versus time ob-
~
&
tained for HBeta ( ) and Betanano ( ) using 2’-aminochalcone (1 mmol) in tol-
uene (0.5 mL) at 1008C.
When the reaction was performed in the presence of the de-
laminated zeolite ITQ-2(Si/Al=12), a significant increase in the
conversion of trans-2’-aminochalcone with respect to the tri-
directional zeolites was observed (see Figure 1 and Table 3, en-
tries 2, 4, and 5). This behavior should be attributed to the de-
crease of the diffusional limitations of reactants and products,
owing to the much larger external surface of ITQ-2. Neverthe-
less, from the shape of the conversion versus time curve for
ITQ-2, it can be inferred that the catalyst also deactivates with
time (see Figure 1). The cause of the deactivation was studied
by stopping the reaction after 6 h when the maximum yield of
dihydroquinolinone (2) was 72% (with 100% selectivity). Then,
extraction of the solid catalyst with a Soxhlet apparatus
showed that 34 wt% (with respect to the catalyst) of organic
material was retained on the catalyst surface. Moreover, when
the extracted catalyst was reused in a second cycle, it was ob-
served that the maximum yield of dihydroquinolinone ach-
ieved after 6 h was only 45%. As in the case of ITQ-2 the diffu-
sion limitations are less than with Mordenite, HBeta, or USY
zeolites, we infer that the deactivation of ITQ-2 zeolite occurs
by the adsorption of basic products. Indeed, IR analysis of the
delaminated zeolite after use in the reaction shows a band at
1630 cmÀ1, which can be assigned to the carbonyl group of
the dihydroquinolinone (Figure S1 in the Supporting Informa-
tion).
crystallite size becomes smaller and consequently the ratio of
the external to the internal surface area increases, the initial re-
action rate considerably increases, achieving a 92% yield of di-
hydroquinolinone after 6 h with the nanocrystalline Beta zeo-
lite (Table 3, entry 3). These results confirm diffusional restric-
tions for the reactants and products in our reaction, also in
a tridirectional zeolite such as Beta.
Although a batch reactor is not the best-suited reactor to
study catalyst deactivation, by looking at the shape of the
curves in Figure 1, it can already be inferred that an important
deactivation of the catalysts is occurring during the reaction.
Indeed, with the microporous 3D zeolites, conversion practical-
ly stops at low conversions and, in a first approximation, it
could be said that the order of catalyst deactivation is Morden-
ite>Beta>USY.
The deactivation of the catalysts is probably due to the fact
that both 2’-aminochalcone and dihydroquinolinone have
a weakly basic character, which favors their strong adsorption,
blocking the pores and/or acid sites. As can be seen in
Figure 1, catalyst deactivation appears to be more important
on HBeta than on USY and, in fact, the thermogravimetric anal-
ysis of the used catalysts showed that although on the USY
zeolite 17 wt% (with respect to the catalyst) of organic materi-
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To decrease the impact of catalyst deactivation by adsorp-
tion of the mildly basic reactant and product, we thought to
use a mesoporous catalyst such as the aluminosilicate MCM-41
with weak acidity and pore diameter of 3.2 nm. It is expected
that this catalyst should allow an easier diffusion of reactant
and product and lower irreversible adsorption of the product.
The results presented in Figure 3 indicate that it is possible
with the MCM-41(15) sample to achieve a TOF six times larger
than that with ITQ-2, and a total conversion of trans-2’-amino-
chalcone of 94% with 100% selectivity to dihydroquinolinone
(2; see Table 3). When these results are compared with those
previously reported by using alumina-supported CeCl3·7H2O-
NaI,[22] it is possible to see that similar yields of dihydroquinoli-
none are achieved (Table 1); however, the amount of catalyst
required was between 17–30 times larger.
much smaller than that of the zeolite catalysts. In addition,
analysis of the extract showed that the organic material was
mainly composed by dihydroquinolinone (2).
A pure silica sample (Si-MCM-41) with a surface area of
1100 m2 gÀ1 gave very poor activity (5% yield after 8 h). This
result indicates that weak acid sites such as silanol groups do
not contribute significantly to the catalytic activity of the Al-
MCM-41 material and that the aza-Michael reaction is mainly
catalyzed by the bridging hydroxyl groups of the aluminosili-
cate. Moreover, thermogravimetric analysis of the used Si-
MCM-41 after Soxhlet extraction showed that only 1 wt% of
organic material remains adsorbed on the catalyst, which indi-
cates that the amount of organic material adsorbed on silanol
groups do not contribute significantly to catalyst deactivation
by pore blocking.
Catalysis by solid Lewis acid catalysts
From a mechanistic viewpoint, the success of the acid-cata-
lyzed aza-Michael reaction relies on the increase of the electro-
philicity of the conjugated alkene by interaction of the carbon-
yl group with the acidic site. The increase in electrophilicity of
the conjugated alkene can also be achieved by using a Lewis
acid catalyst, as said in the Introduction. It is well accepted
that the metal ion from a Lewis acid forms strong coordinate
bonds with the electron-withdrawing groups in conjugated al-
kenes, and thereby increases their electrophilicity to facilitate
the addition of nitrogenous nucleophiles[18,30] (see Scheme 2).
Taking this into account, we have also studied the catalytic ac-
tivity of microporous and mesoporous solid catalysts bearing
Lewis acid sites. Thus, Sn and Zr were incorporated into the
framework of MCM-41 (Sn-MCM-41) and Beta zeolite (Sn-Beta
and Zr-Beta). In these materials, the Sn and Zr atoms can act
as isolated Lewis acid sites, as has been found to occur in vari-
ous chemical transformations.[31,32]
Figure 3. Yield of 2-phenyl-2,3-dihydroquinolin-4(1H)-one (2) versus time
when the aza-Michael addition was performed using MCM-41 with different
~
&
*
^
Si/Al ratios. Si/Al=15 ( ), 30 ( ), 50 ( ), Si-MCM-41 ( ). Reaction conditions:
2’-aminochalcone (1 mmol), MCM-41 (8 wt%), at 1008C, in toluene (0.5 mL).
When the reaction was performed in the presence of the Sn-
MCM-41 sample, the initial reaction rate was very low, achiev-
ing only 12% yield of dihydroquinolinone after 8 h. Better re-
sults were obtained with Sn-Beta (see Table 3, entry 11), al-
though in this case the yield of dihydroquinolinone does not
surpass 60% after 8 h. Similar results were obtained with a Zr-
Beta catalyst (Table 3, entry 12), indicating that the Lewis acid
sites associated with Sn4+ or Zr4+ although they can perform
the aza-Michael addition, present relatively low activity and de-
activate rapidly.
On the other hand, when samples with higher Si/Al ratios
were used (entries 7 and 8, Table 3), the activities were consid-
erably decreased owing to the number of Brønsted acid sites
associated with the Al content decrease. These results indicate
that a good compromise between number and strength of
acid sites exist in the MCM-41(15) sample.
When the MCM-41(15) sample was reused without any pre-
vious treatment in a second cycle, only 50% yield of dihydro-
quinolinone (2) was obtained after 8 h reaction time, indicating
that a significant catalyst deactivation also occurs with MCM-
41. As the XRD patterns of the fresh and used catalyst showed
that the crystallinity of the catalyst was maintained (see Fig-
ure S2 in the Supporting Information), this deactivation could
still be due to the adsorption of the basic reactant and product
on the acid sites. In fact, the IR spectrum of the used catalyst
shows the adsorption band at 1630 cmÀ1, which is attributed
to the carbonyl group of the dihydroquinolinone (Figure S3 in
the Supporting Information).
For comparison purposes, the aza-Michael addition was per-
formed by using p-toluenesulfonic acid (p-TSA) as a homogene-
ous Brønsted acid catalyst under the same reaction conditions.
The results obtained show a strong oligomerization of the 2’-
aminochalcone, achieving only 4% dihydroquinolinone (2)
after 4 h reaction time. Moreover, when the temperature was
decreased at 308C, only 11 % conversion of 2’-aminochalcone
with 50% selectivity to dihydroquinolinone (2) was obtained,
whereas high molecular weight compounds were detected in
the reaction media. These results indicated again that strong
Brønsted acid catalysts are not adequate for this reaction and,
at least in the case of p-TSA, secondary reactions, mainly oligo-
The used catalyst was subsequently submitted to extraction
with a Soxhlet apparatus, and 9 wt% of organic (with respect
to the amount of catalyst) was recovered, this amount being
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merization of 2’-aminochalcone, are promoted. In fact, when
the reaction was performed by using a mixture of acetic acid
and orthophosphoric acid (1:1 v/v) as a homogeneous acid cat-
alyst, 85% yield of dihydroquinolinone was obtained after 6 h
reaction time (Table 3, entry 14).
tion rates when the reaction was carried out with ethanol as
the solvent, whereas better results were obtained with toluene
and, particularly, with the polar and aprotic acetonitrile. Never-
theless, when the catalyst was reused the conversion was low,
indicating that product adsorption was still high under these
conditions. Therefore, by considering that product adsorption
is an exothermic process, one could expect the adsorption
equilibrium constant for the product and, consequently, the
amount of product adsorbed to decrease when increasing the
reaction temperature. Thus, the reaction was also performed at
1008C and the results given in Figure 5 clearly show less deac-
tivation of the catalyst upon reuse, particularly with acetonitrile
as the solvent, and a smaller amount of product remained ad-
sorbed after the reaction was completed (3 wt% with respect
to the catalyst). In any case, catalyst deactivation still occurs
and regeneration of the catalyst by calcination was required
(Figure 6). However, when the reaction temperature was fur-
ther increased (to 1508C), similar yields of dihydroquinolinole
were achieved with the fresh and used catalyst (see Figure S4
in the Supporting Information)
Catalysis by solid bases
As it has been reported that homogeneous bases can catalyze
the cyclization of 2’-aminochalcones, heterogeneous basic cat-
alysts such as MgO and Al/Mg mixed oxides[33,34] were also
tested as they showed high activity for performing the intra-
molecular Michael addition of 2’-hydroxychalcones into flava-
nones.[35,36] We have also studied the aza-Michael cyclization of
trans-2’-aminochalcone by using a MgO sample with Lewis
basic sites and high surface area (660 m2 gÀ1). However, only
5% conversion of 2’-aminochalcone was obtained after 7 h,
with the retro-aldol condensation found to be the predomi-
nant process. Similar results were reported by Loh and Wei
when using a strong basic solid catalyst such as FK-supported
alumina (at 708C), where complete decomposition of the 2’-
aminochalcone was found.[37]
Influence of the solvent
We have shown that solid catalysts with weak acidity and
good accessibility to the active sites, such as MCM-41, exhibit
the best performance for the cyclization of trans-2’-aminochal-
cone into dihydroquinolinole. However, owing to the basicity
of the compounds involved in the reaction, significant adsorp-
tion of organic material on the catalyst surface still takes place,
leading to catalyst deactivation. A strategy to overcome the
catalyst deactivation problem is to use an adequate solvent,
which can help to desorb the products from the solid catalyst.
Thus, we have studied one polar protic solvent (ethanol), an
aprotic polar solvent (acetonitrile), and an apolar solvent (tolu-
ene) at 808C. The results given in Figure 4 indicate low reac-
Figure 5. Cyclization of 2’-aminochalcone with MCM-41(15) in the presence
~
&
of different solvents: acetonitrile ( ), toluene ( ). Second cycle in acetonitrile
*
(
^
) and in toluene ( ). Reaction conditions: 2’-aminochalcone (1 mmol),
8 wt% MCM-41(15), 1008C, 0.5 mL of solvent.
Figure 4. Kinetic curves of the intramolecular aza-Michael cyclization of 2’-
aminochalcone in the presence of MCM-41(15) catalyst in different solvents:
Figure 6. Reusability of MCM-41(15) catalyst in the synthesis of dihydroqui-
nolinone (2). Reaction conditions: 2’-aminochalcone (1 mmol), 8 wt% MCM-
41(15), 1008C, 0.5 mL toluene.
~
acetonitrile at 808C, with 8 wt% catalyst ( ), toluene at 808C, with 8 wt%
&
*
catalyst ( ), and ethanol at 1008C with 15 wt% catalyst ( ).
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Reaction kinetics
Scope of the reaction
Kinetic experiments were conducted at different initial concen-
trations of 2’-aminochalcone in toluene using MCM-41(15) as
the catalyst and the initial rates were obtained. The plot of the
initial rates versus the initial concentration of 2’-aminochalcone
(Figure 7) indicates a first-order reaction with respect to the
As MCM-41 (15) represents a good compromise between acidi-
ty and reactant accessibility, it was selected as the catalyst to
examine the scope for aza-Michael cyclizations of various sub-
stituted 2’-aminochalcones into dihydroquinolinones of phar-
macological interest.
In all cases, the usual 6-endo ring-closure reaction to give di-
hydroquinolinones occurs, whereas no 5-exo cyclocondensa-
tion to obtain indolinones was observed, as was theoretically
predicted by Reyes et al.[27]
Excellent yields and selectivities (>97%) were obtained by
using 2’-aminochalcones with electron-withdrawing groups
(Table 5, entries 2 and 3) or electron-donating groups (Table 5,
Table 5. Results of the intramolecular aza-Michael cyclization of 2’-amino-
chalcone
derivatives
in
the
presence
of
MCM-41(15).
Figure 7. Plot of initial cyclization reaction rates versus different molar con-
centrations of 2’-aminochalcone. Reaction conditions: initial concentration
of 2’-aminochalcone varied between 0.6–2 molLÀ1, toluene (0.5 mL), catalyst
(32 mg), 608C.
Entry
R
T
Conv.
[%]
Yield
[%]
Selec.
[%]
[min]
1
2
3
4
5
H
15
180
60
5
98
100
100
100
100
95
98
97
99
98
97
98
97
99
98
Cl (a)
CN (b)
OMe (c)
Me (d)
concentration of 2’-aminochalcone. Similarly, a first-order de-
pendency was also found in the isomerization of 2’-hydroxy-
chalcone into flavanone by using homogeneous[38,39] or hetero-
geneous catalysts.[40] The influence of the reaction product on
the rate of the reaction was studied by measuring the initial re-
action rate at 1.20 molLÀ1 concentration of 2’-aminochalcone
with no dihydroquinolinone added and in the presence of
0.24 and 0.45 molLÀ1 of dihydroquinolinone. Thus, the initial
reaction rates measured were 0.90”10À3 and 0.71”
10À3 molminÀ1 gÀ1, respectively. These results clearly show the
negative effect of the reaction product on the initial rate of
the reaction owing to a strong competitive adsorption of the
reaction product, in agreement with the IR spectra of the used
catalyst (Figure S2), which showed the adsorption of the dihy-
droquinolinone.
5
Reaction conditions: 2’-aminochalcone (1 mmol), catalyst (8 wt%), tolu-
ene (0.5 mL) at 1008C.
entries 4 and 5) on the aromatic ring. As shown in Table 5, the
activities appear to be influenced by the structure and the
electronic properties of the 2’-aminochalcone derivatives. For
instance, when electron-donating groups are present in the
benzaldehyde derivative moiety, the corresponding cyclic
products were obtained with excellent yields in short times,
whereas with electron-withdrawing substituents, longer reac-
tion times were required to achieve high yields. The selectivity
was not affected by the electronic nature of the substituents.
Comparison of the present results with previously reported
ones (see Table 1), where higher amounts of catalyst and
higher temperature or microwave irradiation are required
along with poor or null reusability of the catalyst, indicates
that the mesoporous molecular sieve MCM-41(15) represents
a clear alternative for the cyclization of 2’-aminochalcones into
dihydroquinolinones owing to the combination of accessibility
and mild acidity.
Initial reaction rates were also obtained at different tempera-
tures in the 50–1008C range and the first-order kinetic rate
constants were calculated. The Arrhenius plot of the reaction
rate constants is shown in Figure S5 (in the Supporting Infor-
mation), and an apparent activation energy of 16 kcalmolÀ1
(69 kJmolÀ1) was obtained for the 2’-aminochalcone cyclization
using the MCM-41(15) catalyst. It is interesting to note that
a higher activation energy (57 kcalmolÀ1) was reported for the
cyclization of 2’-aminochalcone into dihydroquinolinone in the
presence of an ionic liquid ([bmim]BF4) and microwave (MW) ir-
radiation.[41] This difference is probably related to differences in
the heat of adsorption of the reactant or the stabilization of
the transition state in the two catalytic systems, the stabiliza-
tion being larger for the solid catalyst.
One-pot synthesis of dihydroquinolinones starting from 2’-
nitrochalcones
As the synthesis of 2’-aminochalcones by Claisen–Schmidt con-
densation between o-aminoacetophenones and benzaldehyde
derivatives in the presence of strong bases leads, in general, to
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low yields of 2’-aminochalcones, owing to the fact that amino
compounds are prone to oligomerization reactions,[7,42] there is
an alternative process to obtain these amino compounds by
hydrogenation of the corresponding 2’-nitrochalcones.[26,43]
With this in mind, we thought to obtain dihydroquinolinones
starting from 2’-nitrochalcones in a one-pot process in the
presence of a bifunctional metal–acid catalyst (Scheme 3).
can be obtained in excellent yields directly from 2’-nitrochal-
cones in a reasonable time (1.3 h) in a one-pot system (see
Figure 8) with the catalyst able to be reused several times. This
process avoids intermediate separation, purification, and neu-
tralization steps as will be necessary when using homogeneous
catalysts.
Conclusions
It has been shown that the use of zeolites (with
Brønsted or Lewis acid sites) as catalysts for the intra-
molecular aza-Michael cyclization of 2’-aminochal-
cones leads to low yield of dihydroquinolinone
owing to deactivation of the catalyst. These results
Scheme 3. One-pot process for 2,3-dihydroquinolinone synthesis from 2’-nitrochalcone.
are attributed to the existence of diffusional limita-
Thus, bifunctional catalysts with Pt on MCM-41 (0.1 wt% and
0.5 wt% platinum content) were prepared. When 2’-nitrochal-
cone (0.5 mmol) was dissolved in toluene (0.5 mL) and heated
at 708C under 9 bar of H2 in the presence of 0.1Pt/MCM-41(15)
(20 mg), only 5% of 2’-aminochalcone (100% selectivity) was
obtained after 3 h reaction time. When the amount of Pt was
increased to 0.5 wt%, 85% of 2’-nitrochalcone was converted
in 3 h but, unfortunately, only 3% yield of the final product di-
hydroquinolinone (4% selectivity) was obtained. In this case,
the major products were 2’-aminochalcone (55%) and 2’-ami-
nochalcone with the CÀC double bond hydrogenated (1-(2-
aminophenyl)-3-phenylpropan-1-one; 19%). Note that 2’-nitro-
sochalcone, which is an intermediate reduction product of the
2’-nitrochalcone, was also detected (8%) (Scheme 4).
Figure 8. Synthesis of 2-phenyl-2,3-dihydroquinolin-4(1H)-one in the one-
pot process starting from 2’-nitrochalcone. Reaction conditions: 2’-nitrochal-
cone (0.5 mmol), toluene (0.5 mL), 0.2%Pt/TiO2 (15 mg), MCM-41(15)
(15 mg). First step: 708C, 9 bar hydrogen pressure. Second step: 1008C, N2
~
*
atmosphere. 2’-Nitrochalcone ( ), 2’-aminochalcone ( ), dihydroquinolinone
&
( ), (”) 1-(2-aminophenyl)-3-phenylpropan-1-one.
tions for the reactants and products in the pores of the zeolite
and particularly to the strong adsorption of the product.
Higher catalytic activity was observed with a delaminated ITQ-
2 zeolite, but catalyst deactivation as a result of the strong ad-
sorption of the basic dihydroquinolinone was still found. Meso-
porous aluminosilicate MCM-41(Si/Al=15), with much larger
pore diameter and milder acidity than zeolites, was the most
active catalyst, achieving 94% conversion of 2’-aminochalcone
with 100% selectivity to dihydroquinolinone. A variety of dihy-
droquinolinones of pharmaceutical interest have been ob-
tained with excellent yields and selectivities (95–99%). Finally,
it has been showed that dihydroquinolinone can be chemose-
lectively prepared in a one-pot–two-step process starting from
2’-nitrochalcone in the presence of MCM-41(15) and 0.2%Pt/
TiO2. Excellent yields (97%) and selectivity (98%) in a short re-
action time (1.5 h) were obtained and the catalyst can be
reused in at least five consecutive cycles without loss of activi-
ty.
Scheme 4. Products obtained in the reduction of 2’-nitrochalcones.
However, it is possible to achieve high yields of the final
product in a one-pot–two-step reaction. The best results in
terms of yield and selectivity to 2,3-dihydro-2-phenyl-4(1H)-
quinolinone were obtained in the presence of a mixture of
MCM-41(15) and 0.2%Pt/TiO2, with the following experimental
procedure: in a first step, the hydrogenation of 2’-nitrochal-
cone was carried out under 9 bar hydrogen pressure and 708C
in toluene as the solvent. After 40 min reaction time, a 60%
yield of dihydroquinolinone and 40% of 2’-aminochalcone
were obtained, whereas only traces of 1-(2-aminophenyl)-3-
phenylpropan-1-one were detected in the reaction mixture. At
this point, H2 was changed to N2, the temperature was raised
to 1008C, and the reaction was continued for an additional
40 min. After that time, 97% yield with 98% selectivity of dihy-
droquinolinone was obtained. Therefore, dihydroquinolinones
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Reaction procedures
Experimental Section
General procedure for the preparation of 2-phenyl-2,3-dihy-
Reagents
droquinolin-4(1H)-one
2’-Aminochalcones were prepared starting from the corresponding
2’-nitroacetophenones and benzaldehyde derivatives by following
the one-pot process developed previously.[26] Toluene (ꢀ99.9%),
acetonitrile (ꢀ99.9%), THF (ꢀ99.9%), and p-toluenesulfonic acid
(99.8%) were purchased from Aldrich and ethanol (ꢀ99.9%) was
purchased from Scharlau.
A
mixture of 2’-aminochalcone (1 mmol) and 1,1’-biphenyl
(0.5 mmol) as internal standard was dissolved in toluene (0.5 mL)
and added over 8 wt% of the activated catalyst in a closed reactor
vessel. The resultant suspension was stirred at the desired temper-
ature under an inert atmosphere.
One-pot procedure for the preparation of 2-phenyl-2,3-dihy-
droquinolin-4(1H)-one from o-nitrochalcone
Catalysts preparation and characterization
2’-Nitrochalcone (0.5 mmol) and 1,1’-biphenyl (0.5 mmol) as inter-
nal standard were dissolved in toluene (0.5 mL) and added over
a mixture of 0.2%Pt/TiO2 (15 mg) and MCM-41(15) (15 mg). The
first step of hydrogenation of 2’-nitrochalcone was carried out at
a hydrogen pressure of 9 bar and at 708C for 40 min under stirring.
Then, the temperature was raised to 1008C and the atmosphere of
H2 was changed to N2 to carry out the cyclization step into 2-
phenyl-2,3-dihydroquinolin-4(1H).
H-Mordenite (CBV-20A) with crystal diameter 100–200 nm, H-Al-
Beta (CP 811) with crystal diameter between 25–40 nm, USY (CBV
712) with crystal diameter between 25–30 nm, were purchased
from PQ ZEOLITES B.V. and before use they were calcined at 5808C
for 10 h.
The following catalysts were prepared according to the literature:
Al-MCM-41 with different Si/Al ratios,[44] Sn-MCM-41,[45] Si-MCM-
41,[46] and nanocrystalline Beta with crystal diameter between 10–
20 nm.[47] The samples Sn-Beta (2 wt%) and Zr-Beta (1 wt%) were
prepared by following the method described in the literature.[48,49]
The delaminated ITQ-2 and the MCM-22 zeolite precursor were
synthesized according to a previously described method.[29]
Samples of the reaction mixture were periodically taken by a filter-
ing syringe and analyzed by gas chromatography (HP spectrometer
with a 30 m”0.25 mm capillary column of 0.25 mm cross-linked
5% phenylmethylsiloxane and a FID detector). Mass spectra were
performed by using a GC-MS HP Agilent 5973 with a 6980 mass-se-
lective detector.
The acidity of the catalysts was measured by IR spectroscopy
(Nicolet 750 Spectrophotometer) combined with the adsorption–
desorption of pyridine. Pyridine was adsorbed on the catalysts and
desorbed at different temperatures and the pyridine remaining on
the catalysts was followed by using infrared spectroscopy (IR).
More specifically, wafers of 10 mgcmÀ2 were degassed overnight
under vacuum (10À9 to 10À10 bar) at 4008C. The spectra were re-
corded, and pyridine was then introduced. After equilibration, the
samples were outgassed at 150, 250, and 3508C for 1 h under
vacuum. After each desorption step, the spectrum was recorded at
room temperature and the background subtracted. Hence, by fol-
lowing the above procedure, the acidity of the catalysts was deter-
mined on the basis of a method already described in the litera-
ture.[50]
For catalyst recycling studies, the solid was collected by filtration,
washed thoroughly with CH2Cl2, and calcined at 5408C in an air
flux for 10 h after each run to remove the adsorbed species.
Spectral data of the reaction products
1H NMR spectra were recorded at 300 MHz and 13C at 75 MHz in
a Bruker Avance 300 spectrometer, and the chemical shifts in parts
per million (ppm) were reported to internal TMS.
1-(2-Aminophenyl)-3-phenylprop-2-en-1-one (1): 1H NMR (CDCl3,
300 MHz): d=7.87 (dd, J=8.29, 1.32 Hz, 1H), 7.75 (d, J=15.45 Hz,
1H), 7.65–7.59 (m, 3H), 7.44–7.39 (m, 3H), 7.31 (dd, J=15.45,
1.51 Hz, 1H), 6.72 (td, J=8.29, 1.13 Hz, 2H), 6.51 ppm (broad, 2H);
13C NMR (CDCl3, 75 MHz): d=192 (C), 150 (C), 143 (CH), 135 (C), 134
(CH), 131 (CH), 130 (CH), 129 (CH), 128 (CH”3), 126 (C), 123 (CH),
117 (CH), 116 ppm (CH); MS: m/z (%): 222 [M+ÀH] (89), 194 (12),
146 (100), 120 (15), 92 (21), 65 (24), 39 (7).
Thermogravimetric analysis (TGA) was performed by using
a Netzsch STA 409 EP thermal analyzer with approximately 20 mg
of sample and a heating rate of 108CminÀ1 until 6008C in an air
flow. The solids were characterized by X-ray diffraction with a Phi-
lips PW diffractometer using CuKa radiation. Surface area measure-
ments and pore volumes were obtained with a Micrometrics ASAP-
2000 apparatus by nitrogen and argon adsorption experiments at
77 and 85 K, respectively, following the Brunauer–Emmett–Teller
(BET) procedure. The main characteristics of the catalysts are sum-
marized in Table 2.
2-Phenyl-2,3-dihydroquinolin-4(1H)-one (2): 1H NMR (CDCl3,
300 MHz): d=7.89 (ddt, J=7.95, 1.6, 0.6 Hz, 1H), 7.51–7.31 (m, 6H),
6.55 (dd, J=7.21, 1.05 Hz, 1H), 6,73 (dq, J=8.25, 0.6 Hz, 1H), 4.69
(dd, J=13.41, 4.17 Hz, 1H), 4.51 (s, 1H), 2.96 (dd, J=16.23,
13.41 Hz, 1H), 2.83 ppm (ddd, J=16.23, 4.17, 1.7 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d=193 (C), 151 (C), 141 (C), 135 (CH), 129 (CH),
128 (CH), 127 (CH), 126 (CH), 119 (C), 118 (CH), 116 (CH), 58 (CH),
46 ppm (CH2); MS: m/z (%): 223 [M+] (100), 206 (12), 180 (7), 146
(87), 119 (22), 105 (10), 92 (16), 76 (16), 51 (7).
0.2%Pt/TiO2 with a Pt particle size of 1.5 nm was prepared accord-
ing to ref. [51]. 0.1Pt/MCM-41(15) and 0.5Pt/MCM-41(15) were pre-
pared by impregnation[52] of the support previously calcined (at
5408C in air flow for 10 h) with the required amount of
H2PtCl6·6H2O in a 0.1m aqueous solution of HCl (3 mL per gram of
solid). The mixture was stirred for 30 min and then the solvent was
evaporated. The recovered solid was dried at 1008C for 12 h, then
calcined at 5008C in an N2 flow for 3 h, and finally reduced under
a H2 flow at 4508C for 3 h. The nominal platinum content was 0.1
and 0.5 wt% for 0.1Pt/MCM-41(15) and 0.5Pt/MCM-41(15), respec-
tively.
1-(2-Aminophenyl)-3-phenylpropan-1-one:
1H NMR
(CDCl3,
300 MHz): d=7.66 (dd, J=8.01, 1.41 Hz, 1H), 7.25–7.12 (m, 6H),
6.57 (d, J=8.34 Hz, 1H), 6.54 (td, J=1.45, 7.08 Hz, 1H), 6.10 (s, 2H),
3.25 (t, J=8.4 Hz, 2H), 3.00 ppm (t, J=8.34 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d=201 (C), 150 (C), 142 (C), 141 (C), 134 (CH), 131
(CH), 129 (CH), 128 (CH”2), 127 (CH), 126 (CH), 117 (CH), 116 (CH),
41 (CH2), 30 ppm (CH2).
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1-(2-Aminophenyl)-3-(4-chlorophenyl)prop-2-en-1-one
(1a):
1H), 6.61 (dd, J=8.28, 1.2 Hz, 1H), 6.22 (s, 2H), 2.30 ppm (s, 3H);
13C NMR (CDCl3, 75 MHz): d=192 (C), 151 (C), 142 (CH), 140 (C), 136
(CH), 135 (C), 132 (CH), 129 (CH), 128 (CH), 122 (CH), 119 (CH), 117
(C), 115 (CH), 21 ppm (CH3); MS: m/z (%): 236 [M+ÀH] (81), 146
(100), 115 (16), 92 (13), 65 (18), 39 (4).
1H NMR (CDCl3, 300 MHz): d=7.75 (dd, J=8.43, 1.53 Hz, 1H), 7.55
(q, J=15.6 Hz, 2H), 7.45 (dt, J=8.41, 7.1 Hz, 2H), 7.30 (dt, J=8.49,
1.83 Hz, 2H), 7.20 (td, J=8.37, 1.5 Hz, 1H), 6.61 (tt, J=7.14, 1.14 Hz,
1H), 6.62 (dd, J=8.28, 1.26 Hz, 1H), 6.27 ppm (broad, 2H); 13C NMR
(CDCl3, 75 MHz): d=191 (C), 151 (C), 141 (CH), 136 (C), 134 (CH),
133 (C), 131 (CH), 129 (CH”2), 123 (CH), 119 (C), 117 (C), 116 ppm
(C); MS: m/z (%): 256 [M+ÀH] (33), 146 (100), 120 (9), 92 (13), 65
(12), 39 (3).
2-(p-Tolyl)-2,3-dihydroquinolin-4(1H)-one (2d): 1H NMR (CDCl3,
300 MHz): d=7.80 (d, J=7.92 Hz, 1H), 7.30–7.10 (m, 5H), 6.71 (t,
J=7.11 Hz, 1H), 6.62 (d, J=8.13 Hz, 1H), 4.65 (dd, J=13.56,
3.93 Hz, 1H), 4.40 (s, 1H), 2.81 (dd, J=16.23, 13.62 Hz, 1H), 2.67
(dd, J=16.23, 3.9 Hz, 1H), 2.34 ppm (s, 3H); 13C NMR (CD3CN,
75 MHz): d=193 (C), 160 (C), 162 (C), 135 (CH), 133 (C), 129 (CH),
128 (CH), 127 (CH”2), 119 (C), 118 (CH), 116 (CH), 114 (CH), 58 (CH),
55 (CH3), 47 ppm (CH2); MS: m/z (%): 237 [M+] (100), 222 (24), 194
(7), 165 (4), 146 (91), 119 (31), 115 (12), 92 (18), 77 (9), 65 (9), 39 (3).
2-(4-Chlorophenyl)-2,3-dihydroquinolin-4(1H)-one (2a): 1H NMR
(CDCl3, 300 MHz): d=7.87 (d, J=7.86 Hz, 1H), 7.43–7.26 (m, 5H),
6.82 (t, J=7.2 Hz, 1H), 6.72 (d, J=8.19 Hz, 1H), 4.76 (dd, J=12.78,
4.53 Hz, 1H), 4.48 (s, 1H), 2.81 (dd, J=16.11, 12.09 Hz, 1H),
2.70 ppm (dd, J=16.11, 4.44 Hz, 1H); 13C NMR (CD3CN, 75 MHz):
d=192 (C), 152 (C), 140 (C), 135 (CH), 129 (CH), 128 (CH”2), 127
(CH), 126 (CH), 118 (C), 117 (CH), 116 (CH), 56 (CH), 45 ppm (CH2);
MS: m/z (%): 259 [M+ +2H] (31), 257 [M+] (91), 256 (38), 242 (10),
222 (7), 167 (6), 146 (100), 119 (35), 92 (19), 77 (12).
Acknowledgments
Financial support from Consolider-Ingenio 2010 (project MULTI-
CAT), Spanish MICINN Project (CTQ-2011-27550), Generalitat Va-
lenciana (Prometeo program), and Program Severo Ochoa are
gratefully acknowledged.
4-(3-(2-Aminophenyl)-3-oxoprop-1-en-1-yl)benzonitrile
(1b):
1H NMR (CDCl3, 300 MHz): d=7.76 (dd, J=8.7, 1.5 Hz, 1H), 7.63 (s,
4H), 7.61 (s, 2H), 7.40 (d, J=15.51 Hz, 1H), 7.24 (td, J=8.3, 1.5 Hz,
1H), 6.63 (m, 2H), 6.32 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d=
191 (C), 151 (C), 140 (CH), 139 (C), 135 (CH), 133 (CH), 131 (CH), 128
(CH), 126 (CH), 119 (C), 118 (C), 117 (CH), 116 (CH), 113 ppm (C);
MS: m/z (%): 247 [M+ÀH] (67), 219 (10), 146 (100), 120 (16), 92
(19), 65 (21), 39 (6).
Keywords: 2’-aminochalcones · dihydroquinolinones · fine
chemicals · ITQ-2 zeolite · MCM-41 · one-pot process
[1] P. Hradil, J. Hlavµc, M. Soural, M. Hajdfflch, M. Kolµr, R. Vecerovµ, Mini-
Rev. Med. Chem. 2009, 9, 696–702.
4-(4-Oxo-1,2,3,4-tetrahydroquinolin-2-yl)benzonitrile
(2b):
1H NMR (CDCl3, 300 MHz): d=7.87 (d, J=7.92 Hz, 1H), 7.79 (d, J=
8.01 Hz, 2H), 7.59 (d, J=8.13 Hz, 2H), 7.39 (t, J=6.9 Hz, 1H), 6.86
(t, J=7.53 Hz, 1H), 7.74 (d, J=8.22 Hz, 1H), 4.86 (dd, J=10.2,
6.9 Hz, 1H), 4.51 (s, 1H), 2.83 (dd, J=16.32, 10.44 Hz, 1H),
2.81 ppm (dd, J=16.32, 3.4 Hz, 1H); 13C NMR (CD3CN, 75 MHz): d=
192 (C), 151 (C), 146 (C), 136 (CH), 133 (CH), 129 (CH), 128 (CH), 127
(CH), 119 (C), 118 (C), 116 (CH), 112 (C), 58 (CH), 46 ppm (CH2); MS:
m/z (%): 248 [M+] (100), 233 (21), 219 (9), 205 (9), 177 (6), 146 (99),
119 (29), 105 (16), 92 (24), 87 (13), 64 (10), 39 (4).
[2] R. D. Larsen, D. Cai in Six-Membered Hetarenes with One Nitrogen or
Phosphorus Atom, (Ed.: P. Black), Thieme, Stuttgart, 2005, pp. 551–660.
[3] Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E. Hamel, T.
Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155–1162.
[4] O. Prakash, D. Kumar, R. K. Saini, S. P. Singh, Synth. Commun. 1994, 24,
2167–2172.
[5] V. N. Kalinin, M. V. Shostakovsky, A. B. Ponomaryov, Tetrahedron Lett.
1992, 33, 373–376.
[6] A. S. Wagman, M. P. Wentland in Comprehensive Medicinal Chemistry II
(Ed.: J. B. T. J. Triggle), Elsevier, Oxford, 2007, pp. 567–596.
[7] J. A. Donnelly, D. F. Farrell, J. Org. Chem. 1990, 55, 1757–1761.
[8] A. Fournet, B. Vagneur, P. Richomme, J. Bruneton, Can. J. Chem. 1989,
67, 2116–2118.
[9] S. Torii, H. Okumoto, L. H. Xu, Tetrahedron Lett. 1991, 32, 237–240.
[10] O. E. O. Hormi, C. Peltonen, L. Heikkila, J. Org. Chem. 1990, 55, 2513–
2515.
[11] J. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734–736.
[12] X. Zheng, H. Jiang, J. Xie, Z. Yin, H. Zhang, Synth. Commun. 2013, 43,
1023–1029.
[13] S. Chandrasekhar, K. Vijeender, C. Sridhar, Tetrahedron Lett. 2007, 48,
4935–4937.
1-(2-Aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one
(1c):
1H NMR (CDCl3, 300 MHz): d=7.80 (dd, J=8.4, 1.56 Hz, 1H), 7.65 (d,
J=15.51 Hz, 1H), 7.50 (dt, J=9.63, 2.88 Hz, 2H), 7.40 (d, J=
15.51 Hz, 1H), 7.20 (dd, J=7.05, 1.44 Hz, 1H), 6.87 (dt, J=9.63,
2.88 Hz, 2H), 6.62 (td, J=7.1, 1.14 Hz, 1H), 6.61 (dd, J=8.25,
1.24 Hz, 1H), 6.20 (s, 2H), 2.30 ppm (s, 3H); 13C NMR (CDCl3,
75 MHz): d=192 (C), 161 (C), 151 (C), 143 (CH), 134 (CH), 131 (CH),
130 (CH), 128 (C), 121 (CH), 119 (C), 117 (CH), 116 (CH), 114 (CH),
55 ppm (CH3); MS: m/z (%): 252 [M+ÀH] (100), 236 (31), 209 (22),
180 (13), 164 (10), 146 (99), 120 (22), 92 (31), 65 (25), 39 (6).
[14] D. Kumar, G. Patel, B. G. Mishra, R. S. Varma, Tetrahedron Lett. 2008, 49,
6974–6976.
2-(4-Methoxyphenyl)-2,3-dihydroquinolin-4(1H)-one
(2c):
1H NMR (CDCl3, 300 MHz): d=7.87 (dd, J=7.95, 1.05 Hz, 1H), 7.4–
7.3 (m, 4H), 6.94 (d, J=8.7 Hz, 1H), 6.83 (t, J=7.08 Hz, 1H), 6.7 (d,
J=8.22 Hz, 1H), 4.70 (dd, J=13.65, 3.84 Hz, 1H), 3.90 (s, 3H), 2.85
(dd, J=16.23, 13.65 Hz, 1H), 2.74 ppm (dd, J=16.23, 3.93 Hz, 1H);
13C NMR (CD3CN, 75 MHz): d=193 (C), 160 (C), 152 (C), 135 (CH),
133 (C), 129 (CH), 128 (C), 127 (CH”2), 119 (C), 118 (CH), 115 (CH),
114 (CH), 58 (CH), 55 (CH3), 47 ppm (CH2); MS: m/z (%): 253 [M+]
(100), 238 (10), 222 (10), 209 (6), 180 (4), 167 (4), 146 (82), 134 (26),
119 (24), 92 (13), 65 (7), 39 (3).
[15] C. Yang, L. Fang, L. Wu, F. Yan, Asian J. Chem. 2010, 22, 6031–6034.
[16] E. Tang, B. Chen, L. Zhang, W. Li, J. Lin, Synlett 2011, 707–711.
[17] V. K. Rao, M. S. Rao, A. Kumar, J. Heterocycl. Chem. 2011, 48, 1356–1360.
[18] U. P. Lad, M. A. Kulkarni, U. V. Desai, P. P. Wadgaonkar, C. R. Chim. 2011,
14, 1059–1064.
[19] R. Sakirolla, M. Yaeghoobi, N. A. Rahman, Monatsh. Chem. 2012, 143,
797–800.
[20] N. Ahmed, J. E. van Lier, Tetrahedron Lett. 2006, 47, 2725–2729.
[21] P. T. P. K. H. Kumar, Can. J. Chem. 2006, 84, 1079–1083.
[22] N. Ahmed, J. E. van Lier, Tetrahedron Lett. 2007, 48, 13–15.
[23] R. S. Varma, J. Heterocycl. Chem. 1999, 36, 1565–1571.
[24] M. J. Climent, A. Corma, S. Iborra, Chem. Rev. 2011, 111, 1072–1133.
[25] a) D. Tichit, C. Gerardin, R. Durand, B. Coq, Top. Catal. 2006, 39, 89–96;
b) M. J. Climent, A. Corma, S. Iborra, M. J. Sabater, ACS Catal. 2014, 4,
870–891.
1-(2-Aminophenyl)-3-(p-tolyl)prop-2-en-1-one
(1d):
1H NMR
(CDCl3, 300 MHz): d=7.80 (dd, J=8.4, 1.5 Hz, 1H), 7.65 (d, J=
15.54 Hz, 1H), 7.50 (d, J=15.54 Hz, 1H), 7.45 (s, 1H), 7.20 (td, J=
8.4, 1.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 6.62 (td, J=8.28, 1.14 Hz,
ChemCatChem 2016, 8, 1335 – 1345
www.chemcatchem.org
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Papers
[26] M. J. Climent, A. Corma, S. Iborra, L. Martí, ACS Catal. 2015, 5, 157–166.
[27] A. Reyes, P. A. Cuervo, F. Orozco, R. Abonia, M. Duque-NoreÇa, P. PØrez,
E. Chamorro, J. Mol. Model. 2013, 19, 3611–3618.
[28] G. Giordano, A. Macario, A. Aloise, J. B. Nagy, Silica Silic. Mod. Catal.
2010, 121–149.
[41] D. Kumar, G. Patel, A. Kumar, R. K. Roy, J. Heterocycl. Chem. 2009, 46,
791–795.
[42] S. Wattanasin, W. S. Murphy, Synthesis 1980, 647–650.
[43] A. I. R. N. A. Barros, A. F. R. Dias, A. M. S. Silva, Monatsh. Chem. 2007, 138,
585–594.
[44] C. T. Kresge, M. E. Leonowicz, W. J. Roth, J. C. Vartuli, J. S. Beck, Nature
1992, 359, 710–712.
[29] I. Rodriguez, M. J. Climent, S. Iborra, V. FornØs, A. Corma, J. Catal. 2000,
192, 441–447.
[45] A. Corma, M. T. Navarro, L. Nemeth, M. Renz, Chem. Commun. 2001,
2190–2191.
[30] M. J. Bhanushali, N. S. Nandurkar, S. R. Jagtap, B. M. Bhanage, Catal.
Commun. 2008, 9, 1189–1195.
[46] J. S. Beck, J. C. Vartuli, W. J. Roth, M. E. Leonowicz, C. T. Kresge, K. D.
Schmitt, C. T. W. Chu, D. H. Olson, E. W. Sheppard, J. Am. Chem. Soc.
1992, 114, 10834–10843.
[47] M. A. Camblor, A. Corma, A. Mifsud, J. PØrez-Pariente, S. Valencia in
Stud. Surf. Sci. Catal. 1997, 105A, 341–348.
[48] S. Valencia, A. Corma, US Patent 5968473, 1999.
[49] Y. Zhu, G. Chuah, S. Jaenicke, J. Catal. 2004, 227, 1–10.
[50] C. A. Emeis, J. Catal. 1993, 141, 347–354.
[51] A. Corma, P. Serna, J. J. Calvino, J. Am. Chem. Soc. 2008, 130, 8748–
8753.
[31] M. Boronat, P. Concepción, A. Corma, M. T. Navarro, M. Renz, S. Valencia,
Phys. Chem. Chem. Phys. 2009, 11, 2876–2884.
[32] A. Corma, M. Renz, M. Susarte, Top. Catal. 2009, 52, 1182–1189.
[33] D. Tichit, B. Coq, CATTECH 2003, 7, 206–217.
[34] R. Chebout, D. Tichit, G. Layrac, A. Barama, B. Coq, I. Cota, R. E. Ramirez,
F. Medina, Solid State Sci. 2010, 12, 1013–1017.
[35] M. T. Drexler, M. D. Amiridis, J. Catal. 2003, 214, 136–145.
[36] M. J. Climent, A. Corma, S. Iborra, J. Primo, J. Catal. 1995, 151, 60–66.
[37] T.-P. Loh, L.-L. Wei, Synlett 1998, 975–976.
[38] J. J. P. Furlong, N. S. Nudelman, J. Chem. Soc. Perkin Trans. 2 1985, 633–
639.
[52] A. Corma, A. Martínez, V. Martínez-Soria, J. Catal. 1997, 169, 480–489.
[39] J. J. P. Furlong, N. S. Nudelman, J. Chem. Soc. Perkin Trans. 2 1988,
1213–1217.
Received: December 23, 2015
[40] M. T. Drexler, M. D. Amiridis, Catal. Lett. 2002, 79, 175–181.
Published online on March 7, 2016
ChemCatChem 2016, 8, 1335 – 1345
www.chemcatchem.org
1345
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim