Applied Clay Science 143 (2017) 250257

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Applied Clay Science

journal homepage: www.elsevier.com/locate/clay

Research paper

Acid clay minerals as eco-friendly and cheap catalysts for the synthesis of - MARK
amino ketones by Mannich reaction
Fernando Gmez-Sanza, Mara Virtudes Morales-Vargasa, Beatriz Gonzlez-Rodrguezb,
Mara Luisa Rojas-Cervantesa, Elena Prez-Mayorala,
a
Departamento de Qumica Inorgnica y Qumica Tcnica, Facultad de Ciencias, UNED, Paseo Senda del Rey 9, E-28040 Madrid, Spain
b
Departamento de Qumica Inorgnica, Facultad de Ciencias Qumicas, Universidad de Salamanca, Plaza de la Merced s/n, E-37008 Salamanca, Spain

A B S T R A C T

The characterization and catalytic performance of dierent smectites, one raw saponite and some commercial
montmorillonites, exhibiting mesoporous and acid character are herein reported. The catalysts under study are
able to catalyze eciently via Mannich-type reactions the synthesis of -amino ketones, which are important
building blocks for the drugs synthesis and biologically active natural products. Montmorillonite K10 (Mt-K10)
was the most ecient catalyst for the Mannich reaction between the pre-formed imine, N-benzylideneaniline,
and cyclohexanone resulting in a recyclable catalyst for at least three catalytic cycles without activity loss.
Almost quantitative yield to the -amino carbonyl compound was obtained after 240 min when operating under
the most favorable conditions. The catalytic performance of the smectites seemed to be inuenced by their
porosity, but also by both Brnsted and Lewis acid site concentrations. In fact, the concentration of the Lewis
acid catalytic sites would be the key in the Michael addition of cyclohexanone to the imine, although the
Brnsted acid sites contribution cannot be neglected. The -amino carbonyl compound was also synthesized in
an excellent yield (86%) in only 15 min of reaction time through the one-pot three component reaction, by
reaction between benzaldehyde, aniline and cyclohexanone.

1. Introduction
CeC and CeN bond forming reactions are widely investigated since
they are involved in the most relevant bio-transformations.
Methodologies implying the formation of CeC and CeN bonds through
cascade reactions are the key in the synthesis of natural products,
pharmaceuticals or even in materials science. Our research group
possesses a wide experience in this type of reactions aimed at the
development of synthetic methodologies based on catalytic synthesis of
biologically heterocyclic compounds (Prez-Mayoral et al., 2015a,b). In
this respect, the Friedlnder reaction is one of the most explored
transformation by us (Marco-Contelles et al., 2009), involving CeC and
CeN bond forming cascade reactions, catalyzed by a great variety of
dierent porous systems (Domnguez-Fernndez et al., 2009; Lpez-
Sanz et al., 2010; Lpez-Sanz et al., 2012; Smuszkiewicz et al., 2013a,b;
Prez-Mayoral and Cejka, 2011; Prez-Mayoral et al., 2012; Polozij
et al., 2013; Lpez-Sanz et al., 2013; Godino-Ojer et al., 2014).
Multicomponent reactions (MCRs) are considered as a powerful tool
in the drug discovery. The MCRs, one-pot processes requiring very
simple experimental procedures, are source of a great molecular
diversity allowing the fast, safe, highly selective and ecient synthesis
of structurally complex molecules (Zhu and Bienaym, 2005). Among
the MCRs the Mannich reaction is important for CeC and CeN bond
formation; it consists of the condensation of a non-enolizable aldehyde,
a primary or secondary amine and frequently an enolizable ketone
leading to the corresponding -amino ketone. This synthetic approach
requires acid or basic conditions taking place through two processes in
cascade constituted by i) an initial imination reaction, often between
benzaldehydes and aromatic amines, and ii) subsequent Michael
addition of ketone, as its enol form, to the previously formed imine
providing the corresponding -amino carbonyl compounds. Mannich
bases are structural components of many biologically active natural
products and synthetic drugs, such as peptides, hormones, vitamins,
alkaloids, and antibiotics showing a broad range of biological activities
(Mller et al., 1999, Arend et al., 1998; Heravi et al., 2016).
Dierent heterogeneous catalytic systems have been developed for
Mannich-type reactions such as Amberlyst-15 (Dasa et al., 2009),
sulfated ceria-zirconia (Reddy et al., 2006), tungstated zirconia
(Reddy et al., 2008), Cu nanoparticles (Kidwai et al., 2009),
SiO2eOAlCl2 (Li et al., 2007), and SiO2eH2SO4 (Wu et al., 2007).

Corresponding author.
E-mail address: eperez@ccia.uned.es (E. Prez-Mayoral).

http://dx.doi.org/10.1016/j.clay.2017.03.033
Received 23 November 2016; Received in revised form 21 March 2017; Accepted 22 March 2017
0169-1317/ 2017 Elsevier B.V. All rights reserved.
F. Gmez-Sanz et al.
Modied clays catalyzing the Mannich-type reactions have been also
reported. For instance, the phosphomolybdic acid supported on sulfate
grafted Zr-Pillared clay (Samantaray et al., 2011) is active in the
synthesis of -amino carbonyl compounds, in aqueous media, while Ag
(I)-exchanged K10 montmorillonite was used in one of the variants for
Mannich reaction yielding propargyl amines (Jeganathan et al., 2014a).
The goal of this paper is aimed to study dierent clay minerals,
exhibiting acid character, able to eciently catalyze the synthesis of -
amino ketones via direct Mannich-type reactions, under mild condi-
tions. With this purpose, a raw and some commercial smectites have
been selected, all of them showing dierent composition, Lewis and
Brnsted acid site concentrations, and porosity. The advantage of using
these catalysts regarding other clay minerals previously reported for
Mannich-type reactions is that in our case no modication of the
samples was required. In this work, the inuence of various parameters
such as the amount of the catalyst, the acid-base and textural proper-
ties, and the eect of the temperature on the catalytic performance of
clay minerals under study has been investigated. Both the reaction
between the pre-formed imine (N-bencylildenaniline) and cyclohexa-
none and the one-pot three component reaction have been explored.
The reactants selected in this study were benzaldehyde, aniline and
cyclohexanone because the Mannich-type reaction involving dierently
substituted both benzaldehyde and anilines gives the corresponding -
amino ketones biologically active by themselves as good antioxidants
inducing acute oxidative stress of cancer cell lines (Petrovic et al.,
2014).
2. Experimental
2.1. Catalysts
The catalysts under study are clay minerals belonging to the
smectites group: one raw saponite from Cabaas (Toledo, Spain) and
four commercial montmorillonites. The nomenclature and the suppliers
of the catalysts used in this work are given in Table 1.
2.2. Characterization
The textural characterization of all samples was accomplished by
nitrogen adsorption. The adsorption isotherms for N2 at 196 C were
measured using a Micromeritics ASAP 2010 equipment. Previously to
the adsorption measurements, the samples were out-gassed at 40 C for
2 h and 150 C for 5 h up to 102 mm Hg. The specic surface areas and
the micropore size distribution were calculated by the BET method and
the Horvath-Kawazoe method, respectively (Gregg and Sing, 1991). The
mesopore size distribution as well as the mesopore volume and the
average mesopore diameter were determined by the BJH method
(Gregg and Sing, 1991). The pore size distributions are in the micropore
and mesopore range and were calculated by applying the DFT method
(Lastoskie et al., 1993).
The X-ray powder diraction patterns between 5 and 80 of 2 were
obtained using a X'Pert diractometer with ltered Cu-K radiation
operating at 40 kV and 30 mA and with 0.04 and 2 s step over non-
oriented powder samples.
FTIR spectroscopy of adsorbed pyridine was used to investigate the
Table 1
Nomenclature of the clay minerals used as catalysts.
Catalyst Nomenclature Supplier
Saponite Sap Tolsa
Montmorillonite K10 Mt-K10 Sigma-Aldrich
Montmorillonite K30 Mt-K30 Sigma-Aldrich
Montmorillonite KSF Mt-KSF Sigma-Aldrich
Montmorillonite pillared (Al) Mt-pil Sigma-Aldrich
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Applied Clay Science 143 (2017) 250257
acidity of samples, according to the method reported in (del Rey-Perez-
Caballero and Poncelet, 2000). The spectra were recorded with a
Perkin-Elmer Spectrum-One spectrometer. In a typical experiment,
20 mg of samples were contacted with 1 mL of pyridine in a desiccator
and were evacuated for 1 h at room temperature. Afterwards, the
samples were pressed into wafers with KBr (dilution ratio sample/KBr
of 10/600) and the IR spectra were recorded in the 4000450 cm 1
range. Subsequent spectra were recorded after stepwise heating for 1 h
in a vacuum oven, at temperature intervals of 100 C, between 100 and
400 C and cooling down. The Brnsted and Lewis acid contents, qH and
qL (mol/g), respectively, were calculated with the Eq. 1 (Barzetti et al.,
1996):
qH,L = (AI D2) (4w I)1 (1)
where D (cm) is the diameter of the wafer, and w (g) the sample weight.
The integrated area AI (in arbitrary units) of the bands at 1545 (Py-B)
and 1450 cm 1 (Py-L) were provided by the software of the instru-
ment, after baseline optimization. The extinction coecients I with
Brnsted and Lewis sites given by Emeis, 1993,
1.67 0.12 cm mol 1 and 2.22 0.21 cm mol 1, respectively,
were adopted. The qH and qL values were established from the
recordings of samples outgassed at 100 C.
2.3. Reaction procedure
The used reactants were N-benzylideneaniline (Alfa Caesar), cyclo-
hexanone (Sigma-Aldrich), benzaldehyde (Sigma-Aldrich) and aniline
(Sigma-Aldrich).
In a typical experiment, a solution of N-benzylideneaniline (2 mmol)
and cyclohexanone (3 mmol) was heated under stirring at the appro-
priate reaction temperature and the catalyst was added. Aliquots of the
reaction crude were successively extracted at predetermined times and
diluted in ethyl acetate (0.5 mL), the catalyst was removed by ltration
through 0.45 m Durapore membrane syringe lters and the solvent
was removed in vacuo. The reaction was qualitatively monitored by TLC
on silica gel (Merck F254) using a mixture of hexane/ethyl acetate (9:1)
as eluent. The reaction products were characterized by 1H RMN (Bruker
DPX 300 MHz, CDCl3) and the results were analysed by MestRec, v.
4.8.6.0 Software. In the case of the one pot three-component reaction
the reactants used were benzaldehyde (2 mmol), aniline (2 mmol) and
cyclohexanone (3 mmol) following the same experimental protocol as
explained above.
2.3.1. Recyclability of the catalyst
The reusability of the catalyst was investigated using, Mt-K10. The
rst cycle was carried out at 35 C using 100 mg as catalyst, by
sampling only once at the longest reaction time, i.e., 240 min. Due to
the slight loss of catalyst between two successive cycles, the reactant
amounts were rescaled in order to keep constant the catalyst/reactants
ratio. After each reaction cycle, the used catalyst was washed with ethyl
acetate for several times, ltered and dried in an oven at 60 C for 16 h,
before being used in the following cycle.
3. Results and discussion
3.1. Catalyst characterization
The diraction patterns of the catalysts together with the assigna-
tion of the corresponding basal and (hk0 + hkl) reections are shown
in Fig. 1. In some of the samples, additionally to the reection lines
typical from saponite or montmorillonite, others assigned to impurities
of quartz and mica were detected. In the case of Mt-K10, Mt-K30 and
Mt-KSF catalysts, the presence of these impurities could be due to the
acid treatment applied during their preparation (Tabernero et al.,
2010).
F. Gmez-Sanz et al. Applied Clay Science 143 (2017) 250257

Table 2
Textural properties of the clay minerals used as catalysts.

Catalyst SBET Smic VP Vmes Vmic dp

(m2/g) (m2/g) (cm3/g) (cm3/g) (cm3/g) ()

Mt-K10 230 55 0,473 0,382 0,091 62

Mt-K30 170 38 0,360 0,296 0,064 54
Mt-KSF 4 1 0,017 0,015 0,002 92
Mt-pil 203 134 0,269 0,184 0,085 82
Sap 131 70 0,177 0,122 0,055 55

SBET = specic surface area; Smic = micropore surface area determined by t-plot;
VP = total pore volume at P/P0 = 0.99; Vmes = mesopore volume by BJH;
Vmic = micropore volume by Hortvath-Kawazoe method; dp = average pore diameter
(4V/A) by BJH.

character. The isotherms showed a hysteresis loop of type H3 for Mt-

Fig. 1. Diraction patterns of the catalysts.
Fig. 2. Adsorption-desorption isotherms of the catalysts.
K10 and Mt-K30 typical of non-rigid aggregates of plate-like particles
and type H4 for Sap (Thommes et al., 2015), the form of the isotherm
for Mt-pil being intermediate between H3 and H4 types. The isotherm
of Sap presented a vertical section at the closing of hysteresis loop (P/
P0 0.44), typical from the mesoporosity associated with the inter-
tactoid pores inside the aggregates (Neaman et al., 2003). The adsorp-
tion and desorption branches of the isotherm for Mt-KSF, represented in
the inset of Fig. 2 because of its dierent scale, were steeply sloped in
the relative pressure range of 0.981.00, suggesting the presence of
macropores, which were not lled with nitrogen.
The specic surface area of the natural saponite was 131 m2/g,
rather higher than the values reported in general for the natural
saponites (3050 m2/g). This circumstance could be attributed to the
very small particle size of the clay minerals in Madrid Basin, due to
their sedimentary origin (Casal et al., 1997; Prieto et al., 1999; Vicente
et al., 1996). The montmorillonites showed specic surface areas
comprised between 170 and 230 m2/g, with the exception of Mt-KSF,
exhibiting the lowest area, 4 m2/g.
Montmorillonites K are commercial catalysts designed for satisfying
the demand of industrial processes that require the use of the catalysts
showing a very strong acidity. It is well known that the acidity of
natural montmorillonites can be enhanced by thermal or acidic treat-
ment. However, the layered structures can be disrupted largely after
acid treatment, showing a card-house-like structure, and containing
larger pore size than the usual ones in the montmorillonites. This must
be the case of Mt-KSF sample, which showed a very low specic surface
area and the presence of macropores, as mentioned above.
As shown in Table 2 the samples were mainly mesoporous, the
mesopores contributing to the total pore volume ranging between 68
and 82%. Remarkably, Mt-K10 sample was the catalyst showing the
highest mesopore volume.
The pore size distributions of the clay minerals determined by
Density Functional Theory were depicted in Fig. 3. All the catalysts
showed a maximum in the microporus region at approximately 15 ,
corresponding to the interlayer pores, with Mt-KSF being an exception.
In addition Mt-pil and Sap presented a small contribution of micropores
of lower size, around 78 . In the mesoporous region, a major
contribution of mesopores was observed for Mt-K10 and Mt-K30
montmorillonites, which showed two maxima at approximately 60
and 90 , corresponding to the pores closed into the tactoids. The
lowest mesopore volume for Mt-KSF (0,015 cm3/g, Table 2) was
associated with the existence of mesopores with larger size, as seen in
its corresponding DFT curve. The presence of macropores correspond-
ing to inter aggregate space was also detected.

3.2. Catalytic performance

The nitrogen adsorption-desorption isotherms of samples are de-
picted in Fig. 2 and their textural properties are given in Table 2. From 3.2.1. Catalytic behaviour of the catalysts
the shape of the isotherms, type IV according to the BDDT classication, The catalysts under study were tested in the Mannich-type reaction
it was deduced that most of the samples showed mainly mesoporous from the pre-formed N-benzylideneaniline 1 and cyclohexanone 2, at

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Table 4
Concentration of Brnsted (B) and Lewis (L) acid centres (mol/g) of the catalysts
determined by pyridine adsorption.

Catalyst 25 C 100 C 45 Ca

B acid L acid sites B acid L acid sites B acid L acid (B + L)

sites sites sites sites acid
sites

Mt-K10 27.52 163.98 37.55 115.60 30 147 177

Mt-K30 19.92 168.70 30.17 160.21 23 167 190
Mt-KSF 19.12 0 26.12 0 22 0 22
Mt-pil 7.20 77.26 17.86 61.1 10 72 82
Sap 3.11 172.15 14.18 163.73 8 170 178

a
Data at 45 C were calculated by extrapolation.

absence of reactivity when using Mt-KSF, the sample with the lowest
porosity, after 30 min of reaction time, could be due to the low SBET.
Fig. 3. Distributions of porosity of the catalysts determined by DFT.
The low porosity of the sample could be behind the low conversion of
compound 1 (8%), similarly to that obtained in the blank experiment.
This eect was almost insignicant if considering the conversion to 3,
after 300 min of reaction time, with the order of reactivity being Mt-
K10 Mt-K30 Sap > Mt-pil Mt-KSF. It is important to note that
although small dierences in the conversion of N-benzylideneaniline 1
to products 3 (7382%) were observed, Mt-KSF is the least ecient
catalyst.
Scheme 1. Mannich-type reaction between N-benzylideneaniline 1 and cyclohexanone 2. The investigated clay minerals exhibited acid character provided by
the presence of Brnsted and Lewis acid functions. In order to
45 C, under solvent-free conditions (Scheme 1). determine the concentration of both acid centres, at the edges/external
The conversion of N-benzylideneaniline 1 as well as the selectivity surfaces of particles and the interlayer space, experiments of pyridine
to 3-anti/3-syn diatereoisomers at two reaction times are given in adsorption at several temperatures were carried out (Table 4).
Table 3. For purposes of comparison, the reaction was also carried out As far as we know both types of acid centres, Brnsted and Lewis
in the absence of any catalyst aording a mixture of the corresponding ones, are able to catalyze the direct Mannich-type reaction. In general,
isomers, 3-anti and 3-syn (isomers ratio, 1:1), in 40% of yield, after 5 h the concentration of Lewis acid sites into the samples was notably
of reaction time. higher than that of Brnsted ones, with the exception of Mt-KSF sample
Remarkably, a signicant enhancement of the conversion to pro- which did not contain Lewis centres (Table 4). Considering the
ducts 3 was observed when the reaction was carried out in the presence observed catalytic performance, it seems that the main contribution
of all investigated catalysts. In general, even at the shortest reaction to the activity is provided by the Lewis acid sites. In addition, analyzing
times, mixtures of the isomers 3 were obtained with increased yields the Brnsted (B), Lewis (L) and total (B + L) acid site concentrations of
and selectivities. The selectivity to 3-anti, the most stable isomer, was the samples at the reaction temperature, i.e., 45 C, the following
slightly higher ( 60%), and maintained during the process, when sequences were found:
operating in the presence of clay minerals, this feature being attributed
to the connement eects. B Mt-K10 > Mt-K30 Mt-pil > Mt-KSF Sap
According to data of Table 3, the order of the conversion at the L Sap Mt-K30 > Mt-K10 > Mt-pil > Mt-KSF
lowest reaction time was Mt-K10 Mt-pil > Sap Mt-K30 > Mt- B + L Mt-K30 > Sap Mt-K10 > Mt-pil > Mt-KSF
KSF. This order was in good agreement with those for SBET and
micropore volume values. This fact strongly suggests the importance The last sequence was in agreement with the order of catalytic
of the existence of micropores for the reactants connement and their activity at 300 min (M-K10 M-K30 Sap > M-pil > M-KSF).
diusion towards the catalytic active centres. Particularly, the almost Therefore, besides factors such as the porosity of the sample, the
concentration of the Lewis acid sites seems to be the key in the Michael
Table 3
addition of cyclohexanone 2 to the imine 1, although the participation
Conversion of N-benzylideneaniline and isomer anti/syn ratio. of Brnsted acid sites cannot be neglected. Because both acid sites are
located at the edges/external surfaces of particles and in the interlayer
Catalyst Time (min) Conversion (%) 3-Anti (%) 3-syn (%) space, the results reported herein seem to indicate that the addition
None 30 7 50 50
reaction of 2 to 1 could take place at both environments.
300 40 51 49
Mt-K10 30 49 59 41
300 81 60 40 3.2.2. Inuence of the amount of the catalyst
Mt-K30 30 32 60 40 Since the highest conversion ( 50%) was obtained in the presence
300 82 62 38
Mt-KSF 30 8
of Mt-K10, after the lowest reaction time, 30 min, this sample was the
300 73 63 37 catalyst of our choice to further studies. In this sense, dierent amounts
Mt-pil 30 45 59 41 of Mt-K10 (50, 100 and 200 mg) were tested in the reaction between N-
300 75 60 40 benzylideneaniline 1 and cyclohexanone 2, under solvent free-condi-
Sap 30 33 58 42
tions, at 45 C. The conversion of N-benzylideneaniline and the
300 80 56 44
distribution of diastereoisomers 3, after 30 min of reaction time, are
Reaction conditions: N-benzylideneaniline (2 mmol), cyclohexanone (3 mmol) and 50 mg depicted in Fig. 4.
of catalyst at 45 C. As can be seen, higher conversions of compound 1 (Fig. 4A) and also

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100
A)
80
Conversion (%)

60

40
68
60
49
20

0
50 100 200
Catalyst amount (mg)

% Anti % Syn
100
B) Fig. 6. Inuence of the reaction temperature on the stereoselectivity using 100 mg of Mt-
Stereoisomer (%)

80 K10 as catalyst after 240 min of reaction time.

60

40

20

0
50 100 200
Catalyst amount (mg)

Fig. 4. Inuence of the amount of Mt-K10 on (A) the conversion of N-benzylideneaniline;

and (B) distribution of diastereoisomers (tr = 30 min, T = 45 C).

diastereoselectivity values (Fig. 4B) were observed when using in-

creased amounts of catalyst, as expected. The enhancement of the 3-
anti/3-syn isomers ratio is noteworthy when the catalyst amount was
doubled from 50 to 100 mg (60/40 to 70/30), with this ratio
remaining almost constant (72/28) in the presence of 200 mg of the
catalyst. Therefore, 100 mg were selected as the optimum catalyst
amount yielding reasonable conversion to products 3 with high
diastereoselectivity.
3.2.3. Inuence of the reaction temperature
Conversion of compound 1 vs time and 3-anti/3-syn isomers ratio at
three temperatures, 35, 45 and 60 C, are depicted in Figs. 5 and 6,
respectively. An increase of conversion was observed with increasing
temperature, as expected. Only small changes in the conversion were
produced when operating at the highest temperatures. Although the
reaction at 35 C aorded lower conversion to products 3 after short
reaction times, approximately 85% of conversion were reached at
180 min when working at the three reaction temperatures. It is
important to stress that a mixture of isomers 3 was obtained with
quantitative yield, after 240 min of reaction time, operating at the
lowest temperature, 35 C.
Surprisingly, the reaction diastereoselectivity was barely inuenced
when the reaction temperature was increased (Fig. 6), the 3-anti/3-syn
isomers ratio approximately being 70:30.
Additionally, Fig. 7 depicts a comparative study of catalytic
Fig. 5. Inuence of the reaction temperature on the conversion of N-benzylideneaniline
using 100 mg of Mt-K10 as catalyst.
Fig. 7. Conversion of N-benzylideneaniline 1 vs time at 35 C using 100 mg of catalysts.
performance for Mt-K10 sample with the other catalysts showing
dierent structures, such as Sap and Mt-pil, operating at 35 C and
using 100 mg of catalysts. Note that Mt-K10 was the catalyst leading to
the highest conversion of compound 1, at all reaction times; this trend
was already observed when working at higher reaction temperature,
45 C, and using lower catalyst amount, 50 mg (Table 3). These results
were also in accordance with the decreasing SBET and Vmeso values for
Mt-K10, Mt-pil and Sap, consecutively. Besides the porosity as inuen-
cing factor on the reactivity, in these cases, it could be observed a
relationship between the catalytic behaviour of the samples and their
Brnsted acid site concentrations. In this sense, the results indicated
that Mt-K10 was much more reactive than Sap, Mt-pil containing higher
concentration of Brnsted acid centres but also a lower concentration of
Lewis acid sites. It seems that the decrease of the Brnsted acid site
concentration on Mt-pil and Sap, determined at all the investigated
temperatures (Table 4), led to the lowest conversion of compound 1, at
all the reaction times. In summary, although the Lewis acid centres in
Mt-K10, Mt-K30 and Mt-KSF samples could be probably the most active
catalytic species, it is reasonable to think that the Brnsted acid sites in
Mt-pil and Sap samples are the predominant catalytic active species.
The selectivity to 3-anti isomer was also aected by the structure of
the catalyst or the catalytic sites in the sample. While the isomers ratio
3-anti/3-syn was 70:30 when the reaction was catalyzed by Mt-K10,
the reaction in the presence of Mt-pil or Sap led to mixtures of the
diastereoisomers 3-anti and 3-syn with decreased selectivity to 3-anti
isomer ( 60%). Therefore, Mt-K10 sample presented the best catalytic
behaviour in terms of activity as well as stereoselectivity.
In summary, the addition reaction of cyclohexanone 2 to imine 1
could take place at the edges, external surface of the clay particles and
in the interlayer space as above commented, diastereoselectivity being
probably inuenced by the structure and porosity of the samples. In this
sense, while the reaction under catalyst-free conditions yielded a
mixture of 3-anti/3-syn isomers (1:1), the selectivity to isomer 3-anti
was enhanced in the presence of the investigated catalysts, probably
due to reactants organization within physically conned environments

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F. Gmez-Sanz et al.
Fig. 8. Conversion of N-benzylideneaniline 1 vs time in the presence of 100 mg of catalyst
at 35 C.
or simply to the adsorption eects limiting the movement of the
reactant molecules.
3.2.4. Inuence of the activation of catalyst
Some previous works showed an improvement on the reaction
yields in the presence of montmorillonites when the interlayer water
was removed (Loh and Li, 1999). In order to evaluate the inuence of
this treatment on the catalytic activity, an activation of Mt-K10 was
carried out, consisting of sample heating in an oven at 60 C for 24 h.
In this sense, the reaction of the imine 1 with cyclohexanone 2, at
35 C, catalyzed by Mt-K10 as received aorded a mixture of isomers 3-
anti/3-syn with almost quantitative yield, after 240 min of reaction
time (Fig. 8), with selectivity to 3-anti isomer being maintained (70%).
The conversion to compounds 3, as function of the reaction time,
followed a similar trend at the shorter reaction times, when using the
activated sample. Remarkably, the nal conversion to 3 was signi-
cantly higher in the presence of the non-activated Mt-K10. Hence, the
activation process of the montmorillonite under study did not produce
any improvement on its catalytic activity. This circumstance, among
others, makes Mt-K10 a promising environmental-friendly catalyst for
the synthesis of valuable chemicals through cascade reactions involving
imination and Michael addition reactions.
3.2.5. Study of the recyclability of the catalyst
Mt-K10 has been reported as reusable catalyst in several reactions
(Liu et al., 2013; Jeganathan et al., 2014a,b). In order to check its
recyclability in the direct Mannich-type reaction, the study of its
catalytic performance for three consecutive cycles, at 35 C, using
100 mg of Mt-K10, was investigated. As seen in Fig. 9, the conversion
of N-benzylideneaniline 1, after 240 min of reaction time, were 98, 96,
94%, consecutively, the yield to products 3 slightly decreasing just 2%
for each cycle.
3.2.6. Three-component Mannich reaction
The MCR between benzaldehyde 4, aniline 5 and cyclohexanone 2,
at 35 C, under solvent-free conditions, catalyzed by Mt-K10 (Scheme 2)
was also investigated.
Fig. 9. Conversion of N-benzylideneaniline 1, at 35 C, after 240 min of reaction time,
using 100 mg of Mt-K10 as catalyst.
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Applied Clay Science 143 (2017) 250257
Scheme 2. Synthesis of -amino ketones 3 from benzaldehyde 4, aniline 5 and
cyclohexanone 2.
Fig. 10. Synthesis of imine 1 from benzaldehyde 4 and aniline 5 catalyzed by 100 mg of
Mt-K10, at 35 C, under solvent-free conditions.
Firstly, the reaction of benzaldehyde 4 and aniline 5 to obtain the
imine 1 in the presence of Mt-K10 was explored (Fig. 10). Note that the
non-catalyzed reaction often takes place slowly, the imination reaction
being normally an acid-catalyzed reaction by Lewis or Brnsted acids
and Mt-K10 contains both types of catalytic acids sites. Surprisingly, the
almost total transformation of benzaldehyde 4 to the imine 1 occurred
in only 5 min of reaction time.
Finally, the non-catalyzed and catalyzed by Mt-K10 three-compo-
nent Mannich reaction from benzaldehyde 4, aniline 5 and cyclohex-
anone 2, at 35 C, under solvent-free conditions, was examined
(Fig. 11). Thus, the reaction in absence of any catalyst provided a
mixture of compounds 3 with lower yields than the process in the
presence of catalytic amounts of Mt-K10, as expected. In both cases, the
almost total conversion of benzaldehyde 4 to products occurred,
yielding mixtures of isomers 3 in 90 and 94%, respectively, in
approximately 60:40 3-anti/3-syn ratio, after 120 min of reaction time.
Obviously, the reaction in the presence of Mt-K10 (100 mg) gave higher
conversion of 1, at the shorter reaction times (86% in only 15 min), the
selectivity to 3-anti being maintained during the process along
120 min. Additionally, selectivity changes were observed as a function
of reaction time. Surprisingly, when the reaction was maintained
during 5 h in the presence of Mt-K10, a mixture of 3-anti/3-syn isomers
was obtained in almost quantitative yield and also a notably increased
selectivity to 3-anti (90%) was produced. These results strongly suggest
Fig. 11. Three-component Mannich reaction from benzaldehyde 4, aniline 5 and
cyclohexanone 2, at 35 C, under solvent-free conditions.
F. Gmez-Sanz et al.
Table 5
Heterogeneous catalysts catalyzing Mannich reaction.
Catalyst Reaction conditionsa
MA/SZr-P 1:1:1, 50 mg, H2O, rt
Amberlyst-15 0.6:0.5:0.5, 30 mg, CH3CN, rt
Cu-nanoparticles 1:1:1, 20% mol, MeOH, rt
SO42 /TiO2 3:1:1, 50 mg, rt
WOxZrO2 4:1:1, 50 mg, rt
SSA 2.1:2:2, 110 mg, EtOH, rt
Mt-K10 3:2:2, 100 mg, 35 C
Mt-K10 3:2:2, 100 mg, 35 C
a
Reaction conditions: number of mmol of cyclohexanone: benzaldehyde: aniline, catalyst amount, solvent and reaction temperature.
that an interconversion reaction of 3-syn to 3-anti, the most stable
isomer, is produced. This feature was also observed by some of us when
studying the synthesis of 2-amino-4H-chromenes catalyzed by meso-
porous niobiosilicate NbMCF modied with alkali metals
(Smuszkiewicz et al., 2016).
In order to be compared with the catalytic performance of the
smectites under study, Table 5 shows the results obtained with some
solid catalysts explored in the Mannich-type reaction between benzal-
dehyde, aniline and cyclohexanone.
It can be observed that all of them work at room temperature, in the
presence of the corresponding solvent, WOxZrO2 being an exception.
Although the catalytic performance cannot be apparently compared
because of the dierent reaction conditions used in each case, it is clear
that Mt-K10 checked in this work led to similar conversion than the
previously reported catalysts at the shortest reaction time (86% in only
15 min). Remarkably, although the 3-anti/3-syn isomer ratio was 60:40,
after 15 min of reaction time, the selectivity to isomer 3-anti was
substantially increased at prolonged reaction times (5 h); isomer 3-anti
being isolated in 90% of selectivity. These results prove the advantages
of using montmorillonites as catalysts in the one pot three-component
Mannich reaction, particularly Mt-K10. In fact, Mt-K10 as received,
avoiding any post-synthetic treatment, was found to be an ecient and
environmental catalyst with improved catalytic performance under
mild conditions.
4. Conclusions
An eco-friendly methodology for the clean and ecient synthesis of
-amino ketones through Mannich reaction, catalyzed by a raw
saponite and some commercial montmorillonites is reported herein.
The reaction from the pre-formed imine 1 and cyclohexanone 2 occurs
under free-solvent and mild conditions aording compounds 3 with
good to excellent yields, the catalyst activation even being not required.
The three component reaction between benzaldehyde 4, aniline 5 and
cyclohexanone 2 was also explored under the most favorable condi-
tions, observing the total conversion of reactants to imine 1 in only
5 min. A mixture of isomers 3-anti/3-syn (60:40) was obtained in high
yield (86%) in 15 min of reaction time.
The clay minerals under study are mainly mesoporous solids;
although the porosity of the samples had barely any eect at the higher
reaction times, it could be behind the reactivity dierences at short
reaction times. In fact, the reactivity order was in accordance with
those for SBET and micropore volume values, strongly suggesting the
importance of the existence of micropores. The presence of both
Brnsted and Lewis acid sites in smectites of our choice inuenced their
catalytic performance. The concentration of the Lewis acid catalytic
sites seems to be the determinant key in the Michael addition of
cyclohexanone 2 to the imine 1, although obviously the Brnsted acid
sites contribution cannot be neglected. In general, the reaction tem-
perature had not any eect on the reaction diastereoselectivity,
probably due to the connement into mesopores or adsorption eects.
Applied Clay Science 143 (2017) 250257
Time/yield (h/%) Anti/syn Reference
3.5/85 Samantaray et al., 2011
2/90 91/9 Dasa et al., 2009
9/88 Kidwai et al., 2009
3/87 89/11 Samet et al., 2009
2.25/90 20/80 Reddy et al., 2008
36/96 85/15 Wu et al., 2007
0.25/86 60/40 This work
5/91 90/10 This work
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