Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of Polysubstituted 2-Amino-4H-Chromene Derivatives

Article abstract of DOI:10.1007/s10562-019-03089-8

Abstract: In this report, we documented novel strategy for the synthesis of bioactive polysubstituted 2-amino-4H-chromine derivatives under a heterogeneous Al-MCM-41-LDH@APTES (ALAM) catalysis. A synthetic procedure is developed to prepare Al-MCM-41-LDH@APTES (ALAM) heterogeneous basic catalysts. Mesoporous Al-MCM-41 is functionalized by known grafting chemistry via layered double hydroxide (LDH) nanosheets and (3-aminopropyl)triethoxysilane (APTES) moiety as a basic organocatalyst. The resulting catalysts contain amino group functionality on the external surface as well as inside the layers and the basicity can be tuned by the loading of APTES. The samples were fully characterized by ²⁹Si and ¹³C CP/MAS NMR, infrared absorption spectroscopy, TEM, XPS, EDX, TGA, XRD, CO₂-TPD, N₂ adsorption isotherms measurements, and they were successfully examined for the cascade type Knoevenagel–Michael addition reactions. The product yields associated with these substrates were optimized, and key reaction parameters affecting the yields were identified. The present catalytic method is simple and robust for diversity oriented synthesis which proceeds good to excellent yields without generating any hazards waste. The broad substrate scope, excellent functional group compatibility makes this protocol highly useful towards synthesis of polysubstituted α-cyanoacrylates, α-cyanoacrylonitriles and 2-amino-4H-chromenes with an electron-donating or electron-withdrawing group. We have also successfully established a flow reaction system, gram-scale synthesis as well as catalyst recyclability up to six catalytic cycles without appreciable loss of its activity. Graphic Abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s10562-019-03089-8

Catalysis Letters
https://doi.org/10.1007/s10562-019-03089-8
Organocatalytic Cascade Knoevenagel–Michael Addition Reactions:
Direct Synthesis of Polysubstituted 2‑Amino‑4H‑Chromene Derivatives
Sanjay N. Jadhav1 · Seema P. Patil1 · Dipti Prava Sahoo2 · Dharitri Rath2 · Kulamani Parida2 ·
Chandrashekhar V. Rode1
Received: 25 August 2019 / Accepted: 26 December 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
In this report, we documented novel strategy for the synthesis of bioactive polysubstituted 2-amino-4H-chromine deriva-
tives under a heterogeneous Al-MCM-41-LDH@APTES (ALAM) catalysis. A synthetic procedure is developed to prepare
Al-MCM-41-LDH@APTES (ALAM) heterogeneous basic catalysts. Mesoporous Al-MCM-41 is functionalized by known
grafting chemistry via layered double hydroxide (LDH) nanosheets and (3-aminopropyl)triethoxysilane (APTES) moiety
as a basic organocatalyst. The resulting catalysts contain amino group functionality on the external surface as well as inside
the layers and the basicity can be tuned by the loading of APTES. The samples were fully characterized by 29Si and 13C CP/
MAS NMR, infrared absorption spectroscopy, TEM, XPS, EDX, TGA, XRD, CO2-TPD, N2 adsorption isotherms measure-
ments, and they were successfully examined for the cascade type Knoevenagel–Michael addition reactions. The product
yields associated with these substrates were optimized, and key reaction parameters afecting the yields were identifed. The
present catalytic method is simple and robust for diversity oriented synthesis which proceeds good to excellent yields without
generating any hazards waste. The broad substrate scope, excellent functional group compatibility makes this protocol highly
useful towards synthesis of polysubstituted α-cyanoacrylates, α-cyanoacrylonitriles and 2-amino-4H-chromenes with an
electron-donating or electron-withdrawing group. We have also successfully established a fow reaction system, gram-scale
synthesis as well as catalyst recyclability up to six catalytic cycles without appreciable loss of its activity.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-03089-8) contains
supplementary material, which is available to authorized users.
* Sanjay N. Jadhav
sanjaychempd@redifmail.com
* Chandrashekhar V. Rode
cv.rode@ncl.res.in
Kulamani Parida
kulamaniparida@soauniversity.ac.in
1
Chemical Engineering and Process Development Division,
CSIR—National Chemical Laboratory, Pune, M.S. 411008,
India
2
Centre for Nano Science and Nano Technology, Institute
of Technical Education and Research, Siksha ‘O’
Anusandhan University, Khandagiri, Bhubaneswar,
Odisha 751 030, India
Vol.:(0123456789)
1 3

S. N. Jadhav et al.
Graphic Abstract
Keywords Cascade synthesis · 2-Amino-4H-chromines · Amine functionalized solid catalysts · Flow chemistry · Diversity
oriented syntheses (DOS)
active and challenging topic in modern synthetic chemis-
try; [15, 16] particularly, providing diverse spectrum of
novel and medicinally privileged heterocycles [17, 18].
The chromene scafolds are important structural motifs
in a vast number of natural products (Fig. 1a–c), which
are used as building blocks in the synthesis of biologically
active molecules [19–22]. Among the chromene family,
2-amino-4H-chromenes and 2-amino-4H-benzo [b]pyrans,
constitute an important class of compounds and fnd applica-
tions in the feld of biodegradable agrochemicals, pigments
and cosmetics [23, 24]. In recent years, chromenes are most
frequently encountered scafolds in bioactive heterocyclic
compounds showing wide spectrum of pharmaceutical prop-
erties, such as sex pheromone, mutagenicity, antibacterial,
antimicrobial, antiviral, antitumor, antihypertensive, antiox-
idant, hypotensive, anticoagulant, antitubercular activities
[25–34]. Chromene scafolds also act as cognitive enhancers
in the treatment of neodegradable diseases like insomnia,
Alzheimer’s, Schizophrenia disorder etc [16, 35]. Selected
examples of pharmacologically active compounds based on
2-amino-4H-chromenes and related scafolds possessing
anticancer, antibacterial and anti-rheumatic activities are
depicted in Fig. 1d–g.
1 Introduction
Heterocyclic [1, 2] scafolds represent a broad spectrum
of organic moieties and they are indispensable structural
motifs owing to their biological relevance as medicinally
relevant compounds having industrial signifcance and
extensively used as valuable building blocks in modern
synthetic organic chemistry [3, 4]. In light of the impor-
tance of these compounds, the ongoing interest for devel-
oping new versatile and efcient syntheses of heterocycles
has always been a hot topic in organic chemistry. In the
past several years, great eforts have been made to develop
productive concepts of multi-component processes involv-
ing cascade and sequential transformations [5–8]. Com-
plex and highly diverse structures are created in a one-pot
fashion instead of multistep synthesis which also created
considerable encouragement for academia as well as indus-
try researchers [5–8]. Multi-component reactions (MCRs)
simultaneously engage three or more substrate molecules,
to form desired products that incorporate the elements of
all starting materials in their frameworks [9–11]. MCRs
in cascade synthesis enable to achieve high atom-economy
[12], reduce the number steps, multiple-bond-forming ef-
ciency, synthetic efciency, convergence, selectivity, and
operational simplicity, etc [12–14]. Over last two decades
witnessed remarkable development of new MCRs to be the
A traditional approach to the synthesis of 2-amino-4H-
chromenes involves a base catalyzed one-pot multicompo-
nent cascade type reaction between aldehyde (or isatin) and
two diferent active methyl motifs [36]. Among the known
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
OCH3
OCH3
CH3
CH3 CH3
O
O
O
O
H3CO
O
CH3
O
O
O
O
O
O
OH OCH3
OH
OH
Arisugacin A
Laccaridione A
antiproliferatives
anti-alzheimer's
(+)-Calanolide-anti-HIV
(C)
(A)
(B)
OMe
OMe
NO2
MeO
Br
MeO
Br
OH
O
CN/SO2Ph
CN/SO2Ph
NH2
CN/SO2Ph
NH2
CN/SO2Ph
NH2
O
NH2
N
O
MX58151
H2N
O
O
NH2
Crolibulin (EPC2407)
Antibacterial
Anti-breast, lungs, colorectal cancer agent
Anti-rheumatic
(D)
(E)
Anti(-cFa)ncer
(G)
Fig. 1 Selected examples of natural products and pharmacologically active compounds based on synthetic 4H-chromenes and related scafolds
procedures, most of the protocols for the synthesis of this
heterocyclic system involves substrates like dimedone, bar-
bituric acid, naphthols, resorcinol, 4-hydroxycoumarin,
4-hydroxyquinolin-2-one, Kojic acid, indane-1,3-dione,
2-hydroxy naphthoquinone, etc. one of the C–H acids, while
limited choice exists for the use of malononitrile or alkyl
cyanoacetate as a other C–H acid [16, 37–45]. Although,
the compounds bearing a sulfone functional moiety are
found to possess important applications in pharmaceuti-
cals, agrochemicals, polymers, etc. [46], there are only a few
reports for the multicomponent synthesis of 2-amino-4H-
chromenes wherein alkyl/(phenylsulfonyl)acetonitrile has
been used as C–H acid [16, 43, 47–51]. In light of promis-
ing pharmaceutical applications associated with 2-amino-
3-cyano-4H-chromenes (Fig. 1d–g) and the pharmaceuti-
cal properties associated with the compounds containing a
sulfonyl group [46], we explore the choice of (phenylsul-
fonyl)acetonitrile as well as malononitrile as a C–H acid
source for the diversity oriented synthesis of 2-amino-4H-
chromene scafolds. Ideally, the synthesis of 2-amino-4H-
chromenes is desirable with one basic catalytic system in
a single pot, instead of multiple sequential steps. Thus, we
focused our attention to design heterogeneous catalytic pro-
cesses in cascade reactions in one vessel for the synthesis of
2-amino-4H-chromenes.
high textural properties, mesoporosity, high thermal and
mechanical or structural stability, strong covalent char-
acter, high surface area, wide pore volume and narrow
pore diameter [56–59]. MCM-41 containing siliceous
mesoporous material in its neat form having lack of active
sides on the surface. Surface functionalization increases
its applications as a catalyst rather than only as a solid
support. Layered double hydroxide (LDH) is another class
of materials having two dimensional (2D) brucite type
octahedral nanostructured clays consisting of positively
charged layers with charge-balancing anions between
charged layers [60–64]. LDHs nanosheets have progres-
sively received much attention as supports due to their
surface acid–base properties, large surface areas which
not only can increase the anchoring sites (–OH groups),
but also can facilitate the transport of reagents to and from
the surface [63, 65, 66]. In view of the unique character-
istics of MCM-41, alumina and LDH, there becomes the
potential support for preparation of amine-functionalized
catalysts.
In this present study, we introduced a novel methodol-
ogy involving amine functionalized grafting of molecu-
lar structures on the solid surface (Al-MCM-41-LDH) to
prepare mesoporous nanosheets of Al-MCM-41-LDH@
NH2 (ALAM) catalysts. The resulting amine functionalized
ALAM catalysts were thoroughly characterized with vari-
ous analytical techniques to corroborate the success of the
synthetic approach. The catalytic performances were exam-
ined for a diversity oriented synthesis of α-cyanoacrylates,
There has been an increasing attention towards MCM-
41 grafted with various amines for numerous base cata-
lyzed organic syntheses [52–55]. MCM-41 and alumina,
have been mainly used as catalyst supports due to their
1 3

S. N. Jadhav et al.
α-cyanoacrylonitriles, 2-amino-4H-chromenes scafolds fol-
lowed by cascade Knoevenagel–Michael addition reactions.
The details of this work follow.
and condenser, 4-chlorobenzaldehyde (1.0 mmol), (phenyl-
sulfonyl)acetonitrile (1.0 mmol), 70% ALAM (5 mol%) and
95% EtOH (5 mL) were added. The fask was immersed in
a heating oil bath and the reaction mixture was stirred at
80 °C. Upon complete consumption of starting materials as
analysed by TLC (hexane : ethyl acetate, 8 : 2), then the cata-
lyst was separated by centrifuge, washed with water, ethanol
and acetone. Resulting reaction mixture was extracted with
diethyl ether (3×10 mL). The combined organic layer was
dried over anhydrous Na2SO4 and concentrated to aford
crude products, which were purifed by column chromatog-
raphy. It was observed that on MCM-41 surfaces there is
always some residual adsorbed water left behind, even after
heating under vacuum as it was done here. Nevertheless,
that does not seem to afect the model reaction, which has in
fact been reported to take place even in aqueous media [72,
73]. Moreover, our fnal product, 2-amino-4H-chromenes,
requires a subsequent cascade type Knoevenagel–Michael
addition, and that also appears to be promoted readily by our
optimized catalytic protocol.
2 Experimental Details
All the reagents including the (3-aminopropyl)triethox-
ysilane (APTES) were commercially sourced from Sigma
Aldrich and Spectrochem (research purity) chemical compa-
nies and used as supplied. Solvents were dried and purifed
by standard methods. 1H-NMR and 13C-NMR spectra of the
pure compounds were recorded on a Bruker Avon 200 MHz,
400 MHz or 500 MHz spectrometers. Chemical shifts for 1H
NMR are referred to internal TMS (0 ppm) and chemical
shifts for 13C NMR are referenced to the carbon resonance
of the solvent (CDCl3: δ 77.0 ppm). Data are reported as
follows: chemical shift (δ ppm), multiplicity (s = singlet,
d=doublet, t=triplet, q=quartet, m=multiplet), coupling
constant (Hz) and integration. The 29Si and 13C cross-polar-
ization magic-angle spinning (CP/MAS) NMR data were
acquired on a Bruker Avance 400 spectrometer equipped
with a 4 mm H/X CP-MAS probe operating at 79.43 MHz
[67–70].
3 Results and Discussion
Mass spectra were recorded on a Shimadzu QP2010
GCMS instrument. The size distribution and morpholo-
gies of the catalyst samples were examined by transmis-
sion electron microscopy (TEM, FEI Tecnai F-20) at an
acceleration voltage of 200 kV and specimens for TEM
analysis were prepared on carbon-coated copper grids. The
chemical analysis of the prepared catalyst was carried out
by surface characterization with XPS analysis (ESCA-3000,
VG Scientifc Ltd, UK) with a base pressure of lower than
1.0×10−9 Pa. Mg Ka radiation (1253.6 eV) was used as an
X-ray source and operated at 150 W. TGA analysis was car-
ried out to investigate the thermal stability of catalysts were
acquired on a Dimond TG/DTA analyser at rate of tempera-
ture 10.00 °C/min under N2 atmosphere. Fourier transform
infrared absorption spectra (FTIR) were acquired in trans-
mission mode using a Perkin Elmer spectrometer [67–71].
The solids were directly placed at the focal point of the sam-
ple compartment. The data correspond to averages of 1024
scans, taken at 4 cm−1 resolution and referenced to spectra
for pure MCM-41. The surface area, pore volumes, and pore
size distributions were estimated from N2 adsorption–des-
orption isotherms obtained using a commercial 2000e Model
25 Nova Win vacuum volumetric gas sorption system. The
data were analyzed by using the Barrett–Joyner–Halenda
(BJH) isotherm equations on both adsorption and desorp-
tion branches of the data. The surface concentrations of the
amine groups were quantifed by using CO2-TPD analysis.
The catalytic model reaction was carried out as follows:
In a Schlenk fask equipped with a magnetic stirrer, septum
3.1 Synthesis of Base Catalysts
Basic (amine) moieties where tethered to a Al-MCM-
41-LDH layered mesoporous support [74] according to the
synthetic steps displayed in Fig. 2, relying on well-known
grafting chemistry based on alkyltrialkoxysilane linkers [55,
59, 68, 73, 75–78]. The former benchmark reaction condi-
tion was applied to preparation of variety of amine tethered
Al-MCM-41-LDH heterogeneous catalysts and synthetic
steps were the following:
1. Grafting of Al to surface of MCM-41 by hydrothermal
method [55, 59, 68, 75–78] (Step 1, to make Al-MCM-41):
CTAB (1 g) and PEG (200) (0.88 ml) were introduced
into the beaker containing 50 mL DI water and dissolved
completely at 40 °C water bath. Aluminium isopropoxide
(C9H21O3Al) (1.93 g) and TEOS (16.77 ml) (Al:Si= 10)
are added slowly into it. The pH of the solution was main-
tained at 10 by adding 1 M NaOH solution. The prepared
white precipitate was stirred at 40 °C for 1 h in a water
bath. The resultant solution was transferred to Tefon-lined
autoclave and heated at 110 °C for 24 h and cooled to room
temperature. The solid was fltered and washed several times
with deionized water and dried at 80 °C for overnight under
vacuum. The sample was calcined at a heating rate of 2 °C
min−1 to 550 °C for 6 h to remove the template.
2. Grafting of ZnCrLDH to surface of Al-MCM-41 by
in-situ co-precipitation method [60, 79] (Step 2, to make
Al-MCM-41/LDH (LAM):
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
Fig. 2 Synthetic strategy used in this research for the making of functionalized amine catalysts
In a typical synthesis, a certain amount of Al-MCM-41
power catalyst was taken in a 50 mL deionized water con-
taining beaker and sonicate for 30 min. The 1000 mL of solu-
tion containing 500 mL 0.05 M solution of Zn(NO3)2·6H2O
and 500 mL 0.025 M solution of Cr(NO3)3·9H2O (Solution
A) and another a mixture of solution containing 1 M NaOH
and 1 M Na2CO3 (Solution B) were added drop wise sepa-
rately to the Al-MCM-41 suspension with maintaining the
pH at 7–8. The resulting precipitate was stirred for 15 h.
The solid was fltered and washed thoroughly with deion-
ized water to remove the presence of excess soluble ions.
The resulting solid was then dried overnight under vacuum
at 80 °C. Pure ZnCrLDH (LDH) was also prepared by above
procedure.
diethyl ether and DCM (300 mL), and then modifed solid
was then dried overnight under vacuum at 50 °C to aford a
grey solid (ALAM). By varying the wt% amount of APTES
(40%, 50% 60%, 70% and 80%), amine modifed LAM were
obtained and designed as 40ALAM, 50ALAM, 60ALAM,
70ALAM and 80ALAM.
3.2 Catalyst Characterization: IR
FTIR spectra were measured to assure the existence of
bonding which identify the infuence of nature of tethered
species. Typical FTIR spectral data for LDH, LAM, Al-
MCM-41, 40 ALAM, 50 ALAM, 60 ALAM, 70 ALAM
and 80 ALAM are shown in Fig. 3. In FTIR spectra, sev-
eral identical peaks can be seen associated with the tethered
functionalities. We have highlighted the very intense and
broad peak seen at about 3200–3600 cm−1 due to stretching
vibration of surface hydroxyl groups and intercalated water
molecule of LDH and also hydroxyl group of Al-MCM-41
[80, 81]. The broadness of the peak illustrated H-bonding
with a large range of vibrational frequency. The intensity
of this broad peak decreased once the tethering of func-
tionalities increases from 40 ALAM to 80 ALAM. A weak
band was observed at 1630–1650 cm−1 for H–O–H bending
vibration of water molecule. The symmetric and asymmetric
stretching mode of carbonate anion in inter gallery space
3. Tethering of APTES to surface of LAM by standard
refux method (Step 3, to make 40–80 wt% ALAM): [55,
76, 77]
An oven-dried Schlenk fask, equipped with a magnetic
stir bar, septum and a condenser was charged with LAM
(1 g) sample was suspended with 60 ml toluene and then
0.4 to 0.85 mL of organic APTES was added in drop wise
manner and then it was refuxed for 2 h. After distillation
of a small toluene fraction containing ethanol from reac-
tion mixture, the heating and distillation sequences were
repeated four times. The resulting solid was recovered by
centrifuge method, washed in a Soxhlet apparatus with
1 3

S. N. Jadhav et al.
organic amine on the surface of LAM nanocomposites. All
the APTES functionalized composites showed the charac-
teristic asymmetric vibration of the –CH2 group of propyl
chain in APTES at 2927 cm1 [73]. The symmetric stretching
vibration of –NH2 group overlap with O–H stretching vibra-
tion of LAM composite to generate a broad spectrum in the
range of 3200–3600 cm−1 [82]. All the LDH based compos-
ites except Al-MCM-41 showed the bands at low frequency
region of the spectrum were due to lattice vibration modes
of Zn/Cr–OH (660 cm−1) and Zn–O–Cr (585, 500 cm−1)
bond [80]. Moreover in the case Al-MCM-41, LAM and
all the APTES functionalised catalyst, spectra from 1024 to
1230 cm−1 and 790 cm−1 were attributed for Si/Al–O–Si and
Si/Al–OH vibration band. After the fabrication of LDH with
Al-MCM-41 the broadness of –OH stretching peak suddenly
decreased due to close interaction between LDH and Al-
MCM-41 [83]. All the above FTIR results produce a strong
evidence in support of the functionalization of APTES on
the surface of LAM.
3.3 Catalyst Characterization: 29Si CP/MAS NMR
Fig. 3 Fourier-transform infrared absorption (FTIR) spectra from the
solid samples obtained after key steps of the synthesis of our cata-
lysts. Traces are shown for the making of LDH, LAM, AL-MCM-41
and 40 ALAM to 80 ALAM catalysts
The success and efciency of the tethering –NH2 groups and
the preservation of the tethered amine groups were evaluated
by using 29Si CP/MAS NMR and characteristic spectral data
of MCM-41 and 70 ALAM reported in Fig. 4. The peaks
observed in those data attest to the existence of the tethered
species on the surface of the LAM as well as provide infor-
mation about the type of bonding involved. The observed
peak assignment clearly follows what has been reported
were appeared at 1493 cm−1 and 1370 cm−1 respectively
in the case of LAM and diferent wt% of ALAM compos-
ites. Presence of N–H bending vibration at 690 cm−1 and
–NH2 symmetric bending vibration at 1532 cm−1 in all%
of ALAM materials confrmed the successful grafting of
Fig. 4 29Si cross-polarization
magic-angle-spinning (CP/
MAS) NMR spectra for our
70 ALAM fresh catalyst and
MCM-41. The peak assignment
is provided on the right
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
previously for similar systems [73, 84–86], is illustrated in
the right-hand side of Fig. 4. It can be evident from the 29Si
CP/MAS NMR data that bonding between tethering group to
the surface can occur via one, two, or three Si–O−Si links,
but more than two-thirds of the total bonding is with two
bonds and has been seen in other cases which is reported
previously [73, 84–88].
The peak assignments is straightforward [73, 90, 91], as
illustrated for the case of the APTES supported on MCM-
41 as solid support. It is also interesting to note that the
spectrum for 70 ALAM, shows some signifcant peaks,
including the following: (1) the main peaks associated
with APTES functionalised material exhibits three peaks
i.e. at 10.5, 22.4 and 43.1 ppm. The maximum shielded
C-atom (at 10.5 ppm) is the one attached directly to Si
atom. 22.4 ppm corresponds to the middle carbon atom
and 43.1 ppm peak is for the carbon atom attached to –NH2
group. From the above study it is clear that there is bond-
ing between the Si atom and the organic amine with the
–NH2 group at the free end [72, 73].
The parent MCM-41 exhibits peaks at −93.2, −102.6
and 111.7 ppm which correspond to SiO2(OH)2 (Q2 sites),
SiO3–OH (Q3 sites) and SiO4 (Q4 sites) respectively.
These peaks show slight shift in their position compared
to LAM [88] due to presence of Al in the framework. In
addition to the above peaks some Tn peaks are present in
70ALAM material for amino silane groups. The peak
observed at −66.80 ppm corresponds to T1 (C–Si(OSi)3)
and −58.27 ppm corresponds to T2 (C–Si(OSi)2OH) sites
[73, 84–86, 89].
3.5 Catalyst Characterization: N2 Adsorption
Isotherms
3.4 Catalyst Characterization: 13C CP/MAS NMR
Further catalyst characterization was carried out by record-
ing N2 adsorption isotherms for the determination of specifc
surface area, average pore diameter and pore volume. The
well-defned structure of the pores in mesoporous materi-
als like Al-MCM-41, the pore diameter distributions can be
used to determine substitutions of such pores from the sur-
face of Al-MCM-41. Figure 6 displayed data obtained from
our studies, and the results are summarized in Table 1. It can
be seen that the calculation of specifc surface area and pore
size of our samples showed Barrett–Joyner–Halenda (BJH)
type IV isotherm behaviour, which confrmed the character-
istic of ordered mesoporous nature of the materials [92, 93].
After the completion of the adsorption, immediately desorp-
tion was started and resulted a narrow hysteresis loop which
attributed to type H3 with presence of irregular pores and
non uniform size [94]. According to our previous literature
the calculated specifc surface area of LDH was 56 m2/g
and measured pore size was 3-5 nm [95]. The surface area
of Al-MCM-41 was found to be 1089 m2/g (Table 1) [60,
79]. There are signifcant losses of surface area and vol-
ume of Al-MCM-41 support upon the initial tethering of
the LDH and the average pore diameter is reduced nearly
about 1 nm, suggesting that the newly tethered active sites of
LDH were uniformly distributed over the Al-MCM-41 sup-
port and stick out of the surface area (1089 to 305.7 m2g−1)
(Table 1). Further functionalization of APTES on the sur-
face of LAM, the surface area was gradually decreased with
increasing of amine content (305.7 to 136.7 m2g−1) due to
the tethering of APTES groups with Si–OH and Zn/Cr–OH
in the framework. The pore volume and pore diameter of
the samples displayed the same order that of surface area.
After the composite formation with amine modifcation, the
pore size was calculated to be<3 nm which suggests all the
nanocomposites were in mesoporous range.
The integrity of the tethered organic moieties was also
characterising with 13C CP/MAS NMR and typical 13C CP/
MAS NMR characterization data is illustrated in Fig. 5.
Fig. 5 13C CP/MAS NMR spectra for our 70 ALAM fresh catalyst.
The peak assignment is provided by the carbon atom numbering
shown at the top. A 13C NMR spectrum (bottom blue) for untethered
APTES in a CDCl3 solution is also provided as reference, to highlight
the preservation of the integrity of the molecular structure upon teth-
ering
1 3

S. N. Jadhav et al.
Fig. 6 N2 adsorption isotherms (right) and calculated pore diameter distributions for our ALAM based catalysts, as indicated in Table 1
3.6 Catalyst Characterization: CO2‑TPD Analysis
Table 1 N2 adsorption isotherms data summary
Catalysts
A (m2g−1
)
VT (cm3g−1
)
〈d〉 (nm)
The integrity of basicity of the tethered organic moieties
was investigated with CO2 TPD analysis within the tempera-
ture range 30 to 1000 °C. The typical spectral data from a
CO2 TPD characterization sequence is shown in Fig. 7, for
Al-MCM-41, LAM, 50 ALAM, 60 ALAM and 70 ALAM.
Brønsted acid sites mainly represented the surface hydroxyl
groups and Lewis basic sites are corresponded to oxygen
groups. In the case of Al-MCM-41 and LAM, showed broad
ZnCr LDH
Al-MCM-41
LAM
40 ALAM
50 ALAM
60 ALAM
70 ALAM
56
–
5.3–5
5.63
4.59
4.0
3.8
3.78
3.67
1089
305.7
238-2
160.3
148.5
136.7
0.61
0.35
0.24
0.15
0.14
0.12
Fig. 7 CO2-TPD profles of the solid samples obtained after key steps
of the synthesis of our catalysts. The integrity of basicity of the teth-
ered organic moieties was investigated with CO2 TPD analysis of
LAM, AL-MCM-41 and 40 ALAM to 70 ALAM catalysts. Thermal
stability of 70 ALAM catalyst evaluated by TG-DTA analysis
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
CO2 desorption peaks in the temperature range of 30–200 °C
with a peak maxima at 100 o C, indicating the presence of
weak/medium basic sites of similar strength due to the teth-
ered aluminium in the framework [58, 59]. The peak inten-
sity of CO2 desorption at 300 °C and 400 °C was higher for
amine functionalized 70 ALAM catalyst compared to other
catalysts indicated that it possessed higher basic strength
(0.441 mmolg−1). When the amine content increased from
50 weight percent to 70 weight percent, two intense distinct
peaks were appeared and the basic strength increased in the
order of 50 ALAM<60 ALAM<70 ALAM. These peaks
indicated the highest physisorbed and chemosorbed CO2.
bioactive 2-amino-4H-chromenes. When the reaction carried
out in aqueous medium, it was observed that only moderate
yield (15%) of the Knoevenagel product in 12 h (Table 2,
entry 6).
Diferent amine based heterogeneous organocatalysts
were explored for their performance in the synthesis of
α-cyanoacrylonitriles. A standard amount of 5 mol% cata-
lyst was used in the reaction mixture, regardless of the amine
loading and the results are illustrated in Table 3. Our frst
task here was to make sure that basic functionalities are
necessary for the synthesis of cyanoacrylonitrile. The con-
version of benzaldehyde and malononitrile was tested with
MCM-41, Al-MCM-41, LAM and ALAM catalysts contain-
ing –NH2 basic sides. It was clearly indicates, none of those
catalysts promote the complete conversion to cyanoacry-
lonitrile: MCM-41, Al-MCM-41 and LAM showed only
trace amount of conversion in 12 h (Table 3, entries 2 to
4). Interestingly, one more important point should be made
at this stage of our discussion; blank experiment with pure
LAM indicated that those sites alone cannot promote the
rate of the reaction. Only the catalyst containing –NH2 basic
sites is capable of carrying out the complete conversion
with 94% yield of desired product within very short period
(2 h) (Table 3, entry 7). The organic amine templates are
anchored on the layers of functionalized MCM-41, which
provide highly active basic sides in mild reaction condi-
tions as recyclable catalyst. The organo silane is linearly
distributed on the LAM surface and having highly active
basic sides is due to the presence of alkoxy anions located
in layers of modifed LAM material [76]. As can be seen
from these results for the model reaction, the formation of
cyanoacrylonitrile increased from 35% to 94% with increase
in amine content from 40 to 70 wt% loading. The percentage
of conversion stable with further increase in amine content
(80%) (Table 3, entry 9). The results reveal that, the 5 mol%
of 70 ALAM catalyst was found to be the most efective with
a maximum yield, in 2 h (Table 3, entry 8). 70 ALAM cata-
lyst showed excellent catalytic activity as compare with pre-
viously reported amine functionalized MCM-41 catalyzed
Knoevenagel condensation reaction [76, 98]. Next, the per-
formance of the catalyst was optimized in terms of the load-
ing of highly active basic (–NH2) sites present on the surface
of modifed LAM material, which could be controlled by
tuning the time and mol% exposure of the ALAM catalyst
as indicated in Table 3. As the mol% amount of 70 ALAM
catalyst increased, the reaction rate also increased and short
exposures result in catalysts with an insufcient concen-
tration of active basic sites, making the catalysis slow: the
catalyst made 100% conversion within 2 h exposure with
5 mol% (Table 3, entry 14), if the mol% of catalyst reduces
it takes longer time to reach full conversion of 4-chloroben-
zaldehyde and (phenylsulfonyl)acetonitrile (Table 3, entries
10–13). No signifcant improvement was observed on using
3.7 Catalyst Characterization: TG‑DTA Analysis
TG-DTA analysis was carried out to evaluate the thermal
stability of 70 ALAM catalyst. TGA profle of 70 ALAM
(Fig. 7) indicated that the catalyst is stable up to 300 °C.
The weight loss at 100–150 °C is attributed to the physi-
cal adsorbed water molecules and intercalated water mol-
ecules in LDH without collapse of hydrotalcite structure.
The signifcant decrease in weight loss observed at a tem-
perature between 300 and 470 °C is likely to correspond to
the removal of CO2 from the CO32− ions physically bound
in LDH and H2O from dehydroxylation of OH groups in the
hydrotalcite along with decomposition of the aminopropyl
group tethered on the surface of LAM catalyst. The diferen-
tial thermal analysis (DTA) graph (Fig. 7) is in good agree-
ment with the TG curve as the exothermic peak [96, 97].
3.8 Catalytic Performance
After well characterization of catalysts, we screened catalyst
performance for the sequential cascade type synthesis of bio-
active 4H-chromene scafolds. Hence, we directed our initial
eforts toward screening of various reaction parameters such
as various base catalysts, loading of the catalyst, efect of
solvent, concentration of substrate, time and temperature.
Initially our investigation started with the Knoevenagel con-
densation reaction of 4-chlorobenzaldehyde with (phenylsul-
fonyl)acetonitrile chosen as model reaction.
The infuence the solvents were investigated by perform-
ing the model reaction with diferent solvents and results are
summarized in Table 2. Solvent plays a crucial role on the
reaction rate and yield of desired product of Knoevenagel
Condensation. Solvents screening revealed that non-polar
solvents such as CHCl3, THF and CH3CN shows moder-
ate conversions (Table 2, entries 1, 3 and 5). Among polar
green solvents, 95% ethanol was the only solvent candidate
to favour this transformation (Table 2, entry 8), probably
because 95% ethanol perform more hydrogen bonding with
catalyst than other polar solvents which makes this proto-
col quite practical and amenable for large-scale synthesis of
1 3

S. N. Jadhav et al.
Table 2 Efect of solvent on condensation of 4-chlorobenzaldehyde with (phenylsulfonyl)acetonitrile over 70 ALAM
NC
SO2Ph
O
70 ALAM
70 ALAM
CN
H
+
Solvent, T oC
SO2Ph
Cl
Cl
NH2
Yield
(%)a
Solvent
Entry
Time (h)
1
2
3
4
5
6
CHCl3
DMC
57
66
53
70
45
15
12
12
12
12
12
THF
MeOH
CH3CN
H2O
12
Abs. EtOH
95% EtOH
7
8
94
94
02
02
Reaction conditions: 4-chlorobenzaldehyde (1 mmol) and (phenylsulfonyl)acetonitril (1 mmol), 70 ALAM (5 mol%), Solvent (5 mL), at 80 °C
aIsolated product
increased amount of catalyst up to 5–10 mol% (Table 3,
entries 15–17). APTES is more evenly tethered on the LAM
surface in case of the post-synthesis (refux) method than
that of co-condensation method (Table 3, entry 18).
In the optimization study, these dependencies of reac-
tion rate could be confrmed for the current model reaction
and results presented in Fig. 8b. The model reaction carried
out in various eight steps from 15 to 135 min. The percent-
age yield of desired product line linearly increased with the
increase in the reaction time from 15 to 120 min and after
that it remained constant giving 94% yield.
To improve the efciency of the model reaction, the reac-
tion conditions were optimized by varying the temperature
of reaction (40–95 °C) and the results are shown in Fig. 8a.
Both the yield increases and time decreases signifcantly (to
94% and 2 h, respectively) when the reaction temperature
was elevated to 80 °C, and similar results were obtained
when the reaction was conducted in 80–95 °C. In general,
activation energy close to zero often indicates mass trans-
fer limitations at ambient temperature. Since reaction takes
place in an efciently at 80 °C, mass transfer limitation can
be neglected due to the activation energy increases [99].
3.9 Substrate Scope
Having identifed optimal reaction conditions, we next inves-
tigated the substrate scope for Knoevenagel condensation
by examining a variety of aldehydes with malononitriles
and (phenylsulfonyl)acetonitrile (Table 4). Knoevenagel
condensation allows the formation of a C–C double bond
from carbonyl compounds and C–H acid is a widely used
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
Table 3 Efect of catalyst precursors on condensation of 4-chlorobenzaldehyde with (phenylsulfonyl)acetonitrile
NC
SO2Ph
O
70 ALAM
Catalyst
95 % EtOH, 80 oC
CN
H
+
SO2Ph
Cl
Cl
NH2
Entry
Catalysts
Time (h)
Yield (%)a
Mol%
1
2
Wihout Catalyst
MCM-41
–
–
–
06
06
06
NR
07
10
3
Al-MCM-41
4
LAM
06
06
–
16
35
5
40 ALAM
5.0
6
61
06
50 ALAM
5.0
7
80
94
93
06
02
60 ALAM
70 ALAM
5.0
5.0
8
9
5.0
02
24
12
08
04
80 ALAM
70 ALAM
70 ALAM
70 ALAM
70 ALAM
30
70
80
93
10
1.0
2.0
3.0
4.0
11
12
13
94
94
14
15
70 ALAM
70 ALAM
70 ALAM
70 ALAM
70 ALAM
02
02
02
5.0
6.0
16
17
94
7.0
94
88
02
02
10.0
5.0
18b
Reaction conditions: 4-chlorobenzaldehyde (1 mmol) and (phenylsulfonyl)acetonitril (1 mmol), catalysts (1–10 mol%), 95% EtOH (5 mL), 80
°C, in 2 h
NR no reaction
aIsolated product
bCatalyst prepared by cocondensation method [76]
1 3

S. N. Jadhav et al.
Fig. 8 Kinetic data for a Knoevenagel condensation reaction for
the synthesis of α-cyanoacrylonitriles promoted by our optimized
70 ALAM catalyst. [a] Time evaluation of conversion, [b] tempera-
ture vs conversion. Reaction Conditions: 4-chlorobenzaldehyde, (1
mmol) and (phenylsulfonyl)acetonitrile (1 mmol), 70 ALAM (5 mol
%), 95 % EtOH (5 mL), 40-95 °C, in 0-135 min
reaction in research and industry and has been of impor-
tance for several therapeutic drugs, such as niphendipine
and nitrendipine, and pharmacological products, for example
calcium channel blockers and antihypertensives may also
be produced using this reaction [100, 101]. Generally, this
reaction is catalyzed by using wide range of organo-bases,
such as pyridine or piperidine. Although these homogeneous
base catalyzed protocols reported by others fnd certain mer-
its of their own, still they sufer from a number of demerits
such as work-up procedures, undesired side-reactions like
oligomerizations can occur, and catalyst recovery is dif-
cult task [102]. Hence, we directed our attention to explore
the choice of (phenylsulfonyl)acetonitrile as well as malo-
nonitrile as a C–H acid source for the diversity oriented
synthesis of α-cyanoacrylates and α-cyanoacrylonitriles
scafolds by using recovered and regenerated heterogene-
ous 70 ALAM catalyst. The desired α-cyanoacrylates and
α-cyanoacrylonitriles were produced in good to excellent
yields (78–94%), using various benzaldehydes with an
electron-donating or electron-withdrawing group. Chlo-
rine, mehyl, methoxy and nitro substituted aldehydes
with malononitrile/(phenylsulphonyl)acetonitrile were
tolerant to the reaction conditions, and the corresponding
α-cyanoacrylonitrile and α-cyanoacrylates was produced
with 84% to 94% yield. It is noteworthy that the desired reac-
tion of sterically hindered aldehyde a6, a11, a12 and b6, b11,
b12 also reacted with malononitrile as well as (phenylsul-
phonyl)acetonitrile under the optimized conditions to ofer
the desired products in moderate to good yields (78–88%)
in 2 h. The ortho-substituted aldehydes reaction proceeded
smoothly and gave the desired product in good to excellent
isolated yields (Table 4 entries a3, a5, a10 and b5).
We then investigated the substrate scope of active
methyl dimedone (Table 5) for the synthesis of 2-amino-
4H-chromenes, which involves a three component conden-
sation among aldehyde, (phenylsulfonyl)acetonitrile, and
dimedone. The multicomponent reaction follows the Kno-
evenagel–Michael-cyclocondensation pathway and success
toward their atom economical synthesis is mainly concerned
with the ease of Knoevenagel condensation reaction between
an aldehyde and active methyl group viz. malononitrile/(phe-
nylsulfonyl)acetonitrile. In a prototype reaction, a mixture
of 4-chlorobenzaldehyde, (phenylsulfonyl)acetonitrile, and
dimedone, (1 mmol, each), was stirred together in 95% EtOH
as solvent at 80 °C in the presence of 70 ALAM (2 mol%)
as the catalyst.
Upon completion of the reaction (TLC), followed by
workup and chromatographic separation indicated the selec-
tively formation of the desired product with 93% yield in 8 h
without formation of tetraketone. It was concluded that in 70
ALAM catalyzed reaction of 4-chlorobenzaldehyde with two
diferent C–H acids, compared to (phenylsulfonyl)acetoni-
trile (pKa=12) dimedone being more acidic (pKa=5.23),
70 ALAM only promotes Knoevenagel–Michael-cyclocon-
densation pathway which prevents carba-Michael-domino
reaction to furnish tetraketone [16]. Interestingly, a variety of
aryl aldehydes (ortho-, meta-, and para-substituted) includ-
ing electron withdrawing or electron releasing substituents
with malononitrile/(phenylsulfonyl)acetonitrile participated
well in this reaction and gave the Tetrahydrobenzo [b]pyran
derivatives in good to excellent yield (Table 5 entries c1–c12
and d1–d12). The ortho-substituted aldehydes showed
slightly decreasing yields of desired product due to their
sterically hinderance skeleton (Table 5 entries c4, c7 and d7,
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
Table 4 70 ALAM catalyzed Knoevenagel condensation reactions of aromatic aldehydes with malononitrile/(phenylsulfonyl)acetonitrile
NC
SO2Ph
NC
CN
CN
SO2Ph
O
CN
CN
70 ALAM
70 ALAM
H
R
R
R
95 % EtOH, 80 o
C
95 % EtOH, 80 oC
a 1-12
b 1-12
NC
CN
NC
SO2Ph
NC
CN
NC
CN
NC
SO2Ph
NC
SO2Ph
Cl
Cl
a3, 92%
Cl
Cl
Cl
b2, 91%
b3, 89%
b1, 96%
a2, 94%
NC
a1, 95%
NC
NC
SO2Ph
NC
CN
NC
SO2Ph
NC
SO2Ph
CN
CN
MeO
MeO
OMe
MeO
MeO
OMe
OMe
OMe
a5, 89%
a4, 90%
NC
a6, 88%
b5, 89%
b6, 84 %
b4, 93 %
NC
SO2Ph
NC
SO2Ph
NC
CN
NC
SO2Ph
NC
CN
CN
H3CS
O2N
O2N
NO2
a8, 88%
Br
b9, 96%
b7, 91 %
b8, 90%
a9, 90%
a7, 94%
NC
NC
SO2Ph
NC
SO2Ph PhO2S
CN NC
SO2Ph
CN
NC
CN
NC
CN NC
CN
MeO
HO
OH
OH
OMe
OMe
b11, 85%
b12, 78 %
a12, 80%
a11, 90%
a10, 87%
b10, 91%
Reaction conditions: aldehydes (1 mmol) and malononitrile/(phenylsulfonyl)acetonitrile
(1 mmol), 70 ALAM (5 mol%), 95% EtOH (5 mL), 80 °C, in 2 h. Isolated product
d12). Gratifyingly, the bulky aldehydes was well tolerated
with malononitrile and aforded the desired product in 86
to 95% yield (Table 5 entries c3, c6 and c12). Notably, the
bulky aldehydes was reacted with (phenylsulfonyl)acetoni-
trile to aford moderate yield of product in 77% yield under
optimized conditions (Table 5 entry d2).
catalytic potential of 70 ALAM in multi component conden-
sation of α-naphthol, malononitrile/(phenylsulfonyl)acetoni-
trile, and aldehydes in 95% EtOH at 80 °C.
Initially, model reaction were carried out for the synthe-
sis of benzo [h]chromen-2-amine using 3,5-dichloroalde-
hyde, (phenylsulfonyl)acetonitrile, and α-naphthol, as the
substrates following the reaction conditions established for
the synthesis of 2-amino-3-phenylsulfonyl tetrahydrobenzo
[b]pyran derivatives. Upon completion of the reaction
(TLC), followed by workup and chromatographic separa-
tion indicated the resultant solid were identifed to be the
desired benzo [h]chromen-2-amine with 88% yield in 10 h.
To examine the scope of the protocol and generality of the
reaction conditions, substituted aromatic aldehydes were
allowed to react with α-naphthol using (phenylsulfonyl)
acetonitrile as well as malononitrile as the C–H acids. In
As we know that the similar 1,3-diketones, phenols,
naphthols and resorcinols do serve as enolizable C–H
acids. In consequence, we became interested in replac-
ing the dimedone component of the model reaction by
α-naphthol (pKa=9.31). As per the literature survey there
is only two earlier reports involving a multicomponent con-
densation among aldehydes, (phenylsulfonyl)acetonitrile,
and α-naphthol and that the synthesized compounds were
shown to possess important pharmaceutically active proper-
ties [103]. These specifc reports encouraged us to screen the
1 3

S. N. Jadhav et al.
Table 5 70 ALAM catalyzed cascade reactions of aromatic aldehydes with malononitrile/(phenylsulfonyl)acetonitrile and dimedone
R
O
R
O
O
O
CN
CN
CN
SO2Ph
70 ALAM
H
70 ALAM
+
SO2Ph
NH2
CN
R
95 % EtOH, 80 oC
95 % EtOH, 80 o
C
O
O
O
NH2
d 1-12
c 1-12
Cl
NO2
Cl
Cl
Cl
Cl
Cl
O
O
O
O
O
O
CN
CN
SO2Ph
NH2
SO2Ph
NH2
CN
SO2Ph
NH2
O
NH2
O
NH2
O
O
d3, 91 %
O
NH2
O
d1, 93%
d2, 77%
c1, 93%
c2, 92%
c3, 90%
OMe
OMe
OMe
NO2
OMe
O
OMe
SO2Ph
O
Cl
CN
O
O
O
O
SO2Ph
NH2
CN
CN
SO2Ph
NH2
O
d6, 85 %
Br
NH2
O
NH2
O
O
c5, 95%
NH2
O
NH2
O
d4, 89 %
c4, 85%
c6, 86%
d5, 88%
SCH3
OH
O
OMe
CN
O
O
O
O
O
CN
SO2Ph
NH2
SO2Ph
NH2
SO2Ph
NH2
CN
O
NH2
O
NH2
O
O
O
O
NH2
c8, 95%
d7, 92%
c7, 84 %
c9, 86%
OH
d8, 84%
d9, 87 %
NO2
Br
Br
MeO
OMe
O
Br
O
O
O
O
SO2Ph
CN
SO2Ph
NH2
CN
CN
O
NH2
O
NH2
O
O
NH2
O
NH2
c10, 96%
d10, 90%
c12, 95%
c11, 94%
d11, 86%
Reaction conditions: aldehydes (1 mmol), malononitrile/(phenylsulfonyl)acetonitrile
(1 mmol), dimedone (1 mmol) and 70 ALAM (5 mol%), 95% EtOH (5 mL), 80 °C, in 8 h.
Isolated product
all the cases with malononitrile, corresponding Benzo [h]
chromen-2-amine were obtained in moderate to excellent
yield (80–90%) (Table 6, entries e1–e10). It was observed
that the aromatic aldehyde containing electron-donating
groups, dramatically afected by the yield of desired prod-
uct (Table 6, entries e1 and e6). Furthermore, the yield of
benzo [h]chromen-2-amine was slightly decreases (77–85%
yield) when using bulky (phenylsulfonyl)acetonitrile instead
of malononitrile (Table 6, entries f1–f5). Notably, the bulky
aldehydes was reacted with malononitrile/(phenylsulfonyl)
acetonitrile to aford moderate yield of product in 77–81%
yield under optimized conditions (Table 6 entries e3, e6 and
f5).
Following this initial success, our attention was focused
on resorcinol as the possible C–H acid for the synthesis
of 2-amino-7-(dimethylamino)-4-aryl-3-phenylsulphonyl-
4H-chromenes and 2-amino-7-(dimethylamino)-4-aryl-4H-
chromene-3-carbonitriles. From the earlier reports has been
demonstrated one-pot protocol for the synthesis of 2-amino-
7-(dimethylamino)-4-aryl-4H-chromene-3-carbonitriles
resulting by, three component condensation among alde-
hydes, malononitrile, and 3-dimethylaminophenol are known
to plays key role as anticancer as well as apoptosis inducer
activities which is highly active in the growth inhibition of
the cancer cell [104, 105]. However, there is only one report
on the synthesis of 2-amino-7-(dimethylamino)-4-aryl-
3-phenylsulfonyl-4H-chromenes [16]. Therefore, we next
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
Table 6 70 ALAM Catalyzed cascade reactions of aromatic aldehydes with malononitrile/(phenylsulfonyl)acetonitrile and α-naphthol
OH
R
O
CN
SO2Ph
CN
CN
R
70 ALAM
70 ALAM
H
+
SO2Ph
NH2
R
CN
95 % EtOH, 80 oC
95 % EtOH, 80 o
C
O
O
NH2
e 1-10
f 1-5
Cl
Br
NO2
Cl
Cl
Cl
CN
SO2Ph
NH2
CN
CN
SO2Ph
NH2
O
O
NH2
O
NH2
O
f1, 80%
NO2
O
NH2
e2, 92%
e3, 81%
e1, 88%
OMe
f2, 85%
OMe
OH
OMe
OMe
CN
CN
SO2Ph
NH2
SO2Ph
NH2
CN
O
NH2
O
NH2
O
O
O
NH2
e4, 83%
e6, 80%
f3, 84 %
f4, 82%
e5, 90%
NO2
NO2
Cl
Cl
CN
CN
CN
SO2Ph
NH2
O
NH2
O
NH2
O
NH2
O
e9, 87%
e8, 92%
e7, 90%
f5, 77 %
SCH3
CN
NH2
O
e10, 90%
Reaction conditions: aldehydes (1 mmol), malononitrile/((phenylsulfonyl)acetonitrile
(1 mmol), 1-naphthol (1 mmol) and 70 ALAM (5 mol%), 95% EtOH
(5 mL), 80 °C, in 10 h. Isolated product
1 3

S. N. Jadhav et al.
Table 7 70 ALAM catalyzed cascade reactions of aromatic aldehydes with malononitrile/(phenylsulfonyl)acetonitrile and 3-dimethylaminophe-
nol
R
R
CN
SO2Ph
95 % EtOH, 80 oC
O
CN
CN
70 ALAM
70 ALAM
H
+
N
OH
SO2Ph
NH2
CN
R
95 % EtOH, 80 o
C
N
O
N
O
NH2
g 1-11
h 1-12
Cl
Cl
Cl
Cl
Cl
Cl
SO2Ph
CN
CN
SO2Ph
NH2
SO2Ph
NH2
CN
N
O
NH2
N
O
NH2
N
O
NH2
N
O
N
O
N
O
NH2
h3, 92%
g2, 90%
g3, 85%
h2, 90%
h1, 91%
g1, 92%
OMe
OMe
OH
OMe
OMe
OMe
OMe
OMe
OMe
CN
CN
CN
SO2Ph
NH2
SO2Ph
NH2
SO2Ph
NH2
N
O
NH2
N
O
NH2
N
O
NH2
N
O
N
O
N
O
g6, 86%
h6, 84%
g4, 90%
g5, 84%
h4, 89%
h5, 85%
NO2
SCH3
NO2
NO2
NO2
CN
CN
CN
SO2Ph
NH2
SO2Ph
NH2
SO2Ph
NH2
N
O
NH2
N
O
NH2
N
O
NH2
N
O
N
O
N
O
g7, 91%
g8, 89%
g9, 90%
h9, 85%
h7, 89%
h8, 90%
SCH3
OH
MeO
OMe
Br
OH
Br
SO2Ph
SO2Ph
NH2
CN
SO2Ph
NH2
CN
N
O
NH2
N
O
N
O
NH2
N
O
N
O
NH2
g10, 91%
g11, 88%
h12, 92%
h10, 86%
h11, 82%
Reaction conditions: aldehydes (1 mmol), malononitrile/(phenylsulfonyl)acetonitrile (1 mmol),
3-dimethylaminophenol (1 mmol) and 70 ALAM (5 mol%), 95% EtOH (5 mL), 80 °C, in 6 h. Isolated product
planned to extend the scope and generality of the developed
protocol for the synthesis of 2-amino-7-(dimethylamino)-
4-aryl-3-phenylsulfonyl-4H-chromenes derivatives and
2-amino-7-(dimethylamino)-4-aryl-4H-chromene-3-car-
bonitriles.
g1–11 and h1–12) were obtained in good to excellent yields
(84–92%). The ortho-substituted aldehydes showed slightly
decreasing yields (84% and 82%) of desired product due to
their sterically hinderance skeleton under optimized condi-
tions (Table 7 entries g5 and h11). All of the synthesized
compound structures were fully established by various
spectral methods and further detailed study is in progress
in our laboratory to investigate the biological activities of
the synthesized 2-amino-3-phenylsulphonyl-4H-chromenes
derivatives.
In an efort to measure the contribution of the diferent
p, o, m-donor and withdrawing aromatic aldehydes, we ana-
lyzed and the results are summarized in Table 7. The trend
was clearly pointing out to a superior performance of 70
ALAM over di and tri-substituted based structures (Table 7,
entry g3, g6, g11 and h3, h5, h6), even with very bulky ones
(Table 7, entry g11). In all the cases, corresponding desired
product 2-amino-3-phenyl-sulfonyl-4H-chromenes (Table 7,
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
OH
OMe
NC
SO2Ph
2 hrs
10 mmol
SO2Ph
10 hrs
I
IV
O
NH2
MeO
93 % (2.78 gm)
O
81 % (3.67 gm)
OMe
CN
SO2Ph
+
70 ALAM, 95 % EtOH, 80 °C
70 ALAM, 95 % EtOH, 80 °C
O
MeO
10 mmol
10 mmol
OMe
N
OH
10 mmol
6 hrs
O
III
NH2
II
10 mmol
O
SO2Ph
NH2
91 % (4.10 gm)
SO2Ph
8 hrs
N
O
O
NH2
91 % (4.10 gm)
Scheme 1 Gram scale synthesis of α-cyanoacrylonitriles and 2-amino-3-aryl sulphonyl-4H-chromene
continuous fow reactor is illustrated in Scheme 2. The fxed
bed continuous fow reactor was charged with the 70 ALAM
catalyst (1 g). 4-Hydroxy-3,5-dimethoxybenzaldehyde
(0.5 M) and (phenylsulfonyl)acetonitrile (0.5 M) in 95%
EtOH were mixed in a T-piece and the resulting fow stream
was directed into the fxed bed column packed with the cata-
lyst (packed bed reactor volume: 1.0 mL). The fow rate was
varied and optimised at 80 °C (0.2 mL min−1) to promote the
condensation reaction. The fxed bed continuous fow device
was kept in operation for 12 h, the corresponding desired
product was observed, as conversion ≤ 98% were reached
within a residence time 5 min (fow rate 0.2 mL min−1), at
80 °C and atmospheric pressure.
3.10 Gram Scale Synthesis
As part of our ongoing research program, we report scalable
synthetic approach to widely used Knoevenagel and Michael
addition reactions by using optimized protocol (Scheme 1).
The model reactions proceeded in excellent yield, even on a
gram scale synthesis. Treatment of 10 mmol of 4-methoxy-
benzaldehyde gave 2.78, 4.10, 4.10 and 3.67 g of respective
desired product yield. Final products were provided in good
overall yields, were amenable to purifcation using column
chromatography, and signifcantly, could be synthesised on
gram scale. This demonstrated the repeatability and potential
for practical methods in organic laboratory as well as indus-
trial applications of our standard protocol.
Finally, a scale-up study was performed for continuous
operation up to 12 h, the percentage yield of desired prod-
uct did not decrease up to 9 h of operation with residence
times of 5 min. A slight decrease in conversion was observed
after 9 h of continuous fow operation. The process run for
12 h successfully aforded a total of 33.8 mmols of the tar-
get product could be isolated with good productivity, atom
efciency and sustainability [110–112]. Thus, it was found
that our fow reaction system is applicable to the continu-
ous fow synthesis of α-cyanoacrylonitrile molecules which
acts as pharmaceutical intermediates and is amenable to
gram scale production. Further detailed study is in progress
in our laboratory to investigate, our optimized fow reac-
tion system is applicable to the synthesis of a wide variety
of α-cyanoacrylates, 2-amino-3-cyano-4H-chromenes and
2-amino-3-aryl sulphonyl-4H-chromene molecules which
acts as pharmaceutically active scafolds and is amenable to
gram scale production.
3.11 Continuous Flow Operation
In organic synthesis, functionalized molecular building
blocks are pivotal to the design and engineering of innova-
tive synthesis, being the starting point for the efcient prepa-
ration of new bioactive organic moieties. As the synthetic
advancement of viable core units typically aims to follow
the principles of modern synthetic chemistry. The original
synthetic route of these building blocks should also strive
to embrace the same criteria, such as use of green solvents,
sustainability, atom efciency, and environmentally benign
processes. In order to these modern synthesis techniques
which enhance productivity, waste reduction, catalyst reus-
ability and synthetic efciency should also be embraced,
such as fxed bed continuous fow processing technologies
[106–109].
Monitoring efciency of our present protocol, we have
also performed the Knoevenagel condensation reaction of
4-hydroxy-3,5-dimethoxybenzaldehyde and (phenylsulfo-
nyl)acetonitrile on fxed bed continuous fow processing
technology. The schematic representation of the fxed bed
3.12 Heterogeneity of Catalyst
It is obligatory to study the catalyst stability in terms of
leaching of tethered active basic motifs (APTES) from the
1 3

S. N. Jadhav et al.
O
MeO
HO
H
CN
SO2Ph
+
OMe
80 oC
0.2 mL/min
95 % EtOH
Fixed Bed Reactor
: 70 ALAM
Pump
NC
SO2Ph
MeO
HO
Product
Substrate
Time (h):
aYield %:
OMe
0.5
1
2
3
4
5
6
7
8
9
10
12
96 96 96 96 96 96 96 96 96 93 90 88
Conditions: 4-hydroxy-3,5-dimethoxybenzaldehyde (0.5 M) and
(phenylsulphonyl)acetonitrile (0.5 M) in 95 % EtOH, at 80 °C, flow rate of
0.2 mLmin-1. aby GC.
Scheme 2 Knoevenagel condensation reaction using fxed bed continuous fow reactor
solid support LAM [113]. To evaluate the heterogeneity of
the catalyst, we performed hot fltration test for model reac-
tion of 4-chlorobenzaldehyde and (phenylsulfonyl)acetoni-
trile by using optimized protocol. The catalyst was separated
from the reaction mixture by centrifuge method at 80 °C
after 30 min and the reaction mixture was stirred without
catalyst for 2 h at 80 °C. The GC analysis showed high initial
rate of the reaction with 44% of α-cyanoacrylonitriles within
30 min. The model reaction did not proceed after removal of
catalyst in 2 h. This result strongly suggest that the catalyst
is characteristic heterogeneous in nature.
3-(4-chlorophenyl)-2-(phenylsulfonyl)acrylonitrile. The
recyclability of 70 ALAM catalyst also examined for
synthesis of 2-amino-4-(4-chlorophenyl)-7,7-dimethyl-
3-(phenylsulfonyl)-4,6,7,8-tetrahydro-5H-chromen-5-
one scafold. On the basis of catalyst recycling results
in Fig. 9, catalyst showed 10–20% loss in product yield
after 6th catalytic cycle. As per the literature, silane-based
bonds used for tethering are quite robust and the propyl
amino groups are also quite stable [73], but other factors
may play a role in this subtle loss in catalytic activity dur-
ing the reaction. Further detailed study is in progress in
our laboratory to investigate the various reasons to better
understand the slow deactivation of our catalyst.
3.13 Catalyst Stability
Finally, the recyclability of the catalysts was tested for
the batch process. In case of molecularly modifed oxides
tend to deteriorate over time, and because of this reason
many anchored catalysts tend to leach out over time during
the reaction. In our case, some deterioration was observed
as well, but the problem was not too severe due to the
catalyst stability. As can be seen from the six sequential
catalytic runs in Fig. 9, catalyst showed excellent activ-
ity with loss of approximately 3–5% in total activity is
seen by the 5th and 6th run in 2 h for the synthesis of
4 Conclusions
Amine functionalized 70 ALAM catalyst was developed
using a simple protocol which can be adapted for the synthe-
sis of other acid–base heterogeneous catalysts. Our approach
involved the tethering of molecular moieties to Al-MCM-
41-LDH solid support having oxide surfaces via triethox-
ysilane as a linker between active sites and backbone. CP/
1 3

Organocatalytic Cascade Knoevenagel–Michael Addition Reactions: Direct Synthesis of…
Fig. 9 Recyclability of heterogeneous 70 ALAM catalyst
Acknowledgements One of the authors, Sanjay Jadhav, is grateful
MAS NMR, CO2-TPD and FT-IR absorption spectroscopic
studies confrmed that the amine groups retained within the
framework of Al-MCM-41-LDH. Crystalographic structure,
surface chemistry and atomic composition of catalyst were
confrmed by XRD, XPS, TEM, CHN and EDX analysis.
N2 adsorption isotherm measurements showed surface area
(305.7 m2g−1), pore diameter (4.56 nm) and pore volume
(0.35 cm3g−1) decrease with increase in amine content to
fully characterize with and corroborate the success of each
of the steps associated with this synthesis.
to the Science & Engineering Research Board, Department of Sci-
ence and Technology (SERB-DST), New Delhi, Government of India,
for the award of the National Post-Doctoral Fellow (N-PDF; File no.
PDF/2015/000569).
Compliance with Ethical Standards
Conflicts of interest There are no conficts to declare.
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