MnO2 on hydroxyapatite: A green heterogeneous catalyst and synthesis of pyran-carboxamide derivatives

Article abstract of DOI:10.1016/j.inoche.2019.107706

Three different loadings of MnO₂ on hydroxyapatite (MnO₂/Hap) were synthesized and the hydroxyapatite supported MnO₂ materials were characterized by several analytical techniques including FT-IR, P-XRD, TEM and SEM analysi

Full text of DOI:10.1016/j.inoche.2019.107706

Journal Pre-proofs
MnO2 on Hydroxyapatite: A green heterogeneous catalyst and Synthesis of
pyran-carboxamide derivatives
Surya Narayana Maddila, Suresh Maddila, Sandeep V. H. S. Bhaskaruni,
Nagaraju Kerru, Sreekantha B Jonnalagadda
PII:
S1387-7003(19)31029-9
DOI:
https://doi.org/10.1016/j.inoche.2019.107706
INOCHE 107706
Reference:
To appear in:
Inorganic Chemistry Communications
Received Date:
Revised Date:
Accepted Date:
10 October 2019
25 November 2019
27 November 2019
Please cite this article as: S. Narayana Maddila, S. Maddila, S. V. H. S. Bhaskaruni, N. Kerru, S.B. Jonnalagadda,
MnO2 on Hydroxyapatite: A green heterogeneous catalyst and Synthesis of pyran-carboxamide derivatives,
Inorganic Chemistry Communications (2019), doi: https://doi.org/10.1016/j.inoche.2019.107706
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MnO2 on Hydroxyapatite: A green heterogeneous catalyst and Synthesis of
pyran-carboxamide derivatives
Surya Narayana Maddila, Suresh Maddila, Sandeep V. H. S. Bhaskaruni, Nagaraju Kerru, and
Sreekantha B Jonnalagadda*
*School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern
Hills, Durban-4000, South Africa
*Corresponding Author: Prof. Sreekantha B. Jonnalagadda
School of Chemistry & Physics,
University of KwaZulu-Natal,
Durban 4000, South Africa.
Tel.: +27 31 2607325,
Fax: +27 31 2603091
E-mail: jonnalagaddas@ukzn.ac.za
Abstract
Three different loadings of MnO2 on hydroxyapatite (MnO2/Hap) were synthesized and the
hydroxyapatite supported MnO2 materials were characterized by several analytical techniques
including FT-IR, P-XRD, TEM and SEM analysis. 3% MnO2/HAp material proved highly
efficient catalyst for the synthesis of a series of ten pyran-carboxamide derivatives (yield 91-98
%) in aqueous medium at room temperature (RT) conditions, via one-pot multi-component
reaction, of which nine were new moieties. The prominent features of the protocol are excellent
yields, high atom efficiency, short reaction times (15 min), recyclable catalyst and no need for
column separation.
Keywords: Hydroxyapatite; Reusable catalyst; Lewis acid sites; Multi component reaction; atom
efficiency; Green synthesis.
Introduction
In recent years, the use of multicomponent reactions (MCRs) have gained prominence to
synthesize compound collections in the field of biological, pharmaceutical and combinatorial
chemistry [1-3], due to their proficiency to react three or more reactants, to achieve the target
molecule in one-pot process. MCRs indicate a very potent process, from both cost and synthetic
prospective [4]. Further, MCRs have many benefits such as green procedures, high atom efficacy

and easy to do drug discovery process [5]. Short reaction times, easy workup procedure, simple
reaction conditions, efficient product selectivity and good to excellent yields are the other
advantages of MCRs [6].
With increasing green perception in organic research and chemical industry, the challenges
for viable benign and safe procedures that decrease or eradicate waste production and restrict the
use of toxic solvents and reagents are growing [7, 8]. In recent past, significant growth was
recorded in use of heterogeneous catalysts for different heterocyclic conversions in the MCRs and
in green reaction protocols. This was mainly due to distinct chemical and physical properties of
the catalyst materials, such as eco-friendliness, compatibility, cost-effectiveness, non-volatility,
non-inflammability, good thermal stability, operational simplicity, mild reaction conditions, ease
of isolation, reusability, non-hazardous and good activity [9, 10]. Calcium phosphate
hydroxyapatite (HAp = Ca10(PO4)6(OH)2) is one of the effective materials, which displays good
affinity and high stability, with variety of applications [11]. HAp draws attention because of its
potential effectiveness in biomaterials, bio-ceramics, adsorbents, and ion-exchangers [11-13].
Recently, a new approach for the design of high-performance heterogeneous catalysts employing
HAp as a macro-ligand for catalytically active centers was revealed [14]. HAp possesses many
advantages such as (i) nonporous construction that can support to subdue the difficulties to mass
alteration and (ii) weak acidic–basic possessions diminishing side-reactions influenced by the
support. Here, we report the preparation of new hydroxyapatite supported metal catalysts and their
utility in the synthesis of carbon–carbon bond developing reactions.
Ample attention has been paid to the preparation of different heterocyclic moieties [15-18].
Amongst the several heterocycles, the pyran ring structure received substantial attention because
of its noticeable biological and pharmaceutical activity. Interestingly, the pyran and their
derivative scaffolds gained importance in the field of drug discovery, due to their activity as
efficient protein kinase inhibitors, which is one of the vital areas in the improvement of
chemotherapeutic agents [19]. Further, pyrans exist as crucial subunits in various drug
constituents, with a wide range of biological properties, including cytotoxic [20], anticancer [21],
anti-inflammatory [22], analgesic [23], anticonvulsant [24], anti-proliferative [25], antifungal [26]
and antimicrobial activities [27]. Thus, pyran scaffolds have established as privileged units in
heterocyclic chemistry and also most essential pharmacophore in drug chemistry. In the recent
years, several procedures have been developed for the preparation of this type of compounds. The

reported methods employed different catalysts, MgO [28], piperidine [29], nano SiO2 [30], Mg/La
metal oxides [31], D,L-proline [32], 4-(dimethylamino)-pyridine (DMAP) [33],
tetrabutylammonium fluoride [34] etc. Although, these approaches are attractive, they suffer from
one or more disadvantages such as inadequate availability of reagents, expensive, non-recyclable
or toxic catalysts, need for high temperatures or prior purifications, low reaction rates, use of toxic
solvents, low yields, and tedious work-ups. Therefore, taking into consideration the limitations in
those reports, in this communication, we submit the scope of MnO2 supported hydroxyapatite as
an efficient recyclable catalyst for the synthesis of pyran-carboxamide derivatives at room
temperature with water as solvent. As a part of our investigations to develop swift reactions under
mild and green conditions, we earlier have reported various heterogeneous catalysts for synthesis
of series of different heterocyclic moieties [35-39].
Experimental section
Catalyst Preparation:
A co-precipitation method was adopted to synthesize Ca-hydroxyapatite (HAp). In a
typical procedure, the calcium nitrate tetra hydrate solution, Ca (NO3)2.4H2O (23.7 g) (0.167 mol)
in 250 mL distilled water was adjusted to a pH 11 using concentrated ammonium solution. The
pH of the diammonium hydrogen orthophosphate solution (5.6 g) (1.00 mol) was also adjusted to
11 with concentrated ammonia solution. Thereafter, both the solutions were separately diluted with
250 mL of distilled water. Under constant and vigorous stirring, a solution of diammonium
hydrogen orthophosphate was drop-wise added to the Ca (NO3)2.4H2O solution over a period of 2
h and throughout the reaction, the mixture was maintained at pH 11 with help of ammonia solution.
The obtained milky white gelatinous precipitate was heated for 40 min and the precipitate brought
to room temperature. Afterwards, the white precipitate was filtered under vacuum and washed
thoroughly with deionizer water and dried at hot air oven and calcined at 500°C for over six hours
in presence of air. The prepared HAp metrical was characterized by XRD and FT-IR techniques
(Figures S1 and S2 in supporting information, ESI). A wet impregnation technique was used for
synthesis of the HAp supported metal catalysts. The required amount of prepared and calcined
HAp was dispersed in 200 mL of distilled water under vigorous stirring. Afterwards, the desired
amounts of manganese oxide (Sigma Aldrich, XRD in ESI) was added based on the requisite
equivalent weight amounts. Then, the resultant slurry was evaporated under constant stirring and
°
the mixture was dried at 100-120 C for overnight in an oven. Materials with various weight

percentages (1, 3 and 5% w/w) of the MnO2 on HAp were prepared and subsequently calcined at
450oC for five hours.
Synthesis of pyran-carboxamide derivatives: General Procedure
Aromatic aldehyde one equivalent, malononitrile 1.1 equivalent acetoacetanilide one
equivalent and MnO2/HAp (50 mg) were dissolved in 10 mL of aqueous solvent in a clean flask.
Then the reaction mixture was stirred for 15-20 min at RT (scheme 1). Using TLC, the reaction
progress was monitored. After completion of the reaction, the solid catalyst was separated from
the mixture by simple filtration and washed with water, then dried for further reuse. To reaction
product that extracted into ethyl acetate, anhydrous Na2SO4 was added for drying. Further, to
obtain the pure target molecules, ethyl acetate was removed under reduced pressure (4a-j).
Scheme 1: Three-component green synthetic route for pyran carboxamide derivatives
Result and discussion
SEM & TEM analysis:
Fig. 1 and Fig. 2 illustrate the SEM and TEM morphological profiles respectively of 3%
MnO2/HAp calcined catalyst. An observation of the SEM (Fig. 1a and 1b) images reveal the
unequal cube-like shapes of the catalyst material. Some agglomeration was detected, which
probably owes to the manganese loading. Further, it can be observed that the dimensions of the
average particles were of the order of 23 nm. SEM–EDX (Fig. 1c) image indicates that manganese
was homogenously dispersed on the surface of the hydroxyapatites. The TEM micrograph shows
black crystalline oval-shaped particles of dimension ranging from 45-59 nm (Fig 2) on the material
surface. No extreme variation was perceived on the morphology of the used catalyst.

1 (a)
1(b)
1 (c)
Figure 1: (a) SEM micrograph (b) elemental mapping and(c) EDS spectrum of of 3% MnO2/HAp
catalyst.
Figure 2: TEM micrograph of 3% MnO2/HAp catalyst.

P-XRD study:
Figure 3 illustrates the XRD patterns of the MnO2-HAp complex and the pure crystalline
structure of the hydroxyapatite can be seen in the diffraction patterns. This diffraction patterns
were correlated with the JCPDC file no. 09-432 for HAp and JCPDC file no. 44-0141 for MnO2.
The intensity planes (310), (300) and (002) were allotted to MnO2 and other diffraction peaks were
attributed to HAp. The higher intensity planes (002), (211), (300), (310), (222) and (213) altered
significantly with the standard HAp phase. The additional MnO2 concentration did not impact
much distortion in HAp phase. This is attributed that the reactants proportions were well-interacted
to afford the MnO2-HAp composite.
HAp
250
(21 1 )
200
1 50
1 00
50
0
20
30
40
50
60
70
80
90
2 theta (Degree)
Figure 3. Powder XRD diffractogram of 3% MnO2/HAp catalyst
Pyridine IR analysis
The nature of acidic sites on the prepared 3% MnO2-HAP surface was examined by
employing ex-situ pyridine FT-IR spectroscopy (Figure 4). The prominent band at 1448 cm−1
confirms the presence of Lewis acidic sites (L) on the surface of catalyst, suggesting that prepared
material has Lewis acidic character. The Lewis acidic sites on the surface were due to the Ca2+ and
phosphorous of PO4 and the vacant metal orbitals, so that it is capable to attack the electron rich
site to accept electron pairs.

Figure 4: Pyridine IR spectrum of 3% MnO2/HAp catalyst.
Optimization:
To achieve good efficiency in the production pyran-carboxamides, the title reaction was
investigated under different reaction conditions including comparing the efficacy of different
catalyst materials, solvents and temperature conditions.
To improve the reaction performance, a series of investigations were carried out using the
model reaction of 2-methhoxybenzaldehyde, malononitrile and acetoacetanilide in absence and
presence of catalysts, under varied temperatures and solvent systems. The results obtained are
summaries in Table 1. In absence of any catalyst, no reaction was perceived for 24 h, under R.T.
or reflex conditions (Table 1 entry 1 & 2). Using basic catalysts such as sodium hydroxide,
pyridine, triethylamine, potassium carbonate and urea in aqueous media, no reaction occurred at
R.T. event after 12 h (Table 1 entry 3-7). The presence of ionic liquid catalysts, such as 1-Butyl-
3-methylimidazolium tetrafluoroborate and N-heterocyclic carbene gave a very small amount of
the product at R.T. (Table 1, entries 8 & 9). By employing various acidic catalysts, namely,
tetrafluoroboric acid, acetic acid and p-toluenesulfonic acid in aqueous solution at R.T. only low
yields were perceived (Table 1, entries 10–12). Further, the model reaction was screened with
various solid materials (MnO2, SiO2, Al2O3, HAp and hydrotalcites (HTAl) as catalysts in water,
which showed moderate to good yields after 1 h (Table 1, entries 13-17). Among the various solid
catalysts tested, MnO2 and HAp offered better results with higher product yields. From the
encouraging response with MnO2 and Hap as catalysts, to enhance the reaction efficiency by

harvesting the synergic effect of the two, materials with different loadings of MnO2 on HAP were
prepared and efficacy of the 1% MnO2/HAp, 3% MnO2/HAp and 5% MnO2/Hap materials as
catalysts was assessed, and all the reactions gave excellent yields (89-98%) at R.T. in short reaction
time of 15 min (Table 1, entries 18-20). Although, all the three mixed oxide catalysts offered small
particle sizes, more surface than the single oxide homologues, among the three loadings of MnO2,
the 3% MnO2/supported hydroxyapatite catalyst showed higher activity.
Table 1: Optimization for the synthesis of 4a by 3% MnO2/HAp catalysta
Entry
Catalyst
Solvent
Condition
Time / h
Yield / %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
--
--
--
--
RT
Reflux
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
24
24
12
12
12
12
12
8.0
10
5.5
4.5
4.0
1.0
2.5
3.0
1.0
3.5
0.75
0.25
0.50
--
--
--
--
--
NaOH,
pyridine
TEA
K2CO3
Urea
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
--
--
[Bmim][BF4]
[NHC][BF4]
HBF4,
11
09
18
22
15
76
54
48
80
68
91
98
96
AcOH
PTSA
MnO2
SiO2
Al2O3
HAp
HTal
1% MnO2/HAp
3% MnO2/HAp
5% MnO2/HAp
a All products were characterized by 1H-NMR, 15N NMR, 13C-NMR and HRMS spectral analysis.
b Isolated yields.
-- No reaction
To optimize the solvent system for the reaction for target molecule (4a), reactions were
investigated using THF, dioxane, CH3CN, DCM, DMSO, CH3OH, C2H5OH and H2O as solvents
in presence of 3 mol% MnO2/HAp at R.T. The results compiled in Table 2 show that with non-
polar solvent, n-hexane facilitated no reaction, however low yields were afforded using various
other polar aprotic solvents like THF, dimethylformamide, CH3CN and DCM (Table 2). Further,
the reactions in CH3OH and C2H5OH provided better yields than those with the other organic
solvents, but best result was with H2O.

Table 2: Optimization of different solvent conditionsa
Entry
Solvent
Reaction time / min
Yield / %
n-Hexane
THF
120
60
60
50
45
30
30
15
1
2
3
4
5
6
7
8
--
23
27
32
25
72
84
98
Dioxane
CH3CN
DCM
CH3OH
C2H5OH
H2O
aReaction conditions: aromatic aldehyde one equivalent malononitrile one equivalent and
acetoacetanilide one equivalent, catalyst (50 mg) and H2O (10 mL) as solvent were stirred at R.T.
To improve the efficacy of the reaction, the optimized reaction was investigated with
different amounts of the 3% MnO2/HAp (Table 3). With lower amount of catalyst, the reaction
times got prolonged and yields were lowered. An increase for catalyst amount from 20 mg to 50
mg not only reduced the reaction time, but also improved the product yield from 90% to 97%.
However, the use of 60 mg of catalyst, reaction time remained unaffected, but the yield was
marginally reduced to 95%. Therefore, 50 mg MnO2/HAp was considered as ideal amount to
catalyze the reaction under chosen conditions.
Table 3: Optimization of the amount of 3% MnO2/HAp as catalyst in the model reactiona
Entry
Catalyst
Time (min)
Yield (%)
1
2
3
4
5
6
10
20
30
40
50
60
60
50
45
30
20
20
85
90
92
94
98
95
aReaction conditions: aromatic aldehyde one equivalent malononitrile one equivalent and
acetoacetanilide one equivalent catalyst and H2O (10 mL) solvent were stirred at R.T.

To broaden the scope of the title reaction, reactions were conducted using different
aldehydes containing different electron donating and withdrawing substituents. Nine new
derivatives (4a–j) were synthesized under otherwise similar reaction conditions as for 4a (Table
4). All the substituted aldehydes, both with electron-donating or electron-withdrawing groups
reacted effectively to generate the corresponding target molecules with excellent yields. All
structural assignments of these novel molecules were confirmed by 1H NMR, 13C NMR, 15N NMR
and HRMS spectral analysis. All the instrumentation and spectral details are incorporated in (ES1-
II)
Table 4: Synthesis of pyran-carboxamides catalyzed by 3% MnO2/HAp catalyst
o
Entry
R
Product
Yield (%)
Mp C
1
2
3
4
5
6
7
8
9
2-MeO
2,3-(OMe)2
3-Br
3-Cl
2,5-(OMe)2
4-Et
2,4,6-(OMe)3
3,4,5-(OMe)3
4-N(Me)2
3-Meo
4a
4b
4c
4d
4e
4f
4g
4h
4i
98
94
91
90
96
92
92
94
96
92
159-161
204-205
189-190
221-223
209-210
232-233
197-198
217-218
199-201
165-167
10
4j
-- New compounds/no literature available.
A probable reaction mechanism for the generation of pyran-carboxamides is proposed as
presented in Scheme 2. With primary condensation of aromatic aldehyde and malononitrile on the
surface of MnO2 loaded hydroxyapatite, leads to the formation benzylidenemalnonitrile
intermediate (I). Further, the Michael addition of phenylbutnamide to the intermediate followed
by intra-molecular cyclization, the second intermediate (II) is produced. Finally, the cyclization of
(II) affords the final product, 6-amino-5-cyano-2-methyl-N,4-diphenyl-4H-pyran-3-carboxamide
derivatives.

Scheme 2: Plausible reaction mechanism for the formation of pyran-carboxamide derivatives.
Recyclability
This is noteworthy to emphasize that recyclability of the catalyst is a significant feature of
heterogeneous catalysis. The used Mn/HAp catalyst was separated from reaction mixture by
filtration after each reaction. The recovered material washed with DCM several times, and dried
in a vacuum oven at 80°C for period of two hours to reuse in consequent reactions. The collected
catalyst was recycled at least six additional times in successive reactions without any significant
loss in product yield.
Conclusion
In this communication, we reported a detailed mechanistic investigation for synthesis of
novel pyran-carboxamide derivatives, through one-pot MCR using MnO2/HAp as reusable catalyst
with water as solvent at R.T. giving excellent yields. The attractive features of this protocol are
high atom efficacy, short period of time, green solvent, cost-effective reagents, easy operational
workup procedure, simple separation, higher yields and reusable catalyst. The above-mentioned

benefits make this procedure green and valid for industrial, pharmaceutical as well as other
academic applications.
Acknowledgements:
The authors are thankful to the National Research Foundation (NRF) of South Africa, and
University of KwaZulu-Natal, Durban, for financial support and research facilities.
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Highlights
 3% MnO2/HAp as highly efficient heterogeneous catalyst
 Three component one-pot synthesis in water
 Nine new pyran-carboxamide derivatives
 Excellent yields (91-98%) in short reaction times (15 min).

MnO2 on Hydroxyapatite: A green heterogeneous catalyst and Synthesis of
pyran-carboxamide derivatives
Surya Narayana Maddila, Suresh Maddila, Sandeep V. H. S. Bhaskaruni, Nagaraju Kerru, and
Sreekantha B Jonnalagadda*
*School of Chemistry & Physics, University of KwaZulu-Natal, Westville Campus, Chiltern
Hills, Durban-4000, South Africa
*Corresponding Author: Prof. Sreekantha B. Jonnalagadda
School of Chemistry & Physics,
University of KwaZulu-Natal,
Durban 4000, South Africa.
Tel.: +27 31 2607325,
Fax: +27 31 2603091
E-mail: jonnalagaddas@ukzn.ac.za
Graphical Abstract:

Conflict of interest statement
All the author hereby declare that we have no conflict of interest and no funding is received for this
research. This work is unpublished and solely submitted to this journal

We here by certify that all authors have seen and approved the final version of the manuscript
being submitted. This work is our original work, hasn't received prior publication and isn't under
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