An eco-friendly approach for synthesis of novel substituted 4H-chromenes in aqueous ethanol under ultra-sonication with 94% atom economy

Article abstract of DOI:10.1016/j.molstruc.2019.03.006

An operational approach for synthesis of eleven substituted 4H-chromene derivatives by one-pot, three-component reaction of aromatic aldehyde, methyl cyanoacetate and cyclic diketone through ultrasound irradiation, in the presence of aqueous ethanol under

Full text of DOI:10.1016/j.molstruc.2019.03.006

Accepted Manuscript
An eco-friendly approach for synthesis of novel substituted 4H-chromenes in aqueous
ethanol under ultra-sonication with 94% atom economy
Surya Narayana Maddila, Suresh Maddila, Mandlenkosi Khumalo, Sandeep V.H.S.
Bhaskaruni, Sreekantha B. Jonnalagadda
PII:
S0022-2860(19)30258-3
DOI:
https://doi.org/10.1016/j.molstruc.2019.03.006
MOLSTR 26275
Reference:
To appear in: Journal of Molecular Structure
Received Date: 12 September 2018
Revised Date: 26 February 2019
Accepted Date: 3 March 2019
Please cite this article as: S.N. Maddila, S. Maddila, M. Khumalo, S.V.H.S. Bhaskaruni, S.B.
Jonnalagadda, An eco-friendly approach for synthesis of novel substituted 4H-chromenes in aqueous
ethanol under ultra-sonication with 94% atom economy, Journal of Molecular Structure (2019), doi:
https://doi.org/10.1016/j.molstruc.2019.03.006.
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ACCEPTED MANUSCRIPT
An eco-friendly approach for synthesis of novel substituted 4H-chromenes in
aqueous ethanol under ultra-sonication with 94% atom economy
Surya Narayana Maddila, Suresh Maddila, Mandlenkosi Khumalo, Sandeep V. H. S. Bhaskaruni,
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 address: jonnalagaddas@ukzn.ac.za
Graphical Abstract
:

ACCEPTED MANUSCRIPT
An eco-friendly approach for synthesis of novel substituted 4H-chromenes in
aqueous ethanol under ultra-sonication with 94% atom economy
Surya Narayana Maddila, Suresh Maddila, Mandlenkosi Khumalo, Sandeep V. H. S. Bhaskaruni,
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
An operational approach for synthesis of eleven substituted 4H-chromene derivatives by
one-pot, three-component reaction of aromatic aldehyde, methyl cyanoacetate and cyclic
diketone through ultrasound irradiation, in the presence of aqueous ethanol under catalyst-free
1
condition is reported. Different spectral methods, including H, 13C and 15N NMR and HRMS
were utilized to characterize the new molecules. Benefits of the eco-friendly method are fast
reaction (10 min), excellent yields (92-98%), no column chromatography and no byproducts.
Reaction offers 94% atom economy and 100 % carbon capture.
Keywords: Green synthesis; Heterocyclic compounds; Multicomponent reaction; Ultra
sonication; atom efficiency

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1.
Introduction
Several investigations emphasized on novel synthetic organic approaches and
prominence of one-pot multi-component reactions (MCRs) [1-3]. MCRs play a enormous role in
the biological discovery, medicinal, pharmaceuticals and agrochemical industries [4,5]. MCRs
afford higher chemical yields compared to multistep syntheses, by employing simple protocols,
inexpensive reactants and green principles. These reactions, could generate different heterocyclic
molecules with high yields, with no need to isolate the reaction intermediates [6,7]. Other
advantages of MCRs are reduced reaction times, improved selectivity, simple work procedure,
atom economy and scope for use of green solvents [6-8].
These days, green chemistry principles are highly encouraged to minimize environmental
pollution, while accomplishing the set goals [8,9]. Advent of ultrasound irradiation has led to
vital modifications in synthetic procedures for heterocyclic moieties and allowed the exploration
of relatively less reactive substrates. Ultrasound (US) is an effect of acoustic wave cavitation,
which accelerates appropriate chemical reactions [10,11]. These waves promulgate through
alternating compressions and infrequent faction phases, induced in the assigning liquid, with the
expansion cycles using destructive pressure on the liquid [12,13]. This applied destructive
pressure is capable to breakdown the intermolecular van der Waals forces of the liquid, creating
minor cavities or micro-bubbles [14]. These cavities continuously attract energy from ultrasonic
waves and reach a stage, where they can no longer absorb energy and burst [12-14]. These fast
and forceful breakdowns produce short-term regions with very high temperature and pressure.
This cavitation-induced occurrence is known to activate the reactants inflowing into cavity and
subsequently translate them into reaction intermediates.

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Many studies have been focused on the development of novel heterocyclic frameworks,
because of their prominence in therapeutic, pharmacological, biological fields and pivotal role in
computational, drug discovery and pharmaceutical industries [15-17]. Among the heterocyclic
compounds, the oxygen containing heterocyclic compounds of 4H-chromenes or benzopyrans
received ample attention, due their unique properties [18]. 4H-chromene derivatives form
important class of structures, exhibiting notable biological properties, such as anticancer [19],
antioxidant [20], antimicrobial [21], anti-mycobacterial [22], Alzheimer [23], anti-inflammatory
[24] and antidiabetic [25] activities. Many molecules with chromene moiety display a broad
range of pharmacological activities against urinary diseases, asthma, ischemia, blood pressure
and central nervous system [26,27]. Literature survey reveals several synthetic approaches for
substituted 4H-chromene derivatives using different catalysts, including NbCl5 [28], Amberlite
IRA-400 Cl [29], mesoporous silica [30], nano ZnO [31], CaO-ZrO2 nanocomposite oxide [32],
bovine serum albumin [33], silica gel supported polyamine [34] and fluoride ion [35], to mention
a few. These methods have certain confines like lengthy reaction times, tedious handle
approaches, harmful solvents, harsh reaction conditions or low yields. Therefore, the design of
new greener and efficient methods for the synthesis of 4H-chromene derivatives is well sought
after.
Invigorated by the success in preparation of different substituted heterocyclic frameworks
[36-38], we have earlier reported green methods for synthesis of few medicinally valuable
heterocyclic scaffolds [39,40]. In this communication, we describe the synthesis of
functionalized 4H-chromenes, via a three-component/one-pot reaction at the room temperature
through ultrasonication.
2. Experimental Section

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2.1 Typical procedure for the preparation of 4H-chromenes (4a-j)
2-methoxybenzaldehyde (1 mmol), methyl cyanoacetate (1 mmol) and 5,5 dimethyl 1,3-
cyclohexadione (1 mmol) were dissolved in aqueous ethanol in a conical flask (scheme1). The
reaction mixture was ultra-sonicated in water bath at room temperature (RT). The reaction
progress was monitored by TLC. After completion of the reaction, the residue was concentrated
under vacuum. With no further purification needed, the target product was obtained. All the
reaction products were characterised and confirmed by different spectral techniques. The
experimental details and product characterization data (4a-k) are summarised in ESI
Scheme 1: Three-component ultra wave assisted synthesis of 4H-chromene derivatives
3.
Results and Discussion
In initial experiments, 2-methoxybenzaldehyde (1.0 mmol), methyl cyanoacetate (1.0
mmol) and dimedone (1.0 mmol) taken in 1:1 EtOH/H2O (v/v) were reacted at RT, under silent
and ultrasound irradiation conditions and the efficacy of reaction was also investigated with
different solvents, catalysts, and reaction times. The model reaction was performed with no
catalyst or solvent at RT. No reaction occurred even after long time (Table 1, entries 1 and 2).
Next, the model reaction was conducted at RT without any catalyst, but in presence of a different

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of polar or non-polar solvents like n-hexane, toluene DMF, THF, CH3CN, EtOH or MeOH.
Table 1, entries 3-9 summarize the obtained results. Reaction gave impressive results in equal
mixture of EtOH and H2O with high yield of the anticipated product under US condition(Table
1, entry 10). To enhance the yield, the model reaction was investigated in the presence of EtOH
and H2O, with catalysts like NaHCO3, K2CO3, TEA and pyridine at RT. All the reactions gave
relatively low yields, both under silent and US conditions (Table 1 entries 11-14), proving ultra-
sonification in aqueous ethanol is ideal.
Table 1: Optimization of different reaction methods for the formation of 4H-chromene
derivatives under sonication and conventional conditions*
No
Reagent
Solvent
Without sonication
With sonication
Time (h) Yield (%) Time (h) Yield (%)
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
No Catalyst
NaHCO3
no solvent
no solvent
n-Hexane
Toluene
THF
CH3CN
DMF
MeOH
EtOH
12.0
10.0
10.0
10.0
5.0
5.5
6.0
3.5
3.0
2.5
2.5
2.0
2.0
--
--
--
--
5
6.0
6.0
4.0
4.0
2.5
3.0
2.5
2.5
0.50
0.10
0.50
0.45
0.50
0.45
--
--
--
1
2
3
4
5
6
7
8
9
10
11
12
13
14
--
13
10
15
71
84
98
78
81
79
85
6
9
67
71
79
58
62
65
55
Aqueous ethanol
Aqueous ethanol
Aqueous ethanol
Aqueous ethanol
Aqueous ethanol
K2CO3
TEA
Pyridine
2.0
Using the identified optimal reaction conditions, the versatility and substrate scope of the
proposed protocol was examined for synthesis of diverse substituted 4H-chromenes via choice of
varied substituted aromatic aldehydes to react with methyl cyanoacetate and cyclic diketone with
aqueous ethanol as solvent (Table 2). An observation the results in Table 2 show that reactions
involving all aromatic aldehydes, irrespective of electron withdrawing or donating substituents in
ortho, meta and para positions, participated in the reaction smoothly, affording the target

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molecules with excellent yields. No byproducts were observed. The structures of all newly
synthesized molecules (4a-k) were confirmed by appropriate spectral techniques. All the
characterization related spectral data is incorporated in the supplementary material file.
The probable reaction mechanism for the formation of 4H-cromene derivatives under
ultrasound irradiation is demonstrated in scheme 2. In the primary step, through the Knoevenagel
condensation [2,3] between aromatic aldehyde and methyl cyanoacetate, formation of an
intermediate, cyanophenylacrylate is predicted. In the next step, cyanophenylacrylate participate
in Michel addition, and react with active methylene moiety to build the corresponding
intermediate, which finally undergoes intramolecular cyclisation [9] to afford the anticipated
functionalized 4H-chromene derivative.
Table 2: Preparation of new 4H-chromene derivatives in aqueous ethanol as solvent using US
Entry
R
Product Yield (%)
Mp °C
Lit Mp °C
1
2
3
4
5
6
7
8
2-OMe-C6H4
4-OMe-C6H4
2,3-OMe-C6H3
2,5-OMe-C6H3
3-OMe-C6H4
2-NO2-C6H4
98
97
95
94
96
92
96
95
196-197
205-207
186-188
218-219
230-231
211-213
237-239
218-220
--
--
--
--
--
--
--
--
4a
4b
4c
4d
4e
4f
2-F-C6H4
2-OMe,4-OH-C6H3
4g
4h
9
10
11
2,3-Cl--C6H3
4-CF3-C6H4
3-C5H4N
92
96
95
201-203
222-224
222-223
--
--
--
4i
4j
4k
-- New compounds/no literature available.

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Scheme 2: Possible reaction mechanism for formation of 4H-chromene derivative.
4.
Conclusions:
In the current study, we described a clean and eco-friendly one-pot three-component
catalyst free scheme, for ultrasound irradiation assisted synthesis of functionalized 4H-chromene
derivatives in aqueous ethanol. The effectiveness of the environment-friendly ultrasound
technique offering nine novel 4H-chromene derivatives in excellent yields (92-98%) is
confirmed. The title reaction comprises 94% atom efficiency and 100% carbon capture. Other
advantages of the protocol are mild conditions, short reaction times and inexpensive starting
materials. This method proves an ideal alternate for synthesis of 4H-chromenes with high
efficacy.
Acknowledgements:

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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
•
•
•
•
•
Ultrasound synthesis of novel substituted 4H-chromene derivatives
One-pot three component protocol with excellent yields (92-98%).
10 derivatives and 8 are new compounds
Short reaction times (10 min)
Reaction offers 94% atom economy and 100 % carbon capture.