Facile one-pot green synthesis of 2-amino-4H-benzo[g]chromenes in aqueous ethanol under ultrasound irradiation

Article abstract of DOI:10.1080/00397911.2020.1761393

We report an efficient green one-pot approach for the synthesis of eighteen novel dihydro-4H-benzo[g]chromene derivatives under ultrasound irradiation conditions. The three-component condensation reaction proceeded through Knoevenagel-Michael reaction of

Full text of DOI:10.1080/00397911.2020.1761393

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Facile one-pot green synthesis of 2-amino-4H-
benzo[g]chromenes in aqueous ethanol under
ultrasound irradiation
Shabalala Nhlanhla Gracious, Nagaraju Kerru, Suresh Maddila, Werner E.
van Zyl & Sreekantha B. Jonnalagadda
To cite this article: Shabalala Nhlanhla Gracious, Nagaraju Kerru, Suresh Maddila, Werner E.
van Zyl & Sreekantha B. Jonnalagadda (2020): Facile one-pot green synthesis of 2-amino-4H-
benzo[g]chromenes in aqueous ethanol under ultrasound irradiation, Synthetic Communications
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https://doi.org/10.1080/00397911.2020.1761393
Facile one-pot green synthesis of 2-amino-4H-benzo[g]
chromenes in aqueous ethanol under ultrasound
irradiation
Shabalala Nhlanhla Gracious, Nagaraju Kerru, Suresh Maddila, Werner E. van Zyl,
and Sreekantha B. Jonnalagadda
School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
ABSTRACT
ARTICLE HISTORY
Received 9 December 2019
We report an efficient green one-pot approach for the synthesis of
eighteen novel dihydro-4H-benzo[g]chromene derivatives under
ultrasound irradiation conditions. The three-component condensation
reaction proceeded through Knoevenagel-Michael reaction of chosen
active methylene compounds and 2-hydroxynaphthalene-1,4-dione
with different substituted aldehydes in the presence of ammonium
acetate in water and ethanol mixture at room temperature, which
furnished high yields of products (91–98%) in a rapid reaction time
of 5–15 min. This procedure offers 95% of the atom economy and
100% of carbon efficiency together with other eco-friendly benefits.
KEYWORDS
Dihydro-4H-benzo[g]chro-
menes; green solvent
medium; multi-component;
room temperature;
ultrasound irradiation
GRAPHICAL ABSTRACT
Introduction
Benzo[g]chromenes are an exciting class of natural products and valued targets in the
therapeutic field, because of their exhibition of various biological activities such as anti-
cancer,[1] antimalarial, antibacterial,[2] antiallergic,[3] anti-inflammatory[4] and pesticide
activities. Naturally occurring benzo[g]chromenes, such as b-lapachone, a-xiloidone,
lambertellin and pyranokunthone, which possess one of the most complex
CONTACT Sreekantha B. Jonnalagadda
jonnalagaddas@ukzn.ac.za
School of Chemistry and Physics, University of
KwaZulu-Natal, Westville Campus, Chiltern Hills, Durban 4000, South Africa.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

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S. N. GRACIOUS ET AL.
pharmacophores, are used as drugs for the treatment of antitumor activity.[5,6] Both
1,4-naphthoquinones and pyran motifs containing these scaffolds have been great con-
siderable interest in drug development and discovery. Over the years, different synthetic
methods have been reported for their synthesis. Most of these techniques endure certain
disadvantages such as multistep synthesis, use of expensive catalysts,[7] long reaction
times,[8] low selectivity, tedious work-up,[9] and low yields. Therefore, there is a need
for more efficient, green and environmentally friendly methods, such as utilizing one-
pot reaction strategies.[10,11] In addition, because of their advantages over conventional
heating methods, the microwave and ultrasound irradiations have been in use as an
energy source for reaction activation.[12,13]
Sonochemistry is a modern and eco-friendly technique to accelerate organic syn-
thesis. Ultrasound irradiation induces chemical effects through the development of
cavitation,[14] which promotes the growth, formation and instant collapse of bubbles
in a liquid medium.[15] The bubble collapse produces intense local heating, which is
used as an energy source for chemical reactions.[16] The generated heat promotes
mass transfer and dispersion of present species in the exposed liquid. Therefore,
ultrasound can be used to facilitate synthetic reactions with enhanced reaction
rates,[17] high product yields, improved selectivity, atom-economy, and conversions,
thus minimizing the waste generation.[12] In recent years, there has been increasing
interest in the applications of multicomponent reactions (MCRs) in synthetic organic
chemistry.[18–22] MCRs are a one-step procedures in which three or more reactive
species come together in the reaction pot to form a single product with high select-
ively and atom efficiency.[23–27] MCRs improve the environmental friendliness, cost
efficiency linked with the synthesis of significant value-added organic molecules in
short reaction times.[28–32] The synthesis of scores of biologically active compounds
of importance for organic, medicinal and combinatorial chemistry, and in drug
discovery have been enabled by one-pot multicomponent reactions.[33–39] MCRs
occupy a vital position in organic syntheses, as they produce highly pure products
with biological relevance with efficacy.[40–45]
In the recent past, the MCR approach for the synthesis of a benzo[g]chromene skel-
eton containing heterocyclic compounds has gained much prominence. Literature sur-
vey shows various reports on the synthesis of 4H-benzo[g]chromene derivatives from
aromatic aldehyde, 2-hydroxynaphthalene-1,4-dione and malononitrile using different
catalyst materials, including triethyl-benzyl ammonium chloride (TEBA),[46] imid-
azole,[47] propylpiperazine-N-sulfamic acid (SBPPSA),[48] triethylammonium hydrogen
sulfate [Et3NH][HSO4],[49] triethylamine (Et3N),[50] urea,[51] [bmim]OH,[52] and L-pro-
line.[53,54] However, still, the space exists for development of new improved and efficient
methodologies that can lead to novel derivatives with enhanced yields under
green conditions.
To the best of our knowledge, there are no reports on the synthesis of dihydro-
4H-benzo[g]chromene derivatives employing methyl or isopropyl cyanoacetates under
ultrasound irradiation and ammonium acetate as catalyst. Herein, we report for the first
time, a method for the synthesis of dihydro-4H-benzo[g]chromenes catalyzed by ammo-
nium acetate in aqueous ethanol under ultrasound irradiation (Scheme 1).

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3
Scheme 1. Synthesis of dihydro-4H-benzo[g]chromene derivatives in aqueous ethanol.
Table 1. Effect of catalyst amount on the synthesis of compound 4a.a
Ultrasound
Entry
Mol%b
Time (min)
Yield (%)
1
2
3
4
5
5
10
15
20
30
25
20
10
5
75
84
92
98
98
10
aReaction conditions: Stoichiometric ratio of all the reactants with the catalyst in ethanol and
water at RT. bNH4OAc.
Results and discussion
Initially, the model reaction was carried out between the 2-methoxy benzaldehyde (1a,
1.0 mmol), 2-hydroxynaphthalene-1,4-dione (2, 1.0 mmol) and methyl cyanoacetate (3a,
1.0 mmol) in the presence of ammonium acetate in ethanol and water mixture under
ultrasound irradiation at room temperature. The effect of the amount of catalyst on the
yield and reaction rate was studied under ultrasound irradiation. It was observed that
an increase in the amount of ammonium acetate from 5% to 20 mol%, decreased the
reaction time (25–5 min) and increased the yield of the product, from 75% to 98%
(Table 1, entries 1–4). Moreover, no change in the yield (98%) of the product was
noticed by an increase in the amount of ammonium acetate (30 mol%), but with longer
reaction time (5–10 min) (Table 1, entry 5). Evident from the results, 20 mol% of
ammonium acetate was proved the ideal amount for successful conversion.
The effect of solvent for the model reaction was investigated by using 20 mol% of
NH4OAc at room temperature under ultrasound irradiation. A lower yield of the
desired product was noticed under the solvent-free condition, when methanol, dichloro-
methane or acetonitrile were used as solvents and the reaction took longer (Table 1,
entries 1–4). Water and ethanol as solvents gave the excellent returns (82% and 84%
respectively) for 30 min reaction time (Table 2, entries 5 and 6). Based on the results,
the reaction mixture was subjected to equal amounts of both water and ethanol mixture
(EtOH:H2O(1:1 v/v), which facilitated the improved the yield (98%) of the product in
5 min (Table 2, entry 7). Therefore, the aqueous ethanol medium proved superior solv-
ent system for the synthesis of dihydro-4H-benzo[g]chromene derivatives under ultra-
sound irradiation, in the presence of 20 mol% of NH4OAc at room temperature.
The efficiency of different catalysts on the model reaction was tested in aqueous etha-
nol at room temperature under ultrasound irradiation (Table 3). Low yields (39% and

4
S. N. GRACIOUS ET AL.
Table 2. Solvent optimization for the synthesis of compound 4a.a
Ultrasound
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
No solvent
MeOH
DCM
MeCN
H2O
60
60
60
60
30
30
5
Trace
69
38
44
82
EtOH
EtOH/H2O(1:1)
84
98
aThe reaction was performed with 2-methoxybenzaldehyde (1a, 1.0 mmol), 2-hydroxy-
naphthalene-1,4-dione (2, 1.0 mmol), methyl cyanoacetate (3, 1.0 mmol), NH4OAc
(20 mol%) and solvent (10.0 mL). bIsolated yield.
Table 3. Assessment of catalytic activity for different catalyst applied for
the synthesis of compound 4a.
Ultrasound
Entry
Catalyst
Time (min)
Yielda (%)
1
2
3
4
7
8
9
No catalyst
Et3N
DBU
45
60
60
Trace
50
55
53
39
42
98
K2CO3
60
Cs2CO3
Pyridine
NH4OAc
120
120
5
aReaction conditions: 2-methoxybenzaldehyde (1a, 1.0 mmol), 2-hydroxynaphthalene-1,4-
dione (2, 1.0 mmol), methyl cyanoacetate (3, 1.0 mmol), catalyst (20 mol%) and
EtOH:H2O (10.0 mL).
42%) of product 4a was achieved after 2 h, when Cs2CO3 and pyridine were applied
(Table 3, entries 7 and 8). Moderate yields (50–53%) were obtained, when Et3N, DBU,
and K2CO3 were used as a catalysts (Table 3, entries 2–4), and a trace amount of final
derivative was attained in the absence of a catalyst (Table 3, entry 1). Therefore, ammo-
nium acetate proved to be most effective in terms of reaction rate and excellent yield
(98%) of product 4a (Table 3, entry 9).
Further, the effect of temperature on the yield under ultrasound condition was inves-
tigated with aqueous ethanol as a medium (Table 1S, entry 1–5). The decrease in the
yield of the product (98–88%) and increase in reaction time (5–15 min) were observed,
when the temperature was increased from 30 to 60 ꢀC. This decrease in yields and an
increase in reaction time observed in the ultrasonic reaction is conceivable, because
ultrasound provides good alternative heating for chemical reactions. This implies that
increase temperature is not necessary, to improve the yields and reduce reaction time.
Furthermore, higher heat is detrimental to the implosion of the cavity. This cushioning
of the bubble collapse, then lowers the temperature and pressure conditions that created
during the implosion, negating the same high temperature and pressure conditions that
are needed to activate the reaction.
After optimizing the reaction conditions (20 mol% of NH4OAc, ethanol: water (1:1)),
the efficiency of the current protocol was investigated using various aliphatic/aromatic

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5
Table 4. Synthesis of dihydro-4H-benzo[g]chromene derivatives 4a–x.a
Ultrasound
Entry
R
X
Product
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
2-OCH3C6H4
2,3-(OCH3)2C6H3
2,5-(OCH3)2C6H3
3,4-(OCH3)2C6H3
2-Cl C6H4
2,4-(Cl)2C6H3
4-ClC6H4
2-NO2C6H4
2-Cl,6-FC6H3
2-CF3C6H4
4-FC6H4
2-BrC6H4
2-Furfuryl
2-Thienyl
n-butyl
2-Cl,6-FC6H3
2-BrC6H4
4-CH2CH3C6H4
2-Cl,6-FC6H3
2,3,4-(OCH3)3C6H2
3,4,5-(OCH3)3C6H2
4-FC6H4
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOiPr
COOiPr
CN
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
5
7
15
5
5
6
15
10
8
5
7
98
98
96
95
96
97
96
95
97
95
98
97
94
96
91
98
95
95
96c
92c
98c
96c
96c
98c
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
10
9
11
12
10
10
15
7
10
6
15
CN
CN
CN
CN
CN
CN
4s
4t
4u
4v
4w
4x
2-BrC6H4
4-BrC6H4
6
7
aReaction conditions: various aldehydes (1a–s, 1.0 mmol), 2-hydroxynaphthalene-1,4-dione (2, 1.0 mmol), active methy-
lene compounds (3, 1.0 mmol), NH4OAc (20 mol%) and EtOH:H2O (10.0 mL) under ultrasound at RT. bIsolated yields;
cKnown compounds.
Table 5. Comparison of present method with other reported protocols for the synthesis of 4H-ben-
zo[g]chromenes derivatives.
Catalyst
Solvent
Condition
60 ꢀC
Time (min)
% Yield[Ref]
Zn(L-proline)2
DBU
o-Benzenedi-sulfonimide
Fe2O3@SiO2 NPs
Diethyl amine
L-proline
Solvent-free
Water
Solvent-free
Ethanol
EtOH
EtOH
CH3CN
4–15
40–180
5–12
15–45
270–300
240–360
105–120
5–15
80–94[1]
Reflux
85–90[4]
60 ꢀC
82–93[10]
70–93[56]
US/80 ꢀC
Reflux
Reflux
Reflux
US/RT
87–96[57]
88–98[58]
Fe(ClO4)3/SiO2
NH4OAc
94–96[59]
EtOH:H2O
91–98[Present work]
and heterocyclic aldehydes (1a–s) and different active methylene compounds (3a–c)
reacted with the 2-hydroxynaphthalene-1,4-dione (2) at room temperature for the
synthesis of dihydro-4H-benzo[g]chromene derivatives (4a–x), results are shown in
Table 4. It was evident that ammonium acetate was involved in this reaction as a cata-
lyst, not a nitrogen source. Ammonium acetate is known to have a dual function in
chemical reactions,[55] both as a catalyst or a reactant. Out of the twenty-four deriva-
tives, eighteen derivatives were novel and six were known. The target products were
offered in excellent yields (91–98%) in rapid reaction time (5–15 min) and were charac-
terized by different spectroscopic methods (NMR, HRMS, and IR). It was found that
the structural dissimilarity of the aldehydes and different substitutions on the aromatic
phenyl ring showed no significant effect on this condensation and proceeded effectively
as corresponding derivatives in high yields. Different active methylene compounds such

6
S. N. GRACIOUS ET AL.
Scheme 2. The possible mechanism for the synthesis of dihydro-4H-benzo[g]chromenes.
as malononitrile, methyl, and isopropyl cyanoacetates were well-tolerated and contrib-
uted in this multi-component reaction with the high conversion rate.
The proposed protocol for the synthesis of 4H-benzo[g]chromene derivatives offers
many advantages in terms of yield and reaction conditions, compared with the literature
reported methods with different catalysts. Table 5 summarizes the comparison results
with the other literature reported methods of relevance, with the present ultrasonication
method. Based on the experimental results, the ammonium acetate proved an ideal cata-
lyst under the ultrasound irradiation for the synthesis of 4H-benzo[g]chromene deriva-
tives, as compared to the other reported protocols, which offered excellent yields with
short reaction time at RT. This protocol is a substantial improvement over literature
reported protocols, with excellent selectivity and conversions using eco-friendly and
inexpensive inorganic catalysts under ultrasound condition. In addition, the protocol
requires short reaction times, avoids the use of hazardous reagents or solvents, and does
not require any chromatography separation procedures. Therefore, the application of
ultrasound in this procedure makes it beneficial through the process of cavitation, rapid
reaction time so that the formation of new bonds happened swiftly at room tempera-
ture. The isolated products were achieved in high yields and the reaction and work-up
were simple to perform.
1
The H NMR spectra of the obtained product 4a shown characteristic singlets at d
7.17 ppm and d 4.92 ppm, attributed to the two protons of the NH2 group and one pro-
ton of CH of pyran moiety. The peaks at d 3.80 and 3.84 ppm as singlets are due to the
three protons of methoxy groups. The remaining aromatic ring protons were at their
respective aromatic chemical shift region. The signals at 177.4 and 182.1 ppm in 13C
NMR due to the carbonyl carbon of the naphthalene-1,4-dione moiety. In the IR spec-
trum, the prominent vibrational frequencies observed at 3396 cmÀ1 and 1654 cmÀ1
were for NH2 and carbonyl groups further support the identification of product 4a
(supplementary file).

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SYNTHETIC COMMUNICATIONSV
7
The possible explanation and reported mechanism[4] for this reaction are given in
Scheme 2. In the first step, ammonium acetate acts as a catalyst and reacted with the
aldehydes (1), resulted in the iminium ion (I). The iminium ion undergoes condensa-
tion with the active methylene compounds (3), this route is more feasible because of
iminium ion was highly reactive than the carbonyl group. The resulting Knoevenagel
intermediate (II) attacked by the C-H activated acid of 2-hydroxynaphthalene-1,4-dione
(2). This is followed by the structural rearrangement and intramolecular cyclization
afforded the target product (4).
Conclusion
A highly efficient and green methodology for the synthesis of biologically potent dihy-
dro-4H-benzo[g]chromene derivatives under ultrasound irradiation method is reported.
The target products obtained from the reaction of various aldehydes with different
chosen active methylenes’ and 2-hydroxynaphthalene-1,4-dione in the presence of
ammonium acetate catalyst in aqueous ethanol at room temperature. High yields
(91–98%) of twenty-four derivatives were achieved, of which eighteen were novel com-
pounds in 5–15 min reaction time. Simple workup, green solvents, excellent yields, rapid
synthesis, and avoidance use of column chromatography are the benefits of the pre-
sent protocol.
Experimental section
All chemicals used were reagent grade and were used as received without further purifi-
cation. 1H NMR and C NMR spectra were recorded at 25 ꢀC at 400 MHz and
13
100 MHz (Bruker Avance) instrument, respectively, using TMS as an internal standard.
Chemical shifts are given in parts per million (ppm). The FT-IR spectroscopy of sam-
ples was carried out on a Perkin Elmer Precisely 100 FT-IR spectrometer in the
400–4000 cmÀ1 region. The HRMS were recorded on a Waters Micromass LCT premier
mass spectrometer using electrospray ionization in the positive or negative mode. High-
resolution mass data were acquired on a Bruker micro TOF-Q II ESI, it is operating at
ambient temperature. The ultrasonic-assisted reactions are carried out in a Scientech
ultrasonic cleaner with a frequency of 50 kHz and a nominal power 150 W. Melting
points were recorded on a hot stage melting point apparatus Ernst Leitz Wetzlar,
Germany, and were uncorrected. All the reactions and the purity of products were
monitored using thin-layer chromatography (TLC) on aluminum-backed plates coated
with Merck Kieselgel 60 F254 silica gel, visualizing the spots under ultraviolet light in
an iodine chamber.
General procedure for the synthesis of dihydro-benzo[g]chromenes (4a–u) under
ultrasound irradiation
A mixture of aldehydes (1a–s) (0.200 g, 1.0 mmol), 2-hydroxynaphthalene-1,4-dione (2)
(0.255 g, 1 mmol) appropriate active methylene compounds (malononitrile (0.097 g) or
methyl cyanoacetate (0.1456 g) or isopropyl cyanoacetate (0.186 g)) (3a–c, 1.0 mmol),
and ammonium acetate (0.022 g, 20 mol%) in the 1:1 mixture of ethanol:water (10 mL),

8
S. N. GRACIOUS ET AL.
was irradiated at room temperature for the 5–15 min. The reaction progress was moni-
tored by TLC. Later completion of the reaction, the obtained product was cooled and
rinsed with water and ethanol and filtered under vacuum. All the synthesized com-
1
pounds were characterized by FTIR, HRMS, H and 13C NMR spectroscopic techniques.
Full experimental data of new and known (4a–x) compounds spectral details can be
found in Supporting information via the “Supplementary Content” section of this
article’s webpage.
Acknowledgments
The authors thank the National Research Foundation (NRF) of South Africa for the financial
support, and the University of KwaZulu-Natal for research facilities.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Sreekantha B. Jonnalagadda
http://orcid.org/0000-0001-6501-8875
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