Meglumine catalyzed one pot synthesis of new fluorescent 2-amino-4-pyrazolyl-6-aryldiazenyl-4H-chromene-3-carbonitriles

Article abstract of DOI:10.1080/00397911.2021.1934875

Meglumine, a biodegradable basic organo-catalyst has been efficiently explored for the one-pot synthesis of new fluorescent 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-6-aryldiazenyl-4H-chromene-3-carbonitriles in an aqueous medium at room temperature. The synthesized compounds were found highly fluorescent when screened for photoluminescence properties. The planar structure equipped with substituted aryldiazenyl group led to the extension of conjugation that facilitated fluorescence emission in the visible region with a large stokes shift of 290–294 nm. The novelty of work is a synthesis of highly conjugated molecular assembly, high yield in shorter reaction time, energy efficiency, atom economy, utilization of water as a universal green solvent and meglumine as an eco-benign organo-catalyst.

Full text of DOI:10.1080/00397911.2021.1934875

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Meglumine catalyzed one pot synthesis of new
fluorescent 2-amino-4-pyrazolyl-6-aryldiazenyl-4H-
chromene-3-carbonitriles
Suyog N. Korade, Pradeep M. Mhaldar, Prafulladatta P. Kulkarni, Gajanan S.
Rashinkar & Dattaprasad M. Pore
To cite this article: Suyog N. Korade, Pradeep M. Mhaldar, Prafulladatta P. Kulkarni, Gajanan
S. Rashinkar & Dattaprasad M. Pore (2021) Meglumine catalyzed one pot synthesis of
new fluorescent 2-amino-4-pyrazolyl-6-aryldiazenyl-4H-chromene-3-carbonitriles, Synthetic
Communications, 51:15, 2336-2348, DOI: 10.1080/00397911.2021.1934875
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 15, 2336–2348
https://doi.org/10.1080/00397911.2021.1934875
Meglumine catalyzed one pot synthesis of new fluorescent
2-amino-4-pyrazolyl-6-aryldiazenyl-4H-chromene-3-
carbonitriles
Suyog N. Koradea, Pradeep M. Mhaldara, Prafulladatta P. Kulkarnib,
Gajanan S. Rashinkara, and Dattaprasad M. Porea
b
aDepartment of Chemistry, Shivaji University, Kolhapur, India; Department of Chemistry,
Gogate-Jogalekar College, Ratnagiri, India
ABSTRACT
ARTICLE HISTORY
Received 22 January 2021
Meglumine,
a biodegradable basic organo-catalyst has been
efficiently explored for the one-pot synthesis of new fluorescent 2-
amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-6-aryldiazenyl-4H-chro-
mene-3-carbonitriles in an aqueous medium at room temperature.
The synthesized compounds were found highly fluorescent when
screened for photoluminescence properties. The planar structure
equipped with substituted aryldiazenyl group led to the extension of
conjugation that facilitated fluorescence emission in the visible
region with a large stokes shift of 290–294nm. The novelty of work
is a synthesis of highly conjugated molecular assembly, high yield in
shorter reaction time, energy efficiency, atom economy, utilization of
water as a universal green solvent and meglumine as an eco-benign
organo-catalyst.
KEYWORDS
Diazo compounds; green
chemistry; heterocycles;
multicomponent reaction;
optical properties
GRAPHICAL ABSTRACT
CONTACT Dattaprasad M. Pore
p_dattaprasad@rediffmail.com
Department of Chemistry, Shivaji University, Vidya
Nagar, Kolhapur 416004, India.
Supplemental data for this article can be accessed on the publisher’s website
ß 2021 Taylor & Francis Group, LLC

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SYNTHETIC COMMUNICATIONSV
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Introduction
In the last few decades, environmental pollution associated with the vast utilization of
volatile organic solvents and corrosive metal-based catalysts in industrial processes has
become a serious concern. The researchers working in the field of synthetic organic
chemistry have been constantly striving to develop eco-safe methods for small hetero-
cyclic molecules which would incorporate a maximum number of principles of green
chemistry thereby minimization of environmental depletion.
In this context, water as a universally accepted green solvent is the best choice to
carry out organic transformations owing to its unique advantages such as non-toxicity,
abundance and non-flammability.[1] On account of its exceptional physico-chemical vir-
tues, it is possible to achieve the desired reactivity or selectivity that cannot be attained
in organic media.[2] This is why nature itself adopted water as a solvent for life proc-
esses.[3] The hydrophobic effect and hydrogen bonding ability of water is believed to be
responsible for the drastic acceleration of reaction rate in the water despite low solubil-
ity of organic reactants in it.[4]
Heterocyclic compounds certainly represent a huge part of organic chemistry which
has a high impact on the development of pharmaceuticals and medicinal chemistry. It is
noteworthy that, nearly 65% of the literature on organic chemistry is conquered by dif-
ferent kinds of heterocycles .[5] Amongst various heterocycles, functionalized chromenes
are considered to be a promising tool in the synthetic attempts to design bioactive com-
pounds in the drug discovery process.[6] As far as various functionalized chromene
frameworks are considered, 2-amino-4H-chromenes are particularly assumed as the
privileged medicinal scaffolds on account of their presence in many small drug-like
molecules possessing significant bioactivities such as anticoagulant, spasmolytic, anti-
anaphylactic and diuretic activities.[7] Recently, 2-amino-4H-chromene derivatives have
been found to have potential applications in the treatment of inflammatory TNFa-medi-
ated diseases, such as cancer, psoriasis and rheumatoid arthritis.[8]
Similar to chromenes, substituted 2-pyrazolin-5-ones have gained an immense atten-
tion of organic researchers due to their presence in many bioactive frameworks.[9] 2-
Pyrazolin-5-ones are important components in pharmaceutical formulations, such as
antipyretics, analgesics, etc. It is noteworthy that, N-methyl analog of 3-methyl-1-phe-
nyl-2-pyrazolin-5-one, “antipyrin” is the first truly synthetic analgesic as well as antipyr-
etic drug, approved as a non-steroidal anti-inflammatory drug (NSAID) by WHO.[10]
Moreover, a variety of 4-substituted 3-methyl-2-pyrazolin-5-ones have been reported as
antidiabetic,[11] antihyperlipidemic,[12] anticonvulsant,[13] gastric secretion stimulatory
agents,[14] and neuroleptic,[15] as well as used in cancer and antimicrobial therapy.[16]
Some representative 2-amino chromenes exhibiting potent biological activities and
therapeutically used pyrazolone-containing drug molecules are depicted in Figure 1.
Recently, diazo-group-containing compounds are being extensively studied worldwide
on account of their remarkable medicinal, photochemical and photophysical properties.
Light-driven, reversible cis-trans isomerization is observed in the azo bond of azochro-
mophores leading to change in the structural geometryrelated properties such as dipole
moment and optical properties.[17] Diazo compounds have became pharmaceutically
important molecules as they are found to exhibit bioactivities such as antidiabetic,[18]

2338
S. N. KORADE ET AL.
NH2
H2N
O
NH2
CN
O
NH2
O
NH2
CN
Br
CN
O
O
MeO
Br
O
O
OMe
NO2
Anticancer and
Bcl-2 inhibitor
EPC2407
anticancer activity
LY290181
tabulin inhibitor
N
O
N
N
H C
H C
O
3
O
H C
3
N
3
N
N
O
S
OH
CH
3
H C
NH
H C
NH
3
O
3
H C
3
CH
CH
3
3
Ramifenazone
( NSAID)
Antipyrine
(Anti-pyretic)
Novalgine
(Analgesic)
Figure 1. Representative bioactive molecules containing 2-aminocromine and pyrazolone rings.
antineoplastic,[19] antitumor,[20] antiseptic,[21] antibacterial,[22] anti-inflammatory, herbi-
cidal, antiparasitic, antiulcer, antifungal, antitubercular and antibiotic properties.[23]
Interestingly, like diazo compounds; chromenes coupled with transition metals have
been found to exhibit “Turn on fluorescence” chemosensing properties.[24]
Hence we envisaged that, if the chromene framework is grafted at different
positions with electron-rich nitrogen-bearing heterocycle “pyrazolone” (or their
hydroxyl tautomer) and aryldiazenyl group as a conjugation extender, the modified
hybrid 2-amino-4H-chromene with the unique combination would exhibit enhanced
photoluminescence activity. With this intention, we planned to design and synthesize a
new class of 6-aryldiazenyl tethered 4-pyrazole substituted 2-aminochromenes using
cheap and easily available precursors under the umbrella of green chemistry.
In continuation with our previous research on the development of ecological methods
for new molecules,[25] and with the motive of synthesis of 2-amino-4H-chromenes
equipped with aryldiazenyl and pyrazole components, we report herein “Meglumine”
catalyzed one-pot synthesis of novel 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-
6-aryldiazenyl-4H-chromene-3-carbonitriles in aqueous medium at room temperature
(Scheme 1).
Results and discussion
As far as environmental safety is concerned, water is the best solvent for chemical trans-
formations due to its ample availability, inexpensiveness and eco-benign nature. Water
also possesses special physicochemical properties such as high dielectric constant, ability
to form H-bonding, better stabilization of charged intermediate formed during the

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SYNTHETIC COMMUNICATIONSV
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H2N
NH2
H
N
N
2
N
R
CHO
OH
CN
H3C
OH
CN
Meglumine
N
+
N
R
Water, RT
1 - 2 Hrs
3
CN
N
4
NH2
O
5
O
O
H3C
O
CH3
1
Scheme 1. Meglumine catalyzed synthesis of novel 2-amino-4-pyrazolyl-6-aryldiazenyl-4H-chromene-
3-carbonitriles.
Table 1. Screening of different catalyst for synthesis 2-amino-4-(5-hydroxy- 3-methyl-1H-pyrazol-4-
yl)- 6-aryldiazenyl-4H- chromene-3-carbonitrilesa.
b
Loading
(mol%)
Time
(h)
Yield
(%)
Entry
Catalyst
1
2
3
4
5
6
7
8
No catalyst
No catalyst
K2CO3
K3PO4
Triethylamine
Morpholine
DABCO
2-(N,N’-dimethyl-amino)-ethanol
Triethanolamine
2-Hydroxymethyl pyridine
Meglumine
6.0
2.0
4.0
3.3
3.0
2.5
3.0
2.5
3.0
2.25
2.0
3.0
2.67
2.0
68
48c
74
77
75
78
75
80
76
82
85
79
82
86
20
20
20
20
20
20
20
20
20
10
15
30
9
10
11
12
13
14
Meglumine
Meglumine
Meglumine
aReaction conditions: Ethyl acetoacetate (1.1 mmol), Hydrazine hydrate (1.1 mmol), Phenyldiazenyl salicylaldehyde
(1 mmol), Malononitrile (1 mmol), Catalyst: specified in table, Solvent: Water (10 ml), Temp.: RT, bisolated yields,
cReaction carried out at elevated temperature.
reaction, optimum boiling point and freezing point, etc. It is noteworthy that, the
hydrophobic effect of water often accelerates the rate of reaction and also improves
product selectivity despite less solubility of reactants in water.[26]
Considering merits of the water and referring to some previously published reports
on comparable analogous reactions,[27] initially model reaction of ethyl acetoacetate (1),
hydrazine hydrate (2), 5-phenyldiazenyl salicylaldehyde (3a), and malononitrile (4) was
carried out in the water at room temperature without any catalyst (Table 1, Entry 1).
The reaction was completed in 6 h. monitored by TLC. Desired product 5a was
obtained in 68% yield along with the generation of undesired impurities confirmed by
TLC. The model reaction was then carried out at an elevated temperature, 80 ꢀC.
However, the high temperature was found to be detrimental for the reaction leading to
the formation of only 48% of desired product 5a along with many undesired impurities
(Table 1, Entry 2). Then to improve the quality, yield as well as to reduce time, a variety
of catalysts such as K2CO3, K3PO4, triethylamine, morpholine, DABCO, etc. were tested
for the model reaction at room temperature (Table 1, Entries 3–7). With inorganic
bases viz. K2CO3 and K3PO4, the product 5a was obtained in 74 and 77% yield,

2340
S. N. KORADE ET AL.
Figure 2. Meglumine organo-catalyst with basic 2ꢀ amino and H-bonding sites.
respectively. Reactions with organic bases such as triethylamine, morpholine, and
DABCO offered 75, 78, and 75% yield, respectively.
Based on our earlier experience of reactions in water, we envisioned that if the pre-
sent transformation is carried out using catalyst possessing hydroxyl groups along with
basic amino functionality; the reaction would offer better results with respect to yield,
quality and time. In this viewpoint, we performed model reaction using catalysts viz. 2-
hydroxymethyl pyridine, 2-(N,N’-dimethylamino)-ethanol, triethanolamine, and N-
methyl-glucamine (Meglumine) under experimental reaction conditions (Table 1,
Entries 8–11). Gratifyingly, the best result was obtained for Meglumine furnish desired
product in 85% yield in 2 h (Table 1, Entry 11).
N-methyl-glucamine commercially known as meglumine is an amino sugar equipped
with the secondary amino group as well as hydroxyl groups which can activate not only
electrophilic but also nucleophilic reaction centers in the reaction via Lewis basicity of
amino group and hydrogen bonding through –OH groups, respectively. Moreover, from
nature safety and industrial application viewpoint; meglumine comes with unique vir-
tues, such as inexpensive , non-corrosive nature, low toxicity, biodegradability, reusabil-
ity, etc. (Fig. 2).
Marking “Meglumine” as a catalyst of choice, optimization of the amount of cata-
lyst was performed for the model reaction employing 10, 15, and 30 mol % of cata-
lyst (Table 1, Entries 10-12). It was observed that decreasing the catalyst loading
lead to lower yields with slightly extended reaction times (Table 1, Entries 12 and
13) whereas high catalyst load was insignificant with respect to reaction time and
yield as nearly similar results were obtained as that with 20 mol % catalyst loading
(Table 1, Entry 14). As the product remains insoluble in reaction mass, isolation of
product was carried out by simple filtration followed by washing with hot water.
The formation of desired product was confirmed by IR, 1H NMR, 13C NMR, MS
and elemental analysis.
To validate the generality of the developed protocol, diversely substituted 5-aryldia-
zenyl salicylaldehydes were screened under optimum reaction conditions as depicted in
Table 2. Pleasingly, we noticed that reaction endured a variety of functional groups on
aryldiazenyl moiety such as methyl, methoxy, chloro, bromo, iodo, naphthyl, etc. fur-
nishing good yields of desired products with high purity (Table 2, Entries b–i,).
However, when aryldiazenyl salicylaldehyde having a nitro group on the m-position
of phenyl ring was subjected to reaction, it did not go to completion even after 8 h, and
formation of desired product was observed in nearly 5–10% only. The probable cause
for the failure of this reaction could be the very poor solubility of nitro substrate in the
solvent system (Table 2, Entry j).

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Table 2. Synthesis of library of 2-amino-4-(5-hydroxy- 3-methyl-1H-pyrazol-4-yl)- 6-aryldiazenyl-4H-
chromene-3-carbonitrilesa
H2N
NH2
N
NH
2
N
R
CHO
OH
CN
CN
H3C
OH
CN
Meglumine
Water, RT
N
+
N
R
3
N
4
NH2
O
5
O
O
H3C
O
CH3
1
Product
(5)
Time
(hrs)
Yieldb
(%)
Entry
H
N
N
H3C
OH
CN
N
N
a
2.0
85
NH2
O
H
N
N
CH
N
3
H C
OH
CN
3
N
N
N
b
c
d
e
2.5
2.0
83
86
85
81
NH
2
O
H
N
CH
3
N
H C
OH
CN
3
N
NH
2
O
H
N
OMe
N
H C
OH
CN
3
N
2.25
2.75
NH
2
O
H
N
N
MeO
H C
OH
CN
3
N
N
NH
O
2
(continued)

2342
S. N. KORADE ET AL.
H
N
N
Cl
N
H C
OH
CN
3
N
f
1.25
1.75
88
86
NH
O
2
H
N
N
Br
H C
OH
CN
3
g
N
N
NH
O
2
H
N
N
I
H C
OH
CN
3
N
N
h
2.0
80
NH
O
2
H
N
N
H C
OH
CN
3
N
N
i
j
2.25
78
NH
O
2
H
N
N
NO2
H3C
OH
CN
N
8.0
Trace
N
O
NH2
aReaction conditions: Ethyl acetoacetate (1.1 mmol), Hydrazine hydrate(1.1 mmol), Aryldiazenyl salicylaldehyde (s)
(1 mmol), Malononitrile (1 mmol), catalyst: Meglumine (20 mol %) Solvent: Water (10 ml), Temp.: RT, bisolated yields.
The plausible mechanism for the formation of 2-amino-4-(5-hydroxy-3-methyl-1H-
pyrazol-4-yl)-6-aryldiazenyl-4H-chromene-3-carbonitriles 5 is illustrated in Scheme 2.
Initially, ethyl acetoacetate 1 and hydrazine hydrate 2 undergo condensation in neat
conditions to form 5-hydroxy-3-methyl-1H-pyrazole 7. Then, meglumine promoted
Knoevenagel condensation between 5-aryldiazenyl-salicylaldehyde(s) 3 and malononitrile
4 takes place in water thereafter consequent cyclization by the nucleophilic attack of the
hydroxyl group on cyano group generates intermediate 6. Ultimately, meglumine
assisted Michael’s addition of 5-hydroxy-3-methyl-1H-pyrazole 7 to intermediate 6 fur-
nish desired product 5. It can be anticipated that, the catalyst meglumine facilitates
effective chemical interactions between hydrophobic substrates in an aqueous medium
by its H-bonding ability and basic secondary amino site leading to rate acceleration and
better yield.

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2
H2
N
H3
C
NH2
1
O
O
HO
HO
CH3
NH
..
O
O
OH
- H2
O
HO
HO
OH
H
- EtOH
CN
CN
H
O
OH
R
H
N
N
OH
HO
4
N
H3
C
NH
OH
3
N
NH
- H2O
OH
H
NH
H3
C
OH
CN
7
N
N
R
NC
N
O
NH2
R
N
5
R
C
N
CN
O
N
N
H
H
O
6
NH
HO
O
NH
HO
H
OH
HO
HO
OH
N+
H
H bonding
HO
OH
OH
Scheme 2. Plausible mechanism for formation of 2-amino-4-pyrazolyl-6-aryldiazenyl-4H-chromene-3-
carbonitriles
Photoluminescence properties of synthesized molecules
A fully conjugated extended p electron system is an important prerequisite for a
molecule to exhibit fluorescence. The aryldiazenyl linkage in synthesized compounds
facilitates an extension of conjugation of base chromene core making them suitable
candidates to be screened for photoluminescence properties. Therefore, we investi-
gated UV absorption and fluorescence emission characteristics of synthesized aryldia-
zenyl tethered 2-amino-4H-chromene-3-carbonitrile derivatives in the solid-state
(Fig. 3(A,B)).
It was observed that all compounds exhibited UV absorption in the range of
ꢁ
290–294 nm owing to n ! p electronic transition. We then irradiated synthesized
compounds at 290–284 nm corresponding to UV absorption maxima of each compound
and recorded the fluorescence emission spectra. Remarkably, for all the synthesized
derivatives, fluorescence emission was observed in the visible region wavelength range
of 582–586 nm with a large stokes shift of 290–294 nm from the excitation wavelength.
Interestingly, the 2-methyl derivative (5b) exhibited the highest intensity with the largest
stokes shift. It was noteworthy that, in halogen-substituted derivatives, fluorescence with
significant intensity was recorded which might be due to loan pair induced mesomeric
effect of halogens facilitating possible minimization in the HOMO-LUMO gap.
Conclusions
In conclusion, a simple, green, efficient and economical method for 2-amino-4-(5-
hydroxy-3-methyl-1H-pyrazol-4-yl)-6-aryldiazenyl-4H-chromene-3-carbonitriles
is
developed employing eco-benign, cheap and biodegradable catalyst “Meglumine” in an
aqueous medium at ambient temperature. The present method seems equally efficient
for 5-aryldizenyl salicylaldehydes having electron-withdrawing as well as electron-donat-
ing substituents. The main advantages are the use of water as a green solvent, energy

2344
S. N. KORADE ET AL.
Figure 3. Solid state UV absorption spectra (A) and solid state fluorescence emission spectra (B) of
compounds 5a–5h.
efficiency, atom economy, and simple workup procedure avoiding tedious column chro-
matography, good to moderate yields of products that make the method significant.
Moreover, synthesized molecules exhibited strong fluorescence properties with consider-
able stokes shift of 290–293 nm. The excellent fluorescent nature of the synthesized
compounds makes them reliable candidates for their future applications as photolumi-
nescent agents in various fields such as in fluorescence chemo-sensing, in UV rays fil-
ters, etc.
Experimental
General
Ethyl acetoacetate, hydrazine hydrate (Spectrochem), malononitrile, and Meglumine
(Sigma-Aldrich) were utilized as received. Various 5-aryldiazenyl aldehydes were synthe-
sized in laboratory.[28] An open capillary method was used for recording M.P. which
was uncorrected. NMR spectra were recorded on Bruker AC-400 spectrometer
1
(Irradiation frequency: 400 MHz for H NMR and 100 MHz for 13C NMR) in DMSO-d6

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2345
using TMS as an internal standard while d values are expressed in ppm. IR spectra were
analyzed on Perkin-Elmer-Spectrum-2 spectrophotometer (ATR) and Mass spectra were
recorded on a Shimadzu LCMS-2020 (Spectral threshold setting for peak visibility: m/
z ¼ 20 above) and Thermo Scientific TSQ 8000 GC-MS, UV absorption spectra and
fluorescence emission spectra were recorded on Jasco spectrophotometer V-770 and
Jascospectrofluorometer FP-8200. Elemental analysis was done on an Exeter CE440
model instrument.
General procedure for synthesis of 2-amino-4-(5-hydroxy-3-methyl-1H-pyrazol-4-
yl)-6-[(E)-aryldiazenyl]-4H-1-benzopyran-3-carbonitrile (5)
In 25 ml round bottom flask, ethyl acetoacetate 1 (0.13 ml, 1.1 mmol) and hydrazine
hydrate 2 (0.05 ml, 1.1 mmol) were charged and kept for 5 min to allow generation of 5-
hydroxy-3-methyl-1H-pyrazole 7. Then, 10 ml water, Meglumine (0.04 gm, 20 mol %),
and malononitrile 4 (0.06 ml,1 mmol) were added and stirred for 5 min followed by the
addition of 5-aryldiazenyl salicylaldehyde(s) 3 (1 mmol). The resultant mixture was
stirred at room temperature for the time specified in Table 2. The progress of the reac-
tion was monitored by TLC. After completion of the reaction, the reaction mixture was
filtered and washed with 2 ml hot water to furnish the corresponding product 2-amino-
4-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-6-aryldiazenyl-4H-chromene-3-carbonitriles 5.
1
Finally products were characterized by spectral techniques viz. H, 13C NMR, IR, MS,
and elemental analysis.
1
Full experimental detail, IR, H, 13C NMR, elemental analysis, and mass spectra can
be found via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
The authors are thankful to Shivaji University, Kolhapur, Maharashtra, India for providing
research facilities.
Disclosure statement
The authors declare no competing financial interest.
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