β-Cyclodextrin: A supramolecular catalyst for metal-free approach towards the synthesis of 2-amino-4,6-diphenylnicotinonitriles and 2,3-dihydroquinazolin-4(1 H)-one

Article abstract of DOI:10.1039/d0ra09562a

β-Cyclodextrin, a green and widespread supramolecular catalyst, has been explored as a highly proficient promoter for the metal-free one-pot multi-component synthesis of a vast range of highly functionalized bioactive heterocyclic moiety, 2-amino-4,6-diphenylnicotinonitriles and 2,3-dihydroquinazolin-4(1H)-one, from easily available precursor aldehydes. The main endeavor of these protocols is to explore this organic supramolecule in one-pot multi-component synthesis. Absence of metal catalyst or toxic acid and harsh reaction conditions, excellent functional group tolerance, inexpensive, greener and environmentally safe protocol are the key advantages of this work.

Full text of DOI:10.1039/d0ra09562a

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b-Cyclodextrin: a supramolecular catalyst for
metal-free approach towards the synthesis of 2-
amino-4,6-diphenylnicotinonitriles and 2,3-
dihydroquinazolin-4(1H)-one†
a
Cite this: RSC Adv., 2021, 11, 1271
Bijeta Mitra,a Gyan Chandra Pariyarb and Pranab Ghosh
*
b-Cyclodextrin, a green and widespread supramolecular catalyst, has been explored as a highly proficient
promoter for the metal-free one-pot multi-component synthesis of a vast range of highly functionalized
bioactive heterocyclic moiety, 2-amino-4,6-diphenylnicotinonitriles and 2,3-dihydroquinazolin-4(1H)-
one, from easily available precursor aldehydes. The main endeavor of these protocols is to explore this
organic supramolecule in one-pot multi-component synthesis. Absence of metal catalyst or toxic acid
and harsh reaction conditions, excellent functional group tolerance, inexpensive, greener and
environmentally safe protocol are the key advantages of this work.
Received 10th November 2020
Accepted 8th December 2020
DOI: 10.1039/d0ra09562a
rsc.li/rsc-advances
to the development of geometrical constraints developed in the
guest molecules because it gets included within the cavity of
1. Introduction
CDs. Similar to b-cyclodextrin, it uses the hydrophobic cavity to
encapsulate biologically active molecules from aqueous solu-
tions, which eventually enhances the bioavailability and
stability of drug molecules. These properties have made CDs an
important asset for pharmaceutical industries. Moreover, CDs
are easily recyclable, easily available, cheaper, and non-toxic.13,14
In the past few decades, for producing a diverse array of
heterocyclic molecules and making the synthetic route simpler,
one-pot multi-component organic synthesis has played an imper-
ative role in chemistry. Three or sometimes more starting mate-
rials coalesce together in the same pot to exclusively develop the
target molecule in multi-component synthesis without separating
the intermediate, which aids in reducing the reaction time, solvent
waste, and energy consumption and therefore have considerable
compensation over the multistep procedure.15
The pyridine motif is an essential scaffold because of its
occurrence in natural products, biological and medicinal products.
Among pyridine ring systems, 2-aminonicotinonitrile derivatives
have achieved elevated synthetic attention as an imperative
heterocyclic molecule because of its existence as bio-active species
such as IKK-b inhibitors,16 potent inhibitor of HIV-1 integrase,17
A2A adenosine receptor antagonist18 as well as in antitubercular,19
anticancer, anticardiovascular20 and antimicrobial drugs.21 More-
over, pyridines are valuable in materials and surfaces,22 organo-
catalysis,23 supramolecular structures,24 and coordination
chemistry.25 Furthermore, these compounds serve as useful inter-
mediates for preparing diverse heterocyclic compounds.26
In organic transformations, a major apprehension focuses on
catalysts and solvents. Pyrophoric property and the hazardous
nature of solvent with high volatility and poor recovery are the
major limitations of solvents. The main limitation of the metal
catalyst is that it leads to metal contagion at the end of the reac-
tion, which is not good for our Mother Earth. These disadvantages
could be overcome using any green solvent and organocatalyst,
which is good for the environment. We have developed a metal-
free protocol using a supramolecular catalyst, b-cyclodextrin.1 In
terms of environmentally friendly and atom economy, water2 as
a reaction medium is highly advantageous.
Given the advancements in supramolecular chemistry and
homogeneous catalysis, the supramolecular catalyst has been
emerging as an important tool in synthesizing organic hetero-
cyclic compounds.3 Among the array of supramolecular hosts,
cyclodextrins (CDs) are one of the important enzyme models.4–7
Being cyclic oligosaccharides, cyclodextrins possess hydro-
phobic cavities, which enable them to bind with substrates
selectively, because of which they are able to catalyze chemical
reactions and ensure high selectivity.8–12 During the course of
the reaction, CDs can reversibly bind to a host–guest complex
with the substrates via non-covalent bonding, thus forming
a complex, which is responsible for altering product distribu-
tion during organic reactions. The characteristics are attributed
aDepartment of Chemistry, University of North Bengal, Dist. Darjeeling, West Bengal,
India. E-mail: pizy12@yahoo.com; Fax: +91 353 2699001; Tel: +91 353 2776381
bDepartment of Food Technology, University of North Bengal, Dist. Darjeeling, West
Bengal, India
For the past few years, 2,3-dihydroquinazolin-4(1H)-one has
gained considerable interest and has been utilized in preparing
various drug molecules27,28 due to its potential biological and
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra09562a
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Fig. 1 Some bioactive molecules having 2-amino-3-cyanopyridine and 2,3-dihydroquinazolin-4(1H)-one skeleton.
pharmaceutical activities, which may be either antidepressant, 4(1H)-one via a one-pot three-component strategy using aldehydes,
analgesic, sedative, diuretic, or antihistamine.29–31 Anticancer isatoic anhydride, and amines are reported in the literature.53 We
activities, such as cell proliferation, inhibition of tubulin forma- have utilized the environmentally benign supramolecular catalyst b-
tion,32 and inhibition against VEGFR2 tyrosine kinase, are cyclodextrin as a promoter for these two different one-pot multi-
extraordinarily important features of these compounds. Plant component organic reactions using aldehyde and ammonium
growth regulatory33 is another important activity of this molecule acetate as the two main precursors (Schemes 1 and 2).
with a huge application. Some examples are given below in Fig. 1.
Many diverse protocols have been reported for synthesizing
2. Experimental
2.1. Materials and apparatus
2-amino-3-cyanopyridine derivatives such as Fe3O4,34 acetic acid,35
ultrasound irradiation,36,37 DMF,38 Lewis acid catalysts,39 and gra-
phene oxide.40 However, a straightforward and efficient one-pot
reaction without a transition metal catalyst and hazardous
solvent in mild conditions is still unexplored. Although several
methods for preparing 2-amino-4,6-diphenylnicotinonitrile are
well documented in the literature, most of them have a few limi-
tations such as the use of hazardous solvents such as benzene or
toluene, very high temperature, multiple-step pathway, long reac-
tion times with low yields, use of transition metal that leads to
metal contamination at the end of the reaction, and harsh reaction
conditions that are not environmentally friendly.
All compounds were purchased from commercial suppliers and
used without further purication. H NMR, 13C NMR, and 19F
1
NMR were recorded using 300 MHz, 400 MHz and 75 MHz, 100
MHz and 376 MHz, respectively, on Bruker AV 300 NMR spec-
trometer and Bruker AV 400 NMR spectrometer using TMS as
the internal standard. IR spectra were recorded on KBr disc in
the range of 4000–400 cmꢀ1 on a Shimadzu FT-IR 8300 Spec-
trometer. The splitting patterns of protons were described as s
(singlet), d (doublet), t (triplet), br (broad), and m (multiplet).
Many strategies have been designed for synthesizing 2,3-
dihydroquinazolin-4(1H)-ones in the literature; however, the
most widely used method is the straightforward condensation
reaction between 2-aminobenzamide and aldehyde. Most of these
methodologies use metal salts,41 metal nano-particles42 of Co, Fe, La,
Ag, In, and Cu, p-TSA,43 amberlyst-15,44 acidic silica,45 tri-
uoroethanol,46 cyanuric chloride,47 heteropoly acid,48 organic acid,49
I2,50 NH4Cl,51 and b-cyclodextrin.52 Synthesis of this molecule via
a one-pot three-component protocol in a greener pathway is very
tricky. Few methodologies for synthesizing 2,3-dihydroquinazolin-
2.2. General procedure for the synthesis of 2-amino-4,6-
disubstituted nicotinonitriles
b-Cyclodextrin (10 mol%) and water were added to a mixture of
aromatic aldehydes (1 mmol), acetophenone (1 mmol), malo-
nonitrile (1 mmol), and ammonium acetate (1 mmol) in
a round-bottom ask. The resulting mixture was stirred at 90 ꢁC
for 2 h in the open air. The reaction progress was monitored
using TLC with a mixture of ethyl acetate and n-hexane as the
eluent system. Aer reaction completion, the mixture was
quenched to room temperature and extracted with ethyl acetate
Scheme 1 One-pot four-component synthesis of 2-amino-4,6-diphenylnicotinonitriles.
Scheme 2 One-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-one.
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twice (2 ꢂ 20 ml). The combined extracts were washed with 3H), 7.68–7.82 (m, 3H), 8.14–8.26 (m, 2H); 13C NMR (75 MHz,
distilled water, dried over anhydrous Na2SO4, and concentrated. DMSO-d6) d (ppm): 88.4, 110.0, 114.2, 117.8, 127.8, 129.4, 129.9,
The crude product was then puried by passing through 130.3, 130.5, 138.1, 155.6, 158.8, 160.7, 161.9.
a column packed with silica gel. The products obtained were
2.4.2 2-Amino-4-(4-methoxyphenyl)-6-phenylnicotinonitrile.
known compounds and identied by melting points, FT-IR and Yellow solid; mp: 192–195 ꢁC; 1H NMR (300 MHz, DMSO-d6)
1H, 13C NMR spectroscopy.
d (ppm): 3.64 (s, 3H), 7.06 (d, J ¼ 7.8 Hz, 2H), 7.20 (s, 1H), 7.42–
7.68 (m, 3H), 7.65 (d, J ¼ 7.8 Hz, 2H), 7.88 (d, J ¼ 7.2 Hz, 2H); 13
C
NMR (75 MHz, DMSO-d6) d (ppm): 55.6, 86.9, 109.5, 114.6, 117.8,
2.3. General procedure for the synthesis of 2,3-
dihydroquinazolin-4(1H)-ones
127.7, 129.1, 129.5, 130.3, 130.5, 138.1, 154.9, 158.9, 160.8, 161.4.
2.4.3 2,3-Dihydro-2-phenylquinazolin-4(1H)-one.
White
Aldehydes (1 mmol), isatoic anhydride (1 mmol), and ammo-
nium acetate (1 mmol) were added in a round-bottom ask and
then b-cyclodextrin (10 mol%) was added to the mixture under
a solvent-free condition. The resulting mixture was stirred at
1
ꢁ
solid; mp: 224–226 C; H NMR (400 MHz, DMSO-d6) d (ppm):
5.73 (s, 1H), 6.65 (t, J ¼ 7.6 Hz, 1H), 6.72 (d, J ¼ 8 Hz, 1H), 7.09 (s,
1H), 7.20–7.24 (m, 1H), 7.30–7.39 (m, 3H), 7.47 (d, J ¼ 8 Hz, 2H),
7.59 (d, J ¼ 8 Hz, 1H), 8.27 (s, 1H); 13C NMR (100 MHz, DMSO-
d6) d (ppm): 67.1, 114.9, 115.5, 117.6, 127.4, 127.9, 128.8, 129.0,
133.8, 142.1, 148.4, 164.1.
ꢁ
90 C for 1 h in the open air. The reaction progress was moni-
tored using TLC with a mixture of ethyl acetate and n-hexane as
the eluent system. Aer reaction completion, the mixture was
quenched to room temperature and extracted with ethyl acetate
twice (2 ꢂ 20 ml). The combined extracts were washed with
distilled water, dried over anhydrous Na2SO4 and concentrated.
The residue obtained was recrystallized using a mixture of
petroleum ether and ethyl acetate and then ltered to afford the
desired pure solid products. All products were separated
without column chromatography. The products obtained were
known compounds and identied by melting point, FT-IR and
1H, 13C NMR spectroscopy.
2.4.4 2,3-Dihydro-2-(4-methoxyphenyl)quinazolin-4(1H)-one.
White solid; mp: 178–180 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d (ppm): 3.72 (s, 3H), 5.68 (s, 1H), 6.67 (t, J ¼ 7.6 Hz, 1H), 6.71 (d, J
¼ 8 Hz, 1H), 6.92 (d, J ¼ 8.8 Hz, 2H), 6.98 (s, 1H), 7.21 (t, J ¼
8.4 Hz, 1H), 7.39 (d, J ¼ 8.4 Hz, 2H), 7.58 (d, J ¼ 8 Hz, 1H), 8.16 (s,
1H); 13C NMR (100 MHz, DMSO-d6) d (ppm): 55.4, 66.8, 114.1,
114.9, 115.5, 117.6, 127.8, 128.7, 133.7, 134.0, 148.5, 159.9, 164.2;
IR (KBr) cmꢀ1: 757, 1251, 1505, 1654, 2363, 2922, 3295, 3424.
2.4.5 2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one.
White solid; mp: 201–203 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d (ppm): 5.90 (s, 1H), 6.67 (t, J ¼ 7.6 Hz, 1H), 6.76 (d, J ¼ 8 Hz,
1H), 7.24 (t, J ¼ 7.6 Hz, 1H), 7.31 (s, 1H), 7.60 (d, J ¼ 7.6 Hz, 1H),
2.4. Spectroscopic data of the synthesized compounds
7.73 (d, J ¼ 8.8 Hz, 2H), 8.23 (d, J ¼ 8.8 Hz, 2H), 8.51 (s, 1H); 13
C
2.4.1 2-Amino-4,6-diphenylpyridine-3-carbonitrile.
Pale
NMR (100 MHz, DMSO-d6) d (ppm): 65.8, 115.4, 118.0, 124.1,
yellow solid; mp: 210 ꢁC; 1H NMR (300 MHz, DMSO-d6) d (ppm):
5.48 (s, 2H), 6.98 (d, J ¼ 7.8 Hz, 2H), 7.20 (s, 1H), 7.40–7.47 (m,
126.4, 127.9, 128.5, 129.8, 134.1, 147.7, 149.8, 163.8.
Table 1 Optimisation of the reaction parameters for 2-amino-4,6-diphenylnicotinonitrilesa,b
Entry
Catalyst (mol%)
Temperature (ꢁC)
Time (h)
Yieldc (%)
1
2
3
4
5
6
30
20
10
10
10
5
90
90
90
90
90
90
8
8
8
2
1
8
88
86
86
84
74
62
7
4
90
8
40
8
9
10
11
12d
2
90
90
50
8
12
2
12
2
Trace
—
73
68
Trace
—
10
10
10
Room temperature
90
a
b
The bold numbers represent the most optimized protocol/conditions. Reaction of benzaldehyde (1 mmol), acetophenone (1 mmol),
c
malononitrile (1 mmol), and ammonium acetate (1 mmol) in water with b-cyclodextrin. Isolated yield of the product by column
chromatography. d Solvent-free reaction.
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Table 2 Synthesis of certain diversified 2-amino-4,6-diphenylnicotinonitrilesa
a
Reaction condition: aldehyde (1 mmol), acetophenone (1 mmol), malononitrile (1 mmol), and ammonium acetate (1 mmol) in the presence of b-
CD (10 mol%) in water at 90 ꢁC for 2 h.
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2.4.6 2-(4-Fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one.
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Table 1. Initially, the reaction was performed at 90 ꢁC with
30 mol% of catalyst for 8 h, and 88% product was then formed
(Table 1, entry 1). Then, we reduced the amount of the catalyst;
when only 10 mol% of the catalyst was used, the yield was
almost comparable with the yield of 30 mol% of catalyst (Table
1, entry 3). The same observation was seen in the case of opti-
mization of time. By decreasing the time to 2 h, the yield was
still 84% (Table 1, entry 4). Further decrease in the temperature
(Table 1, entries 10, 11) and time (Table 1, entry 5) of the
reaction did not increase the yield of the desired product. In the
absence of a catalyst, no product was formed and only inter-
mediates were formed, which was concluded by monitoring
TLC (Table 1, entry 9). When we performed the same reaction in
the solvent-free condition, a gummy solid was obtained (Table
1, entry 12). From this, it can be concluded that the reaction
catalyzed by b-cyclodextrin and water is mandatory to perform
the conversion.
Subsequently, the scope and efficiency of the reagent were
explored under the optimized reaction conditions for the
condensation of acetophenone with a broad range of structur-
ally diverse aldehydes to furnish the related products. The
structural diversity of the reactants is displayed in Table 2. The
reactants bearing both electron-withdrawing and electron-
donating substituents on the phenyl ring and the heterocyclic,
aliphatic aldehydes are well tolerated under the reaction
conditions to afford the nal products in moderate to good
yields (Table 2, entries 2–20). Electronic effects could be noticed
in the reaction process. Aldehydes having electron-withdrawing
groups give a better performance than those having electron-
donating groups. Aldehydes having a hydroxyl group at the 2-
position gave a better result, which may be attributed to H-
bonding, whereas those with a hydroxyl group at the 4-posi-
tion, the yield was moderate. Because of steric hindrance, 2-
naphthylaldehyde moiety gave a better result than 1-naph-
thylaldehyde. 4-Substituted acetophenone gave a better result
White solid; mp: 202–204 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d (ppm): 5.73 (s, 1H), 6.67 (t, J ¼ 7.6 Hz, 1H), 6.74 (d, J ¼ 8 Hz, 1H),
7.09 (s, 1H), 7.18–7.25 (m, 2H), 7.51–7.54 (m, 2H), 7.61 (d, J ¼
7.6 Hz, 1H), 8.29 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d (ppm):
66.5, 115.0, 115.6 (d, J ¼ 21.5 Hz, 1C), 117.8, 127.9, 129.6 (d, J ¼
8.3 Hz, 1C), 133.9, 138.3 (d, J ¼ 2.2 Hz, 1C), 148.3, 161.4, 163.8,
164.1; 19F NMR (376 MHz, DMSO-d6) d (ppm): ꢀ113.76 (s, 1F).
2.4.7 2,3-Dihydro-2-(thiophen-2-yl)quinazolin-4(1H)-one.
White solid; mp: 213–215 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d (ppm): 6.01 (s, 1H), 6.69 (t, J ¼ 7.6 Hz, 1H), 6.75 (d, J ¼ 8 Hz, 1H),
6.96 (dd, J ¼ 5.2 Hz & 3.6 Hz, 1H), 7.11 (s, 1H), 7.22–7.29 (m, 2H),
7.43 (dd, J ¼ 4.8 Hz & 0.8 Hz, 1H), 7.61 (d, J ¼ 7.6 Hz, 1H), 8.44 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d (ppm): 63.1, 115.2, 115.6,
118.0, 126.2, 126.4, 127.0, 127.8, 133.9, 146.9, 147.7, 163.6.
2.4.8 2,3-Dihydro-2-(pyridin-3-yl)quinazolin-4(1H)-one.
Pale yellow solid; mp: 219–221 ꢁC; 1H NMR (400 MHz, DMSO-d6)
d (ppm): 5.85 (s, 1H), 7.69 (t, J ¼ 7.6 Hz, 1H), 6.75 (d, J ¼ 8 Hz,
1H), 7.17 (s, 1H), 7.25 (t, J ¼ 7.2 Hz, 1H), 7.40 (dd, J ¼ 7.6 Hz &
4.8 Hz, 1H), 7.62 (d, J ¼ 7.2 Hz, 1H), 7.88 (d, J ¼ 8 Hz, 1H), 8.39
(s, 1H), 8.53 (d, J ¼ 4 Hz, 1H), 8.66 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) d (ppm): 65.2, 115.1, 115.5, 118.0, 124.1, 127.9, 134.0,
135.2, 137.3, 148.2, 148.9, 150.2, 164.1.
3. Results and discussion
3.1. Optimisation of reaction conditions
To begin our study, we have taken benzaldehyde, acetophe-
none, malononitrile and ammonium acetate for a model reac-
tion in the water medium. For the optimization of reaction
conditions, parameters such as temperature, time and amount
of catalyst were reported to have an inuence on the reaction
and it was monitored by TLC. Because b-cyclodextrin is soluble
in water than any other organic solvent, we performed all
reactions in water. The experimental results are summarized in
Table 3 Screening of reaction conditions for 2,3-dihydroquinazolin-4(1H)-one derivativesa,b
Temperature
Entry
Catalyst (mol%)
(ꢁC)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
20
10
5
90
90
90
90
90
90
50
rt
5
5
5
8
8
1
2
5
92
90
78
Trace
—
90
74
58
2
—
10
10
10
a
b
The bold numbers represent the most optimized protocol/conditions. Reaction of isatoic anhydride (1 mmol), benzaldehyde (1 mmol),
ammonium acetate (1 mmol), and b-cyclodextrin. c Isolated yield of the product by column chromatography.
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Table 4 Synthesis of the functionalized 2,3-dihydroquinazolin-4(1H)-one derivativesa
Entry
Reactant
Product
Yieldb (%)
1
90
2
3
84
88
4
5
78
92
6
7
75
89
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Table 4 (Contd.)
Entry
Reactant
Product
Yieldb (%)
8
90
9
86
10
11
12
72
79
83
13
14
80
92
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Table 4 (Contd.)
Entry
15
Reactant
Product
Yieldb (%)
95
16
17
84
89
93
18
a
Reaction of isatoic anhydride (1 mmol), aldehyde (1 mmol), and ammonium acetate (1 mmol) in the presence of b-CD (10 mol%) for 1 h at 90 ꢁC
b
under solvent-free condition. Isolated yield of the product by column chromatography.
except for the amino group, which yielded only a trace product entry 5). Aer xing the amount of catalyst, we started to screen the
because of a self-condensation reaction.
time and temperature. With reduction in temperature to room
For screening reaction conditions, isatoic anhydride, temperature, the yield again decreased (Table 3, entries 7, 8). From
benzaldehyde and ammonium acetate are considered for the this, temperature has considerable inuence on this protocol. The
model reaction (Table 3). Reaction parameters such as further reduction of time from 5 h to 1 h with 10 mol% of catalyst
temperature, time, solvent, and amount of catalyst showed loading at 90 ꢁC yielded the same yield; therefore, 1 h may be
a profound effect in performing the reaction, which was enough to perform this protocol (Table 3, entry 6).
evident while monitoring the reaction using TLC. We started
With these optimized reaction conditions, we tested the
investigating the reaction under solvent-free condition using reactions with various aldehydes in Table 4, and all the aldehydes
a different loading of catalyst. At rst, we attempted the reaction gave good yields. The aldehydes used were aromatic aldehydes
ꢁ
with 20 mol% of catalyst per mmol of substrates at 90 C where having electron-withdrawing and electron-donating groups,
a good yield of the product was observed (Table 3, entry 1). We then aliphatic aldehyde (Table 4, entry 18), and ve- and six-
started to reduce the amount of catalyst. Surprisingly, 10 mol% of membered heterocyclic aldehydes (Table 4, entries 13, 14, 15,
catalyst at the same temperature yielded almost the same yield 16). The electron-withdrawing group in the benzene ring gave
(Table 3, entry 2). Keeping the temperature constant and further a slightly better yield than the electron-donating group. This may
reducing the amount of catalyst, the yield decreased (Table 3, be due to the increase in the electrophilicity of carbonyl carbon of
entries 3, 4). Furthermore, in the absence of a catalyst, only the the aldehyde moiety. Substitution at the ortho position gave
intermediate was formed, which was conrmed from TLC (Table 3, a poor yield than others, which may be due to the steric repulsion
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Scheme 3 Mechanism for the formation of the pyridine motif.
(Table 4, entries 6, 10). Amazingly, the hydroxyl group at the 2- aldehyde and acetophenone derivatives as the active electro-
position increased the yield than others, which may be due to its phile species. The reaction of malononitrile and ammonium
H-bonding effect (Table 4, entry 8).
acetate with these two activated electrophiles generates the
corresponding intermediates 2 and 3, respectively; intermediate
2 was then isolated. Aerwards, the reaction between these two
intermediates will produce the corresponding intermediate 4. A
sequence of tautomerization, cyclization, and again tautomeri-
zation generates the intermediate 7, which possesses a struc-
ture having a lone pair on the nitrogen atom sharing electrons
from both –NH2 and –NH functional groups through C]C
3.2. Mechanism
A plausible mechanism54 has been discussed in Scheme 3. b-CD
with its seven free primary –OH groups synergistically behaves
as an efficient host and a supramolecular catalyst. b-CD, our
potential catalyst, simultaneously activates both the aryl
Scheme 4 Mechanism for the formation of the 2,3-dihydroquinazolin-4(1H)-ones.
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double bonds in the presence of the described catalyst and
yields the desired products.
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A plausible mechanism was described for synthesizing 2,3-
dihydroquinazolin-4(1H)-one (Scheme 4). In the rst step, isatoic
anhydride coordinates to the b-CD cavity; by the reaction of
ammonium acetate, it forms 2-aminobenzamide as an interme-
diate, which is then isolated. In the next step, it facilitates the
nucleophilic attack by the electron-rich nitrogen of the amine
group to the electrophilic carbonyl carbon centre of aldehydes,
which is activated by b-CD. Then, the elimination of water fol-
lowed by another nucleophilic attack by the amine group of the
amide to the carbon centre on the substituted imine leads to the
expected product 2,3-dihydroquinazolin-4(1H)-one.
6 K. Surendra, N. S. Krishnaveni, R. Sridhar and K. R. Rao,
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4. Conclusion
In conclusion, we have developed a straightforward, robust and
facile eco-friendly strategy for preparation of 2-amino-4,6-
diphenylnicotinonitrile and 2,3-dihydroquinazolin-4(1H)-one 10 A. Gonzalez and S. Holt, J. Org. Chem., 1982, 47, 3186–3188.
derivatives using a bio-based supramolecule, b-cyclodextrin, in 11 H. J. Schneider and N. K. Sangwan, J. Chem. Soc., Chem.
water and solvent-free condition, respectively, without using any
additional catalyst or metal salt, which further enhances the 12 D. D. Sternbach and D. M. Rossana, J. Am. Chem. Soc., 1982,
advantage of the protocol. The replacement of toxic and expen- 104, 5853–5854.
sive metal catalysts by an environment-friendly and inexpensive 13 A. L. Laza Knoerr, R. Gref and P. J. Couvreur, J. Drug
organocatalyst is the novelty of this protocol. This environmen- Targeting, 2010, 18, 645–656.
tally benign protocol is expected to achieve wide applications in 14 J. Heng-Bing, S. DongPo, S. Ming, L. Zhong, W. Le-Fu,
Commun., 1986, 24, 1787–1789.
the pharmaceutical industry and natural product synthesis.
H. B. Ji, D. P. Shi, M. Shao, Z. Li and L. F. Wang,
Tetrahedron Lett., 2005, 46, 2517–2520.
15 (a) P. Choudhury, P. Ghosh and B. Basu, Mol. Diversity, 2020,
24, 283–294; (b) B. Mitra, S. Mukherjee, G. C. Pariyar and
P. Ghosh, Tetrahedron Lett., 2018, 59, 1385–1389.
Author contributions
BM and GCP contribute equally to these methodologies.
Scheme 1 is done by BM, and Scheme 2 is done by GCP under 16 T. Murata, M. Shimada, S. Sakakibara, T. Yoshino,
the guidance of Prof. P. Ghosh.
H. Kadono, T. Masuda, M. Shimazaki, T. Shintani,
K. Fuchikami, K. Sakai, H. Inbe, K. Takeshita, T. Niki,
M. Umeda, K. B. Bacon, K. B. Ziegelbauer and
T. B. Lowinger, Bioorg. Med. Chem. Lett., 2003, 13, 913–918.
Conflicts of interest
¨ ¨
17 M. Mantri, O. De Graaf, J. Van Veldhoven, A. Goblyos,
The authors declare no conict of interest.
¨
J. K. Von Frijtag Drabbe Kunzel, T. Mulder-Krieger,
R. Link, H. De Vries, M. W. Beukers, J. Brussee and
A. P. Ijzerman, J. Med. Chem., 2008, 51, 4449–4455.
18 J. Deng, T. Sanchez, L. Q. Al-Mawsawi, R. Dayam,
R. A. Yunes, A. Garofalo, M. B. Bolger and N. Neamati,
Bioorg. Med. Chem., 2007, 15, 4985–5002.
19 H. M. Kanjariya, T. V. Radhakrishnan, K. R. Ramchandran
and P. Hansa, Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem., 2004, 43, 1569–1573.
Acknowledgements
B. M. is thankful to CSIR, New Delhi for nancial support.
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